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US005378729A

United States Patent Patent Number 5378729

Kohn et Date of Patent Jan 1995

AMINO ACID DERIVATIVE FOREIGN PATENT DOCUMENTSANTICONVULSANT

0885303 3/1981 Belgium

Inventors Harold Kohn Houston Darrell 0194464 2/1980 European Pat Off

Watson Belton both of Tex 0007441 10/1980 European Pat Off

0038758 10/1981 European Pat Off

Assignee Research Corporation Technologies 0042626 12/198 European Pat Off

Inc Tucson A.riz0046707 3/1982 European Pat Off

0263506 10/1987 European Pat Off

AppI No 7106100400400 5/1990 European Pat Off

1927692 12/1969 Germany

Filed Jun 19910393355 10/1965 Switzerland

1051220 12/1966 United Kingdom

Related U.S Application Data OTHER PUBLICATIONS

Continuation-in-part of Ser No 354057 May 19Chemical Abstracts vol 92 No 751712r Feb 18

1989 abandoned and Ser No 392870 Aug Ii 1989 1990

abandoned which is continuation of Ser No 80528 Chemical Abstracts vol 96 No 535710r FebJul 31 1987 abandoned which is continuation-in- 1982part of Ser No 916254 Oct 1986 abandoned Chemical Abstracts vol 101 No 72124v Aug 27which is continuation-in-part of Ser No 702195

1984Feb 15 1985 abandoned said Ser No 354057 is

continuation-in-part of Ser No 80528 Feb 15 1985 Chemical Abstracts vol 91 No 21175147 Nov 19

1979

mt Cl.6 A61K 31/535 A61K 31/445 List continued on next pageCO7D 21 1/72 CO7D 261/04

U.S Cl 514/231.2 514/315Primary ExaminerMariamie Cintins

514/397 514/406 514/415 514/424 514/461Assistant .Examiner.-T Criares

514/468 514/486 546/292 548/371.4Attorney Agent or FirmScully Scott Murphy

Presser548/245 564/148 564/152 564/154

Field of Search 564/148 155 154 152 ABSTRACF548/616 245 371.4 14/461 548 549 The present invention relates to compounds exhibiting

546/292central nervous system CNS activity which are useful

References Citedin the treatment of epilepsy and other CNS disorders

The compounds of this invention have the followingU.S PATENT DOCUMENTS

general formula

2676188 4/1954 Bruce et al 564/155

2721197 10/1955 Sheehan 564/155

3340147 9/1967 Martin etal 514/616

3657341 4/1972 Thorne et al 260/558 R_NHf_NH_RI3707559 12/1972 Mazur et al 564/158

R3

4018826 4/1977 Gless Jr et al 564/215

4260684 4/1981 Schuit 564/155

4303673 12/1981 Biedermann et al 564/155 and pharmaceutically acceptable salts thereof

4513009 4/1985 Roques et al 564/155

4595700 6/1986 Donaldetal 514/616

4618708 10/1986 Roques at ai 564/154

4873241 10/1989 Napier et ai 514/237.8 150 Claims No Drawings

MYLAN - EXHIBIT 1009

5378729

Page

OTHER PUBLICATIONS chemical Synthesis of 1234-Tetrahy-

Kohn et al 1988 Brain Research 457 371375 droisoquinolin-3ones from NChloroacetylbenzyla

Marked Sterospecificity in New Class of Anticonvul- mines

sants Katritzky et at 1990 Org Chem 55 22062214

Chemical Abstracts vol 97 145266d 1982 BenzotriazoleAssisted Synthesis of Monoacyl Animals

White et al 1981 JACS 10342314239 Ac- and Their Peptide Derivatives

tiveSiteDirected Inhibition of aiphaChymotrypsin Lipshutz et al 1983 Am Chem Soc 105

by Deanilnatively Produced Carbonium Ions An Ex- 770377 13 Heterocycles as Masked Diamide/Dipep

ample of Suicide of Enzyme-Activated-Substrate Inhi- tide Equivalents Formation and Reactions of Substi

bition tuted 5Acylamino Oxazoles as Intermediates en

Legall et al 1988 mt Protein Res 12279291 Route to the Cyclopeptide Alkaloids

Synthesis of Functionalized NonNatural Amino Acid Lipshutz et al 1983 Org Chem 4837453750 AnDerivatives via Amidoalkylation Transformations Approach to the Cyclopeptide Alkaloids Phenylcy

Conley et al 1987 Med Chem 303574580 clopeptines via Heterocyclic Diamide/Dipeptide

Functionalized DLAmino Acid Derivatives Potent Equivalents Preparation and NAlkylation Studies of

New Agents for the Treatment of Epilepsy 245Disubstituted Iniidazoles

Garcia et al 1984 Tetrahedron Letters 2542 Rogues 1987 193rd ACS National Meeting Amer48414844 New Synthetic Tricks Triphenylphos- Chem Society Apr 1510 1987 Use of Various Metal

phine-Mediated Amide Formation from Carboxylic lopeptidase Inhibitors to Study the Physiogical Rate of

Acids and Azides Endogenous Neuropeptides

Rebek et al 1979 Am Chem Soc lOl3737 On Kohn et al 1990 Med Chem 33919926 Preparathe Rate of SiteSite Interactions in Functionalized tion and Anticonvulsant Activity of Series of Func

Polystyrenes tionalized /3Aromatic and Heteroaromatic Amino

Cortes et al 1985 Med Chem 28601606 Effect Acids

of Structural Modification of the Hydantion Ring on Lipshutz et al Heterocycles in Synthesis. Imidaz

Anticonvulsant Activity oles Journal of the American Chemical Society vol

Ikeda et al 1977 Tetrahedron 335 489495 Photo- 106 No pp 457459 CA 10219 160030n 1985

5378729

ZY taken together is NR4NRSR7 NR4OR5AMINO ACID DERIVATIVE ANICONVULSANT ONR4R7 OPR4R5 PR4OR5 SNRiR7 NR4SR7

SPR4RS or PR4SR7 NR4PR5RS or PR4NR5R7This invention was made with Government support

under NS15604 awarded by the National Institutes of

Health The Gvemment has certain rights in the in-NR4CR5 SCR5 NR4C0R5 SC0R

vention

The present-application is continuation-in-part of

copending U.S patent application Set No 07/354057 R5 and R6 are independently hydrogen lower

filed on May 1989 and CIP of U.S patent applica-10 alkyl aryl aryl lower alkyl lower alkenyl or lower

tion Ser No 07/392870 filed on Aug 11 1989 both alkynyl wherein R4 Rand R6may be unsubstituted or

substituted with an electron withdrawing group or annow abandoned U.S patent application Ser Noelectron donating group and

07/354057 flIed on May 19 1989 now abandoned being

continuation-in-part of U.S patent application havingR7 is R6 or COORs or COR8

Set No 07/080528 filed on Jul 31 1987 now aban-15 R8 is hydrogen or lower alkyl or aryl lower alkyl

and the aryl or alkyl group may be unsubstituted ordoned which is continuation-in-part of U.S patent

substituted with an electron withdrawing group or anapplication Ser No 06/9 16254 filed Oct 1986 now

electron donating group andabandoned which is continuation-in-part of U.S pa-

is 1-4 andtent application Ser No 06/702195 ified Feb 15 1985

20 is 13now abandoned said U.S patent application Set No The predominant application of anticonvulsant drugs07/392870 filed Jul 11 1989 abandoned being con-

is the control and prevention of seizures associated withtinuation application of U.S patent application having

epilepsy or related central nervous system disordersSet No 07/080528 filed on Jul 31 1987 now aban- Epilepsy refers to many types of recurrent seizures

doned which is continuation-in-part of U.S patent 25 produced by paroxysmal excessive neuronal dischargesapplication Ser No 06/916254 filed Oct 1986 now in the brain the two main generalized seizures are petit

abandoned which is continuation-in-part of U.S pa- mal which is associated with myoclonic jerks akinetic

tent application Ser No 06/702195 filed on Feb 15 seizures transient loss of consciousness but without

1985 now abandoned convulsion and grand mal which manifests in continu

The present invention relates to compounds and 30 ous series of seizures and convulsions with loss of con-

pharmaceutical compositions having central nervous sciousness

system CNS activity which are useful in the treatment The mainstay of treatment for such disorders has

of epilepsy and other CNS disorders More specifically been the long-term and consistent administration of

the compounds of this invention can be characterized as anticonvulsant drugs Most drugs in use are weak acids

protected amino acid derivatives having the following 35 that presumably exert their action on neurons glial

general formula cells or both of the central nervous system The majority of these compounds are characterized by the presence of at least one amide unit and one or more benzene

rings that are present as phenyl group or part of

R_NHrNHrR1 cyclic system

Much attention has been focused upon the develop-OR3ment of anticonvulsant drugs and today many such

is hydrogen lower alkyl lower alkenyl lower drugs are well known For example the hydantions

alkynyl aryl aryl lower alkyl heterocycic heterocy-such as phenytoin are useful in the control of generalized seizures and all forms of partial seizures The ox

clic lower alkyl lower alkyl heterocyclic lower cyclo-azolidinediones such as trimethadione and parametha

alkyl lower cycloalkyl lower alkyl and is unsubsti-dione are used in the treatment of nonconvulsive sei

tuted or is substituted with at least one electron with-zures Phenacemide phenylacetylurea is one of the

drawing group or electron donating group most well known anticonvulsants employed todayRi is hydrogen or lower alkyl lower alkenyl lower

50 while much attention has recently been dedicated to thealkynyl aryl lower alkyl aryl heterocycic lower alkyl

investigation of the diazepines and piperazines Forheterocyclic lower cycloalkyl lower cycloalkyl lower

example U.S Pat Nos 4002764 and 4178378 to Allalkyl each unsubstituted or substituted with an electron

geier et al disclose esterified diazepine derivatives

donating group or an electron withdrawing group anduseful in the treatment of epilepsy and other nervous

R2 and R3 are independently hydrogen lower alkyl disorders U.S Pat No 3887543 to Nakanishi et allower alkenyl lower alkynyl aryl lower alkyl Y1 describes thieno compound also

heterocycic heterocycic lower alkyl lower alkyl het-having anticonvulsant activity and other depressant

erocyclic lower cycloalkyl lower cycloalkyl loweractivity U.S Pat No 4209516 to Heckendom et al

alkyl or Z-Y wherein R2 and R3 may be unsubstituted relates to triazole derivatives which exhibit anticonvul

or substituted with at least one electron withdrawing 60 sant activity and are useful in the treatment of epilepsy

group or electron donating group and conditions of tension and agitation U.S Pat Nois SSOa NR.j PRor chemical bond 4372974 to Fish et al discloses pharmaceutical for

is hydrogen lower alkyl aryl aryl lower alkyl mulation containing an aliphatic amino acid compoundlower aikenyl lower alkynyl halo heterocycic heter- in which the carboxylic acid and primary amine are

ocyclic lower alkyl lower alkyl and may be unsubsti- 65 separated by three or four units Administration of these

tuted or substituted with an electron donating group or compounds in an acid pH range are useful in the treat-

an electron withdrawing group provided that when ment of convulsion disorders and also possess anxiolytic

is halo is chemical bond or and sedative properties

5378729

Unfortunately despite the many available pharmaco- E--4-methyl-2-pentenyl pentadienyl e.g 13 or 24-

therapeutic agents significant percentage of the popu- pentadienyl and the like

lation with epilepsy or related disorders are poorly The term alkynyl include alkyene substituents con-

managed Moreover none of the drugs presently avail- taming to carbon atoms and may be straight chained

able are capable- of achieving total seizure control and as well as branched It includes such groups as ethynyl

most have disturbing side-effects Clearly current ther- propynyl 1-butynyl 2-butynyl 1-pentynl 2-pentynyl

apy has failectto seize control of these debilitating 3-methyl-l-pentynyl 3-pentynyl 1-hexynyl 2-hexynyl

diseases 3-hexynyl and the like

It is therefore one object of the present invention to The term cycloalkyl when used alone or in combina

provide novel compounds exhibiting CNS activity10 tion is cycloalkyl group containing from to 18 ring

particularly anticonvulsant activitycarbon atoms and up to total of 25 carbon atoms The

Another object of this invention is to provide phar- cycloalkyl groups may be monocyclic bicyclic tricy

maceuticai compositions useful in the treatment of epi-clic or polycycic and the rings are fused The cycloal

lepsy and other CNS disorders kyl may be completely saturated or partially saturated

further object of this invention is to provide15 Examples include cyclopropyl cyclobutyl cyclopen

method of treating epilepsy and related convulsant dis- tyl cyclohexyl cycloheptyl cyclooctyl cyclodecyl

orders cyclohexenyl cyclopentenyl cyclooctenyl cyclohep

These and other objects are accomplished herein bytenyl decalinyl hydroindanyl indanyl fenchyl pine-

providing compounds of the following general formula nyl adamantyl and the like Cycloalkyl includes the cis

20 or trans forms Furthermore the substituents may either

be in endo or exo positions in the bridged bicyclic sys

tems12 The term electron-withdrawing and electron donat

RNHI-C cMc R1 ing refer to the ability of substituent to withdraw orII 25 donate electrons relative to that of hydrogen if the0R3

hydrogen atom occupied the same position in the mole

cule These terms are well understood by one skilled inwherein R1 R2 R3 R4 R5 R6 R7 Rg are as

the art and are discussed in Advanced Organic Chemistydefmed hereinabove

by March John Wiley and Sons New York N.Y ppThe present invention contemplates employing the

30 1618 1985 and the discussion therein is incorporatedcompounds of Formula in compositions of pharma- herein by reference Electron withdrawing groups inceutically acceptable dosage forms Where the appro- dude halo including br .o fluoro chloro iodo andpriate substituents are employed the present invention

the like nitro carboxy iwer alkenyl lower alkynylalso includes pharmaceutically acceptable addition

formyl carboxyamido tryl quatemary ammoniumsalts Moreover the administration of an effective

trifluoromethyl aryl lower alkanoyl carbalkoxy andamount of the present compounds in their pharmaceuti- the like Electron donating groups include such groupscally acceptable forms or the addition salts thereof can

as hydroxy lower alkoxy including methoxy ethoxyprovide an excellent regime for the treatment of epi- and the like lower alkyl such as methyl ethyl and thelepsy nervous anxiety psychosis insomnia and other

like amino lower alkylamino diloweralkyl aminorelated central nervous disorders

40 aryloxy such as phenoxy mercapto lower alkylthioThe alkyl groups when used alone or in combination lower alkylmercapto disulfide lower alkyldithio and

with other groups are lower alkyl containing from to the like One skilled in the art will appreciate that thecarbon atoms and may be straight chain or branched aforesaid substituents may have electron donating or

These groups include methyl ethyl propyl isopropyl electron withdrawing properties under different chemibutyl isobutyl tertiary butyl amyl hexyl and the like

45 cal conditions Moreover the present invention con-The aryl lower alkyl groups include for example templates any combination of substituents selected from

benzyl phenethyl phenpropyl phenisopropyl phenbu- the above-identified groupstyl and the like diphenylmethyl 11-diphenylethyl The term halo includes fluoro chloro bromo iodo

12-diphenylethyl and the like and the like

The term aryl when used along or in combination 50 The term acyl includes lower alkanoylrefers to an aromatic group which contains from up to As employed herein the heterocyclic substituent

18 ring carbon atoms and up to total of 25 carbon contains at least one sulfur nitrogen or oxygen but also

atoms and includes the polynuclear aromatics These may include one or several of said atoms The heterocyaryl groups may be monocyclic bicyclic tricyclic or clic substituents contemplated by the present invention

polycycic and are fused rings Polynuclear aromatic 55 include heteroaromatics and saturated and partially

compound is meant to encompass bicyclic tricyclic saturated heterocyclic compounds These heterocyclicsfused aromatic ring system containing from 1018 ring may be monocyclic bicyclic tricyclic or polycycliccarbon atoms and up to total of 25 carbon atoms The and are fused rings They may contain up to 18 ring

aryl group includes phenyl and the polynuclear aro- atoms and up to total of 17 ring carbon atoms and

matics e.g naphthyl anthracenyl phenanthrenyl 60 total of up to 25 carbon atoms The heterocycics are

azulenyl and the like The aryl group also includes also intended to include the so-called benzoheterocy

groups like ferrocenyl des Representative heterocyclics include furyl thi

Lower alkenyl is an alkenyl group containing from enyl pyrazolyl pyrrolyl imidazolyl indolyl thiazolyl

to carbon atoms and at least one double bond These oxazolyl isothiazolyl isoxazolyl piperidyl pyrrolinyl

groups may be straight chained or branched and may be 65 piperazinyl quinolyl triazolyl tetrazolyl isoquinolylin the or form Such groups include vinyl pro- benzofuryl benzothienyl morpholinyl benzoxazolyl

penyl 1-butenyl isobutenyl 2-butenyl 1-pentenyl Z- tetrahydrofuryl pyranyl indazolyl purinyl indolinyl

2-pentenyl E-2-pentenyl Z-4-methyl-2-pentenyl pyrazolidinyl imidazolinyl imadazolidinyl pyrrolidi

5378729

nyl furazanyl N-methylindolyl methylfuryl pyridazi- but when is is CH or heterocyclic selected

nyl pyrimidinyl pyrazinyl pyridyl epoxy aziridino from the group consisting of NH and with the

oxetanyl azetidinyl the N-oxides of the nitrogen con- proviso that at most two of and are hetero

taming heterocycles such as the nitric oxides of pyri- atoms

dyl pyrazinyl and pyrimidinyl and the like The pre- If the ring depicted hereinabove contains nitrogenferred heterocycic are thienyl furyl pyrrolyl bejizofu- ring atom then the N-oxide forms are also contem

ryl benzothienyl indolyl methylpyrrolyl morpholi- plated to be within the scope of the invention

nyl pyridyl pyrazinyl imidazolyl pyrimidinyl or When R2 or R3 is heterocyclic of the above formula

pyridazinyl The preferred heterocycic is or 6-mem- it may be bonded to the main chain by ring carbon

bered heterocycic compound The especially preferred 10 atom When is R2 or R3 may additionally be

heterocycic is furyl pyridyl pyrazinyl imidazolyl bonded to the main chain by nitrogen ring atom

pyrimidinyl or pyridazinyl The most preferred hetero- It is preferred that one of R2 and R3 is hydrogen

cyclic is furyl and pyridyl In preferred embodiment one of P.2 and P.3 is hyThe preferred compounds are those wherein is drogen and that the other is heterocyclic It is preferred

but di tn and tetrapeptides are also contemplated to be 15that one of P.2 and P.3 is heterocycic having Formula

within the scope of the claims XI The preferred heterocydics include furyl thienylThe preferred values of is aryl lower alkyl espe- benzothienyl benzofuryl oxazolyl thiazolyl isoxazo

cially benzyl and the preferred Ri is or lower alkyl lyl indolyl pyrazolyl isoxazolidinyl ben.zothienylThe most preferred P.1 group is methyl benzofuryl morpholinyl indolyl pyrrolyl furfuryl

The most preferred electron donating substituent and 20and methylpyrrolyl pyridyl pyrazinyl imidazolyl

electron withdrawing substituent are halo nitro alkan- pynimidinyl or pynidazinyl In another preferred emoyl formyl arylalkanoyl aryloyl carboxyl carbalk-

bodiment one of P.2 and R3 is alkyl e.g methylisoprooxy carboxamide cyano sulfonyl sulfoxide heterocy- pyl aryl e.g phenyl 2-thiomethylethyl lower alkclic guanidine quaternary ammoniuni lower alkenyl oxy e.g ethoxy methoxy anilino propenyl alkyllower aikynyl sulfoniurn salts hydroxy lower alkoxy 25

amino e.g ethylamino or methylaxnino In anotherlower alkyl amino lower alkylaniino dioweralkyl- preferred embodiment one of R2 and R3 is hydrogenamino amino lower alkyl mercapto mercaptoalkyl and the other is heterocyclic lower alkyl lower alkenylalkylthio and alkyldithio The term sulfide encom- amino lower alkoxy amino N-lower alkylhydroxpasses mercapto mercapto alkyl and alkylthio while

yaniino lower alkoxyamino N-lower alkyl-0-lowerthe term disulfide encompasses alkyldithio These pre-

30

alkylhydroxyamino or aralkoxycarbonyihydrazinoferred substituents may be substituted on any one of Ri Preferred compounds of the present invention haveR2 R3 R4 R5 or R6 R7 or R8 as defmed herein the following general formula

The ZY groups representative of R2 and R3 include

hydroxy alkoxy such as methoxy ethoxy aryloxy

ethoxy thioaryloxy such as thiophenoxy amino alkyl- CH2NHC CNHCRjsuch as phenoxy thioalkoxy such as thiomethoxy thio-

amino such as methylamino ethylamino arylamino Am II

R3such as anilino lower dialkylamino such as dimethyl

amino trialkyl aromonium salt hydrazino alkyihy

drazino and arylhydrazino such as N-methylhydrazino wherein R1 is or lower alkyl R2 and P.3 are as defmed

N-phenylhydrazino carbalkoxy hydrazino aralkox- above and is hydrogen or an electron donating groupycarbonyl hydrazino aryloxycarbonyl hydrazino hy- or electron-withdrawing group and is 0-5 It is predroxylamino such as N-hydroxylamino NHOH ferred that is hydrogen i.e m0 However valueslower alkoxy amino wherein R18 is lower of equalling or are also preferredalkyl N-lower alkylhydroxyl amino Preferred embodiments include compounds of For-wherein R1 is lower alkyl N-lower alkyl-0-lower mula

alkyl hydroxyaniino i.e wherein P.13 and

P.19 are independently lower alkyl and o-hydrox

ylamino 0NH2 alkylamido such as acetamido

tnifluoroacetamido lower alkoxyamino e.g50

R_NH_NH_RlNHOCH3 and heterocycicamino such as

k3pyrazoylamino

The hetereocyclic groups representative of R2 andwherein and R1 independently are hydrogen lower

R3 have the formulaalkyl lower alkenyl lower alkynyl aryl lower alkyl

aryl heterocyclic lower alkyl heterocycic each unsubstituted or substituted with at least one substituentEJ P.2 and R3 independently are hydrogen lower alkyl

lower alkenyl lower alkynyl aryl lower alkyl aryl

60 heterocycic lower alkyl heterocydic each unsubsti

CH tuted or substituted with at least one substituent halo

gen or heteroatom containing oxygen nitrogen sulfur

or those corresponding partially or fully saturated form or phosphorous substituted with hydrogen lower alkyl

thereof wherein is or or aryl said lower alkyl or aryl groups being substituted

Land are independently CII or heteroatom 65 or unsubstituted and

selected from the group consisting of and is to

is CH or heteroatom selected from the group Another preferred embodiment is compound hay-

consisting of and ing Formula

5378729

Another preferred embodiment is compound of

Formula

RNTht-CCNT1CRj

RNBtCCNHCRiwherein is ai3r1 aryl lower alkyl heterocyclic lower R3

aikyl heterocyclic polynuclear aromatic or lower alkyl

polynuclear aromatic each unsubstituted or substituted wherein is aryl aryl lower alkyl heterocyclic or

with at least one electron withdrawing substituent or at 10heterocyclic lower aikyl and is unsubstituted or is

least one electron donating substituent substituted with at least one electron withdrawing

Ri is or lower alkyl unsubstituted or substituted group or electron donating groupwith at least one electron withdrawing substituent or at Ri is hydrogen or lower alkyl unsubstituted or substi

least one electron donating substituent tuted with an electron donating group or an electron

R2 and R3 independently are hydrogen lower alkyl withdrawing group and

lower alkenyl lower alkynyl aryl aryl lower alkyl R2 and R3 are independently hydrogen lower alkyl

heterocycic lower alkyl heterocydic polynuclear lower alkenyl lower alkynyl aryl lower alkyl aryl

aromatic lower alkyl polynuclear aromatic each un- heterocyclic heterocyclic lower alkyl or Z-Y wherein

substituted or substituted with at least one electron20 R2 and R3 may be unsubstituted or substituted with at

donating substituent halogen or heteroatom contain- least one electron withdrawing group or electron doing oxygen nitrogen sulfur or phosphorous substituted nating groupwith hydrogen lower alkyl or aryl said lower alkyl or is SSOa NR4 PR4 or chemical bondaryl groups being substituted or unsubstituted and

is hydrogen lower alkyl aryl aryl lower alkylis to 25 lower alkenyl lower alkynyl heterocyclic heterocy

Another preferred embodiment of the present inven- clic lower alkyl or halo and may be unsubstituted ortion is compound of Formula substituted with an electron donating group or an elec

tron withdrawing group provided that when is halo

as is chemical bond or

RNH-t-CCNHt-CR30 ZY taken together is NR4NRR7 NR40R

IIONR4R7 OPR4R5 PR4OR5 SNR4R7 NR4SR7SPR4RS or PR4SR7 NR4PRSR6 or PR4R5R7

wherein is aryl lower alkyl heterocyclic lower alkyl

heterocycic polynuclear aromatic or lower alkyl poly- 35NR4CR5 SCR5 NR4COR5 SCOR5

nuclear aromatic each of which may be unsubstituted

or substituted with at least one halo nitro acyl car

boxyl carboalkoxy carboxamide cyano sulfonyl sulf- R4 R5 and R6are independently hydrogen lower

oxide sulfmyl heterocyclic guanidine quaternary alkyl aryl aryl lower alkyl lower alkenyl or lower

ammonium hydroxy alkoxy alkyl amino phenoxy 40 alkynyl wherein R.4 R5 and R6 may be unsubstituted or

mercapto sulfide or disulfide substituted with an electron withdrawing group or an

R1 is or lower alkyl which may be unsubstituted or electron donating group-and

substituted with at least one halo nitro acyl carboxam- R7 is R6 or COORs or COR8 R8 is hydrogen or lower

ide cyano sulfonyl sulfoxide sulfmyl heterocyclic alkyl or aryl lower alkyl wherein the aryl or lower

guanidine quaternary ansnaonium hydroxy lower alk- alkyl groups may be unsubstituted or substituted with

oxy amino phenoxy sulfide or disulfide an electron withdrawing or electron donating group

R2 is hydrogen lower alkyl lower alkenyl lower is 1-4 and

alkynyl aryl heterocyclic lower alkyl heterocyclic is 13polynuclear aromatic lower aJ.kyl polynuclear aro-

50Another class of preferred compounds of the For

inatic each unsubstituted or substituted with at least mula have the formula

one electron withdrawing substituent or at least one

electron donating substituent halogen or heteroatom a2

consisting of oxygen nitrogen sulfur or phosphorous RNH--CCNH CRsaid heteroatom being substituted with hydrogen lower

alkyl or aryl said lower alkyl or aryl groups being R3

substituted or unsubstituted

R3 is hydrogen lower alkyl lower alkenyl lower wherein is aryl aryl lower alkyl heterocyclic or

alkynyl aryl heterocyclic lower alkyl heterocydic heterocyclic alkyl which is unsubstituted or substituted

polynuclear aromatic lower alkyl polynuclear aro- with at least one electron withdrawing group or at least

matic each unsubstituted or substituted with at least one electron donating group

one electron withdrawing substituent or at least one R1 is hydrogen or lower alkyl which is unsubstituted

electron donating substituent halogen or heteroatom or substituted with at least one electron withdrawing

consisting of oxygen nitrogen sulfur or phosphorous group or one electron donating groupsaid heteroatom being substituted with hydrogen lower 65 R2 and R3 are independently hydrogen lower alke

alkyl or aryl said lower alkyl or aryl groups being nyl lower alkynyl aryl aryl lower alkyl Z-Y or

substituted or unsubstituted heterocyclic group which may be unsubstituted or sub-

and is to stituted with at least one electron withdrawing or one

537872910

electron donating group with the proviso that R2 and In the principal chain there exists asymmetry at the

R3 cannot both be hydrogen carbon atoms to which the groups R2 and R3 are atis NR4 PR4 or chemical bond

tached as substituted When is the compounds of theis hydrogen lower alkyl aryl aryl lower alkyl

lower alkenyl lower alkynyl or halo and may be present invention is of the formula

unsubstituted substituted with an electron donating

group or an elctron withdrawing group provided thatR2

when is hato is chemical bond or IIRNHCCNCR1ZY taken together is NR4NRSR6 NR4ORSONR4R5 OPR4R5 PR4OR5 SNR4R5 NR4SR5 10

