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By Old.A.Z.4Awe Attorneys 3,754,086 United States Patent Office Patented Aug

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By Old.A.Z.4Awe Attorneys 3,754,086 United States Patent Office Patented Aug Aug. 21, 1973 SHOKE FUJISAWA 3,754,086 STABLE OILY PREPARATIONS OF EPITHIO-STEROIDS Filed June 7, l97. (POV-l.0) (POV-6.0) 5O (POV-22) 40 30 O O 2 4. 6 8 lO (WEEKS) SHOKEI FUJISAWA, Inventor By old.A.Z.4Awe Attorneys 3,754,086 United States Patent Office Patented Aug. 21, 1973 2 or unsaturated double bond; and they may further include 3,754,086 nor- or homo-derivative thereof. Typical examples of Said STABLE OLY PREPARATIONS OF EPTHO-STERODS epithio-steroid are as follows: Shokei Fujisawa, amishi, Japan, assignor to 20,3c-epithio-5a-pregnane, Shionogi & Co., Ltd., Osaka, Japan 20,3a-epithio-5a-estrane, Fied June 7, 1971, Ser. No. 150,529 20,3oz-epithio-56-cholane, Claims priority, application Japan, Stune 8, 1970, 2cy,3cy-epithio-56-cholamic acid methyl ester, 45/49,279, 45/49,280 20,3a-epithio-5a-chloestane, in C. C67. I73/00 26,36-epithio-5oz-androstan-17B-ol, U.S. C. 424-24 35 Caias O 2c,3oz-epithio-5cy-androstan-178-ol, 2c,3c-epithio-5oz-androstan-17f8-ol acetate, 2c,3c-epithio-5oz-androstan-17B-ol propionate, ABSTRACT OF THE DISCLOSURE 2a,3oz-epithio-5oz-androstan-175-ol valerate, Stable oily preparations of eipthio-steroids useful as a 2c,3oz-epithio-5a-androstan-17 3-ol caprylate, pharmaceutical or veterinary medicine in their strong 5 2c,3c-epithio-5o-androstan-17(3-ol enanthate, anti-progestational, anti-estrogenic myogenic, anti-lipeam 2c,3oz-epithio-5o-androstan-176-ol phenylpropionate, ic, androgenic, and other hormonal activities are prepared 2c,3oz-epithio-5a-androstan-17(3-ol benzoate, by adding an epithio-steroid to an oil having a low 2c,3oz-epithio-2,3-methyl-5oz-androstane, peroxide value. 2c,3c-epithio-10-methyl-5oz-androstan-176-ol, 20 28,36-epithio-10-methyl-5a-androstan-17B-ol, This invention relates to stable oily preparations of 2c,3o-epithio-1 cy-methyl-5cz-androstan-17(3-ol acetate, epithio-steroids and to a process for preparing the same. 2c,3c-epithio-36-methyl-5o-androstan-175-ol, The oily preparations of epithio-steroids comprise essen 2o.3oz-epithio-7cy-methyl-5a-androstan-17(3-ol, tially an epithio-steroid and an oil having a low peroxide 2c,3c-epithio-88-methyl-5c-androstan-17(3-ol, value (the peroxide value hereinafter referred to as POV 25 2,3c-epithio-17a-methyl-5a-androstan-17B-ol, represents amount in mg. of active oxygen in 100 g. of 2c,3oz-epithio-17 oz-ethyl-5a-androstan-17B-ol, oil). Said preparations can be prepared by adding an 2c,3oz-epithio-17a-vinyl-5a-androstan-17B-ol, epithio-steroid to an oil having a low POV. The prepara 2,3oz-epithio-17 oz-ethynyl-5a-androstan-17 3-ol, tions of the present invention are useful as a pharmaceu 2c,3c-epithio-18-methyl-5o-androstan-17 3-ol, tical or veterinary medicament, because they show strong 30 2c,3oz-epithio-17-methylene-5o-androstane, anti-progestational, anti-astrogenic, myogenic, anti-lipe 20,3oz-epithio-5oz-androstane-7 oz,173-diol, amic, androgenic, or other hormonal activity. 2cy,3c-epithio-5cy-androstane-63,17,3-diol, The epithio-steroids available in the present invention 2cy,3oz-epithio-17 3-(1-cyclopentenyl)oxy-5oz-androstane, are androstane, pregnane, estrane, cholane, cholestane 2,3-epithio-176-(1-cyclohexenyl)oxy-5oz-androstane, and other similar steroids, having an epithio group at the 35 2c,3c-epithio-176-(1-methoxycyclopentyl)oxy-5oz position 1,2; 2,3; 34; 4,5; 5,6; 6,7; 11,12; 14,15; 15, 16; androstane, or 16, 17 of the steroid nucleus. Although the epithio 2cy,3oz-epithio-176-(1-methoxycyclohexyl)oxy-5oz steroids, e.g. 2c,3o-epithio-androstan-176-ols show strong androstane, anabolic, anti-estrogenic, and anti-fertility activities 40 2o.,3c-epithio-17f8-(1-methoxycycloheptyl)oxy-5oz tetrahedron, 21, 329 (1965), their practical uses are androstane, considerably limited, because they cannot be stored for 2c,3oz-epithio-176-(1-ethoxycyclopentyl)oxy-5oz a long time. The same is substantially true for other androstane, epithio-steroids. It was believed that such instability was 2cy,3oz-epithio-176-(1-ethoxycyclohexyl)oxy-5oz probably due to less resistance of the epithio group to androstane, acids at the position 2o,3c of the steroid nucleus. During 2o.,3c-epithio-5cy-androstan-17-one, the course of investigation on an oily preparation, the 10,20-epithio-A-nor-5 cy-androstan-17B-ol, present inventor found that the stability of an epithio 20,3oz-epithio-17-methyl-D-homo-5-androstan-17,3-ol, steroid in oil greatly depends on the lot