Derivativebenzaldoxime-Östra-4,9-diene, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to derivatives of 11-benzaldoxime-4,9-diene of the General formula I

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where Z denotes-CO-CH3; -CO-O-C2H5; -CO-NH-phenyl; -CO-NH-C2H5; -CH3or-CO-phenyl,

and the way they are received by esterification of the corresponding 11-benzaldoxime-östra-4,9-Dien-3-one to a complex or a simple ester. Pharmaceutical composition containing compound I, has a strong antigestagens activity with a minor glucocorticoid activity. 3 S. and 1 C.p. f-crystals, 4 PL.

The invention relates to new derivatives of 11 - benzaldoxime-extra 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 described already, for example, in European patent 057 115; 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 - formylphenyl group, and 3-ketogroup. In addition, in position C-3 are formed SYN - and anisometry. In the action described compounds is still unknown.

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 weak 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 of the uterine orifice in the AI process of ovulation. It is known that progesterone in high doses has antiovulatory 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, so-called "positive feedback" with progesterone secretion of gonadotropin/ play, as you know, the important role /Lautradie D.; Human Reproduction 6, 1991, 1238-1240/.

Less well analyzed the function of progesterone in the maturing follicle and 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 also need to assume a 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 C. N. With. /meningioma/. The role of these receptors in the growth of these pathologically relevant tissues for ntse as antagonists of progesterone, RU 486 = Mifepristone /European patent 0057115/ and ZK 98299 = Onapristone /with the description of the invention to unaccepted application for patent 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., and others, Endocrinology, 129, 317-322, 1991/.

Actions of progesterone in the tissues of the genital organs and other tissues are due to the interaction with the progesterone receptor. In the cell progesterone with high affinity contact 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 the dissociation of protein /HSP 90/; linking hormone-responsible of DNA elements. Finally, regulates the transcription of certain genes /Gronemeyer H., and others, J. Steroid Biochem. Molec. Biol. 41, 3-8, 1992/.

The action of progesterone or progesterone antagonists depends not only on their concentration of progesterone in most tissues. Progesterone inhibits the synthesis of estrogen receptors and the synthesis of its own receptor. You probably have these and other interactive [language] 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 /maturation/ 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 do not have any sredstvami estrogen. From the respective effects of endometriosis foci, respectively, in tumor tissues, which are equipped with receptors of estrogen and progesterone, can be expected 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 was added to the 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 done in a calm state.

Also for contraception 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 properties. Especially therapeutically relevant in this antiglucocorticoid properties. For therapeutic applications, in which the goal of therapy is suppression of progesterone receptor, they are negative, as necessary therapeutic 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 indications that require long weeks or months of treatment /treatment/.

The present invention is to obtain new derivatives 11 - benzaldoxime-östra-4,9-diene of General formula /1/:

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and their pharmaceutically acceptable salts, as well as the development of the retrieval method. Another objective is to obtain drugs, which contain the compound of General formula /1/ or its pharmaceutically acceptable salt.

In the General formula /1/:

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Z represents - CO-CH3; -CO-O-C2H5; -CO-NH-phenyl; -CO-NH-C2H5; -CO-C2H5; -CH3or-CO-phenyl.

Predpochtitelnei-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;

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

The invention further relates to a method of obtaining compounds of General formula /1/ and their pharmaceutically acceptable salts, which is characterized in that the compound of General formula (II):

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atrificial to simple or complex ester and, if necessary, the compound obtained was transferred to salt.

Obtaining compounds of General formula /1/ by esterification to complex ester, esterification to simple ester or education urethane can make itself known through alleluya funds, as the anhydrides of the acids or acid anhydrides, in the presence of bases, preferably pyridine; the etherification to p the pet. -butyl potassium or using diazomethane in methanol; the formation of urethane can be achieved by reaction with alkyl - or arylisocyanate in inert solvents, preferably toluene, or by reaction with carbamylcholine in the presence of bases, preferably triethylamine.

