Pharmaceutical compositions containing the derivatives Östra-1, 3,5(10)-triens

 

(57) Abstract:

The invention relates to medicine. Pharmaceutical compositions containing as active ingredients derived östra-1,3,5(10)-triens, bearing in their C3-position a group of the General formula R-SO2-O-, where R denotes a group R1R2N, in which R1and R2do not depend on each other and denote a hydrogen atom, a C1-C5alkyl radical or together with the nitrogen atom denote polyethylenimine containing 4-6 carbon atoms, or morpholinopropan are for hormonal contraception and for hormonesensitive therapy (HRT). They are low astrogenetix in the liver. 2 C. p. F.-ly, 10 PL.

The invention relates to pharmaceutical compositions containing as active ingredients derived östra-1,3,5(10)-triens, carrying the group R-SO2-About in the C3-position.

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

For HRT and contraceptive estrogens in OSM, norethisterone, diprotonation, chlormadinone, dienoguesta.

When used for contraception estrogen is needed for safe suppression of maturation of follicles and ovulation, however, they also replace the suppressed largely endogenous secretion by the ovaries estradiol. This substitution is important for maintaining an artificial menstrual cycle and other sexual functions that cannot be performed sufficiently even when using progestogen.

Moreover, endogenous estrogens have important functions in the Central nervous system and metabolic processes of the female body.

Normal estrogen levels play a significant role in the health of individuals (L. Zichella; Clinical Management of the Menopausal Woman; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pp. 15-22). Estrogens act against the development of cardiovascular diseases through various mechanisms, such as creating a "preferred" modes of lipoproteins in the blood (G. Samsioe; Hormone Replacement and Cardiovascular Disease; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pages 23-29), inhibiting the deposition of lipids in the vascular wall (C. Clarkson; Experimental Effects of Progesterone versus Progestins on Arterial Wall; Gynecol. Endocrinol. , 6, Suppl. 1 (1992), page 15), providing blagofrog Acad. Sciences, 592 (1990), pp. 286-294), reducing the resistance to blood flow in critical areas of vessels and reducing contractile stimuli to the muscles of the 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 (prostacyclin) that counteract the development of blood clots in the blood.

Estrogens are necessary to protect the bone structure in women. Their deficiency may be the cause of destruction of the bones (osteoporosis) (C. Cristiansen; Prevention and Treatment of Osteoporosis with Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pp. 45-54). These last effects of estrogen on the Central nervous system and metabolism are a major aspect of HRT.

However, despite all the positive aspects estrogen therapy, there are also unresolved issues that limit therapeutic use of estrogen or cause unwanted effects.

Natural estrogens (estradiol, estrone, astrosolar, esters of estradiol, estriol) to a very limited extent, become biologically available with the introduction oral route (K. C. Lokind and others ; Oral bioavailability of 17-estradiol and various ester prodrugs in the rat; Int. J. Pharmaceutic is uumu, what cannot be given General advice on dosing. These pharmacokinetic factors have led to a negative assessment of natural estrogens as a means of contraception (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), pp. 966-973). Another problem is the rapid removal of substances from the blood. Replacement of estrogen in HRT often must be adjusted individually. Therefore, the development of a prodrug of estradiol aimed at improving bioavailability, had no success (K. C. Lokind and others ; see above).

Synthetic estrogens also have significant disadvantages. The most important modified by synthetic estrogenic steroid is ethinylestradiol (EE). This estrogen is essential when contraception oral route. Unlike EE mestranol used in a small number of cases; it is a "prodrug" that the body in the metabolism becomes uh (J. W. Goldzieher; Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications; Am. J. Obstet. Gynecol, 163 (1990), pp. 318-322). EE when administered to humans oral route has significantly better bioavailability than ukazannimi varies from individual to individual. Goldzieher noted with negative pharmacodynamic point of view, the value changes in the area under the curve (AUC) according to the time of half-life and time that yields the maximum concentration in the blood. The highest AUC value found in this study when measured from 0 to 24 h after injection, was 2121 PPP/ml Lowest AUC value was $ 284 PPP/ml Similar to the 6 - or 7-fold change 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), pp. 35-39).

