Claims for Patent: 6,541,521

Summary for Patent: 6,541,521

Title:	Benzene butyric acids and their derivatives as inhibitors of matrix metalloproteinases
Abstract:	Benzene butyric acid compounds and derivatives are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A, collagenase-3, and stromelysin-1 and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurysm, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, inflammation, pain, arthritis, osteoporosis, renal disease, 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):	Purchase, Jr.; Claude Forsey (Ann Arbor, MI), Roth; Bruce David (Plymouth, MI), White; Andrew David (Pinckney, MI)
Assignee:	Warner-Lambert Company (Morris Plains, NJ)
Application Number:	09/351,549
Patent Claims:	1. A compound of Formula I ##STR72## wherein R.sup.1 is hydrogen, alkyl, arylalkyl, or aryl substituted by 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, fluorine, bromine, iodine, trifluoromethyl, amino, alkylamino, dialkylamino, nitro, cyano, carboxy, guanidine, amidino, SO.sub.3 H, ##STR73## wherein n.sup.2 is an integer of 1 to 5; R.sup.2, R.sup.2a, R.sup.3, and R.sup.3a are either the same of different and are each independently selected from hydrogen, fluorine, --(C.sub.1-10 alkyl).sub.n --R.sup.5 wherein n is zero or an integer or 1, alkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from --OR.sup.7 wherein R.sup.7 is hydrogen or alkyl, --SR.sup.7 wherein R.sup.7 is as defined above, --CH.sub.2 --S--CO-alkyl, ##STR74## wherein R7 is defined as above, --CO-alkyl, --CO.sub.2 -alkyl, --O--CO-alkyl, --S--CO-alkyl, ##STR75## wherein R7 is as defined above, --SO-alkyl, --SO.sub.2 -alkyl, --CN, --CF.sub.3, or --HN--SO.sub.2 -alkyl and, R.sup.5 is hydrogen, aryl, heteroaryl, N-phthalimido, N-2,3-naphthylimido, indol-3-yl, imidazol-4-yl, 2-,3-, or 4-pyridyl, 2,4-dioxo-1,5,5-trimethyl-imidazolidin-3-yl or a side chain of a naturally occurring or unnaturally occurring amino acid; R.sup.4 is OH; X is ##STR76## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl, ##STR77## ##STR78## wherein R.sup.6 is as defined above, ##STR79## wherein R.sup.6 is as defined above, ##STR80## wherein R.sup.6 is as defined above, ##STR81## ##STR82## wherein R.sup.6 is as defined above, ##STR83## wherein R.sup.6 is as defined above, ##STR84## wherein R.sup.6 is as defined above, Z is ##STR85## wherein R.sup.7 is as defined above, ##STR86## wherein R.sup.7 is as defined above, ##STR87## F is fluorine; and m is zero or an integer of 1 to 4; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 wherein X is ##STR88## 3. The compound according to claim 1 wherein X is ##STR89## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 4. The compound according to claim 1 wherein X is ##STR90## 5. The compound according to claim 1 wherein X is ##STR91## 6. The compound according to claim 1 wherein X is ##STR92## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 7. The compound according to claim 1 wherein X is ##STR93## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 8. The compound according to claim 1 wherein X is ##STR94## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 9. The compound according to claim 1 wherein ##STR95## 10. The compound according to claim 1 wherein ##STR96## 11. The compound according to claim 1 wherein ##STR97## 12. The compound according to claim 1 wherein X is ##STR98## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 13. The compound according to claim 1 wherein X is ##STR99## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 14. The compound according to claim 1 wherein X is ##STR100## wherein R.sup.6 and R.sup.6a are either the same or different and are each independently as defined for R.sup.6, wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl. 15. The compound according to claim 1 wherein ##STR101## 16. The compound according to claim 1 wherein ##STR102## 17. The compound selected from the group consisting of: 