Derivatives sulpham, method for their production and pharmaceutical compositions

 

(57) Abstract:

The invention relates to a sulphamate derivatives derivatives of 1,3,5(10)-estratriene General formula (I), where R1- COR3, -COOR4, -CONR5R6, -SO2R4or-SO2NR5R6where R3and R4independently C1- C5alkyl, C3- C6cycloalkyl or phenyl, R5and R6independently C1- C5alkyl; R2is a hydrogen atom or a C1- C5alkyl; R7and R8independently a hydrogen atom or a C1- C5alkoxygroup; R9and R10is a hydrogen atom or together a methylene group; R11- R13independently a hydrogen atom or hydroxyl group, optionally esterified physiologically acceptable inorganic or organic acids, or R12and R13quinil to 5 carbon atoms and R8, R11and R12independently located in the or position. In addition, the described method of preparing compounds I and pharmaceutical compositions containing these compounds. Compounds according to the invention have estrogenic effects. 3 S. and 1 C. p. F.-ly, 4 PL.

(I)

The invention relates to new sulphamate proizvedeniya.

Estrogens play a significant role in hormonal contraception and climax in the treatment of replacement hormones, as well as in the treatment of gynecological (for example, breast cancer) and male (e.g., prostate cancer) paintings of the disease. In the treatment of replacement hormones for contraception estrogen used in most cases in combination with a gestagen, such as levonorgestrel, desogestrel, norethisteron, cyproterone, chlormadinone, dienoguest.

In the case of contraceptive estrogens necessary, on the one hand, in order to reliably suppress the maturation of the follicle and ovulation, on the other hand, they then replace the largely suppressed endogenous and ovarian secretion of estradiol. This substitution is essential for maintaining an artificial menstrual cycle and other functions of the genital organs that one gestagen is achieved in an unsatisfactory degree. Along with this, endogenous and exogenous estrogens are the female body functions related to the Central nervous system, and metabolic functions: normal estrogen levels is crucial for good health. Their prisutstvuet" structures lipoprotein in the blood, deterrence deposition of lipids on the walls of blood vessels, lowering blood pressure due to favorable effects on vascular tone, reduction of perfusion resistance in important areas of vessels, dullness contraction stimuli of the muscles of the vessel. Under the influence of estrogen inner walls of blood vessels secrete factors which counteract the formation of blood clots. For women, estrogens are vital to the preservation of bone structure. Their loss may be the cause of the destruction of the bones (osteoporosis). The above "related to the Central nervous system and metabolic functions of estrogen are essential to ensure filling of the hormones. Can be considered proven that the estrogen in the male body performing similar functions, and their absence leads to the same violations as in women. Only the fact that the production of hormones in men is less regular and is terminated at a later age than women, defines the difference between the sexes.

With all the positive aspects of estrogen therapy there are unresolved issues that limit therapeutic use of estrogen or cause nieletni (estradiol, estrone, astrosolar, ester of estradiol, estriol) for oral use only to a small extent, become biologically available. This number individually changed so that the General recommendations regarding the dosage is impossible. The problem is also rapid elimination of substances from the blood. Replacement of estrogen in the treatment of replacement hormones are very often should be adjusted individually.

The same applies to synthetic estrogens. The most important modified synthetic estrogenic steroid is levonorgestrel. This estrogen is most often used in oral hormonal contraception. Along with levonorgestrel in some products use mestranol, which is a "prodrug" and by metabolism in organism changes into estrogens. Levonorgestrel for oral use (man) biologically much more affordable than the aforementioned natural estrogens, however, oral bioavailability individually changed very much. Many authors have pointed to this fact, and partly chaotic changing its level in the blood after oral administration of this ve the estrogens have pharmacodynamic deficits. For oral use of the active substance after resorbtive from the lumen of the intestine through the liver into the body. For estrogenic active substances this fact is of particular importance, because the liver is the organ-effector for estrogen and oral application and the associated passage through the liver leads to a strong estrogenic effects in the liver. To the secretory activity, which in human liver is regulated by estrogen, owns, among other things, the synthesis of transport proteins CBG, SHBG, TBG, angiotensinogen, various factors that play an important role in the physiology of blood purification, and lipoproteins. If the female body is injected natural estrogens bypassing the liver, for example, transdermal application, called liver function remain virtually unchanged. Therapeutically equivalent dose of natural estrogen (definition see above) lead for oral use to obvious reactions hepatitis parameters: increase SHBG, CBG, angiotensinogen, high density lipoprotein. Significantly more pronounced than for natural estrogen, appropriate hepatitis estrogenic effects aquinnah estrogenic compounds, the so-called conjugated the ol and DES.

