Unsaturated 14, 15-cyclopropanoandrostanes, a method for their production and pharmaceutical compositions containing these compounds
Patent References 2895969 3201427 3239512 InventorsAssigneeApplicationNo. 11008758 filed on 11/21/2000US Classes:514/178, Oxygen single bonded to a ring carbon of the cyclopentanohydrophenanthrene ring system552/510The cyclopentanohydrophenanthrene ring system is part of a polycyclo ring system having at least five cyclosExaminersPrimary: Badio, Barbara P.Attorney, Agent or FirmForeign Patent References
International ClassesA61K 31/56C07J 53/00 Description.[.This application is a 371 ofPCT/EP00/11557 filed Nov. 21, 2000..]. .Iadd.The invention described and claimed hereinbelow is also described in PCT International Patent Application PCT/EP 00/11557, filed on Nov. 21, 2000, which provides the basis for a claim of priority ofinvention for the claims appended hereinbelow under 35 U.S.C. 365..Iaddend. The invention relates to new unsaturated .[.14,15-cyclopropane-androstanes.]. .Iadd.14,15-cyclopropanoandrostanes.Iaddend., a method for their production and pharmaceutical compositions containing these compounds. Unsaturated.[.14,15-cyclopropane-androstanes.]. .Iadd.14,15-cyclopropanoandrostanes .Iaddend.of the following formula.Iadd.:.Iaddend. ##STR00002## are described in the German .[.application.]. .Iadd.Patent Application .Iaddend.No. 198 27 523.4 (PCT/DE99/01794),which claims a priority earlier than that of the present application, but was published after the latter was filed. In the formula, R1 is a hydrogen atom, a hydroxy group, an alkyloxy .Iadd.group.Iaddend., .Iadd.an .Iaddend.acyloxy .Iadd.group.Iaddend., .[.alryloxy.]. .Iadd.an aryloxy group, .Iaddend..[.or.]. .Iadd.an .Iaddend.alkylaryloxy group, an--OCONHR9 .Iadd., .Iaddend.or --OCOOR9 group, in which R9 represents a hydrogen atom, an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl .Iadd.group, .Iaddend.or alkylaryl group with, ineach case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. R2 represents a hydrogen atom, a hydroxyl group, an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.acyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an.Iaddend.aralkyl .Iadd.group.Iaddend., or .Iadd.an .Iaddend.alkylaryl group with, in each case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. a --(CH2)nCH.sub.2Y group, with n=0, 1.Iadd., .Iaddend.or 2, in which Y represents a fluorine.Iadd.atom.Iaddend., .Iadd.a .Iaddend.chlorine .Iadd.atom.Iaddend., .Iadd.a .Iaddend.bromine .[.or.]. .Iadd.atom, an .Iaddend.iodine atom, a cyano .Iadd.group.Iaddend., .[.azide or rhodanide.]. .Iadd.an azido group, a thiocyanato .Iaddend.group, an--OR10 .Iadd.group .Iaddend.or .Iadd.a .Iaddend.--SR10 group.[.,.]. in which R10 represents a hydrogen atom, an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl .Iadd.group, .Iaddend.or.Iadd.an .Iaddend.alkylaryl .[.groups.]. .Iadd.group .Iaddend.with, in each case, 1 to 10 carbon atom.Iadd.s .Iaddend.or a COR9 acyl group in which R9 represents an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend.,.Iadd.an .Iaddend.aralkyl .Iadd.group, .Iaddend.or .Iadd.an .Iaddend.alkylaryl group with, in each case, 1 to 10 carbon atoms, .Iadd.or .Iaddend.a --OR9.[.,.]. .Iadd.group .Iaddend.in which R9 represents a hydrogen atom, an alkyl.Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl .Iadd.group, .Iaddend.or .Iadd.an .Iaddend.alkylaryl group with, in each case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. a--(CH2)m--CH=CH(CH2)n--R.sub.8 group in which m=0, 1, 2.Iadd., .Iaddend.or 3 and n=0, 1.Iadd., .Iaddend.or 2 and R8 represents a hydrogen atom.[.or.]. .Iadd., .Iaddend.an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl.Iadd.group.Iaddend., .Iadd.an .Iaddend.aralkyl .Iadd.group, .Iaddend.or .Iadd.an alkylaryl .Iaddend.group with, in each case, 1 to 10 carbon atoms.[.or.]