OA11024A - Sulfonamides and derivatives thereof that modulatethe activity of endothelin - Google Patents

Sulfonamides and derivatives thereof that modulatethe activity of endothelin Download PDF

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OA11024A
OA11024A OA9900058A OA9900058A OA11024A OA 11024 A OA11024 A OA 11024A OA 9900058 A OA9900058 A OA 9900058A OA 9900058 A OA9900058 A OA 9900058A OA 11024 A OA11024 A OA 11024A
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methyl
sulfonamide
chloro
isoxazolyl
thiophene
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Chengde Wu
Bore Gowda Raju
Timothy P Kogan
Natalie Blok
Patricia Woodard
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Texas Biotechnology Corp
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Claims (83)

011024 -132- WHA7 IS CLAIMEO IS:
1 . A suronamide communs oî formula (Ai:." Γ— SCr N— .-Γ or a pharmacG’Jtica;.'y accaptable sait, acid or ester thereot, wnerein: Ar’ is a substîtuted with one cr more substituer,ts or an unsubstitutod monocyciic or poiycyclic aryl or hetercar/l croup in which each substituent is10 independently selected from the croup consisting of H, Nl-i-, haiice, pseudohalidc, aikyl, alkylcarbonyl, formyl, aryl, hetercar/l, alkoxyalkyl,alkyiamino, alkylthio. aryicarbonyl, aryioxy. arylamino, arylthio, naioalkyl,haloaryi, and carbor.yi, ;n .vhich the aryl and alkyl portions are unsubstitutcd orsubst.-tuted with any of the precceding grouos, and straight or branchée chaîne 15 oî from about ’ up te anout 12 carbon:;; Ar bas the formula: R' 20 -M \\ /- \ R5 RJ or 25
in which M is (CH2)mC(Oi(CH2)„ (CH,)mCiO)NH(CH:)„ (Cri,!JCH = CK)(CK.;(CH;)mCÎO)(CH:),NH(CH;)r, iCH2)JCH = CH)(CH2)„ C = N(OH)(CH;)„ 35 (CH;)mC(O)(CH == Cri)sNH(CH,),, CH(OH)(CH2)„ CH(CH3)C(O)(CH CH(CH3)C(OHCH2îJCH = CHHCH2),, (CH;}„ (CH,),O, (CH,)S(O)n wherôin n is 0-2,C(O)O, in which m, s and r are each indepenaently 0 to 6, preferably 0 to 2,more preferably M is (CH2!mC(O)(CH2)„ (CH2)mC(O)NH(CH2i„ 01 1 -133- (CHJJCH - CH,(CH,,„ (CH2)mCiO)(CHî)!NH{CH,)„ (CHJJCH = CH!(CH,,„ C = N(OH)(CH,,„ CH(OK)(CH,)„ (CH,,f, (CH,,,O, (CH,)S(O)n, C(O)O; and R’, R2, R3, F* aria R5 are each indeoendenîly selected from(i, or (iï, as foilows: 5 (î, R:, R2, R3, R* and R5 are each independently selectec from among H, OH, NHF.38, CONR28R33 , NO,, cyano, naiide, pseudohaiice, alkyl,alkeny!, alkynyl, aryi, arylalkyi, heteroaryi, aikoxy, alkylamino, alkylthic.haloalkyi, alkylsulfinyl, aikyisulfonyl, alkoxycarbonyl, alkylcarbonyi, alkenvithro,alkenyiamino, alkenyioxy, alkenyl sulfinyl, aikenyisuifonyl, alkoxycarbcryi, 10 aryiaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocar-bonyDalkyl, acetoxy, hycroxyi, carboxyi, carboxyaikyl, carboxyaikenyl,alkylsuifonyiaminoalkyl, cyanoalkyl, acctyl, acetoxyalkyi, hydroxyalkyl, alkvcxy·aikoxy, hydroxyalkyl, (acetoxy,aikoxy, (hydroxy)aikoxy, formyl, sulfcny.chforides, amino acics, hexoses, O-glycosides, riboses, lower alkyl, CN, 15 _(cH2)xC(O)(CH2,„ — (CH,)X, (CHJ.N-lower alkyl, -(CH3)XC(O)NH2, a C-, L- c- racemic amino acid, a primary or secondary amide, O-glycoside, a hexcse crriboce, —S(O),NH;, hydroxy, aikoxy, alkoxycarbonyl, acetoxyalkyi, — (CH2)XCOOH; — {CH2)XCOOH —, C02-lower alkyl, CN, heteroaryi, — COC(O)(CH2)XCH3, — (CH;)xN(CH3);,, a suifonyl chloride, S(O)3NHR5Û, aikyiary , 20 alkylheteroaryl, C(O)NHR'J°, -<CH;)XOH, -C(O)N(H)N(H)M, or; (iï) at least two of R’, R2, R3, R4 and Rs, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy oralkylenedithioxy, which is unsubstituted or substituted by replacina one cr morehydrogens with naiide, loweralkyl, loweralkoxy or halo loweralkyl, and the othe* 25 of R1, R2, R3, R4 and R' are selected as in (i); and at least four of R’, R2, R3, R4 and R5 are not hydrogen, unless: (a, R' and R3 are alkyl and Rs is R20, which is selected from thegroup consisting of ar/i, heteroaryi, heterocycle, OH, CN, C(O)R16, CO;R,C SH,S(O)nR'6 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an 20 O-glycoside, a sulfonyi chloride, -(CH3)XOH, NHOH, NRI2R’6, NO:, N3, OR-5,R12NCOR'° and CONR’^R15, then R2 and R4 may be H; or -134- 011024 (b) when M is -CONHCiR;2)(R,G)-. then R', R2, R3, R4 and R5 may ail oe H; (c) when M is -COCHRb-, Ar: is noî an isoxazolyl, R’ is alkyl, andR3 and R‘ form alkyleneaioxy, then R2 and R5 may be H; 5 R3a and R39 are each independently selected from hydrogen, alkyl, alkenyi, alkynyl, aryl, haloalkyl alkylaryl, heterocycle, arylaikyl, arylalkoxv, alkoxy,aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl, and is preferably hydrogen,loweralkyl, loweralkoxy and lowerhaloalkyl; R6 is H, or substituted or unsubstituted alkyl or aryl, preferably H or10 substituted or unsubstituted lower alkyl, more preferably H, methyi or carboxymethyl; X is S, O or NR”, where R" contains up to about 30 carbon atoms ana isselected from the group consisting of hydrogen, alkyl, alkenyi, alkynyl, aryl,alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, 15 C{O)R'5 and S(O)nR’s in which n is 0-2; R’5 is hydrogen, alkyl, alkenyi, alkynyl, aryl, alkylaryl, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl; R11 and R15 are unsubstituted or are substituted with one or moresubstituents each selected independently from Z; 20 Z is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyi, alkynyl, aryl, amino acids, primary and secondary amides, O-glycosides, hexoses, riboses,alkylaryl, alkylheteroaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, OH, CN, C(O)R16, OCtOlR'6, CO,R'6, OCO2R’6, SH, S(O)nR16 inwhich n is 0-2, NHOH, NR'2R’6, N03, N3, OR’6, R’2NCOR’6 and CONR’2R16; R'6 is 25 hydrogen, alkyl, alkenyi, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHR50, alkylaryl, alkylheteroaryl,or — (ΟΗ2),ΟΗ; R50 is a substituent such as hydrogen, lower alkyl, or loweralkoxy; R’2, which is selected independently from R” and Z, is selected fromhydrogen, alkyl, alkenyi, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, 30 cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R’7 and S(O)nR’7 in which n is 0-2; R17is hydrogen, alkyl, alkenyi, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl or cycloalkynyl; R12 and R’6 may together form alkylene; 011024 -135- each of R'2, R1'-* and R,E may be further substituted with any grcup those setforth for Z; and further provided that the compounds are not selected frcm the groupconsisting of: 5 N-(4-chloro-3-methyl-5-isoxazolyi)-2-{3-cyanomethyi-2,4.6- trimethylphenylaminocarbonyl)thiophene*3-suifonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxyrTiethyl-2.4,6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4.6-trimethylphenyl-10 aminocarbonyl)thiophene-3-sulfonamide; N-{4-chioro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2.4,6- trimethylphenylaminocarbonyl)thiophene-3-suifonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4.6-trimethylphenvl- aminocarbonyl)thiophene-3-sulfonamide; 15 N-(4-chloro-3-methyl-5-isoxazolyi)-2-{3-methanesulfonyl-2,4.6- trimethylphenyiaminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{3-{2-hydroxyethyl)-2,4.3- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chtoro-3-methyl-5-isoxazolyl)-2-<3-cyanomethyl-2,4,6-20 trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6- trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chioro-3-methyl-5-isoxazolyi)-2-(3-cyano-2,4-6- trimethylphenylacetyl}îhiophene-3-sulfonamide; 25 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,5- trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazoiyl)-2-(3-carboxyl-2,4>6- trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-30 trimethylphenyiacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-(2-hydroxyethyl)-2,4,6- trimethylphenylacetyl)thiophene-3-sulfonamide; 011024 -136- N-(4-chloro-3-methvl-5-isoxazolyU-2-(6-meThvl-2,3,'i-rrirneTnoxyphenyi- aminocarbony|)thiophene-3-sulfonamide; N-(4-ch!oro-3-meÎhyl-5-isoxazolyl)-2-(6-acetyl-2,3,4-trifTiethoxypnenyl- aminocarbonylÎthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-meÎhoxycarbony!