Derivatives of 16-hydroxy-11-(substituted phenyl)-Östra-4,9 - diene, a compound, pharmaceutical composition

 

(57) Abstract:

The invention relates to derivatives of 16-hydroxy-11-(substituted phenyl)-östra-4,9-diene corresponding to the formula I, where R1- C1-6- alkyl, triflate or phenyl, where the phenyl group is optionally substituted by one or more substituents selected from cyano, halogen and C1-4-alkyl, R2is hydrogen or carboxy-1-oxo-C1-6-alkyl; R3is hydrogen, halogen or1-6- alkyl, optionally substituted by one or more1-6-alkoxy, R4is hydrogen or C1-6-alkyl, and X, O or NOH; or their pharmaceutically acceptable salts or MES; describes the methods for their preparation and the pharmaceutical composition is intended for use in medical therapy particularly for the treatment or prevention glucocorticoidavoid diseases or symptoms. 3 S. and 6 C.p. f-crystals, 1 PL.

The invention relates to certain derivatives of 16-hydroxy-11-(substituted phenyl)-östra-4,9-diene, methods for their preparation, containing their pharmaceutical compositions and to their use in medical therapy particularly for the treatment or prevention glucocorticoidavoid diseases.

chicoine action. In the European patent 0057115 described 19-nor steroids and 19-nor-D-Domostroy with antiglucocorticoid activity.

Currently found a number of derivatives of 16-hydroxy-11-(substituted phenyl)-östra-4,9-diene, which have a high selective affinity for glucocorticoid receptors and have a powerful antiglucocorticoid activity in vivo.

Accordingly, the present invention relates to compounds of the formula I

< / BR>
where R1represents C1-6-alkyl, C3-6-cycloalkyl, C1-6-alkoxy, triplet, pyridyl or phenyl, where the phenyl group is optionally substituted by one or more substituents selected from cyano, halogen and C1-4-alkyl;

R2represents hydrogen, C1-6-alkyl, 1-oxo-C1-6-alkyl or carboxy-1-oxo-C1-6-alkyl;

R3represents hydrogen, halogen or C1-6-alkyl, optionally substituted by one or more substituents selected from C1-6-alkoxy and halogen;

R4represents hydrogen, C1-6-alkyl, 1-oxo-C1-6-alkyl or carboxy-1-oxo-C1-6-alkyl; and

X is (H, HE, O or NOH;

or their pharmaceutically acceptable salts or MES.

The present and the 1 represents phenyl, triflate or C1-6-alkyl, for example tert-butyl, isopropyl or methyl.

2. R2represents hydrogen.

3. R3represents hydrogen, halogen, for example chlorine, C1-6-alkyl, for example methyl, ethyl, propyl or tert-butyl, optionally substituted C1-6-alkoxy, such as methoxy.

4. R4represents hydrogen or methyl.

5. X represents O.

6. R1, R2, R3, R4and X are as defined in the PP.1-5 above, or its pharmaceutically acceptable salt or solvate.

7. R1represents C1-6-alkyl, C3-6-cycloalkyl, triflate or phenyl; R2represents hydrogen, C1-6-alkyl, 1-oxo-C1-6-alkyl or carboxy-1-oxo-C1-6-alkyl; R3represents hydrogen, halogen or C1-6-alkyl, optionally substituted by one or more substituents selected from C1-6-alkoxy and halogen; R4represents hydrogen, C1-6-alkyl, 1-oxo-C1-6-alkyl or carboxy-1-oxo-C1-6-alkyl; and X is (H, HE, O or NOH; or its pharmaceutically acceptable salt or MES.

Additional examples of compounds of formula I above include examples 1-4.< is. Such alkyl groups include methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and neohexyl. An indication of cycloalkyl includes cyclopropyl, cyclopentyl and cyclohexyl.

The term "alkoxy" has the meaning understood by the experts, and includes straight and branched chains. Examples of alkoxygroup include methoxy, ethoxy. Preferred alkoxygroup include C1-4-alkoxy.

The term "halogen" includes chlorine, bromine, fluorine and iodine.

Triplet means triftorbyenzola.

1-Oxo-C1-6-alkyl or carboxy-1-oxo-C1-6the alkyl groups include 1-oxoethyl, 1-oxoethyl, 1-oxopropyl, 3-carboxy-1-oxopropyl, 3-carboxy-1-oxobutyl and 3-carboxy-1-oxobutyl.

Preferred examples of R1are phenyl and C1-6-alkyl, for example tert-butyl (1,1-dimethylethyl), isopropyl (1-methylethyl) or methyl, most preferably tert-butyl and phenyl.

R2preferably represents hydrogen.

Preferred examples of R3include C1-6-alkyl, most preferably methyl.

R4preferably represents hydrogen or C1-6-alkyl, CLI I include those in which R1represents phenyl or C1-6-alkyl, for example tert-butyl, isopropyl or methyl; R2is hydrogen; R3represents C1-6-alkyl, most preferably methyl; R4represents hydrogen or C1-6-alkyl, preferably methyl; and X is O; or their pharmaceutically acceptable salt or solvate.

