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Details for Patent: 5,378,729

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Details for Patent: 5,378,729

Title: Amino acid derivative anticonvulsant
Abstract:The present invention relates to compounds exhibiting central nervous system (CNS) activity which are useful in the treatment of epilepsy and other CNS disorders. The compounds of this invention have the following general formula: ##STR1## and pharmaceutically acceptable salts thereof.
Inventor(s): Kohn; Harold L. (Houston, TX), Watson; Darrell (Belton, TX)
Assignee: Research Corporation Technologies, Inc. (Tucson, AZ)
Filing Date:Jun 04, 1991
Application Number:07/710,610
Claims:1. An anticonvulsant composition comprising an anticonvulsant effective amount of a compound having the following general formula: ##STR23## wherein R is aryl, aryl lower alkyl, heterocyclic lower alkyl, lower alkyl, or heterocyclic, 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, or heterocyclic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; halogen or a heteroatom containing oxygen, nitrogen, or sulfur said heteroatom being substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted;

n is 1 to 4; and

a pharmaceutically acceptable carrier.

2. The composition according to claim 1 wherein R is aryl lower alkyl, heterocyclic lower alkyl or heterocyclic, each of which may be unsubstituted or substituted with at least one halo, nitro, acyl, carboxyl, carboalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, hydroxy, lower alkoxy, lower alkyl, amino, or phenoxy;

R.sub.1 is H or lower alkyl which may be unsubstituted or substituted with at least one halo, nitro, acyl, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, ammonium, hydroxy, lower alkoxy, amino, or phenoxy;

R.sub.2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, heterocyclic lower alkyl, or heterocyclic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; or R.sub.2 is halogen or a heteroatom consisting of nitrogen oxygen or sulfur each 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, or heterocyclic, each unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent; or

R.sub.3 is halogen, or a heteroatom consisting of oxygen, nitrogen, or sulfur substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups being substituted or unsubstituted and n is 1-4.

3. The composition according to claim 1 wherein one of R.sub.2 and R.sub.3 is other than hydrogen.

4. The composition according to claim 1 wherein n is 1.

5. The composition according to claim 1 wherein n is 1 and one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic or lower alkyl heterocyclic.

6. The composition according to claim 1 wherein n is 1 and one of R.sub.2 and R.sub.3 is hydrogen and the other is aryl.

7. The composition according to claim 1 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is thienyl, furyl, pyrrolyl or phenyl.

8. The composition according to claim 1 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkenyl or lower alkynyl.

9. The composition according to claim 1 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkoxy.

10. The composition according to claim 1 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkyl.

11. The composition of claim 1 having a unit dosage form containing from about to 5 to about 1000 mg of said compound.

12. The composition of claim 1 wherein R.sub.1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl or hexyl.

13. The composition of claim 12 wherein said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl or hexyl are unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent.

14. The composition of claim 12 wherein R.sub.1 is methyl.

15. The composition of claim 1 wherein R is benzyl, unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent.

16. The composition of claim 1 wherein said electron withdrawing substituent is halo, nitro, acyl, carboxyl, carboalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine or quaternary ammonium.

17. The composition of claim 1 wherein said electron donating substituent is hydroxy, alkoxy, alkyl, amino or phenoxy.

18. The composition of claim 1 wherein R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is methyl and n is 1 or the D or L steroisomer.

19. The composition of claim 1 wherein R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is phenyl and n is 1 or the D or L stereoisomer.

