Claims for Patent: 4,124,707

Summary for Patent: 4,124,707

Title:	7α-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor
Abstract:	Novel 3,20-dioxo-7 alpha -halogeno-1,4-pregnadienes are described and their use as anti-inflammatory agents. Preferred are 7 alpha -bromo- and 7 alpha -chloro- derivatives, particularly 7 alpha -bromo- and 7 alpha -chloro-1,4-pregnadienes-11 beta ,17 alpha ,21-triol-3,20-dione 17,21-dihydrocarboncarboxylates, the 16-methyl and 16-methylene derivatives thereof being particularly valuable as topical anti-inflammatory agents.
Inventor(s):	Michael J. Green, Ho-Jane Shue
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US05/848,856
Patent Claims:	1. A 3,20-dioxo-7-halogeno-1,4-pregnadiene of the following formula: ##STR10## wherein A is hydrogen, and provided Y is (H,βOH), chlorine, fluorine or methyl; B is hydrogen or, together with Q, is a 14α,17α-alkylideneoxy derivative;X is a member selected from the group consisting of hydrogen having an atomic weight less than 100; Y is a member selected from the group consisting of (H,H) provided X is hydrogen, oxygen, (H,βOH), (H,βOCOH); and (H,β-halogen) provided X is chlorine or bromine, said β-halogen having an atomic weight of less than 100 and being at least as electronegative as X; Z is fluorine, chlorine, bromine and iodine; Q is a member selected from the group consisting of hydrogen provided W is a member selected from the group consisting of (H,H) and (H, lower akyl); chlorine; bromine; and OV wherein V is a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms or of benzoic acid substituted by a halogen or methoxy group; W is a member selected from the group consisting of (H,H); (H, lower alkyl); (H,α-OV1) wherein V1 is a member selected from the group consisting of hydrogen and an acyl radical of an acid selected from the group consisting of a hydrocarbonacarboxylic acid having up to 12 carbon atoms, benzoic acid substituted by a halogen or methoxy group, retinoic acid, and isonicotinic acid; ═CHT wherein T is a member selected from the group consisting of hydrogen, lower alkyl, fluorine and chlorine, and W and Q taken together is a member selected from the group consisting of 16α,17α-lower alkylidenedioxy; 16α,17α-cycloalkylidenedioxy; the grouping ##STR11## wherein R is lower alkyl; and the grouping ##STR12## wherein R1 is lower alkyl or phenyl; M is a member selected from the group consisting of --OR2 when Q is O-acyl, R2 being lower alkyl or halogeno lower alkyl; --CHO, acetals, hemiacetals and acylals thereof; --COOR3 wherein R3 is an alkyl having up to 12 carbon atoms; --CH2 G wherein G is a member selected from the group consisting of hydrogen, halogen having an atomic weight of less than 100, OV2 wherein V2 is a member selected from the group consisting of hydrogen and 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, phosphoric acid and mono- and dialkali, and alkaline earth metals salts thereof; and OV2 together with OV is a member selected from the group consisting of alkylidene dioxy and alkylorthoalkanoate; when W is hydrogen, the D-homo analogs thereof. 2. A compound of claim 1 wherein Z is chlorine or bromine. 3. A compound of claim 2 wherein X is hydrogen and Y is (H,βOH). 4. A 7α-Z compound of claim 1 wherein M is CH2 OV2, Q is OV and A and B are hydrogen. 5. A compound of claim 4 wherein X is hydrogen, Y is (H,βOH), W is (H,CH3) or ═CH2, and Z is chloro or bromo, said compound having the following formula: ##STR13## wherein Z' is chlorine or bromine; W' is (H,CH3) or ═CH2 ;V and V2 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms. 6. A compound of claim 5 wherein V and V2 are acyl radicals of hydrocarboncarboxylic acids having up to 8 carbon atoms. 7. A compound of claim 6 wherein V is propionyl. 8. A compound of claim 6 wherein V is n-butyryl. 9. A compound of claim 6 wherein V is benzoyl. 10. A compound of claim 5 wherein W is (H,α--CH3) and V and V2 are acid residues of hydrocarboncarboxylic acids having up to 8 carbon atoms. 