Derivatives 11-benzaldoxime-Östra-4,9-diene, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 11 - benzylidenemalonate General formula I, where the values of R1, R2, R3, R5, R6, R7Z specified in paragraph 1 of the claims, and their pharmaceutically acceptable salts, method of production thereof and containing these compounds in pharmaceutical compositions. Described compounds have a strong antigestagens properties at lower glucocorticoid activity. 3 S. and 13 C.p. f-crystals, 2 tab., 3 Il.

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

11-Substituted phenyl-estratriene already known. The 11-aryl - 17 - propionyl östra-4,9-dienes already described, for example, in European patent 057115; interaction 11-(4-formylphenyl)-östra-4,9-Dien-3-ones with hydroxylamine already described in the patent Germany 3504421. In the specified way examineda as 11 - formyl-phenyl group and 3-ketogroup. In addition, in position C-3 are formed SYN - and anisometry. The action of the described compounds is still unknown.

Progesterone in large quantities allocated is not in all aspects.

Guaranteed that progesterone when interacting with estrogen causes cyclic changes in the endometrium in the menstrual cycle and during pregnancy. Under the influence of elevated levels of progesterone after ovulation, the mucous membrane of the uterus is transferred in a state that allows the implantation of the embryo (blastocyst). Preservation of tissues in which "expands" the growing embryo, also depends on progesterone.

When pregnancy occurs "dramatic" change in muscle function of the uterus. The muscle of the uterus during pregnancy responds very oslablennoy or does not respond to hormonal and mechanical stimuli that are outside of pregnancy cause pain. There is no doubt that progesterone plays a key role, although in some phases of pregnancy, for example, directly before the birth, there is a high reaction willingness extremely high blood levels of progesterone.

Other typical processes of pregnancy is also associated with very high levels of progesterone. Examples of this are the structure of the mammary glands and durable obturation uterine throat until near the time of delivery.

Progesterone subtle way p is Wyrowski properties. They arise from the suppression hypofyse secretion of gonadotropin, the prerequisites for the maturation of the follicle and ovulation. On the other hand, it is known that relatively small selection of progesterone ripening follicle plays an active role in the preparation and triggering ovulation. This hypofyse mechanisms (time-limited to so-called "positive feedback" with progesterone secretion of gonadotropin) are, as is well known, an important role (Loutradie, D.; Human Reproduction 6, 1991, 1238 - 1240).

Less well analyzed the function of progesterone in the ripening and potentially in the yellow body, the existence of which there is no doubt. Ultimately there is also a need to assume stimulatory and suppressive effects on the endocrine function of the follicle and yellow body.

You should also consider the significant role of progesterone and progesterone receptor in pathophysiological processes. Progesterone receptors found in the foci of endometriosis, but also in tumors of the uterus, breast and ZNS (meningioma). The role of these receptors for the growth process of these pathologically relative tissue need not be associated with the presence of progesterone in the blood. It turned out that wexe = Onapristone (with the description of the invention to unaccepted application for patent in Germany 3504421), in these tissues cause profound functional changes also when in the blood there is little that can be neglected, the level of progesterone.

It is possible that the changes in the transcriptional action not employed by the progesterone receptor progesterone by antagonists play an important role (Chwalisz, K. et al., Endocrinology, 129, 317 - 322, 1991).

Actions of progesterone in the tissues of the genital organs and other tissues carry out due to the interaction with the progesterone receptor. In the cell progesterone with high affinity binds with its receptor. Thus caused by changes of the receptor proteins: conformational changes; the reaction of 2-x receptor units in the complex; the outcrop sections of DNA binding of the receptor by removing due to dissociation of the protein (HSP 90); the binding of the hormone responsible DNA elements. Finally, regulates the transcription of certain genes (Gronemeyer, H. et al., J. Steroid. Biochem. Molec. Biol. 41, 3 - 8, 1992).

The action of progesterone or progesterone antagonists depends not only on their concentration in the blood. The concentration of receptors in the cell is also highly regulated. Estrogen stimulates the synthesis of progesterone receptor in bolshinstvo, there are these and other interactive relationship between estrogen and progestogen, which may explain why the gestagen and antigestagen can affect estrogen-dependent processes without their binding to the estrogen receptor. These relationships, of course, are of great importance for therapeutic use of antigestagens. These substances are suitable for the target participation in reproductive processes in women, for example, after ovulation to prevent nidali, in later pregnancy, to increase the reaction readiness of the uterus to prostaglandins and oxytocin or to achieve disclosure and softening ("ripening") neck.

Antigestagen at various higher Primate species suppress ovulation. The mechanism of this action is clearly outstanding. Along with the suppression of gonadotropin secretion are discussed also ovarian mechanisms at the expense of para - and autocrine functions of progesterone in the ovary.

Antigestagen have the ability to modulate or reduce the action of estrogens, although they predominantly have no means to the estrogen receptor in the cytoplasmic area and although they can cause an increase in the concentration of prescriptions which which is equipped with estrogen receptors and progesterone, you can expect a favorable impact on the disease condition. Special advantages for favourable influence on painful conditions such as endometriosis, can be when the suppressive effects of antigestagen due to the action of the tissue would be added suppression of ovulation. Suppression of ovulation there would not be a part of the ovarian production of hormones and thus disappearing from this part of the stimulatory effect on the diseased tissue. It would be desirable if severe endometriosis suppress ovulation and are usually constantly in the rebuilding of the fabric of genital tract reversible lead to a state of calm.

For contraception also discussed the way in which processing antigestagens suppresses ovulation, and due to subsequent treatment with progestogen induced secretory transformation of the endometrium, so that from the days of processing antigestagen and gestagen and days in which processing is not performed, follows approximately 28-day cycle with regular bleeding (Baulieu, E. E., Advances in Contraception 7, 345 - 51, 1991).

Antigestagen can have a variety of hormonal and antihormonal properties. Especially therapeu the th therapy is suppression of progesterone receptor, they are negative because when therapeutically necessary doses they cause undesirable side effects, prevent the introduction of therapeutically rational dose or can cause harm treatment. Partial or complete reduction antiglucocorticoid properties is an important prerequisite for therapy using antigestagens, especially for those readings that require lasting for weeks or months.

The present invention is to obtain new derivatives 11 - benzaldoxime-4,9-diene of the General formula I and their pharmaceutically acceptable salts, as well as the development of the retrieval method

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Another object of the invention is to obtain drugs, which contain the compound of General formula I or its pharmaceutically acceptable salt.

In the General formula I

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where R1denotes a hydrogen atom or an alkyl residue with 1 to 6 C-atoms;

R2denotes a hydrogen atom; alkyl, aryl, aracelio or alcylaryl group with 1 to 10 C-atoms; acyl residue with 1 to 10 C-atoms or a residue-CONHR4or-COOR4,

and R4denotes a hydrogen atom, alkyl, aryl, Ara is s, aracelio or alcylaryl group with 1 to 10 C-atoms; the remainder - (CH2)n-CH2X, and n = 0, 1, or 2, X represents an atom of fluorine, chlorine, bromine or iodine, cyano, azido or Romanorum, the remainder OR5or SR5,

and R5denotes a hydrogen atom, alkyl, aryl, Aracely or alcylaryl residue with 1 to 10 C-atoms or acyl residue with 1 to 10 C-atoms;

the remainder OR5and R5has the above meaning;

balance -(CH2)o-CH=CH(CH2)p-R6and o = 0, 1, 2 or 3 and p = 0, 1 or 2 and R6denotes a hydrogen atom, Elgiloy, aryl, aracelio or alcylaryl group with 1 to 10 C-atoms, hydroxyl group, CNS group, or alloctype with 1 to 10 C-atoms;

balance -(CH2)qC CR7and q = 0, 1 or 2 and R7denotes a hydrogen atom, fluorine atom, chlorine, bromine or iodine, alkyl, aryl, Aracely or alcylaryl residue with 1 to 10 C-atoms or acyl residue with 1 to 10 C-atoms;

Z denotes a hydrogen atom, alkyl, aryl, Aracely or alcylaryl residue with 1 to 10 C-atoms, acyl residue with 1 to 10 C-atoms, the remainder - CONHR4or-COOR4and R4denotes a hydrogen atom, alkyl, th metal.

Preferred compounds in which:

R1denotes a methyl or ethyl group;

R2denotes a hydrogen atom, alkyl group with 1-10 C-atoms, acyl residue with 1-10 C-atoms or a residue-CONHR4or-COOR4and R4denotes a hydrogen atom, alkyl or aryl residue with 1-10 carbon atoms;

R3denotes a hydrogen atom; alkyl, aryl, aracelio or alcylaryl group with 1-10 C-atoms;

R3denotes a residue -/CH2/n-CH2X, and n = 0, 1, or 2, X represents an atom of fluorine, chlorine, bromine or iodine, cyano, azido or Romanorum, the remainder OR5or SR5and

R5denotes an alkyl residue with 1-6 C-atoms or acyl residue with 1 to 6 C-atoms;

the remainder OR5and R5denotes a hydrogen atom, an alkyl residue with 1-10 C-atoms or acyl residue with 1-10 C-atoms;

the remainder -/CH2/o-CH=CH/CH2/p-R6and o = 0, 1, 2 or 3 and p = 0, 1 or 2 and R6denotes a hydrogen atom, alkyl group with 1-10 C-atoms, hydroxyl group, CNS group, or alloctype with 1-10 C-atoms; or

balance -(CH2)qC CR7and q = 0, 1 or 2 and R7indicates the ATA; and Z denotes a hydrogen atom; an alkyl residue with 1-10 C-atoms; acyl residue with 1-10 C-atoms; the remainder-CONHR4or-COOR4and R4denotes a hydrogen atom or an alkyl residue with 1-10 C-atoms; or an atom of alkali or alkaline earth metal. Especially preferred compounds in which:

R2denotes an alkyl group with 1-6 C-atoms, acyl residue with 1-6 C-atoms or a residue-CONHR4or COOR4and R4denotes a hydrogen atom, alkyl or aryl residue with 1-6 C-atoms;

R3denotes a hydrogen atom or alkyl group with 1-6 C-atoms; the remainder -/CH2/n-CH2X, and n = 0, 1, or 2, X represents an atom of fluorine, chlorine, bromine or iodine, cyano, asado or Romanorum, the remainder OR5or SR5and R5denotes an alkyl residue with 1-6 C-atoms or acyl residue with 1 to 6 C-atoms; the remainder OR5and R5denotes alkyl with 1-6 C-atoms or acyl residue with 1 to 6 C-atoms;

the remainder -/CH2/o-CH=CH/CH2/p-R6and o = 0, 1, 2 or 3 and p = 0, 1 or 2 and R6denotes an alkyl group with 1-6 C-atoms, CNS group, or alloctype with 1-6 C-atoms; or a residue -(CH2)qC CR7the being who represents the alkyl residue with 1-6 C-atoms, acyl residue with 1-6 C-atoms, the remainder-CONHR4or-COOR4and R4denotes a hydrogen atom, alkyl or aryl residue with 1-6 C-atoms.

