Heterocyclic hydroxamic acid derivatives as MMP inhibitors

Details Heterocyclic hydroxamic acid derivatives as MMP inhibitors Heterocyclic hydroxamic acid derivatives as MMP inhibitors

2000-01-19

2001-09-25

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S255020, C514S255030, C514S255050, C544S358000, C544S386000

Reexamination Certificate

active

06294539

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to heterocyclic hydroxamic acid derivatives which inhibit matrix metalloproteinases and such are useful in the treatment of diseases and conditions in which matrix metalloproteinases are involved, such as cancer, arthritis, tumor metastasis and multiple sclerosis (MS).
BACKGROUND OF THE INVENTION
The matrix metalloproteinases (MMP) are a family of zinc containing enzymes that degrade extracellular matrices. They are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. Most are excreted as inactive proenzymes and then activated extracellularly by serine proteases or other MMPs. Over the last decade the MMP family has grown rapidly. At least 16 members have now been identified, which are divided into four families by virtue of similarities of their domain structures (W. C. Powell, et al,
Curr. Top. Microbiol. Immunol.
213, 1, 1996). They include the Minimal Domain family with the only member (MMP-7), the Hemopexin Domain family (e.g. MMP-1, MMP-3, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13), the Fibronectin Domain family (e.g. MMP-2 and MMP-9) and the most recently discovered Transmembrane Domain family (e.g. MMP-14-MMP-17).
The MMPs have been extensively reviewed including a book (“Matrix Metallo-proteinases”, edited by William C. Parks and Robert P. Mecham, 1998, Academic Press). A role for these enzymes has been implicated in both normal and pathological processes. The loss of control of MMP activity and the elevated levels in MMP expression have been associated with several diseases. The proposed pathogenic roles for MMPs include the destruction of cartilage and bone in rheumatoid arthritis and osteoarthritis (T. E. Cawston,
Pharm. Ther.
70, 163, 1996; E. M. O'Byrne, et al;
Inflam. Res.
44, S117, 1995), tissue breakdown and remodeling during invasive tumor growth and tumor angiogenesis (L. A. Liotta, et al,
Sem. Camer Biol.
1, 99, 1990), degradation of myelin-basic protein in neuroinflammatory diseases (K. Gijbels, et al,
J. Neuroimmunol.
41, 29, 1992; S. Chandler, et al,
Neurosci. Lett.
201, 223, 1995), opening of the blood-brain barrier following brain injury (G. A. Rosenberg,
J. Neurotrauma,
12, 833,1995), increased matrix turnover in restenotic lesions (B. H. Strauss, et al,
Circ. Res.
79, 541, 1996), loss of aortic wall strength in aneuryms (R. W. Thompson, et al,
Ann. N.Y. Acad. Sci.
800, 157, 1996), and tissue degradation in gastric ulceration (U. K. Saarialho-Kere, et al,
Am. J. Pathol.
148, 519, 1996).
In view of the involvement of MMPs in a variety of disease states, the inhibition of these enzymes as a therapeutic target is now an area of intense interest within the pharmaceutical industry. A large number of such inhibitors have been identified and disclosed in the literature. Examples include WO9633166, WO9718207, and WO9633176 (Dupont Merck Pharm. Co.); U.S. Pat. No. 5,691,382, WO9625156, WO9702239, WO9719053, WO9718183, WO9719050, WO9633161, GB-2298423-A, WO9633165, WO9535275, WO9535276, WO9626233, and WO9703783 (British Biotech Pharm. Ltd.); WO9506031 and WO9641624 (Immunex Corp.); WO9709420 and WO9709430 (Celltech Therapeutics Ltd.); WO9742168 (Zeneca Ltd.); WO9749674, WO9732846, WO9740031, and WO9748688 (Pharmacia & Upjohn); WO9602240, WO9725981, WO9726257, WO9743250, WO9743249, and WO9523790 (SmithKline Beecham); WO9633991, WO9715553, and WO9731892 (Sankyo Co. Ltd.); WO9747599 (Fujisawa Pharm. Co. Ltd.); WO9633968 (Fuji Yakuhin Kogyo KK); WO9421612, JP8081443-A, and JP8325232-A (Otsuka Seiyaku KK); EP-0606046 (Ciba-Geigy AG); WO9722587 (Novartis AG); WO9720824 (Agouron Pharm., Inc.); WO9633172 (Pfizer, Inc.); WO9718194 (Hoechst AG); EP-0757984, WO9745402, EP-0757037, and WO9749679 (Ono Pharma Co. Ltd.); WO9727174 (Shionogi & Co. Ltd.); WO9719068, WO9744315, WO9723459, and WO9638434 (Warmer-Lambert Co.); EP-0780386-A1 (Hoffmann-La Roche AG & Agouron Pharm., Inc.); WO9724117 (Rhone-Poulenc Rorer Pharm., Inc.); WO9718469 and WO9718188 (Abbott Lab.); WO9615096, WO9743237, WO9743245, WO9743238, WO9743240, WO9743247, and WO9743239 (Bayer Corp.); WO9221360, WO9412169, and WO9711936 (Merck & Co., Inc.); WO9635711, WO9635712, WO9635714, WO9635687, WO9712861, WO9712902, WO9719075, WO9737973, WO9737974, and WO9738007 (Chiroscience Ltd.); WO9640204 (Affymax Tech. NV); WO9748685 (Glaxo Group Ltd.); WO9640745 (Osteoarthritis Sciences, Inc.); EP-0758021 (Polifarma SPA); EP-0758649 (Kureha Chem. Ind. Co. Ltd.). However, the majority of these inhibitors are peptidyl or peptide-like compounds which may exhibit a lack of bioavailability and poor pharmacokinetic profile. There is a continuing need for small molecule-based highly potent and orally bioavailable inhibitors useful in treating such diseases.
SUMMARY OF THE INVENTION
The present invention relates to heterocyclic hydroxamic acid derivatives of the general formula:
These compounds are useful in the treatment of diseases and conditions in which matrix metalloproteinases are involved, such as cancer, arthritis, tumor metastasis and multiple sclerosis (MS).
DESCRIPTION OF THE INVENTION
The present invention provides novel compounds of Formula (I) or pharmaceutical
acceptable salts thereof; wherein the broken line represents an optional double bond;
X is H, O, S;
n is 0 or 1;
R
1
is hydrogen, hydroxy, thio, nitro, cyano, azido, amino, trifluoromethyl, trifluoromethoxy, C
1
-C
6
alkyl, C
1
-C
6
alkyloxy, C
1
-C
6
alkylthio, C
1
-C
6
alkylamino, C
1
-C
6
alkenyl, C
1
-C
6
alkenyloxy, C
1
-C
6
alkenylamino, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkyloxy, C
3
-C
8
cycloalkylamino, C
3
-C
8
cycloalkylthio, C
1
-C
6
alkylcarbonylamino, C
3
-C
8
cycloalkylcarbonylamino, C
5
-C
10
aryl, C
5
-C
10
heteroaryl or C
5
-C
10
saturated heteroaryl; said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
2
, R
3
, R
4
, R
5
, and R
6
independently are H, trifluoromethyl, C
5
-C
10
aryl, C
5
-C
10
heteroaryl, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, saturated C
5
-C
10
heteroaryl, C
5
-C
10
aryl-C
1
-C
10
alkyl, C
5
-C
10
heteroaryl-C
1
-C
10
alkyl, COR
8
, CO
2
R
8
, CONR
8
R
9
, SO
2
NR
8
R
9
, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
7
is C
5
-C
10
aryl, C
5
-C
10
heteroaryl, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
6
cycloalkyl, saturated C
5
-C
10
heteroaryl, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
8
and R
9
independently are H, hydroxy, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
3
-C
10
cycloalkyl, C
5
-C
10
aryl, C
5
-C
10
heteroaryl, said aryl, heteroaryl, alkyl, alkenyl, and cycloalkyl optionally substituted with 1 to 3 groups of R
s
;
R
s
represents a member selected from the group consisting of halo, cyano, nitro, trihalomethyl, carbamoyl, hydroxy, OCF
3
, acyl, aryl, heteroaryl, S(O)R
8
, ═N(OR
8
), SO
2
R
8
, COOR
8
, —CONR
8
R
9
, —C
1
-C
6
alkylCONR
8
R
9
, C
1
-C
6
alkyloxy, aryloxy, arylC
1
-C
6
alkyloxy, thio, C
1
-C
6
alkylthio, arylthio, arylC
1
-C
6
alkylthio, NR
7
R
8
, C
1
-C
6
alkylamino, arylamino, arylC
1
-C
6
alkylamino, di(arylC
1
-C
6
alkyl)amino, C
1
-C
6
alkylcarbonyl, arylC
1
-C
6
alkylcarbonyl, C
1
-C
6
alkylcarboxy, arylC
1
-C
6
alkylcarboxy, —NR
7
CO
2
R
8
, —NR
7
COR
8
, —NR
9
O
2
R
8
, —NR
9
O
2
R
8
, —CONR
8
R
9
, —SO
2
NR
8
R
9
, —OCONR
8
R
9
, —C
1
-C
6
alkylaminoCONR
8
R
9
, arylC
1
-C
6
alkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, or a saturated or partial saturated cyclic 5,6 or 7 membered amine or lactam; said aryl, and heteroaryl optionally substituted with 1 to 3 groups of halo or C
1
-C
6
alkyl; wherein R
8
and R
9
are defined as above.
Definitions
As used herein, the “-” (e.g. —COR
8
which indicates the carbonyl attachment point to the scaffold) signifies a stable covalent bond, certain preferred points

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