Aryl compounds as ppar ligands and their application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

 

The scope of the invention

The present invention relates to a compound represented by the formula (I), as PPAR ligand (Receptor peroxisome proliferator-activated), and its hydrate, MES, stereoisomer, and a pharmaceutically acceptable salt that can be used for the treatment of obesity, hyperlipidemia, arteriosclerosis and diabetes, and to pharmaceutical compositions, cosmetic compositions, strengthening tool, a means to improve memory, therapeutic tool for the treatment of dementia and Parkinson's disease, the composition is a functional food and feed product containing such a compound.

The formula I

Background of the invention

Among the nuclear receptors PPAR (receptor peroxisome proliferator-activated) is known as having three subtypes, which are PPARα, PPARγ and PPARδ (Nature, 1990, 347, p645-650, Proc. Natl. Acad. Sci. USA 1994, 91, p7335-7359). PPARα, PPARγ and PPARδ have tissue-specific functions in vivo and different areas for expression. PPARα mainly expressed in heart, kidney, skeletal muscle and the human colon (Mol. Pharmacol. 1998, 53, p14-22, Toxicol. Lett. 1999, 110, p119-127, J. Biol. Chem. 1998, 273, p16710-16714), and he is involved in β-oxidation in peroxisomes and mitochondria (Biol. Cell. 1993, 77, p67-76., J. Biol. Chem. 1997, 272, p27307-27312). PPARγ is expressed in skeletal muscle at low levels, but primary is about, is expressed in adipose tissue, inducyruya differentiation of adipocytes and the accumulation of energy in the form of fat, and is involved in the homeostatic regulation of insulin and glucose (Moll. Cell. 1999, 4, p585-594, p597-609, p611-617). PPARδ evolutionary preserved in mammals, including humans and vertebrates, including rodents and ascidians. First PPARδ found in Xenopus laevis, was known as PPARβ (Cell 1992, 68, p879-887), and PPARδ, found the man received another name NUC1 (Mol. Endocrinol. 1992, 6, pl634-1641), PPARδ (Proc. Natl. Acad. Sci. USA 1994, 91, p7355-7359), NUC1 (Biochem. Biophys. Res. Commun. 1993, 196, p671-677), FAAR (J. Bio. Chem. 1995, 270, p2367-2371) and so on, but now they are renamed and referred to as PPARδ. It is known that human PPARδ exists in the chromosome 6p21.1-p21.2. In rats PPARδ mRNA was detected in various cells, but lower than the level of mRNA PPARα or PPARγ (Endocrinology 1996, 137, p354-366, J. Bio. Chem. 1995, 270, p2367-2371, Endocrinology 1996, 137, p354-366). Previously conducted studies have confirmed that PPARδ plays an important role in the reproductive cell expression (Genes Dev. 1999, 13, pl561-1574) and has physiological functions differentiation of nerve cells (J. Chem. Neuroanat 2000, 19, p225-232) in the Central nervous system (CNS) and wound healing with anti-inflammatory effect (Genes Dev. 2001, 15, p3263-3277, Proc. Natl. Acad. Sci. USA 2003, 100, p6295-6296). The recent studies also confirmed that PPARδ is involved in the differentiation of adipocytes and lipid metabolism (Proc. Natl. Acad. Sci. USA 2002, 99, p303-308, Mol. Cell Biol. 2000, 20, p5119-5128). For example, activates PPARδ expression of a key gene involved in β-oxidation catabolism of fatty acids and nesvezhije proteins (UCP), a gene involved in energy metabolism, which gives effect in the treatment of obesity (Nature 2000, 406, p415-418, Cell 2003, 113, pl59-170, PLoS Biology 2004, 2, p1532-1539). Activation of PPARδ increases the level of HDL, provides an improvement in type 2 diabetes without weight change (Proc. Natl. Acad. Sci. USA 2001, 98, p5306-5311, 2003, 100, p15924-15929, 2006, 103, p3444-3449) and contributes to the treatment of arteriosclerosis by inhibiting gene associated with arteriosclerosis (Science, 2003, 302, p453-457). Therefore, studies of the regulation of lipid metabolism using PPARδ provide the key to developing a treatment for obesity, diabetes, hyperlipidemia and arteriosclerosis.

