HK1060135B - 4-halogenated 17-methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds - Google Patents

Description

4-halo 17-methylene steroids, process for their preparation and pharmaceutical compositions containing them

Technical Field

The present invention relates to 17-methylene steroids, a process for their preparation and pharmaceutical compositions containing them.

Background

The compounds according to the invention have a hybrid-type action in the sense that they act both as inhibitors of the 5 alpha-reductase and as progestogen. Thus, these compounds are suitable for the treatment of diseases in men as well as in women which are caused by elevated androgen levels in certain organs and tissues. The compounds according to the invention are suitable, together with other hormonal substances, such as estrogens, testosterone or potent androgens, for use as contraceptives for women and men.

In women, 5 α -dihydroxyprogesterone can cause severe sensory disturbances during premenstrual syndrome. These disorders can also be favorably affected by inhibition of 5 α -reductase. The concomitant presence of progestogenic effects may lead to an inhibitory effect on gonadal function in both males and females. This effect is desirable if it is desired to achieve an antifertility effect or to suppress the secretion of gonadal hormones by therapy. The elimination of fertility accompanied by antiandrogen therapy is also highly desirable because inhibition of 5 alpha-reductase irreversibly destroys the sexual development of the fetus in women carrying a male fetus. Possible indications are prostate disease, male pattern baldness, acne, and hirsutism. Symptoms during premenstrual syndrome can be alleviated in correspondingly susceptible women.

It has been found that, surprisingly, the 17-methylene steroids of the general formula I have both a 5 alpha-reductase inhibitor and a progestogen effect.

Disclosure of Invention

Accordingly, the present invention relates to 17-methylene steroids of general formula I:

wherein:

R⁴represents a hydrogen atom, a halogen atom or a pseudo halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

Detailed Description

In addition to hydrogen atoms, R⁴May represent a halogen atom, such as a fluorine, chlorine, bromine or iodine atom, or a pseudohalogen, such as a cyanato, thiocyanate, cyano or azido group, with a bromine atom or a cyano group being preferred and a chlorine atom being particularly preferred.

R¹⁰May represent a hydrogen atom or a branched or linear C_1-4Alkyl, wherein C is branched or unbranched_1-4Alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. R¹⁰Preferably represents a hydrogen atom or a methyl group.

In one aspect, R²⁰And R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4An alkyl group. In this case, R²⁰And R^20aIndependently of one another preferably represents a hydrogen atom, a methyl group or-CH₂An OH group.

In addition, R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom, such as a fluorine, chlorine, bromine or iodine atom, or a pseudohalogen, such as a cyanato, thiocyanato, cyano or azido group. Straight or branched C_1-4Examples of alkyl radicals with R¹⁰The same as described in (1). Straight-chain or branched hydroxyl group C_1-4The alkyl radicals being derived from straight or branched chains C as defined above_1-4Alkyl, wherein one or more hydrogen atoms are substituted by hydroxyl.

In this case, R²⁰And R^20aOne preferably represents a hydrogen atom or a methyl group and the other a halogen atom, preferably a fluorine atom, particularly preferably a chlorine or bromine atom, or a pseudohalogen, preferably an azido and thiocyanate group, particularly preferably a cyano group.

For R²⁰And R^20aStraight or branched C_1-4Examples of alkyl radicals with R¹⁰The same as described in (1). Straight or branched hydroxy-C_1-4The alkyl radicals being derived from straight or branched chains C as defined above_1-4Alkyl in which one or more hydrogen atoms are replaced by hydroxy groups, e.g. - (CH)₂)_n-OH group, wherein n ═ 1-4.