20. The composition of claim 1 wherein R is benzyl, R.sub.1 is methyl, R.sub.2 and R.sub.3 are hydrogen and n is 1.

21. The composition of claim 1 wherein R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is isopropyl and n is 1 or the D or L stereoisomer;

R is benzyl, R.sub.1 is t-butyl, R.sub.2 is hydrogen, R.sub.3 is methyl and n is 1 or the D or L stereoisomer;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is (2-thiomethyl)ethyl and n is 1 or the D or L stereoisomer;

R is (3-fluoro)benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is methyl and n is 1 or the D or L stereoisomer;

R is (3-methoxy)benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is methyl and n is 1 or the D or L stereoisomer;

R is benzyl, R.sub.1 is methyl, R.sub.2 is (3-thienyl), R.sub.3 is hydrogen and n is 1 or the D or L stereoisomer;

R is benzyl, R.sub.1 is methyl, R.sub.2 is (2-thienyl), R.sub.3 is hydrogen and n is 1 or the D or L stereoisomer;

R is benzyl, R.sub.1 is methyl, R.sub.2 is (2-furyl), R.sub.3 is hydrogen and n is 1 or the D or L stereoisomer;

R is benzyl, R.sub.1 is methyl, R.sub.2 is (2-pyrrolyl), R.sub.3 is hydrogen and n is 1 or the D or L steroisomer;

R is benzyl, R.sub.1 is methyl, R.sub.2 is ethoxy, R.sub.3 is hydrogen and n is 1 or the D or L stereoisomer; or

R is benzyl, R.sub.1 is methyl, R.sub.2 is methoxy, R.sub.3 is hydrogen and n is 1 or the D or L steroisomer.

22. The composition of claim 1 wherein said compound is in the D isomer form, L isomer form, mixtures of the D,L isomer form or D,L racemic form.

23. An anticonvulsant composition comprising an anticonvulsant effective amount of a compound having the formula: ##STR24## and pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;

R.sub.1 is hydrogen or lower alkyl which is unsubstituted or is substituted with at least one electron withdrawing substituent or at least one electron donating substituent;

R.sub.2 and R.sub.3 are independently each hydrogen, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, lower alkyl, 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, NR.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 at least one electron withdrawing group or electron donating 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, SNR.sub.4 R.sub.5, or NR.sub.4 SR.sub.5,

R.sub.4, R.sub.5 and R.sub.6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl and 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

n is 1-4, and

a pharmaceutically acceptable carrier therefor.

24. The composition of claim 23 having a unit dosage form containing from about 5 to about 1000 mg of said compound.

25. The composition of claim 23 wherein R.sub.1 is methyl.

26. The composition of claim 23 wherein R is aryl lower alkyl.

27. The composition of claim 26 wherein R is benzyl.

28. The composition of claim 23 wherein the electron withdrawing group is halo, nitro, lower alkanoyl, aryloyl, aryl lower alkanoyl, carboxy, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine or quaternary ammonium.

29. The composition of claim 23 wherein the electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, or phenoxy.

30. The composition according to claim 23 wherein R.sub.2 and R.sub.3 are independently hydrogen, phenyl, hydroxy, phenoxy, alkyl containing 1-4 carbon atoms, lower alkoxy, amino, lower alkylthio, morpholinyl, thienyl, furyl, pyrrolyl, methylfuryl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, lower alkenyl, anilino, arylamino, lower alkylamino, hydrazino, lower alkyl hydrazino, mercapto, arylthio, N-phenylhydrazine, N-hydroxylamino or O-hydroxylamino.

31. The composition according to claim 23 wherein one of R.sub.2 and R.sub.3 is hydrogen.

32. The composition according to claim 23 wherein n is 1.

33. The composition according to claim 23 wherein n is 1 and R.sub.1 is methyl.

34. The composition according to claim 23 wherein n is 1 and R is aryl lower alkyl.

35. The composition of claim 34 wherein R is benzyl.

36. The composition of claim 23 wherein n is 1 and wherein the electron withdrawing group is halo, nitro, lower alkanoyl, aryloyl, aryl lower alkanoyl, carboxy, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine or quaternary ammonium.

37. The composition of claim 23 wherein n is 1 and the electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, or phenoxy.

