Derivatives of 1-n-phenylamino-1h-imidazole and pharmaceutical compositions containing them

FIELD: chemistry; pharmaceutical compositions.

SUBSTANCE: imidazole derivatives have general formula (I) where each of R1 and R2 independently represents hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl; n=0.1 or 2; each of R3, R4, R5 and R6 independently represents hydrogen or (C1-C6)alkyl, halogen, cyano, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulphonyl or (C1-C6)alkoxycarbonyl; R3 and R6 together with their carrier phenyl ring can also form N-methylbenzotriazole and to its acidic-additive salts, solvates and stereoisomer forms. Also, the given invention relates to pharmaceutical compositions, inhibitory aromatiser and application of derived imidazole of formula (I) for producing of medication.

EFFECT: new compounds, with useful biological properties.

23 cl, 2 tbl, 33 ex

 

The present invention relates to derivatives of 1-N-phenylamino-1H-imidazole as an aromatase inhibitor and pharmaceutical compositions containing these derivatives. Aromatase is a physiological enzyme responsible for the specific conversion of androgens, such as Androstenedione or testosterone, estrogens such as estrone and estradiol, respectively (Simpson E.R. et al., Endocrine Reviews, 1994, 15: 342-355). Therefore, the principle of the approach is the inhibition of aromatase, allowing to interfere with normal or pathological estrogen-induced or estrogen-dependent biological processes, such as the female sexual differentiation, ovulation, implantation, pregnancy, cell proliferation of breast and endometrial cell proliferation, and to ensure the regulation of spermatogenesis or proliferation of cells of the prostate gland in men, or preproductive functions, such as osteogenesis or immune balance by T-cells and cytokines (Simpson E.R. et al., Recent Progress in Hormone Research, 1997, 52: 185-213 and the whole issues of Endocrine Related Cancer (1999, volume 6, n 2) and Breast Cancer Research Treatment (1998, volume 49, supplement No. 1)).

There are a large number of derivatives of asola used as antifungal agents. Some derivatives of imidazole or triazole already described as inhibitors of the enzyme aromatase. As a rule, imidazolidine Il is triazolinone group linked to the aromatic cycles, as found for letrozole (EP-A-236940; Lamb HM and Adkins JC, Drugs, 1998, 56: 1125-1140):

or anastrozole (EP-A-296749; Wiseman LR and Adkins JC, Drugs Aging, 1998, 13: 321-332):

The imidazoles or triazoles connected through a methylene group benzotriazoles described in EP-A-293978:

Di-tert-butylphenol containing N-aminoimidazole group paraprotein described in U.S. patent 4908363 and presented as having any abscopal inflammation and Eden properties:

Later M. OKADA and others (Chem. Pharm. Bull., 44 (10), 1996, 1871-1879) described a series of [4-(brompheniramine)-4-(cyanophenyl)amino]azole and azine stains analogues:

Found that imidazole derivatives, which invariably contain 1-[N-phenylamino]-group, show unexpectedly high efficacy in the inhibition of aromatase.

Therefore, one of the objectives of the present invention is to obtain derivatives of 1-[N-phenylamino]imidazole, which is an effective aromatase inhibitors.

Another objective of the present invention is to develop a pharmaceutical composition containing as active ingredient a derivative of 1-[N-phenylamino]imidazole below, or a pharmaceutically acceptable acid additive salt is pointed to by the first connection.

Another objective of the present invention is the use of the derivative 1-[N-phenylamino]imidazole to obtain a medicinal product intended for the treatment or prevention of various diseases and for control of reproductive functions in women, men, and male and female specimens of wild and domestic animals.

Derivatives of 1-[N-phenylamino]imidazole according to the present invention represented by the following General formula (I):

and acid additive salts, solvate and the stereoisomeric forms of these compounds, where

• each of R1and R2independently means hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl;

• n = 0, 1, 2;

• each of R3, R4, R5and R6independently mean hydrogen or (C1-C6)alkyl, halogen, cyano, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, sulfonamide, acyl, (C1-C6)alkoxycarbonyl or carboxamido;

• R3and R6along with carrying their phenyl ring can also form benzofuran or N-methylbenzotriazole.

It is understood that in the description and the claims, the term "(C1-C6)alkyl" means a linear or branched uglevodorodno the chain with 1-6 carbon atoms. Radical (C1-C6)alkyl means, for example, the radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl.

It is implied that the term "halogen" means chlorine atom, bromine, iodine or fluorine.

It is implied that the term "(C3-C8)cycloalkyl" means a saturated monocyclic hydrocarbon with 3-8 carbon atoms. Radical (C3-C8)cycloalkyl means, for example, the radical: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

It is implied that the term "(C1-C6)alkoxy" means the group OR in which R means the above-mentioned (C1-C6)alkyl. Radical (C1-C6)alkoxy means, for example, the radical: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentyloxy or isopentane.

It is implied that the term "acyl" means a group

where R' denotes hydrogen or above (C1-C6)alkyl.

The compounds of formula (I) form acid additive salts, for example, with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic carboxylic acids such as acetic acid, propionic sour is a, glycolic acid, pyruvic acid, oxalic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid and the like.

Preferred compounds of formula (I) are compounds in which

• n is 0 or 1;

• each of R1and R2independently mean hydrogen or (C1-C6)alkyl;

• R3means cyano or trifluoromethyl;

• R4means hydrogen, (C1-C6)alkyl, halogen, cyano, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl or (C1-C6)alkoxycarbonyl;

• R5means hydrogen, halogen, (C1-C6)alkoxy or trifluoromethyl;

• R6means hydrogen;

• or R3and R6together with the phenyl cycle form N-methylbenzotriazole.

Also preferred compounds of formula (I), where

• n is 0 or 1;

• each of R1, R2and R6means hydrogen;

• R4means halogen, cyano or trifluoromethyl.

Particularly preferred compounds of formula (I) are compounds in which R3means cyano; in which R5means hydrogen or trifluoromethyl; and n Rav is about 1.

Particularly useful compounds are selected from the group including

4-[N-(1H-imidazol-1-yl)-N-(4-triftormetilfullerenov)amino]benzonitrile,

4-[N-(1H-imidazol-1-yl)-N-(4-chloroformate)amino]benzonitrile,

4-[N-(1H-imidazol-1-yl)-N-(4-cyanovinylene)amino]benzonitrile,

4,4'-[N-(1H-imidazol-1-yl)amino]bis-benzonitrile,

4-[N-(1H-imidazol-1-yl)-N-(4-performer)amino]benzonitrile,

4-[N-(1H-imidazol-1-yl)-N-(3,4-differenlty)amino]benzonitrile and

an acid additive salt, solvate, or stereoisomeric forms of these compounds.

Due to the ability of the considered compounds to inhibit aromatase and, therefore, remove all sources of endogenous estrogens, compounds of the present invention can be used alone or in combination with other active ingredients for the treatment or prevention of any estrogen-dependent disorders or for the control of estrogen-regulated reproductive functions in humans, as well as in wild or domestic animals.

Because the mammary glands are the most susceptible objects estrogen-stimulated proliferation and/or differentiation, aromatase inhibitors are particularly useful in the treatment or prevention of benign diseases of the breast in women, gynecomastia in males and benign or malignant is puhala breast cancer with the presence or absence of metastases in both men and women (Brodie A.M. and Njar V.C., Steroids, 2000, 65: 171-179; Pritchard KI, Cancer, 2000, 85, suppl 12: 3065-3072), or in male and female animals.

Thanks to the involvement of estrogens in the mechanisms of ovulation, implantation and pregnancy rates, aromatase inhibitors according to the present invention can be used accordingly in the contraceptive, contragestive or abortive purposes in women (Njar V.C. and A.M. Brodie, Drugs, 1999, 58: 233-255), and females of wild or domestic animals.

The uterus is another reproductive organ that responds to estrogen stimulation, and inhibition of aromatase is therefore useful for the treatment or prevention of endometriosis, benign disease of the uterus or benign or malignant tumors of the uterus with the presence or absence of metastases in women (Njar V.C. and A.M. Brodie, Drugs, 1999, 58: 233-255) or in female animals.

Because the ovary is a physiological source of estrogen, aromatase inhibitors can be used to treat abnormal or delayed ovarian production of estrogen, such as polycystic ovary syndrome or premature sexual relost respectively (Bulun et al., J Steroid Biochem Mol Biol, 1997, 61: pages 133-139). Ovarian and newvariable, but estrogen is produced benign or malignant tumor with the presence or absence of m is of tastetv (Sasano H. and Harada N., Endocrine Reviews, 1998, 19: 593-607) also can be effectively cured with aromatase inhibitors according to the present invention.

