17-deformation-estratriene, the compounds and method of production thereof

 

(57) Abstract:

Describes the new connection - 17-deformation-estratriene General formula I, where R1denotes a hydrogen atom or a C1-C10-alkyl; R5denotes methyl or ethyl; R2denotes a hydrogen atom or a C1-C10-alkyl - or-position; R3denotes a hydrogen atom or a C1-C10-alkyloxy in - or-position; R4denotes a hydrogen atom in the or position; a, b, D, E and G represent each a hydrogen atom and, if necessary, additionally at least one of the pairs of substituents G and R2, R2and R4, R4and And And and R3, D and E represents a double bond. The compounds exhibit antioxidant and vascular protective properties and may therefore find use for the treatment and prevention of various diseases.

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3 S. and 9 C.p. f-crystals, 2 ill., table 1.

The invention relates to 17-deformation-estratriene, to a method for their production and to their use for pharmaceutical products (medicines).

17-deformation-estratriene according to this invention are distinguished General formula I:

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where R1denotes a hydrogen atom ilet a hydrogen atom or or - a permanent group C1-C10-alkyl,

R3denotes a hydrogen atom or - or - a permanent group WITH1-C10-alkyloxy,

R4means or constant hydrogen atom, and A, B, D, E and G each represent a hydrogen atom, and, if necessary, optionally, at least one of the pairs of substituents G and R2, R2and R4, R4and And And and R3, And D, D and E represents a double bond.

The invention relates preferably to compounds of General formula I,

where

R1denotes a hydrogen atom or a group1-C10-alkyl,

R5denotes methyl or italgroup, and

A, B, D, E, G, R2and R3denote a hydrogen atom and R4means or constant hydrogen atom, or R2with R4, R4with a, And R3B c D, D E or G with R2designate an additional bond and the other of these substituents represent hydrogen atom, or

R2means a permanent group WITH1-C10-alkyl, and in this case a, b, D, E, G, R3and R4represent respectively a hydrogen atom, or

R3means a permanent group WITH1-C10-alkyloxy, and in this case a, b, D, E,R3if they are1-C10-Alila or alkoxy, then we are talking about the rest of methyl, ethyl, n-propyl, isopropyl, n-butyl, ISO-butyl or tert.- butyl or higher straight or branched homologues or in the case of R3on the relevant alkoxylate. It is preferable for the remainder of the methyl or methoxy. For R1preferred is a hydrogen atom.

For R5first of all , we are talking about the methyl group.

Also preferred are compounds of General formula 1, where a, b, D, E, G, R2, R3and R4represent hydrogen atoms, or where a, b, D, E, R3and R4represent hydrogen atoms, and G with R2designate an additional bond.

According to the invention particularly preferred are the following named compounds:

17-deformation-östra-1,3,5 (10) -triene-3-ol,

17-deformation-östra-1,3,5 (10)6-tetraen-3-ol,

17-deformation-11-methoxy-östra-1,3,5(10)-triene-3-ol,

17-deformation-östra-1,3,5(10),7-tetraen-3-ol,

17-deformation-östra-1,3,5(10),8-tetraen-3-ol,

17-deformation-östra-1,3,5(10),9(11)-tetraen-3-ol,

17-deformation-3-methoxy-östra-1,3,5(10),15-tetraen,

17-DIN-8-östra-1,3,5(10)-triene-3-ol,

17-deformation-3-methoxy-18-methyl-östra-1,3,5(10) -triene,

17-deformation-18-methyl-östra-1,3,5(10)-triene-3-ol.

The connection closest to the data of the compounds according to the structure described in EP-A 0 320 438 and are 17-monohalogenated-estratriene.

Famous 17-halogenmethyl-estratriene show less affinity for estrogen receptors, as estradiol, and cause compared with estradiol increased permeability of the membranes of cells and blood/lymphatic vessels. Therefore, these compounds are especially suitable for the treatment of phenomena that appear in the second period of action of estradiol (climacteric complaints).

New 17-deformation-estratriene according to the invention show a new, totally unexpected, so far not described for the aforementioned 17-monohalogenated-estratriene and other steroids pharmacological properties.

17-deformation-estratriene we are talking about a very weak estrogen, as you can install using the standard communication studies on the estrogen receptor and the test transactionware, in which 17--estradiol served as comparative substance (M. T. Bocquel, etc., Nucleic Acid Research 17: 2571-95; S. Green and others, Nucleic Acid R is ilen-estratriene have unexpectedly antioxidant and vascular protective properties and are used therefore for the treatment and prevention of various diseases (e.g.Siegfried and others, JPET 260: 668, 1992; Chao and others, J. Immunol. 149:2736, 1992; Corbett & Mc Daniel, Diabetes, 41:897, 1992; Siminiak, etc., Intl.J.Cardiol.,45:171, 1994).

