NZ524485A

NZ524485A - 4-halogenated 17-methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds

Info

Publication number: NZ524485A
Application number: NZ524485A
Authority: NZ
Inventors: Bernd Menzenbach; Walter Elger; Peter Droescher; Alexander Hillisch; Gunter Kaufmann; Hans-Udo Schweikert; Gerd Muller
Original assignee: Schering Ag
Priority date: 2000-09-04
Filing date: 2001-08-29
Publication date: 2005-11-25
Also published as: CA2421302C; IL154666A0; CA2421302A1; CN1452628A; WO2002019971A1; ATE319733T1; MEP14408A; HRP20030256A2; EE200300087A; HUP0300936A3; EP1423407B1; SK2442003A3; UA74592C2; PL360669A1; EE05186B1; RS50305B; PT1423407E; AU1047002A; EA006387B1; BG107594A

Abstract

Disclosed are compounds 17-Methylene steroid of formula I in which R4 is a halogen atom or a pseudohalogen, R10 is a hydrogen atom or a straight-chain or branched C1-C4 alkyl group, R20 and R20a are, independently of one another, a straight-chain or branched C1-C4 alkyl or hydroxy- C1-C4 alkyl group, or one of radicals R20 and R20a is a hydrogen atom, a straight-chain or branched C1-C4 alkyl or hydroxy- C1-C4 alkyl group, and the other radical is a halogen atom or a pseudohalogen. The compounds have an active profile with a hybrid character of such that they act as inhibitors of the 5 alpha -reductase and, at the same time, as gestagens. Said compounds are thus suited for treating medical disorders that, in men and women, are a result of an increased androgen level in certain organs and tissues. The inventive compounds combined with other hormonal substances such as estrogen, testosterone or a potent androgen are suited as contraceptives for women and men.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 524485 5244 WO 02/019971 PCT/EP01/09943 4-HALOGENATED 17-METHYLENE STEROIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS 5 The invention relates to 17-methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds. The compounds of the invention have a profile of 10 actions which are hybrid in character in such a way that they act as inhibitors of 5a-reductase and simultaneously as progestins. They are therefore suitable for the treatment of disorders resulting from elevated androgen levels in particular organs and 15 tissues in men and women. In conjunction with other hormonal substances such as an estrogen, testosterone or a strong androgen, the compounds of the invention are suitable as contraceptives for women and for men. 2 0 In women, elevated levels of 5a-dihydroprogesterone may contribute to severe disturbances of wellbeing associated with the premenstrual syndrome. These disturbances can likewise be influenced beneficially through inhibition of 5a-reductase. The simultaneous 25 presence of a progestational effect leads to inhibition of male and female gonadal function. This effect is desired if the treatment is intended to achieve an antifertility effect or else an inhibition of hormone secretion by the gonads. Since inhibition of 30 5a-reductase in women pregnant with a male fetus may irreversibly impair the sexual development of the fetus, an abolition of fertility associated with an antiandrogenic therapy is very desirable. Possible indications are prostate disorders, male-type alopecia, 35 acne and hirsutism. The symptoms of premenstrual syndrome can be alleviated in women predisposed thereto. - 2 - It is therefore an object of the present invention to provide compounds which act as inhibitors of 5cc-reductase and simultaneously as progestins. 5 This object is achieved by 17-methylene steroids of the general formula I 10 in which R4 is a hydrogen atom, a halogen atom or a pseudo-halogen, R10 is a hydrogen atom or a straight-chain or branched Ci-4-alkyl group, 15 R20 and R20a are, independently of one another, a hydrogen atom, a a straight-chain or branched Ci-4-alkyl or hydroxy-Ci-4-alkyl group or one of the radicals R20 and R20a is a hydrogen atom, a a straight-chain or branched Ci-4-alkyl or hydroxy-20 Ci-4-alkyl group, and the other radical is a halogen atom or a pseudohalogen. R4 may, besides a hydrogen atom, be a halogen atom such as a fluorine, chlorine, bromine or iodine atom, or a 25 pseudohalogen such as a cyanate, thiocyanate, cyan or azide group, with a bromine atom or a cyano group being preferred, and a chlorine atom being particularly preferred. 