The active ingredient of a drug, a steroid, a method thereof and pharmaceutical composition

 

(57) Abstract:

Describes the new steroids of General formula

< / BR>
where R1- O, (H,OH) or (H2; R2- OH, possibly etherified or esterified; R3- C2-C6-quinil, possibly substituted by a hydroxy-group; R4- CN, C1-C6-alkyl, C1-C6-alkoxy, C2-C6alkenyl, C2-C6-quinil, C2-C6-alkyliden, possibly substituted with halogen, hydroxy or C1-C6-alkoxy; R5- H or C1-C6-alkyl. Steroids are an active component of a drug or pharmaceutical composition intended for treating or preventing menopausal diseases, especially osteoporosis. Also described is a method of obtaining these steroids. 4 C. and 10 C.p. f-crystals, 3 tables.

The present invention relates to the use of steroids for obtaining a medicinal product intended for treating or preventing menopausal diseases, especially for the treatment or prevention of osteoporosis.

Many of the steroids of the present invention, which is used to treat menopausal disorders, are known compounds.

In this patent it is found that compounds having a General formula I

< / BR>
where R1represents O, (H, OH) or two hydrogen atom,

R2represents a hydroxy-group, possibly turned into a group of simple or complex ester,

R3is a (2-6 C)-quinil, possibly substituted by a hydroxy-group,

R4represents CN or one of the hydrocarbon groups selected from (1-6 C)alkyl, (1-6 C)-alkoxygroup, (2-6 C)-alkenyl, (2-6 C)-quinil and (2-6 C)-alkylidene, and each of these hydrocarbon groups can be substituted with halogen, hydroxy or (1-6 C)-alkoxygroup, and

R5predstavliali, especially osteoporosis.

One of the most serious menopausal disorders is the bone loss (osteoporosis), which is characteristic affects women. The aim of the present invention is the provision of a medicinal product which is able to prevent bone loss and may improve bone mass and even to treat menopausal disorders. Preferably the active ingredients of these drugs have strong estrogenic and weak (or not have) androgenic activity. Preferred drugs are also favorable, contributing to the bleeding properties, does not induce the proliferation of endometriotic tissue and have a favorable ratio of HDL/LDL (lipid ratio of high and low density).

In a preferred embodiment of the invention the compounds have the General formula I, where R1represents O or two hydrogen atoms, R2represents a hydroxy-group, R3is ethinyl, R4selected from the group consisting of methyl, (2-6 C)-quinil, (2-6 C)-alkylidene and one (2-6 C) alkyl, (2-7 C)-alkoxyalkyl, (1-6 C)-alkoxygroup or (2-6 C)alkenyl, each of cotoran the use of steroids, having the General formula I, where R1represents O, R2represents a hydroxy-group, R3is ethinyl, R4represents an ethyl, 2-foretel, ethinyl, (2-6 C)-alkenyl, possibly substituted by fluorine, or (2-6 C)-alkyliden, possibly substituted by fluorine, and R5represents hydrogen or methyl. In a preferred embodiment, R5represents hydrogen.

Even more preferably the use of steroids having the formula I, where R1represents O, R2represents a hydroxy-group, R3is ethinyl, R4represents ethyl or ethinyl and R5represents hydrogen.

The invention also relates to novel steroids having the formula I, where

R1represents O,

R2represents a hydroxy-group, possibly turned into a group of simple or complex ester,

R3is a (2-6 C)-quinil, possibly substituted by a hydroxy-group,

R4represents CN, (2-6 C) alkyl, possibly substituted with halogen, or (2-6 C)-alkenyl, substituted with halogen, and

R5represents hydrogen or (1-6 C) alkyl, or where

R1predstavu simple or complex ester,

R3is a (2-6 C)-quinil, possibly substituted by a hydroxy-group,

R4represents CN or one of the hydrocarbon groups selected from a (2-6 C) alkyl, (1-6 C)-alkoxygroup, (2-6 C)-alkenyl, (2-6 C)-quinil and (2-6 C)-alkylidene, and each of these hydrocarbon groups can be substituted with halogen, hydroxy or (1-6 C)-alkoxygroup, and

R5represents (1-6 C) alkyl.

Steroids of General formula I, where R1represents O, R2represents a hydroxy-group, R3is ethinyl, R4is a 2-foradil or 2-toretail and R5represents hydrogen, are preferred steroids.

Other preferred steroids are the steroids of General formula I, where R1represents two hydrogen atoms, R2represents a hydroxy-group, R3is ethinyl, R4is a (2-6 C) alkyl, (2-6 C)-alkylidene or (2-6 C)-alkenyl, each of which may be replaced by fluorine, and R5represents methyl.

In the definition for R2the hydroxy-group can be converted into a group of simple or complex ester. The term transformation in the group about carbon atoms, for example, methyl, propyl, sec-butyl and the like alkyl. The term transformation in the group of ester indicates that the hydroxy-group etherification lower alkanoyl, preferably having 2-6 carbon atoms, such as acetyl, propionyl and similar alkanoyl. In principle any suitable ester, in which the ether group is cleaved when the connection type.

