Halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids, their using, methods for their preparing, pharmaceutical composition

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 5 dwg, 1 tbl, 10 ex

 

The present invention relates to a new 17-methylene-4-azasteroid General formula I

in which

R20and R20aeach independently of one another represent fluorine, chlorine, 25 bromine and cyano,

R4and R10represent respectively a hydrogen atom or methyl group,

R1and R2together represent a hydrogen atom or form an additional link.

The invention relates also to methods of obtaining new compounds and their pharmaceutical compositions.

Proposed in the invention of 17-methylene-4-azasteroid are new compounds and their obtain, as well as their biological properties, up to the present time in any publications is not described.

According to the invention preferred compounds of the number of offer presents in paragraph 3 of the claims. The object of the present invention are hereinafter pharmaceutical composition containing as active ingredient at least one 17-methylene-4-azasteroid General formula I, and the composition of these compositions may include, if necessary, appropriate excipients and carriers.

Proposed in the invention compounds are inhibitors of 5α-reductase. Because of this they can be used for Les is possible diseases, due to high levels of testosterone and ultimately of dihydrotestosterone in the blood and tissues.

Diseases associated with excessive activity of androgens may be at a normal level of testosterone in the blood, when the tissue is too intensive conversion of testosterone into dihydrotestosterone. A similar effect is observed, for example, idiopathic forms of hirsutism (according to literary sources).

Progesterone plays an important role for the tight closure of the uterine orifice (Mahendra). The decrease in the density of such closure before the birth is the result of local collapse of progesterone under the influence 5α-reductase and its transformation into dihydroprogesterone, which is a weak gestagen. Therefore, due to the suppression of catabolism of progesterone in this part of the uterus proposed in the invention compounds also suitable for effective prevention of premature development and disclosure of uterine throat.

Restored position 5α metabolites of progesterone (according to information published in the Lancet) and the other With21-steroids and formed in the body metabolites, for example allopregnanolone, have the properties of neurosteroids and able to interact with neurosteroids. Violations of these functions can in one way or another tricatel affect health. Possible indications for the use proposed in the invention compounds are diseases of the prostate, alopecia male type, acne and hirsutism, as well as gynecological disorders, such as premenstrual syndrome, in the case of which an important role plays the restored position 5α metabolites of progesterone in the CNS. Premature opening of the fallopian throat can be induced enhanced dissolution of progesterone in this tissue and its transformation into dihydroprogesterone. Proposed in the invention compounds are able to prevent the catabolism and thereby prevent the premature development of cervical cancer. Proposed in the invention compounds can demonstrate their efficiency by suppressing the recovery position 5α testosterone or progesterone in organs and tissues prone to such violation. In addition, it is possible to reduce the level of content in the blood of relevant metabolites recovered in position 5α.

Proposed in the invention compounds are further intermediate products suitable for the synthesis of other pharmacologically highly effective steroid products.

Methods of obtaining the proposed compounds are presented in paragraphs 4 and 5 of the claims.

Compounds according to claim 1 m which should be obtained according to the invention of the 17-meilensteine General formula II and the General formula VII

According to one variant of the connection according to claim 1 receive the following method.

First, compounds of General formula II is subjected to a known interaction with NaIO4when catalysis using KMnO4in proton solvent, preferably in tert-BuOH, obtaining 3,5-scottkelby. Then this acid with NH4OAc in glacial acetic acid cyclist with the formation of unsaturated lactam and using HCOOH/K2CO3in DMF restore to the saturated lactam of General formula III

further compounds of General formula III interaction with MeI and NaH in a dipolar aprotic solvent, preferably DMF) is converted into 4-methylamine compounds of General formula IV

or compounds of General formula III by silyl oxidation of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDH) in a dipolar aprotic solvent such as dioxane, in turn dehydrogenated lactams of General formula V

Compounds of General formula V is analogous to compounds of General formula III interaction with MeI and NaH in turn 4-methylsiloxane the lactams of General formula VI

