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Lecture № 13 Condensed azines. Condensed azines. Quinoline. Quinoline. Isoquinoline. Isoquinoline. Acridine. Acridine. Diazines. Diazines. Purine. Purine. Ass. Medvid I.I., ass. Burmas N.I.

Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

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Page 1: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Lecture № 13

Condensed azines. Condensed azines. Quinoline. Isoquinoline. Quinoline. Isoquinoline.

Acridine.Acridine. Diazines.Diazines. Purine. Purine.

Ass. Medvid I.I.,

ass. Burmas N.I.

Page 2: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

OutlineOutline1. 1. Receipt of quinoline and his derivatives. Synthesis of Skraupa and synthesis Receipt of quinoline and his derivatives. Synthesis of Skraupa and synthesis

of Debner—Miller. Physical and chemical properties of quinoline. of Debner—Miller. Physical and chemical properties of quinoline. 2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and 2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and

chemical properties of isoquinoline.chemical properties of isoquinoline.3. Structure, nomenclature, methods of getting and physical and chemical 3. Structure, nomenclature, methods of getting and physical and chemical

properties of acridine. properties of acridine.

4. Methods of getting of 4. Methods of getting of sixmember heterocyclic connections with two sixmember heterocyclic connections with two heteroatomsheteroatoms

5. 5. Structure, classification, nomenclature, physical and chemical properties of Structure, classification, nomenclature, physical and chemical properties of pyridazine. pyridazine.

6. 6. Structure, nomenclature, physical and chemical properties of pyrimidine. Structure, nomenclature, physical and chemical properties of pyrimidine.

7. 7. Structure, nomenclature, physical and chemical properties of barbituric acidStructure, nomenclature, physical and chemical properties of barbituric acid

8. 8. Structure, nomenclature, physical and chemical properties of pyrazine.Structure, nomenclature, physical and chemical properties of pyrazine.

9. 9. Structure, nomenclature, physical and chemical properties of purine.Structure, nomenclature, physical and chemical properties of purine.

10. 10. Structure, nomenclature, physical and chemical properties of uric acid.Structure, nomenclature, physical and chemical properties of uric acid.

Page 3: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

11.11. Structure, nomenclature and properties of azepinesStructure, nomenclature and properties of azepines. . Benzazepine.Benzazepine.

12.12. Structure, nomenclature and properties of diazepine. Structure, nomenclature and properties of diazepine. Benzodiazepine. Benzodiazepine.

13. Oxazepam. Radedrol (nitrazepam). Seduxen (diazepam). 13. Oxazepam. Radedrol (nitrazepam). Seduxen (diazepam). 14.Classification of alkaloids.14.Classification of alkaloids.15. Alkaloids group of pyridine and piperine (nicotine, 15. Alkaloids group of pyridine and piperine (nicotine,

anabasine, lobeline).anabasine, lobeline).16. Alkaloids group of quinoline (quinine).16. Alkaloids group of quinoline (quinine).17. Alkaloids of group of quinoline and 17. Alkaloids of group of quinoline and

phenanthreneisoquinoline phenanthreneisoquinoline (papaverine, morphine, codeine).(papaverine, morphine, codeine).18. Alkaloids group of purine (18. Alkaloids group of purine (caffeine, theobromine, caffeine, theobromine,

theophyllinetheophylline).).19. Alkaloids group of tropane (atropine, scopolamine, cocaine).19. Alkaloids group of tropane (atropine, scopolamine, cocaine).20. Alkaloids group of i20. Alkaloids group of indole ndole (reserpine, strychnine).(reserpine, strychnine).

Page 4: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

1. Obtaining of quinoline and his derivatives. Synthesis of 1. Obtaining of quinoline and his derivatives. Synthesis of Skraup and synthesis of Debner—Miller. Physical and Skraup and synthesis of Debner—Miller. Physical and

chemical properties of quinoline.chemical properties of quinoline.

The impotent condensed of The impotent condensed of sixmembered heterocycles sixmembered heterocycles connections are with one heteroatom is: connections are with one heteroatom is:

quinoline isoquinoline acridine

Quinoline, also known as 1-azanaphthalene, 1-benzazine, or benzo[b]pyridine, is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown.

Page 5: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Quinoline is only slightly soluble in cold water but dissolves Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic solvents. Quinoline is readily in hot water and most organic solvents. Quinoline is mainly used as a building block to other specialty chemicals. mainly used as a building block to other specialty chemicals. Approximately 4 tonnes are produced annually according to a Approximately 4 tonnes are produced annually according to a report published in 2005. Its principal use is as a precursor to report published in 2005. Its principal use is as a precursor to 8-hydroxyquinoline, which is a versatile chelating agent and 8-hydroxyquinoline, which is a versatile chelating agent and precursor to pesticides. Its 2- and 4-methyl derivatives are precursor to pesticides. Its 2- and 4-methyl derivatives are precursors to cyanine dyes. Oxidation of quinonline affords precursors to cyanine dyes. Oxidation of quinonline affords quinolinic acid (pyridine-2,3-dicarboxylic acid), a precursor to quinolinic acid (pyridine-2,3-dicarboxylic acid), a precursor to the herbicide sold under the name "Assert". the herbicide sold under the name "Assert".

Page 6: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

The The Skraup synthesisSkraup synthesis is a chemical reaction used to synthesize is a chemical reaction used to synthesize quinolines. It is named after the Czech chemist Zdenko Hans quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-1910). In the archetypal Skraup, aniline is heated Skraup (1850-1910). In the archetypal Skraup, aniline is heated with sulphuric acid, glycerol, and an oxidizing agent, like with sulphuric acid, glycerol, and an oxidizing agent, like nitrobenzene to yield quinoline. The nitrobenzene to yield quinoline. The Skraup synthesisSkraup synthesis place is place is taken in three stages. taken in three stages.

On the first stage glycerin is under the action of On the first stage glycerin is under the action of сoncentrated Hсoncentrated H22S0S044 to dehydration with formation of to dehydration with formation of akrolein:akrolein:

Page 7: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

On the second stage appearing akrolein enters into the reaction of On the second stage appearing akrolein enters into the reaction of

condensation with an aniline:condensation with an aniline:

-H2O

Page 8: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

On the third stage of reaction of 1,2-On the third stage of reaction of 1,2-dihydroquinoline oxidizes nitrobenzol in to dihydroquinoline oxidizes nitrobenzol in to quinoline:quinoline:

Page 9: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Synthesis of Debner —Miller.Synthesis of Debner —Miller. The reaction is opened in 1881. On the first stage there is krothonic The reaction is opened in 1881. On the first stage there is krothonic condensation of two molecules of aldehydecondensation of two molecules of aldehyde ..

Further there is cooperation of krothonic aldehyde with aniline.Further there is cooperation of krothonic aldehyde with aniline.

2-methyl-1,2-dihydroquinoline 2-methyl-quinoline

Page 10: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Chemical properties:Chemical properties:

1. Reactions of heteroatom.1. Reactions of heteroatom.

quinoline chloride

N-methylquinoline iodide

N-acethylquinoline chloride

Page 11: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

2. Reactions of electrophilic and nukleophilic substitutions .2. Reactions of electrophilic and nukleophilic substitutions .

Reactions ofReactions of electrophilielectrophilicc substitution in the molecula of substitution in the molecula of quinoline quinoline is entered in position of 5 and 8.is entered in position of 5 and 8.

6- quinoline sulphatic acid

Reactions of nukleophilic substitution (is entered in position of 2) .

2- hydroxyquinoline 2- aminoquinoline

Page 12: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

3. Reactions of reduction and oxidization.3. Reactions of reduction and oxidization.

quinolinic acid

Page 13: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Derivatives of quinolineDerivatives of quinoline

8-Hydroxyquinoline8-Hydroxyquinoline is an organic compound with the is an organic compound with the formula Cformula C99HH77NO. It is a derivative of the heterocycle NO. It is a derivative of the heterocycle quinoline by placement of an OH group on carbon quinoline by placement of an OH group on carbon number 8. This colorless compound is widely used number 8. This colorless compound is widely used commercially, although under a variety of names. It is commercially, although under a variety of names. It is usually prepared from quinoline-8-sulfonic acid and usually prepared from quinoline-8-sulfonic acid and from the Skraup synthesis from 2-aminophenol.from the Skraup synthesis from 2-aminophenol.

-Na2SO3

NaOH

Page 14: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

8-Hydroxyquinoline is a monoprotic bidentate 8-Hydroxyquinoline is a monoprotic bidentate chelating agent. Related ligands are the Schiff bases chelating agent. Related ligands are the Schiff bases derived from salicylaldehyde, such as salicylaldoxime derived from salicylaldehyde, such as salicylaldoxime and salen. The roots of the invasive plant and salen. The roots of the invasive plant Centaurea Centaurea diffusadiffusa release 8-hydroxyquinoline, which has a release 8-hydroxyquinoline, which has a negative effect on plants that have not co-evolved negative effect on plants that have not co-evolved with it. The complexes as well as the heterocycle with it. The complexes as well as the heterocycle itself exhibit antiseptic, disinfectant, and pesticide itself exhibit antiseptic, disinfectant, and pesticide properties. Its solution in alcohol are used as liquid properties. Its solution in alcohol are used as liquid bandages. It once was of interest as an anti-cancer bandages. It once was of interest as an anti-cancer drug.drug.

Page 15: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

OH OH

NO2

[H]

OH

NH2

CH2=CH-CO

H

N

OH

N

OH

H2SO4

H

+

2

SO4

2-

quinozol

Page 16: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

2. Receipt of isoquinoline. Synthesis of Bischler-Napieralsk2. Receipt of isoquinoline. Synthesis of Bischler-Napieralskii. .

Physical and chemical properties of isoquinoline.Physical and chemical properties of isoquinoline. Isoquinoline, also known as Isoquinoline, also known as

benzo[c]pyridine or 2-benzanine, benzo[c]pyridine or 2-benzanine, is a is a heterocyclic aromatic organic heterocyclic aromatic organic compound. It compound. It is a structural isomer of is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. 1-Benzylisoquinoline is the to isoquinoline derivatives. 1-Benzylisoquinoline is the structural backbone in naturally occurring alkaloids including structural backbone in naturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine. compound derives from the aromatic amino acid tyrosine. Isoquinoline is a colourless hygroscopic liquid at room Isoquinoline is a colourless hygroscopic liquid at room temperature with a penetrating, unpleasant odour. Impure temperature with a penetrating, unpleasant odour. Impure samples can appear brownish, as is typical for nitrogen samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether, carbon water but dissolve well in ethanol, acetone, diethyl ether, carbon disulfide, and other common organic solvents. It is also soluble disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.in dilute acids as the protonated derivative.

Page 17: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

In the Bischler-Napieralski reactionIn the Bischler-Napieralski reaction an an ββ-phenylethylamine is acylated -phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. can then be dehydrogenated using palladium. The following Bischler-The following Bischler-Napieralski reaction produces papaverine.Napieralski reaction produces papaverine.

