Derivatives 11,21-bisphenyl-19-norpregnane, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to a derivative 11,21-bisphenyl-19-norpregnane formula I, in which R1selected from H, halogen, NR5R6and R5and R6independently are hydrogen or C1-6-alkyl; R2represents hydrogen; R1and R2together are C1-3-alkylenedioxy, optionally substituted by one or more halogen atoms; R3represents methyl; R4choosing among C(O)-NR5R6, SOnC1-6-alkyl, optionally substituted by one or more halogen atoms, SOnC3-6-cycloalkyl, SO2-NR5R6, 2-oxopyrrolidin or NR5R6where R5and R6independently are hydrogen, C1-6-alkyl, or R5and R6together form a C3-6-alkylen, n = 1 or 2, R7represents N or C1-7-alkyl; R8represents H; X is chosen among the (H, HE, O and MO; or their pharmaceutically acceptable salts. Compounds of the invention possess antiglucocorticoid activity and can be used for treatment or prevention is dependent on glucocorticoids diseases. Also described is OSISA derivatives 11, 21 - bisphenyl-19-norpregnane, method of production thereof, pharmaceutical compositions containing such compounds and to the use of such derivatives for the production of medicinal drugs.

There are various derivatives 11,21 - bisphenyl-19-norpregnane. For example, in U.S. patent 4447424 disclosed derivative of 11- [4-(N,N-dimethylamino)-phenyl] -21-phenyl-19 - norpregnane. Class of steroids that is described in this patent may contain a number of substituents in positions 11 - and 17, respectively. Compounds have antiglucocorticoid action.

At the same time they have protivoprotosanoe activity, which is also a property of the derivatives of 11-(alkanolamine)phenyl-21-phenyl-19-norpregnane disclosed in European patent 245170. This is a serious limitation, as protivogistaminnye properties (like antiinflationary and abortifacient action) limit therapeutic options in the treatment of diseases dependent on glucocorticoids such as Cushing's syndrome, diabetes, glaucoma, depressive syndrome, arteriosclerosis, obesity, hypertension, sleep disorders and osteoporosis.

So now in this area of research, which Dol is then the search for such compounds are only partially successful. Although the compounds obtained with indicators of more selective antiglucocorticoid activity in vitro, these compounds lack antiglucocorticoid activity in vivo (see D. Philibert et al. in Agarwal MK (ed): Antihormones in Health and Disease. Front Horm. Res. Basel, Karger, 1991, vol. 19, pp. 1-17).

The present invention is the creation of new derivatives 11, 21-bisphenyl-19-norpregnane, having voting antiglucocorticoid activity, and pharmaceutical preparations based on them.

This object is achieved in these derivatives 11, 21-bisphenyl-19-norpregnane formula I

< / BR>
in which R1choose among H, halogen, (1-6C) alkoxygroup and NR5R6and R5and R6independently represent hydrogen or (1-6C)alkyl, or R5and R6together represent a (3-6C)alkylene;

R2is hydrogen; or R1and R2together is (1-3C)alkylenedioxy, optionally substituted by one or more halogen atoms;

R3represents methyl or ethyl;

R4choosing among C(0)-NR5R6, SOn-(1-6C)alkyl, optionally substituted by one or more halogen atoms, SOnis(3-6C)cycloalkyl, and or (1 - 6C)alkyl;

R8represents H or carboxy-1-oxo(1-6C)alkyl; and

X is chosen among the (H, HE), and NOH; or their pharmaceutically acceptable salts discover how selectivity in vitro and antiglucocorticoid activity in vivo, or metabolized in the body in connection with such properties.

These derivatives 11,21-bisphenyl-19-norpregnane form a new class of compounds that have a selective affinity for glucocorticoid receptors and antiglucocorticoid activity in vivo.

Preferred compounds corresponding to the invention are derived 11,21-bisphenyl-19-norpregnane, in which R3represents methyl, and R4choose among SO2-(1-6C)alkyl, optionally substituted by one or more fluorine atoms, SO2is(3-6C)cycloalkyl and NR5R6. Mention should be made of derivatives, in which R4represents N(CH3)2or SO2CH3. Particularly suitable are derivatives in which R4represents the SO2CH3.

Other preferred compounds are derivatives 11,21-bisphenyl-19-norpregnane, in which R1represents NR5R6and R2saw are derived, in which R1represents N(CH3)2and R2represents hydrogen; or R1and R2together form methylenedioxy or Ethylenedioxy.

The most preferred derivative 11,21-bisphenyl-19-norpregnane is(11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-21-[4- (methylsulphonyl)phenyl]-19-norpregna-4,9-Dien-20-in-3-one.

The term "halogen" means fluorine atom, chlorine, bromine or iodine. The preferred halogen is fluorine.

The term "(1-6C)alkyl" used in the definition of R5TO5and R7means an alkyl group containing 1-6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.

