Amino acid derivative anticonvulsant

The present invention relates to compounds of the formula ##STR1##

BACKGROUND OF THE INVENTION 
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: 
##STR2## 
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, loweralkyl 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.sub.1 is hydrogen or lower alkyl, lower alkenyl, 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 
R.sub.2 and R.sub.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, SO.sub.3.sup.- or Z--Y wherein R.sub.2 and R.sub.3 may be 
unsubstituted or substituted with at least one electron withdrawing group 
or electron donating group; 
Z is O, S,S(O).sub.a, NR.sub.4, PR.sub.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.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, 
ONR.sub.4 R.sub.7, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 
R.sub.7, NR.sub.4 SR.sub.7, SPR.sub.4 R.sub.5, PR.sub.4 SR.sub.7, NR.sub.4 
PR.sub.5 R.sub.6 PR.sub.4 NR.sub.5 R.sub.7, 
##STR3## 
R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, 
aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, 
R.sub.5 and R.sub.6 may be unsubstituted or substituted with an electron 
withdrawing group or an electron donating group and 
R.sub.7 is R.sub.6 or COOR.sub.8 or COR.sub.8 
R.sub.8 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. Epilepsy refers to many types of recurrent seizures 
produced by paroxysmal excessive neuronal discharges in the brain; the two 
main generalized seizures are petit mal, which is associated with 
myoclonic jerks, akinetic seizures, transient loss of consciousness, but 
without convulsion; and grand mal which manifests in a continuous series 
of seizures and convulsions with loss of consciousness. 
The mainstay of treatment for such disorders has been the long-term and 
consistent administration of anticonvulsant drugs. Most drugs in use are 
weak acids that, presumably, exert their action on neurons, glial cells or 
both of the central 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 or part of a cyclic 
system. 
Much attention has been focused upon the development of anticonvulsant 
drugs and today many such drugs are well known. For example, the 
hydantions, such as phenytoin, are useful in the control of generalized 
seizures and all forms of partial seizures. The oxazolidinediones, such as 
trimethadione and paramethadione, are used in the treatment of 
nonconvulsive seizures. Phenacemide, a phenylacetylurea, is one of the 
most well known anticonvulsants employed today, while much attention has 
recently been dedicated to the investigation of the diazepines and 
piperazines. For example, U.S. Pat. Nos. 4,002,764 and 4,178,378 to 
Allgeier, et al. disclose esterified diazepine derivatives useful in the 
treatment of epilepsy and other nervous disorders. U.S. Pat. No. 3,887,543 
to Nakanishi, et al. describes a thieno[2,3-e][1,4]diazepine compound also 
having anticonvulsant activity and other depressant activity. U.S. Pat. 
No. 4,209,516 to Heckendorn, et al. relates to triazole derivatives which 
exhibit anticonvulsant activity and are useful in the treatment of 
epilepsy and conditions of tension and agitation. U.S. Pat. No. 4,322,974 
to Fish, et al. discloses a pharmaceutical formulation containing an 
aliphatic amino acid compound in which the carboxylic acid and primary 
amine 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 epilepsy and other CNS disorders. 
A further object of this invention is to provide a method of treating 
epilepsy and related convulsant disorders. 
These and other objects are accomplished herein by providing compounds of 
the following general formula: 
##STR4## 
wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n, Z, Y, 
A and Q are as defined hereinabove. 
The present invention contemplates employing the compounds of Formula I in 
compositions of pharmaceutically acceptable dosage forms. Where the 
appropriate substituents are employed, the present invention also includes 
pharmaceutically acceptable addition salts. Moreover, the administration 
of an effective amount of the present compounds, in their pharmaceutically 
acceptable forms or the addition salts thereof, can provide an excellent 
regime for the treatment of epilepsy, nervous anxiety, psychosis, insomnia 
and 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, amyl, 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-diphenylethyl, and the like. 