11. A compound of claim 10 wherein V is propionyl. 12. A compound of claim 10 wherein V and V2 are each propionyl and Z' is chlorine, said compound being 7α-chloro-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. 13. A compound of claim 10 wherein V and V2 are each propionyl and Z' is bromine, said compound being 7α-bromo-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. 14. A compound of claim 10 wherein V is benzoyl. 15. A compound of claim 10 wherein V is benzoyl, V2 is acetyl and Z' is bromine, said compound being 7α-bromo-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17-benzoate 21-acetate. 16. A compound of claim 5 wherein W is ═CH2, V and V2 are each propionyl and Z' is chlorine, said compound being 7α-chloro-16-methylene-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. 17. A compound of claim 1 wherein X, Y and Z are chlorine, W is (H,α-CH3), V and V2 are propionyl, said compound being 7α,9α,11β-trichloro-16α-methyl-1,4-pregnadiene-17.alpha.,21-diol-3,20-dione 17,21-dipropionate. 18. A compound of claim 4 wherein X is hydrogen, Y is oxygen, and W is (H,CH3) or ═CH2, said compound having the following formula: ##STR14## wherein Z' is chlorine or bromine; W' is (H,CH3) or ═CH2 ;V and V2 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms. 19. A pharmaceutical composition for use in the treatment of inflammation, which comprises an effective amount of a 3,20-dioxo-7α-halogeno-1,4-pregnadiene of claim 1 together with a non-toxic, pharmaceutically acceptable carrier. 20. A pharmaceutical composition of claim 19 for use in the topical treatment of inflammation, which comprises an effective amount of a 3,20-dioxo-7α-halogeno-1,4-pregnadiene of claim 5,together with a non-toxic, pharmaceutically acceptable carrier. 21. A pharmaceutical composition of claim 20 comprising an effective amount of 7α-Z'-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17-propionate 21-lower alkanoate, Z' being chlorine or bromine, together with a non-toxic, pharmaceutically acceptable carrier. 22. A pharmaceutical composition of claim 20 comprising an effective amount of 7α-Z'-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17-benzoate 21-lower alkanoate, Z' being chlorine or bromine, together with a non-toxic, pharmaceutically acceptable carrier. 23. The method of treating an inflammatory condition in a warm-blooded animal responsive to treatment with anti-inflammatory agents which comprises administering to said animal a non-toxic, anti-inflammatory effective amount of a 3,20-dioxo-7α-halogeno-1,4-pregnadiene of claim 1 together with a non-toxic, pharmaceutically acceptable carrier. 24. The method according to claim 23 for the treatment of a topical inflammatory condition which comprises applying to the inflamed area in a concentration effective for the topical treatment of inflammation, a 3,20-dioxo-7α-halogeno-1,4-pregnadiene of claim 5, together with a non-toxic, pharmaceutically acceptable carrier. 25. The method of claim 24 wherein said 7α-halogeno-3,20-dioxo-1,4-pregnadiene is 7α-chloro-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. 26. The method according to claim 24 wherein said 7α-halogeno-3,20-dioxo-1,4-pregnadiene is 7α-bromo-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17-benzoate 21-acetate. 27. The method according to claim 24 wherein said 7α-halogeno-3,20-dioxo-1,4-pregnadiene is 7α-bromo-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate. 28. A compound of claim 1 wherein A, B and X are hydrogen, Y is (H,βOH); W is (H,α--CH3); Q is benzoyloxy; M is --CH2 OCOCH3, and Z is fluorine, said compound being 7α-fluoro-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17-benzoate 21-acetate. 29. A compound of claim 1 wherein A, B and X are hydrogen; Y is (H,βOH); Q and W together are isopropylidenedioxy; M is --CH2 OCOCH3, and Z is bromine, said compound being 7α-bromo-16α,17α-isopropylidenedioxy-1,4-pregnadiene-11.beta.,21-diol-3,20-dione 21-acetate.