Patent GB-1211836-A (GB)
Title: Novel 15,16-alkylidene-steroids and a process for the manufacture thereof
IPC: A47B96/16
Filed: 1969-04-21
Abstract: 1,211,836. 15#,16#-(Methylene or isopropylidene)-steroids. F. HOFFMANN-LA ROCHE & CO. A.G. 21 April, 1969 [22 April, 1968], No. 20171/69. Heading C2U. The invention comprises compounds of the formulµ wherein both R's are H or Me; R 2  is H or halo; R 3  is a 3-oxo-#<SP>4</SP>, 3-oxo-#<SP>1,4</SP>, 3-oxo-#<SP>4,6</SP>, 3-oxo- #<SP>1,4,6</SP>, 3 - acyloxy - #<SP>3,5</SP>, 3 - acyloxy - #<SP>2,4,6</SP>, 3 - acyloxy - #<SP>3,5,7</SP>, 3 - " alkoxy " - #<SP>3,5</SP> or 3 - " alkoxy " - #<SP>3,5,7</SP> system; R 6  is H, halo or C 1-5  alkyl; R 17 α is OH, acyloxy or " alkoxy "; R 21  is H, halo, OH, acyloxy or " alkoxy "; and R<SP>1</SP> 21  is H or acyloxy. The term " alkoxy "  denotes C 1-20  etherified hydroxy groups which are aliphatic, cycloaliphatic or araliphatic in nature. Compounds I are prepared (a) by oxidizing the #<SP>17(20)</SP> double bond of compounds IIA (wherein R<SP>1</SP> 21  has any of the values defined for R 21 ) to a 17α-hydroxy-20-oxo grouping; or (b) by isomerizing the 6-methylene group of compounds IX to a 6-methyl-#<SP>6</SP> grouping; or (c) by 17-hydroxylating compounds I wherein R 17 α is H. Compounds I are interconvertible by (i) 2-halogenation, (ii) 6-halogenation, (iii) 6- alkylation, (iv) 1,2- and/or 6,7-dehydrogenation, (v) 21-hydroxylation, (via 21-diiodide and 21- acetate), (vi) 17- and/or 21-etherification and esterification and (vii) 3-enol etherification and esterification. Compounds IIA are prepared by oxidation of the corresponding #<SP>5</SP>-3-ols and may be treated to introduce 2-halo, 6-halo or 6-alkyl substituents when these are not already present. In addition, compound IIA (wherein R = R 2  = R 6  = H and R<SP>1</SP> 21  = acetoxy) is prepared by esterification of the corresponding 21-ol. Compounds IX are prepared by dehydration and hydrolysis of the corresponding 3-methoxy- 6-hydroxymethyl-3,5-dienes. 3# - Hydroxy - 15#,16# - methylenepregna- 5,17(20)-diene is prepared from 3#-hydroxyandrosta - 5,15 - dien - 17 - one via 3# - acetoxyandrosta - 5,15 - dien - 17 - one, 3# - acetoxy- 15#,16# - methyleneandrost - 5 - en - 17 - one and 3# - acetozy - 15#,16# - methylenepregna - 5,17(20)- diene (Wittig reaction). The corresponding 15#,16# - isoporpylidene compound is prepared analogously. 21 - Hydroxy - 15#,16# - methylenepregna- 4,17(20) - dien - 3 - one is prepared from 15#,16# - methyleneandrost - 4 - ene - 3,17- dione via 3 - methoxy - 15#,16# - methyleneandrosta - 3,5 - dien - 17 - one, 3 - methoxy- 15#,16# - methylenepregna - 3,5,17(20) -trien-21- oic acid ethyl ester and 21-hydroxy-3-methoxy- 15#,16# - methylenepregna - 3,5,17(20) - triene. 17α - Hydroxy - 21 - diiodopregn - 4 - ene - 3,20- dione is prepared from the corresponding 21- unsubstituted compound. 3 - Methoxy - 6 - hydroxymethyl - 17α - acetoxy- 15#,16# - methylenepregn - 3,5 - dien -20-one is prepared from the corresponding 6-unsubstituted compound via 3-methoxy-6-formyl-17α- acetoxy - 15#,16# - methylenepregna - 3,5 - dien- 20-one. 17α,20 - Dihydroxy - 15#,16# - methylenepregn- 4-en-3-one is obtained as a by-product in the preparation of the corresponding 17α-ol-20-one of Formula I by method (a). Compounds of Formula I are stated to possess hormonal (e.g. progestational) activity and to influence the gonadotropin economy, and may be made up with carriers into pharmaceutical compositions for oral, parenteral, rectal and topical administration.