According to another variant is soedineniya according to claim 1 receive the same chemical transformation of compounds of General formula VII, the compounds of General formula II, to form compounds of the General formulae VIII, IX, X and XI

Results

Research antiandrogenna activity conducted on castrated, not Mature male rats (see figure 1-5 and table). Experimental animals (5-10 individuals in each group) for 7 days were injected subcutaneous testosterone propionate (TP) and proposed in the invention substance (0.1 mg TP individually and respectively 1 mg of inhibitor 5α-reductase/animal/day). Due to the introduction of the TA has been a significant increase in the mass acessory gonads (prostate and seminal vesicles). The animals, which were introduced only media, and only inhibitor 5α-reductase, such an increase in the mass of the examined organs were observed. Thus, it was found that proposed in the invention compounds in tested systems provide the effect of suppression. The table below shows results show that the compounds J 1879 and J 1924 help reduce (attenuate) the impact of TA on the prostate gland and seminal vesicles.

Table

Suppressed the e effects of testosterone propionate (TP) on the growth of the seminal vesicles and prostate gland. Test immature castrated male rats, n=5-10 individuals in the group, dosage: TA: 0.1 mg/animal/day subcutaneously, inhibitor 5α-reductase: 1 mg/animal/day subcutaneously, the results obtained when applying the filler and TA, was taken as reference and set to 100%.
EM 01.31:ProstateSeminal vesicle
< / br>
TA+J 1879
3425
< / br>
TA+J 1924
3941

Research to identify IC50values for 5A-reductase using steroids J 1879 and J 1924 outside the genital tract were performed on cells of human bone tissue 4 different lines (hOB-cells). Cells within 6 h were incubated with the use of in each case 0.5 µm of Androstenedione (0.1 ám [3H]-Androstenedione, 0.4 µm of Androstenedione) with or without added inhibitors in increasing concentrations (1011-1018).

After incubation, the medium was extracted with chloroform/methanol (volume ratio 2:1) and steroids (substrate and restored to position 5α metabolites) were separated using thin-layer chromatography and determined the DNA content in samples of cells. Activity 5α-reductase (the amount of the formed metabolites, ustanovlennyh position 5α : 5α-androstendion, 5α-dihydrotestosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3α,17β-diol expressed in pmash/µg DNA/h) were determined respectively by double samples. Relative activity 5α-reductase (activity 5α-reductase in the samples with addition of inhibitors compared with benchmarks, i.e. in samples without added inhibitors) are indicated on the drawings, respectively, as the average value of ± standard deviation. IC50-values of compounds J 1879 and J 1924 5α-reductase in bone cells, respectively <1010M

In the course of the research to identify IC50values for compounds J 1879 and J 1924 for the purpose of comparison was additionally determined the inhibitory efficiency connections LY 191704, nonsteroidal specific inhibitor 5α-reductase type 1, finasterida, 4-azasteroid with a predominantly inhibitory effect against 5α-reductase type 2 and progesterone, the physiological substrate 5α-reductase in the cells of all 4 lines at a concentration of 10 M. the Data shown on the accompanying description of the drawings clearly show that the proposed in the invention compounds to inhibit 5A-reductase studied in types of cells harder and significantly more low end is ntrace compared with those of natural substrates and test compounds.

Below the invention is explained in more detail in the examples.

Example 1

E-17-chlormethine-4-Aza-5α-androstane-3-one

To a solution of 3.1 mmole (1.0 g) E-17-chlormethine-4-Asandros-5-ene-3-one in 140 ml of dimethylformamide added under stirring 59 ml of formic acid (85%) and 115, 8mm mmole (16 g) of potassium carbonate and the reaction mixture for 8 h heated under reflux. Then the reaction solution is mixed with toluene and concentrated in vacuo. The residue is dissolved in water and extracted with methylene chloride. The combined extracts are treated with a saturated solution of sodium carbonate, washed with water until neutral pH, dried over sodium sulfate and concentrated. The resulting crude product is recrystallized from acetone/n-hexane and in this way receive 543 mg of solid product (54%).

tPL=148-151°; [α]D20=+16° (CHCl3).