After resorption of the cavity of the intestine introduced oral route, the active ingredients penetrate into the body through the liver. This fact is especially important for estrogenic agents, because the liver is a target organ for estrogen; oral absorption of estrogen causes a strong estrogenic effect on the liver. Secretory activity, which is controlled by estrogens in human liver, involves the synthesis of transport proteins, corticosteroidresponsive globulin (CBG), globulin, sex hormone binding (SHBG), tyrosinaemia globulin (TBG), angiotensinogen, several factors important clanism, without going through the liver (e.g., by transdermal injection) above the liver actually remain unchanged (U. Larsson-Cohn and others ; Some biochemical consequences of post-menopausal hormone replacement treatment; in The Controversial Climacteric, editor : R. A. van Keep and others ; MTP Press Ltd. (1982)). Therapeutically equivalent dose of natural estrogen in the introduction oral route lead to marked changes in operation parameters of the liver: increase SHBG, CBG, angiotensinogen, HDL (high density lipoprotein) (J. S. Stevenson, and others ; Oral Versus Transdermal Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 (1993), pp. 30-35). These effects of estrogen on liver are more pronounced if instead of natural estrogen use compositions containing equiestrogenic (the so-called conjugated estrogens) (C. A. Mashchak and others ; Comparison of pharmacodynamic properties of various estrogen formulations; Am. J. Obstet. Gynecol, 144 (1982), pp. 511-518). Levonorgestrel and diethylstilbestrol (DPP) have even higher estrogenicity in the liver. In relation antigonadotropic properties of EE has approximately 8-10 times stronger estrogenic effects on the liver than the input oral route of natural estrogens. This is a very undesirable distinction of properties (B. von Schoultz and others ;anywayt, that undesirable hepatic reactions to 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 in each case in combination with 150 μg of the same progestogen does not reduce significantly increased level of angiotensin three months and resulted in only a slight decrease in 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), pages 193-204).

A known complication that can occur after high doses of estrogen to men suffering from carcinoma of the prostate, is fatal thromboembolism (B. von Schoultz and others ; see above).

The ability of EE to cause side effects on the liver, although in a weaker form, defines the strategy of oral hormonal contraception.

Whereas, on the one hand, the desired contraceptive effect and the maintenance of the menstrual process, and on the other hand, the need to take into account the significant potential side effects, the task of regulating levels of EE in the blood can be compared to walking a tightrope. It is likely, is Vaticani, or because estrogen related side effects that exceed the tolerance threshold.

Hormonal contraceptives significantly increase the risk of disease and death from certain cardiovascular diseases (V. Wynn; Oral contraceptives and coronary disease; J. Reprod. Med. , 36 Suppl. 3, (1991), pp. 219-225). Because such risks depend on age (J. I. Mann; Oral contraceptives and myocardial infarction in young women; Pharmacol. steroid. Contracept. Drugs, red sizes: s Garrattini and H. W. Berendes, Raven Press, New York, (1977), pages 289-296), some authorities in the field of medicine warned women over 35 years of hormonal contraceptives. Women smokers older than 35 years and use hormonal contraceptives are at strong risk of cardiovascular disease (F. A. Leidenberger; Klinische Endokrinologie fur Frauenarzte, pages 382-383; J. I. Mann; see above). The risk of fatal cardiovascular disease increases by 5-6 times in women using oral contraceptives compared with control groups (F. A. Leidenberger; see above). These findings indicate that large group of fertile women absolutely can not use oral contraceptives or can use them, only exposing yourself to undue risk.

In accordance with this technical field this Am (Skouby, etc. ; J. Obstet. Gynekol. ; (1990), 1535-1537). "Consensus meeting" concluded that the risk of fatal myocardial infarction does not depend on the duration of the injection. This discovery proves that the formation of blood clots that cause death, is not in the heart due to defects in the walls of arteries (atherosclerosis), and in the liver due to acute effects on hemostatic function (R. A. Lobo, see above). Consequently, reducing estrogenic effects on the liver is considered to be a promising way to avoid risks associated with hormonal contraception, and eliminate these limitations on the application. Described for EE risks are largely excluded in the case of natural estrogens, i.e. estrogen, have lower hepatic estrogenicity compared to EE (R. A. Lobo, see above).

HRT, based on the use of natural hormones, requires individual selection of doses with the use of modern methods. This treatment includes a number of a non-accounting factors; there is a pronounced risk as re-, and insufficient dosage.