Particularly preferred derivatives of 16-hydroxy-11-(substituted phenyl)-östra-4,9-diene of the formula I include:

(11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one;

(11,16,17)-11-(4-isopropylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one;

(11,16,17)-11-(4-were)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one;

(11,16,17)-11-(1,1'-biphenyl-4-yl)-16,17-dihydroxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one;

(11,16,17)-16,17-dihydroxy-11-[4-[(trifluoromethyl-sulfonyl)oxy] phenyl]-17-(1-PROPYNYL)östra-4,9-Dien-3-one

or their pharmaceutically acceptable MES.

For therapeutic use those suitable salts of the compounds of the formula I, in which the pharmaceutically acceptable the counterion. However, salts of acids and bases, which are pharmaceutically unacceptable, can also find use, for example, upon receipt or purification of pharmaceutically priemel admit of the present invention.

Salts according to the invention include ammonium salts, alkali metal salts, such as salts of sodium or potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, salts with organic bases, such as dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.

The solvate according to the invention include hydrates.

In the following aspect, the invention provides compounds of formula I and their pharmaceutically acceptable salt or solvate for use in therapy, more particularly for the treatment and prevention of dependent glucocorticoid diseases or symptoms, such as Cushing's syndrome, diabetes, glaucoma, sleep disorders, depression, anxiety, atherosclerosis, hypertension, obesity, osteoporosis, addiction to drugs or drugs and in the treatment of symptoms of deprivation of familiar substances, such as drugs, cocaine and alcohol. The compounds also find use in the treatment of neurodegenerative diseases such as Alzheimer's disease, and mental disorders such as schizophrenia, mania, hyperactivity, addiction to substances, vomiting and schizophreniathe disorders.

The compounds of formula I and their pharmaceutically in the treatment of depression.

The present invention further includes a method of treating an animal, such as a mammal, including humans, suffering from or susceptible to disease dependent glucocorticoid disease, including any of the aforementioned diseases or symptoms, which includes the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES.

In another aspect the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt or MES for the preparation of drugs for treatment or prevention of any of the above diseases or symptoms.

The amount of the compounds of formula I or its pharmaceutically acceptable salt or MES, referred to here as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary depending on the particular compound, the route of administration, the age and condition of the patient and the particular disorder or disease being treated.

A suitable daily dose for any of the above disorders is in the range from 0.001 to 50 mg per kilogram body weight of the patient (for example is preferably in the range from 0.1 to 10 mg per kilogram of body weight per day. The required dose can be entered as one, two, three, four, five or more sub-doses, administered at appropriate intervals throughout the day.

Although the active ingredient may be administered in pure form, it is preferable to introduce it in the form of pharmaceutical compositions. Accordingly, the present invention provides further a pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt or MES together with its pharmaceutically acceptable carrier and optionally other therapeutic agents. The carrier must be "acceptable" from the viewpoint of compatibility with other ingredients of the composition and safety for the patient.

Compositions include carriers suitable for oral, rectal, nasal, topical (including transdermal, cheek and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and through the vitreous body) introduction. The composition can be prepared by any means well known in the pharmaceutical practice, for example, using techniques such as described in Gennaro et al. . Remington''s Pharmaceutical Sciences (18th ed., Mack Publishing company, diente with the carrier, which consists of one or more accessory ingredients. Such auxiliary ingredients include those additives that are usually used in practice, such as fillers, binders, diluents, disintegrating agents, lubricating, dyes, fragrances and moisturizing agents.

Compositions intended for oral administration may constitute discrete units such as pills, tablets or capsules, each of which contains a certain amount of the active ingredient; can be in the form of powders or granules; as solution or suspension. The active ingredient may also be a bolus or pasta or may be contained in the fat balls.

Compositions for rectal injection may constitute a suppository or enema.

Compositions for parenteral administration include aqueous and non-aqueous sterile injection. The compositions can be presented in a single dose or mnogochasovykh containers, such as sealed containers and vials, and can be stored in a freeze dried (lyophilized) form, requiring only the addition of sterile liquid carrier, for example water, before use.

Kok obtained through the compressed aerosols with metered dosage, spray or apparatus for injection.

The present invention further includes methods of producing the compounds of formula I or its pharmaceutically acceptable salt or MES.

The compounds of formula I can be obtained by various methods known generally in the practice of organic chemistry. Starting materials are either known and readily available from chemical sources, or can be obtained by known methods.

In the following description, the symbols R1, R2, R3, R4and X have the meanings ascribed to them in formula I, unless otherwise indicated.

In accordance with the first General method (A) the compounds of formula I can be obtained by dehydration and removal of protection from the compounds of formula II:

< / BR>
where R is a protected ketogroup and R5represents a group R4as defined for formula I, or a suitably protected group, R4. Suitable protective groups and methods for their removal are known in practice, for example in T. W. Green: Protective Groups in Organic Synthesis (Wiley, NY, 1981). The most suitable protective groups for protecting ketogroup are acetals, for example 1,2-atlantal. Such groups can BBY. Usually the reaction is carried out in the presence of a mineral acid, such as hydrochloric acid or sulfuric acid, in a suitable solvent, for example acetone, in the temperature range from -20 to 25oC.