The term aryl, when used along or in combination, refers to an aromatic 
group which contains from 6 up to 18 ring carbon atoms and up to a total 
of 25 carbon atoms and includes the polynuclear aromatics. These aryl 
groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused 
rings. Polynuclear aromatic compound is meant to encompass bicyclic, 
tricyclic fused aromatic ring system containing from 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, 
pentadienyl, e.g., 1,3 or 2,4-pentadienyl, and the like. 
The term alkynyl include alkyene substituents containing 2 to 6 carbon 
atoms and may be straight chained as well as branched. It includes such 
groups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynl, 2-pentynyl, 
3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the 
like. 
The term cycloalkyl when used alone or in combination is a cycloalkyl group 
containing from 3 to 18 ring carbon atoms 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 or 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 exo 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 N.Y., 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, 
trifluoromethyl, aryl lower alkanoyl, carbalkoxy and the like. Electron 
donating groups include such groups as hydroxy, lower alkoxy, including 
methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl, and the 
like; amino, lower alkylamino, di(loweralkyl)amino, aryloxy such as 
phenoxy, mercapto, 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 of 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 may include one or several of said 
atoms. The heterocyclic substituents contemplated by the present invention 
include heteroaromatics and saturated and partially saturated heterocyclic 
compounds. These heterocyclics may be monocyclic, bicyclic, tricyclic or 
polycyclic and are fused rings. They may contain up to 18 ring atoms and 
up to a total of 17 ring carbon atoms and a total of up to 25 carbon 
atoms. The heterocyclics are also intended to include the so-called 
benzoheterocycles. Representative heterocyclics include furyl, thienyl, 
pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, 
isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, 
triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, 
benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, 
pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolidinyl, furazanyl, 
N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, 
pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, the N-oxides of the 
nitrogen containing heterocycles, such as the nitric oxides of pyridyl, 
pyrazinyl, and pyrimidinyl and the like. The preferred heterocyclic are 
thienyl, furyl, pyrroly, benzofuryl, benzothienyl, indolyl, 
methylpyrrolyl, merpholinyl, pyridyl, pyrazinyl, imidazolyl, 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, but 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.sub.1 is H or lower alkyl. The most preferred R.sub.1 group is 
methyl. 
The most preferred electron donating substituent and electron withdrawing 
substituent are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, 
carboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, 
heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower 
alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower 
alkylamino, di(loweralkyl)amino, amine lower alkyl mercapto, 
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.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 or R.sub.6, 
R.sub.7 or R.sub.8 as defined herein. 
The ZY groups representative of R.sub.2 and R.sub.3 include hydroxy, 
alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, 
such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino; 
alkylamino, such as methylamino, ethylamino; arylamino, 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, 
aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino 
(--NH--OH), lower alkoxy amino [(NHOR.sub.18) wherein R.sub.18 is lower 
alkyl], N-lower alkylhydroxyl amino [(NCR.sub.18)OH wherein R.sub.18 is 
lower alkyl], N-lower alkyl-O-lower alkyl hydroxyamino, i.e., 
[N(R.sub.18)OR.sub.19 wherein R.sub.18 and R.sub.19 are independently 
lower alkyl] and o-hydroxylamino (--O--NH.sub.2); alkylamido such as 
acetamido, trifluoroacetamido, lower alkoxyamino, (e.g. NH(OCH.sub.3); and 
heterocyclicamino, such as pyrazoylamino. 
Furthermore, in still another embodiment Z may be O, S, NR.sub.4 or 
PR.sub.4 and Y may be hydrogen, lower alkyl or aryl and R, R.sub.1, 
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are 
as defined hereinabove. 
In a still further embodiment, ZY may be 
##STR5## 
and R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, n and a are as defined hereinabove. 
