ANNUAL DRUG DATA REPORT

Vol I – 1971

J. R. PROUS, Editor

Prof. A. Dept. Anim. Physiol.

Fac. Cienc., University of Barcelona (Spain)

D. VEDRILLA, Ass. Editor

Phil D of the University of Vienna (Austria)

Medicamentos de Actualidad • Drugs of Today

Barcelona (Spain)

PREFACE

This volume initiates a new series of annual publications designed to provide an up-to-date and useful reference tool for all researchers concerned with the chemical and biological aspects of drugs and other substances of pharmacological or biochemical interest. The source material for Annual Drug Data Report are the drugs which during the year, have gained place in clinical practice, those to which have been assigned a new non-proprietary name, and others which are under study, and are mentioned in about 600 biomedical journals, and congress and symposium proceedings. Each drug is described in monograph form to provide whenever possible, the following data: non-proprietary name, research code number, commercial name, chemical or biologic identity, inclu ding pertinent properties, synthesis, pharmacological action toxicity, manufacturer and references; the latter giving access to the international literature on drugs. For the drugs which are in clinical practice uses, dosage and preparations are also set out. Monographs are arranged alphabetically according to their nonproprietary name or research codes. The data given in the monographs has been taken from literature, and does not represent specifications for products available commercially from the manufacturers. To facilitate location of drugs, four indexes are provided. The Cross Index of Names, which contains entries enabling the reader to locate drugs by proprietary. chemical and generic names, and research code numbers. The Pharmacological Index, in which the drugs are grouped according to pharmacological action. The Manufacturer's Index, where the drugs are listed under the manufacturer's name, and finally the Chemical Formula Index, which permits the location of drugs by means of their chemical composition. The publication of cumulative indexes every four years is under consideration.

CONTRIBUTORS

Chemistry Dr. J . Castaner. Lic. Quim., Invest. Numer., Instituto de Quimica, CSIC, Barcelona J . J . Taratiel. Lic. Quim., Bec. Invest. Aerospacial, Instituto de Quimica, CSIC. Barcelona

Pharmacology Dr. J. Balasch. Prof. Dept. Physiology. Fac. Ciene., University of Barcelona Dr. M. Neuman, MD, Prof. Laureat Acad. Med. Paris Dr. C. Villaverde. Lic. Med, Dept. Pharmacology, CSIC. Barcelona

Microbiology P. Blancafort. Lic. BioI., Dept. Microbiology, Fac. Ciene . University of Barcelona

ABBREVIATIONS AND SYMBOLS

[α]D

25 Specific optical rotation at 25° for D (sodium) line

abs abstract Appl Application approx approximately aq aqueous BAN British Approved Name Belg Belgian bp boiling point Brit British C concentration by volume

(after optical rotation only)

ca (circa) about Can Canadian Cis stereochemical opposite

of trans d density; specific gravity d dextro (rotatory) D dextro (in configurations!

sense only) dec decomposes dil dilute dl and DL racemic E (1%, 1 cm) The absorbancy of a

solution containing one gram per 100 ml contained in a cell having an absorption path of one centimeter

e.g for example et al (et alii) and others FDA Food and Drug

Administration Fr French g gram g/kg gram per kilogram γ (gamma) microgram Ger German ibid at the same place

IAN Italian Approved Name ICI Imperial Chemical

Industries im intramuscular ip intraperitoneal IU international unit iv intravenous Jap Japanese kg kilogram I levo (rotatory) L levo (in configurational

sense only) Ib pound LD50 lethal dose in 50% of

cases Log logarithm m meta M molar max. maximum mg milligram µg microgram min minimum ml milliliter (cubic

centimeter) mm millimeter µm millimicron mp melting point no index of refraction

(sodium light) n normal N normal Neth Netherlands NF National Formulary o- ortho O denoting attachment to

oxygen p- para pat patent pk log 1/K po oral

CONTENTS

Preface............................................................................... vii Contributors ....................................................................... ix Abbreviations..................................................................... xi Monographs............................................................... 1 - 202 Pharmacological Index .............................................. Manufacturer's Index.................................................

MONOGRAPHS

1

A 025 7-Chloro-2H-1,2,4-benzothiadiazine-1,1-dioxide

Action

A 025, an analogue of diazoxide without the methyl group in position 3, has proved to have hyperglycemic, but not antidiuretic, activity in rats and monkeys, and weakly hypotensive activity. The results of investigation of the mode of action have indicated that the primary mechanism of hyperglycemia is inhibition of insulin release and that this inhibition is reversible.

Toxicity

LD50 ip in mice: 560 mg/kg

References

1. J. K. Wales et al. J Pharmacol Exptl Ther 164, 421-432 (1968). 2. Mode of action of a diazoxide analog (A 025). Its effects on insulin secretion A. M. Grant et al. Diabetes 19,630-639 (1970).

A 124

2-Acetyl-10-[3-(4-methoxypiperidyl) propyl] phenothiazine

Action

A 124 is a new phenothiazine derivative closely related in its chemical structure to thioridazine and propericiazine. It exhibits a mildly neuroleptik effect.

Manufacturer

Siegfried AG (Switzerland)

References

Clinical study on a new piperidyl-phenothiazine derivative (A 124) H. Berzewski et al. Arzneim-Forsch 20 (7), 949-952 (1970).

A-396-I

Production

Isolated from a culture broth of Streptoverticillium eurocidicus A-396.

Description

Water-soluble basic material; [α]D=+11,60º (in water).

Action

Antibiotic active against gram-positive and gram-negative bacteria, mycobacteria and some fungi and protozoa.

Toxicity

LD50 iv in mice: 12.50 mg/kg.

Manufacturer

Shionogi and Co, Ltd (Japan)

References

Isolation of a new water-soluble basic antibiotic A-396·I J. Shoji et al. J. Antibiotics 23(6), 291-294 (1970).

2

Acetylenic Gallamine

Triethiodide

[ν-Phenenyltris-(oxybutynylene)]-tris(triethylammonium iodide)

Description

Amorphous powder, mp 205°.

Action

The introduction of an acetylenic group in each lateral chain of gallamine enhances the curarizing activity in vitro as well as in vivo. It has been shown that the neuromuscular blockade produced by the acetylenic compound is not strictly competitive as has been shown for gallamine.

Toxicity

LD50 po in mice: 350 mg/kg and LD50 ip in mice: 3.1 mg/kg. The corresponding values for gallamine are respectively 700 and 9.6 mg/kg.

References

1. Evaluation pharmacodynamique d'un nouveau curarisant de synthese: La Gallamine-Acethylenique G. Cloutier at al. Arch Int Pharmacodyn Ther 184 (1), 75-92 (1970). 2. Etude in vitro du mecanisme de raction curarisante de la GallamineAcetylenique. G. Cloutier and G. R. Goyer. Arch Int Pharmacodyn Ther 184 (2), 299-308 (1970).

AET

S-(2-Aminoethyl) isothiouronium bromide hydrobromide

Synthesis

From thiourea and bromoethylamine hydrobromide.

Description

Crystals, mp 194-195°.

Action

Radioprotective drug. The effects of AET on bone-marrow, heart and circulation, and intestine have been reported3,4,5.

Manufacturer

SVST Bratislava (Czechoslovakia); Abbott (USA).

References

1. Clinton et al. J Am Chem Soc 70, 950 (1948). 2. Doherty et al. J Amer Chem Soc 79, 5667 (1957). 3. Effect of prophylactic administration of AET on hematological changes in irradiated rats. M. Arient et al. Strahlentherapie 139 (5),619-625 (1970). 4. Studies on the effect of AET on heart and circulation of cats and guinea pigs. K. Gutschow and A. Schmid. Arzneim-Forsch 20 (4), 509-511 (1970). 5. Studies on the effect of AET on the intestine (rabbit, guinea pig, rat). A. Schmidt and K. Gutschow. Arzneim-Forsch 20 (4),511-513 (1970).

Agr 614

3-(Morpholinoethoxy)-4-methyl-6-(2-naphthyl)-pyridazine hydrochloride 4-Methyl-3-(morpholinylethoxy)-6-(2-naphthyl) pyridazine hydrochloride

Action

Agr 614 is a powerful analgesic agent of long duration. The analgesic activity of this compound appears to involve a medullary mechanism.

References

1. A stereotaxic study of the analgesic activity of 3-ethoxymorpholinyl-4-methyl-2-naphtyl-6-pyridazine hydrochloride (Agr 614).

3

H. Laborit et al. Agressologie 11 (3), 221-242 (1970). 2. A pharmacological approach 10 the analgesic properties of Agr 614. B. Weber et al. Agressologie 11 (3),243-253 (1970). 3. The medullar localisation of the action of an analgesic. Agr 614: synergy with strychnine. B. Weber et al. Agressologie 11 (3), 255-267 (1970). 4. The action of 3-ethoxymorpholinyl-4-methyl· (2·naphtyl)-6-pyridazine hydrochloride (Agr 614) on rabbit ventilation. G. Laborit and C. Baron. Agressologie 11 (3). 269-273 (1970).

AH 5183

2-(4-Phenylpiperidino) cyclohexanol

Action

Neuromuscular curariform blocking agent.

Manufacturer

Allen Hanburys Ltd (England)

References

1. The neuromuscular blocking action of AH 5183. R. T. Brittain et al. Eurap J Pharmacal 8, 93-99 (1969). 2. Studies on the blocking action of AH 5183. I. G. Marshall. Brit J Pharmacal 38 (3), 503-516 (1970).

AH 6405

1,4,5,6-Tetrahydro-5-phenoxypyrimidine

Action

Muscarinic agent.

Manufacturer

Allen Hanburys Ltd (England)

References

A new muscarinic agent. R. J. Marshall. Brit J Pharmacol 39(1), 191P (1970).

AHR-800B

Diphenylcarbamic acid, 1-methyl-3-pyrrolidinyl ester maleate 1-Methyl-3-pyrrolidinyl diphenylcarbamate maleate

Synthesis

Prepared by the reaction of 1-methyl-3-pyrrolidinol with sodium amide and N, N-diphenylcarbamyl chloride.

Description

Crystals, mp 133-134°. The free base melts at 63-64°

Action

AHR 800B, an anticholinergic compound with antitremorine activity comparable to desmethylimipramine in the laboratory, is under clinical study to assess its efficacy as an antidepressant.

Manufacturer

A. H. Robins (USA)

References

1. A. H. Robins Co Inc. US pat 3,228,835; Belg pat 639,009. 2. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology.

4

L. J. Hekimian et al. Int Pharmacopsychiat 3, 65-76 (1970).

AHR 1118

3-(Diphenylmethylene)-1-ethyl-pyrrolidine hydrochloride

Synthesis

Prepared by dehydration of 1-ethyl-α,α-diphenyl-3-pyrrolidinemethanol1,2.

Description

White crystalline powder, readily soluble in water. The free base boils at 140° (5 mm); the methiodide melts at 164-166°.

Action

Neuropharmacological tests have proved that AHR 1118 is an antidepressant drug. The weak anticholinergic properties coupled with the presence of paradoxical sleep during AHR 1118 administration, may offer distinct advantages for this drug in the treatment of mental depression.

Manufacturer

A. H. Robins Co (USA)

References

1. F. Hamaguchi et al. Yakugaku Zasshi 86 (2), 148 (1966). 2. Sadao Ohzi. Jap pat 68 18,545. 3. Preclinical evaluation of AHR-1118 a potential antidepressant drug. D. N. Johnson et al. Curr Ther Res 12 (6), 402-413 (1970).

AHR 1900

1-[3-(p-Fluorobenzoyl)-propyI]-3-(o-methoxyphenoxy)-pyrrolidine hydrochloride 4'-Fluoro-4-[(3-o-methoxyphenoxy)-1-pyrrolidinyI]-butyrophenone hydrochloride

Synthesis

Prepared by the reaction of 3-(o-methoxyphenoxy)-pyrrolidine with p-fluoro-γ-chlorobutyrophenone and sodium bicarbonate in refluxing methyl isobutyl ketone,

Description

Crystals, mp 166-168° (methyl isobutyl ketone)

Action

AHR 1900 is a fluorobutyrophenone compound which in animal studies has shown pharmacological properties resembling those of phenothiazine and butyrophenone antipsychotic drugs. The drug has appeared to lack efficacy in the treatment of chronic schizophrenic patients at doses up to 300 mg daily.

Manufacturer

A. H. Robins (USA)

References

1, A. H. Robins Co, Inc, S African Appl 67 05,136. 2. A butyrophenone derivative, D M Gallant et al. Curr Ther Res 11 (12),793-795 (1969). 3. A pilot study o(AHR-1900 in chronic schizophrenic patients, A. A. Sugerman et al. Curr Ther Res 12 (4), 234-236 (1970).

AHR 1911

2-Thio-2-(10-undecen-1-yl) pseudourea monohydroiodide 2-Undecenyl-2-thiopseudourea hydroiodide

5

Synthesis

Prepared by treating undecenylalcohol with benzenesulfonylchloride, and subsequent reaction with thiourea.

Description

White crystalline powder, mp 65.5-68°,

Action

AHR 1911 is a non-steroid compound with local anti-inflammatory and anti-pruritic effects.

Manufacturer

A. H. Robins Co, Inc (USA)

References

1. A. H. Robins Co, Inc. South African pat 67 06, 822. 2. The treatment of contact dermatitis with AHR-1911, a new non-steroid anti-inflammatory agent. C. J. Riobueno. Curr Ther Res 12 (11), 718-723 (1970).

AHR 2776

N-Ethyl-3-(m-trifluoromethylphenyl)-1-pyrrolidinecarboxamide

Action

AHR 2776 is a new centrally acting muscle relaxant. Initial studies have shown the drug to be more potent than mephenesin in preventing the convulsive and lethal effects of strychnine in mice.

Manufacturer

A. H. Robins Laboratories (USA)

References

Pharmacology of AHR 2776, a new centrally acting muscle relaxant drug. D. N. Johnson at al. Fed Proc 29 (2) 779 abs (1970).

Alanosine

L-2-Amino-3-(N-nitrosohydroxylamino) propionic acid

Production

Isolated from the fermentation broth of Streptomyces alanosinicus.

Description

Crystalline powder, decomposes at 190°.[ α]D= + 8° (in 0.1 N HCI); [α]D =-460 (in 0.1 N NaOH). Ultraviolet absorption max. in 0.1N HCI at 228 µm [E(1%, 1cm) = 505]; in 0.1 N NaOH at 250 µm [E (1%, 1cm) = 630]. It is slightly soluble in water.

Action

Alanosine is a new antibiotic with antiviral antitumor activity. It has been found to inhibit several immunological reactions in animals.

Manufacturer

Lepetit (Italy)

References

1. C. Coronelli et al. Farmaco, Ed Sci, 21, 269-277 (1966). 2. Y. K. S.Murthy et al. Nature 211,1198-1199 (1966). 3. J. E. Thiemann and G. Beretta. J. Antibiot 19,155-160 (1966), 4. Preliminary studies on the immunosuppressive action of alanosine. D. Fumarola. Pharmacology 2,107-112 (1970).

6

5. Further investigations on the immunosuppressive effect of alanosine. D. Fumarola. Pharmacology 3, 215-219 (1970).

Albutoin (USAN)

Bax-422 Z

3-Allyl-5-isobutyl-2-thiohydantoin

Synthesis

By reacting leucine with allyl isothiocyanate under alkaline conditions 5-allyl-2-isobutyl-4-thiohydantoic acid is obtained, which is converted upon heating to albutoin.

Description

Crystals, mp 110-111°.

Action

Albutoin is a potent anticonvulsant agent. In man, it has anticonvulsant potency equal to that of diphenylhydantoin. Recent laboratory studies suggest no pharmacologic incompatibilities based on potency or toxicity for albutoin paired with phenobarbital, diphenylhydantoin or trimethadione.

Manufacturer

Baxter Laboratories Inc (USA) Proprietary Name Euprax

References

1. A. Berger et al. (to Baxter Laboratories Inc). US pat 3,121,111. 2. R. M. Gesler et al. Fed Proc 18. 1553 (1959). 3. R. M. Gesler et al. Toxicol Appl Pharmacol 3, 107-121 (1961). 4. J. G. Millichap and W. R. Ortiz. Neurology 17, 162-165 (1967). 5. Clinical evaluation of albutoin. John R. Green et al. Neurology 19,1207-1212 (1969). 6. Pharmacologic interactions of albutoin with other anticonvulsant drugs Richard F. Wallin et al. J Pharmacol Exp Ther 174. 276-282 (1970).

7. Albutoin in the teatment of epilepsy. C. H. Carter. Clin Med 78 (1), 33 (1971).

Alclofenac (USAN; Rec INN)

CP 1044CG 24

Alclofenacum (Lat). Alclofenaco (Sp) [4-(Allyloxy)-3-chlorophenyI] acetic acid

Action

Alclofenac is a new potent analgesic, antipyretic and anti-inflammatory agent. In clinical studies the drug has proved to be equivalent in analgesic and anti-inflammatory activity to phenylbutazone and indomethacin, but with fewer side effects.

Manufacturer

Continental Pharma (Belgium) Proprietary Name Mervan

References

1. N. P. Buu-Hoi et al. Belg pat 704,368. 2. Pharmacology of a new analgesic, antipyretic, and anti-inflammatory agent, 4-allyloxy-3-chlorophenylacetic acid. G. Lambelin et al. Arzneim-Forsch 20 (5), 610-618 (1970). 3. Toxicity studies of 4-allyloxy-3-chlorophenylacetic acid, a new analgesic, antipyretic, and anti-inflammatory agent. G. Lambelin et al. Arzneim-Forsch 20 (5), 618-630 (1970). 4. Metabolic patterns of 4-allyloxy-3-chlorophenylacetic acid in rat, rabbit, dog, monkey, and man. A. Roncucci et al. Arzneim-Forsch 20 (5), 631-636 (1970). 5. Therapeutic activity of 4-allyloxy-3-chlorophenylacetic acid. F. Lambotte. Arzneim-Forsch 20 (4), 569-571 (1970). 6. Double-blind comparison between alclofenac and phenylbutazone in osteoarthritis. J. Van Hoek et al. Curr Ther Res 12 (9), 351-556 (1970).

7

Alisol A 24 Monoacetate

ALMA

Isolation Alisol A 24-monoacetate is a triterpene isolated from the rhizoma of AIisma Plantagoaquatica L var orientale1,2

Description

Crystals, mp 194-196°; [ α]D=+86° (chloroform,at 21-28°)

Action

Alisol A 24-monoacetate has proved to show a hypocholesterolemic action in the cholesterolfed rats. It has been suggested that this action depends at least partly, on the inhibition of intestinal absorption of cholesterol.

Manufacturer

Takeda Chemical Industries Ltd (Japan)

References

1. T. Murata et al. Tetrahedron Letters 1. 103 (1968). 2. T. Murata et al. Tetrahedron Letters 7, 849 (1968). 3. Hypocholesterolemic effect of alisol A-24-monoacetate and its related compounds in rats. Y. Imai et al. Jap J Pharmac 20 (2), 222-228 (1970). 4. Effect of alisol A-24-monoacetate on the intestinal absorption of cholesterol and fatly acids in rats. Y. Imai and H. Matsumura. J Takeda Res Lab 29 (3), 462-466 (1970). 5. Effect of·alisol A-24-monoacetate on the cholesterol esterification in the rat small intestine. S. Tamura and Y. Imai J Takeda Res Lab 29 (3), 467-469 (1970).

Alletorphine (BAN; Prop INN)

R &S 218M

17-Allyl-17-demethyl-7α-(R)-1-hydroxy-1-methylbutyl-6,14-endo-ethenotetrahydrooripavine

Synthesis

Prepared by the reaction of 7α-(1-hydroxy-1-methylbutyl)-6,14-endo-ethenotetrahydrothebaine with cyanogen bromide. Combined hydrolysis and O-demethylation with sodium hydroxide of the N-cyano analog obtained and subsequent reaction with allyl bromide yields alletorphine, mp 126°; th e hydrochloride melts at 254°.

Action

Alletorphine hydrochloride has been found to be a potent analgesic, after parenteral administration to rats, mice and dogs, using a variety of antinociceptive assays. It has been shown that in the drug there is a dissociation of analgesic and respiratory depressant properties4.

Manufacturer Reckitt and Sons (England)

References

1. WHO Chron 25 (3), 124 (1971). 2. Chem Drug 194, 446 (1970). 3. K. W. Bentley and D. G. Hardy. J Am Chem Soc 89, 3281-3292 (1967). 4. Dissociation of analgesic and respiratory depressant properties of N-substituted analogues of etorphine. G. F. Blane et al. J Pharm Pharmacol 20 (10), 796-798 (1968).

Althiomycin

Production

It is produced by Streptomyces althioticus1.2 Its chemical structure has been reported3.

8

Description

Crystals, mp 180-181.6° (dec). [ α]D= +37.8° (c=2 in alcohol/methylene chloride)

Action

Althiomycin is an antibiotic which inhibits the growth of both gram-positive and gram-negative bacteria. The mode of action of this antibiotic has been recently described4.

Manufacturer

National Institute of Health (Japan)

References

1. H. Yamaguchi et al. J Antibiotics, Ser A 10,195 (1957). 2. K. Maeda et al. Jap pat 34-6248. 3. D. J. Cram et al. J Am Chern Soc 85, 1430-1437 (1963). 4. Studies on the mode of action of althiomycin. H. Fujimoto et al. J Antibiotics 23 (6), 271-275 (1970).

Alufibrate

Hydroxyaluminum bis-[2-(p-chlorophenoxy)-2-methylpropionate] Hydroxyaluminum bis-[α-(p-chlorophenoxy) isobutyrate]

Description

White amorphous powder.

Action and Uses

Alufibrate is a new anti hypercholesteremic agent. It is the aluminum salt of 2-(p-chlorophenoxy)-2-methyl-propionic acid, and is closely related to clofibrate, which is the ethyl ester of the same acid. For use in the treatment of the hyperchlolesterolemia and hyperlipemia.

Dosage

1.44 to 2.16 g daily in divided doses.

Supplied as

Tablets, 360 mg.

Proprietary Name

Atherolip.

Manufacturer

Lab Solac (France); Vifor SA (Switzerland).

References

1. J. Daver et al. Therapie 24. 419-428 (1969). 2. Med Act (Drugs of Today) 6 (1), 6-8 (1970).

Amadinone Acetate (USAN)

RS 2208

6-Chloro-17-hydroxy-19-norpregna-4, 6-diene-3, 20-dione, acetate

Synthesis

Prepared by converting 17-α-acetoxy-6-chloro-4,6-pregnadien-19-ol-3,20-dione to the 19-oic acid, followed by decarboxylation.

Description

Crystals, mp 159-161º (methylene chloride-petroleum ether); UV max. 284 µm ε=24.100)

Action

Amadinone acetate is a new progestogen

Manufacturer

Syntex Laboratories Inc (USA)

9

References

1. JAMA 213 (13), 2247 (1970). 2. CIBA Ltd. Belg pat 620,226.

Ambenoxan (Rec INN)

Ambenoxanum (Lat). Ambenoxano (Sp) N-[2-(2-Methoxyethoxy)ethyl]-1,4-benzodioxan-2-methylamine 2-(β-methoxyethoxyethyl) aminomethyl-1,4-benzodioxan

Synthesis

Prepared by the reaction of 2-aminomethyl-1,4-benzodioxan with β-methoxyethoxyethylchloride

Description

Light yellow oil, bp 180-186º (11.5 mm). The hydrochloride salt (white crystals), mp 104-106º.

Action

Ambenoxan is a centrally acting muscle relaxant. The results of a detailed pharmacological investigation have been reported

Manufacturer

Ward Blenkinsop and Co, Ltd (England)

References

1. Ward Blenkinsop and Co, Ltd. Neth Appl 6.410,198. 2. The pharmacology of ambenoxan [2-(3',6'-dioxaheptyl)-aminomethyl-1:4-benzodioxane]. a centrally acting muscfe relaxant. M. Shapero and P. J. Southgate. Br J Pharmac 38, 263-270 (1970).

Amcinafal (USAN)

SQ 15,102

9-Fluoro-11β,16α,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione, cyclic 16,17-acetal with 3-pentanone.

Triamcinolone, 16,17-acetal with diethyl ketone

Synthesis

Prepared by reacting triamcinolone with 3-pentanone

Description

Crystals, mp 265-268°; [ α]D= 91° (c=0.69 in chloroform)

Action

Amcinafal is a new topical anti-inflammatory agent. It is closely related to amcinafide which is the acetal with acetophenone.

Manufacturer

E. R. Squibb and Sons (USA)

References

1. JAMA 214, 741 (1970). 2. Josef Fried at al. J Am Chem Soc 80, 2338-9 (1958). 3. Olin Mathieson Chemical Corp. Ger pat 1,099,529. 4. Olin Mathieson Chemical Corp. US pat 3,048,581.

Amcinafide (USAN; Prop INN)

SQ 15112

9-Fluoro-11β,16α,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione, cyclic 16,17-acetal with acetophenone Triamcinolone, 16, 17-acetal with acetophenone

10

Synthesis

Prepared by reacting triamcinolone with propiophenone

Description

Crystals mp 281-283°; [ α]D= 23° (c=0.98 in chloroform)

Action

Amcinafide is a new topical anti-inflammatory agent. It is closely related to amcinafal, which is the acetal with 3-pentanone.

Manufacturer E. R. Squibb and Sons (USA)

References

1. JAMA 213, 325 (1970). 2. WHO Chron 25 (3), 125 (1971). 3. Josef Fried et al. J Am Chem Soc 80, 2338-9 (1958). 4. Olin Mathieson Chemical Corp. Ger pat 1,099,529. 5. Olin Mathieson Chemical Corp. US pat 3,048,581.

Amedalin Hydrochloride

(USAN) UK 3540-1

3-Methyl-3-(3-methylaminopropyl)-1-phenyl-2-indolinone hydrochloride

Synthesis

Prepared in several steps, starting by the reaction of diphenylamine with α-chloropropionylchloride

Description

Buff colored crystals, mp 168-170° (chloroform-ethylacetate)

Action

Both the neurophysiologic animal and clinical data has indicated that this compound does possess antidepressant properties. However, the inconvenient side effect of difficulty in initiating urination and scrotal discomfort might outweigh the therapeutic advantages of this compound.

Manufacturer

Pfizer Inc (USA).

References

1. JAMA 213 (13), 2247 (1970). 2. Manuf Chem 41 (3),29 (1970). 3. Pfizer Corp. S African Appl 68 01.099. 4. A preliminary evaluation of a potential antidepressant compound: animal and human correlation. D. M. Gallant et al. Curr Ther Res 11 (5), 296-299 (1969).

Amfonelic Acid

Win 25,978

7-Benzyl-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

Action

Amfonelic acid is known to be a potent locomotor stimulant drug1,2. The pharmacological properties and mechanism of action of the drug have been described3. The drug is under clinical study to assess its efficacy as an antidepressant4.

11

Manufacturer

Sterling-Winthrop (England)

References

1. M. D. Aceto at al. Pharmacologist 8,222 (1966). 2. M. D. Acato et al. J Pharmacal Exptl Therap 158, 286 (1967). 3. Pharmacologic properties and mechanism of action of amfonelic acid M. D. Aceto et al. Europ J Pharmacal 10, 344-354 (1970). 4. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology. L. J . Hekiminian et al. Int Pharmacopsychiat 3, 65-76 (1970).

Amiloride (USAN; BAN)

MK 870

N-Amidino-3,5-diamino-6-chloropyrazine-carboxamide (3,5-Diamino-6-chloropyrazinoyl) guanidine

Synthesis

Prepared by the reaction of methyl 3-aminopyrazinoate with sulfuryl chloride, followed by the reaction with ammonia and finally with guanidine

Description

Crystals, mp 240.5-241.5°. Hydrochloride salt, mp 293.5°

Action

Amiloride is a potassium-sparing diuretic agent. In a recent study the long-term effect of amiloride has been appraised, either alone or combined with hydrochlorothiazide, on the ionic metabolism of hypertensive patients.

Manufacturer

Merck Sharp Dohme (USA)

Proprietary Name

Colectril

References

1. Merck Co, Inc. Belg pat 639,386. 2. Tolerance and ionic effects in hypertensive patients of prolonged administration of an aldosterone antagonist (amiloride) as compared with a thiazide. J. C. Demanet et al. J Clin Pharmac 10 (4), 269-273 (1970).

AminagIutethimide

α-(p-Aminophenyl)-α-ethylglutarimide

Description

White crystalline powder, mp at about 151°. Soluble in organic solvents, and very slightly soluble in water.

Action

New inhibitor of adrenal steroidogenesis which has the advantage that its main site of inhibition lies early in the biosynthetic pathways. A recent clinical study has suggested that aminoglutethimide may be used with advantage for the treatment of selected patients with secondary hyperaldosteronism and oedema. The drug was used as an anticonvulsant agent; it was withdrawn from the U. S. market in 1966 because its prolonged use produces untoward effects.

Manufacturer

Ciba Pharmaceutical Co (USA)

Proprietary Name

Elipten

References

1. R. L. Dexter et al. J Clin Endocr 27, 473 (1967). 2. L. M. Fishmann et al. J Clin Endocr 27,481 (1967).

12

3. The treatment of secondary hyperaldosteroism with oedema by aminoglutethimide. O. Kuchel et al. Pharmacol Clin 2, 138-142 (1970).

Amiquinsin Hydrochloride

(USAN, Rec INN) U-935

Amiquinsinum (Lat). Amiquinsina (Sp) 4-Amino-6, 7-dimethoxyquinoline hydrochloride monohydrate

Synthesis

By reacting 4-chloro-6,7-dimethoxy-quinoline with ammonia

Description

White crystalline powder, mp 266-267° (dec). It is soluble in water (at least 50 mg/ml) with a pH of 5.3 at saturation.

Action

Amiquinsin hydrochloride is a new hypotensive drug. The absorption, distribution and elimination of the drug in dog has been recently studied.

Manufacturer

Eaton Laboratoires (USA)

References

1. Norwich Pharmacol Co. Fr pat 1,388,756. 2. B. S. Jandhyala et al. Arch Int Pharmacodyn 167 (1), 217-226 (1967). 3. Studies on the absorption. distribution. and elimination of amiquinsin hydrochloride, a hypotensive drug. J. D. Conklin and R. D. Hollifield. EurJ Pharmacol10, 360-368 (1970).

AP 237

1-Butyryl-4-cinnamyl-piperazine hydrochloride

Synthesis

Prepared from butyryl chloride and 1-cinnamylpiperazine

Description

White crystalline powder, mp 202-204º; easily soluble in water. The free base boils at 203-207º (0.6 mm Hg).

Action

Pharmacological studies have shown AP-237 to possess significant analgesic effects. It has been suggested that AP-237 might exert some modes of action different from that of antipyretic analgesics

Manufacturer

Kyorin Pharmaceutical Co, Ltd (Japan)

References

1. Kyorin Pharmaceutical Co, Ltd. Fr pat 1.537.552. 2. T. Irikura et al. J Med Chern 11 (4),801-804 (1968). 3. Analgesic effect of AP 237. T. Irikura et al. Jap J Pharmac 20. 287-293 (1970).

ara-IC

1-β-D-Arabinofuranosyl-5-iodocytosine

Action

A comparison of the activities of ara-IC with several other structurally related nucleosides has indicated that ara-IC is unique in its activity. These conclusions are based on the spectrum of DNA viruses inhibited. the agents which block the

13

antiviral activity. the cytotoxicity. and the blocking of the cytotoxicity.

Manufacturer

The Upjohn eo (USA)

References

1. H. E. Renis et al. Antimicrobial Agents and Chemotherapy. 675-679 (1967). 2. Comparison of cytotoxicity and antiviral activity of 1-β-D-arabinofuranosyl-5-iodocytosine with related compounds. H. E. Renis. Cancer Res 30 (1). 189-194 (1970).

Aranoflavin

Aranoflavin is a new antibiotic which has been isolated from the culture broth of Arachniotus flavoluteus. It was separated into two related components designated as aranoflavin A (C23H33NO6) and aranoflavin B (C26H39NO9). The two components occur as a colorless powder.

Action

Aranoflavin inhibits growth of bacteria, protozoa and tumor cells in vivo.

Manufacture Toyo Jozo Co, Ltd (Japan)

References

Aranoflavia a new antibiotic. K. Mizuno et al. J Antibiotics, 23 (10) 493-496 (1970).

Aspochracin

Production

Obtained from the culture filtrate of Aspergillus ochraceus

Description

Pale yellow powder

Action

Aspochracin is a new insecticidal antibiotic

References

1. R. Myokei et al. Agr and Bioi Chem 33, 1491 (1969). 2. Jap Med Gazz 7 (4), 9 (1970).

AY 11483

3-Acetoxy-17α-[3-furyI]-1,3,5(10)-7-oestratetraen-17-ol

Action

AY-11483 has proved to be a potent orally active oestrogen in the vaginal cornification test in rats and mice with weak effect on the uterine weight in rats, mice and rabbits and endometrium in rabbits. It has been suggested that the compound might be a useful drug in the menopause, and for contraception.

Manufacturer

Ayerst Laboratories (Canada)

References

1. Prepalation and biological properties of 17-substituted estradiol derivatives in the 8-normal and 8-iso series. Y. Lefebvre et al. Am Chem Soc Meet Chicago, abstr no 154, p 10(1967).

14

2. Orally active oestrogens and Plogestins in prevention of pregnancy in rats. U. K. Banik et al. J Reprod Fert 18, 509 (1969). 3. AY-11483, a new type of orally active oestrogen. C. Revesz et al. J Reprod Fert 22,27-32 (1970). 4. Induction of ovulation in progestin-treated adult rats. U. K. Banik et al. Acta endocrino! 63 (4), 747 (1970).

Azabicyclane Citrate

4β-Methoxy-1-methyl-4α-phenyl-3α,5α-propanopiperidine hydrogen citrate

Description

White crystalline powder, soluble in water

Action

Azabicyclane is a new analgesic agent. It has proved to show an analgesic potency about 3 times greater than meperidine.

Toxicity LD50 po in mouse: 300 mg/kg; iv 56 mg/kg; sc 200 mg/kg

Manufacturer

Sankyo Co, Ltd (Japan)

References

1. S. Oida et al. Chern Pharm Bull 14. 1418-1424 (1966). 2. The pharmacology of azabicyclane, a new analgesic agent. s. Kobayashi at al. Toxicol Appl Pharmaeol 17. 344-354 (1970).

Azacosterol (USAN; Rec INN)

SC 12937 IMD

760

17β-[1-[(3-Dimethylaminopropyl)methylamino]androst-5-en-3β-ol 20, 25-Diazacholesterol

Synthesis

Prepared by the reaction of 3β-hydroxyandrost-5-en-17-one, 3-dimethylaminopropylamine with formic acid and the reduction of the resulting formamido intermediate with lithium aluminum hydride

Description

Crystals, mp 146-148° (acetone-methanol); [ α]D= -54.5° (chloroform). Hydrochloride: [ α]D= -32° (methanol)

Action

Azacosterol was found to be a potent anticholesteremic agent, but untoward side effects precluded its use in humans. Now it is used to sterilize pigeons without harming them. Azacosterol works on a physiological principle entirely different from that of human oral contraceptives.

Manufacturer

G. D. Searly and Co (USA)

Proprietary Name

Ornitrol

References

1. D. Klimstra et al. J Med Chem 9 (3), 323-326 (1966). 2. R. E. Counseil et al. (to G D Searle and Co), US pat 3.084,156. 3. The Wall Street J. p 8 (Feb 16. 1970). 4. Drug Topics. p 3 (March 2. 1970).

15

Azaphen Hydrochloride

Azafen hydrochloride

2-(4-Methyl-piperazinyl)-10-methyl-3,4-diazaphenoxazine dihydrochloride 5-Methyl-3-(4-methylpiperazinyl)-5H-pyridazino [3,4-b][1,4] benzoxazine dihydrochloride

Action

Azaphen is a new antidepressant, which has been approved for use in medical practice.

Manufacturer

All Union Chemo-Pharmaceutical Research Institute, Moscow (USSR)

References

1 . Pharmacological properties of azaphen a new antidepressant. M. D. Mashkovsky and A. I. Polezhaeva. Farmakol Toksikol 32, 656-662 (1969). 2. A new Soviet made antidepressant agent azaphen. A. I. Polezhaeva et al. Khim-Farm Zh 4 (2), 59 (1970).

8-Aza quinestrol AQ

3-Cyclopentyloxy-17-ethynyl-8-azaestra-1,3,5(10)-trien-17-ol 3-Cyclopentyloxy-8-aza-19-nor-pregna-1,3,5(10)-trien-20-yn-17-ol

Synthesis

Prepared by the reaction of 3-hydroxy-8-azaestra-1,3,5(10)-trien-17-one with sodium methoxide and cyclopentyl bromide. The resulting 3-cyclopentyloxy-derivate is allowed to react with lithium acetylide.

Description

Crystals, mp 83-85° (water)

Action

8-Aza quinestrol is an orally active oestrogenic steroid. In a recent study the biological properties of the same were compared to quinestrol and ethynyl oestradiol. It has been concluded that substitution of a nitrogen atom in position 8 decreased both the biological and fat storage properties of quinestrol.

Manufacturer

Warner-Lambert (USA)

References

1. Warner-Lambert Pharm Co Ger Offen 1,902,840. 2. J. Bowler et al. J Chem Soc (C), 2111 (1968). 3. The biological profile of 8-aza quinestrol. T. W. Mischler and D. Gawlak. J Reprod Fert 22, 49-56 (1970).

Azaribine (Rec INN)

6-Azauridine 2',3',5'-triacetate 2-β-D-Ribofuranosyl-as-triazine-3,5(2H,4H)-dione, 2',3',5' triacetate

Synthesis

Prepared by the reaction of 6-azauridine with acetyl chloride or with acetic anhydride.

Description

Crystals, mp 102-103º

Action

16

Azarabine is an antitumor agent that has recently found new uses in human therapy, especially in the treatment of psoriasis4,6 and viral eye infections5. Promising results were obtained with smallpox.

Proprietary Name

Triazure (Calbio, USA)

References

1. J. Beranek et al. Coll Czech Chem Commun 28, 469 (1963); 29, 625 (1964). 2, J. Pitha et al. Coll Czech Chem Commun 28, 1507 (1963); 29, 410 (1964). 3, V. Cerneckij et al. Coll Czech Chem Commun 27, 87 (1962). 4. R. W. Turner and P. Calabresi. J Inv Derm 43, 551 (1964). 5. V. Miska et al. Lancet 2, 1230 (1967). 6, Therapeutic effects of 6-azauridine-lriacetate in psoriasis. M. Slavik et al. Pharmacal Clin 2, 120-125 (1970). 7. Toxicity of 6-azauridine triacetate. J. Plenova at al. Toxicol Appl Pharmacol 17 (2), 511-518 (1970). 8. The deacetylation of 6-azauridine-triacetate in the plasma of various species correlated with toxicity. J. Planova et al. The Problems of Species Differences and Statics in Toxicology. Proceedings of the European Society for the Study of Drug Toxicity. Excerpta Medica International Congress Series No 198, Vol XI. 240-243 (1970). 9. The antifertility effect of 2'-3'-5'-tri-O-acetyl-6-azauridine. S. K. Saksena and R. R. Chandhury. Ind J Med Res 57, 1940-1945 (1969). 10. Abortifacient and teratogenic effects of triacetyl-6-azauridine. G. van Wagenen and R. C. De Conti. Amer J Obstet Gynecol 108 (2), 272 (1970). 11. Side effects of 6-azauridine triacetate in rheumatoid arthritis. J. Elis et al. Clin Pharmacol Ther 11 (3),404-407 (1970). 12. Treatment of polycythemia vera with azauridine and azaribine. R. C. Deconti and P. Calabresi. Ann Intern Med 73 (4),575 (1970). 13. American Druggist. pg 57 (Jan 12, 1970).

Ba 41,799

4-[2-(p-Chlorophenyl)tetrahydro-2-furyl] piperidine 2-(p-Chlorophenyl)-2-(4-piperidyl) oxolan

Synthesis

Prepared in 3 steps from 4-p-chlorobenzoylpyridine and 3-dimethylaminopropyl magnesium chloride. The resulting carbinol is treated with sodium hydride to give 4-[2-(p-chlorophenyl) tetrahydro-2-furyl]-pyridine, which is reduced catalytically1,2.

Description

The free base, bp 134-135° (0.02 mm). The hydrochloride salt, mp 240-242°.

Action

Ba 41,799, one of a series of 14 substituted tetrahydrofurans, has been found to have marked antimalarial activity.

Manufacturer

Ciba Ltd (Switzerland)

References

1. A. Marxer. Helv Chim Acta 52, 262 (1969). 2. Ciba Ltd. Brit pat 1,133,302. 3. The chemotherapy of rodent malaria, XII. Substituted tetrahydrofurans, a new Chemical family of antimalarials. The action of 2-(p-chlorophenyl)-2-(4-piperidyl)-tetrahydrofuran against Plasmodium berghei and Plasmodium chabaudi. W. Peters. Ann Trop Med Parasitol 64 (2), 189-202 (1970).

Baclofen (Prop INN)

BA 34,647

Baclofenum (Lat). Baclofeno (Sp) β-(Aminomethyl)-p-chlorohydrocinnamic acid γ-Amino-β-(p-chlorophenyl) butyric acid

17

Synthesis

Prepared from β-(p-chlorophenyl) glutaric acid amide, from 4-(p-chlorophenyl)-2-pyrrolidone, from γ-acetylamino-β-(p-chlorophenyl) butyric acid2. Also from β-cyano-p-chlorohydrocinnamic acid ethyl ester3.

Description

Crystals, mp 206-208º (water)

Action

Baclofen is a new skeletal muscle relaxant. It has been suggested that it acts at the spinal level.

Manufacturer

Ciba (Switzerland)

References

1. WHO Chran 24(9). 414 (1970). 2. CIBA Ltd. Neth Appl 6,407.755. 3. CIBA, Swiss pat 449,046. 4. A new agent for the control of spasticity. R. F. Janes et al. J Neural Neuro Surg 33(4). 464-468 (1970).

BAY 1433

α-Isopropylmandelic acid, 3-(dimethylamino)propyl ester hydrochloride α-Phenyl-α-isopropyl-glycolic acid 3-(N, N-dimethylamino) propylester hydrochloride

Synthesis

By reacting α-isopropylmandelic acid with 3-(dimethylamino)propyl chloride. Bay 1433 hydrochloride melts at 135-136°.

Action

Antidepressant

Manufacturer

Bayer (Germany)

References

1. Farbenfabriken Bayer AG. Ger. pat. 1.135.007. 2. Present Status Psychotr Drugs (Proc VI Internat Coni Coil Internat Neuro-Psychopharm. Tarragona. Spain. Apr 1968): 180. 1969.

BC-347

1 (2H)-Quinoline carboxylic acid, ethyl ester N-Ethoxycarbonyl-1, 2-dihydroquinoline 1-Carbethoxy-1, 2-dihydroquinoline

Synthesis

Prepared by treating 1, 2-dihydroquinoline with ethyl chloroformate in the presence of triethylamine1. Also by reducing 1-carbethoxyquinolinium chloride with sodium borohydride1,2, bp: 98-1000 (0.04 mm); bp: 108-114° (0.05-0.08 mm).

Action

With a preclinical profile of a tranquilizer BC-347 clinically has proved to be a stimulant for schizophrenics and depressives with neither antipsychotic nor antidepressant effects4.

Manufacturer

Bristol Laboratories (USA)

References

1. Bristol-Myers Co. Neth Appl 6,614,408. 2. B. Bellean et al. J Amer Chern Soc 90 (3), 823-824 (1968) . 3. R. R. Martel et al. J Pharmacol Exp Ther 166 (1), 44-51 (1969).

18

4. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology. L. J. Hekimian et al. Int Pharmacopsychiat 3, 65-76 (1970).

Beloxamide (USAN;

Rec INN) W1372

Beloxamidum (Lat). Beloxamida (Sp) N-(Benzyloxy)-N-(3-phenylpropyl) acetamide N-γ-Phenylpropyl-N-benzyloxy acetamide Benzyl-N-γ-phenylpropyl acetohydroxamate

Synthesis

By saponification and decarboxylation of benzyl-N-(3-phenylpropyl) carbethoxyhydroxamate to yield N-(3-phenylpropyl) benzyloxyamine, and by reaction of this amine with acetylchloride.

Description

Beloxamide is a bitter oily liquid essentially insoluble in water and readily miscible with most organic solvents. bp 155º (0.03 mm Hg); [n]D = 1, 5500.

Action

Beloxamide is a new hypolipidemic agent that has been shown to reduce the extent of atherosclerotic lesions and to lower serum cholesterol levels in animals maintained on a highcholesterol diet4,5.

Manufacturer

Carter-Wallace (USA)

References

1. JAMA 211, 2149 (1970). 2. WHO Chron 24 (11), 527 (1970). 3. B. J. Ludwig et al. J Med Chern 10 (4), 556-564 (1967). 4. F. M. Berger et al. J Pharmacol Exp Ther 170, 371-381 (1969). 5. F. M. Berger et al. Proc Exp Bioi Med 132, 293-297 (1969). 6. Metabolic fate of N-γ-phenylpropyl-N-benzyloxy acetamide (W-1372) in rats, dogs. and monkeys.

J. Edelson et al. J Pharm Sci 59(5), 680-682 (1970). 7. Oxidation of cholesterol by rat liver mitochondria: Effect of N-γ-phenylpropyl-N-benzyloxy acetamide. D. Kritchevsky and S. A. Tepper. Arzneim-Forsch 20 (4).384-385 (1970). 8. Gas chromatography determination of W1372 in blood. J. F. Douglas and J. A. Stockage. J Pharm Sci 59(6), 850 (1970).

Bendazac (Rec INN)

AF 983

Bendazacum (Lat). Bendazaco (Sp) [(1-Benzyl-1-H-indazol-3-yl) oxy] acetic acid

Description

White crystalline powder, mp 158-159°. Insoluble in water, rather soluble in chloroform, ethanol and acetone. UV max 306 µm [E(1%, 1 cm)=191].

Action

Bendazac is a topical anti-inflammatory drug.

Manufacturer

A. C. R. Angelini Francesco (Italy)

References

1. WHO Chron 24 (11), 527 (1970). 2. Pharmacological properties of bendazac (AF 983) with particular reference to its topical action on some experimental inflammatory processes. B. Silveslrini el al. Arzneim-Forsch 19 (1),30 (1969). 3. Studies on the mechanism of action of bendazac (AF 983). B. Silveslrini et al. Arzneim-Forsch 20 (2), 250-253 (1970).

19

Beneprizine Hydrochloride

BRL1288

Benzilic acid, 2-(ethylpropylamino)ethyl ester hydrochloride α,α-Diphenylglycolic acid, 2-(ethylpropylamino)ethyl ester hydrochloride

Synthesis

Prepared from the methyl ester of α,α-diphenylglycolic acid and 2-ethylpropylaminoethanol.

Description

Plates, mp 164-166° (butanone)

Action

Anticonvulsant-anti-parkinson agent, which is under clinical study. In patients with Parkinson's disease beneprizine has been shown to relieve the symptoms without showing psychotoxic or peripheral antiacetylcholine activity.

Manufacturer

Beecham Research Laboratories (U.K.)

References

1. Beecham Group Ltd. Neth. Appl. 6.409,696. 2. Nature 223, 416-417 (1969). 3. B. O. Hughes and B. Spicer. Brit J Pharmacol Chemotherapy 37, 501 P-502P (1969). 4. Mad. Praticienne 26(399), 3 (1970) .

Benfurodil Hemisuccinate

(Rec INN) CB 4091

2-(1-Hydroxyethyl)-β-(hydroxymethyl)-3-methyl-5-benzofuranacrylic acid γ-lactone succinic acid ester 4-[2-(1-Hydroxyethyl)-3-methyl-5-benzofuranoyl]-2-(5H)furanone succinate (ester)

2-[1-(Succinoyloxy)ethyl]-3-methyl-5-(2-oxo-2,5-dihydro-4-furyl)benzo-[b]-furan

Synthesis

Prepared from 4-(3-acetyl-4-hydroxyphenyl)-2(5H)-furanone in several steps; the last being the esterification of 4-[2-(1-hydroxyethyl)-3-methyl-5-benzofuranoyl]-2(5H)-furanone with succinic anhydride.

Description

White to pale yellow crystalline powder, mp 144°. Soluble in alkaline solutions.

Action and Uses

Benfurodil hemisuccinate is a new coronary vasodilator. For use in the treatment of arteriopathies; vasomotor disorders; coronaritis.

Toxicity

LD50 (oral) in mice: 520±32 mg/kg

Supplied as

Tablets 50 mg

Dosage

50 to 100 mg three times daily

Proprietary Name

Eudilat

Manufacturer

Clin Byla (France)

References

1. Establissements Clin Byla Fr pat 1 408,721. 2. J. Schmitt et al. Chim Ther 305-308 (1966). 3. J. Schmitt et al. Bull Soc Chim Fr 74-84 (1967). 4. Med Act (Drugs of Today) 6 (6), 202-205 (1970). (Review with 10 references).

20

Benorylate (BAN) Win 11450

Salicylic acid, acetate, ester with 4'-hydroxyacetanilide 4-Acetamidophenyl-2-acetoxybenzoate

Synthesis

Prepared by the reaction of N-acetyl-p-aminophenol with acetylsalicyloylchloride.

Action

Benorylate is a recently synthesized analgesic compound at present being evaluated in clinical trials for the treatment of rheumatoid arthritis.

Manufacturer

Sterling-Winthrop (England)

References

1. Sterling Drug Inc. US pat 3.431,293. 2. Sterwin A. G. Neth Appl 6,504,517. 3. Pharmacology of 4-acetamidophenyl-2-acetoxybenzoate. I. Rosner et al. Therapie 23 (3), 525 (1968). 4. Comparison of 4-acetamidophenyl-2-acetoxybenzoate (Win 11450), aspirin, and placebo in stomatology. V. Vialatel et al. Therapie 23 (3). 535 (1968). 5. 4-Acetamidophenyl-2-acetoxybenzoate, a new antipyretic for padiatric use. Jean Weill et al. Therapie 23 (3), 541 (1968). 6. The treatment of rheumatoid disease. A double-blind trial comparing buffered aspirin with benorylate. L. S. Bain and R. A. P. Burt. Clin Trials J 7 (2), 307-312 (1970). 7. The treatment of rheumatoid disease. Preliminary assessment of a new drug: benorylate. N. Cardoe. Clin Trials J 7 (2), 313-318 (1970).

Bensuldazic Acid (Rec INN)

Acidum Bensuldazicum (Lat). Bensuldacico Acido (Sp)

5-Benzyldihydro-6-thioxo-2H-1,3,5-thiadiazine-3(4H) acetic acid 2-Thioxo-3-benzyl-5-carboxymethyl-tetrahydro-1,3,5-thiadiazine

Synthesis

By the reaction of benzylamine with carbon disulfide and by the condensation of the dithiocarbamate formed with formaldehyde and aminoacetic acid

Action

Bensuldazic acid is a veterinary fungicide. For use in the treatment of trichophytosis in cattle.

Manufacturer

Hoechst (Germany)

Proprietary Name

Defungit (is the sodium salt)

References

1. WHO Chron 24 (11). 526 (1970). 2. A. Rieche et al. Arch Pharm 296(11) 770-784 (1963). 3. Deutsche Akademie der Wissenschaften zu Berlin. Gar pat 1,220,429. 4. Arzneim-Forsch 19(11), 1817 (1969).

Benzbromarone

L-2214

3,5-Dibromo-4-hydroxyphenyl-2-ethyl-3-benzofuranyl ketone 2-Ethyl-3-(3,5-dibromo-4-hydroxybenzoyl) benzofuran 2-Ethyl-3-(4-hydroxy-3,5-dibromobenzoyl)coumarone

21

Synthesis

Prepared by demethylating 2-ethyl-3-anisoylcoumarone and subsequent bromination.

Description

Yellowish prisms, mp 151°.

Action

Benzbromarone first experimented as a spasmolytic agent was recently shown to decrease plasma uric acid by increasing acid clearance and urinary excretion of uric acid.

Manufacturer

Societe Beige de I'Azote and Laboratories Labaz (France)

References

1. Societe des Laboratoires Labaz. Belg pat 553,621. 2. Societe Beige de I'Azote. US pat 3,012,042. 3. Buu Hoi et al. J Chem Soc, 625 (1957). 4. R. Kotzaurek et al. Wien Med Wochenschr 118 (47), 1014-18 (1968). 5. N. Zoelineret al. Klin Wochenschr 46 (24), 1318-19 (1968). 6. Florian Delbarre et al. Chim Ther 3 (6), 470-4 (1968). 7. Die Wirkung von Benzbromaronum auf die renale Harnsaureausscheidung Gesunder. N. Zollner et al. Klin Wochenschr 48 (7), 426-32 (1970).

Benzoctamine Hydrochloride

(Rec INN) Ba 30803

N-Methyl-9,10-ethanoanthracene-9-(10H)-methylamine hydrochloride 1-Methylaminomethyl-dibenzo-[b,e]-bicyclo-[2,2,2]-octadiene hydrochloride 1-Methylaminomethyl-[2,3:5,6]-dibenzo-[2,2,2]-bicyclooctane hydrochloride

Description

White crystalline powder, mp 320-322°; soluble in water, insoluble in ether.

Action and Uses

Pharmacologically, benzoctamine has a profile midway between chlorpromazine and imipramine. For use in the treatment of psychoneurotic states manifested by anxiety and tension, and psychovegetative syndrome.

Dosage

10 mg three times daily.

Supplied as

Scored tablets, 10 mg.

Registered Name

Tacitine

Manufacturer

CIBA (Switzerland; France)

References

1. CIBA Ltd. Belg pat 610,863. 2. Med Act (Drugs of Today), 6 (4), 122-124 (1970). (Review with 11 references) . 3. Effects of benzoctamine (30803-Ba, tacitin), a new psychoactive drug, on catecholamine metabolism. L. Maitre et al. Biochem Pharmac 19, 2875-2892 (1970).

Benzpiperylone (Rec INN; NFN)

KB 95

4-Benzyl-1-(1-methyl-4-piperidyl)-3-phenyl-3-pyrazolin-5-one

Synthesis

22

Prepared from (N-methyl-piperidyl)-hydrazine and ethyl-2-benzyl-3-oxo-3-phenylpropionate.

Description

Crystals, mp 181-183° (ethanol).

Action

Benzpiperylone, a pyrazol derivative, shows antiphlogistic and antiserotonin activity. In a recent study no influence of the drug on blood coagulation could be found2.

Manufacturer

Sandoz (Switzerland)

Proprietary Name

Reublonil

References

1. Ebnöther et al. Helv Chim Acta 42, 1201 (1959). 2. The behaviour of the blood coagulation factors under the influence of a new pyrazol derivative in long-term therapy with anticoagulants. H. Wolf. Arzneim-Forsch 20 (9), 1252-1218 (1970).

Benzquinamide (USAN;

Rec INN) P 2647

Benzquinamidum (lat) . Benzquinamida (Sp) N,N-Diethyl-1,3,4,5,6,11b-hexahydro-2-hydroxy-9,10-dimethoxy-(2H)-benzo-(a)-quinolizine-3-carboxamide acetate

Description

Crystals mp 130-131.5°.

Action

Benzquinamide is a well-tolerated and effective antiemetic agent.

Manufacturer

Pfizer Co, Inc (USA)

Proprietary Name

Quantril

References

1. Pfizer Co and Inc. US pat 3,053,845. 2. A clinical pharmacological evaluation of benzquinamid,. a new antiemetic agent. N. E. Pitts. Curr Ther Res 11, 325 (1969). 3. 8enzquinamide parenteral for the treatment of postoperative nausea and vomiting. R. M. Larrauri. Curr Ther Res 11,118 (1969). 4. Inhibition of apomorphine-induced vomiting by benzquinamide. R. L. Klein, Clin Pharmacal Ther 11 , 530 (1970). 5. A double-blind evaluation of the anti-emetic efficacy of benzquinamide, prochlorperazine and trimethobenzamide in office practice. J. Medoff. Curr Ther Res 12, 706-710 (1970).

Bezitramide (Prop INN)

1-[1-(2-Cyano-3,3-diphenylpropyl) piperid-4-yl]-3-propionyl-2-benzimidazolinone 1-(3-Cyano-3,3-diphenylpropyl)-4-(2-oxo-3-propionyI-1-benzimidazolinyl) piperidine

Action

Bezitramide is an orally active analgesic. From the results of a recent double blind study it has been concluded that benzitramide 5 mg given orally has a more potent and longer-acting analgesic effect than dextromoramide on postoperative pain.

Manufacturer

Janssen Pharmaceutica (Belgium)

References

Bezitramide, an orally active analgesic. An investigation on pain following operations for lumbar disc protrusion (preliminary report). H. Knape. Brit J Anaesth 42, 325-328 (1970).

23

Bisobrin Lactate (USAN)

EN 1661L

meso-1,1'-Tetramethylene-bis-[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline] dilactate

Synthesis

Bisobrin base is allowed to react with lactic acid in ethanolic solution.

Description

White crystalline powder, mp 217-218° (95% ethanol).

Action

Bisobrin has been found highly active in dissolving blood clots in the veins of animals. The drug is under clinical study.

Manufacturer

Endo (USA)

References

1. JAMA 207, 2272 (1969). 2. Endo Laboratories Inc. S. African pat 677730. 3. Clinical pharmacologic study of an isoquinoline derivative (EN 1661) and of its ability to induce fibrinolytic activity in the circulation of man. J. L. Ambrus et al. Curr Ther Res 12 (7), 451-473 (1970).

Bithionol Sulfoxide

Bis-(3,5-dichloro-2-hydroxyphenyl) sulfoxide

Synthesis

Prepared by the reaction of thionyl chloride with 2,4-dichlorophenol.

Action

Bithionol sulfoxide has been proved to have a stronger anthelmintic activity than bithionol1. The metabolic fate and distribution of the drug have been reported2,3.

Manufacturer

Tanabe Seiyaku Co, Ltd (Japan)

Proprietary Name

Bitin S

References

1. M. Hamada. Med J Kagoshima Univ 16, 236 (1964). 2. Studies on the distribution of radioisotopes by whole body autoradiography (XIX) Distribution of S-bis (3,5-dichlor-2-hydroxyphenyl) sulfoxide in mice, rats and cockerels. T. Takahashi et al. Radioisotopes 18 (12), 552·558 (1969). 3. Metabolic fate of bis (3,5·dichloro-2-hydroxyphenyl)-sulfoxide (bithianol sulfoxide). T. Meshi et al. Biochem Pharmacol 19, 1351-1361 (1970).

Bitipazone (Prop INN)

Bitipazonum (Lat). Bitipazona (Sp) 2,3-Butandione, bis [4-(2-piperidinoethyl)-3-thiosemicarbazone]

24

Synthesis

Prepared in three steps from acetophenone methyldithiocarbazate which is condensed with (β-piperidino)ethylamine. The resulting acetophenone 4'-[β-piperidino) ethyl] thiosemicarbazone is steam distilled to remove acetophenone and finally condensed with butan-2,3-dione. The compound obtained melts at 235º (ethanol).

Action

Bitipazone shows coccidiostatic activity.

References

1. WHO Chron 24 (9), 415 (1970). 2. Well come Foundation Ltd. Belg pat 667,355.

Bitoscanate

Isothiocyanic acid, p-phenylene ester p-Phenylene bis (dithiocarbamate) p-Phenylene-1, 4-diisothiocyanate

Synthesis

From 1,4-diaminobenzol and thiophosgene1; from p-phenylenediamine2.

Description

Nearly tasteless, odorless, and colorless crystalline product, mp 132°.

Action and Uses

Bitoscanate has been found to be effective in helminthiasis in laboratory animals and in man. For

use in the treatment of infections due to Ancylostoma duodenale and Necator americanus.

