Derivatives Östra-1,3,5(10)-triens, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

Describes the new östra-1,3,5(10)-transliterate General formula (I), where R denotes a group R1R2N, in which R1and R2independently of each other a hydrogen atom, a C1-C5alkyl group, or together with the nitrogen atom - polyethylenimine containing 4-6 carbon atoms, or morpholinopropan; R3denotes a hydrogen atom or a C1-C5alkyl group, R4is a hydrogen atom, a hydroxyl group etherified hydroxyl group, haloalkyl group containing 1-5 carbon atoms, or alkoxygroup containing 1-5 carbon atoms; R5and R6each is a hydrogen atom or together represent a methylene group; R7, R8and R9independently from each other represent a hydrogen atom or a hydroxyl group and the ring can contain one or two double bonds, or R8means alkynylaryl residue, containing up to 5 carbon atoms, or R8and R9together can be an oxygen atom in the case when at least one of the residues R3-R7different from hydrogen. Compounds suitable for hormonal contraception and for zamestnavani. Thus compounds exhibit low estrogenicity effect on the liver. Also described methods of making the compounds and pharmaceutical compositions. 3 c. and 1 C.p. f-crystals, 1 PL.

The invention relates to new derivatives östra - 1,3,5(10)-triens, in particular to new östra-1,3,5(10)- transliterate, method for their production and pharmaceutical compositions containing these compounds.

Estrogens play a major role in hormonal contraception and replacement therapy menopause hormone (HRT), and in the treatment of gynecological (e.g. breast carcinoma) and male (e.g., carcinoma of the prostate) diseases.

For HRT and contraceptive estrogens are mostly used in combination with a gestagen, for example, levonorgestrel, desogestrel, gestodene, drospirenone, norethisterone, tsiproteronatsetat, chlormadinone and dienoguesta.

When contraceptive estrogens are necessary for reliable suppression of maturation of follicles and ovulation. They also replace the suppressed largely endogenous secretion of estradiol by the ovaries. This substitution is important for maintaining artificial menstrual qi one gestagen.

Endogenous estrogens also perform important functions in the Central nervous system and metabolic processes of the female body.

Normal levels of estrogen play an important role for the comfort and health of individuals (L. Zichella; Clinical Management of the Menopausal Woman; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 15-22). Their presence through various mechanisms may contribute to the prevention of cardiovascular diseases, for example, by creating a "preferred" modes of lipoproteins in the blood (G. Samsioe; Hormone Replacement Therapy and Cardiovascular Disease; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 23-29), by inhibiting the deposition of lipids in the walls of blood vessels (T. B. Clarkson; Experimental Effects of Progesterone versus Progestins on Arterial Wall; Gynecol. Endocrinol., 6, Suppl. 1 [1992] , 15), by reducing blood pressure as a result of favorable effects on vascular tone (R. A. Lobo; Estrogen and Cardiovascular Disease; Ann. New York Acad. Sciences, 592 [1990], 286-294), by reducing the flow resistance in important areas of vessels and weakening of the contractile stimuli of the muscles of blood vessels (C. Jiang and others, Acute effect of 17-estradiol on rabbit coronary artery contractile responses to endothelin-1; Am. J. Physiol., 263 [1992] , H271-H275). The inner walls of blood vessels under the influence of estrogen release factors (prostacyclins) that counteract the OBR is the lack of Them can cause destruction of the bone (osteoporosis) (C. Cristiansen; Prevention and Treatment of Osteoporosis with Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 45-54). These effects of estrogen on the Central nervous system and metabolism are key aspects when HRT.

Despite the many valuable aspects of estrogen therapy, there are still some unsolved problems, which impose restrictions on therapeutic use of estrogen or can cause unwanted symptoms.

The bioavailability of natural estrogens (estradiol, estrone, etranslate, esters of estradiol, estriol) becomes minimum when the introduction oral route (K. B. Lokind and others; Oral bioavailability of 17-estradiol and various ester prodrugs in the rat; Int. J. Pharmaceutics, 76 [1991], 177-182). This minimum number has considerable individual variability and, therefore, General recommendations for dosing cannot be given. The use of natural estrogens (estradiol) for hormonal contraception received a negative evaluation because of their pharmacokinetic limitations (W. Kuhnz and others; Pharmacokinetics of Estradiol, Free and Total Estrone in Young Women Following Single Intravenous and Oral Administration of 17-Estradiol; Arzneimittel-Forschung/Drug Res., 43 (II), 9, [1993] , 966-973). Another problem is the rapid destruction of mu development of prodrugs based on estradiol, aimed at improving bioavailability for oral use, with no success (K. B. Lokind and others; see above).

Synthetic estrogens also have serious disadvantages. Ethinylestradiol (EE) is the most important estrogenic steroid, modified synthetically. It is an estrogen, which plays a major role in oral hormonal contraception. Unlike EE mestranol, "prodrug", turning the body in the metabolism of EE used in a small number of cases (J. W. Goldzieher; Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications; Am J. Obstet. Gynecol, 163 [1990], 318-322). EE in oral introduction (recipient) has significantly better bioavailability than the above natural estrogen, but its bioavailability for oral administration can very much be reduced depending on the individual recipient. Goldzieher from a pharmacodynamic point of view emphasized the negative consequences associated with the variability of the area under the curve (AUC), as well as variability, time-life, and the time required to reach maximum levels in the blood. The highest AUC value, Beauchene AUC was 284 PG x h/ml Similar to the 6 - or 7-fold variation in AUC values described by Humpel and others (Humpel and others; Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives; Horm. Res., 33 [1990], 35-39).

With the introduction oral route active substances after absorption fall from the cavity of the intestine into the body through the liver. This fact is especially important for estrogenic substances, because the liver is a target organ for estrogen and, therefore, their introduction oral route may cause severe intrahepatically estrogenic effects. Secretory activity regulated by estrogen in the liver include the synthesis of transport proteins, corticosteroidresponsive globulin (CBG), globulin, sex hormone binding (SHBG), tyrosinaemia globulin (TBG), angiotensinogen various factors that play a major physiological role in blood coagulation, and lipoproteins.