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

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The introduction of a group-CH2-O-CH3in the 17-position exercise in itself known through the Spiro-epoxide of the formula /V/ due to interaction with trimethylsulfonium and tert. -butyl potassium in dimethyl sulfoxide [Hubner and other J. prakt.Chem. 314, 667 /1972/; Arzneim. Forsch. 30, 401/1973]

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and the subsequent disclosure of the loop with an alcoholate - [Ponsold, etc., Z. Chem. 11, 106/1971] . The resulting CH2-O-CH3connection formula /VI/:

ch and others, patent Germany 2801416], to decompose to the corresponding aldehydes or by the esterification of simple esters of the free hydroxyl groups with alkylhalogenide in the presence of tert. -potassium butyl first to translate in a simple 5, 17 - diesters /Kasch and others, patent GDR 290 893], then by acid hydrolysis, preferably using p-toluenesulfonic acid in acetone, to turn into the corresponding aldehydes, and then then the thus obtained aldehydes by reacting with hydroxylamine transferred to compounds of General formula (II).

If necessary, obtained according to the invention a compound of General formula /1/ translate in salt accession acid, preferably the salt of physiologically acceptable acids. Conventional, physiologically acceptable inorganic and organic acids are, for example, hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other applicable acids are described, for example, in Fortschritte der Arzneimittel forschung so 10, S. 224-225, Birkhauser Verlag, Base the mod on its own in a known manner by mixing the free base or solutions with appropriate acid or its solution in an organic solvent, for example in a lower alcohol, like methanol, ethanol, 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 /1/ in aqueous acidic solution.

Salt accession acid compounds of General formula /1/ itself in a known manner, for example by means of alkalis or ion exchangers, can be converted to free base. Of the free bases by introducing the interaction with inorganic or organic acids, especially those which are suitable for obtaining therapeutically applicable salts, you can get other salts. These or other salts of the new compounds, such as the picrate, can 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, Obedinenie General formula /1/ or its salt accession acid as biologically active substances.

Drugs of the invention are prepared in a known manner using a conventional, solid or liquid carriers or diluents and commonly used in pharmaceutical technology excipients, respectively desired kind introduction, with appropriate dosage. Preferred compositions are in the form of introduction, which is suitable for oral administration. Such forms of introduction are, for example, tablets, coated tablet, coated tablets, capsules, pills, powders, solutions or suspensions or extended form.

Needless to say, take into consideration parenterally composition as solutions for injection. Further, as the compositions should also be called, for example, 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 with means for achieving a prolonged effect as of carboxypolymethylene, is the space of a few layers.

Accordingly, it is possible to prepare tablets by coating obtained similarly pills cores /core/ using commonly used for coating tablets means, such as polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. This also shell beans can 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, for example, aromatic substances such as vanillin or orange extract. In addition, they may contain auxiliary for the suspension of the substance, as sodium-karboksimetilcelljuloza, 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 not what retenu 11 - substituted benzaldoxime-östra-4,9-diene are antigestagen active substances, when exceeding the action in vivo (see table 2) have clearly reduced in comparison with RU 486, antiglucocorticoid activity detected in the reduced binding of glucocorticoid-receptor (see table 1).

This combination of properties allows to expect from proposed according to the invention of antigestagens excellent inhibition of progesterone at low 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, superior RU 486 suppression weight of the uterus in the cycle of the Guinea pig is an indication of [indirect] antiestrogenic properties 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 hypertrophy of the prostate].

the CSOs introduction on the 5th - day 7 of pregnancy [introduction 0.2 ml per animal per day in a mixture of benzyl benzoate with castor oil /1 + 4 volume/] (see table 2).

The following examples explain the invention:

Examples.

Example 1.

180 mg of 11- [4-/Gidroksimetil/-phenyl] -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-it will acetimidoyl in 5 ml of a mixture of acetanhydride with pyridine /1:1/. After the addition of water is shaken out three times with ethyl acetate, the organic phase is washed with diluted hydrochloric acid and water, dried over sodium sulfate and concentrate under reduced pressure. Obtain 172 mg of crude product which is purified by preparative thin layer chromatography on silica gel PF245+366, elwira mixture solvent of toluene/acetone in a ratio of 4:1.

