Method for preparing heterocyclic compounds

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

 

This invention relates to a new method of obtaining well-known heterocyclic compounds.

A method of obtaining unsaturated heterocyclic compounds by alkylation of atoms unsubstituted cyclic compounds which may be including in alcohol (European patent application EP-A-259 738).

Also known alkylation reaction in an aprotic solvents (European patent application EP-A-259 738).

In these cases, in order to achieve sufficient purity required follow-up product, in addition, achieved in the known processes the outputs of the target product are unsatisfactory.

It was found that the compounds of formula (I)

in which

R1represents a hydrogen atom or alkyl group

And represents an ethylene group which may be substituted by alkyl, or trimethylene group which may be substituted by alkyl,

D represents a nitro or cyano group, X represents an oxygen atom or sulfur, or a group

in whichor

R3represents a hydrogen atom or alkyl group, and

Z represents an optionally substituted 5 - or 6-membered heterocyclic group that contains, p is at least two heteroatoms selected from oxygen atoms, sulfur and nitrogen, or optionally substituted 3-or 4-pyridyloxy group,

produced by interaction of the compounds of the formula (II)

in which

A, D and X have the above values,

with base in the presence of a diluent, followed by the interaction of the reaction mixture with a mixture of HHMP/HMP (2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridin) with corresponding hydrochloride.

In accordance with the invention unexpectedly found that the above compounds can be produced simpler with a smaller number of stages in the manner and with the best output.

In the General formulas (I) and (II) the radicals have the following meanings:

R1preferably means hydrogen or alkyl with 1-3 carbon atoms, particularly preferably hydrogen;

And means preferably ethylene or trimethylene group, which respectively may be substituted by alkyl groups with 1-3 carbon atoms, particularly preferably ethylene group;

D signifies nitro or cyano,

X preferably denotes an atom of oxygen or sulfur or a group

particularly preferably an oxygen atom or a group

Z preferably means halogenerator the 5 - or 6-membered heterocyclic group, which contains two heteroatoms selected from the group of oxygen, sulfur and nitrogen, or halogenated 3 - or 4-pyridyl, particularly preferably halogenated triazole or 3-pyridyl, very particularly preferably 2-chloro-pyrid-5-yl.

Especially preferred compound of formula (I) is a compound of formula (Ia)

obtained by the interaction of the compounds of formula (IIa)

with base in the presence of a diluent, followed by the interaction of the reaction mixture with a mixture of HHMP/HMP with relevant hydrochloride.

The most preferred compound of formula (I) is a compound of formula (Ib)

obtained by the interaction of the compounds of formula (IIb)

with base in the presence of a diluent, followed by the interaction of the reaction mixture with a mixture of HHMP/HMP with relevant hydrochloride.

The solvent can be used proton and dipolar-aprotic solvents, in particular water, alcohols, ketones (mainly MILK - isobutyl ketone), esters (mainly butyl ester of acetic acid), NITRILES (mainly acetonitrile, n-propionitrile, butyronitrile), pyridine (mainly he), the ministries of foreign Affairs (DMF) - dimethylformamide), DMSO (dimethyl sulfoxide) or carbonates or mixtures thereof with water. When using alcohols as solvents it is possible to obtain the compounds of formula (I) advantageous modifications and the required purity, directly used as plant protection products.

Examples of alcohols used are:

primary alcohols, such as methanol, ethanol, propanol, butanol, 2-methyl-1-propanol, 1-pentanol, benzyl alcohol;

secondary alcohols such as isopropanol, sec.-butanol, 2-pentanol, tertiary alcohols such as tert.-butanol.

As particularly preferred solvents not miscible with water or only partially miscible with water, alcohols, such as n-butanol, amyl alcohol, in particular, n-butanol, or NITRILES, such as n-propionitrile or butyronitrile, in particular n-propionitrile.

The process is carried out optionally in the presence of a base. As examples include: alkali and alkaline-earth hydroxides, such as NaOH, KOH, CA(Oh)2, carbonates or bicarbonates of alkali metals such as Na2CO3,Li2CO3, K2CO3Cs2CO3or NaHCO3and knso3. Preferred referred To2CO3, NaOH, knso3in particular2CO3.

Compounds of General formula (II) may use the I in the form of alkaline or alkaline-earth salts in solid or dissolved form.