Example 2

E-17-chlormethine-4-methyl-4-Aza-5A-androstane-3-one

To a suspension of 1.06 mmole (340 mg) E-17-chlormethine-4-Aza-5A-androstane-3-one in 9 ml of dimethylformamide added at room temperature in an argon atmosphere is 3.08 mmole (123 mg) of sodium hydride (60%in oil). The reaction mixture was stirred for 30 min and then added dropwise a solution of 5.3 mmole (0.33 ml) under the conditions in 3.0 ml of dimethylformamide. After about 60 min, add 2 ml of a saturated methanol, and after 10 min add 9 ml of a saturated aqueous solution of ammonium chloride. After that, the reaction mixture is diluted with water and extracted with toluene. The combined extracts washed with water, dried over sodium sulfate and concentrated. The resulting crude product is recrystallized from acetone/n-hexane and in this way obtain 154 mg of solid product (43%).

tPL=150-162°; [α]D20=-7° (CHCl3).

Example 3

E-17-chlormethine-4-Aza-5α-androst-1-EN-3-one

1.34 mmole (430 mg) E-17-chlormethine-4-Aza-5α-androstane-3-one is suspended in an argon atmosphere at room temperature in 9 ml of dioxane, and then add 1.5 mmole (340 mg), 2,3-dichloro-5,6-dicyano-n-benzoquinone and 6.4 mmole (1.7 ml) of bis(trimethylsilyl)trifurcated. Next is stirred first for 3 hours at room temperature and then for 3 h in an oil bath at about 100-110°C. the Reaction mixture is diluted with methylene chloride and successively washed with 2%aqueous solution of sodium hydrosulphate, 2 N. hydrochloric acid and water. The resulting extract is dried over sodium sulfate and concentrated. After recrystallization from acetone obtain 243 mg of solid product (57%).

tPL=275-282°; [α]D20=-41° (CHCl3).

Example 4

E-17-chlormethine-4-methyl-4-Aza-5α-androst-1-EN-3-one

To a suspension of 0.87 mmole (279 mg) E-17-chlormethine-4-Aza-5α-androst-1-e the-3-one in 7 ml of dimethylformamide added at room temperature in an argon atmosphere, 2.4 mmole (98 mg) of sodium hydride (60%in oil). The reaction mixture was stirred for 30 min and then added dropwise a solution of 7.5 mmole (0,47 ml) under the conditions in 3 ml of dimethylformamide. After about 60 min, add 2 ml of methanol and after another 10 min add 9 ml of a saturated aqueous solution of ammonium chloride. After diluting the reaction mixture with water is extracted with toluene, the extract washed with water, dried over sodium sulfate and concentrated. The resulting crude product is recrystallized from ethyl ester of acetic acid and in this way obtain 122 mg of solid product (42%).

tPL=160-165°; [α]D20=-47° (CHCl3).

Example 5

E-17-chlormethine-4-Aza-5α-estran-3-one

To a suspension of 3.27 mmole (1 g) E-17-chlormethine-4-asiactr-5-ene-3-one in 150 ml of dimethylformamide are added during the mixing 73,3 ml of formic acid (85%) and 121,55 mmole (16,8 g) of potassium carbonate and the reaction mixture is heated for 12 hours under reflux. Then the reaction solution is mixed with toluene and concentrated in vacuo. The residue is dissolved in water and extracted with methylene chloride. The combined extracts are treated with a saturated solution of sodium carbonate, washed with water until neutral pH, dried over sodium sulfate and concentrate.

The resulting crude product is recrystallized from acetone/n-hexane and in this way receive 461 m the solid product (46%).

tPL=(178-200) 262-282°; [α]D20=-21° (CHCl3).

