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United States Patent 0 " 1C6 3,087,942 Patented Apr. 30, 1963 1 2 3,087,942 The novel compounds of this invention conform to the following structural generic formula: PREPARATION OF ANABOLIC AGENTS Klaus Briickner, Klaus Irmscher, and Josef Gillissen, Darmstarlt, Germany, assignors to E. Merck Aktienge sellschaft, Darmstadt, Germany No Drawing. Filed Oct. 25, 1961, Ser. No. 147,469 Claims priority, application Germany Oct. 29, 1960 4 Claims. (Cl. 260—397.4) This invention relates to the preparation of novel steroid compounds having a high anabolic activity and 10 a low androgenic activity. _ An anabolic agent, sometimes called a myotrephic wherein R is selected from the group consisting of: CH3—CO-S— and hydrogen, and wherein at least one R represents -CH3—CO--S—; and wherein X is selected agent, promotes storage of protein and generally stimu lates tissues. These agents are useful for the treatment of persons debilitated by various metabolic and endocrine 15 from the ‘group consisting of: 1H,H and methylene. disorders. Unfortunately, though, anabolicagents usu As typical examples of the novel steroids of this inven ally also exhibit a signi?cant androgenic effect, and, there tion, there are included: fore, debilitated females cannot be treated with these 7 u-acetylthiod 7 a-methyl-testosterone anabolic agents without the danger of imparting mascu 20 la-acetylthio-l7a-methyl-testosterone line characteristics to the females. '1a,7u-di-acetylthio- li7a-methyl-testosterone A classical example of an anabolic agent having an 7a-acetylthio-l6-methylene~l7a-methyl-testosterone excessive androgenic activity is the compound testos -l a- acetylthio- l~6 -methylene~l 7a-methyl-testo sterone terone. 1a,7a-di-acetylthio-lo-methylene-17a-methyl-testosterone A great deal of effort has been expended to upgrade 25 the anabolic-androgenic activity of testosterone, but usu To demonstrate the improved anabolic-androgenic ally with no outstanding success. For example, in a ratios of the compound of this invention, reference is paper by R. M. Dodson and Robert C. Tweit, in the made to the following table, wherein the anabolic-andro Journal of the American Chemical Society, volume ‘81, genic ratios of the 7a- and lloc-acetylthio substitution prod pages 12-24 (1959‘), there is reported a modi?cation of nets are compared to the same compound devoid of the 30 testosterone by the introduction of a 7- as well as a 1 acetylthio groups: acetylthio group into both testosterone, the li7-ester there of, and 4-androstene-3,l7-dione. These 7- and l-acetyl ' thio derivatives were tested and the results indicated a Oompound Ratio of ana bolic/andro genie activity decrease in both the androgenic and anabolic activities of these. steroids. In contrast to these results, it is to be appreciated that modi?ed testosterones are sought which exhibit a decreased androgenic activity, but simul methyl-testosterone _______________________________ __ 1 7a-acetylthio:lhmethyl-testosterone _________________ .c 3. 71 1a,7a-di-acety1thio-17a-methyl-test0sterone ___________ _. 4. 55 taneously either maintaining or increasing the anabolic la-acetylthi0;16-methylene-lM-methyl-testosterone_____ 4. 14 la-acetylthioLl7a-methyl-testosterone _______________ __ 1. 86 activity. The object of this invention, therefore, is to provide new steroid compounds having a high anabolic activity and a low androgenic activity. 40 The anabolic-androgenic ratios thus obtained are com pared to the well known anabolic compound methyl testosterone, the ratio of which is l. The trials were Upon further study of the speci?cation and appended conducted according to the commonly used method of claims, other advantages and objects of the present in 45 Hershberger et al. described in proceedings of the Society vention will become apparent. for Experimental Biology and Medicine, vol. 83, page To attain the objects of this invention, it has been un expectedly discovered that by the incorporation of an v1-75 (1953), the dose being 1 or ill) mg. per animal. The novel compounds of this invention are particularly e?‘icacious anabolic agents which can be administered acetylthio group in the 70:. or lot positions, or both, in 17a-methyl-testosterones, there are obtained steroids which 50 perorally, preferably in 5 mg. doses. These drugs may exhibit a high anabolic effect and a low androgenic effect. be manufactured in the form of tablets, pills, dragees, These novel derivatives, capable of oral administration, solutions or emulsions with the aid of the usual phar exhibit an increased anabolic effect and a substantially maceutical auxiliary agents and excipients. The preferred reduced androgenic effect, as compared to the unsub concentration of the solutions is 1 mg./cc. stituted 17a-methyl-testosterone. 