-2.3,4- trimethoxyphenytaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-meÎhyl-5-isoxazolyi)-2-{6-carboxyl-2,3,4-trimethoxYphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-mexhyl-5-isoxazolyl}-2-(6-methanesulfonyl-2,3,4- trimethoxyphenylaminocarbonyl)Xhiophene-3-sulfonamide; N-{4-chioro-3-meÎhyl-5-isoxazplyl)-2-{6-cyanomethyl-2,3,4- trimethoxyphenylaminocarbonyl)thiophene'3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-{2-hydroxyethYl)-2,3,^- trimethoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyano-2,3,4-trimethoxyphenyl- amÎnocarbonylJthiophene-3-suifonamide; N-{4-chloro-3-mexhyl-5-isoxazolyl)-2-(6-mexhyl-2,3,4- trimexhoxyphenylacexyl)xhiophene-3-suIfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-acetyl-2,3,4- trimethoxyphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-mexhyl-5-isoxazolyl)-2-(6-methoxycarbonyl-2,3,4- trimethoxyphenyiacexyl)Xhiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-carboxyl-2,3,4- Xrimexhoxyphenylacexyl)xhiophene-3-sulfonamide; N-{4-chloro-3-mexhyl-5-isoxazolyl)-2-(6-mexhanesulfonyl-2,3,4- trimeÎhoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3'methyl-5-isoxazolyl)-2-(6-cyanomethyl-2,3,4- xrimexhoxyphenylacetyl)xhiophene-3-su!fonamide: N-<4-chloro-3-mexhyl-5-ispxazolyl)-2-(6-{2-hydroxyexhyl)-2,3,4- XrimexhoxyphenylaceXyt)xhiophene-3-sulfonamide; N-(4-chloro-3-meXhyl-5-isoxazolyl)-2-(6-rriethyi-3,4-(mexhyienedioxy)-2- rnethoxyphenylaminocarbonyl)xhiophene-3-sulfonamide; 011024 •137· N-(4-chloro-3-methyl-5-isoxazolyl)-2-<6-acetyl-3,4-(methylenedioxy}-2- methoxyphenylaminocarbonyl)thiopnene-3-sulfonamide; N-{4-chioro-3-methyl-5-isoxazoiyl)-2-(6-meThoxycarbonyl-3,4-(methyiene- dioxy)-2-methoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chtoro-3'meÎhyl-5-isoxazolyl)-2-(6-carboxyl-3,4-(methylenedioxy)-2- methoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-methanesulionyl-3,4-{methylene- dioxy)-2-methoxyphenylaminocarbonyl)thiophene-3-suifonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyanomethyl-3,4-(methylene- dioxy)-2-methoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chioro-3-methyl-5-isoxazolyl)-2-{6-(2-bydroxyethyi)-3,4-(methylene- dioxy)-2-methoxyphenylaminocarbonyi)thiophene-3-sulfonamide; N-(4-chioro-3-methyl-5-isoxazolyl)-2-{6-cyano-3,4-(methylenedioxy)-2- methoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{2,6-dimethyl-3,4-(methylene- dioxy)phenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-acetyl-3,4-(methylenedioxy)-2- methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methoxycarbonyl-3,4-(methylene- dioxy)-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-meÎhyl-5-isoxazolyl)-2-{6-carboxyl-3,4-(methylenedioxy}-2- methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methanesulfonyl-3,4-(methylene- dioxy)-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-cyanomethyl-3,4~{methylene- dioxy)-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-(2-hydroxyeÎhyl)-3,4-{methylene- dioxy)-2-methylphenylaminocarbonyl)thiophene-3-suifonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyano-3,4-<methylenedioxy)-2- methylphenylaminocarbonyi)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl>-2-(6-methoxy-3,4-(methylenedioxy)-2- methylphenylaminocarbonyl)Îhiophene-3-sulfonamide; > «r %* · 01 1024 -138- N-(4-cbloro-3-meîhyl-5-isoxazolyll-2-(2-cYano-3,4-(methyienedioxy)-ô- methylphenylaminocarbonyl)thiophene-3-sulfonarriide: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-cyano-3.4-(rnethYlenedioxy)-ô- methoxyphenylaminocarbonyi)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-acetyl-3.4-(rnethylenedioxy)-6- methylpbenylaminocarbonylHhiophene-3-sutfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-acetyl-3,4-(metbylenedioxy)-6- methoxyphenYlaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methyl-3,4-(methyienedioxy)-2- methoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-acetyl-3,4-(methyienedioxy)-2- methoxypbenyiacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{6-methoxycarbonyl-3,4-(metbylene- dioxy)-2-methoxyphenylacetyl)Îhiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolYt|-2-(6-carboxyl-3,4-(methylenedioxy)-2- methoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-methanesulfonyl-3,4-tmethylene- dioxy)-2-meÎhoxYphenylacetyl)thiophene-3-sulfonamtde; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyanomethyl-3,4-(methylene- dioxy)-2-methoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyn-2'(6-(2-hydroxyethyn-3,4-(rnethyiene- dioxy)-2-methoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-cyano-3,4-(rnethylenedioxy)-2- meÎhoxyphenylacetyl>thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(2,6-dimethyl-3,4-(methylene- dioxy)phenylacetyI)thiophene-3-sulfonamide; N-(4-chloro-3-meÎhyl-5-isoxazolyl}-2-(6-acetYl-3i4-(methyienedioxy)-2- methylphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{6-methoxycarbonyl-3,4-{methylene- dioxy)-2-methylpbenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-meÎhyl-5-isoxazolyl)-2-(6-carboxyl-3,4-(methylenedioxy|-2- methy|phenylacetyl)thiophene-3-sulfonamide;
011024 -139· N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-methanesulfonyl-3,4-(methyfenedioxy)-2- methylphenylacetyl)thiophene-3-sulfonamide; N-{4-chioro’3-methyl-5-isoxazolyl)-2-{6-cyanomethyl-3,4-(methylenedioxy)-2- methylphenylacetylJthiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{6-(2-hydroxyethyl)-3,4-(methylenedioxY)-2- methylpheny(acetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyano-3,4-{methylenedioxy)-2- methylphenylaceryl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{6-methoxy-3,4-(methylenedioxYJ-2- methylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methYl-5-isoxazolyl)-2-{2-cyano-3,4-(methylenedioxy)-6- methylphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-meÎhyl-5-isoxazolyl)-2-(2-cyano-3,4-(methylenedioxy)-6- methoxyphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{2-acetyl-3,4-{methylenedioxy)-6- methylphonylacetyl)thiophene-3-sijlfonamtde; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-acetyl-3,4-(methylenedioxy)-6- methoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-!2,6-bis(cyanomethyl)-3,4-(methylene- dioxy)phenylaminocarbonyl)thiophene-3-sulfonamide,· N-{4-bromO'3-methyl-5-isoxazolyt)-2-(N-benzylaminocarbonyl)thiophene-3- sulfonamide.
2. A compound or pharmaceuticaily acceptable sait, acid or ester thereof ofclaim 1, wherein M is o O o N r OR** in which R40 is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl, haloalkyl, and morepreferably loweralkyl, loweralkoxy, or halo loweralkyl, and is more preferably hydrogenor loweralkyl, particularly methyl or ethyl, and is most preferably hydrogen.
*140' 011024
3. A compound or phsrmaceutically acceptable sait, acid or esterthereof of daim 1, wherein M is C|O)CH2, C(O)NH, -CH»CH-,CH2CH2C(OKCH)2, CHjCHCîOJCHj.
4. A compound or pharmaceutically acceptable sait, acid or esterthereof of claim 1, wherein M is selected from among: 10 and
5. A sulfonamide compound or pharmaceutically acceptable sait, acid orester thereof of claim 1 that has formula II): 15 Ar’ / 20 25 30 35
II) X SO7NH wherein: Ar’ is a substituted with one or more substituents or an unsubstitutedmonocyclic or polycyclic aryl or heteroaryl group in whcih the each substituent is 40 independently selected from the group consisting of H, NH2, halide,pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl,alkylamino, alkylthio, arylcarbonyl. aryloxy, arylamino, arylthio, haloalkyl, I -141- ci 1024 haioaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted orsubstituted with any of the preceeding groups, and straight or brancfied chainsof from about 1 up to about 12 carbons; X is S, O or NH, preferably S; 5 R’5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl; R11 and R’s are unsubstituted or are substituted with one or moresubstituents each selected independently from Z; 2 is selected from the group consisting of hydrogen, halide, pseudohaiide, 10 alkyl, alkoxy, alkenyl, alkynyl, aryl, amino acids, primary and secondary amides,O-glycosides, hexoses, riboses, alkylaryl, alkylheteroaryl, heterocycle, aralkyt.aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R'e, 0C(O)R'\CO2R,e. OCO2R”, SH, S(0)nR’6 in which n is 0-2, NHOH, NR’2R’e, NO2, N3. OR’6,R’2NCOR16 and CONR,2R’e; 15 R'6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHRSO, alkylaryl,alkylheteroaryl. or — {CH2)„OH; Rso is hydrogen, lower alkyl, or lower alkoxy; R12, which is selected independently from R” and Z, is selected from the 20 group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R’7 and S(O)„R’7 inwhich n is 0-2; R” is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle. aralkyl,aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; 25 R12 and R’6 may together form alkylene; each of R”, R12, R'5 and R’6 may be further substituted with the any of the appropriate groups of those set forth for Z; W is =C(halo)2, —(CH2)X —, =N(lower alkyl), — C(O) —, = Cllower alkyl)2, -NH-, =NCOR’6,-NHC(R’2)(R’6)-, = NCO2R’6, -CH2- or =CHR6; and 30 each „ is 0-3. • νί*.ί*ϊ;Ά~·. 011024 -142-
6. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 1, wherein the compounds of formula (A) are of formula (II): Ar’
wherein: Ar1 is a substituted or unsubstituted monocyclic or polycyclic aryl grouowith one or more substituents, selected from the group consisting of H, NH2,halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl,alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl,haloaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted orsubstituted with any of the preceeding groups, and straight or branched chainsof from about 1 up to about 10-12 carbons; R7 is R', R8 is R3, R9 is R4 and R10 is R5.
7. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 6, wherein R7, R® and R'° are alkyl, haloalkyl, polyhaloalkyl,alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds,cycloalkyi, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. . 1 -, A, . <·,. ( V 4. ,**·, I 011024 -143-
8. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 7, wherein R7, R® and R’° are lower alkyl, lower alkenyl, loweralkynyl, or aryl.
9. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 8, wherein R7, R® and R’° are methyl.
10 in which R* and RB are either (i), (ii) or (iii) as follows: (i) R* and RB are each independently selected from H, NH2, NO2,halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy,alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy, 15 arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstitutedamido, substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and are eitherstraight or branched chains or cyclic, and the aryl portions contain from about 4 20 to about 16 carbons, except that R2 is not halide or pseudohalide; or, (ii) RA and RB together form -(CH2)n, where n is 3 to 6; or, (iii) RA and RB together form 1,3-butadienyl.
10. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 6, wherein R7, R®, R9 and R’° do not contain cyano groups, andW is not -CH2-.
11. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 6, wherein: Ar is benzo-1,2,7-thiadiazol-4-yl, benzo-1,2,7-oxadiazol-4-yl, 3-rnethoxy-2-pyrazinyl, 3,4-dimethyl-5-isoxazolyl, 4-chloro-3-methyl-5-isoxazolyl or 4-chloro-5-methyl-3-isoxazolyl; W is -NH-, =sNCO2R'g, or is -CH2- when R9 is hydroxyl; R7, R® and R10 are methyl; and R9 is selected from the group consisting of Z-substituted andunsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, OC(O)R’6,OCO2R’6, NR’2R'6 and S(O|nR’6 in which n is 0-2.
12. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 11, wherein R9 is selected from the group consisting ofmethoxy, methoxycarbonylmethoxy, 2-{2-methoxyethoxy)ethoxyacetoxy. 2-hydroxyethoxy, Ν,Ν-dimethylthiocarbonyloxy, N,N- dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxy, hydroxy,cyanomethyl, acetoxymethyl, hydroxymethyl, carboxylmethyl,methanesuiîonylamino, Ν,Ν-dimethylaminomethyl, SO2NH2, andmethoxycarbonylmethyl.
13. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 11, wherein R9 does not contain a cyano group.
14. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 1 1, wherein R9 is selected from the group consisting ofmethoxy, methoxycarbonylmethoxy, 2-(2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, Ν,Ν-dimethylthiocarbonyloxy, N,N- ***^È2ÎÎ*X!i 011024 -144- dimethylthiocarbonvloxymethyl, dimethylamino, pyrrolidinyl, acetoxymethyi,methoxycarbonylmethyl, hydroxy and acetoxy.
15. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 6, selected from the group consisting of: N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-carboxylmethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-H-chloro-S-methyl-S-isoxazolyn^-O-acetoxY^^e-trÎmethylpnenvI- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-pyrrolidinyl-2,4,6-tnmethvtpheny -aminocarbonyl)thiophene-3-sulfonamide; N-|4-chloro-3-methyl-5-isoxazolyl)-2-{3-dimethylamino- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N- dimethylthiocarbonyloxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N-dimethylthiocarbonyloxy)- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethoxy)- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-{2-{2- methoxyethoxy)ethoxy)acetoxy-2,4,6-trimethylphenylaminocarbony0thiopnene- 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethoxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxy-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxymethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; Ν-(4-εΐΊΐθΓθ-3-ΓηβΐήγΙ-5-ί5θΧ3ΖθΙγΙ)-2-(3-ήγάΓθχγ-2,4,6-ΐΓΪΓΤΐθΐήνίρΗ6ηνι- aminocarbonyl)thiophene-3-sulfonamide; 011024 •145· N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-dimethylaminomethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-fnethyl-5-isoxazolyl)-2-(3’methanesulfonyiamino- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide,· N-{4-chloro-3-methyl-5-isoxazolyl)-2-<3-suifamoyl-2,4,6-trimethylphenyi- aminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-5-methyl-3-isoxazolyl)-2-{3-cyanomethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-fnethyl-3-isoxazolyl)-2-(3-methoxycarbonylmethyl- 2.4.6- trimethylphenylarninocarbonyl)thiophene-3-sulfonamide; N-<4-chloro-5-methyl-3-isoxazolyl)-2-(3-carboxylmethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-acetoxymethyl- 2.4.6- tnmethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-tsoxazolyl)-2-{3-hydroxymethyl- 2.4.6- trimethylphenylaminocarbonyI)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-{3-dimethylaminomethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-{3-methanesulfonylamino- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-{3-hydroxy-2,4»6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-5-methyl-3-isoxazolyl)-2-(3-carboxy-2,4,6-trimethylphenyl- aminocarbonyl)thiopher>e-3-sulfonamide; N-(4-chloro-5'methyl-3-isoxazolyl)-2-{3-cyano-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-sulfamoyl-2,4,6-trimethylphenyi- aminocarbonyl)ihiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-{3-cyanomethyl-2,4,6-trirr»eihylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-{3,4-dimeÎhyl-5-isoxazolyl)-2-(3-methoxycarbonylmethyl- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; 011024 -146- N-{3,4-dimeÎhyl-5-isoxazolyl)-2-{3-carboxyltneîhyl-2,4,6-tnrT»ethylphenyl- amtnocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-{3-acetoxymethyl-2,4,6-tnmethylphenyf- aminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethyiphenyf- aminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-(3-dimethylaminomethyl- 2.4.6- trimethylphenyiaminocarbonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl-5-isoxazolyl)-2-{3-methanesulfonylamino- 2.4.6- trimeÎhyiphenylaminocarbonyl)thiophene-3-sulfonamide; N-{3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxy-2,4.6-trirnethylphenylamino- carbonyl)thiophene-3-sulfonamide; N-{3,4-dimethyl-5-isoxazolyl)-2-(3-carboxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-(3,4-dimethyl'5-isoxazolyl)-2-(3-cyano-2,4.6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-{3,4-dimethyl-5-isoxazolyl)-2-(3-sulfamoyl-2,4,6-Îrimethylpnenylamino- carbonyl)thiophene-3-sulfonamide; N-(benzo-1,2,7-thiadiazol-4-yl>-2-(3-cyanomethyl-2,4,6-trimethylphenyl-aminocarbony|)thiophene-3-sulfonamide; N-(benzo-1,2,7-thiadiazol-4-yl)-2-(3-methoxycarbonylmethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(benzo-1,2,7-thiadiazol-4-yl)-2-(3-carboxylmethyl-2,4,6-Îrimethylpnenyl-aminocarbonyl)thiophene-3-sulfonamide; N-{benzo-1 ^^-thiadiazol^-yO^-O-aceîoxymeÏhyl^^.e-tnmethylphenyl-aminocarbony|)thiophene-3-sulfonamide; N-(benzo-1,2,7-thiadiazol-4-yl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyl-aminocarbonyl)thiophene-3-sulfonamide; N-<benzo-1,2,7-thiadiazol-4-yl)-2-(3-dimeThylaminomethyl- 2.4.6- Îrimethy|phenyiaminocarbonyl)thiophene-3-sulfonamide; N-(benzo-1,2,7-Îhiadiazol-4-yl)-2-{3-methanesulfonylamino- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; 011024 -147- N-(benzo-1,2,7-thiadiazol-4-yl)-2-{3-hydroxy-2,4,6-tnmethyjphenylamino- carbonyl)thiophene-3-sulfonamide; N-(benzo-1,2,7-thiadiazol-4-y|)-2-{3-carboxy-2,4,6-trwnethylphenylamino- carbonyf)thiophene-3-sulfonamide; N-(benzo-1,2.7-thiadiazol-4-yl)-2-(3-cyano-2,4,6-trimethylphenylaminocar bonyl)thiophene-3-sulfonamide; N-(benzo-1,2,7-thiadiazol-4-yl)-2-{3-sulfamoyl-2,4,6-trimethylphenyl-aminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-{3-cyanomethyl-2,4,6-tnmetbyiphenyiaminO' carbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-methoxycarbonylmethyl- 2.4.6- trÎmethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2’pyrazinyl)-2-(3-carboxylmethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-{3-methoxy-2-pyrazinyl)-2-(3-acetoxymethyl-2,4,6-trimethyiphenyl- aminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-hydroxymethyl-2,4/6-trimethyiphenyl- aminocarbonyl)thiophene-3-suIfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-dimethylaminomethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-methanesulfonylamino- 2.4.6- tnmethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-{3-methoxy-2-pyrazinyl)-2-{3-hydroxy-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-{3-methoxy-2-pyrazinyl)-2-{3-carboxy-2,4.6-trimethylphenylaminocar- bonyUthiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-{3-cYano-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-(3-methoxy-2-pyrazinyl)-2-(3-sulfamoyl-2,4,6-trimethylphenylaminocar- bonyl)thiophene-3-sulfonamide; N-(4-chloro-3-meîhyl-5-isoxazolyl)-2-( 1 -methyl-1 -phenyl-1 -ethylaminocar- bonyl)thiophene-3-suifonamide; 011024 -148- N-{4-chloro-3-methyl-5-isoxazolyn-2-((R)-1 -phenyl-l-ethyiaminocar- bonyOthiophene-S-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-((S)-1 -phenyl-1-ethylaminocar- bonyl)thiophene-3-sulfonamide; and 5 pharmaceutically acceptable salts, acids and esters thereof.
