Nonaromatic estrogenic steroid, pharmaceutical composition

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

 

This invention relates to the field of estrogenic compounds with steroid structure having a non-aromatic A-ring and a free or blocked hydroxyl group at carbon atom 3. It is widely known that estrogenic compounds are useful in contraception, also in the treatment of disorders associated with estrogen-deficiency, such as the symptoms of menopause and osteoporosis.

Known from the literature many estrogenic compounds. For example, a publication giving information on estrogenic compounds with non-aromatic A-ring and the free or blocked hydroxyl group at carbon atom 3 is U.S. patent 3413287. Other documents describing estrogenic or hormonal effects of non-aromatic steroids with a 3-hydroxyl-substituted group and a double bond in position 4-5, are the patents WO 94 18224, US 3465010, FR 2099385, US 3652606 and EP 145 493. The document, which revealed non-aromatic steroids with a 3-keto-substituted group and a double bond in position 5-10, is U.S. patent 3377366, Baran and other Such compounds are described in General as agents, having, among other properties, estrogenic or antiestrogenic effects. Recently in the development of drugs having affinity to the estrogen receptor (ER), attention focused on the opening of two special types of receptors estrogen is s, markedand ERβ (Mosselman and others, FEBS Letters 392 (1996) 49-53, as well as EP-A-0 798 378). Because these receptors are differently distributed in human tissues, the detection of compounds that have a selective affinity for each of the two, is an important contribution in this area, because it makes possible a more selective treatment of estrogen-deficient States with less severe side effects associated with estrogen.

This invention relates to estrogen, which meets the General formula:

The formula I

in which R1denotes H, (C1-C3)alkyl or (C2-C3)acyl;

R2denotes H, α-(C1-C4)alkyl, α-(C2-C4)alkenyl or α-(C2-C4)quinil;

R3represents H or (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)quinil, everyone can be in position 15 or 16 of the steroid skeleton;

R4represents H or (C1-C5)alkyl, (C2-C5)alkenyl or (C2-C5)quinil, each of which is optionally substituted with halogen, the preferred ethinyl;

R5denotes H, (C1-C3)alkyl or (C2-C3)acyl;

R6means (C1-C5)alkyl, (C2-C5)alkene is l, (C2-C5)quinil or (C1-C5)alkylidene, each of which is optionally substituted with halogen or (C1-C3)alkyloxy, preferably allyl; preferred Halogens in R6are fluorine and chlorine.

Communication, indicated by dots, are optional double bonds. If R6indicates alkyliden, then the points marked line to R6is an additional link that is present in alkylidene link, and if R6denotes alkyl or alkenyl, communication from the atom 11 to R6a simple link.

It was found that such non-aromatic derivatives of estradiol with the substituent in position 11 steroid patterns have selective affinity to ERα-receptors.

Compounds of the present invention are improved estrogen, in the sense that they can be used when estrogen-dependent disorders such as symptoms of menopause and osteoporosis. They also find application in contraception, and, in addition, can be useful in the treatment or prevention of Alzheimer's disease, breast cancer, benign prostate hypertrophy and cardiovascular disorders. The compounds of this invention are particularly suitable for the treatment and prevention of disorders caused by oestrogen deficiency, when slable the AI associated with estrogen side effects.

Described in this description, the terms have the following meanings:

(C1-C5)alkyl is a branched, unbranched or cyclic alkyl group having 1-5 carbon atoms, for example methyl, ethyl, isopropyl, 2-methylcyclopropyl, butyl, sec-butyl, tert-butyl, etc.

(C2-C5)alkenyl is a branched, unbranched or cyclic alkenylphenol group having from 2 to 5 carbon atoms, such as ethynyl, 2-butenyl and other

(C2-C5)quinil represents a branched or unbranched alkylamino group having 2-5 carbon atoms, such as ethinyl and PROPYNYL.

(C2-C3)acyl represents a group having 2-3 carbon atoms and is derived from alkalicarbonate acid, and the alkyl part has the meaning given above.

(C1-C5)alkyliden is a branched, unbranched or cyclic alkylidene group having 1-5 carbon atoms, such as methylene and ethylidene.

Of the compounds of the above General formula are preferred compounds corresponding to General formula II:

Formula II

in which R1denotes H, (C1-C3)alkyl, (C2-C3)acyl;

R2denotes H, α-(C1-C4)alkyl, α-(C2-C4)lceil, α-(C2-C4)quinil;

R3represents H or (C1-C4)alkyl in position 16 of the steroid skeleton;

R4denotes ethinyl;

R5represents H or (C1-C3)alkyl, (C2-C3)acyl;

R6means (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)quinil, each of which can be substituted by chlorine or fluorine. If R6means (C1-C2)alkyl, ethynyl or ethinyl, each of which is optionally substituted by chlorine or fluorine, preferably, R3was stands in position 16 of the steroid skeleton.

Preferable steroids of this invention indicated formula II in which R1denotes N;

R2denotes N;

R3denotes H or 16α-methyl;

R4denotes ethinyl;

R5denotes N;

R6denotes propenyl, allyl or butenyl.

The compounds of this invention can be produced by various methods known in organic chemistry in General and, mainly, in the chemistry of steroids. See, for example: Fried and J. Edwards J.A. "Organic Reactions in Steroid. Chemistry", Volumes I and II, Van Nostrand Reinhold Company, New York, 1972; and .Djerassi "Steroid Reactions", Holden-Day, Inc., San Francisco, 1963.

Suitable, for example, is the synthesis of steroids with specific substituents at position C7 through paired connec is of ORGANOMETALLIC substances to the corresponding 4,6-Dien-3-novym steroids, usually getting 7α-derived steroids (along with getting in a smaller number 7β-steroids, which can be easily removed by crystallization or chromatography). Many examples of such synthesis known from the literature. Introduction of substituents at position C11 steroid skeleton can be done in several ways. This method is the conjugate join ORGANOMETALLIC substances to protected accordingly 5α,10α-epoxy, 9(11)-olefin, which is described Teutsch et al., Steroids, 37, 361 (1981), but to get the claimed compounds can be applied in other ways, using 11-oxo-functional group is protected 19-norandro-5-ene as a reactive group for internal conversion of the functional group, for example, to C11-aldehyde, according to well known chemical methods (see E. Ottow et al., Tetr. Lett., 5253 (1993) and others). Of course, also good is the goal, the combination of the two described methods. The introduction of a double bond at position 5(10) perform, using the so-called recovery Birch A-ring aromatic parts of steroids with suitable functional groups, dissolving regenerating metal Δ-4,5-9,11-dienones, or metallizatsiei 3-keto-Δ-4,5-steroids. The last method gives either directly required selective #x00394; -5(10)-isomers, or a mixture of ketals, which can be separated by chromatography or crystallization at appropriate stages of the synthesis. Careful hydrolysis of ketala on C3 usually gives the desired 3-oxo-Δ-5(10)-isomers, which can be converted into 3-HE-compounds by reduction with hydrides. Saturated steroids (namely, 5αN-derivatives) is easily obtained in reducing conditions, for example by dissolving alkali metals or amines have had ammonia. The introduction of double bonds at C14, C15 usually carried out by introducing first double bond at position C15, C16, followed by isomerization in this regard the position C14, C15 known methods. Alternatively, the double bond introduced by the position of C15, C16, can be used to conduct a paired connection, for example, with cyanide, which allows you to enter deputies C15. Introduction C16-Deputy easy to perform by alkylation with suitable grounds and electrophiles.

