Claims for Patent: 6,037,361

Summary for Patent: 6,037,361

Title:	Fluorinated butyric acids and their derivatives as inhibitors of matrix metalloproteinases
Abstract:	Fluorinated butyric acid compounds and derivatives are described as well as acid methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A (72 kD gelatinase) and stromelysin-1, and also collagenase, matrilysin, and MMP-13, and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, inflammation, pain, arthritis, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer\'s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson\'s disease, Huntington\'s disease, prion diseases, myasthenia gravis, and Duchenne\'s muscular dystrophy.
Inventor(s):	Roth; Bruce David (Plymouth, MI), O\'Brien; Patrick Michael (Stockbridge, MI), Sliskovic; Drago Robert (Saline, MI)
Assignee:	Warner-Lambert Company (Ann Arbor, MI)
Application Number:	09/036,751
Patent Claims:	1. A compound of Formula I ##STR24## wherein one of R or R.sup.1 is hydrogen and the other is ##STR25## wherein ##STR26## wherein R.sup.6 is hydrogen, alkyl, --(CH.sub.2).sub.n -aryl wherein n is zero or an integer of 1 to 5, or --(CH.sub.2).sub.n -cycloalkyl wherein n is as defined above, or ##STR27## R.sup.3, R.sub.3a, R.sup.4, and R.sup.4a are independently the same or different and are hydrogen, fluorine, alkyl, --(CH.sub.2).sub.n -aryl wherein n is as defined above, --(CH.sub.2).sub.n --N-phthalimido wherein n is as defined above, or --(CH.sub.2).sub.n -heteroaryl wherein n is as defined above, and R.sup.5 is OH or NH--OH, or ##STR28## wherein R.sup.7 and R.sup.8 are independently the same or different and are hydrogen or fluorine and Z and R.sup.5 are as defined above; R.sup.2 is hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, nitro, trifluoromethyl, ##STR29## --CO.sub.2 R.sup.9 wherein R.sup.9 is hydrogen or alkyl, --COR.sup.9 wherein R.sup.9 is as defined above, --SO.sub.3 R.sup.9 wherein R.sup.9 is as defined above, ##STR30## wherein R.sup.9 is as defined above, or --(CH.sub.2).sub.n N(R.sup.9).sub.2 wherein n and R.sup.9 are as defined above; R.sup.2a is hydrogen, alkyl, alkoxy, halogen, hydroxy, or cyano; and Y is ##STR31## wherein R.sup.9 is as defined above, --O--, --S(O).sub.m -- wherein m is zero or an integer of 1 or 2, ##STR32## wherein R.sup.9 is as defined above, ##STR33## wherein R.sup.6 is as defined above; with the proviso that at least one of R.sup.3, R.sup.3a, R.sup.4, or R.sup.4a is fluorine and at least one of R.sup.7 and R.sup.8 is fluorine; and corresponding isomers thereof; a pharmaceutically acceptable prodrug thereof; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein R is ##STR34## wherein ##STR35## wherein R.sup.6 is hydrogen, alkyl, --(CH.sub.2).sub.n -aryl wherein n is zero or an integer of 1 to 5, or --(CH.sub.2).sub.n -cycloalkyl wherein n is as defined above, or ##STR36## R.sup.3, R.sup.3a, R.sup.4, and R.sup.4a are independently the same or different and are hydrogen, fluorine, alkyl, --(CH.sub.2).sub.n -aryl wherein n is as defined above, --(CH.sub.2).sub.n --N-phthalimido wherein n is as defined above, or --(CH.sub.2).sub.n -heteroaryl wherein n is as defined above, and R.sup.5 is OH or NH--OH, or ##STR37## wherein R.sup.7 and R.sup.8 are independently the same or different and are hydrogen or fluorine and Z and R.sup.5 are as defined above; R.sup.1 is hydrogen; and Y is --O--, or --CH.sub.2 --. 3. A compound according to claim 2 wherein R.sup.1, R.sup.2, and R.sup.2a are hydrogen. 4. A compound according to claim 3 wherein ##STR38## wherein Z is ##STR39## R.sup.3 and R.sup.3a are hydrogen or fluorine, R.sup.4 and R.sup.4a are hydrogen, --(CH.sub.2).sub.n -aryl wherein n is zero or an integer of 1 to 5, --(CH.sub.2).sub.n --N-phthalimido wherein n is as defined above, or --(CH.sub.2).sub.n -heteroaryl wherein n is as defined above, and R.sup.5 is OH or NH--OH. 5. A compound according to claim 4 wherein R.sup.5 is OH. 6. A compound according to claim 5 wherein Z is ##STR40## and R.sup.5 is OH. 7. A compound selected from the group consisting of: 2-Benzyl-4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid; 4-Dibenzofuran-2-yl-3,3-difluoro-4-hydroxyimino-butyric acid; 4-Dibenzofuran-2-yl-3,3-difluoro-N-hydroxy-4-oxo-butyramide; 4-Dibenzofuran-2-yl-3-fluoro-4-oxo-but-2-enoic acid; 4-Dibenzofuran-2-yl-3,3-difluoro-4-thioxo-butyric acid; 4-Dibenzofuran-2-yl-3,3-difluoro-4-hydroxy-butyric