Method of producing 2-(2-alkyl(dialkyl)amino)adamantylalkyl(aryl)ketones

FIELD: chemistry.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

 

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining 2-(2-alkyl(dialkyl)amino)substituted-alkyl(aryl)ketones of General formula

which are likely biologically active substances. So, the close connection structure are surface-anesthetic (Ishmuratov, Whitecrow, Chassereau. Pharmacology of adamantanes.- Volgograd: Volgograd Medical Academy. 2001, - 320 S. - p.93), anxiolytic (p.87) and anticatholicism activity (s). In addition, the compounds of the claimed formulas are structural analogs of known drugs "midantan and rimantadine," which suggests the manifestation of their high antiviral and antiparkinsonian activity. In the literature information about the methods of preparing compounds of the claimed formula is missing.

A known method of producing propiophenone by the reaction of benzonitrile with Grignard reagents, namely ethylmagnesium. The disadvantage of this method is that it does not lead to obtaining substances claimed sructural formula [travel SCI Organic chemistry: a Textbook for high schools; 2 t/ VF, travel. - M: IR called "Akademkniga", 2005. - 582 C.]. This method is not result of substances claimed structural formulas.

A method of obtaining adamantylidene of ketonitriles by the reaction of 1,3-dicyanobutane with Grignard reagents. [Investigation of the interaction of 1,3-dicyanobutane with Grignard reagents. Ehanourov, Busonline, Entailed, Gaelikaa // Chemistry and technology of caged compounds / abstracts of the IX international conference. - Volgograd, 2001, - S]. This method does not lead to obtaining substances claimed structural formulas.

Closest to the proposed invention is a method for adamantaneacetic ketones interactions NITRILES 1-adamantanecarbonyl and (1-substituted)acetic acid with a Grignard reagents in tetrahydrofuran [Study of the interaction of NITRILES adamantane-carboxylic acids with Grignard reagents. Ehanourov, Busonline, Entailed, Gaelikaa // Chemistry and technology of caged compounds / abstracts of the IX international conference. - Volgograd, 2001, - P.76]. However, this method does not lead to obtaining substances claimed structural formulas.

The task of the invention is to develop technological molestating method of synthesis of 2-(2-alkyl(dialkyl)amino)substituted-alkyl(aryl)ketones proceeding with a high output source 2 alkylamino(dialkylamino)-2-cyanoadamantane.

The technical result is the expansion of the range of the derivative is dmontana, develop a method of synthesis of new derivatives of adamantane with high output.

The technical result is achieved in a new method of obtaining 2-(2-alkyl(dialkyl)amino)adamantylamine(aryl)ketones of General formula

by reacting 2-alkylamino(dialkylamino)-2-cyanoadamantane from a number of: 2-methylamino-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents of the series: methylmagnesium, ethylaniline, allylanisole, phenylmagnesium, benzylaniline in the environment of dried diethyl ether or in a mixture of tetrahydrofuran-ether at a molar ratio of reactants is 1:2-2 .03, respectively, at a temperature of 30-45°C for 4-5 hours.

The essence of the method is the reaction of obtaining 2-alkyl(dialkyl)amino-2-substituted-alkyl(aryl)ketones by the reaction of 2-alkylamino(dialkylamino)-2-cyanoadamantane with Grignard reagents

The method is as follows.

Solution in dried diethyl ether 2-alkylamino(dialkylamino)-2-cyanoadamantane from a number of: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-C is Roadmaster, 2-N-morpholino-2-cyanoadamantane added to a solution of the Grignard reagent from a number: methylmagnesium, ethylaniline, allylanisole, phenylmagnesium, benzylaniline in dried diethyl ether or in a mixture of tetrahydrofuran - diethyl ether (molar ratio of reactants of 1:2-2,03, respectively), and then maintain the reaction mass at 30-45°C and stirring for 4-5 hours. Upon completion of the reaction, the resulting mass is cooled and poured required for decomposition magyarkanizsa complex amount of water. The product yield after isolation and purification is 33-78%.

