Amino acid derivative anticonvulsant
AssigneeResearch Corporation Technologies, Inc.
InventorsHarold L. Kohn, Darrell Watson
Life of this patent
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Abstract
The present invention relates to compounds of the formula ##STR1##
Claims47
A compound of the formula ##STR82## or the N-oxide thereof or pharmaceutically acceptable salts thereof wherein
- R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;
- R.sub.1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic lower cycloalkyl, lower cylcoalkyl, lower alkyl, and R.sub.1 is unsubstituted or substituted with at least one electron withdrawing substituent or at least one electron donating substituent;
- R.sub.1 and R.sub.3 are independently hydrogen, lower alkyl lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, SO.sub.3.sup.31 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, NR.sub.4, mercaptoalkyl, alkylthio;
- or a chemical bond;
- Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic or heterocyclic lower alkyl, cycloalkyl, cycloalkyl lower alkyl and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group provided that Z is a chemical bond only when Y is halo;
- or
- ZY taken together is NR.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, SPR.sub.4 R.sub.5, ##STR83## 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
- M is a lower alkylene chain, and A and Q are independently O or S with the provisio that at least one of A or Q is S.
A compound of the formula ##STR84## or the N-Oxide thereof or pharmaceutically acceptable salts thereof wherein
- R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;
- R.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;
- one of R.sub.2 and R.sub.3 is hydrogen, and the other is SO.sub.3 --,
- A and O are independently O or S and n is 1-4.
A compound of formula ##STR85## or the N-Oxide thereof or pharmaceutically acceptable salts thereof wherein
- R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;
- R.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, 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 S(O).sub.a, mercaptoalkyl, or alkylthio
- Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, cycloalkyl lower alkyl and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group provided that when Y is halo, Z is a chemical bond;
- or
- ZY taken together is NR.sub.4 ##STR86## 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 and
- a is 1-3
- M is lower alkylene, and A and Q are independently O or S with the provisio that at least one of R.sub.2 and R.sub.3 is Z--Y.
A compound of the formula ##STR87## or the N-Oxide thereof or pharmaceutically acceptable salts thereof wherein
- R is aryl, aryl lower alkyl, heterocyclic or heterocyclic lower alkyl, cycloalkyl, lower cycloalkyl, lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;
- R.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.1 and R.sub.3 are independently hydrogen, amino, pyrrolyl, N, N-dimethylamino, morpholinyl, pyrazinyl, --NH OCH.sub.3, methylhydroxyamino, (N,O--)dimethylhydroxyamino ##STR88## or epoxy, and n is 1-4, provided that at least one of R.sub.2 and R.sub.3 is other than hydrogen.
A compound selected from the group consisting of ethyl 2-acetamido-2-aminoacetate, ethyl 2-acetamido-2-(methylamino)acetate, ethyl 2-acetamido-2-(N,N-dimethylamino)acetate, ethyl 2-acetamido-2-(4-morpholine)acetate, ethyl 2-acetamido-2-(N-anilino)acetate, ethyl 2-acetamido-2-(N-(3-pyrazolylamino))acetate, ethyl 2-acetamido-2-(N-hydroxyamino)acetate, ethyl 2-acetamido-2-(N-(N-methylhydroxyamino))acetate, ethyl 2-acetamido-2-(N-(N,O-dimethylhydroxyamino))acetate, 2-acetamido-N-benzyl-2-aminoacetamide, 2-acetamido-N-benzyl-2-(methylamino)acetamide, 2-acetamido-N-benzyl-2-(ethylamino)acetamide, 2-acetamido-N-benzyl-2-(N-anilino)acetamide, 2-acetamido-N-benzyl-2(N-(3-pyrazolylamino))acetamide, 2-acetamido-N-benzyl-2-(N,N-dimethylamino)acetamide, 2-acetamido-N-benzyl-2-(N-hydroxyamino)acetamide, 2-acetamido-N-benzyl-2-(N-hydroxyamino)acetamide, 2-acetamido-N-benzyl-2-(N.sup.2 -phenylhydrazino)acetamide, 2-acetamido-N-benzyl-2-(N.sup.2 -benzyloxycarbonylhydrazino)acetamide, 