To characterize compounds with putative antioxidant and vascular protective properties were attracted by different test methods, the results of which allow us to conclude whether the tested compounds antioxidant and vascular protective properties.

Antioxidant and vascular protective properties of new compounds are based on direct action in the prevention of LDL oxidation, and the indirect effect due to the release of the vasodilator nitric oxide (NO) from endothelial cells.

Experimental methods and results LDL-oxidation (low density lipoprotein)

Since oxidative modification of lipoproteins may represent a genetic factor in the development of arteriosclerosis (Steinberq etc., N. EnqI.J. Med. 320:915, 1989; Esterbauer and other Free Radical Bioloqy & Medicine 13:341, 1992), compounds of General formula I were investigated for their ability to affect the oxidation of LDL' (low density lipoprotein). To determine the antioxidant capacity of the compounds of General formula I, was developed analysis, which is based on the methods Lead (J. Lipid Res. induced by ions of copper oxidation.

Human LDL was ordered in Orqanon Teknika, Rockville M. D. It was diluted free Ca - and Mq-ions PBS (phosphate buffer solution) to a protein concentration of 0.5 mg/ml and to remove EDTA (ethylenediaminetetraacetic acid) before oxidation, spent dialysis relative to this buffer solution at 4oC.

In this case, oxidized LDL by the addition of 10 μm of copper sulfate with subsequent incubation at 37oC in a water bath, in Eppendorf vessel. The test compound dissolved in DMSO (dimethyl sulfoxide) was added in a final volume of 1%. The oxidation was stopped by addition of 1 mm EDTA. The samples were kept up to FPLC analysis (fast-acting liquid chromatography protein) at 4oC. it Was found that the chromatographic behavior of oxidized LDL' more than one week remains constant.

FPLC analysis

Samples (0.1 ml to 0.5 mg LDL protein) were analyzed on a 1 ml Q - supersecret (Hi-Trap Q, pharmacy). The absorbance was measured continuously at 280 nm and integrated peaks for quantization.

The initial buffer solution (buffer solution) consisted of 10 mm Tris-HCl, pH 7.5 with 1 mm EDTA. Under these conditions, LDL fully connected column. Elution was performed with a stepwise gradient of buffer solution B (b is 3 M salt), fraction (0.4 M salt), fraction D (0.5 M salt) and fraction E (0.6 M salt).

Unmodified bought LDL behaves a little unevenly. It completely elute in fractions of A+C. during the incubation period always modify LDL stronger, so that elute it with higher concentrations of salt. During the first hour incubation with copper found part of the protein in fraction C. After 3-4 hours almost completely suirable protein in fractions C and D. After 24 hours, all proteins were transformed into a form or forms which have suirable in fractions of D+E.

Oxidation of LDL is determined by the rate of oxidation.

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The oxidation induced by copper within 3-4 hours, was found in the region of 60-90% for LDL, not processed substance of General formula 1. Only rarely observed lower rate of oxidation. All of the experiments, which were reached oxidation under positive control at least 60%, did not take into account. Supplement 1 mm EDTA during incubation with copper (negative control) prevented the changes in LDL mobility chromatography (oxidation factor of 0%).

Action 17-deformation-estratriene on due to the copper LDL oxidation showed the op perate, than 17-deformation-estratriene).

2. Vasorelaxation on isolated rat aorta

Removed the aorta Spraque-Daweley-rats, male, freed from any adhering fat and connective tissue and cut into rings of size 2 mm, the Endothelium was mechanically removed from the internal surfaces of vessels several rings of aorta. Rings were suspended separately in 10 ml of solutions of bodies at 37oC, which contained a solution of Krebs-Henseleit (S) having a pH of 7.4, if it is saturated with 95% O2and 5% CO2. Before the beginning of the experiment, the tissue was equilibrial 90 minutes under 1 g tension. Isometric tension was measured using a "power Converter" (Grass FT03C) and recorded on a recorder (Gould TA 5000). All tissues were drawn using KCl (30 mm) and then was three times washed in fresh Krebs solution-Henseleit (KHS).Vascular rings were pulled together or with 30 mm KCl or with 100 nm of phenylephrine (PE). To verify the presence or absence of endothelium, the tissue was added to 1 μm acetylcholine (Ach). Curves of the concentration-relaxation for 17-estradiol and 17-deformation-11-methoxy-östra-1,3,5(10), 6-tetraen-3-ol (compound A) was obtained by cumulative accession of the test substance in a semi-log components to eticheski in Fig.1 and 2. While E denotes the endothelium and + or - indicates the fabric with (+) or without (-) endothelium.