Therefore, the object behind the present invention is to provide a pharmaceutical is in accordance with the invention by creating pharmaceutical compositions containing as active ingredients derived östra-1,3,5(10)-triens, bearing in their C3-position a group of the General formula

R-SO2-O-,

where R denotes a group R1R2N, in which R1and R2do not depend on each other and denote a hydrogen atom, a C1-C5alkyl radical or together with the nitrogen atom denote polyethylenimine containing 4-6 carbon atoms, or morpholinopropan.

Derivatives östra-1,3,5(10)-triens included in the pharmaceutical compositions according to the invention and involving C3-R-SO2-O-group, where R has the above significance, in addition, may optionally contain a double bond between the 6 and 7 7 and 8 8 and 9 9 and 11, 8 and 14, 14 and 15 and/or 15 and 16 carbon atoms.

Derivatives östra-1,3,5(10)-triens included in the pharmaceutical compositions according to the invention and involving C3-R-SO2-O-group, where R has the above values may not necessarily be borne by the carbonyl group at 6, 7, 11, 15, 16 and/or 17 carbon atoms.

Derivatives östra-1,3,5(10)-triens included in the pharmaceutical compositions according to the invention and involving C3-R-SO2-O-group, where R has the above values, can carry additional hydroida. Hydroxyl group etherification using normal derivatives of physiologically acceptable inorganic and organic acids, for example phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, valerianic acid, adipic acid and benzoic acid. Other acids that may be used are described, for example, in Fortschritte der Arzneimittelforschung, T. 10, pages 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966, and in the Journal of Pharmaceutical Sciences, I. 66, pages 1-5 (1977).

Hydroxyl group atrificial to simple ester using conventional derivatives of aliphatic alcohols containing up to 6 carbon atoms.

Derivatives östra-1,3,5(10)-triens included in the pharmaceutical compositions according to the invention and involving C3-R-SO2-O-group, where R has the above values, we can 6, 7, 11, 14, 15, 16 and/or 17 carbon atoms optionally carry additional alkyl groups, alkylidene group, alkeline group and alkyline group containing up to 5 carbon atoms, and these groups do not themselves may bear similar groups or halogen.

Derivatives östra-1,3,5(10)-PUF, where R has the above values may not necessarily be held between 14 and 15 or 14 and 17 carbon atoms additional groups of alkylene or Alcanena containing up to 3 carbon atoms.

Among the derivatives of 3-sulfamates-1,3,5(10)-triens included in the pharmaceutical compositions according to the invention and bearing in C3-R-SO2-O-group, where R has the above values, it can be noted, for example,

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

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

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

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-exestr-1,3,5(10)-triene-3-insultant,

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

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

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

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

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

2,17-dihydroxyethane-1,3,5(10)-triene-3-yl-N, N-dimethylsulphamoyl,

2-methoxy-17-hydroxyestra-1,3,5(10)-triene-3-yl-N, N-diethylsulfate,

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

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

17-hydroxy-19-nor-17-pregna - 1,3,5(10)-triene-20-in-3-impersonality,

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-impersonality,

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

17-hydroxy-14,17-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-1,3,5(10)-triene-3,11 - dial-3-N, N-dimethylsulphamoyl-11-nitrate and

17-hydroxy-11-methoxy-19-nor-17 - of the invention include derivatives östra-1,3,5(10)-triens General formula I

< / BR>
where R denotes a group R1R2N, in which

R1and R2do not depend on each other and denote a hydrogen atom, a C1-C5alkyl radical or together with the nitrogen atom denote polyethylenimine containing 4-6 carbon atoms, or morpholinopropan,

R3denotes a hydrogen atom, a hydroxyl group, or alkoxygroup containing 1-5 carbon atoms,

R4denotes a hydrogen atom or a C1-C5alkyl radical,

R5denotes a hydrogen atom, a hydroxyl group esterified hydroxyl group, haloalkyl or alkoxygroup containing 1-5 carbon atoms,

R6and R7denote hydrogen atoms or together form a methylene group,

R8, R9and R10do not depend on each other and denote a hydrogen atom or a hydroxyl group,

moreover, the ring optionally contains one or two double bonds, or optional

R9means alkynylaryl radical containing up to 5 carbon atoms, or

R9and R10together denote an oxygen atom, or

R6and R9denote vanilinovoi or ethylene group.