The present invention also concerns pharmaceutical compositions comprising the steroid compound according to the invention in a mixture with a pharmaceutically acceptable auxiliary agents, such as those described in Gennaro et al., Remington''s Pharmaceutical Sciences (18thed., Mack publishing Company, 1990, mainly Part 8: Pharmaceutical Preparations and Their Manufacture), which can be used as the e links. A mixture of steroid compounds according to the invention and a pharmaceutically acceptable auxiliary agent can be extruded in the form of a standard solid dosage forms such as granules, tablets, or to receive capsules or suppositories. Using appropriate pharmaceutically acceptable liquid, these compounds can also be used in preparations for injection in the form of solutions, suspensions, emulsions or sprays, such as sprays for the nose. To obtain a standard dosage forms, for example tablets, you can use the usual additives such as fillers, dyes, polymeric binder and the like. In General you can use any pharmaceutically acceptable additive, which does not interfere with the action of the active compounds. Steroid compounds according to the invention can also be incorporated into the implants, vaginal rings, patches, gels and any other drugs prolonged.

Suitable carrier materials with which it is possible to apply these compositions include lactose, starch, cellulose derivatives and similar substances, or mixtures thereof, used in the right quantities.

The invention also concerns the use of steroid compounds according to the invention for obtaining a medicinal product for the treatment of disorders associated with estrogen-deficiency, such as symptoms of the Yeri - and/or post-menopausal. Thus, this invention may be of value to this medical condition, as the symptoms of peri - and/or post-menopausal (climacteric) and osteoporosis, and in particular to a method of treatment by HRT (hormone replacement therapy), including the introduction of the patient (woman) described above, compounds (in the form of a suitable pharmaceutical dosage forms).

In addition, the invention concerns the use of steroid compounds of this invention as active ingredients in the manufacture of a drug product with contraceptive activity. Thus, this invention can be used in contraception, namely, the method comprising administration to the patient (woman or female animal) progestogen and estrogen, as is customary in this field, and estrogen is an above-described compound (in the form of a suitable pharmaceutical dosage forms).

In conclusion, this invention relates to the use of this steroid compounds to obtain a drug with selective estrogenic activity, which could find wide application in the field of hormone replacement therapy (HRT).

Metered quantities of these steroids are in the range of normal for estradiolo, from about 0.01 to 10 mg per dose.

Below this the invention is illustrated with some examples not having a restrictive nature, and their respective schemes of formulas.

EXAMPLE 1

The synthesis of compounds (3α,11β,17β)-11-(2-propenyl)-19-norpregna-5(10)-ene-20-in-3,17-diol (compound 11) and (3α,11β,16α,17β)-16-methyl-11-(2-propenyl)-19-norpregna-5(10)-EN-20-in-3,17-diol (compound 16) is described with reference to scheme I. Compounds represented by numbers. The numbers refer to the corresponding structural formulas in schemes I-VII.

Connection 2

To a solution of 17.3 g CuI and of 3.84 g of LiCl in 250 ml of THF added at -70°90,6 ml of 1M solution of allylanisole in diethyl ether. After stirring for 20 min add 11,4 ml trimethylchlorosilane, and then a solution of 7.5 g of the steroid 1 in 100 ml of THF. The temperature of the reaction mixture all the time support below -60°C. After stirring for 1 hour. the reaction mixture is quenched, pouring into a saturated aqueous solution of NH4C1. The product is extracted with ethyl acetate and then purified by way of column chromatography, obtaining 6.25 g 2 as a colorless oil. NMR: 5,20 (m, CH, allyl), 5,0 (CH2, allyl), totaling 3.04 (m, H11).

3

To a solution of 9.6 g 2 in a mixture of 100 ml of methanol and 30 ml of methylene chloride, containing 800 mg of NaOH, add 0.4 g of sodium borohydride at 0-5°C. After stirring for 1.5 h the reaction is terminated and the mixture is treated with 20 ml of acetone for 0.5 h Then the reaction mixture was poured into water and extracted with ethyl what cetecom, getting 9.5 g 3. NMR: 3,59 (t, SNON), 2,98 (m, H11), to 0.92 (s, CH3).

Scheme I

4

To a solution of 9.5 g of 3 in 100 ml of acetone add 8 ml of 6N Hcl. After stirring for 2 h the mixture is neutralized using Panso3and concentrated to small volume, diluted with water and extracted with ethyl acetate. This gives an 8.2 g of 4 as a colorless amorphous substance. NMR: of 5.68 (m, H4), 3,10 (m, H11), the 3.65 (m, SNON).

5

A solution of 8.2 g of 4 in 100 ml of dry THF is added to 500 ml of liquid NH3at -70°C. the mixture is treated with a certain amount of metallic lithium (approximately 500 mg)until the blue coloration of the reaction mixture will not persist for at least 15 minutes, the Reaction mixture was quenched by adding a portion of NH4Cl. The residue that remains after evaporation of NH3, diluted with water and extracted with ethyl acetate. Chromatographic purification gives 4.0 g of 5 as a colorless oil. Rf0,55 (heptane/ethyl acetate = 1/1.vol.). NMR: 2,80 (ab, CH2when C4), of 0.93 (s, CH3).

6

To a solution of 4.0 g 5 in 80 ml of methanol, add 6 ml of triethylorthoformate, and then 0.8 g toluensulfonate acid. After stirring for 2 h perform ketalization. This mixture is treated with 6 ml of pyridine and concentrated to small volume. The residue is diluted with water and extracted with ethyl acetate. Obtained the remainder of 4.7 g consists of almost pure 6; TLC: Rf0,78 (heptane/ethyl acetate = 1/1.vol.). NMR: 3,22, 3,25 (2×s, och3).

7

To a solution of 33 g of 6 in 50 ml of acetone add 6 g of molecular sieves (4A), and then 3.2 g of N-methylmorpholin-N-oxide and 150 mg perruthenate of tetrapropylammonium. The mixture is stirred for 1 h To the reaction mixture are added 5 g of silica gel, and then 50 ml of heptane and stirred for further 5 minutes the mixture is filtered through a high-speed filtering and after partial concentration placed in ethyl acetate, washed with water and concentrated. The residue passed through a short column with silica and obtain 2.9 g 7; Rf0,52 (heptane/ethyl acetate = 7/3). NMR: 1,02 (s, CH3).

8

For etiolirovaniya get litigation of dibromethane, utility.

To a solution of 0.74 ml of 1,2-dibromethane in 20 ml of THF added at -70°With 11 ml of a 1.6 m solution of BuLi in hexane. After stirring for 15 minutes, add a solution of 800 mg of 7 in 2 ml of THF. Mixture is allowed to warm to room temperature for 15 min and after 15 min at room temperature, the reaction mixture was quenched with water and the product extracted with ethyl acetate. Concentration, followed by passing through a short column with silica gel give 810 mg of 8 as a white amorphous substance. Rf0,48 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.52. NMR: 2,61 (with acetylene).

