United States Patent (19) (11) 4,307,087 Tax (45) Dec. 22, 1981

54 BRANCHED CHAIN AND Gould et al., J. Am. Chem. Soc. 79, at 4472-4474, CYCLOALPHATIC ESTERS OF THE (1957). ANDROSTANE AND OESTRANE SERIES AND PHARMACEUTICAL COMPOSITIONS Primary Examiner-Elbert L. Roberts CONTAINING SAME Attorney, Agent, or Firm-Robert H. Falk; Charles A. Wendel; Francis W. Young 75) Inventor: Lambert J. W. M. Tax, Macharen, Netherlands 57 ABSTRACT There are disclosed branched chain and cycloaliphatic 73) Assignee: Akzona Incorporated, Asheville, esters of steroids having the formula: N.C. R7

*) Notice: The portion of the term of this patent subsequent to Jul. 15, 1997, has been disclaimed. (21) Appl. No.: 120,609 22 Filed: Feb. 12, 1980 Related U.S. Application Data 63) Continuation of Ser. No. 852,326, Nov. 17, 1977, aban doned. where (30) Foreign Application Priority Data R is H or CH3; R1 is H or CH3; Nov. 26, 1976 NL Netherlands ...... 7613248 R2 is H or CH3; R3 is H, OH, CH3 or Cl; 51) Int. Cl...... A61K 31/56 R4 is H or C1 to C4 alkyl; 52 U.S. C...... 424/243; 260/397.4 R5 is H, C1 to C4 alkyl or CF3; (58) Field of Search ...... 260/397.4; 424/243 R6 is H, C1 to C4 alkyl, C1 to C4 alkoxy, halogen or (56) References Cited R-OH providing that when R6 is 6-OH, the steroid also contains 9a-F and further providing that R1, R2, U.S. PATENT DOCUMENTS R3, R4, R5 and R5 represent at least 4 and at most 5 3,134,792 5/1964 Kaspar et al...... 260/397.4 hydrogen atoms, except in the case of a Al-steroid, 3,226,991 12/1968 Wettstein et al. 260/.397.4 in which case R1, R2, R3, R4, R5 and R6 are all hydro 4,071,623 1/1978 Van der Vies. ... 424/238 gen; 4,098,802 7/1978 Van der Vies ...... 260/397.4 R7 is H or CH3; 4,119,626 10/1978 Schulze et al...... 260/.397.4 4,147,783 4/1979 Van der Vies ...... 260/397.4 R8 is 4,220,599 9/1980 Van der Vies ...... 260/.397.4 O FOREIGN PATENT DOCUMENTS -OCR9 304505 3/1955 Sweden ...... 260/397.4 826790 1/1960 United Kingdom ...... 260/.397.4 899026 12/1960 United Kingdom ...... 260/397.4 providing the R8 is -OH or 1152226 6/1969 United Kingdom...... 260/397.4 O OTHER PUBLICATIONS Steroid Drugs, by Applezweig, 559-561 (1962). -OCR9 J.A.C.S. 79, at 4472-4475, (1957). J. Med. Chem. 11, at 1079-1080, (1968). when the steroid has an aromatic ring A. Chem. Abstr. 76, at 54570y, (1972). 17 Claims, No Drawings 4,307,087 1 2 of 1-methyl-Al-5aH-androsten-1743-ol (See also U.S. BRANCHED CHAIN AND CYCLOALIPHATIC Pat. No. 3, 134,792). U.S. Pat. No. 3,526,648 describes ESTERS OF THE ANDROSTANE AND OESTRANE 1713-esters of 11 (3-alkoxy-18-methyl-oestradiol. Esters SERIES AND PHARMACEUTICAL - of 6-methyl-19-nor-testosterone are shown in U.S. Pat. COMPOSITIONS CONTAINING SAME 5 No. 3,047,592. This is a Continuation of application Ser. No. 852,326 GENERAL DESCRIPTION OF THE INVENTION filed Nov. 17, 1977, now abandoned. A novel group of steroid esters based on substituted The invention relates to novel esters of organic car steroid alcohols from the androstane and oestranese boxylic acids and steroid alcohols of the androstane and 10 oestrane series, and to pharmaceutical compositions ries, and possessing interesting biological properties, has now been found. The invention therefore consists of the containing the novel steroid esters. novel esters of branched chain carboxylic acids and the BACKGROUND OF THE INVENTION steroid alcohols noted, said novel esters possessing the Many steroid esters which have found applications in 15 formula: medicine are already known. The ester derivative