Especially prefer the formula I, where R5and R6denote hydroxyl group.

In addition, especially preferred are pharmaceutical compositions according to the invention containing derivatives östra-1,3,5(10)-triens General formula I, in which R3and R4together denote a methylene group.

Most preferred are pharmaceutical compositions containing

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

17-hydroxy-19-nor-17-pregna - 1,3,5(10)-triene-20-in-3 - impersonality,

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

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

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

östra-1,3,5(10)-triene-17-one-3-yl-N, N - diethylsulfate,

17-hydroxy-19-nor-17-pregna - 1,3,5(10)-triene-20-in - 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.

Derivatives östra-1,3,5(10)-triens included in the pharmaceutical compositions according to the invention, obtained using the well known way by reacting a derivative östra-1,3,5(10)-triens with line is 0)-triens.

The reaction is carried out in the usual way using a two-phase system in the presence of a Quaternary ammonium salt as phase transfer catalyst. The temperature of reaction is in the range from room temperature to 100oC. solvents Used are standard two-phase system, such as chloroform-water, dichloromethane-water, toluene-water, etc.

Some compounds included in the composition according to the invention are known.

So, in the application WO 93/05064 described the use of estrone-3-sulfamate as inhibitors of steroid sulfatase.

In GDR patent DD 207447 described the use of N, N-dialkylamide ethinyl estradiol derivatives as agents for the control of rodents.

In addition, in tiled applications to German patent DE-OS 2426779, DE-OS 2426778 and in DE-OS 2426777 described 3-sulphamate derivatives of estratriene carrying additional hydroxyl group in position 1.

In addition, patents GDR DD 77709 and DD 114806 described the active ingredients included in pharmaceutical compositions according to the invention.

However, hitherto unknown to pharmaceutical compositions that include contraception, HRT and treatment of carcinoma.

Another object of the present invention is the use of derivatives östra-1,3,5(10)-triens, bearing in their C3-position a group of the General formula

R-SO2-O-,

where R denotes a group R1R2N, in which

R1and R2do not depend on each other and denote a hydrogen atom, a C1-C5alkyl radical or together with the nitrogen atom denote polyethylenimine containing 4-6 carbon atoms, or morpholinopropan to obtain medications for hormonal contraception, drug substitution therapy, menopausal hormone and treatment of gynecological and andrological diseases, such as breast carcinoma and prostate cancer.

Preferred for obtaining medications for hormonal contraception, drug substitution therapy, menopausal hormone and treatment of gynecological and andrological diseases, such as breast carcinoma and prostate cancer, are derived östra-1,3,5(10)-triens General formula I

< / BR>
where R denotes a group R1R2N, in which

R1and R2do not depend on each other and denote a hydrogen atom,

R3denotes a hydrogen atom, a hydroxyl group, or alkoxygroup containing 1-5 carbon atoms,

R4denotes a hydrogen atom or a C1-C5alkyl radical,

R5denotes a hydrogen atom, a hydroxyl group esterified hydroxyl group, haloalkyl or alkoxygroup containing 1-5 carbon atoms,

R6and R7denote hydrogen atoms or together form a methylene group,

R8, R9and R10do not depend on each other and denote a hydrogen atom or a hydroxyl group,

moreover, the ring optionally contains one or two double bonds, or optional

R9means altenergy radical containing up to 5 carbon atoms, or

R9and R10together denote an oxygen atom, or

R6and R9denote vanilinovoi or ethylene group.

For example, compounds

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

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

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

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

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

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

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

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

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

2,17-dihydroxyethane-1,3,5(10)- triene-3-yl-N, N-dimethylsulphamoyl,

2-methoxy-17-hydroxyestra - 1,3,5(10)-triene-3-yl-N, N-diethylsulfate,

17-hydroxy-9-nor-17-pregna - 1,3,5(10)-triene-20-in-3-insultant, 2 17-hydroxy-19-nor-17-pregna - 1,3,5(10)-triene-20-in-3-yl-N-methylsulfonate,

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

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

17-hydroxy-19-nor-17-pregna-1,3,5(10)- triene-20-in-3 - impersonality,

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 - impersonality,

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-dimethyl who tilemaster-1,3,5(10), 8-tetraen - 3-yl - N, N-dimethylsulphamoyl,

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

17-hydroxy-14, 17-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-1,3,5(10)-triene-3,11- -deel-3-N, N-dimethylsulphamoyl - 11-nitrate and

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

used for obtaining medications for hormonal contraception, drug substitution therapy, menopausal hormone and treatment of gynecological and andrological diseases, such as breast carcinoma and prostate cancer.

