AU2002210470B2 - 4-halogenated 17-methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds - Google Patents

Abstract

The invention relates to 17-Methylene steroids. Method for the production thereof and pharmaceutical compositions containing these compounds. The inventive 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

WO 02/019971 PCT/EP01/09943 4-HALOGENATED 17-METHYLENE STEROIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS 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 actions which are hybrid in character in such a way that they act as inhibitors of Sa-reductase and simultaneously as progestins. They are therefore suitable for the treatment of disorders resulting from elevated androgen levels in particular organs and 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.

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 5c-reductase. The simultaneous 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 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, 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 and simultaneously as progestins.

This object is achieved by 17-methylene steroids of the general formula I in which

R

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

R

10 is a hydrogen atom or a straight-chain or branched C1_4-alkyl group,

R

20 and R 2 O are, independently of one another, a hydrogen atom, a a straight-chain or branched C 1 4 -alkyl or hydroxy-C 1 4 -alkyl group or one of the radicals R 20 and R 20 a is a hydrogen atom, a a straight-chain or branched Ci_--alkyl or hydroxy-

C

1 -4-alkyl group, and the other radical is a halogen atom or a pseudohalogen.

R

4 may, besides a hydrogen atom, 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, with a bromine atom or a cyano group being preferred, and a chlorine atom being particularly preferred.

R

10 may be a hydrogen atom or a a straight-chain or branched Ci- 4 -alkyl group, with examples of straightchain or branched Ci-a-alkyl groups being methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. R 10 3 is preferably a hydrogen atom or a methyl group.

R

20 and R 2 0a may on the one hand be, independently of one another, a hydrogen atom, a straight-chain or branched

C

1 -4-alkyl or hydroxy-C.

4 -alkyl group. In this case, R 20 and R 20 are preferably, independently of one another, a hydrogen atom, a methyl group or a -CH 2 0H group.

A further possibility is for one of the radicals R 20 and

R

20a to be a hydrogen atom, a straight-chain or branched

C

1 4 -alkyl or hydroxy-C1- 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.

Examples of straight-chain or branched C-_ 4 -alkyl groups are the groups mentioned for R 10 Straight-chain and branched hydroxy-Ci.

4 -alkyl groups are derived from the aforementioned straight-chain or branched C 1 4 -alkyl groups, with one or more hydrogen atoms being replaced by hydroxyl groups.

In this case, one of the radicals R 20 and R 20 is preferably a hydrogen atom or a methyl group and the other radical is a halogen atom, preferably a fluorine atom, particularly preferably a chlorine or bromine atom, or a pseudohalogen, preferably an azide or thiocyanato group, particularly preferably a cyano group.

In the case of R 20 and R 20a examples of straight-chain and branched C 1 -4-alkyl groups are the groups mentioned for R 10 Straight-chain and branched hydroxy-CI-4-alkyl groups are derived from these C 1 -4-alkyl groups, with one or more hydrogen atoms being replaced by hydroxyl groups, such as, in particular, from a group -(CH 2 )n-OH with n 1 to 4.

The most preferred compounds are the following: -4- 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)dien-3-one, 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, 9) Z-4,20-dichloro-19-norpregna-4,17(20)-dien- 3-one, Z-20-bromo-4-chloro-19-norpregna-4,17(20)dien-3-one, 11) E-17-chloromethylene-4-cyanoandrost-4-en- 3-one, 12) E-17-chloromethylene-4-chloroandrost-4-en- 3-one, 13) E-21-hydroxy-4-chloro-19-norpregna-4,17(20)dien-3-one, and 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 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.

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, the amount of the compound administered can be 0.01 gg/kg-10 mg/kg of body weight, preferably 0.04 gg/kg-1 mg/kg of body weight, per day.

In humans, this corresponds to a dose of 0.8 ug to 800 mg, preferably 3.2 gsg to 80 mg, a day. [Are 5 statements of doses in order or would it be better to omit them?] A dose unit comprises according to the invention from 1.6 #g 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.

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 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 example, those recommended or indicated in the following references as excipients for pharmacy, cosmetics and adjacent areas: Ullmans Encyklop&die der technischen Chemie, volume 4 (1953), page 1 to 39; Journal of Pharmaceutical Sciences, volume 52 (1963), 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 fUr Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG. Aulendorf in WUrttemberg 1971.

The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted into tissue.

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 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.

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 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.

Suitable for producing intravaginal vaginal rings) or intrauterine devices 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, 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 are reacted with P- 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 encapsulated with liposomes.

