Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-05-15
1997-11-11
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514378, 514379, 514380, 548111, 548113, 548119, 548240, 548242, 548243, 548244, 548245, C07D26104, C07D26110, C07D26112, A61K 3142
Patent
active
056864345
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a series of 3-aryl-2-isoxazoline compounds which are selective inhibitors of phosphodiesterase (PDE) type IV and as such are useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases.
This invention also relates to the pharmaceutically acceptable salts of said compounds; to a method of using such compounds in inhibiting PDE.sub.IV, the treatment of inflammatory conditions and the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis and dermatitis in mammals, especially humans; and to pharmaceutical compositions useful therefor.
The "inflammatory conditions" which can be treated according to this invention include, but are not limited to, chronic obstructive pulmonary disease, septic shock, atopic dermatitis, bronchitis, rheumatoid arthritis and osteoarthritis.
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.sub.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.sub.IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
Certain isoxazoline phosphonic acid compounds are disclosed to be useful for the treatment of diseases of the immune system in U.S. Pat. No. 5,006,515.
Certain catechol diethers are disclosed to be useful as PDE.sub.IV inhibitors and as such are useful in the treatment of inflammatory diseases, AIDS, asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis and dermatitis, in copending U.S. patent application, Ser. No. 07/984,408 filed Dec. 2, 1992, which application is assigned to the assignee hereof.
Certain pyrimidone compounds have been disclosed to be useful as antidepressants by Saccomano et al., in European Patent Application EPO 247 725 A2. The same pyrimidone compounds have been disclosed to be useful against asthma and certain skin disorders in International Patent Application No. PCT/US90/02162, published May 30, 1991 as International Publication Number WO 91/07178.
SUMMARY OF THE INVENTION
This invention is concerned with a series of 3-aryl-2-isoxazoline compounds and to the pharmaceutically acceptable salts of such compounds. These new compounds are selective inhibitors of PDE.sub.IV, and as such are useful in the treatment of inflammatory conditions, AIDS, asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis and dermatitis in mammals, especially humans.
The compounds of the present invention are of the formula (I) ##STR1## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds and the pharmaceutically acceptable salts thereof wherein 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 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl, fluoro, chloro, bromo, iodo, --OR.sup.1 and --OR.sup.2 ; the aromatic portion of the optionally substituted phenoxyalky
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Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Rao Deepak R.
Richardson Peter C.
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