Androstane derivatives

In 1959 Clinton and coworkers reported the first synthesis of some pyrazole fused androstane derivatives and described their biological activity (B-76MI40404). Stanazolol (695) or 17-methyl-2iT-5o -androst-2-eno[3,2-c]pyrazol-17/3-ol was 10 times as active as 17a -methyltestosterone in improving nitrogen retention in rats (B-80MI40406), and its myotrophic activity was only twice that of 17a-methyltestosterone. It is used as an anabolic steroid with no lasting adverse side effects. 

Preparation of IQ- C-testosterone acetate has been achieved by methyla-tion of a 19-nor-seco-androstane derivative (266) with C-methyl iodide. 

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

The study of the best reaction conditions revealed that among the Bi(III) salts screened, Bi(0Tf)3-xH20 (0.05 eq.) gave the best results and 50 °C was found to be the best temperature. 5(3,6(3-Epoxy-20-oxopregnan-3(3-yl acetate and 5 (3,6(3-epoxy-17-oxoandrostan-3(3-yl acetate [119] were also studied under similar reaction conditions and several interesting compounds could be obtained (Scheme 32). With the androstane derivative, due to the lack of a 17a-H, a full backbone... 

Preparation of 19-14C-testosterone acetate has been achieved by methyla-tion of a 19-nor-seco-androstane derivative (266) with 14C-methyl iodide.144 A sequence of standard transformations of the oxo-steroid intermediate (267) then ultimately led to the desired product (268). In our opinion, this sequence could be applied equally well to the preparation of 19-d3-testosterone acetate in high isotopic purity by methylating (266) with d3-methyl iodide. 

The list of 4,508 names of chemicals associated with reproductive effects is given in the Appendix I to this chapter. This list could be made more practical in a shorter version, to post in the laboratory, for example. The list of 4,508 names contains many clusters of names of various derivatives of a particular compound. For example, entry 239 in the list is androsta-l,4-diene-3.17-dione, the first of 110 androstane derivatives listed in numerical order. Thus, the list could be shortened by containing only the first of the derivatives under its original entry 239. followed by the next type of compound under its entry (in this case, angiotensin II, 349). The gap between the entries would indicate the number of toxic derivatives of the foregoing entry type. A quick check of the "androsta" entry and the gap between the entries provides a chemist with the valuable information that a large number of androstane derivatives exhibit reproductive effects. 

A Lewis-acid-catalysed Diels-Alder reaction of the diene (70) and the quinone (71) is the key step in the synthesis of compound (72) with the appropriate stereochemistry and functionality for conversion into quassin.53 The androstane derivative (73) has been transformed into (74) in model experiments towards the synthesis of quassin.54... 

Introduction of a 6/3-methyl group in the androstane series results in an increase of androgenic activity compared to the unsubstituted androstane derivative, while 6a-substitution does not decrease the activity. 

I7)3-Hydroxy-5a-androstane derivatives containing a ring A unsaturation, excluding testosterone derivatives. 

Tables IV.1-IV.7 are comprised of 17j8-hydroxy-5a-androstane derivatives, excluding testosterone derivatives.

Variation within the phylum Mollusca has been noted before. More species from the order Mesogastropoda again show that squalene and sterols can be synthesized. Although previous work with the class Bivalvia was unable to demonstrate the ability to synthesize steroids, androstane derivatives were metabolized.Detailed studies with the slug Ariolimax (order Stylommato-phora) showed how cholesterol was metabolized to pregnenolone, 17a-hydroxy-pregnenolone, and thus to androstane derivatives. 

Various accounts report the synthesis of heterocyclic androstane derivatives. 17)8-Acetoxy-4-oxa-androst-2-ene (215) has been prepared in three steps from the hemiacetal (214). Since various 4-aza-steroids exhibit antimicrobial activity, several new 4-aza-androstanes have been prepared. The reduction of ring a enamine lactams, such as 4-aza-androst-5-ene-3,17-dione (216a), under conditions of the Leuckart-Wallace reductive amination, provided 17/ -(iV-methyl-... 

Phase transitions may be a particularly important property of membranes as they occur at around physiological temperatures and may result in large permeability changes in the membrane. The crystalline/liquid crystalline transition in dipalmitoyl lecithin has been examined in detail [147] using the spin labelled androstane derivative (D). 

