Patent GB-1044304-A (GB)
Title: Pregneno- and pregnadieno-[3,2-c]pyrazoles
IPC: C07J17/00
Filed: 1963-06-07
Abstract: Novel steroid of the formulae <FORM:1044304/C2/1> or <FORM:1044304/C2/2> (wherein R2 is hydrogen, fluorine or methyl; R3 is hydrogen, a -fluorine, a - or b -methyl or methylene; R* is hydrogen, acyl, C1- 4 alkyl, hydroxyalkyl, phenylalkyl, cycloalkyl, phenyl, halophenyl, methylphenyl, alkoxyphenyl or nitrophenyl; and R4 is hydrogen, fluorine, hydroxy, acyloxy or dihydrogen phosphate or alkali metal salts thereof; and the D 6-double bond is optional) and their acid-addition salts are prepared by reacting steroids of the formulae <FORM:1044304/C2/3> wherein R5 is tetrahydropyranyl) with an alkyl formate and sodium hydride in an inert atmosphere to form the corresponding 2-hydroxymethylene derivatives optionally treating the 2-hydroxymethylene derivatives with a C1- 5 alkanol in the presence of an acid reagent to form 2-alkoxymethylene derivatives, treating these or the 2-hydroxymethylene derivatives with slightly more than one equivalent of a hydrazine compound R1NHNH2 (wherein R1 has any of the values of R* except acyl) and oxidizing the 20-hydroxy-17a -pyranyloxy-[3,2-c]-pyrazolo-steroids so obtained and hydrolysing off the tetrahydropyranyl group to give the required 17a  - hydroxy - 17b - acetyl compounds, or hydrolysing the 17a ,20; 20,21-bis-methylenedioxy - [3,2 - c]pyrazolo - steroids so obtained to give the required 17a -hydroxy-17b -hydroxyacetyl compounds.  The structure of the products i.e. whether they have structure A or structure B, depends on whether a 2-hydroxymethylene or 2-alkoxymethylene compound is reacted with the hydrazine, and also on the nature of R1.  21-Hydroxy products may be acylated or converted to 21-fluoro or 21-unsubstituted compounds by standard methods involving 21-mesylates and 21-iodo compounds. In these processes compounds wherein R1 is hydrogen are preferably protected by conversion to N-carbamyl derivatives, the N-carbamyl group being subsequently removed by treatment with nitrous acid. N-unsubstituted compounds may also be alkyled or acylated, and on heating N-acyl-21-acylates with aqueous acetic acid the N-acyl group is selectively removed. 21-Acyl groups may be removed with sodium methoxide in methanol.  21-Dihydrogen phosphate esters are prepared from the 21-iodo steroids, silver phosphate and phosphoric acid, and are converted to alkali metal salts with an alkali methoxide, from which the free di-hydrogen phosphate is regenerated by contact with an ion exchange resin.  17a ,20; 20,21-bismethylenedioxy steroid starting materials of the above formula are prepared from the corresponding steroids containing a dihydroxyacetone side chain and formaldehyde in the presence of a strong acid. 17a  - Tetrahydropyranyloxy 20 - hydroxy steroid starting materials of the above formula are prepared from the corresponding free 20-keto-17a -ols and dihydropyran in the presence of an acidic reagent, with subsequent reduction e.g. with lithium aluminium hydride, and oxidation of the thus formed 3,20-diol.  17a ,20; 20,21 - bismethylenedioxy - 16a -fluoro - 4,6 - pregnadiene - 3,20 - dione is prepared by the sequence: 21-acetoxy-4,17(20)-pregnadien - 3 - one --> 21 - acetoxy - 16a -hydroxy - 4,17(20) - pregnadien - 3 - one --> 20-chloro - 21 - acetoxy - 4,16 - pregnadien - 3 - one --> 20,21 - epoxy - 4,16 - pregnadien - 3 - one --> 21 - acetoxy - 16a  - fluoro - 4,17(20) - pregnadien - 3 - one --> 16a  - fluoro - 17a  - hydroxy-21 - acetoxy - 4 - pregnene - 3,20 - dione --> free 21 - ol --> 17a ,20; 20,21 - bismethylenedioxy-16a  - fluoro - 4 - pregnene - 3,20 - dione --> required 4,6-pregnadiene.  The sequence of the last 3 processes can be changed.  Similarly are prepared 6a  - methyl - and 6a  - fluoro - 17a ,20; 20,21 - bismethylene - dioxy - 16a  - fluoro - 4-pregnene - 3,20 - dione and the corresponding D 4,6 - compounds, the 6a  - fluoro - 21 acetoxy-4,17(20) - pregnadien - 3 - one starting material being prepared by the sequence:  progesterone --> methyl 3 - oxo 4,17(20) - pregnadien - 21 - oate --> 3 - enol ether --> methyl 6(a  and b ) - fluoro - 3 - keto - 4,17(20) -pregnadien-21-oates -> required compound.  The anti-inflammatory pyrazolo-steroids of the invention and their acid-addition salts may be made up into pharmaceutical compositions for topical use.