New derivatives of 3-keto delta 4,9,19-nor steroids,their preparation,their application as medicaments,the compositions containing them and the new intermediates obtained

Description: TECHNICAL FIELD [Detailed description of the invention]

The present invention is 3-keto-Δ^4,9,19-Regarding new derivatives of norsteroids, their production, use as drugs, compositions containing them and new intermediates obtained. Therefore, the subject of the present invention is the following general formula ().<img file="JPH054397B2_D0001.tif" /> [Here, R₁Is a thienyl group, a frill group, a cycloalkyl group having 3 to 6 carbon atoms, which may be optionally substituted with halogen, and optionally hydroxyl, halogen, trifluormethyl, alkyl, alkoxy, alkylthio (sometimes sulfoxide). Or oxidized in the form of a sulfone), representing a phenyl group optionally substituted with one or more groups selected from the group consisting of alkenyloxy and phenyloxy groups having up to 6 carbon atoms. Or, or R₁Represents a naphthyl or phenyl-phenyl group or an alkyl or alkenyl group having up to 6 carbon atoms (the alkenyl group may optionally have several unsaturateds). R₂Represents a methyl or ethyl group R₃Has a hydrogen atom, a hydroxyl, an acetyl or a hydroxyacetyl group, a carboxy-alkoxy group having 2 to 4 carbon atoms and may be esterified or salted, or optionally esterified. Represents a hydroxyalkyl group R₄Represents an alkyl or alkynyl group that has a hydrogen atom, a hydroxyl group, or up to 12 carbon atoms and may optionally be substituted with an amino, alkylamino or dialkylamino group, halogen. R₅Represents a hydrogen atom or a methyl group at the α or β position. X represents an oxygen atom, or a hydroxyimino at the syn or anti position, or an alkoxyimino group having 1 to 4 carbon atoms. A and B represent the presence of an α-epoxy functional group or a second bond between the 9th and 10th carbons] and R₄Is a salt of the compound with an acid (where A, B, R) when represents a group containing an amino functional group.₁, R₂, R₃, R₄, R₅And X have the following meanings, i.e. A and B represent the second bond between the carbons X represents an oxygen atom, R₅Represents a hydrogen atom and a R₂Represents a methic group, and α R₃Represents a hydroxyl group, R₁Represents an ethyl or phenyl group and R₄Represents a hydrogen atom, or R₁Represents ethyl, propyl, isopropyl, vinyl, allyl, isopropanol, phenyl, p-fluorphenyl, methoxyphenyl or thienyl groups and R₄Represents an ethynyl group, or R₁Represents a propyl, isopropyl, pinyl, allyl, isopropanol, p-methoxyphenyl or thienyl group and R₄Represents a methyl group β R₃Represents an acetyl group, R₁Represents an ethyl, vinyl or phenyl group and R₄Represents a hydroxyl group, or R₁Represents a vinyl group and R₄Represents a methyl group b R₂Represents an ethyl group, R₁Represents a vinyl group, R₃Represents a hydroxyl group and R₄Represents a hydrogen atom (Excluding compounds). In the formula (), as the substituent of the thienyl group, a halogen group such as fluor, chlor, or prom can be mentioned. The cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. R₁Substituents present in the case of phenyl can be represented by alkyl groups such as methyl, ethyl, propyl, isopropyl, petit, isoptyl, sec-putyl, t-putyl, pentyl, isopentyl and hexyl. Alkoxy and alkylthio groups are derived from the above alkyl groups. Alkoxy and alkylthio groups are preferred. The alkenyloxy group is preferably a pinyloxy or allyloxy group. R₁Examples of the alkyl group that can be represented by are the above-mentioned alkyl groups. Examples of the alkenyl group include vinyl and allyl groups. Also mentioned are groups containing several unsaturated groups, such as 1,2-propazienyl groups. R₂Methyl is preferable as the meaning of. R₃In addition to those described above, t-ptoxycarbonylmethoxy group and carboxymethoxy group are preferable, and the latter salt is formed in the form of a salt of an alkali metal or an alkaline earth metal, magnesium, ammonium or an organic base, for example. It may have been done. For example, sodium, potassium, lithium, calcium, magnesium or ammonium salts can be mentioned. Organic bases include methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picolin, dicyclohexylamine, morpholine, benzylamine, prokine. , Lysine, arginyl, histidine, N-methylglucamine. Sodium salt is preferred. R₄In particular, the meaning of is methyl, ethyl, ethynyl or 1-propynyl group. Moreover, 3-dimethylamino-1-propynyl group or 3-amino-1-propynyl group can be mentioned. R₃And R₄As the meaning of, a group having a maximum of 4 carbon atoms, particularly an ethynyl or propynyl group is preferable. As the alkyloxime that X can represent, methyloxime is preferable. Examples of the acid addition salt include salts formed of hydrochloric acid, acetic acid, trifluoracetic acid, aleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, phosphoric acid, sulfuric acid and hydrobromic acid. .. In particular, the present invention is based on R.₁Represents a cycloalkyl group or a substituted thienyl group having 3 to 6 carbon atoms, or X represents a hydroxyimino group at the syn or anti position or an alkoxyimino group having 1 to 4 carbon atoms, or symbolic A and B represent α-epoxy functional groups or R₅The subject is the compound of the above general formula (), wherein is represented by a methyl group. More specifically, the subject matter of the present invention is R.₃Represents a hydroxyl group, R₄Represents a propynyl group, R₂Represents a methyl group and R₅The compound of the above formula () and R representing a hydrogen atom₃Represents an acetyl group, R₄Represents a methyl group or a hydrogen atom and R₁Is in the compound of formula () above, which represents a phenyl group which may optionally be substituted. Among the preferred compounds of the present invention, the group R₁Represents a phenyl group, or a chlortienyl group, which may be substituted with one of the groups selected from the group consisting of a cyclopropyl group, optionally chlor, fluor, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy groups and R.₄Can be mentioned as representing a propynyl group. The preferred type of compound comprises a compound of the formula () in which the symbols A and B represent an epoxy group. Of course, the compounds further described in the Examples are particularly preferred compounds, especially the following compounds. 11β-[(4-Chlor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(5-chloro) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(3-Chlor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one 11β-[(4-methylthio) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(3-fluor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(4-Methylthio) phenyl] -17α-methyl-19-norpregna-4,9-diene-3,20-dione, 11β-[(4-Methylthio) phenyl] -16α-methyl-19-norpregna-4,9-diene-3,20-dione, 11β-Cyclopropyl-17β-Hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β- [3- (2-propenyloxy) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 9α, 10α-epoxy-17β-hydroxy-11β- (4-methoxyphenyl) -17α- (1-propynyl) estra-4-en-3-one, 9α, 10α-epoxy-17β-hydroxy-11β-[(4-methylsulfonyl) phenyl] -17α- (1-propynyl) estra-4-en-3-one, 11β-[(3-fluor) phenyl] -3-hydroxyimino-17α- (1-propynyl) estra-4,9-diene-17β-ol, anti isomer, 17β-Hydroxy-17α- (1-propynyl) -11β- (4-Hydroxyphenyl) estra-4,9-diene-3-one, and especially 11β-[(4-methylthio) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one. Further, the subject of the present invention is the following general formula () in producing a compound of the general formula ().<img file="JPH054397B2_D0002.tif" /> (Here, K represents a ketone group blocked in the form of ketal, thioketal, oxime or methyloxime, R'.₃Is the above-mentioned R₃Has the meaning of and the meaning of the blocked acetyl group, R'₁Is the above-mentioned R₁And has the meaning of a phenyl group substituted with a protected hydroxyl group, R₂, R₄And R₅Has the above meaning) A dehydrating agent capable of liberating a protected functional group is allowed to act on the compound of_A) <img file="JPH054397B2_D0003.tif" />(This corresponds to the compound of formula () where X represents an oxygen atom and A and B together form a second bond between carbons), and if desired the formula (_A) Compound the following reaction: a Oxidation of A and B to obtain compounds forming epoxy functional groups and R₁If contains a sulfur atom, oxidize this atom to sulfoxide or sulfone, b The action of hydroxylamine or any derivative of hydroxylamine so that X obtains a compound representing a hydrochimino or an alkoxyimino group, c R₃Hydrolysis and salt formation, which may be carried out in the case of compounds representing esterified carboxy-alkoxy groups. d R₄Salt formation of compounds representing alkyl, alkenyl or alkynyl groups substituted with gaamino, alkylamino or dialkylamino groups, It is in the method for producing a compound of the general formula (), which comprises attaching one or more of the above in any order. In a preferred embodiment of the above process, the dehydrating agent capable of liberating one or more protected functional groups has a sulfonic acid resin (acid form), such as a polystyrene carrier or a styrene / divinylbenzene polymer carrier. Although it is a commercially available sulfonic acid resin, inorganic acids such as hydrochloric acid or sulfuric acid in lower alkanol, perchloric acid in acetic acid, or sulfonic acid such as p-toluenesulfonic acid can also be used. The oxidant is preferably a peracid such as m-chlorperbenzoic acid, peracetic acid or perphthalic acid. Hydrogen peroxide can also be used alone or in the presence of hexachloro or hexafluoracetone. Of course, one equivalent or more of the oxidizing agent can be used, depending on the number of functional groups to be oxidized. Therefore, for example, R₁Of course, at least 3 equivalents of oxidant must be used if one wishes to oxidize the sulfur atoms contained in the sulfur atoms to sulfones and the double bonds to epoxides. The action of hydroxylamine or an alkyl derivative of hydroxylamine is preferably carried out in an alcohol such as ethanol. Further, it is preferable to use a salt, particularly a hydrochloride salt. R₃Hydrolysis and salt formation, if necessary, for compounds containing esterified carboxyalkoxy groups are carried out under normal conditions. Hydrolysis can be carried out in an organic solvent such as benzene in the presence of an acid such as p-toluenesulfonic acid. Base hydrolysis in the presence of a base, followed by acidification, can also be performed. Salt formation is carried out under normal conditions. For example, it can be carried out in ethanol in the presence of sodium hydroxide. Sodium carbonate, acidic sodium carbonate or potassium can also be used. Salt formation with acid is also carried out under normal conditions. For example, it is preferable to carry out with hydrochloric acid in the form of an ether solution. In a preferred method, the above production method is R'.