Patent EA-003993-B1 (EA)
Title: Sulfonamides for treatment of endothelin-mediated disorders
Inventor: WU CHENGDE
IPC: A61K31/421
Filed: 1998-04-02
Abstract: 1. A pharmaceutically acceptable salt of a compound that has formula (I): wherein: Ar<1> is a group selected from unsubstituted or substituted five membered heteroaromatic rings; Ar<2> is selected from the group consisting of unsubstituted or substituted thienyl and thianaphthyl; and the salts are selected from the group consisting of pharmaceutically acceptable salts of alkali metals and salts of mineral acids. 2. The pharmaceutically acceptable salt of claim 1, wherein Ar<2> is thienyl. 3. The pharmaceutically acceptable salt of claim 1 that is an alkali metal salt. 4. The pharmaceutically acceptable salt of claim 1 that is a sodium salt. 5. The pharmaceutically acceptable salt of any of claims 1-3, wherein Ar<1> is selected from the group consisting of isoxazolyl and thiazolyl. 6. The pharmaceutically acceptable salt of any of claims 1-5, wherein Ar<2> has the formula IV: X is S, R<8> is (CH2)rC(O)(CH2)nR<18>, CO2R<18> or (CH2)rC(O)NH(CH2)nR<18>, wherein n and r is independently 0 to 6; R<9> and R<10> are each independently selected as follows from (i) or (ii): (i) R<9> and R<10>, which each contain hydrogen or up to about 50 carbon atoms, are each independently selected from hydrogen, halide, pseudohalide, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C5-C10)aryloxy, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl, cyclo(C3-C10)alkynyl, OH, CN, C(O)R<18>, acetoxy-(CH=CH)-, CO2R<18>, SH, (CH2)rC(O)(CH2)nR<18>, (CH2)r(CH=CH)s(CH2)nR<18>, (CH2)rC(O)(CH=CH)s(CH2)nR<18>, (CH2)r(CH=CH)sC(O)(CH2)nR<18>, (CH2)rNH(CH=CH)s(CH2)nR<18>, (CH2)r(CH=CH)sNH(CH2)nR<18>, (CH2)rC(O)NH(CH2)nR<18>, C(O)(CH2)rNH(CH2)nR<18>, (CH2)rNH(CH2)nR<18>, (CH2)rR<18>, S(O)mR<18>, in which m is 0-2, s, n and r are each independently 0 to 6, HNOH, NR<18>R<19>, NO2, N3, OR<18>, R<19>NCOR<18> and CONR<19>R<18>, in which R<19> is selected from hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C1-C6)alkyl(C5-C10)aryl, (C1-C)alkoxy, (C5-C10)aryloxy, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl, cyclo(C3-C10)alkynyl, C(O)R<20> and S(O)nR<20>, in which n is 0-2; R<18> and R<20> are independently selected from hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, hetero(C5-C10)aryl, (C1-C6)alkyl(C5-C10)aryl, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C1-C6)alkoxy, (C5-C10)aryloxy, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl and cyclo(C3-C10)alkynyl; any of the groups set forth for R<9> and R<10> are unsubstituted or substituted with any substituents set forth for Z, which Z is hydrogen, halide, pseudohalide, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C5-C10)aryloxy, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl, cyclo(C3-C10)alkynyl, OH, CN, C(O)R<21>, CO2R<21>, SH, S(O)n R<21> in which n is 0-2, NHOH, NR<22>R<21>, NO2, N3, OR<21>, R<22>NCOR<21> or CONR<22>R<21>; R<22> is selected from hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C1-C6)alkyl(C5-C10)aryl, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(C1-C6)alkyl, (C1-C6)alkoxy, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl, cyclo(C3-C10)alkynyl, C(O)R<23> and S(O)n R<23> in which n is 0-2; and R<21> and R<23> are independently selected from hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, ((C1-C6)alkyl(C5-C10)aryl, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl and cyclo(C3-C10)alkynyl; or (ii) any two of R<9> and R<10> with the carbon to which each is attached form aromatic ring, containing from about 3 to about 16 members in a ring that is substituted with one or more substituents, each substituent is independently selected from Z. 7. The pharmaceutically acceptable salt of claim 6, wherein Ar<1> is an isoxazolyl. 