Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-07
2004-09-14
Balasubramanian, Venkataraman (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254040, C514S269000, C514S326000, C514S340000, C546S272100, C546S209000, C544S111000, C544S367000, C544S315000
Reexamination Certificate
active
06790846
ABSTRACT:
TECHNICAL FIELD
The present invention is directed to certain isoxazolone compounds that inhibit the release of inflammatory cytokines such as interleukin-1 (1L-1) and tumor necrosis factor (TNF) from cells. The compounds of the invention, therefore, are useful in treating diseases involving unwanted cytokine activity.
BACKGROUND
Many cytokine-mediated diseases and conditions are associated with excessive or unregulated production or activity of one or more cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 8 (IL-8). IL-1 and TNF are important proinflammatory cytokines, which along with several other related molecules, mediate inflammatory cellular response in a wide variety of diseases and conditions. Proinflammatory cytokines such as IL-1 and TNF stimulate other inflammatory mediators such as nitric oxide, cyclooxygenase-2, matrix metalloproteinases. The inhibition of these cytokines is consequently both directly and indirectly beneficial in controlling, reducing and alleviating many of these disease states.
Elevated levels of proinflammatory cytokines are implicated in many disease states, including rheumatoid arthritis (Dinarello, C. A., et al. 1984
, Rev. Infect. Disease
6:51; Maini, R. E. 1999
, The Lancet
354:1932; Weinblatt, M. E. 1999
, New Eng. J. Med.
340:253), osteoarthritis (Pelletier and Pelletier 1989
, J. Rheum.
16:19; Pelletier, et al. 1993
, Am. J. Path.
142:95; Farahat, et al. 1993
, Ann. Rheum. Dis.
52:870; Tiku, et al. 1992
, Cell Immunol.
140:1; Webb, et al. 1997, O. & C. 5:427; Westacott, et al. 2000, O. & C. 8:213), diabetes (McDaniel, et al. 1996
, Proc. Soc. Exp. Biol. Med.
211:24), HIV/AIDS (Kreuzer, et al. 1997
, Clin. Exp. Immunol.
45:559), acute and chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, Crohn's disease and ulcerative colitis (Rankin, E. C. C., et al. 1997
, British J. Rheum.
35:334; Stack, W. A., et al. 1997
, The Lancet
349:521); congestive heart failure Han et al. 2000
, Trends Cardiovasc. Med.
10:19; Hunter et al. 1999
, N. Engl. J. Med.
341:1276; Behr et al. 2000
, Circ.
102:II-289;Shimamoto et al. 2000
, Circ:
102:II-289; Aukrust et al. 1999
, Am. J. Cardiol.
83:376, hypertension (Singh, et al. 1996
J. Hypertension
9:867), chronic obstructive pulmonary disease, septic shock syndrome (Dinarello, C. A. 1995
, Nutrition
11:492), tuberculosis, adult respiratory distress, asthma (Renzetti, et al.
Inflammation Res.
46:S143), atherosclerosis (Elhage, et al. 1998
, Circulation
97:242), muscle degeneration, periodontal disease (Howells 1995
, Oral Dis.
1:266), cachexia, Reiter's syndrome, gout, acute synovitis, eating disorders including anorexia and bulimia nervosa (Holden, et al. 1996
, Med. Hypothesis
47:423), fever, malaise, myalgia and headaches (Beisel 1995
Am. J. Clin. Nutr.
62:813). Inhibition of proinflammatory cytokine production, therefore, may offer the opportunity to treat or prevent a wide range of diseases and conditions involving elevated levels of proinflammatory cytokines.
Numerous small molecule inhibitors of cytokine production have been disclosed. (See Salituro, F. G. et al. 1999, 6, 807-823 and references cited therein). In particular, 1,2,4-triazoles (WO 00/10563 and WO 97/47618), isoxazoles (WO 01/12621), and imidazoles (WO 00/26209, WO 99/03837 and references therein) have been disclosed. However, certain liver toxicities, such as increased liver size and increased cytochrome P450 induction, have recently been reported (Foster, M. L. et al.,
Drug News Perspect,
2000, 13(8), 488-497 and Adams, J. L. et al.,
Bioorg Med Chem Lett,
1998, 8, 3111-3116). In light of the this potential toxicity and the risks associated with developing human drugs, a continuing need exists for potent new small molecule inhibitors of cytokine production with improved pharmacokinetic and safety profiles.
All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
SUMMARY OF THE INVENTION
The invention provides compounds which are potent cytokine inhibitors and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention is directed to compounds having a structure according to Formula (I):
wherein R
1
, m, A, B, and are defined herein.
The invention also includes optical isomers, diastereomers, and enantiomers of the structure above, and pharmnaceutically-acceptable salts thereof.
The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted cytokine activity. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for diseases associated with unwanted cytokine activity using these compounds or the compositions comprising them.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to a novel group of compounds which are potent inhibitors of cytokines and which are effective in treating conditions characterized by excess activity of these enzymes.
Terms and Definitions
“Alkenyl” is a monovalent hydrocarbon chain having 2 to 18 carbon atoms, preferably 2 to 12, more preferably 2 to 6 carbon atoms and at least one (preferably only one) carbon—carbon double bond. Alkenyl groups may be straight or branched. Preferred branched alkenyl groups have one or two branches, preferably one branch. Alkenyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkenyl groups have 1 to 3 substituents unless otherwise specified. Alkenyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkenyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term “lower alkenyl” refers to an alkenyl group having from 2 to 6, preferably from 2 to 4, carbon atoms.
“Alkyl” is a monovalent saturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6 carbon atoms. Alkyl groups may be straight or branched. Preferred branched alkyl groups have one or two branches, preferably one branch. Alkyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkyl groups have 1 to 3 substituents unless otherwise specified. Alkyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term “lower alkyl” refers to an alkyl group having from 1 to 6, preferably from 1 to 4, carbon atoms.
“Alkoxy” refers to the group —OR where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl. Preferred alkoxy groups include methoxy, ethoxy, and iso-propoxy.
“Alkynyl” is a monovalent hydrocarbon chain having 2 to 18 carbon atoms, preferably 2 to 12, more preferably 2 to 6 carbon atoms and at least one (preferably only one) carbon—carbon triple bond. Alkynyl groups may be straight or branched. Preferred branched alkynyl groups have one or two branches, preferably one branch. Alkynyl groups may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkynyl groups have 1 to 3 substituents unless otherwise specified. Alkynyl group substituents include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and c
Clark Michael Philip
De Biswanath
Djung Jane Far-Jine
Laughlin Steven Karl
Natchus Michael George
Balasubramanian Venkataraman
Echler Sr. Richard S.
The Procter & Gamble & Company
Upite David V.
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