1-substituted-3,4-dihydroisoquinoline

1-substituted isoquinoline

Page 18: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Chemical properties:Chemical properties:

1. Reactions of electrophilic and nukleophilic substitutions .1. Reactions of electrophilic and nukleophilic substitutions .

Reactions ofReactions of electrophilielectrophilicc substitution in the molecula of iso substitution in the molecula of isoquinoline quinoline is is entered in position of 5 and 8. Reactions of nukleophilic substitutions tare entered in position of 5 and 8. Reactions of nukleophilic substitutions tare place in position of 1.place in position of 1.

N-methylisoquinoline of iodide

isoquinoline of chloride

Page 19: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

2. Reaction of reduction 2. Reaction of reduction

1,2,3,4- tetrahydroisoquinoline

3. Reaction of oxidization

3,4- pyridinedicarbonic acid

Page 20: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

3. Structure, nomenclature, methods of getting and physical 3. Structure, nomenclature, methods of getting and physical

and chemical properties of acridine.and chemical properties of acridine. Acridine was first isolated in 1871 Acridine was first isolated in 1871 by Carl Gräbe and Heinrich Caro. by Carl Gräbe and Heinrich Caro. Acridine occurs naturally in coal tar. Acridine occurs naturally in coal tar.

It It is separated from coal tar by is separated from coal tar by extracting with dilute sulfuric acid; addition of potassium extracting with dilute sulfuric acid; addition of potassium dichromate to this solution precipitates acridine bichromate. The dichromate to this solution precipitates acridine bichromate. The bichromate is decomposed using ammonia. Many synthetic bichromate is decomposed using ammonia. Many synthetic processes are known for the production of acridine and its processes are known for the production of acridine and its derivatives. A. Bernthsen condensed diphenylamine with derivatives. A. Bernthsen condensed diphenylamine with carboxylic acids, in the presence of zinc chloride in the Bernthsen carboxylic acids, in the presence of zinc chloride in the Bernthsen acridine synthesis. With formic acid as the carboxylic acid the acridine synthesis. With formic acid as the carboxylic acid the reaction yields acridine it self, and with the higher homologues the reaction yields acridine it self, and with the higher homologues the derivatives substituted at the meso carbon atom are generated. derivatives substituted at the meso carbon atom are generated. Other older methods for the organic synthesis of acridines include Other older methods for the organic synthesis of acridines include condensing diphenylamine with chloroform in the presence of condensing diphenylamine with chloroform in the presence of aluminium chloride, by passing the vapours of aluminium chloride, by passing the vapours of orthoaminodiphenylmethane over heated litharge, by heating orthoaminodiphenylmethane over heated litharge, by heating salicylic aldehyde with aniline and zinc chloride to 260 °C or by salicylic aldehyde with aniline and zinc chloride to 260 °C or by distilling acridone (9-position a carbonyl group) over zinc dust.distilling acridone (9-position a carbonyl group) over zinc dust.

Page 21: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

A general method for acridine synthesis is the A general method for acridine synthesis is the cyclisation of cyclisation of NN-phenylanthranilic acid or 2--phenylanthranilic acid or 2-(phenylamino)benzoic acid with phosphoric acid. A (phenylamino)benzoic acid with phosphoric acid. A classic method for the synthesis of acridones is the classic method for the synthesis of acridones is the Lehmstedt-Tanasescu reaction.Lehmstedt-Tanasescu reaction.

Acridine and its homologues are stable Acridine and its homologues are stable compounds of weakly basic character.It also shares compounds of weakly basic character.It also shares properties with quinoline which is the single fused properties with quinoline which is the single fused homologue. Acridine crystallizes in needles which homologue. Acridine crystallizes in needles which melt at 110 °C. It is characterized by its irritating melt at 110 °C. It is characterized by its irritating action on the skin, and by the blue fluorescence action on the skin, and by the blue fluorescence shown by solutions of its salts. shown by solutions of its salts.

Page 22: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Methods of getting:Methods of getting:

1. Condensation of diphenylamine with 1. Condensation of diphenylamine with carboniccarbonic acids acids ::

2. Cyclization N-fenilanthranilic acid on the reaction of Drozdov2. Cyclization N-fenilanthranilic acid on the reaction of Drozdov—Mahidson—Hrihorovsky:—Mahidson—Hrihorovsky:

diphenylamine acridine

N-fenilanthranilic acid anhidride chlorideN-fenilanthranilicacid

acridone-9

Page 23: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

acridole-9 9-chloracridine

9,10-dihydroacridine acridine

Page 24: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Chemical properties:Chemical properties:

Acridine combines readily with alkyliodides to form alkyl Acridine combines readily with alkyliodides to form alkyl acridinium iodides, which are readily transformed by the action of acridinium iodides, which are readily transformed by the action of alkaline potassium ferricyanide to alkaline potassium ferricyanide to NN-alkyl acridones. On oxidation -alkyl acridones. On oxidation with potassium permanganate it yields acridinic acid with potassium permanganate it yields acridinic acid CC99HH55N(COOH)N(COOH)22 or quinoline-1,2-dicarboxylic acid. Acridine is or quinoline-1,2-dicarboxylic acid. Acridine is easily oxidized by peroxymonosulfuric acid to the acridine amine easily oxidized by peroxymonosulfuric acid to the acridine amine oxide. The carbon 9-position of acridine is activated for addition oxide. The carbon 9-position of acridine is activated for addition reactions. The compound is reduced to the 9,10-dehydroacridine reactions. The compound is reduced to the 9,10-dehydroacridine and reaction with potassium cyanide gives the 9-cyano-9,10-and reaction with potassium cyanide gives the 9-cyano-9,10-dehydro derivative. Numerous derivatives of acridine are known dehydro derivative. Numerous derivatives of acridine are known and may be prepared by methods analogous to those used for the and may be prepared by methods analogous to those used for the formation of the parent base. 9-Phenylacridine is the parent base of formation of the parent base. 9-Phenylacridine is the parent base of chrysaniline or 3,6-diamino-9-phenylacridine, which is the chief chrysaniline or 3,6-diamino-9-phenylacridine, which is the chief constituent of the dyestuff phosphine (not to be confused with constituent of the dyestuff phosphine (not to be confused with phosphine gas), a by-product in the manufacture of rosaniline. phosphine gas), a by-product in the manufacture of rosaniline. Chrysaniline forms red-coloured salts, which dye silk and wool a Chrysaniline forms red-coloured salts, which dye silk and wool a fine yellow; and the solutions of the salts are characterized by their fine yellow; and the solutions of the salts are characterized by their fine yellowish-green fluorescence. Chrysaniline was synthesized fine yellowish-green fluorescence. Chrysaniline was synthesized by O. Fischer and G. Koerner by condensing ortho-by O. Fischer and G. Koerner by condensing ortho-nitrobenzaldehyde with aniline, the resulting ortho-nitro-para-nitrobenzaldehyde with aniline, the resulting ortho-nitro-para-diamino-triphenylmethane being reduced to the corresponding diamino-triphenylmethane being reduced to the corresponding orthoamino compound, which on oxidation yields chrysaniline.orthoamino compound, which on oxidation yields chrysaniline.

Page 25: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

1.1. Reactions of heteroatom.Reactions of heteroatom.

2. Reactions of electrophilic and nukleophilic substitutions . 2. Reactions of electrophilic and nukleophilic substitutions .

acridinium chloride

N-oxide of acridine N-methylacridine iodide

9-hydroxacridine, 9- oxoacridine,acridole-9 acridone-9

Page 26: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

3.3. Reactions of oxidization.Reactions of oxidization.

4. Reactions of reduction.4. Reactions of reduction.acridinic acid

9,10-dehydroacridine,acridane

Page 27: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Derivatives of acridineDerivatives of acridine

9- Aminoacridine is an antiseptic and disinfectant .

Acidylating flows on aminogroup:

9-N-acethylaminoacridine

9-aminoacridine chloride

Page 28: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

arcihine rivanol

medicinal preparations

Page 29: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

COOH

O2N Cl NH2

OC2H5 COOH

O2N NH

OC2H5

POCl3

-HClO2N NH

OC2H5

N

OC2H5

OH

O2N

POCl3

C

O

N

OC2H5

Cl

O2N

NH3

-HClN

OC2H5

NH2

O2N

[H]

9-amino-2-ethoxy-6-nitroacridine

Page 30: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

N

OC2H5

NH2

NH2

CH

CH3

OH

COOH

N

OC2H5

NH2

NH2

CH

CH3

OH

COOH

+

.

ethacridine lactate, rivanol,6,9 – diamimo-2-ethoxyacridine lactate

Page 31: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Sixmembered heterocycles connections are with two Sixmembered heterocycles connections are with two heteroatomsheteroatoms

In addition to these three diazines, the In addition to these three diazines, the bicyclic tetraaza compound, purine, is bicyclic tetraaza compound, purine, is an important heterocyclic system. an important heterocyclic system.

These ring systems, particularly that of pyrimidine, occur commonly These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, thymine, and uracil in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they are components of nucleic are especially important because they are components of nucleic acids, as are the purine derivatives adenine and guanine.acids, as are the purine derivatives adenine and guanine.

Page 32: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

The рininе nucleus also occurs in such The рininе nucleus also occurs in such compounds as caffeine (coffee and tea) and compounds as caffeine (coffee and tea) and

theobromine (cacao beans).theobromine (cacao beans).

Page 33: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

4. 4. Methods of getting of Methods of getting of sixmember heterocyclic connections with two heteroatoms

NN

CH

CO

O

CCH H

H

NH2

NH2

- H2O

pyridazine

C H2

C

C

O

O

O C2H

5

O C2H

5

C

NH2

NH2

O

C2H

5O N a

-C2H

5O H N

N

O HOH

O H

N

N

O

O O

H

H

H

H

+C

barbituric acid

барбітурова

maleinaldehidemaleinaldehide

uricuricMalene ephirMalene ephir

POCl 3

N

N

Cl

Cl

ClN

N6H (Zn)

pyrimidine

Page 34: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

These method use for obtaining pyridazine and his derivatives

Page 35: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

N

N

NH2

NH2

C HO

OH- H2O

N

N NH

N+

2

NH2

CH2

CH2

NH2

C

C

O

O

H

H

- H2O - H2O

O

N

N

N

N+

to

2

2,3- dihydropyrazine2,3- dihydropyrazine

ethylendiamineethylendiaminehlioxahlioxall

pyrazinepyrazine

purinepurine

Page 36: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

5. 5. Structure, classification, nomenclature, physical Structure, classification, nomenclature, physical and chemical properties of pyridazine. and chemical properties of pyridazine.

Pyridazine is a heteroaromatic organic compound with the molecular formulaC4H4N2, sometimes called 1,2-diazine. It contains a six-membered ring with two adjacent nitrogen atoms. It is a colorless liquid with a boiling point of 208 °C. Pyridazine has no household use. It is mainly used in research and industry as building block for more complex compounds. The pyridazine structure is found within a number of herbicides such as credazine, pyridafol and pyridate. It is also found within the structure of several pharmaceutical drugs such as cefozopran, cadralazine, minaprine, hydralazine, and cilazapril.