Example 6

E-17-chlormethine-4-methyl-4-Aza-5α-estran-3-one

To a suspension of 0.65 mmole (200 mg) E-17-chlormethine-4-Aza-5α-estran-3-she 5.8 ml of dimethylformamide added at room temperature in an argon atmosphere 1.7 mmole (73 mg) of sodium hydride (60%in oil). The reaction mixture was stirred for 30 min and then added dropwise a solution of 3.2 mmole (0.2 ml) under the conditions in 2 ml of dimethylformamide. After about 60 min add 1 ml of methanol and after another 10 min add 4 ml of a saturated aqueous solution of ammonium chloride. After that, the reaction mixture is diluted with water and extracted with methylene chloride. The combined extracts washed with water, dried over sodium sulfate and concentrated. The resulting crude product was then purified by chromatography on silica gel 60 (eluent:methylene chloride/acetone in a ratio of 8:2) and recrystallization from ethyl acetate to obtain 131 mg of solid product (62%).

tPL=161-171°; [α]D20=-88° (CHCl3).

Example 7

E-17-chlormethine-4-Aza-5α-variety-1-EN-3-one

1 mmol (310 mg) E-17-chlormethine-4-Aza-5α-estran-3-one is suspended in an argon atmosphere at room temperature in 6.3 ml of dioxane, and then successively add 2.3 mmole (522 mg), 2,3-dichloro-5,6-dicyano-p-benzoquinone and 9.8 mmole (2,6 ml) is IP(trimethylsilyl)trifurcated. Next is stirred first at room temperature for 3 h, and then for 15 h in an oil bath at 100-110°C. the Reaction solution is diluted with methylene chloride and successively washed with 2%hydrogen sulfite solution sodium, 2 N. hydrochloric acid and water. The resulting extract is dried over sodium sulfate and concentrated. After purification by chromatography on silica gel 60 (eluent: methylene chloride/methanol in the ratio 98:2) to obtain 57 mg of solid product (18,5%).

[α]D20=37° (CHCl3).

Example 8

Z-1-(1')-Chlorotoluidines-4-EN-3-one

9,74 mmole (3.28 g) 17β-(1'-chloroethyl-17-hydroxyestra-4-EN-3-one was dissolved in 34 ml of pyridine. Then with a weak cooling and with stirring was added 12,66 mmole (0,92 ml) of thionyl chloride. The reaction mixture was stirred in an argon atmosphere for approximately 1 h, and then cooled in an ice bath was added water, acidified with hydrochloric acid to pH 3-4. Adhesive (sticky) the precipitate was extracted with methylene chloride, the extracts were combined, washed until neutral pH, dried over sodium sulfate and concentrated. The sediment in the form of a solid substance was purified rapid chromatography on silica gel (eluent: toluene/methyl/ethyl)acetate, 95:5) and not necessarily by recrystallization from methanol, was obtained 0.6 g of the product as a solid. tthe l 138-141°, [α]D20+104° (CHCl3).

Example 9

Z-1-(1')-Biometricians-4-EN-3-one

9.7 mmole (3.7 g) 17β-(1')-bromacil-17-hydroxyestra-4-EN-3-one was dissolved in 39 ml of pyridine. Then with a weak cooling and with stirring was added 12,61 mmole (0,91 ml) of thionyl chloride. The reaction mixture was stirred in an argon atmosphere for approximately 1 h, and then cooled in an ice bath was added water, acidified with hydrochloric acid to pH 3-4. The precipitate was extracted with methylene chloride, the extracts were combined, washed until neutral pH, dried over sodium sulfate and concentrated. The precipitate in the form of a yellow foam was purified rapid chromatography on silica gel (eluent: n-hexane/methyl/ethyl)acetate, 95:5) and not necessarily by recrystallization from methanol/acetone, was received 536 mg of the product as a solid light yellow color. tpl.153-158°, [α]D20+109° (CHCl3).

Example 10

E-17-Promotional-4-EN-3-one

28,58 mmole (10.5) 17β-methyl bromide-17-hydroxyestra-4-EN-3-one was dissolved in 90 ml of pyridine. Then with a weak cooling and with stirring was added 37,16 mmole (2.7 ml) of thionyl chloride. The reaction mixture was stirred in an argon atmosphere for approximately 1 h, and then cooled in an ice bath was added water, acidified with hydrochloric acid the same to a pH of 3-4. The precipitated yellow was separated by filtration and purified rapid chromatography on silica gel (eluent: n-hexane/methyl/ethyl)acetate, 85:16), to receive 4,85 g solid of light yellow color. After recrystallization from acetone received 3.1 crystals white. tpl.153-164°C [α]D20+15° (CHCl3).

