Pregnanes

With very few exceptions, the biological activities of synthetic steroids tend to parallel those of the naturally occurring hormones on which they are patterned. Compounds with distant pharmacological activity are, as a rule, quite rare. It is thus intriguing that inclusion of a tertiary amine at the 11 position of a pregnane leads to a compound with activity far removed from its close analogues. The agent in question, minaxalone (47), exhibits anesthetic activity. 

Preparation of the newest of these, spirorenone (61), starts by 7-hydroxylation of dehydroepiandrosterone derivative Though this transformation has also been 

As noted above, the steroid nucleus has been a favorite for the design for site directed alkylating antitumor drugs. Thus reaction of prednisolone (62) with anhydride 63 affords the 21 acylated derivative, prednimustine (64).  

A preponderance of the work devoted to steroids, as judged from the number of compounds bearing generic names, has clearly been that in the area of corticosteroids related 

Because skin exhibits many of the properties of a lipid membrane, dermal penetration can often be enhanced by increasing a molecule s lipophilicity. Preparation of an ester of an alcohol is often used for this purpose since this stratagem simultaneously time covers a hydrophilic group and provides a hydrophobic moiety the ready cleavage of this function by the ubiquitous esterase enzymes assures availability of the parent drug molecule. Thus acylation of the primary alcohol in flucinolone (65) with propionyl chloride affords procinonide (66) the same transform 

18-Methylideneprogesterone has been synthesized from the readily available 3 -acetoxy-18-cyanopregn-5-en-20-one which may be transformed into the amine oxide (280). Cope degradation of this intermediate gave the 18-methylidene derivative (281)/ which was readily converted into 18-methylideneprogesterone. Alternative syntheses employ the lactone (282) which in one instance was trans- 

A synthesis of the B-ring aromatic corticosteroid (286), the analogue of cortex-olone, started with the previously reported B-ring aromatic norpregnane (285). Development of the corticosteroid side-chain employed bromination of the 17a-hydroxy-20-oxo-derivative with trimethylphenylammonium bromide perbromide. Reaction of perchloryl fluoride with the mixed enol ethers (287) and (288) provided, after hydrolysis, the 17a-fluoro-20-oxo-compound (290) and the 21-fluoro-20-oxo-compound (291). In contrast, the enamine (289) led only to the 17a,21-difluoro-20-oxo-compound. A series of 17a-acyloxy-21-deoxy- 

Kalvoda, J. Grob, and G. Anner, Helv. Chim. Acta, 1977,60, 1579. 

Kocovsky and Z. Prochazka, Coll. Czech. Chem. Comm., 1977, 42, 553. 

Reagents i, LiNEt2-THF ii, Ac20-pyridine iii, A-methylmorpholine A-oxide-Os04-Bu 0H-THF-H20 iv, NaI04 v, K2C03 

The hydroxy-lactone (233) was obtained204 by treatment of the 16,17-epoxy-20-oxo-21-acetate (232) with KOBu. The trifluoroacetoxypregnan-20-ones (234) were converted into the spirofuranones (235) with DBU in benzene.205 The conversion 

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C21H36O2. M,p. 238°C. There are four isomeric pregnane-3,20-diols differing only in the orientation of the hydroxyl groups at positions 3 and 20 and with the 5/ configuration. Only the 3a,20a occurs naturally. It is formed by reduction of progesterone in the liver and is the chief urinary metabolite of it, being... 

Methods for reconstmcting the C-17 side chain from intermediates such as androstendione have been developed. These are used when commercial considerations favor the production of androstanes, but pregnanes are the ultimate goal (25,30). 

AHopregnanolone and similar A-ring-reduced pregnanes potentiate GABA effects at these receptors. These steroids mimic the effects of the benzodiazepines, changing chloride ion conductance and producing sedative and hypnotic behavioral effects (276,277). Neuroactive steroids can be therapeutically useful as anticonvulsants, anxiolytics, or anesthetics (qv) (see also Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Chemical Analysis. Chemically, the various progestogens belong to one of three classes. Estranes are 19-nortestosterone derivatives (Fig. 1) gonanes are 19-nortestosterone derivatives with a C-13 ethyl group (Fig. 2) and pregnanes are 17-alpha-OH progesterone derivatives similar in stmcture to progesterone itself. 

The pregnanes include megestrol, medroxyprogesterone acetate [71-58-9] C24H34O4 (6), chlormadinone acetate [302-22-7] C23H2QCIO4, and cyproterone acetate [427-51-0], C24H2gC104 (7). 

Bisnorcholanic acid (pregnane-20-carboxylic acid) [28393-20-6] M 332.5, m 214 (a-form), 242 (p-form), 210-211 (y-form), 184 (5-form), 181 (e-form), pKe -5.0. Crystd from EtOH (a-form), or acetic acid (all forms). 

A solution of 7.2 g of sodium borohydride (analyzing at 87 % purity) in 300 ml of pyridine is added dropwise, with vigorous stirring, over 7 hr to a solution of 50 g of pregnane-3,11,20-trione in 100 ml of pyridine and 18 ml of water. The temperature is kept at 18-20°. The stirring at this temperature is continued for another 2 hr, after which the reaction mixture is poured slowly into dilute hydrochloric acid (575 ml of cone hydrochloric acid in 5.2 liters of water) and the stirring continued for 1 hr. The precipitate is filtered, washed with... 

A solution of 2 g of sodium borohydride in 5 ml of water is added at room temperature to a solution of 1 g of 3a-hydroxy-5jS-pregnane-l 1,20-dione in 15 ml of methanol. Almost immediately, crystals begin to form. After the mixture has been kept overnight, the precipitate is collected with suction to yield 0.8 g of the diol, mp 230-232°. The analytical sample, crystallized once more from aqueous methanol, melts at 231.4-232.6° [a]p 31.2° (acetone). Reported mp 236-238°. 

Refluxing 3a-hydroxy-5)5-pregnane-ll,20-dione in methanol overnight with sodium borohydride gives the 3a,llj5,20jS-triol in 85% yield with mp 233-235°, [ ][) 38.9° (dioxane). 

When 3a,17a-dihydroxy-5jS-pregnane-ll,20-dione is allowed to react at room temperature overnight with sodium borohydride in aqueous methanol, no crystals form and only 5j5-pregnane-3a,l ljS,17a,20j5-tetrol is isolated in good yield. If the reaction is halted at the end of 3 h y the addition of water and extraction with chloroform, it is possible xo obtain a 55% yield of 3a,17a,20jS-trihydroxy-5j5-pregnan-ll-one, mp 218-220°,after recrystallization of the chloroform residue from aqueous methanol. The analytical sample, crystallized once more, has mp 219.0-220.6° [a][, 36° (acetone), reported mp 220° [aJu 38°. 

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