30 R10 may be a hydrogen atom or a a straight-chain or branched Ci-4-alkyl group, with examples of straight-chain or branched Ci_4-alkyl groups being methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. R10 - 3 - is preferably a hydrogen atom or a methyl group. R20 and R20a may on the one hand be, independently of one another, a hydrogen atom, a straight-chain or branched 5 Ci-4-alkyl or hydroxy-Ci-4-alkyl group. In this case, R20 and R20a are preferably, independently of one another, a hydrogen atom, a methyl group or a -CH2OH group. A further possibility is for one of the radicals R20 and 10 R20a to be a hydrogen atom, a straight-chain or branched Ci_4-alkyl or hydroxy-Ci-4-alkyl group, and for the other radical to be a halogen atom such as a fluorine, chlorine, bromine or iodine atom, or a pseudohalogen such as a cyanate, thiocyanate, cyan or azide group. 15 Examples of straight-chain or branched Ci_4-alkyl groups are the groups mentioned for R10. Straight-chain and branched hydroxy-Ci-4-alkyl groups are derived from the aforementioned straight-chain or branched Ci-4-alkyl groups, with one or more hydrogen atoms being replaced 20 by hydroxy1 groups. In this case, one of the radicals R20 and R20a is preferably a hydrogen atom or a methyl group and the other radical is a halogen atom, preferably a fluorine 25 atom, particularly preferably a chlorine or bromine atom, or a pseudohalogen, preferably an azide or thiocyanato group, particularly preferably a cyano group. 30 In the case of R20 and R20a, examples of straight-chain and branched Ci-4-alkyl groups are the groups mentioned for R10. Straight-chain and branched hydroxy-Ci-4-alkyl groups are derived from these Ci-4-alkyl groups, with one or more hydrogen atoms being replaced by hydroxyl 35 groups, such as, in particular, from a group -(CH2)n-0H with n = 1 to 4. The most preferred compounds are the following: Intellectual Propdrtv Office of N.2. 29 SEP 2005 4" receive[ 1) E-17-chloromethylene-4-chloroestr-4-en-3-one, " ~ 2) E-17-cyanomethylene-4-chloroestr-4-en-3-one, 3) Z-17-cyanomethylene-4-chloroestr-4-en-3-one, 4) Z-20-cyano-4-chloro-19-norpregna-4,17(20)-5 dien-3-one, 5) Z-4-chloro-19-norpregna-4,17(20)-dien-3-one, 6) E-4-chloro-19-norpregna-4,17(20)-dien-3-one, 7) E-17-bromomethylene-4-chloroestr-4-en-3-one, 8) Z-20-chloro-19-norpregna-4,17(20)-dien-3-one, 10 9) Z-4,20-dichloro-19-norpregna-4,17(20)-dien- 3-one, 10) . Z-20-bromo-4-chloro-19-norpregna-4,17(20)- dien-3-one, 11) E-17-chloromethylene-4-cyanoandrost-4-en-15 3-one, 12) E-17-chloromethylene-4-chloroandrost-4-en-3-one, 13) E-21-hydroxy-4-chloro-19-norpregna-4,17(20)-di en-3-one, and 20 14) Z-21-hydroxy-4-chloro-19-norpregna-4,17(20)- dien-3-one. The present invention further relates to pharmaceutical compositions which comprise as active ingredients at 25 least one 17-methylene steroid of the general formula I, these compositions optionally containing suitable excipients and carriers, and to the use of these compounds for producing medicaments, in particular for the following indications. 30 The amount to be administered of a compound of the general formula I varies within a wide range and may cover every effective amount. Depending on the condition to be treated and the mode of administration, 35 the amount of the compound administered can be 0.01 jzg/kg-10 mg/kg of body weight, preferably 0.04 ng/kg-1 mg/kg of body weight, per day. In humans, this corresponds to a dose of 0.8 fig to 800 mg, preferably 3.2 /xg to 80 mg, a day. - 5 Intellectual Property Office of N.Z. 29 SEP 2005 received A dose unit comprises according to the invention from 5 1.6 ng to 200 mg of one or more compounds of the general formula I. The compounds of the invention are suitable for producing pharmaceutical compositions and preparations. 10 The pharmaceutical compositions or medicaments comprise as active ingredient one or more of the compounds of the invention, where appropriate mixed with other pharmacologically or pharmaceutically active substances . The medicaments are produced in a known 15 manner, it being possible to use the known and customary pharmaceutical excipients and other customary carriers and diluents. Suitable carriers and diluents of these types are, for 20 example, those recommended or indicated in the following references as excipients for pharmacy, cosmetics and adjacent areas: Ullmans Encyklopadie der technischen Chemie, volume 4 (1953), page 1 to 39; Journal of Pharmaceutical Sciences, volume 52 (1963), 25 page 918 et seq. H. v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind., No. 2, 1961, page 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG. Aulendorf in Wtirttemberg 1971. 30 The compounds can be administered orally or parenter-ally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted into tissue. 