The term "(1-6C)alkoxygroup" used in the definition of R1means alkoxygroup containing 1-6 carbon atoms, and the alkyl part has previously set values.

The term "(1-3C)alkylene" in the definitions of R1and R2means alkylenes group containing 1-3 carbon atoms, such as methylene and ethylene.

The term "(3-6C)alkylene" in the determination of R5and R6means alkylenes group having 3-6 carbon atoms, for example, Buti is">

Derivatives 11,21-bisphenyl-19-norpregnane corresponding to the present invention, a receiving method, wherein the compound of formula II

< / BR>
in which P represents a protected ketogroup, dehydration and otscheplaut protective group, and arbitrarily converted into the corresponding 3-hydroxy - or 3-oxime derived, after which the compound obtained randomly transformed into a pharmaceutically acceptable salt.

Derivatives of formula II can be obtained in accordance with well known methods described and used to obtain steroids.

Derivatives of the formula II are obtained on the basis of östra-4,9-diene-3,17-dione or its 18-methyl derivative. Selective reduction of 17-ketogroup to 17-OH,17-H, for example, sodium borohydride, followed by removal of protective groups from 3-ketogroup, for example, by acetalization glycol, triethyl-orthoformate and p-toluensulfonate acid, and re-oxidation of 17-hydroxy-group, for example, pyridinylamino, gives extra-5(10), 9(11)-the diene-3,17-dione with a protected group in position 3, or 18-methyl analogue.

Etiolirovannye in position 17 (giving 17-ethinyl,17-OH derivative), followed epoxitiolan is accordance with the method, disclosed in the application for the European patent EP 0298020 gives 5,10-epoxy-17-ethinyl-17 - hydroxy-variety-9(11)-EN he protected group in position 3, or 18-methyl analogue.

Then the epoxide may be substituted in position 11 group R1R2C6H3in which R1and R2have previously established values, for example, by the Grignard reaction, catalyzed Cu. In the resulting connection in position 21 can be entered group R4R7C6H4in which R4and R7have previously established values, for example, by means of the Heck reaction (Heck) with Pd/Cu catalyst (see R. F. Heck, Palladium Reagent in Organic Synthesis, Academic Precc, 1985) in the corresponding secondary or tertiary Amina, which leads to compounds of formula II.

Suitable protective groups and methods for their removal known in the art, for example, from the work of T. W. Green, "Protective Groups in Organic Synthesis", /Wiley, NY, 1981).

Particularly suitable protective groups for protecting ketogroup are acetals, for example, 1,2-atlantal.

The new compounds of formula I is recovered from the reaction mixture in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts can also be obtained by treating the free is B>3PO4, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonate acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.

Compounds according to the invention can be administered to the patient through the intestinal or parenteral, preferably in a daily dose of 0.001-100 mg / kg body weight, preferably 0.01 to 10 mg per kg of body weight. Mixed with pharmaceutically suitable auxiliary means, such as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences, (18th ed. Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), compounds pressed into a solid unit dose, such as pills, tablets, or may be made in the form of capsules or suppositories.

With a pharmaceutically acceptable liquid compounds may also be used in the form of solutions, suspensions, emulsions, for example, for use in the form of injections or eye drops, or in the form of a sprayable solution, for example, for use as a nasal spray.

In the manufacture of single doses of drugs will be applied and any pharmaceutically acceptable additive, it does not interfere with the function of active connections.

Suitable carrier materials that can be entered compositions include lactose, starch, cellulose derivatives and similar substances, or mixtures thereof, which are used in suitable amounts.

In tables I and II provides the receptor affinity of compounds of the invention for the glucocorticoid receptor (GR), referred to progesterone receptors (PR), compared with a ratio of GR/PK for(11,17)- 11-[4-(dimethylamino)phenyl] -17-hydroxy-21-phenyl-19 - norpregna-4,9-Dien-20-in-3-one, which is disclosed in U.S. patent 4447424.

The affinity of glucocorticoid compounds measured for glucocorticoid receptors present in intact cells of multiple myeloma person, and compared with the affinity of dexamethasone (in accordance with the method described by H. J. Kloosterboer et al, J. Steriod Biochem., Vol. 31, 567-571 (1988)).

Progesterone the affinity of the compounds of measure for cytoplasmic progesterone receptors present in the tumor cells of the breast of man, and is compared with the affinity of ( 16)- 16-ethyl-21-hydroxy-19-nocleg-4-ene - 3,20-dione (in accordance with the method described by E. W. Bergink et. al., J. Steroid Biochem., Vol. 19, 1563-1570 (1983)).

From the data, to see a greater selectivity for the glucocorticoid receptor when compared with known derivative 11,21-bisphenyl-19 - norpregnane-(11,17)- 11-[4-(dimethylamino)phenyl] -17-hydroxy-21-phenyl-19 - norpregna-4,9-Dien-20-in-3-one.