(1-6 C) Alkyl in the definition of formula I is alkyl, normal or branched structure having 1-6 carbon atoms, such as stands, ethyl, propylene, bootrom, tert-bootrom, Pentium and hexyl. Preferably the alkyl is stands (especially for R5) and ethyl (especially for R4). The term (2-6 C) alkyl has the same meaning except as noted.

(2-6 C)-Alkenyl is alkenyl normal or branched structure having 2-6 carbon atoms, for example vinyl, 2-propanolol and 1,3-butadienyl.

(2-6 C)-Quinil is quinil normal or branched structure having 2-6 carbon atoms, such as atenolol, PROPYNYL, butanolom and similar quinil.

(2-6 C)-Alkyliden is alkylidene normal or branched structure having 2-6 carbon atoms, for example, the text in the definition of formula I, denotes fluorine, chlorine, bromine or iodine. The preferred halogen is fluorine.

The term (1-6 C)-alkoxygroup refers to a group, the alkyl of which is indicated above (1-6 C) alkyl.

The term (2-7 C-alkoxyalkyl means defined above, (1-6C)-alkyl, substituted by the above (1-6 C)-alkoxygroup, and the total number of carbon atoms in alkoxyalkyl between 2 and 7.

The new compounds of the present invention can be obtained by condensation of 11-ketosteroids General formula II

< / BR>
where R1represents O,

R2represents a hydroxy-group, possibly turned into a group of simple or complex ester,

R3is a (2-6 C)-quinil, possibly substituted by a hydroxy-group, and

R5represents hydrogen or (1-6 C)-all,

or where

R1represents two hydrogen atoms,

R2represents a hydroxy-group, possibly turned into a group of simple or complex ester,

R3is a (2-6 C)-quinil, possibly substituted by a hydroxy-group, and

R5represents (1-6 C) alkyl,

active group which may secure connection (like linking Wittig is displaced by halogen, hydroxy - or (1-6 C)-alkoxygroup defined above (2-6 C)-alkylidene, or a compound of the formula R"'4Li, where R"'4is a (2-6 C) alkyl or (2-6 C)-alkenyl, possibly substituted with halogen, hydroxy or (1-6 C)-alkoxygroup, which reactive groups can be protected by protective groups which are known in organic chemistry (see, for example, T. W. Green. Protective Groups in Organic Synthesis, Wiley, NY, 1981), and W represents the balance of the connection, such connection Wittig, Witting-Horner or Peterson, followed by the possible halogenoalkanes and dehydration or hydration, after which the compound obtained is converted into a nitrile or condense with the compound of the Wittig or similar compound of formula R6W, where W has the above meaning and R6represents independently hydrogen, halogen or (1-6 C) alkyl, with the subsequent gidroborudovaniya and maybe then alkylation, halogenoalkanes or halogenoalkanes and dehydrohalogenation, or (partial) hydrogenation, and then you can remove the present protective groups.

Suitable reagents are triphenylphosphorane, for example, of the formula R'4R4CH-P(Hal)Ph3and this connection is UB>3)3where Hal represents halogen, for example chlorine or bromine.

The steroids of the invention can be used for prevention or treatment-induced estrogen deficiency disorders, such as menopausal disorders, as shown in the analysis to determine the estrogen-induced bone rarefaction. In this definition, young Mature female rats of Wistar remove the ovaries and introduce them to the test compound for 1 month. After 1 month away blood in lithium heparin plasma determine the parameter of bone functional cycle (osteocalcin) method Verhaegne et al., J. Endrocrinol. 120, 143-151. During the autopsy the right femoral bone cut and the bone density of the distal metaphysis measured x-ray densitometric method. Bone density in mm aluminum equivalent expressed in percentage relative to the bone density of the intact control group, which was defined as 100%, and relative bone density in the control group with remote ovaries, which was defined as 0%.

The magnitude of osteocalcin defined as 100% for the group with remote ovaries and 0% for the intact group. Active compounds inhibit the functional cycle of the bone and, sledovatel is 2">

Compounds of the invention can enter interline or parenteral, preferably to humans in the form of a daily dose of 0.001-10 mg per kg of body weight. In a mixture with a pharmaceutically acceptable auxiliary components, such as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences (18th ed., Mack Publishing Compani, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), the connection can be pressed into solid preparations in doses at one time, for example pills, tablets, or be processed for conversion into capsules or suppositories. With the help of pharmaceutically acceptable liquids compounds can also be used as an injectable preparation in the form of solution, suspension, emulsion or spray of the drug, e.g., for nasal administration. For the manufacture of preparations in doses at one time, for example tablets, assumes the use of conventional additives, such as fillers, dyes, polymeric binder and the like. In General, you can apply any pharmaceutically acceptable additive, which does not impede the functioning of the active compounds.