Summing up, we can establish that the new 17-deformation-estratriene on isolated rat aorta causes the relaxation of smooth muscles; in contrast, 17-estradiol, which has a relaxing effect on the aorta regardless of the endothelium, new connections, induce vasorelaxation thanks to the release of NO from the endothelium.

These results of pharmacological tests show that the compounds of General formula I have a vascular-protective properties, as:

vascular relaxation protects the blood vessels from the effects of increasing local (vasospasm in coronary and cerebral arteries) or General (e.g., hypertension) muscle tone of smooth muscles;

- the release of NO from the endothelium leads to vascular relaxation (Furchqott & Zawadski, Nature 288:373, 1980), prevents platelet aggregation (Radomcki and others,Lancet 2:1057, 1987) and inhibits the migration of leukocytes to the vessel wall (Chao and others, J. lmmunol., 149:2736, 1992).

The antioxidant properties of the compounds can prevent vascular damage by free radicals, which have been caused by activated leukocytes (polimorfnogo and its progression (Steinberq and others, N. Engl.J.Med. 320:915, 1989).

Based on these unexpected pharmacological properties the new compounds according to the invention of General formula I are used for the prevention and treatment of, in particular, the following diseases: atherosclerosis, hypertension, vasospasm (coronary and cerebral), diabetic vasculopathy (e.g., neuropathy, nephropathy, retinopathy), ischemia of the heart and brain, myocardial infarction, stroke, reperfusion syndrome after ischemia (heart, brain, and so on ), inflammation, rheumatoid arthritis, bronchial asthma, kidney disease (e.g. , glomerulonephritis, neurodegenerative diseases (e.g., Alzheimer's disease).

These actions were not documented for 17 - halogenmethyl-estratriene and represent a completely new and unexpected possibilities in the prevention and treatment of the aforementioned diseases.

The invention relates also to pharmaceutical preparations which contain compounds of General formula I.

The use depends on the application.

For oral use, for example, use the form of tablets, capsules, soft gelatin shell, which contain the solutions used in soft gelatin capsules, water is taralom the use of compounds of General formula I can be used in the form of a depot injection, implants or muscle, subcutaneous and intravenous injections.

Obtaining pharmaceutical preparations which contain compounds of General formula I, is carried out with the known from the prior art methods (literary source). Pharmaceuticals were supposed to contain 17-deformation-estratriene in the concentration of the active substance is 0.1-100 mg/kg/day. The corresponding concentration of the active substance depends on the disease, which is treated, or the severity of the corresponding disease.

The invention relates also to method of obtaining compounds of General formula I. They receive according to the invention by the interaction of the 17-keto-compounds of General formula II.

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where R1'means hydroxyamino group and a, b, D, E, G, R2, R3, R4and R5are specified in the formula I is, with deformity-diphenyl-phosphine oxide or diethyl-(deformity)phosphonate in the presence of a strong base in an aprotic solvent at a temperature of phlegmy 50-100oC, then, if necessary, 3-hydroxyamino group otscheplaut under the action of acid, and optionally 3-hydroxyamino group atrificial.

3-hidroxizina group R1'is, or easy group silila with three of the same, the same two or three different residues WITH1-C4-alkyl and/or aryl straight or branched chain, such as, for example, a group of trimethyl, tert.-butultimately, methylbiphenyl or tert. -butylphenylmethyl or a methyl group (R1=R1'=CH3), which, of course, can be removed only under specific conditions.

As strong bases according to the invention take into account sitedisability, sodium hydride, tert.-butyl potassium, utility etc.

The interaction of the ketone of General formula II is carried out in an aprotic solvent, such as tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dioxane or mixtures of these solvents.

The reaction temperature should be preferably between 50oC and 100oC.

Conditions for removal of 3-hydroxyamino group depends on its nature: protective groups, as TNR group or the residue silila, you can delete under the action of weak acids as oxalic acid, or acidic ion exchanger, while the methyl group can be split as a result of strong Lewis acids, for example, hydride dibutylamine.

The etherification of the free 3-hydroxy groups is imich to differmaterially 17-ketones-protected 3-hydroxypoly carry out the corresponding interaction, known 3-hydroxycodone with dihydropyrano under the influence of para-toluenesulfonic acid in tetrahydrofuran or other well-known specialist methods for protecting hydroxy groups.

The following examples serve for a more detailed explanation of this invention, without limiting it.