is usually chosen for its effect of intensifying or prolong O ing the activity of the steroid used. A depot-effect is obtained on parenteral (subcutaneous or intramuscular) -OCR9 administration of steroid esters in solution; in this in 20 stance a slow absorption of the ester from the depot into or the 5aH analog thereof, the plasma takes place. In the plasma, or elsewhere in where the body, the ester is hydrolysed and the steroid alcohol R is selected from the group consisting of H and CH3; released may then, optionally after being metabolized, R1 is selected from the group consisting of H and CH3; exert its action on the target organ. 25 R2 is selected from the group consisting of H and CH3; The choice of the ester influences both the rate of R3 is selected from the group consisting of H, OH, CH3 absorption from the depot and the rate of hydrolysis in ... and Cl; the body. The choice of the ester may also affect the R4 is selected from the group consisting of H and C1 to administration form. For example, it is known from ; C4 alkyl; copending application Ser, No. 550,397 corresponding 30 R5 is selected from the group consisting of H, C1 to C4 to Belgian Pat. No. 826,086 filed Feb. 2, 1975 that tes alkyl and CF3; tosterone esters derived from aliphatic carboxylic acids R6 is selected from the group consisting of H, C1 to C4 with 9 to 16 carbon atoms are much more active than alkyl, C1 to C4 alkoxy, halogen and 6-OH with the testosterone esters having less than 9 or more than 16 proviso that when Ré is 9-OH, the steroid also con carbon atoms in the carboxylic acid residue when ad 35 tains 9a-F; with the further proviso that R1, R2, R3, ministered orally in the presence of a lipoid substance, R4, R5 and R5 represent at least 4 and at most 5 hydro for example a vegetable or an animal oil. gen atoms, except in the case of a A-steroid, in DISCUSSION OF PRIOR ART which case R1, R2, R3, R4 and R5 are all H; R7 is H or CH3; Esters of steroids are known. For example, U.S. Pat. 40 No. 2,109,400 discloses esters of testosterone such as . R8 is testosterone propionate and testosterone n-butyrate. Phenyl alkanoates of 19-nortestosterone are described O in U.S. Pat. No. 2,868,809 while the U.S. Pat. No. -OCR9 2,933,514 teaches testosterone chloral-hemiacetals, 45 ... Both U.S. Pat. No. 2,998,423 and U.S. Pat. No. , with the proviso that R8 is OH or 3,016,388 describe various esters of 19-nor-testosterone. In U.S. Pat. No. 3,264,285, there is disclosed various 19-nor-testosterone-17-hemi-acetals and hemiacetal es O ters whereas bridged esters of testosterone are shown in 50 -OCR9 each of U.S. Pat. No. 3,433,813, U.S. Pat. No. 3,515,720 and U.S. Pat. No. 3,523,126. In U.S. Pat. No. 3,523,958, when the steroid has an aromatic A-ring Al3,5(10) there is described 4,17-dialkyl 9p,10a steroids of the and the 3-position is substituted by androstane series having 2 to 5 carbon atoms in the 4-alkyl group and a keto, alkoxy or acyloxy group at the 3-position. Esters of 2-alkyl-17g-hydroxy-Al'-andros 55. O tadien-3-ones are shown in U.S. Pat. No. 3,092,644. -OCR9; In British Pat. No. 988,529, there is described esters of Al-testosterone. British Pat. No. 879,622 discloses R9 is 4-hydroxy-19-nor-testosterone cyclohexylpropionate, U.S. Pat. No. 2,762,818 discloses 4-hydroxy-testoster one cyclohexylacetate, and British Pat. No. 826,790 o describes 4-chloro-testosterone cyclohexylcarboxylate. -(CH)--Rs In U.S. Pat. No. 3,966,713, there is disclosed 116 R fluoro-testosterone decanoate. In German "Offen 