Acceptable carriers, with which you can enter the composition, include lactose, starch, cellulose derivatives and similar substances and>/P>To a solution of 115 g (7 , 11 )-11-hydroxy-7-methylestr-4-ene-3,17-dione in 5 ml of acetone was added dropwise at 0.5oC 110 ml of 8 N chromic acid. After stirring for 1 hour was added 50 ml of propanol-2 and after 15 min the mixture was partially concentrated and diluted with 3 l of water. After stirring for several hours the precipitate was separated by filtration, transferred to a small volume of dichloromethane and dried over sodium sulfate, getting after evaporation of organic solvent 107 g triketone- (7 )-7-methylestr-4-ene-3,11,17-trione. Rf= 0,54 (elution with a mixture of toluene and ethyl acetate, 4:6, vol/vol).

A mixture of 115 g (7 )-7-methylestr-4-ene-3,11,17-trione, 8 g of p-toluenesulfonic acid and 40 ml identicial in 1 l of absolute ethanol was boiled under reflux for 1 hour. After cooling, the mixture was diluted with 1 l of water and stirred in the cold for several hours. The precipitate was separated by filtration and washed with 1N NaOH, water and cold methanol. After drying received 134 g (7 )-3,3-idendity-7-methylestr-4-ene-11,17-dione. Rf= 0,62 (toluene-ethyl acetate, 8:2).

The solution containing 36 g (7 )-3,3-idendity-7-methylestr-4-ene-11,17-dione, 300 ml of dichloromethane, 85 ml triethylorthoformate, 70 ml of ethylene glycol and 2 g of p-toluenesulfonic acid was stirred Therese a column of silica gel, receiving 44 g of the product, (7 )-3,3-idendity-17,17-Ethylenedioxy-7-methylestr-4-ene. Rf= 0,65 (toluene-ethyl acetate, 8:2).

A mixture of 9.2 g of tert-butoxide potassium, 34.8 g of methyl methyltriphenylphosphonium in 260 ml of toluene was boiled under reflux for 1 hour. Then added to 7.8 g (7 )-3,3-idendity-17,17-Ethylenedioxy-7-methylestr-4-ene and the mixture is boiled for another 2 hours. Then the reaction mixture was cooled, washed with water, dried and concentrated. The residue was chromatographically, receiving of 6.1 g (7 )-3,3-idendity-17,17-Ethylenedioxy-7-methyl-11-methylenethf-4-ene. Rf= 0,77 (toluene-ethyl acetate, 9:1).

A mixture of 6.1 g (7 )-3,3-idendity-17,17-Ethylenedioxy-7-methyl-11-methylenethf-4-ene, 90 ml of acetone, 50 ml of tetrahydrofuran and 3 ml of 6N hydrochloric acid was stirred at room temperature. After 1 hour the mixture was diluted by adding 700 ml of 5% sodium carbonate solution and was stirred 1/2 hour. The precipitate was separated by filtration and dried, obtaining of 5.4 g (7 )-3,3-idendity-7-methyl-11-methylenethf-4-EN-17-she. Rf= 0,74 (toluene-atlanata, 9:1).

Gaseous acetylene was passed through a solution of 50 g of tert-butoxide potassium in 500 ml of dry tetrahydrofuran. After 2 hours was introduced dropwise at 0oC a solution of 30 g (7 )-3,3-idendity-7-methyl-11-methylenethf-4-EN-17-she Vivoli another 1/2 hour. The precipitate was separated by filtration and dried, obtaining 31 g (7 , 17 ) -3,3-idendity-17-hydroxy-7-methyl-11-methylene-19-norpregna-4-EN-20-she. Rf= 0,64 (toluene-ethyl acetate, 9:1).

To a solution of 8 g of sodium in 300 ml of liquid ammonia at -50oC was added dropwise a solution of 16 g (7 , 17 )-3,3-idendity-7-methyl-11-methylene-19-norpregna-4-EN-20-in-17 - ol in 75 ml of tetrahydrofuran. After stirring the reaction mixture for 1 hour, the excess sodium was destroyed by adding 10 ml of ethanol. After evaporation of the ammonia the residue was distributed between dichloromethane and water. The organic layer was separated, washed and dried. The residue after evaporation of the solvent was chromatographically, receiving of 5.4 g (7 , 17 )-7-methyl-11-methylene-19-norpregna-4-EN-20-in-17-ol. Rf= 0,59 (toluene-ethyl acetate, 9:1).

Example 2.

A mixture of 15 g (7 , 17 )-3,3-idendity-7-methyl-11-methylene-19-norpregna-4-EN-20-in-17-ol, 300 ml of methanol, 20 ml of water, 6 g of calcium carbonate and 51 ml iodotope bromide was heated under reflux for 6 hours. After filtration of the mixture through hyflo the filtrate was concentrated, transferred in dichloromethane, washed, dried and evaporated. The obtained residue was chromatographically getting 6.5 g (7 , 17 )-17-hydroxy-7-methyl-11-methylene-19-norpregna-4-EN-20-in-3-one. Rf= 0.40 in 5 l of dry tetrahydrofuran was added in parts 110 g of tri-tert-butoxylated lithium at 0-5oC. After stirring for 3 h the mixture was poured into 10 l of ice water and slightly acidified by adding 1 liter of 2N hydrochloric acid. The product was extracted with ethyl acetate. After drying with sodium sulfate the organic material was treated with diethyl ether, getting 133 g of essentially pure (7 , 17 )-3,3-idendity-17-hydroxy-7-methylestr-4-EN-11-she. Rf= 0,45 (toluene-ethyl acetate, 6:4).

