Patent GB-1009912-A (GB)
Title: Steroid compounds
IPC: C07J75/00
Filed: 1961-11-21
Abstract: The invention comprises steroids of the general formula <FORM:1009912/C2/1> wherein R1 represents a b -halogen atom or a b -hydroxy or keto group but b -halogen is present at R1 only when X represents halogen, R11 represents a hydrogen or fluorine atom or a methyl group, R* represents a hydrogen atom or an a -methyl, b -methyl or methylene group, R represents a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl, aryl or acyl group, R0 represents a hydrogen, iodine or fluorine atom or a hydroxy or acyloxy methylsulphonyloxy or dihydrogen phosphate group or an alkali metal salt of a dihydrogen phosphate group and X represents a hydrogen or halogen atom but hydrogen is present at not more than three, and where R represents acyl, not more than two of the four positions R11, R*, R and X, and the pyrazole ring structure has the structure shown above or the following isomeric structure <FORM:1009912/C2/2> and a process for the preparation thereof by a process commencing at any stage of the following synthesis: steroids of the general formula <FORM:1009912/C2/3> wherein R*, R1, R11 and X have the above significance but hydrogen is present at not more than two of the three positions R11, R* and X, are reacted with an aqueous formaldehyde solution in the presence of a strong acid to form steroids of the general formula <FORM:1009912/C2/4> wherein R1, R11, R* and X have the above significance but hydrogen is present at not more than two of the three positions R11, R* and X (the 11-keto compound of the last general formula may also be prepared by oxidizing the corresponding 11b -hydroxy compound with chromium trioxide in a nonaqueous base such as pyridine); the steroids of the last general formula are reacted with an alkyl formate and sodium hydride in an inert atmosphere to form the corresponding 17a ,20; 20,21 - bis - (methylenedioxy) - 2 - hydroxymethylene - 4 - pregnene - 3 - ones of the general formula <FORM:1009912/C2/5> (in the case of a reactant containing an 11b -hydroxy group, a product containing an 11b -formyloxy group is obtained); the steroids of the last general formula and the corresponding 11b -formyloxy compounds are reacted with hydrazine hydrate to form steroids of the general formula <FORM:1009912/C2/6> (which may then be reacted with an acylating agent to form products in which R represents an acyl radical), or the said steroids may be reacted with the required substituted hydrazine to form steroids of the first general formula above wherein R is other than hydrogen or acyl which steroids can also be obtained by the reaction of the corresponding steroids, wherein R is hydrogen with the required alkyl or aralkyl halide (a 17a ,20; 20,21-bis-(methylenedioxy)-9a  - halogen - [3,2-c] pyrazolo - 4 - pregnene-11-one or a corresponding 11-substituted compound may be reduced to the corresponding 11b -hydroxy compound, for example by reaction with sodium borohydride); and the 17a ,20; 20,21 - bis - (methylenedioxy) - [3,2-c]-pyrazolo - 4 - pregnene compounds prepared by any of the previous processes are then treated with a dilute carboxylic acid to form steroids of the general formula <FORM:1009912/C2/7> wherein R1, R11, R* and X have the above significance, R111 represents an acyl, alkyl, aryl or aralkyl radical and R1111 represents hydrogen, an acyl group corresponding to the acid used or a mixture of the two which may be separated by chromatography.  Any acyl groups present at R111 and/or R1111 may be removed by treatment with methanolic sodium methoxide. Compounds in which the 11-acyl-21-acylate grouping are derived from the same carboxylic acid are prepared by reacting a 17a ,21 - dihydroxy - [3,2-c] pyrazolo - 4 - pregnene-20-one with an acylating agent or by treating a 11-acyl-21-hydroxy compound with the same acylating agent (the use of a different acylating agent provides compounds in which the 11-acyl and 21-acyloxy groups are derived from different carboxylic acids).  The 11-unsubstituted 21-acyloxy compounds are prepared by heating 11-acyl-21-acyloxy compounds with acetic acid.  A 17a ,21-dihydroxy-[3,2-c] pyrazolo - 4 - pregnene - 20 - ones of the first general formula above may be reacted with methane sulphonyl chloride in a non-aqueous base to the 21-methane sulphonates (it is preferable to convert a compound in which R is hydrogen to acyl before carrying out this reaction).  The 21-methanesulphonates may be converted to the 21-iodo compounds by reaction with an alkali metal iodide, and the 21-iodo compounds may be reacted with an alkali metal bisulphite to form the 21-desoxy compounds. The 21-dihydrogen phosphate esters are prepared by reacting the above 21-iodo compounds or the corresponding 21-chloro or 21-bromo compounds with a mixture of silver phosphate and phosphoric acid from which the mono- and dialkali metal salts may be obtained by neutralization with an alkali metal hydroxide (the 21-bromo compounds may be obtained by treating the 21-desoxy compounds with bromine in chloroform as described in Specification 877,085, the 21-chloro compounds may be obtained by treating the above 21 -methanesulphonates with lithium chloride in acetic acid, and the 21-bromo and the 21-chloro compounds may be obtained by treating the 21-hydroxy compounds with an excess of benzene sulphonyl bromide and chloride respectively).  The 21-fluoro compounds of the first general formula above are prepared by treating the above 21-methanesulphonates with an alkali metal fluoride and are formed in a mixture with the 17a ,21-epoxy compounds of the third general formula above (the two products may be separated by chromatography. The [3,2-c] pyrazolo compounds of the invention form acid addition salts such as the hydrochloride, sulphate, chlorate, perchlorate, picrate and trichloroacetate salts.  Pharmaceutical compositions having anti-inflammatory activity and are particularly useful in the treatment of arthritis contain as the active ingredients the [3,2-c] pyrazolo steroid compounds of the first two general formulae above.