Selenazole derivative, having ligand activating peroxisome proliferator-activated receptor (ppar), method for production thereof and use of chemical compounds

FIELD: chemistry.

SUBSTANCE: compound has formula I: |Chemical formula 1| where A is O, NR, S, S(=O), S(=O)2 or Sc; B is hydrogen or ; R1 is hydrogen, C1-C8 alkyl or halogen; R2 is hydrogen, C1-C8 alkyl, or ; Xa and Xb is independently CR or N; R is hydrogen or C1-C8 alkyl; R3 is hydrogen, C1-C8 alkyl; R4 and R5 are independently hydrogen, halogen or C1-C8 alkyl; R6, is hydrogen. C1-C8 alkyl, or a pharmaceutically acceptable organic salt; R21, R22 and R23 are independently hydrogen, halogen, NO2, C1-C7 alkyl, unsubstituted or substituted with halogen, C3-C12 heteroaryl, containing one or more heteroatoms selected from N, O and S; m equals an integer from 1 to 4; p equals an integer from 1 to 5; s equals an integer from 1 to 5; u equals an integer from 1 to 3; w equals an integer from 1 to 4; and alkyl in R1, R3, R4, R5 and R6 can further be substituted with one or more halogens, C3-C7 cycloalkyl or C1-C5 alkylamine. Also disclosed are methods of producing selenazole derivatives, a pharmaceutical composition, a functional feed additive composition, a functional beverage, a food additive, animal feed, a functional cosmetic composition, a peroxisome proliferator-activated receptor (PPAR) activator composition.

EFFECT: invention enables to obtain a selenazole derivative which activates a peroxisome proliferator-activated receptor.

15 cl, 1 dwg, 6 tbl, 298 ex

 

The technical field

The present invention relates to a derivative of selenate connection represented by the chemical formula I used as a ligand that activates the receptor-activated proliferation peroxisome (PPAR), which can be used for the treatment of obesity, hyperlipemia, fatty infiltration of the liver, atherosclerosis and diabetes, hydrate, MES, stereoisomer, and a pharmaceutically acceptable salts, and pharmaceutical compositions, cosmetic compositions, functional food composition, composition, functional beverage and feed composition for animals containing specified connection:

[Chemical formula I]

The level of technology

Receptors activated proliferation peroxisome (PPAR)are nuclear receptors. Identified three subtypes: PPARα, PPARγ and PPARδ (Nature, 1990, 347, p. 645-650, Proc. Natl. Acad. Sci. USA 1994, 91, p. 7335-7359). PPARα, PPARγ and PPARδ have different functions and expressed in various tissues. PPARα is mainly expressed in heart, kidney, skeletal muscle and tissues of the large intestine of man (Mol. Pharmacol. 1998, 53, p. 14-22, Toxicol. Lett. 1999, 110, p. 119-127, J. Biol. Chem. 1998, 273, p. 16710-16714) and is involved in β-oxidation peroxisome and mitochondria (Biol. Cell. 1993, 77, p. 67-76 (in Russian), J. Biol. Chem. 1997, 272, p. 27307-27312). PPARγ is weakly expressed in the tissues of skeletal muscles, but is expressed mainly in adipose tissue. As you know, involved in the differentiation of fat cells, energy storage in the form of fat and regulation of homeostasis insulin and glucose (Moll. Cell. 1999, 4, p. 585-594, p. 597-609, p. 611-617). PPARδ evolutionary stored in mammals, including humans, rodents, and ascidians. He was identified as PPARβ inXenopus laevis(Cell 1992, 68, p. 879-887) and in humans as NUCI (Mol. Endocrinol. 1992, 6, p. 1634-1641), PPARδ (Proc. Natl. Acad. Sci. USA 1994, 91, p. 7355-7359), NUCI (Biochem. Biophys. Res. Commun. 1993, 196, p. 671-677) or FAAR (J. Bio. Chem. 1995, 270, p. 2367-2371). Recently he received a unified name - PPARδ. In humans, PPARδ, as it is known, is present on chromosome 6p21,1-p21,2. In mice, PPARδ mRNA was detected in various areas, but in smaller numbers than mRNA PPARα or PPARγ (Endocrinology 1996, 137, p. 354-366, J. Bio. Chem. 1995, 270, p. 2367-2371, Endocrinology 1996, 137, p. 354-366). According to research conducted to date, PPARδ plays a very important role in the expression of genes (Genes Dev. 1999, 13, p. 1561-1574). In addition, it is known to be involved in the differentiation of nerve cells in the Central nervous system (CNS) (J. Chem. Neuroanat. 2000, 19, p. 225-232), the healing of wounds through anti-inflammatory action (Genes Dev. 2001, 15, p. 3263-3277, Proc. Natl. Acad. Sci. USA 2003, 100, p. 6295-6296) or the like. Recent research has shown that PPARδ is involved in the differentiation of fat cells and the metabolism of fat cells (Proc. Natl. Acad. Sci. USA 2002, 99, p. 303-308, Mol. Cell. Biol. 2000, 20, p. 5119-5128). Was the OBN is hidden, what activates PPARδ expression of critical genes associated with β-oxidation and cleavage of proteins (UCP)related to energy metabolism, the breakdown of fatty acids, and thus improves the condition of obesity and increases stamina (Nature 2000, 406, p. 415-418, Cell 2003, 113, p. 159-170, PLoS Biology 2004, 2, e294, Cell, 2008, 134, 405415). In addition, activation of PPARδ makes it possible to increase the level of HDL (high density lipoprotein) and improve the condition of diabetes mellitus type 2 without changes in body weight (Proc. Natl. Acad. Sci. USA 2001, 98, p. 5306-5311, 2003, 100, p. 15924-15929, 2006, 103, p. 3444-3449) and contributes to the treatment of atherosclerosis, by inhibiting associated with atherosclerosis genes (Science, 2003, 302, p. 453-457, PNAS, 2008, 105, 42714276). Accordingly, the regulation of fat metabolism through PPARδ provides an important tool for the treatment of obesity, diabetes, hyperlipemia and atherosclerosis.

Description

Technical task

The present invention is to obtain a new compound that selectively activates PPARδ. Another objective of the present invention to provide pharmaceutical compositions, cosmetic compositions, functional food composition, composition, functional beverage and feed composition for animals containing the new connection in accordance with the present invention.

The solution of the technical problem

Present from retina refers to the connection - derived selenate represented by chemical formula I, which activates the receptor-activated proliferation peroxisome (PPAR), MES, stereoisomer and its pharmaceutically acceptable salts, process for the preparation of the compounds, and to pharmaceutical compositions, cosmetic compositions, functional food composition, composition, functional beverage and feed composition for animals containing specified connection:

[Chemical formula I]

where A represents O, NR, S, S(=O), S(=O)2or Se; B represents hydrogen or; R1represents hydrogen, C1-C8 alkyl or halogen; R2represents hydrogen, C1-C8 alkyl,or; Xaand Xbindependently represent CR or N; R represents hydrogen or C1-C8 alkyl; R3represents hydrogen, C1-C8 alkyl or halogen; R4and R5independently represent hydrogen, halogen or C1-C8 alkyl; R6represents hydrogen, halogen, C1-C8 alkyl, C2-C7 alkenyl, allyl, alkali metal, alkaline earth metal or pharmaceutically acceptable organic salt; R21, R22and R23independently represent hydrogen, halogen, CN, NO2, C1-C7 alkyl, C6-C12 aryl, C3-C2 heteroaryl, containing one or more heteroatom(s)selected from N, O and S, 5-7-membered heteroseksualci or C1-C7 alkoxy; m is an integer from 1 to 4; p is an integer from 1 to 5; s is an integer from 1 to 5; u is an integer from 1 to 3; w is an integer from 1 to 4; and alkyl and alkoxy in R1, R3, R4, R5, R6, R21, R22and R23may be optionally substituted by one or more halogen, C3-C7-cycloalkyl or C1-C5-alkylamino.

Especially preferred derivatives of selenate, activating PPAR represented by the chemical formula I is derived, in which: R1represents hydrogen, C1-C5 alkyl substituted by one or more fluorine, or fluorine; R2represents hydrogen, C1-C8 alkyl,or; Xaand Xbindependently represent CR or N; R represents hydrogen or C1-C8 alkyl; R3represents hydrogen, C1-C5 alkyl, substituted or unsubstituted by halogen, or halogen; R4and R5independently represent hydrogen, C1-C5 alkyl, substituted or unsubstituted by halogen; R6represents hydrogen, C1-C8 alkyl, halogen, allyl, C2-C7 alkenyl, pharmaceutically acceptable organic salt, alkali metal and alkaline-earth metal; and R21, R22and R23independently represent hydrogen, halogen, CN, NO2, C1-C7 alkyl, substituted or unsubstituted by halogen, C6-C12 aryl, C3-C12 heteroaryl containing one or more heteroatom(s)selected from N, O and S, 5-7-membered heteroseksualci or C1-C5 alkoxy, substituted or unsubstituted by halogen.

In chemical formula I, R1can represent hydrogen, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foretel, pentafluoroethyl, fluorine, bromine, iodine or chlorine; R2can represent hydrogen or substituted or unsubstituted benzyl, phenylbenzyl or pyridylmethyl, where phenyl, pyridyl or benzyl, R2may be optionally substituted by fluorine, chlorine, stands, ethyl, n-propylene, ISO-propylene, tert-bootrom, formation, deformation, trifluoromethyl, 2-foretel, pentafluoroethyl, methoxy, ethoxy, propyloxy, n-butoxy, tert-butoxy, formatosi, deformedarse, triptoreline, 2-floratone, pentaborate, CN, NO2, C6-C12-aryl or C3-C12-heteroaryl containing one or more heteroatom(s)selected from N, O and S; R3can represent hydrogen, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foretel, pentafluoroethyl, fluorine, chlorine;R 4and R5can independently represent hydrogen, halogen, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foradil or pentafluoroethyl; and R6can represent hydrogen, methyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foretel, pentafluoroethyl, allyl, ethynyl, 2-propenyl, 2-butenyl, 3-butenyl, pharmaceutically acceptable organic salt, Li+, Na+, K+Ca2+or Mg2+.

The new compounds of the present invention can be obtained by the methods provided in schemes 1-5. In figure 1, A represents O, NR, S, or Se. In scheme 2, And represents NR. In figure 3, And represents O.

[Diagram 1]

[Scheme 2]

[Scheme 3]

In schemes 1-3, A represents O, NR, S, or Se; R1, R2, R3, m, p and s are as defined in chemical formula I; R6arepresents a C1-C8 alkyl or allyl; R6brepresents hydrogen, alkali metal (Li+, Na+, K+), alkaline-earth metal (Ca2+, Mg2+or pharmaceutically acceptable organic salt; Prot represents a protective group pheno is a, selected from C1-C4 alkyl, allyl, alkylsilane, allylanisole or tetrahydropyranyl; X1represents a bromine or iodine; X2and X3independently represent chlorine, bromine, iodine or other discardable group suitable for nucleophilic substitution.

