2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids

Details 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids

2000-01-27

2003-04-08

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S573000

Reexamination Certificate

active

06544984

ABSTRACT:

FIELD OF INVENTION
This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-hydroxamic acids which act as matrix metalloproteinase inhibitors and as inhibitors of TNF-&agr; converting enzyme(TACE). The compounds of the present invention are useful in disease conditions mediated by matrix metalloproteinases and TACE, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenases, stromelysins and gelatinases. Of these, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors.
For example, it is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology as reported in “Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy”,
Drugs and Aging,
11:229-244 (1997).
Other conditions mediated by MMPs include restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/ neo-vascularization and corneal graft rejection. Studies relating to these conditions are set forth, e.g., in “Recent Advances in Matrix Metalloproteinase Inhibitor Research”, R. P. Beckett et al.,
Research Focus,
1:16-26, (1996);
Curr. Opin. Ther. Patents.
4(1): 7-16, (1994);
Curr. Medicinal Chem.,
2: 743-762, (1995);
Exp. Opin. Ther. Patents,
5(2): 1087-110, (1995);
Exp. Opin. Ther. Patents,
5(12): 1287-1196, (1995); “Inhibition of Matrix Metallo-proteinases: Structure Based Design”,
Current Pharmaceutical Design,
2:524-661, (1996). “Matrix Metalloproteinase Inhibitor Drugs”,
Emerging Drugs,
2:205-230 (1997).
TNF-&agr; converting enzyme (TACE) catalyzes the formation of TNF-&agr; from membrane bound TNF-&agr; precursor protein. TNF-&agr; is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIV infection, in addition to its well-documented antitumor properties. Research with anti-TNF-&agr; antibodies in transgenic animals has demonstrated that blocking the formation of TNF-&agr; inhibits the progression of arthritis. This observation has recently been extended to humans as described in “TNF-&agr; in Human Diseases”,
Current Pharmaceutical Design,
2:662-667 (1996).
It is expected that small molecule inhibitors of MMPs and TACE would have the potential for treating a variety of disease states. Although a variety of MMP and TACE inhibitors are known, many of these molecules are peptidic and peptide-like which demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above.
U.S. Pat. No. 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) hydroxyamic acids and their use as MMP inhibitors. WO 97/18194, discloses N-(arylsulfonyl)tetrahydroisoquinolone-hydroxamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors. WO 97/20824 and U.S. Pat. No. 5,753,653 disclose 1-(arylsulfonyl)-4-(substituted)piperazine-2-hydroxamic acids,
4-(arylsulfonyl)morpholine-3-hydroxamic acids, 4-(arylsulfonyl)-tetrahydro-2H,1,4-thiazine-3-hydroxamic acids, 3-(substituted-1-(arylsulfonyl)hexahydro-2-hydroxamic acids and related compounds as useful MMP inhibitors.
WO 98/08822, WO 98/08823 and WO 98/08825, disclose 6-membered 1-(arylsulfonyl)hexahydropyrimidine-2-hydroxamic acids, 1-substituted-3-[(4-methoxybenzenesulfonyl)]hexahydropyrimidine-4-hydroxamic acids, 4-(arylsulfonyl)-tetrahydro-1,2-thiazine-3-hydroxamic acids and (arylsulfonyl)-4-substitutedpiperazine-2-hydroxamic acids. WO 98/08827 discloses 4-(arylsulfonyl)-hexahydrothiazepine-3-hydroxamic acids and 4-(arylsulfonyl)-hexadydro[1,4]diazepine-3-hydroxamic acids.
SUMMARY OF THE INVENTION
This invention relates to novel derivatives of substituted 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxamide which exhibit inhibitory activity against MMPs. The compounds of the present invention are represented by the following formula 1
 
wherein
R is selected from hydrogen, (C
1
-C
3
)alkyl, —CN, —OR′, —SR′, —CF
3
, —OCF
3
, Cl, F, NH
2
, NH(C
1
-C
3
)alkyl, —N(R′)CO(C
1
-C
3
)alkyl, —N(R′)(R′), NO
2
, —CONH
2
, —SO
2
NH
2
, —SO
2
N(R′)(R′), or —N(R′)COCH
2
O—(C
1
-C
3
)alkyl, wherein R′ is (C
1
-C
3
) alkyl or hydrogen;
R
4
is (C
2
-C
6
) alkyl-O— containing one triple bond;
 
