[3,2-c]pyrazolo steroids

摘要

Novel steroids of the formulae (wherein X is H or halogen; R1 is H, b -OH, b -Cl or =O but is only Cl when X is Cl, and is only H when X is H; R2 is H, a -F or a -CH3; R3 is H, a - or b -CH3, a -F or =CH2; R4 i alkyl; R5 is alkyl, cycloalkyl, aralkyl, aryl or heteroaryl and may be halogenated; A and B are H, alkoxy, alkyl or aryl (but not both alkoxy) or may be joined in an alkylene chain and R6 is CO2H, CO2 alkyl, CH2OH or CH3) and the 4,6-pregnadieno and 5a -pregnano analogues thereof are prepared by alkylating the 21-unalkylated compounds (B) which may also be N-unalkylated (in which case N-alkylation also occurs) and, if desired, reacting the products with an acidic reagent to form compounds (A). The starting materials are prepared by reaction of the corresponding compounds with a free dihydroxy acetone side chain with compounds of the formula (R0O)2C.A.B, wherein R0 is alkyl. In the hydrolysis of (B) to (A), if hydrochloric acid at room temperature or oxalic acid with heating is used a mixture of 17a - and 21-mono-formates is formed; they can be separated by standard methods, or the 17-mono-esters can be converted to the 21-monoesters by refluxing with p-toluene sulphonic acid in benzene; both mono-esters can be hydrolysed to the free ols by heating with hydrochloric acid. Acid-addition salts of the products are described. 11b ,17a ,21 - Trihydroxy - 20 - oxo - 5a - pregnano-[3,2-c] pyrazole is prepared by the sequence 11b ,17a ,21 - trihydroxy - 4 - pregnene - 3,20-dione--> 17a ,20: 20,21 - bismethylenedioxy-11b -hydroxy - 4 - pregnen - 3 - one --> corresponding 5a -pregnane (the foregoing reaction steps can be reversed) --> 17a ,20: 20,21-bismethylenedioxy - 11b - hydroxy - 2 - hydroxymethylene 5a - pregnano - [3,2-c] pyrazole --> required product; 11b ,17a ,21 - trihydroxy - 51 - methyl-20-oxo - 21 - phenyl - 4 - pregneno - [3,2-c] pyrazole is prepared from the first intermediate above via 17a ,20: 20,21 - bond - 2 - ethoxalyl - 11b - ethoxalyloxy - 4 - pregnen - 3 - one, 21 - phenyl - 17a , 20: 20,21 - b.m.d. - 11b - ethoxalyloxy - 51 - ethoxycarbonyl - 4 - pregneno - [3,2-c] pyrazole, 51-hydroxymethyl compound, 51 - tosyloxymethyl compound and 51-methyl compound and is subsequently converted to the 21-acetate. The 51-carboxy compound is prepared by hydrolysis of the ethyl ester referred to above and subsequent removal of the protecting group. Similarly, the protecting group may be removed from the 51-hydroxymethyl compound. The anti-inflammatory steroids of the invention may be made up into pharmaceutical compositions with suitable carriers.