AMINO ACID DERIVATIVE ANTICONVULSANT

Abstract: The present invention relates to compounds of formula (I).

Description: AMINO ACID DERIVATIVE ANTICONVULSANT 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 characterized as protected amino acid derivatives of the formula: or the N-oxides thereof or pharmaceutically acceptable salts thereof wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic -> lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; R__ is hydrogen or lower alkyl, lower alkenyl, 0 lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group and 5 R_ and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, S0 3 ~" or Z-Y wherein R 2 and R 3 may be unsubstituted ° or substituted with at least one electron withdrawing group or electron donating group; 5 ^ 2 is O, S,S(0) a , NR 4 , PR 4 or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, cycloalkyl, cycloalkyl lower -. alkyl and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided Z is a chemical bond only, when Y is halo, or ZY taken together is NR 4 NR 5 R- 7 , NR 4 OR 5 , 0NR__R-7, OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR V , SPR 4 R 5 , PR 4 SR V , NR 4 PR 5 R β PR 4 NR 5 R V , NR 4 C-R S , SCR 5 , NR 4 C-OR 5 , NR__CNR s S(0) a R 6 , NR 4 CNR S R S , NR 4 CMNR 5 COR s , or C-NH 2 , R 4/r R 5 and R e are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4/ R 5 and R 6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and R-7 is R 6 or COORβ or C0R β R s is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and A and Q are independently O or S, M is an alkylene chain containing up to 6 carbon atoms or a chemical bond; n is 1-4 and a is 1-3. The predominant application of anticonvulsant drugs is the control and prevention of seizures associated with epilepsy or related central nervous system disorders. Epileps 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 bee 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 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 a phenyl group o 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 hydantions, such as phenytoin, are useful in the control of generalized seizures and all forms of partial seizures. The oxazolidinediones, such as trimethadion and para ethadione, are used in the treatment of loncoπvulsive seizures. Phenacernide, a phenylacetylurea, is one of the most well known anticonvulsants employed today, while much attenti has recently been dedicated to the investigation of the diazepines and piperazines. For example, U.S. Patent Nos. 4,002,764 and 4,178,378 to Λllgeier, et al. disclose esterifi diazepine derivatives useful in the treatment of epilepsy and other nervous disorders. U.S. Patent No. 3,887,543 to Nakanishi, et al. describes a thieno [2,3-e][l,4] diazepine compound also having anticonvulsant activity and other depressant activity. U.S. Patent No. 4,209,516 to Heckendorn. et al. relates to triazolc derivatives which exhibit anticonvulsant activity and are useful in the treatment of epilepsy and conditions of tension and agitation. U.S. Paten No. 4,372,974 to Fish, et al. discloses a pharmaceutical formulation containing an aliphatic amino acid compound in which the carboxylic acid and primary a ine are separated by three or four units. Administration of these compounds in an 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 epilep 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: wherein R, R_, R 2/ R 3/ R., RS , Rβ/ n/ Z/ Y/ A and Q are a _ defined hereinabove. The present invention contemplates employing the compounds of Formula I in compositions of pharmaceutically acceptable dosage forms. Where the appropriate substituents arc employed, the present invention also includes pharmaceutically acceptable addition salts. Moreover, the administration of an effective amount of the present compound in their pharmaceutically acceptable forms or the addition salts thereof, can provide an excellent regime for the treatment of epilepsy, nervous anxiety, psychosis, insomnia a other related central nervous disorders. The alkyl groups when used alone or in combination with other groups, 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, a yl, hexyl, and the like. The aryl lower alkyl groups include, for example, benzyl, phenethyl, phenpropyl, phenisopropyl, phenbutyl, and the like, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenyl- ethyl, and the like. The term aryl, when used along or in combination, refers to an aromatic group which contains from 6 up to 18 ri carbon atoms and up to a total of 25 carbon atoms and include the polynuclear aromatic? These aryl groups may be onocyclic, bicyclic, tricyclic or polycyclic and are fused rings. Polynuclear aromatic compound is meant to encompass bicyclic, tricyclic fused aromatic ring system containing fro 10-18 ring carbon atoms and up to a total of 25 carbon atoms. The aryl group includes phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. The aryl group 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)-2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E-)-4-methyl-2-pentenyl, pentadieπyl, e.g., 1,3 or 2,4- pentadienyl, and the like. The term alkynyl include alkyene εubstituents 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-pentynyl, 3-methyl-l-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like. The term cycloalkyl when used alone or in combinatio is a cycloalkyl group containing from 3 to 18 ring carbon atom and up to a total of 25 carbon atoms. The cycloalkyl groups may be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. The cycloalkyl may be completely saturated o partially saturated. Examples include cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl, adamantyl, and the like. Cycloalkyl includes the cis or trans forms. Furthermore, the substituents may either be in endo or ex positions in the bridged bicyclic systems. The term "electron-withdrawing and electron donating refer 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 Organic Chemistry, by J. March, John Wiley and Sons, New York NY, pp. 16-18 (1985) and the discussion therein is incorporated herein by reference. Electron withdrawing groups include halo, including bromo, .fluoro, chloro, iodo and the like; nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, tri luoromethyl, aryl lower alkanoyl, carbalkoxy and the like. Electron donating groups include such groups as hydroxy, lower alkoxy, including me hoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl, and the like; amino, lower alkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio. and the like. 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 o substituents selected from the above-identified groups. The term halo includes fluoro, chloro, bromo, iodo and the like. The term acyl includes lower alkanoyl. As employed herein, the heterocyclic substituent contains at least one sulfur, nitrogen or oxygen, but also ma 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 monocycli bic_._:lic, 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 benzoheterσcycles. Representative heterocyclics include fury thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzσthienyl, morpholinyl, benzoxazolyl. Letrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolidinyl, imidazolinyl, i adazolidinyl, pyrrolidinyl, furazanyl, N-mcthylindolyl, methylCuryl, pyridaziπyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetaπyl, 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, furyl, pyrroly, benzofuryl, benzothienyl, indolyl, methylpyrrolyl . morpholinyl, pyridyl, pyrazinyl, i idazolyl, pyrimidinyl, pyrazolyl or pyridazinyl. The preferred heterocyclic is a 5 or 6-membered heterocyclic compound. The especially preferred heterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, epoxy, pyrimidinyl, or pyridazinyl. The most preferred heterocyclics are furyl, pyrazolyl, pyrrolyl and pyridyl. The preferred compounds are those wherein n is 1, bu di, tri and tetrapeptides are also contemplated to be within the scope of the claims. The preferred values of R is aryl lower alkyl, especially benzyl, and the preferred R. is H or lower alkyl. The most preferred R. group is methyl. The most preferred electron donating substituent and electron withdrawing substituent are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, c rboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, amino lower alkyl ercapto, mercaptoalkyl, alkylthio; and alkyldithio. The term "sulfide" encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkyldithio. These preferred substituents may be substituted on any one of , , R_ R 3 , R., R g or Rg, R ? or R g as defined herein. -9- The ZY groups representative of R- and R 3 include hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkσxy, such as thiσmethoxy, thiocthσxy; thioaryloxy such as thiophenoxy; amino; alkylamino, such as methyla ino, ethylamino; aryla ino, such as anilino; lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt, hydrazino, alkylhydrazino and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, arylσxycarbonyl hydrazino, hydroxylamino, such as N-hydrσxylamino (-NH-OH), lower alkox amino I(NH0 18 ) wherein R 18 is lower alkyl], N-lower alkyltiydroxyl amino t(NCR 18 )OH wherein lg is lower alkyl], N-lower alkyl-O-lσwer alkyl hydroxyarnino, i.e., [H( 18 )OR lg wherein ^ 8 and ιg are independently lower alkyl] and o-hydroxylamino (-0-NH 2 ); alkylamido such as acetamido, trifluoroacetarnido, lower alkoxya inσ, (e.g. NH(0CH-.); and heterocyclicamino, such as pyrazoylamino. Furthermore, in still another embodiment Z may b O, S, NR 4 or PR 4 and Y may be hydrogen, lower alkyl or ary and R, R α , R 2 , R 3 , R 4 , R s , Re, R 7 , Re, n and a are as defined hereinabove. In a still further embodiment, ZY may be NR 4 CR S , or SCR S or NR 4 C-OR 5 , or SC-OR 5 and R, Ri, R 2 , R 3 , R 4 , R s , R 6 , R_, R β n and a are as defined hereinabove. When R 2 or R 3 is heterocyclic, the preferred heterocyclics are furyl, tetrahydrofuryl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolvl. oxadiazolyl or epoxy. The most preferred heterocyclic is pyridyl, pyrazoyl and pyrrolyl. The preferred heterocyclic groups representative of R 2 and R 3 have the formula ' (CH) n or those corresponding partially or fully saturated form thereof wherein n is 0 or 1 A, Z, L and J .are independently CH, or a he eroatom selected from the group consisting of N, O, S, and G is CH, or a heteroatom selected from the group consisting of N, O and S, but when n is O, G is CH, or a heterocyclic selected from the group consisting of NH, O and S with the proviso that at most two of A, E, L, J and G are heteroatoms. If the ring depicted hereinabove contains a nitrogen ring atom, then the N-oxide forms are also contemplated to be within the scope of the. invention. When ' 2 or R 3 "~ is a heterocyclic of the above formul it may be bonded to the main chain by a ring carbon atom. h n is O, R 2 or 3 may addi ionall y be bonded to the main chai by a nitrogen ring atom. R 2 or R 3 may independently also be SO^ , or Furthermore, ZY may also be NR 4 C NR 5 R 6 , NR 4 CNR s S(0)aR 6 , NR 4 C-NR S R 6 , C - NH 2 or II II II O 0 0 or R 4 CM NR 5 C 0R 6 . I) II Q A When R 2 is alkenyl the alkenyl group is a lower alkenyl group having 1-6 carbon atoms. The alkenyl group may be substituted with an electron donating group and more preferably with an electron withdrawing group,,such as COOH. 5 As indicated hereinabove, Q and A may be 0 or S; in other words, the main chain may contain only C=0, only -C=S or combinations thereof. All such permutations are contemplated herein. It is preferred that the compounds of 0 the present invention contain no more than 2 C=S moieties, it is even more preferred that the compounds of the present invention contain no more than 1 C=S moiety. The most preferred embodiment are when A and Q are both oxygen. An embodiment of the present application is one -*-5 in which the compounds are of Formula I wherein R is lower cycloalkyl or lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group and R^ . , R 2 , R 3/ Z, Y or ZY taken together, R 4 , R 5 , R β , R 7 , Re, n and a 20 are as defined herein. Another embodiment of the present invention include compounds of Formula I wherein R x is lower cycloalkyl or lower cycloalkyl lower alkyl and R__ may be unsubstituted or substituted with an electron donating 2 5 group or electron withdrawing group and R 1; R 2 , R 3 , Z, Y, or ZY taken together, R 4 , R s , R 6 , R-. Rβ n and a are as defined hereinabove. 30 35 Another embodiment of the present invention includes compounds of Formula I wherein R 2 is lower cycloalkyl or lower cycloalkyl lower alkyl and R 2 may be unsubstituted or substituted with an electron donating group or electron withdrawing group, and R, R x , R 3/ R 4 , R s , R 6 , R v , s and a are as defined hereinabove. Still another embodiment of the present invention include compounds of Formula I wherein R 3 is lower cycloalkyl or lower cycloalkyl lower alkyl and R 3 may be unsubstituted or substituted with an electron donating or electron withdrawing group and R, R^, R 2 , R 4 , R s , R β , R 7 f R s , n and a are as defined hereinabove. A further embodiment of the present invention include compounds of Formula I wherein Z is S(0) a and R, Ri, R 2 , R 3 , Y, R 4 , R s/ R 6 , -7. R s . n and a are as defined herein. It s preferred that one of 2 and R 3 is hydrogen. In a preferred embodiment, one of R 2 and R 3 is hydrogen and that the other is heterocyclic. It is preferred that one of R ? and 3 is a heterocyclic having Formula XI. T preferred heterocyclics include furyl, thienyl, benzothienyl, benzofuryl, σxazolyl, thiazolyl, isoxazolyl, indolyl, pyrazolyl, iεoxazolidinyl, benzothienyl, benzofuryl, morpholiny . indolyl, pyrrolyl, furfuryl, and methyl- p yrr lyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl or pyridazinyl, pyrazolyl, or epoxy. In another preferred embodiment, one of R 2 and R 3 is alkyl (e.g. methylisopropyl), aryl (e.g., phenyl), 2-thiomethylethyl, lower alkoxy (e.g., phenyl), 2-thiomethylethyl, lower alkoxy (e.g., ethoxy, methoxy) , anilino, propenyl, alkylamino (e.g., ethylamino or methylamino) . In another preferred embodiment, one of R 2 and R 3 is hydrogen and the other is heterocyclic lower alkyl, lower alkenyl, amino, lower alkoxy amino, N-lower alkylhydroxyamino, lower alkoxyamino, N-lower alkyl-O-lower alkylhydroxya ino or aralkoxycarbonylhydrazino. Preferre d compounds of the present invention have the following general formula: wherein 1 is H or lower alkyl, R 2 and R 3 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=0). However, values of m equalling 1, 2 or are also preferred. Preferred embodiments include compounds of Formula wherein R and R., independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl. aryl lower alkyl. «*1. heterocyclic, lower alkyl heterocyclic, each unsu b st i tuted substituted with at least one substituent ; R 2 and R 3 , independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, lower alkyl heterocyclic, each unsubstituted or substituted with at least one substituent; halogen or a heteroatom containing oxygen, nitrogen, sulfur or phosphorous substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; and n is 1 to 4. Another preferred embodiment is a compound having Formula I wherein R is aryl, aryl lower alkyl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic or lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; R^ is H or lower alkyl, unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; Ry and R 3 , independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron donating substituent, halogen or a heteroatom containing oxygen, nitrogen, sulfur or phosphorous substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; and n is 1 to .. Another preferred embodiment of the present invention is a compound of Formula I wherein R is aryl lower alkyl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic or lower alkyl polynuclear aromatic, each of which may be unsubstituted or substituted with at least one halo, _nitro, acyl, carboxyl, carboalkoxy, carboxa ide, cyano, sulfonyl, sulfoxide (sulfinyl) t heterocyclic, guanidine, quaternary ammonium hydroxy, alkoxy, alkyl, amino, phenoxy, mercapto, —llfide or disulfide; R. is H or lower alkyl which may be unsubstituted or substituted with at least one halo, nitro, acyl, carboxamide, cyano, sulfonyl, sulfoxide (sulfinyl), heterocyclic, guanidine, quaternary ammonium, hydroxy, lower alkoxy, amino, phenoxy, sulfide, or disulfide; R 2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; halogen or a heteroatom consisting of oxygen, nitrogen, sulfur or phosphorous, said heteroatom being substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; 3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, lower alkyl polynuclear aromatic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; halogen or a heteroatom consisting of oxygen, nitrogen, sulfur, or phosphorous said heteroatom being substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted; and n is 1 to 4; Another preferred embodiment is a compound of Formul wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl 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 R 2 and R 3 are.independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, or Z-Y wherein R and R 3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; Z is 0, S,S(0) , NR., .PR. or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, or halo and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, provided that when Y is halo, Z is a chemical bond, or ZY taken together is R 4 R 5 R ? , NR.0R 5 , ONR.R.,, OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , R 4 SR-, SPR 4 R- or PR 4 SR ? , NR 4 PR 5 Rg or PR4.NR5 r R7_.,' NR4.|C|R5 C ,' S|C | R-5,' NR4-Ci|OR5.,' SCi|-OR5- O O 0 O R., R- and R g are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.,' R5_. and R6, may be unsubstituted or substituted with an electron withdrawing group or an electron donating group and R-, is R, or COORg or COR g , R g is hydrogen or lower alkyl, or aryl. lower alkyl, wherein the aryl or lower alkyl groups may be unsubstituted or substituted with an electron withdrawing or electron donating group, n is 1-4 and a is 1-3. Another class of preferred compounds of the Formula I have the formula 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; . j is hydrogen or lower alkyl which is unsubstituted or substituted with at least one electron withdrawing group or one electron donating group, R 2 and R 3 are independently hydrogen, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, Z-Y or a heterocyclic group which may be 'unsubstituted or substituted with at least one electron withdrawing or one electron donating group, w th the proviso that R 2 and R3 cannot both be hydrogen; Z is 0, S, NR 4 , PR 4 or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl or halo, and Y may be unsubstituted or substituted with an electron donating group o an electron withdrawing group, provided that when Y is halo, Z is a chemical bond; or ZY taken together is R 4 R 5 R β , R 4 OR 5 , O R 4 R-, OPR 4 R 5 , PR 4 0R-, SNR 4 R 5 , N 4 SR c , SPR 4 R,., or PR 4 SR c , R 4 PR 5 R g or PR 4 NR 5 R 6 , R«, R e and R g are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R Λ „ R-- and Rg may be unsubstituted or substituted with an electron withdrawing group or an electron donating g . ip; n is 1-4. Of this preferred group, it is especially preferred that n is 1. The preferred compounds are those in which R is aryl, aryl lower alkyl, heterocyclic, or heterocyclic lower alkyl, R. is hydrogen or lower alkyl, R-, and R~ are independently hydrogen, heterocyclic, lower alkyl, aryl, lower alkoxy, lower alkenyl, amino, hydroxylamino, lower alkoxy amino, N-lower alkyl hydroxyamino, N-lower alky1-o-lower alkyl hydroxyamino, aralkoxy carbonyl hydrazino or alkylmercapto and η is 1. In another preferred embodiment, n is 1, R and R^ ar as defined hereinabove and one of R 2 and 3 is hydrogen and th other is heterocyclic, heterocyclic lower alkyl, aryl • . N-hydroxylamino, lov/er alkoxyamino, N-lower alkylhydroxylammo N-lower alkyl-O-lower alkylhydroxyamino. Another preferred embodiment is wherein n is 1, R an R. are as defined hereinabove, one of R 2 and R 3 is as defined hereinabove or the other is heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, aryl, N-hydroxylamino, lower alkoxy amino, N-lower alkyl hydroxylamino, N-lower alkyl-o-lower alkyl hydroxylamino, lower alkoxy, dialkyl lower amino, lower alkyla ino, aryl lower alkyloxy hydrazino, or lower alkylmercapto. The various combination and permutations of the Markush groups of R., R 2 , 3 R and n described herein are contemplated to be within the scope of the present invention. Moreover, the present invention also encompasses compounds and compositions which contain one or more elements of each of the Markush groupings in R., R 2 , R 3 » n and R and the various combinations thereof. Thus, for example, the present inventio contemplates that R.. may be one or more of the substituents listed hereinabove in combination with any and all of the substituents of R 2 , R-. and R with respect to each value of n. The compounds of the present invention may contain one (1) or more asymmetric carbons and may exist in racemic an optically active forms. The configuration around each asymmetric carbon can be in either the D or form. (It is well known in the art that the configuration around a chiral carbon atoms can also be described as R or S in the Cahn-Prelog-Ingold 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 a contemplated by the present invention. In the principal chain, there exists asymmetry at t carbon atoms to which the groups 2 and R 3 are attached as substituted. When n is 1, the compounds of the present invention is of the formula R - NH - if - C - N - C - R, wherein R, R., R 2 , R 3 _, R 4 l, R $ , Rg, Z and Y are as defined previously. As used herein, the term configuration shall ref to the configuration around the carbon atom to which R 2 and R are attached, even though other chiral centers may be present in the molecule. Therefore, when referring to a particular configuration, such as D or L, it is to be understood to mean the stereoisomer, including all possible enantiomers and diastereomers. The compounds of the present invention are directed to all of the optical isomers, i.e., the compounds o the present invention are either the L-stereoisomer or the D-stereoisomer. These stereoisomers may be found in mixtures of the and D„ stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred. Depending upon the substituents, the present compounds may form addition salts _s well. All of these form are contemplated to be within the scope of this invention including mixtures of the stereoiso eric forms. The following three schemes of preparation are generally exemplary of"the process which can be employed for the preparation of the present complex. A1 though the compou in the schemes hereinabove contain only the C moiety, it is O just as applicable to compounds of Formula I wherein either A or Q is sulfur or both A or Q are sulfur. Sch erne I Scheme li y ainiπ, CO 2 + V wherein "17- lower a__ yl , „_,. ary . . ower ^ Scheme III o 00 o OIIO II II II II I II R 1 CNI! n r^ccoπ Il.CHH-C-COII 1 I R 17 OII/Π 0 0R.-0 I I OR 0 II I J-'M .1 I 1 II R, CHII-C — CKHR HKΠ. R.CNil-C — C0R j 7 1 I ll 2 with" or H. without catalyst R 3 I1 (i.e., H'CM-) Lewis acid, such as BF-." o(Et). wherein 3 = aryl, heteroaromatic and R7 is as defined hereinabove. More specifically, these compounds can be prepared by art-recognised procedures from known compounds or readily preparable ii._erm_dic.t_s. For instance, compounds of Formula I can be prepared by reacting amines of Formula II with an acylating derivative of a carbo.:ylic acid of Formula III under amide forming conditions: wherein R, R , R , \\ Λlχr _ ace as defined hereinabove and 11 = 1 The amide forming conditions referred to herein involve the use of known derivatives of the described acids, such as the acyl halidcs, (e.g., R--C-X, 1 » 0 wherein X is Cl, Br and the like), anhydrides O O il 'I (e.g., R.-C-O-C-R. ) , mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazolcs, and the like. It is preferred that the acylating derivative used is the if π anhydride, R.-C-O-C-R- . 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 R 7 and R, is aromatic or heteroaromati is depicted in Scheme IV. The ester (IV) is reacted with halogen and ultraviolet light in the presence of a catalyst, e.g., ΛIBN, t 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, suc as alkylchloroformate in the presence of a tertiary amine to generate the mixed N-acyl amino acid carbonic ester anhydride (VIII). This intermediate is reacted w: .h an amine under amid forming conditions to give the compound of Formula I. Alternatively, (VI) can be reacted directly with an amine (RNH-) 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 VIII can be prepared by an independent method and converted to VI which is then reacted with an amine with or without catalyst to form the compound of Formula I. cid χ= halogen (i.e., d, Br ) R_=lower alkyl, aryl, arly lower al k yl M+=metal cation (i.e., Na , K ) Two additional synthetic routes may be employed for the preparation of compounds wherein R 2 or R 3 is Z-Y as defined hereinabove. In one scheme, for the preparation of these complexes, a substitution reaction is used: Scheme V H RN R. excess HR~ or MR 2 THF (-78°C) or compound of Formula I, 1) Et 3 N 2) HR THF (-78 β C) In the above scheme, R g is lower alkyl, R 2 is Z-Y and Z, Y, R, 3 and R.. are as defined hereinabove. The ether functionality on IX can be cleaved by treatment with Lewis acids, such as BBr 3 in an inert solvent such as methylene chloride to form the corresponding halo (bromo) derivative. Addition of either an excess of the H-R-, or MR-, or the sequential addition of triethylamine and H-R_ to a THF mixture containing the halo derivative furnishes the desired product. For example, in the case wherein the compound of Formula IX is 2-acetamido-N-benzyl-2-ethoxy acetamide, its treatment with BBr., in CH-C1-, led to the- formation of the α-bromo derivative, 2-acetamido-N- benzyl-2-bromoacetamide. Addition of an excess of HR 2 or the sequential addition of I1R_ to a THF mixture containing the bromo adduct furnishes the desired product. In another procedure, the product wherein R 2 or R 3 is Z-Y can also be prepared by substitution reaction on a quaternary ammonium derivative of the compound of Formula I as outlined below Scheme VI excess R_ _,H y y desired product In scheme VI, R, R-, 3 and R are as defined hereinabove, R 2 is Z-Y and R g and R 1Q are independently lower alkyl. In scheme VI, methylation of compound X with a methylation reagent, such as trimethyloxonium tetrafluoroborate provided the corresponding ammonium derivative. Subsequent treatment of the ammonium salt with HR-, furnishes the desired product. For example, methylation of 2-acetarnido-N-benzyl-2-(N,N-dimethylamino) acetamide with trimethyloxonium tetrafluoroborate in nitromethane furnishe the quaternary ammonium derivative, 2-acetamido-N-benzyl-(N,N,N- trimethylammσnium) acetamide tetrafluoroborate in high yields. Subsequent treatment of salt with the IIR 2 reagent .in. the methanol leads to the production of the desired ^ product. AS " i_τ any -organic " eacrfϋrr, ∑ϊ TvenπEs"can be emplo such as methanol, ethanol, propanσl, acetone, tetrahydrofur dioxane, dimethylforma ide, dichloromethane, chloroform, an the like. The reaction is normally effected at or near roo temperature, although temperatures from 0 β C up to the reflu temperature of the reaction mixture can be employed. As a further convenience, the amide forming react can be effected in the presence of a base, such as tertiary organic amine, e.g., triethylamine, pyridine, 4-methylmorpholine, picolines and the like, particularly wh hydrogen halide is formed by the amide forming reaction, e. the reaction acyl halide and the amine of Formula II. O f course, in those reactions where hydrogen halide is produce any of the commonly used hydrogen halide acceptors can also used. The exact mineral acid or Lewis acid employed in rea c tion will vary depending on the given transformation, t temperature required for the conversion and the sensitivity the reagent toward the acid in the reaction employed. ' C ompounds of the present invention in which Q o A is S are prepared from the corresponding compounds in which Q or A is O by art recognized techniques. For example, one reagent that can be used is Lawesson's reage i.e, [2,4-bis-( -methoxyphenyl)-1,3-dithia-2,4- diphosphetane-2-,4-disulfideJ. This reagent is a known reagent for the thiation of such compounds as ketones, carboxamides, esters, lactones, lactams, i ides, enamines -27a- and S -su b stituted thioesters. Thus, this reagent can e ^ 1 used to transform compounds of Formula I wherein Q or A i s 0 to compounds wherein one or both of Q or A is S. The number of C groups in the final product is dependent upon 5 s the amount of reagent added and the number of C groups present (i.e., the value of n) in the reactants having 10 Formula I. For example, if n is 1, and both Q and A are oxygen, than the compounds of Formula I have two C groups. Thus, if it is desired that both C groups be transformed to ι_> o II C then approximately eguimolar amount or a slight excess of is added to compounds of Formula I. On the other hand, if 20 only one C group is desired in the final product, then approximately § molar equivalent of Lawesson's reagent i 25 Furthermore, it is not necessary to add the reagent at the last step of the synthesis; the reagent can be added at any stage of the syntheses outlined in Schemes I-VI hereinabove. As before, the amount of the reagent 30 added depends upon the number of C desired in the product, an S number of C groups in the reactant. 