9

To a suspension of 3.2 g 8V 60 ml of ethanol is added 0.16 g of oxalic acid in 16 ml of water. The mixture is stirred for 2.5 h, and it gradually becomes homogeneous. The reaction mixture is treated Panso3and concentrated to small volume. Then add water and extracted the product with ethyl acetate. Allocated thus the crude product was passed through a short column with silica gel and crystallized from diisopropyl ether, obtaining 2.3 g 9, so pl. 136°C. Rf0,66 (heptane/ethyl acetate = 1/1). NMR: 2,78 (ab, 2, N4), 2,61 (with acetylene).

10, 11

To a solution of 1 g 9 in 12 ml of THF added 1.6 g three-tert-butoxycarbonylamino lithium. After stirring for 1 h at room temperature the mixture is treated with water and neutralized by adding 2N Hcl. The product is extracted with ethyl acetate and chromatographic on silica gel (heptane/ethyl acetate = 8/2 as eluent). This gives 0.56 g 3β-alcohol 10 (TPL 121-123° (C) and 0.24 g 3α-alcohol 11 (TPL 84-87°). Rf0,53 (10) and 0.45 (11), heptane/ethyl acetate = 1/1. NMR: (3αHE) is 3.82 (m, SEN); (3βHE): 4,08 (m, SNON).

12

To a solution of hexamethyldisilazide lithium (derived from 1,9 ml of a 1.6 m solution of BuLi in hexane and 0.71 ml hexamethyldisilazane in 4 ml dry THF) is added at -40°With 1 g 7 and 0.7 ml of DMPU (N,N'-dimethylpropyleneurea) in 5 ml of THF. The mixture is stirred for 0.5 h at -40°and then add the syringe 225 ál of CH3I. After stirring for a further 0.5 h at -40°the reaction is finished. The mixture is diluted with water and extracted with ethyl acetate. Chromatography selected so crude product gives 1.3 g 12, Rf0,43 (heptane/ethyl acetate = 8/2).

13

According to the method described for obtaining 8, 1.3 g 12 is transformed into the desired compound 13, receiving 1.2 g, Rf0,46 (heptane/ethyl acetate = 7/3); Rf(12) of 0.55.

14

To a solution of 800 mg 13 in 20 ml of ethanol is added a solution of 80 mg of oxalic acid in 5 ml of water. The mixture is stirred for 1 h and then neutralized by adding NaHCO3. After dilution with water and extraction with ethyl acetate remains 0.7 g 14 in the form of a crystalline substance. Rf0,47 (heptane/ethyl acetate = 7/3).

15, 16

To a solution of 725 mg 14 in 20 ml of a 1/1 mixture of ethanol and THF added 130 mg of sodium borohydride. After stirring for 1 h, add 2 ml of acetone to decompose excess reagent. After 15 min the mixture was poured into water and the product extracted with ethyl acetate. Thus obtained substance is purified chromatographically on silica gel using a mixture of methylene chloride/acetone or a mixture of hexane/ethyl acetate as eluent. This gives 300 mg 16 (3α-HE) and 75 mg 15 (3β-HE). Rf(15) to 0.47 (methylene chloride/acetone = 95/5) and Rf(16) 0,54 (methylene chloride/acetone = 95/5).

EXAMPLE 2

Synthesis of compound (3β,5α,11β,17β)-11-deformity-19-norpregna-20-in-3,17-diol (compound 21) is described with reference to scheme II.

Scheme II

18

It races the thief 4 g of the known aldehyde 17 in 200 ml of methylene chloride, add 10 ml of dimethylterephthalate. The mixture is stirred for 48 h at ambient temperature and then poured into ice water and extracted with methylene chloride, followed by washing Panso3. After concentration and chromatography (SiO2- heptane/ethyl acetate = 2/1) to obtain 2.5 g 18, TPL 138-139°C. NMR (Dl3): 6,05 ppm double triplet CHF2and 5.9 (s, H4), of 0.95 (s, CH3).

19

Gaseous acetylene is passed within 45 min after degassed mixture of 1.3 g of trebuchet potassium and 1 g 18 in 7 ml of THF and 2 ml of tert-butanol at 0°C. the mixture is Then poured into water and extracted with ethyl acetate. After washing and concentrating the remaining substance is treated with diisopropyl ether, receiving of 0.85 g of 19 as a white solid. TPL 178-180°C. Rf0,43 (heptane/ethyl acetate = 1/1).

20

To a solution of 20 mg Li in 10 ml of liquid NH3add at -60°With a solution of 300 mg 19 in 6 ml of THF. After stirring for 1 min the mixture was treated with 0.5 g of NH4Cl. NH3is evaporated, and the residue is treated with water and extracted with ethyl acetate. Thus obtained substance is purified chromatographically, receiving 140 mg 20. TPL 224-225°C. Rf0,64 (heptane/ethyl acetate = 7/3).

21

To a solution of 25 mg LiAlH4in 4 ml of THF added at -60°With 85 20 mg in 1 ml THF. After stirring for 5 min the mixture was quickly warmed to room temperature and srabatyvayut, adding 45 μl of water, 45 μl of 3N NaOH solution and 140 μl of water. The precipitates are then filtered, and the filtrate is transferred into ethyl acetate and washed with 2N Hcl and water. The residue remaining after drying and concentration, treated with diisopropyl ether and receive 50 mg 21. TPL 168-169°C. Rf0,30 (toluene/ethyl acetate = 7/3). NMR: 3,6 ppm SNON, 2,65 (CH acetylene), 6,0 (double triplet CHF2).

EXAMPLE 3

The synthesis of compounds (3β,5α,11β,17β)-11-(2-foradil)-19-norpregna-20-in-3,17-diol (compound 31) and (3α,5α,11β,17β)-11-(2-foradil)-19-norpregna-20-in-3,17-diol (compound 32) is described with reference to scheme III.

23

To a solution of 4.95 g 11β-hydroxycholesterol-3-methyl ether (22) in 115 ml of THF added 66 g of molecular sieves 4A, and then 45 ml of 1M TBAF in THF (dry) and then 5.3g of desilvered. The mixture is stirred and refluxed for two hours. Then the reaction mixture is cooled, poured onto 700 ml of 10% aqueous solution of NaHCO3and extracted with ethyl acetate. After concentration of the solution and chromatography allocate 3.4 g 23. Rf0,39 (heptane/ethyl acetate = 7/3).

Scheme III

24

A solution of 4 g 23 in a mixture of 30 ml of THF and 30 ml of methanol is treated with 0.1 ml of 4N NaOH and then 0,23 g NaBH4. After stirring for 1 h the reaction mixture was poured into water and extracted with ethyl acetate. The crude substance filter is t through a short column with silica gel, obtaining 3.8 g 24. Rf0,26 (heptane/ethyl acetate = 7/3). Rf(23) 0,33.

25

To a solution of 3.8 g 24 in a mixture of 40 ml of THF and 230 ml of liquid NH3add at -33°5 g Li. The mixture is stirred for 5 hours and Then the excess lithium is removed by processing 45 ml of ethanol. The ammonia is allowed to evaporate and the residue is diluted with water and extracted with ethyl acetate. After drying and concentrating obtain 3.7 g of crude 1,2,5 (10)vinolevure. It is dissolved in 30 ml of acetone and add 3 ml of 6N Hcl. After stirring for 3 h the mixture was neutralized Panso3, then diluted with water and extracted with ethyl acetate, obtaining 2.8 g 25. Rf0,10 (heptane/ethyl acetate = 4/6).