Because antigonadotropic properties ethinyl estradiol in the liver, about 4-18 times more effective as estrogen than the natural oral estrogens (C. Campbell and staff, 1981). Thus, there is a very severe dissociation properties.

These deficits are of great clinical importance for the application of the known natural and synthetic estrogens.

In the case of estrogen therapy with large doses of estrogen for men with prostate cancer known complication of thromboembolic disease with a fatal outcome. In the weaker form of the possible side effects of normal estrogen in the liver determines the strategy of oral hormonal contraception. In relation to the desired contraceptive effect and save the monthly menstruation, on the one hand, and address the significant potential side effects, on the other hand, the complexity of managing the desired level of ethinyl estradiol in the blood is a big problem in terms of migration. A significant percentage of the number of women unable to use oral contraception means possible because any abnormal bleeding or caused by estrogen is ri modern technology requires throughout the individual dosage. Appropriate treatment is largely unsafe and contains specific risk of overdose and negotatiate.

Therefore, the objective of the invention is the creation of new estrogeno effective compounds that do not have the abovementioned disadvantages.

The task according to the invention is solved by the creation of new derivatives sulpham General formula I

< / BR>
where R1is a group-CO-R3-, -CO-OR4-, -CO-NR5R6-, -SO2-R4- or-SO2- NR5R6- where R3is a hydrogen atom or has a value of R4, R4represents a C1-C5-alkyl, C2-C5alkenyl, C3-C6-cycloalkyl or aryl with the carbon atoms by up to 9, R5and R6independently from each other represent a hydrogen atom, a C1-C5is alkyl, aryl of up to 9 carbon atoms or together with the nitrogen atom represent polyethylenimine balance with 3-6 carbon atoms or morpholinyl the remainder, R2is a hydrogen atom or a physiologically acceptable metal or has a value of R4,

R7and R8independently from each other represent a hydrogen atom, a hydroxy group or a residue of C1-C5 group

R11, R12and R13independently from each other represent a hydrogen atom or a hydroxy group which is optionally etherification physiologically acceptable inorganic or organic acids, or R12or R13is alkinilovymi balance of up to 5 carbon atoms,

rings B and C, if necessary, contain one or two double bonds,

and R8, R11and R12independently from each other are located in or position.

Physiologically acceptable metals that may be present in the residue R2are, for example, alkali or alkaline earth metals. Particularly preferred are sodium and potassium.

Conventional physiologically acceptable inorganic and organic acids, which can be tarifitsirovana hydroxyl group residue R11, R12and R13are, for example, phosphoric, sulfuric, oxalic, maleic, fumaric, lactic, tartaric, malic, citric, salicylic acid, adipic and benzoic acid.

Other possible to use acids are described, for example, in the collection Fortschritte der Arzneimittelforschung, volume 10, pages 224-225, publisher Birkhauser Verlag, Basel and Stuttgart, 1966, nilestriol system oral estrogen efficiency. They have a more favorable ratio therapeutically desirable and undesirable effects. When the maximum estrogenic effects in the uterus, respectively, in the vagina, these substances in the liver no more than estrogen than natural estrogens parenteral application of a system of equipotent doses. Due to this relationship with the help of new, estrogeno effective compounds according to the invention are achieved advantages in comparison with all currently used in oral therapy or known natural and synthetic estrogens.

Unexpectedly, it was found that the acylation, sulfonation or amidosulfuron 3-sulphamate group of derivatives of 1,3,5(10)-estratriene, in contrast to the alkylation, does not reduce systemic estrogenic effects, and amplifies it. Proven to compounds according to the invention weaker estrogenic effect on hepatitis estrogenic parameters compared to a strong system activity is a further advantage of the compounds according to the invention in comparison with the presently used in the oral treatment of natural and synthetic estrogens.

