Novel steroids and processes for the manufacture thereof

摘要

The invention comprises steroids of the pregnane series characterized by possessing a double bond in the 4-position or double bonds in the 1- and 4-positions, ketonic oxygen atoms in the 3- and 20-positions, a 17a -hydroxyl group, a b -hydroxy group or a ketonic oxygen atom in the 11-position, a hydroxy or an esterified hydroxy group in the 21-position, which compounds are also characterized by a b -alkyl group containing up to 6 carbon atoms in the 16-position, and which may be further substituted by halogen at the 9a -position (the 21-esters may be derived from organic and inorganic mono- and poly-basic acids); and processes for the preparation of a 16b -alkyl-17a -hydroxy steroid by reacting a steroid have the pregnane carbon skeleton and containing a 16,17-double bond and a 20-keto group with a diazoalkane, pyrolysing the resulting 16,17-alkylidene-diazo-steroid e.g. by heating above the melting point of the alkylene-diazo compound or by heating in a high boiling solvent, to form a 16-alkyl-16(17)-dehydro-steroid and introducing a 17a -hydroxy group either by epoxidising the 16,17-double bond, reacting the resulting 16a ,17a -epoxide with a hydrogen halide and hydrogenating the resulting halohydrin to remove the halogen atom or by catalytically hydrogenating the 16(17)-dehydro compound, 20-enol-acylating the resulting 16(17)-saturated compound, epoxidising the resulting enol acylate containing a 17(20)-double bond to form a 17,20-epoxide, and hydrolysing the 17,20-epoxide. In the above processes, the initial reactant may be a 3,11-dioxygenated steroid such as a 3,11-diketo steroid. The preferred 16b -alkyl compounds have the general formulae wherein X represents keto or b -hydroxy, Y represents hydrogen, bromine, chlorine or fluorine, R1 is an alkyl group having not more than six carbon atoms, R represents hydrogen or a carboxylic acyl group having from 1 to 8 carbon atoms such as an alkanoyl, cyclopentylacetyl, phenoxyacetyl, benzoyl, phthaloyl, or nicotinoyl. The invention also includes the following compounds:- 16-methyl-16-pregnen3a -ol-11,20-dione 3-esters; 16b -methyl-pregnan3a -ol-11,20-dione 3-esters; 16b -methyl-pregnane-3a ,17a -diol-11,20-dione and 3-esters thereof; 16b -methylpregnane-3a ,17a ,21-triol-11,20-dione 21-esters; 16b -methylpregnane-17a ,21-diol-3,11,20-trione 21-esters; 16(a or b )-methylcortisone-3,20-bis-semicarbazone 21 - acetate; 16(a or b )-methylhydrocortisone-3,20-bis-semicarbazone; 16(a or b ) - methyl - 4 - pregnene-11a ,17a ,21 - triol - 3,20 - dione; 16(a or b ) - methyl - 1,4 - pregnadiene - 11a ,17a ,21 - triol - 3,20 - dione; 16(a or b ) - methyl - 1,4,9(11) - pregnatriene - 3,20 - dione - 17a ,21 - diol and the 21 - esters thereof; 9b ,11b - oxido - 16(a or b )-methyl - 1,4 - pregnadiene-17a ,21-diol-3,20-dione and 21-esters thereof; 16(a or b )-methyl-4,9(11)-pregnadiene-3.20-dione-17a ,21-diol and the 21-esters thereof; 9b ,11b -oxido-16(a or b )-methyl-4-pregnene-17a ,21-diol-3,20-dione and the 21-esters thereof; 9a -(chloro, bromo or iodo)-16(a or b )-methyl-1,4-pregnadiene - 11b ,17a ,21-triol-3,20-dione and the 21-esters thereof; 9a -(chloro, bromo or iodo)-16(a or b )-methyl-4-pregnene-11b ,17a ,21-triol-3,20-dione and the 21-esters