Patent EA-003585-B1 (EA)
Title: alpha-HYDROXY, -AMINO AND -FLUORO DERIVATIVES OF beta-SULPHONYL HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASES INHIBITORS
Inventor: WARPEHOSKI MARTHA A
IPC: C07D487/04
Filed: 1998-11-18
Abstract: 1. A compound of formula I or pharmaceutical acceptable salts thereof wherein: R1 is phenyl, substituted with C1-4 alkyl, C1-4 alkoxy, halogen or phenyl; R2 is phenylsulfonyl, substituted with C1-4 alkyl, C1-4 alkoxy, halogen or phenyl; or represents a group -CH2NHC(=O)R3, wherein R3 is C5-6 alkoxy; Y is OH. 2. A compound of claim 1 which is N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4phenylbenzenesulfonyl)-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4fluorobenzenesulfonyl)-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-n-butylbenzenesulfonyl)-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4methoxybenzenesulfonyl)-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-benzenecarbonylamino)-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-[N(cyclopentylcarbonyl)amino]-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-(4-methoxybenzenecarbonyl) amino)-propionamide, 3. A compound of formula 8 or pharmaceutical acceptable salts thereof wherein R1, R2 and Y are as defined in claim 1. 4. A compound of claim 3, which is N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4fluorobenzenesulfonyl)-propionamide, N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-n-butylbenzenesulfonyl)-propionamide, or N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4methoxybenzenesulfonyl)-propionamide. 5. A method of inhibiting excess matrix metalloproteinase which comprises administering to a patient in need thereof an effective amount of a compound of claim 1. 6. A method of claim 5 wherein matrix metalloproteinases comprises stromelysin, collagenase, and gelatinase. 7. The method of claim 5 wherein the effective amount of the compound of claim 1 is administered orally, parenterally, or topically in a pharmaceutical composition. 8. The method of claim 5 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day. 9. A method of treating a human suffering from or susceptible to diseases involving connective tissue degradation which comprises administering to a patient in need thereof an effective amount of a compound of claim 1. 10. A method of claim 9 wherein the diseases related to connective tissue degradation are osteoarthrits, rheumatoid arthritis, septic arthritis, and osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, or asthma. 11. The method of claim 9 wherein the effective amount of the compound of claim 1 is administered orally, parenterally, or topically in a pharmaceutical composition. 12. The method of claim 9 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day. 13. A pharmaceutical composition, which comprises an amount of the compound of claim 1, effective to inhibit excess matrix metalloproteinase and a pharmaceutically acceptable carrier. 14. A compound of claim 1 for use as a medicament. 15. Use of a compound of claim 1 for the manufacture of a medicament for inhibiting excess matrix metalloproteinase in a human suffering from or susceptible to a diseases involving connective tissue degradation. 16. The use of claim 15 wherein matrix metalloproteinases comprises collagenases, stromelysins, or gelatinases. 17. The use of claim 15 wherein the disease related to connective tissue degradation is osteoarthrits, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, or gastric ulceration.