16. A sulfonamide or pharmaceutically acceptable sait, acid or ester thereof of claim 6, selected from the group consisting of: N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-methoxycarbonylmethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide,· 10 N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-acetoxymethyl- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-hydroxy-2,4,6-trimethylphenyf- aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl>-2-(3-methoxy-2,4,6-trimethylphenyl-15 aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonylmethoxy- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-(2- methoxyethoxy)ethoxy)acetoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene- 3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethoxy)- 2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-(N,N-dimethylthiocarbonyloxy|- 2.4.6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; 25 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(N,N- dimethylthiocarbonyloxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3- sulfonamide; N-(4-chloro-3-methyl’5-isoxazolyl!-2-(3-dimethylamino- 2.4.6- trimethylphenylaminocarbonyl)îhiophene-3-sulfonamide; 30 N-(4-chioro-3-methyl-5-isoxazolyl)-2-(3-pyrrolidinyl-2,4,6-tnmethylphenyl- aminocarbonyl)thiophene-3-suifonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxy-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfonamide; and pharmaceutically acceptable saits, acids and esters thereof.
17. A sulfonamide compound or pharmaceutically acceptable sait, acid 5 or ester thereof of claim 1, wherein Ar’ has formula: 011024 -149-
.N -Ό O N 15 in which RA and R® are either (i), (ii) or (iii) as follows: <i) R* and R0 are each independently selected from H, NH2, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy,alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy,arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl, 20 alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstitutedamido, substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and are eitherstraight or branched chains or cyclic, and the aryl portions contain from about 4to about 16 carbons, except that R2 is not halide or pseudohalide: or, 25 (ii) RA and R8 together form -(CH2)„, where n is 3 to 6; or, (iii) RA and RB together form 1,3-butadienyl.
18. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 17, wherein RA and RB are each selected independentiyfrom among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, 30 pseudohalide or H, except that RB is not halide.
19. A sulfonamide compound or pharmaceutically acceptable sait, acid orester thereof of claim 1 that is a thiophene-3-sulfonamide.
20. A sulfonamide compound or pharmaceutically acceptable sait, aador ester thereof of claim 6, wherein Ar1 has formula: 35 * JlL.ir- «' JUm«Î 011024 -150-
Ra R3 \_/ in which RA and R0 are either (i), iii) or (iii) as follows: (i) RA and RB are each independently seiected from H, NH2, NC2,hafide, pseudohaiide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, aikoxy,alkylamino, aikylthio, alkyloxy, haioalkyl, alkylsufinyl, alkylsulfonyl, aryioxy,arylamino, aryithio, arylsufinyl, arylsulfonyl, haioalkyl, haloaryl, alkoxycarbor.yl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstitutedamido, substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and are eitherstraight or branched chains or cyclic, and the aryl portions contain from about 4to about 16 carbons, except that R2 is not halide or pseudohaiide; or, (ii) RA and Rs together form -(CHZ)„, where n is 3 to 6; or, (iii) RA and R° together form 1,3-butadienyl.
21. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 20, wherein RA and Ra are each seiected independentlyfrom among alkyl, lower alkenyl, lower alkynyl, lower haioalkyl, halide,pseudohaiide or H, except that Re is not halide.
22. A sulfonamide compound or pharmaceutically acceptable sait, acicor ester thereof of claim 6 that is a thiophene-3-sulfonamide.
23. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 1 that has formula III: jÛÛîIftA» 011024 -151- Ar /
SOrNH Ar' /
(III) wherein: X is S, O or NR”; each G and R is.independently selected from lower alkyl, CN,-(CHJ.CfOHCHJ,, -(CH2)X, (CH2)MN-lower alkyl, -(CH2)XC(O)NH2. a D-. L-orracemic amino acid, a primary or secondary amide, O-glycoside, a hexose orribose, — S(O)2NH2, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyi, — (CH2)„COOH; — (CH2),,COOH—, CO2-lower alkyl, CN, heteroaryl, — COC(O)(CH2),CH „ — (CH2)xN(CH3)2, a sulfonyl chloride, S(O)2NHR50, alkylaryl,alkylheteroaryl, CiOINHR50, -(CH2)„OH, -C(O)N(H)N(H)M; R50 is hydrogen, lower alkyl, or lower alkoxy; M is H or Rso; R' is independentlyl selected from hydrogen, G and R; W is =C(halo)2, = N(H), — (CH2),-, = NOower alkyl), —C(O) —, = C(lower alkyl)/, and each x is independently is 0-3. 011024 -152-
24. The sulfonamides of claim 23, wherein Ar' is an isoxazolyl, athiazolyl, a pyrimidinyl, a pyridazinyl or a phenyl group;
25 wherein: Ar1 is selected with the proviso that Ar' is not 4-chloro-3-methyl-5-isoxazolyl, 4-chloro-5-methyl-3-isoxazolyl or 3,4-dimethyl'5-isoxazolyl when R6 isH; and 30 R6 is H, or substituted or unsubstituted alkyl or aryl.
25. The sulfonamides of claim 23, wherein Ar1 is an isoxazolyl.
26. The sulfonamides of claim 23, wherein: R, G and R' are selected 5 where the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the heteroarylis triazolyl, and X is S.
27. The sulfonamides of claim 25, wherein: R, G and R' are selectedwhere the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the heteroarylis triazolyl, and X is S.
28. The sulfonamides of claim 23, wherein: R, G and R' are selected where the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the neteroarylis triazolyl, and X is S.
29. The sulfonamides of claim 25, wherein: R, G and R' are selectedwhere the amino acid is L-Asp or L-Glu; the hexose is D-mannose, the heteroaryl 15 is triazolyl, and X is S.
30. The sulfonamides of claim 23, wherein: W is =CH2, =NH, = NCH3, = NCH2CH3, = C(CH3)2 or CF2; andG is -CH3, -CN, -COCH3, -CH2CH3, -<CH2>xCO2H.
31. The sulfonamides of claim 24, wherein: 20 W is =CH2, =NH, =NCH3, =NCH2CH3, =C|CH3)2 or CF2; and G is -CH3, -CN, -COCH3, -CH2CH3, -{CH2)xCO2H.
32. The sulfonamides of claim 25, wherein: W is =CH2, = NH, =NCH3, =NCH2CH3, =C{CH3)2 or CF2; andG is -CH3, -CN, -COCH3, -CH2CH3, -<CH2)xCO2H. 25
33. A sulfonamide or pharmaceutically acceptable sait, acid or ester thereof of claim 23 is selected from the group consisting of: N2-(3-cyanomethy!-2,4,6-tnmethylphenyl)-3-(4-chloro-3-methyl-5-isoxa- zolylsulfamoyl)-2-thiophenecarboxamide; methyl-2-(3-{3-(4-chloro-3-methyl-5-isoxazolylsulfa- 30 moyl)-2-thienylcarboxamido)-2,4,6-trimethylphenyl)acetate; 2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyl- carboxamido)-2,4,6-trimethylphenyl)acetic acid; i •Λ.