The invention also further illustrated by the following examples.

Raw materials: examples 1-IV

EXAMPLE 1

4-[(Trifluoromethyl)sulfonyl]oxo-2-methyl-(methylsulphonyl)benzene

a) a Solution of 90 g oxone in 1800 ml of water is added with vigorous stirring to a solution of 15,43 g of 4-(methylthio)-m - cresol. The temperature is maintained at a level below the 15oC and continue stirring for 3 hours. At the final stage perform the extraction with dichloromethane and then the organic layer was washed with sodium thiosulfate and saturated salt solution.

Evaporation gives an 18.4 g of 4-hydroxy-2-methyl - (methylsulphonyl)- benzene; so pl. 105oC.

b) Dissolving 7 g of 4-hydroxy-2-methyl-(methylsulphonyl)benzene in 210 ml of dichloromethane and 14 ml of pyridine. After cooling the mixture to 0 to 5oC for 30 minutes, add a solution of triflic anhydride in 70 ml of dichloromethane. Stirring is continued for 1 hour at room temperature. Work complete, pouring the mixture into ice water, and extragere her dichloromethane. Evaporation and purification of column chromatography (heptane: ethyl acetate = 5:4) give to 9.9 g of 4-[(trifluoromethyl)sulfonyl] -hydroxy-2-methyl- (methylsulphonyl) benzene; so pl. 51oC.

EXAMPLE II

A. 4-bromothiophene in 50 ml of water. Stirring is continued for 30 minutes at room temperature and then for 2 minutes, add 4.5 ml (56 mmol) of ethyliodide. After 16 hours the mixture was poured into water, and extracted with diethyl ether, then the organic layer was washed with saline solution. Drying over MgSO4and evaporation give 11 g of 4-bromophenylacetate ether.

In accordance with the procedure described in example Ia), make 10 g of the previously obtained compound 12.4 g of 4 - bromo-(ethylsulfonyl)benzene; so pl. 53oC.

In a similar fashion from 4-bromothiophene through interaction with relevant alkylhalogenide get the following reagents:

4-bromo-(isopropylphenyl)benzoyl; so pl. 63oC;

4-bromo-(cyclopentylacetyl)benzene; so pl. 76oC;

(1H NMR, 200 MHz, CDCl3: 3,47 ppm, m, 1H).

EXAMPLE III

N-(4-Bromophenyl)-2-pyrrolidinone

Dissolve 8.06 g N phenylpyrrolidine in 33 ml of glacial acetic acid; the mixture is cooled to 0-5oC, and then added dropwise a solution of 2.65 ml of bromine in 12 ml of glacial acetic acid. Stirring is continued for 30 minutes at room temperature. Work complete, pouring the mixture into 1 l of water, and neutralizing the mixture CON. Solid is the disappearance of the brown color; then washed with brine, dried over MgSO4and obtain 8.5 g of a white crystalline mass, which can be recrystallized from ether; so pl. 102oC.

EXAMPLE IV

4-Bromo-N,N-dimethylsulfone

In accordance with the General method described in J. Am. Chem. Soc. 45, 2697 (1923), from 4-brompheniramine-chloride receive the following reagents:

And 4-bromophenylacetate; so pl. 167oC;

4-bromophenyl-N-methylsulfonate; so pl. 77oC;

4-bromophenyl-N,N-dimethylsulfone; so pl. 93oC;

D N-(4-brompheniramine)pyrrolidin; so pl. 95oC.

Similarly, on the basis of 4-bromperidol-chloride receive the following connections:

E 4-bromobenzene; so pl. 190oC;

F 4-bromo-N-methylbenzamide; so pl. 169oC;

G 4-bromo-N,N-dimethylbenzamide; so pl. 72oC;

H 4-paperrollingmachine; so pl. 80oC.

Example 1

(11,17)- 11,21-Bis[4-(dimethylamino)phenyl]-17-hydroxy-19 - norpregna-4,9-Dien-20-in-3-one

a) Dissolve 27 g (100 mmol) extra-4,9-diene-3,17-dione in 270 ml of tetrahydrofuran (THF) and 270 ml of methanol, cooled to - 10oC and process of 2.27 g (60 mmol) of sodium borohydride. The solution is stirred for 30 minutes at -10oC. At the final stage devam solution dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, the result of 27.2 g of 17 - hydroxy-variety-4,9-Dien-3-one.

b) a Solution of 25 g of the previously obtained substances in 375 ml of dichloromethane; add 125 ml of ethylene glycol, 75 ml of triethylorthoformate and 250 mg of p-toluensulfonate acid, and the mixture is refluxed for 20 minutes. After cooling, add 200 ml of saturated sodium hydrogen carbonate solution, and the resulting mixture extracted with dichloromethane. Evaporation under vacuum, followed by purification of the resulting oil column chromatography on silica gel to give 19.9 g of [3-(cyclic 1,2-atangential]- -17 - hydroxy-östra-5(10), 9(11)-Dien-3-one in the form of butter.