Page 37: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Pyridazine

Other names1,2-diazine, orthodiazine,

oizine

Properties

Molecular formula C4H4N2

Molar mass 80.09 g mol−1

Appearance colorless liquid

Density 1.107 g/cm3

Melting point -8°C

Boiling point 208°C

Page 38: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

NN

NN

+

H

Cl-

NN

CH3

CH3I

NN

O

CH3COOOH

HCl (í àäë .)+ I-

+_

Pyridazine Pyridazine chloridechloride

N-methulpyridazine iodideN-methulpyridazine iodide

N-oxide pyridazineN-oxide pyridazine

thethramethyleldiaminethethramethyleldiamine

Page 39: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Derivatives of pyridazineDerivatives of pyridazine

Page 40: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

6. Structure, nomenclature, physical and chemical properties of pyrimidine.

Three nucleobases found in nucleic acids (cytosine, thymine, and uracil) are pyrimidine derivatives: In DNA and RNA, these bases form hydrogen bonds with their complementary purines. Thus the purines adenine (A) and guanine (G) pair up with the pyrimidines thymine (T) and cytosine (C), respectively.

Page 41: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Pyrimidine

Properties

Molecular formula C4H4N2

Molar mass 80.088

Melting point 20–22 °C

Boiling point 123–124 °C

Page 42: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Chemical propertiesChemical propertiesA pyrimidine has many properties in common with A pyrimidine has many properties in common with

pyridine, as the number of nitrogen atoms in the ring pyridine, as the number of nitrogen atoms in the ring increases the ring pi electrons become less energetic and increases the ring pi electrons become less energetic and electrophilic aromatic substitution gets more difficult while electrophilic aromatic substitution gets more difficult while nucleophilic aromatic substitution gets easier. An example nucleophilic aromatic substitution gets easier. An example of the last reaction type is the displacement of the amino of the last reaction type is the displacement of the amino group in 2-aminopyrimidine by chlorine and its reverse. group in 2-aminopyrimidine by chlorine and its reverse. Reduction in resonance stabilization of pyrimidines may Reduction in resonance stabilization of pyrimidines may lead to addition and ring cleavage reactions rather than lead to addition and ring cleavage reactions rather than substitutions. One such manifestation is observed in the substitutions. One such manifestation is observed in the

Dimroth rearrangement. Compared to pyridine, N-alkylation Dimroth rearrangement. Compared to pyridine, N-alkylation and N-oxidation is more difficult, and pyrimidines are also and N-oxidation is more difficult, and pyrimidines are also

less basic.less basic.

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N

NN

NOH

NH2

ê. HNO3

ê. H2SO4

N

N

NH2

Br2

N

N NaNH2

N

NH

ClN

NOH

NH2

NO2

N

N

NH2

Br

N

N

NH2

N

N

_

+HCl

4-amino-2-hydroxypyridine4-amino-2-hydroxypyridinepyrimidine chloridepyrimidine chloride

2- aminopyridine2- aminopyridine

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Derivatives of pyrimidineDerivatives of pyrimidineBarbituric acid (2,4,6-trihydroxypyrimidine)Barbituric acid (2,4,6-trihydroxypyrimidine)

Keto-enole and lactam-lactim tautomery

Page 45: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

7. 7. Structure, nomenclature, physical and chemical properties of Structure, nomenclature, physical and chemical properties of barbituric acid.barbituric acid.

Barbituric acidBarbituric acid or or malonylureamalonylurea or or 4-4-hydroxyuracilhydroxyuracil is an organic compound based is an organic compound based on a pyrimidine heterocyclic skeleton. It is an on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in hot water. Barbituric odorless powder soluble in hot water. Barbituric acid is the parent compound of a large class of acid is the parent compound of a large class of barbiturates that have central nervous system barbiturates that have central nervous system depressant properties, although barbituric acid depressant properties, although barbituric acid itself is not pharmacologically active. itself is not pharmacologically active.

The compound was discovered by the German The compound was discovered by the German chemist Adolf von Baeyer on 4. December 1864chemist Adolf von Baeyer on 4. December 1864—the feast of St Barbara and therefore the name —the feast of St Barbara and therefore the name given to the compound—by combining urea and given to the compound—by combining urea and malonic acid in a condensation reaction. Malonic malonic acid in a condensation reaction. Malonic acid has since been replaced by diethyl acid has since been replaced by diethyl malonate.malonate.

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Bases of pyrimidine (important derivativesBases of pyrimidine (important derivatives ) )

These bases are present in nucleinic acids

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Vitamin BVitamin B11 (thiamine) (thiamine) contain pyrimidine and thyazole ring connect contain pyrimidine and thyazole ring connect through methyl group. through methyl group.

Physiological active form of vitaminPhysiological active form of vitamin B1 in living organisms is cocarboxilaza, which B1 in living organisms is cocarboxilaza, which take part in enzyme processes, in hydrocarbon exchangetake part in enzyme processes, in hydrocarbon exchange

Orotic acid is primary compound in biosynthesis of pyrimidine bases

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8. 8. Structure, nomenclature, physical and Structure, nomenclature, physical and chemical properties of pyrazine.chemical properties of pyrazine.

PyrazinePyrazine is a heterocyclic aromatic organic compound. is a heterocyclic aromatic organic compound. It is found in folic acid in the form of pterin. Derivatives It is found in folic acid in the form of pterin. Derivatives

like Phenazine are well known for their antitumor, like Phenazine are well known for their antitumor, antibiotic and diuretic activity. Pyrazine is less basic in antibiotic and diuretic activity. Pyrazine is less basic in nature than pyridine, pyridazine and pyrimidine. nature than pyridine, pyridazine and pyrimidine. Tetramethylpyrazine (also known as ligustrazine) is Tetramethylpyrazine (also known as ligustrazine) is reported to scavenge superoxide anion and decrease reported to scavenge superoxide anion and decrease nitric oxide production in human polymorphonuclear nitric oxide production in human polymorphonuclear leukocytes. Tetramethylpyrazine is also a component of leukocytes. Tetramethylpyrazine is also a component of some herbs in Traditional Chinese Medicine.some herbs in Traditional Chinese Medicine.

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Pyrazine

Other names1,4-Diazabenzene, p-Diazine, 1,4-

Diazine, Paradiazine, Piazine, UN 1325

Properties

Molecular formula C4H4N2

Molar mass 80.09 g/mol

Appearance White crystals

Density 1.031 g/cm3

Melting point 52 °C

Boiling point 115 °C

Solubility in water Soluble

Page 50: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Synthesis of pyrazineSynthesis of pyrazine

Many methods exist for the organic synthesis of Many methods exist for the organic synthesis of pyrazine and derivatives and some of them very pyrazine and derivatives and some of them very old. old. Staedel-Rugheimer pyrazine synthesisStaedel-Rugheimer pyrazine synthesis (1876) is the condensation of 1,2-diamine with (1876) is the condensation of 1,2-diamine with 1,2-dicarbonil compounds and then oxidation to 1,2-dicarbonil compounds and then oxidation to a pyrazine. A variation is the a pyrazine. A variation is the Gutknecht Gutknecht Pyrazine SynthesisPyrazine Synthesis (1879) also based on this (1879) also based on this selfcondensation but differing in the way that selfcondensation but differing in the way that alpha-ketoamine is synthesised (the chlorine alpha-ketoamine is synthesised (the chlorine compound in the above method is a compound in the above method is a lachrymatory agent). lachrymatory agent).

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The The Gastaldi synthesisGastaldi synthesis (1921) is another variation: (1921) is another variation:

Page 52: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Chemical properties of pyrazineChemical properties of pyrazine

N

N H

(Na + CH3CH2OH)NH

NH

N

N NaNH2, NH3

N

N

NH2

N

N CH3COOOHN

N

O_

+

pyperazinepyperazine

2-aminopyrazine2-aminopyrazine

N- oxide pyrazineN- oxide pyrazine

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9. 9. Structure, nomenclature, physical and chemical Structure, nomenclature, physical and chemical properties of purine.properties of purine.

Purine Purine is a heterocyclic aromatic organic is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, fused to an imidazole ring. Purines, including substituted purines and their including substituted purines and their tautomers, are the most widely distributed tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in kind of nitrogen-containing heterocycle in nature. Purines and pyrimidines make up nature. Purines and pyrimidines make up the two groups of nitrogenous bases, the two groups of nitrogenous bases, including the two groups of nucleotide including the two groups of nucleotide bases. bases. Notable purinesNotable purines

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Purine

Properties

Molecular formula C5H4N4

Molar mass 120.112

Melting point 214 °C

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HistoryHistoryThe name 'purine' (The name 'purine' (purum uricumpurum uricum) was coined by the German ) was coined by the German

chemist Emil Fischer in 1884. He synthesized it for the first chemist Emil Fischer in 1884. He synthesized it for the first time in 1899. time in 1899.

Laboratory synthesisLaboratory synthesisIn addition to in vivo synthesis of purines in purine metabolism, In addition to in vivo synthesis of purines in purine metabolism,

purine can also be created artificially.purine can also be created artificially.Purine (Purine (11) is obtained in good yield when formamide is heated ) is obtained in good yield when formamide is heated

in an open vessel at 170 oC for 28 hours. in an open vessel at 170 oC for 28 hours. Procedure:Procedure: Formamide (45 gram) was heated in an open Formamide (45 gram) was heated in an open

vessel with a condenser for 28 hours in an oil bath at 170-190 vessel with a condenser for 28 hours in an oil bath at 170-190 oC. After removing excess formamide (32.1 gram) by vacuum oC. After removing excess formamide (32.1 gram) by vacuum

distillation, the residue was refluxed with methanol. The distillation, the residue was refluxed with methanol. The methanol solvent was filtered, the solvent removed from the methanol solvent was filtered, the solvent removed from the

filtrate by vacuum distillation, and almost pure purine obtained; filtrate by vacuum distillation, and almost pure purine obtained; yield 4.93 gram (71 % yield from formamide consumed). yield 4.93 gram (71 % yield from formamide consumed). Crystallization from acetone afforded purine as colorless Crystallization from acetone afforded purine as colorless

crystals; melting point 218 oC.crystals; melting point 218 oC.

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Synthesis of purineSynthesis of purineTraube method: condnsation 4,5-Traube method: condnsation 4,5-

diaminopyrimidines with carbonic acidsdiaminopyrimidines with carbonic acids

Page 57: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

The The Traube purine synthesisTraube purine synthesis (1900) is a classic (1900) is a classic reaction (named after Wilhelm Traube) between an reaction (named after Wilhelm Traube) between an

amine substutited pyrimidine and formic acidamine substutited pyrimidine and formic acid

Page 58: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Chemical properties of purine.Chemical properties of purine.