011024 -153- N2-{3-acetyioxymethyl-2,4,6-trimethyiphenyl)-3-(4-chloro-3-fnethyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-{3-hydroxymethyl-2,4,6-trimethylphenyl)-3-{4-chloro-3-methyf-5-isoxa· zolylsulfamoyl)-2-thiophenecarboxamide; 5 N2-(3-dimethylaminomethyl-2,4,6-trimethytphenyl)-3-{4-chloro- 3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide trifiuoroacetate; N2-{3-(4,5-dihydro-1,3-oxazol-2-yl)-2,4»6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsutfamoyl)-2-thiophenecarboxamide;3-{3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyl- 10 carboxamido)-2,4,6-trimethylbenzoic acid; N-[3-{3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox-amido)-2,4,6-trimethylbenzoyllgiutamic acid; N-[3-(3-(4-chloro-3-methyl-5-isoxazolyisulfamoyl)-2-thienylearbox-amido)-2,4,6-trimethylbenzoyl]aspartic acid; 15 N-[2-{3-{3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-2,4,6-trimethylphenyl)acetyl]glutamic acid; N-(2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox-amido)-2,4,6-trimethylphenyl)acetyllaspartic acid;N2-(3-cyano-2,4,6-trimethylphenyl)-3-<4-chloro-3-methyl-5-isoxazolyl- 20 sulfamoyD-2-thiophenecarboxamide; 2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcar-boxamido)-2,4,6-trimethylphenoxy)acetic acid; N2-(3-alkylsulfonamido-2,4.6-trimethylphenyl)-3-(4-chloro-3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 25 N2-{3-arylsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-suifamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl- 5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-alkylsulfamoyl'2,4.6-trimethylphenyl)-3-(4-chloro-3-methyl-5-30 isoxazolylsulfamoyl)-2-thiophenecarboxamide; N?-(3-aryisulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; &amp; 011024 -154- N2-(3-f1 H-1,2.3,4-tetraazol-5-ylmethyl)-2,4»6-trimethylphenyl)-3-(4-chioro3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-(2-pyrïdylmethyI)-2,4.6-trimethylphenyl)-3-{4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-{3-hydraztnocarbonyl-2,4,6-tnmethylphenyl)-3-(4-chloro-3-rnexhyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-(3-aminomethyl-2,4,6-trimethylphenylJ-3-(4-chloro-3-methyl-5- isoxazolylsulfamoyl)-2-thiophenecarboxamide; N2-{3-{a-D-mannopyranosyloxymethyl)-2,4,6-trimethylphenyl)-3-(4-chloro- 3- methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide; 5-(3’{4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyicarboxamido)-4-cyano-6-methylbenzo(dH 1,3]dioxole; 5-{3-{4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 6-cyano-4-methylbenzo{dH 1,3]dioxole; 2-(5-{3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyicarboxamido)- 4- methylbenzo{d)I1,3ldioxole)-6-acetic acid; 5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienyicar-boxamido)-4-aceTyl-6-methyibenzo(dH1,3Jdioxole; 5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)- 6-acetyl-4-methylbenzo(d][1,3]dioxole; 5- (3-{4-chloro-3-meîhyl-5-isoxazolylsuifamoyl)-2-thienylcarbox-amido)-7-cyano-4,6-dimethy!benzo[dJÎ1,3]dioxole; 6- (3-<4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox-amido)-5,7-dimethylbenzo[d][1,3]dioxole-4-carboxylic acid; 7- (3-(4-chioro-3-methyl-5-isoxazolylsulfarnoyl)-2-thienylcarbox-amido)-5,6-dimethylbenzo[d][1,3]dioxole-4-carboxylic acid; 7-(3-(4-chloro-3-methyl-5-isôxazolylsulfamoyl)-2-thienylcarboxamido>-4-cyano-5,6-dimethyibenzo[d][ 1,3ldioxole; 7-(3’(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-4-acetyl-5,6-dimethylbenzo{d][1,3]dioxole; 7-{3-(4-chloro-3-methyi-5-isoxazolylsulfamoyl)'2-thienylcarboxarnido)-4- carboxamido-5,6-dimethylbenzoidl[1,3]dioxole; 011024 -155- 7-(3-(4-chloro-3-methyl-5-isoxazolylsuifamoyl)-2-thienyIcar-boxamido)-4-aminomethyl-5,6-dimethylbenzo(dl[1,3]dioxole; 7-(3-<4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarbox- amido)-4-dimethylaminomethyl-5,6-dimethylbenzoId)[1,3Jdioxole; N-|4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylpbenylaminocarbonyllthiophene-3-sulfonamide, N-{4-chioro*3-methyl-5-isoxazoiyll-2-(3-carboxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl}-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenyl-aminocarbonyl)thiophene-3-sulfonamide; and pharmaceutically acceptable salts, esters and acids thereof.
34. A compound of claim 33 that is a sodium sait.
35 wherein: W is -NH-; and R20 is selected from the group consisting of aryl, heteroaryl, heterocycle,OH, CN, C(O)R'e, CO2R'6, SH, S(O}„R'a in which n is 0-2, a D, Lor racemicamino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, —(CH2)XOH, 40 NHOH, NR12R'e, NO2, N3, OR'6, R’2NCOR16 and CONR12R16; II I 11 Ni I I>|| !i llj 011024 159- R'6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R12 is selected from hydrogen, aikyl, alkenyl, alkynyl, aryl, alkylaryl,heterocycle, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R'7 andS(O)„R'7 in which n is 0-2; R” is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocycle, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and each of R’2, R1S and R’6 may be further substituted with the any of thegroups set forth for Z.
35. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 23, wherein Ar’ has formula: Ra R0 RA Rb
O N in which R* and RB are either (i), (ii) or (iii) as follows: (i) RA and RB are each independently selected from H, NH2, NO2, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy,alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy,arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstitutedamido, substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and are eitherstraight or branched chains or cyclic, and the aryl portions contain from about 4to about 16 carbons, except that R2 is not halide or pseudohalide; or, -, jHfiig'y.iu TOifl
011024 -156- iii) R* and RB together form -(CH2I„, where n is 3 to 6; or, (iii) RA and R8 together form 1,3-butadienyl.
36. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 35, wherein R* and RB are each selected independentiy 5 from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide,pseudohalide or H, except that RB is not halide.
37. A sulfonamide compound or pharmaceutically acceptable sait, acid orester thereof of claim 23 that is a thiophene-3-sulfonamide.
38. A sulfonamide or pharmaceutically acceptable sait, acid or ester10 thereof of claim 1, wherein the compounds of formula (A) are of formula (IV):
39. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 38, wherein: Ar1 is benzo-1,2,7-oxadiazol-4-yl or 2-methoxy-3-pyrazinyl; and R6 is H, or substituted or unsubstituted alkyl. 35
40. A sulfonamide or pharmaceutically acceptable sait, acid or ester thereof of claim 38, wherein R6 is methyl or carboxymethyl. 1 . - ,. . ·< 1 011024 , -157-
41. A suifonamide compound or pharmaceutically acceptable sait, acid or ester thereof of claim 38, wherein Ar’ has formula: R* R0 R* Rb
42. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 41, wherein RA and R8 are each selected independently 25 from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide,pseudohalide or H, except that RB is not halide.
43. A sulfonamide compound or pharmaceutically acceptable sait, acid orester thereof of claim 38 that is a thiophene-3-sulfonamide.
44. A sulfonamide or pharmaceutically acceptable sait, acid or ester 30 thereof of claim 38, selected from the group consisting of: N-(benzo-1,2,7-oxadizaol-4-yl)-2-(2-methyl-4,5-methylene-dioxyphenylacetyl)thiophene-3-sulf onamide; N-(3-methoxy-2-pyrazinyl)-2-(2-methyl-4,5-methylene- dioxyphenylacetyl)thiophene-3-sulfonamide; 011024 -158- N-i4-chloro-3-methyl-5-isoxazolyl)-2-{2-{2-methyl-4,5-methylene- dioxyphenyl)propanoyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl}-2-{3-carboxyl-2-{2-methyl-4,5-methylenedioxyphenyl)propanoyl)thiophene-3-sulfonamide; and pharmaceutically acceptable salts, esters and acids thereof.
45. A compound of claim 44 that is a sodium sait.
46. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 1, wherein the compounds of formula (A) are of formula (V): 10 15 20 25 30
47. A sulfonamide compound or pharmaceutïcally acceptable sait, acidor ester thereof of claim 46, wherein Ar' has formula: R* Ra R* Rb
in which RA and R® are either (i), (ii) or (iii) as follows: (i) RA and RB are each independently selected from H, NH2, NO2,halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy,alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl, alkylsulfonyl, aryloxy,arylamino, arylthio, arylsufinyl, arylsulfonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstitutedamido, substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions contain from 1 up to about 14 carbon atoms and are eitherstraight or branched chains or cyclic, and the aryl portions contain from about 4to about 16 carbons, except that R2 is not halide or pseudohalide; or, (ii) RA and R® together form -(CH2)n, where n is 3 to 6; or, (iii) RA and R® together form 1,3-butadienyl.
48. A sulfonamide compound or pharmaceutically acceptable sait, acid or ester thereof of claim 47, wherein RA and R® are each selected independently from among alkyi, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide or H, except that R® is not halide. vi%uzr?&amp;’^'- IL>^» k»,i /d x< ' ,< , ! 011024 -160- >
49. A sulfonamide compound or pharmaceutically acceptable sait, acidor ester thereof of claim 46 that is a thiophene-3-sulfonamide.
50. A sulfcnamide or pharmaceutically acceptable sait, acid or esterthereof of claim 36, wherein: 5 Ar1 is 4-chloro-3-methyl-5-isoxazolyl; W is -NH-; and R20 is CONH2, COOH, or phenyl.
51. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 1, wherein the compound is N2-(3-hydroxy-2,4,S- 10 trimethyl)phenyl-3-‘4-chloro-3-methyl-5-isoxazolyl)sulfamoyl-2-thio-phenecarboxamide or a pharmaceutically acceptable sait thereof.
52. The compounds of claim 1 that are pharmaceutically acceptablesodium salts.
53. A pharmaceuîical composition, comprising an effective amount of a15 compound of claim 1 or a pharmaceutically acceptable sait, acid or ester thereof in a pharmaceutically acceptable carrier, wherein the amount is effective forameliorating the symptoms of an endothelin-medîated disease.
54. The composition of claim 53 that is formulated for single or multipledosage administration.
55. An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable sait, acid or ester thereof of claim 1contained within the packaging material, wherein the compound is effective forantagonizing the effects of endothelin, ameliorating the symptoms of anendotheiin-medîated disorder, or inhibiting the binding of an endothelin peptide 25 to an ET receptor with an IC50 of less than about 10 μΜ, and the packaging ma-terial includes a label that ïndicates that the sulfonamide or sait thereof is usedfor antagonizing the effects of endothelin, inhibiting the binding of endothelin toan endothelin receptor or treating an endotheiin-medîated disorder.