Dosage

Adults, three doses of 100 mg, each at 12 hour intervals after food.

Supplied as

Capsules, 50 mg

Proprietary Name

Jonit

Manufacturer

Hoechst (Germany)

References

1. A. Billeter and A. Steiner. Ber Dtsch Chem Ges 20, 230 (1887). 2. Nederlandse Centrale Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek. Brit pat 793,802. 3. Farbwerke Hoechst. Brit pat 1,001,314. 4. Med Act (Drugs of Today) 6 (5), 162 (1970). (Review with 6 references). 5. Evaluation of bitoscanate-Jonie. in intestinal parasitic infection: a field study. G. S. Mutalik et al. Ann Trop Med Parasitol 64 (1), 79 (1970).

BL-P 1654

6-[R-α-(Guanylureido) phenylacetamido] penicillanic acid

Action

BL-P 1654 a new orally absorbed, semi-synthetic penicillin with a very broad spectrum of activity. In systemic P. aeruginosa infections it has proved to be 6-8 times more active than carbenicillin and almost 100 times more active than ampicillin.

Manufacturer

Bristol Laboratories (USA)

25

References

Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct 18-21 (1970); abstr. 107-108.

BP 400

9-(N-Methyl-4-piperidylidene) thioxanten maleate

Action

BP 400 is an antamine (anti-histamine, serotonin, bradykinin) with slight sedative effects1. Its distribution has been studied in 65 structures of the rat brain, using autoradiography2.

Manufacturer

Sandoz AG (Switzerland)

References

1. Wien Klin Wschr 80, 250 (1968). 2. Autoradiographic studies on the distribution of the thioxanthene derivative 14C-BP400 in the rat brain. H. Eckert and A. Hopi. Arzneim-Forsch 20 (11), 1712-1716 (1970).

Bromazepam (USAN;

Rec INN) Ro 5-3350

Bromazepamum (Lat) 7-Bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one

Synthesis

Prepared from 2-amino-5-bromophenyl-2-pyridyl ketone

Description

Colorless prisms, mp 237-238.5° (acetone).

Action

Bromazepam is a new psychoactive agent of the 1,4-benzodiazepine class of compounds, which has some qualitative similar pharmacological actions to those of diazepam in most animal laboratory tests.

Manufacturer

Hoffmann-La Roche Inc (USA)

References

1. WHO Chron 24 (11), 527 (1970). 2. Hoffmann-La Roche Inc. US pat 3,182,065; US pat 3,100,770; Belg pat 619.101; US pat 3.182.067. 3. R. Ian Fryer et al. J Pharm Sci 53 (3). 264 (1964). 4. A behavioral and autonomic nervous system study of Ro-5-3350 and diazepam in conscious dogs. B. Korol at al. Pharmacology 1(2).115-128 (1968). 5. Effects of a new benzodiazepine compound (Ro 5-3350) on subcortical and cortical nervous system structures in the cat. C. Guerrero Figueroa et al. Vll lnternat Congr Collinternationale Neuro-Psychopharm. Prague. Czechoslovakia. Aug. 11-15 (1970) p. 175.

26

Bromebric Acid

(BAN; Prop INN)

Acidum bromebricum (Lat) cis-3-p-Anisoyl-3-bromoacrylic acid cis-3-Bromo-4-(4-methoxybenzoyl)acrylic acid

Synthesis

By hydrolisis of γ-4-methoxyphenyl-α,β-dibromo-∆α,β-∆α,β-crotonolactone3,5. Also by splitting off

hydrobromic acid from p-(4-methoxybenzoyl) acrylic acid dibromide3,4,5

Description

Crystals, mp 146-147°. UV max 223 µm [Ig = 4.17] and 301 µm [lg =4.18] at pH 2.8; 218 µm [lg =4.17] and 299 µm [lg =4.19] at pH 8.16.

Action

Prophylaxis of migraine.

Manufacturer

Leciva (Poland)

References

1. Chem Drug 194, 446 (1970). 2. WHO Chron 25 (3), 123 (1971). 3. M. Semonsky et al. Coll Czech Chem Commun 28, 377 (1963). 4. Robert E. Lutz et al. J Org Chem 26, 746 (1961). 5. Spofa. Brit pat 881,617. 6. B. Kakac et al. Coll Czech Chem Commun 33, 1256 (1968).

Bucrylate (USAN)

Bucrilate (Rec INN). Bucrilatum (Lat). Bucrilato (Sp) Isobutyl 2-cyanoacrylate

Action

Bucrylate is a tissue adhesive.

Manufacturer

Ethieon, Inc (USA)

Proprietary Name

Coapt

References

1. WHO Chron 24 (11), 527 (1970). 2. JAMA 209. 406 (1969). 3. Healing of skin wounds under butyl cyanoacrylate dressing. S. N. Bhaskar and D. E. Cutright. J D Res 48, 294-297 (1969). 4. Modified delayed closure of facial wounds with isobutyl cyanoacrylate. E. H. Hunsuck et al. Oral Surg, Oral Med, Oral Path 29 (2), 305-312 (1970).

Bufexamac

(Rec INN; BAN) CP 1044 J3

Bufexamacum (Latin). Bufexamaeo (Sp) 2-(p-Butoxyphenyl)-acetohydroxamic acid

Synthesis

Prepared in several steps from p-hydroxyacetophenone; the last being the reaction of ethyl-p-butoxyphenylacetate with hydroxylamine.

Description

Crystalline powder, which melts at 153-155°.

Action

27

Non-steroidal analgesic and anti-inflammatory agent.

Toxicity

LD50 orally in rats: 4,600 mg/kg; in mice orally: 8,000 mg/kg.

Manufacturer

Continental Pharma Laboratories (Belgium)

Proprietary Name

Droxaryl

References

1. Pharm. J. 202, 719 (1969). 2. Madan AG. Belg. pat. 661226 (1965). 3. Teratological studies of p-butoxyphenylacetohydroxamic acid in rats and rabbits. J. Roba et al. Arzneim-Forsch 20 (4). 565-569 (1970). 4. Therapeutic efficacy of bufexamac in rheumatoid arthritis; a doubleblind comparison with indomethacin. K. Pavelka and F. Wagenhauser. Curr Ther Res 12 (2), 69-72 (1970). 5. Use of bufexamac for rheumatoid arthritis. B. S. Rose et al. Curr Ther Res 12 (3). 150-153 (1970). 6. Pharmacological studies of bufexamac topically applied on the skin. G. Lambelin et al. Arch Int Pharmacodyn Ther 187 (2),394 (1970). 7. Preliminary study of the action of p-butoxyphenylacethydroxamic acid in the treatment of osteoarthritis of the hip. H. Bloch-Michel and M. Parrot, Therapie 25 (5), 969 (1970).

Bulgerin

Production

Bulgerin has been isolated from a culture broth of a streptomyces strain S-288 Streptomyces aburaviensis var tuftformis.

Description

Bulgerin is a water-soluble amphoteric subsstance. UV max 289 µm, and shoulder 230 µm, in 0.05 N HCI. [α]D= +24° (in water).

Action

Bulgerin is a new antibiotic, active against some phytopathogenic fungi.

Manufacturer

Shionogi and Co, Ltd (Japan)

References

A new antibiotic, bulgerin, active against phytopathogenic fungi. J. Shoji et al. J Antibiotics 23 (6), 295-299 (1970).

Bunolol Hydrochloride (USAN;

Rec INN) W 6412A

Bunololum (Lat) (±)-5-[3-(tert-Butylamino)-2-hydroxypropoxy]-3,4-dihydro-1(2H)-naphthalenone hydrochloride

Synthesis

By the reaction of 5-hydroxy-1-tetralone with t-butylamino-2,3-epoxy-propane in the presence of sodium hydroxide. Also by the reaction of 5-hydroxy-1-tetralone with t-butylamine3.

Description

White crystalline powder, mp 224-226° (ethanol)

Action

Bunolol is a new potent beta receptor antagonist recently described4. It exhibits much less local anesthetic and nonspecific antiarrhythmic activity than propranolol5.

Manufacturer

Warner Lambert (USA)

References·

1. JAMA 212, 2247 (1970). 2. WHO Chron 24 (11), 527 (1970).

28

3. Derivatives of 3,4-dihydro-1 (2H)-naphthalenone as β-adrenergic blocking agents, 1. Bunolol and related analogs. C.F. Schwender et al. J Med Chem 13(4), 684-688 (1970). 4. The cardiovascular pharmacology of bunolol, a new beta adrenergic blocking agent. R. D. Robson and H. R. Kaplan. J Pharmacal Exp Ther 175, 157-167 (1970). 5. Antiarrythmic activity of bunolol, a new beta adrenergic blocking agent H. R. Kaplan and R. D. Robson. J Pharmacal Exp Ther 175, 168-177 (1970).

Buquinolate (USAN)

6, 7-Diisobutoxy-4-hydroxy-3-quinolinecarboxylic acid ethyl ester

Synthesis

Prepared in five steps from pyrocatechol and isobutyl bromide. Nitration, followed by reduction gives 3, 4-diisobutoxyaniline which is condensed with ethyl ethoxymethylenemalonate and finally cyclized.

Description

Crystals, mp 288-291º (dimethylformamide).

Action

Buquinolate is a broad-spectrum coccidiostat for poultry.

Manufacturer

Eaton Laboratories (USA)

References

1. The Norwich Pharmacal Co. Belg pat 659,237.

2. C. F. Spencer et al. J Med Chem 9 (6), 934-936 (1966). 3. E. C. McManus et al. J Parasit 54, 1190-1193 (1968). 4. T. V. Raines, Poultry Sci 47, 1425-1432 (1968). 5. Efficacy of buquinolate against ten strains of Eimeria tenella and the development of a resistant strain. D. K. McLoughlin. Avian Dis 14 (1), 126-130 (1970).

Calcium polystyrene sulfonate

Description

Calcium polystyrene sulfonate, a cation-exchange resin charged with calcium, is available as an insoluble buff colored, finely ground powder.

Action and Uses

The calcium ions of the exchange resin are released and replaced by potassium ions in the alimentary canal. The excretion of potassium ion decreases serum potassium ion concentration. For use in the treatment of hyperkalemia.

Dosage

Adults. 15 g 3 or 4 times daily by mouth or 30 g as a retention enema.

Proprietary Name

Calcium Resonium

Manufacturer

Bayer Prod (England)

References

1. Pharm J 203. 59 (1969). 2. Med Act (Drugs of Today) 6(1), 9-10 (1970).

Calusterone

(USAN; Rec INN) U-22,550

Calusteronum (Lat). Calusterona (Sp) 17β-Hydroxy-7β,17-dimethylandrost-4-en-3-one 7β,17α-Dimethyltestosterone

29

Synthesis

The reaction of 6-dehydro-17α-methyltestosterone with methylmagnesium bromide and cuprous chloride in anhydrous tetrahydrofurane gives a mixture of 7α and 7β-methyl isomers which is separated chromatographically to give 7β, 17α-dimethyltestoterona.

Description

Crystals. mp 127-129° (acetone).

Action

Calusterone has been reported to have potent antitumor efficacy in women with advanced breast cancer. and to be better tolerated than most chemotherapeutic or steroidal antitumor agents.

Manufacturer

The Upjohn Co (USA)

References

1. JAMA 211, 819 (1970). 2. WHO Chron 24 (11), 527 (1970). 3. J. C. Babcock et al (to the Upjohn Co). US pat 3.341.557. 4. Progress in the treatment of advanced breast cancer. R. M. Walter and G. S. Gordan. Calif Med 111. 38-45 (1969). 5. Antitumor efficacy of calustelone in advanced female breast cancer. G. S. Gordan et al. Calif Med 113. 1-10 (1970).

Cambendazole

(USAN; Prop INN)

Isopropyl 2-(4-thiazolyl)-5-benzimidazole-carbamate 2-(4-Thiazolyl)-5-isopropoxy-carbonylamino-benzimidazole

Action

Cambendazole, a derivative of thiabendazole, is a new broad spectrum anthelmintic. It has all the advantages of the parent chemical plus a considerably longer effective half-life in animals

Manufacturer

Merck Sharp and Dohme (USA)

References

1. JAMA 212, 466 (1970). 2. WHO Chron 24 (9), 416 (1970). 3. Chem Engineer News, p 77 (June 8.1970). 4. The efficacy of 5-isopropoxy-carbonylamino-2-(4-thiazolyl) benzimidazole against helminths of sheep. J. R. Egerton and W. C. Campbell. Res vet Sci 11, 193-195 (1970). 5. The efficacy of cambendazole against gastrointestinal nematodes of cattle. J. R. Egerton et al. Res vet Sci 11, 495-499 (1970). 6. A new broad spectrum anthelminthic. D. R. Hoff et al. Experientia 26, 550 (1970). 7. Anthelmintic efficacy of cambendazole in cattle. N. F. Baker and G. T. Walters. Amer J Vet Res 32 (1), 29 (1971).

Campesteryl Acetate

(24R)-24-Methyl-3-β-acetoxycholesten-5-ene

Synthesis

The isolation of campesterol from many plant sources has been described1. Its synthesis has been recently accomplished starting from the

30

optically active (-)-3,4-dimethylpentylmagnesium bromide and pregnenolone acetate2.

Description

Crystals mp 138º (ethanol); [α]D= -33° (c=1) Rf=0.86 (TLC), hexane-ether-acetic acid (20:4:1 ).

Action

Biological tests have revealed that synthetic campesteryl acetate has considerable utility for larval growth of Dermestes maculatus.

References

1. Fernholz and McPhiliamy. J Am Chem Soc 63,1155 (1941). 2. Synthesis of campesteryl acetate [(24R)-24-methyl-3-β-acetoxycholesten-5-ene] and its 24S-epimer. R. Ikan et al. Steroids 16 (5), 517-522 (1970).

Camptothecin NSC100880

4-α-Ethyl-4,12-dihydroxy-1H-pyrano [3',4',6,7] indolizino [1,2-b] quinolin-3,14-dione

Synthesis

Camptothecin is a novel alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. The structural elucidation of this alkaloid has been reported by Wall and co-workers1. Attempts to synthesize it have been examined, but have not yet succeeded2,3,4.

Description

Pale yellow needles, mp 264-267° dec. [ α]D= +31.3° (chloroform/methanol, 8:2). UV max 220 µm [ε=37.320], 254 µm [ε=29,320], 290 µm [ε=4,980] and 370 µm [ε=19,900].

Action

Camptothecin has been found effective in treatment of advanced cancer of the intestine and rectum, investigators from the National Cancer Institute said at the recent annual meeting of the American Asssociation for Cancer Research.

References

1. M. E. Wall et al. J Am Chem Soc 88, 3888 (1966). 2. J. A. Kepler et al. J Org Chem 34, 3853 (1969). 3. M. Shamma and L. Novak. Tetrahedron 25, 2275 (1969). 4. T. Kametan; et al. Chem Ind (41),1323 (1970). 5. Proc Am Canc Res 11, abs 121 (March 1970). 6 Preliminary pharmacologic and clinical evaluation of camptothecin sodium. Jeffrey A. Gottlieb et al. Cancer Chemother Rep, Pt 1, 54 (6), 461-470 (1970)

l-Canadine Methochloride

Isolation Alkaloid isolated from the bark of Zanthoxylum martinicense DC1.

Action

Pharmacological studies have shown that l-canadine methochloride causes a significant fall in blood pressure in intact anesthetized cats and dogs and that it shows ganglion-blocking activity.

Toxicity

LD50 ip in mice: 84±2.8 mg/kg.

References

1. J. Tomko et al. Lloydia 30. 231 (1967). 2. A pharmacological study of the alkaloids I-canadine methochloride and d-tembetarine chloride. D. G. Patel et al. Lloydia 33. 36-42 (1970).

31

Capuride

(USAN; Rec INN) McN-X-94

α-Ethyl-β-methylvaleric acid, ureide (Ethyl-sec-butylacetyl) urea

Synthesis

Prepared form the α-ethyl-β-methylvaleric acid chloride.

Description

Crystals, mp 172º

Action

Capuride is a non barbiturate sedative. Early animal and human pharmacological studies of this investigational drug have suggested it may have anxiolytic activity. In recent double-blind studies its efficacy as presurgical anxiolytic has been evaluated.

Manufacturer

McNeil Laboratories (USA)

Proprietary Name

Pacinox

References

1. E. H. Wolwilder et al. J Am Chem Soc 58, 1352 (1936). 2. A double-blind evaluation of Capuride (Pacinox) as a presurgical aid to sleep. J. Katz et al. Curr Ther Res 12, 255-260 (1970). 3. Capuride versus methyprylon and placebo in treating sleeplessness due to presurgical anxiety. F. J. Tornetta. Anesthesia and Analgesia 49 (6), 862-865 (1970) .

O-Carbamyl-D-Serine O-CS

D-Serine carbamate (ester)

Production

From the broth filtrate of Streptomyces No 547.

Action

O-Carbamyl-D-serine inhibits the growth of Mycobacterium tuberculosis at relatively high concentrations and potentiates the inhibitory activity of D-cycloserine. The synergism exhibited by the combination of D-cycloserine with O-carbamyl-D-serine makes the latter antimicrobial agent of potential interest in therapy because of the importance of D-cycloserine in the treatment of tuberculosis.

Manufacturer

Commercial Solvents Corp (USA)

References

1. Y. Okami et al. J Antibiotics Ser A, 15. 147-151 (1962). 2. C. Neuhaus. Antibiotics 1. 40-83 (1967). 3. Effect of O-carbamyl-D-serine on the growth of mycobacterium tuberculosis. H. L. David. Amer Rev Resp Dis 102 (1). 68-74 (1970). 4. Susceptibility of mycobacterium intracel/ulare to O-carbamyl-D-serine. H. L. David. Amer Rev Resp Dis 102 (1),105-106 (1970).

Carbazochrome Salicylate

3-Hydroxy-1-methyl-5,6-indolinedione semicarbazone compound with sodium salicylate Adrenochrome semicarbazone compound with sodium salicylate

Description

32

A fine, orange-red odourless powder with a sweetish taste. A solution in water has a pH of about 7. Soluble in water and alcohol, and practically insoluble in ether and chloroform. Melting point, 196-197.5° (dec).

Action and Uses

Carbazochrome salicylate has been used for over a decade as a systemic hemostatic agent. Recently it has been studied for possible effectiveness in psichiatry. Quantitative EEG amplitude analysis has provided evidence of effects of carbazochrome on the brain of the schizophrenic.

Manufacturer

S. E. Massengill Co (USA)

References

Electroencephalographic effects of adrenochrome semicarbazone in schizophrenia: quantitative amplitude analysis. A. A. Sugerman and L. Hyams. Res Comm Chem Pathol Pharmacol 1 (1), 86-98 (1970).

Carboxypyridine Disulfide

CPDS

2, 2'-Dithiodiisonicotinic acid

Synthesis

Prepared by the reaction of 2-chloroisonicotinic acid with potassium bisulfide, and by subsequent oxidation with iodine.

Description

White microcrystalline powder, dec 277°.

Action

Carboxypyridine disulfide has been found to prevent the spread of cancerous tumor cells in mice, from one area of the body to another.

References

1. H. H. Fox and J. T. Gibas. J Org Chem 23, 64 (1958). 2. D. R. Grassetti et al. J Med Chem 13 (2), 273-276 (1970). 3. D. R. Grassetti. Chem Eng News 48 (44). 71 (1970).

Carmustine (USAN; Prop INN)

NSC 409962 BCNU

Carmustinum (Latin). Carmustina (Sp) 1, 3-bis (2-Chloroethyl)-1-nitrosourea

Action

Carmustine, an alkylating agent, has been proved to be definitely beneficial in Hodgkin's disease, useful in gastrointestinal cancer, and promising in brain tumors.

Supplied by The Cancer Chemotherapy National Service Center, Public Health Service (USA)

References

1. WHO Chron 24 (9), 416 (1970). 2. T. P. Johnston et al. J Med Chem 6 (6), 669-81 (1963). 3. T. P. Johnston et al. J Med Chem 9 (6), 892-910 (1966). 4. Medical World News 11 (2), 13 (1970). 5. BCNU in the treatment of malignant brain tumor-a preliminary report. Michael D. Walker et al. Cancer Chemother Rep 54 (4), 263-270 (1970). 6. BCNU in the treatment of brain tumors. Charles B. Wilson et al. Cancer Chemother Rep 54 (4), 273-280 (1970). 7. 1,3-bis (2-Chloroethyl)-1-nitrosourea (BCNU; NSC-409962) given concomitantly with cytosine arabinoside (NSC-63878) in the treatment of cancer. E. B. van Eden et al. Cancer Chemother Rep (Pan 1) 54 (5), 347-359 (1970). 8. Studies on the chemotherapy of experimental brain tumors: Evaluation of 1,3-bis (2-chloroethyl)-1-nitrosourea. cyclophosphamide, mithramycin. and methotrexate.

33

W. R. Shapiro et al. Cancer Research 30, 2401-2413 (1970).

Carnitine Orotate DAN-221

D, L-Carnitine orotate D, L-(2-Hydroxy-3-carboxypropyl)-trimethylammonium, 2,4-dihydroxypyrimidine-6-carboxylate D, L-(2-Hydroxy-3-carboxypropyl)-trimethylammonium uracil-6-carboxylate

Synthesis

Monohydrated orotic acid is dissolved in hot methanolic solution of carnitine base and the mixture is allowed to cool.

Description

White crystalline powder, mp 191-193°.

Action and Uses

Regulator of the protein and the enzyme metabolism, lipotropic and antilipemic protector of the liver cells.

Dosage

The usual oral dose for adults is 600 to 900 mg per day, divided into two or three doses.

Supplied as

Effervescent tablets, 300 mg. Solution for oral use, each 10 ml containing 300 mg. Injectable solution, each vial containing 300 mg.

Proprietary Names

Hepadif and Dif-Hepal

Manufacturer

Lab Andreu (Spain)

References

1. Dr. Andreu, S A Sp pat 331,061, 2. Med Act (Drugs of Today) 6 (1), 11-19 (1970). (Review with 6 references).

Carperone (Prop INN)

AL 1021

Carperonum (Latin); Carperona (Sp) Isopropylcarbamic acid, ester with 4'-fluoro-4-(4-hydroxy-piperidino) butyrophenone 1-[3-(4-Fluorobenzoyl) propyl]-4-piperidyl N-isopropylcarbamate.

Synthesis

Prepared by reacting 1-[3-(4-fluorobenzoyl)-propyl]-4-piperidinol with isopropyl isocyanate; also, from 1-[3-(4-fluorobenzoyl) propyl]-4-piperidinol chloroformate and isopropylamine.

Description

White, fine needles, mp 105-105.5°.

Action

Carperone is a fluorobutyrophenone compound which in animal studies has showed calming or tranquilizing effects resembling those of haloperidol and chlorpromazine. The results of pilot studies in chronic schizophrenic patients has suggested that carperone has definite antipsychotic effects.

Manufacturer

Bristol Laboratories (USA)

References

1. Aldrich Cemical Co. S African Appl 680.029. 2. Effects of a new butyrophenone compound (AL-1021) on subcortical and cortical nervous system structures in cat. R. Guerrero Figueroa et al. Curr Ther Res 11 (3), 121-133 (1969). 3. A pilot study of AL-1021 in chronic schizophrenic patients. A. Arthur Sugerman. Curr Ther Res 11 (12), 775-778 (1969).

34

4. Pilot study on the use of AL-1021 in the treatment of chronic schizophrenia. J. W. S. Angus et al. Curr Ther Res 11 (12),779-783 (1969). 5. WHO Chronicle 24 (9),416 (1970).

CCB Hydrochloride

3,3'-(Iminodimethylene) dipyridine hydrochloride Bis-(4-pyridylmethyl) amine hydrochloride

Synthesis

Prepared by Rosenmund reduction of 3-methylaminopyridine1,2. Also by catalytic reduction of 3~cyanopyridine in the presence of rhodium3 or in the presence of Raney nickel4.

Description

Crystals, mp 263-265°. UV max 258 µm in 0.2M KCI-HCI buffer pH 2.2.

Action

CCB has been found to be a coronary vasodilatator which may possibly be used for treatment of angina pectoris5,6. The drug has proved to exert some sedative action depressing the spontaneous locomotor activity in rats and mice7.

Manufacturer

Polfa (Poland)

References

1. S. Biniecki et al. Ann Pharm Franc 22, 685 (1964). 2. Polfa, Belg pat 647,723. 3. M. Freifelder et al. J Org Chem 26, 3805 (1961). 4. H. Adkins et al. J Am Chem Soc 66, 1293 (1944). 5. W. Kostowski and J. Majcharzyk. Acta Physiol Pol 26, 2 (1965). 6. E. Kostka-Trabka et al. Dissert Pharm Pharmacol 21(2), 93-106 (1969). 7. The central action of CCB. Z. Kleinrok et al. ibid 22(1), 1-6 (1970).

CCNU NSC 79037

1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea

Action

CCNU is an antitumor agent of the family of nitrosoureas, which is at least as active as carmustine, or more so, against mouse leukemia L 1210. Its physiological disposition has been studied in animals in hopes of better elucidating its own metabolic fate and mode of action and that of the class of nitrosoureas.

Supplied by The Cancer Chemotherapy National Service Center, Public Health Service (USA)

References

1. The absorption, distribution. excretion, and biotransformation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in animals. Vincent T. Oliverio et al. Cancer Res 30, 1330-1337 (1970). 2. The uptake, distribution, and antitumor activity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in the murine glioma. V. A. Levin et al. Cancer Res 30. 2451-2455 (1970).

Cefazolin (Prop INN)

7-[1-(1H)-Tetrazolylacetamido]-3-[2-(5-methyl-1,3,4-thiadiazolyl)-thiomethyl]-∆3-cephem-4-carboxylic acid

Synthesis

35

Acylation of 7-aminocephaloporanic acid with 1-(1H)-tetrazolylacetic acid chloride yields 7-[1-(1 H)-tetrazolylacetamido]cephalosporanic acid. By displacement of the acetoxyl group of the latter by 2-mercapto-5-methyl-1,3,4-thiadiazole cefazolin is obtained.

Description

Colorless needles, mp 198-200° (dec). Ultraviolet absorption maximum at 272 µm [ε=13150].

Action

Cefazolin is a new semisynthetic antibiotic derived from 7-aminocephalosporanic acid. It is active in vitro against most Gram-positive and Gram-negative species of bacteria except for Ps. aeruginosa and is also active against penicillinase-producing strains of Staph. aureus. After parenteral administration in rats and rabbits, and in human volunteers, the serum levels and urinary recovery of cefazolin were higher than those of cephaloridine, cephalothin and ampicillin.

Manufacturer

Fujisawa Pharmaceutical Co, Ltd (Japan)

Proprietary Name

Cefamezin

References

1. WHO Chron 25 (3), 129 (1971). 2. Cefazolin a new semisynthetic cephalosporin antibiotic. I. Synthesis and chemical properties of cefazolin. K. Kariyone et al. J. Antibiotics. 23 (3), 131-136 (1970). 3. II. In vitro and in vivo antimicrobial activity. M. Nishida at al. J. Antibiotics 23 (3), 137-148 (1970). 4. III. Absorption. excretion and tissue distribution in parenteral administration. M. Nishida et al. J. Antibiotics 23 (3). 184-194 (1970). 5. IV. Antigenicity of cefazolin and its cross reactivity with benzylpenicillin-ampicilin and cephaloridine. Y. Mine et al. J. Antibiotics 23 (3), 195-203 (1970).

Cellaburate (USAN; Rec INN)

Cellaburatum (Lat.). Celaburato (Sp.) Cellulose acetate butyrate

Synthesis

By the reaction of purified cellulose with acetic and butyric anhydrides in the presence of sulfuric acid as catalyst and glacial acetic acid as solvent.

Description

White flakes or granules. Soluble in ketones, organic acetates and ethylene chloride.

Action

Plastic film former.

Manufacturer

Tennessee Eastman, Division of Eastman Kodak Co. (USA)

References

1. WHO Chron 24 (11), 528 (1970). 2. JAMA 211. 818 (1970).

Celluline

A mixture of lignin and methycellulose (99.5:0.50 w/w)

Action

Celluline is a new hypocholesteremic agent. The drug absorbs bile acids in the gastrointestinal tract and enhances their fecal excretion, thus stimulating hepatic conversion of cholesterol to bile acids.

References

Traitement de I'hyperlipoproteinemie essentielle de type II par un nouvel agent therapeutique, la celluline. C. Thiffault et al. Can Med Ass J 103, 165-167 (1970).

36

Cephacetrile Sodium (USAN;

Prop INN) BA 36278A

Sodium 7-(2-cyanacetamido)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate acetate (ester) Sodium 7-(2-cyanoacetamido) cephalosporanic acid

Synthesis

Prepared by the reaction of 7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate acetate (ester) with cyanoacetylchloride.

Description

The free acid melts at 160-170º (dec).

Action

Cephacetrile is a new broad-spectrum semisynthetic antibiotic. It has proved to be more potent than cephalothin and less potent and less toxic than cephaloridine.

Manufacturer

Ciba Pharmaceutical Co (USA)

References

1. JAMA 214, 741 (1970). 2. CIBA Ltd. Neth Appl 6,600,586. 3. Abstr Intersc Conf Antimicr 10:6, Oct 1970.

Cephalexin (USAN)

Lilly 66873

7-(D-2-Amino-α-phenylacetamido)-3-methyl-3-cephem-5-carboxylic acid 7-(D-2-Amino-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid

Cephalexin is a desacetoxycephalosporanic acid derivative, structurally related to cephaloridine, cephalothin and cephaloglycin. It differs from the latter in having a methyl group at position 3 instead of an acetoxyl group

Description

White crystalline powder, soluble at approximately 2 mg/ml in water at 25°.

Action and Uses

Cephalexin has interesting pharmacological properties; its excellent absorption after oral administration provides high concentrations in serum and urine. The spectrum of antibacterial activity is virtually identical to that of other cephalosporins.

Dosage

For use in the treatment of bacterial infections due to susceptible organisms; Adults: 1 to 4 g daily in divided doses. Children: usually 60 mg per kg body weight daily in divided doses (15 mg/kg six hourly).

Supplied as

Capsules 250 and 500 mg; Granules for syrup; 250 mg in 5 ml.

Proprietary Names and Manufacturer

Ceporex (Glaxo); Keflex (Eli Lilly); Kefloridina (Eli Lilly)

References

Med Act (Drugs of Today) 6 (5), 164 (1970). (Review with 17 references).

Cephaloglycin (USAN)

7-(D-α-Aminophenylacetamido) cephalosporanic acid 7-(Amino-2-phenylacetamido)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid acetate

37

Cephaloglycin is a new cephalosporanic acid derivative, structurally related to cephaloridine, cephalothin and cephalexin. It differs from the latter in having an acetoxyl instead of a methyl group

Description

White powder, slightly soluble in water, ethanol and acetone, and practically insoluble in chloroform [α]D = 88 to 98º. UV max at about 262 µm [E(1 %, 1 cm) =214 to 227].

Action and Uses

Cephaloglycin dihydrate is a new orally active member of the cephalosporin family. For use in the treatment of acute and chronic infections of the urinary tract due to susceptible strains of E. coli, Klebsiella-Aerobacter, staphylococci, certain of the Proteus species, and enterococci.

Dosage

Usually, 250 mg every six hours. For more severe infections 500 mg every six hours.

Supplied as

Pulvules and capsules 250 mg (in Japan)

Proprietary Name and Manufacturer

Kafozin (Eli Lilly, USA); Kefglycin (Shionogi, Japan)

References

Med Act (Drugs of Today) 6 (5), 168 (1970). (Review)

Cephapirin Sodium

(USAN; INN) BL-P 1322

Cefapirinum sodium (Lat); Cefapirina sodica (Sp) 3-(Hydroxymethyl)-8-oxa-7-[2-(4-pyridylthio)acetamido)]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid acetate (ester) sodium salt 7-[α-(4-Pyridylthio )acetamido] cephalosporanic acid sodium salt

Synthesis

Prepared from 7-(α-bromoacetamido)-cephalosporanate and 4-mercaptopyridine.

Description

White crystalline solid, soluble in water.

Action

Cephapirin sodium, a new semisynthetic derivative of 7-aminocephalosporanic acid, has been selected from a cephalosporin screening program as an interesting candidate for clinical use.

Manufacturer

Bristol Laboratories (USA)

References

1. Bristol Mayers Co. South African Appl 677783; US pat 3,422,100. 2. JAMA 211, 1362 (1970). 3. WHO Chronicle 24(3), 134 (1970). 4. Laboratory studies with a new cephalosporanic acid derivative. D. R. Chisholm et al. Antimicrobial Agents Chemotherapy, p. 244-246 (1969).

CG 603

N-[1-(Morpholinomethyl)-2, 6-dioxo-3-piperidyl] phthalimide

Synthesis

By heating 4-phthalimidopiperidine-2,6-dione with aq formaldehyde and morpholine. mp 203-5° (dioxane-ether).

38

Action

CG 603 has proved to show curative action on DMBA-induced tumors in rats and to increase the antitumor activity of drostanolone propionate.

Manufacturer

Chem Grunenthal (Germany)

References

1. Chemie Grunenthal GmbH. Neth Appl 6,606,210. 2. H. Muckter et al. Z Krebsfarch 69, 60-69 (1967). 3. H. Muckter et al. Cancer Res 29, 1212-17 (1969). 4. Experimental investigations with CG 603 and drostanolone propionate in dimethylbenz-anthracene-induced tumors of Sprague-Dawley rats. H. Mucker et al. Cancer Res 30, 430-8 (1970).

Chaetocin

Isolation Chaetocin has been isolated from Chaetomium minutum.

Description

Colorless crystals, mp 240º (dec), [α]D = 379° (c=1, pyridine) and [α]D = 789° (c=1, dimethylsulfoxide). UV max 306 µm (lgε=3.78) in dimethylsulfoxide).

Action

Chaetocin shows antibacterial and cytostatic activity.

Manufacturer

Sandoz (Switzerland)

References

Isolierung und Strukturaufklarung von Chaetocin. D. Hauser et al. Helv Chim Acta 53 (5), 1061 (1970).

Chloramphenicol Arginine

Succinate

Arginine salt of the 3-monosuccinic ester of chloramphenicol

Description

White to faintly yellow needle-like crystals, mp 135-145° (dec). Very soluble in water, slightly soluble in ethanol and practically insoluble in methanol and acetone.

Action and Uses

Chloramphenicol arginine succinate has been recently marketed in Japan with the purpose of alleviating pain at the site of injection, as a result of the replacement of the sodium salt of the mono-succinic ester of chloramphenicol by the arginine salt. It is used for the treatment of infections due to chloramphenicol susceptible organisms.

Dosage

The usual intramuscular dosage for adults is 1 g (potency) 1 to 2 times daily.

Supplied as

Vials, 0.25, 0.5 and 1 g (potency).

Propritary Name Paraxin Succinate A

Manufacturer

39

Yamanouchi Pharmaceutical Co Ltd (Jap)

References

Med Act (Drugs of Today) 7 (1), 8 (1971). (Review)

Chlorflavonin

Production

It is obtained from cultures of Aspergillus candidus.

Description

Yellow microcrystalline solid, mp 212°.

Action

Chlorflavonin is a new antifungal antibiotic.

Manufacturer

Beecham Research Laboratories (England)

References

1. M. Richards et al. J Antibiotics 22, 388-389 (1969). 2. Jap Med Gazz 7 (4), 13 (1970).

Chlorophillipe

Description

Greenish microcrystalline substance, soluble in organic solvents.

Action

Chlorophillipe exhibits anti-staphylococcal activity. It has proved to be highly effective in clinic as topical and visceral rinse.

References

1. Chlorophillipe. a new antibacterial drug. V. L. Nadtoka Antibiotiki 15 (10). 888 (1970). 2. Soviet pat (Author Certificate) 240.932.

Cholestyramine

Cholestyramine is the chloride of an anion-exchange resin containing quaternary ammonium groups which are attached to a styrene-divinyl benzene copolymer

Description

Cholestyramine is a white, tasteless powder. It is slightly acid in reaction (pH about 5,6) insoluble in water and not hydrolyzed by digestive enzymes.

Action and Uses

Cholestyramine lowers the amount of cholesterol in the blood. It seems that cholestyramine forces the body to use up its supply of cholesterol by interfering with the fat absorption process in the intestines and thereby lower the serum cholesterol content.

Dosage

Usually 4 g three times daily before meals.

Supplied as

Dry powder.

Proprietary Name

Questran

Manufacturer

Bristol (England)

References

Med Act (Drugs of Today) 6 (5), 174 (1970). (Review)

Chymostatin

40

Production

Chymostatin can be obtained from the culture filtrate of actinomycetes.

Description

White crystals, mp 205-207º (dec). [α]D = 9º (c=0.25 in acetic acid). Ultraviolet absorption maxima at 253 µm, 260 µm, 265 µm and 270 µm. The infrared absorption spectrum indicates a peptide nature.

Action

Chymostatin is an inhibitor of chymotrypsin and papain.

Manufacturer

Institute of Microbial Chemistry, Tokyo (Japan)

References

1. Chymostatin a new chymotrypsin inhibitor produced by actinomycetes. H. Umezawa et al. J Antibiotics 23 (8),425-427 (1970).

CI 601

4-[2-(o-Ethoxyphenoxy)ethylaminoj-4'-fluoro-butyrophenone hydrochloride.

Synthesis

Prepared by the reaction of 2-(o-ethoxyphenoxy)-ethylamine with -γ-chloro-p-fluoro-butyrophenone ethylene ketal in refluxing xylene and by refluxing the ketal intermediate with isopropyl alcohol and 1 N aqueous hydrochloric acid.

Description

Crystals, mp 108-110°.

Action

CI 601 is a butyrophenone derivative showing pharmacological action in animals, similar to that of major tranquilizers. In a double-blind controlled clinical study, the drug has been found to be comparable in overall therapeutic effectiveness to haloperidol.

Manufacturer

Parke Davis and Co (USA)

References

1. Parke, Davis and Co. Belg pat 668,124 2. CI-601, a butyrophenone derivative, in the treatment of chronically withdrawn schizophrenic patients. C. Villeneuve et al. Curr The, Res 12 (4), 223-229 (1970).

CI 679

2,4-Diamino-6-[(3,4-dichlorobenzyl)-nitrosamino]quinazoline

Action

Antimalarial agent.

Manufacturer

Parke Davis (USA)

References

Antimalalial activity of 2, 4-diamino-6-[(3, 4-dichlorobenzyl) nitrosamino] quinazoline (CI-679 base) and CI-679 acetate. Laboratory studies in mice and rhesus monkeys. P. E. Thompson et al. Amer J Trop Med Hyg 19,12 (1970).

Cintazone (USAN) AHR-3015

Scha-306

Cinnopentazone (Rec INN)

Clintazone (FDAN)

2-Pentyl-6-phenyl-1 H-pyrazolo [1, 2-a] cinnoline-1,3(2H)-dione 1,2-(Pentylmalonyl)-4-phenyl-1,2-dihydrocinnoline

41

Synthesis

By the reaction of 4-phenyl-1, 2-dihydrocinnoline with triethylamine and n-pentylmalonyldichloride.

Description

Crystals, mp 122-123°.

Action

Cintazone is a new anti-inflammatory agent.

Manufacturer

A H Robins Co, Inc (USA)

References

1. Fed Reg 35 (179), 14450-14451 (1970). 2. Siegfried Aktiengesellschait. Brit pat 1,054,291. 3. H. Jahn et al. Arzneim-Folsch 18 (1), 121-124 (1968).

Citiolone (Prop INN)

BO 714

N-(Tetrahydro-2-oxo-3-thienyl) acetamide 2-Acetamido-4-mercaptobutyric acid, thio lactone N-Acetylhomocysteinethiolactone

Synthesis

From homocysteine thiolactone hydrochloride and acetic anhydride2. Other methods have been described3,5.

Description

Needles, mp 111.5-112.5°.

Action and Uses

Citiolone is an hepatic anticytolytic agent, recently marketed in France. Indications: Hepatitis, cholecystitis, biliary dyskinesia, cirrhosis, chronic alcoholism.

Dosage

Orally 200 mg 2 to 3 times daily before meals.

Supplied as

Granules, 4%. Vials, 500 mg.

Manufacturer

Laboratories Bottu (France)

Proprietary Name

Thioxidrene

References

1. WHO Chron 24 (3). 123 (1970). 2. R. Laliberte et al. J Chem Soc 2756 (1963). 3. R. Benesch et al. J Am Chem Soc 78. 1597 (1956). 4. Yoshimoto Pharm Ind Ltd, Jap pat 16,712 (62). 5. Sumitomo Chemical Co Ltd, Jap pat 3420 (64) and 1376 (65). 6. Med Act (Drugs of Today), 7 (1). 14-15 (1971). (Review)

Clindamycin (USAN)

U 21251

Methyl 7-chloro-6,7,8-trideoxy-6-trans-(1-methyl-4-propyl-L-2-pyrrolidine-carboxamido)-1-thio-D-erythro-α,D-galacto-octopyranoside hydrochloride monohydrate 7-Chloro-7-deoxylincomycin hydrochloride hydrate

42

Synthesis

It is prepared from lincomycin and thionylchloride.

Action and Uses

Clindamycin is a semi-synthetic derivative of lincomycin. The antibacterial spectrum of clindamycin is identical with that of parent antibiotic, but is more rapidly and completely absorbed from the gastrointestinal tract.

Dosage

Adults, 150 to 300 mg 6-hourly, or more forsevere infections.

Supplied as

Capsules 75 and 150 mg.

Proprietary Names and Manufacturer

Dalcin C (Upjohn, England); Sobelin (Upjohn, Germany); Cleocin (Upjohn, USA)

References

Med Act (Drugs of Today) 6 (5). 171-174 (1970). (Review with 10 references)

Clindamycin-2-palmitate

Hydrochloride

Action

Clindamycin-2-palmitate hydrochloride is a water soluble ester of ciindamycin and palmitic acid. It has been found to be safe and well tolerated with good absorption and effective blood levels when administered to children and infants. It is particularly effective in the treatment of infections due to gram-positive organisms. It has been found virtually devoid of the characteristic bitter taste of clindamycin.

Manufacturer

The Upjohn Co (USA)

References

1. Absorption and tolerance of clindamycin-2-palmitate in infants below 6 months of age. N. Lwin et al. Curr Ther Res 12 (10), 648-657 (1970). 2. Am Pharm Ass 117th Annual Meeting, April 12-17, 1970, Washington, abstr. 74.

Clindamycin-2-phosphate

43

Action

Clindamycin hydrochloride is poorly soluble at pH values above 6 and its intramuscular administration is painful. The phosphate ester exhibits a higher water solubility near neutral pH and improves muscle tolerance. The phosphate ester is rapidly hydrolyzed in vivo and gives acceptable blood levels of free clindamycin.

Manufacturer

The Upjohn Co (USA)

References

1. Hydrolysis of Iincomycin-2-phosphate and clindamycin-2-phosphate. T. O. Oesterling and E. I. Rowe. J Pharm Sci 59 (2), 175-179 (1970). 2. Am Pharm Ass 117th Annual Meeting, April 12-17, 1970, Washington abstr 73.

Clioxanide (Rec INN)

SYD 230

Clioxanidum (Lat). Clioxanida (Sp) 4-Chloro-3,5-diiodo-salicylanilide, acetate (ester) 2-Acetoxy-4'-chloro-3,5-diiodobenzanilide

Synthesis

By condensing 3,5-diiodosalicylic acid with p-chloroaniline, and subsequent acetylation with acetic anhydride.

Description

Crystals, mp 215-216°.

Action

Clioxanide has proved to be highly active against mature and immature fluke. Recently a series of studies designed to determine the tolerance of sheep in the field to clioxanide, has been reported.

Manufacturer

Parke Davis (USA)

Proprietary Name

Tremerad

References

1. Parke Davis Co. Neth Appl 6,604,303. 2. A. Campbell et al. Experientia 23 (12), 992-993 (1967). 3. H. C. Tewari. Aust Vet J 44 (9), 401-402 (1968). 4. Clioxanide, a new anthelmintic active against Fasciola hepatica and Haemonchus contortus in sheep. I. G. Pearson et al. Aust Vet J 46 (10), 480-484 (1970). 5. The anthelmintic efficiency of clioxanide and rafoxanide against fasciola hepatica and haemonchus contortus in sheep. N. J. Campbell and I. K. Hotson. Aust Vet J 47 (1), 5 (1971).

Clofazimine (USAN; Rec INN)

G-30320 B 663

Clofaziminum (Lat). Clofacimina (Sp)Rimonophenazine 3-(p-Chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropyliminophenazine

44

Synthesis

Prepared by heating in the autoclave at 80º a solution of 3-p-chloroanilino-10-p-chlorophenyl-2,10-dihydro-2-iminophenazine hydrochloride and isopropylamine in ethanol1.

Description

Orange dye. Insoluble in water; fat soluble. UV max 284 µm [E(1%, 1 cm) about 1000], and a visible max between 486 and 492 µm in ethanolic solution (1 to 10 µg/ml)2.

Action and Uses

Clofazimine is a substituted iminophenazine dye with anti-micobacterial and anti-inflammatory properties. For use in the treatment of all forms of leprosy and inflammatory episods that frequently complicate lepromatous leprosy.

Dosage

For previously untreated adults, 100 mg three times weekly. For patients with sul phoneresistant bacilli, 600 mg weekly. To suppress lepra reactions up to 400 mg daily may be needed.

Supplied as

Brown, hard gelatin capsules, which contain a suspension of 100 mg of very fine particles of clofazimine in an oil/wax base.

Proprietary Name

Lamprene

Manufacturer

Geigy

References

1. V. C. Barry et al. J Chem Soc 896 (1956); 3347 (1956); 859 (1958). 2. E. Regazzi. Boll Chim Farm 100, 402-410 (1961). 3. Med Act (Drugs of Today) 6 (2), 47-51 (1970). (Review with 16 references)

Clomacran (USAN; Rec INN)

SKF14336

(for the phosphate) Clomacranum (Lat). Clomacrano (Sp) 2-Chloro-9-[3-(dimethylamino) propyl] acridane

Synthesis

Prepared by the reaction of 2-chloroacridine with 3-dimethylaminopropyl-magnesium chloride in refluxing tetrahydrofurane.

Action

Clomacran, a new neuroleptic structurally related to phenothiazines, has been found to have significant antidepressant and antipsychotic effects in clinical studies. The toxic side effects of the drug have been recently reviewed5.

Manufacturer

Smith Kline and French Laboratories (USA)

References

1. Smith Kline and French Lab. US pat 3,131,190. 2. J. L. Claghorn et al. Psychosomatics 8 (4), 212-215 (1968). 3. Double-blind study comparing the intramuscular usage of an acridan derivative, SKF 14336, to chlorpromazine. Ching-Piao Chien et al. Cun Ther Res 12 (1), 52-56 (1970). 4. Clinical trial of clomacran phosphate (SKF-14336) in chronic psychotic male patients. K. C. Radhakrishnan Nair et al. Cun Ther Res 12 (6), 394-401 (1970). 5. Adverse effects with clomacran. W. T. Lampe. J Clin Pharmacol 10 (3), 171-174 (1970).

Clonazepam (USAN; Rec INN)

Ro 5-4023

5-(o-Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzo-diazepin-2-one

45

Description

Almost white crystals, mp 236.5-238.5° (ethanol-methylene chloride).

Action

Clonazepam is a new, very active, anticonvulsive benzodiazepine.

Manufacturer

Hoffman-La Roche

References

1. JAMA 209, 926 (1969). 2. WHO Chron 24 (11), 528 (1970). 3. Drug Trade News, p 43 (October 20, 1969). 4. Experimental properties of a new anticonvulsive benzodiazepine:Ro 5-4023. M. Boucard et al. Therapie 25 (5), 893 (1970). 5. Risposte cerebrali evocate da stimoli visivi e somatici in soggetti affetti da mioclano-epilessia familiare. Effetti di una nuova benzodiazepina. F. Giunta et al. Boll Soc It Bioi Sper 45 (22), 1471-1473 (1969). 6. Evaluation of anticonvulsant drugs: Methodological considerations. R. A. Hanson at al. Pharmacologist 12 (2), 219 (1970).

Clonixeril (USAN; Ree INN)

Sch 12707

Clonixerilum (Lat) 2,3-Dihydroxypropyl 2-(3-chloro-o-toluidino) nicotinate Glyceryl 2-(2-methyl-3-chloroanilino) nicotinate

Synthesis

Prepared in several steps from 2-chloronicotinic acid and 2-methyl-3-chloroaniline.

Description

Crystals, mp 113-114° (benzene).

Action

Clonixeril is a new anti-inflammatory-analgesic agent.

Manufacturer

Schering Corp (USA)

References

1. JAMA 209, 2044 (1969). 2. WHO Chron 24 (11), 528 (1970). 3. Scherico Ltd. S African pat 6.802,185.

Clonixin (USAN; Rec INN)

Sch 10304

2-(3-Chloro-o-toluidino) nicotinic acid 2-(2-Methyl-3-chloroanilino) nicotinic acid

Synthesis

Prepared by heating 2-methyl-3-chloroaniline with 2-chloronicotinic acid or 2-chloronicotinic acid ethyl ester, followed by hydrolysis.

Description

Crystals, mp 233-235° (isopropylacetate). The diethanolamine salt, mp 129-131°.

46

Action

Clonixin exhibits analgesic, anti-inflammatory and antipyretic properties.

Manufacturer

Schering Corp (USA)

References

1. WHO Chron 24 (11), 528 (1970). 2. Scherico Ltd. Neth Appl 6.603.357. 3. Fed Proc 27 (3), 533, abstr 1780, 1781 (1968).

Clorgiline Hydrochloride (Rec

INN) M&B 9302

Clorgilinum (Lat). Clorgilina (Sp) N-[3-(2,4-Dichlorophenoxy)propyl]-N-methyl-2-propynylamine hydrochloride N-Methyl-N-propargyl-3-(2,4-dichlorophenoxy) propylamine hydrochloride

Synthesis

Prepared by condensing 3-(2,4-dichlorophenoxy) propyl bromide with methylamine and subsequent treatment with propargyl bromide. Also prepared from 2, 4-dichlorophenoxypropyl bromide and N-methyl propargylamine.

Description

Crystals, mp 102-103° (ethyl acetate).

Action

Clorgiline hydrochloride is a new mono-amine oxidase inhibitor, reported to be a highly potent antidepressant. The results of a recent comparative trial indicate that both therapeutic effects and side-effects were similar with clorgiline and the control drug, imipramine.

Manufacturer

May and Baker Ltd (England)

References

1. WHO Chron 24 (11). 528 (1970).

2. May and Baker Ltd. Brit pat 1,027,611. 3. J. P. Johnston. Biochem Pharmacol 17, 1285 (1968). 4. J. A. Herd. Clin Trials J 6, 219-227 (1969). 5. Comparative trial of a new mono-amine oxidase inhibitor in depression. D. Wheatley Brit J Psychiat 117, 573-574 (1970).

Clortermine Hydrochloride

(USAN; Rec INN) Su10568

o-Chloro-α,α-dimethylphenethylamine hydrochloride 1-(o-Chlorophenyl)-2-methyl-2-propylamine hydrochloride

Synthesis

Prepared from 1-(o-chlorophenyl)-2-methyl-2-propanol.

Description

Crystals from ethanol, which melt at 245-246°. The free base boils at 116-118° (16 mm).

Action

Anorexiant. It is the o-chloro derivative of phentermine while chlorphentermine is the p-chloro derivative.

Manufacturer

Ciba Pharmaceutical Co. (USA)

Proprietary Name

Voranil

References

1. JAMA 208, 1399 (1969). 2. WHO Chronicle 24 (11), 528 (1970). 3. Ciba S. A. Belg pat 665,244 (1965). 4. J Amer Osteop Ass 89,161-164 (1969).

47

Closiramine Aceturate (USAN;

Rec INN) Sch 12169

8-Chloro-11-[2-(dimethylamino)ethyl]-6,11-dihydro-5H-benzo [5,6]-cyclohepta [1,2-b] pyridine compound with N-acetyl-glycine (1:1)

Action

Closiramine aceturate is a new anti histaminic agent.

Manufacturer

Schering Corp (USA)

References

1. WHO Chron 24 (11), 528 (1970). 2. JAMA 209, 2044 (1969).

Clotrimazole

(USAN.BAN.PropINN)

Bay b 5097 FB 5097

1-(o-Chloro-α,α-diphenylbenzyl) imidazole 1-(o-Chlorotrityl)imidazole

Synthesis

By the reaction of o-chlorophenyl-bisphenylchloromethane with imidazole.

Description

White crystalline powder.

Action

Clotrimazole is a new broad spectrum orally effective antifungal.

Manufacturer

Bayer (Germany). Delbay Pharmaceuticals (USA)

References

1. Farbenfabriken Bayer AG. S African Appl 68 05.590. 2. Erste Erfahrungen mit dem Breitbandantimykotikum Bay b 5097. W. Marget and D. Adam. Med Klin 64. 1235 (1969). 3. Erste klinische Erfahrungen bei System-Mykosen mit einem neuen oralen Antimykotikum. H. Oberste-Lehn et al. Dtsch med Wschr 94. 1365 (1969). 4. Experimentelle Befunde libar ein neues. oral wirksames Antimykotikum mit breitem Wirkungsspektrum. M. Plempel at al. Dtsch med Wschr 94. 1356 (1969). 5. Keine Liquorwirksamkeit des Antimykoticums Bay b 5097 einem Fall von Candida-Meningitis. U. Keuth and J. Wilhelmi. Monatsschr Kinderheilk 118.654-655 (1970). 6. A new broad spectrum antifungal agent. W. E. Herrell. Clin Med 77 (2), 13-16 (1970).

Clozapine (USAN; Ree INN)

HF1854

Clozapinum (Lat). Clozapina (Sp) 8-Chloro-11-(4-methyl-1-piperazinyI)-5H-dibenzo [b,e]-1,4-diazepine

Synthesis

Prepared in several steps from 8-chloro-10,11-dihydro (5H)-dibenzo [b,e]-1 ,4-diazepin-11-one.

48

Description

Yellow crystals, mp 183-184º (acetone/petroleumether); ultraviolet absorption max. at 215 µm [ε=27,400], 230 µm [ε=25,800], 261 µm [ε=16,800] and 297 µm [ε=10,500].

Action

Sedative.

Manufacturer

Dorsey Laboratories (USA); Wander AG (Switzerland)

References

1. WHO Chron 24 (11). 528 (1970). 2. JAMA 209, 407 (1969). 3. F. Hunziker et al. Helv Chim Acta 50, 1588-1599 (1967). 4. Dr. Wander AG. Brit. pat. 1,042,634. 5. Wien Med Wschr 116, 814 (1966).

Colestipol (USAN; Ree INN)

U 26,597A

Colestipolum (Lat) Tetraethylenepentamine polymer with 1-ehloro-2,3-epoxypropane Tetraethylenepentamine polymer with epichlorhydrin

Description

Colestipol is an insoluble high molecular weight copolymer of tetraethylenepentamine and epichlorhydrin with approximately one out of five amine nitrogens protonated (chloride salt). The native material is essentially odorless and tasteless.

Action

Colestipol is a new hypocholesteremic agent. The drug is not absorbed into the blood stream but binds with bile acids in the gastrointestinal tract and enhances their fecal excretion, thus stimulating hepatic conversion of cholesterol to bile acids.

Manufacturer

The Upjohn Co (USA)

References

1. JAMA 209, 926 (1969). 2. WHO Chron 24 (11), 528 (1970) . 3. Chem and Engineer News 47 (48), 39 (1969). 4. Arner Drug 161 (9), 63 (1970) . 5. Effects of colestipol (U-26. 597 A), a new bile acid sequestrant, on serum lipids in experimental animals and man. T. M. Parkinson et a!. Atherosclerosis 11, 531-537 (1970).

Compound VI

6·α-Bromo-17β-hydroxy-17-methyl-4-oxa-5α-androstan-3-one

Synthesis

By bromination of 17β-hydroxy-17α-methyl-5-oxo-3,5-seco-A-norandrostane-3-carboxylic acid, followed by cyclization.

Description

Crystals, mp 163-174° dec (ethanol); [ α]D = -9.6° (c 0.39; methanol).

Action

Experimental studies have shown compound VI to be an antiandrogen agent.

Manufacturer

Hoffmann-La Roche Inc (USA)

References

1. F. Hoffmann-La Roche Co, AG. Ger Offen 1,805,857. 2. A new antiandrogen, 6α-bromo-17β-hydroxy-17α-methyl-4-oxa-5α-androstan-3-one. A. Boris and M. Uskokovic. Experientia 26, 9 (1970).

49

Cortivazol (USAN; Rec INN)

11-β,17,21-Trihydroxy-6,16-α-dimethyl-2'-phenyl-pregna-4,6-dieno [3,2-c]pyrazol-20-one 21-acetate 6,16-α-Dimethyl-4,6-pregnadiene-11-β,17,21-triol-20-one [3,2-c]-2'-phenylpyrazole 21-acetate

Synthesis

From 17-α,20,20,21-bis (methylendioxy)-11-β-hydroxy-6,16,-dimethyl-4,6-pregnadiene-3-one1,2. Also from 6-α,16-α-dimethyl-3,11-dioxo-2-hydroxymethylene-4,6,17(20) pregnatriene-21-oic acid methyl ester3.

Description

Crystals, double mp: 160-165º and 229-230º (ethyl acetate-benzene). [α]D = +14° (chloroform). UV max 283 µm [ε=15.700] and 315 µm [ε=19,000] in methanol.

Action

Cortivazol is a new anti-inflammatory agent.

Manufacturer

Merck Sharp and Dohme (USA)

References

1. J. H. Fried et al. J Am Chem Soc 85, 236 (1963). 2. M. Tishler et al. (to Merck Co Inc). US pat 3,067,194, 3. R. Hirschmann et al. (to Merck Co Inc) US pat 3,233.70. 4. JAMA 211, 1363 (1970). 5. WHO Chron 24 (3). 124 (1970).

CP 264

2-Allyloxy-4-chloro-N-(2-piperidinoethyl)-benzamide

Action

264 CP has proved to show much more potent antitussive action, weaker toxicity and milder adverse effects than 264 CE (Hexacol). 264 CP differs from the latter only in having a piperidinoethyl group instead of a diethylaminoethyl group. This has supported the hypotesis of Kase et al that a piperidino group strengthens antitussive activity.

Toxicity

LD50 sc in mice: 204 mg/kg.

Manufacturer

Fujisawa Pharmaceutical Co, Ltd (Japan)

References

Antitussive activity and other related pharmacological properties of 2-allyloxy-4-chloro-n-(2-piperidinoethyl) benzamide and its congeners. Y. Kase et al. Jap J Pharmacol 20, 1-9 (1970).

Cryptosporiopsin

(1S,5S)-(E)-3,5-Dichloro-1-hydroxy-4-oxo-2-propenyl-2-cyclopentene-1-carboxylic acid, methyl ester

50

Production

By a species of Cryptosporiopsis1. The total synthesis of the racemic compound has been reported2.

Description

Colorless crystals, mp 133-137°; [α]D = +129° (c=1.35, chloroform); UV max 292 µm [ε= 22,800 in alcohol).

Action

Cryptosporiopsin is a fungitoxic antibiotic; it inhibits sporangial germination (Phytospora infestans).

References

1. G. M. Strunz et al. Can J Chem 47, 2087 and 3700 (1969). 2. The total synthesis of racemic cryptosporiopsin, a fungitoxic antibiotic. G. M. Slrunz and A. S. Court. Experientia 26 (10), 1054 (1970).

Cyanothepin

8-Cyano-10-(4-methylpiperazino)-10,11-dihydrodibenzo [b.f] thiepine

Synthesis

Prepared in several steps from 8-bromo-10,11-dihydroxydibenzo [b,f] thiepin-10-one.