In accordance with the second General method (C) the compounds of formula I, where X is (H,OH), can be obtained by reacting the corresponding compounds of formula I in which X represents Oh with a suitable reducing agent, for example, the recovery of the sodium borohydride in the presence of a solvent, such as methanol, typically in the temperature range from 0 to 25oC.

According to the third General method (C) the compounds of formula I, where X is NOH, can be obtained by condensation of compounds of formula I in which X represents Oh with a suitable oximoron agent, for example, by reaction of the corresponding 3-catasetinae with hydroxylamine in the presence of a suitable solvent, such as pyridine.

If necessary or desirable, after the above-described process may be performed by any one or more of the following additional stages in any order:

(i) converting the compounds of formula I, pharmaceutically acceptable salt is of formula I to compound of formula I; and

(iii) converting a pharmaceutically acceptable salt or MES the compounds of formula I in other pharmaceutically acceptable salt or MES the compounds of formula I.

In a suitable method of obtaining derivatives of the formula II as starting product is used östra-5(10),9(11)-the diene-3,17-dione-3-(cyclic 1,2-ethandiyl acetal), which can be obtained by methods described in EP 0683172, or by the method described herein below in example A. This compound is first converted into 17-ellenby ester using well-known methods, for example by interaction with diisopropylamide lithium and trimethylsilylpropyne, then immediately interact with tribromides of phenyltrimethylammonium in pyridine. Received 16-bromo derivatives are then converted into the corresponding 3-reserved 16-hydroxysteroid sodium hydroxide in water and pyridine according to the method described in J. Am.Chem.Sc., 102, 5402 (1980). Alkilirovanie on C17 with later (optional) protection 16-hydroxy-group (e.g. as a TBDMS ether - see T. W. Green: Protective Groups in Organic Synthesis, Wiley, NY, 1981) and epoxidation 5(10) double bond (for example, with hydrogen peroxide, trifurcation and pyridine in dichloromethane at EP 0298020) gives 16-hydroxy(or protected)-3-the oxide eventually leads to compounds of formula II.

Alternatively the compounds of formula II can be easily obtained using östra-5(10),9(11)-the diene-3, 17-dione-3-(cyclic 1,2-ethandiyl acetal) as the starting material, as described here previously. This compound can be converted to the corresponding 510-epoxide, for example, using hydrogen peroxide, trifurcation and pyridine in dichloromethane according to the method described in EP 0298020. Catalyzed by copper reaction of the Grignard reagent gives the corresponding 3-protected-11-aryl-5-hydroxy-variety-9,10-EN-17-one. Subsequent transformation into semiprozine 17-enol (processing LDA and trimethylsilylpropyne) with subsequent bromirovanii tribromide of phenyltrimethylammonium in pyridine gives the corresponding 16-bromide. Required 16-hydroxy-group introduced by nucleophilic substitution [sodium hydroxide, pyridine/water in accordance with the method described in J. Am.Chem Sc., 102, 5402 (1980)] . Propanediamine (propyne, n-BuLi) in the end lead to the desired compound II.

The compounds of formula I can be converted into pharmaceutically acceptable 1-oxo-C14-alkyl or carboxy-1-oxo-C14-alkyl by reacting with a suitable etherification agent, such as interaction with accordingly AK is acid, as, for example, cyclic anhydride, using well known methods.

The compounds of formula I can be converted into their pharmaceutically acceptable salts in the usual manner, for example by interacting with the appropriate acid.

The present invention further includes everything described here, the new intermediate compounds and, in particular, the compounds of formula II.

The most preferred intermediate compounds include:

3-(cyclic 1,2-ethandiyl acetal) 5,16,17-trihydroxy-11-[4-tert-butylphenyl]-17-PROPYNYL-variety-9-EN-3-one;

3-(cyclic 1,2-ethandiyl acetal) 5,16,17-trihydroxy-11-[4-tert-butylphenyl]-17-pentenyl-variety-9-EN-3-one;

3-(cyclic 1,2-ethandiyl acetal) 5,16,17-trihydroxy-11-[4-tert-butylphenyl]-17-hexenyl-variety-9-EN-3-one;

3-(cyclic 1,2-ethandiyl acetal) 5,16,17-dihydroxy-11-[4-tert-butylphenyl]-16-methoxy-17-PROPYNYL-variety-9-ene-

3-(cyclic 1,2-ethandiyl acetal)21-chloro-11-(4-tert-butylphenyl)-5,16,17-trihydroxy-19-norpregna-9-EN-20-in-3-one;

or their pharmaceutically acceptable salt or MES.