EXAMPLE 1

17-deformation-östra-1,3,5(10)-triene-3-ol

757 mg nitric-oxide deformity-diphenyl-phosphine (M. L. Edwards and other Tetrahedron Letters page 5571, 1990) in 38 ml of tetrahydrofuran is slowly mixed at -50oC with 1.5 ml of 2-molar solution of liedeseplein, stirred for 1 hour, mixed with a solution of 1.06 g of 3-tetrahydropyranyloxy-östra-1,3,5(10)-triene-17-she's in 11 ml of tetrahydrofuran. 15 minutes, stirred at -50oC, left to return to room temperature and stirred for 3.5 hours at a temperature of 80 solutionoC. For processing add water, three times extracted with acetic ether, washed organic phase to neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum to dryness. Obtain 1.3 g of crude 17-deformation - 3-(tetrahydro-Piran-2-yl-oxy)-östra-1,3,5 (10)-triens.

1.3 g of crude 17-deformation-3-(tetrahydro-Piran-2-yl-oxy) östra-1,3,5(10)-triens with the UP>oC. Then add water, extracted three times with dichloromethane, washed until neutral, dried over sodium sulfate and concentrated in vacuum to dryness. Obtain 1.0 g of crude 17-deformation-östra-1,3,5(10)-triene-3-ol, which chromatographic on silica gel with hexane/acetic ether. Obtain 480 mg of pure 17-deformation-östra-1,3,5 (10)-triene-3-ol in the form of colorless crystals with a melting point of 154-156oC.

EXAMPLE 2

17-deformation-östra-1,3,5(10),6-tetraen-3-ol

a) 3-tetrahydropyranyloxy-östra-1,3,5(10), 6-tetraen-17-he

A suspension of 2.6 g of 3-hydroxy-östra-1,3,5(10), 6-tetraen-17-she's in 26 ml of tetrahydrofuran and 2.6 ml dihydropyran mix from 12.3 mg of para-toluenesulfonic acid for 3 hours at room temperature. Then dilute acetic ether, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. Obtain 3.0 g of 3-tetrahydropyranyloxy-östra-1,3,5(10), 6-tetraen-17-it is in the form of colorless crystals.

b) 17-deformation-3-tetrahydropyranyloxy-östra-1, 3, 5 (10), 6-tetraen

A solution of 715 mg oxide diftormetilirovaniya in 36 ml of tetrahydrofuran is slowly mixed at a temperature of -50 solutionoC of 1.42 ml of 2-solaranlage-östra-1,3,5 (10),6-tetraen-17-she's in 10 ml of tetrahydrofuran, 15 minute mix, slowly heated when the temperature of the solution from -50oC to 100oC and boiled for 2.5 hours under reflux. To process, water is added, extracted with acetic ether, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. Obtain 1.1 g of 17-deformation-3-tetrahydropyranyl-hydroxy-östra-1,3,5(10), 6-tetraene in the form of colorless crystals.

C) 17-deformation-östra-1,3,5(10),6-tetraen-3-ol

A suspension of 1.1 g of 17-deformation-3-tetrahydropyranyloxy-östra-1,3,5 (10), 6-tetraene in 25 ml of methanol and 2.5 ml of water is refluxed with 1.1 mg of oxalic acid for 1.5 hours at the temperature of the solution 100oC. Then, water is added, extracted with dichloromethane, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether. Obtain 0.6 g of 17 - deformation-östra-1,3,5 (10), 6-tetraen-3-ol in the form of colourless crystals with a melting point 132-134oC []2D2=- 167,9oC (=worn: 0.505% in pyridine).

EXAMPLE 3

17-deformation-11-methoxy-östra-1,3,5 (10)-triene-3-ol

a) 11-methoxy-3-Tetra in 20 ml of toluene, 5 ml of tetrahydrofuran and 3.0 ml dihydropyran mixed with 20 mg of para-toluenesulfonic acid 24 hours at room temperature. Then add 0.5 ml of pyridine, diluted with acetic ether, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone. Get 1,9 g 11-methoxy-3-tetrahydropyranyloxy-östra-1,3,5(10)-triene-17-it is in the form of colorless crystals with a melting point of 147oC []2D2=+to 147.2o(C=0.5% in pyridine).

b)17-deformation-11-methoxy-3-tetrahydropyranyloxy-östra-1,3,5(10)-triene.

A solution of 3 g of oxide diftormetilirovaniya in 80 ml of tetrahydrofuran at a temperature of -50 solutionoC slowly mix from 5.85 ml of 2-molar solution of sitedisability and stirred for 1 hour. Then slowly add a solution of 1.8 g of 11 - methoxy-3-tetrahydropyranyloxy-östra-1,3,5(10)-triene-17 - she's in 40 ml of tetrahydrofuran, stirred for 15 minutes, slowly heated under -50oC until the solution temperature 100oC and boiled for 2.5 hours under reflux. For treatment of dilute acetic ether and water, sucked off celite, optionally washed with acetic the IU and chromatographic on silica gel with hexane/acetic ether/triethylamine. Obtain 1.3 g of 17 - deformation-11-methoxy-3-tetrahydropyranyloxy-östra-1,3,5(10)- triens with a melting point of 124-125oC []2D2=+60,0o(=worn: 0.505% in pyridine).

