Patent GB-843211-A (GB)
Title: Pregnadienes
IPC: C07J5/00
Filed: 1955-08-03
Abstract: The invention comprises compounds of the pregnane series having therapeutic activity and possessing a double bond in the 4-position which compounds are substituted by ketonic oxygen at the 3- and 20- positions, by a hydroxyl group or ketonic oxygen at the 11-position, by a hydroxyl or an esterified hydroxyl group at the 21-position and by a hydroxyl group at the 17 a -position and which may be substituted by halogen at the 9 a -position, which compounds are also characterised by the presence of a double bond at the 1-position. The most important compounds of this series are 1-dehydrocortisone and 1-dehydrocortisol and their 9 a -fluoro derivatives, and the 21-esters of any of these compounds.  The compounds may be prepared by a number of methods, the preferred method being the introduction of a double bond at the 1(2)-position in a suitable starting compound.  The compounds may also be prepared by the introduction of a 1(2)-double bond into an intermediate compound with one or more of the following steps to obtain the desired compounds:-  1. Introduction of a 4(5)- or 5(6)-double bond (such 5(6)-double bond ultimately shifting to the 4(5)-position).  2. Introduction of an 11-oxygen function.  3. Introduction of a 17 a -oxygen function.  4. Introduction of a 21-oxygen function.  5. Introduction of a 9 a -halogen function.  The introduction of the 1(2)-double bond and one or more of the above steps may be carried out in any desired order. The introduction of the 1(2)-double bond may be carried out with the dehydrogenating activity produced by growing micro-organisms of the family Corynebacteriacae e.g. of the genus Corynebacterium such as C. simplex or C. hoagii, or the micro-organism Bacillus sphaericus var. fusiformis.  This type of dehydrogenation (which is described in Specifications 807,227 and 843,217) may be applied to a 3-keto-4-pregnene or a 3-hydroxy (or esterified hydroxy)-5-pregnene system (in the latter case the 3-substituent is also converted to a 3-keto group) with or without any of the remaining required substituents.  Under certain conditions this type of dehydrogenation also converts a 20-hydroxy group to a 20-keto group but may also reduce a 20-keto group to a 20-hydroxy group.  The remaining required substituents may be introduced, if required, by methods detailed below.  Thus this type of 1(2)-dehydrogenation may be applied to a 3-keto-11 a -hydroxy-4-pregnene, a 4,6-pregnadiene, a 4,16-pregnadiene or a 4,9(11)-pregnadiene system in which case it is necessary at a later stage to oxidise the 11 a -hydroxy group in the resulting 3-keto-11 a -hydroxy-1,4-pregnadiene system to an 11-keto group, hydrogenate the resulting 1,4,6-pregnatriene to a 1,4-pregnadiene, to convert the resulting 1,4,16-pregnatriene to a 17 a -hydroxy-1,4-pregnadiene, or to convert a 1,4,9 (11)-pregnatriene to a 9-halo-1,4-pregnadiene respectively.  The Specification refers to a large number of reactants which are suitable for this type of dehydrogenation.  The 1(2)-double bond may also be introduced by chemical means as follows:-(a) treating 4-pregnene-2,17 a ,21-triol-3,20-diones having an 11-keto, 11b -hydroxy or 11b -alkanoyloxy substituent or a 21-ester thereof or the corresponding 2-alkanoyloxy compounds (the 2-hydroxy and 2-alkanoyloxy compounds and the preparation thereof are described in Specification 843,214, with a dehydrating agent e.g. hydrogen bromide in acetic acid; and (b) treating 1-hydroxy or 1-acyloxy derivatives of cortisone or cortisol or 21-esters thereof with an acid or base such as alumina or tetramethylammonium hydroxide, (the 1-hydroxy and 1-alkanolyoxy-compounds and the preparation thereof are described in Specification 843,219).  The double bonds at the 1(2) and 4(5)- positions may be introduced by treating 21-esters of pregnane (or allopregnane)-17 a ,21-diol-3,11,20-trione and the 21-esters and 11,21-diesters of pregnane (or allopregnane)-11 (a  or BETA), 17a , 21-triol-3,20-dione with chlorine, bromine or iodine to form the corresponding 2,4-dihalo-compounds in one or two steps (in the latter case different halogens may be employed), and then dehydrohalogenating, e.g. by refluxing with collidine, quinaldine or dimethylaniline.  Ester groups in the 1,4-pregnadiene products may then be hydrolysed.  The preferred halogenating agent is bromine and the modification of this process using bromine as the halogenating agent is described in Specification 843,213.  The introduction of the 11-oxygen function may be carried out using an 11-hydroxylating micro-organism e.g., Aspergillus niger, Rhizopus nigricans Rhizopus arrhizus Rhizopus delmar or Phycomyces blakesleeanus for 11 a -hydroxylation, or curvularia lunata or Cunninghamella blakesleana for 11b -hydroxylation.  