Most preferred:

11- [4-/gidroksimetil/phenyl]- 17 - hydroxy - 17 - methoxymethyl-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl] - 17 - hydroxy - 17 - ethoxymethyl-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl] - 17 - hydroxy - 17 - n-propoxymethyl-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl]- 17 - hydroxy - 17 - isopropoxyphenyl-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl] - 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl] - 17 - methoxy - 17 - ethoxymethyl-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl] - 17 - hydroxy - 17- /3-hydroxyprop-1-in-Il/-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl]- 17 - methoxy - 17- /3-hydroxyprop-1-in-Il/-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/phenyl]- 17 - hydroxy - 17 - Z- /3-hydroxypropyl/-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/-phenyl]- 17 - methoxy - 17 - Z-/3 - hydroxypropyl/-östra-4,9-Dien-3-one;

17 - chloromethyl - 11- [4-/gidroksimetil/-phenyl]- 17 - hydroxy-östra-4,9-Dien-3-one;

17 - chloromethyl - 11- [4-/gidroksimetil/-phenyl]- 17 - methoxy-östra the Il - 11- [4-/gidroksimetil/-phenyl] - 17 - methoxy-östra-4,9-Dien-3-one;

17 - azidomethyl - 11- [4-/gidroksimetil/-phenyl] - 17 - methoxy-östra-4,9-Dien-3-one;

11- [4-/gidroksimetil/-phenyl] - 17 - methoxy-17 - methylthiomethyl-östra-4,9-Dien-3-one;

11- [4-/methoxymethyl/-phenyl] - 17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one;

11- [4-/acetoxymethyl/-phenyl] - 17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one;

11- [4-/methoxymethyl/-phenyl] - 17 - hydroxy-17 - methoxymethyl-östra-4,9-Dien-3-one;

11- {4-[/etoxycarbonyl/-oksiminomyetil]phenyl}- 17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one;

11- {4-[/ethylaminomethyl/-oksiminomyetil]phenyl}- 17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one;

17 - methoxy - 17 - methoxymethyl - 11- [4-{/phenylenecarbonyl/-oksiminomyetil}-phenyl]-östra-4,9-Dien-3-one; and

11- [4-/gidroksimetil/phenyl]- 17 - ethoxy 17 - ethoxymethyl-östra-4,9-Dien-3-one.

The invention relates further to a method for producing compounds according to General formula I and their pharmaceutically acceptable salts, which is characterized in that the compound of General formula II

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where R1, R2and R3have the above meaning;

enter into interaction with the compound of General formula IIa

NH2- O - Y

where Y denotes a hydrogen atom, alkiline>4denotes a hydrogen atom, alkyl, aryl, Aracely or alcylaryl residue with 1-10 C-atoms;

and the compound of General formula IIa, if necessary, is in the form of such connection or from which the compound of General formula IIa is released under the selected reaction conditions.

If necessary, existing hydroxylamino group atrificial to ester or a simple ester group and, if necessary, the compound obtained was transferred to salt.

It is preferable to carry out the interaction of the compounds of General formula II with compounds of General formula IIa, in which the use of the compounds in equimolar amounts.

If desired, according to the esterification to complex ester, esterification to simple ester or education urethane compounds of General formula I, R2- or Z-Deputy which represents a hydroxyl group, etherification to complex ester can be accomplished by itself in a known manner by using an alkylating funds, as anhydrides or acid chlorides of the acids, in the presence of bases, preferably pyridine; the etherification to simple ester can be accomplished using under the conditions in the presence of interaction with the alkyl - or arylisocyanate in inert solvents, preferably in toluene or by entering into interaction with carbamylcholine in the presence of bases, preferably triethylamine.

The initial compounds of General formula II is carried out on the basis of 5,10-epoxide of formula III

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(see, for example, Nedelec Bull. Soc. Chim. France (1970), 2548).

The introduction of a phenyl residue in the 11 - position in education 9(10),5 - hydroxy-structure of formula IV reach due to salt catalyzed copper -/1/ the Grignard reaction [Tetrahedron Letters, 1979, 2051] p-bromobenzaldehyde, preferably p-bromobenzaldehyde, at temperatures of 0 - 30oC.

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Introduction grouping -/CH2/nCH2X exercise in itself known through the Spiro-epoxide of the formula /V/ by interacting with trimethylsulfonium and tert-butyl potassium in dimethyl sulfoxide [Hubner, etc., J. prakt. Chem, 314, 667 (1972); Arzneim. Forsch, 30, 401 (1973)] and

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and subsequent ring opening with nucleophiles as halides and pseudohalogen, alcoholate and mercaptide [Ponsold, etc., Z. Chem, 11, 106/1971/]. The resulting 17-CH2X-the compounds of formula VI

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you can either by acid hydrolysis, preferably using p-toluenesulfonic acid in ACE, the for by the esterification of simple esters of the free hydroxyl groups with alkylhalogenide in the presence of potassium tert-butylate first transfer simple 5,17-diesters /Kasch and others, patent GDR 290893/, then by acid hydrolysis, preferably using p-toluenesulfonic acid in acetone is converted into the aldehydes of General formula (II) with R2in the meaning of alkyl residue, preferably a methyl residue.

Introduction residues/CH2/oCH = CH/CH2/pR6carried out by reacting the ketone of formula /IV/ simple propyne-1-ol-tetrahydropyranyl ether and tert-butyl potassium with getting 17- /3-hydroxy-1-PROPYNYL/-17-hydroxy compounds of formula VII

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either by acid hydrolysis under the above conditions it is possible to hydrolyze to aldehydes of type II with R2in the meaning of a hydrogen atom, or by simple education 5,17-diapir on the above method and subsequent acid hydrolysis can hydrolyze to aldehydes of type II with R2in the meaning of alkyl residue, or, however, in itself well-known reaction with detektirovanie the catalyst, 10% palladium-on-barium sulphate, in the presence of amine can gidrirovanii type II.

Introduction residues -(CH2)qC CR7carried out in a known manner by reacting the ketone of formula IV with acetylene, propyne or higher homologues in the presence of alkali metals such as lithium, sodium or potassium, in combination with alcohol or ammonia, or, however, with the help of utility in ethers, like tetrahydrofuran. Acid hydrolysis of these compounds leads to a 17-C CR7-substituted aldehydes of type II.

If necessary, obtained according to the invention a compound of General formula I transferred to additive salt accession acid, preferably the salt of physiologically acceptable acids. Conventional physiologically acceptable inorganic and organic acids are, for example, hydrochloric, Hydrobromic, phosphoric, sulfuric, oxalic, maleic, fumaric, lactic, tartaric, malic, citric, salicylic acid, adipic and benzoic acid. Other applicable acids are described, for example, in Fortschritte der Arzneimittelforschund, T. 10, S. 224-225, Birkhauser Verlag, Basel und Stuttgart, 1966, and in the Journal of Pharmaceutical Sciences, I. 66, S. 1-5 (1977).

Additive salt accession receive, as a rule, by itself, in a known manner by mixing the free base or solutions with relevant to the n-propanol or isopropanol, or a lower ketone, such as acetone, methyl ethyl ketone or methyl-isobutylketone, or in simple ether like diethyl ether, tetrahydrofuran or dioxane. For best separation of crystals can also be used mixtures of these solvents. Moreover, it is possible to prepare physiologically acceptable aqueous solutions of salts of accession acids of compounds of formula I in an aqueous acidic solution.

Additive salt accession acid compounds of General formula I itself then himself in a known manner, for example by means of alkalis or ion exchangers, can be converted to free base. Of the free bases by reacting with inorganic or organic acids, in particular those which are suitable for obtaining therapeutically applicable salts, you can get other salts. These and other salts of the new compounds, such as the picrate, can also serve for the purification of the free bases of the fact that the free base was transferred to salt, it is separated from the salt again release the base.

The object of the present invention are also medications for oral, rectal, subcutaneous, intravenous or intramuscular injection, which along with the usual nonbiologically active substances.

Medicines inventions get in a known manner using conventional solid or liquid carriers or diluents and commonly used in pharmaceutical technology auxiliary substances, respectively, the desired kind of application with the appropriate dosage. Preferred compositions are in the form of application, which is suitable for oral administration. Such applications are, for example, tablets, coated tablet, coated tablets, capsules, pills, powders, solutions or suspensions or extended form.

Needless to say, take into consideration parenteral compositions, such as solutions for injection. Further, as the compositions should be called, for example, also candles.

Appropriate tablets can be obtained, for example, by mixing a biologically active substance with known excipients, for example inert diluents, as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone; fillers like corn starch or alginic acid, binders, such as starch or gelatin; lubricants like magnesium stearate or talc and/or means for achieving a prolonged effect as carboxysome several layers.

Accordingly, pills can be obtained by coating prepared analogously to the tablets nuclei (cores) using commonly used for coating tablets means, such as polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. When the shell drops may consist of several layers, and you can apply the above in the case of tablets excipients.

A solution or suspension of proposed according to the invention the biologically active substance may additionally contain improves the taste of funds, as saccharin, cyclamate or sugar, and, for example, fragrances, like vanilla or orange extract. In addition, they may contain auxiliary for the suspension of the substance, as sodium carboxymethylcellulose, or preservatives, such as p-hydroxy-benzoate. Contains biologically active substances of the capsule can prepare, for example, the fact that biologically active substance is mixed with an inert carrier, as lactose or sorbitol, and encapsulation in gelatin capsules.

Suitable candle you can do, for example, by mixing with a prescribed for this purpose by the media as neutral imadene benzaldoxime-östra-4,9-diene are antigestagen active substances, when the same activity as RU 486 (Mifepristone) in relation to the progesterone receptor (see table 1), respectively, when exceeding the action in vivo (see Fig. 1 and table 2) have clearly reduced in comparison with RU 486 antiglucocorticoid activity detected in the reduced binding of glucocorticoid-receptor (see table 1), as well as reduced ten-fold suppression of induction of enzymes in the cell lines (see Fig. 2 and 3).

Selected according to the invention antigestagen /J 687/ in the case of Guinea pigs in the cycle lead to statically significantly reduced weights of the uterus when the dosages in which the RU 486 in comparison with the control increases the weight of the uterus.

This combination of properties allows to expect from proposed according to the invention of antigestagens excellent suppression of inhibition of progesterone, while at the same time reduced antiglucocorticoid activity. This advantage is especially relevant in regard to the testimony that because of the duration of application require a particularly good acceptability. In the cycle, the weight of the uterus, the crucial is determined by circulating estrogens. Reduced weight of the uterus show suppression of the function of estrogen. Installed the genetic properties of the proposed according to the invention compounds. From the respective effects are to be expected especially favorable effect on the diseased tissue, in which estrogen promotes the growth impulses /foci of endometriosis, fibroids, genital carcinoma and breast carcinoma, benign prostatic hypertrophy/.

