Patent GB-1007757-A (GB)
Title: 19-nor-steroids and process for their manufacture
IPC: A61K31/57
Filed: 1962-07-11
Abstract: The invention comprises (1) a process for the preparation of a 19-nor-steroid-diene wherein a D 4,6-3-oxo-19-hydroxy-steroid is oxidized to the corresponding steroid 19-acid and the latter is thermally decarboxylated; (2) as a new class of steroids, 21-unsubstituted D 4,6-3,20-dioxo-19-nor-pregnadienes having in the 17a -position a hydrogen atom or a free or esterified hydroxyl group and optionally having in the 4-or 6-position a halogen atom; and (3) as a further new class of steroids, D 5(10),6-3-oxo-19-nor-steroids of the androstane and pregnane series.  The oxidation may be effected directly with compounds of hexavalent chromium in an inert solvent and advantageously in the presence of a strong acid, or it may be performed in stages, oxidation with chromium trioxide in pyridine giving D 4,6-3,19-dioxo-steroids and oxidation of these with, for example, the reagent referred to for the direct oxidation giving the 19-acids.  Thermal decarboxylation of these in an acidic medium gives D 4,6-3-oxo-19-nor-steroids while in a weak alkaline to neutral medium the products are D 5(10),6-3-oxo-19-nor-steroids, which may be isomerized to the D 4,6-compounds by treatment with an acidic agent or with a basic reacting salt of an alkali metal. The D 4,6-compounds may be halogenated in the 4-position by treatment with a halogen in an organic solvent, and in the 6-position by treatment with an organic peracid to give the corresponding D 4-3-oxo-6a ,7a -oxido-19-nor-steroid, reaction of this with a hydrohalic acid to give the 6-halogen-7-hydroxy-compound, esterification of this with a sulphonylating agent, and treatment of the 6-halogen-7-sulphonyloxy compound with a basic agent.  Steroids used as starting materials in the present processes may be of the androstane, pregnane, cholane, cholestane, spirostane and cardanolide series and may contain free, ketalized or enolized oxo groups, free, esterified or etherified hydroxyl groups, alkyl, alkenyl or alkynyl groups and/or halogen atoms as substituents in the ring or 17-side chain, and they may also contain additional double bonds and oxido groups. Particularly mentioned are 17-oxo, 17b -hydroxy and 17b -hydroxy-17a -(alkyl, alkenyl or alkynyl)-androstane compounds and 20-oxo-pregnane compounds which may contain 17a -hydroxy, 21-hydroxy, 6- and 16-methyl, 6-halo and 16,17-oxido substituents and D 16 double bonds; and esters of these compounds with a wide variety of organic carboxylic and carbonic acids; and 17-ethers.  The D 4,6-3-oxo-19-nor-steroids may be partially hydrogenated to D 4-3-oxo-19-nor-steroids.  Examples describe these processes and the conversion of D 4,6 - 3 - oxo - 6 - chloro - 17a  - methyl - 17b -acetoxy - 19 - nor - androstadiene to the corresponding 17b -ol.  D 4,6 - 3 - oxo - 17a  - methyl - 17b  - acetoxy - 19 - nor - androstadiene is prepared by converting D 4 - 3 - oxo - 17a  - methyl - 17b  - acetoxy - 19-nor-androstene to the 3-ethyl enol ether, reacting this with N-bromo-succinimide to give D 4-3-oxo-6 - bromo - 17a  - methyl - 17b  - acetoxy - 19 - nor-androstene and dehydrobrominating this, a by-product being D 4 - 3 - oxo - 17a  - methyl - 17b -acetoxy-19-nor-androstene.  The steroids of (1) and (2) above, which variously have androgenic-anabolic, gestagenic and oral progestative action, may be made up into pharmaceutical compositions with suitable carriers.  They may take the form of solutions, suspensions, emulsions, implants, tablets, dragees, ointments or creams, and may contain preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. Specifications 994,746, 994,748, 1,007,756 and 1,007,758 are referred to.