Organic compounds -- part of the class 532-570 series – Organic compounds – Hydroxamic acids – chalcogen analogs or salts thereof
Reexamination Certificate
2001-02-26
2003-04-22
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Hydroxamic acids, chalcogen analogs or salts thereof
C564S153000, C514S575000, C514S616000
Reexamination Certificate
active
06552223
ABSTRACT:
This invention relates to (N-hydroxy)acylamino compounds and in particular to such compounds with a peptidic structure. This invention further relates to processes for preparing such compounds, to pharmaceutical and veterinary compositions containing them and to their use in methods of therapeutic treatment.
The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified into families and subfamilies as described in N. M Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMP) such as the collagenases (MMP1, MMP8, MMP13), the gelatinases (MMP2, MMP9), the stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloelastase (P12), enamelysin (MMP19), the MT-MMPs (MMP14, MMP15, MMP16, MMP17); the reprolysin or adamalysin or MDC family which includes the secretases and sheddases such as TNF converting enzymes (ADAM10 and TACE); the astacin family which include enzymes such as procollagen processing proteinase (PCP); and other metalloproteinases such as aggrecanase, the endothelin converting enzyme family and the angiotensin converting enzyme family.
Metalloproteinases are believed to be important in a plethora of physiological disease processes that involve tissue remodelling such as embryonic development, bone formation and uterine remodelling during menstruation. This is based on the ability of the metalloproteinases to cleave a broad range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of biological important cell mediators, such as tumour necrosis factor (TNF); and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (for a more complete list see N. M. Hooper et al., (1997) Biochem J. 321:265-279).
Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastro-intestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema, dermatitis); in tumour metastasis or invasion; in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; in bone resorptive disease (such as osteoporosis and Paget's disease)); in diseases associated with aberrant angiogenesis; the enhanced collagen remodelling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, ulceration of the skin, post-operative conditions (such as colonic anastomosis) and dermal wound healing; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer's disease; and extracellular matrix remodelling observed in cardiovascular diseases such as restenosis and atheroscelerosis.
A number of metalloproteinase inhibitors are known; different classes of compounds may have different degrees of potency and selectivity for inhibiting various metalloproteinases. We have discovered a new class of compounds that are inhibitors of metalloproteinases and are of particular interest in inhibiting MMP-13. The compounds of this invention have beneficial potency and/or pharmacokinetic properties.
MMP13, or collagenase 3, was initially cloned from a cDNA library derived from a breast tumour [J. M. P. Freije et al. (1994) Journal of Biological Chemistry 269(24: 16766-16773]. PCR-RNA analysis of RNAs from a wide range of tissues indicated that MMP13 expression was limited to breast carcinomas as it was not found in breast fibroadenomas, normal or resting mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1). Subsequent to this observation MMP13 has been detected in transformed epidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ. 8(2):243-250], squamous cell carcinomas [N. Johansson et al., (1997) Am. J. Pathol. 151(2):499-508] and epidermal tumours [K. Airola et al., (1997) J. Invest. Dermatol. 109(2):225-23 1]. These results are suggestive that MMP13 is secreted by transformed epithelial cells and may be involved in the extracellular matrix degradation and cell-matrix interaction associated with metastasis especially as observed in invasive breast cancer lesions and in malignant epithelia growth in skin carcinogenesis.
Recent published data implies that MMP13 plays a role in the turnover of other connective tissues. For instance, consistent with MMP13's substrate specificity and preferential to degrade type II collagen [P. G. Mitchell et al., (1996) J. Clin Invest. 97(3):761-768; V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550], MMP13 has been hypothesised to serve a role during primary ossification and skeletal remodelling [M. Stahle-Backdahl et al., (1997) Lab. Invest. 76(5):717-728; N. Johansson et al., (1997) Dev. Dyn. 208(3):387-397], in destructive joint diseases such as rheumatoid and osteo-arthritis [D. Wernicke et al., (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al., (1996) J. Clin. Invest. 97(3):761-768; O. Lindy et al., (1997) Arthritis Rheum 40(8):1391-1399]; and during the aseptic loosening of hip replacements [S. Imai et al., (1998) J. Bone Joint Surg. Br. 80(4):701-710]. MMP13 has also been implicated in chronic adult periodontitis as it has been localised to the epithelium of chronically inflamed mucosa human gingival tissue [V. J. Uitto et al., (1998) Am. J. Pathol 152(6):1489-1499] and in remodelling of the collagenous matrix in chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol. 109(1):96-101].
The present invention provides a compound of the formula (I):
R
1
—CO—N(OH)—CR
2
R
3
—CR
4
R
5
—CONH—CR
6
R
7
—CONR
8
R
9
(I)
wherein:
R
1
is C
1-6
alkyl, aryl or arylC
1-6
alkyl;
R
2
is hydrogen, C
1-6
alkyl, C
3-8
,cycloalkyl, aryl or arylC
1-6
alkyl;
R
3
is hydrogen, C
1-6
alkyl or arylC
1-6
alkyl;
or R
2
and R
3
, together with the carbon atom to which they are joined, form a C
3-8
cycloalkyl ring;
R
4
is hydrogen, C
1-6
alkyl or arylC
1-6
alkyl;
R
5
is hydrogen, C
1-6
alkyl or arylC
1-6
alkyl;
R
6
is hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
3-8
cycloalkylC
1-6
alkyl, arylC
1-6
alkyl, heteroarylC
1-6
alkyl or the side-chain of a naturally occurring amino acid;
R
7
is hydrogen or C
1-6
alkyl;
R
8
is hydrogen, C
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkenyl, arylC
1-6
alkyl, heteroarylC
1-6
alkyl or heterocyclylC
1-6
alkyl;
R
9
is hydrogen or C
1-6
alkyl;
or R
8
and R
9
, together with the nitrogen atom to which they are joined, form a heterocyclic ring;
wherein any group or ring in R
1
-R
9
is optionally substituted;
or a pharmaceutically-acceptable salt or in vivo hydrolysable precursor thereof
“Aryl in the terms “aryl” and “arylC
1-6
alkyl” typically means phenyl or naphthyl, preferably phenyl. “Heteroaryl” in the terms “heteroaryl” and “heteroarylC
1-6
alkyl” means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of ‘heteroaryl’ include thienyl, pyrrolyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolinyl and isoquinolinyl. “Heterocyclyl” in the terms “heterocyclyl” and heterocyclylC
1-6
alkyl” means a non-aromatic mono- or bicyclic 5-10 membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur. Examples of ‘heterocyclyl’
Cartwright Rebecca J
Dowell Robert I
AstraZeneca AB
Kumar Shailendra
Ropes & Gray
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