thereof; 4-bromo-16(a or b )-methylpregnane-17a ,21-diol-3,11,20-trione 21-ester; 2,4-dibromo-16(a or b )-methyl-5(a or b )-pregnane-17a ,21-diol-3,11,20-trione 21-ester; 2,4-dibromo-16(a or b )-methyl-5(a or b )-pregnane-17a ,21-diol 21-ester; 16(a or b )-alkyl-17a -hydroxy-20-keto-5(a or b )-pregnane having a 3-X-21-R substituent wherein R represents hydrogen, bromine, hydroxy or alkanoyloxy, X represents hydroxy, alkanoyloxy or oxo, and the 16-alkyl group contains 1 to 6 carbon atoms; 16(a or b )-alkyl-21-alkanoyloxy-17(20)-pregnene (5a or 5b )-3-ol, wherein the 16-alkyl group contains 1 to 6 carbon atoms, and the 3-alkanoyl esters thereof; 16(a or b )-alkyl-17,20-oxido-20-alkanoyloxy-5(a or b )-pregnan-3-ol, wherein the 16-alkyl group contains 1 to 6 carbon atoms, and the 3-alkanoyl esters thereof; 16(a or b )-alkyl-20-keto-21-R-5(a or b )-pregnane-3,17a -diol wherein R represents hydrogen or bromine or an alkanoyloxy group, and the 16-alkyl group contains 1 to 6 carbon atoms and the 3-alkanoyl esters thereof; 16(a or b )-alkyl-3,20-diketo-5(a or b )-pregnane-17a ,21-diol wherein the 16-alkyl group contains 1 to 6 carbon atoms, and the 21-alkanoyl esters thereof; 16(a or b ) - alkyl-3,20-diketo-4-pregnene-17a ,21-diol, wherein the 16-alkyl group contains 1 to 6 carbon atoms, and the 21-alkanoyl esters thereof; 16(a or b )-alkyl-3,20-diketo-1,4-pregnadiene-17a ,21-diol wherein the 16-alkyl group contains 1 to 6 carbon atoms, and the 21-alkanoyl esters thereof; 16(a or b )-methyl-5(a or b )-pregnane-11a ,17a ,21-triol-3,20-dione; and 4-bromo-16(a or b ) - methyl - pregnane-17a ,21-diol-3,20-dione 21-ester. The invention also includes the following processes:- a process for the preparation of a 16(a or b )-methyl-1,4,9(11)-pregnatriene-3,20-dione-17a ,21-diol or a 21-carboxylate thereof which comprises dehydrating e.g. by reacting with an alkyl or aryl sulphonyl chloride in an alkaline medium, a 16(a or b )-methyl - 1,4 - pregnadiene-11b ,17a ,21-triol-3,20-dione or a 21-carboxylate thereof (this process may also be carried out using the corresponding 11a -hydroxy-compound); a process for the preparation of 9a (chloro, bromo or iodo)-16(a or b )-methyl-1,4-pregnadiene (or 4-pregnene)-11b ,17a ,21-triol-3,20-dione or a 21-carboxylate thereof by reacting a 16(a or b )-methyl-1,4,9(11)-pregnatriene (or 4,9(11)-pregnadiene)-3,20-dione-17a ,21-diol, or a 21-carboxylate thereof, with the required hypohalous acid; a process for the preparation of a 9b ,11b -oxido-16(a or b )-methyl-1,4-pregnadiene (or 4- pregnene)-3,20-dione-17a ,21-diol, or a 21-carboxylate thereof, which comprises reacting a 9a -halo-16(a or b )-methyl-1,4-pregnadiene (or 4-pregnene)-11b ,17a ,21-triol-3,20-dione, or a 21-carboxylate thereof, with a base, with the optional further step of oxidising the product to the corresponding 11-keto compound; a process for the preparation of 2,4-dibromo16(a or b )-methyl-5(a or b )-pregnane-17a ,21-diol-3,11,20-trione 21-ester by dibrominating 16(a or b )-methyl-5(a or b )-pregnane-17a ,21-diol-3,11,20-trione e.g., with bromine; a process for the preparation of 16(a or b )-methyl-1,4-pregnadiene-17a ,21-diol-3,11,20-trione 21-ester by dehydrobrominating 2,4-dibromo-16(a or b )-methyl-5(a or b )-pregnane-17a ,21-diol-3,11, 20-trione 