Synthesis of tertbutyl ester of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid and its intermediate products

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining hydrochloride of tertbutyl ester of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid (I). Method includes reduction of tertbutyl ester of (4-fluoro-3-pyridin-4-yl-benzyl) carbamic acid under conditions of reducing hedrogenisation and then HCl processing with output of hydrochloride of tertbutyl esther of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid. Also claimed are methods of obtaining intermediate products, namely 5-((tert-butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid and tertbutyl ester of (4-fluoro-3-pyridin-4-yl)benzyl-carbamic acid.

EFFECT: invention makes it possible to considerably simplify obtaining hydrochloride of tertbutyl esther of (4-fluoro-3-pyperidin-4-yl-benzyl)-carbamic acid.

30 cl, 1 ex

 

The scope of the invention

This invention is directed to a method for the synthesis of tert-butyl ether complex (4-fluoro-3-piperidine-4-yl-benzyl)-carbamino acid (I) and its intermediates.

Background of the invention

WO2001/13811 discloses compounds, including [(benzylamino)-piperidine-1-yl] (aryl or heteroaryl)methanon as inhibitors of tryptase and describes the possible applications of these compounds because of tryptase involved in many biological processes, including the breakdown of vasodilator and bronhorasshiryayushim cortex (Caughey, et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951; and Tam, et al., Am. J. Respir. Cell Mol. Biol., 1990, 3, pages 27-32) and modulation of bronchial sensitivity to histamine (Sekizawa et al., J. Clin. Invest., 1989, 83, pages 175-179).

WO2005/097780 more detail (benzylamino)-piperidine-1-Il titillation, i.e. the compound of formula A, its preparation and use for the treatment of painful conditions

amenable to modulation by inhibition of tryptase. WO2005/097780 also discloses that the compound of the formula A receive through a combination of the following compounds 14 and I, which is shown in Scheme A, and the subsequent removal of the protective groups associated with the product.

Scheme A

The connection I got with synthesis, which includes seven stages, as shown in the Diagram below, B.

Scheme B

While the above synthesis is to obtain compounds I in laboratory scale, the connection I had better get with the use of a smaller number of stages. This invention represents a significant improvement in the way of synthesis according to Scheme B, as it is much shorter.

The invention

This invention is directed to an improved method of obtaining tert-butyl ether complex (4-fluoro-3-piperidine-4-yl-benzyl)-carbamino acid (I); more specifically for its synthesis in three stages. The first stage involves the formation of Bronevoy acid by treating tert-butyl ether complex (4-fluoro-benzyl)-carbamino acid conditions Borisovna. The second stage includes the introduction of the resulting first stage 5-((tert-butoxycarbonyl)aminomethyl)-2-ferbinteanu acid in the reaction with 4-halo-pyridine, such as 4-chloro-pyridine or 4-bromo-pyridine combining Suzuki with access tert-butyl ether complex (4-fluoro-2-pyridin-4-yl-benzyl)-carbamino acid. The third stage includes the application of the conditions of the selective hydrogenation of the product of the second stage with the release of compound I. This and the finding is also directed to intermediate products 5-((tert-butoxycarbonyl)aminomethyl)-2-ferbinteanu acid (compound 11) and tert-butyl ester (4-fluoro-2-pyridin-4-yl-benzyl)-carbamino acid (compound 13).

Detailed description of the invention

Used in this description, the following abbreviations and definitions unless otherwise stated, it should be understood as having the following values:

List of abbreviations

n-BuOAcn-butyl acetate
n-BuLin-utility
t-Butert-butyl
t-BuOHtert-butanol
DCMdichloromethane, CH2Cl2or methylene chloride
DMFdimethylformamide
DMSOthe sulfoxide
dppf1,1'-bis(diphenylphosphino)ferrocene
EQ.equivalent(s)
Etethyl
Et2Odiethyl ether
EtOHethanol
EtOAc the ethyl acetate
HPLChigh performance liquid chromatography
Memethyl
MTBEmethyl t-butyl ether
MeOHmethanol
Na2CO3sodium carbonate
Na2SO4the sodium sulfate
NMRnuclear magnetic resonance
Pd(PPh3)4tetranitroaniline palladium
Pd(PPh3)2Cl2the dichloride bescription palladium (II)
PdCl2dppfdichloride, 1,1'-bis(diphenylphosphino)ferrocene palladium (II)
Pd(dtbpf)Cl2dichloride 1.1 bis(di-t-butylphosphino)ferrocene palladium
Pd2(dba)3Tris(dibenzylideneacetone)diplegia(0)
Pd(OAc)2 the palladium(II) acetate
P(Cy)3tricyclohexylphosphine
t-Bu3Pthree t-butylphosphine
PPh3triphenylphosphine
Dpropanol
i-Disopropanol
i-PrOAcisopropylacetate
t-BuOKtert-butyl potassium
PPSEcomplex trimethylsilyloxy ether
polyphosphoric acid
rtroom temperature
Rtthe retention time
TFAtriperoxonane acid
TFAAtriperoxonane anhydride
THFtetrahydrofuran
TLCthin-layer chromatography

"Water acid" means an aqueous solution of inorganic (mineral) acids, such as hydrochloric acid, phosphoric acid, etc. or an aqueous solution of organic acid such as acetic acid, etc.,

"Conditions Borisovna" means conditions using superocean, means forming Bronevoy acid, solvent for Borisovna and the reaction temperature of Borisovna.

"Superocean" means an extremely strong base, such as a combination of organolithium reagent of the formula RLi, where R is an alkyl or aryl group having 1-12 carbon atoms, and the bulk of the potassium alkoxide such as potassium tert-butyl or potassium tert-pentoxide, etc.,

"The tool forming Bronevoy acid" means trialkylborane, such as trimethylboron, triethylborane, tripropellant, triisopropylsilyl, tributional etc.

"Solvent for Borisovna" means simple ether solvent such as diethyl ether, THF, 2-methyltetrahydrofuran, MTBE, dimethoxyethane etc.

"Temperature Borisovna" means from about -30 to -100°C.

"4-halogenfrei" means 4-(iodine, bromine or chlorine)pyridine or its salt.

"Conditions for the combination of Suzuki" means conditions using a solvent for the combination according to Suzuki, the catalyst combination of Suzuki and tempera on the URS of combination reaction Suzuki.

"Solvent for combining Suzuki" means an alcohol solvent with a boiling point ≥ that of isopropyl alcohol, such as n-propyl alcohol, n-butyl alcohol, etc.; polar aprotic solvent, such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide or etc.; ether solvent such as THF, 2-THF, dimethoxyethane, MTBE, or so on; or a mixture of any of the above solvents and water or toluene.

"The catalyst combination Suzuki" means a Pd catalyst such as Pd(PPh3)4Pd(PPh3)2Cl2Pd2(dba)3, PdCl2dppf, Pd(dtbpf)Cl2or similar; or Pd catalyst such as Pd(OAc)2Pd2(dba)3or, etc., in combination with a ligand, a phosphine, such as PPh3, dppf, t-Bu3P, P(Cy)3or, etc.

"The reaction temperature combinations Suzuki" means a temperature from about 60°C to about 100°C, i.e. the temperature of the boiling point of the reaction mixture combinations Suzuki.

"Hydrogenation conditions" means conditions using a catalyst of hydrogenation, solvent hydrogenation temperature of the hydrogenation reaction and pressure hydrogenation.

The solvent for the hydrogenation reaction" means a solvent on the basis of ester, such as EtOAc, i-PrOAc, BuOAc, etc.; alcohol solvent such as methanol, is tonal, isopropyl alcohol, etc.; or AcOH; or a mixture of an alcoholic solvent or solvent on the basis of ester and water, and acetic acid

"Hydrogenation catalyst" means Pt/C, PtO2Pd/C, Pd(OH)2, Rh/C, etc., with or without the addition of inorganic acid, such as HCl, etc. or organic acids such as acetic acid, etc.,

The temperature of the hydrogenation reaction" means from about 10 to about 60°C.