FFor purinor purinee is characteristic is characteristic of of azoazolele tautomer tautomeryy : :

N H

N

N

N

ClCl

Cl

N H 3H

N H

N

N

N

ClCl

N H 2

N H

N

N

N

N H 2

K O H

N H

N

N

N

Cl

Cl

O H

N H 3

N H

N

N

N

NH 2

Cl

O H

H

N H

N

N

N

NH 2

O H

H

NH

N NH

N

O

H N O 2

NH

NH

NH

N

O

O

(1:1)

adenine

(1:1)

guanine

hypoxanthine xanthine

Page 59: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Purine is an amphoteric compoundPurine is an amphoteric compound

Page 60: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Derivatives of purineDerivatives of purine

Main derivatives of purine are oxopurines:Main derivatives of purine are oxopurines:

Uric acid is colorless crystal compound, bad soluble in water, ethanol and ether, soluble in dilute base solutions and glycerin. Uric acid is dibases acid.

Page 61: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Thauthomeric formsThauthomeric forms

NH

NH

NH

NH

O

O

O

N

N NH

NO H

OH

O H

uric acid

NH

NH

NH

N

O

O

N

N NH

N

OH

O H

xanthine

N

N NH

N

O HNH

N NH

N

O

hypoxanthine

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10. 10. Structure, nomenclature, physical and Structure, nomenclature, physical and chemical properties of uric acid.chemical properties of uric acid.

Uric acidUric acid (or (or urateurate) is an organic compound of carbon, nitrogen, ) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3. oxygen and hydrogen with the formula C5H4N4O3. Uric acidUric acid is is produced by xanthine oxidase from xanthine and hypoxanthine, produced by xanthine oxidase from xanthine and hypoxanthine, which in turn are produced from purine. Uric acid is more toxic to which in turn are produced from purine. Uric acid is more toxic to tissues than either xanthine or hypoxanthine.tissues than either xanthine or hypoxanthine.

In humans and higher primates, uric acid is the final oxidation In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism and is excreted in urine. (breakdown) product of purine metabolism and is excreted in urine. In most other mammals, the enzyme uricase further oxidizes uric In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin. The loss of uricase in higher primates parallels the acid to allantoin. The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid. Both uric acid similar loss of the ability to synthesize ascorbic acid. Both uric acid and ascorbic acid are strong reducing agents (electron donors) and and ascorbic acid are strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid. blood plasma comes from uric acid.

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Salts of uric acid called urats. Urats is bad soluble Salts of uric acid called urats. Urats is bad soluble in water, except salts with litium (Li).in water, except salts with litium (Li).

In hydroxyform uric acid gives reactions of In hydroxyform uric acid gives reactions of nucleophilic substitutions.nucleophilic substitutions.

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Chemical propertiesChemical properties

N

NN

N

O

O

O

H H

HH

N

NN

N

O

NaO

ONa

H

H

H2NaOH

+ _

+_

N

N NH

NOH

OH

OH

POCl3

NH

N

N

N

Cl

Cl

Cl

disodium salt of uric acid disodium salt of uric acid

2,6,8-threechlorpurine2,6,8-threechlorpurine

Reactions of oxidationReactions of oxidation

alantoinealantoinealoxanealoxane ureaurea

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Murexidne’s reaction is the qualitative Murexidne’s reaction is the qualitative reaction on uric acidreaction on uric acid

By heating uric acid with nitrate acid and next By heating uric acid with nitrate acid and next adding of ammonium observe purpur-violet color adding of ammonium observe purpur-violet color

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purpure purpure acid (enole acid (enole form)form)

murexidemurexide

Reactions of reductionReactions of reduction

xanthinexanthine

Page 67: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Hypoxantine and xantine have the same Hypoxantine and xantine have the same chemical properties as uric acidchemical properties as uric acid

N-methyl derivatives of hypoxantine and xantine widely used in pharmacy

Page 68: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

AminopurinesAminopurines Maine aminoderivatives of purine – Maine aminoderivatives of purine –

adenine and guanine present in nucleinic adenine and guanine present in nucleinic acids as purine’s bases.acids as purine’s bases.

Page 69: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Sources of uric acidSources of uric acid

In many instances, people have elevated uric acid levels for In many instances, people have elevated uric acid levels for hereditary reasons. hereditary reasons. Diet may also be a factor.Diet may also be a factor.

Purines are found in high amounts in animal internal organ food Purines are found in high amounts in animal internal organ food products, such as liver. A moderate amount of purine is also products, such as liver. A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ.beans, oatmeal, wheat bran and wheat germ.

Examples of high purine sources include: sweetbreads, anchovies, Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.herring, mackerel, scallops, game meats, and gravy.

Moderate intake of purine-containing food is not associated with an Moderate intake of purine-containing food is not associated with an increased risk of gout.increased risk of gout.

Serum uric acid can be elevated due to high fructose intake , Serum uric acid can be elevated due to high fructose intake , reduced excretion by the kidneys, and or high intake of dietary reduced excretion by the kidneys, and or high intake of dietary purine.purine.

Added fructose can be found in processed foods and soda Added fructose can be found in processed foods and soda beverages as sucrose, or in some countries, as high fructose corn beverages as sucrose, or in some countries, as high fructose corn syrup.syrup.

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PhenothiazinePhenothiazine Phenothiazine (dibenzo-1,4-thiazine) – colorless crystal compound, Phenothiazine (dibenzo-1,4-thiazine) – colorless crystal compound,

insoluble in water, diethyl ether, well soluble in hat ethanol.insoluble in water, diethyl ether, well soluble in hat ethanol.

Method of getting

Chemical properties

1. Alkylation and acylation

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2. Oxidation2. Oxidation

3. Reaction of electrophilic sybstitution go in location 3 and 7 with oxidation of sulphur

Derivatives of phenothiazine

Page 72: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Pteridine (pyrazino[2,3-d]pyrimidine)Pteridine (pyrazino[2,3-d]pyrimidine)

Method of getting: condensation of 4,5-diaminopyrimidins with 1,2-dicarbonile compounds

Pteridine is light yellow crystal compound, soluble in water, ethanol, less soluble in Pteridine is light yellow crystal compound, soluble in water, ethanol, less soluble in diethyl ether and benzole. Pteridine is stable to oxidation, by acting of acids and diethyl ether and benzole. Pteridine is stable to oxidation, by acting of acids and bases pteridine cycle decompose. Gives reaction of electrophilic substitution, bases pteridine cycle decompose. Gives reaction of electrophilic substitution, protonate on nitrogen atom in 1 location. protonate on nitrogen atom in 1 location.

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Derivatives of pteridineDerivatives of pteridine Folic acid (vitamin Bc)Folic acid (vitamin Bc)

Page 74: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

Aloxasine and isoaloxasineAloxasine and isoaloxasine These compounds include benzyl, These compounds include benzyl,

pyrazine and hydrate pyriidine cyclespyrazine and hydrate pyriidine cycles

Flavine is a primery compound of riboflavin:

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11. Structure, nomenclature and properties of 11. Structure, nomenclature and properties of

azepines. Benzazepine. Sevenmember heterocyclic ring Sevenmember heterocyclic ring

compounds have received much attention in the compounds have received much attention in the past few years owing to its wide range of past few years owing to its wide range of biological activity. biological activity.

AzepinesAzepines are heterocycles are heterocycles of seven atoms, with a of seven atoms, with a nitrogen replacing a carbon nitrogen replacing a carbon at one position.at one position.

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A well known azepine is A well known azepine is caprolactamcaprolactam

Skeletal formula of caprolactam. Skeletal formula of caprolactam.

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Sevenmember heterocycles which containing nitrogen

Page 78: Condensed azines. Quinoline. Isoquinoline. Acridine. Diazines. Purine

BenzazepineBenzazepine: bicyclic structure consisting of : bicyclic structure consisting of fused benzene and azepine rings; many fused benzene and azepine rings; many compounds with this structure react with compounds with this structure react with

biogenicamine receptors, and so are psychotropic biogenicamine receptors, and so are psychotropic and neurotropic.and neurotropic.

Examples of benzazepine include fenoldopam and Examples of benzazepine include fenoldopam and galantamine. galantamine.

ffenoldopamenoldopam galantaminegalantamine

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12.12. Structure, nomenclature and properties Structure, nomenclature and properties

of of diazepine. Benzodiazepine..

DiazepineDiazepine is a sevenmember is a sevenmember heterocyclic compound with two heterocyclic compound with two

nitrogen atoms (e.g., in ring nitrogen atoms (e.g., in ring positions 1 and 2) and positions 1 and 2) and three three double bonds. double bonds.

When diazepine combined with a benzene ring, these is When diazepine combined with a benzene ring, these is the basis of the benzodiazepine family . In these the basis of the benzodiazepine family . In these compounds the nitrogen atoms are at the 1 and 4 compounds the nitrogen atoms are at the 1 and 4 positions as, for example, in clobazam (depending on positions as, for example, in clobazam (depending on the position of the fused benzene ring, the nitrogen the position of the fused benzene ring, the nitrogen atoms are also in positions number 1 and 4).atoms are also in positions number 1 and 4).

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5-Phenyl-1,3-dihydro-2H-1,4- 5-Phenyl-1,3-dihydro-2H-1,4- benzodiazepin-2-on benzodiazepin-2-on

forms the skeleton on many of forms the skeleton on many of the most common the most common

benzodiazepine benzodiazepine pharmaceuticals, such as diazepam pharmaceuticals, such as diazepam

(chloro-substituted).(chloro-substituted).

The The benzodiazepinesbenzodiazepines are a class of psychoactive drugs with are a class of psychoactive drugs with varying hypnotic, sedative, anxiolytic (anti-anxiety), anticonvulsant, varying hypnotic, sedative, anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic properties, which are mediated by muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system. Benzodiazepines are slowing down the central nervous system. Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and muscle useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. They can also be used spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies or dental before certain medical procedures such as endoscopies or dental work where tension and anxiety are present, and prior to some work where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce sedation and unpleasant medical procedures in order to induce sedation and amnesia for the procedure. Benzodiazepines are also used to treat amnesia for the procedure. Benzodiazepines are also used to treat the panic that can be caused by hallucinogen intoxication.the panic that can be caused by hallucinogen intoxication.

Benzodiazepines can cause a physical dependence and a Benzodiazepines can cause a physical dependence and a benzodiazepine addiction to develop and upon cessation of long benzodiazepine addiction to develop and upon cessation of long term use a benzodiazepine withdrawal syndrome can occur.term use a benzodiazepine withdrawal syndrome can occur.

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Benzodiazepine receptors also appear in a Benzodiazepine receptors also appear in a number of non nervous-system tissues and are number of non nervous-system tissues and are mainly of the peripheral benzodiazepine mainly of the peripheral benzodiazepine receptor (PBRs) type. These receptors are found receptor (PBRs) type. These receptors are found in various tissues such as heart, liver, adrenal, in various tissues such as heart, liver, adrenal, and testis. In lymphatic tissues, they modulate and testis. In lymphatic tissues, they modulate apoptosis of thymocytes via reduction of apoptosis of thymocytes via reduction of mitochondrial transmembrane potential. PBRs mitochondrial transmembrane potential. PBRs have many other actions on immune cells have many other actions on immune cells including modulation of oxidative bursts by including modulation of oxidative bursts by neutrophils and macrophages, and inhibition of neutrophils and macrophages, and inhibition of macrophage secretion of cytokines inhibition of macrophage secretion of cytokines inhibition of the proliferation of lymphoid cells and secretion the proliferation of lymphoid cells and secretion of cytokines by macrophages.of cytokines by macrophages.