₃Represents a hydroxyl group, R₄Represents a propynyl group, R₂Represents a methyl group, and R₅Is a compound of formula () representing a hydrogen atom, or R'₃Represents an acetyl group, R₄Represents a methyl group or a hydrogen atom, and R'₁A compound representing a phenyl group, which may optionally be substituted, and further R'₁Represents a phenyl group, and a chlortienyl group, even if substituted with one of the groups selected from the group consisting of cyclopropyl, optionally chlor, fluor, methylthio, methylsulfonyl, methoxy, hydroxy and allyloxy groups, and R₄Is carried out by using a compound that represents a propynyl group. The compounds of formula () and their addition salts with pharmaceutically acceptable acids are particularly beneficial compounds from a pharmacological point of view. In particular, they have significant anti-glucocorticoid activity, as the test results below show. Studies of the activity of this compound on hormone receptors have demonstrated progesterone-like or anti-progesterone-like, androgen or anti-androgen activity. Therefore, the compounds of formula () and their addition salts with pharmaceutically acceptable acids can be used mainly as agents for suppressing the side effects of glucocorticoids. They also treat disorders resulting from hypersecretion of glucocorticoids, especially when aging, specifically for hypertension, atherosclerosis, osteoporosis, diabetes and insomnia. It can also be used for immunosuppression and insomnia. In addition, the compounds of formula () having antiprogesterone-like activity and their addition salts with pharmaceutically acceptable acids can be used as pregnancy regulators. They can also be used for irregular hormone secretion and are also beneficial in the treatment of hormone-dependent cancers. Certain compounds of formula () and their pharmaceutically acceptable acid addition salts exhibit progesterone-like activity and can therefore be used in the treatment of amenorrhea, dysmenorrhea and luteal insufficiency. In addition, compounds of formula () exhibiting antiandrogen activity and their pharmaceutically acceptable acid addition salts can be used to treat benign prostatic hyperplasia, prostate cancer, hirsutism, anemia, hirsutism, and spasm. it can. Thus, the present invention is directed to a drug comprising a pharmaceutically acceptable compound of formula (), i.e. a non-toxic compound at an effective dosage, and an addition salt with a pharmaceutically acceptable acid thereof. In particular, the subject of the present invention is a drug comprising the following compounds. 11β-[(4-Chlor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(5-chloro) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(3-Chlor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one 11β-[(4-methylthio) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(3-fluor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β-[(4-Methylthio) phenyl] -17α-methyl-19-norpregna-4,9-diene-3,20-dione, 11β-[(4-Methylthio) phenyl] -16α-methyl-19-norpregna-4,9-diene-3,20-dione, 11β-Cyclopropyl-17β-Hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 11β- [3- (2-propenyloxy) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one, 9α, 10α-epoxy-17β-hydroxy-11β- (4-methoxyphenyl) -17α- (1-propynyl) estra-4-en-3-one, 9α, 10α-epoxy-17β-hydroxy-11β-[(4-methylsulfonyl) phenyl] -17α- (1-propynyl) estra-4-en-3-one, 11β-[(3-fluor) phenyl] -3-hydroxyimino-17α- (1-propynyl) estra-4,9-diene-17β-ol, anti isomer, 17β-Hydroxy-17α- (1-propynyl) -11β- (4-Hydroxyphenyl) estra-4,9-diene-3-one, especially 11β-[(4-methylthio) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one. The effective dosage depends on the disorder to be treated and the route of administration. For example, it would be 10 mg to 1 g per day by oral administration in the case of men. The compounds of the formula () as described above and their salts can be used in the production of pharmaceutical compositions containing at least one of these active ingredients. The compounds of formula () and their salts are administered by gastrointestinal, parenteral or topical application. They can be provided in the form of pharmaceuticals commonly used in human medicine, such as tablets or sugar-coated tablets, capsules, granules, suppositories, injectable formulations, ointments, creams, gels. They are manufactured by conventional methods. The active ingredient is an adjunct commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or plant origin fatty substances, paraffin derivatives. , Glycol, various wet, disperse or emulsifiers and preservatives. Accordingly, the subject of the present invention is a pharmaceutical composition containing at least one of the compounds of the formula () or at least one of a pharmaceutically acceptable salt thereof as an active ingredient. Further, as an intermediate necessary for producing the compound of the formula () as described above of the present invention, the following general formula (_a) <img file="JPH054397B2_D0004.tif" /> [Here, R'₁Is optionally substituted with a thienyl group, a frill group, a cycloalkyl group having 3 to 6 carbon atoms, optionally a halogen, hydroxy, trifluormethyl, alkyl, alkoxy, sulfoxide which may be protected. Alternatively, it represents an alkylthio which may be oxidized in the form of a sulfone, a phenyl group which may be substituted with one or more groups selected from the group consisting of an alkenyloxy having a maximum of 6 carbon atoms and a phenyloxy group. Or R'₁Represents a naphthyl or phenyl group or an alkyl or alkenyl group having up to 6 carbon atoms (the alkenyl group may optionally have several unsaturated groups). R₂Represents a methyl or ethyl group R ₃Is an esterification with hydrogen atoms, optionally substituted alkyl, alkoxy or alkynyl groups, hydroxyl groups, acetyl groups optionally protected in the form of ketals, hydroxyacetyl groups, 2-4 carbon atoms. Represents a carboxyalkoxy group or an acyloxyalkyl group and R'₄Alkyl having a hydrogen atom, a hydroxyl group, or up to 12 carbon atoms and optionally substituted with an amino, alkylamino or dialkylamino group, halogen, alkylthio, alkoxy, trialkylsilyl or cyano group. , Representing an alkenyl or alkynyl group, or R ₃Represents a cyanide group and R'₄Represents a blocked OH group in the form of an easily ruptured ether, R₅Represents a hydrogen atom or a methyl group at the α or β position X represents a ketone group blocked in the form of a ketal, thioketal, oxime or methyl oxime] Compound (however, R'₁, R₂, R ₃, R₄, R₅And X have the following meanings, i.e. K represents the (1,2-ethandyl) acetal group and R₅Represents a hydrogen atom and a R₂Represents a methyl group, and α R ₃Represents a cyano group and R'₄Represents a trimethylsilyloxy group and R₁Represents a phenyl, methyl, ethyl, propyl, isopropyl, t-butyl, vinyl, allyl, isopropanol, o- or p-methoxyphenyl, thienyl, methoxyvinyl or p-fluorphenyl group. β R ₃Represents a hydroxyl group, R'₄Represents an ethynyl group and R'₁Represents an ethyl, propyl, isopropyl, vinyl, isopropanol, allyl, o- or p-methoxyphenyl or thienyl group. γ R ₃Represents an acetyl group, and R'₄Represents a hydroxyl group and R'₁Represents an ethyl, phenyl or vinyl group, or R'₄Represents a methyl group and R'₁Represents a vinyl group, b R₂Represents an ethyl group, and R ₃Represents a hydroxyl group, R'₁Represents a vinyl group and R'₄Represents a hydrogen atom Compounds are excluded] can be particularly exemplified. Among these compounds, the substituent of the thienyl group may be the one described above. The same is true for cycloalkyl groups, and R₁R'equivalent to the meaning of₁The meaning of is also true. The hydroxyl groups may be protected by standard protecting groups in organic chemistry. For example, acyl groups such as acetyl, chloracetyl, trifluolacetyl and phenoxyacetyl groups can be mentioned. Also mentioned are groups such as tetrahydropyranyl, trityl, benzyl, benzhydryl or trimethylsilyl. R ₃The acyloxyalkyl group represented by is preferably a 1-acetoxyethyl group. R'₄The easily decomposable ether that can be represented by is preferably trimethylsilyl. Ketone groups are preferably blocked in the ethanediyl form. formula(_a) Among the compounds, R ₃Represents a hydroxyl group, R'₄Represents a propynyl group, R₅Represents a hydrogen atom, and R₂Is preferably a methyl group. R'₁Preferred meanings are cycloalkyl, in particular phenyl, which may be substituted with one of the groups selected from the group consisting of chlor, fluor, methylthio, methylsulfonyl, hydroxy, methoxy and allyloxy, and chlor. It is a thienyl group. formula(_a) Is the compound of the following formula ()<img file="JPH054397B2_D0005.tif" /> (Here, K, R₂, R ₃, R'₄And R₅Has the meaning shown above) In the presence of catalytic amounts of cuprous halogenated, if necessary, in the compounds of (R'₁)₂CuLi or R'₁MgHal or R'₁Li (Here, R'₁Has the meaning shown above, Hal stands for halogen atom) The formula (_a), And if desired, react with this compound as follows: a R ₃Represents a cyano group and R'₄R by reacting a lithium ethylenediamine acetylide complex with a compound representing an OH group, which is blocked in the form of an ether that can be easily cleaved.₃Represents a hydroxyl group and R'₄Is an equation representing an ethynyl group (_a) Compound, or b R ₃Represents a cyano group and R'₄R by allowing methylmagnesium halide to act on the same compound representing the OH group, which is blocked in the form of an ether that can be easily cleaved.