Proof produkcija growth of the uterus and vaginal cornification after a single oral administration to ovariectomized rats (test Allen-Doisy): test for the quantitative assessment of systemic estrogenic effect.

2. Measurement system and hepatitis estrogenic effects on ovariectomized rats during and after a 7-day treatment: test for the determination of systematic and hepatitis estrogenic effects.

In the test Allen-Doisy produced a single use of the test substance, respectively medicinal basis, day 1 (= dl). The observation and the experiment was ended on day 4 (= d4). Prior to this daily controlled vaginal Cytology. At the end of the experiment measured the weight of females.

In the test on the system and hepatitis estrogenic activity start of treatment was designated as day 1 (= dl), end of treatment was day 7 (=d7). Day 8 animals were killed, were removed and weighed various organs (uterus, adrenal gland, liver). Blood was taken under ether anesthesia before treatment (= d0) in d4 and d8 from the retro-bulbar plexus. In the obtained serum was determined angiotensin 1, cholesterol, HDL cholesterol, and other factors. Angiotensin 1 is an indicator of direct estrogenic effects in the liver, this refers to the total cholesterol and HDL cholesterol.

Methods of measurement:

Angiotensin - modified RIA for renin activity, firm Zorin;

">

Test results:

1. Systemic estrogenic effects: dosage, which is induced by vaginal estrus.

2. Hepatitis estrogenic effects: dosage, which doubles the weight of the uterus compared with ovariectomised the control group of animals: doses which cause a 50% increase, respectively decrease, certain parameters compared with the control animals or with the original values.

Experimental animals:

Adult females of Wistar rats (kennel: firm Circuit Schönwald GmbH) was ovariectomized. After two weeks started treatment. See dosage esters belong to the steroid component substances. The connection of individual animals in the group made randomizirovannye.

The results of experiments on animals are presented in tables 1 and 2:

1. Systemic estrogenic activity.

Table 1 shows that arylsulfonate estrone and estradiol cause 100% vaginal cornification at a lower dosage than the original estrogens. These compounds are superior even ethinylestradiol. Higher system activity arylsulfonate should also compared aliroot the growth of the uterus, than the rest of the subjects featured estrogens.

Hepatitis estrogenic activity.

Table 2 shows the dosage of the investigated substances in comparison with the control groups, double the weight of the uterus, respectively 50% change the level of blood angiotensin-1 and HDL cholesterol. For ethinyl estradiol determined in this way is hepatitis activity is a lower dose than that which leads to a doubling of the weight of the uterus. Partly this also applies to the investigated natural estrogen. Arylsulfonate estrogens are hepatitis activity according to the definition only at doses much greater than the effects on the uterus.

As follows from tables 1 and 2, the derivatives according to the invention are natural and synthetic estrogens are compared with their original estrogen greatly increased systemic estrogenic effects. Due to this, it is easier achieved therapeutic effects, i.e., with lower doses than oral use initial estrogen. Reduction of adverse effects of metabolism is confirmed by the observed decrease in hepatitis estrogenic effects in comparison with high sista General formula I

< / BR>
where the residues R1-R13have the above values, which is known in itself by the way is subjected to interaction

a) derivatives östra-1,3,5(10)-triene-3-yl-sulpham, in which with the nitrogen atom sulphamate residue is connected to at least one hydrogen atom, with an activated carboxylic acid, urea, acid, acid or amidosulfonic

or

b) derivatives of 3-hydroxy-östra-1,3,5(10)-triens subjected to interaction, if necessary, in the presence of a base with an activated N-acyl-aminosalicylates, N-sulfonyl-aminosalicylate or N-aminosulfonyl-aminosalicylates,

obtained in this way, the products, if necessary, appropriately subjected to further interaction and, if necessary, the thus obtained products are transferred in a physiologically acceptable metal salts.

Another object of the present invention are pharmaceutical compositions containing at least one derivative of the General formula I

< / BR>
where the residues R1- R13have the above values, if necessary, together with pharmaceutically acceptable excipients and fillers the STV for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular use, which together with the usual excipients and diluents contain a compound of General formula I.

