Patent GB-1476179-A (GB)
Title: Radioactively marked steroid derivatives
IPC: C12P33/00
Filed: 1974-06-03
Abstract: 1476179 Radioactively marked steroid amides SCHERING AG 3 June 1974 [8 June 1973] 24447/74 Heading C2U Novel radioactively marked steroid amines have the formula wherein St is a steroid group having -XNR<SP>1</SP>R<SP>2</SP> directly attached to the A, B, C or D ring or to the 21-position; -NR<SP>1</SP>R<SP>2</SP> is a tritium- or <SP>14</SP>C- marked amino group; and X is an R<SP>3</SP>, group in which R<SP>3</SP> is -(CH 2 ) n CO- wherein n, when X is R<SP>3</SP>, is zero, 1, 2, 3 or 4 and, when X is other than R<SP>3</SP>, is 1, 2, 3 or 4. They are prepared by reacting steroids of the formula St-X-OH or reactive derivatives thereof with amines NHR<SP>1</SP>R<SP>2</SP>. Suitable amines include primary amines such as methylamine, ethylamine, benzylamine, tyramine, tryptamine, serotonine and histamine, secondary amines such as dimethylamine, diethylamine and dibutylamine, cyclic secondary amines such as piperidine, piperazine and morpholine, and amino-acids such as glycine, alanine, valine, leucine, phenylalanine, tyrosine, thryroxine, L-dopa, proline, tryptophane and histidine, marked as indicated above. St may be substituted in any desired manner and may contain one or more double bonds. Preferably -XNR<SP>1</SP>R<SP>3</SP> is in the 6-, 7-, 11- or 12-position of the steroid ring. The novel radioactively marked steroids may be combined with suitable carriers for use as diagnosticagents. Starting materials: 6-keto-estradiol 17-acetate is converted via 6-keto-estradiol diacetate, 6 - ethoxycarbonylmethyl - #<SP>1,3,5(10),6</SP> - estratetraene - 3,17# - diol and the corresponding 6,7- saturated - 6 - ethoxycarbonylmethylene compound and 6# - ethoxycarbonylmethyl - #<SP>1,3,5(10)</SP>- estratriene - 3,17# - diol (II) to 6# - carboxymethyl - #<SP>1,3,5(10)</SP> - estratriene - 3,17# - diol. (II) is converted to the corresponding 17-one and this is converted to (a) 3-hydroxy-6#-carborymethyl- #<SP>1,3,5(10)</SP> - estratrien - 17 - one, (b) 17α - ethynyl- 6# - carboxymethyl - #<SP>1,3,5(10)</SP> - estratriene- 3,17#-diol, and (c) via the corresponding 3- acetate, 3,17 - diacetoxy - 6# - ethoxycarbonylmethyl - #<SP>1,3,5(10),16</SP> - estratetraene, the corresponding 16α,17α - epoxide, 3,16α - diacetoxy- 6# - ethoxycarbonylmethyl - #<SP>1,3,5(10)</SP> - estratrien- 17 - one, and 16α - acetoxy - 6# - ethoxycarbonylmethyl - #<SP>1,3,5(10)</SP> - estratriene - 3,17# - diol and the corresponding triol to 6#-carboxymethyl- #<SP>1,3,5(10)</SP> - estratriene - 3,16α,17# - triol (also obtainable from 6-keto-estriol acetate). 3,17#- Dihydroxy - 17α - ethynyl - #<SP>1,3,5(10)</SP> - estratrien- -6-one is converted directly or via the corresponding 3-acetate to 6-carboxymethoxyimino-17α- ethynyl - #<SP>1,3,5(10)</SP> - estratriene - 3,17# - diol. 17#- Acetoxy - 6 - oximino - #<SP>1,3,5(10)</SP> - estratrien - 3 - ol is prepared from 6-keto-estradiol diacetate and is converted via (3#,17#-dihydroxy-#<SP>1,3,5(10)</SP>- estratrien - 6# - yl) - ammonium chloride to 6# - (3<SP>1</SP> - carboxypropionylamino) - #<SP>1,3,5(10)</SP>- estratriene - 3,17# - diol. 16α,17# - Diacetoxy - 6- oximino - #<SP>1,3,5(10)</SP> - estratrien - 3 - ol is prepared from 6-keto-estriol triacetate and is converted via (3,16α,17# - trihydroxy - #<SP>1,3,5(10)</SP> - estratrien- 6# - yl)ammonium chloride to 6# - (3<SP>1</SP> - carboxypropionylamino) - #<SP>1,3,5(10)</SP> - estratriene - 3,16α, 17# - triol. (3,20 - Dioxo - #<SP>4</SP> - pregnen - 6α - yl)- hydrogen succinate is prepared from 6α-hydroxyprogesterone and succinic anhydride. Similarly are prepared (17# - hydroxy - 3 - oxo - 17α- ethynyl - #<SP>4</SP> - estren - 11α - yl) - hydrogen succinate; (6α - fluoro - 11# - hydroxy - 3,20 - dioxo- 16α - methyl - #<SP>1,4</SP> - pregnadien - 21 - yl)hydrogen succinate; and (1 - methyl - 3 - oxo - 5α - androst- 1 - en - 17# - yl)hydrogen succinate. 17# - Hydroxy - 18 - methyl - 17α - ethynyl - #<SP>4</SP> - estren- 3-one is microbiologically hydroxylated using Mucor griseocyanus to give 6#,17#-dihydroxy-18- methyl - 17α - ethynyl - #<SP>4</SP> - estren - 3 - one and this is acylated to give (17#-hydroxy-3-oxo-18- methyl - 17α - ethynyl - #<SP>4</SP> - estren - 6# - yl)- hydrogen succinate. Similarly 6-chloro-11α-hydroxy - 17 - acetoxy - 1α,2α - methylene - #<SP>4,6</SP>- pregnadiene-3,20-dione is prepared from the corresponding 11 -unsubstituted compound using Glomerella cingulata and is acylated to give (6- chloro - 17 - acetoxy - 3,20 - dioxo - 1α,2α- methyl - #<SP>4,6</SP> - pregnadien - 11α - yl) - hydrogen succinate; and 7α-hydroxy-#<SP>4</SP>-androstene-3,17- dione is similarly prepared using Absidia orchidis and is ethynylated to give 7α,17#-dihydroxy- 17α-ethynyl - #<SP>4</SP> - androsten - 3 - one and this is acylated to give (17#-hydroxy-3-oxo-17α-ethynyl- #<SP>4</SP> - androsten - 7α - yl)hydrogen succinate. 3#- Heptanoyloxy - 7α - hydroxy - #<SP>5</SP> - androsten - 17- one is prepared from 3#-heptanoyloxy-#<SP>5</SP>, androsten-7,17-dione 17-ethyleneketal and is acylated to give (3#-heptanoyloxy-17-oxo-#<SP>5</SP>- androsten-7α-yl)hydrogen sucoinate.