For these reactions were obtained the following compounds:

Disclosure And cycles were performed similarly as described for the E-17-chloromethylene compounds in examples 1-7 describe the application.

This Appendix provides the rationale that the compounds according to the invention can inhibit the factors that prevent the occurrence/progression of acne.

The origin of acne is a complex process and is the result of the interaction of many factors. A crucial event in the pathogenesis is the blockade follicularly channels hair near the sebaceous glands. A significant contribution to this process makes the production of sebum (sebum) sebocyti and proliferation of keratinocytes. It is proved that the excessive production of sebum is in direct connection with increased stimulation by androgen. It can be proved clinically in the treatment of patients with acne with anti-androgens or estrogens and also is inadequate for the th sebum and the absence of acne in individuals with congenital deficiency of androgen receptors (Tan J.K. and other Oral Contaceptive in the treatment of acne. Skin Therapy Lett., 6, 1 (2001), Miller J.A. and other Anti-androgen treatment in women with acne; a controlled tial, Br. J. Dermatol., 114, 705 (1986), Greenwood R.L. and other Acne: a double blind clinical and laboratory trial of tetracycline, oesrogen-cyproterone acetate and combined treatment, Br. Med. J., (Clin. Res. Ed.), 291, 1231 (1985), Imperato-McGiniey, The androgen control of sebum production. Studies of subjects with dihydrotestjsterone deficiency = MKD and complete androgen insensitivity, J. Clin. Endocrinol. Metab., 76, 524 ff.(1993)).

Inhibitors 5α-reductase inhibition prevents the conversion of testosterone into highly active androgen, 5α-dihydrotestosterone, because they block the enzyme 5A-reductase. Both isoforms of the enzyme (5α-reductase type I and type II) are distributed in the body tissue-specific manner and therefore can provide meets the needs of the organism subtle regulation of androgen status in various organs. For example, in such androgenisation the body, as the prostate gland, and is dominated by 5α-reductase type II, and skin type I. Timeselection lowering of androgen action in the skin by suppressing the transformation of testosterone into 5α-dihydrotestosterone, respectively in skin appendages, requires nevertheless blockade (inhibition) isoenzyme type I.

Proof that the compounds according to the invention, furthermore, in vivo-specific increase sebaceous gland, exprimarea 5α-reductase type I, obtained in the test of Hershberger in the analysis of the prep the territorial glands in rats (see 3).

In contrast insensitive prostate significantly reduces the weight prepucialna cancer when exposed to the compounds according to the invention. Therefore, the inhibitory activity of the compounds by the formation of acne due to excess production of sebum in the sebaceous glands seems reasonable enough.

1. Halogen and pseudohallucinations 17-methylene-4-azasteroid General formula I

in which

R20and R20aeach independently of one another represent fluorine, chlorine, bromine, C1-C4alkyl, cyano or hydrogen,

R10represents a hydrogen atom or methyl group,

R4selected from the group comprising hydrogen and C1-C4alkyl,

R1and R2together represent respectively a hydrogen atom or form an additional link.

2. Halogen and pseudohallucinations 17-methylene-4-azasteroid according to claim 1, with

R4denotes N or CH3,

R20and R20aeach represents F, Cl, Br, N.

