Patent ID: 6323219
Filing Date: 2001-11-27
Classification: A61K,A61Q,Y10S

Abstract:
A method of treating an inflammatory disorder in a subject in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula (I) ##STR7##wherein:A is selected from the group consisting of C.sub.1-8 alkyl, carboxyC.sub.1-4 alkyl, C.sub.1-4 alkoxycarbonyC.sub.1-4 alkyl, phenylC.sub.1-4 alkyl, substituted phenylC.sub.1-4 alkyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), formyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-2 alkylcarbonyl, phenylC.sub.1-4 alkoxycarbonyl, C.sub.3-7 cycloalkylcarbonyl, phenylcarbonyl, substituted phenylcarbonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkoxysulfonyl, perfluoroC.sub.1-4 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 10-camphorsulfonyl, phenylC.sub.1-4 alkylsulfonyl, substituted phenylC.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfinyl, perfluoroC.sub.1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsulfinyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), phenylC.sub.1-4 alkylsulfinyl, substituted phenylC.sub.1-4 alkylsulfinyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl or substituted naphthylsulfonyl (where the naphthyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or C.sub.1-4 alkoxycarbonyl ), 1-naphthylsulfinyl, 2-naphthylsulfinyl or substituted naphthylsulfinyl (where the naphthyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.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.sub.1-8 alkylglycine, proline, 1-amino-1 -cycloC.sub.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 acidwhere the amino terminus of said amino acid is connected to a member selected from the group consisting of C.sub.1-4 alkyl, tetrazol-5-yl-C.sub.1-2 alkyl, carboxyC.sub.1-4 alkyl, C.sub.1-4 alkoxycarbonylC.sub.1-4 alkyl, phenylC.sub.1-4 alkyl, substituted phenyl C.sub.1-4 alkyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 1,1-diphenylC.sub.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.sub.1-4 alkoxycarbonyl, C.sub.1-2 alkylcarbonyl, perfluoroC.sub.1-4 alkylC.sub.0-4 alkylcarbonyl, phenylC.sub.1-4 alkylcarbonyl, substituted phenylC.sub.1-4 alkylcarbonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl) 1,1-diphenylC.sub.1-4 alkylcarbonyl, substituted 1,1-diphenylC.sub.1-4 alkylcarbonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 alkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), perfluoroC.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkoxysulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 10-camphorsulfonyl, phenylC.sub.1-4 alkylsulfonyl, substituted phenylC.sub.1-4 alkylsulfonyl, perfluoroC.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsulfinyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), phenylC.sub.1-4 alkylsulfinyl, substituted phenylC.sub.1-4 alkylsulfinyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 -alkoxycarbonyl), 1-naphthylsulfonyl 2-naphthylsulfonyl, substituted naphthylsulfonyl (where the naphthyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.3-4 dialkylamino, carboxy or C.sub.1-4 -alkoxycarbonyl), 1-naphthylsulfinyl, 2-naphthylsulfinyl, and substituted naphthylsulfinyl (where the naphthyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-2 -dialkylamino, carboxy or C.sub.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.sub.1-8 alkylglycine, alanine, 2-azetidinecarboxylic acid, proline, thiazolidine-carboxylic acid, 5,5-dimethylthiazolidine-4-carboxylic acid, oxazolidine-4-carboxylic acid, 1-amino-1-cycloC.sub.3-8 alkylcarboxylic acid, 3-hydroxyproline, 4-hydroxyproline, 3-(C.sub.1-4 alkoxy)proline, 4-(C.sub.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.sub.1-4 alkyl ester and glutamic acid-5-C.sub.1-4 alkyl esterand 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.sub.0-2 alkyl)phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.