35 O Regardless of which step in the synthesis the reagent is added, the reagent and the compound of Formula I having at least one C group or an intermediate thereof is dissolved in an inert solvent, such as THF and heated at a temperature effective to convert the C group to a C. Temperatures ranging from room temperature to the reflux temperature of the solvent can be used. In cases when n = 1, it is preferred that the reaction is heated to about reflux if both Q and A are converted to S and that about room temperature be used if one of Q or A is converted to S. The various substituents on the present new compounds, e.g., as defined in R, R- L , 2 and R 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 a_ 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 off-Kishner reduction and Clem ensσn reduction. -Amino groups can be alkylated to form mono, dialkylamino and trialkylamino groups; and mercapto and ' hydroxy groups can be alkylated to form corresponding thioethers or ethers, 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 form ketones. Thus, substitution or alteration reactions can be employed to provide a variety of substituents 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. . Greene, John Wiley & Sons, 1981. Resulting mixtures of iso ers can be separated in th pure isomers by methods known to one skilled in the art, e.g., by fractional distillation, crystallization and/or chromotagraphy. The present compounds obviously exist in stereoisomeric forms and the products obtained thus can be mixtures of the isomers. which can be resolved. Optically pur functionalized amino acid derivatives can be prepared directly from the corresponding pure chiral intermediate. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof. e.g., by fractional crystallization, by selective enzymatic hydrolysis, e.g., papain digestion, or by use of a chiral stationary phase in chromotagraphy (HPLC). For a discussion chiral stationary phases for HPLC, See, DeCamp, Chirality, JL, 2-6 (1989), which is incorporated herein by reference with th 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., q R- o ll 1 2 li R. C - NH - C - COR- 7 wherein R. 7 is H R 3 (which can be prepared according to the procedures of Schemes 1, 2, 3 or 4) is reacted with an optically active amine, RNH- e.g., (R) (+) -methylbenzylamine to form a pair of diasteroomeric salts. Diastereomers can then be separated by recognized techniques known in the art, such as fractional . recrystallization and the like. 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 t separate the racemic modification, since it will preferentiall 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(+)α-acetamido-2-furanacetic acid. It acts on the L (+)α-acetamido-2-furanacetic acid, but will not act on the D enantiomer. In. this way, the D(-) -acetamido-2-furanacetic acid can be isolated. The intermediate can then react with th amine (RNH-) under amide forming conditions as described hereinabove to form teh compound of Formula I. . ~ The active ingredients of the therapeutic compositions and the compounds of the present invention exhibit excellent anticonvulsant activity when administered in amounts ranging from about 10 mg to about 100 mg per kilogram of body v/eight 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 cf from about 1.0 gram to about 3.0 grams of the active compound for a subject of about 70 kg of ■ body v/eight are administered in a 24-hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response and is preferably administered one to three times a day in dosa-ges of about 600 mg per administration. For example, several divided doses may be . "administered daily or the dose 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, intraveneouε (where water soluble) , 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 incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be - - incorporated with excipients and used in the form of ingestibl tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. 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 con iently 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 inventio are prepared so that an oral dosage unit form contains between about 5 and lOOOmg of active compound. The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintergrating agent such as corn starch, potato starch, alginic acid and the liek; a lubrican such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin mauy be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. 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 o to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the acitve compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. 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 Y cne release properties of the resin. -35- . The active compound may also be administered pnrenterr.l.y or intraperitoncαl . y. 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 microorganisms. 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 and storage and must be preserved against the contaminating action of microorganisms 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 oil:.. 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 microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. 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, aluminum mcnostearate and gelatin. -36- Sterile injectύble 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 tlie preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the reeze-drying technique which yield n powder of the active ingredient plus any additional desired ingredient from previously sterile- filtered solution thereof. Λs 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. It 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 -37- speci ication for the novel dosr.ge unit forms of the invention arc 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 v/ith a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed. Λ unit dosage form can, for example, contain the principal active compound in amounts ranging from about 5 to about 1000 mg, with from about 250 to about 750 mg being preferred. 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 co. aining 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 administe ' red in combination with other anti-convulsan 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. 48 -38- General Methods. Melting points were determined with a Thomas-Hoover melting point apparatus and are uncorrected. Infrared spectra (IR) were run on a Deck aπ IR-.250 and Perkin-Elmer 1330 and 283 εpectrophotσmeters and calibrated against the 1601-cm ~ band of polysytrene. Absorption values are expressed in wavenumbers • (cm -1 ). Proton nuclear magnetic resonance ( H NMR) spectra were recorded on Varian Associates Models T-60 and FT-80Λ, General Electric QE 300, and Nicol ? t NT-300 NMR spectrometers. Carbon nuclear magnetic resonance ( -*C NMR) spectra were run on a Varian Associates Models FT-80Λ General Electric QE 300 and Nicolet NT-300 instrument. Chemical shifts are in parts per million (fø values) relative to Me^Si, and coupling constants (J values) are in hertz. Mass spectral data were obtained at an ionizing voltage of 70 eV on a Hewlett-Packard 5930 gas chromotagraph-mass spectrometer and a Bell-Mo ell 21-.91 spectrometer as well as at the Eli Lilly Laboratories on a Varian MΛT-CH-5-spectrometer. High-resolution (El mode) mass spectra were performed by Drs. James Hudson and John Chinn at tlie Department of Chemistry, University of Texas at Austin, on a CEC21-110D double- ocusing 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 fro CaII 2 , while dichloromethane was distilled from 2°5» Acetic anhydride, benzaldehyde and ethyl chlorσfσrmate were fractionally distilled. - - «.-p .. __ 7 e e pce P are_ a.cocdin . to this procedure. ™P 139-141°C. H NMR (DKSO-d ) 6 61.22 ( d.J = 7.1 „_, 3li), 1. 8 4 (s , 3H , , - - mi, 311) 7.26 (5 ςπ . o 1 . ,, lin a .. ,., . ' 8*11 (br d ' J = 7 -3 H 13 ' 2 (br t ' J = 6 »z, 1H) . C HMR (DMSO -d 6 ) 8 18 .2, 22.4, 41.9, 48.2, 126 5 126 9 ' 120.1, 139.4, 168.9, 172.4 ppm. ' & ^ ' IR (CIIC1 ) 3440, 3300, 3005 1660, 1515 cm -1 Mass spectrum (CI mode) , m /e ; 221 ( P+l ) ; mol wt 220.1208 ( Calculated for c i2 H i6 '2 0 2' 220 - 1212 ) - -41- 1 EXAMPLE 2 ' N-Λcetyl-D-alanine-N'-benzylamide. Yield: 1.36 g (56.) . mp 139-141°C J [[C_] p 3 = +36.2 (c 2.5, MeOII) 1 H NMR (80 MHz, DMSO-d,) : _ 1.25 (d,J = 7.1 Hz, 311), 1.86 (s, o 311), 4.10-4.50 (m, 1H) , 4.30 (d,J = 6.0 Hz, 2H) , 7.26 (s, 511), 8.09 (d,J = 7.3 Hz, III), 8.40 (t,J = 6.0 Hz, 1-H) . 0 13 C NMR (80 MHz, DMSO-dg) : 18.3, 22.5, 42.0, 48.4, 126.6, 127.0 (2C) , 128.2 (2C) , 139.4, 169.2, 172.5 ppm. IR (KBr) : 3290, 1635 (br) , 1540, 1455, 700, 695 cm "1 . Mass spectrum, m/e (relative intensity) : 221 (30) , 114 (20) , 106 (40) , 91 (80) , 87 (100), 77 (5), 72 (20), 65 (5). • ^ Elemental analysis Calculated for C- 2 II 16 2 0 2 65.42% C; 7.34% H; 12.72% N. Found 65.31% C; 7.28% H; 12.63% N. 20 25 30 35 O 92/21648 -42- EXAMPLE 3 N-Acetyl-L-alanine-N'-benzylami e. Yield: 1.11 g (46%) . r mp 139-142°C. lot].o 3 « -35.3 (c 2.5, MeOH) . 1 H NMR (80 MHz, DMSO-dg}: 61.23 (d,J = 7.2 Hz, 3H) , 1.86 (s, 3H) , 4.26-4.35 ( , 111), 4.29 (d . J = 5.8 Hz, 211), 7.22-7.33 (s, 5H) , 8.10 (d,J = 7.4 Hz, 1H) , 8.42 (t,J = 5.8 Hz, III) . 0 13 C NMR (80 MHz, DMSO-dg): 18.3, 22.6, 42.0, 48.4, 126.7, 127.0 (2C), 128.3 (2C) , 139.5, 169.2, 172.6 ppm. IR (KBr) : 3290, 1635 (br) , 1545, 1450, 700, 695 cm "1 . Mass spectrum, m/e (relative intensity): 221 (40), 114 (40), 106 (00) , 106 (80), 91 (75) , 87 (100), 77 (5), 72 (15), 15 65 (5). Elemental analysis Calculated for c 12 π i6 I, '2 0 2 65 - 42% C; 7.34% H; 12.72% N. Found 65.58% C; 7.32% H; 12.43% N. 20 25 30 35 -43- 1 EXAMPLE 4. Preparation of N-Λcetyl-D, -phenylqlycine-N'-methylamide. Acetic anhydride (2.90 g, 28 mmol) was added dropwise to D,L-phenylglycine-N-methylamide (3.4 g, 20 mmol) " . and allowed to stir at room temperature (1.5 h) . During this time, a copious white precipitate formed. This material was collected by filtration, dried n vacuo and recrystallized from absolute alcohol. Yield: 2.00 g (49%) . 10 p 232-235°C (dec) . " " " Il NMR. (DMSO-d D-) : § 1.89 (s, 311) , 2.58 (d,J = 4.6 Hz, 3H_ , 5.42 (d,J = 8.1 Hz, III) , 7.35 (s, 5H) , 8.18 (br q,J = 4.2 Hz, III) , 8.47 (d,J = 8.1 Hz, 1H) . 13 C NMR (DMSO-d 6 ) : 22.4, 25.5, 56.3, 127.1, 127.3, 128.1, 15 139.0, 168.9, 170.3 ppm. IR (KBr) : 3310, 1645 cm "1 . Mass spectrum (CI mode) , m/e: 207 (P+l) . Elemcr.tal analysis .Calculated for C. -H..N_0_, 64.06% C; 6.86% II; 13.58% N. on 20 Found • 63.79% C; 6.66% H; 13.27% N. 5 0 5 _ 44 _ EXAMPLE 5 Preparation of N-Acetylqlycine-N-benzylamide. The D,L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic anhydride (1.23 g, 1.40 L, 12 mmol) was added dropwise. The solution was stirred at room temperature (4-6 h) and then concentrated to dryness. The residue was recrystallized from chloroform/ hexane. Yield: 1.84 g (81%) . p 140-142°C. 1 H NMR. (DMSO-d 6 ) : $ 1.88 (s, 3H) , 3.74 (d,J = 5.3 Hz, 2H) , 4.30 (d,J = 5.1 Hz, 211), 7.27 (s, 5H) , 8.37 (br s, 1H) , 8.75 (br s, 1H) . 13 C NMR (DMΞO-dg) : 22.5, 42.0, 42.5, 126.6, 127.1 (2C) , . 128.1 (2C), 139.3, 169.0, 169.6 ppm. IR (KBr) : 3060, 1655, 1640, 1560, 1545, 1450, 1300, 740, 710 Mass spectrum, m/e (relative intensity): 206 (3), 147 (12), .106 (100) , 91 (75) , 73 (50) . Elemental' analysis Calculated for C 1.1.H1. . .N 2.0__ 64.05% C; 6.86% H; 13.58% N. Found 64.03% C; 6.79% H; 13.61% N. -45- EXAMPLE 6. Preparation of N-Λcetyl-D,L-valine-N-benzylamide. The D,L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic anhydride (1.23 g, 1.40 L, 12 mmol) was added dropwise. The solution was stirred at room temperature (4-6 h) and then concentrated to dryness. The residue was recrystallized from chloroform/ hexane. Yield: 2.35 g (86%) . 10 mp 192-193°C. 2 I1 NMR.(DMSO-dg) : $ 0.83 (d,J = 6.7 Hz, 611) , 1.87 (s, 311) , 1.73-2.09 (m, III) , 4.11 (d,J = 8.8 Hz, 1H) , 4.27 (d,J = 5.8 Hz, 2H) , 7.26 (s, 5H) , 7.89 (d.J = 8.8 Hz, 1H) , 8.84 (t,J = 5.8 Hz, 1H) . ^5 13 C NMR (DMΞO-d-) : 18.1, 19.2, 22.4, 30.2, 41.9, 57.8, 126.6, 127.1 (2C) , 128.1 (2C) , 139.4, 169.2, 171.1 ppm. IR (KBr) : 1625, 1540, 1535, 1450, 1380, 1290, 750, 695 cm "1 . Mass spectrum, m/e (relative intensity) : 142 (1 ) , 114 (43) , .106 (29) , 91 (57) , 72 (100) . 20 Elemental analysis Calculated for C. ,H_ n N_0_ 67.70% C; 8.13% H; 11.28% N. Found 67.58% C; 8.05% H; -11.101 N. 25 30 35 - - EXAMPLE 7 • Preparation of N-Acetyl-D,L-phenylglycine-N-benzylarnide. The D,L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic anhydride (1.23 g, 1.40 mL, 12 mmol) v/as added dropwise. The solution was stirred at room temperature (4-6 h) and then concentrated to dryness. The residue was recrystallized from chloroform/ hexane. Yield: 2.05 g (66%) . p 202-203°C. 1 H NMR- (DMSO-dg) : , 1.91 (s, 311) , 4.27 (d,J = 5.6 Hz, 211), 5.50 (d . J = 7.9 Hz, 111) , 7.21 |s, 5H) , 7.36 (s, 5H) , 8.38-8.86 (m, 211) . 13 C NMR (DMSO-dg) : 22.3, 42.0, 56.3, 126.6 (2C) , 127.0, . 127.1 (2C) , 127.4 (2C) , 128.1 (2C) , 138.9, 139.0, 168.9, 169.9 ppm. IR (KBr) : 3020, 1635, 1580, 1540, 1450, 1265, 745, 690 cm "1 . Mass spectrum, m/e (relative intensity): 283 (20) , 264 (21), ■ 149 (100) , 131 (20) , 118 (34) , 106 (92) , 91 (70) , 79 (56) ' , 77 (54) , 65 (45) , 51 (37) . Elemental analysis Calculated for C. 1./.I'1 EN λ_02_ 72.31% C; 6.44% H; -9.92% N. Found 72.49% C; 6.47% H; 9.89% N. -47- -*- Preparation of N-Acetyl-D- and • L-phenylqlycine-N-benzylamide. General Procedure. The chiral Boc-protected phenylglycine-N-benzylamide was dissolved in trifluoroacetic acid (0.04 M) and was stirred at room temperature (30 min), 5 during which time gas evolved. The solution was concentrated irv vacuo and the residue was redissolved in enough methanol to form a solution of 0.2 M. Methanesulfonic acid (1 equiv) was added dropwise and stirred for 5 min. After concentrating the solution jln vacuo, the residue was 0 repeatedly dissolved in methanol and the solvent was removed (3 times) . The residue was then dried under vacuum (18 h) , leaving a yellow oil. Without further purification, the phenylglycine-N- benzylamide methanesulfonate v/aε dissolved in tetrahydrofuran 5 (0.2 M) and then was cooled in an ice bath. Triethylamine (2 equiv) was added dropwise, followed by acetyl chloride (1 equiv) . The ice bath was removed and stirring was continued at room temperature (18 h) . The solution was concentrated ji vacuo and the residue was recrystallized from 0 1:1 95% ethaπol/water. Examples 8 and 9 were prepared according to this . procedure. - - N-Acety -D-phenylglycine-N-benzylamide. The reaction was run on an 11.9 mmol scale. Yield: 2.97 g (88% ) . mp 219-221°C. (c . . D = -103.0 (c 1%, EtOH ) . 1 H NMR ( DMSO-dg) : .1.91 (s, 311) , 4.27 ( d,J = 5.5 Hz, 211 ) , 5.50 ( d,J = 7.8 Hz, III) , 7.14-7.44 ( m, 10H ) , 8.56 ( d.J = 7.8 Hz, III ) , 8.79 (t,J = 5.5 Hz, 1H ) . 13 C NMR (DMSO-d6 ,) : 22.4, 42.0, 56.4, 126.7, 127.0 (2C ) , 127.2 ( 2C ) , 127.4, 127.9 (2C) , 128.1 ( 2C ) , 138.9, 139.0, 168.9, 170.0 ppm. IR ( KBr ) : 3260, 1620, 1525, 1450, 1370, 720, 690 cm " . Mass spectrum, m/e ( relative intensity ) : 203 ( 2 ) , 149 ( 94 ) , 106 ( 100 ) , 91 (32) , 86 (43 ) , 77 ( 14 ) . Elemental analysis Calculated for 72.32% C ; 6.43% H; " .92% N. Found 72.04% C; 6.22% H ; 9.78 % N. - - N-Acetyl-L-phenylqlycine-N-benzylamide. Beginning with 16.1 mmol N-t-Boc-L-ph.enylglycine- 5 N-benz lamide. Yield: 2.99 g (66% ) . . . mp " 221-222°C. l c ] D = +105.1 (c 1%, EtOH ) . 1 H NMR ( DMSO-dg ) : .1.99 (s, 311) , 4.36 ( d,J = 5.6 Hz, 2H) , 10 5.60 ( d,J = 8.0 Hz, III ) , 7.23-7.53 ( , 1011 ) , 8.60 ( d,J 8.0 Hz, III ) , 8.83 (t,J = 5.6 Hz, 1H ) . 13 C NMR ( DMSO-dg ) : 22.4, 42.1, 56.5, 126.8, 127.1 ( 2C ) , 127.3 ( 2C ) , 127.5, 128.2 (4C) , 139.0, 139.1, 169.1, 170.1 ppm. 1 IR ( KBr ) : 3295, 1630, 1530, 1450, 1395, 720, 695 cm" 1 . Mass spectrum, m/e ( relative intensity ) : 223 ( 1 ) , 203 ( 2 ) , 149 ( 98 ) , 106 ( 100) , 91 (32) , 86 (43 ) , 77 ( 11 ) . Elemental analysis Calculated for C _.L_..Hl. c bi___.0___. 72.32% C ; 6.43% H ; 9.92% N. 20. Found 72.53% C; 6.49 % II ; 9.67% N. 5 0 -50- EXAMPLE 10 Preparation of N-Acetyl-D,L-alanine-N- (3-melhoxy) enzylamide The D,L-amino acid amide (11 mmol) was dissolved i dichloromethane (15mL) and then acetic anhydride (1.23 g, 1.40 mL, 12 mmol) was added dropwise. The solution was stirred at room temperature (4-6 h) and then concentrated to dryness. Tlie residue was recrystallized from chloroform/ hexane. Yield: 0.47 g (17%) . mp H2-115°C. 1 H NMR. (DMΞO-db..) : £ 1.23 (d,J = 7.1 Hz, 3H) , 1.85 (s, 311), 3.73 (s, 311), 3.99-4.48 (m, III) , 4.25 (d,J = 6.1 Hz, 211), 6.58-7.35 ( , 411) , 8.05 (d,J = 7.4 Hz, III), 8.35 (t,J = 6.0 Hz, 111) . ' 13 C NMR (DMSO-d-): 18.1, 22.5, 41.8, 48.3, 54.9, 112.2, 112.3, 119.0, 129.2, 141.0, 159.3, 169.0, 172.4 ppm. IR (KBr) : 3270, 3065, 1625, 1580, 1450, 1260, 1150, 1095, 900, 775, 700, 690 cm "1 . Elemental analysis Calculated for C 1.3-II1. r 8 2_03_ 62.37% C; 7.26% II; 11.19% N. Found - 62.29% C; 7.13% H; 11.08% N -51- EXΛHPLE ' 11 Preparation of N-Trimethylacetyl-D, -alanine-N-benzylamide. D,L-Λlanine-N-benzylamide (3.56 g, 20 mmol ) was dissolved in dichloromethane (25 L) and trimefhylacetic anhydride (4.10 g, 4.46 L, 22 mmol) was added dropwise. The solution was stirred at room temperature (18 h) and then concentrated to dryness. The solid residue was recrystallized from benzene/petroleum ether (30-60°C ) . Yield: 2.07 g (40%) . mp 123-124°C. l ll NMR- (DMSO-dg) : S 1.12 (s, 911) , 1.27 (d,J = 7.1 Hz, 3H) . 4.23-4.42 (m, III) , 4.31 (d,J = 5.4 Hz, 211) , 7.23-7.30 ( , 5H) , 7.38 (d,J = 7.4 Hz, III) , 8.26 (t,J = 5.4 Hz, HI) - 13 C NMR (DMSO-dg) : 18.1, 27.2 (3C) , 37.9, 42.0, 48.4, 126.6, 127.0 (2C) , 128.2 (2C) , 139.4, 172.5, 177.1 ppm. IR (KBr) : 3300, 1630, 1535 (br) , 1455, 745, 695 cm "1 . Mass spectrum, m/e (relative intensity) : 262 (2.= , 203 (19) , .156 (18), 128 (51) , 106 (31) , 91 (100) , 77 (15), 65 (28). Elemental analysis Calculated for C I, _DH__.__,.II 2-02. 68.66% C; 8.47% II; 10.68% N. Found 68.91% C; 8.14% II; 10.61% N. -52- EXΛMP E 12 Preparation of N-Acetyl-D,L-methionine-N-benzylamide. N-Λcetyl-D,L-methionine (4.78 g, 25 mmol) was combined with acetonitrile (75 mL) and the mixture was placed ' 5 into an ice/salt water bath (-5°C) . Triethylamine (2.53 g, 3.48 L, 25 mmol) was added dropv/ise, followed by ethyl chloroformate (2.71 g, 2.39 mL, 25 mmol) . All additions were done slowly so that the temperature of the mixture did not rise above 0°C. The mixture was then stirred at -5 C C (20 0 min) . Benzylamine (3.00 g, 3.06 mL, 28 mmol) in acetonitrile (5 D.was added dropwise and the mixture was stirred at -5°C (1 h) and then room temperature (18 h) . The mixture was filtered and a white precipitate was collected and dried i j n vacuo and identified as the 5 desired product ( H NMR and 13 C NMR analyses) . The filtrate 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 of a white precipitate. The mixture was filtered and the precipitate was collected, dried 0 i_n vacuo, 'and identified as triethylammonium hydrochloride. The latter filtrate containing tetrahydrofuran was concentrated in vacuo and the resulting residue was purified by flash column chromatography (ethyl acetate) . A white solid (R f = 0.50, ethyl acetate) was isolated and was 1 13 5 identified-as the desired product ( II NMR ^ and C NMR analyses). The two solids identified as N-acetyl-D,L- methionine-N-benzylamide were combined and recrystallized from benzene/petroleum ether (30-60°C) . . Yield: 2.98 g (43%) . 0 mp 134-135°C. 1 H NMR (DMSO-dg) : 6 1.69-1.94 (m, 211) , 1.87 (s, 31!) , 2.02 (s, 3H) , 2.29-2.59 (m, 2H) , 4.10-4.53 ( , 1H) , 4.29 (d,J = 6.0 Hz, 2H) , 7.26 (s, 5H) , 8.12 (d,J = 8.5 Hz, III) , 8.47 (t,J = 6.0 Hz, 111) . 5 -53- 3 C NMR ( DMSO-dg) : 14.6, 22.5, 29.7, 31.8, 42.0, 52.0, 126.6, 127.0 (2C) , 128.2 (2C) , 139.4, 169.5, 171.4 ppm. IR ( KBr ) : 3280, 1630, 1545, 1460, 750, 700 cm "1 . Mass spectrum, m/e (relative intensity) : 280 (3) , 206 (100), 164 ( 29 ) , 146 (20), 106 (54), 91 (76) , 77 (14), 65 (24). Elemental analysis Calculated for C 1 " 2 o N 2°2 S 59.96% C; 7.20% H; 9.99% N. Found 60.02% C; 7.14% H; 9.91% N. - - Preparation of N-Acetylnlanine-N'- (3-fluoro) benzylamide. N-Λcetylalanine (3.28 g, 25 mmol) was combined with acetonitrile (100 L) and the mixture was placed into an ice/salt bath at -5°C. Triethylamine (2.53 g, 3.5 L, 25 mmol) was added dropwise followed by the addition of ethyl chloroformate (2.71 g, 2.40 L, 25 mmol) . All additions v/ere done slowly so that the temperature of the mixture did not rise above 0°C. The mixture was then stirred at -5°C for 20 minutes. 3-Fluorobenzylamine (3.58 g, 28 mmol) and acetonitrile (5 mL) was added dropwise and was stirred at -5°C for one hour and then at room temperature for 18 hours. The reaction became homogenous during this time interval. The solution was concentrated in vacuo and the residue was combined witli hot tetrahydrofuran (100 mL) and cooled in the freezer for 3 hours resulting in the formation of a white precipitate. The mixture was filtered and the precipitate was collected, dried _i i vacuo and identified as triethylammonium hydrochloride (3.51 g, mp 253-257°C) . The filtrate was concentrated _i_n vacuo and the resulting yellow solid was recrystallized from chloroform/diethyl ether. Yield: 3.22 g (54%) . mp 120-121°C. " " II NMR (DMSO-dg) : <5 1.27 (d,J = 7.1 iiz , 311) , 1.90 (s, 311) , 4.23-4.41 (m, II!) , 4.33 (d,J = 6.1 Hz, 211), 7.05-7.37 (m, 411) , 8.19 (d,J = 7.1 Hz, III) , 8.53 (t,J = 6.1 Hz, III) . 13 C NMR (DMSO-dg) : 17.9, 22.4, 41.5, 48.5, 113.3 (d,J = 20.4 Hz) , 113.5 (d,J = 21.7 Hz) , 122.8, 130.1 (d,J = 7.9 Hz), 142.4 (d . J = 7.4 Hz) , 162.3 (d,J = 243.6 Hz) , 169.6, 172.8 ppm. IR (KBr) : 3280, 1645, 1545, 1450, 745, 680 cm "1 . -55- Mass spectrum, m/e (relative intensity) : 238 (18 ) , 151 ( 22 ) , 124 (49 ) , 114 (47) , 109 (100) , 87 (76) , 72 ( 27 ) . Elemental analysis Calculated 60.48% C; 6.36% H; * 11.76% N. Found 60.55% C; 6.32% II; 11.71% N. -56- EXAMPLE 14 Preparation of D,L- <__-Acetamido-N-benzyl-3-thiopheneacetamide. D, - θ-.-Λcetamido-3-thiopheneacetic acid (2.99 g, 15 mmol) was combined v/ith acetonitrile (60 mL) and the mixture was placed into an ice/salt water bath (-5 C C) . Triethylamine (1.51 g, 2.10 mL, 15 mmol) was added dropwise, followed by ethyl chlorofor ate (1.63 g, 1.43 mL, 15 mmol). All additions v/ere done slowly so that the temperature of the mixture did not rise above 0 C C. The mixture v/as then stirred at -5°C (20 min) . Benzyla ine (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 iτ\ vacuo and the residue v/as combined with hot tetrahydrofuran (50 mL) and cooled in the freezer (3 h) , resulting in the formation of a v/hite precipitate. The mixture was filtered and the precipitate was collected, dried in_ vacuo, and identified as triethylammonium hydrochloride { II NMR analysis) . The filtrate was concentrated i vacuo and the resulting yellow solid was recrystallized from 1:1 95% ethanol/v/ater. Yield: 1.91 g (44%) . p 198-199°C. 1 H NMR (DMSO-dg) - . 1.91 (s, 311) , 4.29 (d,J = 5.2 Hz, 211), 5.61 (d,J = 7.9 Hz, 1H) , 7.15-7.50 (m, 3H) , 8.55 (d,J « 7.9 Hz, 1H) , 8.74 (t,J = 5.2 Hz, III). 13 C NMR (DMSO-dg): 22.3, 42..0, 52.5, 122.4, 126.1, 126.7, 127.0 (3C), 128.2 (2C) , 139.0, 139.2, 169.0, 169.8 ppm. IR (KBr) : 3460, 1675, 1570, 1400, 720, 695 cm "1 . Mass spectrum, m/e (relative intensity) : 288 (2) , 245 (3) , 155 (88), 112 (100) , 91 (31) , 85 (17), 65 (7) . Elemental analysis Calculated for C.^gN^S 62.48% C; 5.59% H; 9.71% N. Found 62.41% C; 5.47% -II; 9.55% N. -57- EXAMPLE 15 • Preparation of D,L- o.-Acetamido-N-benzyl-2-thiopheneacetamide N-Λcetyl-D,L-ethoxyglycine-N-benzylamide (6.26 g, r 25 mmol) was combined with dry ether (175 mL) and .then boron trifluoride etherate (5.68 g. 5.0 mL, 40 mmol) was added dropwise, resulting in a homogeneous solution. After stirring a short time, a small amount of a yellow oil separated from the solution. Thiophene (8.41 g, 8.0 mL ' , 100 10 mol) was then added dropwise via syringe and the reaction was stirred at room temperature (4 d) . The mixture was cooled, in an ice bath and cold aqueous saturated NaHCO- (200 mL) was added and the aqueous layer was extracted v/ith ethyl acetate (2 x 100 L) . The organic washings and the original ether layer were combined, dried (Na_S0.) , and concentrated • 15 ^ ^ in vacuo. The residue v/as purified by flash column chromatography, using 94:6 chlorofor /methanol as an eluant [R, = 0.7 94:6 chloroform/methanol) , and then recrystallized from benzene. Yield: 2.67 g (37%) . 20 mp 167-169°C. 1 II NMR (DMSO-d r υ) : . 1.91 Is, 311) , 4.31 (d,J = 6.0 Hz, 211), 5.74 (d,J = 7.9 Hz, III), 6.99-7.44 (m, 811), 8.64 (d,J = 7.9 Hz, III) , 8.85 (t,J = 6.0 Hz, III) . 13 C NMR (DMSO-d 5 o,) : 22.4, 42.3, 52.2, 125.6, 125.8, 126.6, 126.9, 127.3 (2C) , 128.3 (2C) , 139.0, 141.4, 169.2, 169.3 ppm. Mass spectrum, m/e (relative intensity) : 289 (2) , 181 (6) , 155 (100), 112 (100) , 91 (100) , 85 .