However, if natural estrogen is introduced into the female body, without going through the liver, for example, by transdermal administration, the above liver function will not be rendered effects, and they will remain unchanged (U. Larsson-Cohn and others ; Some biochemical consequences of post-menopausal hormon is x doses of natural estrogens leads to strong reactions of various operation parameters of the liver: increase SHBG, CBG, angiotensin, HDL (high density lipoprotein) (J. C. Stevenson and others; Oral Versus Transdermal Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 30-35). As has been well established, the effects of estrogen on liver caused by mixtures containing equiestrogenic (the so-called conjugated estrogens) are significantly more pronounced than those characteristic of natural estrogens (C. A. Mashchak and others; Comparison of pharmacodynamic properties of various estrogen formulations; Am. J. Obstet. Gynecol., 144 [1982], 511-518). Levonorgestrel and diethylstilbestrol (DPP) have even higher estrogenicity in the liver. In relation antigonadotropic properties oestrogenic effect of EE on the liver is approximately 8-10 times stronger compared with that in oral introduction of natural estrogens. Thus, it is very undesirable difference in their properties (B. von Schoultz and others; Estrogen Therapy and Liver Function - Metabolic Effects of Oral and Parenteral Administration; The Prostate, 14, [1989], 389-395).

The following data show that the undesirable hepatic effects of estrogen cannot be avoided by reducing the dose of EE in the contraceptives. Confirmed that the reduction in the content of EE 30 mcg to 20 mcg or doses in combination with 150 μg of the same progestogen drank only a minor reduction of these parameters after 6 months (A. Basdevant and others; Hemostatic and metabolic effects of lowering the ethinyl estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel; Contraception, 48 [1993], 193-204).

It is known that the real problem in the treatment with high doses of estrogen carcinoma of the prostate gland in men are fatal complications caused by embolism (B. von Schoultz and others; see above).

The strategy of oral hormonal contraception is defined somewhat weaker manifestation of the possible side effects of EE on the liver.

Whereas, on the one hand, the need for contraceptive effectiveness, while maintaining a regular menstrual cycle and, on the other hand, the possible severe side effects, the serious problem of regulating the desired levels of EE in the blood level of complexity can be compared to walking a tightrope. A large percentage of women cannot use oral contraceptives because their threshold of acceptability is exceeded due to menstrual irregularities or due to estrogen related side effects.

The risk of cardiovascular disease, even fatal, has a pronounced upward trend in the use of hormonal contraceptives (V. Wynn; Otives and myocardial infrarction in young women; Pharmacol. steroid. Contracept. Drugs, ed-ry S. Garrattini and H. W. Berendes, Raven Press, New York, [1977], 289-296). Therefore, some authorities in the field of medicine warned women over 35 years of hormonal contraceptives. The risk of acquiring cardiovascular disease is even higher for women smokers older than 35 years who use hormonal contraceptives (F. A. Leidenberger; Klinische Endokrinologie fur Frauenarzte, pages 382-383; J. I. Mann; see above).

It was found that the risk of fatal cardiovascular diseases using oral contraceptives increases 5-6 times compared to the control groups (F. A. Leidenberger; see above). These findings indicate that there are significant subgroups pubescent women who can use a normal hormonal contraceptives, putting themselves at undue risk, or should not use them at all.

Recent studies suggest that the above problems are likely to must be related to the estrogenic component of hormonal contraceptives than gestagenna component (Skouby and others; J. Obstet. Gynekol.; [1990] , 1535-1537). "Consensus meeting" concluded that the actual risk of fatal myocardial infarction does not depend on prodoljatsja not due to chronic damage of the arteries of the heart (atherosclerosis), but due to the acute effects on hemostatic function in the liver (R. A. Lobo, see above). Consequently, reducing estrogenic effects on the liver, probably is a way, excluding the above-mentioned negative effects of hormonal contraception and related limitations on the application.

Described for ER negative phenomena are largely excluded in the case of natural estrogens, i.e. estrogen, having weaker estrogenicity effects on the liver compared to EE (R. A. Lobo, see above).

For HRT, based on the use of natural hormones, usually require individual selection of doses based on the most modern techniques. It was confirmed that in this context, the treatment is accompanied by many beyond consideration of factors related to the risk of overdose or under-dose.

Therefore, the object behind the present invention is the creation of derived östra-1,3,5(10)-triens, which do not possess the above undesirable characteristics and side effects.

This problem is solved in accordance with the invention by creating new derivatives östra-1,3,5(10)-triens total from each other represent a hydrogen atom, WITH1-C5alkyl group or together with the nitrogen atom form polyethylenimine containing 4-6 carbon atoms, or morpholinopropan, and

R3denotes a hydrogen atom or a C1-C5alkyl group,

R4denotes a hydrogen atom, a hydroxyl group esterified hydroxyl group, haloalkyl group containing 1-5 carbon atoms, or alkoxygroup containing 1-5 carbon atoms,

R5and R6each denotes a hydrogen atom or together represent a methylene group,

R7, R8and R9independently from each other represent a hydrogen atom or hydroxyl group, and

the ring may contain one or two double bonds, or

R8represents alkynylaryl radical containing up to 5 carbon atoms,

or

R8and R9together denote an oxygen atom in the case when at least one of the residues R3, R4, R5, R6or R7different from hydrogen,

R5and R8can optionally designate vanilinovoi or ethylene group.

Derivatives östra-1,3,5(10)-triens of the present invention, bearing R-SO2-O-group in the floor is 9 and 11, 8 and 14, 14 and 15 and/or 15 and 16 carbon atoms.

Derivatives östra-1,3,5(10)-triens of the present invention, bearing R-SO2-O-group in position 3, where R has the above values may contain the carbonyl group in position 6, 7, 11, 15, 16 and/or 17.

