Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-12
2004-04-13
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S342000, C514S339000, C514S336000, C546S015000, C546S152000, C546S268100, C546S276400, C546S279700, C546S281700
Reexamination Certificate
active
06720329
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel spiro-cyclic &bgr;-amino acid derivatives as matrix metalloproteinases (MMP), TNF-&agr; converting enzyme (TACE), and/or aggrecanase inhibitors, pharmaceutical compositions containing the same, and methods of using the same.
BACKGROUND OF THE INVENTION
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP's.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al.
J. Bone Joint Surg
. 1970, 52A, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al.
Arthritis Rheum
. 1978, 21, 761-766, Woessner et al.
Arthritis Rheum
. 1983, 26, 63-68 and Woessner et al.
Arthritis Rheum
. 1984, 27, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al.
Arthritis Rheum
. 1993, 36, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al.
Ann. Rep. Med. Chem
. 1990, 25, 175-184, AP, San Diego).
Tumor necrosis factor-&agr; (TNF-&agr;) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF-&agr; has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-&agr; has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-&agr; with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al.
Lancet
1994, 344, 1105), non-insulin dependent diabetes melitus (Lohmander, L. S. et al.
Arthritis Rheum
. 1993, 36, 1214-22) and Crohn's disease (MacDonald et al.
Clin. Exp. Immunol
. 1990, 81, 301).
Compounds which inhibit the production of TNF-&agr; are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-&agr; converting enzyme (TACE), the enzyme responsible for TNF-&agr; release from cells, were purified and sequenced (Black et al.
Nature
1997, 385, 729; Moss et al.
Nature
1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-&agr; from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF-&agr; production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-&agr; production may also have a particular advantage in diseases where both mechanisms are involved.
EP 0,780,286 describes MMP inhibitors of formula A:
wherein Y can be NHOH, R
1
and R
2
can combine to form a cycloalkyl or heterocyclo alkyl group, R
3
and R
4
can be a variety of groups including H, and R
5
can be substituted aryl.
WO 97/20824 depicts MMP inhibitors of formula B:
wherein ring V contains six atoms, Z is O or S, and Ar is an aryl or heteroaryl group. Ar is preferably a monocyclic aryl group with an optional para substituent or an unsubstituted monocyclic heteroaryl group.
EP 0,818,442 illustrates MMP inhibitors of formula C:
wherein Ar is optionally substituted phenyl or naphthyl, Z can be absent and X and Y can be a variety of substituents. Compounds of this sort are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TACE, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel spiro-cyclic hydroxamic acids useful as MMP, TACE, and/or aggrecanase inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
It is another object of the present invention to provide novel compounds of the present invention for use in therapy.
It is another object of the present invention to provide the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPS, TACE, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by
Chen Xiao Tao
Duan Jingwu
Ott Gregory R.
Voss Matthew E.
Belfield Jing S.
Bristol-Myers Squibb Pharma
Desai Rita
Vance David H.
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