Catechol diethers derivatives useful as pharmaceutical agents

Details Catechol diethers derivatives useful as pharmaceutical agents Catechol diethers derivatives useful as pharmaceutical agents

1998-06-01

2000-02-22

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546297, 546309, C07D21375, A61K 3144

Patent

active

060280867

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to catechol diethers containing a long lipophilic sidechain 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 a is 0, 1, 2, 3 or 4; or unsaturated (C.sub.4 -C.sub.7) heterocyclic group 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; optionally be substituted by 1 to 6 halo, (C.sub.1 -C.sub.4)alkyl, trifluoromethyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy, cyano, nitro, (C.sub.2 -C.sub.4)alkenyl, (C.sub.3 -C.sub.6)cycloalkoxy, NR.sup.5 R.sup.6, CONR.sup.5 R.sup.6, CO.sub.2 R.sup.6 and SO.sub.2 NR.sup.5 R.sup.6 groups wherein R.sup.5 and R.sup.6 are each independently hydrogen or (C.sub.1 -C.sub.4)alkyl;
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above.
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The positions on the pyridinyl ring of formula I, as used herein, are defined as follows: ##STR3##
The compounds of formula I include only those structures known to be stable to those skilled in the art.
Preferred compounds of formula I include those wherein b is 1.
Other preferred compounds of formula I include those wherein V is O.
Other preferred compounds of formula I include those wherein W is (C.sub.4 -C.sub.8)alkyl, X is O and Y is (C.sub.3 -C.sub.7)alkyl.
Other preferred compounds of formula I include those wherein Z is (C.sub.6 -C.sub.10)aryl.
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