The development of a 21 -alkylation reaction which proceeds via the lithium 20(21)-enolate is described and its scope demonstrated by the preparation of a variety of 21 -alkylpregnane derivatives. Application of this process to 1 l~-acetoxy-l6a,l7a-dimethyl-5ct-pregnane-3,2O-dione (28a) and its 5P-analogue (28b) led to the corresponding 16a,l7a,21 -trimethyl derivatives. Several routes from these saturated trimethylpregnane-3,2O-diones to 1 1 P-hydroxy-l6a,17a,21 -trimethylpregna-l,4-diene-3,20-dione (Org 621 6) were explored. The best method gave Org 621 6 in 75% yield. (61 000); vmSx. 1 707 cm-l (11-ketone) (Found, M+, 592.4262. C12Hb802 requires M , 592.4280) with zinc in acetic acid.

The seven possible 3-amino-2-hydroxy and 2-amino-3-hydroxy isomers of the anti-arrhythmic steroid, 3a-amino-2P-hydroxy-5a-androstan-1 -/-one, were prepared from 5a-androst-2-en-17-one. The intermediate 2a,3a-and 2@,3P-epoxides and aziridines were cleaved to vicinal frans-diaxial amino-and azido-alcohols, which in turn yielded the isomers by a series of functional group inversions and transformations.* An alternative route to the aziridine (30) involved reaction of (25) with p-nitrophenylsulphonyloxyurethane and triethylamine, leading t o the N-ethoxycarbonylaziridine (3 1) which was converted into (30) by potassium hydroxide in ethanol.* Photochemical ring-expansions were unsuccessful, and it is of interest that thermolysis led only to the oxazoline (59), none of the alternative 2p,Sp-isomer being isolated.

No abstract

An improved process for the preparation of 16a.17a-dimethylpregnanes (1 b)-(9bJ 'from pregn-16-en-20-ones has been developed and applied to ring c functionalised steroids (1 a)-(9a) as a route to corticosteroid analogues.Good to excellent yields of the 16a,17~-dimethyl derivatives were achieved in all cases except With 11 p-hydroxycompounds and this w a s overcome by using the acetate. Two by-products, formed in variable amounts, were the 1 6a-methyl and 16a.17a.21 -trimethyl derivatives (c) and (d) respectively.

The antiarrhythmic efficacy of 17 beta-amino- and 17 beta-amino-16 alpha-hydroxyestratrien-3-ols and 3-acetates (group 1) was compared with the efficacy of corresponding 3-[2-hydroxy-3-(isopropylamino)propyl] and 3-[2-hydroxy-3-(tert-butylamino)propyl] ethers (group II), substituents which are usually associated with beta-adrenoceptor blocking activity. Group I compounds exerted potent antiarrhythmic activity against both aconitine-induced arrhythmias in mice and ischemia-induced arrhythmias in rats and reduced the maximum following frequency of isolated guinea pig atria. Electrophysiological studies indicated that their mechanism of action is due to an ability to reduce the fast inward sodium current in cardiac cells (class I antiarrhythmic action). Group II compounds were inactive in the aconitine and atrial tests and electrophysiological studies confirmed that they were devoid of class I activity. However, these compounds, like both class I antiarrhythmic and beta-adrenoceptor blocking drugs, were active against ischemia-induced arrhythmias. Group II compounds, unlike group I compounds, exerted nonspecific beta-adrenoceptor blocking actions, which may account for their activity in the rat test. It was concluded that introduction of the 3-substituted ether group did not confer any advantage over the parent 3-ol or 3-acetate compounds.