Patent EA-004146-B1 (EA)
Title: Sulfonamides and derivatives thereof that modulate the activity of endothelin
Inventor: WU CHENGDE
IPC: C07D261/10
Filed: 1997-09-26
Abstract: 1. A sulfonamide compound of formula (A): or a pharmaceutically acceptable salt, acid or ester thereof, wherein: Ar<1> has the formula wherein R<A> R<B> is each independently selected from (C1-C12)alkyl, (C2-C6)alkynyl, halo(C1-C6)alkyl, halide, pseudohalide and H, unless that R<B> is not halide; Ar<2> has the formula: or in which M is C(O)NH, C(O)CH2, CH=CH, (CH2)x, and x is 0-3; and R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from (i) or (ii) as follows: (i) R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from among H, OH, NHR<38>, CONR<38>R<39>, NO2, cyano, halide, pseudohalide, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, (C4-C16)aryl (C1-C12)alkyl, hetero(C4-C16)aryl, (C1-C12)alkoxy, (C1-C12)alkylamino, (C1-C12)alkylthio, halo(C1-C12)alkyl, (C1-C12)alkylsulfinyl, (C1-C12)alkylsulfonyl, (C1-C12)alkoxycarbonyl, (C1-C12)alkylcarbonyl, (C2-C12)alkenylthio, (C2-C12)alkenylamino, (C2-C12)alkenyloxy, (C2-C12)alkenylsulfinyl, (C2-C12)alkenylsulfonyl, (C1-C12)alkoxycarbonyl, (C4-C16)arylaminocarbonyl, (C1-C12)alkylaminocarbonyl, aminocarbonyl, ((C1-C12) alkyl-aminocarbonyl) (C1-C12)alkyl, acetoxy, carboxyl, carboxy(C1-C12)alkyl, carboxy(C2-C12)alkenyl, (C1-C12)alkylsulfonylamino(C1-C12)alkyl, cyano(C1-C12)alkyl, acetyl, acetoxy(C1-C12)alkyl, hydroxy(C1-C12)alkyl, (C1-C12)alkoxy(C1-C12)alkoxy, (acetoxy) (C1-C12)alkoxy, (hydroxy) (C1-C12)alkoxy, formyl, sulfonylchlorides, amino acids, hexoses, O-glycosides, riboses, (C1-C6)alkyl, -(CH2)xC(O)(CH2)x, -(CH2)x, (CH2)xN-(C1-C6)alkyl,-(CH2)xC(O)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, -S(O)2NH2, (C1-C12)alkoxy, (C1-C12)alkoxycarbonyl, -(CH2)xCOOH, -(CH2)xCOOH-, CO2-(C1-C6)alkyl, hetero(C4-C16)aryl, -COC(O)(CH2)xCH3, -(CH2)xN(CH3)2, a sulfonylchloride, S(O)2NHR<50>, (C1-C12)alkyl(C4-C16)aryl, (C1-C12)alkylhetero(C4-C16)aryl, C(O)NHR<50>, -(CH2)xOH, and -C(O)N(H)N(H)R<50>, or; (ii) at least two of R<1>, R<2>, R<3>, R<4> and R<5>, 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, (C1-C6)alkyl, (C1-C6)alkoxy or halo(C1-C6)alkyl, and the others of R<1>, R<2>, R<3>, R<4> and R<5> are selected as in (i); and at least four of R<1>, R<2>, R<3>, R<4> and R<5> are not hydrogen, unless: (a) R<1> and R<3> are (C1-C12)alkyl groups and R<5> is R<20>, which is selected from the group consisting of (C4-C16)aryl, hetero(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, OH, CN, C(O)R<16>, CO2R<16>, SH, S(O)nR<16> in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, O-glycoside, a sulfonylchloride, (CH2)xOH, NHOH, NR<12>R<16>, NO2, N3, OR<16>, R<12>NCOR<16> and CONR<12>R<16>, then R<2> and R<4> may be H; R<38> and R<39> are each independently selected from hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, halo(C1-C12)alkyl, (C1-C12)alkyl(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C16)aryl(C1-C12)alkyl, (C4-C16)aryl(C1-C12)alkoxy, (C1-C12)alkoxy, (C4-C16)aryloxy, cyclo(C3-C12)alkyl, cyclo(C4-C16)alkenyl and cyclo(C8-C12)alkynyl, and is preferably hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy and halo(C1-C6)alkyl; R<6> is H, or substituted or unsubstituted (C1-C12)alkyl or (C4-C16)aryl, preferably H or substituted or unsubstituted (C1-C6)alkyl, more preferably H, methyl or carboxymethyl; X is S, O or NR<11>, where R<11> contains up to about 30 carbon atoms and is selected from the group consisting of hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, (C1-C12)alkyl(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C12)aryl(C1-C12)alkyl, (C4-C12)aryl(C1-C12)alkoxy, cyclo(C3-C12)alkyl, cyclo(C4-C12)alkenyl, cyclo(C8-C12)alkynyl, C(O)R<15>, and