26

A solution of 0.84 g of 25 in a mixture of 30 ml of liquid NH3and 6 ml of THF is treated at -60°small pieces of lithium up until the blue coloration of the reaction mixture will not be kept for at least 5 minutes and Then the excess reagent is removed by adding a small amount of NH4Cl, and evaporated NH3. The remainder of the substance was diluted with water and extracted with ethyl acetate. The concentration of the solution gives 0,80 g of practically pure substance; Rf0,39 (heptane/ethyl acetate = 1/1), Rf(25) to 0.24.

27

To a solution of 0.8 g 26 in 8 ml of dichloromethane added to 2.8 ml of ethylene glycol, 2.5 ml of triethylorthoformate and 5 mg toluensulfonate acid. The mixture is stirred over night, then howled who live in a saturated solution Panso 3and extracted with ethyl acetate. Thus obtained crude substance is purified by passing through a short column with silica gel, receiving 0,72 g 27. Rf0,46 (heptane/ethyl acetate = 1/1), Rf(26) 0,38.

28

To a solution 0,72 g 27 in 15 ml of acetone was added 1 g of molecular sieves (4A), and then 0,70 g N-methylmorpholin-N-oxide and 30 mg perruthenate of tetrapropylammonium. The mixture is stirred for 1 h To the reaction mixture was added 1 g of silica gel, and then 15 ml of heptane and stirred for further 15 minutes the Mixture is filtered through a high-speed filtering and after partial concentration placed in ethyl acetate, washed with water and concentrated. The residue passed through a short column with silica and get 0,59 g 28. Rf0,62 (heptane/ethyl acetate = 1/1).

29

For etiolirovaniya get litigation of dibromethane, utility.

To a solution of 0.74 ml of 1,2-dibromethane in 20 ml of THF added at -70°With 11 ml of a 1.6 m solution of BuLi in hexane. After stirring for 15 minutes, add a solution of 590 mg 28 in 2 ml of THF. Mixture is allowed to warm to room temperature for 15 min and after 15 min at room temperature, the reaction mixture was quenched with water and extracted the product with ethyl acetate. Concentration, followed by passing through a short column with silica gel gives 430 mg 29 in the form of a white amorphous substance. Rf0,11 (hepta the/acetone = 9/1), Rfthe original substance of 0.21.

30

To a solution of 0.43 g 29 in 15 ml of acetone was added 1 ml of 2N Hcl. The mixture is stirred for 2 h and then treated with saturated aqueous Panso3followed by extraction with ethyl acetate, getting 0.40 g of essentially pure 30; Rf0,18 (heptane/acetone = 7/3), Rf(29) of 0.23.

31/32

To a solution of 0.40 g 30 in 4 ml of THF and 4 ml of ethanol is added 30 mg of sodium borohydride. After stirring for 0.5 h add a few drops of acetone to decompose excess reagent. Even after 15 min of stirring the reaction mixture was poured into water and extracted with ethyl acetate, thus obtained crude substance is subjected to column chromatography, receiving 80 mg 3αHE isomer 32 and 160 mg 3βHE derived 31. Rf(31) of 0.37, Rf(32) 0.42 and Rfthe original substance of 0.48 (heptane/acetone = 6/4).

EXAMPLE 4

The synthesis of compounds (3α,11β,17β)-11-(3-butenyl)-19-norpregna-5(10)-ene-20-in-3,17-diol (compound 42) and (3β,11β,17β)-11-(3-butenyl)-19-norpregna-5(10)-ene-20-in-3, 17-diol (compound 43) described with reference to scheme IV.

Scheme IV

33

A solution of 55 g of the steroid 1 in a mixture of 300 ml of THF and 300 ml of methanol is treated with a solution of 2.7 g of sodium borohydride in 30 ml of water containing 3 mg of NaOH). After stirring for 1 h the restoration is complete and the excess hydride is removed is aballea 75 ml of acetone. After stirring for 1 h the reaction mixture was poured into water and extracted with ethyl acetate. Concentration of the organic phase gives 54 g 33,

Rf0,31 (heptane/ethyl acetate = 4/6), Rfthe original substance of 0.42.

34

To a solution of 54 g 33 in 350 ml DMF added 35 g of imidazole, and then 37 ml trimethylsilylpropyne at -10°C. After stirring for 0.5 h the reaction is finished. The mixture is then poured into 1.5 liters of water and extracted with ether. The residue obtained after concentration of organic matter, triturated in 80% aqueous ethanol, getting 50 grams of pure 34. TPL 90-91°, Rf0,79 (heptane/ethyl acetate = 4/6), Rfthe original substance of 0.36.

35

To a solution of butylmagnesium obtained from 0,51 ml of 4-bromo-1-butene and 119 mg MD in 20 ml of THF, added at -10°With 100 mg of CuI. After stirring for 0.5 h the mixture is cooled to -30°and add 1 g 34 in 5 ml of THF. The reaction mixture is allowed to warm to room temperature about 1 hour. Then add 100 ml of a saturated aqueous solution of NH4Cl followed by extraction with ethyl acetate. Chromatography gives 0.9 g 35. Rf0,54 (heptane/ethyl acetate = 6/4), Rfthe original substance of 0.60.

36

To a solution of 8.65 g 35 in 80 ml of acetone is added 2 ml of 2N Hcl. The mixture is stirred for 2 h, then neutralized with a saturated aqueous solution of NaHCO3concentrate to a small volume which, dilute with water and then extracted with ethyl acetate. Thus obtained crude substance is passed through a short column with silica gel, receiving 5.3g 36; Rf0,18 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.51.

37

Small pieces of lithium metal are added to a solution of 5.3 g 36 in a mixture of 340 ml of liquid NH3with 110 ml of THF and 9 ml of tert-butanol at -70°up until a blue coloration of the reaction mixture will not be kept for 45 min ± 350 mg). The excess reagent is removed by adding NH4Cl. The ammonia is evaporated and the residue diluted with water and extracted with ethyl acetate. Thus obtained crude substance is passed through a short column with silica gel, obtaining 3.8 g 37. Rf0,46 (heptane/ethyl acetate = 6/4), Rfthe original substance is 0.22.

38

To a solution of 3.3 g of 37 in 60 ml of methanol, add 5 ml of triethylorthoformate and 0.3 g of para-toluensulfonate acid. After stirring at room temperature for 1 h the mixture was neutralized by adding 1 ml of pyridine. This mixture is concentrated to one-third the original volume, poured into water and extracted with ethyl acetate, getting after chromatographic purification 3.7 g 38. Rf0,60 (heptane/ethyl acetate = 1/1), Rfthe original substance of 0.48.

39

To a solution of 3.7 g 38 in 45 ml of acetone add 5 g of molecular sieves (4A), and then 3.6 g of N-methylmorpholin-N-about the sid and 100 mg perruthenate of tetrapropylammonium. The mixture is stirred for 1 h To the reaction mixture are added 5 g of silica gel, and then 100 ml of heptane and stirred for further 5 minutes the Mixture is filtered through a high-speed filtering and after partial concentration placed in ethyl acetate, washed with water and concentrated. The residue passed through a short column with silica and get a 3.3 g 39. Rf0,51 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.38.

40

For etiolirovaniya get litigation of dibromethane, utility.