"Pressure hydrogenation" means from about 10 to about 1000 pounds per square inch of hydrogen (the upper limit is dictated by technical equipment).

Specific embodiments of

In a specific embodiment of the method according to this invention superocean means the combination of n-utility and potassium tert-butyl (based shlosser").

In another specific embodiment of the method according to this invention the solvent for Borisovna" means THF.

In another specific embodiment of the method according to this invention the means forming Bronevoy acid" means triisopropylsilyl.

In another specific embodiment of the method according to this invention the temperature of Borisovna ranges from approximately -70°C to about -45°C.

In another specific embodiment, the procedure of this invention the solvent for a combination of Suzuki is dimethoxyethane.

In another specific embodiment of the method according to this invention, the catalyst combination Suzuki is a Pd(PPh3)4.

In another specific embodiment of the method according to this invention a combination of Suzuki is carried out at about 85°C.

In another specific embodiment of the method according to this invention the solvent for the hydrogenation represents EtOAc.

In another specific embodiment of the method according to this invention, the hydrogenation catalyst is a Pt/C.

In another specific embodiment of the method according to this invention the temperature of the hydrogenation reaction is equal to approximately ambient temperature.

In another specific embodiment of the method according to this invention the pressure of the hydrogenation is from about 10 to about 60 pounds per square inch.

The details of receiving

The source materials for producing the compounds I according to the following Scheme 1 is available.

Scheme 1

4-((tert-butoxycarbonyl)aminomethyl)-torbenson (compound 10), obtained according to the method Tetrahedron 2965, 57, 2001, which is incorporated into this document by reference, is introduced into reaction with superocean in the ether will dissolve the Le at a sufficiently low temperature, as for example, from about -100°C to about -30°C. the Resulting mixture is introduced into reaction with means forming Bronevoy acid. Quenching the resulting mixture of aqueous acid gives 5-((tert-butoxycarbonyl)aminomethyl)-2-ferbinteanu acid (compound 11). The connection 11 is introduced into the reaction with 4-halogenopyrimidines (compound 12) or hydrohalogenation salt form in an alcohol solvent with a boiling point at least as isopropyl alcohol, a polar aprotic solvent or ether solvent. Compound 11 and compound 12 in a mixture of any of the above solvents and water in the presence of an appropriate catalyst combination for Suzuki at the reaction temperature combinations Suzuki gives compound 13.

The connection 13 to restore the conditions of hydrogenation to compound I by treatment with hydrogen in the presence of a hydrogenation catalyst with or without added inorganic acid, such as HCl, etc. or organic acids such as acetic acid, etc. in a solvent for the hydrogenation reaction; when the temperature of the hydrogenation reaction and the pressure hydrogenation.

Example

The invention will become easier to understand with reference to the following non-limiting Example, which illustrates this is sabreena. The following example is presented to more fully illustrate particular implementation of the present invention. However, they in no way be construed as limiting the broad scope of this invention.

In the spectra of nuclear magnetic resonance (NMR), are reported below, the chemical shifts are expressed in parts per million (ppm) relative to tetramethylsilane was. Abbreviations have the following meanings: br = broad, dd = double doublet, s = singlet; m = multiplet.

EXAMPLE 1

Stage A: Obtain 5-((tert-butoxycarbonyl)aminomethyl)-2-ferbinteanu acid (11)

To a mixture of 4-((tert-butoxycarbonyl)aminomethyl)-fervently (Tetrahedron 2001, 57, page 2965, which is included in this document by reference) (2,84 g, 12.6 mmol) and t-BuOK (2.83 g, 12.6 mmol) in THF (40 ml) at -60 to -70°C add n-BuLi (of 15.75 ml of 1.6 M, 25,2 mmol) over a period of about 10 minutes, the Reaction mixture is then stirred at this temperature for additional 1.5 h, after which add triisopropylsilyl (2.37 g, 12.6 mmol). Mixture was allowed to warm to -45°C, after which it was quenched with 2 N. aqueous HCl. The reaction mixture was allowed to warm to room temperature with stirring over night. The resulting suspension allocate by filtration and dried in a vacuum oven to obtain 1.9 g (56%) of compound (11) in the form of b the logo solids.