. .Iadd., .Iaddend.a hydroxyl group, .Iadd.or .Iaddend.an alkoxy group or an acyloxy group with, ineach case, 1 to 10 carbon atoms.[.,.]. .Iadd.;.Iaddend. .[.a --(CH2)oC=CR.sub.11 group.]. .Iadd.a --(CH2)oC≡CR.sub.11 group .Iaddend.in which o=0, 1, or 2 and R11 represents a hydrogen atom, a fluorine.Iadd.atom.Iaddend., .Iadd.a .Iaddend.chlorine .Iadd.atom.Iaddend., .Iadd.a .Iaddend.bromine .[.or.]. .Iadd.atom, an .Iaddend.iodine atom.Iadd., .Iaddend.or an alkyl .Iadd.group.Iaddend., .Iadd.an .Iaddend.aryl .Iadd.group.Iaddend., .Iadd.an.Iaddend.aralkyl .Iadd.group, .Iaddend.or .Iadd.an alkylaryl .Iaddend.group with, in each case, 1 to 10 carbon atoms.[.,.]. .Iadd.; or .Iaddend. R1 and R2 independently of one another represent a keto, methylene, or difluoromethylenegroup.[.,.]. .Iadd.;.Iaddend. .[.there possibly being.]. .Iadd.optionally .Iaddend.a double bond .Iadd.is present .Iaddend.between C-6 and C-7, .[.if there is.]. an α or β cyclopropane group X .Iadd.is present .Iaddend.between C-14 andC-15, .Iadd.with .Iaddend.X representing a CZ2 in which Z represents a hydrogen, .Iadd.a .Iaddend.fluorine .Iadd.atom.Iaddend., .Iadd.a .Iaddend.chlorine .Iadd.atom.Iaddend., .Iadd.a .Iaddend.bromine .Iadd.atom, .Iaddend.or .Iadd.an .Iaddend.iodineatom, R3 and R4 independently of one another represent a hydrogen atom.[.,.]. .Iadd.or .Iaddend.an α or β alkyl group with 1 to 10 carbon atoms.Iadd., .Iaddend.and R5 represents an alkyl group with 1 to 3 carbon atoms. From the EP 0 768 316 A1, steroids are known with .[.at 14,15 methylene.]. .Iadd.at 14,15-methylene .Iaddend.group, which have progesterone activity and, with that, in combination with at least one suitable estrogen, are suitable for hormonalcontraception and menopausal hormone replacement therapy (HRT) as well as for the treatment of endometriosis .[.and.]. .Iadd.or .Iaddend.gestagen-dependent tumors. With this state of the art as background, it is an object of the present invention to prepare new, unsaturated, 14,15-cyclopropano-androstanes. The objective was accomplished by unsaturated 14,15-cyclopropano-androstanes of the general formula (I).Iadd.:.Iaddend. ##STR00003## in which R1 represents a hydrogen atom, a hydroxy group, a C1-10 alkyl .Iadd.group.Iaddend., aC1-10 alkyloxy .Iadd.group.Iaddend., a C1-15 acyloxy .Iadd.group.Iaddend., a C4-15 aryloxy .Iadd.group.Iaddend., a C7-15 aralkyloxy .Iadd.group.Iaddend., or a C7-15 alkylaryloxy group.[., in which.]. .Iadd.;.Iaddend. R2represents a hydrogen atom, a hydroxy group, a C1-10 alkyl .Iadd.group.Iaddend., a C1-10 acyl .Iadd.group.Iaddend., a C1-10 acyloxy .Iadd.group.Iaddend., a C6-15 aryl .Iadd.group.Iaddend., a C7-15 aralkyl .Iadd.group, .Iaddend.ora C7-15 alkylaryl group.Iadd.;.Iaddend. a --(CH2)nCH.sub.2Y group, in which n=0, 1.Iadd., .Iaddend.or 2 and Y represents a halogen atom, especially a fluorine, chlorine, bromine.Iadd., .Iaddend.or iodine atom, .Iadd.or .Iaddend.apseudohalogen, especially a cyano, .[.azide or rhodanide.]. .Iadd.an azido, or a thiocyanato .Iaddend.group.[.,.]. .Iadd.;.Iaddend. a --(CH2)m--CH=CH(CH2)p--R.sub.6 group in which m=0, 1, 2.Iadd., .Iaddend.or 3 and p=0,1.Iadd., .Iaddend.or 2 and R6 represents a hydrogen atom, a C1-10 alkyl .Iadd.group.Iaddend., a C6-15 aryl .Iadd.group.Iaddend., a C7-15 aralkyl .[.or.]. .Iadd.group, .Iaddend.a C7-15 alkylaryl group.[.or.]. .Iadd., .Iaddend.ahydroxyl group, a C1-10 alkyloxy group.Iadd., .Iaddend.or a C1-10 acyloxy group.[.,.]. .Iadd.;.Iaddend. .Iadd.a --(CH2)oC≡CR.sub.7 group.Iaddend. in which o.[.-.]. .Iadd.=.Iaddend.0, 1 or 2 and .[.R7.]. .Iadd.R7.Iaddend.represents a hydrogen atom, a halogen atom, especially a fluorine, chlorine, bromine.Iadd., .Iaddend.or iodine atom, a C1-10 alkyl .Iadd.group.Iaddend., a C6-15 aryl .Iadd.group.Iaddend., a C7-15 aralkyl .Iadd.group.Iaddend., aC7-15 alkylaryl .Iadd.group, .Iaddend.or a C1-10 acyl group.[.,.]. .Iadd.; or.Iaddend. R1 and R2 together represent a keto .Iadd.group.Iaddend., .Iadd.a .Iaddend.methylene .