4-[4-(4-Bromo-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-(4-Benzoylamino-phenyl)-4-oxo-butyric acid; 4-[4-(2-Fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3-Fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2-Iodo-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2,4-Dichloro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2,6-Dichloro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3,4-Dichloro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2,4-Difluoro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-(4-Bromo-phenyl)-butyrylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-(4-Bromo-phenyl)-acetylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3-Cyano-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(Benzo[1,3]diozol-5-yl-carbonylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(Biphenyl-4-yl-carbonylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Cyano-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2-Methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3-Methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2,4-Dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2,5-Dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2,6-Dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3,5-Dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-Oxo-4-[4-(3,4,5-trimethoxy-benzoylamino)-phenyl]-butyric acid; 4-[4-(4-Methyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Decyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Ethyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Tert-Butyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Butoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(Cyclohexanecarbonyl-amino)-phenyl]-4-oxo-butyric acid; 4-Oxo-4-[4-(phenylacetyl-amino)-phenyl]-butyric acid; 4-Oxo-4-[4-(3-phenyl-propionyl-amino)-phenyl]-butyric acid; 4-[-4-(Dodecanoyl-amino)-phenyl]-4-oxo-butyric acid; 4-[-4-(Heptanoyl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(3-Nitro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Nitro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(Butyryl-amino)-phenyl]-4-oxo-butyric acid; 4-[-4-(Decanoyl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Chloro-phenoxy-acetylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3,4-Dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3,4-Dimethoxy-phenylacetyl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(Naphthyl-2-yl-carbonylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(Adamantan-1-yl-carbonylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(Oleoyl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(Nonanoyl-amino)-phenyl]-4-oxo-butyric acid; 4-Oxo-4-[4-(propionylamino)-phenyl]-butyric acid; 4-Oxo-4-[4-(phenoxy-acetylamino)-phenyl]-butyric acid; 4-[4-(Oxalamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Chloro-3-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-Oxo-4[4-(phenylazo-benzoylamino)-phenyl]-butyric acid; 4-[4-(Cinnamoylamino)-phenyl]-4-oxo-butyric acid; (.+-.)-2-(Acetylthio)methyl-4-[4-(4-methyl-benzoylamino)-phenyl]-4-oxo-buty ric acid; (.+-.)-3-(Acetylthio)methyl-4-[4-(4-methyl-benzoylamino)-phenyl]-4-oxo-buty ric acid; (.+-.)-2-(2,4-Dioxo-1,5,5-trimethyl-imidazolidin-3-yl)methyl-4-[4-(4-methyl -benzoylamino)-phenyl]-4-oxo-butyric acid; (.+-.)-2-(4-Benzyloxy-phenyl)methyl-4-[4-(4-methyl-benzoylamino)-phenyl]-4- oxo-butyric acid; (.+-.)-4-[4-(4-Methyl-benzoylamino)-phenyl]-4-oxo-2-(3-phenyl-propyl)-butyr ic acid; (.+-.)-4-[4-(4-Methyl-benzoylamino)-phenyl]-4-oxo-2-(2-phthalimido-ethyl)-b utyric acid; (.+-.)-2-(4-Methyl-benzenesulfonyl)amino-4-[4-(4-methyl-benzoylamino)-pheny l]-4-oxo-butyric acid; (.+-.)