The following examples are intended for illustration only and are not intended to in any way limit the subject and the l triethylorthoformate, 92 ml of ethylene glycol and 0.9 g of p-toluenesulfonic acid is stirred for 30 minutes at room temperature, then heated to boiling under reflux. The resulting ethanol is distilled off in a mixture with cyclohexane, but maintain a constant volume by adding cyclohexane. After 4.5 hours the residue is distilled cyclohexane and 1 EQ. balance add as a catcher of water in the atmosphere of nitrogen to 1 g östra-4,9-diene-3,17-dione, 0.1 EQ. hydrogen chloride in dioxane and 1.5 EQ. ethylene glycol 15 ml dimethoxyethane at -10oC. After 75 min, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The crystal mass is filtered off, washed with water and dried in vacuum, and then get 1.1 g of 3,3-atelectasia östra-5(10), 9(11)-the diene-3,17-dione. After crystallization from ethanol, 1 g of product having a purity of above 97%.

Example 1. (11,16,17)-11-(4-Tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one

a) 16-Bromo-östra-5(10),9(11)-the diene-3,17-dione-3-(cyclic 1,2-candirectly)

A solution of 192 mmol of LDA (obtained by adding 120 ml of a 1.6 M solution of n-BuLi to a solution of 34 ml of Diisopropylamine in 340 ml of dry THF) is added dropwise to a cold (-30oC) a solution of 50 g (159 mmol) na 15 min at -30oC. and Then added dropwise 60 ml (473 mmol) trimethylsilylpropyne and the solution is allowed to warm to 0oWith for about 1 hour. To this solution of enol ether is added slowly tribromide of phenyltrimethylammonium (60 g, 160 mmol), dissolved in 60 ml of pyridine and, after one hour, the reaction mixture is heated to room temperature. TLC shows complete disappearance of the starting material and the formation of more lipophilic product (toluene/ethyl acetate; 85/15). The process is completed by pouring the reaction mixture into a cold solution of ammonium chloride followed by extraction with dichloromethane. Drying over magnesium sulfate, filtration and evaporation of the solvent give a semi-solid mass. Crystallization from ethanol gives 41.8 g of the target bromide (mainly alpha) in the form of whitish crystals (so pl. 166,8-167,8oC).

b) 16-Hydroxy-östra-5(10), 9(11)-the diene-3,17-dione-3-(cyclic 1,2-candirectly)

40 g (101 mmol) of product obtained in stage a), is dissolved in 840 ml of dry pyridine. With stirring, add 240 ml of water and then 120 ml of 1 n NaOH solution. Keep the temperature below 25oC. After stirring for 30 min at room temperature, TLC shows complete conversion. The mixture is then poured into nasy the firs give crude gidroksosoedinenii in the form of oil. Column chromatography (silica gel, heptane/ethyl acetate, 8/2) gives 18,8 g of pure 16-hydroxy-östra-5(10),9(11)-the diene-3,17-dione-3-(cyclic 1,2-candirectly) in the form of foam. The sample for analysis, recrystallized from diethyl ether gives white crystals;

so pl. EUR 188.4-190,6oC.

c) 16,17-Dihydroxy-17-PROPYNYL-östra-5(10),9(11)-the diene-3,17-dione-3-(cyclic 1,2-candirectly)

In a three-neck flask equipped with a tube for gas inlet and a dropping funnel containing 130 ml of dry THF at -70oTo add 106 ml of a 1.6 n solution of n-BuLi in hexane. The solution becomes yellow. Through the solution bubbled gaseous propyne to the disappearance of the yellow colour. Formed white suspension and stirring is continued for 15 min at -70 oC. and Then to a cold solution of propyne-anion added dropwise a solution of 18 g (54,3 mmol) obtained before this product in 150 ml of dry THF. After addition the solution is allowed to slowly warm to -20oC. After 2 hours stirring at this temperature TLC shows complete Preobrazhenie the original product. Operation complete, pouring the mixture into a saturated solution of ammonium chloride followed by extraction with dichloromethane. Drying over magnesium sulfate and vepari the ethyl acetate 1/1) to give 15.9 g of the pure target compound. Crystallization of a sample for analysis from diethyl ether gives white crystals, so pl. 71oC.

d) 16-TBDMS ether 16,17-dihydroxy-17-PROPYNYL-östra-5(10),9(11)-the diene-3,17-dione-3-(cyclic 1,2-etadirect)

15.9 g (42,9 mmol) of product obtained in stage C), dissolved in 60 ml of dry DMF. To this solution was added 15 g of imidazole and then 15 g (120 mmol) of tert-butyldimethylsilyloxy. After stirring for 3 h at 40oWith the TLC analysis shows the quantitative conversion of the starting compound in one lipophilic product. The mixture was quenched with ammonium chloride solution, then extracted with dichloromethane. Drying over magnesium sulfate, followed by evaporation of the solvent gives 35 g of crude silyl compounds, which are used as such in the next stage.

e)16-TBDMS-ever,10-epoxy-17-PROPYNYL-17-hydroxy-variety-9(11)-EN-3-on-3-(cyclic 1,2-candirectly)