number of the 36,48-epithio-5cy-androstan-17 3-ol, preparation. As the result of various studies, it has been 50 2o,3c-epithio-5o-androst-9(11)-en-17.3-ol, confirmed that the epithio-steroid contained therein is 2c,3c-epithio-5o-androst-6-en-17B-ol, decomposed by the action of peroxides in the oil used. 20,30-epithio-5 ce-androst-6-en-176-ol acetate, Usually, oils in market have a variety of high POV of 163,175-epithio-4-androsten-3-one, 3-8, and their POV turns to higher than 100 by the 20,3oz-epithio-5oz-estran-17 3-ol, all toxidation after exposed to air for a long time. It is 26,36-epithio-5oz-estran-176-ol acetate, therefore very much difficult to prepare a stable and 20,3oz-epithio-5o-pregnan-20-one, long-acting preparation of said epithio-steroid by using 20,3o-epithio-1120-dioxo-17 oz-acetyloxy-5o-pregnane, an oil having a high POV. In this connection, the present 20,30-epithio-1,20-dioxo-17c-hydroxy-5oz-pregnane, inventor has succeeded in reducing a high POV to a low 20,30-epithio-17o-acetyloxy-5a-pregnan-20-one, one by treating the oil with an active adsorbent. Thus, 60 20.3o-epithio-170,21-dihydroxy-5oz-pregnan-11,20-dione, stable oily preparations of the epithio-steroids can be 20,30-epithio-21-acetyloxy-17a-hydroxy-5o-pregnane prepared by using an oil having a low POV. The present 11,20-dione, invention has been completed on the basis of these 20.3c-epithio-17 oz,21-dihydroxy-5oz-pregnane-1120-dione, observations. 20,30-epithio-9o-fluoro-11p,17a-dihydroxy-5a-pregnan As mentioned above, the epithio-steroids available in 65 20-one, this invention are androstane, estrane, pregnane, cholane, 1 10,120-epithio-5a-pregnane-36,20oz-diol and cholestane, and other similar steroids, having an epithio 148,158-epithio-3p3-hydroxy-5B,143-card-20 (22)-enolide. group at the position 1,2; 2,3; 3,4; 4,5; 5.6; 6,7; 11,12; They can be prepared according to the methods described 14,15; 15,16, or 16, 17 of the steroid nucleus. These as in Tetrahedron, 21, 329 (1965) and Ann. Rept. epithio-steroids may have substituent(s) such as lower 70 Shionogi Res. Lab., 19, 1-19 (1969). alkyl, lower alkenyl, acyloxy, alkoxycycloalkyloxy, cyclo The oils in this invention are derived from those of alkenyloxy, hydroxy, Oxo, ketal, carboxyl, ester, halogen, animal, vegetable, and/or synthetic sources commercially 3,754,086 3 4. available to make many oily preparations. As example day. The administration is as often as required by the of the oils are vegetable oils (e.g. sesame oil, olive oil, physicians' or veterinary indication. cottonseed oil, corn oil, peanut oil, castor oil, wheat The following examples are given only by Way of germ oil, rice-bran oil, palm oil, sunflowerseed oil, linseed illustration and are not intended as limitations of the oil, soya bean oil), alkyl esters of fatty acids wherein the present invention, many apparent variations of which are alkyl moiety contains up to 10 carbon atoms, and the possible without departing from the spirit and scope fatty acid contains 6-18 carbon atoms (e.g. methyl lau thereof. rate, ethyl laurate, isopropyl laurate, butyl laurate, In the working examples, the amount of remaining methyl myristate, ethyl myristate, isopropyl myristate, epithio-steroid was determined in the following method. butyl myristate, isopropyl palmitate, butyl palmitate, amyl O Two-mi. of the solution (1%) was pipetted into a 20-ml. palmitate, isopropyl stearate, butyl stearate, decyl oleate, messflask and diluted with ethyl ether-ether (1:1 by diisopropyl adipate), glycerides of fatty acids wherein volume). To a 5-ml. aliquot of the diluted solution was the fatty acid contains 8-10 carbon atoms (e.g. glyceryl added 10 ml. of 0.004 M mercuric acetate. After the monocaprylate, glyceryl dicaprylate, glycerely tricapry mixture was allowed to stand for 4 minutes with occa late, glyceryl monoperalgonate, glyceryl diperalgonate, sional stirring, 10 ml. of 0.01 N hydrochloric acid was glyceryl triperalgonate, glyceryl monocaprate, glyceryl added and the mixture was titrated potentiometrically dicaprate, glyceryi tricaprate) and mixture thereof, with 0.002 M mercuric acetate. Titration was carried out among which sesame oil is the most preferable one. The along with a blank run concurrently. oils available in this invention must have a low POV, preferably 0-2.5. As mentioned above, the oils in market EXAMPLE 1. usually have a high POV of 3–8, and it is therefore 2a,3c-epithio-5oz-androstan-176-ol (1 g.) is dissolved necessary to reduce the POV to a low one within a POV in a treated sesame oil (80 ml, POV-0.4) at 40-50° C. range of 0–2.5, before use.
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