The pharmaceutical compositions according to the invention additionally contain one or more of the above gestagens such as levonorgestrel, desogestrel, gestodene, drospirenone, norethisteron, tsiproteronatsetat, chlormadinone, dienoguest.

Moreover, the pharmaceutical preparations according to the invention can be presented in the form of multi-step or complex compositions.

Complex composition according to the invention can be what strogen, synthetic estrogen, progestin and/or derived östra-1,3,5(10)-triens, which is in the C3-position group R-SO2-O, where R has the above values, and optionally one or more additional steps of, containing or pharmaceutically safe placebo, either natural or synthetic progestin, either biogenic or synthetic estrogen, or derived östra-1,3,5(10)-triens, which is in the C3-position group R-SO2-O, where R has the above significance, or a combination of several components, i.e. biogenic estrogen, synthetic estrogen, progestogen derived östra-1,3,5(10)-triens, which is in the NW-position group R-SO2-O, where R has the above significance, or a combination of synthetic estrogen or derived östra-1,3,5(10)-triens, which is in the C3-position group R-SO2-O, where R has the above values, and gestagen.

Biogenic estrogen includes, for example, ingredient, representing estradiol, estrone, estran, astrology group and other biogenic estrogen, or at least the connection from which soon after penetration cleaved one of the above estrogenic ingredients.

Syntheti is levonorgestrel, mestranol group and other synthetic estrogens, or at least one connection, which soon after penetration cleaved one of the above estrogenic ingredients.

Gestagen includes in accordance with the invention, at least one ingredient that represents levonorgestrel, desogestrel, dienoguest, progesterone, norethisterone, chlormadinone, tsiproteronatsetat and other natural and/or synthetic progestogen, or at least one connection, which soon after penetration it one of the above gestagenna ingredients.

Another object of the present invention are 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.

Another object of the present invention are pharmaceutical compositions in the form of tablets, tablets with controlled-release tablets, pills, capsules, film-coated tablets and film-coated tablets with the adjustable visvobodi what you or solvents and conventional adjuvants, used for the preparation of pharmaceutical products, with the appropriate dosage depending on the intended method of administration. Preferred compositions are those forms that are suitable for oral administration, for example, pills, tablets, film-coated, tablets, capsules, pills, powders, solutions, suspensions or in the form of a depot.

Tablets can be obtained, for example, by mixing the active substance with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, with agents that promote disintegration, such as corn starch or alginic acid, binders, such as starch or gelatin, oiling agents, such as magnesium stearate or talc and/or materials with which they receive a depot effect, such as carboxypolymethylene, carboxymethylcellulose, acetated cellulose or polyvinyl acetate. Tablets may consist of several layers.

Tablets can be obtained, respectively, by covering the core, made by analogy with the production of the tablets, with agents commonly used to cover pass the lozenges may also consist of several layers, which can be used adjuvants mentioned above in the paragraph about the pills.

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

As usual, used in medicine, estrogen derivatives have serious disadvantages, therefore there is an urgent need in the relevant pharmaceutical drugs that are devoid of these shortcomings.

Despite the fact that some active ingredients in the pharmaceutical compositions according to the invention have already been known for some time and have been thoroughly studied by pharmacologists, their preferred properties in relation to liver function have not been previously described.

Unexpectedly, it was found that the active agents used in accordance with the invention, are better than EE, from the point of view of their estrogenic efficiency, showing that the maximum estrogenic actions in respect of the uterus, and does not have a strong estrogenic effect on the liver compared to natural ESTRO is according to the invention in comparison with natural or synthetic estrogens.

Contraceptives according to the invention containing derivatives östra-1,3,5(10)-triens, which are in the C3-position group R-SO2-O, where R has the above values, require the development of entirely new approach to the determination of limits for hormonal contraception, because they have small or do not have quite the impact on the hemostatic system.