C) Dissolve to 19.9 g (62,9 mmol) [3-(cyclic 1,2-ethane-vilareal)] --17 - hydroxy-östra-5(10), 9(11)-Dien-3-one in 400 ml of dichloromethane. Type of 27.6 g (336 mmol) of sodium acetate followed by add and 36.2 g (168 mmol) pyridinylamino, and the mixture was stirred at ambient temperature. After 2 hours add to 43.5 ml of 2-propanol and stirring is continued for 1 hour. The mixture is filtered through celite, evaporated and distributed between ethyl acetate (1350 ml) and water (675 ml). The organic layer is blowing purification column chromatography using silica gel to give up 10.9 g of [3-(cyclic 1,2 - candirectly)]-östra 5(10), 9(11)-diene-3,17-dione. So pl. 152oC.

d) a Mixture of 13 g (to 116.2 mmol) of tert-butoxide potassium, 55 ml of THF and 18.7 ml of tert-butanol is cooled to 0-5oC in an inert atmosphere. Through the mixture for one hour bubbled acetylene; then add 9,43 g (30 mmol) [3-(cyclic 1,2-candirectly)]-östra-5(10), 9(11)-the diene-3,17-dione, dissolved in 50 ml of THF. Stirring is continued for 1.5 hours at 0-5oC in an atmosphere of acetylene. At the final stage the mixture is then poured into a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated, and obtain 10.4 g of [3- (cyclic 1,2-candirectly)] -17-etanol-17 - hydroxy - östra- 5(10), 9(11)-Dien-3-one.

e) Dissolve 10 g (29.4 mmol) [3-(cyclic 1,2 - candirectly)] -17A-ethinyl-17 - hydroxy-östra-5(10), 9(11)-Dien - 3-one in 150 ml of dichloromethane. After this type of 0.91 ml of pyridine, 2,84 ml trifurcation and 18.8 ml of 30% hydrogen peroxide, and the resulting two-phase system is vigorously stirred at room temperature for 36 hours.

The mixture was poured into water, and the organic layer washed twice with a saturated solution of thiosulfate NAT is epoxides. Poroshkovaya with toluene gives 4,22 g of [3-(cyclic 1,2-candirectly)] -5,10-epoxy-17-ethinyl-17 - hydroxy-variety-9(11)-EN - 3-one.

f) Added 158 mg CuCl at 0-5oC to a solution of p - dimethyl-aminophenylacetamido in THF obtained of 1.49 g of magnesium (61 mmol), 30 ml of THF and 11.8 g (of 58.9 mmol) 4 - bromo - N,N-dimethylaniline. After stirring for 30 minutes at 0-5oC is added dropwise to 4.2 g of [3-(cyclic 1,2 - candirectly)] -5,10 - epoxy - 17-ethinyl-17 - hydroxy-variety-9(11)-EN-3-one in 42 ml of THF.

After stirring for 2.5 hours at ambient temperature the solution was poured in a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer is washed until neutral, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum, and the residue chromatographic using silica gel.

After crystallization from ether-heptane obtain 3.2 g of pure [3-(cyclic 1,2 - candirectly)] -5,17-dihydroxy-11- [4-(N,N - dimethylamino)phenyl]-17 - ethinyl-variety-9-EN-3-one.

Melting point 198oC.

g) Dissolved 3.0 g (6.3 mmol) [3-(cyclic 1,2-ethandiyl)] -5,17-dihydroxy-11- [4-(N, N-dimethylamino)-phenyl] 17 - ethinyl-variety-9-EN-3 - one in 39 ml Piri 99 mg of triphenylphosphine, and the mixture is refluxed for one hour in an inert atmosphere.

After cooling, the mixture was poured into 50% aqueous solution of ammonium chloride, and extracted with ethyl acetate.

The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, obtaining a crystalline mass. Poroshkovaya with diethyl ether gives of 2.45 g of pure [3-(cyclic 1,2-candirectly)] -11,21-bis (dimethylamino)phenyl] -5,17 - dihydroxy-pregn-9 - EN-20-in-3-one. Melting point 150oC.

h) Dissolving of 2.45 g (4.0 mmol) [3-(cyclic 1,2-candirectly)] -11,21 - bis[(dimethylamino)phenyl] -5,17 - dihydroxy-pregn-9-EN-20-in-3-one in 123 ml of acetone, and added under stirring to 4.9 ml of 6N N2SO4. After stirring for 30 minutes at ambient temperature the mixture is neutralized with sodium bicarbonate, and then extracted with ethyl acetate.

The organic layer is washed until neutral, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue is purified column chromatography on silica gel. Obtain 1.2 g of pure (11,17)- 11,21-bis[4-(dimethylamino)phenyl] -17-hydroxy-19-norpregna-4,9-Dien-20-in-3-one.