Derivatives östra-1,3,5(10)-triens of the present invention, bearing R-SO2-O-group in position 3, where R has the above values may contain additional hydroxyl group in position 6, 7, 9, 11, 14, 16 and/or 17, and these hydroxyl groups can be tarifitsirovana to simple or complex ester. Etherification to complex ester can be carried out using the normal derivatives of physiologically acceptable inorganic or organic acids. These acids may be a phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, valeric acid, adipic acid and benzoic acid. Information about other acceptable acids described, for example, in Fortschritte der Arzneimittelforschung", so 10, pages 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966, and in the Journal of Pharmaceutical Sciences, I. 66, pages 1-5 (1977). The etherification to simple esters of>Derivatives östra-1,3,5(10)-triens of the present invention, bearing R-SO2-O-group in position 3, where R has the above values can be substituted in position 6, 7, 11, 14, 15 16 and/or 17 alkyl groups, alkylidene groups, alkenylamine groups and alkenylamine groups containing up to 5 carbon atoms, and these groups in turn can be substituted in a similar way alkyl, alkylidene, alkenylamine or alkenylamine groups or halogen.

Derivatives östra-1,3,5(10)-triens of the present invention, bearing R-SO2-0-group in position 3, where R has the above values can be substituted alkionovymi groups or alkenylamine groups containing up to 3 carbon atoms, in positions between 14 and 15 or 14 and 17 carbon atoms.

Derivatives of 3-sulfamates-1,3,5(10)-triens of the present invention, bearing R-SO2-O-group in position 3, where R has the above values may represent, for example, the following preferred compounds:

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-yl-N, N-dimethylsulphamoyl,

17-hydroxy--14,15-methyltetra-1,3,5(10)-triene-3-yl-N, N-diethylsulfate,

17-hydroxy--14,15-methyltetra-1,3,5(10)-triene-3-yl-Pirro is linestra - 1,3,5(10)-triene-3-yl-methylsulfonate,

17-hydroxy--14,15-methyltetra-1,3,5(10)-triene-3 - insultant,

17-hydroxy--14,15-methyltetra-1,3,5(10), 7-tetraen-3-yl - N,N-dimethylsulphamoyl,

17-hydroxy-14,15-methyltetra -1,3,5(10),6,8 - pentaen-3-yl-N,N-diethylsulfate,

17-hydroxy-14,15-methyltetra-1,3,5(10), 8-tetraen-3-yl - N,N-dimethylsulphamoyl,

11 chloromethoxy- -17-hydroxyestra-1,3,5(10)- triene-3-yl-N,N-dimethylsulphamoyl,

17-hydroxy-14,15-vinylenes-1,3,5 (10) -triene-3-yl - N, N-diethylsulfate,

14,17-ethylene- -17-hydroxyestra-1,3,5(10) - triene-3 - impersonality,

16,17-dihydroxy-14,17-etelemetry - 1,3,5(10)-triene-3-yl-N, N-diethylsulfate,

17-hydroxy-7-methylestra-l, 3,5(10)-triene-3,11-diyl-N, N-dimethylsulphamoyl-11-nitrate,

17-hydroxy-11-methoxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3-yl-N, N-dimethylsulphamoyl,

17-hydroxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3 - insultant,

17-hydroxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3-yl - N-methylsulfonate,

17-hydroxyestra-1,3,5(10),7-tetraen - 3-yl-N,N-diethylsulfate,

17-hydroxyestra-1,3,5(10),6,8-pentaen-3-yl-N,N - dimethylsulphamoyl,

17-hydroxy-14,15-methyltetra - 1,3,5(10),8-tetraen-3-insultant,

11-methoxy-17-exestr-1,3,5(10)-triene-3 - insultant,

17-hydroxyestra-1,3,5(10)-triene-3-yl-N-methylsulfonate,

17 - hydroxyestra-1,3,5(10)-triene-3-insultant the Stra-1,3,5(10)-triene-3,17 - dial-3-sulpham-17-pentanoate,

östra-1,3,5(10)-triene-3,17 - dial-3,17-sulpham,

16,17 - dihydroxyethane -1,3,5 (10)-triene-3-yl-N, N - diethylsulfate,

16,17 - dihydroxyethane-1,3,5(10) -triene-3-yl-N,N-dimethylsulphamoyl,

16,17 - dihydroxyethane-1,3,5(10)-triene-3 - immortalisation,

16,17 - dihydroxyethane - 1,3,5(10) -triene-3-yl-N-methylsulfonate,

16,17 - dihydroxyethane-1,3,5(10) -triene-3-insultant,

11 chloromethoxy-17-hydroxyestra - 1,3,5(10) -triene-3-insultant,

17-hydroxy-14,17 - vinylenes-1,3,5(10)-triene-3 - insultant,

14,17-ethylene-17 - hydroxyestra-1,3,5(10)- triene-3-yl-N-methylsulfonate,

16,17 - dihydroxy-14,17 - etelemetry - 1,3,5(10) -triene-3-insultant,

17 - hydroxy-7 - methylestra-1,3,5(10)-triene- -3,11 - dial-3 - sulpham-11-nitrate,

17 - hydroxy-11 - methoxy-19-nor-17 - pregn-1,3,5(10)- triene-20-in-3-insultant.

Especially preferred are derivatives östra-1,3,5(10)-triens General formula I, in which R7and R9denote hydroxyl group.

In addition, especially preferred are derivatives östra-1,3,5(10)-triens General formula I, in which R5and R6together denote a methylene group.

The following derivatives östra-1,3,5(10)-triens of the present invention are particularly predpochtitelnye-3-yl-N,N - dimethylsulphamoyl,

17 - hydroxy-14,15 - methyltetra-1,3,5(10) -triene-3-yl-N,N - dimethylsulphamoyl and

16,17 - dihydroxyethane-1,3,5(10)-triene-3-yl-N,N - diethylsulfate.

The present invention also relates to a method for obtaining derivatives of östra-1,3,5(10)-triens of General formula I according to the invention the essence of which is that 3 HE-a group derived östra-1,3,5(10)-triens atrificial appropriately substituted aminosulfonyl.

The reaction is usually carried out using a two-phase system in the presence of Quaternary ammonium salts as phase transfer catalyst. The reaction temperature is in the range from room temperature to 100oC. as solvents used conventional two-phase system, such as chloroform-water, dichloromethane-water, toluene-water, etc.

