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US 5,668,137 AGranted
N-heterocyclic sulfonamides having endothelin receptor activity
AssigneeZeneca Limited
InventorsPaul John Phillips, Peter Grahame Ballard, Robert Hugh Bradbury, Roger James
Life of this patent
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Abstract
The invention concerns pharmaceutically useful compounds of the formula I, in which R.sup.1, R.sup.2, R.sup.3, n, m and Het have any of the meanings defined herein, and their pharmaceutically-acceptable salts, and pharmaceutical compositions containing them. The novel compounds possess endothelin receptor antagonist activity and are useful, for example, in the treatment of diseases or medical conditions in which elevated or abnormal levels of endothelin play a significant causative role. The invention further concerns processess for the manufacture of the novel compounds and the use of the compounds in medical treatment.
Claims9
A compound of the formula I:
- wherein
- R.sup.1 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy or (1-6C)alkythio, each of which of the last five groups bear a substituent selected from carboxy, (1-6C)alkoxy-carbonyl, carbamoyl, N-(1-6C)alkylcarbamoyl and N, N-di(1-6C)alkylcarbamoyl;
- R.sup.2 is an optional substituent selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, N-(1-6C)alkylcarbamoyl, N, N-di(1-6C)alkylcarbamoyl, cyano, amino, N-(1-6C)alkylamino and N, N-di(1-6C)alkylamino;
- R.sup.3 is an optional substituent selected from (1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-6C)-alkyl, N-[(1-4C)alkyl]amino(1-6C)alkyl, N, N-[di(1-4C)alkyl]amino(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl(1-6C)alkyl, carbamoyl(1-6C)alkyl, (1-6C)alkylcarbamoyl(1-6C)alkyl, di(1-6C)alkylcarbamoyl(1-6C)alkyl, carboxy(1-6C)alkoxy, carboxy(1-6C)alkylthio, (1-6C)alkoxycarbonyl(1-6C)alkoxy, (1-6C)alkoxycarbonyl(1-6C)alkylthio, carbamoyl(1-6C)alkoxy, (1-6C)alkylcarbamoyl(1-6C)alkoxy, di(1-6C)alkylcarbamoyl(1-6C)alkoxy, carbamoyl(1-6C)alkylthio, (1-6C)alkylcarbamoyl-(1-6C)alkylthio, di(1-6C)alkylcarbamoyl(1-6C)alkylthio, (2-6C)alkenyl, carboxy(2-6C)-alkenyl, (2-6C)alkynyl, carboxy(2-6C)alkynyl, (1-6C)alkoxycarbonyl(2-6C)alkenyl, carbamoyl(2-6C)alkenyl, N-(1-6C)alkylcarbamoyl(2-6C)alkenyl, N, N-di(1-6C)alkylcarbonyl(2-6C)alkenyl, (1-6C)alkoxycarbonyl(2-6C)alkynyl, carbamoyl(2-6C)alkynyl, N-(1-6C)alkylcarbamoyl(2-6C)alkynyl, N, N-di(1-6C)alkylcarbamoyl(2-6C)alkynyl, halogeno(2-6C)alkyl, trifluoromethyl, trichloromethyl, tribromomethyl, (1-6C)alkoxy, dihalogeno(1-6C)alkoxy, trihalogeno(1-6C)alkoxy, (2-6C)alkenyloxy, (1-4C)alkoxy-(1-6C)alkyl, (1-4C)alkylthio(1-6C)alkyl, (1-4C)alkylsulphinyl(1-6C)alkyl, (1-4C)alkyl-sulphonyl(1-6C)alkyl, (1-4C)alkylenedioxy, (3-6C)cycloalkyl, (3-8C)cycloalkyl(1-6C)alkyl, phenyl, phenyl(1-6C)alkyl, phenoxy, phenyl(1-6C)alkoxy, halogeno, hydroxy, mercapto, cyano, nitro, carboxy, (1-6C)alkoxycarbonyl, (2-6C)alkenyloxycarbonyl, phenyloxy-carbonyl, phenyl(1-6C)alkoxycarbonyl, (1-6C)alkanoyl, benzoyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, (1-6C)alkanoylamino, trifluoroacetyl, trifluoroacetamido, N-[(1-4C)alkyl]-trifluoroacetamido, benzamido, N-[(1-4C)alkyl]benzamido, carbamoyl, (1-4C)alkyl-carbamoyl, di-(1-4C)alkylcarbamoyl, phenylcarbamoyl, sulphamoyl, N-(1-4C)alkyl-sulphamoyl, N, N-di(1-4C)alkylsulphamoyl, N-phenylsulphamoyl, (1-6C)alkane-sulphonamido, benzenesulphonamido, ureido, 3-(1-6C)alkylureido, 3-phenylureido, thioureido, 3-(1-6C)alkylthioureido, 3-phenylthioureido and a group --NRyRz in which Ry and Rz are independently selected from hydrogen, (1-6C)alkyl, phenyl(1-4C)alkyl and (1-6C)alkyl beating a carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkylcarbamoyl or di(1-6C)alkylcarbamoyl group, or the group --NRyRz taken together complete a 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 1-piperidinyl or 2-oxo-1-piperidinyl ring;
- Het is a heterocyclic ring of formula IIa:
- ##STR2## wherein Ra is selected from hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy and trifluoromethoxy;
- and Rb is selected from hydrogen, halogeno, (1-4C)alkyl, methoxy, ethoxy, trifluoromethyl and ethynyl;
- m is zero, 1, 2 or 3;
- n is zero, 1, 2 or 3;
- and wherein any of said phenyl or benzene moieties of R may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl;
- or a pharmaceutically-acceptable salt thereof.
8 more elements
Dependencies are inferred from the claim text.