(34) , 74 (24) . Elemental analysis 0 Calculated for C 1,5 r Hl-b,N λ_02_S 62.48% C; 5.59% H; 9.71% N. Found 62.64% C; 5.73% H; 9.61% N. 5 -58- EXAMPLE 16 Preparation of D,L- &-Acetamido-N-benzyl-2-furanaceta ide. N-Λcetyl-D,L-2- (2-furyl)glycine (0.47.g, 2.56 mmol) was combined with acetonitrile (10 L) 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 L, 2.56 mmol) was added dropwise beween -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 L, 2.82 mmol) was carefully added. During the addition of benzyiamine 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 then concentrated _in vacuo. The residue v/as then triturated v/ith hot tetrahydrofuran (5 mL) , cooled at -16°C (3 h) , and the resulting white precipitate was filtered and identified as triethylamine hydrochloride I 1 !! NMR, 60 MHz, δl.00 (t,J = 7.5 Hz, CH j ), 2.82 (q,J « 7.5 Hz, CII-) , 3.83 (s, NH) ) . The filtrate was evaporated to dryness _iή. 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: R 0.-30 (98:2 chloroform/methanol) . p 178-179°C. * l NMR (300 MHz, DMSO-dg) : 81.90 (s, CH.) , 4.31 (d,J = 6.0 Hz, CII_) , 5.58 (d,J = 8.1 Hz, CH) , 6.27-6.33 (m, C * II) , 6.40-6.44 (m, ^ * H) , 7.20-7.36 (m, Ph) , 7.60-7.64 ( , C-'H), 8.57 (d,J - 8.1 Hz, NH)-, 8.73 (t,J = 6.0 Hz, NH) . 13 C NMR (300 MHz, DMSO-dg) : 22.35 (CI^) , 42.27 (CI 2 ), 50.95 (CH) , 107.60 (C- * ) , 110.55 I ^ ' ) , 126.82 (2C 2 " or 2C_"), 127.08 (2C-." or 2_ 3 "), 128.27 (C 4 "), 139.05 (C, ) , 142.58 (C * ) 151.16 (C-'), 168.02 (CH-CO) , 169.30 (NIICO) ppm. -59- IR ( KBr ) : 3230, 1625 (br) ιr.,ς ,. . 890 cm "1 (br) ' 1375 (br) ' 1230 ' l09 °' El e mental analysis C alculated for C H N O ' _-.- -. ^ Found C 15 H 16 N 2°3 66.16 %. C ; 5.83% H; 10.29% N. 65.92% C; 5.83% H; 10.15 % N . 92/216 -60- EXAMPLE 17 Preparation of D,L- c.-Acetamido-N-benzyl-2-pyrroleacetamide. 2-Λcetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) was suspended in anhydrous ethyl ether (60 L) , and -' then boron trifluoride etherate (1.82 g, 1.57 mL, 12.8 mmol) was added in one portion and the resulting solution was stirred (15 min). The pyrrole (2.14 g, 2.22 mL, 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 furnisli a green solid. This material was purified by flash chromatography (95:5 chloroform/methanol) to yield 0.94 g 5 (35%) of the desired product as a white solid: R f 0.29 (96:4 chloroform/methanol) . p 174-175°C. 1 H NMR (300 MHz, CD-CN) : < _ 1.93 (s, CII 3 ) , 4.35 (d,J = 6.0 Hz, CH 2 ) , 5.42 (d,J = 6.9 Hz, CH) , 6.00-6.18 (m, C- j 'H, 20 C 4. • __ " ) , 6.68-6.72 (m, C D * II) , 7.04 (d,J = 6.9 Hz, NH) , 7.17 (t,J = 6.0 Hz, NH) , 7.10-7.47 ( , Ph) , .9.10-9.80 (br s, NH) . 13 C NMR (300 MHz, CD- j CII) : 23.02 (CH 3 ), 43.83 (CH 2 ) , 52.65 (CH) , 107.57 (C--), 108.85 (C 4 ') , 119.33 (C_ * ), 127.96 25 (C 2 * ), 128.01 (2C- * * or 2C 3 "), 128.09 (2_ 2 * * or 2C-") 129.49 (C 4 ") , 140.01 (C-") , 170.94 (COCIL j ) , 171.21 (CONH) ppm. IR (KBr) : 3320, 1570 (br) , 1470 (br) , 1330, 1230, 950, 890, 860, 760, 710, 690, 655 cm "1 . 30 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 C--H 17 3 0 2 271.13208. 35 Found 271.13144. -61- EXAMPLE 18 Preparation of D,L-2-Acetamido-N-benzvl-2-ethoxvacetamide. An ethanolic solution (420 mL) of ethyl 2-acetamido-2-ethoxyacetate (27.92 g, 147 mmol) and benzyiamine (23.70 g, 24 mL, 221 mmol) was stirred at 40-45°C for 3 days. The reaction mixture was evaporated ir 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: R f 0.59 (95:5 chloroform/methanol) . p 153-155°C. II NMR. (300 MHz, CDC1-) : S 1.20 (t,J = 7.0 Hz, CH.) , 2.07 (s, CH 3 ) , 3.60-3.76 (m, CI^CII..), 4.40-4.54 ( , CI^HH) , 5.60 (d,J = 8.7 Hz, CH) , 6.63 (d,J = 8.7 Hz, Nil) , 7.00 (br s, MID , 7.26-7.36 (m, Ph) . C NMR (300 MHz, CDC1 3 ) : 15.06 (CI_ 3 CH 2 ) , 23.25 (CH 3 CO) , 43.60 (CH 2 NH) , 64.51 (CIUCH. , 77.43 (CH) , 127.69 (2C 2 " or 2C 3 '-, C 4 - * ) , 128.79 (2C- - - or 2C 3 - * ), 137.57 (C 1 "), 168.13 (COCH 3 ), 171.29 (CONH) ppm. IR (KBr) : 3260, 1630 (br) , 1550 (sh) , 1505 (br) , 1380, 1360, 123.0, 1115, 1060, 1015, 890, 745, 690 cm "1 . Mass spectrum, m/e (relative intensity) : 251 (4) , 163 (9), 116 (98), 106 (34) , 91 (98) , 74 (100) . Elemental analysis Calculated for C, U,H,15 r H 2_03, 62.38% C; 7.25% H; 11.19% N. Found 62.49% C; 7.27% H; 11.24% N. -62- EXAMPLE 19 Prepar tion of D,L-2-Acetami o-N-benzy1-2-me hoxyacetamide. To a methanolic solution (180 mL) of methyl 2-acetamido-2-methoxyacetate (8.73 g, 54 mmol) was rapidly added benzyiamine (8.68 g, 8.80 mL, 81 mmol) and then the mixture was stirred at 50°C (3 days) during which time a beige precipitate appeared. The solvent was removed iη_ vacuo and the resulting precipitate was recrystallized from tetra¬ hydrofuran (2x) to give 7.67 g (32%) of the desired product as beige crystals: R f 0.35 (95:5 chloroform/methanol) . mp 145-146°C. H NMR (300 MHz, CDCl- j ) : 52.06 (s, CH CO) , 3.37 (s, CH 3 0) , 4.40-4.35 ( , CII 2 ) , 5.52 (d,J = 8.7 Hz, CH) , 7.12 (d,J = 8. " 7 Hz, NH) , 7.20-7.40 (m . Ph, Nil) . 3 C NMR (300 MHz, CDC1 3 ) : 23.03 (CII- j CO) , 43.51 (CH 2 ) , 55.84 {CH 3 0) , 78.94 (CH) , 127.62 (C 4 "), 127.70 (2C_' * or 2C 3 * -), 128.70 (2C 2 '- or 2C 3 ") , 137.45 (C- ") , 166.91 (COCII 3 ), 171.57 (CONH) ppm. IR (KBr) : 1260, 1825 (br) , 1550, 1505, 1435, 1390, 1370, 1230, 1120, 1050, 935, 890, 690 cm "1 . Mass spectrum, m/e (relative intensity) : 237 (1), 205(2), 177 (2) , 163 (4) , 146 (1) , 134 (1) , 121 (2) , Ϊ06 (26), 102 (98) , 91 (95) , 77 (13) , 61 (100) . Elemental analysis Calculated for c 2 H i6 N 2°3 61.00% C; 6.83% H; 11.86% N. 60.91% C; 6.85% H; 11.66% N. -63- E AMPLE 20 pronnrntioi. or rD. Vrr.-Acetnmido-N-bonzyl-Σ-fS-mnthvirurnn^ncctnmide. N-Λcetyl-D.L-cthoxyglycine-N-benzylamide (2.00 g, 8.0 mniol) was suspended anhydrous ethyl ether, and then boron trifluoride etherate (1.82 g, 12.8 mmol) rapidly added, and th ' e resulting solution was stirred for 15 .min. 2-methylfuran (2.63 g, 32.0 mmol) was then added and the reaction was stirred room temperature (3 d). The reaction mixture was poured into an aque 0 saturated NaIICθ3 solution and extracted with ethyl acetate (3 x). The et acetate extracts were combined, dried (Na2Sθ4) and evaporated jn ypcuσ to giv beige solid, which was purified by flash chromatography (9 chloroform/methanol) to give the desired product as a white crystalline solid. 5 Yield: 1.40 g (61%) R 0.25 (98:2 chloroform/methanol). mp 148-150 °C. o 1 H NMR (DMSO-dG. δ 1.88 (s, CII3 CO), 2.23 (s, CII3), 4.24-4.3G (m, CII2), 5.49 (d = 8.0 Hz, CII), 6.01 Cbr s, C -II), 6.14 (d, J = 2.4 Hz, C4Η), 7.20-7.31 (m. Ph), 8.52 J =8.0 Hz, Nil), 8.69 (t, J = 5.6 Hz, Nil). !3c NMR CDMSO-d 6 ) 13.44 (CH3), 22.35 CCH3CO), 44.11 (CH 2 ), 53.23 (CH), 107. (C3- or C4 , 110.40 (C3 > or C4 , 128.13 (C40, 128.18 (2C2" or 2C3O, 129.43 (2C or 2C3"), 139.69 (Cι « ), 149.18 (C 2 ' or C5 , 153.81 (C 2 - or C5 , 170.78 (CH3C 173.03 (CONH) ppm. IR (IO3r) 3270, 1620 (br), 1520 (br), 1440, 1300, 1210, 1010 cm" 1 . Mass spectrum, m/e (relative intensity) 286 (3), 179(8), 153 (57), 152 (57), 111 ( 110 (100), 97 (23), 91 (31). Elemental Analysis Calculated: 67.12% C; G.34% H; 9.78% N. Found: 66.92% C; - 6.52% If; 9.52% N. -64- EXAMPLE 2_ .Preparation of (D.T. .-r. -A cc π m i o- N-b e ιr_. yI -2- cn zofii rn .i n cc ln i.-Acetyl-D,L-ct oxyglycine-N-bcnzylamide (1.00 g, 4 mmol) was suspend anhydrous ethyl ether (30 mL) and then boron triΩuoride etherate (0.91 mmol) was rapidly added, and tlie resulting solution was stirred for 15 rain. benzofuran (1.89 g, 16 mmol) was then added and tlie reaction was stirred at temperature (3 d). The reaction mixture was poured into an ice-cold satu aqueous solution of NaIICθ3, and tlιen tlie mixture was maintained at temperature for an additional 15 min. The mixture was extracted with acetate (2 x), and the organic layers were combined, dried Na2SO4) evaporated in vacuo. The residue was purified by flash cliromntography ( chloroform, then 99:1 chloroform/methanol) to yield the desired product. Yield: 0.43 g (33%). Rf 0.30 (98:2 cliloroform metlianol). • mp 195-195 °C; !__ NMR (DMSO-dc) δ 1.94 (s, CII3CO), 4.34 (d, J = 5.7 Hz, CII 2 ), 5.77 (d, J = 8 CH), 7.24-7.32 (m, C3 -I. C5Η. C G -II, P ). 7.54 (d, = 7.0 Hz, C4 II or Cyll), (d, J = 7.0 Hz, C -i-II or Cyll), 8.74 f ' . J = 8.1 Hz, Nil), 8.86 (t, J = 5.7 Hz, Nil). 3C NMR (DMSO-d 6 ) 22.27 (CH3CO), 42.30 (CH 2 ), 51.22 (CH), 104.34 (C3 , 1 (C7 , 121.05 (C4 , 122.90 (C5 , 124.28 (C G , 126.73 (C 3 - a ), 127.01 (2C 2 » or 127.69 (2C2" or 2C3 » ), 128.14 (C4O, 138.87 (Cι » ). 154.10 (C 7 - a ), 154.30 (C2 , - (CH3CO), 169.26 (CONH) ppm. IR (KBr) 3230, 1625 (br), 1520 (br), 1440, 1090, 1085, 890, 735, 690 cm" 1 ; Mass spectrum, m/e (relative intensity) 322 (5), 279 (1), 264 (1), 234 (1), 215 ( '45), 146 (100), 130 (11), 118 (7), 91 (87), 65 (16). High resolution mass spectrum, Calcd for CιgHι 8 N 2 θ3 322.1317. Found 322.1318. -65- EXAMPLE 2 Prennrntion of rD.L)-α-Acetn πιido-N-bcnzvI-2-bcnzoπ. Uhiopheneace nmide N-Ace.yl-D.L-ethoxyglycine-N-benzylamide (1.00 g, 4 mmol) was suspended i anhydrous ethyl ether (15 mL) and then boron trifiuoride etherate (0.91 g, 6. mmol) Λvas rapidly added, and the resulting solution was stirred for 15 min. Th benzo[b]thioρhene (2.14 g, 16 mmol) was then added and tlie reaction was stirre at room temperature (3 d). Tlie solution was poured into an ice-cold saturate aqueous solution of NaIICθ3, and then stirred for 15 min at 0 °C. The mixtur was extracted with ethyl acetate (2 x), and the organic layers were combine dried (Na2SU ) and evaporated in vnctio to give an orange oil. The oil wa triturated with ethyl ether to yield a crystalline product which was filtered an further purified by flash chromatograpby (99:1 chloroform/methanol) to give th desired product. Yield: 0.06 g (4%). o Rf 0.32 (99:1 .chloroform/methanol). mp 226-227 °C. ll NMR (DMSO-de) δ 1.94 (s, CII3CO). 4.34 (d, J = 5.7 Hz, CII 2 ). 5.86 (d, J = 8. Hz, CII), 7.20-7.38 (m, C 3 -II, C G -II, C7Η. Pb ). 1.11-1. B0 (m, ' C 'II or C5Η 5 7.89-7.93 (m, C -II or C 5 'II), 8.76 (d, J = 8.1 Hz, NH), 8.97 (t, J = 5.7 Hz, NH). 13C NMR (DMSO-d 6 ) 22.34 (CH3CO), 42.38 (CH 2 ), 52.70 (CH), 122.15 (C 4 - or C7 122.32 (C4' or C7-). 123.45 (C3 . 124.37 (C 5 « or C G , 124.41 (C 5 - or C G , 126.8 (C4O, 127.27 (2C 2 " or 2C 3 O, 128.27 (2C 2 " or 2 C3"), 138.84 (C ' a or C 7 < a ). 138.9 ° (C3' a or C7' a ). 142.58 (Cy), 168.65 (CII3CO), 169.12 (CONH) ppm. [A distinc signal for the C2' carbon was not detected and .is presumed to coincide with th C_p carbon at 142.58 ppm.]. IR(KBr) 3240, 1610 (br), 1510 (br), 1420, 1360, 1215, 1085, 885, 730, 710, 685 cra"l. 5 Mass spectrum, m/e (relative intensity) 338 (8), 295 (2), 205 (76), 162 (100), 135 (22 10S (12), 91 (59). Elemental Analysis: Calculated: (• 7.43% C; 5.36% II; ' 8.28% N. Found: G 7-21%C; 5.37 %H; 8 . 12%N> O 92/21 -67- 1 EXAMPLE 23 Pren ' nrn tion of (D.D-α - A c c tn m i d o - N - 1) c n yl - - i n d o 1 c a r.c n m i N-Λcetyl-D.L-ethoxyglycine-N-benzylamide (0.69 g, 2.75 mol) was suspende 5 anhydrous ethyl ether ( 20 mL) and then boron trifluoride etherate (0.63 g, 4 mmol) was rapidly added, and the resulting solution was stirred for 15 min. indole (1.30 g, 11.00 mmol) was then added and the reaction was stirred at ro temperature ( 22 h). Petroleum ether (35-60 °C) was added to the reaction, 0 the resulting semϊsoHd material filtered, and washed with petroleum ether (35 °C). Purification of the reaction mixture was accomplished by fl chromatography (98:2 chloroform/methanol) to produce the title compound a -, _- white solid. Yield: 0.25 g (18%). Rf 0.14 (95:5 chloroform/methanol) p 213-214 °C. 20 *H NMR (DMSO-d G ) δ 1.90 (s, CII3CO), 4.30 (d, J =6.0 Hz, CII 2 ), 5.72 (d, J = 7.2 CII), 6.90-7.37 (m, P , C 2 -II), 7:02 (dd, J = 7.5 Hz, J = 7.5 Hz, Cg-II or C 6 -II), 7 (dd, J= 7.5 Hz, J = 7.5 Hz, C 5 'II or C G -II), 7.39 (d, J= 7.5 Hz, C 4 'II or Cyll), 7.65 J = 7.5 Hz, C_$'II or C 7 -H), 7.86 (d, J = 7.2 Hz, NTIH). 8.13 (t, J = 6.0 Hz, NIICH 2 5 10.30-10.80 (br s, NH). 3C NMR (DMSO-dc) 22.32 (CH3CO), 42.23 (CH2), 49.98 (CH), 111.51 (C 7 , 112. (C3 , HS.76 (C 4 - or C G . 119.24 (C 4 - or C G '), 121.37 (C5 , 123.94 (C 2 •), 126.58 (C 3 126.71 (C4-). 127.33 (2C 2 " or 2C3O, 128.18 (2C2" or 2C3O, 136.28 (C ^ , 139 30 (Cι « ).169.13(CH3CO), 170.81(COMI)ppm. IR(I_Br)3260, 1610(br), 1515(br), 1450, 1420, 1370, 1350, 1235, 1095,895, 735, 695,600cm- 1 . Mass spectrum, m/e (relative intensity) 321 (5), 278 (1), 264 (1), 233 (1), 214 (6), 35 (85). 171 (3), 145 (100), 118 (18), 91 (39). Elemental Anal3'sis: Calculated: 71.01% C; 5.96% H; 13.06% N. Found: 70.87% C; 6.15% II; 12.78% N. -69- - J - EXAMPLE 24 Preparation of (D. L)-c_-Accta nii o-N-benzyl-2-(..-metlivh)yrrole)nccta N-Λcetyl-D,L-cthoxyglycine-N-bcnzylamide (2.00 g, $ mmol) was suspe ^ in anhydrous ethyl ether (175 mL), and then boron trifluoride etherate (1.38 mmol) was added and the resulting solution stirred (15 min). 2-methyIpyrrole (0.85 g, 10 mmol) was then added and tlie reaction mixtur stirred under N (6 d), during which time tlie color of tlie reaction mixture t 0 reddish brown and a dark-brown deposit formed at the bottom of fhe flask. clear solution was decanted and treated with an aqueous saturated Na solution containing ice (100 mL) for 30 min. The aqueous reaction mixture extracted with ethyl acetate (3 x 30 mL). The combined extracts were 5 (Na2S0 ) and the solvent removed in vacuo. The brown oily residue was pu by flash column chromatography using 98:2 chloroform/methanol as the elue yield the desired compound. The product was r.crystallized from acetate/hexane to give a light 3'ellow amorphous solid. Yield 0.20 g (94%) Rf 0.44 (95:5, chloroform/methanol). p 167-168 °C. H NMR (DMSO-d G ) δ 1.87 (s, CII3). 2.13 (s, COCII3), 4.27 (br s, CII 2 ), 5.33 (d 7.4 Hz, CII). 5.60 (s, C4II), 5.77 (s, C3II), 7.19-7.30 (m, 5 PIiII), 8.22 (d, J = 7. Nil). 8.45 (t, J = 5.5 Hz, Nil). 10.3S (s. NH). 3C NMR (DMSO-d G ) 12.74 (CII3). 22.49 (COCII3). 42.11 (CH 2 ), 51.21 (CII), 10 (C4), 10G.07 (C3), 126.16 (C5), 126.64 (C4-). 126.85 (C 2 ), 127.09 (2C 2 - or 2C 3 , 12 (2C 2 ' or 2C3 , 139.33 (Ci * ), 168.SS (COCH3), 169.79 (CONH) ppm. IR(KBr) 3250, 1630, 1520, 1420, 1360, 1300. 1260, 1230, 1160, 1110, 1020 cm'l. Mass spectrum, m/e (relative intensity) 285 (M + , 10), 178 (20), 152 (24). 151 ( 110 (12), 109 (93), 108 (22), 107 (25), 94 (16), 91 (43). Elemental Analysis: Calculated: 67.35% C; 6.71% II; 14.73% N. Pound : 67.57 %C: 6.90% H; 14.52% N. 92/21648 -71- - Synthesis of Unsubstituted and- Sub.stitιιtcd-σ-Λ cc tarn irIn-N-benzy furnnπcel amides. .General Procedure. 4-Methylmorpholine (1 equiv) was added to a solutio ς α-acetamido-2-furanacetic acid (1 equiv) in dry tetrahydrofuran (75 mL 10 m at -10 to -15 °C under N2. After stirring (2 min), isobutyl chloroformate (1 eq was added leading to the precipitation of a white solid. Tlie reaction was allo to proceed for 2 additional minutes and then a solution of the substit 0 benzyiamine (1 equiv) in tetrahydrofuran (lOmL/lO mmol) was added over 5 a -10 to -15 °C. The reaction mixture v/as allowed to stir at room temperatur 5 min and then the 4-methylmorpholine hydrochloride salt filtered. The org layer was concentrated in vacuo. and the residue was triturated witli e 5 acetate, and the remaining white solid filtered. Concentration of the ethyl ace layer led to additional amounts of the white solid. The desired product purified by either recrystallization, or flash chromatography of the combined s material. Examples 25-32 were prepared according to 0 this " procedure . 5 0 5 -72- EXAMPLE ? .. • ( D. L- . -α- A cctamido-N-bcnzyl-2-f ran acetamide. Using benzyl ami ne (0.27 g, 2.56 mmol) and rac α-acctamido-2-furanacetic acid (0.47 g, 2.56 mmol) gave the desired compo The product was recrystallized from ethyl acetate to give a white solid. Yield: 0.46 g (65%) Rf 0.30 (98:2 chloroform/methanol). mp 177-178 °C. !H NMR GDMSO-dβ) δ 1.90 (s. CII3), 4.31 (d, J = 6.0 Hz, CII ), 5.58 (d. J = 8. CII), 6.27 - 6.33 (m, C3II). 6.40 - 6.44 ( , C4II) . 7.20 - 7.36 (m. 5 Phil), 7.60 - 7. C5II), 8.57 (d, J = 8.1 Hz, Nil), 8.73 (t, J = 6.0 Hz, NH). 92/21648 _ 73 _ EXAMPLE 26 1 fD.T,-)-rt-Acetamido-N-r2-fiuoroI)enzyl)-2-furanacctam?de. Using 2-fluorobenzylamine (1.13 g, 9.0 mmol) and race 5 α-acetamido-2-furanacetic acid (1.50 g, 8.2 mmol) gave the desired product. Yield: 1.20 g (50%). Rf 0.36 (96:4 chloroform/methanol). mp 193-195 °C (recrystallized from EtOAc). 0 iH NMR (DMSO-dg) δ 1.89 (s, COCI_3), 4.33 (d. J = 5.5 Hz, CII 2 ), 5.58 (d, J = 8.0 CH), 6.28 (s, C II), 6.29 (s, C3II), 7.62 (s, C5H), 7.13-7.35 (in, 4 Λrll), 8.61 (d, J= Hz, Nil), 8.76 (t, J = 5.5 Hz, Nil). 1 c NMR (DMSO-d G ) 22.35 (COCII3), 36.12 (d. JQF = ^ Hz. CH 2 ), 50.88 (C l 107.64 (C4), 110.43 (C3), 115.04 (d, JQF= 21.4 PIz, C3 , 124.29 (d, JQF = - 2 Hz, 125.64 (d, JcF = 15-0 Hz, Cr), 128.94 (d. JcF = 9-0 Hz, C 4 - or C G , 129.27 (d, J 5.5 Hz, C4' or Cy), 142.66 (C5). 151.07 (C2), 159.99 (d, JQF = 244.4 Hz, C2 . 108 (COCH3), 169.24 (CONH) ppm. 20 mα0 r) 3270, 1630, 1520. 1440, 1360, 1220, 1180, 1140, 1100, 1000, 740 cm "1 . Mass spectrum, m e (relative intensity) 291 (M++1, 3), 274 (2), 247(3), 165 (4), (10). 139 (98), 138 (46). 126 (7). 110 (10). 109 (65), 97 (93), 96 (100). c __ Elemental Analysis: Calculated: 62.02% C; 5.21% II; 9.65% N. Found: 62.20% C; 5.19% H; 9.69% N. 30 35 -74- Λ EXAMPLE 27 • ■ D. .-α-Acc .nnιido-N- .3-πιιorobcn7.yl .-2-furπnncctamidc. Making use of 3-fluorobenzylamine (1.13 g, 9.0 mmol) and race 5 ' ' σ-acctamido-2-furanacetic acid (1.50 g, 8.2 mmol) gave the desired product. Yield 1.90 g (80%). Rf 0.30 (96:4 chloroform/methanol). 0 m P 163-165 °C (recrystallized from ethyl acetate). *H NMR (DMSO-d G ) δ 1.89 (s, COCII3), 4.31 (d, J = 5.5 Hz, Cπ 2 ). 5.55 (d, J = 7.8 CII), 6.31 (s, C4II), 6.42 (s, C3II). 6.98-7.37 (m, 4 Λrll), 7.62 (s, C5II), 8.61 (d, J = Hz, Nil), 8.70 (t, J = 5.5 Hz, Nil). 15 3c NMR (DMSO-dg) 22.35 (COCIJ3), 41.71 (CH 2 ). 51.01 (CH), 107.73 (C4), 110 (C3), 113.50 (d, JcF = 21.6 Hz, C2 1 or C4 , 113.60 (d, JcF = " 22.3 Hz, C2' or 122.95 (br, C G , 130.18 (d, J C F = 8.G Hz, Cδ . 142.21 (d, J C F = 7.5 Hz. Ci'). 142 (C ), 151.03 (C 2 ). 162.2S (d. J C F = 2-13.3 Hz. C3 , 16S.23 (COCH3). 169.31 (CO 2C ppm. IR (KBr) 3230. 1630, 15-10, 1440. 1360. 1220, 1140. 1000, 730 cm "1 . Mass spectrum, m/e (relative intensity) 290 (M+,71), 231 (7), 165 (18). 140 (23), (100), 126 (16), 109 (6). 97 (118), 96 (100), 96 (30). 2. Elemental Analysis: Calculated: 62.027. C; 5.21% H; 9.65% N. Found: 61.97% C; 5.35% H; 9.53% N. 30 35 -75- E AMPLE 28 ( D. T..-α-Amt .ιm?do-N-(4-πunrohp nzγl)-9-rπranacctamide. Using racemic α-acetamido-2-furanacetic acid (1.50 - g, 8.2 mmol) an 4-fluorobenzylamine (1.13 g, 9.0 mmol) gave the desired product. Yield 2.10 g (88%). Rf 0.30 (96:4 chloroform/methanol). mp 188-190 °C (recrystallized from ethyl acetate). iHNMR (DMSO-d 6 ) δ 1.88 (s, COCII3), 4.27 (d, J = 5.5 Hz, CII2), 5.55 (d, J = 8.0 Hz CH) , 6.27 (s, 1H) , 6.41 (s, III) , 7.09-7.15 (m, 2ArH) , 7.12- 7.27 (m, 2 Aril) , 7.61 (s, HI) , 8.58 (d, J = 8.0 Hz, NH) , • 8.75 ( t, J = 5.5 Hz, NH) . 13 C NMR (DMSO-d 6 ) 22.28 (COCH3), 41.51 (CH2), 50.87 (CH), 107.52 (C4), 110.46 (C3), 114.90 (d, JcF = 21.1 Hz, C3 , 129.48 (d, JcF = 8-3 Hz, C2 . 135.23 (d, JcF 3.2 Hz, Ci » ), 142.53 (C5), 151.08 (C2). 161.12 (d. JCF = 242.2 Hz, C4 , 167.9 (COCH3), 169.13 (CONH) ppm. IR (KBr) 3230, 1620, 1500. 1360. 1220. 1260, 1210, 1140, 1000, 820, 780, 730 cm *1 . Mass spectrum, m/e (relative intensity) 291 (M++1, 4), 165 (4), 140 (9), 139 (92), 13 (52), 124 (6), 109 (71). 97 (60), 96 (100). Elemental Analysis: Calculated: 62.02% C; 5.21% H; 9.65% N. Found: 61.76% C; 5.41% H; 9.43% N. -76- EXAMPLE 9 • ( P. Vnc-Acctam?do-N- ( 2.5-fππuorohπn7.yl -2-furanacetamide. Using 2, 5-difluorobenzylaraine (1.30 g, 9.0 mmol) and race c.-acetamido-2-furanacetic acid (1.50 g, 8.2 mmol) gave the desired product. Yield 1.60 g (64%). Rf 0.38 (96:4 chloroform/methanol). p 177-178 °C (recrystallized from ethyl acetate). *H NMR (DMSO-d 6 ) δ 1.89 (s, COCH 3 ), 4.31 (d, J = 5.5 Hz, CH 2 ), 5.55 (d, J = 7. Cπ), 6.32 (s, C4II), 6.43 (s, C3II), 7.22-7.25 (m, 3 Aril), 7.62 (s, C5II), 8.62 (d. J Hz, Nil), 8.78 (t, J= 5.5 Hz, Nil). 13 c NMR (DMSO-d 6 ) 22.30 (COCH3), 35.98 (d, JcF = 5.8 Hz, CH 2 ), 51.02 ( 107.81 (C4), 110.58 (C3), 115.06 (dd, JcF = 19-5, 25.6 Hz, C3< or ' c G , 115.16 (dd, = 15.6, 24.7 Hz, C3 « or C G , 116.52 (dd, cF = 10.1, 23.9 Hz, C4 , 127.98 (dd, J 9.2, 17.7 Hz, Ci'). 142.69 (C5). 150.78 (C2), 155.89 (d, JcF = 239.0 Hz. C 2 ' or 158.18 (d, CF = 238.8 Hz. C 2 ' or C5 . 168.3S (COCH3), 169.35 (CONH) ppm. IR GvBr) 3230, 1620, 1520. 1480, 13G0, 12G0, 1230, 1180, 1140. 1000, 860, 810, 730 cm * *. Mass spectrum, m/e (relative intensity) 309 (M++1, 1), 266 (1), 222(1), 165 (5) (5), 139 (61), 138 (36), 127 (37), 97 (44). 96 (100). Elemental Analysis: Calculated: 58.44% C; 4.58% H; 9.09% N. Found: 58.68% C; 4.69% H; 8.877_- N. __ 7 _ EXAMPLE 30- 1 - CD. ) -r_-Acctamido-N- ( 2.6-diπιιorohp.ηzyl)-2-furaπacctamide. Making use of 2,6-difluorobenzylaιr ne (1.-30 g, 9.0 rmol) and racemic -acetaιαido-2-furanacetic acid (1.50 g, 8.2 irmol) the desired product was f 5 Yield 1.90 g (73%). mp 237-239 °C (recrystallized from ethanol). *H NMR (DMSO-dβ) δ 1.86 (COCII3), 4.33 (d, J = 4.5 Hz, CII 2 ) . 5.53 (d, J = 8.3 CII), 6.17 (s, C4II), 6.38 (s, C3II), 7.05-7.10 (m, 2 Λrll), 7.36-7.41 (m, 1 Λrll), 7.60 0 C5II), 8.52 (d, J = 8.3 Hz, Nil), 8.66 (t, J = 4.5 Hz, Nil). 1 C NMR (DMSO-dβ) δ 22.33 (COCII3), 30.74 (t, J " CF = 4.4 Hz, CH 2 ), 50.48 (C 107.24 (C4), 110.40 (C3), 111.61 (dd, Jc = 8- , 25.1 Hz, C 3 ', C5 . 113.67 (t, J C 19.5 Hz, Ci , 129.98 (t, J C p = 10.5 Hz, C4 , 142.50 (C5), 151.23 (C 2 ), 160.93 ( , J = 248.1, C 2 ' or C G . 161.10 (d, JcF = 248.1 Hz, C 2 ' or C G , 167.59 (COCH3), 169 (CONH) ppm. IR (KBr) 3230, 1620. 1530, 1460, 1360, 1320, 1260, 1220, 1160, 1140, 1030, 1000, 0 7. 80, 750, 740, 710 cm' 1 . Mass spectrum, m/e (relative intensity) 309 (M++1, 4), 265 (2). 165 (4), 147 (7), (S), 139 (87), 13S (36), 127 (54), 97 (58). 96 (1C0). Elemental Analysis: _, Calculated: 58.44% C; 4.58% H; 9.09% N. Found: 5S.62% C; 4.74% II; 8.99% N. - EXΛMPLE 31 ( O ) - ( - ) -A(;ctnmi(lo-N-henzyl-2-furanacetamide. Starting with D-α-acetamido-2-furanacctic acid (2.45 g,* 13.38 mmol) an 5 . benzyiamine (1.43 g, 13.38 mmol), the desired product was obtained. Yield: 2.54 g (70%) The product was further recrystallized from ethyl acetate t give the title compound. Yield: 2.30 g mp 196-197 °C. -C _ 2G ]-)r c _ -^ MeQH] = -78.3°. Addition of R(-)-mandelic acid to a CDCI3 solution the product gave only one signal for the acetamide methyl protons. 3.5 Mass spectrum, m/e (relative intensity) 272 (M + , 2), 184 (2), 165 (2), 140 (8), 139 (88 138 (34), 97 (46), 96 (100), 91 (63). Elemental Analysis: Calculated: 66.16% C; 5.92% H; 10.29% N. 20 Found: 66.09% C; 6.01% H; 10.38% N. 25 30 35 A EXAMPLE 32 .! ) - ( . . -ft- A_ p _amido-N-bcnzyl-2-furannrr . mide. Using L-α-acetamido-2-furanacetic acid (2.83 g, 15.46 mmol) and 5 benzyiamine (1.65 g, 15.46 mmol) gave 3.80 g of the enriched desired product. ^11 NMR analysis with R(-)-mandelic acid showed that it was greater than 80% enriched in the title compound. The pure L-enantiomer was obtained by recrystallization from absolute ethanol. Yield: 1.60 g. mp 196-197 °C. [cc) 26 D[c = 1, MeOH] = +79.0°. Mass spectrum, m e (relative intensity) 273 (M+ + 1, 3), 229 (2), 214 (2), 184 (1). 165 (7), 157 (4), 140 (33), 139 (100), 138 (95), 97(98), 96 (100), 91 (98). Elemental Analysis: Calculated: 66.16% C; 5.92% H; 10.29% N. Found: 65.89% C; 5.86% H; 10.42% N. _ 80 _ 1 EXAMPLE 33 Resolution of (D, L)-,A-Λcetamido-2-furanacetic acid Using (R)-(+)-_/ N -Methylbenzylamine (13.22 g, 0.11 mol) was added to an absolute ethanol solution (550 mL) of racemic ".-acetamido- 2-furanacetic acid (20.00 g, 0.11 mol). The resulting solution was cooled in the freezer overnight. The white precipitate 10 (12.00 g) which separated upon cooling was filtered/ and the mother liquid evaporated to give a salt which was later used for obtaining L- .-acetamido-2-furanacetic acid. The initial salt was recrystallized (3 x) from, absolute ethanol ■ 15 to yield 4.00 g of the pure diastero eric salt, p 173-175°C. „_ Elemental Analysis Calculated: 63.14% C; 6.62% H; 9.21% N. Found: 63.19%'C; 6.62% H; 9.12% N. The purified salt was treated with 5% aqueous NH.OH solu' on. 5 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 yield 2.45 g(25%) of D-o<- -acetamido- 2-furanacetic acid. 30 mp 169-171 β C. Elemental Analysis: Calculated: 52.46% C; 4.95% H; 7.65% N. 35 Found: 52.17% C 4.09% _J; 7.56% N. The salt obtained after evaporation of the main mother liquor was hydrolysed with 5% aqueous NH.OH solution to give 10.10 g of the enriched L-c.-acetamido-2-furanacetic acid [l*] D[c=l,_ NeOH] = +.7.7°]. (S)-(-) -me hylbenzylamine (6.70 g, O.055 mol) was added to a solution of enriched L-_ -acetamido- 2-furanacetic acid (10.10 g, 0.055 mol) in absolute ethanol (275 mL). The white precipitate of the diasteroe eric salt (8.10 g) that separated upon cooling the solution in the 10 freezer (1 h) was filtered. The salt was recrystallized from absolute ethanol (3 x) to yield 3.00g of the salt/ mp 172-174 6 C. _>fi Λ & ] D[c=l. MeOHj^+106 *5 . • 15 Elemental Analysis: Calculated: 63.14% C; 6.62% H; 9.21% N. Found: 63.18% C; 6.47% H; 9.00% N. 20 The salt from the third recrystallization was treated with a 5% aqueous NH.OH solution and extracted with ethyl ether (3 x 50 mL)/ and then acidified with a 8.5% aqueous solution of H,P0 and then extracted with ethyl acetate (3 x 100 mL) to give 1.63g (32%) of L-. -acetamido-2-furanacetic acid. mp 169-171°C. 30 5 _ - EXΛMPLE 34 Enzymatic Separation of D(-)°<-acetamido-2-furanacetic acid (R from DL ( " 1 )σ -acetamido-2- uranacetic acid. DL (i) c. -acetamido-2-furanacetic acid (2.00 g, 10.9 mmol) was suspended in deionized H_0 (600mL). An aqueous solution of LiOH (IN) was added to this suspension dropwise until all of the acid had dissolved and the pH was 7.2-Acylase 1, Grade II (20 mg, activity = 900 units/mg, Sigma Chemical Company, Cat. No. A 8376) was then added to the above solutio o and the mixture stirred at 34-37- C (41h). The suspension was then cooled to room temperature and acidified to pH 1.5 with aqueous IN HCl. The suspended material was filtered, and the filtrate was saturated with solid NaCl, and then extracted with ethyl acetate (3x250 mL). The combined ethyl acetate extracts was dried (Na-SO.). The solvent was removed in vacuo and the residue was triturated with ethyl acetate (lO L). The white solid (0.75 g) that remained was' filtered and was pure D(-)o( - acetamido-2-furanacetic acid; mp 168-169 mixed p ith an authentic sample 168-169°C; (c . MeOH] =-184.3" _ . -O J- 1 EXAMPLE 35 Pre p aration of π. -π-Acctamido-Σ-fui-anacctic Acid. Λn ethereal solution of ZnCl2. 1 N, 28 mL, 0.028 mol) was added to a stirre ς solution of ethyl acetamido-2-bromoacetate (4.40 g, 0.019 mol) and furan (11.23 0.165 mol) in dry tetrahydrofuran (100 mL), and allowed to stir at roo temperature (5 h). The mixture was then treated with H2O (50mL), the organi phase separated, and the aqueous layer extracted with CH2CI (2 x 100 mL). Th 10 organic layers were combined, dried (Na2SO- and the volatile materials wer removed by distillation in vacuo to give approximately 4.00 g (97%) of light-brow semi-solid material. TLC analysis showed a major spot at Rf 0.30 (99: chloroform/methanol). The desired compound, D ,L-elhy - -5 α-acetamido-2-furanacetate, was purified by flash column chromatography o silica gel using 99:1 chloroform/methanol as the eluent to give 3.60 g (87%) of beige solid. mp 68-70 °C. 20 D, L-Ethyl cc-acetamido-2-furanacetate (4.00 g, 19 mmol) was dissolved i 90:10 ethanol/water (150 mL) and then KOH (2.00 g, 35 mmol) was added and th resulting solution stirred at room temper_._ure (48 h). The reaction wa concentrated in vacuo and the residue diluted with H2O and then washed wit ethyl ether (3 x 50 mL). The aqueous layer was then made acidic with a 8.5 aqueous solution of H3PO4 and extracted with ethyl acetate (3 x 150 mL). Th 0 organic layers were combined, dried (Na2S04), evaporated to dryness in vacuo t give the desired compound. Yield: 2.65 g (76%). Rf 0.37 (8:1:1 isopropanol NH.iOH/ II2O). 