Progestational Compounds

Clinical trials of these orally active progestins showed that they were effective as contraceptives with a success rate that exceeded 99%. These compounds were then marketed as obtained from the reaction sequence after appropriate purification. As the analytical methodology improved it became apparent that a small amount of an impurity was present in all active samples. An examination of the reaction scheme allowed ready identification of that by-product. Any unreduced estradiol methyl ether (13-1) will go to estrone methyl ether on oxidation this will then afford the potent orally active estrogen mestranol (9-1) on ethynylation. Subsequent 

Oral progestational activity is retained when the ketone at the 3 position is reduced to an alcohol. Treatment of ethindrone (13-6) with the bulky reducing agent lithium aluminum-tri-ferf-butoxy hydride leads to attack from the more open a face and the formation of the 3 3 hydroxy derivative (14-1). Acylation under forcing conditions affords the 3,17-diacetate derivative, ethynodiol diacetate (14-2) [17]. 

The compound in which the 3-keto group is reduced to a hydrocarbon interestingly still acts as an orally active progestin. The preparation of this compound starts with the hydrolysis of dihydrobenzene (13-2) to afford 19-nortestosterone (15-1). Reaction with ethane-1,2-thiol in the presence of catalytic acid leads to the cyclic thioacetal (15-2). Treatment of this intermediate with Raney nickel in the presence of alcohol leads to the reduced desulfurized derivative (15-3). The alcohol at 17 is then oxidized by any of several methods, such as chromic acid in acetone (Jones reagent), and the resulting ketone (15-4) treated with hthium acetylide. There is thus obtained the progestin lynestrol (15-5) [18]. 

In much the same vein as above, hydrolysis of the enol ether (13-2) with a weak acid gives the unconjugated 5,9 olefin (16-1). This is then successively converted to a thioacetal, desulfurized, oxidized, and ethynylated. There is thus obtained the orally active progestin tigestol (16-2) [18]. 

The almost immediate commercial success of the gonane-based oral contraceptives spurred an impressive amount of work in this series aimed at developing new market entries. Describing each of those in detail is beyond the scope of this volume instead, we present below some examples chosen almost arbitrarily because their synthesis involves some interesting chemistry. 

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In addition to the classical tests usually applied for the assay of androgenic and anabolic activities, another method is reported by the same workers for the evaluation of androgenic properties of progestational compounds in the rat by the female fetal masculinization test [201]. It should be pointed out that inversion of configuration at C-10 does not necessarily bring about abolition of androgenic activity, in view of the new theory, as will be seen later. 

The 16-methylene derivative (10) of chlormadinone (11) is twice as active as 11 in the modified Me Phail assay on oral administration- --. The deciduogenic activity of substituted estradiols has been used as another parameter for assessing intrinsic progestational activity. Both 17-(2-butenyl)-estradiol 3-acetate (12) and the 17-(2-methyl-allyl) derivative (13) were active in this assay. The totally synthetic 18-homolog 14 of norethisterone (15) has proven to be a potent progestational compound in animals and in man 20,21 6a-methyl derivative 16 has 85 times the... 

Progestogen—A term referring to progesterone and the synthetic progestational compounds (sometimes referred to as progestins). 

The term progestin has evolved to refer to synthetic analogs that have progestational effects. They have been developed to provide useful oral, as well as longer, duration of action. A generic term to denote all progestational compounds is progestogens. 

The 116-chloro-19-norsteroids 9 and 10 are among the most active progestational compounds so far reported.98 The related 16-methylene compound 11... 

The orally active progestational agent 17a-ethynyltestosterone (56) was subsequently obtained by Oppenauer Oxidation. Similarly ethynyla-tion of 3-ethoxyandrosta-3,5-dien-17-one followed by acid hydrolysis afforded the 17a-ethynyl compound (56). ... 

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p-toluene-sulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41). This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42) the progestational component of Riglovic . Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,173-diol iffords ethynodiol diacetate, one of the most potent oral proves tins (44). ... 

The lack of oral activity of progesterone proper has already been mentioned. Even after the orally active 19-nor agents, which showed progestational activity, had been elaborated, the search continued for an orally active compound that contained the full pregnane nucleus (115). At the time such a compound would have had the economic advantage of sidestepping the then burdensome ring A aromatization reactions. 

Elaboration of a commercially viable route for total synthesis of 19-nor steroids led to the introduction of the totally synthetic product norgestrel (71) as the progestational component of an oral contraceptive. As was observed in the "natural" 19-nor-compounds, reduction of the 17-ethynyl group to 17-ethyl affords compounds with androgenic/anabolic... 

Oppenauer oxidation of the enol ether (34) affords the corresponding 17 ketone (37) (the enol ether is stable to the basic oxidation conditions). This ketone affords the corresponding 17a-ethynyl compound on reaction with metal acetylides. Hydrolysis of the enol ether under mild conditions leads directly to ethynodrel (39), an orally active progestin. This is the progestational component of the first oral contraceptive to be offered for sale. Treatment of the ethynyl enol ether with strong acid leads to yet another oral progestin employed as a contraceptive, norethindrone (40). ° In practice these and all other so-called combination contraceptives are mixtures of 1-2% mestranol... 

Therapeutic indications for the progestational drugs based on pregnanes described above are rather limited. This is particularly true when compared to the reduced estrane-based nor compounds that are used in oral contraceptives. This circumstance, combined with the availability of the half-dozen or so C-19 progestins, posed as a disincentive to further research on the synthesis of new compounds. This is reflected in the pubhcation dates of reports on the synthesis of these compounds. 

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