N-Alkyl, N-Alkenyl, N-Alkynyl, N-Aryl and N-fused bicyclo or tricyclo thienyl-, furyl-,and Pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin

• US 6,331,637 B1
• Filed: 03/22/1999
• Issued: 12/18/2001
• Est. Priority Date: 10/21/1993
• Status: Expired due to Fees

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Kois, Adam, Wu, Chengde, Yalamoori, Venkatachalapathi, Chan, Ming Fai, Kogan, Timothy, Raju, Bore Gowda, Balaji, Vitukudi Narayanaiyengar, Castillo, Rosario Silvestre, Verner, Erik Joel
• Primary Examiner(s): Higel, Floyd D.
• Application Number:
  US09/274,280
• Time in Patent Office: 1,002 Days
• Field of Search: 514/380, 514/311, 514/312, 514/313, 514/314, 514/378, 514/379, 548/244, 548/245, 548/247, 548/241, 548/243
• US Class Current: 548/241
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

N-alkyl, N-alkenyl, N-alkynyl, N-aryl and N-fused bicyclo or tricyclo thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, (phenyl) and (phenoxy)thienylsulfonamides, (phenyl) and (phenoxy)furylsulfonamides, and (phenyl) and (phenoxy)pyrrolylsulfonamides and methods of using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

Claims

1. A sulfonamide compound of formula (I):

wherein;

Ar¹ is a substituted or unsubstituted group, having from 1 to 30 carbon atoms, selected from the group consisting of alkyl, alkenyl and alkynyl groups, which are straight or branched chains or have cyclic portions;

aryl groups; and

fused bicyclic or tricyclic rings; and

Ar² has formula IV;

in which X is S, O or NR¹¹ in which R¹¹ 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)R¹⁵ and S(O)_nR¹⁵ in which n is 0-2;

R¹⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

R¹¹ and R¹⁵ 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)R¹⁶, CO₂R¹⁶, SH, S(O)_nR¹⁶ in which n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶, CONR¹²R¹⁶, a sulfonyl chloride, (CH₂)_xS(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, —

(CH₂)_xC(O)NHR⁵⁰, —

(CH₂)_xOH or —

(CH₂)_xCOOH;

x is 0 to 6;

R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, —

C(O)NHR⁵⁰ or —

(CH₂)_xOH;

R⁵⁰ is H, alkyl, lower alkyl or lower alkoxy;

R¹², which is selected independently from R¹¹ and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁷ and S(O)_nR¹⁷ in which n is 0-2; and

R¹⁷ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

each of R¹¹, R¹², R¹⁵ and R¹⁶ are unsubstituted or substituted with the any of the groups set forth for Z; and

R⁸, R⁹ and R¹⁰ are each independently selected as follows from (i) or (ii);

(i) R⁸, R⁹ and R¹⁰, which each is hydrogen or has up to about 50 carbon atoms are each independently selected from halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸, acetoxy-(CH═

CH)—

, CO₂R¹⁸, SH, (CH₂)_rC(O)(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_rC(O)(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_sC(O)(CH₂)_nR¹⁸, (CH₂)_rNH(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_sNH(CH₂)_nR¹⁸, (CH₂)_rC(O)NH(CH₂)_nR¹⁸, C(O)(CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rR¹⁸, S(O)_mR¹⁸, —

(CH₂)_xC(O)-W-aryl, —

(CH₂)_xC(O)-W-heteroaryl, —

(CH₂)_xN(H)-W-aryl, —

(CH₂)_xN(H)-W-heteroaryl, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which;

R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²⁰ and S(O)_nR²⁰ in which n is 0-2; and

R¹⁸ and R²⁰ 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 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(CH₂)_x(halo)2, ═

N(H), ═

C(CH2)_xCOOH, ═

N(lower alkyl), ═

C(O), lower alkyl, alkyl which is straight or branched having 1 to 6 carbons, ═

C(lower alkyl)₂, ═

CH₂, ═

NH, ═

NCH₃, ═

NCH₂CH₃, ═

C(CH₃)₂ or CF₂;

m is 0-2, s, n and r are each independently 0 to 6; and

any of the groups set forth for R⁸, R⁹ and R¹⁰ 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)R²¹, CO₂R²¹, SH, S(O)_nR²¹ in which n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹;

R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ and S(O)_nR²³ in which n is 0-2; and

