Patent GB-911814-A (GB)
Title: Steroid compounds and preparation thereof
IPC: C07J5/00
Filed: 1959-03-13
Abstract: The invention comprises steroido[3,2-c]pyrazoles, the said steroid residues having from 18 to 23 carbon atoms exclusive of ester radicals, and the preparation thereof by reacting the required 2-(1-hydroxyalkylidene)-3-oxo-steroids with hydrazine or a hydrazine monosubstituted by a radical inert under the reaction conditions, if desired, reacting the steroido[3,2-c]pyrazoles so obtained with unsubstituted hydrazine, with a carboxylic acid anhydride or with cyanic acid and, if desired, forming acid addition or quaternay salts of the said steroido[3,2-c]pyrazoles. The 2-(1-hydroxyalkylidene)-3-oxo-steroid reactant may react in any of the tautomeric forms which exist in tautomeric equilibrium in solution in accordance with the formulae <FORM:0911814/IV (b)/1> wherein Q represents the remaining portion of the steroid nucleus so that the steroidopyrazoles produced by the above method may comprise one or both of the isomeric compounds having the structures <FORM:0911814/IV (b)/2> where Q has the above significance and R and R1 have the significance indicated below. The preferred compounds of the invention have the general formula <FORM:0911814/IV (b)/3> where R represents hydrogen or a lower alkyl radical; R1 represents hydrogen, a lower alkyl, a monocarbocyclic aryl, a lower alkanoyl, a monocarbocylic aryloxy-lower alkanoyl, the carbamyl or the guanyl radical; R1 represents hydrogen, a lower alkyl, lower alkenyl, lower alkynl, the acetyl, a ketalised acetyl, the hydroxyacetyl, a ketalised hydroxyacetyl, the 1,2-dihydroxyethyl or the 1-hydroxyethyl radical; X represents H2(H)(OH) or O; and Y and Y1 represents hydrogen or the methyl radical at least one being methyl; Z represents hydrogen or the hydroxy radical, Z being restricted to hydroxy when R11 represent hydrogen, a lower alkyl, a lower alkenyl or a lower alkynl radical; and carboxylic esters thereof derived from carboxylic acids having from 1 to 10 carbon atos and having a molecular weight less than 250 and the corresponding D 4- and D 4,6-compounds.  The lower alkyl, lower alkenyl, lower alkynyl and lower alkanoyl radicals contain up to 6 carbon atoms.  However, the steroid moiety may be an estrane, androstane, etiocholane, pregnane or allopregnane, and may contain substituents and double bonds conventionally employed in the steroid art such as a 17-hydroxy, -acyloxy or -oxo substituents, or both hydroxy and lower alkyl substituents at the 17-positions a lower alkenyl, lower alkynyl, acetyl, hydroxyacetyl, 1,2-dihydroxyethyl or 1-hydroxyethyl substituent optionally together with a hydroxy substituent at the 17-position, a hydroxy or oxo substituent at the 11-position, a halogen atom - particularly fluorine, at the 9-position, or lower alkyl substituents at the 4- or 6-position.  The steroid moiety may also have double bonds at the 4,5- and/or 6,7-positions, and may be an 18- or 19-nor-steroid moiety.  When the symbol R1 in the above formula represents acyl, carbamyl or guanyl, the starting mono-substituted hydrazine reactants are a mono-acyl hydrazine, semicarbazide and aminoguanidine respectively, alternatively, the corresponding compounds of the agove general formula wherein R1 represents hydrogen may be reacted with carboxylic acid anhydrides and cyanic acid to form compounds in which R1 represents an acyl and carbamyl radical respectively.  If the steroid reactant has a double bond in the 1,2-position, the essential steroid reactant is a 2-formyl- or 2-alkanoyl-D 1-steroid which reacts in accordance with the equation <FORM:0911814/IV (b)/4> wherein R, R1 and Q have the above significance. Steroido-pyrazoles having an aromatic ring A of the formula <FORM:0911814/IV (b)/5> wherein R and R1 have the above significance, may be prepared by dehydrogenating the corresponding D 4-19-nor-steroido-pyrazoles e.g. by heating with palladium on carbon. If keto groups are present in the reactants in positions other than the 3-position, the keto groups are preferably protected by conversion to ketal groups e.g. to diethylene ketal groups by reaction with ethylene glycol-particularly at the 20-position. Alternatively, when the reactant contains a 17,21-dihydroxy-20-keto grouping, protection may be effected by conversion to a 17,20; 20,21-bismethylenedioxy derivative.  A steroido-pyrazole having a 17-hydroxy group and a carbamyl group attached to the pyrazole ring may be oxidised to the corresponding 17-oxo compound, and the 17-oxo compound may then be reacted with potassium acetylide to form a 17-ethynyl-17-hydroxy compound.  In addition, a streoido-pyrazole having a 1-hydroxyethyl radical attached to the 17-position may be oxidised to form the corresponding 17-acetyl compound (in oxidising reactions it is preferable to have the carbamyl group attached to the pyrazole ring to prevent rupture of the pyrazole ring).  The quaternary salts are preferably formed from esters of strong inorganic and organic sulphonic acids.  A large number of examples are given of the preparation of the steroido [3,2-c]-pyrazoles defined above by the methods referred to above. In addition, an example describes the preparation of 5a ,6a -epoxy-17b -hydroxy - 17a - methylandrostano[3,2-c]pyrazole by treating 17b -hydroxy-17a -methyl-4-androsteno[3,2-c]pyrazole with monoperphthalic acid. 2-Hydroxyalkylidene - 3 - oxo-steroids which may exist in tautomeric equilibrium as follows:- <FORM:0911814/IV (b)/6> wherein R and Q have the significance indicated above, are prepared by the methods described in Specification 911,815. Additional examples are given of the preparation of the said steroids.  2-Acyl-3-keto-D 1-steroids are prepared by brominating or chlorinating 2-acyl-steroids and dehydrohalogenating the resulting 2-chloro (or bromo)-3-keto-steroids.  Therapeutic compositions having anabolic, androgenic, pituitary inhibiting, estrogenic, progestational or adrenal cortical activity contain as the active ingredient steroido[3,2-c]-pyrazoles, the steroid moiety of which contains 18 to 23 carbon atoms exclusive of ester radicals.  The compositions may be in the form of aqueous suspensions, oil-water emulsions, or oil solutions for parenteral administration, or in the form of tablets for oral administration.