To a solution of 0.74 ml of 1,2-dibromethane in 20 ml of THF added at -70°With 11 ml of a 1.6 m solution of BuLi in hexane. After stirring for 15 minutes, add a solution of 0.8 g 39 in 2 ml of THF. Mixture is allowed to warm to room temperature for 15 min and after 15 min at room temperature, the reaction mixture was quenched with water and extracted the product with ethyl acetate. Concentration, followed by passing through a short column with silica gel gives 0.96 g 40 in the form of a white amorphous substance. Rf0,15 (heptane/acetone = 95/5), Rfthe original substance of 0.30.

41

To a solution of 0.95 g 40 in 20 ml of ethanol is added 0.6 g of oxalic acid in 3 ml of water. The mixture is stirred for 1.5 hours, the Reaction mixture is treated Panso3and concentrated to small volume. Then add water and extracted the product with ethyl acetate. Selected t is thus the crude product was passed through a short column with silica gel, getting 0.55 g 41. Rf0,33 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.40.

42/43

To a solution of 0.55 g 41 in 4 ml of THF and 4 ml of ethanol is added 30 mg of sodium borohydride. After stirring for 0.5 h add a few drops of acetone to decompose excess reagent. After stirring for 15 min the reaction mixture was poured into water and extracted with ethyl acetate, thus obtained crude substance is subjected to column chromatography, receiving 90 mg 3αHE isomer 42, TPL 159°and 150 mg 3βHE derived 43, TPL 90°C. Rf(42) 0,31, Rf(43) of 0.23, Rfthe initial substance 0,41 (heptane/ethyl acetate = 6/4).

EXAMPLE 5

The synthesis of compounds (3β,7α,11β,17β)-11-(2-foradil)-7-methyl-19-norpregna-5(10)-ene-20-in-3,17-diol (compound 54) and (3α,7α,11β,17β)-11-(2-foradil)-7-methyl-19-norpregna-5(10)-ene-20-in-3,17-diol (compound 55) described with reference to scheme V.

45

To a solution of 4 g 44 in 35 ml of methanol, add 12 ml of triethylorthoformate, then 0.3 g toluensulfonate acid. After stirring for 1 h starting material is consumed, and the reaction mixture is neutralized by adding 1 g of NaHCO3and concentrate. The residue is diluted with water and extracted with ethyl acetate. Chromatography of the crude substance gives 3.4 g 45. Rf0,61 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.35.

Scheme V

46

To a solution of 3.4 g 45 in 50 ml of methanol is added 0.5 g of NaOH. After stirring for 2 h the saponification is completed. The mixture is concentrated, diluted with water and extracted with ethyl acetate, receiving 3 g 46 in the form of a colorless oil. Rf0,31 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.65.

47

To a solution of 3.6 g 46 in 30 ml DMF added 2.8 g of imidazole, and then 2 g of tert-butylmethacrylate. After stirring for 2 h the mixture was poured into water and extracted with ethyl acetate. The crude substance is passed through a short column with silica gel, obtaining 3.8 g 47 in the form of oil. Rf0,70 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.61.

48

A solution of 9-BBN get out of 1.75 ml of 1,5-cyclooctadiene and 1.4 ml of the complex, borane-dimethyl sulfoxide in 40 ml of THF. Added 3.8 g 47 in 5 ml of THF. The mixture is stirred for 2 h and then quenched carefully adding water (5 ml), and then 10 ml of 2N NaOH and 8 ml of 30% H2O2. After vigorous stirring for 2 h the reaction mixture even diluted with water, extracted with ethyl acetate and washed with 10% aqueous solution PA2SO3. After concentration and chromatography allocate 2.8 g 48. Rf0,27 (heptane/ethyl acetate = 7/3), Rfthe initial substance 0,70.

49

A mixture of 1 g 48 and 0.5 g of tosylchloramide in 5 ml of pyridine is stirred for 5 h at 0-5°C. Then add 1 ml of water and continue the var is shivanie within 15 minutes The reaction mixture is still diluted with water, extracted with ethyl acetate and the crude product is purified chromatographically, receiving 1.1 g 49, TPL 120°, Rf0,57 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.30.

50

A solution of 400 mg 49 in 5 ml of dry 1M TBAF in THF is stirred for 5 h, which leads to the formation of fluoride and concomitant removal of silyl functions. The mixture was poured into water and extracted with ethyl acetate. Purification by chromatography method gives 185 50 mg, MP 161-162°, Rf0,35 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.53.

51

To a solution of 180 50 mg in 5 ml of acetone add 0.5 g of molecular sieves (4A), and then 200 mg of N-methylmorpholin-N-oxide and 10 mg perruthenate of tetrapropylammonium. The mixture is stirred for 1 hour is Added to the reaction mixture, 0.5 g of silica gel, followed by 10 ml of heptane and stirred for further 5 minutes the Mixture is filtered through a high-speed filtering and after partial concentration placed in ethyl acetate, washed with water and concentrated, receiving 150 mg 51, TPL 166°, Rf0,45 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.35.

52

For etiolirovaniya get litigation of dibromethane, utility.

To a solution of 0.30 ml of 1,2-dibromethane in 6 ml THF added at -70°With 4.5 ml of a 1.6 m solution of BuLi in hexane. After stirring for 15 minutes, add a solution of 150 mg 51 1 m is THF. Mixture is allowed to warm to room temperature for 15 min and after 15 min at room temperature, the reaction mixture was quenched with water and extracted the product with ethyl acetate. Concentration and treatment with heptane to give 140 mg 52 in the form of a white solid, TPL°, Rf0,38 (heptane/acetone = 95/5), Rfthe original substance of 0.40.

53

To a solution of 145 mg 52 in 3 ml of ethanol and 1.5 ml of THF, add 0.2 g of oxalic acid in 3 ml of water. The mixture is stirred for 1.5 hours, the Reaction mixture is treated Panso3and concentrated to small volume. Then add water and extracted the product with ethyl acetate. Allocated thus the crude product was passed through a short column with silica gel, receiving 125 mg 53. Rf0,23 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.38.

54/55

To a solution of 125 mg 53 in 2 ml of THF and 1 ml of ethanol is added 20 mg of sodium borohydride. The recovery is complete after 0.5 h the Mixture was diluted with water and extracted with ethyl acetate. Allocated thus the crude product is purified by passing through a column of reversed phase C-18, using as eluent a mixture of acetonitrile-water and receiving 40 mg 3αHE was 55 and 20 mg 3βHE was 54, both amorphous substances with the same values of Rfon silica gel; Rf0,43 (CH2Cl2/acetone = 9/1), Rfthe initial substance 0,70.

EXAMPLE 6

Connect the Oia this example receive under the scheme VI.

57

A solution of 80 mg of sodium borohydride and 112 mg of sodium hydroxide in 12 ml of methanol is added drop by drop at 0°to a solution of 7α,11β-dimethylester-4-ene-3,17-dione (56) in a mixture of 18 ml of methanol and 4 ml of methylene chloride. After stirring for one hour the excess borohydride is removed by adding 12 ml of acetone, and stirred for further 15 minutes the Mixture was poured into water and extracted with ethyl acetate. The combined organic phases are washed once with saturated NaCl solution and dried, concentrated and purified on a column of silica, getting 0.74 g 57, which is accompanied by a number 3,17-diol (the latter is removed at the next stage); Rf0,40 (heptane/ethyl acetate = 6/4). NMR (CDCl3) δ: of 3.60 (t, 1, 17αN)of 0.77 (d, 3, 7αCH3), a 1.08 (d, 3, 11βCH3).

