Patent EA-000952-B1 (EA)
Title: Endothelin receptor antagonists
Inventor: LUENGO JUAN IGNACIO
IPC: A61K31/4025
Filed: 1996-08-02
Abstract: 1 A compound of Formula (I):   wherein (Z) is radical   in which R1 and R2 are independently hydrogen, R4 is Cl, or n.alkoxy group, R5 is a -O-CH2-Ar group in which Ar is phenyl substituted by one or two substituents selected from COOH, Cl, or Ar is pyridyl substituted by COOH, R15 is lower alkyl; P is COOH; R2 is a group   in which Z1 and Z2 are independently hydrogen or n. alkoxy group; R<a> is hydrogen or pharmaceutically acceptable salts therof. 2. A compound of claim 1 selected from: (E)-3-[l-n-Butyl-5-[2-(2-carboxy-6-chlorophenyl)methoxyA-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid; (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoate; (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-methoxyphenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid; (E)-3-[1- n-Butyl-5-[2-(2-carboxy-6-chlorophenyl)methoxy-4-methoxyphenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid; (E)-3-[1-n-Butyl-5-[2-(2-carboxy-5-chlorophenyl)methoxy-4-methoxyphenyl]-1Hpyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid; (E)-3-[1-n-Butyl-5-[2-(3-carboxy-2-pyridyl)methoxy-4-methoxyphenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid; or (E)-[1-n-Butyl-5-[2-(2-carboxy-5-chlorophenyl)methoxy 4-chlorophenyl]-1H pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid. 3. A compound of claim 1 which is (E)-3-[1-n-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3 dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid. 4. A compound of Formula (II):   wherein R<a> , R3, R4, R5 and R15 are as described in claim 1 for Formula (I). 5. A pharmaceutical composition comprising a compound of claim 1 in an effective amount and a pharmaceutically acceptable carrier. 6. A compound of claim 1 for use as an endothelin receptor antagonist. 7. A method of treatment of diseases caused by an excess of endothelin comprising administering to a subject in need thereof, an effective amount of an endothelin receptor antagonist of claim 1. 8. A method of treating hypertension, renal failure or cerebrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 9. A method for the treatment of chronic renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 10. A method of treatment of benign prostatic hypertrophy which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 11. A method of treatment of congestive heart failure which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 12. A method of treatment of unstable angina, coronary vasospasm and myocardial salvage. which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 13. A method of preventing or treating restenosis which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 14. A method of treatment of pulmonary hypertension which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 15. A method of treatment of atherosclerosis which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 16. A method of preventing and treating the sequelae of diabetes which comprises administering to a subject in need thereof, an effective amount of a compound of claim  17. A method of treatment of stroke or subarachnoid hemorrhage which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1. 18. A process for preparing a compound of Formula (I)(d)   wherein one B is CH2 and the other is O, and Z1, R<a> , P R1, R3-R5, R15 and n are as described in claim 1 by a) reaction of a compound of Formula (II)   or a protected form or precursor thereof with a compound of Formula (8)   wherein one B is CH2 and the other is O and R2 and R16 are as described in claim 1 for Formula (1d); followed if necessary or desired by: (b) conversion of one compound of Formula (Id) into a different compound of Formula (Id) by a method well known in the art and/or (c) salt formation.