IE84051B1 - Amino acid derivative anticonvulsant - Google Patents

Description

CLAIMS "Amino Acid Derivative Anticonvulsantfi The present invention relates to compounds and pharmaceutical compositions having central nervous system (CNS) activity which are useful in the treatment of epilepsy and other CNS disorders. More specifically, the compounds of this invention can be characterised as protected amino acid derivatives having the following general formula: wherein 'R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower atkyl and R is unsubstituted or is substituted with at least one electron withdrawing group, or electron donating group; R, is hydrogen or lower alkyl, unsubstituted or substituted with an electron donating group or an electron withdrawing group and R2 and R3 are independently hydrogen or Z—Y which may be unsubstituted or substituted with at least one electron withdrawing group or one electron donating group with the proviso that R2 and R3 cannot both be hydrogen; Z is O, S, NR4, or PR; Y is aryl lower alkyl, lower alkenyl or lower alkynyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or ZY taken together is NFLNRSRB, NFLOR5, OPR4R5, PFt4OR5, SNFLR5, NFLR5, - 2 _ NR4SFl5, SPFLR5, PR,,SR5, NR4PR5R5 or PFl.,NR5R6, R4, R5 and R6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R4, R5 and R5 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and n is -4; or wherein R is benzyl 'R, is methyl R2 is hydrogen R3 is 2-(5—methylfuryl), 2-benzofuryl, 2-benzo[b]-thienyl, 2(5-methylpyrrolyl), or 2—pyridyl; and n is 1; or wherein R is 2—fluorobenzyl, 3—fluorobenzyl, 4-fluorobenzyl, 2, 5-difluorobenzyl, or 2,6- ditluorobenzyl, R, is methyl, R2 is hydrogen R3 is furyl, and n is 1, and the pharmaceutical acceptable salts thereof.

The predominant application of anticonvulsant drugs is the control and prevention of seizures associated with epilepsy or related central nervous system disorders. Epilepsy refers to many types of recurrent seizures produced by paroxysmal excessive neuronal discharges in the brain; the two main generalized seizures are petit mal, which is associated with myoclonic jerks, akinetic seizures, transient loss of consciousness, but without convulsion; and grand mal which manifests in a continuous series of seizures and convulsions with loss of consciousness.

The mainstay of treatment for such disorders has been the long-term and consistent administration of anticonvulsant drugs. Most drugs in use are weak acids that, presumably, exert their action on neurons, glial cells or both of the central nen/ous system. The majority of these compounds are characterised by the presence of at least one amide unit and one or more benzene rings that are present as a phenyl group or part of a cyclic system.

Much attention has been focused upon the development of anticonvulsant drugs and today many such drugs are well known. For example, the hydantoins, such as phenytoin, are useful in the control of generalized seizures and all forms of partial seizures. The oxazolidinediones, such as trimethadione and paramethadione, are used in the treatment of nonconvulsive seizures. Phenacemide, a phenyl- acetylurea, is one of the most well known anticonvulsants employed today, while much attention has recently been dedicated to the investigation of the diazepines and piperazines.

EP-A-263 506 concerns anticonvulsant compositions containing amino acid derivatives. The compounds described therein represent a (substituted formic amide) acetic amide derivatives having a substituent at the nitrogen and which may further be substituted at the Cl C atom with a substituent via RC/C bond.

Furthermore, US Patent Nos. 4,002,764 and 4,178,378 to Allgeier, et al. disclose esterified diazepine derivatives useful in the treatment of epilepsy and other nervous disorders. US Patent No. 3,887,543 to Nakanishi, et al. describes a thieno [2,3—e] [1,4] diazepine compound also having anticonvulsant activity and other depressant activity. US Patent No. 4,209,516 to Heckendorn, et.a|. relates to triazole derivatives which exhibit anticonvulsant activity and are useful in the treatment of epilepsy and conditions of . US Patent No. 4,375,974 to Fish, et al. discloses a pharmaceutical formulation containing an aliphatic amino acid compound in which the tension and agitation. carboxylic acid and primary amine are separated by tree or four units. Administration of these compounds in acid pH range are useful in the treatment of convulsion disorders and also possess anxiolytic and sedative properties.

Unfortunately, despite the many available pharmacotherapeutic agents, a significant percentage of the population with epilepsy or related disorders are poorly managed.

Moreover, none of the drugs presently available are capable of achieving total seizure control and most have disturbing side—effects. Clearly, current therapy has failed to "seize control" of these debilitating diseases.

It is therefore one object of the present invention to provide novel compounds exhibiting CNS activity, particularly anticonvulsant activity.

Another object of this invention is to provide pharmaceutical compositions useful in the treatment of epilepsy and other CNS disorders.

A further object of this invention is to provide a method of treating epilepsy and related convulsant disorders.

These and other objects are accomplished herein by providing compounds of the following general formula: |...

R-NHéCCHH% C-R ll l "ll OR} wherein R, R,, R2, R3, R4, RERSVZ, Y are as defined hereinabove.

The present invention contemplates employing the compounds of Formula l in compositions of pharmaceutically acceptable dosage forms. Where the appropriate substituents are employed, the present invention also includes pharmaceutically acceptable addition salts. Moreover, the administration of an effective amount of the present compounds, in their pharmaceutically acceptable forms or the addition salts thereof, can provide an excellent regime of the treatment of epilepsy, nervous anxiety, psychosis, insomnia and other related central nervous system disorders.

The alkyl groups when used alone or in combination with other groups, exemplary of the substituents are lower alkyl containing from 1 to 6 carbon atoms and may be straight chain or branched. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, and hexyl.

The aryl lower alkyl groups include, for example, benzyl, phenethyl, phenpropyl, phenisopropyl, phenbutyl, and the like, disphenylemethyl, 1, 1 — diphenylethyl, and 1, 2 ’ diphenylethyl.

The term aryl refers to an aromatic group which contains up to 18 ring carbon atoms and up to a total of 25 carbon atoms and includes the polynuclear aromatic substituents. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. This group includes phenyl, naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. It also includes groups like ferrocenyl.

Lower alkenyl is an alkenyl group containing from 2 to 6 carbon atoms and at least one double bond. These groups may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2- butenyl, 1-pentenyl, (Z)pentenyl, (E)pentenyl, (Z)methylpentenyl, (E-)—4— methyl—2-pentenyl, pentadienyl, e.g., 1, 3 or 2, 4-pentadienyl.

The term alkynyl include alkyne substituents containing 2 to 6 carbon atoms and may be straight chained as well as branched. It includes such groups as ethynyl, propynyl, 1—butynyl, 2—butynyl, 1-pentynl, 2—pentyny|, 3-methyl—1—pentyn|, 3—pentynyl, -hexynyl, 2—hexynyl, and 3-hexynyl.

The term "electron-withdrawing and electron donating" refers to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if the hydrogen atom occupied the same position in the molecule. These terms are well understood by one skilled in the art and are discussed in Advanced gggic Cherndistry, by J. March, John Wiley and Sons, New York NY, pp. 16-18 (1985). Electron withdrawing groups include halo, including bromo, fluoro, chloro, and iodo; nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxamldo, aryl, quaternary ammonium and the like. Electron donating groups include such groups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl and the like; amino, lower alkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto, alkylthio and disulfide. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above—identified groups.

The term halo includes fluoro, chloro, bromo, and iodo.

As employed herein, the heterocyclic substituent contains at least one sulfur, nitrogen or oxygen, but also may include one or several of said atoms. The heterocyclic substituents contemplated by the present invention include heteroaromatics and saturated and partially saturated heterocyclic compounds.

These heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. They may contain up to 18 ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25 carbon atoms. The heterocyclics are also intended to include the so—called benzoheterocycles. Representative heterocyclics include furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, is othiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, trlazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolidinyl, furazanyl. N- methylindolyl, methylfuryl, puridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxides of the nitrogen containing heterocycles, such as the nitric oxides of pyridyl, pyrazinyl, and pyrimidinyl and the like. The preferred heterocyclic are thienyl, furryl, pyrroiyl, benzofuryl, The preferred heterocyclic is a 5 or 6-membered benzothienyl, indolyl, methypyrrolyl, morphoiinyl. heterocyclic compound. The especially preferred heterocyclic is furyl.

The preferred compounds are those wherein n is 1, but di, tri and tetrapeptides are acceptable.

The preferred values of R is aryl lower alkyl, especially benzyl, and the preferred R1 is H or lower alkyl. The most preferred R, group is methyl.

The most preferred electron donating substituent and electron donating substituent for R1 e.g. are halo , nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralky|) amino, amino lower alkyl, mercapto and alkylthlo.

The ZY groups representative of R2 and R3 include aldoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy, alkylamino, such as methylamino, ethylamino, arylamino, such as aniline, lower dialkylamino, such as, dimethylamino, hydrazine, alkylhydrazino and such as aryl hydrazine, N—methy|hydrazino and N-phenylhydrazino, and hydroxylamino, such as N—hydroxy|amino (-NH-OH) and O—hydroxylamino (—O—NH2).

It is preferred that at least one of R2 and R3 is hydrogen and that the other is heterocyclic. The preferred heterocycllcs include furyl, thienyl, benzothienyl, benzofuryl, morpholinyl, indolyl, pyrrolyl, methylpyrrolyl. It is also preferred that one of R2 and R3 is methyl, phenyl, isopropyl, 2-thiomethylethyl, ethoxy, methoxy, aniline, propenyl, ethylamino and methylamlno.

Preferred compounds of the present invention have the following general formula: . R 2 l ACHZNHC-CNHC-R1 A I1 I H M? / o as o Wherein R1 is H or lower alkyl, R2 and R3 are as defined above and A is hydrogen or an electron donating group or electron—withdrawing group and m is 0-5. It is preferred that A is hydrogen (i.e.), m=o). However, values of m, equalling 1, 2, or 3 are also preferred.

The compounds of the Formula I have the formula l" 32 0 R-NHC— -~- ..

\ H <5 Zx:iC R1 L__O E3 :1 wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic alkyl which is unsubstituted or substituted with at least one electron withdrawing group or at least one electron donating group; R, is hydrogen or lower aikyl which is unsubstituted or substituted with at least one electron withdrawing group or one electron donating group, R2 and R3 are independently hydrogen or Z-Y which may be unsubstituted or substituted with at least one electron withdrawing or one electron donating group, with the proviso that R2 and R3 cannot both be hydrogen; Z is O, S, NR4, or PR4; Y is aryl lower alkyl, lower alkenyl or lower alkynyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or ZY taken together is NR,,NR5R6, NR,,OR5, OPFLR5, PFLOR5, SNR4R5, NFLR5, NR,,SR5, SPR4R_.,, PR,,SFi5, NFLPRSRG or PFLNRSRG, R4, R5 and R8 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R4, R5 and R6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and n is 1-4; or wherein R is benzyl R, is methyl R2 is hydrogen R3 is 2-(5-methylfuryl), 2-benzofuryl, 2-benzo[b]-thienyl, 2(5-methylpyrrolyl), or —pyridyl; and n is 1; or wherein ‘R is 2-fluorobenzyl, 3—fluorobenzy|, 4-fluorobenzyl, 2, 5—difluorobenzyl, or 2,6- difluorobenzyl, R, is methyl, R2 is hydrogen R3 is furyl, and n is 1, and the pharmaceutical acceptable salts thereof. Of this preferred group, it is especially preferred that n is 1.

The compounds of the present invention may contain one (1) or more asymmetric carbons and may exist in racemic and optically active forms. The configuration around each asymmetric carbon can be in either the D or L form. (it is well known in the art that the configuration around a chiral carbon atom can also be described as R or S in the Cahn—Prelog—lngold nomenclature system). All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers as well as racemic mixtures and mixtures of enantiomers, diastereomers or both are contemplated by the present invention.

In the principal chain, there exists asymmetry at the carbon atoms to which the groups R2 and R3 are attached as substituted. When n is 1, the compounds of the present invention is of the formula ' R2 I » 'Z-.I'.'H'' - - - .. ' ea <5 N E R1 0 R3 0 wherein R, R,, R2, R3, R4, R5, R5, Z and Y are as defined previously. As used herein, the term configuration shall refer to the configuration around the carbon atom to which R2 and R3 are attached, even though other chiral centers may be present in the molecule. Therefore, when referring to a particular configuration, such as Q or LJ it is to be understood to mean the stereoisomer, including all possible enantiomers and disastereomers. The compounds of the present invention are directed to the optical isomers, i.e., the compounds of the These stereoisomers may be found in mixtures of the l__ and Q stereoisomer, e.g., racemic present invention are either the l__-stereoisomer or the D— stereoisomer. mixtures.