Contraceptives according to the invention containing derivatives östra-1,3,5(10)-triens, which are in the C3-position group R-SO2-O, where R has the above meanings, can be administered in such high doses due to greatly reduced compared to the control estrogenic effects on menstrual cycle, which is also an advantage compared to traditional derivatives EE.

The use of ethinyl estradiol (EE) in hormone-replacement therapy at present is strictly prohibited due to the potential side effects. When using derivatives östra-1,3,5(10)-triens according to the invention, which are in the C3-position group R-SO2-O, where R has the above values, eliminated the risk that exists when using non-natural (biogenic) of estrogen. When compared with natural estrogen, which vlautin significantly improved, as defined bioavailability in oral introduction, and it does not change from individual to individual, as in the case of biogenic estrogens.

Estrogenicity effect on the liver was confirmed in rats with oophorectomy. Laboratory animals adult female rats (line: HSD/WIN: WU) were subjected oophorectomy on day 14. Treatment was started two weeks later by once daily oral administration of the respective test substance. With the introduction in the form of esters dose correlated with steroid part connections. The experimental group and the number of laboratory animals are shown in table 1.

Studies were conducted on three groups (a, b and C) at different points in time. This is the reason that there are deviations in the values for the control group. Therefore, the tests of series a, b and C can be mapped to each other, if we take into account the values for the respective control groups.

The procedure of allocation of animals to groups was random. The experiment was carried out in the form of a unit test. Animals were weighed at the beginning and at the end of the experiment.

Start of treatment was designated as day 1 (= 1), treatment zaveshivali and subjected to deep freezing (-196o(C) for further evaluation.

Blood was taken from the retro-bulbar plexus under anesthesia with diethyl ether before treatment (D0) and (D4) and (d). In the obtained serum was determined by the content of IGF1(insulin-like growth factor 1), angiotensin I, cholesterol and HDL-cholesterol.

Methods definitions:

IGF1: radioimmunoassay (RIA) bioMerieux Co;

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

cholesterol/NDL-cholesterol: enzymatic tests, photometric determination, reagents company Dr Bruno Lange GmbH.

The results of the experiment are presented below in tables 2-7.

Impact on the growth of the uterus (see table 2)

The action of the compounds obtained in accordance with example 2, reaches a plateau at an oral dose of 0.01 mg/animal/day. This clearly shows the superiority compared to EE and significant advantage compared to estradiol.

Influence on the weight of the adrenal glands (see table 3)

Depending on the dose see weight gain adrenal glands.

Exception: estradiol, marked reduction in growth compared to EE.

Effects on IGF1(see table 4)
is>: estradiol.

Angiotensin I (AI) (see tables 5A and 5B)

AI at different doses (1.0 or 10.0, or to 100.0 μg/animal/day, sampling connection)

At the lowest dose, the increase in the values of AI see only under the influence of J 824. Estradiol did not show visible effects in any of the doses used in the experiment. EE and J 824 has led to a marked increase in the content of AI, which can be found already on the 4th day at doses of 10 or 100 μg. J 271 not had a strong impact on the AI in the dose of 10 µg/day. When using this compound at a dose of 100 mg/day appears to increase the content of AI, but it is significantly lower than that observed under the influence of EE or J 824 in the same dose.

According to the steps of the dose on day 4 and 8 for angiotensin I, total cholesterol and HDL-cholesterol (cf. tables 5A, 5B, 6A, 6b, 7a and 7b)

Angiotensin I (cf. table 5A and 5B)

Estradiol at best has a slight stimulating effect on the level of angiotensin I. the Data for the compounds obtained in accordance with example 2, was significantly lower compared to EE.

The levels of total cholesterol (cf. tables 6A and 6b) and HDL-cholesterol (cf. tables 7a and 7b)

In rats, estrogen in SNAC similar levels of HDL-cholesterol and total cholesterol. Doses from 10 to 100 µg lead to very low concentrations of cholesterol in the blood for most of the investigated compounds. Multiple connections lead to significant changes in the dose of 1 μg/animal. Only estradiol (all doses) and the compound obtained in accordance with example 2 (10 g), does not reduce the levels of cholesterol in the blood. Even when using the highest dose of a compound obtained in accordance with example 2, the falling levels of total cholesterol and HDL-cholesterol in the blood is considerably lower compared with that caused by EE.