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13. Oxazepam. Radedrol (nitrazepam). Seduxen (diazepam).

N

NO

Cl

O H

Oxazepam7-clorine-3-hydroxy-5-phenil-1,3-dihydro-2H-1,4-benzodiazepin-2-on

Oxazepam (marketed in English speaking countries under the following brand names Alepam, Medopam, Murelax, Noripam, Ox-Pam, Purata, Serax and Serepax), is a drug which is a benzodiazepine derivative. Oxazepam has moderate amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties compared to other benzodiazepines.

Oxazepam is an intermediate acting benzodiazepine. Oxazepam acts as inhibitor on the central nervous system. The half-life of oxazepam is 4-15 hours. Oxazepam has been shown to suppress cortisol levels.

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Oxazepam is an active metabolite formed during the Oxazepam is an active metabolite formed during the breakdown of diazepam, nordazepam, and certain breakdown of diazepam, nordazepam, and certain similar drugs. Oxazepam may be safer than many other similar drugs. Oxazepam may be safer than many other benzodiazepines in patients with impaired liver function benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather because it does not require hepatic oxidation, but rather it is simply metabolized via glucuronidation. Such means it is simply metabolized via glucuronidation. Such means as oxazepam is less likely to accumulate and cause as oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver adverse reactions in the elderly or people with liver disease. Oxazepam is similar to lorazepam in this disease. Oxazepam is similar to lorazepam in this respect. There is preferential storage of oxazepam in respect. There is preferential storage of oxazepam in some organs including the heart of the neonate. some organs including the heart of the neonate. Absorption by any administered route and the risk of Absorption by any administered route and the risk of accumulation is significantly increased in the neonate accumulation is significantly increased in the neonate and it is recommended to withdraw oxazepam during and it is recommended to withdraw oxazepam during pregnancy and breast feeding as oxazepam is excreted pregnancy and breast feeding as oxazepam is excreted in breast milk. in breast milk.

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Nitrazepam is a nitrobenzodiazepine It is a 1,4 benzodiazepine, with the

chemical name 7-nitro-5-phenyl-1,3-

dihydro-2H-1,4- benzodiazepin-2-on. Nitrazepam is a type of benzodiazepine

drug and is marketed in English speaking countries under the following brand names -

Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm,

Remnos and Somnite.

N

NO

O 2N

NitrazepamNitrazepam

It is a hypnotic drug with sedative and motor impairing properties, anxiolytic, anticonvulsant and skeletal muscle relaxant properties. It is long acting drug, has lipophilic and hepatometabolitic properties via oxidative pathways. It acts on benzodiazepine receptors in the brain which are associated with the GABA receptors (gamma-aminobutyric acid). GABA is a major inhibitor neurotransmitter in the brain, involved in inducing sleepiness, muscular relaxation and control of anxiety and seizures, and slows down the central nervous system.

H

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In sleep laboratory studies, nitrazepam In sleep laboratory studies, nitrazepam decreased sleep onset latency. In decreased sleep onset latency. In psychogeriatric in-patients nitrazepam was psychogeriatric in-patients nitrazepam was found to be no more effective than placebo found to be no more effective than placebo tablets in increasing total time spent asleep. tablets in increasing total time spent asleep. Nitrazepam is most often used to treat short-Nitrazepam is most often used to treat short-term sleeping problems (insomnia), namely term sleeping problems (insomnia), namely difficulty falling asleep, frequent awakening, difficulty falling asleep, frequent awakening, early awakenings or a combination of theme. early awakenings or a combination of theme. Nitrazepam is long acting and is sometimes Nitrazepam is long acting and is sometimes used in patients who have difficulty in used in patients who have difficulty in maintaining sleep. Nitrazepam shortens the time maintaining sleep. Nitrazepam shortens the time required to fall asleep and lengthens the required to fall asleep and lengthens the duration of sleep. It is also useful for the duration of sleep. It is also useful for the treatment of myoclonic seizures and has been treatment of myoclonic seizures and has been used in the treating of seizure disorders in used in the treating of seizure disorders in children and also for infantile spasmschildren and also for infantile spasms ..

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DiazepamDiazepam first marketed as first marketed as ValiumValium by by Hoffmann-La Roche, is a benzodiazepine Hoffmann-La Roche, is a benzodiazepine derivative drug. It possesses anxiolytic, derivative drug. It possesses anxiolytic,

anticonvulsant, hypnotic, sedative, skeletal anticonvulsant, hypnotic, sedative, skeletal muscle relaxant and amnestic properties. It is muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, commonly used for treating anxiety, insomnia, seizures, muscle spasms, alcohol withdrawal seizures, muscle spasms, alcohol withdrawal

and benzodiazepine withdrawal. and benzodiazepine withdrawal.

N

NO

Cl

CH3

O

diazepam(4N-oxide 7-chlorine-1-methyl-5-phenil-1,3-dihydro-2Н- 1,4-benzodiazepin-2-оne )

Diazepam occurs as solid white or yellow Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1:16 in ethyl alcohol, 1:2 in diazepam as soluble 1:16 in ethyl alcohol, 1:2 in chloroform, 1:39 in ether, and practically insoluble in chloroform, 1:39 in ether, and practically insoluble in water.water.

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The pH of diazepam is neutral (i.e., pH = The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf-life of 5 years for oral 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution. Diazepam tablets and 3 years for IV/IM solution. Diazepam should be stored at room temperature (15°-should be stored at room temperature (15°-30°C). The solution for parenteral injection 30°C). The solution for parenteral injection should be protected from light and kept from should be protected from light and kept from freezing. The oral forms should be stored in air-freezing. The oral forms should be stored in air-tight containers and protected from light. If tight containers and protected from light. If diazepam is to be administered concomitantly diazepam is to be administered concomitantly with other drugs, attention should be paid to the with other drugs, attention should be paid to the possible pharmacological interactions. Particular possible pharmacological interactions. Particular care should be taken with drugs that enhance care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.phenothiazines, narcotics and antidepressants.

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Qualitative reactions on benzodiazepinesQualitative reactions on benzodiazepines

1. 1. With concentrated acids (H2SO4, HCl, HClO4) With concentrated acids (H2SO4, HCl, HClO4) derivatives of benzodiazepines form color salts.derivatives of benzodiazepines form color salts.

2. Heterocyclic nitrogen atom gives positive reaction with 2. Heterocyclic nitrogen atom gives positive reaction with common alkaloids precipitate reagents. common alkaloids precipitate reagents.

3. Specific reaction on benzodiazepines derivatives is 3. Specific reaction on benzodiazepines derivatives is formation of green color after pyrolisis.formation of green color after pyrolisis.

4. Formation of azodays after primary hydrolysis:4. Formation of azodays after primary hydrolysis:

Nozepam

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5. Belshteine probe use for determination of halogens.5. Belshteine probe use for determination of halogens.

6. Noozepam by heating with conc. H2SO4 hydrolyzed with 6. Noozepam by heating with conc. H2SO4 hydrolyzed with formation of formaldehyde, which forms violet color with formation of formaldehyde, which forms violet color with fuxinsulfite acid.fuxinsulfite acid.

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14.Classification of alkaloids.14.Classification of alkaloids.AlkaloidsAlkaloids are naturally occurring chemical compounds are naturally occurring chemical compounds

containing basic nitrogen atoms. The name derives from the word containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of the group of bacteria, fungi, plants, and animals and are part of the group of natural products (also called secondary metabolites). Many natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and use as medications and have pharmacological effects and use as medications and recreational drugs. Examples are the local anesthetic and stimulant recreational drugs. Examples are the local anesthetic and stimulant cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or cocaine, the stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Some alkaloids have a bitter taste. the antimalarial drug quinine. Some alkaloids have a bitter taste. Alkaloids are usually classified by their common molecular Alkaloids are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the precursors, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium molecules' structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were isolated from. When more is learned the plants or animals they were isolated from. When more is learned about a certain alkaloid, the grouping is changed to reflect the new about a certain alkaloid, the grouping is changed to reflect the new knowledge, usually taking the name of a biologically-important knowledge, usually taking the name of a biologically-important amine that stands out in the synthesis process.amine that stands out in the synthesis process.

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Methods of extraction

1. Extraction as salts: to raw material add water or ethanol with few drops of tartaric acid. All alkaloids forms salts with tartaric acid. For purification to this extract add base and all alkaloids form bases, which obtained by organic solutions. Operation of purification repeat few times. Then solvent separated from alkaloids. Sum of alkaloids is separated on individual compounds.

2. Extraction as bases: to raw material add alkali solution (ammonium, sodium hydrocarbonate or carbonate). Alkaloids bases are extracted by organic solutions. Purification realize by transferring alkaloids to salts and then to bases. Operation of purification repeat few times.

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Common precipitate reagents on alkaloids

1.Lyugol, Vagner, Bushard reagents (I2 in KI in different concentraions).

2. Dragendorph reagent (K[BiI4]).3. Maier reagent (K2[HgI4]).4. Marme reagent (CdI3 in KI).5. Zonnenshten reagent

(H3PO4·12MoO3·2H2O).6. Sheibler reagent (H3PO4·12WO3·2H2O).7. Berthran reagent (SiO2·12WO3·2H2O).8. 5% Tannin solution.9. Saturated solution of picric acid.

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Special reagents on alkaloids

1. Conc. H2SO4.2. Conc. HNO3.3. Erdman reagent (H2SO4 conc.+HNO3

conc.).4. Phrede reagent ((NH4)2MoO4+H2SO4

conc.).5. Marki reagent (HCOH+H2SO4 conc.).6. Mandelin reagent (NH4VO3+H2SO4

conc.).7. Sodium nithroprusid

(Na2[Fe(CN5)No]·2H2O).

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Pyridine and piperidine group: piperine, coniine, trigonelline, arecoline, Pyridine and piperidine group: piperine, coniine, trigonelline, arecoline, arecaidine, guvacine, cytisine, lobeline, nicotine, anabasine, sparteine, arecaidine, guvacine, cytisine, lobeline, nicotine, anabasine, sparteine, pelletierine.pelletierine.

Pyrrolidine and pyrolisidine group: hygrine, cuscohygrine, platyphylline, Pyrrolidine and pyrolisidine group: hygrine, cuscohygrine, platyphylline, nicotine.nicotine.

Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine.Tropane group: atropine, cocaine, ecgonine, scopolamine, catuabine.

Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, Quinoline group: quinine, quinidine, dihydroquinine, dihydroquinidine, strychnine, brucine, veratrine, cevadine.strychnine, brucine, veratrine, cevadine.