56. A method for the treatment of endothelin-mediated aiseases, 30 comprising administering to a subject an effective amount the pharmaceutical composition of claim 43, wherein the effective amount is sufficient to ameiiorate one or more of the symptoms of the disease. * '•H M Wl 011024 -161-
57. The method of claim 53, wherein the disease is selected from thegroup consisting of hypertension, cardiovascular disease, asthma. pulmonaryhypertension, inflammatory diseases, ophthalmologic disease, menstruaidisorders, obstetric conditions, wounds, gastroenteric disease, rénal faikire,immunosuppressant-mediated rénal vasoconstriction, erythropoietin-mediatedvasoconstriction endotoxin shock, pulmonary hypertension, anaphylactic shockand hémorrhagie shock.
58. The method of claim 57, wherein the disease is selected from thegroup consisting of asthma and inflammatory diseases.
59. A method for inhibiting the binding of an endothelin peptide toendotheiinA (ETA) or endothelinB ÎETe) receptors, comprising contacting thereceptors an endothelin peptide and with a compound or pharmaceutialiyacceptable sait, acid or ester thereof of claim 1, wherein: the contacting is effected prior to, simultaneously with or subséquent tocontacting the receptors with the endothelin peptide.
60. A method for altering endothelin receptor-mediated activity,comprising contacting endothelin receptors with a compound or pharmaceutialiyacceptable sait, acid or ester thereof of claim 1.
61. The pharmaceutical composition of claim 53, that comprises a sodiumphosphate buffer solution containing a sugar and a sulfonamide of claim 1dissolved therein.
62. The pharmaceutical formulation of claim 61, wherein thesulfomamide is a pharmaceutically-acceptable sait that is an alkali métal.
63. A lyophilized powder, comprising a sait of compound of claim 1.
64. The lyophilized powder of claim 63 produced by a process,comprising: (a) dissolving a pharmaceutically-acceptable sait of the sulfonamidecompound in a sodium phosphate buffer solution containing a sugar orcarbohydrate; (b) sterile-filtering the resulting solution; and (c) lyophilizing the filtered solution under standard conditions to proaucea stérile powder. JM I41,1 « dAû . 'U W ίίΙΟΗ*»>«· 011024 -162-
65. The powder of ciaim 64, wherein the surgar or carobohvdrate iscontains dextrose.
66. An article of manufacture, comprising packaging material and a thepowder of daim 63, contained within the packaging material, wherein the 5 compound is effective for antagonizing the effects of endothelin, amelioratingthe symptoms of an endotheiin-mediated disorder, or inhibiting the bincing of anendothelin peptide to an ET receptor with an ICS0 of less than about 1 μΜ, andthe packaging material includes a label that indicates that the sulfonamide or saitthereof is used for antagonizing the effects of endothelin, inhibiting the binairg 10 of endothelin to an endothelin receptor or treating an endotheiin-mediateddisorder.
67. A sulfonamide or pharmaceutically acceptable acid, sait or ester cf acompound of ciaim 1, wherein Ar! is selected with the proviso that where Ar: is 4-chloro-3-methyl-5-isoxazolyl and W is -NH-: 15 (a) if R’, R3 and R5 arc methyl, and R4 is H; then R2 is not cyanomethyl, hydroxymcthyl, cyano, methoxycarbonyl, carboxyl,methanesulfonyl, 2-hydroxyethyl; (b) if R1 is methoxy or is methyl when R2 and R3 together formmethylenedioxy, R2 and R3 are methoxy or together form methylenedioxy, anc 20 R4 is H; then R5 is not methyl, cyano, acetyl, methoxycarbonyl, carboxyl. methanesulfonyl, cyanomethyl or 2-hydroxyethyl, and is not methoxy when R’ ismethyl; (c) if R’ is cyano or acetyi, R2 and R3 together form methylene-dioxy, and R4 is H; then R5 is not methyl or methoxy; 25 (d) if R1 is cyanomethyl, R2 and R3 together form methylenedioxy, and R4 is H; then Rs is not cyanomethyl.
68. A sulfonamide compound or pharmaceutically acceptable acid,sait or ester of a compound of ciaim 67, wherein, when Ar1 is 4-chioro-3-methyl-5-isoxazolyl and W is -CH2-: HBMH
011024 -163- (a) if R', R3 and R5 are methyl, and R-4 is H; then R2 is notcyanomethyl, hydroxymethyl, cyano, methoxycarbonyl, carboxyl,methanesulfonyl, 2-hydroxyethyl; {b, if R' is methoxy when R2 and R3 are methoxy or together formmethylenedioxy, or is methyl when R2 and R3 together form methylenedioxy, andR4 is H; then R5 is not: (i) methyl, acetyl, methoxycarbonyl, carboxyl, meîhanesulfonyl, cyanomethyl or 2-hydroxyethyl, and additionally (ii) is notmethoxy or cyano when R' is methyl, and (iii) is not cyano when R' is methoxyanc R2 and R3 together form methylenedioxy; and fc) if R' is cyano or acetyl, R2 and R3 together form methyiene-dioxy, and R4 is H; then R5 is not methyl or methoxy.
69. A sulfonamide compound or pharmaceutically acceptable acid,sait or ester of a compound of ciaim 6, wherein, when Ar' is 4-chloro-3-methyl· 5-isoxazolyl and W is -NH-: (a) if R7, R8 and R'° are methyl; then R9 is not cyanomethyl,hydroxymethyl, cyano, methoxycarbonyl, carboxyl, meîhanesulfonyl, or 2-hydroxyethyl; (b) if R’° is methoxy or is methyl when Ra and R3 together formmethylenedioxy and R8 and R3 are methoxy or together form methylenedioxy;then R7 is not methyl, cyano, acetyl, methoxycarbonyl, carboxyl, methanesulfonyl, cyanomethyl or 2-hydroxyethyl, and is not methoxy when R'°is methyl; (c) if R'° is cyano or acetyl and R3 and R9 together formmethylenedioxy; then R7 is not methyl or methoxy; and (d) if R'° is cyanomethyl and R8 and R9 together form methylene-dioxy; then R7 is not cyanomethyl; and further R7, R8, R9 and R'° may be H when W is -NHC(R,2)(R'6)-.
70. The combination comprising: a stérile vial containing the pharmaceutical formulation of ciaim 63.
71. The combination of ciaim 70, wherein the stérile vial contains anamount of the powder that is for single dose administration. àât ί '-^fei; 011024 < -164-
72. The combination of claim 102, wherein the stérile vial also containsan amount of stérile water for injection; and the final concentration of the sulfon*amide sodium sait is between about 1 and 250 mg/mL.
73. The pharmaceutical composition of claim 53 that is formulated as5 a tabiet or capsule.
74. The compsition of claim 72, wherein the compound is N2-{3-hydroxy-2,4,6-trimethyl)phenyl-3-(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl-2-thiophenecarboxamide.
75. A composition of claim 73, further comprising an enteric coating.
76. The compositon of claim 73, wherein the coating is selected from cellulose acetate phthalate, polyethyiene glycol, polyoxyethylene sorbitan, castoroil, ethyl cellulose pseudolatex, phenyl salicylate, n-butyl stéarate, stearic acidand carnuba wax.
77. A sulfonamide or pharmaceutically acceptable sait, acid or ester 15 thereof of claim 1, wherein Ar’ selected from the group consisting of isoxazolyl,pyridazinyl, thiazolyl, pyrimidinyl and phenyl groups.
78. A sulfonamide or pharmaceutically acceptable sait, acid or esterthereof of claim 6, wherein Ar1 selected from the group consisting of isoxazolyl,pyridazinyl, thiazolyl, pyrimidinyl and phenyl groups. 20
79. A sulfonamide or pharmaceutically acceptable sait, acid or ester thereof of claim 6, wherein Ar’ is a substitued or unsubstituted 3- or 5-isoxazolyl, benzo-1,2,7-thiadiazol-4-yl, 2-pyrazinyl or benzo-1,2,7-oxadiazol-4-ylgroup, and the substituents are H, NH2, halide, CH3, CHaO or another aromaticgroup. 25
80. A sulfonamide or pharmaceutically acceptable sait, acid or ester thereof of claim 1, wherein: Ar1 is a substitued or unsubstituted 3- or 5-isoxazolyl, benzo-1,2,7-thiadiazol-4-yl, 2-pyrazinyl or benzo-1,2,7-oxadiazol-4-ylgroup, and the substituents are independently selected from H, NH2, halide, CH3, CH3O or another aromatic group; R11 contains 1-6 carbon atoms; and 20 R® is selected from the group consisting of H or substituted or unsubstituted lower alkyl.
-165-
sîSS’
81. Use of a sulfonamide or a pharmaceuticaily acceptable sait, acid or ester thereof of claim 1 for the formulation of a médicament for the treatment ofendothelin-mediated disorders.
82. Use of a sulfonamide or a pharmaceuticaily acceptable sait, acid orester thereof of claim 1 for the treatment of endothelin-mediated disorders.
