Connection kit, androgenic composition

 

(57) Abstract:

The invention relates to steroids of General formula I

where R1- Oh, (H,H), (H,OR), NOR, where R is H1-6alkyl, C1-6acyl; R2- H or C1-6alkyl, R3- H, or R3- C1-6alkyl, C2-6alkenyl,2-6quinil, possibly substituted with halogen, R4- H, C1-6alkyl or C2-6alkenyl; R5- C1-6alkyl, R5- H, R7- H, C1-6alkyl, R8Is H, OH, halogen;

R9and R10independently H, or R9and R10independently C1-6alkyl, possibly substituted C1-4alkoxy or halogen;

R11- H, SO3H1-15acyl, dashed line indicates a possible link of 4, 5(10)or 4,9-diene system. The compounds have the General androgenic activity and can be used to obtain an agent for male contraception. 6 N. and 3 C.p. f-crystals, 2 PL.

The present invention relates to steroid compounds having a cyclopropane ring, which includes the carbon atoms 14 and 15 of the steroid skeleton. More specifically, the invention relates to such steroid compounds that possess androgenic activity.

Steroi the region of the women's contraceptive and hormone therapy against endometriosis or menopausal complaints. Steroids are described as having a progestogenic activity, examples are 14 , 15-methyltetra-4,9-Dien-3-one-17-ol and 3-oxo-14 ,15-methyltetra-4,9-Dien-17-yl-(N-phenyl)-carbamate. Neither efficiency nor any other receptor activity of these Progestogens can not be inferred from this description.

In the patent application PCT/DE99/01795 (published December 29, 1999 as WO 99/67276) was described group 14,15-cyclopropylamino, among which there are 17-hydroxy-substituted steroids.

Another patent application WO is 00/53619, which describes a group of androgens, which are 14 , 17 configuration, namely (14 , 17 )-17-(hydroxymethyl)-steroids.

The present invention covers a new group of steroids of the General type as described above which have unexpected androgenic activity. Unlike Progestogens described in the known technology, the androgens of the present invention, including a very potent androgens, among other things, satisfy the requirements that the cyclopropane ring was oriented so the carbon atom number 17 was attended by hydroxymethylene group, which is focused. As a consequence of the steroids of the invention have 14-configurations is the tenant 14 , 17 .

Steroids according to the invention correspond to the structural formula I:

where R1represents O, (H,H), (H,OR), NOR, and R represents hydrogen, (C1-6)alkyl, (C1-6)acyl;

R2represents hydrogen or (C1-6)alkyl;

R3represents hydrogen or R3is (C1-6)alkyl, (C2-6)alkenyl or (C2-6)quinil, each of which is optionally substituted with halogen;

R4represents hydrogen, (C1-6)alkyl or (C2-6)alkenyl;

R5is (C1-6)alkyl;

R6represents hydrogen, halogen or (C1-4)alkyl;

R7represents hydrogen or (C1-6)alkyl;

R8represents hydrogen, hydroxy, (C1-6)alkoxy, halogen or (C1-6)alkyl;

R9and R10independently, represent hydrogen or R9and R10independently represent a (C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl, (C5-6)cycloalkenyl or (C2-6)quinil, each of which is optionally substituted C1-4)alkoxy or halogen;

R11represents hydrogen, SO3N, (C1-15)acyl and poli 4,9or 4,11-diene system.

The invention relates not only to the steroids, which correspond to the structural formula I, but also their pharmaceutically acceptable salts or esters, prodrugs and predecessors.

The term (C1-6)alkyl used in the definition of formula I means a branched or unbranched alkyl group having 1-6 carbon atoms, such stands, ethyl, propylene, isopropyl, butile, isobutyl, tertiary butila, pentile and hexyl. Similarly, the term (C1-4)alkyl means an alkyl group having 1-4 carbon atoms. Preferred alkyl groups have 1-4 carbon atoms, and very preferred alkyl groups are methyl and ethyl.

The term (C2-6)alkenyl means a branched or unbranched alkenylphenol group having at least one double bond and 2 to 6 carbon atoms. Preferred alkeneamine groups have 2-4 carbon atoms, such as vinyl and propenyl.

The term (C2-6)quinil means a branched or unbranched alkylamino group having at least one triple bond and 2 to 6 carbon atoms. Preferred alkyline groups have 2-4 atom threats the abuser 3-6 carbon atoms, similar to cyclopropane, CYCLOBUTANE, cyclopentane and cyclohexane.

The term (C5-6)cycloalkenyl means the ring of cycloalkene having at least one double bond and 5 or 6 carbon atoms.

The term (C1-6)alkoxy means a branched or unbranched alkyloxy having 1-6 carbon atoms, such metiloksi, acyloxy, propyloxy, isopropoxy, bucalossi, isobutoxy, tertiary, bucalossi, pentyloxy, hexyloxy. Similarly, the term (C1-4)alkoxy means a branched or unbranched alkyloxy having 1-4 carbon atoms. Preferred alkyloxy have 1-4 carbon atoms, and very preferred is metiloksi.

The term (C1-6)acyl means an acyl group, formed from carboxylic acids having 1-6 carbon atoms such as formyl, acetyl, propanol, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl and hexanoyl. Similarly, the term (C1-15)acyl means an acyl group, formed from carboxylic acids having 1 to 15 carbon atoms. In the definition (1-6)acyl or (C1-15)also includes acyl acyl group, formed from dicarboxylic acids, such Hemi is Yes halogen is a Deputy in the alkyl groups, as in the definition of R3, R6, R8, R9AND R10preferred Halogens are C1 and F, and it is preferable F.

Derivatives 14 ,15-methylene-17-methanosarcina of the present invention have a natural configuration 5 , 8 , 9 , 10 and 13 . The configuration at C-17 is 17 . Compounds of the invention may also have one or more chiral atoms of hydrogen. They can, therefore, be obtained in the form of a pure diastereoisomer or mixture of diastereoisomers. Methods of obtaining pure diastereomers are well known in the art, such as crystallization or chromatography.

For therapeutic use, salts of the compounds of formula I are salts in which the counterion is pharmaceutically acceptable. However, salts of acids according to formula I may also find use, for example, upon receipt or purification of pharmaceutically acceptable compounds. All salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of the present invention. Examples of salts of the acids according to the invention are mineral salts such as sodium salt, potassium salt and a salt, such.

Compounds in accordance with the invention as described here above, have unexpected androgenic activity. Androgenic activity can be measured in different ways. Thus, the efficiency of androgens can be determined in vitro using tsitoplazmaticheskogo androgen receptor of the tumor cells of the breast man (cell line MCF-7); see Bergink, E. W. et al., “Comparison of binding the receptor properties of nandrolone and testosterone in vitro and in vivo”, J. Steroid Biochem. 22, 831-836 (1985). You can also use the cells of the Chinese hamster ovary (Cho), transfection receptor androgen person (the incubation time of 16 h, temperature 4° C) and compared with the affinity of 5-dihydrotestosterone [in accordance with the procedure described Bergink, E. W. et al., J. Steroid Biochem. 19, 1563-1570 (1983)]. Transactivism androgenic activity of the compounds of the invention can be measured, for example, in the cells of the Chinese hamster ovary (Cho), transfection the androgen receptor of human (hAR) in combination with the virus of breast cancer (MMTV) and receptor gene luciferase (incubation time of 16 h, temperature 37° C) and compared with the activity of 5-dihydrotestosterone [in accordance with the procedure described Schoonen, W. G. E. J. et al., Analyt. Biochem. 2tohm test androgenic (weight gain of the prostate) and anabolic activity [muscle gain, levator anus (MLA)] compounds were tested in immature castrated rats after daily injection within 7 days; see Hershberger, L. G. et A1., “Mitrovitsa activity 19-nortestosterone and other steroids determined by the modified method on the muscle, levator anus”. Proceedings of the society for experimental biology and medicine 83, 175-180 (1953). In addition, the influence of androgenic compounds in the suppression of luteinizing hormone (LH) can be tested on Mature castrated rats according to Kumar, N. et al., “Biological activity alpha-methyl-19-nortestosterone not amplificates in genital tract specimens of the male sex, as amplificates biological activity of testosterone”, Endocrinology, 130, 3677-3683 (1992).

Preference is given to compounds in accordance with the invention which exhibit relatively high androgenic activity. Thus, preferred compounds of the invention are compounds which correspond to the above formula I, in which R1represents oxo and dashed lines indicate 4-double bond. More preferred are compounds in which R3is 7-methyl. Especially preferred connection and the different hormones steroids of the present invention can be used, inter alia, in male contraception and male HRT (hormone replacement therapy). For example, male contraception may include a scheme of introducing hormones, in which the progestogen is used to achieve the contraceptive action and androgen serves to replenish testosterone, low levels of which are observed. Another option is that male contraception is performed only with androgenic hormone. Androgens can also be used for replenishment of androgen in aging males with partial androgen deficiency. As for the use of androgens for individuals male androgens invention can also be used for females, such as androgen replacement therapy in postmenopausal women or in children with androgen deficiency.