Medicinal product according to the invention are produced in a known manner in suitable doses with conventional solid or liquid fillers or diluents and is usually applied pharmaceutically-technical assistive devices in accordance with the desired method of application. The preferred forms of cooking are applications that are suitable for oral administration. Such applications are, for example, tablets, coated tablet, coated tablets, capsules, pills, powders, solutions or suspension, or sustained-release preparations.

It is also possible, of course, parenteral forms of cooking, such as injectable solutions. In addition, as a form of preparation shall be referred to as, for example, suppositories and means for vaginal use.

Appropriate tablets can be obtained by mixing the active substance with known excipients, for example inert razbavitelyami, corn starch or alginic acid, binding means, such as starch or gelatin, with softeners, such as magnesium stearate or talc, and/or with means to provide prolonged action, as, for example, carboxypolymethylene, carboxylmethylcellulose, acetated cellulose or polyvinyl acetate. Tablets can also consist of several layers.

Accordingly tablets can be manufactured by covering the basics, produced analogously to the tablets used in the production of tablets by means of, for example polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. When this shell beans can also consist of several layers, which can be used are listed for tablets excipients.

A solution or suspension of active substance according to the invention can contain additional, improves the taste of funds, such as saccharin, cyclamate or sugar, and, for example, aromatic substances such as vanillin or orange extract. In addition, they may contain suspendresume tools, such as sodium carboxymethyl cellulose, or preservatives such as p-oxybenzoic. It is estva with an inert filler, for example, milk sugar or sorbitol, and placed in gelatin capsules.

Appropriate suppositories can be manufactured, for example, by mixing provided for this purpose fillers, such as neutral fats or polyethylene glycol or derivatives thereof.

The invention is illustrated by the following examples:

Example 1.

17-oxo-östra-1,3,5(10)-triene-3-yl-(N-acetyl)sulpham (J 1046)

Istranslated (2.0 g) is dissolved in pyridine. To this solution add acetanhydride (100 ml) and stir the mixture for 2 hours at +23oC. Then decomposed with ice, the precipitate is filtered off, washed neutral with water and dried in air stream. Recrystallization from acetone leads to the formation specified in the connection header.

Temperature fluidity: 218-223oC (acetone).

Example 2

17-hydroxy-östra-1,3,5(10)-triene-3-yl-(N-butyryl)-sulpham

Istranslated (1.3 g) dissolved in a mixture of dichloromethane (45 ml) and triethylamine (0.5 ml). While stirring add at +23oC p-dimethylaminopyridine (0,455 g) and butyric acid anhydride (12 ml). After stirring for 20 hours at +23oC 5 ml of the reaction solution is washed with water each time (70 ml), sushi is (50 ml), followed by crystallization. Part of the filtered crystals (0.9 g), which are 17-oxo-östra-1,3,5(10)-triene-3-yl-(N-butyryl)sulpham, dissolved in a mixture of tetrahydrofuran (36 ml) and methanol (36 ml). To a cooled to +5oC the solution while stirring add sodium borohydride (0.36 g). After the restoration (DC control), the mixture is neutralized with acetic acid and the product precipitated with water. Recrystallization from acetone/n-hexane leads to the formation specified in the connection header.

Temperature fluidity: 197-201oC (acetone/n-hexane).

Example 3

17-oxo-östra-1,3,5(10)-triene-3-yl-(N-propionyl)-sulpham

In the solution etranslate (1.0 g) in dichloromethane (35 ml) are added one after the other triethylamine (0.4 ml), p-dimethylaminopyridine (0.35 g) and propionic anhydride acid (7,4 ml). The reaction mixture is stirred for 20 hours at +23oC, then decomposed with ice. The organic phase is washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in a rotary vacuum evaporators, resulting in a gain specified in the header of the connection.

Temperature fluidity: 209-211oC.

Note the config in dichloromethane (70 ml), analogously to example 3 atrificial BOC-anhydride (2.5 g) in the presence of triethylamine (0.8 ml) and p-dimethylaminopyridine (0.7 g). The reaction ends after one hour at +23oC. Obtained after processing the product chromatographic on silica gel (solvent: dichloromethane/ethyl acetate; 7/3 by volume) and then recrystallized from acetone/n-hexane.