Men's prostate and testicular tissues also respond to estrogen stimulation (Abney T.O., Steroids, 1999, 64: 610-617; Carreau S. et al., Int j Androl, 1999, 22: 133-138). Therefore, aromatase inhibitors can be used for treating or preventing benign (F. Sciarra and Toscano V., Archiv Androl, 2000, 44: 213-220) or malignant tumors of the prostate gland with the presence or absence of metastases (Auclerc g, et al., Oncologist, 2000, 5: 36-44) or for treatment, prevention of infringement or regulation spermatogenetic functions or dysfunctions of males, and males of wild or domestic animals.

It is also known that estrogens are involved in the regulation updates bones; therefore, aromatase inhibitors may be useful individually or in combination with other antiresorptive or proteogenic means, in the treatment or prevention of bone disorders according to the relevant therapeutic schemes or modes. In addition, estrogens are involved in the regulation of the balance between predominantly immune functions Th1and Th2and can be, therefore, useful in the treatment or prevention of gender-dependent autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis and the like.

It is when the compounds of formula (I) is administered for treating or preventing estrogen-dependent disorders, these compounds can be combined with one or more other therapeutic endocrine hormones related to sexual function. If the regulation or control of reproductive functions, such as male or female fertility, pregnancy, abortion or delivery, the compounds of formula (I) can be combined, for example, an agonist or an antagonist of LH-RH, astroprojection contraceptive, a progestin, antiprogestins or prostaglandin. When the compounds of formula (I) are intended for treating or preventing benign or malignant diseases of the breast, uterus or ovaries, these compounds can be combined, for example, antiprogestins, a progestin or agonist or antagonist of LH-RH. In the case of treating or preventing benign or malignant diseases of the prostate or testis, the compounds of formula (I) can be combined, for example, antiandrogens, a progestin, an inhibitor of LiAZ or agonist or antagonist of LH-RH.

The term "combined" means any Protocol for joint introduction of the compounds of formula (I) and one or more other pharmaceutical substances, regardless of the nature, time of administration and dose changes over time for any of the substances. Joint introduction is s may be for example, serial or parallel.

Thus, the invention relates also to a method of treating or preventing the above diseases, including introduction to the needy in this patient a therapeutically effective amount of the compounds of formula (I) or pharmaceutically acceptable acid additive salts of the compounds, optionally in combination with another active ingredient.

For the treatment/prevention of any of these diseases, the compounds of formula (I) can be introduced, for example, orally, topically, parenterally, standard dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and diluents. These dosage forms are provided as examples, but experts in the field of pharmacy can be developed by other pharmaceutical forms for administration of the compounds of formula (I). The term parenteral as used in the description, includes subcutaneous injections, intravenous, intramuscular, intrasternally ways injection or infusion. In addition to the use for the treatment of people of compounds according to the invention is effective for the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, etc.

Pharmaceutical compositions containing the active ingredient may be the ü suitable for oral use form, for example, such as tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be obtained by any method known from the prior art to obtain pharmaceutical compositions, and such compositions may contain one or more means selected from the group comprising sweeteners, corrigentov, dyes and preservatives that provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which are easy to obtain tablets. These fillers can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja means, such as corn starch or alginic acid; binders, for example starch, gelatin or gum acacia, and lubricants, for example magnesium stearate, stearic acid or talc. Tablets can be without shell, or tablets may be coated by known methods sheath, preventing disintegration and absorption in the gastrointestinal tract, thereby slowed down the action for a long period. For example, there may be used such material for the time delay, as glyceryl the monostearate or glyceryl distearate.

The shell can also be caused by the method described in U.S. patent 4256108; 4166452 and 4265874, with the aim of obtaining an osmotic therapeutic tablets for controlled release. Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredient in a mixture with fillers, suitable for receiving water suspensions. Such fillers are suspendresume means, for example, sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum acacia; dispersing or wetting means, for example, natural phosphatides, such as lecithin, or condensation products of accelerated with fatty acids, for example, polyoxyethyleneglycol, or condensation products of ethylene oxide with long-chain, alipate the definition alcohols, for example, heptadecafluorooctane, or condensation products of ethylene oxide with partial esters formed from fatty acids and hexitol, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters formed from fatty acids, and anhydrides of hexitol, for example, with polyethylenterephthalat. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more dyes, one or more corrigentov and one or more sweeteners, such as sucrose, saccharin or aspartame.

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil or mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. To obtain a palatable oral preparation can be added to the above sweeteners and corrigentov. For the security of such compositions may be added an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for receiving the aqueous slurry by adding water, contain the active ingredient is mixed with a dispersing or wetting agent, suspendium means and one or more preservatives. Examples of suitable dispersing or wetting means and suspendida funds are above. May also contain additional excipients, for example, sweeteners, corrigentov and dyes. The pharmaceutical compositions of the present invention may also be in the form of an emulsion of oil-in-water. The oil phase can serve as a vegetable oil, such as peanut oil, olive oil, or mineral oil, for example, liquid paraffin, or a mixture thereof. Suitable emulsifying means can serve as natural phosphatides, for example soylecithin, and esters or partial esters formed by fatty acids and the anhydrides of hexitol, for example, servicemanual, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and corrigentov.

The pharmaceutical compositions can be in the form of a sterile aqueous or oily suspension for injection. Such a slurry may be prepared in accordance with the prior art using the above-mentioned suitable dispersing or wetting means and suspendida funds. A sterile preparation for injection may also be in the form of sterile RA is down or sterile suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. As an acceptable diluents and solvents may also be used water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically use sterile non-volatile oil. For this purpose, can be used in any non-volatile emollient oil, including mono - or diglycerides. In addition, fatty acids such as oleic acid find use in preparations for injection. For treatment of the above conditions using dosages in the range of from about 0,0001 mg to about 20 mg/kg of body weight per day, or alternatively, in the range of from about 0.1 mg to about 2000 mg per patient per day.

The amount of active ingredient that may be combined with carriers to obtain a single dosage form varies depending on the patient being treated and the particular route of administration. Standard dosage forms typically contain from about 0.1 mg to 400 mg, preferably 1 mg to 100 mg, of active ingredient, mostly 0.1 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg or 400 mg

It is clear, however, that the specific dose level for each individual patient varies depending on factors including the age, body weight, General health status, the ol, diet, time of administration, route of administration, rate of excretion, combination of drugs and specific gravity of curable diseases.

Derivatives of 1-N-phenylamino-1H-imidazole of the formula (I) according to the invention and the corresponding acid additive salts can be obtained according to the following General scheme 1.

According to the scheme 1 aniline derivative (1) condense with the aldehyde of formula (2) and intermediate Imin restore detribalized or hydrogenizing using the oxide of palladium or platinum as a catalyst, giving N,N-disubstituted aniline (3). The specified aniline (3) can also be obtained by reacting a halogen derivative (8) with the aniline of formula (1).

N,N-disubstituted aniline (3) is transformed into the corresponding nitroso-derivative, using standard conditions, then restore, receiving 1,1-disubstituted hydrazine of the formula (4). Alternatively, a 1,1-disubstituted hydrazine (4) can be obtained by selective N-alkylation of compounds of formula (7) compound of formula (8) using the conditions described U. LERCH and J. KÖNIG (Synthesis,1983, 2, 157-8).

Then the condensation of (4) with dialkyldimethylammonium or ethylenediaminedisuccinate derivative gives thiosemicarbazide (5), which is converted into 1-aminoimidazole-2-tion (6) by processing the key is lotay, such as acetic acid or sulfuric acid.

Desulfurization (6) in acetic acid under the conditions described S.GRIVAS and E.RONNE inActa Chemica Scandinavia,1995, 49, 225-229, gives the final derivative of 1-N-phenylamino-1H-imidazole (I), which is optionally converted into one of the pharmaceutically acceptable acid additive salts. Alternatively, the compound (I), where R3or R6means electron-withdrawing group, can be obtained by condensation of N-imidazolinone (9) with a halogen derivative (8).

The following examples and tests are given to illustrate the invention and should not be viewed as limiting.