55 The novel compounds of this invention can be pro These excellent physiological properties of the new derivatives are quite surprising in view of the aforemen tioned Dodson and Tweit paper which teaches that the duced by conventional methods from 17a-methyl-testos terone derivatives which are unsaturated in the .1,2. and/ or the 6,7-positions. These aforesaid raw materials are reacted with thioacetic acid under conventional con introduction of a 7- and l-acetylthio group into testoster one and the l7-esters thereof, result in a decrease in the 60 ditions. anabolic effect of the parent compound. This inven tion, on the other hand, teaches that there is an in crease in the anabolic effect when the 7:1- and lot-acetyl thio groups are introduced into the 17a-methyl-testoster ones. Furthermore, it was discovered that upon the intro duction of the 70c- and lot-acetylthio groups to the 16 methylene derivatives of l7-u~methyl-testosterones an even further reduction in the androgenic effect is obtained, while the anabolic effect is maintained constant, as com Preferably it is advantageous to conduct the reaction in contact with ultra-violet radiation, and in the presence of an inert solvent, such as benzene, dioxane, toluene, carbon tetrachloride, etc. It is to be appreciated that the foregoing brief descrip 65 tion of the method of producing the novel steroids of this invention is adequate to teach a steroid chemist skilled in the art how to produce the novel compounds of this invention. The following examples, therefore, are merely preferred 70 speci?c embodiments of this invention, and are not in pared to the corresponding substitution product which tended to be limitative of the speci?cation and appended does not have a 16-methylene group. claims. 8,087,942 3 4 Example 1 further recrystallization at 157—160° C.; (ocD+30° C. (dioxane); Amax240 ma, El'?’m, 450 Example 5 According to Example 1, the 7a-acetylthio-16-methyl ene-l7a-methyl-testosterone is produced from 6-dehydro 7 g. 6-dehydro-»17a-methyl-testosterone are heated in 20 ml. thioacetic acid on a steam bath for 1.5 hours. The thioacetic acid is thereafter extracted by vacuum and the residue is crystallized from methanol. The 7 a-acetyl thio --17a - methyl - testosterone melts at 162-163 ° C.; Amax'238 ml‘, 16-methylene-17a-methyl-testosterone. Eli’... 500; (a)n—-69.3° C. Example 2 Melting point 147—149° C.; Amax 238 mp, 10 El'?'m 500; (a)n—149.3° (dioxane) Example 6 4 g. 17a-methyl-1,4,6-androstatriene-ll7?-ol-3-one are According to Example 2, the 1a,7a-di-acetylthio-l6 boiled in 12 ml. thioacetic acid under re?ux for 11/: methylene-17a-methyl-testosterone is produced from tl6~ hours. This reaction mixture is thereafter concentrated 15 methylene-17a-methyl-1,4,6-androstatriene-3-one-175 - ol. in vacuum to dryness and the 1a,7a-di-acetylthio-17a Melting point 1‘94-196° C.; Amax238 ma, Elli... 421 methyl-testosterone is crystallized from the residue after treatment with methanol; melting point 202-204" C.; (u)D—74.6° C. (dioxane); 7\max237.5 ma, Ell’... 449 From the foregoing description, one skilled in the art 20 can readily appreciate the essential characteristics of this invention, and without departing from the spirit and scope of these essential characteristics, one can modify and adapt this invention into varying usages and conditions. Example 3 Consequently, such modi?cations and adaptations should, 2.9 g. l-dehydro-l7a-methyl-testosterone are dissolved in 10 ml. thioacetic acid and are boiled under re?ux 25 and are intended to be, within the full range of equivalents of the following claims. for 1.5 hours. The reaction composition is thereafter concentrated in vacuum and the residue is crystallized What we claim is: 1. la,~7a-di-acetylthio-17a-methyl-testosterone. from ether. The obtained 1a-acetylthioa17a-methyl 2. 7a-acetylthio-1=6-methylene-l7a-methyl-testosterone. testosterone melts at 160a161° C.; (a)D+98° (Chlf.); 30 3. la-acetylthio-l6-methylene-17a-methyl-testosterone. Amax240 ml", 4. 1a,7a-di-acetylthio-16-methylene-1‘7a~methyl-testos Ell’... 426 terone. References Cited in the ?le of this patent Example 4 13.25 g. 1-dehydro-16-methy1ene-17a - methyl-testoster 35 one are boiled in 15 ml. thioacetic acid under reflux for 1%, hours. The solution is thereafter concentrated in vacuum, the residue is crystallized from ether/petroleum ether, and the l-acetylthio-16-methylene-17a-methyl-tes 40 tosterone is puri?ed by recrystallization from ether. The melting point is 154~155° C. The product melts after UNITED STATES PATENTS 2,859,222 Dodson et al ___________ __ Nov. 4, 1958 2,875,215 2,929,763 Dodson et a1 __________ .._ Feb. 24, 1959 Wettstein et a1 _________ __ Mar. 22, 1960 OTHER REFERENCES Iriarte et al.: 81 J.A.C.S. 436-438 (1959).