Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-15
1998-02-10
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514378, 514379, 546176, 548240, 548241, 548245, C07D26104, A61K 3142
Patent
active
057169675
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a series of 3-aryl-2-isoxazoline-5-hydroxamic acid compounds which are selective inhibitors of phosphodiesterase type IV (PDE.sub.IV) and as such are useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory conditions.
This invention also relates to the pharmaceutically acceptable salts of said compounds; to a method of using such compounds in inhibiting PDE.sub.IV, and in the treatment of inflammatory conditions, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary 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, 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, 1:2, 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 pyrimidone compounds have been disclosed to be useful as antidepressants by Saccomano et al., in European Patent Application EPO 247 725 A2 published Dec. 2, 1987. 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-5-hydroxamic acid compounds and to the pharmaceutically acceptable salts of such compounds. These new compounds possess inhibitory activity against PDE.sub.IV and as such are useful in treating inflammatory conditions, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis or dermatitis in a mammal, 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
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3; 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, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, --OR.sup.1 and --OR.sup.2 ; the aromatic portion of the optionally substituted phenoxyalkyl are optionally independently substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ; R.sup.1 is (C.sub.1 -C.sub.4)alkyl, phenylalkyl having one to four carbon atoms in the alkyl portion fluoromethyl, difluoromethyl, trifluoromethyl, or --(CH.sub.2).sub.q -quinoline wherein q is 1,2 or 3; alkoxyalkyl having 3 to 7 carbons in the alkoxy portion and 2 to 4 carbons in the alkyl portion, o
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Gottlieb, M.S. et al. (ed.), "Current Topics in AIDS: vol. 1", John Wiley & Sons, 1988, pp. 51-55.
CA 71:124413, corresponding to GB patent 1,164,510, "Analgesic isoxazole derivatives", Inperial Chemical Industries Ltd., 1969.
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Benson Gregg C.
Ivy C. Warren
Pfizer Inc.
Richardson Peter C.
Smith Lyman H.
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