The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude oxime is subjected to chromatographic separation using silica gel, and the result is 550 mg of (3E, 11,17 11,21-bis[4-(dimethylamino)-phenyl] -17-hydroxy-19 - norpregna-4,9-Dien-20-in-3-noxema having a specific rotation []2D0= -19o(C = 0,5, dioxane), and 230 mg (3Z, 11,17-11,21-bis[4-(dimethylamino)phenyl] -17-hydroxy-19-norpregna - 4,9-Dien-20-in-3-noxema having a specific rotation []2D0= -9o(C = 0,5, dioxane).

Example 3

3 - a and 3-(11,17) -11,21-di[4-(dimethylamino) phenyl] -19 - norpregna-4,9-Dien-20-in-3,17-diols

A solution of 1.26 g (5 mmol) three(tert-butoxy)of lithium aluminum hydride in 7 ml of dry THF is added to a cooled with ice to a solution of 1.07 g (2 mmol) of the product obtained in example 1h. Stirring is continued for two hours. The mixture was poured in water, slightly acidified with 50% acetic acid is raidou. The separation column chromatography using silica gel yields 180 mg of pure (3,11,17) -11,21-bis[4-(dimethylamino)phenyl]-19-norpregna-4,9-Dien-20-in - 3,17-diol with a specific rotation of []2D0= 32o(C = 0,5, dioxane), and 110 mg of pure (3,11,17) -11,21-bis[4- (dimethylamino)phenyl]-19-norpregna-4,9-Dien-20-in-3,17-diol with a specific rotation of []2D0= -111o(C = 0,5, dioxane).

Example 4

The following products are obtained from [3- (cyclic 1,2-candirectly)] -5,17-dihydroxy-11- [4-(N,N - dimethylamino)phenyl]-17 - ethinyl-variety-9 - EN-3-one (see example 1f) from the reaction of a combination of Hake (in accordance with the procedure of example 1g), using the reaction of an appropriate starting material, followed by acid dehydration and the removal of the protective group as described in example 1h.

A. Use in the reaction of 4-bromo-(1-pyrrolidinyl)benzene results in(11,17) -11-[4-(dimethylamino)phenyl]-17-hydroxy-21-[4- (1-pyrrolidinyl)phenyl]-19-norpregna-4,9-Dien-20-in-3-one,

having a specific rotation []2D0= -19o(C = 1, chloroform).

C. Use in the reaction of 4-bromo-(methylsulphonyl)benzene results in(11,17) -11-[4-(dimethylamino)phenyl]-17-hydroxy-21-[4- (metals> (C = 0,5, dioxane).

D. Use in the reaction of 4-bromophenylacetonitrile results in 4- [ (11,17) -1-[4-(dimethylamino)phenyl] -17-hydroxy-3-oxo - 19-norpregna-4,9-Dien-20-in-21-yl]benzosulfimide;

[]2D0= -26o(C = 0,5, dioxane).

E. Use in the reaction of 4-bromo-N-methylphenylsulfonyl results in 4-[ (11,17) -11-[4-(dimethylamino)phenyl]-17 - hydroxy-3-oxo-19-norpregna-4,9-Dien-20-in-21-yl]- N-methylbenzenesulfonamide;

[]2D0= -30o(C = 0,5, dioxane).

F. Use in the reaction of 4-bromo-N,N-dimethylbenzenesulfonamide results in 4-[ (11,17) -11-[4-(dimethylamino)-phenyl]-17 - hydroxy-3-oxo-19-norpregna-4,9-Dien-20-in-21-yl]-N,N - dimethylbenzenesulfonamide;

[]2D0= -34o(C = 0,5, dioxane).

G. Use in the reaction of 4-bromidrosiphobia results in[ (11,17) -11-[4- (dimethylamino)phenyl]-17 - hydroxy-21-[4-(1-pyrrolidinylcarbonyl)phenyl]-19-norpregna - 4,9-Dien-20-in-3-one;

[]2D0= -37oC (C = 0,5, dioxane).

N. Use in the reaction of 4-bromobenzene results in 4-[ (11,17) -11-[4-(dimethylamino)-phenyl] -17-hydroxy-3-oxo-19 - norpregna-4,9-Dien-20-in-21-yl] benzamide;

[]2D0= -28o the e(11,17) -11-[4-(dimethylamino)- phenyl]-17-hydroxy-21-[4-(1-pyrrolidinylcarbonyl) phenyl]-19-norpregna-4,9-Dien-20-in-3-one;

[]2D0= -30o(C = 0,5, dioxane).

J. Use in the reaction of 4-bromo-N,N-dimethylbenzamide results in 4-[ (11,17) -11-[4-(dimethylamino)-phenyl]-17 - hydroxy-3-oxo-19-norpregna-4,9-Dien-20-in-21-yl]-N,N - dimethylbenzamide;

[]2D0= -26o(C = 0,5, dioxane).