R3

SPR4RS or PRsSR5 NR4PR5R6 or PRiNRSR6R.4 R5 and R6 are independently hydrogen lower wherein R1 R2 R3 R4 R5 R6 and are as de

alkyl aryl aryl lower alkyl lower alkenyl or lowerfined previously As used herein the term configuration

alkynyl wherein R4 R5 and R6 may be unsubstituted or

substituted with an electron withdrawing group or an 15 shall refer to the configuration around the carbon atom

electron donating groupto which R2 and R3 are attached even though other

is 14 chiral centers may be present in the molecule There

Of this preferred group it is especially preferred that fore when referring to particular configuration such

isas or it is to be understood to mean the stereoiso

The preferred comrounds are those in which is20

mer including all possible enantiomers and diastereoaryl aryl lower alkyl heterocydic or heterocycic

mers The compounds of the present invention are di-lower alkyl Ri is hydrogen or lower alkyl R2 and R3

are independently hydrogen heterocycic lower alkylrected to all of the optical isomers i.e the compounds

aryl lower alkoxy lower alkenyl amino hydrox-25

of the present invention are either the L-stereoisomer or

ylamino lower alkoxy amino N-lower alkyl hydroxy- the D-stereoisomer These stereoisomers may be found

amino N-lower alkyl-O-lower alkyl hydroxyamino in mixtures of the and stereoisomer e.g racemic

aralkoxy carbonyl hydrazino or alkylmercapto and is mixtures The stereoisomer is preferred

In another preferred embodiment is and R1 are30

Depending upon the substituents the present com

as defined hereinabove and one of R2 and R3 is hydro- pounds may form addition salts as well All of these

gen and the other is heterocycic heterocyclic lower forms are contemplated to be within the scope of this

alkyl aryl N-hydroxylamino lower alkoxyamino N- invention including mixtures of the stereoisomeric

lower alkylhydroxylaniino N-lower alkyl-O-lower al- forms

kylhydroxyamino 35 The following three schemes of preparation are genAnother preferred embodiment is wherein is

erally exemplary of the process which can be employedand Rj are as defined hereinabove one of R2 and R3 is

as defined hereinabove or the other is heterocyclicfor the preparation of the present complex

heterocycic lower alkyl lower alkyl heterocydic aryl

N-hydroxylamino lower alkoxy amino N-lower alkYl Scheme

hydroxylamino N-lower alkyl-O-lower alkyl hydrox

ylamino lower alkoxy dialkyl lower amino lowerexcess

alkylamino aryl lower alkylcarbonyl hydrazino or HO0CNH2 MeOH RNH2lower alkylmercapto R3

The various combination and permutations of the

Markush groups of R1 R2 R3 and described herein

are contemplated to be within the scope of the present r-2 II

R1CO Riinvention Moreover the present invention also encom- RNH NH2passes compounds and compositions which contain one

or more elements of each of the Markush groupings in 5oR3

R1 R2 R3 ii and and the various combinationsR2thereof Thus for example the present invention con-

II

templates that R1 may be one or more of the substituents

listed hereinabove in combination with any and all of II

the substituents of B.2 R3 and with respect to eachR3

value of

The compounds of the present invention may contain

one or more asymmetric carbons and may exist rn Scheme II

racemic and optically active forms The configuration

around each asymmetric carbon can be in either the 60 R2 R2

R1C0CR IIor form It is well known in the art that the configu- HOOCCNH2 HOOCCNH CR1ration around chiral carbon atoms can also be de-

scribed as or in the Calin-Prelog-Ingold nomencla- R3 R3

ture system All of the various configurations around

each asymmetric carbon including the various enantio- 65

mers and diastereomers as well as racemic mixtures and

mixtures of enantiomers diastereomers or both are con- tertiary amine

templated by the present invention

537872911 12

-continuedmixed anhydrides or lower alkyl esters and the like It

Scheme is preferred that the acylating derivative used is the

R2 R2 anhydrideII II R112 II II II

RNHCC--NHCR1 R17OCOCCNHCR1

R3 R3 II II

R1C---0CRj--

co2 RI7OH When alkyl esters are employed amide bond formation

can be catalyzed by metal cyanides such as sodium or

Scheme III

00liii

OHOII R2CCOH II II

R1CNH2 R1CNHCCOH

R2

R17OHIH

0R170

R1CNHCCNHR RNHOR17

R1CNHCC0R17withor

R2 without catalyst R2i.e MCN

R3H

jewisacid such as BF3OEtz

R30II II

R1CNHCCNHRR2

potassium cyanides

wherein R3aryl heteroa.romatic and R7 is as definedAnother exemplary procedure for preparing corn-

hereinabove pounds wherein at least one of R2 and R3 is aromatic or

More specifically these compounds can be preparedheteroaromatic is depicted in Scheme IV

by art-recognized procedures from known compoundsThe ester IV is reacted with halogen and ultraviolet

or readily preparable intermediates For instance corn-light in the presence of catalyst e.g AIBN to form

pounds of Formula can be prepared by reactingthe halo derivative is reacted in the presence of

arnines of Formula II with an acylating derivative ofLewis acid such as zinc chloride with an aromatic or

carboxylic acid of Formula III under amide formingheteroaromatic compound to form the compound VI

conditions VI in turn is hydrolyzed and then reacted with alkyl

haloformate such as alkylehioroformate in the presenceof tertiary amine to generate the mixed N-acyl amino

r0 R2acid carbonic ester anhydride VIII This intermediate

is reacted with an amine under amide forming condi

RNH_j_C_j_NH4_H RiCOH tions to give the compound of Formula Alternatively

R3 50 VI can be reacted directly with an amine RNH2optionally in the presence of metal catalyst such as

metal cyanides e.g potassium or sodium cyanide

wherein R1 R2 R3 and are as defined hereinaboveunder amide forming conditions to form compound of

andFormula Alternatively compound VIII can be pre

The amide forming conditions referred to hereinpared by an independent method and converted to VI

involve the use of known derivatives of the describedwhich is then reacted with an amine with or without

acids such as the acyl halides e.gcatalyst to form the compound of Formula

Scheme IV

RjCX 60

II II x2 II Ii

R1CNHiHCORi7 hv AIBN RICNH__C0R17

wherein is Cl Br and the like anhydrides e.gR3 R3

Iv

65

ii II

LewisAcid

RjCOCRi R2H

537872913 14

-continued sequential addition of triethylamine and HR2 to THFScheme IV mixture containing the bromo adduct furnishes the de

R2 R2 sired product

1OH M0H In another procedure the product wherein R2 or R3RICNH COR7R1CNH

H30 is Z-Y can also be prepared by substitution reaction on

R3 R3 quaternary ammothum derivative of the compound of

VII VI Formula as outlined below

__II Scheme VIC1C ORi 10

tertiary

amine RIO\ /9ONHII CH33OBF4RNCCNCRi

CH3NO2R20 II

II II II 15 R3

R1CNHCCOCR17 NH2

R3 withW

viiiwithout catalyst

Rio\H3/RSi.e MCN NH

excess R2HRNCCNCRi BF4 desired productH2NR 20 ________II

R3

R20In scheme VI R1 R3 and are as defined herein

R1CNHCCNHR 25 above R2 is Z-Y and R9 and Rio are independentlyII

R3lower alkyl In scheme VI methylation of compoundwith methylation reagent such as trimethyloxonium

tetrafluoroborate provided the corresponding ammoXrhalogen i.e C1 Br nium derivative Subsequent treatment of the ammoR16lower alkyl aryl any lower alkyl

30 niuni salt with HR2 furnishes the desired product For

metai cation i.e Na example methylation of 2-acetamido-N-benzyl-2-NN-

Two additional synthetic routes may be employed for dimethylamino acetamide with trimethyloxoniurn tet

the preparation of compounds wherein R2 or R3 is Z-Y rafluoroborate in nitromethane furnished the quateras defined hereinabove In one scheme for the prepara- nary ammonium derivative 2-acetamido-N-benzyl-tion of these complexes substitution reaction is used NNN-trimethylammonium acetamide tetrafluorobo

rate in high yields Subsequent treatment of the salt with

the HR2 reagent in the methanol leads to the productionScheme of the desired product

R3 As in any organic reaction solvents can be employed

CH2CIsuch as methanol ethanol propanol acetone tetrahyRNCCN CRi

II drofuran dioxane dimethylformaniide dichiorometh0R9

ane chloroform and the like The reaction is normallyIx

effected at or near room temperature although temper-

R3 atures from up to the reflux temperature of the

II II reaction mixture can be employedRNCCNCRAs further convenience the amide forming reaction

Br can be effected in the presence of base such as tertiary

excess HR2 or MR2organic amine e.g triethylamine pyridine 4-methyl-

_______________niorpholine picolines and the like particularly where

THF 78compound of Formula

50

hydrogen halide is formed by the amide forming reacor

Et3N tion e.g the reaction acyl halide and the amine ofHR2 Formula II Of course in those reactions where hydroTHF 78

gen halide is produced any of the commonly used hy

In the above scheme R9 is lower alkyl R2 is Z-Y and 55 drogen halide acceptors can also be used

R3 and R1 are as defined hereinaboveThe exact mineral acid or Lewis acid employed in the

The ether functionality on IX can be cleaved by treat-reaction will vary depending on the given transforma

ment with Lewis acids such as BBr3 in an inert solvent tion the temperature required for the conversion and

such as methylene chloride to form the correspondingthe sensitivity of the reagent toward the acid in the

halo bromo derivative Addition of either an excess of 60 reaction employed

the H-R2 or MR2 or the sequential addition of triethyl-The various substituents on the present new corn-

amine and H-B.z to THF mixture containing the halo pounds e.g as defmed in R1 R2 and R3 can be pres

derivative furnishes the desired product For example ent in the starting compounds added to any one of the

in the case wherein the compound of Formula IX isintermediates or added after formation of the fmal prod

2-acetamido-N-benzyl-2-ethoxy acetaniide its treat- 65 ucts by the known methods of substitution or conver

ment with BBr3 in CH2C12 led to the formation of the sion reactions For example the nitro groups can be

a-bromo derivative 2-acetamido-N-benzyl-2- added to the aromatic ring by nitration and the intro

bromoacetainide Addition of an excess of HR2 or the group converted to other groups such as amino by

537872915 16

reduction and halo by diazotization of the amino group can be isolated The intermediate can then react with

and replacement of the diazo group Alkanoyl groups the amine RNH2 under amide forming conditions as

can be substituted onto the aryl groups by Friedel- described hereinabove to form the compound of For-Crafts acylation The acyl groups can be then trans- mulaformed to the corresponding alkyl groups by various The active ingredients of the therapeutic composimethods including the Woff-Kishner reduction and tions and the compounds of the present invention exClemmenson iduction Amino groups can be alkylated hibit excellent anticonvulsant activity when administo form mono dialkylamino and triaikylamino groups tered in amounts ranging from about 10mg to about 100and mercapto and hydroxy groups can be alkylated to mg per kilogram of body weight per day preferredform corresponding thioethers or ethers respectively 10 dosage regimen for optimum results would be fromPrimary alcohols can be oxidized by oxidizing agents about 20 mg to about 50 mg per kilogram of bodyknown in the art to form carboxylic acids or aldehydes

weight per day and such dosage units are employedand secondary alcohols can be oxidized to form ke-

that total of from about 1.0 gram to about 3.0 grams oftones Thus substitution or alteration reactions can be

the active compound for subject of about 70 kg ofemployed to provide variety of substituents through-

body weight are administered in 24-hour period Thisout the molecule of the starting material intermediates

or the fmal productdosage regimen may be adjusted to provide the opti

In the above reactions if the substituents themselvesmum therapeutic response and is preferably adminis

are reactive then the substituents can themselves betered one to three times day in dosages of about 600

protected according to the techniques known in the 20mg per administration For example several divided

variety of protecting groups known in the art may bedoses may be administered daily or the dose may be

employed Examples of many of these possible groupsproportionally reduced as indicated by the exigencies

may be found in Protective Groups in Organic Synthe-of the therapeutic situation decided practical advan

sis by Greene John Wiley Sons 1981 tage is that the active compound may be administered in

Resulting mixtures of isomers can be separated in the 25an convenient manner such as by the oral intraveneous

pure isomers by methods known to one skilled in the where water soluble intramuscular or subcutaneous

art e.g by fractional distillation crystallization and/or routes

chromotagraphyThe active compound may be orally administered for

The present compounds obviously exist in stereoiso- example with an inert diluent or with an assimilable

meric forms and the products obtained thus can be 30edible carrier or it may be enclosed in hard or soft shell

mixtures of the isomers which can be resolved Opti- gelatin capsule or it may be compressed into tablets or

cally pure functionalized amino acid derivatives can be it may be incorporated directly with the food of the

prepared directly from the corresponding pure chiral diet For oral therapeutic administration the active

intermediate Racemic products can likewise be re- compound may be incorporated with excipients and

solved into the optical antipodes for example by sepa-used in the form of ingestible tablets buccal tablets

ration of diastereomeric salts thereof e.g by fractional troches capsules elixirs suspensions syrups wafers

crystallization by selective enzymatic hydrolysis e.gand the like Such compositions and preparations should

papain digestion or by use of chiral stationary phase contain at least 1% of active compound The percent-

in chromotagraphy HPLC For discussion of chiral age of the compositions and preparations may of

stationary phases for HPLC See DeCamp Chirality course be varied and may conviently be between about

26 1989 which is incorporated herein by reference to about 80% of the weight of the unit The amount of

with the same force and effect as if fully set forth herein active compound in such therapeutically useful compoFor example racemic mixture of any of the interme- sitions is such that suitable dosage will be obtained

diate in any of the schemes e.g Preferred compositions or preparations according to

the present invention are prepared so that an oral dos

R2 age unit form contains between about and 1000 mg of

II II active compound

RIC_NH__C0RI7 The tablets troches pills capsules and the like may

R3 also contain the following binder such as gum traga

50 canth acacia corn starch or gelatin excipients such as

wherein R17 is which can be prepared according to dicalcium phosphate disintergrating agent such as

the procedures of Schemes or is reacted with corn starch potato starch alginic acid and the lick

an optically active amine RNH2 e.g Ra-methyl- lubrican such as magnesium stearate and sweetening

benzylamine to form pair of diasteroomeric salts Dia- agent such as sucrose lactose or saccharin mauy be

stereomers can then be separated by recognized tech- 55 added or flavoring agent such as peppermint oil of

niques known in the art such as fractional recrystalliza- wintergreen or cherry flavoring When the dosage unit

tion and the like form is capsule it may contain in addition to materials

In another method racemic mixture of fmal prod- of the above type liquid carrier Various other materi

ucts or intermediates can be resolved by using enzy- als may be present as coatings or to otherwise modify

matic methods Since enzymes are chiral molecules it 60 the physical form of the dosage unit For instance tab-

can be used to separate the racemic modification since lets pills or capsules may be coated with shellac sugar

it will preferentially act on one of the compounds with- or both syrup or elixir may contain the acitve comout affecting the enantiomer For example acylase pound sucrose as sweetening agent methyl and pro-

such as acylase can be used to separate the racemic pylparabens as preservatives dye and flavoring such

modification of an intermediate DLa-acetamido-2- 65 as cherry or orange flavor Of course any material used

furanacetic acid It acts on the a-acetamido-2- in preparing any dosage unit form should be pharmafuranacetic acid but will not act on the enantiomer ceutically pure and substantially non-toxic in the

In this way the Da-acetamido-2-furanacetic acid amounts employed In addition the active compound

537872917 18

may be incorporated into sustained-release preparations material calculated to produce the desired therapeuticand formulations For example sustained release dosage effect in association with the required pharmaceuticalforms are contemplated wherein the active ingredient is carrier The specification for the novel dosage unit

bound to an ion exchange resin which optionally can forms of the invention are dictated by and directlybe coated with diffusion barrier coating to modify the dependent on the unique characteristics of the active

release properties of the resin material and the particular therapeutic effect to beThe active mpound may also be administered par- achieved and the limitations inherent in the art of

enterally or intraperitoneally Dispersions can also be compounding such an active material for the treatment

prepared in glycerol liquid polyethylene glycols and of disease in living subjects having diseased conditionmixtures thereof and in oils Under ordinary conditions 10 in which bodily health is impaired as herein disclosed in

of storage and use these preparations contain preser- detail

vative to prevent the growth of microorganisms The principal active ingredient is compounded for

The pharmaceutical forms suitable for injectable use convenient and effective administration in effectiveinclude sterile aqueous solutions where water soluble amounts with suitable pharmaceutically acceptableor dispersions and sterile powders for the extemporane- 15

carrier in dosage unit form as hereinbefore disclosedous preparation of sterile injectable solutions or disper- unit dosage form can for example contain the principalsions In all cases the form must be sterile and must be

active compound in amounts ranging from about tofluid to the extent that easy syringability exists It must about 1000 mg with from about 250 to about 750 mgbe stable under the conditions of manufacture and stor-

being preferred Expressed in proportions the active

age and must be preserved against the contaminating 20compound is generally present in from about 10 to

action of microorganisms such as bacteria and fungi about 750 mg/mI of carrier In the case of compositionsThe carrier can be solvent or dispersion medium con-

containing supplementary active ingredients the dos-taming for example water ethanol polyol for exam-

ages are determined by reference to the usual dose andple glycerol propylene glycol and liquid polyethylene

manner of administration of the said ingredientsglycol and the like suitable mixtures thereof and veg- 25

etable oils The proper fluidity can be maintained forThe compounds of the present invention may be

administered in combination with other anti-convulsantexample by the use of coating such as lecithin by the

maintenance of the required particle size in the case of agents such as phenytoin phenbarbitol mephenytoin

dispersion and by tile use of surfactants The preventionand phenacemide and the like This combination is

of the action of microorganisms can be brought about 30likely to exhibit synergistic effects

by various antibacterial and antifungal agents for exam-For better understanding of the present invention

pIe parabens chiorobutanol phenol sorbic acid tin- together with other and further objects reference is

merosal and the like In many cases it will be prefera-made to the following description and examples

ble to include isotonic agents for example sugars orGeneral Methods Melting points were determined

sodium chloride Prolonged absorption of the injectable 35with Thomas-Hoover melting point apparatus and are

compositions can be brought about by the use in theuncorrected Infrared spectra IR were run on Beck-

compositions of agents delaying absorption for exam- man IR-4250 and Perkin-Elmer 1330 and 283 spectro

ple aluminum monostearate and gelatin photometers and calibrated against the 1601-cm1 band

Sterile injectable solutions are prepared by incorpo-of polysytrene Absorption values are expressed in

rating the active compound in the required amount inwavenumbers cmi Proton nuclear magnetic reso

the appropriate solvent with various of the other ingre-nance NMR spectra were recorded on Varian

dients enumerated above as required followed by fil-Associates Models T-60 and FT-80A General Electric

tered sterilization Generally dispersions are prepared QE 300 and Nicolet NT-300 NMR spectrometers Car-

by incorporating the various sterilized active ingredient bon nuclear magnetic resonance 13C NMR spectra

into sterile vehicle winch contains the basic dispersion 45 were run on Varian Associates Models FT-SOA Genmedium and the required other ingredients from those eral Electric QE 300 and Nicolet NT-300 instrument

enumerated above In the case of sterile powders for the Chemical shifts are in parts per million values rela

preparation of sterile injectable solutions the preferredtive to Me4Si and coupling constants values are in

methods of preparation are vacuum drying and the hertz Mass spectral data were obtained at an ionizing

freeze-drying technique winch yield powder of the 50 voltage of 70 eV on Hewlett-Packard 5930 gas

active ingredient plus any additional desired ingredient chromotagraph-mass spectrometer and Bell-Howell

from previously sterile-filtered solution thereof 21-491 spectrometer as well as at the Eli Lilly Laborato

As used herein pharmaceutically acceptable car- ries on Varian MAT-CH-5 spectrometer High-resolu

rier includes any and all solvents dispersion media tion El mode mass spectra were performed by Drs

coatings antibacterial and antifungal agents isotonic 55 James Hudson and John Chinn at the Department of

and absorption delaying agents and the like The use of Chemistry University of Texas at Austin on CEC21-

such media and agents for pharmaceutical active sub- lOB double-focusing magnetic-sector spectrometer at

stances is well known in the art Except insofar as any 70 eV Elemental analyses were obtained at Spang Mi-

conventional media or agent is incompatible with the croanalytical Laboratories Eagle Harbor Mich and at

active ingredient its use in the therapeutic compositions 60 the Eli Lilly Research Laboratories

is contemplated Supplementary active ingredients can The solvents and reactants were of the best commeralso be incorporated into the compositions cial grade available and were used without further pun

It is especially advantageous to formulate parenteral fication unless noted All anhydrous reactions were run

compositions in dosage unit form for ease of administra- under nitrogen and all glassware was dried before use

tion and uniformity of dosage Dosage unit form as used 65 In particular acetonitrile and triethylamine were dis

herein refers to physically discrete units suited as uni- tilled from CaH2 while dichioromethane was distilled

tary dosages for the mammalian subjects to be treated from P2O Acetic anhydride benzaldehyde and ethyl

each unit containing predetermined quantity of active chloroformate were fractionally distilled

537872919 20

Elemental analysis Calculated for C121116N202Preparation of N-Acetyl-D- and L-amino

65.42% 7.34% 12.72% Found 65.58%acid-N-benzylainides 7.32% 12.43%

General Procedure The D- or L-amino acid amideEXAMPLE

11 mmol was dissolved in dichloromethane 15 rnLand then aceticanhydride 1.23 1.40 mL 12 rnmol Preparation of

was added drop-wise The solution was stirred at room N-Acetyl-DL-phenylglycine-N-methylamide

temperature 18 and then concentrated to dryness Acetic anhydride 2.90 28 mmol was added drop-The residue was recrystallized from chloroform/hex-

10wise to DL-phenylglycine-N-methylarnide 3.4 20

ane The following examples 17 were prepared accord- mmol and allowed to stir at room temperature 1.5

ing to this procedure During this time copious white precipitate formed

This material was collected by filtration dried in vacuoEXAMPLEand recrystallized from absolute alcohol

Preparation of N-Acetyl-DL-alanine-N-benzylamide15

Yield 2.00 49% mp 232-235 dccAcetic anhydride 2.20 0.022 mol was slowly

1H NMR DMSO-d6 61.89 3H 2.58 dJ4.6added to methylene chloride solution 30 mL of DL- Hz 3H 5.42 dJ 8.1 Hz 111 7.35 511 8.18 br

alanine-N-benzylamide 3.80 0.021 mol and allowed qJ4.2 Hz lH 8.47 dJ 8.1 Hz 111

to stir at room temperature The mixture was then 13C NMR DMSOd6 22.4 25.5 56.3 127.1 127.3

successively washed with 1120 15 mL 1% aqueous20 128.1 139.0 168.9 170.3 ppm

NaOH 15 mL and H20 15 mL dried Na2SO4 and IR KBr 3310 1645 cm1concentrated in vacuo The residue was recrystallized

Mass spectrum CI mode rn/c 207 PIfrom CH2C12

Elemental analysis Calculated for Ci 1H14N202

Yield 2.50 54% mp 139l4l 64.06% 6.86% 13.58% Found 63.79%

25 6.66% 13.27%1H NMR DMSO-d6 61.22 dJ7.1 Hz 311 1.84

311 4.044.50m 311 7.26 511 8.11 br dJ7.3 EXAMPLEHz 111 8.42 br tJ6 Hz 1H

Preparation of N-Acetylglycine-N-benzylamide3C NMR DMSO-d6 18.2 22.4 41.9 48.2 126.5

126.9 128.1 139.4 168.9 172.4 ppm The DL-amino acid amide 11 mmol was dissolved

JR CHC13 3440 3300 3005 1660 1515 cm130

dichiorornethane l5mL and then acetic anhydride

Mass spectrum CI mode rn/c 221 PI mol wt 1.23 1.40 mL 12 mmol was added dropwise The

220.1208 solution was stirred at room temperature 46 and

Calculated for C12Hi6N2O2 220.1212then concentrated to dryness The residue was recrystallized from chloroforrn/hexane

EXAMPLE Yield 1.84 81% mp 140-142

N-Acetyl-D-alanine-N-benzylamideNMR DMSO-d6 6188 311 3.74 dJ5.3 Hz

211 4.30 dJ5.1 Hz 211 7.27 511 8.37 br 111Yield 1.36 56% rnp l39l41 36.2

8.75 1H2.5 MeOH 13C DMSO-d6 22.5 42.0 42.5 126.6 127.1

111 NMR 80 MHz DMSO-d6 81.25 dJ7.1 Hz 2C 128.1 2C 139.3 169.0 169.6 ppm311 1.86 311 4.104.50 111 4.30 dJ6.0 Hz JR KBr 3060 1655 1640 1560 1545 1450 13002ff 7.26 5H 8.09 dJ7.3 Hz lH 8.40 tJ6.0 740 710 cm1liz 1H Mass spectrum rn/c relative intensity 206 147

13C NMR 80 MHz DMSO-d6 18.3 22.5 42.0 48.4 12 106 100 9175 73 50126.6 127.0 2C 128.2 2C 139.4 169.2 172.5 ppm Elemental analysis Calculated for C11H4N202

JR KBr 3290 1635 br 1540 1455 700 695 cm1 64.05% 6.86% 13.58% Found 64.03%Mass spectrum rn/c relative intensity 221 30 114 6.79% 13.61%

20 106 40 9180 87 100 77 72 20 65

Elemental analysis Calculated for C12H16N202 50EXAMPLE

65.42% 7.34% 12.72% Found 65.31% Preparation of N-Acetyl-DL-valine-N-benzylamide7.28% 12.63%

The DL-amino acid amide 11 mmol was dissolved

EXAMPLE in dichloromethane 15 mL and then acetic anhydride

N-Acetyl -L-alanine-N-benzylaxnide1.23 1.40 mL 12 mmol was added dropwise The

solution was stirred at room temperature 46 andYield 1.11 46% mp 139l42 35.3 then concentrated to dryness The residue was recrys2.5 MeOH tallized from chloroform/hexane

1H NMR 80 MHz DMSO-d6 61.23 dJ7.2 Hz Yield 2.35 86% mp 19219Y3H 1.86 3H 4.264.35 111 4.29 dJ5.8 Hz 1H NMR DMSO-d6 60.83 dJ6.7 Hz 6H 1.87

211 7.227.33 511 8.10 dJ7.4 Hz 111 8.42 3ff 1.732.09 111 4.11 dJ8.8 Hz 111 4.27

tJ5.8 Hz 1ff dJ5.8 Hz 2H 7.26 511 7.89 dJ8.8 Hz 111l3 NMR 80 MHz DMSO-d6 18.3 22.6 42.0 48.4 8.84 tJ5.8 Hz 111

126.7 127.0 2C 128.3 2C 139.5 169.2 172.6 ppm 13C NMR DMSO-d6 18.1 19.2 22.4 30.2 41.9

JR KBr 3290 1635 br 1545 1450 700 695 cm1 ts 57.8 126.6 127.1 2C 128.1 2C 139.4 169.2 171.1

Mass spectrum m/e relative intensity 221 40 114 ppm40 106 80 106 80 9175 87 100 77 72 15 JR KBr 1625 1540 1535 1450 1380 1290 750 695

65 crn1

537872921 22

Mass spectrum mle relative intensity 142 16 114 Mass spectrum rn/c relative intensity 203 149

43 106 29 9157 72 100 94 106 100 9132 86 43 77 14Elemental analysis Calculated for C14H20N2O2 Elemental analysis Calculated for C17H18N202

67.70% 8.13% 11.28% Found 67.58% 72.32% 6.43% 9.92% Found 72.04% 6.22%

8.05% 11.10% 9.78%

EXAMPLE EXAMPLE

Preparation of N-Acetyl-L-phenylglycine-N-benzylarnide

N-Acetyl-DL-phenylglycine-N-benzylamideBeginning with 16.1 mmol N-t-Boc-L-phenylglycine

The DL-amino acid amide 11 mmol was dissolved10

N-benzylamidein dichloromethane l5mL and then acetic anhydride Yield 2.99 66% mp 221222 105.1