35 g of crude product obtained in stage d) (maximum number pure substance of 20.8 g, 42,9 mmol), dissolved in 300 ml of dichloromethane; successively added 2 ml of pyridine, with 5.3 ml of trifurcation and 70 ml of 30% hydrogen peroxide and the resulting two-phase system is intensively stirred at temperatures which Sydenham solution of sodium thiosulfate. Drying over anhydrous magnesium sulfate, filtration and evaporation to give a semi-solid residue. Purification of column chromatography gives 16,4 g target-epoxide in the form of an amorphous substance.

f) 16-TBDMS-ether 3-(cyclic 1,2-candirectly) 5,16-17-dihydroxy-11-[4-tert-butylphenyl]-17-PROPYNYL-variety-9-EN-3-one

330 mg of CuCl was added when the temperature of 0-5oTo a solution of bromide 4-tert-butylaniline (prepared from 0,83 g (35 mmol) SB and 6.0 ml (34.5 mmol) of 4-bromo-tert-butylbenzene in 50 ml dry THF). After stirring for 30 min at 0-5oWith added dropwise 2.5 g (5 mmol) previously obtained epoxide, dissolved in 30 ml of dry THF, maintaining the temperature below 10oC. Stirring is continued for one hour at ambient temperature. Operation complete, pouring the mixture into a saturated solution of ammonium chloride and extragere with ethyl acetate (2x). The combined organic layers washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography (silica gel, heptane/ethyl acetate 7/3) to give 2.7 g of pure 11-substituted compounds in the form of a white amorphous substance.

g) (11,16,17)-11-(4-Tert-butylphenyl) -16,17-dihydroxy-17-(1-at room temperature, add 3 ml of 6 N. H2SO4and the mixture is stirred for two hours. Then a cold solution was poured into a saturated solution of sodium bicarbonate and the mixture extracted with ethyl acetate (2x). The combined organic layers washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated. Chromatography (dichloromethane/acetone 8/2) to give 1.6 g of the target (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one as a white solid. Crystallization from diethyl ether to give 1.2 g of white crystals, so pl. 251,6-253,8oC.

An alternative technique

a) 5,10-Epoxy-östra 9(11)-diene-3,17-dione-3-(cyclic 1,2-candirectly)

150 g östra-5(10),9(11)-the diene-3,17-dione-3-(cyclic 1,2-candirectly) (478 mmol) dissolved in 2.2 l of dichloromethane, successively added 14.4 ml of pyridine, 48 ml of trifurcation and 666 ml of 30% hydrogen peroxide and the resulting two-phase system is intensively stirred at ambient temperature for 48 hours. The mixture was poured on water, the organic layer is separated and washed twice with saturated solution of sodium thiosulfate. Drying over anhydrous magnesium sulfate, filtration and evaporation to give a semi-solid residue. Crystallization is S="ptx2">

b) 5-Hydroxy-11-(4-tert-butylphenyl)-variety-9-ene-3,17-dione-3-(cyclic 1,2-candirectly)

900 mg of CuCl was added when the temperature of 0-5oTo a solution of 20 g (60 mmol) previously obtained epoxide, dissolved in 30 ml of dry THF. The mixture is stirred for 20 min and added slowly dropwise a solution of bromide 4-tert-butyl-vinylmania (prepared from 5 g (200 mmol) of MD and is 32.8 ml (200 mmol) of 4-bromo-tert-butylbenzene in 150 ml dry THF), keeping the temperature below 10oC. Stirring is continued for one hour at ambient temperature. Operation complete, pouring the mixture into a saturated solution of ammonium chloride and extragere with ethyl acetate (2x). The combined organic layers washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography (silica gel, heptane/ethyl acetate 7/3) to give 28 g of the target 5-hydroxy-11-(4-tert-butyl-phenyl)-variety-9-EN-3-on-3-(cyclic 1,2-candirectly).

C) 16-Bromo-5-hydroxy-11- [4-tert-butylphenyl} östra-9-EN-3-on-3-(cyclic 1,2-candirectly)

A solution of 181 mmol of LDA (obtained by adding 113 ml of a 1.6 M solution of n-BuLi to a solution of 25.6 ml Diisopropylamine in 400 ml of dry THF) is added dropwise to holodets) in 700 ml of dry THF. Stirring is continued for 30 min at -50oC. and Then added dropwise to 38.3 ml trimethylsilylpropyne and the solution stirred at -45oC for 1 hour. After cooling the reaction mixture to -60oWith added dropwise to 27.7 g (to 72.4 mmol) tribromide of phenyltrimethylammonium dissolved in 100 ml of pyridine. After 2 hours of stirring at -60oWith TLC shows complete disappearance of the starting material and the formation of more lipophilic product (heptane/ethyl acetate; 6/4). The operation is completed by pouring the reaction mixture into a solution of ammonium chloride followed by extraction with ethyl acetate. Drying over magnesium sulfate, filtration and evaporation of the solvent give a semi-solid mass. Crystallization from heptane followed by crystallization from ethanol gives 20 g of the target of bromide in the form of white crystals (so pl. 164-165oC).