35 Suitable for oral administration are capsules, pills, tablets, coated tablets etc. The dosage units may, besides the active ingredient, comprise a pharmaceutically acceptable carrier such as, for example, starch, sugar, sorbitol, gelatin, lubricant, - 6 - silica, talc etc. For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically tolerated diluent. The diluents very often used are 5 oils with or without the addition of a solubilizer, of a surface-active agent, of a suspending or emulsifying agent. Examples of oils which are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. 10 The compounds can also be used in the form of a depot injection or of an implant product, each of which may be formulated so that delayed release of active ingredient is made possible. Implants may comprise as inert materials for example 15 biodegradable polymers, or synthetic silicones such as, for example, silicone rubber. The active ingredients may additionally be incorporated for percutaneous administration for example in a plaster. 2 0 Suitable for producing intravaginal (e.g. vaginal rings) or intrauterine devices (e.g. pessaries, coils, IUDs, Mirena®) loaded with active compounds of the general formula I for local administration are various polymers such as, for example, silicone polymers, 25 ethylene/vinyl acetate, polyethylene or polypropylene. In order to improve the bioavailability of the active ingredient, the compounds can also be formulated as cyclodextrinclathrates. For this purpose, the compounds 30 are reacted with a-, |3- or y-cyclodextrin or derivatives thereof (PCT/EP95/02656). It is possible according to the invention for the compounds of the general formula I also to be 35 encapsulated with liposomes. The compounds can be employed, both after oral and parenteral administration, for the following indications . _ 7 - Intellectual ^ropttty Office of N.Z. 29 SEP 2005 received The compounds of the invention have a profile of actions which are hybrid in character. They are inhibitors of 5a-reductase and additionally act as progestins. They are therefore suitable for the 5 treatment of disorders which result from elevated androgen levels in particular organs and tissues in men and women. ^ In women, elevated levels of 5a-dihydroprogesterone may contribute to severe disturbances of wellbeing 10 associated with the premenstrual syndrome. This can be beneficially influenced through inhibition of 5a-reductase. The simultaneous presence of a progestational effect with the compounds of the invention leads to an 15 inhibition of gonadal function in the male and female sex. This effect is desired if the treatment is intended to achieve an antifertility effect or else an inhibition of hormone secretion by the gonads. This is frequently the case in disorders of the prostate 20 (benign prostate hyperplasia). Possible indications besides prostate disorders are contraception in both sexes, male-type alopecia, acne and hirsutism. In conjunction with other hormonal substances such as an estrogen, testosterone or a strong androgen, the 25 compounds of the invention are suitable as contraceptives for women and for men. In the latter case, the effect of testosterone in the prostate is diminished through inhibition of 5a-reductase, while the progestational activity enhances the effect in the male 30 gonads, that is to say the inhibition of spermatogenesis . If the compounds of the invention are employed for female contraception, they can be used alone or in 35 conjunction with an estrogen. Suitable estrogens are in principle all compounds with estrogenic activity: estrogens which can be used are, for example, ethynylestradiol, 17fi-estradiol and its esters such as estradiol 3-benzoate, estradiol 17-valerate, lnt«!!ecJuan^eptity Office of N.z. 29 SEP 2005 - 8 - received -cypionate, -undecylate, -enanthate and/or other estradiol esters (US-A-2,611,773, US-A-2,990,414, US-A-2,054,271, US-A-2,225,419 and US-A-2,156,599) and conjugated estrogens. Estradiol 3-sulfamates, ethynyl-5 estradiol 3-sulfamates and estrone 3-sulfamates, for example estrone N,N-dimethylsulfamate, estrone N,N-di-ethylsulfamate, ethynylestradiol 3-N,N-dimethyl-sulfamate, ethynylestradiol 3-N,N-diethylsulfamate, ethynylestradiol 3-N,N-tetramethylenesulfamate, estrone 10 sulfamate, estradiol 3-sulfamate, estradiol 3-N,N-dimethylsulfamate, estradiol 3-N,N-diethylsulfamate, ethynylestradiol 3-sulfamate, all of which are prodrugs of the corresponding 3-hydroxy compounds (W. Elger et al., in J. Steroid Biochem. Molec. Biol., vol. 55, 15 No. 3/4, 395-403, 1995; DE 44 29 398 Al (available on request) and DE 44 29 397 Al (available on request) ) , can likewise be used according to the invention. If the compounds of the invention are employed for male 20 