To a solution of 132 g (7 , 17 )-3,3-idendity-17-hydroxy-7-methylestr-4-EN-11-she's in 800 ml of pyridine was added at 0oC 182 ml of chloride trimethylsilyl. After stirring for 1 hour the mixture was poured into ice water and the product was extracted with ethyl acetate. After washing, drying and evaporation of the solvent, the obtained residue is again evaporated with toluene and then treated with hexane, getting 137 g (7 , 17 )-3,3-idendity-7-methyl-17-trimethylsilyloxy-7-methylestr-4-EN-11-she. Rf= 0,63 (toluene-ethyl acetate, 6: 4).

In the suspension 334 g chloride methoxybutyrophenone in 6 l of dry diethyl ether was added dropwise to 600 ml of 1.6 M utility at 0.5oC. After stirring 1 hour the solution was added to 44.6 g (7 , 17 )-3,3-idendity-17 trimethylsilyloxy-7-methylestr-4-EN-11-she's in 1.5 l of diethyl ether and the mixture was stirred 24 hours. Organic is the basics, distributed system hexane-methanol-water (1: of 0.7:0.3, and the ratio of volume) and stirred for 15 minutes Hexane phase was dried and concentrated, gaining 47 g (7 , 17 )-3,3-idendity-11-methoxymethyl-17 trimethylsilyloxy-7-methylestr-4-ene. Rf= 0,50 (hexane-ethyl acetate, 3:1).

To a solution of 265 g (7 , 17 )-3,3-idendity-11-methoxymethyl-17 trimethylsilyloxy-7-methylestr-4-ene in 800 ml of acetone was added 80 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature. After stirring for 1 hour the mixture was poured into water and was extracted with ethyl acetate. After washing, drying and evaporation of the organic solvent, the obtained residue was passed through a column of silica gel and was suirable a mixture of dichloromethane-acetone (9:1) to give 63 g(7 , 11 , 17 )-3,3-idendity-17-hydroxy-7-methylestr-4-EN-11-carboxaldehyde. Rf= 0,38 (toluene-ethyl acetate, 7:3).

Into a solution of 55 g(7 , 11 , 17 )-3,3-idendity-17-hydroxy-7-methylestr-4-EN-11-carboxaldehyde and 165 ml dihydropyran in 1100 ml of dry tetrahydrofuran was added 1.3 g of p-toluenesulfonic acid. After stirring for 2 h the mixture was poured into 5 l of 5% aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate. After concentration organ">

A mixture of 1 g(7 , 11 , 17 )-3,3-idendity-17 tetrahydropyranyloxy-7-methylestr-4-EN-11-carboxaldehyde and 2 g of hydroxylamine hydrochloride in 12 ml of pyridine was stirred at 80oC for 1 hour. Then the reaction mixture was cooled, poured into water and was extracted with ethyl acetate. After washing, drying and concentration was obtained 0.9 g of amorphous oxime(7 , 11 , 17 )-3,3-idendity-17 tetrahydropyranyloxy-7-methylestr-4-EN-11-carboxaldehyde, Rf= 0,60 (toluene-ethyl acetate, 8:2).

The reaction digitately 0.8 g of the oxime(7 , 11 , 17 )-3,3-idendity-17 tetrahydropyranyloxy-7-methylestr-4-EN-11-carboxaldehyde conducted in 8 ml of acetic anhydride for 45 minutes was Observed concomitant substitution 17-tetrahydropyranyloxy on acetyloxy. The reaction mixture was poured into 50 ml ice water and stirred 30 minutes After neutralization with 2N sodium hydroxide solution and extraction with ethyl acetate was obtained 0.75 g(7 , 11 , 17 )-3,3-idendity-17-atomic charges-7-methylestr-4-EN-11-carbonitrile. Rf= 0,58 (toluene-ethyl acetate, 9:1).

An acetate group omilami mixing 0.75 g(7 , 11 , 17 )-3,3-idendity-17-atomic charges-7-methylestr-4-EN-11-carbonitrile for 30 min in a mixture of 20 ml of tetrahydrofuran and 10 ml of water containing 1 g of sodium hydroxide. A mixture of rasb the-methylestr-4-EN-11-carbonitrile. Rf= 0,34 (toluene-ethyl acetate, 9:1).

In a solution of 20 g(7 , 11 , 17 )-3,3-idendity-17-hydroxy-7-methylestr-4-EN-11-carbonitrile in 600 ml of dry dichloromethane was added 20 g of sodium acetate, then 85 g Harrogate pyridinium. After stirring for 3 hours the reaction was finished. The excess oxidant was removed by adding 40 ml of propanol-2. The mixture was filtered through hyflo, concentrated and chromatographically, obtaining 13 g (7 , 11 )-3,3-idendity-17-keto-7-methylestr-4-EN-11-carbonitrile. Rf= 0,75 (toluene-ethyl acetate, 8:2).

