Peptidyl heterocycles useful in the treatment of thrombin related disorders

Claim 1

A compound of the formula I: ##STR160## wherein: A is selected from the group consisting of C 1-8 alkyl, carboxyC 1-4 alkyl, C 1-4 alkoxycarbonylC 1-4 alkyl, phenylC 1-4 alkyl, substituted phenylC 1-4 alkyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, formyl, C 1-4 alkoxycarbonyl, C 1-12 alkylcarbonyl, phenylC 1-4 alkoxycarbonyl, C 3-7 cycloalkylcarbonyl, phenylcarbonyl, substituted phenylcarbonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkoxysulfonyl, perfluoroC 1-4 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 10-camphorsulfonyl, phenylC 1-4 alkylsulfonyl, substituted phenylC 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, perfluoroC 1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsulfinyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, phenylC 1-4 alkylsulfinyl, substituted phenylC 1-4 alkylsulfinyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl or substituted naphthylsulfonyl where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or C 1-4 alkoxycarbonyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl or substituted naphthylsulfinyl where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl; a D or L amino acid which is coupled at its carboxy terminus to the nitrogen depicted in formula I and is selected from the group consisting of alanine, asparagine, 2-azetidinecarboxylic acid, glycine, N-C 1-8 alkylglycine, proline, 1-amino-1-cycloC 3-8 alkylcarboxylic acid, thiazolidine-4-carboxylic acid, 5,5-dimethylthiazolidine-4-carboxylic acid, oxazolidine-4-carboxylic acid, pipecolinic acid, valine, methionine, cysteine, serine, threonine, norleucine, leucine, tert-leucine, isoleucine, phenylalanine, 1-naphthalanine, 2-naphthalanine, 2-thienylalanine, 3-thienylalanine, [1,2,3,4]-tetrahydroisoquinoline-1-carboxylic acid and [1,2,3,4]-tetrahydroisoquinoline-2-carboxylic acid where the amino terminus of said amino acid is connected to a member selected from the group consisting of C 1-4 alkyl, tetrazol-5-yl-C 1-2 alkyl, carboxyC 1-4 alkyl, C 1-4 alkoxycarbonylC 1-4 alkyl, phenylC 1-4 alkyl, substituted phenyl C 1-4 alkyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 1,1-diphenylC 1-4 alkyl, 3-phenyl-2-hydroxypropionyl, 2,2-diphenyl-1-hydroxyethylcarbonyl, [1,2,3,4]-tetrahydroisoquinoline-1-carbonyl, [1,2,3,4]-tetrahydroisoquinoline-3-carbonyl, 1-methylamino-1-cyclohexanecarbonyl, 1-hydroxy-1-cyclohexanecarbonyl, 1-hydroxy-1-phenylacetyl, 1-cyclohexyl-1-hydroxyacetyl, 3-phenyl-2-hydroxypropionyl, 3,3-diphenyl-2-hydroxypropionyl, 3-cyclohexyl-2-hydroxypropionyl, formyl, C 1-4 alkoxycarbonyl, C 1-12 alkylcarbonyl, perfluoroC 1-4 alkylC 0-4 alkylcarbonyl, phenylC 1-4 alkylcarbonyl, substituted phenylC 1-4 alkylcarbonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl) 1,1-diphenylC 1-4 alkylcarbonyl, substituted 1,1-diphenylC 1-4 alkylcarbonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, perfluoroC 1-4 alkylsulfonyl, C 1-4 alkylsulfonyl, C 1-4 alkoxysulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 10-camphorsulfonyl, phenylC 1-4 alkylsulfonyl, substituted phenylC 1-4 alkylsulfonyl, perfluoroC 1-4 alkylsulfinyl, C 1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsulfinyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, phenylC 1-4 alkylsulfinyl, substituted phenylC 1-4 alkylsulfinyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, substituted naphthylsulfonyl where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, and substituted naphthylsulfinyl where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl; or a poly peptide comprised of two amino acids, where the first amino acid is a D or L amino acid, bound via its carboxy terminus to the nitrogen depicted in formula I and is selected from the group consisting of glycine, N-C 1-8 alkylglycine, alanine, 2-azetidinecarboxylic acid, proline, thiazolidine-4-carboxylic acid, 5,5-dimethylthiazolidine-4-carboxylic acid, oxazolidine-4-carboxylic acid, 1-amino-1-cycloC 3-8 alkylcarboxylic acid, 3-hydroxyproline, 4-hydroxyproline, 3-(C 1-4 alkoxy)proline, 4-(C 1-4 alkoxy)proline, 3,4-dehydroproline, 2,2-dimethyl-4-thiazolidine carboxylic acid, 2,2-dimethyl-4-oxazolidine carboxylic acid, pipecolinic acid, valine, methionine, cysteine, asparagine, serine, threonine, leucine, tert-leucine, isoleucine, phenylalanine, 