6-Acyloxy-1,4,6-pregnatrienes, their use as anti-inflammatory agents, methods for their manufacture, and 6-oxo-1,4-pregnadiene intermediates
AssigneeSchering Corporation
InventorRichard W. Draper
Life of this patent
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Abstract
Novel 6-acyloxy-3,20-dioxo-1,4,6-pregnatrienes and 6-acyloxy-3,20-dioxo-4,6-pregnadienes, useful anti-inflammatory agents, are prepared by reaction of the corresponding 3,6,20-trioxo-1,4-pregnadiene or 3,6,20-trioxo-4-pregnene with an acyl halide or an acid anhydride in pyridine. Preferred anti-inflammatory agents are 6-alkanoyloxy-9.alpha.-halogeno-16-methyl-1,4,6-pregnatriene-3,20-diones. Also described are novel 6-oxo-9.alpha.-halogeno-16-substituted-1,4-pregnadienes, useful as intermediates in preparing the corresponding 6-acyloxy-1,4,6-pregnatrienes and which also exhibit anti-inflammatory activity per se.
Claims30
A 6-acyloxy-3,20-dioxo-1,4,6-pregnatriene of the following formula I:
- ##STR13## wherein A is hydrogen or, provided Y is (H,.beta.OH), A is chlorine, fluorine or methyl;
- B is hydrogen or, together with Q, is a 14.alpha.,17.alpha.-alkylidenedioxy derivative;
- X is hydrogen, fluorine or chlorine;
- Y is oxygen, (H,.beta.OH), (H,.beta.OCOH);
- or (H,.beta.-chlorine) or (H,.beta.-fluorine) provided X is chlorine;
- Z is hydrocarboncarbonyl, alkoxycarbonyl, thioalkoxycarbonyl, or thioalkoxythiocarbonyl wherein Z has up to 12 carbon atoms;
- Q is hydrogen provided W is (H, lower alkyl);
- or OV wherein V is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms or an acyl radical of benzoic acid substituted by a halogen or methoxy group or an acyl radical of retinoic acid provided W is other than (H,.alpha.-retinoyloxy);
- W is (H, lower alkyl);
- (H,.alpha.-OV.sub.1) wherein V.sub.1 is hydrogen or an acyl radical of an acid selected from the group consisting of a hydrocarboncarboxylic acid having up to 12 carbon atoms, benzoic acid substituted by a halogen or methoxy group, retinoic acid, and isonicotinic acid;
- .dbd.CHT wherein T is hydrogen, lower alkyl, fluorine or chlorine, and
- W and Q taken together is a 16.alpha.,17.alpha.-lower alkylidenedioxy;
- a 16.alpha.,17.alpha.-cycloalkylidenedioxy;
- the grouping ##STR14## wherein R and R.sub.1 are lower alkyl;
- or the grouping ##STR15## wherein R.sub.2 is lower alkyl or phenyl;
- M is --OR.sub.3 when Q is O-acyl, R.sub.3 being lower alkyl or halogeno lower alkyl;
- --CHO, acetals, hemiacetals and acylals thereof;
- --COOR.sub.4 wherein R.sub.4 is alkyl having up to 12 carbon atoms;
- --CH.sub.2 G wherein G is halogen having an atomic weight of less than 100 provided Q is not hydrogen, or G is OV.sub.2 wherein V.sub.2 is hydrogen, an acyl radical of an acid selected from the group consisting of a hydrocarboncarboxylic acid having up to 12 carbon atoms, benzoic acid substituted by a halogen or methoxy group, retinoic acid, isonicotinic acid, or phosphoric acid and mono- and dialkali and alkaline earth metal salts thereof;
- and G together with Q is an alkylidenedioxy or an alkylorthoalkanoate;
- and the 1,2-dihydro analogs of the foregoing.
A 3,6,20-trioxo-1,4-pregnadiene of the following formula:
- ##STR17## wherein X is hydrogen, fluorine, or chlorine;
- Y is (H,.beta.OH), or (H,.beta.-chlorine) provided X is chlorine;
- Q is hydroxy or OV wherein V is an acyl radical of a hydrocarboncarboxylic acid having up to 8 carbon atoms;
- V.sub.2 is hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 8 carbon atoms;
- and OV.sub.2 together with Q is an alkylidenedioxy or an alkylorthoalkanoate;
- W is (H,CH.sub.3), methylene, (H,.alpha.OV.sub.2) wherein V.sub.2 is as hereinabove defined;
- or together, W and Q form an alkylidenedioxy group or the grouping ##STR18## wherein R and R.sub.1 are lower alkyl;
- or the grouping ##STR19## wherein R.sub.2 is lower alkyl or phenyl.
Dependencies are inferred from the claim text.