When R.sub.2 or R.sub.3 is heterocyclic, the preferred heterocyclics are 
furyl, tetrahydrofuryl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, 
triazolyl, tetrazolyl, oxadiazolyl or epoxy. The most preferred 
heterocyclic is furyl, pyridyl, pyrazoyl and pyrrolyl. 
The preferred heterocyclic groups representative of R.sub.2 and R.sub.3 
have the formula 
##STR6## 
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 heteroatom 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 R.sub.2 or R.sub.3 is a heterocyclic of the above formula, it may be 
bonded to the main chain by a ring carbon atom. When n is O, R.sub.2 or 
R.sub.3 may additionally be bonded to the main chain by a nitrogen ring 
atom. 
R.sub.2 or R.sub.3 may independently also be SO.sub.3.sup.-, or 
SO.sub.2.sup.-. 
Furthermore, ZY may also be 
##STR7## 
When R.sub.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. 
As indicated hereinabove, Q and A may be O or S; in other words, the main 
chain may contain only C.dbd.O, only --C.dbd.S or combinations thereof. 
All such permutations are contemplated herein. It is preferred that the 
compounds of the present invention contain no more than 2 C.dbd.S 
moieties, it is even more preferred that the compounds of the present 
invention contain no more than 1 C.dbd.S moiety. The most preferred 
embodiment are when A and Q are both oxygen. 
An embodiment of the present application is one 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.sub.1, R.sub.2, 
R.sub.3, Z, Y or ZY taken together, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, n and a are as defined herein. 
Another embodiment of the present invention include compounds of Formula I 
wherein R.sub.1 is lower cycloalkyl or lower cycloalkyl lower alkyl and 
R.sub.1 may be unsubstituted or substituted with an electron donating 
group or electron withdrawing group and R.sub.1, R.sub.2, R.sub.3, Z, Y, 
or ZY taken together, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 n and a 
are as defined hereinabove. 
Another embodiment of the present invention includes compounds of Formula I 
wherein R.sub.2 is lower cycloalkyl or lower cycloalkyl lower alkyl and 
R.sub.2 may be unsubstituted or substituted with an electron donating 
group or electron withdrawing group, and R, R.sub.1, R.sub.3, R.sub.4, 
R.sub.5, R.sub.6, R.sub.7, R.sub.8 and a are as defined hereinabove. 
Still another embodiment of the present invention include compounds of 
Formula I wherein R.sub.3 is lower cycloalkyl or lower cycloalkyl lower 
alkyl and R.sub.3 may be unsubstituted or substituted with an electron 
donating or electron withdrawing group and R, R.sub.1, R.sub.2, R.sub.4, 
R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined hereinabove. 
A further embodiment of the present invention include compounds of Formula 
I wherein Z is S(O).sub.a and R, R.sub.1, R.sub.2, R.sub.3, Y, R.sub.4, 
R.sub.5, R.sub.6, R.sub.7, R.sub.8, n and a are as defined herein. 
It is preferred that one of R.sub.2 and R.sub.3 is hydrogen. 
In a preferred embodiment, one of R.sub.2 and R.sub.3 is hydrogen and that 
the other is heterocyclic. It is preferred that one of R.sub.2 and R.sub.3 
is a heterocyclic having Formula XI. The preferred heterocyclics include 
furyl, thienyl, benzothienyl, benzofuryl, oxazolyl, thiazolyl, isoxazolyl, 
indolyl, pyrazolyl, isoxazolidinyl, benzothienyl, benzofuryl, morpholinyl, 
indolyl, pyrrolyl, furfuryl, and methylpyrrolyl, pyridyl, pyrazinyl, 
imidazolyl, pyrimidinyl or pyridazinyl, pyrazolyl, or epoxy. In another 
preferred embodiment, one of R.sub.2 and R.sub.3 is alkyl (e.g. 
methylisopropyl), aryl (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.sub.2 and 
R.sub.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 alkylhydroxyamino or 
aralkoxycarbonylhydrazino. 