₃Represents an acetyl group and R'₄To obtain a compound that represents a hydroxyl group, c Remove the protected hydroxyl or acetyl protecting groups, It can be manufactured by attaching one or more of the above in any order. Equation (R'₁)₂When CuLi compounds are used, it is preferably carried out at a temperature of -100 ° C to 0 ° C. When a compound of formula R'MgHal is used, Hal preferably represents a bromine or chlorine atom, and in the presence of a catalytic amount of chloride or cuprous bromide, preferably at -40 ° C to 0 ° C. Performed at temperature. Equation R'₁When a compound of Li is used, it is carried out at a temperature of -40 ° C to 0 ° C in the presence of a catalytic amount of chloride or cuprous bromide. Copper halide may be used in the form of a complex with dialkylsulfide. In either case, it is preferably carried out in an organic solvent or solvent mixture, such as ethyl ether, isopropyl ether or tetrahydrofuran. In a preferred embodiment of the invention, R'₁When represents a group different from the allyl group, a compound of formula R'MgBr is used in the presence of a catalytic amount of cuprous chloride to introduce the 11β substituent, and in ethyl ether and / or tetrahydrofuran. It is carried out at a temperature of -40 ° C to -20 ° C. R'₁When represents an allyl group, the formula (R'₁)₂CuLi compounds are used and are carried out at temperatures from -90 ° C to -10 ° C. Also, R ₂Represents a hydroxyl group and R'₄Represents an alkyl, alkenyl or alkynyl group having up to 12 carbon atoms (_a) Is the compound of the following formula ()<img file="JPH054397B2_D0006.tif" /> (Here, K, R'₁, R₂And R₅Has the meaning mentioned above) It can be obtained by allowing an alkyl halide, an alkenyl or an alkynyl to act on the compound of. The compound of formula () is the following formula ()<img file="JPH054397B2_D0007.tif" />Formula (R'₁)₂CuLi, R'₁MgHal or R'₁It can be produced by reacting a compound of Li. The compounds of formula () or () are mostly known in the literature or can be readily prepared starting from the compounds known in the literature. In general, these compounds have the following formula:<img file="JPH054397B2_D0008.tif" /> (Here, Ri₃And Ri₄Is R ₃And R'₄Has the meaning shown above, or Ri₃And Ri₄Together to form a keto group) It is produced by allowing an oxidizing agent such as hydrogen peroxide or an organic peracid to act on the compound of the above in the presence of a catalyst. In the experimental section below, production examples of starting materials of formula () or () are also shown. The following examples exemplify the present invention and do not limit it in any way. The following compounds are compounds that can be obtained within the scope of the present invention. Manufacture 1: 3,3-ethylenebis (oxy) -17α- (1-propynyl) -11β- (2'-thienyl) estra-9-ene-5α, 17β-diol 0.82 g of cuprous chloride and 162 c.c. of thienyl magnesium bromide are introduced into tetrahydrofuran at -25 ° C under nitrogen (1.05 M / l). Stir the mixture for 15 minutes, then add 15 g of 3,3-ethylenebis (oxy) -5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -en-17β-ol to 80 c.c. The solution dissolved in tetrahydrofuran is added dropwise so that the temperature does not exceed -20 ° C. Stir under nitrogen at -25 ° C for 17 hours and at 0 ° C for 2 hours, then pour into a cold aqueous solution of ammonium chloride. Further, the mixture was stirred and extracted with ether, the organic phase was washed with water, dried, and concentrated under reduced pressure to obtain 18.8 g of a crude product. This was chromatographed on silica and purified (eluent: chloroform / ethyl acetate (9-1)) to give 9.85 g of product. MP = 250 ° C. Manufacture of starting material The 3,3-ethylenebis (oxy) -5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -en-17β-ol used at the start of production 1 was produced as follows. did. a 3,3-bismethoxy-17α- (1-propynyl) estra-5 (10), 9 (11) -diene-17β-ol α Propin Magnesium Bromide A 350 c.c. Ethylmagnesium bromide solution is introduced into tetrahydrofuran under nitrogen (1,1 M / l). Cool the mixture to 0 ° C and blow propyne for 2 hours while keeping the temperature at + 10 ° C in an ice bath. The temperature is then raised to 20 ° C while continuing to blow propylene. β condensation A solution consisting of 50 g of 3,3-bismethoxyestra-5 (10), 9 (11) -diene-17-one dissolved in 240 c.c. tetrahydrofuran over 50 minutes in the above solution and 2 drops. Triethylamine is introduced and the whole is stirred for 75 minutes and then poured into a cold aqueous solution of ammonium chloride. It was stirred for 15 minutes, extracted with ether, washed with 2 drops of saturated aqueous sodium carbonate solution containing pyridine, dried and concentrated under reduced pressure to give 62.4 g of crude product. 974 g of this product was chromatographed with silica (eluent: ethyl ether / petroleum ether (BP: 60-80 ° C) (3-1)) to give 744 mg of purified product, which was 5.5 Thermally recrystallize from a mixture containing cc of isopropyl ether, 0.4 cc of methylene chloride and trace amounts of pyridine. After passing, concentrating, initiating crystallization, separating crystals, washing with isopropyl ether and drying, 444 mg of crude product was obtained. MP = 138 ° C. b 3,3-Ethylene bis (oxy) -17α- (1-propynyl) estra-5 (10), 9 (11) -diene-17β-ol 88.5 g of the product obtained in a above is introduced into 442.5 cc of glycol. The mixture is heated to 60 ° C under nitrogen with stirring, then 4.425 g of viridin hydrochloride is introduced. After stirring at 60 ° C for 15 minutes, the mixture is cooled to 20 ° C and 17.7 cc of triethylamine is added while cooling (at 40 ° C). Pour the 20 ° C suspension into 3 ice-cold water. It was left at 0 ° C. for 1 hour, separated, washed with water and dried to obtain 75.4 g of product. MP = 135 ~ 140 ° C. c 3,3-Ethylene bis (oxy) -5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -en-17β-ol 30 g of the product obtained in b above is cooled to 0 ° C. in 150 c.c. Methylene chloride containing 2 drops of pyridine, then 1.8 cc of hexafluoracetone sesquihydrate is added, then 4.35. Drop 85% water peroxide of cc. The mixture is kept at 0 ° C for 72 hours and then poured into a mixture of 250 g ice and 500 c.c. Sodium 0.2N thiosulfonate. After stirring, extracting with methylene chloride, washing the organic phase, drying and concentrating under reduced pressure, 31.6 g of the desired product was obtained. Manufacture 2: 3,3-ethylenebis (oxy) -11β- (p-fluorphenyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol Under the same conditions as in Production 1, the same compound, namely 3,3-ethylenebis (oxy) -5α, 17α-epoxy-17α- (1-propynyl) estra-9 (11) -ene-17β-ol in tetrahydrofuran. In the presence of cuprous chloride, p-fluorphenylmagnesium bromide is reacted. After chromatography, the desired product was obtained. [Α]_D=-57.5 ° ± 1.5 ° (c = 1% CHCl)₃). Manufacture 3: 3,3-ethylenebis (oxy) -11β- (p-trifluolmethylphenyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol The same compound was allowed to act on p-trifluolmethylphenylmagnesium bromide as in Productions 1 and 2 to give the desired product. [Α]_D= -56 ° ± 2.5 ° (c = 0.4% CHCl)₃). Manufacture 4: 3,3-bismethoxy-11β-methyl-17α- (1-propynyl) estra-9-ene-5α, 17β-diol A mixture of 11.4 g of cuprous acid and 120 c.c. of ether is cooled to 0 ° C. under nitrogen, then 69 c.c. of 1.74 M methyllithium ether solution is added over 30 minutes. Stir the mixture at 0 ° C for an additional 10 minutes, then 5.5 g of 3,3-bismethoxy-5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -en-17β-ol 50 c.c. The solution dissolved in tetrahydrofuran is added dropwise over 30 minutes. Continue to stir the mixture at 0 ° C for 2 hours, then pour into a cold aqueous solution of ammonium chloride. After stirring at ambient temperature for 1 hour, extracting with ether, washing, drying and concentrating to dryness under reduced pressure, 5.7 g of crude product was obtained. The 6.8 g product obtained as described above is chromatographed on silica (eluent: methylene chloride / acetone (9-1), containing 1 of triethylamine). A desired product of 4.05 g was obtained. MP = 155 ° C. [Α]_D= 80 ° ± 2 ° (c = 1% CHCl)₃). Manufacture of starting material The 3,3 = bismethoxy-5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -en-17β-ol used at the start of Production 4 was produced as follows. 62.4 g of 3,3-bismethoxy-17α- (1-propynyl) estra-5 (10), 9 (11) -diene-17β-ol obtained in Production 1 to 280 c.c. Methylene chloride under nitrogen Introduce. Cool to 0 ° C with stirring, add 8.5 cc of hexafluolacetone sesquihydrate at once, and then add 10.1 cc of 85% hydrogen peroxide solution. The mixture is left at 0 ° C for 41 hours with stirring, then poured into a mixture of 1.4 sodium bisulfite solution (0.5 M / l), 200 g of ice and 5 drops of pyridine. The mixture was stirred for 15 minutes, then extracted with 2 drops of methylene chloride containing pyridine, the organic phase was washed with water containing trace amounts of pyridine, dried and concentrated under reduced pressure to give 63.8 g of the desired product. Production 5: 3,3-bismethoxy-11β- (propa-1,2-dienyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol α-alenyl lithium (CH)₂= C = CHLi) Cool 300 c.c. of dry tetrahydrofuran to 0 ° C and infuse with allen gas until approximately 18-20 g is dissolved. The solution is then cooled to -70 ° C and a 180c.c. 1.35Nn-butyllithium n-hexane solution is added dropwise over 30 minutes and stirred at -70 ° C for 1 hour. β Diarenyl kyuprolithium [(CH₂= C = CH)₂CuLi] Introduce 24.66 g of dimethylsulfide-copper bromide complex into the above suspension in small portions in about 15 minutes. Then stir this at -70 ° C for another 1 hour and 30 minutes. Condensation with γ epoxide A solution of 11 g of 3,3-pismethoxy-5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -ene-17β-ol in 60 c.c. of dry tetrahydrofuran is -70. Drop at ° C for 10 minutes and gently return to approximately -20 ° C (± 5 ° C). Stir the mixture under nitrogen at this temperature for 18 hours. Then, it is poured into a cold aqueous solution of ammonium chloride while stirring. After stirring at ambient temperature for 1 hour, extracting with ether, washing, drying and concentrating under reduced pressure, 11.2 g of the desired crude product was obtained. This was chromatographed on silica (eluent: methylene chloride / acetone (9-1), containing 1 of triethylamine) to give 6.6 g of the desired product. [Α]_D=-25 ° ± 1 ° (c = 1% CHCl)₃). Manufacture 6: 3,3-bismethoxy-17α- (1-propynyl) -11β-t-butylestra-9-ene-5α, 17β-diol Tetrahydrofuran and 1.1g 3,3-bismethoxy-5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -ene- of 13.8cc 0.65M t-butylmagnesium chloride as shown in Production 1. It is carried out by starting from 17β-all. After stirring at -20 ° C for 3 hours, the desired product was obtained. MP = 148 ~ 150 ° C. Manufacture 7: 3,3-bismethoxy-11β- (2-furyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol Performed as in Production 5 and difurylkyupro to the same compound, namely 3,3-bismethoxy-5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -en-17β-ol. Lithium was condensed to give the desired product. [Α]_D= -62 ° ± 1.5 ° (c = 1% CHCl)₃). Manufacturing 8 ~ 28 The following products were obtained as in Production 1.

