Patent GB-1365469-A (GB)
Title: Steroids of the d-homopregnane series
IPC: A61K31/22
Filed: 1973-03-29
Abstract: 1365469 D-homosteroids F HOFFMANNLA ROCHE & CO AG 29 March 1973 [29 March 1972] 15112/73 Headings C2U and C2C The invention comprises compounds of formula (wherein R<SP>6</SP> is H, F, Cl or Me; R<SP>9</SP> is H, F, Cl or Br; and R<SP>17</SP> and R<SP>21</SP> are each hydroxy or acyloxy), and the 1,2-dehydro derivatives thereof; and their preparation by (i) microbial 11#- hydroxylation of the corresponding 11-unsubstituted compounds; (ii) reaction of the corresponding 21-halo compounds with alkali metal acylates to give 21-acyloxy compounds; (iii) addition of HOCl or HOBr across the double bond of the corresponding #<SP>9(11)</SP>-compounds; (iv) hydrohalogenation of the corresponding 9#,11#-epoxides; (v) 4,5-dehydration of the corresponding 5α-ols; (vi) reduction of the corresponding 11-ones (with protection of the 3- and 20-oxo groups); (vii) oxidation of the corresponding 17a(20)-enes to introduce the 17aα-hydroxy-20-oxo-grouping; and (viii) 4,5- dehydrohalogenation of the corresponding 5#,6#-dichloro compounds. Interconversions of compounds I are: (i) 1,2-dehydrogenation (chemical or microbial); (ii) saponification of 17- or 21-acyloxy groups; (iii) 6# # 6α isomerization; (iv) 6-halogenation; and (v) acylation of 17- and 21-hydroxy groups. D-Homocortisone 21-acetate is formed as a by-product in the preparation of 9α-fluoro-D- homocortisol 21-acetate by preparation (iv). 11#,17aα - Dihydroxy - D - homopregn - 4- ene - 3,20 - dione (XXI) is prepared from 3,11#- diacetoxyandrosta-3,5-dien-17-one (XX) by the sequence: XX # 3,11# - diacetoxy - 17,17 - ethylenedioxyandrosta - 3,5 - diene # 3# - hydroxy- 11# - acetoxy - 17, 17 - ethylenedioxyandrost-5- ene # 3# - hydroxy - 11# - acetoxyandrost - 5- en - 17 - one # 3# - hydroxy - 11# - acetoxy- 17,20 - epoxy - 21 - norpregn - 5 - ene # 3#,17#- dihydroxy - 11# - acetoxy - 17#- aminomethylandrost - 4 - ene # 3# - hydroxy - 11# - acetoxy- D - homoandrost - 5 - en - 17a - one # 3#,11#- dihydroxy - D - homoandrost - 5 en - 17a - one # 3#,11# - dihydroxy - D - homopregna - 5,17a(20)- diene # 11# - hydroxy - D - homopregna - 4,17a- (20)-dien-3-one # XXI. 11#,17aα - Dihydroxy - 21 - iodo - D - homopregn - 4 - ene - 3,20 - dione is prepared from XXI with I 2 /CaO/CaCl 2 /MeOH. 11#,17aα - Dihydroxy - D - homopregna- 1,4 - diene - 3,20 - dione is prepared from XXI with Arthrobacter Simplex. 6α- and 6# - Fluoro - 11#,17aα - dihydroxy- D - homo - pregn - 4 - ene - 3,20 - dione are prepared from XXI via 3-ethoxy-11#,17aα-dihydroxy - D - homopregna - 3,5 - dien - 20 - one. The 6#-isomer can be isomerized to the 6α- isomer using HBr/AcOH. 17aα - Hydroxy - 21 - acetoxy - D - homopregna - 4,9(11) - diene - 3,20- dione and the corresponding 1,4,9(11)-triene are prepared by dehydration of the corresponding 11#-ols. 9#,11# - Epoxy - 17aα - hydroxy - 21 - acetoxy- D - homopregn - 4 - ene - 3,20 - dione and the #<SP>1,4</SP> and 6α-fluoro-#<SP>1,4</SP> analogues thereof are prepared from the corresponding 9α-bromo- 11#-ols by refluxing with KOAc/EtOH. 3 - Ethoxy - 11#, 17aα- dihydroxy - 21 - acetoxy- D - homopregna - 3,5 - dien - 20 - one is prepared from the corresponding 4-en-3-one with triethyl orthoformate. 5α,6α - Dichloro - 11#,17aα - dihydroxy - 21- acetoxy - D - homopregnane - 3,20 - dione is prepared from 11#,17aα-dihydroxy-21-acetoxy- D-homopregn-4-ene-3,20-dione via 3,3-ethylenedioxy - 11#,17aα - dihydroxy - 21 - acetoxy - D- homopregn-5-en-20-one (XXII). 5α,11#,17aα - Trihydroxy - 6# - chloro - 21 acetoxy - D - homopregnane - 3,20 - dione is prepared from XXII via 3,3, - ethylenedioxy- 5,6 - epoxy - 11#, 17aα - dihydroxy - 21 - acetoxy- D - homopregnan - 20 - one and 3,3 - ethylenedioxy - 5α,11#,17aα - trihydroxy - 6# - chloro- 21-acetoxy-D-homopregnan-20-one. A 3,20-disemicarbazone is prepared from 17aα- hydroxy - 21 - acetoxy - D - homopregn - 4- ene-3,11,20-trione. Anti-inflammatory compositions for oral, parenteral, rectal and topical administration comprise a compound of Formula I and a carrier.