-4-[4-(4-Methyl-benzoylamino)-phenyl]-4-oxo-3-(pyridin-3-yl)methyl-bu tyric acid; 4-[4-(Octanoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Heptyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(2-Naphthoylamino)-phenyl]-4-oxo-butyric acid; 4-Oxo-4-[4-(4-trifluoromethyl-benzoylamino)-phenyl]-butyric acid; 4-Oxo-4-[4-(2,3,4,5,6-pentafluoro-benzoylamino)-phenyl]-butyric acid; 4-[4-(2-Fluoro4-trifluoromethyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3-Fluoro-4-trifluoromethyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Hexyloxy-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Dipropylaminosulfonyl-benzoylamino)-phenyl]-4-oxo-butyric acid; 4-Oxo-[4-3-phenyl-ureido)-phenyl]-butyric acid; {4-[3-(4-Chloro-phenyl)-ureido]-phenyl}-4-oxo-butyric acid; {4-[3-(4-Bromo-phenyl)-ureido]-phenyl}-4-oxo-butyric acid; {4-[3-(4-Fluoro-phenyl)-ureido]-phenyl}-4-oxo-butyric acid; 4-Oxo-{4-[3-(4-trifluoro-phenyl)-ureido]-phenyl}-butyric acid {4-[3-(4-Methoxy-phenyl)-ureido]-phenyl}-4-oxo-butyric acid; {4-[3-(4-Methyl-phenyl)-ureido]-phenyl}-4-oxo-butyric acid; 4-Oxo-4-(4-[phenoxycarbonylamino)-phenyl]-butyric acid; 4-{4-[(4-Chloro-phenoxy)-carbonylamino]-phenyl}-4-oxo-butyric acid; 4-{4-[(4-Bromo-phenoxy)-carbonylamino]-phenyl}-4-oxo-butyric acid; 4-{4-[(4-Fluoro-phenoxy)-carbonylamino]-phenyl}-4-oxo-butyric acid; 4-{4-[(4-Methoxy-phenoxy)-carbonylamino]-phenyl}-4-oxo-butyric acid; 4-{4-[(4-Methyl-phenoxy)-carbonylamino]-phenyl}-4-oxo-butyric acid; 4-Oxo-4-{4-[(4-trifluoromethyl-phenoxy)-carbonylamino]-phenyl}-butyric acid; 4-[4-(4-Bromo-benzoylamino)phenyl]-4-hydroxyimino-butyric acid; 4-[4-Benzoylamino-phenyl)-4-hydroxyimino-butyric acid 4-[4-(4-Chloro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(2-Fluoro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(3-Fluoro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Fluoro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(2-iodo-benzoylamino)-phenyl]-butyric acid; 4-[4-(2,4-Dichloro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(2,6-Dichloro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(3,4-Dichloro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(2,4-Difluoro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-(4-Bromo-phenyl)-butyrylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-(4-Bromo-phenyl)-acetylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(3-Cyano-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid 4-[4-(Benzo[1,3]dioxol-5-yl-carbonylamino)-phenyl]-4-hydroxyimino-butyric acid 4-[4-(Biphenyl-4-yl-carbonylamino)-phenyl]-4-hydroxyimino-butyric acid 4-[4-(4-Cyano-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid 4-Hydroxyimino-4-[4-(2-methoxy-benzoylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(3-methoxy-benzoylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(4-methoxy-benzoylamino)-phenyl]-butyric acid; 4-[4-(2,4-Dimethoxy-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(2,5-Dimethoxy-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(2,6-Dimethoxy-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(3,5-Dimethoxy-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(3,4,5-trimethoxy-benzoylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(4-Methyl-benzoylamino)-phenyl]-butyric acid; 4-[4-(4-Decyl-benzoylamino)phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Ethyl-benzoylamino)phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Tert-Butyl-benzoylamino)phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Butoxy-benzoylamino)phenyl]-4-hydroxyimino-butyric acid; 4-[4-(Cyclohexanecarbonyl-amino)phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(phenylacetyl-amino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(3-phenyl-propionyl-amino)-phenyl]-butyric acid; 4-[4-(2,2-Dimethyl-pentanoyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(Dodecanoyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(Heptanoyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(3-nitro-benzoylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(4-nitro-benzoylamino)-phenyl]-butyric acid; 