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Bromide 3-Trifluo 3,3-Ethylene bis (Oki 3,3-Ethylene bis (oxy)-30. Lumethylphenylma shi) -5α, 10α at -20 ° C -Epoki 11β- (3-trifluolmethi Gnesium Si-17α- (1-propini le) phenyl-17α-(1-pro le) Estra-9 (11)- E-Pinil) Estra-9-en- N-17β-all 5α, 17β-diol MP = 179 ° C α_D= -58 ° ± 2 ° (c = 0.8%, CHCl₃) [ table]

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Manufacture 29: 3,3-ethylenebis (oxy) -17α-trimethylsilyloxy-11β- (2'-methyl-1'-propenyl) -5α-hydroxyestra-9-ene-17β-carbonitrile A suspension consisting of 3.1 g of a dimethylsulfide-cupulous bromide complex added to 30 c.c. of tetrahydrofuran was added to a suspension of 32 c.c. of a 0.95 M2-methyl-1-propenyl lithium ether solution at -40 ° C. Drop with. Then 4.16 g of 5α, 10α-epoxy-17α-trimethylsilyloxy-17β-cyano-9 (11) -en-3-one 3- [(1,2-ethanediyl) acetal] is added. After 30 minutes at -30 ° C, the mixture is poured into an ammonium chloride solution and extracted with ether. The organic phase is dried and the solvent is expelled under reduced pressure. 5.45 g of crude product was obtained, from which 570 mg was dissolved and chromatographed on silica for purification (eluent: benzine / ethyl acetate 8-2) to isolate 450 mg of pure product. MP = 154 ° C. Analysis: C₂₈H₄₂O₄NSi Calculation: C% 69.38 H% 8.73 N% 2.89 Actual measurement: 69.4 9.0 2.9 Manufacture 29A: Ethylenebis (oxy) -17α-ethynyl-11β- (2'-methyl-1'-propenyl) estra-9-ene-5α, 17β-diol 5. 45 g of the crude product obtained in Production 29 is dissolved in 50 c.c. of ethylenediamine. Stir the solution under nitrogen at 50 ° C, then add 6 g of lithium ethylenediamine acetylide complex in small portions. After 3 hours at the same temperature, the reaction mixture is poured into an ice-water mixture and extracted first with ether and then with chloroform. The organic phase is dried and then the solvent is evaporated under reduced pressure. The crude product was chromatographed on silica (eluent: benzine / ethyl acetate 7-3, containing 0.1% triethylamine) to give 2.763 g of the desired product. Rf = 0.3. This is recrystallized from isopropyl ether. MP = 208 ° C. (A 0.26 g 17-keto product was also obtained as a by-product). Analysis: C₂₆H₃₆O₄ Calculation: C% 75.69 H% 8.80 Actual measurement: 75.9 8.8 Manufacture 30: 3,3-ethylenebis (oxy) -17α-trimethylsilyloxy-11β- (3-methoxyphenyl) -5α-hydroxyestra-9-ene-17β-carbonitrile A method similar to that described in Production 1 was carried out, starting with the same compound and 3-methoxyphenylmagnesium bromide as in Example 29 to give 9.406 g of the desired product. MP = 166 ° C. Analysis: C₃₁H₄₃NO₅Si Calculation: C% 69.23 H% 8.06 N% 2.60 Actual measurement: 69.4 8.1 2.6 Manufacture 30A: 3,3-ethylenebis (oxy) -5α,17α-dihydroxy-11β- (3-methossiphenyl) -19-norpregna-9-en-20-one 20c.c. 1.3M methylmagnesium bromide solution is concentrated in tetrahydrofuran to give a 2M solution (7c.c. tetrahydrofuran removed). 2. 79 g of the product obtained in Production 30 is added and the whole is heated to reflux overnight. Add 10c.c. of 1.3M magnesium solution, distill off 5c.c. Tetrahydrofuran, and heat the residual solution to 100 ° C. for 7 hours. It is then hydrolyzed in a cold aqueous solution of ammonium chloride, extracted with ether, dried and the solvent evaporated under reduced pressure. Chromatographing with silica (solvent: benzene / ethyl acetate 6-4, containing 0.1% triethylamine) yielded a desired crude product of 1.722 g, which was combined with isopropyl ether and methylene chloride. Recrystallize from the mixture. MP = 190 ° C. Analysis: C₂₉H₃₈O₆ Calculation: C% 72.17 H% 7.94 Actual measurement: 72.5 8.0 Manufacture 31: 17 α-Methyl-11β-Propyl-5α-Hydroxy-19-Norpregna-9-ene-3,20-dione 3,20-bisethylene ketal Propyl 17α-methyl-5α, 10α-epoxy-19-norpregna-9 (11) -ene-3,20-dione 3,20-bisethylene ketal and propyl bromide in a manner similar to that described in Production 1. Start with magnesium (2 hours at -30 ° C). Manufacture of starting material The 17α-methyl-5α, 10α-epoxy-19-norpregna-9 (11) -ene-3,20-dione 3,20-bisethylene ketal used at the start of production 31 was produced as follows. a 17 α-methyl-19-norpregna-5 (10), 9 (11) -diene-3,20-dione 3,20-bisethylene ketal 21 g of 17α-methyl-19-norpregna-4,9-diene-3,20-dione in a mixture of 200 c.c. methylene chloride, 200 c.c. of ethylene glycol and 100 c.c. of ethyl orthostate. Add 1.5 g of p-toluenesulfonic acid monohydrate to the dissolved solution. The reaction mixture is heated to reflux for 7 hours, then 2c.c. Triethylamine is added. A portion of the solvent is removed by distillation, water is added, the precipitate is collected by passing, then washed with water, dissolved in methylene chloride and dried. After isopropyl ether was added and concentrated, the desired product crystallized (22.65 g), chromatographed, and then recrystallized from isopropyl ether to obtain a sample for analysis. MP = 175 ° C. Analysis: C₂₅H₃₆O₄ Calculation: C% 74.96 H% 9.06 Actual measurement: 75.0 9.1 b 17α-methyl-5α, 10α-epoxy-19-norpregna-9 (11) -en-3,20-dione 3,20-bisethylene ketal Dissolve 100 mg of the product obtained in a) above in 2c.c. Methylene chloride. Add 450 mg of acidic sodium carbonate with stirring at 0 ° C. Add 0.1 cc of chloral, then 0.1 cc of hydrogen peroxide (110 volumes). The reaction is stopped after 4 hours, the reaction mixture is poured into a sodium thiosulfate solution, extracted with methylene chloride, dried and the solvent is evaporated under reduced pressure. Isolate 98 mg of the desired epoxide. Manufacture 31A: 17α-methyl-11β-vinyl-19-norpregna-9-en-5α-ol 3,20-bisethylene ketal Start with the starting material of Production 31 and vinyl magnesium bromide (2 hours at -30 ° C) in a manner similar to that described in Production 1. The desired product was obtained. MP = 192 ° C. Analysis: C₂₇H₄₀O₅ Calculation: C% 72.94 H% 9.07 Actual measurement: 72.7 9.2 Manufacturing 32 ~ 35 The following products were obtained as in Production 1.

