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United States Patent (19) 11) Patent Number: 4,507,290 Archer Et Al

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United States Patent (19) 11) Patent Number: 4,507,290 Archer Et Al United States Patent (19) 11) Patent Number: 4,507,290 Archer et al. 45) Date of Patent: Mar. 26, 1985 54 ESTERS OF 17 a-ETHYNYL 52 U.S. Cl. ................................. 514/172; 260/397.4; 19-NOR-TESTOSTERONE AND 17 260/.397.5; 514/179 C-ETHYNYL-18 HOMO-19-NOR-TESTOST 58 Field of Search ...................... 260/.397.4; 424/243 ERONE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME 56) References Cited U.S. PATENT DOCUMENTS 75 Inventors: Sydney Archer, Troy, N.Y.; Giuseppe 3,959,322 5/1976 Hughes et al. ... 260/.397.4 Benagiano, Rome, Italy; Pierre 4,027,019 5/1977 Shroff............. ... 260/397.4 Crabbe, Paris, France; Egon 4,089,952 5/1978 Itil et al. .............................. 424/243 Diczfalusy, Stockholm, Sweden; Carl 4, 119,626 10/1978 Schulze et al. ... 260/397.4 Djerassi, Stanford, Calif.; Josef 4,181,721 1/1980 Speck et al. ......................... 424/243 Fried, Chicago, Ill. Primary Examiner-Elbert L. Roberts 73) Assignee: World Health Organization, Geneva, Attorney, Agent, or Firm-Cushman, Darby & Cushman Switzerland 57 ABSTRACT 21 Appl. No.: 251,914 Esters of 17 a-ethynyl 19-nor-testosterone and 17 a ethynyl-18-homo-19-nor-testosterone and the 3-oximes 22 Filed: Apr. 7, 1981 thereof having long-active contraceptive activity. 51) Int. Cl. .............................................. A61K 31/56 21 Claims, No Drawings 4,507,290 1 2 wherein R2 is acyl derived from an alicyclic carbox ESTERS OF 17 o-ETHYNYL ylic acid wherein the alicyclic moiety can have 19-NOR-TESTOSTERONE AND 17 3-6, preferably 3 and 4, carbon atoms in the ring; o-ETHYNYL-18-HOMO-19-NOR-TESTOSTERONE (d) the corresponding oxime of the ester defined in AND PHARMACEUTICAL COMPOSITIONS 5 (c); CONTAINING THE SAME (e) an ester of levo-norgestrel having the formula (II) above, wherein R2 is acyl derived from an aliphatic BACKGROUND AND SUMMARY OF THE carboxylic acid containing 5 carbon atoms, in ex INVENTION tenso pentanoic acid isomers, i.e. Heretofore, active steroid type contraceptive agents O included such material as 17 a-hydroxyprogestrone, norethisterone (norethynyl testosterone, NET) and -C-(CH2)3CH3, -C-CH2-CH(CH3)2, -C-CCH3)3, and levonorgestrel. Subsequently the art developed, as long acting injectable steroid type contraceptives, depo- 15 medroxyprogesterone acetate (Depo-Provera) and -C-CH-CH2-CH3; norethisterone enanthate (NET enanthate), these latter th two agents providing some sustained-release advan tages over the earillier known contraceptive agents. (f) the corresponding oxime of the ester defined in (e); It has now been found that certain other novel steroid 20 (g) an ester of levo-norgestrel having the formula (II) esters exhibit improved sustained release characteristics above, wherein R2 is an acyl derived from an ali when administered to a human, particularly a female, as phatic carboxylic acid containing 3 and 4 carbon an injectable contraceptive or fertility suppressing aoms, i.e., propionic acid and butyric acid isomers; agent.The novel steroid esters of the present invention are 25 (h) R. the and corresponding p 2 oxime of the ester defined in selected from the group consisting of (i) an ester of levo-norgestrel having the formula (II) (a) an ester of D-17 a-ethynyl-19-nortestosterone above, wherein R2 is an acyl chain as defined in (a). having the following formula Representative steroid esters defined in (a) (1) and (i) 30 above are those produced by the esterification of D-17 (I) a-ethynyl-19-nortesterone and levo-norgestrel with a f3-(5-lower alkylene-2 furyl) lower alkanoic acid, pref. erably a propanoic acid derivative, wherein the 5-lower alkylene substituent, i.e. -(CH2)n has 1-6 carbon atoms is and preferably is methyl or ethyl Examples of pre ferred acids include (3-(5-methyl-2-furyl) propionic acid and 6-(5-ethyl-2-furyl) propionic acid. With these pre ferred acids, R in Formula I and Formula II can be wherein R is selected from the group consisting of defined as (1) 40 O O -C-CH2-CH2-----/ \ CH3 or -C-(CH2)l / \ R1, O 45 O / \ wherein R1 is lower alkyl, preferably methyl or -C-CH2-CH2 CH2-CH3. ethyl and n is 1-6, and (2) acyl derived from an alicyclic carboxylic acid 50 O wherein the alicyclic moiety can have 3-8 car Representative steroid esters defined in (a)(2) above bon atoms in the ring, the ring being substituted are those produced by the esterification of D-17 a-ethy by alkyl having 1-8 carbon atoms and preferably nyl-19-nortesterone and an alicyclic carboxylic acid by methyl or ethyl; wherein the alicyclic moiety has 3-8 carbon atoms in (b) the corresponding oxime of the ester defined in 55 the ring. The ring is also