b) 17-deformation-11-methoxy-östra-1,3,5(10)-triene-3-ol

A suspension of 1.2 g of 17-deformation-11-methoxy-3 - tetrahydropyranyloxy-östra-1,3,5(10)-triens in 25 ml of methanol and 2.6 ml of water is refluxed with 1.2 g of oxalic acid 0.5 hour at a temperature of solution 100oC. Then concentrated in vacuo, diluted with acetic ether, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone. After crystallization from hexane obtain 0.9 g of 17-deformation-11-methoxy-östra-1,3,5(10)-triene-3-ol in the form of colourless crystals with a melting point 245-247oC = []2D2+77,3o(C=0,535% in pyridine).

EXAMPLE 4

17-deformation-östra-1,3,5(10),7-tetraen-3-ol

a) 3-tetrahydropyranyloxy-östra-1,3,5(10),7-tetraen-17-he

A suspension of 2.0 g of 3-hydroxy-östra-1, 3,5(10),7-tetraen-17-she's in 20 ml of tetrahydrofuran and 2.0 ml dihydropyran mixed with 9.6 mg of para-toluenesulfonic acid 24 hours at room Teya and a saturated solution of sodium chloride, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone. Gain of 1.9 g of 3-tetrahydropyranyloxy-östra-1,3,5(10), 7-tetraen-17-it is in the form of colorless crystals with a melting point 147-149oC []2D2= + 209,7 (C=0.5% in pyridine).

b) 17-deformation-3-tetrahydropyranyloxy-östra-1,3,5 (10),7-tetraen

A solution of 3 g of oxide diftormetilirovaniya 85 mm tetrahydrofuran at a temperature of -50 solutionoC slowly mixed with 6 ml of 2-molar solution of sitedisability and stirred for 1 hour. Then slowly add a solution of 1.7 g of 3-tetrahydropyranyloxy-östra-1,3,5(10),7-tetraen-17-she's in 42 ml of tetrahydrofuran, stirred for 15 minutes, slowly heated from -50oC to 100oC solution temperature and boiled for 2.5 hours under reflux. For treatment of dilute acetic ether and water, sucked off celite, optionally washed with acetic ether and a saturated solution of sodium chloride, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether/triethylamine. Obtain 1.0 g of 17 - deformation-3-tetrahydropyranyloxy-östra-1,3,5(10), 7 - tetraene in the form of colorless crystals with a melting point of 83 etrain-3-ol

Suspension 950 mg 17-deformation-3-tetrahydropyranyloxy-östra-1,3,5(10), 7-tetraene in 20 ml of methanol and 2.0 ml of water is heated under the phlegm with 950 mg of oxalic acid 0.5 hour at a temperature of solution 100oC. Then concentrated in vacuo, diluted with acetic ether, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether. Obtain 0.6 g of 17-deformation-östra - 1,3,5(10)7-tetraen-3-ol in the form of colourless crystals with a melting point 126-129oC []2D2= +of 163.7o(=worn: 0.505% in pyridine).

EXAMPLE 5

17-deformation-östra-1,3,5(10),8-tetraen-3-ol

a) 3-tetrahydropyranyloxy-östra-1,3,5(10),8-tetraen-17-he

A suspension of 2.0 g of 3-hydroxy-östra-1,3,5(10), 8-tetraen-17-she's in 20 ml of tetrahydrofuran and 2.0 ml dihydropyran mix from 9.4 mg of para-toluenesulfonic acid for 3 hours at room temperature. Then add 0.3 ml of pyridine, diluted with acetic ether, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone/triethylamine. Obtain 2.4 g of 3-TC []2D2=+0,00o(C=0,515% in pyridine).

b) 17-deformation-3-tetrahydropyranyloxy-östra-1,3,5 (10),8-tetraen

A solution of 2.7 g of oxide diftormetilirovaniya in 85 ml of tetrahydrofuran is slowly mixed at a temperature of -50 solutionoC with 5.3 ml of 2-molar solution of sitedisability and 1 hour mix. Then slowly add a solution of 1.5 g of 3 - tetrahydropyranyloxy-östra-1,3,5 (10),8-tetraen-17-she's in 42 ml of tetrahydrofuran, stirred for 15 minutes, slowly heated when the temperature of the solution from -50oC to 100oC and boiled for 2.5 hours under reflux. For treatment of dilute acetic ether and water, washed with water, dried over sodium sulfate, concentrated in vacuum, chromatographic on silica gel with hexane/acetic ether. Obtain 1.0 g of 17-deformation-3-tetrahydropyranyloxy - östra-1,3,5 (10), 8-tetraene in the form of colorless crystals with a melting point of 124-125oC []2D2= + 2,0 (C=0,525% in pyridine).