Obtain 115 mg of 11- [4-/acetoxymethyl/-phenyl] -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one. The product is crystallized from ethyl acetate. So pl. = 115 - 120oC [ethyl acetate].

//D= + 218o/CHCl3/;

IR spectrum in KBr /cm-1: 1754 /OAc/; 1654 /C=C-C=C-C=O/; 1602 /phenyl/.

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, OCOCH3/; 3,247 /c. , 3H, 17-OCH3/; 3,408 /s, 3H, 3,386, 3,43 the ski protons /;/ 8,315 /s, 1H, CH - NOAc/.

Mass spectrum: m/e = 446; C28H32NO4M+- CH2OCH3+< / BR>
Example 2.

To 210 g of 11- [4-/Gidroksimetil/phenyl] -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one in 5 ml of pyridine was added dropwise 0.3 ml of ethylchloride cooling water. A white precipitate is formed. After 30 minutes, mixed with water, forms a solution, then roll a 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 hydrochloric acid and water, dried and concentrated under reduced pressure. Output = 66 mg. Both solids are combined and purified by preparative chromatography on silica gel PF245+366, elwira mixture solvent of toluene/acetone = 4:1.

Receive 150 mg of 11- [4-/ethoxycarbonylmethyl/-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 //D= +204o/CHCl3/.

UV-spectrum in methanol;max= 270 nm = 27094max= 297 nm = 25604

1H-NMR spectrum in CDCl3/ M. D./: 0,507 /s, 3H, H-18/; 1,383 /so, 3H, J = 7,0 Hz, OCH2CH3/; 3,246 /c. 3H, 3,410 /s, 3H, 3,39-3,56 /m , 2H, CH2

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

Example 3.

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, sucked off white precipitate 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 PF245+366, elwira mixture solvent 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] + 178oC /CHCl3/.

UV-spectrum in methanol: max= 238 nm = 2944max= 300 nm = 29649

1H-NMR spectrum in CDCl3/ M. D./: 0,474 /s, 3H, H-18/; 3,245 /s, 3H, 17 - OCH3/; 3,405 /c. 3H, 17 - CH2OCH3/; 3,406-3,545 /m, 2H, ABX system, 17 - CH2OCH3/; 4,413 /e, 1H, J = 6,8 Hz, 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 /is/BR> Example 4.

708 mg of 11- [4-/Gidroksimetil/-phenyl] -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one is dissolved in 15 ml of toluene. Consistently add 1.5 ml utilizationof and 3 ml of triethylamine. Stirred for 6 hours at room temperature, allowed to stand over night, add 20 ml of aqueous ammonia solution, the phases are separated, optionally extracted with toluene, washed with water, an aqueous solution of ammonium chloride and water, dried over sodium sulfate and concentrate under reduced pressure. Receive 800 mg light getlogo solid, which is purified by preparative chromatography on silica gel 60 PF254+366, elwira mixture solvent of toluene/acetone = 9: 1. Allocate 610 mg of 11- [4-{/ethylaminomethyl/-oksiminomyetil}-phenyl]- -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one.

So pl. = 142-147oC; decomposition of light; [ether/acetone/hexane].

1H-NMR spectrum in CDCl3/ M. D./: 0,522 /s, 3H, H-18/; 1,241 /so, 3H, J = 7.5 Hz, NHCH2CH3/; 3,253 /c. 3H, 17 - OCH3/; 3,415 /s, 3H, 17 - CH2OCH3/; 3,366-3,574 /m, 4H, ABX-system, 17 - CH2OCH3/; 4,410 /e, 1H, J = 7.2 Hz, H-11/; 5,790 /s , 1H, H-4/; 6,238 /m, 1H, NHCO/; 7,258, 7,286, 7,561, 7,589 /m , 4H, AA' BB'system, aromatic protons/; 8,294 /m, 1H, CH= N-/.