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Manufacture 36: [3,3-ethylenebis (oxy) -11β- (3-methoxyphenyl) -17α- (1-propynyl) -17β-estra-9-ene-5α-hydroxy-17-yl] oxyacetic acid t-butyl 30 c.c. tetrahydrofuran of 3,3-ethylenebisoxy-11β- (3-methoxyphenyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol prepared in 960 mg production 13. The solution dissolved in is cooled to -40 ° C, and then 3.2 cc of butyl lithium n-hexane solution (1.25 M / l) is added dropwise. Raise the temperature to ambient temperature, then add 1.3 cc of t-butyl bromacetate. After 1 hour and 30 minutes, the mixture was poured into aqueous ammonium chloride solution, extracted with ether, washed, dried and evaporated to give the desired product. Manufacturing 39 ~ 41 [table]

Manufacture 42: 3,3-ethylenebisoxy-11β-thien-2-yl-17α-methyl-5α, 21-dihydroxy-19-norpregna-9-ene-20-one Add 300 mg of cuprous chloride to a solution of 40 c.c. in 0.5 M thienylmagnesium bromide in tetrahydrofuran. After cooling to -20 ° C to -25 ° C and contacting for 30 minutes, 2.02 g of 3,3-ethylenebis (oxy) -17α-methyl-5α, 10α-epoxy-21-hydroxy-19-norpregna A solution of -9 (11) -ene-20-one dissolved in 20 c.c. of dry tetrahydrofuran is added dropwise. The solutions are contacted at -20 ° C to -25 ° C for 2 hours and then hydrolyzed with aqueous ammonium chloride solution. Extraction with ethyl ether gave 2.218 g of a resinous product, which was chromatographed with silica (eluent: benzine-ethyl acetate 1-1) to give 701 mg of the desired product. Rf = 0.29, MP = 204 ° C. Manufacture of starting material a A mixture of 120 c.c. tetrahydrofuran and 6.6 cc of N-cyclohexyl isopropylamine is cooled to -50 ° C and 19.6 cc of n-butyllithium hexane solution is added in 12 minutes. After stirring, add 8.9 g of 3,3-ethylenebis (oxy) -17α-methyl-19-norpregna-5 (10), 9 (11) -diene-20-one. Stir the mixture at -35 ° C to -40 ° C for 1 hour, then add 17.4 g of oxidant [oxodiperoxopyridino (hexamethylphosphoramide) molybdenum: described in Bull.Soc.1481 (1969)]. In addition, stir at -30 ° C to -35 ° C for 1 hour and 30 minutes. The whole is then poured into ice water, extracted with ethyl acetate, washed, then dried and concentrated. The residue is chromatographed with silica (eluent: benzine) to obtain 4.03 g of product, which is used as is in the next step. b Dissolve 3,3-ethylenedioxy-17α-methyl-21-hydroxy-19-norpregna-5 (10), 9 (11) -diene-20-one obtained on 1.826 g in 18.3 cc of methylene chloride The solution is cooled to 0 ~ + 5 ° C, then 7.8 cc of 1 mol of hexafluolacetone hydroperoxide in methylene chloride is added. After allowing to stand at 0 ~ + 5 ° C for 75 minutes, pour the mixture onto a 0.5 M sodium thiosulfate solution. After extraction with chloroform, washing and drying, 2.02 g of product was obtained, which was used as is. Manufacturing 43 [table]

Manufacture 48: 20 R-acetoxy-3,3-ethylenebis (oxy) -11β- (3-methyloxyphenyl) -17α-methyl-19-norpregna-9-en-5α-ol 80c.c. Bromide 3-methyloxyphenylmagnesium in 0.9M tetrahydrofuran and 7.5g 20R-acetoxy-5α, 10α-epoxy-3,3-ethylenebisoxy--17α-methyl-19-norpregna- 9 (11)-Start from En and carry out as described above. After stirring at -20 ° C for 18 hours and chromatographing under pressure, 5.4 g of the desired product was obtained. This is crystallized with ether. MP = 160 ° C, [α]_D= + 19.5 ° ± 1 ° (c = 1%, CHCl₃). Manufacture of starting material a 45g of 20R-acetoxy-17α-methylpregna-4.9-diene-3-one added to 180c.c. Glycol and 180c.c. Ethyl orthophosphate in a suspension with stirring at 25 ° C. Add 2.7 g of p-toluenesulfonic acid hydrate, then 40 c.c. of methylene chloride. The mixture is stirred under nitrogen at ambient temperature for 45 minutes, then 10 c.c. of triethylamine is added. The solvent is expelled under reduced pressure, then 500 c.c. of water is added in 1 hour and the whole is poured into ice-cold water containing pyridine 2 while stirring. After stirring, separating, washing and drying at 0 ° C, 50.5 g of product was obtained, which was dissolved under reflux in 10 c.c. isopropyl ether containing 1 of triethylamine and crystallized under cooling. It recrystallizes by forming. 27.6 g of the desired product was obtained. MP = 166 ° C, [α]_D= -4.5 ° ± 1 ° (c = 1% CHCl₃). Manufacturing 49 [table]

Manufacture 55: 17α- [3- (dimethylamino-1-propynyl)]-5α,17β-dihydroxy-11β- (3-methoxyphenyl) estra-9-en-3-one cyclic 1,2-ethanediyl Acetal a 3,3-Ethylene bisoxy-11β- (3-methoxyphenyl) -5α-hydroxyestra-9-ene-17-one It consists of 5 g of 3,3-ethylenebisoxy-5α, 10α-epoxy estra-9 (11) -ene-17-one and 50 c.c. tetrahydrofuran and contains 310 mg of cuprous chloride and 195 mg of lithium chloride. Stir the mixture to dissolve at ambient temperature. The solution is cooled to -20 ° C and a 0.75 M tetrahydrofuran solution of 3-methoxyphenylmagnesium bromide at 31 c.c. is added dropwise. Leave at -20 ° C for 1 hour, then warm to -15 ° C and then add the same amount of magnesium salt again. The mixture is poured into a cold aqueous solution of ammonium chloride, stirred, extracted with ether, then extracted with methylene chloride, the organic phase washed with saturated aqueous sodium chloride solution and the solvent evaporated. After chromatography, the desired product was obtained. b 17α- [3- (dimethylamino-1-propynyl)]-5α,17β-dihydroxy-11β- (3-methoxyphenyl) estra-9-ene-3-one cyclic 1,2-ethanediyl acetal 30 ml of an ether solution of lithium diisopropylamide (0.67 M / l) (manufactured according to J.Org.Chem.43, 704 (1978)) at -50 ° C, 3.9 cc of N, N-dimethylaminopro Gently add pins. The temperature was returned to 0 ° C, then cooled to -40 ° C, and 4 g of 3,3-ethylenebisoxy-11β- (3-methoxyphenyl) -5α-hydroxyestra-9-ene obtained in the above step. A solution of -17-one dissolved in 11c.c. tetrahydrofuran is added dropwise. The temperature was returned to 0 ° C in 1 hour, then the mixture was poured into a saturated solution of ammonium chloride at 500 c.c., extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried and the solvent evaporated to 4.9 g. The desired product was obtained. 600 mg of this product was chromatographed on silica (eluent: methylene chloride / methanol 92-8) to give 200 mg of pure product. [Α]_D= -62 ° ± 2.5 ° (c = 0.5%, CHCl₃). analysis: Calculation: C% 73.6 H% 8.3 Actual measurement: 73.3 8.3 Manufacture 57: 3,3-ethylenebisoxy-11β- (4-hydroxyphenyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol a Manufacture of 4-trimethylsilyloxyphenylmagnesium bromide To a solution of 50 c.c. of isopropyl magnesium chloride in 0.9 M tetrahydrofuran is added 7.8 g of p-bromphenyl dissolved in 50 c.c. of tetrahydrofuran, followed by 5.75 cc of trimethylsilyl chloride. Pour the solution onto a 1.2 g piece of magnesium. Add a small amount of 1,2-dibromuethane, then 2c.c. of hexamethylphosphotriamide, then superheat reflux the whole for 2 hours. b 3,3-Ethylene bisoxy-11β- (4-hydroxyphenyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol 350 mg of cuprous chloride in the above magnesium derivative solution, then 1.45 g of 3,3-ethylenebisoxy-5α, 10α-epoxy-17α- (1-propynyl) estra-dissolved in 15c.c. tetrahydrofuran. Add 9 (11) -ene-17β-ol. The mixture is poured into aqueous ammonium chloride solution, extracted with ether, the organic phase is washed with 1N sodium hydroxide solution, dried, then the solvent is evaporated under reduced pressure and chromatographie (eluent: benzene / ethyl acetate 7) with silica. -3) After that, 207 mg of the desired product was separated. Analysis: C₂₉H₃₆O₅ Calculation: C% 74.97 H% 7.81 Actual measurement: 75.0 7.9 [Α]_D= -58.5 ° ± 2.5 ° (c = 0.5%, CHCl₃). Example 1: 17β-Hydroxy-17α- (1-propynyl) -11β- (2'-thienyl) estra-4,9-diene-3-one 9.85 g of the product obtained in Production 1 is introduced into 330 c.c. Ethanol at 95 ° C. The mixture is heated to reflux and then 9.85 g of Redex CF resin is added at one time. This is refluxed under nitrogen for 4 hours, allowed to pass, washed with anhydrous alcohol, concentrated under reduced pressure, and then 9 g of crude product is obtained and chromatographed with silica (eluent: chloroform / acetate). Ethyl 9-1). 6.5 g of the desired product is separated and recrystallized from isopropyl ether. After separation, washing with isopropyl ether and drying, 5.315 g of pure product was obtained. MP = 192 ° C. Analysis: C₂₅H₂₈O₂S Calculation: C% 76.4 H% 7.18 S% 8.16 Actual measurement: 76.4 7.5 8.0 [Α]_D= + 83 ° ± 2 ° (c = 1%, CHCl₃). Example 2-35 The following compounds were prepared according to the method of Example 1.