Description

Cyanothepin melts at 171-173° (ethanol). Ultraviole t absorption max at 231 µm [log ε = 4.22] and 294 µm [log ε = 4.05]. The maleate melts at 187-189° (ethanol).

Action

Cyanothepin is a new member of the parathiepin group of neuroleptics. The drug has proved to be less efficient in the cataleptic test than trifluthepin,

and more active as a central sedative than octoclothepin.

Manufacturer

Res Inst Pharm Biochem Prague (Czechoslovakia)

References

J. O. Jilek et al. Coll Czech Chem Commun 35 (1), 276 (1970).

Cyasterone

Description

Screening of Israeli plants for insect moulting hormones (ecdysones) has led to the isolation and identification of cyasterone from Ajuga and Achyrantes species.

References

Insect hormones (phytoecdysones) from Israeli plants. R. Ikan at a!. Israel J Chem 8 Suppl Proc Israel Chem Soc (1970).

Cyclacillin (USAN; Prop INN)

WY 4508

Ciclacillinum (Lat). Ciclacilina (Sp) 6-(1-Aminocyclohexanecarboxamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 6-(1-Aminocyclohexanecarboxamido) penicillanic acid

51

Synthesis

Prepared by condensation of 6-aminopecillanic acid with the N-carboxyanhydride of 1-aminocyclohexanecarboxylic acid.

Action

Cyclacillin is a new semisynthetic penicillin, which was found to resemble ampicillin in its antibacterial spectrum. In a recent study cyclacillin was compared with ampicillin and cephalexin. Cyclacillin was superior to cephalexin in vitro and in vivo against penicillin-sensitive S. aureus and Strep. pyogenes. Against penicillinase-producing staphylococci, cyclacillin was clearly superior to cephalexin in vivo, while in vitro cephalexin was the more active of the two. Cyclacillin and ampicillin were about equally active in vivo against Strep. pyogenes, D. pneumoniae and penicillin-sensitive staphylococci, while in vitro cyclacillin was somewhat less active than ampicillin. Against penicillin-resistant staphylococci, cyclacillin was active while ampicillin was not. Against gram-negative organisms cyclacillin was less active both in vitro and in vivo than ampicillin.

Manufacturer

Wyeth Lab Inc (USA)

References

1. H. E. Album et al. (American Home Prod Corp). US pat 3,194,802. 2. M. W. Hopper et al. Antimicrobial Agents and Chemotherapy-1967, 597 (1968). 3. S. B. Rosenman et al. ibid-1967. 590 (1968). 4. J. A. Yurchenco et al. ibid-1967. 602 (1968). 5. Cyclacillin a semisynthetic aminoalicyclic penicillin. J. A. Yurchenco et al. Chemotherapy 15, 209-221 (1970).

Cyclofenil F 6066 H

3452 ICI 48,213

α-Cyclohexylidene-α-(p-hydroxyphenyl)-p-cresol diacetate bis-(p-Acetoxyphenyl) cyclohexylidene methane p, p'-Diacetoxybenzhydrylidene cyclohexane

Synthesis

By acetylation of p,p'-dihydroxybenzhydrylidene-cyclohexane with acetic anhydride. p,p'-Dihydroxybenzhydrylidene cyclohexane can be obtained either from p-hydroxy-p'-methoxybenzhydrylidene-cyclohexane or from p,p'-dibenzylbenzhydrylidene cyclohexane or from p,p'dimethoxybenzhydrylidene cyclohexane.

Description

Crystals, mp 135-136°.

Action and Uses

Cyclofenil is an ovulation stimulant. For use in the treatment of menopause, amenorrhea, hypomenorrhea, irregular cycles, premenstrual syndrome, menometrorrhagia and sterility.

Dosage

Menopause, 400 mg daily during 20 days each month. In other indications: 400 mg daily from the first day of the cycle for 10 days; or 800 mg daily from sixth day of the cycle for 5 days.

Supplied as

Tablets, 400 mg.

Manufacturer

Ferrosan (Sweden), Roussel (France)

Proprietary Name

Sexovid; Ondogyne.

References

1, J.F. Miquel et al. J Med Chem 6, 774 (1963). 2. US pat. 3,287,397. 3. Med Act (Drugs of Today) 7 (1), 10-12 (1971). (Review with 7 references)

52

Cylindrochlorin

The partial structure is:

Production

Isolated from the mycelium of a fungus, Cylindroc!adium Sp.

Description

Pale yellow crystals, mp 150-150.5°

Action

Cylindrochlorin is a new antiviral antibiotic.

Manufacturer

The University of Tokyo (Japan)

References

1. Jap Med Gazz 7(4), 9 (1970). 2. Cylindrochlorin. a new antibiotic produced by Cylindrocladium. A. Kato et al. J Antibiot 23 (3). 168 (1970).

Cyproterone (Rec INN)

SH 80881

6-Chloro-17-hydroxy-1α,2α-methylenepregna-4,6-diene-3,20-dione

Description

Crystals, mp 237.5-240° (ethyl acetate).

Action

Cyproterone has been reported to be a potent anti-androgen in animal experiments2. The antiandrogenic effect of the drug is based on the competitive inhibition of the action of testosterone. The use of cyproterone has been reported in the treatment of precocious sexual development, congenital adrenal virilism and hirsutism3.

Manufacturer

Schering AG (Germany)

References

1. R. Wiechert (Schering AG). Ger pat 1.158,966 and 1,189,991. 2. F. Neuman et al. In: Wirkungsmechanismen der Hormone. 18th Symp of Gesellschaft für Physiologische Chemie, Karlson P., Ed., Mosbach (1967), p 218. 3. Acta Pediat Scand 58. 203 (1969). 4. Biodinamics of cyproterone in man following oral and intravenous administration. E. Gerhards et al. Acta Endocrin 64, 228-252 (1970). 5. Investigations on the cyproterone-induced effect on the testosterone metabolism in normally developing children and adult males. D. Gupta and J. R. Bierich. Third International Congress on Hormonal Steroids, Hamburg, 7-12 Sept 1970. Excerpta Medica, International Congress Series No 210, abs 414.

Cyproterone Acetate

SH 714

Cyproterone 1-α-acetate

Description

Crystals, mp 200-201º (diisopropyl ether). UV max 281 µm [ε=17,280] in methanol.

Action

In contrast to cyproterone, cyproterone acetate possesses marked progestational properties in addition to antiandrogenic activity.

Manufacturer

Schering AG (Germany)

53

References

1. F. Neuman et al. In: Wirkungsmechanismen der Hormone, 18th Symp of Gesellschaft fur Physiologische Chemie, Karlson P., Ed., Mosbach (1967) p 218. 2. K. H. Kolb and H. Roepke.lntJ Clin Pharmacol 1(3),184-190 (1968). 3. H. Hoffet. Praxis 57 (7), 221-230 (1968). 4. Antagonism between masculinizing steroids and cyproterone acetate in the rat fetus. T. Mischler and D. Gawlak. Eur J Pharmacol 9 (3),391 (1970). 5. Effect of the antiandrogen cyproterone acetate on estradiol production and metabolism in man. J. Fishman and J. Geller. Steroids 16 (4), 351 (1970). 6. Adrenocortical function. corticotrophic responsiveness and fertility of men during long-term treatment with cyproterone acetate. U. Lashet and U. Laschet. Third International Congress on Hormonal Steroids, Hamburg, 7-12 Sept 1970. Excerpta Medica, International Congress Series No 210, abs 415.

L-Cystathionine

L-2-Amino-4-[(2-amino-2-carboxyethyl)-thio]-butyric acid

Synthesis

Prepared by condensation of L-cystine with L-3,6-bis-(β-chloroethyl)-2,5-diketopiperazine followed by hydrolysis1.

Description

Crystals, mp 312º dec (darkening at 270°); [α]D = 23.7° (c=1 in N HCI).

Action

Many biochemical and clinical studies have suggested that cystathionine may have a function in the brain other than its being an intermediary in the formation of cysteine from methionine. From the results of a recent experimental study in cats, it has been concluded that in the free form cystathionine, or its cleavage product cysteine, may be important in the normal functioning of the brain and play a role in the pathogenesis of certain in born errors of metabolism independent of their importance as metabolic intermediaries.

References

1. V. du Vigneaud et al. J Biol Chem 143, 59 (1942). 2. S. Weiss et al. J Am Chem Soc 73. 2497 (1951). 3. A. Schoberl and G. Tauber, Ann 599, 23 (1956). 4. Neuropharmacological comparison of cystathionine. cysteine, homoserine and alpha-ketobutyric acid in cats. B. J. Key and R. P. White. Neuropharmacol 9, 349-357 (1970).

D 58 SI

2,3-Dihydro-N-methyl-7-nitro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-carboxamide

Synthesis

Prepared by the reaction of 7-nitro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one with methyl isocyanate.

Description

Crystals, mp 160-161°.

Action

New benzodiazepine compound which exhibits hypnotic and sedative properties.

Manufacturer

Takeda Yakuhin Kogyo KK (Japan)

54

References

1. Takeda Chemical Industries ltd. Jap pat 70 06.544. 2. J Takeda Res Lab 29 (1). 153-169 (1970). 3. Shinryo to Sinyaku 7 (8), 1553 (1970).

DA 2047

6-(α-Cyclogeranoyl)penicillanic acid sodium salt

Synthesis

Prepared from a-cyclogeranoyl chloride and 6-aminopenicillanic acid.

Description

Colourless solid. mp 192-193° (dec).

Action

Semisynthetic penicillin with an activity in all alike to methicillin.

Manufacturer

Instituto De Angeli (Italy)

References

1. Terpene compounds as drugs. VIII. Bacteriological and pharmacological properties of terpenyl penicillins. G. Pala et al. Arzneim-Forsch 20 (1). 62-68 (1970) .

Dacuronium Bromide (Rec INN;

BAN) Org NB 68

Dacuronii bromidum (Lat). Dacuronio bromuro (Sp) 2β,16β-Dipiperidino-5α-androstane-3α,17β-diol 3-acetate dimethobromide

Synthesis

Prepared in several steps from 3,17-diacetoxyandrosta-2,16-diene.

Action

Dacuronium bromide is a non-depolarising muscle relaxant based on a steroid nucleus. It is similar to pancuronium bromide but has the acetoxy group at position 17 replaced by a hydroxyl group. Its clinical effects are very similar to those of gallamine.

Manufacturer

Organon Laboratories Ltd.

References

1. Organon Laboratories Ltd. Neth. Appl. 6,602,098. 2. A new steroid muscle relaxant. S. A. Feldman and M. F. Tyrrell. Anesthesia 25 (3), 349-355 (1970).

Daledalin Tosylate UK-3557-15

(USAN; Prop INN)

3-Methyl-3-(3-methylaminopropyl)-1-phenylindoline mono-p-toluenesulfonate

Synthesis

Prepared by the reduction of 3-methyl-3-(3-methylaminopropyl)-1-phenyl-2-indolinone hydrochloride (amedalin HCI) with diborane, followed by neutralization with p-toluensulfonic acid.

55

Description

Crystals, mp 122-122.5º (acetone). Maleate: crystals, mp 130-131º (ethyl acetate).

Action

Daledalin tosylate is an antidepressant agent.

Manufacturer

Pfizer Inc (USA)

References

1. JAMA 213 (13), 2248 (1970). 2. WHO Chron 25 (3), 130 (1971). 3. Pfizer Corp. S African Appl 68 01.099.

Dantrolene (USAN; Rec INN)

F 368 F 440 (sodium)

Dantrolenum (Lat) 1-[[5-(p-Nitrophenyl) furfurylidene] amino] hydantoin

Synthesis

By condensing 5-(p-nitrophenyl)-2-furaldehyde with 1-aminohydantoin hydrochloride.

Description

Crystals, mp 279-80° (aq. dimethylformamide).

Action

Dantrolene sodium is a muscle relaxant that seems to act directly upon muscles rather than through the central nervous system. The drug is under clinical studies.

Manufacturer

Eaton Laboratories (USA)

References

1. Norwich Pharmacal Co. Neth Appl 6,612,588.

2. Harry R. Snyder et al. J Med Chem 10 (5),807-10 (1967). 3. The Pharmacologist 12 (2), 301, abs 553 (Fall, 1970). 4. Studies relaxant in hemiplegies. Drug Trade News 39, March 23, 1970.

Decadonium

N, N'-Bis-(adamantanyl)-bis-(dimethyl)-decamethylenediammonium diiodide

Action

Decadonium is a curariform muscle relaxant.

References

1. Comparative sensitivity of neuromuscular synapses at different muscles to diadonium and decadonium. V. K. Lepakhin at al. Farmakol Toksik 33 (3), 288 (1970). 2. On the curariform activitv of decadonium diiodidum. D. A. Kharkevich. Farmakol Toksik 33 (4), 395 (1970).

Decloxizine (Rec INN)

UCB1402

Decloxizinum (Lat). Decloxizina (Sp) 2-[2-[4-(Diphenylmethyl)-1-piperazinyl] ethoxy] ethanol 1-Benzhydryl-4-[2-(2-hydroxyethoxy) ethyl] piperazine

56

Synthesis

Prepared by the reaction of 2-[(4-diphenylmethyl)-1-piperazinyl] ethanol with thionyl chloride, and subsequent reaction with monosodium ethylene glycolate1. Also by reaction of diphenylmethylpiperazine with 2-(2-chloroethoxy) ethanol2.

Action

The free base boils a 185º (0.005 mm). Decloxizine is a new bronchodilator and antihistaminic agent.

Manufacturer

UCB (Belgium)

References

1. H. G. Morren. Belg pat 523,899. 2. H. G. Morren et al. Ind Chim Belg 19, 1176-1185 (1954). 3. J. Lulling et al. Arzneim-Forsch. 18 (8), 995 (1968). 4. Clinical investigation of a new broncholyticum-decloxizine-as compared with franol and placebo treatment. J. Keihla et al. Respiration 27 (6), 582 (1970).

DEHT

5-(3,4-Dichlorophenyl)-5-ethyl-barbituric acid 5-(3,4-Dichlorophenyl)-5-ethylhexahydropyrimidine-2,4,6-trione

Action

DEHT, a dichlorinated analogue of phenobarbital, is a potent inhibitor of Coxsakie A21 virus multiplication in mice.

Toxicity

LD50 po in mice: 190 mg/kg (24 hour observation period)1.

Manufacturer

Eli Lilly and Co (USA)

References

1. E. A. Swinyard et al. J Pharm Sci 52, 463-465 (1963). 2. Preclinical studies with DEHT. D. C. DeLong et al. Ann NY Acad Sci 173, 516-526 (1970).

Delmadinone Acetate (USAN;

RecINN; BAN) RS 1301

Delmadinonum (Lat). Delmadinona (Sp) 6-Chloro-17-hydroxypregna-1,4,6-triene-3,20-dione acetate ∆

1-Dehydroxychlormadinone acetate

Synthesis

Prepared by oxidation of 6α-chloro-17α-acetoxyprogesterone with chloranil, followed by oxidation with SeO2

1.2.

Description

Crystals, mp 168-170° (acetone-hexane); [ α]D = -83° (chloroform). UV max 229 µm [lgε=4.00], 258 µm [lgε=4.00] and 297 µm [lgε=4.03].

Action

Delmadinone acetate exhibits progestational, anti-androgenic and anti-estrogenic activity.

57

Manufacturer

Syntex Laboratories (USA)

References

1. WHO Chron 24 (11). 528 (1970). 2. Upjohn Co. Brit pat 890,315; Ger pat 1,243,682. 3. H. J. Ringold et al. J Am Chem Soc 81, 3485 (1959). 4. F. A. Kincl. Endokrinol 40, 257-266 (1961). 5. R. I. Dorfman et a!. Steroids 1, 185-209 (1963). 6. R. Wiechert et al. Arzneim-Forsch 17 (9), 1103-1107 (1967).

Demethylcoclaurine

Hydrochloride

dl-Demethylcoclaurine hydrochloride 1-(p-Hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

Isolation and Synthesis Isolated from the embryo of the seeds of Nelumbo nucifera collected in Taiwan. Synthesized from dl-coclaurine.

Description

Colorless prims, mp 242-244° (dec); mp of the synthesized product: 256-263°; UV max 228.5 µm [ε=14,400] and 288 µm [ε=5,100].

Action

Demethylcoclaurine is an active alkaloid from Nelumbo nucifera, which possesses a significant activity to relax the smooth muscle and uterine strips.

Manufacturer

Bristol-Banyu (Japan)

References

Isolation of 1-(p-Hydroxybenzyl)-6. 7-dihydroxy-l, 2. 3, 4-tetrahydroisoquinoline (demethylcoclaurine), an active alkaloid from Nelumbo nucifera H. Koshiyama et al. Chem Pharm Bull 18 (12), 2564-2568 (1970).

Demoxepam (USAN; Rec INN)

Ro 5-2092

7-Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-4-oxide 7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one-4-oxide

Synthesis

Several methods have been described1-5.

Description

Plates, mp 245-246° dec (ethanol) 1; 238-239° also reported2.

Action

Demoxepam is a tranquilizer of the 1,4-benzodiazepine series.

Manufacturer

Hoffmann-La Roche

References

1. L. H. Sternbach et al. J Org Chem 26, 4936 (1961). 2. S. C. Bell et al. J Org Chem 27. 562 (1962). 3. A. Stempel et al. J Org Chem 30, 4267 (1965). 4. Hoffmann-La Roche. Ger pat 1,145,625; Neth Appl 6,412,484; Ger pat 1,190,946. 5. American Home Products Corp. US pat 3,313,805; Fr pat 1,378,343; Brit pat 1.067.745. 6. Fed Proc 26 (2), 505 (1967). 7. JAMA 211, 2149 (1970). 8. WHO Chron 24 (11). 528 (1970).

58

Denofungin (USAN) U 28009

Production

An unspecified substance from Streptomyces hygroscopicus.

Action

Denofungin is a new antifungal and antibacterial antibiotic.

Manufacturer

The Upjohn Co (USA)

References JAMA 212. 466 (1970).

Deoxynybomycin

Deoxynybomycin is an antibiotic which was derived chemically from nybomycin1. Recently it has been isolated from the culture broth of a Streptomyces, isolated from a soil sample collected in Okinawa.

Description

Colorless needles, which do not melt up to 300º

Action

Deoxynybomycin exhibits antibacterial activity.

Manufacturer

Institute of Microbial Chemistry, Tokyo (Japan)

References

1. K. L. Rinehart et al. J Am Chem Soc 83. 3729-3731 (1961). 2. Deoxynybomycin from a streptomyces. H. Naganawa et al. J Antibiotics 23 (7), 365-368 (1970).

Desonide (USAN; Prop INN)

D 2083

Desonidum (Lat). Desonida (Sp) 11β,16α,17,21-Tetrahydroxy-pregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone 16α-Hydroxy-prednisolone 16,17-acetonide 11β,21-Dihydroxy-16α,17α-isopropylidenedioxy-1,4-pregnadiene-3,20-dione

Synthesis

By the reaction of 16α-hydroxy-prednisolone with refluxing acetone and a catalityc amount of hydrochloric acid.

Description

Crystals, mp 263-266º (ethyl acetate/petroleum ether). [α]D = +122° (methanol). UV max 242 µm [ε=15,800].

Action

Anti-inflammatory agent.

Manufacturer

Miles (USA)

References

1. JAMA 213, 1325 (1970). 2. WHO Chron 24 (9), 419 (1970). 3. S. Bernstein et al. J Am Chem Soc 81. 4573-4574 (1959) . 4. I. Ringler et al. Proc Soc Exptl Biol Med 107, 451-455 (1961).

59

Deterenol Hydrochloride

(USAN; Prop INN) AL842

dl-p-Hydroxy-α-[(isopropylamino) methyl] benzyl alcohol hydrochloride dl-1-(p-Hydroxyphenyl)-2-isopropylaminoethanol hydrochloride dl-1-(p-Hydroxyphenyl)-1-hydroxy-2-isopropylaminoethane hydrochloride

Synthesis

Prepared by catalytic hydrogenation of 1-(phydroxyphenyl)-1-keto-2-isopropylaminoethane hydrochloride.

Description

White crystals, which melt at 155-157°. The free base melts at 138-140° and its d-tartrate at 183-184° (dec).

Action

Anti-glaucoma agent. It reduces experimental ocular hypertension in rabbits without causing mydriasis.

Manufacturer

Alcon Laboratories, Inc (USA)

References

1. JAMA 213 (13), 2247 (1970). 2. WHO Chron 25 (3), 130 (1971) . 3. M. L. Moore et al. (to Sterling Drug Inc) US pat 2,460,144. 4. Pharmacology of AL 842, an ocular hypotensive agent in rabbits. M. Van Hoose et al. Fed Proc 29 (2), 273 Abs (1970).

Dexetimide (Prop INN)

R 16470

Dexbenzetimide. Dextrobenzetimide (+)-2-(1-Benzyl-4-piperidyl)-2-phenylglutarimide (+)-1-Benzyl-4-[(2,6-dioxo-3-phenyl)-3-piperidyl] piperidine

Synthesis

Prepared from 1-benzyl-4-(1,3-dicyano-1-phenylpropyl)-piperidine hydrochloride.

Description

dl-Dexbenzetimide hydrochloride occurs as a white amorphous powder, mp 299-301.5°.

Action

dl-Benzetimide is a potent periferally and centrally long-acting anticholinergic agent. The pharmacological activities of the drug are exclusively due to the (+)-isomer.

Manufacturer

Janssen Pharmaceutica (Belgium)

References

1. WHO Chron 25 (3), 149 (1971). 2. B. Hermans et al. J Med Chem 11, 797-800 (1968). 3. N. V. Research Lab. Dr C Janssen. US pat 3,125,578, 4. Dexbenzetimide in neuroleptic-induced parkinsonism. A double-blind crossover study with a 16-week follow-up. R. De Smedt et al. J elin Pharmacal 10 (3), 207-211 (1970). 5. Prognosis of the absolute configuration of the anticholinergic drug dextrobenzetimide. I. van Wijngaarden et al. Life Sciences 9 (1). 1289-1302 (1970).

Dextranase

α-1,6-Glucan 6-glucanohydrolase

Production

Derived from Penicillium funiculosum.

60

International Unit One International Unit of enzyme is that amount producing one micromole of reducing sugar per minute at 35 to 40º and pH ranges from 6 to 8 using a Somogyi assay.

Action

Dextranase attacks dextrans to produce oligosacharides of various lengths and the end product of the reaction appears to be isomaltose with trace amounts of glucose. In both in vitro and animal studies it has been shown that certain dextranases lyse some of the dextrans formed by certain types of acidogenic streptococci found in the oral cavity inthe presence of sucrose. These dextrans appear to favor not only the colonization of bacteria on surfaces of teeth but also the formation of plaques with a highly destructive and invasive potential. The effect of dextranase on human dental plaque is under clinical study.

References

1. Dextranase and dental caries. S. A. Leach, Brit Dent J 127, 325 (1969). 2. Effect of dextranase on caries in rats harbouring an indigenous cariogenic bacterial flora. B. Guggenheim et al. Arch Oral Biol 14, 555 (1969). 3. The effect of dextranase mouthwash on dental plaque in young adults and children. R. C. Caldwell et al. J Amer Dent Ass 82 (1), 123 (1971). 4. A clinical study of the effect of dextranase on human dental plaque. R. R. Lobene. J Amer Dent Ass 82 (1), 132 (1971). 5. Dispersion of dextranous bacterial plaques on human teeth with dextranase. P. H. Keyes et al. J Amer Dent Ass 82 (1), 136 (1971).

Diadonium

Diadoniy

Action

Diadonium is a new potent non-depolarizing myorelaxant and spasmolytic agent.

References

1. Comparative sensitivity of neuromuscular synapses at different muscles to diadonium and decadonium, V. K. Lepakhin et al. Farmakol Toksik 33 (3), 288 (1970).

Diapamide (USAN) Tiamizide

Thiamizide CI456 D 1593

4-Chloro-N-methyl-3-(methylsulfamoyl) benzamide 4-Chloro-3-(N-methylsulfonamido)-N-methylbenzamide

Synthesis

By reacting 4-chloro-3-(methylsulfamoyl)benzoyl chloride with methylamine.

Description

Crystals, mp 165-166°.

Action

Diapamide is a new diuretic and antihypertensive agent. Experimental studies in dog have proved that its main site of action is in the ascending limb of the loop of Henle.

Manufacturer

Parke Davis and Co (USA)

Proprietary Name

Vectren

References

1. Parke Davis and Co US pat 3.203.987: Ger pat 1.158.957. 2. L. T. Blouin et al. J New Drugs 3, 302-308 (1963). 3. Amer Soc Nephrol 3. 27 (1969). 4. Med J Aust 1. 607-612 (1969). 5. Renal effects of Vectren: a new diuretic agent. C. G. Duarte. Fed Proc 29 (2).481 Abst (1970) .

61

DIC NSC 45388

5 (or 4)-(3,3-Dimethyl-1-triazeno) imidazole-4 (or 5)-carboxamide

Synthesis

Prepared by the reaction of 5-aminoimidazole-4-carboxamide with sodium nitrite in acid solution, and by the reaction of the resulting 5-diazoimidazole-4-carboxamide with a solution of dimethylamine in methanol.

Description

Ivory microcrystalline substance, explosive dec 250-255°.

Action

DIC is an antineoplastic agent which has shown significant antitumr activity in mice3,4, and in man during preliminary clinical trials5,6,8. AIC [4(5)-aminoimidazole-5(4)-carboxamide] has been identified as a metabolite of DIC7. The ribotide of DIC occupies a central position in the de novo purine synthetic pathway2.

References

1. Y. Fulmer Shealy et al. J Org Chem 27, 2150 (1962). 2. J. M. Buchanan and S. C. Hartman. Adv Enzymol 21, 199 (1959). 3. Y. F. Shealy et al. J Biochem Pharmac 11, 674 (1962). 4. K. Hano et al. Gann 56, 417 (1965). 5. C. MacDonald et al. Proc Am Ass Cancer Res 8, 43 (1967). 6. J. L. Skibba et al. Cancer Res 29, 1944 (1969). 7. J. L. Skibba et al. Biochem Pharmac 19,2043-2051 (1970). 8. J. K. Luce et al. Cancer Chemother Rep 54 (2), 119-124 (1970).

Dichlorvos (Rec INN)

2,2-Dichlorovinyl dimethyl phosphate

Action

Dichlorvos, an orally administered, single-dose drug, has proved to be effective against a variety of helminths infecting the gastrointestinal tract in a variety of mammals1,2,3. Recently, the safety and anthelmintic efficacy for man of dichlorvos has been evaluated4. Pharmacologically, the drug is a cholinesterase inhibitor.

Manufacturer

Shell Chemical Co (USA)

Proprietary Name

Dichlorman

References

1. E. F. Batte and A. C. Todd. Vet Med / Sm An Clin 60, 539-545 (1966). 2. E. G. Batte at al. ibid 60, 567-570 (1966). 3. N. F. Baker et al. Am J Vet Res 20, 278-280 (1969). 4. A. Pena Chavarria et al. Am J Trap Med Hyg 18 (6), 907-911 (1969).

Dienomycins

Dienomycin A: 4-isobutyroyloxy-3-methyl-2-(4-phenylbutadienyl) piperidine Dienomycin B: 4-acetoxy-3-methyl-2-(4-phenyl-butadienyl) piperidine Dienomycin C: 4-hydroxy-3-methyl-2-(4-phenylbutadienyl) piperidine

62

Production

Dienomycins A, B and C have been isolated from the culture filtrate of the strain MC 67-CI by a chemical screening method using Wood reagent.

Action

Dienomycins are weakly antibacterial, and dienomycin A is the most active. The same is active against mycobacteria.

References

1. A new antibiotic, dienomycin. I Screening method, isolation and chemical studies. S. Umezawa et al. J Antibiot 23 (1), 20-27 (1970). 2. Studies on dienomycins. II Chemical structures of dienomycins A, B and C. S. Umezawa et al. J Antibiot 23 (1). 28-34 (1970).

Difemerine (Rec INN)

Benzilic acid, 2-(dimethylamino)-2-methyl propyl ester hydrochloride 2-Dimethylamino-2-methylpropyl diphenylglycolate hydrochloride

Synthesis

Prepared from potassium benzilate or benzilic acid with 2-(dimethylamino)-2-methyl-1-propanol.

Description

White crystalline powder, soluble in alcohol, mp 182°. The free base melts at 56°; the hydrobromide at 173°, and the nitrate at 175°.

Action and Uses

Difemerine hydrochloride is a new aminopropanol compound which exerts a pronounced antispasmodic effect. In addition to this it also exhibits psychosedative and local anesthetic effects. The drug is proposed for the treatment of spasm of the gastrointestinal and genitourinary tracts.

Dosage

The oral dose is 7.5 to 10 mg daily. The daily parenteral dose is 1 to 3 mg intramuscularly, or 1 to 2 mg intravenously. The rectal dose is 15 to 30 mg daily.

Supplied as

Gelules, 2.5 mg. Suppositories, 7.5 mg. Solution (injection) 1 mg/ml

Proprietary Name

Luostyl

Manufacturer

Lab UPSA (France)

References

1. Lab UPSA Fr pat M 3406. 2. S. G. Kuznetsov et al. Zh Obshch Khim 32, 511 (1962). 3. Med Act (Drugs of Today) 6 (6), 205-207 (1970). (Review with 7 references)

Diflumidone Sodium

Ba 4164-8 MBR 4164-8

(USAN; Rec INN)

3'-Benzoyl-1,1-difluoromethanesulfonanilide sodium salt

63

Synthesis

Prepared by N-sulfonylation of 3-aminobenzophenone with difluoromethanesulfonyl chloride.

Description

White crystalline powder, mp 228-230° (dec). Diflumidone melts at 99-100.5°.

Action

Diflumidone is a new anti-inflammatory agent, In a carrageenin rat paw edema test and in a uv erythema test the ED50 potency values for the drug were approximately 1.5-2.0 and 2.2 times that of phenylbutazone, respectively, It was equipotent with phenylbutazone in the adjuvant arthritis test.

Toxicity

LD50 po in male rats: 450±26 mg/kg; in the male mouse: 720±62 mg/kg.

Manufacturer

Minnesota Mining and Mfg Co (USA)

References I

1. Anti-inflammatory activity of 3-benzayldifluoromethanesulfonanilide, sodium salt. K. F. Swingle et al. The Pharmacologist 11 (2), abs 204 (1969). 2. Absorption disposition and excretion of an anti-inflammatory agent in the rat. D. R. Hoogland et al. The Pharmacologist 11 (2), abs 291 (1969). 3. Anti-inflammatory agents. I. Benzoylfluoro-alkanesulfonanilides. J. Kenneth Harrington et al. J Med Chem 13 (1), 137 (1970). 4. Diflumidone Sodium, MBR 4164-8: a new anti-inflammatory agent K. F. Swingle et al. Arch Int Pharmacodyn Ther 189 (1), 129 (1971).

6,6-Difluoronorethindrone

17-Hydroxy-6,6-difluoro-19-nor-17α-pregn-4-en-20-yn-3-one 17α-Ethynyl-6,6-difluoro-17β-hydroxyestr-4-en-3-one

Action

By means of 6, 6-difluoro substitution, both the oral pregestational and oral anti-uterotrophic activities of norethindrone have been enhanced. 6,6-Difluoronorethindrone may therefore be a more potent oral contraceptive agent than norethindrone itself.

Manufacturer

Syntex (USA)

References

The biological activity of a series of 6, 6-difluoro norethindrone derivatives. W. H. Rooks and R. I. Dorfman. Contraception 1 (6). 403-407 (1970).

Difluprednate (USAN; Rec INN)

W6309

Difluprednatum (Lat). Difluprednato (Sp) 6α,9-Difluoro-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione-21-acetate 17-butyrate 6α, 9α-Difluoroprednisolone 17-butyrate 21-acetate

Synthesis

Prepared by the reaction of 6α,9α-difluoroprednisolone with methyl butyrate and p-toluenesulfonic acid in dimethylformamide and by

64

the reaction of the resulting 17-monoester with acetic anhydride.

Description

Crystals, mp 191-194°; [ α]D = +31.7° (c=0.5, in dioxane). UV max 237-238 µm [E(1%, 1 cm) =320] in ethanol.

Action

Anti-inflammatory

Manufacturer

Warner-Lambert (USA)

References

1. JAMA 212, 2247 (1970). 2. Warner-Lambert Pharmaceutical Co. S African Appl 68 03,686. 3. Comparative anti-inflammatory properties of systemically administered betamethasone 17-and 6α,9α-difluoroprednisolone 21-acetate 17-butyrate. G. DiPasquale et al. Steroids 16 (6), 663-678 (1970). 4. The local anti-inflammatory properties of betamethasone 17-benzoate and 6α,9α-difluoroprednisolone 21-acetate 17-butyrate. G. DiPasquale et al. Steroids 16 (6), 679-692 (1970). 5. Effect of betamethasone 17,benzoate and 6α,9α-difluoroprednisolone 21-acetate 17-butyrate on the survival of adrenalectomized rats. G. DiPasquale et al. Steroids 16 (6), 693-701 (1970).

21,25 Dihydroxycholecalciferol

21,25DHCC

Isolation It has been isolated in pure form from the plasma of pigs given large doses of vitamin D3.

Action

21,25-Dihydroxycholecalciferol is a metabolite of vitamin D3. It has proved to be one-half as active as vitamin D3 in the rat in the cure of rickets and in intestinal calcium transport, but to be more active than vitamin D3 in the mobilization of bone mineral.

References

21,25-Dihydroxycholecalciferol. A metabolite of vitamin D3 preferentially active on bone. T. Suda at at. Biochemistry 9,2917-2922 (1970).

Dimepregnen (BAN)

3β-Hydroxy-6α,16α-dimethyl-pregn-4-en-20-one 6α,16α-Dimethyl-pregn-4-en-3β-ol-20-one

Synthesis

Prepared by reducing 6α,16α-dimethylprogesterone with lithium aluminium tri-ter-butoxyhydride.

Description

Crystals, mp 131-134°.

Action

Antiestrogenic

References

1. Chem Drug 193, 228 (1970). 2. E. Merck AG. Brit pat 1,130,115.

65

Dimethylphaeanthine Diiodide

N, N'-Dimethylphaeanthine diiodide N, N'-Dimethyl-I-tetrandrine diiodide

Isolation From Triclisia dictyophylla and T. patens.

Description

The di-iodide, mp 231 ° and [α]D = -253° in ethanol. The diperchlorate, mp 259°.

Action

D imethylphaeanthine is a new quaternary alkaloid with muscle relaxant effect.

References

The occurrence af phaeanthine and N, N'-dimethylphaeanthine in Triclisia dictyaphylla and T. patens. A new simple method far estimation of muscle relaxant effect. A. Kronlund et al. Acta Pharm Suecica 7, 279-284 (1970).

Dimpylate (Prop INN)

Dimpylatum (Lat) O,O-Diethyl-O-(2-isopropyl-6-methyl-4-pyrimidinyl)ester of phosphorothioic acid O,O-Diethyl-O-[2-isopropyl-4-methylpyrimidinyl-(6)] thiophosphate

Synthesis

Prepared from 2-isopropyl-4-methyl-6-hydroxypyrimidine

Description

Liquid, bp 123-125° (0.03 mm); bp 83-84° (0.002 mm). nD = 1.4978-1.4981.

Action

Dimpylate, an insecticide of great commercial value, has recently been found to possess nematocidal activity.

Manufacturer

J. R. Geigy AG (Switzerland)

Proprietary Name

Diazinon, Basudin

References

1. Gasser Z Naturforsch 8b, 225 (1953). 2. J. R. Geigy AG US pat 2,754,243. 3. Methods for controlling nematodes with compositions containing Diazinon. A. Margot and C. Kocher (to J. R. Geigy AG) US pat 3,492,404 (1970).

Dioxopromethazine

Hydrochloride Wu

3227

10-[2-(Dimethylamino)propyl]-phenothiazine 5,5-dioxide hydrochloride

Synthesis

Prepared by the oxidation of promethazine with hydrogen peroxide. Also by oxidation of

66

phenothiazine with hydrogen peroxide and treatment with 2-dimethylaminopropylchloride1.

Description

White to faint yellow, practically odorless, crystalline powder. Soluble in water, slightly soluble in alcohol and practically insoluble in ether. mp 265-268°; th e free base melts at 128-130°. UV max in 0,1N hydrochloric acid 264 µm [E(1%, 1 cm) = 365 ± 15] and at 328 µm [E(1%, 1 cm) = 165 ± 15].

Action and Uses

When applied rectally dioxopromethazine hydrochloride exhibits antihistaminic, local anesthetic, spasmolytic and anti-inflammatory properties. For use in the treatment of hemorrhoids. Dioxopromethazine hydrochloride was introduced into the pharmaceutical market in 1968 as an anti histaminic agent for oral use.

Supplied as

Suppositories, 10 mg

Proprietary Name

Prothanon

Manufacturer

VEB Arzneimittelwerk (Germany, East)

References

1. VEB Arzneimittelwerk Dresden. Fr pat 1.470,195; Fr pat 1.470,196; Ger (East) pat 51855; Gar (East) pat 54,363. 2. Die Pharmazie 25 (1), 78-121 (1970) . 3 . Protanon Suppositorien K. Zieloff. Zbl Pharm 109 (1), 41 (1970). 4. Dioxopromethazinhydrochlorid Zbl. Pharm 109 (1), 46 (1970). 5. Med Act (Drugs of Today) 6 (6), 208-212 (1970). (Review with 16 references)

Disopyramide (USAN)

SC7031

α-[2-(Diisopropylamino )ethyl]-α-phenyl-2-pyridineacetamide 4-Diisopropylamino-2-phenyl-2-(2-pyridyl) butyramide

Synthesis

Prepared from 4-diisopropylamino-2-phenyI-2-(2-pyridyl) butyronitrile2.

Description

Crystals, mp 94.5-95°.

Action and Uses

Disopyramide is a new anti-arrhythmic drug. Its major clinical uses are for the prevention or abolition of certain cardiac arrhythmias. These include extrasystoles, paroxysmal supraventricular and ventricular tachycardia, atrial fibrillation, and atrial flutter.

Supplied as

Capsules, 100 mg. Also gelules, 75 mg of disopyramide and 20 mg of amobarbital.

Proprietary Names and Manufacturer

Rythmodan (Roussel, France); Norpace [for the phosphate (Searle, USA)].

References

1. G. D. Searle Co. Belg pat 617.730; US pat 3.225.054. 2. Med Act (Drugs of Today) 6 (6).212-215 (1970). (Review with 23 references)

Disparlure

cis-7,8-Epoxy-2-methyloctadecane

Synthesis

Prepared in several steps from 6-methyl-1-heptene

67

Action

Disparlure is a sex attractant substance of female gypsy moth. It is used for insect control.

Manufacturer

USDA Agric Res Service (USA)

References

Chem Eng News 48 (41), 35 (1970).

DithiogIycol-bis-choline

ChSSCh

Action

Dithioglycol-bis-choline, a new analogue of acetylcholine, possesses a strong nicotinic activity, and a very weak muscarinic activity.

References

1. I. Janczarki et al. Acta Physiol Polon 19, 256 (1968). 2. Cholinergic activity of dithioglycol-bis-choline, a new analogue of acetylcholine. P. Kubikowski and S. Chustecki. Dissert Pharm Pharmacol 22 (2/3), 97-104 (1970).

DOET Hydrochloride

2,5-Dimethoxy-4-ethyl-α-methylphenethylamine hydrochloride 2,5-Dimethoxy-4-ethylamphetamine hydrochloride 1-(2, 5-Dimethoxy-4-ethylphenyl)-2-aminopropane hydrochloride

Synthesis

Prepared by the reduction of 1-(4-ethyl-2,5-dimethoxyphenyl)-2-nitropropane with aluminum lithium hydride1.

Description

Crystals, mp 195°. The free base melts at 61-61.5°.

Action

DOET is a methoxylated amphetamine compound related to both mescaline and amphetamine. This new psychotropic agent, in low doses, appears to be particularly effective in altering normal cognition without producing disorganization in thinking or perception.

References

1. A. T. Shulgin (Dow Chemical Co) Brit pat 1,147,739. 2. DOET. a new psychotropic agent: Psychological and physiological effects in man. S. H. Snyder et al. Arch Gen Psych 21, 95-101 (1969). 3. DOM (STP) a new hallucinogenic drug, and DOET: effects of low doses in man. S. H. Snyder et al. Amer J Psychiat 125,357-364 (1968). 4. Altered free associations: some cognitive effects of DOET. H. Weingartner et al. Behav Sci 15 (4), 297-303 (1970). 5. DOET, a new psychotropic drug. S. H. Snyder et al. Arch Gen Psych 24, 50-56 (1971).

DOM STP

2.5-Dimethoxy-4-α-dimethyl phenethylamine 2.5-Dimethoxy-4-methylamphetamine 1-(2. 5-Dimethoxy-4-methylphenyl)-2-aminopropane

68

Synthesis

By the reduction of 1-(4-methyl-2.5-dimethoxyphenyl)-2-nitropropane with aluminum lithium hydride. DOM melts at 60.5-61°.

Action

DOM is a new hallucinogenic drug. The data from a recent clinical evaluation has indicated that low doses of DOM produced significantly increased feelings of anxiety, euphoria, dysphoria with somatic and LSD-like symptoms.

Toxicity

LD50 ip in mouse: 82±4.2 mg/kg.

References

1. A. T. Shulgin (Dow Chemical Co) Brit pat 1.147.739. 2. 2,5-Dimethoxy-4-methyl-amphetamine (STP): A new hallucinogenic drug. S. H. Snyder et al. Science 158. 669-670 (1967). 3. DOM (STP) A new hallucinogenic drug and DOET: Effects in normal subjects. S. H. Snyder at al. Amer J Psychiat 125.357-364 (1968). 4. Analogs of α-methylphenethylamine (amphetamine). 1. Synthesis and pharmacological activity of some methoxyand/or methyl analogs. B. T. Ho et al. J Med Chem 13 (1). 26-30 (1970). 5. 2,5-Dimethoxy-4-methylamphetamine: Clinical evaluation of a new hallucinogenic drug. L. A. Faillace at al. J Nerv Ment Dis 150 (2). 119-126 (1970). 6. 2,5-Dimethoxy-4-methyl-amphetamine-Tissue distribution and neurochemical action. J. E. Idanpaan-Heikkila and W. M. Mcisaac. Biochem Pharmac 19. 935-937 (1970). 7. Analogs of Amphetamine. 4. Synthesis of metabolites of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. B. T. Ho and L. W. Tansey. J Med Chemistry 14 (2). 156-157 (1971). 8. Analogs of amphetamine. 5. Studies of excretory metabolites of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats. B. T. Ho. J Med Chemistry 14 (2). 158-160 (1971).

Dorastine Hydrochloride

(USAN; Prop INN) Ro

5-9110/1

Dorastinum (Lat). Dorastina (Sp) 8-Chloro-2,3,4,5-tetrahydro-2-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b] indole dihydrochloride

Synthesis

Prepared in several steps from 2-methyl-5-vinyl pyridine and p-chloroaniline.

Description

Crystals, mp 264-266° (ethanol-ether); the free bas e melts at 114.5-115.5° (ethyl acetate).

Action

Dorastine hydrochloride is a new anti histaminic agent.

Manufacturer

Hoffmann-La Roche (USA)

References

1. JAMA 211, 1363 (1970). 2. WHO Chron 24 (3). 126 (1970). 3. Hoffmann-La Roche Inc US pat 3.409.628. 4. Clin Pharm Ther 10, 250 (1969).

Doxepin Hydrochloride (USAN;

Rec INN)

11-(3-Dimethylaminopropylidene)-6,11-dihydrodinbenz[b,e]oxepine hydrochloride (isomeric mixture)

69

Synthesis

Doxepin may be prepared by treatment of the corresponding dibenzoxepinone with a dimethylaminopropylmagnesiumhalide Grignard reagent, followed by hydrolysis and dehydration of the carbinol formed thereby1-4. It may be also prepared by reaction of the dibenzoxepinone with 3-dimethylaminopropyltriphenylphosphonium-bromide hydrobromide in presence of butyl lithium5. In both processes a mixture of cis and trans isomers is obtained; in the mixture prepared by the organo-phosphorous reaction the more pharmacological active cis-isomer predominates, (approx. 75%) and when the Grignard reagent is used, the trans-isomer of lesser activity predominates.

Description

White crystalline powder. A mixture of the cis/trans hydrochlorides obtained by the Grignard route has been reported to melt at 188-189°4. From this mixture the isomers were separated; the tr.ans-isomer hydrochloride melts at 192-193°, and the cis -isomer (cidoxepin) at 209-210.5°.

Action and Uses

Experimental studies in animals have demonstrated that doxepin possesses both tranquillizing and antidepressant activity; also a potent spasmolytic and muscle-relaxant activity, and mild peripheral vasodililtor properties. Doxepin is useful clinically in the treatment of patients with anxiety, depression, and mixed anxiety/depression.

Dosage

30 to 300 mg daily, usually administered in three divided doses.

Supplied as

Capsules, 10 mg, 25 mg and 50 mg.

Proprietary Names and Manufacturer

Aponal (Boehringer, Germany); Sinequan (Pfizer, USA Germany, Switzerland, U.K.)

References

1. Stach and Bickelhaupt. Monatsch 93, 896 (1962). 2. Bickelhaupt et al. ibid. 95, 485 (1964).

3. C. F. Boehringer and Sohne GmbH Belg pat 623,259. 4. Chas Pfizer and Co, Inc Belg pat 641.498. 5. Chas Pfizer and Co, Inc Brit pat 1,085,406. 6. Med Act (Drugs of Today) 6 (2), 51-55 (1970). (Review with 14 references)

Dropropizine (Rec INN)

UCB 1967

Dropropizinum (Lat). Dropropizina (Sp) 1-Phenyl-4-(2,3-dihydroxypropyl)-diethylenediamine 3-(4-Phenyl-1-piperazinyl)-1,2-propane-diol

Action

Pharmacological screening has indicated that dropropizine shows antitussive activity similar to that of codeine.

Toxicity LD50 po in mice: 450 mg/kg; in rats: 650 mg/kg

Manufacturer

UCB (Belgium)

Proprietary Name

Katril

References

1. Dropropizine (UCB 1967), an antitussive: Oral toxicity study in pure bred dogs. P. R. B. Noel. Arzneim-Forsch 19 (8), 1246 (1969). 2. Chem Drug 193, 228 (1970).

Ecdysterone

70

Description

Screening of Israeli plants for insect moulting hormones (ecdysones) has led to the isolation and identification of ecdysterone from Ajuga and Achyrantes species. Insect hormones (phytoecdysones) from Israeli plants.

References

R. Ikan et al. Israel J Chem 8 Suppl Proc Israel Chem Soc (1970).

Enflurane (USAN; Prop INN)

Compound 347

2-Chloro-1,1,2-trifluoroethyl difluoromethyl ether

Action

Enflurane is a new inhalation anesthetic.

Manufacturer

Ohio Medical Products Division of Air Reduction Co, Inc (USA)

Proprietary Name

Ethrane

References

1. JAMA 214,1693 (1970). 2. WHO Chron 25 (3), 131 (1971).

Enpiprazole Hydrochloride

(BAN; Prop INN) H 3608

Enpiprazolum (Lat). Empiprazol (Sp) 1-(o-Chlorophenyl)-4-[2-(1-methylpyrazol-4-yl) ethyl] piperazine dihydrochloride

Synthesis

Prepared by the condensation of 1-methyl-4-(2-chloroethyl)pyrazol with N-(o-chlorophenyl)piperazine. The dihydrochloride salt of the product so obtained melts at 223-225°.

Action

Enpiprazole dihydrochloride is a new psychotropic agent.

References

1. Chem Drug 193, 228 (1970). 2. WHO Chron 24 (9), 421 (1970). 3. E. Merck AG Neth Appl 6,514,242.

Enpromate (USAN; Rec INN)

NSC 112682 59156 Lilly

Enpromatum (Lat). Empromato (Sp) Cyclohexanecarbamic acid, 1,1-diphenyl-2-propynyl ester 1, 1-Diphenyl-2-propynyl cyclohexanecarbamate

71

Synthesis

Prepared by the reaction of 1,1-diphenyl-2-propyn-1-ol with phenyl chloroformate and by the reaction of the resulting carbonate with cyclohexylamine. Also by the reaction of 1,1-diphenyl-2-propyn-1-ol with cyclohexyl isocyanate.

Description

Crystals, mp 160-161º

Action

Enpromate has proved to have potent antitumor effects against various tumor systems in mice.

Manufacturer

Eli Lilly and Co (USA)

References

1. JAMA 211. 2148 (1970). 2. WHO Chron 24 (11), 529 (1970). 3. Acetylenic carbamates. A new class of potential oncolytic agents. R. D. Dillard et al. J Med Chem 10 (1). 40-47 (1967). 4. Eli Lilly and Co. Neth Appl 6,516.922. 5. Clinical trial of acetylenic carbamate: 1, 1-diphenyl-2-propynyl cyclohexanecarbamate (NSC-112682). S. Gailani and M. Blais. Cancer Chemotherapy Rep (Pt-1) 54(3) 187-190 (1970).

Enramycin Hydrochloride (Prop

INN)

Enramycinum (Lat). Enduracidin Antibiotic of polypeptide nature which contains chlorine in its molecule

Production

Enramycin is obtained from cultures of Streptomyces fungicidicus No. B 5477.

Description

White or pale yellow powder, mp 234-238° (dec). Very soluble in diluted hydrochloric acid, soluble in methanol and insoluble in ether and benzene; [α]D = 89.2° (c=0.5% in dimethylformamide).

Action

Enramycin hydrochloride is a new antibiotic which has been recently marketed in Japan. It is very active against gram-positive bacteria, active against Neisseria and Mycobacterium and Treponema, but inactive against gramnegative bacteria. Indications: Treatment of infections due to sensitive organisms including infections affecting skin, respiratory tract, and ear, nose and throat.

Dosage

The initial intramuscular dose in adults is 200 mg divided into 1 to 4 doses, followed by a daily dosage of 100 mg divided into 1 to 2 doses.

Supplied as

Vials, 50 and 100 mg (potency).

Proprietary Name

Enradin

Manufacturer

Takeda Chemical Industries Ltd (Japan)

References

1. WHO Chronicle 24 (3), 126 (1970). 2. Med Act (Drugs of Today) 7 (1). 15-17 (1971). (Review)

Epicillin (USAN; Prop INN)

SQ-11,302

6-[D-2-Amino-2-(1,4-cyclohexadien-1-yl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

72

Synthesis

Prepared by coupling 6-aminopenicillanic acid with the methyl acetoacetate enamine of D-2-amino-2-(1,4-cyciohexadienyl)acetic acid in the form of a mixed anhydride.

Description

Crystals, the hemihydrate decomposes at 202°.

Action

Epicillin is a new semi-synthetic penicillin, which has proved to be active in vitro against a wide range of gram-positive bacteria.

Manufacturer

Squibb (USA)

References

1. JAMA 213 (13). 2247 (1970). 2. WHO Chron 25 (3), 132 (1971). 3. E. R. Squibb and Sons, Inc US pat 3,485,819. 4. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct 18-21 (1970); abst 119-120.

EpimestroI (USAN; Rec INN)

Org 817

Epimestrolum (Lat) 3-Methoxyestra-1,3,5(10)-triene-16α,17α-diol 17-Epiestriol 3-methyl ether

Synthesis

By reacting 17-epiestriol with dimethyl sulphate.

Action

Epimestrol is a new ovulation stimulant.

Manufacturer

NV Organon (Netherlands)

References

1. JAMA 209,1212 (1969). 2. WHO Chron 24 (11), 529 (1970) . 3. Organon Laboratories Ltd Brit pat 911.600.

Eprazinone Hydrochloride (Rec

INN) CE 746

Eprazinonum (Lat). Eprazinona (Sp) 3-[4-(β-Ethoxyphenethyl)-1-piperazinyl]-2-methylpropiophenone dihydrochloride 1-(2-Ethoxy-2-phenylethyl)-4-(3-keto-2-methyl-3-phenyl-propyl)piperazine dihydrochloride 1-[(2-Phenyl-2-ethoxy)ethyl]-4-[(3-phenyl-2-methyl)propan-3-one] piperazine dihydrochloride

Synthesis

Prepared by reacting2-phenyl-2-ethoxyethyl bromide with piperazine, and subsequent condensation with trioxymethylene and propiophenone.

Description

White crystalline powder, mp 160º; soluble in water.

Action

73

Eprazinone hydrochloride is an antitussive compound; it also exhibits analgesic activity.

Toxicity

LD50 po in mice: 730 mg/kg.

Manufacturer

Centre Europ Rech Mauvernay (France).

References

1. WHO Chron 24 (9), 421 (1970). 2. Roland Mauvernay Brit pat 1,097,572. 3. J. Vacher et al. Arch Int Pharmacodyn Ther 165 (1), 1-13 (1967).

Etidronic Acid (USAN; Rec

INN) EHDP

Acidum etidronicum (Lat). Etidronico Acido (Sp) (1-Hydroxyethylidene) diphosphonic acid Hydroxyethane diphosphonic acid

Synthesis

Prepared by the reaction of acetic acid with phosphorus trichloride or tribromide. By the reaction of ketene with phosphoric acid and also by the reaction of acetic anhydride with dimethyl phosphite.

Action

Etidronic acid is a calcium homeostatic agent.

Manufacturer

Monsanto Co (USA)

References

1. JAMA 211. 819 (1970). 2. WHO Chron 24 (11). 526 (1970) . 3. Monsanto Co. Fr pat 1,521,962; Fr pat 1,521,963; Fr pat 1,521,961; Fr pat 1,548,936; US pat 3,475,486; Fr pat 1.546.145.

Etifoxine (Prop INN)

HOE 36801

Etifoxinum (Lat)r Etifoxina (Sp) 6-Chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine

Synthesis

Prepared from 2-amino-5-chloro-α-methyl-α-phenylbenzylalcohol.

Description

Crystals, mp 90-92°. The hydrochloride salt melts a t 150-151°. UV max 273 µm [ ε=21,200]

Action

Etifoxine is a new psychotropic compound. According to the action on animal behaviour it may be considered a tranquiliizing drug with additional stimulating properties.

Manufacturer

Farbwerke Hoechst A.G. (Germany)

References

1. Farbwerke Hoechst A. G. S African pat 67 06,887. 2. WHO Chron 24 (9), 422 (1970) . 3. 2-Ethylamino-6-chloro-4-methyl-4-phenyl·4H 3,1-benzoxazine a new psychotropic compound. I. Hoffmann et al. Arzneim-Forsch 20 (7), 975 (1970).

74

Etorphine Hydrochloride (BAN;

Rec INN) M 99

Tetrahydro-7α-(1-hydroxy-1-methyl-butyl)-6,14-endoethenooripavine hydrochloride 19-Propylorvinol hydrochloride

Description

Crystals, mp 266-267°; the free base, mp 215°.

Action

Etorphine has a potency in laboratory animals approximately 1,000 times that of morphine2. Like the latter, it is addictive in monkeys and causes respiratory depression. I n a recent pilot study of safety and efficacy, the drug has been found to be a clinically efficacious analgesic at doses of 1 µg/kg having rapid onset and moderately short duration of action after intramuscular injection3.

Manufacturer

Reckitt and Colman Pharm Div (England)

References

1. J. F. Macfarlan and Co Belg pat 618,392. 2. G. F. Blane et al. Brit J Pharmac 30, 11-22 (1967). 3. Trial of etorphine hydrochloride (M99 Reckitt) in carcinoma pain: preliminary report. G. F. Blane and D. S. Robbie. Brit J Pharmac 39 (1), 252P (1970).

Etoxadrol Hydrochloride

(USAN; Rec INN) CL1848C

Etoxadrolum (Latin) (+)-2-(2-Ethyl-2-phenyl-1,3-dioxolan-4-yl )piperidine hydrochloride (+)-2-Ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxalane hydrochloride

Synthesis

By condensing 2-piperidyl-1,2-ethanediol hydrochloride with propiophenone a racemic mixture (HCI) is obtained which melts at 256-257°. The use of the separated alpha or beta racemate of the starting glycol leads to the corresponding alpha or beta racemate. The alpha racemate (HCI) melts at 251.5-253°, and the beta racemate (HCI) at 250-251°. The gamma racemate (HCI) has also been obtained, melting at 175-177°, resolidifying at 195 ° and remelting at 241°

Action

Etoxadrol hydrochloride is a new parenterally administered dissociative anesthetic that has appeared promising in non-human primates and other animals. In a group of normal human volunteers the drug has been found to be psychologically acceptable, physiologically safe and apparently useful.

Manufacturer

Cutter Laboratories (USA)

References

1. JAMA 211, 2149 (1970). 2. WHO Chronicle 24 (11), 527 (1970). 3. W. Richard Hardie (to Cutter Lab. Inc.) US pat 3,262,938, 4. Cardiopulmonary response to CL-7848C, a new dissociative anesthetic. D. L. Traber and R. D. Wilson. Pharmacologist 11 (2), 236 (1969). 5. The cardiovascular effects of CL-1848C in normal human volunteers. R. D. Wilson and C. R. Allen. Fed. Proc. 29. 354 (1970). 6. Effects of CL-1848C, a new dissociative anesthetic on the cardiovascular and respiratory systems. D. L. Traber. Fed Proc 29. 354 (1970). 7. Evaluation of CL-1848C: a new dissociative anesthetic in normal human volunteers. R. D. Wilson et al. Anesthesia and Analgesia 49 (2). 236-241 (1970). 8. Effects of CL-1848C, a new dissociative anesthetic, on the canine cardiovascular and respiratory systems. A. H. Goldberg at al. J Pharmacal Exptl Ther 175 (2). 395 (1970).

75

Famotine Hydrochloride

(USAN; Rec INN) UK

2054

1-[( p-Chlorophenoxy)methyl]-3,4-dihydroisoquinoline hydrochloride

Synthesis

Prepared by cyclodehydration of N-(p-chlorophenoxyacetyl)-β-phenylethylamine with phosphorus pentoxide.

Description

Colorless needles, mp 205-207°.

Action

Famotine hydrochloride is a weak, non-competitive inhibitor of bacterial and viral neuraminidases5. It has been found to have a spectrum of antiviral activity which includes those viruses which possess neuraminidase, namely, the influenza and parainfluenza viruses responsible for a large proportion of common respiratory infections. It is also effective however against many other viruses, such as rubella and respiratory syncytial viruses, which do not possess neuraminidase. Inhibition of influenza virus multiplication by famotine might result from interaction of the inhibitor with both virus and cells7. In experimental trials the overall protective effect of famotine has proved to be significant in volunteers infected with B influenza virus6.

Manufacturer

Chas Pfizer and Co, Inc (USA)

References

1. WHO Chron 24 (11), 529 (1970). 2.JAMA 210,1454 (1969). 3. Pfizer Corp. Neth Appl 6,516,328. 4. K. W. Brammer et al. Nature 219 (5153), 515-517 (1968).

5. Prophylaxis of influenza B with UK 2054. P. N. Meenan and I. B. Hillary. Lancet, ii, 614-615 (1969). 6. The effects of UK 2054 on the multiplication of influenza viruses. R. D. Barry and P. Davies. J Hyg Camb 68, 151-158 (1970). 7. Studies of isoquinoline derivatives (UK 2371 and UK 2054) in respiratory infections of volunteers, using influenza viruses, a parainfluenza virus and a rhinovifus. Sylvia E. Reed et al. Ann NY Acad Sci 173, 760-769 (1970).

Fenaftic Acid

1-Diethylamino-3-phenyl-6,6-dimethyl-1,2,3,4,5,6,7,8-octahydro-8-oxo-2-naphthoic acid

Action and Uses

Fenaftic acid increases bile secretion and improves its composition. For use in the treatment of dyspepsia, cholelithiasis, postcholecystectomy.

