Claims for Patent: 4,743,587

Summary for Patent: 4,743,587

Title:	Hydroxamic acid based collagenase inhibitors
Abstract:	Thid disclosure relates to a novel class of hydroxamic acid based collagenase inhibitor derivatives. The disclosure further relates to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in the treatment of collagenase induced diseases.
Inventor(s):	Dickens; Jonathan P. (High Wycombe, GB2), Donald; David K. (High Wycombe, GB2), Kneen; Geoffrey (West Wycombe, GB2), McKay; William R. (High Wycombe, GB2)
Assignee:	G. D. Searle & Co. (Chicago, IL)
Application Number:	06/880,130
Patent Claims:	1. A compound of the formula ##STR38## wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl; R.sup.2 is C.sub.1 -C.sub.6 alkyl, benyl, hydroxybenzyl, benzyloxybenzyl, (C.sub.1 -C.sub.6 alkoxy)benzyl, or benzyloxy(C.sub.1 -C.sub.6 alkyl); a is a chiral center with optional R or S stereochemistry; A is a ##STR39## group or a--(CR.sup.3 .dbd.CR.sup.4)-- group wherein b and c are chiral centers with optional R or S stereochemistry; R.sup.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, or phenyl (C.sub.1 -C.sub.6 alkyl); and R.sup.4 is hydrogen or C.sub.1 -C.sub.6 alkyl, phenyl (C.sub.1 -C.sub.6 alkyl), cycloalkyl, or cycloalkyl (C.sub.1 -C.sub.6 alkyl). 2. A compound according to claim 1 wherein A is a ##STR40## group. 3. A compound according to claim 2 wherein R.sup.2 is (C.sub.1 -C.sub.6 alkoxy)benzyl. 4. A compound according to claim 3 wherein R.sup.2 is 4-methoxybenzyl, R.sup.4 is C.sub.1 -C.sub.4 alkyl, and R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl, or phenyl(C.sub.1 -C.sub.6 alkyl). 5. A compound according to claim 4 wherein R.sup.1 is methyl and R.sup.3 is hydrogen or methyl. 6. A compound according to claim 5 wherein R.sup.4 is 2-methylpropyl. 7. A compound according to claim 6 wherein chiral center a has S stereochemistry. 8. A compound according to claim 7 wherein R.sup.3 is hydrogen. 9. A compound according to claim 8 having the following NMR spectrum: NMR (d.sub.6 -DMSO) 0.7-0.9 (6H, m, {CH.sub.3 }.sub.2 CH); 1.3 (1H, m, {CH.sub.3 }.sub.2 CH); 1.9-2.2 (3H, 2.times.m, CH.sub.2 CH); 2.50 (3H, m, CHCH.sub.2 CO+CH.sub.2 CHCO); 2.6 (2H, m, ArCH.sub.2); 2.6 (3H, d, NHCH.sub.3); 3.7 (3H, s, OCH.sub.3); 4.3-4.4 (1H, m, ArCH.sub.2 CH); 6.75-7.1 (4H, 2.times.d, J=8 Hz, aromatic); 7.9 (1H, m, NHCH.sub.3); 8.05 (1H, d, CONHCH); 8.65 (1H, s, NHOH {D.sub.2 O exchange}); 10.4 (1H, s, NHOH {D.sub.2 O exchange}). 10. A compound according to claim 7 wherein R.sup.3 is methyl. 11. A compound according to claim 10 having the following NMR spectrum; NMR (d.sub.6 -DMSO) 0.64-0.92 (9H, m, {CH.sub.3 }.sub.2 CHCH.sub.2); 1.30 (3H, m, CH.sub.3 CH); 2.20-2.40 (2H, m, CH.sub.3 CH and CH.sub.3 CHCH); 2.45 (2H, m, ArCH.sub.2); 2.55 (3H, d, J=4 Hz, NHCH.sub.3); 3.68 (3H, s, OCH.sub.3); 4.45 (1H, m, ArCH.sub.2 CH); 6.80 and 7.16 (4H, two d's, J=7 Hz, aromatic); 7.72 (1H, m, NHCH.sub.3); 8.18 (1H, d, J=7 Hz, CONHCH.sub.3); 8.72 (1H, s, NHOH {D.sub.2 O exchange}); 10.37 (1H, s, NHOH {D.sub.2 O exchange}). 