Below the invention is illustrated in the examples.

Example 1

A General method of obtaining derivatives östra-1,3,5(10)-triens, bearing 3-amidosulfonic

Subjected to esterification to complex ester derived östra-1,3,5(10)-triens, aminosulfonyl, hydroxide of alkali or alkaline earth metal and Quaternary ammonium salt as phase transfer catalyst is added under vigorous stirring to a mixture of the appropriate solvent and water. The mixture continued to stir until you obtain analytical confirmation (using thin-layer chromatography) complete the esterification. D With up to 100oC. then divided in two phases. The aqueous phase is re-extracted and the combined organic phases are washed in the following order: in dilute hydrochloric acid, saturated sodium hydrogen carbonate solution 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 271)

Getting 17-hydroxy-19-nor-17-pregna-1,3,5(10)-triene - 20-in-3-yl-N, N - diethylsulfate

1 g of 17-ethinyl estradiol, 0.4 g of sodium hydroxide, 0.08 g of chloride of benzyltriethylammonium and of 1.16 g of N, N-diethylaminoethylamine subjected to interaction by the method described in example 1, a mixture containing 5 ml of dichloromethane and 2.5 ml of water. Specified in the title compound is obtained after appropriate treatment and recrystallization of the crude product from diisopropyl ether.

tPL113-115oC; [] D: +3o(chloroform, C= 1).

Example 3 (= J 272)

Getting 17-hydroxy-19-nor-17-pregna-1,3,5(10)- triene-20-in-3-yl-N, N - pyrrolidinedione

1 g of 17-ethinyl estradiol, or 0.57 g of potassium hydroxide, 0.08 g of chloride of benzyltriethylammonium, and 1.15 g of pyrrolidinecarboxamido subjected to vzaimodei connection receive after appropriate treatment and recrystallization of the crude product from diisopropyl ether.

tPL121-122oC; [] D: +10o(chloroform, C= 1).

Example 4 (= J 981)

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

0,92 g of estradiol, 0.4 g of sodium hydroxide, 0.08 g of chloride of benzyltriethylammonium and of 1.16 g of N, N-diethylaminoethylamine subjected to interaction by the method described in example 1, a mixture containing 5 ml of dichloromethane and 2.5 ml of water. Specified in the title compound is obtained after appropriate treatment and recrystallization of the crude product from methanol.

tPL175-176oC; [] D: +57o(chloroform, C= 1).

Example 5 (= 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 with 30 ml of toluene, 4 ml of water, 0.32 g of the chloride of benzyltriethylammonium, 2,94 g of N, N-diethylaminoethylamine and 2.1 ml of 40% aqueous sodium hydroxide solution and heated under stirring for 2 hours until the internal temperature 80oC. After the mixture is allowed to cool to room temperature, it is subjected to appropriate processing as described in example 1. The crude product chromatographic on silica gel (particle size from 0,063 to 0.2 mm). Castellinaria from methanol.

tPL68-73oC; [] D: +98o(chloroform, C= 1).

Example 6 (= J 989)

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

Under stirring unite 120 ml of water, was 1.58 g of the chloride of benzyltriethylammonium, 7,44 ml of N, N-dimethylaminoacetonitrile and 4 ml of 40% aqueous sodium hydroxide solution with a solution of 2 g of estriol in 800 ml of toluene at a temperature of 80oC. This mixture is heated to 80oC. during this time the pH value of the reaction solution is maintained at 10 by adding 40% aqueous sodium hydroxide solution. The mixture is allowed to cool to room temperature, when the original connection is fully react, and subjected to appropriate processing as described in example 1. The obtained residue is recrystallized from acetone/n-hexane and receive specified in the header of the connection.

tPL180-181oC; [] D: +48o(chloroform, C= 1).

Example 7 (= J 804)

Getting östra-1,3,5(10)-triene-17-one-3-yl-N, N-diethylsulfate

of 0.91 g of estrone, 1.73 g of barium hydroxide, 0,089 g of the chloride of cyclohexyldimethylamine and of 1.16 g of N, N-diethylaminoethylamine subjected to interaction by the method described in example 1, a mixture containing 5 ml chetvertki and recrystallization of the crude product from methanol.

tPL: 176-180oC; [] D: +109o(chloroform, C= 1).