R²¹ and R²³ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl, with the proviso that if R⁸ is NR¹⁸R¹⁹, OR¹⁸, R¹⁹NCOR¹⁸, CONR¹⁹R¹⁸, CO₂R¹⁸, (CH₂)_rNH(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_sNH(CH₂)_nR¹⁸, (CH₂)_rC(O)NH(CH₂)_nR¹⁸, C(O)(CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rNH(CH₂)_nR¹⁸ or (CH₂)_rR¹⁸ and R¹⁸ is an aryl group having 5 or 6 members, then the aryl group has at least two substituents, or

(ii) any two of R⁸, R⁹ and R¹⁰ 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 16 members and which is substituted with one or more substituents, each substituent is independently selected from Z;

the other of R⁸, R⁹ and R¹⁰ is selected as in (i); and

the heteroatoms are NR¹¹, O, or S, with the proviso that Ar² is not 5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl or 5-halo-3-loweralkylbenzo[b]pyrrolyl.

2. A compound of claim 1, wherein Ar¹ is

wherein R is H, NH₂, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl or carbonyl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceding groups, and the alkyl portions are straight or branched chains of from about 1 up to about 12 carbons.

3. A compound of claim 1, wherein Ar¹ is a phenyl group.

4. A compound of claim 3 in which Ar² has formula IVA or IVB:

wherein;

X is NR¹¹, O, or S;

R⁸ is selected from among (CH₂)_rC(O)(CH₂)_nR¹⁸, (CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_rC(O)(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_sC(O)(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_sNH(CH₂)_nR¹⁸, C═

N(OH)(CH₂)_rR¹⁸, (CH₂)_rC(O)NH(CH₂)_nR¹⁸, C(O)(CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rNH(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_rC(O)NH(CH₂)_nR¹⁸, (CH₂)_rNH(CH₂)_nR¹⁸ and (CH₂)_rR¹⁸, with the proviso that if R⁸ is (CH₂)_rC(O)NH(CH₂)_nR¹⁸, (CH₂)_rC(O)NH(CH₂)_nR¹⁸ or (CH₂)_rR¹⁸, and R¹⁸ is phenyl, the phenyl group is substituted in at least two positions;

and R⁹ and R¹⁰ are independently selected from hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸, (OAC)CH═

CHR¹⁸, CO₂R¹⁸, SH, (CH₂)_rC(O)(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_rC(O)(CH═

CH)_s(CH₂)_nR¹⁸, (CH₂)_r(CH═

CH)_sC(O)(CH₂)_nR¹⁸, (CH₂)_rNH(CH═

CH)_s(CH₂)_nR¹⁸, C═

N(OH)(CH₂)_rR¹⁸, (CH₂)_r(CH═

CH)_sNH(CH₂)_nR¹⁸, (CH₂)_rC(O)NH(CH₂)_nR¹⁸, C(O)(CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rNH(CH₂)_nR¹⁸, (CH₂)_rR¹⁸, S(O)_mR¹⁸ in which m is 0-2, s, n and r are each independently 0 to 6, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²⁰ and S(O)_nR²⁰ in which n is 0-2; and

R¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.

5. A compound of claim 4, wherein R¹⁸ is aryl or heteroaryl having 5 to 7 members in the ring.

6. A compound of claim 5, wherein R¹⁸ is phenyl or pyrimidinyl.

7. A compound of claim 6, wherein R⁹ and R¹⁰ are hydrogen, halide, loweralkyl, or halo loweralkyl.

8. A compound of claim 1, wherein R¹⁹ is hydrogen or lower alkyl;

and R¹⁸ is aryl.

9. A compound of claim 3, wherein R¹⁹ is hydrogen or lower alkyl;

and R¹⁸ is aryl.

10. A compound of claim 1, wherein Ar² is phenylaminocarbonylthienyl, phenylaminocarbonylfuryl, aminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl, phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl or acetoxystyrylpyrrolyl, with the proviso that, when Ar² is a phenylaminocarbonylthienyl, phenylaminocarbonylfuryl or aminocarbonylpyrrolyl group, the phenyl group is substituted with at least two substituents selected from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_nR²¹ in which n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹;

R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ and S(O)_nR²³ in which n is 0-2; and

R²¹ and R²³ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.