[.or.]. .Iadd.group, a .Iaddend.difluoromethylenegroup.Iadd., .Iaddend.or, with inclusion of .Iadd.a .Iaddend.C-17, form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane.[., there being a double bond between C-1 and C-2, there being.]. ; an α or β cyclopropane group .Iadd.is present.Iaddend.between C-14 and C-15.[.,.]. .Iadd.;.Iaddend. R3 represents a hydrogen atom or an α or β C1-10 alkyl group.[.,.]. .Iadd.;.Iaddend. R4 represents .Iadd.a hydroxyl group, a perfluoroalkyl group, a halogen atom,especially a fluorine atom, a chlorine atom,.Iaddend. or .Iadd.a .Iaddend.bromine atom.Iadd., .Iaddend.or a pseudohalogen, especially .[.a rhodanide or an azide group, or a hydroxyl or perfluoroalkyl group and.]. .Iadd.an azido group or a thiocyanatogroup;.Iaddend. R5 represents a C1-4 alkyl group.[.,.]. .Iadd.; and.Iaddend. .Iadd.optionally a double bond is present between C-1 and C-2;.Iaddend. with the proviso that, if .[.there is a.]. .Iadd.the .Iaddend.double bond .Iadd.is present.Iaddend.in the 1,2 position, R4, in addition to the meanings given above, may be a hydrogen atom.[., as well as their pharmaceutically tolerated salts.]. .Iadd.; or.Iaddend. .Iadd.pharmaceutically tolerated salts thereof.Iaddend.. Surprisingly, it was found that the inventive, unsaturated .[.14,15-cyclopropane-androstanes.]. .Iadd.14,15-cyclopropanoandrostanes .Iaddend.of the general formula (I) are compounds with gestagenic and/or androgenic activity. Within the sense of the invention, pharmaceutically tolerated salts are alkali or alkaline earth salts, especially sodium, potassium or ammonium salts. These salts can be synthesized by standard techniques and methods, which are well known inthe art. Within the sense of the present invention, a "C1-4 or C1-10 alkyl group" is understood to be a branched or linear alkyl group with 1 to 4 or 1 to 10 carbon atoms. As examples, a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl ort-butyl, n-pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group are mentioned. Within the sense of the present application, the concept of "C1-10 alkoxy group" is understood to include cyclic or acyclic groups, the alkyl portion of which contains 1 to 10 carbon atoms. "Cyclic groups" are understood to include alsoheterocyclic groups, which may have one or two hetero atoms in the ring, which may be selected from a nitrogen atom, an oxygen atom and a sulfur atom. A methoxy group, an ethoxy group or an n- or iso-propoxy group or an iso- or t-butoxy, a1'-methoxy-cyclopentoxy or a tetrahydropyranyloxy group are examples. In the sense of the present application, the concept of C1-10 or C1-15 acyl or acyloxy group" is understood to be a group with 1 to 10 or 1 to 15 carbon atoms of the linear or branched alkane carboxylic acids, such as formic acid,acetic acid, propionic acid, butyric acid, iso-butyric acid, heptanoic acid or undecanoic acid. Within the sense of the present application, the concept of a "C6-15 aryl group" is understood to include a substituted or unsubstituted aryl group with 6 to 15 carbon atoms, such as a phenyl group, a substituted phenyl group, such as ahalogenated phenyl group or a nitrophenyl group, or a naphthyl group. Within the sense of the present application, the concept of a "C4-15 aryloxy group" is understood to include a carbocyclic or heterocyclic group with 4 to 15 carbon atoms. Examples are a benzoyloxy group, a 1- or 2-naphthinyloxy group, a 2-or 3-furanyloxy group, a 2- or 3-thienyl group and a 2-, 3- or 4-pyridinyloxy group. Within the sense of the present application, the concept of a "C7-15 alkylaryl group" is understood to include an aryl group, which is substituted by an alkyl group, the two group together having 7 to 15 carbon atoms. The aryl group mayhave additional substituents, such as a halogen atom. Examples are a toluenyl group (methylphenyl group), a