65 . legungsschrift" No. 2,439,083, there is described esters where of 1a-methyl-dihydrotestosterone, and in German n = 0, 1 or 2; "Auslegeschrift" No. 1,122,947, there is disclosed esters R10 is C1 to C10 alkyl; 4,307,087 3 4. R1 is selected from the group consisting of H and C1 to 1-methyl-17.6-hydroxy-Al-5a-androsten-3-one; C10 alkyl; 2a-methyl-17(3-hydroxy-5a-androstan-3-one; R12 is an aliphatic group having 1 to 18 carbon atoms, or 176-hydroxy-All-androstadien-3-one; R10 and R12 taken together with the carbon atom to 4-methyl-17,3-hydroxy-A-androsten-3-one; which they are attached form a C7 to C12 cycloali 4-methyl-1713-hydroxy-A-Oestren-3-one; phatic group with the proviso that the total number 4-methyl-17(3-hydroxy-5aH-androstan-3-one; of carbon atoms in the carboxylic acid residue is 8 to 4-chloro-17A-hydroxy-A-androsten-3-one; 20; 4, 17.6-dihydroxy-A-oestren-3-one; ring A is either saturated or has one of the following 6a-methyl-17g-hydroxy-A-oestren-3-one; types of unsaturation: Al; A4, A14, A5(10); A1,3,5(10), O 7a-methyl-1718-hydroxy-A-oestren-3-one; and 6a,7a-dimethyl-17(3-hydroxy-A-oestren-3-one; X is selected from the group consisting of-O, OH and la,7a-dimethyl-17,3-hydroxy-A-oestren-3-one; 9a-fluoro-11p,1713-dihydroxy-A-androsten-3-one; 7a-ethyl-176-hydroxy-A-oestren-3-one; 15 7a-methyl-1713-hydroxy-As(10)-oestren-3-one; O 7(3-methyl-1713-hydroxy-A-androsten-3-one; -OCR9 la,7a-dimethyl-17g-hydroxy-A-androsten-3-one; 11.6-fluoro-1743-hydroxy-A-androsten-3-one; providing that X is OH or 116-chloro-1713-hydroxy-A-oestren-3-one; 20 7a-methyl-Al3,5(10)-oestratrien-3,176-diol; O 7a-methyl-Al3,5(10)-oestratrien-3,17a-diol; I 7a-ethyl-A 1,3,5(10)-oestratrien-3,176-diol; -OCR9 7a-trifluoromethyl-A1,3,5(10)-oestratrien-3,1713-diol; 116-methyl-A1,3,5(10)-oestratrien-3,1743-diol; when the steroid has an aromatic ring A. 25 11g-methoxy-A1,3,5(10)-oestratrien-3,176-diol; Among preferred embodiments of the invention, 116-ethoxy-Al3,5(10)-oestratrien-3,1713-diol; there are those steroid esters, where R1, R2, R3, R4, R5 and R6 represent 5 hydrogen atoms; where R1 is in the 7a-methyl-1113-methoxy-A1,3,5(10)-oestratrien-3,176 a-configuration; where R2 and R4 are H; where R3 is H 11a-methoxy-A1,3,5(10)-oestratrien-3,176-diol;diol; or Cl; where R5 is H when R5 is not H and conversely; 30 11(3-methyl-17 (3-hydroxy-A-oestren-3-one. where R5 when not H is methyl or methoxymethyl and Examples of branched-chain (cyclo)aliphatic carbox R6 when not H is methyl, methoxy or 6-OH (in con ylic acids which can be utilized in making the steroids junction with 9a-F); where n is 0 or 1; where R10 is C1 constituting the present invention are: to C4 alkyl with methyl and ethyl most preferred; R11 is 2-methyl-decanoic acid; H; and R12 contains from 4 to 14 carbon atoms and most 35 3'-methyl-decanoic acid; preferred 6 to 12 carbon atoms. R12 may also contain at 2,2'-dimethyl-decanoic acid; least one ring having 5 to 12 carbon atoms, preferably 6 2'-ethyl-tetradecanoic acid; to 9 carbon atoms. It is also preferred to have 7 to 9 2'-propyl-pentanoic acid; carbon atoms in the cycloaliphatic group formed by the 2'-propyl-hexanoic acid; combination of R10 and R12 and the cycloaliphatic 40 4',4'-diethyl-hexanoic acid; group may be optionally substituted with a C to C6 2'-octyl-dodecanoic acid; alkyl, preferably C1 to C3 alkyl. 2,2'-dimethyl-octadecanoic acid; The carboxylic acid residue R8 is preferably in the 2'-ethyl-heptanoic acid; As-configuration. 