5 mp 172-174 °C. O 92/21648 _ 84 _ α EXAMPLE 36 Synthesis of .D.T.)-2-Acctnmido-4-pcntc;ήo?c Acid-N-hcnzylnmidc. 4-Methylmorpholine (0.55 g, 5.40 mmol) was added to a stirred solutio 2-acetamido-4-pentenoic acid (0.81 g, 5.18 mmol) in dry tetrahydrofuran (60 mL 5 -10 to -15 °C under N2. After stirring (2 min), isobutyl chloroformate (0.75 g, 5 mmol) was added leading to the precipitation of a white solid. The reaction allowed to proceed for 2 additional minutes and then a solution of benzyiam (0.61 g, 5770 mmol) in tetrahydrofuran (10 mL) was added slowly at -10 to -15 After stirring (5 min) at room temperature, the insoluble salt was removed filtration. The filtrate was evaporated to dryness and the residue was tritura with ethyl acetate, and the remaining white solid was filtered to yield the desi 5 product. Yield 0.81 g (64%). Rf 0.36 (4% methanol/chloroform). mp 118-120 °C (recrystallized from ethyl acctatc/cyclohcxane). 20 lH NMR (DMSO-dG) δ 1.83 (s, COCII3), 2.22-2.49 (m, CIl2CH=CH 2 ), 4.26 (d, J = Hz, CII2 Ph), 4.25-4.33 (m, CII), 4.99-5.09 ( , CH2CH=Cir 2 ), 7.21-7.29 (m, 5 Ph 8.05 (d, J = 7.6 Hz, NH), 8.46 (br s, Nil). • 13c NMR (DMSO-d 6 ) 22.41 (COCH3), 36.24 (CH 2 CH=CH 2 ), 41.91 (CH 2 Ph), 5 25 (CH). 117.15 (CH 2 CH=CH 2 ), 126.54 (C4 , 126.99 (2C 2 - or 2C 3 , 128.04 (2C 2C 3 , 134.25 (CH 2 CH=CH 2 ). 139.22 Ci . 1G9.02 (COCH3), 170.96 (CONH) ppm Mass spectrum, m e (relative intensity) 246 (M+, 4), 205 (4), 163 (15), 140 (8), 10 (33), 91 (77), 70 (100). 30 Elemental Analysis: Calculated: 68.27%C; 7.37% H; 11.37% N. Found: 68.55% C; 7.31% H; 11.48% N. 35 Mass spectrum m/e (relative intensity) 2.92 (M++1. 1), 233 (8). 158 (19). 157 ( 100) • HO (26). 115 (100), 106 (29), 91 (72). Elemental Analysis: Calculated: 61.84% C; 7.26% H; 14.42% N. Found: 61.67 % C; 7.10% H; 14.14% N. _ 86 _ EXAMPLE 37 S y nthesis of (D.T.)-2-Acetπmido-N-bcιτ/.yl-2-(l-morτ.ho]ine)acctnmide. Λ mixture of ethyl 2-acetamido-2-(l-morpholine)acetate (0.59 g, 2.56 mmol), benzyiamine (0.28 g, 2.82 mmol) and sodium cyanide (0.01 g, 0.26 mmol) in methanol (5 mL) was stirred at 50-55 °C for 18 hr. The solvent was removed in y. C Q and the residue triturated with ethyl acetate (5 mL). The white solid (0.35 g) that remained was collected by filtration and identified as the desired compound. The . filtrate was concentrated and the residue purified by flash column chromatography (2% methanol/chloroform) on Siθ2- The initial fractions gave a trace amount (0.09 g) of (D,L)-2-acetamido-N-benzyl-2- (N-benzylamine)acetamide. Continued elution gave additional amounts (0.20 g) of the title compound. . J 5 (D,L)-2-Λcetamido-N'benzyl-2-(N-bcnzylamine)acctamide: Yield: 0.09 g (11 %). mp 135-138 °C. H NMR (DMSO-d 6 ) δ 1.83 (s, COCII3), 3.56 (d, J = 13.6 Hz, NIICII), 3.66 (d, J = 0 13.6 Hz, NHCII), 4.23 (d, J = 5.4 Hz, CII 2 ), 4.89 (d, J = 8.0 Hz, CII), 7.05-7.38 (m, 10 Phil), 8.20 (d, J = 8.0 Hz, NH), 8.51 (t, J = 5.4 Hz, Nil). 13c NMR (DMSO-d 6 ) 22.63 (COCH ), 42.11 (CH 2 ), 48.57 (NHCH 2 ), 64.41 (CH), 126.65(C 4 ), 126.70(C40, 127.13, 128.00, 128.13, 128.22, 139.24 (Ci or Cy), 140.12(C orCi-), 169.61(COCH3), 169.90(CONH)ppm. (D,L)-2-Acctamido-N-benzyl-2-(l-morpholine)acetamide. Yield: 0.48 g (64%). 0 Rf 0.35 (4% methanol/chloroform). mp 171-172 ° (recrystallized from ethyl acetate). . lH NMR (DMSO-d 6 ) δ 1.86 (s, COCH3), 2.30-2.40 (m, CII2NCII2). 3.51 (br s, CII2OCH2) . 4.18-4.33 (m. CII 2 ). 5.07 (d, J = 8.9 Hz, CII), 7.18-7.25 (m, 5 Phil), 8.2 35 (d, J = 8.9 Hz, Nil), 8.58 (br s, NH). 13 C (DMSO-d G ) 22.39 (COCH3). 42.20 (CH 2 ), 48.43 (CH 2 NCH 2 ), 66.03 (CH), 69.2 (CII2OCH2). 126.76 (C4 , 127.13 ( 2C 2 ' or 2C 3 , 128.23 (2C 2 > or 2C , 139.42 (C T •) EXAMPLE 38 Svnth. «ή<. nr .D.LVEthyl 2-ncctnmido-2-(etbylaιτιinσ .acetate. Λ cold (-78 °C) solution of ethyl 2-acetamido-2-bromoacetate (2.10 g, 9.38 mmol) in dry tetrahydrofuran (80 mL) was added slowly into, a cooled (-78 °C) tetrahydrofuran (20 mL) solution of methylamine (1.40 g, 31.04 mmol) over a period of 20 min. The reaction was stirred at -78 °C (1 h), and then at room temperature (1 h). The precipitated salt was filtered and the filtrate concentrated. O The residue was purified by flash column chromatography on S1O using 3% methanol chloroform as the eluent to yield the desired compound as a light yellow oil. Yield: 0.90 (51%). -5 Rf 0.36 (4% methanol/chloroform). !H NMR (CDCI3) 0.93 (t, J = 6.7 Hz, NHCH2CII3), 1.12 (t, J = 6.8 Hz, OCH2CII3), 1.87 (s, COCII3), 2.48 (q. J = 6.7 Hz, NIICII2CH3), 4.05 (q, J = 6.8 Hz, OCII 2 CH 3 ), 5.05 (d, J = 7.1 Hz, CII), 7.09 (d, J = 7.1 Hz, Nil). • 0 3C NMR (CDCI3) 13.64 (NHCH 2 CH 3 ), 14.55 (OCH 2 CH 3 ), 22.53 (COCH3), 39.06 (NHCH 2CH3), 61.38 (CH), 64.14 (OCH 2 CH 3 ), 170.09 (CO CII 3), 170.20 (COOCH 2 CH 3 ) ppm. 5 EXAMPLE 39 Using the procedures described herein, the following examples are also prepared.' ( D,L ) ,VAcetamido- N - b enzyl-3-furanacetamide 5 ( D.,L ) . > -Λcetamido-N- ( 2-fluorobenzyl ) -3-furanacetamide ( D,LU -Acetamido-N- ( 3-fluorobenzyl ) -3-furanacetamide ( D . L ) ,-, -Ace amide-N-(4-fluorobenzyl)-3-furanacetamide Λ-Λcetamide-N-benzyl-2-an_inoacetarnide 0 ' 5 0 -89- Pre p aration of cc-Hr eronion. Substituted Λmino Acids. Synthesis ofEtliyl 2- Ac Q tamido-2-sυbstitπ ( .pfl A. elates. General Procedure. Λ cooled (-78 °C) solution of ethyl 2-bromo-2-acetamidoacetatc ( 1 equiv) in THF (1 mmol/10 mL) was added slowly to a THF (1 mmol/4 L) solution of the nitrogen nucleophile (5-10 equiv) at -78 °C. The reaction was stirred at this temperature (0.5 h) and then at room temperature (1 h). The insoluble materials were filtered and washed with THF. The filtrate was concentrated in vacua and the residue was purified by flash chromatography on SΪO 2 gel (using the indicated solvent as the eluent) to give thc . desircd product. Using -. this - procedure the following examples were prepared . S y nthesis of Ethyl 2-Acc.amido-2-aminoacetate. Ethyl 2-bromo-2-acetamidoacelate (2.00 g, 8.93 mmol) and liquid NH3 (5-6 equiv) yielded a light brown residue, which on purification by flash column chromatography on S?0 2 gel (5% MeOH/CHCl 3 ) gave the desired product as a yellow oil. Yield: 1.00 g (70%). Rf 0.21 (5% MeOH/ CHCI 3 ). *H NMR ( CDCI3) δ 1.31 (t, J = 7.1 IIz, 3 II), 2.03 (s, 3 PI), 2.61 (br s, 2 H), 4.24 (q, J = 7.1 Hz, 2 H), 5.21 (d, J = 7.1 Hz, 1 H), 7.50 (d, J = 7.1 Hz, 1 II). 13 C NMR ( C CI3) 13.72, 22.68, 59.70, 61.73, 170.40, 170.68 ppm. EXΛMPLE 41 Synthesis of Ethyl 2-Acelamido-2-(mcthylamino.acetate. Use of ethyl 2-bromo-2-acctamidoaccta_e (2.00 g, 8.93 mmol) and MeNH 2 (2.50 g, 80.6 mmol) gave an oily residue (1.50 g). The residue was purified by flash column chromatography on Siθ 2 gel (3% MCOII/CIICI3) to yield the desired product as an oil. Yield: 1.00 g (65%). H NMR (CDCI 3 ) δ 1.32 (t, J = 7.1 Hz, 3 II), 2.07 (s, 3 H), 2.36 (s, 3 H), 4.26 (q, J = 7.1 Hz, 2 H), 5.20 (d, J = 7.4 Hz, 1 II), 6.60 (br s, 1 H). U NMIKCDCI 3 ) 14.02, 23.06, 0.84, 62.04, 65.72, 170.09, 170.40 ppm. Synthesis of Ethyl 2-Acetamifln-2-(N.N-dimethylnmino)acctale. Ethyl 2-bromo-2-acetamidoacetate (2.00 g, 8.93 mmol) and Me 2 NH ( 5-6 equiv) gave the desired product as a yellow oil. Yield: 1.50 g (89%). IH NMR (CDC1 3 ) δ 1.25 (t, J = 7.1 Hz, 3 II), 2.02 (s, 3 H), 2.23 (s, 6 11), 4.10-4.25 (m, 2 H), 5.24 (d, J = 8.3 Hz, 1 H), G.59 (d, J = 8.3 Hz, 1 H). "C NMR (CDCI 3 ) 14.05, 23.00. 40.28 (2 C), 61.84, 69.24, 169.38, 170.57 ppm. EXAMPLE - Synthesis of Elhyl 2-Λcc .amido-2-.4-mor»holinc acc la to. Using morpholine (1.71 g, 19÷64 mmol) and ethyl 2-bromo-2- acetamidoacetate (2.00 g, 8.93 mmol) gave an oily residue, which was purified by flash column chromatography on Si0 2 gel (2% MeOH/CIICl 3 ) to give the desired product as a thick oil. Yield: 1.90 g (93%). R f 0.29 (3% MeOH/CHCl 3 ). IH NMR (CDC1 3 ) δ 1.32 (t, J = 6.8 Hz, 3 H), 2.07 (s, 3 H), 2.43-2.72 ( m, 4 H), 3.58-3.78 (m, 4 H), 4.26 (q, J = 6.8 Hz, 2 H), 5.27 (d, J = 7.9 Hz, 1 H), 6.39 (cl, J = 7.9 Hz, I H). 13C NMR (CDCI 3 ) 14.21, 23.25, 48.47 (2 C), 62.06, 66.71 (2 C ) , 69.22, 169.00, 170.46 ppm. EXAMPLE 44 1 Synthesis of Ethyl 2-Acetamido-2-(N-anilino)acetate. Use of aniline (1.83 g, 19.6 mmol) and ethyl 2-bromo-2- acetamidoacetate (2.00 g, 8.93 mmol) provided a brown residue which was ^ purified by flash column chromatography on Si0 2 gel (CHCl 3 -2% MeOH/CHCtø gradient) to yield the desired product. Yield: 1.80 g (85%). Rf 0.52 (4% MeOH/CHCl 3 ). 0 mp 87-89 °C (recrystallized from ethyl acetate/petroleum ether). m NMR (CDC1 3 ) δ 1.29 (t, J = 7.1 Hz, 3 II), 1.84 (s, 3 II), 4.27 (q, J= 7.1 Hz, 2 II), 5.89 (d, J = 8.2 Hz, 1 H), 6.43 (d, J = 8.2 Hz, 1 H), 6.68-6.71 (m, 2 H), 6.80-6.83 (m, 1 H), 7.17-7.22 (m, 2 H). The remaining amino proton was not detected. 5 13 C NMR (CDCI3) 13.96, 22.98, 60.19, 62.41, 113.87 (2 C), 119.29, 129.37 (2 C), 144.09, 169.77, 170.14 ppm. IR(KBr)3340, 1720, 1635, 1590, 1490,730, 710cπr*. Mass spectrum (FD) 237 (M + +1). 0 Elemental analysis Calculated for C 12 II 1G N 2 O 61.00% C; 6.83% H; 11.86% N. Found 60.88%C; 6.56% H; 12.00% N. 5 0 5 1648 EXAMPLE 45 Synthesis of Ethyl 2-Ace.amido-2-,N-.3-ι_yrazoIylamino). acetate. Using ethyl 2-bromo-2-acetamidoacetate (2.00 g, 8.92 mmol) and 3- aminopyrazole (1.85 g, 22.32 mmol) and purification of the reaction product by chromatography on SiO_ gel (2% MeOII/CIICIs) gave the desired product as a yellow oil. Yield: 1.80 g (89%). Rf 0.35 (8% MeOH/CHCl3). m NMR (CDC1 3 ) δ 1.21 (t, J = 7.1 Hz, 3 H), 1.89 (s, 3 H), 4.20 (q, J = 7.1. Hz, 2 H), 5.64 (d, J = 1.8 Hz, 1 H), 5.71 (br s, 1 H), 5.73 (d, J = 7.1 Hz, 1 H), 7.29 (d, J 1.8 Hz, 1 H), 7.98 (d, J = 7.1 Hz, 1 H). The remaining amino proton was n detected. 13 C NMR (CDCI 3 ) 13.73, 22.49, 61.41, 62.02, 91.79, 130.53, 153.02, 169.96, 170.93 p EXAMPLE 46 Synthesis of Ethyl 2-Acctamido-2-(N-lι vdroxyamino.acctate.. Using ethyl 2-bromo-2-acetamidoacetate (2.10 g, 9.37 mol) and anhydrous NH 2 OH (0.93 g, 28.00 mmol) gave an oily residue. Tlie residue was purified by flash column chromatography on Si0 2 gel (5% MeOH/CIICl3) to giv the desired product. The product was recrystallized from EtOII to give a white flaky solid. Yield: 1.00 g (61%). Rf O.24 (5% MeOH/CHCl 3 ). mp 119-121 °C. H NMR (DMSO-d 6 ) δ 1.19 (t, J = 6.9 Hz, 3 H), 1.87 (s, 3 H), 4.10 (q, J = 6.9 Hz, 2 5.09 (dd, J = 4.0, 8.0 Hz, 1 II), 6.06 (br s, 1 H), 7.63 (s, 1 H), 8.50 (d, J = 8.0 1 H). 1 C NMR (DMSO-d 6 ) 14.05, 22.46, 60.82, 67.37, 169.19, 169.48 ppm. IR .KBr) 3300, 1750, 1660, 1540, 1390, 610 cm-1. Mass spectrum (FD) 177 (M++1). Elemental analysis Calculated for C 6 Hi 2 N 2 0 4 40.91% C; 6.87% H; 15.90% N. Found 40.79% C; 6.87% II; 15.90% N. EXAMPLE 47 -L Synthesis of Ethyl 2-Acetamido-?.-(N-fN-methylhvdroxvamino )acetate. MeNHOH (17.39 mmol) (prepared from MeNHOH-HCI (2.00 g, 23. mmol) and NaOMe (0.94 g, 17.39 mmol)), and ethyl 2-bromo-2-acelamidoaceta_ j - (1.00 g, 4.46 mmol) gave an oily residue. The residue was triturated with ElO mL) and the solid that remained was filtered and recrystallized from EtOH to the desired product as a white solid. Yield: 0.70 g (82%). Rf 0.34 (5% MeOH/CHCl 3 ). mp 148-150 °C. J H NMR (DMSO-d 6 ) δ 1.17 (t, J = 7.0 Hz, 3 H), 1.89 (s, 3 H), 2.37 (s, 3 H), 4.00-4.2 (m, 2 II), 5.04 (d, J = 9.2 Hz, 1 H), 8.17 (s, 1 H), 8.43 (d. J = 9.2 Hz, 1 II). 13 C NMR (DMSO-d 6 ) 14.04, 22.28, 43.78, C?.ld, 71.46, 168.29, 170.23 ppm. IR (KBr) 3320, 3200 (br), 1760, 1660, 1530, 1470, 720, 640 cπχ-1. Mass spectrum (FD) 192 (M++1). Elemental analysis Calculated for C 7 II 14 N 2 O 4 O.25 H 2 O 43.18% C; 7.51% II; 14.39% N. Found 43.28% C; 7.25% II; 14.64% N. EXAMPLE 48 Synthesis of Ethyl 2-Λcc .nmido-2-fN-(N.O-dinιc.hylhvdroxyamino..acetate. MeNHOMe (17.40 mmol) (prepared from MeNHOMe-IICl (2.18 g, 22.32 mmol) and NaOMe (0.94 g, 17.40 mmol)) and ethyl 2-bromo-2-acetamido- acetate (1.00 g, 4.46 mmol) gave a residue which was purified by flash column chromatography on SiU 2 gel (1% MeOH/CHCtø) to give the desired product as an oil. Yield: 0.60 g (66%). Rf 0.53 (2% MeOU/CHCl 3 ). J H NMR (CDC1 3 ) δ 1.35 (t, J = 7.0 Hz, 3 H), 2.12 (s, 3 H), 2.62 (s, 3 H), 3.46 (s, 3 H), 4.30 (q, J = 7.0 Hz, 2 II), 5.36 (d, J = 8.9 Hz, 1 H), 6.66 (d, J = 8.9 Hz. 1 H). 13 C NMR (CDCI 3 ) 14.06, 22.89, 40.30, 60.01, 61.89, 70.16, 168.14, 170.53 ppm. Synthesis of 2-Acctamido-N-benzyl- -subsli luted Acctamides. General Procedure. Λ mixture of the ethyl 2-subsliluled-2-acelamidoaceta .e (1 equiv), benzyiamine (1.2 equiv), and NaCN (0.1 equiv) in MeOH (1 mmoI/25 mL) was stirred at 45-50 °C (18 h). The solvent was removed m vacuo and the residue was purified using cither trituration with ElOΛc or flash column chromatography on S1O2 gel with the indicated solvent as the oluent. Using this procedure the following examples were prepared. EXAMPL E 49 nthesis of 2-Ace . amido-N-benzvI-2-aminn ,. cclamide. Ethyl 2-acctamido-2-aminoacetate (1.00 g, 6.25 mmol), benzyiamine (0.80 g, 7.5 mmol) and NaCN (0.03 g, 0.61 mol) gave a residue which solidified on standing (18 h). The reaction mixture was triturated with EtOAc (20 mL). The white solid which remained was filtered and then further purified by recrystal- lization from EtOΛc. Yield: 1.00 g (72%). Rf 0.21 ( 5% MeOH/CHCl 3 ). mp 131-133 °C (dec). IH NMR ( DMSO-d G ) δ 1.83 ( s, 3 H ) , 2.35 (br s, 2 H), 4.28 ( d, J = 4.4 Hz. 2 II ) , 4.91 ( d. ■ J = 7.0 Hz, 1 H), 7.20-7.32 ( m, 5 H), 8.31 (br s, 1 H ) , 8.51 ( br s, 1 H ) . 3 C NMR ( DMSO-d 6 ) 22.66, 42.05, 60.29, 126.67, 127.10 ( 2 C ) , 128.18 ( 2 C ) , 139.23, 169.24, 170.67 ppm. IR ( KBr) 3300, 1650 ( br),1530 (br), 1450, 740 cm-1. Mass spectrum, m/e (relative intensity) 222 (M++ 1, 100), 221 (M\ 29), 133 (8). Elemental analysis • Calculated for C11II15N3O2 59.71% C; 6.83% H; 18.99% N. Found 59.86%C; 6.88% II; 18.72% N. _ 101 _ EXAMPLE 50 Synthesis of 2-Acctamido-N-bcnzyl-2-(methvIamino)acelamide. Ethyl 2-ncelamido-2-(mclhylamino)acclale (1.50 g, 8.63 mmol), benzyiamine (1.11 g, 10.35 mmol) and NaCN (0.04 g, 0.82 mmol) gave a brown residue which was purified by flash column chromatography on SiU2 Kcl (2% Me ' OH/CHCl 3 ) to yield the desired product. Yield: 1.00 g (49%). Rf 0.33 (3% MeOH/CHC-3). mp 115-117 °C (recrystallized from ethyl acelate/petroleum elher). IH NMR (DMSO-d 6 ) δ 1.87 (s, 3 H). 2.18 (s, 3 H), 4.20-4.29 ( , 2 H), 4.87 (d, J = 7.9 Hz, 1 H), 7.24-7.35 (m, 5 H), 8.14 (d, J = 7.9 Hz, 1 H), 8.55 (br s, 1 H). The remaining amino proton was not delected. 13C NMR (DMSO-d 6 ) 22.52, 31.37, 42.04, 65.99, 126.68, 127.12 (2 C), 128.18 (2 C). 139.28, 169.51, 169.83 ppm. IR (KBr) 3240, 1610 (br), 1500 (br), 1430, 725, 670 cm" 1 . Elemental analysis Calculated for Cι 2 HπN 3 0 2 61.26% C; 7.28% H; 17.86% N. Found 61.12% C; 7.01% H; 17.71% N. EXΛMPL E 51 Synthesis of 2-Λcetamido-N-bcnzyl-2-(c.lιylamino)ncclamide. Using ethyl 2-acetamido-2-(clhylamino)acclate (0.90 g, 4.79 mmol), benzyiamine (0.62 g, 5.75 mmol), and NaCN (0.03 g, 0.51 mmol) gave an oily residue which was purified by flash column chromatography on Si0 2 gel (3% Me0H/CHCl3) to give the desired product as a white solid. Yield: 0.35 g (29%). Rf 0.34 (4% MeOH CHCl ). mp 123-125 °C (recrystallized from ethyl acetale/hexane). *H NMR (DMS0-d 6 ) δ 0.93 (t, J = 6.8 Hz, 3 II), 1.81 (s, 3 H), 2.08 (br s, 1 H). 2.40-2.4 (m, 2 H), 4.22 (d, J = 5.5 Hz, 2 H), 4.90 (d, J = 7.8 Hz, 1 H), 7.20-7.27 (m, 5 H 8.08 (d, J = 7.8 Hz, 1 H), 8.48 (I, J = 5.5 Hz, 1 H). 1 C NMR .CDCI3) 15.14, 22.97, 37.65. 43.53, 65.68, 127.44 (2 C), 127.50, 128.64 (2 C) 137.73, 169.75, 171.20 ppm. IR (KBr) 3250, 1620 (br), 1510 (br), 1450 (br), 740, 680 cm- . Elemental analysis Calculated for C 1 3H 1 .0N 3 O2 62.63% C; 7.68% H; 16.857. N. Found 62.69% C; 7.49% II ; 16.6570 N. EXAMPLE 52 1 Synthesis of 2-Acclamidσ-N-benzyl-2-(N-aniIino)acctamide. Employing ethyl 2-acctamido-2-(N-anilino)acctate (2.00 g, 8.47 mmol), benzyiamine (1.09 g, 10.00 mmol), and NaCN (0.04 g, 0.84 mmol) gave a white 5 solid which separated during the course of the reaction. The precipitate was filtered and purified by recrystallization from absolute EtOH to give the desired product. Yield: 1.10 g (44 %). ° mp 183-185 °C. *H NMR (DMSO-d 6 ) δ 1.84 (s, 3 H), 4.31 (d, J = 5.8 Hz, 2 II), 5.67 (t, J = 8.1 Hz, 1 II), 6.04 (d, J = 8.1 Hz. 1 H), 6.59-6.64 (m. 1 H). 6.70-6.72 (m. 2 H). 7.06-7.11 (m, 2 H). 7.20-7.33 (m, 5 H), 8.41 (d, J = 8.1 Hz, 1 H), 8.72 (t, J = 5.8 Hz. 1 H). 5 13 C NMR (DMSO-d 6 ) 22.46, 42.25, 60.42, 113.21 (2 C), 117.22, 126.72, 127.16 (2 C), 128.18 (2 C), 128.77 (2 C). 138.99. 145.88, 168.65, 169.70 ppm. IR (KBr) 3270, 1630. 1520. 1490, 1430. 740. 690 cm * l. Mass spectrum, m/c (relative intensity) 297 (M\ 2), 239 (7), 164 (28), 163 (100), 122 0 (20), 121 (100), 106 (47), 104 (65). 93 (63). 91 (77). Elemental analysis Calculated for Ci 7 IIi9 3 0 2 68.67% C; 6.44% H; 14.13% N. 5 Found 68.94% C; 6.42% H; 13.92%, N. 0 5 EX AMPL E 53 1 Synthesis of 2-Λcc.anιido-N-bcnzyl-2-(N-.3-oyrazplvln inn) .clamide. Λ solution of ethyl 2-acctnmido-2-(N-(3-pyrazolylamino))acel.al.e (1.60 g, 7.1 mmol) in MeOH (40 mL) containing benzyiamine (0.83 g, 7.8 mmol) and 5 NaCN (50 mg, 1 mmol) was stirred al 45-55 °C (18 h). TLC analysis (8% McOII/CIICls) or the reaction mixture indicated the presence of only a minor amount of product. Λ second lot of NaCN (50 mg, 1 mmol) was then added and the reaction was allowed to proceed at 45-55 °C (6 h) and then at room temperature 0 (48 h). The solvent was removed in vacuo and the residue was Irituralcd with ElOΛc (15 mL). The insoluble solid that remained was filtered and purified by flash column chromatography on SiO 2 gel (7% MeOII/CIICl3) to give the desired product. 15 Yield: 0.90 g (44%). Rf O.35 (8% McOII/CIICl 3 ). mp 135-137 °C. UI NMR (DMSO-d G ) δ 1.82 (s, 3 I I). 4.29 (d. J = 5.9 Hz, 2 II). 5.51-5.55 (111, 3 I I), 7.18- 20 7.40 (m, 0 II), 8.30 (br s, 1 II). 8.53 (br s, 1 II). 11.66 (br s. 1 H). 13C NMR (DMSO-d G ) 22.59, 42.29, 61.79, 90.68, 126.67, 127.07 (2 C), 128.17 ( C), 129.10, 139.41, 153.53, 169.19, 169.67 ppm. - 5 IR (Iϋ3r) 3230 (br), 1620 (br), 1500 ibr), H30, 730, 690 cm- . Mass spectrum, m/c (relative intensity) 288 (M + +1, 64). 287 (M \ 2), 230 (28), 229 (100). 153 (46). Elemental analysis 30 Calculated for CHII ΠNΓ^ .S 11 2 0 56.47% C; 6.12% II; 23.637. N. Found 56.637_ C; 5.797* 11; 23.437 σ N. 5 rrcparatiσn of Functionalized α-Hgtoroalom Substituted Λ ino Λcids. General rroccdure.. Λ BBι- solution (1 M in CII 2 CI2, 1.1 equiv) was added to n solution of 2-acelamido-N-benzyl-2-elhoxyacclnmidc (1. equiv) in CII 2 CI 2 ( 10 mmol/125 mL). The mixture was stirred at room temperature (5 h) and then concentrated to dryness in vacuo to give 2-ncelnmido-N-bcn7.yl-2-bromoacelamide as a pale yellow crystalline material. The bromo adducl was then dissolved in THF (10 mmol/250 mL), cooled (-78 °C), and then added over a 15 min interval to a cooled (-78 °C) solution of the heteroatom nucleophile in THF (1 mmol/1 L). The reaction mixture was stirred at this temperature (30 min) and then al room temperature (90 min). The insoluble salts were filtered and the filtrate concentrated in vacuo. The residue was then pui-ificd by flash column chromatography on Siθ 2 gel using the indicated solvent as the clucnt. Using this procedure the following examples were prepared . EXAMPLE 54 1 Synthesis of 2-Acclamido-N-bcnzyl-2-(N.N-dime _hylamino)acctamide. By making use of 2-acelamido-N-benzyl-2-clhoxyacclamidc (3.00 g, 12.0 mmol), B Br 3 (1 M in CH 2 C1 2 . 13.2 mL, 13.2 mmol), and Mc 2 NH (5-6 equiv) was 5 obtained a brown residue which was purified by flash column chromatography on Siθ2 gel (2.5% MeOH/CHCl 3 ) to give the desired product. The product was recrystallized from ethyl acelnlc/hexanc to give light yellow cubic crystals. Yield: 1.20 g (40%). 0 Rr 0.39 (5% MCOII/CHCI3). mp 104-106 °C. l K NMR (DMSO-dc) δ 1.91 (s, 3 H). 2. 1 (s, 6 II), 4.22 (dd, J = 5.2, 14.7 Hz, 1 H), 4.34 (dd, J = 6.1, 14.7 Hz, 1 II), 5.11 (d, J = 8.3 Hz, 1 H), 7.23-7.31 (in, 5 II), 8.18 (d, 5 J = 8.3 Hz, I II), 8.55 (br s, I II). 13 C NMR (DMSO-d 6 ) 22.43, 40.33 (2 C). 42.28, 69.42, 126.73, 127.27 (2 C), 128.21(2 C), 139.49, 168.49, 170.31 ppm. Q IR (KBr) 3280, 1670 (br), 1500 (br), 1460, 760, 700 cm-1. Mass spectrum (FD) 250 (M + +l). Elemental analysis Calculated for C13H19N3O2 62.63% C; 7.68% PI; 16.85% N. 5 Found 62.82% C; 7.66% H; 16.69% N. 0 EXAMP LE 55 Synthesis of 2-Λcclamido-N-bcnzyl-2-(N-hvdroxyamino /acetamide. Using 2-acctamido-N-bcnzyl-2-elhoxyacetamide (2.00 g, 8.0 mmol), BBr 3 (1 M in CH 2 CI2, 8.8 mL, 8.8 mmol), and anhydrous NH 2 OH (5-6 equiv) gave 5 an oily residue. The residue was separated into three components by flash chromatography on Siθ2 gel (7.5% MeOH/CHCl 3 ). 2-Λcctamido-N -benzyl -2-(N-hvdroxyamino)acelamidc. Yield: 0.14 g (7%). 10 Rf 0.30 (8% McOII/CIICl 3 ). mp 144-146 °C (dec.) (recrystallized from EtOH) *H NMR (DMSO-d 6 ) δ 1.88 (s. 3 II), 4. 1 (d, J = 5.7 Hz, 2 H), 5.08 (dd, J = 4.4. 8.1 Hz, I H), 5.94 (dd, J = 2.8, 4.4 Hz. 1 II), 7.19-7.35 (m, 5 II). 7.52 (d. J = 2.8 Hz. 1 II), 5 8.26 (d, J = 8.1 Hz, 1 II), 8.42 (I, J = 5.7 Hz, 1 H). 13C NMR (DMSO-d 6 ) 22.69, 42.25, 67.86, 126.69, 127.14 (2 C), 128.18 (2 C), 139.08, 168.53, 169.67 ppm. IR(KBr) 3320 (br), 1660 (br), 1540 (br), 1460, 750, 700 cm- . 0 Mass spectrum (FD) 238 (M + + 1). Elemental analysis Calculated for Ci ill 15N3O3 55.697_ C; 6.377o H; 17.717_ N. 5 Found 55.867. C; 6.377o II; 17.38% N. Dimer Λ. Yield: 0.05 g (3%). Rf O.27 (87o MeOH/CHCI ). ° p 177-179 °C (recrystallized from EtOH). *H NMR (DMSO-d 6 ) δ 1.82 (s, 6 II), 4.25-4.34 (m, 4 H), 5.21 (d, J = 9.3 Ilz, 2 H), 7.20- 7.33 (m, 10 H), 8.16 (d, J = 9.3 Hz, 2 II), 8.26 (t, J = 5.8 Hz, 2 H), 8.51 (s. 1 II). "C NMR(DMSO-d 6 ) 22.54 (2 C). 42.30 (2 C). 67.55 (2 C), 126.63 (2 C), 127.13 (4 C), 128.11 (4 C), 139.02 (2 C), 168.24 (2 C), 169.33 (2 C) ppm. IR (KBr) 3240 (br), 1640 (br), 1510 (br), 1450, 690 cm * l. Mass spectrum (FD) 442 (M + +l ). U Elemental analysis Calculated for C22H 2 7N r ,Or, 59.85% C; 6.16% H; 15.86% N. Found 59.5 . % C; 6.08% H; 15.64% N. • 5 Dimer B. Yield: 0.10 g (67.). Rr O.18 (8% M0OH/CHCI3). mp 184-186 °C (recrystallized from McOIl). 10 " II NMR (DMSO-d 6 ) δ 1.87 (6 H), 4.20 (dd, J = 5.3, 15.3 Hz, 2 II), 4.44 (dd, J = 6.2, 15.3 Hz, 2 H), 5.28 (d, J = 9.0 Hz, 2 II), 7.15-7.31 (m, 10 II), 8.00 (d, J = 9.0 Hz, 2 H), 8.39 (dd, J = 5.3 , 6.2 Hz, 2 II), 8.51 (s, 1 H). "C NMR (DMSO-d 6 ) 22.50 (2 C), 42.58 (2 C), 69.98 (2 C), 126.73 (2 C), 127.23 (4 C), ■ 15 128.22 (4 C), 139.08 (2 C), 167.60 (2 C), 169.57 (2 C) ppm. IR (KBr) 3300 (br), 1660 (br), 1530 (br), 1450, 740, 700 cm- . Mass spectrum (FD) 442 (M + +1). pπ Elemental analysis Calculated for C 22 II 27 N 5 O 5 59.85% C; 6.16% H; 15.86% N. Found 60.09% C; 5.937. H; 15.70% N. 25 35 EXΛMPLE 56 Imnrovcd S y nthesis of 2-Λcctamido-N-bcnzyl-2-(N-hvdro v γπminn)ar . elamide. 2-Λcetamido-N-benzyl-2-brυmoacetamide (prepared from 2- acetamido-N-benzyI-2-ethoxyacetamide (3.00 g, 12.0 mmol) and BBr 3 (1 M in CH 2 C1 2 , 17.2 mL, 17.2 mmol)) was dissolved in TIIF (250 mL), cooled (-10 °C), and then added dropwise (30 min) lo a suspension of NII2OII (5-6 equiv) in TIIF (50 mL) at -10 °C. The reaction mixture was stirred (30 min) at this temperature and then allowed lo warm to room temperature (1 h). The insoluble materials were filtered and the filtraLe was concentrated in vacuo. The residue was separated into two components by flash column chromatography on Siθ2 gel (7.5% McOII/CIICl 3 ). 2-Acetamido-N-bcnzyl-2-(N-hydroxyamino ) acclamide. Yield: 0.66 g (23%). mp 144-146 °C (dec.) (recrystallized from EtOH). Dimer . Yield: 0.10 g (5%). p 184-186 °C (recrystallized from McOII). Dimcr Λ was not observed under these conditions. EXAMPLE 57 Synthesis or 2-Λcctamido-N-bcnzyl-2-(N 2 -phenylhvdrazipn)ncolamide. Using 2-acetamido-N-bcnzyl-2-ethoxyace ιmide (2.00 g, 8.0 mmol ) , BBr 3 (1 M in CH 2 C1 2 , 10.0 mL, 10.0 mmol), and phenylhydrazine (2.60 g, 24.0 5 mmol) gave a pale yellow oily residue which was purified by flash column chroinalography on Siθ2 gel (27σ MeOH/CIICl3) to give the desired product. The product was recrystallized from chloroform/hexane as a light yellow solid. Yield: 0.75 g (297.). 10 Rr O.26 (27_ McOII/CIIC- 3 .. mp 132-134 °C. m NMR (DMSO-dc) δ 1.89 (s, 3 II), 4.28 (d. J = 5.8 Hz, 2 H), 4.89 (d, J = 5.2 Hz, 1 II), 5.09 (dd, J = 5.2, 7.4 Hz, 1 H), 6.61 (t, J = 7.4 Hz, 1 H), 6.70-7.28 (m, 10 II), 8.29 ' 15 (d, J = 7.4 Hz, 1 H), 8.60 (I, J = 5.8 Hz, 1 H). 13C NMR (DMSO-dc) 22.88, 42.22, 66.22, 112.66 (2 C), 117.57, 126.65. 127.08 (2 C), 128.15 (2 C), 128.53 (2 C), 139.12, 149.90, 168.66, 170.01 ppm. 2o L (KBr) 3300, 1640 (br), 1610, 1520 (br), 1460, 760, 700 cm- . Mass spectra (FD) 313 (M + +l). Elemental analysis Calculated for 0 1 711 20 ^0 65.37% C; 6.457o II; 17.947. N. 25 Found 65.157. C; 6.257. H; 17.717, N. 0 5 27.6 mmol), 0.95 g (21%) of the desired product was obtained. The product was recrystallized from chloroform/hcxane lo give a while amorphous solid. RrO.32 (2%> MeOII/CHCl 3 ). mp 152-154 °C. HI NMR (DMSO-d 6) δ 1.85 ( s, 3 II), 4.27 (d, J = 4.4 Hz, 2 II ) , 5.00 ( s, 2 II ) . 5.14 ( dd, J = 3.1. 8.0 Hz, 1 H), 5.23 (t, J = 3.1 Hz, 1 H), 7.25-7.35 (m, 10 II), 8.26 (d, J = 8.0 Hz, 1 H), 8.56 (br s, 1 ID. 8.66 ( br s, 1 II ) . 1 3 C NMR (DMSO-d 6) 22.71, 42.23. 65.56. 65.97, 126.69, 127.16 ( 2 C ) , 127.61 ( 2 C), 127.77. 128.13 (2 C). 128.27 (2 C), 136.74, 138.87, 168.04, 169.95 ppm. IR (KBr ) 3325, 1620 (br), 1500 (br), 1440, 740, 680 cπr*. Mass spectrum (FD) 371 (M + + 1 ) . Elemental analysis Calculated for C 19 H 22 4 θ 4 61.61 * 4 C; 5.99% H; 15.13% N. Found 61.40% C; 6.21% II; 15.39% N. EXAMPLE 59 Synthesis of 2-Acclamido-N-bcnzyl-2-nhcnoxyacctamide. Using 2-acctamido-N-benzyl-2-elhoxyacctamide (3.00 g, 12.0 mmol), BBr 3 (1 M in CH 2 C1 2 , 15.0 mL. 15.0 mmol), and NaOPh (4.18 g, 30 mmol) gave a brown oily residue which was purifed by flash column chromatography on Siθ2 gel using first CIICI 3 and then 27. MeOII/CHCb as the eluents to give the desired product. The compound was recrystallized from chloroform/hexane. Yield: 0.80 g (22%). Rf 0.58 (37. MeOH/CHCl 3 ). mp 125-128 °C (soRens at 122 °C). J H NMR (DMSO-dc) δ 1.83 (s, 3 II), 4.35 (d, J = 5.7 Hz, 2 H), 6.18 (d, J = 9.4 Hz, 1 H), 6.94-6.99 (m, 2 H), 7.02-7.33 (in, 8 II), 8.98 (t, J = 5.7 Hz, 1 II), 9.10 (d, J = 9.4 Hz, 1 1-I). "C NMR (DMSO-dc) 22.54, 42.24, 76.44. 116.09 (2 C), 121.78, 126.84, 127.26 (2 C), 128.25 (2 C), 128.44 (2 C), 138.84, 155.97, 166.63, 170.73 ppm. Ut (KBr) 3300, 1650 (br), 1600, 1530 (br), 1490, 1450, 760, 700 cnr . Mass spectrum (FD) 299 (M + + l). Elemental analysis Calculated for Ci7Hι 8 N 2 O 0.5 II 2 0 66.437. C; 6.237. H; 9.117 0 N. 'ound 66.627. C; 6.23% II; 9.167c- N. EXAMPLE. 