17-EPIMERIZATION OF 17-ALPHA-METHYL ANABOLIC-STEROIDS IN HUMANS - METABOLISM AND SYNTHESIS OF 17-ALPHA-HYDROXY-17-BETA-METHYL STEROIDS

The 17-epimers of the anabolic steroids bolasterone (I), 4-chlorodehydromethyltestosterone (II), fluoxymesterone (III), furazabol (IV), metandienone (V), mestanolone (VI), methyltestosterone (VII), methandriol (VIII), oxandrolone (IX), oxymesterone (X), oxymetholone (XI), stanozolol (XII), and the human metabolites 7alpha,17alpha-dimethyl-5beta-androstane-3alpha,17beta-diol (XIII) (metaholite of I), 6beta-hydroxymetandienone (XIV) (metabolite of V), 17alpha-methyl-5beta-androst-1-ene-3alpha,17beta-diol (XV) (metabolite of V), 3'-hydroxystanozolol (XVI) (metabolite of XII), as well as the reference substances 17beta-hydroxy-17alpha-methyl-5beta-androstan-3-one (XVII), 17beta-hydroxy-17alpha-methyl-5beta-androst-1-en-3-one (XVIII) (also a metabolite of V), the four isomers 17alpha-methyl-5alpha-androstane-3alpha,17beta-diol (XIX) (also a metabolite of VI, VII, and XI), 17alpha-methyl-5alpha-androstane-3beta,17beta-diol (XX), 17alpha-methyl-5beta-androstane-3alpha, 17beta-diol (XXI) (also a metabolite of V, VII, and VIII), 17alpha-methyl-5beta-androstane-3beta,17beta-diol (XXII), and 17-beta-hydroxy-7alpha,17alpha-dimethyl-5beta-androstan-3-one (XXIII) were synthesized via a 17beta-sulfate that spontaneously hydrolyzed in water to several dehydration products, and to the 17alpha-hydroxy-17beta-methyl epimer. The 17beta-sulfate was prepared by reaction of the 17beta-hydroxy-17alpha-methyl steroid with sulfur trioxide pyridine complex. The 17beta-methyl epimers are eluted in gas chromatography as trimethylsilyl derivatives from a capillary SE-54 or OV-1 column 70-170 methylen units before the corresponding 17alpha-methyl epimer. The electron impact mass spectra of the underivatized and trimethylsilylated epimers are in most cases identical and only for I, II, and V was a differentiation between the 17-epimers possible. H-1 nuclear magnetic resonance (NMR) spectra show for the 17beta-methyl epimer a chemical shift for the C-18 protons (singlet) of about 0.175 ppm (in deuterochloroform) to a lower field. C-13 NMR spectra display differences for the 17-epimeric steroids in shielding effects for carbons 12-18 and 20. Excretion studies with I-XII with identification and quantification of 17-epimeric metabolites indicate that the extent of 17-epimerization depends on the A-ring structure and shows a great variation for the different 17alpha-methyl anabolic steroids.