As studies have shown, the most convenient reaction conditions is its implementation in the environment of diethyl ether in the presence 2-2,03-fold excess of the Grignard reagent. Less excess in some cases resulted in reduction of the yield of target products due to possible complex formation of the Grignard reagent from 2-alkyl-amino-2-cyanoadamantane liaison NH. In any case, the excess Grignard reagent was not given rise to by-products due to steric hindrances created at the joining of the first molecule of the Grignard reagent to the corresponding 2-alkylamino(dialkylamino)-2-cyanoadamantane. A further increase in excess of the Grignard reagent had no effect on the yield of the target about the of aktov and was impractical.

The structure of the synthesized compounds was confirmed by NMR1N-spectroscopy and elemental analysis.

The invention is illustrated by the following examples:

Example 1.

2-(2-Methylamino)adamantylamine.

To the Grignard reagent derived from 1 g (0.0417 mol) of magnesium and 3.5 g (0.0321 mol) of ethylbromide in 20 ml of absolute diethyl ether, add a solution of 3 g (0.0158 mol) of 2-methylamino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2,03:1). The reaction mass is maintained at 35°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 1 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Obtain 2.5 g (0.0110 mol) of 2-(2-methylamino)adamantylidene in the form of a white crystalline substance, TKIP-135°C/10 mm Hg 75%Yield. An NMR spectrum1N, δ, ppm: 0.81 t (3H, -NHCH3, J=0.8); 1.02 t (3H, -C(O)CH2CH3, J=1.1); 1.41-2.40 m (14N,2,2-Ad, 2H, -C(O)CH2-, 1H, -NH).

Example 2.

2-(2-Methylamino)adamantylidene.

To the Grignard reagent derived from 0.6 g (0.0250 mol) of magnesium and 1.4 g (0.0178 mol) of allyl chloride in 10 ml of a mixture of diethyl ether and tetrahydrofuran, add a solution of 1.7 g (0.0089 mol) of 2-aminomethyl-2-cyanoadamantane in 10 ml of absolute diety the new ether (molar ratio 2:1) and stirred in a flask under reflux at 45°C for 4 hours. Upon completion of the reaction mass is then cooled and poured 1 g of water. After separating the solid phase from the filtrate distilled off the solvent, the product is distilled under vacuum with decomposition. TKIP-160°C/20 mm Hg Obtain 0.8 g (0.00325 mol) of 2-(2-methylamino)adamantylidene. Exit 33%. An NMR spectrum1H, δ, ppm: 2.33 t (3H, CH3, -NHCH3J-0.8); (1.2-2.42 m (14N,2,2-Ad, 2H, -C(O)CH2-, 1H, -NH); 4.95-5.05 m, (2H,=CH2); 5.67-5.82 m (1H, CH=).

Example 3.

2-(2-N-Piperidino)adamantylamine.

To the Grignard reagent derived from 0.9 g (0,0368 mol) of magnesium, 4 g (0.0282 mol) of methyl iodide in 20 ml of absolute diethyl ether, add a solution of 3.4 g (0.0141 mol) 2-piperidino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2:1). The reaction mass is maintained at 35°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 1 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Get 4 g (0.0153 mol) of 2-(2-N-piperidino)adamantanemethylamine, yield 75%. TKIP-150°C/20 mm Hg nD20=1.5312. An NMR spectrum1N, δ, ppm: 1.195-2.245 m (14N,2,2-Ad: 6H, (CH2)3); 1.86 (3H, CH3); 2.78 t (4H, -N(CH2)2, J=0.9).

Example 4.

2-(2-N-Piperidino)adamantylamine.

The reaction is willow Grignard, obtained from 0.9 g (0,0369 mol) of magnesium, 3.1 g (0.0283 mol) of methyl ethyl in 20 ml of absolute diethyl ether, add a solution of 3.4 g (0.0140 mol) 2-piperidino-2-cyanoadamantane (molar ratio 2,02:1) in 10 ml of absolute diethyl ether. The reaction mass is maintained at 40°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 1 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Obtain 3.8 g (0.0138 mol) of 2-(2-N-piperidino)adamantylamine, yield 68%. TPL 72-74°C. an NMR Spectrum1N, δ, ppm: 0.77 (3H, CH3); 1.11-2.17 m (14N,2,2-Ad; 6N (CH2)3); 1.88 (2H, COCH2); 2.32 t (4H, -N(CH2)2, J=0.82).

