Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-05
1999-02-09
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514307, 514380, A61K 3147, A61K 3142
Patent
active
058695117
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is the national stage of International Application No. PCT/IB95/00078, filed Feb. 3, 1995, designating, inter alia, the United States which is a continuation-in-part of U.S. application Ser. No. 08/209,125, filed Mar. 9, 1994, now abandoned.
BACKGROUND OF THE INVENTION
This invention relates to a method of inhibiting production of TNF (tumor necrosis factor) in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound of the formula (I) (shown below) or a pharmaceutically acceptable salt thereof, which, as such are also useful in the treatment or alleviation of inflammatory conditions or disease including, but not limited to rheumatoid arthritis, osteoarthritis, asthma, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and inflammatory bowel disease, sepsis, septic shock, tuberculosis, graft versus host disease and cachexia associated with AIDS or cancer; and this invention also relates to pharmaceutical compositions useful therefor.
TNF is produced by monocytes/macrophages and has a variety of biological activities relevant to the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). Firstly, TNF can promote the accumulation of all leukocyte types by stimulating the endothelium to express adhesion molecules (T. H. Pohlman et al., J. Immunol, 136, pp. 4548-4553, 1986) and to release secondary chemotactic cytokines such as interleukin 8 (R. M. Strieter et al., Science, 243, pp. 1467-1469, 1989). Secondly, TNF can stimulate cells within the joint to synthesize and express the inducible cyclooxygenase enzyme (COX 2) and the inducible NO synthase. The products of these enzymes, prostaglandins and NO, are important mediators of pain and inflammation. Thirdly, and perhaps most importantly, TNF, like IL-1, can activate chondrocytes to degrade their own extracellular matrix and suppress synthesis of cartilage matrix components leading to cartilage destruction. In addition to these effects, TNF plays a pivotal role in the regulation of the production of other cytokines. This has been demonstrated in cultures of dissociated RA synovial cells where blocking the activity of TNF can inhibit the secretion of IL-1 (F. M. Brennan et al., Lancet, 2, pp. 244-247, 1989). Thus, blocking TNF production should prevent the synthesis of other downstream cytokines such as IL-1. Finally, TNF has been immunolocalised in both RA and OA synovial membranes(M. N. Farahat et al., Ann. Rheum. Dis., 52, pp. 870-875, 1993).
TNF is recognized to be involved in many infectious and auto-immune diseases (W. Fiers, FEBS Letters, 1991, 285, p. 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al., Clinical Immunology and Immunopathology, 1992, 62, p. S11).
The compounds utilized in the present invention are disclosed and claimed in co-pending PCT Publication Number WO 95/14681 published Jun. 1, 1995 and PCT Publication Number WO 95/14680 published Jun. 1, 1995, both of which are assigned to the assignee hereof, and wherein said compounds are disclosed as having phosphodiesterase type IV (PDE.sub.IV) inhibiting activity. The teachings thereof are incorporated herein by reference.
SUMMARY OF THE INVENTION
This invention is concerned with a method of inhibiting production of TNF (tumor necrosis factor) in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound selected from the group consisting of compounds of the formula (I) ##STR1## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds, and the pharmaceutically acceptable salts thereof, wherein CON(R.sup.6)(OH); is (C.sub.1 -C.sub.4)alkyl; and R.sup.6 is hydrogen or (C.sub.1 -C.sub.3)alkyl; hydrogen, (C.sub.1 -C.sub.6)alkyl, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 1 to 6 c
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Cohan Victoria Lee
Kleinman Edward Fox
Benson Gregg C.
Goddard Carl J.
Pfizer Inc.
Richardson Peter C.
Travers Russell
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