58

To a solution of 0.74 g 57 in 15 ml of methanol and 1.1 ml of triethylorthoformate add 0.2 g of para-toluensulfonate acid. The mixture is stirred for 2 hours Then add 0.1 ml of pyridine and poured into water. The product is extracted with ethyl acetate and purified chromatographically on silica gel, using as eluent a mixture of heptane/ethyl acetate and receiving of 0.59 g of 3,3-Dimethylbutane 58, Rf0,47 (heptane/ethyl acetate = 6/4); NMR, δ: 3,20 (2, 6, och3), the 3.65 (t, 1, 17αN)0,86 (C, 3, ZN3), was 0.77 (d, 3, 7αCH3), of 0.90 (d, 3, 11βCH3).

Scheme VI

p> 59

To a solution of 0.59 g of the steroid 58 in 10 ml of acetone successively added 0.6 g of N-methylmorpholin-N-oxide and 40 mg perruthenate of tetrapropylammonium. After stirring for 1 h, add 10 ml of heptane and 1 g of silicon dioxide. The mixture is stirred for another 15 min and then filtered through celite, concentrated and the residue passed through a short column with silica, getting 0.56 g 59; Rf0,55 (heptane/ethyl acetate = 6/4); NMR, δ: 0,98 (s, 3, 18 CH3), of 0.82 (d, 3, 7αCH3), to 0.92 (d, 3, 11βCH3), 3,20 (2×s, 6, och3).

60

Hexamethyldisilazide lithium receive, adding to 1.24 ml 1,55M solution of BuLi in hexane at -40°to a solution of 0.44 ml bis-trimethylsilane in 4 ml of THF. After stirring for 1/2 h add a solution of 0.56 g 59 and 0.46 ml of DMPU in 8 ml of THF. The stirring is continued for 45 min at -40°and then add 140 ál of methyliodide. After stirring for another 30 min alkylation is completed. The mixture is then poured into 40 ml of a saturated solution of NH4Cl and extracted with ethyl acetate. Chromatographic purification gives 0.55 g 16α-methylated product 60. Rf0,73 (heptane/ethyl acetate = 1/1). Rfthe initial substance 0,69; NMR, δ: 1,11 (d, 3, 16αCH3), of 1.02 (s, 3, ZN3), of 0.82 (d, 3, 7αCH3), of 0.91 (d, 3, 11βCH3).

61

Get litigation, adding a solution of 9.5 ml of 1,55M BuLi in hexane to 0,60 ml of 1,2-dibromethane is in 20 ml of THF at -60° C. After stirring for 1/2 h add a solution of 0.55 g of the ketone 60 in 2 ml of THF and clean cooling, to the mixture was gradually warmed to room temperature. Then add water and extracted the product with ethyl acetate. After chromatographic purification obtain 0.50 g 61; Rf0,22 (heptane/ethyl acetate = 9/1), Rfthe initial substance 0,42; NMR, δ: of 1.18 (d, 3, 16αCH3), of 1.02 (s, 3, ZN3), to 0.78 (d, 3, 7αCH3), were 0.94 (d, 3, 11βCH3), to 2.66 (s, 1, acetylene).

62

To a solution of 0.49 g 61 in 20 ml of ethanol is added 50 mg of oxalic acid in 3 ml of water. The mixture is stirred for 4 h, the Reaction mixture was treated with 5% aqueous sodium bicarbonate solution and the product extracted with ethyl acetate and passed through a column with silica, removing impurities and receiving 250 mg 62. Rf0,40 (heptane/ethyl acetate = 6/4), Rfthe initial substance 0,49; NMR, δ: 2,80 (m, 2, N4), to 1.19 (d, 3, 16αCH3), was 1.04 (s, 3, ZN3), of 0.82 (d, 3, 7αCH3), of 0.93 (d, 3, 11βCH3), to 2.67 (s, 1, acetylene).

63/64

To a solution of 240 mg 62 5 ml THF added 360 mg of lithium(tert-butoxy)3l. The mixture is stirred for 1 h and poured into water, the product extracted with ethyl acetate. Thus obtained isomeric alcohols separated by preparative HPLC (reversed phase C18)using a gradient of acetonitrile in water. Obtained after concentration e is enta products crystallized from a mixture of water/ethanol. This gives 68 mg 3α-hydroxy-derived 64 and 70 mg 3β-isomer 63, Rf(63/64) 0,36 (heptane/ethyl acetate = 6/4), Rfthe original substance of 0.54. TPL (63) 165-167°, TPL (64) 171-172°C. NMR (64), δ: of 3.80 (m, 1, H3), to 2.67 (s, 1, acetylene), of 1.17 (d, 3, 16αCH3), of 1.02 (s, 3, ZN3), was 0.77 (d, 3, 7αCH3), of 0.90 (d, 3, 11βCH3).

NMR (63), δ: of 4.05 (m, 1, H3), to 2.67 (s, 1, acetylene), of 1.18 (d, 3, 16αCH3), of 1.02 (s, 3, ZN3), was 0.77 (d, 3, 7αCH3), of 0.93 (d, 3, 11βCH3).

EXAMPLE 7

The compounds of this example receive under the scheme VII

Scheme VII

66

To a solution of 10 g 11α-hydroxyarginine 65 in 45 ml of DMF, add 10 g of imidazole, and then at 0°From 8.6 ml trimethylsilylpropyne. After stirring for 1 h the mixture was poured into ice water and extracted the product with ethyl acetate. The crude substance chromatographic and then triturated with heptane, getting 7,8 g 11 trimethylsilyloxy-derived 66. TPL 89-90°C, NMR, δ: 4,08 (m, 1, 11αCH3), 5,80 (s, 1H, H4), and 6.25 (m, 2, h6,7), and 0.15 (s, 9, trimethylsilyl).

67

To a solution of 5.3 g 66 and 500 mg of Cu(Oac)2in 20 ml of THF added drop by drop in -30°With 9.8 ml of 1M methylmagnesium in THF. The mixture is stirred for 1 h and poured into a solution of 6 ml of concentrated sulfuric acid in 300 ml of water and stirred over night. The product is extracted with ethyl acetate, dried and conc is t, receiving 4.8 g of solid, pure enough for further interaction. NMR, δ: of 5.85 (s, 1, H4), 3,92 (m, 1, H11α), or 0.83 (d, 3, 7αCH3), of 0.95 (s, 3, ZN3); Rf0,22 (heptane/ethyl acetate=7/3), Rfthe original substance of 0.65.

68

To a solution of 4.8 g 67 and 6.6 g of NMO (N-methylmorpholine-N-oxide) in 100 ml of acetone added 130 mg of perruthenate of tetrapropylammonium. After stirring for 2 h, add 2 g of silica gel, and then 100 ml of heptane. The mixture is stirred for another 1/2 h and filtered through celite. The filtrate is concentrated and the residue is treated with diisopropyl ether, receiving 4 grams of practically pure triona 68. NMR, δ: of 5.89 (s, 1, H4), of 0.89 (s, 3, ZN3), to 0.92 (d, 3, 7αCH3); Rf0,46 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.24.

