Patent ID: 6469036
Filing Date: 2002-10-22
Classification: A61P,C07D,C07K

Abstract:
A compound of the formula I: wherein:A is selected from the group consisting of â€ƒa 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 dehydroproline, proline, substituted proline (where the the substituents on the proline are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, oxo, halo, amido, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyloxy, phenylalkyloxy, phenyl or C1-4alkoxycarbonyl) , where the amino terminus of said amino acid is connected to a member selected from the group consisting of [1,2,3,4]-tetrahydroisoquinoline-1-carbonyl, [1,2,3,4]-tetrahydroisoquinoline-3-carbonyl, formyl, C1-4alkoxycarbonyl, C1-8alkylcarbonyl, perfluoroC1-4alkylsulfonyl, C1-4alkylsulfonyl, amido, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, sulfonamido, arylsulfonyl, substituted arylsulfonyl (where the aryl substituents are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl), camphorsulfonyl, C1-4alkylsulfinyl, arylsulfinyl, substituted arylsulfinyl (where the aryl substituents are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl), and arylcarbonyl; 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 proline and substituted proline (where the the substituents on the proline are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, oxo, halo, amido, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkylcarbonyloxy, aralkyloxy, aryl or C1-4alkoxycarbonyl), 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 aspartic acid, aspartic acid-4-C1-4alkyl ester, glutamic acid, glutamic acid-5-C1-4alkyl ester, serine, phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of, C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy or C1-4alkoxycarbonyl), cyclohexylglycine, and cyclohexylalanine, where the amino terminus of said second amino acid is monosubstituted with a member of the group consisting of C1-6alkyl, carboxyC1-8alkyl, and C1-10alkylcarbonyl; R, and R1 are each independently selected from the group consisting of hydrogen and C1-5alkyl; R2 is selected from the group consisting of aminoC2-5alkyl, guanidinoC2-5alkyl, C1-4alkylguanidinoC2-5alkyl, diC1-4alkylguanidino-C2-5alkyl, amidinoC2-5alkyl, C1-4alkylamidinoC2-5alkyl, diC1-4alkylamidinoC25alkyl, C1-3alkoxyC2-5alkyl, phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyrimidylC1-4alkyl, substituted pyrimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazoC1-4alkyl, substituted imidazoC1-4alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazolinylC1-4alkyl, N-amidinopiperazinyl-Nâ€”C0-4alkyl, hydroxyC2-5alkyl, C1-5alkylaminoC2-5alkyl, C1-5dialkylaminoC2-5alkyl, N-amidinopiperidinylC1-4alkyl and 4-aminocyclohexylC0-2alkyl; R5 is selected from the group consisting of hydrogen, C1-4alkyl and C1-4alkylcarbonyl; E is an unsubstituted or substituted heterocycle selected from the group consisting of imidazolin-2-yl, imidazol-2-yl, oxazolin-2-yl, oxazol-2-yl, thiazolin-2-yl, thiazol-2-yl, thiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, tetrazol-5-yl, isoxazol-3-yl, 1,2,3,4-oxatriazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-pyrazolin-3-yl, pyrazol-3-yl, 1H-indazole-3-yl, benzoxazol-2-yl, benzimidazol-2-yl, benzothiazol-2-yl, 4,5,6,7-tetrahydro-benzothiazol-2-yl, wherein the substituents on the heterocycle are independently selected from C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, C1-4alkoxycarbonyl, phenylC1-4alkylaminocarbony, aryl, or substituted aryl where the substituents on the aryl are independently selected from one or more of C1-4alkyl, perfluoro C1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, Nâ€”C1-4alkylamido, N,Nâ€”C1-4dialkylamido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy, or C1-4alkoxycarbonyl; provided that whenA is a polypeptide wherein the first amino acid is unsubstituted proline, and the second amino acid is selected from the group consisting of aspartic acid, aspartic acid-4-C1-4alkyl ester, glutamic acid, glutamic acid-5-C1-4alkyl ester, phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of, C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy or C1-4alkoxycarbonyl), cyclohexylglycine, and cyclohexylalanine, where the amino terminus of said second amino acid is monosubstituted with a member of the group consisting of C1-6alkyl, carboxyC1-8alkyl, and C1-10alkylcarbonyl; then R2 is selected from the group consisting of substituted phenyl (where the substituents are independently selected from one or more of amidino, hydrazino, amidrazonyl), substituted benzyl (where the substituents on the benzyl are independently selected from one or more of hydrazino, amidrazonyl), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), pyrimidylC1-4alkyl, substituted pyrimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazoC1-4alkyl, substituted imidazoC1-4alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro), imidazolinylC1-4alkyl, and N-amidinopiperazinyl-Nâ€”C0-4alkyl; and pharmaceutically acceptable salts and prodrugs thereof.