The following compounds are particularly preferred:

1) e-17-chloromethylene-4-chloro-estra-4-en-3-one,

2) e-17-cyanomethylene-4-chloro-estra-4-en-3-one,

3) z-17-cyanomethylene-4-chloro-estra-4-en-3-one,

4) z-20-cyano-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one,

5) z-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one,

6) e-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one,

7) e-17-bromomethylene-4-chloro-estra-4-en-3-one,

8) z-20-chloro-19-nor-pregn-4, 17(20) -dien-3-one,

9) z-4, 20-dichloro-19-nor-pregn-4, 17(20) -dien-3-one,

10) z-20-bromo-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one,

11) e-17-chloromethylene-4-cyano-androst-4-en-3-one,

12) e-17-chloromethylene-4-chloro-androst-4-en-3-one,

13) e-21-hydroxy-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one, and

14) z-21-hydroxy-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one.

The invention also relates to pharmaceutical compositions comprising at least one 17-methylene steroid of the general formula I as active ingredient, wherein these compositions may also comprise suitable auxiliaries and carriers. The invention also relates to the use of said compounds for the preparation of a medicament, in particular for the treatment of the following indications.

The amount of the compound of formula I administered can vary over a wide range and can cover the active amount. Depending on the disease to be treated and the route of administration, the compounds are administered in amounts of 0.01. mu.g/kg to 10mg/kg body weight, preferably 0.04. mu.g/kg to 1mg/kg body weight, per day. For humans, the daily dose is 0.8. mu.g-800 mg, preferably 3.2. mu.g-80 mg.

According to the invention, a unit dose contains 1.6. mu.g to 200mg of one or more compounds of the formula I.

The compounds according to the invention are suitable for the preparation of pharmaceutical compositions and formulations. Pharmaceutical compositions or pharmaceutical preparations comprise one or more compounds according to the invention as active ingredient, optionally in admixture with other pharmacologically or pharmaceutically active substances. The pharmaceutical preparations are carried out according to methods known in the art, wherein known and customary pharmaceutical auxiliaries and other customary carriers and diluents can also be used.

Such carriers and adjuvants are, for example, those recommended or indicated for use as adjuvants in the pharmaceutical, cosmetic and related fields in the following documents: ullmans encyklopadie der technischen Chemie (Ullman encyclopedia of chemical engineering), volume 4 (1953), pages 1-39; journal of pharmaceutical Sciences, vol.52 (1963), 918 and related pages, h.v. czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und grenzeden Gebiete (excipients for pharmaceutical and related fields); ind, No. 2, 1961, page 72 and related pages: Dr.H.P.Fiedler, Lexikon der Hilfsstuffe fuel Pharmazie, Kosmetik undangrenzende Gebiete (dictionary of auxiliary materials for pharmaceutical, cosmetic and related fields), Cantor KG, Aulendorf in Wuerttemberg 1971.

The compounds of the invention may be administered by oral or parenteral routes, including intraperitoneal, intramuscular, subcutaneous or transdermal. The compound may also be implanted in tissue.

In oral administration, capsules, pills, tablets, coated tablets and the like are suitable. In addition to the active ingredient, the dosage unit may contain pharmaceutically compatible carriers such as starches, sugars, sorbitol, gelatin, lubricants, silica, talc and the like.

For parenteral administration, the active ingredient may be dissolved or suspended in a physiologically compatible diluent. As diluents, very customary oils can be used, with or without the addition of solubilizers, surfactants, suspending agents or emulsifiers. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds may also be in long acting injectable or implantable formulations which may be formulated to provide delayed release of the active ingredient.

The implant may comprise an inert material such as a biodegradable polymer or a synthetic siloxane, for example silica gel. In addition, the active ingredient may be added to a patch for transdermal administration.

In the preparation of intravaginal systems (e.g. pessaries) or intrauterine systems (e.g. pessaries, rings, IUDs, Mirena ) containing an active compound of formula I for topical administration, various polymers are suitable, such as silicone polymers, ethylene vinyl acetate, polyethylene, or polypropylene.

To achieve better bioavailability of the active ingredient, the compounds may also be formulated as cyclodextrin inclusion compounds. In this case, the compounds can be reacted with alpha-, beta-or gamma-cyclodextrins or derivatives thereof (PCT/EP 95/02656).

According to the invention, the compounds of formula I may also be encapsulated in liposomes.