Example 5.

Idrija with pyridinol in the ratio 1:1 /the volume of/ is stirred for 2.5 hours in an atmosphere of protective gas. Poured into ice water, the adhesive mass is extracted with chloroform, the organic phase is washed with diluted hydrochloric acid and water, dried over sodium sulfate and concentrate under reduced pressure. Light yellow foam purified by chromatography and recrystallized from ethyl acetate. Output = 306 mg of 11- [4-/propionoxypiperidine/-phenol]- 17 - methoxy-17 - methoxy-methyl-östra-4,9-Dien-3-one. So pl. = 110-114oC [ethyl acetate].

1H-NMR with CDCl3/ M. D./: 0,515 /s, 3H, H-18/; 1,241 /so, 3H, J = 7,6 Hz, OCOCH2CH3/; 3,253 /c. , 3H, 3,415 /s, 3H, 17 - CH2OCH3/; 3,4-3,6 /m , 2H, ABX system, 4,128 /e, 1H, J = 7.2 Hz, H-11/; 5,790 /s, 1H, 4-/; 7,244, 7,271, 7,627, 7,655 /m, 4H, AA' BB'system, aromatic protons/; 8,322 /s, 1H, CH=N-1/.

Example 6.

To 170 mg of 11- [4-/gidroksimetil/-phenyl] -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one in 5 ml of methanol while cooling with ice add the ethereal solution diazomethane until a faint yellow color. Stirred for 2 hours at 5oC, add dilute sodium hydroxide solution, extracted with ether, washed until neutral, dried over sodium sulfate and the organic phase is evaporated under reduced pressure. Yellow resin purified by preparative thin-layer chromatogr the [4/methoxyisobutyl/-phenyl] -17 - hydroxy-17 - methoxymethyl-östra-4,9-Dien-3-one as colourless leaflets. So pl. = 83-89oC. //D= +197o/CHCl3/;

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 = 23098max= 300 nm = 22872

1H-NMR spectrum in CDCl3/ M. D./: 0,529 /s, 3H, H-18/; 3,247 /s, 3H, 17 - OCH3/; 3,408 /s, 3H, 17 - CH2OCH3/; 3,39-3,598 /m, 2H, ABX system, 17 - CH2OCH3/; 34,381 /e , 1H, J = 7.5 Hz, H-11/; 5,773 C., 1H, H-4/; 7,173, 7,201, 7,463, 7,491 /m, 4H, AA' BB'system, aromatic protons/; 8,023 /s, 1H, CH-phenyl/.

Example 7.

To 500 mg of 11- [4-/gidroksimetil/-phenyl] -17 - methoxy-17 - methoxymethyl-östra-4,9-Dien-3-one add a filtered mixture of 2 ml of benzoyl chloride and 3 ml of pyridine. After 2 hours, stirred into 150 ml of ice water. The steroid is precipitated in the form of adhesive. Add 5 ml of dilute hydrochloric acid, treated with ethyl acetate, the phases are separated, the organic phase is washed with aqueous bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated under reduced pressure. Yellow oil [-1,57 g] by chromatography on 40 g of silica gel 60 using a gradient of toluene/ethyl acetate released from the non-polar products, the main faction /0.7 g/ purify by preparative thin-layer chromatography on si, odorou will recrystallized from methanol. Obtain 263 mg of [4-/benzoyloxymethyl/-phenyl] -17 - methoxy-17 - methoxy-methyl-östra - 4,9-Dien-3-one as colourless crystals, So pl. = 115-122oC /methanol/. //D= +216o/CHCl3/.

UV-spectrum in methanol:max= 279 nm = 33720max= 299 nm = 30120

1H-NMR spectrum in CDCl3/ M. D./: 0,527 /s, 3H, H-18/; 3,253 /s, 3H, 17 - OCH3/; 3,415 /s, 3H, 17 - CH2OCH3/; 3,403 - 3,589 /m, 2H, ABX system, 17 - CH2OCH3/; 4,416 /e, 1H, J = 7.2 Hz, H-11/; 5,792 /s, 1H, H-4/; 7,299-7,615 /m, 5H, aromatic protons, CO-phenyl/; 7,701, 7,729, 8,111, 8,140 /m, 4H, AA' BB'system, aromatic protons/; 8,520 /s, 1H, CH-phenyl/.

