Patent GB-1336434-A (GB)
Title: 14,18- epoxy-ethanoimino steroids their preparation and compositions containing them
IPC: A23K1/165
Filed: 1970-10-23
Abstract: 1336434 14,18-Epoxyethanoimino steroids J R GEIGY AG 23 Oct 1970 [24 Oct 1969 24 July 1970] 50425/70 Heading C2U The invention relates to compounds of formula wherein R 1  is H, C 1-8  alkyl or benzyl; R 2  is H 2  or oxo; R 3  is free or ketalized oxo or is a hydrogen atom with a free, esterified or etherified OH group; R 4  is defined as R 3  or is a free or etherified OH group and, together with R 8 , a 3α,9α-epoxy radical; R 5  and R 6  are each defined as R 3 , or may be H 2 , or, when occurring at a double bond, H; R 7  is H; R 8  is α-H, α-OH or, together with R 4 , 3α,9α-epoxy; and R 9  is H or free, esterified or etherified OH; and wherein double bonds may be present in position 5 or 4 (in the latter only when R 4  is free oxo), and in positions 7, 9(11) and 16 corresponding to the dotted lines and with the elimination of R 7 , R 8  and/or R 9 ; and the acid-addition salts of the above compounds wherein R 2  is H 2 . Compounds (I) and their acid-addition salts are claimed per se with the exception of the following compounds and their acid-addition salts: (a) batrachotoxinin A and its 20-pbromobenzoate, and the derivatives of these compounds and also of batrachotoxin and homobatrachotoxin in which the 3α,9α-epoxy group has been replaced by a 9-hydroxy group; (b) the 20-esters of batrachotoxinin A with 2- or 3- pyrrolecarboxylic acids or their alkylated and/or N-acylated derivatives (including batrachotoxin and homobatrachotoxin); and (c) the specific compounds claimed in Claims 7, 8 and 10-19 of Specification 1,268,568. Compounds (I) (including the compounds excepted from the per se claims) are prepared from compounds of formula  (wherein X is halo) by cyclization in the presence of an acid-binding agent, to give compounds (I) wherein R 2  is oxo which may then be reduced with a complex hydride to give compounds (I) wherein R 2  is H 2  which may then be  salified.  Compounds (I) are further interconvertible by hydrolysis of ether, ester, ketal and epoxy  groups; esterification, etherification and oxidation of hydroxy groups; and reduction of  oxo to hydroxy. 3# - Methoxy - 3α,9α - epoxy - 11α,20# - diacetoxy - 18 - (N - methyl - 2 - chloroacetamido)- 5#,17α - pregnan - 14# - ol (XIII) is prepared from 3,3 - ethylenedioxy - 20# - hydroxypregna- 5,9(11) - dien - 18 - oic acid (18 -# 20) - lactone (XII) by the sequence: XII -# 3,3- ethylenedioxypregna - 5,9(11) - diene - 18,20#- diol -# 18,20# - dihydroxypregna - 4,9(11)- dien - 3 - one -# 18,20# - dihydroxy - 5# - pregn- 9(11) - en - 3 - one -# 18 - acetoxy - 20#- hydroxy - 5# - pregn - 9(11) - en - 3 - one (+18,20- diacetate as by-product) -# 18 - acetoxy - 5#- pregn - 9(11) - ene - 3,20 - dione -# 3#,11α - dihydroxy - 3α,9α - epoxy - 18 - acetoxy - 5# - preg-  nan - 20 - one -# 3# - methoxy - 3α,9α - epoxy- 11α,18 - diacetoxy - 5# - pregnan - 20 - one -# 3# - methoxy - 3α,9α - epoxy - 11α,18 - diacetoxy - 5# - pregn - 16 - en - 20 - one -# 3# - methoxy- 3α,9α - epoxy - 11α,18 - diacetoxy - 5# - pregna- 14,16 - dien - 20 - one -# 3# - methoxy - 3α,9α; 14#,15# - diepoxy - 11α,18 - diacetoxy - 5# - pregn- 16 - en - 20 - one -# 3# - methoxy - 3α,9α - epoxy- 11α,18 - diacetoxy - 14# - hydroxy - 5#,17α - pregnan - 20 - one -# 3# - methoxy - 3α,9α - epoxy- 11α,18,20# - triacetoxy - 5#,17α - pregnan - 14#- ol -# 3# - methoxy - 3α,9α - epoxy - 11α,20- diacetoxy - 5#,17α - pregnane - 14#,18 - diol -# 3# - methoxy - 3α,9α - epoxy - 11α,20# - diacetoxy- 14# - hydroxy - 5#,17α - pregnan - 18 - al -# 3#- methoxy - 3α,9α - epoxy - 11α,20# - diacetoxy - 18- methylimino - 5#,17α - pregnan - 14# - ol -# 3#- methoxy - 3α,9α - epoxy - 11α,20# - diacetoxy - 18- methylamino - 5#,17α - pregnan - 14# - ol -# XIII. (Example 8). 3#,20# - Diacetoxy - 18 - (N - methyl - 2- chloroacetamido) - 5α,17α - pregnan - 14# - ol (XI) is prepared from 3#-acetoxy-5α-pregnan-20#-ol (X) by the sequence: X -# 3#-acetoxy-18,20- epoxy - 5α - pregnan - 20# - ol -# 3#,18 - diacetoxy - 5α - pregnan - 20 - one -# 3#,18 - diacetoxy - 17# - bromo - 5α,17# - pregnan - 20 - one -# 3#,18 - diacetoxy - 5α - pregn - 16 - en - 20- one -# 3#,18 - diacetoxy - 5α - pregna - 14,16- dien - 20 - one -# 3#,18 - diacetoxy - 14#,15#- epoxy - 5α - pregn - 16 - en - 20 - one -# 3#,18- diacetoxy - 14# - hydroxy - 5α,17α - pregnan - 20- one -# 3#,18 - diacetoxy - 5α,17α - pregnane- 14#,20# - diol -# 3#,18,20# - triacetoxy - 5α,17α- pregnan - 14# - ol -# 3#,20# - diacetoxy - 5α,17α- pregnane - 14#,18 - diol -# 3#,20# - diacetoxy- 14# - hydroxy - 5α,17α - pregnan - 18 - al -# 3#,20# - diacetoxy - 18 - methylimino - 5α,17α- pregnan - 14# - ol -# 3#,20# - diacetoxy - 18- methylamino - 5α,17α - pregnan - 14# - ol -# XI. (Example 7).  Cardioactive compositions for oral, parenteral and topical administration comprise a carrier and a compound (I) (subject to the above exceptions) or an organic or inorganic acidaddition salt thereof. Reference has been directed by the Comptroller to Specification 1,268,568.