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Example 36: [[11β- (3-methoxyphenyl) -3-oxo-17α- (1-propynyl) (17β) estra-4,9-diene-17-yl] oxy] t-butyl acetate Obtained in Production 36 [[3,3-ethylenebisoxy-11β- (3-methoxyphenyl) -17α- (1-propynyl (17β) eltra-9-ene-5α-hydroxy-17-yl] oxy] Dissolve t-butyl acetate in 40 c.c. of methanol and 4 c.c. of 2N hydrochloric acid. After stirring at ambient temperature for 1 hour, pour the mixture into a 50% aqueous bicarbonate solution, stir for 5 minutes, ether. Extract with, wash with saturated sodium chloride solution, dry, evaporate to dryness under reduced pressure. Chromatograph the residue with silica (eluent: petroleum ether (BP = 60-80 ° C) / ethyl acetate 7) -3), 720 mg of the desired product is obtained, and this is used as it is. Example 37: [[11β- (3-methoxyphenyl) -3-oxo-17α- (1-propynyl) (17β) estra-4,9-diene-17-yl] oxy] acetic acid A mixture of 5 g of the compound thus obtained in Example 36, 500 mg of p-toluenesulfonic acid and 100 c.c. of benzine is heated to reflux for 5 hours. The obtained resin was evaporated to dryness and chromatographed with silica (eluent: methylene chloride / methanol 92.5-7.5) to recover 886 mg of the desired product. [Α]²⁰_D= + 50.5 ° (c = 0.3%, CHCl₃). Example 38: [[11β- (3-methoxyphenyl) -3-oxo-17α- (1-propynyl) (17β) estra-4,9-diene-17-yl] oxy] sodium salt of acetic acid The mixture of the acid obtained in Example 37 at 305 mg and an ethanol solution of 3c.c. Sodium hydroxide (0.2 M / l) is dissolved and stirred until finished, then the insoluble layer is separated. After evaporating to dryness under reduced pressure, the residue was ground until it aggregated with isopropyl ether, then stirred, separated, washed with isopropyl ether and dried to give 280 mg of the desired product. MP&gt; 270 ° C analysis Calculation: Na% 4.63 Actual measurement: 4.45 Example 39 ~ 43 The following compounds were obtained as in the above example.

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Example 44: 9α, 10α-epoxy-17β-hydroxy-11β- (4-methoxyphenyl) -17α- (1-propynyl) estra-4-en-3-one 11β- (4-methoxy) phenyl-17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one prepared as in Example 14 of 1.3 g to 25 c.c. Methylene chloride Add 700 mg of 85% m-chloroperbenzoic acid in small portions while stirring the dissolved 0 ° C solution. After 1 hour at 0 ° C, the temperature is returned to ambient temperature, washed with 0.5N aqueous sodium thiosulfate solution, then saturated solution of sodium bicarbonate, dried, then the solvent is evaporated and the residue is chromatographed with silica. Eat (eluent: methylene chloride / acetone 95-5) to give 1.075 g of the desired product, which is recrystallized from a mixture of methanol and isopropyl ether. MP = 185 ° C ~ 189 ° C. Example 45: 9α, 10α-epoxy-17β-hydroxy-11β- (4-methylsulfonyl) phenyl-17α- (1-propynyl) estra-4-en-3-one 570 mg of 11β-[(4-methylthio) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one as obtained in Example 23 and 13c.c. Methylene chloride Add 960 mg of 85% m-chloroperbenzoic acid in small portions over 5 minutes to a solution that has been dissolved in and cooled to 0 ° C. Stir the mixture under nitrogen for 1 hour and 30 minutes, then pour into a 100 c.c. aqueous solution of 0.5 M sodium thiosulfate with stirring and stir for a while at ambient temperature. The product is extracted with methylene chloride, washed with aqueous sodium bicarbonate solution, dried, concentrated to dryness, and then chromatographed with silica (eluent: benzene / ethyl acetate 1-1). 750 mg of the desired product is obtained and recrystallized from a mixture of isopropyl ether and methylene chloride. MP = 205 ~ 208 ° C. [Α]_D= + 67.5 ° ± 1.5 ° (c = 1%, CHCl₃). Example 46: 3-Methoxyimino-11β- (4-promuphenyl) -17α- (1-propynyl) estra-4.9-diene-17β-ol (syn (Z) and anti (E) isomers] About 700 mg of 11β-[(4-brom) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one as obtained in Example 22 in 10 c.c. ethanol Add 170 mg of methylhydroxylamine hydrochloride to the solution dissolved in, and stir at ambient temperature for 2 hours. The mixture is then poured into water and extracted with ether and then with methylene chloride. The organic phase is dried, the solvent is evaporated and the residue is chromatographed on silica (eluent: benzene / ethyl acetate 9-1). This gave 408 mg of anti-isomer (E) compound. MP = 185 ° C. Then 200 mg of syn isomer (Z) was obtained. MP = 217 ° C. Analysis of anti-compounds Calculation: C% 68.01 H% 6.52 N% 2.83 Actual measurement: 68.3 6.6 2.9 Calculation: Br% 16.16 Actual measurement: 16.0 Example 47: 11 β- (3-fluorphenyl) -3-hydroxyimino-17α- (1-propynyl) estra-4.9-diene-17β-ol (syn (Z) and anti (E) isomers] 3.7 g of 11β-[(3-fluor) phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one as obtained in Example 26 in 44.4 cc of absolute ethanol And 7.6 g of hydroxylamine hydrochloride is added at a time to the solution consisting of the solution in 7.6 cc of pyridine. The mixture is heated to reflux for 1 hour, cooled to 0 ° C. and then added to the 450c.c. Ice-water mixture with stirring. This is extracted with methylene chloride, the organic phase is washed with water, dried and then concentrated under reduced pressure. The crude product is chromatographed under pressure (eluent: cyclohexane / ethyl acetate 7-3). This gave 2.7 g of the anti isomer (E) and 857 mg of the syn isomer (Z). The anti-product was recrystallized from a mixture of 20 c.c. of isopropyl ether and 10 c.c. of methylene chloride to give 2.145 g of pure product. MP = 210 ° C. [Α]_D= + 35 ° ± 2.5 ° (c = 0.5%, CHCl₃). analysis Calculation: C% 77.3 H% 7.21 N% 3.34 Actual measurement: 77.3 7.5 3.3 Examples 48 and 49 The following compounds were obtained as described above.