Example 8.

Measurement of the affinity of the receptor binding.

The affinity of the receptor binding is determined by competitive binding specifically bind 3H-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 from the following incubation conditions:

The glucocorticoid-receptor: thymus-cytosol rat with a remote adrenal gland; thymus stored at -30oC; buffer: TED. Labeled substance:3H-Dexamethasone, 20 nm; statset separation of bound and free steroid by mixing activated carbon with dextran [1% /0,1%], centrifugation and measurement of the associated3H - activity in the supernatant.

From measurements at a range of concentrations will determine 1C50for the test compounds and standard substances and in the form of both private value /x 100%/ get the relative molar affinity for binding.

Example 9.

Suppression of early pregnancy in rats.

Female rats copulate in Prooestruus. Upon detection of sperm in the vaginal smear on the next day this day is considered as day 1 /= D. 1/ pregnancy. The processing of the test substance or indifferently the basis of the medicinal product is carried out in the days 5 to 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 917 and J 900 installed superior RU 486 suppression of nidali (see tables 3,4).

Example 10.

50.0 mg-11- [4-(acetylacetonate)phenyl] -17 - methoxy-17 - ethoxymethylene-4,9-Dien-3-one.

130,0 mg lactose

32,0 mg - corn starch

20.0 mg - talc

2.5 mg, polyvidone

2.0 mg - Aerosil

0.5 mg - stearate

3.0 mg - is m it is also possible joint pressing in one tablet, divided line, activitiesthese substances according to the invention and each half of the above additives.

Example 11.

50.0 mg-11- [4-(ethoxycarbonylmethyl)phenyl] -17 - methoxy-17 - methoxymethyl östra-4,9-Dien-3-one.

130,0 mg lactose

25.0 mg - corn starch

15,0 mg - talc

2.5 mg of poly - N-vinyl pyrrolidone

5.0 mg - gelatin

0.5 mg - stearate

2.0 mg titanium dioxide

230,0 mg is the total weight of the tablets obtained in the usual way on a tablet press. It is also possible joint pressing in one pill, separated by a line, activitiesthese substances according to the invention and each half of the above additives.

Example 12.

100.0 mg-17 - methoxy-17 - methoxymethyl-11- {4-[(phenylenecarbonyl)-östra-4,9-Dien-3-one.

to 100.0 mg lactose

25.0 mg - corn starch

15,0 mg - talc

2.5 mg of poly - N-vinyl pyrrolidone

5.0 mg - alginic acid

2.0 mg titanium dioxide

250.0 mg is the total weight of the tablets obtained in the usual way on a tablet press. It is also possible joint pressing in one pill, separated by a line, activitiesthese substances according to the invention and each of the Teal]phenyl-17 - methoxy-17 - methoxymethyl östra-4,9-Dien-3-one.

130,0 mg lactose

25.0 mg - corn starch

15,0 mg - talc

2.5 mg of poly - N-vinyl pyrrolidone

5.0 mg - Aerosil

0.5 mg - stearate

2.0 mg titanium dioxide

220,0 mg is the total weight of the tablets obtained in the usual way on a tablet press. It is also possible joint pressing in one pill, separated by a line, activitiesthese substances according to the invention and each half of the above additives.

Example 14.

50.0 mg-11- [4-(propionylacetate)phenyl-17 - methoxy-17 - methoxymethyl östra-4,9-Dien-3-one.

130,0 mg lactose

25.0 mg - corn starch

15,0 mg - talc

2.5 mg of poly - N-vinyl pyrrolidone

5.0 mg - gelatin

0.5 mg - stearate

2.0 mg titanium dioxide

230,0 mg is the total weight of the tablets obtained in the usual way on a tablet press. It is also possible joint pressing in one pill, separated by a line, activitiesthese substances according to the invention and each half of the above additives.

