Patent GB-1480038-A (GB)
Title: D-homosteroids
IPC: A61K31/22
Filed: 1975-10-06
Abstract: 1480038 D-homo steroids F HOFFMANNLA ROCHE & CO AG 6 Oct 1975 [7 Oct 1974 2 Dec 1974 13 March 1975] 40804/75 Heading C2U The invention comprises compounds of formulae wherein R<SP>1</SP> and R<SP>2</SP> are each H or together represent an extra bond or a 1α,2α-methylene group; R<SP>5</SP> is F, Cl, Br or OH; R<SP>6</SP> is H, F, Cl, or Me; R<SP>61</SP> is H or Me; R<SP>62</SP> is F, Cl or Me; R<SP>10</SP> is Me or, when R<SP>1</SP>=R<SP>2</SP>=H, R<SP>10</SP> can also be H; R<SP>17a</SP> is OH, alkoxy, acyloxy or C 1-4  alkyl; R<SP>21</SP> is H, F or Cl; the 6,7-broken line in Formula I and VIII denotes an optional extra bond; and X and the broken lines in Formula XI denote a 3-(alkoxy, alkylthio or tert-amino)-#<SP>2,6(10)</SP> or 3,3-alkylenedioxy or alkylenedithio)-#<SP>4</SP>, -#<SP>5</SP> or -#<SP>5(10)</SP> grouping. Compounds I are prepared (a) from compounds II by oxidizing the 3-hydroxy-#<SP>5</SP> grouping to 3-oxo-#<SP>4</SP>,#<SP>4,6</SP> or #<SP>1,4,6</SP>; (b) from compounds VIII by 21-halogenation optionally via the 21-mesylates or tosylates; (c) from compounds IX by cleavage of HR<SP>5</SP> to give #<SP>4</SP>; or (d) from compounds XI by hydrolysis. Interconversions of compounds I: (a) 1,2- and/or 6,7- dehydrogenation (chemical or microbial); (b) 6-halogenation, optionally via 6α,7α-epoxy, 6#- halo - 7α - hydroxy and 6# - halo - 7α - mesyloxy intermediates, and optional epimerization of 6(3-products; (c) 6-methylation, optionally via 6 - trihalomethyl and 6 - dihalomethylene intermediates or via (6-formyl), 6-hydroxymethyl and 6-methylene intermediates; (d) acylation of 17aα-OH; (e) 1α,2α-methylenation. Compounds II, VIII and XI are produced by, or in analogy with the reaction sequences infra. In addition compounds XI are obtainable conventionally from compounds I. Compounds IX are produced from the corresponding 3,3 - ethylenedioxy - #<SP>5</SP> compounds by halogenation or by epoxidation followed by 6-halogenation or methylation then ketal hydrolysis. 3# - Hydroxy - D - homopregna - 5,17(17a)- dien - 20 - one (XX)#3# - (2 - tetrahydropyranyloxy - D - homopregna - 5,17(17a) - dien- 20 - one#3# - (2 - tetrahydropyranyloxy)- 17aα- alkyl - D - homopregna - 5,16 - dien - 20 - one# 3# - hydroxy 3# - hydroxy - 17aα - alkyl - D - homopregna - 5,16 - dien - 20 - one (II) (where "alkyl" is Me, Et or Bu) (Exx. 1, 11, 12). XX#3#,17aα - dihydroxy - D - homopregna- 5,16 - dien - 20 - one (II) (of which a 3,17- diacetate and 17-monoacetate (II) (are prepared) #3#,17aα - dihydroxy - 21,21 - diiodo - D - homopregna - 5,16 - dien - 20 - one#3#,17aα - dihydroxy - 21 - acetoxy - D - homopregna - 5,16- dien - 20 - one#17aα - hydroxy - 21 - acetoxy - D- homopregna - 4,16 - diene - 3,20 - dione#17α,21- dihydroxy - D - homopregna - 4,16 - diene - 3,20- dione (VIII) (Exx. 2, 3, 4). D - homoestrone methyl ether#3 - methoxy- 17aα - chloro - D - homoestra - 1,3,5(10) - triene- 17a# - carboxaldehyde#3 - methoxy - D - homoestra - 1,3,5(10),17(17a) - tetraene - 17a - carboxaldehyde, which by the successive actions of MeLi, Na/NH 3 (l), ethylene glycol and CrO 3 /py# 3,3 - ethylenedioxy - 19 - nor - D - homopregna- 5(10),17(17a) - dien - 20 - one#3,3 - ethylenedioxy - 17aα - 17aα - hydroxy - 19 - nor - D - homopregna - 5(10),16 - dien - 20 - one (XI) (Ex. 23). Progestational compositions for oral, parenteral, topical and rectal administration comprise a compound I and a carrier.