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Example 50: 11 β-t-butyl-9α, 10α-epoxy-17β-hydroxy-17α- (1-propynyl) estra-4-en-3-one Performed as in Example 44, 11β-t-butyl-17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one and 2.92 g as obtained in 2.11 g of Example 6. Starting from m-chloroperbenzoic acid, 0.5 g of the desired compound was obtained after chromatographie. MP = 186 ~ 187 ° C. analysis Calculation: C% 78.49 H% 8.96 Actual measurement: 78.4 9.0 [Α]_D= + 1 ° (c = 1%, CHCl₃). Example 51: 11 β-cyclopentyl-9α, 10α-epoxy-17β-hydroxy-17α- (1-propynyl) estra-4-en-3-one 1.5 g of 11β-cyclopentyl-17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one and 0.8 g of m-chlorperbenzoic acid as obtained in 1.5 g of Example 43 By starting from the above and performing as in Example 44, 0.7 g of the desired compound was obtained after chromatographing. MP = 170 ° C analysis Calculation: C% 79.15 H% 8.68 Actual measurement: 79.6 8.7 [Α]_D= + 6.5 ° ± 1 ° (c = 1%, CHCl₃). Example 52: 11 β- (3-methoxyphenyl) -9α, 10α-epoxy-17β-hydroxy-17α- (1-propynyl) estra-4-en-3-one 11β- (3-methoxyphenyl) -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one and 0.608 g of m-chlor as obtained in 1.05 g of Example 13. Starting from perbenzoic acid and performing as in Example 44, 0.65 g of the desired compound was obtained after chromatographie. [Α]_D= + 44 ° ± 2.5 ° (c = 0.6%, CHCl₃). Example 53: 11 β-phenyl-9α, 10α-epoxy-17β-hydroxy-17α- (1-propynyl) estra-4-en-3-one Starting with 11β-phenyl-17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one as obtained in 1.15 g of Example 20 and 0.608 g of m-chloroperbenzoic acid. By performing as in Example 44, 0.85 g of crystals were obtained after chromatographing. MP = 186 ~ 187 ° C. analysis Calculation: C% 80.56 H% 7.51 Actual measurement: 80.6 7.3 [Α]_D= + 47.5 ° ± 1.5 ° (c = 1%, CHCl₃). Example 54: 11 β- [4- (3-methyl) Butylsulfonyl] phenyl-9α, 10α-epoxy-17β-hydroxy-17α- (1-propynyl) estra-4-en-3-one Starting from 11β- [4-[(3-methyl) butylthio] phenyl] -17β-hydroxy-17α- (1-propynyl) estra-4,9-diene-3-one as obtained in Example 49 The desired product was obtained by performing as in Example 45. MP = 174 ° C. [Α]_D= + 62 ° ± 2.5 ° (c = 0.6%, CHCl₃). Example 55: 23-N, N-dimethylamino-17β-hydroxy-11β- (3-methoxyphenyl) 19,21,24-trinor-17α-cola-4,9-diene-20-in-3-one Cyclic of 17α- [3-dimethylamino-1-propynyl) -5α, 17β-hydroxy-11β- (3-methoxyphenyl) estra-9-en-2-one as obtained in 4.3 g production 55 Stir 1,2-ethanediyl acetal in 100 c.c. of methanol and 3 c.c. of 2N hydrochloric acid at ambient temperature for 1 hour. The whole is then poured into a mixture of 300 c.c. of ethyl acetate and 200 c.c. of 0.25 M aqueous sodium carbonate solution. Decantation, re-extract with ethyl acetate, combine organic phases, wash with saturated aqueous sodium chloride solution, dry, evaporate solvent and chromatograph the residue with silica (eluent: methylene chloride / methanol) After 95-5, acetone / ethyl acetate 3-1), 1.7 g of the desired product is obtained, which is used as it is in the next step. [Α]_D= + 40 ° ± 1 ° (c = 1%, CHCl₃). Example 56: 23-N, N-dimethylamino-17β-hydroxy-11β- (3-methoxyphenyl) 19,21,24-trinor-17α-cola-4,9-diene-20-in-3-one Hydroxide Dissolve 1.5 g of the product obtained in Example 55 in 50 c.c. Ether and stir at ambient temperature for 10 minutes to remove the insoluble layer. Then, 16.5 cc of an ether solution of hydrochloric acid gas is added dropwise. The suspension was stirred for 10 minutes, then separated and washed with ether to give 1.4 g of the desired product. MP = 190 ° C. [Α]_D= + 49 ° ± 2 ° (c = 0.5%, water). analysis Calculation: C% 72.63 H% 7.72 N% 2.82 Actual measurement: 72.5 7.7 2.7 Example 57: 17 β-Hydroxy-17α- (1-propynyl) -11β- (4-Hydroxyphenyl) Estra-4,9-diene-3-one 2c.c of 3,3-ethylenebisoxy-11β- (4-hydroxyphenyl) -17α- (1-propynyl) estra-9-ene-5α, 17β-diol as obtained in 90 mg production 57 Stir the solution in methanol and 0.3 cc of 2N hydrochloric acid at ambient temperature for 2 hours. The mixture is then poured into a cold aqueous solution of 50% acidic sodium carbonate and extracted with ether and then methylene chloride. The organic phase is washed with saturated aqueous sodium chloride solution, dried, concentrated to dryness under reduced pressure, and the residue is chromatographed with silica (eluent: methylene chloride / acetone 92.5-7.5). A desired product of 71 mg was obtained. [Α]_D= + 67 ° (c = 0.25%, CHCl₃). Example 58: 11 β- (3-Hydroxyphenyl-17β-Hydroxy-17α- [1-propynyl) estra-4,9-diene-3-one Step A: 3,3-Ethylenebis (oxy) -11β- [3- (2H-tetrahydropyranyloxy) phenyl] -17α- (1-propynyl) estra-9-ene-5α, 17β-diol a Manufacture of magnesium compounds Under nitrogen, 20.6 g of 3- (2-tetrahydropyranyloxy) -1-prombenzene is introduced into 160 c.c. tetrahydrofuran. 10 g of this mixture is poured onto a 2.2 g piece of magnesium, then the reaction is initiated and then the rest of the mixture is poured slowly, keeping the temperature at 52 ° ± 2 ° C. The mixture is then heated to reflux for 30 minutes and then cooled to 20 ° C. b Addition of magnesium compound 5.55 g of 3,3-ethylenebis (oxy) -5α, 10α-epoxy-17α- (1-propynyl) estra-9 (11) -ene-17β-ol under an inert gas 55 c.c. tetrahydrofuran Then add 0.36 g of cupric chloride and 0.18 g of lithium chloride. The solution of 102 c.c. obtained above is introduced into this mixture at 0-3 ° C for 30 minutes. The mixture is allowed to stand for 1 hour with stirring at 0 ° C, then poured into a cold aqueous solution of ammonium chloride at 50 c.c. Decantation, extraction with ethyl acetate, washing with water, drying and then evaporation of solvent. The resulting residue is chromatographed with silica (eluent: methylene chloride / acetone / 95-5 containing 1 of triethylamine). 6.3 g of the desired product is obtained and then crystallized from ethyl ether. MP = 216 ° C. Step B: 11β- (3-Hydroxyphenyl) -17β-Hydroxy-17α- (1-Propinyl) Estra-4,9-diene-3-one The product obtained on 5.42 g under an inert gas is mixed with 100 c.c. of 95 ° ethanol at 20 ° C, 5.5 g of Redex CF resin is added, and then the mixture is heated to reflux for 1 hour and 30 minutes. The mixture is allowed to evaporate, the solvent is evaporated and the residue is chromatographed on silica (eluent: cyclohexane / ethyl acetate 1-1). 3.8 g of the desired product is obtained and then crystallized with ethyl acetate and then acetone. MP = 215 ° C, [α]_D= + 34.5 ° ± 1 ° (c = 1%, CHCl₃). Analysis: C₂₇H₃₀O₃(402.51) Calculation: C% 80.56 H% 7.51 Actual measurement: 80.5 7.5 Example 59: 17 β-Hydroxy-17α- (3-Hydroxy-1-propynyl) -11β- [4- (Methylthio) phenyl] Estra-4,9-diene-3-one 4.7 g of 5α, 10α-epoxy-17β-hydroxy-17α- [3- (2-tetrahydropyranyloxy) -1-propynyl] estra-9 (11) -en-3-one, 15 c.c. tetrahydrofuran And 470 mg of a mixture of cupric chloride, stirred and cooled to 0 ° to ± 5 ° C, to which 0.9 M magnesium bromide (4-methylthiophenyl) solution is added in small portions. The whole is kept at ambient temperature for 1 hour, then poured onto a cold ammonium chloride solution and extracted with ethyl acetate. After evaporation under reduced pressure, the residue is chromatographed on silica (eluent: cyclohexane / ethyl acetate (7-3), then (1-1)). 5.8 g of product is obtained and dissolved in 40 c.c. of methanol, 10 c.c. of methylene chloride and 20 c.c. of 2N hydrochloric acid. Stir at ambient temperature for 17 hours, then make it alkaline with sodium bicarbonate and extract with methylene chloride. After evaporation under reduced pressure, the residue (6.75 g) is chromatographed on silica (eluent: diethyl ether-ethyl acetate (6-4)). This crude product (3.4 g) was recrystallized from ethanol to give 2.93 g of the desired compound. [Α]_D= + 125 ° (c = 1%, CHCl₃) (Ethanol solvate). Analysis: C₂₈H₃₂O₃S Calculation: C% 74.96 H% 7.19 S% 7.14 Actual measurement: 74.9 7.2 6.9 Example 60: 17α- (3-brom-1-propynyl) -17β-hydroxy-11β- [4- (methylthio) phenyl] estra-4,9-diene-3-one Add 660 mg of carbon tetrabromide to a solution of 0.9 g of Example 59 compound (solvent removed by azeotropic distillation) in 10 c.c. of methylene chloride. After cooling to 0 ° C, add 707 mg of triphenylphosphine and then stir for 25 minutes. The mixture is then chromatographed on silica (eluent: cyclohexane-ether (3-7), then ether only). 820 mg of the desired compound was obtained. Analysis: C₂₈H₃₁BrO₂S Calculation: C% 65.73 H% 6.10 Br% 15.62 Actual measurement: 65.1 6.1 15.1 Calculation: S% 6.26 Actual measurement: 6.0 Example 61: 17α- (3-fluor-1-propynyl) -17β-hydroxy-11β- [4- (methylthio) phenyl] estra-4,9-diene-3-one To a solution prepared by dissolving 1.6 g of the compound thus obtained in Example 60 in 32 c.c. of acetonitrile, 1.6 g of potassium fluoride and 1.6 g of crown ether (18 crown 6) are added. The mixture is heated to reflux for 1 hour and 15 minutes and then evaporated to dryness under reduced pressure. The residue is dissolved in methylene chloride, washed with water, dried, and concentrated to dryness under reduced pressure. The residue (1.79 g) is chromatographed on silica (eluent: cyclohexane-ether (1-1)). 1.05 g of the desired compound was obtained. [Α]_D= + 129.5 ° (c = 1%, CHCl₃). Analysis: C₂₈H₃₁FO₂S Calculation: C% 74.63 H% 6.93 F% 4.21 Actual measurement: 74.4 7.1 4.1 Calculation: S% 7.11 Actual measurement: 6.8 Example 62: 17 α- (3-chloro-1-propynyl) -17β-hydroxy-11β- [4- (methylthio) phenyl] estra-4,9-diene-3-one Starting with 0.9 g of compound obtained in Example 59 and using carbon tetrachloride instead of carbon tetrabromide, as in Example 60. 0.77 g of the desired compound was obtained. [Α]_D= + 122 ° (c = 1%, CHCl₃). Analysis: C₂₈H₃₁ClO₂S Calculation: C% 72.00 H% 6.68 S% 6.86 Actual measurement: 72.0 7.0 6.6 Calculation: Cl% 7.59 Actual measurement: 7.4 Pharmacological study of the compounds of the present invention Study of the activity of the compounds of the present invention on hormone receptors A Ratt's kidney mineralocorticoid receptor Weighing 140-160 g, kill male rats (Sprague-Dawley EOPS) whose adrenal glands were resected 4-8 days ago, and in-situ 50 ml buffer (Tris 10 mM. Satsukarose 0.25 M, HCL pH 7.) To those kidneys. Cover with 4). The kidneys are then excised, the skin peeled off, and homogenized at 0 ° C with a potter Teflon-glass homogenizer (1 g of tissue per 3 ml of buffer). Centrifuge the homogenate at 0 ° C. at 800 G for 10 minutes. Top 11β, 17β-dihydroxy-21-methylpregna-1,4,6-triene-20-in-3-onesteroids that bind only to the glucocorticoid receptor to remove the fixation of tritated aldosterone to the glucocorticoid 10 in clear liquid^-6Add at the final concentration of M. The supernatant is ultracentrifuged at 105000 G at 0 ° C for 60 minutes. An equal amount of the supernatant thus obtained was increased in concentration (0-2500 × 10) with a constant concentration of T of tritated aldosterone.^-9Ink uvate at 0 ° C in the presence of cold aldosterone or cold compound to be tested in M). After an incubation time t, the concentration of bound tritated aldosterone B is measured by dextran-carbon adsorption techniques. B-Ratt Prostate Androgen Receptor Castrate a male rat (Sprague-Dawley EOPS) weighing 160-200 g. Animals were killed 24 hours after castration, their prostates were resected, weighed and homogenized at 0 ° C in buffer solution TS (tris 10 mM, satuculus 0.25 M, HCL pH 7.4) with a potter Teflon-glass homogenizer. To do. The homogenate is then ultracentrifuged at 0 ° C (105000 G for 60 minutes). Equal volumes of the supernatant so obtained were increased in concentration (0 to 1000 x 10) with a constant concentration of T of tritylated testosterone.^-9Ink-Ubation at 0 ° C. for Ink-Uvation Time E in the presence of cold testosterone or test compound of M). The concentration of bound tritized testosterone B in each ink ubate is then measured by dextran-carbon adsorption techniques. C Rabbit uterus progestogen receptor 25 μg of estradiol is intradermally administered to immature rabbits weighing approximately 1 kg. Five days after this treatment, the animals were killed, their uteri were excised, weighed and in buffer solution TS (Tris 10 mM, Satsukarose 0.25 M, HCL pH 7.4) (1 g tissue for 50 ml TS). Homogenize at 0 ° C with Potter's Teflon-glass homogenizer. The homogenate is then ultracentrifuged at 0 ° C (105000 G for 90 minutes). An equal volume of the thus obtained supernatant is augmented with a constant concentration of T of tritiumized compound R (17,21-dimethyl-19-nor-4,9-pregnadien-3,20-dione). Concentration (0 ~ 2500 × 10^-9M) Incubation at 0 ° C. for a predetermined time t in the presence of cold R, cold progesterone, or cold test compound. The concentration of bound tritized R in each ink ubate is then measured by dextran-carbon adsorption technology. D-Ratt thymus glucocorticoid receptor A male rat (Sprague Dawley EOPS) weighing 160-200 g is adrenally resected. 4-8 days after excision, the animals were killed, their thymus was excised, and Potter's polytetrafluorethylene in buffer TS (Tris 10 mM, satuccarose 0.25 M, dithiothreitol 2 mM, HCL pH 7.4). -Homogenize at 0 ° C with a glass homogenizer (1 g tissue for 10 ml TS). The homogenate is then ultracentrifuged at 0 ° C (105000 G for 90 minutes). An equal amount of the supernatant thus obtained was added to an increased concentration (0-2500 x 10) with a constant concentration of T tritiumized texametazone.^-9Ink uvate at 0 ° C for a predetermined time t in the presence of cold dexamethasone or cold test compound of M). The concentration of bound tritated dexamethasone B in each incubation is measured by dextran-carbon adsorption techniques. E-mouse uterine estrogen receptors 18-21 day old immature female mice were killed, their uteri were resected, then in buffer solution TS (Tris 10 mM, Satsukarose 0.25 M, HCL pH 7.4) with Potter's Teflon-glass homogenizer 0. Homogenize at ° C (1 g tissue for 25 ml TS). The homogenate is then ultracentrifuged at 0 ° C (105000 G, 90 minutes). An equal amount of the supernatant thus obtained was added to an increased concentration (0 to 1000 x 10) with a constant concentration of T tritated estradiol.^-9Ink eubate at 0 ° C or 25 ° C for a predetermined time t in the presence of cold estradiol or cold test compound of M). The concentration of bound tritated estradiol P in each incubation is measured by dextran-carbon adsorption techniques. Calculation of relative affinity of binding Relative binding affinity RAB is equivalent for all receptors. Draw two curves as follows: the percentage B / T of the bound tritylated hormone as a function of the logarithm of the concentration of the reference cold hormone and the B / T as the function of the logarithm of the concentration of the cold test compound. Then the equation I₅₀= (B / Tmax + B / Tmin) / 2 Determine the straight line of. Here, B / Tmax is the percentage of the bound tritation hormone to the ink ubiquity of the tritium hormone at a concentration of T. B / Tmin, large excess of cold hormone (2500 × 10)^-9At a concentration of T in the presence of M) is the percentage of the bound tritationhormone to the inscription of the tritiumization hormone. This straight line I₅₀By finding the intersection of and the curve, it is possible to evaluate the concentrations of the cold reference hormone CH and the cold test compound CX, which suppress the binding of tritium hormone to the receptor by up to 50%. The relative affinity RAB for the binding of the test compound is as follows. RAB = 100 (CH) / (CX) Is determined by. The results obtained are as follows.