The compounds according to the invention have a hybrid-type action. They are inhibitors of 5 alpha-reductase and may also act as progestogens. They are therefore suitable for the treatment of diseases which are caused by elevated androgen levels in certain organs and tissues in men and women. In women, elevated levels of 5 α -dihydroxyprogesterone can lead to severe sensory disturbances during premenstrual syndrome. This can advantageously be influenced by inhibiting the 5 α -reductase.

The simultaneous presence of progestogenic effects in the compounds according to the invention produces an inhibitory effect on gonadal function in both males and females. This effect is desirable if antifertility or suppression of gonadal hormone secretion is achieved by therapy. This is often the case in prostate disease (benign prostatic hyperplasia). In addition to prostate disorders, possible indications are contraception in both sexes, male pattern baldness, acne and hirsutism. The compounds according to the invention are suitable as contraceptives for women or men, together with other hormonal substances such as estrogens, testosterone or potent androgens. In the latter case, testosterone effects in the prostate are reduced by 5 α -reductase inhibition, while progestagenic activity enhances effects in the male gonads, such as suppression of spermatogenesis.

If the compounds according to the invention are used in female contraception, they can be used alone or in combination with estrogens. For estrogens, essentially all estrogenic active compounds are suitable: estrogens which may be used are, for example, ethinyl estradiol, 17 β -estradiol and esters thereof, such as estradiol-3-benzoate, estradiol-17-valerate, estradiol-cypionate, estradiol-undecanoate, estradiol-heptanoate and/or other estradiol esters (USA-A-2,611,773, USA-A-2,990,414, USA-A-2,054,271, USA-A-2,225,419, and USA-A-2,156,599) and conjugated estradiol.

Estradiol-, ethinyl estradiol-and estrone-3-sulfamates, such as estrone-N, N-dimethylsulfamate, estrone-N, N-diethylsulfamate, ethinyl estradiol-3-N, N-dimethylsulfamate, ethinyl estradiol-3-N, N-diethylsulfamate, ethinyl estradiol-3-N, N-tetramethylenesulfonate, estrone sulfamate, estradiol-3-N, N-dimethylsulfamate, estradiol-3-N, N-diethylsulfamate, and ethinyl estradiol-3-sulfamate, which are all prodrugs of the corresponding 3-hydroxy compounds, may also be used according to the invention (W.Elger et al, J.Steroid biochem.molec.biol., Vol.55, No.3/4, 395-403, 1995; DE 4429398 a1 and DE 4429397 a 1).

If the compounds of the invention are to be used for male contraception, they may be used alone or in combination with potent androgens such as testosterone and testosterone esters.

Data for 5 α -reductase type 2 activity in genital integuments and in vivo data for progestagen activity are shown, for example, in tables 1 and 2 below.

Table 1: 5 alpha-reductase type 2 activity (IC) in genital integuments at pH 5.5 under optimal conditions₅₀(nM))

Progesterone receptor binding in uterine-cytosol, rabbit, tracer that has been exposed to antigen: 3H-ORG 2058/incubation conditions 0-4 ℃; 18 hours

Reference substance: progesterone 100%

Table 2: in vivo data for progestagen activity

Mouse pregnancy maintenance test after subcutaneous administration

The data in tables 1 and 2 demonstrate that the compounds according to the invention act in a hybrid-type manner, both as inhibitors of 5 α -reductase and as progestogen.

The compounds according to the invention may also be intermediates for the synthesis of other pharmaceutically active steroid products.

The 17-methylene steroids of the formula I according to the invention are obtainable from compounds of the formula II (K.Ponsold et al, Pharmazie 33, 792(1978)) and compounds of the formula V.

The compounds of the general formula V are obtainable from the corresponding 17 α -epoxy compounds (G.Drefahl, Ber.98, 604(1965)), by reaction with halides, such as hydrogen chloride or hydrogen bromide, or pseudohalides, such as hydrogen thiocyanate or hydrogen nitride, in a bipolar aprotic solvent, preferably DMSO or DMPU.