Example 5.

2-(2-N-Piperidino)adamantylidene.

To the Grignard reagent obtained from 0.5 g (0,0206 mol) of magnesium, 1.3 g (0.0172 mol) of allyl chloride in 20 ml of absolute diethyl ether, add a solution of 2.1 g (0.0086 mol) of 2-piperidino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2:1). The reaction mass is maintained at 35°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 1 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Get 2 g (0.007 mol) of 2-(2-N-piperidinecarbonitrile, yield 57%. nD20=1.5400 an NMR Spectrum1N, δ, ppm: 1.08-2.25 m (14N,2,2-Ad 6H (CH2)3); 2.37 t (4H, -N(CH2)2, J=0.8); d (2H, PINES2-); 4.80-4.96 m (2H, =CH2); 5.75-5.90 m (1H, CH=).

Example 6.

2-(2-N-Piperidino)adamantylamine.

To the Grignard reagent derived from 0.9 g (0,0369 mol) of magnesium, 3.8 g (0.0246 mole) of methyl phenyl in 20 ml of absolute diethyl ether, add a solution of 3 g (0.0121 mol) of 2-piperidino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2,03:1). The reaction mass is maintained at 35°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 3 g of water. The formed precipitate was separated by filtration, the filtrate the solvent is distilled off. Obtain 2.7 g (0.0083 mol) of 2-(2-N-piperidino)adamantylamine. TPL 176-178°C, yield 69%. An NMR spectrum1N, δ, ppm: 1.06-M (14N,2,2-Ad 6N (CH2)3); 2.36 t (4H, -N(CH2)2, J=0.86); 7.01-7.21 m(5H,6H5).

Example 7.

2-(2-N-Piperidino)adamantylamine.

To the Grignard reagent derived from 0.4 g (0,0167 mol) of magnesium, 1.2 g (0.0104 mol) of benzyl chloride in 20 ml of absolute diethyl ether, add a solution of 1.3 g (0.0052 mol) of 2-piperidino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2:1). The reaction mA is su incubated at 35°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 3 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Obtain 1.4 g (0.0042 mol) of 2-(2-N-piperidino)adamantylamine, yield 75%. TPL 68-70°C. an NMR Spectrum1N, δ, ppm: 1.19-2.21 m (14N, Ad, 6N (CH2)3); 2.53 t (4H, -N(CH2)2, J=0.95); 2.40 (2H, CH2); 7.01-7.16 m (5H,6H5).

Example 8.

2-(2-N-Morpholino)adamantylamine

To the Grignard reagent derived from 0.4 g (0,0170 mol) of magnesium, 1.6 g (0.0114 mol) of methyl iodide in 20 ml of absolute diethyl ether, add a solution of 1.4 g (0.0057 mol) of 2-morpholino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2:1). The reaction mass is maintained at 30°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 3 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Obtain 1.3 g (0.0043 mol) of 2-(2-N-morpholino)adamantanemethylamine, 71%yield. TPL=40-42°Sspects NMR1N, δ, ppm: 0.92 (3H, CH3), 1.22-2.48 m (14N,2,2-Ad); 3.39 t (4N, N(CH2)2, J=1.1); 3.65 t (4N, (CH2)2O, J=0.9).

Example 9.