Another object of the present invention is a pharmaceutical composition with contraceptive action applied to germanosilicate therapy in menopause, which contains as active substance derived östra-1,3,5(10)-triens General formula I, and pharmaceutically acceptable excipients or carriers.

Pharmaceutical compositions norgestrel, desogestrel, gestodene, drospirenone, norethisteron, tsiproteronatsetat, chlormadinone or dienoguest.

The pharmaceutical compositions according to the invention can also be prepared in the form of multi-stage or combined products.

The combined product is intended for contraception, for example, consists of a first stage, which can be a combination of several components, namely, biogenic estrogen, synthetic estrogen, progestogen and/or derived östra-1,3,5(10)-triens of the present invention, and one or more additional steps, which may consist of pharmaceutically safe placebo, either biogenic or synthetic progestogen, either biogenic or synthetic estrogen, or derived östra-1,3,5(10)-triens of the present invention, or a combination of several components, namely, biogenic estrogen, synthetic estrogen, progestogen derived östra - 1,3,5(10)-triens of the present invention, or a combination of synthetic estrogen or derived östra-1,3,5(10)-triens of the present invention and progestogen.

Biogenic estrogen includes, for example, a component from the group consisting of of which immediately after rapidly cleaved one of the above estrogenic components.

Synthetic estrogen according to the present invention includes at least one component from the group consisting of ethinyl estradiol, mestranol and other synthetic estrogens, or at least one connection, which immediately after the introduction of rapidly cleaved one of the above estrogenic components.

Gestagen of the present invention includes but at least one component from the group consisting of levonorgestrel, desogestrel, progesterone, norethisterone, chlormadinone, gestodene, cyproterone and other natural and/or synthetic progestogen, or at least one connection, which immediately after the introduction of rapidly cleaved one of the above gestagenna components.

The present invention relates also to methods for pharmaceutical compositions that can be used for hormonal contraception, drug substitution therapy, menopausal hormone and treatment of gynecological and andrological diseases, such as breast carcinoma and prostate cancer.

In addition, the present invention relates to pharmaceutical compositions in the form of tablets, tablets with reguline coated with controlled release.

Medicines are made known and accepted in the art ways depending on the intended route of administration with the appropriate dosage, using standard solid or liquid carriers or diluents and standard pharmaceutical adjuvants. Preferred are compositions for oral administration. Such compositions can be a pill, tablet film-coated, coated tablets, capsules, pills, powders or shaped in the form of a depot.

Appropriate tablets can be obtained by mixing the active ingredient with known adjuvants, such as inert diluents type dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, agents, contributing to the disintegration of the type of corn starch or alginic acid, binders of the type of starch or gelatin, oil type stearate or talc and/or agents, by means of which reach a depot effect, such as carboxypolymethylene, carboxymethylcellulose, acetochlor cellulose or polyvinyl acetate. Tablets can also consist of several layers.

Coated tablets may be obtained, respectively, by coating ser is tov, such as polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. The coating may consist of several layers and can be used adjuvants specified above in the section on the tablets.

Capsules containing active substances, for example, can be obtained by mixing the active substance with an inert carrier such as lactose or sorbitol, and encapsulating in gelatin capsules.

However, given that used for medical purposes standard estrogen derivatives have serious shortcomings, there is an urgent need for compounds that are devoid of these shortcomings.

Unexpectedly it was found that the compounds of the present invention is superior to its estrogenic action of EE, while showing maximum genital estrogenic actions in respect of the uterus and not providing a stronger estrogenic actions on the liver compared with estradiol, a natural estrogen. This combination is characteristic of the compounds of the present invention, should lead to a significant improvement of therapeutic properties compared to natural and synthetic estrogens.

Contraceptives containing derivatives östra-1,3,5(10)-triens of the present invention, with regard to their significantly reduced estrogenic effects on the liver can be successfully used in high enough doses for better cycle control than is possible using traditional contraceptives-based EE.

The application of EE in hormone replacement therapy currently is strictly prohibited due to its inherent side effects. When using derivatives östra-1,3,5(10)-triens of the present invention eliminated the negative effects that exist when using non-natural (biogenic) of estrogen. In contrast to natural estrogens, which are currently dominant in hormone replacement therapy, the advantage is achieved due to a significantly higher degree of accountability, because in oral introduction bioavailability is more pronounced and less fraught with considerable individual variability, typical of biogenic estrogens.

Estrogenicity effect on the WIN:WU) were subjected oophorectomy (on day 14). Treatment was started two weeks after oophorectomy by once-daily oral administration of the respective investigated substances. All animals were divided into groups randomly. The experiment was carried out according to the block diagram. All animals were weighed twice - before and at the end of the experiment.

The beginning and the end of treatment was defined as day 1 (= 1) or day 7 (= d). Animals were killed on day 8. Removed various organs (the uterus, adrenal gland, liver), weighed and subjected to deep freezing (-196oC) for further investigation.

Blood was taken from the retro-bulbar plexus under anesthesia with diethyl ether before treatment (up) and (D4) and (d). Thus obtained serum was used for determination of IGF1(insulin-like growth factor 1), angiotensin I, cholesterol and HDL-cholesterol.

Methods definitions:

IGF1: radioimmunoassay (RIA) With bioMerieux;

angiotensin: a modified RIA for determining the activity of renin by Sorin Co.;

cholesterol/HDL: enzymatic tests, photometric determination, reagents supplied by the company Dr. Bruno Lange GmbH.

The results of the experiments the debate on the effectiveness of the uterus is equivalent to or greater than the ethinyl estradiol (EE). In addition, the effect on the parameters of estrogenicity action on the liver are absent or significantly reduced in comparison with those using comparable doses of ethinyl estradiol (EE).

Blood levels derived östra-1,3,5(10)-triens of the present invention significantly higher compared with those for similar compounds, i.e., estradiol (E2), ethinyl estradiol (EE) and estriol (E3 effects).

