Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-27
1999-12-21
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 82, A61K 3144, C07D47112
Patent
active
06004974&
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to tricyclic 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-.alpha.]pyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases as well as AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF. Compounds of the present invention may have combined PDE IV and TNF inhibitory activity.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans and to pharmaceutical compositions useful therefor.
Since the recognition that cyclic AMP is an intracellular second messenger (E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J. A. Beavo and D. H. Reifsnyder, TiPS, 1990, 11, 150), and their selective inhibition has led to improved drug therapy (C. D. Nicholson, R. A. Challiss and M. Shahid, TiPS, 1991, 12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M. W. Verghese et al., J. Mol. Cell Cardiol., 1989, 12 (Suppl. II), S 61) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases, including cachexia (W. Friers, FEBS Letters, 1991, 285, 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, S11).
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula ##STR2## and the pharmaceutically acceptable salts thereof; wherein R.sup.1 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.2 -C.sub.4)alkenyl, phenyl, dimethylamino, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl (C.sub.1 -C.sub.3)alkyl or (C.sub.1 -C.sub.6)acyl wherein the alkyl, phenyl or alkenyl groups may be substituted with up to two hydroxy, (C.sub.1 -C.sub.3)alkyl, or trifluoromethyl groups, or up to three halogens;
R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.14)alkyl, (C.sub.1 -C.sub.7)alkoxy(C.sub.1 -C.sub.7)alkyl, (C.sub.2 -C.sub.14)alkenyl, (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.3 -C.sub.7)cycloalkyl(C.sub.1 -C.sub.2)alkyl, a saturated or unsaturated (C.sub.4 -C.sub.7)heterocyclic(CH.sub.2).sub.n group wherein n is 0, 1 or 2, containing as the heteroatom one or two of the group consisting of oxygen, sulphur, sulphonyl, nitrogen and NR.sup.4 wherein R.sup.4 is hydrogen or (C.sub.1 -C.sub.4)alkyl; or a group of the formula ##STR3## wherein a is an integer from 1 to 5; b and c are 0 or 1; R.sup.5 is hydrogen, hydroxy, (C.sub.1 -C.sub.5)alkyl, (C.sub.2 -C.sub.5)alkenyl, (C.sub.1 -C.sub.5)alkoxy, (C.sub.3 -C.sub.6)cycloalkoxy, halogen, trifluoromethyl, CO.sub.2 R.sup.6, CONR.sup.6 R.sup.7, NR.sup.6 R.sup.7, NO.sub.2 or SO.sub.2 NR.sup.6 R.sup.7 wherein R.sup.8 and R.sup.7 are each independently hydrogen or (C.sub.1 -C.sub.4)alkyl; wherein Z is oxygen, sulphur, SO.sub.2, CO or NR.sup.8 wherein R.sup.8 is hydrogen or (C.sub.1 -C.sub.4)alkyl; and Y is (C.sub.1 -C.sub.5)alkylene or (C.sub.2 -C.sub.6)alkenyl optionally substituted with up to two (C.sub.1 -C.sub.7)alkyl
REFERENCES:
patent: 3697532 (1972-10-01), Hoehn
patent: 5545647 (1996-08-01), Tanaka
Nicholson CD et al. TIPS. 12, 19-27, Jan. 1991.
Cooper Kelvin
Duplantier Allen J.
Ginsburg Paul H.
Huang Evelyn Mei
Pfizer Inc
Richardson Peter C.
Speer Raymond M.
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