Compounds of chemical formula III-A, III-B and III-C can be obtained in accordance with scheme 4.

[Schema]

In scheme 4, R1, R2and p are as defined in chemical formula I; R31represents a C1-C4 alkylsulfonyl or C6-C12 arylsulfonyl, substituted or unsubstituted C1-C4-alkyl; R101represents a C1-C4 alkyl; and X2represents chlorine, bromine, iodine or other discardable group suitable for nucleophilic substitution.

[Map 5]

Next, the method of obtaining, in accordance with the present invention are described in more detail.

[Phase A] Obtain compounds represented by the chemical formula (IV-A)

To obtain compounds represented by the chemical formula (IV-A), the phenolic group of compounds represented by the chemical formula (II), input a security group using the Grignard reagent without separation process. Then, the compound obtained is subjected to interaction with ORGANOMETALLIC R the agent and sulfur (S) or selenium (Se), and then with the compound represented by chemical formula (III-A). This stage includes chetyrehskatnye interactions that are executed immediately.

Detailed description presented below.

[Protection of the phenolic group with Grignard reagent]

As anhydrous solvent used diethyl ether, tetrahydrofuran, hexane, heptane or a mixture of two or more of these substances. Of them diethyl ether, tetrahydrofuran or a mixed solvent consisting of diethyl ether and tetrahydrofuran are preferred. Especially preferred is a polar solvent. Most preferred is tetrahydrofuran.

The Grignard reagent may be chloride Metalmania, chloride of etermine, chloride n-Propylamine, chloride Isopropylamine, chloride n-butylamine, chloride Deut-butylamine or bromide alkaline. Of these the most preferred is the chloride Isopropylamine ((CH3)2CHMgCl).

The reaction temperature may vary depending on the solvent. Usually the reaction is carried out at a temperature in the range from -20 to 40ºC, preferably, at temperatures ranging from 0ºC to room temperature (25ºC). The reaction time may vary depending on the reaction temperature and solvent used. Usually the reaction is performed for 10-60 minutes, predpochtitelno for 10-30 minutes.

[Halogen-lithium substitution and the introduction of sulfur (S) or selenium (Se)]

When the halogen-lithium substitution can be used ORGANOMETALLIC reagent, such as n-utility, second-utility, tert-utility and so on. Of these, tert-utility is preferred.

Preferably, sulfur (S) or selenium (Se) is presented in the form of a fine powder and added directly or in the form of a solution in anhydrous tetrahydrofuran.

The reaction temperature may vary depending on the solvent. Typically, the interaction is carried out at a temperature of from -78 to 25 ºC. Preferably, the halogen-metal substitution is carried out at-75ºC, and the introduction of sulfur (S) or selenium (Se) begin at a temperature of 75ºC and performed at room temperature (25ºC). Halogen-metal substitution is carried out for from 10 to 30 minutes, and the introduction of sulfur (S) or selenium (Se) is carried out for from 30 to 120 minutes.

[Add compounds represented by the chemical formula (III-A)]

The connection represented by the chemical formula (III)are synthesized through stages H and K. the Halogen in the compounds represented by the chemical formula (III-A), can be chlorine, bromine or iodine. Of these, chlorine is preferred.

The reaction temperature may vary depending on the solvent. Usually, the reaction is carried out in which the temperature from -78 to 25 ° C, preferably, at a temperature of from 0 to 10ºC. The reaction time is usually from 10 to 120 minutes, preferably from 10 to 60 minutes.

[Phase B] Obtain compounds represented by the chemical formula (V-A)

To obtain compounds represented by the chemical formula (V-A), the compound represented by the chemical formula (IV-A)may be subjected to interaction with the connection normally used for introducing a protective group of the phenol in the presence of a base.

The protective group of the phenol can be C1-C4 alkyl, allyl, alkylsilane, such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and so forth, alkylaryl, tetrahydropyranyl or the like. Of these, tert-butyl, tetrahydropyranyl and sill are preferred.

At this stage, can be used aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane or the like. Can also be used a simple ether, such as tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether of diethylene glycol, dimethyl ether of triethylene glycol, or the like. Can also be used aromatic hydrocarbons such as benzene, toluene, xylene or the like. Of them, up the otonic polar solvent is preferred. Most preferred are N,N-dimethylformamide, chloroform, and dichloromethane.

May be base on the basis of an amine, such as pyridine, triethylamine, imidazole, N,N-dimethylaminopyridine or the like. The reaction of formation of alkyl or allyl ether protective groups are using as the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or the like. Of these, imidazole and potassium carbonate are preferred.

Tetrahydropyranyl protective group is produced by the interaction of 3,4-dihydro-2H-Piran with alkyl or allyl-triphenylphosphorane in the presence of a catalyst.

The reaction temperature may vary depending on the solvent. Usually, the reaction is carried out at a temperature of from -10 to 80ºC, preferably at a temperature from 0ºC to room temperature (25ºC). The reaction time may vary depending on the reaction temperature and solvent used. Usually, the reaction is carried out for from 1 hour to 1 day, preferably for at least 4 hours or less.

[Stage C] Obtain compounds represented by the chemical formula (V-B)

The connection represented by the chemical formula (V-B), obtained by processing of the α-proton thio - or selenoamino compounds represented by chemical formula the (V-A), with a strong base to obtain the nucleophile, and further interaction with various electrophiles.

At this stage, as anhydrous solvent used diethyl ether, tetrahydrofuran, hexane, heptane or a mixture of two or more of them. Of these, diethyl ether, tetrahydrofuran or a mixture of solvents diethyl ether and tetrahydrofuran are preferred.

For the extraction of α-proton can be used in a strong base such as tert-piperonyl potassium (tert-BuOK), diisopropylamide lithium (LDA), n-utility, second-utility, tert-utility or the like. Of them, LDA is the most preferred.

The electrophile, which interacts with the nucleophile may be a known compound, which is readily available or can be easily obtained in accordance with the known method. It may contain a highly reactive group of halogen, aldehyde or ketone, and it was added directly or dissolved in an anhydrous solvent.

The reaction temperature may vary depending on the solvent. Usually, the reaction is carried out at a temperature of from -78 to 25 ºC. Preferably, the extraction of the α-proton using a strong base, is carried out at a temperature from-75ºC. The electrophile was added at a temperature of 75ºC and then the temperature of the slow flashing, and than whom but increase to room temperature (25ºC). The reaction time may vary depending on the stages. Extraction of α-proton using a strong base, is carried out for from 10 to 30 minutes, and the interaction with the electrophile is carried out for from 30 to 90 minutes.

[Stage D] Obtain compounds represented by the chemical formula (IV-B)

The connection represented by the chemical formula (IV-B), obtained by removal of the protective group of the phenol compounds represented by the chemical formula (V-B).

At this stage, can be used in a polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane or the like. As ether can be used tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether or the like. As alcohol may be used methanol, ethanol or the like. As the aromatic hydrocarbon may be used benzene, toluene, xylene or the like. Of them, the polar solvent is preferred. Most preferred is tetrahydrofuran.

For removal of the protective group of the phenol using a Lewis acid such as trimethylsilyl iodide, tantially sodium, lithium iodide, aluminum halide, boron halide, triflora susnow acid and so forth, for methyl, ethyl, tert-butilkoi, benzyl and allyl ether protective groups, and use of fluoride, such as tetrabutylammonium fluoride (Bu4N+F-), halogenerator (for example, hydrofluoric acid, hydrochloric acid, bromobutyl acid or adnovate acid), potassium fluoride and so forth, silyl protective groups, such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and so on. Of them, fluoride is the preferred method for removing silyl protective group. More preferably, can be used tetrabutylammonium fluoride.

The reaction temperature may vary depending on the solvent. Usually, the reaction is carried out at a temperature from 0-120ºC, preferably at a temperature from 10ºC-25ºC. The reaction time may vary depending on the reaction temperature. Usually, the reaction is carried out for from 30 minutes to 1 day, preferably within 2 hours or less.

[Stage E] Obtain compounds represented by the chemical formula (VII)

To obtain compounds represented by the chemical formula (VII), the compound represented by the chemical formula (IV)is subjected to interaction with alkilany ether halogenases acid or alkilany ether alkylhalogenide acid in the presence of the core is found.

Alkilany ether halogenases acid or alkilany ether alkylhalogenide acid can be easily accessed by a known connection. Available alkilany ether alkylhalogenide acid can be obtained by bromirovanii Olkiluoto ether alkyloxy acid. The halogen may be chlorine, bromine, iodine or the like.

At this stage, the solvent may be used water-soluble solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, acetone, ethanol and methanol, or a mixture containing 1-10% water. Of them, acetone or dimethylsulfoxide containing 1-5% of water, is preferred.

The base can be either a weak base or strong base, without restrictions, to the extent that there is no negative effect on the reaction. A strong base can be an alkali metal hydride such as sodium hydride, lithium hydride and so on, hydride alkaline earth metal, such as potassium hydride, etc., or an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and so on. In addition, there may be used a carbonate of an alkali metal such as lithium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and so forth. Preferably, the base is a carbonate of alkaline metal is, more preferably, potassium carbonate.

The reaction temperature is not particularly limited in the extent it is below the boiling point of the solvent. However, the reaction at high temperature is not preferable, because it can be adverse reactions. Usually, the reaction is carried out at a temperature of from 0 to 90ºC. The reaction time may vary depending on the reaction temperature. Usually, the reaction is carried out for from 30 minutes to 1 day, preferably within 30-120 minutes.

[Stage F-1] To Obtain compounds represented by the chemical formula (VIII).

The connection represented by the chemical formula (VIII), obtained by hydrolysis of ester carboxylic acid compounds represented by the chemical formula (VII), in a solution of water-soluble inorganic salt and / or alcohol, or by hydrolysis of ester compounds represented by the chemical formula (VII), in a solution of 2.0 M of lithium hydroxide in THF and water.

At this stage use miscible with water, alcohol solvent such as methanol or ethanol.

Depending on the specific alkali metal salts of carboxylic acids, bases use from 0.1 to 3n aqueous solution of alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and so on. Preferably, the acid used to obtained the I connection represented by the chemical formula (VIII), as the carboxylic acid may be acetic acid, sodium bisulfate (NaHSO4) or from 0.1 to 3n HCl. Usually, to obtain compounds represented by the chemical formula (VIII)as a carboxylic acid, can be used 0,5M NaHSO4.

Low reaction temperature is preferred to prevent adverse reactions. Usually, the reaction is carried out at a temperature from 0ºC to room temperature. The reaction time may vary depending on the reaction temperature. Usually, the reaction is carried out for from 10 minutes to 3 hours, preferably for from 30 minutes to 1 hour. In the case when the reaction is carried out in a solution of 2.0 M of lithium hydroxide in THF and water, the reaction temperature is usually 0, and the reaction time preferably amounts to 1 to 2 hours.

[Stage F-2] To Obtain compounds represented by the chemical formula (VIII).