Below the invention is illustrated by the following examples.

Example 1

A General method of obtaining N, N-disubstituted 3-sulfamate derivatives östra-1,3,5(10)-triens.

Derived östra-1,3,5(10)-triens used for esterification to complex ether, aminosulfonyl, hydroxide of alkali or alkali earth metal hydroxide, and Quaternary ammonium salt as phase transfer catalyst is added under vigorous stirring to a mixture of the appropriate organic solvent and water. Stirring is continued to obtain analytical confirmation (using thin-layer chromatography) complete the esterification, if necessary, reduce the time of reaction can be run at temperatures between yennie organic extracts are successively washed with diluted hydrochloric acid, a saturated solution of sodium bicarbonate and water. Then the extract is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from the appropriate solvent.

Example 2 (= J 983)

Getting 17 - hydroxy-14,15 - methyltetra-1,3,5 (10) - triene-3-yl - N, N-diethylsulfate

2 g-14,15 - methyltetra-1,3,5(10)-triene-3,17 - diol suspended in 30 ml of toluene, 4 ml of water, 0.32 g of the chloride of benzyltriethylammonium, 2,94 ml of N, N-diethylaminoethylamine and 2.1 ml of 40% sodium hydroxide solution, and then stirred and heated for two hours to the temperature of the reaction mixture 80oC. After cooling to room temperature, operate according to the method described in example 1. Thus obtained crude product chromatographic on silica gel (particle size from 0,063 to 0.2 mm). Specified in the title compound is obtained after elution in chloroform/ethyl acetate (9:1) and recrystallization from methanol.

tPL: 68-73oC;1H-NMR: 0,26 (m, CH2), 0,99 (s, 18-H), to 3.38 (q, 7.2 Hz, CH3-CH2-N), 3,55 (dd, 16 Hz), 7,31 (d, 8,8 Hz, 1-H) ppm million (CDCl3).

Example 3 (= J 989)

Getting 16,17 - dihydroxyethane-1,3,5 (10)-triene-3-yl-N,N-dimethylcarbamate

SetVar sodium hydroxide and at a temperature of 80oC are added to a solution containing 2 g of estriol in 800 ml of toluene. Continue heating to a temperature of 80oC. During the process the pH of the reaction mixture is maintained at 10 by adding 40% aqueous sodium hydroxide solution. After the interaction of all of the parent compounds, the mixture is cooled to room temperature and operate according to the method described in example 1. Thus obtained residue is recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 180-181oC;1H-NMR: 0,67 (s, 18-H), 2,89 (s, CH3-N) of 3.32 (m, 17-H), a-3.84 (m, 16-H), with 4.64, 4,71 (each d, 4,9 Hz each), 7,34 (d, 8,8 Hz, 1-H) ppm m (D6-DMSO).

Example 4 (= J 982)

Getting 17 - hydroxy-14,15 - methyltetra-1,3,5(10)-triene-3 - yl-N, N-dimethylcarbamate

The reaction between 1 g 14,15-methyltetra-1,3,5(10)- triene-3,17-diol, 2.4 g of sodium hydroxide, 0.24 g of chloride of triethylenediamine and 3.6 ml of N,N-dimethylaminoacetonitrile carried out similarly as described in example 1, a mixture containing 30 ml of dichloromethane and 6.6 ml of water. Specified in the title compound is obtained after the above processing, purification using chromatography and recrystallization of the reaction product from ACAT to 7.32 (d, 8.6 Hz, 1-H) ppm million (CDCl3).

Example 5 (= J 984).

Getting 16,17 - dihydroxyethane-1,3,5(10) -triene-3-yl - N,N-diethylsulfate

The reaction between 2 g of estriol of 5.2 g of sodium hydroxide, 1,72 g of the chloride of triethylenediamine and 9.75 ml of N,N - diethylaminoethylamine carried out similarly as described in example 1, a mixture containing 800 ml of toluene and 128 ml of water. Specified in the title compound is obtained after the above processing, purification using chromatography and recrystallization of the reaction product of acetone.

tPL: 121-124oC; 1H-NMR: 0,67 (s, 18-H), 1,11 (t, 7,1 Hz, CH3-CH2-N) to 3.33 (q, 7,1 Hz, CH3-CH2-N), 3,83 (m, 16-H), 4,65, 4,72 (all d, 4 Hz, 3.5 Hz, 16-HE, 17-Oh), 7,33 (d, 8,4 Hz, 1-H) ppm m (D6-DMSO).

Example 6

A General method of obtaining N-monosubstituted and N-unsubstituted 3 - sulfamate derivatives östra-1,3,5(10)-triens.

Mix the base (triethylamine or 2,4-di-tert-butyl-4 - methylpyridine) and monosubstituted or N-unsubstituted aminosulfonyl and added in several portions to a solution derived östra 1,3.5(10)of triens in an appropriate solvent (dichloromethane, pyridine or dimethylformamide). The reaction temperature should not exceed +20oC. Fullness the overall processing of the reaction solution is washed in a dilute aqueous solution of hydrochloric acid, in a saturated aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness in a vacuum rotary evaporator. The residue is purified on silica gel and/or by recrystallization using column chromatography.

Example 7 (= J 1044)

Getting 14,15 - methyltetrazol-3-(N-methyl)sulpham

The reaction between methyltetrazol (1,17 g) and (N-methyl)aminosulfonyl (1 ml) was carried out according to the method described in example 6, a solution containing pyridine (12,7 ml) and 2,6-di-tert-butyl-4 - methylpyridine (5,1 g). The crude product after the above processing is cleaned by column chromatography (chloroform/ethylacetate 9:1) and recrystallized from acetone/n-hexane, obtaining 14,15 - methyltestos-(N-methyl)sulpham. A solution of borane (25 ml) obtained from a solution of boron hydride (1 g) and a complex of boron TRIFLUORIDE-diethyl ether (3.5 ml) in tetrahydrofuran (44 ml), add parts at a temperature of from 0oC to +5oC in argon in the absence of moisture and with stirring to a solution of 14,15 - methyltestos-(N-methyl)amidosulfonic (809,5 mg) in tetrahydrofuran (15 ml). The reaction solution was incubated for 20 hours at a temperature of from 0oC to +5oC and then kapli using column chromatography (chloroform/ethylacetate 9:1) and recrystallization from acetone.

tPL: 192-193,5oC:1H-NMR: 0,20 (m, CH2), 0,2555 (m, CH2), to 0.89 (s, H-18), 2,71 (d, 3.8 Hz, CH3-NH), 3,43 (m, H-17), 4,43 (d, 5.3 Hz, HE), 7,39 (d, 8.5 Hz, H-1), 8,12 (m, NH) ppm m (D6-DMSO).