The compounds can be employed, both after oral and parenteral administration, for the following indications.

7 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 treatment of disorders which result from elevated androgen levels in particular organs and tissues in men and women, such as, for example, [examples]. In women, elevated levels of Sa-dihydroprogesterone may contribute to severe disturbances of wellbeing associated with the premenstrual syndrome. This can be beneficially influenced through inhibition of The simultaneous presence of a progestational effect with the compounds of the invention leads to an 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 (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 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 Sa-reductase, while the progestational activity enhances the effect in the male 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 conjunction with an estrogen. Suitable estrogens are in principle all compounds with estrogenic activity: estrogens which can be used are, for example, ethynylestradiol, 170-estradiol and its esters such as estradiol 3-benzoate, estradiol 17-valerate, 8- -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-sulfaznates, ethynylestradiol 3-sulfainates and estrone 3-sulfainates, for example estrone N,N-dimethylsulfamate, estrone N,N-diethylsulfanate, ethynylestradiol 3-N,N-dimethylsulfainate, ethynylestradiol 3-N, N-diethylsulfamate, ethynylestradiol 3-N,N-tetramethylenesulfaiate, estrone sulfamate, estradiol 3-sulfarnate, estradiol -3-N,Ndimethylsulfamate, estradiol 3-N,N-diethylsulfamate, ethynylestradiol 3-sulfarnate, all of which are prodrugs of the corresponding 3-hydroxy compounds Elger et al., in J. Steroid Biochem. Molec. Biol., vol. No. 3/4, 395-403, 1995; DE 44 29 398 Al and DE 44 29 397 Al1), can likewise be used according to the invention.

If the compounds of the invention are employed for male contraception, they can be used alone or in conjunction with testosterone or a strong androgen, with examples of a strong androgen being the following compounds: [examnples] Tables 1 and 2 below list data of Sc-reductase type 2 activity in genital skin homogenates and in viva data on the progestational activity.

9- Table 1: 5a-Reductase .type 2 activity in genital skin homogenates under optimized conditions at pH1 (ICso nN) Progesterone receptor binding on uterus cytosol, rabbits, primed Tracer: 314-ORG 2058/incubation conditions 0-4 0 C; 18 h Reference substance: progesterone 100% Compound IC50 (nim) Progesterone= 100% 250 Table 2: in vivo data on the progestational activity Mouse pregnancy maintenance test after s.c. administrati on Compound Dosage Mg/animal/day Proportion of maintained pregnancies S.C.

0.1 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 inhibitors of and as progestins [are the tests mentionied familiar to the skilled worker?].

10 The compounds of the invention are moreover intermediates for synthesizing other pharmacologically highly active steroid products.

[Are starting materials known?].

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.

i0 S0 V They are obtained by reacting a compound of the general formula II 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 III subjecting the latter in a manner known per se to an epoxidation with H 2 0 2 /NaOH in an alcohol, preferably methanol or ethanol, opening the resulting with nucleophiles such as halide (hydrogen halide [further examples]) or pseudohalide ([further examples]), 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 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 R 4 is a halogen atom or pseudohalogen, where

R

10 has the meaning given above, and R 20 is a C 1 -4-alkyl or hydroxy-C4--alkyl group, a halogen atom or a pseudohalogen.

Also obtained are 17-methylene steroids of the general formula I, by reacting a compound of the general 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

R

0

VI

subjecting the latter in a manner known per se to an epoxidation with H 2 0 2 /NaOH in an alcohol, preferably methanol or ethanol, opening the resulting with a nucleophile such as a halide (hydrogen halide [further examples]) or pseudohalide [further examples], in a dipolar aprotic solvent, preferably DMSO or DMPU, 12 dioxane or acetone, to give a halo- or pseudohalohydrin, and then dehydrating the latter with catalytic promotion by mineral acid, carboxylic acid or sulfonic acid, such as hydrochloric acid, oxalic acid or p-toluenesulfonic acid, in a protic or aprotic solvent, methanol or acetone, to give a compound of the general formula VII.

VI

Finally, further 17-methylene steroids of the general formula I can be obtained by reacting compounds of the general formulae III and VI in a manner known per se Haase-Heid, M. Mattis J. Mann, J. Chem. Soc. Perkin Trans. 1, 2999, 1992) with NaI0 4 /KMn0 4 in alcohols, preferably in t-BuOH, to give the 3,5-seco keto acids, converting the latter with Ac2O/AcC1 into the unsaturated lactones, and reacting the latter with n-BuLi/CH 3 CN in a dipolar aprotic solvent such as THF to give the compounds of the general formulae VIII and IX.