OBTAINING N-ALKYLAMINO (3)

EXAMPLE 1

N-(4-chloroformate)-4-cyanoaniline

To a solution of 4-chlorobenzaldehyde (35,69 g, 0,253 mol) in absolute ethanol (250 ml) is added in portions with 4-aminobenzonitrile (30 g, 0,253 mol). The reaction mixture was stirred at room temperature for 3 h, the precipitate filtered, washed with diethyl ether and poured into a 1/1 mixture of THF/ethanol (250 ml). The resulting suspension is cooled with ice, add portions NaBH4(4.8 g, to 0.127 mol) and the reaction mixture was stirred at room temperature 0,75 hours After adding acetic acid (3 ml) and water (500 ml), the precipitate filtered, washed with water and dried, obtaining white solid (51,27 g, 84%), TPL 130° C.

1H NMR (CDCl3): of 4.35 (d, 2H), and 4.75 (s, 1H), 6,55 (d, 2H), 7,20 is 7.50 (m, 6N).

Using a similar methodology, but substituting 4-chlorobenzaldehyde

- 4-methoxybenzaldehyde,

- 3-fluoro-4-methoxybenzaldehyde,

get

- 4-cyano-N-(4-methoxyphenethyl)aniline (TPL 109°C)

- 4-cyano-N-(3-fluoro-4-methoxyphenethyl)aniline (TPL 108°C), respectively.

EXAMPLE 2

4-cyano-N-(4-methylphenylethyl)aniline

A mixture of p-tolualdehyde (40,68 g, 0,338 mol), 4-aminobenzonitrile (40 g, 0,338 mol) and 5% Pd/C (4 g) in absolute ethanol (300 ml) hydronaut at room temperature over night. The reaction mixture is diluted with methylene chloride, filtered to celite and concentrate to dryness. Crystallization from ethanol gives a white solid (74,9 g, 99%), TPL 100°C.

1H NMR (CDCl3): 2,35 (s, 3H), 4,3 (d, 2H), 4,7 (s, 1H), 6,55 (d, 2H), 7,10-7,30 (m, 4H), 7,35 (d, 2H).

Using a similar methodology, but substituting p-tolualdehyde

- 4-cyanobenzaldehyde,

3,4 - dimethoxybenzaldehyde,

get

- 4-cyano-N-(4-cyanovinylene)aniline (TPL 156°C)

- 4-cyano-N-(3,4-dimethoxyphenethyl)aniline (TPL 150°C), respectively.

OBTAINING N,N-DISUBSTITUTED HYDRAZINES (4)

These compounds are usually obtained by the method described in Tetrahedron 1982, 38(3): 419-423 and Organic Fonctional Group Preparations 1968, 1: 374-376.

EXAMPLE 3

N1-(4-shall orfanelli)-N 1-(4-cyanophenyl)hydrazine

To a cooled ice suspension of 4-cyano-N-(4-chloroformate)aniline (30 g, 0.125 mol) in 2 N. H2SO4(150 ml) add a solution of sodium nitrite (9,48 g, 0,137 mol) in water (30 ml). The reaction mixture was stirred at room temperature for 2 hours Add a solution of sodium nitrite (9,48 g, 0,137 mol) in water (30 ml) and the reaction mixture was stirred over night. Add a solution of sodium nitrite (6.6 g, 0,095 mol) in water (20 ml) and the reaction mixture stirred for 1 h After extraction with ethyl acetate the organic layer is washed successively with a saturated solution of sodium bicarbonate, water, saturated salt solution, dried over sodium sulfate and evaporated in vacuum, obtaining white solid (30.5 g). To a suspension of the obtained solid in a mixture of diethyl ether (60 ml), AcOH (60 ml) and water (60 ml) is added zinc powder (24.5 g, the 0.375 mol) at such a speed as to maintain the temperature below 35°C. the Mixture is stirred for 2 h, added AcOH (60 ml), water (60 ml) and zinc (6 g) and stirring is continued for 0.5 hours After addition of ether (200 ml) the reaction mixture is filtered, the inorganic substance is washed with ethyl acetate, the product extracted with ethyl acetate and the organic layer washed with water, saturated salt solution and dried over sodium sulfate. Solvent is concentrated in vacuo and crystallization from diisopropyl ether get a solid substance (18,78 g, 58%), TPL 90aboutC.

1H NMR (CDCl3): of 3.75 (s, 2H), 4,69 (s, 2H), 7,05 (d, 2H), 7,15 (d, 2H), 7,35 (d, 2H), 7,49 (d, 2H).

Using a similar methodology, but substituting 4-cyano-N-(4-chloroformate)aniline in

- 4-cyano-N-(4-methoxyphenethyl)aniline,

- 4-cyano-N-(3-fluoro-4-methoxyphenethyl)aniline,

- 4-cyano-N-(4-methylphenylethyl)aniline,

- 4-cyano-N-(4-cyanovinylene)aniline,

- 4-cyano-N-(3,4-dimethoxyphenethyl)aniline,

- 4-bromo-N-(4-cyanovinylene)aniline,

get

- N1-(4-methoxyphenethyl)-N1-(4-cyanophenyl)hydrazine (TPL 74°C)

- N1-(3-fluoro-4-methoxyphenethyl)-N1-(4-cyanophenyl)hydrazine (TPL 102°C)

- N1-(4-methylphenylethyl)-N1-(4-cyanophenyl)hydrazine (TPL 74°C)

- N1-(4-cyanovinylene)-N1-(4-cyanophenyl)hydrazine (TPL 215°C)

- N1-(3,4-dimethoxyphenethyl)-N1-(4-cyanophenyl)hydrazine (TPL 134°C)

- N1-cyanovinylene)-N1-(4-bromophenyl)hydrazine (TPL 114°C), respectively.

EXAMPLE 4

N1-(4-triftormetilfullerenov)-N1-(4-cyanophenyl)hydrazine

In nitrogen atmosphere powdered sodium amide (95%, 4.8 g, 0,117 mol) contribute with stirring in a flask containing THF (100 ml). The solution is cooled with ice and add portions 4-cyanopyrimidine (obtained by José L.Castro et al. J. Med. Chem. 1994, 37, 3023-3032) 10 g, 0,058 mol). The ice bath is removed and after the orange suspension is passed a stream of nitrogen for 1 h to remove most of the dissolved ammonia. While cooling with ice, add 4-cryptomaterial (12 g, 0,062 mol), then the reaction mixture was stirred at room temperature for 1.5 h and poured into water (100 ml). After extraction with ethyl acetate the organic layer was washed with water, dried over sodium sulfate and evaporated in vacuum. Trituradora from diisopropyl ether gives a yellow solid (7.5 g, 43%), TPL 98°C.

1H NMR (CDCl3): of 3.8 (s, 2H), and 4.8 (s, 2H), 7,05 (d, 2H), 7,33 (d, 2H), 7.5 (d, 2H), and 7.6 (d, 2H).

Using a similar methodology, but substituting 4-cryptomaterial

- 4-perbenzoate,

- 4-florantyrone,

- 4-methylthiophenethylamine,

3,4 - differentinherit,

- 2,4-differentinherit,

- 3,5-differentinherit,

- 4-bromobenzylamine,

get

- N1bis-(4-cyanophenyl)hydrazine (TPL 222°C)

- N1-(4-performer)-N1-(4-cyanophenyl)hydrazine (TPL 114-115°C)

- N1-(4-methylthiophenyl)-N1-(4-cyanophenyl)hydrazine (TPL 72°C)

- N1-(3,4-differenlty)-N1-(4-cyanophenyl)hydrazine (TPL 72°C)

- N1-(2,4-differenlty)-N1-(4-cyanophenyl)hydrazine (TPL 70°C)

- N1-(3,5-differenlty)-N1-(-cyanophenyl)hydrazine (TPL 124°C)

- N1-brompheniramine)-N1-(4-cyanophenyl)hydrazine (TPL 90°C), respectively.

EXAMPLE 4A

N1-(4-cyanovinylene)-N1-(4-methoxyphenyl)hydrazine

Chloromethylbenzene (25 g, 164,90 mmol) contribute with stirring in a flask containing toluene (200 ml) and triethylamine (46,40 ml, 329,80 mmol). Add portions 4-cyanopyrimidine (obtained by José L. Castro et al., J. Med. Chem. 1994, 37, 3023-3032) (28,80 g, 164,90 mmol) and the reaction mixture stirred for 3 h when heated to the boil under reflux. After cooling, the mixture is filtered, washed with toluene (50 ml) and water (200 ml) and receive a white solid (27,20 g, 65%), TPL 115°C.