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41 0.3 0.1 18 6.4 8.2 3.6 171/117 0.01 44 1.4 0.1 13 5.6 41 67 136 140 0.01 45 0.5 0.07 8.3 2.4 24 62 40 64 0.01 47 0.35 0.04 0.13 0.05 19 16 160 100 3.5 0.80 Conclusion The test compound, in particular the compound of Example 23, shows a very pronounced affinity for the glucocorticoid and progestogen receptors, and a modest affinity for the androgen receptor. From the obtained results, it can be concluded that the compound of the present invention exhibits an action activity and an antagonistic activity against glucocorticoids, progestogens and androgens. Anti-glucocorticoid activity The method used was derived from the method described by Dauss et al. In Molecular Pharmacology 13, 948-955 (1977) (Relationships between Glucocorticoid Structures and Effects on Thymocytes) for mouse thymocytes. It is a thing. 5 × 10 thymocytes of the adrenally resected rat^-8In a nutritional medium containing M's dexamethasone, the ink is incubated at 37 ° C. for 3 hours in the absence or presence of various concentrations of the test compound. Add tritated uridine and continue ink ubiquity for 1 hour. Determine the filter-protected radioactivity by cooling the incubate, treating with 5% trichloroacetic acid, passing with Whatman GF / A filter paper and washing 3 times with 5% trifluoracetic acid solution. Glucocorticoids, especially dexamethasone, reduce the binding of tritized uridine, but compounds of Examples 10,11,12,23,26,32,34,35,41,44,45 and 47 oppose this effect. In addition, it was proved that the test compound used alone did not produce a glucocortic type effect.

[table]

[table]

Conclusion The test compound exhibits very remarkable anti-glucocorticoid activity and lacks glucocorticoid activity.Comparison of Relative Activity and Anti-Glucocorticoid Activity of Compounds of the Invention and Known Compounds on Hormone Receptors The procedure of the test used was as described in the tests "C Rabbit uterine progestogen receptor" and "D Rat thymus glucocorticoid receptor" above for relative activity to hormone receptors. For the anti-glucocorticoid activity, the procedure described in the test "Anti-glucocorticoid activity" in the above-mentioned) was followed. However, the latter test is 5x10^-810 in nutritional media containing M dexamethasone^-7It went in the presence of the test compound of M. The compound used was 11β- (p-methoxyphenyl) -17α-methyl-Δ as a known compound.^4,9-Estradiene-17β-all-3-one (Compound X, described in Example 30 of JP-A-53-92752), 11β- (p-fluorphenyl) -17α-ethynyl-Δ^4,9-Estradiene-17β-all-3-one (Compound Y, described in Example 33 of JP-A-53-92752) and 11β- (2-thienyl) -17α-ethynyl-Δ^4,9-Estradiene-17β-all-3-one (Compound Y, described in Example 15 of JP-A-53-92752) is used, and Examples 2,10,11,12,19, as the compound of the present invention. The compounds described in 23, 26, 28 and 29 were used. The results obtained for the relative binding affinity of the test compound for the two receptors and the anti-glucocorticoid activity are shown in Table c below.

[table]

Pharmaceutical composition Tablets corresponding to the following formulations were produced. Compound of Example 23 ...... 50 mg Auxiliary agents (talc, starch, magnesium stearate) ...... Amount required for 120 mg per tablet.