4-[4-(Butyryl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(Decanoyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(Diphenylacetyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Chloro-phenoxy-acetylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(3,4-Dimethoxy-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(3,4-Dimethoxy-phenylacetyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(naphthyl-2-yl-carbonylamino)-phenyl]-butyric acid; 4-[4-(Adamantan-1-yl-carbonylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(oleoyl-amino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(nonanoyl-amino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(propionylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(2-phenoxy-propionylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(phenoxy-acetylamino)-phenyl]-butyric acid; 4-Hydroxyimino-4-[4-(oxalamino)-phenyl]-butyric acid; 4-[4-(4-Chloro-3-nitro-benzoylamino)-phenyl]-4-hydroxyimino-butyric acid; 4-Hydroxyimino-4-[4-(phenylazo-benzoylamino)-phenyl]-butyric acid; 4-[4-(Cinnamoylamino)-phenyl]-4-hydroxyimino-butyric acid; (.+-.)-2-(Acetylthio)methyl-4-Hydroxyimino-4-[4-(4-methyl-benzoylamino)-phe nyl]-butyric acid; (.+-.)-3-(Acetylthio)methyl-4-hydroxyimino-4-[4-(4-methyl-benzoylamino)-phe nyl]-butyric acid; (.+-.)-2-(2,4-Dioxo-1,5,5-trimethyl-imidazolidin-3-yl)methyl-4-hydroxyimino -4-[4-(4-methyl-benzoylamino)-phenyl]-butyric acid; (.+-.)-2-(4-Benzyloxy-phenyl)methyl-4-hydroxyimino-4-[4-(4-methyl-benzoylam ino)-phenyl]-butyric acid; (.+-.)-4-Hydroxyimino-4-[4-(4-methyl-benzoylamino)-phenyl]-2-(3-phenyl-prop yl)-butyric acid; (.+-.)-4-Hydroxyimino-4-[4-(4-methyl-benzoylamino)-phenyl]-2-(2-phthalimido -ethyl)-butyric acid; (.+-.)-4-Hydroxyimino-2-(4-methyl-benzenesulfonyl)amino-4-[4-(4-methyl-benz oylamino)-phenyl]-butyric acid; and (.+-.)-4-Hydroxyimino-4-[4-(4-methyl-benzoylamino)-phenyl]-3-(pyridin-3-yl) methyl-butyric acid; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof. 18. The 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. 19. The 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. 20. The 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. 21. The method of inhibiting collagenase-3 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in unit dosage form. 22. A pharmaceutical composition comprising a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 23. 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. 24. A compound of Formula I ##STR103## wherein R.sup.1 is C.sub.2 -C.sub.8 alkyl, arylalkyl, aryl substituted by 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, fluorine, bromine, iodine, trifluoromethyl, amino, alkylamino, dialkylamino, nitro, cyano, carboxy, amidino, SO.sub.3 H, ##STR104## wherein n.sup.2 is an integer of 1 to 5, or a saturated hydrocarbon ring having 4 to 8 carbon atoms; R.sup.2, R.sup.2a, R.sup.3, and R.sup.3a are either the same of different and are each independently selected from hydrogen, fluorine, --(C.sub.1-10 alkyl).sub.n --R.sup.5 wherein n is zero or an integer or 1, alkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from --OR.sup.7 wherein R.sup.7 is hydrogen or alkyl, --SR.sup.7 wherein R.sup.7 is as defined above, --CH.sub.2 --S--CO-alkyl, ##STR105## wherein R7 is defined as above, --CO-alkyl, --CO.sub.2 -alkyl, --O--CO-alkyl, --S--CO-alkyl, ##STR106## wherein R7 is as defined above, --SO-alkyl, --SO.sub.2 -alkyl, --CN, --CF.sub.3, or --HN--SO.sub.2 -alkyl and, R.sup.5 is hydrogen, aryl, heteroaryl, N-phthalimido, N-2,3-naphthylimido, indol-3-yl, imidazol-4-yl, 2-,3-, or 4-pyridyl, 2,4-dioxo-1,5,5-trimethyl-imidazolidin-3-yl or a side chain of a naturally occurring or unnaturally occurring amino acid; R.sup.4 is OH; X is ##STR107## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl, ##STR108## ##STR109## wherein R.sup.6 is as defined above, Z is ##STR110## wherein R.sup.7 is as defined above, ##STR111## wherein R.sup.7 is as defined above, ##STR112## F is fluorine; and m is zero or an integer of 1 to 4; and corresponding isomers thereof; or pharmaceutically acceptable salt thereof. 