Depending upon the substituents, the present compounds may form addition salts as well. All of these forms are contemplated to be within the scope of this invention including mixtures of the stereoisomeric forms.

The following three schemes of preparation are generally exemplary of the process which can be employed for the preparation of the present complexi £9162-"l-e___I.

R .,2.

HOOC-C—NH2 I R [2 HOOC-%—NH on 0 _.nn2 H RKH-C-C—NHCR | CD2 + Rffil wherein u :2 SOCl excess 'R—NH—C—C—NH 2 \ x | 2 MeOH ’ RNH2 ’ R3 0 R H I2 RHN—c—o—NH—fi—R1 R3 o~ o o R -. 0 H n _ 12 u -R COCR HOOC—C-NH—CR 1 1 . 1 -———————> R3 . 0 H ClCO R7 ‘ gergiary amine 0 o R 0 u u :2 u RNH2 R7OC0C—C-NH—CR1 4——- £3 R7 = lower alkyl, aryl. aryl lower alkyl, .5;" . by art—recogni:ed procedures preparable intermediates.

Scheme Iil (3 .3? (3 one ll RICNHZ RZCCOH RlCNH—$—COH . ——-——> R2 ’ R7OH/H+ . 0 on o ‘ ll ,1 7n , 8 $378 R1CNh—c——CNHR RN52 RlCNn—C-—COR7 R <——— ,3 2 with or 2 without catalyst R3" (i,e., m+cN') ‘ Lewis acid, such as BF3 O(Et)2 O R O u |3H P.1CNH—C—CNHR ~ I R2 wherein R3 = aryl, heteroaromatic and R7 is as defined hereinabove. ' More s ecificall", these com ounds.can be re ared 1 from known compounds or readily For instance, compounds of Formula I can be prepared by reacting amines of Formula II with an acylating derivative of a carboxylic acid of Formula III under amide forming conditions: RNH NH H A + H 73-O‘-73 I II III wherein R, R1, R2, R3 and are as defined hereinabove and n=1.

The amide forming conditions referred to herein involve the use of known derivatives of the described acids, such as the acylhaiides, (e.g., R1-(P—X, wherein X is Cl, Br, and the like), anhydrides O O O (e.g., R1—lC‘3—O-‘Cg-R1), mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazoles, and the like. It is preferred that the acylating derivative used is the O O anhydride, R10-'Cl3-R1. When alkyl esters are employed, amide bond formation can be catalyzed by metal cyanides such as sodium or potassium cyanides.

Another exemplary procedure for preparing Compounds wherein at least one of R2 and R3 is aromatic or heteroaromatic is as depicted in Scheme IV.

The ester (IV) is reacted with halogen and ultraviolet light in the presence of a catalyst, e}g.,7 AIBN, to form the halo derivative (V). (V) is reacted in the presence of a Lewis acid, such as zinc chloride, with an aromatic or heteroaromatic compound to form the Compound (VI). (VI)_in turn_is hydrolyzed and then reacted with alkylhaloformate, such as alkylchloroformate in the presence of a tertiary amine to generate the mixed N—acyl amino acid carbonic ester anhydride (VIII). This in"ermediate is reacted with an amine under amide forming conditions to give the compound of Formula I. Alternatively, (VI) can be reacted directly with an amine (RNH2) optionally in the presence of a metal catalyst, such as metal cyanides, e.g., potassium or sodium cyanide, under amide forming conditions to form a compound of Formula I.

Alternatively, compound VII can be prepared by an independent method and converted to V1 which is then reacted with an amine, with or without catalyst to form the compound of Formula I. -17..

RlCNH‘f-CCR7 ' without gatelyst (i.e., M‘CN ) VIII R3 H2NR ‘F2? RlCNH-C-C-NHR I R3 \ X = halogen (i.e., Cl, Br) R7 = loweralkyl, aryl, arylloweralkyl M+ = metal cation (i.e., Na+,.K+) -18..

Another useful method for preparing a compound of Formula 1 involves simple substitution reactions.

An exemplary procedure is as follows: it a W R1 - c-[N-ti-c-1m=.a + R3 - L—-—-—-—-) I n IX "-2 x Wherein R, R, R2, R4 and n have the aforesaid meanings and R3 is defined heretofore except it is not aryl, heteroaromatic or polynuclear aromatic and L and L’ are independently a good leaving group, such as halide, tosylates, mesoylates, brosylates, benzyloxy. In this procedure the amine of Formula IX is reacted with a compound of Formula X under substitution conditions. The reaction may take place in the presence of an acid, such as inorganic acid, e.g., hydrochloric acid, sulphuric acid or Lewis acid, such as boron trifluoride and the like or in the presence of a vase, such as triethylamine.

However, when R3 is heteroaromatic, aryl or polynuclear aromatic, L is hydrogen. in the procedure under these circumstances, the reaction should take place in the presence of an acid catalyst, such as an inorganic acid, e.g., hydrochloric acid or a Lewis acid, such as borontrifluoride. reaction can be eff .As in any organic reaction, solvents can be employed such as methanol, ethanol, propanol, acetone, tetrahydrofuran, dioxane, dimethylformamide, dichloromethane, chloroform, and the like. The reaction is normally effected at or near room temperature, although temperatures from 0°C up to the reflux ' temperature of the reaction mixture can be employed; 9 As a further convenience, the amide forming ected in the presence of a base, such as tertiary organic amine, 6 g., triethylamine,, pyridine, 4-methylmorpholine, picolines and the like, particularly where hydrogen halide is formed by the amide forming reaction, e.g., acyl halide and the amine of Formula II. Of course, in those reactions where hydrogen halide is produced, any of the commonly used hydrogen halide acceptors can also be used.

The exact mineral acid or Lewis acid employed in the reaction will vary depending on the given" transformation, the temperature required for the conversion and the sensitivity of the reagent toward the acid in the reaction employed As an example of the process described hereinabove, D-(-)—a-acetamido—N-benzyl—2-furanacetamide can be prepared by reacting under amide forming conditions d—acetamide—2—furanacetic acid or an acylating derivative thereof, i.e., esters, e.g. alkyl esters containing 1- atoms, or acid anhydrides and the like. carbon The diastereomers formed from the reactions can then be separated by techniques known to one skilled in the art.

The o—acetamido~2-furanacetic acid can be prepared by reacting under substitution conditions, furan with an acylating derivativeof2-acetamidohaloacetic acid wherein the halo group is bromo or chloro. By an acylating derivative of 2—acetamido—2—ha1oacetic acid, it is meant to include lower alkyl esters thereof or the known carboxy protecting groups. compounds, e.g., R and R The various substituents on the present new . as defined in R, R1, i 3 can be present in the starting compounds, added to any one of the intermediates or added after formation of the final products by the known methods of substitution or conversion reactions.

For example, the nitro groups can be added to the aromatic ring by nitration and the nitro group converted to other groups, such as amino by reduction, and halo by diazotization' of the amino group and replacement of the diazo group.

Alkanoyl groups can be substituted onto the aryl groups by Friedel—Crafts acylation. The acyl groups can be then transformed to the corresponding alkyl groups by various methods, including the Wolff-Kishner reduction and Clemmenson reduction. Amino groups can be alkylated to form mono[ dialkylamino and trialkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding thioethcrs or others, respectively. Primary alcohols can be oxidized by oxidizing agents known in the art to form Carboxylic acids or aldehydes, and secondary alcohols can be oxidized to fo;m_ketones. Thus, substitution or alteration reactions can be employed to provide a variety of substitucnts throughout the molecule of the starting material, intermediates, or the final product.

In the above reactions, if the substituents themselves are reactive, then the substituents can themselves be protected according to the techniques known in the art. A variety of protecting groups known in the art may be employed_ Examples of many of these possible groups may be found in "Protective Groups in Organic Synthesis," by T.W.

Greene,John Wiley & Sons, 1981. ' skilled in the art, e.g., by fractional distillation, crystallization and/or chromotagraphy. stereoisomeric forms and the products obtained thus can be mixtures of the isomers, which can be resolved. antipodes, for example, by separation of diastereomeric salts thereof, e.g., by fractional crystallization,-by selective . ., papain digestion, or by use hase in chromotagraphy (HPLC). al stationary phases for HPLC, incorporated hereiulby reference with the same force and effect as if fully set forth herein. ' For example, a racemic mixture of any of the intermediate in any of the schemes, e.g., $9 ‘32 R R1 C — NH — C — COR7, wherein R7 is H \ R3 (which can be prepared according to the procedures of Schemes 1, 2, 3, cr 4) is reacted with an optically active amine, RNH2, e.g., (R)(+)1)~methylbenzylamine to form a pair of diastereomeric salts. The diastereomers can then be separated by recognized techniques known in the art, such as chromotagraphy (HPLC), fractional recrystallization.

In another method, a racemic mixture of final products or intermediates can be resolved by using enzymatic methods.

Since enzymes are chiral molecules, it can be used it will to separate the racemic modification, since preferentially act on one of the compounds, without affecting the enantiomer. For example, acylase, such as acylase I, can be used to separate the racemic modification of an intermediate D,L(i)2%-acetamido- —furanacetic acid. It acts on the Q (:)3¢acetamido- ~furanacetic acid, but will not act on the Q enantiomer.

In this way, the D(-)Ex—acetamido-2—furanacetic acid can be isolated. the intermediate can then react with the amine (RNH2) under amide forming conditions as described hereinabove to form the compound of Formula I. ‘administered daily or the dose may be incorporated directly with the food of the diet.

The active ingredients of the therapeutic Compositions and the compounds of the present invention exhibit excellent anticonvulsant activity when administered in amounts ranging firom about 10 mg to about 100 mg per kilogram of body weight per day. A preferred_dosage regimen for optimum results would be from about 20 mg to about 50 mg per kilogram of body weight per day, and such dosage units are employed that a total of from about 1.0 gram to about 3.0 grams of the active compound for a subject of about 70 kg of - This dosage regimen may be adjusted to provide the optimum body weight are administered in a 24-hour period. therapeutic response and is preferably administered one to three times a day in dosages of about 600 mg per For administration. example, several divided doses may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

A decided practical advantage is that the.active compound may be administered in an convenient manner such as by the oral,’ intraveneous (where water sfiluble), intramuscular or subcutaneous routes.

The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers. Such compositions and preparations should contain at least 1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and t0OOmg of active compound.

The tablets, troches, pills, capsules may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; A lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated wit shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non—toxic in the amounts employed. in addition, the active compound may be incorporated into sustained—re|ease preparations and formulations. _.25_ The active compound may also be administered parenterally or intraperitoneally.

Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of micro organisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture an storage and must be preserved against the contaminating action of micro organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

The prevention of the action of micro organisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle_which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze—drying technique which yield a powder of the active ingredient plus anyi additional desired ingredient from previously sterile- filtered solution thereof.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known-in the art. Except insofar as any conventional media :or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.

Supplementary active ingredients can also be incorporated into the compositions. lt is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The . specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can} for example, contain the principal active compound in amounts ranging from about 5 to about 1000 mg, with about 750 mg being preferred. from about 250 to Expressed in proportions, the active compound is generally present in from about 10 to about 750 mg/ml of carrier., In the case of compositions containing supplementary active ingredients, the dosages are _ determined by reference to the usual dose and manner of administration of the said ingredients.

The compounds of the present invention may be administered in combination with other anti—convu1sant agents, such as phenytoin, phenbarbitol, mephenytoin, and phenacemide, and the like. This combination is likely to exhibit synergistic effects For a better understanding of the present invention together with other and further objects, reference is made to .the following description and examples -28: General Methods. Melting points werer determined with a Thomas—Hoover melting point apparatus and are uncorrected. Infrared spectra (IR) were run on a Beckman IR-4250 and Perkin-Elmer 1330 and 283 spectrophotometers and calibrated against the l60l—cm’l band of polysytrene.

Absorption values are expressed in waves numbers (cm‘1).