The connection represented by the chemical formula (VIII)is obtained by substitution of salt allyl ether compounds represented by the chemical formula (VII)in an organic solvent using a catalyst based on a metal and a salt of an alkali metal salt or alkaline earth metal 2-ethylhexanoate.

At this stage, the use of anhydrous organic solvent, such as chloroform, dichloromethane, etelaat and so on.

The catalyst based on metal is tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), and the catalyst based on metal can be used in amounts of from 0.01 to 0.1 equivalent.

Low reaction temperature is preferred to prevent adverse reactions. Usually the reaction is carried out at a temperature from 0ºC to room temperature. The reaction time may vary depending on the reaction temperature. Usually, the reaction is carried out for from 10 minutes to 3 hours, preferably for from 30 minutes to 1 hour.

The obtained salt of a compound is separated by centrifugation or using ionoobmennoi resin. The obtained salt of a metal compound represented by the chemical formula (VIII), it is easier to separate than the salt of the compound obtained in stage F-1 (hydrolysis).

[Stage G] Obtain compounds represented by the chemical formula (IV-B)

The connection represented by the chemical formula (IV-B), obtained by protection of the phenolic group of compounds represented by the chemical formula (IV-A), using the Grignard reagent without separation process, the processing of the α-proton obtained thio - or selenoamino strong basis with receipt of the nucleophile, and the subsequent interaction with various electrophiles. This stage includes two-stage interaction that run SRAS is.

Next follows a detailed description.

[Protection of the phenolic group with Grignard reagent]

At this stage, as anhydrous solvent used diethyl ether, tetrahydrofuran, hexane, heptane or a mixture of two or more of these substances. Of these the most preferred is diethyl ether, tetrahydrofuran or diethyl ether and tetrahydrofuran. Especially preferred is a polar solvent. Most preferred is tetrahydrofuran.

The Grignard reagent can be Metalmania chloride, etimani chloride, n-Propylamine chloride, Isopropylamine chloride, n-butylamine chloride, sec-butylamine chloride or alkilani bromide. Of these the most preferred is Isopropylamine chloride ((CH3)2CHMgCl).

The reaction temperature may vary depending on the solvent. Usually the reaction is carried out at a temperature of from -20 to 40ºC, preferably in the range from 0ºC to room temperature (25ºC). The reaction time may vary depending on the reaction temperature and solvent used. Usually, the reaction is performed for 10-60 minutes, preferably for 10 to 30 minutes.

[Extraction of α-proton and electrophilic attach]

α-proton thio - or selenoamino treated with a strong base to obtain the nucleophile, the which then reacts with various electrophiles.

At this stage, as anhydrous solvent used diethyl ether, tetrahydrofuran, hexane, heptane or a mixture of two or more of these substances. Of these, diethyl ether, tetrahydrofuran or diethyl ether and tetrahydrofuran are preferred.

The reagent is a strong base used for the extraction of α-proton, may be tert-piperonyl potassium (tert-BuOK), diisopropylamide lithium (LDA), n-utility, second-utility, tert-utility or the like. Of them LDA is the most preferred.

The electrophile, which is subjected to vzaimodeistvie with a nucleophile thio - or selenopyran, can be easily accessed by a known compound or can be easily obtained in a known manner. It may contain a highly reactive group of halogen, aldehyde or ketone, and it was added directly or dissolved in an anhydrous solvent.

The reaction temperature may vary depending on the solvent. Usually the reaction is carried out at a temperature ranging from -78 to 25 ºC. Preferably, the extraction of the α-proton using a strong base, perform at-75ºC. The electrophile was added at-75ºC and then the temperature is slowly increased to room temperature (25ºC). The reaction time may vary depending on the stage. The extraction of α-Pro is she using a strong base, hold for 10-30 minutes, and interaction with the electrophile spend within 30-90 minutes.

[Stage H] Obtain compounds represented by the chemical formula (III-2)

The connection represented by the chemical formula (III-2)may be obtained by reduction of metallic selenium strong regenerating agent sodium borohydride in an alcohol solvent to obtain hydroselenic sodium, its interaction with arylnitrenes compound represented by the chemical formula (III-1), in the environment of a strong acid such as HCl at reflux with getting selenocosmia. At this stage in the solvent used alcohol, such as methanol and ethanol, as well as a large number of pyridine. Preferably using sodium borohydride and a metal powder of selenium in equivalent quantities and use 2-3 M HCl acid.

[Stage I] Obtain compounds represented by the chemical formula (III-3)

The connection represented by the chemical formula (III-3), produced by interaction of the compounds represented by the chemical formula (III-2), with C1-C4 alkyl 2-chloroacetoacetate.

At this stage, the solvent can be used an alcohol such as methanol, ethanol, propanol, butanol, and so forth, or an ether such as ethyl ether, tetrahydrofuran, 1,4-dioxane, and so forth. Of these ethanol and tetrahed furan are preferred.

The reaction temperature may vary depending on the solvent. Usually, the reaction is carried out at a temperature of from 25 to about 150ºc, preferably at 60-120ºC. The reaction time may vary depending on the reaction temperature and solvent used. Usually, the reaction is carried out for 6 hours to 1 day, preferably for 16 hours or less.

[Stage J] Obtain compounds represented by the chemical formula (III-4)

Alcohol compound represented by chemical formula (III-4), obtained by recovery of ester compounds represented by the chemical formula (III-3), using a reducing agent.

Reducing agent is used to recover the ether may be a reducing agent is a hydride of aluminium, such as alumalite lithium (LiAlH4), hydride diisobutylaluminum (DIBAL-H), and so forth, or the reducing agent is a borohydride such as sodium borohydride, lithium borohydride, and so forth. Of them reducing agent is a hydride of aluminum is preferred. Most preferred are LiAlH4and DIBAL-H.

At this stage, as anhydrous solvent can be used diethyl ether, tetrahydrofuran, dichloromethane or the like. Dichloromethane is preferable.

The time re the options may vary depending on the solvent used and the reducing agent. Usually, the reaction is carried out at a temperature of from -100 to 60ºC, preferably, at-78ºC - 25ºC. The reaction time may vary depending on the reaction temperature and solvent used. Usually, the reaction is carried out for from 30 minutes to 6 hours, preferably within 2 hours or less.

[Stage K] Obtain compounds represented by the chemical formula (III)

The connection represented by the chemical formula (III-A), can be obtained by halogenation of an alcohol group of the compound represented by chemical formula (III-4). The connection represented by the chemical formula (III-B), can be obtained from compounds represented by the chemical formula (III-4), using NaN3. And, the connection represented by the chemical formula (III-C), can be obtained by introducing an alkyl - or aryl-substituted sulphonylchloride, preferably, methanesulfonamido or p-toluensulfonate, on the hydroxyl group of compound represented by chemical formula (III-4).

When galogenirovannyie and the introduction methanesulfonate or p-toluensulfonate group as a solvent can be used N,N-dimethylformamide, diethyl ether, tetrahydrofuran, carbon tetrachloride, chloroform, dichloromethane, pyridine or the like. Of these, dichloromethane is preferred in most cases is when galogenirovannyie, and the pyridine is preferred in most cases, the introduction of methanesulfonate or p-toluensulfonate group.

Halogenoalkane alcohol can be carried out using triphenylphosphine (TPP) and N-chlorosuccinimide (NCS), triphenylphosphine and gaseous chlorine (Cl2), triphenylphosphine and carbon tetrachloride (CCl4), pentachloride phosphorus (PCl5), thionyl chloride (SOCl2or methanesulfonyl chloride (MeSO2Cl) or the like for the introduction of chlorine, using triphenylphosphine and N-bromosuccinimide (NBS), triphenylphosphine and gaseous bromine (BR3), triphenylphosphine and tetrabromide carbon (CBr4), pentabromide phosphorus (PBr5or thienylboronic (SOBr2) or the like for introducing bromine, and using triphenylphosphine and N-jodatime, triphenylphosphine and solid iodine, triphenylphosphine and tetraiodide carbon (CI4) or the like for the introduction of iodine or by halogen-iodine substitution of chlorine or bromine compounds represented by the chemical formula (IV-A), in acetone. Introduction methanesulfonate or p-toluensulfonate group can be accomplished through interaction with methanesulfonamido or p-toluensulfonate in solvent pyridine. The most preferred group is removed by chlorine or bromine, and most preferably the m method of obtaining is a method using triphenylphosphine and N-chlorosuccinimide or N-bromosuccinimide.

At this stage, the reaction temperature may vary depending on the method of preparation and the used solvent. Usually, the reaction is carried out at a temperature in the range from -10 to 40ºC, preferably, with a 10-25ºC. The reaction time may vary depending on the reaction temperature and solvent used. Usually the reaction is carried out for from 30 minutes to 1 day, preferably within 2 hours or less.

[Phase-L] Getting connection represented by the chemical formula (L-1) or (L-2)

The connection represented by the chemical formula (L-1)may be obtained by dissolving the compound represented by the chemical formula (VII)obtained in stage E, in methylene chloride (CH2Cl2) and adding 1 equivalent of m-chloroperbenzoic acid (m-CPBA), maintaining the reaction temperature at from 0 to 5ºC. And, the connection represented by the chemical formula (L-2), can be obtained by adding 2 equivalents of m-CPBA.

Thus obtained compound represented by chemical formula I, is an important ligand protein PPAR. Since the compound has a chiral carbon, there are its stereoisomers. The present invention includes a compound derived selenate chemical formula I, a stereoisomer, its MES and its salt.

Derived selenate connection, presents chemical is armoloy I, according to the present invention or a pharmaceutically acceptable salt of the compounds are used as activators of PPAR. In addition, the derived selenate represented by chemical formula I, according to the present invention, its hydrate, MES, stereoisomer and its pharmaceutically acceptable salt for use in the pharmaceutical composition, the composition is a functional food additive, composition, functional drink, song, food additives, functional cosmetic compositions or the animal feed composition for the prevention or treatment of atherosclerosis, fatty infiltration of the liver or hyperlipemia, prevention or treatment of hypercholesterinemia, prevention or treatment of diabetes, prevention or treatment of obesity, strengthen muscles, improve endurance, improve memory, or prevention or treatment of dementia or Parkinson's disease, because they activate PPAR. Derived selenate represented by chemical formula I, in accordance with the present invention, its hydrate, MES, stereoisomer and its pharmaceutically acceptable salt is used for functional cosmetic composition for the prevention or treatment of obesity, prevention or treatment of fatty infiltration of the liver, muscle strengthening or improving endurance. Functional cosmetic composition may be recip is in the form of ointments, lotion or cream, and may be applied topically to the desired area of the body before and/or after exercise to strengthen muscles and increase endurance. In addition, the derived selenate represented by chemical formula I, in accordance with the present invention, its hydrate, his MES, its stereoisomer and its pharmaceutically acceptable salt can be obtained in the form of ointment and applied topically for prevention or treatment of diabetes or diabetic ulcers of the feet.