2,2'-dimethyl-heptanoic acid; The new esters may be prepared in ways which are in 45 2-methyl-octanoic acid; themselves known, for example by allowing the hy 2'-methyl-hexadecanoic acid; droxysteroid to react with the appropriate organic car 2'-ethyl-hexanoic acid; boxylic acid or with a functional derivative thereof, 2'-butyl-hexanoic acid; such as the acid chloride or the acid anhydride, in a 3'-butyl-heptanoic acid; solvent and in the presence of a water-binding agent for 50 3',3'-dimethylnonanoic acid; example dicyclohexylcarbodiimide or a base, for exam 3',3'-diethyl-hexanoic acid; ple pyridine or dimethylaniline. 2-methyl-tridecanoic acid; The reaction is a conventional reaction involving 2'-methyl-2'-ethyl-hexanoic acid; simple ester formation, is well known and easy to carry cyclononyl-acetic acid; out. The standard techniques are represented in the 55 cycloheptyl-carboxylic acid; working examples herein. Generally the reaction is cyclo-octyl-carboxylic acid; carried out at a temperature ranging from about -10 cyclo-octyl-acetic acid; C. to about 50° C. Pressure is not a critical factor in the p-methyl-cyclohexyl-acetic acid; reaction process and atmospheric pressure is normally p-isopropyl-cyclohexyl-acetic acid; used although subatmospheric and superatmospheric 60 3'-cyclohexyl-butyric acid; pressure can also be employed. 2'-methyl-3'-cyclohexyl-propionic acid, and Among the solvents that can be used during the cyclododecyl-carboxylic acid. course of the reaction are pyridine, acetone, tetrahydro In those instances where a free hydroxy group is to be furan or mixtures thereof. present in the new steroid ester, for example a 4 Examples of steroids which may be utilized in making 65 hydroxy-nandrolone-1713-ester, this hydroxy group is the steroids of the present invention are: introduced after esterification. The 4,5-epoxide of the la-methyl-17(3-hydroxy-A-androsten-3-one; nandrolone derivative is first made, for example with la-methyl-17 (3-hydroxy-5a-androstan-3-one; H2O2 in caustic soda. The 4,5-epoxy-1713-ol is then es 4,307,087 5 6 terified in the usual way, after which the epoxy-ring is less than the amount of the lipoid substance present. A opened to give the 4-OH-A group, for example using daily dosage of the steroid ester of about 0.01 mg to BF3 in benzene. In the case of an oestradiol derivative, about 200 mg is acceptable for treating disorders or the usual esterification results in the 3, 1743-diester which diseases requiring treatment with an androstane or oes if desired may then be partially hydrolysed to give the trane series steroid, whereby the daily dosage of an 176-ester. The 3-ester of an oestradiol derivative is androgenic and/or anabolic steroid ester is usually in prepared by starting from the corresponding oestrone the higher region of the said range, i.e. from about 0,5 derivative, preparing the 3-ester of this derivative and mg to about 200 mg, preferably from about 1 mg to subsequently reducing the 17-oxo group. about 50 mg, and the daily dosage of an oestrogenic The new steroid esters according to the invention 10 steroid ester is usually in the lower region of the said prove pharmacologically to be highly active com range, i.e. from about 0.01 mg to about 2 mg, preferably pounds. The steroid esters with a 3-oxo-5aH, 3-oxo-A, from about 0.05 mg to about 1 mg. The techniques 3-oxo-A-, 3-oxo-Alt- or 3-oxo-As(0)-group possess disclosed in copending application Ser. No. 550,397 interesting androgenic and/or anabolic properties, filed Feb. 2, 1975 for compounding and administration while