K. Use in the reaction of 4-bromo-N,N-methylbenzamide results in 4-[ (11,17) -11-[4-(dimethylamino)-phenyl]-17 - hydroxy-3-oxo-19-norpregna-4,9-Dien-20-in-21-yl]-N-methylbenzamide;

[]2D0= -30o(C = 0,5, dioxane).

L. Use in the reaction of N-[(4-bromo)phenyl]-2-pyrrolidinone results in 1-[4-[ (11,17) -11-[4-(dimethylamino)-phenyl]-17-hydroxy-3-oxo - 19-norpregna-4,9-Dien-20-in-21-yl]phenyl]-2-pyrrolidinone;

[]2D0= -32o(C = 0,5, dioxane).

M Use in the reaction of 4-[(trifluoromethyl)sulfonyl] hydroxy-2 - methyl - (methylsulphonyl)benzene results in(11,17) -11-[4-(dimethylamino) phenyl] -17-hydroxy - 21-[3-methyl-4-(methylsulphonyl)phenyl]-19-norpregna-4,9 - Dien-20-in-3-one having a specific rotation []2D0= -30o(C = 0,5, dioxane).

N. Use in the reaction of 4-bromo-(ethylsulfonyl)benzene (example II) results in(11,17) -11-[4- (dimethylamino)-phenyl]-21-[4-(SUP>o
(C = 0,5,dioxane).

O. Use in the reaction of 4-bromo(isopropylphenyl)benzene (example II) results in(11,17) -11-[4-(dimethylamino)phenyl]-17 - hydroxy-21-[4-(isopropyl-sulfonyl)phenyl] - 19-norpregna-4,9-Dien-20-in-3-one having a specific rotation []2D0= -30,8o(C = 0,5, dioxane).

P. Use in the reaction of 4-bromo(cyclopentylacetyl)benzene (example II) results in(11,17) -21-[4-(cyclopentylacetyl)phenyl]-11- [4-(dimethylamino)phenyl] -17-hydroxy-19-norpregna-4,9-Dien-20-in-3-one having a specific rotation []2D0= -31,8o(C = 0,5, dioxane).

Q. Use in the reaction of 4-bromo-(pharmacysulfacet)benzene [obtained in accordance with the method described in J. Org. Chem.; 58, (1993); 1H NMR (200 MHz, CDCl3: 5,13 ppm, doublet 2H1JH,F= 47 Hz;19F NMR (188 MHz, CDCl3: 211,7 ppm)] results in(11,17) -11-[4-(dimethylamino)phenyl] -21-[4-(permitil-sulfonyl)phenyl] -17-hydroxy-19-norpregna-4,9-Dien - 20-in-3-one having a specific rotation []2D0= 20, 8Co(C = 0.5 dioxane).

R. Use in the reaction of 4-bromo-(deformaty - sulfonyl)benzene (C. A., 80, 70488r, 1974) gives the result(11,17) -21-[4-(diplomatischer)phenyl] -11- [4-(dimethylamino)phenyl] -17-Hidan).

S. Use in the reaction of 4-bromo-(trifloromethyl)benzene (J. Org. Chem. 25, 60 (1960)) results in(11,17) -11-[4-(dimethylamino)phenyl] -17-hydroxy-21-[4- (trifloromethyl)phenyl]-19-norpregna-4,9-Dien-20-in-3-one having a specific rotation []2D0= -32o(C = 0,5, dioxane).

Example 5

In accordance with the procedure described in example 1f, Cu catalyzed reaction of Grignard phenylmagnesium with [3-(cyclic 1,2-candirectly)] -5,10-epoxy-17-ethinyl-17 - hydroxy-östra 9(11)-EN-3 - one gives [3-(cyclic 1,2-candirectly)]- 5,17-dihydroxy-17-ethinyl-11 - phenyl-variety-9 - EN-3-one. Melting point 187o.

The following products are obtained from [3-(cyclic 1,2-candirectly) -5,17 - dihydroxy - 17-ethinyl-11 - phenyl-variety-9-EN-3-one, using the appropriate starting material of example 1g), followed by carrying out the acid dehydration and removal of the protective group as described in example 1h.

A. Using 4 - bromo-N,N-dimethylaniline results in(11,17) -21-[4-(dimethylamino)-phenyl] -17-hydroxy-11-phenyl-19 - norpregna-4,9-Dien-20-in-3-one having a specific rotation []2D0= -83o(C = 0,5,dioxane).