Pharmaceutically acceptable salt may be a salt of carboxylic acid derived selenate represented by chemical formula I, or any other pharmaceutically acceptable organic salt (e.g., dicyclohexylamine or N-methyl-d-glucamine). Preferred inorganic salt includes a salt of an alkali metal salt and alkaline earth metal Li+, Na+, K+Ca2+, Mg2+or something.

Of course, the number derived selenate represented by chemical formula I, its hydrates, its MES, its stereoisomer or pharmaceutically acceptable salt required to achieve therapeutic effect depends on the particular compound, the route of administration, the subject in need of treatment, and the disease requiring treatment, and can be defined in the same way as for other drugs. Bol is E. preferably, effective input the dose of a compound represented by the chemical formula I is in the range from 1 to 100 mg/kg (body weight)/day. In the volume of daily effective input dose, it can be entered one or more times a day. Also, depending on the type of drugs, it can be administered orally or topically. Pharmaceutical composition for oral administration may be in the form of any of the existing forms, including, for example, tablets, powders, dry syrups, chewable tablets, granules, capsules, soft capsules, pills, drink, sublingually tablets or the like. Tablets in accordance with the present invention can be administered to the patient in any bioavailable way or form, that is, by oral route. Adequate path or route of administration may be easily selected depending on the extent of disease that should be prevented or treated, the disease development, or other related situations. When the composition of the present invention are tablets, they may contain one or more pharmaceutically acceptable excipients. The composition and properties of the filler can be determined on the basis of solubility and chemical properties of selected tablets, chosen route of administration and conventional pharmaceutical practices.

Description of the drawings

The above and other objects, the prize is Aki and advantages of the present invention will be clear from the following description of the preferred embodiments, presented in conjunction with the accompanying drawings, in which:

In Fig. 1 shows the results of the study of therapeutic effect with fatty infiltration of the liver.

Methods of carrying out the invention

The following examples and experiments. The following examples and experiments are presented only for purposes of illustration and are not intended to limit the scope of the present invention.

[Example]

[Preparative example 1] Obtain compound III-2a

[Stage H]

To ethanol (50 ml) under nitrogen atmosphere was added a powder of selenium (of 3.95 g, 50 mmol). Then carefully added sodium borohydride (2,02 g, 53 mmol)slowly over 30 minutes (formed hydrogen gas). To the obtained ethanol solution of hydroselenic sodium was added 4-(trifluoromethyl)benzonitrile (11.9 g, 70 mmol) and pyridine (8 ml). Then slowly, was added dropwise during 1.5 hours 2M hydrochloric acid (25 ml) by boiling under reflux at a temperature of 80ºC. After subsequent stirring for about 30 minutes, dropped in the sediment target compound was filtered and washed with hexane and water. Recrystallization solvent benzene gave compound III-2a (15,1 g, yield: 91%) as a solid yellow color.

1H NMR (300 MHz, CDCl3) δ 11,07 (width, 1H), 10,43 (width, 1H), to 7.99 (d, 2H, J=8.5 Hz), to 7.77 (who, 2H, J=8,3 Hz).

[Preparative example 2] to Obtain compound III-3a

[Stage I]

Compound III-2a (2,52 g, 10.0 mmol) was dissolved at room temperature in tetrahydrofuran (35 ml) and slowly for 20 minutes was added ethyl 2-chloroacetoacetate (1,22 ml, 10.0 mmol, 1.0 equivalent). After complete addition, the mixture was further stirred at room temperature for 30 minutes and boiled under reflux for 12 hours at a temperature of from 75 to 80ºC. After completion of the reaction the temperature was lowered to room temperature and was added 50%aqueous sodium hydroxide solution (20 ml). After stirring for 20 minutes the organic layer was extracted with ethyl acetate and saturated saline and dried with magnesium sulfate. After filtration distillation under reduced pressure gave compound III-3a (3.33 g, yield: 95%).

1H NMR (300 MHz, CDCl3) δ 8,02 (d, 2H, J=8.1 Hz), 7,69 (d, 2H, J=8,2 Hz), 3,88 (s, 3H), and 2.79 (s, 3H).

[Preparative example 3] Obtain compound III-4a

[Stage J]

Ethyl ester (compound III-3a, 2.1 g, 6.0 mmol)obtained in preparative example 2 was completely dissolved in anhydrous dichloromethane (100 ml) under nitrogen atmosphere and was cooled to a temperature-78ºC. Slowly over 30 minutes was added diisobutylaluminium hydride (DIBAL-H, 1.6 ml, a 1.0 M solution in hexane, 2.5 equivalent). After the interaction at the same temperature for 30 minutes, the reaction is then conducted at a temperature of-10ºC for 30 minutes. After completion of the reaction, the reaction was stopped using ethyl acetate. After extraction with 10%sulfuric acid and ethyl acetate, the product was dried using magnesium sulfate. Filter using a short column with silica gel and subsequent removal of the solvent under reduced pressure gave compound III-4a (1,74 g, yield: 94%).

1H NMR (300 MHz, CDCl3) δ of 7.96 (d, 2H, J=8.1 Hz), the 7.65 (d, 2H, J=8,2 Hz), 4,88 (d, 2H, J=5.3 Hz), a 2.45 (s, 3H).

[Preparative example 4] Obtain compound III-A-1

[Stage K-1]

Compound III-4a (1.13 g, 3,66 mmol)obtained in preparative example 3 was dissolved in anhydrous dichloromethane (30 ml). Then was added triphenylphosphine (TPP, 1.06 g, a 4.03 mmol, 1.1 equivalent) and completely dissolved. At room temperature was slowly added N-chlorosuccinimide (717 mg, a 4.03 mmol, 1.1 equivalent). After additional stirring for 1 hour the solvent was removed by distillation under reduced pressure. After planting the triphenylphosphine oxide using hexane and ethyl acetate (5:1), filtration, followed by distillation under reduced pressure gave compound III-A-1 (1.07 g yield: 90%).

1H NMR (300 MHz, CDCl3) δ of 7.95 (d, 2H, J=8,2 Hz), 7,66 (d, 2H, J=8,3 Hz), 4,84 (s, 2H), 2,48 (s, 3H).

[Preparative example 5] Obtain compound III-B-1

[Stage K-2]

Compound III-4a (352 mg, 1.1 equivalent)obtained in preparative example 3 was slowly dissolved in CCl4-DMF (1:4, 5 ml). After adding dropwise PPh3(508 mg, 2.2 equivalents) and NaN3(78 mg, 1.2 equivalent), the temperature was slowly raised up to 90ºC. When using TLC was established that the source reagent is consumed, the temperature was lowered to 25ºC. After further stirring for about 10 minutes, the reaction was stopped with distilled water (4 ml). After extraction with ethyl ether, the temperature was lowered to 0ºC. The formed crystals triphenylphosphine was removed by filtration. Flash chromatography on silica gel remaining product gave the compound III-B-1 (271 mg, yield: 85%) (FABMS: 321[M+H]+).

[Preparative example 6] Obtain compound III-C-1

[Stage K-3]

Compound III-4a (352 mg, 1.1 equivalent)obtained in preparative example 3 was dissolved in methylene chloride (MC, 5 ml) and cooled to a temperature of 0ºC. Then, after careful adding p-toluensulfonate (p-TsCl, 190 mg, 1.0 equivalent) and Et3N (1.5 equivalents), the mixture was additionally stirred. After the arsenia reaction the concentration of the organic layer (MC layer of solvent) with subsequent flash chromatography on a column of silica gel gave compound III-C-1 (431 mg, yield: 91%) (FABMS: 476[M+H]+).

[Example 1] Get S1

[Phase A]

4-Iodine-2-METHYLPHENOL (468 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere and the temperature was maintained at 0ºC. After slow addition of isopropylacrylamide (2 M, 1.5 ml) the reaction was carried out for 10 minutes. The mixture was cooled to a temperature-78ºC and was slowly added tert-utility (2.00 ml of 1.7 M solution in hexane, 1.0 equivalent). After stirring for 10 minutes, one portion was added solid sulfur (S, 64 mg, 2 mmol, 1.0 equivalent) at the same temperature. After the reaction for 40 minutes to raise the temperature to 15 ° C, slowly at the same temperature was added compound III-A-1 (652 mg, 2 mmol, 1.0 equivalent)obtained in preparative example 4, dissolved in anhydrous THF (10 ml). After further interaction within about 1 hour, the reaction was stopped with an aqueous solution of ammonium chloride. After extraction of the organic solvent with ethyl acetate and saturated saline, the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (705 mg, yield: 82%).

1H NMR (300 MHz, CDCl3) δ ,91 (d, 2H, J=8.1 Hz), 7,63 (d, 2H, J=8.0 Hz), 7,21 (m, 1H), 7,12 (m, 1H), to 6.67 (d, 2H, J=8,2 Hz), is 4.15 (s, 2H), 2,19 (s, 3H), 2,17 (s, 3H).

[Example 2] the connection S2

[Phase A]

4-Iodine-2-METHYLPHENOL (468 mg, 2 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) under nitrogen atmosphere, and the temperature was maintained at 0ºC. After slow addition of isopropylacrylamide (2 M, 1.5 ml) the reaction was carried out for 10 minutes. The mixture was cooled to a temperature-78ºC and was slowly added tert-utility (2.00 ml of 1.7 M solution in hexane, 1.0 equivalent). After stirring for 10 minutes, was added in one portion at the same temperature solid selenium (Se, 158 mg, 2 mmol, 1.0 equivalent). After reaction for 40 minutes to raise the temperature to 15 ° C, slowly at the same temperature was added compound III-A-1 (652 mg, 2 mmol, 1.0 equivalent)obtained in preparative example 4, dissolved in anhydrous THF (10 ml). After further interaction within about 1 hour, the reaction was stopped with an aqueous solution of ammonium chloride. After extraction of the organic solvent with ethyl acetate and saturated salt solution and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target is connected to the e (773 mg, yield: 81%).

1H NMR (300 MHz, CDCl3) δ 7,89 (d, 2H, J=8.1 Hz), 7,63 (d, 2H, J=8,2 Hz), 7,24 (m, 1H), 7,14 (m, 1H), to 6.67 (d, 2H, J=8,2 Hz), 4,17 (s, 2H), 2,18 (s, 3H), 2.13 and (s, 3H).

[Example 3] the connection S3

[Phase B]

Compound S1 (860 mg, 2 mmol) and imidazole (290 mg, 2.0 equivalent) was completely dissolved in dimethylformamide (20 ml). After slow addition of tert-butyldimethylsilyl chloride (165 mg, 1.1 equivalents), the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the organic solvent was extracted with an aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was dried using magnesium sulfate. Purification using a column of silica gel, followed by distillation under reduced pressure gave the target compound (1053 mg, yield: 95%). (FABMS: 558 [M+H]+).

[Example 4] Getting connection S4

[Phase B]

Compound S2 (954 mg, 2 mmol) and imidazole (290 mg, 2.0 equivalent) was completely dissolved in dimethylformamide (20 ml). After slow addition of tert-butyldimethylsilyl chloride (165 mg, 1.1 equivalents), the reaction was carried out at room temperature for 4 hours. After completion of the reaction, the organic solvent was extracted with an aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was dried with MAG sulfate is Oia. Purification on a column of silica gel, followed by distillation under reduced pressure gave the target compound (1099 mg, yield: 93%). (FABMS: 606[M+H]+).