Proton nuclear magnetic resonance ' (¥H NMR) spectra were recorded on Varian Associates Models T—6O and FT-80A, General Electric QE 300, and Nicolet NT-300 NMR spectrometers. Carbon nuclear magnetic resonance (l3C NMR) spectra were run on a Varian Associates Models FT-80A General Electric ow 300 and Nicolet NT—3OO instrument. Chemical shifts are in parts per million (‘ values) relative to Me4Si, and coupling constants (J values) are in hertz. Mass spectral data were obtained at an ionizing voltage of 7C ev on a Hewlett-Packard 5930 gas chromotagraph-mass spectrometer and a Bell~Howell 21-491 spectrometer as well as at the Eli Lilly Laboratories on a Varian MAT-CH-5 spectrometer.. High—resolution (EI mode) mass spectra were performed by Drs. James Hudson and John Chinn at the Department of Chemistry, University of Texas at Austin, on a CEC2l@ll0B double-focusing A magnetic-sector spectrometer at 70eV. Elemental analyses were"obtained at Spang Microanalytical Laboratories, Eagle Harbor, MI and at the Eli Lilly Research Laboratories.

The solvents and reactants were of the best commercial grade available and were used without further purification unless noted. All anhydrous reactions were run under nitrogen, and all glassware was dried before use. In particular, acetonitrile and triethylamine were distilled from CaH2, while dichloromethane was distilled from P205. Acetic anhydride, benzaldehyde and ethyl chloroformate were frgctionally distilled. _2g_ Preparation of N—Acetyl—D— and L—amino acid~N—benzvlamides.

General Procedure. The D— or L-amino acid amide (ll mmol) was dissolved in dichloromethane (15 mL) and then acetic anhydride (l.23 g, l.4O mL, 12 mmol) was added dropwise. The solution was stirred at room temperature (l8h) and then concentrated to dryness. The residue was recrystallized from chloroform/hexane.

For the following examples, unless otherwise stated, the D—isomer was prepared by the above general _ procedure followed by separation of the diastereomers, e.g. enzymatically, chromatographic methods and the like, or by one of the procedures outlined on Pages 21-22. »—3o— EXAMPLE 1 Preparation of D,L-ct—Acetamido—N—benzv1—3—thi9pheneacetamide, D,L—(X—Acetamido—3—thiopheneacetic acid (2.99 g, mmol) was combined with acetonitrile (60 mL) and the mixture was placed into an ice/salt water bath (-5°C).

‘Triethylamine (1.51 g, 2.10 mL, 15 mmol) was added dropwise, followed by ethyl chloroformate (1.63 g, 1.43 mL, 15 mmol).

All additions were done slowly so that the temperature of the mixture did not rise above 0°C. at —5°C (20 min).

The mixture was then stirred Benzylamine (1.77 g, 1.80 mL, 16.5 mmol) in acetonitrile (10 mL) was added dropwise and the mixture was stirred at -5°C,(1 h) and then room temperature (18 h).

The mixture was concentrated in vacuo and the residue was combined with hot tetrahydrofuran (50 mL) and cooled in the freezer (3 h), resulting in the formation ofla white precipitate. The mixture was filtered and the precipitate was collected, dried in vacuo, and identified as triethylammonium hydrochloride (lfl NMR analysis). The filtrate was concentrated in vacuo and the resulting yellow‘ solid was recrystallized from 1:1 95% ethanol/water.

Yield: 1.91 g (44%). mp 198*199°C. 1 H NHR (DHsofd6): 5 1.91 (s, 3H), 4.29 (d,J = 5.2 Hz, 2H), .61 (d,J = 7.9 Hz, 1H), 7.15-7.50 (m, 33), 8-55 (d,J = 7.9 Hz, 1H), 8.74 (t,J = 5.2 Hz, 1H). c NMR (omso-as): 22.3, 42.0, 52.5, 122.4, 126.1, 126.7, 127.0 (3c), 128.2 (2c), 139.0, 139.2, 169.0, IR (KBr): 3460, 1675, 1570, 14oo,‘72o, 695 cm’1 Mass spectrum, m/e (relative intensity): .8 ppm. (2), 245 (3), 155 (88), 112 (100), 91 (31), 85 (17), 65 (7).

Elemental analysis Calculated for C Found i l5Hl6N2O2S 62.48% C; 5.59% H; 9.71% N. 6,. 62.41% C; 5.47% H; 9.55% N. . separated from the solution.

EXAMPLE 2.

Preparation of D,L—:1—Acetamido—N—benzy1—2—thiopheneacetamide.

N—Acety1-D,L—ethoxyg1ycine—N—ben2ylamide (6.26 g, mmol) was combined with dry ether (175 mL) and then boron trifluoride etherate (5.68 g. 5.0 mL, 40_mmol) was-added dropwisc, resulting in a homogeneous solution. After ‘ stirring a short time, a small amount of a yellow oil Thiophene (3.41 g, 8.0 mL, 100 mmol) was then added dropwise via syringe and the reaction (4 d). cooled in an ice bath and cold aqueous saturated NaHCO3 (200 was stirred at room temperature The mixture was mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic washings and the original ether layer were combined, dried (Na2SO,), and concentrated in vacuo. The residue was purified by flash column chromatography, using 94:6 chloroform/methanol as an eluant (Rf — 0.7 94:6 chloroform/methanol), and then recrystallized‘ " from benzene.

Yield: 2.67 g mp 167—169°C. (37%).

NMR (0ns0—a6): 6 1.91 (s, 33), 4.31 (d,J = 6.0 Hz, 2H), .74 (d,J = 7.9 Hz, 1H), 6.99-7.44 (m, an), 8.64 (d,J =_7,9 uz, 1H), 8.85 (t,J = 6.0 Hz, lH). c NHR (nm50—d6): 22.4, 42.3, 52.2, 125.6, 125.3, 126.6, .9, 127.3 (2C), 128.3 (2C). 139.0, 141.4, 169.2, 169.3 ppm. ' Mass spectrum, m/e (relative intensity): 289 (2), 181 (100), 112 (100), 91 (100), 85 (34), 74 (24).

Elemental analysis (6).

Calculated for C15Hl6N2O2S 62.48% C; 5.59% H; 9.71% N.

Found 62.64% C; 5.73% H; 9.61% N.

. EXAMPLE 3 Preparation of D,L—(1—Acetamido-N—benzvlfuranacetamide.

N—hcety1—D,L—2—(2-fury1)g1ycine-(0.47 g, 2.56 mmol) was combined with acetonitrile (10 mL) and cooled to -5°C (ice/salt water bath). Triethylamine (0.26 g, 0.36 mL, 2.56 mmol) was then rapidly added and the mixture stirred_at -5°C (3 min). Ethyl chloroformate (0.28 g, 0.25 mL, 2.56 mmol) was added dropwise béween —4°C and -3°C, and the resulting suspension was stirred at -4°C (20 min), and then an acetonitrile solution (2 mL) of benzyiamine (0.30 g, 0.31 mL, 2.82 mmol) was carefully added. During the addition of benzylamine the temperature of the solution did not go above 0°C. The mixture was stirred at -5°C (1 h) and at room temperature (18 h), and the: concentrated in vacuo. The residue was then triturated with hot tetrahydrofuran (5 mL), cooled at -16°C (3 h), and the resultind white precipitate was filtered and identified as triethylamine hydrochloride (la NHR, 60 MHz, 51.00 (t,J = 7.5 Hz, CH3), 2.82 (q,J = 7.5 Hz, CH2), 3.83 (s, NH)). The filtrate was evaporated to dryness in vacuo and the resulting oil purified by flash chromatography (98:2 chloroform/methanol) to give 0.09 g (13%) of the desired product as a white solid: Rf 0.30 (98:2 chloroform/methanol). mp 178-179°C.

H NMR (300 MHZ, DMSO-d6): 5 1.90 (s, CH3), 4.31 (d,J = 6.0 Hz, CH2). 5.58 (d,J = 8.1 Hz, CH), 6.27-6.33 (m, C3'H), 6.40-6.44 (m, C4’H), 7.20-7.36 (m, Ph), 7.60-7.64 (m, C5'H), 3.57 (d,J = 8.1 Hz, NH), 3.73 (t,J = 6.0 Hz, NH). c NMR (300 MHz, DMSO-d6): 22.35 (CH3), 42.27 (CH2), 50.95 (CH), 107.60 (C3'), 110 55 (C4'l, 126.82 CZC " or C3"), 127.08 (2C2" or 2C3"), 128.27 (C4"), 139,05 (c1"), 142.58 (c5'), .

IR (RBI): 3230, 1625 (br). 1525 (br),. 1375 (br). 1230, 1090, S90 cm_1. T ‘ Mass spectrum, m/e (relative intensity): 273 (1), 139 (100), 96 (94), 91 (51), 65 (9).

Elemental analysis ‘ ’ .

Calculated £0; C15Hl6N2O3 66.16% C; 5.83% H;_lO.29% N, Found .92% C; 5.83% H; I0.l5% N, _34- Example 4 Preparation of D, L-or-Acetamido-N—benzvlDvrroleacetamide -Acetamido-N-benzylethoxyacetamide (2.00 g, 8.0mmo|) was suspended in anhydrous ethyl ether (60 mL), and then boron trifluoride etherate (1.82g, 1.57 mL, 12.8 mmol) was added in one portion and the resulting solution was stirred (15 min).

The pyrrole (2.14 g, 2.22mL, 32 mmol) was then added in one portion and the solution was stirred at room temperature (48 h) during which time a precipitate formed. Hexanes (80 mL) were then added to the suspension, and the mixture was filtered and the brown semi-solid was triturated with 95:5 chloroform/methanol (30 mL) to furnish a green solid. This material was purified by flash chromatography (95:5 chloroform/methanol) to yield 0.94 g (35%) of the desired product as a white solid: Rf 0.29 (96:4 chloroform/methanol). mp 174—175°C.

‘H NMR (300 MHz, CD3CN): 6 1.93 (s, CH3), 4.35 (d,J=6.0 Hz, CH2), 5.42 (d, J = 6.9 Hz, CH), 6.00-6.18 (m, C3 ‘H, C4 'H), 6.68-6.72 (m, C5 ‘H), 7.04 (d,J = 6.9 Hz, NH), 7.17 (t,J = 6.0 Hz, NH), 7.10-7.47 (m, Ph), 9.10-9.80 (br s, NH).

C NMR (300 MHZ, CD3CN): 23.02 (CH3), 43.83 (CH2), 52.65 (CH), 107.57 (C3 ), 108.85 (C4 ), 119.33 (C5 '), 127.96 (C2 '), 128.01 (2C2 " or 2C3" ), 128.09 (2C2 " or 2C3 "), 129.49 (C4 " ), 140.01 (C1 "), 170.94 (COCH3), 171.21 (CONH) ppm.

IR (KBr): 3320, 1570 (br), 1470 (br), 1330, 1230, 950, 890, 860, 760, 710, 690, 655 cm‘.

Mass spectrum, m/e (relative intensity): 171 (12), 228 (2), 213 (1), 180 (2), 164 (9), 137 (93), 108 (20), 95 (100), 91 (38), 82 (35), 68 (15).

High resolution mass spectral analysis Calculated for C15H17N3O2 271 .13208.

Found 271.13144. »—35— EXAMPLE 5 Preoaration of D,L-2—Acetamido-H—benzv1-2—ethoxvacetamide.

An ethanolic solution (420 mL) of ethyl ~ 2—acetamido—2-ethoxyacetate (27.92 g, 147 mmol) and benzylamine (23.70 g, 24 mL, 221 mmol) Gas stirred at 40—45°c for 3 days. The reaction mixture was evaporated 13 vacuo and the residue recrystallized (1:3.5 tetrahydrofuran/hexanes -(650 mL)) to yield 25.80 g (70%) of the desired product as beige crystals: Rf 0.59 (9S:5 chloroform/methanol). mp 153—15S°C. 1 H NHR (300 M02, CDC13): 6 1.20 (t,J = 7.0 Hz, CH3), 2.07 (s, CH3), 3.60-3.76 (m, CHZCH3). 4.40-4.54 (m, CH2NH). 5.60 (d,J = 8.7 Hz, CH), 6.63 (d,J = 8.7 Hz, NH), 7.00 (br s, nu), 7.26-7.36 (m, pn). , .

C NHR (300 MHZ, CDC13): 15.06 (CH3CH2), 23.25 (CH3CO), 43.60 (CHZNH), 64.51 KCHZCH3), 77.43 (CH), 127.69 (2C or 2c3", c4"), 128.79 (2c2" or 2c3"), 137.57 (cl"), 168.13 (COCH3), 171.29 (coma) ppm.

IR (RBI): 3260, 1630 (br), 1550 (sh), 1505 (br), 1380, 1360, 1230, 1115, 1060, 1015, 890, 745, 690 cm—l ‘ Mass spectrum, m/e (relative intensity): 251 (4), 163 (9), 116 (98). 106 (34), 91 (98), 74 (100).

Elemental analysis Calculated for c 62.38% c; 7.25% H; 11.19% N. .49% C; 7.27% H; 11.24% N. "1sN2O3 Found -1—..