In Fig. 1 shows the effect antigestagens processing cyclic Guinea pigs on the weight of the uterus when comparing J 867 with RU 486.

High doses of RU 486 [6 mg/24 hours] reduce the weight of the uterus treated animals. Low dosages of this substance, on the contrary, lead to a slight increase of the weight of the uterus. All tested dosages J 867 [1,3, respectively, 6 mg/24 hours], on the contrary, suppress statistically significantly the weight of the uterus.

In Fig. 2 presents antiglucocorticoid action J 867 in the human cell line breast ZR 75/AGP-763 compared with RU 486.

Dexamethasone in this cell line induces gene chloramphenicolchloramphenicol (CAT). This induction is suppressed antiglucocorticoids substances. J 867 unexpectedly in a wide concentration ranges suppresses CAT less than RU 486 (Mifepristone).

In Fig. 3 shows antiglucocorticoid action J 867 in TAT-model in the case of hepato tyrosine amino-transferase (TAT). This action is suppressed antiglucocorticoid activity. J 867 accordingly acts clearly antiglucocorticoids weaker than RU 486.

Example 1.

434 mg 11- /4-formylphenyl/- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one at room temperature is dissolved in 8 ml of pyridine and mixed with 65 mg of hydroxylaminopurine and stirred at 25oC. After 2 hours, add the following 5 mg hydroxylaminopurine and the solution after 15 minutes, diluted with water, mixed with 1H. aqueous hydrochloric acid and extracted with chloroform, the organic phase is washed with diluted HCl and water, dried over sodium sulfate and potassium carbonate and the solvent is evaporated under reduced pressure. Obtain 420 mg of crude product. After the addition of acetone are crystals, which is sucked off and recrystallized from a mixture of isopropanol with CH2Cl2.

Obtain 305 mg of 11- [4-/gidroksimetil/phenyl]- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one.

So pl.: 118oC with decomposition.

()D= +197o/CHCl3/.

IR spectrum in CHCl3/cm-1/: 3575, 3300 /OH/, 1705 /C=NOH/; 1649 /C=C-C= C-C=O/; 1599 /phenyl/.

UV-spectrum in methanol:

max= 264 nm, = 20366,

X - system /; 4,381 /e , 1H, J = 6,9 Hz, H-11/; 5,788 /s, 1H, H-4/; 7,187 - 7,487 /m , 4H, AA'BB'system, aromatic protons/; 8,05 /s, 1H, OH/; 8,097 /s, 1H, /.

Mass spectrum m/e: 449,25509; C29H35NO4M+.

Getting the initial connection.

Stage A.

50 g of 4-Bromobenzaldehyde and 30 ml teeterboro ester of formic acid in 60 ml of methanol together with 0.8 ml of thionyl chloride is stirred for 5 hours at room temperature. Then add again 0.2 ml of thionyl chloride and after 30 minutes, poured into aqueous bicarbonate and extracted with chloroform, washed with an aqueous solution of bicarbonate and water, dried over sodium sulfate and concentrated under reduced pressure and obtain 68 g of 4-bromobenzaldehyde in the form of a colorless oil.

To 2.3 g of magnesium in 20 ml of anhydrous THF in an atmosphere of argon as a protective gas add 0.2 ml of dibromomethane and after start of the reaction was added dropwise 21,96 g of 4-bromobenzaldehyde in 70 ml anhydrous THF so that the temperature did not exceed 40oC. after adding the optional stirred for 2 hours at 30oC, then cooled to -10oC and mixed with 511 mg CuCl. Continue to mix for 15 minutes GF. Leave to warm to room temperature and a solution of the Grignard reagent is decomposed with an aqueous solution of ammonium chloride. The product distinguish by extraction with ethyl acetate, the organic phase is washed until neutral and dried over sodium sulfate. After removal of the solvent under reduced pressure allot of 19.7 g of crude product.

Chromatography on 300 g of silica gel and 20 g of aluminum oxide with toluene/ethyl acetate: gradient gives 7,38 g of 3,3-dimethoxy - 11-[4-/dimethoxymethyl/phenyl]-5-hydroxy-variety-9-EN-17-it is in the form of a yellow foam.

Stage B.

7,38 g of 3,3-Dimethoxy-11-[4-/dimethoxymethyl/phenyl]- 5 - hydroxy-variety-9-EN-17-she dissolved in 85 ml of dimethyl sulfoxide and in the atmosphere of argon as a protective gas is mixed with 10,38 g trimethyl-sulfanilimide and portions of 7.64 with of potassium tert-butylate. After 1.5 hours, cooled to 0-5oC and mixed with an aqueous solution of ammonium chloride. Eye-catching adhesive product is extracted with methylene chloride, washed until neutral, dried over sodium sulfate and after evaporation of the solvent is isolated in the form of a brown resin. Output: 8,63 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - Spiro-1',2'-oxiran-variety-9-EN-5-ol.

Stage Century.

8,63 g of 3,3-Dimethoxy. solution of sodium methylate and refluxed for 2-3 hours. Under reduced pressure the solvent is evaporated, the residue is treated with methylene chloride, washed until neutral, the solution is dried over sodium sulfate and evaporated under reduced pressure.

Get a total of 8.74 g of crude product as a brown foam. Chromatography on 260 g of silica gel and 90 g of alumina with toluene/ethyl acetate gradient gives 1.92 g of 3,3-dimethoxy-11-[4-/dimethoxymethyl/-phenyl]- 17 - methoxymethyl-variety-9-ene-5,17-diol.

Stage,

To 1.92 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/phenyl]- 17 - methoxy-methyl-variety-9-ene-5,17-diol in 120 ml of toluene in an atmosphere of inert gas added 8.65 g of potassium tert-butylate. The suspension is stirred for 5 minutes at room temperature and added dropwise to 6.35 ml under the conditions in 6 ml of toluene so that the temperature did not rise above 40oC. After 1 hour, add 20 ml of water and 20 ml of ethyl acetate, the phases are separated and the aqueous phase is additionally extracted with ethyl acetate. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

Obtain 1.55 g simple 3,3-dimethoxy - 11- [4-/3,3-dimethoxymethyl/phenyl] - 17 - m3,3-dimethoxy - 11- [4-/3,3-dimethoxymethyl/-phenyl]- 17 - methoxymethyl-variety-9-ene - 5,17 - dimethyl ester dissolved in 12.6 ml of acetone and mixed with 1.3 ml of water. In a protective gas atmosphere added 158 mg of 4-toluenesulfonic acid. Stirred for 40 minutes at room temperature and the slurry of crystals are sucked off, washed with acetone and crystallized from a mixture of methylene chloride with acetone.

Output = 0.55 g of colorless crystals.

New recrystallization from a mixture of methylene chloride with acetone give 440 mg of 11- [4-formylphenyl]- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one.

So pl. = 233-240oC.

()D= +189o/CHCl3/.

IR spectrum in CHCl3/cm-1/: 1710 /CHO/; 1660 /C=C-C=C=O/; 1610 /phenyl/.

UV-spectrum in methanol:

max= 262 nm, = 10775,

max= 299 nm, = 13999.

1H-NMR spectrum in CDCl3/, M. D./: 0,48 /s, 3H, H-18/; 3,25 /s, 3H, /; 3,38 /s , 3H, /; 4,40 /e, 1H, J = 7.2 Hz, H-11/; 5,78 /s , 1H, H-4/; 7,28-7,93 /m, 4H, AA'BB-system of the aromatic protons/; 9,95 /s, 1H, /.

Mass spectrum m/e: 434,24771; C28H34O4M+.

Example 2.

217 mg 11- /4-Formylphenyl/- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one in 4 ml of pyridine along with 40 mg of methoxyacetanilide stirred at room temperature. An hour later add further to 5.2 g methoxyacetanilide. Add 10 ml of water and ethyl acetate, the phases are separated, the aqueous phase254+366when elution with a mixture of toluene with acetone /4:1/ give 188 mg of the product as a foam.

Recrystallization from a mixture of acetone-hexane gives 11- [4-/methoxyisobutyl/-phenyl] - 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one as colourless leaflets.

So pl. = 83-89oC.

()D= +197o(chloroform).

IR spectrum in CHCl3/cm-1/: 1700 /C= NOCH3/; 1649 /C=C-C=C-C=O/; 1590 (aromatic).

UV-spectrum in methanol:

max= 275 nm, = 23098,

max= 300 nm, = 22872,

1H-NMR spectrum in CDCl3/, M. D./: 0,529 /s, 3H, H-18/; 3,247 /s, 3H, /; 3,408 /s , 3H, /; 3,39-3,598 /m, 2H, AVH-system /; 4,381 /e , 1H, J = 7.5 Hz, H-11/; 5,773 /s, 1H, H-4/; 7,173, 7,201, 7,463, 7,491 /m, 4H, AA'BB'system, aromatic protons/; 8,023 /s, 1H, phenyl/.

Mass spectrum m/e: 463,26950; C29H37NO4M+.

Example 3.

180 mg of 11- [4-/Gidroksimetil/phenyl]- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-it will acetimidoyl for 12 hours in 5 ml of a mixture of acetanhydride with Perignon /1:1/. After the addition of water extracted three times with ethyl acetate, the organic phase is washed A product, which is purified by preparative thin layer chromatography on silica gel PF254+366by elution with a mixture of toluene with acetone /4:1/.

Yield: 115 mg of 11- [4-/acetylacetonates/-phenyl]- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-4-it. The purified product is crystallized from ethyl acetate.

So pl. = 115-120oC /ethyl acetate/.

()D= +218o/CHCl3/.

UV-spectrum in methanol:

max= 271 nm, = 28157,

max= 297 nm, = 26369,

1H-NMR spectrum in CDCl3/, M. D./: 0,511 /s, 3H, H-18/; 2,227 /s, 3H, /; 3,247 /s , 3H, /; 3,408 /s, 3H, /; 3,386, 3,431, 3,544, 3,580 /m, 2H, /; 4,399 /e, 1H, J = 7.2 Hz, H-11/; 5,785 /s , 1H, H-4/; 7,242, 7,266, 7,618, 7,647 /m, 4H, AA'BB'system, aromatic protons/; 8,315 /s, 1H, /.

Mass spectrum m/e: 491,26971; C30H37NO5M+.

Example 4.

To 210 mg of 11- [4-/gidroksimetil/-phenyl]- 17 - methoxy - 17 - ethoxymethylene-4,9-Dien-3-one in 5 ml of pyridine while cooling water was added dropwise 0.3 ml of ethylchloride. A precipitate of white. After 30 minutes, mixed with water, forms a solution, and then precipitated white precipitate, which is sucked off and washed with water. The yield after drying is 133 mg Aqueous phase is extracted with chloroform, washed with diluted HCl and the efficient chromatography on silica gel 60 PF254+366purified by elution with a mixture of toluene with acetone /4 : 1/.