Isoquinoline group: opium alkaloids (papaverine, narcotine, narceine), Isoquinoline group: opium alkaloids (papaverine, narcotine, narceine), sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine.sanguinarine, hydrastine, berberine, emetine, berbamine, oxyacanthine.

NN

H

3N CH

N

N

N N

H

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Phenanthrene alkaloids: opium alkaloids (morphine, codeine, Phenanthrene alkaloids: opium alkaloids (morphine, codeine, thebaine)thebaine)

Phenethylamine group: mescaline, ephedrine, dopaminePhenethylamine group: mescaline, ephedrine, dopamine

Indole group: Indole group:

Tryptamines: serotonin, bufotenine, psilocybinTryptamines: serotonin, bufotenine, psilocybin Ergolines (the ergot alkaloids): ergine, ergotamine, lysergic acidErgolines (the ergot alkaloids): ergine, ergotamine, lysergic acid Beta-carbolines: harmine, harmaline, tetrahydroharmineBeta-carbolines: harmine, harmaline, tetrahydroharmine Yohimbans: reserpine, yohimbineYohimbans: reserpine, yohimbine Vinca alkaloids: vinblastine, vincristineVinca alkaloids: vinblastine, vincristine Kratom (Kratom (Mitragyna speciosaMitragyna speciosa) alkaloids: mitragynine, 7-) alkaloids: mitragynine, 7-

hydroxymitragyninehydroxymitragynine Tabernanthe ibogaTabernanthe iboga alkaloids: ibogaine, voacangine, coronaridine alkaloids: ibogaine, voacangine, coronaridine Strychnos nux-vomicaStrychnos nux-vomica alkaloids: strychnine, brucine alkaloids: strychnine, brucine

Purine group: Purine group:

Xanthines: caffeine, theobromine, theophyllineXanthines: caffeine, theobromine, theophylline

N

H

N

N

N

N

H

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15. Alkaloids group of pyridine and piperine 15. Alkaloids group of pyridine and piperine (nicotine, anabasine, lobeline).(nicotine, anabasine, lobeline).

Systematic (IUPAC) name

3-3-[2’-(N-[2’-(N-methylpyrrolidimethylpyrrolidil)l)]pyridine]pyridine

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) which constitutes approximately 0.6–3.0% of dry weight of tobacco, with biosynthesis taking place in the roots, and accumulating in the leaves.

It functions as an antiherbivore chemical with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine analogs such as imidacloprid continue to be widely used.

CH3

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ChemistryChemistryNicotine is a hygroscopic, oily liquid that is miscible with water in its Nicotine is a hygroscopic, oily liquid that is miscible with water in its

base form. As a nitrogenous base, nicotine forms salts with acids that are base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308 K (35 °C; 95 °F) in below its boiling point, and its vapors will combust at 308 K (35 °C; 95 °F) in air despite a low vapor pressure. Because of this, most of the nicotine is air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects. The amount of nicotine inhaled with tobacco smoke is a the desired effects. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves.fraction of the amount contained in the tobacco leaves.

PharmacologyPharmacology PharmacokineticsPharmacokinetics

As nicotine enters the body, it is distributed quickly through As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two when inhaled. The half life of nicotine in the body is around two hours. The amount of nicotine absorbed by the body from smoking hours. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco and snuff, which are held in the mouth between the dipping tobacco and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

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PharmacodynamicsPharmacodynamicsNicotine acts on the nicotinic acetylcholine Nicotine acts on the nicotinic acetylcholine

receptors, specifically the ganglion type nicotinic receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. In receptor and one CNS nicotinic receptor. In small concentrations, nicotine increases the small concentrations, nicotine increases the activity of these receptors. Nicotine also has activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters effects on a variety of other neurotransmitters through less direct mechanisms.through less direct mechanisms.

In adrenal medullaIn adrenal medullaBy binding to ganglion type nicotinic By binding to ganglion type nicotinic

receptors in the adrenal medulla nicotine receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a increases flow of adrenaline (epinephrine), a stimulating hormone. By binding to the stimulating hormone. By binding to the receptors, it causes cell depolarization and an receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium influx of calcium through voltage-gated calcium channels. channels.

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Anabasine is a pyridine alkaloid found in the Tree Tobacco (Nicotiana glauca) plant, a close relative of the common tobacco plant (Nicotiana tabacum). It is similar to nicotine. Its principal (historical) industrial use is as an insecticide. Anabasine is present in trace amounts in tobacco smoke, and can be used as an indicator of a person's exposure to tobacco smoke.

PharmacologyAnabasine is a nicotinic acetylcholine receptor agonist. In high doses, it produces a depolarizing block of nerve transmission, which can cause symptoms similar to those of nicotine poisoning and, ultimately, death by asystole. In larger amounts it is thought to be teratogenic in swine.

β-(α’-pyperidile)pyridine

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Systematic (IUPAC) nameSystematic (IUPAC) name

L-(-)-2benzoilmethyle-6-(2’-hydroxy-L-(-)-2benzoilmethyle-6-(2’-hydroxy-2’-phenylethyl)-1-methylpyperidine2’-phenylethyl)-1-methylpyperidine

Lobeline is a natural alkaloid found in "Indian tobacco" (Lobelia inflata), "Devil's tobacco" (Lobelia tupa), "cardinal flower" (Lobelia cardinalis), "great lobelia" (Lobelia siphilitica), and Hippobroma longiflora. In its pure form it is a white amorphous powder which is freely soluble in water. Lobeline has been used as a smoking cessation aid, and may have application in the treatment of other drug addictions such as addiction to amphetamines or cocaine.

Lobeline has multiple mechanisms of action, acting as a VMAT2 ligand, which stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamphetamine.

CH3

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16. Alkaloids group of quinoline (quinine).16. Alkaloids group of quinoline (quinine).

QuinineSystematic (IUPAC) name (R)-(6-

methoxyquinolin-4-yl)- (8’-vinylquinuclidin-2’-yl)methanol

QuinineQuinine is a natural white crystalline alkaloid having is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. It is a stereoisomer of anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine.quinidine.Quinine was the first effective treatment for malaria caused by Quinine was the first effective treatment for malaria caused by Plasmodium falciparumPlasmodium falciparum, appearing in therapeutics in the 17th century. , appearing in therapeutics in the 17th century. Since then, many effective antimalarials have been introduced, Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical although quinine is still used to treat the disease in certain critical situations. Quinine is available with a prescription in the United situations. Quinine is available with a prescription in the United States. Quinine is also used to treat nocturnal leg cramps and States. Quinine is also used to treat nocturnal leg cramps and arthritis. arthritis.

Chemical structureChemical structureQuinine contains two major fused-ring systems: The aromatic quinoline and Quinine contains two major fused-ring systems: The aromatic quinoline and the bicyclic quinuclidinethe bicyclic quinuclidine ..

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Qualitative reaction on quinineThaleyoquine test: emerald-green color

– with conc. H2SO4 – blue fluorescence;

– with sodium nitroprusside - yellow sediment.

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Because of its relatively constant and Because of its relatively constant and well-known fluorescence quantum yield, well-known fluorescence quantum yield, quinine is also used in photochemistry as quinine is also used in photochemistry as a common fluorescence standard. Quinine a common fluorescence standard. Quinine (and quinidine) are used as the chiral (and quinidine) are used as the chiral moiety for the ligands used in Sharpless moiety for the ligands used in Sharpless asymmetric dihydroxylation. Quinine is asymmetric dihydroxylation. Quinine is sometimes added to the recreational drugs sometimes added to the recreational drugs cocaine, heroin and others in order to "cut" cocaine, heroin and others in order to "cut" the product and make more profit. the product and make more profit.

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PapaverineSystematic (IUPAC) name

1-(3’,4’-dimethoxybenzyl)-6,7-dimethoxyisoquinoline

Papaverine is an opium alkaloid used primarily in the treatment of visceral spasm, vasospasm (especially those involving the heart and the brain), and occasionally in the treatment of erectile dysfunction. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the other opium alkaloids (opiates).

17. Alkaloids of group of quinoline and 17. Alkaloids of group of quinoline and phenanthreneisoquinoline phenanthreneisoquinoline (papaverine, morphine, codeine). (papaverine, morphine, codeine).

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Qualitative reactions on papaverine

1. With conc. H2SO4 by heating – violet color after heating.

2. With conc. HNO3 – yellow color, that after heating becomes orange.

3. With bromine water – yellow precipitate.

N

H3CO

H3CO

CH2

H3CO OCH3

HNO3

N

H3CO

H3CO

CH2

H3CO OCH3

NO2

O2N

N

H3CO

H3CO

CH2

H3CO OCH3

NO2

HNO3

жовте забарвлення оранжеве забарвлення

t 0C

Yellow Orange

4. With Erdman reagent (H2SO4 conc.+HNO3 conc.) – red color.5. With Phrede reagent ((NH4)2MoO4+H2SO4 conc.) – violet color after heating. 6. With Mandelin reagent (NH4VO3+H2SO4 conc.) – blue-green color becomes blue.

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7. With Marci reagent (HCOH+H2SO4 conc.) – at first forms red color, then yellow and at the end orange. By adding bromine water and ammonium appears violet precipitate, which dissolves in alcohols.

CH2

N+ N+

CH2

CH2

H H

H3CO

H3CO OCH3

OCH3

OCH3H3COOCH3OCH3

SO42-

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UsesUsesPapaverine is approved to treat spasms of Papaverine is approved to treat spasms of

the gastrointestinal tract, bile ducts and ureter the gastrointestinal tract, bile ducts and ureter and for use as a cerebral and coronary and for use as a cerebral and coronary vasodilator in subarachnoid hemorrhage vasodilator in subarachnoid hemorrhage (combined with balloon angioplasty) and (combined with balloon angioplasty) and coronary artery bypass surgery. Papaverine may coronary artery bypass surgery. Papaverine may also be used as a smooth muscle relaxant in also be used as a smooth muscle relaxant in microsurgery where it is applied directly to blood microsurgery where it is applied directly to blood vessels. It is also commonly used in vessels. It is also commonly used in cryopreservation of blood vessels along with the cryopreservation of blood vessels along with the other glycosaminoglycans and protein other glycosaminoglycans and protein suspensions. Functions as a vasodilator during suspensions. Functions as a vasodilator during cryopreservation when used in conjunction with cryopreservation when used in conjunction with verapamil, phentolamine, nifedipine, tolazoline verapamil, phentolamine, nifedipine, tolazoline or nitroprusside. or nitroprusside.

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Systematic (IUPAC) nameSystematic (IUPAC) name 3,6-dihydroxy-N-methyl- 4,5-3,6-dihydroxy-N-methyl- 4,5-epoxymorphinene-7epoxymorphinene-7

Morphine is a highly potent opiate analgesic drug, is the principal active agent in opium, and is considered to be the prototypical opioid. Morphine was in 1803 the first alkaloid isolated from a plant source. Like other opioids, e.g. oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain, particularly at the synapses of the nucleus accumbens. Morphine has a high potential for addiction; tolerance and both physical and psychological dependence develop rapidly.