8. The pharmaceutically acceptable salt of any of claims 1-6, wherein the compound has any of formulae V: wherein: R<1> and R<2> are either (i), (ii) or (iii) as follows: (i) R<1> and R<2> are each independently selected from H, NH2, NO2, halide, pseudohalide, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C5-C10)ara(C1-C6)alkyl, hetero(C5-C10)aryl, (C1-C6)alkoxy, (C1-C6)alkylamino, (C1-C6)alkylthio, (C1-C6)alkyloxy, halo(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, (C5-C10)aryloxy, (C5-C10)arylamino, (C5-C10)arylthio, (C5-C10)arylsulfonyl, (C5-C10)arylsulfonyl, halo(C1-C6)alkyl, halo(C5-C10)aryl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, aminocarbonyl, (C5-C10)arylcarbonyl, formyl, substituted or unsubstituted amido and substituted or unsubstituted ureido groups, in which the(C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the (C5-C10)aryl portions contain from about 4 to about 16 carbons, except that R<2> is not halide or pseudohalide; or (ii) R<1> and R<2> together form -(CH2)n, where n is 3 to 6; or (iii) R<1> and R<2> together form 1,3-butadienyl. 9. The pharmaceutically acceptable salt of claim 6, wherein: if R<9> and R<10> are each independently selected from (i), then each is selected with the proviso that if R<8> is CO2R<18> or (CH2)rC(O)NH(CH2)nR<18> and R<18> is an (C5-C10)aryl group containing 5 or 6 members, then the (C5-C10)aryl group has at least two substituents; and if R<9> and R<10> are each independently selected from (ii), then each is selected with the proviso that Ar<2> is not 5-halo-3-(C1-C6)alkylbenzo[b]thienyl. 10. The pharmaceutically acceptable salt of claim 8, wherein R<8> is phenylacetyl or phenylaminocarbonyl. 11. The pharmaceutically acceptable salt of claim 10, wherein R<9> and R<10> are each hydrogen. 12. The pharmaceutically acceptable salt of claim 8, wherein: R<1> is H, -(C1-C6)alkyl, halide or pseudohalide; and R<2> is -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl or hydrogen. 13. The pharmaceutically acceptable salt of claim 12, wherein R<1> is Br, Cl or -(C1-C6)alkyl and R<2> is -(C1-C6)alkyl, -(C1-C6)haloalkyl, or hydrogen. 14. The compound of claim 8, wherein: R<9> and R<10> are each independently selected from H, halide, pseudohalide, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C5-C10)aryloxy, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl, cyclo(C3-C10)alkynyl, OH, CN, C(O)R<18>, (OAc)CH=CHR<18>, CO2R<18>, SH, CH2)rC(O)(CH2)nR<18>, (CH2)r(CH=CH)s(CH2)nR<18>, (CH2)rC(O)(CH=CH)s(CH2)nR<18>, (CH2)r(CH=CH)sC(O)(CH2)nR<18>, (CH2)rNH(CH=CH)s(CH2)nR<18>, C=N(OH)(CH2)rR<18>, (CH2)r(CH=CH)sNH(CH2)nR<18>, (CH2)rC(O)NH(CH2)nR<18>, C(O)(CH2)rNH(CH2)nR<18>, (CH2)rNH(CH2)nR<18>, (CH2)rR<18>, S(O)mR<18>, in which m is 0-2, s, n and r are each independently 0 to 6, HNOH, NR<18>R<19>, NO2,N3, OR<18>, R<19>NCOR<18> and CONR<19>R<18>, in which R<19> is selected from hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, (C1-C6)alkyl(C5-C10)aryl, (C1-C)alkoxy, (C5-C10)aryloxy, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl, cyclo(C3-C10)alkynyl, C(O)R<20> and S(O)nR<20>, in which n is 0-2; R<18> and R<20> are independently selected from hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C5-C10)aryl, hetero(C5-C10)aryl, (C1-C6)alkyl(C5-C10)aryl, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C1-C6)alkoxy, (C5-C10)aryloxy, (C5-C10)ara(C1-C6)alkyl, (C5-C10)ara(C1-C6)alkoxy, cyclo(C3-C12)alkyl, cyclo(C3-C10)alkenyl and cyclo(C3-C10)alkynyl. 15. The pharmaceutically acceptable salt of claim 14, wherein R<8> is selected with the proviso that if R<8> is (CH2)rC(O)NH(CH2)nR<18>, and R<18> is phenyl, the phenyl group is substituted at least two positions. 16. The pharmaceutically acceptable salt of claim 14, wherein R<9> and R<10> are each independently hydrogen, halide, (C1-C6)alkyl, or halo(C1-C6)alkyl. 17. The pharmaceutically acceptable salt of any of claims 1-8 and 16, wherein Ar<2> is phenylaminocarbonylthienyl, or acetoxystyrylthienyl. 18. The pharmaceutically acceptable salt of claim 17, wherein Ar<2> is selected with the proviso that, when Ar<2> is a phenylaminocarbonylthienyl, the phenyl group is substituted with at least two substituents selected from Z, which is hydrogen, halide, pseudohalide, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl (C2-C6)alkynyl, (C5-C10)aryl, (C5-C10)aryloxy, heterocyclyl, containing one ring, a plurality of rings or condensed rings, usually two or three rings, and one or two heteroatoms in a ring or in rings, (C5-C10)ara(