Patent ID: 6087360
Filing Date: 2000-07-11
Classification: A61K,A61P

Abstract:
A method of preventing or treating heart failure and ventricular dysfunction in a warm-blooded animal, comprising administering to a warm blooded animal in need thereof a therapeutically effective amount of an endothelin antagonist of the formula: ##STR3## or pharmaceutically acceptable salt thereof wherein: each of Ar.sup.1 and Ar.sup.2 is independently phenyl or thienyl, which are optinally substituted by 1 to 4 groups selected from the group consisting of halogen, hydroxyl, amino, carboxyl, C.sub.1 -C.sub.6 alkoxycarbonyl, mono- or di-C.sub.1 -C.sub.6 alkylaminocarbonyl, carbamoyl, tetrazol-5-yl, methylenedioxy, C.sub.1 -C.sub.6 alkoxy, alkenyloxy, mono- or di-C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 C.sub.6 alkynyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyloxy, wherein the mono- or di-C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl, are optionally substituted by 1 to 3 groups selected from the group consisting of a phenyl, pyridyl, imidazolyl, hydroxyl, C.sub.1 -C.sub.6 alkoxy, amino, mono- or di-C.sub.1 -C.sub.6 alkylamino, hydroxy C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.1 -C.sub.6 acyloxy C.sub.1 -C.sub.6 alkylcarbonyl, carboxy C.sub.1 -C.sub.6 alkoxycarbonyl, carboxy C.sub.1 -C.sub.6 alkoxycarbonyl C.sub.1 -C.sub.6 alkoxycarbonyl, C.sub.1 -C.sub.6 alkoxycarbonyl, mono- or di- C.sub.1 -C.sub.6 alkyl aminocarbonyl, carbamoyl, C.sub.1 -C.sub.6 alkylsulfonylaminocarbonyl, tetrazol-5-yl-aminocarbonyl, carboxyl, SO.sub.3 H, PO.sub.3 H.sub.2, 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 present as substituents, they together optionally form a lactone ring;each R.sup.1, R.sup.2 and R.sup.3 is independently hydrogen, hydroxyl or C.sub.1 -C.sub.6 alkyl, or R.sup.1 and R.sup.2, R.sup.2 and R.sup.3 together form a single bond;Y is a group of --CO--R.sup.4, wherein R.sup.4 is hydroxyl, group C.sub.1 -C.sub.6 alkoxy, mono- or di-C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkylsulfonylamino, or arylsulfonylamino or aryl C.sub.1 -C.sub.6 alkylsulfonylamino, which are optionally substituted C.sub.1 -C.sub.6 alkyl, SO.sub.3 H, PO.sub.3 H.sub.2, a tetrazol-5-yl, 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl or 5-oxo-4H-1,2,4-oxadiazol-3-yl; andA is a group which forms together with the adjacent carbon--carbon double bond a 5- or 6-membered heteroaromatic ring comprising 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, which heteroaromatic ring is optionally substituted with hydroxyl, amino, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogen, cyano, nitro, mono- or di-C.sub.1 -C.sub.6 alkylamino which is optionally substituted by hydroxyl at the alkyl moiety, C.sub.3 -C.sub.8 cycloalkylamino which is optionally substituted by hydroxyl at the alkyl or alkylene moiety, C.sub.3 -C.sub.8 cycloalkyl C.sub.1 -C.sub.6 alkylamino which is optionally substituted by hydroxyl at the alkyl or alkylene moiety, N--C.sub.1 -C.sub.6 alkyl)--N--(C.sub.3 -C.sub.8 cycloalkyl)amino which is optionally substituted by hydroxyl at the alkyl or alkylene moiety, N--(C.sub.1 -C.sub.6 alkyl)--N--(aroyl)amino which is optionally substituted by hydroxyl at the alkyl moiety, C.sub.4 -C.sub.7 cyclic imino which is optionally substituted by hydroxyl at the alkylene moiety, carboxyl, C.sub.1 -C.sub.6 alkoxycarbonyl, formyl, C.sub.2 -C.sub.6 alkanoyl, aroyl, or C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl which is optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, amino, C.sub.1 -C.sub.6 alkoxy and mono- or di- C.sub.1 -C.sub.6 alkylamino, and when the heteroaromatic ring comprises one or more nitrogen atoms, the nitrogen atom(s) are optionally oxidized to form an N-oxide group, or a pharmaceutically acceptable salt thereof.