1.23 1.40 mL 12 mmol was added dropwise The 1% EtOHsolution was stirred at room temperature 46 and 1H NMR DMSO-d6 61.99 311 4.36 dJ5.6then concentrated to dryness The residue was recrys-

15 Hz 211 5.60 dJ8.0 Hz 111 7.237.53 1011tallized from chloroform/hexane 8.60 dJ8.0 Hz lii 8.83 tJ5.6 Hz 1H

Yield 2.05 66% mp 202203 3C NMR DMSO-d6 22.4 42.1 56.5 126.8 127.1

111 NMR DMSO-d6 61.91 311 4.27 dJ5.6 2C 127.3 2C 127.5 128.2 4C 139.0 139.1 169.1Hz 211 5.50 dJ7.9 Hz 111 7.21 511 7.36 170.1 ppm511 8.388.86 211 IR KBr 3295 1630 1530 1450 1395 720 695

NMR DMSO-d6 22.3 42.0 56.3 126.6 2C 20

cm1127.0 127.1 2C 127.4 2C 128.1 2C 138.9 139.0 Mass spectrum rn/c relative intensity 223 203

168.9 169.9 ppm 149 98 106 100 9132 86 43 77 11JR KBr 3020 1635 1580 1540 1450 1265 745 690 Elemental analysis Calculated for C17H13N202

cm1 72.32% 6.43% 9.92% Found 72.53% 6.49%Mass spectrum rn/c relative intensity 283 20 264

25

9.67%

21 149 100 131 20 118 34 106 92 9170 79

56 77 54 65 45 5137 EXAMPLE 10

Elemental analysis Calculated for C17H18N2O2 Preparation of N-Acetyl-DL-alanine-N-3-rnethoxy72.31% 6.44% 9.92% Found 72.49% 6.47%

30 benzylamide9.89%

The DL-amino acid amide 11 mmol was dissolved

Preparation of N-Acetyl-D- and in dichloromethane l5mL and then acetic anhydride

L-phenylglycine-N-benzylamide 1.23 1.40 rnL 12 mmol was added dropwise The

General Procedure The chiral Boc-protected phe-solution was stirred at room temperature 46 and

nylglycine-N-benzylaxnide was dissolved in trifluoro- then concentrated to dryness The residue was recrys

acetic acid 0.04M and was stirredat room temperaturetallized from chloroform/hexane

30 mm during which time gas evolved The solution Yield 0.47 17% mp 12i 15

was concentrated in vacuo and the residue was redis-NMR DMSO-d6 61.23 d.J7 Hz 311 1.85

solved in enough methanol to form solution of 0.2M 311 3.73 311 3.994.48 111 4.25 dJ 6.1

Methanesulfonic acid equiv was added dropwise and Hz 211 6.587.35 in 4H 8.05 dJ7.4 Hz lH 8.35

stirred for mm After concentrating the solution in tJr 6.0 Hz lHvacuo the residue was repeatedly dissolved in methanol 13C NMR DMSOd6 18.1 22.5 41.8 48.3 54.9

and the solvent was removed times The residue was 112.2 112.3 119.0 129.2 141.0 159.3 169.0 172.4 ppmthen dried under vacuum 18 leaving yellow oil IR KBr 3270 3065 1625 1580 1450 1260 1150

Without further purification the phenylglycine-N- 1095 900 775 700 690 cm1benzyiamide methanesulfonate was dissolved in tetra- Elemental analysis Calculated for C13H18N2O3

hydrofuran 0.2M and then was cooled in an ice bath 62.37% 7.26% 11.19% Found 62.29%

Triethylamine equiv was added dropwise followed 7.13% 11.08%

by acetyl chloride equiv The ice bath was removed EXAMPLE 11and stirring was continued at room temperature 18The solution was concentrated in vacuo arid the residue Preparation of

was recrystallized from 11 95% ethanol/water Exam- N-Trimethylacetyl-DL-alanine-N-benzylamide

pies and were prepared according to this procedure DL-Alanine-N-benzyiamide 3.56 20 mmoi was

EXAMPLE dissolved in dichlorornethane 25 mL and triinethyi

acetic anhydride 4.10 4.46 mL 22 mmol was addedN-Acetyl-D-phenylgylcine-N-benzylamide dropwise The solution was stirred at room temperature

The reaction was run on an 11.9 nimol scale 18 and then concentrated to dryness The solid resi

Yield 2.97 88% mp 2l922l 103.0 due was recrystallized from benzene/petroleum ether

1% EtOH 60 3060 C.111 NMR DMSO-d6 61.91 3ff 4.27 dJ5.5 Yield 2.07 40% mp 123l24

Hz 211 5.50 dJ7.8 Hz 111 7.147.44 1011 1H NMR DMSO-d6 61.12 911 1.27 dJ7.l8.56 dJ7.8 Hz 151 8.79 tJ5.5 Hz 111 Hz 311 4.234.42 111 4.31 dJ5.4 Hz 211

13C NMR DMSO-d6 22.4 42.0 56.4 126.7 127.0 7.237.30 in 511 7.38 dJ7.4 Hz 111 8.26 tJ5.42C 127.2 2C 127.4 127.9 2C 128.1 2C 138.9 65 Hz 1H139.0 168.9 170.0 ppm NMR DMSO-d6 18.1 27.2 3C 37.9 42.0

JR KBr 3260 1620 1525 1450 1370 720 690 48.4 126.6 127.0 2C 128.2 2C 139.4 172.5 177.1

cm1 ppm

537872923 24

IR KBr 3300 1630 1535 br 1455 745 695 cm1 mL was added dropwise and was stirred at

Mass spectrum m/e relative intensity 262 203 for one hour and then at room temperature for 18 hours

19 156 18 128 51 106 31 91 100 77 15 65 The reaction became homogenous during this time in28 terval

Elemental analysis Calculated for C15H22N202 The solution was concentrated in vacuo and the resi68.66% 8.47% 10.68% Found 68.91%

due was combined with hot tetrahydrofuran 100 mL8.14% 10.6%

and cooled in the freezer for hours resulting in the

EXAMPLE 12 formation of white precipitate The mixture was flu-

Preparation of N-Acetyl-D 10tered and the precipitate was collected dried in vacuo

L-methionine-N-benzylamide and identified as triethylammonium hydrochloride 3.51

N-Acetyl-DL-methionine 4.78 25 mmol wasmp 253257 C. The filtrate was concentrated in

vacuo and the resulting yellow solid was recrystallizedcombined with acetonitrile 75 mL and the mixture

was placed into an ice/salt water bath C. Trieth-from chioroform/diethyl ether

ylamine 2.53 3.48 mL 25 mmol was added drop- 15Yield 3.22 54% mp 120121

wise followed by ethyl chloroformate 2.71 2.39 mL NMR DMSO-d6 81.27 dJ7.l Hz 3ff 1.90

25 mmol All additions were done slowly so that the 3H 4.234.41 111 4.33 dJ6.1 Hz 2Htemperature of the mixture did not rise above The 7.057.37 4H 8.19 dJ7.l Hz 1ff 8.53 tJ6.lmixture was then stirred at 20 mm Benzyl- Hz 1Hamine 3.00 3.06 mL 28 mniol in acetonitrile mL 20 13C NMR DMSO-d6 17.9 22.4 415 48.5 113.3

was added dropwise and the mixture was stirred dJ20.4 Hz 113.5 dJ21.7 Hz 122.8 130.1

at and then room temperature 18 dJ7.9 Hz 142.4 dJ7.4 Hz 162.3 dJ243.6The mixture was filtered and white precipitate was Hz 169.6 172.8 ppm

collected and dried in vacuo and identified as the de-IR KBr 3280 1645 1545 1450 745 680 cm1

sired product NMR and 3C NMR analyses The 25

filtrate was concentrated in vacuo and the residue wasMass spectrum m/e relative intensity 238 18 151

combined with hot tetrahydrofuran 50 mL and cooled 22 124 49 114 47 109 100 87 76 72 27Elemental analysis Calculated 60.48% 6.36%

in the freezer resulting in the formation of white

precipitate The mixture was filtered and the precipitate11.76% Found 60.55% 6.32% 11.71%

was collected dried in vacuo and identified as trie- 30 EXAMPLE 14

thylammonium hydrochlorideThe latter filtrate containing tetrahydrofuran was Preparation of

concentrated in vacuo and the resulting residue-was DL-a-Acetamido-N-benzyl-3-thiopheneacetamide

purified by flash column chromatography ethyl ace-DL-a-Acetaxnido-3-thiopheneacetic acid 2.99 15

tate white solid Rj 0.50 ethyl acetate was iso-mmol was combined with acetonitrile 60 mL and the

lated and was identified as the desired product 1HNMR and 13C NMR analyses The two solids identi-

mixture was placed into an ice/salt water bath C.

fled as N-acetyl-DL-methionine-N-beazylainide wereTriethylamine 1.51 2.10 mL 15 mmol was added

combined and recrystallized from benzene/petroleumdropwise followed by ethyl chloroforrnate 1.63 1.43

ether 3060 C. mL 15 mrnol All additions were done slowly so that

Yield 2.98 43% mp 134135 the temperature of the mixture did not rise above

1H NMR DMSO-dt 81.691.94 2H 1.87 The mixture was then stirred at 20 mm Ben

3H 2.02 311 2..292.59 in 2H 4.104.53 lH zylamine 1.77 1.80 rnL 16.5 mmol in acetonitrile 104.29 dJ6.0 Hz 2ff 7.26 5ff 8.12 dJ8.5 Hz mL was added dropwise and the mixture was stirred at

111 8.47 tJr6.0 Hz 1H and then room temperature 18 The

13C NMR DMSO-d6 14.6 22.5 29.7 31.8 42.0 mixture was concentrated in vacuo and the residue was52.0 126.6 127.0 2C 128.2 2C 139.4 169.5 171.4 combined with hot tetrahydrofuran 50 niL and cooled

ppm in the freezer resulting in the formation of whiteJR KBr 3280 1630 1545 1460 750 700 cm1

precipitate The mixture was filtered and the precipitateMass spectrum m/e relative intensity 280 206

50 was collected dried in vacuo and identified as trie

100 164 29 146 20 106 54 9176 77 14 65thylaminoniurn hydrochloride NMR analysis The

24filtrate was concentrated in vacuo and the resulting

Elemental analysis Calculated for C4H20N202S59.96% 7.20% 9.99% Found 60.02% 7.14% yellow solid was recrystallized from 11 95% ethanol

9.91%water

Yield 1.91 44% mp 198l99EXAMPLE 13 NMR DMSO-d6 81.91 3I 4.29 dJ5.2Preparation of Hz 2H 5.61 dJ7.9 Hz 1H 7.157.50 3H 8.55

N-Acetylalanine-N-3-fluorobenzylaniide dJ 7.9 Hz 1ff 8.74 tJ5.2 Hz 11113C NMR DMSO-d6 22.3 42.0 52.5 122.4 126.1

N-Acetylalanine 3.28 25 mol was combined with 60

acetonitrile 100 mL and the mixture was placed into126.7 127.0 3C 128.2 2C 139.0 139.2 169.0 169.8

an ice/salt bath at Triethylamine 2.53 3.5 ppmmL 25 mmol was added dropwise followed by the JR KBr 3460 1675 1570 1400 720 695 cm1addition of ethyl chloroformate 2.71 2.40 mL 25 Mass spectrum m/e relative intensity 288 245

nimol All additions were done slowly so that the tern- 65 155 88 112 100 9131 85 17 65

perature of the mixture did not rise above The Elemental analysis Calculated for CH16N202Smixture was then stirred at for 20 minutes 3- 62.48% 5.59% 9.71% Found 62.41% 5.47%

Fluorobenzylamine 3.58 28 mmol and acetonitrile 9.55%

537872925 26

2C2 or 2C3 127.08 2C2 or 2C3 128.27 C4EXAMPLE 15

139.05 Ci 142.58 C5Preparation of 151.16 C2 168.02 CH3CO 169.30 NHCO ppm

DL-a-Acetamido-N-benzyl-2-thiopheneacetamide JR KBr 3230 1625 br 1525 br 1375 br 1230

N-Acetyl-DL-ethoxyglycine-N-berizylamide 6.26 1090 890 cm25 mmol wasombined with dry ether 175 mL and Mass spectrum m/e relative intensity 273 139

then boron triJluoride etherate 5.68 5.0 mL 40 100 96 94 9151 65

mmol was added dropwise resulting in homogeneous Elemental analysis Calculated for C15H6N203

solution After stirring short time small amount of 66.16% 5.83% 10.29% Found 65.92%

yellow oil separated from the solution Thiophene 8.41 lO 5.83% 10.15%

8.0 mL 100 mmol was then added dropwise viaEXAMPLE 17

syringe and the reaction was stirred at room tempera-

tare The mixture was cooled in an ice bath and Preparation of

cold aqueous saturated NaHCO3 200 mL was added DL-a-Acetamido-N-benzyl-2-pyrroleacetamideand the aqueous layer was extracted with ethyl acetate 15

2x 100 mL The organic washings and the original2-Acetantido-N-benzyl-2-ethoxyacetaniide 2.00

ether layer were combined dried Na2SO4 and con-8.0 mmol was suspended in anhydrous ethyl ether 60

centrated in vacuo The residue was purified by flash mL and then boron trifluoride etherate 1.82 1.57

column chromatography using 946 chloroform/me- mL 12.8 mmol was added in one portion and the re

thanol as an eluant Rj0.7 94 chloroform/me- 20 suiting solution was stirred 15 mm The pyrrole 2.14

thanol and then recrystallized from benzene 2.22 mL 32 mmol was then added in one portion and

Yield 2.67 37% mp 167169 the solution was stirred at room temperature 481H NMR DMSO-d6 61.91 311 4.31 dJ 6.0 during which time precipitate formed Hexanes 80

Hz 211 5.74 dJ7.9 Hz 111 6.997.44 in 8H 8.64 mL were then added to the suspension and the mixture

dJ 7.9 Hz 111 8.85 tJ 6.0 Hz 1H 25 was filtered and the brown semi-solid was triturated

NMR DMSO-d6 22.4 42.3 52.2 125.6 125.8 with 955 chloroform/methanol 30 mL to furnish

126.6 126.9 127.3 2C 128.3 2C 139.0 141.4 169.2 green solid This material was purified by flash chroma

169.3 ppm tography 955 chloroform/methanol to yield 0.94

Mass spectrum m/e relative intensity 289 181 35% of the desired product as white solid Rf 0.29

155 100 112 100 91100 85 .34 74 24 30 964 chloroform/methanolElemental analysis Calculated for C15H6N202S mp 174175

62.48% 5.59% 9.71% Found 62.64% 5.73% 111 NMR 300 MHz CD3CN 61.93 CH3 4.35

9.61% dJ6.0 Hz CH2 5.42 dJ6.9 Hz CH 6.006.18

EXAMPLE 16in C3H C4H 6.686.72 C5H 7.04 dJ6.9 Hz

35 NH 7.17 tJ6.0 Hz NH 7.107.47 PhPreparation of 9.109.80 br NH

DL-a-Acetaniido-N-beazyl-2-furanacetainide 3C NMR 300 MHz CD3CN 23.02 CH3 43.83

N-Acetyl-DL-2-2-furylglycine 0.47 2.56 mmol CH2 52.65 CH 107.57 C3 108.85 C4 119.33

was combined with acetonitrile 10 mL and cooled to C5 127.96 C2 128.01 2C2. or 2C3 128.09 2C2 or

ice/salt water bath Triethylamine 0.26 40 2C3 129.49 C4 140.01 Ci 170.94 COCH30.36 mL 2.56 mmol was then rapidly added and the 171.21 CONIH ppmmixture stirred at mm Ethyl chioroforinate JR KBr 3320 1570 br 1470 br 1330 1230 950

0.28 0.25 mL 2.56 mniol was added dropwise be- 890 860 760 710 690 655 cmween and and the resulting suspension Mass spectrum m/e relative intensity 171 12 228

was stirred at 20 mm and then an acetonitrile 213 180 164 137 93 108 20 95 100solution mL of benzylamine 0.30 0.31 mL 2.82 9138 82 35 6815mmol was carefully added During the addition of High resolution mass spectral analysis Calculated for

benzylaniine the temperature of the solution did not go C15H17N302 27l.13208 Found 271.13144

above The mixture was stirredat and

at room temperature 18 and then concentrated in 50 EXAMPLE 18

vacuo The residue was then triturated with hot tetra- Preparation of

hydrofuran mL cooled at 16 and the DL-2-Acetamido-N-benzyl-2-ethoxyacetamide

resulting white precipitate was filtered and identified as

triethylamine hydrochloride NMR 60 MHz 61.00An ethanolic solution 420 mL of ethyl 2-acetamido-

tJ7.5 Hz CH3 2.82 qJ7.5 Hz CH2 3.83 55 2-ethoxyacetate 27.92 147 minol and benzylamine

NH The filtrate was evaporated to dryness in vacuo 23.70 24 mL 221 minol was stirred at 4045 for

and the resulting oil purified by flash chromatography days The reaction mixture was evaporated in vacuo

982 chloroform/methanol to give 0.09 13% of theand the residue recrystallized 13.5 tetrahydrofuran/

desired product as white solid Rf 0.30 982 chloro- hexanes 650 mL to yield 25.80 70% of the desired

form/methanol 60 product as beige crystals RJ0.59 955 chloroform/me

mp 178179 thanol

1H NMR 300 MHz DMSO-dó 61.90 CH3 4.31 mp 153l55

dJ6.0 Hz CH2 5.58 dJ8.1 Hz CH 6.276.33 1H NMR 300 MHz CDC13 61.20 tJ7.0 HzC3-H 6.406.44 in C4H 7.207.36 Ph CH3 2.07 CH3 3.603.76 in CH2CH3 4.404.54

7.607.64 in CsH 8.57 dJ8.l Hz NH 8.73 65 in CH2NH 5.60 dJ8.7 Hz CH 6.63 dJ8.7 HztJ6.0 Hz NH NH 7.00 br NH 7.267.36 in Ph

13C NMR 300 MHz DMSO-d6 22.35 CH3 42.27 3C NMR 300 MHz CDC13 15.06 CH3CH2 23.25

CH2 50.95 CH 107.60 C3 110.55 C4 126.82 CH3CO 43.60 CH2NH 64.51 CH2CH3 77.43

537872927 28

CII 127.69 2Czor 2C3 C4 128.79 2C2 or 2C3 JR KBr 3270 1620 br 1520 br 1440 1360 1210137.57 C1- 168.13 COCH3 171.29 CONH ppm 1010 cm

JR KBr 3260 1630 br 1550 sh 1505 br 1380 Mass spectrum m/e relative intensity 286

1360 1230 1115 1060 1015 890 745 690 cm1 1798 153 57 152 57 111 23 110 100 9723 91

Mass spectrum m/e relative intensity 2514 163 31116 98 106 34 9198 74 100 Elemental Analysis Calculated 67 12% 6.34%

Elemental nalysis Calculated for C13H18N203 9.78% Found 66.92% 6.52% 9.52%

62.38% 7.25% 11.19% Found 62.49%7.27% 11.24%

EXAMPLE 21

10 Preparation ofEXAMPLE 19

DL-a-Acetamido-N-benzyl-2-benzofuranacetamide

Preparation ofN-Acetyl-D L-ethoxyglycune-N-benzylamide 1.00

L-2-Acetamido-N-benzyl-2-methoxyacetamide mmol was suspended in anhydrous ethyl ether 30To methanolic solution 180 mL of methyl 2-

15mL and then boron trifluoride etherate 0.91 6.3

acetamido-2-methoxyacetate 8.73 54 mmol was mmol was rapidly added and the resulting solution

rapidly added benzylamine 8.68 8.80 mL 81 mmol was stirred for 15 miii The benzofuran 1.89 16

and then the mixture was stirred at 50 days dur- mmol was then added and the reaction was stirred at

ing which time beige precipitate appeared The sol- room temperature The reaction mixture wasvent was removed in vacuo and the resulting precipitate

20poured into an ice-cold saturated aqueous solution of

was recrystallized from tetrahydrofuran to give NaBCO3 and then the mixture was maintained at this

7.67 32% of the desired product as beige crystals Rf temperature for an additional 15 miii The mixture was0.35 955 chloroform/methanol extracted with ethyl acetate 2x and the organic lay

mp l45146 ers were combined dried Na2504 and evaporated in

1H NMR 300 MHz CDC13 82.06 CH3CO25

vacuo The residue was purified by flash chromatogra

CH3O 4.404.35 CH2 5.52 dJ8.7 Hz CII phy 100% chloroform then 991 chloroform/me-

7.12 dJ8.7 Hz NH 7.207.40 Ph NH thanol to yield the desired product13C NMR 300 MHz CDC13 23.03 CH3CO 43.51 Yield 0.43 33% Rf 0.30 982 chloroform/me

CH2 55.84 CH3O 78.94 CII 127.62 C4 127.70 thanol mp l951962C2 or 2C3 128.70 2C2 or 2C3 137.45 C1

301H NMR DMSO-d6 61.94 CH3CO 4.34

166.91 COCH3 17 1.57 CONH ppm dJ5.7 Hz CH2 5.77 dJ8.l Hz CII 7.247.32

JR KBr 1260 1825 br 1550 1505 1435 1390 C3II CsH C6H Ph 7.54 dJ7.0 Hz C4H or

1370 1230 1120 1050 935 890 690 cm1 Cr11 7.62 dJ7.0 Hz C4H or Cr11 8.74 dJ8.1Mass spectrum m/e relative intensity 237 205 Hz NH 8.86 tJ 5.7 Hz NH1772 163 1461 1341 121 106 26 102 13C NMR DMSO-d6 22.27 CHiCO 42.30 CH2

98 9195 77 13 61100 51.22 CH 104.34 C3 110.90 C7 121.05 C4Elemental analysis Calculated for C12H16N203 122.90 C5 124.28 C6 126.73 C3a 127.01 2Cr or

61.00% 6.83% 11.86% 60.91% 6.85% 2C3 127.69 2Cr or 2C3 128.14 C4 138.87 C111.66% 154.10 C7a 154.30 C2 167.40 CII3CO 169.26

CONH ppmEXAMPLE 20IR KBr 3230 1625 br 1520 br 14-40 1090 1085

Preparation of 890735 690 cm1DL-a-Acetamido-N-benzyl-2-5-methylfuranaceta- Mass spectrum m/e relative intensity 322 279

mide 2641 234 215 189 45 146 100 130 11N-Acetyl-DL-ethoxyglycine-N-benzylamide 2.00 45

118 9187 65 168.0 minol was suspended in anhydrous ethyl ether and High resolution mass spectrum Calcd for

then boron trifluoride etherate 1.82 12.8 mmol was C19H18N203 322.1317 Found 322.1318

rapidly added and the resulting solution was stirred for EXAMPLE 2215 mm The 2-methylfuran 2.63 32.0 mmol was then

added and the reaction was stirred at room temperature 50Preparation of

The reaction mixture was poured into an aqueousDL-a-Acetamido-N-benzyl-2-benzobthio-

saturated Na1C03 solution and extracted with ethylpheneacetamide

acetate The ethyl acetate extracts were com- N-Acetyl-DL-ethoxyglycune-N-benzylamide 1.00

bined dried Na2SO4 and evaporated in vacuo to give mmol was suspended in anhydrous ethyl ether 15beige solid which was purified by flash chromatogra- 55 niL and then boron trifluoride etherate 0.91 6.3

phy 982 chloroform/methanol to give the desired mmol was rapidly added and the resulting solution

product as white crystalline solid was stirred for 15 miii The benzo 2.14Yield 1.40 61% Rj 0.25 982 chloroform/me- 16 mmol was then added and the reaction was stirred at

thanol mp 148 150 room temperature The solution was poured into

1H NMR DMSO-d6 61.88 CH3CO 2.23 60 an ice-cold saturated aqueous solution of NaHCO3 and

CH3 4.244.36 CH2 5.49 dJ8.0 Hz CII 6.01 then stirred for 15 miii at The mixture was exbr CII 6.14 J2.4 Hz C4H 7.207.3 tracted with ethyl acetate 2x and the organic layers

Ph 8.52 J8.0 Hz NH 8.69 tJ5.6 Hz NH were combined dried Na2SO4 and evaporated in

13C NMR DMSO-do 13.44 CII3 22.35 CHiCO vacuo to give an orange oil The oil was triturated with

44.11 CII2 53.23 CII 107.51 C3 or C4 110.40 65 ethyl ether to yield crystalline product which was

C3 or C4 128.13 C4 128.18 2C2 or 2C3 129.43 filtered and further purified by flash chromatography

2Cr or 2C3 139.69 Ci 149.18 C2 or C5 153.81 991 chloroform/nethanol to give the desired prod-

C2 or C5 170.78 CH3CO 173.03 CONH ppm uct

537872929 30

Yield 0.06 4% Rj 0.32 991 chloroform/me- mxnol was added and the resulting solution stirred 15thanol mp 226227 mm The 2-methylpyrrole 0.85 10 mmol was then

NMR DMSO-d6 61.94 CH3CO 4.34 added and the reaction mixture was stirred under N25.7 Hz CH2 5.86 8.1 Hz CH 7.207.38

during which time the color of the reaction mixture

C3H C6H C7H Ph 7.777.80 C4H or C5H turned reddish brown and dark-brown deposit formed7.897.93 C4H or CsH 8.76 8.1 Hz NH

at the bottom of the flask The clear solution was de8.97 tJ5.7 NH

canted and treated with an aqueous saturated NaHCO33C NMR DMSO-d6 22.34 CH3CO 42.38 CH2solution containing ice 100 mL for 30 mm The aque52.70 CH r22.15 C4 or C7 122.32 C4 or C7

123.45 C3 124.37 C5 or C6 124.41 C5 or C6 10ous reaction mixture was extracted with ethyl acetate

126.89 C4 127.27 2C2 or 2C3 128.27 2C2 or 30 mL The combined extracts were dried Na2C3 138.84 C3a or C7a 138.95 C3a or C7a 142.58 SO4 and the solvent removed in vacuo The brown oily

Ci 168.65 CH3CO 169.12 CONH ppm dis- residue was purified by flash column chromatography

tinct signal for the C2 carbon was not detected and is using 982 chloroform/methanol as the eluent to yield

presumed to coincide with the Ci carbon at 142.5815

the desired compound The product was recrystallized

ppm. from ethyl acetate/hexane to give light yellow amorJR KBr 3240 1610 br 1510 br 1420 1360 1215 phous solid

1085 885 730 710685 cm1 Yield 0.20 94% RjO.44 955 chloroform/me-

Mass spectrum m/e relative intensity 338 295 thanol nip 167168205 76 162 100 135 22 108 12 9159

20 1H NMR DMSO-d6 61.87 CH3 2.13

Elemental Analysis Calculated 67.43% 5.36% COCH3 4.27 br CH2 5.33 dJ7.4 Hz CR 5.60

8.28% Found 67.21% 5.37 %H 8.12% CH 5.77 C3H 7.197.30 PhH 8.22

EXAMPLE 23 dJ7.4 Hz NH 8.45 tJ5.5 Hz NH 10.38

NHPreparation of

25 13C NMR DMSO-do 12.74 CH3 22.49 COCH3DL-a-Acetamido-N-benzyl-3-indoleacetamide

42.11 CH2 51.21 CR 105.09 C4 106.07 C3N-Acetyl-DL-ethoxyglycine-N-benzylamide 0.69 126.16 C5 126.64 C4 126.85 C2 127.09 2C2 or

2.75 mmol was suspended in anhydrous ethyl ether 20 2C3 128.17 2C2 or 2C3 139.33 Ci 168.88

mL and then boron trifluoride etherate 0.63 4.40 COCH3 169.79 CONH ppmmmol was rapidly added and the resulting solution 30 IR KBr 3250 1630 1520 1420 1360 1300 1260was stirred for 15 mm The indole 1.30 11.00 mmol 1230 1160 1110 1020 cm1was then added and the reaction was stirred at room

Mass spectrum mle relative intensity 285 M10temperature 22 Petroleum ether 3560 was

178 20 152 24 151 100 110 12 109 93 108 22added to the reaction and the resulting semisolid mate-