the steroid esters with an aromatic ring A are of 15 are incorporated herein by reference. particular interest on account of their oestrogenic and The ester is preferably dissolved in the lipoid sub antioestrogenic properties...... stance and processed as a solution, optionally a solid Thus, for example, -la-methyl-dihydrotestosterone solution, to give a pharmaceutical formulation for oral cyclo-octylacetate is in the MLA-test orally 8 times administration, for example a tablet, a lozenge or a soft more active than 1a-methyl-dihydrotestosterone; 9a 20 fluoro-11p,17(3-dihydroxy-A-androsten-3-one 176 or hard gelatine capsule. cyclo-octylacetate has in the MLA-test a threshold dose The invention is illustrated by means of the following of 2x0.5 mg, which is interesting in comparison with examples wherein the new steroid esters are formed, the known 9a-fluoro-11p-hydroxy-17a-methyltestost EXAMPLE I erone, which has the disadvantage of containing a 17a 25 A solution of 2, 1 g of 1-methyl-17f8-hydroxy-Al-5a methyl group (effect on the liver); 7a-methyl-17.6- androsten-3-one and 3,5g 2'-methyl-decanoyl chloride hydroxy-A5(0)-pestren-3-one 17{3-cyclo-octylacetate in a mixture of 10 ml pyridine and 15 ml acetone was has a favourable anabolic/androgenic, ratio, and more stirred for 24 hours at 0°C., after which 5 ml pyridine over has oestrogenic properties. Typical oestrogenic and 10 ml water were added. The mixture was stirred compounds are for example 7a-methyl-oestradiol-2'- 30 for a further 2 hours at 0°C, and 2 hours at 45° C., after propylpentanoate (active in Allen-Doisy test at 0,004 which it was poured out into 200 ml of ice water. Ex mg); 11 S-methoxy-oestradiol 17(3-cyclo-octylacetate traction with diethyl ether, neutralization of the extract, (active in Allen-Doisy test at 0,016 mg). 11a-Methoxy removal of the diethyl ether by evaporation and chro oestradiol 17g-esters according to the invention are of matography of the residue on silica gel with toluene interest for their anti-oestrogenic properties. 35 /ethyl acetate (8:2) gave 3,0g 1-methyl-1713-hydroxy The esters of the present invention, may be adminis A-5a-androsten-3-one 179-2'-methyldecanoate, oil tered parenterally or enterally, generally after mixing with ap20 = +37 (in CH2Cl2). ' with excipients and optionally with other active constit Starting from the appropriate steroids and acid chlo uents, in the form of solutions, suspensions, emulsions or rides, the following esters were prepared in a similar solid pharmaceutical formulations such as tablets, pills way: 1a-methyl-17,3-hydroxy-5a-androstan-3-one 1713 or dragees. cyclo-octylacetate, m.p. 147-149 C., ap20 = +20.7 The new steroid esters have been shown to be highly (in CH2Cl2); 176-hydroxy-Alt-androstadien-3-one 17g active on oral administration in the presence of a phar cyclo-octylacetate, 4-chloro-1713-hydroxy-A-andros maceutically acceptable lipoid substance. It is then sur ten-3-one 17,3-3'-cyclohexylbutyrate, 9a-fluoro prisingly found that the novel steroid esters of the a-, 3 45 11f8,1743-dihydroxy-A-androsten-3-one 1743-3'-methyl or y-branched-chain carboxylic acids, as specified decanoate oil with ap20 = +78 (in CH2Cl2), 9a above, are much more active. than the corresponding fluoro-lig, 1743-dihydroxy-A-androsten-3-one 176 known steroid esters of straight-chain carboxylic acids cyclo-octylacetate m.p. 148-149 C., ap20 = --88 (in or of carboxylic acids having less than 8 carbon atoms. CH2Cl2), 6a-methyl-17.6-hydroxy-A-oestren-3-one It proves therefore to be of prime importance for the 50 17(3-2'-butylhexanoate, and 7a-methyl-17.6-hydroxy surprising oral activity of steroid esters on administra tion in or with a lipoid substance that the ester group A5(10)-oestren-3-one . . 