GB932857A - Steroid compounds and compositions thereof - Google Patents

Abstract

The invention comprises compounds having the formulae: <FORM:0932857/IV(a)/1> and <FORM:0932857/IV(a)/2> and the corresponding D 1,4, D 1,4,6 and D 4,6 compounds, wherein X is hydrogen, hydroxyl or an acylated hydroxyl, the acyl group being derived from monocarboxylic acids containing 1-10 carbon atoms and R2 and R3 are the same or different and represent hydrogen, or alkyl groups containing 1-4 carbon atoms or together with a nitrogen atom form a heterocyclic ring; and pharmaceutically acceptable acid addition salts and quaternary alkyl ammonium derivatives thereof, and therapeutic compositions thereof. The D 1,4- and D 1,4,6-compounds in which R2 and R3 are both alkyl groups or form a heterocyclic ring are obtained by reacting the corresponding progesterone derivative with an amine addition salt and formaldehyde. For D 4- and D 4,6-, and also D 1,4- and D 1,4,6-compounds in which R2 and R3 are hydrogens, the 3-hydroxy compound is reacted with an amine salt and formaldehyde to form a 3-hydroxy-21-dimethylamino-methyl compound, a molecule of dimethylamine is eliminated by forming a quaternary ammonium compound which is treated with water or aqueous alkali to form a 21-methylene compound, the 3-hydroxy group is oxidised to 3-keto and the resulting compound is treated with ammonia or free amine to form the desired 3-keto-D 4-21-substituted compound. For the preparation of 6-bromo or chloro or 6-methyl compounds pregnenolone or 17-hydroxypregnenolone is treated with a peracid to form a 5a ,6a -epoxide, the epoxide ring is opened with CH3MgBr, HCI, or HBr to form 5a -hydroxy-6b -methyl, 5a -hydroxy-6b -chloro and 5a -hydroxy-6b -bromo steroids, which are converted to 21-methylene compounds as above, oxidised with chromic acid and dehydrated to form 3-keto-D 4-21-methylene compounds and reacted with ammonia or an amine to obtain the desired 3-keto-D 4,6-substituted 21-amino compounds. For the preparation of 6-fluoro compounds, pregnenolone or 17-hydroxypregnenolone is reacted with N-bromoacetamide and anhydrous HF to obtain a 5a -bromo-6b -fluoro compound, this compound is converted to a 21-methylene compound as above, the 3-hydroxy group is oxidised to 3-keto, the bromine atom removed with alkaline agent and the resulting 3-keto-D 4-6b -fluoro-21-methy-lene compound is reacted with an amine to produce a 21-amino compound. Double bonds may be introduced in the intermediate 21-methylene compounds in 1,2-position with selenium dioxide or in 6,7-position with chloranil. The therapeutic compositions, having progestational activity, comprise the active compounds of a pharmaceutical carrier. Specifications 897,839 and 924,981 are referred to.