107 25 94 16 9143rial filtered and washed with petroleum ether 3560

Elemental Analysis Calculated 67.35% 6.71%C. Purification of the reaction mixture was accom-14.73% Found 67.57% 6.90% 14.52%

plished by flash chromatography 982 chloroform/me

thanol to produce the title compound as white SolidSynthesis of Unsubstituted and

Yield 0.25 18% Rf 0.14 955 chloroform/me-Substituted-a-Acetamido-N-benzyl-2-furanacetamides

thanol mp 213214General Procedure 4-Methylmorpholine equiv1H NMR DMSO-d6 1.90 CH3CO 4.36

dJ6.0 Hz CH2 5.72 dJ7.2 Hz CR 6.907.37 was added to solution of a-acetamido-2-furanacetic

Ph C2H 7.02 ddJ7.5 Hz J7.5 Hz CsH or acid equiv in dry tetrahydrofuran 75 mL/10 mmolC6H 7.12 ddJ7.5 Hz J7.5 Hz CsH or C6H at 10 to 15 under N2 After stirring miii

7.39 dJ7.5 Hz C4H or C7H 7.65 J7.5 Hz isobutyl chloroformate equiv was added leading to

C4H or C7H 7.86 dJ 7.2 Hz NHCH 8.13 tJ6.0 the precipitation of white solid The reaction was

Hz NHCH2 10.3010.80 br NH allowed to proceed for additional minutes and then

13C NMR DMSO-de 22.32 CH3CO 42.23 CH2 solution of the substituted benzylamine equiv in

49.98 CR 111.51 C7 112.08 Ci 118.76 C4 or tetrahydrofuran lOmL/lO mmol was added over

C6 119.24 C4 or C6 121.37 Cs 123.94 C2 126.58 50 miii at 10 to 15 The reaction mixture was al

C3a 126.71 C4 127.33 2Cror 2C3 128.18 2C2 lowed to stir at room temperature for miii and then theor 2Cr 136.28 Cm 139.44 Ci 169.13 CH3CO 4-methylmorpholine hydrochloride salt filtered The170.81 CONE ppm organic layer was concentrated in vacuo and the resi

JR KBr 3260 1610 br 1515 br 1450 1420 1370 due was triturated with ethyl acetate and the remaining1350 1235 1095 895 735 715 695 600 cm1

55 white solid filtered Concentration of the ethyl acetateMass spectrum m/e relative intensity 321 278

layer led to additional amounts of the white solid The264 233 214 187 85 171 145 100

118 18 9139desired product was purified by either recrystallization

Elemental Analysis Calculated 71.01% 5.96%or flash chromatography of the combined solid mate

rial Examples 25-32 were prepared according to this13.06% Found 70.87% 6.15% 12.78%

procedureEXAMPLE 24

EXAMPLE 25Preparation of

DL-a-Acetamido-N-benzyl-2-5-methylpyr- DL-a-Acetaniido-N-benzyl-2-furanacetamide

roleacetamide 65 Using beazyl amine 0.27 2.56 rnmol and racemic

N-Acetyl-DL-ethoxyglycine-N-benzylaunide 2.00 a-acetamido-2-furanacetic acid 0.47 2.56 mmolmmol was suspended in anhydrous ethyl ether 175 gave the desired compound The product was recrystal

mL and then boron trifluoride etherate 1.38 9.7 lized from ethyl acetate to give white solid

537872931 32

Yield 0.46 65% Rj 0.30 982 chloroform/me- EXAMPLE 28

thanol mp 1771781H NMR DMSO-d6 61.90 CH3 4.31 dJ6.o DLaAcetamido-N-4-fluorobenzYl-2-fUraflaCeta-

Hz CH2 5.58 dJ8.l Hz CH 6.276.33 C3Hmide

6.406.44 C4H 7.207.36 PhH 7.607.64 Using racemic a-acetamido-2-furanacetic acid 1.50

C5H 8.57 dJ.1 Hz NH 8.73 tJ6.0 Hz NH 8.2 mmol and 4-fluorobenzylainine 1.13 9.0

mmol gave the desired product

EXAMPLE 26 Yield 2.10 88% Rj 0.30 964 chloroform/me

DLaAcetamido-N-2-fluorobenzY1-2-furaflaCeta- 10thanol mp 188190 recrystallized from ethyl

mideacetate

1H NMR DMSO-d6 81.88 COCH3 4.27

Using 2-Fluorobenzylanline 1.13 9.0 mmol and dJ5.5 ui CH2 5.55 dJ8.OHz CH 6.27 1Hracemic a-acetarnido-2-furanacetic acid 1.50 8.2 6.41 1H 7.097.15 2ArH 127.27 ArH

minol gave the desired product 157.61 1H 8.58 dJ8.0 Hz NH 8.75 tJ5.5 Hz

Yield 1.20 50% Rf 0.36 964 chloroform/me- NHthanol mp 19319Y recrystallized from EtOAc 13C NMR DMSOd6 22.28 COCH3 41.51 CH2

NMR DMSO-d6 61.89 COCH3 50.87 CH 107.52 C4 110.46 C3 114.90

dJ5.5 Hz CH2 5.58 dJ8.0 Hz CH 6.28jCF21.1 Hz C3 129.48 dJCF8.3 Hz C2

C4H 6.29 C3H 7.62 C5H 7.137.35 ArH 20135.23 dJCF 3.2 Hz C1 142.53 C5 151.08 C2161.12 dJcp242.2 Hz C4 167.95 COCH3 169.13

8.61 dJ8.0 Hz NH 8.76 tJ5.5 Hz CONH ppm3C NMR DMSO-d6 22.35 COCH3 36.12 JR K.Br 3230 1620 1500 1360 1320 1260 1210

dJCF6.6 Hz CH2 50.88 CH 107.64 C4 110.43 1140 1000 820 780 730 cm1C3 115.04 dJCF21.4 Hz C3 124.29 dJCF4.2 25 Mass spectrum m/e relative intensity 291

Hz C5 125.64 dJCF 15.0 Hz Ci 128.94 14 165 140 139 92 138 52 124

dJCF9.O Hz C4 or C6 129.27 dJCF5.5 Hz C4 109 71 97 60 96 100

or C6 142.66 C5 151.07 C2 159.99 dJCF 244.4 Elemental Analysis Calculated 62.02% 5.21%

Hz C2 168.17 COCH3 169.24 CONH ppm 9.65% Found 61.76% 5.41% 9.43%

IR KBr 3270 1630 1520 1440 1360 1220 1180 30 EXAMPLE 29

1140 1100 1000 740 cmDL-a-Acetamido-N-25-difluorobenzyl-2-

Mass spectrum m/e relative intensity 291 furanacetaniide

274 2473 165 145 10 139 98 138 46Using 25-difluorobenzylamine 1.30 9.0 mmol and

126 110 10 109 65 97 93 96 100 racemic a-acetarnido-2-furanacetic acid 1.50 8.2

Elemental Analysis Calculated 62.02% 5.21% mmol gave the desired product9.65% Found 62.20% 5.19% 9.69% Yield 1.60 64% Rf 0.38 964 chloroform/me-

EXAMPLE 27 thanol mp 17Tl78 recrystallized from ethyl

acetate

DLa.Acetamido-N-3-fluorobenzYl-2-furanaCeta- 1H NMR DMSO-d6 61.89 COCH3 4.31

mide dJ5.5 Hz CH2 5.55 dJ7.7 Hz CH 6.32

Making use of 3-fluorobenzylamine 1.13 9.0 C4H 6.43 C3H 7.227.25 ArH 7.62 C5H

mmol and racemic a-acetaxmdo-2-furanacetic add 1.508.62 dJ 7.7 Hz NH 8.78 tJ 5.5 Hz NH

13C NMR DMSO-d6 22.30 COCH3 35.98

8.2 mmol gave the desired product 45 dJCF5.8 Hz CH2 51.02 CH 107.81 C4 110.58

Yield 1.90 80% Rf 0.30 964 chloroform/me- C3 115.06 ddJcp 19.5 25.6 Hz C3 or Có 115.16

thanol mp 163165 recrystallized from ethyl ddJCF 15.6 24.7 Hz C3 or C6 116.52

acetate ddJCF 10.1 23.9 Hz C4 127.98 ddJCF9.2 17.7

1H NMR DMSO-d6 81.89 COCH3 4.31 Hz Ci 142.69 Cs 150.78 C2 155.89 dJCF239.O

dJ5.5 Hz CH2 5.55 dJ7.8 Hz CH 6.3150 Hz C2 or C5 158.18 dJCF238.8 Hz C2 or C5

C4H 6.42 C3H 6.987.37 ArH 7.62 C5H 168.38 COCH3 169.35 CONH ppm

8.61 dJ7.8 Hz NH 8.70 tJ5.5 Hz NH JR KBr 3230 1620 1520 1480 1360 1260 1230

3C NMR DMSO-d6 22.35 COCH3 41.71 CH2 1180 1140 1000 860 810 730 710 cm51.01 CH 107.73 C4 110.59 C3 113.50

Mass spectrum m/e relative intensity 309 MldJCF2l.6 Hz C2 or C4 113.60 dJCF22.3 Hz 266 2221 165 1405 139 61 138 36 127

C2or C4 122.95 br C6 130.18 dJCF8.6 Hz C5 37 97 44 96100Elemental Analysis Calculated 58.44% 4.58%

142.21 dJcF7.5 Hz C1 142.66 C5 151.03 C2 9.09% Found 58.68% 4.69% 8.87%

162.28 dJCF243.3 Hz C3 168.23 COCH3 169.31

CONH ppm60 EXAMPLE 30

JR KBr 3230 1630 1540 1440 1360 1220 1140

1000 730 cm1 furanacetainide

Mass spectrum m/e relative intensity 290 Mt 71 Marking use of 26-difluorobenzylamine 1.30 9.0

231 165 18 14023 139100 126 16 109 9765 mnaol and racemic a-acetamido-2-furanacetic acid

118 96 100 96 30 1.50 8.2 mmol the desired product was formed

Elemental Analysis Calculated 62.02% 5.21% Yield 1.90 73% mp 237239 recrystallized

9.65% Found 61.97% 5.35% 9.53% from ethanol NMR DMSO-d6 61.86 COCH3

537872933 34

4.33 dJrr4.5 Hz CM2 5.53 dJ 8.3 Hz CM 6.17 salt was recrystallized from absolute ethanol to

C4H 6.38 C3H 7.057.10 ArH 7.367.41 yield 4.00 of the pure diasteromeric salt

ArH 7.60 C5H 8.52 dJ8.3 Hz NH 8.66 mp 173175 MeOH108tJ4.5 Hz NH Elemental Analysis Calculated 63.14% 6.62%

3C NMR DMSO-ds 622.33 COCH3 30.74 9.21% Found 63.19% 6.62% 9.12%

tJCF4.4 CH2 50.48 CH 107.24 C4 l.40 The purified salt was treated with 5% aqueous

C3 111.61 @dJCF8.0 25.1 Hz C3 C5 113.67 NH4OH solution extracted with ethyl ether 3X50

tJCF 19.5 Hz Ci 129.98 tJCF 10.5 Hz C4 mL and then acidified with 8.5% aqueous solution of

142.50 C5 151.23 C2 160.93 dJCF248.l C2 or H3P04 and then extracted with ethyl acetate 100

C6 161.10 dJCF248.l Hz C2 or C6 167.5910 mL to yield 2.45 g25% of D-a-

COCH3 169.00 CONH ppm -acetamido-2-furanacetic acid

JR KBr 3230 1620 1530 1460 1360 1320 1260 mp 169l7l

1220 1160 1140 1030 1000 820 780 750 74.0 710 MeOH184.2cm1 Elemental Analysis Calculated 52.46% 4.95%

Mass spectrum m/e relative intensity 309 Ml 15 7.65% Found 52.17% 4.89% 7.56%

265 165 147 140 139 87 138 36 The salt obtained after evaporation of the main

127 54 97 58 96 100 mother liquor was hydrolysed with 5% aqueous

Elemental Analysis Calculated 58.44% 4.58% NH4OH solution to give 10.10 of the enriched L-aacetamido-2-furanacetic acid

9.09% Found 58.62% 4.74% 8.99%20 MeOH 47.70 S--methylbenzylamine 6.70

EXAMPLE 31 0.055 mol was added to solution of enriched L-aacetamido-2-furanacetic acid 10.10 0.05 mol in

D--a-Acetarnido-N-benzyl-2-furanacetamideabsolute ethanol 275 mL The white precipitate of the

Starting with D-a-acetamido-2-furanacetic acid 2.45 diasteroemeric salt 8.10 that separated upon cooling13.38 mmol and benzylamine 1.43 13.38 mmol 25 the solution in the freezer was filtered The salt

the desired product was obtained Yield 2.54 70% was recrystallized from absolute ethanol 3x to yield

The product was further recrystallized from ethyl ace- 3.00 of the salt

tate to give the title compound mp l72174 MeOH 106Yield 2.30 mp 196l97 Elemental Analysis Calculated 63.14% 6.62%

MeOH78.3 Addition of R-mandelic acid to30 9.21% Found 63.18% 6.47% 9.00%

CDC13 solution the product gave only one signal for the The salt from the third recrystallization was treated

acetamide methyl protons Mass spectrum m/e rela- with 5% aqueous NH4OH solution and extracted with

tive intensity 272 1842 165 140 ethyl ether 50 mL and then acidified with 8.5%

13988 138 34 97 46 96 100 9163 aqueous solution of H3P04 and then extracted with

Elemental Analysis Calculated 66.16% 5.92% ethyl acetate 100 mL to give 1.63 32% of L-a

10.29% Found 66.09% 6.01% 10.38% acetaxnido-2-furanacetic acid

mp 169l71 MeOH182EXAMPLE 32

EXAMPLE 34L--a-Acetamido-N-benzyl-2-furanacetamide

40 Enzymatic Separation ofUsing L-a-acetamido-2-furanacetic acid 2.83 Da-acetamido-2-furanacetic acid from DL

15.46 mmol and benzylamine 1.65 15.4G mmol a-acetamido-2-furanacetic acid

gave 3.80 of the enriched desired product 111 NMRanalysis with R-mandelic acid showed that it was

DL a-acetamido-2-furanacetic acid 2.00 10.9

greater than 80% enriched in the title compound The 45mmol was suspended in deionized 1120 600 rnL An

pure L-enantiomer was obtained by recrystallizationaqueous solution of LiOH iN was added to this sus

from absolute ethanolpension dropwise until all of the acid had dissolved and

Yield 1.60 mp 196l97the pH was 7.2 Acylase Grade II 20 mg ac

tivity 900 units/mg Sigma Chemical Company CatMeOH 79.0 No 8376 was then added to the above solution andMass spectrum m/e relative intensity 273 50

the mixture stirred at 3437 41 The suspension13 229 2142 184 165 157 140

was then cooled to room temperature and acidified to

33 139 100 138 95 9798 96 100 9198 pH 1.5 with aqueous iN HC1 The suspended material

Elemental Analysis Calculated 66.16% 5.92%was filtered and the filtrate was saturated with solid

10.29% Found 65.89% 5.86% 10.42% NaC1 and then extracted with ethyl acetate 25055

EXAMPLE 33 mL The combined ethyl acetate extracts was dried

Na2SO4 The solvent was removed in vacuo and the

Resolution of DL.a-Acetamido-2-furanacetic acid residue was triturated with ethyl acetate 10 mL The

Using R--a-Methylbenzylamine and white solid 0.75 that remained was filtered and wasS--a-Methylbenzylamine pure Da-acetaanido-2-furanacetic acid mp60

R--a-Methylben.zylaniine 13.22 0.11 mol l68169 mixed mp with an authentic sample

was added to an absolute ethanol solution 550 mL of 168169 MeOH 184.3

racemic a-acetamido-2-furanacetic acid 20.00 0.11 EXAMPLE 35

mol The resulting solution was cooled in the freezer

overnight The white precipitate 12.00 which sepa- 65Preparation of DL-a-Acetaxnido-2-furanacetic Acid

rated upon cooling was filtered and the mother liquid An ethereal solution of ZnC121N 28 mL 0.028 molevaporated to give salt which was later used for ob- was added to stirred solution of ethyl acetamido-2-

taming L-a-acetaniido-2-furanacetic acid The initial bromoacetate 4.40 0.0 19 mol and furan 11.23

537872935 36

0.165 mol in dry tetrahydrofuran 100 mL and al- Elemental Analysis Calculated 61.84% 7.26%

lowed to stir at room temperature The mixture 14.42% Found 61.67 7.10% 14.14%

was then treated with 1120 50 mL the organic phase EXAMPLE 37separated and the aqueous layer extracted with

CH2C12 100 mL The organic layers were com- Synthesis of

bined dried Na2SO4 and the volatile materials were DL-2-Acetamido-N..benzyl-2-l-morpholineaceta-

removed by ditilation in vacuo to give approximately mide

4.00 97% of light-brown semi-solid material TLC mixture of ethyl 2-acetamido-2-l-morpholineace-analysis showed major spot at Rf 0.30 991 chloro-

tate 0.59 2.56 mmol benzylamine 0.28 9..82

form/methanol The desired compound DL-ethyl10

mniol and sodium cyanide 0.01 0.26 mmol in rnetha-acetamido-2-furanacetate was purified by flash col- anol mL was stirred at 5055 for 18 hr Theumn chromatography on silica gel using 991 chloro- solvent was removed in vacuo and the residue triturated

form/methanol as the eluent to give 3.60 87% of with ethyl acetate mL The white solid 0.35 that

beige solid remained was collected by filtration and identified as15

mp 6870 the desired compound The filtrate was concentrated

DL-Ethyl a-acetamido-2-furanacetate 4.00 19 and the residue purified By flash column chromatogrammol was dissolved in 9010 ethanol/water 150 niL phy 2% methanol/chloroform on Si02 The initial

and then KOH 2.00 35 mmol was added and the fractions gave trace amount 0.09 of DL-2-resulting solution stirred at room temperature 48

20 acetamido-N-benzyl-2-N-benzylamineacetainideThe reaction was concentrated in vacuo and the residue Continued elution gave additional amounts 0.20 of

diluted with H20 and then washed with ethyl ether the title compound50 mL The aqueous layer was then made acidic DL-2-Acetamido-N-benzyl-2-N-ben-

with 8.5% aqueous solution of H3P04 and extracted zylanineacetamidewith ethyl acetate 3X 150 mL The organic layers 25 Yield 0.09 11% mp 135138were combined dried Na2SO4 evaporated to dryness 111 NMR DMSO-d6 81.83 COCH3 3.56

in vacuo to give the desired compound dJ 13.6 Hz NHCH 3.66 dJ 13.6 Hz NHCHYield 2.65 76% Rf 0.37 811 isopropanol/N- 4.23 dJ5.4 Hz CH2 4.89 d38.0 Hz CH

H4OH/H20 nip 172174 7.057.38 10 PhH 8.20 dJ8.0 Hz NH 8.51

30 tJ5.4 Hz NHEXAMPLE 3613C NMR DMSO-d6 22.63 COCH3 42.11 CH2

Synthesis of DL-2-Acetamido-4-pentenoic 48.57 NHCH2 64.41 CH 126.65 C4 126.70 C4Acid-N-benzylamine 127.13 128.00 128.13 128.22 139.24 C1 or Ci 140.12

4-Methylmorpholine 0.55 5.40 mmol was added Ci or Ci 169.61 COCH3 169.90 CONH ppmto stirred solution of 2-acetamido-4-pentenoic acid DL-2-Acetamido-N-benzyl-2-l-morpholuneaceta-

0.81 5.18 mmol in dry tetrahydrofuran 60 mL atmide

10 to 150 under N2 After stirring mm isobu- Yield 0.48 64% R1 0.35 4% methanol/

tyl chloroformate 0.75 5.70 mmol was added lead- chloroform mp 171l72 recrystallized from ethyl

ing to the precipitation of white solid The reaction acetate

was allowed to proceed for additional minutes and40 111 NMR DMSO-d6 61.86 COCH3 2.30-2.40

then solution of benzylamine 0.61 5.70 mmol in CH2NCH2 3.51 br CH2OCH2 4.184.33

tetrahydrofuran 10 mL was added slowly at 10 to CH2 5.07 dJ 8.9 Hz CH 7.187.25 PhH15 After stirring mm at room temperature the 8.23 dJ8.9 Hz NH 8.58 br NH

insoluble salt was removed by filtration The filtrate13C DMSOd6 22.39 COCH3 42.20 CEz 48.43

was evaporated to dryness and the residue was tritu- CH2NCH2 66.03 CH 69.24 CH2OCH2 126.76

rated with ethyl acetate and the remaining white solid C4 127.13 2C2 or 2C3 128.23 2C2 or 2C3 139.42

was filtered to yield the desired product Ci 168.02 COCH3 170.20 CONE ppmYield 0.81 64% R0.36 4% methanol/- EXAMPLE 38

chloroform mp 11 8l20 recrystallized from ethyl50

acetate/cyclohexane Synthesis of

1H NMR DMSO-d6 81.83 COCH3 2.222.49 DL-Ethyl-2-acetamido-2-ethylaminoacetate

CH2CHCH2 4.26dJ5.3 Hz CH2Ph cold 78 solution of ethyl 2-acetamido-2-

4.254.33 CH 4.995.09 CH2CHCH2 bromoacetate 2.10 9.38 minol in dry tetrahydrofu

7.217.29 PhH 8.05 dJ7.6 Hz NH 8.46 br ran 80 niL was added slowly into cooled 78NH tetrahydrofuran 20 mL solution of methylamine 1.40

NMR DMSO-d6 22.41 COCH3 36.24 31.04 mmol over period of 20 miii The reaction

CH2CHCH2 41.91 CH2Ph 52.20 CH 117.15 was stirred at 78 and then at room temperaCH2CHCH2 126.54 C4 126.99 2C2 or 2C3 ture The precipitated salt was filtered and the

128.04 2C2 or 2C3 134.25 CH2CHCH2 139.22 60 filtrate concentrated The residue was purified by flash

Ci 169.02 COCH3 170.96 CONH ppm column chromatography on Si02 using 3% methanol/Mass spectrum ni/e relative intensity 246 chloroform as the eluent to yield the desired compound

205 163 15 140 106 33 9177 70 100 as light yellow oil

Elemental Analysis Calculated 68.27%C 7.37% Yield 0.90 1%11.37% Found 68.55% 7.31% 11.48% 65 RfO.36 4% methanol/chloroform

Mass spectrum m/e relative intensity 292 1H NMR CDC13 0.93 tJ6.7 Hz NHCH2CH3233 158 19 157 100 116 26 115 100 106 1.12 tJ6.8 Hz OCH2CH3 1.87 COCH3 2.48

29 9172 qJ6.7 Hz NHCH2CH3 4.05 qJ6.8 Hz

537872937 38

OCH2CH3 5.05 dJ 7.1 Hz CH 7.09 dJ 7.1 Hz EXAMPLE 42NH3c NMR CDC13 13.64 NHCH2CH3 14.55 Synthesis of Ethyl

OCH2CH3 22.53 COCH3 39.06 NHCH2CH3 2-Acetamido-2-NN-dimethylaminoacetate

61.38 CH 64.14 OCH2CH3 170.09 COCH3 170.20 Ethyl 2-bromo-2-acetamidoacetate 2.00 8.93

COOCH2CH ppm mrnol and Me2NH 5-6 equiv gave the desired product as yellow oilEXAMPLE 39

Yield 1.50 89%Using the procedures described herein the following 10

1H NMR CDCI3 81.25 tJ7.1 Hz 3H 2.02

examples are also prepared 3H 2.23 6H 4.104.25 2ff 5.24 dJ8.3 HzDLa-Acetamido-N-benzyl-3-furanacetatnide 1H 6.59 dJ 8.3Hz 111

DLa-Acetaniido-N-2-fluorobenzyl-3-furanaceta- 3C NMR CDC13 14.05 23.00 40.28 6184

mide 69.24 169.38 170.57 ppmDLa-Acetamido-N-3-fluorobenzyl-3-furanaceta- 15 EXAMPLE 43

mide

DLa-Acetamide-N-4-fluorobenzyl-3-furanaceta- Synthesis of Ethyl

mide 2-Acetamido-2-4-morpholineacetate

a-Acetamide-N-benzyl-2-arninoacetamide Using morpholine 1.71 19.64 mmol and ethyl20 2-bromo-2-acetamidoacetate 2.00 8.93 mmol gave

Preparation of a-Heteroatom Substituted Amino Acidsan oily residue which was purified by flash column

Synthesis of Ethyl 2-Acetamido-2-substituted Acetateschromatography on Si02 gel 2% MeOH/CHC13 to

General Proceduregive the desired product as thick oil

cooled 78 solution of ethyl 2-bromo-2- Yield 1.90 93% RjO.29 3% MeOH/CHC13acetamidoacetate equiv in THF mmol/lO mL

251H NMR CDC13 61.32 tJ6.8 Hz 3H 2.07

was added slowly to THF tnmol/4 mL solution of 3H 2.432.72 4H 3.583.78 in 411 4.26 qJ6.8the nitrogen nucleophile 510 equiv at 78 The Hz 2H 5.27 dJ7.9 Hz 111 6.39 dJ7.9 Hz 1Hreaction was stirred at this temperature 0.5 and then

13C NMR CDC13 14.21 23.25 48.47 62.06

at room temperature The insoluble materials were 3066.71 2C 69.22 169.00 170.46 ppm

filtered and washed with THF The filtrate was concen- EXAMPLE 44trated in vacuo and the residue was purified by flash

Synthesis of Ethyl 2-Acetamido-2-N-anilinoacetatechromatography on Si02 gel using the indicated sol

vent as the eluent to give the desired product Use of aniline 1.83 19.6 mmol and ethyl 2-bromo-

Using this procedure the following examples were 2-acetamidoacetate 2.00 8.93 mmol provided

preparedbrown residue which was purified by flash column

chromatography on Si02 gel CHCI8-2%EXAMPLE 40 MeOH/CHC13 gradient to yield the desired product

Yield 1.80 85% R10.52 4% MeOH/CHC13 mpSynthesis of Ethyl 2-Acetamido-2-aminoacetate40 8789 recrystallized from ethyl acetate/petroleum

Ethyl 2-bromo-2-acetanildoacetate 2.00 8.93 ethermmol and liquid NH3 56 equiv yielded light brown NMR CDC13 81.29 tJ7.l Hz 3H 1.84

residue which on purification by flash column chroma- 311 4.27 qJ 7.1 Hz 211 5.89 dJ 8.2 Hz 111 6.43

tography on Si02 gel 5% MeOH/CHC13 gave the dJ8.2 Hz 111 6.686.71 211 6.806.83 111desired product as yellow oil 45 7.177.22 211 The remaining amino proton was not

Yield 1.00 70% RfO.2l 5% MeOH/CHC13 detected

1H NMR CDC13 61.31 tJ7.l Hz 311 2.03 13C NMR CDC13 13.96 22.98 60.19 62.41 11.87

311 2.61 br 2H 4.24 qJ7.l Hz 2H 5.21 2C 119.29 129.37 2C 144.09 169.77 170.14 ppmdJ7.1 Hz IH 7.50 dJ7.l Hz 111 IR KBr 3340 1720 1635 1590 1490 730 710

13C NMR CDC13 13.72 22.68 59.70 61.73 170.4050 cm1

170.68 ppm Mass spectrum FD 237

Elemental analysis Calculated for C12H16N203EXAMPLE 41 61.00% 6.83% 11.86% Found 60.88%C

6.56% 12.00%Synthesis of Ethyl 55

2-Acetamido-2-methylaminoacetate EXAMPLE 45

Use of ethyl 2-bromo-2-acetamidoacetate 2.00 Synthesis of Ethyl8.93 mmol and MeNH2 2.50 80.6 mmol gave an oily 2-Acetamido-2-N-3-pyrazolylaminoacetateresidue 1.50 The residue was purified by flash col

umn chromatography on Si02 gel 3% MeOH/CHC13Using ethyl 2-bromo-2-acetamidoacetate 200 8.92

mmol and 3-aminopyrazole 1.85 22.32 rental andto yield the desired product as an oil

purification of the reaction product by chromatographyYield 1.00 65% on Si02 gel 2% MeOH/CHCI3 gave the desired prod-

NMR CDCI3 61.32 tJ7.l Hz 311 2.07uct as yellow oil

3H 2.36 3ff 4.26 qJ7.l Hz 2H 5.20 dJ7.4 65 Yield 1.80 89% RfO.35 8% MeOH/CHC13Hz 111 6.60 br 111 1H NMR CDC13 61.21 tJ7.l Hz 3H 1.89

13C NMR CDC13 14.02 23.06 30.84 62.04 65.72 311 4.20 qJ7.1 Hz 211 5.64 dJ 1.8 Hz 1H 5.71

17009 170.40 ppm br IH 5.73 dJ7.1 Hz 1H 7.29 dil.8 Hz

537872939 40

1ff 7.98 dJ7.1 Hz 111 The remaining amino pro- NMR CDC1I 14.06 22.89 40.30 60.01 61.89

ton was not detected 70.16 168.14 170.53 ppmNIMR CDC13 13.73 22.49 61.41 62.02 91.79

130.53 153.02 169.96 170.93 ppm Synthesis of 2-Acetamido-N-benzyl-2-substitUted

Acetarnides General Procedure

EXAMPLE 46mixture of the ethyl 2-substituted-2-acetamidoace-

Synthesis of Ethyl

2-Acetamido-2-N-hydroxyaminOaCetatetate equiv benzylamine 1.2 equiv and NaCN 0.1

equiv in MeOH mmol/25 mL was stirred at 45SOUsing ethyl 2-bromo-2-acetamidoacetate 2.10 9.37

10 18 The solvent was removed in vacuo and the

mmol and anliydrous NH2OH 0.93 28.00 mmol residue was purified using either trituration with

gave an oily residue The residue was purified by flash EtOAc or flash column chromatography on Si02 gel

column chromatography on Si02 gel 5%MeOH/CHC13 to give the desired product The prod-

with the indicated solvent as the eluent

uct was recrystallized from EtOH to give white flayUsing this procedure the following examples were

solid15

prepared

Yield 1.00 1% R10.24 5% MeOH/CHC13 mp EXAMPLE 49119121

1H NMR DMSO-d6 81.19 tJ6.9 Hz 3H 1.87 Synthesis of 2-Acetamido-N-benzyl-2-aminoacetaflhide

3H 4.10 qJ 6.9 Hz 2H 5.09 ddJ 4.0 8.0 Hz 20 Ethyl 2-acetamido-2-aminoacetate 1.00 6.25

1H 6.06 br lii 7.63 lH 8.50 dJ8.O Hz 1H13C NMR DMSO-d6 14.05 22.46 60.82 67.37

mmol benzylamine 0.80 7.5 mmol and NaCN 0.03

169.19 169.48 ppm0.61 mmol gave residue which solidified on stand

IR KBr 3300 1750 1660 1540 1390 610 cm1 ing 18 The reaction mixture was triturated with

Mass spectrum FD 177 25EtOAc 20 mL The white solid which remained was

Elemental analysis Calculated for C6H12N204 filtered and then further purified by recrystallization on

40.91% 6.87% 15.90% Found 40.79% from EtOAc

6.87% 15.90% Yield 1.00 72% RfO.21 5% MeOH/CHC13 mp

EXAMPLE 47131133 dec.

