Sulfonamides and derivatives thereof that modulate the activity of endothelin

A compound that has formula VII:

• and pharmaceutically acceptable derivatives thereof, where R1 and R2 are either (i), (ii) or (iii) as follows:
• (i) R1 and R2 are each independently selected from H, NH2, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, except that R2 is not halide or pseudohalide;
• or,
• (ii) R1 and R2 together form —(CH2)n—, where n is 3 to 6;
• or,
• (iii) R1 and R2 together form 1,3-butadienyl (—CH═CH—CH═CH—);
• W is O, NH or (CH2)z wherein z is 0 to 6;
• and
• Y is O, S, or, together with R8 and the atoms to which they are attached, form a 3 to 16 membered unsubstituted or substituted cyclic or heterocyclic ring;
• R3 and R4 are independently selected from among hydrogen, halo, cyano, cyanoalkyl, C(O)R41, alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene or alkenylene, where R41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino;
• Y1 and Y2 are each independently carbon;
• a and b are each independently 1;
• R5, R6, R7, R8 and R9 are each independently selected from (i) or (ii) as follows:
• (i) R5, R6, R7, R8 and R9 are each independently selected from among H, NHR38, CONR38R39, NO2, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkoxyalkoxy, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, —(CH2)xC(O)(CH2)yCH3, —(CH2)xCH3, (CH2)xNH-lower alkyl, —(CH2)1 to 14C(O)NH2, a primary or secondary amide, —(CH2)xCOOH, —(CH2)xCH(COOH)(CH2)yCH3, C(O)(CH2)xS(O)2(CH2)yCH3, C(═N—OR38)(CH2)yCH3, —C(O)C(O)(CH2)yCH3, —(CH2)xN(CH3)2, S(O)2NHR50, OS(O)2NR38R39, alkylaryl, alkylheteroaryl, —C(O)NH-heteroaryl and —C(O)N(H)N(H)R50;
• R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
• x and y are each independently 0 to 14;
• R50 is a substituent such as hydrogen, lower alkyl, lower alkoxy or heteroaryl;
• or
• (ii) at least two of R5, R6, R7, R8 and R9, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo lower alkyl, and the others of R5, R6, R7, R8 and R9 are selected as in (i).

A compound that has formula X:

• or pharmaceutically acceptable derivatives thereof, where R1 and R2 are either (i), (ii) or (iii) as follows:
• (i) R1 and R2 are each independently selected from H, NH2, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, except that R2 is not halide or pseudohalide;
• or,
• (ii) R1 and R2 together form —(CH2)n—, where n is 3 to 6;
• or,
• (iii) R1 and R2 together form 1,3-butadienyl (—CH═CH—CH═CH—);
• Y1 and Y2 are each independently carbon or nitrogen;
• a and b are each independently 0 or 1;
• R5, R6, R7, R8 and R9 are each independently selected from (i) or (ii) as follows:
• (i) R5, R6, R7, R8 and R9 are each independently selected from among H, NHR38, CONR38R39, NO2, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkoxyalkoxy, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, —(CH2)xC(O)(CH2)yCH3, —(CH2)xCH3, (CH2)xNH-lower alkyl, —(CH2)1 to 14C(O)NH2, a primary or secondary amide, —(CH2)xCOOH, —(CH2)xCH(COOH)(CH2)yCH3, C(O)(CH2)xS(O)2(CH2)yCH3, C(═N—OR38)(CH2)yCH3, —C(O)C(O)(CH2)yCH3, —(CH2)xN(CH3)2, S(O)2NHR50, OS(O)2NR38R39, alkylaryl, alkylheteroaryl, —C(O)NH-heteroaryl and —C(O)N(H)N(H)R50;
• R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
• x and y are each independently 0 to 14;
• R50 is a substituent such as hydrogen, lower alkyl, lower alkoxy or heteroaryl;
• or
• (ii) at least two of R5, R6, R7, R8 and R9, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo lower alkyl, and the others of R5, R6, R7, R8 and R9 are selected as in (i).