SUBSTITUTED DERIVATIVES OF 2(5H) FURANONE, 2(5H)-THIOPHENONE OR 2(5H) PYRROLE AND AND PHARMACEUTICAL COMPOSITION BASED THEREON

摘要

Compounds of formula (I), or a tautomeric open chain keto-acid form thereof or a pharmaceutically acceptable salt thereof wherein: R1 is alkyl substituted or unsubstituted, straight, or branched, of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms, phenyl substituted with from 1 to 5 substituents, naphthyl unsubstituted or substituted with from 1 to 5 substituents, or heteroaryl unsubstituted or substituted with from 1 to 5 substituents; R2 is alkyl substituted or unsubstituted, straight, or branched of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms, aryl which is unsubstituted or substituted with from 1 to 5 substituents, heteroaryl wich is unsubstituted or substituted with from 1 to 3 substituents; R3 is alkyl substituted or unsubstituted, straight, or branched, of from 1 to 12 carbon atoms, cycloalkyl substituted or unsubstituted of from 3 to 12 carbon atoms, aryl which is unsubstituted or substituted with from 1 to 5 substituents, heteroaryl which is unsubstituted or substituted with from 1 to 3 substituents; R4 is hydrogen, hydroxy, halogen, SR5, OR5 wherein R5 is alkyl or substituted alkyl of from 1 to 7 carbon atoms, NR6R7 wherein R6 and R7 are each independently hydrogen, alkyl, substituted alkyl, substituted or unsubstituted phenyl, and (CH2)nOR5 wherein n is an integer of from 1 to 3; X is oxygen, S or NR8 wherein R8 is hydrogen, alkyl or substituted alkyl with the proviso that when R1 is monosubstituted phenyl and the substituent is p-methoxy, R3 is not unsubstituted phenyl, monosubstituted phenyl, or mesityl and with the further proviso when R2 is alkyl substituted, the substituent is not oxygen at the α-position to the furanone ring and with the further proviso that R1 and R3 are not both alkyl or alkyl substituted in the same molecule, their use as nonpeptide antagonists of endothelin I, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, myocardial ischemia, cerebral vasospasm, cerebral ischemia, cerebral infarction, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, stroke, and diabetes.