13 VmI Compounds of the formulae III and IV can also be obtained by WITTIG, HORNER, PETERSON carbonylolefination.

[too general; reference; statement of compounds obtained with this process] 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 mmol (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 0 C; [al]Do +1040 (CHC1 3 14 B) Z-2 0-Chloro-4 5 -e2oM- 19 -noEpreqn-l17 (2 0) -en-3 -one 2.80 rnol (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 to 000C. To the cooled solution are successively added dropwise, while stirring and under protective gas (argon), 6.31 mmol (0.63 ml) of hydrogen peroxide and 1.26 mmol (0.3 mmol) of sodium hydroxide solution (c 4 mol/l). After the dropwise addition is complete, 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 yellow solid are obtained.

C) Z-4,20-Dichloro-19-norpre2gna-4,17 (20)-dien-3-one 2.71 minol (896 mg) of Z-20-chloro-4 5 -epoxy- 19-norpregn-17 (20) -en-3-one are dissolved in 25 ml of 1, 3-dimethyltetrahydro-2 (lI) -pyrirnidinone (DMPU), and 26.54 mmol (2.2 ml) of hydrochloric acid are slowly added dropwise. Af ter stirring 'under protective' gas (argon) for 1 hour, the reaction solution is poured into ice-cold aquLeous sodium bicarbonate solution, and 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 353 mg of solid product.

M.p. =182-185 0 C; [ct]D 2 0 +1370 (CHCl 3 Example 2 Z-20-Brouro-4-chloro-19-norpr.gna-4, 17(20) -dien-3-one A) Z-20-Bromo--19-norpregna-4, 17 (20) -dien-3-one 9.7 rnmol (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 inmol (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.

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; 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 0 C; [a]n 2 0 +1090 (CHC1 3 B) Z-20-Bromo-4k, 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 dropwise, while stirring and under protective gas (argon), 4.7 mmol (0.48 ml) of hydrogen peroxide 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.

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 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.

C) Z-20-Bromo-4-chloro-19-norpregna-4,17(20)-dien-3-one 2.57 mmol (975 mg) of Z-20-bromo-4k,5t-epoxy-19norpregn-17(20)en-3-one are dissolved in 25 ml of DMPU, and 25.2 mmol (2.09 ml) of hydrochloric acid 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.

Flash chromatography on silica gel (eluent toluene) and subsequent recrystallization from methanol/acetone result in 600 mg of white crystals.

M.p. 164-173 0 C; [a]D 20 +1380 (CHC1 3 Example 3 E-17-Chloromethylene-4-chloroestt-4-en-3-one A) E-17-Chloromethyleneestr-4-en-3-one 18.27 mmol (5.9 g) of 17a-chloromethyl-17-hydroxyestr- 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 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 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. 143-146OC; []D 20 +200 (CHC1 3 B) E-17-Chloromethylene-4 5-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 (argon) and cooled to OQC. To the cooled solution are successively added dropwise while stirring 9.2 mmol (0.94 ml) of hydrogen peroxide 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 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 epoxyestran-3-one are dissolved in 26 ml of DMPU, and 33 mmol (2.74 ml) of hydrochloric acid 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 suction and dried in a desiccator over potassium hydroxide. Recrystallization from acetone results in 760 mg of white crystals.

M.p. 182-194 0 C; [M]D 20 +630 (CHC1 3 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- 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 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 are obtained. Recrystallization from acetone results in 3.1 g of white crystals.

M.p. 153-164°C; [a]D 20 +150 (CHC1 3 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 ml of methylene chloride under protective gas (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 and 1.26 mmol (0.32 ml) of sodium hydroxide solution (c 4 mol/1).

After the dropwise addition is complete, the 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 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-4t,5tepoxyestran-3-one are dissolved in 23 ml of DMPU under protective gas (argon), and 23.33 mmol (1.93 ml) of hydrochloric acid are slowly added dropwise.

After 1 hour, the reaction solution is poured into icecold aqueous sodium bicarbonate solution, and the 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.

M.p. 169-176C; 20 +450 (CHC1 3 29-06-'06 17:34 FROM-DCC SYDNEY +61292621080 T-386 P008/012 F-379 P.\LwPoouis.apcn 2?7FLImat-2 l

VO

-18Aci SThe reference in this specification to any prior O publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or 0 known matter forms part of the common general knowledge in C-i the field of endeavour to which this specification relates.

