Patent ID: 6380195
Filing Date: 2002-04-30
Classification: A61K,A61P

Abstract:
A pharmaceutical composition for preventing or treating heart failure, which comprises an endothelin antagonist of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier: wherein:each of Ar1 and Ar2 is independently phenyl or thienyl, which are each optionally substituted by 1 to 4 groups selected from the group consisting of halogen, hydroxyl, amino, carboxyl, C1-C6 alkoxycarbonyl, mono- or di-C1-C6 alkylaminocarbonyl, carbamoyl, tetrazol-5-yl, methylenedioxy, C1-C6 alkoxy, C2-C6 alkenyloxy, mono- or di-C1-C6 alkylamino, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, wherein the C1-C6alkoxy, C2-C6 alkenyloxy, mono- or di-C1-C6 alkylamino, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are each optionally substituted by 1 to 3 groups which are selected from the group consisting of phenyl, pyridyl, imidazolyl, hydroxyl, C1-C6 alkoxy, amino, mono- or di-C1-C6 alkylamino, hydroxy C1-C6 alkylcarbonyl, C1-C6 acyloxy C1-C6 alkylcarbonyl, carboxy C1-C6 alkoxycarbonyl, carboxy C1-C6 alkoxycarbonyl C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonyl, mono- or di-C1-C6 alkylaminocarbonyl, carbamoyl, C1-C6 alkylsulfonylaminocarbonyl, tetrazol-5-yl-amino carbonyl, carboxyl, SO3H, PO3H2, tetrazol-5-yl, 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl and 5-oxo-4H-1,2,4-oxadiazol-3-yl; and wherein when hydroxyl and carboxyl are selected as substituents, they optionally together form a lactone ring; each of R1, R2 and R3 is independently hydrogen, hydroxyl or C1-C6 alkyl, or R1 and R2, or R2 and R3 together form a single bond; Y is â€”COâ€”R4, wherein R4 is a hydroxyl, amino, a C1-C6 alkoxy, mono- or di-C1-C6 alkylamino, C1-C6 alkylsulfonylamino, or arylsulfonylamino or aryl C1-C6 alkylsulfonylamino, wherein hydrogen atom(s) on the aryl ring thereof are optionally replaced by C1-C6 alkyl, SO3H, PO3H2, tetrazol-5-yl, 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl or 5-oxo-4H-1,2,4-oxadiazol-3-yl; and A is a group which forms together with the adjacent carbon-carbon double bond a 5- or 6-membered heteroaromatic ring including 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein 1 or 2 hydrogen atoms on the heteroaromatic ring are optionally replaced with hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylthio, halogen, cyano, nitro, mono- or di-C1-C6 alkylamino which are optionally substituted by hydroxyl at the alkyl moiety, C3-C8 cycloalkylamino which is optionally substituted by hydroxyl at the alkyl or alkylene moiety, C3-C8 cycloalkyl C1-C6 alkylamino which is optionally substituted by hydroxyl at the alkyl or alkylene moiety, N-(C1-C6 alkyl)-N-(C3-C8 cycloalkyl) amino which is optionally substituted by hydroxyl at the alkyl or alkylene moiety, N-(C1-C6 alkyl)-N-(aroyl) amino which is optionally substituted by hydroxyl at the alkyl moiety, C4-C7 cyclic imino which is optionally substituted by hydroxyl, the alkylene moiety, carboxyl, C1-C6 alkoxycarbonyl, formyl, C2-C6 alkanoyl, aroyl , or C1-C6alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, which are each optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C1-C6 alkoxy and mono- or di-C1-C6 alkylamino, and wherein when the heteroaromatic ring includes one or more nitrogen atoms, the nitrogen atom(s) are optionally oxidized to form an N-oxide group.