60 Synthesis of 2-Λcetamido-N-bcnzyl-2-(methylmerr.anto acetamide. Λ cooled (-78 °C) solution of Et 3 N (4.85 g, 48.0 mmol) in TIIF (20 mL) was added to a cooled (-78 °C) solution of 2-acetamido-N ._ enzyl-2-bromoacetam.ide (prepared from 2-acetamϊdo-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol) and BBr (1 M in CH 2 C1 2 , 20.0 mL, 20.0 mmol)) in THF (275 mL). Λ cooled (-78 °C) solution of excess MeSH (5-6 equiv) in THF (55 mL) was then added. The reaction mixture was stirred at this temperature (30 min) and then at room temperature ( h). The insoluble materials were filtered and the filtrate was evaporated to dryness in vacuo. The oily residue obtained was purified by flash column chromatography on Siθ2 gel (2% MeOH/CHC ) to give 1.10 g (27%) of the desired product as a yellow orange oil. The product was purified by a second flash column chromatography on Siθ2 gel (27σ MeOH/CHCl3) to give 0.72 g of the pure product as a white solid. Rf 0.65 (37. MeOH/CHCl 3 ). p 155-157 °C. IH NMR (CD3NO2) δ 1.98 (s, 3 H), 2.08 (s, 3 II), 4.39 (dd, J = 6.1, 15.2 Hz, 1 II), 4.49 (dd, J = 6.1, 15.2 Hz, 1 II), 5.51 (d, J = 7.8 Hz. 1 H), 7.15 (d. J = 7.8 Hz. 1 H), 7.17-7.41 (m, 6 H). I3 C NMR (CD3NO2) 12.28, 22.94, 4.26, 56.03, 128.46, 128.60 (2 C), 129.77 (2 C), 140.17, 169.19, 171.06 ppm. IR (KBr) 3320, 1650 (br), 1520 (br), 1460, 750 cm- . Mass spectrum (FD) 253 (M + + 1). Elemental analysis Calculated for CI2H IGN 2 0 2 S 57.127. C; 6.39% H; 11.107. N. Found 57.067c C; 6.577. H; 11.28% N. EXAMPLE 61 mp 146-148 °C. Elemental analysis ' Calculated for C :3 H 18 N 2 O 2 S0.25 H 2 0 5765% C- r __*>■ x, Found a .fao Λ C. 6.88% H; 10.34% N. 57.48% C; 6.84% H; 10.23% N. prepared. Using this procedure the followin g examples were .. ___ Synthesis of 2-Λcctamido-N-hcn7.yl-2-.N-methoxynmino)ncetnrnidc. Using a MeOH solution of MeONI_2 (prepared from MeONH^HCl (2.83 g, 33.9 mmol) and NaOMe (1.41 g, 26.1 mmol)), and 2-acetamido-2-(N,N,N- ^ trimcthylammonium . acetamide tctrafluoruborate (2.70 g, 7.67 mrnol) gave an oily residue which was purified by flash column chromatography on Siθ2 gel ( 2% MeOH/CHCl 3 ) to give the desired product. The product was recrystallized from chloroform/hexane. 10 Yield: 0.80 g (42%). Rf 0.23 (2% MeOH/CHCl 3 ) mp 95-97 °C. ! __ NMR (DMSO-de) δ 1.88 (s, 3 H). 3.38 (s, 3 H), 4.22-4.41 (m, 2 H), 5.18 (dd, J = 4.9, 15 7.8 Hz, 1 H), 6.78 (d, J = 4.9 Hz, 1 H), 7.21-7.32 (m, 5 H), 8.33 (d, J = 7.8 Hz, 1 H). 8.56 (br s, 1 H). 13 C NMR (DMSO-de) 22.64, 2.28, 61.42, 66.25, 126.74, 127.19 (2 C), 128.19 (2 C), 139.11, 167.95, 169.66 ppm. 20 IR (KBr) 3300, 1650, 1620, 1510 (br), 1440, 750, 680 cm" 1 . Mass spectrum (FD) 252 (M + +l). Elemental analysis Calcula: _d for C_ 2 H 17 N 3 θ 3 57.63% C; G.82% H; 16.727. N. Found 57.06.. C; 6.63% H; 16.659. N. 30 - 35 92/2164 EXAMPLE 63 Synthesis of 2-Λcetπmido-N-bcπzyl-2-(N-.(N-mcthylhvdrpτy_ιmino))ncetnmidc. An MeOH solution (30 mL) of MeNHOH (21.74 mmol) (prepared from McNHOH-HCl (2.36 g. 28.26 rnmol) and NaOMe (1.17 g. 21.74 mmol)) and 2- acctamido-2-(N,N,N-trimethylammonium)acetamide tetrafluoroborate (2.20 g, 6.25 mmol) gave a residue which was purified by flash column chromatography on Si0 2 gel (6% MeOH/CHCfø) to give the desired product as a white solid. The product was then purified by recrystallization from EtOH. Yield: 0.95 g (61%). Rf 0.32 (8% MeOH/CHCI 3 ). mp 159-161 °C. H NMR (DMSO-dg) δ 1.95 (s, 3 H).2.43 (s. 3 H), 4.26 (dd, J = 5.7, 15.1 Hz, 1 H), 4.35 (dd, J = 5.7 , 15.1 Hz, 1 H), 5.09 (d, J = 9.1 Hz. 1 H), 7.21-7.29 (m, 5 H), 8.05 (s, 1 H), 8.18 (d, J = 9.1 Hz. 1 H).8.23 (t, J = 5.7 Hz, 1 H). J3 C NMR (D SO-dβ) 22.40.42.34, 43.92, 71.49, 126.62, 127.12 (2 C), 128.12 (2 C), 139.14. 67.82. 170.28 ppm. IR (KBr) 3440 (br), 3300, 16*10, 1530, 1460. 750, 700 cπr*. Mass spectrum (FD) 252 (M++ 1). Elemental analysis Calculated for C 12 H 1 7N 3 O 3 57.36% C; 6.82% H; 16.72% N. Found 57.65% C; 6.59% H; 16.66% N. EXAMPLE 64 Synthesis of 2-Acctnmido-N-benzyl-2-fN-(N.O-dimcthylhvdroxynmiπo))acet«πmide. An MeOH solution (20 mL) of MeNHOMe (17.39 mmol) (prepared from McNHOMe-HCl (2.20 g, 23.02 mmol) and NaOMe (0.94 g, 17.39 mmol)) and 2- acetamido-2-(N,N,N-trimethylammonium)acetamide tetrafluoroborate (2.10 g, 5.97 mmol) gave a solid residue. Flash column chromatography of the solid on Si0 2 gel (2% MeOH/CHCl 3 ) yielded pure desired product. The product was recrystallized from EtOH. Yield: 1.30 g (82%). Rf 0.39 (2% MeOH/CHCI 3 ). mp 165-167 °C. NMR (DMSO-dc) δ 1.93 (s, 3 H), 2.43 (s. 3 H), 3.32 (s. 3 H), 4.25 (dd, J = 5.9, 14.9 Hz, 1 H), 4.37 (dd, J = 5.9, 14.9 Hz, 1 H), 5.19 (d, J = 9.4 Hz, 1 H), 7.21-7.35 (m, 5 H), 8.31 (d, J = 9.4 Hz, 1 H), 8.56 (t, J = 5.9 Hz, 1 H). "C NMR (DMSO-de) 22.36, 39.68.42.34, 59.16, 70.33, 126.74, 127.41 (2 C), 128.21 (2 C). 139.30, 167.38, 170.30 ppm. IR (KBr) 3300, 1640 (br), 1540 (br), 1400, 750, 700 cπr*. Mass spectrum (FD) 266 (M + +1). Elemental analysis Calculated for C 13 H 19 N 3 O 3 58.85% C; 7.22% H; 15.84%> N. Found 59.05% C; 7.37% H; 15.75% N. EXAMPLE 65 ^ whitt.e a a m m o o r r p p h h o o u u s s S s 0 olid P . r W3S rCCI75ta,liZCd f - ^ <>™/h____. to .i e _ Yield: 0.80 g (64%). 10 K 0.29( 4 %MeOH7CHCl 3 ), mp 149-151 °C. 1H _0 128.X3 _ C, 133 ,2. 1G7 _ 3 , 170 , 7 ppm ' GS - 77 ' 12G - G4 ' 12 '- 02 * I IR ( KBr ) 3400 (br) 3_nn irm .. - . _ Wr, 3300, 1650, 1530, 1470, 740.700.610 cm- 1 Mass spectrum (FD) 278 (M++1 ) . Elemental analysis 60.16% C; 7.04% H; 15.07% N. 0 Pre p aration of Functionalized σ-Hctcrontom Substituted Λminσ Λcids. Gcncrnl Proce ure 2-Λcetomido-N-ben7.yl-2-ctlιoxyacctamide (1 equiv) was suspended i Et 2 0 (100 mlVlO mmol), and tiien BF. Et 2 0 ( 1.6-2.4 eηuiv) was rapidly added and the resulting solution was stirred (10 min). The nucleophile (H2O or EtSIl) (1.6-4. equiv) was then added and the reaction was stirred at room temperature (18-48 h Tl i e reaction was then quenched by the addition o. an aqueous N IICθ3 (100 L . 10 mmoD/ice mixture. The experimental workup varied slightly for each compound and is descr i bed in the following exampl es along with the observed spectra l properties . EXAMPLE 66 Synthesis of 2-Λcctamido-N-beπ yl-2-bvdroxyacetamide. Reacting 2-acctamido-N-bcnzyl-2-ethoxyacetamide (1.00 g, 4.0 mmol) BF 3 -Et 2 0 (0.91 g, 6.4 mmol) and H 2 O (0.12 g, 6.7 mmol) followed by aqueous NaIIC03 workup gave an aqueous reaction mixture. The solution was then extracted with EtOΛc (3 X 50 mL), and the combined EtOΛc extracts were dried Na2S0,j) f and concentrated in vacua. The residue was purified by flash column chromatography on S1O2 gel (3% MeOH/CHCl3) to give the desired product as a white solid. Yield: 0.30 g (34%). Rr0.14 (3% MeOH/CHC- 3 ). mp 136-138 °C. J H NMR (DMSO-d 6 ) δ 1.85 (s, 3 H), 4.29 (d, J = 5.9 Hz, 2 H), 5.48 (dd, J = 5.5, S.6 Hz, 1 H), 6.47 (d, J = 5.5 Hz, 1 H), 7.21-7.35 (m, 5 H), 8.52 (t, J = 5.9 Hz, 1 H), S.59 (d, J = S.6 Hz, 1 H). "C NMR (DMSO-d 6 ) 22.66, 41.99, 71.42, 126.66, 127.22 (2 C). 128.13 (2 C), 139.20, 169.47, 169.62 ppm. IR (KBr) 3300, 1620, 1530 (br), 1430 (br), 730, 690 cm' 1 . Mass spectrum, m/e (relative intensity) 223 (M + + 1, 1), 163 (11), 134 (9), 106 (46), 91 (100).77 (22).65 (38). Elemental analysis Calculated for C 11 H 14 N 2 O 3 59.45% C; 6.35% H; 12.61% N. Found 59.24% C; 6.36% H; 12.50% N. EX AM PL E $7 Us i ng 2-acetamido-N-bcnzyl-2-etlιoxyacetamide (2.00 g. 8.0 mmol), BF 3 -EL 2 0 (2.72 g. 19.2 mmol) and EtSII (2.38 g, 38.4 mmol) gave an aqueous reaction mixture. The solution was extracted with CHCI 3 (3 x 100 mL). The combined CHCI3 layers were dried (Na 2 S0 4 ). and then concentrated in vπcuo to give the desired product as white solid. Yield: 1.90 g (89%). Rf 0.60 (4% MeOH/CHCl 3 ). mp 148-149 °C (mixed melting point with an authentic sample of Sxa i rr le 61 was undepressed) . Yield: 1.20 g (92%). mp 265-267 °C (dec). 7.20-7.31 (m. 5 H). 8.44 (d. J . 7.6 Hz. 2 H). 8.48 (, J . 5.8 Hz 1 H) DMSO-d 6 ) 22.44 (2 C). 42.26. 56.99. 126.62. 127.02 (2 C). 128.12 (2 C) ∞ 15 168.19, 169.39 (2 C) ppm. 5 ' 0 HI (I Br) 3260. 1530. 1500. 740. 690 cm-i. Mass spectrum (FD) 264 (M++1). Elemental analysis Calculated for C13H17N3 J O3 3 5 J 9^ 30U%_ pC-, r 6.5.1. %_-H__-; 15.96% N 5 Found 9.16% C; 6.49%H; 15.86% N. 0 EXAMPLE 69 Synthesis of 2-Acetnmido-N-bcn_yl-2-triπuoroacctamidoacctamide. Ice cold trϊΩuoroacetic anhydride (8 mL) was added in one portion ice cold 2-acetamido-N-benzyl-2-aminoacetamide (1.00 g, 4.53 mmol). The ' reaction was accompanied by the evolution of heat. After stirring (5 min), the volatile materials were removed in vacuo. The residue was treated with a saturated aqueous N HC03 solution (20 mL), and the solid that remained was filtered and washed with H2O to give the desired product. Tlie product was 0 recrystallized from EtOH. Yield: 1.00 g (70%). Rf 0.34 (8% MeOH/CHCI 3 ). mp 228-230 °C. ~:5 ^H NMR (DMSO-de) δ 1.90 (s. 3 H). 4.30 (d, J = 5.1 Hz, 2 H), 5.S5 (d. J = 8.0 Hz. 1 7.21-7.35 (m, 5 H). 8.64 (d, J = 8.0 Hz. 1 H), 8.75 (t, J = 5.1 Hz, 1 H), 10.04 (s H). 20 13 C NMR (DMSO-d 6 ) 22.52, 42.52, 57.42, 117.4 (q, JCF = 28S.3 Hz), 126.80, 127.16 ( C), 12S.21 (2 C), 13S.93. 156.14 (cj, JCF = 35.3 Hz). 166.39. 169.88 ppm. IR (KBr) 3300. 1720, 1650, 1520. 1380, 760, 700 cm- . Mass spectrum (FD) 318 (M + + 1). 2 ElemciiLal analysis Calculated for C1 HMN3O F3 49.21% C; 4.45% H; 13.24% N. Found 49.48% C; 4.43% H; 13.10% N. 30 35 EXAMPLE 70 S y nthesis of 2-Acctnmido-N-hcn7.v1-2-(N.N.N-trimπthylammonium ncetan idG Tctrnflunroborate. Λ solution of 2-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide (1.93 g, 7.76 mmol) in nitromethane (7 mL) was added slowly to' an ice cold solution of trimethyloxonium tetrafluoroborate (1.26 g, 8.54 mmol) in nitro¬ methane (6 mL). The reaction mixture was stirred at this temperature (15 min) and then at room temperature (2 h). Anliydrous E_2θ (-50 mL) was added to the reaction mixture and the white solid that separated was filtered, washed with E_2θ, and dried in vacuo. Yield: 1.95 g (72%). mp 171-173 °C (dec). NMR (CD3NO2) δ 2.14 (s, 3 H), 3.18 (s, 9 H), 4.50 (d, J = 5.8 Hz. 2 H). 5.70 (d, J = 9.3 Hz. 1 H), 7.30-7.41 (m, 5 H). 7.57 (d. J = 9.3 Hz. 1 H). 7.70 (br s. 1 H). IR (KBr) 3300. 1680 (br). 1530, 1490. 710 cm-1. Mass spectrum (FD) 264 (M + ). Elemental analysis Calculated for C14H22N3O2BF4 47.897. C; 6.31% H; 11.97% N. Found 47.80% C; 6.33% H; 12.00% N. EXAMPLE 71 1 Synthesis of 2-Acctnmido-N-beπ7yl-2-fcthylmcrcnnto)acetnrnide-S-oxide. A solution of m-chloroperbcnzoic acid (1.00 g (-65%), 3.76 mmol) in CH2C12 (10 mL) was added dropwise into a stirred, cooled (-10 to -15 °C) CH2CI2 5 solution (125 mL) of 2-acetamido-N-benzyl-2-(ethylmercapto)acetamide (1.00 g, 3.7 mmol) under N2. The reaction was stirred (30 min) at this temperature and then the m-chlorobenzoic acid was precipitated as its ammonium salt by passing NH3 gas over the surface of the reaction solution. The excess NH 3 was removed by passing N 2 gas through the solution (20 min) at room temperature. The ammonium salt was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on S1O 2 gel (2% MeOH CPICI 3 ) to give the desired product. The product was recrvstallized from chloroform/hexan 15 as a white granular solid. Yield: 0.55 g (52%). Rf O.23 (2% MeOH/CHC. 3 ). 20 mp 135-137 °C. IH NMR (DMSO-d 6 ) δ 1.15 (t, J = 7.5 Hz. 3 H), 1.99 (s. 3 H). 2.49-2.56 (m, 1 H), 2.65- 2.72 (m. 1 H), 4.34 (d. J = 5.7 Hz, 2 H). 5.55 (d, J = 9.5 Hz, 1 H), 7.23-7.34 (m, PI), 8.74 (d, J = 9.5 Hz, 1 PI), 8.77 (t, J = 5.7 Hz, 1 H). 25 13 C NMR (DMSO-de) 7.03. 22.34, 42.40.42.47, 67.15, 126.89, 127.27 (2 C), 128.24 (2 C 138.55, 164.66, 170.18 ppm. IR (KBr) 3300 (br), 1640 (br), 1510 (br), 1370, 1230, 1100, 1020, 900 cπr . Mass spectrum (FD) 2S3 (M + +1). - > Elemental analysis Calculated for C 13 H 18 2 O S 55.30% C; 6.43% H; 9.92% N. Found 55.17% C; 6.38% H; 9.70% N. " 35 EXAMPLE 2 1 Synthesis of 2-Acetamido-N-bGnzyl-2-rS-cthylmercπnto)acetamide-S-oxide. A solution of NaI0 4 (1.77 g, 8.27 mmol) in H2O (20 mL) was added dropwise into a stirred solution of 2-acetaπ_ido-N-benzyl-2-(e_hylmercapto)aceta- _ 5 mide (2.00 g, 7.52 mmol) in MeOH (25 mL). A predpitate appeared rapidly. H 2 O (-30 mL) was added to the mixture to dissolve most of the suspension, and the reaction was stirred (4 h) at room temperature. The reaction was concentrated i vacuo and the remaining aqueous mixture was extracted with CHCI3 (3 x 100 0 mL). The combined CHCI3 extracts were dried (Na 2 S0 4 ) and the solvent was removed in vacuo. The oily residue (1.95 g, 92%) solidified on drying in v&___LQ.. NMR analysis (DMSO-dg) of the product showed that it was a 2:1 mixture of the two diastereomers of the desired product. The reaction was recrystallized from 5 .EtOAc to give nearly pure diastereomer A (1.20 g) that was obtained from the rn.- chloroperbenzoic arid reaction. The EtOAc mother liquor was concentrated and the remaining residue (0.75 g) was recrystallized from ethyl ace ate hexane to _ give a diastereomeric mixture (0.41 g) of the two diastereomers A and B. in a 2:3 ratio, respectively. Rf 0.60 (4% MeOH CHCl 3 ). p 135-137 °C (softens at 117 °C). 25 IR (KBr) 3300 (br). 1640 (br Λ 1510 (br). 1370. 1230, 1100, 1020, 900 cπr . Mass spectrum (FD) 283 (M++1). Elemental analysis: Calculated for CJ 3 H 18 N 2 O 3 S: 55.30% C; 6.43% H; 9.92% N. Found: 55.58% C; 6.49% H; 9.97% N. 3° The following NMR spectral properties have been assigned to compounds and B. Piaster? , m . r A. *H NMR (DMSO-d 6 ) δ 1.16 (t, J = 7.5 Hz. 3 H). 2.00 (s, 3 H), 2.49-2.72 (m, 2 H). 4.28- 35 4.39 (m, 2 H), 5.56 (d, J = 9.7 Hz, 1 H), 7.21-7.34 (m, 5 H), 8.71-8.77 (m, 2 H). «C NMR (DMSO-d G ) 7.10.22.43.42.48.42.57, 67.23, 126.98, 127.36 (2 C), 128.33 (2 C) 13S.63, 164.73, 170.25 ppm. 1 iast rr. n nr P. l H NMR (DMSO-d 6 ) δ 1.13 (t, J = 7.6 Hz, 3 H) ' , 1.94 (s, 3 H), 2.49-2.72 (m. 2 H). 4.28- 4.39 (m, 2 H), 5.71 (d, J = 9.9 Hz, 1 H), 7.21-7.34 (m, 5 H), 8.83 (d, J = 9.9 Hz, 1 • 5 H), 8.98 (t, J = 5.6 Hz, 1 H). 13 C NMR (DMSO-d 6 ) 6.47, 22.43, 41.53, _2.55, .67.90, 126.98, 127.36 (2 C), 128.33 (2 C), 138.39, 164.43, 169.82 ppm. 10 15 20 25 30 ' 35 EXAMPLE 73 Synthesis or 2-Acetamido-N-bcπ7.yl-2-.e_.ιnπcsuironyl acetnπ.ide. An aqueous solution (20 mL) of NaI0 4 (3.00 g, 14.02 mmol) was added to a MeOH solution (20 mL) of 2-acctamido-N-benzyl-2-(ethylmcrcapto)acetamide (0.95 g, 3.57 mmol). The initial homogeneous solution rapidly became turbid. H2O (-10 mL) was then added dropwise until the system became homogeneous. The solution was stirred (18 h) at 50-60 °C. MeOH (50 mL) was added to the reaction solution and the prcdpitated salt was filtered and washed with MeOH (10 mL). The filtrate was concentrated and the remaining solution was extracted with CHCI3 (3 x 50 mL). The combined CHCI3 extracts were dried (Na2Sθ4), and concentrated in vacuo. The residue was purified by flash chromatography on Siθ2 gel (1% MeOH/CHCl3) to give the desired product. The product was further purified by recrystallization from EtOH:. Yield: 0.34 g (32%>). Rf 0.34 (3% MeOH/CHCl 3 ). mp 161-163 °C. H NMR (DMSO-de) δ 1.22 (t, J = 7.4 Hz. 3 H), 1.99 (s, 3 H), 3.04-3.24 (m, 2 H). 4.31 (dd, J = 5.7, 15.3 Hz, 1 H), 4. 1 (dd. J = 5.7, 15.3 Hz, 1 H), 5.93 (d, J = 9.8 PIz, 1 H), 7.22-7.35 (m, 5 PI). 9.13 (t, J = 5.7 Hz, 1 H), 9.17 (d, J = 9.8 Hz, 1 H). 13C NMR (DMSO-de) 5.72, 22.27, 42.63, 45.43, 69.14, 127.02, 127.28 (2 C), 128.33 (2 C), 138.16, 161.88, 169.83 ppm. IR (KBr) 3300. 2940. 1660. 1520, 1310. 1230, 1120, 900 cm' . Mass spectrum (FD) 29S (M + ). Elemental analysis Calculated for C13H18N2O S 52.33% C; 6.08% H; 9.39% N. Found 52.52% C; 6.06% PI; 9.53% N. EXAMPLE 74 1 Synthesis of 2-Λcctamido-N-benzyl-2-(N.N.N-trimc hv1ammonuιm . acetamide Tetrnfluoroboratc. A solution of 2-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide 5 (1.93 g, 7.76 mmol) in nitromcthanc (7 mL) was added slowly to * an ice cold solution of trimethyloxonium tetrafluoroborate (1.26 g, 8.54 mmol) in nitro- methane (6 mL). The reaction mixture was stirred at this temperature (15 min) and then at room temperature (2 h). Anhydrous Et 2 θ (-50 mL) was added to the - reaction mixture and the white solid that separated was filtered, washed with E_ 2 θ, and dried in vacuo. Yield: 1.95 g (72%). mp 171-173 °C (dec). 5 *H NMR (CD 3 NO 2 ) δ 2.14 (s, 3 H), 3.18 (s, 9 H), 4.50 (d, J = 5.8 Hz, 2 H), 5.70 (d, J = 9.3 Hz, 1 PI), 7.30-7.41 (m, 5 H), 7.57 (d, J = 9.3 Hz, 1 H), 7.70 (br s, 1 H). IR (KBr) 3300, 1680 (br), 1530, 1490, 710 cm-l. Mass spectrum (FD) 264 (M + ). 0 Elemental analysis Calculated for C 14 H 2 2N 3 O 2 BF 4 47.89% C; 6.317. H; 11.97% N. Found 47.80% C; 6.33% H; 12.00% N. 5 0 5 Example 75 Synthesis of2Αcetaτnido-N-benzyl'2-(l-pyrrole)acetamide. A βoltition of 2- acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2- ethoxyacetamide (2.00 g, 8.0 mmol) and BBr3 (1 M CH2CI2 solution, 8.8 mL, 8.8 mmol)) was prepared in THF (225 mL) and cooled to -78 °C. It was then added under N 2 gas atmosphere to a cooled (-78 °C) suspension of potassium pyrrole (2.71 g, 25.8 mmol) in THF (25 mL). The reaction mixture was stirred at -78 °C (1 h) and then at room temperature (1 h). It was then treated with water (10 rαL) and acidified with 5% citric add to pH 4.0 after which it was made basic with aqueous saturated Na 2 CO 3 solution. The aqueous mixture was extracted with EtOAc (2 x 250 L) and the organic layers were dried (Na2SO ). The volatile materials were removed in vacuo and the residue was purified by flash column chromatography on silica gel using 3% MeOPI CHCl 3 as the eluant to give 0.4 g (18%) of the desired product. It was purified by recrystallization from EtOH: mp 182-184 °C; Rf 0.44 (4% MeOH/CHCI ); H NMR (DMSO-d 6 ) δ 1.91 (s, COCH3), 4.30 (d, J = 5.5 Hz. CH 2 ), 6.01 (s, 2 x C 3 H) , 6.38 (d, J = 8.7 Hz, CH), 6.85 (ε, 2 x C 2 H). 7.11- 7.35 (xn. 5PhH), 8.96 (t, J = 5.5 Hz, NH), 9.14 (d, J = 8.7 Hz, NH); "C NMR (DMSO- c_ ) 22.22 (COCH 3 ), 42.15 (CPI 2 ), 62.86 (CH), 107.79 (2C 3 ), 119.19 (2C 2 ), 126.76 (C4 . 127.01 (2C 2 - or 2C 3 , 128.11 (2C 2 - or 2C 3 '), 138.34 (C r ). 166.37 (CONH), 169.41 (COCK 3 ) ppm; mass spectrum, m/e (relative intensity) 272 (M + +1, 22), 271 (M+, 100). Anal. Calcd for C15H 17 N 3 O 2 O.2 H 2 0: C, 65.53; H, 6.37; N, 15.28. Found: C, 65.80; H, 6.22; N, 15.13. Example 16 Synthesis of2Αceta ido-N-benzyl-2-(l-imidazole)acctamide. Making use of the experimental procedure described in the above experiment, 2-acetamido-N benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BBr3 (1 M CH2CI2 solution, 8.8 mL 8.8 mmol), E_3N (1.62 g, 1.60 mmol), and imidazole (0.60 g, 8.8 mmol) gave 0.60 ( 30%) of the desired product. It was recrystallized from ethyl acetate/liexane as beige colored solid: mp 146-148 °C; f 0. (7% MeOH CHCl 3 ); *H NMR (DMSO-d 6 ) 1.85 (s, COCH 3 ), 4.30 (br s, CH 2 ), 6.53 (d, J = 8.0 Hz, CH), 6.89 (s, C 5 H). 7.12-7.3 ( m, C H, 5PhH), 7.69 (s, C 2 H), 9.06 (br s, Nil), 9.29 (d, J = 8.0 Hz, NH); "c NM ( DMSO-dβ) 22.28 (COCH 3 ), 42.36 (CH 2 ), 61.18 (CH), 117.56 (C δ ). 126.92 (C 4 . 127.1 ( 2C 2 - or 2C 3 0, 128.19 (C 4 ). 128.26 (2C 2 - or 2C 3 , 136.21 (C 2 ), 138.27 (Cy). 165.7 (CONH), 169.77 (COCH 3 ) ppm; mass spectrum, FD (relative intensity) 274 (M + + 2 12), 273 (M++ 1, 77), 272 (100), 205 (34), 274 (18). Anal. Calcd for C 1 H 16 N 4 O2: C, 61.75; H, 5.92; N, 20.57. Found: C, 61.95 H, 6.09; N, 20.32. Example ' 77 Synthesis of -Acetaτnido-N'benzyl-2-(l-pyrazole) acetamide. A solution of 2- acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2- ethoxyacelamide (3.60 g, 14.4 mmol) and BBr 3 (1 M CH CI 2 solution, 15.8 mL, 15.8 mmol)) was prepared in THF (250 mL) and cooled to -78 β C. A solution of triethylamine (2.91 g, 28.8 mmol) in THF (20 mL) was then added to the above solution. This was followed by the addition of THF (30 mL) solution of pyrazole (1.17 g, 17.28 mmol) and the mixture thus obtained was stirred at -78 °C (30 min) and room temperature (1 h). The insoluble materials were filtered and the solvents removed from the filtrate in vacuo. The residue was then purified by flash column chromatography on silica gel using 4% MeOH CHCl 3 as the eluant to give 0.80 g (22%) of the desired product. It was then recrystallized from EtOAc as a white solid: mp 158-160 °C; Rf 0.51 (6% MeOH/ CHCI3) . X H NMR (DMSO-d 6 ) δ 1.93 (s, COCH3), 4.29 (d, J = 5.8 Hz, NH), 6.26 (s, C 4 II), 6.57 (d, J = 8.8 Hz, CH), 7.15-7.33 (m, 5PhII), 7.48 (br s, C 5 II), 7.76 (br s. C 3 H). 8.96 (t, J = 5.8 Hz, NH), 9.23 ( . J = 8.8 Hz, Nil); "c NMR (DMSO-d 6 ) 22.41 (COCH3), 42.40 (CPI 2 ), 65.51 (CH), 105.37 (C 4 ), 126.87 (C 4 , 127.14 (2C 2 - or 2C , 128.25 (2C 2 - or 2C 3 -), 129.00 (C5), 13S.59 (C3) . 139.17 (Cr). 165.68 (CONH), 169.81 (COCH3) ppm; mass spectrum, m/e (relative intensity) 273 (M++1, 11), 272 (M + , 2), 139 (63), 138 (100), 9°- (37). Anal. Calcd for Ci 4 pIi 6 N 0 2 : C, 61.75; H, 5.92; N, 20.57. Found: C, 61.95; H, 5.96; N, 20.28. Synthesis of 2-Acetamido-N-bcnzyl-2-(l-(l t 2,4-triazole)) acetamide. Using 2 acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol), BBr3 (1 M CPI2CI solution, 17.6 mL, 17.6 mmol), Et 3 N (4.85 g, 48.0 mmol), and 1,2,4-triazole (1.43 g 20.8 mmol), 1.20 g (28%) of the desired product was obtained. It was recrystallize from EtOAc as an amorphous white solid: p 146-148 C C; Rf 0.48 (6% MeOH CHCI3); NMR (DMSO-d 6 ) δ 1.85 (s, COCH 3 ), 4.32 (br s, CII 2 ), 6.70 (d, J = 7.8 Hz CH), 7.21-7.29 (m, 5PhH), 8.01 (8/C 3 H), 8.57 (s, C 5 H), 9.04 (br s, Nil), 9.39 (d, J = 7. Hz, Nil); 1 3 Q NMR (DMSO-d 6 ) 22.39 (COCH3), 42.59 (CH 2 ), 65.02 (CH), 126.97 (C 4 127.25 (2C 2 - or 2C 3 , 128.32 (2C 2 - or 2C 3 , 138.47 (Cr), 143.93 (C 5 ), 151.50 (C3) 164.77 (CONH), 170.23 (COCH 3 ) ppm; mass spectrum, FD (relative intensity) 27 (M++2, 12), 274 (M+ -1, 100), 273 (11), 205 (19), 204 (13), 140 (67), 139 (31). Anal. Calcd for Cι 3 H 15 N 5 θ 2 : C, 57.13; H, 5.53; N, 25.63. Found: C, 57.37 H, 5.66; N, 25.38. Anal. Cal.d for C _H... . .0 2 : C, 52.55; H, 5.15; N, 30.6 . . Found: C. 52 75- H, 5.33; N, 30.64. ' ' Example 80 Preparation of α-acetam_do-N-bcnz} * l-2-pyridyla_etamide and 2-acctamido-N- bcnzyl-2-(2 ' -pyridone)acctamide. Pre p aration of 2-ncetamido-2-bromo-N-l>C!izyla .ctn_ni.de. A solution of 2-acc_amido-2-c_hoxy-N-benzylacetam.de (2.00 g, 8 mmol) in dry CH2CI2 (200 mL) was stirred at room temperature as a solution of BDr3 (8.8 mL, 8.8 mmol, 1.0 M in CH2CI2) was introduced by means of a syringe under a nitrogen atmosphere. A white mist formed and after it disappeared, the N2 Hne was removed and the reaction sealed. The resulting yellow solution was stirred (3.5 h) and then concentrated i n va cu o to give yellow crystals of α-acetamido-2-bromo-N-benzyl acetamido which was stored under vacuum ^ overnight. Preparation of 2-P vridylli . lium. The generation of 2-pyrid\ .lithium i n gitu was run under nitrogen. A olution in hexane, 18 mmol) was added to dry ether (GO mL), cooled to -20 °C, and stirred as 2-bromopyridine (1.6 mL, 17 mmol) in dry ether (15 mL) was added dropwise (15 min). Tlie resulting blood red solution was stirred at -20 °C for an additional 5 minutes and then transferred 5 through a doubled-ended needle under a stream of nitrogen to an addition funnel where it was cooled to -78 °C. Q Prcππratipn of α,-pcctarnido-N-benzyl-2-pyridylacetarnide and 2-acetamido-N- hcn_yl-2-(2'-nyridone)ncctamidc. The cooled 2-pyridyllithium solution was added dropwise (approximately 2 drops per second; to the solution of 2-ace _a_r_ido-2-bromo-N-bcnzylacetamide in dry 5 TIIF (200 niL) nnd maintained at -78 °C. The reaction mixture was stirred for an additional 30-45 minutes at -78 °C. Tlie reaction was quenched with saturated aqueous solution of NH4CI (-10 mL) at -78 °C producing a heterogenous mixture Na 2 C0 3 a8 ndd «d dropwise until the precipitate dissolved. The organic laye was separated and then the aqueous layer was extracted with ether (2 x 50 mL) Tlie combined organic layers were dried (N 2Sθ ), concentrated under vacuu and separated using flash chromatography on silica gel with ' ethyl acetate as th 5 eluent. The fractions containing the products were concentrated under vacuum separated and then further purified by column chromatography on alumin (80-200 mesh, Grade 1, Fisher) employing ethyl acetate as the solvent. Fraction -, Q containing α-acetamido-N-benzyl-2-pyridylacetamide was concentrated to drynes and gave a white amorphous solid (250 rag, 11% yield); Rf = 0.39 (5 CH3OH CHCI3); mp 146-147 β C; IR (KBr) 3290, 3180, 3020, 1620 br, 1580, 1520 br, 1480, 1420, 1370, 1310, 1260 cπr 1; *H NMR (300 MHz, DMSO-dg) δ 1.96 (ε, 3H), 4.28 15 (d, J = 5.8 Hz, 2H), 5.59 (d, J = 8.0 Hz, IH), 7.18 -7.30 (m, 5H), 7.32 (dd, J = 7.7, 5. Hz, IH), 7.47 (d, J = 7.7 Hz, IH), 7.80 (dt, J = 7.7, 1.5 Hz, IH), 8.55 (m, 2H), 8.78 (b t, J = 5.8 Hz, IH); 13c NMR (75 MHz, DMSO-dg) 22.5, 2.1, 58.3, 121.7, 122.8, 126.6 126.9 (2C), 12S.1 (2C). 136.8, 139.1, 148.6, 157.2, 169.0, 169.2 ppm; FD (Lilly) mas 20 spectrum, m/e (relative intensity) 284 (M++1, 6), 283 (M+, 0.8), 151 (8), 150 (100), 141 (4). C16H17 3O2 Anal. Calcd for C 67.83, H, 6.05, N, 14.83 Found: C, 6S.11, H, 6.00. N, 14.89. -> Fractions containing 2-acetamido-N-benzyl-2-(2'-pyridone)acetaraide wer combined, concentrated in vacup and yielded a white amorphous solid: (150 mg, 6T0 yield). Rf 0.34 (5.. CH3OH/ CHCJ3); mp 226 decomposed (recrystallized in ethanol) *H NMR (300 MHx, DMSO-dβ) δ 1.94 s, 4.26 (dd, J = 15.2, 5.7 Hz, IH), 4.33 30 (dd, J = 15.2, G.l Hz, lH),6.2υ (br t, J = 6.8 Hz, IH), 6.37 (br d, J =9.1 Hz, IH), 6.69 (d J = 8.7 Hz, IH), 7.22-7.33 (m, 5H), 7.42 (ddd, J = 9.1, 6.8, 1.6 Hz. IH), 7.58 (dd, J = 6. £.1.6 Hz, IH), S.93 (br t, J = 5.8 Hz, IH), 9.20 (d, J = 8.7 Hz, IH); 13c NMR (75 MHz, DMSO-d G ) 22.5. 42.5, G2.5, 105.1, 119.4, 126.81. , 127.10. (2C), 128.2 (2C), 135.6, 138.8, 35 140.2, 161.2, 166.0, 170.0 ppm. Hydrogen and carbon assignments were verified with 1 Η.- 1 ll COSY, lH- 13 C-COSY, zero quantum NMR experiments. Th structure was confirmed bv X-rav crystaIlo_rraDh . Prrp_r nf j ' pp oT aut entic 5-nr (.. i π-N-hnn7r , .'1-2J?'-p^ on'?)a 'π(:ππ.ide. The generation of 2-hydroxypyridylsodium _____ situ was done under anhydrou conditions. A solution of 2-hydroxypyridine (1.57 g, 16 mmol, vacuum dried, 9790 Aldrich) in dry THF (200 mL) was stirred and cooled to 0°C and then NaH (0.77 g 60S. in mineral oil, 19.2 mmol) was added in one portion leading to the evolution o H 2 and the generation of a heterogeneous mixture. A solution o 2-acetamido-2-hromo-N-b enzylacetamide (8 mmol based o 2-acetamido-2-e_ o ' xy-N-benzylacetamide) in dry THF (160 L) was the transferred through a double-ended needle by means of a stream of nitrogen. Th resulting mixture was quenched with saturated aqueous solution of NH4CI (5 mL) at 0°C producing a white precipitate. Λ saturated aqueous solution Na2CO was added dropwise while stirring at 0°C until all of the white precipitat dissolved. The two layers were separated while cold and then the aqueou fraction was extracted with TKF (2 x 100 L). The combined organic layers wer dried (N32SO4), and concentrated to dryness. Tlie crude reaction mixture residu was dissolved in a minimum of CHCl ατύ. a__lash chromatographed on a silica ge column using ethyl acetate as the eluer, . and gave a white amorphous solid (1.1 g, 46 ό yield) which was identical to properties previously observed fo 2-acetamido-N-benzyl-2-(2'-py_ _done)ace_amide: P-f 0.34 (59_ f I3OH CHCI3); m 162-163.5 °C (recrystallized in ethyl acetate); HI (KBr) 3300, 3280, 3260, 3080, 1690 16S0, 1650 br, 1580, 1570, 1520, 1490, 114- cm-*; *H NMR (300 MHz, DMSO-dg) δ 1.9 (s. 3H), 4.27 (dd, J = 15.3, 5.8 Hz, IH), 4.3G (dd, J = 15.3, 6.2 Hz, IH), G.27 (dt, J = 6.8 1.1 Hz, IH), 6.39 (bd, J = 8.9 Hz, IH), G.71 (d, J = 8.7 Hz, IH), 7.22-7.34 (m, 5H), 7.4 (ddd, J = 8.9, 6.8, 1.9 Hz, IH), 7.59 (dd, J = 6.8, 1.9 Hz, IH), 8.93 (br t, J = 5.9 Hz IH), 9.20 (d, J = 8.7 Hz, IH); 13 C NMR (75 MHz, DMSO-d 6 ) 22.4, 42.5, 62.5, 105.1 119.4, 126.8, 127.1 (2C), 128.2 (2C). 