Preferred compounds of the present invention have the following general 
formula: 
##STR8## 
wherein R.sub.1 is H or lower alkyl, R.sub.2 and R.sub.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 3 are also 
preferred. 
Preferred embodiments include compounds of Formula I 
##STR9## 
wherein R and R.sub.1, 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; 
R.sub.2 and R.sub.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 
##STR10## 
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.sub.1 is H or lower alkyl, unsubstituted or substituted with at least one 
electron withdrawing substituent or at least one electron donating 
substituent; 
R.sub.2 and R.sub.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 4. 
Another preferred embodiment of the present invention is a compound of 
Formula I 
##STR11## 
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, carboxamide, cyano, sulfonyl, sulfoxide (sulfinyl), 
heterocyclic, guanidine, quaternary ammonium hydroxy, alkoxy, alkyl, 
amino, phenoxy, mercapto, sulfide or disulfide; 
R.sub.1 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.sub.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; 
R.sub.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 of aryl groups being substituted or 
unsubstituted; 
and n is 1 to 4; 
Another preferred embodiment is a compound of Formula I 
##STR12## 
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.sub.1 is hydrogen or lower alkyl, unsubstituted or substituted with an 
electron donating group or an electron withdrawing group and 
R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl, lower alkenyl, 
lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower 
alkyl, or Z--Y wherein R.sub.2 and R.sub.3 may be unsubstituted or 
substituted with at least one electron withdrawing group or electron 
donating group; 
Z is O, S,S(O).sub.a, NR.sub.4, PR.sub.4 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 NR.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, 
ONR.sub.4 R.sub.7, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 
R.sub.7, NR.sub.4 SR.sub.7, SPR.sub.4 R.sub.5 or PR.sub.4 SR.sub.7, 
NR.sub.4 PR.sub.5 R.sub.6 or PR.sub.4 NR.sub.5 R.sub.7, 
##STR13## 
R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, 
aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, 
R.sub.5 and R.sub.6 may be unsubstituted or substituted with an electron 
withdrawing group or an electron donating group and 
R.sub.7 is R.sub.6 or COOR.sub.8 or COR.sub.8, R.sub.8 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 
##STR14## 
wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic alkyl 
which is unsubstituted or substituted with at least one electron 
withdrawing group or at least one electron donating group; 
R.sub.1 is hydrogen or lower alkyl which is unsubstituted or substituted 
with at least one electron withdrawing group or one electron donating 
group, 
R.sub.2 and R.sub.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, with the proviso that R.sup.2 and R.sup.3 cannot 
both be hydrogen; 
Z is O, S, NR.sub.4, PR.sub.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 or an electron withdrawing group, provided that 
when Y is halo, Z is a chemical bond; or 
ZY taken together is NR.sub.4 NR.sub.5 R.sub.6, NR.sub.4 OR.sub.5, 
ONR.sub.4 R.sub.5, OPR.sub.4 R.sub.5, PR.sub.4 OR.sub.5, SNR.sub.4 
R.sub.5, NR.sub.4 SR.sub.5, SPR.sub.4 R.sub.5, or PR.sub.4 SR.sub.5, 
NR.sub.4 PR.sub.5 R.sub.6 or PR.sub.4 NR.sub.5 R.sub.6, 
R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, aryl, 
aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R.sub.4, 
R.sub.5 and R.sub.6 may be unsubstituted or substituted with an electron 
withdrawing group or an electron donating group; 
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.sub.1 is hydrogen or lower 
alkyl, R.sub.2 and R.sub.3 are independently hydrogen, heterocyclic, lower 
alkyl, aryl, lower alkoxy, lower alkenyl, amino, hydroxylamino, lower 
alkoxy amino, N-lower alkyl hydroxyamino, N-lower alkyl-o-lower alkyl 
hydroxyamino, aralkoxy carbonyl hydrazino or alkylmercapto and n is 1. 