176-cyclo-octylacetate, oil has a side-chain or a branching in the a-, 3-ory-posi ap20 = +91.6 (in CH2Cl2). tion, preferably in the a- or 6-position. R EXAMPLE II As the pharmaceutically acceptable lipoid substance, 55 A solution of 4 ml of 2'-methyl-3'-cyclohexylpropio there can be used vegetable and animal oils and fats nyl chloride in 12 ml acetone was added dropwise to a which consist of mono-, di- and triglycerides of various solution of 2 g 116-methoxy-Al35(0)-oestratrien-3,1743 fatty acids or contain these as main constituent; fatty diol in a mixture of 8 ml pyridine and 8 ml acetone, acid esters of alcohols, higher aliphatic alcohols; satu cooled to -10°C. The mixture was stirred for 24 hours rated and unsaturated fatty acids, glycerol ethers, waxes 60 at 0°C. and 6 hours at room temperature. After cooling and mixtures of two or more of the above-named sub to -10° C., a further 1 ml of a solution of 2'-methyl-3'- stances. Examples are: arachis oil, sesame oil, olive oil, cyclohexylpropionyl chloride in 5 ml acetone was ethyl oleate, oleyl oleate, glycerol tri-oleate, glyceryl added and the mixture was stirred for a further 16 hours mono-oleate, cetyl alcohol, stearyl alcohol, capric acid, at room temperature. The reaction mixture was poured undecanoic acid, oleic acid, and polyethylene deriva 65. out into 8 g ice-water and stirred for a while in order to tives of glycerol...... ". . . decompose excess acid chloride. The mixture was ex The active ingredienti.e. the steroid ester is present in tracted with methylene chloride, and the extract, which the usual dosage forms in an amount which is preferably contained the 11g-methoxy-Al3.5(10)-oestratrien-3,1713 4,307,087 7 diol 3, 1713-diester, was evaporated to dryness. The resi due was dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) and the resultant solution was cooled, after which a solution of 350 mg potassium hydroxide in a mixture of 4,8 mil methanol and 2 ml tetrahydrofuran was added. The reaction mixture was stirred for 4 hours, after which it was poured out into ice-water. Extraction with methylene chloride, chromatogra 10 of the 5ah analog thereof, phy on silica gel with toluene/ethyl acetate (95:5) and crystallization from ether gave 1.5 g (3-methoxy A13,5(10)-oestratrien-3,1713-diol 17(3-2'-methyl-3'- of the 5aH analog thereof, cyclohexylpropionate, m.p. 227 C., a D20 = -- 40 (in wherein CH2Cl2). 15 R is H or CH3; Starting from the appropriate steroids and acid chlo R1 is H or CH3; rides, the following esters were prepared in a similar R2 is H or CH3; way: 11a-methoxy-Al3,5(10)-oestratrien-3,17(3-diol 17(3- R3 is selected from the group consisting of H, OH, 4',4'-diethyl-hexanoate, m.p. 126-127 C., CH3, and Cl; ap20 = +56 (in CH2Cl2); 7a-methyl-A1,3,5(10)-oestra 20 R4 is H or C1 to C4 alkyl; trien-3,17g-diol 176-cyclo-nonyl acetate, ap20 = +38 R5 is selected from the group consisting of H, C1 to (in CH2Cl2), 7a-methyl-A1,3,5(10)-oestratrien-3,176-diol C4 alkyl, and CF3; Ré is selected from the group consisting of H, C to 17(3-2'-propylpentanoate, m.p. 131-132 C.; C4 alkyl, C1 to C4alkoxy, halogen, and (3-OH with ap20 = +38.3 (in CH2Cl2); 11 (3-methoxy-A1,3,5(10). 