1H NMR (300 MHz, CDCl3) δ 7,72 (m, 1H), 7,38 (m, 1H), 7,01 (m, 1H), 5,22 (d, J=6,1 Hz, 2H), 4,28 (d, J=5.4 Hz, 2H), 1,45 (s, 9H).

Stage B: Obtain tert-butyl ether complex (4-fluoro-3-pyridin-4-yl-benzyl)-carbamino acid (13)

A mixture of compound 11 (135 mg, 0.5 mmol), 4-glacialinterglacial (107 mg, 0,713 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol) and Na2CO3(160 mg and 1.51 mmol) in a mixture of dimethoxyethane (2.2 ml) and water (0.7 ml) was heated to 85°C for 5 hours the Mixture is cooled to rt and share between water and EtOAc. The organic phase is dried using Na2SO4and concentrated in a rotary evaporator to obtain 100 mg (59%) of compound 13.

1H NMR (300 MHz, CDCl3) δ 8,68-to 8.62 (m, 2H), 7,80-7,42 (m, 2H), 7,40-7,35 (m, 1H), was 7.36-7,24 (m, 1H), 7.18 in-was 7.08 (m, 1H), 5,26-5,18 (Shir. s, 1H), 4,25 (d, J=5.5 Hz, 2H), of 1.44 (s, 9H).

Stage C: Getting hydrochloride tert-butyl ether complex (4-fluoro-3-piperidine-4-yl-benzyl)-carbamino acid (I)

A mixture of compound 13 (1,25 g, 4.1 mmol) and PtO2(200 mg) in EtOAc (20 ml) and acetic acid (10 ml) hydrogenizing in a Parr shaker at H2(50 psi to 60 psi) overnight. To this mixture n-BuOAc (40 ml). The resulting suspension is filtered through brownmillerite and concentrated to approximately 30 ml of the crude solution. The crude solution Breslev a solution of 2 N. HCl in ethyl ether (5 ml) and MTBE (35 ml) at 0°C. the resulting solid is collected by filtration followed by washing with additional MTBE and dried in an oven at 50°C with getting 0,93 (65%) g of the product I in the form of HCl salt.

1H NMR (300 MHz, DMSO-d6) δ of 9.30-9,10 (Shir. s, 2H), 7,44-7,35 (m, 1H), 7,16-7,03 (m, 3H), 4,08 (d, J=6.0 Hz, 2H), 3,31 (Shir. s, 2H), 3,20-2,87 (m, 3H), 1,95-of 1.80 (m, 4H), of 1.39 (s, 9H).

1. The way to obtain 5-((tert-butoxycarbonyl)aminomethyl)-2-ferbinteanu acid, including Borisovna 4-((tert-butoxycarbonyl)aminomethyl)-fervently agent, forming Bronevoy acid, in terms of Borisovna and then quenching the resulting mixture of aqueous acid to yield 5-((tert-butoxycarbonyl)aminomethyl)-2-fluoro-benthivorous acid.

2. The method according to p. 1, where in terms of Borisovna use superocean.

3. The method according to p. 2, where superocean is a combination of organolithium reagent of the formula RLi, where R is an alkyl or aryl group having 1-12 carbon atoms, and the bulk of the potassium alkoxide such as potassium tert-butyl or potassium tert-pentoxide, etc.,

4. The method according to p. 3, where superocean is a combination of n-utility and potassium tert-butyl.

5. The method according to p. 1, where in terms of Borisovna use the tool, forming Bronevoy acid, which is a Tr alkylboronic.

6. The method according to p. 5, where trialkylborane choose from trimethylborane, triethylborane, Tripropylamine, triisopropylsilane, tributyrate etc.

7. The method according to p. 6, where trialkylborane is triisopropylsilyl.

8. The method according to p. 1, where in terms of Borisovna use solvent for Borisovna, which is a volatile solvent selected from diethyl ether, THF, 2-methyltetrahydrofuran, MTBE, dimethoxyethane etc.