Receive 150 mg of 11- {4-[/etoxycarbonyl/-oksiminomyetil]- phenyl}- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one, which is recrystallized from a mixture of acetone with hexane.

So pl. = 137 - 148oC /decomposition/.

()D= + 204o/CHCl3/.

UV-spectrum in methanol:

max= 270 nm, = 27094,

max= 297 nm, = 25604,

1H-NMR spectrum in CDCl3/, M. D./: 0,507 /s, 3H, H-18/; 1,383 /so, 3H, J = 7,0 Hz, /; 3,246 /s, 3H, /; 3,410 /s, 3H, /; 3,39 - 3,56 /m, 2H, /; 4,35 /e, 1H, J = 7,0 Hz, H-11/; 5,784 /s, 1H, H-4/; 7,23, 7,26, 7,61, 7,64 /m, 4H, AA'BB'system, aromatic protons/; 8,303 /s, 1H, /.

Mass spectrum m/e: 431,24701; C28H33NO3M+- C2H5OCOOH.

Example 5.

244 mg 11- /4-Formylphenyl/- 17 - hydroxy - 17 - chloromethyl-östra-4,9-Dien-3-one in 4 ml of pyridine together from 32.2 mg hydroxylaminopurine stirred at room temperature. After an hour add the following to 6.9 mg hydroxylaminopurine. Then add 10 ml of water and ethyl acetate, the phases are separated, the aqueous phase is additionally extracted, the organic phase is washed with 10 ml of diluted HCl and distilled water until neutral, dried and evaporated under p is chromatography on silica gel 60 PF254+366when using solvent mixtures of toluene with acetone /4 : 1/ gives 87,7 mg 17 - chloromethyl - 11- [4-/gidroksimetil/-phenyl] - 17 - hydroxy-östra-4,9-Dien-3-one in the form of foam.

()D= + 185o/CHCl3/.

UV-spectrum in methanol:

max= 264 nm, = 20797,

max= 299 nm, = 20439,

1H-NMR spectrum in CDCl3/, M. D./: 0,607 /s, 3H, H-18/; 3,628, 3,664, 3,824, 3,861 /m , 2H, ABX-system /; 4,428 /e, 1H, J = 6,9 Hz, H-11/; 5,807 /s , 1H, H-4/; 7,185, 7,212, 7,482, 7,509 /m, 4H, AA'BB'system, aromatic protons/; 8,05 /s, 1H, OH/; 8,104 /s, 1H, phenyl/.

Mass spectrum m/e: 439,19070; C26H30ClNO3M+.

Getting the initial connection.

To 4.12 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - Spiro-1', 2'-oxiran-variety-9-EN-5-ol /obtained according to example 1, stage B) in 84 ml of dimethylformamide at 0oC was added dropwise and 16.6 ml of concentrated HCl. An hour later admixed in 420 ml of water, forming a flocculent precipitate. Using an aqueous solution of bicarbonate set pH 6, the precipitate is sucked off and dried.

Crude yield: 3,38 g painted in the color of ochre crystals, which are purified by column chromatography on 90 g of silica gel 60 using toluene/ethyl acetate gradient. Output: 1,16 g 17 - chloromethyl - 11- [4-Faure.

()D= +161o/CHCl3/.

IR spectrum in CHCl3/cm-1/; 3600 /OH/; 1695 /CHO/; 1650 /C=C-C=C-C=C/; 1590 /phenyl/.

UV-spectrum in methanol:

max= 262 nm, = 19993,

max= 297 nm, = 22755.

1H-NMR spectrum in CDCl3/, M. D./: 0,583 /s, 3H, H-18/; 3,30 /s, 1H, OH/; 3,63 - 3,85 /m, 2H, ABX system CH2Cl/; 4,45 /e, 1H, J = 7,0 Hz, H-11/; 5,809 /s, 1H, H-4/; 7,355, 7,282, 7,799, 7,826 /m, 4H, AA'BB'system, aromatic protons/; 9,977 /s, 1H, /.

Mass spectrum m/e: 424,18280; C28H29ClO3M+.

Example 6.

136 mg 11- /4-Formylphenyl/- 17 - hydroxy - 17 - methoxymethyl - östra-4,9-Dien-3-one at room temperature is dissolved in 2.2 ml of pyridine and mixed with 18 mg of hydroxylaminopurine and stirred at 25oC. After 1.5 hours, add the following 4 mg hydroxylaminopurine and the solution after 15 minutes, diluted with water, mixed with 1H. aqueous HCl and extracted with chloroform, the organic phase is washed with diluted HCl and water, dried over sodium sulfate and potassium carbonate and the solvent is evaporated under reduced pressure.

Obtain 146 mg of the crude product, which was purified by preparative thin layer chromatography on silica gel 60 PF254+366using a solvent mixture of toluene-acetone /4 : 1/.

So pl. = 104odecomposition /isopropanol/.

()D= + 195o/CHCl3/.

UV-spectrum in methanol:

max= 263 nm, = 21170,

max= 299 nm, = 20188.

1H-NMR spectrum in CDCl3/, M. D./: 0,517 /s, 1H, H-18/; 3,418 /s, 3H, /; 3,206, 3,237, 3,552, 3,582 /m, 2H, ABX-system /; 4,384 /e , 1H, J = 7.2 Hz, H - 11 /; 5,784 /s, 1H, H-4/; 7,179, 7,206, 7,456, 7,483 /m, 4H, AA'BB'system

aromatic protons/; 7,9 /s, 1H, OH/; 8,088 /s, 1H, /.

Mass spectrum m/e: 435,24289; C27H33NO4M+.

Getting the initial connection.

Stage g

860 mg of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - methoxymethyl-östra-9-ene - 5,17 - diol /obtained according to example 1, stage b/ dissolved in 80 ml of acetone. After addition of 7.7 ml of water and 430 ml of 4-toluenesulfonic acid for another 1.5 hours, refluxed, and concentrate under reduced pressure, the residue is treated with chloroform, using 8 ml of dilute ammonia establish pH 8 and the phases are separated. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

Obtain 590 mg of 11- /4-formylphenyl/- 17 - hydroxy - 17 - methoxymethyl-östra-4,9-Dien-3-one as a crude product, which is recrystallized from ethyl>IR spectrum in CHCl3/cm-1/: 3590 /OH/; 1710 /CHO/; 1660 /C=C-C=C-C=O/; 1605 /aromatic/.

UV-spectrum in methanol:

max= 263 nm, = 20683,

max= 298 nm, = 20749,

1H-NMR spectrum in CDCl3/, M. D./: 0,509 /s, 3H, H-18/; 2,666 /s, 1H, OH/; 3,196, 3,226, 3,550, 3,580 /m, 2H, ABX-system /; 3,417 /s, 3H, /; 4,446 /e, 1H, J = 6,9 Hz, H - 11/; 5,797 /s, 1H, H-4/; 7,360 7,386, 7,786, 7,813 /m, 4H, AA'BB'system, aromatic protons/; 9,970 /s, 1H, /.

Mass spectrum m/e: 420,23300; C27H32O4M+.

Example 7.

480 mg of 17 - Ethoxymethyl - 11- /4-formylphenyl/- 17 - methoxy-östra-4,9-Dien-3-one at room temperature is dissolved in 6 ml of pyridine, mixed with 74 mg of hydroxylaminopurine and stirred at 25oC. After 30 minutes, add the following to 8.5 mg hydroxylaminopurine and the solution after 15 minutes, diluted with water, mixed with 1H. aqueous HCl and extracted with methylene chloride, the organic phase is washed with diluted HCl and water, dried over sodium sulfate and potassium carbonate and the solvent is evaporated under reduced pressure.

Obtain 410 mg of the crude product by preparative thin layer chromatography on silica gel 60 PF254+366give 230 mg of 17 - ethoxymethyl - 11- [4-/gidroksimetil/-phenyl]- 17 - methoxy-östra-4,9-Dien-3-one in = 264 nm, = 20366,

max= 299 nm, = 20228.

1H-NMR spectrum in CDCl3/, M. D./: of 0.533 /s, 1H, H-18/; 1,267 /so, 3H, J = 6,9 Hz, /; 3,252, /s, 3H, 17-OCH3/; 3,423 - 3,623 /m, 2H, ABX system, /; 4,355 /e, 1H, J = 7.2 Hz, H-11/; 5,783 /s, 1H, H-4/; 7,191, 7,219, 7,460, 7,488 /m, 4H, AA'BB'system, aromatic protons/; 8,097 /s, 1H, /.

Mass spectrum m/e: 463,27069; C29H37NO4M+.

Getting the initial connection.

Stage z

5,33 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/phenyl]- 17 - Spiro-1', 2'-oxiran-variety-9-EN-5-ol /obtained according to example 1, stage B is dissolved in 5 ml of ethanol, mixed in 25 ml of a 1.5 n solution of sodium methylate and refluxed for 1 hour. The solvent is evaporated under reduced pressure, the residue is treated with methylene chloride, washed until neutral, the solution is dried over sodium sulfate and evaporated under reduced pressure.

Get 5,85 g crude product as a brown foam. Chromatography on silica gel using toluene/ethyl acetate: gradient gives 1,14 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - ethoxymethyl-variety-9-ene - 5,17-diol.

Stage I.

To 1,14 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - ethoxymethyl-variety-9-ene-5,17-diol in 70 ml of toluene in an argon atmosphere in to the Yes in 4 ml of toluene. After 2 hours due to supplementation with 20 ml water and 20 ml ethyl acetate the reaction is interrupted. The organic phase is washed twice with water, dried over sodium sulfate and evaporated under reduced pressure.

Crude yield: 1,14 g of 3,3-dimethoxy - 11- [4-/3,3-dimethoxymethyl/-phenyl]- 17 - ethoxymethyl - 17 - methoxy-variety-9-EN-5-ol.

Stage K.

To 1,14 g of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - ethoxymethyl - 17 - methoxy-variety-9-EN-5-ol in 10 ml of acetone in the atmosphere of inert gas was added 1 ml of water and 116 mg of 4-toluenesulfonic acid. After 30 minutes, diluted with water, extracted twice with ethyl acetate, the organic solution is washed and dried over sodium sulfate. After evaporation of the solvent remain 900 mg 17 - ethoxymethyl-11- /4-formylphenyl/- 17 - methoxy-östra-4,9-Dien-3-one as a yellow foam. Chromatography on silica gel 60 using a gradient of toluene/ethyl acetate to give 480 mg of yellow crystals.

Example 8.

244 mg 11- /4-Formylphenyl/- 17 - hydroxy - 17-/3-hydroxyprop-1-in-Il/-östra-4,9-Dien-3-one at room temperature is dissolved in 4.5 ml of pyridine and mixed from 35.5 mg hydroxylaminopurine and stirred at 25oC. After 30 minutes, add the following to 4.8 mg hydroxyl-americanled and after 15 minutes rastvorimyv water, dried over sodium sulfate and potassium carbonate, and the solvent is evaporated under reduced pressure.