Example 15.

100.0 mg-11- [4-(methoxybenzoyl)phenyl] -17 - methoxy-17 - methoxymethyl östra-4,9-Dien-3-one.

100.0 mg - dextrose

25.0 mg potato starch

15.0 XID titanium

250.0 mg is the total weight of the tablets obtained in the usual way on a tablet press. It is also possible joint pressing in one pill, separated by a line, activitiesthese substances according to the invention and each half of the above additives.

Example 16.

100.0 mg-11- [4-(benzoyloxymethyl)phenyl-17 - methoxy-17 - methoxymethyl östra-4,9-Dien-3-one.

to 100.0 mg lactose

25.0 mg - corn starch

15,0 mg - talc

2.5 mg of poly - N-vinyl pyrrolidone

3.0 mg - glycol 3500

0.5 mg - stearate

2.0 mg titanium dioxide

2.0 mg - iron oxide (E 172)

250.0 mg is the total weight of the tablets obtained in the usual way on a tablet press. It is also possible joint pressing in one pill, separated by a line, activitiesthese substances according to the invention and each half of the above additives.

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

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where Z denotes-CO-CH3; -CO-O-C2H5; -CO-NH-phenyl; -CO-NH-C2H5; -CO-C2H5; -CH3or-CO-phenyl.

2. Connection on p. 1, namely 11-[4-(acetoxymethyl)phenyl] -17-methoxy-17-methoxymethyl östra-4,9-Dien-3-one. 11-[4-{ /atmometer}phenyl] -17-methoxy-17-methoxymethyl östra-4,9-Dien-3-one. 17-methoxy-17-methoxymethyl-11-[4-{ (phenylamino-carbonyl)-oksiminomyetil}-phenyl]östra-4,9-Dien-3-one. 11-[4-(propionylacetate)phenyl] -17-methoxy-17-methoxymethyl östra-4,9-Dien-3-one. 11-[4-(methoxymethyl)phenyl]-17-methoxy-17-methoxymethyl östra-4,9-Dien-3-one, 11-[4-(benzoyloxymethyl)phenyl] -17-methoxy-17-methoxymethyl östra-4,9-Dien-3-one.

3. The method of obtaining derivatives 11--benzaldoxime-östra-4,9-Dien-3-one, characterized in that the compound of General formula II

< / BR>
atrificial to complex or simple ether.

4. Pharmaceutical composition having antigestagens activity, characterized in that it contains at least one compound according to any one of paragraphs.1 and 2.

 

Same patents:

The invention relates to new derivatives of 17,20-epoxides Pregnana, to a method for their production and to their use as intermediates in the synthesis of biologically active products, specifically to derived 17,20-epoxides of General formula I

< / BR>
where R-=0,-OH, and In the remains of

< / BR>
and K=O, or group

< / BR>
or

< / BR>
where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate the mixture of isomers

The invention relates to inhibitors of steroid alpha-reductase have the following formula:

< / BR>
where Y is oxygen or sulfur; R is the group: (a) OR4where R4is hydrogen or C1-C6alkyl group; b)where each of R5and R6independently hydrogen or C1-C6alkyl group;)where R7is hydrogen or C1-C6alkyl group, W is a group; (I)where R8- C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group, phenyl group or benzilla group; or (II)where R9- C1-C6alkyl group or a C5-C6cycloalkyl group, or (III)where R5and R6defined above; g)where each of R10and R11- independently hydrogen or C1-C6an alkyl group or both in the static ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; n is an integer from 2 to 4; R1is hydrogen, C1-C6alkyl group, a C5-C6cycloalkyl group, C6-C9cycloalkylation group or aryl group; each of R2and R6independently selected from the group consisting of hydrogen, C1-C6of alkyl, C5-C6cycloalkyl, C6-C9cycloalkenyl and aryl, or R2and R3together with the nitrogen atom to which they are bound, form pentatominae or hexatone rich heterophilically ring, optionally comprising at least one additional heteroatom selected from oxygen and nitrogen; the symboldenotes a single or double bond, provided that when is a double bond, the hydrogen in the 5-position is absent, and its pharmaceutically acceptable salts

