Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-04-08
1992-06-02
Brust, Joseph Paul
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 80, 514418, 548414, 548468, 548486, A61K 3140, C07D40306
Patent
active
051187035
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is concerned with antiinflammatory agents and, in particular, with enol esters and ether prodrugs of 3-acyl-2-oxindole-1-carboxamides, a class of known nonsteroidal antiinflammatory agents.
The use of oxindole as antiinflammatory agents was first reported in U.S. 3,634,453, and consisted of 1-substituted-2-oxindole-3-carboxamides. Recently, a series of 3-acyl-2-oxindole-1-carboxamides was disclosed in U.S. Pat. No. 4,556,672 to be inhibitors of the cyclooxygenase (CO) and lipoxygenase (LO) enzymes and to be useful as analgesic and antiinflammatory agents in mammalian subjects.
SUMMARY OF THE INVENTION
The present invention provides antiinflammatory ether and ester prodrugs of the formula ##STR2## wherein X and Y are each hydrogen, fluoro or chloro; R.sup.1 is 2-thienyl or benzyl; and R is alkanoyl of two to ten carbon atoms, cycloalkylcarbonyl of five to seven carbon atoms, phenylalkanoyl of seven to ten carbon atoms, chlorobenzoyl, methoxybenzoyl, thenoyl, omega-alkoxycarbonylalkanoyl said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms; alkoxy carbonyl of two to ten carbon atoms; phenoxycarbonyl; 1-(acyloxy)alkyl said acyl having one to four carbon atoms and said alkyl having two to four carbon atoms; 1-(alkoxycarbonyloxy)alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms; alkyl of one to three carbon atoms; alkylsulfonyl of one to three carbon atoms; methylphenylsulfonyl or dialkylphosphonate said alkyl each of one to three carbon atoms.
Particularly preferred are compound of formula (I) where R.sup.1 is 2-thienyl, X is chloro, Y is hydrogen and R is alkanoyl of two to ten carbon atoms. Preferred within this group are compounds where R is acetyl, propionyl and i-butyryl.
A second preferred group of compounds of formula (I) are those where R.sup.1 is 2-thienyl, X is chloro, Y is hydrogen and R is phenylalkanoyl of seven to ten carbon atoms. Especially preferred within this group is the compound where R is phenylacetyl.
A third preferred group of compounds are those of formula (I) where R.sup.1 is 2-thienyl, X is chloro, Y is hydrogen and R is omega alkoxycarbonylalkanoyl, said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms. Especially preferred within this group is the compound where R is omega ethoxycarbonylpropionyl.
A fourth group of preferred compounds of formula (I) are those where R.sup.1 is 2-thienyl, X is chloro, Y is hydrogen and R is alkoxycarbonyl of two to ten carbon atoms. Especially preferred within this group are compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl.
A fifth group of preferred compounds of formula (I) are those where R.sup.1 is 2-thienyl, X is chloro, Y is hydrogen and R is 1-(alkoxycarbonyloxy)alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms. Especially preferred within this group is the compound where R is 1-(ethoxycarbonyloxy)ethyl.
A sixth group of preferred compounds of formula (I) are those where R.sup.1 is 2-thienyl, X is chloro, Y is hydrogen and R is alkylsulfonyl of one to three carbon atoms. Especially preferred within this group is the compound where R is methylsulfonyl.
A seventh group of preferred compounds of formula (I) are those where R.sup.1 is 2-thienyl, X is fluoro, Y is chloro and R is alkanoyl of two to ten carbon atoms. Especially preferred within this group are the compounds where R is acetyl, propionyl and i-butyryl.
An eighth group of preferred compounds of formula (I) are those where R.sup.1 is 2-thienyl, X is fluoro, Y is chloro and R is alkoxycarbonyl of two to ten carbon atoms. Especially preferred within this group are the compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl.
The ninth group of preferred compounds of formula (I) are those where R.sup.1 is benzyl, X is hydrogen, Y is fluoro and R is alkanoyl having two to ten carbon atoms. Especially preferred within thi
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Crawford Thomas C.
Reiter Lawrence A.
Brust Joseph Paul
Haley Jacqueline
Lumb J. Trevor
Olson A. Dean
Pfizer Inc.
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