The compounds of formula I are prepared as follows: the compound of formula II is reacted with an acid chloride, preferably thionyl chloride or phosphorus oxychloride, in an aprotic solvent, preferably pyridine or triethylamine, to produce the compound of formula III,

the compound is reacted with H according to methods known to those skilled in the art₂O₂NaOH in alcohol, preferably methanol or ethanol, and the resulting 4, 5-epoxideRing opening with a nucleophilic agent such as a halide (e.g. hydrogen chloride or hydrogen bromide) or a pseudohalide (e.g. hydrogen thiocyanate or hydrogen nitride) in a dipolar aprotic solvent, preferably DMSO or DMPU, dioxane or acetone, to form a halohydrin or pseudohalohydrin, which is catalytically dehydrogenated with a mineral acid, carboxylic acid or sulfonic acid such as hydrochloric acid, oxalic acid or p-toluenesulfonic acid in a protic or aprotic solvent such as methanol or acetone to form a compound of formula IV,

wherein R is⁴Represents a halogen atom or a pseudohalogen, and R¹⁰As defined above, R²⁰Represents C_1-4Alkyl or hydroxy-C_1-4Alkyl, halogen atom or pseudohalogen.

In addition, the 17-methylene steroids of the general formula I are obtainable as follows: the compound of formula V is reacted with an acid chloride, preferably thionyl chloride or phosphorus oxychloride, in an aprotic solvent, preferably pyridine or triethylamine, to form the compound of formula VI,

the compound is reacted with H in an alcohol, preferably methanol or ethanol, according to methods known in the art₂O₂NaOH, and the 4, 5-epoxides obtained are subjected to ring-opening reactions with nucleophiles such as halides (for example hydrogen chloride or hydrogen bromide) or pseudohalides (for example hydrogen thiocyanate or hydrogen nitride) in dipolar aprotic solvents, preferably DMSO or DMPU, dioxane or acetone, to form halohydrins or pseudohalohydrins which are subjected to dehydrogenation reactions with mineral acids, carboxylic acids or sulfonic acids such as hydrochloric acid, oxalic acid or p-toluenesulfonic acid in protic or aprotic solvents such as methanol or acetone by catalysis to form compounds of the formula VII,

finally, other 17-methylene steroids of formula I can be prepared from compounds of formulae III and VI as follows:

the above compounds were reacted with NaIO according to methods known in the art (M.Haase-Held, M.Mattis and J.Mann, J.Chem.Soc.Perkin Trans.1, 2999, 1992)₄/KMnO₄Reaction in an alcohol, preferably t-butanol, to form a 3, 5-seco (seco) keto acid, the keto acid being substituted with Ac₂O/AcCl to unsaturated lactone, which is then reacted with n-BuLi/CH₃CN is reacted in a bipolar aprotic solvent, such as Tetrahydrofuran (THF), to form compounds of formulas VIII and IX.

E-17-chloromethylene-estr-4-en-3-one can also be prepared by WITTIG reaction with chloromethyltriphenylphosphonium chloride (s.miyano et al, j.c.s.chem.comm., 446 (1978)). The isomer 17-cyanomethylene-estr-4-en-3-one can also be obtained from cyanomethylene diethyl phosphate according to the carbonyl olefination process by HORNER or from trimethylsilylacetonitrile according to the PETERSON olefination process (EP-A-0077040 or I.OjimｃA et al, Tetrahedron Lett.46(1974) 4005-.

Z-20-cyano-19-nor-pregn-4, 17(20) -dien-3-one was synthesized by PO activation of 2-diethylphosphonopropionitrile by carbonyl activation (R.W. Freurksen et al, journal American Chemical Society (1977) 1536).

The present invention is described in more detail below by way of examples.