halogenated toluenyl group, an ethylphenyl group, a dimethylphenyl group or a trimethylphenyl group. Within the sense of the present application, the concept of a "C7-15 alkylaryloxy group" is understood to be a "C7-15 aralkyl group", such as a 3- or a 4-methylphenyloxy group, which is extended by an oxygen atom. Within the sense of the present application, the concept of a "C7-15 aralkyl group" is understood to include an alkyl group, which is substituted by an aryl group, the two groups together having 7 to 15 carbon atoms. The aryl group may havefurther substituents, such as a halogen atom. Examples are a free or an aromatically substituted benzyl group, such as a benzyl group or a halogenated benzyl group. Within the sense of the present application, the concept of "C7-15 aralkyloxy group" is understood to include "C7-15 aralkyl groups", which has been extended by an oxygen atom, such as a benzyloxy group. Within the sense of the present invention, the concept of "halogen" comprises a fluorine, chlorine, bromine or iodine atom. Within the sense of the present application, the concept of "pseudohalogen" comprises a .[.cyanate, rhodanide,.]. .Iadd.cyanato, thiocyanato, .Iaddend.cyano.Iadd., .Iaddend.or .[.azide.]. .Iadd.azido .Iaddend.group. Within the sense of the present application, the concept of "perfluoroalkyl group" comprises a branched or linear fluoroalkyl group with 1 to 3 carbon atoms, such as a trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl orheptafluoro-i-propyl group. R1 represents preferably a hydroxy or acyloxy group, especially a hydroxy group, formyloxy group, acetyloxy group, propionyloxy group, n-butyryloxy group, i-butyryloxy group, heptanyloxy group or undecanyl group. If R2 represents a --(CH2)nCH.sub.2Y group, n preferably is 1 and Y preferably represents a fluorine atom, a cyano or rhodanide group. If R2 is a --(CH2)m--CH=CH(CH2)p--R.sub.6 group, m preferably is 1and R6 preferably represents a methyl or ethyl group or a methoxy or ethoxy group. .Iadd.If R2 represents a --(CH2)oC≡CR.sub.7 group, o preferably is 1 and R7 preferably represents a fluorine atom, a methyl group, or an ethyl group..Iaddend. It is particularly preferred if R2 represents a hydrogen atom or a C1-6 alkyl group, especially a methyl or ethyl group. R3 preferably represents a C1-4 alkyl group, especially a methyl group. R4 preferably represents a fluorine, chlorine or bromine atom or a trifluormethyl or hydroxy group. R5 preferably represents a methyl or ethyl group. The most preferred compounds are the following: 1) 4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne 2) 4-chloro-17α-hydroxy-14α,15α-methylene-androst-4-e- ne-3-one 3)4-chloro-17β-hydroxy-14β,15β-methylene-androst-4-ene-3-one 4) 4-chloro-17α-hydroxy-14β,15β-methylene-androst-4-ene-3- -one 5) 4-bromo-17β-hydroxy-14α,15α-methylene-androst-4-e- ne-3-one 6)4-bromo-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne 7) 4-bromo-17β-hydroxy-14β,15β-methylene-androst-4-ene-3- -one 8) 4-bromo-17α-hydroxy-14β,15β-methylene-androst-4-en- e-3-one 9)4-fluoro-17β-hydroxy-14α,15α-methylene-androst- -4-ene-3-one 10) 4-fluoro-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-- one 11) 4-fluoro-17β-hydroxy-14β,15β-methylene-androst-4-en- e-3-one 12)4-fluoro-17α-hydroxy-14β,15β-methylene-androst-4-ene-3-on- e 13) 4,17β-dihydroxy-14α,15α-methylene-androst-4-ene-3-o- ne 14) 4,17α-dihydroxy-14α,15α-methylene-androst-4-ene-3- -one 15)4,17β-dihydroxy-14β,15β-methylene-androst-4-ene-3-- one 16) 4,17α-dihydroxy-14β,15β-methylene-androst-4-ene-3-- one 17) 4-trifluoromethyl-17β-hydroxy-14α,15α-methylene-a- ndrost-4-ene-3-one 18)4-trifluoromethyl-17α-hydroxy-14α,15α-methylene-androst- -4-ene-3-one 19) 4-trifluoromethyl-17β-hydroxy-14β,15β-methylene-androst-4-- ene-3-one 20)4-trifluoromethyl-17α-hydroxy-14β,15β-methylene-androst-4- -ene-3-one 21) 17β-hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one 