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.