Patent GB-1445945-A (GB)
Title: Steroids of the d-homo-pregnane series
IPC: A61K31/573
Filed: 1974-09-25
Abstract: 1445945 D-Homopregnenes F HOFFMANNLA ROCHE & CO AG 25 Sept 1974 [26 Sept 1973] 41707/74 Heading C2U The invention comprises #<SP>4</SP> and #<SP>1</SP>'<SP>4</SP> compounds of formulµ wherein R<SP>6</SP> is H, F, Cl, Br, Me; R<SP>91</SP> is H, F, Cl, Br; R<SP>92</SP> is Cl or Br; R<SP>110</SP> is F or Cl; R<SP>211</SP> is halo or OR; R<SP>213</SP> is halo, OH, monocarboxylic acyloxy or OR; R is a monoacyl radical of sulphuric or phosphoric acid or of a di- or tricarboxylic acid, said radical optionally being in the form of a water-soluble salt; and R<SP>17a</SP> is OH or acyloxy. Compounds I-1 and I-2 are prepared and/or interconverted by one or more reactions selected from: (a) 11#-hydroxylation (microbial or enzymatic) of corresponding 11 -unsubstituted compounds; (b) adding halogen, HOCl or HOBr across the double bond of corresponding #<SP>9</SP>(<SP>11</SP>)-compounds; (c) reacting corresponding 9#,11#-epoxides with HF, HCl or HBr; (d) 1,2- dehydrogenation (chemical or microbial); (e) 21-halogenation of corresponding 21-unsubstituted or 21-hydroxy compounds with protection of the 3-oxo group as an enamine or enaminium salt; (f) 21-esterification of 21-hydroxy, 21- halo or 21-diiodo; (g) hydrolysis of 17a- and 21-ester groups; (h) 6-halogenation of corresponding 6-unsubstituted-3-oxo-#<SP>4</SP> compounds or their enol ethers or esters; (i) 6# # 6α isomerization; (j) dehydration or dehydrohalogenation of corresponding 5α-Cl, Br, F or OH compounds; (k) 6-methylation; (1) oxidizing the double bond of corresponding #<SP>17a(20)</SP>- compounds to a hydroxyketone grouping; (m) oxidizing corresponding 3#-hydroxy-#<SP>5</SP> compounds to 3-oxo-#<SP>4</SP>. D - Homocortisone 21 - acetate # 17ahydroxy - 21 - acetoxy - D - homopregna - 4,9,(11)- diene - 3,20 - dione (XX) # 17a - hydroxy- 21 - acetoxy - D - homopregna - 1,4,9(11) - triene- 3,20 - dione (Examples 1 and 2). 11#,17α - Dihydroxy - D - homopregn - 4- ene - 3,20 - dione (XXI)#  11#,17a - dihydroxy - 21,21 - diiodo - D - homopregn - 4- ene-3,20-dione (Example 5). 17a,21 - Dihydroxy - D - homopregn - 4 - ene- 3,20 - dione # 17a - hydroxy - 21 - chloro - D- homopregn - 4 - ene - 3,20 - dione (Example 9). XX#  17a,21 - dihydroxy - D - homopregna- 4,9(11) - diene - 3,20 - dione and the 21- (hydrogen succinate) thereof (Example 10). 9α - Bromo - 11#,17a - dihydroxy - 21 - acetoxy - D - homopregn - 4 - ene - 3,20 - dione # 9,11# - epoxy - 17a - hydroxy - 21 - acetoxy - D- homo - 9# - pregn - 4 - ene - 3,20 - dione # 9,11# - epoxy - 17a,21 - dihydroxy - D - homo- 9# - pregn - 4 - ene - 3,20 - dione # 9,11#- epoxy - 17a - hydroxy - 21 - chloro - D - homo - 9# pregn-4-ene-3,20-dione (Example 11). XXI # 3 - (1 - pyrrolidinyl) - 11#,17adihydroxy - D - homopregna - 3,5 - dien - 20- one # 3 - (1 - pyrrolidinio) - 11#,17a - dihydroxy - 21 - bromo - D - homopregn - 4 - en- 20-one bromide (Example 13). 9α - Chloro - 11# - fluoro - 17a - hydroxy - 21- acetoxy - D - homopregn - 4 - ene - 3,20 - dione (XXII) # 3 - ethoxy - 9α - chloro - 11#- fluoro - 17a - hydroxy - 21 - acetoxy - D - homopregna-3,5 dien-20-one (Example 16). XXII # 3,3-ethylenedioxy-9α-chloro-11#- fluoro - 17a - hydroxy - 21 - acetoxy - D - homopregn - 5 - en - 20 - one # 3,3 - ethylenedioxy- 5α,6#,9α - trichloro - 11# - -fluoro - 17a - hydroxy 21 - acetoxy - D - homopregnan - 20 - one # 5α,6#,9α - trichloro - 11# -fluoro - 17a - hydroxy- 21 - acetoxy - D - homopregnane - 3,20 - dione (Example 18). 3# - Hydroxy - 11# - acetoxy - 17,20 - epoxy- 21 - norpregn - 5 - ene (XXIII) # 3#,17#- dihydroxy - 11# - acetoxy - 17# - (aminomethyl)- androst - 5 - ene # 3# - hydroxy - 11# - acetoxy- D - homoandrost - 5 - en - 17a - one # 3#,11#- dihydroxy - D - homoandrost - 5 - en - 17a - one #ethyl 3#,11# - dihydroxy - D - homopregna- 5,17a(20) - dien - 21 - oate # 3#,11#,21- trihydroxy - D - homopregna - 5,17a(20) - diene # 3#,11# - dihydroxy - 21 - (triphenylmethoxy). D - homopregna - 5,17a(20) - diene # 11#- hydroxy - 21 - (triphenylmethoxy) - D - homopregna - 4,17α(20) - dien - 3 - one # 11#,21- dihydroxy - D - homopregna - 4,17a(20) - dien- 3 - one # 11# - hydroxy - 21 - chloro - D- homopregna - 4,17a(20) - dien - 3 - one (Example 19). 3#,11# - Dihydroxy - D - homopregna- 5,17a(20) - diene # 3#,11#,17a - trihydroxy- D - homopregn - 5 - en - 20 - one# 3#,11#,17a trihydroxy - 21,21 - diiodo - D - homopregn - 5- en - 20 - one # 3#,11#,17a - trihydroxy - 21- acetoxy - D - homopregn - 5 - en - 20 - one # 3#,11#,17α,21 - tetrahydroxy - D - homopregn- 5 - en - 20 - one # 3#,11#,17a - trihydroxy - 21- chloro - D - homopregn - 5 - en - 20 - one (Example 20). The preparation of XXI (Example 13), XXIII (Example 19) and 9α - fluoro - D - homoprednisolone (Example 7) is as described in Specification 1,365,469. Antiinflammatory compositions for oral, parenteral, rectal and topical administration comprise a compound (I-1) or (I-2) and a carrier. Reference has been directed by the Comptroller to Specification 1,365,469.