38. The composition according to claim 23 wherein n is 1 and R.sub.2 and R.sub.3 are independently hydrogen, phenyl, hydroxy, phenoxy, alkyl containing 1-4 carbon atoms, lower alkoxy, amino, lower alkylthio, morpholinyl, thienyl, furyl, pyrrolyl, methylfuryl, benzofuryl, benzotheinyl, indolyl, methylpyrrolyl, lower alkenyl, anilino, arylamino, lower alkylamino, hydrazino, lower alkyl hydrazino, mercapto, arylthio, N-phenyl hydrazino, N-hydroxylamino or O-hydroxylamino.

39. The composition according to claim 23 wherein said compound is in the p isomer form, the L isomer form, mixtures of the (D,L) isomer form or the D,L racemic form.

40. The composition according to claim 23 wherein n is 1 and one of R.sub.2 and R.sub.3 is hydrogen.

41. The composition of claim 23 wherein R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 5-methyl-2-furyl and n is 1 or the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-benzofuryl, n is 1 or the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-benzothienyl, n is 1 and the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 3-indolyl, n is 1 or the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 5-methyl-2-pyrrolyl, n is 1 or the D or L stereoisomer thereof;

R is 2-fluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-furyl, n is 1 or the D or L stereoisomer thereof;

R is 3-fluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-furyl, n is 1 or the D or L stereoisomer thereof;

R is 4-fluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-furyl, n is 1 or the D or L stereoisomer thereof;

R is 2,5-difluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-furyl, n is 1 and the D or L stereoisomer thereof;

R is 2,6-difluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-furyl, n is 1 and the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 2-propenyl, n is 1 and the p or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is 1-morpholino, n is 1 and the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is anilino, n is 1 and the D or L stereoisomer thereof;

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is methylamino, n is 1 and the D or L stereoisomer thereof; or

R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is ethylamino, n is 1 and the D or L stereoisomer thereof.

42. An anticonvulsant composition comprising an anticonvulsant effective amount of a compound having the formula: ##STR25## or pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic heterocyclic lower alkyl, lower cycloalkyl, or lower cycloalkyl lower alkyl wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;

R.sub.1 is hydrogen or lower alkyl and R.sub.1 is unsubstituted or is substituted with at least one electron withdrawing substituent or at least one electron donating substituent;

R.sub.2 and R.sub.3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R.sub.2 and R.sub.3 may be unsubstituted or substituted with at least electron withdrawing group or electron donating group;

Z is O, S, S(O), or NR.sub.4 ;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, cycloalkyl, or 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.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, ONR.sub.4 R.sub.7, SNR.sub.4 R.sub.7, NR.sub.4 SR.sub.7, ##STR26## 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,

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,

n is 1-4, and

a is 1-3.

43. The composition according to claim 42 wherein one of R.sub.2 and R.sub.3 is other than hydrogen.

44. The composition according to claim 42 wherein n is 1.

45. The composition according to claim 42 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is cycloalkyl, cycloalkyl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkenyl, lower alkynyl, 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,

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower cycloalkyl or lower 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.sub.4 NR.sub.5 R.sub.7, NR.sub.4 OR.sub.5, ONR.sub.4 R.sub.7, SNR.sub.4 R.sub.7, NR.sub.4 SR.sub.7, ##STR27## 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,

R.sub.7 is R.sub.6 or COOR.sub.8 or COR.sub.8,

R.sub.8 is hydrogen or lower alkyl,

n is 1-4, and

a is 1-3.

46. The composition according to claim 42 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic.

47. The composition according to claim 46 wherein heterocyclic has the formula ##STR28## wherein n is 0 or 1

A, E, L and J are independently CH, or a heteroatom selected from the group consisting of O, N and S;

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 heteroatom selected from the group consisting of NH, O and S,

with the provision that at most two of A, E, L, J and G are heteroatoms.

48. The composition according to claim 47 wherein one of A, E, L, J and G is a heteroatom.

49. The composition according to claim 47 wherein the heterocyclic is furyl, thienyl, pyrrolyl, pyrazolyl, isoxazolidino or pyridyl.

50. The composition according to claim 42 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is N-hydroxylamino, lower alkoxyamino, N-lower alkylhydroxyamino, or N-lower alkyl-O-lower alkyl hydroxyamino.