12. A compound according to claim 5 wherein R.sup.4 is butyl. 13. A compound according to claim 12 wherein R.sup.3 is hydrogen. 14. A compound according to claim 13 having the following NMR spectrum: NMR (d.sub.4 -methanol): 0.86 (3H, t, J=7 Hz, CH.sub.3); 1.0-1.5 (6H, M, 3.times.CH.sub.2); 2.0-2.4 (2H, m, CH.sub.2 CH); 2.5-2.7 (1H, m, CH.sub.2 CH); 2.8-3.2 (2H, m, --CH.sub.2 ArOMe); 3.76 (3H, s, OCH.sub.3); 4.46 (1H, m, CHCH.sub.2 Ar); 6.84 (2H, d, J=7 Hz, ArH); 7.14 (2H, d, J=7 Hz, ArH). 15. A compound according to claim 2 wherein R.sup.2 is hydroxybenzyl. 16. A compound according to claim 15 wherein R.sup.1 is methyl, R.sup.3 is hydrogen, and R.sup.4 is 2-methylpropyl. 17. A compound according to claim 16 having the following NMR spectrum: NMR (d.sub.6 -DMSO): 0.74 (6H, m, [CH.sub.3 ].sub.2 CH); 0.90-1.06 (1H, m, [CH.sub.3 ].sub.2 CH); 1.19-1.43 (2H, m, CHCH.sub.2 CH); 1.94-2.24 (2H, m, COCH.sub.2 CH); 2.59 (3H, d, J=6 Hz, NHCH.sub.3); 2.60-3.02 (3H, m, CH.sub.2 CH and CH.sub.2 Ar); 4.29 (1H, m, NHCH[CH.sub.2 ]CO); 6.61 and 6.99 (4H, AA.sup.1 BB.sup.1 system, J.sub.AB =8 Hz, Ar); 7.88 (1H, m, CONHCH); 8.00 (1H, d, J=7 Hz, NHCH.sub.3); 8.80 (1H, s, NHOH); 9.15 (1H, s, ArOH); 10.44 (1H, s, NHOH). 18. A compound according to claim 16 having the following NMR spectrum: NMR (d.sub.6 -DMSO): 0.62 and 0.73 (each 3H, each d, J=5 Hz, [CH.sub.3 ].sub.2 CH); 0.75-0.87 (2H, m, CHCH.sub.2 CH); 2.20 (1H, m, [CH.sub.3 ].sub.2 CH); 1.91-2.24 (2H, m, COCH.sub.2 CH); 2.45-2.60 (2H, m, CH.sub.2 Ar); 2.63 (3H, d, J=5 Hz, NHCH.sub.3); 3.12 (1H, m, CH.sub.2 CH[CH.sub.2 ]CO); 4.28 (1H, m, NHCH[CH.sub.2 ]CO); 6.61 and 7.01 (4H, AA.sup.1 BB.sup.1 system, J.sub.AB =8 Hz, Ar); 7.91 (1H, d, J=5 Hz, CONHCH); 8.30 (1H, d, J=7 Hz, NHCH.sub.3); 8.79 (1H, s, NHOH); 9.16 (1H, s, ArOH); 10.55 (1H, s, NHOH). 19. A compound according to claim 2 wherein R.sup.2 is benzyl. 20. A compound according to claim 19 wherein R.sup.1 is methyl, R.sup.3 is hydrogen, and R.sup.4 is 2-methylpropyl. 21. A compound according to claim 20 having the following NMR spectrum: NMR (d.sub.6 -DMSO): 0.71 (3H, d, J=6 Hz, [CH.sub.3 ].sub.2 CH); 0.76 (3H, d, J=6 Hz, [CH.sub.3 ].sub.2 CH); 0.92 (1H, m, [CH.sub.3 ].sub.2 CH); 1.26 (2H, m, CHCH.sub.2 CH); 1.95 (2H, m, COCH.sub.2 CH); 2.50-2.85 (1H, m, CH.sub.2 CH[CH.sub.2 ]CO); 2.57 (3H, d, J=5.5 Hz, NHCH.sub.3); 2.76-3.08 (2H, m, CH.sub.2 Ar); 4.37 (1H, m, NHCH(CH.sub.2 CO); 7.21 (5H, m, Ar); 7.92 (1H, d, J=4.5 Hz, CONHCH); 8.07 (1H, d, J=8 Hz, CONHCH.sub.3); 8.79 (1H, s, CONHOH); 10.42 (1H, s, NHOH). 22. A method of promoting an antiarthritic effect in a mammal in need thereof comprising administering thereto a collagenase inhibiting effective amount of a compound according to claim 1. 23. A compound according to claim 1 of the formula ##STR41## 24. A compound according to claim 1 of the formula ##STR42##

Details for Patent 4,743,587

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2039-03-29