2-acetamido-N-benzyl-2-phenoxyacetamide, 2-acetamido-N-benzyl-2-(methylmercapto)acetamide, 2-acetamido-N-benzyl-2-(ethylmercapto)acetamide, 2-acetamido-N-benzyl-2-(N-methoxyamino)acetamide, 2-acetamido-N-benzyl-2-(N-(N-methylhydroxyamino))acetamide, 2-acetamido-N-benzyl-2-(N-(N,O-dimethylhydroxyamino))acetamide, 2-acetamido-N-benzyl-2-(N-isoxazolidino)acetamide, 2-acetamido-N-benzyl-2-hydroxyacetamide, 2-acetamido-N-benzyl-2-(ethylmercapto)acetamide, 2,2-diacetamido-N-benzylacetamide, 2-acetamido-N-benzyl-2-trifluoracetamidoacetamide, 2-acetamido-N-benzyl-2-(N,N,N-trimethylammonium)acetamide tetrafluoroborate, 2-acetamido-N-benzyl-2-(ethylmercapto)acetamide-S-oxide, 2-acetamido-N-ben zyl-2-(S-ethylmercapto)acetamide-S-oxide, 2-acetamido-N-benzyl-2-(ethanesulfonyl)acetamide, 2-acetamido-N-benzyl-2-(N,N,N-trimethylammonium)acetamide tetrafluoroborate, 2-acetamido-N-benzyl-2-(1-pyrrole)acetamide, 2-acetamido-N-benzyl-2-(1-imidazole)acetamide, 2-acetamido-N-benzyl-2-(1-pyrazole)acetamide, 2-acetamido-N-benzyl-2(1-(1,2,4-triazole))acetamide, 2-acetamido-N-benzyl-2(1-tetrazole))acetamide, .alpha.-acetamido-N-benzyl-2-pyridylacetamide, .alpha.-acetamido-N-benzyl-2-pyridyl acetamide N-oxide, .alpha.-acetamido-N-benzyl-2-(S-thiophenoxy)-acetamide, .alpha.-acetamido-N-benzyl-2-(tetrahydrofuran)acetamide, methyl .alpha.-acetamido-2-methyl-2-furanacetate, .alpha.-acetamido-2-methyl-2-furanacetic acid, .alpha.-acetamido-N-benzyl-2-methyl-2-furanacetamide, .alpha.-thioacetamido-N-benzyl-2-furanacetamide, .alpha.-thioacetamido-N-benzyl-2-furanthioacetamide, .alpha.-acetamido-N-(3-pyridinylmethyl)-2-furanacetamide, .alpha.-acetamido-N-(4-pyridinylmethyl)-2-furanacetamide, .alpha.-acetamido-N-(1-oxo-3-pyridinylmethyl)-2-furanacetamide, .alpha.-acetamido-N-(1-oxo-4-pyridinylmethyl)-2-furanacetamide, R(-).alpha.-acetamido-N-(4-fluorobenzyl)-2-furanacetamide, R(-).alpha.-acetamido-N-(4-trifluoromethylbenzyl)-2-furanacetamide, methyl[acetamido(benzylcarbamoyl)methyl]carbomate, phenyl[acetamido(benzylcarbamoyl)methyl]carbomate, 1-[acetamido(benzylcarbamoyl)methyl]-3-methylurea), 1-[acetamido(benzylcarbamoyl)methyl]-3-phenylurea), 1-[acetamido(benzylcarbamoyl)methyl]-3-benzenesulfonylurea), 1-[acetamido(benzylcarbamoyl)methyl]-3-methylthiourea), 1-[acetamido(benzylcarbamoyl)methyl]-3-phenylthiourea), N-[acetamido(benzylcarbamoyl)methyl]phthalamic acid), 2-acetamido-N-benzyl-2-(N-succinimidyl)acetamide), benzyl N-[acetamido(benzylcarbamoyl)methyl]malonamate, ethyl N-[acetamido(benzylcarbamoyl)methyl]glycinate, benzyl N-[acetamido(benzylcarbamoyl)methyl]glycinate, N-[acetamido(benzylcarbomoyl)methyl]glycine, 2-acetamide-N-benzyl-2-(1-pyrrole)acetamide, 2-acetamido-N-benzyl-2-(1-pyrazole)acetamide, 2-acetamido-N-benzyl-2-(1-imidazole)acetamide, 2-acetamido-N-benzyl-2-(1-(1,2,4-triazole))acetamide, 2-acetamido-N-benzyl-2-(1-tetrazole))acetamide, .alpha.-acetamido-N-benzyl-1-(dimethylsulfamoyl)imidazole-4-acetamide, .alpha.-acetamido-N-benzyl-4-imidazole acetamide, .alpha.-acetamido-N-benzyl-2-imidazole acetamide, .alpha.-acetamido-N-benzyl-5-(tetrazole)acetamide, .alpha.-acetamido-N-benzyl-3-(1,2,4-triazole)acetamide, .alpha.-acetamido-N-benzyl-2-(carboxamide oxime)acetamide, .alpha.-acetamido-N-benzyl-2-(carboxamide oxime-(O-acetate))-acetamide, .alpha.-acetamido-N-benzyl-3-(1,2,4-oxadiazole)acetamide, .alpha.-acetamido-N-benzyl-2-(thioamide)acetamide), 2-acetamido-N-benzyl-2-vinylacetamide, 2-acetamido-N-benzyl-2-epoxyacetamide, potassium 2-acetamido-N-benzylacetamide-2-sulfonate, 2-acetamido-4-pentenic acid-N-benzylamide, .alpha.-acetamido-N-benzyl-2-(2-oxazole)-acetamide, and .alpha.-acetamido-N-benzyl-2-(2-thiazole)-acetamide.
A compound of the formula ##STR90## or the pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, 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 substituted with at least one electron withdrawing group or at least one electron donating group;
- A and Q are both O;
- one of R.sub.2 and R.sub.3 is hydrogen and the other is lower alkyl which is substituted with an electron donating group or a electron withdrawing group and n is 1-4.
Dependencies are inferred from the claim text.