135.6, 138.8, 140.1, 161.1, 166.0, 169.9 ppm; F (Lilly) mass spectrum, m/e (relative intensity) 598 (2M, 2), 300 (M++1, 17). 29 (M+, 100), 96 (2), 95 (26). C16H17 3O3. Λnal. Calcd for C. 64.20, H 5.73, N 14.04. EXAMPLE 81 α.-acctamido-N-benzyl-2-pyridyl acetamide N-σxide To a cooled solution of 2-α-acctamido-N-benzyl- 2-pyridylacctamide dissolved in dry THF is added m-pαrchloroperbcnzoic acid to give the resulting'product. Similarly, using the procedure described hereinabove, the following examples are prepared. 2-acetamido-N-benzyl-2-{3-pyridyl)acetamide and the N-oxide thereof, 2-acctamido-N-benzyl-2-( -pyridyl)acetamide and the N-oxide thereof, 2-acetamido-N-bαn∑yl-2-(2-pyrimidinyl)acetamide and the N-oxide thereof 2-acetamido-N-benzyl-2-{ -pyrimidinyl)acetamide and the N-oxide thereof, 2-acetamido-N-benzyl-2-(5-pyrimidinyl)acetamide and the N-oxide thereof, 2-acctamido-N-benzyl-2-(3-pyridazinyl)acetamide and the N-oxide thereof, 2-acetamido-N-benzyl-2-( -pyridazinyl)acetamide and the N-oxide thereof, 2-acetamido-N-bcπzyl-2-( -pyrazinyl) acetamide and the N-σxide thereof, 2-ace amido-N-benzyl-2-(2-thiazolyl)acetamide, 2-acetamido-N-benzyl-2-(2-oxazolyl) cetamide, 2-acetamido-N-benzyl-2-(3-isoxazolyl)acetamide, 2-acetamido-N-benzyl-2-(5-isoxatolyl)acetamide, 2-acetamido-N-bεnzyl-2-(3-isothiazolyl)acetamide, an ' 2-acetamido-N-benzyl-2-(5-isothiazolyl)acetamide. ' Λnal calc. f o r C 17 H 18 N-0 2 S: C 6.. 4, H 5.77. Foun d : C 65.27, H 5.54. Example 83 1 Synthesis of cc-Acetamido-N-benzyl.2-(tetrahydrofuran)acetamide (3 methanolic solution (70 mL) of α-acetamido-N-benzyl-2-furanacetamide (3.5 12.85 mmol) was hydrogenated (35-40 psi) in the presence of Pd C (10%, 0.44 g) 5 h). The catalyst was filtered tlirough celite, washed with MeOH (10 mL) and filtrate concentrated to dryness in υacuό to give & and 2 (3.50 g) as a white so The products were fractionally recrystallized from EtOAc to give 1.30 g (37%) of mp 159-161 °C; 11 0.38 (6% MeOH/CHCl 3 ). IR (KBr) 3340 (br), 3000, 1600, 1550 ( 10 1420, 1350, 720, 680 cm- l ; IH NMR (DMSO-d 6 ) δ 1.66-1.90 (m, C 3 H 2 , C 4 H 2 ), 1 (C(0X_H 3 ), 3.62-3.68 (m, C 5 HH'). 3.75-3.80 (m, C 5 HH * ), 3.98-4.00 (m, C 2 H), 4.26-4 (m, CH, CH 2 ), 7.18-7.32 (m, 5 Phil), 8.11 (d, J = 8.8 Hz, NH), 8.52 (t, J = 5.8 NH); 13 C NMR (DMSO-d 6 ) 22.52 (C(0)CH 3 ), 24.78 (C 3 ), 27.82 (C 4 ), 41.96 (CH 2 ), 55 15 (CH), 67.54 (C 5 ), 78.48 (C 2 ), 126.58 (C 4 * ), 127.97 (2C 2 ' or 2C 3 '), 128.12 (2C 2' or 2C 139.27 «V ) . 169.09 ( C ( O ) NH ) , 170.09 (C(O)CH 3 ) ppm; mass spectrum m/e ( relat intensity ) 277 ( M + +1. 4 ) , 206 (52), 142 (13), 106 (38), 91 (100), 71 ( 97). An (Cι 5 H 20 N 2 O 3 ) C, H, N. 25 0 $5 1 The remaining EtOAc mother liquor after recrystallization w concentrated to half its volume and hexane was added dropwise while heati until the solution became turbid. A white solid (0.65 g, 18%) separated on cooli 5 and was collected by filtration to give diastereoisomer 2h * mp 130-132 °C; R/- 0. (6% MeOH/CHCl 3 ); W NMR (DMSO-d 6 ) δ 1.55-1.86 (m, C 3 H 2 , C H 2 ), 1.89 C(0)CH 3 ), 3.55-3.64 (m, CsHH'), 3.70-3.78 (m. C5HID, 4.08-4.11 (m, C 2 H), 4.27 (d = 5.8 Hz, CH 2 ), 4.36 (dd, J = 4.7, 8.6 Hz, CII), 7.21-7.32 (m, 5 Phil), 7.94 (d, J = 10 Hz, NH), 8.39 (t, J = 5.8 Hz, Nil); C NMR (DMSO-d 6 ) 22.45 (C(0)CH 3 ). 25.16 ( 27.53 (C 3 ), 42.04 (CH 2 ), 55.48 (CH), 67.53 (C 5 ), 78.26 (C2), 126.59 (C 4 '), 127.04 (2C2 2C 3 '), 128.10 (2C 2 ' or 2C3'), 139.21 (Ci'). 169.55 (C(O)NH), 169.79 (C(0)CH 3 ) p mass spectrum m/e (relative intensity) 277 (M++1, 4), 206 (50), 142 (23), 106 (39), (100), 71 (96). Anal. (Cι 5 H 2 oN 2 0 3 ) C, II, N. 20 25 .0 - . ^ Example 34 O o o Br II II CH 3 CNH ■ c II II I 3 II COCH I ° C_πH 33 C V_NI HΠ »_, C _ υOC . HH 3 CH 2 I CH 3 _L_> ιe Example 85 Synthesis of -Acetamido-2-methyl-2-furan celϊc Acid (Jg). A 95% EtO solution (150 mL) of 1Z (5.00 g, 23.6 mmol) and KOH (3.00 g, 53.5 mmol) was stirre at room temperature (48 h). The solvent was removed and the residue wa dissolved in H2O (50 mL). The aqueous solution was washed with t2θ (3 x 50 m and then acidified to pH 1.5 with 10% H3PO 4 . The acidified solution was extracte with EtOAc (3 x 200 mL) and the combined extracts were dried (Na2SO4 , an concentrated in vacuo to give 2.90 g (62%) of 1_5: mp 178-180 °C (d) (recrystallize from CH 3 CN); IR (KBr) 3400 (br), 1700 (br) cπr ; *H NMR (DMSO-d 6 ) δ 1.67 ( CHs), 1.83 (ε, C(O)Cπ 3 ), 6.39 (m, C 3 II. C 4 II), 7.59 (s, C5II), 8.34 (s, Nil), 12.63 ( C(O)OH); I3 c NMR (DMSO-d 6 ) 22.20 (C(θyCH 3 ), 22.59 (CH 3 ), 57.65 (C(CH 3 )), 107.0 (C 4 ), 110.49 (C s ) . 142.33 (C 5 ), 153.36 (C 2 ), 168.86 (C(O)NH), 171.78 (C(O)OH) pp mass spectrum, m/e (relative intensity) 198 (M++1, 4), 143 (97), 152 (63), 140 (23 111 (73), 110 (100), 94 (24). Anal. (C 9 H 11 NO 4 ) C, H, N_ Example 86 Synthesis of a-Acetamido-N'benzyϊ-2-methyl-2-furanacetamide ( Employing the mixed carbonic anhydride coupling procedure & & with 1£ (2.4 12.2 mmol), 4-methylmorpholine (1.23 g, 12.2 mmol), isobutylchloroformate (1 g, 13.4 mmol), and benzyiamine (1.43 g, 12.7 mmol) gave 4 (l._50 g, 43%) as a th oil: R/-0.29 (2% MeOH/CHCl 3 ); H NMR (CDCI3) δ 1.94 (s, CII3), 1.98 (s, C(0)CI 4.40 (d, J " = 5.6 Hz, CH 2 ) . 6.20 (br ε, NH), 6.34-6.37 (m, C 3 H, C 4 H), 7.05-7.36 (m, C5H, 5 PhH); 13C NMR (CDCI3) 22.31 (C(0)CH 3 ), 23.81 (CH 3 ), 43.77 (CH 2 ), 58 (C ( CH 3 )), 107.94 (C 4 ), 110.67 (C 3 ), 126.99 (2C 2 ' or 2C 3 '), 127.41 (0 4 '), 128.60 (2C2 2C 3 '), 137.52 (Ci*), 142.38 (C 5 ), 152.94 (C 2 ), 169.03 (C(O)NH), 171.16 (COCH 3 ) p mass spectrum, m e (relative intensity) 287 (M++ 1, 4), 228 (4), 153 (99), 152 (96), (15), 111 (63), 110 (100), 91 (75); M τ (El) 286.13074 (calcd for Cι 6 Hi8N 2 θ3, 286.1317 Example 87 Synthesis of a-ThioacetamidoJ^benzyl^-furanacetamide (5). A TH solution (80 mL) of 2 (1.00 g, 3.68 mmol) and Lawesson's reagent (0.73 g, 1.8 mmol) was stirred at room temperature (4 h). The THP was removed in vacu __ and the residue was purified by flash colum chromatography on Siθ2 gel usin _> 1% MeOH CHCl 3 to give 0.75 g (71%) .of £ mp 78-80 °C; R -0.51 (1% MeOH/CHCl 3 ) IR (KBr) 3200 (br), 1630, 1500, 1440, 1350, 790, 710, 680 cm- i ; IH NMR (DMSO-d 6 ) 2.46 (s, C(S)CII 3 ), 4.27-4.35 (m, CH 2 ), 6.22 (d, J = 7.7 Hz, CH), 6.32 (d, J = 3.3 Hz C 3 II), 6.41-6.44 (m, C 4 H), 7.15-7.33 (m, 5 PhH), 7.64 (s, C 5 H), 8.81 (t, J = 5.9 Hz NH), 10.54 (d, J = 7.7 Hz, NH); 13 C NMR (DMSO-d G ) 32.70 (s, C(S)CH 3 ), 42.39 (CH 56.82 (CH), 108.76 (C 3 ), 110.67 (C4), 126.81 (CJ), 127.12 (2C2 * or 2C 3 '), 128.23 (2C 2 ' 2C 3 '). 139.98 (C-.'), 143.06 (C 5 ), 149.53 (C 2 ), 166.55 (C(O)NH), 200.68 (C(S)CH 3 ) pp mass spectrum (FD) 288 (M + ). Anal. (Ci5Hι 6 N 2 0 2 S) C, H, N. Z Example 88 2_ Synthesis ofa-Thiocιcetanιido N z benxyl-2-furanthioa etajnide (Q). A T solution (90 mL) of 2 (2.00 g, 7.35 mmol) and Lawesson's reagent (3.27 g, 8 mmol) was heated to reflux (4 h). The THF was removed in vacuo and the resi c was purified by two successive flash column chromatographies on Siθ 2 gel us 0.5% MeOH CHCl 3 as the eluant in the first chromatography and CHC1 3 in second chromatography. Compound £ (0.50 g, 22%) was then further purified preparative TLC (CHCI 3 ): mp 99-101 °C; R 0.74 (1% MeOH/ CHCI 3 ); IR (KBr) 31 0 1580, 1500 (br) cm- l ; H NMR (DMSO-d 6 ) δ 2.58 (s, C(S)CII 3 ), 4.86 (dd, J = 5.4, 1 Hz, CHH), 4.96 (dd, J = 5.4, 15.0 Hz, CHH), 6.49-6.55 (m, C 3 H, C H), 6.65 (d, J = Hz, CH), 7.31-7.43 (m, 5 PhH), 7.75 (s, C 5 II) 10.64 (d, J = 7.5 Hz, NH), 10.95 (t, 5.4 Hz, NH); 13 Q NMR (DMSO-d 6 ) 32.79 (s, C(S)CH 3 ), 48.30 (CH 2 ) . 61.88 (C 5 108.50 (C 3 ), 110.53 (C 4 ), 127.05 (C 4 * ). 127.48 (2C 2 * or 2C 3 '), 128.19 (2C 2 ' or 2C 136.67 (Ci'), 142.91 (C 5 ), 150.15 (C 2 ), 197.45 (C(S)NH), 200.56 (C(S)CH 3 ) ppm; m spectrum (FD) 304 (M + ). Anal. (C15H16N2OS2) C, H, N. 0 Z C 5 - - Example 89 Synthesis of a-Acetamifo-N- ~ (3-pyπ ~ dinylmethyl)-2-furanacetamide Using racemic 12 (3.00 g, 16.39 mmol), 4-methylmorpholine (1.66 g, 16.39 mm isobutyl chloroformate (2.24 g, 16.39 mmol), and 3-aminomethylpyridine (1.77 16.39 mmol) in the mixed carbonic anhydride protocol gave 3.35 g (75%) of 2: 172-174 °C (recrystallized from EtOAc); Ry 0.27 (8% MeOH. CHC1 3 ); IR (KBr) 34 3300, 1640, 1540, 1420, 1360, 820, 740 cm- 1 ; J H NMR (DMSO-d 6 ) δ 1.89 (s. C(0)C 4.32 (d, J = 5.8 Hz, CH 2 ), 5.55 (d, J = 7.9 Hz, CH), 6.28-6.29 (m, C 3 H), 6.41-6.43 C 4 H), 7.32 (dd, J = 4.8, 7.7 Hz, C 5 'H), 7.58-7.62 (m, C 'H, C 5 H), 8.44 (br ε, C 2 C 6 Η), 8.62 (d, J = 7.9 Hz, Nil), 8.81 (t, J = 5.8 Hz, NH); ^C NMR (DMSO-d 6 ) 22 (C(0)CH 3 ), 39.98 (CH 2 ). 50.94 (CH), 107.67 (C4). 110.54 (C 3 ), 123.38 (C G '), 134 (C 3 '), 134.83 (C 4 '), 142.64 (C 5 ), 148.06 (C G '), 148.55 (C 2 '), 150.94 (C 2 ), 168 (C(O)NH), 169.26 (C(O)CH 3 ) ppm; mass spectrum (FD) 274 (M++1). An (C 14 H 15 N 3 0 3 ) C, H, N. Example 90 Synthesis of a-Acetarnido-N-(4-pyridinylιnethyl)-2-furanacetaτnide ( Malcing use of racemic 12 (3.00 g, 16.39 mmol), 4-methylmorpholine (1.66 g, 16, mmol), isobutylchloroformate (2.24 g, 16.39 mmol), and 4-aminomethylpyridi (1,77 g, 16.39 mmol) in the mixed carbonic anhydride method- gave 3.40 g (7 of fi: mp 168-170 °C (recrystallized from EtOAc); Rf 0.31 (8% MeOH/CHCl 3 ); (KBr) 3180, 1650 (br), 1480, 1400, 1340, 780, 740 cur*; *H NMR (DMSO-d 6 ) δ 1.90 C(0)CH 3 ), 4.32 (d, J = 5.7 Hz, CH 2 ), 5.57 (d, J = 7.8 Hz, CH), 6.32-6.34 (m, C 3 6.42-6.43 (m, C H). 7.19 (d, J = 4.9 Hz, C 3 'H, C 5 'H) , 7.64 (s, C 5 H), 8.46 (d, J = 4.9 C 2 'H, C 6 Η), 8.64 (d, J = 7.8 Hz, NH), 8.84 (t, J = 5.7 Hz, NH); "C NMR (DMSO- 22.27 (C(0)CH 3 ), 41.26 (CH 2 ), 50.99 (CH), 107.74 (C 4 ), 110.54 (C 3 ), 121.87 (C 3 \ C 142.63 (C 5 ), 148.17 (C 4 '), 149.35 (C C β '), 150.82 (C 2 ), 168.35 (C(O)NH), 169 (C(0)CH 3 ) ppm; mass spectrum (FD) 274 (M .+..+1) _.. Anal. (Cι Hι 5 N 3 0 3 ) C, H, N. H 12 Example 91 Synthesis of a-Acetaτrάdo-N-(l-oxo-3-pyridinylnιethyl)-2-furanacetamid (9). A solution of X (1.50 g, 5.49 mmol) and m-chloroperoxybenzoic acid (1.90 6.04 mmol) in THF (175 mL) was heated to reflux (3 h) and then cooled to roo temperature. The THF solution was concentrated to approximately half i volume, and then cooled to give 1.00 g (63%) of 2 . p 159-161 °C (recrystallize from EtOH); Rf 0.30 (20% MeOH/CHCl 3 ); IR (KBr) 3400 (br), 1620, 1500 (br), 142 1350, 750 em- l ; *H NMR (DMSO-d 6 ) δ 1.89 (s, C(0)CH 3 ), 4.27 (d, J = 5.0 Hz, CH 2 5.53 (d, J = 7.6 Hz, CII), 6.31 (br s, C 3 π), 6.42 (br s, C H), 7.14-7.18 (m, 1 ArH), 7.3 7.37 (m, 1 ArH), 7.61 (br s, C 5 H), 8.07 (s, 2 ArH), 8.63 (br s, Nil), 8.80 (br s, NH 13 C NMR (DMSO-d 6 ) 22.29 (C(0)CH 3 ), 39.36 (CH 2 ), 50.99 (CH), 107.79 (C 4 ). 110.5 (C 3 ), 124.03 (C '). 126.10 .C 5 * ), 137.16 (C 3 '), 137.31 (C 6 '). 138.70 (C 2 '), 142.69 (C 5 150.72 (C 2 ), 168.40 (C(O)NH), 169.32 (C(0)CH 3 ) ppm; mass spectrum (FD) 289 (M+ M r (El) 289.10554 (calcd for Ci 4 H 15 N 3 0 4 , 289.10626). Anal. Calcd for Ci 4 Hι 5 N 3 θ -2.0 H 2 0: C, 51.69; H, 5.89; N, 12.92. Found: 52.03; H, 5.56; N, 13.36. Example 92 Synthesis of a-Acetamido-N-(l-oxo-4-pyridinylmethyl)-2-furanacetam (10). Following the preceding procedure and using £ (1.50 g, 5.49 mmol) and chloroperoxybenzoic acid (1.90 g, 6.04 mmol) gave a light yellow solid (0.96 g, 6 directly upon cooling the THF solution. The precipitate was filtered recrystaUized from EtOH to give IQ: mp 210-212 °C (d); R 0.25 (20% MeOH/CH IR (KBr) 3300, 1620, 1500, 1410, 1350, 740 cm-1; *H NMR (DMSO-d G ) δ 1.89 C(0)CII 3 ), 4.26 (d, J = 5.8 Hz, Cπ 2 ), 5.52 (d, J = 7.7 Hz, CH), 6.30 (br s, C 3 H), 6. 6.42 (m, C 4 H), 7.21 (d, J = 6.8 Hz, C 3 Η, C 5 'H), 7.63 (s, C 5 H) . 8.14 (d, J = 6.8 C 2 Η, Ce'H), 8.62 (d, J = 7.7 Hz, Nil), 8.82 (t, J = 5.8 Hz, Nil); "C NMR (DMSO 22.35 (C(0)CH 3 ), 40.68 (CH 2 ), 51.14 (CH), 107.87 (C 4 ), 110.62 (C 3 ), 124.83 (C 3 ', 137.43 (C 4 '), 138.39 (C 2 ', C G '), 142.72 (C 5 ), 150.77 (C 2 ), 168.48 (C(O)NH), 16 (C(0)CH ) ppm; mass spectrum (FD) 289_(M+). Λnal. (Ci Hι 5 N 3 0 4 ) C, II, N. Example 93 1 Synthesis of -Acetamido-2-furanacetic-2'-pyridinehydrazide (11) Following the mixed carbonic anhydride procedure and using racemic 12 (2.0 g, 10.39 mmol), 4-methylmorpholine (1.10 g, 10.93 mmol), isobutyl chloroformat (1.49 g, 10.93 mmol), and 2-hydrazinopyridine (1.20 g, 11.00 mmol) gave a insoluble material upon workup containing H. and 4-methylmorpholin hydrochloride. The reaction products were suspended in EtOH (25 mL), and (1.00 g) was collected by filtration. Concentration of the THF filtrate an I® trituration of the residue with EtOΛc gave an additional 0.70 g of H to give combined yield of 1.70 g (64%): mp 226-228 °C (recrystallized from EtOH); Rf 0.3 (10% MeOH/CHCl 3 ); IR (KBr) 3400, 1650, 1580, 1440, 1360, 1320, 770, 730 cm- 1 ; _ NMR (DMSO-d 6 ) δ 1.83 (s, C(0)CII 3 ), 5.64 (d, J = 8.0 Hz, CII), 6.41-6.50 (m, C 3 15 C 4 II, C 5 T_), 6.67 (dd, J = 5.4, 6.7 Hz, C 3 'II), 7.44-7.52 (m, C 4 Η), 7.66 (s, C 5 H), 8.0 (d, J = 4.0 Hz, C 6 'H) . 8.40 (s, C(O)NHNII), 8.66 (d, J = 8.0 Hz, Nil), 10.20 ( C(O)NHNH); 13c NMR (DMSO-d 6 ) 22.26 (C(0)CH 3 ), 49.56 (CH), 105.93 (C 3 '), 107.8 (C 3 ), 110.57 (C 4 ), 114.50 (Cβ'), 137.48 (C 4 '). 142.76 (C 5 ), 147.45 (C G '), 150.60 (C 2 0 159.59 (C 2 '), 167.88 (C(O)NII), 169.28 (C(0)CH 3 ) ppm; mass spectrum (FD) 27 (M+); M τ (El) 274.10649 (calcd for Cι 3 Hi N θ 3 , 274.10659). 0 H ιa 5 Example 94 Synthesis ofR(-)a-A etamidc-N-(4-fluorobenzyl)-2-furanacetanύde (( Using (_ . )-____. (0.94 g, 5.1 mmol), 4-methylmorpholine (0.52 g, 5.1 isobuty chloroformate (0.70 g, 5.1 mmol), and 4-fluorobenzylamine (0.65 g mmol) in the mixed carbonic anhydride method gave 1.00 g (68%) of (i_)-1 205-207 °C (recrystalUzed from EtOAc); Rf 0.30 (4% MeOH/CHCl 3 ); [α] M D = (c=l, MeOH); IR (KBr) 3400 (br), 1620, 1580, 1500 (br), 1350, 770, 720 cm-l; _H (DMSO-d 6 ) δ 1.89 (s, C(0)CH 8 _ _ 4.27 (d, J = 5.9 Hz, CH 2 ), 5.54 (d, J = 8.0 Hz 6.27 (d, J = 3.0 Hz, C 3 H), 6.41 (dd, J = 1.9, 3.0 Hz, C H), 7.08-7.15 (m, 2 ArH) 7.26 (m, 2 ArH), 7.61 (d, J = 1.9 Hz, C 5 H), 8.58 (d, J = 8.0 Hz, NH), 8.74 (t, Hz, NH) ppm; addition of IK-) mandelic acid to a CDC1 3 solution of (R)-]_2 gav one signal for the acetamide methyl protons. Mass spectrum (FD) 290 Anal. (Cι 5 Hι 5 FN 2 0 3 ) C, H, N. Synthesis o R(-)ct-Λcet{iτniιlι>-N-(<J-mct}ιylbcιvzyl)-2-fιιranacctami<.Ie ((1 Employing the mixed carbonic anhydride procedure and making use of ( (1.50 g, 8.20 mmol), 4-methylmorpholine (0.83 g, 8.20 mmol), isobutylchlo mate (1.12 g, 8.20 mmol), and 4-mcthylbenzyl mine (0.99 g, 8.20 mmol) gave (77%) of (R)-_UL mp 210-212 °C (recrystallized from EtOΛc); Rf 0.5 MeOH/CHCl 3 ); [α] 2 ^ = -74.43 (c=l, MeOH); IR (KBr) 3400 (br), 1610 (br), 150 1350, 1320, 780, 720 cm- l ; l jj NMR (DMSO-d 6 ) δ 1.89 (s, C(0)CII 3 ), 2.25 (s, 4.24 (d, J = 5.5 Hz, CII 2 ), 5.56 (d, J = 8.1 Hz, CH), 6.28 (br s, C 3 H), 6.41 (br s, 7.09 (br s, 4ΛrH), 7.61 (br s, C 5 II), 8.58 (d, J = 8.1 Hz, NH), 8.72 (t, J = 5.5 Hz, addition of (RX-)mandelic acid to a CDC1 3 solution of (J?)-12. gave only one for the acetamide methyl protons. 13 C NMR (DMSO-d 6 ) 20.G4 (CH 3 ), (C(0)CH 3 ), 42.00 (CH 2 ), 50.88 (CH), 107.52 (C ), 110.50 (C 3 ), 127.06 (2C 2 * or 128.77 (2C 2 ' or 2C 3 " ), 135.82 (Ci' or CV), 135.98 Ci' or C 4 '), 142.51 (C 5 ), 151.2 167.87 (C(O)NH), 169.17 (C(0)CH 3 ) ppm; mass spectrum (FD) 287 (M++ 1). (Cι 6 Hi 8 N 2 θ 3 ) C, H, N. Example 95 1 Synthesis ofR(-) -Acetamido-N-(4-triftuoromethylbenzyl)-2-furanacet mide ((R)-14)> Usin (_ _)-_]__ (1.00 g, 5.46 mmol), 4-methylmorpholine (0.55 g, 5.4 mmol), isobutylchloroformate (0.75 g, 5.46 mmol), and 4-trifluoromethylbenzy 5 amine (0.96 g, 5.46 mmol) in the mixed carbonic anhydride protocol - gave 1.15 (59%) of (7. )-14: mp 193-195 °C (recrystallized from EtOAc/hexane); [α] 2 6 = -69.2 (c=l, MeOH); IR (KBr) 3220, 1610, 1520, 1400, 1350, 800, 720 cm- 1 ; Η NMR (DMS de) δ 1.89 (ε, C(0)CH 3 ), 4.37 (d, J = 5.8 Hz, CH 2 ), 5.56 (d, J = 7.9 Hz, Cn), 6.30-6.3 0 (m, C 3 H), 6.41-6.43 (m, C 4 H), 7.40-7.43 (m, 2ArII), 7.63-7.68 (m, 2ArH, C 5 H), 8.6 (d, J = 7.9 Hz, NH), 8.44 (t, J = 5.8 Hz, Nil); addition of (RX-)- andelic acid to CDCI3 solution of (7. )-14 gave only one signal for the acetamide methyl proton Mass spectrum (FD) 340 (M+). Anal. (Ci6Hi5F 3 N 2 0 3 ) C, H, N. 5 GENERAL SYNTHESIS General Synthesis - Several preparative routes were utilized for the construction the targetted compounds. In most cases, 2-acetamido-_V-benzyl-2-aminoacet 0 mide * (2r) served as the starting material. Treatment of ΣJr with the appropria chloroformate, isocyanate, isothiocynnate, anhydride, or use of the mix anhydride protocol advanced for peptide synthesis led to the preparation of the acyl substituted adducts 2e-2l auu 2___l- Correspondingly, the preformed α-bro 5 derivative 2s * *s employed ns the immediate precursor for 2m and 2___l, while acetamido-_V-benzyl-2-(trimethylaτnmonio)acctamide tetrafluoroborate- (2 ) w utilized for the synthesis of __\. Finally, alkaline hydrolysis of 2p. followed o neutralization of the dipeptide by passage through an ion exchange resin yielde 2fl. In Examples 96-108 , reference is made to the following compounds O R 2 O • II I II CH 3 CNH CH - CNHCH 2 Ph NHC(0)CH 2 NHC(0)OCH 2 P NHCH 2 C(0)OCH 2 CH 3 NHCH 2 C(0)OCH 2 Ph ftH 2 CH 2 C0 2 " NH 2 r N(CH 3 ) 3 . BF 4 * NHC(0)CH 3 NHC(0)CF 3 Example 96 Chemistry - Synthesis ofMethyI{acetanddo(benzy :arbanioyl)methyl]carba- niate (2e). Methyl cliloro formate (0.33 g, 3.35 mmol) was added to a solution of 2r (0.70 g, 3.16 mmol) and Et 3 N (0.39 g, 3.80 mmol) in THF (75 mL), and then th reaction mixture was stirred at 55-60 °C (2 h). The Et 3 N HCl that precipitated wa filtered and the filtrate was concentrated to dryness in vacuo. The residue wa triturated with EtOΛc (20 mL), and tlie remaining white solid (0.55 g, .62%) wa filtered and recrystallized from EtOH: mp 202-204 °C (d); R f 0.53 (10 MeOH/CHCl 3 ); IR (KBr) 3260, 1650, 1500, 1440, 1360, 780, 690 cm- 1 ; IH NM (DMSO-d 6 ) δ 1.86 (s, C(0)CH 3 ), 3.54 (s, OCH 3 ), 4.27 (d, J = 5.6 Hz, CH 2 ), 5.56 (t, J 7.8 Hz, CH), 7.18-7.32 (m, 5PhII), 7.70 (br s, NHC(0)OCH 3 ), 8.40 (d, J = 7.8 Hz, NH), 8.51 (t, J = 5.6 Hz, NH); ^C NMR (DMSO-d 6 ) 22.38 (C(0)CH 3 ), 42.29 (CH 2 ) 51.46 (OCH 3 ), 58.57 (CH), 126.52 (C , 126.98 (2C 2 - or 2C 3 , 127.99 (2C 2 - or 2C 3 139.03 (Cr), 167.83 (C(O)NH), 169.33 (C(0)CH 3 ) ppm, the carbamate carbony signal was not detected. Mass spectrum (FD) 279 (M + ). Anal. Calcd for Cι 3 Hι 7 N 3 0 4 : C, 55.91; H, 6.14; N, 15.05. Found: C, 56.16; H, 6.10; N, 14.89. - Example 97 Synthesis of Phenyl[acetamido(benzytearbamoyl)methyl]carbaιnate ( Compound _2 ∑ (0.80 g, 3.62 mmol) was dissolved in warm THF (75 L), and t Et 3 N (0.44 g, 4.35 mmol), and phenyl chloroformate (0.62 g, 3.98 mmol) w added. The reaction mixture was stirred at 45-50 °C (2' h), and the vola materials were removed in vacuo. The residue was triturated with EtOAc (20 and the remaining white solid material (0.80 g, 65%) was filtered, washed H 2 0 (10 mL), and then recrystallized from MeOH: mp 201-203 °C; Rf 0.38 ( MeOH/CHCl 3 ); IR (ΪO_ r) 3400 (br), 3240, 1700, 1630, 1500, 1460, 1320, 1200, 740, cm- 1 ; IH NMR (DMSO-d 6 ) δ 1.89 (s, C(0)CH 3 ), 4.29-4.35 (m, CH 2 ), 5.66 (t, J = Hz, CII), 7.08-7.42 (m, lOArH), 8.43 ( , J = 7.6 Hz, NH), 8.58 (d, J = 7.6 Hz, N 8.67 (t, J = 5.0 Hz, NH); 13 C NMR (DMSO-d 6 ) 22.58 (C(0)CH 3 ), 42.51 (CH 2 ), 5 (CH), 121.70 (2C 2 ), 125.18 (C 4 ), 126.76 (C 4 , 127.19 (2C 2 > or 2C 3 , 128.21 (2C 2C 3 . 129.30 (2C 3 ), 139.14 (Cr), 150.91 (Ci), 167.73 (C(O)NH), 169.75 (C(0)C ppm, the signal for the carbamate carbonyl was not detected. Mass spectr (FD) 341 (M+). Anal. Calcd for Cι 8 Hι 9 N 3 0 : C, 63.33; H, 5.61; N, 12.31. Found: C, 63. H, 5.64; N, 12.12. Example 98 - Synthesis ofl-[Acetamido(benzylcarbamoyl)rnethyl]-3-methylurea (2g) Methyl isocyanate (0.20 g, 3.48 mmol) was added to a solution of £r (0.70 g, 3.1 mmol) in THF (75 mL), and then the reaction was stirred at 45-50 °C (2 h). Th - white solid (0.80 g, 91%) that separated put was filtered and recrystallized fro MeOH to give 2g: p 229-230 °C (d); Rf 0.25 (10% MeOH/CHCl 3 ); IR (KBr) 3200 3060, 1630, 1500 (br), 1350, 1300, 740, 680 cm *1 ; *H NMR (DMSO-d 6 ) 6 1.82 (s C(0)CH 3 ), 2.54 (d, J = 4.5 Hz, NHCH 3 ), 4.26 (d, J = 5.8 Hz, CH 2 ) , 5.59 (t, J = 7.8 Hz 0 CH), 6.19 (d, J = 4.5 Hz, NHCH 3 ), 6.52 (d, J = 7.8 Hz, NHC(0)NHCH 3 ), 7.20-7.31 (m 5PhH), 8.38 t, J = 5.8 Hz, NH), 8.46 (d, J = 7.8 Hz, NH); 13C NMR (DMSO-d 6 ) 22.3 (C(0)CH 3 ), 26.03 (NHCH 3 ), 42.Ϊ9 (CH 2 ), 57.92 (CH), 126.54 (C 4 '), 126.93 (2C 2' o 2C 3 , 128.06 (2C 2 « or 2C 3 0, 139.16 (Cr). 157.30 (NHC(O)NH), 168.89 (C(O)NH) 5 169.37 (C(0)CH 3 ) ppm; mass spectrum (FD) 279 (M++1). Anal. Calcd for C_ 3 Hι 8 N 0 3 : C, 56.10; H, 6.52; N, 20.13. Found: C, 56.31 H, 6.41; N, 20.12. 0 5 0 5 Example 99 Synthesis ofl-[Acetamido(benzylcarbamoyl)methyl]-3-phenylurea (2 Phenyl isocyanate (0.42 g, 3.5 mmol) was added to a solution of 2 (0.70 g, 3. mmol) in THF (75 mL), and then the reaction was stirred at 45-50 °C (2 h). T white solid (0.95 g, 89%) that precipitated . was filtered and dried: mp 242-2 °C (d); Rf .0.30 (5% MeOH/ CHC1 3 ); IR (KBr) 3200 (br), 1600 (br), 1430 (br), 1300, 8 700 cm- 1 ; IH NMR (DMSO-d 6 ) δ 1.86 (s, C(0)CH 3 ), 4.30 (d, «/ = 5.9 Hz, CH 2 ), 5.67 J = 7.6 Hz, CII), 6.86-6.93 (m, 2ArH), 7.20-7.32 (m, NH, 5PhH, lArH), 7.37-7.40 ( 2ArII), 8.56 (t, J = 5.9 Hz, NH), 8.68 (d, J = 7.6 Hz, NH), 8.89 (s, NH); "c N (DMSO-d 6 ) 22.38 (CXO)CH 3 ), 42.29 (CH_), 57.59 (CH), 117.61 (2C 2 ), 121.37 (C 4 ), 126 (C4 . 126.95 (2C_' or 2C 3 , 128.07 (2C 2 - or 2C 3 . 128.62 (2C 3 ), 139.12 (Ci or C 139.98 (Ci or Cr), 153.98 (NHC(O)NH), 168.55 (C(O)NH), 169.58 (C(0)CH 3 ) p mass spectrum (FD) 340 (M+). Anal. Calcd for Cι 8 H 20 N O 3 : C, 63.52; H, 5.92; N, 16.46. Found: C, 63. H, 5.92; N, 16.20. ..xample 100 . Synthesis ofl-[Acetcmύdo(benzylc ιτi)cmtJ yl)τn thyl]-3-b€nzenesulfonylure (2i). Benzenesulfonyl isocyanate (0.64 g, 3.48 mmol) was added to a solution of (0.70 g, 3.16 mmol) in THF (75 mL), and then the reaction was stirred at 50-55 ° 5 (22 h). The white solid (0.84 g, 66%) that separated on cooling was filtered a dried: mp 188-191 °C (d); RfO.ll (10% MeOH/CHCl 3 ); IR (KBr) 3250, 1630 (br), 15 (br), 1460, 1330, 870, 700 cm- 1 ; .H NMR (DMSO-d 6 ) 6 1.80 (s, C(0)CH 3 ), 4.24 (d, J 5.7 Hz, CH 2 ), 5.47 (t, J= 1.1 Hz, CH), 7.18-7.30 (m, 5PhH, NH), 7.57-7.71 (m, 3ArH 0 7.89-7.92 (d, J = 7.5 Hz, 2ArII), 8.54 (t, J = 5.7 Hz, NH), 8.70 (d, J = 7.7 Hz, NH 10.80 (s, NH); iSC NMR (DMSO-d 6 ) 22.29 (C(0)CH 3 ), 42.30 (CH 2 ), 57.14 (CH), 126.5 (C , 126.89 (2C 2 ), 127.12 (2C 2 - or2C 3 0, 128.05 (2C 2 '.or 2C 3 , 128.96 (2C 3 ), 133.2 (C4), 138.88 (Ci or Cr), 139.87 (Ci or Cr). 150.36 (NHC(O)NH), 167.55 (C(O)N 5 169.55 (C(0)CH 3 ) ppm; mass spectrum (FD) 405 (M++1). Anal. Calcd for Cι 8 H 2 oN 4 θ 5 S: C, 53.46; H, 4.98; N, 13.85. Found: C, 53.2 H, 5.04; N, 13.62. 20 25 35 Example 101 Synthesis ofl-[Acetanύά^(benzylccLrbanιoyl)τnethyl]-3-ττιethylthiourea (2 A solution of 2r (0.50 g, 2.26 mmol) and methyl isotliiocyanate (0.20 g, 2.27 mm in THF (75 mL) was heated to reflux (4 h), and then the vola * tile materials we removed in vacuo. The residue was recrystallizedfrom absolute EtOH to give 2j. a white solid (0.22 g, 33%): mp 162-163 °C (d); Rf 0.45 (10% MeOH CHCl 3 ); IR (K 3400 (br), 3220 (br), 1620, 1500, 1430, 1340, 740 cm" 1 ; Η NMR (DMSO-d 6 ) δ 1.83 C(0)CH 3 ), 2.85 (br s, NHCH 3 ), 4.27 (d, J = 5.8 Hz, CH 2 ), 6.10 (br s, CH), 7.17-7. (m, 5PhH), 7.80 (br s, NH), 7.96 (br s, NH), 8.44 (br 8, NH), 8.72 (s, NH); "C N (DMSO-d G ) 22.39 (C(0)CH 3 ), 30.92 (NHCH 3 ), 42.45 (CH 2 ), 61.33 (CH), 126.68 (C 127.06 (2C 2 - or 2C 3 , 128.16 (2C 2 - or 2C 3 , 139.15 (Cr), 168.17 (C(O)NH), 170. (C(0)CH 3 ) ppm, the signal for the thiocarbonyl carbon group was not detecte Mass spectrum (FD) 294 (M+). Anal. Calcd for Cι 3 Hι 8 N 4 0 2 S: C, 53.04; H, 6.16; N, 19.03. Found: C, 53.1 H, 6.31; N, 18.89. Example 102 1 Synthesis oflJAcetamido(benzylcarbcuιwyl)methyl]-3-pJιenylthiourea (2 A solution of 2r (0.70 g, 3.16 mmol) and phenyl isothiocyanate (0.47 g, 3.48 mm in THF (75 mL) was heated to reflux (3 h), and then the volatile materials we c removed in vacuo. The residue was triturated with EtOH (15 mL), and the whi solid material (0.70 g, 62%) that remained was filtered and recrystallized fro absolute EtOH: mp 196-197 °C (d); R/ 0.65 (10% MeOH/CHCl 3 ); IR (KBr) 3400 (b 3240 (br), 1620, 1470 (br), 1330, 750, 670 cm- 1 ; *H NMR (DMSO-d 6 ) δ 1.89 C(0)CH 3 ), 4.32 (d, J = 5.8 Hz, CH 2 ), 5.24 (t, J = 6.9 Hz, CH), 7.09-7.43 (m, 3Ar 5PhH), 7.52-7.55 (m, 2ArH), 8.13 (d, J = 6.9 Hz, NH), 8.55 (br s, NH), 8.85 (br NH), 10.11 (s, NH); ^C NMR (DMSO-d 6 ) 22.22 (C(0)CH 3 ), 42.36 (CH 2 ), 61.18 (C 122.76 (2C 2 ), 124.29 (C ). 126.53 (C^), 126.90 (2C 2 - or 2C 3 , 128.00 (2C 2 ' or 2C 128.40 (2C 3 ), 138.94 (Ci or Cr). 139.01 (Ci or Cr). 167.82 (C(O)NH), 169 (C(0)CH 3 ), 180.02 (C(S)) ppm; mass spectrum (FD) 356 (M+). Anal. Calcd for Cι 8 H 20 N 4 O 2 S: C, 60.65; H, 5.66; N, 15.72. Found: C, 60. H, 5.70; N, 15.62. Example 103 Synthesis ofN-[Acetamido(beJizylc_arbaτnoyl)methyl]phthalamic acid (2 To a warm pyridine solution (7.0 mL) containing 2L (0.63 g, 2.83 mmol), phtha anhydride (0.43 g, 2.87 mmol) was added, and the reaction was stirred at 50-55 (5 h). Pyridine was removed by distillation in vacuo and the residue was treat with H 2 0 (20 mL). The aqueous mixture was extracted with EtOAc (2 x 20 m and then acidified with aqueous 1 N HCl solution. The white solid (0.70 g, 70 that precipitated was filtered, washed with H 2 O (10 mL), and dried: 186-188 °C; IH NMR (DMSO-d 6 ) δ 1.90 (s, C(0)CH 3 ), 4.36 (d, J = 6.0 Hz, CH 2 ), 5. (t, J = 7.2 Hz, CII), 7.20-7.31 (m, 5PhII), 7.43 (d, = 7.3 Hz, C 6 II), 7.50-7.63 (m, C 4 C5II). 7.82 (d, J = 7.3 Hz, C 3 II), 8.41-8.48 (m, 2NII), 9.01 (d, J = 7.2 Hz, NH), 13. (br s, CO2II); 1 C NMR (DMSO-d G ) 22.46 (C(O)CH 3 ), 42.39 (CH 2 ), 57.44 (CH), 126. 126.92, 127.81, 128.09, 128.72, 129.36, 129.85, 131.49, 137.78, 138.99 (ΛrC, Ph 167.85, 167.93, 168.48, 169.47 (C(O)) ppm; mass spectrum (FD) 370 (M++1). Anal. Calcd for Cι 9 Hι 9 N 3 0 5 : C, 61.78; H, 5.18; N, 11.38. Found: C, 61. H, 5.05; N, 11.16. Exa ple 104 1 Synthesis of 2-Acetamido-N-benzyl-2-(N-succinimidyl) acetamide (2m). cooled (-78 °C) THF solution (150 mL) of 2g (prepared from 2-acetamido-N-benz 2-ethoxyacetamide 4 . 5 (2.00 g, 8.0 mmol) and BBr 3 (2.51 g, 10.05 mmol)) was add 5 slowly into a cooled (-78 °C) THF suspension (50 mL) of sodium succinimide (3. g, 25.25 mmol). The reaction mixture was stirred at -78 °C (30 min) and at room temperature (90 min), and then treated with a 10% aqueous citric a solution (50 mL). The resulting solution was neutralized with a saturat ° aqueous NaHC0 3 solution, and the reaction mixture extracted with EtOAc (3 x 1 mL). The combined extracts were dried (Na 2 S0 4 ), and the volatile materials w removed by distillation in vacuo. The residue was purified by flash colu chromatography on Si0 2 gel (6% MeOH/CHCl 3 ) to give 1.10 g (45%) of 2m: mp 1 5 183 °C (recrystallized from EtOH); Rf 0.26 (6% MeOH/CHCl 3 ); IR (KBr) 3340 (b 1620 (br), 1480 (br), 1340, 780, 670 cm" 1 ; J H NMR (DMSO-d 6 ) δ 1.90 (s, C(0)CH 2.67 (s, CH 2 CH 2 ), 4.23-4.36 (m, CH 2 ), 6.31 (d, J = 9.0 Hz, CH), 7.17-7.35 (m, 5 Ph _ 8.63 (t, J = 5.9 Hz, NH), 8.72 (d, J = 9.0 Hz, NH); i3C NMR (DMSO-d 6 ) 22. (C(0)CH 3 ), 27.99 (s, CH 2 CH 2 ), 42.59 (CH 2 ), 55.19 (CH), 126.63 (C4'), 126.96 (2CV 2C 3 " ), 128.08 (2C 2 « or 2C 3 '), 138.91 (Ci '), 165.41 (C (O)NH), 169.86 (C(0)CH 3 ), 176. (C(0)CH 2 CH 2 C(0)) pp ; mass spectrum (FAB) 304 (M++1, 17), 163 (12), 155 (4 5 152 (51), 135 (68), 119 (100). Anal. Calcd for Cι 5 Hι 7 N 3 0 4 : C, 59.40; H, 5.65; N, 13.85. Found: C, 59.6 H, 5.70; N, 13.66. 