The 11-hydroxylation of 1,4-pregnadiene-17a , 21-diol-3,20-dione and the 21-acyloxy esters thereof is described in Specification 843,218.  Hydroxylation at the 17 a -position may be effected using oxygenating substances produced by growing micro-organisms of the genus Tricothecium e.g. T.roseum, or by splitting a 16,17-epoxide ring in a suitable reactant e.g. by treating the epoxide compound with an acid such as hydriodic or hydrobromic acid, to form a 16,17-halohydrin, and removing the halogen with Raney nickel or with hydrogen in the presence of palladium or charcoal.  16,17-Oxido-3-keto-1,4-pregnadienes from which suitable 17 a -hydroxy compounds may be prepared, and the preparation thereof, are described in Specification 843,216.  The introduction of a 21-hydroxy group may be carried out by treating p a suitable pregnane with the oxygenating activity produced by growing micro-organisms of the genus Ophiobolus e.g. O. herbotrichus.  The substitution of the 9 a -halogen atom is preferably carried out following the dehydrogenation of the A ring of the pregnane nucleus. Thus a 1,4-pregnadiene containing an 11(a  or b )-hydroxy group may be treated to form a 1,4,9(11)-pregnatriene (suitable 1,4,9(11)-pregnatrienes and the preparation thereof are described in Specification 843,215), and the pregnatriene may then be treated in a number of ways to introduce the 9-halogen atom and at the same time an 11b -hydroxy group which may be subsequently oxidised to an 11-keto group e.g. by treatment with a compound which provides a bromium ion such as N-bromoacetamide or N-bromosuccinimide, in a strong acid such as sulphuric and perchloric acid whereby a 9 a -bromo-11b -hydroxy compound is obtained, the 9 a -bromo compound may then be dehalogenated by the action of a weak base such as potassium or sodium acetate to form a 9,11-epoxide which is then treated with hydrogen fluoride or hydrogen chloride to form the corresponding 9 a -fluoro-11-hydroxy and 9 a -chloro-11-hydroxy compounds respectively. The 21-esters of the desired compounds of the pregnane series may be formed at the last stage or at any desired intermediate stage.  In certain of the intermediate stages, however, 21-ester groups may be hydrolysed to 21-hydroxy groups so that re-esterification may be necessary.  The Specification refers to a large number of organic acids including polybasic, cyclo-aliphatic acids (and alkali and alkaline earth metal salts thereof), and unsubstituted or cycloalkyl-substituted lower alkanoyl acids where the alkanoyl radical contains not more than 8 carbon atoms from which the 21-ester group may be derived. Organic acids particularly referred to are acetic, trimethyl-, t-butyl-, cyclopentyl-, phenoxy-, 41-chlorophenoxy-, 21,41-dichloro-phenoxy-, 21,41, 51-trichlorophenoxy-, 41-bromophenoxy-, 41-t-butylphenoxy- and 41-methoxyphenoxy-acetic acids, cyclopentylpropionic and cyclohexylpropionic acids, and succinic, hexahydrophthalic, 21-furoic, 51-t-butyl-21-furoic, 51-chloro-21-furoic and 51-bromo-21-furoic acids.  Inorganic acids such as phosphoric and sulphuric acids may also be used for the 21-ester formation.  The Specification includes a large number of examples describing the preparation of compounds of the pregnane series defined above-particularly the most important members of this series detailed above, and intermediates therefore.  The Specification also includes a number of reaction schemes outlining various ways of introducing the required double bonds and substituents into the pregnane nucleus.ALSO:A theapeutic composition contains a pharmaceutical carrier and as the active ingredient a compound of the pregnane series having therapeutic activity and possessing a double bond in the 4-position, which compounds are substituted by ketonic oxygen in the 3-ml 20-positions, by a hydroxyl group or ketonic oxygen at the 11-position, by a hydroxyl or an esterified hydroxyl group at the 21-position and by a hydroxyl group at the 17 a -position and which may be substituted by halogen the 9 a -position, which compounds are also characterised by the presence of a double bond at the 1-position.  The preferred active ingredients are 1-dehydrocortisone and 1-dehydrocortisol and their 9 a -fluoro derivatives and the 21-esters of any of these compounds.  The composition may be in the form of an oral dosage unit form, a cream, an aqueous suspension an ointment, a suppository, a lotion, or solution.  Thus the compositions are suitable for oral, topical or parenteral use. Suitable pharmaceutical carriers are starch, sugar, clay, gum, oil and water.