51. The composition according to claim 42 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkoxy, amino, lower alkylamino or dilower alkylamino.

52. The composition according to claim 42 wherein R.sub.2 is heterocyclic, heterocyclic amino, amino, lower alkylamino, lower dialkylamino, hydroxylamino, N-alkyl hydroxylamino, N,O-diloweralkylhydroxylamino, lower alkoxyamino, lower alkoxy, hydrogen, or lower arylalkyloxy carbonyl hydrazino.

53. The composition according to claim 42 wherein R.sub.2 is furyl, pyrrolyl, isoxazolidino, amino, methylamino, ethylamino, N,N-dimethylamino, 4-morpholinyl, N,N,N-trimethylammonium, N-anilino, 3-pyrazolylamino, trifluoroacetamido, acetamido, hydroxylamino, N,O-dimethylhydroxyamino, N-methoxyamino, isoxazolidino, benzyloxycarbonyl-hydrazino, hydroxy, methoxy, ethoxy, phenoxy, ethylsulfonyl, ethylsulfinyl or phenyl.

54. The composition according to claim 42 wherein R.sub.2 is furyl, pyrrolyl, phenyl benzyloxycarbonylhydrazino, isoxazolidino, N,O-dimethylhydroxyamino, N-methylhydroxyamino, N-methyoxyamino, ethylamino or methylamino.

55. The composition according to claim 42 wherein R.sub.1 is lower alkyl.

56. The composition according to claim 42 wherein R.sub.1 is methyl.

57. The composition according to claim 42 wherein R is aryl lower alkyl.

58. The composition according to claim 57 wherein R is benzyl.

59. The composition according to claim 42 which is in the D form, the L form, a mixture of the (D,L) form or a racemic mixture of the (D,L) form.

60. The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-amino acetamide, 2-acetamido-N-benzyl-2-methylamino acetamide, 2-acetamido-N-benzyl-2-(ethylamino)acetamide, 2-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide, 2-acetamide-N-benzyl-2-(4-morpholino)acetamide, 2-acetamido-N-benzyl-2-(N.sup.2 -phenylhydrazine)acetamide, 2-acetamido-N-benzyl-2-(N.sup.2 -benzyloxy carbonylhydrazino)acetamide, 2-acetamido-N-benzyl-2-hydroxy acetamide, 2-acetamido-N-benzyl-2-methoxy acetamide, or 2-acetamido-N-benzyl-2-ethoxyacetamide, acetamide or the D or L stereoisomer thereof.

61. The composition according to claim 42 where the compound is 2-acetamide-N-benzyl-2-(N-methoxy-amino) acetamide or the D or L steroisomer thereof.

62. The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-(N-(N-methylhydroxyamino))acetamide or the D or L steroisomer thereof.

63. The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-(N-(N,O-dimethylhydroxyamino)acetamide or the D or L stereoisomer thereof.

64. The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-(N-isoxazolidino) acetamide or the D or L isomer thereof.

65. The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-(2-pyridyl)acetamide or the D or L steroisomer.

66. The composition according to claim 42 wherein the compound is 2-acetamido-N-benzyl-2-(1-pyrazolyl)acetamido or the D or L stereoisomer thereof.

67. A compound of the formula ##STR29## and pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, or lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;

R.sub.1 is hydrogen or lower alkyl and R.sub.1 is unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent;

R.sub.2 and R.sub.3 are independently hydrogen, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, 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(O).sub.a or NR.sub.4 ;

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 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, SNR.sub.4 R.sub.7, NR.sub.4 SR.sub.7, ##STR30## 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;

R.sub.7 is R.sub.6, COOR.sub.8 or COR.sub.8 ;

R.sub.8 is hydrogen or lower alkyl or aryl lower alkyl;

n is 1-4 and

a is 1-3.