d) 5,16-dihydroxy-11-[4-tert-butylphenyl] variety-9-ene-3,17-dione-3-(cyclic 1,2-candirectly)

12.5 g (23,0 mmol) of product obtained in stage a) are suspended in 400 ml of 75% pyridine in water. Added 27.5 ml of 1M NaOH. After stirring for 30 min at room temperature, the original substance is dissolved and TLC shows complete conversion. The reaction mixture was pouring is ritala and joint evaporation with toluene to give crude gidroksosoedinenii. Crystallization from diisopropyl ether gives 9.0 g of target compound (so pl. 180-182oC).

e) 5,16,17-trihydroxy-11-[4-tert-butylphenyl] -17-(1-PROPYNYL)-variety-9-EN-3-on-3-(cyclic 1,2-tenderheaded)

In a three-neck flask equipped with a tube for gas inlet and a dropping funnel containing 130 ml of dry THF, at a temperature of -70oTo add 95 ml of a 1.6 n solution of n-BuLi in hexane. The solution becomes yellow. Through the solution bubbled gaseous propyne to the disappearance of the yellow colour. Formed white suspension and stirring is continued for 15 min at -70oC. and Then to a cold solution of propanedione added dropwise a solution of 18 g (38 mmol) obtained before this product in 150 ml of dry THF. After addition the solution is allowed to slowly warm to -20oC. After 2 hours stirring at this temperature TLC shows complete conversion of the original product. Operation complete, pouring the mixture into a saturated solution of ammonium chloride followed by extraction with dichloromethane. Drying over magnesium sulfate and evaporation of solvent gives 19,8 g crude product. Purification using a short column (silica gel, heptane/ethyl acetate 1/1) to give 18.5 g of the pure target compound in g (4.26 deaths mmol) of the compound, obtained in stage e), dissolved in 50 ml of acetone. At room temperature, add 3 ml of 6 N. H2SO4and the mixture is stirred for two hours. Then a cold solution was poured into a saturated solution of sodium bicarbonate and the mixture extracted with ethyl acetate (2x). The combined organic layers washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated. Chromatography (dichloromethane/acetone 8/2) to give 1.6 g of the target (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one as a white solid. Crystallization from diethyl ether to give 1.2 g of white crystals, so pl. 251,6-253,8oC.

When replacing 4-bromo-tert-butylbenzene 4-bromoisophthalate, 4-bromthymol and 4-bromobiphenyl receive the following products:

1A. (11,16,17)-11-(4-isopropylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one; so pl. 153,4-154,9oC.

1B. (11,16,17)-11-(4-were)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one; so pl. 212,2-213,8oC.

1C. (11,16,17)-11-(1,1'-biphenyl-4-yl)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one; so pl. 254,8-256,2oC.

1D. 3E and 3Z-oxime (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one:

Polucheniya in 1f) dissolved in 1 ml of pyridine. Add 70 mg (0.88 mmol) of hydroxylaminopurine and the mixture is stirred at the boiling point under reflux for 40 minutes. The mixture was poured into water, neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered and evaporated to a dry residue. The crude oxime is subjected to separation HPLC (acetonitrile/water 40/60-->60/40) to give 39 mg 3y-oxime (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one ([]20D=+30o(C=0,2, dioxane)) and

75 mg 3E-oxime (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL) östra-4,9-Dien-3-one([]20D=+60o(C=0.6, dioxane)).

Example 2. (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-19,21,27-trinorprosta-4,9-Dien-20(22)-INF-3-one

a) 3-(cyclic 1,2-candirectly) 5,16,17-trihydroxy-11-[4-tert-butylphenyl]-17-hexenyl-variety-9-EN-3-one

1-Hexyne (2,88 g, 4 ml, 35 mmol) is dissolved in 75 ml of dry THF; after cooling the solution to -20oWith added dropwise 20 ml of a 1.6 M solution of n-BuLi and the mixture is stirred at -20oC for 15 minutes Then added dropwise a solution of 2.4 g of 3-(cyclic 1,2-candirectly) 5,16,17-LASS="ptx2">

The operation is completed by pouring the mixture into a saturated solution of ammonium chloride followed by extraction with ethyl acetate (2x), washing the combined organic layers with saturated saline, dried over magnesium sulfate and evaporation of the solvents. This gives the crude product as oil. Rubbing with diisopropyl ether gives 800 mg of pure 3-(cyclic 1,2-candirectly) 5,16,17-trihydroxy-11-[4-tert-butylphenyl]-17-hexenyl-variety-9-EN-3-one as white crystals; so pl. 182-183oC.

b) (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-19,21,27-three-noroeste-4,9-Dien-20(22)-INF-3-one

3-(Cyclic 1,2-candirectly)5,16,17-trihydroxy-11-[4-tert-butylphenyl]-17-hexenyl-variety-9-EN-3-one, obtained in the preceding stage, dissolved in 50 ml of acetone; add 1 ml of 6 n H2SO4and continue stirring for 30 minutes TLC (heptane/ethyl acetate 1/1) shows the educt in two lipophilic product. Operation completes by adding a saturated solution of Panso3followed by extraction with ethyl acetate (2x), washing the combined organic layers with saturated saline solution and dried over magnesium sulfate. Evaporation of the solvent gives the crude compound in view-dihydroxy-19,21,27-three-noroeste-4,9-Dien-20(22)-INF-3-one as an amorphous white substance; []20D=34,2 (C=0,5, dioxane).