Example 1

Z-4, 20-dichloro-19-nor-pregna-4, 17(20) -dien-3-one

A) 7-20-chloro-19-nor-pregn-4, 17(20) -dien-3-one

9.74mmol (3.28g) of (20) R-chloro-19-nor-pregn-4-en-3-one-17-ol were dissolved in 34ml of pyridine. While cooling slightly, 12.66mmol (0.92ml) of thionyl chloride was added dropwise with stirring. After stirring under a protective gas (argon) for about 1 hour, the reaction solution was added to ice-cooled diluted hydrochloric acid at pH 3-4. The sticky precipitate is extracted with dichloromethane, the combined, washed to neutral extracts are dried over sodium sulfate and then concentrated by evaporation. The solid product which has accumulated is purified by chromatography on silica gel (eluent: toluene/ethyl acetate 95/5) and optionally recrystallized from methanol. 0.6g of solid product was obtained.

Melting point: 138 ℃ and 141 ℃; [ alpha ] to]_D ²⁰＝+104°(CHCl₃)

B) Z-20-chloro-4 ζ,5 ζ -epoxy-19-nor-pregn-17 (20) -en-3-one

2.80mmol (894mg) of Z-20-chloro-19-nor-pregn-4, 17(20) -dien-3-one are dissolved in a mixture of 9ml of methanol and 7.3ml of dichloromethane and then cooled to 0 ℃. To the cooled solution were added 6.31mmol (0.63ml) of hydrogen peroxide (30%) and 1.26mmol (0.3ml) of sodium hydroxide solution (c 4mol/l) sequentially under stirring and under a protective gas (argon). After the completion of the dropwise addition, the temperature was slowly raised to room temperature. After a reaction time of about 1.5 hours, the mixture was added to ice water, followed by extraction with dichloromethane. The combined extracts were dried over sodium sulfate and then concentrated by evaporation. 926mg of a pale yellow solid were obtained.

¹H-NMR/(CDCl₃/ppm)0.94(18-H)，1.99(21-H)，3.04(4-H)

C) Z-4, 20-dichloro-19-nor-pregna-4, 17(20) -dien-3-one

2.71mmol (896mg) of Z-20-chloro-4 ζ,5 ζ -epoxy-19-nor-pregn-17 (20) -en-3-one were dissolved in 25ml of 1, 3-dimethyltetrahydro-2 (1H) -pyrimidinone (DMPU), and 26.54mmol (2.2ml) of hydrochloric acid (37%) were slowly added dropwise. After stirring for 1 hour under a protective gas (argon), the reaction solution was added to ice-cooled aqueous sodium bicarbonate solution, the precipitate was withdrawn, and finally dried with potassium hydroxide in a dryer. Purification by flash chromatography on silica gel (eluent: toluene/ethyl acetate 99/1) and recrystallisation from methanol/acetone gave 353mg of solid product.

Melting point: 182 ℃ and 185 ℃; [ alpha ] to]_D ²⁰＝+137°(CHCl₃)

Example 2

Z-20-bromo-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one

A) Z-20-bromo-19-nor-pregn-4, 17(20) -dien-3-one

9.7mmol (3.7g) of (20) R-bromo-19-nor-pregn-4-en-3-one-17-ol were dissolved in 39ml of pyridine. While cooling slightly, 12.61mmol (0.91ml) of thionyl chloride was added dropwise with stirring. After stirring under a protective gas (argon) for about 1 hour, the reaction solution was added to ice-cooled diluted hydrochloric acid at pH 3-4. The sticky precipitate is extracted with dichloromethane, the combined, washed to neutral extracts are dried over sodium sulfate and then concentrated by evaporation. The accumulated solid product is purified by chromatography on silica gel (eluent: toluene/ethyl acetate 95/5) and optionally recrystallized from methanol/acetone. 536mg of solid product are obtained.

Melting point: 153-156 ℃; [ alpha ] to]_D ²⁰＝+109°(CHCl₃)

B) Z-20-bromo-4 ζ,5 ζ -epoxy-19-nor-pregn-17 (20) -en-3-one

2.09mmol (760mg) of Z-20-bromo-19-nor-pregn-4, 17(20) -dien-3-one are dissolved in a mixture of 7.8ml of methanol and 6.3ml of dichloromethane and then cooled to 0 ℃. To the cooled solution were added sequentially under stirring and under protective gas (argon) 4.7mmol (0.48ml) of hydrogen peroxide (30%) and 0.94mmol (0.24ml) of sodium hydroxide solution (c 4 mol/l). After the completion of the dropwise addition, the temperature was slowly raised to room temperature. After a reaction time of about 1 hour, 50ml of water were added to the mixture. The system was separated into two phases and then extracted with dichloromethane. The combined extracts, which were washed to neutrality, were dried over sodium sulfate and then concentrated by evaporation. The remaining pale yellow solid was purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 95/5). 680mg of a pale yellow solid were obtained.