2-(2-N-Morpholino)adamantylamine

To the Grignard reagent derived from 0.4 g (0,mol) magnesium, 1.1 g (0.010 mol) of methyl ethyl in 20 ml of absolute diethyl ether, add a solution of 1.2 g (0.0050 mol) of 2-morpholino-2-cyanoadamantane in 10 ml of absolute diethyl ether (molar ratio 2:1). The reaction mass is maintained at 35°C and stirring for 5 hours. Upon completion of the reaction, it is cooled and added 1 g of water. The formed precipitate was separated by filtration. From the filtrate the solvent is distilled off, the product is distilled in a vacuum. Obtain 2.1 g (0.0076 mol) of 2-(2-N-morpholino)adamantylamine, yield 75%. TPL 64-66°C. an NMR Spectrum1N, δ, ppm: 0.84 t (3H, CH3); 1.19-2.28 m (14N, Ad); d (2H, CH2N, J=1.0); 3.60 t (4N, (CH2)2O, J-0.9); d (2H, PINES2, J=0.65).

Thus, the above data confirm that the implementation of the use of the claimed invention the following cumulative conditions:

the tool embodying the claimed invention in its implementation, is intended for use in various industries;

for the claimed invention in the form as it is described in the independent clause following claims, confirmed the possibility of its implementation using the above described in the application or known before the priority date tools and methods;

- a means of embodying the invention in its implementation, is capable of ensuring the achievement of the technical result.

Therefore, the claimed invention meets the requirement of "industrial applicability".

Conclusions

Developed technologically melastatin method of synthesis of 2-(2-alkyl(dialkyl)amino)substituted-alkyl(aryl)ketones or its derivatives, which allows to obtain a wide range of compounds with high yield. The structure of the synthesized compounds was confirmed by NMR1N-spectroscopy and elemental analysis.

The method of obtaining 2-(2-alkyl(dialkyl)amino)substituted-alkyl(aryl)ketones of General formula




which consists in the interaction of 2-alkylamino(dialkylamino)-2-cyanoadamantane from a number of: 2-methylamino-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents of the series: methylmagnesium, ethylaniline, allylanisole, phenylmagnesium, benzylaniline in the environment of dried diethyl ether or in a mixture of tetrahydrofuran-ether at a molar ratio of reactants is 1:2-2,03, respectively, at a temperature of 30-45°C for 4-5 hours



 

Same patents:

The invention relates to the synthesis of biologically active compounds, namely, salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula:

< / BR>
where X 0(1a), CH2(1B), NH(1B)

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) and its pharmaceutically acceptable salts. In general formula (I) , Y represents group -CONH(Q)- or -NHCONH(Q)-; Q represents 6-member aromatic ring or 5-10-member heteroaromatic ring, containing one or two N heteroatoms or two O heteroatoms; R represents hydrogen, halogen, linear or branched (C1-C6)alkyl; (C1-C6)alkoxy; di-(C1-C6)alkylamino, 5-member heteroaromatic ring, containing one O or S heteroatom; 6- or 9-member heteroaromatic ring, containing one or two N heteroatoms; phenyl, mono- or disubstituted with halogen, (C1-C6)alkyl, halogeno(C1-C6)alkyl, (C1-C6)alkoxy, acyl; hydroxy; piano; di-(C1-C6)alkylamino, acylamino' carbamoyl; X represents group : where Z represents CH2, N or O; m represents integer number from 1 to 3; p is equal 0, 1; R" is selected from group, consisting of di-( C1-C6)alkylaminocarbonyl, (C1-C6)alkyl, acyl. Invention also relates to pharmaceutical composition, containing as active ingredient, invention compound, to application of invention compound for manufacturing pharmaceutical composition, to method of inhibition of nicotinic acetylcholine receptor α7.

EFFECT: obtaining compound, which possesses agonistic activity with respect to nicotinic acetylcholine receptor (nAChR) α7.