Temperature fluidity: 166-169oC (acetone/n-hexane).

Example 5

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

17-hydroxy-19-nor-17-pregna-1,3,5(10)-triene-20 - in-3-yl-sulpham (2 g) dissolved in pyridine (50 ml). To the solution add acetanhydride (50 ml) and stirred the mixture for 2 hours at +23oC. is Treated in accordance with example 1 to the education specified in the title compound, which was recrystallized from acetone.

Temperature fluidity: 218 to 221oC (acetone).

Example 6

16,17-dihydroxy-östra-1,3,5(10)-triene-3-yl-(N,N-dimethylcarbamoyl) sulpham

16,17-bis-(tert-butyl-dimethyl) silyloxy-östra-1,3,5 10)-triene-3-yl-sulpham (1.98 g) was dissolved in dichloromethane (50 ml) and triethylamine (4.9 ml). After adding p-dimethylaminopyridine (0,22 g) and dimethylcarbamodithioato (3,3 ml) the reaction mixture peremeshayte aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in a rotary vacuum evaporators. The residue is dissolved in a mixture (75 ml) of acetic acid, water and tetrahydrofuran (3/1/1 by volume). After settling in for 60 hours at +23oC the mixture is neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined extracts washed with water, dried over anhydrous sodium sulfate m concentrated in rotary vacuum evaporators. Get listed in the title compound as an amorphous white mass.

Example 7

17-oxo-östra-1,3,5(10)-triene-3-yl[N-methyl-N-(N'-methyl) sulfamoyl]sulpham

To a solution of estrone (3.0 g) in dichloromethane (1.2 l) and triethylamine (28,5 ml) was added dropwise N-methylsulfinylpropyl (3 ml). The mixture is stirred for 1.5 hours at +23oC, then decompose water (200 ml), the organic phase is washed successively with diluted hydrochloric acid (1/1 by volume), water, saturated aqueous sodium bicarbonate and water, dried the organic phase with anhydrous sodium sulfate and concentrated it in a rotary vacuum evaporators. The resulting intermediate product is purified by chromatography on silica gel (solvent: toluene/chloroform/methanol; 80/15/5 by volume). After peregrini: 179-185oC (acetone/n-hexane).

Example 8

17-oxo-östra-1,3,5(10)-triene-3-yl(N-tert-butyl-N-tert-butoxycarbonyl)sulpham

Istranslated (2.0 g) dissolved in dichloromethane (70 ml), analogously to example 3 atrificial BOC-anhydride (2.5 g) in the presence of triethylamine (0.8 ml) and p-dimethylaminopyridine (0.7 g), the reaction mixture is left overnight at +23oC. Obtained after processing the product chromatographic on silica gel (solvent: dichloromethane/ethyl acetate; 7/3 by volume) and then recrystallized from acetone/n-hexane.

Temperature fluidity: 162-167oC (acetone/n-hexane).

Example 9

17-hydroxy-extra-1,3,5(10)-triene-3-yl-(N-acetyl)-sulpham (J 1045)

17-oxo-östra-1,3,5(10)-triene-3-yl-(N-acetyl)sulpham (1.0 g) obtained in example 1, restore at 0oC in a mixture of tetrahydrofuran (100 ml) and methanol (100 ml) borane, sodium (0.68 g). After neutralizing the reaction solution with acetic acid (2 ml) is condensed in a rotary vacuum evaporators until dry. The residue is dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). Separate the organic phase, washed with water, dried with anhydrous sodium sulfate and concentrated in a rotary vacuum evaporators. The remainder of perakis the 198-200oC (acetone/n-hexane).