EXAMPLES Preparation of D,L-2—Acetamido—N—ben2V1—2—methoxvacetamide.

I To a methanolic solution (180 mL) of methyl 2¥acetamido—2—methoxyacetate (8.73 g, 54 mmol) was rapidly added benzylamine (8.68 g, 8.80 mL,‘a1 mmol) and then the mixture was stirred at 50°C (3 days) during which time a beige precipitate appeared. and the resulting precipitate was recrystallized from tetra- -hydrofuran (2x) to give 7.67 g (32%) of the desired product as beige crystals: R mp 145-146°C.

NMR (300 M02, c0c13): 5 2.06 (s, CH3CO), 3.37 (s, CH3O), 4.40-4.35 (m, CH2), 5.52 (d,J = 8.7 Hz, CH), 7.12 (d,J = 8.7 Hz, NH), 7.20-7.40 (m, Ph, NH). 13 C NHR (300 MHZ, CDCI3): 23.03 (CH3CO), 43.51 (CH2), 55.84 (CH.O), 78.94 (CH): 127.62 (C4"), 127.70 (2C2" or C3"), 128.70 (2C2" or 2C3"), 137.45 (C1'°), 166.91 (cocn,), 171.57 (coma) ppm.

IR (xs:): 1260, 1825 (br), 1550, 1505, 1435, 1390, 1370, 1230, 1120, 1050, 935, 890, 690 cm'1.

E 0.35 (9S:5 chloroform/methanol).

Mass spectrum, m/e (relative intensity): 237 (1), 205(2), 177 (2), 163 (4), 146 (1), 134 (1), 121 (2), 106 (26), 102 (98). 91 (95), 77 (13), 61 (100).

Elemental analysis Calculated for C H N O Z 3 61.00% C; 6.83% H; 11.86% N. .91% C; 6.85% H; 11.66% N.

The solvent was removed in vacuo EXAMPLE 7 Pram raiinfi or (17-41 1)-(ii-il\"¢et.i:imid6éN-iheiiiivlléiffiilrh (31111-I mgr ma ceta ;n:a"e." W" 7 N-Acetyl—D,L-ethoxyglycine-N-benzylamide. (2.00 g, 8.0 mmolliwas suspended in anhydrous ethyl ether. and then boron trifluoride etherate (1.82 g, 12.8 mmol) was rapidly added, andilthe resulting solution was stirred for -15 .min. The -methylfuran (2.63 1:, 32.0 mmol) has then added and the reaction was stirred" at Rf 0.25 (98:2 chloroforzri/methanol). mp 148-150 °c. 4 H NMR (DMSO-d(_?,) 5 1.88 (S, CI‘I3CO), 2.23 (5, CH3), 4.24-4.36 (in, CH2), 5.49 (Cl, J = so Hz, cm, 6.01 (br s, C3-H). 6.14 (d. J = 2.4 Hz,pC4.'H).7.20-7.31(m,Ph).8.52(d.

J =s.o Hz, NI-I), 8.69 (t, J’: 5.6 Hz, ml). _ mm (DMSO-d'5) 13.44 (CH3). v2.35 (GH3CO).44.11(CH2), 53,23 (CH), 107.51 (C3' or C4'), 110.40 (C3' or C4‘), 128.13 (C4-v), 128.18 (2C2" or 2C3"),'129.43 (2C2" or 2C3"). 139.69 (C1")i 149.18 (02 or C5‘). 153.81 (C9; or C5‘). 170.78 (CH3CO). 173.03 (CONH) ppm. ’ . 1 ‘ IR (KBr) 3270, 1620 (br), 1520 (hr), 1440, 1360, 1210, 1010 cm‘)-.

Mass spectrum, m/e (relative intensity) 286 (3), 179(8), 153 (57), 152 (57), 111 (23), 110 (mp), 97 (23), 91 (531). _ ' Elemental Analysis Calculated: Found: 1 ‘:1: ~' .12% C; 6.34% H; 9.78% N.

Ge.92%C;- 6.52% H; 9.52‘_}bN. :431-1pLs 3 ' Preparation of (UL)-rr.-/\cetamido-N-henzvlhcnznfuranacetamidg_ N—Acetyl-D,L-ethoxyglycine-N—benzylamide (1.00 g, 4 mmol) was suspended in anhydrous ethyl ether (3() mL) and then boron trifluoride etherate (0.91 g, 6.3 mmol) was rapidly added, and the resulting solutioniwas stirred tor 15 min. The bcnzofuran (1.89 g, 16 mmol) was then added and the reaction was stirred at room temperature (3 d). The reaction mixture was poured into an ice-cold saturated aqueous solution of NaHCO3, and then the mixture was maintained at this temperature for an additional 15 nein. The mixture was extracted with ethyl acetate (2 x), and theiorganic layers were combined, d1-ied‘(Na2SO4) and evaporated i_n The residue was purified by flash. chromatography (100% chloroform, then 99:1 chloroform/methanol) to yield the desired product Yield: 0.43 g (33%).

Rf 0.30 (98:52 chloroform/methanol). - mp 195-196 °C; I\*1\'_U"~(DMSO-d5)5 1.94 (s. CH3CO). 4.34 (5, J = 5.7 Hz, CH2). 5.77 (d, J = 3.1 Hz, cm, 7.24.732 (:11, C311, C511, C511, Ph), 7.54 (d, J .—. 7.0 Hz, C4-H or C7-H), 7.52 (d, J = 7.0 Hz, C4='H or C7-H). 8.74 (d, J = 3.1 Hz, NH), 8.86 (t, J: 5.7 Hz, NH).

NMR (DMSO-d(;) 22.27 (CH3CO), 42.30 (CH2), 51.22 (CH), 104.34 (C-3'), 110.90 (C71), 121.05 (C4-), 122.90 (051), 124.25 (050, 125.73 (C3-a), 127.01 (2c2«- or 203-»), 127.59 (2c2-v or 2c3-0, 125.14.(c4--1, 133.57 (C1--), 154.10 (C73), 154.30 (C20, 157.40 (CH3CO). 159.25 (CONH) ppm. 1 1 >. (KBr) 3230, 1525 (br), 1520 (br), 1440, 1090, 1055, 590, 735, 590 cm-1; ‘Mass spectrum, m/e (relative intensity) 322(5), 279 (1), 254 (1), 234 (1), 215 (5), 139 (45), 145 (100), 130 (11), 11512), 91 (57), 55(15). i i \ High resolution mass spectrum, Calcd for C1gH1gN2O3 322.1317.

Found 322.1315.

EXAMPLE 9 )1gp'nmt.ion of (D,l1)—(1-Acctamido—l’\l—hcn7:\{lhcnznlhlll1lODl1CnC8CCtamide_ lN—Acctyl-D,L-ethoxyglycine-N-benzylarriide (1.00 g, 4 mmol) was suspended in «anhydrous ethyl ether (15 mL)'and then boron trifluoride etherate (0.91 g, 6.3 mmol) was rapidly added, and the resulting solutionwas stirred for 15 min. The benzo[b]th1'ophene (2.14 g, 16 mrnol) uias then added and the reaction was stirred 'at room temperature (3 d). '-The solution was poured into an ice—cold saturated aqueous solution of NaHCO3, and then stirred for 15 min at 0 °C. The mixture was extracted» with ethyl acetate (2 x), and the organic layers were combined, dried (Na2SO4) and evaporated i_n_y;z_c_1_1_Q_ to givevan orange. oil. The oil was triturated with ethyl ether to yield a crystalline product which was filtered and further purified by flash chromatography (9921 chloroform/miethanol) to give the desired product. " Yield: 0.00 g (470).! Rf 0.32 (9921 chloroform./methanol). mp 229227 °C.

H mm (DMSO-d5) 3 1.94 (s, CH3CO), 4.34 (d, J = 5.7_Hz, CH2), 5.35 (d, J = 3.1 Hz, CII), 7.20.-33 (m, C3~H, C511, C711, Pb), 7.77-7.30 (m. C4-H or C5-H), ’ 7.89-7.93 (m, C4°H or C511), 8.76 (d, J = 8.1 Hz, NH), 8.97 (t, J = 5.7 Hz, NH).

NMR (DMSO.—d5) 22.34 (CH3CO), 42.33 (CH2), 52.70 (CH), 122.15 (C4- or C7v),‘ 122.32 (C4- or C7-), 123.45 (C3-), 124.37 "(C5 or (150, 124.41 (c5~ or C50», 123.39 .(c4--1, 127.27 (2C;;-- or 2c3n-), 123.27 (2c2-- or (2 C3"), 133.34 <03-a or cm), 133.95 (c3~a or C7'a). 142.53 (C1-), 168.65 (CH3Co), 139.12 (CONH) ppm. [A distinct signal for the ('12- carbon was not.detected and.is presumed to coincidewith the C1- carbon at 142.58 ppm.].‘_3__ IR (KBr) 3240, 1610 (br), 1510 (br), 1420, 1360, 1215, 1085, 885,730, 710, 685 curl.

Mass spectrum, m/e (relativeliritensity) 338 (8), 295 (2), 205 (76)&, 162 (100).. 135 (22). (12). 91 (59). ' . K Elemental Analysis: Calculated: 67.43% C; 5.3e%H; 8.2S%N.

Found: 67.21% C; 5.37.%H; 8.12%N.V . gféé’ EXAMPLE10 ' ,Rren':1rnj.i()n of‘ (D.T,)-(1-Acctamido-"N-bonzvlindoleacetagggg N-Acetyl-D,L-ethoxyglycine—N-benzylamide (0.69 g, 2.75 mmol)» was suspended in (anhydrous ethyl ether ( 20 mL) and then boron trilluoride etherate (0.63 "g, 4.40 mmol) was rapidly added, and the resulting solution was stirred for’ 15 The indole (1.30 g, 11.00 mmol) was then addedland the reaction was stirred at room 'ternperature ( 22 h). Petroleum ether (35-60 °C) was added to the reaction, and the resulting semisolid material filtered, and washed with petroleum ether (35-60 °C).

Purification of the reaction mixture was accomplished by flash chromatography (98:2 c‘hloroform/methanol) to produce the title compound as a white solid. .

Yield: 0.25,); (13%). .

Rf 0.14 (955 chloroform/methanol) mp 213-214 °c. . , . 1H NMR (DMSO-d5) 5 1.90 (s, or-1300). 4.35 (0, J :50 Hz, CH2), 5.72 (0, J = 7.2 Hz, CH). 5.90-7.37 (m. P11, C2-H), 7.02 (dd, J = 7.5 Hz, J g 7.5 Hz, C5-H or C5'H), 7.12 (dd, J = 7.5 Hz, J = 7.5 Hz, C5-H or 05-11), 7.39 ('0, J = 7.5 Hz. (14-11 or 07-11). 7.55 (0, J = 7.5 Hz, C4'H-‘or (37-11), 7.35 ((1, J = 7.2 Hz, NHCH), 3.13 Ct, J = 5.0 Hz, NHCH2), .30-1030 Cbr 5,0101). . 7 . . _ NMR (DMSVO-d5) 22.32 (CH3CO). 42.23 (CH2), 49.93 (CH), 111.51 (C7-), 112.08 (C3'), 118.76 (C4' or C50, 119.24 (C4' or C5‘), 121.37 (Cfi-4), 123.94 (C20, 126.56 (C3'a), 125.71 (C4"). 127.33 (2c2»- or 203-0, 128.18 (2c2-- or 2C3--3. 135.23 (GT3). 139.44 (of), 1s9.13(c113co), 170.31 (CONH) ppm.

(IG3r) 3250, 1510 (br), 1515 (br), 1450, 1420, 1370, 1350, 1235, 1095,1995, 735, 715. 595, 000 cm-1. 7' ’ x.v' \ ‘Mass spectrum, m/e (relative intensity) 321 (5), 278 (1), 264 (1), 233 (1), 214(6), 1 (85), 171 (3), 145 (100), 118 (185.91 (39).

Elemental Analysis: Calculathdz 71.01950; 5.96%H; 13.06%N.

Found: 70.87% C; 6.15% H; 12.78% N- _ % . " _2-methylpyrrole (0.85 g, 10 mmol) was theniadded and the reaction mixture EXAMPLE 1 1‘ Eoéarntinn 0!‘ (T), T.)-n.-Acntnniido-Néhoniyl(S-methylnvrrolclacetamidc.