The present invention relates also to pharmaceutical compositions comprising steroid compound in accordance with the invention, mixed with pharmaceutically acceptable auxiliary means, as described in the standard reference, Gennaro et al., Remmington's Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, see especially part 8: Pharmaceutical preparations and their manufacture”). The mixture steroiddependent in solid dosage forms, such as pills, tablets, or enter into capsules or suppositories. With the help of pharmaceutically acceptable liquids compounds can also be used as a drug for injection in the form of solution, suspension, emulsion or spray, for example a nasal spray. For the manufacture of dosage forms such as tablets, discusses the use of conventional additives such as fillers, dyes, polymeric binder, and the like. In General, you can use any pharmaceutically acceptable additive, which prevents the action of the active compounds. Steroid compounds of the invention can also be incorporated into the implant, vaginal ring, patch, gel or any other product for prolonged release (active connection).

Suitable carrier materials with which you can enter the composition, include lactose, starch, cellulose derivatives and the like or mixtures thereof, used in the right quantities.

In addition, the invention relates to the use of steroid compounds in accordance with the invention for the manufacture medicines used in the treatment of androgen deficiency, such as male or female HRT (mountains is male or female HRT, includes introduction to the patient the male or female suffering from androgen deficiency, compounds as described herein before (in a suitable pharmaceutical dosage form).

In addition, the invention relates to the use of steroid compounds in accordance with the invention for the manufacture of a medicinal product with contraceptive activity (which in this area also use the term “contraceptive agent”). Thus, the invention relates to medical indication of contraception, i.e., the method comprising introducing to a subject, which is the individual male, preferably male human connection as described here previously (in a suitable pharmaceutical dosage form) in combinational therapy with or without progestogen.

Androgens in accordance with the invention can also be used in the set for male contraception. Although this set may include only one or more androgens, it is preferable to include means for introducing a progestogen and a means for introducing an androgen. The last resort is finished pharmaceutical preparative form, including a CLASS="ptx2">The invention relates also to method of treatment, including the introduction of the male or female (especially a man) who needs androgenic replenishment, a therapeutically effective amount of a derivative 14 ,15-methylene-17-methanosarcina, as described here previously. Such treatment does not depend on whether you receive the need for androgen replenishment as a result of male contraception, including the introduction of a sterilizing agent, such as progestogen.

In addition, the invention relates to a method of contraception, including the introduction of fertile males, especially male human-derived 14 ,15-methylene-17-methanosarcina, as described here earlier in dosed quantities and according to the scheme, which is sufficient for the specified connection was per se contraceptive effective. In the alternative case, the method provided by the present invention, includes the introduction of fertile males, especially male human, contraceptive effective combination of the sterilizing agent, such as a progestogen, and derivative 14 ,15-methylene-17-methanosarcina, as described here previously.

Connection izobretatel chemistry of steroids (see, for example: Fried, J. et al., “Organic Reactions in Steroid Chemistry”, Volumes I and II, Van Nostrand Reinhold Company, New York, 1972). Significant is the introduction of 14 ,15-methylene group and (substituted) 17 -(hydroxymethylene) group in the steroid ring.

A suitable source material for producing compounds of formula I, where R1is oxo; R2, R7, R8and R11represent hydrogen; R3and R4represent hydrogen or (C1-6)alkyl; R5is methyl; R6, R9and R10have the above values, and the dotted line means a double bond 4that is, for example, the compound of General formula II, where R3and R4represent hydrogen or (C1-6)alkyl, the synthesis of which is known in the literature or which can be obtained using standard methods [see, for example, U.S. patent 3407217 (1965; R3=N, R4=N), French patent 1434172 (1966; R3=CH3, R4=N), the German patent 2539300 (1976; R3=N, R4=CH3), WO 99/26962 (R3=CH3, R4=CH3)].

A possible way of synthesis of compounds in accordance with the invention begins with the transformation of compounds of formula II in 14the compounds of formula III with ispolnenii link 14results derived(14 , 15 , 17 )-3-methoxy-14,15 methyltetra-1,3,5(10)-trien-17-ol [Helquist, P., in the monograph “Comprehensive Organic Synthesis”, Vol. 4, R. 951, Pergamon Press, Oxford, New York (1991); Nair, V., ibid, Vol. 4, p. 999 (1991); Larock, R. C., “Comprehensive Organic Transformations”, VCH Publishers, Inc., 1989, p. 71]. Oxidation of 17-hydroxy-group gives the derivative (14 ,15 )-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-she (for okislenii see Hudlicky, M., “Oxidations in Organic Chemistry, ACS Monograph 186, Washington, DC, 1990), which serves as the starting material for introduction of fragment 17-carbinol.

The conversion of 17-oxa-17-(CH2OH) can be done in several ways:

(a) 1: the Wittig Reaction or Peterson for derivative 17-methyltetra-1,3,5(10)-triens [Maercker, A., “Org. Reactions” 14, R. 270, Wiley, New York, 1965; Adeg, D. J., “Org. Reactions”, 38, of R. 1, Wiley, New York, 1990]; 2: gidroborudovaniya, for example, through the use of 9-BBN, disabiliry or vexillary [see, for example, Zweifel, G. et al., in “Org. Reactions” 13, R. 1, Wiley, New York, 1963], leading to the formation of a derivative (17 )-östra-1,3,5(10)-triene-17-methanol and/or of the corresponding 17-isomer.

(b) 1: the Transformation of the 17-ketone in (17 )-spirometry-1,3,5(10)-triene[17,2 ]oxiran interaction, for example, with a system of iodide trimethylsulfonium/n-BuLi [Corey, E. J. et al., J. Am. Chem. Soc. 87, 1353 (1965)]; 2: catalyzed ss, Oxford, New York (1991)]; 3: recovery-17-formyl 17 -(CH2IT).

(C ) 1: the Transformation of the 17-ketone in the 17-methylenediamine; 2: epoxydecane, for example, peroxyketal, such as m-chloroperbenzoic acid, (17 )-spirometry-1,3,5(10)-triene[17,2 ]oxiran; 3: acid catalyzed (Lewis) isomerization 17-formyl as described in (b); 4: recovery 17-formyl 17 -(CH2OH).

(d) Converting the 17-ketone in the 17-oxiran, as described in (b) and (C); 2: catalyzed by Lewis acid recovery 17-methanosarcina [using, for example, NaBH3CN/BF3·Et2O, see: Tone, H. et al. Tetrahedron Lett. 28, 4569 (1987)].

(e) 1: the Transformation of the 17-ketone in the 17-lanosterol interaction with toiletrieschoice [TosMIC, see Bull, J. R. et al., Tetrahedron 31, 2151 (1975)]; 2: recovery ceanography in formyl-diisobutylaluminium; 3: recovery-17-formyl group in 17-(CH2IT).

(f) 1: Wittig Condensation with participation (Ph)3P=Sname; 2: hydrolysis of the resulting simple enol ester; 3: recovery-17-formyl 17-(CH2OH).

(g) 1: the Transformation of the 17-ketone in the 17-oxiran, as described in (b) and (C); 2: elimination in the derived östra-1,3,5(10),16-tetraen-17-methanol; 3: hydrogenation of double bonds 1616.

(i) 1: the Transformation of the 17-ketone in alkylester-1,3,5(10),16-tetraen-17-carboxylate, as described in (h); 2: 1,4-recovery, for example, by hydrogenation or by recovery of lithium or sodium in liquid ammonia, derived alkylester-1,3,5(10)-triene-17-carboxylate; 3: recovery of ether 17-(CH2IT).

Some of these methods (for example, b, C) lead to the stereoselective formation of 17 -(CH2OH)-isomer. Other (e.g., a) can give a mixture that can be separated by chromatography or crystallization.

Thus obtained derivative(14 ,15 ,17 )-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-methanol is subjected to recovery Birju and then hydrolysis to obtain derivatives(14 ,15 ,17 )-17-(hydroxymethyl)variety-4-EN-3-she of the present invention.

(14 ,15 ,17 )-3-Methoxy-14,15-methyltetra-1,3,5(10)-triene-17-carboxaldehyde above, can optionally be subjected to interaction with (ORGANOMETALLIC which M is Li, Na, K, YFC, ZnX, CeX2, SiR3or SnR3while receiving 17-(CHR9OH)-derivative, which is usually a mixture of C20-epimeres. The latter can be divided, after which the recovery Birju and hydrolysis, as described above, to give derivatives (14 ,15 ,17 )-17(R9IT)-14,15-methyltetra-4-EN-3-she of the invention, in which R9 has the above values, with the exception of hydrogen.