Example 8 (= J 665)

Getting 17-hydroxy-19-nor-17-pregna-1,3,5(10)- triene-20-in-3-yl-N, N - dimethylcarbamate

1 g of 17-ethinyl estradiol, 2.4 g of sodium hydroxide, 0.24 g of chloride of triethylenediamine and 3.6 ml of N, N-dimethylaminoacetonitrile subjected to interaction by the method 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 appropriate processing, chromatographic purification and recrystallization of the reaction product from acetone/n-hexane.

tPL: 157-160oC; [] D: +4o(chloroform, C= 1).

Example 9 (= J 982)

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

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 subjected to interaction by the method 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 appropriate processing, chromatographic purification and recrystallization of the reaction product of acetone.

tPL: 193-196o

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 subjected to interaction by the method described in example 1, a mixture containing 800 ml of toluene and 128 ml of water. Specified in the title compound is obtained after appropriate recycling, chromatographic purification and recrystallization from acetone.

tPL: 121-124oC; [] D: +44o(chloroform, C= 1).

1. Pharmaceutical composition in the form of tablets, tablets with controlled-release tablets, pills, capsules, film-coated tablets and film-coated tablets with controlled release intended for hormonal contraception, drug substitution therapy, hormone menopause, and for the treatment of gynecological and andrological diseases, such as breast carcinoma and prostate cancer, containing as an active ingredient derived extra-1,3,5(10)-triens, bearing in their C3-position a group of the General formula

R-SO2-O-,

where R denotes a group R1R2N, in which R1and R2do not depend on each other and denote a hydrogen atom, a C1-C5alkyl rayograph, with the exception of the following compounds:

17-hydroxyestra-1,3,5(10)-triene-3-yl-N, N-dis1-C5alkylarylsulfonate,

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

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

17-exestr-1,3,5(10)-triene-3-yl-N, N-dimethylaminoethanol,

17-exestr-1,3,5(10)-triene-3-yl-N, N-diethylaminosulfur,

17-exestr-1,3,5(10)-triene-3-yl-pyrrolidineethanol,

17-exestr-1,3,5(10)-triene-3-yl-morpholinoethyl,

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

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

17-hydroxy-19-nor-17-pregna-1,3,5(10)-triene-20-in-3-impersonality,

17-hydroxy-19-nor-17-pregna-1,3,5(10)-triene-20-in-3-immortalisation.

2. The pharmaceutical composition according to p. 1, containing the active ingredient of General formula 1

< / BR>
where R denotes a group R1R2N, in which R1and R2do not depend on each other and denote a hydrogen atom, a C1-C5alkyl radical or together with the nitrogen atom denote polyethylenimine containing 4-6 carbon atoms, or morpholinopropan;

R3denotes a hydrogen atom, hydroxyl/SUB>-C5alkyl radical;

R5denotes a hydrogen atom, a hydroxyl group esterified hydroxyl group, haloalkyl or alkoxygroup containing 1-5 carbon atoms;

R6and R7denote hydrogen atoms or together form a methylene group;

R8, R9and R10do not depend on each other and denote a hydrogen atom or a hydroxyl group,

moreover, the ring optionally contains one or two double bonds, or optional R9means alkynylaryl radical containing up to 5 carbon atoms, or R9and R10together denote an oxygen atom, or R6and R9denote vanilinovoi or ethylene group.

3. The pharmaceutical composition under item 1 or 2, containing

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

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

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

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-exestr-1,3,5(10)-triene-3-insultant,

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

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

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

2, 17-dihydroxyethane-1,3,5(10)-triene-3-yl-N, N-dimethylsulphamoyl,

2-methoxy - 17-hydroxyestra-1,3,5(10)-triene-3-yl-N, N-diethylsulfate,

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

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

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

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

17-hydroxy-19-nor-17-pregna-1,3,5(10)-triene-20-in-3-impersonality,

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-impersonality,

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-chlorodimethylsilane,

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-methyltetra-1,3,5(10)-triene-3, 11-dial-3-N, N-dimethylsulphamoyl-11-nitrate or

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

 

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