The invention relates to new esters estramustine and the way they are received, namely esters of the General formula I:

< / BR>
(I) where R1hydrogen atom, a lower alkyl WITH1-C4;

R2a hydrogen atom, a lower alkyl WITH1-C4;

R3a hydrogen atom, a lower alkyl WITH1-C4; or R2and R3together-CH2-CH2-CH2-CH2-,

n is 0,1 or 2

or their pharmaceutically acceptable salts have anti-tumor properties

The invention relates to a new method of crystallization of organic substances and especially of saraivanov, it astrana, androstane, pregnane, 19-nor-pregnane, cholestan or their esters at positions 3 and/or 7

The invention relates to a new method of crystallization of organic substances and especially of saraivanov, it astrana, androstane, pregnane, 19-nor-pregnane, cholestan or their esters at positions 3 and/or 7

-carboxylic acid as an intermediate product, the method of obtaining connection" target="_blank">

The invention relates to a series of new derivatives of steroids, which have the ability to suppress the activity or action of testosterone-alpha-reductase and therefore can be used for the treatment or prevention of prostate hypertrophy

-substituted 4-azaandrostane-3-ones and method for producing substituted 7-alkyl-androst-5-ene-3-ones" target="_blank">

The invention relates to a new method of obtaining 7-substituted 4-Aza-5-androstane-3-ones and related compounds and to the use of such compounds as inhibitors-5-reductase

The invention relates to a series of new derivatives of steroids, which have the ability to suppress the activity or action of testosterone-alpha-reductase and therefore can be used for the treatment or prevention of prostate hypertrophy

The invention relates to covered bridge in position 1417thestratriene General formula I

< / BR>
where

if OR3is set tothen

R1, R2and R3independently from each other represent a hydrogen atom, acyl groupin which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and

if OR3is in "beta", then

R1, R2and R3independently from each other represent a hydrogen atom, acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or ethano-bridge,

the method of production thereof, pharmaceutical preparations that contain these compounds and to the use for the preparation of Lech
The invention relates to aerosol compositions used for administering drugs via inhalation

The invention relates to new biologically active compounds, specifically to C-O-succinoyl-11-oxo-ursolic acid, its giammarino salt of the formula

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

The invention relates to medicine, venereology, obstetrics, gynecology
The invention relates to medicine, in particular to the gynecologist and is related to the menstrual regulation and conduct of oral contraceptive

The invention relates to a new method of crystallization of organic substances and especially of saraivanov, it astrana, androstane, pregnane, 19-nor-pregnane, cholestan or their esters at positions 3 and/or 7

The invention relates to new derivatives of 17,20-epoxides Pregnana, to a method for their production and to their use as intermediates in the synthesis of biologically active products, specifically to derived 17,20-epoxides of General formula I

< / BR>
where R-=0,-OH, and In the remains of

< / BR>
and K=O, or group

< / BR>
or

< / BR>
where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate the mixture of isomers

The invention relates to new androstane derivative of formula I, where R1is a hydrogen atom or alkanoyl: R2- alkanoyl; W1and W2- same or differentor one of the symbols means a chemical bond, and the otheror W1-and W2-; one of R3and R4- the hydrogen atom and the other is - OR1or R3and R4together mean oxoprop or C2-5- alkylenedioxy; E, R5- alkyl or alkenyl; provided that derivatives containing a cyclic structure with two atoms of nitrogen, only the Deputy E means the above group, which is connected by a chemical bond with the nitrogen atom not directly related to steroid skeleton of the molecule, while the other alternate E mean free pair of electrons; X-anion, and n and m independently of each other - 2 or 4 provided that the sum of n and m in one cyclic structure is from 4 to 6, regardless of their values in a different cycle
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