Get 216 g of crude product which, after preparative thin layer chromatography on silica gel 60 PF254+366using a solvent mixture of toluene/acetone [4:1] give 192 mg of 11- [4-/gidroksimetil/phenyl]- 17 - hydroxy - 17- /3-hydroxyprop-1-in-Il/-extra-4,9-Dien-3-one as a colourless foam.

So pl. = 171-179oC /ether/.

()D= + 82o/dioxane/.

UV-spectrum in methanol:

max= 264 nm, = 21495,

max= 299 nm, = 20236.

Mass spectrum m/e: 445,22369; C28H31NO4M+.

Getting the initial connection.

Stage L

To 3 ml of a simple prop-1-in-Il-3-hydroxytetrahydrocannabinol ether in 27 ml of anhydrous THF at -5oC was added dropwise 12 ml of 15% n-utility in hexane. After 15 minutes, to this solution was added dropwise 1.2 g of 3,3-dimethyl - 11- [4-/dimethoxymethyl/-phenyl] - 5- -hydroxyestra-9-EN-17-it /obtained according to example 1, stage B) in 16 ml of anhydrous THF. Stirred for 30 minutes at room temperature, the reaction solution was poured into 150 ml of ice water and extracted with ethyl acetate. The organic phase is washed up neitralnogo oil, which is purified by chromatography on silicagel 60 using a gradient of toluene/ethyl acetate. Get 422 mg of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl] - 17- /3-tetrahydropyranyloxy-1-in-Il/the-variety-9-EN-5, 17-diol in the form of foam.

Stage M

540 mg of 3,3-Dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17- /3-tetrahydropyranyl-prop-1-in-Il/the-variety-9-ene - 5,17 - diol in 40 ml of acetone together with 100 mg of 4-toluenesulfonic acid is stirred for 2 hours at room temperature. Then concentrate to a volume of 10 ml, is mixed with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure.

Crude yield: 330 mg Purification by preparative thin-layer chromatography on silica gel 60 PF254+366give 310 mg of 11- /4-formylphenyl/- 17 - hydroxy - 17- /3-hydroxyprop-1-in-Il/-östra-4,9-Dien-3-one. Recrystallization from acetone gives white crystals.

So pl. = 225-231oC.

()D= +59o/chloroform/.

UV-spectrum in methanol:

max= 302 nm, = 23608,

1H-NMR spectrum in CDCl3/, M. D./: 0,496 /s,

3H, H-18/; 4,375 /s, 2H, /; 4,497 /e, 1H, J = 7.2 Hz, H - 11 ; 5,810 /s. 1H, H-4/; 7,353, 7,380, 7,797, 7,824 /m, +.

Example 9.

190 mg of 11- [4-/Gidroksimetil/-phenyl]- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one are suspended in 10 ml of toluene. Consistently add 0.5 ml of phenylisocyanate and 1 ml of triethylamine. Stirred for 3 hours at room temperature, refluxed for 2 hours, the precipitate is sucked off white color and the solvent concentrated under reduced pressure. Obtain 310 mg of light brown solid, which was purified by preparative thin layer chromatography on silica gel 60 PF254+366when using a solvent mixture of toluene/acetone [9:1]. Allocate 65 mg 17 - methoxy - 17 - methoxymethyl - 11- [4-{ /phenylenecarbonyl/oksiminomyetil}-phenyl]-östra-4,9-Dien-3-one.

So pl. 241 - 246oC /acetone/.

()D= + 178o/CHCl3/.

UV-spectrum in methanol:

max= 238 nm, = 29444,

max= 300 nm, = 29649.

1H-NMR spectrum in CDCl3/, M. D./: 0,474 /s, 3H, H-18/; 3,245 /s, 3H, /; 3,405 /s . 3H, /; 3,406-3,545 /m, 2H, ABX-system /; 4,13 /e, J = 6,8 Hz, 1H, H-11/; 5,797 /s, 1H, H-4/; UAH 7,264 /m, 5H, aromatic/; 7,272, 7,293, 7,548, 7,575 /m, 4H, AA'BB' system, aromatic protons/; 8,0 /s, 1H, /.

Mass spectrum m/e: 431,24249; C28H33NO3M+- C6H5CNO + H2oC. After 50 minutes, the solution was diluted with water, mixed with ethyl acetate and the phases are separated. The organic phase is washed with diluted HCl and water, dried over sodium sulfate and the solvent is evaporated under reduced pressure.

Obtain 127 mg of crude product as a pale yellow foam, which, after preparative thin layer chromatography on silica gel 60 PF254+366give 62 mg of 17 - ethoxymethyl - 11- [4-/gidroksimetil/-phenyl]- 17 - hydroxy-östra-4,9-Dien-3-one as a colourless foam.

()D= + 226o/CHCl3/.

UV-spectrum in methanol:

max= 265 nm, = 22696,

max= 299 nm, = 21960.

1H-NMR spectrum in CDCl3/, M. D./: 0,520 /s, 1H, H-18/; 1,249 /so, 3H, J = 7.2 Hz, /; 3,228-3,609 /m, 4H, HSN2/; 4,381 /e, 1H, J = 7.2 Hz, H-11/; 5,781 /s, 1H, H-4/; 7,181, 7,209, 7,459, 7,486 /m, 4H, AA'BB'system, aromatic protons/; 8,098 /s, 1H, /.

Mass spectrum m/e: 449,25540; C28H35NO4M+.

Getting the initial connection.

Stage N.

3240 mg of 3,3-dimethoxy - 11- [4-/dimethoxymethyl/-phenyl]- 17 - ethoxymethyl-variety-9-ene-5,17-diol [obtained according to example 7, step 3] is dissolved in 2.5 ml of acetone, mixed with 0.25 ml of water and 35 mg t, the aqueous phase is additionally extracted twice, the organic solution is washed and dried over sodium sulfate. After evaporation of the solvent remain 300 mg of yellowish crystals.

By preparative thin-layer chromatography on silica gel 60 PF254+366, elwira using a mixture of toluene with acetone /9:1/ receive 200 mg of 17 - ethoxymethyl - 11- /4-formylphenyl/- 17 - hydroxy-östra-4,9-Dien-3-one as yellowish crystals.

So pl. = 144 - 150oC /acetone with hexane/.

()D= + 171o/CHCl3/.

UV-spectrum in methanol:

max= 263 nm, = 17842,

max= 299 nm, = 20083.

1H-NMR-spectrum CDCl3/, M. D./: 0,512 /s, 1H, H-18/; 1,249 /so, 3H, J = 4,6 Hz, /; 3,321 - 3,613 /m, 4H, 2 x CH2/; 4,447 /e, 1H, J = 6,9 Hz, H-11/; 5,799 /s, 1H, H-4/; 7,361, 7,388, 7,788, 7,816 /m, 4H, AA'BB'system, aromatic protons/; 9,972 /s, 1H, /.

Example 11. Measurement of the affinity of the receptor binding.

The affinity of the receptor binding is determined by competitive binding specifically bind3H-labeled hormone /labeled substance and the test compound with the receptor in the cytosol of animal organs. It strives to saturation of the receptor and the reaction equilibrium. Choose a trail, ranamese at -30oC, in TED buffer [20 mol TRIS/HCl, pH 7,4; 1 mmol ethylenediaminetetraacetate; 2 mm dithiothreitol with 250 mm sucrose. Labeled substance:3H-ORG 2058,6 nm; standard substance: progesterone.

The glucocorticoid-receptor: cytosol from rat thymus with a remote adrenal gland; thymus stored at -30oC; buffer: TED. Labeled substance:3H-Dexamethasone, 20 nm; standard substance: Dexamethasone. Estrogen-receptor: the cytosol from the uterus of immature rabbit stored at -30oC, in TED buffer with 250 mm sucrose. Labeled substance:3H-ethinylestradiol, 3 nm; standard substance: 17-estradiol.

After the duration of incubation for 18 hours at 0-4oC carry out the separation of bound and free steroid by applying activated carbon with dextran [1%/ 0,1%], centrifugation and measurement of the associated3H-activity in the supernatant.

From measurements at a range of concentrations to determine 1C50for the test compounds and standard substances and in the form of both private values /X100%/ get the relative molar affinity for binding.

Example 12. Suppression of early pregnancy in rats.

Female rats copulate in Prooestrus. When detecting the test substance or indifferent basis of medicines is carried out in 5 days - 7, the autopsy is carried out in a day 9. Substances inyeccion in 0.2 ml of excipient [benzyl benzoate/castor oil = 1 + 4] subcutaneously. The number of completely suppressed pregnancies in different groups can be seen from table 1. For J 867 installed superior by a factor of 3 RU 486 suppression of nidali.

Example 13. Antigestagen processing (treatment) of female Guinea pigs.

Treatment of adult female Guinea pigs on days 10 - 18 loop (autopsy). The introduction of these doses by subcutaneous osmotic pump /ALZET type 2 MLI/; indifferent basis of medicines: 2.0 ml propylene glycol/ 24 hours.

Example 14. Antiglucocorticoid action J867 in the human cell line of breast cancer ZR 75 /AGP-763.

Experiments with cell cultures carried out in R PM1 1640, mixed with 10% fetal calf serum /FKS/ in an incubator with 95% air and 5% CO2at 37oC. For experiments, cells were seeded in Petri dishes with a diameter of 60 mm. Environment confluent cells replace the medium with 5% FKS [processed the dextran-coated charcoal /DCC/] . For SAT-induction type Dexamethasone at a concentration of 10-7M in ethanol /0,2%; the volume/. Harvesting stimulated cells carry out after 16 h the t using ELISA firm Boehringer according to the description for the quantitative SAT-identify transfected cells.

Example 15. Antiglucocorticoid action J867 in TAT-model in hepatoma cells of rats.

The cultivation is carried out in DMEM under other equal conditions as in example 14. Seeding cells for experiments carried out on plates with 24-I of the grooves. Additive substances to confluent hepatoma cells is carried out in a 0.2 per cent /amount/ ethanol for 16 hours. After careful harvesting of cells with a scraper to collect the cells and extract cells by ultrasound spend the definition of TAT-enzyme by Diamondstone.

Additional examples of the compounds.

Annex 1.

1. 11- [4-(gidroksimetil)phenyl] - 17 - methoxy - 17- (i-propoxymethyl)-östra-4,9-Dien-3-one.

920 mg (2 mmol) of 11- [4-(formylphenyl]- 17 - methoxy - 17- (i-propoxymethyl)-östra-4,9-Dien-3-one was dissolved in 20 ml of pyridine and enter into interaction with 345 mg hydroxylamine sulfate for 2 hours at room temperature. Then added dropwise to ice water, the precipitate is sucked off, washed with water and dried. 940 mg of the crude product purified preparative thin-layer chromatography on silica gel PF254+366HM(MERCK AG) with a mixture solvent of toluene/acetone 4: 1 and recrystallized from acetone/hexane. Get the()D= +199o(CHCl3).