11. A compound of claim 2, wherein Ar² is phenylaminocarbonylthienyl, phenylaminocarbonylfuryl, aminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl, phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl or acetoxystyrylpyrrolyl, with the proviso that, when Ar² is a phenylaminocarbonylthienyl, phenylaminocarbonylfuryl or aminocarbonylpyrrolyl group, the phenyl group is substituted with at least two substitutents selected from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_nR²¹ in which n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹;

R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ and S(O)NR²³ in which n is 0-2; and

R²¹, and R²³ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.

12. A compound of claim 3, wherein Ar² is phenylaminocarbonylthienyl, phenylaminocarbonylfuryl, aminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl, phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl or acetoxystyrylpyrrolyl, with the proviso that, when Ar² is a phenylaminocarbonylthienyl, phenylaminocarbonylfuryl or aminocarbonylpyrrolyl group, the phenyl group is substituted with at least two substitutents selected from Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_nR²¹ in which n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹;

R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ and S(O)_nR²³ in which n is 0-2; and

R²¹ and R²³ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.

13. A compound of claim 4, wherein X is S, O, NR¹¹ in which R¹¹ is hydrogen, or loweralkyl, or aryl, which is unsubstituted or substituted with loweralkyl or halogen hydrogen or loweralkyl;

R¹ is hydrogen, halide, pseudohalide, loweralkyl or lower haloalkyl;

R² is hydrogen, loweralkyl or lower haloalkyl.

14. A compound of claim 4, wherein R¹¹ is phenyl.

15. A compound of claim 1, wherein Ar² has formula VI:

wherein;

M is (CH₂)_mC(O)(CH₂)_r, (CH₂)_mC(O)NH(CH₂)_r, CH(OH)(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, (CH₂)_mC(O)(CH₂)_sNH(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, C═

N(OH)(CH₂)_r, (CH₂)_mC(O)(CH═

CH)_sNH(CH₂)_r, CH(CH₃)C(O)(CH₂)_r, CH(CH₃)C(O)(CH₂)_m(CH═

CH)(CH₂)_r, (CH₂)_r, (CH₂)_rO or C(O)O, in which m, s and r are each independently 0 to 6;

R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from (i) or (ii) as follows;

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from among H, OH, 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, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy and formyl;

or

(ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵, 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, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R³¹, R³², R³³, R³⁴ and R³⁵ are selected as in (i); and

R³⁸ and R³⁹ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl,

with the proviso that when M is (CH₂)_mC(O)NH(CH₂)_r, then at least two of R³¹, R³², R³³, R³⁴ and R³⁵ are not hydrogen.

16. A compound of claim 3, wherein Ar² has formula VI:

wherein;

M is (CH₂)_mC(O)(CH₂)_r, (CH₂)_mC(O)NH(CH₂)_r, CH(OH)(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, (CH₂)_mC(O)(CH₂)_sNH(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, C═

N(OH)(CH₂)_r, (CH₂)_mC(O)(CH═

CH)_sNH(CH₂)_r, CH(CH₃)C(O)(CH₂)_r, CH(CH₃)C(O)(CH₂)_m(CH═

CH)(CH₂)_r, (CH₂)_r, (CH₂)_rO or C(O)O, in which m, s and r are each independently 0 to 6;

R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from (i) or (ii) as follows;

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from among H, OH, 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, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy and formyl;

or

(ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵, 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, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R³¹, R³², R³³, R³⁴ and R³⁵ are selected as in (i); and

R³⁸ and R³⁹ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, with the proviso that when M is (CH₂)_mC(O)NH(CH₂)_r, then at least two of R³¹, R³², R³³, R³⁴ and R³⁵ are not hydrogen.

17. A compound of claim 15, wherein M is (CH₂)_mC(O)(CH₂)_r, (CH₂)_mC(O)NH(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, (CH₂)_mC(O)(CH₂)_sNH(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, C═

N(OH)(CH₂)_r, CH(OH)(CH₂)_r, (CH₂)_r, (CH₂)_rO or C(O)O.

18. A compound of claim 15, wherein R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i) or (ii)

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from among loweralkyl, halide, haloloweralkyl, and loweralkoxy;

and

(ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵ form ethylenedioxy or methylenedioxy and the others are selected as in (i).

19. A compound of claim 17, wherein R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i) or (ii)

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from among loweralkyl, halide, haloloweralkyl, and loweralkoxy;

and

(ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵ form ethylenedioxy or methylenedioxy and the others are selected as in (i).