contraception, they can be used alone or in conjunction with testosterone or a strong androgen. Tables 1 and 2 below list data of 5a-reductase type 2 activity in genital skin homogenates and in vivo data on the progestational activity. Table Is 5a-Reductase .type 2 activity in genital skin homogenates under optimized conditions at pH 5.5 (IC50 (nM) ) Progesterone receptor binding on uterus cytosol, rabbits, primed Tracer: 3H-0RG 2058/incubation conditions 0-4°C; 18 h Reference substance: progesterone = 100% Compound (1) IC50(nM) PR Proges terone=10 0 % 250 60 10 Table 2s In vivo data on the progestational activity Mouse pregnancy maintenance test after s.c. administration Compound Dosage Mg/animal/day s.c. Proportion of maintained pregnancies (1) 1.0 0.1 5/5 0/5 15 The data listed in table 1 and 2 demonstrate the profile of actions which are hybrid in character of the compounds of the invention, which act as inh^bitjjrp. of 5oc-reductase and as progestins. pro 01 Intellectual Property Office of N.Z. 29 SEP 2005 RECEIVED 10 - intellectual Property Office of N.z. 29 SEP 2005 RECEIVED The compounds of the invention are moreover intermediates for synthesizing other pharmacologically highly active steroid products. The 17-methylene steroids of the invention, of the general formula I, can be obtained from compounds of the general formula II and of the general formula V. They are obtained by reacting a compound of the general formula II in an aprotic solvent, preferably in 15 pyridine or triethylamine, with an acid chloride, preferably thionyl chloride or phosphorus oxychloride, to give a compound of the general formula III 20 subjecting the latter in a manner known per se to an epoxidation with H202/Na0H in an alcohol, preferably methanol or ethanol, opening the resulting 4,5-epoxide with nucleophiles such as halide (for example 25 hydrogen halide) or pseudohalid®, in a dipolar aprotic solvent, preferably DMSO or DMPU, dioxane or acetone, to give halo- or pseudohalohydrins, and then dehydrating the latter with catalytic promotion by mineral acid, carboxylic acid or - 11 - 'ntoltectual Property Office of N.Z. 29 SEP 2005 recel vet sulfonic acid, such as hydrochloric acid, oxalic acid or p-toluenesulfonic acid, in a protic or aprotic solvent such as methanol or acetone, to give a compound of the general formula IV in which R4 is a halogen atom or pseudohalogen, where >io has the meaning given above, and R20 is a Ci_4~alkyl 10 or hydroxy-Ci_4-alkyl pseudohalogen. group, a halogen atom or a Also obtained are 17-methylene steroids of the general formula I, by reacting a compound of the general 15 formula V in an aprotic solvent, preferably in pyridine or triethylamine, with an acid chloride, preferably thionyl chloride or phosphorus oxychloride, to give a compound of the general formula VI 20 subjecting the latter in a manner known per se to an epoxidation with H2C>2/NaOH in an alcohol, preferably methanol or ethanol, opening the resulting 4,5-epoxide 25 with a nucleophile such as a halide (for example hydrogen halide) or psaudohalide, in a dipolar aprotic solvent, preferably DMSO or DMPU, - 12 - dioxane or acetone, to give a halo- or pseudo-halohydrin, and then dehydrating the latter with catalytic promotion by mineral acid, carboxylic acid or sulfonic acid, such as hydrochloric acid, oxalic acid 5 or p-toluenesulfonic acid, in a protic or aprotic solvent, methanol or acetone, to give a compound of the general formula VII. 10 Finally, further 17-methylene steroids of the general formula I can be obtained by reacting compounds of the general formulae III and VI 15 in a manner known per se (M. Haase-Heid, M. Mattis & J. Mann, J. Chem. Soc. Perkin Trans. 1, 2999, 1992) with NaI04/KMnC>4 in alcohols, preferably in t-BuOH, to 20 give the 3,5-seco keto acids, converting the latter with AC2O/ACCI into the unsaturated lactones, and reacting the latter with n-BuLi/CHsCN in a dipolar aprotic solvent such as THF to give the compounds of the general formulae VIII and IX. Intellectual Property— Office of N.z. 29 SEP 2005 rece i v e d - 13 O CN CN 10 15 Compounds of the formulae III and IV can also be obtained by WITTIG, HORNER, PETERSON carbonyl-olefination. The invention is explained in detail by the following examples. Example 1 Z-4,20-Dichloro-19-norpregna-4,17(20)-dien-3-one A) Z-20-Chloro-19-norpregna-4,17(20-dien-3-one 9.74 rnmol (3.28 g) of (20) R-chloro-19-norpregn-4-en-3-on-17-ol are dissolved in 34 ml of pyridine. While cooling slightly and stirring, 12.66 mmol (0.92 ml) of thionyl chloride are added dropwise. The reaction solution is stirred under protective gas (argon) for about 1 hour and then poured into water which has been adjusted to pH = 3-4 with hydrochloric acid and is cooled in ice. The gummy precipitated product is extracted with methylene chloride, and the combined extracts which have been washed to neutrality are dried with sodium sulfate and concentrated. The resulting solid product is purified by flash chromatograpy on silica gel (eluent: toluene/ethyl acetate = 95/5) and, where appropriate, recrystallization from methanol. 