9. The method according to p. 8, wherein the ether solvent is a THF.

10. The method according to p. 1, where in terms of Borisovna use a reaction temperature of Borisovna from about -100°C to about -30°C.

11. The method according to p. 10, where the reaction temperature of Borisovna ranges from approximately -70°C to about -45°C.

12. The method according to p. 1 wherein the aqueous acid is a HCl or H3PO4.

13. The method according to p. 12, where the aqueous acid is a HCl.

14. The way to obtain tert-butyl ether complex (4-fluoro-3-pyridin-4-yl-benzyl)-carbamino acid comprising a combination of 5-((tert-butoxycarbonyl)aminomethyl)-2-ferbinteanu acid on p. 1 and 4-halogenpoeten combining Suzuki with access tert-butyl ether complex (4-fluoro-3-pyridin-4-yl-benzyl)-carbamino acid.

15. The method according to p. 14, where the combination of Suzuki used the comfort solvent for combining Suzuki, selected from an alcoholic solvent with a boiling point at least as i-propyl alcohol, a polar aprotic solvent, or solvent type simple ether, or a mixture of any of the above solvents and water or toluene.

16. The method according to p. 15, where the solvent for a combination of Suzuki is a solvent - simple ether selected from THF, toluene, 2-methyl-THF or dimethoxyethane.

17. The method according to p. 16, where the ether solvent is dimethoxyethane.

18. The method according to p. 14, where the combination of Suzuki used catalyst Suzuki, selected from Pd catalyst such as Pd(PPh3)4Pd(PPh3)2Cl2Pd2(dba)3, PdCl2dppf, Pd(dtbpf)Cl2or similar; or Pd catalyst such as Pd(OAc)2Pd2(dba)3or, etc., in combination with a ligand, a phosphine, such as PPh3, dppf, t-Bu3P, P(Cy)3or similar, and a strong base.

19. The method according to p. 18, where the catalyst combination Suzuki is a Pd(PPh3)4.

20. The method according to p. 14, where the combination of Suzuki used the reaction temperature combinations Suzuki from approximately 60°C to about 100°C.

21. The method according to p. 20, where the reaction temperature combinations Suzuki is approximately 85°C.

22. The method according to p. 14, where 4-halogenerator is a 4-chlorine is pyridine.

23. The method of obtaining hydrochloride tert-butyl ether complex (4-fluoro-3-piperidine-4-yl-benzyl)-carbamino acid (I), including the restoration of the tert-butyl ether complex (4-fluoro-3-pyridin-4-yl-benzyl)-carbamino acid on p. 14 under conditions of reductive hydrogenation and then the processing of HCl with access hydrochloride tert-butyl ether complex (4-fluoro-3-piperidine-4-yl-benzyl)-carbamino acid.

24. The method according to p. 23, where the reductive hydrogenation using a hydrogenation catalyst selected from Pt/C, PtO2Pd/C, Pd(OH)2, Rh/C, etc., with or without the addition of inorganic acid, such as HCl, etc. or organic acids such as acetic acid, etc.,

25. The method according to p. 24, where the hydrogenation catalyst is a PtO2.

26. The method according to p. 23, where the reductive hydrogenation using solvent for hydrogenation is selected from a solvent on the basis of ester, such as EtOAc, i-PrOAc, BuOAc, etc.; an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, etc.; or AcOH; or a mixture of an alcoholic solvent or solvent on the basis of ester and water and acetic acid.

27. The method according to p. 26, where the solvent for the hydrogenation is an i-PrOAc.

28. The method according to p. 23, where the recovery hydrogenases and use the temperature of the hydrogenation reaction is from about 10°C to about 60°C.

29. The method according to p. 28, where the temperature of the hydrogenation reaction is equal to approximately ambient temperature.

30. The method according to p. 23, where the reductive hydrogenation using pressure hydrogenation of from about 10 to about 1000 pounds per square inch.

