US4743587A
Expired / Lapsed
US
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Hydroxamic acid based collagenase inhibitors
Assignee: GD Searle LLC
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Filing: 1986-07-07
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Granted: 1988-05-10
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Expires: 2006-07-07
Abstract
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.
Inventors
- 👤 Jonathan P. Dickens
- 👤 David K. Donald
- 👤 Geoffrey Kneen
- 👤 William R. McKay
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-10 01:04
CPC Classifications
C; C07; C07C; C07C233/00; C07C233/01; C07C233/02; A; A61; A61P; A61P29/00; A61P43/00; C07C237/00
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
115 words
A compound of the formula ##STR38## wherein R 1 is C 1 -C 6 alkyl; R 2 is C 1 -C 6 alkyl, benyl, hydroxybenzyl, benzyloxybenzyl, (C 1 -C 6 alkoxy)benzyl, or benzyloxy(C 1 -C 6 alkyl); a is a chiral center with optional R or S stereochemistry; A is a ##STR39## group or a--(CR 3 ═CR 4 )-- group wherein b and c are chiral centers with optional R or S stereochemistry; R 3 is hydrogen, C 1 -C 6 alkyl, phenyl, or phenyl (C 1 -C 6 alkyl); and R 4 is hydrogen or C 1 -C 6 alkyl, phenyl (C 1 -C 6 alkyl), cycloalkyl, or cycloalkyl (C 1 -C 6 alkyl).
Claim 2
Dependent Claim
115 words
A compound of the formula ##STR38## wherein R 1 is C 1 -C 6 alkyl; R 2 is C 1 -C 6 alkyl, benyl, hydroxybenzyl, benzyloxybenzyl, (C 1 -C 6 alkoxy)benzyl, or benzyloxy(C 1 -C 6 alkyl); a is a chiral center with optional R or S stereochemistry; A is a ##STR39## group or a--(CR 3 ═CR 4 )-- group wherein b and c are chiral centers with optional R or S stereochemistry; R 3 is hydrogen, C 1 -C 6 alkyl, phenyl, or phenyl (C 1 -C 6 alkyl); and R 4 is hydrogen or C 1 -C 6 alkyl, phenyl (C 1 -C 6 alkyl), cycloalkyl, or cycloalkyl (C 1 -C 6 alkyl).
Claim 3
Dependent Claim
12 words
A compound according to claim 1 wherein A is a ##STR40## group.
Claim 4
Dependent Claim
15 words
A compound according to claim 2 wherein R 2 is (C 1 -C 6 alkoxy)benzyl.
Claim 5
Dependent Claim
36 words
A compound according to claim 3 wherein R 2 is 4-methoxybenzyl, R 4 is C 1 -C 4 alkyl, and R 3 is hydrogen, C 1 -C 4 alkyl, phenyl, or phenyl(C 1 -C 6 alkyl).
Claim 6
Dependent Claim
18 words
A compound according to claim 4 wherein R 1 is methyl and R 3 is hydrogen or methyl.
Claim 7
Dependent Claim
11 words
A compound according to claim 5 wherein R 4 is 2-methylpropyl.
Claim 8
Dependent Claim
13 words
A compound according to claim 6 wherein chiral center a has S stereochemistry.
Claim 9
Dependent Claim
11 words
A compound according to claim 7 wherein R 3 is hydrogen.
Claim 10
Dependent Claim
101 words
A compound according to claim 8 having the following NMR spectrum: NMR (d 6 -DMSO) 0.7-0.9 (6H, m, {CH 3 } 2 CH); 1.3 (1H, m, {CH 3 } 2 CH); 1.9-2.2 (3H, 2×m, CH 2 CH); 2.50 (3H, m, CHCH 2 CO+CH 2 CHCO); 2.6 (2H, m, ArCH 2 ); 2.6 (3H, d, NHCH 3 ); 3.7 (3H, s, OCH 3 ); 4.3-4.4 (1H, m, ArCH 2 CH); 6.75-7.1 (4H, 2×d, J=8 Hz, aromatic); 7.9 (1H, m, NHCH 3 ); 8.05 (1H, d, CONHCH); 8.65 (1H, s, NHOH {D 2 O exchange}); 10.4 (1H, s, NHOH {D 2 O exchange}).
Claim 11
Dependent Claim
11 words
A compound according to claim 7 wherein R 3 is methyl.
Claim 12
Dependent Claim
106 words
A compound according to claim 10 having the following NMR spectrum; NMR (d 6 -DMSO) 0.64-0.92 (9H, m, {CH 3 } 2 CHCH 2 ); 1.30 (3H, m, CH 3 CH); 2.20-2.40 (2H, m, CH 3 CH and CH 3 CHCH); 2.45 (2H, m, ArCH 2 ); 2.55 (3H, d, J=4 Hz, NHCH 3 ); 3.68 (3H, s, OCH 3 ); 4.45 (1H, m, ArCH 2 CH); 6.80 and 7.16 (4H, two d's, J=7 Hz, aromatic); 7.72 (1H, m, NHCH 3 ); 8.18 (1H, d, J=7 Hz, CONHCH 3 ); 8.72 (1H, s, NHOH {D 2 O exchange}); 10.37 (1H, s, NHOH {D 2 O exchange}).