The following products were obtained according to examples 2A and 2b for, respectively, 1-pentene, 3-methoxy-propene and acetylene.

2A. (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-pentenyl) östra-4,9-Dien-3-one; []20D=37,8 (C=1, dioxane).

2B. (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(3-methoxy-1-PROPYNYL) östra-4,9-Dien-3-one; so pl. 171,0-171,6oC.

2C. (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-19-norpregna-4,9-Dien-20-in-3-one; []20D=46,9 (C=1, dioxane).

2D. (11,16,17)-16,17-dihydroxy-11-(4-[(trifluoromethyl-sulfonyl)oxyl] phenyl)-17-(1-PROPYNYL)östra-4,9-Dien-3-one; []20D=8,9 (C=1 dioxane).

Example 3. (11,16,17)-11-(4-Tert-butylphenyl)-17-hydroxy-16-methoxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one

a) 3-(Cyclic 1,2-candirectly) 5-hydroxy,11-[4-tert-butylphenyl]-16-methoxy-variety-9-ene-3,17-dione

2.0 g (4,16 mmol) 3-(Cyclic 1,2-candirectly) 5,16,17-trihydroxy-11-[4-tert-butylphenyl]-variety-9-ene-3,17-dione is dissolved in 150 ml of dry dichloromethane. To this solution was added 4.5 g of 2,6-di-tert-butyl-4-methylpyridine (of 15.75 mmol) and 1.3 g trimethylhexane-tetrafluoroborate (8.3 mmol) and the solution stirred at room temperature. After three cha is Reut by adding a saturated solution of sodium bicarbonate, followed by extraction with dichloromethane. Evaporation of solvent gives 2.6 g of crude product, sufficiently pure to be used in the next stage.

b) 5,17-dihydroxy-11-[4-tert-butylphenyl] -16-methoxy-17-PROPYNYL-variety-9-EN-3-on-3-(cyclic 1,2-candirectly)

The substance obtained in the preceding stage, dissolved in 10 ml of dry THF and added dropwise to a solution of propylaia (obtained by adding gaseous propene to a solution of 20 ml of 1.3 M n-BuLi to the disappearance of the yellow colour and the transition to the white suspension) at -60oC. the Solution is allowed to warm to -20oWith and continue stirring for 1 h the Operation is complete, pouring the mixture into a saturated solution of ammonium chloride followed by extraction with dichloromethane. Drying with magnesium sulfate and evaporation of the solvent gives the crude product, which was purified column chromatography (heptane/ethyl acetate 1/1).

Output: 1,15 g target 5,17-dihydroxy-11-[4-tert-butylphenyl] -16-methoxy-17-PROPYNYL-variety-9-EN-3-on-3-(cyclic 1,2-candirectly) as a white amorphous substance.

with) (11,16,17)-11-(4-tert-butylphenyl)-17-hydroxy-16-methoxy-17-(1-PROPYNYL)-östra-4,9-Dien-3-one

The substance obtained in the preceding reaction (1,15 g), dissolved in 20 ml azelastina sodium bicarbonate and extraction with ethyl acetate after washing with saturated saline solution and drying over magnesium sulfate to give the crude product. Column chromatography (heptane/ethyl acetate 1/1) to give 700 mg of pure target compound as an amorphous substance;

[]20D=50,1 (c=0.5, dioxane).

Example 4. (11,16,17)-21-chloro-11-(4-tert-butylphenyl)-16,17-dihydroxy-19-norpregna-4,9-Dien-20-in-3-one

a) 3-(cyclic 1,2-candirectly) 21-chloro-11-(4-tert-butylphenyl)-5,16,17-trihydroxy-19-nocleg-9-EN-20-in-3-it

Motility (11 ml of a 2.2 M solution in diethyl ether) is added dropwise at 0oTo a solution of 1.2 g of TRANS-1,2-dichlorethene (12 mmol) in 5 ml of dry diethyl ether. Stirring is continued at room temperature for 1.5 hour. Then add dropwise a solution of 1.4 g (3 mmol) of 3-(tsiklicheskogo,2-candirectly)5,16,17-trihydroxy-11-[4-tert-butylphenyl] -variety-9-ene-3,17 dione in 20 ml of dry toluene and continue stirring for 1 h at ambient temperature. Operation completes by adding a saturated solution of ammonium chloride followed by extraction with ethyl acetate. Wash the organic layer with saturated saline, dried over magnesium sulfate and evaporation of the solvent gives 2 g of crude product. Column chromatography (heptane/ethyl acetate 1/1) to give 1.2 g of the target 3-(cyclic 1,2-candirectly) 21-chloro-11-(4-tert-butylthiophene at the next stage.

b) (11,16,17)-21-chloro-11-(4-tert-butylphenyl)-16,17-dihydroxy-19-norpregna-4,9-Dien-20-in-3-one

Obtained in the previous phase of the substance according to the method described in example 3C, yields after column chromatography 460 mg of the target (11,16,17)-21-chloro-11-(4-tert-butylphenyl)-16,17-dihydroxy-19-norpregna-4,9-Dien-20-in-3-one, which can be recrystallized from diethyl ether; so pl. 202,2-202,7oC (decomposes).