When carrying out the process in an aqueous, aqueous-alcoholic or aqueous-nitrile mixtures the process is carried out at a pH between 6 and 13.

As catalysts may be used phase transfer catalysts, if necessary, Quaternary ammonium halides, such as tetrabutylammonium or chloride, or Cs salts and so on.

When using compounds of General formula (II) optionally in the form of alkaline or alkaline-earth salts of the reaction can be conducted by heating in the presence of a base at a temperature of from 40°to 130°C, optionally under vacuum, mainly at from 100 to 500 mbar, and then adding the mixture HHMP/he at from 50 to 90°C, optionally under vacuum, mostly in the 60°C to 80°C.

The reaction is expediently carried out at atmospheric pressure, however, you can also work at reduced or increased pressure. Particularly preferably carrying out the process in a vacuum.

In the practical carrying out of the process, for example, 1 mol of a mixture of HHMP/HMP subjected to interaction with a 0.95-3 moles of the compounds of formula (II), mainly from 1.0 to 2.5 moles, in a solvent such as butanol, in the presence of from 1 to 3 moles, mostly from 1.5 to 2.5 moles, of a base, for example potassium carbonate, and optionally in the presence of a catalyst, such as tetrabutyl dibromide or cesium carbonate.

When using water in a two-phase system, the process is carried out predominantly at pH 8-10.

The reaction time is 3 to 12 hours, preferably from 5 to 10 hours. After completion of the reaction can be performed if necessary, a change of solvent. When this is distilled a large part of the diluent of the reaction in vacuum (1-1000 mbar) and complement a number of one of the above diluents. Replacement of the solvent can occur before or after hydrolysis.

The reaction suspension hydrolyzing at a temperature of from 50°to 100°and separating the organic phase with 50°S-80°C. Then cooled, separate the precipitated active agent, washed and recrystallized.

Located in the uterine alkaline solution HMP (temperature range from 50°to 130°C, pressure of 1-1000 mbar) can be re-extracted and returned back to the process: in the resulting alkaline mother liquor add the solvent of crystallization (1 part alkaline mother liquor / 4 parts of solvent to 1 part alkaline mother liquor / 0.5 parts of solvent), the suspension is cooled and the precipitated active substance is filtered off.

The initial compounds of the formula (II) are known and/or can be obtained in a known manner (see JACS 79, (1957), 3565; Arch. Pharm. 305, (1972). 731-736; Heterocycles 31 (1990), 1601-1604; Biosci. Biotechnol. Biochem. 57, (1993). 127-128; Biosci. Biotechnol. Biochem. 56, (1992) 364-365).

2-Chloro-5-chloromethylpyridine can be obtained in the same manner as the process (European patent application EP-A-458109, EP-A-260485). 2-Chloro-5-methylpyridin glorious at boiling organic solvent (acetonitrile, carbon tetrachloride, water with controlled pH) with a radical initiator (AIBN - azobis-isobutyronitrile). In order to obtain a high selectivity for 2-chloro-5-chloromethylpyridine, the reaction stops at about 40%of the first currency. Then the organic solvent is distilled off in vacuum.

The mixture HHMP/CHMP after distillation of the solvent contains 5-15% residual solvent, 30-50% HMP and 25-45% HHMP with relevant hydrochloride.

This mixture of 2-chloro-5-methylpyridine and 2-chloro-5-chloromethylpyridine and related hydrochloride enter into reaction with the active substance. This mixture can be used undiluted or in a diluent in which it is also advisable to carry out the reaction of the active substance.

The compounds of formula (I) are suitable, for example, for use as insecticides (European patent application EP A2 0235752, EP A2 0259738).

The following examples illustrate the subject matter of the invention without any restrictions.

Example 1

of 0.615 mol of potassium carbonate and 0.3 mole of 2-linkintegrity suspended in 100 ml of n-butanol and stirred for 1 hour at 60°C. In ECENA 2 hours at 70° To add 0,315 mole of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine (HHMP/HMP, 23% HHMP in the mixture), suspended in 100 ml of n-butanol, and stirred for 2 hours at 72°C. After cooling to 65°add 400 g of water and the phases are separated. Then the organic phase is stirred for 3 hours at 50°and then 18 hours at -5°C. the Precipitated product is filtered and dried; to 59.6 g (78% of theory).