69

A mixture of 3.5 g of the steroid 68, 1.3 ml identicial, 300 mg para-toluensulfonate acid and 35 ml of ethanol is refluxed for 1 h, the Reaction mixture was cooled to room temperature and add 80 ml of cold 0,5N NaOH. After stirring for 1 h the product was filtered and washed with cold water. After drying in vacuum at 50°To obtain 4.6 g 69; NMR, δ: to 5.66 (s, 1, H4), 3,22, and 3.38 (m, 4, thioketal) of 0.85 (s, 3, ZN3), to 0.88 (d, 3, 7αCH3); Rf0,88 (toluene/acetone = 7/3), Rfthe original substance of 0.59.

70

To a solution of 4.0 g 69 in a mixture of 100 ml methanol and 50 ml of methylene-chloride on billaut at -20° With 450 mg of NaBH4small portions. After stirring for a further 1 h the restoration completes and the reaction mixture is treated with 5 ml of acetone, and then concentrated to small volume, diluted with 100 ml of water and extracted with methylene chloride. After drying and concentration gain of 3.9 g of essentially pure 70; NMR, δ: 3,90 (m, 1, 17αN)of 0.82 (s, 3, 7αCH3), to 0.73 (s, 3, ZN3); Rf0,39 (heptane/ethyl acetate = 1/1), Rfthe original substance of 0.65.

71

A solution of 2.5 ml of tributyltinchloride in 20 ml of ether is added drop by drop to a mixture of 4.7 g of 70 and 2.6 g of imidazole in 50 ml of DMF at 0°C. After stirring for 1 h the reaction mixture was diluted with ice water and extracted the product with ethyl acetate. After drying and concentrating the organic phase, the residue triturated with 80% aqueous ethanol in a bath with ice, filtered and dried in vacuum at 50°receiving 5,2 g 71; NMR, δ: 3,76 (t, 1, 17αN)of 0.65 (s, 3, ZN3), to 0.80 (d, 3, 7αCH3), the ceiling of 5.60 (s, 1, H4); Rf0,86 (heptane/ethyl acetate = 1/1), Rfthe original substance of 0.37.

73

A suspension of 4.4 g of tert-butoxide potassium and 16.2 g of methyltriphenylphosphonium in 130 ml of toluene is heated at 100°C for 1/2 h in nitrogen atmosphere. The yellow mixture is cooled to 50°and add a solution of 4.6 g of the steroid 71 in 20 ml of toluene. The reaction mixture was stirred for further 1 h at 100°C, cooled and poured into 50 ml ice water. The product is extracted with toluene, washed, dried and concentrated. The remainder chromatographic on silica gel with toluene, removing most of the dirt. Thus obtained crude product 72 (6.3 g) was dissolved in 20 ml of THF and added dropwise a solution of 18 ml of 1M TBAF in THF. After stirring for 1/2 h the mixture is diluted with water and extracted with ethyl acetate. Thus obtained product was then purified by chromatography method, receiving 4.7g 73; TPL 177-180°C; NMR, δ: 4,77 and a 4.86 (AB, 2, methylene c H), ceiling of 5.60 (s, 1 H4), and 3.72 (m, 1, 17αH)to 0.70 (s, 3, ZN3), was 0.77 (d, 3, 7αCH3); Rf0,10 (heptane/ethyl acetate = 9/1), Rfthe initial substance to 0.73.

74

A solution of 2.45 g periodni acid in a mixture of 12 ml of water and 12 ml of methanol are added to a solution of 4.7 g 73 in 40 ml of methylene chloride. The mixture is stirred for 45 min and then diluted with water. The product is extracted with methylene chloride. The organic layer is washed several times with 5% aqueous sodium thiosulfate solution and water, then dried and concentrated. The residue is purified by way of column chromatography on silica gel, obtaining 2.6 g 74; NMR, δ: to 0.73 (s, 3, SN), of 0.79 (d, 3, 7αCH3), 5,88 (s, 1, H4), a 4.83, 4,94 (AB, 2, methylene c H), of 3.78 (m, 1, 17αN); Rf0,25 (heptane/ethyl acetate = 6/3), Rfthe original substance of 0.48.

75

A mixture of 2.6 g 74, 7 ml triethylorthoformate, 480 mg paratoluenesulfonyl acid and 50 ml of methanol is stirred at room the first temperature, monitoring the reaction by way of TLC. After 2.5 h the reaction mixture was poured into saturated aqueous NaHCO3and extracted with ethyl acetate. After drying and concentration in vacuo obtain 3.1 g of a mixture of 1/1 Δ5,6 Δ5 (10)-ketals. Rf0,46 (heptane/ethyl acetate = 6/4), Rfthe original substance of 0.25; NMR (mixture of ketals 1/1), δ: 3,15, 3,22, 3,24 (s, 6, signals for co3), 0,77, 0,87 (2×d, 3, 7αCH3), 0,65, 0,71 (2×s, 3, ZN3).

76

The crude product is dissolved in 75 60 ml of acetone. Add 3.7 g N-methylmorpholin-N-oxide and 75 mg perruthenate tetrapropyl-ammonium. The mixture is stirred for 2 h, then add 1 g of silica gel and 60 ml of heptane. After stirring for 15 min the reaction mixture was filtered through celite and the filtrate concentrated to dryness. The residue passed through a short column with silica and get 1.9 grams of ketone 76 in the form of mixtures Δ5(10) and Δ5,6-ketals; typical NMR signals when δ: 0,82, 0,93 (2×d, 3, 7αCH3), of 0.79 to 0.85 (2×s, 3, ZN3), 3,15, 3,22, of 3.25 (s, 6, signals for co3), 4,70, 4,85 and 4,87 and 4.93 (2×AB, 2, methylene c H); Rf0,58 (heptane/ethyl acetate = 6/4), Rfthe original substance of 0.45.

77

A solution of 500 mg 76 in 10 ml of THF and 0.4 ml of DMPU was added drop at -40°With 1.6 ml of a solution 1M Li-hexamethyldisilazide in 10 ml of THF. After stirring for a further 45 min add 120 ál of methyliodide. Mixing food is destroying another 1 h at -20° C and then the reaction mixture was poured into water and extracted the product with ethyl acetate. Obtained after washing, drying and concentrating the organic phase, the substance is passed through a column with silica and receive 510 mg 16α-methyl-derivative 77 in the form of a mixture of isomers on double bond; Rf0,56 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.48. NMR, δ: 1,15, 1,17 (2×d, 16αCH3).

78

Get Li-acetylide, adding one drop of 7.1 ml of 1.6 m BuLi in hexane to and 0.46 ml of 1,2-dibromethane in 10 ml of THF at -60°C. After stirring for 1/2 h add a solution of 500 mg of steroid 77 in 10 ml THF and the reaction mixture is stirred for 1/2 h, during this time the temperature rises to room temperature. Then add water and extracted the product with ethyl acetate. Thus obtained substance is passed through a short column with silica and get 540 mg, 78 in the form of a mixture of isomers on double bond. NMR, δ: 2,74 and was 2.76 (2×s, 1, acetylene), 1,17, 1,19 (2×d, 3, 16αCH3), 0,78, 0,88 (2×d, 3, 7αCH3); Rf0,50 (heptane/ethyl acetate = 7/3), Rfthe original substance of 0.60.