C. Use 4-bromo-(methylsulphonyl)Besobrasova []2D0= -71o(C = 0,5, dioxane).

Example 6

In accordance with the procedure described in example 1f, Cu-catalyzed Grignard reaction of 3,4-methylenedioxyphenethylamine -[3-(cyclic 1,2-candirectly)] -5,10-epoxy-17-ethinyl-17 - hydroxyestra-9(11)-EN-3-one gives [3(cyclic 1,2-candirectly)] -5,17-dihydroxy-17-ethinyl-11- (1,3-benzodioxol-5-yl)-variety-9-EN-3-one. Melting point 155oC.

The following products are obtained from [3-(cyclic 1,2-candirectly)] -5,17 - dihydroxy - 17-ethinyl-11- (1,3-benzodioxol-5-yl)-variety-9-EN-3-one, using the appropriate starting material in the reaction of a combination of Hake (in accordance with the procedure of example 1g), followed by carrying out the acid dehydration and removal of the protective group as described in example 1h.

A. Use in the reaction of 4-bromo-N,N-dimethylaniline yields (11,17)- 11-(1,3-benzodioxol-5-yl)-21-[4-(dimethylamino)-phenyl]-17 - hydroxy-19-norpregna-4,9-Dien-20-in-3-one;

[]2D0= 63o(C = 1, chloroform).

C. Use in the reaction of 4-bromo-methylsulfonylbenzoyl yields (11,17)- 11-(1,3 - benzodioxol-5-yl)-21-[4- (methylsulphonyl)phenyl]-17-hydroxy-19-norpregna-4,9-Dien-20-in-3 - one; temperature result 1-[4-[ (11,17)- 11-(1,3- benzodioxol-5-yl)-17-hydroxy-3-oxo-19 - norpregna - 4,9-Dien-20-in-21-yl)phenyl]- 2 - pyrrolidinone;

[]2D0= -72o(C = 0,5, dioxane).

D. Use in the reaction of 4-bromo- (cyclopentylacetyl)benzene yields (11,17)- 11-(1,3-benzodioxol-5-yl)-21-[4-(cyclopentylacetyl)phenyl]- 17-hydroxy-19-norpregna-4,9-Dien-20-in-3-one;

[]2D0= -61,2o(C = 0,5, dioxane).

Example 7

In accordance with the procedure described in example 1f, Cu catalyzed reaction of Grignard reagent 4-performancebased with [3-(cyclic 1,2 - candirectly)] -5,10-epoxy-17-ethinyl-17 - hydroxy-variety-9(11)- EN-3-one gives [3-(cyclic 1,2-candirectly)]- 5,17-dihydroxy-17-ethinyl-11- (4-forfinal)-variety-9-EN-3-one.

The following products are obtained from [3-(cyclic 1,2-candirectly)] -5,17 - dihydroxy - 17-ethinyl-11- (4-forfinal)-variety-9 - EN-3-one, using the appropriate starting material in the reaction of a combination of Hake (in accordance with the procedure of example 1g), followed by carrying out the acid dehydration and removal of the protective group as described in example 1h.

A. Use in the reaction of 4-bromo-(methylsulfanyl)benzene yields (11,17)- 11-(4-forfinal)-17 - hydroxy-21-[4-(methylsulphonyl)phenyl]-19-norpregna-4,9-Dien-20-in-3-one; melting point 256oC.

Century And what about the-19 - norpregna-4,9-Dien-20-in-21-yl]phenyl]-2-pyrrolidinone; melting point 166oC.

C. Use in the reaction of 4-pomerainiansforsale yields (11,17)- 11-(4-forfinal)-17-hydroxy-21-[4-(1 - pyrrolidinylcarbonyl)phenyl] -19-norpregna-4,9-Dien-20-in-3-one; []2D0= -68o(C = 0,5, dioxane).

D. Use in the reaction of 4-bromo-N,N - dimethylaniline results in(11,17)- -11-(4- forfinal)-17-hydroxy-21-[4-(dimethylamino)phenyl]-19-norpregna - 4,9-Dien-20-in-3-one;

[]2D0= -92o(C = 0,5, dioxane).

Example 8

In accordance with the procedure described in example 1f, Cu-catalyzed Grignard reaction of 3,4-ethylenedioxyphenacylbromide with [3-(cyclic 1,2-candirectly)] -5,10-epoxy-17-ethinyl-17 - hydroxy-variety-9(11)-EN-3-one gives [3-(cyclic 1,2-candirectly)] -5,17-dihydroxy-17-ethinyl-11- (2,3-dihydro-1,4-benzodioxin-6 - yl)-variety-9-EN-3-one.

Melting point 253oC.

The following products are obtained from [3-(cyclic 1,2 - candirectly)] -5,17-dihydro-17-ethinyl-11- (2,3-dihydro-1,4-benzodioxin-6-yl) variety-9-EN-3-one, using the appropriate starting material in the reaction of a combination of Hake (in accordance with the procedure of example 1g), followed by acidic dehydration and religion results in 1-[4- [ (11,17)- 11-(2,3-dihydro-1,4 - benzodioxin-6-yl)-17-hydroxy-3-oxo - 19-norpregna-4,9-Dien-20 - in-21-yl)phenyl]-2-pyrrolidinone;

[]2D0= -53o(C = 0,5, dioxane).