30 111 NMR DMSO-d6 61.83 311 2.35 br 2HSynthesis of Ethyl 4.28 dJ4.4 Hz 211 4.91 J7.0 Hz 1H

7.207.32 5H 8.31 br 111 8.51 br 1HMeNHOH 17.39 mmol prepared from MeNHOH- 13C NMR DMSO-d6 22.66 42.05 60.29 126.67

HC1 2.00 23.95 mmol and NaOMe 0.94 17.39 127.10 2C 128.18 2C 139.23 169.24 170.67 ppmmmol and ethyl 2-bromo-2-acetamidoacetate 1.00 IR KBr 3300 1650 br1530 br 1450 740 cm14.46 rnmol gave an oily residue The residue was tritu

rated with EtOAc mL and the solid that remainedMass spectrum m/e relative intensity 222

was filtered and recrystallized from EtOH to give the 100 221 29 133

desired product as white solidElemental analysis Calculated for

Yield 0.70 82% Rj0.34 5% MeOH/CHCI3 mp40 C11H15N30259.71% 6.83% 18.99% Found

148l50 59.86%C 6.88% 11 18.72%

NMR DMSO-d6 81.17 tJ7.0 Hz 311 1.89 EXAMPLE 50311 2.37 3H 4.004.20 2H 5.04 dJ9.2 HzIH 8.17 111 8.43 dJ9.2 Hz 1H Synthesis of

NMR DMSOd6 14.04 22.28 43.78 60.79 2-Acetamido-N-benzyl-2-xnethylaminOacetamide

71.46 168.29 170.23 ppmIR KBr 3320 3200 br 1760 1660 1530 1470 720 Ethyl 2-acetamido-2-methylaminoacetate 1.50

640 cm1 8.63 mmol benzylamine 1.11 10.35 mmol and

Mass spectrum FD 192 NaCN 0.04 0.82 mmol gave brown residue which

Elemental analysis Calculated for C7H14N204.0.2550

was purified by flash column chromatography on SiOz

1120 43.18% 7.5 1% 14.39% Found 43.28% gel 2% MeOH/CHC13 to yield the desired product

7.25% 14.64% Yield 1.00 49% R10.33 3% MeOH/CHC13 mp115i 17 recrystallized from ethyl acetate/peEXAMPLE 48troleum ether

Synthesis of Ethyl 1H NMR DMSO-d6 61.87 311 2.18 3H4.20-4.29 211 4.87 dJ7.9 Hz 111 7.247.35

tate511 8.14 dJ7.9 Hz 111 8.55 br 111 The remain

MeNHOMe 17.40 mmol prepared from MeN-ing amino proton was not detected

HOMe-HC1 2.18 22.32 mmol and NaOMe 0.94 60 13c NMR DMSO-d6 22.52 31.37 42.04 65.99

17.40 mmol and ethyl 2-bromo-2-acetamidoacetate126.68 127.12 2C 128.18 2C 139.28 169.51 169.83

1.00 4.46 mmol gave residue which was purified

by flash column chromatography on Si02 gel 1% ppm

MeOH/CHC13 to give the desired product as an oilIR KBr 3240 1610 br 1500 br 1430 725670

Yield 0.30 66% RjO.53 2% MeOH/CHC13 65cm1

1H NMR CDC1I 81.35 tJ7.O Hz 311 2.12 Elemental analysis Calculated for CI2H17NIO2

311 2.62 311 3.46 3H 4.30 qJ7.O Hz 211 61.26% 7.28% 17.86% Found 61.12%

5.36 dJ8.9 Hz 1H 6.66 dJ8.9 Hz 111 7.01% 17.71%

537872941 42

remained was filtered and purified by flash columnEXAMPLE 61

chromatography on Si02 gel 798 MeOH/CHC13 to

Synthesis of give the desired product

2-Acetamido-N-benzyl-2-ethylaminoacetanuide Yield 0.90 44% RfO.35 8% MeOH/CHC13 nip

Using ethyl 2-acetamido-2-ethylaininoacetate 0.90 135137

4.79 mmo1benzylamine 0.62 5.75 mniol and NMR DMSO-d6 61.82 3114.29 dJ5.9 HzNaCN 0.03 g-0.51 mmol gave an oily residue which 2H 5.515.55 3H 7.187.40 6H 8.36 br

was purified by flash column chromatography on Si02 111 8.53 br 111 11.66 br 111

gel 3% MeOH/CHC13 to give the desired product as 13C NMR DMSO-d6 22.59 42.29 61.79 90.68

white solid 10126.67 127.07 2C 128.17 2C 129.10 139.41 153.53

Yield 0.35 29% RjO.34 4% MeOH/CHCL3 nip 169.19 169.67 ppm123125 recrystallized from ethyl acetate/hex- JR KBr 3230 br 1620 br 1500 br 1430 730

ane 690 cm11H NMR DMSO-d6 60.93 tJ6.8 Hz 311 1.81 Mass spectrum m/e relative intensity 288

311 2.08 br 111 2.402.48 211 4.22 dJ5.5 15 64 287 M2 230 28 229 100 153 46Hz 2H 4.90 dJ7.8 Hz 111 7.207.27 5H 8.08 Elemental analysis Calculated for C14H17N502.0.5dJ7.8 Hz 111 8.48 tJ5.5 Hz 111 1120 56.47% 6.12% It 23.63% Found 56.63%

13C NMR CDC13 15.14 22.97 37.65 43.53 65.68 5.79% 23.43%127.44 2C 127.50 128.64 2C 137.73 169.75 171.20

20 Preparation of Functionalized a-HeteroatomppmJR KBr 3250 1620 br 1510 br 1450 br 740 Substituted Amino Acid General Procedure

680 cmBBr3 solution 1M in CH2C12 1.1 equiv was added

Elemental analysis Calculated for C13H19N302to solution of 2-acetamido-N-benzyl-2-ethoxyaceta-

62.63% 7.68% 16.85% Found 62.69%

7.49% 16.65% 25mide equiv in CH2C12 10 mmol/l25 mL The mixture was stirred at room temperature and then

EXAMPLE 52 concentrated to dryness in vacuo to give 2-acetamido-

Synthesis of N-benzyl-2-bromoacetaunide as pale yellow crystal

2-Acetamido-N-benzyl-2-N-anilinoacetamideline material The bromo adduct was then dissolved in

Employing ethyl 2-acetamido-2-N-anilinoacetat30 THF 10 tnmol/250 niL cooled 78 and then

added over 15 miii interval to cooled 782.00 8.47 mmol benzylaniine 1.09 10.00 mmol solution of the heteroatom nucleophile in THFand NaCN 0.04 0.84 mmol gave white solid which

mmol/1 niL The reaction mixture was stirred at this

separated during the course of the reaction The precip-temperature 30 miii and then at room temperature 90

itate was filtered and purified by recrystallization frommiii The insoluble salts were filtered and the filtrate

absolute EtOH to give the desired product concentrated in vacuo The residue was then purifiedYield 1.10 44 mr 183l85

by flash column chromatography on Si02 gel using the1H NMR DMSO-d6 61.84 311 4.31 dJ 5.8

indicated solvent as the eluentHz 211 5.67 tJ 8.1 Hz 111 6.04 dJ 8.1 Hz

Using this procedure the following examples were6.596.64m 111 6.706.72 211 7.067.11 2H7.207.33 5H 8.41 dJ8.1 Hz 1ff 8.72 tJ5.8 prepared

Hz 111 EXAMPLE 54

3C NMR DM50-il6 22.46 42.25 60.42 113.21

2C 117.22 126.72 127.16 2C 128.18 2C 128.77 Synthesis of

2C 138.99 145.88 168.65 169.70 ppm 2-Acetaunido-N-benzyl-2-NN-dimethylamunoaceta-

JR KBr3270 1630 1520 1490 1430 740690cm1 wide

Mass spectrum m/e relative intensity 297 By making use of 2-acetamido-N-benzyl-2-ethox-

239 164 28 163 100 20 121 100 106 47 104 yacetamide 3.00 12.0 mmol BBr3 lM in CH2C12

65 93 63 9177 13.2 mL 13.2 mmol and Me2NH 56 equiv was obElemental analysis Calculated for C17H19N302

50tamed brown residue which was purified by flash

68.67% 6.44% 14.13% Found 68.94% column chromatography on Si02 gel 2.5%6.42% 13.92% MeOH/CHC13 to give the desired product The prod-

EXAMPLE 53uct was recrystallized from ethyl acetate/hexane to

give light yellow cubic crystals

Synthesis of Yield 1.20 40% R10.39 5% MeOH/CHC13 mp2-Acetaniido-N-benzyl-2-N-3-pyrazolylaminoaceta- 1o4lo6

mide 111 NMR DMSO-d6 61.91 311 2.11 611 4.22

solution of ethyl 2-acetamido-2-N-3- ddJ5.2 14.7 Hz 111 4.34 ddJ6.l 14.7 Hz 111

pyrazolylaininoacetate 1.60 7.1 mmol in MeOH 5.11 dJ8.3 liZ 111 7.237.31 511 8.18

40 mL containing beazylaunune 0.83 7.8 mmol and J8.3 Hz 111 8.55 br 111

NaCN 50 mg mmol was stirred at 4555 18 NMR DMSO-d6 22.43 40.33 2C 42.28 69.42

TLC analysis 8% MeOH/CHC13 of the reaction mix- 126.73 127.27 2C l28.2l2C 139.49 168.49 170.31

ture indicated the presence of only minor amount of PPmproduct second lot of NaCN 50 mg mmol was IR KBr 3280 1670 br 1500 br 1460 760700then added and the reaction was allowed to proceed at 65 cm1 Mass spectrum FD 250

4555 and then at room temperature 48 Elemental analysis Calculated for C13H19N302The solvent was removed in vacuo and the residue was 62.63% 7.68% 16.85% Found 62.82%

triturated with EtOAc 15 mL The insoluble solid that 7.66% 16.69%

537872943 44

of NH2OH 5-6 equiv in THF 50 mL at 10 TheEXAMPLE 55reaction mixture was stirred30 mm at this temperature

Synthesis of and then allowed to warm to room temperature

2-Acetarnido-N-benzyl-2-N-hydroxyaxninoacetainide The insoluble materials were filtered and the filtrate

Using 2-acetamido-N-benzyl-2-ethoxyacetamide was concentrated in vacuo The residue was separated

2.00 8.0 mwol BBr3 1M in CH2C12 8.8 mL 8.8 into two components by flash column chromatography

mmoland arthydrous NH2OH 56 equiv gave an oily on Si02 gel 7.5% MeOH/CHC13residue The residue was separated in three components

by flash chromatography on Si02 gel 5% 2-Acetamido-N-benzyl-2-N-hydroxyaminoacetamide

MeOH/CHC13 10 Yield 0.66 23% mp 144l46 dec recrystallized from EtOH

2-Acetaxnido-N-benzyl ..2-N-hydroxyaminoacetamide

Yield 0.14 7% R0.30 8% MeOH/CHC13 mpDimer

144146 dec recrystallized from EtOH Yield 0.10 5% mp 184i 86 recrystallized1H NMR DMSO-d6 61.88 311 4.31 dJ5.7 15 from MeOH

Hz 211 5.08 ddJ4.4 8.1 Hz 5.94 ddJ2.8 Dimer was not observed under these conditions4.4 Hz 111 7.197.35 5H 7.52 dJ2.8 Hz 1118.26 dJ8.l Hz 111 8.42 tJ5.7 Hz 111 EXAMPLE 57

13C NMR DMSO-d6 22.69 42.25 67.86 126.69 Synthesis of127.14 2C 128.18 2C 139.08 168.53169.67 ppm 20

2-Acetamido-N-benzyl-2-N2-phenylhydrazinoaceta-JR K.Br 3320 br 1660 br 1540 br 1460 750 mine

700cm1Mass spectrum FD 238 Using 2-acetamido-N-benzyl-2-ethoxyacetamide

Elemental analysis Calculated for c11H18N303 2.00 8.0 mmol BBr3 1M in CH2C12 10.0 mL 10.0

55.69% 6.37% 17.71% Found 55.86% 25 mmol and phenylhydrazine 2.60 24.0 mmol gave

6.37% 17.38% pale yellow oily residue which was purified by flash

column chromatography on Si02 gel 2%Dirner

MeOH/CHCL3 to give the desired product The prod-

Yield 0.05 3% Rf 0.27 8% MeOH/CHC13 mp uct was recrystallized from chioroform/hexane as

177179 recrystallized from EtOH 30 light yellow solid

1H NMR DMSO-d6 61.82 611 4.254.34 Yield 0.75 29% Rj0.26 2% MeOH/CHC13 mp411 5.21 dJ9.3 Hz 2H 7.207.33 1011 8.16 132134dJ9.3 Hz 2H 8.26 tJ5.8 Hz 211 8.51 lii 1H NMR DMSO-d6 81.89 3H 4.28 dJ5.8

13C NMR DMSO-d6 22.54 2C 42.30 2C 67.55 Hz 211 4.89 dJ5.2 Hz 111 5.09 ddJ5.2 7.4 Hz2C 126.63 2C 127.13 4C 128.11 4C 139.02 2C 35 111 6.61 tJ7.4 Hz 111 6.707.28 1OFI 8.29

168.24 2C 169.33 2C ppm dJ7.4 Hz 111 8.60 tJ5.8 Hz 111JR KBr 3240 br 1640 br 1510 br 1450 690 13C NMR DMSO-d6 22.88 42.22 66.22 112.66

cm1 2C 117.57 126.65 127.08 2C 128.15 2C 128.53

Mass spectrum FD 442 2C 139.12 149.90 168.66 170.04 ppmElemental analysis Calculated for C22H27N505 40 JR KBr 3300 1640 br 1610 1.520 br 1460 760

59.85% 6.16% 15.86% Found 59.5G% 7YJ cm16.08% 15.64% Mass spectra FD 313 Ml

Dimer Elemental analysis Calculated for Cj7H2N4O265.37% 6.45% 17.94% Found 65.15%

Yield 0.10 6% R10.18 8% MeOH/CHCI3 mp 45 6.25% 17.71%184186 recrystallized from MeOH

1H NMR DMSO-d6 61.87 611 4.20 ddJ5.3 EXAMPLE 5815.3 Hz 211 4.44 ddJ6.2 15.3 Hz 211 5.28

Synthesis ofdJ 9.0 Hz 211 7.157.31 1011 8.00 dJ 9.02-Acetanuido-N-benzyl-2-N2-benzyloxycarbonylhy-Hz 211 8.39 ddJ5.36.2 Hz 211 8.51 111 so

drazinoacetamide13C NMR DMSO-d6 22.50 2C 42.58 2C 69.98

2C 126.73 2C 127.23 4C 128.22 4C 139.08 2C Employing 2-acetamido-N-benzyl-2-ethoxyaceta-

167.60 2C 169.57 2C ppm mide 3.00 12.0 mmol BBr3 1M in CH2C12 15.0 mLJR KBr 3300 br 1660 br 1530 br 1450 740 15.0 mmol and benzyl carbazate 4.58 27.6 mmol

700cm1 0.95 1% of the desired product was obtained TheMass spectrum FD 442 product was recrystallized from chloroform/hexane to

Elemental analysis Calculated for give white amorphous solid Rf 0.32 2%C22H27N50559.85% 6.16% 15.86% Found MeOH/CHC13 mp 152l5460.09% 5.93% 15.76% NMR DMSO-d6 61.85 3H 4.27 dJ4.4

EXAMPLE 56 Hz2H 5.00s2H 5.14 ddJ 3.18.0Hz 111 5.23

tJ3.1 Hz 1H 7.257.35 1OH 8.26 dJ8.0 HzImproved Synthesis of iH 8.56 br 111 8.66 br 111

2-Acetamido-N-benzyl-2-N-hydroxyaminoacetamide 13C NMR DMSO-d6 22.71 42.23 65.56 65.97

2-Acetamido-N-benzyl-2-bromoacetamide prepared 126.69 127.16 2C 127.61 2C 127.77 128.13 2Cfrom 2-acetamido-N-benzyl-2-ethoxyacetaxriide 3.00 65 128.27 2C 136.74 138.87 168.04 169.95 ppm12.0 mmol and BBr3 IM in CH2C12 17.2 mL 17.2 JR KBr 3325 1620 br 1500 br 1440 740680

rental was dissolved in THF 250 mL cooled 10 cmand then added dropwise 30 miii to suspension Mass spectrum FD 371

537872945 46

Elemental analysis Calculated for C19H22N40461.61% 5.99% 15.13% Found 61.40%

EXAMPLE 61

6.21% 15.39% Synthesis of

2-Acetamido-N-benzyl-2-ethylmercaptoacetamideEXAMPLE 59

Synthesis ofUsing the procedure described for the synthesis of

2-acetamido-N-benzyl-2-methylmercaptoacetamide2-Acetamido-N-benzyl-2-phenoxyacetaxnide

2-acetaniido-N-benzyl-2-ethoxyacetamide 2.00 8.0

Using 2-acetarnido-N-beazyl-2-ethoxyacetaniide mmol and EtSH 0.65 10.4 mmol were converted to

3.00 12.0 mmol BBr3 1M in CH2C12 15.0 mL 15.0 0.80 38% of the desired product The compoundinmol and NaOPh 4.18 30 mmol gave brown oily

10

was further purified by recrystallization from chiororesidue which was purified by flash column chromatog- form/hexane to give beige solid Rf 0.60 4%raphy on Si02 gel using first CHCI3 and then 2% MeOH/CHC13 mp 146148MeOH/CHCI3 as the eluents to give the desired prod- 1H NMR DMSO-ds 1.56 tJ7.4 Hz 3H 1.88

uct The compound was recrystallized from chloro-15 3H 2.492.67 2H 4.23 ddJ5.9 15.2 Hz 1H

form/hexane4.32 ddJ5.9 15.2 Hz 1H 5.55 dJ9.1 Hz lii

Yield 0.80 22% 7.207.35 5H 8.59 dJ9.1 Hz 1H 8.75 tJr5.9R10.58 3% MeOH/CHC13 nip 125128 soft- Hz 1H

ens at 122 C. 13C NMR DMSO-d6 14.73 22.43 23.73 42.101H NMR DMSO-d6 61.83 3H 4.35 dJ5.7 20 53.70 126.87 127.14 2C 128.32 2C 139.01 167.89

Hz 2H 6.18 dJ9.4 Hz 1H 6.946.99 2H169.02 ppm

7.027.33 8H 8.98 tJ5.7 Hz 1H 9.10 dJ9.4 IR KBr 3240 1620 br 1510 br 1415 680 640Hz lii cm1

13c NMR DMSO-d6 22.54 42.24 76.44 116.09Mass spectrum FD 267 M12C 121.78 126.84 127.26 2C 128.25 2C 128.44 25 Elemental analysis Calculated for C13H1SN2O2S.0.252C 138.84 155.97 166.63 170.73 ppm H20 57.65% 6.88% 10.34% Found 57.48%

JR KBr 3300 1650 br 1600 1530 br 1490 14506.84% 10.28%

760 700 cm1Mass spectrum FD 299 Preparation of Fimctionalized a-Heteroatom

Elemental analysis Calculated for C17H18N2O3.0.5 30 Substituted Amino Acids General Procedure

H20 66.43% 6.23% 9.11% Found 66.62%mixture of 2-acetanildo-2-NNN-trimethylam-

6.23% 9.16%moniumacetamide tetrafluoroborate eqiuv and the

EXAMPLE 60 nitrogen nucleophile 45 equiv in MeOH mmol/l

Synthesis of mL was stirred at 5560 The solvent was

2-Acetamido-N-benzyl-2-methylmercaptoacetamideremoved in vacuo and the residue was purified by flash

column chromatography on Si02 gel using the indicooled 78 solution of Et3N 4.85 48.0 cated solvents as the eluent

mmol in THF 20 mL was added to cooled 780 Using this procedure the following examples weresolution of 2-acetaniido-N-benzyl-2-bromoaceta- prepared

mide prepared from 2-acetamido-N-benzyl-2-ethox-

yacetamide 4.00 16.0 mmol and BBr3 1M in EXAMPLE 62

CH2C12 20.0 niL 20.0 mmol in THF 275 niL Synthesis ofcooled 78 solution of excess MeSH 56 equiv

2-Acetamido-N-benzyl-2-N-methoxyaminoacetamidein THF 55 niL was then added The reaction mixture

was stirred at this temperature 30 mm and then at Using MeOH solution of MeONH2 prepared from

room temperature The insoluble materials were MeONH2.HC1 2.83 33.9 inmol and NaOMe 1.41

filtered and the filtrate was evaporated to dryness in26.1 mmol and 2-acetamido-2-NNN-trimethylam-

vacuo The oily residue obtained was purified by flash moniumacetaanide tetrafluoroborate 2.70 7.67

column chromatography on Si02 gel 2% 50mmol gave an oily residue which was purified by flash

MeOH/CHC13 to give 1.10 27% of the desired column chromatography on Si02 gel 2%product as yellow orange oil The product was iuri- MeOH/CHC13 to give the desired product The prod-

fled by second flash column chromatography on 5i02 uct was recrystallized from chloroform/hexane

gel 2% MeOH/CHCI3 to give 0.72 of the pure prod- Yield 0.80 42% RfO.23 2% MeOH/CHC13 mpuct as white solid 55

9597

Rf 0.65 3% MeOH/CHC13 mp 155157 1H NMR DMSO.d6 81.88 3ff 3.38 3H1H NMR CD3NO2 61.98 3H 2.08 4.39 4.224.41 2H 5.18 ddJ4.9 7.8 Hz lii 6.78

ddJ6.1 15.2 Hz 1H 4.49 ddJ6.l 15.2 Hz lH dJ4.9 Hz 1H 7.217.32 5H 8.33 dJ7.8 Hz5.51 dJ7.8 Hz 1H 7.15 dJ7.8 Hz 1H 7.177.41 1ff 8.56 br lii

6H 60 13C NMR DMSO-d6 22.64 42.28 61.42 66.25

13C NMR CD3NO2 12.28 22.94 44.26 56.03 126.74 127.19 2C 128.19 2C 139.11 167.95 169.66

128.46 128.60 2C 129.77 2C 140.17 169.19 171.06 ppmppm IR KBr 3300 1650 1620 1510 br 1440 750 680

JR KBr 3320 1650 br 1520 br 1460 750 cm1 cm1Mass spectrum FD 253 65 Mass spectrum FD 252

Elemental analysis Calculated for C12H16N202S Elemental analysis Calculated for C12H17N303

57.12% 6.39% 11.10% Found 57.06% 57.63% 6.82% 16.72% Found 57.06%

6.57% 11.28% 6.63% 16.65%

537872947 48

lized from chioroform/hexane to give white amorEXAMPLE 63

phous solid

Synthesis of Yield 0.80 64% RfO.29 4% MeOH/CHC13 mp

2-Acetamido-N-benzyl-2-N-N-methylhYdrOx- 149-i 51

yaminoacetainide NMR DMSO-d6 61.91 3H 2.052.20 in2H 2.452.89 1ff 2.983.07 111 3.743.90

An MeOH sution 30 mL of MeNHOH 21.74211 4.25 ddJ6.1 15.3 Hz 111 4.35 ddJ6.l 15.3

mmol jrepart from MeNHOH.HC1 2.36 28.26Hz 1H 5.23 dJ9.2 Hz 1H 7.157.35 in 5H 8.49

mmol and NaOMe 1.17 21.74 mmol and 2-

acetamido-2-NNN-trimethylammOniUmaCetafl1idedJ9.2 Hz 1H 8.56 hr

tetrafluoroborate 2.20 6.25 mmol gave residue10 NMR DMSO-d6 22.26 28.26 42.15 18.91

66.19 68.77 126.64 127.02 2C 128.13 2C 139.22which was purified by flash column chromatography

167.43 170.27 ppmon Si02 gel 6% MeOH/CHC13 to give the desired

JR KBr 3400 br 3300 1650 1530 1470

product as white solid The product was then purified740700610 cm1

by recrystallization from EtOH15 Mass spectrum FE 278

Yield 0.95 61% Rj0.32 8% MeOH/CHC13 Xfl Elemental analysis Calculated for C14H19N303159-161 60.64% 6.91% 15.15% Found 60.16%

1H NMR DMSO-d6 81.95 3H 2.43 3H 4.267.04% 15.07%

ddJ5.7 15.1 Hz 1H 4.35 ddJ5.7 15.1 Hz 1H5.09 dJ9.1 Hz 111 7.217.29 in 511 8.05 111 20 Preparation of Functionalized a-Heteroatom

8.18 dJ9.1 Hz 111 8.23 tJ5.7 Hz 111 Substituted Amino Acids General Procedure

NMR DMSO-d6 22.40 42.34 43.92 71.49 2-Acetamido-N-benzyl-2-ethoxyacetamide equiv126.62 127.12 2C 128.12 2C 139.14 167.82 170.28

was suspended in Et20 100 mL/10 mmol and then

PPin BF3.Et20 1.62.4 equiv was rapidly added and the

JR KBr 3444 br 3300 1640 1530 1460 750 700 25resulting solution was stirred 10 mm The nucleophileC1 1120 or EtSH 1.6-4.0 equiv was then added and the