22) 17α-hydroxy-14α,15α-methylene-androsta-1,4-diene-3-- one 23)17β-hydroxy-14α,15α-methylene-androsta-1,4-diene-- 3-one 24) 17β-hydroxy-14β,15β-methylene-androsta-1,4-diene-- 3-one 25) 17α-hydroxy-14β,15β-methylene-androsta-1,4-diene- -3-one 26)4-chloro-17α-hydroxy-14α,15α-methylene-andros- ta-1,4-diene-3-one 27) 4-chloro-17β-hydroxy-14α,15α-methylene-androsta-1,4-dien- e-3-one 28) 4-chloro-17β-hydroxy-14β,15β-methylene-androsta-1,4-diene--3-one and 29) 4-chloro-17α-hydroxy-14β,15β-methylene-androsta-1,4-diene- -3-one The inventive compounds and their pharmaceutically acceptable salts can be synthesized in that, in compounds of the general formula (II) ##STR00004## in which R1, R2, R3, and R5, which have the meanings given above, and thereis an α or β cyclopropane group between C-14 and C-15, the 4,5 double bond is epoxidized under alkaline conditions with hydrogen peroxide and the resulting epoxide mixture is treated in a suitable solvent with acids of the general formulaHR8, in which R8 may be a halogen atom or a pseudohalogen. Moreover, the corresponding 4-bromo compounds can also be synthesized by the addition of bromine by means of bromine, N-bromosuccinimide or N-bromoacetamide to compounds of the generalformula (II) in a mixture of acetic acid and ether in the presence of a proton acceptor, such as collidine, (X. S. Fei et. al., J. Chem. Soc. Perkin Trans. 1, 1998, 1139-1142). 4-Hydroxy compounds are obtained by reacting the epoxide mixture above with catalytic amounts of mineral acid, such as sulfuric acid (P. S. Furth et. al. J. Enzyme Inhibition, 1990, Vol. 4, 131-135). Compounds of the general formula (I) with an additional double bond in the 1,2 position can be obtained easily by methods known to those skilled in the art, such as the dehydrogenation of the 4-ene-3-one system by means of2,3-dichloro-5,6-dicyanobenzoquinone in a suitable solvent, such as dioxane, toluene or t-butanol. 4-Trifluormethyl compound of the general formula (I) can be obtained by the reaction of the 4-bromo compounds of the general formula (I), which are mentioned above, with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in dimethylformamide thepresence of CuI (X. S. Fei et. al., J. Chem. Soc., Perkin Trans. 1, 1998, 1139-1142). The starting compounds of formula (II) can be synthesized by known methods or by the method described in the German application with the application No. 198 27 523.4(PCT/DE99/01794). The introduction of the groups, which are analogous to the groups R1, R2, R3 and R5 occurring there and are claimed here, is described in the protective right mentioned. Pharmaceutical compositions for the oral, rectal, subcutaneous, intravenous or intramuscular applications, which contain at least one compound of the general formula (I) and/or their acid addition salts as active ingredient, together with theconventional vehicles and diluents are also an object of the present invention. Pharmaceutical preparations of the invention are prepared with the usual solid or liquid vehicles and/or diluents and the inactive ingredients, the use of which is generally customary in accordance with the desired type of application, in asuitable dosage and by a known procedure. In the case of a preferred oral form of administration, preferably tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions are prepared also in sustained release form. In addition, parenteral forms of medicinal drugs, such as injection solutions or suspensions, can also be considered. Medicinal drug forms as tablets can be obtained for example by mixing the active ingredient with the known inert materials, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid,binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents, which can achieve a sustained release effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Thetablets may also consist of several