Through a solution of 10.5 g of tert-butoxide potassium in 60 ml of dry tetrahydrofuran for 1 hour at 0oC missed gaseous acetylene. Then was added dropwise a solution of 9.3 g (7 , 11 )-3,3-idendity-17-oxo-7-methylestr-4-EN-11-carbonitrile in 100 ml of tetrahydrofuran. After stirring 1 hour at 0-5oC the mixture was poured into 500 ml of saturated solution of ammonium chloride and the product was extracted with ethyl acetate. After washing, drying and concentration was obtained 9,5 (7 , 11 , 17 )-3,3-idendity-17-hydroxy-7-methyl-19-norpregna-4-EN-20-in-11-carbonitrile. Rf= 0,28 (toluene-ethyl acetate, 9:1).

A mixture of 6.5 g(7 , 11 , 17 )-3,3-idendity-17-hydroxy-7-methyl-19-norpregna-4-EN-20-in-11-carbonitrile, 200 ml of methanol, 100 ml tetraconch hours added from time to time additional amounts of methanol and after the disappearance of starting material the mixture was cooled, filtered and concentrated. The residue was passed through a column of silica gel, obtaining 2.5 g of pure( 7 , 11 , 17 )-17-hydroxy-7-methyl-3-oxo-19-norpregna-4-EN-20-in-11-carbonitrile. So pl. 234oC. Rf= 0,33 (toluene-ethyl acetate, 7:3).

Example 4.

Hydroporinae 11-methylene group 3,3,17,17-bis(Ethylenedioxy)-11-methylenethf-5-ene was carried out as follows.

In a solution of 2.18 ml of 10 M complex boron hydride-dimethyl sulfoxide in 10 ml of dry tetrahydrofuran was added at 0oC 2,7 ml cyclooctadiene. After boiling under reflux for 1 hour the mixture was added a solution of 2.7 g 3,3,17,17-bis(Ethylenedioxy)-11-methylenethf-5-ene in 30 ml of tetrahydrofuran. The mixture was stirred 16 h and then was treated with 10 ml of 10% sodium hydroxide solution and then with 10 ml of 30% hydrogen peroxide. After stirring for an additional 4 h the mixture was poured into water and the product was extracted with dichloromethane. Final purification was performed by chromatography, receiving 2 g (11 )-3,3,17,17-bis-(Ethylenedioxy)-11-(hydroxymethyl)variety-5-ene. Rf=0,25 (toluene-ethyl acetate, 1:1).

Wmutil)variety-5-ene in 100 ml of dichloromethane. After stirring for 1 hour the excess oxidant was destroyed by addition of 40 g of sodium bisulfite in 200 ml of water and then the product was extracted with ethyl acetate. After drying and concentrating the organic phase the residue was purified by chromatography, receiving of 5.4 g (11 )-3,3,17,17-bis(Ethylenedioxy)-variety-5-ene-11-carboxaldehyde. Rf=0,50 (hexane-ethyl acetate, 1:1).

A solution of 1.6 M utility in hexane (44 ml) was added dropwise to a suspension of 24.4 g of chloride chloromethylphosphonic in 500 ml of diethyl ether. After stirring 15 min was added dropwise a solution of 5.4 g (11 )-3,3,17,17-bis(Ethylenedioxy)variety-5-ene-11-carboxaldehyde in 30 ml of tetrahydrofuran. After 12 h the mixture was poured into 0.5 l of water and the organic phase was separated, washed, dried and concentrated. The residue was chromatographically, gaining 3.7 g E/Z (11 )-3,3,17,17-bis(Ethylenedioxy)-11-(2-chloranil)extras-5-ene. Rf=0,4 (hexane-ethyl acetate, 7:3).

To a suspension of lithium amide derived from 920 mg of lithium in 130 ml of ammonia (liquid) were added at -45oC a solution of 3.6 g (11 )-3,3,17,17-bis(Ethylenedioxy)-11-(2-chloranil)extras-5-ene in 30 ml of tetrahydrofuran. After stirring 1 hour, the excess reagent was destroyed by adding 15 g of ammonium chloride and subsequent evaporation of ammonia. The remainder Luca 1.8 g (11 )-3,3,17,17-bis(Ethylenedioxy)-11-tinyest-5-ene. So pl. 200oC. Rf=0,45 (hexane-ethyl acetate, 7:3).

A mixture of 8 g (11 )-3,3,17,17-bis(Ethylenedioxy)-11-tinyest - 5-ene, 200 ml of acetone, 100 ml of methanol and 100 ml of tetrahydrofuran was treated with 5 ml of 6 N hydrochloric acid and was stirred overnight. After treatment with sodium bicarbonate and concentration the residue was chromatographically, receiving of 5.1 g (11 )-11-tinyest-4-ene-3,17-dione. Rf=0,48 (hexane-ethyl acetate, 1:1).