PPARδ is involved in the formation of mitochondria and conversion of muscle fibers in the muscles to increase endurance. Muscle contains muscle fiber catabolism of fatty acids (Type I), which increases stamina, and glycolate muscle fiber (Type II), which increases the strength. Muscle fiber catabolism of fatty acids (Type I), which is responsible for increasing endurance, red because it contains a large number of mitochondria and myoglobin. While glycolate muscle fiber (Type II), which is responsible for increasing strength, white. When artificially obtained when AirExpress PPARδ in the muscles of rats, 've seen a significant increase in muscle fiber Type I, in addition to the increase in myoglobin, enzymes electronic transport (cytochrome c oxidase II and IV of cytochrome c) and oxidase β fatty acids. Therefore, the running time and distance increased, respectively, 67% and 92% compared with wild-type rats (PLoS Biology, 2004, 2:e294).

Synthetic PPARδ ligands, developed to date, have lower selectivity compared to other PPARα and PPARy ligands. One of the first selective ligands was L-631033 developed Merk (J. Steroid Biochem. Mol. Biol. 1997, 63, p1-8), which was obtained by introducing a functional group capable of taking a side chain on the basis of its natural fatty acid morphology. The same research group later presented the message more effective ligand L-165041 (J. Med. Chem. 1996, 39, p2629-2654), where a compound known as agonist leukotriene has action aimed at the activation of PPARδ person. This compound showed high selectivity for hPPARδ, which is 10 times the selectivity for PPARα or PPARγ. And this connection mattered EC50530 nm. Other ligands L-796449, and L-783483 have improved affinity (EC50=7,9 nm), but have only modest selectivity against other subtypes hPPAR.

Selective PPARδ ligand,GW501516 ([2-methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methyl]sulfanyl]phenoxy]acetic acid), developed by GlaxoSmithKline, demonstrates a much better physiological effect in comparison with other ligands, developed previously (Proc. Natl. Acad. Sci. USA 2001, 98, p5306-5311).

GW501516 has excellent affinity (1-10 nm) in respect of PPARδ, and excellent selectivity for PPARα or PPARγ, which is at least 1000 times higher than the selectivity of the previous ligands.

Thiazole compound represented by formula A, as a selective activator of PPARδ has been described in WO 2001-00603 and WO 2002-62774 declared by the company Glaxo group, and WO 2003-072100 declared by the company Eli Lilly.

Formula And

where R' represents CF3or F, R" represents H, CH3or Cl, R"' represents H, CH3or CH2CH3and R ' " represents H, alkyl or arylalkyl.

However, PPARδ activity induced by all ligands that are developed today, is the result of only 30-40% of the total number landscapebased “pockets”.

Disclosure of invention

Technical task

The aim of the present invention is to provide new compounds with high selectivity for PPAR, and pharmaceutical compositions, cosmetic compositions, tonic, tool to improve memory, therapeutic environment the STW for treatment of dementia and Parkinson's disease, composition for functional food and feed product containing such a compound.

Technical solution

The present invention relates to a compound represented by the formula (I)with activity against receptor peroxisome proliferator-activated PPAR (hereinafter in this application is listed as “PPAR”), and its hydrate, MES, stereoisomer, and a pharmaceutically acceptable salt, method for their production and to their containing pharmaceutical compositions, cosmetic compositions, strengthening tool, a means to improve memory, therapeutic tool for the treatment of dementia and Parkinson's disease, the composition is a functional food and feed product.