S(O)nR<15> in which n is 0-2; R<15> is hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, (C1-C12)alkyl, (C4-C6)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C12)aryl(C1-C12)alkyl, (C4-C12)aryl(C1-C12)alkoxy, cyclo(C3-C12)alkyl, cyclo(C4-C12)alkenyl, or cyclo(C8-C12)alkynyl; R<11> and R<15> are unsubstituted or are substituted with one or more substituents each selected independently from Z; Z is hydrogen, halide, pseudohalide, (C1-C12)alkyl, (C1-C12)alkoxy, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, amino acids, primary and secondary amides, O-glycosides, hexoses, riboses, (C1-C12)alkyl(C4-C16)aryl, (C1-C12)alkylhetero(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C12)aryl(C1-C12)alkyl, (C4-C12)aryl(C1-C12)alkoxy, cyclo(C3-C12)alkyl, cyclo(C4-C12)alkenyl, cyclo(C8-C12)alkynyl, chloride, NHR<50>, OH, CN, C(O)R<16>, OC(O)R<16>, CO2R<16>, OCO2R<16>, SH, S(O)nR<16> in which n is 0-2, NHOH, NR<12>R<16>, NO2, N3, OR<16>, R<12>NCOR<16> and CONR<12>R<16>; R<16> is hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, (C1-C12)alkyl(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C12)aryl(C1-C12)alkyl, (C4-C12)aryl(C1-C12)alkoxy, cyclo(C3-C12)alkyl, cyclo(C4-C12)alkenyl, cyclo(C8-C12)alkynyl, chloride, NHR<50>, (C1-C12)alkyl(C4-C16)aryl, (C1-C12)alkylhetero(C4-C16)aryl, or -(CH2)xOH; R<50> is a substituent such as hydrogen, (C1-C6)alkyl, or (C1-C6)alkoxy; R<12>, which is selected independently from R<11> and Z, is selected from hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, (C1-C12)alkyl(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C12)aryl(C1-C12)alkyl, (C4-C12)aryl(C1-C12)alkoxy, cyclo(C3-C12)alkyl, cyclo(C4-C12)alkenyl, cyclo(C8-C12)alkynyl, C(O)R<17> and S(O)nR<17> in which n is 0-2; R<17> is hydrogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C4-C16)aryl, (C1-C12)alkyl(C4-C16)aryl, heterocycle, comprising one ring, a plurality of rings or condensed rings, optionally two or three rings and one or two heteroatoms in a ring or in rings, (C4-C12)aryl(C1-C12)alkyl, (C4-C12)aryl(C1-C12)alkoxy, cyclo(C3-C12)alkyl, cyclo(C4-C12)alkenyl, or cyclo(C8-C12)alkynyl; R<12> and R<16> may together form alkylene; each of R<12>, R<15> and R<16> may be further substituted with any group those set forth for Z; and further provided that the compounds are not selected from the group consisting of: N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethyl)-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chioro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-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-trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfony)-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(2-hydroxyethyl)-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methyl-2,3,4-trimethoxyphenyl-aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-acetyl-2,3,4-trimethoxyphenyl-aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methoxycarbonyl-2,3,4-trimethoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-carboxyl-2,3,4-trimethoxyphenyl-aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methanesulfonyl-2,3,4-trimethoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyanomethyl-2,3,4-trimethoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-(2-hydroxyethyl)-2,3,4-trimethoxyphenylaminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-cyano-2,3,4-trimethoxyphenyl-aminocarbonyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-methyl-2,3,4-trimethoxyphenylacetyl)thiophene-3-sulfonamide; 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-methoxycarbonyl-2,3,4-trimethoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6-carboxyl-2,3,4-trimethoxyphenylacetyl)thiophene-3-sulfonamide; N-(4-chloro-3-methyl-5-isoxazolyl)-2-(