(14 ,15 ,17 )-17-(R9HE)-3-Methoxy-14,15-methyltetra-1,3,5(10)-triene is possible, optionally, to oxidize to obtain the 20-ketone, which can then be subjected to interaction with (ORGANOMETALLIC) of the compound of formula R10M, and R10has the previously indicated meanings, with the exception of hydrogen, and M have the previously indicated meanings. In this case, the recovery Birju and hydrolysis will give 17-(CR9R10IT)-derivatives of the invention, where R9and R10have the previously indicated meanings, with the exception of hydrogen.

the 20-Ketone is possible, optionally, to restore communication with LiAlH4, NaBH4or other reducing agents. In this case, get the 17-(CHR9OH)-derivatives with inverted stereochemistry at C-20. The epimerization at C-20 can be performed by using the reaction of Mitsunobu (Mitsunobu) [Dodge, J. A the brilliant interaction with an oxygen nucleophile [for example, the potassium superoxide, see Corey, E. J. et al., Tetrahedron Lett. 3183 (1975)].

Derived(14 ,15 ,17 )-3-methoxy-14,15-methyltetra-2,5(10)-diene-17-methanol, i.e., the product obtained after recovery Birju, it is possible, optionally, to oxidize to the corresponding 17-carboxaldehyde. Interaction with the compound of the formula R9M, as described above, and the hydrolysis give 17(CHR9OH)-derivatives in accordance with the invention, as already described above. The sequence of the specified interaction allows you to enter the substituents R9and, similarly, R10that may not withstand the recovery Birgu. 3-Methoxy-2,5(10)-diene can also, optionally, be converted into a more stable system, for example, derived 3,3-dimethoxyethan-5(10)-ene derivatives of cyclic 1,2-ethandiyl(dithio)acetal variety-4-EN-3-one before oxidation and interaction with R9M and so on

The compounds of formula I with substituents at C-3, C-4, C-7, C-11, C-13, C-1’, C-16 and C-17, other than the substituents described in the definition of formula II, or compounds with R11other than hydrogen, or compounds without double bonds in the steroid ring or nenasyshchennosti, other than the double bond 4can be obtained as follows.

Connection soborno be obtained from compounds of the formula I, in which R1is oxo.

Compounds in which R2is (C1-6)alkyl, are obtained from compounds of the formula I, in which R2represents hydrogen.

Connection with the substituent R3other than hydrogen, can be obtained, for example, from (7 ,17 )-7-ethynyl-17-hydroxyestra-4-EN-3-one, which can be obtained catalyzed by copper (I) 1,6-attach vinylite or connection vinylmania, for example, (17 )-17-(atomic charges)östra-4,6-Dien-3-ONU [Syntex, German patent 1143199 (1963)]. The transformation (7 )-7-ethynyl-3-petoksista-1,3,5(10)-triene-17-she and construction of functionalized and/or unsaturated side chain at C-7 of 7-Attila performed using standard methods and the introduction of 14 ,15-methylene group and the side chain at C-17 performs, as described above. The exact sequence of stages of reactions required for these operations and to restore Birju and hydrolysis of the resulting östra-2,5(10)-diene, dictated by methods conventional in the synthetic strategy.

Compounds with substituents R4other than hydrogen or (C1-6)alkyl, can be obtained, for example, from cyclic 1,2-candirectly (11 )-11(hydroxymethyl)-3-petoksista-1,3,5(10)-triene-17-she [A. J. van et al. The Reel. Trav. Chim. Pays-Bas 94, 35 (1975).

Compounds in which R5is, for example, ethyl, can be obtained, for example, 13-atilgan-4-ene-3,17-dione [Brito, M. et al., Synth. Somme. 26, 623 (1996)].

16-Substituted compounds can be obtained by alkylation of the derived C16 (14 ,15 )-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-it.

(17 )-Alkylated compounds of formula I can be obtained, for example, by alkylation of alkyl(14 ,15 ,17 )-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-carboxylate. The compounds of formula I in which R8represents hydroxy, (C1-6)alkoxy or halogen, can be obtained from (17 )-spirometry-1,3,5(10)-triene[17,2’]oxirane.

Compounds of the invention in which R11is SO3N or (C1-15)acyl, are obtained from compounds of the formula I, in which R11represents hydrogen.

Compounds in accordance with the invention, containing no unsaturated bonds in the steroid ring, obtained from 4-compounds, where R1is oxo.

Compounds of the invention having a double bond 5,(10)or diene system 4,9receive from 2,5(10)-dienes obtained after recovery Birgu.

Connection with dual SV is the buy will be further explained hereinafter with reference to the following examples.

Example 1

(7 ,14 ,15 ,17 )-17(Hydroxymethyl) -7-methyl-14,15-methylenethf-4-EN-3-one

i) a Solution of (7 ,17 )-3-methoxy-7-methylestra-1,3,5(10),14-tetraen-17-ol [Segaloff, A. et al. Steroids 22, 99 (1973); 25.4 g] and diiodomethane (27 ml) in anhydrous dichloromethane (500 ml) cooled to 0° C. Add a solution of diethylzinc in hexane (15 wt.%, 300 ml) for 1 hour and the reaction mixture is stirred for 21 hours at room temperature. Add ice and the mixture is then poured into a saturated aqueous solution of ammonium chloride. The product is extracted with diethyl ether; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-trien-17-ol (6.50 g).

ii) a solution of the product obtained in the previous phase (6.50 g) in acetone (325 ml) is cooled to 5° C, treated with Jones reagent (8 M, 11.9 ml). After 15 min stirring at 5-10° add 2-propanol and the mixture is filtered. The filtrate is concentrated; water is added and the product extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced davidhouse stage without additional purification.

iii) tert-Piperonyl potassium (6,1 g) is added in several portions to a solution of the product obtained in the previous phase (3,81 g) in a mixture of anhydrous tetrahydrofuran (26 ml) and anhydrous dimethyl sulfoxide (65 ml) containing iodide trimethylsilane (8,4 g). The reaction mixture was stirred at room temperature for 3 h and then poured into an aqueous solution of ammonium chloride. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methylandrosta-1,3,5(10)-triene[17,2’]oxirane (3,76 g). The product is used in the next stage without additional purification).

iv) a solution of the product obtained in the previous stage (3,76 g) in 1,4-dioxane (113 ml) was treated with an aqueous solution perchloro acid (70%, 1.80 ml). The reaction mixture was stirred at room temperature for 2 h and then treated with another portion perchloro acid (0,36 ml). The mixture is stirred for another 2 h and then poured into a saturated aqueous solution of sodium bicarbonate. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, s,15-methyltetra-1,3,5(10)-triene-17-carboxaldehyde (4.11 g). The product is used in the next stage without additional purification.

v) a solution of the product obtained in the previous stage (3.7 g) in anhydrous tetrahydrofuran (24 ml) is added dropwise to ice suspension sociallyengaged (1.90 g) in tetrahydrofuran (24 ml). After stirring 1 h, the reaction mixture was quenched by adding saturated aqueous solution of sodium sulfate. Add ethyl acetate and the mixture filtered through dicalite. The organic phase is separated from the aqueous phase and washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-triene-17-methanol (1.30 grams).

vi) the Product obtained in the previous phase (1,30 g) in anhydrous tetrahydrofuran (27 ml) is added to boiling under reflux to a solution of lithium (0,82 g) in liquid ammonia (54 ml). The reaction mixture is stirred at the boiling temperature of phlegmy for 45 minutes Add tert-butanol (2.7 ml) and the mixture is stirred for 30 minutes Add the ethanol and allow to evaporate the ammonia. Add water and the product extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous chloride and getting(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-diene-17-methanol (1,17 g). The product is used in the next stage without additional purification.

vii) a solution of the product obtained in the previous phase (1,17 g) in acetone (23 ml) is treated with hydrochloric acid (6 M, 2 ml). After stirring for 1 h at room temperature, add saturated aqueous solution of sodium bicarbonate and the product extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17(hydroxymethyl)-7-methyl-14,15-methylene-variety-4-EN-3-one (0.40 g). So pl. 137-140° C. [ ]20D=+73,0° (C=1,00, dioxane),1H NMR (CDCl3) 5,80 (Shir.s, 1H), 3,69 (m, 1H), 3,50 (m, 1H), 1,09 (s, 3H), and 0.62 (d, 3H, J=7,1 Hz), 0,47 (DD, 1H, J=8,3 and 5.1 Hz), 0,28 (DD, 1H, J=5.1, 3.5 Hz).

Example 2

(7 ,14 ,15 ,17 )-17(Hydroxymethyl)-7-methyl-14,15-methylenethf-5(10)-EN-3-one

The solution(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-diene-17-methanol (example 1, stage vi; 7,38 g) in a mixture of methanol (68 ml) and tetrahydrofuran (48 ml) is treated with a solution of oxalic acid (2.38 g) in water (40 ml). After stirring for 1 h at room temperature, the reaction mixture was poured into saturated aqueous rastvornym salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17(hydroxymethyl)-7-methyl-14,15-methylenethf-5(10)-EN-3-one (4,27 g).1H NMR (CDCl3) of 3.69 (m, 1H), 3,51 (t, 1H, J=9.0 Hz), 2,72 (Shir.s, 2H), 2,46 (Shir.s, 2H), was 1.04 (s, 3H), 0.69 (d, 3H, J=7,1 Hz), 0,48 (DD, 1H, J=8,3 and 5.1 Hz), 0,27 (DD, 1H, J=5.1 and 3.1 Hz).