0.6 g of a solid product is obtained. M.p. = 138-141°C; [a]D20 = +104° (CHC13) Intellectual Property Office of N.Z 2 9 SEP 2005 - 14 - B) Z-20-Chloro-4^, 5E,-epoxy-19-norpregn-17 (20) -en-3-one 2.80 mmol (894 mg) of Z-20-chloro-19-norpregna-4,17 (20) -dien-3-one are dissolved in a mixture of 9 ml of methanol and 7.3 ml of methylene chloride and cooled 5 to 0°C. To the cooled solution are successively added dropwise, while stirring and under protective gas (argon), 6.31 mmol (0.63 ml) of hydrogen peroxide (30%) and 1.26 mmol (0.3 mmol) of sodium hydroxide solution (c = 4 mol/1). After the dropwise addition is complete, 10 the temperature is slowly raised to room temperature. After a reaction time of about 1.5 hours, the mixture is poured into ice-water and then extracted with methylene chloride. The combined extracts are dried with sodium sulfate and concentrated. 926 mg of a pale 15 yellow solid are obtained. C) Z-4,20-Dichloro-19-norpregna-4,17(20)-dien-3-one 2.71 mmol (896 mg) of Z-20-chloro-4£, 5^-epoxy-19-norpregn-17(20)-en-3-one are dissolved in 25 ml of 20 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), and 26.54 mmol (2.2 ml) of hydrochloric acid (37%) are slowly added dropwise. After stirring under protective gas (argon) for 1 hour, the reaction solution is poured into ice-cold aqueous sodium bicarbonate solution, and 25 the precipitate is filtered off with suction and finally dried in a desiccator with potassium hydroxide. Flash chromatography on silica gel (eluent: toluene/ethyl acetate = 99/1) and subsequent recrystallization from methanol/acetone result in 30 353 mg of solid product. M.p. = 182-185°C; [a]D20 = +137° (CHC13) Example 2 Z-20-Bromo-4-chloro-19-norpregna-4,17(20)-dien-3-one 35 A) Z-20-Bromo-19-norpregna-4,17(20)-dien-3-one 9.7 mmol (3.7 g) of (20)R-bromo-19-norpregn-4-en-3-on-17-ol are dissolved in 39 ml of pyridine. While cooling slightly and stirring, 12.61 mmol (0.91 ml) of thionyl - 15 - chloride are added dropwise. The reaction solution is stirred under protective gas (argon) for about 1 hour and then poured into water which has been adjusted to pH = 3-4 with hydrochloric acid and is cooled in ice. 5 The gummy precipitated product is extracted with methylene chloride, and the combined extracts which have been washed to neutrality are dried with sodium sulfate and concentrated. The resulting yellow foam is purified by flash chromatograpy on silica gel (eluent: 10 n-hexane/ethyl acetate = 95/5) and, where appropriate, recrystallization from methanol/acetone. 536 mg of a pale yellow solid are obtained. M.p. = 153-158°C; [a]D20 = +109° (CHC13) 15 B) Z-20-Bromo-4£, 5£-epoxy-19-norpregn-17 (20) -en-3-one 2.09 mmol (760 mg) of Z-20-bromo~19-norpregna-4,17(20)-dien-3-one are dissolved in a mixture of 7.8 ml of methanol and 6.3 ml of methylene chloride and cooled to 0°C. To the cooled solution are successively added 20 dropwise, while stirring and under protective gas (argon), 4.7 mmol (0.48 ml) of hydrogen peroxide (30%) and 0.94 mmol (0.24 mmol) of sodium hydroxide solution (c = 4 mol/1). After the dropwise addition is complete, the temperature is slowly raised to room temperature. 25 After a reaction time of about 1 hour, 50 ml of water are added to the mixture. A two-phase system is produced and is extracted with methylene chloride. The combined extracts which have been washed to neutrality are dried with sodium sulfate and concentrated. The 30 resulting yellow solid product is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 95/5) . 680 mg of a white solid product are obtained. 35 C) Z-20-Bromo-4-chloro-19-norpregna-4,17(20)-dien-3-one 2.57 mmol (975 mg) of Z-20-bromo-4£, 5^-epoxy-19-norpregn-17(20)en-3-one are dissolved in 25 ml of DMPU, and 25.2 mmol (2.09 ml) of hydrochloric acid (37%) are slowly added dropwise. After stirring under protective - 16 - gas (argon) for 1 hour, the reaction solution is poured into ice-cold aqueous sodium bicarbonate solution, and the precipitate is filtered off with suction and finally dried in a desiccator with potassium hydroxide. 