1H NMR (DMSO d6): the 3.65 (s, 3H), 4,30 (s, 2H), 4,57 (s, 2H), 6,77 (d, 2H), 6,94 (d, 2H), of 7.48 (d, 2H), 7,76 (d, 2H).

GETTING IMIDAZOLES of FORMULA (I)

EXAMPLE 5

4-[N-(1H-imidazol-1-yl)-N-(4-triptoreline)amino]benzonitrile

To a cooled solution (10-15° (C) tert-BuOK (1.06 g, 0,00895 mol) in DMSO (18 ml) is added in portions of N-(1H-imidazol-1-yl)-4-triptorelin (1.85 g, 0,00814 mol) (obtained by desulfurization of the corresponding 2,3-dihydro-1H-imidazole-2-thione, J. G. Schantl, Heterocycles, 37(3), 1873, 1994). The reaction mixture was stirred at room temperature for 1 h, then add 4-perbenzoate (0,936 g, 0,00773 mol) in DMSO (18 ml), the reaction mixture was paramesh who live within 2 h and poured into water concentrated solution of sodium hydroxide. The precipitate is collected and dried in vacuum. Flash chromatography on silica gel (mixture of toluene/dioxane: 7/3) and crystallization from diisopropyl ether to give a solid (1.6 g, 60%), TPL 104°C.

Analysis Calculated: C: 62,2; N: 3,38; F: 17,36; N: 17,07

Found: C: 62,22; N: 3,40; F: 17,3; N: 17,1

1H NMR (DMSO d6): of 6.96 (d, 2H), 7,15 (s, 1H), 7,31 (d, 2H), 7,68 (s, 1H), 7,6-a 7.85 (m, 4H), 7,87 (s, 1H).

EXAMPLE 6

4-[N-(1H-imidazol-1-yl)-N-(4-triftormetilfullerenov)amino]benzonitrile

a)4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-tion)-N-(4-triftormetilfullerenov)amino]benzonitrile

To a suspension of N1-(4-triftormetilfullerenov)-N1-(4-cyanophenyl)hydrazine (7.5 g, 0,025 mol) in ethanol (100 ml) is added dropwise 2,2-dimethoxymethylsilane (4 g, or 0.027 mol) and the reaction mixture is heated to boiling point under reflux for 2 hours, After cooling the solvent is evaporated in vacuo, the obtained residue was poured into 2 N. H2SO4(20 ml) and the suspension is heated to the boiling temperature under reflux within 0.3 hours After extraction with ethyl acetate the organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica gel (toluene/dioxane: 8/2) and trituradora from a mixture of diisopropyl ether/ethanol to give yellow solid (2.7 g, 28%), TPL 200°C.

1H NMR (DMSO d6: 5-5,4 (m, 2N), of 6.65 (d, 2H), 6,95 (d, 1H), 7,15 (d, 1H), and 7.7 (m, 6N).

b) 4-[N-(1H-imidazol-1-yl)-N-(4-triftormetilfullerenov)amino]benzonitrile

35% hydrogen peroxide (1.1 ml, 0.035 mol) is added dropwise to a cooled ice suspension of 4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-tion)-N-(4-triftormetilfullerenov)amino]benzonitrile (2.7 g, 0,0072 mol) in acetic acid (20 ml). After TLC confirmed the completion of the interaction, the reaction mixture is diluted with water, adjusted to pH 11 with sodium hydroxide, treated with hydrosulfite sodium and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica gel (mixture of toluene/ethyl acetate: 7/3, then 6/4) and crystallization from diisopropyl ether to give a solid (1 g, 41%), TPL 134°C.

Analysis Calculated: From: To 63.1; H: 3,8; N: 16,3

Found: C: 63,4; N: To 3.58; N: 16,3

1H NMR (DMSO d6): of 5.15 (s, 2H), 6,65 (d, 2H), 7 (s, 1H), and 7.4 (s, 1H), 7,5-7,9 (m, 7H).

M+ =342.

Using a similar methodology, but substituting N1-(4-triftormetilfullerenov)-N1-(4-cyanophenyl)hydrazine on

- N1-(4-chloroformate)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-methoxyphenethyl)-N1-(4-cyanophenyl)hydrazine,

- N1-(3-fluoro-4-methoxyphenethyl)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-methylphenylethyl)-N1-(4-cyanophenyl)hydrazine,

- N1 -(4-cyanovinylene)-N1-(4-cyanophenyl)hydrazine,

- N1-(3,4-dimethoxyphenethyl)-N1-(4-cyanophenyl)hydrazine,

- N1bis-(4-cyanophenyl)hydrazine,

- N1-(4-performer)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-methylthiophenyl)-N1-(4-cyanophenyl)hydrazine,

- N1-(3,4-differenlty)-N1-(4-cyanophenyl)hydrazine,

- N1-(2,4-differenlty)-N1-(4-cyanophenyl)hydrazine,

- N1-(3,5-differenlty)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-brompheniramine)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-cyanovinylene)-N1-(4-bromophenyl)hydrazine,

- N1-(4-cyanovinylene)-N1-(1-methylbenzothiazol-6-yl)hydrazine,

- N1-(4-cyanovinylene)-N1-(3-trifluoromethyl-4-cyanophenyl)hydrazine,

- N1(phenylmethyl)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-cyanophenyl)-N1-(3-trifluoromethyl-4-cyanophenyl)hydrazine,

- N1-(3-performer)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-methoxycarbonylmethyl)-N1-(4-cyanophenyl)hydrazine,

- N1-(4-cyanophenyl)-N1-(4-forfinal)hydrazine,

- N1-(3-triftormetilfullerenov)-N1-(4-cyanophenyl)hydrazine,

receive, respectively, the following connections:

EXAMPLE 7

4-[N-(1H-imidazol-1-yl)-N-(4-chloroformate)amino]b is somethingthere

TPL 190°C.

Analysis Calculated: C: 59,15; N: 4.09 To; Cl: 20,54; N: 16,23

Found: C: 59,04; N: 3,99; Cl: 20,5; N: 16,2

1H NMR (DMSO d6): of 5.15 (s, 2H), 6,95 (d, 2H), and 7.4 (s, 4H), to 7.75 (m, 3H), 8,10 (s, 1H), and 9.6 (s, 1H).

EXAMPLE 8

4-[N-(1H-imidazol-1-yl)-N-(4-methoxyphenethyl)amino]benzenetricarboxylate

TPL 178°C.

Analysis Calculated: C: 63,44; N: 5,03; Cl: The 10.40; N: 16,44

Found: C: 63,4; N: 5,01; Cl: 10,4; N: 16,6

1H NMR (DMSO d6): 3,70 (c, 3H), of 5.05 (c, 2H), 6,85 (d, 2H), 7 (d, 2H), 7,25 (d, 2H), 7,79 (s, 1H), 7,80 (d, 2H), 8,1 (c, 1H), 9,50 (c, 1H).

EXAMPLE 9

4-[N-(1H-imidazol-1-yl)-N-(3-fluoro-4-methoxyphenethyl)amino]benzenetricarboxylate

TPL 190°C.

1H NMR (DMSO d6): of 3.80 (s, 3H), of 5.05 (s, 2H), 7 (d, 2H), 7,05-to 7.15 (m, 2H), 7,30 (d, 1H), and 7.8 (d, 2H), of 7.75 (s, 1H)and 8.1 (s, 1H), 9,50 (s, 1H).

EXAMPLE 10

4-[N-(1H-imidazol-1-yl)-N-(4-methylphenylethyl)amino]benzonitrile

TPL 156°C.

Analysis Calculated: C: 74,98; N: 5,59; N: 19,43

Found: C: 74,55; N: 5.56mm; N: 19,3

1H NMR (DMSO d6): of 2.25 (s, 3H), of 4.95 (s, 2H), 6,65 (d, 2H), 6,98 (s, 1H), 7,10 (d, 2H), 7,2 (d, 2H), 7,35 (s, 1H), of 7.70 (m, 3H).

EXAMPLE 11

4-[N-(1H-imidazol-1-yl)-N-(4-cyanovinylene)amino]benzenetricarboxylate

TPL 195°

Analysis Calculated: C: 64,38; H: 4,2; Cl: 10,56; N: 20,86

Found: C: 64,31; N: 4,29; Cl: 10,6; N is 20.9

1H NMR (DMSO d6): 5,30 (c, 2H), 7,10 (d, 2H), a 7.62 (d, 2H), 7,70-8 (m, 5H), 8,17 (c, 1H), 9,7 (c, 1H)

EXAMPLE 12

4-[N-(N-imidazol-1-yl)-N-(3,4-dimethoxyphenethyl)amino]benzenetricarboxylate

TPL 167°C.

