Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-05-08
1994-08-30
Fay, Zohreh
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514395, A61K 31505, A61K 31415
Patent
active
053428420
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Racemic or optically active compounds of the formula (I) as defined below are useful in the treatment of asthma, or inflammatory airway or skin diseases, particularly chronic asthma, hay fever, psoriasis, atopic dermatitis and dermatitis due to contact hypersensitivity.
There is currently little useful therapy for the treatment of chronic asthma. Dexamethasone, a steriod used in such therapy, has many side effects, and there is a continuing need for therapeutic agents which, even though they may enjoy less potent activity than dexamethasone are relatively free of such side effects at dosages effective in the treatment of asthma. The same is true of atopic dermatitis, a chronically relapsing, pruritic, inflammatory skin disease, which, like asthma, generally occurs in individuals with familial history of allergic condition.
Compounds of the formula (I) and their utility as antidepressants have been recently disclosed by Saccomano et al., in published International Patent Application WO87/06576.
A particularly valuable method for the synthesis of the optically active compounds of the formula (I) wherein X is oxygen, R.sup.2 is methyl, R.sup.1 is exo-bicyclo-[2.2.1]hept-2-yl, and Y is 3,4,5,6-tetrahydropyrimid-2(1H)-on-4-yl, which is detailed below, is also disclosed in International Patent Application No. PCT/US89/05228, filed Nov. 13, 1989.
SUMMARY OF THE INVENTION
We have now found that racemic and optically active compounds of the structural formula ##STR3## wherein X is O or NH; ##STR4## R.sup.3 is hydrogen, (C.sub.1 -C.sub.3)alkyl, (C.sub.2 -C.sub.3)alkenyl, benzyl or phenethyl; and and the pharmaceutically acceptable salts thereof when X is NH; are valuable in the treatment of asthma and inflammatory airway and skin diseases, particularly chronic asthma, hay fever, psoriasis, atopic dermatitis and dermatitis due to contact hypersensitivity.
Exemplary of R.sup.1 as (C.sub.7 -C.sub.10)polycycloalkyl are bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bycyclo[3.2.1]octyl, tricyclo[5.2.1.0.sup.2,6 ]decyl, and tricyclo [3.3.1.1.sup.3,7 ]decyl.
The preferred compounds have R.sup.2 as methyl, and X as oxygen. The more valuable compounds have Y as 3,4,5,6-tetrahydropyrimid-2(1H) -on-4-yl: ##STR5## and R.sup.1 as bicyclo[2.2.1]hept-2-yl: ##STR6##
The most valuable compound of the present invention, in addition to having the preferred values of R.sup.2, X and Y which are noted above, R.sup.1 as exo-bicyclo [2.2.1]hept-2-yl: ##STR7## including the racemic form thereof and each of the optically active isomers which make up the racemate.
The present invention is specifically directed to pharmaceutical compositions and a method of treating humans suffering from asthma or an inflammatory airway or skin disease with a compound of the formula (I), as defined above. These compounds are particularly valuable in the treatment of chronic asthma, psoriasis and atopic dermatitis.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of treating asthma or an inflammatory disease as noted above, the compounds of the formula (I) are readily prepared by the preparative methods of Saccomano et al., cited above.
A preferred method for the synthesis of the optically active compounds of the formula (I) wherein X is oxygen R.sup.1 is exo-bicyclo[2.2.1]hept-2-yl, is R.sup.2 is methyl and Y is 3,4,5,6-tetrahydropyrimid-2(1H)-on-4-yl is specifically exemplified below.
As noted at page 25 of patent application WO87/06576cited above, the compounds of present utility possess in vitro activity as inhibitors of phosphodiesterases prepared from cerebral cortices of rats. More pertinent to its utility in the treatment of asthma are their activity as inhibitors of phosphodiesterases derived from guinea pig lung, as detailed below in Example 1. Utility in the treatment of asthma is further reflected by the ability of the present compounds of formula (I) to inhibit in vivo eosinophil migration into sensitized lung tissue in antigen challenged guinea pigs, as detailed in Example 2. Utility of the present compounds in
REFERENCES:
patent: 4582834 (1986-04-01), Stenzel et al.
Patent Abstracts of Japan, vol. 10, No. 178 (C-355) [2234], Jun. 21st 1986; & JP-A-61 27 973 (Fujisawa Pharmaceut. Co.) Jul. 2, 1986.
Journal of Investigative Dermatology, vol. 84, 1985, pp. 477-482, The Williams & Wilkins Co.; K. D. Cooper et al.: "Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro".
Journal of Investagative Dermatology, vol. 73, No. 4, 1979, pp. 261-263 The Williams & Wilkins Co.; M. A. Stawiski et al.: "Ro 201724: An agent that significantly improves psoriatic lesions in double-blind clinical trails".
Scott R. Grewe et al., "Elevated leukocyte cyclic AMP-phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness", J. Allerbgy Clin. Imnul., vol. 70, No. 6, pp. 452-457 (1982).
Fay Zohreh
Ginsburg Paul H.
Holtrust Gezina
Pfizer Inc.
Richardson Peter C.
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