N—Acetyl-D,L-ethoxyglycine-N-benzylamide (2.00 g, 8 mmol) was suspended in anhydrous ethyl ether (175 mL), and then boron trilluoride etherate (1.38 g, 9.7 mmol) was addediand the resulting solution stirred (15 min). The ‘W85 stirred under N2 (6 cl), during ivliich time the color ofthe reaction mixture turned reddish brown and a dark-brown deposit formed at the bottom of the flask. The clear solution was decanted and treated with an aqueous saturated NaHCO3 solution containing ice (100 mL) for 30 rnin. The aqueous reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined extracts were dried (Na2SO4) and the solvent removed i_n_vz=.cuo.:'The brown oily residue was purified by flash column chromatography using 98:2 chloroform/methanol as the eluerrtuto yield the desired compound. The product was recrystallized from ethyl acetatefnexane to give a light yellow amorphous solid.

Yield 0.20 g (94%) Rf0.44 (95:5, chloroform/methanol). , mp 167-168 °C.

H NMR (DMSO-d5) 8 1.87 (s. CH3). 2.13 (s. CQCH3), 4.27 (br s, CH2), 5.33 (d, J = 7.4 Hz, CH). 5.60 (s, C4H), 5.77 (s, ’33H), 7.19-730 (m, 5 PhH), 8.22 (d, J 3 7.4 Hz, NH). 8.45 (t, J = 5.5 Hz, NH). 10.38 (s, NH). V V NMR (DMSO-d5)i12.74 (CH3), 22.49 (COCH3), 42.11 (CH2). 51.21 (CH), 105.09 (C4), 106.07 (C3), 126.16 (C5), 126.64 (C40. 126.85 (C2), 127.09 (2C2"or 203-), 128.17 (209; or 203-), 139.33 ‘(C1'), 168.88 (COCH3), 169.79 (CONH) ppm.

LR (KBr) 3250, 1630, 1520, r'4‘20,_ 1360, 1300, 1260, 1230,1160,1110, 1020 cm-1.

Mass spectrum, m/e (relative intensity) 285 (M+, 10), 178 (20), 152 (24), 151 (100), 110 (12), 109 (93), 108 (22). 107 (25), 94 (16), 91 (43). A Elemental Analysis: Calculated: F ‘Found: -44.. .35% C; 6._71%H;. 14.73%N. 57_57c7,c; 6.90‘/oH; 14'.52%N. .3 4-Methylmorpholine (lequiv) was’ added" to a solution of _ at -10 to -15 vnthésié of Unsub- oz;-aeetamido-2—furanacetied acid (1 equiv) in dry tetrahydrofuran (75 m'L/10 mmol) °C under N2. After stirring (2 min), isobutyl chloroformate (1 equiv) wasiadded leading to the precipitation of a w1'iite solid. The reaction was allowed to proceed for 2 additional minutes and then a solution of the substituted benzyla.-mine (1 equiv) in ‘tetrahydrofuran (10lrnI../10 mmol) was added over 5 min at -10 to -15 °C; The reaction mixture was allowed to stir at room temperature for .’ 5 min and tlien the 4-‘rnethylmorpholine hydroclfloride salt filtered. The organic layer was concentrated i_r_i_var-un, and the residue‘ was triturated with ethyl acetate. and the remaining white solid filtered. ‘Concentration of the ethyl acetate ' layer led to additional amounts of the white solid. The desired product iva's purified by either reervstallization, or flash chromatography of the combined solid Examples 12-19» were prepared according to this procedure.‘ M ' material.

AoL-ace£amid0—2-furfinacctic acid (0.47 g, 2.56 mmo1)‘gaV'e the -46..

EXAMFLE_l2’ fl1.Lcz-Acctamido-N-hcnzvlrumnacntamidc.

Using) benzyl‘ amine (0.27 7g, 2.56 nimo1)'and racemic désired compofind.

The product was rebryétallized from ethyl-aceta te to give a white solid.

Yield: 0.46 g (05%) A R-fO.3O (9812 chloroform/methandl). mp 177-178 °C.

H mm (DMSO-d5) 5 1.90 (s, CH3), 4.31 (d, J = 6.0 Hz, CH2), 5.58 (d, J = 3.1 Hz, CH), 6.27 — 6.33 (m, C3H), 6.40 - 5.44 (m, C4H), 7.20 - 7.36 (:n, 5 PhH), 7.30 - 7.64 (In, C5H), 3.57 (d, J = 3.1 Hz, NH), 3.73 (t, J = 6.0 Hz, NH). .' EXAMPLE.1g‘ LD_l,-‘lit;/\;ctnn1i(ln—N-(2-fluornhenzvl)fgxrgqnnr-Qtninidgl . I Using 2-Iluorobenzylamine . 01-acetamido-2~l'm-anaceti Yield: 1.20 g (50%).. (1.13 g,. 9.0 mmol)'and racemic eacid (1.50 g, 8.2 mmol) gave the desired product.

Rf 0.36 (9G:4 chlorofofrnlmefhanol). mp 193-195 °C (recrystallized from EtOAc). 111 14115111 $5150.56) 5 1.59 (s, COCH3), 4.33 (0, J = 5.5 Hz, CH2), 5.55 <5, J = s._o Hz, CH). 5.25 (5, cm), 5.29 (5. (2311), 7.52 (s, lC5H),' 7.13-7.35 (m, 4 ArH), 5.51 (d, J = 5.0 Hz, NH), 9.75 (1, J = 5.5 H2, NH). ‘ c NM11 (DMSO-d5) 22.35 (COCH3), 35.12 (:1. Jcp 5 5.5112, CH2), 50.55 (CH), .51(C,;), 110.43 (C3), 115.04 (d, Jcpz 21.4 Hz, C3-), 124.29 Cd, JCF = 4.2 H2, C5-), 125.54 (5, .131": = 15.0112, 01»), 125.94 (5, Jcp = 9.0 Hz, c4- or C5-). 129.27 (d, Jcp :- .5 Hz, C4. or 05-). 142.55 (05). 151,07 (C2), 159.99 (:1, JG}: .—. 244.4 Hz, 02-), 155.17 (COCH3). 159.24 (coma) ppm. % _ 1 IRGG31") 3270, 1530, 1520, 1440, 1350,1220, 1150,1140, 1100, 1000, 740 cm-1.

- Elemental Analysis: Calculated: ' .02% C; i 5.21% H; 9.55%" N.

Found: F .20% C; 5.19% H; 9.59% N. _48..

EXAMPLE ,1__4_V LD.Ll-(‘(-Acet.zimi(l0-N-(3-flunr0bcnii'l)furanacetamide.

» Making use of 3-fluorobenzylamine (1.13 g, 9.0 11011101) and racemic a-acctamidofuranacetic acid (1.50 g, 8.2’ ramol) gave the desired pr_oduct.. A A Yield 1.90 g (30%). ' ' ' Rf 0.30 (9014 clilorofoi-rn/n'1eLl1anol). mp 163-165 °C (recrystallized frora ethyl aeetate)‘. 1H I\'MR (DMSO-dg) 5 1.39 (s, COCH3). 4.31 (5, J = 5.5 Hz, CH2), 5.55 (d, J = 7.3 Hz, CH), 5.31 (s. (3411), 5.42 (s, C3H), 5.93-737 (m, 4 ArI-I), 7.52 (s, C5H). 3.51 (d, J = 7.3 -Hz, N11), 3.70 (1, J = 5.5 Hz, NH).

N1~I1>. (DMSO-d5) 22.35 (COCH3),41.71(CH2),51.O1 (CH), 107.73 (C4), 110.59 (C3), 113.50 (d, Jcp = 21.6 Hz, C2' or C4‘), 113.60 (d, JCF = 22.3 Hz, C2' or C4‘), 122.95 (hr, C(;'). 130.13 (d, Jcp = 3.5 Hz, C51), 142.21(d,JcF = 7.5 Hz,C1'), 142-55 (C5). 151.03 (cg). 152.23 (5, JCF =243.3 Hz, C3»). 153.23 (COCH3). 159.31 (CONH) PPm- I IR(KBr) 3230, 1630. 1540, 1440, 1360, 1220, 1140, 1000, 730 cm’1.

Mass spectrum, m/e (relative intensity) 290 (M+,71), 231 (7), 165 (18), 140 (23), 139 _ (100), 125 (15), 109 (5), 97 (113), 95 (100), 95 (30); Elemental Analysis: I Calculated: Found: .02% C; ' 5.21% H; 9.55% N. 51.97% C; 5.35% ‘H; 9.53% N. _49..

EXAMPLE 15 (D, l;l-(I—.’\(‘Cl-Z1ml(l0~l\l-M-@)rnl1cn21'l)-'Z-l"ur;1nn(‘Cl;nmldQ. ' Using—ra4cem\ic <1-acetamido—2-furanacetic acid. (1.50 g, 8.2 mmol) and -Iluorobenzylarrminc (1.13 g, 9.0‘r‘nmol) gave the desired product.

Yield 2.10 g (88%).. 1 _ t ‘ ‘ 'Rf,O.3O (96:4 clxloroforrn/methanol). mp 188-190 °C (recrystallized frornlethyl acetate); H NMR (DMSO-d5) 5 1.88 (5, C001-I3), 4.27 (d, J = 5.5 Hz, CH2). 5.55 (d, J = 3.0 Hz, CH), 6.27 (s, 1H), 5.41 (s, 1H), 7.09-7.15 (m, ZAIH). 7-125 .27 (m, 2 AIH), 7.61 (s, 111), 3.53 (<1, J 8.75 (t, .7 = 5.5 Hz, NH). .0 Hz, NH), mm (D.\ISO-d5) 22.25 (000113). 41.51 (CH2), 50.37 (CH). 107.52 (C4), 110.45 (C3), 114.911 (cl, Jcp =‘ 21.1 Hz, C3‘). 129.48 (d, Jcp = _8.3 Hz, .C:'3'L 135.23 (d._JCF = 3.2 Hz, Cy). 142.53 (C5), 151.08 (C2), 161.12 (d. JCF =' 42.2 Hz, C4-), 167.95 (COCH3). 169.13 (CONH) ppm. m (KBr) 3230, 1020, 1500. 1350, 1320, 1260. 1210, 1140, 1000, 820,780, 730 cm-1.‘ Mass spectrum, m/e (relative intensity) 291 (1\I++1, 4), 165 (4), 140 (9). 139 (92), 138 (52), 124 (5). 109 (.71). 97 (G0). 95 (100).

Elemental Analysis: ' Calculated: Found: .02% C; _ 5.21% H; 9.65’-7b«N. 61.76% C, 5.41% H; 9.43% N. ;5O_ EXAMPLE 16 (D. Ll-(Y-./\CQtnn)irln-N-(25-dill ur)rr)l).en7.\'l )—2—f'ur:‘maCetam)'r_l(3.

Using.2,G-glifluorobenzylamine (1.30 g,V9.0 mttlol) and racemic (1-acetamido«2-furanaeetie acid (1.50 g, 8.2 mmol) gzlve the desired product.

Yield 1.50 g(6r1%). ‘ l ' Rf 0.38 (9614 chloroform/rricthanol). mp 177-178 °C (recrystallized f1-elm ethyl acetate). ,.

H N1r12(DM5o-55) 5 1.59 (s, COCH3), 4.31 (5, J = 5.5 Hz, CH2), 5.55 (5, J = 7.7 Hz, C11), 5.32 (s, C411), 5.43.(s,_'c3H), 7,227.25 (51, 3 71:11), 7.52 (s, C5H), 5.52 (d, J = 7.7 ;, NH). 5.75 (1, J: 5.5 Hz, NI-I). _ c NMR (DMSO-d5) 22.30 (COCH3). 3595 (d, .7311": 515.112, CH2), 51.02 (CH). 107.51 (C4). 110.55 (C3), 115.06 (dd, JCF = 19.5, 25.5 Hz, c3v 5566-), 115.15 (dd,_JC;_.~ = 15.5, 24.7 Hz, c3- or cg-),_115.s2 (55,331: =_10.1, 23.9 Hz, C4').127..98(dd,JCF = 9.2, 17.7 Hz. C10. 142.59 (C5), 150.75 (C2). 155.59 (5, J01.‘ = 239.0 Hz, C2» or C5-), 155.15 (d, JCF = 235.5 Hz, Cgv or C5»), 155.35 (COCH3), 159.-35 (CONH) ppm.

IR (Km) 3230, 1520, 1520, 1450,1350, 1250, 1230, 1150, 1140, 1000, 550, 510, 730,710 cm’1.

