17a-Methyltestosterone

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. 

Under mild conditions and in a variety of solvents, tertiary steroid alcohols are inert to the fluoroamine. At elevated temperatures, however, they afford exclusively, and in high yield, products resulting from dehydration with or without rearrangement. Thus, 17a-methyltestosterone (10) furnishes in 42% yield the 18-norsteroid (11). 

The orally effective androgen 17a-methyltestosterone (51) is prepared from 3jS-hydroxyandrost-5-en-17-one (49) by treatment with methylmagnesium iodide to give the 17a-methyl compound (50) which is then oxidized to yield... 

Testosterone (5.45) is the prototypic androgen sex hormone. Testosterone is synthesized by the testes, and must be reduced to dihydrotestosterone (5.46, DHT) before it will bind to the receptor. Among highly active synthetic testosterone analogs, 7a-methyl-19-nortestosterone (5.47) and oxandrolone (5.48) have about 100 times greater activity than testosterone as androgens. 17a-Methyltestosterone (5.49) is orally active. 

Methyl 3a,6a-dihydroxycholanate, 240 1-Methylestrone 3-methyl ether, 10, 27 4b/3-Methyl-7-ethylenedioxy-1,2,3,4, 4a ,4b/3,5,6,7,8,10,1 Oaa-dodecahydro-phenanthrene-1 /3,4/3-diol, 236 14C-Methyl iodide, 211 ds-Methyl iodide, 210, 214 Methyl lithocholate tosylate, 329 1-Methyl-19-nortestosterone, 27 6a-Methylprednisolone, 410 6a-Methylprednisolone BMD, 410 16/3-Methylprednisone, 87 18-Methylpregn-4-ene-3/3,17a,20f-triol, 243 20-Methylpregn-5-en-3/3-ol, 415 17a-Methylpregnenolone acetate, 48 17a-Methyltestosterone, 438 16/3-Methyl- 11a,17a,21 -trihydroxy- 5 /3-pregnane-3,20-dione 21-acetate, 299, 300 20-Methyl-3/3-trityloxypregn-5-ene, 415 3/3-Methoxycholestane, 136 1-Methoxycyclohexene, 18 3-Methoxyestra-3,5(10)-diene, 18, 27... 

A solution of 1.0 g of crude 4,5-oxido-17a-methyltestosterone in 50 ml of methanol is allowed to stand at room temperature overnight with 10 ml of water and 1 ml of concentrated sulfuric acid. It is then poured into water containing sodium chloride and extracted three times with ethyl acetate. The solvent is washed with water, then with 10% sodium bicarbonate solution and again with water to neutrality. The residue remaining after evaporation of the solvent is crystallized from methanol, giving 17a-methyl-androstane-4p,5a,17p-triol-3-one with a melting point of 203°-205°C. 

Figure 18-2. Separation of hormones on ChromSpher UOP colnmn at 30°C at different eluent inlet temperatnres a, 5°C b, 10°C c, 22°C d, 30°C. Componnds 1, thiourea 2, hydrocortisone 3, nortestosterone 4, dehydro-17a-methyltestosterone 5, testosterone 6,17a-methyItestosterone. (Reprinted from reference 12, with permission from Elsevier.)...

The 2a-methyl substitution decreases the androgenic activity and increases the anabolic activity of the parent steroid. 2a-Methyldihy-drotestosterone was found to be as active orally as 17a-methyltes-tosterone as an anabolic agent and to have very low androgenicity. 2a,17a-Dimethyldihydrotestosterone possesses 20% of the androgenic and 400% of the anabolic activity of 17a-methyltestosterone when administered orally. 

Hydroxymethylene substitution in the 17a-methyldihydrotes-tosterone series decreases the androgenic activity to 20% that of 17a-methyltestosterone while increasing the anabolic activity to 400% that of the same compound. 

Comparison of 17a-methyltestosterone (S-2), 17a-methyl-5a-dihydro-testosterone (D-2), and 17o -methyl-d -testosterone (S-107) revealed that the presence of the double bond in the 4,5-position enhanced the anabolic activity and did not alter the androgenic activity, according to Beyler et al. [124]. Additional unsaturation lowered both anabolic and androgenic activities, but decreased the anabolic activity to a lesser degree. 