In another preferred embodiment, n is 1, R and R.sub.1 are as defined 
hereinabove and one of R.sub.2 and R.sub.3 is hydrogen and the other is 
heterocyclic, heterocyclic lower alkyl, aryl N-hydroxylamino, lower 
alkoxyamino, N-lower alkylhydroxylamino, N-lower alkyl-O-lower 
alkylhydroxyamino. 
Another preferred embodiment is wherein n is 1, R and R.sub.1 are as 
defined hereinabove, one of R.sub.2 and R.sub.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 alkylamino, aryl lower alkyloxy hydrazino, or 
lower alkylmercapto. 
The various combination and permutations of the Markush groups of R.sub.1, 
R.sub.2, R.sub.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.sub.1, R.sub.2, R.sub.3, n and R and 
the various combinations thereof. Thus, for example, the present invention 
contemplates that R.sub.1 may be one or more of the substituents listed 
hereinabove in combination with any and all of the substituents of 
R.sub.2, R.sub.3 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 and optically active forms. 
The configuration around each asymmetric carbon can be in either the D or 
L form. (It is well known in the art that the configuration around a 
chiral carbon 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 are contemplated by the present invention. 
In the principal chain, there exists asymmetry at the carbon atoms to which 
the groups R.sub.2 and R.sub.3 are attached as substituted. When n is 1, 
the compounds of the present invention is of the formula 
##STR15## 
wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, Z and Y 
are as defined previously. As used herein, the term configuration shall 
refer to the configuration around the carbon atom to which R.sub.2 and 
R.sub.3 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 
of the present invention are either the L-stereoisomer or the 
D-stereoisomer. These stereoisomers may be found in mixtures of the L and 
D stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred. 
Depending upon the substituents, the present compounds may form addition 
salts as well. All of these forms are contemplated to be within the scope 
of this invention including mixtures of the stereoisomeric forms. 
The following three schemes of preparation are generally exemplary of the 
process which can be employed for the preparation of the present complex. 
Although the compounds in the schemes hereinabove contain only the 
##STR16## 
moiety, it is just as applicable to compounds of Formula I wherein either 
A or Q is sulfur or both A or Q are sulfur. 
##STR17## 
wherein 
R.sub.17 =lower alkyl, aryl, aryl lower alkyl, 
##STR18## 
wherein R.sub.3 =aryl, heteroaromatic and R.sub.17 is as defined 
hereinabove. 
More specificically these compounds can be prepared by art-recognized 
procedures from known compounds or readily preparable intermediates. For 
instance, compounds of Formula I can be prepared by reacting amines of 
Formula II with an acylating derivative of a carboxylic acid of Formula 
III under amide forming conditions: 
##STR19## 
wherein R, R.sub.1, R.sub.2, R.sub.3 and are as defined hereinabove and 
n=1. 
The amide forming conditions referred to herein involve the use of known 
derivatives of the described acids, such as the acyl halides, (e.g., 
##STR20## 
wherein X is Cl, Br and the like), anhydrides (e.g., 
##STR21## 
mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazoles, 
and the like. It is preferred that the acylating derivative used is the 
anhydride, 
##STR22## 
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.sub.2 and R.sub.3 is aromatic or heteroaromatic is depicted in Scheme 
IV. 
The ester (IV) is reacted with halogen and ultraviolet light in the 
presence of a catalyst, e.g., AIBN, to form the halo derivative (V). (V) 
is reacted in the presence of a Lewis acid, such as zinc chloride, with an 
aromatic or heteroaromatic compound to form the compound (VI). (VI) in 
turn is hydrolyzed and then reacted with alkylhaloformate, such as 
alkylchloroformate in the presence of a tertiary amine to generate the 
mixed N-acyl amino acid carbonic ester anhydride (VIII). This intermediate 
is reacted with an amine under amide forming conditions to give the 
compound of Formula I. Alternatively, (VI) can be reacted directly with an 
amine (RNH.sub.2) 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. 