[Example 5] Getting connection S5

[Stage E]

Compound S1 (430 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl ether bromoxynil acid (134 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (480 mg, yield: 93%).

1H NMR (300 MHz, CDCl3) δ of 7.90 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8,2 Hz), 7,25 (m, 1H), 7,14 (m, 1H), to 6.67 (d, 2H, J=8,2 Hz), br4.61 (s, 2H), 4,23 (m, 2H), 4.16 the (s, 2H), 2,24 (s, 3H), of 2.21 (s, 3H), of 1.28 (t, 3H, J=3,7 Hz).

[Example 6] Getting connection S6

[Stage E]

Compound S2 (477 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After to the Alenia ethyl ester bromoxynil acid (134 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (523 mg, yield: 93%).

1H NMR (300 MHz, CDCl3) δ of 7.90 (d, 2H, J=8.1 Hz), to 7.64 (d, 2H, J=8,2 Hz), 7,27 (m, 1H), 7,20 (m, 1H), of 6.68 (d, 2H, J=8,2 Hz), br4.61 (s, 2H), 4,23 (m, 2H), 4,19 (s, 2H), of 2.23 (s, 3H), of 2.15 (s, 3H), of 1.27 (t, 3H, J=3,7 Hz).

[Example 7] Getting connection S7

[Stage E]

Compound S1 (430 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl-2-bromo-2-methylpropanoate (210 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours, adding acetone, and heated at a temperature of 60-90ºC. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography is and a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (326 mg, yield: 60%). (FABMS: 558 [M+H]+).

[Example 8] Getting connection S8

[Stage E]

Compound S1 (430 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl-2-bromobutyrate (146 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours, adding acetone, and heated at a temperature of 60-90ºC. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (451 mg, yield: 83%). (FABMS: 558 [M+H]+).

[Example 9] Getting connection S9

[Stage E]

Compound S1 (430 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl-2-bromopropionate (155 μl, 1.2 mmol, 1.2 equivalents), the mixture was vigorously stirred for 4 hours, adding acetone, and heated at a temperature of 60-90ºC. After completion of the reaction, an organic solvent of EC who was tragically saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (429 mg, yield: 81%). (FABMS: 544 [M+H]+).

[Example 10] Getting connection S10

[Stage E]

Compound S2 (478 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl-2-bromo-2-methylpropanoate (210 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours, adding acetone, and heated at a temperature of 60-90ºC. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (349 mg, yield: 59%). (FABMS: 606 [M+H]+).

[Example 11] Get connection S11

[Stage E]

Compound S2 (478 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 to whom quivalent) were well mixed at room temperature. After adding ethyl-2-bromobutyrate (146 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours, adding acetone, and heated at a temperature of 60-90ºC. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (490 mg, yield: 83%). (FABMS: 606 [M+H]+).

[Example 12] Get connection S12

[Stage E]

Compound S2 (478 mg, 1 mmol), acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl-2-bromopropionate (155 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours, adding acetone, and heated at a temperature of 60-90ºC. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using sm is si hexane/ethyl acetate (vol./about.=5:1) gave the target compound (462 mg, yield: 80%). (FABMS: 592 [M+H]+).

[Example 13] Get connection S13

[Stage C]

Compound S3 (544 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding benzylbromide (137 μl, 1.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes, the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (526 mg, yield: 83%). (FABMS: 648 [M+H]+).

[Example 14] Get connection S14

[Stage C]

Connection S4 (591 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding benzylbromide (137 μl, 1.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes, the reaction was stopped in the s ' solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (538 mg, yield: 79%). (FABMS: 694 [M+H]+).

[Example 15] Getting connection S15

[Stage C]

Compound S3 (699 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2-chloro-5-ftorangidridy (270 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (531 mg, yield: 76%). (FABMS: 700 [M+H]+).

[Example 16] Get connection S16

[Stage C]

Connection S4 (746 mg, 1 mmol) was dissolved in beswt the om tetrahydrofuran (20 ml, and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2-chloro-5-ftorangidridy (270 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (552 mg, yield: 74%). (FABMS: 746 [M+H]+).

[Example 17] Getting connection S17

[Stage C]

Compound S3 (700 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 3,4,5-triterpenoid (282 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried with sulfa is and magnesium. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (525 mg, yield: 75%). (FABMS: 702 [M+H]+).

[Example 18] Get connection S18

[Stage C]

Connection S4 (747 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 3,4,5-triterpenoid (282 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes, the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (523 mg, yield: 70%). (FABMS: 750 [M+H]+).

[Example 19] Getting connection S19

[Stage C]

Compound S3 (682 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After you add the value of 2.5-diferenciada (259 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (518 mg, yield: 76%). (FABMS: 684 [M+H]+).

[Example 20] Get connection S20

[Stage C]

Connection S4 (724 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2.5 diferenciada (259 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target with the Association (514 mg, yield: 71%). (FABMS: 732 [M+H]+).

[Example 21] Get connection S21

[Stage C]

Compound S3 (715 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2.5 dichlorobenzamide (300 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (529 mg, yield: 74%). (FABMS: 716 [M+H]+).

[Example 22] Get connection S22

[Stage C]

Connection S4 (762 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2.5 dichlorobenzamide (300 μl, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction of the OST is alibali aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (541 mg, yield: 71%). (FABMS: 762 [M+H]+).

[Example 23] Get connection S23

[Stage C]

Compound S3 (732 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2-fluoro-5-triftormetilfosfinov (514 mg, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (534 mg, yield: 73%). (FABMS: 734 [M+H]+).

[Example 24] Get connection S24

[Stage C]

Connection S4 (779 mg, 1 mmol) was dissolved the anhydrous tetrahydrofuran (20 ml), and the temperature was lowered to-78ºC. Then slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding 2-fluoro-5-triftormetilfosfinov (514 mg, 2.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (545 mg, yield: 70%). (FABMS: 782 [M+H]+).

[Example 25] Get connection S25

[Stage G]

Compound S1 (430 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) under nitrogen atmosphere, and the temperature was maintained at 0ºC. After slow addition of isopropylacrylamide (2M, 1 ml) the reaction was carried out for 10 minutes. After sufficient cooling to the temperature-78ºC was slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding benzylbromide (137 μl, 1.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes the reaction was stopped by water races is the thief of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (426 mg, yield: 80%). (FABMS: 534 [M+H]+).

[Example 26] Get connection S26

[Stage G]

Compound S2 (478 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) under nitrogen atmosphere, and the temperature was maintained at 0ºC. After slow addition of isopropylacrylamide (2 M, 1 ml) the reaction was carried out for 10 minutes. After sufficient cooling to the temperature-78ºC was slowly added diisopropylamide lithium (LDA, 1.8 ml, 1.8 M, 2.0 equivalent). After adding benzylbromide (137 μl, 1.0 mmol), the temperature was slowly raised to room temperature. After further interaction within 30 minutes, the reaction was stopped with an aqueous solution of ammonium chloride. The organic solvent was extracted with ethyl acetate and saturated saline solution, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (457 mg, yield: 78%). (FABMS: 82 [M+H] +).

[Examples 27-36]

Connection S27-S46 shown in table 1, were obtained in accordance with the method according to examples 25 and 26. The table shows MS analysis.

[Example 47] Get connection S47

[Stage D]

Connection S13 (646 mg, 1 mmol) were completely dissolved in tetrahydrofuran (10 ml). Then at room temperature was slowly added tetrabutylammonium fluoride (TBAF, 2.5 ml, 1M solution in tetrahydrofuran, 2.5 equivalent). After interaction within 30 minutes, the organic solvent was extracted with an aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (479 mg, yield: 92%). (FABMS: 534 [M+H]+).

[Example 48] Get connection S48

[Stage D]

Compound S14 (693 mg, 1 mmol) were completely dissolved in tetrahydrofuran (10 ml). Then at room temperature was slowly added tetrabutylammonium fluoride (TBAF, 2.5 ml, 1 M solution in tetrahydrofuran, 2.5 equivalent). After interaction within 30 minutes the solvent content of inorganic fillers were extracted with an aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel gave the target compound (521 mg, yield: 90%). (FABMS: 582 [M+H]+).

Connection S27 - S46 can be obtained in accordance with the method in examples 47 and 48.

[Example 49] Get connection S49

[Stage E]

Connection S25 (532 mg, 1 mmol) and acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 equivalents) was well mixed at room temperature. After adding ethyl ether bromoxynil acid (134 μl, 1.2 mmol, 1.2 equivalent) and the mixture was vigorously stirred for 4 hours. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (575 mg, yield: 93%). (FABMS: 620 [M+H]+).

[Example 50] Get connection S50

[Stage E]

Connection S26 (579 mg, 1 mmol) and acetone (10 ml)containing 5% water, and potassium carbonate (346 mg, 2.5 mmol, 2.5 EQ is Valens) were well mixed at room temperature. After adding ethyl ether bromoxynil acid (134 μl, 1.2 mmol, 1.2 equivalents), the mixture was vigorously stirred for 4 hours. After completion of the reaction, the organic solvent was extracted with saturated salt solution and ethyl acetate, and the organic layer was dried using magnesium sulfate. After filtration, followed by distillation under reduced pressure, purification of the residue by chromatography on a column of silica gel using mixtures of hexane/ethyl acetate (vol./about.=5:1) gave the target compound (605 mg, yield: 91%). (FABMS: 668 [M+H]+).

[Examples 51 - 136]

Connection S51-S136 shown in table 2, were obtained in accordance with the method in examples 49 and 50. The table shows MS analysis.

[Example 137] Getting connection S137

[Stage F]

Connection S49 (618 mg, 1 mmol) was well mixed with the THF (15 ml) and water (10 ml) at 0ºC and slowly added a 2.0 M aqueous solution of lithium hydroxide (0.6 ml). After additional stirring for 60 minutes at 0ºC, after completion of the reaction was added a 0.5 M NaHSO4(2.5 ml). Then organic is the cue solvent was extracted with saturated salt solution and ethyl acetate, was filtered and distilled under reduced pressure. Purification of the residue by chromatography on a column of LH-20 gave the target compound (566 mg, yield: 96%). (FABMS: 592 [M+H]+).

[Example 138] Get connection S138

[Stage F]

Connection S50 (665 mg, 1 mmol) was well mixed with the THF (15 ml) and water (10 ml) at 0ºC and slowly added a 2.0 M aqueous solution of lithium hydroxide (0.6 ml). After additional stirring for 60 minutes at 0ºC, after completion of the reaction was added a 0.5 M NaHSO4(2.5 ml). Then the organic solvent was extracted with saturated salt solution and ethyl acetate, filtered and distilled under reduced pressure. Purification of the residue by chromatography on a column of LH-20 gave the target compound (605 mg, yield: 95%). (FABMS: 640 [M+H]+).