Example 10

Östra-1,3,5(10)-triene-3-yl-(N-acyl)sulpham

To a solution of östra-1,3,5(10)-triene-3-yl-sulpham (1 mmol) and p-dimethylaminopyridine (1.1 mmol) in a mixture of dichloromethane (14 ml) and triethylamine (1 mmol) at room temperature was added chloride or anhydride of the acid (from 10 to 40 mmol). In 1.5-3 hours and washed reaction solution 5 times with 10% aqueous solution of potassium hydroxide and then with water until neutral. Then the solution was dried over anhydrous magnesium sulfate and was agglomerated in a rotary vacuum evaporator. Arylsulfonate was isolated by column chromatography on silica gel using a mixture of toluene/chloroform/methanol in a volume ratio 25/25/10 as eluent and conducted crystallization using a suitable solvent.

Example 11

17-hydroxy-2-methoxy-östra-1,3,5(10)-triene-3-yl-(N - pentanoyl)sulpham

According to example 10 was obtained 2-methoxy-17-oxo - östra-1,3,5(10)-triene-3-yl-N-pentanoyl/sulpham on the basis of 2-methoxy - 17-oxo-östra-1,3,5(10)-triene-3-yl-sulpham anhydride and pentanol acid. Melting point 60-63oC (n-hexane). The recovery of this compound with sodium borohydride in a mixture of methanol and tetrahydrofuran in accordance with clause,67 (3H, s, 18-H); of 0.85 (3H, t, 8 Hz, CH3-(CH2)3, -); to 3.52 (1H, t, 9 Hz, 17-H); to 3.73 (3H, s, 2-CH3O); 4,50 (1H, broad signal, NH); make 6.90 (1H, s, 4-H); of 6.96 (1H, s, 1-H) ppm.

Example 12

17-hydroxy-1415-methylene-östra-1,3,5(10)-triene-3-yl-(N-benzoyl) sulpham

According to example 10 was obtained on 17-oxo-14,15 - methylene-östra - 1,3,5(10)-triene-Z-yl-(N-benzoyl)sulpham from 17-oxo-1415-methylene-östra-1,3,5(10)-triene-3-yl-sulpham anhydride and benzoic acid. The melting point of 232-234oC (diethyl ether). The recovery of this compound with sodium borohydride in a mixture of methanol and tetrahydrofuran in accordance with example 9 leads to the production of the target product as a colorless foam.

1H-NMR (DMSO/H2Oh, TMS): 0,225 (2H, m, 14 15-CHg); to 0.88 (3H, s, 18-H); 3,375 (1H, dd, 9 Hz, 6 Hz, 17 - H); 6,93 (1H, d, 1.5 Hz, 4-H); , 99 (1H, dd, 8 Hz, 1.5 Hz, 2-H); 7,44 (1H, d, 9 Hz, 1-H); 7,89 (2H, d, Hz,,-H-CO-aryl) ppm.

Example 13

Östra-1,3,5(10)-triene-3,1617/-trial-1617-di-p-hexanoate - 3-(H-hexanoyl)sulpham

According to example 10 from estriol-3-sulpham and hexanoic acid anhydride get the target connection. Melting point 212-217oC (n-hexane).

Example 14

17-hydroxy-östra-1,3,5(10), 9(11)-tetraen-3-yl-N(heptanoyl) sulpham

According to the EN-3-yl-sulpham and anhydride heptane acid. The recovery of this compound with sodium borohydride according to example 9 was obtained target compound.

Melting point 148-154oC (tert-butyl methyl ether).

Example 15

17-hydroxy-11-methoxy-östra-1,3,5(10)-triene-3-yl-N-etoxycarbonyl)sulpham

According to example 10 was obtained the 11 - methoxy-17-oxo-1,3,5(10)-triene-3-yl-(N-etoxycarbonyl)sulpham on the basis of 11 - methoxy-17-oxo-östra-1,3,5(10)-triene-3-yl-sulpham and ethylchloride. Recovering the obtained compound with sodium borohydride according to example 9 to obtain the target compound in the form of an amorphous mass.1H-NMR (DMSO/D2Oh, TMS): or 0.83 (3H, s, 18-H); to 1.19 (3H, t, Hz, CH3-CH2-); 3,17 (3H, s, 11 - OCH3); 4.09 to (2H, q, Hz, CH3-CH2); to 4.16 (1H, m, 11 - H); 6,875 (1H, d, 3 Hz, 4-H); of 6.96 (1H, dd, 2 Hz, 8.5 Hz, 2-H); 7.23 percent (1H, d, 9 Hz, 1-H) ppm.