Mass spectrum FE 252 reaction was stirred at room temperature 1848 The

Elemental analysis Calculated for C12H17N303 reaction was then quenched by the addition of an aque57.36% 6.82% 16.72% Found 57.65% ous NaHCO3 100 mL/10 mmol/ice mixture The ex6.59% 16.66% 30 perimental workup varied slightly for each compound

EXAMPLE 64 and is described in the following examples along with

the observed spectral propertiesSynthesis of

EXAMPLE 66

yaminoacetamide Synthesis of

An MeOH solution 20 inmol of MeNHOMe 17.39 2-Acetamido-N-benzyl-2-hydroxyacetamidO

mmol prepared from MeNHOMe.HC1 2.20 23.02 Reacting 2-acetamido-N-benzyl-2-ethoxyacetamide

mmol and NaOMe 0.94 17.39 mmol and 2- 1.00 4.0 mmol BF3.Et20 0.91 6.4 mmol and

acetajnido-2-NNN-triinethylainmoniumacetamide HO 0.12 6.7 mmol followed by aqueous NaHCO3tetrafluoroborate 2.10 5.97 mmol gave solid resi- workup gave an aqueous reaction mixture The solution

due Flash column chromatography of the solid on was then extracted with EtOAc 50 mL and the

Si02 gel 2% MeOH/CHC13 yielded pure desired combined EtOAc extracts were dried Na2SO4 and

product The product was recrystallized from EtOH concentrated in vacuo The residue was purified byYield 1.30 82% Rr0.39 2% MeOH/CHC13 mp flash column chromatography on Si02 gel 3%

165167 MeOH/CHC13 to give the desired product as white

NMR DMSO-d6 61.93 311 2.43 3H 3.32 solid

4.25 ddJ5.9 14.9 HZ 111 4.37 ddJ5.9 Yield 0.30 34% Rj0.l4 3% MeOH/CHC13 mp14.9 Hz 1H 5.19 dJ9.4 Hz 1H 7.217.35 in 1361388.31 dJ9.4 Hz 111 8.56 tJ5.9 Hz 111

50NMRDMSO-d6 61.85 3H 4.29 dJ5.9 Hz

13C NMR DMSO-d6 22.36 39.68 42.34 59.16 211 5.48 ddJ5.5 8.6 Hz 111 6.47 dJ5.5 Hz70.33 126.74 127.41 2C 128.21 2C 139.30 167.38 111 7.217.35 in 5H 8.52 t35.9 Hz 111 8.59

170.30 ppm dJ8.6 Hz 111

JR KBr 3300 1640 br 1540 br 1460 750 700 NMR DMSO-d6 22.66 41.99 71.42 126.66

cm1 127.22 2C 128.13 2C 139.20 169.47 169.62 ppmMass spectrum FE 266 JR KBr 3300 1620 1530 br 1430 br 730690

Elemental analysis Calculated for C13H19N303 cm158.85% 7.22% 15.84% Found 59.05% Mass spectrum mle relative intensity 223

7.37% 15.75% 163 11 134 106 46 91100 77 22 65 38Elemental analysis Calculated for C11H14N203

EXAMPLE 6559.45% 6.35% 12.61% Found 59.21%

Synthesis of 6.36% 12.50%

2-Acetamido-N-benzyl-2-N-isoxazolidinOacetaiflide EXAMPLE 62

Using 2-acetamido-2-NNN-trimethylammonium-synthesis of

acetamide tetrafluoroborate 1.60 4.55 mmol isox- 652-Acetamido-N-benzyl-2-ethylmercaptOaCetatflide

azolidine prepared from isoxazolidine hydrobromide

2.41 15.65 mmoi and NaOMe 0.70 13.04 mmol Using 2-acetamido-N-benzyl-2-ethoxyacetamide

gave the desired product The product was recrystal- 2.00 8.0 mmol BF3.Et20 2.72 19.2 mmol and

537872949 50

EtSH 2.38 38.4 mmol gave an aqueous reaction in nitromethane mL The reaction mixture wasmixture The solution was extracted with CHC13 stirred at this temperature 15 mm and then at room

100 mL The combined CHC13 layers were dried temperature Anhydrous Et20 -50 mL was

Na2SO4 and then concentrated in vacuo to give the added to the reaction mixture and the white solid that

desired product as white solid separated was filtered washed with Et20 and dried in

Yield 1.90 89% R10.60 4% MeOH/CHC13 mp vacuo148149 tinixed melting point with an authentic Yield 1.95 72% mp 171173 dec.staple of Example 61 was undepressed NMR CD3NO2 62.14 3H 3.18 9H 4.50

EXAMPLE 68 dJ5.8 Hz 5.70 dJ9.3 Hz 111 7.307.41 in10 5H 7.57 dJ9.3 Hz IH 7.70 br 111

Synthesis of 22-Diacetamido-N-benzylacetamide lB KBr 3300 1680 br 1530 1490 710 cm1Ac20 mL was added to solution of 2-acetamido- Mass spectrum PD 264

N-ben.zyl-2-aminoacetamide 1.10 4.98 mmol in dry Elemental analysis Calculated for C4H22N302BF4

pyridine 10 mL and then CH2CI220 mL was added 47.89% 6.3l%H 11.97% Found 47.80%

The mixture was stirred at room temperature and 15 6.33% 12.00%

then the volatile materials were removed in vacuo The EXAMPLE 71residue was then treated with saturated aqueous Nail

C03 solution 50 mL The white solid that remained Synthesis of

was the desired product and was filtered dried Na2 2-Acetaniido-N-benzyl-2-ethylmercaptoacetamide-S-

SO4 and recrystallized from MeOH 20 oxide

Yield 1.20 92% mp 265267 dec. solution of m-chloroperbenzoic acid 100NMR DMSO-d6 61.84 611 4.26 dJ5.8 65% 3.76 mmol in CH2C12 10 mL was addedHz 2H 5.71 tJ7.6 Hz 1H 7.20-7.3 511 8.44

dropwise into stirred cooled 10 to 150

dJ7.6 Hz 211 8.48 tJ5.8 Hz 111 CH2C12 solution 125 mL of 2-acetanlido-N-benzyl-2-DMSO-d6 22.44 2C 42.26 56.99 126.62 25

ethylmercaptoacetamide 1.00 3.76 inmol under127.02 2C 128.12 2C 139.15 168.19 169.39 2C N2 The reaction was stirred 30 mm at this temperappm ture and then the m-chlorobenzoic acid was precipi

JR KBr 3260 1530 1500 740 690 cm1tated as its ammonium salt by passing NH3 gas over the

Mass spectrum FD 264surface of the reaction solution The excess NH3 was

Elemental analysis Calculated for C3H7N303 30removed by passing N2 gas through the solution 20

59.30% 6.51%H 15.96% Found 59.16%rain at room temperature The ammonium salt was

6.49%H 15.86%filtered and the filtrate was concentrated in vacuo The

EXAMPLE 69 residue was purified by flash chromatography on SiO2

gel 2% MeOH/CHC13 to give the desired productSynthesis of

The product was recrystallized from chloroform/hex2-Acetamido-N-benzyl-2-trifluoroacetamidoacetamide ane as white granular solid

Ice cold trifluoroacetic anhydride mL was added Yield 0.55 52% RfO.23 2% MeOH/CHCI3 mpin one portion to ice cold 2-acetamido-N-benzyl-2- l35137aminoacetaniide 1.00 4.53 mmol The reaction was NMR DMSO-d6 61.15 tJ7.5 Hz 311 1.99

accompanied by the evolution of heat After stirring 3H 2.492.56 111 2.652.72 in 111 4.34

mm the volatile materials were removed in vacuo The dJ5.7 Hz 2H 5.55 dJ9.5 Hz 1H 7.237.34

residue was treated with saturated aqueous Nal-ICO3 511 8.74 dJ9.5 Hz IH 8.77 tJ5.7 Hz 1Hsolution 20 mL and the solid that remained was flu- 3C NMR DMSO-d6 7.03 22.34 42.40 42.47 67.15

tered and washed with H20 to give the desired product 126.89 127.27 2C 128.24 2C 138.55 164.66 170.18

The product was recrystallized from EtOH ppmYield 1.00 70% RfO.34 8% MeOH/CHC13 mp IR KBr 3300 br 1640 br 1510 br 1370 1230

228230 1100 1020 900cm11H NMR DMSO-d6 61.90 s3H 4.30 dJ5 Hz Mass spectrum PD 283

211 5.85 dJ8.0 Hz 7.217.35 511 8.64 Elemental analysis Calculated for C13H18N2O3S

dJ8.0 Hz 111 8.75 tJ5.1 Hz 1H 10.04 111 55.30% 6.43% 9.92% Found 55.17% 6.38%13C NMR DMSO-d6 22.52 42.52 57.42 117.4 9.70%

qJCF288.3 Hz 126.80 127.16 2C 128.21 2C EXAMPLE 72138.93 156.14 qJCF35.3 Hz 166.39 169.88 ppm

lB KBr 3300 1720 1660 1520 1380 760700 cm1 Synthesis of

Mass spectrum PD 318 2-Acetamido-N-benzyl-2-S-ethylmercaptoacetamide-Elemental analysis Calculated for C3H4N3O3F3 S-oxide

49.21% 4.45% 13.24% Found 49.48%solution of Na104 1.77 8.27 mmol in H20 20

4.43% 13.10% mL was added dropwise into stirred solution of 2-

EXAMPLE 70 60 acetamido-N-benzyl-2-ethylmercaptoacetamide 2.00

7.52 mmol in MeOH 25 mL precipitate apSynthesis of

peared rapidly 1120 30 mL was added to the mix2-Acetamido-N-benzyl-2-NNN-trimethylammomum- ture to dissolve most of the suspension and the reaction

acetarnide Tetrafluoroboratewas stirred at room temperature The reaction was

solution of 2-acetamido-N-benzyl-2-NN-dime- 65 concentrated in vacuo and the remaining aqueous mixthylaminoacetamide 1.93 7.76 mmol in nitrometh- ture was extracted with CHC13 100 mL The coin

ane mL was added slowly to an ice cold solution of bined CHC13 extracts were dried Na2SO4 and the

trimethyloxonium tetrafluoroborate 1.26 8.54 mmol solvent was removed in vacuo The oily residue 1.95

537872951 52

92% solidified on drying in vacuo NMR analysis NMR DMSO-d6 5.72 22.27 42.63 45.t3 69.14

DMSO-d6 of the product showed that it was 21 127.02 127.28 2C 128.33 2C 138.16 161.88 169.83

mixture of the two diastereomers of the desired prod- ppmuct The reaction was recrystallized from EtOAc to IR KBr 3300 2940 1660 1520 1310 1230 1120

give nearly pure diastereomer 1.20 that was ob- 900 cm1mined from thm-chloroperbenzoic acid reaction The Mass spectrum FD 298

EtOAc motheiliquor was concentrated and the remain- Elemental analysis Calculated for C13H18N204S

ing residue 0.75 was recrystallized from ethyl aceta-52.33% 6.08% 9.39% Found 52.52% 6.06%

te/hexane to give diastereomeric mixture 0.41 of10

9.53%

the two diastereomers and in 23 ratio respec- EXAMPLE 74

tivelySynthesis of

Rf 0.60 4% MeOH/CHC13 mp 135137 soft-2-Acetamido-N-benzyl-2-NNN-trimethylammonium-

ens at 117 C.acetainide Tetrafluoroborate

IR KBr 3300 br 1640 br 1510 br 1370 1230

1100 1020 900 cm1 solution of 2-acetamido-N-benzyl-2-NN-dime-

Mass spectrum FD 283 thylaminoacetamide 1.93 7.76 mmol in nitrometh

Elemental analysis Calculated for C3H1gN203S ane mL was added slowly to an ice cold solution of

55.30% 6.43% 9.92% Found 55.58% trimethyloxonium tetrafluoroborate 1.26 8.54 mmol6.49% 9.97% 20

in nitromethane ml The reaction mixture was

The following NMR spectral properties have been stirred at this temperature 15 mm and then at room

assigned to compounds and temperature Anhydrous Et20 50 mL wasadded to the reaction mixture and the white solid that

Diastereomer separated was filtered washed with Et20 and dried in

NMR DMSO-d6 1.16 tJ7.5 Hz 311 2.00 25vacuo

Yield 1.95 72% mp 171173 dec.311 2.492.72 in 4.284.39 2H 5.56

1H NMR CD3NO2 2.14 3H 3.18 9H 4.50dJ9.7 Hz 1H 7.217.34 in 5H 8.718.77 2H

NMR DMSO-d6 7.10 22.4342.4842.5767.23dJ5.8 Hz 211 5.70 dJ9.3 Hz 1H 7.307.41 in

126.98 127.36 2C 128.33 2C 138.63164.73 170.25511 7.57 dJ9.3 Hz 1H 7.70 br 1H

JR KBr 3300 1680 br 1530 1490 710 cm1ppm Mass spectrum FD 264

Diastereomer Elemental analysis Calculated for C14122N302BF447.89% 6.31% 11.97% Found 47.80%NMR DMSO-d6 l.13 tJ7.6 Hz 3H 1946.33% 12.00%

311 2.492.72 2H 4.284.39 211 5.71

dJ9.9 Hz 1H 7.217.34 5H 8.83 dJr9.9 Hz EXAMPLE 75

1H 8.98 tJ5.6 Hz 1H Synthesis of 2-Acetamido-N-benzyl-2-l-pyr-13C NMR DMSO-d6 6.47 22.4341.5342.55 67.90 roleacetamide solution of 2-acetamido-N-benzyl-2-

126.98 127.36 2C 128.33 2C 138.39 164.43 169.82 bromoacetamide prepared from 2-acetaniido-N-ben-

ppm zyl-2ethoxyacetamide 2.00 8.0 mmol and BBr3

EXAMPLE 73CH2C12 solution 8.8 mL 8.8 mmol was prepared in

THF 225 rnL and cooled to 78 It was then

Synthesis of added under N2 gas atmosphere to cooled 782-Acetainido-N-benzyl-2-ethanesulfonylacetamide suspension of potassium pyrrole 2.71 25.8 mmol in

An aqueous solution 20 mL of Na104 3.00 14.02 45 THF 25 mL The reaction mixturewas stirred at 78mmol was added to MeOH solution 20 mL of 2-

and then at room temperature It was then

acetamido-N-benzyl-2-ethylmercaptoacetamide 0.95treated with water 10 mL and acidified with 5% citric

3.57 mmol The initial homogeneous solution rapidlyacid to pH 4.0 after which it was made basic with aqueous saturated Na2CO3 solution The aqueous mixture

became turbid H20 10 mL was then added drop-

wise until the system became homogeneous The solu-so was extracted with EtOAc 250 mL and the or

tion was stirred 18 at 5060 MeOH 50 mL wasganic layers were dried Na2SO4 The volatile materi

als were removed in vacuo and the residue was purifiedadded to the reaction solution and the precipitated Saltby flash column chromatography on silica gel using 3%

was filtered and washed with MeOH 10 mL TheMeOH/CHC13 as the eluant to give 0.4 18% of the

filtrate was concentrated and the remaining solution

was extracted with CHC13 50 mL The combined55 desired product It was purified by recrystailization

from EtOH mp 182184 Rf 0.44 4%CHC13 extracts were dried Na2SO4 and concentrated MeoH/CHCI3 111 NMR DMSO-d6 l.91in vacuo The residue was purified by flash chromatog- COCH3 4.30 dJ 5.5 Iii CH2 6.01 s2 C3H 6.38

raphy on Si02 gel 1% MeOH/CHC13 to give the dJ8.7 Hz CH 6.85 2XC2H 7.117.35desired product The product was further purified by 60 5PhH 8.96 tJ5.5 Hz NH 9.14 dJ8.7 Hz NHrecrystallization from EtOH 13C NMR DMSO-d6 22.22 COCH3 42.15 CH2

Yield 0.34 32% Rj0.34 3% MeOH/CHC13 mp 62.86 CH 107.79 2C3 119.19 2C2 126.76 C4161163 127.01 2C2 or 2C3 128.11 2C2 or 2C3 138.34 C1

1H NMR DMSO-d6 öl.22 tJ7.4 Hz 3H 1.99 166.37 CONH 169.41 COCH3 ppm mass spectrum3H 3.043.24m 4.31 ddJ5.7 15.3 Hz 111 65 m/e relative intensity 272 M1 22 2714.41 ddJ5.7 15.3 Hz 1H 5.93 dJ9.8 Hz 1H 1007.227.35 5H 9.13 tJ5.7 Hz lH 9.17 dJ9.8 Anal Calcd for C15H7N302.0.2 H20 65.53

Hz 111 6.37 15.28 Found 65.80 6.22 15.13

537872953 54

NH 13C NMR DMSO-d6 22.39 COCH3 42.59EXAMPLE 76 CH2 65.02 CH 126.97 C4 127.25 2C2 or 2C3

Synthesis of 2-Acetamido-N-benzyl-2-1- 128.32 2C2 or 2C3 138.47 Ci 143.93 C5 151.50

imidazoleacetamide Making use of the experimental C3 164.77 CONH 170.23 COCH3 ppm mass spec-

procedure described in the preceding experiment 2- trum FD relative intensity 275 M2 12 274

acetamido-N-benzyl-2-ethoxyacetaniide 2.00 8.0 100 273 11 205 19 204 13 140 67 139

mmol BBr3 1M CH2C12 solution 8.8 mL 8.8 mmol 31Et3N 1.62 1.60 mmol and imidazole 0.60 8.8 Anal Calcd for C13H15N502 57.13 5.53

mmol gave 0.60 30% of the desired product It was 25.63 Found 57.37 5.66 25.38

recrystallized from ethyl acetate/hexane as beige col- 10

ored solid mp 146148 Rf 7% MeOH/CHC13 EXAMPLE 79

NMR DMSO-d6 81.85 COCH3 4.30 br Synthesis of2-Acetarnido-N-benzyl-2-1-tetrazole-

CH2 6.53 dJ8.0 Hz CH 6.89 CH 127.33 acetamide Making use of 2-acetamido-N-benzyl-2-

C41 5PhH 7.69 C2H 9.06 hr NH 9.29 ethoxyacetamide 3.00 12.0 mmol BBr3 lMdJ8.0 Hz NH NMR DMSO-d6 22.28 15 CH2C12 solution 13.2 mL 13.2 mmol Et3N 2.42

COCH3 42.36 CH2 61.18 CH 117.56 C5 126.92 24.0 mmol and tetrazole 1.10 15.6 mmol 0.90

C4 127.16 2Cr or 2C3 128.19 C4 128.26 2C2 or 27% of the desired product was obtained as white

2C3 136.21 C2 138.27 165.72 CONH 169.77 solid It was recrystallized from EtOH mp 169l71COCH3 ppm mass spectrum FD relative intensity R10.22 4% MeOH/CHC13 NMR DMSO-d6274 M2 12 273 Ml 77 272100 205 34 20 61.97 COCH3 4.254.40 in CH2 7.05 dJ8.4274 18 Hz CH 7.217.38 5PhH 9.23 tJ5.5 Hz NH

Anal Calcd for C4H6N402 61.75 5.92 9.44 C5H 9.69 dJ8.4 Hz NH 13C NMR20.57 Found 61.95 6.09 20.32 DMSO-d6 22.38 COCH3 42.78 CH2 63.62 CH

EXAMPLE 77127.10 C4 127.39 2C2 or 2C3 128.38 2C2 or 2C3

25 138.26 143.67 C5 163.88 CONH 170.62

Synthesis of 2-Acetantido-N-benzyl-2-l- COCH3 ppm mass spectrum FD relative intensity

pyrazoleacetamide solution of 2-acetamido-N-ben- 275 M79 273 14 206 100 205 50zyl-2-bromoacetamide jrepared from 2-acetamido-N- Anal Calcd for C12H14N602 52.55 5.15

benzyl-2-ethoxyacetamide 3.60 14.4 mmol and 30.64 Found 52.75 5.33 30.64

BBr3 1M CH2C12 solution 15.8 mL 15.8 mmol was 30

prepared in THF 250 mL and cooled to 78 EXAMPLE 80

solution of triethylamine 2.91 28.8 minol in THF 20 Preparation of

mL was then added to the above solution This was a-acetamido-N-benzyl-2-pyridylacetamide and

followed by the addition of THF 30 mL solution of 2-acetamido-N-benzyl-2-2-pyridoneacetamide

pyrazole 1.17 17.28 mmol and the mixture thus 35

obtained was stirred at 78 30 mm and roomPreparation of

temperature The insoluble materials were filtered2-acetaimdo-2-bromo-N-benzylacetamide

and the solvents removed from the filtrate in vacuo solution of 2-acetaniido-2-ethoxy-N-benzylaceta-

The residue was then purified by flash column chroma- iinde 2.00 mmol in dry CH2CI2 200 niL was

tography on silica gel using 4% MeOH/CHC13 as the 40 stirred at room temperature as solution of BBr3 8.8

eluant to give 0.80 22% of the desired product It mL 8.8 mmol l.OM in CH2C12 was introduced by

was then recrystallized from EtOAc as white solid means of syringe under nitrogen atmosphere

nap 158-160 Rf 0.51 6% MeOH/CHCI3 1H white mist formed and after it disappeared the N2 line

NMR DMSO-d6 61.93 COCH3 4.29 dJ 5.8 Hz was removed and the reaction sealed The resulting

NH 6.26 C4H 6.57 dJ8.8 Hz CH 7.157.33 45 yellow solution was stirred 3.5 and then concen

5PhH 7.48 hr C5H 7.76 hr C3H 8.96 trated in vacuo to give yellow crystals of a-acetamido

tJ5.8 Hz NH 9.23 dJ8.8 Hz NH 13C NMR 2-bromo-N-benzyl acetamido which was stored under

DMSO-d6 22.41 COCH3 42.40 CH2 65.51 CH vacuum overnight

105.37 C4 126.87 C4 127.14 2C2 or 2C3 128.25

2C2 or 2C3 129.00 C5 138.59 C3 139.17 Ci 50 Preparation of 2-pyndylhthium

165.68 CONH 169.81 COCH3 ppm mass spectrum The generation of 2-pyridyllithium in situ was run

m/e relative intensity 273 11 272 under nitrogen solution of n-butyllithium 7.2 mL139 83 138 100 92 37 2.5M solution in hexane 18 nimol was added to dry

Anal Calcd for C4H6N402 61.75 5.92 ether 60 mL cooled to 20 and stirred as 2-

20.57 Found 61.95 5.96 20.28 55 bromopyridine 1.6 mL 17 mmol in dry ether 15 mlwas added dropwise 15 miii The resulting blood red

EXAMPLE 78solution was stirred at 20 for an additional miii-

Synthesis of 2-Acetamido-N-benzyl-2-l-l24- utes and then transferred through doubled-ended nee

triazoleacetamide Using 2-acetaxnido-N-benzyl-2- die under stream of nitrogen to an addition funnel

ethoxyacetamide 4.00 16.0 mmol BBr3 lM 60 where it was cooled to 78CH2C12 solution 17.6 mL 17.6 nimol Et3N 4.85

48.0 mmol and 124-triazole 1.43 20.8 mmol 1.20Preparation of

28% of the desired product was obtained It wasa-acetaimdo-N-benzyl-2-pyridylacetamide and

recrystallized from EtOAc as an amorphous white 2-acetamido-N-benzyl-2-2-pyridoneacetamide

solid mp i46l48 Rj0.48 6% MeOH/CHC13 65 The cooled 2-pyridyllithium solution was added

NMR DMSO-d6 61.85 COCH3 4.32 hr CH2 dropwise approximately drops per second to the

6.70 dJ7.8 Hz CH 7.217.29 5PhH 8.01 solution of 2-acetantido-2-bromo-N-benzylacetamide in

C3H 8.57 C5H 9.04 hr NH 9.39 dJ7.8 Hz dry THF 200 mL and maintained at 78 The

537872955 56

reaction mixture was stirred for an additional 3045 then the aqueous fraction was extracted with THFminutes at 78 The reaction was quenched with 100 mL The combined organic layers were dried

saturated aqueous solution of NH.4C1 40 mL at 78 Na2SO4 and concentrated to dryness The crude reac

producing heterogenous mixture Na2CO3 was tion mixture residue was dissolved in minimum of

added dropwise- until the precipitate dissolved The CHCl3and was flash chromatographed on silica gel

organic layer was separated and then the aqueous layer column using ethyl acetate as the eluent and gavewas extractedith ether 50 mL The combined white amorphous solid 1.10 46% yield which was

organic layers were dried Na2SO4 concentrated identical to properties previously observed for 2-

under vacuum and separated using flash chromatogra- acetanñdo-N-benzyl-2-2-pyridoneacetamide Rf 0.34

phy on silica gel with ethyl acetate as the eluent The 10 5% CH30HCHC13 mp 162163.5 recrystallized

fractions containing the products were concentrated in ethyl acetate IR KBr 3300 3280 3260 3080 1690under vacuum separated and then further purified by 1680 1650 br 1580 1570 1520 1490 1140 cmcolumn chromatography on alumina 80-200 mesh NMR 300 MHz DMSO-d6 81.96 3H 4.27

Grade Fisher employing ethyl acetate as the solvent ddJ 15.3 5.8 Hz 111 4.36 ddJ 15.3 6.2 Hz 1ffFractions containing a-acetaniido-N-benzyl-2- 15 6.27 dtJ6.8 1.1 Hz 111 6.39 bdJ8.9 Hz 111pyridylacetamide was concentrated to dryness and gave 6.71 dJ 8.7 Hz 1H 7.22-7.34 5H 7.43

white amorphous solid 250mg 11% yield Rj0.39 dddJ8.9 6.8 1.9 Hz 1H 7.59 ddJ6.8 1.9 Hz5% CH3OH/CHC13 mp 146147 JR KBr 3290 1H 8.93 br tJ5.9 Hz 1H 9.20 dJ8.7 Hz 1H3180 3020 1620 br 1580 1520 br 1480 1420 1370 3C NMR 75 MHz DMSO-d6 22.4 42.5 62.5 105.1

13101260 cm1 IHNMR300MHz DMSO-d6 81.96 20 119.4 126.8 127.1 2C 128.2 2C 135.6 138.8140.1

3H 4.28 dJ5.8 Hz 2H 5.59 dJ8.0 Hz lii 161.1 166.0 169.9 ppm FD Lilly mass spectrum rn/c

7.187.30 511 7.32 ddJ7.7 5.2 Hz 111 7.47 relative intensity 598 2M 300 Ml 17 299

dJ7.7 Hz 111 7.80 dtJ7.7 1.5 Hz 111 8.55 100 96 95 26 C16H17N3O3211 8.78 br tJ5.8 Hz 111 13C NMR 75MHz Anal Calcd for 64.20 5.73 14.04

DMSO-d6 22.5 42.1 58.3 121.7 122.8 126.6 126.9 25

2C 128.1 2C 136.8 139.1 148.6 157.2 169.0 169.2 EXAMPLE 81

ppm FD Lilly mass spectrum xn/e relative intensity a-acetamido-N-benzyl-2-pyridyl acetamide N-oxide284 M1 283 0.8 151 150 100 141

C16H17N3O2To cooled solution of 2-a-acetamido-N-benzyl-2-

Anal Calcd for 67.83 6.05 14.83 Found 30 pyridylacetamide dissolved in dry THF is added rn-per

68.11 6.00 14.89 chloroperbenzoic acid to give the resulting product

Fractions containing 2-acetamido-N-benzyl-2-2- Similarly using the procedure described herein

pyridoneacetarnide were combined concentrated in above the following examples are prepared

vacuo and yielded white amorphous solid 150 mg 2-acetamido-N-benzyl-2-3-pyridylacetamide and

6% yield Rf 0.34 5% CH3OH/CHC13 mp 226 dc 35the N-oxide thereof

composed recrystallized in ethanol lH NMR 300 2-acetamido-N-benzyl-2-4-pyridylacetamide and

MHx DMSO-d6 81.94 4.26 ddJ 15.2 5.7 Hz 111 the N-oxide thereof

4.33 ddJ 15.2 6.1 Hz 1H6.26 br tJ6.8 Hz lii 2-acetamido-N-benzyl-2-2-pyrirnidinylacetamide