0 5 Exa ple 105 Synthesis of Benzyl £[-[Acelamido(l>enzylcarbamoyl)methyl]malonaιn (2n). 4-Methylmorpholine (0.35 g, 3.56 mmol) was added to a solution of N-C glycine (0.74 g, 3.55 mmol) in TIIF (75 mL) at -10 to -15 °C. The solution c stirred (5 min), and then isobutylchloroformate (0.49 g, 3.55 mmol) was added a the mixture was stirred for an additional 20 min. A cooled (-10 °C) solution of (0.79 g, 3.55 mmol) in THF (125 mL) was then added slowly (30 min). The reacti mixture was stirred at this temperature (2 h) and then at room temperature (2 0 The insoluble materials were filtered and the filtrate was concentrated in vacu The residue was triturated with EtOAc (20 mL) and the white solid (0.60 g) th remained was filtered, washed with H 2 0 and dried to give 2n. The initi insoluble material on trituration with H 2 0 gave an additional 0.40 g of 2_H to giv 5 combined yield of 1.00 g (68%); mp 177-179 °C (recrystallized from EtOH); Rr 0. (10% MeOH/CHCl 3 ); IR (KBr) 3400 (br), 3260, 1640 (br), 1540 (br), 1480, 1450, 13 760, 690 cm- 1 ; NMR (DMSO-d 6 ) δ 1.86 (s, C(0)CII 3 ), 3.60-3.77 (m, C(0)CII 2 N 4.28 (d, J = 5.8 Hz, CH 2 ), 5.01 (s, OCH 2 Ph), 5.79 (t, J = 7.7 Hz, CII), 7.18-7.34 (m 0 PhH, 5 ArH), 7.49 (t, J = 5.8 Hz, NH), 8.43-8.55 (m, 3 x NH); C NMR (DMSO- 22.36 (C(0)CH 3 ), 42.28 (CH 2 ), 43.39 (C(0)CH 2 NH), 56.77 (CH), 65.42 (OCH 2 P 126.55 (2C), 126.94 (2C), 127.54, 127.66, 128.04 (2C), 128.22 (2C), 136.89, 138.96 (A PhC), 156.40 (NHC(0)OCH 2 Ph), 167.86 (NHC(0)CH 2 ), 168.96 (C(O)NH), 169 5 (C(0)CH 3 ) ppm; mass spectrum (FD) 413 (M++1, 100), 278 (75). Λnal. Calcd for C2iH2 4 N 4 0 5 : C, 61.16; H, 5.87; N, 13.58. Found: C, 60. H, 5.77; N, 13.35. 0 5 Example 106 Synthesis of Ethyl N-[Acetamido(benzylcarbωnoyl)methyl]glycinate (2o). methanolic solution (70 mL) containing 2_ (1.50 g, 4.28 mmol) and ethyl glycina (prepared from ethyl glycinate hydrochloride (3.10 g, 22.2 mmol), NaOMe (1.17 c - 21.74 mmol)) was heated to reflux (2h). The reaction was concentrated in vacuo give an oily residue that' was purified by flash column chromatography on Si gel (5% MeOH/CHCl 3 ) to give 0.60 g (46%) of £a: mp 125-127 °C (recrystallized fro EtOAc); R f 0.43 (5% MeOH CHCl 3 ); IR (KBr) 3400 (br), 3200, 1710, 1600, 1500, 143 1350, 740, 680 cm- 1 ; *H NMR (DMSO-d 6 ) δ 1.17 (t, J = 7.1 Hz, OCH 2 CH 3 ), 1.86 C(0)CH 3 ), 2.65-2.74 (m, NHCH 2 C(0)), 3.26-3.33 (m, NHCII 2 C(0)), 4.07 (q, J = 7 Hz, OCH 2 CH 3 ), 4.28 (d, J = 5.8 Hz, CH 2 ), 5.01 (t, J = 8.2 Hz, CII), 7.19-7.35 (m, PhH), 8.25 (d, J = 8.2 Hz, NH), 8.58 (t, J = 5.8 Hz, NH); 13 C NMR (DMSO-d 6 ) 13. (OCH 2 CH 3 ), 22.46 (C(0)CH 3 ), 42.13 (CH 2 ), 46.22 (NHCH 2 C(0)), 60.07 (OCH 2 CH 3 63.96 (CH), 126.67 (C '), 127.09 (2C 2 * or 2C 3 '), 128.13 (2C 2 ' or 2C 3 '), 139.07 (Ci 169.07 (C(O)NH), 170.09 (C(0)CH 3 ), 171.56 (C(0)OCH 2 CH 3 ) ppm; mass spectru (FD) 342 (M+). Anal. Calcd for Cι 5 H 2 ιN 3 0 4 : C, 58.62; H, 6.89; N, 13.67. Found: C, 58.8 H, 7.00; N, 13.73. Example 107 Synthesis of Benzyl N-[Aceta ido eτιzylcarbamoyl)methylJglycinate (2 A suspension of benzyl glycinate hydrochloride (5.00 g, 24.8 mmol) in THF (4 mL) containing Et 3 N (4.90 g, 48.5 mmol) was stirred (4 h) at room temperatu The reaction mixture was cooled (-78 °C) and then a cooled (-78 °C) THF soluti (150 mL) of 2s. (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 16.0 mmol) and BBr 3 (1 M in CH 2 C1 2 , 20.0 mL, 20.0 mmol)) was added (30 mi The reaction mixture was stirred at -78 °C (30 min) and then at room temperatu (16 h). The insoluble materials were filtered, the filtrate concentrated in vacu and the residue was purified by flash column chromatography on Si0 2 gel (3 MeOH/CHCl 3 ) to give 1.56 g (26%) of 2^. as a white solid: mp 133-135 (recrystallized from EtOH); Rf 0.36 (3% MeOH/CHCl 3 ); IR (KBr) 3400, 3220, 171 1620, 1510, 1440, 1350, 740, 680 cm *1 ; IHNMR(DMSO-d 6 )δ 1.85 (s,C(0)CH 3 ), 2.7 2.82 (m, NHCH 2 C(0)), 3.39 (d, J = 6.1 Hz, NΗCHHC(O)), 3.40 (d, J = 6.1 NHCHHC(O)),4.27 (d, J= 6.1Hz, CH 2 ), 5.02(t, J=8.2Hz, CH), 5.11 (s, 0CH 2 P 7.19-7.36 (m, 5 PhH, 5 ArH), 8.24 (d, J = 8.2 Hz, Nπ), 8.57 (t, J = 6.1 Hz, NH); NMR (DMSO-d 6 ) 22.42 (C(0)CH 3 ), 42.11 (CH 2 ). 46.22 (NHCH 2 C(0)), 63.94 (C 65.53 (OCH 2 Ph), 126.62, 127.05 (2C), 127.80 (2C), 127.91, 128.08 (2C), 128.29 (2 135.87, 139.02 (ArC , PhC), 169.01 (C(O)NH), 170. . (C (0)CH 3 ), 171. (C(0)OCH 2 Ph) ppm; mass spectrum (FD) 370 (M + +1). Anal. Calcd for C 20 H 23 N 3 O 4 : C, 65.03; H, 6.28; N, 11.37. Found: C, 65. H, 6.53; N, 11.31. Example 108 Synthesis ofN-[Acetamido(benzyl6arbanιoyl)methyl]glycine (2g). A solutio of methyl N-[acetamido(benzylcarbamoyl)methyl]glycinate (0.60 g, 2.05 mmol) an KOH (0.30 g, 5.36 mmol) in 90% aqueous EtOH (50 mL) .was stirred at roo temperature (48 h). The volatile materials were then removed in vacuo, and t residue dissolved in H 2 0 (10 mL). The aqueous solution was extracted with EtO (2 x 20 mL), and the aqueous layer was acidified to pH -2.0 with aqueous 1 N HC A column containing ion exchange resin Dowex 50X W4 was prepared using 10 aqueouβ pyridine. The column was thoroughly washed with H 2 O. The acid aqueous reaction solution was added to the top of the column, and the column w eluted with H 2 0 (300 mL) or until the eluate was neutral. The column was the eluted with 10% aqueous pyridine (400 mL). The aqueous pyridine fraction w concentrated in vacuo to give a white solid, dried in vacuo, and then triturate with absolute EtOH (7 mL). The insoluble materials that remained were filter and dried to give 0.29 g (50%) of 2fl: mp 124-126 °C (d); IR (KBr) 3400, 3200, 163 1500, 1370, 690 cm- 1 ; IH NMR (DMSO-d 6 ) δ 1.84 (a, C(O)CH 3 ), 3.26 (s, CH 2 C(0) 4.29 (d, J = 5.7 Hz, CHjf), 4.98 (d, J = 8.2 Hz, CH), 7.21-7.33 (m, NH, 5 PhH), 8.39 ( J = 8.2 Hz, NH), 8.47 (t, J = 5.7 Hz, NH); 13 C NMR (DMSO-d 6 ) 22.41 (C(0)CH 3 41.98 (CH 2 ), 47.48 (CH 2 C(0)), 64.08 (CH), 126.75 (C 4 " ), 127.21 (2C 2 * or 2C 3 '), 128. (2C 2 ' or 2C 3 *), 139.23 (Ci'), 169.91 (C(O)NH), 170.02 (C(0)CH 3 ), 170.20 (CH 2 C(0 ppm. Anal. Calcd for Cι 3 Hι 7 N 3 0 4 : C, 55.91; H, 6.13; N, 15.04. Found: C, 55.6 H, 6.06; N, 14.74. Example 109 Synthesis of2-Acetamido-N-beτιzyl-2-(l-pyτ~role)acetarmde. A cooled (-78 THF solution (225 mL) of 2-acetamido-N-benzyl-2-bromoacetamide (prepared fr 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and BBr 3 (1 M CH2 c - solution, 8.8 mL, 8.8 mmol)) was added under N 2 to a cooled .-78 °C) suspensio potassium pyrrole (2.71 g, 25.8 mmol) in THF (25 mL). The reaction mixture stirred at -78 °C (1 h) and then at room temperature (1 h), and then treated H 2 O (10 mL) and acidified ("pH" 4.0) with 5% citric acid. The reaction was m 0 basic with aqueous saturated Nβ2C0 3 solution, and the aqueous mixture extracted with EtOAc (2 x 250 mL) and the combined organic layers were d (Na 2 S0 4 ). The volatile materials were removed in vacuo and the residue purified by flash column chromatography on Si0 2 gel using 3% MeOH/CHCl 5 the eluant to give 0.40 g (18%) of the desired product. The compound 2 purified by recrystallization from EtOH: mp 182-184 °C; Rf 0.44 MeOH/CHCl 3 ); IR (KBr) 3400, 3280, 1630, 1520, 1370, 740, 720 cm- 1 ; IH N (DMSO-d 6 ) δ 1.91 (s, C(0)CH 3 ), 4.30 (d, J = 5.5 Hz, CH 2 ), 6.01 (s, 2 x C 3 H), 6.38 ( = 8.7 Hz, CII), 6.85 (s, 2 x C 2 H), 7.11-7.35 (m, 5PhH), 8.96 (t, J = 5.5 Hz, Nil), 9.1 J = 8.7 Hz, NH); 3 C NMR (DMSO-d 6 ) 22.22 (C(0)CH 3 ), 42.15 (CH 2 ), 62.86 ( 107.79 (2C 3 ), 119.19 (2C 2 ), 12* 76 (C , 127.01 (2C 2 - or 2C 3 , 128.11 (2C 2 - or 2 138.34 (Cr). 166.37 (C(O)NII), 169.41 (C(0)CII 3 ) ppm; mass spectrum, m/e (rela intensity) 272 (M++1, 22), 271 (M+, 100). Λnal. Calcd for Cι 5 Hι 7 N 3 O 2 0.2 H 2 0: C, 65.53; H, 6.37; N, 15.28. Found: 65.80; H, 6.22; N, 15.13. Example 110 Synthesis of 2-Acetamido-N-benxylr2-(l-pyrazole) acetamide. To a cooled (-7 °C) solution (250 mL) of 2-acetamido-N-benzyl-2-bromoacetamide (prepared fro 2-acetamido-N-benzyl-2-ethoxyacetamide (3.60 g, 14.4 mmol) and BBr 3 (1 CH 2 C1 2 solution, 15.8 mL, 15.8 mmol)), a THF solution (20 mL) of Et 3 N (2.91 g, 28. mmol) was added, followed by the addition of THF solution (30 mL) of pyrazol (1.17 g, 17.28 mmol). The mixture was stirred at -78 °C (30 min) and roo temperature (1 h). The insoluble materials were filtered and the solvents remove in vacuo. The residue was purified by flash column chromatography on Si0 2 ge using 4% MeOH/ CHC1 3 as the eluant to give 0.80 g (22%) of the desired produc The compound X was recrystallized from EtOAc as a white solid: mp 158-160 °C Rf 0.51 (6% MeOH/CHCl 3 ); IR (KBr) 3400, 3180, 1650, 1530, 1470, 1370, 1350, 740, 70 cm- 1 ; IH NMR (DMSO-d 6 ) δ 1.93 (s, C(0)CH 3 ), 4.29 (d, J = 5.8 Hz, CH 2 ), 6.26 (s C 4 H), 6.57 (d, J = 8.8 Hz, CH), 7.15-7.33 (m, 5PhH), 7.48 (br s, C5H), 7.76 (br s, C 3 H 8.96 (t, J = 5.8 Hz, NH), 9.23 (d, J = 8.8 Hz, NH); 13 C NMR (DMSO-d 6 ) 22.4 (C(O)CHs), 42.40 (CH 2 ), 65.51 (CH), 105.37 (C 4 ). 126.87 (C , 127.14 (2C 2 ' or 2C 3 128.25 (2C 2 ' or 2C 3 , 129.00 (C 5 ), 138.59 (C 3 ), 139.17 (Cr), 165.68 (C(O)NH), 169.8 (C(0)CH 3 ) ppm; mass spectrum, m e (relative intensity) 273 (M++1, 11), 272 (M + 2), 139 (83), 138 (100), 92 (37). Anal. Calcd for Cι 4 Hι 6 N 0 2 : C, 61.75; H, 5.92; N, 20.57. Found: C, 61.95 H, 5.96; N, 20.28. Example 111 1 Synthesis of2-Λcetamido-N-benzyl-2-(l-imidazole)acetaτnide. Using preceeding procedure, 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, mmol), BBr 3 (1 M CH 2 C1 2 solution, 8.8 mL, 8.8 mmol), Et 3 N (1.62 g, 1.60 m 5 and imidazole (0.60 g, 8.8 mmol) gave 0.60 g (30%) of the desired prod Compound X was recrystallized from ethyl acetate/hexane as a beige col solid: mp 146-148 °C; Rf 0. (7% MeOH/ CHCI3); IR (KBr) 3400 (br), 1640, 1560, 1 1360, 720, 670 cm- 1 ; IH NMR (DMSO-d 6 ) δ 1.85 (s, C(0)CH 3 ), 4.30 (br s, Cπ 2 ), ° (d, J = 8.0 Hz, CH), 6.89 (s, C5II), 7.12-7.33 (m, C 4 II, 5PhH), 7.69 (ε, C 2 π), 9.06 ( NH), 9.29 (d, J = 8.0 Hz, NH); 13 C NMR (DMSO-d 6 ) 22.28 (C(0)CH 3 ), 42.36 (C 61.18 (CH), 117.56 (C 5 ), 126.92 (C 4 , 127.16 (20^ or 2C 3 . 128.19 (C 4 ), 128.26 (2 2C3 , 136.21 (C 2 ), 138.27 (Cr), 165.72 (C(O)NH), 169.77 (C(0)CH 3 ) ppm; spectrum, FD (relative intensity) 274 (M++2, 12), 273 (M++1, 77), 272 (100), 205 274 (18). Anal. Calcd for Cι 4 Hι 6 N 4 0 2 : C, 61.75; H, 5.92; N, 20.57. Found: C, 6 H, 6.09; N, 20.32. Example 112 1 Synthesis of 2-Acetamido-N-benzyl-2-(l-(l T 2,4-tHazole)) acetamide. Using acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol), BBr 3 (1 M CH C solution, 17.6 mL, 17.6 mmol), Et 3 N (4.85 g, 48.0 mmol), and 1,2,4-triazole (1.43 5 20.8 mmol), 1.20 g (28%) of the desired product was obtained. Compound ∑. w recrystallized from EtOAc as an amorphous white solid: mp 146-148 °C; R f 0. (6% MeOH/ CHC1 3 ); IR (KBr) 3400, 1660, 1470, 1370, 830 cm- 1 ; H NMR (DMSO-de) 1.85 (s, C(0)CH 3 ), 4.32 (br s, CH 2 ), 6.70 (d, J = 7.8 Hz, CH), 7.21-7.29 (m, 5Ph ° 8.01 (s, C 3 H), 8.57 (s, C 5 H), 9.04 (br s, NH), 9.39 (d, J = 7.8 Hz, NH); 3 C NM (DMSO-de) 22.39 (C(0)CH 3 ), 42.59 (CH 2 ), 65.02 (CH), 126.97 (C , 127.25 (2C_- 2C 3 <), 128.32 (2C 2 * or 2C 3 , 138.47 (Cr), 143.93 (C ), 151.50 (C 3 ), 164.77 (C(O)N 170.23 (C(0)CH 3 ) ppm; mass spectrum, FD (relative intensity) 274 (M++1, 100), 2 (11), 205 (19), 204 (13), 140 (67), 139 (31). Anal. Calcd for C13H15N5O2: C, 57.13; H, 5.53; N, 25.63. Found: C, 57.3 H, 5.66; N, 25.38. Example 113 Synthesis of2-Λcetarnido-N-benzyl-2-(l-tetrxtzoIe))acetarnidc. Making u 2-acetamido-N-benzyl-2-ethoxyacetaraide (3.00 g, 12.0 mmol), BBr 3 (1 M CH solution, 13.2 mL, 13.2 mmol), Et 3 N (2.42 g, 24.0 mmol), and tetrazole (1.10 g, * mmol), 0.90 g (27%) of the desired product was obtained as a white solid. compound X. was recrystallized from EtOH: mp 169-171 °C; Rf 0.22 MeOH/CHCl 3 ); IR (KBr) 3300 (br), 1660, 1510, 1360, 870, 740 cm" 1 ; IH NMR (D de) δ 1.97 (s, C(0)CII 3 ), 4.25-4.40 (m, CH 2 ), 7.05 (d, J = 8.4 Hz, CH), 7.21-7.3 5PlιH), 9.23 (t, J = 5.5 Hz, NH), 9.44 (s, C 5 H), 9.69 (d, J = 8.4 Hz, NH); 13 C (DMSO-dc) 22.38 (C(0)CH 3 ), 42.78 (CH 2 ), 63.62 (CH), 127.10 (C 4 . 127.39 (2 2C 3 , 128.38 (2C 2 ' or 2C 3 , 138.26 (Cr), 143.67 (C 5 ), 163.88 (C(O)NH), 1 (C(0)CH 3 ) ppm; mass spectrum, FD (relative intensity) 275 (M + , 79), 273 (14) (100), 205 (50). Anal. Calcd for Cι 2 Hι 4 N 6 0 2 : C, 52.55; H, 5.15; N, 30.64. Found: C, 5 H, 5.33; N, 30.64. Example 114 Synthesis of a-Acetamido-N-benzyl-l-(diιnethylsulfamoyl)imidazole acetamide. To a cooled (-78 °C) THF solution (150 mL) of 2-acetamido-N-benzyl bromoacetamide (prepared from 2-acetamido-N-be_ιzyl-2-ethoxyaceta_mde (2.00 _ 8.0 mmol) and BBr 3 (1 M solution in CH 2 C1 2 , 9.0 mL, 9.0 mmol)) was added Et 5 (1.62 g, 16.0 mmol), and then a 'THF solution of the 2-lithio salt of N, dimethylimidazole-1-sulfonamide (generated by the addition of n-BuLi (2.5 M hexane, 3.9 mL, 9.68 mmol) into a cooled (-78 °C) THF solution (25 mL) of N, dimethylimidazole-1-sulfonamide (1.54 g, 8.8 mmol)) was added during a 15 m interval. The reaction mixture was stirred at this temperature (30 min) and th at room temperature (45 min). A saturated aqueous NH 4 C1 solution (50 mL) a H 2 O (50 mL) were then sucessively added to the reaction, and the aqueous mixtu was extracted with EtOAc (3 x 50 mL). The combined extracts were dri (Na 2 S0 ), and the volatile materials were removed by distillation in vacuo. T residue was purified by flash column chromatography on Si0 2 gel ( MeOH/CHCl 3 ) to give 0.50 g (17%) of the desired product: mp 145-147 (recrystallized from EtOAc/liexane); Rf 0.35 (4% MeOH/CHCl 3 ); IR (KBr) 34 1640, 1530, 1380, 720 cm- 1 ; i H NMR (DMSO-d 6 ) δ 1.96 (s, C(0)CH 3 ), 2.77 N(CH 3 ) 2 ), 4.25 (dd, = 6.0, 15.5 Hz, CHH), 4.34 (dd, = 6.0, 15.5 Hz, CHH), 5.43 J = 8.0, Hz, CH), 7.19-7.30 (m, υ PhH), 7.40 (s, C 5 H), 8.17 (s, C 2 H), 8.42 (d, J = Hz, NH), 8.67 (t, J = 6.0 Hz, NH); 3 C NMR (DMSO-d 6 ) 22.42 (C(0)CH 3 ), 37. (N(CH 3 ) 2 ), 42.11 (CH 2 ), 51.40 (CH), 115.50 (C 5 ), 126.64 (C 4 '), 126.94 (2C 2 * or 2C 3 128.12 (2C_' or 2C 3 '), 136.70 (C 2 ), 139.17 (Ci'), 140.26 (C ), 168.93 (C(O)NH), 169. (C(0)CH 3 ) ppm; mass spectrum (FD) 380 (M++ 1, 34), 248 (13), 247 (100), 108 (64). Anal. Calcd for Ci6H 21 N 5 0 4 S: C, 50.65; H, 5.58; N, 17.87. Found: C, 51. H, 5.65; N, 18.09. Example 115 Synthesis of a-Acetamido-N-benzyl-4-imidazole acetamide. A 75% aqu EtOH (16 mL) solution of α-acetamido-N-benzyl-l-(N,N-dimethylsulfamido)i zole-4-acetamide (0.85 g, 3.05 mmol) was acidified ("pH" -1.5) with ethanolic and the solution was heated to reflux (8 h). The reaction was neutralized wi saturated aqueous NaHC0 3 solution and the EtOH-H2θ azeotrope remove distillation in vacuo. The remaining aqueous layer was made basic ("pH" with aqueous NaOH. The aqueous mixture was extracted with EtOAc (3 x 50 and the combined extracts were dried (Na 2 S0 4 ). The reaction was concentrat vacuo to give 0.35 g (57%) of the desired product: mp 189-191 °C (d) (recrystal from acetone); Rf 0.19 (10% MeOH/CHCl 3 ); IR (KBr) 3400, 3260, 1650, 1600, 1 1430, 1360, 1330, 730, 710 cm" 1 ; l ∑I NMR (DMSO-d 6 ) δ 1.88 (s, C(0)CH 3 ), 4.28 (d 5.9 Hz, CH 2 ), 5.38 (d, J = 6.8 Hz, CII), 5.38 (br s, C 5 H), 7.15-7.30 (m, 5 PhH), 7. C 2 H), 8.26 (br s, NH), 8.53 (br s, NH), 12.01 (br s, NH) ppm; mass spectrum 273 (M++1). Anal. Calcd for Cι Hι 6 N 4 0 2 : C, 61.75; H, 5.92; N, 20.58. Found: C, 6 H, 5.98; N, 20.37. Example 116 Synthesis ofa.-Acetamido-N-benzyl-2-imidazole acetamide. Preparation of . -die.hoxymethyl-2-lithioiπ.idazole. n-BuLi (2.5 M hexane, 6.8 mL, 17.0 mmol) was added to a cooled (-46 °C) solution of diethoxymethylimidazole (2.90 g, 17.06 mmol) in THF (45 mL) under N 2 atm. T solution was stirred at -46 °C (15 min) to- give the desired product. Preparation of q-Acetamido-N-benzyl-∑-imidazoleacetamide. The 2-lit salt solution of 1-diethoxymethylimidazole was added dropwise (15 min) into cooled (-78 °C) THF solution (130 mL) of 2-acetarnido-N-benzyl-2-bromoacetami (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) a BBr 3 (1 M in CH C1 2 , 10 mL, 10.0 mmol)). The reaction was stirred at -78 °C (1 and then quenched with a saturated aqueous NH 4 C1 (50 mL) solution. T mixture was stirred at room temperature (30 min), and made basic ("pH" 9.2) adding aqueous K 2 C0 3 . The aqueous mixture was extracted with EtOAc (3 x 1 mL), and the combined extracts were dried (Na 2 S0 ). The solvents were remov in vacuo and the residue was purified by flash column chromatography on Si gel (2.5% MeOH/CHCl 3 ) to give 0.14 g (7%) of the desired product: mp 228-230 (recrystallized from EtOH); R f 0.46 (10% MeOH/CHCl 3 ); IR (KBr) 3200 (br), 16 1500 (br), 1430, 1350, 740, 680 cm- 1 ; *H NMR (DMSO-d 6 ) δ 1.91 (s, C(0)CH 3 ), 4.29 J = 5.6 Hz, CH 2 ), 5.51 (d, J = 7.7 Hz, CH), 6.85 (br s, C H), 7.05 (br s, C 5 H), 7.18-7. ( , 5 PhH), 8.42 (d, J = 7.7 Hz, NH), 8.65 (t, J = 5.6 Hz, NH), 11.91 (br s, NH); 1 NMR (DMSO- 6 ) 22.49 (C(0)CH 3 ), 42.21 (CH 2 ), 51.62 (CH), 126.60 (C 4 '), 126.98 (2 or 2C 3 '), 127.21 (C ), 128.09 (2C 2 ' or 2C 3 '), 128.32 (C 5 ), 139.05 (Ci 1 ), 143.74 (C 168.12 (C(O)NH), 169.30 (C(0)CH 3 ) ppm; mass spectrum (FD) 273 (M++1, 65), 2 (M + , 100). Anal. Calcd for C 14 H 16 N 4 0 2 : C, 61.75; H, 5.92; N, 20.58. Found: C, 61. H, 5.92; N, 20.37. Example 117 , Synthesis of a-Acetamido-N-benzyl-5-(tetrazole) acetamide. A mixture acetamido-N-benzyl-2-cyanoacetamide (1.00 g, 4.33 mmol), potassium azide ( g, 20.96 mmol) and Et 3 N-HCl (1.78 g, 13.0 mmol) in l-methyl-2-pyrrolidinone ( _ mL) was stirred at 110 °C (7 h). After cooling, aqueous concentrated HCl (1 5 was added, and the reaction mixture was filtered. The solvent was remove vacuo. The residue was dissolved in aqueous 1 N NaOH (20 mL), and t aqueous 1 N HCl (20 mL) was added. The precipitate was filtered to give 0. 0 (65%) of the desired product. The compound was recrystallized from EtOH: 236-238 °C; R f 0.20 (30% MeOH/CHCl 3 ); H NMR (DMSO-d 6 ) δ 1.94 (s, C(OX_ 4.33 (d, = 5.7 Hz, Cπ 2 ), 5.89 (d, = 7.8 Hz, CII), 7.18-7.33 (m, 5 PhH), 8.86 (d, 7.8 Hz, NH), 8.92 (t, J = 5.7 Hz, NH), 16.54 (br s, NH); 13 C NMR (DMSO-d 6 ) 2 5 (C(0)CH 3 ), 42.37 (CH 2 ), 48.13 (CII), 126.67 (C 4 'λ 127.00 (2C 2 * or 2C 3 '). 128.05 (2C 2C 3 *), 138.52 (Ci'), 166.18 (C(O)NH), 169.58 (C(0)CH 3 ) ppm; mass spectrum, (relative intensity) 275 (M++1, 73), 274 (100). M r (+CI) 274.119201 (calcd Cι 2 Hι 4 N 6 0 2 : 274.117824. 0 25 30 35 Example 118 1 Synthesis of a-Acetamido-N-benzyl-3-(l,2,4-triazole)acetamide. ethanolic solution (250 mL) of 2-acetamido-N-benzyl-2-cyanoacetaιnide (3.00 g, mmol), formic hydrazide (1.60 g, 26.0 mmol) and K 2 C0 3 (6.00 g, 2.90 mmol) c : heated at reflux (?.0h) . The reaction mixture was allowed to cool, filtered, the solvent was removed in vacuo. The residue was purified by flash colu chromatography on Si0 2 gel using 13% MeOH/CHCl 3 as the eluant to give 1. (40%) of the desired product. The compound X was purified by recryε talliza 10 from EtOH: mp 205-207 °C; Rf 0.35 (16% MeOH CHCl 3 ); *H NMR ωMSO-de) δ (s, C(0)CH 3 ), 4.30 (d, J = 5.7 Hz, CH 2 ), 5.62 (d, J = 7.8 Hz, CH), 7.18-7.32 ( PhH), 8.53 (s, C 5 H), 8.56 (d, J = 7.8 Hz, NH), 8.71 (t, J = 5.7 Hz, NH), 13.98 (s, 13 C NMR (DMSO-de) 22.48 (C(0)CH 3 ), 42.41 (CH 2 ), 51.30 (CH), 126.63 (C 4 " ), 12 1 (2C 2 ' or 2C 3 " ), 128.11 (2C 2 ' or 2C 3 '), 139.05 (Ci'), 167.92 (C(O)NH), 169.32 (C(OX_ ppm; mass spectrum, FD (relative intensity) 274 (M++1, 100), 273 (66). Anal. Calcd for Cι 3 Hι 5 N 5 0 2 : C, 57.13; H, 5.53; N, 25.63. Found: C, 57 H, 5.57; N, 25.53. 20 25 30 _. _> - - Exa ple 119 Synthesis of a-Acetamido-N-benzyl-2-(carboxamide oxirne) acetamide. suspension of NH 2 OHHCI (1.80 g, 25.9 mmol), K 2 C0 3 (4.85 g, 35.0 mmol), acetamido-N-benzyl-2-cyanoacetamide (2.00 g, 8.65 mmol) in absolute EtOH ( _ mL) was heated at reflux (16 h). The reaction mixture was cooled, filtered, a 5 concentrated under vacuum. The residue was purified by flash colu chromatography on Si0 2 gel using 8% MeOH/CHCl 3 as the eluant to give 1.2 (54%) of the desired product. The compound X. was further purified 0 recrystallization from ethyl acetate/liexane: mp 172-173 C C; Rf 0.40 (1 MeOH/CHCl 3 ); IH NMR (DMSO-d 6 ) δ 1.87 (s, C(0)CH 3 ), 4.27 (d, J = 6.0 Hz, C 4.88 (d, J = 8.4 Hz, CII), 5.37 (s, NH 2 ), 7.21-7.30 (m, 5 Phil), 8.21 (d, J = 8.4 Hz, N 8.48 (t, J = 6.0 Hz, NH), 9.28 (s, OH); 3 C NMR (DMSO-d 6 ) 22.46 (C(0)CH 3 ), 42 5 (CH 2 ), 53.65 (CH), 126.60 (C '), 126.99 (2C 2 ' or 2C 3 '), 128.108 (2C 2 * or 2C 3 '), 139 (Ci'), 149.63 (CNH 2 ). 167.88 (C(O)NH), 169.07 (C(0)CH 3 ) ppm; mass spectrum, (relative intensity) 265 (M++1, 36), 264 (100). Anal. Calcd for Cι 2 Hι 6 N 4 0 3 : C, 54.54; H, 6.10; N, 21.20. Found: C, 54. 0 H, 6.01; N, 21.41. 5 0 5 Example 120 Synthesis of a-Acetamido-N-benzyl-2-(carboxamide oxime-(0 -acetate)) acetamide. To a stirred solution of α-acetamido-N-benzyl-2-(carboxamid oxime)acetamide (0.72 g, 7.25 mmol) in pyridine (8 mL), acetyl chloride (0.25 mL X mmol) was added dropwise. Upon addition of the acetyl chloride a smal exotherm was detected (25 °C to 37 °C). The reaction mixture was stirred at roo temperature (1 h). The solvent was then removed in vacuo, and the residue wa dissolved in CH 2 Cl 2 (100 mL). The solution was washed with an aqueous 0.5 HCl solution (20 mL). The organic phase was dried (Na2S0 4 ), and the solvent wa removed in vacuo to give 0.60 g (72%) of the desired product. The compound X wa recrystallized from chloroform/hexane: mp 131-133 °C; Rf 0.35 (4 MeOH CHCl 3 ); Η NMR (DMSO-d 6 ) δ 1.90 (s, C(0)CH 3 ), 2.06 (s, OC(0)CH 3 ), 4.29 (t J= 5.3 Hz, CH 2 ), 5.00 (d, J= 8.4 Hz, CH), 6.48 (br s, NH 2 ), 7.19-7.33 (m, 5 PhH), 8.2 (d, J = 8.4 Hz, NH), 8.66 (t, J= 5.3 Hz, NH); 13 C NMR (DMSO-de) 19.86 (OC(0)CH 3 ) 22.77 (C(0)CH 3 ), 42.50 (CH ), 53.45 (CH), 126.89 (C 4 '), 127.28 (2C 2 * or 2C 3 * ), 128.3 (2C 2 * or 2C 3 '), 139.00 (Ci*), 156.13 (CNH 2 ), 167.19 (C(O)NH), 168.49 (OC(0)CH 3 ) 169.55 (C(0)CH 3 ) ppm; mass spectrum, FD (relative intensity) 307 (M++1, 100), 30 (43). Anal. Calcd for Cι 4 Hι 8 N 4 0 4 : C, 54.89; H, 5.92; N, 18.29. Found: r., 54.86 H, 5.84; N, 18.19. Example 121 Synthesis of a-Acetamido-N-benzyl-3-(l,2,4-oxadiazole)acetamide. Acetamido-N-ben7.yl-2-(carboxamide oxime)acetamide (0.90 g, 3.4 mmol) dissolved in trimethylorthoformate (10 mL) containing BF 3 -Et 2 θ (6 drops). solution was warmed to 55 °C (20 min), and then evaporated under redu pressure to give a white-blue solid. The material was dissolved in MeOH treated with norit, filtered, and evaporated under reduced pressure to fur crude product (0.79 g, 85%). The compound was purified by recrystallization f chloroform hexane: mp 164-166 °C; Rf 0.37 (6% MeOH/CHCl 3 ); J H NMR (DM de) δ 1.92 (B, C(0)CH 3 ), 4.31 (d, J = 6.0 Hz, Cπ 2 ), 5.82 (d, J = 8.4 Hz, CII), 7.15- (m, 5 PhH), 8.88 (d, J = 8.4 Hz, Nil), 8.96 (t, J = 6.0 Hz, Nil), 9.62 (s, C 5 H); 13 C N (DMSO-d 6 ) 22.22 (C(0)CH 3 ), 42.35 (CH 2 ), 49.44 (CH), 126.77 (C 4 '), 127.06 (2C 2C 3 '), 128.18 (2C 2 ' or 2C 3 '), 138.70 (Ci'), 166.25 (C(O)NH), 166.74 (C 3 ), 16 (C(0)CH 3 ), 169.52 (C 5l CH) ppm; mass spectrum, FD (relative intensity) (M + +l, 28), 274 (100). Λnal. Calcd for Cι 3 Hι N 4 0 3 : C, 56.93; H, 5.14; N, 20.43. Found: C, 56 H, 5.01; N, 20.28. Example 122 1 Synthesis of -Acetamido-N-benzy.l-2-(thioamide) acetamide. 2-Acetam N-benzyl-2-cyanoacetamide (4.00 g, 34.64 mmol) and O.O-dietlvyldithiophosph acid (6.45 g, 34.64 mmol) were dissolved in a binary MeOH (80 mL)-EtOH (80 5 solution containing H 0 (0.32 mL) and heated at 70 °C (6 h) and then allowe remain at room temperature (13 h). The reaction mixture was filtered, and solvent was removed in vacuo. The residue was triturated with EtOAc to give 2 g (44%) of the desired compound. The thioamide was recrystallized from et ° acetate/hexane: mp 170-171 °C; R f 0.51 (8% MeOH/CHCl 3 ); I H NMR (DMSO-d 1.93 (a, C(0)CH 3 ), 4.29 (d, = 5.0 Hz, CH 2 ), 5.21 (d, J = 8.0 Hz, CH), 7.15-7.31 ( PhH), 8.03 (d, J = 8.0 Hz, NH), 8.69 (t, J = 5.0 Hz, NH), 9.27 (a, NHH), 9.91 NHH « ); 13 C NMR (DMSO-d 6 ) 22.68 (C(0)CH 3 ), 42.24 (CH 2 ), 62.95 (CH), 126.63 ( 126.96 (2C 2 * or 2C 3 '), 128.087 (2C 2 * or 2C3'), 138.83 (Ci'), 166.42 (C(O)NH), 16 (C(0)CH 3 ), 200.28 (C(S)NH 2 ) ppm; mass spectrum, FD (relative intensity) (M++1, 42), 265 (100). Anal. Calcd for Cι 2 H 15 N 3 0 2 S: C, 54.32; H, 5.70; N, 15.84. Found: C, 54. H, 5.74; N, 15.54. Example 123 Synthesis of Ethyl 2-Acetamido-2-υinylacetate. Vinyl magnesium bromi (10.9 mL, 1 N, 10.9 mmol) was slowly added to a cooled (-78 °C) solution of ethyl acetamido-2-bromoacetate (1.10 g, 4.91 mmol) in THF (50 mL). The reaction w stirred at -78 °C (2 h), and was then quenched with a 1 N citric acid solution (7 mL). The mixture was allowed to warm to room temperature, and then the T was removed in vacuo. The aqueous mixture was extracted with CHC1 3 (3 x 1 mL), and the combined CHC1 3 extracts were dried (Na 2 S0 4 ) and concentrated dryness. The residue was purified by flash chromatography using Si0 2 gel a 2% Me0H/CHO 3 as the eluant to give 0.50 g (60%) of the desired product as a lig yellow colored oil: Rf 0.51 (4% MeOH/CHCl 3 ); *H NMR (DMSO-d 6 ) δ 1.17 (t, J = 7 Hz, OCH 2 CH 3 ), 1.88 (s, C(0)CH 3 ), 4.09 (d, J = 7.1 Hz, OCH 2 CH 3 ), 4.80-4.86 (m, CH), 5.22-5.35 (m, CH=CH 2 ), 5.82-5.92 (m, CH=CH 2 ), 8.47 (d, J = 7.4 Hz, NH); 13 NMR (DMSO-d 6 ) 13.96 (OCH 2 CH 3 ), 22.12 (C(0)CH 3 ), 54.65 (α-CH), 60. (OCH 2 CH 3 ), 117.89 (CH=CH 2 ), 132.48 (CH=CH 2 ), 169.16 (C(0)CH 3 ), 170. (C(O)NH) ppm. _ E__x___a__m__p_-l_e_-_- 1--2-4-> Synthesis of Vinyl Glycine. A mixture of ethyl 2-acetamido-2-vinyl acetat (5.20 g, 30.40 mmol) and aqueous 6 N HCl (200 mL) was heated to reflux (2 h). Th mixture was cooled to room temperature, and then extracted with CHC1 3 (3 x 10 mL). The aqueous solution which was dark brown in color was decolorized wit norit (15 min) at 60 °C, and then the mixture was filtered, and the filtrate wa concentrated to dryness to give aude vinyl glycine hydrochloride. The salt wa dissolved in a minimum amount of H 2 O and acidified to pH 2.0 with aqueous 1 HCl. The solution was applied to an ion exchange resin (Dowex 50XW ammonium form) and eluted with H 0 until the eluate was neutral. The io exchange column was then eluted with an aqueous 1 N NH OH solution (-50 mL). Removal of volatile materials from the NH 4 OH eiΛate gave 1.80 g (60%) vinyl glycine: mp 218-220 °C (d); i ll NMR (D 2 0) δ 4.09 (d, J = 7.2 Hz, cc-Cπ), 5.2 5.35 (m, CH=CH 2 ), 5.80-5.87 (m, CH=CH 2 ). Example 125 Synthesis of 2-Acetamido-2-υinylacetic acid. Acetic anhydride (2.50 g, 24 mmol) was added slowly into a cooled (-10 °C) solution of vinyl glycine (2.20 g, 21 mmol) in AcOH (100 mL). The mixture was stirred at this temperature (30 _ and then at room temperature (3 h). The solution was concentrated repeate - • from H 2 0. The residue was dissolved in absolute EtOH (200 mL) and t decolorized (norit, 60 °C), and filtered. The filtrate was concentrated in vac and the residue was triturated with Et 2 0 to give 1.70 g (55%) of the desired prod as a low melting yellow solid: IH NMR (DMSO-d 6 ) δ 1.87 (s, C(0)CH 3 ), 4.75 (dd, 6.2, 7.5 Hz, α-CH), 5.13-5.27 (m, CH=CH 2 ), 5.84-5.96 (m, CH=CH 2 ), 8.24 (d, J = Hz, NH). Exa ple 126 Synthesis of 2-Acetamido-N-benzyl-2-υinylacet amide. 