##STR23## 
X=halogen (i.e., Cl, Br) R.sub.17 =lower alkyl, aryl, arly lower alkyl 
M+=metal cation (i.e., Na.sup.+, K.sup.+) 
Two additional synthetic routes may be employed for the preparation of 
compounds wherein R.sub.2 or R.sub.3 is Z--Y as defined hereinabove. In 
one scheme, for the preparation of these complexes, a substitution 
reaction is used: 
##STR24## 
In the above scheme, R.sub.9 is lower alkyl, R.sub.2 is Z--Y and Z, Y, R, 
R.sub.3 and R.sub.1 are as defined hereinabove. 
The ether functionality on IX can be cleaved by treatment with Lewis acids, 
such as BBr.sub.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.sub.2 or MR.sub.2 or the sequential addition of triethylamine and 
H--R.sub.2 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.sub.3 in CH.sub.2 Cl.sub.2 led to the formation of the .alpha.-bromo 
derivative, 2-acetamido-N-benzyl-2-bromoacetamide. Addition of an excess 
of HR.sub.2 or the sequential addition of HR.sub.2 to a THF mixture 
containing the bromo adduct furnishes the desired product. 
In another procedure, the product wherein R.sub.2 or R.sub.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 
##STR25## 
In scheme VI, R, R.sub.1, R.sub.3 and R are as defined hereinabove, R.sub.2 
is Z--Y and R.sub.9 and R.sub.10 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.sub.2 
furnishes the desired product. For example, methylation of 
2-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide with trimethyloxonium 
tetrafluoroborate in nitromethane furnished the quaternary ammonium 
derivative, 2-acetamido-N-benzyl-(N,N,N-trimethylammonium)acetamide 
tetrafluoroborate in high yields. Subsequent treatment of the salt with 
the HR.sub.2 reagent in the methanol leads to the production of the 
desired product. 
As in any organic reaction, solvents can be employed such as methanol, 
ethanol, propanol, acetone, tetrahydrofuran, dioxane, dimethylformamide, 
dichloromethane, chloroform, and the like. The reaction is normally 
effected at or near room temperature, although temperatures from 0.degree. 
C. up to the reflux temperature of the reaction mixture can be employed. 
As a further convenience, the amide forming reaction 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 where 
hydrogen halide is formed by the amide forming reaction, e.g., the 
reaction acyl halide and the amine of Formula II. Of course, in those 
reactions where hydrogen halide is produced, any of the commonly used 
hydrogen halide acceptors can also be used. 
The exact mineral acid or Lewis acid employed in the reaction will vary 
depending on the given transformation, the temperature required for the 
conversion and the sensitivity of the reagent toward the acid in the 
reaction employed. 
Compounds of the present invention in which Q or 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 
reagent, i.e., 
[2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2-,4-disulfide]. 
This reagent is a known reagent for the thiation of such compounds as 
ketones, carboxamides, esters, lactones, lactams, imides, enamines, and 
S-substituted thioesters. Thus, this reagent can be used to transform 
compounds of Formula I wherein Q or A is O to compounds wherein one or 
both of Q or A is S. The number of 
##STR26## 
groups in the final product is dependent upon the amount of reagent added 
and the number of 
##STR27## 
groups present (i.e., the value of n) in the reactants having Formula I. 
For example, if n is 1, and both Q and A are oxygen, than the compounds of 
Formula I have two 
##STR28## 
groups. Thus, if it is desired that both 
##STR29## 
groups be transformed to 
##STR30## 
then approximately equimolar amount or a slight excess of is added to 
compounds of Formula I. On the other hand, if only one 
##STR31## 
group is desired in the final product, then approximately 1/2 molar 
equivalent of Lawesson's reagent is used. 
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 added 
depends upon the number of 
##STR32## 
desired in the product, and the number of 
##STR33## 
groups in the reactant. 
