Patent GB-941122-A (GB)
Title: 3-enol-ethers of 6-methyl-3-oxo-í¸-steroids
Inventor: KIRK DAVID NEVILLE
IPC: A61K31/568
Filed: 1961-02-22
Abstract: The invention comprises (1) a process for the preparation of 3-OR1- D 3,5-6-methyl-steroids (wherein R1 is alkyl, hydroxyalkyl, cycloakyl or aralkyl) wherein a 3-OR1- D  3, 5-6-(CH2NR11 R111X)-steroid (wherein R11 is an alkyl group of at most 6 carbon atoms, R111 is an alkyl group of at most 6 carbon atoms or an aryl group or R11 and R111 together form a ring wherein NR11R111 is piperidino, pyrrolidino or morpholino, and X is an electron pair which may be associated with a borane or hydrogen or oxygen, viz., an N-oxide, or an alkyl or aralkyl group) is hydrogenolysed; and (2) as new steroids, 17b -acetoxy-3-ethoxy-6-methylandrosta-3, 5-diene and the corresponding 2a -methyl compound; 6-methyl-cortisone acetate 3-enol ethyl ether and the corresponding cyclohexyl, n-propyl, n-butyl, sec-butyl, n-amyl, methyl, b -hydroxy-ethyl, cyclopentyl, 31-phenyl-propyl, isopropyl, n-hexyl, n-heptyl, benzyl and n-octyl ethers; 6-methyl-hydrocortisone acetate 3-enol methyl ether; 17a , 20:20,21-bismethylenedioxy-3-ethoxy-6-methylpregna-3, 5-dien-11b -ol and the corresponding 11 - one; 3 - ethoxy-6-methyl-androsta-3, 5-diene-17-one and the corresponding 3-methoxy compound; 17a -acetoxy-3-ethoxy-6-methylpregna-3, 5-dien-20-one; 6a , 17a -dimethyl-17b -hydroxy-3-methoxyandrosta-3 5-diene; 17a -acetoxy-3-methoxy-6, 16a -dimethylpregna-3, 5-dien-20-one; 21-acetoxy-3-ethoxy-6-methylpregna -3, 5 - dien - 20 - one; 21 - acetoxy -17a -hydroxy-3-methoxy-6-methylpregna-3, 5, 9(11)-trien-20-one; 3-methoxy-6-methyloestra-3, 5-dien-17-one; 6-methylcortisone 17a , 21 - acetonide 3-enol methyl ether; 17a -ethyl-17b -hydroxy-3-methoxy-6-methyl-androsta-3, 5-diene; 6-methyl-3-ethoxypregna-3, 5, 17(20)-trien-21-oate ethyl ester; 6-methyl-3-ethoxy-21-acetoxypregna-3, 5, 17(20)-triene; 17a -hydroxy-3-methoxy-6, 21-dimethylpregna-3, 5-diene-11, 20-dione; 21-acetoxy-17a -hydroxy-3-methoxy-6-methylpregna-3, 5, 9(11)-trien - 20 - one; - 20 - one; 16a , 17a -epoxy - 3 - methoxy - 6-methylpregna-3, 5-dien-20-one; 6-methyl-3-methoxy - 17b  - acetoxy - 19 - nor - androsta-3, 5-diene; 3-ethoxy-6, 16a -dimethylpregna-3, 5-dien-20-one; 21-acetoxy-3-methoxy-6-methylpregna-3, 5, 17(20)-trien-11-one; and steroids of the formula <FORM:0941122/C2/1> wherein R is an alkyl or cycloalkyl radical of at most 7 carbon atoms. The hydrogenolysis may be effected with Raney nickel, or with Raney nickel, platinum or palladium catalysts and hydrogen or a source thereof. Concomitant hydrogenation or hydrogenolysis of other groups present in the steroid may also occur, and a detailed discussion of this is given.  