Supplied as

Sugar coated tablets, 250 mg.

Dosage

0.5 to 1 g daily.

Registered Name Vesifluyl

Manufacturer

Allard (France)

References

Med Act (Drugs of Today) 6 (5), 177-178 (1970). (Review)

76

Fenclexonium Methylsulfate

(Rec INN) HOE 019

Fenclexonii Metilsulfas (lat.) Fenclexonio Metilsulfato (Sp.) 1-[3-(1-Cyclohexenyl)-3-phenylpropyl]-1-methyl piperidinium methylsulfate

Synthesis

Prepared in several steps from benzyl cyanide and cyclohexanone.

Description

Crystals, mp 106-107°.

Action

Spasmolytic agent.

Manufacturer

Farbwerke Hoechst AG (Germany)

References

1. Anticholinergic effects in relation to chemical constitution in a series of tertiary and quaternary propylamine-derivalives. G. Ehrhart et al. Arzneim Forsch 20 (8), 1094-6 (1970). 2. The influence of HOE 019 on gastric secretion in the rat. G. Aus! and P. A. van Zwieten. Arzneim Forsch 20 (8), 1097-1100 (1970).

Fenclonine (USAN)

CP-10188

3-(p-Chlorophenyl)alanine

Synthesis

Several methods have been described1-4.

Description

Crystals mp 265-266°.

Action

Fenclonine is a potent selective inhibitor of serotonin synthesis. In recent experiments its aphrodisiac activity has been investigated in laboratory animals.

Manufacturer

Chas Pfizer and Co (USA)

References

1. Judd C. Nevenzel et al. J Am Chem Soc 71,3024 (1949). 2. A. H. Cook et al. J Chem Soc (London)., 1947-54 (1950). 3. J. H. Burckhalter et al. J Am Chem Soc 73, 56 (1951). 4. George H. Cleland. J Org Chem 26, 3362 (1961). 5. Pfizer. Fr pat M 5,734. 6. Science 166 (3911) (1969). 7. Experimental drug makes rats sexy. Med World News 11 (4),20 (Jan 23, 1970). 8. Behavioral effects of serotonin depletion and of p-chlorophenylalanine (a serotonin depletor) in rats. J. F. Brody. Psychopharmacologia (Berl) 17, 14-33 (1970). 9. The effect of parachlorophenylalanine on social interaction of male rats. E. E. Shillito. Br J Pharmac 38, 305-315 (1970). 10. Inhibitory effect of p-chlorophenylalanine on the sexual maturation of female rats. A. B. Fajer et al. J Reprod Fert 22, 379-380 (1970). 11. Serotonin Now: Clinical implications of inhibiting its synthesis with para-chlorophenylaline. A. Sjoerdsma et al. An Int Med 73 (4), 607-629 (1970). 12. The effects of p-chlorophenylalanine on behavior: III. Facilitation of brightness discrimination in satiated rats. D. A. Stevens. Life Sci 9 (P 1) 1127-1134 (1970). 13. Effect of para-chlorophenylalanine on basal forebrain stimulation. J. A. Wada and A. Terao. Experimental Neurology 28,501-506 (1970).

77

Fenclozic Acid

lCI 54,450

2-(4-Chlorophenyl)thiazol-4-ylacetic acid

Synthesis

Prepared from p-chlorothiobenzamide.

Description

Colorless solid mp 155-156°; soluble in most organic solvents, but only sparingly soluble in water.

Action

Fenclozic acid is one representative of a new class of compounds, which exhibit anti-inflammatory, analgesic and antipyretic effects. Preliminary clinical trials have shown the drug to be effective in the treatment of rheumatoid arthritis in man.

Manufacturer

Imperial Chemical Ind, Ltd (England)

Proprietary Name

Myalex

References

1. Brit pat 1,099,389. 2. W. Hepworth et al. Nature (London) 221, 582-583 (1969). 3. Pharmacology of fenclozic acid; a new compound with antiinflammatory, analgesic and antipytetic activity. B. B. Newbould. Brit J Pharmacal 35 (3),487-497 (1969). 4. Evaluation in man of fenclozic acid. Serum concentration studies. T. M. Chalmers et al. Ann Rheum Dis 28 (6), 590 (1969). 5. II. Clinical trial in patients with rheumatoid arthritis. T. M. Chalmers et al. Ann Rheum Dis 28 (6), 595 (1969). 6. Fenclozic acid Lancet 1 (7648), 662 (1970). 7. Hepatic effects of fenclozic acid.

F. D. Hart et al. Ann Rheum Dis 29 (6), 684 (1970). 8. The metabolism of C14-Myalex in various species. An in vivo NIH shift. D. M. Foulkes. J Pharmacal Exp Ther 172,115-121 (1970).

Fenoxazolin Hydrochloride (Rec

INN)

2-(2-lsopropylphenoxymethyl)-2-imidazoline hydrochloride

Synthesis

Prepared starting by the reaction of 2-isopropylphenol with chloroacetonitrile.

Description

White or almost white, odorless, crystalline powder with a bitter taste, mp 134-135°. Soluble in water, insoluble in benzene and ether.

Action and Uses

Fenoxazolin, a new imidazoline compound, causes vasoconstriction when applied topically to the nasal mucosa. It is used as nasal decongestant.

Supplied as

Solution (spray), 10 mg/10 ml.

Proprietary Name

Snup

Manufacturer

Karlspharma (Germany)

References

1. L Dausse ·SA, Fr pat 1,312,410. 2. Med Act (Drugs of Today) 6 (1), 19-21 (1970).

78

Fezatione (Rec INN)

3-[(p-Methylbenzylidene)amino]-4-phenyl-4-thiazoline-2-thione

Synthesis

Prepared by the condensation of 4-phenyl-3-aminothiazoline-2-thione with p-tolualdehyde.

Description

Light yellow needle-crystalline powder, mp 120-126° (dec) Freely soluble in chloroform and acetone, slightly soluble in ethanol and practically insoluble in water.

Action and Uses

Fezatione is active against bacteria, yeasts and fungi. It is used for the treatment of trichophytia.

Toxicity

LD50 po in mouse and rat> 10,000 mg/kg.

Manufacturer

Takeda Chemical Industries Ltd (Japan)

Proprietary Name

Polydin

Supplied as

Ointment and solution 2%.

References

1. Takeda Chemical Industries Ltd. Jap pat 3382 (,67). 2. Jap Med Gaz 7 (9), 9 (1970).

Filipin (Rec INN) Filimarisin.

NSC 3364

Filipinum (Lat). Filipina (Sp)

14-Deoxylagosin 3,5,7,9,11,13,15,26,27-Nonahydroxy-2-(1-hydroxyhexyl}-16-methyl-16,18,20,22,24-octocosapentaenoic acid 1,27-lactone. 4,6,8,10,12,14,16,27-Octohydroxy-3-(1-hydroxy-hexyl)-17,28-dimethyloxacyclooctacosa-17,19,21,23,25-pentaen-2-one

Production

Antibiotic produced by Streptomyces filipinensis

Description

Yellow, feathery, needles, mp 195-205°.

Action

Filipin is an antifungal antibiotic. Recently, it has also shown to block cholesterol assimilation by the insects and to be effective against cereal leaf beatles.

Toxicity

LD50 ip in mice: 17 mg/kg.

Manufacturer

The Upjohn Co (USA)

References

1. Whitfield et al. J. Am. Chem. Soc. 77, 4799 (1955).

2. Golding-Rickards. Tetrahedron Letter 2615 (1964). 3. US pat. 3,188,272. 4. Chem. Week 107 (25), 60 (1970).

Flavodate Disodium

[( 4-0xo-2-phenyl-4H-1-benzopyran-5,7-diyl)dioxy] diacetic acid disodium salt 5,7-Flavone-bis (oxyacetic acid) disodium salt

79

Flavodate is chemically related to rutin and quercetin.

Synthesis

By reaction of 5,7-dihydroxy-flavone with bromoacetic acid in alkaline solution a mixture of 5,7-flavone-bis (oxyacetic) acid and 5-hydroxy-7-flavonoxyacetic acid is obtained. The difference of solubility of the ammonium salts permit the separation of the two acids1. Flavodic acid melts at about 280°.

Action and Uses

Flavodate disodium, a new flavone derivative, protects the capillaries, increasing their resistance and hence reducing their permeability. The main indications for use of flavodate are:arteritis, varicose vein, capillaritis, ulcus cruris, hemorrhoids, cerebral and peripheral vascular disorders.

Dosage

In acute cases, 600 to 800 mg daily; in prolonged treatment, 300 to 600 mg daily.

Supplied as

Gelules, 100 mg.

Proprietary Name

Intercyton

Manufacturer

Lab Roland-Marie (France)

References

1. M. R. Blaise. Fr Addn 80,122. 2. Med Act (Drugs of Today) 6 (3), 82·84 (1970). (Review)

Floctafenine (Prop INN)

Floctateninum (Lat). Floctatenina (Sp) N-[8-(Trifluoromethyl)-4-quinolinyl]anthranilic acid 2,3-dihydroxypropyl ester

2,3-Dihydroxypropyl N-[8-(trifluoromethyl)-4-quinolinyl] anthranilate

Synthesis

Prepared by condensing 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolan with 4-[(o-methoxycarbonyl)phenyl] amino-8-trifluoromethylquinoline and subsequent hydrolysis of the resulting aceton ketal.

Description

Colorless crystals, mp 179-180º (methanol). Soluble in alcohols, acetone; slightly soluble in ether and chloroform, and insoluble in water.

Action

Analgesic and anti-inflammatory. It differs from glafenine in having a 8-trifluoromethyl group instead of a 7-chloro.

Manufacturer

Roussel Uclaf (Fance)

References

1. WHO Chron 24 (9), 423 (1970). 2. Roussel-Uclaf. Ger Offen 1,815,467.

Flucloxacillin

BRL 2039 FK 900

6-[3-(2-Chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarboxamidoj-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0] heptane-2-carboxylic acid 3-(2'-Chloro-6'-fluorophenyl)-5-methyl-4-isoxazolylpenicillin

80

Synthesis

Prepared by reacting 6-amino-penicillanic acid with 3-(2'-chloro-6'-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride.

Action and Uses

Flucloxacillin is a new isoxazolyl penicillin. Like cloxacillin it is acid stable and well absorbed after oral administration, and earlier work has shown that serum levels are twice as high as those obtained after an equivalent oral dose of cloxacillin. Flucloxacillin is active against staphylcocci, streptococci and pneumococci. It is stable to staphylococcal penicillinase. Indications; Infections due to sensitive gram-positive organisms, including infections affecting skin, respiratory tract, and ear, nose and throat.

Dosage

Orally or intramuscularly: Adults, 250 mg four times a day Children (2 to 10 years), half the adult dose; (under 2 years), one quarter the adult dose. In severe infections, dosages may be safely increased. Oral doses should be taken one hour before meals.

Supplied as

Capsules and vials, 250 mg (flucloxacillin, as the monohydrate of the sodium salt).

Manufacturer

Beecham Research Laboratories (England)

Proprietary Name

Floxapen

References

1. Beecham Research Laboratories. Brit pat 978,299. 2. Med Act (Drugs of Today) 7 (1), 18-21 (1971). (Review with 5 references)

Flucrylate (USAN)

BA 4197 MBR 4197

Flucrilate (Rec INN). Flucrilatum (Lat). Flucrilato (Sp) 2,2,2-Trifluoro-1-methylethyl 2-cyanoacrylate

Action

Flucrylate is a new fluoroalkyl cyanoacrylate surgical adhesive. In both rodent and dog experiments, this substance has proved to have high bond strength, good handling properties, improved flexibility, and good hemostasis.

Manufacturer

Minnesota Mining and Mfg Co (USA)

References

1. JAMA 210, 713 (1969). 2. WHO Chron 24 (11), 529 (1970). 3. A new fluoroalkyl cyanoacrylate surgical adhesive. R. A. Nelson et al. Arch Surg 100,295-298 (1970).

Flufenisal (USA; Rec INN)

MK835

Flufenisalum (Lat) 4'-Fluoro-4-hydroxy-3-biphenyl carboxylic acid acetate 2-Acetoxy-5-(4-fluorophenyl) benzoic acid

Synthesis

Prepared by the reaction of 4-(4'-fluorophenyl)phenol with potassium carbonate and carbon dioxide at 175° C under pressure, and

81

subsequent acetylation with acetic anhydride and pyridine at 100°.

Description

Crystals, mp 134-137° (benzene).

Action

Flufenisal is related to aspirin structurally and pharmacologically. In most tests for analgesia in animals, flufenisal administered orally has been found to be twice as potent as aspirin and in equianalgesic doses appeared to produce substantially longer periods of analgesia. In a recent clinical study, it has been suggested that in some clinical conditions the drug may be effective in providing prolonged pain relief.

Manufacturer

Merck Sharp and Dohme (USA)

References

1. JAMA 209, 2044 (1969). 2. WHO Ch,on 24 (11), 530 (1970). 3. Merck and Co, Inc. S African Appl 67 01,021. 4. Analgesic efficacy of flufenisal in patients with episiotomy pain. S. Bloomfield et al. Fed Proc 29 (2), 686 (1970). 5. Clinical evaluation of flufenisal. a long-acting analgesic. S. Bloomfield et al. Clin Pha,mac The, 11 (5), 747-754 (1970).

Flumedroxone (BAN; Rec INN)

WC 537

17-Hydroxy-6α-(trifluoromethyl)-pregn-4-ene-3,20-dione acetate 6-Trifluoromethyl-17α-acetoxyprogesterone .

Synthesis

Flumedroxone is prepared in several steps from 17α-acetoxyprogesterone.

Description

White crystalline powder, mp 206º Very slightly soluble in water. [α]D =¨300 (in chloroform); UV max 234 µm [ε=15,600].

Action and Uses

Flumedroxone is useful as a prophylactic treatment for migraine.

Dosage

5 to 20 mg daily.

Supplied as

Sugar coated tablets, 10 mg.

Proprietary Names

Demigran

Manufacturer

Leo (Sweden, Denmark, Germany and Austria)

References

1. Lovens Kemiske Fabrik. Brit pat 905,694. 2. Med Act (Drugs of Today), 6 (5),178-181 (1970). (Review with 11 references)

Flunarizine (USAN; Ree INN)

R 14,950

Flunarizinum (Lat). Flunarieina (Sp) 1-Cinnamyl-4-[bis(p-fluorophenyl) methyl] piperazine

Action

Vasodilator

Manufacturer

Janssen Pharmaeeutiea (Belgium)

82

References

1. WHO Chron 24 (11). 530 (1970). 2. JAMA 212. 466 (1970) .

Flunidazole (USAN)

5 NI

Flunidazol (Rec INN). Flunidazolum (Lat) 2-(p-Fluorophenyl)-5-nitro-imidazole-1-ethanol 1-(2-Hydroxyethyl)-2-(p-fluorophenyl)-5-nitroimidazole

Synthesis

Prepared by the reaction of 2-(p-fluorophenyl)-4(5)-nitroimidazole with ethylene oxide in anhydrous acetic acid by means of boron trifluoride ethearate. Also, by the reaction of 2-(p-fluorophenyl)-4( 5)-nitroimidazole with β-ethoxyethyl tosylate at 170-5°, followed by hydrolysis of the reaction product with sulfuric acid at 100º.

Description

Crystals, mp 165-168º (benzene).

Action

Flunidazole is an antitrichomonal compound, which is rapidly absorbed in both man and dog after oral administration.

Manufacturer

Merck Sharp and Oohme (USA)

References

1. Merck Co, Inc. Belg pat 660,836; US pat 3,349,096; Neth Appl 6,605,106. 2. Excretion and metabolism of 1-(2-hydroxyethyl)-2-(p-fluorophenyl)-5-nitroimidazole-2-C14 in rat, dog and human. A. G. Zaechei et al. Fed Proc 29 (2), 677 (1970).

Fluocinonide (USAN; Prop

INN)

The former USAN for this compound was fluocinolide 6α,9-Difluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, cyclic 16,17-acetal with acetone, 21-acetate 16α,17α-lsopropylidene 6α-fluorotriamcinolone Fluocinolone acetonide acetate

Synthesis

6α-Fluorotriamcinolone is allowed to react with acetone in the presence of strong bases; the resulting 16α,17α-acetonide is treated with acetic anhydride3.

Action

Fluocinonide is a glucocorticoid.

Manufacturer

Syntex Laboratories Inc (USA)

Proprietary Name

Lidex

References

1. JAMA 214, 1693 (1970). 2. WHO Chron 25 (3), 133 (1971). 3. US pat 3,197,469. 4. B. J. Poulsen et al. J Pharm Sci 57 (6), 928-933 (1968).

83

Flurazepam Dihydrochloride

(Prop INN) RO 5-6901

7-Chloro-1-[2-(diethylamino) ethyl]-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride

Synthesis

Prepared from 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride.

Description

Pale yellow, crystalline compound, mp 190-220°. Freely soluble in alcohol and very soluble in water.

Action and Uses

Flurazepam dihydrochloride, a new benzodiazepine derivative, is a hypnotic agent useful in all types of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.

Supplied as

Capsules, 15 mg and 30 mg.

Dosage

The usual adult dosage is 30 mg before retiring.

Proprietary Name

Dalmane

Manufacturer

Roche Lab (USA)

References

1. F. Hoffmann La Roche. Neth Appl 6,401,335. 2. Med Act (Drugs of Today), 6 (6). 216 (1970). (Review with 7 references) 3. Metabolism of flurazepam, a benzodiazepine in man and dog. M. A. Schwartz and E. Postma. J Pharm Sci 59 (12), 1800-1806 (1970).

Fluspirilene (USAN; Rec INN)

R 6218 McN-JR-6218

8-[4,4-bis( p-Fluorophenyl)-butyl]-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one

Description

White to yellowish amorphous or crystalline solid, mp 187.5-190°. It is almost insoluble in water.

Action

Fluspirilene belongs to a new class of neuroleptic agents, the diphenylbutyl-piperidines, and has been extensively tested pharmacologically in animals where it has been found to be a potent and incisive neuroleptic. The drug is under clinical studies as a long-acting neuroleptic.

Manufacturer

Janssen (Belgium); McNeil Laboratories (USA)

Proprietary Name

IMAP-7

References

1. JAMA 211, 2148 (1970). 2. Janssen Pharm. US pat 3.238.216. 3. The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug. P. A. J. Janssen et al. Arzneim-Forsch 20 (11), 1689-1698 (1970). 4. Clinical evaluation of fluspirilene (R 6218), A long acting injectable neuroleptic. P. Sterkmans et al. elin Trials J 6, 19-25 (1969). 5. Experience with fluspirilene (R 6218). a long-acting neutoleptic. J. H. Van Epen. Psychiat Neurol Neurochir 73, 277-284 (1970). 6. Clinical study of an injectable long-acting neuroleptic agent: Fluspirilene (R 6218). L. A. Onkenhout and W. Scheffer. Psychiat Neurol Neurochir 73, 285-291 (1970).

84

7. Joint clinical study of the long-term neuroleptic drug fluspirilene. H. Immich et al. Arzneim-Forsch 20 (11), 1699-1701 (1970).

Flutiazin (USAN; Rec INN)

Flutiazinum (Lat). Flutiazina (Sp) 8-(Trifluoromethyl)phenothiazine-1-carboxylic acid

Synthesis

Prepared by the reaction of 3-amino-4-mercapto-benzotrifluoride with potassium carbonate and 2-bromo-3-nitrobenzoic acid in refluxing dimethylformamide.

Description

Crystals, mp 248-250°. The ethyl ester melts at 95-96°.

Action

Flutiazin is a new anti-inflammatory agent for veterinary use.

Manufacturer

Smith Kline and French Laboratories (USA)

References

1. JAMA 209, 926 (1969). 2. WHO Chron 24 (11), 530 (1970). 3. Smith Kline and French. Brit pat 1,085,926. 4. Some anti-inflammatory properties of 8-trifluoromethylphenothiazine-carboxylic acid. H. Birnie et al. Med Pharmac Exp 17 (1), 51-59 (1967).

Formocortal

3-(2-Chloroethoxy)-9α-fluoro-11β,16α,17,21-tetra hydroxy-20-oxo-pregna-3,5-diene-6-carboxaldehyde, cyclic 16,17-acetal with acetone, 21-acetate

Synthesis

Prepared in two steps from 9α-fluoro-∆4-pregnen-11β,16α,17α,21-tetrol-3,20-dione-16,17-acetonide-21-acetate, the last one being the reaction of 3-(2'-chloroethoxy)-9α-fluoro-∆3,5-pregnadien-11β,16α,17α,21-tetrol-20-one-16,-17-acetonide-21-acetate with dimethylformamide and phosphorus oxychloride.

Description

White crystalline powder, mp 180-182º (ether-petroleum ether). UV max 217 µm [ε=12,100] and 323 µm. [ε=17,100] in ethanol. [α]D = 260 (c=1 in chloroform).

Action and Uses

Formocortal is a new highly active topical anti-inflammatory agent, just marketed in England and Italy. The clinical indications are those of other topical anti-inflammatory steroids.

Supplied as

Cream, ointment, lotion and spray, 0.025%. Also, cream: formocortal, 0.025% and amminosidine, 0.5%.

Manufacturer

Farmitalia

Proprietary Names

Fluderma and Deflamene.

References

1. Societa Farmaceutica Italia. Brit pat 1.059.603. 2. Mad Act (Drugs of Today) 7(1). 22-23(1971). (Review)

85

Fosfomycin (USAN; Prop INN)

MK 955

Phosphonomycin (-)-cis-1 ,2-Epoxypropyl phosphonic acid

Production Fosfomycin is a new antibiotic produced by several species of Streptomyces.

Description

The calcium salt (C3H5O4PCa.H2O) is a crystalline powder, mp up to 250º ; soluble in water (7 mg/ml); [α]D=3.8 (c = 7, in water).

Action

Fosfomycin appears to be a promising broad spectrum antibiotic, effective orally and parenterally against various gram-negative and grampositive bacteria. It is under clinical studies.

Manufacturer

Fosfomycin is a development of Merck Co (USA) in co-operation with Compania Espanola de Penicilina y Antibioticos SA (Spain)

References

1. JAMA 214, 1693 (1970) . 2. WHO Chron 25 (3), 134 (1971) . 3. D. Hendlin et al. Science 166, 122 (1969) . 4. Fosfomycin: isolation from fermentation sources. L. Chaiet et al. J Antibiotics 23 (7). 336-347 (1970). 5. Phosphonomycin I. Discovery and in vitro biological characterization. E. O. Stapley et al. Antimicrob Agents Chemother-1969, p 284-290 (1970). 6. II. Fermentation studies. M. Jackson and E. O. Stapley. Antimicrob Agents Chemother-1969, p 291-296 (1970) . 7. III. Evaluation in vitro. D. Handlin et al. Antimicrob Agents Chemother-1969, p 197-302 (1970) . 8. IV. Susceptibility testing method and survey. S. B. Zimmerman et al. Antimicrob Agents Chemother-1969, p 303-309 (1970).

9. V. Evaluation in mice. A. Kathrine Miller et al. Antimicrob Agents Chemother-1969, p 310-315 (1970). 10. Pharmacodynamics of phosphonomycin after intravenous administration in man. E. L. Foltz and H. Wallick. Antimicrob Agents Chemother-1969, p 316-321 (1970). 11 . Pharmacodynamics of Phosphonomycin aftel olal administration in man E. L. Foltz et al. Antimicrob Agents Chemother-1969, p 322-326 (1970). 12. Preliminary clinical trials with phosphonomycin. W. J. Holloway et al. Antimicrob Agents Chemother-1969, p 327-331 (1970) . 13. Clinical pharmacology and in vitro activity of phosphonomycin. D. G. Kestle and W. M. M. Kirby. Antimicrob Agents Chemother-1969. p 332-337 (1970). 14. Evaluation of phosphonomycin. a new cell wall-active antibiotic. H. Clark et al. Antimicrob Agents Chemother-1969, p 338-342 (1970) 15. Acute gonococcal urethritis: Failure of response to phosphonomycin therapy. P. M. Southern et al. Antimicrob Agents Chemother-1969, p 343-345 (1970). 16. Activity of phosphonomycin in nasal carriers of coagulase-positive staphylococci. J. W. Smith and J. P. Sanford. Antimicrob Agents Chemother-1969, p 346-348 (1970). 17. Efficacy of phosphonomycin in treatment of urinary-tract infections. J. A. Barnett et al. Antimicrob Agents Chemother-1969 p 349-351 (1970).

Fubromegan

Diethyl (3-hydroxybutyl) methylammonium iodide, 5-bromo-2-furoate 1-Methyl-3-diethylaminopropyl-5-bromofuroate methyl iodide α-Methyl-γ-(diethylamino) propyl 5-bromofuran-2-carboxylate methyl iodide

Action

Fubromegan is used clinically for bronchial asthma and gastric ulcers. Recent pharmacological studies have shown the drug to have a broader profile of antiarrhythmic activity than procainamide.

86

Antiarrhythmic properties of fubromegan on various types of experimental arrhythmias.

References

V. M. Samvelyan and M. V. Lvov. Farmakol Toksikol. 33 (3). 309-313 (1970).

Fumigachlorin

Production

From the fermentation broth of a fungus, identified as Sartorya fumigata var spinosa (Aspergillus ficheri var spinosus).

Description

Colorless needles, mp 112-113°. [ α]D = -77.5° (c=1, in chloroform). UV max 238 µm [E(1%, 1 cm) = 383], 273 µm [E(1 %, 1 cm) = 225] and 325 µm [E(1 %, 1 cm) = 217].

Action

Fumigachlorin is a new antibiotic which is principally active against filamentous fungi, but inactive against yeasts and bacteria.

Toxicity

LD50 po in mice: 18.5 mg/kg; ip: 4.6 mg/kg.

Manufacturer

Toyo Jow Co, Ltd (Japan)

References

Fumigachlorin a new antifungal antibiotic. K. Atsumi et al. J Antibiotics 23 (4), 223-224 (1970).

Funiculosin

Production

Obtained from the fermentation of Penicillium funiculosum, lAM 7013 strain.

Description

Colorless needles, which decomposeat 154-155°. UV absorption max 290 µm [ε=5,500].

Action

Funiculosin is a new antifungal antibiotic.

References

Jap. Med Gazz. 7 (4), 12 (1970).

Gamolenic Acid (Rec INN)

Acidum gamolenicum (Lat). Gamolenico acido (Sp) cis,cis,cis-6,9,12-octadecatrienoic acid γ-Linolenic acid

Synthesis

By hydrogenation of the corresponding acetylenic acid in the presence of a selective catalyst2.

Action

Gamolenic acid is an essential fatty acid.

References

1. WHO Chron 24 (11), 526 (1970). 2. Roche Products Ltd. Brit pat 859,897. 3. J. M. Osbond et al. Proc Chem Soc, 221 (1960). 4. J. M. Osbond et al. J Chem Soc, 2779 (1961).

GC 4072 SD 7859 ENT

24969

Chlorfenvinphos Diethyl-1-(2,4-dichlorophenyl)-2-chlorovinyl phosphate

87

Description

Light amber-colored liquid with a density of 1.345 and bp 167-170º (0.5 mm). It is soluble in most organic solvents and sparingly soluble in water.

Action

GC 4072 is a new organophosphate pesticide. Toxicologic studies on this compound have been undertaken in several animal species to characterize toxicity and assess safety·.

Manufacturer

Allied Chemical Co (USA)

References

1 . US pat 3,003.916. 2. Toxicologic studies on diethyl-1-(2.4-dichlorophenyl)-2-chlorovinylphosphate. A. M. Ambrose et al. Toxicol Appl Pharmacol 17, 323-336 (1970).

Geldanamycin

Production

It has been discovered in the culture filtrates of Streptomyces hygroscopicus var geldanus, var nova.

Description

Yellow needles, mp 252-255º; [α]D = +55° (c=0.638 in chloroform).

Action

Geldanamycin is a new antibiotic which is moderately active in vitro against protozoa, bacteria and fungi.

Manufacturer

The Upjohn Co (USA)

References

1 . Geldanamycin, a new antibiotic. C. DeBoer et al. J. Antibiotics 23 (9), 442-447 (1970).

Genimycin

Production

Genimycin is a new antibiotic isolated from the fermentation materials of a soil culture, which has been isolated and classified as belonging to the germs of Actinosporangium.

Action

Genimycin possesses antifungal activity.

Toxicity

LD50 ip in mice: 17 mg/kg.

Manufacturer

Leningrad Institute for Antibiotics (USSR)

References

Genimycin, iI membero f a new group of antifungal pentaenic antibiotics. L. Va. Severinets et al. Antibiotiki 15, 5-9 (1970).

Germine-3-acetate GMA

MK-981

88

Synthesis

Prepared by esterification of the natural alkaloid germine1.

Description

Needles, mp 219-221° (ether); [ α]D = +100 (c=1.05 in pyridine).

Action

Germine-3-acetate has been found to have typical veratrinic effects in frog and cat neuromuscular preparations but relatively little effect on the central nervous and cardiovascular systems. The neuromuscular pharmacology of the drug has been recently described. It has proved to be useful in the treatment of myastenia gravis and neuromuscular disorders.

Manufacturer

Merck (USA)

References

1. S. M. Kupchan and C. R. Narayanan. J Am Chem Soc 81,1913-1924 (1959). 2. The neuromuscular pharmacology of germine-3-acetate and germine 3.16-diacetate. F. G. Standaert and P. B. Detwiler. J Pharmacol Exp Thar 171,223-241 (1970) . 3. The effects of germine monoacetate in patients with myasthenia gravis. W. Flacke and R. P. Blume. Fed Proc 29. 194 (1970). 4. Med World News 11 (19), 23 (1970).

Gestaclone (USAN; Rec INN)

SH 1040

Gestaclonum (Lat). Gestaclona (Sp) 17β-Acetyl-6-chloro-1β,1α,2β,8β,9α,10,11,12,13,14α,15,16β,16α,17-

tetradecahydro-10β,13β-dimethyl-3H-dicyclopropa[1,2:16,17] cyclopenta [α] phenanthren-3-one 6-Chloro-1,2α:16,17α-bis methylene-∆4,6-pregnadiene-3,20-dione 6-Chloro-dicyclopropa [1,2:16,17]-6-dehydro-progesterone

Synthesis

The reaction of 1,2-α-methylene-∆4,6,16 pregnatriene-3, 20-dione with trimethylsulfoxonium iodide and sodium hydride in dimethylsulfoxide, or with diazomethane in ether-methylene chloride gives an intermediate which is allowed to react with m-chloroperbenzoic acid in etherethylene chloride giving an epoxide derivative which in turn reacts first with dry hydrogen chloride in anhydrous acetic acid, then with refluxing collidine, and finally with potassium hydroxide in refluxing methanol to give 6-chloro-1,2α:16,17α-bis methylene-∆4,6-pregnadiene-3,20-dione.

Description

Crystals, mp 231-232° (ethyl acetate). UV max 282 µm [ε = 17,100] in methanol.

Action

Gestaclone is a progestogen.

Manufacturer

Schering AG (West Berlin)

References

1. JAMA 210, 713 (1969). 2. WHO Chrcn 24 (11), 530 (1970). 3. Schering AG. Brit pat 1,095,958.

Glydanile Sodium (USAN)

SH 1051

Glidanile (Prop INN). Glidanilum (Lat). Glidanilo (Sp)

89

5'-Chloro-2-[p-[(5-isobutyl-2-pyrimidinyl) sulfamoyl] phenyI]-o-acetanisidide monosodium salt

Action

Glydanile sodium is a new oral hypoglycemic drug.

Manufacturer

Schering AG (Germany)

References

1. JAMA 210, 714 (1969). 2. WHO Chron 24 (3), 129 (1970). 3. Schering AG. S African Appi 6806,929,

Go 2825

2-(1-Piperidino)-2-(2-thenyl) ethylamine maleate

Description

Colorless crystalline substance, mp 115-117°; soluble in water at pH 6-7 and in alcohol.

Action

Go 2825 has been found to possess an antidepressant property. The toxicopathological effects of the compound in laboratory animals have been evaluated.

Manufacturer

Ciba Pharmaceutical Co (USA)

References

Toxicopathologic studies of a piperidino thenyl ethylamine (ClBA Go 2825). R. Rao Rupanagudi et al. JET (2), 110-115 (1970).

Gougeroxymycin

Production

Obtained from thefermentation culture of a streptomyces, strain MA 428 CI, which resembles Streptomyces gougeroti.

Description

White powder, mp 103-105°.

Action

Gougeroxymycin is a new antifungal antibiotic.

References

Jap Med Gazz 7 (4), 6-7 (1970).

HA 966

3-Amino-1-hydroxy-2-pyrrolidinone 1-Hydroxy-3-amino-2-pyrrolidinone

Synthesis

Prepared by cyclization of γ-bromo, γ-p-tosyloxy-,or γ-mesyloxy-α-aminobutylhydroxamic acid with LiOH. Also by reaction of γ-chloro-α-aminobutyric acid methyl ester with hydroxylamine, followed by cyclization with a base.

Description Crystals, mp 182-183° (ethanol).

Action HA 966 possesses muscle-relaxant, tranquillizing and anticonvulsant effects. It has been shown to produce effects similar to those ascribed to L-dopa in patients with extrapyramidal disorders.

Manufacturer

Organon (Holland)

90

References

1. N. V. Organon. Belg pat 629,596 and 660,704, 2. HA 966. I Behaviour and motor effects. I. L. Bonta et al. Arch int pharmacodyn 182 (2), 391-393 (1969). 3. HA 966. II Extrapyramidal aspects. I. L. Bonta et al. ibid 182 (2),394-395 (1969). 4. HA 966, III, Neurochemical aspects. F. C. Hillen et al. ibid 182 (2), 396-397 (1969). 5. HA 966 IV Clinical aspects. K. H. M. Van Der Velden. ibid 182 (2), 398 (1969).

Haloprogin M 1028

3-lodo-2-propynyl-2,4,5-trichorophenyl ether 2,4,5-Trichlorophenyl-γ-iodopropargyl ether

Synthesis

By Seki et al as part of a series of new acetylenic compounds closely related to capillin and lenamycin1.

Description

Crystals, mp 113-114°.

Action

Haloprogin possesses potent antifungal activity both in vitro and in vivo. Its spectrum of activity also includes yeast, yeastlike fungi, and grampositive bacteria. Based on its broad spectrum of antimicrobial activity, haloprogin may prove to be a superior topical agent in the treatment of dermatophytic and monilial infections in man.

Manufacturer

Meiji Seika Kaisha Ltd (Japan)

Proprietary Name Halotex (Mead Johnson, USA); Polik (Meiji Seika Kaisha, Japan)

References

1. S. Seki et al. Agr BioI Chem (Tokyo) 27, 150-151 (1963). 2. S. Seki et al. Antimicrob Agents Chemother 569-572 (1963).

3. Haloprogin: a topical antifungal agent. E. F. Harrison et al. Appl Microbiol19 (5), 746-750 (1970).

Harpagoside

Isolation From the roots of Harpagophytum procumbens1,2.

Description

Colorless hygroscopic powder, with bitter taste, mp 116-121°. UV max 215.5 µm (lg ε = 4.19), 221.5 µm (Igε = 4.12) and 276 µm (Igε = 4.36).

Action

In the granuloma pouch test and in the rabbit ear test for analgesic activity harpagoside has proved to produce an effect similar to phenylbutazone. In contrast to phenylbutazone no activity has been found with the following screening methods: edema of the rat paw produced by ovalbumin, formalin produced edema and formalin-induced arthritis.

References

1. H. Licht; et al. Tetrahedron Letters 15, 835-843 (1964). 2. H. Lichti et al. Helv Chim Acta 49 (5), 1552-1580 (1966). 3. On the antiphlogistic, analgesic and spasmolytic effects of harpagosid a glycoside from the root of harpagothytum procumbens DC. O. Eichler and Ch Koch. Arzneim-Forsch 20 (1), 107-109 (1970).

Homprenorphine (BAN, Prop

INN) R&S 5205-M

22-Cyclopropyl-7α-((R)-1-hydroxy-1-methylpropyl)-6,14-endo-ethenotetrahydrothebaine

91

Action

Homprenorphine is a new analgesic agent.

Manufacturer

Reckitt and Sons (England)

References

1. Chem Drug 194, 446 (1970). 2. WHO Chron 25 (3), 135 (1971). 3. N. Schmiedeberg. Arch Exp Path 259 (2), 154 (1968).

Hoquizil Hydrochloride

(USAN) CP14,185-

1

4-(6,7-Dimethoxy-4-quinazolinyl)-1-piperazinecarboxylic acid 2-hydroxy-2-methylpropyl ester hydrochloride

Synthesis

Prepared from 4-chloro-6,7-dimethoxy-quinazoline.

Description

Crystals, mp 199-200° (chloroform-ethylacetate).

Action

Hoquizil hydrochloride is a new oral bronchodilator, which has been discovered as a metabolite of CP-12,521-1 (the corresponding isobutylester). The bronchodilator effects of the drug are the result of direct relaxation of respiratory smooth muscle.

Manufacturer

Chas Pfizer and Co (USA)

References

1. Pfizer Co, Inc. S African pat 67 06,512. 2. Hoquizil-a new 01al bronchodilator. A double blind, randomized, coded clinical study using body plethysmography. B. Scillitani et al. Acta Anaesth Scandinav Suppl 37. 299-302 (1970).

HS 2314

4-(3,4-Dihydro-2-phenyl-1-naphthyl)-1-methylpiperidine 1-(4-Methylpiperidino)-2-phenyl-3, 4-dihydronaphthalene

Synthesis

Starting by a Grignard reaction of 2-phenyltetralone with 4-chloro-N-methyl piperidine. The free base melts at 118-119°; the hydrochloride salt at 258-262°.

Action

Sedative, tranquilizer.

Manufacturer

Merck AG (Germany)

References

1. E. Merck AG. Neth Appl 6.413.199. 2. G. Sierra et al. Int J Neuropharmacol B (2). 153-160 (1969).

92

3. Effects of different sedatives on self-ratings depending on sex and personality. P. Mikus. Arzneim-Forsch 20 (9 ). 1235-1238 (1970).

Hycanthone Hydrochloride

(USAN) Win 24933

Hycantone (Rec INN) 1-[[2-(Diethylamino) ethyl] amino] 4·(hydroxymethyl) thioxanthen·9·one

Production

By the fermentation of 1-(2·diethylaminoethylamino)-4·methyl·thioxanthen·9·one with Aspergillus sclerotiorum (SWRI A26) in an appropriate culture medium.

Description

Orange·yellow microcrystals, mp 173-176º (dec). The free base melts at 92.5-95.4º.

Action

Hycanthone has been reported to be schistosomicidal in the mouse, hamster and monkey2,3,4. The drug is under clinical trials5-8.

Manufacturer

Sterling Winthrop (USA)

References

1. D. Rosi et al. (to Sterling Drug, Inc). US pat 3,312,598_ 2. D. Rosi et al. Nature 208, 1005-1006 (1965). 3. D. A. Berberian et al. Arner J trop Med Hyg 16, 487-491 (1967). 4. J. Pellegrino et al. J Parasit 53, 55-59 (1967). 5. N Katz et al. Arner J trop Med Hyg 17, 743·746 (1968). 6. V. V. Clarke et al. Centr Air J Med 15, 1-6 (1969).

7. Preliminary clinical trials with hycanthone, a new antischistosomal agent. N. Katz et al. Arner J trop Med Hyg 17 (5), 743-746 (1968). 8. Further clinical trials with hycanthone, a new antischistosomal agent. N. Katz et al. Arner J trop Med Hyg 18 (6),924-929 (1969). 9. The uptake of tritiated hycanthone by male and female schistosoma mansoni worms and distribution of the drug in plasma and whole blood of mice following a single intramusculat injection. A. Yarinsky et al. Bull Org rnond Sante 42, 445-449 (1970).

Hydrocortisone 17-Butyrate

Action

Hydrocortisone 17-butyrate, a simple non-fluorinated modification of hydrocortisone, shows remarkable skin penetration and offers promise as a dermatological corticosteroid.

Manufacturer

Royal Netherlands Fermentation Industries Ltd (Netherlands)

References

1. Hydrocortisone 17-butyrate, a new corticoid with a favourable ratio of topical vs systemic activity. K. D. Jaitly et al. Third International Congress on Hormonal Steroids, abst 365. Excerpta Medica, International Congress Series No 21 0 (1970).

93

2. Clinical trial with hydrocortisone butyrate. M. K. Polano et al. Br J Derm 83, 93-97 (1970).

Hydrotalcite (Rec INN)

Hydrotalcitum (Lat). Hidrotalcita (Sp) Aluminum magnesium hydroxyde carbonate hydrate

Description

Synthetic mineral crystalline substance.

Action

After oral ingestion, hydrotalcite produces and maintains for a long time, an optimum pH in the gastric juice.

Manufacturer

Kyowa Chemical Industry Co, Ltd (Japan)

Proprietary Name

HITI

References

1. WHO Chron 24 (11), 530 (1970). 2. Jap Med Gaz 7 (4), 4 (1970). 3. Process for the preparation of hydrotalcite antacid. Kyowa Chem Industries. US pat 3,539,306.

2 5-HydroxycholecaIciferol

Isolation and Synthesis 25-Hydroxycholecalciferol is one of the biologically active metabolites of vitamin D3, which was extracted from plasma of pigs which had been fed large amounts of regular vitamin D3. The synthesis of 25-HCC was completed by irradiation of cholesta-5,7-diene-3β,25-diol.

Biological Activity By antirachitic assay in both rats and chickens, 25-HCC has proved to be 1.5 times more biologically active than cholecalciferol. When tested for its ability to stimulate calcium transport, it was not only more effective, but produced a response more rapidly than does a similar dose of vitamin D3. 25-HCC is under clinical study.

References

1. J. W. Blunt and H. F. De luca. Biochem 8 (2), 671-674 (1969). 2. Med Act (Drugs of Today) 6 (3), 102-105 (1970). (Review with 7 references) 3. Treatment of vitamin D·resistant hypoparathyroidism with 25-hydroxycholecalciferol. Charles Y. C. Pak et al. Arch Intern Med 126 (2), 239-247 (1970). 4. 25-Hydroxycholecalciff'rol. Effet d'une dose unique chez I'enfant normal. Sonia Balsan et al. Rev Europ Etudes elin Biol15 (5), 515-521 (1970). 5. Treatment of renal osteodystrophy with 25-hydroxycholecalciferol. H. F. Deluca et al. Arch Intern Med 126,896-899 (1970).

25-Hydroxydihydrotachysterol3

94

Synthesis

By lithium-ammonium reduction of 25-hydroxytachysterol,

Action

It is a potent bone mobilization agent. Its biological activity suggests that it may be the drug of choice in the treatment of hypoparathyroidism and other similar bone diseases.

References

25-Hydroxydihydrotachysterol: synthesis and biological activity. T. Sude et al. Fed Proc 29. 367 (1970).

L-255

1-(2-Piperidinoethyl)-4,4-bis-( p-methoxyphenyl)-2,5-imidazolidinedione hydrochloride 3β-(1-Piperidino )ethyl-5,5-bis (p-methoxyphenyl) hydantoine hydrochloride

Synthesis

Prepared from 4,4-bis (p-methoxyphenyl)-2,5-imidazolidinedione and β-piperidinoethyl chloride in the presence of sodium amide1.

Description

Crystals, mp 130º dec. UV max at about 230 and 213 µm

Action

L-255 is a spasmolytic agent. Some pharmacodynamic properties of this compound have been recently reported.

Manufacturer

Instituto Biochimico Italiano Sperimentale (IBIS)

References

1. W. Chiti et al. Farmaco (Ed Sci) 15. 809 (1960). 2. Report on some pharmacodynamic properties of 1-(2-piperidinoethyl)-4,4-bis-(p-methoxyphenyl)-2.5-imidazolidinedione chlorhydrate (1255). Studies of its effect on the muscular system of duodenum. gall and urinary bladder uterus and trachea. E. Marmo and A. Annunziata. Arzneim-Forsch 20. 277-281 (1970).

Imidocarb Hydrochloride

(USAN; Prop INN) 4A65

Imidocarbum (Lat). Imidocarbo (Sp) 3,3'-di-2-Imidazolin-2-ylcarbanilide dihydrochloride

Synthesis

By the reaction of m-aminophenylimidazoline with phosgene in dimethylformamide. The product obtained melts at 370º (dec)3.

Action

Antiprotozoal (babesicidal).

Manufacturer

Burroughs Wellcome (USA)

References

1. JAMA 211,2149 (1970). 2. WHO Chron 24 (9), 424 (1970). 3. Dr A Wander AG. Brit pat 1,007,334. 4. Babesicidal effect of basically substituted carbanilides. II. Imidocarb in rats and mice: toxicity and activity against Babesia rodhaini. E. Beveridge. Res Vet Sci 10 (6), 530 (1969).

95

Indolacin

1-Cinnamoyl-2-methyl-5-methoxy-indolyl-3-acetic acid

Synthesis

By the reaction of cinnamoyl chloride with p-methoxyphenylhydrazine hydrochloride and triethylamine in toluene at 5º to 0°, and by the reaction of the resulting intermediate hydrazine hydrochloride with levulinic acid in acetic acid at 80-85°.

Description

Crystals, mp 164-165° (acetone-water). The ethyl ester, mp 162-163° (acetone-water).

Action

Indolacin exhibits anti-inflammatory, antipyretic and analgesic activities.

Manufacturer

Sumitomo Chemical Co, Ltd (Japan)

References

1. Sumitomo Chemical Co, Ltd. S African Appl 67,02,683. 2. Sogo Rinsho 19, 427 (1970) .

Indoramin (BAN; Prop INN)

Wy 21901

3-[2-(4-Benzamido-1-piperidyl) ethyl] indole

Synthesis

Prepared in three steps from 4-aminopyridine and benzoylchloride.

Description

Crystals, mp 208-210º (ethanol).

Action

Indoramin is a new antihypertensive agent.

Manufacturer

Wyeth (England)

References

1. Chem Drug 194, 446 (1970).

2. WHO Chron 25 (3), 135 (1971). 3. Chim Ther 3, 397 (1968). 4. John Wyeth and Brother Ltd. S African Appl 6803,204.

Indriline Hydrochloride (Rec

INN) MJ1986

Indrilinum (Lat). Indrilina (Sp) N, N-Dimethyl-1-phenyl-indene-ethylamine hydrochloride 1-(2-Dimethylaminoethyl)-1-phenylindene hydrochloride

96

Synthesis

Prepared by the reaction of sodium 3-phenylindene with β-dimethylaminoethyl chloride2,3.

Description

White prisms, mp 203-204.5°.

Action

Indriline, a stimulant and antidepressant in the preclinical profile, has no antidepressant properties clinically, although it shows stimulant properties4.

Manufacturer

Mead Johnson (USA)

References

1. WHO Chron 24 (11). 530 (1970). 2. C. R. Ganellin et al. Chem Ind (London) 28, 1256-1257 (1965). 3. S. J. Dykstra et al. J Med Chem 10 (3).418-428 (1967). 4. The clinical evaluation of four proposed antidepressants. Relationship to their animal pharmacology. L. J. Hekimian at al. Int Pharmacopsychiat 3. 65-76 (1970).

Inokosterone

Description

Screening of Israeli plants for insect moulting hormones (ecdysones) has led to the isolation and identification of inokosterone from Achyrantes species. Insect hormones (phytoecdysones) from Israeli plants.

References

R. Ikan et al. Israel J Chem 8 Suppl Proc Israel Chem Soc (1970).

Intrazole (USAN; Rec INN)

BL-R 743

1-(p-Chlorobenzoyl)-3-(1 H-tetrazol-5-ylmethyl) indole 5-[1-(p-Chlorobenzoyl)-3-indolylmethyl] tetrazole

Synthesis

Prepared by treating 5-(3-indolylmethyl) tetrazole with sodium hydride and p-chlorobenzoyl chloride.

Description

Crystals, mp 233-234°.

Action

Intrazole is a new non-steroid anti-inflammatory compound.

Manufacturer

Bristol Laboratories (USA)

References

1. JAMA 211,819 (1970). 2. WHO Chron 24 (3), 129 (1970). 3. Bristol Myers Co. Neth Appl 6,609,235. 4. D. R. Van Harken. Pharmacologist 11 (2), 241 (1969).

lOB 82

3-[Bis(2-chloroethyl)amino]-p-toluic acid 4-Methyl-3-N,N-bis(2-chloroethyl) aminobenzoic acid

97

Synthesis

Prepared by the reaction of ethyleneoxide with 3-amino-3-methylbenzoic acid methyl ester, followed by treatment with phosphorus oxychloride, and hydrolysis of the ester group with hydrochloric acid.

Description

lOB 82 melts at 115º (Iigroine).

Action

lOB 82, a new cytostatic drug, is an alkylating agent with pronounced antitumor activity on a spectrum of 10 experimental tumors which have varying hystologic structures and degrees of sensitivity. Efficient doses of the drug have been proved to be well-tolerated by the organism.

Toxicity

LD50 ip in rats: 17.4 mg/ kg.

Manufacturer

Oncological Institute, Bucharest (Romania)

References

1. I. Niculescu-Duyaz et al. J Med Chem 11 (3). 500-3 (1968). 2. Romania, Ministry of the Chemical Industry. Rom pat 51,132, 3. 3-N,N-bis (2-chloroethylamino) p-toluic acid, a new cytostatic drug active in cancer. V. Dobre and G. Maltezeanu. Cancer Chemother Rep (part 1) 54(5), 319-323 (1970).

Iphosphamide (Rec INN)

Z4942

Ifosfamide. Ifosfamidum (Lat). Ifosfamida (Sp) 3-(2-Chloroethyl)-2-(2-chloroethylamino)-tetrahydro-2H-1,3,2-oxazophosphorin-2-oxide

Action

New cyclophosphamide cytostatic drug, which has been shown to be effective in clinic.

Manufacturer

Asta-Werke AG (Germany)

References

1. WHO Chron. 24 (11), 530 (1970). 2. Results obtained with two new phosphamide derivatives. P. Drings et al. Deutsche Med. Wochenschr. 95 (10),491-497 (1970).

Ipronidazole (Rec INN)

2-lsopropyl-1-methyl-5-nitroimidazole

Synthesis

Prepared by nitration of 2-isopropylimidazole, and by methylation of the resulting nitroimidazole.

Description

White plates, mp 60º

Action

Ipronidazole has been reported to be highly effective and well tolerated in the prevention and therapy of turkey histomoniasis. In addition it has proved to be an effective growth promotant for turkeys.

Manufacturer

Hoffmann-La Roche Inc (USA).

References

98

1. Hoffmann-La Roche. Brit pat 1.119.636. 2. Antihistomonal activity of 1.2-disubstituted 5-nitroimidazoles. M. Mitrovic et al. Antimicrobial Agents and Chemotherapy. 445-448 (1968). 3. Antihistomonal activity of ipronidazole in turkeys. M. Mitrovic and E. G. Schildknecht. Poultry Sci 49 (1). 86-92 (1970). 4. Toxicity and safety studies with the antihistomonal agent. ipronidazole in turkeys. W. L. Marusich et al. Poultry Sci 49 (1). 92-98 (1970). 5. Ipronidazole. an antihistomonal agent as a turkey growth promotant. W. L. Marusich et al. Poultry Sci 49 (1), 98-101 (1970).

Isoprednidene

StC 407

11β,17α,21-Trihydroxy-16-methylene-pregna-4,6-diene-3,20-dione 6-Dehydro-16-methylene-hydrocortisone

Synthesis

16β-Methyl-16α,17α-oxido-4-pregnen-21-ol-3,20-dione 21-acetate is heated with chloranil. The resulting 17,21-dihydroxy-16-methylenepregna-4,6-diene-3,20-dione 21-acetate is hydroxylated in the 11β-position in a culture of Curvularia lunata.

Description

Crystals, mp 234-236º (acetone). Ultraviolet absorption maximum at 283 µm [ε=24,900]; [α]D = +81° (dioxane).

Action

ACTH inhibitor.

Manufacturer

E. Merck A.G. (Germany)

References

1. E. Merck AG. Ger pat 1.159.945. 2. H. J. Karl-L. Raith. Klin Wochenschr 48 (6), 347 (1970).

Isoprinosine NP 113

NPT 10381

Acetamidobenzoate salt of inosine-dimethylaminoisopropanol complex (1:3)

Action

Isoprinosine is a member of a new class of drugs, inosine-alkylamino alcohol compounds, which are claimed to enhance learning and to act against viruses in animals. The drug is being used in clinical trials.

Toxicity

LD50 in the mouse, rat and cat are greater than 5 g/kg.

Manufacturer

Newport Pharmaceuticals Inc (USA)

References

1. Chem Engin News 48 (22), 12 (25 May, 1970). 2. Med World News, 22 (17 April, 1970). 3. Med World News, 15 (14 August, 1970). 4. Inosine-alkylamino alcohol complexes: enhancement of avoidance learning in rats. B. Doty and P. Gordon. Fed Proc 29 (2), 684 Abs (1970). 5. Inosine-alkylamino alcohol complexes: enhancement of polyribosome function. P. Gordon. Fed Proc 29 (2), 684 Abs (1970). 6. Inosine-alkylamino alcohol complexes: anti-viral actions. E. R. Brown and P. Gordon. Fed Proc 29 (2), 684 Abs (1970). 7. The Pharmacologist 12 (2), 271 abst 389-390 (1970).

Janiemycin

99

Production

Janiemycin is a new peptide antibiotic produced by a strain of Streptomyces macroporeus isolated from soil.

Description

Amorphous, light tan powder.

Action

Janiemycin is a bactericidal compound, active primarily against gram-positive bacteria.

Manufacturer

Squibb (USA)

References

Janiemycin a new peptide antibiotic. E. Meyers et al. J Antibiotics 23 (10), 502-507 (1970).

Jatrophone

Isolation From Jatropha gossypii folia.

Description

Crystals, mp 152-153°; [ α]D = 292° (c=1,23 in ethanol). UV max 285 µm [ε=10.200]; sh 225 µm.

Action

Jatrophone, a novel macrocyclic diterpenoid, is a tumor inhibitor.

References

1. S. Morris Kupchan et al. Chem Eng News 48 (30), 42 (1970). 2. S. M. Kupchan et al. J Am Chem Soc 92. 4476 (1970).

JB 318

Benzilic acid, 1-ethyl-3-piperidyl ester N-Ethyl-3-piperidyl benzilate N-Ethyl-3-piperidyl diphenylglycolate

Synthesis

Prepared from N-ethyl-3-chloropiperidine and benzilic acid.

Description

The free base boils at 194-198° (0.12-0.18 mm Hg). The hydrochloride occurs as a white crystals, mp 186-187°.

Action

The Director of the Bureau of Narcotics and Dangerous Drugs has proposed that JB 318 be listed in the category of «depressant or stimulant » drugs subjected to control, because of their hallucinogenic effects.

References

1. Lakeside Laboratories, Inc. US pat 2,995,492. 2. J. H. Biel et al. J Am Chem Soc 77, 2250-6 (1965). 3. Fed Reg 35 (47), 4305-4306 (1970).

JB 336

Benzilic acid, 1-methyl-3-piperidyl ester N-Methyl-3-piperidyl benzilate N-Methyl-3-piperidyl diphenylglycolate

100

Synthesis

Prepared from N-methyl-3-chloropiperidine and benzilic acid.

Description

The free base boils at 175-176° (0.03 mm Hg). The hydrochloride melts at 212-213°.

Action

The Director of the Bureau of Narcotics and Dangerous Drugs has proposed that J B be listed in the category of «depressant or stimulant» drugs subjected to control, because of their hallucinogenic effects.

References

1. Lakeside Laboratories, Inc. US pat 2.995,492. 2. J . H. Siel et al. J Am Chem Soc 77. 2250-6 (1965). 3. Fed Reg 35 (47).4305-4306 (1970).

K 76

2-Methyl-3-(4-phenylpiperidino) propionohydroxamic acid hydrochloride

Action

K 76 is a new hypotensive agent. It has been suggested that this compound produces a fall in the blood pressure by blocking sympathetic ganglia.

References

1. β-Aminopropionohydroxamic acids and β-aminopropionic esters with hypotensive properties. R. T. Cautts et al. J Med Chem 12 (5). 940-941 (1969). 2. 2-Methyl-3-{4-phenylpiperidino) propionohydroxamic acid hydrochloride: a new hypotensive agent. K. K. Midha et al. Eur J Pharmacol 11. 48-55 (1970).

Kanendomycin Sulfate NK1006

2'-Amino-2'-deoxy-kanamycin sulfate 4-O[α-2',6'-Diamino-2',6'-dideoxy-D-glucopyranosyl(1')]-6-0-[α-3"-amino-3"-deoxy-D-glucopyranosyl (1")]-1,3-diamino-1,2,3-trideoxymyoinositol sulfate

Action and Uses

Kanendomycin is a new broad spectrum antibiotic, recently marketed in Japan. It was isolated from the culture medium of mutant strains of Streptomyces kanamyceticus.

Dosage

Kanendomycin Sulfate is administered intramuscularly. Adults, 400 to 600 mg daily in 2 to 3 divided doses. Children, 10 to 20 mg/kg per day in two divided doses,

Supplied as

Vials, 200 mg.

Manufacturer

Meiji Seika Kaisha Ltd (Japan).

References

Med Act (Drugs of Today) 6 (5), 181-182 (1970).

101

Ketamine Hydrochloride

(USAN; Rec INN) CI-

581

2-(o-Chlorophenyl)-2-methylaminocyclohexanone hydrochloride

Synthesis

The method for producing ketamine involves a rearrangement at 190º of the carbon skeleton of (o-chlorophenyl)-(hydroxycyclopentyl)(N-methylimino) methane, which manifests itself in a ring expansion. The compound used in the above reaction is prepared in several steps from o-chlorobenzonitrile and the Grignard reagent prepared from cyclopentylbromide and magnesium.

Description

White crystalline powder, mp 262-263°; it is freely soluble in water.

Action and Uses

Ketamine, an arycycloalkylamine, is a parenteral anesthetic agent with good analgesic properties.

Supplied as

Solution (injection). 11.53 mg/ml (equivalent to 10 mg of ketamine base). Solution (injection) 57.67 mg/ml (equivalent to 50 mg of ketamine base).

Proprietary Names

Ketalar and Ketanest.

Manufacturer

Parke Davis

References

1. Parke Davis Co. Brit pat 1.01.4 ,060. 2. Med Act (Drugs of Today) 6 (2),44-47 (1970). (Review with 21 references)

Kethoxal (USAN)

Ketoxal(Rec INN). Ketoxalum(Lat) 3-Ethoxy-1,1-dihydroxy-2-butanone 3-Ethoxy-2-oxobutyraldehyde hydrate

Action

Kethoxal has a broad spectrum of virucidal activity (except for the picornaviruses), and it is also highly active as an inhibitor of intracellular virus multiplication in vitro a nd in vivo.

Manufacturer

The Upjohn Co (USA)

References

1. WHO Chron 24 (11), 530 (1970). 2. Antiviral studies with Kethoxal. H. E. Renis. Ann NY Acad Sci 173 (Art 1), 527-535 (1970).

Ketimipramine (Rec INN;

USAN) G 35259

5-[3-(Dimethylamino)propyl]-5,11-dihydro-10H-dibenz[b,f] azepin-10-one

Synthesis

Prepared by the reaction of 10-methoxy-5H-dibenz [b,f] azepine with 3-(dimethylamino) propylchloride in the presence of NaNH2 followed by the hydrolysis of the methoxy group with HCI.

Description

102

Ketimipramine melts at 87º, and boils at 174º (0.005 mm).