C) 17-deformation-östra-1,3,5 (10),8-tetraen-3-ol

Suspension 927 mg 17-deformation-3-tetrahydropyranyloxy-östra-1,3,5(10),8-tetraene in 20 ml of methanol and 2.0 ml of water is boiled with 950 mg of oxalic acid under reflux for 0.5 hours at a temperature of solution 100is bonate sodium and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. After crystallization from hexane receive 0.5 g 17-deformation - östra-1,3,5(10), 8-tetraen-3-ol in the form of colorless crystals with a melting point of 127-128oC []2D2=-1,5o(C=0,515% in pyridine).

EXAMPLE 6

17-deformation-östra-1,3,5(10),9(11)-tetraen-3-ol

a) 3-tetrahydropyranyloxy-östra-1,3,5(10),9(11)-tetraen-17-he

A suspension of 2.0 g of 3-hydroxy-östra-1,3,5(10),9(11)-tetraen-17-she's in 20 ml of tetrahydrofuran and 3.0 ml dihydropyran mixed with 15 mg of para-toluenesulfonic acid 29 hours at room temperature. Then add 0.3 ml of pyridine, diluted with acetic ether, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/ acetone/triethylamine. Obtain 2.3 g of 3-tetrahydropyranyloxy-östra-1,3,5(10), 9(11)-tetraen-17-it is in the form of a colourless oil []2D2= +122,5o(C=0,515% in pyridine).

b) 17-deformation-3-tetrahydropyranyloxy-östra-1,3,5 (10),9(11)-tetraen

A solution of 3.85 g of diftormetilirovaniya in 107 ml of tetrahydrofuran is slowly mixed at a temperature of -50 solutionoC from 7.6 ml of 2-molar, Rassi-östra-1,3,5(10),9(11)-tetraen-17-she's in 42 ml of tetrahydrofuran, stirred for 15 minutes, slowly heated when the temperature of the solution from -50oC to 100oC and boiled for 2.5 hours under reflux. For treatment of dilute acetic ether and water, sucked off celite, optionally washed with acetic ether, water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether/triethylamine. Obtain 1.0 g of 17-deformation-3-tetrahydropyranyloxy-östra- 1,3,5(10), 9(11)-tetraene in the form of a colourless oil []2D2= +52,6o(C=0.5% in pyridine).

C) 17-deformation-östra-1,3,5(10),9(11)-tetraen-3-ol

A suspension of 900 mg 17-deformation 3 tetrahydropyranyloxy-östra-1,3,5(10),9(11)-tetraene in 19 ml of methanol and 1.9 ml of water is boiled with 900 mg of oxalic acid 0.5 hours under reflux at a temperature of solution 100oC. Then concentrated in vacuo, diluted with acetic ether, washed three times with water, once with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether. After crystallization from hexane receive 0.5 g 17-deformation-östra- 1,3,5(10),9(11-tetr 0,515% in pyridine).

EXAMPLE 7

17-deformation-3-methoxy-östra-1,3,5(10),15-tetraen

A solution of 9.4 g of diethyl-(deformity)phosphonate in 150 ml of tetrahydrofuran is slowly admixed with the solution temperature -50oC to 25 ml of 2-molar solution of sitedisability and stirred for 1 hour. Then slowly add a solution of 5.6 g of 3-methoxy-östra-1,3,5(10),15-tetraen-17-she's in 173 ml of tetrahydrofuran, stirred for 15 minutes, slowly heated when the temperature of the solution from -50oC to 100oC and refluxed for 6 hours. To handle concentrated in vacuo to half volume, diluted with acetic ether, washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether/triethylamine. Obtain 3.0 g of 17-deformation-3-methoxy - östra-1,3,5(10), 15-tetraene in the form of colorless crystals with a melting point of 122-123oC []2D2=-120,9o(C=0,515% in pyridine).

EXAMPLE 8

17-deformation-östra-1,3,5(10),15-tetraen-3-ol

A solution of 2.4 g of 17-deformation-3-methoxy-östra-1,3,5 (10), 15-tetraene in 49 ml of toluene is refluxed with 49 ml of a 1.6 molar solution of diisobutylaluminium in toluene for 1 hour at tewalt to 400 ml of 2-normal sulfuric acid, stirred for 1 hour at room temperature, three times extracted with acetic ether, washed the organic phase with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether. Get 1,37 g 17 - deformation-östra-1,3,5(10), 15-tetraen-3-ol in the form of colorless crystals with a melting point of 126-127oC []2D2= -120,4 (=worn: 0.505% in pyridine).