Example 3

(7 ,14 ,15 ,17 )-17-(Hydroxymethyl)-7-methyl-14,15-methyltetra-4,9-Dien-3-one

Bromide of phenyltrimethylammonium (1.01 g) are added to a solution(7 ,14 ,15 ,17 )-17(hydroxymethyl)-7-methyl-14,15-methylenethf-5(10)-EN-3-one (example 2, of 0.85 g) in anhydrous pyridine (25 ml). After stirring 1.5 h at room temperature the mixture was poured into a mixture of ice-water and the product extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium thiosulfate and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17(hydroxymethyl)-7-methyl-14,15-methyltetra-4,9-Dien-3-one (0.18 g).1H NMR (CDCl3) of 5.68 (s, 1H), and 3.72 (m, 1H), 3,60 (m, 1H), 3,01 (Shir.s, 1H), 1,11 (s, 3H), 0.69 (d, 3H, J=7,1 Hz), 0,52 (DD, 1H, J=8,3 and 5.5 Hz), 0,38 (DD, 1H, J=5.5 and 3.9 Hz).

Example 4

(7 ,14 ,15 ,17 )-17(Hydroxymethyl)-4,7-dimethyl-14,15-methylenethf-4-EN-3-on is a mixture of formaldehyde (37 wt.% the solution in water, of 0.24 ml), triethylamine (in 0.288 ml), thiophenol (0,276 ml) and ethanol (0,721 ml) was stirred at room temperature overnight. The reaction mixture was poured into an aqueous solution of potassium hydroxide (0.5 M) and the product extracted with ethyl acetate. The combined organic phases are washed with aqueous solution of potassium hydroxide (0.5 M) and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17(hydroxymethyl)-7-methyl-4-[(phenylthio)methyl]-14,15-methylenethf-4-EN-3-one (0,13 g).

ii) a solution of the product obtained in the previous phase (0,13 g) in acetone (4.8 ml) is treated with Raney Nickel (slurry in ethanol, 0.5 ml) and the mixture is heated at the boiling temperature of phlegmy within 45 minutes the Mixture is filtered and the filtrate concentrated under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17(hydroxymethyl)-4,7-dimethyl-14,15-methylenethf-4-EN-3-one (0,050 g).1H NMR (CDCl3) of 3.69 (dt, part a of AB system, 1H, J=10.6 and a 5.1 Hz), 3,50 (DDD, a part of AB system, 1H, J=10,6, to 8.3 and 4.7 Hz), was 2.76 (DD, 1H, J=13,4 and 3.1 Hz), 1,78 (t, 3H, J=1.2 Hz), a 1.08 (s, 3H), and 0.61 (d, 3H, J=7,1 Hz),0,47 (DD, 1H, J=8,3 and 5.1 Hz), 0,27 (DD, 1H, J=5.1, 3.5 Hz).

Example 5

(7 ,14 ,15 ,17 )-7-Ethyl-17-(hydroxymethyl)14,15-methylenethf-4-EN-3-one

the-3-one [Syntex S.A., patent UK 935116 (1958); 18.0 g] in a mixture of dichloromethane (300 ml) and pyridine (25 ml), cooled to 0° C. After 2 h stirring at 0° C, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The product is extracted with dichloromethane; the combined organic phases are washed with water and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining (17 )-17-[(trimethylsilyl)oxy]-19-norpregna-4,6-Dien-20-in-3-one (22,3 g). The product is used in the next stage without additional purification.

ii) a Mixture of lithium (5.0 g) and anhydrous diethyl ether (200 ml) is cooled to -30° C. added dropwise bromatan (26,9 ml), after which the resulting solution atellite transferred into a suspension of copper iodide(1) (30,6 g) in anhydrous tetrahydrofuran (140 ml), cooled to -30° C. the Resulting solution cuprate stirred for 45 min at the same temperature and added dropwise a solution of the product obtained in the previous phase (20,0 g) in anhydrous tetrahydrofuran (160 ml). After 45 min stirring at -25° With add chlorotrimethylsilane (20 ml) and stirring is continued for a further 30 minutes the Reaction mixture was poured into a saturated aqueous solution of chlorite is a solution of ammonium chloride and a saturated solution of salt, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining (7 ,17 )-7-ethyl-3,17-bis[(trimethylsilyl)oxy]-19-norpregna-3,5-Dien-20-in (29.5 g). The product is used in the next stage without additional purification.

iii) a solution of the product obtained in the previous phase (29.5 g) in acetone (400 ml) is treated with hydrochloric acid (2.3 M, 20 ml). After stirring 1.5 h at room temperature, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The acetone is removed under reduced pressure and the product extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining (7 ,17 )-7-ethyl-17-hydroxy-19-norpregna-4-EN-20-in-3-one (19.5 g). The product is used in the next stage without additional purification.

iv) Hydrochloric acid (6 M, 240 ml) is added dropwise to a suspension dicalite (240 g) in methanol (1200 ml). After stirring 20 min at room temperature dicalite filtered and washed with water until neutrality. He was then suspended in water (960 ml). With vigorous stirring, the nitrate trihydrate copper (II) (145 g) the product is filtered off and washed with water until neutrality. The product is dried at 80° C under reduced pressure, thus obtaining the carbonate copper(II) on dicalite (310 g). A mixture of the product obtained in stage iii (19.5 g), and carbonate of copper (II) on dicalite (70 g) in toluene (330 ml) is heated at the boiling temperature of phlegmy for 9 hours while removing water using traps Dean-stark. The reaction mixture is filtered, the residue washed thoroughly with ethyl acetate and the filtrate concentrated under reduced pressure. Column chromatography gives (7 )-7-ethylester-4-ene-3,17-dione (9,14 g).

v) a solution of the product obtained in the previous phase (9,14 g), copper bromide (II) (13,6 g) and lithium bromide (2.64 g) in acetonitrile (285 ml) was stirred at room temperature for 4 h, the Reaction mixture was poured into water and the product extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous ammonium chloride and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives (7 )-7-ethyl-3-hydroxyestra-1,3,5(10)-triene-17-one (6,54 g).

vi) a Mixture of the product obtained in the previous stage (6,54 g), anhydrous potassium carbonate (18.6 g), iodomethane (5.6 ml) and anhydrous dimethylformamide (22 ml) was stirred at room those the organic phases are washed with water, saturated aqueous ammonium chloride and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining (7 )-7-ethyl-3-petoksista-1,3,5(10)-triene-17-one (6,77 g). The product is used in the next stage without additional purification.

vii) Solution Diisopropylamine (6,15 ml) in anhydrous tetrahydrofuran (70 ml) is cooled to -30° C. are added dropwise n-BuLi (1.6 M solution in hexano, 27.5 ml) and stirring continued for 30 minutes, the Reaction mixture is cooled to -50° C and added dropwise a solution of the product obtained in the previous stage (of 6.95 g) in anhydrous tetrahydrofuran (100 ml). Stirring is continued for 1 h After cooling to -60° With add chlorotrimethylsilane (11,1 ml). The mixture is stirred for 20 min and then treated with a solution of tribromide of phenyltrimethylammonium (10.0 g) in anhydrous pyridine (31 ml). After stirring 1 h at -60° C the mixture was poured into water and the product extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives (7 ,16 )-16-bromo-7-ethyl-omega lithium (12.7 g) and lithium carbonate (10,9 g) in anhydrous dimethylformamide (77 ml) is heated at boiling under reflux in a period of 3.25 hours After cooling, the reaction mixture was poured into water and the product extracted with ethyl acetate. The combined organic phases are washed with water and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives (7 )-7-ethyl-3-petoksista-1,3,5(10),14-tetraen-17-one (or 4.31 g) and (7a,14 )-7-ethyl-3-petoksista-1,3,5(10),15-tetraen-17-one (1.0 g).

ix) a Solution of sodium borohydride (0.21 g) and sodium hydroxide (0,44 g) in methanol (50 ml) is added dropwise to a solution of (7 )-7-ethyl-3-petoksista-1,3,5(10),14-tetraen-17-she (or 4.31 g) in dichloromethane (12 ml) and methanol (20 ml), cooled to 0° C. the Reaction mixture was stirred for 1.5 h, quenched with acetone (4 ml) and then poured into a saturated aqueous solution of ammonium chloride. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining (7 ,17 )-7-ethyl-3-petoksista-1,3,5(10), 14-tetraen-17-ol (4,28 g). The product is used in the next stage without additional purification.