Action

Ketimipramine is a new antidepressant, closely related to imipramine; it differs from the latter only in having a 10-keto group. Ketimipramine fumarate is under clinical trials, and so far has proved to be largely free of the troublesome side effects sometimes encountered with imipramine.

Manufacturer

J. R. Geigy AG (Switzerland)

References

1. J. R. Geigy AG. Ger pat 1.161,279. 2. Amer Druggist, 41 (Sept 21,1970).

KL 255

1-t-Butylamino-3-(6-chloro-m-tolyloxy)-2-propanol hydrochloride

Synthesis

Prepared from 2-chloro-5-methylphenyl glycidylether and tert-butylamine.

Description

Crystals, mp 224-225°.

Action

KL 255 is a potent beta receptor antagonist both in vitro and in vivo. An analysis of the mechanism for the in vivo myocardial depressant effects of this drug has been reported4. It has been suggested that they are due to a blockade of endogenously released catecholamines. The drug has been recently marketed in Germany.

Manufacturer

Pharma Schwarz GmbH (Germany); Smith Kline and French Laboratories (USA)

Proprietary Name

Betadrenol (Germany).

Supplied as

Tablets, 40 mg.

References

1. Wilhelm Kunz et al. US pat 3,309,406; Brit pat 1.147.032. 2. H. Jacobi and R. Fontaine. Fortschr Med 85, 749 (1967). 3. E. Waterloh et al. Arzneim-Forsch 19 (2). 153-156 (1969). 4. Studies on the myocardial depressant effect of KL 255: a beta adrenergic receptor antagonist. R. G. Pendleton et al. Arch Int Pharmacodyn Ther 187 (1).75-87 (1970).

Ko 592

ICI 45763

1-lsopropylamino-3-m-tolyloxy-2-propanol hydrochloride 1-(3-Methylphenoxy)-2-hydroxy-3-isopropyl-aminopropanehydrochloride

Description

Crystals, mp 120-121º (ethanol/ether).

Action

Ko 592 is a new potent and specific beta receptor antagonist, which has been recently marketed in Germany.

Supplied as

Tablets, 10 and 50 mg.

Manufacturer

C. H. Boehringer Sohn (Germany); ICI Ltd (England)

Proprietary Name

Doberol (Germany).

References

1. C. H. Boehringer Sohn. Neth Appl 6.409,883.

103

2. ICI Ltd. Neth AppI 301.580; Brit pat 1.079.534; Neth AppI 6.410.522. 3. J. V. Levy and V. Richards. Proc Soc Exp Biol Med 122. 373-379 (1966). 4. Cardiopulmonary actions of 1-isopropyl-3-(3-tolyloxy)-2-propanol hydrochloride: a new adrenergic beta receptor antagonist. B. R. Madan et al. Indian J Med Res 58. 246-252 (1970). 5. Effects of beta-blocking agent Ko 592 in massive doses upon catecholamines in arterial tissue and plasma and peripheral blood flow in anesthetized dogs before and after electric stimulation of sympathetic ganglia. E. N. Terry et al. J Cardiovasc Surg 11 (2). 146-150 (1970). 6. Wirkungen eines adrenergischen Beta-Receptorenb/ockers (KG 592) auf die Atmung. J. Hamm et al. Klin Wschr 48 (8).457-464 (1970).

Ko 1173

1-(2',6'-Dimethyl phenoxy)-2-aminopropane

Synthesis

Prepared by catalytic reduction of 1-(2,6-dimethylphenoxy)-2-propanone oxime. The hydrochloride melts at 203-205°.

Action

Pharmacological studies have indicated that Kö 1173 is as effective as phenytoin in experimental cardiac arrhythmias.

Manufacturer

Boehringer, Ingleheim (Germany),

References

1. C. H. Boehringer Sohn. Fr pat 1,551,055. 2. The effect on experimental cardiac arrhythmias of a new anticonvulsant agent, K6 1173, and its comparison with phenytoin and procainamide. J. D. Allen et al. Br J Pharmac 39 (1), 183P (1970).

KT 125

1-(p-Methoxyphenyl)-6,8-dimethylimidazoline[1,2-f] xanthine

Action

KT 125, chemically related to KT 136, shows hypertensive action.

References

Pharmacology of 6,8-dimethylimidazoline-[1,2-fJ-xanthines. V. V. Viasov and I. V. Komissarov. Farmakol Toxikol 33 (5), 582 (1970).

KT 136

1-Allyl-6,8-dimethylimidazoline[1,2-f]-xanthine

Action

KT 136 has proved to be a positive inotropic and respiratory analeptic agent

References

104

Pharmacology of 6,8-dimethylimidazoline [1,2-]xanthines. V. V. Vlasov and I. V. Komissarov. Farmakol Toxikoi 33 (5), 582 (1970).

L 7108

2-(3,4,5-Trimethoxybenzoyl) isoxazolidine

Action

Neurodepressant

Manufacturer

Lepetit SpA (Italy)

References

Neuro and psychopharmacological profile of a new compound L 7108. E. Arrigoni-Martelli et al. VII International Congress Collegium Internationale Neuro-Psychopharmacology, Prague, Czechoslovakia, Aug 11-15 (1970); abstr. 12.

Lapachol

2-Hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone

Synthesis

Lapachol is derived from the heartwood of certain Asian and South American biguoniaceous plants. The synthesis was reported by Fieser and Hooker2.

Description

Yellow crystalline material, mp 140º. Soluble in chloroform, alcohol, benzene and slightly soluble in ether.

Action

Lapachol was first investigated for vitamin K effect and for antimalarial activity. Recently, lapachol has proved to exhibit high antitumor activity against the Walker 256 carcinosarcoma tumor in rats3. The toxicology studies conducted prior to the clinical investigation have been reported4. The drug is now under clinical study as a cancer chemotherapeutic agent5.

Toxicity

LD50 po in the male mouse: 487 mg/kg; in the female: 792 mg/kg.

Manufacturer

Chas Pfizer and Co, Inc (USA)

References

1. J Am Chem Soc 49, 857 (1936). 2. J Am Chem Soc 58.1181 (1936). 3. K. V. Rao et al. Proc Am Ass Cancer Res 8. 55 (1967). 4. Oral toxicology studies with lapachol R. K. Morrison et al. Toxicol Appl. Pharmacol 17. 1-11 (1970). 5. Early clinical studies with lapachol. J. B. Block et al. Fed Proc 29 (2), 684 abst (1970).

Largomycin

Production

Largomycin is a new antibiotic isolated from the culture filtrate of Streptomyces pluricolorescens MCRL-0367. Three active components have been separated, of which largomycin FII was the most biologically active.

Description

Largomycin FII is an acidic yellow, amorphous powder. UV absorption max. 278 µm (in 0,1N HCI) and 540 µm (in 0,1N NaOH).

Action

Antitumor antibiotic.

Manufacturer

105

Tanabe Seiyaku Co, Ltd (Japan)

References

1. Studies on a new antitumor antibiotic, largomycin. 1 Taxonomy of the largomycin-producing strain and production of the antibiotic. T. Yamaguchi et al. j Antibiotics 23 (8), 369-372 (1970). 2. II. Isolation, purification and physicochemical properties. T. Yamaguchi et al. j Antibiotics 23 (8), 373-381 (1970). 3. III. Biological properties and antitumor activity of largomycin F-II. T. Yamaguchi et al. J Antibiotics 23 (8), 382-387 (1970).

LD 2855

2-Xylidino-2-oxazoline

Synthesis

Prepared by the condensation of xylidine with chloroethylisocyanate and subsequent treatment with water at 100°.

Description

White crystals, mp 81°; insoluble in water.

Action

LD 2855 was reported to exert antihypertensive effects in man. Its pharmacological properties are complex and have been described recently.

Manufacturer

Centre de Recherche Therapeutique (France)

References

1. Rene Giudicelli et al. Compt. rend. 247, 2494-7 (1958). 2. Henry Najer et al. Bull soc chim France, 352-359 (1959). 3. Henry Najer et al. Bull soc chim France, 1650-2 (1960).

4. Mechanism of the antihypertensive properties of LD 2855. Rene Giudicelli and Henri Schmitt. J Pharmacol 1(3),339-358 (1970).

Lentysine

Lentinacin meso-α,β-Dihydroxy-adenine-9-butyric acid meso-6-Amino-α,β-dihydroxy-9H-purine-9-butyric acid

Synthesis

Lentysine was first extracted from the mushroom lentinus edodes, and later its structure was established, and it was prepared by total synthesis starting from 2,3-O-isopropylidene-D-erythronolactone.

Description

Colorless needles, mp 279°; [ α]D = +50° (in 0.1 N sodium hydroxide) and [α]D = +10° (in N hydrochloric acid). UV max 261 µm [ε=14,300, in water and in 0,5 N sodium hydroxide]; 260 µm [ε=14,000 in 0,5 N hydrochloric acid].

Action

Lentysine has been shown to lower serum total cholesterol, phospholipids and triglycerides in animal experiments. It is under clinical trials.

Toxicity

LD50 ip in mice: 2,600 mg/kg; po in mice: 9,200 mg/kg; ip in rats: 1,600 mg/ kg and po in rats: 4,700 mg/ kg.

Manufacturer

Tanabe Seiyaku Co, Ltd (Japan)

References

1. Structure and synthesis of lentysine. a new hypocholesterolemic substance. T. Kamiya et al. Tetrahedron Lett 53, 4729 (1969).

106

2. Jap Med Gaz 6(12),10 (1969). 3. Lentysine: a new hypolipemic agent from a mushroom. T. Rokujo et al. Life Sciences 9, 379-385 (1970) .

Letimide Hydrochloride (USAN;

Prop INN) MA 1443

3-[2-(Diethylamino)ethyI]-2H-1,3-benzoxazine-2,4(3H)-dione hydrochloride

Synthesis

Prepared by the reaction of diethylaminoethylsalicylamide with ethyl chloroformiate.

Description

Crystals, mp 232-233° (methanol/ether).

Action

Letimide is an analgesic agent.

Manufacturer

Miles Lab Inc (USA)

References

1. JAMA 213, 1326 (1970). 2. WHO Chron 25 (3), 135 (1971). 3. Miles Lab Inc. Fr pat 1,536,546.

Levamisole R12564

L-Tetramisole

(-)-2,3,5,6-Tetrahydro-6-phenylimidazo [2,1-b]-thiazole

Description

The free base melts at 60-61.5º; the hydrochloride salt at 227-229º ; [α]D = -85.1° (c = 10, chloroform); [α]D = -124±2° (c = 0.9 in water).

Action

Levamisole is the physiologically active I (-) isomer of the broad spectrum veterinary anthelmintic tetramisole.

Manufacturer

American Cyanamid Co (USA), Janssen (Belgium)

Proprietary Name

Tramisol (American Cyanamid Co)

References

1. JAMA 212, 467 (1970). 2. A. H. M. Raeymaekers et al. Tetrahedron Lett 1467-1470 (1967). 3. American Cyanamid Co. Brit pat 1.120.406.

Levodopa Ro 5-4759

3-(3,4-Dihydroxyphenyl)-L-alanine β-(3.4-Dihydroxyphenyl)-α-alanine 2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid

L-Dopa is a natural amino a eid found in Vicia alba L. (velvet beans) and in seeds of Mucuna pruriens L.D.C. Leguminosae

Synthesis

Prepared from 3-(3,4-methylenedioxyphenyl)-L-alanine methyl ester1. A microbiological synthesis has recently been described which utilizes the inexpensive starting material L-tyrosine2.

107

Description

White crystalline powder, mp 276-278° (dec); slightly soluble in water, [α]D = -13.1° (c=5,12 in 1 N HCI).

Action and Uses

Levodopa is an anticholinergic agent. It is used in the treatment of Parkinson's disease and syndrome.

Supplied as

Tablets and capsules 100, 250, and 500 mg.

Dosage

Usual initial dosage 0.5 to 1.0 g daily. Dosage should be adjusted to the needs of the individual patient as determined by clinical response and appearance of side effects.

Proprietary Name and Manufacturer

Larodopa (Roche) ; Dopalfher (Fher, Spain); Dopar (Endo, USA) ; Eldopal (Brocades-Steeman, Netherlands); Sobiodopa (Fanee).

References

1. S. Yamada et al. Chem Pharm Bull 10, 693 (1962). 2. Ch. J. Sih et al. J Amer Chem Soc 91 (22), 6204 (1969). 3. Med Act (Drugs of Today) 6 (4), 125-132 (1970). (Review with 27 references)

Lidoflazine (Rec INN)

R

7904

4-[4,4-bis(p-Fluorophenyl) butyl]-1-piperazine-aceto-2',6'-xylidide

Description

White or slightly yellow amorphous powder, mp 159-161°; practically insoluble in water, and very solu ble in chloroform and in glacial acetic acid.

Action and Uses

Lidoflazine is a coronary vasodilator. Indications angina pectoris, coronary sclerosis; prophylaxis and treatment of patients with myocardial infarction.

Dosage

Initially, 60 mg three times daily.

Supplied as

Tablets, 60 mg.

Proprietary Name

Clinium

Manufacturer

Janssen (Germany)

References

Med Act (Drugs of Today) 6 (1), 21-24 (1970). (Review with 13 references)

Lincomycin-2-phosphate

Synthesis

Reaction of 3,4-O-anysilidene lincomycin with trityl chloride gives 7-O-trityl-3,4-O-anisylidene lincomycin. Treatment of the latter with phosphorus oxychloride and subsequent hydrolysis gives the phosphate ester.

108

Description

White crystalline powder, mp 223-225º (dec)

Action

In vivo lincomycin 2-phosphate has proved to be as active as the parent compound in mice infected with Staphylococcus. The taste of the new ester is less bitter than that of lincomycin. The stability of lincomycin-2-phosphate has been studied in aqueous solutions in order to supply basic information for the formulation in liquid dosage forms.

Manufacturer

The Upjohn Co (USA)

References

1. Synthesis and bioactivity of lincomycin 2-phosphate. W. Morozowich et al. J Pharm Sci 58 (12), 1485-1492 (1969). 2. Hydrolysis of lincomycin-2-phosphate and clindamycin-2-phosphate. T. O. Oesterling and E. L. Lowe. J Pharm Sci 59 (2), 175-179 (1970).

Lipoxamycin Sulfate

Production

From Streptomyces virginiae var lipoxae.

Action

Lipoxamycin is a new antifungal antibiotic.

Manufacturer

The Upjohn Co (USA)

References

Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct 18·21, 1970; abstr 25.

Lividomycin

Production

Lividomycin is a basic antibiotic produced by Streptomyces lividus 2230 (ATCC-21178).

Action

Lividomycin has proved effective against Pseudomonas aeruginosa and tuberculosis bacilli.

Manufacturer

Kowa Co (Japan)

References

Jap Med Gaz 7(8),12(1970).

LL-BH 872a

D-1-Hydroxy-3-(1'-cis-hexenylazoxy)-2-butanone

Production

Obtained from Streptomyces hinnulinus.

Description

Light yellow oil, very unstable. [α]D = +157°±1.7° (c=1.7, methanol). UV max 238 µm (ε=9000).

Action

Antifungal antibiotic.

Manufacturer

Lederle (USA)

References

1. A novel α,β-unsaturated azoxy-containing antibiotic. W. J. McGahren et al. J Am Chem Soc 91, 2808 (1969).

109

Lopramine Hydrochloride (Prop

INN) Leo 640

Lopraminum (Lat). Lopramina (Sp) 4'-Chloro-2-[[3-(10,11-dihydro-5H-dibenz [b,f] azepin-5-yl) propyl] methylamino] acetophenone hydrochloride N-Methyl-N-(4-chlorobenzoyl methyl)-3-(10,11-dihydro-5 H-dibenz [b, f] azepin-5-yl)-propylamine hydrochloride

Synthesis

Prepared from N-methyl-3-(10,11-dihydro-5H-dibenz [b,f] azepin-5-yl)-propylamine and 2-bromo-4'-chloroacetophenone.

Description

Crystals, mp 152-154º. The free base melts at 104-106º.

Action

Lopramine is a new potential antidepressant, closely related to imipramine and desipramine. It differs from the two latter in having a N-(4-chlorobenzoylmethyl) group instead of a N-methyl or hydrogen respectively. Preliminary studies in man have shown promising results.

Toxicity

LD50 po in mice> 1000 mg/kg; ip: 920 mg/kg.

Manufacturer

AB Leo (Sweden)

References

1. WHO Chron 24 (9),425 (1970). 2. Chemistry and pharmacology of a new potential antidepressant. E. Erikson and O. Rohte. Arzneim-Forsch 20 (10), 1561-1568 (1970).

3. A quantitative approach to the initial clinical trial of tricyclic antidepressants. A comparison of Leo 640 and nortriptyline. B. Siwers et aJ. Eur J Clin Pharm 3 (1), 22 (1970). 4. On the pharmacology of Leo 640, a new tricyclic anti-depressant. O. Rohte. VII Internat Congr Colleg Internationale Neuro-Psychopharmacol Prague, Czechoslovakia, Aug 11-15 (1970); abst 365.

Lorazepam (USAN; Rec INN)

Wy 4036

7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one

Synthesis

Prepared by hydrolysis of 3-acetoxy-7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one.

Description

Crystals, mp 166-168°.

Action

Lorazepam is a new tranquilizer of the 1,4-benzodiazepine series.

Manufacturer

Wyeth Laboratories (USA)

References

1. JAMA 209, 1213 (1969). 2. WHO Chron 24 (11), 530 (1970). 3. American Home Corp. Brit pat 1,057,492. Belg pat 621,819. 4. B. D. Berger and L. Stein. Fed Proc 28 (2), 641 (1969).

110

Lorbamate (USAN; Prop INN)

Abbott 19957

Lorbamatum (Lat). Lorbamato (Sp) Cyclopropanecarbamic acid, 2-(hydroxymethyl)-2-methyl-pentylester, carbamate 2-(Hydroxymethyl)-2-methylpentyl cyclopropanecarbamate carbamate (ester) 2-Methyl-2-propyl-1 ,3-propanediol carbamate cyclopropane carbamate

Synthesis

Prepared in several steps from 5-methyl-5-(n) propyl-2-m-dioxanone and cyclopropylamine.

Description

Crystals, mp 72-74° (ether-pentane) .

Action

Centrally acting muscle relaxant.

Manufacturer

Abbott Laboratories (USA)

References

1. WHO Chron 24 (9), 425 (1970) . 2. JAMA 212,2247 (1970). 3. Abbott Laboratories, US pat 3,037,045.

Loxapine (USAN; Rec INN)

SUM 3170 CL 62,362 LW 3170

Loxapinum (Lat). Loxapina (Sp) 2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f] [1,4] oxazepine

Synthesis

Prepared by the reaction of 2-chloro-10,11-dihydro-11-oxo-dibenz [b,f] [1,4] oxazepine with phosphorus oxychloride to yield 2,11-dichloro-dibenz [b, f] [1,4] oxazepine, followed by reaction of the latter with N-methyl piperazine.

Description

Pale yellowish, grainy crystals, mp 109-111°.

Action

Loxapine is considered to be a potent psychoactive agent in laboratory animals. It has calming effects in cats, dogs and monkeys. It is closely related to the dibenzothiazepine clothiapine.

Toxicity

LD50 po in mice: 47 mg/kg.

Manufacturer

Dorsey Laboratories (USA); Lederle Laboratories (USA)

References

1. JAMA 209, 2043 (1969). 2. WHO Chron 24 (11), 530 (1970). 3. Or. A. Wander S. A. Brit pat 1,045,903.

Loxapine Succinate SUM 3170

CL 71563 LE 3170

2-Chloro-11-(4-methyl-1-piperazinyl) dibenz [b,f] [1,4] oxazepine succinate (1:1)

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Action

See Loxapine. The drug is rapidly absorbed from the gastrointestinal tract, well distributed in the tissue and extensively metabolized. In a preliminary clinical study it has been concluded that the drug possesses definite neuroleptic properties without significant toxicity.

Toxicity

LD50 po in rats: 40 mg/kg.

Manufacturer

Lederle Laboratories (USA)

References

1. Clinical pharmacological trial of loxapine succinate. J Clin Pharmacal 10 (3), 175-181 (1970). 2. Antipsychotic properties of loxapine succinate. S. Gershon et al. Curr Ther Res 12 (5), 280-285 (1970).

Lu 3-010

N,3,3-Trimethyl-1-phenyl-1-phthalan-propylamine hydrochloride 1-(3-Methylaminopropyl)-1-phenyl-3,3-dimethylphthalane hydrochloride

Synthesis

Prepared in 3 steps, starting with the reaction of 1-phenyl-3,3-dimethylphthalan-1-ol with LiAIH4. Also prepared in 3 steps, starting by the dehydration of 4-

dimethylamino-1-phenyl-1-[2-(2-hydroxy-2-propyl) phenyl]-1-butanol.

Description

White crystalline powder, mp 190-191°.

Action

Lu 3-010 and Lu-5-003 (the corresponding thiophthalane derivative) are two new drugs currently under investigation for antidepressant properties.

Manufacturer

H. Ludbeck and Co (Denmark)

References

1. Kefalas A/S Neth Appl 6,603,606 and 6,603,603. 2. Preliminary experiences of treated depressive patients with Lu 3-010 and Lu 5-003. J. Ravn and C. Rud. Nord psykiat T 23, 253-261 (1961). 3. Further pharmacological studies of bicyclic thymoleptics. P. V. Petersen at al. Acta Pharmacal Toxicol 28, 241-248 (1970). 4. Inhibitory effect of two newer antidepressants, Lu-5-003 and Lu 3-010 on serotonin uptake in human blood platelets in vitro. O. Lingjaerde. Psychopharmacologia 17, 94-99 (1970).

Lu-5-003

N,3,3-Trimethyl-1-phenyl-1-thiophthalan-propylamine hydrochloride 1-(3-Methylaminopropyl)-1-phenyl-3,3-dimethyl-thiophthalane hydrochloride

Description

Crystals, mp 176-177°.

Action

Lu 5-003 and Lu 3-010 (the corresponding phthalane derivative) are two new drugs currently under investigation for antidepressant properties. Lu 5-003 seems to be the clinically more promising of the two compounds.

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Manufacturer

H. Lundbeck and Co (Denmark)

References

1. Preliminary experiences of treated depressive patients with Lu 3-010 and Lu 5-003. J. Ravn and C. Rud. Nord Psykiat T 23, 253-261 (1961). 2. Further pharmacological studies of bicyclic thymoleptics. P. V. Petersen et al. Acta Pharmacol Toxicol 28, 241-248 (1970). 3. Metabolism, distribution and excretion of the thiophthalane Lu 5-003 a bicyclic thymoleptic. K. Fredricson Overo et al. Acta Pharmacol Toxicol 28, 81-96 (1970).

Macarbomycin

Production

Antibiotic isolated from the culture broth of a Streptomyces, Str phaeochromogenes C715-7 strain.

Description

White powder. The ammonium salt is readily soluble in water and is dextrorotatory, [α]D = + 150 (c=1, in methanol).

Action

Macarbomycin has strong antibacterial activity in vivo and in vitro and gives good results in weight gain and feed conversion with both broilers and swine.

Toxicity

LD50 iv in mice: 750 mg/kg.

Manufacturer

Meiji Seika Kaisha, Ltd (Japan)

References

1. Macarbomycin a new antibiotic containing phosphorus. S. Takahashi et al. J Antibiotics 23 (1), 48-50 (1970). 2. Jap Mad Gaz 7(3).4(1970).

Maprotiline (Rec INN)

Ciba 34,276 Ba

Maprotilinum (Lat). Maprotilina (Sp) N-Methyl-9,10-ethanoanthracene-9-(10H)-propylamine hydrochloride 1-(Methylaminopropyl)-dibenzo-[b,e]-bicyclo-[2,2,2] octadiene hydrochloride

Synthesis

Prepared by the reduction of N-methyl-9,10-ethanoanthracene-9(10H)-propionic acid amide with lithium aluminum hydride.

Description

Crystals, mp 230-232º (isopropanol).

Action

Maprotiline, a benzoctamine analog, inhibits the uptake and potentiates the action of noradrenaline and antagonizes mescaline-induced excitation in the animal. Its effect on the cortical EEG has been recently studied in healthy volunteers3. The results of clinical trials have been reported4.

Manufacturer

CIBA Ltd (Switzerland)

References

1. WHO Chron 24 (3), 130 (1970). 2. CIBA Ltd. Neth Appl 6.516.749. 3. The effect of compound ClBA 34,276-8a on the cortical electroencephalogram of healthy persons. U. J. Jovanovic and B. Tan-Eli. Europ Neurol 4. 39-56 (1970). 4. On the antidepressive effect of Ciba 34,276-8a. Observations on 562 cases. W. Gruter. Coll Intern Neuro-psycho-pharm. VII Congress Abstracts, Vol II. abst 482 (1970).

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Matchamycin

Production

Matchamycin has been isolated from a culture broth of a Streptomyces E-753.

Description

Green material, mp 150-156º (green to brown); [α]D = + 33°±12° (c=1, in dimethylsulfoxide).

Action

Matchamycin is a new antibacterial substance.

Manufacturer

Shionogi and Co, Ltd (Japan)

References

Matchamycin: a new antibiotic produced by Streptomyces E-753. A. Kinuera and H. Nishimura J Antibiotics 23 (9), 461-463 (1970).

Mazindal (USAN; Prop INN)

42-548

5-(p-Chlorophenyl)-2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol 5-(p-Chlorophenyl)-5-hydroxy-2,3-dihydro-5H-imidazo[2,1-a] isoindol

Synthesis

Prepared by air oxidation of 5-(p-chlorophenyl)-2,3-dihydro-5H-imidazo [2,1-a] isoindol, and subsequent treatment of the resulting 5-hydroperoxy derivate with methanol.

Description

Crystals, mp 202-203°.

Action

Mazindol has been found to produce moderate to marked central nervous system stimulation, appetite suppression and anti-depressant activity in mice, rats and monkeys.

Manufacturer

Sandoz Pharmaceuticals (USA)

References

1. JAMA 211, 1363 (1970). 2. WHO Chron 24 (3), 130 (1970). 3. Sandoz AG. Ger Offen 1,814,540; Ger Offen 1,901,497; Ger Offen 1,930,488. 4. Fed Proc 27, Abst 1603. 2152 (1968) . 5. Curr Ther Res 11. 256 (1969). 6. American Druggist pg 32 (June 29. 1970).

MDA Hydrochloride

3,4-Methylenedioxy-α-methylphenethylamine hydrochloride 3,4-Methylenedioxyamphetamine hydrochloride 1-(3,4-Methylenedioxyphenyl)-2-aminopropane hydrochloride

Description

Crystals, mp 181-182°.

Action

MDA is a mild euphoriant, which increases need for interpersonal relationships. It induces changes in vision and hearing. This drug is subjected to control.

References

1. C. Mannich and W. Jacobson. Ber 43, 189 (1910). 2. Analogs of a-methylphenethylamine (amphetamine). I. Synthesis and pharmacological activity of some methoxy and/or methyl analogs. B. T. Ho et al. J Med Chem 13 (1), 26-30 (1970). 3. JAMA 211, 830 (1970). 4. Fed Reg 35 (47) 4305·4306 (1970)

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Meclofenamic Acid (Rec INN)

CI 583

N-(2,6-Dichloro-m-tolyl) anthranilic acid

Synthesis

Several methods have been described1-3.

Description

Crystals, mp 257-259°.

Action

Meclofenamic acid is an anti-inflammatory drug. It has proved to be effective in clinic.

Manufacturer

Parke Davis (USA)

References

1. Parke Davis Co. Neth Appl 6,507,783; Ger pat 1,149,015; US pat 3,313,848; Brit pat 1,046,319. 2. Bristol-Myers Co. Neth Appl 6,604,860. 3. P. J. Juby et al. J Med Chem 11(1),111-116(1968). 4. Hormones 1(4),193 (1970).

Medrysone (USAN) U 8471

11 β-Hydroxy-6 α-methylpregn-4-ene-3,20-dione 11 β-Hydroxy-6 α-methylprogesterone 6 α-Methyl-11 β-hydroxyprogesterone

Synthesis

Prepared in several steps from 11-keto-6-β-methylprogesterone.

Description

White crystalline powder, mp 155-158°. [ α]D = 189º (in chloroform).

Action and Uses

Medrysone is a new corticoid which has topical anti-inflammatory and antiallergic activity. It is effective in the treatment of allergic conjunctivitis, vernal conjunctivitis and apiscleritis.

Supplied as

5 ml sterile suspension in plastic dropper bottles.

Dosage

One drop instilled in the conjunctival sac up to every four hours.

Proprietary Name

HMS

Manufacturer

Allergan (USA)

References

1. The Upjohn Co. US pat 2,864,837. 2. Med Act (Drugs of Today), 6(5),183-185 (1970). (Review)

Mefenorex Hydrochloride (Prop

INN) Ro 4-5282

N-(3-Chloropropyl)-α-methyl-phenethylamine hydrochloride 1-Phenyl-2-(3-chloropropylamino) propane hydrochloride α-Methyl-β-phenyl-N-(γ-chloropropyl) ethylamine hydrochloride

Synthesis

Prepared from 1-phenyl-2-(3-hydroxypropylamino) propane.

115

Description

Crystals, mp 128-130°.

Action and Uses

Mefenorex exerts an appetite-depressant effect. For use in the management of obesity.

Dosage

40 mg one or two times daily.

Supplied as

Tablets, 40 mg.

Proprietary Name

Pondinil

Manufacturer Roche (Fance)

References

1. F. Hoffmann La Roche and Co. Ger pat 1,210,873. 2. Med Act (Drugs of Today), 6(4),133-135(1970). (Review with 8 references).

Meglucycline (Rec INN)

Meglucyclinum (Lat). Megluciclina (Sp) 2-Deoxy-2-[[[4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacene-carboxamido] methyl] amino]-β-D-glucopyranose

Synthesis

Prepared by reacting 2-amino-2-deoxyglucose with formaldehyde and tetracycline in an aqueous-organic medium.

Description

Yellow powder, mp 143º (dec).

Action

Meglucycline is a new highly soluble Mannich base of tetracycline.

Manufacturer Laboratorios Prodes SA (Spain)

References

1. WHO Chron 24 (11). 531 (1970). 2. Prodes SA. Sp pat 355.262. 3. G. Barrenechea et al. Simposium Quimica Medica Farmaceutica Barcelona Sept 28-30 (1970).

Memotine Hydrochloride

(USAN) UK 2371

3.4-Dihydro-1-[(p-methoxy-phenoxy)-methyl] isoquinoline hydrochloride

Synthesis

Prepared by cyclodehydration of N-(p-methoxyphenoxyacetyl)-β-phenylethylamine with phosphorus pentoxide.

Description

Crystals. mp 187º

Action

Memotine is an antiviral agent closely related to famotine. It has been reported that the oral administration of the drug to volunteers reduced by half the incidence of virus infection and of clinical illness after intranasal instillation of living influenza B virus2. Recent experiments failed to show protection of volunteers challenged with influenza A2/Hong Kong/19683,4.

Manufacturer

Chas Pfizer and Co. Inc (USA)

References

1. Pfizer Corp. Neth Appl 6.516.328. 2. Prophylaxis of influenza with a synthetic isoquinoline.

116

A. S. Beare et al. Lancet 1. 843 (1968). 3. Studies of isoquinoline derivatives (UK 2371 and UK 2054) in respiratory infections of volunteers, using influenza viruses, a parainfluenza virus and a rhinovitrus. Sylvia E. Reed et al. Ann NY Acad Sci 173. 760-769 (1970). 4. A trial of chemoprophylaxis of natural influenza infection with UK 2371. J. E. Stark et al. Thorax 25. 649-655 (1970) .

Menitrazepam (Rec INN)

CB 4875

Menitrazepamum (Lat) 5-(1-Cyclohexen-1-yl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one

Action

Muscle relaxant. It is structurally related to tetrazepam; it differs from the latter in having a 7-nitro group instead of a 7-chloro.

Manufacturer

Clin Byla (France)

References

1. Pharm J 203, 753 (1969). 2. WHO Chronicle 24 (11), 531 (1970).

Menphegol

p-Menthanyl-phenyl polyoxyethylene ether

Synthesis

Prepared by reaction of phenol and ethyl oxide with a substance produced by isomerization and reduction of terpene oil.

Action

Menphegol is a newly developed non-ionic surface active spermicide. It is available in the form of effervescent vaginal tablets.

Manufacturer

Eisai Co, Ltd (Japan)

Proprietary Name

Neo Sampoon

References

Jap Med Gaz 7 (4).4(1970).

Mepiprazole Dihydrochloride

(BAN; Prop INN) H 4007

Mepiprazolum (Lat) 1-(m-Chlorophenyl)-4-[2-(5-methylpyrazol-3-yl) ethyl] piperazine dihydrochloride

Synthesis

Prepared by the reaction of 3-(2-chloroethyl)-5-methylpyrazol with N-(3-chlorophenyl) piperazine. Also by the reaction of 3-chlorophenyl bis-(2-chloroethyl) amine with 3-(2-aminoethyl)-5-methylpyrazol.

Description

Crystals, mp 238-240° (ethanol); the trisulfate, mp 198-200°.

Action

117

Mepiprazole dihydrochloride is a new psychotropic drug.

References

1. WHO Chron 24 (9), 426 (1970). 2. Chem Drug 193, 228 (1970). 3. E Merck AG. Brit pat 1,124,710.

Mesoridazine (USAN)

TPS-23

10-[2-(1-Methyl-2-piperidyl}ethylj-2-(methylsulfinyl) phenothiazine

Synthesis

Prepared from 2-(methylsulfinyl) phenothiazine and 2-(1-methyl-2-piperidyl)-1-chloroethane.

Description

The free base is an oily product. The tartrate melts at 115-120° (foam formation) and sisters above 80°.

Action and Uses

Mesoridazine is a new major tranquilizer drug, chemically and pharmacologically related to thioridazine. Mesoridazine is useful in the following disease states: alcoholism-acute and chronic; schizophrenia; behavioral problems in mental defficiency and chronic brain syndrome; psychoneurotic manifestations.

Dosage

By oral route, 50-400 mg daily. Intramuscularly, 25-200 mg daily.

Supplied as

Tablets, 10, 25, 50, 100 mg mesoridazine (as the besylate). Ampules, 25 mg/ml mesoridazine (as the besylate).

Proprietary Name and Manufacturer

Serentil (Sandoz, US); Inofal (Sandoz, Germany)

References

1. Renz et al. US pat 3.084,161. 2. Med Act (Drugs of Today) 6 (6). 219 (1970). (Review with 9 references).

Metampicillin Sodium (Rec

INN)

Metampicillinum (Lat). Metampicilina (Sp) 3,3-Dimethyl-6-[2-(methylenamino)-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo (3.2.0) heptane-2-carboxylic acid sodium salt 6-[D(-)-α-Methylenaminophenylacetamido] penicillanic acid sodium salt

Synthesis

A solution of equimolecular amounts of ampicillin and sodium bicarbonate is treated at 50 with formaldehyde solution. The resulting solution is filtered and then lyophilized.

Description

White powder, freely soluble in water.

Action and Uses

Metampicillin is an analogue of the ampicillin, with a methylenamino α-substituent. It shows a broad spectrum of activity against gram-positive and gram-negative bacteria, similar to that of ampicillin, but it is claimed to have the advantage of being relatively stable against staphylococcal penicillinase.

Dosage

Adults, 250 mg orally every 6 hours, or 250 mg intramuscularly every 8-12 hours. Children 25-40 mg/kg daily.

Supplied as

Capsules, 250 mg. Vials, 150 mg and 250 mg.

Proprietary Name

118

Suvipen

Manufacturer

Midy (France, Italy)

References

1.· Soc Et Res Appl Sci Med ERASME. Brit pat 1.081,093. 2. M. Londe. Presse Med. 78, 805 (1970). 3. Med Act (Drugs of Today) 6 (3), 84-87 (1970). (Review with 6 references).

Metazamide (USAN; Rec INN)

GPA 878

Metazamidum (Lat) 1-(p-Methoxyphenyl)-5-methyl-4-imidazolin-2-one

Synthesis

Prepared from p-anisidine, formaldehyde and isonitrosoacetoacetate in several steps, the last being the decarboxylation of 1-(p-methoxyphenyl)-4-carboxy-5-methyl-2-imidazolone by treatment with quinoline and copper powder.

Description

Glittering needles, mp 195-196º (methanol). Ultraviolet absorption max at 240 µm ε=6580, in methanol).

Action

Anti-inflammatory

Manufacturer

Geigy Chemical Corp (USA)

References

1. Geigy Chemical Corp. US pat 3,303,199. 2. The biological disposition of GPA 878, an anti-inflammatory imidazolone derivative. S. B. Zak et al. Fed Proc 29, 677 (1970) .

Methasquin

N-[p-[[(2,4-Diamino-5-methyl-6-quinazolinyl) methyl] amino] benzoyl] aspartic acid L-form

Synthesis

Prepared by hydrolysis of the corresponding diethyl ester.

Description

Insoluble in water, soluble in alkaline solutions; mp 269-271º (dec).

Action

Antitumor qgent. It inhibits folate reductase.

Manufacturer

Parke Davis

References

1. Parke, Davis and Co. Brit pat 1,104,576 and US pat 3,471,498. 2. Quinazoline antifolates: biologic activities. Dorris J Hutchinson. Cancer Chemother Rep 52(7), (pI.1) 697-705 (1968). 3. Folate reductase of the amethopterin-resistant Streptococcus faecium var durans/Ak /. Inhibition by amethopterin and methasquin a new quinazoline antifolate. M. Alberta et al. Mol Pharmacol 6(4), 323 (1970).

Methoxyellipticine Lactate

ICI180

9-Methoxyellipticine Lactate 9-Methoxy-5,11-dimethyl-6H-pyrido [4,3-b] carbazole lactate

119

Description

Methoxyellipticine lactate is an alkaloid extracted from the leaves of Ochrosia borbonica. Yellow crystals, mp 295°. UV max 245 µm [Igε = 4.34], 275 µm [Igε = 4.53], 290 µm [Igε = 4.64], 340 µm [Igε = 3.71], 400 µm [Igε = 3.56]. It is soluble in water.

Action

Methoxyellipticine has proved to possess experimental antitumor activity. Recently it has shown to be capable of inducing apparently complete remissions in patients with acute myeloblastic leukaemia.

Toxicity

LD50 sc in mice: 150 mg/kg.

Manufacturer Roger Bellon Lab (Fr)

References

1. L. K. Dalton et al. Aust J Chem 20 (12), 2715-27 (1967).

2. J. Poisson et al. Ann Pharm Fr 25, 523-4 (1967). 3. G. H. Svoboda et al. J Pharm Sci 57 (10). 1720-5 (1968). 4. Methoxy-9-ellipticine lactate. I. Experimental study (oncostatic and immunosuppressive actions; preclinical pharmacology). J. Le Men et al. Rev Europ Etudes Clin Biol 15 (5), 554-538 (1970). 5. II. Analysis in vitro of the mechanism of action. E. Garcfa-Giralt and A. Macieira-Coelho ibid. 15 (5). 539-541 (1970). 6. III. Clinical screening: its action in acute myeloblastic leukaemia. G. Mathe et al. ibid. 15 (5), 541-545 (1970).

Methylcobalamin

Cobinamide Co methyl deriv. phosphate 3'-ester with 5,6-dimethyl-1-α-D-ribofuranosyl benzimidazole inner salt 5,6-Dimethylbenzimidazolylmethylcobamide

Methylcobalamin differs in chemical structure from cyanocobalamin in that a methyl group is attached to the cobalt in place of a cyanide group.

Synthesis and Isolation Methylcobalamin is prepared by reduction of cyanocobalamin with zinc followed by an alkylation with methyl bromide, methyl sulfate or diazomethane, or also, by reduction of hydroxocobalamin with sodium borohydride followed by an alkylation with methyl iodide1-6. The isolation of methylcobalamin from a microorganism7 and liver8 have been reported.

Description

Red crystalline powder; sparingly soluble in water, insoluble in acetone, ether and benzene. In aqueous solution absorbancy peak at about 520 µm (characteristic of cobamide compounds containing a benzimidazolyl group); in acid solution the absorbancy peak is shifted to about 460 µm. In aqueous solution the values of ε.10-4, at 268, 343 and 525 µm are respectively 2.27, 1.20 and 0.766.

Action

Methylcobalamin participates in several enzymic reactions, including transmethylation and other reactions of methyl or carboxymethyl groups. From recent experimental studies in partially hepatectomized rats it has been assumed that methylcobalamin can accelerate liver regeneration9. Methylcobalamin appears to be a major component of vitamin B12 in normal human plasma and to occur in the human liver as well10. It has proved to have a therapeutic effect in vitamin B12 deificiency in parenteral doses of 4 to 6.5 µg. It has been assayed clinically; in the treatment of diabetic neuropathy11.

References

1. E. L. Smith et al. Nature 194, 1175 (1962). 2. E. L. Smith and L. Mervyn. Biochem J 86, 2p (1963).

120

3. H. P. C. Kogenkamp and T. G. Oikawa. J Biol Chem 239,1911 (1964). 4. Hoffmann-La Roche and Co-A. G. Belg pat 631,589. 5. Glaxo Group Ltd. Brit pat 963,373. 6. W. A. Johnson at al. J Chem Soc 4146 (1963). 7. K. Lindstrand. Acta Chem Scand 19 (7), 1762-3 (1965). 8. K. Lindstrand. ibid 19 (7), 1785-7 (1965). 9. T. Koizumi et al. Experientia 26 (3), 282 (1970). 10. K. G. Stahlberg. Scand J Haematol Suppl No 1 (1967). 11. Shinryo to Shinyaku 6, 1959 (1969). 12. Med Act (Drugs of Today) 6 (3), 106-112 (19770). (Review with 16 references).

3-O-Methyldopa

3-OMD

3-(4-Hydroxy-3-methoxyphenyl) alanine

Synthesis

Prepared by hydrolysis of N-benzoyl-4-hydroxy-3-methoxyphenylalanine with dil hydrochloric acid1, or by hydrolysis of 5-(4-hydroxy-3-methoxybenzyl) hydantoin with barium hydroxide2.

Description

Crystals, mp 255-256° dec. Very soluble in hot water, in hydrochloric acid and ammonium hydroxide.

Action

3-O-Methyldopa is a metabolite of dopa. It is under clinical study as an antiparkinson drug.

References

1. Bloch, Zeitschrift für physiologische chemie 98, 236. 2. Johnson at al. J Am Chem Soc 35, 1613. 3. Metabolic fate of 1-dopa-14C in cerebrospinal fluids and blood plasma of humans. A. Pletscher et al (Hoffmann-La Roche). Brain Res 4 (1), 106-109 (1967) . 4. A. Pletscher et al. Communication on IV Symposium of Bel-Air: Monoamines et noyaux gris

centraux, Geneve-1970; Med Hyg (933), 1500 (1970). 5. Therapeutique substitutive des syndromes de Parkinson. G. Gauthier et al. Press Med 79 (3), 91 (1971).

α-Methyldopahydrazine

MK458

α-Hydrazino-3,4-dihydroxy-α-methylhydrocinnamic acid (3,4-Dihydroxyphenyl)-α-hydrazino-α-methyl propionic acid

Synthesis

By the reaction of the potassium bisulphate adduct of 1-(3-methoxy-4-hydroxyphenyl)-2-propanone or of 1-(3,4-dimethoxyphenyl)-2-propanone with hydrazine hydrate and potassium cyanide. The hydrazino nitrile so obtained, upon hydrolysis with acid, yields the corresponding hydrazino amide salt and the treatment of this amide with strong hydrobromic acid finishes the hydrolysis to the free acid and dealkylates the ring methoxyl groups.

Description

Crystals, mp 209-210° (dec).

Action

α-Methyldopahydrazine is a peripheral decarboxylase inhibitor, which has been shown to potentiate the behavioural and biochemical effects of peripherally administered I-dopa in animals. Preliminary clinical experience has suggested that the drug may well facilitate the administration of I-dopa to psychiatric and neurological patients heretofore unable to tolerate high doses of I-dopa because of peripheral side-effects.

Manufacturer

Merck Sharp and Dohme (USA)

References

1. Merck Co Inc. Fr pat M 1553; Brit pat 940,596; Ger pat 1,173,487. 2. M. Sletzinger et al. J Med Chem 6, 101-103 (1963).

121

3. Dopa effects on motility in mice; Potentiation by MK 485 and dexchlorpheniramine. U. Stromberg. Psychopharmac (Berl) 18, 58-67 (1970). 4. Administration of a peripheral descarboxylase inhibitor with I-dopa to depressed patients. F. K. Goodwin et al. Lancet i, 908-911 (1970). 5. Effect of I-dopa alone and in combination with an extra cerebral decarboxylase inhibitor on blood pressure and some cardiovascular reflexes. A. M. Watanabe et al. Clin Pharmac Ther 11 (5), 740-746 (Sept-Oct 1970).

7 α-Methylnorethindrone

U 13,851

17-Hydroxy-7α-methyl-19-nor-17α-pregn-4-en-20-yn-3-one 7-Methyl-19-nor-17α-ethinyt-4-androsten-17β-ol-3-one 17-Ethinyl-7α-methyl-19-nortestosterone

Synthesis

Prepared by the condensation of 7α-methyl-19-nor-4-androstene-3,17-dione with pyrrolidine and the reaction of the resulting 3-pyrrolidinyl enamine with sodium acetylide.

Description

Crystals, mp 197-199.5°; UV max 240.5 µm

Action

7α-Methylnorethindrone exhibits both estrogenic and progestogenic properties in several biological test systems, and has been found to be 10 to 40 times as potent as norethindrone in comparative assays.

Manufacturer

The Upjohn Co (USA)

References

1. Upjohn Co. US pat 3,341,557; Belg pat 610.385 ; Neth AppI 6,604,702.

2. G. D. W. Duncan et al. Exptl Biol Med 116 (3), 800-802 (1964) . 3. Biological properties of 17-ethinyl-7α-methyl-19-nortestosterone. B. B. Pharris. Contraception 1(2), 87-100 (1970).

N-Methyl-N-(β-phenylethyl)-

1,2,3,4-tetrahydro-6-methoxy-4,4-

dimethyl-2-naphthylamine

hydrochloride

Synthesis

Prepared in three steps from 6-methoxy-4,4-dimethyl-2-tetralone1.

Description

Colorless needles, mp 208°.

Action

This compound has been investigated for its cardioactive properties, and has proved to be a myocardial depressant and potent antifibrillatory agent in mice and guinea pigs.

References

1. A. R. Martin el al. J Pharm Sci 58, 340 (1969). 2. A new myocardial depressant and antifibrillatory agent. W. E. Johnson et al. Life Sci 9 (Pt 1), 471-476 (1970).

Metiapine (USAN; Rec INN)

Metiapinum (Lat). Metiapina (Sp) 2-Methyl-11-(4-methyl-1-piperazinyl)dibenzo[b,f] [1.4]thiazepine

122

Synthesis

Prepared by the reaction of 2-methyl-10,11-dihydro-11-oxo-dibenzo[b, f] [1,4] thiazepine with phosphorus oxychloride and by reaction of the resulting 11-chloro derivate with N-methylpiperazine.

Description

Crystals, mp 99-107° (petroleum ether).

Action

Metiapine has been shown to have pharmacological properties consistent with those of potent neuroleptics. It is under clinical study.

Manufacturer

The Wm S Merrell Co (USA); Dr A Wander AG (Switzerland)

References

1. WHO Chron 24 (11), 531 (1970). 2. JAMA 208, 1400 (1969). 3. J. Schmutz et al. Helv Chim Acta 50 (1), 245-254 (1967). 4. J. Schmutz et al. Chim Ther 2 (6), 424-429 (1967). 5. Metiapine: Neuroleptic and peripheral autonomic attributes. H. J. Ketteler and W. L. Kuhn. Fed Proc 29, 620 Abs (1970). 6. Metiapine: a new antipsychotic agent. D. M. Galiant et al. Curr Ther Res 12 (12), 794-797 (1970).

Metizoline Hydrochloride

(USAN; Rec INN) EX 10-781

Metizolinum (Lat). Metizolina (Sp) The former USAN for this compound was benazoline. 2-[(2-Methylbenzo[b]thien-3-yl)methyl]-2-imidazoline monohydrochloride

2-Methyl-3-(∆2-imidazolin-2-ylmethyl) benzo [b] thiophene hydrochloride

Synthesis

Prepared from (2-methylbenzo[b]thien-3-yl) acetonitrile.

Description

Crystals, mp 248-250° (alcohol/ether). The free base melts at 156-157° (cyclohexane/petroleum-ether).

Action

Vasoconstrictor-nasal decongestant.

Manufacturer

Lakeside Laboratories (USA)

References

1. WHO Chron 24 (11), 531 (1970). 2. JAMA 211, 1362 (1970). 3. E. Merck AG. Fr pat M. 1614.

Metolazone (USAN; Rec INN)

SR 720-22

Metolazonum (Lat). Metolazona (Sp) 7-Chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-o-tolyl-6-quinazolinesulfonamide 2-Methyl-3-(o-tolyl)-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone

Synthesis

123

Sulfamation of N-acetyl-5-chloro-2-methylaniline with chlorosulfonic acid and concentrated NH4OH, followed by an oxidation with KMnO4, in water at 83° gives an anthranilic acid derivative, which is allowed to react with o-toluidine and phosphorus trichloride in refluxing toluene to give a product which is finally reduced with sodium borohydride in diglyme.

Description

Colorless crystals, mp 253-259° (95% ethanol).

Action

Metolazone is a new diuretic agent.

Manufacturer

Strasenburgh Laboratories (USA)

Proprietary Name

Zaroxolyn

References

1. Wallace and Tiernan Inc. US pat 3,360,518. 2. The study of metalazone, a new diuretic, in human body fluids using thin layer separation, liquid chromatographic measurements and 14C-counting techniques. O. N. Hinsvark and A. I. Cohen. Fed Proc 29(2),276 Abs (1970). 3. Human pharmacokinetics studies with 14Zaroxolyn, a new type of diuretic agent. K. N. Modi et al. Fed Proc 29 (2), 27 Abs (1970).

Metopimazine (BAN; USAN)

PP 9965 2167 Th

1-[3-[2-(Methylsulfonyl) phenothiazin-10-yl] propyl] isonipecotamide 10-[3-(4-Carbamoyl piperidino)-propyl]-2-(methanesulfonyl) phenothiazine

Synthesis

Prepared from 3-methylsulfonyl-10-[3-(chloropropyl)] phenothiazine.

Description

Crystals, mp 170-171°. UV max about 263 µm [E(1%,1 cm) about 600] in 0,1N HCI.

Action as Uses

Metopimazine is a new potent antiemetic agent. In experimental studies in dogs, it was found to be 100 times more active than chlorpromazine. For use in the treatment of nausea and vomiting produced by certain drugs; radiation sickness; nausea and vomiting associated with certain hepato-digestive disorders; postanesthetic and postoperative nausea and vomiting.

Dosage

Orally or rectally, 5 to 15 mg daily. Parenterally, 10 to 20 mg daily.

Supplied as

Sugar coated tablets, 2.5 mg; suppositories, 5 mg; solution (injection) 10 mg/ml.

Proprietary Name

Vogalene

Manufacturer Theraplix (France)

References

1. Societe des Usines-Chimiques Rhone Poulenc. Ger pat 1.092.476. 2. Med Act (Drugs of Today) 6 (4). 135-138 (1970). (Review with 9 references).

Metrifonate

O,O-Dimethyl-1-hydroxy-2,2,2-trichloroethylphosphonate

Synthesis

Prepared from chloral and dimethyl phosphite.

Description

Crystals which melt at 83-84°.

Action

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Metrifonate has been found effective against Schistosoma hematobium, the parasite that causes juvenile urinary schistosomiasis in tropical countries. The compound was originally used as an insecticide and anthelmintic, known generically as trichlorfon.

Manufacturer

Farbenfabriken Bayer AG (Ger)

References

Farbenfabriken Bayer AG US pat 2,701,225

Metrifudil (Rec INN)

Metrifudilum (Lat). Metrifudilo (Sp) N-(α-Methylbenzyl) adenosine 6-(o-Methylbenzylamino)-9β-D-ribofuranosyl-9H-purine

Synthesis

Prepared from triacetyl-6-chloropurine-(β-D-riboside) and 2-methyl-benzylamine.

Description

Crystals, mp 157-158°.

Action

Metrifudil is a member of a family of N'-aralkyladenosine derivatives, which have an action on the blood vessels and circulation.

References

1. WHO Chron 24 (11), 531 (1970). 2. C. F. Boehringer and Soehne GmbH. South African Appl. 67 7414.

Mianserin Hydrochloride

(USAN) Org GB 94

1,2,3,4,10,14b-Hexahydro-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine hydrochloride 2-Methyl-1 ,2,3,4,10,14b-hexahydro-2H-pyrazino[1,2-f] morphanthridine hydrochloride

Synthesis

Prepared in several steps from benzylaniline, the last being the reduction of the respective 2,3-diketopiperazine with diborane in tetrahydrofurane.

Description

Crystals, mp 282-284° (ethanol).

Action

Mianserin has proved to have an antiserotonin potency of the same order as cyproheptadine.

Manufacturer

NV Organon (The Netherlands)

References

A novel type of substituted piperazine with high antiserotonin potency.

W. J. van der Burg. J Med Chem 13 (1),35-39 (1970).

MICA

5-Methoxyindole-2-carboxylic acid

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Synthesis

Prepared by saponification of ethyl 5-methoxyindole-2-carboxylate.

Description

Crystals, mp 199.5-200°.

Action

MICA is a hypoglycemic agent which has been found to be effective both in normal and alloxan-induced diabetic rats.

Manufacturer

Lederle Laboratories (USA)

References

1. G. Pappalardo et al. Gazz Chim Ital 88, 574-590 (1958). 2. Method of inducing hypoglucemia with a substituted indole. S. Gordon et al. (to American Cyanamid Co). USA pat 3,332,846. 3. Indole-2-carboxylic acids. a new class of hypoglycemic compounds. N. Bauman et al. Biochem Pharmacol 18, 1241-1243 (1969).

Miconazole Nitrate (USAN; Rec

INN) R14889

Miconazolum (Lat). Miconazolo (Sp) 1-[2,4-Dichloro-β-[(2,4-dichlorobenzyl) oxy] phenethyl] imidazole mononitrate

Synthesis

Prepared in several steps from 2,4-dichloroacetophenone, the last being the reaction of α-(2,4-dichlorophenyl) imidazole-1-ethanol with 2,4-dichlorobenzylchloride.

Description

Crystals, mp 170.5º (isopropanol-diisopropylether). Two optical isomers have been described; (+) miconazole nitrate, mp 135.3º, [α]D = +59º (c=1, in methanol) and (-) miconazole nitrate, mp 135°, [ α]D = -58° (c=1, in methanol).

Action

It has been reported that, in vitro, low concentrations of miconazole nitrate are fungistatic against Phycomycetes, Ascomycetes, and Adelomycetes (eg, Saprolegnia; Candida, Cryptococcus, Aspergillus, dermatophytes; Phialophora, Spororichum, fungicidal against Trichophyton mentagrophytes and Microsporum canis, and bacterial against gram-positive cocci and bacilli. In guinea-pigs, doses administered topically and orally cure skin lesions caused by T mentagrophytes, canis, and C albicans. The results of a recent controlled, double-blind trial have shown the high effectiveness and excellent tolerance of miconazole nitrate in the topical treatment of chronic tinea pedis.

Manufacturer

Janssen Pharmaceutica (Belgium)

References

1. JAMA 212, 467 (1970). 2. WHO Chron 24 (11), 531 (1970). 3. Janssen Pharmaceutica N. V. Ger Offen 1,940,388. 4. Treatment of long· term tinea pedis with miconazole. Jo P. Brugmans et al. Arch Derm 102, 428·432 (1970).

Mitocromin

Antibiotic composed of an equilibrium mixture of two components A and B. It is related to daunomycin

Production

It is produced by two unidentified species of Streptomyces.

Description

Bright red amorphous powder, mp 170-175°.

Action

Mitocromin, a new member of the family of anthracycline antibiotics, exhibits antitumor activity.

Manufacturer

Chas Pfizer and Co (USA)

References

126

1. Mitocromin: an antibiotic with antitumor activity. Wen Chin Liu et al. J Antibiotics 22 (12), 608-611 (1969) 2. Jap Med Gaz 7 (7), 15 (1970).

Mitomalcin NSC 113233

Action

Mitomalcin is a new proteinaceous antileukemic antibiotic, of unknown structure. isolated from cultures of Streptomyces mafayensis.

References

1. T. J. McBride et al. Proc Soc Exp Bioi Med 130, 1188-1190 (1969). 2. Toxicology studies with mitomalcin in dogs. R. K. Morrison et al. Cancer Chemother Rep 54 (4), 217-223 (1970).

Mitosper (USAN; Prop INN)

A-35595C

Mitosperum (Lat). Mitospero (Sp)

Action

Mitosper is an antineoplastic antibiotic obtained from cultures of an Aspergillus of the glaucus group.

References

1. JAMA 212, 2246 (1970). 2. WHO Chron 24 (9), 426 (1970).

Mitotane (USAN; Rec INN)

CB 313

Mitotanum(Lat); Mitotano(Sp) 1,1-Dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane o, p'-DOD

Synthesis

Prepared from 2,2-dichloro-1-(o-chlorophenyl)ethanol with chlorobenzene in presence of sulfuric acid.

Description

Crystals, mp 76-78°.

Action

Antineoplastic; treatment of adrenal neoplasms.

Manufacturer

Calbiochem (USA)

Proprietary Name

Lysodren

References

1. JAMA 212, 1361 (1970). 2. Haller et al. J Arn. Chem Soc 67, 1600 (1945).

MJ 1978

N-[[2-(o-Methoxyphenyl)-1-piperazinyl] ethyl]-1,1-cyclopentanediacetimide 8-[2-(4-o-Methoxyphenyl-1-piperazinyl) ethyl]-8-azaspiro[4,5] decane-7,9-dione

Synthesis

Prepared by the reaction of 3,3-tetramethyleneglutaric anhydride with 1-(2-aminoethyl)-4-(o-methoxyphenyl)piperazine. Also, by the condensation of 8-(2-chloroethyl)-8-azaspiro[4, 5]-decane-7,9-dione with 1-(o-methoxyphenyl)piperazine.

127

Description

The free base boils at 220-240° (0.35 mm Hg) and the dihydrochloride melts at 196.5-198.5° (dec).

Action

MJ 1978 has been found to have psychotropic and antiemetic properties consistent with those of major tranquilizers.

Manufacturer

Mead Johnson Laboratories (USA)

References

1. Mead Johnson and Co. US pat 3,398,151. 2. Shin Hayao et al. J Org Chem 26, 3415 (1961). 3. The pharmacology of MJ 1978. a novel azaspirodecanedione and potential tranquillizing agent. L. E. Allen et al. The Pharmacologist 11, 247 (1969).

MK 910

2-(p-Fluorophenyl)-1-methyl-5-nitro-imidazole

Synthesis

Prepared in four steps from p-fluorobenzonitrile.

Description

Crystals, mp 187-188° (chloroform).

Action

M K 910 is a new amebicidal, which has proved to be effective in clinic.

Manufacturer

Merck Sharp and Dohme (USA)

References

1. Merck Co, Inc. Belg pat 660,836.

2. Therapeutic efficacy of new nitroimidazoles for experimental trichomoniasis; amebiasis and trypanosomiasis. A. C. Cuckler at al. Amer J Trop Med Hyg 19, 916 (1970). 3. A new drug (MK 910) in the therapy of intestinal and hepatic amebiasis. First results of clinical trial. M. V. Chari and B. N. Gadiyar. Amer J Trop Med Hyg 19, 927 (1970).