6.37 br dJ9.l Hz 111 6.69 J8.7 Hz and the N-oxide thereof

7.227.33 511 7.42 dddJ9.1 6.8 1.6 Hz 1ff 2-acetamido-N-benzyl-2-4-pyrimidinylacetamide

7.58 ddJ6.8 1.6 Hz 1H 8.93 br tJ5.8 Hz iiiand the N-oxide thereof

9.20 dJ 8.7 Hz 111 13C NMR 75 MHz DMSO-d6 2-acetamido-N-benzyl-2-5-pyrimidinylacetamide

22.5 42.5 62.5 105.1 119.4 126.8..6 127.lO2C 128.2 and the N-oxide thereof

2C 135.6 138.8 140.2 161.2 166.0 170.0 ppm Hy- 2-acetamido-N-benzyl-2-3-pyridazinylacetamide

drogen and carbon assignments were verified with 45 and the N-oxide thereof

1H-1H COSY 1H-13C-COSY zero quantum NMR cx- 2-acetamido-N-benzyl-2-2-pyridazinylacetamide

periments The structure was conformed by X-Ray and the N-oxide thereof

crystallography 2-acetamido-N-benzyl-2-4-pyrazinyl acetamide and

the N-oxide thereofPreparation of authentic

50 2-acetamido-N-benzyl-2-2-thiazolylacetamide2-acetainido-N-benzyl-2-2-pyridoneacetamide 2-acetantido-N-benzyl-2-2-oxazolylacetamide

The generation of 2-hydroxypyridylsodium in situ 2-acetamido-N-benzyl-2-3-isoxazolylacetamide

was done under anbydrous conditions solution of 2-acetamido-N-benzyl-2-5-isoxazolylacetamide

2-hydroxypyridine 1.57 16 mmol vacuum dried 2-acetamido-N-benzyl-2-3-isothiazolylacetamide

97% Aldrich in dry THF 200 mL was stirred and 55 and

cooled to and then NaH 0.77 60% in mineral 2-acetaniido-N-benzyl-2-5-isothiazolylacetamide

oil 19.2 mmol was added in one portion leading to the General Procedure 2-Acetamido-N-benzyl-2-ethox-

evolution of H2 and the generation of heterogeneous yacetamide lequiv was suspended in anhydrous ethyl

mixture solution of 2-acetarnido-2-bromo-N-ben- ether and then boron trifluoride etherate 1.6-6.3

zylacetamide mmol based on 2-acetainido-2-ethoxy- 60 equiv was rapidly added and the resulting solution was

N-benzylacetamide in dry THF 160 mL was then stirred for 15 mm The aromatic substrate 1.616

transferred through double-ended needle by means of equiv was then added and the reaction was stirred at

stream of nitrogen The resulting mixture was room temperature 17 daysquenched with saturated aqueous solution of NH.Cl 50 EXAMPLE 82mL at producing white precipitate saturated 65

aqueous solution Na2CO3 was added dropwise while z-Acetamido-N-benzyl-2-S-thiophenoxy-acetamide

stirring at until all of the white precipitate dis- II The reaction mixture was treated wtih an aqueous

solved The two layers were separated while cold and saturated NaHCO3 solution and the white insoluble

537872957 58

solid was filtered and then washed successively with eight mice at each dose Table includes an evaluation

H20 and hexanes The desired product was purified by of the Median Effective Dose ED5O and the Median

recrystallization from chloroform hexanes to give II in Toxic Dose TD5O of representative compounds Mice

94% yield Rj 0.43 973 chloroform/methanol m.p were tested with varying doses of the anticonvulsant to

165167 i.r KBr 3280 1630 br 1520 br 1430 1365 defme the limits of complete protection or toxicity and

1280 1245 1180 cm1 n.m.r DMSO-d6 81.83 no protection or no toxicity as well as three points in

CH3CO 4.221.36 CH2 5.90 dJ9.0 Hz NH between these limits The Median Effective Dose

884 tJ5.4Hz NH n.m.r DMSO-d6 22.34 ED5O was defmed as the dose which produced the

CH3CO 42.25 CH2 57.65 Cli 126.86 C4 127.20 desired endpoint in 50% of the animals The Median

2C2 123.73 C4 128.28 2C2 or 2C3 128.88 2C2 or 10 Toxicity Dose TD5O was the dose which elicited

2C3 132.36 2C3 132.51 Ci 138.76 C1 167.09 evidence of minimal neurological toxicity in 50% of the

CONH 168.97 CH3CO ppm mass spectrum m/e animals

relative intensity 315 11 205 17 163 40 138 More specifically data tabulated in Table were110 90 109 29 106 96 93 35 91 100 generated as follows

Anal calc for C17H8N202S 64.94 5.77 15 The compound was given in various dose levels i.eFound 65.27 5.54 10 30 100 300 mg and subsequently compared with

Pharmacology Using male Carworth Farms phenytoin phenobarbital inephenytoin arid phenacemice compounds of the present invention were tested mide See Table N-Acetyl-DL-alanine-N-benzyla

for anti-convulsant activity according to the following mide was tested at 600 mg/mL as well Seizures were

procedure In the rotorod test the animal was placed on 20 then artifically induced by either electroschock or pen-one-inch diameter knurled plastic rod rotating at tylenetetrazole Maximal electroshock seizures MES

rpm after the administration of the drug Normal mice were elicited with 60 cycle alternating current of

can remain on rod rotating at this speed indefinitely 5OmA intenstiy 57 times that necessary to elicit mini

Neurologic toxicity was defmed as the failure of the mal electroshock seizures delivered for 0.2 sec via

animal to remain on the rod fox one minute In the 25 corneal electrodes drop of 0.9% saline was instilled

horizontal screen test previously trained mice were in the eye prior to application of the electrodes so as to

dosed with the compound and placed individually on prevent the death of the animal Protection in this test

top of square 13 cmx 13cm wire screen no mesh was defmed as the abolition of the hind limb tonic exten

which was mounted on metal rod The rod was ro- sion-component of-the seizure The Subcutaneous Pentated 180 and the number of mice that returned to the 30 tylenetetrazole MetrazolR Seizure Threshold Test sc

top of the screen was determined Inability to climb to Met entailed the administration of 85 mg/kg of pen-the top within one minute was defined as neurological tylenetetrazole as 0.5% solution subcutaneously in the

impairment This procedure is described in Pharmacol posterior midline This amount of pentylenetetra.zole

Biochem Behav 351353 1977 and is incorporated was expected to produce seizures in greater than 95%herein by reference with the same force and effect as if 35 of mice The animal was observed for 30 minutes Pro-

fully set forth herein tection was defmed as failure to observe even thresh-

The dose effect behavior of the compounds was eval- old seizure single episode of clonic spasms of at least

uated using the above-described procedures by the ad- sec duration The results of these tests are tabulated in

ministration of varying dose levels treating normally Table

TABLEComparative Median Effective Dosage

Tox MES so Met

Compound TD5O mg/kg EDSO mg/kg ED5O mg/kg

N.acetyl-DL-alanine 454 77

N-benzylamide 417_501 67_89N-acetyl-D-alaninc- 214 55 55

N-benzylamide 148262 506O 4367N-acetyl-1.-alanine 841 548

N-benzylamide 691594 463741N.acetyl.DLphenylglycine-N- 40 32.1

benzylamide

N-acetyl.D-phenyl- 80 26.4

glycine-N-benzyl

amide

N-acetyl-L-phenyl- 100-300 300glycine-N-benzyl

amide

DL.a-acetamido.N- 100 87.80

benzyl-3.thiophene

acetamide

DL-a-acetamido-N- 30100 44.80

benzyl-2.thiopheneacetamide

DL-a-acetamido-N- 40 10.33

benzyl-2-furan-

acetamide

DL-a-acetamido-N- 100 16.10

benzyl-2.pyrrole-

acetamide

DL-2-acetamido-N- 112 62.01

benzyl-2-ethoxy-

acetasnide

537872959 60

TABLE I-continued

Comparative Median Effective Dosage

Tox MES sc Met

Compound TD5O mg/kg ED5O mg/kg ED5O mg/kg

DL-2-acetamido-N- 300 98.30

benzy1-2-methoxyacetamide

DL-a-Acetamido-N- 19.2

benzyl-2-5-methylfuran 16.4_23.8acetamide

DL-a-Acetamido-N- 100 300 100 300benzyl-2-benzofuran-

acetaniide

DL-a-Acetamido-N- 100 300 100 300benzyl-2-benzopheneacetamide

DL-a-Acetamido-N- 36.5

henzyl-2-5-methylpyrrole 30.657acetamide

DL-z-Acetaniido-N-2- 40.0

fluorobenzyl-2-furan-

acetamide

DL-a-Acctamido-N-3- 135.6 13.3

fluorobenzyl-2-furan- 114.9161.8 11.5_15.3acetamide

2-acetamido-N-benzyl-2- 65.1

aminoacetamide 56.275.32-acetamido-N-benzyl-2- 80.2

l-Pyrrolyl acetamide

2-acetamido-N-benzyl-2- 100l-imidazoyl acetamide

2-acetamido-N-benzyl-2- 45.3

NN-dimethylaminoacetamide

2-acetamido-N-benzyl-2- 30 1004-morpholineacetamide

2-acetamido-N-benzyl-2- 100NNN-trimethylammoniumacetaniide tetrafluoroborate

2-acetamido-N-benzyl-2- 300N-anilinoacetamide

2-acetamido-N-benzyl-2- 100N-3-pyrazolylaminoacetamide

22-diacetaniido-N-benzyl- 100 300acetamide

2-acetamido-N-benzyl-2- 300trifluoroacetaniidoacetamide

2-acetamido-N-benzyl-2- 100

N-hydroxyaminoacetamide

2-acetamido-N-benzyl-2- 46.O 6.2

N-methoxyaminoacetamide 38.056.0 5.47.22-acetamido-N-benzyl-2- 30N-N-methylhydroxyaminoacetamide

2-acetamido-N-benzyl-2- 50.5 6.7

N-NO-dimethylhydroxy- 40.459.9 5.77.7aminoacetamide

2-acetamido-N-benzyl-2- 31.4

N-isoxazolidinoacetaniide 26.737.82-acetamido-N-benzyl.2- 100N2-phenylhydrazino

acetamide

2-acetamido-N-benzyl-2- 55.6

N2-benzyloxycarbonyl- 49.363.9hydrazinoacetamide

2-acetaniido-N-benzyl-2- 80.1

hydroxyacetamide 70.691.02-acetamido-N.benzyl-2- 16.5

1-Pyrazolyl acet.amide 14.122.52-acetamido-N-benzyl-2- 100phenoxyaoetamide

2-acetamido-N-benzyl-2- 100methylmercaptoacetamide

2-acetamido-N-benzyl-2- 30 100ethylmercaptoacetamide

2-acetamido-N-benzyl-2- 300S-thiophenoxyacetamide

2-acetamido-N-benzyl-2- 100ethylmercaptoacetamide

S-oxide diastereomer

2-acetamido-N-benzyl-2- 100ethylmercaptoacetamide

S-oxide diastereomers

537872961 62

TABLE I-continued

Comparative Median Effective Dosage

Tox MES sc Met

Compound TD5O mg/kg ED5O mg/kg ED5O mg/kg

2-acetamido-N-benzyl-2- 100ethylsulfonylaceiamide

DL-a-Acetamicr-N-4- 144.4 12.7

fluorobenzyl-2-furan- l22.S_170.9xx 10.415acetamide

DL-a.Acetamido-N-25- 23.8

difluorobenzyl-2-furan- 20.228.4acetamide

DL-a-Acetainido-N-26- 25 100difluorobenzyl-2-furan-

acetamide

D--a-Acetamido-N-benzyl- 238xx 332-furanacetamide 2.83.9L-a-Acetamido-N-benzy1- 300 100 3002-furanacetantide

DL-2-Acetamido-4-pentenoic 33.6

acid-N-benzylamide

2-acetamido-N-benzyl-2- 8.5

2-Pyridyl acetamide

DL-2-Acetamido-N-benzyl- 95.0 44.5

2-methylaminoacetamide 37.0_52.4DL-2-Acetamido-N-benzyl- 42.4

2-ethylaminoacetamide 37.2_47.8DL-2-Acetamido-N-benzyl- xxx

3-indoleacetasnide

phenytoin 66 10 not effective

phenobarbital 69 22 13

mephenytoin 154 61 31

phenacernide 421 87 116

337...549S 74_100 71_150

95% confidence intervals

or The TD5O for this substrate was not computed

xx The TD5O value was determined using the horizontal screen test

XXX No activity was noted at 3OO mg/kg

Thus while the invention has been described with pharmaceutically acceptable carrier

35 The composition according to claim wherein is

reference to certain preferred embodiments thosearyl lower alkyl heterocycic lower alkyl or heterocy

skilled in the art will realize that changes and modifica-clic each of which may be unsubstituted or substituted

tions may be made thereto without departing from thewith at least one halo nitro acyl carboxyl carboalk

full and intended scope of the appended claims

We claim oxy carboxamide cyano sulfonyl sulfoxide heterocy

An anticonvulsant composition comprising an anti-clIc guanidine quaternary ammonium hydroxy lower

convulsant effective amount of compound having thealkoxy lower alkyl amino or phenoxy

R1 is or lower alkyl which may be unsubstituted orfollowing general formula

substituted with at least one halo nitro acyl car

boxamido cyano sulfonyl sulfoxide heterocydic

amino or phenoxy

45 guanidine animonium hydroxy lower alkoxy

_cNH_1_._Rl R2 is hydrogen lower alkyl lower alkenyl lower

alkynyl aryl heterocycic lower alkyl or hetero

cyclic each unsubstituted or substituted with at

50 least one electron withdrawing substituent or at

wherein is aryl aryl lower alkyl heterocyclic lower least one electron donating substituent or R2 is

alkyl lower alkyl or heterocycic each unsubstituted halogen or heteroatom consisting of nitrogen

or substituted with at least one electron withdrawing oxygen or sulfur each substituted with hydrogensubstituent or at least one electron donating substituent lower alkyl or aryl said lower alkyl or aryl groups

R1 is or lower alkyl unsubstituted or substituted 55 being substituted or unsubstituted

with at least one electron withdrawing substituent R3 is hydrogen lower alkyl lower alkenyl lower

or at least one electron donating substituent alkynyl aryl heterocyclic lower alkyl or hetero

R2 and R3 independently are hydrogen lower alkyl cyclic each unsubstituted or substituted with at

lower alkenyl lower alkynyl aryl aryl lower al- least one electron withdrawing substituent or at

kyl heterocycic lower alkyl or heterocyclic each 60 least one electron donating substituent or

unsubstituted or substituted with at least one elec- R3 is halogen or heteroatom consisting of oxygentron withdrawing substituent or at least one elec- nitrogen or sulfur substituted with hydrogentron donating substituent halogen or heteroatom lower alkyl or aryl said lower alkyl or aryl groups

containing oxygen nitrogen or sulfur said hetero- being substituted or unsubstituted and is 1-4

atom being substituted with hydrogen lower alkyl 65 The composition according to claim wherein one

or aryl said lower alkyl or aryl groups being substi- of R2 and R3 is other than hydrogentuted or unsubstituted The composition according to claim wherein is

nislto4

537872963 64

The composition according to claim wherein is is benzyl R1 is methyl R2 is ethoxy R3 is hydrogenand one of R2 and R3 is hydrogen and the other is and is or the or stereoisomer or

heterocyclic or lower alkyl heterocyclic is benzyl Ri is methyl R2 is methoxy R3 is hydroThe composition according to claim wherein is gen and is or the or steroisomer

and one of R2 and R3 is hydrogen and the other is aryl 22 The composition of claim wherein said comThe composition according to claim wherein one pound is in the isomer form isomer form mixtures

of R2 and R3 is-hydrogen and the other is thienyl furyl of the DL isomer form or DL racemic form

pyrrolyl or phenyl 23 An anticonvulsant composition comprising an

The composition according to claim wherein one anticonvulsant effective amount of compound havingof R2 and R3 is hydrogen and the other is lower alkenyl 10 the formula

or lower alkynylThe composition according to claim wherein one

of R2 and R3 is hydrogen and the other is lower alkoxy R2

10 The composition according to claim wherein

one of R2 and R3 is hydrogen and the other is lower 15 RNH1-NH R1alkyl t.o R3

11 The composition of claim having unit dosageform containing from about to to about 1000 mg of

said compoundand pharmaceutically acceptable salts thereof wherein

12 The composition of claim wherein R1 is hydro- 20is aryl aryl lower alkyl heterocyclic or heterocy

gen methyl ethyl propyl isopropyl butyl isobutyldie lower alkyl wherein is unsubstituted or is

tertiary butyl amyl or hexylsubstituted with at least one electron withdrawing

13 The composition of claim 12 wherein said methyl group or an electron donating group

ethyl propyl isopropyl butyl isobutyl tertiary butylRi is hydrogen or lower alkyl which is unsubstituted

amyl or hexyl are unsubstituted or substituted with at 25 or is substituted with at least one electron with-

least one electron withdrawing substituent or at lt drawing substituent or at least one electron donat

one electron donating substituent mg substituent

14 The composition of claim 12 wherein Ri isR2 and R3 are independently each hydrogen lower

methyl alkenyl lower alkynyl aryl lower alkyl aryl het

15 The composition of claim wherein is benzyl 30 erocyclic lower alkyl heterocyclic lower alkyl or

unsubstituted or substituted with at least one electron Z-Y wherein R2 and R3 may be unsubstituted or

withdrawing substituent or at least one electron donat- substituted with at least one electron withdrawing

ing substituent group or electron donating group

16 The composition of claim wherein said electronis NR.4 or chemical bond

withdrawing substituent is halo nitro acyl carboxylis hydrogen lower aikyl aryl aryl lower alkyl

carboalkoxy carboxamide cyano sulfonyl sulfoxide lower alkenyl lower alkynyl or halo and may

heterocyclic guanidine or quaternary animonium be unsubstituted or substituted with at least one

17 The composition of claim wherein said electron electron withdrawing group or electron donating

donating substituent is hydroxy alkoxy alkyl amino or group provided that when is halo is chemi

phenoxy 40 cal bond or

18 The composition of claim wherein is benzyl ZY taken together is NR4NRSRó NR4OR5Rj is methyl R2 is hydrogen R3 is methyl and is ONR4R5 SNR4R5 or NR4SR5the or steroisomer R4 R5 and R6 are independently hydrogen lower

19 The composition of claim wherein is benzyl alkyl aryl aryl lower alkyl lower alkenyl lower

R1 is methyl R2 is hydrogen R3 is phenyl and is or 45 alkynyl and R4 R5 and R6 may be unsubstituted or

the or stereoisomer substituted with an electron withdrawing group or

20 The composition of claim wherein is benzyl an electron donating group and

R1 is methyl R2 and R3 are hydrogen and is is 1-4 and

21 The composition of claim wherein is benzyl pharmaceutically acceptable carrier therefor

Rj is methyl R2 is hydrogen R3 is isopropyl and is 50 24 The composition of claim 23 having unit dosage

or the or stereoisomer form containing from about to about 1000 mg of said

is benzyl R1 is t-butyl R2 is hydrogen R3 is methyl compoundand is or the or stereoisomer 25 The composition of claim 23 wherein Ri is

is benzyl R1 is methyl R2 is hydrogen R3 is 2-thi- methylomethylethyl and is or the or stereoiso- 55 26 The composition of claim 23 wherein is aryl

mer lower alkyl

is 3-fluorobenzyl R1 is methyl R2 is hydrogen 27 The composition of claim 26 wherein is benzyl

R3 is methyl and is or the or stereoisomer 28 The composition of claim 23 wherein the electron

is 3-methoxybenzyl R1 is methyl R2 is hydrogen withdrawing group is halo nitro lower alkanoyl aryl

R3 is methyl and is or the or stereoisomer 60 oyl aryl lower alkanoyl carboxy carbalkoxy carbox

is benzyl Rj is methyl R2 is 3-thienyl R3 is hy- amido cyano sulfonyl sulfoxide heterocyclic guani

drogen and is or the or stereoisomer dine or quaternary ammoniumis benzyl Rj is methyl R2 is 2-thienyl R3 is hy- 29 The composition of claim 23 wherein the electron

drogen and is or the or stereoisomer donating group is hydroxy lower alkoxy lower alkyl

is benzyl R1 is methyl R2 is 2-furyl R3 is hydro- 65 amino lower alkylamino diloweralkylamino or phegen and is or the or stereoisomer noxyis benzyl Rj is methyl R2 is 2-pyrrolyl R3 is 30 The composition according to claim 23 wherein

hydrogen and is or the or steroisomer R2 and R3 are independently hydrogen phenyl hy

537872965 66

droxy phenoxy alkyl containing 1-4 carbon atoms is benzyl Rj is methyl R2 is hydrogen R3 is 1-mor-

lower alkoxy amino lower alkylthio morpholinyl pholino is and the or stereoisomer thereof

thienyl furyl pyrrolyl methylfuryl benzofuryl benzo- is benzyl R1 is methyl R2 is hydrogen R3 is

thienyl indolyl methylpyrrolyl lower alkenyl anilino anilino is and the or stereoisomer thereofarylamino lower alkylamino hydrazino lower alkyl is benzyl R1 is methyl R2 is hydrogen R3 is mehydrazino mercapto arylthio N-phenylhydrazine N- thylamino is and the or stereoisomer

hydroxylaminor 0-hydroxylamino thereof or

31 The composition according to claim 23 whereinis benzyl R1 is methyl R2 is hydrogen R3 is

one of R2 and R3 is hydrogen ethylamino is and the or stereoisomer32 The composition according to claim 23 wherein 10 thereof

is 42 An anticonvulsant composition comprising an33 The composition according to claim 23 wherein anticonvulsant effective amount of compound having

is and R1 is methyl the formula34 The composition according to claim 23 wherein

is and is aryl lower alkyl 15

35 The composition of claim 34 wherein is benzyl

36 The composition of claim 23 wherein is and

wherein the electron withdrawing group is halo nitro RNHNH rRilower alkanoyl aryloyl aryl lower alkanoyl carboxy

carbalkoxy carboxamido cyano suifonyl sulfoxide 20

heterocydic guanidine or quaternary ammonium37 The composition of claim 23 wherein is and or pharmaceutically acceptable salts thereof wherein

the electron donating group is hydroxy lower aikoxyis aryl aryl lower alkyl heterocyclic heterocycic

lower alkyl amino lower alkylamino diloweralkyl- lower alkyl lower cycloalkyl or lower cycloalkyl

amino or phenoxy 25lower alkyl wherein is unsubstituted or is substi

38 The composition according to claim 23 wherein tuted with at least one electron withdrawing group

is and R2 and R3 are independently hydrogen phenyl or an electron donatmg group

hydroxy phenoxy alkyl containing 14 carbon atoms R1 is hydrogen or lower alkyl and R1 is unsubstituted

lower alkoxy amino lower alkylthio morpholinyl or is substituted with at least one electron with

thienyl furyl pyrrolyl methylfuryl benzofuryl benzo- 30 drawing substituent or at least one electron donat

theinyl indolyl methylpyrrolyl lower alkenyl anilino ing substituent

arylamino lower alkyiamino hydrazino lower alkyl R2 and R3 are independently hydrogen lower alkyl

hydrazino mercapto arylthio N-phenyl hydrazino lower alkenyl lower alkynyl aryl lower alkyl

N-hydroxylamino or O-hydroxylaniino aryl heterocyclic heterocyclic lower alkyl cyclo

39 The composition according to claim 23 wherein 35 alkyl lower cycloalkyl lower alkyl or Z-Y

said compound is in the isomer form the isomer wherein R2 and R3 may be unsubstituted or substi

form mixtures of the DL isomer form or the DL tuted with at least electron withdrawing group or

racemic form electron donating group40 The composition according to claim 23 wherein is S0 or NR4

is and one of R2 and R3 is hydrogen 40 is hydrogen lower alkyl aryl aryl lower alkyl

41 The composition of claim 23 wherein is benzyl lower alkenyl lower alkynyl halo heterocyclic

R1 is methyl R2 is hydrogen R3 is 5-methyl-2-furyl and heterocyclic lower alkyl cycloalkyl or cycloalkyl

is or the or stereoisomer thereof lower alkyl and may be unsubstituted or substi

is benzyl R1 is methyl R2 is hydrogen R3 is 2-ben- tuted with an electron donating group or an elec

zofuryl is or the or stereoisomer thereof 45 tron withdrawing group provided that when is

is benzyl Ri is methyl R2 is hydrogen R3 is 2-ben- halo is chemical bond or

zothienyl is and the or stereoisomer ZY taken together is NR4NR5R7 NR4OR5thereof ONR4R7 SNR4R7 NR4SR7is benzyl R1 is methyl It2 is hydrogen It3 is 3-indo-

lyl is or the or stereoisomer thereof 50NR4C-R5 SC-R5 NRCOR5 or SCOR5

is benzyl It1 is methyl R2 is hydrogen R3 is 5-ii

ii

methyl-2-pyrrolyl is or the or stereoiso-

mer thereof

is 2-fluorobenzyl Ri is methyl R2 is hydrogen R3 R4 R5 and R6 are independently hydrogen lower

is 2-furyl is or the or stereoisomer thereof 55 alkyl aryl aryl lower alkyl lower alkenyl or lower

is 3-fluorobenzyl Itj is methyl R2 is hydrogen R3is alkynyl wherein R4 R5 and R6 may be unsubsti

2-furyl is or the or stereoisomer thereof tuted or substituted with an electron withdrawing

is 4-fluorobeazyl R1 is methyl R2 is hydrogen R3 group or an electron donating groupis 2-furyl is or the or stereoisomer thereof It7 is R6 or COORs or COR8is 25-difluorobenzyl Rj is methyl R2 is hydrogen 60 R8 is hydrogen or lower alkyl or aryl lower alkyl

R3 is 2-furyl ii is and the or stereoisomer is 14 and

thereof is 13It is 26-difluorobenzyl Ri is methyl R2 is hydrogen 43 The composition according to claim 42 wherein

R3 is 2-furyl is and the or stereoisomer one of R2 and R3 is other than hydrogenthereof 65 44 The composition according to claim 42 wherein

is benzyl It1 is methyl it2 is hydrogen R3 is 2- is

propenyl is and the or stereoisomer 45 The composition according to claim 42 wherein

thereof one of R2 and R3 is hydrogen and the other is cycloal

537872967 68

kyl cycloalkyl lower alkyl aryl heterocyclic hetero-alkyl hydroxylamino NO-diloweralkylhydrox

cyclic lower alkyl lower alkenyl lower alkynyl or ylamino lower alkoxyarnino lower alkoxy hydrogenZ-Y wherein R2 and R3 may be unsubstituted or substi-

or lower arylaikyloxy carbonyl hydrazinotuted with at least one electron withdrawing group or

53 The composition according to claim 42 whereinelectron donating group

is SO0 NR R2 is furyl pyrrolyl isoxazolidino amino meis hydron lower alkyl aryl aryl lower alkyl thylamino ethylamino NN-dimethylamino 4-mor-

lower alkenyl lower alkynyl halo heterocyclic pholinyl NNN-trimethylammonium N-anilino 3-

heterocyölic lower alkyl lower cycloalkyl or pyrazolylamino trifluoroacetainido acetamido hylower cycloalkyl lower alkyl and may be unsub- 10 droxylammo NO-dimethylhydroxyainino N-methoxstituted or substituted with an electron donating yarnino isoxazolidino benzyloxycarbonyl-hydrazinogroup or an electron withdrawing group provided

hydroxy methoxy ethoxy phenoxy ethylsulfonylthat when is halo is chemical bond or

ethylsulfinyl or phenylZY taken together is NR4NRSR7 NR4OR554 The composition according to claim 42 wherein

ONR4R7 SNR4R7 NR4SR7 15R2 is furyl pyrrolyl phenyl benzyloxycarbonylhy

drazino isoxazolidino NO-dimethylhydroxyaminoNR4CR SCR5 NRCOR5 or SCOR5

ii II II

N-methylhydroxyamino N-methyoxyamino

ethylamino or methylarnino

20 55 The composition according to claim 42 whereinR1 R5 and R6 are independently hydrogen lower