The process may be applied to steroids of the androstane, 9b , 10a -androstane, 19-norandrostane, pregnane, 9b , 10a -pregnane and 19-norpregnane series which may contain hydroxy, acyloxy, hydroxymethyl, acyloxymethyl, alkylenedioxy, carbonyl, carboxy, alkoxycarbonyl, alkyl, alkeryl, methylene, ethylidene or acylated ketol groups, lactone, ether or spiroketal residues, halogen atoms, unsaturated linkages at most positions of the steroid nucleus and 17-side chain, and protected conticoid side chains. Examples describe the preparation of all the above specified steroids and others, and the conversion of some 1,7-ester products to the corresponding 17b -ols by treatment with lithium aluminium hydride; and a list of further starting materials which includes diosgenone and testololactone is also provided. Conversion of some of the products to (1) the corresponding 6-methyl-3-oxo-D 4, 6-steroids by addition of halogen followed by dehalogenation or by the action of chloranil or other similar quenonoidal oxidants; or (2) the corresponding 6a -methyl-3-oxo-D 4-steroids by hydrolysis.  The preparation of 6-methyl-cortisone acetate 3-enol cyclohexyl ether from the corresponding ethyl ether and cyclohexanol is also described.  17a - Acetoxy - 3 - ethoxy-6-trimethylammonium-methylpregna-3, 5-dien-20-one iodide is prepared from the tertiary anine and methyl iodide. Methiodides of 6-dimethylaminomethyl cortisone acetate 3-enol ethyl ether; 17a , 20:20,21-bis-methylenedioxy-6-dimethylaminomethyl -3-ethoxy-pregna-3, 5-dien-11b -ol; 6-dimethylaminomethyl-3-ethoxy-16a , 17a -isopropylidenedioxypregna-3, 5-dien-20-one; 3-(6-dimethylaminomethyl-3-ethoxy-17b -hydroxy-androsta-3, 5-dien-17a -yl)-propionic acid lactone; 17b -acetoxy-6-dimethylaminomethyl-17a -ethyl-3-methoxyandrosta -3, 5-diene; and 3-ethoxy-6-dimethylaminomethylandrosta-3, 5-dien-17-one are prepared similarly, as are the metho-bromides of 17a -acetoxy-6-dimethylaminomethyl-3-ethoxypregna-3, 5-dien-20-one and 6-dimethyl-aminomethylcortisone acetate 3-enol methyl ether. Methacetates of 17b -acetoxy-6-dimethylamino-methyl - 3 - ethoxyandrosta - 3, 5 - diene and 21-acetoxy-6-dimethylaminomethyl-3-ethoxy-pregna-3, 5-dien-20-one are prepared from the corresponding methiodides and silver acetate. 6-Dimethylaminomethyl-3-methoxy-17b -acetoxy-19-norandrost-3, 5-diene borane is prepared from 17b -acetoxy-3-methoxyoestra-2, 5(10)-diene and lithium borohydride. The-N-oxide of 17a -acetoxy-3-methoxy-6-dimethylaminomethyl-pregna - 3, 5-dien-20-one is prepared from the parent steroid and hydrogen peroxide.  21 - Acetoxy - 17a  - hydroxy - 6 -dimethylamino-methyl-3-n-propyloxy-pregna-3, 5-diene-11, 20-dione is prepared by treating cortisone acetate 3-enol-n-propyl ether with the Vilsneier reagent and reducing the product.  Similarly 16a - and b -methylcortisone acetate 3-enol n-propyl ethers (prepared from 16a - and b -methylcortisone acetates and ethyl orthoformate) give the 6-dimethylaminomethyl derivatives. 6-Methylcortisone acetate 3-enol-n-propyl ether, which is stated to show anti-inflammatory activity, may be made up into pharmaceutical preparations with suitable carriers.  Tablets are described. Specifications 911,740, 941,121, and U.S.A. Specifications 2,846,452 and 3,099 858 are referred to.