Patent GB-1048027-A (GB)
Title: Pregneno and pregnadieno[3,2-c]pyrazoles
IPC: C07J75/00
Filed: 1963-05-29
Abstract: Novel steroids of the formulae <FORM:1048027/C2/1> (wherein R2 is hydrogen, chlorine, fluorine or methyl; X is hydrogen or halogen; R0 is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or heterocyclic which may be halogen, hydroxy, alkyl, alkoxy, nitro or aryl substituted, or R0 is acyl; R1 is b -hydroxy or keto, or, when X is halogen, b -halogen; and R3 is hydrogen, fluorine, hydroxy, acyloxy, dihydrogen phosphate or alkali metal salts of dihydrogen phosphate; and the D 6-double bond is optional) and their acid-addition salts, are prepared by reacting steroids of the formula <FORM:1048027/C2/2> (wherein R* is hydrogen or alkyl; and R1 has the above values for R1 and may additionally be b -formyloxy) with an appropriate hydrazine compound (excluding acyl hydrazines) in an inert atmosphere and hydrolysing the bismethylenedioxy products with a dilute aqueous organic acid.  Any 21-O acyl group formed during the acid hydrolysis and any N-acyl group formed as indicated below may be hydrolysed with sodium methoxide in methanol.  Acylation of the 21-ols which are also N-unsubstituted leads to N,21-diacylates, from which the N-acyl group is selectively removed with aqueous acetic acid.  N-alkyl products may be prepared by alkylation of N-unsubstituted products. The precise structure of the pyrazole ring in the products depends on the nature of R4 and R* in the starting materials, and the isomeric [3,2-c] pyrazoles may be separated by chromatography. 21-Ols may be converted to 21-unsubstituted products via 21-mesylates (N-unsubstituted compounds being protected by conversion to N-carbamoyl derivatives) and 21-iodo compounds, to 21-fluoro compounds via 21-mesylates and to 21-dihydrogen phosphates and their alkali metal salts via the 21-mesylates and 21-iodo compounds. 11-Keto products may be reduced to 11b -ols.  Alkali metal salts of 21-dihydrogen phosphates may be converted to the free dihydrogen phosphates by contact with an ion exchange resin.  By-products in the preparation of the 21-fluorides are 17a ,21-epoxides, which may be separated by chromatography.  6a  - Fluoro - 11b ,21 - dihydroxy - 4,17(20)-pregnadien-3-one-21-acetate is prepared by the sequence methyl 3,11-diketo-4,17(20)-pregnadien - 21 - oate --> 3 - enol ethyl ether --> 6-fluoro - 3,11 - diketo - 4,17(20 - pregnadien - 21 - oate --> required product, and the 6a -chloro compound is prepared similarly.  17a ,20; 20,21 - Bismethylenedioxy - 16a -fluoro - 4,6 - pregnadiene - 3,20 - dione is prepared by the sequence 21-acetoxy-11b -hydroxy-4,17(20) - pregnadien - 3 - one --> 21 - acetoxy-11b ,16a  - dihydroxy - 4,17(20) - pregnadien - 3-one --> 20 - chloro - 21 - acetoxy - 11b  - hydroxy-4,16 - pregnadien - 3 - one --> 20,21 - epoxy-11b  - hydroxy - 4,16 - pregnadien - 3 - one --> 21 - acetoxy - 16a  - fluoro - 11b  - hydroxy-4,17(20) - pregnadien - 3 - one --> 16a  - fluoro-11b ,17a  - dihydroxy - 21 - acetoxy - 4 - pregnene-3,20 - dione --> 21 - ol --> bis - methylenedioxy derivative --> required product, the last stage optionally preceding the hydrolysis to the 21-ol. The above 6a -halo compounds and the 6a -methyl compound are similarly converted to 6-substituted 17a ,20; 20,21 - bismethylenedioxy-16a  - fluoro - 4,6 - pregnadien - 3,20 - diones, which, for the 6-halo compounds, may also be prepared by the sequence 11-keto-progesterone --> 6-dehydro-11-keto-progesterone --> 6a ,7a  - oxido - 11 - keto - progesterone --> 6-chloro - or fluoro - 6 - dehydro - 11 - keto - progesterone --> methyl 6 - halo - 3,11 - diketo-4,6,17(20) - pregnatrien - 21 - oate --> required products by the sequences indicated above.  21 - Acetoxy - 9a ,11b  - dichloro - 16a  - fluoro-17a  - hydroxy - 4 - pregnene - 3,20 - dione and the corresponding D 6 - 6 - methyl compound are prepared from the corresponding 9-unsubstituted-11b -ols via the D 9(11)-compounds.  21 - Acetoxy - 9a ,16a  - difluoro - 11b ,17a  - dihydroxy - 4 - pregnane - 3,20 - dione is prepared by the sequence 21-acetoxy-16a -fluoro-11b ,17a -dihydroxy - 4 - pregnene - 3,20 - dione --> 21-acetoxy - 16a  - fluoro - 17a  - hydroxy - 4,9(11)-pregnadiene - 3,20 - dione --> 21 - acetoxy - 9a -bromo - 16a  - fluoro - 11b ,17a - dihydroxy - 4-pregnene - 3,20 - dione --> 21 - acetoxy - 9b ,11b -epoxy - 16a  - fluoro - 17a  - hydroxy - 4 - pregnene-3,20-dione --> required product, which is then converted to the corresponding D 6-compound.  The pyrazolo-steroids of the invention, which are stated to possess anti-inflammatory activity, may be made up into pharmaceutical compositions with suitable carriers.