Example 5. Affinity binding receptors glucocorticoid (GR) and progesterone receptor (PR)

The table presents data on the affinity with the receptor of the compounds according to the invention for receptors glucocorticoid (GR) compared to the progesterone receptor (PR).

Glucocorticoid binding affinity of the compounds was measured for receptors glucocorticoid present in intact cells of multiple myeloma person, and compared with the affinity of dexamethasone (according to the method described by H. J. Kloosterboer et al. , J. Steroid Biochem., Vol.31, 567-571 (1988)). Progesterone affinity of the compounds was determined for the cytoplasmic progesterone receptor present in breast cancer cells human, and compared with the affinity (16)-16-ethyl-21-hydroxy-19-norpregna-4-ene-3,20-dione (according to the method described by E. W. Bergink et al., J. Steroid Bioc the C-17-(1-PROPYNYL)östra-4,9-Dien-3-one (compound "11 n-acetyl"), described in U.S. patent 5089635 and RU (38)486. Compounds of the present invention showed high values Grcic, while unwanted Prcic activity was low.

EXAMPLES of 6.7 pharmaceutical composition in the form of capsules

Ingredient mg

Active connection (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one - 1

Hydroxypropylcellulose (binder) - 9,45

Corn starch (powder) - 157,50

Magnesium stearate (lubricant) - 1,58

Lactose (diluent) To the total mass in 315,0

Ingredient mg

Active connection (11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL)östra-4,9-Dien-3-one - 50

Hydroxypropylcellulose - 9,45

Corn starch - 157,50

Magnesium stearate is 1.58

Lactose - Up to total mass in about 315,0

1. Derivatives of 16-hydroxy-11-(substituted phenyl)-östra-4,9-diene of the General formula I

< / BR>
where R1represents a C1-6-alkyl, triflate or phenyl, where the phenyl group is optionally substituted by one or more substituents selected from cyano, halogeno and C1-4-alkyl;

R2represents hydrogen or carboxy-1-oxo-C1-6-alkyl;

R3represents hydrogen, g is represents hydrogen or C1-6-alkyl;

X represents O or NOH,

or its pharmaceutically acceptable salt or MES.

2. Connection on p. 1, where R1represents phenyl, triflate or1-6-alkyl; R2represents hydrogen; R3represents hydrogen, halogen, C1-6-alkyl, optionally substituted C1-6-alkoxy; R4represents hydrogen or methyl; X represents O; or its pharmaceutically acceptable salt or MES.

3. Connection under item 1 or 2, where R1represents phenyl or1-6-alkyl; R2represents hydrogen; R3represents a C1-6-alkyl; X represents O or its pharmaceutically acceptable salt or MES.

4. The compound according to any one of paragraphs.1-3, where R1represents phenyl, tert-butyl, isopropyl or methyl;2represents hydrogen; R3represents methyl; R4represents hydrogen or methyl; X represents O or its pharmaceutically acceptable salt or MES.

5. The compound according to any one of paragraphs.1-4, chosen from:

(11,16,17)-11-(4-tert-butylphenyl)-16,17-dihydroxy-17-(1-PROPYNYL) östra-4,9-Dien-3-one;

(11,16,17)-11-(4-isopropylthio-4,9-Dien-3-one;

(11,16,17)-11-(1,1'-biphenyl-4-yl)-16,17-dihydroxy-17-(1-PROPYNYL) östra-4,9-Dien-3-one;

(11,16,17)-16,17-dihydroxy-11-[4-(trifloromethyl)oxy] phenyl] -17-(1-PROPYNYL) östra-4,9-Dien-3-one;

or its pharmaceutically acceptable salt or MES.

6. The compound according to any one of paragraphs.1-5 or its pharmaceutically acceptable salt or MES, possessing activity by binding to glucocorticoid receptors.

7. The compound according to any one of paragraphs.1-5 or its pharmaceutically acceptable salt or MES as the active ingredient of the medicinal product with antiglucocorticoid activity.

8. Pharmaceutical composition having antiglucocorticoid activity containing a compound according to any one of paragraphs.1-5 or its pharmaceutically acceptable salt or MES in a mixture with a pharmaceutically acceptable carrier.

9. The compound of formula II

< / BR>
where R1, R2and R3are as defined in paragraph 1;

R5represents a group R4as defined in paragraph 1, or suitably protected group, R4;

R is a protected ketogroup.

 

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the dashed line in position 1, 2 means possible double bond

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