Example 8 (= J 1011)

Getting estrone-(N-methyl)sulpham

The reaction between estrone (3 g) in a solution of dichloromethane (1200 ml) and triethylamine (28,2 ml) with N-methylaminoanthraquinone (3 ml) was carried out according to the method described in example 6. The crude product after the above processing is recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 192.5 kg-196,5oC;1H-NMR: 0,91 (s, H-18), 2,95 (d, 5.1 Hz, CH3-NH), 4,58 (m, NH), 7,30 (d, 8.2 Hz, H-1), part./million (CDCl3).

Example 9 (= 1012 J)

Obtaining estradiol-(N-methyl)sulpham

Estrone-(N-methyl)aminosulfonyl (1 g) restore the sodium borohydride (624,2 mg) in a mixture of tetrahydrofuran (20 ml) and methanol (20 ml). The crude product after the above processing is recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 194-198,5oC;1H-NMR: 0,78 (s, H-18), to 2.94 (d, 5.2 Hz, CH3-NH), 4.53-in (m, NH), of 3.73 (dd and 16.9 Hz, H-17), 7,30 (d, 8,4 Hz, H-1), part./million (CDCl3).

Example 10 (= J 1036)

The floor is ω (1 g) in a solution of dichloromethane (25 ml) and 2,6-di-tert-butyl-4 - methylpyridine (3,3 g) and (N-methyl)aminosulfonyl (0,72 ml) was carried out according to the method described in example 6. The reaction mixture is stirred for five hours per diluted with water in ratio of 1:1 hydrochloric acid until complete removal of salelologa ether, after which the crude product is purified by column chromatography (toluene/chloroform/methanol 80:15:5) and recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 156-162,5oC;1H-NMR: 0,88 (s, H-18), 2,61 (s, CH), 2,94 (d, 5.2 Hz, CH3-NH), 4.53-in (m, NH), 7,31 (d, 8,8 Hz, H-1) ppm million (CDCl3).

Example 11 (= J 994)

Getting etranslate

Estrone (1 g) dissolved in dimethylformamide (20 ml). Then to this solution add aminosulphonylphenyl (2.14 g). After stirring for six hours carry out the precipitation in water and the product is recrystallized from ethyl acetate, getting listed at the beginning of the connection.

tPL: 199-202oC;1H-NMR: 0,83 (s, H-18), 7,35 (d, 8.7 Hz, H-1), and 7.9 (s, NH2) part./m (D6-DMSO).

Example 12 (= J 995)

Obtaining estradiol-3-sulpham

Istranslated (1.4 g) restore the sodium borohydride (960 mg) in a solution of tetrahydrofuran (28 ml) and methanol (28 ml). After the above processing are UP recrystallization>C;1H-NMR: 0,67 (s, H-18), 3,53 (t,d, 7.9 Hz, 4,7 Hz, H-17), 4,55 (d, 4.8 Hz, HE), 7,34 (d, 8.6 Hz, H-1), of 7.90 (s, NH2) part./m (D6-DMSO).

Example 13 (= 1018 J)

Getting 14,15 - methyltetrazol-3-sulpham

The reaction between 14,15 - methyltetrazol-17-tert-butyldimethylsilyl ester (100 mg) and amidosulfonic (145 mg) in a solution of dichloromethane (3 ml) and 2,6-di-tert-butyl-4-methylpyridine (180 mg) carried out by the method described in example 6. The crude product after the above processing is cleaned by column chromatography (toluene/acetone 4:1) and recrystallized from acetone/n-hexane, obtaining in this way 14,15 - methylene-17 - tert-butyldimethylsilyloxy-1,3,5(10)-triene-3-insultant. 14,15 - methylene-17--tert-butyldimethylsilyloxy-1,3,5(10)-triene-3-isalphabet (2.2 g) dissolved in tetrahydrofuran (100 ml). To this solution was added a mixture of acetic acid/water/tetrahydrofuran (3: 1:1) (220 ml). The reaction mixture was incubated for seven days at room temperature, then treated by the method described above, the product is purified by column chromatography (cyclohexane/ethyl acetate 3:2) and recrystallized from acetone/n-hexane.

tPL: 210-214oC; 1H-NMR: 0,20 (m, CH2), 0,26 (m, Smmer 14 (= J 1028)

Getting 17 - ethinyl estradiol - 3 - sulpham

The reaction between 17 - ethinyl estradiol-17-trimethylsilyloxy ether (1.5 g) and amidosulfonic (8 g) in a solution of dichloromethane (40 ml) and triethylamine (16 ml) was carried out according to the method described in example 6. The crude product after removal of group salelologa ether and processing by the method described above purified using column chromatography (chloroform/ethyl acetate 7:3) and recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 209-211oC;1H-NMR: 0,76 (s, H-18), to 3.35 (s, CH), to 5.35 (s, HE), 7,35 (d, 8.7 Hz, H-1), 7,89 (s, NH2), part./m (D6- DMSO).

Example 15 (= J 1034)

Receiving estriol-3-sulpham

The reaction between estriol-16,17-bis-tert-butyldimethylsilyl ether (2 g) and amidosulfonic (7.9 g) in a solution of dichloromethane (13 ml) and triethylamine (15,5 ml) was carried out according to the method described in example 6. The crude product is treated by the above method and otscheplaut silloway ester in accordance with example 13, and then a dedicated connection purified using column chromatography (chloroform/methanol/acetic acid 90:13:1) and recrystallized from acetone/n-hexane, obtaining the decree HE), to 7.32 (d, 8,4 Hz, H-1) ppm m (D6- DMSO).