Mass spectrum, m/e (relative intensity) 309 (M'++1, 1), 266 (1), 259.2(1), 165 (5), 140 (5), 139 (51). 135 (35). 127 (37). 97 (44). 95 (100); 4 Elemental Analysis: I 7 ' Calculated: Founldz .44% C; 4.55% H; 9.09% N. 55.55% C; 4.59% H-, 5.57% N.

EXAMPLE 17 , 5 (T).L3-(1-Acntnnfido-N-(2.,G—diHun1'ohr~nzv1Wfxxranacctémide.

Making use of 2,6-difluorobcnzylamine (1.30 g, 9.0 mm01) and racemic (‘I-acetamidofuranacct A ic acid (1.50 g, 8.2 11111101) ga1i'.0 the desiréd product.- Yield 1.90 g(73‘7o). " " ' ' ;: 237-239 °C (recrystallized from ethimol). 4 H NMR (DMSO-d5) 5 1.3.5 (005113), 4.33(d, .1’: 4.5 Hz, CH2), 5.53 (:1, .1 = 5.3 Hz, CH), 5.17 (5, C411), 5.35 (s, C3H), 7.05-710 (m,,1Z _ArH), 7.35-7.41 (m, 1 AIH). 7.50 (s, C5H). 5.52 (5, J = 5.3 Hz, NH), 5.55 (1, J 94.5 Hz, NII). ' mm (DMSO-d5) 5 22.33 (COCH3). 50.74 (:,.1cp = 4.4 Hz, CH2), 50.45 (CH). 107.24 (C4). 110.»-.0 (C3), 111.51 (dd, Jcp -_— 5.0, 25.1 Hz, C31, (:50, 113.57 (t.JCI.1 —_— 19.5 Hz, C1-), 129.93 (t, JCF = 10.5 Hz, C40, 142.50 (C5), 151.23'(C2), 150.93 (d, JCF = 245.1, (:2- or C5‘). 151.10 (:1. JCF .—. 245.1 Hz, C2' or Cgj). 157.59 (COCH3), 159.00‘ (CONH) ppm. _ = ’ __ IR (K131) 3220. 1520,1530, 1450, 1350, 1320, 1250, 1220,1150, 1140, 1030, 1000, 520. 750, 750, 740, 710 cm-1. - ’ ' Mass spectrum, In/e (relative intensity) 309 (Mf*'+l, 4), 265 (2), 165 (4), 147 (7), 140 (5). 139 (57). 135 (35). 127 (54). 97 (55), 95 (100). ' Elemental Analysis: Calculated: 58.44% C;’ 4.5592111; 9.092» N, , Found: , 58.62% C; 4.74% H; 8.99% N. .

EXAMPLE 18 .._____ T77-(-‘lo.-A . nmido-N—l70nzvl-2—f‘1ir;inncz‘(amide.

Starting with Dacetamidofuranacetic acid (2.45 g, .38 11111101)? and benzylamine (1.43 g, l3133 mmol), the desired product was obtained, Yield: 2.54 g (7O‘/72‘) The product_v.—'as further recrystallized from ethyl. acetate to give the title compound. ' ' 1 3 ' Yield: 2.30 g A mp 196-197 °C. [0t]2GD[c = 1, Mcom = -,78.3°. Addition ofR(—V)-mandelic acid to a CDCI3 solution of the product gave only one signal for the acetamide methyl protons.

Mass spectrum, m/e (relative intensity) 272 (M"',.2), 184(2); 165(2), 140(8), 139 (S8), (34). 97 (45). 96 (100). 91 (53), ‘ Elemental Analysis: Calculated: ' 66.16% C; 5.92‘/BI-I; 10.29% N.

Found: 66.09% C; -5.01% H; 10.39% N.

EXAMPLE 19: H1lil—(+l.g-AC0fnmirlo-N-honzvlfinrnn:‘xCr‘tnniidc.

Using L-(1-acetamidofuranacetic acid(.2.83 g. 15.315 mmol) and bctnzylaminc (1.65 g, 15.46 mmol) gave 3.80 g oflthe enriched de_'sirediproduct.' 1H NMR ianalysis with R(-)-mzindclic acid showed that it was greater than 80% enriched in the title compound. The pureiL-enantiomier was obtained by vrécrystallization from absolute ethanol.

Yield: 1.60 g. mp 196-197 °c. _ [fll26D[c = 1, MeOH] = +79l0°- .

Mass spectrum", m/c (relative intensity) 273 (M+ + 1, 3). 229 (2), 214 (2). 184 (1), 165 (7), 157 (4), 140 (33). 139 (100), 138 (95). 97033). seuoo), 91 (98). " Elemental‘ Analysis: Calculatcdi 66.16% C; 5.92% H; 1o.‘29;% N.

Found: 65.89% C; .86% H; .1o._42% N. -54..

EXAMPLE 2d Resolution of (D, L)-A—Acetamido—2—furanacetic acid Using Methylbenzvlamine.

(R)-(+)—d¢Methylbenzylamine (13.22 gfl-O-ii ma1)'uas added .to an absolute ethanol solution (550 mL) of racemic 5Fecetamido- 2—furanacetic acid (20.00 g( 0.l1 moll. The resulting solution Vwas cooled in the freezer overnight. ‘The white precipitate (12.00 g) which separated upon cooling was filteredfi and the mother liquid evaporated to give a salt which was later used for obtaining L-d—acetamidofiuranacetic acid. The initial salt was recrystallized (3-x) from absolute ethanol to yield 4.00 g of the pure diasteromeric salt. mp.l73—l75‘C. 26 -' » 9 [ad D[c=l; MeOH]=—1os.

Elemental Analysis Calculated: ’ 63.14% c; 6.62% H; . 9.21% N.

Found: 63.19%'C; 6.62% H; . 9.12% N. . _o.

The purified salt was treated with 5% aqueous NH4OH solution{ extracted with ethyl ether (3 x 50 mL)‘ and then acidified with a 8.5% aqueous solution of HBPO4 ahd then extracted with ethyl acetate (3 x 100 mL) to yield 2.45_g(25%) of b-d- —acetamido— Zéfuranacetic acid. mp l69—l7l°C, [¢]26D[c¥1. MeQH]=-184.2°.

Elemental Analysis:" " ix Calculated: i52.46$ C: 4.95% H; 7.65% N, Found: 52.17% C: 4.89% H; 7.56% N, The salt obtained after evaporation of the main mother liquor was hydrolysed with 5% aqueous NH4OH solution to give lO.lO g of the enriched Lw%~acetamido—2—furanacetic acid [[¢]26D[C:lC Neon] = +47'7o]' (5)"(‘) ‘—methYlbenzYlamine (6.70 gt 0.055 mol) was added to a solution of enriched hw4-acetamido~ —furanacetic acid (10.10 g, 0.055 mol) in absolute ethanol (275 mL). The white precipitate of the diasteroemeric salt (8-10 g) that separated upon cooling the solution in the freezer (l h) was filtered. The salt was recrystallized from absolute ethanol (3 x) to yield 3.009 of the saltc mp l72—l74‘C. 26D [c=l, MeOH]='+106;.

Elemental Analysis: Calculated: 63.14% C; 6.62% H; Found: 63.18% C: 6.47% H: The salt from the third recrystallization was treated with a 5% aqueous NH4OH solution and extracted with ethyl ether (3 x 50 mL)( and then acidified with a 8.5% aqueous solution of H po . and-then extracted with ethyl acetate (3 x 100 mL) to give l.63g (32%) of L-A-acetamido—2-furanacetic acid. mp l69—17l°C. [¢]26D[cél( MeOH]= +182‘.

EXAMPLE 21 Enzymatic Separation of D(-)¢<~a:etamidofuranacetic acid from DL (i)0(—acetamido—2—furanacetic acid.

DL (i)d_—acetamidofuranacetic acid (2:60 gi 10.9 mmol) was suspended in deionized H20 (600mL). An aqueous solution of LiOH (lN) was added to this suspension dropwise until all of the acid had dissolved and the pH was 7.2-Acylase Grade II (20 mgfi activity = 900 units/mgn Sigma Chemical Company, Cat. No. A 8376) was then added to the above solution and the mixture stirred at 34;379C (4lh). The suspension was then cooled to room temperature and acidified_to pH 1.5 with aqueous 1N HCl. The suspended material was filtered‘ and the filtrate was saturated with solid Nacli and then extracted with ethyl acetate (3x25O mL). The combined ethyl acetate extracts was dried (Na2SO4). The solvent was removed in 15333 and the residue was triturated with ethyl acetate (10mL). The;white solid (0.75 g) that remained was filtered and was pure D(—)d - acetam53o42—furanacetic acid: mp 168—l69°C5 mixed mp with an authentic sample l685l69°C: [d%f6[c=1. MeOH] =—1a4.3°. ' ..- .¢:nr‘ VRT_CD.'\r:1tinn of l7,l.- r EXAMPLE 22 n.5¢5cnnudn-2Juranncouc Acid.-" An ethereal solutionlof ZnCl2( 1 N, 28 mL, 0.028l~m'ol) was added to a stirred solution of ethyl acetamidobromoacetate (4.40 g, 0.019 mol) and furan (11.23 g, 0.165 mol) in dry tetrahydrofuran (100. mL), and V allowed to‘-stir at room temperature (5 h). The mixture was thenltreatedr with H20 (50rnL), the organic Pllase Separated, and the aqueous layer extracted with VCH2Cl2 (2 X 100 mL). The organic layers were combined, dried (NagSO4) and the volatile materials were - removed by distillation i_r_i_;g~.<~,g;o to give approximately 4.00 g (97%) of light-brown semi-solid material. TLAC analysis showed a major _spot at Rf 0.30 (99:1 chloroform/methanol).

The desired ‘compound, D,L-ethyl :1-acetamidofuranacetate, was purified by flash columri.chromatog'raphy_on silica gel using 99:1 chloroform/methanol as the eluent to give 3.60 g (87-%) o-fa beige solid. H I . mp 68-70 °C.

D, L-Ethyl oL—acetamidofuranacetate (4.00 g, 19 mmol) was dissolved in :10 ethanol/‘water (150 mL) "and then KOH (2.00 g, 35 mmol) was added and the resulting solution stirred at room temperature (48 h). The reaction was concentrated i_r_i_ vacuo and the residue diluted with H20 and then washed with ethyl ether (3 x 50 mL). The aqueousrlayer was then made acidic with a 8.5% aqueous solution of H3PO4 and extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried (Na2SO4), evaporated to dryness i_uy_a_c;;Q to give the desired compound. . .

Yield: 2.55 g(76%). ' gm ’ Rf 0.37 (8:1:1 isopropanol/NI-l4OT'J H20). xnp17zi74°c. (0.61 g, 5.70 mmol) in tetrahydrofuran (10 mL) was added slowly ._53_ EXAMPLE 23! S.\'ntliosis of T)_l,)Acetnmiirlnpentonnic .(\cid-N-henzvlnmidg, .

‘-Methylmorpholinc (0.55 g, 5.40 mmol) was added to a stirred "solution of 0 2-acetamidopentenoic acid (0.81 g, 5.18 mmol) in dry tetra.h)'drofi1ran (60 mL) at -10 to -15 °C under N2. After stirring (2 min), isobutyl‘chloroformate (0.75 g, 5.70 Tfimoll was added leading to the precipitation of a white solid. The reaction was allowed to proceed for 2 additional minutes and then a solution of benzylamine at -10 to -15 °C. ' After stirring (5 min) at room temperature, the insoluble salt was removed by filtration. The filtrate was evaporated to dryness and the residue was triturated with ethyl acetate, and the remaining white solid wasifiltered to yield the desired product. ' Yield 0.31 g (64%).

Rf 0.36 (4% methanol/chloroform). mp 118-120 °C (rec'rystallized from ethylacetate/cyclohekane).

H mm (D.\-ISO-d5) 5 1.83 (s. COCH3), 2.22-2.49 (m, CHgCH=CH2), 4.26 ca, J = 5.3 Hz, CH3 Ph). 4_.25_-4.33 (m, CH), 4.99-5.09 (m, CHgCH=cH2), 7.21-7.2 (m, 5 PhH), 3.05 (d, J = 7.6 Hz, NH).‘8.r16('br s,»NH).

NMR (DMSO-d5) 22.41 (COCH3). 36.24 (CH2CH=CH.2), -41.91(CH_9_Ph), 52.20 (CH), 117.15 (CH2CH=CH2), 126.54 (C49,-126.99 (2c2- or 203-), 123.64 (2C2- or 203-). 134.25 (CHgCH=CH2), 139.22 (Cy). 169.02 . 170.96 (CONH) ppm.