83. A sulfonamide compound of formula (A): Ar— SO- N— Ar’i 10 15 20 or a pharmaceuticaily acceptable sait, acid or ester thereof, wherein: Ar’ is a substituted with one or more substituents or an unsubstituted monocyclic or polycyclic aryl or heteroaryl group in which each substituent isindependently selected from the group consisting of H, NH2, halide,pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl,alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl,haloaryl, and carbonyl, in which the aryl and alkyl portions are unsubstituted orsubstituted with any of the preceeding groups, and straight or branched chainsof from about 1 up to about 12 carbons; Ar2 has the formula:
in which M is {CH2)mC(O)(CH2)r, {CH2)wC(O)NH(CH2)r, (CH2)m(CH = CH)(CH2)„(CH2)mC(OKCH2)tNH{CH2)r, (CHJJCH = CH)(CH2}„ C = N(OH|(CH2)„(CH2)mC(O)(CH = CH),NH(CH2)r, CH(OH)(CH2)„ CH(CH3)C(O)(CH2,„ -Ι6ό- 011024 CH(CH,)CiO;(CH.;,(CH=CH)(CH.i„ (CH.:., :CH;),O. :CH,!StOI„ whera.'n n isC(O)O, in which m, s and r are each indeoendently 0 to 6, preferabiy 0 to 3,more preferabiy M is (CH.)mC(OHCH,)„ (CH^CiOINHiCH.),, (CH,}rn(CH = CH)(CH,)r, (CH,)q,C(O)(CH2;5NH(CH-,),, (CH,)m(CH = CH)(CH,)„ C = N(OH)(CH,)r, CH(0H)(CH,)r, |CH:)r, ;CH,)rO, (CH,)S(O)„, C(O)O; anc R', R2, R3, R4 and R5 are each inoeoendently seiected fromfi) or (ii) as rcllows: (i) R!, R*, R3, R4 and R5 are each independenîly seiecteo fromamong H, OH, NHRj3DC, CONR3SR33 , NC;, cyano, halide, pseudohalide, alkyl,alkenyl, aikynyl, aryi, arylalkyl, heteroaryl, alkoxy, aikylamino, aikyithic,haloaikyl, alkyisulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenyitniç,alkenylamino, alkenvloxy, alkenyl sulfinyl, alkenyisulfonyl, alkoxycarbcnyl,3rylarninocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocar-bonyDalkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxynlkenyl,alkylsulfonylaminoalkyl, cyanoalkyl, acctyf, acetoxyalkyl, hydroxyalkyl, alkyoxy-alkoxy, hydroxyalkyl, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, suifonylchlorides, amino acids, hexoscs, O-glycosides, riboses, lower alkyl, CN,-(CH^CiOXCH,},, -(CH,)„ (CH,),N-!ower alkyl, -<CH2),C(O)NH2, a D-, L- orracémie amino acid, a primary or secondary amide, O-glycoside, a hexose orribose, — 5(O)2NH,, hydroxy, alkoxy, alkoxycarbonyl, acetoxyalkyl, — (CH2)XCOOH; — (CH2)XCOOH —, C02-lower alkyl, CN, heteroaryl, — COC(O)(CH2)XCH3, — (CH2)xN(CH3)2, a suifonyl chloride, S(O)2NHR‘j0, alkylaryl,alkylheteroaryl, C(O)NHR50, —(CH,),OH, -C(Q)N(H)N(H)M, or; (ii) at least two of R', R2, R3, R4 and R5, which substitute adjacentcarbons on the ring, together form alkylenedioxy, alkylenethioxyoxy oralkylenedithioxy, which is unsubstitutec or substituted by replacing one or morehydrogens with halide, loweraikyl, loweralkoxy or halo loweraikyl, and the othersof R1, R2, R3, R4 and R5 are seiected as in (i); and at least four of R’, R2, R3, R4 and R5 are not hydrogen, unless; (a) R’ and R3 are alkyl anc R5 is R20, which is seiected from thegroup consisting of aryl, heteroaryl, heterocycle, OH, CN, C(O)R'Ü, CO,R16, SH,S(O)nR,G in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an — J..« -il .1 Ht Ib X. -1ό7- 011024 O-giycoside, a sulfonyl chloride, — (Cri-),OH, NKOH, NR,2R15, NO,, N,, 0R’s,R'2NCOR'5 and CONR12R15, then R2 and R* may be H; or (b) wnen M is -CONHC(R'2)(R16)-, then R', R2, R3. R4 and R5 may ail be H; (c) wnen M is -COCHR'3-, Ar! is no: an isoxazolyl, R' is aikyl, andR3 and R4 form alkylenea'ioxy, îhen R2 and R5 may be H; R3a and R33 are sach independently selected from hydrogen, aikyl, aikenyi,alkynyl, aryi, haloaikyi alkylaryl, hetsrocycle, arylalkyl, aryialkoxy, alkoxy,aryloxy, cycioalkyl, cycloalkenyl and cycioalkynyl, and is preferably hvcrcgen,loweraikyl, loweraikoxy and lowernaloaikyl; Rb is H, or substituted or unsubstituted aikyl or aryi, preferably H orsubstitutcd or unsuostituted lower aikyl, more preferably H, metnyl orcarboxymethyl; X is S, O or NR'1, wnere R” contains up to about 30 carbon atcms and isselected from the group consisting of hydrogen, aikyl, alkcnyl, alkynyl, aryi,alkylaryl, heterocycie, aralkyl, aralkoxy, cycioalkyl, cycloalkenyl, cycloaikyny.,C(O)R'S and S(O)„R,s in which n is 0-2; R'5 is hydrogen, aikyl, alkcnyl, alkynyl, aryi, alkylaryl, heterocycie, ara.kyi,aralkoxy, cycioalkyl, cycloalkenyl, or cycioalkynyl; R” and R'5 are unsubstituted or are substitutcd with one or moresubstitucnts each selected independently from Z; Z is hydrogen, halide, pseudohalide, aikyl, alkoxy, alkenyl, alkynyl, ary.,amino acids, primary and secondary amides, O-glycosides, hexoses, riboses,alkylaryl, alkylheteroaryl, heterocycie, aralkyl, aralkoxy, cycioalkyl, cycloalkenyl,cycioalkynyl, OH, CN, C(Û)R'6, 0C(0)R'6, CO2R'6, OCO2R'S, SH, S(0)nR'5 inwhich n is 0-2, NHOH, NR’2R’6, NO2, N3, OR15, R,2NCOR'6 and CONR,2R'6; R'5 ishydrogen, aikyl, alkenyl, alkynyl, aryi, alkylaryl, heterocycie, aralkyl, araikoxy,cycioalkyl, cycloalkenyl, cycioalkynyl, chloride, NHR50, alkylaryl, alkylheteroarvi,or — (CH2)xOH; Rso is a substituent such as hydrogen, lower aikyl, or loweralkoxy; R'2, which is selected independently from R11 and Z, is selected fromaikyl, alkenyl, alkynyi, aryi, alkylaryl, heterocycie, aralkyl, aralkoxy, cycioalkyl,cycloalkenyl, cycioalkynyl, C(O)R'7 and S(O)nR'7 in which n is 0-2; R'7 is /✓s; -16S- 011024 hydrogsn, aikyl, alkenyi, aikynyl, aryl, alkvlaryl, hsterocycie, araikyl, aralkoxy,cycioaikyi, cycioalkenyï or cycioalkynyl; F': and F'G may together form alkyiene;each or R’2, F’5 and R’6 may be further suostituted with any group thcse se*forth for Σ; and further proviced that the ccmpouncs are not selected from the çroucconsisîing of: N-{4-chloro-3-methyl-5-isoxazoÎyl)-2-{3-cyanomethyi-2,41ë- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymcthvl-2,4,5- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyi-5-isox3Zolyl}-2-t3-cyano-2,4,o-trimetr.ylphenyi- aminocarbonyl,thiophene-3-sulfonamide; N-(4-chioro-3-mcthyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,S- trimethylphenylaminocarbonyl)thiophene-3-suifonamidc; N-(4-chioro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,5-trimethy!pr.enyi- aminocarbonyl}thiophene-3-sulfonamide; N-(4-chioro-3-methyl-5-isoxazolyl)-2-(3-methanesulfony!-2,4,6- trimethylphenylaminocarbonyllthiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-(2-hydroxyethyl)-2,4(6- trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyi)-2-(3-cyanomethyl-2,4,5- trimethylphenylacetylithiophene-3-sulfonamÎde; N-{4-chloro-3-methyl-5-isoxazoly,)-2-(3-hydroxymethyl-2,4,5- trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chIoro-3-methyl-5-isoxazolyl)-2-{3-cyano-2,4,6- trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-<3-methoxycarbonyl-2,4,6- trimethylphenyiacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazoiyl)-2-(3-carboxyl-2,4,6- trimethylphenylacetyl)thiophene-3-sulfonamide; N-{4-chlorO'3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,5- trimethylphenylacetyl)thiophene-3-sulfonamide; -169- 011024 r , N-(4-chloro-3-methyl-5-isox3Zolyl)-2-i3-(2-hydroxyethyl)-2,4,6- ÎrirnethylphenylacetYl)thioDhene-3-sulfonamia'e; N-{4-chioro-3-mexhyl-5-isoxazolyl)-2-{6-meÎhyl-2,3,4-trimethoxypnenyf- aminocarbonyi)thiophene-3-sulfonamide: 5 N-(4-chloro-3-meÎhyl-5-isoxazoiyl)-2-(6-acetyl-2,3,4-tnmeîhaxyphenyl- aminocarbonyl)thiophene-3-sulfor.arnide,· N-(4-chloro-3-meîhyl-5-isoxazolyl)-2-{6-methoxycarbonyl-2.3,4- trimetbaxyphsnylaminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-meTftyl-5-isoxazolyl)-2-f6-carboxyl-2,3,4-trifTistboxvphenvi-10 aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-i5oxazolyl)-2-(6-methanesulfonyl-2,3,4- •nmethoxyphcnylaminocarbanyl)thtophene-3-5ulfonamide; N-(4-chloro-3-mcthyl-5-isoxazolyl)-2-(6-cyanomethyl-2,3,4- trimethoxyphenyiaminacarbonyl>thtophcne-3-5ulfonamice; T 5 N-{4-chloro-3-methyl-5-i3cxazolyl)-2-(6-(2-hydroxyethyl)-2,3.4- trimethaxyphenylaminocarbonyl)thiophene-3-sulfonamidû; N-{4-chlaro-3-methy!