17a-Alkylation

The alkynylation of estrone methyl ether with the lithium, sodium and potassium derivatives of propargyl alcohol, 3-butyn-l-ol, and propargyl aldehyde diethyl acetal in pyridine and dioxane has been studied by Miller. Every combination of alkali metal and alkyne tried, but one, gives the 17a-alkylated products (65a), (65c) and (65d). The exception is alkynylation with the potassium derivative of propargyl aldehyde diethyl acetal in pyridine at room temperature, which produces a mixture of epimeric 17-(3, 3 -diethoxy-T-propynyl) derivatives. The rate of alkynylation of estrone methyl ether depends on the structure of the alkyne and proceeds in the order propar-gylaldehyde diethyl acetal > 3-butyn-l-ol > propargyl alcohol. The reactivity of the alkali metal salts is in the order potassium > sodium > lithium. 

Application of the reductive alkylation process to the -20-ketone (4) yields the 17a-alkyl derivatives (5a-c). As expected, the presence of the angular 13-methyl group favors the approach of the alkyl iodide from the a-side. ... 

Most of the alkylations were carried out by adding a solution of 3,3-ethylenedioxypregna-5,16-dien-20-one in tetrahydrofuran to a solution of lithium in liquid ammonia to the point of color discharge. Treatment with the alkyl halide then furnishes the corresponding 17a-alkyl derivative (10). After hydrolysis of the 3-ketal group, 17a-methyl-, ethyl-, propyl-, butyl-, hexyl-, octyl-, allyl-, and benzylprogesterones are obtained. 

One of the important mechanisms by which orally administered steroids are inactivated involves the formation of water-soluble derivatives at the 17 position, a process that is greatly reduced in 17a-alkyl-17(3-hydroxy derivatives. Extensive use of the resulting orally active compounds has since revealed that 17 alkylation also leads to increased liver toxicity. Preparation of the first of these compounds, nor-methandrolone (32-3), starts by addition of methylmagnesium iodide to estrone methyl ether (9-1) to give the 17a methyl derivative. Birch reduction followed by acid hydrolysis leads to normethandrolone (32-3) [16]. 

In addition to the protective effect of 17a-alkylation, methyl substitution in positions 1,2, and 6 and the position of unsaturation in ring A also have an important influence on the relative activity of 17/3-hydroxy-dehydrogenase [5]. The relative activities of 17/3-hydroxy-5a-androstan-... 

It is interesting to point out that 1-methyl-17/3-hydroxy-5a-androst-1-en-3-one (Methenolone, A-86), an orally active anabolic agent lacking the 17a-alkyl substituent, also caused a slight increase in sulfobromophthalein retention and an increase in the blood coagulation factors V... 

It remains to consider the role of 17a-alkyl substituents in the attachment to the receptor. We can see that the steroid-receptor attachment can accommodate a 17a-methyl or 17a-ethyl group but there is a sharp decrease in activity when a 17a-propyl, or ethynyl group is introduced and the importance of the third-dimensional attachment becomes immediately evident. Inspection of molecular models reveals that a 17ar propyl or 17a-ethynyl substituent protrudes well beyond the molecular dimensions of steroids in the a and in the planar direction. In order to obtain the molecular dimensions of steroids we draw a plane perpendicular to the a- and /S-faces, which connects along the equatorially oriented substituents at carbons 1,2, 11, and 12 on one side, 16 and 17 on the other, and 6 and 7 on the third side. We postulate, therefore, that the steric requirements of the steroid-receptor attachment can accommodate 17a-methyl and 17a-ethyl substituents and the attachment of Ha-alkyl group is two-dimensional at the /3-face and in the third dimension as defined above. 

Substituted l-methyl-5oc-androst-l-en-3-one. l-Methyl-17/8-hy-droxy-5a-androst-I-en-3-one (Methenolone, A-86), 1-methyl-17/3-acetoxy-5a-androst-l-en-3-one (Methenolone acetate, A-6), and 1-methyl-17/3-hydroxy-5a-androst-1 -en-3-one 17-oenanthate (Methenolone-oenanthate) compounds were the first compounds introduced [277,278] among the anabolic agents which do not have a 17a-alkyl substituent and still possess a substantial oral activity compared to I7a-methyltestos-terone. The side effects normally associated with orally active compounds... 

With prolonged treatment, as in long-term use of androgens in mammary carcinoma, male pattern baldness, excessive body hair, prominent musculature, and hypertrophy of the clitoris may develop and may be irreversible. Patients receiving the 17a-alkyl substituted androgens may develop hepatic adenocarcinoma, the complications may be more common in people with Fanconi s anemia. 

Norethandrolone, methyltestosterone, and other 17a-alkyl substituted testosterone-like steroids increase the plasma retention of BSP in man (A16, H6, K14, L6) and sometimes cause hyperbilirubinemia (A16, A17) and elevation of alkaline phosphatase (H6). However, the retention of indocyanine green is not affected by norethandrolone (L6). Natural estrogens in very high dosage also increase the plasma retention of BSP in man (M33) and in rats (G2). Steroidal oral contraceptives in therapeutic dosage have a similar effect in a proportion of women (A6, LI). In the child-bearing age, these rarely produce other biochemical signs of liver dysfunction (R7, R8), but in postmenopausal women the effect of oral contraceptives on liver function tends to be more frequent and more severe (E3, P3). 

Thia-A-nor-5a-pregnan-20-one and a series of 7a-methyl, 17a-alkyl and 19-nor derivatives of 2-thia-A-nor-5a-androstan-17jS-ol have been synthesised by treatment of the bisnorseco-dibromide (169) with sodium sulphide. 

Drill and coworkers (18), investigating the properties of a large number of 17a-alkyl-19-nortestosterones, showed that the 17a-ethyl compound possessed the most favorable combination of relatively low androgenicity and relatively... 

ALKYLATED ANDROGENS Adding an alkyl group to the 17a position of testosterone (Figure 58-5) retards its hepatic metabolism. Consequently, 17a-alkylated androgens are androgenic when administered orally however, they are less androgenic than testosterone itself and cause hepatotoxicity, whereas native testosterone does not. 

The principal side effects of the 17a-alkylated androgens are hepatic, including cholestasis, and uncommonly, peliosis hepatis (blood-filled hepatic cysts). Hepatocellular cancer has rarely been reported. When administered at high doses, these androgens are more likely than others to affect serum lipid concentrations, specifically to decrease high-density lipoprotein cholesterol and increase low-density lipoprotein cholesterol. 

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