21-ester with a dehydrobrominating agent e.g. dimethylformamide or a tertiary amine; a process for the preparation of 4-bromo-16(a or b )-methyl-pregnane-17a ,21-diol-3,11,20-trione 21-ester by brominating 16b -methyl-pregnane-17a ,21-diol 21-ester with a brominating agent e.g. bromine; a process for the preparation of 16(a or b )-methyl-4-pregnene-17a ,21-diol-3,11,20-trione 21-ester by dehydrobrominating 4-bromo-16(a or b )-methyl-pregnane - 17a ,21 - diol - 3,11,20-trione 21-ester with a dehydrobrominating agent e.g. dimethyl formamide or a tertiary amine or by reaction with semicarbazide followed by hydrolysis of the resulting 3-mono-semicarbazone; a process for the preparation of an 11-desoxy-16(a or b )-alkyl-17a -hydroxy-20-keto compound of the 5a -or 5b -pregnane series which compound may contain a 3-hydroxy substituent by enol acylating the required 11-desoxy-16-alkyl-20-keto compound, where the alkyl group contains 1 to 6 carbon atoms, with a lower alkanoic acid anhydride in the presence of a strong acid catalyst, treating the resulting 17(20)-unsaturated compound with a peroxy acid and hydrolysing the resulting 17,20-epoxide; and a process for the preparation of 16(a or b )-alkyl-4 - pregnene (or 1,4 - pregnadiene)-17a ,21-diol-3,20-dione, where the alkyl group contains 1 to 6 carbon atoms, by brominating at C21 an 11-desoxy-16(a or b )-alkyl-3,17a -dihydroxy-20-keto compound of the 5a - or 5b -pregnane series (prepared by the previous process), treating the resulting 21-bromo compound with an alkali metal lower alkanoate to form the corresponding 21-alkanoate, oxidising the 3-hydroxy group to a 3-keto group and introducing 4- or 1,4-unsaturation into the A ring e.g. by halogenation at the 4-position or 2,4-positions followed by dehydrohalogenation to form 4-or 1,4-unsaturation respectively or by a microbiological reduction using Corynebacterium simplex or Bacillus sphaericus to form 1,4-unsaturation, with the optional further step of hydroxylating at the 11-position e.g. by means of Rhizopus nigricans or Curvularia lunata. In the 16b -alkyl compounds defined in the opening sentence above, an 11-keto group may be reduced to an 11b -hydroxy group with sodium borohydride, lithium borohydride or lithium aluminium hydride in which case the keto groups at the 3- and 20-positions are protected either by forming 3,20-bis-semicarbazone derivatives which may be subsequently removed with pyruvic acid, or by forming 3,20-bis-ethylene ketal groups which may be subsequently removed by acid hydrolysis; a 21-ester group may be hydrolysed to a 21-hydroxy group; a 21-hydroxy group may be esterified as required; or an 11-hydroxy group may be oxidised to an 11-keto group (in this case it is preferable to oxidise the corresponding 11a -hydroxy compounds which may be prepared by a similar series of reactions as for the preparation of the 16b -alkyl-11b -hydroxy compounds). In addition, the D 1,4-16b -alkyl compounds defined in the opening sentence above may also be obtained by dehydrogenating the corresponding D 4-compounds with Bacillus sphaericus or with Corynebacterium simplex, or by dehydrogenating the corresponding D 4- or saturated-compounds with selenium dioxide or chloranil. 16b - and 16a -alkyl-steroids may be prepared by reacting a 17a -hydroxy