20. A compound of claim 15, wherein M is selected from

in which R⁴⁰ is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl.

21. A compound of claim 15, wherein at least two of R³¹, R³², R³³, R³⁴ and R³⁵, 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, loweralkyl, loweralkoxy or halo loweralkyl.

22. A compound of claim 16, wherein at least two of R³¹, R³², R³³, R³⁴ and R³⁵, 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, loweralkyl, loweralkoxy or halo loweralkyl.

23. A compound of claim 17, wherein at least two of R³¹, R³², R³³, R³⁴ and R³⁵, 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, loweralkyl, loweralkoxy or halo loweralkyl.

24. A compound of claim 18, wherein at least one of R³¹ and R³⁵ is other than hydrogen.

25. A compound of claim 20, wherein at least one of R³¹ and R³⁵ is other than hydrogen.

26. A compound of claim 15, wherein Ar² has formula VII:

in which W is CH₂ or NH.

27. A compound of claim 15, wherein M is selected from

28. A compound of claim 20, wherein R⁴⁰ is methyl, ethyl or hydrogen.

29. A compound of claim 15, wherein R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i) or (ii):

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from loweralkyl, haloloweralkyl, phenyl, alkoxy, loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl, loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy loweralkyl, acetoxy loweralkoxy and loweralkoxycarbonyl;

or

(ii) R³² and R³³ or R³³ and R³⁴ form alkylene dioxy, and the others of R³¹, R³², R³³, R³⁴ and R³⁵ are selected as in (i).

30. A compound of claim 11, wherein R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i) or (ii):

(i) R³³, R³⁵ are other then hydrogen and are selected from loweralkyl or lower alkoxy, or

(ii) at least one of R³¹ or R³⁵ is other than hydrogen, and R³² and R³³ or R³³ and R³⁴ form methylenedioxy or ethylenedioxy.

31. A compound of claim 1, wherein Ar² is thienyl.

32. A compound of claim 1, wherein Ar² is furyl.

33. A compound of claim 1, wherein Ar² is pyrrolyl.

34. A compound of claim 3, wherein Ar² is thienyl.

35. A compound of claim 3, wherein Ar² is furyl.

36. A compound of claim 3, wherein Ar² is pyrrolyl.

37. A compound of claim 1 that is a (phenoxy)thiophenesulfonamide.

38. A compound claim 1, wherein:

aryl is phenyl so that Ar² is

that is substituted at the 2, 3, 4 and 6 position and each substituent R³¹-R³⁵ is selected independently from among methyl, cyano, amino, di-alkyl amino, alkylene dioxy that bridges any two positions, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, —

(CH₂)_xCOOH, —

(CH₂)_xCOOH—

, CO₂-lower alkyl, CN, —

COC(O)(CH₂)_xCH₃, —

(CH₂)_xN(CH₃)₂, an amino acid, a primary or secondary amide, a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰ and —

(CH₂)_xOH;

W is —

C(halo)₂—

, —

N(H)—

, —

(CH₂)_x—

, —

N(lower alkyl)—

, —

C(O)—

or —

C(lower alkyl)₂—

;

x is 0-2; and

R⁵⁰ is hydrogen, lower alkyl or lower alkoxy.

39. A compound of claim 1, wherein Ar² has the formula:

wherein;

X is S, O or NR¹¹;

each G and R is independently selected from lower alkyl, CN, —

(CH₂)_xC(O)(CH₂)_x, —

(CH₂)_x, (CH ₂)_xN-lower alkyl, —

(CH₂)_xC(O)NH₂, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, —

S(O)₂NH₂, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, —

(CH₂)_xCOOH, —

(CH₂)_xCOOH—

, CO₂-lower alkyl, CN, heteroaryl, —

COC(O)(CH₂)_xCH₃, —

(CH₂)_xN(CH₃)₂, a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰, —

(CH₂)_xOH and —

C(O)N(H)N(H)M;

R⁵⁰ is hydrogen, lower alkyl or lower alkoxy;

M is H or R⁵⁰;

R′

is selected from hydrogen, G and R;

W is ═

C(halo)₂, ═

N(H), —

(CH₂)_x—

, ═

N(lower alkyl), —

C(O)—

or ═

C(lower alkyl)₂; and

x is 0-3.