Example 16

17-hydroxy-östra-1,3,5(10),7-tetraen-3-yl-(N-acetyl) sulpham

According to example 10 get 17-oxo-1,3,5(10),7 - tetraen-3-yl-(N-acetyl)sulpham from 17-oxo-östra-1,3,5(10),7-tetraen-3-yl-sulpham and acetanhydride. The recovery of this compound with sodium borohydride according to example 9 was obtained target compound.

Melting point 224-227oC (n-hexane).

The example is made according to example 10 based on 17 gelaksi-östra-1,3,5(10)-triene-3-yl - sulpham and cyclopentanecarbonitrile in the form of butter.

1H-NMR (DMSO, TMS): 0,752 (3H, s, 18-H); was 4.76 (1H, d, 6 Hz, 17-H); 6.89 in (1H, d, 2.4 Hz, 4-H), 6,97 (1H, dd, and 8.4 Hz, 2.4 Hz, 2-H); 7,40 (1H, d, and 8.4 Hz, 1-H) ppm.

Example 18

17-hydroxy-östra-1,3,5(10)-triene-3-yl-(N-propionyl) sulpham 17-oxo-östra-1,3,5(10)-triene-3-yl-(N-propionyl) sulpham obtained in example 3, was restored with sodium borohydride according to example 9 and was obtained target compound.

Melting point 199-203oC (acetone/n-hexane).

Example 19

17-hydroxy-östra-1,3,5(10)-triene-3-yl-(N-phenylacetyl) sulpham

According to example 10 was obtained on 17-oxo-1,3,5(10)-triene-3-yl-(N-decanoyl)sulpham from 17-oxo-östra-1,3,5(10)- triene-3-yl-sulpham and phenylacetylide. The recovery of this compound with sodium borohydride according to example 9 was obtained target compound.

Melting point 182,5-185oC (acetone/n-hexane).

Example 20

17-hydroxy-östra-1,3,5(10)-triene-3-yl- (N-tert-butoxycarbonyl)sulpham

According to example 10 was obtained on 17-oxo-1,3,5(10)-triene-3-yl-(N - tert-butoxycarbonyl)sulpham from 17-oxo-östra-1,3,5(10)-triene-3-yl-sulpham and BOC-anhydride. Melting point 159-165oC (acetone/n-hexane). The recovery of this compound with sodium borohydride the tx2">

Example 21

16,17-dihydroxy-östra-1,3,5(10)-triene-3-yl-(N-acetyl) sulpham

According to example 10 were subjected to interaction 1617-bis-(tert-butyl-dimethyl)silyloxy-östra-1,3,5(10) -triene-3-yl-sulpham with acetanhydride. Then silylamine group was removed as described in example 6. Received noncrystalline the target connection.

1H-NMR (DMSO/N2Oh, TMS): 0,672 (3H, s, 18-H); to 1.75 (3H, s, CH3CO); 3,30 (1H, d, 5,4 Hz, 17-H); of 3.85 (1H, dd, 7.8 Hz, 6 Hz, 16-H); 6,834 (1H, d, 2.1 Hz, 4-H); 6.89 in (1H, dd, and 8.4 Hz, 2.4 Hz, 2-H); then 7.20 (1H, d, 8.7 Hz, 1-H) ppm.

Example 22

17-hydroxy-östra-1,3,5(10),9(P)-tetraen-3-yl-(N-acetyl)sulpham

According to example 10 was obtained on 17-oxo-1,3,5(10),9(11)- tetraen-3-yl-(N-acetyl)sulpham from 17-oxo-östra-1, 3,5(10), 9(11)-tetraen-3-yl-sulpham and acetanhydride. The recovery of this compound with sodium borohydride according to example 9 was obtained target compound.

Melting point 200-203oC (acetone/n-hexane).

Example 23

17-hydroxy-östra-1,3,5(10)-triene-3-yl-(N-acetyl) sulpham

According to example 10 were subjected to interaction 17- (tert-butyl-dimethyl)silyloxy-östra-1,3,5(10)-triene-3-yl-sulpham with acetanhydride. Then silylamine group was removed as described in example 6. By chromatography and Chris is).