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.sub.1-4 alkylsilylalanine, cyclohexylglycine, diphenyiglycine, phenylglycine, methionine sulfoxide, methionine sulfone, 2,2-dicyclohexylalanine, 2-(1-naphthylalanine), 2-(2-naphthylalanine), phenyl substituted phenylalanine (where the substituents are selected from C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), aspartic acid, aspartic acid-4-C.sub.1-4 alkyl ester, glutamic acid, glutamic acid-5-C.sub.1-4 alkyl ester, cycloC.sub.3-8 alkylalanine, substituted cycloC.sub.3-8 alkylalanine (where the ring substituents are carboxy, C.sub.1-4 alkylcarboxy, C.sub.1-4 alkoxycarbonyl or aminocarbonyl), 2,2-diphenylalanine and all alpha-C.sub.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.sub.1-12 alkyl, tetrazol-5-ylC.sub.1-2 alkyl, carboxyC.sub.1-8 alkyl, carboalkoxyC.sub.1-4 alkyl, phenyl C.sub.1-4 alkyl, substituted phenylC.sub.1-4 alkyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 1,1-diphenylC.sub.1-4 alkyl, C.sub.1-6 alkoxycarbonyl, phenylC.sub.1-6 alkoxycarbonyl, C.sub.1-12 alkylcarbonyl, perfluoroC.sub.1-4 alkylC.sub.0-4 alkylcarbonyl, phenylC.sub.1-4 alkylcarbonyl, substituted phenylC.sub.1-4 alkylcarbonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 1,1-diphenylC.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkoxysulfonyl, perfluoroC.sub.1-4 alkylsulfonyl, phenylsulfonyl, substituted phenylsufonyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 10-camphorsulfonyl, phenylC.sub.1-4 alkylsulfonyl, substituted phenylC.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfinyl, perfluoro C.sub.1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsufinyl (where the phenyl substituents are independently selected from one or more of, C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), phenylC.sub.1-4 alkylsulfinyl, substituted phenylC.sub.1-4 alkylsulfinyl 1-naphthylsulfonyl, 2-naphthylsulfonyl, substituted naphthylsulfonyl (where the naphthyl substituent is selected from C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl), 1-naphthylsulfinyl, 2-naphthylsulfinyl and substituted naphthylsulfinyl (where the naphthyl substituent is selected from C.sub.1-4 alkyl, perfluoroC.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy or C.sub.1-4 alkoxycarbonyl);R.sub.1 is selected from the group consisting of hydrogen and C.sub.1-5 alkyl.R.sub.2 is selected from the group consisting of aminoC.sub.2-5 alkyl, guanidinoC.sub.2-5 alkyl, C.sub.1-4 alkylguanidinoC.sub.2-5 alkyl, diC.sub.1-4 alkylguanidinoC.sub.2-5 alkyl, amidinoC.sub.2-5 alkyl, C.sub.1-4 alkylamidinoC.sub.2-5 alkyl, diC.sub.1-4 alkylamidinoC.sub.2-5 alkyl, C.sub.1-3 alkoxy C.sub.2-5 alkyl, phenyl, substituted phenyl (where the substituents are independently selected from one or more of, amino, amidino, guanidino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkyl, C.sub.1-3 alkoxy or nitro), benzyl, phenyl substituted benzyl (where the substituents are independently selected from one or more of, amino, amidino, guanidino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, halogen, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkyl, C.sub.1-3 alkoxy or nitro), hydroxyC.sub.2-5 alkyl, C.sub.1-5 alkylaminoC.sub.2-5 alkyl, C.sub.2-5 dialkylaminoC.sub.2-5 alkyl, 4-aminocyclohexylC.sub.0-2 alkyl and C.sub.1-5 alkyl;p is 0 or 1B is ##STR8##where n is 0-3, R3 is H or C.sub.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, imidazol-2-yl, 4-oxo-2-quinoxalin-2-yl, 2-pyridyl, 3-pyridyl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl, triazol-4-yl, triazol-6-yl, tetrazol-2-yl pyrimidin-2-yl, quinolin-2-yl, indol-2-yl, pyrazol-2-yl, 4,5,6,7-tetrahydrobenzothiazol-2-yl, naphtho[2,1-d]thiazol-2-yl, naphtho[1,2d]thiazol-2-yl quinoxalin-2-yl, isoquinolin-1-yl, isoquinolin-3-yl, benzo[b]furan-2-yl, pyrazin-2-yl, quinazolin-2-yl, isothiazol-5-yl, isothiazol-3-yl, purin-8-yl and a substituted heterocycle where the substituents are independently selected from C.sub.1-4 alkyl, perfluoro C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, carboxy, C.sub.1-4 alkoxycarbonyl, hydroxy or phenylC.sub.1-4 alkylaminocarbonyl;and pharmaceutically acceptable salts and prodrugs thereof.