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US 2001/0056088 A1Published application
Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
AssigneeAmerican Cyanamid Company
InventorsJeremy I. Levin, James M. Chen
Life of this patent
Estimating the term…
Abstract
Hydroxamic acids having the formula 1 are useful in treating disease conditions mediated by TNF-α, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.
Claims15
Hydroxamic acids having the formula:
- 24
- where the C(═O)NHOH moiety and the —NR5— moiety are bonded to adjacent carbons of group A;
- wherein A is phenyl, naphthyl, or phenyl fused to a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5 to 9 membered saturated or unsaturated heterocycloalkyl ring having 1 or 2 heteroatoms selected from N, NR9, O or S, or a heteroaryl ring having 5-10 members and from 1-3 heteroatoms selected from N, NR9, O or S;
- X is SO2 or —P(O)R10;
- Y is phenyl, naphthyl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;
- Z is O, NH,CH2 or S;
- R5 is hydrogen or alkyl of 1-6 carbon atoms;
- or R5—N—A—, can form a benzazepine, benzoxazepine, benzothiazepine, benzodiazepine, benzazocine, benzodiazocine, benzoxazocine or benzothiazocane ring which may be optionally fused to another benzene ring;
- R6 and R7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, —CCH;
- and R8 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- R9 is hydrogen, phenyl, naphthyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms;
- and R10 is phenyl, naphthyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- or a pharmaceutically acceptable salt thereof.
10 more elements
A compound of the formula:
- 25
- wherein R6 and R7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, —CCH;
- and R8 is alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S.
A compound of the formula
- 26
- wherein R6 and R7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, —CCH;
- R8 is of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- and
- J is fluorine, bromine, chlorine, 1,2,4triazolyl, benzotriazolyl or imidazol-yl.
2 more elements
A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula
- 27
- where the C(═O)NHOH moiety and the —NR5— moiety are bonded to adjacent carbons of group A;
- wherein A is phenyl, naphthyl, or phenyl fused to a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5 to 9 membered saturated or unsaturated heterocycloalkyl ring having 1 or 2 heteroatoms selected from N, NR9, O or S, or a heteroaryl ring having 5-10 members and from 1-3 heteroatoms selected from N, NR9, O or S;
- X is SO2 or —P(O)R10;
- Y is phenyl, naphthyl or 5-10 membered heteroaryl having from 1 to 3 heteroatoms selected from N, NR9, O or S;
- with the proviso that X and Z may not be bonded to adjacent atoms of Y;
- Z is O, NH,CH2 or S;
- R5 is hydrogen or alkyl of 1-6 carbon atoms;
- or R5—N—A—, can form a benzazepine, benzoxazepine, benzothiazepine, benzodiazepine, benzazocine, benzodiazocine, benzoxazocine or benzothiazocane ring which may be optionally fused to another benzene ring;
- R6 and R7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, —CCH;
- R8 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- R9 is hydrogen, phenyl, naphthyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms;
- and
- R10 is phenyl, naphthyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- or a pharmaceutically acceptable salt thereof.
12 more elements
A pharmaceutical composition comprising a compound having the formula
- 28
- where the C(═O)NHOH moiety and the —NR5— moiety are bonded to adjacent carbons of group A;
- wherein A is phenyl, naphthyl, or phenyl fused to a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5 to 9 membered saturated or unsaturated heterocyclo-alkyl ring having 1 or 2 heteroatoms selected from N, NR9, O or S, or a heteroaryl ring having 5-10 members and from 1-3 heteroatoms selected from N, NR9, O or S;
- X is S or —P(O)R10;
- Y is phenyl, naphthyl or 5-10 membered heteroaryl having from 1 to 3 heteroatoms selected from N, NR9, O or S;
- with the proviso that X and Z may not be bonded to adjacent atoms of Y;
- Z is O, NH, CH2 or S;
- R5 is hydrogen or alkyl of 1-6 carbon atoms;
- or R5—N—A—, can form a benzazepine, benzoxazepine, benzothiazepine, benzodiazepine, benzazocine, benzodiazocine, benzoxazocine or benzothiazocane ring which may be optionally fused to another benzene ring;
- R6 and R7 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, —CN, —CCH;
- R8 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- R9 is hydrogen, phenyl, naphthyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms;
- and
- R10 is phenyl, naphthyl, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, 5 to 10 membered heteroaryl having from 1 to 3 heteoatoms selected from N, NR9, O or S, or 5 to 9 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR9, O or S;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12 more elements
Dependencies are inferred from the claim text.