40. A compound of claim 3, wherein Ar² has the formula:

wherein;

X is S, O or NR¹¹;

each G and R is independently selected from lower alkyl, CN, —

(CH₂)_xC(O)(CH₂)_x, —

(CH₂)_x, (CH₂)_xN-lower alkyl, —

(CH₂)_xC(O)NH₂, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, —

S(O)₂NH₂, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, —

(CH₂)_xCOOH, —

(CH₂)_xCOOH—

, CO₂-lower alkyl, CN, heteroaryl, —

COC(O)(CH₂)_xCH₃, —

(CH₂)_xN(CH₃)₂, a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰, —

(CH₂)_xOH and —

C(O)N(H)N(H)M;

R⁵⁰ is hydrogen, lower alkyl or lower alkoxy;

M is H or R⁵⁰;

R′

is selected from hydrogen, G and R;

W is ═

C(halo)₂, ═

N(H), —

(CH₂)_x—

, ═

N(lower alkyl), —

C(O)—

or ═

C(lower alkyl)₂; and

x is 0-3.

41. The compound of claim 39, wherein:

R, G and R′

are selected where the amino acid is L-Asp or L-Glu;

the hexose is D-mannose, the heteroaryl is triazolyl, and X is S.

42. The compound of claim 40, wherein:

R, G and R′

are selected where the amino acid is L-Asp or L-Glu;

the hexose is D-mannose, the heteroaryl is triazolyl, and X is S.

43. The compound of claim 39, wherein:

R, G and R′

are selected where the amino acid is L-Asp or L-Glu;

the hexose is D-mannose, the heteroaryl is triazolyl, and X is S.

44. The compound of claim 40, wherein:

R, G and R′

are selected where the amino acid is L-Asp or L-Glu;

the hexose is D-mannose, the heteroaryl is triazolyl, and X is S.

45. The compound of claim 39, wherein:

W is ═

CH₂, ═

NH, ═

NCH₃, ═

NCH₂CH₃, ═

C(CH₃)₂ or CF₂; and

G is —

CH₃, —

CN, —

COCH₃, —

CH₂CH₃ or —

(CH₂)_xCO₂H.

46. The compound of claim 40, wherein:

W is ═

CH₂, ═

NH, ═

NCH₃, ═

NCH₂CH₃, ═

C(CH₃)₂ or CF₂; and

G is —

CH₃, —

CN, —

COCH₃, —

CH₂CH₃ or —

(CH₂)_xCO₂H.

47. A pharmaceutical composition, comprising a compound of claim 1, or a pharmaceutically acceptable salt, acid or ester thereof, in a pharmaceutically acceptable carrier.

48. A pharmaceutical composition, comprising the compound of claim 3, or a pharmaceutically acceptable salt, acid or ester thereof, in a pharmaceutically acceptable carrier.

49. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount a compound of claim 1, or a pharmaceutically acceptable salt, acid or ester thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

50. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount a compound of claim 3, or a pharmaceutically acceptable salt, acid or ester thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

51. The method of claim 49, wherein the disease is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction endotoxin shock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

52. The method of claim 49, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

53. A method for inhibiting the binding of an endothelin peptide to endothelin_A or endothelin_B receptors, comprising contacting the receptors an endothelin peptide and with a compound of claim 1, or a pharmaceutically acceptable salt, acid or ester thereof, wherein:

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

54. A method for inhibiting the binding of an endothelin peptide to endothelin_A or endothelin_B receptors, comprising contacting the receptors an endothelin peptide and with a compound of claim 3, or a pharmaceutically acceptable salt, acid or ester thereof, wherein:

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.

55. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with a compound of claim 1, or a pharmaceutically acceptable salt, acid or ester thereof.

56. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with a compound of claim 3, or a pharmaceutically acceptable salt, acid or ester thereof.

57. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, acid or ester thereof, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

58. A pharmaceutical composition formulated for single dosage administration, comprising an effective amount of a compound of claim 3, or a pharmaceutically acceptable salt, acid or ester thereof, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

59. An article of manufacture, comprising packaging material and a compound of claim 1, or a pharmaceutically acceptable salt, acid or ester thereof, contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC₅₀ of less than about 10 μ

M, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.

60. An article of manufacture, comprising packaging material and a compound of claim 3, or a pharmaceutically acceptable salt, acid or ester thereof, contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC₅₀ of less than about 10 μ

M, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.