Example 16 (= J 1040)

Receiving estriol-3-(N-methyl)sulpham

The reaction between estriol-16,17-bis-tert-butyldimethylsilyl ether (1.7 g) and (N-methyl)aminosulfonyl (of 0.87 ml) in a solution of dichloromethane (51 ml) and 2,6-di-tert-butyl-4-methylpyridine (4,05 g) carry out according to the method described in example 6. The crude product after the above processing is cleaned by column chromatography (toluene/chloroform/methanol 80:15: 5), and then otscheplaut silloway ester in accordance with example 13. The compound obtained purified using column chromatography (chloroform/methanol/acetic acid 90: 13: 1) and recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 199-202oC;1H-NMR: 0,67 (s, H-18), 2,70 (s, NH-CH3, 3,30 (m, H-17), a-3.84 (m, H-16), 4,7 (t, HE), 7,33 (d, 8.7 Hz, H-1) ppm m (D6-DMSO).

Example 17 (= J 1050).

Getting 17 - estradiol-3-sulpham

The reaction between 17 - estradiol-tert-butyldimethylsilyl ether (1,94 g) and amidosulfonic (2,75 g) in a solution of dichloromethane (70 ml) and 2,6-di-tert-butyl-4-methylpyridine (3.6 g) is carried out according to the method described in example 6. The crude product is described after Cetona/n-hexane. Thus obtained 17--tert-butyldimethylsilyloxy-1,3,5 (10)-triene-3-yl-sulpham subjected to cleavage salelologa ester in accordance with example 13. The compound obtained purified by column chromatography (toluene/ethyl acetate/chloroform 6:3:1) and recrystallized from acetone/n-hexane, obtaining specified in the header of the connection.

tPL: 192-196oC;1H-NMR: 0,62 (s, H-18) and 3.59 (d, 5.5 Hz, H-17), was 7.36 (d, 8,8 Hz, H-1), 7,88 (s, NH2) part./m (D6-DMSO).

Example 18 (= J 1010)

Getting 14,15 - methylnitrosoamino.

The reaction between 14,15-methyltetrazol (765 mg) and amidosulfonic (11,7 g) in a solution of dichloromethane (50 ml) and triethylamine (7.7 ml) is done according to the procedure described in example 6. The crude product after the above processing is cleaned by column chromatography (chloroform/ethylacetate 9:1)and recrystallized from acetone/n-hexane, thus obtaining specified in the header of the connection.

tPL: 191-195oC;1H-NMR: -0,40 (m, CH2), 0,80 (m, CH2), 1,12 (s, H-18), 7,40 (d, 8 Hz, H-1), to 7.93 (s, NH2) part./m (D6- DMSO).

Example 19 (= J 1021)

The 11 - methoxyethylamine

Sodium hydride (0.4 g, 80%) dobavlyayut aminosulphonylphenyl (6.2 g) and the reaction mixture was stirred over night at room temperature. This is followed by precipitation in water and the product was then purified using column chromatography (chloroform/acetone 7:3). Specified in the title compound was prepared by recrystallization from acetone/n-hexane.

tPL: 191-195oC;1H-NMR: 0,99 (s, H-18), 3,20 (s, CH3O), 4,24 (m, H-11), 7,26 (d, 8.7 Hz, H-1), to 7.93 (s, NH2) part./m (D6-DMSO).

Example 20 (= J 1038)

Getting östra-1,3,5(10)-triene-3,17 - dial-3-sulpham,17 - pentanoate

The reaction between estradiol-17-pentanoate (2 g), dissolved in dimethylformamide (37 ml), sodium hydride (336 mg, 80%) and amidosulfonic (6,47 g) carry out according to the method described in example 6. After the above processing is specified in the title compound was produced using column chromatography (chloroform/ethylacetate 9:1) and recrystallization from acetone/n-hexane.

tPL: 107-108oC;1H-NMR: 0,78 (s, H-18), of 0.87 (t, 7,3 Hz, CH3(CH2)3-CO), to 2.29 (t, 7.2 Hz, C3H7-CH2-CO), 4,63 (dd, 15,5 Hz, H-17), 7,34 (d, 8,4 Hz, H-1), 7,89 (s, NH2) part./m (D6-DMSO).

Example 21 (= J 1051)

Getting 17 - hydroxy-14,15 - methyltetra-1,3,5(10), 8-tetraen-3-inculpate

The reaction between 14,15 - methylene-17 - trimethylsilyloxy-1,3,5(10)-triene-3-I (100 mg) and AMI is the method described in example 6. The crude product after removal of group salelologa ether and the above-described processing is cleaned by column chromatography (cyclohexane/ethyl acetate 3:2) and recrystallized from acetone/n-hexane.

White foam; tPL: 189-194oC;1H-NMR: 0,46 (m, CH2), to 0.92 (s, H-18), of 1.28 (m, CH2), 3,90 (d, 6.0 Hz, H-17) part./million (CDCl3), 7,35 (d, 8,8 Hz, H-1), 7,88 (s, NH) ppm m (D6-DMSO).

Example 22 (= J 992)

Getting estrone-(N,N-dimethyl)sulpham

Estrone (1 g) with dichloromethane (30 ml), water (3 ml), chloride of benzyltriethylammonium (0.24 g), N,N - dimethylaminoacetonitrile (3.6 ml) and sodium hydroxide solution (40%, 6 ml) was stirred at room temperature for 2 hours. After that, the mixture is treated according to the method described above in example 1, and the product is recrystallized from ethyl acetate.

tPL: 192-194oC;1H-NMR: 0,91 (s, H-18), 2,98 (s, N-CH3), 7,28 (d, 9.9 Hz, H-1) ppm million (CDCl3)

Example 23 (= J 991)

Obtaining estradiol-3-(N,N-dimethyl)sulpham

Interaction with estradiol (1 g) is carried out according to the method described in example 22. After the above processing are recrystallization of the product from chloroform/methane/m (CDCl3).