25. The compound of claim 24, wherein Z is ##STR113## 26. The method of inhibiting a matrix metalloproteinase comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 24 in unit dosage form. 27. The method of inhibiting gelatinase A comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 24 in unit dosage form. 28. The method of inhibiting stromelysin-1 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 24 in unit dosage form. 29. The method of inhibiting collagenase3 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 24 in unit dosage form. 30. A pharmaceutical composition comprising a compound according to claim 24 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 31. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 24 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 32. A compound of Formula I ##STR114## wherein R.sup.1 is hydrogen, alkyl, arylalkyl, aryl substituted by 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, fluorine, bromine, iodine, trifluoromethyl, amino, alkylamino, dialkylamino, nitro, cyano, carboxy, guanidine, amidino, SO.sub.3 H, ##STR115## wherein n.sup.2 is an integer of 1 to 5, or a saturated hydrocarbon ring having 4 to 8 carbon atoms; R.sup.2, R.sup.2a, R.sup.3, and R.sup.3a are either the same of different and are each independently selected from hydrogen, fluorine, --(C.sub.1-10 alkyl).sub.n --R.sup.5 wherein n is zero or an integer or 1, alkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from --OR.sup.7 wherein R.sup.7 is hydrogen or alkyl, --SR.sup.7 wherein R.sup.7 is as defined above, --CH.sub.2 --S--CO-alkyl, ##STR116## wherein R7 is defined as above, --CO-alkyl, --CO.sub.2 -alkyl, --O--CO-alkyl, --S--CO-alkyl, ##STR117## wherein R7 is as defined above, --SO-alkyl, --SO.sub.2 -alkyl, --CN, --CF.sub.3, or --HN--SO.sub.2 -alkyl and, R.sup.5 is hydrogen, aryl, hereroaryl, N-phthalimido, N-2,3-naphthylimido, indol-3-yl, imidazol-4-yl, 2-,3-, or 4-pyridyl, 2,4-dioxo-1,5,5-trimethyl-imidazolidin-3-yl or a side chain of a naturally occurring or unnaturally occurring amino acid; R.sup.4 is OH; X is ##STR118## wherein R.sup.6 is hydrogen, methyl, or optionally R.sup.1 and R.sup.6 are taken together to form a ring containing from 4 to 7 carbons which may be unsubstituted or substituted with alkyl, aryl, arylalkyl, hereroaryl, heteroarylalkyl, heterocycle, or heterocyclealkyl, Z is ##STR119## F is fluorine; and m is zero or an integer of 1 to 4; and corresponding isomers thereof, or a pharmaceutically acceptable salt thereof. 33. The method of inhibiting a matrix matalloproteinase comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 32 in unit dosage form. 34. The method of inhibiting gelatinase A comprising administering to a host suffering therefrom therapeutically effective amount of a compound according to claim 32 in unit dosage form. 35. The method of inhibiting stromelysin-1 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 32 in unit dosage form. 36. The method of inhibiting collagenase-3 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 32 in unit dosage form. 37. A pharmaceutical composition comprising a compound according to claim 32 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 38. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 32 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier. 39. The compound 4-[4-(3-Carboxy-propionyl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Carboxy-butyryl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(4-Carboxy-acetyl-amino)-phenyl]-4-oxo-butyric acid; 4-[4-(2-Acetoxy-2,2-dimethyl-acetylamino)-phenyl]-4-oxo-butyric acid; 4-[4-(3-Carboxy-propionyl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Carboxy-butyryl-amino)-phenyl]-4-hydroxyimino-butyric acid; 4-[4-(4-Carboxy-acetyl-amino)-phenyl]-4-hydroxyimino-butyric acid; or 4-[4-(2-Acetoxy-2,2-dimethyl-acetylamino)-phenyl]-4-oxo-butyric acid.

Details for Patent 6,541,521

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