79

To a solution of 440 mg 78 in 20 ml of acetone add 4 ml of 4N Hcl. After stirring for 1 h the reaction is complete and the mixture was poured into saturated aqueous Panso3and extracted with ethyl acetate. After washing, drying and concentration of p is to obtain 380 mg of essentially pure 79, which is directly used in the next stage; NMR, δ: 5,88 (s, 1, H-4), 5,90 (AB, 2, methylene), was 2.76 (s, 1, acetylene), of 1.18 (d, 3, 16αCH3), to 0.88 (s, 3, 18-CH3), of 0.79 (d, 3, 7αCH3).

80

To a solution of 280 mg 79 in a mixture of 30 ml of liquid NH3and 10 ml of THF at -40°add small pieces of Li-foil, until the blue coloration of the reaction mixture will not be kept on for 15 minutes Then a slight excess Li quickly quenched by adding solid NH4Cl, and the ammonia allowed to evaporate. The remaining substance was added 100 ml of water and the mixture extracted with ethyl acetate. Selected after washing, drying and concentrating the organic substance contains almost pure 80. Rf0,57 (heptane/ethyl acetate = 6/4); NMR, δ: 4,78, 4,88 (AB, 2, methylene), 2,66 (s, 1, acetylene), to 1.19 (d, 3, 16αCH3), 0,86 (C, 3, ZN3), of 0.90 (d, 3, 7αCH3).

81

To a solution of 160 mg 80 in 10 ml of THF was added when 0°With small portions LiAlH4until the end of the reaction. Then add 0.1 ml of saturated aqueous Na2SO4and then a certain amount of solid Na2SO4. The mixture is stirred for 15 min and then filtered through celite. The filtrate is concentrated and the residue is purified by passing through preparative HPLC column reversed-phase C-18 silica using as eluent a mixture of acetonitrile-water and getting 55 the g 81, TPL 198-199°S; Rf0,33 (heptane/ethyl acetate = 6/4), Rfthe original substance of 0.57. NMR, δ: to 3.67 (m, 1, 3αN), 4,70, 4,82 (AB, 2, methylene), 2,65 (s, 1, acetylene), of 1.18 (d, 3, 16αCH3), or 0.83 (s, 3, ZN3), to 0.89 (d, 3, 7αCH3).

EXAMPLE 8

Join explore on their activity to the estrogen receptors in tests on linking and tests for transactivation.

The definition of competitive binding to the cytoplasmic estrogen receptor human of recombinant cells SNO is used to estimate the relative affinity ratio (strength) of the studied compounds to the estrogen receptors present in the cytosol of recombinant cells Chinese hamster ovary (Cho constantly transfinitely with estrogen receptor human, compared with estradiol (E2). The cytosol obtained from recombinant cells SNO, constantly transfinitely with estrogen receptor of human rights. Cell line obtained at the Department of Biotechnology and Biochemistry (air force) (N.V.Organon) and known as the SNO-ER (2B1). Comparative connections are ethinyl estradiol and estriol.

Antiestrogenic activity of compounds is determined in biological studies in vitro with recombinant cells Chinese hamster ovary (Cho constantly atransferrinemia with α (hERαor β (hRβ) estrogen receptor of human rights, the promoter oxido the Sina rats (RO) and luciferase reporter gene (LUC). Antiestrogenic activity (the ratio of force) of the investigated compounds on the inhibition of TRANS-activation of the enzyme luciferase via estrogen receptor estrogen Org 2317 (estradiol, 1,3,5(10)-estratrien-3,17β-diol) compare with standard Org 34790 (ICI 164.384; (7α,17β)-N-butyl-3,17-dihydroxy-N-methylestra-1,3,5(10)-triene-7-undecane-amide).

The studied environment: whole recombinant cells SNO, constantly atransferrinemia with estrogen receptor human promoter oxitocina rats and luciferase reporter gene. Cell line produced at the Department of Biotechnology and Biochemistry (air force) (N.V.Organon) and known under the name CHO-ERRO 2B1-1E9.

The results are presented below in table 1. Data are expressed as percentages from the comparative effect of the compounds in this study.

TABLE 1
Connectionαbindingα-transactivationβbindingβ-transactivation
1157581,10,8
1535270,30,3
218,67,70,20,1
31379,6 0,10,2
322,62,4<0,10,1
422920,1<0,04
4311,91,30,1<0,1
5427,529,70,11,0
553661,50,11,9
6325220,40,1
6435290,20,2
81n.t.r.27n.t.r.0,1
n.t.r.: no results found

1. Nah estrogenic steroid of General formula I

in which R1denotes H, (C1-C3)alkyl, (C2-C3)acyl;

R2denotes H, α-(C1-C4)alkyl, α-(C2-C4) alkenyl, α-(C2-C4)quinil;

R3represents H or (C1-C4) alkyl in position 16 of the steroid skeleton;

R4denotes ethinyl;

R5represents H or (C1-C3)alkyl, (C2-C3)the cylinder;

R6means (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)quinil, each of which can be substituted by chlorine or fluorine,

the dotted line indicates an optional double bond.

2. Nah estrogenic steroid according to claim 1, wherein R1denotes H; R2denotes H; R3denotes H, 16α-methyl or 16α-ethyl; R4denotes ethinyl; R5denotes H; R6denotes propenyl, allyl or butenyl.

3. Pharmaceutical composition having anti-estrogenic activity, including steroid compound according to any one of the preceding paragraphs and pharmaceutically acceptable adjuvants.

4. Steroid compound according to any one of claims 1 to 3 in the manufacture of a pharmaceutical composition having anti-estrogenic activity.



 

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The invention relates to compounds of General formula I in the form 22R and 22S-ephemerol, where X1and X2are the same or different and each represents a hydrogen atom or a fluorine atom, provided that X1and X2at the same time are not hydrogen atoms; methods for their preparation; pharmaceutical preparations containing them; and the use of these compounds in the treatment of inflammatory and allergic diseases

The invention relates to methods for furostanol glycosides from plant material with antioxidant activity in comparison with structural analogue with similar biological properties, and thereby expands the Arsenal of tools that can be used in medicine as a therapeutic agent

The invention relates to new steroid of General formula I, which manifest themselves as effective antagonists progestins and as mixed or partial agonists progestin

where

R1- (R2R3N(O)r)-, where r=0, 1, each of R2and R3independently - H, C1-6alkyl; or R1-

where q=0, - 1, Y-(CH2)m-, where m=1, 2, 3, 4, 5; or

R1- C1-6alkyl-CO-; R12Is n; X Is O or

,

where -(CH2)m-, where m=2; R6=H; R7=H, C1-6alkyl, C2-6alkenyl,2-6quinil, perhaps HE or substituted BASED; S=0, 1; each of the8and R9independently - H, HE, C1-6alkyl, R10CO., where R10’- H, C1-6alkyl

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The invention relates to labeled steroids, specifically to vysokomernoa tritium-hydroxyestra-1,3,5(10)-triene-17-huili-östra-1,3,5(10)-triene-3,17-diolo General formula I, where R = 0 or R = -HE

The invention relates to an improved method of obtaining on-arilpirolii acids of the formula ArOCH2COOH

The invention relates to an improved method of obtaining a known anti-inflammatory agents - furoate mometasone (I)
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