In tables 3 and 4 show data on the toxicity of N-arylsulfatase. The data in these tables confirm therapeutic suitability of N-arylsulfatase.

Compounds according to the invention (substitutes extrogen) increase the desired uterotrophic activity compared to the original substances.

The same uterotrophic activity is achieved in the case of estradiol at 280 mg/day compared with 2.5-4 mg/day is proposed according to the invention N-arylsulfonate derivatives.

In the case of estriol by the appropriate substitution is achieved by increasing the uterotrophic activity of factor 4.

With increasing uterotrophic activity decrease undesirable toxic effect.

In the case of estradiol observed a distinct change in lipoprotein (HDL) and angiotensinogen at the dosage, which doubles the weight of the uterus compared to control. Compounds according to the invention, derived estrogen, show this effect only in the case of a factor 20 larger dosages. In the case of estriol threshold effects on the liver lies lower than the threshold effects on the uterus. Offer according to izobreteny the effects on the liver by a factor of 4, i.e., proposed according to the invention the connection by about a factor of 16 is better tolerated, less toxic than the original estriol.

These data allow us to conclude that estrogen according to the invention is more effective in astroventure and is less toxic than known compounds.

1. Derivatives sulpham General formula I

< / BR>
where R1- group-CO - R3, -CO - OR4, -CO - NR5R6, -SO2- R4or SO2NR5R6where R3and R4independently from each other - C1- C5- alkyl residue, a C3- C6- cycloalkenyl residue or a phenyl residue, R5and R6independently from each other - C1- C5is an alkyl residue;

R2is a hydrogen atom or a C1- C5is an alkyl residue;

R7and R8independently of each other a hydrogen atom or a C1- C5- alkoxygroup;

R9and R10each is a hydrogen atom or together a methylene group;

R11, R12and R13independently of each other a hydrogen atom or a hydroxyl group, which is optionally etherification physiologically acceptable inorganic or organic acid is>1and R12independently from each other are located in or position.

2. The method of obtaining derivatives of sulpham under item 1, characterized in that subject interaction derived östra-1,3,5(10)-triene-3-yl-sulpham, in which nitrogen atoms sulphamate residue is connected to at least one hydrogen atom, with an activated carboxylic acid, urea, acid, acid or amidosulfonic if necessary in the presence of a base and if necessary, the resulting products are transferred to a physiologically acceptable salt.

3. Pharmaceutical compositions exhibiting estrogenic activity that contains at least one sulphamate derived by p. 1 optionally together with pharmaceutically acceptable excipients and carriers.

 

Same patents:

acyl(hydr)oxosteroid with antitumor activity" target="_blank">

The invention relates to the chemistry of steroids and related specifically to 3-OR-di-(2-chloroethyl)aminecontaining 11-acyl(HYDR)oxosteroid with antitumor activity General formula (I), where R = COCH2C6H4N(CH2CH2Cl)2; R1=-OCOCH3+-CCH;-OCOC2H5+-H; R2= H, OCOH, COCH3

The invention relates to compounds that perform new functions inhibitors of bone ratably/promoters osteogenesis

-benzaldoxime-Östra-4,9-diene, the method of production thereof, and pharmaceutical composition" target="_blank">

The invention relates to new derivatives of 11-benzaldoxime-östra 4-9-diene, the way they are received and containing these compounds medicines

The invention relates to the field of synthesis of steroid compounds

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

Hypotensive agent // 2142802
The invention relates to medicine, primarily to cardiology

The invention relates to a transdermal therapeutic system for the controlled delivery of estradiol or its pharmaceutically acceptable derivatives individually or in combination with gestagens, as levonorgestrel, in the skin of a human or animal, its application and how you can get

acyl(hydr)oxosteroid with antitumor activity" target="_blank">

The invention relates to the chemistry of steroids and related specifically to 3-OR-di-(2-chloroethyl)aminecontaining 11-acyl(HYDR)oxosteroid with antitumor activity General formula (I), where R = COCH2C6H4N(CH2CH2Cl)2; R1=-OCOCH3+-CCH;-OCOC2H5+-H; R2= H, OCOH, COCH3
Up!