Example 2

of 0.615 mol of potassium carbonate and 0.3 mole of 2-linkintegrity suspended in 100 ml of n-butanol and stirred for 1 hour at 60°C. for 2 hours at 70°add 0,315 mole of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine (HHMP/HMP, 23% HHMP in the mixture), suspended in 100 ml of n-butanol, and stirred for 2 hours at 72°C. After cooling to 65°add 400 g water and the phases are separated. Then the organic phase is stirred for 3 hours at 50°and then 18 hours at -5°C. the Precipitated product is filtered and dried. The alkaline mother liquor is treated with butanol in the ratio of 1:1 and cooled to 0°With falling solid is filtered off and dried. Total yield: 66,1 g (85% of the selected product).

Example 3

of 0.3 mole of 2-linkintegrity and 4.2 g of tetrabutylammonium bromide are suspended in 300 ml of water and heated to 70°C. Add 0,315 mole mixture HMP/HHMP. Using NaOH continuously maintain the pH value of the reaction mixture from 8 to 8. After 2 hours of interaction at 60°To carry out the separation of phases and the organic phase is diluted with 150 ml of butanol and stirred. For 3 hours, cooled to 3°and the precipitated product is sucked off; will receive 58.5 g (76% of theory).

Example 4

a 1.5 mol ethylnitrosourea (content of N2O 16,5%) is dissolved in 600 g of n-propionitrile and distilled water azeotrope. Then at 95°add 342 g of potassium carbonate (2,5 mol). Then served 2 g of cesium carbonate. Within 30 minutes add 521 g HMP/HHMP (31% HHN) at 95-100°C. After 5 hours reaction at 100-105°add 1.2 litres of water. Using HCI maintain the pH of the reaction mixture between 6 and 7. From the organic phase is distilled off propionitrile at 180 mbar. Then add 500 g of n-butanol, heated to 80°and separate phases. The organic phase is cooled to 0°C. the Precipitated product is filtered and dried; 187,4 g (73% of theory).

1. The method of obtaining compounds of formula (I)

in which

R1represents a hydrogen atom,

And represents an ethylene group which may be substituted by alkyl, or trimethylene group which may be substituted by alkyl,

D represents nitro or cyano,

X represents an oxygen atom or sulfur, or a group

or

in which

R3represents a hydrogen atom or alkyl group, and

Z represents a 2-chloropyrid-5-yl,

characterized in that the compound of formula (II)

in which

A, D and X have the above values,

subjected to interaction with base in the presence of a diluent, followed by the interaction of the reaction mixture with a mixture of HHMP/HMP (2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridin) with corresponding hydrochloride.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes new substituted derivatives of pyrazole of the general formula (I): wherein n = 0 or 1; group A represents independently hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms or phenyl group having substituting groups optionally; group D represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkoxy-group with 1-4 carbon atoms, cycloalkyl group with 3-6 carbon atoms, halogen atom, alkoxycarbonyl group with 1-4 carbon atoms, alkylsulfonyl group with 1-4 carbon atoms or phenyl group; group E represents hydrogen atom, halogen atom or phenyl group; groups R1 and R2 both represent halogen atom; group R3 represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms or benzyl group; groups R4 and R5 are similar or different and each represents hydrogen atom, alkyl group with 1-4 carbon atoms, halogenalkyl group with 1-4 carbon atoms, cycloalkyl group with 3-8 carbon atoms that can be substituted with alkyl group with 1-4 carbon atoms, alkenyl group with 2-4 carbon atoms, alkynyl group with 2-4 carbon atoms, cyanomethyl group or phenyl group; or each R4 and R5 group means benzyl group; or each R4 and R5 group represents α- or β-phenethyl group having substituting groups at benzyl ring optionally. Indicated substituting groups represent alkoxy-groups with 1-4 carbon atoms wherein indicated substituting groups substitute hydrogen atom at the arbitrary positions 0-2 of the benzyl ring; or groups R4 and R5 form in common 5-membered or 6-membered aliphatic ring wherein the indicated ring can be substituted with alkyl groups with 1-4 carbon atoms and indicated ring can comprise one or two heteroatoms chosen from nitrogen oxygen and sulfur atom, and a method for their preparing. Also, invention describes herbicide compositions based on compound of the formula (I). Invention provides preparing herbicide compositions showing the strong herbicide effect and broad herbicide spectrum of their effect.

EFFECT: improved preparing method, valuable properties of derivatives and compositions.

7 cl, 6 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

7 cl, 47 ex

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