Through a mixture of 2.7 g of tert-butoxide potassium in 12 ml of tetrahydrofuran and 5 ml of tert-butanol under nitrogen atmosphere for 1.5 hours at 0oC missed the bubbles of gaseous acetylene. Then he introduced a suspension of 1.85 g (11 ) -11-tinyest-4-ene-3,17-dione in 5 ml of tetrahydrofuran and stirring continued for another 1 hour. The mixture was diluted with water (200 ml), neutralized by addition of 2N hydrochloric acid and was extracted with ethyl acetate, dried and concentrated. The residue was chromatographically, receiving 1.6 g (11 , 17 )-11-ethinyl-17-hydroxy-19-norpregna-4-EN-20-in-3-one. So pl. 168oC. Rf= 0,60 (hexane-ethyl acetate, 1:1).

Example 5.

To a solution of 4 ml of borane-metilsulfate (10 M in tetrahydrofuran) in 20 ml of tetrahydrofuran was added dropwise 5 ml of 1,5-cyclooctadiene. After stirring for 1 hour dropwise domovini-3,3,17,17-bis(Ethylenedioxy)-11-tinyest-5-ene in 25 ml of tetrahydrofuran. After stirring additionally for 1 hour was added 20 ml of 15% aqueous sodium hydroxide solution and 20 ml of 30% hydrogen peroxide. The mixture was stirred overnight, then the product was extracted with ethyl acetate, and the thus obtained organic layer was purified by chromatography, obtaining 3.4 g of 11 -(2-hydroxyethyl)-3,3,17,17-bis(Ethylenedioxy)variety-5-ene. So pl. 190oC.

To a solution of 5 g of 11 -(2-hydroxyethyl)-3,3,17,17-bis(Ethylenedioxy)variety-5-ene in 7 ml of tetrahydrofuran was added at -30oC 500 mg of 2,6-di-tert-butylpyridinium and then 800 mg anhydride of triftoratsetata. After stirring for an additional 15 min at -30oC was added 10 ml of 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and the mixture was stirred 2 hours at room temperature and then poured into 30 ml of 10% sodium bicarbonate solution. Then the mixture was extracted with ethyl acetate and the organic layer was purified by chromatography, receiving 600 mg of 11 -(2-foradil)-3,3,17,17-bis(Ethylenedioxy)variety-5-ene. So pl. 196oC.

To a solution of 580 mg of 11 -(2-foradil)-3,3,17,17-bis(Ethylenedioxy)variety-5-ene in the mixture of 3 ml of acetone and 3 ml of tetrahydrofuran was added 6 ml of 3 M hydrochloric acid. After stirring for 2 hours was added bicarbonate intothree the Wali diisopropyl ether, receiving 400 mg of 11 -(2-foradil)variety-5-ene-3,17-dione. So pl. 85oC.

In a solution of 0.7 g of tert-butoxide potassium in 5 ml of tetrahydrofuran and 1 ml of tert-butanol missed gaseous acetylene. After 15 min the solution was added 400 mg of 11 -(2-foradil)variety-5-ene-3,17-dione in 5 ml of tetrahydrofuran. After stirring additionally for 15 min the solution was poured into water and the product was extracted with ethyl acetate. Thus obtained organic portion was purified column chromatography and treated with ether, receiving 320 mg(11 , 17 )-11-(2-foradil)-17-hydroxy-19-norpregna-4-EN-20-in-3-one. So pl. 212oC.

Example 6.

In the solution diisopropylamide lithium (from 250 mg of Diisopropylamine and 1.6 ml of a 1.6 M solution of utility in hexane) in 3 ml of tetrahydrofuran was added a solution of 600 mg oxide diftormetilirovaniya in 2 ml of tetrahydrofuran at -50oC. After stirring for 15 min was added 800 mg of 11-3,3,17,17-bis(Ethylenedioxy)variety-5-ene-11-carboxaldehyde in 3 ml of tetrahydrofuran and the mixture was stirred over night at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. Chromatography of the organic part of the received 465 mg of 11 -(2,2-deperately)-3,3,17,17-bis(Ethylenedioxy)variety-5-ene. So pl. 180-181oali 2 ml of 4 N hydrochloric acid. After stirring 2 hours the mixture was neutralized with solid sodium bicarbonate and the product was extracted with ethyl acetate. Thus obtained organic material was led from diisopropyl ether, receiving 270 mg 11 -(2,2-defloration)variety-5-ene-3,17-dione. So pl. 150oC.

In a solution of 0.48 g of tert-butoxide potassium in a mixture of 5 ml of tetrahydrofuran and 0.5 ml of tert-butanol missed gaseous acetylene. After 15 min the solution was added 250 mg of 11 -(2,2-defloration)variety-5-ene-3,17-dione in 3 ml of tetrahydrofuran, and after 15 min the mixture was treated with water, the product was extracted with ethyl acetate.

Selected thus organic material was treated with diisopropyl ether, receiving 160 mg(11 , 17 )-11-(2,2-deperately)-17-hydroxy-19-Norring-4-EN-20-in-3-one. So pl. 196oC.

Example 7.

