Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin

A compound of formula (I) ##STR14## or a pharmaceutically acceptable salt, acid or ester thereof, wherein:

• Ar.sup.1 is a substituted or unsubstituted heterocyclic group, having from 1 to 30 carbon atoms;
• and
• Ar.sup.2 has formula IV:
• ##STR15## in which X is S, O or NR.sup.11 in which R.sup.11 is hydrogen or has up to about 30 carbon atoms and is selected from 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;
• R.sup.15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
• R.sup.11 and R.sup.15 are unsubstituted or are substituted with one or more substituents each selected independently from Z,
• Z is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy, a D, L or racemic amino acid, a primary and secondary amide, an O-glycoside, hexose, ribose, alkylaryl, alkylheteroaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R.sup.16, CO.sub.2 R.sup.16, SH, S(O).sub.n R.sup.16 in which n is 0-2, NHOH, NR.sup.12 R.sup.16, NO.sub.2, N.sub.3, OR.sup.16, R.sup.12 NCOR.sup.16, CONR.sup.12 R.sup.16, a sulfonyl chloride, (CH.sub.2).sub.x S(O).sub.2 NHR.sup.50, alkylaryl, alkylheteroaryl, --(CH.sub.2).sub.x C(O)NHR.sup.50, --(CH.sub.2).sub.x OH or --(CH.sub.2).sub.x COOH;
• x is 0 to 6;
• R.sup.16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, a sulfonyl chloride, S(O).sub.2 NHR.sup.50, alkylaryl, alkylheteroaryl, --C(O)NHR.sup.50 or --(CH.sub.2).sub.x OH;
• R.sup.50 is H, alkyl, lower alkyl or lower alkoxy;
• R.sup.12, which is selected independently from R.sup.11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R.sup.17 and S(O).sub.n R.sup.17 in which n is 0-2;
• and R.sup.17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;
• each of R.sup.11, R.sup.12, R.sup.15 and R.sup.16 may be further substituted with the any of the groups set forth for Z;
• and
• R.sup.8, R.sup.9 and R.sup.10 are each independently selected as follows from (i) or (ii):
• (i) R.sup.8, R.sup.9 and R.sup.10, which each are hydrogen or have up to about 50 carbon atoms and are each independently selected from halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R.sup.18, acetoxy-(CH.dbd.CH)--, CO.sub.2 R.sup.18, SH, (CH.sub.2).sub.r C(O)(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r (CH.dbd.CH).sub.s (CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r C(O)(CH.dbd.CH).sub.s (CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r (CH.dbd.CH).sub.s C(O)(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r NH(CH.dbd.CH).sub.s (CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r (CH.dbd.CH).sub.s NH(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r C(O)NH(CH.sub.2).sub.n R.sup.18, C(O)(CH.sub.2).sub.r NH(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r NH(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r R.sup.18, S(O).sub.m R.sup.18, --(CH2).sub.x C(O)--W-aryl, --(CH2).sub.x C(O)--W-heteroaryl, --(CH2).sub.x N(H)--W-aryl, --(CH2).sub.x N(H)--W-heteroaryl, 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, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
• aryl is a single or two or three fused rings that has 5 to 7 members in the ring that is unsubstituted or substituted with Z, at one or more positions, each substituent selected independently;
• heteroaryl is a single or two or three fused rings that has 5 to 7 members in each ring, and one to two heteroatoms in each ring, and is unsubstituted or substituted with Z at one or more positions, each substituent selected independently;
• W is =C(CH.sub.2),(halo)2, =N(H), =C(CH2).sub.x COOH, =N(lower alkyl), =C(O), lower alkyl, alkyl which is straight or branched having 1 to 6 carbons, =C(lower alkyl).sub.2, =CH.sub.2, =NH, =NCH.sub.3, =NCH.sub.2 CH.sub.3, =C(CH.sub.3).sub.2 or CF.sub.2 ;
• m is 0-2, s, n and r are each independently 0 to 6;
• and any of the groups set forth for R.sup.8, R.sup.9 and R.sup.10 are unsubstituted or substituted with 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,
• with the proviso that if R.sup.8 is NR.sup.18 R.sup.19, OR.sup.18, R.sup.19 NCOR.sup.18, CONR.sup.19 R.sup.18 CO.sub.2 R.sup.18, (CH.sub.2).sub.r NH(CH.dbd.CH).sub.s (CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r (CH.dbd.CH).sub.s NH(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r C(O)NH(CH.sub.2).sub.n R.sup.18, C(O)(CH.sub.2).sub.r NH(CH.sub.2).sub.n R.sup.18, (CH.sub.2).sub.r NH(CH.sub.2).sub.n R.sup.18 or (CH.sub.2).sub.r R.sup.18 and R.sup.18 is an aryl group having 5 or 6 members, then the aryl group has at least two substituents, or
• (ii) any two of R.sup.8, R.sup.9 and R.sup.10 with the carbon to which each is attached form an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, having from 3 to about 1 6 members and which is substituted with one or more substituents, each substituent is independently selected from Z;
• the other of R.sup.8, R.sup.9 and R.sup.10 is selected as in (i);
• and the heteroatoms are NR.sup.11, O, or S, with the proviso that Ar.sup.2 is not 5-halo-3-loweralkylbenzo›b!thienyl, 5-halo-3-loweralkylbenzo›b!furyl or 5-halo-3-loweralkylbenzo›b!pyrrolyl.