EXAMPLE 9

17-deformation-7-methyl-östra-1,3,5(10)-triene-3-ol

a) 7-methyl-3-tetrahydropyranyloxy-östra-1,3,5(10)-triene-17-one

A suspension of 1.2 g of 3-hydroxy-7-methyl-östra-1,3,5 (10) -triene-17-she's in 12 ml of toluene and 1.2 ml dihydropyran mixed with 5.6 mg of para-toluenesulfonic acid for 2 hours at room temperature. Then dilute acetic ether, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone. Obtain 1.22 g of 7-methyl - 3-tetrahydropyranyloxy-östra-1,3,5(10)-triene-17-it.

b) 17-deformation-7-methyl-3-tetrahydropyranyloxy - östra-1,3,5(10)-triene

A solution of 2 g of oxide diftormetilirovaniya in 55 ml of tetrahydrofuran at temperatues. Then add a solution of 1.15 g of 7-methyl-3-tetrahydropyranyloxy-östra-1,3,5(10)-triene-17-she's in 20 ml of tetrahydrofuran, is slowly stirred for 15 minutes, slowly heated when the temperature of the solution from -50oC to 100oC and refluxed for 2.5 hours. For treatment of dilute acetic ether and water, sucked off celite, optionally washed with acetic ether, washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether/triethylamine. Obtain 1.3 g of the substance in the form of colorless crystals with a melting point of 85-86oC []2D2=-59,4o(C= 0,535% in pyridine).

C) 17-deformation-7-methyl-östra-1,3,5(10)-triene - 3-ol

A suspension of 1.2 g of 17-deformation-7-methyl-3 - tetrahydropyranyloxy-östra-1,3,5(10)-triens in 25 ml of methanol and 2.5 ml of water is refluxed with 1.2 g of oxalic acid for 1 hour at the temperature of the solution 100oC. Then concentrated in vacuo, diluted with acetic ether, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone is different crystals with a melting point of 119-120oC []2D2=-10,6o(C=0.5% in pyridine).

EXAMPLE 10

17-deformation-8 östra-1,3,5(10)-triene-3-ol

a) 3-tetrahydropyranyloxy-8 östra-1,3,5(10)- triene-17-one

A suspension of 2.0 g of 3-hydroxy-8 östra-1,3,5(10)-triene-17-she's in 20 ml of tetrahydrofuran and 2.0 ml dihydropyran mixed with 15 mg of para-toluenesulfonic acid 24 hours at room temperature. Then add 0.3 ml of pyridine, diluted with acetic ether, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetone. Obtain 2.2 g of 3-tetrahydropyranyloxy - 8-östra-1,3,5(10)-triene-17-it is in the form of colorless crystals with a melting point of 153 to 155oC []2D2= +47,5 (C=0.53% in pyridine).

b) 17-deformation-3-tetrahydropyranyloxy-8-extra-1,3,5(10)-triene

A solution of 3.5 g of oxide diftormetilirovaniya in 100 ml of tetrahydrofuran, admixed with the solution temperature from -50oC slowly to 7 ml of 2-molar solution of sitedisability and stirred for 1 hour. Then slowly add a solution of 2 g of 3-tetrahydropyranyloxy-8-östra-1,3,5(10)-triene-17-she's in 50 ml of tetrahydrofuran, stirred for 15 minutes, slowly nagrody dilute acetic ether and water, suck on celite, optionally washed with acetic ether, washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether/triethylamine. Obtain 1.3 g of 17-deformation-3-tetrahydropyranyloxy-8-östra-1,3,5 (10)-triens in the form of colourless crystals with a melting point 90-91oC []2D2= 9.2 pero(c=0.5% in pyridine).

C) 17-deformation-8-östra-1,3,5(10)-triene-3-ol

A suspension of 1.2 g of 17-deformation-3-tetrahydropyranyloxy-8-östra-1,3,5(10)-triens in 25 ml of methanol and 2.5 ml of water is refluxed with 1.2 mg of oxalic acid 0.5 hour at a temperature of solution 100oC. Then concentrated in vacuo, diluted with acetic ether, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether. Obtain 0.9 g of 17 - deformation-8-östra-1,3,5(10)-triene-3-ol in the form of colorless crystals with a melting point of 119-120oC []2D2=-10,6 (C=0.5% in pyridine).