Claim 13
Dependent Claim
11 words
A compound according to claim 5 wherein R 4 is butyl.
Claim 14
Dependent Claim
11 words
A compound according to claim 12 wherein R 3 is hydrogen.
Claim 15
Dependent Claim
71 words
A compound according to claim 13 having the following NMR spectrum: NMR (d 4 -methanol): 0.86 (3H, t, J=7 Hz, CH 3 ); 1.0-1.5 (6H, M, 3×CH 2 ); 2.0-2.4 (2H, m, CH 2 CH); 2.5-2.7 (1H, m, CH 2 CH); 2.8-3.2 (2H, m, --CH 2 ArOMe); 3.76 (3H, s, OCH 3 ); 4.46 (1H, m, CHCH 2 Ar); 6.84 (2H, d, J=7 Hz, ArH); 7.14 (2H, d, J=7 Hz, ArH).
Claim 16
Dependent Claim
11 words
A compound according to claim 2 wherein R 2 is hydroxybenzyl.
Claim 17
Dependent Claim
20 words
A compound according to claim 15 wherein R 1 is methyl, R 3 is hydrogen, and R 4 is 2-methylpropyl.
Claim 18
Dependent Claim
105 words
A compound according to claim 16 having the following NMR spectrum: NMR (d 6 -DMSO): 0.74 (6H, m, [CH 3 ] 2 CH); 0.90-1.06 (1H, m, [CH 3 ] 2 CH); 1.19-1.43 (2H, m, CHCH 2 CH); 1.94-2.24 (2H, m, COCH 2 CH); 2.59 (3H, d, J=6 Hz, NHCH 3 ); 2.60-3.02 (3H, m, CH 2 CH and CH 2 Ar); 4.29 (1H, m, NHCH[CH 2 ]CO); 6.61 and 6.99 (4H, AA 1 BB 1 system, J AB =8 Hz, Ar); 7.88 (1H, m, CONHCH); 8.00 (1H, d, J=7 Hz, NHCH 3 ); 8.80 (1H, s, NHOH); 9.15 (1H, s, ArOH); 10.44 (1H, s, NHOH).
Claim 19
Dependent Claim
117 words
A compound according to claim 16 having the following NMR spectrum: NMR (d 6 -DMSO): 0.62 and 0.73 (each 3H, each d, J=5 Hz, [CH 3 ] 2 CH); 0.75-0.87 (2H, m, CHCH 2 CH); 2.20 (1H, m, [CH 3 ] 2 CH); 1.91-2.24 (2H, m, COCH 2 CH); 2.45-2.60 (2H, m, CH 2 Ar); 2.63 (3H, d, J=5 Hz, NHCH 3 ); 3.12 (1H, m, CH 2 CH[CH 2 ]CO); 4.28 (1H, m, NHCH[CH 2 ]CO); 6.61 and 7.01 (4H, AA 1 BB 1 system, J AB =8 Hz, Ar); 7.91 (1H, d, J=5 Hz, CONHCH); 8.30 (1H, d, J=7 Hz, NHCH 3 ); 8.79 (1H, s, NHOH); 9.16 (1H, s, ArOH); 10.55 (1H, s, NHOH).
Claim 20
Dependent Claim
11 words
A compound according to claim 2 wherein R 2 is benzyl.
Claim 21
Dependent Claim
20 words
A compound according to claim 19 wherein R 1 is methyl, R 3 is hydrogen, and R 4 is 2-methylpropyl.
Claim 22
Dependent Claim
109 words
A compound according to claim 20 having the following NMR spectrum: NMR (d 6 -DMSO): 0.71 (3H, d, J=6 Hz, [CH 3 ] 2 CH); 0.76 (3H, d, J=6 Hz, [CH 3 ] 2 CH); 0.92 (1H, m, [CH 3 ] 2 CH); 1.26 (2H, m, CHCH 2 CH); 1.95 (2H, m, COCH 2 CH); 2.50-2.85 (1H, m, CH 2 CH[CH 2 ]CO); 2.57 (3H, d, J=5.5 Hz, NHCH 3 ); 2.76-3.08 (2H, m, CH 2 Ar); 4.37 (1H, m, NHCH(CH 2 CO); 7.21 (5H, m, Ar); 7.92 (1H, d, J=4.5 Hz, CONHCH); 8.07 (1H, d, J=8 Hz, CONHCH 3 ); 8.79 (1H, s, CONHOH); 10.42 (1H, s, NHOH).
Claim 23
Dependent Claim
28 words
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.
Claim 24
Dependent Claim
10 words
A compound according to claim 1 of the formula ##STR41##
Claim 25
Dependent Claim
10 words
A compound according to claim 1 of the formula ##STR42##
References Cited (Backward Citations)
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US4105789A
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1991-05-10 | 1991-11-09 | 1992-05-10 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1995-05-10 | 1995-11-09 | 1996-05-10 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1999-05-10 | 1999-11-09 | 2000-05-10 | $7700.00 | Window Closed / Lapsed |