layers. Similarly, coated tablets can be prepared by coating cores, prepared similarly to the tablets, with agents used in conventional tablet coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The tabletcoating may consist of several layers, the inert materials, named above, for example being used. To improve the taste, the solutions or suspensions with the inventive active ingredient can be mixed with materials such as saccharin, cyclamate or sugar and/or with aromatic and flavoring materials such as vanillin or orange extract. Moreover,they may be mixed with suspending agents, such as sodium carboxymethylcellulose, or preservatives, such as p-hydroxybenzoic acid. Capsules can be prepared by mixing medicinal drugs with vehicles, such as lactose or sorbitol, which are then brought into the capsules. Suppositories are prepared preferably by mixing active ingredients with suitable vehicles, such as neutral fats or polyethylene glycols or their derivatives. The pharmaceutical forms of preparations furthermore can be percutaneous forms, such as transdermal therapeutic systems (TTS) or gels, sprays or ointments or intranasal forms, such as nose sprays or oral nose drops. The inventive 14,15-cyclopropanoandrostanes of the general formula (I) are compounds with hormonal (gestagenic and/or androgenic) activity. For example, the compound of the general formula (I), in which R1 is a hydroxyl group, R2 and R3 are hydrogen atoms, R5 is a methyl group and X is a CH2 group and the 14,15 cyclopropane ring is in the α position,namely 4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne is an androgen. The 4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-- 3-one binds to the extent of 42%. -.3% to the androgen receptor of the rat prostate (reference substance. 17β-hydroxy-17α-methyl-estra-4,9,11-triene-3-one; R1881). On the other hand, there is practically no binding to the progesterone receptor of the rabbit uterus (reference substance: progesterone). It was possible to demonstrate distinct androgenic activity in the Hershberger test. On the other hand,there is hardly any gestagenic activity in the pregnancy maintenance test. These test results open up various possibilities for the inventive compounds of the general formula (I) for fertility control in men, hormone replacement therapy (HRT) in men and women or the treatment of hormonally induced diseases in men andwomen, such as endometriosis, breast cancer or hypogonadism. The following examples are intended to explain the invention in greater detail without limit it. EXAMPLES Example 1 17β-Hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one Synthesis of 4,5-Epoxides 17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one (2 g) is dissolved in 80 mL of methanol and treated at 0° C. with 26 mL of a hydrogen peroxide solution (35%). While stirring, 5.2 mL of a 10% sodium hydroxide solutionare added, the stirring being continued at 0° C. for 30 hours. The reaction solution is mixed with 50 mL of dichloromethane and 25 mL of water and the organic phase is removed, washed with semi-concentrated thiosulfate solution, dried andevaporated to dryness. The residue obtained consists of a mixture of 4α,5α- or 4β,5β-epoxides and is used in the subsequent step without further purification. Example 2 17α-Hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one The compound, named above, can be obtained from 17α-hydroxy-14α,15α-methylene-androst-4-ene-3-one by a method, similar to that of Example 1. Example 3 4-Chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-on- e 17β-hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one (1.5 g) is dissolved in 150 mL of acetone and treated at 0° C. with 5.5 mL of concentrated hydrochloric acid. After 24 hours at 0° C., the reaction mixtureis neutralized with sodium carbonate solution and the acetone is evaporated. The residue is extracted with dichloromethane. The organic extracts are dried and concentrated. After crystallization from ethanol,4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne is obtained. 