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US 6,387,915 B2Granted
Isoxazole-sulfonamide endothelin antagonists
AssigneePfizer Inc.
InventorsBernard Joseph Banks, Nathan Anthony Logan Chubb, James John Eshelby, Michael Stephen Pacey, Darren John Schulz
Life of this patent
Estimating the term…
Abstract
Isoxazole-sulfonamide endothelin antagonists of formula (I) below having good affinity for endothelin receptors and selectivity for ETA over ETB are described herein. Such compounds are useful in the treatment of conditions mediated by endothelin, in particular, conditions mediated by endothelin ETA.
Claims32
A compound of formula (I)
- wherein
- R1 is
- (a) a phenyl group,
- (b) a 5- or 6-membered heterocyclic group containing one to three heteroatoms each independently selected from the group consisting of N, O and S, said heterocyclic group being optionally fused to a benzo group,
- (c) CHR6CHR7Ph, or
- (d) CR6═CR7Ph,
- where groups (a), (b), (c) and (d) are optionally each independently substituted with one to three substituents selected from the group consisting of halo, C1-6 alkyl optionally substituted by OH, halogen, NR4R5, OCOR4, CO2R4, CN, O(C1-6 alkyl optionally substituted by one or more halogens), and CO2R4, where R4 and R5 are each independently H or C1-6 alkyl optionally substituted by one or more halo, and R6 and R7 are each independently H or C1-3 alkyl;
- R2 is aryl1 or het1;
- and
- R3 is H, C1-6 alkyl, C(O)R4, CONHaryl1, CONHhet1, aryl1 and het1;
- where aryl1 is a phenyl or a naphthyl group, said phenyl and said naphthyl groups being optionally substituted with one to three substituents each independently selected from the group consisting of C1-3 alkyl, CF3, halo, C1-3 alkoxy, OCF3, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(═NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2,
- het1 is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting N, O and S, said heterocyclic group being optionally fused to a benzo group and optionally substituted with one to three substituents each independently selected from the group consisting of C1-3 alkyl, CF3, halo, C1-3 alkoxy, (C1-5 alkyl)OH, (C1-5 alkyl)CO2H, CF3O, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(═NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2, with the proviso that when R3 is het1, the het1 group is linked to the adjacent O atom by a carbon atom,
- het2 is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting of N, O and S,
- and p is0, 1 or 2;
- or a pharmaceutically acceptable derivative thereof.
12 more elements
A pharmaceutical composition comprising
- (a) a compound of formula (I)
- wherein
- R1 is
- (a) a phenyl group,
- (b) a 5- or 6-membered heterocyclic group containing one to three heteroatoms each independently selected from the group consisting of N, O and S, said heterocyclic group being optionally fused to a benzo group,
- (c) CHR6CHR7Ph, or
- (d) CR6═CR7Ph,
- where groups (a), (b), (c) and (d) are optionally each independently substituted with one to three substituents selected from the group consisting of halo, C1-6 alkyl optionally substituted by OH, halogen, NR4R5, OCOR4, CO2R4, CN, O(C1-6 alkyl optionally substituted by one or more halogens), and CO2R4, where R4 and R5 are each independently H or C1-6 alkyl optionally substituted by one or more halo, and R6 and R7 are each independently H or C1-3 alkyl;
- R2 is aryl1 or het1;
- and
- R3 is H, C1-6 alkyl, C(O)R4, CONHaryl1, CONHhet1, aryl1 and het1;
- where aryl1 is a phenyl or a naphthyl group, said phenyl and said naphthyl groups being optionally substituted with one to three substituents each independently selected from the group consisting of C1-3 alkyl, CF3, halo, C1-3 alkoxy, OCF3, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(═NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2,
- het1 is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting N, O and S, said heterocyclic group being optionally fused to a benzo group and optionally substituted with one to three substituents each independently selected from the group consisting of C1-3 alkyl, CF3, halo, C1-3 alkoxy, (C1-5 alkyl)OH, (C1-5 alkyl)CO2H, CF3O, OH, NO2, CN, NR4R5, COR4, CO2R4, CONR4R5, S(O)p(C1-3 alkyl), CH2NR4R5, NR4COR5, COCF3, CH2OH, S(O)pCF3, C(═NH)NH2, C2-3 alkynyl, C2-3 alkenyl, phenyl and het2, with the proviso that when R3 is het1, the het1 group is linked to the adjacent O atom by a carbon atom,
- het2 is a 5- to 7-membered fully saturated, partially unsaturated, or fully unsaturated heterocyclic group containing one to three hetero-atoms each independently selected from the group consisting of N, O and S,
- and p is 0, 1 or 2;
- or a pharmaceutically acceptable derivative thereof;
- and
- (b) a pharmaceutically-acceptable adjuvant, diluent or carrier.
15 more elements
Dependencies are inferred from the claim text.