ChemistryChemical structure of morphine in correct 3D configuration. The

benzylisoquinoline backbone is shown in blue. Morphine is a benzylisoquinoline alkaloid with two additional ring closures. Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (diacetylmorphine), hydromorphone, and oxymorphone. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency.

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Morphinene

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Qualitative reactions on morphine1. With Marci reagent – purpur color quickly becomes blue-violet

(distinctive reaction between morphine and codeine).2. With ammonium – white crystal precipitate dissolves in NaOH.3. With Phrede reagent – at first forms violet color, that changes to blue

and by standing – to green.4. With FeCl3 – blue color.6. Oxidation reaction with K3[Fe(CN)6] and FeCl3 – blue color:

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7. With Mandelin reagent – violet color.

8. With Erdmane reagent – intense red color:

9. With conc. HNO3 – red-orange complex compound:

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10. With diazonium salts – azoday (red color).

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Obtaining derivatives of morphine

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Both morphine and its hydrated form are sparingly Both morphine and its hydrated form are sparingly soluble in water. In five litters of water, only one gram of soluble in water. In five litters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical the hydrate will dissolve. For this reason, pharmaceutical companies produce sulphate and hydrochloride salts of companies produce sulphate and hydrochloride salts of the drug, both of which are over 300 times more water-the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of the morphine salts are mixed with small amounts of NaOH to make them suitable for injection. A number of NaOH to make them suitable for injection. A number of salts of morphine are used, and the opioids Morphine-N-salts of morphine are used, and the opioids Morphine-N-Oxide (Genomorphine) which is a pharmaceutical which Oxide (Genomorphine) which is a pharmaceutical which is no longer in common use; and Pseudomorphine, an is no longer in common use; and Pseudomorphine, an alkaloid which exists in opium, form as degradation alkaloid which exists in opium, form as degradation products of morphine.products of morphine.

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Most semi-synthetic opioids, both of the morphine and Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or codeine subgroups, are created by modifying one or

more of the following:more of the following:1. Saturating, opening, or other changes to the bond betwixt positions 7 1. Saturating, opening, or other changes to the bond betwixt positions 7

and 8 on the morphine carbon skeleton, as well as adding, and 8 on the morphine carbon skeleton, as well as adding, removing, or modifying functional groups to these positions; removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7-8 saturating, reducing, eliminating, or otherwise modifying the 7-8 bond and attaching a functional group at 14 yields hydromorphinol; bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the the oxidation of the hydroxyl group to a carbonyl and changing the 7-8 bond to single from double changes codeine into oxycodone.7-8 bond to single from double changes codeine into oxycodone.

2. Attachment, reduction or modification of functional groups to 2. Attachment, reduction or modification of functional groups to positions 3 and/or 6 (dihydrocodeine and related, hydrocodone, positions 3 and/or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine which is 72 from position 3 to 6, codeine becomes heterocodeine which is 72 times stronger, and therefore six times stronger than morphinetimes stronger, and therefore six times stronger than morphine

3. Attachment of functional groups or other modification at position 14 3. Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)(oxymorphone, oxycodone, naloxone)

4. Modifications at positions 2, 4, 5 or 17, usually along with other 4. Modifications at positions 2, 4, 5 or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton.changes to the molecule elsewhere on the morphine skeleton.

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Morphine can be used:Morphine can be used: as an analgesic in hospital settings to relieve as an analgesic in hospital settings to relieve

pain pain atat myocardial infarction myocardial infarction pain at sickle cell crisispain at sickle cell crisis pain associated with surgical conditions, pre- and pain associated with surgical conditions, pre- and

postoperativelypostoperatively pain associated with traumapain associated with trauma

in the relief of severe chronic pain, e.g., in the relief of severe chronic pain, e.g., cancercancer pain from kidney stones (renal colic, ureterolithiasis)pain from kidney stones (renal colic, ureterolithiasis) severe back painsevere back pain

as an adjunct to general anesthesiaas an adjunct to general anesthesia in epidural anesthesia or intrathecal analgesiain epidural anesthesia or intrathecal analgesia as an antitussive for severe coughas an antitussive for severe cough in nebulized form, for treatment of dyspnea, although the evidence in nebulized form, for treatment of dyspnea, although the evidence

for efficacy is slim. for efficacy is slim. Evidence is better for other routes.Evidence is better for other routes. as an antidiarrheal in chronic conditions (e.g., for diarrhea as an antidiarrheal in chronic conditions (e.g., for diarrhea

associated with AIDS, although loperamide (a non-absorbed opioid associated with AIDS, although loperamide (a non-absorbed opioid acting only on the gut) is the most commonly used opioid for acting only on the gut) is the most commonly used opioid for diarrhea).diarrhea).

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CodeineCodeineSystematic (IUPAC) nameSystematic (IUPAC) name

6-hydroxy-N-methyl-3-methoxy- 6-hydroxy-N-methyl-3-methoxy- 4,5-epoxymorphinen-74,5-epoxymorphinen-7

Codeine (INN) or methylmorphine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is by far the most widely used opiate in the world and probably the most commonly used drug overall according to numerous reports over the years by organizations such as the World Health Organization and its League of Nations predecessor agency and others.

It is one of the most effective orally-administered opioid analgesics and has a wide safety margin. It is from 8 to 12 percent of the strength of morphine in most people; differences in metabolism can change this figure as can other medications.

PharmacologyCodeine is considered a prodrug, since it is metabolised in vivo to the primary

active compounds morphine and codeine-6-glucuronide. Roughly 5-10% of codeine will be converted to morphine, with the remainder either free, conjugated to form codeine-6-glucuronide (~70%), or converted to norcodeine (~10%) and hydromorphone (~1%). It is less potent than morphine and has a correspondingly lower dependence-liability than morphine. Like all opioids, continued use of codeine induces physical dependence and can be psychologically addictive. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

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Qualitative reactions on codeine1. With Marci reagent – blue-violet color.2. Formation of apomorphine. After heating with

conc. H2SO4 and FeCl3 appears blue color that becomes red after adding 1 drop of dilute HNO3.

3. With conc. HNO3 – red color becomes yellow.4. With AgNO3 – orange precipitate Ag3PO4.5. With Erdman reagent (H2SO4 conc.+HNO3

conc.) -blue color after heating.6. With Phrede reagent ((NH4)2MoO4+H2SO4

conc.) - green color becomes blue.7. With Mandelin reagent (NH4VO3+H2SO4 conc.)

- green color becomes blue.8. With sodium nithropruside– yellow sediment.

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18. Alkaloids group of purine (18. Alkaloids group of purine (caffeine, theobromine, caffeine, theobromine, theophyllinetheophylline).).

1,3,7-trimethylxanthine, 1,3,7-trimethylxanthine, trimethylxanthine,trimethylxanthine,

Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a psychoactive stimulant drug and a mild diuretic. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term "kaffein", a chemical compound in coffee, which in English became caffeine.

Caffeine is also part of the chemical mixtures and insoluble complexes guaranine found in guarana, mateine found in mate, and theine found in tea; all of which contain additional alkaloids such as the cardiac stimulants theophylline and theobromine, and often other chemicals such as polyphenols which can form insoluble complexes with caffeine. Caffeine is found in varying quantities in the beans, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants. It is most commonly consumed by humans in infusions extracted from the cherries of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut.

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Caffeine present in sugh plants:Coffea arabica, Thea sinensis and Cola acuminata

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Thea sinensis Theobroma cacao

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In humans, caffeine is a central In humans, caffeine is a central nervous system (CNS) stimulant. nervous system (CNS) stimulant. Beverages containing caffeine, such as Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks coffee, tea, soft drinks and energy drinks enjoy great popularity. Caffeine is the enjoy great popularity. Caffeine is the world's most widely consumed world's most widely consumed psychoactive substance, but unlike many psychoactive substance, but unlike many other psychoactive substances it is legal other psychoactive substances it is legal and unregulated in nearly all jurisdictions. and unregulated in nearly all jurisdictions.

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PharmacologyPharmacology

Caffeine stimulates the central nervous system Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts inside the body, it has a complex chemistry, and acts through several mechanisms as described below.through several mechanisms as described below.

Metabolism and half-lifeMetabolism and half-life

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Common reaction on caffeine, theobromine and theophylline – Murexyde reaction

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Specific reactions on caffeine

– with 1% solution of tannin – white precipitate dissolved in excess of reagent;

– with 0,1M solution of I2 by the present of HCl – brown precipitate dissolved in excess of alkali;

– with HgCl3 - white precipitate;

– with sodium nithropruside – yellow sediment;

– with acetylacetone and dimethylamnobenzaldehyde: solution of the substance with acetylacetone and NaOH heat on water bath and then cooling. Add solution of dimethylamnobenzaldehyde and heat ones more, then cooling and add water. Appears intense blue color:

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TheobromineSystematic (IUPAC) name 3,7-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione

Theobromine, also known as xantheose, is a bitter alkaloid of the cacao plant, found in chocolate, as well as in a number of chocolate-free foods made from theobromine sources including the leaves of the tea plant, the kola or cola nut, and acai berries. It is in the methylxanthine class of chemical compounds, which also includes the similar compounds theophylline and caffeine. Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless. It has a similar, but lesser, effect as caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethylxanthine, which means it is a xanthine with two methyl groups.

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Specific reactions on theobromine– theobromine reacts with NaOH and CoCl2, appears evanescent

violet color and separates gray-blue precipitate of cobalt salt. Theophylline in these conditions forms cobalt salt - white sediment with pink tinge:

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– with HgCl3 - white crystal precipitate;

– sodium salt of theobromine reacts with AgNO3 – forms gelatins mass (silver salt):

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A chocolate bar and melted chocolate. Chocolate is made from the cacao bean, which is a natural source of theobromine.

The mean theobromine concentrations in cocoa and carob products are:The mean theobromine concentrations in cocoa and carob products are:

ItemMean theobromine

content (mg/g)

Cocoa 20.3

Cocoa cereals 0.695

Chocolate bakery products

1.47

Chocolate toppings

1.95

Cocoa beverages 2.66

Chocolate ice creams

0.621

Chocolate milks 0.226

Carob products 0-0.504

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TheophyllineSystematic (IUPAC) name 1,3-dimethyl-7H-purine-2,6-dione

SynthesisTheophylline can be prepared synthetically from Theophylline can be prepared synthetically from dimethylurea and ethyl 2-cyanoacetate.dimethylurea and ethyl 2-cyanoacetate.