1H-NMR [CDCl3; TMS] (, nnm): 0,54 (S, 3H, H-18); 1,22 [t, 6H, CH(CH3)2] , 3,26 (S, 3H, OCH3), 3,43, and 3,61 (dd, 2H, J = 10.5 Hz, ); 4,37 (d, 1H, J = 6,9 Hz, H-11); 5,79 (S, 1H, H-4); 7,21 and of 7.48 (dd, 4H, J = 8.1 Hz, aromatic protons); to 7.99 (S, 1H, NOH), 8,10 (S, 1H, ).

Getting the initial connection.

Stage A.

3.0 and 3.3-dimethoxy - 11 {[4-(1,1-dimethoxy)methyl]phenyl}- 17(S)-Spiro-oxiranyl-variety-9-EN - 5 - ol in 25 ml of dimethyl sulfoxide enter into interaction with 2.3 g isopropanolate sodium in 80oC for 3 hours. Poured into 1.5 l of ice water, the precipitate is sucked off, dissolved in acetic ether, dried with sodium sulfate, filter and concentrate the solution under vacuum. Get 3,15 g (94.5% of theory) of 3,3-dimethoxy - 11 {[4-(1,1-dimethoxy)methyl]- phenyl}-17- (i-propoxymethyl)-variety-9-ene-5,17-diol.

Stage B.

3,15 g of 3,3-dimethoxy - 11 {[4-(1,1-dimethoxy)methyl]phenyl}- 17- (i-propoxymethyl)-variety-9-ene - 5,17 - diol are dissolved in 100 ml of toluene is injected into the interaction of 8.12 g (to 72.4 mmol) of tert-butanolate potassium and then to 4.98 ml methyliodide at 25-30oC for 75 minutes. After adding water, the phases are separated, the organic phase is additionally extracted with acetic ether, the combined organic phases are washed with water, dried on simetal)- 17 - methoxy-variety-9-EN-5-ol as a light brown oil.

Stage C.

of 3.77 g of 3,3-dimethoxy- 11- {[4-(1,1-dimethoxy)methyl]phenyl}- 17- (i-propoxymethyl)- 17 - methoxy-variety-9-EN - 5 - ol dissolved in 50 ml tert-butyl methyl ether, mixed with 5 ml of water at room temperature and stirred for 3 hours with 350 mg of p-TsOH. Concentrated in vacuo to half volume and leave the solution

overnight in a refrigeration Cabinet. The solution absorb in CH2Cl2, neutralized by addition of an aqueous solution of bicarbonate, washed with water and dried on sodium sulfate. The solvent is evaporated in vacuum.

Get 2,77 g (76,9% of theory) of 11- [4-(formylphenyl]- 17 - methoxy - 17- (i-propoxymethyl)-östra-4,9-Dien-3-one as a brown foam. The crude product is purified by chromatography on silica gel (0.06 to 0.2 mm MERCK AG) with a mixture solvent of toluene/acetone. Allocate 1.44 g, which precipitated out of Ch2Cl2with tert-butylmethylamine ether. Obtain 1.3 g (60.7% of theory).

Melting point: 122-129oC (CH2Cl2/tert-butyl methyl ether).

D= +173o(CHCl3).

1H-NMR [CDCl3; TMS] (, nnm): 0,50 (s, 3H, H-18); 1,22 [t, 6H, J = 11,6 Hz] at 3.25 (s, 3H, OCH3), 3,44, and to 3.58 (dd, 2H , J = 10.4 Hz, ); 3,6 [m, 1H, OCH(CH3)2], was 4.42 (d, 1H, J = 7,3 Hz, H-11); 5,79 (s, 1H, H-4); 7,37 and 7.78 (dd, 4H, J = 8.1 Hz, aromatic protons); 9,99 (S mg 11- [4-(formylphenyl)] - 17 - hydroxy - 17- (ethylthiomethyl)- östra-4,9-Dien-3-one is dissolved in 5 ml of pyridine and enter into interaction with 172 mg hydroxylammonium 2 hours at room temperature. Was added dropwise in ice water, the precipitate is sucked off, washed with water and dried. The crude product is purified preparative thin-layer chromatography on silica gel PF254+366HM(MERCK AG) with a mixture solvent of toluene/acetone 4:1 and recrystallized from acetone. Obtain 185 mg of colorless crystals.

Melting point: 132-137oC (acetone).

D= +165o(CHCl3).

1H-NMR : [CDCl3; TMS] (, nnm) : 0,56 (s, 3H, H-18); 1,29 [t, 3H, J = 7,2 Hz ]; 2,61 (d, 2H, J = 7.5 Hz, ), 2,71, and of 2.92 (dd, 2H, J = 12.9 Hz, ); 2,90 (S, 1H, OH); was 4.42 (d, 1H, J = 7.2 Hz, H-11); 5,79 (S, 1H, H-4); 7.20 and 7,49 (dd, 4H, J = 8,4 Hz, aromatic protons); to 7.93 (s, 1H, NOH), 8,10 (s, 1H, ).

Getting the initial connection.

Stage A.

992 mg of 3,3-dimethoxy- 11- {[4-(1,1-dimethoxy)methyl]phenyl}- 17(S)-spirooxazine-variety-9-EN - 5 - ol in 7 ml dimethylsulfoxide enter into interaction with 3,36 g (4 mmol) timelinelite sodium in 80oC for 2 hours. Poured into an aqueous solution of NH4Cl, the precipitate is sucked off and get 1.5 g of wet crude product yellow 3,3-dimethoxy - 11 {[4-(1,1-dimethoxy)methyl] phenyl}- phenyl}- 17- (i-ethylthiomethyl)-variety-9-ene - 5,17 - diol is dissolved in acetone and at room temperature, stirred for 3 hours with 180 mg of p-TsOH. The addition of an aqueous solution of bicarbonate precipitated sludge, which is sucked off and dried. The crude product is purified preparative thin-layer chromatography on silica gel (PF254+366HMMERCK AG) with a mixture solvent of toluene/acetone 4:1. Get 460 mg of 11- [4-(formylphenyl)} - 17 - hydroxy - 17- (ethylthiomethyl)-östra-4,9-Dien-3-one which is recrystallized from acetone.

Melting point: 180-182oC (acetone).

D= +160o(CHCl3).

1H-NMR : [CDCl3; TMS] (, nnm): 0,54 (s, 3H, H-18); 1,29 [t, 3H, J = 7,2 Hz ] ; 2,61 (d, 2H, J = 7.5 Hz, ), 2,71, and 2,96 (dd, 2H, J = 12.9 Hz, ); 2,87 (s, 1H, OH); of 4.45 (d, 1H, J = 6,5 Hz, H-11); 5,80 (s, 1H, H-4); 7,38 and 7,81 (dd, 4H, J = 8,4 Hz, aromatic protons); 9,98 (s, 1H, ).

3. 11- [4-(gidroksimetil)phenyl]- 17 - hydroxy - 17- (i-propoxymethyl)-östra-4,9-Dien-3-one.

500 mg of 11-[4-(formylphenyl]-17 - hydroxy - 17- (i-propoxymethyl)-östra-4,9-Dien-3-one in 20 ml of pyridine enter into interaction with 65 mg of hydroxylaminopurine for 2 hours at room temperature. Poured into ice water, sucked off, washed with sediment to a neutral state with water and dried in air. Light brown foam cleanse preparative thin-layer chromatography on silica gel PF254+366HM(MERCK AG) with a mixture of solvents is the exercise: 192-196oC (ether).

D=+215o(CHCl3).

1H-NMR [CDCl3); TMS] (, nnm): 0,52 (s, 3H, H-18); 1,21 [q, 6H, J=9.6 Hz, ], to 3.02 (s, 1H, OH), 3,22 and 3,59 (dd, 2H, J=9,3 Hz ); 3,62 (m, 1H, ); to 4.38 (d, 1H, J=6,6 Hz, H-11); 5,79 (s, 1H, H-4); 7.20 and 7,47 (dd, 4H, J=8,4 Hz, aromatic protons); 8,08 (s, 1H, OH), 8,10 (s, 1H, ).

Getting the initial connection.

Stage A.

3.0 g (6,04 mmol) of 3,3-dimethoxy - 11 {[4(1,1-dimethoxy)-methyl]phenyl}-17 (S)-spirooxazine-variety-9-EN-5-ol in 25 ml of dimethyl sulfoxide enter into interaction with 2.3 g (4 mmol) isopropanolate sodium in 80oC for 3 hours. Poured into 1.5 l of ice water, the precipitate is sucked off, dissolved in acetic ether, dried with sodium sulfate, filter and concentrate the solution under vacuum. Get 3,15 g (94.5% of theory) of 3,3-dimethoxy - 11 { [4(1,1-dimethoxy)methyl]phenyl}- 17- (i-propoxymethyl)-variety-9-ene-5,17-diol.

Stage B.

3.0 g of 3,3-dimethoxy - 11 {[4-(1,1-dimethoxy)methyl]phenyl}- 17- (i-propoxymethyl)-variety-9-ene 5,17-diol is dissolved in 30 ml of tert-butyl methyl ether, mixed with 5 ml of water and stirred at room temperature for 3 hours with 250 mg of p-TsOH. Concentrated in vacuo to half volume, absorb in CH2Cl2, neutralized by addition of an aqueous solution of bicarbonate, washed with water, dried over self-propoxymethyl)östra-4,9-diene as a brown foam. The crude product is purified by chromatography on silica gel (0.06 to 0.2 mm MERCK AG) with a mixture solvent of toluene/acetone. Obtain 1.44 g of purified crude product, which precipitated out of CH2Cl2with tertiary butyllithium ether. Allocate 1.3 g (60.7% of theory).

Melting point: 122oC (decomposition) (tert-butyl methyl ether/hexane).

D=+186o(CHCl3).

1H-NMR: [CDCl3; TMS] (, nnm): 0,51 (s, 3H, H-18); 1,22 [d, 6H, J=9.9 Hz, ], 2,84 (s, 1H, OH), 3,22 and 3,59 (dd, 2H, J=9,3 Hz ); 3,62 (m, 1H, ); of 4.45 (d, 1H, J=6,6 Hz, H-11); 5,80 (s, 1H, H-4); 7,37 and 7,80 (dd, 4H, J=8,4 Hz, aromatic protons); becomes 9.97 (s, 1H, CH=O).

4. 17 - azidomethyl - 11- [4-(gidroksimetil)phenyl]- 17 - hydroxy-östra-4,9-3-one.

800 mg (of 1.85 mmol) 17 - azidomethyl - 11- [4(formylphenyl)]- 17 - hydroxy-östra-4,9-Dien-3-one are dissolved in 22 ml of pyridine and enter into interaction with 245 mg of hydroxylaminesulfate 2 hours at room temperature. A clear solution was added dropwise to ice water, the precipitate is sucked off, washed with water and dried. Output 827 mg preparative thin layer chromatography on silica gel PF254+366HM(MERCK AG) with a mixture solvent of toluene/acetone 3:1 give 649 mg of colorless oil,

which is recrystallized from tert-butyl methyl ether. Get the new ether).

aD=-212o(MeOH).