x) Following the procedure similar to that described in stage i of example 1, the product obtained in the previous phase (24,27 g), in turn(7 ,14 ,15 ,17 )-7-this is saveloy on stage ii of example 1, the product obtained in the previous phase (14,03 g), in turn(7 ,14 ,15 )-7-ethyl-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-one (7,34 g).

xii) Following the procedure similar to that described in stage iii of example 1, the product obtained in the previous phase (6,80 g), in turn(7 ,14 ,15 ,17 )-7-ethyl-3-methoxy-14,15-methylandrosta-1,3,5(10)-triene[17,2’]oxirane (7,24 g).

xiii) Following the procedure similar to that described in stage iv of example 1, the product obtained in the previous phase (7,24 g), in turn(7 ,14 ,15 ,17 )-7-ethyl-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-carboxaldehyde (8,48 g).

xiv) Following the procedure similar to that described in stage v of example 1, the product obtained in the previous phase (8,48 g), in turn(7 ,14 ,15 ,17 )-7-ethyl-3-methoxy-14,15-methyltetra-1,3,5(10)-triene-17-methanol (1.23 g).

xv) Following the procedure similar to that described in stage vi of example 1, the product obtained in the previous phase (1,23 g), in turn(7 ,14 ,15 ,17 )-7-ethyl-3-methoxy-14,15-methyltetra-2,5(10)-diene-17-methanol (1.19 g).

xvi) Following the procedure similar to that described in stage vii of example 1, the product obtained in the previous phase (1.19 g), in turn(7 ,14 ,15 ,17 )-7-ethyl-17-(hydroxymethyl)-14,15-m is the feature of the AV system, 1H, J=10,6, of 7.9 and 4.7 Hz), of 1.09 (s, 3H), of 0.79 (t, 3H, J=7.5 Hz), 0,45 (DD, 1H, J=8,3 and 5.5 Hz), 0,27 (DD, 1H, J=5.5 and 3.5 Hz).

Example 6

(7 ,14 ,15 ,17 )-13-Ethyl-17 - (hydroxymethyl)-7-methyl-14,15-metrogon-4-EN-3-one

i) Perruthenate of tetrapropylammonium (1.3 g) is added to a solution of (7 ,17 )-13-ethyl-3-methoxy-7-methylgene-1,3,5(10)-trien-17-ol (FRAD 87961 (1966); 19.5 g] and N-oxide 4-methylmorpholine (21,5 g) in acetone (513 ml). After stirring 30 min at room temperature, the reaction mixture was filtered through dicalite and silicon dioxide. The filtrate is concentrated under reduced pressure. Column chromatography of the crude product gives (7 )-13-ethyl-3-methoxy-7-methylgene-1,3,5(10)-triene-17-one (11,0 g).

ii) To a solution of the product obtained in the previous phase (9,9 g) in a mixture of ethylene glycol (13.3 ml) and triethylorthoformate (23.9 ml) is added p-toluensulfonate acid (0,41 g). The reaction mixture was stirred at room temperature for 3 hours Add an additional portion of n-toluensulfonate acid (0,41 g) and stirring is continued for 2 hours, water is Added and stirring is continued for a further 1 h the Product is extracted with ethyl acetate; the combined organic phases are washed with saturated aqueous sodium hydrogen carbonate and saturated RAS 1,2-candirectly (7 )-13-ethyl-3-methoxy-7-methylgene-1,3,5(10)-triene-17-she and the original substance (10.5 g, the 1:1 relationship). The procedure is repeated to achieve a complete transformation of the original substance. Product (9.8 g) is used in the next stage without additional purification.

iii) Tribromide of phenyltrimethylammonium (8,25 g) are added to a solution of the product obtained in the previous phase (9.80 g) in anhydrous tetrahydrofuran (55 ml). After stirring 1 h, add additional portion of tribromide of phenyltrimethylammonium (4.12 g) and stirring is continued for an additional 1 h, the Reaction mixture was poured into a saturated aqueous solution of sodium thiosulfate. The product is extracted with ethyl acetate; the combined organic phases are washed with water and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining cyclic 1,2-candirectly (7 ,16 )-16-bromo-13-ethyl-3-methoxy-7-methylgene-1,3,5(10)-triene-17-she (14.5 g). The product is used in the next stage without additional purification.

iv) a solution of the product obtained in the previous stage (14.5 g) in anhydrous dimethylsulfoxide (55 ml) is treated with tert-piperonyl potassium (12.4 g) and the reaction mixture was stirred at room temperature for 1.5 hours Add an additional portion of tert-butoxide potassium (12.4 g) and the and ammonium and the product extracted with ethyl acetate. The combined organic phases are washed with water and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives the cyclic 1,2-candirectly (7 )-13-ethyl-3-methoxy-7-methylgene-1,3,5(10),15-tetraen-17-she (6,30 g).

v) a solution of the product obtained in the previous stage (6.3 g) in anhydrous toluene (162 ml) is treated with p-toluensulfonate pyridinium (4,21 g) and heated at the boil under reflux for 1 h After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the product extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining cyclic 1,2-candirectly (7 )-13-ethyl-3-methoxy-7-methylgene-1,3,5(10),14-tetraen-17-she (6.5 g). The product is used in the next stage without additional purification.

vi) a solution of the product obtained in the previous phase (6.5 g) in anhydrous toluene (251 ml) is treated with p-toluensulfonate acid (3.5 g) and heated at the boil under reflux for 45 minutes After cooling, the reaction mixture was poured into saturated aqueous Radoi and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining (7 )-13-ethyl-3-methoxy-7-methylgene-1,3,5(10),14-tetraen-17-one (5.9 g). The product is used in the next stage without additional purification.

vii) Following the procedure similar to that described in stage v of example 1, the product obtained in the previous phase (5.9 g), make (7 ,17 )-13-ethyl-3-methoxy-7-metrogon-1,3,5(10),14-tetraen-17-ol (4.4 g).

viii) Following the procedure similar to that described in stage i of example 1, the product obtained in the previous phase (5.9 g), in turn(7 ,14 ,15 ,17 )-13-ethyl-3-methoxy-7-methyl-14,15-metrogon-1,3,5(10)-trien-17-ol (1.4 g).

(ix) Following the procedure similar to that described in stage ii of example 1, the product obtained in the previous phase (1.4 g), in turn(7 ,14 ,15 )-13-ethyl-3-methoxy-7-methyl-14,15-metrogon-1,3,5(10)-triene-17-one (1.4 g).

x) Following the procedure similar to that described in stage iii of example 1, the product obtained in the previous phase (1.3 g), in turn(7 ,14 ,15 ,17 )-13-ethyl-3-methoxy-7-methyl-14,15-methylanthracene-1,3,5(10)-triene[17,2’]oxirane (1,36 g).

xi) Following the procedure similar to that described in stage iv of example 1, the product obtained pre the ID (1.35 g).

xii) Following the procedure similar to that described in stage v of example 1, the product obtained in the previous phase (1.35 g), in turn(7 ,14 ,15 ,17 )-13-ethyl-3-methoxy-7-methyl-14,15-metrogon-1,3,5(10)-triene-17-methanol (0,80 g).

xiii) Following the procedure similar to that described in stage vi of example 1, the product obtained in the previous phase (0,60 g), in turn(7 ,14 ,15 ,17 )-13-ethyl-3-methoxy-7-methyl-14,15-metrogon-2,5(10)-diene-17-methanol (0,60 g).

xiv) Following the procedure similar to that described in stage vii of example 1, the product obtained in the previous phase (0,60 g), in turn(7 ,14 ,15 ,17 )-13-ethyl-17-(hydroxymethyl)-7-methyl-14,15-metrogon-4-EN-3-one (0.17 g).1H NMR (CDCl3) 5,79 (Shir.s, 1H), to 3.73 (m, 1H), 3,47 (m, 1H), to 0.92 (t, 3H, J=7.5 Hz), 0,59 (d, 3H, J=7,1 Hz), 0,57 (DD, 1H, J=7,9 and 5.1 Hz), 0,41 (DD, 1H, J=5.1, 3.5 Hz).