EXAMPLE 11

17-deformation-3-methoxy-18-methyl-östra-1,3,5(10)-triene

A Solution Of 9.4 P>C with 25 ml of 2-molar solution of sitedisability and stirred for 1 hour. Then slowly add a solution of 6 g of 3-methoxy-18-methyl-östra-1,3,5 (10)-triene-17-she's in 173 ml of tetrahydrofuran, stirred for 15 minutes, slowly heated when the temperature of the solution from -50o100oC and refluxed for 6 hours. For treatment of dilute acetic ether, washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuum and chromatographic on silica gel with hexane/acetic ether. Get 5,4 g 17-deformation-3-methoxy-18 - methyl-östra-1,3,5(10)-triens in the form of colorless crystals with a melting point of 145-146oC []2D2= +40,2o(C=0,515% in pyridine).

EXAMPLE 12

17-deformation-18-methyl-östra-1,3,5(10)-triene-3-ol

A solution of 5 g of 17-deformation-3-methoxy-18-methyl-östra-1, 3,5(10)-triens in 95 ml of toluene is refluxed with 95 ml of a 1.6 molar solution of diisobutylaluminium in toluene for 3 hours at the temperature of the solution 140oC. Then cooled to room temperature, slowly served on 200 g of ice, stirred into 400 ml of 1-molar sulfuric acid, stirred for 1 hour at room temperature, extracted three times with acetic ester, p is between vacuum and chromatographic on silica gel with hexane/acetic ether. Receive 4.5 g 17-deformation-18-methyl-östra-1,3,5(10)-triene-3-ol in the form of colorless crystals with a melting point of 120-121oC []22D/= +37,8 (C=0.5% in pyridine).

1. 17-Deformation-estratriene General formula I

< / BR>
where R1denotes a hydrogen atom or a C1- C10alkyl;

R5means methyl or ethyl;

R2means a hydrogen atom or a C1- C10alkyl - or situation;

R3means a hydrogen atom or a C1- C10alkoxy - or situation;

R4means a hydrogen atom in the or position;

A, b, D, E and G denote each a hydrogen atom and, if necessary, optionally, at least one of the pairs of substituents G and R2, R2and R4, R4and And And and R3, D and E mean the double bond.

2. 17-Deformation-estratriene under item 1, of General formula I, where R1denotes a hydrogen atom or a C1- C10-alkyl; R5denotes methyl or ethyl; a, b, D, E, G, R2and R3denote each a hydrogen atom and R4means or constant hydrogen atom, or R2with R4, R4with a, And R3D s E or G with R2denote an additional bond, and the other of these sweep, the rich in this case a, b, D, E, G, R3and R4represent respectively a hydrogen atom, or R3means a permanent group WITH1- C10-alkyloxy, and in this case a, b, D, E, G, R2and R4represent respectively a hydrogen atom.

3. 17-Deformation-estratriene under item 1 of General formula I, where R1represents a hydrogen atom.

4. 17-Deformation-estratriene under item 1 of General formula I, where R1represents a methyl group.

5. 17-Deformation-estratriene under item 1 of General formula I, where R2represents a methyl group.

6. 17-Deformation-estratriene under item 1 of General formula I, where R3represents a methoxy group.

7. 17-Deformation-estratriene under item 1 of General formula I, where R5represents a methyl group.

8. 17-Deformation-estratriene under item 1 of General formula I, where a, b, D, E, G, R2, R3and R4represent hydrogen atoms.

9. 17-Deformation-estratriene under item 1 of General formula I, where a, b, D, E, R3and R4represent hydrogen atoms, and G with R2designate an additional bond.

10. 17-Deformation-estratriene General formula I on p. 1 representing:

17-deformation-östra the yen-3-ol,

17-deformation-östra-1,3,5(10),7-tetraen-3-ol,

17-deformation-östra-1,3,5(10),8-tetraen-3-ol,

17-deformation-östra-1,3,5(10),9(11)-tetraen-3-ol,

17-deformation-3-methoxy-östra-1,3,5(10),15-tetraen,

17-deformation-östra-1,3,5(10),15-tetraen-3-ol,

17-deformation-7-methyl-östra-1,3,5(10)-triene-3-ol,

17-deformation-8-östra-1,3,5(10)-triene-3-ol,

17-deformation-3-methoxy-18-methyl-östra-1,3,5(10)-triene,

17-deformation-18-methyl-östra-1,3,5(10)-triene-3-ol.

11. Compounds of General formula I under item 1, with antioxidant and soudsystem properties.

12. The method of obtaining 17-deformation-estratriene General formula I on p. 1, characterized in that the 17-keto-compound of General formula II

< / BR>
where R1'means hydroxyamino group;

A, B, D, E, G, R2, R3, R4and R5are specified in the formula I is,

interact with the oxide diverseylever-phosphine or diethyl-(deformity)-phosphonate in the presence of a strong base in an aprotic solvent at the boiling point under reflux for 50 - 100oC and then, if necessary, otscheplaut hydroxyamino group under the action of acid.

 

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