Patent ID: 6329387
Filing Date: 2001-12-11
Classification: A61K,C07D

Abstract:
A method of altering nitric oxide levels, comprising administering an effective amount of an endothelin antagonist, wherein the endothelin antagonist is a sulfonamide compound of formula (I) ##STR10##wherein:Ar.sup.1, which contains from 1 to 30 carbon atoms, is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl and fused bicyclic or tricyclic rings, wherein the alkyl, alkenyl and alkynyl groups may be straight or branched chains, or straight or branched chains that include cyclic portions; andAr.sup.2 is a group of formula: ##STR11##Y is N or O.sup.+ ; X is S, O, or NR.sup.11 in which R.sup.11, which is hydrogen or contains up to about 30 carbon atoms, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R.sup.15 and S(O).sub.n R.sup.15 in which n is 0-2; and R.sup.15, which is selected independently from R.sup.11, is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;R.sup.3, R.sup.4 and R.sup.5 are selected from (i), (ii), (iii) or (iv):(i) R.sup.3, R.sup.4 and R.sup.5 are each selected independently from among H, NHOH, NH.sub.2, NO.sub.2 N.sub.3, halide, pseudohalide, alkyl, alkenyl, alkynyl, alkylaryl, aryloxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, formyl and amido, where the alkyl, alkenyl and alkynyl portions are straight or branched chains of from about 1 up to about 10 carbons, and the aryl portions contain from 3 up to about 10 carbons; or(ii) two of R.sup.3, R.sup.4 and R.sup.5 form 1,3-butadienyl, 4-dimethylamino-1,3-butadienyl, 1-chloro-1,3-butadienyl, 1-aza-1,3-butadienyl or 2-aza-1,3-butadienyl groups or form alkylenedioxy; and the other of R.sup.3, R.sup.4 and R.sup.5 is as defined in (i); or(iii) two of R.sup.3, R.sup.4 and R.sup.5 are independently selected from alkyl, alkoxy, halide, aminoalkyl and dialkylaminoalkyl, in which the alkyl and alkoxy groups contain from 1 to 10 carbons, and are straight or branched chains and the other is H; or(iv) any two of R.sup.3, R.sup.4 and R.sup.5, which are each selected as in (i), form fused carbocyclic or heterocyclic rings and the other is selected as in (i); andR.sup.7 is hydrogen or contains up to about 50 carbon atoms and is selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R.sup.18, CO.sub.2 R.sup.18, (CH.sub.2.sub.r COR.sup.18, (CH.sub.2).sub.r CO(CH.sub.2).sub.s R.sup.18, SH, (CH.sub.2).sub.r R.sup.18, S(O).sub.n R.sup.18 in which n is 0-2, and r is 0 to 6, HNOH, NR.sup.18 R.sup.19, NO.sub.2, N.sub.3, OR.sup.18, R.sup.19 NCOR.sup.18 and CONR.sup.19 R.sup.18, in which R.sup.19 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R.sup.20 and S(O).sub.n R.sup.20 in which n is 0-2; and R.sup.18 and R.sup.20 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl; and any of the groups set forth for R.sup.7 is unsubstituted or substituted with any substituents set forth for Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R.sup.21, CO.sub.2 R.sup.21, SH, S(O).sub.n R.sup.21 in which n is 0-2, NHOH, NR.sup.22 R.sup.21, NO.sub.2, N.sub.3, OR.sup.21, R.sup.22 NCOR.sup.21 or CONR.sup.22 R.sup.21 ; R.sup.22 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R.sup.23 and S(O).sub.n R.sup.23 in which n is 0-2; and R.sup.21 and R.sup.23 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl, whereby nitric oxide levels are altered.