Patent GB-905844-A (GB)
Title: Steroid compounds and preparation thereof
IPC: C07J41/00
Filed: 1959-07-02
Abstract: The invention comprises an isoxazole compound fused through its 4- and 5-positions to the 2- and 3- positions, respectively, of a steroid nucleus said steroid having from 18 to 23 carbon atoms exclusive of ester radicals, and the preparation thereof by reacting a 2-(1-hydroxyalkylidene)-3-oxo-steroid with hydroxylamine or an acid addition salt thereof and, if desired, forming acid addition or quaternary salts of the isoxazole compound obtained.  The isoxazole compounds may contain in the steroid moiety one or more double bonds especially at the 4(5), and/or 6(7) positions and the said steroid moiety may be of the androstane, etiocholane or pregnane series having at the 17-position a hydroxy, acyloxy or oxo radical or both a hydroxy and a lower alkyl radical, or a lower alkenyl, lower alkynyl, acetyl, hydroxyacetyl, 2,3-dihydroxyethyl or 1-hydroxyethyl radical. The preferred isoxazole compounds have the general formula <FORM:0905844/IV (b)/1> wherein R represents hydrogen or a lower alkyl radical, R1 represents hydrogen or a lower alkyl, lower alkenyl, lower alkynyl, acetyl, hydroxyacetyl, 2,3 - dihydroxyethyl or 1-hydroxyethyl radical, X represents H2,(H)(OH) or O, Y and Y1 represent hydrogen or the methyl radical, and Z represents hydrogen or the hydroxy radical, Z being restricted to hydroxy when R1 represents hydrogen or a lower alkyl, lower alkenyl or lower alkynyl radical and which said compounds may have one double bond in the 4,5-position or two double bonds in the 4,5- and 6,7-positions, and the acid-addition and quaternary salts and carboxylic esters of any of these compounds.  The lower alkyl, lower alkenyl, and lower alkynyl radicals each contain 1 to 4 carbon atoms.  The isoxazole may also be fused to 18- and 19-norsteroids.  In the above process a solution of the 2-(1-hydroxyalkylidene)-3-oxo-steroid reactant exists in toutomeric equilibrium with a 2-aldehyde or 2-keto compound as follows:-  <FORM:0905844/IV (b)/2> wherein Q represents the remaining portion of the steroid residue and R represents hydrogen or the lower alkyl radical.  If the steroid reactant contains a double bond in the 1(2)-position, the reactant is a 2-formyl- or a 2-alkanoyl-D 1-steroid, and the reaction proceeds in accordance with the following equation:-  <FORM:0905844/IV (b)/3> <FORM:0905844/IV (b)/4> wherein Q and R have the significance indicated immediately above.  When the steroid reactant contains a keto group in a position other than the 3-position, it is preferable to protect such a keto group e.g. by ketal formation preferably with ethylene glycol, to prevent side reactions with the hydroxylamine reactant i.e. oxime formation.  The ketal group e.g. in the 20-position, may be removed by treatment with dilute acid following the reaction with hydroxylamine.  The quaternary and acid addition salts may be derived from halides, sulphates and sulphonates.  A steroido [2,3-d]-isoxazole having a 17-hydroxy group may be oxidised to the corresponding 17-keto compound, or a 1-hydroxyethyl radical at the 17-position may be oxidised to the corresponding 17-acetyl compound.  Detailed examples are given including steroido [2,3-d] isoxazoles having a 6 a -methyl substituent and a 4,4-dimethyl substituent.  2 - (1 - Hydroxyalkylidene) - 3 - oxo - steroids (which may be in the form of 2-formyl- or 2-alkanoyl-3-oxo-steroids) are prepared by condensing a 3-oxo-steroid with an alkonate of the formula RCOOR11, wherein R represents hydrogen or an alkyl radical containing 1 to 4 carbon atoms, and R11 represents an alkyl radical containing 1 to 4 carbon atoms, in the presence of a strong base under anhydrous conditions. 2-Acyl-D 1-steroids containing the group O=C(R)- attached to the 2-position, wherein R represents hydrogen or an alkyl radical containing 1 to 4 carbon atoms, are prepared by brominating or chlorinating the required 2-acyl steroids at the 2-position, and dehydrohalogenating the resulting 2 - halo - 2 - acyl-steroids with collidine or with lithium chloride in dimethylformamide solution. Allopregnane-3,20-dione 20-ethylene ketal is prepared by reacting allopregnan-3b -ol-20-one with ethylene glycol and oxidising the resulting allopregnan-3b -ol-20-one 20-ethylene ketal.  Therapeutic compositions having anabolic, androgenic, pituitary inhibiting, estrogenic, progestational and adrenal cortical activities contain as the active ingredient an isoxazole compound fused through its 4- and 5- positions respectively of a steroid nucleus or an acid addition or quaternary salt thereof. The composition may be in the form of an aqueous suspension, a solution in a suitable oil or an oil in water emulsion for parenteral administration, or in the form of a tablet. Specifications 518,571 and 905,845 are referred to.