substituted by alkyl having 1-8 (c)(a); an ester of levo-norgestrel, i.e., d(+) norgestrel carboncis or trans atoms, configuration, this alkyl substituent the trans configuration being either inbeing the having the formula preferred. In these alicyclic carboxylic acids, the ring is preferably cyclohexyl, although certainly it can also be, OR2 (II) for instance cyclopentyl or cycloheptyl. Thus, in For mula I, above, R can be defined as 65 -C-Cyc-alkyl, wherein Cyc is a cycloalkyl ring having 3-8 carbon atoms and the alkyl substituent, in the cis or trans con 4,507,290 3 4. figuration, has 1-8 carbon atoms. Preferably, then, R presence of benzene sulphonyl chloride, as the coupling can be defined as agent. Generally, an equimolar ratio of carboxylic acid:ben zene sulphonyl chloride is employed. The organic acid, O alkyl dissolved in pyridine, is reacted with a molar equivalent ac of benzene sulphonyl chloride and the resulting mixture is left to stand at ambient temperature for a period of time sufficient to provide the corresponding anhydride. Thereafter the D-17 a-ethynyl-19-nortesterone, dis or more preferably as 10 solved in pyridine, is added and the reaction is moni tored by thin layer chromatography. O alkyl At the completion of the reaction, the reaction mix I Y ture is poured onto ice and extracted with chloroform. mC The chloroform layer is washed several times with 15 dilute HCl, water, aqueous sodium carbonate and fi nally with water. wherein - alkyl and - - - alkyl represent, respectively, The resulting organic layer is dried using anhydrous the cis and trans configuration of the alkyl substituent. sodium sulfate, filtered and thereafter the solvent is When the more preferred acids, i.e. trans-4-methyl evaporated. The resulting residue can then be subjected cyclohexane carboxylic acid and trans-4-ethyl 20 to IR, UV and NMR analysis and either recrystallized cyclohexane carboxylic acids are employed, R in For or separated by TLC to yield pure compounds. mula I can be defined as Alternatively, the novel steroid esters of this inven tion can also be prepared by esterifying levo-norgestrel with the organic carboxylic acid in the presence of 25 trifluoroacetic acid anhydride in anhydrous benzene -C -CH3 and -C --CH2-CH3, solution. Several other methods are available for the prepara tion of the steroid esters of the present invention. These respectively. 30 other methods often require the protection of the 3-keto Representative steroid esters defined in (c) above are function (see J. Chem. Soc. 1963,3578, Evans et al), the those produced by the esterification of levo-norgestrel activation of the 17-hydroxy group via a lithium salt and an alicyclic carboxylic acid wherein the alicyclic (see J. Org. Chem., 1970, 35, 1198, Kaiser et al) or a moiety has 3-6, and preferably 3 and 4, carbon atoms. thallium salt (see Synth. Comm. 1977, 7,383, Herz et al) 35 and conversion of the carboxylic acid into the more Thus in Formula II, above, R2 can be defined as reactive chloride (see J.A.C.S. 1957, 79, 4472, Gould et al, Herz et al supra or Kaiser et al supra), or anhydride O I (see Canad. J. Chem., 1968, 46, 351, Crabbé et al). -C-Cyc Specifically, using a thallous salt, the following esteri fication procedure can be employed. wherein Cyc is a cycloalkyl ring having 3-6 carbon To a solution of 8.95 g (0.03 mol) of D-17a-ethynyl 19-nortesterone in 100 ml of dry benzene, there are atoms. Preferably then, R2 can be defined as added, with stirring, 2.3 ml (0.033 mol) of thallous ethoxide. Although the benzene distills off slowly, the 45 volume of the reaction mixture is maintained at about 100 ml by the dropwise addition of dry benzene thereto. -----> After 200 ml of benzene have been distilled off, the reaction mixture is cooled in an ice-water bath and the when cyclopropane and cyclobutane carboxylic acid carboxylic acid, in acyl halide form (0.036 mol), is are employed in the esterification reaction. 50 added dropwise thereto. The resulting mixture is re Representative steroid esters defined in (e) above are fluxed for 5 hours and thereafter cooled and filtered those produced by the esterification of levo-norgestrel through a bed of kieselguhr. The resulting precipitate is and an aliphatic carboxylic acid wherein the aliphatic washed with 20 ml of benzene, five times and the sol moiety has four and five carbon atoms. Thus in formula vent then evaporated. The resulting residue is then (II) above, R2 can be defined as 55 purified by column chromatography (silica gel) using a 20:80 mixture of chloroform and petroleum ether as the O O eluant. Alternatively, the residue can be purified by I HPLC (silica gel) using a 1:1 mixture of chloroform and -C-C3 and -C-C4 aliphatic, wherein C4 aliphatic is n-hexane as the eluant and collecting the main first 60 peak.
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