68. The compound according to claim 67 wherein one of R.sub.2 and R.sub.3 is other than hydrogen.

69. The compound according to claim 67 wherein n is 1.

70. The compound according to claim 67 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is furyl, pyrrolyl, phenyl, benzyloxycarbonyl, hydrazino, isoxozolidino, N, O-dimethylhydroxyamino, N-methylhydroxyamino, N-methoxy amino, ethylamino or methylamino.

71. The compound according to claim 67 wherein R.sub.1 is lower alkyl.

72. The compound according to claim 67 wherein R.sub.1 is methyl.

73. The compound according to claim 67 wherein R is aryl lower alkyl.

74. The compound according to claim 67 wherein R is benzyl.

75. The composition according to claim 67 which is in the D form, the L form, a mixture of the (D, L) form or a racemic mixture of the (D, L) form.

76. The compound according to claim 67 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic.

77. The compound according to claim 67 wherein heterocyclic has the formula ##STR31## wherein n is 0 or 1

A, E, L and J are independently CH or a heteroatom selected from the group consisting of O, N and S

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 heteroatom 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.

78. The compound according to claim 77 wherein one of A, B, L, J and G is a heteroatom.

79. The compound according to claim 77 wherein R.sub.2 is heterocyclic if furyl, thienyl, pyrrolyl, pyrazolyl, isoxazolidinyl or pyridyl.

80. The compound according to claim 67 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is N-hydroxylamino, lower alkoxyamino, N-lower alkylhydroxy, or N-lower alkyl-O-lower alkyl hydroxyamino.

81. The compound according to claim 67 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkoxy, amino, lower alkylamino or dilower alkylamino.

82. A compound of the formula ##STR32## wherein R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower 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 alkyl, lower alkenyl, lower alkynyl, Z-Y or a heterocyclic group each which may be unsubstituted or substituted with at least one electron withdrawing group or one electron donating group, with the proviso that R.sub.2 and R.sub.3 cannot both be hydrogen;

Z is O, S, NR.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, then 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, SNR.sub.4 R.sub.5, or NR.sub.4 SR.sub.5,

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

n is 1-4.

83. The compound according to claim 82 wherein R.sub.1 is methyl.

84. The compound according to claim 82 wherein R is unsubstituted or substituted aryl lower alkyl.

85. The compound according to claim 84 wherein R is benzyl which is either unsubstituted or substituted with fluoro.

86. The compound according to claim 82 wherein the electron withdrawing group is halo, nitro, lower alkanoyl, aryloyl, aryl lower alkanoyl, carboxy, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine or quaternary ammonium.

87. The compound according to claim 82 wherein the electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, or phenoxy.

88. The compound according to claim 82 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkenyl or lower alkynyl.

89. The compound according to claim 88 wherein one of R.sub.2 and R.sub.3 is 2-propenyl.

90. The compound according to claim 82 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is Z-Y.

91. The compound according to claim 90 wherein ZY is lower alkoxy, aryloxy, thioloweralkoxy, amino, thioaryloxy, lower alkylamino, di(loweralkyl)amino, arylamino, hydrazino, lower alkylhydrazino, N-phenylhydrazino or hydroxylamino.

92. The compound according to claim 82 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic or heterocyclic lower alkyl.

93. The compound according to claim 92 wherein one of R.sub.2 and R.sub.3 is thienyl, pyridyl, pyrazinyl, furyl, pyrrolyl, methylfuryl, benzofuryl, benzothienyl, indolyl, isoxazolidinyl, methylpyrrolyl, or morpholino and the other is hydrogen.

94. The compound according to claim 93 wherein R is benzyl, 2-fluorobenzyl, 3-fluorobenzyl, or 4-fluorobenzyl and one of R.sub.2 and R.sub.3 is hydrogen and the other is furyl.

95. The compound according to claim 82 wherein n is 1.

96. The compound according to claim 82 wherein n is 1 and R.sub.1 is methyl.

97. The compound according to claim 82 wherein n is 1 and R is unsubstituted or substituted aryl lower alkyl.

98. The compound according to claim 97 wherein R is benzyl which is either unsubstituted or substituted with fluoro.

99. The compound according to claim 82 wherein n is 1 and the electron withdrawing group is halo, nitro, lower alkanoyl, aryloyl, aryl lower alkanoyl, carboxy, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine or quaternary ammonium.