5 Flash chromatography on silica gel (eluent toluene) and subsequent recrystallization from methanol/acetone result in 600 mg of white crystals. M.p. = 164-173 °C; [a]D20 = +138° (CHC13) 10 Example 3 E-17-Chloromethylene-4-chloroestr-4-en-3-one A) E-17-Chloromethyleneestr-4-en-3-one 18.27 mmol (5.9 g) of 17a-chloromethyl-17-hydroxyestr-15 4-en-3-one are dissolved in 60 ml of pyridine. While cooling slightly and stirring, 21.9 mmol (1.56 ml) of thionyl chloride are added dropwise. The reaction solution is stirred under protective gas (argon) for about 1 hour and then poured into water which has been 20 adjusted to pH = 3-4 with hydrochloric acid and is cooled in ice. The gummy precipitated product is extracted with methylene chloride, and the combined extracts which have been washed to neutrality are dried over sodium sulfate and concentrated. The resulting 25 solid product is purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 85/15). Recrystallization from acetone results in 1.6 g of product. M.p. = 143-146°C; [a]D20 = +20° (CHCI3) 30 B) E-17-Chloromethylene-4i;, 5i;-epoxyestran-3-one 3.93 mmol (1.2 g) of E-17-chloromethyleneestr-4-en-3-one are dissolved in a mixture of 12 ml of methanol and 10 ml of methylene chloride under protective gas 35 (argon) and cooled to 0°C. To the cooled solution are successively added dropwise while stirring 9.2 mmol (0.94 ml) of hydrogen peroxide (30%) and 1.65 mmol (0.4 ml) of sodium hydroxide solution (c = 4 mol/1) . After the dropwise addition is complete, the - 17 - temperature is slowly raised to room temperature. After a reaction time of about 1.5 hours, the mixture is poured into ice-water and extracted with methylene chloride. The combined extracts are dried over sodium 5 sulfate and concentrated. 1.1 g of a white gummy foam are obtained. C) E-17-Chloromethylene-4-chloroestr-4-en-3-one 3.42 mmol (1.1 g) of E-17-chloromethylene-4^, 5^-10 epoxyestran-3-one are dissolved in 26 ml of DMPU, and 33 mmol (2.74 ml) of hydrochloric acid (37%) are slowly added dropwise. After 1 hour, the reaction solution is poured into ice-cold aqueous sodium bicarbonate solution, and the precipitate is filtered off with 15 suction and dried in a desiccator over potassium hydroxide. Recrystallization from acetone results in 760 mg of white crystals. M.p. = 182-194°C; [a]D20 = +63° (CHC13) 20 Example 4 E-17-Bromomethylene-4-chloroestr-4-en-3-one A) E-17-Bromomethyleneestr-4-en-3-one 28.58 mmol (10.5 g) of 17a-bromomethyl-17-hydroxyestr-25 4-en-3-one are dissolved in 90 ml of pyridine. While cooling slightly and stirring, 37.16 mmol (2.7 ml) of thionyl chloride are added dropwise. The reaction solution is stirred under protective gas (argon) for about 1 hour and then poured into water which has been 30 adjusted to pH = 3-4 with hydrochloric acid and is cooled in ice. The yellow precipitated product is filtered off with suction and purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate = 85/15). 4.85 g of pale yellow-colored solids 35 are obtained. Recrystallization from acetone results in 3.1 g of white crystals. M.p. = 153-164°C; [a]D20 = +15° (CHC13) </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 18 - B) E-17-Bromomethylene-4£, 5^-epoxyestran-3-one 2.86 mmol (1 g) of E-17-bromomethyleneestr-4-en-3-one are dissolved in a mixture of 10.5 ml of methanol and 8.5 ml of methylene chloride under protective gas 5 (argon) and cooled to 0°C. To the cooled solution are successively added dropwise while stirring 6.44 mmol (0.66 ml) of hydrogen peroxide (30%) and 1.26 mmol (0.32 ml) of sodium hydroxide solution (c = 4 mol/1) . After the dropwise addition is complete, the 10 temperature is raised slowly to room temperature. After a reaction time of about 1.5 hours, the mixture is poured into ice-water. A two-phase system results and is extracted with methylene chloride. The combined extracts which have been washed to neutrality are dried 15 with sodium sulfate and concentrated. 891 mg of a white gummy foam are obtained. C. E-17-Bromomethylene-4-chloroestr-4-en-3-one 2.38 mmol (about 870 mg) of E-17-bromomethylene-44,5^-20 epoxyestran-3-one are dissolved in 23 ml of DMPU under protective gas (argon), and 23.33 mmol (1.93 ml) of hydrochloric acid (37%) are slowly added dropwise. After 1 hour, the reaction solution is poured into ice-cold aqueous sodium bicarbonate solution, and the 25 precipitate is filtered off with suction and dried in a desiccator with potassium hydroxide. Flash chromatography on silica gel (eluent: toluene/ethyl acetate = 98/2) and subsequent recrystallization from acetone result in 552 mg of white crystals. 30 M.p. = 169-176°C; [a]D20; +45° (CHC13) WO 02/019971 PCT/I - 19 - Intellectual Property Office of N.Z. 2 9 SEP 2005 i v e c Claims