MMDA Hydrochloride

5-Methoxy-3,4-methylenedioxy-α-methylphenethylamine hydrochloride 5-Methoxy-3,4-methylenedioxyamphetamine hydrochloride 1-(5-Methoxy-3,4-methylenedioxyphenyl)-2-aminopropane hydrochloride

Action

MMDA is a new amphetamine derivative. It is subjected to control because of its hallucinogenic effects.

References

Fed Reg 35 (47), 4305-4306 (1970).

Moenomycin

Action

Moenomycin, a new antibiotic isolated from Streptomyces bambergiensis, is a mixture of several very chemically similar components, which are particularly characterized by their phosphorus content.

Manufacturer

Farbwerke Hoechst AG (Germany)

128

References

1. R. Tschesche et al. Tetrahedron Letters 3, 141-144 (1969). 2. Moenomycin VII. Isolation and properties of further components of the antibiotic moenomycin. U. Schacht and G. Huber. J Antibiotics 22 (12), 597-602 (1970).

Moperone (Rec INN)

R 1658 Moperonum (Lat). Moperona (Sp) Methylperidol p-Fluoro-4-(4'-hydroxy-4'-p-tolylpiperidino) butyrophenone 1-[γ-(p-Fluorobenzoyl) propyl]-4-(p-tolyl) piperidine-4-ol

Synthesis

Prepared by condensing γ-chloro-p-fluorophenylbutyrophenone with 4-(p-tolyl)piperidine-4-ol.

Description

Crystals, mp 118-119.5°. The hydrochloride melts at 216-218°.

Action

Moperone is a highly potent and specific neuroleptic drug, closely related to haloperidol -the prototype of the neuroleptics of the butyrophenone series. The distribution and metabolism of the drug in the brain, liver and blood has been recently studied in rats.

Manufacturer

Janssen Pharmaceutica (Belgium)

Proprietary Name

Luvatrena

References

1. P. A. J. Janssen. Brit pat 881,893; J Med Pharm Chem 1,281 (1959).

2. On the distribution and metabolism of neuroleptic drugs. II. Pharmacokinetics of moperone. J. J. P. Heykants et al. Arzneim-Forsch 20 (9), 1238-1242 (1970).

Moquizone (Rec INN)

Rec 14-0127

1-Morpholinoacetyl-3-phenyl-2,3-dihydro-4(1H)-quinazolinone

Description

Moquizone is soluble in water, mp 210-214°. The free base melts at 135-137°.

Action

Moquizone is a member of a family of 1-aminoacyl-2,3-dihydro-4-quinazolinone derivatives, which possess choleretic and arrhythmia-preventing activity1. The toxicologic studies on mequizone have been reported2.

Toxicity

LD50 po in mice: 1.155 mg/kg; iv 237 mg/kg.

Manufacturer

Recordati (Italy)

References

1. G. Bonola et al. J Med Chem 11.1136-1139 (1968). 2. Toxicologic investigations on moquizone. I. Setnikar and V. De Fina. Toxicol Appl Pharmacol 16, 571-584 (1970).

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Morantel Tartrate (USAN)

CP-12,009-18

trans-1,4,5,6-Tetrahydro-1-methyl-2-[2-(3-methyl-2-thienyl) vinyl] pyrimidine tartrate (1:1)

Synthesis

By the condensation of 3-methyl-thiophene-2-carboxaldehyde with 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine in methyl formate and subsequent reaction with tartaric acid in isopropanol.

Description

White, odorless, non-staining crystalline solid. It is readily soluble in water.

Action

Morantel tartrate, the 3-methyl analogue of pyrantel, is an anthelmintic which has proved more potent than pyrantel in mice and dogs. The anthelmintic activity of morantel has been demonstrated in controlled laboratory trials involving natural and experimental infections in sheep3. Field trials in sheep have also been reported4,5.

Manufacturer

Chas Pfizer and Co, Inc (USA)

References

1. JAMA 208, 1399 (1969). 2. Chas Pfizer Co, Inc. S African Appl 68,0516. 3. Controlled laboratory trials in sheep with the anthelmintic morantel. R. L. Cornwell and R. M. Jones. Br Vet J 126, 142 (1970). 4. Field trials in sheep with the anthelmintic morantel tartlate I. Prophylaxis of Nematodirus infection in lambs. R. L. Cornwell and R. M. Jones. Vet Rec 86, 430-433 (1970). 5. Field trials in sheep with the anthelmintic morantel tartrate. R. L. Cornwell and R. M. Jones. Vet Rec 86, 465-469 (1970).

Morphethylbutyne

Hydrochloride

2-Methyl-2-phenoxypropionic acid, 2-morpholinoethyl ester hydrochloride 2-Phenoxy-isobutyric acid, 2-morpholine-ethyl ester hydrochloride

Synthesis

Prepared from a-phenoxyisobutyl chloride and 2-morpholinoethanol1.

Description

Crystals, mp 143-145°. The free base, bp 127-130°.

Action

Morphethylbutyne is a new non-narcotic antitussive agent.

Manufacturer

Instituto Farmacologico Serono (Italy)

References

1. E. Marchetti et al. Farmaco. Ed Sci. 20 (10), 696-706 (1965). 2. Clinical trials on a new antitussive agent. M. Serembe and M. Barbetti. Farmaco Ed Pract, 24, 700-706 (1969). 3. Distribution and metabolic fate of morphethyl-butyne in rats. E. Marchetti and G. Bergesi. Arch Int Pharmacodyn 184 (2), 245-251 (1970).

Moxestrol (Prop INN)

R-2858

11β-Methoxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol 11β-Methoxy-17α-ethynylestra-1,3,5(10)-triene-3,17β-diol 17α-Ethynyl-11-methoxyestradiol

130

Synthesis

The reaction of 4,9-estradiene-11β-ol-3,17-dione with methanol and p-toluenesulfonic acid in methylene chloride gives the corresponding 11β-methoxy derivative, which is refluxed with palladium hydroxide in methanol to give an aromatized monoketonic intermediate. This is treated with potassium acetylide in terc-amyl alcohol-dioxane to give 17α-ethynyl-11β-methoxy-1,3,5(10)-estratriene-3,17β-diol.

Description

Crystals, mp 280º (ethyl acetate). [α]D = +29° (c=0,6 in ethanol). UV max 280 µm [E(1 %,1 cm) = 58.4] and 286 µm [E(1 %, 1 cm) = 53.2]; sh 218, 221 and 229 µm.

Action

Moxestrol exhibits pronounced estrogenic activity. It has been found to be more potent than estradiol and ethinylestradiol. It is under clinical study.

Manufacturer

Roussel Uclaf (France)

References

1. WHO Chron 24 (9), 426 (1970). 2 .Roussel-UCLAF. S African 67 03,381. 3. Controle par la eytologie vaginale des ettets dans la post-menopause d'un nouvel oestrogene, Ie 17α-ethinyl-11-methoxy-oestradiol. J. H. Soutoul et al. C R Soc Fr Gynecol 39 (6), 695-704 (1969). 4. R-2858, a highly potent estrogenic compound. D. Bourquin et al. Third Int Congr Horm Steroids, Hamburg 7-12 Sept 1970, abs 312. Excerpta Medica International Congress Series No 210.

Multhiomycin

Multhiomycin is a new antibiotic obtained from the mycelium of Streptomyces antibioticus 8446-CC.

Description

Yellow needle-shaped crystals, mp above 300º.

Action

Multhiomycin is an antibiotic which only exhibits inhibitory activity against gram-positive bacteria.

References

1. A new antibiotic multhiomycin. T. Tanaka et al. J. Antibiotics 23 (5), 231-237 (1970).

Mycophenolic Acid (USAN;

Prop INN) Lilly 68618

(E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid

Production

Antibiotic isolated from the fermentation broth of Penicillium brevicompactum.

Description

Needles, mp 141º (hot water); freely soluble in alcohol and almost insoluble in water.

Action

Mycophenolic acid is an antibiotic substance which exhibits anti-tumor and immunosuppressive activity.

Manufacturer

Eli Lilly and Co (USA); ICI (UK)

References

1. JAMA 212, 2247 (1970). 2. WHO Chron 24 (9), 413 (1970). 3. Imperial Chemical Industries Ltd. Brit pat 1,158,387; 1,157,099. 4. J. H. Birkinshaw et al. Biochem J 43, 21 q-223 (1948).

131

5. J. H. Birkinshaw et al. Biochem J 50, 630-634 (1952). 6. W. R. Logan et al. J Chem Soc 1946-1951 (1957). 7. Imperial Chemical Industries Ltd. Brit pat 1,157,100 (Pharmaceutical compositions).

Myxin Cupric Complex

6-Methoxy-1-phenazinol-5,10-dioxide cupric complex 1-Hydroxy-6-methoxyphenazin-5,10-dioxide cupric complex

Synthesis

Prepared from myxin and cupric acetate.

Action

Myxin cupric complex has proved to show a high degree of therapeutic activity against gram-positive and gram-negative bacteria, yeats and dermatophytes in cutaneous infections of laboratory animals.

Manufacturer

Roche Laboratories (USA)

References

1. Hoffman La Roche. Ger Offen 1.931.466. 2. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago Oct 18-21 (1970); abs 19.

Nafenopin (USAN; Prop INN)

SU 13437 CH 13437

Nafenopinum (Lat). Nafenopino (Sp)

2-Methyl-2-[p-(1,2,3,4-tetrahydro-1-naphthyl)phenoxy]propionic acid

Synthesis

Prepared by reacting 1-(4-hydroxyphenyl)-1,2,3,4-tetrahydronaphthalene with sodium and 2-bromoisobutyric acid ethyl ester, followed by saponification of the resulting compound.

Description

Crystals, mp 131-132º (ether-hexane).

Action

Nafenopin has been found to be effective in lowering plasma cholesterol and triglycerides in the experimental animal. It has also been shown to be a potent hypolipidaemic agent in man.

Manufacturer

CIBA Pharmaceutical Co (USA) Hoechst AG (Germany)

References

1. JAMA 212, 467 (1970). 2. WHO Chron 24 (9), 426 (1970). 3. CIBA Ltd. Neth Appl 6A13.268. 4. R. Hess and W. L. Bencze. Experientia 24, 410 (196B). 5. G. Hartmann and G. Foster. J Atheroscler Res 10. 235-246 (1969). 6. Effects of SU-13437 on serum lipids in hyperlipoproteinemic patients. P. Weiss etal. Clin Pharmacal Thel 11 (1). 90-96 (1970). 7. Metabolism of SU-13434-a new hypolipidemic drug in man. J. R. Bianchine et al. Clin Pharmacol Ther 11 (6), 97-105 (1970). 8. Effect of a hypolipidaemic drug (CH 13A37) on plasma and tissue lipids, and on the intravenous fat tolerance in man. J. Boberg et al. Atherosclerosis 11. 353-360 (1970). 9. On the effect of the hypolipidaemic phenyl ether CH 13,437 on the liver metabolism of the rat. U. Schacht and E. Granzer, Biochem Pharmacol 19, 2963-2971 (1970). 10. Lipid effects of a phenolic ether (Su-13437) in the rat: Comparison with CPIB.

132

M. M. Best and C. H. Duncan. Atherosclerosis 12 (2), 188 (1970). 11. A. clinical trial with a new hypolipidemic agent (CH-13437). Arteaga et al. Rev Med Chile 98 (9), 111 (1970).

Nafomine Malate (USAN; Prop

INN)

Nafominum (Lat). Nafomina (Sp) 2-Methyl-1-naphthalenemethoxamine malate O-[(2-Methyl-1-naphthyl)-methyl]-hydroxylamine malate

Synthesis

From 1-chloromethylnaphthalene. The hydrochloride melts at 198-199° (methanol-acetonitrile).

Action

Nafomine malate is a centrally acting muscle relaxant.

Toxicity

DL50 ip in mice: 500 mg/kg; po in mice: 1.210 mg/kg.

Manufacturer

The Wm S. Merrell Co (USA)

References

1.JAMA 212.1360 (1970). 2. WHO Chron 24 (3), 132 (1970). 3. Richardson-Merrell Inc. Belg pat 654.632.

Nalbuphine (Rec INN; USAN)

EN 2234A

Nalbuphinum (Lat). Nalbufina (Sp)

17-(Cyclobutylmethyl)-4,5α-epoxymorphinane-3,6α,14-triol

Synthesis

Prepared from 14-hydroxydihydronormorphinone1,2.

Description

Crystals, mp 229-231°.

Action

Analgesic-narcotic antagonist.

Manufacturer

Endo Laboratories (USA)

References

1. Endo Laboratories. Brit pat 1,119,270. 2. Endo Laboratories. US pat 3.332,950. 3. A double blind controiled study on the pharmacologic effects of nalbuphine. H. W. Elliot at al. J Med 1(2), 74 (1970).

Nandrolone Laurate

17β-Hydroxyestr-4-en-3-one 17-dodecanoate 19-Nortestosterone dodecanoate Norandrostenolone dodecanoate

Action

Nandrolone laurate is a new long-acting anabolic agent. In a clinical study on patients with very poor physical condition, the administration of 100 mg of

133

the drug, once a month, for several months has proved to be effective.

Manufacturer

Organon NV (Netherlands and France)

Proprietary Name

Clinibolin

References

Le laurate de nandrolone. nouvel anabolisant a action prolongee. A. Tsougranis. Immex 7 (2). 289-292 (1970).

Naphthypramide DA 992

Naftipramide α-[2-(Dimethylamino) ethyl]-α-isopropyl-1-naphthaleneacetamide α-Isopropyl-α-(2-dimethylaminoethyl)-1-naphthyl acetamide

Synthesis

Prepared by hydrolysis of α-isopropyl-α-(2-dimethylaminoethyl)-1-naphthylacetonitrile.

Description

Colorless crystals, mp 134º (ethanol/water = 3/7); 134-135º (ligroin).

Action

Naphthypramide is a new anti-inflammatory and antipyretic compound, also showing analgesic activity. It has shown to be effective and well tolerated in clinic.

Manufacturer

Instituto De Angeli (Italy)

References

1 . Instituto De Angeli. Neth Appl 6,405,327. 2. S. Casadio et al. J Med Chem 8 (5), 594-8 (1965). 3. Double blind trial of naphthypramide (DA-992) in osteoarthritis. E. Camarri et al. Curr Ther Res 12 (1), 1-9 (1970).

Naproxen (USAN; Prop INN)

(+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid (+)-2-(6'-Methoxy-2'-naphthyl)-propionic acid

Synthesis

Prepared by treating diethyl 6-methoxy-2-naphthalenemalonate with sodium hydride and methyliodide, followed by hydrolysis and decarboxylation.

Action

Naproxen is a new anti-inflammatory, analgesic and antipyretic agent.

Manufacturer

Syntex Laboratories, Inc (USA)

References

1. WHO Chron 25 (3), 138 (1971). 2. Syntex Corp. S African Appl 6,707,597. 3. MNPA, a potent anti-inflammatory and analgesic agent. W. H. Rooks. Fed Proc 29, 420 (1970).

Naproxol (USAN; Prop INN)

RS 4034

(-)-6-Methoxy-β-methyl-2-naphthaleneethanol (-)-β (6-Methoxy-2-naphthyl)-β-methylethanol

134

Synthesis

Prepared by reduction of α-methyl-6-methoxy-2-naphthalene acetic acid with lithium aluminum hydride or diborane. The optical isomer may be prepared by decomposition of the cinchonidine salt of naproxol monophthalate and subsequent saponification.

Action

Naproxol exhibits anti-inflammatory, antipyretic and analgesic activity.

Manufacturer

Syntex Laboratories Inc (USA)

References

1. JAMA 213, 2248 (1970). 2. WHO Chron 25 (3), 138 (1971). 3. Syntex Corp. S African Appl 693229.

Narbomycin

B 62159B

Production

From the culture filtrate of Streptomyces fradiae strain B 62159 two antibiotics have been recently isolated, which have been found to be identical to pikromycin and narbomycin respectively.

Description

mp 109-110°; [ α]D = +42.6 in ethanol and +55° in chloroform.

Action

Broad spectrum antibiotic.

Manufacturer

Takeda Chemical Industries (Japan)

References

Jap Mad Gaz 7 (2), 6 (1970).

Naringenine

Naringetol. Salipurpol 4',5,7-Trihydroxyflavonone

Synthesis

Prepared by hydrolysis of naringine, which is the glycoside,

Description

Needles, mp 251º; UV absorption maxima at 226 and 292 µm.

Action

Naringenine reduces capillary permeability.

Toxicity

LD50 ip in mice: 355 mg/kg.

References

1. Asahina. Ber 61,1514 (1928). 2. Rosenmund. Ber 61, 2608 (1928). 3. Zemplen. Ber 75, 648 (1942). 4. Effect of naringenine on the capillary fragility and permeability. Y. M. Khadzhai. Farmakol Toksikol 33, 313-316 (1970).

135

NC 1140

3-Trifluoromethyl-s-triazolo [3, 4α] isoquinoline

Action

NC 1140 is a substituted isoquinoline, which has been found to possess anti-inflammatory, analgesic and antipyretic activity in the rat. Its absorption, distribution and excretion has been studied in the dog, rat and monkey.

Manufacturer

Neisler Laboratories, Inc (USA)

References

The absorption, distribution and excretion of 3-trifluoromethyl-s-triazolo (3, 4α) isoquinoline. M. J . Bartek et al. Toxicol Appl Pharmacol 17, 41-52 (1970).

NC-3266

8, 9-Dimethoxy-s-triazolo [3,4α] isoquinoline

Action

It has been proved that NC-3266 specifically inhibits the aggressive response in both mousekilling (muricidal) and septal-Iesioned rats at doses below those which produce evidence of neurotoxicity. Pharmacologic activity of a new class of agents which selectively inhibit aggressive behavior in rats.

References

M. E. Goldberg. Arch Int Pharmllcodyn Ther 186 (2), 287-297 (1970).

NC 3539

3-Methyl-8,9-dimethoxy-s-triazolo [3,4α] isoquinoline

Action

It has been proved that NC-3539 specifically inhibits the aggressive response in both mousekilling (muricidal) and septal-Iesioned rats at doses below those which produce evidence of neurotoxicity. Pharmacologic activity of a new class of agents which selectively inhibit aggressive behavior in rats. .

References

M. E. Goldberg. Arch In! Pharmacodyn Ther 186, (2). 287-297 (1970).

NC 7197

2-(3-Ethylsulfinylpropyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

Action

The cardiovascular effects of NC 7197 have been recently described. It has been suggested that the drug is a competitive α-adrenergic blocking agent. It appears to produce its cardiac effects through indirect adrenergic mechanisms.

Manufacturer

136

Warner-Lambert

References

Cardiovascular effects of NC 7197. P. J. Privitera et al. Fed Proc 29 (2), 274 (1970).

Nefopam Hydrochloride (Prop

INN; USAN)

3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2.5-benzoxazocine hydrochloride

Synthesis

Prepared by the reduction of N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide with lithiumaluminum hydride in refluxing tetrahydrofurane and the reaction of the resulting alcohol with p-toluenesulfonic acid in refluxing benzene.

Description

Crystals. mp 238-242°.

Action

Muscle relaxant.

Manufacturer

Riker Laboratories Inc (USA)

References

1. WHO Chron 25 (3). 138 (1971). 2. Drug Trade News. p 26 (February 8. 1971). 3. B. J . Baltes (to Rexal Drug and Chemical Co) . US pat 3.487.153 .

Negamycin

Antibiotic isolated from culture filtrates of three strains of Streptomyces

Description

Colorless powder, mp 110-112° (dec).

Action

Antibiotic of low toxicity and effective in vivo against gram-positive and gram-negative bacteria.

Toxicity

LD50 iv in mice: 400-500 mg/kg.

References

1. A new antibiotic, negamycin. M. Hamada et al. J. Antibiotics 23 (3), 170-171 (1970). 2, Mechanism of action of negamycin in Escherichia coli K 12. I. Inhibition of initiation of protein synthesis. S. Mizuno et al. J Antibiotics 23 (12), 581 (1970).

Neopluramycin

Production

It has been isolated from the cultured broth of a strain of Streptomyces pluricolorescens.

Description

Orange crystals, mp 180-184° (dec). [ α]D = +362° (c=1.05, chloroform).

Action

Neopluramycin is a new antibiotic, which inhibits growth of gram-positive bacteria and shows experimental cytostatic activity, Isolation and characterization of a new antibiotic, neopluramycin.

137

References

S. Kondo et al. J Antibiotics 23 (7), 354-359 (1970).

NF

1-(p-β-Pyrrolidinoethoxyphenyl)-2-phenylnaphto [2, 1-b] furan

Description

Crystals, mp 81°. The hydrochloride salt melts at 211°.

Action

NF is a new oral antifertility agent. Its biologic properties have been described in detail. The compound has a favorable therapeutic index.

Manufacturer

Central Drug Research Institute, Lucknow (India)

References

1. Antifertility agents IV. 2,3-diphenylbenzo-and 5,6-polymethylenebenzofurans, 2-diphenylnaphthofurans, and some related compounds. H. P. S. Chawla et aL J Med Chem 13 (1), 54-59 (1970). 2. Biological properties of 2-phenyl-3-p-(β-pyrrolidinoethoxy)-phenyl (2:1,-b) naphthofuran-a new oral antifertility agent. V. P. Kamboj at al. Contraception 1 (1), 29-45 (1970) .

Nifungin (USAN; Prop INN)

A18894

Nifunginum (Lat). Nifungina (Sp)

Action

Nifungin is an antifungal antibiotic obtained from cultures of Aspergillus giganteus.

References

1. JAMA 212, 2246 (1970). 2. WHO Chron 24 (9), 427 (1970).

Nifuratrone (USAN; Prop INN)

WSM 10,166

Nifuratronum (Lat). Nifuratrona (Sp) N-(2-Hydroxyethyl)-α-(5-nitro-2-furyl) nitrone

Synthesis

By reacting 5-nitrofurfural with N-(2-hydroxyethyl) hydroxylamine hydrochloride.

Description

Yellow needles, mp 151-152°. Very soluble in water.

Action

Antimicrobial; active against a wide spectrum of gram-positive and gram-negative bacteria; effective in clinic.

Manufacturer

Dainippon Pharmaceutical Co, Ltd (Japan); Hess and Clark [Div Richardson Merrell (USA) 1

References

1. JAMA 211,2149 (1970). 2. WHO Chron 24 (9), 427 (1970). 3. Dainippon Pharmaceutical Co, Ltd. Brit pat 1,105,007. 4. The Pharmacologist 12 (2), 220 (Fall) 1970; abs. 115. 5. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, III., Oct. 18-21 (1970); Abstr 49-51.

138

Nifurpirinol (Rec INN)

P 7138

Nifurpirinolum (Lat) Furpyrinol 6-[2-(5-Nitro-2-furyl) vinyl]-2-pyridinemethanol 6-Hydroxymethyl-2-[2-(5-nitro-2-furyl) vinyl] pyridine

Synthesis

Prepared by treating 5-nitrofurfural with 2-methyl-6-acetoxy-methylpyridine, and hydrolyzing the resulting 2-[2-(5-nitro-2-furyl)vinyl]-5-acetoxymethylpyridine with sulphuric acid. Also, by reacting 2-[2-(5-nitro-2-furyl)vinyl]-6-methylpyridine N-oxide with acetic anhydride.

Description

Crystals, mp 170-171º (acetone).

Action

New chemotherapeutic agent against fish diseases.

Toxicity

LD50 ip and po in mice > 2000 mg/kg.

Manufacturer

Dainippon Pharmaceutical Co, Ltd (Japan)

References

1. WHO Chron 24 (11), 531 (1970)_ 2. Dainippon Pharmaceutical Co, Ltd. Brit pat 1,053,730. 3. Abst. Internal Cong. Chemother (Tokyo) 6:385 (Aug 1969).

Nifurtimox (Prop INN)

Bay 2502

Nifurtimoxum (Lat)

Tetrahydro-3-methyl-4-[(5-nitrofurfurylidene) amino]-2H-1,4-thiazine 1,1-dioxide 4-[(5-Nitrofurfurylidene) amino]-3-methylthio-morpholino-1,1-dioxide

Synthesis

Prepared in several steps from 2-mercaptoethanol and propyleneoxide; the last being the condensation of 4-amino-3-methyl-tetrahydro-1,4-thiazine-1,1-dioxide with 5-nitrofurfural.

Description

Orange, crystals, mp 182º (dil. acetic acid).

Action

Antitrypanosomal.

Manufacturer

Bayer (Germany)

Proprietary Name

Lampit.

References

1. WHO Chron 23, 204 (1969). 2. Farbenfabriken Bayer A. G. Ger pat 1,170,957. 3. Manuf Chem 41 (1), 72 (1970). 4. Nouveau medicament contre la maladie algüe de Changas. Med Hyg (922), 1052 (1970).

Nimorazole (Prop INN)

Nitrimidazine 4-[2-(5-Nitroimidazol-1-yl) ethyl]-morpholine N-β-Morpholinoethyl-5-nitroimidazole

139

Synthesis

From 5-nitroimidazol sodium salt and β-chloroethylmorpholine1. Also, from 1-(2'-p-toluensulfonyloxyethyl)-5-nitroimidazole and morpholine2.

Description

Yellow crystalline powder, mp 110-111º1;109-110º2,

Action and Uses

Nimorazole is a new topical and oral antitrichomonal agent. For use in the systemic treatment of infections by Trichomonas vagina/is and management of associated conditions.

Dosage

500 mg daily (250 mg after breakfast and 250 mg after evening meal) for an average of six consecutive days.

Supplied as

Tablets, 250 mg.

Proprietary Name

Noxogin.

Manufacturer

Carlo Erba (England) .

References

1. Carlo Erba S. p. A. US pat 3,399,193, 2. Merck Co, Inc. Neth Appl 6,609,552 and 6,609,553 3. Med Act (Drugs of Today), 6 (5), 185-187 (1970). (Review with 6 references).

Nisobamate (USAN; Rec INN)

W

1015

Nisobamatum (Lat); Nisobamato (Sp) 2-Hydroxymethyl-2,3-dimethylpentyl carbamate isopropylcarbamate 2-sec-Butyl-2-methyl-1,3-propanediol carbamate isopropylcarbamate

Synthesis

Prepared by reacting N-isopropyl-2-methyl-2-sec-butyl-3-hydroxypropyl carbamate with cyanic acid as a carbamating agent.

Description

Crystalline solid, mp 78-80°.

Action

Tranquillizer, sedative and hypnotic.

Toxicity

LD50 ip in mice: 555 mg/kg.

Manufacturer

Carter Wallace (USA)

References

1. JAMA 207,1508 (1969). 2. Cron OMS 23 (10), 534 (1969). 3. Carter Products Inc. Brit pat 889.641.

Nitrofungin

2-Chloro-4-nitrophenol

140

Action

Nitrofungin is an antimycotic agent. In a recent study it has been found that the compound is degraded to four metabolites only on using resistant strains; sensitive strains lacked this property.

References

Microbial degradation of the antifungal agent 2-chloro-4-nitrophenol (nitrofungin). A. Capek et al. Folia Microbiol 15, 350-353 (1970).

Norbolethone (USAN)

Wy 3475

Norboletone (Rec INN). Norboletonum (Lat) dl-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-3-one dl-13, 17α-Diethyl-17-hydroxygon-4-en-3-one

Synthesis

Prepared by treatment of 13β,17α-diethyl-3-methoxygona-2,5(10)-dien-17β-ol with aq hydrochloric acid. Also from 13β,17α-diethyl-17β-hydroxygon-5(10)-en-3-one and methanolic HCl.

Description

Crystals, mp 144-145°. UV max 241 µm [ ε=16.500].

Action

Norbolethone is a new totally synthetic anabolic steroid of the gonone series. A recent trial has

shown the drug to be an effective and safe drug in stimulating linear growth in stunted children.

Manufactuter Wyeth Laboratories (USA)

Proprietary Name

Genabol

References

1. H. Smith et al. J Chem Soc 4472 (1964). 2. Efficacy of norbolethone in stimulating linear growth in stunted children. A. N. Gogate. Curr Ther Res 12 (6), 323-332 (1970).

Norethisterone Enanthate

Norethindrone enanthate 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one heptanoic acid ester

Action

The clinical and biochemical observations of a trial with norethisterone enanthate have been reported. 200 mg of the drug were administered intramuscularly to 10 normal fertile women every twelve weeks over a period of 9 months. No pregnancy was observed.

Manufacturer

Schering AG (Germany)

References

Clinical and biochemical observations under treatment with the depotcontraceptive agent norethisterone enanthate. R. Petry et al. Third International Congress on Hormonal Steroids. Hamburg 7-12 Sept 1970. abstr 462. Excerpta Medica. International Congress Series No 210.

141

d-Norgestrel

d-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one

Description

White crystalline powder. UV max 241 µm [E(1 %, 1 cm) =549] in methanol. Norgestrel is a racemate, that is, a mixture of equal parts of the d and I optical enantiomers.

Action

Experimental studie shave shown that I norgestrel lacks anti estrogenic and progestational properties, and that the d-enantiomer has twice the potency of the racemate. The results of a clinical trial have proved that the combination d-norgestrel (0.25 mg)-ethinylestradiol (0.5 mg) is of equal contraceptive efficiency to the standard combination, norgestrel racemate (0.50 mg)-ethinyl estradiol (0.05 mg). The drug has just been marketed in Switzerland.

Proprietary Name

Stediril-d

Supplied as

Scored tablets with 0.25 mg of d-norgestrel and 0.05 mg ethinylestradiol

Manufacturer

Wyeth (USA)

References

1. Biological effects of racemic and resolved 13β-ethyl-4-gonen-3-ones. R. A. Edgren et al. Steroids 2, 731 (1963). 2. Biological effects of synthetic gonanes. R. A. Edgren et al. Recent Progress in Hormone Research 22, 305 (1966). 3. d-Norgestrel combined with ethinyl oestradiol as an oral contraceptive. W. G. McBride. Curr Ther Res 12 (4), 177-185 (1970).

Noxiptiline Hydrochloride (Rec

INN) BAY 1521

Noxiptilinum (Lat). Noxiptilina (Sp) 10,11-Dihydro-5H-dibenzo [a,d] cyclohepten-5-one, O-[2-(dimethylamino) ethyl] oxime hydrochloride 5-(2-Dimethylaminoethoxyimino)-5H-dibenzo [a,d] cyclohepta-1,4-diene hydrochloride

Synthesis

Prepared by the reaction of 10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-one with hydroxylamine, and the reaction of the resulting ketoxime with β-chloroethyldimethylamine in presence of sodium ethylate. It may also be prepared by the reaction of 10,11-dihydro-5Hdibenzo [a,d] cyclohepten-5-one with β-dimethylamino-ethoxyamine dihydrochloride1-3.

Description

White crystalline powder, mp 189-191°.

Action and Uses

Noxiptiline, a tricyclic oxyimino ether, is a new antidepressive drug. It is used in the treatment of mental depression.

Dosage

Intramuscularly: 25 to 50 mg 2-3 times daily. Orally: for initiating treatment, 25 to 50 mg 2-3 times daily. This dosage may be increased to 300 mg if necessary. The usual maintenance dosage is: 100 to 200 mg daily in endogenous depressions and 25 to 100 mg in other types of depressions.

Supplied as

Tablets 28.1 and 56.2 mg (equivalent respectively to 25 and 50 mg of noxiptiline base). Solution (injection) 50 mg/2 ml.

Proprietary Names

Agedal (Bayer AG, Germany).

Manufacturer

Bayer AG (Germany)

142

References

1. H. Eugelhard. Ger pat 1,198,353, 2. B. B. Wylie at al. J Pharm Sc 54 (9), 1373-1376 (1965). 3. G. Aichinger et al. Arzneim-Forsch 19 (5a), 838-845 (1968). 4. Med Act (Drugs of Today) 6 (2), 58-60 (1970). (Review with 20 references). 5. Su alcuni aspetti tossicologici e farmacodinamici di un nuovo derivato “triciclico” ad azione antidepressiva: [5-(dimetilaminoetiloximino-5Hdibenzo-[a.d)-cicloepta-1,4-diene) cloridrato) (BAY 1521). E. Marmo. II Farmaco (Ed Prac) 25 (9). 519-567 (1970).

NSC1026

1-Aminocyclopentanecarboxylic acid

Description

White crystalline solid with a solubility of 5 g/100 ml of water.

Action

NSC 1026 is a synthetic amino acid, which has shown antitumor activity. The results of a recent clinical study suggest that the drug may be specific in its therapeutic effect upon leiomyosarcoma.

References

1. R. B. Ross et al. J Med Pharm Chem 3, 1-23 (1961). 2. L. Berlinguet et al. Nature 194, 1082-1083 (1962). 3. Phase II study of NSC 1026 in patients with cancer. J. B. Aust at al. Cancer Chemother Rep 54 (4), 237-241 (1970).

NSC-119875

cis-Diamminedichloroplatinum Pt(NH2)2 Cl2

Description

Yellow crystals, decompose at about 270º

Action

This compound has proved to be effective in retarding the growth of the Sarcoma 180 tumor and in regressing large Sarcoma 180 tumors in mice. In a recent study it has shown to inhibit the development of both Dunning leukemia and the intramuscular Walker 256 tumor in rat.

References

1. Platinum compounds: a new class of potent antitumor agents. B. Rosenberg et al. Nature 222, 385-386 (1969). 2. Inhibition of Dunning ascitic leukemia and Walker 256 carcinosarcoma with cis-diamminedichloroplatinum (NSC-119875). R. J. Kociba et al. Cancer Chemother Rep 54 (5), 325-328 (1970).

Octoclothepin

8-Chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo [b,f] thiepin

Synthesis

In several steps from p-chlorothiophenol and o-iodophenylacetic acid1,2.

Description

Crystals, mp 99-101° (aq ethanol). UV max 211 µm [E(1%, 1 cm) = 707] and 265 µm [E (1 %, 1 cm) = 336].

Action

Octoclothepin is a new neuroleptic agent. Clinical trials have revealed that the drug exhibits a remarkable antipsychotic effect.

Manufacturer

143

Spofa (Czechoslovakia)

Proprietary Name

Clotepin.

References

1. J. O. Jilek et al. Coll Czechoslav Chem Commun 33, 1831 (1968). 2. M. Protiva et al. Farmaco, Ed Sci, 20, 721 (1965). 3. J. Metysova and J. Metys. Activ Nerv Super 9, 424 (1967). 4. The fate of octoclothepin in the animal organism. A. Franc et al. Biochem Pharmacol19, 1443-1448 (1970). 5. Experience with octoclothepin in manic syndromes. K. Nahunek et al. Scripta Med 42, 6-7 (1969). 6. Further clinical experience with octoclothepine. K. Nahunek et al. Act Nerv Super 12 (3), 239 (1970). 7. Effects of octoclothepin and chlorpromazine evaluated by a standardized interview. O. Vinar et al. Act Nerv Super 12 (3), 241 (1970). 8. Our experiences with octoclothepin. J. Molean et al. Act Nerv Super 12 (3),243 (1970).

OG 30

2-lmino-4-ethyloxycarbonyl-1,3-diaza-cycloheptane hydrochloride

Description

Crystals, mp 131-132º; [α]D = -74.50 (c=1.04, in water).

Action

OG 30 is a ganglionic stimulant. It has been found to act on the nicotinic receptors of the ganglion cells.

Toxicity

LD50 ip in mice: 58 mg/kg.

Manufacturer

NV Organon (Netherlands)

References

1. A new ganglion-stimulating compound: 2-imino-l, 3-diaza-4-carboxyethylcycloheptane hydrochloride (OG 30). P. R. Saxena. Europ J Pharmacol 7,159-169 (1969). 2. Ganglion-blocking neuromuscular-blocking and other actions of 2-imino-4-ethyloxycarbonyl-1,3-diazacycloheptane hydrochloride (OG 30) a ganglionic stimulant. P. R. Saxena. Europ J Pharmacol 11, 75-83 (1970). 3. Pharmacological properties of some analogues of 2-imino-4-ethyloxycalbonyl-1,3-diazacycloheptane hydrochloride (OG 30), a ganglionic stimulant. P. R. Saxena et al. Arch Intern Pharmacodyn Therap 185 (1). 159-173 (1970).

Orgotein (USAN)

Ormetein Mainly α-helical partly divalent-metal (Mg, Cu, Zn) chelated water soluble protein of fairly low molecular weight (ca 34,000)

Production

From bovine liver in a multi-step process.

Action

Orgotein is a novel modified protein, which exhibits considerable anti-inflammatory potency in several animal models of induced inflammation.

Manufacturer

Beta Labs and Diagnostic Data, Inc (USA)

Proprietary Name

Ontosein.

References

1. JAMA 208, 1399 (1969). 2. Safety evaluation of orgotein. a novel anti-inflammatory protein. S. Carson et al. Fed Proc 29 (2), abs 978 (1970).

Ormetoprim (Prop INN)

Ormetoprimum (Lat). Ormetoprina (Sp)

144

2,4-Diamino-5-(methylveratryl) pyrimidine

Synthesis

Prepared from 2,4-chloro-5-(methylveratryl)pyrimidine.

Description

Crystals, mp 230º

Action

Ormetropim, chemically related to trimethoprim, is used with sulfadiazine in the treatment of infections in dogs.

Supplied as

Film coated tablets containing ormetoprim, 20 mg and sulfadiazine 10 mg. Also, ormetoprim 80 mg and sulfadiazine 400 mg.

Manufacturer

Burroughs Wellcome (England)

Proprietary Name

Trivetrin.

References

1. WHO Chron 23 (4) (1969). 2. F. Hoffmann-La Roche and Co A-G. Neth Appl 6,514,472. 3. F. Hoffmann-La Roche and Co A-G, Neth Appl 6,514,743. 4. Vet Rec 87, xiv (Aug 29, 1970) (advt).

Ornithine Aspartate

I-Ornithine I-aspartate

Synthesis

By reacting I-ornithine with I-aspartic acid1.

Description

Crystals, mp 215-217º (dec); [α]D = + 7.10 (38% in water).

Action

Ornithine aspartate has proved to have a protective effect in the acute ammonia intoxication and carbon tetrachloride poisoning in rats2. Recently, the protective effect of this compound has been studied in conditions in which the organism of the animals would have been submitted to exhaustion of muscular and cardiac strength3.

Manufacturer

Merz Co (Germany)

References

1. Tanabe Seiyaku Co, Ltd. Brit pat 965,637, 2. A. Shioya et al. Jap J Pharmac 14,201 (1964). 3. Protection by ornithine aspartate of the effects of physical exercise. L. Cutinelli et al. Arzneim-Forsch 20 (8), 1064-1067 (1970).

Ornithine-8-vasopressin

POR-8

Ornithine-8-vasopressin is a synthetic derivative of vasopressin.

Action

Ornithine-8-vasopressin is a new haemostatic agent. A double blind trial has shown that the drug

145

is very effective and significantly better than noradrenalin.

Manufacturer

Sandoz (Switzerland)

References

1. R. L. Huguenin et at Helv Chim Acta 46 (5), 1669-76 (1963). 2. Sandoz Ltd. Fr pat 1,396,607. 3. Olin Mathieson Chemical Corp. Fr pat 1,430,140. 4. Ornithine-8-vasopressin, a new vasoconstrictor used for haemostasis during operation for genital prolapse. O Vagn Nielsen and N. Valentin. Acta Obstet Gynec Scand 49, 45-48 (1970).

Oxaflumazine Disuccinate (Rec

INN)

10-[3-[4-(2-m-Dioxan-2-ylethyl)-1-piperazinyl] propyl]-2-(trifluromethyl)-phenothiazine disuccinate

Synthesis

By the reaction of 10-(3-chloropropyl)-2-(trifluoromethyl) phenothiazine with 4-(2-m-dioxan-2-ylethyl) piperazine.

Description

White crystalline powder, mp 1380 ; slightly soluble in water and soluble in methanol. UV max 259.5 µm [E(1 %, 1 cm) = 462] and 310 µm [E(1 %, 1 cm) = 51].

Action and Uses

Oxaflumazine is a new major neuroleptic agent with an action similar to that of trifluorophenazine and fluphenazine. In addition to its main pharmacological action, oxaflumazine also

possesses sedative, analgesic, antihistaminic, antiemetic and weak spasmolytic effects. For use in the treatment of a variety of mental disorders including acute schizophrenia, mania, chronic psychosis, delirium, and certain anxious and delirant forms of melancholia.

Dosage

Oxaflumazine is administered orally and parenterally. The sedative dose ranges from 150 to 400 mg daily. For the treatment of patients with psychosis, dosage ranges from 200 to 500 mg daily.

Proprietary Name

Oxaflumine.

Manufacturer

Diamant (France)

References

1. Societe Industrielle pour la Fabrication des Antibiotiques. Neth Appl 6,508,319. 2. R. Ratouis et al. Bull Soc Chim Fr 9, 2963-5 (1966) . 3. Med Act (Drugs of Today). 6 (3). 87-90 (1970). (Review with 4 (references).

Oxazinomycin

Production

Oxazinomycin is an antibiotic which has been isolated from the culture filtrate of Streptomyces tanesashiensis.

Description

White crystalline compound, mp 164-166º (dec); [α]D = +19,7° (c=1, water). UV max 231-232 µm [E(1%, 1 cm)=168] in water.

146

Action

Oxazinomycin is active against gram positive bacteria and exhibits antitumor activity against Ehrlich mouse ascites carcinoma in vivo.

Toxicity

LD50 iv in mice: 100-120 mg/kg; ip in mice: 10-20 mg/kg.

Manufacturer

Sankyo Co, Ltd (Japan)

References

Oxazinomycin. a new antibiotic. T. Haneishi et al. 174th meeting held July 27. 1970 under the sponsorship of the Japan Antibiotic Research Association (Tokyo).

Oxprenolol Hydrochloride

(Rec INN) Ciba 39089 Ba

1-(o-Allyloxyphenoxy)-3-isopropylamino-2-propanol

Synthesis

By condensing pyrocatechol monoallyl ether with epichlorhydrin, and subsequent reaction with isopropylamine. Also by reacting 3-(o-allyloxyphenoxy)-2-hydroxy-1-chloropropane with isopropylamine1,2,3.

Description

White crystalline powder, mp 107-109°; the free base melts at 75-80°. Freely soluble in water, practically insoluble in ether.

Action and Uses

Oxprenolol is a new potent adrenergic betareceptor blocking agent.

Dosage

Cardiac Arrhythmias - Initially 40-60 mg orally daily, which may be increased to 80 mg if necessary. Angina - Initially 60 mg orally daily which may be increased gradually to 120 mg if necessary.

Registered Names Trasicor.

Manufacturer

Ciba

References

1. ICI Ltd. Neth Appl 6,607,921. 2. CIBA Ltd. Belg pat 669,402. 3. M. Wilhelm et al. Experientia 23 (8), 651-2 (1967). 4. Med Act (Drugs of Today) 6 (1), 25-29 (1970). (Review with 17 references). 5. Oxprenolol-Proceedings of a conference held at Hertford College, Oxford, on April 17, 1970. Postgrad Med J 46 (541, Suppl) (1970).

Oxylidine Hydrochloride

3-Quinuclidinol, benzoate (ester) hydrochloride 3-Benzoylhydroxyquinuclidine hydrochloride 1-Azabicyclo [2.2.2]-3-octanol benzoate (ester) hydrochloride

Synthesis

By reduction of 3-quinuclidinone to yield 3-quinuclidinol, and subsequent reaction with benzoylchloride1.

Description

Crystals, mp 238-240°. The free base boils at 148-150° (0.3 mmHg).

Action

Oxylidine has proved to be useful in the treatment of diseases of the central nervous system and hypertensive diseases. The study of the antiarrhythmic activity of oxylidine has been recently reported.

Manufacturer

All Union Chemo-pharmaceutical Research Institute (USSR)

References

147

1. E. E. Mikhlina et al. Zhur Obshchei Khim 30,163-171 (1960). 2. M. D. Mashkovskii et al. Farmakol Toksikol 25. 32-37 (1962). 3. Antiarrhythmic activity of oxylidine. K. A. Zaitse va and M. D. Mashkovsky. Farmakol Toksikol 33. 305-309 (1970) .

P-1961

4-Amino-1,2,3,4-tetrahydro-1-phenylquinoline hydrochloride

Synthesis

Prepared in three steps from diphenylamine N-propionic acid, the last one being the reduction of 2,3-dihydro-1-phenyl-4-(1 H)-quinolinone oxime 1.2.

Description

Crystals, mp 221-224° (water). The maleate, mp 170-174°, and the free base, bp 110-130° (0.001 mm).

Action

Pharmacological studies have proved that P-1961 shows centrally stimulating and sedating properties. Arousal effects without locomotor component are dominant in the activity profile.

Manufacturer

Chemischen Fabrik Promonta GmbH (Germany)

References

1. Chemische Fabrik Promonta GmbH. Brit pat 1.077,974; Ger pat 1,233,402. 2. O. Hromatka et al. Monatsch Chem 97, 1011 (1966). 3. Pharmacological study on 1-phenyl-4-amino-1,2,3.4-tetrahydroquinoline. P. Marquardt. Arzneim-Forsch 20 (10), 1497-1500 (1970) .

Palmidrol PEA

Palmitoylethanolamide N-(2-Hydroxyethyl) hexadecanamide N-(2-Hydroxyethyl) palmitamide

Synthesis

Prepared by refluxing ethanolamine with palmitic acid1.

Description

Crystals, mp 98-99°. Insoluble in water at room temperature.

Action

Palmidrol is a naturally occurring substance, isolated from soybean lecithin, egg yolk and peanut meal2 and animal tissues. Antianaphylactic, anti-inflammatory effects and an increase of nonspecific resistance to upper respiratory infection have been found after palmidrol treatment. The drug seems also to have moderate stimulating effects, anti-alcvhol activity and extremely low neurotoxicity4.

References

1. E. T. Rooe et al. J Am Chem Soc 74, 3442-3443 (1952). 2. F. A. Kuehl at al. J Am Chem Soc 79, 5577-5578 (1957). 3. Cesk Fysiol 18 (3-4), 346 (1970). 4. Effects of palmitoylethanolamide on the central nervous system. H. Raskova at al. CINP VII Congress Abstracts Vol II. abstr 356 (1970).

Panidazole (BAN)

4-[2-(2-Methyl-5-nitroimidazol-1-yl) ethyl] pyridine 2-Methyl-5-nitro-1-[2-(4-pyridil) ethyl] imidazole

148

Synthesis

Prepared by the reaction of imidazole with 4-vinylpyridine, and by the nitration of the resulting 1-[2-(4-pyridyl) ethyl] imidazole.

Description

Crystals, mp 108-111°.

Action

Panidazole is a new amebicidaI.

References

1. Chem Drug 193, 228 (1970). 2. Ward Blenkinsop and Co, Ltd. Neth Appl 6.606,335.

Parapenzolate Bromide (Prop

INN) SCH 3444

4-Hydroxy-1,1-dimethylpiperidinium bromide benzilate 4-Benziloyloxy-1,1-dimethylpiperidinium bromide N-Methyl-4-piperidylbenzilate methobromide

Synthesis

It is prepared by transhalogenation of N-methyl-4-piperidyl benzilate methiodide with silver bromide, or alternatively by bubbling methyl bromide through a benzene solution of N-methyl-4-piperidylbenzilate. The latter is prepared from N-methyl-4-piperidinol hydrochloride and diphenylchloroacetylchloride.

Description

White crystalline powder, mp 237-238°: the free base melts a 162.5-163°. It is soluble in water.

Action and Uses

Parapenzolate bromide is a new potent anticholinergic. For use in the treatment of peptic ulcers (gastric and duodenal), gastritis, spastic colitis, colopathies and functional digestive

disturbances, such as pain, vomiting and meteorisms.

Dosage

1 to 1.5 mg daily.

Supplied as

Tablets, 0.5 mg.

Registered Names Vagopax.

Manufacturer

Lab Cetrane (France)

References

1. S. B. Coan et al. J Am Chem Soc 78, 3701-3 (1956).

2. Schering Corporation. Brit pat 788,126. 3. Med Act (Drugs of Today), 6 (3), 92-94 (1970). (Review with 12 references).

PC 796

5,5-Diphenyl-1-(phenylsulfonyl) hydantoin

Synthesis

Prepared by rearrangement of 5,5-diphenyl-3-(phenylsulfonyl) hydantoin.

Description

White odorless crystals, mp 222-223°. It is insolub le in water and soluble in alkaline aqueous solution.

Action

PC 796 shows anti-inflammatory, analgesic and antipyretic activity.

149

Manufacturer

Dainippon Pharmaceutical Co, Ltd (Japan)

References

1. Dainippon Pharmaceutical Co. Ltd. Jap pat 6815.186; US pat 3,534,022 2. Pharmacological studies of a new anti-inflammatory drug, 1-phenylsulfonyl-5.5-diphenylhydantoin (PC-796) in experimental animals. H. Nakamura et al. Arzneim-Forsch 20 (8), 1032-1046 (1970).

Pecilocine (Rec INN)

Pecilocin (BAN); Variotin N-(8'-R-Hydroxy-6'-methyl-trans-trans-trans-dodeca-2',4',6'trienoyl)-2-pyrrolidone

Production

Isolated from Paecilomyces varioti banier var antibioticus.

Description

Neutral oil with ester-like odor.

Action

Pecilocine is an antifungal antibiotic marketed in Japan and Denmark as an antitrichophytosis drug. The stereochemical configuration of the antibiotic has been recently elucidated by examining nuclear Overhauser effect.

Manufacturer

Nippon Kayaku Co (Japan) and Leo Pharmaceutical Co (Denmark and England)

References

1. S. Takeuchi et al. J. Antibiotics 12A, 109, 195 (1959); 17 A, 267 (1964). 2. S. Takeuchi et al. Tetrahedron Lett 5197 (1966). 3. Absolute structure of Variotin.

Jap Med Gazz 7 (4), 6 (1970).

Pendecamaine (Prop INN;

USAN)

Pendecamainum (Lat). Pendecamaina (Sp) (Carboxymethyl)-dimethyl-(3-palmitamidopropyl) ammonium hydroxide inner salt

Action

Surfactant and antibacterial compound.

Manufacturer

Th Goldschmidt (Germany)

Proprietary Name

Tego-Betaines.

References

1. WHO Chron 24 (9). 428 (1970) . 2. Chem Drug 193. 228 (1970) .

Penfluridol (Prop INN; USAN)

R 16341

Penfluridolum (Lat) 4-(4-Chloro-α,α,α-trifluoro-m-tolyl)-1-[4,4-bis-(p-fluorophenyl) butyl]-4-piperidinol

150

Description

White microcrystalline powder, mp 105-107°,only slightly soluble in water or in diluted solutions of hydrochloric acid (less than 0.5mg/ml).

Action

Penfluridol is a new member of the potent and long-acting series of diphenylbutyl piperidine neuroleptics of which pimozide is the prototype.

Manufacturer

Janssen Pharmaceutica (Belgium)

References

1. WHO Chron. 24 (9), 429 (1970). 2. JAMA 215,1313 (1971). 3. The pharmacology of Penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug. P. A. J. Janssen et al. Eur J Pharmacol 11, 139-154 (1970). 4. Maintenance therapy of chronic psychotic patients with a weekly oral dose of R 16341. A controlled double-blind study. F. Baro et al. J Clin Pharmacol 10 (5) 330-341 (1970).

Pentamidine Isethionate

MB 800 RP 2512

p,p'-(Pentamethylenedioxy)dibenzamidine bis-(β-hydroxyethanesulfonate)

Synthesis

Prepared from 4,4'-dicyanodiphenoxypentane.

Description

Hygroscopic crystals, mp about 180°

Action

Pentamidine isethionate has been used in the tropics for 30 years in the chemoprophylaxis and treatment of African trypanosomiasis and the treatment of leishmaniasis. The results of a recent study indicate that pentamidine, if given early enough in the course of P. carinii pneumonia, is an effective agent. Since pentamidine is a toxic drug, all efforts should be made to obtain histologic confirmation of P. carinii infection before starting therapy.

Manufacturer

May and Baker Ltd (England)

Proprietary Name

Lomidine.

References

1. May and Baker, Ltd. US pat 2.410.796. 2. Pentamidine isethianate in the treatment of Pneumacystis carinii pneumonia. Karl A. Wester et al. Ann Intern Med 73 (5), 695-702 (1970).

Pentapiperide Methylsulfate

(USAN; Rec INN)

4-Hydroxy-1-methylpiperidinium methylsulfate dl-3-methyl-2-phenyl-valerate

Synthesis

151

Pentapiperide is prepared by the reaction of 3-methyl-2-phenyl valerie acid chloride with 1-methyl-4-piperidinol.

Description

White crystalline powder, mp 110-112°. Very soluble in water and soluble in alcohol. The hydrochloride melts at 85-86°.

Action and Uses

Pentapiperide methylsulfate is a new anticholinergic drug, which is useful as adjunctive therapy in the management of peptic ulcer.

Dosage

10 or 20 mg 3 to 4 times daily .

Supplied as

Tablets 10 mg.

Proprietary Name

Quilene.

Manufacturer

Warner-Chilcott Laboratories (USA)

References

1. Cilag Ltd. Brit pat 781,382. 2. Med Act (Drugs of Today) 6 (2). 61-63 (1970). (Review with 4 references).

Pepstatin

iso-Valeryl-L-valyl-L-valyl-4-amino-3-hydroxy-6-methyl-heptanoyl-L-alanyl-4-amino-3-hydroxy-6-methylheptanoic acid

Production

Pepstatin is obtained from the culture filtrates of four new strains of actinomycetes, including Streptomyces testaceus sp and Streptomyces argenteofus var toyonakensis.

Description

Colorless needles, which melt at 228-229°.[ α]D = -90° (c = 0,228% in methanol). It is soluble in methanol and in ethanol.

Action

Pepstatin is a remarkable inhibitor of pepsin activity in the gastric juice. It is under clinical study and has been shown to be effective in the treatment of peptic ulcer .

Toxicity

LD50 ip in rats: 875 mg/kg.

Manufacturer

Banyu Pharmaceutical Co (Japan)

References

1. Jap Med Gaz 7 (6), 1 (1970). 2. Pepstatin, a new pepsin inhibitor produced by actinomycetes. H. Umezawa et al. J Antibiotics 23 (5), 259-262 (1970). 3. The structure of pepstatin. H. Morishima et al. J Antibiotics 23 (5), 263-265 (1970).

Perhexiline Hydrochloride

(USAN; Rec INN)

Perhexilene (FDA official name)1 2-(2,2-Dicyclohexylethyl) piperidine hydrochloride 1,1-Dicyclohexyl-2-(2-piperidyl)ethane hydrochloride

Synthesis

Perhexiline can be prepared by hydrogenation of the corresponding pyridyl ethylene derivative or by hydrogenation of the corresponding piperidylethylene compound2.

Description

152

Perhexiline hydrochloride is a white crystalline powder, which melts at 243-246°, and is slightly soluble in water and physiologic saline. The acid maleate salt melts at 188.5-191°.

Action

Perhexiline is a new synthetic cardio-vascular agent with interesting effects in both animals and man. It has been shown to reduce exerciseinduced tachycardia in man3,6 and to reduce frequency and/or severity of anginal attacks4. The effects of the drug on the coronary, and peripheral circulation as well as the possible mechanisms of inducing this activity, have been recently reported5.

Manufacturer

The Wm. S. Merrell Co (USA)

Proprietary Name

Pexid.

References

1. Fed Reg 35 (179), 14450-14451 (Sep 15, 1970). 2. Richardson-Merrell Inc. Brit pat 1.025,578. 3. C. A. Bunde et al. Fed Proc 28, 672 (1969). 4. Y. W. Cho et al. Fed Proc 28, 671 (1969). 5. Cardiovascular pharmacology of perhexiline. W. J. Hudak et al. J Pharmacol Exp Ther 123, 287-295 (1970). 6. Clinical evaluation of perhexiline maleate. T. Winsor. Clin Pharmacol Ther 11 (1), 85-89 (1970). 7. Effects of perhexiline maleate on exercise-induced tachycardia. I. L. Grupp et al J Clin Pharmacol 10 (5), 312-315 (1970). 8. Systemic and coronary hemodynamic effects of perhexiline. G. G. Rowe et al. Arch Int Pharmacodyn 187, 377-393 (1970).

Perimetazine (Rec INN)

AN 1317 RP 9159

1-[3-(2-Methoxyphenothiazin-10-yl)-2-methylpropyl]-4-piperidinol 10-[3-(4-Hydroxypiperidino)-2-methylpropyl]-2-methoxyphenothiazine

Synthesis

Prepared from 2-methoxy-10-(3-chloro-2-methylpropyl) phenothiazine and 4-piperidinol1. Also from 3-methoxy-1 0-(3-p-tolylsulfonyloxy-2-methylpropyl) phenothiazine and 4-piperidinol2.

Description

Crystals, mp 137-138º

Action and Uses

Perimetazine is a new neuroleptic agent. It is used for its tranquilizing action in the treatment of neuroses and psychoses in which anxiety, tension and agitation are predominant. Perimetazine exerts an analgesic effect and is useful for the relief of pain of various types. Like chlorpromazine and other phenothiazine derivatives, it exerts an antiemetic effect and may be used for the control of nausea and vomiting.

Supplied as

Tablets, 5, 25 and 100 mg; solution (injection), 10 mg/ml; suppositories, 5 mg.

Dosage

Orally: In psychotic conditions, 100 to 250 mg daily. In neuroses, 10 to 100 mg daily.

Registered Name Leptryl.

Manufacturer

Roger Bellon (France)

References

1. Rhone-Poulenc S. A. Brit pat 904,210. 2. Rhone-Poulenc S. A. Ger pat 1,154,117. 3. Med Act (Drugs of Today) 6 (4), 139-142 (1970). (Revie w with 11 references).

153

Perlapine (Rec INN)

HF 2333

6-(4-Methyl-1-piperazinyl) morphanthridine 6-(4-Methylpiperazin-1-yl)-11H-dibenz [b,e] azepine

Synthesis

In three steps from o-aminodiphenylmethane and phosgene3,7. By cyclization of either o-[4-methyl-1-piperazinyl) carboxamido] diphenylmethane4 or 2-aminodiphenylmethane-2'-thiocarboxylic acid 4-methylpiperazide5. Also by the reaction of 6-aminomorphanthridine with sodium amide and methyl-bis(β-chloroethyl)amine6.

Description

Yellow prismatic crystals, mp 138-138.5°

Action

Perlapine is a new hypnotic agent.

Manufacturer

Wander (Switzerland)

References

1. WHO Chron 24 (11), 532 (1970). 2. Chem Drug 193, 228 (1970). 3. Dr. A. Wander AG. Brit pat 1,006,156. 4. ibid. Swiss pat 436,305. 5. ibid. Swiss pat 436,306, 6. ibid. Swiss pat 436,307. 7. F. Hunziker et al. Helv Chim Acta 49, 1433 (1966). 8. G. Stille. Arzneim-Forsch 16 (2), 255-256 (1966). 9. J. Schmutz et al. Chim Ther 2 (6), 424·429 (1967).

Phencarbamide

Diphenylthiocarbamic acid S-[2-(diethylamino) ethyl] ester S-[2-(Diethylamino) ethyl] diphenylthiocarbamate

Synthesis

Prepared from diphenylcarbamyl chloride and β-diethylaminoethanethiol.

Description

Crystals mp 48-49°. The hydrochloride melts at 180-181°.

Action and Uses

Antispasmodic in clinical practice (component of Spasmo-Dolviran-Bayer, Ger). Recent experiments in dogs and rabbits indicate that it is effective in a variety of experimental cardiac arrhythmias. Phencarbamide also exhibits local anesthetic properties.

Manufacturer

Farbenfabriken Bayer AG (Ger)

References

1. Farbanfabriken Bayer AG, Brit pat 871,774 (1961). 2. A study of the antiarrhythmic and focal anaesthetic actions of phencarbamide. B. R. Madan at al. Arch Intern Pharmacodyn 185 (1), 53-65 (1970).