C) Z-20-bromo-4-chloro-19-nor-pregn-4, 17(20) -dien-3-one

2.57mmol (975mg) of Z-20-bromo-4 ζ,5 ζ -epoxy-19-nor-pregn-17 (20) -en-3-one were dissolved in 25ml of DMPU, and then 25.2mmol (2.09ml) of hydrochloric acid (37%) were slowly added dropwise. After stirring for 1 hour under a protective gas (argon), the reaction solution was added to ice-cooled aqueous sodium bicarbonate solution, the precipitate was withdrawn, and finally dried with potassium hydroxide in a dryer. Purification by flash chromatography on silica gel (eluent: toluene) followed by recrystallization from methanol/acetone gave 600mg of solid product.

Melting point: 164 ℃ to 173 ℃; [ alpha ] to]_D ²⁰＝+138°(CHCl₃)

Example 3

E-17-Chloromethylene-4-chloro-estra-4-en-3-one

A) E-17-Chloromethylene-estr-4-en-3-one

18.27mmol (5.9g) of 17 α -chloromethyl-17-hydroxy-estr-4-en-3-one were dissolved in 60ml of pyridine. While cooling slightly, 21.9mmol (1.56ml) of thionyl chloride were added dropwise with stirring. After stirring under a protective gas (argon) for about 1 hour, the reaction solution was added to ice-cooled diluted hydrochloric acid at pH 3-4. The sticky precipitate is extracted with dichloromethane, the combined, washed to neutral extracts are dried over sodium sulfate and then concentrated by evaporation. The solid product accumulated is purified by chromatography on silica gel (eluent: n-hexane/ethyl acetate 85/15). After recrystallization from acetone, 1.6g of solid product was obtained.

Melting point: 143-146 ℃; [ alpha ] to]_D ²⁰＝+20°(CHCl₃)

B) E-17-Chloromethylene-4 ζ,5 ζ -epoxy-estrane-3-one

3.93mmol (1.2g) of E-17-chloromethylene-estr-4-en-3-one were dissolved in a mixture of 12ml of methanol and 10ml of dichloromethane and then cooled to 0 ℃. To the cooled solution was added, under stirring and under protective gas (argon), 9.2mmol (0.94ml) of hydrogen peroxide (30%) and 1.65mmol (0.4ml) of sodium hydroxide solution (c 4mol/l) in that order. After the completion of the dropwise addition, the temperature was slowly raised to room temperature. After a reaction time of about 1.5 hours, the mixture was added to ice water, followed by extraction with dichloromethane. The combined extracts were dried over sodium sulfate and then concentrated by evaporation. 1.1g of a white viscous foam are obtained.

¹H-NMR/(CDCl₃/ppm)0.87(18-H)，3.04(21-H)，5.70(20-H)

C) E-17-Chloromethylene-4-chloro-estra-4-en-3-one

3.42mmol (1.1g) of E-17-chloromethylene-4 ζ,5 ζ -epoxy-estrane-3-one were dissolved in 26ml of DMPU, and 33mmol (2.74ml) of hydrochloric acid (37%) were slowly added dropwise. After stirring for 1 hour under a protective gas (argon), the reaction solution was added to ice-cooled aqueous sodium bicarbonate solution, the precipitate was withdrawn, and finally dried with potassium hydroxide in a dryer. Purification by flash chromatography on silica gel (eluent: toluene/ethyl acetate 99/1) and recrystallisation from methanol/acetone gave 760mg of the product as a solid.