31. The method according to p. 30, where the pressure of the hydrogenation is from about 50 to about 60 pounds per square inch.



 

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26 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I , where R1 and R2 independently denote hydrogen, C3-C7cycloalkyl, C1-C6alkyl, C2-C6alkynyl, hydrogen or pyridine; or R1 and R2 together with a nitrogen atom which binds them form a pyrroline group; R3 denotes hydrogen, C1-C6halogenalkyl, C1-C6alkyl, halogen, cyano group, nitro group, C1-C4alkoxy group, phenyl, halogen-substituted phenyl, (R51)(R52)(R53)Si-(C2-C6alkynyl)-, where R51, R52, R53 independently denote halogen, cyano group, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C2-C6alkynyl, C1-C6alkoxy group, benzyl or phenyl; R4 denotes hydrogen, halogen, phenyl, imidazolyl, amino group, C1-C6alkoxy group or C1-C6alkyl; R5 denotes C1-C12alkyl or a group A, where A denotes a 3-10-member monocyclic or condensed bicyclic ring system which can be aromatic, partially unsaturated or completely saturated, where said 3-10-member ring system can be mono- or polysubstituted with substitutes independently selected from a group comprising halogen, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy group and C1-C6alkylthio group; R6 denotes hydrogen; and R7 denotes hydrogen or C1-C6alkyl and agronomically acceptable salts/metal complexes/metalloid complexes/isomers/structural isomers/stereoisomers. The invention also relates to methods of controlling infection of useful plants by phytopathogenic microorganisms by applying a compound of formula I onto the plants, a part thereof or place where said plants grow, as well as a composition for controlling infection by phytopathogenic microorganisms.

EFFECT: novel compounds which are suitable for use as microbiocides are obtained and described.

7 cl, 48 ex, 151 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an compound of general formula

(1). In general formula (1), each of R1-R14 is independently selected from a hydrogen atom, an alkyl group with 1-4 carbon atoms, a diphenylamino, a phenyl group, a biphenyl group, a terphenyl group, a fluoranthenyl group, a naphthyl group and a pyridinyl group; wherein the diphenylamino group can have an alkyl group as a substitute; and wherein the phenyl group, the biphenyl group, the terphenyl group, the fluoranthenyl group and the naphthyl group can have an alkyl and an aryl group as a substitute. The invention also relates to an organic light-emitting device, a display device, an image-forming device and an illumination device using said organic compound.

EFFECT: compounds are suitable for emitting blue light and enable to obtain light-emitting devices with good radiation characteristics.

8 cl, 6 tbl, 33 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a borane complex of formula in which R1 and R2 independently denote C1-C8-alkyl, C1-C8-alkoxy group or halogen under the condition that R1 and R2 do not denote methyl at the same time when R2 is in position 4 or 6 of the pyridine ring. The invention also discloses a solution for use in organic reactions, a method of producing the borane complex and use thereof.

EFFECT: invention enables to obtain borane complexes having improved stability and reactivity.

12 cl, 1 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclic compounds with the following general formula I or II and to pharmaceutically acceptable salts thereof and to all stereo isomers and optical isomers thereof:

, , where n equals 1, X and Y are NH; R1 and R2 independently represent one substitute selected from a group consisting of aryl; 2-, 3-, or 4-pyridyl; aryl substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio; R3 and R4 independently represent one substitute selected from a group consisting of aryl; 2-, 3- or 4-pyridyl; aryl substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio; 2-, 3- or 4-pyridyl, substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio. The invention also relates to a method of producing a range of substituted cyclic compounds and their salts in any of subclaims 1-4, to a pharmaceutical composition, to use, to a method of treating and preventing diseases as well as to an assembly.

EFFECT: obtaining new biologically active compounds suitable for treating or preventing diseases or symptoms, arising from or accompanied with violation of secretion and/or function of insulin.

13 cl, 4 ex, 3 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I), in which Ar represents group of formula (A), (B1), (B2) or (C), or (D1), or (D2); R1, R2, R3, R4, R5, n, A1, A2, A3, A4, A5, Ka, Kb, L, M, V, W, X, Y, Z havevalues, determined in i.1 of invention formula, fungicide composition and method of combatting phytopathogenic fungi or their elimination, using compounds of formula (I).