Analysis Calculated: C: 61,54; N: 5,16; Cl: 9,56; N: 15,11

Found: C: 61,39; N: 5,13; Cl: To 9.57; N: 15,1

1H NMR (DMSO d6): 3,70 (s, 3H), of 3.73 (s, 3H), 5 (s, 2H), 6,65-to 7.15 (m, 5H), of 7.75 (s, 1H), 7,80 (s, 2H), 8,10 (s, 1H), and 9.5 (s, 1H).

EXAMPLE 13

4,4'-[N-(1H-imidazol-1-yl)amino]bis-benzenetricarboxylate

TPL 199°C.

Analysis Calculated: C: 63,46; N: 3,76; Cl: 11,02; N: 21,76

Found: C: 63,2; N: 3,81; Cl: 11,0; N: 21,9

1H NMR (DMSO d6): 7,26 (d, 4H), and 7.9 (s, 1H), 7,92 (d, 4H), 8,30 (s, 1H), 9,80 (s, 1H).

EXAMPLE 14

4-[N-(1H-imidazol-1-yl)-N-(4-performer)amino]benzeneethanamine

TPL 176-178°C.

Analysis Calculated: C: 60,45; N: 4,48; F: 5,62; Cl: Of 10.05; N: 16,59

Found: C: 60,71; N: With 4.64; F: 5,54; Cl: 10,6; N: 17, 0mm

1H NMR (DMSO d6): of 5.15 (s, 2H), 7,2 (t, 2H), and 7.4 (q, 2H), and 7.8 (s, 1H), 7,0-7,8 (AB, 4H), and 9.6 (s, 1H).

EXAMPLE 15

4-[N-(1H-imidazol-1-yl)-N-(4-methylthiophenyl)amino]benzonitrile

TPL 128°C.

Analysis Calculated: C: 67,56; N: To 5.03; N: 17,5; S: 10,02

Found: C: 67,12; N: 4,90; N: 17,2; S: 9,51

1H NMR (DMSO d6): of 2.4 (s, 3H), of 5.05 (s, 2H), 6,65 (d, 2H), 7 (s, 1H), 7,15-to 7.3 (m, 4H), 7,35 (s, 1H), and 7.7 (m, 3H).

EXAMPLE 16

4-[N-(1H-imidazol-1-yl)-N-(4-methylsulfinylphenyl)amino]benzonitrile

TPL 190°C.

1H NMR (DMSO d6): 3,2 (s, 3H), and 5.2 (s, 2H), and 6.6 (d, 2H), 7 (s, 1H), 7,45 (s, 1H), about 7.6 to 7.9 (m, 7H).

EXAMPLE 17

4-[N-(1H-imidazol-1-yl)-N-(3,4-deltorphin lmutil)amino]benzonitrile

TPL 132°C.

Analysis Calculated: C: 65,86; H: 3,9; N: 18,07

Found: C: 65,47; N: Of 3.78; N: 18,1

1H NMR (DMSO d6): 5,0 (s, 2H), 6,7 (d, 2H), 6,9-to 7.8 (m, 8H).

EXAMPLE 18

4-[N-(1H-imidazol-1-yl)-N-(2,4-differenlty)amino]benzonitrile

TPL 149°C.

Analysis Calculated: C: 65,86; H: 3,9; N: 18,07

Found: C: 66,0; N: 3,84; N: 18,2

1H NMR (DMSO d6): 5,1 (s, 2H), 6,7 (d, 2H), 6,9-to 7.8 (m, 8H).

EXAMPLE 19

4-[N-(1H-imidazol-1-yl)-N-(3,5-differenlty)amino]benzonitrile

TPL 170°C.

Analysis Calculated: C: 65,86; H: 3,9; N: 18,07

Found: C: 65,73; H: 3,8; N: 18,02

1H NMR (DMSO d6): 5,1 (s, 2H), and 6.6 (d, 2H), 7-7,2 (m, 4H), and 7.5 (s, 1H), of 7.75 (d, 2H), and 7.9 (s, 1H).

EXAMPLE 20

4-[N-(1H-imidazol-1-yl)-N-(4-brompheniramine)amino]benzenetricarboxylate

TPL 125°C.

1H NMR (CDCl3): 5 (s, 2H), 6,8 (d, 2H), 7 (s, 1H), 7,25 (m, 3H), 7,35 (s, 1H), and 7.4 (d, 2H), 7,65 (d, 2H), 9,85 (s, 1H).

EXAMPLE 21

4-[N-(1H-imidazol-1-yl)-N-(4-bromophenyl)aminomethyl]benzonitrile

TPL 138°C.

Analysis Calculated: C: 57,81; N: 3,71; N: 15,86; Br: 22,62

Found: C: 57,85; H: 3,7; N: 15,9; Br: 23,2

1H NMR (DMSO d6): is 4.85 (s, 2H), 6,5 (d, 2H), 7 (s, 1H), and 7.1 (s, 1H), 7,25-of 7.55 (m, 5H), and 7.6 (d, 2H)

EXAMPLE 22

4-[N-(1-methylbenzothiazol-6-yl)-N-(1H-imidazol-1-yl)aminomethyl]benzonitrile

TPL 184°C.

1H NMR (DMSO d6): 4,20 (s, 3H), of 5.1 (s, 2H), 6,5 (DD, 1H), 6,95 (s, 1H), 7,2 (s, 1H), and 7.4 (1H), EUR 7.57 (d, 2H), 7,7-a 7.85 (m, 3H), 7,9 (d, 1H)

EXAMPLE 23

4-[N-(1H-imidazol-1-yl)-N-(4-cyanovinylene)amino]-3-cryptomathematical

TPL 226°C.

Analysis Calculated: C: 62,18; N: 3,29; N: 19,08

Found: C: 61,89; N: 3,35; N: 18,9

1H NMR (DMSO d6): the 5.25 (s, 2H), 6,8-7,05 (m, 3H), 7,45 (s, 1H), 7,55 (d, 2H), 7,8 (d, 3H), with 8.05 (d, 1H)

EXAMPLE 24

4-[N-(1H-imidazol-1-yl)-N-(phenylmethyl)amino]benzonitrile

TPL 107°C.

1H NMR (DMSO d6): of 5.05 (s, 2H), 6,65 (d, 2H), 7 (s, 1H), 7,25 to 7.4 (m, 6H), of 7.65 to 7.75 (m, 3H)

EXAMPLE 25

4-[N-(1H-imidazol-1-yl)-N-(4-cyanophenyl)amino]-3-cryptomathematical

TPL 166°C.

1H NMR (DMSO d6): to 7.2 (m, 3H), and 7.3 (d, 2H), of 7.75 (s, 1H), 7,95 (d, 2H), 8,15 (d, 1H), of 8.25 (s, 1H)

EXAMPLE 26

4-[N-(1H-imidazol-1-yl)-N-(3-performer)amino]benzonitrile

TPL 112°C.

Analysis Calculated: C: 69,9; N: 4,48; N: MT 19 : 18

Found: C: 69,38; N: 4,35; N: 19,3

1H NMR (DMSO d6): of 5.05 (s, 2H), 6,65 (d, 2H), 7 (s, 1H), 7,05-7,25 (m, 3H), 7,3 was 7.45 (m, 2H), 7,7-a 7.85 (m, 3H)

EXAMPLE 27

Methyl 4-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)aminomethyl]benzoate

TPL 178°C.

1H NMR (DMSO d6): 3,85 (s, 3H), of 5.15 (s, 2H), 6,65 (d, 2H), 7 (s, 1H), and 7.4 (s, 1H), 7.5 (d, 2H), 7,65 one-7.8 (m, 3H), 7,9 (d, 2H).

EXAMPLE 28

4-[N-(1H-imidazol-1-yl)-N-(4-forfinal)amino]benzonitrile

TPL 113°C.

1H NMR (DMSO d6): of 6.45 (d, 2H), and 7.1 (s, 1H), 7,25 was 7.45 (m, 2H), and 7.5 to 7.7 (m, 5), of 8.2 (s, 1H)

EXAMPLE 29

4-[N-(1H-imidazol-1-yl)-N-(3-triftormetilfullerenov)amino]benzonitrile

TPL 122°C.