Example 7

(7 ,14 ,15 ,16 ,17 )-17-(Hydroxymethyl)-7,16-dimethyl-14,15-methylenethf-4-EN-3-one

i) a Solution of bis(trimethylsilyl)amide lithium (a 20.2 mmol) in tetrahydrofuran (35 ml) is cooled to -40° C. added dropwise a solution of(7 ,14 ,15 )-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-triene-17-she (example 1, stage ii; the ceiling of 5.60 g) in anhydrous tetrahydrofuran (24 ml) and the reaction mixture is stirred for 30 min. C the aqueous solution of ammonium chloride and the product extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining(7 ,14 ,15 ,16 )-3-methoxy-7,16-dimethyl-14,15-methyltetra-1,3,5(10)-triene-17-one (of 5.99 g). The product is used in the next stage without additional purification.

ii) a Mixture of bromide methyltriphenylphosphonium (17 g), tert-butoxide potassium (4.4 g) and anhydrous toluene (173 ml) is heated at boiling under reflux for 1 h added dropwise a solution of the ketone obtained in the previous phase (5,04 g) in anhydrous toluene (40 ml) and heating continued for 3 hours After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,16 )-3-methoxy-7,16-dimethyl-17-methylene-14,15-methyltetra-1,3,5(10)-triene (3,61 g).

iii) m-Chloroperbenzoic acid (70-75%, 2.3 g) are added to a solution of the product obtained in the previous phase (3.0 g) in anhydrous dichloromethane (51 ml) containing solid sodium bicarbonate (3 g). The reaction mixture paramashiva what barbantini acid (70-75%, of 0.77 g). The reaction mixture was poured into a saturated aqueous solution of sodium sulfite and the product extracted with dichloromethane. The combined organic phases are washed with aqueous solution of sodium hydroxide (10%) and saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining(7 ,14 ,15 ,16 ,17 )-3-methoxy-7,16-dimethyl-14,15-methylandrosta-1,3,5(10)-triene[17,2 ]oxiran (2.85 g). The product is used in the next stage without additional purification.

iv) Following the procedure similar to that described in stage iv of example 1, the product obtained in the previous phase (2.85 g), in turn(7 ,14 ,15 ,16 ,17 )-3-methoxy-1,16-dimethyl-14,15-methyltetra-1,3,5(10)-triene-17-carboxaldehyde (2,99 g).

v) Following the procedure similar to that described in stage v of example 1, the product obtained in the previous phase (2,99 g), in turn(7 ,14 ,15 ,16 ,17 )-3-methoxy-7,16-dimethyl-14,15-methyltetra-1,3,5(10)-triene-17-methanol (0,30 g).

vi) Following the procedure similar to that described in stage vi of example 1, the product obtained in the previous phase (0,30 g), in turn(7 ,14 ,15 ,16 ,17 )-3-methoxy-7,16-dimethyl-14,15-methyltetra-2,5(10)-diene-17-methanol (0.31 g).

vii) Following the procedure similar to(hydroxymethyl)-7,16-dimethyl-14,15-methylenethf-4-EN-3-one (0,053 g).1H NMR (CDCl3) 5,80 (m, 1H), to 3.64 (m, 2H), 1,09 (s, 3H), of 1.01 (d, 3H, J=6,7 Hz), and 0.62 (d, 3H, J=7,1 Hz), 0,38 (DD, 1H, J=7,9 and 5.1 Hz), 0,25 (DD, 1H, J=5.1, 3.5 Hz).

Example 8

(7 ,14 ,15 ,17 )-17-Hydroxy-17 - (hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one

(i) potassium Hydroxide (3.28 g) are added to a solution(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methylandrosta-1,3,5(10)-triene[17,2’]oxirane (example 1, stage iii; 5,00 g) in a mixture of dimethyl sulfoxide (147 ml) and water (25,3 ml). The reaction mixture was stirred at 100° C overnight and then poured into an aqueous solution of ammonium chloride. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17-(hydroxymethyl)-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-trien-17-ol (1,02 g).

ii) Following the procedure similar to that described in stage vi of example 1, the product obtained in the previous phase (1,02 g), in turn(7 ,14 ,15 ,17 )-17-(hydroxymethyl)-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-Dien-17-ol (1,05 g).

iii) Following the procedure similar to that described in stage vii of example 1, the product obtained in the previous phase (1,05 g), Pribram is.with, 1H), 3,63 (DD, part a of AB system, 1H, J=10.6 and a 4.7 Hz), of 3.46 (DD, part b of AB system, 1H, J=10.6 and a 5.1 Hz), 1,11 (s, 3H), 1,10 (DD, 1H, J=4.7 and 3.9 Hz), and 0.61 (d, 3H, J=7,1 Hz), 0,54 (DD, 1H, J=8,3 and 4.7 Hz).

Example 9

(7 ,14 ,15 ,17 )-17[(the atomic charges) methyl]-17-fluoro-7-methyl-14,15-methylenethf-4-EN-3-one (a) and(7 ,14 ,15 ,17 )-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one (b)

i) the Solution(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methylandrosta-1,3,5(10)-triene[17,2’]oxirane (example 1, stage iii, of 1.75 g) in anhydrous diethyl ether (43,7), cooled to -10° C, treated with vetilation of boron TRIFLUORIDE (1.75 ml). The reaction mixture was stirred for 15 min and then quenched with a saturated aqueous solution of sodium bicarbonate. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17-fluoro-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-triene-17-methanol (0.36 g).

(ii) Following the procedure similar to vi of example 1, the product obtained in the previous phase (0.36 g), turn in the mixture(7 ,14 ,15 ,17 )-17-fluoro-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-di) Following the procedure a similar procedure vii of example 1, the product obtained in the previous phase (0.36 g), in turn(7 ,14 ,15 ,17 )-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one and (7 ,14 ,15 ,17a)-17-(hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one (0.32 g, ratio 1:3).

iv) a Solution of the mixture obtained in the previous phase (0.32 g) in a mixture of anhydrous pyridine (1.50 ml) and anhydrous tetrahydrofuran (5 ml) containing 4-(dimethylamino)pyridine (0.005 g), treated with acetic anhydride (0,90 ml). The mixture is stirred at room temperature for 1.5 h and then quenched with a mixture of ice-water followed by the addition of saturated aqueous solution of sodium bicarbonate. The product is extracted with ethyl acetate; the combined organic phases are washed with water, aqueous sulfuric acid (2 M) and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17[(the atomic charges) methyl] -17-fluoro-7-methyl-14,15-methylenethf-4-EN-3-one (0,050 g).1H NMR (CDCl3) 5,81 (Shir.s, 1H), 4,22 (DD, part a of AB system, 1H, J=22,8 and 12.2 Hz), 4,12 (DD, part b of AB system, 1H, J=22,4 and 12.2 Hz), 2,10 (s, 3H), of 1.17 (d, 3H, J=2,8 Hz), and 0.62 (d, 3H, J 7,1 Hz).

v) Solution of the product obtained at stage iv (0,030 g) in methanol (1 ml) is treated plants is Noah temperature for 30 min and poured into a mixture of ice-water. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining(7 ,14 ,15 ,17 )-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one (0,030 g).1H NMR (CDCl3) 5,81 (Shir.s, 1H), 3,74 (DDD, part a of AB system, 1H, J=20.4, the 12,2 and 6.6 Hz), 3,60 (DDD, a part of AB system, 1H, J=22,8, 12,2 and 6.7 Hz) and 1.15 (d, 3H, J=2,8 Hz), and 0.62 (d, 3H, J=7,1 Hz); 19F NMR (CDCl3) -156,08 (s).

Example 10

(7 ,14 ,15 ,17 )-17-[(the atomic charges)methyl]-17-fluoro-7-methyl-14,15-methylenethf-5(10)-EN-3-one

i) Following the procedure similar to that described in example 2, a mixture of(7 ,14 ,15 ,17 )-17-fluoro-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-diene-17-methanol and(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-diene-17-methanol (0,076 g, ratio 1:3) (example 9 stage ii) turn the mixture(7 ,14 ,15 ,17 )-17-fluoro-17-(hydroxymethyl)-7-methyl-14,15-methylenethf-5(10)-EN-3-one and(7 ,14 ,15 ,17 )-17-(hydroxymethyl)-7-methyl-14,15-methyltetra-5(10)-EN-3-one (to 0.060 g, ratio 1:3).

ii) Following the procedure similar to that described in stage iv of example 9, a mixture of products obtained in i (to 0.060 g), acetimidoyl and share column chromatography, thus obtaining(7 ,14 ,15 ,17 )-17[�system, 1H, J=23,6 and 12.2 Hz), 4,12 (DD, part b of AB system, 1H, J=22,4 and 12.2 Hz), 2,73 (Shir.s, 2H), 2,09 (s, 3H), of 1.12 (d, 3H, J=2,8 Hz), 0.69 (d, 3H, J=7,1 Hz).

