Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-04-21
1994-03-01
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514339, 546174, 546176, 546273, C07D40306, C07D40312, A61K 31475, A61K 3147
Patent
active
052907880
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel indole derivatives. The compounds of the present invention inhibit the action of lipoxygenase enzyme, and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of the arachidonic acid metabolism is the release of esterified arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase. Free fatty acids are then metabolized either by cylooxgenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently, several review articles on lipoxygenese inhibitors have been reported. (see H. Masamune and L. S. Melvin, Sr., Annual Reports in Medicinal Chemistry 24 (1989) pp. 71-80 (Academic), B. J. Fitzsimmons and J. Rokach Leukotriens and Lipoxygenases (1989) pp. 427-502 (Elsevier).
Compounds having structural features similar to those of the present invention are disclosed in European Patent Publication Nos. 288962A, 313295A and 313296A and in Japanese Application Publication No. 104584.
SUMMARY OF THE INVENTION
The compounds of the present invention are of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, where R.sub.1 is naphthyl, quinolyl, pyridyl, 2-phenylthiazolyl, 4,6-dimethylpyrimidinyl, benzothienyl, 5-tetrazolyl, or alkylureido of two to six carbon atoms; m is an integer of 1 to 2; Y.sub.1 is hydrogen or alkyl of one to four carbon atoms; Y.sub.2 is hydrogen, alkyl of one to four carbon atoms, pyridylvinylene, benzoyl or substituted benzoyl where said substituent is methyl, methoxy, fluoro, chloro or trifluoromethyl, benzyl or substituted benzyl where said substituent is methyl, methoxy, fluoro, chloro or trifluoromethyl; A is --CH.sub.2 -- or --C(O)--; n is an integer of 0 to 3; and X is hydrogen, alkyl of one to three carbon atoms, pyridyl, hydroxy, thienyl, carboxy, alkoxycarbonyl of two to four carbon atoms, amino, benzyloxycarbonylamine, phenyl or substituted phenyl wherein said substituent is methyl, methoxy, carboxy, alkoxycarbonyl of two to four carbon atoms, fluoro, chloro or trifluoromethyl with the proviso that when A is --C(O)--, n is 1 and when D is 0, X is hydrogen.
A preferred group of compounds are those wherein R is 2-quinolyl; m is 1; Y.sub.2 is hydrogen or alkyl of one to four carbon atoms and A is --CH.sub.2 --. Especially preferred within this group are 1-(3-methoxybenzyl)-5-(2-quinolylmethoxy)-indole, 1-(3-picolyl)-5-(2-quinolylmethoxy)indole, 1-(3-[3-pyridyl]-n-propyl)-5-(2-quinolylmethoxy)indole, 3-ethyl-1-(3-picolyl)-2-n-propyl-5-(2-quinolylmethoxy)-indole, 1-(3-hydroxypropyl)-5-(2-quinolylmethoxy)indole, 3-(5-[2-quinolylmethoxy]indol-1-yl)propionic acid, 4-([5-(2-quinolylmethoxy)indol-1-yl]methyl)benzoic acid and 1-n-heptyl-5-(2-quinolylmethoxy)indole.
A second preferred group of compounds are those wherein R.sub.1 is 2-pyridyl, m is 1, Y.sub.1 and Y.sub.2 are each hydrogen and A is --CH.sub.2 --. Especially preferred within this group are 1-(4-chlorobenzyl)-5-(2-pyridylmethoxy)indole and 1-(3-picolyl)-5-(2-pyridylmethoxy)indole.
The present invention also includes a method for treating an allergic or inflammatory condition in a mammal which comprises administering to said mammal an antiallergic or antiiflammatory effective amount of a compound of formula I.
The present
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Morita Hiromasa
Nakane Masami
Stevens Rodney W.
Benson Gregg C.
Jones James T.
Pfizer Inc.
Richardson Peter C.
Springer David B.
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