7α-Halogeno-3,20-dioxo-1,4-pregnadienes, methods for their manufacture, their use as anti-inflammatory agents, and pharmaceutical formulations useful therefor

Claim 2

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;

Claim 3

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-OV 1 ) wherein V 1 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 R 1 is lower alkyl or phenyl; M is a member selected from the group consisting of --OR 2 when Q is O-acyl, R 2 being lower alkyl or halogeno lower alkyl; --CHO, acetals, hemiacetals and acylals thereof; --COOR 3 wherein R 3 is an alkyl having up to 12 carbon atoms; --CH 2 G wherein G is a member selected from the group consisting of hydrogen, halogen having an atomic weight of less than 100, OV 2 wherein V 2 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 OV 2 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.

Claim 4

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-OV 1 ) wherein V 1 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 R 1 is lower alkyl or phenyl; M is a member selected from the group consisting of --OR 2 when Q is O-acyl, R 2 being lower alkyl or halogeno lower alkyl; --CHO, acetals, hemiacetals and acylals thereof; --COOR 3 wherein R 3 is an alkyl having up to 12 carbon atoms; --CH 2 G wherein G is a member selected from the group consisting of hydrogen, halogen having an atomic weight of less than 100, OV 2 wherein V 2 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 OV 2 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.

Claim 5

A compound of claim 1 wherein Z is chlorine or bromine.

Claim 6

A compound of claim 2 wherein X is hydrogen and Y is (H,βOH).

Claim 7

A 7α-Z compound of claim 1 wherein M is CH 2 OV 2 , Q is OV and A and B are hydrogen.

Claim 8

A compound of claim 4 wherein X is hydrogen, Y is (H,βOH), W is (H,CH 3 ) or ═CH 2 , and Z is chloro or bromo, said compound having the following formula: ##STR13## wherein Z' is chlorine or bromine; W' is (H,CH 3 ) or ═CH 2 ; V and V 2 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms.

Claim 9

A compound of claim 5 wherein V and V 2 are acyl radicals of hydrocarboncarboxylic acids having up to 8 carbon atoms.

Claim 10

A compound of claim 6 wherein V is propionyl.

Claim 11

A compound of claim 6 wherein V is n-butyryl.

Claim 12

A compound of claim 6 wherein V is benzoyl.

Claim 13

A compound of claim 5 wherein W is (H,α--CH 3 ) and V and V 2 are acid residues of hydrocarboncarboxylic acids having up to 8 carbon atoms.

Claim 14

A compound of claim 10 wherein V is propionyl.

Claim 15

A compound of claim 10 wherein V and V 2 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.

Claim 16

A compound of claim 10 wherein V and V 2 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.

Claim 17

A compound of claim 10 wherein V is benzoyl.

Claim 18

A compound of claim 10 wherein V is benzoyl, V 2 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.

Claim 19

A compound of claim 5 wherein W is ═CH 2 , V and V 2 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.

Claim 20

A compound of claim 1 wherein X, Y and Z are chlorine, W is (H,α-CH 3 ), V and V 2 are propionyl, said compound being 7α,9α,11β-trichloro-16α-methyl-1,4-pregnadiene-17.alpha.,21-diol-3,20-dione 17,21-dipropionate.

Claim 21

A compound of claim 4 wherein X is hydrogen, Y is oxygen, and W is (H,CH 3 ) or ═CH 2 , said compound having the following formula: ##STR14## wherein Z' is chlorine or bromine; W' is (H,CH 3 ) or ═CH 2 ; V and V 2 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms.

Claim 22

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.

Claim 23

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.

Claim 24

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.

Claim 25

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.

Claim 26

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.

Claim 27

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.

Claim 28

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.

Claim 29

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.

Claim 30

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.

Claim 31

A compound of claim 1 wherein A, B and X are hydrogen, Y is (H,βOH); W is (H,α--CH 3 ); Q is benzoyloxy; M is --CH 2 OCOCH 3 , 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.

Claim 32

A compound of claim 1 wherein A, B and X are hydrogen; Y is (H,βOH); Q and W together are isopropylidenedioxy; M is --CH 2 OCOCH 3 , and Z is bromine, said compound being 7α-bromo-16α,17α-isopropylidenedioxy-1,4-pregnadiene-11.beta.,21-diol-3,20-dione 21-acetate.