100. The compound according to claim 82 wherein n is 1 and the electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, or phenoxy, thiol, lower alkylmercapto or disulfide.

101. The compound according to claim 82 wherein n is 1 and one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkenyl or lower alkynyl.

102. The compound according to claim 101 wherein one of R.sub.2 and R.sub.3 is 2-propenyl and the other is hydrogen.

103. The compound according to claim 82 wherein n is 1 and one of R.sub.2 and R.sub.3 is hydrogen and the other is Z-Y.

104. The compound according to claim 103 wherein ZY is lower alkoxy, aryloxy, thioloweralkoxy, thioaryloxy, lower alkylamino, di(loweralkyl)amino, arylamino, hydrazino, lower alkylhydrazino, N-phenylhydrazino or hydroxylamino.

105. The compound according to claim 82 wherein n is 1 and one of R.sub.2 and R.sub.3 is hydrogen and the other is heterocyclic or heterocyclic lower alkyl.

106. The compound according to claim 105 wherein one of R.sub.2 and R.sub.3 is hydrogen and the other is thienyl, furyl, pyrrolyl, methylfuryl, benzofuryl, benzothienyl, indolyl, pyridyl, pyrazinyl, methylpyrrolyl, or morpholino.

107. The compound according to claim 82 wherein n is 1 and R is benzyl, 2-fluorobenzyl, 3-fluorobenzyl, or 4-fluorobenzyl and one of R.sub.2 and R.sub.3 is hydrogen and the other is furyl.

108. The stereoisomers of the compound of claim 82 or the mixture thereof or the racemic mixture thereof.

109. The D or L stereoisomer of the compound of claim 95 or the mixture thereof or the racemate thereof.

110. D or L-N-acetyl-phenylglycine-N'-benzylamide, or the (D,L) mixture thereof.

111. D or L .alpha.-acetamido-N-benzyl-3-thiopheneacetamide, or the (D,L) mixture thereof.

112. D or L .alpha.-acetamido-N-benzyl-2-thiopheneacetamide, or the (D,L) mixture thereof.

113. The compound according to claim 82 which is D or L-.alpha.-acetamido-N-benzyl-2-furanacetamide.

114. The compound according to claim 82 which is D or L-.alpha.-acetamido-N-benzyl-2-pyrroleacetamide.

115. The compound according to claim 82 which is or L-2-acetamido-N-benzyl-2-ethoxy-acetamide,

D or L-2-acetamido-N-benzyl-2-methoxyacetamide,

D or L-.alpha.-acetamido-N-benzyl-2-(5-methylfuran)acetamide,

D or L-.alpha.-acetamido-N-benzyl-2-benzo[b]thiopheneacetamide, or

D or L-.alpha.-acetamido-N-benzyl-3-indolacetamide, or

D or L-.alpha.-acetamido-N-benzyl-2-(5-methylpyrrole) acetamide.

116. The compound according to claim 82 which is (D,L)-.alpha.-Acetamido-N-(4-fluorobenzyl)-2-furanacetamide,

D-2-Acetamido-N-(4-fluorobenzyl)-2-furanacetamide; or

L-.alpha.-Acetamido-N-(4-fluorobenzyl)-2-furanacetamide.

117. The compound according to claim 82 which is (D,L)-.alpha.-Acetamido-N-(3-fluorobenzyl)-2-furanacetamide,

D-.alpha.-Acetamido-N-(3-fluorobenzyl)-2-furanacetamide; or

L-2-Acetamido-N-(3-fluorobenzyl)-2-furanacetamide,

118. The compound according to claim 82 which is D- or L-.alpha.-Acetamido-N-(2-fluorobenzyl)-2-furanacetamide,

D or L-.alpha.-Acetamido-N-(2,5-difluorobenzyl)-2-furanacetamide or

D or L-.alpha.-Acetamido-N-(2,6-difluorobenzyl)-2-furanacetamide.

