Patent IE-35461-B1 (IE)
Title: Cardenolides and bufadienolides and a process for the manufacture thereof
Inventor: MEYER K
IPC: C07J43/00
Filed: 1971-07-20
Abstract: 1346350 3-Aminosteroids F HOFFMANNLA ROCHE & CO AG 23 July 1971 [24 July 1970] 34756/71 Heading C2U The invention comprises compounds of formula wherein A signifies a grouping of formula A 1 , A 2 , A 3 , or A 4 wherein R<SP>1</SP> is H, OH or OCOMe; R<SP>2</SP> is OH or OCOMe; R<SP>3</SP> is amino, C 1-6 alkylamino, #- hydroxyethylamino, C 1-6 alkanoylamino, di- (C 1-6 alkyl)amino, di(C 1-6 alkanoyl)amino, N- (C 1-6 alkyl)-N-(C 1-6 alkanoyl)amino, N-(2-acetoxyethyl)acetylamino, pyrrolidino, piperidino, morpholino, 2<SP>1</SP>-oxo-3<SP>1</SP>-oxazolidinyl, or ureido; R<SP>4</SP> is Me; and R<SP>5</SP> is (#-H; alternatively when A is a grouping of Formula A 1 (wherein R<SP>1</SP> is H) then either R<SP>4</SP> may be Me and R<SP>5</SP> is α-H, or R<SP>4</SP> may be CHO, CH 2 OH or CO 2 H and R<SP>5</SP> is #-OH. Preparation of compounds I (wherein R<SP>3</SP>= NH 2 ) is by reduction of the corresponding 3- azido or 3-hydroxyimino compounds, e.g. with aluminium amalgam or by catalytic hydrogenation. Preparation of compounds I (wherein R<SP>3</SP> is other than NH 2 ) is (i) by reacting the corresponding 3-bromo or 3-tosyloxy compounds with an appropriate amine; (ii) by aculation, methylation, hydroxyethylation or carbamoylization of a 3-NH 2 compound; or (iii) by reacting a 3-(#-hydroxyethylamino) compound with phosgene to produce the corresponding 3-(2- oxo-3-oxazolidinyl) compound. The 3 - p - toluenesulphonate and 3 - azido - 3- deoxy derivatives of digitoxigenin, 3-epidigitoxigenin, oleandrigenin, 3-epioleandrigenin, digoxigenin 12-acetate, 3-epidigoxigenin 12-acetate, bufalin and 3-epibufalin, are prepared from said parent compounds by the successive actions of tosyl chloride and sodium azide, the latter reaction involving inversion of configuration at the 3-position. (Ex. 5, 6, 7, 9, 15, 19, 23, 25). The 3α - p - toluenesulphonate and 3# - azido- 3 deoxy derivatives of 3 - epiresibufogenin and of 3-epicinobufagin are prepared from said parent compounds by the successive actions of tosyl chloride and sodium azide (Exx. 33, 34). The 3 - azido - 3 - deoxy derivatives of gitoxigenin and 3-epigitoxigenin are prepared by hydrolysis of the 16-acetates thereof (Exx. 11, 13). 3α - Azido - 3 - deoxydigoxigenin is prepared by hydrolysis of its 12-acetate (Ex. 19). 3# - Azido - 12#,14 - dihydroxy - 5#,14#- card - 20(22) - enolide (XI) is prepared from digoxin (X) by the sequence X # digoxigenin 12 - chloroacetate # digoxigenone 12 - chloroacetate # digoxigenone # digoxigenone 12- formate #3 - epidigoxigenin 12 - formate # 3 - epidigoxigenin # 3 - epidigoxigenin 3- p - toluenesulphonate # 3# - azido - 12#- formyloxy - 14 - hydroxy - 5#,14# - card - 20(22)- enolide # XI (Ex. 17). 3 - Epidigoxigenin 12 - acetate, 3 - epidigoxigenin 12 -formate, 3 - epibufalin, 3 - epiresibufogenin and 3-epicinobufagin are each prepared by sodium borohydride reduction of the corresponding 3-ketones (Exx. 15, 17, 25, 33, 34). Bufalone and uzarigenone are prepared by oxidation of the corresponding 3#-ols using "Kiliani mixture" (Exx. 23, 30). Oximes are prepared from digitoxigenone and uzarigenone by reaction with hydroxylamine hydrochloride (Exx. 1, 30). Compounds of Formula I are said to be cardioactive, and may be made up with carriers into pharmaceutical compositions for oral, parenteral or rectal administration.
[GB1346350A]