IR [(KBr)cm-1]: 1643 and 1657 (C=C-C=C-C=O); 2099 (N3);

UV[MeOH]:

max209 nm = 23692, log = 4,37;

max265 nm = 21765, log = 4,33;

max299 nm = 21389, log = 4,33;

1H-NMR: [DMSO; TMS] (, nnm): 0,43 (s, 3H, H-18); is 3.08 and 3.40 (dd, 2H, J= 12,6 Hz ); 4,43 (d, 1H, J=6.3 Hz, H-11); 4,74 (s, 1H, 17-OH); of 5.68 (s, 1H, H-4); 7,24 and 7,51 (dd, 4H, J=8.1 Hz, aromatic protons); of 8.09 (s, 1H, ), and 11.2 (s, 1H, NOH).

Getting the initial connection.

1 g (2.02 mmol) of 3,3-dimethoxy - 11 [4-(1,1-dimethoxy)-methyl]phenyl}-17(S)-Spiro-1', 2',-oxiranyl-9-EN-5-ol are suspended in 70 ml of ethylene glycol and heated for 3 hours with 1,008 g (of 15.5 mmol) of sodium azide in a boiling water bath. Added dropwise to 600 ml of chilled ice water, sucked off, washed with water and sucked off by air drying. The output of 1.08 g (100% of theory) 17 - azidomethyl-3,3 - dimethoxy - 11- {[4(1,1-dimethoxy)-methyl]phenyl}-variety-9-ene-5,17 - diol.

1.08 mg of this compound is dissolved as the crude product in 20 ml of acetone and 2 ml of water, mixed with 258 mg of p-toluenesulfonic acid and stirred for 5 hours at room temperature. Then neutralize with dilute ammonia, and the precipitated crude product is sucked off. Output: 909 mg 17 - azidomethyl - 11- [4-(formylphenyl)] - 17-hydroxy-östra-4,9-Dien-3-one. Recrystallization from acetone and small is Eton).

D=+156o(CHCl3).

IR (KBr)[cm-1]: 1648 (C=C-C=C-C=O); 1712 (CHO), 2100 (N3).

UV [MeOH]:

max203 nm = 21143, log = 4,32;

max263 nm = 18338, log = 4.26 deaths;

max299 nm = 20712, log = 4,32;

1H-NMR: [CDCl3; TMS] (, nnm): 0,53 (s, 3H,H-18); 2,04 (s, 1H, OH); 3,31 and of 3.60 (dd, 2H, J=12.3 Hz, ); 4,48 (d, 1H, J=7.2 Hz, H-11); of 5.81 (s, 1H, H-4); 7,37 and of 7.82 (dd, 4H, J=8,4 Hz, aromatic protons); 9,98 (s, 1H, ).

5. 11- [4-(gidroksimetil)phenyl]- 17 - hydroxy-östra-4,9-Dien-3-one.

115 mg of 11- [4-(formylphenyl)] - 17 - hydroxy-östra-4,9-Dien-3-one are dissolved in 2 ml of pyridine and enter into interaction with the 22.5 mg hydroxylaminopurine at the 23oC. After 2 hours, diluted with ice water, the precipitate is sucked off, washed with water and dried. Get 99,4 mg. of 11- [4-(gidroksimetil)phenyl]- 17 - hydroxy-östra-4,9-Dien-3-one which purify preparative thin-layer chromatography on silica gel PF254+366recrystallized from methanol.

Melting point: 150 - 153oC (MeOH).

1H-NMR spectrum in CDCl3(, nnm): 0,42 (s, 3H, H-18); 3,68 (t, 1H, H - 17); to 4.38 (d, J=6,9 Hz, 1H, H-11); 5,79 (s, 1H, H-4); 7,20, 7,22, 7,48, 7,51 (m, 4H, A, A', B, B' system, aromatic protons); for 7.78 (s, 1H, OH), 8,11 (s, 1H, ).

6. 11- [4-(gidroksimetil)phenyl] - 17 - hydroxy - 17 - methyl - östra-4,9-Dien-3-one.

Melting point: 154 - 160oC [(CH3)3OCH3].

D=+224o(CHCl3).

IR-spectrum in CDCl3[cm-1] : 3375 (OH), 3284 (associated OH), 1650 (C=C-C= C-C=O); 1600 phenyl.

UV spectrum (MeOH):

max= 264 nm, = 19111,

max= 299 nm, = 18912.

1H-NMR spectrum in CDCl3(, nnm): 0,53 (s, 3H, H-18); of 1.20 (s, 9H, group, tert-butyl funds recrystallization); of 1.27 (s, 3H, 17-CH3); up 3.22 (s, 3H, (CH3)3OCH3); was 4.42 (d, J=6,9 Hz, 1H, H-11); 5,79 (s, 1H, H-4); 7,19, 7,22, 7,48, 7,51 (m, 4H, A, A', B, B' system, aromatic protons); 7,79 (s, 1H, ); 8,11 (s, 1H, ).

Getting the initial connection.

In the solution of Grignard reagent (obtained from 2,43 mg of magnesium and 6.4 ml of methyliodide in 25 ml of methyl tert-butyl ether) was added dropwise at room temperature a solution 5,69 g 11 {[4-dimethoxymethyl]phenyl}-3,3-dimethoxy-5-hydroxy-variety-9-EN-one in 30 ml of tetragidrofurana. Paramesh is, share phase, the aqueous phase is additionally extracted, and the combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. Obtain 4.7 g of product in the form of a yellow foam which is purified by chromatography on silica gel (0,23 - 0.5 mm) with a gradient of toluene/acetic ester. Yield: 1.3 g of 11- [4-dimethoxy-methyl)phenyl] -3,3-dimethoxy - 17 - methyl-variety-9-ene - 5,17 - diol.

The crude product is dissolved in 3.5 ml of acetone, mixed with 0.35 ml of water and 74 mg of p-toluenesulfonic acid and stirred at room temperature for 30 minutes. The initial mixture is diluted with acetic ether and water, split phase and the organic phase is dried over sodium sulfate. Obtain 1.07 g of 11- (4-formylphenyl)- 17 - hydroxy - 17 - methyl-östra-4,9-Dien-3-one as yellow crystals, which are purified by chromatography.

Melting point: 160 - 164oC (acetone).

IR (MeOH) [cm-1] : 3605 (OH); 1704 (CHO); 1657 (C=C-C=C-C=O); 1603 (phenyl).

1H-NMR spectrum in CDCl3(, nnm): 0,50 (s, 3H, H-18); of 1.28 (s, 3H ); 2,18 (acetone); 4,48 (d, J = 7.2 Hz, 1H, H-11); 5,80 (s, 1H, H-4); 7,38 (d, 2H, J = 8.1 Hz, aromatic protons), 7,81 (s, 2H, J = 6,6 Hz, aromatic protons); 9,98 (s, 1H, ).

7. 17 - acetoxy - 11- [4-(gidroksimetil)phenyl]-östra-4,9-Dien-3-one.

450 mg of 17 - acetoxy - 11- (4-formylphenyl)]-östra-4,9-Dien-3-on the ez 40 minutes, diluted with ice water, the precipitate is sucked off, washed with water and dried. Receive 450 mg of 17 - acetoxy - 11- [4-(gidroksimetil)phenyl] -östra-4,9-Dien-3-one. The crude product is purified preparative thin-layer chromatography on silica gel PF254+366and recrystallized from acetone.

Melting point: 130-135oC (acetone).

D= +202o(CHCl3).

IR-spectrum in CDCl3[cm-1]: 3575 (OH); 1711 (OCOCH3); 1656 (C=C-C=C-C=O); 1605 (phenyl).

UV spectrum (MeOH):

max= 264 nm, = 20698,

max= 299 nm, = 20569.

1H-NMR spectrum in CDCl3(, nnm): 0,47 (s, 3H, H-18); 2,03 (s, 3H, COCH3); of 4.35 (d, J = 6,9 Hz, 1H, H-11); 4,63 (t, J = 9,3 Hz, 1H, H - 17); 5,79 (s, 1H, H-4); 7,20, 7,49 (d, J = 8,4 Hz, 2H, aromatic protons); to 7.64 (s, 1H, OH); 8,11 (s, 1H, ).

Getting the initial connection.

Stage 1.

In the solution of Grignard reagent (obtained from 1.6 mg of magnesium and 17.7 g of 4-bromobenzaldehyde-neopentylene in 100 ml of tetrahydrofuran (THF) is added at -20oC 426 mg CuCl is stirred an additional 10 minutes and added dropwise to 5 g of 3,3-dimethoxy - 5,10 - epoxy-variety-9-EN-17-she's in 25 ml of anhydrous tetrahydrofuran. Heated to 0oC, further stirred for 1.5 hours and decomposed with aqueous ammonium chloride. After adding acetic ether based on separate treatment and evaporated under reduced pressure. Light syrup is purified on silica gel with a gradient of toluene/acetic ester. Get 3,24 g crude product. By recrystallization from methyl tert-butyl ether/hexane produce 3,3-dimethoxy - 11- [4-(5,5-dimethyl-1,3-dioxane-2-yl)phenyl]- 5 - hydroxy-extras-9-EN-17-one as colorless crystals.

Melting point: 194-202oC.

D= +64o(CHCl3).

IR spectrum (CHCl3): 1732 cm-1(C=O).

1H-NMR spectrum in CDCl3(, nnm): 0,46 (s, 3H, H-18); 0,80 and 1.31 (2s, 3H, neopentylene); 3,20 and 3.33 (2s, 3H ); 3,63 - 3,79 (q, 4H, Catala); 4,30 (d, J = 6,9 Hz, 1H, H-11); of 4.66 (s, 1H, OH); to 5.35 (s, 1H, ); from 7.24 (d, 2H, J = 7.8 Hz, aromatic protons); 7,41 (s, 2H, J = 8.1 Hz, aromatic protons).

Stage 2.

2.1 g of 3,3-dimethoxy - 11- [4-(5,5-dimethyl-1,3-dioxane-2-yl)phenyl]- 5 - hydroxy-variety-9-EN-17-she dissolved in 25 ml of methanol/tetrahydrofuran and restore at 23oC using 303 mg of sodium borohydride. After 45 minutes, mix in water and the aqueous phase is extracted several times with methylene chloride. The organic phase is dried and evaporated under reduced pressure. The crude product is dissolved in 25 ml of acetone, stirred for 8 hours at room temperature with 2 ml of water and 283 mg of p-toluenesulfonic acid. Then, pour the water and the precipitate is sucked off. On the (4-formylphenyl)- 17 - hydroxy-östra-4,9-Dien-3-one.