Example 11

(7 ,14 ,15 ,17 ,20S)-20-Hydroxy-7-methyl-14,15-methylene-19-norpregna-4-EN-3-one (a) and (7 ,14 ,15 ,17 ,20R)-20-hydroxy-7-methyl-14,15-methylene-19-norpregna-4-EN-3-one (b)

i) the Solution(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-triene-17-carboxaldehyde (example 1, stage iv; 2.50 g) in anhydrous tetrahydrofuran (15,4 ml), cooled to 0° C, treated with methylmagnesium (1.5 M solution in tetrahydrofuran, 62 ml). After stirring 15 min, the reaction mixture was quenched by adding saturated aqueous solution of ammonium chloride. The product is extracted with ethyl acetate; the combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives (7 ,14 ,15 ,17 ,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol (0.84 g) and (7 ,14 ,15 ,17 ,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol (0,23 g)

iia) Following the procedure similar to that described in stage vi of example 1, (7 ,14 ,15 ,17 ,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol (0,48 g) turn in (7 ,14 ,15 ,17 ,20S)-3-methoxy-7-methyl-14,15-m the stage vi of example 1, (7 ,14 ,15 ,17 ,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol (0,23 g) turn in (7 ,14 ,15 ,17 ,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-Dien-20-ol (0.11 g).

iiia) Following the procedure similar to that described in stage vii of example 1, (7 ,14 ,15 ,17 ,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-Dien-20-ol (0,59 g) turn in (7 ,14 ,15 ,17 ,20S)-20-hydroxy-7-methyl-14,15-methylene-19-norpregna-4-EN-3-one (0.33 g).1H NMR (CDCl3) 5,80 (m, 1H), to 3.73 (m, 1H), 1,20 (s, 3H), of 1.12 (d, 3H, J=6.3 Hz), and 0.62 (d, 3H, J=7,1 Hz), 0,44 (DD, 1H, J=7,9 and 5.1 Hz), 0,26 (DD, 1H, J=5.1 and 3.1 Hz).

iiib) Following the procedure similar to that described in stage vii of example 1, (7 ,14 ,15 ,17 ,20R)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-2,5(10)-Dien-20-ol (0.11 g) turn in (7 ,14 ,15 ,17 ,20R)-20-hydroxy-7-methyl-14,15-methylene-19-norpregna-4-EN-3-one (to 0.060 g).1H NMR (CDCl3) 5,80 (m, 1H), of 3.77 (m, 1H), 1,22 (d, 3H, J=6,7 Hz) of 1.16 (s, 3H), 0,63 (DDD, 3H, J=7,1 Hz), 0,45 (DD, 1H, J=8,3 and 5.1 Hz), 0,23 (DD, 1H, J=5.1, 3.5 Hz).

Example 12

(7 ,14 ,15 ,17 )-20-Hydroxy-7,20-dimethyl-14,15-methylene-19-norpregna-4-EN-3-one

i) Following the procedure similar to that described in stage ii of example 1, a mixture of (7 ,14 ,15 ,17 ,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol and (7 ,14 ,15 ,17 ,20S)-3-methoxy-7-methyl-14,15-methylene-19-norpregna-1.3 egna-1,3,5(10)-triene-20-he (0.55 g).

ii) Following the procedure similar to that described in stage i of example 11, the product obtained in the previous phase (0.55 g), in turn(7 ,14 ,15 ,17 )-3-methoxy-7,20-dimethyl-14,15-methylene-19-norpregna-1,3,5(10)-trien-20-ol (0.26 g).

iii) Following the procedure similar to that described in stage vi of example 1, the product obtained in the previous phase (0.14 g), in turn(7 ,14 ,15 ,17 )-3-methoxy-7,20-dimethyl-14,15-methylene-19-norpregna-2,5(10)-Dien-20-ol (0.14 g).

iv) Following the procedure similar to that described in stage vii of example 1, the product obtained in the previous phase (0.14 g), in turn(7 ,14 ,15 ,17 )-20-hydroxy-7,20-dimethyl-14,15-methylene-19-norpregna-4-EN-3-one (0,050 g).1H NMR (CDCl3) 5,80 (m, 1H), 1,32 (s, 3H), 1,21 (s, 3H), of 1.20 (s, 3H), of 0.64 (d, 3H, J=7,1 Hz), 0,42 (DD, 1H, J=7,9 and 5.1 Hz), 0,25 (DD, 1H, J=5.1, 3.5 Hz).

Example 13

(7 ,14 ,15 ,17 ,20S)-17-(1-Hydroxypropyl)-7-methyl-14,15-methylenethf-4-EN-3-one

Specified in the title compound is obtained from(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-1,3,5(10)-triene-17-carboxaldehyde (example 1, step iv) using the procedures described in example 11.1H NMR (CDCl3) 5,80 (m, 1H), 3,75 (m, 1H), 1,21 (s, 3H), of 0.93 (t, 3H, J=7.9 Hz), and 0.62 (d, 3H, J=7,1 Hz), 0,43 (m, 1H), 0,24 (m, 1H).

An example of 1.15 ,17 )-17-(hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one (example 1, 0.20 g) in a mixture of anhydrous pyridine (1,76 ml) and anhydrous tetrahydrofuran (8,8 ml) is treated with acetic anhydride (1.06 g). The mixture is stirred at room temperature overnight and then quenched with water. After stirring for 1 hour the product is extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure, thus obtaining(7 ,14 ,15 ,17 )-17[(the atomic charges) methyl]-7-methyl-14,15-methylenethf-4-EN-3-one (0,22 g).1H NMR (CDCl3) 5,80 (t, 1H, J=2,8 Hz), of 4.05 (DD, part a of AB system, 1H, J=11.0 and 6.3 Hz), 3,95 (DD, part b of AB system, 1H, J=11.0 and a 7.1 Hz), 2,03 (s, 3H), of 1.08 (s, 3H), and 0.62 (d, 3H, J=7,1 Hz), 0,48 (DD, 1H, J=8,3 and 5.1 Hz), 0,27 (DD, 1H, J=5.1, 3.5 Hz).

Example 15

Following a procedure similar to that described in stage v of example 1, and using the compounds of examples 1, 2 and 8, respectively, as starting material, there were obtained the following products:

and) (3 ,7 ,14 ,15 ,17 )-3-Hydroxy-7-methyl-14,15-methylenethf-4-EN-17-methanol

1H NMR (CDCl3) 5,33 (Shir.s, 1H), 4,21 (m, 1H), to 3.67 (m, 1H), 3,48 (m, 1H), of 1.05 (s, 3H), of 0.58 (d, 3H, J=7,1 Hz), 0,45 (DD, 1H, J=7,9 and 5.1 Hz), 0,22 (DD, 1H, J=5.1 and 3.1 Hz).

b1) (3 ,7 ,14 ,15 ,17 )-3-Hydroxy-7-methyl-14,15-methylenes the J=7,1 Hz), 0,46 (DD, 1H, J=8,3 and 5.1 Hz), 0,24 (DD, 1H, J=5.1, 3.5 Hz).

b2) (3 ,7 ,14 ,15 ,17 )-3-Hydroxy-7-methyl-14,15-methylenethf-5(10)-EN-17-methanol

1H NMR (CDCl3) 3,82 (m, 1H), 3,69 (m, 1H), 3,50 (m, 1H), of 1.03 (s, 3H), 0,63 (d, 3H, J=7,1 Hz), and 0.46 (DD, 1H, J=8,3 and 5.1 Hz), 0,24 (DD, 1H, J=5.1, 3.5 Hz).

C1) (3 ,7 ,14 ,15 ,17 )-3,17-Dihydroxy-7-methyl-14,15-methylenethf-4-EN-17-methanol

1H NMR (CDCl3) of 5.53 (m, 1H), 4,21 (m, 1H), 3,61 (DD, part a of AB system, 1H, J=10.6 and a 4.7 Hz), of 3.45 (DD, part b of AB system, 1H, J=10.6 and 5,9 Hz), of 1.09 (s, 3H), of 1.02 (DD, 1H, J=4.7 and 3.5 Hz), of 0.56 (d, 3H, J=7,1 Hz), 0,54 (DD, 1H, J=8,3 and 4.7 Hz).

C2) (3 ,7 ,14 ,15 ,17 )-3,17-Dihydroxy-7-methyl-14,15-methylenethf-4-EN-17-methanol

1H NMR (CDCl3) the 5.51 (m, 1H), 4,12 (m, 1H), 3,62 (DD, part a of AB system, 1H, J=10.6 and a 4.7 Hz), of 3.46 (DD, part b of AB system, 1H, J=10.6 and 5,9 Hz), of 1.09 (s, 3H), of 1.03 (DD, 1H, J=4.7 and 3/9 Hz), 0,59 (d, 3H, J=7,1 Hz), 0,54 (DD, 1H, J=8,6 and 4.7 Hz).

Example 16

(7 ,14 ,15 ,17 )-17-Hydroxy-17(methoxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one (reference compound 3)

i) the Solution(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methylandrosta-1,3,5(10)-triene[17,2’]oxirane (example 1, stage iii, 2.0 g) in anhydrous methanol (106 ml) is treated with sodium methoxide (6,91 g) and refluxed for overnight the United organic phases are washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-3-methoxy-17-(methoxymethyl)-7-methyl-14,15-methyltetra-1,3,5(10)-trien-17-ol (0.50 g).

ii) Following the procedure similar to that described in stage vi of example 1, the product obtained in the previous phase (0.50 g), in turn(7 ,14 ,15 ,17 )-3-methoxy-17-(methoxymethyl)-7-methyl-14,15-methyltetra-2,5(10)-Dien-17-ol (0,69 g).

iii) Following the procedure similar to that described in stage vii of example 1, the product obtained in the previous phase (0,69 g), in turn(7 ,14 ,15 ,17 )-17-hydroxy-17-(methoxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one (0.15 g).1H NMR (CDCl3) 5,80 (m, 1H), 3,42 (d, part a of AB system, 1H, J=8,3 Hz) to 3.33 (s, 3H), and 3.16 (d, part b of AB system, 1H, J=8,3 Hz), 1,11 (DD, 1H, J=4.7 and 3.5 Hz), of 1.09 (s, 3H), of 0.60 (d, 3H, J=7,1 Hz), and 0.50 (DD, 1H, J=8,3 and 4.7 Hz).