Phentonium Bromide (IAN)

Z

326

8-(p-Phenylphenacyl) hyoscyaminium bromide N-(4'-Phenyl)phenacyl-1-hyoscyaminium bromide

154

Synthesis

Prepared from p-phenylphenacyl bromide and 1-hyoscyamine.

Description

Crystals, mp 193-194°.

Action

Phentonium is a quaternary derivative of 1-hyoscyamine which shows a rather high parasympathetic blocking activity with a negligible ganglion blocking and antimuscarinic activity.

Manufacturer

Zambon SpA (Italy)

References

1. Whitefin Holding SA. Brit pat 1,026,640; Neth Appl 6,513,839. 2. UM Teotino et al. Chimie Therap 3, 453-457 (1968). 3. D. Della Bella et al. Chimie Therap 3, 458-462 (1968). 4. Human pharmacology of phentonium. a new autonomic drug. F. Azzollini et al. Curr Ther Res 12 (11), 734-754 (1970).

Pikromycin B 62159A

Amaromycin

Production

From the culture filtrate of Streptomyces fradiae strain B 62159 two antibiotics have been recently isolated, which have been found to be identical to pikromycin and narbomycin respectively.

Description

mp 164º; [α]D = +12.7° in ethanol.

Action

Broad spectrum antibiotic.

Manufacturer

Takeda Chemical Industries (Japan)

References

Jap Med Gaz 7 (2), 6 (1970).

Pimaricin

Production

From the culture filtrate of Streptomyces natalensis

Description

Crystals, dec at about 200°.

Action

Pimaricin is a tetraene antibiotic effective against Candida strains and Trychophyton sp. The results of a comparative study have shown that pimaricin can supplement or replace fungicidin (nystatin) at least in selected cases, especially where fungicidin-resistance has developed.

155

References

1. A. P. Struyk et al. Antibiotics Annual 878 (1957/58). 2. Preliminary report. Comparative study of pimaricin and fungicidin activity in vitro. M. Hejzlar and V. Vymola. J Hyg Epidemiol Microbiol Imn 14, 211-213 (1970).

Pindolol (USAN; Prop INN)

LB 46

1-(Indol-4-yloxy)-3-(isopropylamino )-2-propanol 4-(2-Hydroxy-3-isopropylaminopropoxy) indol

Synthesis

Prepared by the reaction of 4-hydroxyindol with epichlorhydrin, followed by treatment with isopropylamine.

Description

Crystals, mp 171-173°.

Action

Pindolol is a new beta-adrenergic antagonist, which has recently been marketed in Germany and Switzerland.

Manufacturer

Sandoz

Proprietary Name

Visken (Germany); Viskene (Switzerland).

Supplied as

Tablets, 1 and 5 mg.

References

1. Sandoz Ltd. Neth Appl 6,601,040. 2. K. Saameli. Helv physiol pharmacol Acta 25, 219-221; 432-433 (1967).

3. Un nouveau beta-bloquant, Ie LB-46 (Visken): Controles éctrocardiographiques de son action therapeutique chez les angineux. R. Saner. Therapie 25, 393-401 (1970) . 4. Haemodynamics of the new beta-adrenergic antagonist LB 46 in man. M .. H. Frick et al. Pharmac Clin 2, 134-137 (1970). 5. Klinisch Untersuchungen mit ''einem neuen Betarezeptorenblocker aus der Indolreihe (LB 46). H. Sterz. Wien Klin Wschr 82 (50), 894-899 (1970). 6. Die Behandlung der Angina pectoris mit einem neuen β-Rezeptoren Blocker, dem Preparat LB-46 (4-[2-Hydroxy-3-iso-propylaminopropoxy]-indol). R. P. Saner. Schwaiz Med Wschr 100 (4), 174-179 (1970). 7. Klinisch-pharmakologische Untersuchungen mit einer neuen betarezeptoren-blockierenden Substanz (LB 46, Visken). G. Judmaier et al. Wien Klin Wschr 82 (50), 891-893 (1970). 8. A potent β-adrenoreceptor blocking drug: 4-(2-hydroxy-3-isopropylaminopropoxy) indole. G. E. Moore and S. R. O'Doneli. J Pharm Pharmac 22 (3), 180-188 (1970).

Piperacetazine Hydrochloride

(USAN)

10 [3-[4-(2-Hydroxyethyl)piperidino]-propyl] phenothiazin-2-ylmethyl ketone .

Synthesis

Prepared by the reaction of phenothiazin-2-yl methyl ketone with 1-bromo-3-chloropropane and subsequent reaction of the resulting 10-(chloropropyl) phenothiazin-2-yl methyl ketone with 4-(2-hydroxyethyl) piperidine.

Description

White crystalline powder. Soluble in water, insoluble in ether and in benzene; mp 100-110º (with preliminary softening at 90 to 100º).

Action and Uses

Piperacetazine is a new highly potent phenothiazine derivative, possessing tranquilizing and sedative properties. It is used in the control of hyperactivity,

156

agitation and anxiety states associated with acute and chronic schizophrenic reactions in adult patients.

Dosage

Initially, 10 mg 2-4 times daily. Maintenance dosage, up to 160 mg daily in divided doses.

Supplied as

Tablets, 10 and 25 mg.

Proprietary Name

Quide.

Manufacturer

Dow Chemical (USA)

References

1. G. D. Searle. Brit pat 861,807. 2. Med Act (Drugs of Today) 6 (2). 64-66 (1970). (Review).

Pipethanate Ethobromide

Benzilic acid, 2-piperidinoethyl ester ethobromide 2-(1-Piperidino) ethyl benzylate ethobromide

Synthesis

Prepared by treating pipethanate with ethylbromide1.

Description

White crystalline powder, with a bitter taste, mp 218-220°. Soluble in methanol, slightly soluble in ethan ol and in water, and practically insoluble in ether and in benzene.

Action and Uses

Pipethanate ethobromide is a quaternary parasympatholytic agent. It is used for the management of gastroduodenal ulcers and other gastrointestinal disorders associated with hypermotility and spasm. It is also used in the treatment of spasm of the biliary and urinary tracts.

Dosage

Orally, 10-20 mg 3 to 4 times daily. Parenterally, 10 mg once daily.

Supplied as

Tablets, 10 mg. Ampules 10 mg.

Manufacturer

Nippon Shinyaku Co, Ltd (Japan)

Proprietary Name

Panpuron.

References

1. Nippon Shinyaku Co, Ltd. Brit pat 1,148,858. 2. Jap Med Gazz 7 (11), 7 (1970). 3. Med Act (Drugs of Today) 7 (1), 25-26 (1971). (Review).

Pipoxolan Hydrochloride

(USAN) BR-18

5,5-Diphenyl-2-(2-piperidinoethyl)-1,3-dioxalan-4-one hydrochloride

Synthesis

By the reaction of β-chloropropionaIdehyde diethyl acetal with benzilic acid, 2-(β-chloroethyl)-5,5-diphenyl-1,3-dioxalan-4-one is obtained. The latter reacts with piperidine to give pipoxolan1,2.

Description

White, odorless, crystalline powder, mp 207-209°; i t is soluble in water.

Action and Uses

Pipoxolan is a new spasmolytic agent. For use in the treatment of gastrointestinal, genitourinary and biliary spasm.

157

Dosage

The usual dose for adults is 10 mg either orally or rectally three times daily. Children 10 mg up to twice daily.

Supplied as

Tablets, 10 mg. Suppositories, 10 mg.

Proprietary Name

Rowapraxin.

Manufacturer Rowa-Wagner (Germany)

Bibliografia/Bibliography 1. M. Pailer et al. Monatsch Chem 99 (3), 891-901 (1968). 2. Rowa Wager K. G. Neth Appl 6,613,801; Brit pat 1.109,959. 3. Med Act (Drugs of Today) 6 (3), 94-97 (1970). (Review with 8 references).

Piribedil (Rec INN)

ET 495

2-(4-Piperonyl-1-piperazinyl)-pyrimidine 1-(2-Pyrimidyl)-4-(3,4-methylenedioxybenzyl)-piperazine

Synthesis

Prepared from N-(3,4-methylenedioxybenzyl) piperazine and 2-chloropyrimidine2.

Description

White crystalline powder, mp 97-98° (ethanol). It i s insoluble in water and soluble in chloroform.

Action and Uses

It has been demonstrated experimentally that piribedil acts as a vasodilator, decreasing peripheral vascular resistance, as long as the sympathetic system remains intact. In addition, it decreases the action potentials of the sympathetic fibers. It has a direct vasoconstrictor effect on the smooth muscle fibers in the blood vessels when the sympathetic tonus is decreased or abolished. Lastly, it

considerably decreases the blood reservoir contained in the mesenteric vessels. Piribedil has proved to produce remarkable clinical results in the treatment of artheriopathies of the limbs.

Dosage

60-80 mg daily.

Supplied as

Tablets, 20 mg.

Proprietary Name

Trivastal.

Manufacturer

Lab Servier (France)

References

1. WHO Chron 24 (11), 532 (1970). 2. Science Union et Cie-Societe Francaise de Recherche Medicale. Neth Appl 6.413,349, 3. Med Act (Drugs of Today) 6 (1), 29-32 (1970). (Review with 5 references). 4. Preliminary results in the treatment of peripheral arteriopathies with a new pharmacologic substance (ET 495). R. J. Royer. Bibl Cardial 26, 174-179 (1970).

Piromidic Acid

PD 93

8-Ethyl-5,8-dihydro-5-oxo-2-(1-pyrrolidinyl)-pyrido [2,3-d] pyrimidine-6-carboxylic acid

Synthesis

Prepared by heating 5,8-dihydro-6-ethoxycarbonyl-8-ethyl-2-methylthio-5-oxopyrido [2,3-d] pyrimidine with pyrrolidine.

Description

Crystals, mp 314-316°.

158

Action

Piromidic acid is a new anti-infective agent, which has been found active primarily against gram-negative bacteria and staphylococci.

Toxicity

LD50 po in rats and mice: 4000 mg/kg.

Manufacturer

Dainippon Pharmaceutical Co, Ltd (Japan)

References

1. Dainippon Pharmaceutical Co, Ltd. Jap pat 67 25,912. 2. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Oct. 18-21 (1970); abst 46.

Pivampicillin (Rec INN; BAN;

USAN) VD 923

Pivampicillinum (Lat). Pivampicilina (Sp) D-6-(2-Amino-2-phenylacetamido)-3.3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid hydroxymethyl ester pivalate ester

Synthesis

Prepared from pivaloyloxymethyl 6-amino-penicillinate.

Description

Pivampicillin hydrochloride hemihydrate melts at 155-156°; [ α]D = 200º (c=1. H2O).

Action

Pivampicillin is an acyloxymethyl ester of ampicillin. In experimental mouse infections oral pivampicillin has proved to be superior to the parent antibiotic. Studies in human volunteers have revealed that pivampicillin is much better absorbed than ampicillin.

Manufacturer

Leo Pharmaceutical Products (Denmark)

Proprietary Name

Pondocillin (for the hydrochloride).

References

1. WHO Chron 24 (11). 532 (1970). 2. JAMA 213. 1325 (1970). 3. Chem Drug 193. 228 (1970). 4. Tenth Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago (USA), Oct 18-21 (1970); abs 121. 5. Acyloxymethyl esters of ampicillin. W. V. Daehne et al. J Med Chem 13 (4), 607-612 (1970).

Pizotyline (USAN)

BC105

Pizotifen (Rec INN) 4-(9,10-Dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thien-4-ylidene)-1-methylpiperidine

Synthesis

By the reaction of 9,10-dihydro-4H-benzo(4,5)-cyclohepta-(1,2-b)-thiophene-(4)-one with 1-methyl-4-pyperidyl magnesium chloride and subsequent treatment of the resulting alcohol with hydrochloric acid3.

Description

Crystals, mp 261-263° (dec).

Action

Anabolic, antidepressant and migraine prophylactic.

Manufacturer

Sandoz

References

1. JAMA 212. 467 (1970).

159

2. WHO Chron 24 (11), 532 (1970). 3. Sandoz S. A. Belg pat 636,717. 4. An antiaminic drug, BC 705, in the prophylaxis of migraine. F. Sicuteri et al. Int Arch Allergy Appl Immunol 31 (1),78-93 (1967). 5. The influence of maturation on the acute toxicity to rats of the serotonin antagonists pizotyline (BC-705) and cyproheptadine. R. E. Bagdon and J. Dorado. Pharmacologist 12 (2), 531 (1970). 6. Protein metabolic effects of a non-steroidal anabolic agent. A. A. Albanese et al. Nutr Rep Int 2 (1), 29-41 (1970)

Polignate Sodium (USAN)

AHR 24388

Sodium lignosulfonate The structure has not been fully defined but consists of a sulfonated polymer whose subunit is similar in structure to the subunit of coniferyl alcohol polymer. The individual polymer units are considered to be three-dimensional structures with molecular weights in the range of several thousand.

Action

Polignate sodium is a new anti-ulcer (pepsin inhibitor) agent.

Manufacturer

A. H. Robins Co (USA)

References

JAMA 214, 1693 (1970).

Polihexanide (Prop INN)

Polihexanidum (Lat). Polihexanido (Sp) Poly (iminoimidocarbonyliminoimidocarbonylimino-hexamethylene monohydrochloride)

Action

Polihexanide is a polymeric biguanidine bactericide. It has been shown to possess a similar mode of action on vegetative bacteria to that of chlorhexidine, but has certain advantages over the latter, e.g. greater speed of kill, less inactivation by non-ionic surface active agents and greater physical compatibility and activity in the presence of cations and anions commonly present in hard waters.

Manufacturer

Imperial Chemical Industries Ltd (England)

References

1. WHO Chron 24 (9), 429 (1970). 2. Brit pat 702,268. 3. A. Davies et al. J Appl Bact 31 (4), 44B (196B) . 4. Evaluation of teat· dipping formulations containing a germicidal polymeric biguanide. S. F. Forse et al. Vet Record 86, 506-511 (1970).

Poloxalene

Polyoxypropylenepolyoxyethylene glycol non ionic block polymer

Description

Hydroxyl number: 35.7-39.4; cloud point (10 per cent solution): 42-46°.

Action

The new animal drug application proposing the safe and effective use of poloxalene as a drench in cattle has been approved.

Manufacturer

Norden Laboratories Inc (USA)

References

Federal Register 35 (92), 7378 (1970).

160

Polyglycolic Acid (USAN)

Poly (oxycarbonyl methylene)

Synthesis

By polymerization of glycolic acid.

Action

Polyglycolic acid is a surgical suture material.

Manufacturer

Lederle (USA)

Proprietary Name

Dexon.

References

1. JAMA 213. 1326 (1970). 2. The use of a new absorbable suture material (polyglycolic acid) in general surgery. A. R. Anscombe et al. Brit J Surg 57 (12), 921 (1970).

Polytef (USAN) Teflon

Poly(tetrafluoroethylene)

Action Polytef is a prosthetic agent, for vocal cord rehabilitation and plastic and reconstructive surgery.

Manufacturer

Ethicon Co (USA)

Proprietary Name

Ethicon PTFE Paste for Injection (component of)

References

1. JAMA 209. 407 (1969). 2. Polytef injection for nasal deformity. J. J. Schell. Arch Otolaryng 92. 554·559 (1970).

Practolol (USAN; Prop INN)

ICI 50,172 AY 21,011

4-[2-Hydroxy-3-(isopropylamino) propoxy]-acetanilide 1-(4-Acetamido-phenoxy)-3-isopropylamino-2-propanol

Synthesis

Prepared from 4-acetamidophenoxy-2, 3-epoxypropane and isopropylamine. The free base melts at 134-136°, and the hydrochloride at 140-142°.

Action and Uses

Practolol is a cardioselective beta-blocking agent. For use in the treatment of angina pectoris and control of cardiac arrhythmias.

Supplied as

Tablets 100 mg; ampoules 10 mg/5 ml.

Dosage

Angina pectoris: Orally 200 to 600 mg daily. Cardiac arrhythmias: 200 mg daily.

Proprietary Name

Eraldin.

Manufacturer

161

Imperial Chemical Industries Ltd (England)

References

1. Imperial Chemical Industries Ltd. Brit pat 1,078,852. 2. Med Act (Drugs of Today), 6 (5), 188-191 (1970). (Review with 14 references). 3. Coronary and hemodynamic effects of myocardio-selective β-receptor blockade by ICI 50172 in the closed chest dog. W. D. Bussmann et al. Am Heart J 79, 347-360 (1970). 4. Influence of propranolol and ICI 50.172 on the cardiovascular actions of catecholamines as modified by ergotamine. W. Osswald et al. J Pharmacol Exp Ther 174, 315-322 (1970) .

Prajmalium Bitartrate

GT 1012

Prajmalii bitartras (Lat). Prajmalio bitartrato (Sp) N-Propylajmalinium hydrogen tartrate

Synthesis

By treating N-(n-propyl)-ajmaliniumbromide with sodium bicarbonate the crude free aldehyde is obtained, which is subsequently treated with tartaric acid. The product melts at 149-152° dec.

Action

Antiarrhythmic agent.

References

1. WHO Chron 24 (11), 532 (1970). 2. Dr. Karl Thomae GmbH. Ger pat 1,196,207. 3. Treatment of cardiac arrhythmias with N-propylajmaline bitartrate. R. Wegehaupt and W. Hager: Deutsche Med Wochenschr 95, 938-942 (1970). 4. On the pharmacology of N-propylajmaline bromide. E. J. Gendenshtein. Farmakol Toksikol 33 (3), 303-305 (1970).

Pramiverine (BAN; Rec INN)

HSp 2986

Pramiverinum (Lat). Pramiverina (Sp) N-lsopropyl-4,4-diphenylcyclohexylamine 1-lsopropylamino-4,4-diphenylcyclohexane

Synthesis

Prepared by the reaction of isopropylamine with 4,4-diphenylcyclohexylchloride, or 4,4-diphenylcyclohexanol, or 3,3-diphenylcyclohexen-6-one, followed by hydrogenation.

Description

The free base boils at 164-165° (0.05 mm); the hydrochloride melts at 230° (ethanol).

Action

Pramiverine is a new spasmolytic agent with relatively little effect on salivary secretion.

Manufacturer

Merck, Darmstadt (Germany)

References

1. Chem Drug 193, 228 (1970). 2. E. Merck AG. Neth Appi 6,515,046. 3. H. Diamant et al. Arzneim-Forsch 18 (9), 1137 (1968).

162

Prazosin Hydrochloride (Rec

INN) CP-12,199-1

4-Amino-2-[4-(2-furoyl)-1-piperazinyl]-6,7-dimethoxy-quinazoline Hydrochloride 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)-piperazine Hydrochloride

Action

Laboratory3 and human trials4,5 has suggested that prazosin can be an effective anti-hypertensive agent when given orally.

Manufacturer

Pfizer Laboratories (USA)

References

1. WHO Chron 24 (11), 532 (1970). 2. Pfizer, Chas and Co, Inc. Brit pat 1.156,973. 3. A. Schriabine et al. Experientia 24 (11), 1150-1151 (1968). 4. D. W. Richardson et al. Circulation 38, 164 (1968). 5. Prazosin hydrochloride (CP-12,199-1), an oral anti-hypertensive agent: preliminary clinical observations in ambulatory patients. B. M. Cohen. J Clin Pharmac 10 (6), 408-417 (1970).

Prednazoline (Rec INN)

Fenoxazolin prednisolone phosphate 11β,17,21-Trihydroxy-21-(dihydrogenphosphate)-pregna-1,4-dien-3,20-dione compound with 2-[(o-cumenyloxy) methyl]-2-imidazoline

Synthesis

Prednazoline is prepared from 21-prednisolonephosphoric acid and fenoxazolin base in alcohol.

Description

Prednazoline occurs as a white crystalline powder, mp 140-190°. Soluble in methanol, ethanol, and in water in the presence of an equimolecular quantity of sodium bicarbonate.

Action and Uses

Prednazoline, a salt of 21-prednisolonephosphoric acid with fenoxazolin, causes anti-inflammatory and anti-allergic effects when applied topically to the nasal mucosa. It is used in the treatment of nasal congestion of allergic and inflammatory origin, rhinitis, rhinosinusitis, rhinopharingitis, sinusitis.

Supplied as

Nebulizer 25 mg/10 ml.

Proprietary Name

Deturgylone (Dausse, France).

References

1. Nouveau medicament vasoconstricteur et antiinflammatoire. Lab Dausse Fr pat M 4,111. 2. Med Act (Drugs of Today) 7 (1), 26-28 (1971). (Review with 5 references).

Proadifen Hydrochloride

(USAN; Rec INN) SKF

525-A

2-(Diethylaminoethyl) 2,2-diphenylvalerate hydrochloride β-Diethylaminoethyl diphenylpropyl acetate hydrochloride

163

Synthesis

Prepared by the reaction of 2,2-diphenylvaleric acid chloride with 2-diethylaminoethanol.

Description

Needles, mp 122-123° (acetone-ether)

Action

Proadifen hydrochloride has been commonly described as having little or no pharmacologic effect of its own. The drug has proved to inhibit numerous reactions catalyzed by the microsomal enzyme system2. It can antagonize as well as potentiate neuromuscular blocking agents3; can inhibit contractions of vascular smooth muscle induced by potassium without significantly affecting those due to norepinephrine4. It has a protective effect on CCI4 toxicity5, prevents the embryopathic effects of 7-OHM-12-MBA6, and has unespecific effect on the gastrointestinal absorption of drugs in rats7. It shows antiarrhythmic activity on several experimentally induced arrhythmias in the anesthetized dog9.

Manufacturer

Smith Kline and French Laboratories (USA)

References

1. P. N. Craig et al. J Am Chem Soc 73, 1339-1341 (1951). 2. The Pharmacological Basis of Therapeutics. Ed by L S Goodman and A Gilman, 3rd edition p 34. The MacMillan Co 1965. 3. Sites of action of SKF 525-A in nerve and muscle. G. Suarez-Kurtz and C. Paul Bianchi. J Pharmacol Exptl Ther 172 (1), 33-43 (1970). 4. Selective blockade of potassium-induced contractions of aortic strips by β-diethylaminoethyl-diphenylpropylacetate (SKF 525A). S. Kalsner et al. J Pharmacol Exptl Ther 174 (3), 500-508 (1970). 5. The effect of SKF 525A on the distribution of carbon tetrachloride in rats. C. Marchand et al. J Pharmacol Exp Ther 174 (2), 232-238 (1970). 6. Protection from the embryopathic effects of 7-hydroxymethyl-12-methylbenz(α) anthracene by 2-methyl-1,2-bis-(3-pyridyl}-1-propanone (metopirone, Ciba) and β-diethylaminoethyldiphenyl-n-propyl acetate (SKF 525-A). C. C Bird et al. Brit J Cancer 24 (3), 548-553 (1970). 7. The effect of SKF 525-A on drug concentration in the blood. S. McLean and C. Marchand. Life Sci 9 (Part 1),1075-1080 (1970). 8. Effect of SKF 525-A on biliary function. Influence of body temperature. W. G. Levine. Life Sci 9 (Part I), 437-442 (1970). 9. Antiarrhythmic effects of proadifen hydrochloride (SKF 525-A). A. P. Viana and W. Osswald. Arzneim-Forsch 20 (6), 851-853 (1970).

Probucol (USAN; Prop INN)

DH

581

Probucolum (Lat) Bis-(3,5-di-tert-butyl-4-hydroxy-phenyl) mercaptole acetone 4,4'-(Isopropylidenedithio)-bis-(2,6-di-tert-butylphenol)

Synthesis

Prepared by acid-catalyzed condensation of 4-mercapto-2,6-di-t-butylphenol with acetone.

Description

Crystals, mp 125-127°.

Action

Probucol is a new cholesterol-lowering agent found to be effective and safe in mice, rats, dogs and monkeys. It goes into clinical test.

Manufacturer

The Dow Chemical Co (USA)

References

1. WHO Chron 24 (9),429 (1970). 2. JAMA 212, 1360 (1970). 3. J. W. Barnhan et al. Fed Proc 28, 268 (1969). 4. J. W. Barnhan et al. J Med Chem 13 (4), 722-725 (1970). 5. J. W. Drake et al. Metabolism 18, 916-925 (1969). 6. Hypocholesterolemic effect of probucol. J. W. Barnhart et al. Amer J Clin Nutr 23 (9), 1229-1233 (1970).

164

Propionylpromazine

hydrochloride 1497

CB

Propiopromazine Hydrochloride 1-[10-[3-(Dimethylamino) propyl] phenothiazin-2-yl]-1-propanone hydrochloride

Description

Crystals, mp 69-70°.

Action

Propiomazine hydrochloride has been recently approved in the USA for oral administration to dogs as a tranquilizer.

Manufacturer

Diamond Laboratories (USA)

Propiretary Name Tranvet.

Supplied as

Chewable tablets, 10 or 20 mg.

References

1. Etablissements Clin-Byla. Fr Add 71,342. 2. Fed Register 35 (228), 17995 (1970).

Propoxyphene Dibudinate

Probunafon 4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate 2,6-di-tert-butyl-1,5-naphthalene disulfonate Dibudinate is a shorter nonproprietary name for 2,6-di-tert-butyl-1,5-naphthalene disulfonate.

Description

White, odorless, crystalline powder.

Action

Propoxyphene dibudinate is a new antitussive drug.

Manufacturer

Ravensberg Chem Fab (Germany)

Proprietary Name

Sotorni.

References

1. WHO Chron 25 (3), 148 (1971). 2. Z Therapie 8 (2), 99 (1970).

Proxifezone (Prop INN)

PM 6

(+)-4-(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol-propionate (ester) compound with 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione (1:1) Dextropropoxyphene compound with phenylbutazone

Description

White crystalline powder, mp 82-84°. UV max 265 µm.

165

Action and Uses

Proxifezone, a dextropropoxyphene compound with phenylbutazone, has recently been marketed in France. It exercises analgesic, anti-inflammatory and antipyretic actions. It is used chiefly for the treatment of rheumatoid conditions.

Supplied as

Tablets, containing proxifezone 100 mg and creosotamide (myorelaxant) 300 mg. Suppositories, containing proxifezone 300 mg, creosotamide 600 mg and sodium ascorbate 50 mg.

Dosage

The initial dosage is 2 to 4 tablets daily. The maintenance dosage is 1 to 2 tablets daily. Rectally, 1 to 2 suppositories daily.

Manufacturer

Laboratories Midy (France)

Proprietary Name

Midalgyl.

References

1. WHO Chron 24 (9), 430 (1970). 2. A new antirrheumatic drug: Midalgyl. J . Laurent and W. Kopp. Press Med 78 (48). 2145 (1970). 3. Propiedades fisico-quimicas de un nuevo analgésico. N. Sans-A. Alsina, Simposium Quimica Medico Farmaceutica. Barcelona. Septiembre 1970. Quimica e Industria 17 (1), 119-122 (1971) . 4. Med Act (Drugs of Today) 7 (1). 29-31 (1971). (Review).

Pyrantel Tartrate (USAN)

CP-10423-18

1,4,5,6-Tetrahydro-1-methyl-2-[2-(2-thienyl) vinyl] pyrimidine tartrate (1:1)

Synthesis

Pyrantel is prepared by the reaction of 2-thienylacrylamide with 1,3-propanesultone and the reaction of the resulting compound with N-methyl-trimethylendiamine1. Also from thiophene-2-carboxaldehyde and 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine2.

Description

Pale yellow solid, soluble in water.

Action and Uses

Pyrantel is a new highly active anthelmintic compound which exhibits a broad spectrum of activity against both adult and immature worm infections of domestic animals. The drug acts on the neuromuscular system of the parasites. Pyrantel tartrate is used to treat infestations with Strongyloides spp., Oxyuris spp., Parascaris spp., Strongylides and Trichostrongylus axei.

Supplied as

Water soluble powder with 6.25% of pyrantel tartrate.

Proprietary Name

Pyrequan.

Manufacturer Pfizer GmbH (Germany)

References

1. Pfizer Ltd. Brit pat 1,045,838. 2. Pfizer Ltd. Brit pat 1,108,207. 3. Med Act (Drugs of Today), 6 (2), 71-74 (1970). (Review with 9 references).

Pyrazinobutazone

Phenylbutazone piperazine salt

166

Description

White powder, with a bitter taste; mp 140-141°, the n solidifies and remelts at about 180°. Soluble in methanol, ethanol and slightly soluble in water.

Action and Uses

Pyrazinobutazone has proved to be a defined chemical compound and its structure has been established by spectral methods. It is claimed to show the anti-inflammatory, analgesic and antipyretic properties of phenyl butazone, but with lower toxicity and less ulcerogenic effects. It is used with the same indications as phenylbutazone.

Dosage

Orally, 600 to 900 mg daily. Rectally, 425 to 900 mg daily.

Supplied as

Gelules, 300 mg. Suppositories, 425 mg.

Manufacturer

Laboratories Francais de Therapeutique (France)

Proprietary Name

Carudol.

References

1. Etude sur la structure et les proprietes physico-chimiques du pyrazinobutazone. J . Hue. et al. Cahier Medicaux Lyonnais (24), 2111-2119 (1970). 2. Med Act (Drugs of Today) 7 (1), 31-33 (1971) . (Review).

Pyrovalerone Hydrochloride

(USAN; Rec INN)

F1983

4'-Methyl-2-(1-pyrrolidinyl) valerophenone hydrochloride

Synthesis

Prepared by the bromination of p-methylvalerophenone, followed by the treatment with pyrrolidine. Also by hydrogenation of 1-p-tolyl-2-pyrrolidino-4-penten-1-one.

Description

Crystals, mp 178°.

Action

Pyrovalerone is a psychostimulant. Both in pharmacological2 and in clinical experiments3,4,5, it differs markedly from amphetamine. The metabolism of the drug has been recently reported6.

Manufacturer

Dorsey (USA); Dr A. Wander SA (Switzerland)

Proprietary Name

Centroton.

References

1. W. Heffe. Helv Chim Acta 47, 1289 (1964). 2. G. Stille et al. Arzneim-Forsch 13, 871 (1963). 3. H. Heimann and K. Vetter. Schweiz Med Wochenschr 95, 306 (1965). 4. A. R. Holliday at al. Psychopharmacologia 6, 192 (1964). 5. H. Heimann and G. Lukacs. ibid 8, 79 (1965). 6. The metabolism of pyrovalerone hydrochloride. W. Michaelis et al. J Med Chem 13 (3), 497-503 (1970).

Quinestrol (Rec INN)

W 3566

3-(Cyclopentyloxy)-19-nor-17α-pregna-1,3,5(10}-trien-20-yn-17-ol 17α-Ethynylestradiol 3-cyclopentyl ether

Synthesis

167

Prepared by the reaction of 17α-ethynylestradiol with cyclopentyl bromide and potassium carbonate in refluxing ethanol. Also, by the reaction of estrone cyclopentyl ether with potassium acetylide.

Description

Crystals, mp 107-108°; [ α]D = +5° (c=0.5 in dioxane).

Action

Quinestrol is an estrogen which has prolonged activity in animals and in man, as a result of storage in and subsequent release from body fat. The combinations quinestrol-quingestanol2 and quinestrol-6-dehydro-retroprogesterone (Duphaston)3 have been studied as a one dose a month oral contraceptive. The duration of the effect of quinestrol when administered to humans by injection as compared to the oral route4 has been explored.

Manufacturer

Warner-Lambert (USA)

Proprietary Name

Estrovis.

References

1. A. Ercoli. US pat 3,159,343 and 3,231,567. 2. Once-a-month oral contraceptive: quinestrol and quingestanol. B. Rubio and E. Berman. Obst Gynec 35 (6), 933-936 (1970). 3. A trial of a one dose a month oral contraceptive. D. Claman. Arner J Obstet Gynec 107 (3), 461-464 (1970). 4. Duration of estrogenic effect following oral and intramuscular quinestrol administration. F. Brambilla and G. Bruno. Curr Ther Res 12 (8), 493-501 (1970).

Quingestanol Acetate (Rec INN)

W4540

3-(Cyclopentyloxy)-19-nor-17α-pregna-3,5-dien-20-yn-17-ol, acetate 3-Cyclopentylenol ether of 17α-ethinyl-19-nortestosterone acetate Norethindrone acetate-3-cyclopentyl enol ether

Synthesis

By treating 17α-ethinyl-19-nortestosterone 3,17-diacetate with cyclopentanol in the presence of p-toluenesulfonic acid1 and also by treating 3-methoxy-17α-ethinyl-19-norandrosta-2,5(10)dien-17β-ol 17-acetate with cyclopentanol in the presence of pyridine hydrochloride2.

Description

Crystals, mp 182-184° (dioxane); [ α]D = -215° (in dioxane).

Action

Quingestanol acetate is the 3-cyclopentyl enol ether derivative of norethindrone acetate and has the same biological profile as norethindrone acetate but is twice as potent3,4. The results of the use of this progestagen, taken routinely by fertile, married women in a single dose less than 24 hours after coitus, have been reported5. A combination of quingestanol acetate and quinestrol taken by mouth once every four weeks has proved to be effective as a contraceptive.

Manufacturer

Warner-Lambert (USA)

References

1. F. Vismara SA. US pat 3,159,620; Ger pat 1,159,940. 2. F. Vismara SA. Ger pat 1,228,608. 3. T. Giannina et al. Proc Soc exp Biol Med 131. 781-789 (1969). 4. T. Mischler et al. Proc Soc exp Biol Med 132, 323-327 (1969). 5. A new postcoital oral contraceptive. B. Rubio et al. Contraception 1 (5), 303-314 (1970). 6. Once-a-month oral contraceptive: quinestrol and quingestanol. B. Rubio and E. Berman. Obstet Gynec 35 (6), 933-936 (1970).

168

R 2323

13-Ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,9,11-trien-20-yn-3-one

Synthesis

Several methods have been described1.

Description

Crystals, mp 154° (ethyl acetate); [ α]D = 84.6° (c=0.41, in methanol). UV max 239-240 µm (ε=5,920) and 344 µm (ε=29,850) in ethanol.

Action

R 2323 is a new contraceptive compound which has been found to be characterized mainly by its marked and efficient activity following post coitum administration. It acts as an anti-deciduogenic and anti-inplantationagent in non-oestrogenic doses. Preliminary clinical trials have shown that oral administration of the drug once weekly affords efficient protection without inhibiting ovulation.

Manufacturer

Roussel-UCLAF (France)

References

1. Roussel-Uclaf. Neth Appl 6,607,609; Brit pat 1,069,709; Fr pat 1.479,352 and 1,503,984. 2. R 2323-an original contraceptive compound. E. Sakiz and G. Azadian-Boulanger. Third International Congress on Hormonal Steroids, Hamburg 7-12 Sept 1970; Abstr 86 [Excerpta Medica, International Congress Series No. 210].

Ra 101

1-Phenyl-2,3-dimethyI-4-(N-nicotinamido-methyl-N-isopropyl) amino-pyrazolin-5-one

Synthesis

Prepared by the reaction of aqueous 40% formaldehyde, 1-phenyl-2,3-dimethyl-4-isopropylamino-5-pyrazolone, and nicotinamide in hot ethanol.

Description

White needles, mp 162-162.5°. UV max 260 µm in 0.1 N HCI. It is readily soluble in methanol, chloroform, and slightly soluble in ether.

Action

Ra 101 has antipyretic, analgesic, antiphlogistic, and mild sedative effects.

Manufacturer

R. Ravasini and Co (Italy)

References

1. F. Banci and E. Tubaro. US pat 3,420,839. 2. Pharmacology of a nicotinamidomethyl-aminopyrazolone (Ra 201). E. Tubaro and F. Banci. Arzneim-Forsch 20 (8), 1019-1023 (1970).

RA233

2,6-Bis-(diethanolamino)-4-piperidino-pyrimido-[5A-d] pyrimidine

Action

RA 233, an analog of dipyridamole, is a potent inhibitor of experimental arterial thrombosis as measured by the arteriovenous Teflon microshunt technique in rats. Platelet retention by a column of

169

glass beads (platelet adhesiveness) is almost completely inhibited in blood samples drawn from rats during RA 233 infusion. These effects were associated with severe hypolension, but hypotension is not required for the antithrombogenic effect of RA 233.

Manufacturer

Karl Thomae GmbH (Germany)

References

1. Effect of RA-233 on platelet function in vitro. AA Hassanein et al. Brit Med J 2, 83-86 (1970). 2. Prevention of experimental arterial thrombosis and platelet adhesiveness by 2,6-bis-(diethanolamino)-4-piperidinopyrimido-[5,4-d]-pyrimidine (RA 233). Paul Didisheim and C. A. Owen. Mayo Clin Proc 45, 695-699 (1970).

Rabelomycin

3,4-Dihydro-3,6,8-trihydroxy-3-methylbenz [α] anthracene-1,7,12(2H)-trione

Production

Rabelomycin, a new antibiotic, is produced by a strain of Streptomyces olivaceus ATCC 21,549

Description

Yellow needles, mp 193° (dec).

Action

Rabelomycin is active against gram-positive microorganisms.

Manufacturer

Squibb (USA)

References

Isolation characterization, and structure of rabelomycin a new antibiotic.

Wen-Chih Liu et al. J Antibiotics 23 (9). 437-441 (1970).

Rafoxanide (USAN; Rec INN)

MK 990

3'-Chloro-4'-(p-chlorophenoxy)-3,5-diiodosalicylanilide

Synthesis

a) By the reaction of 2-hydroxy-3,5-diiodobenzonitrile with 3-chloro-4-(p-chlorophenoxy) benzenediazonium fluoroborate3. b) By the reaction of 3-chloro-4-(p-chlorophenoxy) aniline with salicylic acid in the presence of phosphorus trichloride, and subsequent reaction with iodine monochloride4. c) By the reaction of p-nitrophenol with 3, 4-dichloroaniline, and subsequent reaction with 3,5-diiodosalicylic acid. The resulting nitro derivative is first reduced to the amino-derivative, then diazotated in the presence of cupric chloride and finally treated with hydrochloric acid5.

Description

Crystals, mp 168-170° (benzene) 3,4; mp 175-177° also reported5.

Action

Anthelmintic. It is used for the treatment of fascioliasis.

Supplied as

Veterinary drench: rafoxanide, 2.27% w/v.

Manufacturer

Merck Sharp and Dohme

Proprietary Name

Flukanide.

170

References

1. JAMA 212, 2247 (1970). 2. WHO Chron 24 (11), 459 (1970). 3. Merck Co, Inc. Ger Offen 1,808,679. 4. Merck Co, Inc. Ger Offen 1,810,821. 5. Merck Co, Inc. Ger Offen 1,810,819.

Ranatensin

It is a decapeptide isolated from the skin of the frog, Rana pipiens with the amino acid sequence: Pyr-Val-Pro-Glu-Trp-Ala-Val-GIy-His-Phe-Met-NH2

Action

Experimental studies have shown that the spectrum of action of ranatensin on blood pressure of various animals and the various isolated smooth muscle preparations is unlike that of any other vasoactive peptide. Ranatensin raises blood pressure in the dog and rabbit, but lowers it in the monkey.

References

1. Isolation and structure of a new vasoactive polypeptide. T. Nakajima et al. Fed Proc 29, 282 (1970). 2. Pharmacology of ranatensin. R. G. Geller et al. Fed Proc 29, 282 (1970). 3. The action of ranatensin, a new polypeptide from amphibian skin on the blood pressure of experimental animals. R. G. Geller et al. Br J Pharmacal 40, 605-616 (1970).

Resorantel (Rec INN)

Resorantelum (Lat) 4'-Bromo-resorcylanilide 4'-Bromo-2,6-dihydroxybenzanilide

Synthesis

Prepared from 2,6-dihydroxybenzoic acid phenylester and 4-bromoaniline.

Description

Crystals, mp 229-230°.

Action

Resorantel is a new drug active against tapeworms in sheep and other rumiants.

Manufacturer

Farbwerke Hoechst AG (Germany)

Proprietary Name

Terenol.

References

1. WHO Chron 24 (11), 532 (1970). 2. Farbwerke Hoechst A. G. Brit pat 1,124,613. 3. H. Lemaire et al. J Pharm Sci 50, 831-7 (1961). 4. Deut Tierarztl Wochenschr 77 (5), 104-107 (1970).

Riboflavin-Tryptophan

Complex

The complex consists of equimolecular amounts of riboflavine and tryptophan

Synthesis

Prepared from riboflavine and tryptofan in acid solution [n-butanol and 12N HCl (7:3), in presence of small amounts of carbon tetrachloride].

Description

Brownish crystals, mp 169.2°. The solubility of the complex, calculated as riboflavine, is five times greater than that of riboflavine.

171

Action

From the nutritional point of view this complex presents the advantage of increasing the solubility of riboflavine, and also its stability against photolysis. It has been suggested that it can be used in patients with vitamin B, defficiency.

References

Preparation and properties of crystalline riboflavin-tryptophan complex. H. Mitsuda, H. Tsuge and F. Kawai. J Vitaminol 16 (3), 119-224 (1970).

Ribostamycin SF733 Vistamycin

O-β-D-Ribofuranosyl-(1-> 5)-O-[α-2,6-diamino-2,6-dideoxy-D-glucopyranosyl-(1-> 4)]-2-deoxystreptamine

Production

It is produced in culture liquids of Streptomyces ribosidicus SF-733 strain, and extracted and purified by an ion-exchange resin process. It has also been synthesized from neamine.

Description

Colorless needles, mp 192-195° (dec); [ α]D = +42° (c=1, water).

Action

Ribostamycin is a broad spectrum antibiotic. Studies in humans so far have shown same to possess good therapeutic effects and few adverse reactions.

Manufacturer

Meiji Seika Kaisha (Japan)

References

1. Jap Med Gazz 7 (3), 12 (1970).

2. Studies on antibiotic SF 733, a new antibiotic. I. Taxonomy, isolation and characterization. T. Shomura et al. J Antibiotics 23, 155-161 (1970). 3. Jap pat 70 17,150, June 13, 1970.

RJ 64

3-(4-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole

Description

White crystalline powder, mp 105-106.5°. Freely soluble in chloroform and poorly soluble in water.

Action

RJ 64 is a new centrally acting muscle relaxant. Its action is similar to that of chlorzoxazone.

Manufacturer

Chinoin (Hungary)

References

Pharmacology of a new centrally acting muscle relaxant (RJ-64). G. P. Leszkovszky and L. Tardos. Arzneim-Forsch 20 (11), 1778-1783 (1970).

Ro 7-0207

α-(Chloromethyl)-2-methyl-5-nitroimidazole-1-ethanol 1-(3-Chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole

172

Synthesis

Prepared by the reaction of 2-methyl-4(5)nitroimidazole with bis-(3-chloro-2-hydroxypropyl) sulfate to yield 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, and by the reaction of this nitroimidazole with hydrochloric acid.

Description

Crystals, mp 77-78° (toluene).

Action

Ro 7-0207 is a potentially potent antiparasitic substance whose range of usefulness may extend from helminthiasis, trichomoniasis, and amebiasis in their several forms, to possibly other infections produced by obligately anaerobic microorganisms.

Manufacturer

Hoffmann-La Roche Inc (USA)

References

1. F. Hoffmann-La Roche Co, AG. Neth Appl 6,606,853. 2. E. Grunberg el al. Anlimicrob Ag Chemother, 513 (1968). 3. α-Chloromethyl-2-methyl-5-nitro-1-imidazoleethanol (Ro 7-0207), a substance exhibiting antiparasitic activity against amebae, trichomonads, and pinworms. E. Grunberg et al. Proc Soc Exp Biol Med 133, 490-492 (1970).

Ro 7-2133

4,6-Dichloro-17-hydroxy-pregna-4,6-diene-3,20-dione, acetate

Synthesis

Prepared from 6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione acetate by treatment with lithium chloride, N-chlorosuccinimide and hydrochloric-satd dioxane. After working up the mixture is treated with pyridine.

Description

Crystals, mp 234-235° (isopropyl ether). [ α]D = +138.7° (c = 0.88, chloroform). UV max 299 µm [ε=16,800] in methanol.

Action

Ro 7-2133 is a new progestational steroid, which has been reported to be 3 to 10 times more potent than its 4-deschloro analogue, chlormadinone acetate1. Some data on the endocrine profile of this steroid has been recently reported2.

Manufacturer

Hoffmann-La Roche

References

1. R. Wiechert. Experientia 24, 767 (1968). 2. Endocrine profile of a new progestational steroid. A. Boris et al. Acta Endocr. 63. 476-488 (1970) .

Robenidine Hydrochloride

(Prop INN)

Robenzidene hydrochloride 1,3-Bis [(p-chlorobenzylidene)amino] guanidine hydrochloride

Synthesis

Prepared from 1,3-diaminoguanidine nitrate and p-chlorobenzaldehyde.

Description

White crystalline powder, mp 289-290° (dec). The nitrate salt melts at 198° (dec).

Action

Robenidine is a new poultry anticoccidial agent, highly effective in preventing chicken coccidiosis

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caused by all eight most common pathogenic Eimeria species.

Manufacturer

Lederle Laboratories (USA).

References

1. WHO Chron 25 (3), 142 (1971). 2. Robenzidene: a new poultry anticoccidial agent. S. Kantor et al. Science 168, 373-374 (1970). 3. Efficacy evaluations of, obenzidene for control of coccidiosis in chickens. W. M. Reid et al. Avian Diseases 14 (4), 788-797 (1970).

Rolicypram (BAN)

EX 4883

Rolicyprine 5-0xo-N-(trans-2-phenylcyclopropyl)-L-2-pyrrolidinecarboxamide

Synthesis

By the condensation of D-trans-2-phenylcyclopropylamine with L-5-oxopyrrolidine-2-carboxylic acid via the dicyclohexylcarbodiimide method2,3.

Description

Crystals, mp 144-147°; [ αlD =+ 104.28° (dimethylformamide).

Action

Antidepressant agent.

Manufacturer

Lakeside

Proprietary Name

Cypromin.

References

1. Chem Drug 194, 446 (1970). 2. Colgate-Palmolive Co. Brit pat 1,000,895. 3. Lakeside Lab Inc. Fr Addn 87,352. 4. J. J. McMonigle. Diss Abstr B28 (7), 2979 (1968).

Salsolinol

1-Methyl-1,2,3,4-tetrahydroisoquinoline

Synthesis

Prepared by the reaction of N-chloroacetylphenethylamine with phosphorus pentoxide, and by the reduction of the resulting 1-chloromethyl-3,4-dihydroisoquinoline with zinc/hydrochloric acid. The free base, bp 119° (19 mm); the hydrochloride, mp 178°.

Action

Salsolinol, a pharmacologically active alkaloid, is formed endogenously by brain tissue from dopamine as substrate in presence of ethanol or its metabolite acetaldehyde. It has been suggested that tetrahydroisoquinoline alkaloids could possibly be responsible for some of the effects either produced by ethanol or associated with alcoholism.

References

1. R. A. Robinson (to G. D. Searly). J Org Chem 16, 1911-1920 (1951). 2. Formation of an alkaloid derivative of dopamine with ethanol or acetaldehyde. Y. Yamanaka. Fed Proc 29 (2), 680 (1970).

Sandoz 42-348

1-Methyl-4-piperidyl bis-(p-chloro-phenoxy) acetate

174

Action

Sandoz 42-348 is a new experimental compound which appears to be a highly active hypolipidemic drug; it has been found to be 9 times more active than clofibrate in animal tests. The drug is undergoing clinical testing.

Manufacturer

Sandoz Pharmaceuticals (USA)

References

1. Am Drug, pg 36-37 (July 28. 1969). 2. Fed Proc 27 (2), abstr 146-147 (1968). 3. A. R. Timms et al. Biochem Pharmacol 18 (8), 1861-1871 (1969). 4. R. M. Welch et al. Fed Proc 29 (2), abstr 683 (1970) . 5. Effect of clofibrate and 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (Sandoz 42-348) on steroId and drug metabolism by rat liver microsomes. R. A. Salvador et al. Life Sci 9 (Pt 2), 397-407 (1970).

Sch 9122 Hydrochloride

2-(p-Anisyl)-3-(2-pyridyl) pentane hydrochloride

Synthesis

Prepared by hydrogenation of the corresponding stibazol1.

Description

Crystals, mp 170-171° (ethanol/ether); the free bas e melts at 50-51° (hexane).

Action

Sch 9122 hydrochloride, a compound structurally related to diethylstilbestrol, has been reported to have significant hypocholesterolemic activity on prolonged administration to male rats. It has been shown that at oral doses which lowered serum cholesterol by as much as 30%, the drug did not produce estrogenic effects2.

Toxicity

LD50 : po in mice: 1632 mg/kg; iv: 94.5 mg/kg.

Manufacturer

Schering Corp (USA)

References

1. Hypocholesteremic agents, I. Substituted stilbazoles and dihydrostilbazoles. F. J. Villani et al. J Med Chem 13 (3), 359·366 (1970). 2. Effects of Sch 9122 HCl, a hypocholesterolemic compound, on mammary tissue, libido, and fertility of male rats. M. Steinberg and A. S. Watnick. Proc Soc Exp Biol Med 134 (3), 696-699 (1970).

Sclerothricin Hydrochloride

Sclerothricin is a new strongly basic antibiotic obtained from the culture filtrate of Streptomyces sclerogranulatus

Description

White amorphous powder, mp 214° (dec).

Action

The antibiotic is active against Gram-positive and Gram-negative bacteria and some fungi. Sclerothricin a new basic antibiotic.

References

Y. Kana at al. J. Antibiotics 22 (12), 583-589 (1969).

175

Scopafungin (USAN)

U 29479

Production

An unspecified substance from Streptomyces hygroscopicus.

Action

Scopafungin is a new antibiotic with antifungal and antibacterial activity.

Manufacturer

The Upjohn Co (USA)

References

JAMA 212, 466 (1970).

SD 1601

1-lsopropylamino-3-(o-methoxyphenoxy)-2-propanol

Synthesis

Prepared by the reaction of o-methoxyphenol with epichlorhydrine, and by the reaction of the resulting 3-(o-methoxyphenoxy)-1-chloro-2-propanol with isopropylamine. The free base melts at 82-83° and the hydrochloride at 110-112°.

Action

SD 1601 is a new β-blocking agent. from the results of a recent pharmacological study it has been concluded that the drug has a slightly greater β-blocking activity than propanolol, and at the same time that its specific side effects, such as myocardial and neurodepressant actions, are much less evident than in propanolol.

Manufacturer

Simes SpA (Italy)

References

1. Imperial Chemical Industries Ltd. Neth Appl 6.301.580. 2. Carl D. Lundsford et al. J Am Chem Soc 82. 1166·71 (1960). 3. β-Adrenergic blocking drugs. III. 1-Aryloxy-and 1-arylamino-3-amino-2-propanols. G. Ferrari et al. Boll Chim Farm 107 (4).234-48 (1968). 4. Pharmacological actions of SD16. a new β-blocking agent. R. Ferrini et al. Arzneim-Forsch 20 (8), 1074-79 (1970).

SDDS

2-Sulfamoyl-4,4'-diaminodiphenylsulfone

Description

White crystalline powder, mp 236-242°. It is slight ly soluble in acetone, sparingly soluble in ethanol and chloroform, and practically insoluble in water.

Action

SDDS was first reported to be effective against Toxoplasma1. After thelapeutic experiments on acute toxoplasmosis in swine both in artificially2,3 and naturally infected animals, it is now widely used in Japan as a potent therapeutic agent against toxoplasmosis in pigs. The prophylactic effects of the drug on toxoplasma infection in pigs have been recently reported4.

Manufacturer

Tanabe Seiyaku Co, Ltd (Japan)

References

1. S. Ohshima et al. Jap J Parasitol 16, 331-338 (1967). 2. S. Ohshima et al. J Jap Vet Med Ass 22, 239-244 (1969). 3. K. Shimizu et al. Jap J Vet Sci 30, 183-195 (1968).

176

4. Toxicology and pharmacology of 2-sulfamoyl-4-4'-diaminodiphenylsulfone (SDDS). S. Sakuma et al. Pharmacometrics 2, 184-195 (1968). 5. Prophylactic effect of SDDS on experimental infection with Toxoplasma in pigs. S. Ohsima et al. Am J Trop Med Hyg 19 (3), 422-426 (1970).

Siccanin (Prop INN)

(13aS)-1,2,3,4,4aβ,5,6,6a,11β,13bβ-Decahydro-4,4,6aβ,9-tetramethyl-13H-benzo[afuro[2, 3, 4-mnj-xanthen-l1-ol .

Production

It is obtained from the mycelium of Helminthosporium siccans, BH 34 strain.

Description

Colorless needles, mp 139-140°, [ α]D = -136° (c = 2, chloroform).

Action

Siccanin is a new antifungal antibiotic.

Toxicity

LD50 ip in mice: 1,590-1,720 mg/kg.

Manufacturer

Sankyo Co, Ltd (Japan)

References

1. WHO Chron 25 (3), 143 (1971). 2. Jap Med Gazz 7 (4), 6 (1970) . 3. Siccanin. a new antifungal antibiotic I. In vitro studies. M. Arai et al. Antimicrob Agents Chemother-1969, p 247-252 (1970) . 4. II. In vivo studies. S. Sugawara. Antimicrob Agents Chemother-1969, p 253·256 (1970).

Silver Allantoinate

Synthesis

By the action of silver nitrate in aqueous solution upon a saturated solution of allantoin at elevated temperatures.

Action

Silver allantoinate has proved to have highly effective antibacterial properties when tested in vitro. The effectiveness of silver allantoinate as an inhibitor of the cutaneous bacterial flora of the hands of operating room personnel has been studied. Silver allantoinate as an inhibitor of cutaneous bacteria upon the hands of operating room personnel.

References

W. F. Ballinger et al. Ann Surg 171 (6), 836-842 (1970).

Simfibrate (Rec INN)

CLAY 503

Simfibratum (Lat). Simfibrato (Sp) 2-(p-Chlorophenoxy)-2-methylpropionic acid trimethylene ester 1,3-Propanediol bis (2-p-chlorophenoxyisobutyrate)

Action

Simfibrate is a new anticholesterol agent. Experimental studies have proved that it shows an hypolipidemic activity more durable in rats. and more potent in rats and cholesterol-fed mice than clofibrate in continued administration.

177

Toxicity

LD50 po in mice (male): 3500 mg/kg; in rats (male): 8000 mg/kg.

Manufacturer

Yoshitomi Pharmaceutical Industries Ltd (Japan)

References

1. WHO Chron 24 (11). 532 (1970). 2. Studies on anti-atherosclerotic agents. II Experimental studies of 1,3-propanediol bis (2-p-chlorophenoxyisobutyrate) (CLY-503) for antiatherosclerotic agents. M. Nakanishi at al. Yakugaku Zasshi 90 (8). 926-932 (1970).

SIN 10

N-Ethoxycarbonyl-3-morpholinosydnonimine

Synthesis

SIN 10 is one of sydnonimine derivatives with mesoionic ring synthesized by Masuda et al1.

Description

White, crystalline powder, mp 140-141°. It is solub le in water.

Action

SIN 10 has proved to show a sustained hypotensive effect in rabbit, dog, cat and rat. It has been suggested that the drug exerts its effect not by affecting peripheral resistance vessels, but by mainly effecting capacitance vessels. The absorption, excretion and tissue distribution of 14C labelled SIN 10 in mice have been reported.

Manufacturer

Takeda Chemical Industries (Japan)

References

1. K. Masuda et al. Pharmacometrics 2. 280 (1968). 2. F. Takenaka et al. Pharmacometrics 2. 298 (1968).

3. Cardiovascular action of mesoionic compounds. 3-substituted sydnonimines. K. Kikuchi at al. Jap J Pharmac 20 (1), 23-43 (1970). 4. Hypotensive action of N-ethoxycarbonyl-3-morpholinosydnonimine. SIN 10. K. Kikuchi et al. Jap J Pharmac 20 (1). 102-115 (1970). 5. Coronary collateral vasodilator action of N-ethoxycarbonyl-3-orpholinosydnonimine (SIN-10) in heart with chronic coronary insufficiency in dogs. M. Hirata and K. Kikuchi. Jap J Pharmac 20 (2), 187-193 (1970). 6. Metabolic fate of 5-ethoxycarbonyl-3-morpholinosydnonimine (SIN-10) 1. Absorption. excretion and tissue distribution in rats and mice. S. Tanayama, et al. Jap J Pharmac 20 (3), 413-423 (1970).

Sodium Hexafluorostannate

Na2SnF6

Action

From the results of a recent study it seems that topical treatment of dentine with a hexafluorostannate solution has a definite caries inhibiting effect.

References

The caries inhibiting effect of topically applied hexafluorostannate on dentine and enamel. F. R. von Der Fehr. Caries Research 4, 269-282 (1970) .

Sodium Tyropanoate

Sodium 3-butyramido-α-ethyl-2,4,6-triiodohydrocinnamate

178

Synthesis

Prepared by the reaction of iopanoic acid with butyric anhydride, and subsequent conversion of the acid so obtained to the sodium salt.

Description

Colorless solid, mp 208-210°. Tyropanoic acid occurs as very pale tan prisms, mp 182-184°; UV max 237µm [ε=33,900] in 95% ethanol.

Action

Sodium tyropanoate is a new oral cholacystographic agent.

Manufacturer

Sterling-Winthrop (USA)

Proprietary Name

Bilopaque

References

Sodium tyropanoate, a new oral cholecystographic agent.

J. O. Hoppe et al. J Med Chem 13 (5),997-999 (1970).

SP 1131

7-[2-Hydroxy-3-[4-(p-chlorobenzyl) piperazino] propyl] theophylline

Description

White crystalline powder, mp 156-157°. It is very slightly soluble in water.

Action

SP 1131 is a coronary dilator. The action of this compound on the circulatory system, using aminophylline as the control agent, has been studied in dogs and rats.

Manufacturer

Chugai Pharmaceutical Co (Japan)

References

Studies on piperazine compounds V. Effects of 7-[2-Hydroxy·3-[4-(p-chlorobenzyl)-piperazino] propyl] theophilline on circulatory system. Y. Shiraki et al. Yakugaku Zasshi 90 (7), 785-795 (1970).

Spiclomazine Hydrochloride

(Prop INN) APY 606

8-[3-(2-Chloro-10-phenothiazinyl) propyl]-1-thia-4,8-diazaspiro[4,5] decane-3-one hydrochloride

Description

White crystalline powder, mp 267°

Action

Spiclomazine exhibits a potent spasmolytic action with a low toxicity. It may prove to be a new type agent having a psychotropic activity in clinical use.

Manufacturer

Yoshitomi Pharmaceutical Industries Ltd (Japan)

References

1. WHO Chron 25 (3), 143 (1971) 2. Pharmacological effects of APY 606. M. Nakanishi et al. Yakugaku Zasshi 90 (7), 800-807 (1970). 3. Metabolic fate of APY 606. Excretion and metabolism in rats. M Nakanishi et al. Yakugaku Zasshi 90 (7), 808-812 (1970).

179

Spirgetine Sulfate LD 3598

[2-(6-Azaspiro [2,5] oct-6-yl) ethyl] guanidine sulfate N-β-Guanidinoethyl-6-azaspiro [2,5] octane sulfate

Synthesis

Prepared from N-(β-aminoethyl)-6-azaspiro [2,5] octane.

Description

White crystalline powder, mp 275-277°. Soluble in water.

Action and Uses

Spirgetine, a derivative of guanidine, is related in chemical structure and pharmacological action to guanethidine. Thus the major effect of the drug is inhibition of responses to sympathetic adrenergic nerve activity. Spirgetine is used for the treatment of moderate to severe (including malignant) hypertension.

Dosage

Treatment should begin with small doses which may be increased depending upon the patient's response. The average maintenance dose is 5 to 7.5 mg daily.

Supplied as

Tablets: 2.5 mg and paraflutizide 5 mg.

Registered Name Divimax.