-5-i3oxazolyl)-2-(6-cyano-2,3,4-trimet:hoxyphe.riyl' aminocarbonyl)thiophenc-3-5ulfonamidc,· N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-methyl-2,3,4-20 inmethoxyphenylaceÎyl)thiaphene-3-sulfonamidc; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-acetyl-2,3,4- trimethoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)'2-(6-merhoxycarbonyl-2,3,4- trimethoxyphenylacetyl)Îhiophene-3-suIfonamide; 25 N-(4-chloro-3-meÎhyl-5-isoxazolyl)-2-(6-carboxyl-2,3,4- trimGthoxyphenylacetyi)thiophcne-3-suifonamide; N-{4-chloro-3-meÎhyl-5-i5oxazolyi)-2-{6-methanesulfonyl-2,3,4- trimcthoxyphenylacetyl)thiophone-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyi)-2-{6-cyanomeÎhyl-2,3,4-30 tri m eth oxyphenyl ace tyi)thiophene-3-suif onamide; N-{4-chloro-3-meÎhyl-5-i3oxazolyi)-2-{6-{2-hydroxyethyli-2,3,4- trimethoxyphenylacetyl)thiophene-3-sulfonamide; -.,-ί joaai -173- 011024 N-(4-chloro-3-meÎhyi-5-isoxazalyl)-2-{6-methyi-3,4-(methylenedÎOxy)-2- methoxyphenylaminocarbonyl)Thiophene-3-sutfonamide; N-(4-chloro-3-methyl-5-isoxazoly(!-2-(6-acetYl-3,4-(meÎhyieneaioxy)-2- meÎhoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-!Soxazolyl)-2-(6-methoxycarbonyi-3,4-(methyler.e dioxy)-2-meÎhoxyphenyl3minocarbonyl)thiophene-3-suifonamide; N-(4-chloro-3-methyi-5-isoxazolyi)-2-(6-carboxyl-3,4-(meÎhylenedioxy)-2- methoxyphenylaminocarbonyl)thiophene-3-sulfonamide: N-(4-chloro-3-methyl-5-isoxazoÎyl)-2-(6-meÎhanesulfonyl-3,4-(rn ethylene-dioxy)-2-methoxyphenytaminocarbonyl)ihiophene-3-suironarnidc; N-(4-chloro-3-methyl-5-isoxazolyl)’2-(6’Cyanomethyl-3,4-(meÎhy!ene- aioxy)-2-methoxyphünyiaminocarbonyl)Îhiopnene-3-sulfonamidc; N-(4-chloro-3-meÎhyl-5-isoxazclyl)-2-(6-(2-hydroxyethyi)-3,4-(methylcne- diaxy)-2-methoxyphenyiaminocarbonyl)thiophenc-3-sulion.-]rnide,· N-(4-chioro-3-methyl-5-isoxazolyl)-2-(6-cyano-3,4-{methylenedioxy)-2- methoxyphcnylaminocarbonyl)t:hiophene-3-sulfonamide; N-{4-chloro-3-mcthyl-5-isoxazolyl)-2-(2,6-dimethyl-3,4-(methylene- dioxy)phcnylaminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-i50xazolyl)-2-(6-acetyl-3,4-(methylenedioxy)-2- methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methoxycarbonyl-3,4-(me*bylene- dioxy)-2-methylphenyiaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-carboxyl-3,4-{meÎhylenedicxy)-2- methylphenylaminocarbonyl)thiaphene-3-sulfonamide; N-(4-chioro-3-meÎhyl-5-isoxazolyf)-2-(6-methanesLiifonyl-3,4-( methyle ne-□ioxy)-2-methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyanomethyl-3,4-(methylene- dioxy)-2-methylphenylaminocarbanyl)Îhiophene-3-suifonamide; N-(4-chloro-3-meÎhyl-5-i50xazolyl)-2-(6-(2-hydroxyethyl)-3,4-(meÎhyÎene- Gioxy)-2-methyiphenylaminocarbonyl)thiophene-3-sulfonamide; N-{4-chloro-3-meÎhyl-5-isoxazoiyl)-2-(6-cyano-3,4-<rneîhylenedioxy)-2- meÎhylphenyiaminocarbonyl)thiophene-3-sulfonamide; ί '4 011024 -171- N-(4-chioro-3-methyl-5-isoxazolyi)-2-{6-methoxy-3.4-(rnethylenedioxyJ-2- methylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-cyano-3,4.-{rnethylenedioxy)-6- methylphenylaminocarbonyl)thiophene-3-sulfonamide; 5 N-(4-chloro-3-meîhyl-5-isoxazolyl)-2-{2-cyano-3,4-(rnethytenedioxy!-6- methoxyphenylaminocarbonyl)Îhiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-acetyl-3,4-(methylenedioxy)-6- methylphenylaminocarbonyl)thiophene-3-suifonamide; N-(4-chloro-3-methyi-5-isoxazolyl)-2-(2-acstyl-3,4-(methyfenedioxy)-c-10 mGthoxyphenylaminocarbonyi)Îhiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-methyl-3,4-(methylenedioxy}-2- mcthoxyphenylacetyi)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-acetyl-3,4-(methylenedioxyj-2- mcthoxyphenylacetyl)thiophene-3-sulfonamidc; 15 N-{4-chloro-3-mcthyl-5-isoxazolyl)-2-(6-mcthoxycarbonyl-3,4-(methylene- dioxY)-2-methoxyphenylacetyl)thiophene-3-sulfonamidc; N-(4-chloro-3-mcthyl-5-isoxazolyl)-2-{6-carboxyl-3,4-(mcthylenedioxy)-2- methoxyphenylacGtyl)thiophcne-3-sulfonamide; N-{4-chloro-3-mcÎhyl-5-isoxazolyl)-2-{6-methanesu(fonyl-3,4-(meÎhylen5-20 dioxy)-2-methoxyphenylacetyl)Îhiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{6-cyanomethyl-3,4-(methylene- dioxy)-2-methoxyphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-meÎhyl-5-îsoxazolyl)-2-(6-(2-hydroxyethyl)-3,4-(methyiene- dioxy)-2-meÎhoxyphenylaceîyl)thiophene-3-sulfonamide; 25 N-(4-chloro-3 -methyl-5-isoxazolyl)-2-{6-cyano-3,4-(methylenedioxy)-2- methoxyphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(2,6-dimethyl-3,4-(rnethylene- dioxy)phenyiacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{6-acetyl-3,4-(meÎhylenedioxy)-2-30 metby)phenyiacetyl)thiophene-3-sulfonamide; Ν-{4-οήΙθΓθ-3-ΓηβΐΓιγΙ-5-ί2θΧ3ΖθΙγΙ)-2-(6-Γη6Χήσχγα3^οηγΙ-3,4-{Γη6ΐΗγΐ6Π6- dioxy)-2-methylphenylacetyl)t:hiophcne-3-sulfc>namide; * J»,,, uLàiJfeak U » 1 M j 1 I » 4 ,! G11G24 -172- « t r N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-carboxyl-3,4-(rneÎnylenedioxy)-2 methylpnenylacetyi)thiophene-3-suIfor,amide; Ν-(4-οΝθΓα-3-ΓηεΐΗγΙ-5-(5σχ3ΖθΙγΙ)-2-(6-Γη6ΐΐΊ3ΠθειιΙίοπγΙ-3,4-(ΓηβΐΗγ(θΠ6· dioxy)-2-methylphenylacetyl)thiophene-3-sulfonamide; 5 N-{4-chloro-3-mcthyi-5-isoxazolyl)-2-(6-cyanomethyi-3,4-<rnethyiene- dioxy)-2-methylphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(6-(2-hydroxyethyl)-3,4-(methyiene- dioxy)-2-methylphenylacetyl)thiophene-3-sulfanamide; N-{4-chloro-3-rnethyi-5-isoxazolyl,-2-(6-cyano-3,4-(methyfenedioxy)-2-10 methylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{6-rncthoxy-3,4-((Tiethylenedioxy)-2 methylphenylacetyOthiophene-S-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-{2-cyano-3,4-(methyienedioxy)-6- methylphenylacetyl)thiophene-3-sulfonamidc; 15 ' N-(4-chloro-3-methy!-5-isoxazolyi)-2-{2-cyano-3,4-(methyienedioxy)-ô- methoxyphenylaceÎyl)thiophene-3-sulfanamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-acctyl-3,4-(methylencdioxy)-6- meÎhylphenylacetyl)thiophene-3-sulfonamide; N-{4-chloro-3-methyl-5-isoxazolyl)-2-(2-acetyl-3,4-(methylenedioxy)-6-20 methoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-meÎhyl-5-isoxazolyl)-2-(2,6-bis(cyanomethyl)-3,4- (methylenediaxy)phenylaminocarbonyl)Îhiophene-3-sulfonarnide.
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US20020091272A1 (en) 2002-07-11
DE69729803T2 (de) 2005-07-14
AU4505997A (en) 1998-04-17
US6420567B1 (en) 2002-07-16
KR100372195B1 (ko) 2003-02-14
CZ85499A3 (cs) 1999-06-16
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