Melting point: 182 ℃ and 194 ℃; [ alpha ] to]_D ²⁰＝+63°(CHCl₃)

Example 4

E-17-bromomethylene-4-chloro-estr-4-en-3-one

A) E-17-bromomethylene-estr-4-en-3-one

28.58mmol (10.5g) of 17 α -bromomethyl-17-hydroxy-estr-4-en-3-one were dissolved in 90ml of pyridine. It was cooled slightly while 37.16mmol (2.7ml) of thionyl chloride was added dropwise with stirring. After stirring under a protective gas (argon) for about 1 hour, the reaction solution was added to ice-cooled diluted hydrochloric acid at pH 3-4. The sticky precipitate is extracted with dichloromethane, the combined, washed to neutral extracts are dried over sodium sulfate and then concentrated by evaporation. The accumulated yellow solid product was purified by chromatography on silica gel (eluent: n-hexane/ethyl acetate 85/15). After recrystallization from acetone, 3.1g of solid product are obtained.

Melting point: 153-164 ℃; [ alpha ] to]_D ²⁰＝+15°(CHCl₃)

B) E-17-bromomethylene-4 ζ,5 ζ -epoxy-estrane-3-one

2.86mmol (1g) of E-17-bromomethylene-estr-4-en-3-one were dissolved in a mixture of 10.5ml of methanol and 8.5ml of dichloromethane and then cooled to 0 ℃. To the cooled solution were added 6.44mmol (0.66ml) of hydrogen peroxide (30%) and 1.26mmol (0.32ml) of sodium hydroxide solution (c 4mol/l) sequentially under stirring and under a protective gas (argon). After the completion of the dropwise addition, the temperature was slowly raised to room temperature. After a reaction time of about 1.5 hours, the mixture was added to ice water, followed by extraction with dichloromethane. The combined extracts, which were washed to neutrality, were dried over sodium sulfate and then concentrated by evaporation. 891mg of a white viscous foam were obtained.

C) E-17-bromomethylene-4-chloro-estr-4-en-3-one

2.38mmol (approx. 870mg) of E-17-bromomethylene-4 ζ,5 ζ -epoxy-estrane-3-one were dissolved in 23ml of DMPU, and 23.33mmol (1.93ml) of hydrochloric acid (37%) were slowly added dropwise. After stirring for 1 hour under a protective gas (argon), the reaction solution was added to ice-cooled aqueous sodium bicarbonate solution, the precipitate was withdrawn, and finally dried with potassium hydroxide in a dryer. Purification by flash chromatography on silica gel (eluent: toluene/ethyl acetate 98/2) and recrystallisation from acetone gave 552mg of the product as a solid.

Melting point: 169 ℃ and 176 ℃; [ alpha ] to]_D ²⁰＝+45°(CHCl₃)

Claims (22)

1. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

2. The 17-methylene steroid of claim 1, wherein R⁴Represents a chlorine or bromine atom or a cyano group.

3. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aOne represents a hydrogen atom or a methyl group and the other represents a fluorine, chlorine or bromine atom, an azido, cyano or thiocyanate group or a hydroxymethyl group.

4. The 17-methylene steroid of claim 1, wherein R¹⁰Represents a hydrogen atom or a methyl group.

5. A 17-methylene steroid selected from the group consisting of:

1) e-17-chloromethylene-4-chloro-estra-4-en-3-one,

2) e-17-cyanomethylene-4-chloro-estra-4-en-3-one,

3) z-17-cyanomethylene-4-chloro-estra-4-en-3-one,

4) z-17- (1') -cyanoethylene-4-chloro-estr-4-en-3-one,

5) z-17-ethylene-4-chloro-estr-4-en-3-one,

6) e-17-ethylene-4-chloro-estra-4-en-3-one,

7) e-17-bromomethylene-4-chloro-estra-4-en-3-one,

8) z-17-chloroethylene-4-chloro-estra-4-en-3-one,

9) z-17-bromoethylene-4-chloro-estr-4-en-3-one,

10) e-17-chloromethylene-4-cyano-androst-4-en-3-one,

11) e-17-chloromethylene-4-chloro-androst-4-en-3-one,

12) e-17- (2') -hydroxyethylidene-4-chloro-estr-4-en-3-one, and

13) z-17- (2') -hydroxyethylidene-4-chloro-estr-4-en-3-one.