EFFECT: high fungicide activity.

22 cl, 142 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: method of obtaining 2-(2-methylaminoethyl)pyridine (I) by interaction of 2-vinylpyridine with methylamine hydrochloride in water medium, carrying out washing extraction of reaction mixture with organic solvent with pH 7.0-8.5 and product extraction with pH 10.0-11.5, with further conversion of base into salts.

EFFECT: possibility to obtain said compositions with high pharmacopeia purity of 99,95% ("ВЭЖХ") and elimination of vacuum-distillation.

1 cl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexane of the formula (I): wherein U means a free electron pair; V means a simple bond, -CH2-, -CH=CH-, -CH=CH-CH2-O-, -C≡C-; W means -COO, -CSO or -SO2; m and n mean independently of one another numbers from 0 to 4; m + n = 0-7; A1 means hydrogen atom (H), lower alkyl, hydroxy-(lower)-alkyl or lower alkenyl; A2 means pyrrolyl, pyrimidinyl, optionally substituted (lower)-alkyl or lower alkyl optionally substituted with R2; or A1 and A2 are bound to form ring; -A1-A2- means lower alkylene optionally substituted with R2 wherein one group -CH2- in -A1-A2- can be optionally replaced for -NR3 or oxygen atom (O); A3, A4, A5, A6, A7 and A8 mean H; R9 means H, lower alkyl; R10 means (lower)-alkyl, phenyl wherein phenyl can be substituted with 1-3 substitutes chosen independently from the group comprising halogen atom, -CF3, (lower)-alkyl; p means 0, 1; R2 means H; R3 means H, lower alkyl, and their pharmaceutically acceptable salts. Compounds of the formula (I) possess the inhibitory effect on activity of enzyme oxidosqualene lanosterol cyclase and can be used in pharmaceutical composition. Also, method relates to a method for treatment and/or prophylaxis of hyperlipemia, artheriosclerosis, hypercholesterolemia and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 9 sch, 10 tbl, 43 ex

The invention relates to N-substituted aminotetralin formula 1

< / BR>
where R1independently selected from the group consisting of hydrogen; hydroxy; halogen; C1-8-alkoxy; substituted C1-8-alkoxy, where the Deputy is a halogen; n is 0-2; Y is methylene; m is 0-3;1means hydrogen;2means hydrogen; R2selected from the group consisting of hydrogen; hydroxy; C1-6-alkyl, C1-6-alkenyl; phenyl; substituted phenyl where the Deputy is chosen from halogen, C1-6-alkyl, C1-6-alkoxy, trifter-C1-6-alkyl, nitro; naphthyl and pyridyl; L is chosen from the group consisting of C1-8-alkylene; C1-4-alkylen-C3-7-cycloalkyl-C1-4-alkylene; C1-4-alkylen-aryl-C1-4-alkylene; R3selected from phenyl; substituted phenyl where the Deputy is chosen from halogen, nitro, C1-8-alkoxy, trifloromethyl and amino-C1-8-alkyl; naphthyl; and tanila and their enantiomers, diastereoisomers and pharmaceutically acceptable salts

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted tetracyclic derivatives of tetrahydropyran, pyrrolidine and tetrahydrothiophene of general formula (I), their pharmaceutically acceptable addition salts, their stereochemically isomeric forms, their N-oxide forms, in which all substitutes are defined in claim 1 of the formula of invention. These compounds have binding affinity to serotonin receptors, particularly 5-HT2A and 5-HT2C receptors, and to dopamine receptors particularly D2 dopamine receptors, and have norepiniphrine reuptake inhibition properties. The invention also relates to a pharmaceutical composition containing said compounds, method of preparing said composition and use of said compounds as medicinal agents, particularly for preventing and/or treating several psychiatric and neurological disorders.

EFFECT: new compounds have useful biological properties.

12 cl, 3 tbl, 49 ex

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