1. 17-Methylene steroids of the general formula I

in which

R4 is a halogen atom or a pseudohalogen,

R10 is a hydrogen atom or a straight-chain or

10 branched Ci-4-alkyl group,

R20 and R20a are, independently of one another, a hydrogen atom, a straight-chain or branched Ci_4-

alkyl or hydroxy-Ci-4-alkyl group or one of the radicals R20 and R20a is a hydrogen atom,

15 a straight-chain or branched C1_4-alkyl or hydroxy-

Ci-4-alkyl group, and the other radical is a halogen atom or a pseudohalogen; with the proviso that the compound of general formula I is not 4-chloro-17-methylene-4-androsten-3-one.

2. 17-Methylene steroids as claimed in claim 1,

20 characterized in that R4 is a chlorine or bromine atom or a cyano group.

3. 17-Methylene steroids as claimed in claim 1 or 2, characterized in that one of the radicals R20 and

25 R20a is a hydrogen atom or a methyl group, and the other radical is a fluorine, chlorine or bromine atom, an azido or cyano group or hydroxymethyl.

30 4. 17-Methylene steroids as claimed in claim 1/2 or 3, characterized in that R10 is a hydrogen atom or a methyl group.

- 20 -

17-Methylene steroids as claimed in claim 1,

namely

15) E-17-chloromethylene-4-chloroestr-4-en-3-one,

16) E-17-cyanomethylene-4-chloroestr-4-en-3-one,

17) Z-17-cyanomethylene-4-chloroestr-4-en-3-one,

18) 2,-11- (1')-cyanoethylidene-4-chloroestr-4-en-3-one,

19) Z-17-ethylidene-4-chloroestr-4-en-3-one,

20) E-17-ethylidene-4-chloroestr-4-en-3-one,

21) E-17-bromomethylene-4-chloroestr-4-en-3-one,

22) Z-17-chloroethylidene-4-chloroestr-4-en-3-one,

23) Z-17-bromoethy1idene-4-chloroes tr-4-en-3-one,

24) E-17-chloromethylene-4-cyanoandrost-4-en-3-one,

25) E-17-chloromethylene-4-chloroandrost-4-en-3-one,

26) E-17-(2')-hydroxyethylidene-4-chloroestr-4-en-3-one and

27) Z-17-(2')-hydroxyethylidene-4-chloroestr-4-en-3-one.

