Phenyl-substituted cycloalkenyl compounds useful as PDE IV inhib

Details Phenyl-substituted cycloalkenyl compounds useful as PDE IV inhib Phenyl-substituted cycloalkenyl compounds useful as PDE IV inhib

1992-10-02

1994-11-08

Richter, Johann

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfur containing

568 42, 568 49, 568 52, 568329, 568330, 568644, C07C 43205, A61K 31075

Patent

active

053629159

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel compounds having pharmacological activity, to a process for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
A French thesis by Michel Marivet entitled `Contribution A L'Etude, Des Inhibiteurs De Phosphodiesterases` which was submitted on 23rd January 1987 to the University of Louis Pasteur in Strasbourg describes the following compounds ##STR3## It has now been discovered that certain novel compounds have potent and selective phosphodiesterase (IV) inhibition activity and elevate cyclic AMP levels. These compounds also inhibit TNF production.
Accordingly, the present invention provides a compound of formula (I): ##STR4## wherein: R.sub.1 is --CH.sub.3 or --CH.sub.2 CH.sub.3 unsubstituted or substituted by 1 to 3 fluorines;
X is O or S(O).sub.s where s=O to 2;
R.sub.2 is C.sub.4 -C.sub.6 cyclic alkyl, optionally substituted by one to three methyl groups or one ethyl group; --CH.sub.2 -cyclopentyl, --CH.sub.2 -cyclopropyl, 3-tetrahydrofuranyl, C.sub.1-7 alkyl, CH.sub.3 or CH.sub.2 CH.sub.3 substituted by one to three fluorines;
--(CH.sub.2).sub.n COO(CH.sub.2).sub.g CH.sub.3, or (CH.sub.2).sub.n O(CH.sub.2).sub.g CH.sub.3, wherein n is 2 to 4 and g is 0 to 2;
R.sub.3 represents a moiety of formula (a); ##STR5## wherein R.sub.4 and R.sub.5 each represent hydrogen or R.sub.4 and R.sub.5 together represent a bond;
B represents >C.dbd.O, >C.dbd.S or >CH--R.sub.6 wherein R.sub.6 represents H, OH, C.sub.1-6 alkoxy or C.sub.1-6 thioalkoxy; and m and r each independently represents zero or an integer in the range of 1 to 4 wherein m+r represents an integer in the range of from 2 to 4; with the proviso that when R.sub.1 is methyl, X is oxygen and, R.sub.2 is methyl or cyclopentyl, R.sub.3 does not represent cyclopent-1,2-ene-3-one.
Suitably, R.sub.1 represents methyl.
Suitably, R.sub.2 represents unsubstituted C4-C6 cycloalkyl.
Favourably, R.sub.2 is cyclopentyl or methyl and X is oxygen.
Suitably R.sub.3 is selected from the following structures: ##STR6## wherein B is C.dbd.O, CH.sub.2, --CH.sub.2 OH or CH.sub.2 OCH.sub.3.
Preferably R.sub.3 is of formula b) or c) and B is carbonyl, CH.sub.2 OH or CH.sub.2 OCH.sub.3.
Suitable salts are pharmaceutically acceptable salts.
It should be appreciated that some compounds of formula (I) may exist as geometric and/or stereo isomers. The present invention includes single geometric and/or stereo isomers and any mixtures thereof.
These compounds by virtue of their PDE IV activity are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophillic granuloma, psoriasis, rheumatoic arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus, (Kidney Int. 37: 362, 1990; Kidney Int. 35: 494, 1989).
These compounds also have a protective effect against the consequences of cerebral metabolic inhibition the said compounds improve data acquisition or retrieval following transient forebrain ischaemia and are therefore useful in the treatment of cerebral vascular and neuronal degenerative disorders associated with learning, memory and cognitive dysfunctions including cerebral senility, multi-infarct dementia, senile dementia of the Alzheimer type, age associated memory impairment and certain disorders associated with Parkinson's disease.
These compounds are also indicated to have neuroprotectant activity. They are therefore useful in the prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events, including cerebral ischaemia due to cardiac arrest, stroke and also after cerebral ischaemic events such as those resulting from surgery

REFERENCES:
patent: 4831059 (1989-05-01), Johnson et al.
Chem. Abs. vol. 110; No. 1, 1989 Jan. 2, B. Deb et al., p. 705, Abstract No. 7698g.
Chem. Abs. vol. 85, No. 25, 1976 Dec. 20, D. A. Pisanenko et al., p. 529, Abstract No. 192459f.
Chem. Abs. vol. 100; No. 1, 1984 Jan. 2, Katsumi Itoh et al., p. 505, Abstract No. 5901n.
Deb, B. et al.; Tet. Lett., vol. 29(17), pp. 2111-2114 (1988).
Psotta, K. et al.; Tetrahedron, vol. 35, pp. 255-257 (1979).
Pisanenko, D. A. et al.; Tezisy Dokl.-Simp. Khim. Tekhnol. Geterotsikl. Soedin. Goryuch. Iskop., 2nd, pp. 200-201 (1973).

Affiliated with

Also associated with

Rating

Phenyl-substituted cycloalkenyl compounds useful as PDE IV inhib does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Phenyl-substituted cycloalkenyl compounds useful as PDE IV inhib, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phenyl-substituted cycloalkenyl compounds useful as PDE IV inhib will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1784351