7 cl, 2 tbl, 4 dwg, 270 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of General formula

where X1-X5denote SN2or one of them denotes NH, and the other X1-X5are CH2; k is 0 or 1, R1is1-8the alkyl, C1-8hydroxyalkoxy; t is 0, 1 or 2; And represents phenyl or pyridinyl; R2is H, hydroxyl, halogen or1-6the alkyl, C1-6alkoxygroup; n is 0, 1-4; p is 0 or an integer from 1 to 5, Y is-C(O)-; Z is CH2or their pharmaceutically acceptable salts

The invention relates to compounds of formula (I), their stereochemical isomeric forms, their salts obtained by the joining of acid or base, their N-oxides or Quaternary ammonium derivative, where the dotted line represents an optional bond; X is absent when the dotted line represents a bond, or X is a hydrogen or a hydroxy-group, when the dotted line is not a bond, R1, R2, R5and R6each independently selected from hydrogen, halogen, hydroxy-group, WITH1-4of alkyl, C1-4alkoxygroup, SO3N and the like; R3and R4each independently selected from hydrogen, halogen, hydroxy-group, WITH1-4of alkyl, C1-4alkoxygroup, nitro, amino, ceanography, trifloromethyl or cryptometer;represents a radical of the formula (a-1), (a-2), (a-3), (a-4), (a-5), (6), (7), (8), (9), (10), where a1represents a direct bond or C1-6alcander; AND2represents a C2-6alcander; R7- R11represents hydrogen, C1-6alkyl, amino1-6alkyl and the like, provided that when L is Soboh the

The invention relates to a new specified in the title of a chemical compound, which are presented below, and to methods for the treatment of painful conditions, modulating allergic, inflammatory or cholinergic activity in mammals, using the new mentioned above in the title of chemicals

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

FIELD: chemistry.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to a method of obtaining saturated aliphatic ketone, represented by the general formula (2), (where n stands for an integer number from 1 to 3; R represents a hydroxyl group, a cyclohexyl group, an alkyl group, which has from 1 to 4 carbon atoms, or an acyl group, which has from 1 to 4 carbon atoms), applied as an initial material for the production of medications, agrochemical preparations, optic functional materials and functional materials for electronics. The method consists in hydrogenation of a nucleus of an aromatic ketone, represented by the general formula (1), (where n stands for an integer number from 1 to 3; R represents a hydroxyl group, a phenyl group, an alkyl group, which has from 1 to 4 carbon atoms, or an acyl group, which has from 1 to 4 carbon atoms), with hydrogen under pressure in the presence of a solvent at a temperature from 20 to 120°C and in the presence of a catalyst, which carries from 0.1 to 20 wt % of the ruthenium atom on a carrier.

EFFECT: method makes it possible to obtain the target product with high selectivity.

6 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for producing 2-(2-hydroxy)adamantylalkyl(aryl)ketones of general formula: , which are intermediate products during synthesis of possibly biologically active substances. The method involves reaction of adamantanone cyanohydrin with Grignard reagents selected from: ethylmagnesium bromide, benzylmagnesium chloride, alkylmagnesium chloride, in a medium of anhydrous diethyl ether or tetrahydrofuran in molar ratio of reagents equal to 1:2, respectively, at temperature 30-45°C for 2-3 hours, with subsequent treatment of the reaction product with water and acetic acid and extraction of the end product.

EFFECT: high output of end products.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemical derivatives of adamantane and specifically to a novel method of producing 2-(2-alkyl(dialkyl)amino)adamantyl-alkyl(aryl)ketones of general formula R=-NHCH3: R1=Et,-CH2-CH=CH2; : R1=Me, Et,-CH2-CH=CH2, Ph,-CH2Ph; : R1= Me, Etwhich can be used as intermediate products in synthesis of certain biologically active substances. The novel method involves reacting 2-alkylamino(dialkylamino)-2-cyanoadamantanes from the group: 2-methylamino-2-cyanoadamantane, 2-N-piperidino-2-cyanoadamantane, 2-N-morpholino-2-cyanoadamantane with Grignard reagents from the group: methylmagnesium iodide, ethylmagnesium bromide, allylmagnesium chloride, phenylmagnesiuim bromide, benzylmagnesium chloride in a medium of dry diethyl ether or a tetrahydrofuran-ether mixture in molar ratio of reagents equal to 1:2-2.03, respectively, at temperature 30-45°C for 4-5 hours.

EFFECT: wider range of adamantane derivatives, design of a method for synthesis of novel adamantane derivatives with high output.

9 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

Up!