Mass spectrum, rn/e (relative intensity) 246 (MC"', 4:’), 205 (4 (33). 91 (77), 70 (100).

Elemental Analysis: ), 163 (15), 140 (8), 106 Found:' 63.55% 0;‘ 7.3162511; 11.43% N. ‘ ~- ¢ 130 NMR (DMSO-d5) 22.83 (COCH3), 42.11 (CH EXAMPLE 2 41. _________ The filtz-‘ate was concentrated and the residue purified by flash column rm) on-SiO2. The initial fractions gave :1 trace amount (0.09 g) of (D,L)~2-acetamido-N-benzyl (N- chromatogfiaphy (2% methanol/chlorofo cnzylamine)acetamide.

Continued elution gave additional amounts (0.20 g)_ of-the (D,L)~2—Aéétamido-N-benzyl-2—(N- Yield: 0.09 g (11 Va). mp 135-138 °C. 1 title compound. bcnzylamincjacctangide: 0 H NMR (DMSO_—d5) 5 1.83 (s, COCH3), 3.55 (d, J = 13.6 Hz, NHCH), 3.66 (d, J: 13.6 Hz, NHCII), 4.23 (d, J = 5.4112, CH2), 4.89 (d, J = 8.0 Hz, CH), 7.05-7.38 (m,.10 Ph‘H), 8.20 (d, .1 38.0 Hz, NH), 8.51 (1, J .-_- 5.4 Hz, NH). .65 (C4), 126.70 (C41), 127.13, 128.00, 128.13, 128.22, or C1'), 169.61 (COCH3), 169.90 (CONH) ppm.

(D,L)Acctamido-N-benzyl(I-morpholfnckzcetamide. 1 1 Yield: o.48‘g(84%). 5 Rf 0.35 (4% mcth_ano1/chloroform). rop 1'1 1-172 ° (rccrystaflizcd from ethyl acetate). -60..

H NMR (D1\ISO-d5)5 1.35 (s, COCH3). 2.30-2.4o[(m. CI-IgNCH2), 3,51 (4,, S, C11goc1-12), 4.13-4.33 (m. CH2). 5.07 (d, J = 3.9 Hz, C11), 7.13-7.25 (m, 5 Phil), 3.23 (d, J = 3.9 Hz, NH), 3.33 (br 3, NI-1)." 2 13c (DMSO-<15) 22.39.(COCH3), 42.20 (CH2). 43.43 (.CH2NCH2). 53.03 (CH). 321.24 (CHgOCH2), 123.75 (C41), 127.13 <2c2- or 203-), 123;23A(2C;;_- or~2c3-), 139.42 (C1-), 153.02 (COQH3), 120.20 (CONH) ppm. ' l 2 Mass spectrum m/c (relative intfiusity) 292 (M++1, 1), 233 (8), 158 (19), 157 (100)! - 116 (26), 115 (100). 106'(29), 91 (72). ' Elemental Analysis: Calculateclz ‘ l 51.34% C; 7.25% H; 14.42% N.

Found: _ ' 3-1.37 % c;V7.1o% H; 14.14% N.

EXAMPLE 25' q T) lfinsls or.(l),l;)Acotnmlcl0-N—lW‘n’/tvltN—ani]in'o)f1(;gtamidc, A mixture of ethyl 2-acetamido(N-Aanilino)acetate (2.00 g, 8.47 mmol), benzjlamine (1.09 g, 10.00 mmol), and sodium c_',"anide (0.04' g, 0.84 mmol) in methanol (20 mL) ‘was heated with stirring at 45-50 °C (18 h)- The white solid‘ which separated during the course of the reaction was filteredand purified by recrystallization from absolute ethanol to give the desired compound. 0 Yield: 1.10 g(72%). ' mp 183-185 °C. _ .

H N.\11z(m1so-d5)5 1.84 (COCH3), 4.31 (d, J = 5.8 Hz, CH2). 8.87 (t, J = 8.1 Hz, CH), 6.04 (d, J -.- 8.1 Hz, NHP10), 8.59-6.64", (m, 1 PhH'). 6.70-8.72 (m, 2 PhH), 7.06-7.11 (m, 2 Phil), 7.20-7.33 (m, 5 P'nH), 8.41 (d, J = 8.1 Hz._NH), 8.72 (1, J =’5.8 Hz, 1m) ' 0 1 c N:\1’I’.(DI\.TSO-d5)22.4G (COCH3), 42.25 (CH2), 60.42 (CH), 113.21(2C2). 117.22 (C4). 126.72 (C40. 127.18 (2c2- or 2.33-). 128.18 (2c2- or2c3~). 128.77 (2c3). 138.99 (C1-), 145.88 (C1), 168.65 (COCH3), 169.70 (CONH) ppm.

Mass spectrum mle (relative intensity) 297 (Mil, 2), 239 (7), 177 (3), 164 (28), 153 (100), 122 (20),’121 (100). 106 (47). 104 (65). 93 (83). 91 (77), 77 (49).

Elemental Analysis: Calculated: 0 Found: .87% C; 6.44% H; 68.94% C; 6.42% H; .13% N. 13.92% N. ‘.4 cl _ Exzu-u>=Lzé 26: Syjhthgsis or (D_L)-‘2-Acct.:1midn-N—‘henzvl—2-(methvla'mlnnlacc-tnrhide_.

. - A mixture of ethyl 2-acetamido(metlhylaminekxcetatc (1.50 g,e8.63 mmol), benzylamine (1.11 g, 10.35. mmol) and sodium cyanide (0.04 g,_O.82 mmol) in methanol (20 mL) 'wz_1s Stirred at 50-55 °C (18 h)‘. ‘The solvent was removed Lg .9112 and then the residue was purified by:-fllash column chromatography on SiO2 ‘using 2% methanol/chlorofolrmAa5Atheieluerit te yield the desired compound.

Yield: 1.00 g (49%). I Rf 0.33 (3% methanol/chloroform). mp 115-117 °C (recrystallized from ethyl acetate/petroleum. ether). c mm (DMSO-d5) 22.52 (COCH3). 31.37 (NHCH3), 42.04 (CH27, 55.99 (CH), H mm (DMSO-d5) 5 1.87 (s. COPH3). .181 (Vs. NHCH-3)", 4.20-429 (m, CH2), 4.37 (d, J =.7.9 HZ, cm, 7.24.135 (rrl, 5 PhH), 5.14 (d, J = 7.9 Hz,1\_IH).8-.55('br_s, ; Elemental Analysis: Calculated: V l 61.25% C} 7.28% H; 17.85% N.

Found: -A .12% C;' 7.01‘3"aH; _ 17.74% N. . _63_ EXAMPLE 273 Synthesis ‘nl'(l7_l.l-llltliyl 2-acet.nmidn-Qhthvlnminnlncetate_ "A cold .(-78 °C) solution of ethyl 2-acetamidobrqmoacetate (2.10 g, 9.38 rnmollin dry tetrahydrofuran (80 mL) was edded slowly into la eooled (-78 °C) tetrahydrofuran (20 mL) solution of methyl-amine (lléll g, 31-04 IIIUIOU Over a period of 20 min. The rcziction was stirred at -78 °C ‘ll 11). and then 31'» I‘00m tempereture (1 h). The precipitated salt was filtered and the filtrate concentrated.

The residue was purified by flash columnichromatoig-raphy on SiO‘-3' using 3% methanol/chloroform as the eluent to yield the desired ‘compound as a light yellow oil. ' A Yield: 0.90 (5192,). , Rf 0.36 (4% methanol/chloroform). A 4' _ , 1H mm (CDCI3) 0.93 (t, J = 6.7 Hz, NHCHQCI-I3). in (t, J = 6.8 Hz, OCHZCH3). 1.87 (s, COCH3), 2.48 (q. J = 5.7 Hz, NHCH-_;CH3),’4.05 (q. J = 6.8 Hz, OCH-2C1-I3). .05 (d, J = 7.1 Hz, CH), 7.09 (d, J 2 7.1 Hz, NH). - V NMR (CDCI3) 13.64 (NHCI-IQCH3), 14.554(OCH2CH3), 22.53 (COCH3), 39.06 l (NHCH2CH3),.G1.38 (CH), 64.14 (OCHZCH3), .17o.o9 (coeH3),. 170.20 (COOCHQCH3) ppm.

- EXAMPLE 278 Synthtziis of (T7 ,1.)-2—AcCtz1mido-I51-l)Cnzvl-'2-(Cthylgminohcctamifi.

A_mixture of ethyl 2-aeetamido-24(ethylamino)a_cetate (0.90 g, 4.79 mmol), bcnzylamine (0.62 g, 5.75 mmol) andlsodium cyenlde (0.03 lg‘. 0.51 mmol) in methanol (10 rnL) wasystirred at 50-55 °C (18 h). The solution .was ‘Concentrated j_r_1_ Veguo, and the reéidue wals purified by flash column chromatography on SiO2 using 3% methanol/chloroform as. the eluent tolgive the desired product as a white solid. ' Yield: 0.35 g (29%). 5 Rf 0.34 (4% ‘methanol/chloroform). mp 123-125 °C (recrystallized from ethyl acetzbtte/hexane). ‘ H NMR '(DI\ISO-d5) 8 0.93 (t,‘J = , NHCH;-gCH3.), 1.81 (s-, COCH3), 2.08 (by; s_, NHCHQCH3). 2.40-2.48 (m, NHCHgCH3), 4.22 (8, J 9 5.5 Hz, CH2), 4.90 (d,'J ; 7.8 Hz, C11)’, 7.20-727 (m, 5 PhH), 8.08 (d, J = 7.8 Hz, NH), 8.48 (br s, NH).

C NMR (CDC13) 15.14 (NH0H2CH3), 22.97 (COCH3), 37.65 (NHCH2CH3). 43.53 (CH2), 65.68 (CH), 127.50 (C4-), 127.44 (2C2v_ or 2C3-),_ 128.64 (2c2» or 2C3»), 137.73 _ » EXAMPLE 287 Using the procedures described herein, the following examples are also preparedf (D,L)Q\-Acetamido—N-(3-fluorobenzyl)-Séfuranacetamide (D,L)a\-Acetamide—N-(4-fluorobenzyl)—3—furanacetamide ck-Acetamide-N-benzyl=2—aminoacetamide 'ExAMPLE‘29 Using the procedure described herein the following compound can also be prepared; H O H H O I H I I H —CH2-N-C-Q-N-C-R . 'R3 wherein R3 is 2 pyridyl.

Pharmacdloay. The following dompounds were'tested for anticonvulsant activity using male Carworth Farms #1 mice: N—Acetyl-D,L¥alanine—N'—benzylamide N—Acetyl—Dea1anine—N'—L;nzY13mide N-Acetyl—L—alanine—N'-benzylamide N~Accty1—D;L—fihenylglycine—N'—methylafiide 'N—Acctylglycine—N—pen2ylamide D,L-d:Acetamido-N-(2,6—difluorobenzy1)-2—furanacetamidé D,L—2-A:etamido—N-benzy1—3-indoleacetamide(reference compound) -67..

The compound was given in various dose levels (i.e., 10, 30, 100, 300mg) and subsequently compared with phenytoin, phenobarbital, mephenytoin and phenacemide (See Table 1). N—Acetyl-D, L—alanlne-N’-benzylamide was tested at 600mg/ml as well. Seizures were then artificially induced by either electroshock or pentylenetetrazole. Maximal electroshock seizures (MES) were elicited with a 60 cycle alternating current of 50 mA intensity (5-7 times that necessary to elicit minimal electroshock seizures) delivered for 0.2 sec via corneal electrodes. A drop of 0.9% saline was instilled in the eye prior to application of the electrodes so as to prevent the death of the animal. Protection in this test was defined as the abolition of the hind limb tonic extension component of the seizure. The Subcutaneous Pentylenetetrazole (Metrazo|") Seizure Threshold Test (sc Met) entailed the administration of 85mg/kg of pentylenetetrazole as a 0.5% solution subcutaneously in the posterior midline. This amount of pentylenetetrazole was expected to produce seizures in greater the 95% of mice. The animal was observed for 30 minutes.

Protection was defined as a failure to observe even a threshold seizure (a single episode of clonic spasms of at least 5 sec duration). The effects of the compounds on forced and spontaneous motor activity were evaluated in mice using the Rotorod Test (Tox) or, in some cases, as indicated herein, a horizontal screen assay (HS).