Manufacturer

Dausse (France)

References

1. Dausse S A. Fr pat M 3013. 2. H. Najer et al. Bull Soc Chim Fr, 2572-2581 (1964). 3. Mad Act (Drugs of Today), 6 (4), 142-144 (1970). (Review with 5 references).

SQ 18571

7-Chloro-2-(p-chlorostyryl)-4-[[4-(diethylamino-1-methyl butyl] amino] quinoline dihydrochloride

Synthesis

Prepared by condensation of p-chlorobenzaldehyde with 7-chloro-2-methyl-4-[[4-{diethylamino)-1-methylbutyljamino] quinoline.

Description

Crystals. mp 260-261°

Action

SQ 18571 is a long-lasting antituberculous agent. It differs from aminoquinol in having a p-chlorostyryl group instead of an o-chlorostyryl group. In the treatment of murine tuberculosis the intragastric potency of SQ 18571 has proved to be twice that of aminoquinol and about 20% that of isoniazide.

Manufacturer

Squibb (USA)

References

1. M. V. Rubtsov et al. J Med Pharm Chem 2, 113-131 (1960). 2. Long-lasting antituberculous activity of derivatives of 2-styrylquinoline. F. Pansy at al. Arner Rev Resp Dis 101 (5). 770-772 (1970).

St 600

2-(5-Fluoro-o-toluidino)-2-imidazoline 2-(5' .Fluoro-2'-methyl)anilino-1,3-diaza-2-cyclopentene

180

Synthesis

Prepared by the reaction of 2-methyl-5-fluoroaniline hydrochloride with ammonium thiocyanate to yield N-(2-methyl-5-fluorophenyl) isothiourea, and by methylation of this isothiourea with methyl iodide and subsequent condensation with ethylenediamine.

Description

The free base melts at 119-121°; the hydrochloride, mp 169-170°.

Action

St 600 is a clonidine-like hypotensive but with relatively less behavioural effect.

Manufacturer

Boehringer Ingelheim (Germany)

References

1. C. H. Boehringer Sohn. Neth Appl 6,613,829. 2. A comparison of the behavioural effects of some hypotensive imidazoline derivatives in rats. R. Laverty. Eur J Pharmacol 9 (2), 163 (1970) .

St 608

2-(2-Chloro-m-toluidino)-2-imidazoline 2-(2'-Chlaro-3'-methyl)anilino-1,3-diaza-2-cyclopentene

Synthesis

Prepared by the reaction of 2-chloro-3-methylaniline with ammonium thiocyanate to yield N-(2-chiaro-3-methyl phenyl) isothiourea, and by methylation of

this isothiourea with methyliodide and subsequent condensation with ethylenediamine.

Description

The free base melts at 159-161°, and the hydrochloride at 220°.

Action

St 608 is a clonidine-like hypotensive. It shows a better hypotensive behavioural effect ratio than clonidine.

Manufacturer

Boehringer Ingelheim (Germany)

References

1. C. H. Boehringer Sohn. Neth Appl 6,613,829. 2. A comparison of the behavioural effects of some hypotensive imidazoline derivatives in rats. R. Laverty. Eur J Pharmacol 9 (2), 163 (1970).

Strontium Carbonate

SrCO3

Description

White, odorless, tasteless powder.

Action

Strontium carbonate has been reported as successful in clinical trials as a tranquilizer and anti-anxiety agent. It appears to be less toxic than lithium carbonate.

References

American Druggist pg 4 (Sept. 21, 1970).

Strophanthidin Arabinoside

Strophanthidin 3 β-I-arabinoside

181

Synthesis

Prepared by the saponification of the triacetylderivate with barium methoxide.

Description

Long needles, mp at about 210° (dec) after preliminary sistering. [α]D = 31° (c=1.1 in alcohol).

Action

The results of a recent clinical study have indicated that the semisynthetic glycoside. strophanthidin arabinoside, can serve as a substitute for ouabain for rapid digitalization by the intravenous route.

References

1. F. C. Uhle et al. J Org Chem 8. 162 (1943). 2. Comparison of a partially synthetic glycoside strophanthidin-arabinoside with ouabain and digitalis in patients with auricular fibrillation. H. Gold et al. J Clin Pharmac 10(3), 145-152 (1970)

SU-5236

2-Methyl-1,2-bis (3-pyridyl)-1-propanol

Action

It has been shown that metyrapone is converted to a reduced metabolite by rat adrenal, kidney and liver in vitro1. This metabolite (SU 5236) has proved to be nearly as effective an inhibitor of 17β-hydroxylation in the rat adrenal cortex as metyrapone itself.

Manufacturer

CIBA Pharmaceuticals (USA)

References

1. I. Kraulis et al. Canad J Biochem 46, 463 (1968). 2. A comparison of the effects produced by metyrapone and its reduced metabolite on the adrenal 11β-hydroxylase system in the rat. H. D. Colby and A. C. Brownie. Steroids 16 (4). 401-413 (1970).

Su-19789 B

2-[p-Methoxy-α-(1-piperidyl)-benzyl] cyclohexanol cyclohexane sulfamate

Action

It has been shown to be a unique stimulant in that it produces an increase in spontaneous motor activity with little, if any, concomitant effect on other parameters. The major sites of action suggested for this compound are the spinal cord and the neuromuscular junction.

Manufacturer

Ciba Pharmaceutical Co (USA)

References

1. Pharmacological properties of Su-19789B, a unique central nervous system stimulant. H. I. Chemov et al. Arch int Pharmacodyn 184, 34-44 (1970).

182

Substance 86

4-Bromo-6-tert-butyl-6-methyl-2H-pyran-2,3,5(4H,6H)-trione

Synthesis

Prepared by bromination of 6-tert-butyl-6-methyl-2H-pyran-2,3,5(4H,6H)-trione1,2.

Description

Crystals, mp 167-168°.

Action

The compound is thought to act on the cell membrane preventing aggregation of platelets and red blood cells.

References

1. Technion Research and Development Foundation Ltd. Fr pat M4126. 2. M. Cais et al. US pat 3,393,204. 3. Prevention by an antiadhesive drug of thrombosis by blood cell aggregation. H. I. Bicher and A. Beemer. Angiology 21, 431-441 (1970).

Sucralfate (Rec INN)

Sucralfatum (Lat). Sucralfato (Sp) Surcrose hydrogen sulfate basic aluminum salt

Synthesis

Prepared by mixing aqueous solutions of sucrose hydrogen sulfate salts with solutions of aluminum salts.

Description

White powder, insoluble in water.

Action

Prevention and treatment of peptic ulcerative disease.

Manufacturer

Chugai (Japan)

Proprietary Name

Ulcerlmin.

References

1. WHO Chronicle 24 (11), 532 (1970). 2. Pharm J 203, 754 (1969). 3. Chugai Pharmaceutical Co. Fr pat 1,500,571. 4. Jap Med News 57, 6 (1968).

Sulfacytine (USAN)

Sulfacitine (Prop..lNN). Sulfacitinum (Lat). Sulfacitina (Sp) , N'-(1-Ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) sulfanilamide N-Sulfanilyl-1-ethylcytosine

Synthesis

Prepared in several steps from 1-ethyl-uracil, the last being the reduction of 1-ethyl-N-(pnitrophenylsulfonyl) cytosine. Also prepared from 1-ethyl-N-(N-acetylsulfanilyl) cytosine.

183

Description

Sulfacytine is highly soluble (1 mg/ml, pH;5) and melts at 167-168° (methanol); ultraviolet absorptio n max. 298 µm [E(1%, 1 cm); 705] and 263 µm [E(1 %, 1 cm) ; 542] in methanol. Sulfacytine monohydrate melts at 104°.

Action

Tests in vivo have proved sulfacytine to be a quickly absorbed,quickly excreted (short acting) antibacterial sulfa drug, potentially and especially suitable for the treatment of urinary tract infections.

Manufacturer

Parke Davis and Co (USA)

References

1. WHO Chron 24 (3), 135 (1970). 2. N-Sulfanilyl-l-alky/cytosines. A new highly active class of “soluble”, short-acting sulfanilamides. L. Doub et al. J Med Chem 13 (2), 242-246 (1970). 3. Parke Davis and Co. Neth Appl 6,610,815.

Sulfamonomethoxine (USAN)

DJ1550

N'-(6-Methoxy-4-pyrimidinyl)sulfanilamide monohydrate 4-Methoxy-6-sulfanilamidopyrimidine monohydrate

Action

In a recent clinical study sulfamonomethoxine has been shown to be effective not only on chloroquine-sensitive malaria, but also on chloroquine-resistant malaria.

Manufacturer

Daiichi Seiyaku Co, Ltd (Japan)

References

1. Studies on the antimalarial property of sulfamonomethoxine and on its effect on the chloroquine-resistant malaria.

T. Yoshinaga et al. Arzneim-Forsch 20 (9), 1206-1210 (1970).

Sulfomycin

Sulfur-containing peptide antibiotic. It consists of three main componets

Production

In the culture liquid and mycelium of Streptomyces viridochromogenes var sulfomycini.

Description

Colorless amorphous powder.

Action

Sulfomycin is a new antibacterial antibiotic.

Manufacturer

Tanabe Seiyaku Co, Ltd (Japan)

References

1. Jap Med Gaz 7 (3). 10-11 (1970). 2. Jap pat 70 06,880.

Sulpiride (Rec INN)

Sulpiridum (Lat). Sulpirida (Sp) N-[(1-Ethyl-2-pyrrolidinyl)methylj-2-methoxy-5-sulfamoylbenzamide

Action

Pharmacological studies have shown that sulpiride is a powerful antagonist of apomorphine emesis in dog. The drug is used as antipsychotic and also in the treatment of gastro-duodenal ulcers, vertigo and digestive migraines.

184

Manufacturer

Laboratoires Delagrange (France)

Proprietary Name

Dogmatil.

Supplied as

Gelules, 50 mg. Tablets, 200 mg. Solution (injection), 100 mg/2 ml.

References

1. J. Besancon et al. C R Acad Sci (Paris) 265, 1253-1254 (1967). 2. M. Thominet et al. Fr pat 1,472,025. 3. G. et B. Vidal. Vie Med 50 (42), 5525 (1969). 4. J. Puech et al. Immex 6 (8-9), 1105 (1969). 5. M. Legre. Therapeutique 45 (10). 1003 (1969). 6. J. Collard. Sem Hop 45 (48), 3028 (1969). 7. Traitement de la pousee ulcereuse par Ie sulpiride. J. Ristelhuober. Gaz Med Fr 77 (1). 120 (1970). 8. Effect du sulpiride sur I´etat psychique de 40 malades mentaux. J. Carriere. J Med Chir Prat 141 (1), 9 (1970). 9. Treatment of gastro-duodenal ulcers by sulpiride. C. Couinaud et al. Ann Gastroenterol Hepatol 7 (1). 85-87 (1970).

Sultroponium (Rec INN)

A 118

3α-Hydroxy-8-(3-sulfopropyl)-1αH, 5αH-tropaniumhydroxide (±) tropate, inner salt ' 8-(3-Sulfopropyl) atropine

Synthesis

Prepared by reaction of atropine with propane 1,3-sultone in acetone.

Description

White crystalline powder, mp about 2200 (dec). Freely soluble in water, insoluble in alcohol, acetone and ether; soluble in hot alcohol. UV max 251.5,

257.5, and 263.5 µm. The spectrum is similar to that of atropine.

Dosage

The oral dose is 15 to 30 mg two to three times daily. The rectal dose is 25 to 75 mg daily.

Supplied as

Tablets, 15 mg. Suppositories, 25 mg.

Proprietary Name

Sultropan

Manufacturer

Biotherax (France)

References

1. J. P. M. Raudnitz et H. Wahl. Fr pat M4,097. 2. Med Act (Drugs of Today) 6 (3), 97-100 (1970). (Review with 4 references).

Suncillin Sodium (USAN; Prop

INN) BL-P 1462

3,3-Dimethyl-7-oxo-6-[2-phenyl-D-2-(sulfoamino) acetamido]-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid disodium salt 6-(D-α-Sulfoaminophenylacetamido) penicillanic acid, disodium salt

Synthesis

Prepared by the treatment of 6-(D-α-aminophenylacetamido) penicillanic acid with trimethylamine-sulfur trioxide complex.

Description

White powder; mp 219-230° (dec).

Action

Suncillin sodium is a new semisynthetic penicillin with anti-pseudomonal activity. It has been shown to be effective in clinic.

185

Manufacturer

Bristol Laboratories (USA)

References

1. Bristol Myers Company. US pat 3,381,001. 2. Antipseudomonal activity of α-sulfoaminopenicillins. K. E. Price et al. Applied Microbiol 17, 881-887 (1969). 3. In vitro studies of a new semisynthetic penicillin. G. P. Bodey et al. Applied Microbicl 18, 76-79 (1969). 4. Preliminary studies of BL-P 1462 in the treatment of pseudomonas infections. G. P. Bodey and V. Rodriguez. Curr Ther Res 12 (6), 363-368 (1970). 5. Abstr Intersc Conf Antimicr 10, 43 . (1970).

Taloximine (Rec INN)

Taloximinum (Lat). Taloximina (Sp) 1-Hydroxyimino-4-(2-dimethylamino) ethoxy-1,2-dihydrophthalazine monohydrochloride monohydrate 4-[2-(Dimethylamino)ethoxy]-1(2H)phthalazinoxime hydrochloride monohydrate

Action

Taloximine has proved to show respiratory stimulant and bronchodilator properties in animals2,3. The results of studies of the drug in man have been described4.

Manufacturer

Riker (England)

References

1. Brit pat 1,094,044, 2. Taloximine, a new respiratory stimulant with bronchodilator properties.

M. Daly et al. Br J Pharmac 35, 283-294 (1969). 3. Investigations into the site of action of taloximine; a new respiratory stimulant molecule. J. A. Pearson and J. P. Griffin. Experientia 25, 716-717 (1969). 4. Human pharmacology of taloximina. J. P. Griffin and P. Turner. Br J Pharmac 39, 249P (1970).

TAT-3

N-(2-Picolyl)-N-phenyl-N-(2-piperidinoethyl) amine hydrochloride

Synthesis

Prepared by the reaction of N-(2-pyridylmethyl)-aniline with 2-piperidinoethyl chloride and sodium amide in refluxing toluene.

Description

Colorless crystals, mp 183-185° (dec). The free base, bp 195-196° (4 mm).

Action

TAT-3 is a non-narcotic antitussive. It has proved to show an antitussive effect equal to or slightly more potent than codeine phosphate in dogs and lower toxicity than codeine in mice.

References

1. Takeda Chemical Industries Ltd. Fr pat 1,511.398. 2. Pharmacology of TAT-3, a new antitussive agent. Y. Kass et al. Arzneim-Forsch 19, 1916-1927 (1969). 3. On the sites of antitussive action of TAT-3. Y. Kass et al. Arzneim-Forsch 20 (1), 37-43 (1970).

186

Taurine N-Carbodithioate

TDT

(2-Sulfoethyl) dithiocarbamic acid N-Dithiocarboxytaurine

Description

The disodium salt melts at 240-243°.

Action

Taurine N-carbodithioate has proved to protect the liver of rats from the toxic action of carbon tetrachloride. It has been concluded that the observed effect may not be due to TOT itself but be due to its metabolites or degradation products, and that the action site of TOT would be located at the early stage of the pathoquietic process of CCI4 liver injury.

Manufacturer

Oainippon Pharmaceutical Co, Ltd (Japan)

References

1. Dainippon Pharmaceutical Co, Ltd. Brit pat 1,094,076. 2. Effect of sodium taurine N-carbodithioate on acute experimental hepatic injury induced in rats by carbon tetrachloride. T. Karasawa et al. Jap J Pharmac 20 (2), 229-236 (1970).

TCMF

1.1-Difluoro-2.2.2-trichloroethyl methyl ether

Description

Nonflammable liquid. bp 124°.

Action

TCMF is a potent general anesthetic when administered by inhalation to man. This compound produces circulatory depression and irritation of the mucous membranes and offers no advantage over those agents currently in common use.

References

1. C. G. Miller and C. Wolf. US pat 2.803.665. 2. The anesthetic properties of 1.1-difluoro-2.2-trichloroethyl methylether. F. G. Rudo et al. Analg Anesth 49 (2). 251-256 (1970).

Tebrofen Tebrophen

Bis-(3,5-dibromo-2,4-dihydroxyphenyl)

Action and Uses

For use in the treatment of herpes keratitis and odenoviral keratoconjuntivitis.

Manufacturer

VNIKhFI (USSR)

Preparations Ophthalmic ointment, 0.1 or 0.25%.

References

A new antiviral preparation. A. N. Grinev et al. Khimiko Farm Zh 4 (9), 61 (1970).

d-Tembetarine Chloride

187

Isolation Alkaloid isolated from the bark of Zanthoxylum martinicense DC1.

Action

Pharmacological studies have shown that d-tembetarine chloride causes a significant fall in blood pressure in intact anesthetized cats and dogs, and that it shows ganglion-blocking activity.

Toxicity

LD50 ip in mice: 63±8.2 mg/kg.

References

1. J. Tomko et al. Lloydia 30, 231 (1967). 2. A pharmacological study of the alkaloids I-canadine methochloride and d-tembetarine chloride. D. G. Patel et al. LIoydia 33 (1), 36-42 (1970) ..

Temazepam (USAN)

WY 3917

7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

Synthesis

Prepared by reaction of 7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one and dimethyl sulphate in presence of sodium hydroxide. Also, by hydrolysis of 3-acetoxy-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one with sodium hydroxide.

Description Action and Uses

White crystalline powder, mp 119-121°. Temazepam is a new 1,4-benzodiazepine compound which is structurally and pharmacologically related to chlordiazepoxide and diazepam. Temazepam is a metabolite of diazepam. It differs chemically from the latter only in having a 3-hydroxy group. It is indicated for the management and control of anxiety, tension agitation, irritability and related symptoms.

Dosage

10 to 60 mg daily.

Supplied as

Capsules, 5 and 10 mg.

Proprietary Name

Levanxol.

Manufacturer

C. Erba (Italy)

References

1. American Home Prod Corp. Brit pat 1,022,642; Brit pat 1,022,645; Brit pat 1,057,492. 2. S. C. Bell et al. J Org Chem 27, 1691 (1962). 3. Med Act (Drugs of Today) 6 (6),223 (1970), (Review with 12 references).

Temekhin Temechin

2,2,6,6-Tetramethylquinuclidine hydrobromide

Synthesis

2,2,6,6-Tetramethylpiperidin-4-one is converted in several steps to 2,2,6,6-tetramethyl-4-(β-bromoethyl) piperidine. By cyclization of the latter temekhin is obtained.

Description

Crystals, mp 270-272°.

188

Action

Temekhin is a new antihypertensive ganglionic blocking agent. It has been approved for clinical use in USSR.

References

The synthesis of a new ganglionic-blocking agent. E. S. Nikitskaya et al. Khim Farm Zh 4 (10), 59 (1970).

Terbutaline (USAN; Rec INN)

KWD 2019

Terbutalinum (Lat). Terbutalina (Sp) α-[(tert-Butylamino) methyl]-3,5-dihydroxybenzyl alcohol

Action

The results obtained from the pharmacological studies indicate that terbutaline is a potent, bronchospasmolytic agent with an effect predominantly on the tracheal and bronchial muscles. It has an action of long duration.

Manufacturer

Draco (Sweden); Astra Pharmaceutical Products (USA)

Proprietary Name

Bronchodil (marketed by Draco, Sweden).

References

1. WHO Chron 24 (11), 533 (1970). 2. JAMA 212, 1360 (1970). 3. Belg pat 704,932. 4. J. Bergman et al. Experientia 25, 899 (1969). 5. Effect of bronchodilator drugs on the peak expiratory rate of asthmatic patients. Oral orciprenaline and terbutaline. M. J. Mattila and A. Maittari. Ann Med Exp Fenn 47,298-302 (1969) .

Tesicam (USAN; Prop INN) CP

13,608

4'-Chloro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxanilide 4'-Chloro-1,4-(2H,4H)-dioxoisoquinoline-4-carboxanilide

Description

mp 243-245° (dec); pKa=4.6. Practically insoluble in water.

Action

Tesicam exhibits anti-inflammatory and uricosuric activity with an extended plasma half-life.

Manufacturer

Pfizer Inc (USA)

References

1. JAMA 213 (13), 2248 (1970). 2. WHO Chron 25 (3), 145 (1971). 3. Chas Pfizer Co, Inc. S African Appl 68 03.465, 4. Dioxoisoquinoline·4-carboxanilides, a new class of non-steroidal anti-inflammatory agents. S. B. Kadin and E. H. Wiseman. Nature 222, 275-276 (1969). 5. Dioxoisoquinoline-4-carboxanilides, novel non-steroidal anti-inflammatory agents with a species-specific effect on basal metabolism. E. H. Wiseman et al. J Pharmac Exp Ther 172 (1), 138-153 (1970).

189

Tetracasactrin (BAN)

ClBA 30920 Ba

Tetracosactride (Rec INN) Synthetic beta 1-24 corticotrophin H-Ser-Tyr-Ser-Met-Glu-H is-Phe-Arg-Try-Gly-Lys-ProVal-Gly-Lys-Lys-Atg-Arg-Pro-Val-Lys-Val-Tyr-Pro-OH

Synthesis

The synthesis of tetracosactrin, a 24-aminoacid polypeptide, was made possible by using N'-t-butoxycarbonyl-L-Iysine and γ-butyl-L-glutamate as intermediates1.

Action and Uses

Tetracosactrin is a tetracosapeptide incorporating the aminoacid residues 1-24 of ACTH. It retains the biological activity of the latter and in a similar manner stimulates the adrenal cortex to produce adrenocortical hormones. Tetracosactrin depot a preparation of tetracosactrin absorbed on zinc hydroxide or zinc phosphate, has been recently introduced in the pharmaceutical market. Absorption after parenteral administration is delayed, its action is thus maintained with less frequent administration. Indications: nearly all conditions for which corticosteroids are prescribed: collagen disease, allergic reactions, skin diseases, except where adrenal function is impaired.

Dosage

Intramuscularly: Adults, 1 mg daily. Intervals between injections may be increased to 2 or 3 days.

Supplied as

Tetracosactrin with zinc hydroxide in aqueous suspension in two strengths: 0.5 mg/ml and 1 mg/ml. Tetracosactrin zinc phosphate complex 1 mg/ml and 2 mg/2 ml.

Proprietary Names and Manufacturers Cortrosyn [Organon (England); Endopancrine (France)]. Synacthen (Ciba, England)

References

1. H. Kappeler and R. Schwyzer. Helv Chim Acta 44,1136·1141 (1961); 46,1550 (1963). 2. Med Act (Drugs of Today) 6 (2), 66-71(1970). (Review with 13 references).

Tetracycline

Cyclohexylsulfamate

Tetracycline cyclamate

Synthesis

An ethanolic solution of tetracycline is added at 45° to an ethanolic solution of cyclohexylsulfamic acid. By addition of ether, tetracycline cyclohexylsulfamate precipitates1.

Description

Yellow powder, mp at about 220° (dec); very soluble in water. UV max 220, 268 and 355 µm.

Action and Uses

Tetracycline cyclohexylsulfamate is a new pleasant tasting salt of tetracycline. It is used for the same indications as other tetracycline preparations.

Supplied as

Capsules, 250 mg (expressed in terms of tetracycline hydrochloride) with 220 mg sodium hexametaphosphate.

Dosage

Adults, 4-6 capsules daily given in two to three divided doses. In more severe cases 8 capsules daily.

Proprietary Name

Sifacycline.

Manufacturer

Diamant (France)

References

1. SIFA. Fr pat M 3004. 2. Med Act (Drugs of Today) 6 (1). 32-34 (1970). (Review).

190

Tetrazepam (Prop INN)

CB-4261

7-Chloro-5-(1-cyclohexen-1-yl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Synthesis

Tetrazepam, a new 1,4-benzodiazepine derivative, is structurally related to diazepam. It differs from the latter in having a 5-cyclohexenyl group instead of a 5-phenyl group. Prepared from 7-chloro-5-(1-cyclohexen-1-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one.

Description

Yellow-brown crystalline powder, mp 144°. UV max 227 µm (ε=28,500) in ethanol.

Action and Uses

Tetrazepam is a new myorelaxant drug. Indications: certain types of hemiplegias; spasmodic paraplegias; lumbago, sciatica, tetanus contractures; functional rehabilitation.

Dosage

Orally, 150 to 400 mg daily.

Registered Name Myolastan.

Manufacturer

Clin Byla (France)

References

1. Clin Byla Neth pat 6,600,095; Fr pat 978,360. 2. S. C. Bell et al. J Org Chem 27, 562 (1962). 3. Med Act (Drugs of Today) 6 (4), 145-150 (1970) . (Review with 12 references) .

Th 1165a

3,5-Dihydroxy-α-[[(p-hydroxy-α-methylphenethyl) amino] methylbenzyl alcohol 1-(3,5-Dihydroxyphenyl)-1-hydroxy-2-[(4-hydroxyphenyl) isopropylamino] ethane 1-(p-Hydroxyphenyl)-2-[[β-hydroxy-β-(3',5'-dihydroxyphenyl)] ethyl] aminopropane

Synthesis

Prepared in several steps from 3,5-diacetoxy-α-bromo-acetophenone and 1-(p-methoxyphenyl)-2-benzylaminopropane; the last being the hydrogenation of 1-(p-hydroxyphenyl)-2-[N-(3,5-dihydroxybenzoyl) methyl] aminopropane. The hydrochloride, mp 182-183°; the hydrobromide, mp 232-233°.

Action

Th 1165, a hydroxyphenyl derivative of orciprenaline, is a beta-adrenergic substance. It has proved to be useful in the resuscitation of patients with cardiac arrest and effective in the treatment of status asthmaticus and acute respiratory insufficiency.

Manufacturer

C. H. Boehringer Sohn, Ingelheim (Germany)

References

1. C. H. Boehringer Sohn. Belg pat 640,433. 2. Hemodynamic studies with the p-hydroxyphenyl derivative of orciprenaline. P. Lichtlen et al. Arzneim-Forsch 19 (2), 147-149 (1969). 3. Airway resistance und intrathoracic gas volume after the inhalation of a hydroxyphenyl derivative of orciprenaline (Th 1165a). D. Nolte. Respiration 27, 396-405 (1970). 4. Spirographischer und atemmechanischer Wirkungsvergleich zwischen Orciprenalin (Alupent) und dem Hydroxyphenyl-Derivat Th 1165a. J. Hamm und H. Wusthofen. Klin Wschr 48 (7),415-418 (1970). 5. Beziehungen zwischen Atemregulation und peripherem Atmungsapparat untersucht mittels CO2-Antwortkurven vor und nach bronchospasmolytischer Therapie. J. Hamm. Klin Wschr 48 (7), 418-426 (1970). 6. A selective β-adrenoreceptor stimulant (Th 1165a) related to orciprenaline. S. R. O'Donneil. Eur J Pharmac 12 (1), 35 (1970).

191

Thiophanate

1,2-Bis-(ethoxycarbonylthioureido) benzene

Synthesis

By reacting ethyl chloroformate with potassium thiocyanate, and subsequent reaction with o-phenylendiamine.

Description

Colorless crystals, mp 195° (dec).

Action

Fungicide.

Manufacturer

Nippon Soda (Japan)

References

1. Japan Soda Co, Ltd. Ger Offen 1,806,123. 2. Oyo Yakuri (Pharmacometrics) 4 (1970).

4-Threonine Oxytocin

Synthesis

The key intermediate required for the synthesis of 4-threonine-oxytocin is the protected nonapeptide, N-benzyloxycarbonyl-5-benzyl-L-cysteinyl-O-benzyl-L-tyrosyl-L-isoleucyl-O-benzyl-L-threonyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-L-Ieucyl-glycinamide. This protected nona peptide is synthesized by the solid phase method1.

Description

White fluffy powder, [α]D = -10.40 (c=0.5, 1 N acetic acid).

Action

4-Threonine-oxytocin is an analogue of oxytocin in which the glutamine residue in the four position is replaced by a threonine residue. This analogue is about twice as active as oxytocin in rat uterus assays in vitro and in vivo and about three times as active in fowl vasodepressor assays than oxytocin itself, and possesses specifically weaker vasopressor and antidiuretic activities than oxytocin.

References

1. Solid-phase synthesis of 4-threonine-oxytocin. A more potent and specific oxytocic agent than oxytocin. M. Manning et al. Biochem 9 (20), 3925-3929 (1970). 2. 4-Threonine-oxytocin: a more active and specific oxytocic agent than oxytocin. M. Manning and W. H. Sawyer. Nature 227 (5259), 715-716 (1970). 3. 4-Threonine analogues of neurohypophysial hormones with selectively enhanced oxytocin-like activities. W. H. Sawyer and M. Manning. J Endocr 49,151-165 (1971).

Thyrotropin-Releasing

Hormone

Pyroglutamylhistidylproline amide pGlu-His-Pro-NH2

Action

Two teams of US investigators have recently succeeded in determining the structure of TRH. It is understood that Dr Rolf Studer et al (Hoffmann-La Roche, Switzerland) have achieved the total synthesis of this hormone.

References

Chem Engineer News 48 (52), 39 (Dec 14, 1970).

192

Tibolone (USAN; Rec INN)

Org OD14

27-Hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one 17α-Ethinyl-17-hydroxy-7α-methyl-5-(10)-estren-3-one

Synthesis

Prepared by the reaction of potassium acetylide with 7α-methyl-∆4-3,17,19-trioxoandrostene in liquid ammonia3. Also by the reaction of lithium acetylide-ethylenediamine with 3-methoxy-7α-methyl-17-oxo-∆

2,5(10)-19-norandrostadiene in dimethylsulfoxide and toluene4.

Description

Crystals, mp 168-169°; [ α]D = +105°(c=0.539).

Action

Tibolone is an anabolic agent.

Manufacturer Organon

References

1. JAMA 209, 1212 (1970). 2. WHO Chron 24 (11), 533 (1970). 3. N. V. Organon. Fr pat 1.527,563. 4. G. Anner and P. Wieland (to Ciba Corp). US pat 3,432,528. 5. P. Wieland et al. Helv Chim Acta 50 (6), 1453-1461 (1967).

Ticlatone (USAN; Rec JNN)

FER-

1443

6-Chloro-1,2-benzisothiazolin-3-one

Synthesis

Prepared from 2-chloromercapto-4-chlorobenzoyl·chloride and aqueous ammonia. From 4,4'-dichloro-2,2'-dithiosalicylic acid diamide and sodium hydroxide. From 4,4'-dichloro-2,2'-dithiosalicylic acid diamide and a solution of bromine in CCI4.

Description

White crystals, mp 271.273°.

Action and Uses

Bacteriostat and fungistat.

Supplied as

Powder, 0.5%; ointment. 0.5% and lotion, 0.1 %.

Manufacturer Dr A Wander (Switzerland). Dorsey Lab (USA)

Proprietary Name

Landromil.

References

1. JAMA 212,466 (1970). 2. WHO Chron 24 (11), 533 (1970). 3. Dr A Wander AG. Ger pat 1,135.468, 4. R. Fischer et al. Arzneim·Forsch 14 (12), 1301·1306 (1964). 5. H. Hurni et al. Arznaim·Forsch 14 (12), 1306·1309 (1964). 6. R. Ponci at al. Farmaco, Ed Sci, 22 (12), 989·998 (1967). 7. T. Vitali et al. Farmaco, Ed Sci, 23 (11), 1075·1080 (1968). 8. Med Act (Drugs of Today) 5 (3), 86 (1969).

193

Tilidine Hydrochloride

Semihydrate (USAN; Prop INN)

W 5759A GO

1261C

dl-trans-2-(Dimethylamino)-1-phenyl-3-cyclohexene-1-carboxylic acid ethyl ester hydrochloride semihydrate

Synthesis

Prepared from atropic acid ethyl ester and 1-dimethylamino-1,3-butadiene.

Description

White crystalline powder, mp 128°. Very soluble in water. The hydrochloride melts at 162°.

Action and Uses

Tilidine hydrochloride is a new potent analgesic agent, recently marketed in Germany. It is useful for the relief of pain associated with surgery, trauma, labor, colic and cancer.

Dosage

Adults: Orally, up to 51.45 mg four times daily; rectally, up to 77.18 mg four times daily; parenterally up to 51.45 mg four times daily. 51.45 mg of tilidine hydrochloride semi hydrate is equivalent to 50 mg of tilidine hydrochloride.

Supplied as

Solution (injection), 51 .45 mg/ml. Drops, 102.9 mg/ml. Capsules, 51.45 mg. Suppositories, 77.18 mg.

Proprietary Name

Valoron.

Manufacturer

Giidecke AG (Germany) Wamer-Lambert (USA)

References

1. Warner-Lambert. Brit pat 1.120,186. 2. Med Act (Drugs of Today) 7 (1). 33·36 (1971). (Review with 7 references) .

Tilorone (USAN; Prop INN)

DEAE-F

Tiloronum (Lat). Tilorona (Sp) Bis-DEAE-fluorenone 2,7-Bis [2-(diethylamino) ethoxy] fluoren-9-one

Action

Tilorone dihydrochloride is a compound that has a broad spectrum of antiviral activity in vivo following oral administration in mice. The compound, stimulates the production of an antiviral protein with properties characteristic of interferon.

Manufacturer

Wm S Merrell (USA)

References

1. WHO Chron 24 (9), 432 (1970). 2. Science 169, 1213 (1970). 3. Antiviral activity of bis-deae-ffuorenone. an oral interferon-inducer. R. F. Krueger and S. Yoshimura. Fed Proc 29, 635 (1970). 4. Bis-deae-fluorenone, an oral inducer of interferon. G. D. Mayer and B. A. Fink. Fed Proc 29, 635 (1970). 5. Effects of an oral interferon-inducer on the hematopopoietic and reticuloendothelial systems. M. W. Rohovsky et al. Toxicol Appl Pharmacol 17, 556-558 (1970).

Tinidazole (USAN)

CP-12,574

1-[2-(Ethylsulfonyl) ethyI]-2-methyl-5-nitroimidazole Ethyl [2-(2-methyl-5-nitro-l-imidazolyl) ethyI] sulfone

194

Synthesis

Prepared by the reaction of 2-methyl-5-nitroimidazole with ethylsulfonylethyl p-toluenesulfonate1,2.

Description

Colorless crystals. mp 127-128° (benzene).

Action

Tinidazole is a potent. orally effective agent against trichomoniasis and amebiasis.

Toxicity

LD50 po in mice > 3600 mg/kg; ip in mouse or rat > 2000 mg/kg.

Manufacturer

Chas Pfizer Co (USA)

Proprietary Name

Fasigyn.

References

1. JAMA 211. 819 (1970). 2. K. Butler (to Chas Pfizer Co. Inc). US pat 3.376.311. 3. Alkylation of 2-methyl-5-nitroimidazole. Some potent antiprotozoal agents. M. W. Miller et al. J Med Chem 13 (5). 849-852 (1970). 4. Tinidazole. a potent new antiprotozoal agent. M. W. Miller et al. Antimicrob Ag Chemother-1969. p 257-260 (1970). 5. Tinidazole. a new anti protozoal agent: effect on Trichomonas and other protozoa. H. L. Howes et al. Antimicrob Ag Chemother 1969. p 261-266 (1970). 6. Tinidazole and metronidazole pharmacokinetics in man and mouse. J. A. Taylor et al. Antimicrob Ag Chemother 1969. p 267-270 (1970).

Tinoridine (Prop INN)

Y

3642

Ethyl 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-3-carboxylate 2-Amino-3-ethoxycarbonyl-6-benzyl-4,5,6,7-tetrahydrothieno [2,3-c] pyridine

Action

This compound exhibits potent analgesic, antipyretic and anti-inflammatory effects with low toxicity.

Toxicity

LD50 po in rats> 10,200 mg/kg; ip 1,250 mg/kg.

Manufacturer

Yoshitomi Pharmaceutical Industries Ltd (Japan)

References

1. WHO Chron 25 (3), 145 (1971). 2. Studies on anti-inflammatory agents. I. Some biological activities of thienopyridine derivatives. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 272-276 (1970). 3. II. Analgesic and anti-edematous activities of Y-3642. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 277-283 (1970). 4. III. Effect of Y-3642 on pyretic reaction, vascular permeability and granuloma formation in experimental animals. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 284-290 (1970). 5. IV. On the appearance of physical dependence and analgesic activity of Y-3642 by repeated administration. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 291-296 (1970). 6. V. Distribution of 14C-Y-3642 in mice. H. Imamura et al. Yakugaku Zasshi 90 (3), 296-301 (1970). 7. VI. Absorption, excretion and metabolism of (14C-Y-3642) in mice. H. Imamura et al. Yakugaku Zasshi 90 (3), 302-307 (1970). 8. VII. Absorption, distribution excretion and metabolism of 14C-Y-3642 in rats. H. Imamura et al. Yakugaku Zasshi 90 (3), 317-323 (1970).

195

9. VIII. Activity of (Y-3642) on central nervous system, respiration and cardiovascular system and the isolated organ. M. Nakanishi et al. Yakugaku Zasshi 90 (3), 329-334 (1970). 10. IX. Effect of (Y-3642) on heat-induced hemolysis. M. Nakanishi et al. Yakugaku Zasshi 90 (5), 548-551 (1970). 11. X. Stabilization of rat liver lysosome by Y-3642. M. Nakanishi et al. Yakugaku Zasshi 90 (5), 557-563 (1970). 12. XI. Inhibitory effects of Y-3642 On platelet aggregation. M. Nakanishi et al. Yakugaku Zasshi 90 (5), 564-569 (1970) . 13. XII. Metabolites of Y-3642 in human urine. E. Matsui et al. Yakugaku Zasshi 90 (9), 1156-1159 (1970). 14. XI/I. Distribution of 35S-Y-3642. H. Imamura et al. Yakugaku Zasshi 90 (9), 1126-1134 (1970). 15. Pharmacological investigations of 2-amino-3-ethoxycarbonyl-6-benzyl-4,5,6,7-tetrahydrothieno-[2,3-]-pyridine. M. Nakanishi at al. Arzneim-Forsch 20 (8), 998-1003 (1970). 16. Pharmacological investigations of 2-amino-3-ethoxycarbonyl-6-benzyl-4,5,6,7-tetrahydrothieno-[2,3-c]-pyridine. M. Nakanishi at al Arzneim-Forsch 20 (8), 1004-1009 (1970).

Tiprenolol (Rec INN, USAN)

DU 21445

1-(lsopropylamino)-3-[O-(methylthio) phenoxy]-2-propanol 1-(2-Methylthiophenoxy)-2-hydroxy-3-isopropylaminopropane

Synthesis

Tiprenolol is prepared by treating 2-(methylthio) phenol with epichlorhydrine, and reacting the resulting compound with isopropylamine.

Description

Tiprenolol base melts at 87.5-90.5° (ligroin). The hydrochloride melts at 125-127° (alcohol-ether).

Action

Tiprenolol is a β-adrenergic blocker. It differs chemically from alprenolol in having an o-methylthio group instead of an o-allyl group.

Manufacturer

N. V. Phillips-Duphar (Netherlands)

References

1. WHO Chron. 24 (11), 533 (1970). 2. JAMA 213,1326 (1970). 3. N.V. Phillips Gloeilampenfabrieken. Neth Appl 6,504,268. 4. Med Klin 63, 1939 (1968).

TMA Hydrochloride

3,4,5-Trimethoxy-α-methylphenethylamine hydrochloride 3,4,5-Trimethoxyamphetamine hydrochloride 1-(3,4,5-Trimethoxyphenyl)-2-aminopropane hydrochloride

Synthesis

Prepared by reduction of 1-(3,4,5-trimethoxyphenyl)-ω-nitropropene.

Description

Crystals, mp 216-217°,

Action

TMA is a new amphetamine derivative. It is subjected to control because of its hallucinogenic effects.

References

1. A. T. Shulgin. Experientia 20, 366 (1964). 2. Analogs of α-methylphenethylamine (amphetamine). 1. Synthesis and pharmacological activity of some methoxy and/or methyl analogs. B. T. Ho et al. J Med Chem 13 (1), 26-30 (1970). 3. Fed Reg 35 (47), 4305-4306 (1970) .

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α-Tocopherylquinone

α-Tocoquinone (3-Hydroxy-3,7,11,15-tetramethylhexadecyl) trimethyl-pbenzoquinone

Synthesis

By oxidation of α-tocopherol.

Description

Yellow-orange oil; insoluble in water and soluble in organic solvents.

Action and Uses -Tocopherylquinone has been marketed in France and is claimed to show myotrophic activity.

Dosage

300 mg daily, in three divided doses.

Preparations Solution (oral) 100 mg per ampoule.

Registered Name Eutrophyl.

Manufacturer

Medial-Riker (France)

References

1. Ch. D. Robeson and D. R. Nelan. US pat 2,856,414. 2. Sogespar SA. Fr pat Addn 75.631. 3. Med Act (Drugs of Today) 6 (1), 34·37 (1970). (Review with 8 references).

Tramadol Hydrochloride

(USAN; Prop INN) U

26,225A

(±)-trans-2-[(Dimethylamino)-methyl]-1-(m-methoxyphenyl) cyclohexanol hydrochloride

Synthesis

The reaction of m-methoxyphenyl magnesium bromide with 2-dimethylaminoethyl-cyclohexanone in tetrahydrofurane at room temperature gives 1-(m-methoxyphenyl)-2-dimethylaminomethyl-cyclohexanol. This product can be separated into two isomers by crystallization of the hydrochloride in moist dioxane: isomer α hydrochloride, mp 162-3° and isomer β hydrochloride, mp 175-7° (moist dioxane). The free base, bp 138-140° (0.6 mm).

Action

Tramodol is an analgesic agent, It has appeared to be effective in clinical investigation, but with gastrointestinal and psychological side effects.

Manufacturer

The Upjohn Co (USA); Chemie Grunenthal (Germany)

References

1. JAMA 209, 925 (1969). 2. Clinical investigation of tramadol hydrochloride. J. S. Finch and T. J. DeKornfeld. Pharmacologist 12 (2), 231 (1970).

Trazodone Hydrochloride

(USAN; Rec INN) AF

1161

2-[3-[4-(m-Chlorophenyl)-1-piperazinyl] propyl]-s-triazolo [4,3-α] pyridin-3(2H)-one hydrochloride

197

Synthesis

Prepared by the reaction of s-triazolo [4,3-α] pyridine-3-one with sodium hydride and 1-(3-chloropropyl)-4-(m-chlorophenyl) piperazine.

Description

Crystals, mp 223º (alcohol); the free base melts at 86-87º.

Action

Trazodone hydrochloride is a central nervous system stimulant. In a controlled clinical study the drug has proved to exert an anti-depressive effect.

Manufacturer

Angelini Francesco (Italy)

References

1. JAMA 211,1362 (1970). 2. WHO Chron 24 (11). 533 (1970). 3. Aziende Chimiche Riunite Francesco Angelini. Brit pat 1,117,068; US pat 3.381.009. 4. Controlled clinical study af trazodane, a new antidepressant drug. M. De Gregorio and A. Dionisio. VII International Congress Collegium Internationale Neuro· Psychopharmacologicum, Prague, Aug 11-15 (1970); abs 107.

Tretinoin (USAN; Prop INN)

all trans-Retinoic acid [3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid]

Description

Crystals, mp 180-182° (ethanol). UV max 351-352 µm (ε=45,000) in methanol.

Action

Keratolytic.

Manufacturer

Hoffmann La Roche

References

1. JAMA 211, 1363 (1970). 2. WHO Chron 25 (11), 147 (1971). 3. BASF. Ger pat 1,025,869; 1,046.612; 1.050.763; 1,068,702. US pat 3,006,939.

Tretoquinol Hydrochloride

(Prop INN) AQ

110 Trimetoquinol

1-(3,4,5-Trimethoxybenzyl)-6,4-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

Action

Trimetoquinol is a new bronchodilator agent, which has been found to be 5 to 10 times more potent than isoproterenol, but with less cardiovascular action. The circulatory effects of the drug have been compared recently with those of isoproterenol and salbutamol.

198

Manufacturer

Tanabe Seiyaku (Japan) May and Baker (England)

Proprietary Name

Inolin (Tanabe Seiyaku).

Supplied as

Tablets, 3 mg. Solution (injection) 1 mg. Inhalation 5 mg/ml.

References

1. Sato at al. Jap J Pharmacal 17. 153-163 (1967). 2. Med Act (Drugs of Today) 5 (3). 109 (1969). 3. A comparison of the cardiovascular actions of AQ 110 with those of isoprenaline and salbutamol. F. Fogelman and H. F. Grundy. Br J Pharmac 38. 416-432 (1970).

Triflocin (USAN; Prop INN)

CL 65,562

Triflocinum (Lat). Triflocino (Sp) 4-(α,α,α,-Trifluoro-m-toluidino) nicotinic acid 4-(m-Trifluoromethylanilino) nicotinic acid

Synthesis

Prepared by the reaction of 4-chloronicotinic acid with m-trifluoromethylaniline3.

Description

Crystals, mp 205-206° (aqueous ethanol).

Action

Triflocin, a nicotinic acid derivative, is a structurally new diuretic agent. It is non-sulfhydryl reactive, and does not inhibit carbonic anhydrase in vitro4. It has proved to be an orally effective natriuretic agent in man, active in the ascending limb of the loop of Henle5. Triflocin while less potent than furosemide and ethacrynic acid, did not require potassium

chloride or aldactone supplementation, as the latter two do, to prevent hypokalemia6.

Manufacturer

Lederle Laboratories (USA)

References

1. JAMA 209, 2044 (1969). 2. WHO Chron 24 (3), 138 (1970). 3. D. Evans and C H. Cashin. J Med Chem 10, 428-431 (1967). 4. J. B. Cummings et al. Pharmacologist 10, 162 (1968). 5. Renal mechanisms of the natriuretic and antiphosphaturic effects of triflocin-a new diuretic. Z. S. Agus and M. Goldberg. J Lab Clin Med 76 (2), 280-292 (1970). 6. Triflocin: a new potassium sparing diuretic. F. Steigmann et al. Fed Proc 29, 481 (1970).

Triflumidate (USAN; Rec INN)

MBR 4223 BA 4223

Triflumidatum (Lat). Triflumidato (Sp) Ethyl m-benzoyl-N-[(trifluoromethyl) sulfonyl] carbanilate N-Ethoxycarbonyl-3-benzoyltrifluoromethane-sulfonanilide

Synthesis

3-Aminobenzophenone is treated with trifluoromethanesulfonic anhydride to give 3-benzoyl-1,1,1-trifluoromethanesulfonanilide. Formation of the sodium salt of the latter with sodium hydroxide followed by reaction with ethyl chloroformate gave triflumidate.

Description

Crystals, mp 131.5-132.5°; it is highly insoluble i n water.

Action

Triflumidate is a new anti-inflammatory agent. It has proved to be approximately equipotent with

199

phenylbutazone in the carrageenin rat paw edema test and in the adjuvant arthritis test.

Toxicity

LD50 po in mice: greater than 2000 mg/kg.

Manufacturer

Minnesota Mining and Mfg, Co (USA)

References

1. Anti-inflammatory agents. I. Benzoylfluoro-alkanesulfonanilides. J. Kenneth Harrington et al. J Med Chem 13 (1), 137 (1970). 2. The metabolism of MBR-4223 (triflumidate), a new non·steroidal anti-inflammatory agent, in man and laboratory animals. S. F. Chang et al. Fed Proc 29 (2), 678 Abs, 2433 (1970).

Trifluthepin

8-Trifluoromethyl-10-(4-methylpiperazino)-10-11-dihydrodibenzo-[b,f] thiepine

Synthesis

Prepared from 8-trifluoromethyl-10-chlaro-10-11-dihydrodibenzo [b,f] thiepine. Trifluthepin maleate melts at 137-138° (acetone/ether).

Action

Tritluthepin, a trifluoromethyl analogue of octoclothepin, is a very potent neuroleptic. This potency is manifested mainly in the cataleptic test in rats, in which trifluthepin is 3 to 4 times stronger than octoclothepin. Its central sedative activity is somewhat lower than that of octociothepin.

References

1. SPOFA United Pharmaceutical Works. Fr pat 1,566,933.

2. K. Pelz et al. Coll Czech Chem Commun 34 (12), 3936-3943 (1969).

Trimebutine Hydrochloride

3.4.5-Trimethoxybenzoic acid, β-(dimelhylamino)-β-ethylphenethylester hydrochloride 3.4.5-Trimethoxybenzoic acid, 2-phenyl-2-dimethylamino-n-butylester hydrochloride

Synthesis

Prepared by reacting 2-phenyl-2-dimethylamino-n-butanol with 3,4,5-trimethoxybenzoic acid chloride.

Description Action and Uses

Crystals, mp 184º Trimebutine exhibits a local antispasmodic activity on the digestive tract. It also possesses analgesic and local anaesthetic properties. It is used in the treatment of nausea and vomiting, abdominal pain, flatulence in the course of esophagitis, gastritis and duodenitis, colitis, and biliary dyskinesia.

Dosage

300 to 400 mg daily.

Supplied as

Tablets, 100 mg. Suppositories, 100 mg. Vials 50 mg (as trimebutine maleate).

Manufacturer

Laboratories Jouveinal (France)

Proprietary Name

Debridat.

References

1. Lab. Jouveinal. Fr pat 1.344.455. 2. Med Act (Drugs of Today) 7 (1), 37-38 (1971). (Review).

200

Trophosphamide (Rec INN)

Trofosfamide Z4828

Trofosfamidum (Lat). Trofosfamido (Sp) 3-(2-Chloroethyl)-2-[bis-(2-chloroethyl) amino]-1-tetrahydro-2H-1,3,2-oxazophosphorin-2-oxide

Action

New cyclophosphamide cytostatic drug, which has been shown to be well tolerated and effective in clinic.

Manufacturer

Asta-Werke AG (Ger)

References

1. WHO Chron 24 (11). 533 (1970). 2. Results obtained with two new phosphamide derivatives. P. Drings at al. Deutsche Med Wochenschr 95 (10).491-497 (1970).

U-5897

3-Chloro-1,2-propanediol α-Chlorohydrin

Synthesis

Prepared from glycerol and hydrochloric acid gas.

Description

Liquid, bp 119º (14 mm); d420 = 1,3214 and nD

20 = 1,4809. Miscible with water, ethanol, ether and acetone.

Action

U 5897 is an effective male rat chemosterilant. Sterility results from a lesion in the initial segment of the caput epididymidis.

Manufacturer

The Upjohn Co (USA)

References

1. Organic Synthesis 1. 294 (1941). 2. Beilstein 1, III, 2150. 3. Male antifertility compounds: V-5897 as a rat chemosterilant. R. J. Ericsson. J Reprod Fert 22, 213-222 (1970). 4. Male antifertility compounds: Structure and activity relationships of V-5897, V-15, 646 and related substances. R. J. Ericsson and G. A. Youngdale. J Reprod Fert 21,263-266 (1970). 5. Male antifertility compounds: Biological properties of V-5897 and V-15,646. R. J. Ericsson and V. F. Baker. J Reprod Fert 21,267-273 (1970). 6. Male antifertility compounds; Efficacy of V-5897 in primates (Macaca Mulatta). K. T. Kirton et al. J Reprod Fert 21, 275-278 (1970). 7. Antifertility activity of 3-chloro-1,2-propanediol (V-5897) on male rats. E. Samojlik and M. C. Chang. Biology of Reproduction 2, 299-304 (1970). 8. Induction of temporary infertility in rams with an orally administered chlorohydrin. J. L. Kreider and R. H. Dutl. J Animal Sci 31 (1), 95-98 (1970).

U 14,624

1-Phenyl-3-(2-thiazolyl)-2-thiourea

Synthesis

Prepared from 2-aminothiazole and phenyl sulfocyanate.

Description

Crystals, mp 178.5°.

201

Action

U 14,624 is a dopamine β-hydroxylase inhibitor. It has proved to decrease brain norepinephrine and to increase brain dopamine in both mice and rats.

Toxicity

LD50 ip in mice: 680 mg/kg.

Manufacturer

The Upjohn Co (USA)

References

1. T. Uno and S. Akihama. Yakugaku Zasshi 80, 1015-1020 (1960). 2. In vivo inhibition of dopamine β-hydroxylase by U-14.624. G. A. Johnson et al. J Pharmacal Exp Ther 171, 80-87 (1970). 3. Behavioral and brain catecholamine depleting actions of U-14,624, an inhibitor of dopamine β-hydroxylase. P. F. von Voigtlander and K. E. Moore. Proc Soc Exp Biol Med 133, 817-820 (1970).

USVC 6524

1-(4-lndanyloxy)-3-(isopropylamino)-2-propanol hydrochloride

Synthesis

Prepared by the reaction of 1-(4-indanyloxy)-3-chloro-2-propanol with isopropylamine. The free base melts at 105°, and the hydrochloride at 153°.

Action

USVC has proved to be a β-adrenoceptor antagonist of considerable potency with relatively weak cardiac depressant properties. It differs structurally from propranolol in that it possesses an indane rather than a naphthyl group.

References

1. Imperial Chemical Industries ltd. Belg pat 641.417.

2. 1-lsopropylamino-3-(4-indanoxy)-2-propanol HCl: A potent β-adrenoceptor antagonist. B. levy and M. Wasserman. Br J Pharmac 39 (1), 139-14B (1970).

V 111

p-Bromo-desoxyephedrine p-Bromo-methamphetamine

Action

V 111 is a new psychotomimetic agent. A detailed pharmacological analysis of the central actions of this compound in comparison with LSD has been reported.

Manufacturer

Chinoin (Hungary)

References

1. Pharmacological studies on para-bromo-methamphetamine (V-111) and LSD. J. Knoll et al. Acta Physiol Acad Sci Hung 37 (1-2), 151-170 (1970). 2. Inhibition of the effects of LSD and p-bromo-methamphetamine (V-111) by p-chlorophenylalanine. J. Knoll and E. S. Vizi. Pharmacol Res Commun 2 (1), 67-70 (1970).

Verticillin A

Production

Obtained from cultures of Verticiflium sp.

202

Description

Pale yellow amorphous powder, mp 203-214° (dec) (tetrahydrofuran).

Action

Verticillin A is a new antibiotic which has been found active against gram-positive bacteria and mycobacteria but not against gram-negative bacteria and fungi. It also exhibits antitumor effects.

Toxicity

LD50 ip in mice 7.6 mg/kg.

Manufacturer

Shionogi Co, Ltd (Japan)

References

Venicillin A a new antibiotic from Verticillium sp. K. Katagiri et al. J Antibiot 23 (8), 420·22 (1970).

WR 4809

1-Methyl-4-[4-(7-chloro-4-quinolylamino) benzoyl] piperazine acetate

Action

New antimalarial agent. Pharmacological studies have shown that WR 4809 is capable of blocking both alpha and beta adrenergic receptors.

Toxicity

LD50 iv in rats: 101 mg/kg.

Manufacturer

Walter Reed Army Institute of Research (USA)

References

Pharmacology of new antimalarial drugs. A piperazine which exerts an unusual type of adrenergic blockade.

P. J. Cambar and D. M. Aviado. Arch int Pharmacodyn 183, 107-126 (1970).

Wy 8678

[(2,6-Dichlorobenzylidene )amino] guanidine acetate

Synthesis

Prepared by the reaction of 2,6-dichlorobenzaldehyde with either aminoguanidine hydroiodide, or aminoguanidine and p-toluensulfonic acid1. The free base melts at 227-229º.

Action

Wy 8678 is an antihypertensive agent. It has been found to lower blood pressure and heart rate in unanesthetized hypertensive animals. The general cardiovascular actions of the compound have been described.

Manufacturer

Wyeth Laboratories Inc (USA)

References

1. Shell Internationale Research Maatschappij NV. Brit pat 1.019,120; Ger Offen 1,802.364. 2. 2,6-Dichlorobenzylidene amino guanidine acetate (Wy 8678). A new hypotensive agent. T. Baum et al. Experientia (Basel) 25. 1066 (1969). 3. Actions of the antihypertensive agent 2,6-dichlorobenzylidene aminoguanidine acetate (Wy-8678) on the cardiac conduction system. T. Baum et al. Arch Int Pharmacodyn Ther 183 (1),75-84 (1970). 4. General pharmacologic actions of the antihypertensive agent 2,6-dichlorobenzylidene aminoguanidine acetate (Wy-8678). T. Baum et al. J Pharmacol Exp Ther 171 (2). 276-287 (1970).

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Xipranolol (Rec INN)

BS 7977D

Xipranololum (Lat) 1-(Di-2,6-xylylmethoxy)-3-(isopropylamino)-2-propanol hydrochloride

Synthesis

Prepared in two steps from di-(2,6-xylyl)-methylchloride, the last one being the reaction of 1,2-epoxy-3-(di-2,6-xylylmethoxy)propane with isopropylamine.

Description

Crystals, mp 189-191° (acetone).

Action

Xipranolol is a potent antiarrhythmic agent, devoid of beta adrenoreceptor blocking activity.

Manufacturer

NV Brocades-Stheeman (Netherlands)

References

1. WHO Chron 24 (11), 534 (1970). 2. Brocades-Stheeman. Neth Appl 6712697 6,712,697. 3. J. De Vries et al. Arzneim-Forsch 18 (9), 1200-3 (1968). 4. Antiarrhythmic activity of BS-7977-D in the dog heart lung preparation. Atul R. Laddu. Eur J Pharmacol 9 (2), 129-135 (1970).

YC 73

Antibiotic isolated from the culture broth of a pseudomona

Description

Dark green needles, mp 199º (dec).

Action

The antibiotic is active against bacteria and fungi.

Manufacturer

Tanabe Seiyaku Co, ltd (Japan)

References

Antibiotic YC 73 of pseudomonas origin. I production isolation and properties. Y. Egawa et al. J Antibiotics 23 (6), 467-470 (1970).

Zeranol (USAN; Rec INN) P-

1496 MK-188 THFES

Zeranolum (Lat) The trivial designation, zearalanol, has been used to identify this compound 1-Resorcylic acid-(6,10-dihydroxyundecyl)-p-µ-Iactone (3S,7X)-3,4,5,6,7,8,9,11,12-Decahydro-7,14,16-trihydroxy-3-methyl-1H-2-benzoxacyclotetradecin-1-one (6X,10)-6,10-Dihydroxyundecyl-β-resorcylic acid-µ-Iactone

Synthesis

Prepared by hydrogenation of zearalenone using reduction conditions sufficient to reduce only the olefinic bond and the ketone group to add four hydrogen atoms3. Zearalenone has also been named as the fermentation estrogenic substance (FES) since a convenient method for producing it is by cultivating on a suitable nutrient medium, the organism Gibberella zeae4. Zearalenone has also been synthesized5. The reduction of the ketone group of zearalen one introduces a second asymetric carbon atom and makes diastereoisomers possible.

Description

There are two diasterioisomers of zeranol, one having a mp 146-148º and a specific rotation [α]D of about 390 in methanol and another having a mp of

204

178-180º and a specific rotation [α]D of about 460 in methanol.

Action

Veterinary anabolic.

Manufacturer

Commercial Solvents Corp (USA)

References

1. JAMA 210, 1454 (1969). 2. WHO Chron 24 (3), 139 (1970) . 3. Commercial Solvents Corp. Brit pat 1,107,738. 4. Nature 196, 1318 (1962). 5. Merck Co. US pat 3,551,455 and 3.551,454 (1970). 6. Chem Eng News 47, 22 (1 Dec 1969). 7. An anabolic agent for rumiants. R. G. Brown. J Amer Vet Med Ass 157 (11). 1537-1539 (1970).

Zorbamycin (USAN)

U 30604

Production An unspecified substance from Streptomyces ikiniensis variant.

Action

Zorbamycin is a new antibacterial antibiotic.

Manufacturer

The Upjohn Co (USA)

References

JAMA 212, 467 (1970).