Mixture of E/Z-11-3,3,17,17-bis(Ethylenedioxy)-11-(2-chloranil)variety-4-ene were separated on a column of silica gel, receiving a pure E-isomer (so pl. 143oC) and Z-isomer (so pl. 182oC). The processing solution of 3 g (E)-11-3,3,17,17-bis(Ethylenedioxy)-11-(2-chloranil)variety-4-ene in 20 ml of acetone and 3 ml of concentrated hydrochloric acid for 1 hour, followed by neutralization of the reaction mixture with a solution of bicarbonate of sodium and extrac which was dissolved in 10 ml of tetrahydrofuran and was added dropwise into the solution acetylide potassium in a mixture of 14 ml of tetrahydrofuran and 3 ml of tert-butanol (acetylide potassium was obtained by passing gaseous acetylene into a solution of 2.9 g of tert-butoxide potassium in the above mixture of tert-butanol and tetrahydrofuran). After stirring 1/2 hour the mixture was treated with water and the product was extracted with ethyl acetate. Organic material was purified by chromatography, obtaining 1.9 g (11 , E, 17 )-11-(2-toretail)-17-hydroxy-19-norpregna-4-EN-20-in-3-one. So pl. 180oC.

Example 8.

Similarly, the received connection, are shown in table 2.

Example 9.

Received tablets having the following composition:

(11 , 17 ) - 17-Hydroxy-11-ethyl-19-norpregna-4-EN-20-in-3-he - 2.5 mg

Starch 10 mg

Ascorbyl palmitate - 0.2 mg

Magnesium stearate 0.5 mg

Lactose - Up to a total weight of 100 mg

Granules of the base was obtained by mixing lactose with a part of the starch. The remaining starch was mixed with water for the formation of a starch suspension was added to the mixture. The whole mixture was granulated and dried. These granules basis was mixed with ascorbyl palmitate and active component, screened, thoroughly mixed with magnesium stearate and then alloy preformed.

Example 10.

Tablets having the same composition as in example 9, was received with use as an active component (11 , 17 )-11-ethinyl-17-hydroxy-19-norpregna-4-EN-20-in-3-one.

Example 11.

Tablets having the same composition as in example 9, is the first by mixing the active component with 10% lactose and ascorbyl palmitate and then mixing this mixture with lactose, starch and starch suspensions. The mixture was dried, thoroughly mixed with magnesium stearate and alloy preformed.

Example 12.

Received capsules having the following composition:

(11 , 17 )-11-Ethyl-17-hydroxy-19-norpregna-4-EN-20-in-3-he - 2.5 mg

Starch 10 mg

Ascorbyl palmitate - 0.2 mg

Magnesium stearate 0.5 mg

Avicel - Up to a total weight of 100 mg

The components were mixed with each other in the same manner as in example 9, was granulated and filled with granules of gelatin capsules.

Table 3 shows the additional data characterizing the compounds of the invention possessing estrogenic activity determined by the method of binding of estrogen and/or method Allty Doisy in vivo, and optional progestogenic activity determined by the method of binding of the progesterone receptor.

Given the substance of the formula given in the description, where R2means OH, and R3means ethinyl.

Techniques

The relative affinity of binding to the receptor and progestin person.

Evaluation of the affinity of binding of test compounds to the progestin receptor from the cytoplasm derived from tumor cells of breast cancer MCF-7 human, spent sravnenie investigated in three concentrations, in the ratio 1:2:4 with three concentrations of standard compounds Org 2058, also in the ratio 1:2: 4. The displacement efficiency labeled compounds Org 2058 of progestin receptor test connection and a standard mixture was measured after incubation for 16 h at 4oC. For each concentration of the standard or the test compound was calculated radioactivity by contacting the receptor (including nonspecific binding), as a percentage of total radioactivity (also taking into account non-specific binding) by contacting the receptor. Then the percentages were replaced with the respective logarithmic values and evaluated statistically using the analysis of the three point parallel lines. If you have not found a significant curvature and there were no significant deviation Parallels at the level of 0.01, we calculated the relative binding affinity of the test compound compared to the Org 2058.

Similarly, to determine the relative affinity of test compounds to extrogen receptors person, compared with estradiol (E2) was used cytoplasmic estrogen receptors present in the cytoplasm of recombinant cells aicn the R-(2B1) was obtained in the Department of biotechnology and biochemistry (BBC, N. V. Organon). The reference compounds were ethinyl estradiol and estriol.

Test Allen-Doisy for determination of estrogenic activity in vivo.

This method is based on the assessment of keratinization of the vaginal epithelium in vaginal smears. In Mature female rats were removed ovaries and on the third week after surgery, animals were subjected to a single dose (1 mg) of estradiol (1st day). Through 7 days after the administration of the newly introduced test connection 1 time in 8 days and 2 times on the 9th day. Vaginal smears were taken in the second half of the 10th day, 2 times on the 11th day and again in the morning on the 12th day. These smears were stained by Giemsa and determined the number of positively stained smears (Van dervies J., De Visser J. 1983. Endocrinological studies with desogestrel. Drug. Res., so 33, S. 231-236). The potency of the compound is expressed as the minimum effective dose.