1H-NMR: 0.12 (1H, dd, I=5.5, 3.3 Hz, CH2-bridge), 0.22 (1H, dd, J=8.2, 5.5 Hz, CH2-bridge), 0.99 (3H, s, H-18), 1.30 (3H, s, H-19), 3.49 (1H, dd, J=9.3, 7.1 Hz, H-17). Example 4 4-Chloro-17α-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne 17α-Hydroxy-14α,15α-methylene-androst-4-ene-3-one is reacted by a method, similar to that of Example 3. 1H-NMR: 0.32 (1H, dd, J=7.7, 4.9 Hz, CH2-bridge), 0.72 (1H, dd, J=4.4, 3.3 Hz, CH2-bridge), 0.99 (3H, s, H-18), 1.29 (3H, s, H-19), 3.80 (1H, d, J=6.0 Hz, H-17). Example 5 4,17β-Dihydroxy-14α,15α-methylene-androst-4-ene-3-one An epoxide mixture (3.5 g), 17β-hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one, (step 1) is dissolved in 50 mL of acetic acid, which contains 2% by volume of concentrated sulfuric acid. The solution is allowed to stand for3 days at 10° C. After that, it is treated with 200 mL ethyl acetate and neutralized with sodium carbonate solution. The organic phase is dried and concentrated. The residue is dissolved in 100 mL of methanol, treated with 4 g of potassiumhydroxide, refluxed for 1 hour and then cooled. After neutralization with 50% acetic acid, it is poured into 1 L of water and the crystals are filtered off with suction, 4,17β-Dihydroxy-14α,15α-methylene-androst-4-ene-3-one beingobtained. 1H-NMR: 0.13 (1H, dd, J=5.6, 3.2 Hz, CH2-bridge), 0.24 (1H, dd, J=8.3, 5.6 Hz, CH2-bridge), 0.99 (3H, s, H-18), 1.30 (3H, s, H-19), 3.50 (1H, dd, J=9.4, 6.8 Hz, H-17), 6.10 (1H, s, 4-OH). Example 6 4-Bromo-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one The target compound is synthesized in a manner similar to the synthesis of 4-Chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne, 48% hydrobromic acid being used instead of hydrochloric acid. 1H-NMR: 0.12 (1H, dd, J=5.5, 3.3 Hz, CH2-bridge), 0.21 (1H, dd, J=8.4, 5.4 Hz, CH2-bridge), 1.00 (3H, s, H-18), 1.33 (3H, s, H-19), 3.49 (1H, dd, J=9.3, 7.1 Hz, H-17). Example 7 4-Trifluoromethyl-17β-hydroxy-14α,15α-methylene-androst-4- -ene-3-one 4-Bromo-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-one (1.5 g) is dissolved in 180 mL of dimethylformamide and stirred at 75° C. for 12 hours with 1 g of CuI as well as 2.8 mL of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate. After working up and chromatographic purification, 4-Trifluoromethyl-17β-hydroxy-14α,15α-methylene-androst-- 4-ene-3-one is obtained. 1H-NMR: 0.14 (1H, dd, J=5.5, 3.0 Hz, CH2-bridge), 0.25 (1H, dd, J=8.2, 5.8 Hz, CH2-bridge), 1.00 (3H, s, H-18), 1.32 (3H, s, H-19), 3.51 (1H, m, H-17). 19F-NMR: -55.3 (3F, s, 4-F3C). Example 8 17β-Hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one 17β-Hydroxy-14α,15α-methylene-androst-4-ene-3-one (4 g) in 160 mL of toluene is stirred for 6 days at 85° C. with 3.2 g of 2,3-dichloro-5-6-dicyanobenzoquinone. The precipitate is filtered off, washed with a littletoluene and the filtrates and washings are evaporated to dryness. The residue is purified by chromatography, 17β-Hydroxy-14α,15α-methylene-androsta-1,4-diene-3-one being obtained. 1H-NMR: 0.13 (1H, dd, J=5.6, 3.2 Hz, CH2-bridge), 0.24 (1H, dd, J=8.3, 5.6 Hz, CH2-bridge), 0.98 (3H, s, H-18), 1.35 (3H, s, H-19), 3.50 (1H, m, H-17), 6.06 (1H, m, H-4); 6.22 (1H, dd, J=12.09; 1.65 Hz, H{2}), 7.04 (1H, d, J=9.9Hz, H-1). Example 9 4-Chloro-17β-hydroxy-14α,15α-methylene-androsta-1,4-diene- -3-one This compound is prepared from 4-chloro-17β-hydroxy-14α,15α-methylene-androst-4-ene-3-o- ne by a method to that of Example 6. 1H-NMR: 0.13 (1d, dd, j=5.6, 3.2 Hz, CH2-bridge), 0.24 (1H, dd, J=8.3, 5.6 Hz, CH2-bridge), 0.98 (3H, s, H-18), 1.35 (3H, s, H-19), 3.50 (1H, m, H-17), 6.22 (1H, dd, j=12.09, 1.65 Hz, H{2}), 7.04 (1H, d, J=9.9 Hz, H-1). * * * * * Other References
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