0 Os COMS ID No: SBMI-04016039 Received by IP Australia: Time 17:37 Date 2006-06-29

Claims (1)

1. 29-06-'06 17:35 FROM-DCC SYDNEY +61292621080 T-386 P009/012 F-379 19 NO 0 The claims defining the invention are as follows: 0 ri 1. 17-Methylene steroids of the general formula I R2 0a 0R 20 C) Rio I in which C R 4 is a halogen atom or a pseudohalogen, SR 1 is a hydrogen atom or a straight-chain or O branched Ci- 4 -alkyl group, RF 0 and R 2 are, independently of one another, a hydrogen atom, a straight-chain or branched CI- 4 alkyl or hydroxy-C_- 4 -alkyl group or one of the radicals R' 2 and R 2 0 is a hydrogen atom, a straight-chain or branched Ci_-alkyl or hydroxy- CI- 4 -alkyl group, and the other radical is a halogen atom or a pseudohalogen with the proviso that the following compounds: 4-chloro-17-methylene-4-androsten-3-one and 4- -fluoro-21-hydroxypregna-4,17(20)- dien-3-one are specifically disclaimed. 2. 17-Methylene steroids as claimed in claim 1, characterized in that R 4 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 R 20 and R 2 0 is a hydrogen atom or a methyl group, and the other radical is a fluorine, chlorine or bromine atom, an azido, cyano or thiocyanato group or hydroxymethyl 4. 17-Methylene steroids as claimed in claim 1, 2 or 3, characterized in that R 10 is a hydrogen atom or a methyl group. COMS ID No: SBMI-04016039 Received by IP Australia: Time 17:37 Date 2006-06-29 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) Z-17- -cyanoethylidene-4-chloroestr-4-en- 3-one, 19) Z-17-ethylidene-4-chloroestr-4-en-3-one, 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-bromoethylidene-4-chloroestr-4-en-3-one, 24) E-17-chloromethylene-4-cyanoandrost-4-en- 3-one, E-17-chloromethylene-4--chloroandrost-4-en- 3-one, 26) E-17- -hydroxyethylidene-4-chloroestr-4- en-3-one and 27) Z-17- -hydroxyethylidene-4-chloroestr-4- en-3-one. 6. A process for preparing 17-methylene steroids as claimed in claim 1, in which R 20 is a hydrogen atom, characterized in that a compound of the general formula II 0~i i is reacted in an aprotic solvent with an acid chloride to give a 17-methylene steroid of the general formula III, 21 o1 m the 4,5-epoxide is generated with H 2 0 2 /NaOH, the latter is then opened with a nucleophilic reagent which is derived from a halogen atom or pseudo- halogen, 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 R 4 is a halogen atom or pseudohalogen, where R 10 has the meaning given in claim 1, and R 20 is a C 1 4 alkyl or hydroxy-C 1 4 -alkyl group, a halogen atom or a pseudohalogen. 7. A process for preparing 17-methylene steroids as claimed in claim 1, characterized in that a compound of the general formula V 22 is reacted with an acid chloride in an aprotic solvent to give a methylene steroid of the general formula VI, RM ,4C VI the 4,5-epoxide is generated with H202/NaOH, the latter is then opened with a nucleophilic reagent which is derived from a halogen atom or pseudo- halogen, 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 VII in which R 4 is a halogen atom or pseudohalogen, where R 10 has the meaning given in claim 1, and R 2 0 is a C 1 -4-alkyl or hydroxy-C 1 4 -alkyl group, and R 20a 29-06-'06 17:35 FROM-DCC SYDNEY +61292621080 T-386 P010/012 F-379 P-wmfoCS"s'ps 2\l ].da-2 &W o -23- Sis a hydrogen atom, a halogen atom or a pseudohalogen. 8. Pharmaceutical compositions comprising at least one 17- methylene steroid as claimed in claim 1, 2, 3, 4 or where appropriate together with pharmaceutically o acceptable excipients and carriers. ci S9. 17-Methylene steroids as claimed in any one of claims 1 Sto 5 for use a therapeutic active ingredients. The use of the compounds as claimed in any one of claims 1 to 5 for the treatment of prostate disorders, male-type alopecia, acne and hirsutism, for contraception in men and women and/or for inhibition of DATED this 29th day of June 2006 SCHERING AG By its Patent Attorneys DAVIES COLLISON CAVE COMS ID No: SBMI-04016039 Received by IP Australia: Time 17:37 Date 2006-06-29