A process for preparing 17-methylene steroids of the general formula I

,20*;Intellectual Property Office of N.Z.;29 SEP 2005;RECEIVED;- 21 -;in which;R4 is a halogen atom or a pseudohalogen,;R10 is a hydrogen atom or a straight-chain or branched;Ci-4-alkyl group,;R20 is a hydrogen atom, a straight-chain or branched Ci-4-alkyl or hydroxy-Ci-4-alkyl group, or a halogen atom or a pseudohalogen, and R20a is a hydrogen atom,;characterized in that a compound of the general formula II;is reacted in an aprotic solvent with an acid chloride to give a 17-methylene steroid of the general formula III,;Intellectual Property Office of N.Z.;29 SEP 2005;RECEIVED;- 22 -;10;the 4,5-epoxide is generated with H2C>2/NaOH, the latter is then opened with a nucleophilic reagent which is derived from a halogen atom or pseudohalogen, in a dipolar aprotic solvent, to give a halo- or pseudohalohydrin and, where appropriate, reacted with mineral acid, carboxylic acid or sulfonic acid in a protic or aprotic solvent with dehydration to give a compound of the general formula IV, in which;15;20;R4 is a halogen atom or pseudohalogen, where R;10;has the meaning given above, and R20 is a Ci-4-alkyl or hydroxy-Ci-4-alkyl group, a halogen atom or a pseudohalogen.;Intellectual Property Office of N.Z.;29 SEP 2005;RECEIVED;- 23 -;A process for preparing 17-methylene steroids of the general formula I;in which;R4 is a halogen atom or a pseudohalogen,;R10 is a hydrogen atom or a straight-chain or branched;Ci-4-alkyl group,;R20 and R20a are, independently of one another, a hydrogen atom, a straight-chain or branched Ci_4-alkyl or hydroxy-Ci-4-alkyl group or one of the radicals R20 and R20a is a hydrogen atom, a straight-chain or branched Ci-4-alkyl or hydroxy-Ci-4-alkyl group, and the other radical is a halogen atom or a pseudohalogen,;characterized in that a compound of the general formula V;Intellectual Property Office of N.Z.;29 SEP 2005;RECEIVED;- 24 -;o;R20*

V

is reacted with an acid chloride in an aprotic solvent to give a methylene steroid of the general formula VI,

the 4,5-epoxide is generated with KhCh/NaOH, the latter is then opened with a nucleophilic reagent which is derived from a halogen atom or pseudohalogen, in a dipolar aprotic solvent, to give a halo- or pseudohalohydrin and, where appropriate, reacted with mineral acid, carboxylic acid or sulfonic acid in a protic or aprotic solvent with dehydration to give a compound of the general formula VII

O

VI

VII

O

in which R4 is a halogen atom or pseudohalogen, where R10 has the meaning given above, and R20 is a Ci-4-alkyl or hydroxy-Ci-4-alkyl group, and R20a

- 25 -

is a hydrogen atom, a halogen atom or a pseudohalogen.

Pharmaceutical compositions comprising at least one 17-methylene steroid of the general formula I

in which

R4 is a halogen atom or a pseudohalogen,

R10 is a hydrogen atom or a straight-chain or branched

Ci-4-alkyl group,

R20 and R20a are, independently of one another, a hydrogen atom, a straight-chain or branched Ci-4-alkyl or hydroxy-Ci-4-alkyl group or one of the radicals R20 and R20a is a hydrogen atom, a straight-chain or branched Ci-4-alkyl or hydroxy-Ci-4-alkyl group, and the other radical is a halogen atom or a pseudohalogen,

where appropriate together with pharmaceutically acceptable excipients and carriers.

17-Methylene steroids as claimed in any one of claims 1 to 5 for use as therapeutic active ingredients.

Intellectual Property Office of N.Z.

29 SEP 2005

RECEIVED

- 26 -

The use of at least one 17-methylene steroid of the general formula I

in which

R4 is a halogen atom or a pseudohalogen,

R10 is a hydrogen atom or a straight-chain or branched

Ci-4-alkyl group,

R20 and R20a are, independently of one another, a hydrogen atom, a straight-chain or branched Ci-4-alkyl or hydroxy-Ci-4-alkyl group or one of the radicals R20 and R20a is a hydrogen atom, a straight-chain or branched Ci-4-alkyl or hydroxy-Ci.4-alkyl group, and the other radical is a halogen atom or a pseudohalogen,

for the treatment of male-type alopecia, acne and hirsutism, and/or for contraception in men and women.

Intellectual Property

Office of N.Z.

2 9 SEP 2005

RECEIVED

- 27 -

11. The use of at least one 17-methylene steroid of the general formula I

Ci-4-alkyl group,

in the manufacture of a medicament for the treatment of prostate disorders and/or for inhibition of 5a-reductase.

12. A compound according to claim 1, substantially as herein described or exemplified.

13. A process according to claim 6, substantially as herein described or exemplified.

0

I

in which

R4 is a halogen atom or a pseudohalogen,

R10 is a hydrogen atom or a straight-chain or branched

Intellectual Property Office of N.Z.

29 SEP 2005

RECEIVED

28

A process according to claim 7, substantially as herein described or exemplified.

A pharmaceutical composition according to claim 8, substantially as herein described or exemplified.

A use according to claim 10, substantially as herein described or exemplified.

A use according to claim 11, substantially as herein described or exemplified.

Intellectual Property Office of N.Z.

2 9 SEP 2005

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