1-naphthalanine, 2-naphthalanine, 2-thienylalanine, 3-thienylalanine, [1,2,3,4]-tetrahydroisoquinoline-1-carboxylic acid, [1,2,3,4]-tetrahydroisoquinoline-2-carboxylic acid, aspartic acid-4-C 1-4 alkyl ester and glutamic acid-5-C 1-4 alkyl ester and the second D or L amino acid, is bound to the amino terminus of said first amino acid, and is selected from the group consisting of phenylalanine, 4-benzoylphenylalanine, 4-carboxyphenylalanine, 4-(carboxy C 0-2 alkyl)phenylalanine, substituted phenylalanine where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 3-benzothienylalanine, 4-biphenylalanine, homophenylalanine, octahydroindole-2-carboxylic acid, 2-pyridylalanine, 3-pyridylalanine, 4-thiazolyalanine, 2-thienylalanine, 3-(3-benzothienyl)alanine, 3-thienylalanine, tryptophan, tyrosine, asparagine, 3-tri-C 1-4 alkylsilylalanine, cyclohexylglycine, diphenylglycine, phenylglycine, methionine sulfoxide, methionine sulfone, 2,2-dicyclohexylalanine, 2-(1-naphthylalanine), 2-(2-naphthylalanine), phenyl substituted phenylalanine where the substituents are selected from C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, aspartic acid, aspartic acid-4-C 1-4 alkyl ester, glutamic acid, glutamic acid-5-C 1-4 alkyl ester, cycloC 3-8 alkylalanine, substituted cycloC 3-8 alkylalanine where the ring substituents are carboxy, C 1-4 alkylcarboxy, C 1-4 alkoxycarbonyl or aminocarbonyl, 2,2-diphenylalanine and all alpha-C 1-5 alkyl of all amino acid derivatives thereof, where the amino terminus of said second amino acid is unsubstituted or monosubstituted with a member of the group consisting of formyl, C 1-12 alkyl, tetrazol-5-ylC 1-2 alkyl, carboxyC 1-8 alkyl, carboalkoxyC 1-4 alkyl, phenyl C 1-4 alkyl, substituted phenylC 1-4 alkyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 1,1-diphenylC 1-4 alkyl, C 1-6 alkoxycarbonyl, phenylC 1-6 alkoxycarbonyl, C 1-12 alkylcarbonyl, perfluoroC 1-4 alkylC 0-4 alkylcarbonyl, phenylC 1-4 alkylcarbonyl, substituted phenylC 1-4 alkylcarbonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 1,1-diphenylC 1-4 alkylcarbonyl, C 1-4 alkylsulfonyl, C 1-4 alkoxysulfonyl, perfluoroC 1-4 alkylsulfonyl, phenylsulfonyl, substituted phenylsufonyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 10-camphorsulfonyl, phenylC 1-4 alkylsulfonyl, substituted phenylC 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, perfluoro C 1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsufinyl where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, phenylC 1-4 alkylsulfinyl, substituted phenylC 1-4 alkylsulfinyl 1-naphthylsulfonyl, 2-naphthylsulfonyl, substituted naphthylsulfonyl where the naphthyl substituent is selected from C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and substituted naphthylsulfinyl where the naphthyl substituent is selected from C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl; R 1 is selected from the group consisting of hydrogen and C 1-5 alkyl, R 2 is selected from the group consisting of aminoC 2-5 alkyl, guanidinoC 2-5 alkyl, C 1-4 alkylguanidinoC 2-5 alkyl, diC 1-4 alkylguanidinoC 2-5 alkyl, amidinoC 2-5 alkyl, C 1-4 alkylamidinoC 2-5 alkyl, diC 1-4 alkylamidinoC 2-5 alkyl, C 1-3 alkoxy C 2-5 alkyl, phenyl, substituted phenyl where the substituents are independently selected from one or more of, amino, amidino, guanidino, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy or nitro, benzyl, phenyl substituted benzyl where the substituents are independently selected from one or more of, amino, amidino, guanidino, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy or nitro, hydroxyC 2-5 alkyl, C 1-5 alkylaminoC 2-5 alkyl, C 1-5 dialkylaminoC 2-5 alkyl, 4-aminocyclohexylC 0-2 alkyl and C 1-5 alkyl; p is 0 or 1 B is ##STR161## where n is 0-3, R3 is H or C 1-5 alkyl and the carbonyl moiety of B is bound to E; E is a heterocycle selected from the group consisting of oxazolin-2-yl, oxazol-2-yl, thiazol-2-yl, thiazol-5-yl, thiazol-4-yl, thiazolin-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, naphtho[2,1-d]thiazol-2-yl, naphtho[1,2-d]thiazol-2-yl, isothiazol-5-yl, isothiazol-3-yl, and a substituted heterocycle where the substituents are independently selected from C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy, C 1-4 alkoxycarbonyl, hydroxy or phenylC 1-4 alkylaminocarbonyl; or pharmaceutically acceptable salts thereof.