Regardless of which step in the synthesis the reagent is added, the reagent 
and the compound of Formula I having at least one 
##STR34## 
group or an intermediate thereof is dissolved in an inert solvent, such as 
THF and heated at a temperature effective to convert the 
##STR35## 
group to 
##STR36## 
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.sub.1, R.sub.2 and R.sub.3 can be present in the starting compounds, 
added to any one of the intermediates or added after formation of the 
final products by the known methods of substitution or conversion 
reactions. For example, the nitro groups can be added to the aromatic ring 
by nitration and the nitro group converted to other groups, such as amino 
by reduction, and halo by diazotization of the amino group and replacement 
of the diazo group. Alkanoyl groups can be substituted onto the aryl 
groups by Friedel-Crafts acylation. The acyl groups can be then 
transformed to the corresponding alkyl groups by various methods, 
including the Woff-Kishner reduction and Clemmenson reduction. Amino 
groups can be alkylated to form mono, dialkylamino and trialkylamino 
groups; and mercapto and hydroxy groups can be alkylated to form 
corresponding 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. W. Greene, John Wiley & 
Sons, 1981. 
Resulting mixtures of isomers can be separated in the 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 pure 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 of chiral stationary phases for HPLC, See, 
DeCamp, Chirality, 1, 2-6 (1989), which is incorporated herein by 
reference with the same force and effect as if fully set forth herein. 
For example, a racemic mixture of any of the intermediate in any of the 
schemes, e.g., 
##STR37## 
wherein R.sub.17 is H (which can be prepared according to the procedures 
of Schemes 1, 2, 3 or 4) is reacted with an optically active amine, 
RNH.sub.2, e.g., (R)(+).alpha.-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 to separate the racemic modification, since it 
will preferentially act on one of the compounds, without affecting the 
enantiomer. For example, acylase, such as acylase I, can be used to 
separate the racemic modification of an intermediate 
D,L(.+-.).alpha.-acetamido-2-furanacetic acid. It acts on the L 
(.+-.).alpha.-acetamido-2-furanacetic acid, but will not act on the D 
enantiomer. In this way, the D(-).alpha.-acetamido-2-furanacetic acid can 
be isolated. The intermediate can then react with the amine (RNH.sub.2) 
under amide forming conditions as described hereinabove to form the 
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 weight per day. A preferred dosage regimen for optimum 
results would be from about 20 mg to about 50 mg per kilogram of body 
weight per day, and such dosage units are employed that a total of from 
about 1.0 gram to about 3.0 grams of the active compound for a subject of 
about 70 kg of body weight 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 dosages 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, intraveneous (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 ingestible 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 conveniently be between about 5 to about 80% of 
the weight of the unit. The amount of active compound in such 
therapeutically useful compositions is such that a suitable dosage will be 
obtained. Preferred compositions or preparations according to the present 
invention are prepared so that an oral dosage unit form contains between 
about 5 and 1000 mg 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 like; a lubricant 
such as magnesium stearate; and a sweetening agent such as sucrose, 
lactose or saccharin may 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 or 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 active 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 sustained-release preparations and formulations. For 
example, sustained release dosage forms are contemplated wherein the 
active ingredient is bound to an ion exchange resin which, optionally, can 
be coated with a diffusion barrier coating to modify the release 
properties of the resin. 
The active compound may also be administered parenterally or 
intraperitoncally. 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 oils. The proper fluidity can be maintained, for example, by the 
use of a coating such as lecithin; by the maintenance of the required 
particle size in the case of dispersion and by the use of surfactants. The 
prevention of the action of 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 monostearate and gelatin. 
Sterile injectable solutions are prepared by incorporating the active 
compound in the required amount in the appropriate solvent with various of 
the other ingredients enumerated above, as required, followed by filtered 
sterilization. Generally, dispersions are prepared by incorporating the 
various sterilized active ingredient into a sterile vehicle which contains 
the basic dispersion medium and the required other ingredients from those 
enumerated above. In the case of sterile powders for the preparation of 
sterile injectable solutions, the preferred methods of preparation are 
vacuum drying and the freeze-drying technique which yield a powder of the 
active ingredient plus any additional desired ingredient from previously 
sterile-filtered solution thereof. 