Example 17

(7 ,14 ,15 ,17 )-17-(Chloromethyl)-17-hydroxy-7-methyl-14,15-methylenethf-4-EN-3-one (reference compound 4)

i) Following the procedure similar to that described in stage vi of example 1, (7 ,14 ,15 )-3-methoxy-7-methyl-14,15-methyltetra-1,2,3(10)-triene-17-one (example 1, stage ii, 8.0 g) in turn(7 ,14 ,15 ,17 )-3-methoxy-7-methyl-14,15-methyltetra-2,5(10)-Dien-17-ol (8.0 g).

ii) the stage (3.0 g), turn in(7 ,14 ,15 ,17 )-17-hydroxy-7-methyl-14,15-methylenethf-4-EN-3-one (of 2.51 g).

iii) Following the procedure similar to that described in stage ii of example 1, the product obtained in the previous phase (of 2.51 g), in turn(7 ,14 ,15 )-7-methyl-14,15-methylenethf-4-ene-3,17-dione (2,23 g).

iv) Diethylether of boron TRIFLUORIDE (0,27 ml) is added to a mixture of the product obtained in the previous phase (2,23 g), 1,2-identicial (of 0.67 ml), anhydrous tetrahydrofuran (10 ml) and anhydrous methanol (20 ml), cooled to 0° C. After stirring 2 h at room temperature the reaction mixture was poured into water. The product is extracted with ethyl acetate; the combined organic phases are washed with aqueous sodium hydroxide (10%) and saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives the cyclic 3-(1,2-atandardization) (7 ,14 ,15 )-7-methyl-14,15-methylenethf-4-ene-3,17-dione (2,68 g). The product is used in the next stage without additional purification.

v) Following the procedure similar to that described in stage iii of example 1, the product obtained in the previous phase (2,68 g), in turn(7 ,14 ,15 ,17 )-3-[(2-mercaptoethyl)thio]-7-methyl-14,15-methylandrosta-3,5-Dien-[17,2’]-oxyanthus concentrated hydrochloric acid (0,73 ml). After stirring 1 h at room temperature, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the product extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over sodium sulfate and concentrate under reduced pressure. Column chromatography gives(7 ,14 ,15 ,17 )-17-(chloromethyl)-17-hydroxy-7-methyl-14,15-methylenethf-4-EN-3-one (0.035 g).1H NMR (CDCl3) of 5.81 (m, 1H), 3,67 (d, part a of AB system, 1H, J=11.0 in Hz) to 3.58 (d, part b of AB system, 1H, J=11,0 Hz), 1,17 (DD, 1H, J=5.1, 3.5 Hz) and 1.15 (s, 3H), of 0.60 (d, 3H, J=6,7 Hz), 0,54 (DD, 1H, J=8,3 and 5.1 Hz).

Example 18

Biological results

Compounds in accordance with the invention and four comparative compounds were tested on androgenic activity (procedure for testing which were described above) and were evaluated according to the following scheme:

(-) not found androgenic activity;

(+) found androgenic activity;

(++) high androgenic activity;

(+++) excellent androgenic activity;

(n.d.) no data; (pro) prodrug.

I. Compounds of the invention

1. Connection sootvetstvyet hydrogen, (C1-6)alkyl, (C1-6)acyl;

R2represents hydrogen or (C1-6)alkyl;

R3represents hydrogen or R3is (C1-6)alkyl, (C2-6)alkenyl or (C2-6)quinil, each of which is optionally substituted with halogen;

R4represents hydrogen, (C1-6) alkyl or (C2-6) alkenyl;

R5is (C1-6) alkyl;

R6represents hydrogen;

R7represents hydrogen or (C1-6) alkyl;

R8represents hydrogen, hydroxy, halogen;

R9and R10independently, represent hydrogen or R9and R10independently represent a (C1-6)alkyl, optionally substituted (C1-4)alkoxy or halogen;

R11represents hydrogen, SO3N, (C1-15)acyl,

the dotted lines indicate the optional connection selected from the 4-, 5(10)or 4,9-diene system.

2. Connection on p. 1, characterized in that the substituent R1represents O.

3. Connection under item 1 or 2, wherein the dotted line means a double bond 4.

4. Connection Lubo-(hydroxymethyl)-7-methyl-14,15-methylenethf-4-EN-3-one.

6. The compound according to any one of the preceding paragraphs for use in therapy.

7. The compound according to any one of paragraphs.1-5 for the manufacture of a medicinal product having androgenic activity.

8. Set, providing hormonal contraception in males and comprising a sterilizing agent and the androgen, wherein the androgen is a compound according to any one of paragraphs.1-5.

9. Androgenic composition comprising a steroid compound according to any one of paragraphs.1-5, mixed with pharmaceutically acceptable auxiliary agent.



 

Same patents:

The invention relates to new chemical substance, specifically to biologically active compounds having immunostimulatory and antiviral activity (anti-HIV and anti-herpes), - N'-{N-[3-oxo-20(29)-lupen-28-oil] -9-aminopentanoic} -3-amino-3-phenylpropionic acid of the formula I

The invention relates to methods of isolating biologically active substances from waste wood, namely the allocation method Betulinol of the outer layer of birch bark (bark)
The invention relates to an improved method of obtaining Betulinol acid

The invention relates to new inclusion complexes of derivatives of 1,2,5-oxadiazol-2-oxide of General formula I, where1=R2=CN or together with the adjacent carbon atoms form annelirovannymi 3,6-bis(lower alkyl)pyridazin-1,2-dioxideis cycle, polycyclic derivatives of glucopyranose General formula II, where if n= 1, R3fragment 11-oxo-18, 20-Olean-12-EN-29-OIC acid of the formula III, R4=H, R5--D-glucuronidase, R6=R7=H and R8= C(O)OH, or, if n= 7, R3=N, R4and R7- simple connection, R5and R6= H or (CH2CH(CH3)O)mH, where m=1 to 14, and R8=CH2OH or CH2O(CH2CH(CH3)O)mH, where m=1-14, generating nitric oxide and activating the soluble form of guanylate cyclase (RGC), antispasmodic, vasodilator and hypotensive means quick action and platelet aggregation inhibitors, method for their production and pharmaceutical compositions based on

The invention relates to a method of extraction of betulin from the outer layer of birch bark

The invention relates to a steroid compound of General formula I

< / BR>
whereis = O, -HE, or SIG or ООСR, where R represents an alkyl group having from 1 to 6 carbon atoms; R6represents H or -(CH2)mN, where m = 1 or 2; R7represents H, C1-4-alkyl, C2-4alkenyl or2-4-quinil; R11represents H, C1-4-alkyl, C2-4alkenyl,2-4-quinil; E represents, including the carbon atoms 16 and 17 of the D ring, a 4-7-membered hydrocarbon ring, where the specified ring is in the-position relative to the D-ring, substituted by a group REand optionally contains one endocyclic double bond; RErepresents H, C1-5-alkyl, C2-5alkenyl,2-5-quinil,1-5-alkyliden, -(CH2)n-N3or -(CH2)n-SP, where n = 1 or 2, and where the alkyl group may be substituted by-OR, -OOCR where R is alkyl with 1-6 carbon atoms; R17is-HE-or SIG or ООСR, where R is alkyl with 1-6 carbon atoms, where the aforementioned steroid compound may be, but neeba is either ring may be aromatic

The invention relates to a method of processing betulin and its derivatives, for example Betulinol acid, betulin diacetate, and can be used in cosmetic, pharmaceutical and chemical, in particular in the manufacture of varnishes and paints industries

The invention relates to new biologically active chemical compound, specifically to 3,28-di-O-nicotinate betulin (1), formula

< / BR>
showing hepatoprotective and anti-HIV activity

The invention relates to the synthesis of allobetulin (19, 28-epoxy-oleana-3-Ola) isomerization of Betulinol(loop-20(29)-EN-3, 28-diol) in the presence of catalysts
The invention relates to medicine, in particular to urology and endocrinology
The invention relates to medicine, in particular to urology and endocrinology
The invention relates to medicine, in particular to urology and endocrinology
The invention relates to medicine, in particular to urology and endocrinology
The invention relates to medicine, in particular to urology and endocrinology
The invention relates to medicine, namely to dermatology
The invention relates to the field of pharmaceutical industry and relates to vaginalnyj suppositories for the treatment of imperative incontinence urination
Up!