Ia-Methyl-A -11-ketotestosterone acetate (S-88), la-methyl-11-keto-testosterone acetate (S-84), 3,11,17-triketo-A -androstene (adrenos-terone) (S-43), and 1 l-keto-17a-methyltestosterone (S-24) all show decreased androgenic and anabolic potencies compared to the those 11-unsubstituted compound. However, introduction of a 9a-fluoro substituent into S-24 will increase both androgenic and anabolic activities to a... 

Testosterone. 9a-Bromo 11/3-chloro (S-123), 9a-chloro 1 IjS-fluoro (S-125), 11/3-hydroxy (S-5), la-methyl 11/3-hydroxy 17-acetate (S-82), la,2a-methylene 11/3-hydroxy 17-acetate (S-83), 4-chloro 11/3-hydroxy 17-acetate. (S-7), 9a-bromo 11/3-fliioro 17-propionate (S-124), 11/3-hydroxy 17-ketone (S-44), A 4-chloro 1 IjS-hydroxy 17a-methyl (S-103), A 9a-bromo 11/3-fluoro 17a-methyl (S-128), and 3-methylene 9a-fluoro lljS-hydroxy 17a-methyl (S-28) substitutions all decrease both androgenic and anabolic potencies. In some cases, the anabolic-androgenic ratio is favorable (S-124, S-83, S-7, S-I27). However, in 9a-fluoro-l 1/3-hydroxy-17a-methyltestosterone (S-19) the androgenic and anabolic potencies have been greatly increased over that of 17a-methyltestos-terone, while the anabolic-androgenic ratio has become 2. 11/3-Hydroxy-17a-methyltestosterone (S-18) and A 9a-chloro 11/3-chloro 17a-methyl (S-127) show a slightly decreased androgenic potency compared to that of 17a-methyltestosterone, while the anabolic potency has been increased by a factor of 3. 

Nitrogen retention evaluation [251] was as good with ]7a-ethylnor-testosterone as with testosterone propionate (subcutaneous administration) or 17a-methyltestosterone (oral administration) [250]. The calcium and phosphorus retention was also favorably affected but as a side effect, mild cholestatic jaundice was observed [256]. Also a marked increase in bromsulfalein retention was observed in humans by administration of 17a-ethylnortestosterone [257]. Other 17o -alkyl substitutions (propyl, allyl, methallyl, ethynyl) caused a decrease of the anabolic activity. A new type of derivatives of 19-nortestosterone was prepared by etherification of the 17/3-hydroxy group [12,143,258]. Among these compounds, 19-nortestosterone-17-(cyclopent-l -enyl) ether (N-81) possesses a favorable anabolic-androgenic ratio without the undesirable side effects. 

Chloro-17(x-methyl-l7 -hydroxyandrost-l,4-dien-3-one. This derivative (S-105) was reported to have a much higher anabolic-androgenic ratio than A -17a-methyltestosterone [263]. It was shown that application of S-105 does not increase the estrogen excretion [234]. 

Oi-Methyl-17Q-hydroxy-5oi-androstan [3,2-c ]isoxazole. Evaluation of this derivative (Androisoxazole, D-33) for anabolic activity by means of nitrogen balance studies gave an oral anabolic activity of 155% of that of 17o -methyltestosterone. At the same time, the androgenic activity (oral administration) was found to he 22% of that of 17a-methyltestosterone on the basis of weight increase of the ventral prostate. In spite of the fact that this compound has found therapeutical application [131,283-285], it soon became apparent that the steroidal [2,3-c/]isoxazoles possessed more noteworthy endrocinological activities [11] than the steroidal [3,2-c ]isoxazoles. 

Azo-17oi-methyl-17 -hydroxy-5oi-androstane. This derivative (Methyldiazirinol, D-150, Lederle Laboratories) was reported [123] to possess 300% of the anabolic and 20% of the androgenic potency of 17a-methyltestosterone when administered orally. 

New derivatives of steroidal hormones, prepared for biological evaluation, include 17-dialkylaminoalkanoates and other novel esters of 17a-hy-droxyprogesterone," trimethylsilyl ethers of 17a-hydroxyprogesterone, testosterone, 19-nortestosterone, 17a-methyltestosterone, and other androstane... 

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