1H NMR (DMSO d6): of 5.15 (s, 2H), 6,7 (d, 2H), 7 (s, 1H), and 7.4 (s, 1H), 7,5-7,8 (m, 7H).

Using a methodology similar to that shown in example 6, but replacing 2-isocyanatopropyltrimethoxysilane

- 2-isothiocyanateconjugated,

- 1-isothiocyanatopropionate-2-onditional,

- 2-isothiocyanatobenzene-3-onditional,

receive the following connections:

EXAMPLE 30

4-[N-(4-methyl-1H-imidazol-1-yl)-N-(4-brompheniramine)amino]benzonitrile

TPL 152°C.

Analysis Calculated: From: To 58.9; H: 4,11; N: 15,26

Found: C: 58,67; N: 4,16; N: 15,3

1H NMR (DMSO d6): 2,1 (s, 3H), 5 (s, 2H), 6,65 (d, 2H), 7,05 (s, 1H), and 7.3 (d, 2H), 7.5 (d, 2H), and 7.6 (s, 1H), 7.7 (d, 2H).

M+ = 366.

EXAMPLE 31

4-[N-(5-methyl-1H-imidazol-1-yl)-N-(4-brompheniramine)amino]benzonitrile

TPL 152°C.

1H NMR (CDCl3): 2 (s, 3H), 4,9-5,2 (m, 2H), 6,65 (d, 2H), 7 (s, 1H), 7,25 (d, 2H), 7.5 (d, 2H), and 7.6 (d, 2H), 9,25 (s, 1H)

M+ = 366.

EXAMPLE 32

4-[N-(4,5-dimethyl-1H-imidazol-1-yl)-N-(4-brompheniramine)amino]benzonitrile

TPL 150°C.

Analysis Calculated: C: 59,8; N: 4,49; N: 14,7

Found: C: 58,7; N: To 4.41; N: 14,6

1H NMR (DMSO d6): 1,9 (s, 3H), 2,1 (s, 3H), 4.95 points-of 5.25 (m, 2H), and 6.6 (d, 2H), 7.3 to 7.8 for (m, 7H)

M+ = 380.

EXAMPLE 33

4-[N-(1H-imidazol-1-yl)-N-(methoxyphenyl)amino]methylbenzonitrile

a) 4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-tion)-N-(4-methoxyphenyl)amino]methylbenzonitrile

To a suspension of N1-(4-cyanovinylene)-N1-(4-methoxyphenyl)hydrazine (27,10 g, 106,98 mmol) in ethanol (250 ml) is added dropwise 2,2-dimethoxymethylsilane (17,30 g, 117,67 mmol) and the reaction mixture is heated to boiling point under reflux for 2 hours, After cooling the solvent is evaporated in vacuo, the resulting oil is diluted with a mixture of acetic acid/water (9/1, 250 ml) and the suspension is heated to the boiling temperature under reflux for 1.5 h and at room temperature over night. The obtained residue was poured into water (1400 ml) and collect the brown precipitate. After tretirovanie with ethanol brown solid gives a white solid product (9.60 g, 27%), TPL: 150°C.

1H NMR (DMSO d6): 3,70 (s, 3H), to 5.08 (s, 2H), 6,60 (d, 2H), 's 6.75 to 7.00 (m, 3H), 7,20 (s, 1H), 7,80 (s, 4H).

b) 4-[N-(1H-imidazol-1-yl)-N-(4-methoxyphenyl)amino]methylbenzonitrile

35% hydrogen peroxide (1.1 ml, 0.035 mol) is added dropwise to a cooled ice suspension of 4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-tion)-N-(4-methoxyphenyl)amino]methylbenzonitrile (9,50 g, 28,24 mmol) in acetic acid (50 ml). After TLC confirmed the completion of the interaction, the reaction mixture is diluted with water, adjusted to pH 11 with sodium hydroxide, treated with hydros what lipitor sodium and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica gel (mixture of toluene/dioxane: 6/4) gives pure orange oil (5,80 g, 67%).

1H NMR (DMSO d6): 3,70 (s, 3H), of 4.90 (s, 2H), 6,60-7,00 (m, 5H), 7,40 (s, 1H), 7,55 (d, 2H), of 7.70 (s, 1H), 7,78 (d, 2H).

Crystallization of hydrochloric ethanol gives white crystals (5,70 g, 66%).

TPL 207°C.

1H NMR (DMSO d6): 3,70 (s, 3H), equal to 4.97 (s, 2H), 6,93 (d, 2H), 7,13 (d, 2H), 7,45 (d, 2H), of 7.70 (s, 1H), to 7.84 (d, 2H), 8,04 (s, 1H), 8,18 (s, 1H), of 9.55 (s, 1H).

The RESULTS of BIOLOGICAL TESTS

Test in vitro

Cell line JEG-3, obtained from placental choriocarcinoma man is, by nature, very rich in aromatase person (Bahn RS, et al., J. Clin Endocrinol Metab, 1981, 52: 447-450) and, therefore, useful practical biological system for screening and assessment of alleged aromatase inhibitorsin vitro(Yue W and Brodie AM, J Steroid Biochem Mol Biol, 1997, 63: 317-328). The original cell line JEG-3 is grown to 80% confluence in monolayers using plastic flasks in minimal medium Needle with 1 g/l glucose and without 10% serum fetal calf at pH 7.4 and 37°C, in an atmosphere of 5% CO2. Then, 24 hours before determining the activity of aromatase, the cells JEG-3 distributed for cultivation in 96-well microplates (60000-100000 of viable cells in 100 ál of culture medium to the cell); the item 24 hours microplates are washed and add fresh medium, containing radioactive substrate of aromatase (1β-3H-Androstenedione, 10 nm) together with the test compound, dissolved 1% dimethylsulfoxide, when the range of the tested concentrations ranging from 10-12up to 10-4M in a total volume of 150 μl. Two hours after the beginning of incubation, 100 μl of supernatant transferred to new homological 96-well microplates. The solution containing loaded dextran coal dust (1%), added to each well (100 μl/cell); after incubation for 10 minutes on ice microplates centrifuged (1500 g) over 10 minutes at 4°C. All steroids, including radioactive substrate and re-biokinesiology estrogens, captured by an integrated binding with coal; only3H-water specific formed by aromatization 1β-3H-Androstenedione, including specific oxidation step removal 1β-3H remains at this stage in the supernatant. Moved to another homologous 96-well microplate supernatant in the amount of 100 μl get some liquid (200 μl/cell), suitable for scintillation measurements β-radioactivity using a counter for microplate Microbeta 1450 Plus (Wallac, EG & G)

In parallel, the reaction of aromatase in containing cells microplate stop the destruction and dissolution to etoc JEG-3 in 10 mm solution of ethylenediaminetetraacetate at a pH of 12.3. Then DNA define a standard fluorescent method using the fluorochrome Hoechst 33258 and Victor2(Wallac, EG & G) fluorimeter for microplates.

Finally, the activity of aromatase is expressed in gmolah/µg DNA for 2 hours and the inhibition of aromatase in percent of the control incubation without inhibitors. Nonlinear analysis of the degree of agreement selected curve with empirical data, the plot of % inhibition concentration,allows to determine the concentration of 50% inhibition (IC50): the smallest IC50corresponds to the most effective inhibitors (table A).

Table A
Inhibition of aromatase manin vitro
ConnectionIC50±the PJC< / br>
(nm)
n
Anastrozole8,21±1,273
Example 281,57±0,743
Example 301,16±0,553
Example 211,12±0,553
Example 250,66±0,143
Example 310,58±0,183
Letrozole0,56±0,10 12
Example 50,54±0,263
Example 230,48±0,133
Example 130,44±0,043
Example 190,40±0,063
Example 160,35±0,073
Example 60,31±0,013
YM 5110,30±0,043
Example 170,24±0,023
Example 200,22±0,053
Example 150,21±0,053
Example 220,20±0,053
Example 290,19±0,053
Example 110,18±0,023
Example 240,18±0,093
Example 90,16±0,063
Example 140,16±0,023
Example 70,14±0,053
Example 80,14±0,053
Example 100,14±0,033
Example 180,14±0,013
Example 260,13±0,053

INHIBITION of AROMATASEIN VIVO

Aromatase is steroidogenic the enzyme responsible for the biosynthesis of estradiol, the primary female sex hormone of estrogen. In rats estradiol physiologically synthesized at high circulating levels in a certain period during the 4-day estrous cycle: this is the so-called preovulatory splash, taking place on the day preceding estrus, just before ovulation, which occurs at night between proestrus and estrous phases. Sensitive physiological model for the assessment ofin vivoinhibition of aromatase developed on the basis of inhibition of this preovulatory surge levels of estradiol.