Example 24 (= J 1052)

Getting 14,15 - methyltetrazol-3-pyrrolidinedione

The reaction between 14,15 - methyltetrazole (1,05 g) and dichloromethane (30 ml), water (3 ml), chloride of benzyltriethylammonium (0.24 g), pyrrolidinecarboxamido (4,5 ml) and sodium hydroxide solution (40%, 8 ml) was carried out according to the method described in example 22.

Specified in the title compound is obtained after the above-described processing in accordance with example 1.

Amorphous solid;1H-NMR: 0,20 (m, CH2), 0,26 (m, CH2), to 0.89 (s, H-18), to 3.33 (m, -CH2-N-CH2-), 3,4 (m, H-17), to 4.41 (d, 5.2 Hz, HE), was 7.36 (d, 8.7 Hz, H-1) ppm m (D6-DMSO).

Example 25 (= J 1053)

Receiving estriol-3-morpholinacetate

The reaction between estriol (2 g) in a mixture of toluene (800 ml) and water (120 ml) and morpholinylformamidine (9,2 ml), chloride of benzyltriethylammonium (1,58 g) and sodium hydroxide solution (40%, 6,5 ml) carried out but the procedure described in example 3. Specified in the title compound is obtained after the above-described processing in accordance with example 1.

tPL: 188-192oC;1H-NMR: 0,67 (s, H-18), 3,28-to 3.36 (m, H-17, -CH2-N-CH2-), 3,65-3,68 (m, -CH2-O-CH2-), 4,7 (m, OH), 7,37 (d, 8,8 Hz, H-1) frequent. /m (D6

Light yellow resin;1H-NMR: 0,69 (s, H-18), 7.23 percent-7,56 (d, 8,4 Hz, d, 8.5 Hz, H-6 and H-7), of 7.82 (d, 9.8 Hz, H-1), and 7.9 (s, NH2) part./m (DE6-DMSO).

1. Derivatives östra-1,3,5(10)-triens General formula I

< / BR>
where R is the group R1R2N, in which R1and R2independently from each other represent a hydrogen atom, a C1-C5alkyl group or together with the nitrogen atom form polyethylenimine containing 4-6 carbon atoms, or morpholinopropan;

R3is a hydrogen atom or a C1-C5alkyl group;

R4denotes a hydrogen atom, a hydroxyl group esterified hydroxyl group, haloalkyl group containing 1-5 carbon atoms or alkoxygroup containing 1-5 carbon atoms;

R5and R6each is a hydrogen atom or together represent a methylene group;

R7, R8and R9independently of each other a hydrogen atom or a hydroxyl group and the ring can contain one or two double bonds, or R8- alkynylaryl residue, containing up to 5 carbon atoms, or R8and R9together may denote an oxygen atom in case the tra-1,3,5(10)-triens under item 1, representing

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-yl-N, N - dimethylsulphamoyl;

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-yl - N, N - diethylsulfate;

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-yl-pyrrolidinedione;

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-immortalisation;

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-yl-N-methylsulfonate;

17-hydroxy-14,15-methyltetra-1,3,5(10)-triene-3-insultant;

17-hydroxy-14,15-methyltetra-1,3,5(10), 7-tetraen-3-yl-N,N-dimethylsulphamoyl;

17-hydroxy-14,15-methyltetra-1,3,5(10), 6,8-pentaen-3-yl-N, N-diethylsulfate;

17-hydroxy-14,15-methyltetra-1,3,5(10), 8-tetraen-3-yl-N,N-dimethylsulphamoyl;

11 chloromethoxy-17-hydroxyestra-1,3,5(10)-triene-3-yl-N, N-dimethylsulphamoyl;

17-hydroxy-7-methylestra-1,3,5(10)-triene-3,11-dial-3-N, N-dimethylsulphamoyl-11-nitrate;

17-hydroxy-11-methoxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3-yl-N, N-dimethylsulphamoyl;

17-hydroxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3-insultant;

17-hydroxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3-yl - N-methylsulfonate;

17-hydroxyestra-1,3,5(10),7-tetraen-3-yl-N,N-diethylsulfate;

17-hydroxyestra-1,3,5(10),6,8-pentaen-3-yl-N,N-dimethylsulphamoyl;

17-hydroxy-14,15-methyltetra-1,3,5(10),8-tetraen-3-yl-sulpham;

17-hydroxyestra-1,3,5(10)-triene-3-insultant;

17-hydroxyestra-1,3,5(10),6,8-pentaen-3-insultant;

17-hydroxyestra-1,3,5(10)-triene-3-insultant;

östra-1,3,5(10)-triene-3,17-dial-3-sulpham,17-pentanoate;

östra-1,3,5(10)-triene-3,17-dial-3,17-diaminoalkyl;

16,17-dihydroxyethane-1,3,5(10)-triene-3-yl-N,N-diethylsulfate;

16,17-dihydroxyethane-1,3,5(10)-triene-3-yl-N,N-dimethylsulphamoyl;

16,17-dihydroxyethane-1,3,5(10)-triene-3-immortalisation;

16,17-dihydroxyethane-1,3,5(10)-triene-3-yl-N-methylsulfonate;

dihydroxyethane-1,3,5(10)-triene-3-insultant;

11 chloromethoxy-17-hydroxyestra-1,3,5(10)-triene-3-insultant;

17-hydroxy-7-methylestra-1,3,5(10)-triene-3,11-dial-3-sulpham-11-nitrate;

17-hydroxy-11-methoxy-19-nor-17-pregn-1,3,5(10)-triene-20-in-3-insultant.

3. The method of obtaining derivatives östra-1,3,5(10)-triens General formula I under item 1 or 2, characterized in that 3-OH-group derived östra-1,3,5(10)-triens atrificial corresponding substituted aminosulfonyl.

4. The pharmaceutical composition of the contraceptive effects used for hormone replacement therapy in menopause, characterized in that it contains a derivative östra-1,3,5(10)-triens under item 1 or 2 in effect and the

 

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