25 the proviso that when Ré is g-OH, the compound oestratrien-3,1713-diol 173-cyclo-octylacetate, m.p. also contains 9a-F; with the further proviso that 205 C., ap20 = + 45° (in CHCl3); 7a-trifluoromethyl R1, R2, R3, R4, R5, and Ré represent at least 4 and A3,5(10)-oestratrien-3,176-diol 1713-2'-butylhexanoate; at most 5 hydrogen atoms; 119-methyl-A1,3,5(10)-oestratrien-3,176-diol 1713-2'- R7 is H or CH3; methyldecanoate; 7a-methyl-11 (3-methoxy-A13,5(10). 30 R8 is oestratrien-3,17a-diol 17a-cyclo-octylacetate, oil with (a) D20= +17° (in CH2Cl2) 11a-methoxy-A1,3,5(10)-oes O tratrien-3,1713-diol 176-cyclo-octylacetate; 1 lo I methoxy-18-methyl-A1,3,5(0)-oestratrien-3,176-diol -OCR9; 17,3-2'-propylpentanoate; 11,6-methoxy-18-methyl 35 Al3,5(10)-oestratrien-3,1713-diol 176-2'-methyldecano R9 is ate, 1-methyl-Al35(10)-oestratrien-3,17(3-diol 176-2'- methyldecanoate, oil with ap20 = -95.5" (in CH2Cl2). By starting from 7a-methyl-oestrone, esterifying this Rio in the 3-position and then reducing the 17-oxo group, 40 -(CH2--Rs 7a-methyl-A3,5(10)-oestratrien-3,176-diol 3-cyclo R octyl acetate was obtained, oil with a D20= +44' (in where CH2Cl2). n=0, 1, or 2; 45 R10 is C1 to C10 alkyl; EXAMPLE III R11 is H or C1 to C10 alkyl; According to standard procedures, soft gelatine cap R12 is an aliphatic group having 1 to 18 carbon atoms, sules with a content composition as indicated below or R10 and R12 taken together with the carbon atom were prepared to which they are attached form a C7 to C12 cyclo 50 aliphatic group with the proviso that the total num ber of carbon atoms in the carboxylic acid residue Content (ml) vehicle amount of active substance is 8 to 20; and 0.30 arachis oil 5 mg A (in suspension) X is selected from the group consisting of -O, OH, 0.24 oleic acid 4 mg B and 0.12 inseed oil 0.05 mg C 55 O. 18 arachis oil 0.1 mg D O A = 1 a-methyl-17 (3-hydroxy-5ah-androstan-3-one -OCR9. 17(3-cyclo-octylacetate B=9a-fluoro-11p3,1713-dihydroxy-A-androsten-3-one 60 2. The compound of claim 1 wherein X is -O and R 17(3-cyclo-octylacetate is CH3. 3. The compound of claim 1 wherein among R, R2, C=7a-methyl-A13,5(10)-oestratrien-3,176-diol R3, R4, R5, and R5 there are represented 5 hydrogen propyl-pentanoate atOS. D = 1 (3-methoxy-A3,5(10)-oestratrien-3,1743-diol 17(3- 65 4. The compound of claim 3 wherein R is methyl. cyclo-octylacetate. 5. The compound of claim 3 wherein R3 is Cl. What is claimed is: 6. The compound of claim 3 wherein R5 is methyl. 1. A compound of the formula 7. The compound of claim 3 wherein R6 is methyl. 4,307,087 9 10 8. The compound of claim 3 wherein R6 is methoxy. with the carbon atom to which they are attached having 9. The compound of claim 3 wherein R6 is 6-OH in 7 to 9 carbon atoms and R1 is H. 14. The compound of claim 1 which is 1a-methyl conjunction with 9a-F. 1713-hydroxy-5a-androstan-3-one 1743-cyclo-octylace 10. The compound of claim 1 or 3 wherein R10 is C1 5 tate. to C4 alkyl. 15. A pharmaceutical composition adapted for oral administration comprising a pharmaceutically effective 11. The compound of claim 1 or 3 wherein R12 has amount of a compound of claim 1 and a pharmaceuti from 4 to 14 carbon atoms. cally acceptable carrier therefor. 12. The compound of claim 11 wherein R12 has from 10 16. The pharmaceutical composition of claim 15 6 to 12 carbon atoms. wherein said carrier is a lipoid substance. 17. The pharmaceutical composition of claim 16 13. The compound of claim 1 or 3 wherein R10 and wherein said lipoid substance is arachis oil. R12 are taken together to form a cycloaliphatic group x k k x 2k 15

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