Monitor adult females of Wistar rats on a regular 4-day estrous cyclicity using daily vaginal smear; after 2 or 3 regular cycles of animals orally administered once a very low differencirovany dose of 10 micrograms/kg in a volume of 4 ml/kg to about 04:00 in the afternoon on the dioestrus, ieon the day before proestrus.

Exactly 24 hours taking samples of blood from the aorta under anesthesia gas. The levels of estradiol in plasma was measured by radioimmunoassay analysis using industrially produced nab the ditch (Diagnostic Systems Laboratories, Webster, Texas, USA). Control subjects and groups usually consist of 7-10 rats, depending on the number of rats with regular cycle allocated to the treatment group. The results are shown in PG/ml and then in % inhibition, where the levels of estradiol control animals receiving oral only solvent, taken as 100%, allowing you to make comparisons between various independent studies as level preovulatory burst may change in each control group when moving from one study to another within about 25 to 40 PG/ml

Table
Inhibition of aromatasein vivo
ConnectionInhibition in % at 10 ág/kgn
Anastrozole18-332
YM 511351
Example 7471
Example 1449-572
Example 6571
Example 1157-592
Example 17601

It is obvious that the compounds described by the General formula (I) present the mu to the invention, cause slightly greater or significantly greater inhibition of the biosynthesis of estradiol by inhibiting aromatasein vivothanYM 511, taken as a structural benchmark N-triazole (Okada et al., Chem Pharm Bull, 1996, 44: 1871-1879), or anastrozole, standard antiaromatase already used therapeutically. Thus, the compounds described by the General formula (I), are a significant improvement compared to the last substances.

Datain vivo(table B) does not have an absolute correlation with datain vitro(table A), but in General, both of the biological results indicate that a number of derivatives of 1-N-phenylamino-1H-imidazole according to the present invention provides numerous nanomolar and subnanomolar aromatase inhibitors, some of which cause the effective inhibition ofin vivobiosynthesis of estrogen. Therefore, these compounds are useful in combating or management of pathological or physiological estrogen-dependent mechanisms, predominantly in females (women and female animals), but also among male (men or male animals).

1. Derived imidazole of the formula (I)

and the acid additive salt, solvate and stereoisomeric forms, where

each of R1and R2independently researched the Simo means hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl;

n=0, 1, or 2;

each of R3, R4, R5and R6independently mean hydrogen or (C1-C6)alkyl, halogen, cyano, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl or (C1-C6)alkoxycarbonyl;

R3and R6together with bearing phenyl their cycle can also form N-methylbenzotriazole.

2. The derivative according to claim 1, where

n is 0 or 1;

each of R1and R2independently mean hydrogen or (C1-C6)alkyl;

R3means cyano or trifluoromethyl;

R4means hydrogen, (C1-C6)alkyl, halogen, cyano, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl or (C1-C6)alkoxycarbonyl;

R5means hydrogen, halogen, (C1-C6)alkoxy or trifluoromethyl;

R6means hydrogen;

or R3and R6together with bearing phenyl their cycle form N-methylbenzotriazole;

and the acid additive salt, solvate and stereoisomeric forms.

3. The derivative according to claim 1 or 2, where

n is 0 or 1;

each of R1, R2and R6snakecord;

R4means halogen, cyano or trifluoromethyl;

and the acid additive salt, solvate and stereoisomeric forms.

4. Derived according to one of claim 1 or 2, where R3means cyano; and an acid additive salt, solvate and stereoisomeric forms.

5. Derived according to one of claim 3, where R3means cyano; and an acid additive salt, solvate and stereoisomeric forms.

6. Derived according to one of claim 1 or 2, where R5means hydrogen or trifluoromethyl; and the acid additive salt, solvate and stereoisomeric forms.

7. The derivative according to claim 3, where R5means hydrogen or trifluoromethyl; and the acid additive salt, solvate and stereoisomeric forms.

8. The derivative according to claim 4, where R5means hydrogen or trifluoromethyl; and the acid additive salt, solvate and stereoisomeric forms.

9. The derivative according to claim 5, where R5means hydrogen or trifluoromethyl; and the acid additive salt, solvate and stereoisomeric forms.

10. The derivative according to claim 1 or 2, where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

11. The derivative according to claim 3 where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

12. The derivative according to claim 4, where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

13. The derivative according to claim 5, the de n is 1; and the acid additive salt, solvate and stereoisomeric forms.

14. The derivative according to claim 6, where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

15. The derivative according to claim 7, where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

16. Derivative of claim 8, where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

17. The derivative according to claim 9, where n is 1; and an acid additive salt, solvate and stereoisomeric forms.

18. The pharmaceutical composition inhibiting aromatase, including derivative according to one of claims 1 to 17 or its pharmaceutically acceptable acid additive salt and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition according p containing from 0.1 to 400 mg of the indicated derivative.

20. The use of a derivative according to one of claims 1 to 17 or its pharmaceutically acceptable acid salt additive to obtain drugs for treating or preventing estrogen-dependent disorders, where the specified derivative, is optional, is used in combination with therapeutic endocrine hormonal drug related to sexual function.

21. The use of a derivative according to one of claims 1 to 17 or its pharmaceutically acceptable acid salt additive to obtain drugs to regulate the treatment or control of reproductive functions, such as male or female fertility, pregnancy, abortion or delivery, where the specified derivative, is not necessarily, is in combination with an agonist or antagonist of LH-RH, astroprojection contraceptive, a progestin, antiprogestins or prosta-llandinam.

22. The use of a derivative according to one of claims 1 to 17 or its pharmaceutically acceptable acid salt additive to obtain drugs for treating or preventing benign or malignant diseases of the breast, uterus or ovaries, where the specified derivative, is not necessarily, is in combination with an antiestrogen, a progestin or agonist or antagonist of LH-RH.

23. The use of a derivative according to one of claims 1 to 17 or its pharmaceutically acceptable acid salt additive to obtain drugs for treating or preventing benign or malignant diseases of the prostate or testicles, where the specified derivative, is not necessarily, is in combination with antiandrogens, a progestin, an inhibitor of LiAZ or agonist or antagonist of LH-RH.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to substituted ω-azolylalkane anilides. Invention describes substituted ω-(1H-azol-1-yl)-N-phenylalkaneamides of the general formula (I): wherein Z and Y mean nitrogen atom of CH-group, or they represent the chain -C-CH=CH-CH=CH-C- simultaneously and forming in common an anellated ring; n means a whole number from 1 to 3; Rm are similar or different and mean hydrogen, halogen atom, alkyl group with number of carbon atoms from 1 to 4, alkoxy group, alkylenedioxy group, benzyloxy group, perfluoroalkyl group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group, carboxyl group, halogenphenylthio group, halogenbenzoyl group; m means a whole number from 0 to 5, their salts with acids. Also, invention describes methods for synthesis of compounds of the formula (I) and their using as anti-aggregative preparations. Invention provides synthesis of novel compounds possessing the useful biological properties.

EFFECT: valuable properties of compounds, improved method of synthesis.