As used herein, "pharmaceutically acceptable carrier" includes any and all 
solvents, dispersion media, coatings, antibacterial and antifungal agents, 
isotonic and absorption delaying agents, and the like. The use of such 
media and agents for pharmaceutical active substances is well known in the 
art. Except insofar as any conventional media or agent is incompatible 
with the active ingredient, its use in the therapeutic compositions is 
contemplated. Supplementary active ingredients can also be incorporated 
into the compositions. 
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 specification for the novel dosage unit forms 
of the invention are dictated by and directly dependent on (a) the unique 
characteristics of the active material and the particular therapeutic 
effect to be achieved, and (b) the limitations inherent in the art of 
compounding such an active material for the treatment of disease in living 
subjects having a diseased condition in which bodily health is impaired as 
herein disclosed in detail. 
The principal active ingredient is compounded for convenient and effective 
administration in effective amounts with a suitable pharmaceutically 
acceptable carrier in dosage unit form as hereinbefore disclosed. A unit 
dosage form can, for example, contain the principal active compound in 
amounts ranging from about 5 to about 1000 mg, with 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 containing supplementary active 
ingredients, the dosages are determined by reference to the usual dose and 
manner of administration of the said ingredients. 
The compounds of the present invention may be administered in combination 
with other anti-convulsant 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. 
General Methods. 
Melting points were determined with a Thomas-Hoover melting point apparatus 
and are uncorrected. Infrared spectra (IR) were run on a Beckman IR-4250 
and Perkin-Elmer 1330 and 283 spectrophotometers and calibrated against 
the 1601-cm.sup.-1 band of polysytrene. Absorption values are expressed in 
wavenumbers (cm.sup.-1). Proton nuclear magnetic resonance (.sup.1 H NMR) 
spectra were recorded on Varian Associates Models T-60 and FT-80A, General 
Electric QE 300, and Nicolet NT-300 NMR spectrometers. Carbon nuclear 
magnetic resonance (.sup.13 C NMR) spectra were run on a Varian Associates 
Models FT-80A General Electric QE 300 and Nicolet NT-300 instrument. 
Chemical shifts are in parts per million (.delta. values) relative to 
Me.sub.4 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-Howell 21-491 
spectrometer as well as at the Eli Lilly Laboratories on a Varian MAT-CH-5 
spectrometer. High-resolution (EI mode) mass spectra were performed by 
Drs. James Hudson and John Chinn at the Department of Chemistry, 
University of Texas at Austin, on a CEC21-110B double-focusing 
magnetic-sector spectrometer at 70 eV. Elemental analyses were obtained at 
Spang Microanalytical Laboratories, Eagle Harbor, Mich. and at the Eli 
Lilly Research Laboratories. 
The solvents and reactants were of the best commercial grade available and 
were used without further purification unless noted. All anhydrous 
reactions were run under nitrogen, and all glassware was dried before use. 
In particular, acetonitrile and triethylamine were distilled from 
CaH.sub.2, while dichloromethane was distilled from P.sub.2 O.sub.5. 
Acetic anhydride, benzaldehyde and ethyl chloroformate were fractionally 
distilled. 
Preparation of N-Acetyl-D- and L-amino acid-N-benzylamides. 
General Procedure. 
The D- or L-amino acid amide (11 mmol) was dissolved in dichloromethane (15 
mL) and then acetic anhydride (1.23 g, 1.40 mL, 12 mmol) was added 
dropwise. The solution was stirred at room temperature (18 h) and then 
concentrated to dryness. The residue was recrystallized from 
chloroform/hexane. The following examples 1-7 were prepared according to 
this procedure.