[Examples 139-288]

Connection S139-S288 presented in table 3, were obtained in accordance with the method in examples 87 and 88. The table shows MS analysis.

img src="https://img.russianpatents.com/1164/11642155-s.jpg" height="166" width="155" />

[Example 289] Get connection S289

Connection S185 (500 mg, 1 mmol) was dissolved in acetonitrile (10 ml). The reaction was carried out for about 20 minutes, carefully dropwise adding dicyclohexylamine (181 mg, 1 mmol). Then, after adding distilled water (8 ml) and additional interaction within about 10 minutes, lyophilization of the solvent gave the target compound (674 mg, yield: 99%). (FABMS: 683 [M+H]+).

[Example 290] Get connection S290

Connection S186 (590 mg, 1 mmol) was dissolved in acetonitrile (10 ml). The reaction was carried out for about 20 minutes, carefully dropwise adding dicyclohexylamine (181 mg, 1 mmol). Then, after adding distilled water (8 ml) and additional interaction within about 10 minutes, lyophilization of the solvent gave the target compound (768 mg, yield: 99%). (FABMS: 731 [M+H]+).

[Example 291] Get connection S291

[Stage L]

CuI (10 mg, 0.05 mmol, 5 mol%), CsCO3(845 mg, 2.6 equivalents) and 4-iodine-2-METHYLPHENOL (234 mg, 1 mmol) was added to anhydrous DMF (0.7 ml) in nitrogen atmosphere. After the ger is lichnogo clogging of Teflon tape filled with nitrogen. Then, after careful addition of 2-isobutylacetophenone (34 mg, 0.2 mmol, 20 mol%) and compound III-B-1 (320 mg, 1 equivalent)obtained in preparative example 5, the mixture was stirred at room temperature for 8 hours. After neutralization of the product to pH 4 with 10%HCl solution, the concentration of the organic layer followed by chromatography on a column of silica gel gave the target compound (355 mg, yield: 79%) (FABMS: 427 [M+H]+).

[Example 292] Get connection S292

[Stage E and F]

The target compound (348 mg, yield: 82%) was obtained from compound S291 (425 mg, 1 equivalent) in accordance with the method in examples 39 and 87 (FABMS: 485 [M+H]+).

[Example 293] Get connection S293

[Stage M]

Compound III-C-1 (474 mg, 1 equivalent)obtained in preparative example 6, was dissolved in acetonitrile (5 ml) and DMF (0.5 ml). Then, after slowly adding CsCO3(490 mg, 1.5 equivalents) and(ethyl 2-(4-hydroxy-3-methylphenoxy)acetate, 210 mg, 1 equivalent), the mixture was stirred at room temperature for 4 hours. The reaction was stopped after spending toiling connection that was established by TLC. Chromatography on a column of silica gel organic layer gave tulevaisuuden (435 mg, yield: 85%) (FABMS: 514 [M+H]+).

[Example 294] Get connection S294

[Stage F]

The target compound (454 mg, yield: 94%) was obtained from compound S293 (510 mg, 1 equivalent) in accordance with the method according to example 87 (FABMS: 486 [M+H]+).

[Example 295] Get connection S295

Compound S5 (530 mg, 1 mmol) was dissolved in CH2Cl2(10 ml). After addition of m-chloroperbenzoic acid (m-CPBA, 170 mg, 1 mmol), the temperature of the reaction mixture maintained at 0-5ºC. The reaction was carried out for about 1 hour at this temperature. After completion of reaction (by TLC), the mixture is divided by chromatography on a column of silica gel gave compound S295 (485 mg, 89%) as a cloudy yellow oil. (FABMS: 546[M+H]+).

[Example 296] Get connection S296

Compound S5 (530 mg, 1 mmol) was dissolved in CH2Cl2(10 ml). After addition of m-chloroperbenzoic acid (m-CPBA, 340 mg, 2 mmol), the temperature of the reaction mixture maintained at 0-5ºC. The reaction was conducted for about 2 hours at this temperature. After completion of reaction (by TLC), the mixture is divided by chromatography on a column of silica gel gave compound S296 (516 mg, 92%) as a solid white color is. (FABMS: 562 [M+H]+).

[Example 297] Get connection S297

[Stage F]

The target compound (476 mg, yield: 92%) was obtained from compound S295 (545 mg, 1 equivalent) in accordance with the method according to example 87 (FABMS: 518 [M+H]+).

[Example 298] Get connection S298

The target compound (490 mg, yield: 92%) was obtained from compound S296 (561 mg, 1 equivalent) in accordance with the method according to example 87 (FABMS: 534 [M+H]+).

[Test example 1] to Test the activity and toxicity

The effect of activation of PPARδ compounds represented by chemical formula I, in accordance with the present invention was determined by transfection study. In addition, he performed the test on the selectivity for other PPAR subtypes, PPARα and PPARγ, a toxicity test was performed using MTT analysis, and the activity ofin vivoconfirmed test on the animal.

[Transfectional analysis]

For transfection analysis used cells CV-1. Cells were cultured in 5% CO2the incubator at 37 degrees C, 96-hole tablet using DMEM containing 10% FBS, DBS (delipidation) and 1% penicillin/streptomycin. The test was performed in four phases: seeding cells, transfection, treatment compound of the present invention and the confirmation result. Cells CV-1 were cultivated in 96-well tablet p and the concentration of 5000 cells per well and were transfusional 24 hours. The study transfections were performed using full-sized plasmid DNA PPAR, reporter DNA, which has the activity of the luciferase and thus enables to confirm the activity of PPAR, and DNA β-galactosidase, which provides information about the efficiency of transfection. The compound of the present invention was dissolved in dimethyl sulfoxide (DMSO), diluted, using a medium, and then treated them with cells at various concentrations. After 24 hours of cultivation in an incubator, the cells were literally using lyse buffer and measured the luciferase activity and the activity of β-galactosidase using a luminometer and microplate reader. The measured luciferase activity compared with the activity of β-galactosidase and the result is depicted on the graph to determine the value EC50.

Table 4
Data EC50
Connection # hPPARδhPPARαhPPARγ
S1850,66 nmiaia
S186 4,27 nmiaia

As can be seen from table 4, the compound of the present invention has a high selectivity for PPARδ.

The compound of the present invention showed activity from 0.66 to 300 nm against PPARδ.

[MTT analysis]

The toxicity of the compounds represented by chemical formula I, according to the present invention was determined using the MTT assay. MTT is a water-soluble yellow substance. However, when introduced into the living cell, it is transformed under the action of mitochondrial dehydrogenase in water-insoluble purple crystals. Cellular toxicity can be measured by dissolving the substance in dimethyl sulfoxide and measuring the light absorption at 550 nm. The test was carried out as follows.

First, CV-1 cells were planted in 96-well-plate at a concentration of 5000 cells per well. After culturing for 24 hours in a humidified system of cultivation at 37°C containing 5%, the cultured cells CV-1 was treated with the compound of the present invention (compound S185) at various concentrations. After 24 hours of cultivation was added MTT reagent. After culturing for about 15 minutes, the purple crystals were dissolved in dimethyl sulfoxide and was measured by absorption through microplans the private reader.

As a result, the connection represented by the chemical formula I, showed no toxicity even at concentrations 100-1000 times greater than EC50relative to PPAR.

[Test on animals]

[The effect of preventing obesity]

To confirm the in vivo effect of the compounds of the present invention, a test was conducted in mice. Used the mouse C57BL/6 (SLC Co.) 8-weeks of age, and gave her food, containing 35% fat, to cause obesity. When the diet with high content of fat in 60 days oral was administered (10 mg/kg/day) media connection S185 or connection S186. As a result, the group treated S185, showed only 39% increase in weight, while the group treated S186, showed only 42% increase in weight compared to the group that was administered the media.

[The effect of preventing atherosclerosis]

To confirm the effect of preventing atherosclerosis compounds of the present invention, in vivo experiment was performed using a model of atherosclerosis in mice ApoE-/-, Ldlr-/-. When the diet with high fat and high cholesterol (20% fat, 1.25% cholesterol; diet AIN-93G), the compound of the present invention (compound S185) was administered orally at a dose of 2 mg/kg/day. After 28 days of arterial plaques were stained with Sudan IV, and the effect of prevention of atherosclerosis compared with control GRU is sing. As a result, the mouse line ApoE-/-, which was introduced connection S185, showed improved by 60%, the effect of preventing atherosclerosis in comparison with the control group. And the mouse line Ldlr-/-, which was introduced connection S185, showed improved by 36%, the effect to prevent atherosclerosis.

[The effect of treatment of diabetes]

To confirm the effect of treatment of diabetes with compounds of the present invention, performed test glucose tolerance (GTT). Mice that oral was administered the investigational compound within 57 days, were injected intraperitoneal glucose (1.5 g/kg) and controlled change of the glucose level. The group, which has introduced the connection S185 or S186 (10 mg/kg/day), showed lower glucose levels when fasting than the control group. In addition, the group, which entered the compound of the present invention, showed a rapid decrease in blood glucose between 20 and 40 minutes and the complete disappearance of glucose in 100 minutes. For comparison, in the group that was administered the media, the level of sugar in the blood does not come to normal even after 120 minutes. This result confirms that the connection S185 and S186 are effective in the treatment of diabetes.

[The effect of improving muscle endurance and muscle function]

Experiment on animals was performed to confirm the effect of improving muscle endurance and muscle function with p the power connection of the present invention. Since the formation of the muscles occurs mainly at the stage of development, the connection S185 or S186 (10 mg/kg/day) oral was administered to mice during pregnancy, lactation, or during pregnancy and lactation. Differences in body weight or growth rate of the embryo between the control group and the group that was administered the compound were observed. After removal of the skin was observed that muscle group, which entered the Union, had a more red color than in the control group. The ATPase staining and immune staining also showed an increase in muscle fiber type I in the group, which was administered connection. To confirm the effect of changes in the muscle fiber to improve muscle endurance and function of muscles, the analysis was performed using the “treadmill” in the form of a wheel. As a result, the group, which entered the Union, showed significantly greater running time compared with the control group.

Table 5
The test results are endurance muscles
The increase compared with the control groupPregnancyLactation Pregnancy + lactation
Time (the number of times)The distance (the number of times)Time (the number of times)The distance (number
time)
While (number
time)
The distance (number of times)
S1852,32,72,12,63,7a 3.9
S1862,12,11,82,03,13,3

In addition, improving muscle endurance and muscle function was confirmed in the case where the compound of the present invention was administered to an adult individual. Mouse C57BL/6 10 weeks of age were subjected to physical activity when administered orally connection S185 or S186 (10 mg/kg). Mice were subjected to physical stress on the “treadmill” in the form of a wheel within 30 days, once a day for 30 minutes. Mode physical activity was as follows: 5 minutes at a speed of 2 m/min, 5 minutes at a speed of 5 m/min, 5 minutes with a speed of 8 m/min, then 5 minutes is about the speed of 20 m/min At the end of the test, the effect of improving muscle endurance and muscle function were analyzed with the use of “treadmill” in the form of a wheel. As a result, the group that was administered the compound showed the best performance as regards time physical activity, and distance in comparison with the control group.