wherein R″ is hydrogen, —CH
2
OH, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkyl-O—CH
2
—, (C
1
-C
6
)alkyl-S—CH
2
—, (C
1
-C
6
)alkyl-NH—CH
2
—, [(C
1
-C
3
)alkyl]
2
-NCH
2
—, (C
1
-C
6
)oydodkyl-O—CH
2
—, ((C
1
-C
3
)dkyl)
2
-N—(CH
2
2-4
NHCH
2
—, [(C
1
-C
3
)dkyl)
2
-N—(CH
2
)
2-4
N(CH
3
)CH
2
—,
 
 
R
1
and R
2
are each, independently, hydrogen or C
1
-C
3
alkyl; R
3
is (C
1
-C
8
)alkyl, NH
2
CH
2
CO—, (C
1
-C
6
)alkylNHCH
2
CO—, HO(CH
2
)
m
CO—, HCO—, Aryl(CH
2
)
n
CO—, Heteroaryl(CH
2
)
n
CO—, (C
1
-C
3
)alkyl-O—(CH
2
)
n
CO—, (C
1
-C
3
)alkylCO—, (C
1
-C
3
)alkylCO—NHCH
2
CO—, (C
3
-C
7
)cycloalkylCO—, (C
1
-C
3
)alkylSO
2
—, Aryl(CH
2
)
n
SO
2
—, Heteroaryl(CH
2
)
n
SO
2
—, (C
1
-C
3
)alkyl-O—(CH
2
)
m
—SO
2
—, (C
1
-C
3
)alkyl-O—(CH
2
)
m
—, (C
1
-C
3
)alkyl-O—(C
1
-C
3
)alkyl-O—(C
1
-C
3
)alkyl, HO—(C
1
-C
3
)alkyl-O—(C
1
-C
3
)alkyl, Aryl-O—CH
2
CO—, Heteroaryl-O—CH
2
CO—, ArylCH═CHCO—, HeteroarylCH═CHCO—, (C
1
-C
3
)alkylCH═CHCO—,
 
Aryl(C
1
-C
3
)alkyl, Heteroaryl(C
1
-C
3
)alkyl, ArylCH═CHCH
2
—,
HeteroarylCH═CHCH
2
—, (C
1
-C
6
)alkylCH═CHCH
2
—,
 
R′OCH
2
CH(OR′)CO—, (R′OCH
2
)
2
C(R′)CO—,
 
[(C
1
-C
6
)alkyl]
2
-N—(C
1
-C
6
)alkyl CO—, or (C
1
-C
6
)alkyl-NH—(C
1
-C
6
)alkylCO—;
wherein
m=1 to 3; n=0 to 3;
Aryl is
 
Heteroaryl is
 
wherein X is hydrogen, halogen, (C
1
-C
3
) alkyl or —OCH
3
and R and R′ are as defined above;
L is hydrogen, (C
1
-C
3
)alkyl, —CN, —OR′, —SR′, —CF
3
, —OCF
3
, Cl, F, NH
2
, —NH—(C
1
-C
3
)alkyl, —N(R′)CO(C
1
-C
3
)alkyl, N(R′)(R′), —NO
2
, —CONH
2
, —SO
2
NH
2
, —SO
2
N(R′)(R′), —N(R′)COCH
2
O—(C
1
-C
3
)alkyl,
 
M is
 
 
 or N(R′)(R′) where R′ is as defined above;
W is O, S, NH or N(C
1
-C
3
)alkyl;
Y is hydrogen, F, Cl, CF
3
or OCH
3
; and X′ is halogen, hydrogen, (C
1
-C
3
)alkyl, O—(C
1
-C
3
)alkyl, or —CH
2
OH; and
pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C
1
-C
3
) alkyl, —CN, —OR′, —SR′, —CF
3
, —OCF
3
, Cl, F, NH
2
, NH(C
1

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