Patent EA-004680-B1 (EA)
Title: Pyrimidine-2,4,6-trione metalloproteinase inhibitors
Inventor: BLAGG JULIAN
IPC: C07D239/60
Filed: 2000-08-03
Abstract: 1. A compound of the formula wherein R<1> is (C1-C8)alkyl or (C3-C8)cycloalkyl; R<2> and R<3> are hydrogen; X is selected from the group consisting of oxygen, sulfur; Y is selected from the group consisting of bond, oxygen and sulfur; Ar<1> is (C6-C10)aryl; and Z is benzyl or (C6-C10)aryl optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents independently selected from F, Cl and Br; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R<2> and R<3> are each hydrogen. 3. A compound according to claim 2, wherein X is oxygen. 4. A compound according to claim 2, wherein X is sulfur. 5. A compound according to claim 2, wherein Y is a bond, oxygen or sulfur. 6. A compound according to claim 2, wherein Y is a bond, oxygen or sulfur. 7. A compound according to claim 4, wherein Y is a bond, oxygen or sulfur. 8. A compound according to claim 2, wherein Y is oxygen. 9. A compound according to claim 3, wherein Y is oxygen. 10. A compound according to claim 2, wherein X and Y are each oxygen. 11. A compound according to claim 2, wherein Ar<1> is phenyl. 12. A compound according to claim 2, wherein Ar<1> is phenyl. 13. A compound according to claim 9, wherein Ar<1> is phenyl. 14. A compound according to claim 10, wherein Ar<1> is phenyl. 15. A compound according to claim 2, wherein Z is (C6-C10)aryl. 16. A compound according to claim 3, wherein Z is (C6-C10)aryl. 17. A compound according to claim 8, wherein Z is (C6-C10)aryl. 18. A compound according to claim 9, wherein Z is (C6-C10)aryl. 19. A compound according to claim 13, wherein Z is (C6-C10)aryl. 20. A compound according to claim 2, wherein Z is substituted on any of the ring carbon atoms capable of forming an additional bond by one to three substituents independently selected from F, Cl and Br. 21. A compound according to claim 1, wherein Y is a bond, oxygen and sulfur, R<1> is (C1-C4alkyl) and R<2> and R<3> is hydrogen. 22. A compound according to claim 1, wherein R<2> and R<3> are each hydrogen; X is oxygen; Y is oxygen. 23. A compound according to claim 1, wherein R<1> is methyl; R<2> and R<3> are each hydrogen; X is oxygen; Y is oxygen; and Z is (C6-C10)aryl. 24. A compound according to claim 1, wherein R<1> is n-butyl; R<2> and R<3> are each hydrogen; X is oxygen; Y is oxygen; and Z is (C6-C10)aryl. 25. A compound according to claim 1, wherein R<1> is methyl; R<2> and R<3> are each hydrogen; X is oxygen; Y is a bond; and Z is (C6-C10) aryl. 26. A compound according to claim 1, wherein R<1> is n-butyl; R<2> and R<3> are each hydrogen; X is oxygen; Y is a bond; and Z is (C6-C10)aryl. 27. A compound according to claim 1, wherein said compound is selected from the group consisting of: 5-Methyl-5-(4-phenoxy-phenoxy)-pyrimidine-2,4,6-trione; 5-Methyl-5-(4-(4'-fluorophenoxy)-phenoxy)-pyrimidine-2,4,6-trione; 5-n-Butyl-5-(4-phenoxy-phenoxy)-pyrimidine-2,4,6-trione 5-n-Butyl-5-(4-(4'-fluorophenoxy)-phenoxy)-pyrimidine-2,4,6-trione; 5-Methyl-5-(4-phenyl-phenoxy)-pyrimidine-2,4,6-trione; 5-Methyl-5-(3-phenyl-phenoxy)-pyrimidine-2,4,6-trione; and 5-Methyl-5-(4-benzyloxy-phenoxy)-pyrimidine-2,4,6-trione; or a pharmaceutically acceptable salt thereof. 28. A pharmaceutical composition for the treatment of a condition selected from the group consisting of arthritis, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Aizheimer'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, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro- degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sderosis, multiple sclerosis, ocular angiogenesis, comeal injury, macular degeneration, abnormal woundhealing, bums, diabetes, comeal 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. 29. A method for treating a condition selected from the group consisting of arthritis, inflammatorybowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, 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, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders, autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain,cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateralsclerosis, multiple sclerosis, ocular angiogenesis, comeal injury, macular degeneration, abnormal woundhealing, bums, diabetes, comeal 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. 30. 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. 31. 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.