The procedure for the rotorod test is described in ¢ A_m_. flag gofc, 4.5, 208-209 (1957). .58. in the rotorod test, the animal was placed on a one-inch diameter knurled plastic rod rotating at 6 rpm after the administration of the drug. Normal mice can remain on a rod rotating at this speed indefinitely. Neurologic toxicity was defined as the failure of the animal to remain on the rod for one minute. in the horizontal screen test, previously trained mice were dosed with the compound and placed individually on top of a square (13cm x 13cm) wire screen (no. 4 mesh) which was mounted on a metal rod. The rod was rotated 180°, and the number of mice that returned to the top of the screen was determined. inability to climb to the top within one minute was defined as "neurological impairment".

Be@, 64 351-353 (1977).

This procedure is described in Pharmacol. Bigherg The dose effect behaviour of the compounds was evaluated using the above- described procedures by the administration of varying dose levels, treating normally eight mice at each dose. Table 1 includes an evaluation of the Median Effective Dose (EDSO) and the Median Toxic Dose (T D50) of representive compounds. Mice were tested with varying doses of the anticonvulsant to define the limits of complete protection (or toxicity) and no protection (or no toxicity), as well as three points in between these limits. The Median Effective Dose (ED50) was defined as the dose which produced the desired endpoint in 50% of the animals. The Median Toxicity Dose (TD50) was the dose which elicited evidence of minimal neurological toxicity in % of the animals. The results are given in Table 1.

TABLE I gpmoarative Median Effective Dosacé Tox was ,. , st Met Comoound TDSO mc/k EDSO mc/k EDSO ma/k (D.L)-(1—/‘~.ccL3mido-N- enzyl(5—meLh3-Ifuran) , 0,) (D,L)-c1-Acct:1r‘m'do-N- bcnzy]benzofurar1— T acctamjde >1oo<3oo>-"K >100<390.

(D.L)-c1-Acctarm'do-N- bcnzy]bc:nzo[b]—th.io- phcncacctaandc >1OO<3D0EX >1OO<3AO, (D.L)-a—AccAL2:r:3do-N- bcnzyl(5-Inethyipyrrole) 35 5 acetarnide ’* (3O‘6_;7.-1)* ..

(D.L)-a-AcctamJc1o-N-(2- fluorobcn.zy1)fu:an- acctamidc X 40-0 (D,L)—u—Acctamido-N-(3- fiuorobenzyl)furan- 135 . 6 , acmmgde (114.9-151.8;""- 13.3 _ . .- (1l.5‘15.3)*:'.

(D.L)—u-AccL:xm5do-N-(4- " '{1uorobcnz_\-l)1'uran- '*i ' ,' - acctamide ‘ 144"’: .xx -1 (122.5-170.9) (D.L)-u-Acct.2:nido-N-(2,'- ’ uorobcnz)'l}furan- acctamide X (D,L)-a-Acct:121ido-N-(2,6- difluorobcnzyl)furan-A (1o.:,15.1)* .8 _ (2o.z2s.4)* .>25<100 .3 (2.8-3.9)* ' TABLE I: Q9LVd Comparative Median Effective Dosage Tox MES sc Met Comppung TD50 mq/kq ED50 mq/kq ED50 mgflgg (D,L)—(+)-d-Acetamido-N-benzyl- —furanacetamide >300 >100<30O 95 (D,L)Acetamido—4-pentenoic acid—N—benzy|acetamide X 33.6 96 (D,L)—2-Acetamido-N-benzyl- -(1-morpholine)acetamide x >30<1OO ¢ reference compound (D,L)Acetamido-N-benzy| (N-aniIino)acetamide XX XXX ¢ (D,L)-2«Acetamido-N-benzyl- —(methy|amino)acetamide 95,0 44.5 ¢ (37.0—52.4)* (D,L)-2—Acetamido-N-benzyl- —(ethy|amino)acetamide X 42.4 ¢ (37.2-47.8)* (D,L)—2—Acetamido-N—benzy|- 3-indoleacetamide x xxx ¢ reference compound phenytoin 66 10 not effective phenobarbital 69 22 13 mephenytoin 154 61 31 phenacemide 421 87 116 (337-549)* (74-1o0)* (71-15o)* 95% confidence intervals at The ED50 for this substrate was not computed. x The TD50 for this substrate was not computed. xx The TDSO value was determined using the horizontal screen test. xxx No activity was noted at 3 300 mg/kg.

Claims (1)

1.wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl which R is unsubstituted or substituted with at least one electron withdrawing group or at least one electron donating group; R1 is hydrogen or lower alkyl which is unsubstituted or substituted with at least one electron withdrawing group or one electron donating group; R2 and R3 are independently hydrogen or Z—Y which may be unsubstituted or substituted with at least one electron withdrawing group or one electron donating group, with the proviso that R2 and R3 cannot both be hydrogen; Z is 0,8, NR4 or PR; Y is aryl lower alkyl, lower alkenyl or lower alkynyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group; or ZY taken together is NR4NR5R6, NR,,OR5, OPR4R5, PR4OR5, SNR4R5, NR4R5, NRASRS, SPR4R5 or PR4SR5, NR4PR5R6 or PR4NR5R5; ‘R4, R5 and R5 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R4, R5 and R6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and n is 1-4; or wherein R is benzyl R, is methyl R2 is hydrogen R3 is 2-(5-methylfuryl), 2-benzofuryl, 2-benzo[b]-thienyl, 2(5- methylpyrrolyl) or 2-pyridyl, and nis1;or wherein R is 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,5—dif|uoro‘oenzyl, or 2,6—difluorobenzyl, R, is methyl, R2 is hydrogen, R3 is furyl, and nis1, and the pharmaceutical acceptable salts thereof. The compound according to Claim 1 wherein n is 1. The compound according to Claim 1 or 2 wherein R, is methyl. The compound according to any of Claims 1-3 wherein R is aryl lower alkyl. The compound according to any of Claims 1-4, wherein R is benzyl which is either unsubstituted or substituted with fluoro. The compound according to any of Claims 1-5 wherein the electron withdrawing group is halo, nitro, lower alkanoyl, aryloyl, aryl lower atlkanoyl, carboxy, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, . guanidine or quaternary ammonium. The compound according to any of Claims 1-5 wherein the electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lowera|kyl)amino, phenoxy, thiol, lower alkylmercapto or disulfide. The compound according to any of Claims 1-7 wherein one of the R2 and R3 is hydrogen. The compound according to any of Claims 1-8 wherein one of the R2 and R3 is hydrogen and the other is Z-Y. The compound according to any of Claims 1-9 wherein Z-Y is hydrazino, lower alkylhydrazino, N—phenylhydrazino, N—hydroxylamino, or O- hydroxylamino. The compound according to any of Claims 1-5 which is ,L)—a-Acetamido-N-benzyl(5-methylfuran)acetamide, D D, L)-or-Acetamido-N-benzy|—2-benzofuranacetamide D, L)—a-Acetamido-N-benzylbenzo[b]—thiopheneacetamide, D, L) —o-Acetamldo-N-benzyl—2—(5—methylpyrrole)acetamide, (D,L —ci-Acetamido—N—(2-fluorobenzyl)furanacetamide, (D , L D L L ) )-d—Acetamido—N—(3-fluorobenzyl)furanacetamide, )-or-Acetamido«N-(4—fIuorobenzyl)-2—furanacetamide, )-oi-Acetamido—N—(2,5—difluorobenzy|)furanacetamide, , —oi—Acetamid0—N—(2,6-difluorobenzyl)furanacetamide, D D L) D,L)-d—Acetamidopentenoic acid-N-benzylamide, D, —d-Acetamid0-N-benzyl(N-anilino)acetamide, D i ( L) ( ,L)—d-Acetamido-N-benzyl(methylamino) acetamide, or (D,L)-a—Acetamido—N-benzyl—2-(ethylamino) acetamide, or the D or L stereoisomer thereof. The compound according to Claim 11 wherein the compound is the D- stereoisomer. An anticonvulsant composition comprising an anticonvulsant effective amount of a compound according to any one of Claims 1-12 and a pharmaceutically acceptable carrier therefor. The composition of Claim 13 having a unit dosage form containing from 5 to 1000 mg of said compound. A process for the preparation of a compound of the formula l 12 ,. R ~ NH c — c — NE f - R1 ll 1 l - 0 R3 ‘ no I as in Claim 1 which comprises .a) reacting an amine of Formula ll 0 R, H I’ RNH c"—c - na H I R3 11 “ II wherein R, R2 and R3 have the same meaning as in formula I with an acylating derivative of a compound of formula Ill R -C-OH III wherein R, has the same meaning as in Claim 1 under amide forming conditions; or b) reacting a compound of formula VI if 1‘??? R CNH"C“COR 1 1 7 v1 R3 wherein R1, R2 and R3 have the same meaning as in Claim 1 and R, is lower alkyl, aryl or aryl lower alkyl or an acylating derivative thereof with an amine of formula RNH2 wherein R has the same meaning as in Claim 1 under amide forming conditions; or c) reacting an amide of formula IX 0 L'O ll H i ll R1 — c~[u—c—c-lwya l 5‘ IX R2 wherein R, R,, R2 and n have the same meaning as in Claim 1 with an acylating derivative of formula X R3—L X wherein R3 has the same meaning as in Claim 1 but is not aryl, hetero- aromatic or polynuclear aromatic and L and L’ are independently a good leaving group, such as halide, tosylates, mesoylates, brosylates and benzyloxy under substitution conditions; and optionally removing protecting groups when present; and optionally introducing substituents into the compounds by substitution or conversion reactions; and optionally separating out the diastereomers, or optionally forming pharmaceutically acceptable salts of said compounds. The process according to Claim 15 wherein n is 1. The process according to Claim 15 or 16 wherein R, is methyl. The process according to any of Claims 15 to 17, wherein R is aryl lower alkyl. The process according to any of Claims 15-18 wherein R is benzyl which is _either unsubstituted or substituted with fluoro. The process according to any of Claims 15-19 wherein the electron withdrawing group is halo, nitro, lower alkanoyl, aryloyl, aryl lower alkanoyl, carboxy, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine or quaternary ammonium. The process according to any of Claims 15-19 wherein the electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(|oweralky|)amino, phenoxy, thiol, lower alkylmercapto or disulfide. The process according to any of Claims 15-21 wherein one of the R2 and R3 is hydrogen. The process according to any of Claims 15-22 wherein one of the R2 and R3 is ‘hydrogen and the other is Z-Y. The process according to any of claims 15-22 wherein Z-Y is hydrazine, lower alkylhydrazino, N—phenylhydrazino, N—hydroxylamino, or O-hydroxylamino. The process according to any of Claims 15-19 wherein the compound formed is selected from (D, L)—o-Acetamido~N—benzyl—2-(5-methylfuran)acetamide, (D, L) -or—Acetamido—N—benzyl-2—ben2ofuranacetamide (D,L)-cx—Acetamido-N—benzyl—2—benzo[b]—thiopheneacetamide, -d-Acetamido-N-benzyl—2-(5-methylpyrrole)acetamide, —a-Acetamido-N-(2-fluorobenzyl)furanacetamide, -a-Acetamido—N-(2,6—difluorobenzyl)furanacetamide, (D L) (D L) (D L) (D L) (D,L)—cx—Acetamido-N-(2,5-difluorobenzyl)furanacetamide, (D L) (D L)—d—Acetamidopentenoic acid—N-benzylamide, (D L) (D (D,L)-cx-Acetamido-N-benzy|—2-(ethylamino) acetamide, or the D or L stereoisomer thereof. The process according to claim 25 wherein the compound formed is the D- ’stereoisomer. The process for the preparation of an enantiomer of Acetamido-N-benzyl furanacetamide which comprises reacting racemic or-acetamidofuranacetic acid or acylating derivative thereof with one of the stereoisomers of an optically active amine having one chiral center under conditions effective to form the corresponding diastereomeric salt, separating the diastereomeric salts to obtain the desired salt, hydrolysing the salt under conditions effective to form the desired a-acetamido—2—furanacetic acid and reacting the product thus formed with benzylamine under amide forming conditions. The process according to claim 27, wherein the racemic d—acetamide furanacetic acid is prepared by reacting furan with an acylating derivative of acetamido—2—haloacetic acid wherein the halo group is bromo or chloro. A compound substantially as hereinbefore described with reference to the Examples. A composition substantially as hereinbefore described with reference to the Examples. 31. A process substantially as hereinbefore described with reference to the Examples. 32. Use of a compound as claimed in any of Claims 1 to 14 for the preparation of a medicament for use in a method of prophylaxis or treatment. 33. Use of compounds according to Claims 1 to 14 for preparing a medicament for treatment of epilepsy and other CNS disorders.