119. The D or L-.alpha.-Acetamido-2-furanacetic acid or the (D,L) mixture thereof.

120. The compound according to claim 82 which is D or L-2-acetamido-4-pentenoic acid-N-benzylamide,

D or L-2-Acetamido-N-benzyl-2-(4-morpholino) acetamide,

D or L-2-Acetamido-N-benzyl-2-(N-anilino) acetamide,

D or L-2-Acetamido-N-benzyl-2-(methylamino) acetamide, or

D or L-ethyl-2-acetamido-2-(ethylamino)acetate.

121. The composition according to claim 23, wherein R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen, R.sub.3 is phenyl, and n is 1 or the D or L-stereoisomer thereof;

wherein R is benzyl, R.sub.1 is methyl, R.sub.2 is hydrogen and R.sub.3 is 2-furyl and n is 1 or the D or L-stereoisomer thereof;

R is 2-fluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen and R.sub.3 is 2-furyl and n is 1 or the D or L-stereoisomer thereof;

R is 3-fluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen and R.sub.3 is 2-furyl and n is 1 or the D or L stereoisomer thereof; or

R is 4-fluorobenzyl, R.sub.1 is methyl, R.sub.2 is hydrogen and R.sub.3 is 2-furyl and n is 2 or the D or L stereoisomer thereof.

122. The compound according to claim 82 which is D or L .alpha.-Acetamide-N-(2-fluorobenzenyl)-3-furanacetamide,

D or L .alpha.-acetamido-N-(3-fluorobenzyl)-3-furanacetamide,

D or L .alpha.-acetamido-N-(4-fluorobenzyl)-3-furanacetamide;

D or L .alpha.-acetamido-N-benzyl-3-furanacetamide;

D or L 2-acetamido-N-benzyl-2-amino acetamide;

D or L -.alpha.-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide, 2-acetamido-N-benzyl-2-(N,N,N-trimethylammonium) acetamide tetrafluoroborate,

D or L 2-acetamido-2-benzyl-2-(N-(3-pyrazolylamino))acetamide,

D or L 2,2-diacetamido-N-benzyl-acetamide, or

D or L 2-acetamido-N-benzyl-2-trifluoroacetamidoacetamide.

123. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(N-hydroxyamino)acetamide or the D or L isomer thereof.

124. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(N-methoxyamino)acetamide or the D or L isomer thereof.

125. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(N-(N-methylhydroxyamino))acetamide or the D or L isomer thereof.

126. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(N-(N,O-dimethylhydroxyamino))acet amide or the D or L isomer thereof.

127. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(N-isoxazolidino)acetamide or the D or L isomer thereof.

128. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(N.sup.2 -phenylhydrazino)acetamide.

D or L 2-acetamido-N-benzyl-2-(N.sup.2 -benzyloxycarbonyl-hydrazino)acetamide,

D or L 2-acetamido-N-benzyl-2-hydroxyacetamide,

D or L 2-acetamido-N-benzyl-2-phenoxyacetamide,

D or L 2-acetamido-N-benzyl-2-ethylmercapto) acetamide-S-oxide or

D or L 2-acetamido-N-benzyl-2-(ethylsulfonyl) acetamide.

129. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(2-pyridyl)acetamide.