If the ketone 5, corresponding to the enol acetate 1, is used, addition syn to the Ci -methyl group is favored. Thus cycloaddition of 5 to 6 catalyzed by SnCI4 results in preferential formation of 7. This product can be converted in several steps to the Kor-androstane derivative 8. ... 

Of particular interest is the bromination of ethyleneketals of ketones, for example, the androstane derivative (1). This affords the 16a-bromoketal (2), in which both... 

The complementary application of film balance and electron spin resonance techniques has given information regarding molecular motion in monolayers. The molecules used, 3-nitroxide androstan 17fi-ol and 3-nitroxide cholestane, have the molecular geometry required for a test of the Cooper-Mann theory of surface viscosity. These ellipsoidal molecules show distinctly different surface behavior as shown by the complete collapse of the hyperfine lines in the case of the cholestane derivative and the apparent lack of exchange broadening for the androstane derivative. These results are modeled in terms of transitional surface regions. 

Nuclear Magnetic Resonance. Ziircher s massive compilation of chemical shifts of 18-H and 19-H signals, and increments produced by structural features in the steroid nucleus, is augmented by the publication of similar data for 344 steroids obtained by microbiological hydroxylations, and subsequent transformations. The compounds are mainly 5a-androstane derivatives, and include hydroxy- and oxo-functions at almost all the ring positions, as well as their derivatives and polyfunctional compounds. Solvent shifts are also reported. A set of diagrams illustrates the profiles and chemical shifts of signals due to methine protons in the C/fOH system at all the main steroid positions. ... 

G.l.c.-m.s. data are reported" for a series of C19O3 (androstane) derivatives with oxygen substituents at either C-2, -6, -7, -11, or -16 in addition to those at C-3 and C-17. Field desorption mass spectra are reported for some saponins (kryptogenin 3-0-/8-D-glucopyranoside, dioscin, etc.) Progress is reported towards the computer-aided recognition of structural features of steroids from low-resolution mass spectra. ... 

The synthesis and activity of sixty-six 5a-androstane derivatives of the forms (50), (51), and (52), with acetylcholine-like fragments (53) incorporated into rings A and d, have been reported. These compounds were tested for neuromuscular blocking potency and one of them [francuronium bromide (50 =... 

Cjg-C2i steroids, e.g., androstane derivatives, may act as hormones. Steroids with longer alkyl chains on C17 are inactive as messengers of biological information. Relatively large amounts of Cjg-C steroids are ubiquitous in cell membranes. Typical foodstuffs and human tissues containing massive amounts of cholesterol (animals) or ph)d osterols (plants) are given in Table 3.2.1. 

Pyrolysis of the 3,3-bis-(2-chloroethoxy)-5cx-androstane derivative (368) gave the A -enol ether (369), which afforded the 2a,3a-methano-derivative (370) with the Simmons-Smith reagent. The 2-chloroethyl group was easily removed by n-butyl-lithium to give the cyclopropanol (371), which rearranged on melting to give the 2a-methyl-3-ketone (372). °... 

The well-known rearrangement of sulphonates of pregnan-20j8-ols to give D-homo-androstane derivatives (511) may also be effected in almost quantitative yield by treating the 20-acetates (510) with BFj-ether for several days, or with... 

Two papers report the synthesis of novel androstane derivatives methylated at C-8a. In the first" (Scheme 8). treatment of the tosylhydrazone of (143) with lithium hydride furnished the diene (144). Reaction with diborane. followed by alkaline hydrogen peroxide, gave the allylic alcohol (145), which was submitted to Simmons-Smith reaction and oxidized to the a-cyclopropyl ketone (146). Cleavage of the 7a.8a-methylene bridge with lithium in liquid ammonia afforded the 8a-methyl derivative (147). This was then converted into 17a-ethynyl-8a-methyltestosterone (148a) by a classical sequence of reactions. ... 

Further unsaturation of the B or C ring of 19-androstane derivatives usually enhances progestin activity. Introduction of a halogen or methyl substituent in the 6a or 7a positions generally increases hormonal activity. Acetylation of the 17p-OH of norethindrone increases the duration of action of the drug. Removal of the 3-keto function of norethindrone allows retention of potent progestin activity and no androgenic effects. 

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