C. Use in the reaction of 4-bromo-(methylsulphonyl)benzene yields (11,17) -11-(2,3-dihydro-1,4-benzodioxin-6 - yl)-17-hydroxy-21-[4-(methylsulphonyl) phenyl]-19-norpregna - 4,9-Dien-20-in-3-one;

[]2D0= - 47o(C = 0,5, dioxane).

C. Use in the reaction of 4-bromo-(methylsulfinyl)benzene yields (11,17)- 11-(2,3-dihydro-1,4-benzodioxin-6-yl)-17 - hydroxy-21-[4-(methylsulfinyl]phenyl]-19-norpregna-4,9-Dien-20-in-3-one;

[]2D0= -47o(C = 0,5, dioxane).

Example 9

(11,17) -11-(2,2-Debtor-1,3-benzodioxol-5-yl)-21-[4-(methylsulphonyl) phenyl]-17-hydroxy-19 - norpregna-4,9-Dien-20-in-3-one

In accordance with the procedure described in example 1f, Cu-catalyzed Grignard reaction of 3,4-(diversitronics) -phenylmagnesium [see J. Org. Chem. 37, 673 (1972)] [3-(cyclic 1,2-candirectly)]- 5,10-epoxy-17-ethinyl-17 - hydroxy-variety-9(11)-EN-3-one gives [3-(cyclic 1,2-candirectly)] -11- (2,2-debtor-1,3-benzodioxol-5-yl) -5,17-dihydroxy-17 - ethinyl-variety-9-EN-3-one.

The reaction mix Hake [3-(cyclic 1,2 - candirectly)] -17- (2,2-debtor-1,3-benzodioxol-5-yl) -5,17-dihydroxy-17 - ethinyl-variety-9-EN-3-one with 4-bromo-(methylsulphonyl)benzamides group, as described in example 1h, result in (11,17)- 1-(2,2-debtor-1,3 - benzodioxol-5-yl)-21-[4-(methylsulphonyl)phenyl] -17-hydroxy-19 - norpregna-4,9-Dien-20-in-3-one, which crystallized from ethanol.

The melting point of 275oC.

1. Derivatives 11,21-bisphenyl-19-norpregnane General formula I

< / BR>
in which R1selected from hydrogen, halogen, NR5R6where R5and R6independently are hydrogen or C1-6-alkyl;

R2is hydrogen;

or R1and R2together are C1-3alkylenedioxy, optionally substituted by one or more halogen atoms;

R3is stands;

R4selected from C(O)-NR5R6, SOnC1-6-alkyl, optionally substituted by one or more halogen atoms, SOnC3-6-cycloalkyl, SO2NR5R6, 2-oxopyrrolidin or NR5R6where R5and R6independently are hydrogen, C1-6-alkyl, or R5and R6together form a C3-6-alkylen, n = 1 or 2;

R7is hydrogen or C1-6-alkyl;

R8is hydrogen;

X is chosen from H, OH), O, NOH.

2. Derived 11,21-bisphenyl-19-norpregna the 1-6-alkyl, optionally substituted by one or more fluorine atoms, SO2C3-6-cycloalkyl or NR5R6where R5and R6independently hydrogen or C1-6-alkyl, or R5and R6together form a C3-6-alkylen, n = 1 or 2.

3. Derived 11,21-bisphenyl-19-norpregnane under item 1 or 2, wherein R4is N(CH3)2or SO2CH3.

4. Derived 11,21-bisphenyl-19-norpregnane according to any one of paragraphs.1 to 3, characterized in that it R1is N(CH3)2and R2represents hydrogen or R1and R2together form methylenedioxy.

5. Derived 11,21-bisphenyl-19-norpregnane under item 1, characterized in that the derivative is a 11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-21-[4-(methylsulphonyl)-phenyl]-19-norpregna-4,9-Dien-20-in-3-one.

6. The method of obtaining derivatives 11,21-bisphenyl-19-norpregnane according to any one of paragraphs.1 -5, characterized in that the compound of General formula II

< / BR>
in which P represents a protected ketogroup, dehydration and otscheplaut protective group and optionally converted into the corresponding 3-hydroxy or 3-oxime derivative.

7. Formats-norpregnane according to any one of paragraphs.1 - 5 and pharmaceutically acceptable excipients.

8. Derivatives 11,21-bisphenyl-19-norpregnane according to any one of paragraphs.1 to 5, with antiglucocorticoid activity.

9. A method of obtaining a pharmaceutical composition having antiglucocorticoid activity, wherein spend mixture derived 11,21-bisphenyl-19-norpregnane on PP.1 - 5 with pharmaceutically acceptable excipients.

 

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