Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-10-22
2001-03-06
Moezie, F. T. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C548S321500, C548S492000, C548S535000, C548S517000, C548S527000, C548S537000, C548S190000, C548S112000, C548S233000, C548S217000, C548S314700, C544S360000, C544S372000, C544S374000, C544S369000, C544S224000, C544S386000, C544S391000, C544S112000, C544S121000, C544S123000, C544S214000, C544S215000, C544S238000, C544S295000, C544S333000, C544S128000, C546S278400, C546S279100, C546S258000, C546S261000, C546S275400, C546S280400, C546S283400, C546S022000, C546S112000, C546S146000, C546S156000, C546S209000, C546S
Reexamination Certificate
active
06197750
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel classes of compounds which are inhibitors of interleukin-1&bgr; converting enzyme and related proteases (ICE/ced-3 family of cysteine proteases), as well as pharmaceutical compositions comprising these compounds and to methods of using such pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Interleukin 1 (“IL-1”) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al.,
Immunology Today,
7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. Mosely, B. S. et al.,
Proc. Nat. Acad. Sci.,
84:4572-4576 (1987); Lonnemann, G. et al.,
Eur. J. Immunol.,
19:1531-1536 (1989).
IL-1&bgr; is synthesized as a biologically inactive precursor, proIL- 1&bgr;. ProIL-1&bgr; is cleaved by a cysteine protease called interleukin-1&bgr; converting enzyme (“ICE”) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P. R. et al.,
J. Biol. Chem.,
265:14526-14528 (1992); A. D. Howard et al.,
J. Immunol.,
147:2964-2969 (1991).
ICE is a cysteine protease localized primarily in monocytes. In addition to promoting the pro-inflammatory and immunoregulatory properties of IL-1&bgr;, ICE, and particularly its homologues, also appear to be involved in the regulation of cell death or apoptosis. Yuan, J. et al.,
Cell,
75:641-652 (1993); Miura, M. et al.,
Cell,
75:653-660 (1993); Nett-Giordalisi, M. A. et al.,
J. Cell Biochem.,
17B::117 (1993). In particular, ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer's and Parkinson's disease. Marx, J. and M. Baringa,
Science,
259:760-762 (1993); Gagliardini, V. et al.,
Science,
263:826-828 (1994).
Thus, disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as the myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Such inhibitors are also useful for the repopulation of hematopoietic cells following chemo- and radiation therapy and for prolonging organ viability for use in transplantation.
ICE/ced-3 inhibitors represent a class of compounds useful for the control of the above-listed disease states. Peptide and peptidyl inhibitors of ICE have been described. However, such inhibitors have been typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J. J. and D. W. Norbeck, in
Drug Discovery Technologies
, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. These undesirable properties have hampered their development into effective drugs.
Accordingly, the need exists for compounds that can effectively inhibit the action of the ICE/ced-3 family of proteases, for use as agents for preventing unwanted apoptosis, and for treating chronic and acute forms of IL-1 mediated diseases such as inflammatory, autoimmune or neurodegenerative diseases. The present invention satisfies this need and provides further related advantages.
SUMMARY OF THE INVENTION
In general, the compounds of this invention incorporate a (N-substituted)oxamyl group as a dipeptide mimetic. The resulting compounds exhibit improved properties relative to their peptidic counterparts, for example, such as improved cell penetration or improved absorption and metabolic stability resulting in enhanced bioavailability.
One aspect of the instant invention is the compounds of the Formula I:
wherein A, B R
1
and R
2
are as defined below, as well as pharmaceutically acceptable salts thereof.
A further aspect of the instant invention is a pharmaceutical composition comprising a compound of the above Formula I and a pharmaceutically-acceptable carrier therefor.
Another aspect of this invention involves a method for treating an autoimmune disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
Yet another aspect of the instant invention is a method for treating an inflammatory disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
A further aspect of the instant invention is a method for treating a neurodegenerative disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
Another aspect of the instant invention is a method of preventing ischemic injury to a patient suffering from a disease associated with ischemic injury comprising administering an effective amount of the pharmaceutical composition discussed above to a patient in need of such treatment.
A further aspect of the instant invention is a method for expanding of hematopoietic cell populations and/or enhancing their survival by contacting the cells with an effective amount of the pharmaceutical composition discussed above. Cell populations included in the method of the invention include (but are not limited to) granulocytes, monocytes, erthrocytes, lymphocytes and platelets for use in cell transfusions.
An alternate aspect of the instant invention is a method of prolonging the viability of an organ that has been removed from the donor for the purpose of a future transplantation procedure, which comprises applying an effective amount of the pharmaceutical composition discussed above to the organ, thereby prolonging the viability of the organ as compared to an untreated organ. The organ may be an intact organ, or isolated cells derived from an organ (e.g., isolated pancreatic islet cells, isolated dopaminergic neurons, blood or hematopoietic cells).
These and other aspects of this invention will be evident upon reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, one aspect of the instant invention is the compounds of the Formula I:
wherein:
A is a natural or unnatural amino acid of Formula IIa-i:
B is a hydrogen atom, a deuterium atom, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, 2-benzoxazolyl, substituted 2-oxazolyl, (CH
2
),cycloalkyl, (CH
2
)
n
phenyl, (CH
2
)
n
(substituted phenyl), (CH
2
)
n
(1 or 2-naphthyl), (CH
2
)
n
(heteroaryl), halomethyl, CO
2
R
12
, CONR
13
R
14
, CH
2
ZR
15
, CH
2
OCO(aryl), CH
2
OCO(heteroaryl), or CH
2
OPO(R
16
)R
17
, where Z is an oxygen or a sulfur atom, or B is a group of the Formula IIIa-c:
R
1
is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, heteroaryl, (heteroaryl)alkyl, R
1a
(R
1b
)N, or R
1c
O; and
R
2
is hydrogen, lower alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or substituted phenylalkyl;
and wherein:
R
1a
and R
1b
are independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, heteroaryl, or (heteroaryl)alkyl, with the proviso that R
1a
and R
1b
cannot both be hydrogen;
R
1c
is alkyl, cycloalkyl, (cycloalkyl)alkyl, phe
Karanewsky Donald S.
Ternansky Robert J.
Idun Pharmaceuticals, Inc.
Moezie F. T.
Seed Intellectual Property Law Group PLLC
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