[The effect of improving memory]

The experiment on the animal (mouse C57BL/6 to 8 weeks of age) was performed to confirm the effect of treatment of dementia and Parkinson's disease using the compounds of the present invention by improving memory. Before the experiment, the model of brain disease on the animal was obtained by injection of LPS in the brain of the animal using stereotaxis. The studied group was divided depending on the introduction of a test compound and physical activity. Mode physical activity was as follows: 5 minutes at a speed of 2 m/min, 5 minutes at a speed of 5 m/min, 5 minutes with a speed of 8 m/min, then 5 minutes at a speed of 20 m/min Test water maze Morris performed at the end of the experiment. The result is presented in the following table. The experiment confirms that the connection is in accordance with the present invention and physical activity is effective in the treatment of dementia and Parkinson's disease by improving memory.

Table 6
The result of the test water maze
Test groupThe result of the test water maze
MediaPhysical activity (x)32 s
Physical activity (o)24 sec
S185Physical activity (x)20 sec
Physical activity (o)14 sec
S186Physical activity (x)27 sec
Physical activity (o)16 sec

[The effect of treatment of adipose, infiltrate liver]

The experiment on the animal (mouse C57BL/6 to 8 weeks of age) was performed to confirm the effect of treatment of fatty infiltration of the liver by using compounds of the present invention. To cause fatty infiltration of the liver used feed containing 35% fat. For 78 days with diets high in fat oral introduced the connection S185 (10 mg/kg/day). At the end of the experiment p who were given tissue and liver were fixed in a solution of paraformaldehyde and then stained with hematoxylin and eosin. The result is shown in Fig. 1. As shown in the figure, the connection of the present invention is effective in preventing fatty infiltration of the liver.

Industrial applicability

As described, the new compounds of the present invention are effective as a ligand that activates PPAR and is used for the pharmaceutical composition, the composition is a functional food additive, composition, functional drink, song, food additives, functional cosmetic compositions or the animal feed composition for the prevention or treatment of fatty infiltration of the liver, atherosclerosis or hyperlipemia, prevention or treatment of hypercholesterinemia, prevention or treatment of diabetes, prevention or treatment of obesity, strengthen muscles, prevention or treatment of muscle diseases, increase endurance, improve memory, or prevention or treatment of dementia or Parkinson's disease.

1. Derived selenate represented by chemical formula I, or its pharmaceutically acceptable salt:

where a represents O, NR, S, S(=O), S(=O)2or Se;
Represents a hydrogen or
R1represents hydrogen, C1-C8 alkyl or halogen;
R2represents hydrogen, C1-C8 alkyl, or
Xaand Xbindependently represent CR or N;
R represents hydrogen or C1-C8 alkyl;
R3represents hydrogen, C1-C8 alkyl;
R4and R5independently represent hydrogen, halogen or C1-C8 alkyl;
R6represents hydrogen, C1-C8 alkyl, or pharmaceutically acceptable organic salt;
R21, R22and R23independently represent hydrogen, halogen, NO2, C1-C7 alkyl, substituted or unsubstituted with halogen, C3-C12 heteroaryl containing one or more heteroatom(s)selected from N, O and S;
m is an integer from 1 to 4;
p is an integer from 1 to 5;
s is an integer from 1 to 5;
u is an integer from 1 to 3;
w is an integer from 1 to 4; and
alkyl, R1, R3, R4, R5and R6may be optionally substituted by one or more halogen, C3-C7-cycloalkyl or C1-C5-alkylamino.

2. Derived selenate according to claim 1 or its pharmaceutically acceptable salt, where:
R1represents hydrogen, C1-C5 alkyl substituted by one or more fluorine atoms or fluorine:
R2represents hydrogen, C1-C8 alkyl,or
Xaand Xbindependently represent CR or N;
R represents vodor the d or C1-C8 alkyl;
R3represents hydrogen or C1-C5 alkyl, substituted or unsubstituted by halogen;
R4and R5independently represent hydrogen, C1-C5 alkyl, substituted or unsubstituted by halogen;
R6represents hydrogen, C1-C8 alkyl, or pharmaceutically acceptable organic salt; and
R21, R22and R23independently represent hydrogen, halogen, NO2, C1-C7 alkyl, substituted or unsubstituted by halogen, or C3-C12 heteroaryl containing one or more heteroatom(s)selected from N, O and S.

3. Derived selenate according to claim 1 represented by the chemical formula IV, or its pharmaceutically acceptable salt:

where a represents O, NR, S, or Se; and
R1, R2, R3, m and p are as defined in chemical formula I in claim 1.

4. Derived selenate according to claim 1 represented by the chemical formula VII, or its pharmaceutically acceptable salt:

where A, R1, R2, R3, R4, R5, m and p are as defined in chemical formula I in claim 1; and
R6arepresents a C1-C8 alkyl.

5. Derived selenate according to claim 1 represented by the chemical formula VIII, or its pharmaceutically acceptable salt:


where A, R1, R2, R3, R4, R5, m and p are as defined in chemical formula I in claim 1; and
R6brepresents hydrogen or pharmaceutically acceptable organic salt.

6. The method of obtaining the derived selenate represented by chemical formula I in claim 1, including:
the interaction of the compounds represented by the chemical formula II with a Grignard reagent and then with a connection orginality;
then add the powder sulfur (S) or selenium (Se);
subsequent interaction with the compound represented by chemical formula III-A, to obtain the compound represented by chemical formula IV-A; and
protection of the phenolic group of compounds represented by the chemical formula IV-A, by introducing alkylsilane group, processing of the α-proton obtained thio - or selenoamino connection strong base, adding a compound represented by the chemical formula VI, and subsequent removal of the protective group to obtain the compound represented by chemical formula IV-B:


where a represents S or Se; R2representsor; R1, R3, R21, R22, R23XaXb, m, p, s, u and w are as defined what about in the chemical formula I in claim 1; X1represents a bromine or iodine; and X2and X3independently represent chlorine, bromine, iodine or another a group to delete.

7. The method of obtaining the derived selenate represented by chemical formula I in claim 1, including:
the interaction of the compounds represented by the chemical formula IV-A, with a Grignard reagent;
subsequent processing of the α-proton obtained thio - or selenoamino connection strong base; and
interaction with the compound represented by chemical formula VI, to obtain the compound represented by chemical formula IV-B:

where a represents S or Sc; R2representsor; R1, R3, R21, R22, R23XaXb, m, p, s, u and w are as defined in chemical formula I in claim 1; and X3represents chlorine, bromine, iodine or another a group to delete.

8. The method of obtaining the derived selenate represented by chemical formula I in claim 1, including:
the interaction of the compounds represented by the chemical formula II with the compound represented by chemical formula III-B, in the presence of copper iodide (CuI) and 2-isobutyryloxy obtaining compounds represented by the chemical formula IV-C:


where R1, R2, R3, m and p are as defined in chemical formula I in claim 1; and X1represents a bromine or iodine.

9. The method of obtaining the derived selenate represented by chemical formula I in claim 1, including:
the interaction of the compounds represented by the chemical formula IV, with the alkyl halogenated or alkilany ether alkylhalogenide acid with obtaining ester compounds represented by the chemical formula VII:

where A, R1, R2, R3, R4, R5, m and p are as defined in chemical formula I in claim 1; and R6arepresents a C1-C8 alkyl.

10. The method of obtaining the derived selenate represented by chemical formula I in claim 1, including:
the interaction of the compounds represented by the chemical formula X with the compound represented by chemical formula III-C, to obtain the compound represented by chemical formula VII-D:

where R1, R2, R3, R4, R5, m and p are as defined in chemical formula I in claim 1; R6arepresents a C1-C8 alkyl; R31represents a C1-C4 alkylsulfonyl or C6-C12 arylsulfonyl, substituted or unsubstituted C1-C4-alkyl.

11. The way the floor is to be placed in the derived selenate, represented by chemical formula I in claim 1, according to claim 9 or 10, including:
the hydrolysis of ester compounds represented by the chemical formula VII, to obtain the compound represented by chemical formula VIII:


where A, R1, R2, R3, R4, R5, m and p are as defined in chemical formula I in claim 1; R6arepresents a C1-C8 alkyl; R6brepresents hydrogen or pharmaceutically acceptable organic salt.

12. Pharmaceutical composition for the prevention or treatment of atherosclerosis or hyperlipemia, prevention or treatment of hypercholesterinemia, prevention or treatment of fatty infiltration of the liver, prevention or treatment of diabetes, prevention or treatment of obesity, strengthen muscles, prevent or treat muscle diseases, increase endurance, improve memory or the prevention or treatment of dementia or Parkinson's disease containing as an active ingredient derived selenate represented by chemical formula I according to claim 1, or its pharmaceutically acceptable salt in a quantity required to achieve a therapeutic effect, and one or more pharmaceutically acceptable excipients.

13. The composition is a functional food additives, NGF is national drink, food additive or animal feed intended for the prevention or treatment of atherosclerosis or hyperlipemia, prevention or treatment of hypercholesterinemia, prevention or treatment of fatty infiltration of the liver, prevention or treatment of diabetes, prevention or treatment of obesity, strengthen muscles, prevent or treat muscle diseases, increase endurance, improve memory or the prevention or treatment of dementia or Parkinson's disease containing as an active ingredient derived selenate represented by chemical formula I according to claim 1, or its pharmaceutically acceptable salt in a quantity required to achieve a therapeutic effect, and one or more pharmaceutically acceptable excipients.

14. Functional cosmetic composition for the prevention or treatment of obesity, muscle strengthening, or increasing endurance, containing as an active ingredient derived selenate represented by chemical formula I according to claim 1, or its pharmaceutically acceptable salt in a quantity required to achieve a therapeutic effect, and one or more pharmaceutically acceptable excipients.

15. The composition of the activator receptor-activated proliferation peroxisome (PPAR), containing as an active ingredient production is the top priority of selenate, represented by chemical formula I according to claim 1, or its pharmaceutically acceptable salt in a quantity required to achieve a therapeutic effect, and one or more pharmaceutically acceptable excipients.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method refers to medicine, namely to therapy, and concerns the correction of vascular microelement oversaving accompanying atherosclerosis. That is ensured by administering effective amounts of bisphosphonates - either xydiphone, or mediphone, or zoledronate.

EFFECT: method provides reducing the deposition of microaggregated calcium salts and other microelements in the vascular walls accompanying experimental atherosclerosis.

1 dwg, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent that can be used for treating the lipid storage disease. A pharmaceutical composition contains calcium rosuvastatin in the therapeutically effective amount, lactose as an excipient containing 94.7-98.3 wt % of lactose monohydrate and povidone, cross povidone as a desintegrant, colloidal silicone dioxide as a glidant, stearate as a lubricant, with the composition containing an inorganic salt with a polyvalent cation. The pharmaceutical composition according to the invention is characterised by the substantial reduction of calcium rosuvastatin storage destruction, fast disintegration, high release rate of the active agent, high breaking and abrasive strength, and has a shelf life of more than 2 years.