6. A process for the preparation of 17-methylene steroids of formula I,

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, halogen atom or pseudohalogen, and

R^20arepresents a hydrogen atom, and is represented by,

characterized in that the compounds of the general formula II

Reacting with acyl chloride in an aprotic solvent to produce a 17-methylene steroid of formula III,

by H₂O₂NaOH produces 4, 5-epoxides which are subjected to a ring-opening reaction with nucleophiles derived from halogen atoms or pseudohalogens in a dipolar aprotic solvent to form halohydrins or pseudohalohydrins, which are optionally dehydrogenated with mineral acids, carboxylic acids or sulfonic acids in a protic or aprotic solventTo form a compound of the general formula IV,

wherein R is⁴Represents a halogen atom or a pseudohalogen, R¹⁰Represents a hydrogen atom or a branched or linear C_1-4Alkyl radical, and R²⁰Represents C_1-4Alkyl or hydroxy-C_1-4Alkyl, halogen atom or pseudohalogen.

7. A process for the preparation of 17-methylene steroids of formula I,

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, and the other group represents a halogen atom or a pseudo halogen,

characterized in that compounds of the general formula V

Reacting with acyl chloride in an aprotic solvent to form a methylene steroid of formula VI,

by H₂O₂NaOH produces 4, 5-epoxides which are subjected to ring-opening reactions with nucleophiles derived from halogen atoms or pseudohalogens in dipolar aprotic solventsIn the presence of a halogen or pseudohalogen alcohol, which is dehydrogenated by reaction with a mineral, carboxylic or sulfonic acid, optionally in a protic or aprotic solvent, to form a compound of the formula VII,

wherein R is⁴Represents a halogen atom or a pseudohalogen, and R¹⁰Represents a hydrogen atom or a branched or linear C_1-4Alkyl radical, R²⁰Represents C_1-4Alkyl or hydroxy-C_1-4Alkyl, and R^20aRepresents a hydrogen atom, a halogen atom or a pseudo halogen.

8. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or an ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

9. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a fluorine, bromine or iodine atom or a pseudohalogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

10. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl radicals, and

R^20arepresents a straight or branched chain C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

11. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a pseudo-halogen of which the halogen atom,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

12. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 8, and optionally a pharmaceutically acceptable adjuvant or carrier.

13. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents an azido group, a thiocyanate group or a cyano group,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aIndependently of one another, represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, or

R²⁰And R^20aOne of them represents a hydrogen atom, a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl and the other group represents a halogen atom or a pseudo-halogen.

14. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 1, and optionally a pharmaceutically acceptable adjuvant or carrier.

15. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 10, and optionally pharmaceutically acceptable adjuvants and carriers.

16. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 11, and optionally pharmaceutically acceptable adjuvants and carriers.

17. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 12, and optionally pharmaceutically acceptable adjuvants and carriers.

18. A pharmaceutical composition comprising at least one 17-methylene steroid according to claim 5, and optionally pharmaceutically acceptable adjuvants and carriers.

19. The 17-methylene steroid of claim 1, wherein R⁴Represents a halogen atom.

20. The 17-methylene steroid of claim 1, wherein R⁴Represents an azido group, a thiocyanate group or a cyano group.

21. The 17-methylene steroid of claim 1, wherein R⁴Represents cyano.

22. A 17-methylene steroid of the general formula I:

wherein:

R⁴represents a halogen atom or a pseudo-halogen,

R¹⁰represents a hydrogen atom or a branched or linear C_1-4An alkyl group, a carboxyl group,

R²⁰and R^20aRepresents a straight or branched chain C_1-4Alkyl or hydroxy C_1-4Alkyl radical, and R²⁰And R^20aThe other of which represents a linear or branched C_1-4Alkyl or hydroxy C_1-4Alkyl, halogen atom or pseudohalogen.