Melting point: 197-200oC (acetone).

D= +225o(CHCl3).

IR (CHCl3) [cm-1]: 3404-3502 (OH); 1707 (CH=O); 1658 (C=C-C=C-C=O); 1603 (phenyl).

UV spectrum (MeOH):

max= 263 nm, = 14756,

max= 299 nm, = 17015.

1H-NMR spectrum in CDCl3(, nnm): 0,40 (s, 3H, H-18); 3,68 (t, J = 9 Hz, 1H, H - 17 ); of 4.44 (d, J = 7.2 Hz, 1H, H-11); 5,80 (s, 1H, H-4); 7,38 (d, 2H, J = 9.8 Hz, 2H, aromatic protons); of 7.82 (d, 2H, J = 8,4 Hz, aromatic protons); 9,98 (s, 1H, ).

Stage 3.

437 mg of 11- (4-formylphenyl)]- 17 - hydroxy-östra-4,9-Dien-3-it will acetimidoyl with 6 ml of acetanhydride/pyridine 1:1 at room temperature for 3 hours. Add ice water precipitated crude product which is purified by recrystallization from acetone. Obtain 226 mg of 17 - acetoxy - 11- (4-formylphenyl)-östra-4,9-Dien-3-one.

Melting point: 188-191oC (acetone).

D= +202o(CHCl3).

IR-spectrum in CDCl3[cm-1]: 1725 (OCOCH3); 1671 ; 1658 (C=C-C=C-C=O); 1604 (phenyl).

UV spectrum (MeOH):

max= 261 nm, = 19289,

max= 298 nm, = 22303.

1H-NMR spectrum in CDCl3(, nnm): 0,44 (s, 3H, H-18); 2,04 (s, 3H, CHCO3); however, 4.40 (d, J = 6,9 Hz, 1H, H-11); 4,63 (t, J = 8,1 Hz, 1H, H-17); 5,80 (s, 1H, H-4); 7,37 (d, J = 8.1 Hz, 2H, aromatic protons); 7,8 (d, J = 8.1 Hz, 2H, aromen-3-one.

127 mg of 11- (4-formylphenyl)- 17 - ethoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one at room temperature under the protection of argon mixed in 2 ml of pyridine from 21.7 mg hydroxylaminopurine and stirred for 1 hour at 25oC. processing the reaction solution was stirred in ice water. Settling with this white precipitate is sucked off and washed with water until neutral state. The crude product is purified preparative thin-layer chromatography on silica gel PF254+366with a mixture of toluene/acetone. Obtain 95 mg of 11- [4-(gidroksimetil)phenyl)] - 17 - ethoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one.

Melting point: 192-197oC (hexane).

D= +213o(chloroform).

Infrared spectrum (CHCl3) [cm-1]: 3380 (associated, OH); 1650 (C=C-C=C-C= O); 1597 (aromatics).

UV spectrum (MeOH):

max= 264 nm, = 23170,

max= 299 nm, = 22847.

1H-NMR spectrum in CDCl3(that nmm): 0,54 (s, 3H, H-18); a 1.11 (t, 3H ); 3.40 in (s, 3H, OCH3); 3,36-to 3.58 (m, 2x2H, ); to 4.38 (d, 1H, J = 6,9 Hz, 11); 5,78 (s, 1H, H-4); 7,21 (d, 2H, J = 8,4 Hz, aromatic protons); was 7.45 (d, 2H, J = 8,4 Hz, aromatic protons), J = 5,8 (s, 1H, OH); 8,10 (1,1 H ).

Getting the initial connection.

Stage 1.

250 mg of sodium and 250 mg of naphthalene stirred in anhydrous, tetramethoxy - 11- [4-(dimethoxymethyl)phenyl)]- 17 - methoxymethyl-variety-9-ene-5,17-diol in 10 ml of anhydrous tetrahydrofuran thus, to green color remained constant. Then added dropwise 3 ml of ethyliodide in 5 ml of anhydrous tetrahydrofuran, and the solution becomes colourless. Additionally stirred for 12 hours at room temperature, add 3 ml of methanol and stirred for another 10 minutes. After adding water and acetic ether separated phases, the organic phase is washed until neutral, dried over sodium sulfate and evaporated under reduced pressure. Get 2,47 g of 3,3-dimethoxy - 11- [4-(dimethoxymethyl)phenyl)]- 17 - ethoxy - 17 - methoxymethyl-variety-9-EN-5-ol as a crude product.

Stage 2.

2,47 g of 3,3-dimethoxy - 11- [4-(dimethoxymethyl)phenyl)]- 17 - ethoxy - 17 - methoxymethyl-variety-9-EN-5-ol is stirred for 50 minutes at room temperature in 6 ml of acetone and 0.6 ml of water with 130 mg of p-toluenesulfonic acid. Then poured into 50 ml of chloroform/water 1:1, split phase, optionally extracted aqueous phase, the organic phase is washed until neutral and dried over sodium sulfate. After removal of the solvent remain 2.1 g of light brown oil. Preparative thin-layer chromatography on silica gel PF254+366with a mixture of toluene/acetone receive 388 mg of 11- (4-formylphenyl)]- 17 - ethoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one.

CLASS="ptx2">

Example R1.

10.0 mg of 11- [4-(gidroksimetil)phenyl)]- 17 - methoxy - 17 - methoxymethyl-östra-4,9-Dien-3-one,

125 mg of lactose,

60 mg of corn starch,

2.5 mg of poly-N-vinylpyrrolidone,

2.0 mg of Aerosil,

0.5 mg of magnesium stearate,

200 mg total weight of the tablet, which is obtained in the usual way on the press for tableting. It also can active substance according to the invention, respectively, with half of the above additives to compress separately tablet with notch.

Example R2.

20.0 mg of 11- [4-(gidroksimetil)-phenyl)] - 17 - hydroxy - 17 - methoxymethyl-östra-4,9-Dien-3-one,

150 mg of dextrose,

75 mg of alginic acid,

2.5 mg of poly-N-vinylpyrrolidone,

6.0 mg gelatin

0.5 mg of magnesium stearate,

254 total weight of the tablet, which is obtained in the usual way on the press for tableting. It also can active substance according to the invention, respectively, with half of the above additives to compress separately in the tablet with the notch.

1. Derivatives of 11-benzaldoxime-östra-4,9-diene of the General formula I

< / BR>
where R1- CH3,

R2is a hydrogen atom, alkyl, C1-C10, acyl residue WITH1-C10or balance CO0
the residue (CH2)n-CH2-X, where X is asiagraph, halogen atom, n = 0...1, or5where R5is a hydrogen atom, alkyl WITH1-C10; or SR5where R5- alkyl WITH1-C10;

or R3the residue (CH2)O-C=CH(CH2)p- R6where 0 = 1, R = 0.1 and R6is a hydrogen atom;

or R3the residue (CH2)q-C=CR7where q = 1,2, R7is a hydrogen atom;

Z is a hydrogen atom, alkyl WITH1-C10, acyl residue WITH1-C10.

2. Connection on p. 1, wherein R1is methyl or ethyl.

3. Connection PP. 1 and 2, wherein R2is a hydrogen atom, a C1-C10alkyl, acyl residue WITH1-C10or the rest CONHR4where R4is phenyl.

4. Connection PP. 1-3, wherein R2- alkyl WITH1-C6, acyl WITH1-C6or the rest CNR4where R4- the hydrogen atom.

5. Connection PP. 1-4, wherein R3- the hydrogen atom.

6. Connection PP. 1-4, wherein R3- alkyl WITH1-C10.

7. Connection PP. 1-6, wherein R3- alkyl WITH1-C6.

9. Connection PP. 1-8, wherein R3- the remainder OR5where R5is a hydrogen atom, alkyl WITH1-C10.

10. Connection PP. 1-9, wherein R3- the remainder -(CH2)o-CH=CH(CH2)p- R6where 0 = 1, R = 0, 1, R6- the hydrogen atom.

11. Connection PP. 1-10, wherein R3the residue (CH2)qC= CR7where q = 1, 2, R7- the hydrogen atom.

12. Connection PP. 1-11, characterized in that Z is a hydrogen atom, alkyl WITH1-C10, acyl residue C1-C10.

13. Connection PP. 1-12, namely: 11-[4-(gidroksimetil)-phenyl] -17-hydroxy-17-methoxymethyl-östra-4,9-Dien-3-one; 11-[4-(gidroksimetil)-phenyl]-17-hydroxy-17-ethoxymethyl-östra-4,9-Dien-3-one; 11-[4-(gidroksimetil)-phenyl]-17-hydroxy-17-isopropoxyphenyl-östra-4,9-Dien-3-one; 11-[4-(gidroksimetil-phenyl] -17-methoxy-17-methoxymethyl-östra-4,9-Dien-3-one; 11-[4-(gidroksimetil)-phenyl] -17-methoxy-17-ethoxymethyl-östra, 4,9-Dien-3-one; 11-[4-(gidroksimetil)-phenyl]-17-hydroxy-17-(3-hydroxyprop-Limeil-11-[4-(gidroksimetil)-phenyl] -17-hydroxy-östra-4,9-Dien-3-one; 17-chloromethyl-11-[4-(gidroksimetil)-phenyl] -17-methoxy-östra-4,9-Dien-3-one;17-azidomethyl-11-[4-(gidroksimetil)-phenyl] -17-metoxi-östra-4,9-Dien-3-one; 11-[4-(gidroksimetil)-phenyl]-17-methoxy-17-methylthiomethyl-östra-4,9-Dien-3-one; 11-[4-(methoxymethyl)-phenyl] -17-methoxy-17-methoxymethyl-östra-4,9-Dien-3-one; 11-[4-(acetoxymethyl)phenyl] -17-methoxy-17-methoxymethyl-östra-4,9-Dien-3-one; 11-{ 4-[etoxycarbonyl)oksiminomyetil] -phenyl} -17-methoxy-17-methoxymethyl-östra-4,9-Dien-3-one, 17-methoxy-17-methoxymethyl-11-{4-[phenylenecarbonyl)-oksiminomyetil] -phenyl} -östra-4,9-Dien-3-one and 11-[4-(gidroksimetil)-phenyl]-17-ethoxy-17-ethoxymethyl-östra-4,9-Dien-3-one.

14. The method of obtaining compounds on p. 1, characterized in that the compound of General formula II

< / BR>
where R1, R2, R3have the values listed in paragraph 1, is subjected to the interaction with the compound of General formula IIA:

H2N-O-Y,

where Y has the values specified in paragraph 1 for Z, and the compound of General formula IIA, if necessary use in the form of such connection, from which the compound of General formula IIA is released under the selected reaction conditions, and, if necessary, available hydroxylamino group atrificial to complex or a simple ester. the activity in equimolar amounts.

16. Pharmaceutical composition having antigestagen and antiglucocorticoid action that is different, in that it contains at least one compound according to any one of paragraphs. 1-13.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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