Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-13
2002-04-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S222200, C514S226800, C514S227800, C514S228800, C514S235500, C514S237200, C514S252010, C514S252030, C514S253010, C514S258100, C544S003000, C544S054000, C544S058400, C544S063000, C544S089000, C544S096000, C544S097000, C544S128000, C544S131000, C544S225000, C544S238000, C544S239000, C544S333000, C544S335000, C544S360000, C544S383000, C544S399000
Reexamination Certificate
active
06365587
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel substituted aryl hydroxamic acid derivatives as metalloproteinase inhibitors, and inhibitors of TNF, pharmaceutical compositions containing the same, and methods of using the same.
BACKGROUND OF THE INVENTION
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. In addition metalloproteinases have been shown to be involved in the processing of cell surface proteins that have been implicated in a number of diseases, including inflammatory disorders.
Tumor necrosis factor alpha (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) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF-&agr; are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase (MMP) or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP's are capable of cleaving TNF-&agr; from its cell associated to soluble form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-&agr; from cells.
The compounds of the current invention inhibit the production of TNF-&agr; from cells stimulated with LPS. Furthermore, some of the present compounds are selective for TNF-C inhibition over matrix metalloproteinases. This selectivity offers a distinct advancement over compounds of the current art, because non-selective MMP inhibitors have been found to produce toxic manifestations related to tendonitis and fibroplasia in clinical trials.
The compounds of the current invention do not inhibit MMPs at concentrations expected to produce a therapeutically positive response through the inhibition of TNF. The compounds of the present invention are therefore expected to be safer to patients taking the drug because of their selective inhibition profile for soluble TNF-&agr; production.
The present novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic 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, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, neuro-denerative diseases 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 mechansisms are involved.
WO 97/20824 describes MMP inhibitors of formula A:
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. WO 97/20824 does not disclose any compounds wherein Ar is a disubstituted phenyl or pyridyl or a bicyclic heteroaryl group.
The compounds of the current invention act as inhibitors of MPs, that process TNF-&agr;. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel substituted aryl hydroxamic acids which are useful as metalloprotease 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.
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 pharmaceutically acceptable salt or prodrug forms thereof, wherein A, p, X, Y, Z, R
b
, R
1
, R
2
, R
3
, and R
4
are defined below, are effective metalloprotease inhibitors with unique and specific inhibitory properties for TNF.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring A is a 5-8 membered heterocyclic ring containing 0-1 additional heteroatoms selected from the group: O, NH, S, SO, and SO
2
, and substituted with 0-3 R
a
;
R
a
, at each occurrence, is independently selected from the group: ═O, CH
3
, CH
2
CH
3
, CF
3
, Cl, F, OH, OCH
3
, and OCF
3
;
R
b
, at each occurrence, is independently F or CH
3
;
X is selected from the group: CH
2
, C(O), C(O)O, C(O)NH, S(O), S(O)
2
, S(O)NH, and S(O)
2
NH;
Y is selected from the group: (CH
2
)
n
, OCH
2
, CH
2
O, OCH(CH
3
), CH(CH
3
)O, OC(CH
3
)
2
, C(CH
3
)
2
O, OCF
2
, CF
2
O, S(O)
p
CH
2
, CH
2
S(O)
p
, NH, NHCH
2
, and CH
2
NH;
Z is CH or N;
R
1
is selected from the group: H, F, Cl, Br, I, CH
3
, CH
2
CH
3
, CH(CH
3
)
2
, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, CF
3
, and OCF
3
;
R
2
is selected from the group: F, Cl, Br, I, CH
3
, CH
2
CH
3
, CH(CH
3
)
2
, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, CF
3
, and OCF
3
;
R
3
is selected from the group: F, Cl, Br, I, CH
3
, CH
2
CH
3
, CH(CH
3
)
2
, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, CF
3
, and OCF
3
;
provided that when Z is N, R
2
and R
3
are other than F, Br, or I;
R
4
is H;
alternatively, R
3
and R
4
are taken together with the carbon atoms to which they are attached to form a 5-6 membered aromatic ring containing 0-2 heteroatoms selected from the group: O, S, NH, and N and substituted with 0-2 R
c
;
R
c
is selected from the group: H, F, Cl, Br, I, NO
2
, CH
3
, CH
2
CH
3
, CH(CH
3
)
2
, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, CF
3
, and OCF
3
;
when R
3
and R
4
are taken together, then R
2
is selected from the group: H, F, Cl, Br, I, CH
3
, CH
2
CH
3
, CH(CH
3
)
2
, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, CF
3
, and OCF
3
;
n is selected from the group: 1, 2, and 3; and,
p is selected from the group: 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides a compound of formula Ia or Ib:
wherein,
X is selected from the group: CH
2
, C(O), C(O)O, C(O)NH, S(O), S(O)
2
, S(O)NH, and S(O)
2
NH;
Y is selected from the group: CH
2
, (CH
2
)
2
, OCH
2
, CH
2
O, NH, NHCH
2
, and CH
2
NH;
Z is CH or N;
R
1
is selected from the group: H, F, Cl, Br, I
Decicco Carl P.
Voss Matthew E.
Wexler Ruth R.
Raymond Richard L.
Vance David H.
LandOfFree
Substituted aryl hydroxamic acids as metalloproteinase... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted aryl hydroxamic acids as metalloproteinase..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted aryl hydroxamic acids as metalloproteinase... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2875473