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Specific reactions on theophylline

– theophylline forms with CoCl2 salt - white sediment with pink tinge (look at the previous slide);

– with alkali solution of sodium nitropruside – green color dissolved in excess of acid;

– with HgCl3 - white crystal precipitate;

– sodium salt of theophylline reacts with AgNO3 – forms gelatins mass (silver salt):

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TheophyllineTheophylline, also known as , also known as dimethylxanthinedimethylxanthine, is a , is a methylxanthine drug used in therapy for respiratory diseases such methylxanthine drug used in therapy for respiratory diseases such as COPD or asthma under a variety of brand names. Due to its as COPD or asthma under a variety of brand names. Due to its numerous side-effects, these drugs are now rarely administered for numerous side-effects, these drugs are now rarely administered for clinical use. As a member of the xanthine family, it bears structural clinical use. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine. It is naturally found in tea, and pharmacological similarity to caffeine. It is naturally found in tea, although in trace quantities (~1 mg/L), significantly less than although in trace quantities (~1 mg/L), significantly less than therapeutic doses.therapeutic doses.

The main actions of theophylline involve:The main actions of theophylline involve: relaxing bronchial smooth musclerelaxing bronchial smooth muscle increasing heart muscle contractility and efficiency: positive inotropic increasing heart muscle contractility and efficiency: positive inotropic

effect effect increasing heart rate: positive chronotropic effectincreasing heart rate: positive chronotropic effect increasing blood pressureincreasing blood pressure increasing renal blood flowincreasing renal blood flow some anti-inflammatory effectssome anti-inflammatory effects central nervous system stimulatory effect mainly on the medullary central nervous system stimulatory effect mainly on the medullary

respiratory center.respiratory center.

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19. Alkaloids group of tropane (atropine, scopolamine, 19. Alkaloids group of tropane (atropine, scopolamine, cocaine).cocaine).

AtropineAtropine is a tropane alkaloid extracted from is a tropane alkaloid extracted from deadly nightshade (deadly nightshade (Atropa belladonnaAtropa belladonna), ), jimsonweed (jimsonweed (Datura stramoniumDatura stramonium), mandrake ), mandrake ((Mandragora officinarumMandragora officinarum) and other plants of the ) and other plants of the Solanaceae family. Solanaceae family.

Systematic (IUPAC) nameSystematic (IUPAC) name (8- (8-methyl-8-azabicyclo[3.2.1]oct-3-methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-yl) 3-hydroxy-2-phenylpropanoate; tropinic ester phenylpropanoate; tropinic ester of tropic acidof tropic acid

Atropine

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Derivatives of tropane

Tropine Scopine Echonine

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It is a secondary metabolite of these plants It is a secondary metabolite of these plants andand

serves as a drug with a wide variety of serves as a drug with a wide variety of effects. It is a competitive antagonist for effects. It is a competitive antagonist for the muscarinic acetylcholine receptor. It the muscarinic acetylcholine receptor. It is classified as an anticholinergic drug. is classified as an anticholinergic drug. Being potentially deadly, it derives its Being potentially deadly, it derives its name from Atropos. name from Atropos.

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Physiological effects and usesPhysiological effects and usesIncreases firing of the sinoatrial node (SA) and conduction Increases firing of the sinoatrial node (SA) and conduction

through the atrioventricular node (AV) of the heart, opposes the through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchiole secretions. Generally, atropine lowers the decreases bronchiole secretions. Generally, atropine lowers the parasympathetic activity of all muscles and glands regulated by the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system. Therefore, it may cause parasympathetic nervous system. Therefore, it may cause swallowing difficulties and reduced secretions.swallowing difficulties and reduced secretions.

Chemistry and pharmacologyChemistry and pharmacology

Atropine is a racemic mixture of D-hyoscyamine and L-Atropine is a racemic mixture of D-hyoscyamine and L-hyoscyamine, with most of its physiological effects due to L-hyoscyamine, with most of its physiological effects due to L-hyoscyamine. Its pharmacological effects are due to the binding with hyoscyamine. Its pharmacological effects are due to the binding with muscarinic acetylcholine receptors. It is an antimuscarinic agent. muscarinic acetylcholine receptors. It is an antimuscarinic agent. The most common atropine compound used in medicine is atropine The most common atropine compound used in medicine is atropine sulfate (Csulfate (C1717HH2323NONO33))22·H·H22SOSO44·H·H22O.O.

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Common reaction on tropane alkaloids – rection of Vitaly-Moren

In a porcelain cup to atropine add conc. HNO3

and heat to dry state – forms yellow polinitrocompound, dissolve this compound in acetone, addo, 0,5M alcohol solution of KOH. Appears violet color disappears by standing.

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Qualitative reactions on atropine– with picric acid – yellow precipitate;

– with Marci reagent – yellow color;

– formation of benzaldehyde:

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ScopolamineScopolamineSystematic (IUPAC) nameSystematic (IUPAC) name

(-)-((-)-(SS)-3-hydroxy-2-phenyl-propionic acid )-3-hydroxy-2-phenyl-propionic acid (1(1RR,2,2RR,4,4SS,7,7SS,9,9SS)-)-9-methyl-3-oxa-9-methyl-3-oxa-9-aza-tricyclo[3.3.1.09-aza-tricyclo[3.3.1.02,42,4]non-7-yl ester]non-7-yl ester;;Scopinic ester of tropic acid Scopinic ester of tropic acid

ScopolamineScopolamine, known by the names , known by the names levo-duboisinelevo-duboisine and and hyoscinehyoscine, is a , is a tropane alkaloid drug with muscarinic tropane alkaloid drug with muscarinic antagonist effects. It is obtained from antagonist effects. It is obtained from plants of the Solanaceae family plants of the Solanaceae family (nightshades), such as (nightshades), such as DaturaDatura Stramonium. Stramonium.

It is among the secondary metabolites of these plants. It is among the secondary metabolites of these plants. Therefore, scopolamine is one of three main active components of Therefore, scopolamine is one of three main active components of belladonna and stramonium tinctures and powders used medicinally belladonna and stramonium tinctures and powders used medicinally along with atropine and hyoscyamine. Scopolamine has anticholinergic along with atropine and hyoscyamine. Scopolamine has anticholinergic properties and has legitimate medical applications in very small doses. properties and has legitimate medical applications in very small doses. An overdose can cause delirium, delusions, dangerous elevations of An overdose can cause delirium, delusions, dangerous elevations of body temperature, stupor and death.body temperature, stupor and death.

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HistoryHistoryScopolamine was one of the earlier alkaloids Scopolamine was one of the earlier alkaloids

isolated from plant sources, purified forms such as isolated from plant sources, purified forms such as free base and various salts, especially free base and various salts, especially hydrochloride, hydrobromide, hydroiodide and hydrochloride, hydrobromide, hydroiodide and sulphate, since its isolation by German chemists in sulphate, since its isolation by German chemists in 1881 and in the form of plant-based preparations 1881 and in the form of plant-based preparations since antiquity and perhaps pre-historic times.since antiquity and perhaps pre-historic times.

PhysiologyPhysiologyScopolamine acts as a competitive antagonist at Scopolamine acts as a competitive antagonist at

muscarinic acetylcholine receptors, specifically M1 muscarinic acetylcholine receptors, specifically M1 receptors; it is thus classified as an anticholinergic,anti-receptors; it is thus classified as an anticholinergic,anti-muscarinic drug. muscarinic drug.

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CocaineSystematic (IUPAC) name methyl (1R,2R,3S,5S)-3- (benzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate; methylester of benzoilechonine

Cocaine (benzoylmethyl ecgonine) is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is both a stimulant of the central nervous system and an appetite suppressant.

Specifically, it is a dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor and a serotonin reuptake inhibitor. Its possession, cultivation, and distribution are illegal for non-medicinal and non-government sanctioned purposes in virtually all parts of the world. Although its free commercialization is illegal and has been severely penalized in virtually all countries.

The coca plant, Erythroxylon coca.

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Qualitative reactions on cocaine– with KMnO4 – violet crystal precipitate:

– heating with conc. H2SO4 (specific smell of methylbenzoate, by standing forms crystals of benzoic acid)

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20. Alkaloids group of i20. Alkaloids group of indole ndole (reserpine, (reserpine, strychnine).strychnine).

Systematic (IUPAC) nameSystematic (IUPAC) name 11,17-dimethoxy-16-11,17-dimethoxy-16-carbmethoxy-18-(3’,4’,5’-carbmethoxy-18-(3’,4’,5’-trimethoxybenzoyloxy)aloyohim-trimethoxybenzoyloxy)aloyohim-banebane

Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic behaviors, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely used today. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines (among the others) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.

NH

NH3CO

H3COOC

OCH3

O C

O

OCH3

OCH3

OCH3

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Rauwolfia serpentina

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Aloyohimbane

NH

NA C

D

E

12

34

56

789

10

1112

13

14

15

1617

18

19

20

21

B

Àëî é î õ³ì áàí

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Reserpine can cause: nasal congestion, nausea, Reserpine can cause: nasal congestion, nausea, vomiting, weight gain, gastric intolerance, gastric vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps tissue and impaired mucosal quality), stomach cramps and diarrhea are noted. The drug causes hypotension and diarrhea are noted. The drug causes hypotension and bradycardia and may worsen asthma. Depression and bradycardia and may worsen asthma. Depression can occur at any dose and may be severe enough to can occur at any dose and may be severe enough to lead to suicide. Other central effects are a high incidence lead to suicide. Other central effects are a high incidence of drowsiness, dizziness, and nightmares. Parkinsonism of drowsiness, dizziness, and nightmares. Parkinsonism occurs in a dose dependent manner. High doses of occurs in a dose dependent manner. High doses of reserpine cause fibroadenoma of the breast and reserpine cause fibroadenoma of the breast and malignant tumors of the seminal vesicles among others. malignant tumors of the seminal vesicles among others. Early suggestions that reserpine causes breast cancer in Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed. women (risk approximately doubled) were not confirmed. It may also cause hyperprolactinemia.It may also cause hyperprolactinemia.

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StrychnineStrychnine is a very toxic (LD50 = 10 mg approx.), colorless is a very toxic (LD50 = 10 mg approx.), colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion. The most common eventually death through asphyxia or sheer exhaustion. The most common source is from the seeds of the source is from the seeds of the Strychnos nux vomicaStrychnos nux vomica tree. Strychnine is one of tree. Strychnine is one of the most bitter substances known. Its taste is detectable in concentrations as the most bitter substances known. Its taste is detectable in concentrations as low as 1 ppm. low as 1 ppm.

PharmacologyPharmacologyStrychnine acts as a blocker or antagonist at the inhibitory or Strychnine acts as a blocker or antagonist at the inhibitory or

strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in the spinal cord and the brain. Although it is best known as a poison, small doses the spinal cord and the brain. Although it is best known as a poison, small doses of strychnine were once used in medications as a stimulant, a laxative and as a of strychnine were once used in medications as a stimulant, a laxative and as a treatment for other stomach ailments. Because of its high toxicity and tendency treatment for other stomach ailments. Because of its high toxicity and tendency to cause convulsions, the use of strychnine in medicine was eventually to cause convulsions, the use of strychnine in medicine was eventually abandoned once safer alternatives became available.abandoned once safer alternatives became available.

Strychnine

N

O

N

O

* HNO3

A B

C

D

E

F

G

12

34

5

6 7

8

9

1011

12

13

14

1516

17 18

19

20

21

2223

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Strychnos Nux Vomica

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Thank you for attention!