Rj is lower alkylalkyl aryl aryl lower alkyl lower alkenyl or lower

56 The composition according to claim 42 whereinalkynyl wherein R4 R5 and R6 may be unsubsti

tuted or substituted with an electron withdrawingR1 is methyl

group or an electron donating group57 The composition according to claim 42 wherein

25R7 is R6 or COOR8 or CORg is aryl lower alkyl

R8 is hydrogen or lower alkyl 58 The composition according to claim 57 wherein

is 1-4 and is beazylis 13 59 The composition according to claim 42 which is

46 The composition according to claim 42 wherein in the form the form mixture of the DL formone of R2 and R3 is hydrogen and the other is heterocy-

30

or racemic mixture of the DL formdie

60 The composition according to claim 42 wherein47 The composition according to claim 46 wherein

heterocyclic has the formulathe compound is 2-acetainido-N-benzyl-2-amino acet

amide 2-acetamido-N-benzyl-2-methylamino acetam

ide 2-acetamido-N-benzyl-2-ethylaminoacetamideXI2-acetamido-N-benzyl-2-NN-dimethylaminoaceta-

mide 2-acetamide-N-benzyl-2-4-morpholinoaceta-

nude 2-acetamido-N-benzyl-2-N2-phenylhy-

drazineacetamide 2-acetamido-N-benzyl-2-N2-ben-CH 40

zyloxy carbonylhydrazinoacetamide 2-acetanuido-N-

wherein benzyl-2-hydroxy acetaniide 2-acetamido-N-benzyl-2-

is or methoxy acetamide or 2-acetamido-N-beazyl-2-ethox-

and are independently CII or heteroatom yacetamide acetamide or the or stereoisomer

selected from the group consisting of and 45 thereof

is CII or heteroatom selected from the group 61 The composition according to claim 42 where the

consisting of and but when is is CH compound is 2-acetamide-N-benzyl-2-N-methoxy-or heteroatom selected from the group consisting amino acetamide or the or steroisomer thereofof NH and 62 The composition according to claim 42 wherein

with the provision that at most two of and 50the compound is 2-acetamido-N-benzyl-2-N-N.

are heteroatoms

48 The composition according to claim 47 wherein methylhydroxyaniinoacetaxnide or the or

steroisomer thereofone of and is heteroatom

49 The composition according to claim 47 wherein 63 The composition according to claim 42 wherein

the heterocyclic is furyl thienyl pyrrolyl pyrazolyl 55 the compound is 2-acetamido-N-benzyl-2-N-N0-

isoxazolidino or pyridyl dimethylhydroxyaminoacetamide or the or stereo

50 The composition according to claim 42 wherein isomer thereof

one of R2 and R3 is hydrogen and the other is N-hydrox- 64 The composition according to claim 42 wherein

ylamino lower alkoxyamino N-lower alkylhydrox- the compound is 2-acetamido-N-benzyl-2-N-isox-yamino or N-lower alkyl-0-lower alkyl hydroxyarn- 60

azolidino acetamide or the or isomer thereofinO 65 The composition according to claim 42 wherein

51 The composition according to claim 42 whereinthe compound is 2-acetamido-N-benzyl-2-2-pyridyl-one of R2 and R3 is hydrogen and the other is lower

alkoxy amino lower alkylatnino or dilower alkyl-acetamide or the or steroisomer

6566 The composition according to claim 42 wherein

52 The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-l-pyrazolyl-

R2 is heterocyclic heterocyclic amino amino lower acetamido or the or stereoisomer thereof

alkylarnino lower dialkylamino hydroxylamino N- 67 compound of the formula

537872969 70

75 The composition according to claim 67 which is

in the form the form mixture of the form

R__R1 one of R2 and R3 is hydrogen and the other is heterocy

R2 or racemic mixture of the form

76 The compound according to claim 67 wherein

it3 cic

77 The compound according to claim 67 wherein

and pharmaceutically acceptable salts thereof heterocyclic has the formula

wherein10

is aryl aryl lower alkyl heterocyclic or heterocy- XI

clic lower alkyl cycloalkyl lower cycloalkyl or

lower alkyl wherein is unsubstituted or is substi-

tuted with at least one electron withdrawing group

or an electron donating group15 CH

R1 is hydrogen or lower alkyl and R1 is unsubstituted

or substituted with at least one electron withdraw

ing substituent or at least one electron donatingwherein

substituentis or

R2 and R3 are independently hydrogen lower alke-20

and are independently CH or heteroatom

nyl lower alkynyl heterocycic heterocycicselected from the group consisting of and

lower alkyl lower alkyl heterocycic lower cyclo-is CH or heteroatom selected from the group

alkyl lower cycloalkyl lower alkyl lower alkyl or consisting of and but when is is CHZ-Y wherein R2 and R3 may be unsubstituted or

or heteroatom selected from the group consisting

substituted with at least one electron withdrawing 25of NH and

group or electron donating groupwith the proviso that at most two of and

is SOa or NR4 are heteroatoms

is hydrogen lower alkyl aryl aryl lower alkyl78 The compound according to claim 77 wherein

lower alkenyl lower alkynyl halo heterocycic or one of and is heteroatom

heterocydic lower alkyl cycloalkyl cycloalkyl 3079 The compound according to claim 77 wherein R2

lower alkyl and may be unsubstituted or substi- is heterocyclic if furyl thienyl pyrrolyl pyrazolyl

tuted with an electron donating group or an elec- isoxazolidinyl or pyridyl

tron withdrawing group provided that when is80 The compound according to claim 67 wherein

halo is chemical bond or one of R2 and R3 is hydrogen and the other is N-hydrox

ZY taken together is NR4NRSR7 NR4OR5 ylamino lower alkoxyaniino N-lower alkyihydroxy or

ONR4R7 SNR4R7 NR4SR7 N-lower alkyl-O-lower alkyl hydroxyamino81 The compound according to claim 67 wherein

one of R2 and R3 is hydrogen and the other is lowerNR4CR5 SCR5 NR4C0R5 or SCOR5

alkoxy amino lower alkylamino or diower alkyl

4oamno82 compound of the formula

R4 R5 and R6 are independently hydrogen lower

alkyl aryl aryl lower alkyl lower alkenyl or

substituted or substituted with an electron with-

drawing group or an electron donating groupRNIi CNIJCR1

lower alkynyl wherein R4 R5 and R6 may be Un-

_f

R2

ii

R7 is R6 COORs or COR3 R3

R8 is hydrogen or lower alkyl or aryl lower alkylis 1-4 and

is 13 whereinSo

68 The compound according to claim 67 wherein is aryl aryl lower alkyl heterocyclic or heterocy

one of R2 and R3 is other than hydrogen clic lower alkyl which is unsubstituted or substi

69 The compound according to claim 67 wherein istuted with at least one electron withdrawing groupor at least one electron donating group

70 The compound according to claim 67 wherein R1 is hydrogen or lower alkyl which is unsubstituted

one of R2 and R3 is hydrogen and the other is furyl or substituted with at least one electron withdraw

pyrrolyl phenyl benzyloxycarbonyl hydrazino isox- ing group or one electron donating group

ozolidino O-dimethylhydroxyamino N-methylhy- R2 and R3 are independently hydrogen lower aikyl

droxyamino N-methoxy amino ethylamino or me- lower alkenyl lower alkynyl Z-Y or heterocy

thylamino tj dc group each which may be unsubstituted or

71 The compound according to claim 67 wherein Rj substituted with at least one electron withdrawing

is lower alkyl group or one electron donating group with the

72 The compound according to claim 67 wherein Ri proviso that R2 and R3 cannot both be hydrogenis methyl is NR4 or chemical bond

73 The compound according to claim 67 wherein 65 is hydrogen lower alkyl aryl aryl lower alkylis aryl lower alkyl lower alkenyl lower alkynyl or halo and may be

74 The compound according to claim 67 wherein unsubstituted or substituted with an electron donatis beazyl ing group or an electron withdrawing group pro

537872971 72

vided that when is halo then is chemical loweralkylamino or phenoxy thiol lower alkylmer

bond or capto or disulfide

ZY taken together is NR4NRSR6 NR4OR5 SNR4RS 101 The compound according to claim 82 wherein

or NR4SRS is and one of R2 and R3 is hydrogen and the other is

R4 R5 and R6 are independently hydrogen lower lower alkenyl or lower aikynyl

alkyl aryLaryl lower alkyl lower alkenyl or lower 102 The compound according to claim 101 wherein

alkynyl sherein R.4 R5 and R6 may be unsubsti- one of R2 and R3 is 2-propenyl and the other is hydrotuted or substituted with an electron withdrawing gengroup or an electron donating group and 103 The compound according to claim 82 wherein

is 14 10is and one of R2 and R3 is hydrogen and the other is

83 The compound according to claim 82 wherein R1 z.yis methyl 104 The compound according to claim 103 wherein

84 The compound according to claim 82 wherein ZY is lower alkoxy aryloxy thioloweralkoxy thi

is unsubstituted or substituted aryl lower alkyl oaryloxy lower alkylamino diloweralkylamino85 The compound according to claim 84 wherein 15

arylamino hydrazino lower alkylhydrazino N-phenylis benzyl which is either unsubstituted or substituted hydrazino or hydroxylaminowith fluoro 105 The compound according to claim 82 wherein

86 The compound according to claim 82 wherein theis and one of R2 and R3 is hydrogen and the other is

electron withdrawing group is halo mtro lower alkan- heterocyclic or heterocyclic lower alkyloyl aryloyl aryl lower alkanoyl carboxy carbalkoxy

20106 The compound according to claim 105 wherein

carboxamido cyano sulfonyl sulfoxide heterocyclic one of R2 and R3 is hydrogen and the other is thienylguanidine or quaternary ammonium

furyl pyrrolyl methylfuryl benzofuryl benzothienyl87 The compound according to claim 82 wherein the indolyl pyridyl pyrazinyl methylpyrrolyl or morpho

electron donating group is hydroxy lower alkoxy linolower alkyl amino lower alkylaxnino diloweralkyl-

25

107 The compound according to claim 82 whereinamino or phenoxy

is and is benzyl 2-fluorobenzyl 3-fluorobenzyl or88 The compound according to claim 82 wherein

4-fluorobenzyl and one of R2 and R3 is hydrogen andone of R2 and R3 is hydrogen and the other is lower

the other is furylalkenyl or lower alkynyl

30 108 The stereoisomers of the compound of claim 8289 The compound according to claim 88 wherein or the mixture thereof or the racemic mixture thereof

one of R2 and R3 is 2-propenyl 109 The or stereoisomer of the compound of90 The compound according to claim 82 wherein claim 95 or the mixture thereof or the racemate thereof

one of R2 and R3 is hydrogen and the other is ZY 110 ID or L-N-acetyl-phenylglycine-N-benzylamide91 The compound according to claim 90 wherein ZY

35 or the DL mixture thereofis lower alkoxy aryloxy thioloweralkoxy amino thi-

111 or a-acetamido-N-benzyl-3-thiopheneaceta-oaryloxy lower alkylamino diloweralkylamino

mide or the DL mixture thereofarylamino hydrazino lower alkylhydrazino N-phenyl- 112 or a-acetamido-N-benzyl-2-thiopheneaceta-hydrazino or hydroxylamino

mide or the DL mixture thereof92 The compound according to claim 82 wherein

40 113 The compound according to claim 82 which is IDone of R2 and R3 is hydrogen and the other is heterocy-

or L-a-acetamido-N-benzyl-2-furanacetamideclic or heterocyclic lower alkyl 114 The compound according to claim 82 which is

93 The compound according to claim 92 whereinor L-cz-acetamido-N-benzyl-2-pyrroleacetamide

one of R2 and R3 is thienyl pyridyl pyrazinyl furyl115 The compound according to claim 82 which is or

pyrrolyl methylfuryl benzofuryl benzothienyl indo-L-2-acetamido-N-benzyl-2-ethoxy-acetamide

lyl isoxazolidinyl methylpyrrolyl or morpholino andID or L-2-acetamido-N-benzyl-2-methoxyacetamidethe other is hydrogenID or L-a-acetamido-N-benzyl-2-5-methylfuran-94 The compound according to claim 93 wherein

is benzyl 2-fluorobenzyl 3-fluorobenzyl or 4-fluoro- acetamide

benzyl and one of R2 and R3 is hydrogen and the otherID or L-a-acetaniido-N-benzyl-2-benzo

is furyl pheneacetamide or

95 The compound according to claim 82 wherein isID or L-a-acetamido-N-benzyl-3-indolacetamide or

ID or L-a-acetamido-N-benzyl-2-5-methylpyrrole

96 The compound according to claim 82 wherein isacet.flude

and R1 is methyl 116 The compound according to claim 82 which is

97 The compound according to claim 82 wherein is DL-a-Acetamido-N-4-fluorobenzyl-2-furanaceta-

and is unsubstituted or substituted aryl lower alkyl mide

98 The compound according to claim 97 wherein D-2-Acetaniido-N-4-fluorobenzyl-2-furanaceta-

is benzyl which is either unsubstituted or substituted mide or

with fluoro L-a-Acetarnido-N-4-fluorobenzyl-2-furanaceta-

99 The compound according to claim 82 wherein ismide

and the electron withdrawing group is halo nitro 117 The compound according to claim 82 which is

lower alkanoyl aryloyl aryl lower alkanoyl carboxy DL-a-Acetamido-N-3-fluorobenzyl-2-furanaceta-

carbalkoxy carboxamido cyano sulfonyl sulfoxide mide

heterocyclic guanidine or quaternary ammonium 65 D-a-Acetamido-N-3-fluorobenzyl-2-furanaceta-

100 The compound according to claim 82 wherein mide or

is and the electron donating group is hydroxy lower L-2-Acetamido-N-3-fluorobenzyl-2-furanaceta

alkoxy lower alkyl amino lower alkylamino di- mide

537872973 74

118 The compound according to claim 82 which is 128 The compound according to claim 82 which is

D- or L-a-Acetmido-N-2-fluorobenzyl-2-furanaceta- 2-acetamido-N-benzyl-2-N2-phenylhydrazinoaceta-

rnide mide

or L-a-Acetaniido-N-25-difluorobenzyl-2- or 2-acetamido-N-benzyl-2-N2-benzyloxycar-

furanacetarnide or bonyl-hydrazinoacetamide

or j-a-Acetainido-N-26-difluorobenzyI-2- or 2-acetamido-N-benzyl-2-hydroxyacetamide

furanacetnide or 2-acetamido-N-benzyl-2-phenoxyacetamide

119 The or L-a-Acetamido-2-furanacetic acid or or 2-acetarnido-N-benzyl-2-ethylmercapto

the DL mixture thereof acetamide-S-oxide or

120 The compound according to claim 82 which is10 or 2-acetamido-N-benzyl-2-ethylsulfonyl acet

or L-2-acetamido-4-pentenoic acid-N-beazylamide amide

or L-2-Acetamido-N-benzyl-2-4-morpholino ac- 129 The compound according to claim 82 which is

etaxnide 2-acetamido-N-benzyl-2-2-pyridylacetamide

or L-2-Acetamido-N-benzyl-2-N-anilino acetam-15

130 The compound according to claim 82 which is

ide 2-acetamido-N-butyl-2-l-pyrazoleacetarnide

or L-2-Acetamido-N-benxyl-2-methylamino ac- 131 The compound according to claim 82 which is

etamide or 2-acetamido-N-benzyl-2-1-pyrrolylacetamide

or L-ethyl-2-acetamido-2-ethylaniinoacetate acetaniido-N-beazyl-2-l -imidazolylacetamide 2-

121 The composition according to claim 23 wherein acetamido-N-benzyl-2-3 -pyridylacetamide 2-

is benzyl Ri is methyl R2 is hydrogen P.3 is phenyl20

acetamido-N-benzyl-2-4-pyridylacetamide 2-

and is or the or L-stereoisomer thereof acetainido-N-benzyl-2-2-pyrimidinylacetamide 2-

wherein is benzyl R1 is methyl R2 is hydrogen and acetamido-N-benzyl-2-4-pyrimidinylacetamide 2-

P.3 is 2-furyl and is or the or L-stereoisomer acetaido-N-benzyl-2-5-pyrimidinylacetamide 2-

thereof 25acetamido-N-benzyl-2-3-pyridazinylacetamide 2-

is 2-fluorobenzyl R1 is methyl P.2 is hydrogen and acetdo-N-benzyl-2-4-pyridazinylacetamide 2-

R3 is 2-furyl and is or the or L-stereoisomer acetamido-N-benzyl-2-2-pyrazinylacetamide 2-

thereof acetamido-N-benzyl-2-2-thiazolylacetamide 2-

is 3-fluorobenzyl R1 is methyl P.2 is hydrogen and acetaniido-N-benzyl-2-3-oxazolylacetamide 2-

P.3 is 2-furyl and is or the or stereoisomer 30acetainido-N-benzyl-2-3-isoxazolylacetamide 2-

thereof or acetamido-N-benzyl-2-5-isoxazolylacetamide 2-

is 4-fluorobenzyl Ri is methyl R2 is hydrogen and acetamido-N-benzyl-2-3-isothiazolylacetarnide or 2-

K3 is 2-furyl and is or the or stereoisomer acetamido-N-benzyl-2-5-isothiazolylacetamide

thereof 132 method of treating central nervous system

122 The compound according to claim 82 which is 35disorders in animals comprising the administration to

or a-Acetamide-N-2-fluorobenzenyl-3-furanaceta-said animal an effective amount of compound accord

mide ing to claim

or a-acetamido-N-3-fluorobexizyl-3-133 method of treating central nervous system

furanacetamidedisorders in animals comprising the administration to

or a-acetamido-N-4-fluorobenzyl-3- 40said animal an effective amount of compound accord

furanacetamideing to claim

134 method of treating central nervous systemor cx-acetamido-N-benzyl-3-furanacetamide

disorders in animals comprising the administration toor 2-acetamido-N-benzyl-2-amino acetamide

said animal an effective amount of compound accordor -a-acetamido-N-benzyl-2-NN-dime-

thylaminoacetamide 2-acetainido-N-benzyl-2-45 ing to claim 23

135 method of treating central nervous systemNNN-trimethylammonium acetamide tetrafluo-

disorders in animals comprising the administration to

roboratesaid animal an effective amount of compound accord

or 2-acetamido-2-benzyl-2-N-3-ing to claim 67

pyrazolylaminoacetamide50 136 method of treating central nervous system

or 22-diacetamido-N-benzyl-acetamide ordisorders in animals comprising the administration to

or 2-acetamido-N-benzyl-2-tri- said animal an effective amount of compound accordfluoroacetamidoacetamide

ing to claim 82123 The compound according to claim 82 which is 137 The method of claim 132 wherein said corn

2-acetamido-N-benzyl-2-N-hydroxyaininoacetamide55 pound is administered in an amount from about 10 to

or the or isomer thereof about 100 mg/kg of body weight per day124 The compound according to claim 82 which is 138 The method of claim 133 wherein said corn

2-acetainido-N-bezizyl-2-N-methoxyaminoacetamide pound is administered in an amount from about 10 to

or the or isomer thereof about 100 mg/kg of body weight per day125 The compound according to claim 82 which is 60 139 The method of claim 134 wherein said corn

2-acetamido-N-benzyl-2-N-N-methylhydroxyamino- pound is administered in an amount from about 10 to

acetarnide or the or isomer thereof about 100 mg/kg of body weight per day126 The compound according to claim 82 which is 140 The method of claim 135 wherein said corn

2-acetaniido-N-benzyl-2-N-NO-dimethylhydrox- pound is administered in an amount from about 10 to

yaminoacet amide or the or isomer thereof 65 about 100 mg/kg of body weight per day127 The compound according to claim 82 which is 141 The method of claim 136 wherein said com

2-acetamido-N-benzyl-2-N-isoxazolidinoacetamide or pound is administered in an amount from about 10 to

the or isomer thereof about 100 mg/kg of body weight per day

537872975 76

142 The method according to claim 135 wherein the 146 The composition according to claim wherein

compound administered is 2-acetamido-N-benzyl-2N.- said electron donating substituent is hydroxy lower

methoxyaminoacetamide 2-acetamido-N-benzyl-2-N- alkoxy lower alkyl amino lower alkylamino dilower

NO-dimethylhydroxy-aminoacetainide N-acetyl- alkylamino phenoxy thiol lower alkylmercapto or

phenylgylcthe-N-benzylaniide a-acetamido-N-benzyl-disulfide

147 The composition according to claim 42 wherein2-furanacetame a-acetainido-N-benzyl-2-5-rnethyl-

said electron withdrawing group is halo nitro carboxyfuranacetamidé a-acetamido-N-3-fluorobenzyl-2- lower alkenyl lower alkynyl formyl carboxyamidofuranacetaniid 2-acetamido-N-benzyl-2-NN- aryl quaternary ammonium trifluoromethyl aryl

methylhydroxyaxnino acetamide 2-acetamido-N-ben- 10 lower alkanoyl and carbalkoxy

zyl-2-N-isoxazolidinoacetamide 2-acetamido-N-ben- 14.8 The composition according to claim 42 wherein

zyl-2-2-pyrroyl acetamide 2-acetamido-N-benzyl-2- said electron donating group is hydroxy lower alkoxy

2-pyridyl acetamide or 2-acetamido..N-benzyl-2-l- lower alkyl amino lower alkylamino dilower alkyl

pyrazolylacetamide or the isomer of the compound axnino phenoxy thiol lower alkylmercapto or disul

isomer of the compound or mixture of the DL 15 fide

isomer of the compound149 The composition according to claim 67 wherein

143 The compound according to claim 82 which issaid electron withdrawing group is halo nitro carboxy

D--a-Acetamido-N-benzyl-2-furanacetamidelower alkenyl lower alkynyl formyl carboxyamidoaryl quatemary ammoniurn trifluoromethyl aryl

144 The compound according to claim 110 which is

20 lower alkanoyl and carbalkoxyN-acetyl-D-phenylglycine-N-benzylamide 150 The composition according to claim 67 wherein

145 The composition according to claim whereinsaid electron donating group is hydroxy lower alkoxy

said electron withdrawing substituent is halo nitro lower alkyl amino lower alkylamino dilower alkylcarboxy lower alkenyl lower alkynyl formyl carbox- amino phenoxy thiol lower alkylmercapto or disul

yamido aryl quaternary ammonium trifluoromethyl 25 fide

aryl lower alkanoyl and carbalkoxy

30

35

40

45

50

55

60

65

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNQ 5378.729 Page of

DATED January 1995

INVENTORS Harold Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 4line 16 cyclodecyl should read

--cyclodecyl-

Column line 49 should read

Column line 12 after hydrogen insert --

Column line 31 after aralkoxycarbony.hydrazino

delete and insert

Column line 32 PR4R4.j should read -- PR4NRcRI--

Column line 38 R6are should read --R6 are--

Column line 43 group-and should read

--group and--

Column 11 Scheme II on line 11 insert the

following --wherein R17 lower alkyl aryl aryl

lower alkylColumn 13 line 30 R16 should read --R17-

Column 17 line 29 tile should read --the--

Column 19 line 32 PI should read --P1--Column 20 line 22 PI should read --P1--

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 5378729 Page of

DATED January 1995

iNVENTORS Harold Kohn et al

It is certified that error appears in the above-indentifed patent and that said Letters Patent is hereby

corrected as shown below

Column 20 line 37 NMR should read --1H NMR-

Column 21 line 63 151 should read --1H--

Column 23 line 22 delete -- --

Column 23 line 33 residuewas should read

residue was-Column 23 line 43 .29 should read --2.29-

Column 23 line 60 mol should read --ninol-

Column 24 line 20 415 should read --41.5--

Column 24 line 56 311 should read --3H--

Column 25 line 30 85 .34 should read

85 34Column 25 line 64 C3 should read --C3--

Column 25 line 68 C4. should read ---C4.--

Column 26 line cm should read cmColumn 26 line 24 C5 should read --C5--

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 5.378.729 Page of

DATED January 1995

INVENTORS Harold Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 26 line 49 271.-13208 should read

-271.13208Column 27 line 30 2C2 should read --2C2Column 27 line 31 17 1.57 should read -171.57-

Column 27 line 65 C3 should read --C --

Column 27 line 66 2C2 should read --2C2--

Column 27 line 67 C2 should read --C2Column 28 line ttjtI should read cm-Column 28 line 24 Na2p4T should read

--Na2SO4--Column 28 line 44 after insert ----Column 28 line 67 chloroform/nethanol should

read --chloroform/methanol

Column 29 line 12 C7 should read --C7a--Column 29 line 66 2.00 should read --2.00 g-

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 5378729 Page of

DATED January 1995

INVENTORS Harold Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 32 line 64 Marking should read ---Making--

Column 33 line 13 820 should read --820--Column 33 line 32 after solution insert --of--

Column 33 line 42 15.4G should read -15.46--

Column 35 line 61 169.02 should read --169.02--

Column 36 line 10 .82 should read 2.82--Column 36 line 17 By should read --by--

Column 37 line 44 Si02 should read --Si02--

Column 38 line 23 Si02 should read --Si02--Column 38 line 26 411 should read --411--Column 38 line 37 cHCl81 should read --dHcl3 --

Column 38 line 47 11.87 should read --113.87Column 38 line 61 Rental should read --ziinol-

Column 39 line 65 30 should read --0.60

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 378 729Page of

DATED January 1995

INVENTORS Harold Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 40 line 40 0259.71% should read

02 5971oColumn 41 line 61 should read --51--

Column 41 line 48 100 20 should read

100 122 20Column 42 line 798 should read --7%Column 42 line 17 It should read --H--

Column 43 line 25 H18t should read --H1Column 43 line 41 59.5G% should read --59.56%-

Column 43 line 67 rental should read --mol-

Column 44 line 40 1.520 should read 1520Column 48 line 10 18.91 should read 48.94-Column 48 line 13 1470 should read --1470--

Column 48 line 14 740700610 should read

740 700 610

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 5378729 Page of

DATED January 1995

INVENTORS Harold Kahn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 48 line 36 hydroxyacetaniido should read

-hydroxyacetamide-

Column 48 line 56 730690 should read

-730 690Column 48 line 61 59.21% should read 59.24%Column 48 line 63 62 should read --67--

Column 48 line 65 synthesis should read

-Synthesis--

Column 49 line staple should read --sample--

Column 49 line 55 760700 should read

-760 700Column 50 line mL should read --6 ml --

Column 51 line 17 MI should read --M1--Column 52 line 45 t3 should read -45.43-Column 52 line 20 ml should read --6 ml.-

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 378 729Page of

DATEDJanuary 1995

INVENTORS Ha Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 52 line 22 -50 mL should read

50 mL-Column 52 line 63 2C2 should read --2C--Column 53 line 43 nap should read --mp-Column 54 line 12 of should read --of 2--

Column 54 line 55 ml should read --mL-Column 54 line 63 2-pyridone should read

--2-pyridone--

Column 55 line 43 1268 .6 should read 126.80Column 55 line 47 conformed should read

--confirmed-

Column 56 line 10 CH3IJ should read --CEH/-

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENTNO 5378729 Page of

DATED January 1995INVENTORS Harold Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 56 line 20 138.8140.1 should read

-138.8 140.1

Column 57 line 25 fox should read --for--

Column 58 line 17 arid should read --and--

Column 59 line 43 after 30 insert -- --

Column 59 line 50 before lOO insert -- --andafter 100 insert -- --

Column 61 line before II 100 insert -- --

Column 61 line 11 28.4 should read __28.4__Column 61 line 15 3.9 should read __3..9__

Column 65 line 36 Claim 39 should read --D-Column 65 line 67 Claim 41 should read --D-

UNITED STATES PATENT AND TRADEMARK OFFICE

CERTIFICATE OF CORRECTION

PATENT NO 5378.729 Page of

DATED January 1995

INVENTORS Harold Kohn et al

It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby

corrected as shown below

Column 66 line 39 Claim 42 SO should read

--SOa-Column 68 line Claim 53 delete

isoxazoldinoColumn 70 line 31 Claim 79 if should read --is-

Column 72 line 44 Claim 115 which is or should

read -which is or-Column 73 line 43 Claim 122 2-acetamido should

ead aacetaznido

Column 73 line 48 Claim 122 2-benzyl should read

-N-benzyl-

Signed and Sealed this

Eleventh Day of June 1996

Attest

BRUCE LEHMAN

Attesting Officer CommLv.swner of Patevc and Tradenzark