Patent GB-1066184-A (GB)
Title: 5ª-pregnano-[3,2-c]pyrazole compounds
IPC: C07J75/00
Filed: 1963-10-15
Abstract: Novel steroids of the formulae <FORM:1066184/C2/1> <FORM:1066184/C2/2> <FORM:1066184/C2/3> <FORM:1066184/C2/4> (in which R1 is hydrogen, b -chlorine, b -hydroxy or keto, being chlorine only when X is halogen; R2 is hydrogen, fluorine, chlorine or methyl; R3 is hydrogen, acyl, carbamyl, C1- 6 alkyl, b -hydroxyethyl, naphthyl, 2- or 3-thienyl, C7- 10 aralkyl, C6- 9 aryl, halophenyl, C1- 6 alkoxyphenyl, nitrophenyl, pyridyl, pyridyloxide or pyrimidinyl; R4 is hydrogen, chlorine, fluorine, iodine, hydroxy, carboxylic acyloxy, tetrahydropyranyloxy, methylsulphonyloxy, or dihydrogen phosphate or alkali metal salts thereof; X is hydrogen, chlorine or fluorine; and P and Q are hydrogen, alkyl or aryl, or together with the carbon atom to which they are attached are cycloalkyl) and acid-addition salts thereof are prepared by reducing the appropriate 16a ,17a  - dihydroxy - 4 - pregnene- 3,20-diones having a protected side-chain to the 5a -pregnano compounds, treating these with an alkyl formate and sodium hydride in an inert atmosphere to give the 2-hydroxymethylene derivatives, reacting these or the 2-alkoxymethylene derivatives prepared therefrom by standard methods with hydrazine or the appropriately substituted hydrazine to give [3,2-c]-pyrazoles and removing the protecting group.  In one method the following sequence of reactions is used <FORM:1066184/C2/5> while in another the following is used <FORM:1066184/C2/6> the pyrazole ring not being shown in full in some of the structures, and 16,17-acetonides being shown as exemplary of 16,17-aldehyde and ketone derivatives.  The first of these methods may also be carried out with the 11-desoxy compounds or with the 9a ,11b -dichloro compounds, prepared by dehydrating the 11b -ols to the D 9(11)-compounds and reacting these with a chlorinating agent.  In the reaction with a substituted hydrazine, the nature of the product, i.e. whether it is a 11- or 21-substituted pyrazole, depends on the nature of the substitution and on whether a 2-hydroxymethylene or 2-alkoxymethylene steroid is used.  The isomers may be separated by chromatography.  N-alkyl pyrazoles may also be prepared by direct N-alkylation.  Acylation of N-unsubstituted 21-ols gives N,21-diacylates from which the N-acyl group may be selectively removed with acetic acid.  N-acylates are prepared by acylation of the 21-tetrahydropyranyl ethers and removal of this protecting group by treatment with methanolic p-toluene-sulphonic acid.  The 21-ols are converted to 21-mesylates, 21-iodo, -chloro and -fluoro compounds, 21-dihydrogen phosphates and their alkali metal salts and 21-unsubstituted compounds by standard procedures, N-unsubstituted compounds being protected by conversion to N-carbamoyl derivatives during these processes and the carbamoyl group being subsequently removed.  The [3,2-c]-pyrazolo steroids of the invention, except those wherein R3 is acyl or carbamyl and those wherein R4 is iodine, tetrahydropyranyloxy or methylsulphonyloxy, are antiinflammatory agents and may be made up into pharmaceutical compositions with suitable carriers.