EFFECT: preparing the agent that can be used for treating the lipid storage disease.

5 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel medication, possessing nootropic and antihypoxic activity, which represents arylamides of 2-[4-oxo-3(4H)quinazolinyl]acetic acid of general formula where R=o-CH3, n-CH3 or 2,3-phenylene. Compounds demonstrated original spectrum of psychotropic action, exceeding in complex of useful properties medications of different pharmacological groups - piracetam, phenibut, phenotropil, mexidol, on experimental models in vivo.

EFFECT: compounds can be widely applied in treatment of patients with organic affection of brain.

3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a therapeutic agent for treating a peripheral artery disease or a cerebrovascular accident. The declared therapeutic agent contains a combination of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril or a salt thereof and L-carnitine or a salt thereof, or carnitine chloride.

EFFECT: invention refers to a method of treating the occlusal peripheral artery disease or cerebrovascular accident that involves administering a therapeutically effective amount of the above combination into the patient in need thereof.

10 cl, 5 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: neovasculgen 1.2 mg is introduced intramuscularly two weeks and one day before a revascularisation surgery.

EFFECT: method enables optimising the regress of lower extremity regression in the patients with arteriosclerosis obliterans ensured by improving the peripheral blood flow and maintaining the bypass patency.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. A method of treating the patients with the complicated forms of diabetic foot by blood sampling, centrifugation, plasma removal, erythrocyte fraction recovery, introduction of the angiotropic drug alprostadil, exposure to laser light at power 12 mWt for 20 minutes, addition of normal saline 100 ml in erythrocyte fraction 200 ml and reinfusion for 1.5-2 hours; ATP 2 ml is combined with the angiotropic drug alprostadil and introduced into the erythrocyte fraction; the erythrocyte fraction is reinfused every second day, alternated with intravenous drop-by-drop introduction of Vessel-DUE-F 600 LSU and actovegin 5 ml per normal saline 100 ml; the therapeutic course is 10 days.

EFFECT: using the method provides higher effectiveness and reduces the length of treatment of the patients with the complicated forms of diabetic foot syndrome, promotes the longer preservation of the achieved therapeutic effect.

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a dual action compound which is characterised by general formula [((S)-N-valeryl-N-{[2'-(lH-tetrazol-5-yl)biphenyl-4-uyl]methyl}valine) ethyl ether (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoic acid]Na1-3·xH2O, in solid form, where x equals 0-3, which is an angiotensin receptor inhibitor and a NEP inhibitor, and can be used to treat hypertension.

EFFECT: high efficiency of using the compound.

19 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is using the cannabinoid substance HU-210 as an agent simulating postconditioning. It is shown that a myocardial necrotic zone tends to decrease both absolutely, and as a percentage of an infarction zone to a hypoperfusion zone.

EFFECT: invention may be used to create a new effective agent simulating cardiac postconditioning.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a cardioprotective agent of echinochrome -2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone prepared either of a natural source (sea biscuits), or synthetically, differing by the fact that it represents an aqueous solution of echinochrome in the molecularly encapsulated form, as a water-soluble associate with a diphilic surfactant having a hydrophilic-lipophilic balance within the range of 12-18, and a method for preparing it. It has been shown that the molecular associates prepared by the above method are freely water-soluble and form stable solutions. The pre-set cardioprotector content is ensured by concentration of the initial working associate solution.

EFFECT: invention enables making the cardioprotective aqueous preparations of echinochrome in the form of the concentrated solutions or water-soluble ointment and tableted drug products, as well as the complex preparations ensured by the enrichment with the additional components via the hydrophobic and/or aqueous phase, thereby improving their bioavailability and bioefficacy.

13 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent that can be used for treating the lipid storage disease. A pharmaceutical composition contains calcium rosuvastatin in the therapeutically effective amount, lactose as an excipient containing 94.7-98.3 wt % of lactose monohydrate and povidone, cross povidone as a desintegrant, colloidal silicone dioxide as a glidant, stearate as a lubricant, with the composition containing an inorganic salt with a polyvalent cation. The pharmaceutical composition according to the invention is characterised by the substantial reduction of calcium rosuvastatin storage destruction, fast disintegration, high release rate of the active agent, high breaking and abrasive strength, and has a shelf life of more than 2 years.

EFFECT: preparing the agent that can be used for treating the lipid storage disease.

5 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition in a dose of 4 g a day containing at least 90 wt % of ethyl eicosapentaenoate is administered into an individual having initial fasting triglycerides within the approximate range of 500 mg/dl to 2000 mg/dl for a period of time effective to reduce fasting triglycerides by at least 15% as compared to initial fasting triglycerides before the first administration of the pharmaceutical composition. The second version involves administering approximately 4 g a day of the pharmaceutical composition containing at least 96 wt % ethyl eicosapentaenoate into an individual with initial fasting triglycerides from approximately 500 mg/dl to approximately 2000 mg/dl receiving neither any pharmaceutical composition, nor a concomitant statin therapy, for a period of time effective to reduce fasting triglycerides by at least 25% as compared to another similar individual. The third version provides reducing triglycerides and apoliprotein B in an individual having initial fasting triglycerides from approximately 500 mg/dl to approximately 2000 mg/dl and receiving no concomitant therapy changing the lipid profile, and involves administering approximately 4 g a day of the pharmaceutical composition containing at least 96 wt % of ethyl eicosapentaenoate for a 12-week period. The individual shows the fasting triglycerides reduction by at least 25% and the fasting apoliprotein B reduction as compared to the reference having initial triglycerides within the range from 500 mg/dl to approximately 2000 mg/dl and receiving neither any pharmaceutical composition, nor a concomitant therapy changing the lipid profile.

EFFECT: method improvement.

4 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-trimethylammonio-butyrates of formula I

,

where A1, R1, m and n are as defined in the description and in the claim, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds inhibit carnitine palmitoyl transferase (CPT) activity, in particular CPT2 activity, and can be used as medicaments for therapeutic or preventive treatment of hyperglycemia, glucose tolerance disorders, diabetes and associated pathologies, non-insulin dependent diabetes mellitus, obesity, hypertension, insulin resistance syndrome, metabolic syndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease, atherosclerosis, congestive heart failure and renal failure.

13 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), or pharmacologically acceptable salts thereof, (I), where R1 is hydrogen, halogen, nitro, amino, cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 alkyl, substituted with a halogen, C1-8 alkoxy, substituted with a halogen, C2-8 acyl or C6-10 aryl; R2 is hydrogen, C1-8 alkyl, C1-8 alkyl, substituted with a halogen, C1-8 alkyl, substituted C1-8 alkoxy, C6-10-aryl or aralkyl, consisting of C6-10 aryl and C1-8 alkylene; each of R3, R4, R5 and R6 is independently hydrogen or C1-8 alkyl; X is sulphur; Y is oxygen, NR8 or a bond, where R8 is hydrogen or C1-8 alkyl; p equals 0 or 1; A is oxygen, CH2 or N-OR9, where R9 is hydrogen, C1-8 alkyl or aralkyl, consisting of C1-8 aryl and C1-8 alkylene; which are used as a PPAR activator.

EFFECT: improved method.

17 cl, 26 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an oral preparation, possessing antihypoxic, nootropic and hypolipidemic action. The oral preparation possessing antihypoxic, nootropic and hypolipidemic action contains a combination of vinpocetine and gingko extract in the relation of 1:(3.5 -16).

EFFECT: preparation possesses the pronounced antihypoxic, nootropic and hypolipidemic action.

2 cl, 6 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology, and can be used for predicting recovery of vasoregulatory function of endothelium in patients with type 2 diabetes mellitus as a result of 6-month long treatment with atorvastatin in 20 mg dose. For this purpose before the beginning of atorvastatin therapy reactive hyperemia test is carried out. After that, assessment of results of endothelium-dependent vasodilatation is performed. For patients with initial endothelium-dependent vasodilatation not less than 8% recovery of vasoregulatory function of endothelium after 6-month long therapy with atorvastatin is predicted.

EFFECT: simple, available, non-invasive method provides possibility of predicting achievement of normal values of endothelium-dependent vasodilatation in patients with type 2 diabetes mellitus, which makes it possible to extend therapeutic possibilities already at early stages of disease, realise complex of preventive measures in due time and prevent development of severe vascular complications in said group of patients.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new phenylimidazole derivatives of general formula , wherein R1 represents a hydrogen atom, a phenyl lower-alkyl group or a pyridyl lower-alkyl group with a benzene ring and a pyridine ring are optionally substituted by 1 or 2 substitutes specified in a group consisting of halogen atoms, cyano group and halogen-substituted lower-alkyl groups; one or R2 and R3 represents a hydrogen atom, and another one represents a lower alkoxy group; R4 represents a lower-alkyl group, a difurylglyoxal group, a thienyl group or a phenyl group optionally substituted by 1 or 2 substitutes specified in a group consisting of lower-alkyl groups, lower-alkoxy groups, halogen atoms, a carboxyl group, lower alkoxycarbonyl groups, and halogen-substituted lower-alkyl groups; R5 and R6 are identical or different, and represent a hydrogen atom or a lower alkyl group; R7 and R8 are identical or different, and represent a hydrogen atom or a lower alkoxy group; provided R1 represents an unsubstituted phenyl lower-alkyl group, R2 represents a lower alkoxy group, R3 represents a hydrogen atom, R4 represents an unsubstituted phenyl group or a phenyl group containing 1 or 2 halogen-substituted lower-alkyl groups, and R5 represents a hydrogen atom, then R6 is other than a hydrogen atom. Also, the invention refers to an LPL activator, an agent for preventing or treating hyperlipidaemia, an agent for treating arteriosclerosis, and an agent for treating obesity on the basis of the compound of formula (1).

EFFECT: there are prepared new phenylimidazole derivatives effective for LPL activation.

23 cl, 10 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely to the application of a probiotic of the species Lactobacillus rhamnosus in preparing a composition for normalising a patient's pathological lipid profile, wherein the above profile comprises lysophospholipid and/or ceramide sphingolipid. A method for normalising the patient's pathological lipid profile by administering the probiotic of the species Lactobacillus rhamnosus in an amount sufficient to achieve the desired effect, into the patient.

EFFECT: using the probiotic of the species Lactobacillus rhamnosus as a part of the composition enables normalising the patient's pathological lipid profile comprising lysophospholipid and/or ceramide sphingolipid.

12 cl, 2 tbl, 4 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to experimental medicine and concerns drug-free blood hyperglycemia relief in experimental animals. For this purpose, beetroot pectin in the amount of 100 mcg/kg a day is introduced into the diet of inbred white rats simultaneously with the atherogenic diet.

EFFECT: method provides decreasing the hyperlipidaemia level ensured by reducing total cholesterol, triglycerides, very low density lipoprotein (VLDLP) and low-density lipoproteins (LDLP) in animal's blood.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

Up!