Phenyl derivatives containing an acidic group, their preparation and their use as chloride channel blockers

Abstract

The present patent application relates to compounds having formula (I) or a pharmaceutically acceptable salt thereof wherein one of R , R and R is a non-cyclic acidic group having a pKa value below 8 or a group which is in vivo convertible to such a group; R , R and the other two of the substituents R , R and R are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amnino, and aryl, aralkyl, arylamino, aryloxy, aryl—CO—, or heteroaryl, wherein the aryl and heteroaryl groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, hydroxy, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino; or R and R or R and R together form a fused 4- to 7-membered carbocyclic ring which may be unsaturated, or partially or fully saturated, while the other substituents R , R , R , R and R are as defined above; Y is —CO—, —CS—, —SO —, or —C(═N—R )—, wherein R is hydrogen, alkyl, or cyano; X is —NH—, —CH —NH—, or —SO —NH—; Z is NR , O, —CH═CH—, —C═C—, —N═CH—, or —CH═N—; wherein R is hydrogen, or alkyl; R , R , R , R and R are each independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, —NHSO —R , —COOR , —SO N(R ) , —SO OR and —CO—R , wherein R is hydrogen alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or aralkyl; and aryl, aralkyl, arylamino, aryloxy, aryl-CO—, or heteroaryl, wherein the aryl and heteroaryl groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, hydroxy, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino; or one of R and R , R and R , R and R or R and R together form a fused 4- to 7-membered carbocyclic ring which may be unsaturated, or partially or fully saturated, while the other substituents R , R , R , R and R are as defined above. The compounds are useful for the treatment of diseases and disorders responsive to the blockage of chloride channels.