acid; 4-(7-Bromo-dibenzofuran-2-yl)-3,3-difluoro-4-oxo-butyric acid; 3,3-Difluoro-4-(8-hydroxy-dibenzofuran-2-yl)-4-oxo-butyric acid; 4-Dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid; 4-Dibenzofuran-2-yl-2,3-difluoro-4-oxo-2-phenethyl-butyric acid; 4-Dibenzofuran-2-yl-2,2-difluoro-4-hydroxyimino-butyric acid; 3-(Dibenzofuran-2-carbonyl)-2-fluoro-5-pyridin-2-yl-pentanoic acid; 2-(2-Dibenzofuran-2-yl-1,1-difluoro-2-oxo-ethyl)-5-(1,3-dioxo-1,3-dihydro-i soindol-2-yl)-pentanoic acid; 3-Fluoro-4-methoxyimino-4-(7-nitrodibenzofuran-2-yl)-butyric acid; 4-(9H-Fluoren-2-yl)-3,3-difluoro-4-oxo-butyric acid; 4-(7-Bromo-9H-fluoren-3-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; 4-(9H-Fluoren-2-yl)-2,3-difluoro-N-hydroxy-4-oxo-butyramide; 4-Dibenzothiophen-2-yl-2,2,3,3-tetrafluoro-4-oxo-butyric acid; 2-Benzyl-4-dibenzothiophen-2-yl-3-fluoro-4-oxo-butyric acid; 4-Dibenzothiophen-2-yl-2,3-difluoro-4-oxo-but-2-enoic acid; 4-(9H-Carbazol-2-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; 3-Fluoro-4-(9-methyl-9H-carbazol-2-yl)-4-oxo-butyric acid; 4-Dibenzofuran-2-yl-2,2-difluoro-4-oxo-butyric acid; 4-(7-Bromo-9H-fluoren-3-yl)-2,2-difluoro-4-oxo-butyric acid; 4-Dibenzofuran-2-yl-2,3-difluoro-4-oxo-butyric acid; 4-Dibenzofuran-2-yl-2-fluoro-4-oxo-butyric acid; 3-Fluoro-4-(7-nitrodibenzofuran-2-yl)-butyric acid; 4-Dibenzothiophen-2-yl-3-fluoro-4-oxo-butyric acid; and 4-(9H-Fluoren-3-yl)-2,2-difluoro-4-hydroxyimino-butyric acid; and corresponding isomers thereof; a pharmaceutically acceptable prodrug thereof; or a pharmaceutically acceptable salt thereof. 8. A compound which is 4-dibenzofuran-2-yl-2,2-difluoro-4-oxo-butyric acid; a pharmaceutically acceptable prodrug thereof; or a pharmaceutically acceptable salt thereof. 9. A compound which is 4-dibenzofuran-2-yl-3,3-difluoro-4-oxo-butyric acid; a pharmaceutically acceptable prodrug thereof; or a pharmaceutically acceptable salt thereof. 10. A method of inhibiting a matrix metalloproteinase comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 11. A method of inhibiting gelatinase A comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 12. A method of inhibiting stromelysin-1 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 13. A method of inhibiting collagenase comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 14. A method of inhibiting matrilysin comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 15. A method of inhibiting MMP-13 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 16. A method of preventing atherosclerotic plaque rupture comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 17. A method of inhibiting aortic aneurism comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 18. A method of inhibiting heart failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 19. A method of preventing restenosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 20. A method of controlling periodontal disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 21. A method of treating corneal ulceration comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 22. A method of treating burns comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 23. A method of treating decubital ulcers comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 24. A method of treatment for healing wounds comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 25. A method of treating cancer comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 26. A method of treating arthritis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 27. A method of treating autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 28. A method of treating multiple sclerosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 29. A method of treating inflammation and pain comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 30. A method of treating acute and chronic neurodegenerative disorders selected from the group consisting of: stroke, head trauma, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson's disease, Huntington's diseases, prion diseases, myasthenia gravis, and Duchenne's muscular dystrophy comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 31. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 32. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.

Details for Patent 6,037,361

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2039-02-26