1. The active ingredient of a drug for treating or preventing menopausal diseases with estrogenic and weak androgenic or not with the last activity, representing a steroid having the General formula I

< / BR>
where R1represents O, (H, HE) or two hydrogen atoms;

R2represents a hydroxy-group, neoblastic, optionally substituted by a hydroxy-group;

R4represents CN or one of the hydrocarbon groups selected from (C1-C6)-alkyl, (C1-C6-alkoxygroup, (C2-C6-alkenyl, (C2-C6)-quinil and (C2-C6)-alkylidene, and each of these hydrocarbon groups may be substituted with halogen, hydroxy or (C1-C6-alkoxygroup;

R5represents hydrogen or (C1-C6)-alkyl.

2. The active ingredient under item 1, where menopausal disease is osteoporosis.

3. The active ingredient under item 1 or 2, where a steroid has the General formula I, in which R1represents O or two hydrogen atoms; R2represents a hydroxy-group; R3is ethinyl; R4selected from the group consisting of methyl, (C2-C6)-quinil, (C2-C6)-alkylidene and one of (C3-C6)-alkyl, (C2-C7)-alkoxyalkyl, (C1-C6-alkoxygroup or (C2-C6-alkenyl, each of which may be substituted with halogen; 5represents hydrogen or (C1-C6)-alkyl.

4. The active ingredient under item 1 or 2, where CTE is y; R3is ethinyl; R4represents an ethyl, 2-foretel, ethinyl, (C2-C6)-alkenyl, optionally substituted by fluorine, or (C2-C6-alkylidene, optionally substituted by fluorine; R5represents hydrogen or methyl.

5. The active ingredient under item 1 or 2, where a steroid has the General formula I, in which R1represents O; R2represents a hydroxy-group; R3is ethinyl; R4represents ethyl or ethinyl; R5represents hydrogen.

6. The steroid of General formula I

< / BR>
where R1represents ABOUT;

R2represents a hydroxy-group, optionally etherified or esterified;

R3is a (C2-C6)-quinil, optionally substituted hydroxy-group;

R4represents CN, (C2-C6)-alkyl substituted by halogen or (C2-C6)-alkenyl, substituted with halogen;

R5represents hydrogen or (C1-C6)-alkyl.

7. Steroid on p. 6, where R1represents O; R2represents a hydroxy-group; R3is ethinyl; R1represents two hydrogen atoms; R2represents a hydroxy-group, optionally etherified or esterified; R3is a (C2-C6)-quinil, optionally substituted hydroxy-group; R4represents CN or one of the hydrocarbon groups selected from the group consisting of (C2-C6)-alkyl, (C1-C6-alkoxygroup, (C2-C6-alkenyl, (C2-C6)-quinil and (C2-C6)-alkylidene, and each of these hydrocarbon groups may be substituted with halogen, hydroxy or (C1-C6-alkoxygroup; R5represents hydrogen or (C1-C6)-alkyl.

9. Steroid under item 8, where R1represents two hydrogen atoms; R2represents a hydroxy-group; R3is ethinyl; R4is a (C2-C6)-alkyl, (C2-C6-alkylidene or (C2-C6)-alkenyl, each of which may be substituted by fluorine; R5represents methyl.

10. Steroid having the General formula I, where R1represents O; R2represents a hydroxy-group; R3represents the method for receiving steroid under item 6 or 8, where 11-ketosteroid General formula II

< / BR>
in which R1represents O;

R2represents a hydroxy-group, optionally etherified or esterified;

R3is a (C2-C6)-quinil, optionally substituted hydroxy-group;

R5represents hydrogen or (C1-C6)-alkyl,

or

where R1represents two hydrogen atoms;

R2represents a hydroxy-group, optionally etherified or esterified;

R3is a (C2-C6)-quinil, optionally substituted hydroxy-group;

R5is a (C1-C6)-alkyl, active group which may be protected,

condense with such connection Wittig compound of the formula R'4R4-CH-W, where R'4R4C forms a group R4which is substituted with halogen, hydroxy or (C1-C6-alkoxygroup defined above (C1-C6-alkylidene, or of the formula R"'4Li, where R"'4'Li is a (C2-C6)-alkyl or (C2-C6)-alkenyl, substituted with halogen, hydroxy or (C1, is the quiet well-known in organic chemistry; W - represents the balance of the connection, such connection Wittig, Wittig-Horner or Peterson, followed by the possible halogenoalkanes and dehydration or hydration, after which the compound obtained is converted into a nitrile or condense with the compound of the Wittig or similar compound of formula R6W, where W has the above meaning and R6represents independently hydrogen, halogen or (C1-C6)-alkyl, with the subsequent gidroborudovaniya and maybe then alkylation, halogenoalkanes and dehydrohalogenation or (partial) hydrogenation, and then you can remove the present protective groups.

12. Pharmaceutical composition for treating or preventing menopausal disease containing as an active ingredient steroid according to any one of paragraphs.6 to 9 and a pharmaceutically acceptable additive.

13. The pharmaceutical composition according to p. 12, containing as an active ingredient the compound (11-beta, 17-alpha)-11-ethyl-17-hydroxy-19-norpregna-4-EN-20-in-3-one).

14. The pharmaceutical composition according to p. 12, containing as an active ingredient the compound (7-alpha, 11TH, 17-alpha)-11-ethylidene-1

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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