3. 17-methylene-4-azasteroid according to claim 1, selected from the group including

E-17-chlormethine-4-Aza-5α-estran-3-one,

E-17-chlormethine-4-Aza-5α-androstane-3-one,

E-17-chlormethine-4-methyl-4-AZ is -5α -estran-3-one,

E-17-chlormethine-4-methyl-4-Aza-5α-androstane-3-one,

E-17-chlormethine-4-Aza-5α-variety-1-EN-3-one,

E-17-chlormethine-4-Aza-5α-androst-1-EN-3-one,

E-17-chlormethine-4-methyl-4-Aza-5α-androst-1-EN-3-one,

E-17-bromethalin-4-methyl-4-Aza-5α-estran-3-one,

E-17-cyanomethyl-4-methyl-4-Aza-5α-estran-3-one,

Z-17-(1')-chloranilide-4-methyl-4-Aza-5α-androstane-3-one,

Z-17-(1')-chloranilide-4-methyl-4-Aza-5α-estran-3-one,

Z-17-(1')-bromethalin-4-methyl-4-Aza-5α-androstane-3-one,

Z-17-(1')-bromethalin-4-methyl-4-Aza-5α-estran-3-one.

4. Method of preparing compounds according to claim 1, where

R20represents fluorine, chlorine, bromine, C1-C4alkyl,

R20adenotes hydrogen,

R10represents a hydrogen atom or methyl group,

R4denotes CH3,

R1and R2together represent respectively a hydrogen atom, characterized in that 17-meilensteine General formula II

in which

R20denotes fluorine, chlorine, bromine, C1-C4alkyl,

R10represents a hydrogen atom or methyl group,

in a known manner is subjected to interaction with NaIO4during the catalysis, using the receiving KMnO 4in proton solvent to obtain 3,5-scottkelby that with NH4OAC in glacial acetic acid cyclist with the formation of unsaturated lactam and using HCOOH in dimethylformamide restore to the saturated lactam of General formula III

in which the substituents R20and R10have the meanings specified for formula II,

then the compounds of General formula III interaction with MeI and NaH in turn 4-methylamine compounds of General formula IV

in which the substituents R20and R10have the meanings specified for formula II.

5. Method of preparing compounds according to claim 1, where R20represents fluorine, chlorine, bromine, C1-C4alkyl, R20adenotes hydrogen, R10represents a hydrogen atom or methyl group, R4denotes CH3, R1and R2together represent respectively a hydrogen atom,

characterized in that 17-meilensteine General formula II

in which

R20denotes fluorine, chlorine, bromine, C1-C4alkyl,

R10represents a hydrogen atom or methyl group,

similarly, item 4 is subjected to interaction with NaIO4the ri catalysis using KMnO 4in proton solvent to obtain 3,5-scottkelby that with NH4OAc in glacial acetic acid cyclist with the formation of unsaturated lactam and using HCOOH in dimethylformamide restore to the saturated lactam of General formula III

in which the substituents R20and R10have the meanings specified for formula II,

which then by oxidation, mediated by silicom, in turn dehydrogenated compounds of General formula V, in which the substituents R20and R10have the meanings specified for formula II,

and then the compounds of General formula V interaction with CH3I and NaH turn 4-methylamine compounds of General formula VI

in which the substituents R20and R10have the meanings specified for formula II.

6. Method of preparing compounds according to claim 1, where R20arepresents fluorine, chlorine, bromine, C1-C4alkyl, R20denotes hydrogen, R10represents a hydrogen atom or methyl group, R4denotes CH3, R1and R2together represent respectively a hydrogen atom,

characterized in that 17-meilensteine General formula VII

in which

R20arepresents fluorine, chlorine, bromine, C1-C4alkyl,

R20denotes a methyl group,

R10represents a hydrogen atom or methyl group,

turn similarly specified in paragraph 4 of the way into the compound of the formula

which then turn similarly specified in paragraph 4 of the method for the compounds of formula III to the compound of formula IX

where the substituents R20aand R10have the meanings indicated for formula VII.

7. Method of preparing compounds according to claim 1, where R20arepresents fluorine, chlorine, bromine, C1-C4alkyl, R20denotes hydrogen, R10represents a hydrogen atom or methyl group, R4denotes CH3, R1and R2together represent respectively a hydrogen atom,

characterized in that 17-meilensteine General formula VII

in which

R20arepresents fluorine, chlorine, bromine, C1-C4alkyl,

R20denotes a methyl group, and

R10represents a hydrogen atom or methyl group, transform likewise specified in section 5 how to connect four is uly II to the compound of formula X,

which then turn similarly specified in section 5 of the method for the compounds of formula V to the compound of formula XI

where the substituents R20aand R10have the meanings indicated for formula VII.

