Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-04-02
1987-09-22
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514338, 514363, 514366, 514367, 514371, 514372, 514375, 514377, 514380, 514411, 544331, 546270, 546271, 546272, 548139, 548151, 548159, 548181, 548214, 548218, 548233, 548246, 548431, 548450, 548486, A61K 3141, C07D49804, C07D491048, C07D51504
Patent
active
046955712
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
Rheumatoid arthritis, which affects 3-4% of the population, is characterized by inflammation and pain of joints. Although the etiology of rheumatoid arthritis is not known both steroid and non-steroidal therapy have been employed to alleviate the symptoms of this illness. It is to this latter class of chemotherapeutic agents that the compounds of the present invention, namely tricyclic oxindole carboxamides, relate.
BACKGROUND ART
The potent non-steroidal antiinflammatory agent, Piroxicam, 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was reported in U.S. Pat. No. 3,591,584. More recently, antiinflammatory activity was found in simple non-steroidal oxindole-3-carboxamides, U.S. Pat. No. 3,634,453.
DISCLOSURE OF INVENTION
In accordance with the present invention, it has now been found that a group of novel tricyclic oxindole carboxamide derivatives are useful as antiinflammatory agents.
The first group of compounds in this series are of the formulae: ##STR1## and the pharmaceutically acceptable base salts thereof, where Y is oxygen or sulfur; X is N, CH or C(CH.sub.3); R.sub.1 is alkyl of one to three carbon atoms or phenyl; R.sub.2 is phenyl, monosubstituted phenyl the substituent being fluoro, chloro, trifluoromethyl, methylthio, methoxy, acetyl, ethoxycarbonyl or methylsulfinyl, disubstituted phenyl each substituent being fluoro or methoxy, or heterocyclic or mono or dimethyl heterocyclic where said heterocyclic is 2-thiazolyl, 2-oxazolyl, 5-isothiazolyl, 3-isoxazolyl, benzothiazolyl, 2-thiazolinyl, 2-thiadiazolyl, 2-pyrimidinyl or pyridyl; R.sub.3 and R.sub.4 are each hydrogen or methyl and n is an integer of 1 or 2.
Preferred within this first group are compounds of formula 1, where Y is oxygen, X is CH, R.sub.3 is hydrogen and R.sub.1 is alkyl as defined. Especially preferred are those compounds where R.sub.1 is ethyl and R.sub.2 is 2-thiazolyl, 4-methyl-2-thiazolyl, 4-fluorophenyl or 5-methyl-2-thiazolyl.
Also preferred are compounds of formula 1 where Y is sulfur, X is CH, R.sub.3 is hydrogen and R.sub.1 is alkyl as defined. Expecially preferred is the compound where R.sub.1 is ethyl and R.sub.2 is 5-methyl-2-thiazolyl.
Also preferred in this first group are compounds of formula 2 where R.sub.1 is alkyl as defined, R.sub.3 and R.sub.4 are each hydrogen and n is 1. Especially preferred is the compound where R.sub.1 is ethyl and R.sub.2 is 4-fluorophenyl.
The second group of compounds of the present invention are of the formulae: ##STR2## and the pharmaceutically acceptable base salts thereof, where Y is oxygen or sulfur; R.sub.1 is alkyl of one to three carbon atoms or phenyl; Z is oxygen or methylene; n is an integer of 1 or 2; and R.sub.5 is phenyl, fluorophenyl, difluorophenyl, chlorophenyl, pyridyl, 2-thiazolyl or monomethyl-2-thiazolyl.
Preferred within this second group are compounds of formula 3 where Y is oxygen and R.sub.1 is alkyl as defined. Especially preferred are those compounds where R.sub.5 is 5-methyl-2-thiazolyl or 2-thiazolyl and R.sub.1 is ethyl.
Also preferred in this second group are compounds of formula 3 where Y is sulfur and R.sub.1 is alkyl as defined. Especially preferred is the compound where R.sub.5 is 5-methyl-2-thiazolyl and R.sub.1 is ethyl.
The third type of compounds of interest are of the formula ##STR3## and the pharmaceutically acceptable base salts thereof, wherein R.sub.1 is alkyl of one to three carbon atoms or phenyl and R.sub.6 is fluorophenyl, difluorophenyl, pyridyl, 2-thiazolyl or 5-methyl-2-thiazolyl.
Preferred within this third group are compounds wherein R.sub.1 is alkyl as defined. Especially preferred is the compound wherein R.sub.6 is 5-methyl-2-thiazolyl and R.sub.1 is ethyl.
Also claimed is a method of treating an inflammatory disease in a mammalian subject, which comprises administering to said mammalian subject an antiinflammatory disease treating amount of a compound of formula 1, 2, 3, 4 or 5 or pharmaceutically acceptable salt thereof wherein R.sub.1 through R.sub.6, n, X, Y and Z are as
REFERENCES:
patent: 3749731 (1973-07-01), Zinnes
patent: 4644005 (1987-02-01), Melvin
Frost Albert E.
Gerstl Robert
McManus James M.
Pfizer Inc.
Richardson Peter C.
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