Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-16
2004-05-25
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S300000, C514S303000, C514S311000, C514S314000, C514S322000, C514S326000, C514S393000, C514S412000, C514S414000, C514S459000, C514S469000, C544S052000, C544S102000, C544S105000, C544S128000, C546S079000, C546S089000, C546S104000, C546S118000, C546S121000, C546S165000, C546S175000, C546S196000, C546S199000, C546S201000, C546S202000, C548S306100, C548S309700, C548S452000, C548S467000, C548S525000, C549S414000, C549S471000
Reexamination Certificate
active
06740649
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel cyclic hydroxamic acids as inhibitors of matrix metalloproteinases (MMP), TNF-&agr; converting enzyme (TACE), aggrecanase or a combination thereof, 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.
Tumor necrosis factor-&agr; (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. Compounds which inhibit the production of TNF-&agr; are of therapeutic importance for the treatment of inflammatory disorders.
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.
Prostaglandins (PG) play a major role in the inflammation process and the inhibition of PG production has been a common target of anti-inflammatory drug discovery. Many NSAIDS have been found to prevent the production of PG by inhibiting the enzyme cyclooxygenase (COX). Among the two isoforms of COXs, COX-1 is constitutively expressed. COX-2 is an inducible isozyme associated with inflammation. Selective COX-2 inhibitor was believed to maintain the efficacy of traditional NSAIDs, which inhibit both isozymes, and produce fewer and less drastic side effects. As a result, development of selective COX-2 inhibitors has attracted major interest in the pharmaceutical industry. Because of the significant roles of PGs and TNF-&agr; in inflammation, combined use of COX-2 and TACE inhibitors may have superior efficacy to either therapy alone in some inflammatory diseases.
WO01/70673 describes matrix metalloproteases and TNF-&agr; inhibitors of the following formula:
wherein ring B is a 3-13 membered non-aromatic carbocyclic or heterocyclic ring; A is a variety of groups including hydroxamic acid; Z is absent, a C
3-13
carbocycle or a 5-14 membered heterocycle; Z
a
is H, a C
3-13
carbocycle or a 5-14 membered heterocycle; U
a
, X
a
and Y
a
are linkers; and, R
1
, R
2
, R
2a
, R
2b
, and R
3
are a variety of groups. Compounds specifically described in WO01/70673 are not considered to be part of the present invention.
It is desirable to find new compounds with improved pharmacological characteristics compared with known MMP and/or TACE inhibitors. For example, it is preferred to find new compounds with improved MMP and/or TACE inhibitory activity and selectivity for an MMP and/or TACE versus other metalloproteases (e.g., specificity for one MMP versus another). It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories, but are not limited to: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages and/or once-daily dosing); (c) factors which decrease blood concentration peak-to-trough characteristics (e.g., clearance and/or volume of distribution); (d) factors that increase the concentration of active drug at the receptor (e.g., protein binding and volume of distribution); (e) factors that decrease the liability for clinical drug—drug interactions (e.g., cytochrome P450 enzyme inhibition or induction); (f) factors that decrease the potential for adverse side-effects (e.g., potential chemical or metabolic reactivity and limited CNS penetration); and, (g) factors that improve manufacturing costs or feasibility (e.g., difficulty of synthesis, number of chiral centers, chemical stability, and ease of handling).
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, the present invention provides novel cyclic hydroxamic acids useful as MMP, TACE and/or aggrecanase inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides 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.
The present invention provides 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.
The present invention provides 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.
The present invention provides 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.
The present invention provides a method for treating inflammatory disorders, comprising: administering, to a host in need of such treatment, a therapeutically effective amount of one of the compounds of the present invention, in combination with one or more additional anti-inflammatory agents selected from selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAP kinase inhibitors, TNF-&agr; inhibitors, TNF-&agr; sequestration agents, and methotrexate.
The present invention provides novel compounds of the present invention for use in therapy.
The present invention provides 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, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):
or a stereoisomer or pharmaceutically acceptable sal
Chen Xiao-Tao
Duan Jingwu
Lu Zhonghui
Ott Gregory R.
Belfield Jing S.
Bristol--Myers Squibb Company
Dentz Bernard
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