8. Pharmaceutical composition having inhibitory alpha-reductase activity and intended for the treatment of diseases due to the increased level of androgens, containing at least one 17-methylene-4-azasteroid according to claim 1 and optionally pharmaceutically acceptable excipient or carrier.

9. Applying at least one 17-methylene-4-azasteroid according to claim 1 to obtain a pharmaceutical preparation for the treatment of acne.



 

Same patents:

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SUBSTANCE: invention relates to the improved method for preparing chemical compounds of steroid order, namely, to a method for preparing epibrassinolide representing (22R,23R,24R)-2α,3α,22,23-tetrahydroxy-B-homo-7-oxa-5α-ergostane-6-one and relating to biologically active substance - a phytostimulator regulating growth of plants. Method involves the successive carrying out the following stages: a) synthesis of ergosterol mesylate by treatment of ergosterol with methanesulfochloride in pyridine; b) synthesis of isoergosterol by boiling ergosterol mesylate in aqueous acetone in the presence of potassium (sodium) hydrocarbonate; c) synthesis of isoergosterone by oxidation of isoergosterol with chrome anhydride in pyridine; d) synthesis of 7,8-dihydroergosterol by reduction of isoergosterone with sodium dithionite in the presence of a solubilizing medium containing cationic, anionic or nonionic surface-active substances of the following order: CnH2n+1X wherein n = 9-18; X means -NMe3, -NEt3, -COOH, -SO3H, -OSO2M, -OP(O)(OM)2 wherein M means alkaline metal, polyethylene glycol, (C2-C6)-aliphatic alcohols or monoesters of ethylene glycol or diethylene glycol as a co-solubilizing agent, electrolyte and water taken in the molar ratio = 1:(5-6):(100-250), respectively; e) steroid rearrangement of 7,8-dihydroisoergosterol; f) formation of 24-epicastasterone by treatment of (22E,24R)-5α-ergosta-2,22-diene-6-one with methanesulfoneamide and potassium carbonate with using catalytic amounts of potassium ferricyanide (III) and osmium tetraoxide; g) dissolving 24-epicastasterone formed in chloroform followed by treatment with trifluoroperacetic acid forming in mixing trifluoroacetic anhydride and hydrogen peroxide in chlorinated organic solvent, and isolation of the end product of the formula (I) with high yield.

EFFECT: improved preparing method.

2 cl, 7 ex

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< / BR>
where X = H, NH4showing immunostimulirutuyu activity

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The invention relates to a new composition has a curing effect in alopecia, hirsutism in women's type, or seborrhea, or having a preventive effect against metastases in bones caused by prostate cancer, containing N-[1-methyl-1-(4-methoxyphenyl)ethyl]-3-oxo-4-Aza - 5-androst-EN-17-carboxamide, or its pharmaceutically acceptable salt or pharmaceutically acceptable derivative

The invention relates to substituted phenylimidazoline, method of production thereof and to pharmaceutical compositions based on them

The invention relates to new benzofuranyl derivatives and to the method of obtaining these derivatives

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.

EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.

53 cl, 10 tbl, 24 ex

FIELD: organic chemistry, steroids, biology.

SUBSTANCE: invention relates to steroid compounds of the general formula (X):

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: method relates to composition containing estrogen as the first active ingredient in amount sufficient to treatment of diseases, disorders, and symptoms associated with deficit of endogen estrogen levels in women; and drospyrenon as the second ingredient in amount sufficient to endometrium protection from unfavorable estrogen effects. Methods for treatment also are disclosed. Preparations of present invention are useful in combination therapy for continuous, subsequent or intermittent administration.

EFFECT: method for replacement hormonotherapy in women of improved efficiency.

46 cl, 7 ex

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