4-Methyl morphoUn 1 (0.71 g, 6.99 mmol) was added to a suspension of 2-acetamido-2-vinylacetic aci (1.00 g, 6.99 mmol) in TIIF (325 mL), and the mixture was stirred at roo ____ * temperature (30 min). The reaction was cooled to -10 to -15 °C and the 5 isobutylchloroformate (1.24 g, 9.08 -mmol) was then added dropwise. Afte stirring (10 min), a solution of benzyiamine (0.75 g, 6.99 mmol) in THF (25 mL was added (15 min). The reaction mixture was allowed to warm to 0 °C. Th _ _ insoluble material was filtered. The filtrate was concentrated in vacuo, and tli residue was purified by flash column chromatography on Si0 2 gel using 3 MeOH/CHCI 3 as the eluant to give 1.00 g (62%) of the desired product: mp 136-13 °C (recrystallized from EtOΛc); Rf 0.24 (3% MeOH/CHCl 3 ); J H NMR (DMSO-d 6 ) 15 1.88 (s, C(0)CH 3 ), 4.27 (d, J ■= 5.6 Hz, CH 2 ), 4.89-4.94 (dd, J = 6.4, 7.8 Hz, α-CH) 5.13-5.30 (m, -CH=CH 2 ), 5.81-5.93 (m, -CH=CH 2 ), 7.20-7.33 (m, 5 Phil), 8.27 (d, J 7.8 Hz, Nil), 8.58 (t, J = 5.6 Hz, Nil); 13 C NMR (DMSO-d 6 ) 22.47 (C(0)CH 3 ), 42.0 (CH 2 ), 55.24 (α-CH), 116.44 (CH=CH 2 ), 126.74 (C * ), 127.05 (2C 2 * or 2C 3 '), 128.2 20 (2C 2 * or 2C 3 '), 134.76 (CH=CH 2 ), 139.25 (Ci'), 168.78 (C(0)CH 3 ), 168.99 (C(O)NH ppm. 25 30 35 Example 127 Synthesis of 2-Acetamido-N-benzyl-2-epoxyacetamide. A solution of acetamido-N-benzyl-2-vinylacetamide (1.00 g, 4.31 mmol) and m-chloroperox benzoic acid (1.76 g, 55%, 5.60 mmol) in dichloromethane (100 mL) was stirred room temperature (24 h), and then heated at reflux (3 h). The reaction soluti was treated with a saturated aqueous Na2S0 3 solution (20 mL) and then t organic layer was extracted with a saturated aqueous NaHC0 3 solution (3 x mL). The organic layer was washed with a saturated aqueous NaCl solution a dried (Na S0 4 ). The CH 2 C1 2 was removed in vacuo, and the residue was th purified by flash column chromatography on Si0 2 gel using 4% MeOH/EtOAc the eluant to give 0.35 g (33%) of the desired product: mp °C (recrystallized fr EtOAc); Rf 0.48 (5% MeOH/CHCl 3 ); X H NMR (DMSO-d 6 ) δ 1.87 (s, C(0)CH 3 ), 2. (dd, J = 2.5, 5.0 Hz, CH(O)CHH), 2.75 (dd, J = 4.3, 5.0 Hz, CH(O)CHH), 3.20 ( CH(O)CHH), 4.25-4.32 (m, α-CH, CH 2 ), 7.21-7.34 (m, 5 PhH), 8.30 (d, J = 8.1 NH), 8.59 (t, J = 5.8 Hz, NH); 3 C NMR (DMSO-d 6 ) 22.18 (C(0)CH 3 ), 41.99 (CH 43.91 (CH(0)CH 2 ), 51.30 (CH(0)CH 2 ), 53.80 (α-CH), 126.49 (C 4 '), 126.83 (2C 2 ' 2C 3 '), 127.98 (2C 2 * or 2C 3 '), 138.86 (Ci'). 168.52 (C(O)NH), 169.24 (C(0_CH 3 ) ppm. • Example 128 1 Synthesis of Potassium 2-Acetamido-N-benzylacetamide-2-sulfonate. solution of 2-acetamido-N-benzyl-2-(trimethylammonium)acetamide tetrafluo borate (0.30 g, 0.85 mmol) and K 2 S0 3 (0.68 g, 4.26 mmol) in H 2 0 (7.0 mL) t . _J heated at 50-55 °C (4 h). The solution was evaporated to dryness, and the resi was extracted with hot MeOH (3 x 10 mL). The MeOH was removed in vacuo give a white solid (-30 mg): IH NMR (D 2 0) δ 1.97 (s, C(0)CII 3 ), 4.33 (CH 2 ), 5. (CII), 7.19-7.28 (m, 5 Phil); 13 C NMR (D 2 0) 22.00 (C(0)CH 3 ), 43.41 (CH 2 ), 67. (CH), 127.18 (2C 2 * or 2C 3 '), 127.53 (C 4 '), 128.83 (2C 2 ' or 2C 3 '), 137.58 (Ci * ), 166 (C(O)NH), 173.65 (C(0)CH 3 ) ppm. Exa ple 129 1 Synthesis of Ethyl 2-Acetamido-4-pentenoic acid ester. Allyltrimeth silane (4.09 g, 31.40 mmol) was added to a stirred solution of ethyl 2-acetamido bromoacetate (1.76 g, 7.86 mmol) in dry THF (90 mL). After stirring (5 min), _ c ethereal solution of ZnCl 2 (1 N, 12.2 mL, 12.2 mmol) was added and the stirri was continued (70 h). The THF was removed by distillation in vacuo and t residue that remained was treated with H 2 0 (50 mL). The aqueous mixture extracted with CH 2 CI 2 (3 x 75 mL), the combined extract was dried (Na 2 S0 4 ) a 0 concentrated to give 1.40 g (97%) of the desired product. The ester was purified distillation in vacuo (65-70 °C, 0.3-0.8 torr) to give the desired product as a colorl oil: R f 0.35 (3% MeOH/CHCI 3 ); IH NMR (CDC1 3 ) δ 1.25 (t, J = 6.8 Hz, OCH 2 CH 1.99 (s, C(O)CHs), 2.44-2.60 (m, CH 2 CH=CH 2 ), 4.17 (q, = 6.8 Hz, OCH 2 CH 3 ), 4. 5 4.66 (m, CH), 5.07-5.11 (m, CH 2 CH=CH 2 ), 5.59-5.7Q (m, CH 2 CH=CH 2 ), 6.15 (b NH); 13 C NMR (CDCI 3 ) 14.09 (OCH 2 CH 3 ), 23.00 (C(0)CH 3 ), 36.46 (CH 2 CH=C 51.58 (CH), 61.39 (OCH 2 CH 3 ), 118.95 (CH 2 CH=CH 2 ), 132.15 (CH 2 CH=CH 2 ), 169 (C(0)CH 3 ), 171.74 (C(0)OCH 2 CH 3 ) ppm; mass spectrum, /e (relative intensi 0 186(M + +1,2), 144 (19), 126(7), 112(31), 102(73), 87(18), 71(100), 70(89). 5 0 5 _ E * _x___a__m___«p___l__e______ 1___3___0-_< ^ Synthesis of 2-Acetamido-4-pentenoic acid. Etliyl 2-acetamido-4-penteno acid ester (1.20 g, 6.50 mmol) was dissolved in 90:5 EtOH:H 2 0 (40 mL), and th KOH (1.50 g, 26.80 mmol) was added and the resulting solution stirred at roo temperature (48 h). The reaction was concentrated in vacuo and the resid diluted with H 2 0 (15 mL) and then washed with Et 2 0 (2 x 30 mL). The aqueo layer was then made acidic with 8.5% H 3 P0 4 and extracted with EtOAc (3 x mL). The combined organic layers were dried (Na 2 S0 4 ), and evaporated in vac 0 to give 0.56 g (55%) of the desired product: mp 113-115 °C (recrystallized fro EtOAc); IH NMR (DMSO-d 6 ) δ 2.00 (C(0)CH 3 ), 2.43-2.65 (m, CH 2 CH=CH 2 ), 4.3 4.43 (m, CH), 5.19-5.30 (m, CH 2 CH=CH 2 ), 5.84-5.98 (m, CH 2 CH=CH 2 ). 8.29 (d, J 7.7 Hz, Nπ), 12.78 (br ε, OH); 13 C NMR (DMSO-d 6 ) 22.35 (C(0)CH 3 ), 35. (CH 2 CH=CH 2 ), 51.68 (CH), 117.70 (CH 2 CH=CH 2 ), 134.07 (CH 2 CH=CH 2 ), 169. (C(0)CII 3 ), 173.11 (C0 2 H) ppm; mass spectrum, m/e (relative intensity) 158 (M++ 2), 139 (6), 116 (20), 112 (8), 74 (73), 70 (47), 42 (100). Anal. Calcd for C 7 HnN0 3 : C, 53.50; H, 7.06; N, 8.91. Found: C, 53.64; 7.15; N, 8.82. Example 131 _ Synthesis of 2-Acetamido-4-pentenoic acid-N -benzylamide. 4-Methyl pholine (0.55 g, 5.40 mmol) was added to a cooled (-10 to -15 °C) THF solution mL) of 2-acetamido-4-pentenoic acid (0.81 g, 5.18 mmol), and then isobutylchl _. formate (0.75 g. 5.70 mmol) was added leading to the precipitation of a white s After 2 min, a solution of benzyiamine' (0.61 g, 5.70 mmol) in THF (10 mL) slowly added at -10 to -15 °C. The reaction was allowed to warm (5 min) at r temperature and the insoluble sεdts were removed by filteration, and the filt 0 was evaporated to dryness. The residue was triturated with EtOAc (10 mL), the remaining white solid was filtered to give 0.81 g (64%) of the desired prod mp 118-120 °C (recrystallized from ethyl acetate/cyclohexane); Rf 0.36 MeOH/CHCl 3 ); IR (KBr) 3200 (br), 3040, 2900, 1650 (br), 1540 (br), 1350, 750, 5 cm- 1 ; IH NMR (DMSO-d 6 ) δ 1.83 (s, C(0)CH 3 ), 2.22-2.49 (m, CH 2 CH=CH 2 ), 4.2 J = 5.3 Hz, CH 2 Ph), 4.25-4.33 (m, CH), 4.99-5.09 (m, CH 2 CH=CH 2 ), 5.65-5.77 CH 2 CH=CH 2 ), 7.21-7.29 (m, 5 PhH), 8.05 (d, J = 7.6 Hz, NH), 8.46 (br s, NH); NMR (DMSO-de) 22.41 (C(0)CH 3 ), 36.24 (CH 2 CH=CH 2 ). 41.91 (CH 2 Ph), 52.20 ( 0 117.15 (CH 2 CH=CH 2 ), 126.54 (C 4 '), 126.99 (2C 2 * or 2C 3 '), 128.04 (2C_ * or 2C 3 '), 13 (Ci'), 134.25 (CH 2 CH=CH 2 ), 169.02 (C(0)CH 3 ), 170.96 (C(O)NH) ppm; spectrum, m/e (relative intensity) 246 (M+, 4), 205 (4), 163 (15), 140 (8), 106 (33) (77), 70 (100). 5 Anal. Calcd for Cι 4 Hι 8 N 2 θ 2 : C, 68.27; H, 7.37; N, 11.37. Found: C, 68 H, 7.31; N, 11.48. 0 5 Example 132 Using the procedures described herein, the following compounds can also be synthesized: α-acetamido-N-benzyl-2-(2-oxazole)-acetamide α-acetamido-N-benzyl-2-(2-thiazole)-acetamide. convu ilss" aantt" _ct t ι h v θ i P ty re a S c Θ c π o t rd ÷™ ing tQ ™ the fon t o ..t.d p f r o o r ce a d n u t r i e ¬ : 5 10 15 20 5 30 '35 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 (13 cm X 13 cm) 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". This procedure .is described n Pharmacol. Biochem. Behav. 6 , 351-353 (1977) and is incorporated herein by reference with the same force and effect as if fully set forth herein. The dose effect behavior 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 I includes an evaluation of the Median Effective Dose (ED50) and the Median Toxic Dose (TD50) of representative compounds. Mice were tested with varying doses c tne 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 50% of the animals. More specifically, data tabulated in Table 1 were generated as follows: The compound was given in various dose levels (i.e., 10, 30, 100, 300 mg) and subsequently compared with phenytoin, phenobarbital, mephenytoi * . and phcnacemide (See Table I). N-Λcetyl-D,L-alanine-N'-benzylamide was tested at 600 mg/mL as well. Seizures were then artifically induced by either electroschock or pentylenetetrazole. Maximal electroshock seizures (MES) were elicited with a 60 cycle alternating current of 50mA intenstiy (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 th death of the animal. Protection in this test was defined as the abolition of the hind limb tonic extension component of th seizure. The Subcutaneous Pentylenetetrazole (Metrazol ) Seizure Threshold Test { sc Met) entailed the administration of 85 mg/kg of pentylenetetrazole as a 0.5% solution subcutaneously in the posterior midline. This amount of pentylenetetrazole v/as expected to produce seizures in greater than 95% of mice. The animal was observed for 30 minutes. Protection was defined as a failure to observe even a threshol seizure (a single episode of clonic spasms of at least 5 sec duration). The results of these tests are tabulated in Table I. TΛD E I Comparative Median Effective Dosage 5 Tox MES sc Met Compound TD50 mq/.kg ED50 mα/):q ED50 mg/kg N-dcety1-D,L-alanine- N'-benzylamide 454 77 . (417-501)* (67-89)* __ N-acetyl-D-alanine- 10 N*-benzylamide 214 55 55 (148-262)* (50-60)* (43-67)* N-acetyl-L-alani-rie- N * -benzylamide 841 548 ≠ (691-594)* (463-741)* - j c N-acetyl-D,I_- phenylglycine-H'- benzylamide »40 32.1 ≠ N-acetyl-D-phenyl- glycine-N'-benzyl¬ amide »80 26.4 ≠ 0 N-acetyl- — henyl— glycine-U'-benz l¬ amide 100-300 >300 ≠ D,L- c -acetamido-N- benzyl-3-thiophene- ' acetamide " > 100 87.80 . 5 D, - d—a etamido-N- benzyl-2-thiophene- acetamide 30-100 44.80 ≠ D ,L- d. -ace tamido-iN- benzyl-2-furan- acetamide 40 10 .33 ≠ 0 D , - ct-acetamido-N- benzyl-2-pyrrole- acetami e < 100 16 . 10 . TΛIJLE I - cont'd, Com p arative Median Effective Dosaαe To* MES sc Met Com p ound TD50 mσ/kq ED50 mσ/kq ED50 mq/kq D, -2-acetamido-M- benzyl-2-ethoxy- - acetamide >112 62.01 D f I_-2-ecetamido-N- benzyl-2-ιnetho>:y- ■ acetamide 4300 98.30 (D, )-u-λcc_amido-N- ber__y]-2-(5-me_h ]fur__r_)- acetamide 75.4 ϊ _ 19.2 (16.4-23.8)* (D. .-α-Λcelamido-N- benzyl-2-benzofuran- acelamide ■ lOO^OO >100<300 (D,I_)-a-Acc__tm_do-N- bcnzyl-2-bcnzoP___.U_io- phcncaceLamide .100<300 >100<300 (D,L. α-AccLamido-N- bcnzyl-2-(5-meLliylpyrroIg) accLamide 36.5 (30.G-57.1)* (D.L. α-Λc_Lamido-N-(2- fluorobcr_zyl)-2-furan- accLamide 40.0 (D,L>α-Ac_tam_do-N-(3- fluorobenzyl)-2-_ " uxa_i- acclamide (114.9-161. β)^ 13.3 (11.5-15.3) + -199- Tox MES scMet TD 50 mg/kg ED 50 mg/kg ED 50 mg/kg 2-acelamido-H-benzyl-2- 65.1 aminoacetamide (56.2-75.3) -' 2-acetam_dσ-N-benzyl-2- (1-Pyrrolyl ) acetamide 80.2 2-acetar_.ido.-N-benzyl-2- (1-imidazo yl) acetamide 2-acetamido-.N-benzyI-2- 10 (N,N-dimethyIamino)acetamide 2-acetamido-,N-benzyl-2- (4-morphoIine)acetamide 2-acetamido-J__-beπzyI-2- (N.N.N-tri ethylamrnonium) -^ acetamide tetrafluoroborate 2-acetam:do-H-benzyi-2- (N-aπiiino)acetamide 2-acetamido-N.-benzyl-2- (N-(3-pyrazolyiamino)) 2C acetamide 2.2-diacetamido-_4-benzyI- acetamide 2-acetamido- J-beπzyl-2- trifiuoroacetamidoacetamide 25 2-acetamido-_l-beπzyI-2- (u-hydroxyamino)acetamide 2-acetamido-JN-benzyI-2- (JNJ-π.etnoxyamino)acetamide 3° 2-acetamido- -beπzyI-2- (_l-(__.-πιethyihydroxyamino)) acetamide 2-acetamido-.N-benzyl-2- (I_-(__.Q-dimethyIhydroxy- „ amino)acetamide 2-ace{amido-H-benzyi-2- (N-isoxazoIidino)acetamide 2^acetamido-^.b e nzyl-2- 2-acetamido- .beπzvl-2- hydroxyacetam ide y _ 0 π~S Cetarnido -N- enzyl-2- 1 0 (l - Pyra 2 oiyl, ac e am i de 2-acetamido-_J-benzyl-2- pheπoxyacelamide 2-acetamido-N-benzyl-2- (met ylmercapto)acetamide 2-acetamido-__-benzyi-2- (ethylmercapto)acetamide 2o 2-acetamido-N-benzyl-2- (£$-tι.iop enoxy)acetamide 25 2-acetar ' do-N-benzyl-2- (ethyimercapto)acetamide- >100 2-oxide (diastereomers A + B) 2-acetamido-N-beπzyl-2- (ethyisulfoπyl)acetamide >100 30 < 35 1 (D.L)-α-Acetaπ . _do-N-4- fluorob'nz3'l)-2-furan- acctau.ide 14.;.4 XX (122.5-170.9) _. 12.7 UO.4-15.1)^ (DX)-α-ΛccL_π_ido-N-(2,5- 5 difluorobeπzyl)-2-_urar_- acetamide 23 Q (20.2-28.4)* (D.L α-ΛccLaπ_ido-N-(2,6- d . ifluorobenz3-)-2-furan- acelamide 2-acetamido-N-benzyl~2- .2-Pyridyl) acetamide 8.5 20. ( D,L)-2-Ace_amϊdo-N-benzyl- 2-( eLh3-amino)aceLaπιide 95.0 44.5 (37.0-52.4)* (D, )-2-Λceta ido-N-beπzyl- 2-(ethyiamino)aceta___ide 42.4 25 (37.2-47.8)* (D, ) -2-Ace amido-N-benzy1- 3-indoleacetamide XXX phenytoin ve _ ~ -?*_ Mo acti ■vit V y al „ u _ e _ w n a o s te d d eL a e t rm <ined usin- ^ t L he e h hnor i .z . „on screen test. Other results from the- pharmacological protocols are summarized in Tables II, III and IV. Table ' n Selected Physical and Pharmacological Data in Mice for α-Acetamido-W-benzyl-2- furanacetamide (2)-Derivatives. a 6 -0 H CHj - Q 0 O 168-170 >100 s H CH 2 0 0 159-161 • 30 J__ -o H CH 2 0 0 210-212 > 100 Table II continued 1 1 - H NHNH 226-228 >100 12 H CH 2 — - r 0 O 188-190 127 144 11.3 (10.4-15.1) (123-171) ' {Rι-12 - H CH 2 H -F 0 0 2(&207 35 14.4 4.1 (2.9-4.4) (7.3-28.9) (/ .-la H CH 2 0 0 210-212 <10 (fl) __ -o H CH 2 -<ζ >_CF_ 0 0 193-195 >10.<30 phenytoin f 95 65.5. 63 (8.1-10.4) (52.5-72.1) phenobarbiial ' 215 69.0 i 32 (15.0-22.5) (62.8-72.9) valproate f 272 426 J- 1.6 (247-338) (369-450) aThe compounds were administered intraperitoπeally. ED50 and TD50 values are in milligrams per kilogram. Numbers in parentheses are 95% conlidence intervals. ' Time of peak effects in hours as determined in Ihe Experimenlal Section is denoted in brackets. Celling PO'nls ( β C) are uncorrecled. C MES = maximal electroshock seizure tesl. Compound was suspended in 30% PEG. °Tox » neurologic toxicity determined Irom horizontal screen unless otherwise noted epi - protective index (TD50/ED50). f Not determined. "Thick oil. " Table ill Selected Physical and Pharmacological Data in Mice for ..-Substituted α,α- Diamino Acid Derivatives. 3 O Tabl e II I cont inued 2. NH 2 CH 2 C0 2 124-126 phenytoin 95 65.5f (8.1-10.4) (525-72.1) phenobarbilal 21_ 69.0f (15.0-22.5) (62.8-72.9) valproate 272 426f (247-338) (369-450) a The compounds were administered intraperilonβally. ED50 and TD50 values are In milligrams per kilogram. Numbers in parentheses are 95% confidence Intervals. Time of peak effects In hours as determined in the Experimental Seclion is denoted In brackets. ^Melting points (°C) are uncorrecled. C MES - maximal electroshock seizure test. Compound was suspended in 30% PEG unless otherwise noted. ^Tox - neurologic toxicity determined from horizontal screen unless otherwise noted. e Nol determined. f Neurologic toxicity determined using the rotorod tesl. Table IV Pharmacological Data in Wice for α-Acetamido-N- Benzyl-2-Heterocyclic Derivatives O H O > 30 , < 100 I l _NH >100 H F' .t 6 _H >100 * MES = maximal electroshock seizure test. Compound was suspended in 30% PEG. b TOX = neurologic toxicity determined from horizontal screen unless otherwise noted.

Claims: -209- WHAT IS CLAIMED IS: 1. A compound of the formula R-NIKC-CNH. n C-Ra. (I) II i II Q R 3 -A - or the N-oxide thereof or pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group; R is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic lower cycloalkyl, lower cylcoalkyl, lower alkyl, and R x is unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; R 2 and R 3 are independently hydrogen, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, S0 3 ~ or Z-Y wherein R 2 and R 3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; Z is O, S(0) β , N _i, PR 4 , mercaptoalkyl, alkylthio; or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic or heterocyclic lower alkyl, cycloalkyl, cycloalkyl lower alkyl and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group provided that Z is a chemical bond only when Y is halo; or ZY taken together is NR 4 NR s R-7, NR 4 OR 5 , ONR__R v , OPR 4 R 5 , PR 4 OR s , SNR 4 R 7 , NR 4 SR V , SPR 4 R 5 , PR 4 SR- 7 , NR 4 PR 5 R 6 , PR 4 NR S R V , NR 4 • • NR 4 C - NR S R 6 , NR 4 C - NR 5 S(0) a R 6 ., NR 4 C - NR S R 6 , NR 4 CMNR 5 COR 6 or C-NH 2 ; II II II Q A s R 4 , R s and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R s and R 6 may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; R- 7 is R 6 , COORβ or C0R β ; R s is hydrogen or lower alkyl or aryl lower alkyl; n is 1-4 and a is 1-3 M is a lower alkylene chain, and A and Q are independently 0 or S with the provisio that at least one of A or is S. 2. The com ound according to Claim 1 wherein A is S. 3. The compound according to Claim 1 wherein A and Q are S. 4. The compound according to Claim 1 wherein one of R 2 and R 3 is H. 5. The compound according to Claim 4 wherein one of R 2 and R 3 is H and the other is heterocyclic. 6. The compound according to Claim 5 wherein heterocyclic is furyl, pyrrolyl, pyrazoyl, epoxy, oxazolyl, imidazolyl, tetraxolyl, triazolyl, or oxadiaxoyl. 7. The compound according to Claim 6 wherein heterocyclic is furyl, pyrrolyl, pyrozolyl, or pyridyl. 8. The compound according to Claim 1 wherein one of R 2 and R 3 is H and the other is Z-Y. 9. The compound according to Claim 8 wherein Z- Y is N,0-dimethylhydroxyamino, " N-methylhydroxyamino N- methyoxyamino, ethylamino or methylamino or hydrazino. 10. A compound of the formula 10 R-NH.C-CNH)- . C-R x (I) II I II Q R 3 A or the N-Oxide thereof or pharmaceutically acceptable salts thereof wherein 15 R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group; 20 R X is hydrogen or lower alkyl and R x is unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; one of R 2 and R 3 is hydrogen, and the other is 25 S0 3 ~ . 11. The compound according to Claim 10 wherein Q and A are both 0. 12. A compound of formula 30 R-NH(C-CNH) . - C-R x (I) II I II Q R 3 A or the N-Oxide thereof or pharmaceutically acceptable salts thereof wherein • 3C R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group; R x is hydrogen or lower ' alkyl and R x is unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; R__ and R 3 are independently hydrogen, alkyl, or Z-Y wherein R 2 and R 3 may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; Z is S(0) a , mercaptoalkyl, or alkylthio Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, cycloalkyl lower alkyl and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group provided that when Y is halo, Z is a chemical bond; or ZY taken together is NR 4 C - NR 5 , NR 4 C - NR S , II II o o SC - s , NR 4 C-OR s , NR 4 C - NR 5 R e , NR__CMNR 5 -C - OR 6 II II II II II O O S Q A C - NH 2 or NR 4 CNR 5 -S ( 0 ) a R e II II s o R 4 , R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5 and R e may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; -213- n is 1-4 and a is 1-3 M is lower alkylene, and A and Q are independently O or S with the provisio that at least one of R 2 and R 3 is Z-Y. 13. The compound of Claim 12 wherein A and Q are both oxygen. 14. A compound of the formula ' R-NH . C-CNH)__ C-R x (I) II I II Q R 3 A or the N-Oxide thereof or pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group; R. is hydrogen or lower alkyl and R x is unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; R 2 and R 3 are independently hydrogen, _mino, pyrrolyl, N, N-dimethγlamino, morpholinyl, pyrazinyl, -NH OCH 3 , methylhydroxyamino, (N,0-)dimethylhydroxyamino -NH C - CH_>NH - C 0CH 2 Ph, or O O or epoxy, and n is 1-4, provided that at least one of R 2 and R 3 is other than hydrogen 15. The compound according to Claim 14 wherein Q and A are both O. 16. The compound according to any one of Claims 1-15 wherein n is 1. 17. The compound according to any one of Claims 1-16 wherein R is lower arylalkyl which is unsubstituted or substituted with an electron donating group or electron withdrawing group. 18. The compound according to Claim 17 wherein R is benzyl which is unsubstituted or substituted with an electron withdrawing group or electron donating group. 19. The compound according to Claim 18 wherein R is unsubstituted benzyl or CH__—(v J 20. The compound according to any of Claims 1-19 wherein R x is lower alkyl. 21. The compound according to Claim 20 wherein R x is methyl. 22. A compound selected from the group consisting of ethyl 2-acetamido-2-aminoacetate, ethyl 2- acetamido-2-(methylamino)acetate, ethyl 2-acetamido-2-(N,N- dimethylamino)acetate, ethyl 2-acetamido-2-(4-morpholine)- acetate, ethyl 2-acetamido-2-(N-anilino)acetate, ethyl 2- acetamido-2-(N-(3-pyrazolylamino))acetate, ethyl 2- acetamido-2-(N-hydroxyamino)acetate, ethyl 2-acetamido-2- (N-(N-methylhydroxyamino) )acetate, ethyl 2-acetamido-2-(N- (N,0-dimethylhydroxy__mino) )acetate, 2-acetamido-N-benzyl-2- aminoacetamide, 2-acetamido-N-benzyl-2- (methylamino)acetamide, 2-acetamido-N-benzyl-2- (ethyla ino)acetamide, 2-acetamido-N-benzyl-2-(N- anilino) cetamide, 2-acetamido-N-benzyl-2(N-(3- pyrazolylamino) )acetamide, 2-acetamido-N-benzγl-2-(N,N- dimethylamino)acetamide, 2-acetamido-N-benzyl-2-(N- hydroxyamino)acetamide, 2-acetamido-N-benzyl-2-(N- hydroxya ino)acetamide, 2-acetamido-N-benzyl-2-(N^- phenylhydrazino)acetamide, 2-acetamido-N-benzyl-2-(N 2 - benzyloxycarbonylhydrazino)acetamide, 2-acetamido-N-benzyl- -215- 2-phenoxyacetamide, 2-acetamido-N .benzyl-2- (methylmercapto)acetamide, 2-acetamido-N-benzyl-2- (ethylmercapto)acetamide, 2-acetamido-N-benzyl-2-(N- methoxyamino)acetamide, 2-acetamido-N-benzyl-2-(N-<N- methylhydroxyamino))acetamide, 2-acetamido-N-benzyl-2-(N- (N,0-dimethylhydroxyamino) )acetamide, 2-acetamido-N-benzγl- 2-(N-isoxazolidino)acetamide, 2-acetamido-N-benzyl-2- hydroxyacetamide, 2-acetamido-N-benzyl-2- (ethylmercapto)acetamide, 2,2-diacetamido-N- benzylacetamide, 2-acetamido-N-benzyl-2- trifluoracetamidoacetamide, 2-acetamido-N-benzyl-2-(N,N,N- trimethylammonium)acetamide tetrafluoroborate, 2-acetamido- N-benzyl-2-(ethylmercapto)acetamide-S-oxide, 2-acetamido-N- benzyl-2-(S-ethylmercapto)acetamide-S-oxide, 2-acetamido-N- benzyl-2-(ethanesulfonyl)acetamide, 2-acetamido-N-benzγl-2- (N,N,N-trimethylaι_monium)acetamide tetrafluoroborate, 2- acetamido-N-benzyl-2-(1-pyrrole)acetamide, 2-acetamido-N- benzyl-2-(l-imidazole)acetamide, 2-acetamido-N-benzyl-2-(1- pyrazole)acetamide, 2-acetamido-N-benzyl-2(1-(1,2,4- triazole))acetamide, 2-acetamido-N-benzyl-2(l- tetrazole) )acetamide " , α-acetamido-N-benzyl-2- pyridylacetamide, α-acetamido-N-benzyl-2-pyridyl acetamide N-oxide, α-acetamido-N-benzyl-2-(S-thiophenoxy)-acetamide, α-acetamido-N-benzyl-2-(tetranydrofuran)acetamide, methyl α-acetamido-2-methyl-2-furanacetate, α-acetamido-2-methyl- 2-furanacetic acid, α-acetamido-N-benzyl-2-methyl-2- furanacetamide, α-thioacetamido-N-benzyl-2-furanacetamide, α-thioacetamido-N-benzyl-2-furanthioacetamide, α-acetamido- N-(3-pyridinylmethyl)-2-furanacetamide, α-acetamido-N-(4- pyridinylmethyl)-2-furanacetamide, α-acetamido-N-(l-oxo-3- pyridinylmethyl)-2-furanacetamide, α-acetamido-N-(l-oxo-4- pyridinylmethyl)-2-furanacetamide, R(-)α-acetamido-N-(4- fluorobenzyl)-2-furanacetamide, R(-)α-acetamido-N-(4- trifluoromethylbenzyl)-2-furanacetatmide, methyl[acetamido(benzylcarbamoyl)methyl]carbomate, phenyl[acetamido(benzylcarbamoyl)methyl]carbomate, 1- [acetamido(benzylcarbamoyl)methyl]-3-methylurea], 1- [acetamido(benzylcarbamoyl)methyl]-3-phenylurea] , 1- [acetamido(benzylcarbamoyl)methyl]-3-benzenesulfonylurea] , 1-[acetamido(benzylcarbamoyl)methyl]-3-methylthiourea] , 1- [acetamido(benzylcarbamoyl)methyl]-3-phenylthiourea] , N- [acetamido(benzylcarbamoyl)methyl]phthalamic acid], 2- acetamido-N-benzyl-2-(N-succinimidyl)acetamide] , benzyl N- [acetamido(benzylcarbamoyl)methyl]malonamate, ethyl N- [acetamido(benzylcarbamoyl)methyl]glycinate, benzyl N- [acetamido(benzylcarbamoyl)methyl]glycinate, N- [acetamido(benzylcarbomoyl) ethyl]glycine, 2-acetamide-N- benzyl-2-(1-pyrrole)acetamide, 2-acetamido-N-benzyl-2-(1- pyrazole)acetamide, 2-acetamido-N-benzyl-2-(l- imidazole)acetamide, 2-acetamido-N-benzyl-2-(l-(1,2,4- triazole) )acetamide, 2-acetamido-N-benzyl-2-(l- tetrazole) )acetamide, α-acetamido-N-benzyl-1- (dimethylsulfamoyl)imidazole-4-acetamide, α-acetamido-N- benzyl-4-imidazole acetamide, α-acetamido-N-benzyl-2- imidazole acetamide, α-acetamido-N-benzyl-5- (tetrazole)acetamide, α-acetamido-N-benzyl-3-(1,2,4- triazole)acetamide, α-acetamido-N-benzyl-2-(carboxamide oxime)acetamide, α-acetamido-N-benzyl-2-(carboxamide oxime- (O-acetate) )-acetamide, α-acetamido-N-benzyl-3-(1,2,4- oxadiazole)acetamide, α-acetamido-N-benzyl-2- (thioa ide)acetamide) , 2-acetamido-N-benzyl-2- vinylacetamide, 2-acetamido-N-benzγl-2-epoxyacetamide, potassium 2-acetamido-N-benzylacetamide-2-sulfonate, 2- acetamido-4-pentenic acid-N-benzylamide, α-acetamido-N- benzyl-2-(2-oxazole)-acetamide, and α-acetamido-N-benzyl-2- (2-thiazole)-acetamide. 23. An anti-convulsant composition comprising an anti-convulsant effective amount of a compound from any one of Claims 1-15 and 22 and a pharmaceutical carrier therefor. 24. An anti-convulsant .composition comprising an anti-convulsant effective amount of a compound from Claim 16 and a pharmaceutical carrier therefor. 25. An anti-convulsant composition comprising an anti-convulsant effective amount of a compound from Claim 17 and a pharmaceutical carrier therefor. 26. An anti-convulsant composition comprising an anti-convulsant effective amount of a compound from Claim 18 and a pharmaceutical carrier therefor. 27. An anti-convulsant composition comprising an anti-convulsant effective amount of a compound of Claim 19 and a pharmaceutical carrier therefor. 28. An anti-convulsant composition comprising an anti-convulsant effective amount of a compound of Claim 20 and a pharmaceutical carrier therefor. 29. An anti-convulsant composition comprising an anti-convulsant effective amount of a compound of Claim 21 and a pharmaceutical carrier therefor. 30. A method of treating CNS disorders in an animal comprising administering to said animal an anti¬ convulsant effective amount of a compound according to any one of Claims 1-15 and 22. 31. A method of treating CNS disorders in an animal comprising administering to said animal an anti- convulsant effective amount of a compound of Claim 16. 32. A method of treating CNS disorders in an animal comprising administering to said animal an anti¬ convulsant effective amount of a compound of Claim 17. 33. A method of treating CNS disorders in an animal comprising administering to said animal an anti¬ convulsant effective amount of a compound of Claim 18. 34. A method of treating CNS disorders in an animal comprising administering to said animal an anti¬ convulsant effective amount of a compound of Claim 19. 35. A method of treating CNS disorders in an animal comprising administering to said animal an anti¬ convulsant effective amount of a compound of Claim 20. 36. A method of treating CNS disorders άn an animal comprising administering to said animal an anti¬ convulsant effective amount of ' a compound of Claim 21.

Inventors: KOHN HAROLD L, WATSON DARRELL, KOHN, HAROLD, L., WATSON, DARRELL
Applicants: RES CORP TECHNOLOGIES INC, RESEARCH CORPORATION TECHNOLOGIES, INC.
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61K38, A61P25, C07C229, C07C233, C07C237, C07C239, C07C243, C07C259, C07C271, C07C275, C07C281, C07C309, C07C311, C07C317, C07C323, C07C327, C07C335, C07D207, C07D209, C07D213, C07D231, C07D233, C07D235, C07D237, C07D239, C07D241, C07D249, C07D257, C07D261, C07D263, C07D265, C07D271, C07D277, C07D295, C07D303, C07D307, C07D333, C07D405, C07D521