130. The compound according to claim 82 which is 2-acetamido-N-butyl-2-(1-pyrazole)acetamide.

131. The compound according to claim 82 which is 2-acetamido-N-benzyl-2-(1-pyrrolyl)acetamide, acetamido-N-benzyl-2-(1 -imidazolyl)acetamide, 2-acetamido-N-benzyl-2-(3 -pyridyl)acetamide, 2-acetamido-N-benzyl-2-(4-pyridyl)acetamide, 2-acetamido-N-benzyl-2-(2-pyrimidinyl)acetamide, 2-acetamido-N-benzyl-2-(4-pyrimidinyl)acetamide, 2-acetamido-N-benzyl-2-(5-pyrimidinyl)acetamide, 2-acetamido-N-benzyl-2-(3-pyridazinyl)acetamide, 2-acetamido-N-benzyl-2-(4-pyridazinyl)acetamide, 2-acetamido-N-benzyl-2-(2-pyrazinyl)acetamide, 2-acetamido-N-benzyl-2-(2-thiazolyl)acetamide, 2-acetamido-N-benzyl-2-(3-oxazolyl)acetamide, 2-acetamido-N-benzyl-2-(3-isoxazolyl)acetamide, 2-acetamido-N-benzyl-2-(5-isoxazolyl)acetamide, 2-acetamido-N-benzyl-2-(3-isothiazolyl)acetamide or 2-acetamido-N-benzyl-2-(5-isothiazolyl)acetamide

132. A method of treating central nervous system disorders in animals comprising the administration to said animal an effective amount of a compound according to claim 1.

133. A method of treating central nervous system disorders in animals comprising the administration to said animal an effective amount of a compound according to claim 2.

134. A method of treating central nervous system disorders in animals comprising the administration to said animal an effective amount of a compound according to claim 23.

135. A method of treating central nervous system disorders in animals comprising the administration to said animal an effective amount of a compound according to claim 67.

136. A method of treating central nervous system disorders in animals comprising the administration to said animal an effective amount of a compound according to claim 82.

137. The method of claim 132 wherein said compound is administered in an amount from about 10 to about 100 mg/kg of body weight per day.

138. The method of claim 133 wherein said compound is administered in an amount from about 10 to about 100 mg/kg of body weight per day.

139. The method of claim 134 wherein said compound is administered in an amount from about 10 to about 100 mg/kg of body weight per day.

140. The method of claim 135 wherein said compound is administered in an amount from about 10 to about 100 mg/kg of body weight per day.

141. The method of claim 136 wherein said compound is administered in an amount from about 10 to about 100 mg/kg of body weight per day.

142. The method according to claim 135 wherein the compound administered is 2-acetamido-N-benzyl-2-(N-methoxyamino)acetamide, 2-acetamido-N-benzyl-2-(N-(N,O)-dimethylhydroxy-amino)acetamide, N-acetyl-phenylgylcine-N'-benzylamide, .alpha.-acetamido-N-benzyl-2-furanacetamide, .alpha.-acetamido-N-benzyl-2-(5-methylfuran)acetamide, .alpha.-acetamido-N-(3-fluorobenzyl)-2-furanacetamide, 2-acetamido-N-benzyl-2-(N,(N-methylhydroxyamino) acetamide, 2-acetamido-N-benzyl-2-(N-isoxazolidino)acetamide 2-acetamido-N-benzyl-2-(2-pyrroyl) acetamide, 2-acetamido-N-benzyl-2-(2-pyridyl) acetamide or 2-acetamido-N-benzyl-2-(1-pyrazolyl)acetamide or the D isomer of the compound, L isomer of the compound or a mixture of the (D,L) isomer of the compound.

143. The compound according to claim 82 which is (D)-(-)-.alpha.-Acetamido-N-benzyl-2-furanacetamide.

144. The compound according to claim 110 which is N-acetyl-D-phenylglycine-N'-benzylamide.

145. The composition according to claim 1 wherein said electron withdrawing substituent is halo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl lower alkanoyl and carbalkoxy.

146. The composition according to claim 1 wherein said electron donating substituent is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, phenoxy, thiol, lower alkylmercapto, or disulfide.

147. The composition according to claim 42 wherein said electron withdrawing group is halo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl lower alkanoyl and carbalkoxy.

148. The composition according to claim 42 wherein said electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, phenoxy, thiol, lower alkylmercapto, or disulfide.

149. The composition according to claim 67 wherein said electron withdrawing group is halo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, aryl lower alkanoyl, and carbalkoxy.

150. The composition according to claim 67 wherein said electron donating group is hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, phenoxy, thiol, lower alkylmercapto, or disulfide.
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