8 tbl, 11 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel 2-(2,6-dichlorophenyl)diarylimidazoles of the general formula (I): possessing inhibitory effect on activity of protein-tyrosine kinase and first of all c-met kinase, and can be used in treatment of oncological diseases. In the compound of the general formula (I) X means hydrogen atom, -OR1, -SR2, -(SO2)R2 or group A1-Q wherein A1 means (C1-C3)-alkylene group; Q means -OR1, -NR3R4, -NHCH2CH2NR3R4; R1 is chosen from group comprising hydrogen atom, (C1-C)-alkyl, dimethylphosphonylmethyl, (R)-2,3-dihydroxy-1-propyl, (S)-2,3-dihydroxy-1-propyl, 1,3-dihydroxy-2-propyl, 3-hydroxy-2-hydroxymethyl-1-propyl, 2-methoxyethoxymethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or group A1-Q1 wherein Q1 means (C1-C2)-alkoxy, cyano group, carboxyl, (C1-C6)-alkoxycarbonyl, and if A1 means 1,2-ethylene- or 1,3-propylene group then Q1 means hydroxy group; R2 means (C1-C6)-alkyl or A1-Q; R3 and R4 are chosen independently from group comprising hydrogen atom, (C1-C6)-alkyl, or form in common 6-membered saturated cycle comprising two heteroatoms chosen from nitrogen (N) or oxygen (O) atoms; Y means hydrogen atom or group A2-R wherein A2 means (C1-C5)-alkylene optionally substituted with (C1-C6)-alkyl, phenyl or hydroxy group; R means hydroxy group, linear or branched (C1-C6)-alkoxy, amino, dimethylamino, diethylamino, tert.-butyloxycarbonylamino group, carboxyl, (C1-C6)-alkoxycarbonyl, triazolyl, 1-pyrrolidinyl, morpholino group, 4-methylpiperazin-1-yl, O-A1-NR3R4, S-A1-NR3R4, 4-carboxyphenyl, furan-3-yl, thiophen-2-yl or 3-methylthiophen-2-yl; Z means one or two substitutes chosen independently from group comprising halogen atom, hydroxy, allyloxy group, methyl, (C1-C5)-alkoxy, methoxymethoxy, (2-methoxyethocy)methyloxy, methylthio, ethoxymethoxy group, ethynyl and benzyloxy group optionally substituted with halogen atom, methoxy, cyano, ethoxy group, and its pharmaceutically acceptable salts. Also, invention elates to novel intermediate compounds and synthesis of compounds, and to their using for preparing drugs and pharmaceutical composition.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 97 ex

FIELD: bioorganic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel aspartyl derivatives of histamine of the general formula (I): , wherein R means hydrogen atom (H), or , or that are able to modulate activity of enzymes of antioxidant protection - superoxide dismutase (SOD) and catalase. Also, invention relates to using the known compounds of the general formula (I) for the same designation wherein at the same values of X the value R represents acetyl group, and to their pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition possessing capacity to modulate activity of SOD and catalase and comprising the effective amount of compound of the general formula (I), and to a method for synthesis of compounds of the general formula (I). Method involves interaction of pentafluorophenyl ester Nα-Z-, β- or α-benzyl ester of aspartic acid with histamine followed by hydrogenolysis without isolation of intermediated protected derivatives of aspartyl histamine.

EFFECT: improved method of synthesis, valuable biochemical properties of derivatives.

12 cl, 3 tbl, 2 sch, 2 dwg, 8 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

Ionic liquids ii // 2272043

FIELD: organic chemistry.

SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.

EFFECT: improved and valuable properties of ionic liquids.

3 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to heterocyclic compounds of the formula I, values radicals cm

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,7-substituted indoles of formula: its pharmaceutical salts, where n represents 0, 1 or 2; p represents 1 or 2; R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, including halogen, C1-C12alkyl, halogenC1-C12alkyl; R2 represents a mono-valent saturated residue, consisting of one ring, containing six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-C12alkyls; R3 represents H, C1-C12alkyl. The compounds have antagonist action to the "5-ГТ6" receptor.

EFFECT: possibility of using these compounds in pharmaceutical compositions in an effective quantity.

8 cl, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: substance of invention includes application of ligand associated with carrier, where ligand is protein FasL, or Fas leukocyte receptor-directed antibody, to reduce leukocyte activity for extracorporal application. Besides, this invention provides method of leukocyte activity reduction my means of specified module.

EFFECT: damaging action of associated activated leukocytes is inhibited by inactivation module within minutes.

9 cl, 1 ex, 1 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: described new bandaging material is applied for stimulating of epithelial cell proliferation and for treatment of superficial wound healing. In bandaging material inorganic elements of silicone and/or calcium are used as biologically active substances for initiative induction of human epithelial cell proliferation, for inhibition of inflammatory wound effluents and for stimulation of rapid superficial wound healing. Bandaging material is dosage form of powder, ointment or plaster. It can be applied safely, economically and effectively for treatment of vast chronic superficial wound, such as incised wounds, bruises, burns, boiling water burns, chemical burns, decubitus ulcers, various ulcers on skin surface and others.

EFFECT: material is safe and cost-saving.

26 cl, 6 dwg, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to production of medicinal agents based on medicinal plants for chronic tiredness syndrome relief. Offered agent for chronic tiredness syndrome relief based on medicinal plants is aqueous tincture of thistle herb made at proportion 3 teaspoons of ground herb for 700 ml of water at temperature 80°C. Agent reliefs extreme tiredness, febrility, sluggishness, sleepiness, memory impairment, sleep disorder, headache, attention concentration problems, depression and etc.

EFFECT: relieved signs of chronic tiredness syndrome.

FIELD: medicine.

SUBSTANCE: not later than 6 minutes after diclofenac injection medicinal infiltrate area is introduced with 10% calcium gluconate. Volume of injected solution is 1/3 of injected diclofenac volume. After injection injured area is covered with half-alcoholic compress.

EFFECT: improves efficiency of developing necrosis prevention due to timely inactivation of diclofenac sodium compounds.

1 ex

FIELD: biotechnology.

SUBSTANCE: The invention proposes variants of methods for selection of compounds by their ability to interact with transmembrane proteins. An isolated cell is exposed, that is transformed by a nucleotide sequence that encodes proteins, including a transmembrane protein comprising at least one NLS and a detectable part of the molecule to be used in the proposed method. A method for detection of the ability to oligomerize proteins, such as transmembrane proteins, is proposed as well.

EFFECT: provides an alternative to existent methods for identification of compounds interacting with transmembrane proteins; provides with an improved method for detecting the oligomerization of transmembrane proteins.

27 cl, 5 dwg, 1 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: 40-0-(2-hydroxiethyl)rapamycin is offered to apply in pharmaceutical formulation for inhibition and control of angiogenesis inadequate regulation or for related diseases. Specifically it is used for tumour treatment of brain, central nervous system, colon, rectum or reproductive system.

EFFECT: proliferation inhibition of vein endotheliocytes and proliferation inhibition stimulated by vascular endothelial growth factor.

3 cl

FIELD: medicine, veterinary.

SUBSTANCE: method implies administration of iodine-containing medicine, which contains organic iodine compound, into human or animal organism. And iodine is bound covalently with substance from the following groups: carbon acids, unsaturated lipid acids, lipids, terpens, terpenoids, isoprenes, peptides, polypeptides, amino acids, protein hydrolisates, polypeptide hydrolisates, proteins of plant and/or animal origin and/or microbiologic origin, mixture of lipids and unsaturated lipid acids, , mixture of isoprenes and terpens, mixture of isoprenes and protein hydrolisates, mixture of isoprenes and unsaturated lipid acids. At the same time, the proteins, peptides, polypeptides, amino acids, polypeptide and protein hydrolisates are taken so as iodine is bound covalently in 5 and 3 or 3 position of phenolic cycle, and amino acids and proteins don't show the hormonal thyroid activity. Single dose of medicine contains the sufficient iodine amount to provide its daily dose, which exceeds the physiologic requirement 10-1000 times.

EFFECT: method provides permanent prevention of lesions caused by radioactive iodine, by use of high dose of stable iodine isotope contained in medicine composition.

12 cl, 26 ex

FIELD: medicine.

SUBSTANCE: method involves introducing fragmented DNA into patient organism. The DNA is allogenic. It is received from genetically and physiologically healthy donors and has fragments which length corresponds to 1-10 units of nucleosomes making up full patient genome in association with nucleus matrix proteins. Fragmented DNA is introduced in the amount that enables one to achieve fragmented DNA concentration in patient blood plasma equal to or greater than the own patient blood plasma DNA concentration but not greater than 1500 ng/l.

EFFECT: enhanced effectiveness in restoring DNA by substituting mutated chromosome sites as homological recombination; widened application field of fragmented DNA preparations.

4 dwg, 7 tbl

FIELD: medicine; obstetrics.

SUBSTANCE: invention refers to control of birth activity associated with pre-birth discharge of amniotic fluid or amniotomy performed to induct birth activity. For this purpose enzaprost is intravenously droplet introduced in dosage 5 mg per 400 ml of 5% glucose solution. If mouth of womb opening is 4-5 cm, woman in birth is introduced with pentamine in dosage 1 ml with 20 ml of physiologic saline. This mixture separated by three equal parts is intravenously introduced every 20 minutes.

EFFECT: provided protective action for contractive womb activity without negative action.

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