Patent EA-004227-B1 (EA)
Title: (4-arylsulfonylamino)-tetrahydropyran-4-carboxylic acid hydroxamides
Inventor: REITER LAWRENCE ALAN
IPC: A61P25/14
Filed: 1999-03-24
Abstract: 1. A compound of the formula wherein Q is (C1-C6)alkyl, (C6-C10)aryl, (C2-C9)heteroaryl. (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C2-C9)heteroaryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C2-C9)heteroaryl(C6-C10)aryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C2-C9)heteroaryl, (C2-C9)heteroaryloxy(C1-C6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkoxy(C6-C10)aryl or (C2-C9)heteroaryl(C1-C6)alkoxy(C2-C9)heteroaryl; wherein each (C6-C10)aryl or (C2-C9)heteroaryl moieties of said (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryloxy(C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6C10)aryl(C2-C9)heteroaryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C2-C9)heteroaryl(C6-C10)aryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C6C10)aryl(C1-C6)alkoxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C2-C9)heteroaryl, (C2C9)heteroaryloxy(C1-C6)alkyl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C2-C9)heteroaryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkoxy(C6-C10)aryl or (C2-C9)heteroaryl(C1-C6)alkoxy(C2-C9)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C3)alkyl, perfluoro(C1-C3)alkoxy and (C6-C10)aryloxy; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein Q is optionally substituted (C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C6C10)aryloxy(C2-C9)heteroaryl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C2-C9)heteroaryl, (C6-C10)aryl(C2-C9)heteroaryl, (C2-C9)-heteroaryl(C6-C10)aryl, (C2-C9)heteroaryloxy(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkoxy(C6-C10)-aryl, or (C2-C9)heteroaryl(C1-C6)alkoxy(C6-C10)aryl. 3. A compound according to claim 1, wherein Q is optionally substituted (C6-C10)aryloxy(C6-C10)aryl. 4. A compound according to claim 3, wherein the (C6-C10)aryloxy ring of said (C6-C10)aryloxy(C6-C10)aryl group is optionally mono-substituted in the 4position of the ring. 5. A compound according to claim 1, wherein said compound is selected from the group consisting of: 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; 4-[4-(4-chlorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; 4-[4-(phenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; 4-[4-(4-pyridyloxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; 4-[4-(4-fluorophenyl)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; 4-[4-(4-fluorophenylmethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; 4-[4-(phenylmethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide; and 4-[4-(4-fluorophenylethoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide;. 6. A pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimers disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier. 7. A method for treating a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neurodegenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, bums, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis and septic shock in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1, effective in treating such a condition. 8. A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of matrix metalloproteinases in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition for the treatment of a condition which can be treated by the inhibition of a mammalian reprolysin in a mammal, including a human, comprising an amount of a compound of claim 1 effective in such treatment and a pharmaceutically acceptable carrier. 10. A method for the inhibition of matrix metalloproteinases in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1. 11. A method for the inhibition of a mammalian reprolysin in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1.