The formula I

where A represents S or Se; B represents H or; R1is an aryl selected from the following structures:

R2represents H, C1-C8 alkyl or; R3represents H, C1-C8 alkyl or halogen; R4and R5independently represent H, C1-C8 alkyl; R6represents H, C1-C8 alkyl, C2-C7 alkenyl, alkali metal or alkaline earth metal; R11and R12independently represent H, C1-C8 alkyl or halogen; R21represents H, ha is oven, C1-C7 alkyl, heterocyclic group, or C1-C7 alkoxy; m and n independently represent integers having a value of 1-4; p is an integer having a value of 1-5; q is an integer having a value of 1-4; r is an integer having a value of 1-3; and s is an integer having a value of 1-5; and alkyl and alkoxy R2, R3, R4, R5, R6, R11, R12and R21may be substituted by one or more halogen atoms or C1-C5-alkylamino. However, the case when R2represents H and A represents S, is excluded.

In particular, R1aryl compounds represented by formula (I), which has activity against receptor peroxisome proliferator-activated (PPAR), preferably is an aryl selected from the following structures:

R2represents a C1-C8 alkyl, substituted or not substituted with halogen or; R3represents a C1-C5 alkyl, substituted or not substituted with halogen, or halogen; R4and R5independently represent H or C1-C5 alkyl, substituted or not substituted with halogen; R6represents H, C1-C7 alkyl, alkali metal or alkaline earth metal; R11and R12regardless, not only is ut a H, C1-C5 alkyl substituted by one or more fluorine atoms, or fluorine; R21represents H, halogen, C1-C5 alkyl, substituted or not substituted with halogen, or C1-C5 alkoxy, substituted or not substituted with halogen; p is an integer having a value of from 1 to 5; q is an integer having a value of from 1 to 4; and s is an integer having a value of from 1-5.

R2compounds represented by formula (I)may be optionally substituted with stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl or tert-bootrom, and benzyl, R2may be optionally substituted by fluorine, chlorine, stands, ethyl, n-propylene, isopropyl, tert-bootrom, formation, deformation, trifluoromethyl, 2-foration, pentatration, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, formatosi, deformedarse, triptoreline, 2-floratone, pentaborate;

R3represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foretel, pentafluoroethyl, fluorine or chlorine;

R4and R5independently represent H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foradil or pentafluoroethyl;

R6represents H, methyl, ethyl, n-p the filing, isopropyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foretel, pentafluoroethyl, ethynyl, 2-propenyl, 2-butenyl, 3-butenyl, Li+, Na+, K+Ca2+or Mg2+;

R11and R12independently represent H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, 2-ethylhexyl, vermeil, deformity, trifluoromethyl, 2-foretel, pentafluoroethyl, fluorine or chlorine.

A new connection according to the present invention can be obtained according to the following reaction formula.

Reaction formula 1

where A represents S or Se; B represents H or; R1is an aryl selected from the following structures:

R2represents H, C1-C8 alkyl or; R3represents H, C1-C8 alkyl or halogen; R4and R5independently represent H or C1-C8 alkyl; R6represents H, C1-C8 alkyl, C2-C7 alkenyl, alkali metal (Li+, Na+, K+or alkaline earth metal (Ca2+, Mg2+); R11and R12independently represent H, C1-C8 alkyl or halogen; R21represents H, halogen, C1-C7 alkyl, heterocyclic group, or C1-C7 alkoxy.

Prot for the scheme is means finansesanu group, which can be a C1-C4 lower alkyl, allyl, alkylsilane, alkylaryl or tetrahydropyranyl; alkyl and alkoxy R2, R3, R4, R5, R6, R11, R12and R21may be substituted by one or more halogen atoms or C1-C5-alkylamino; m and n independently represent integers having a value of 1-4; p is an integer having a value of 1-5; q is an integer having a value of 1-4; r is an integer having a value of 1-3; and s is an integer having a value of 1-5; X1represents a bromine atom or an iodine atom; X2and X3independently represent a chlorine atom, a bromine atom, an iodine atom or a removable group having reactivity with nucleophilic substitution. However, the case when R2represents H and A represents S, is excluded.

Next described is a method of obtaining of the present invention.

Method a: in a compound represented by the formula (IV)

To obtain compounds represented by formula (IV), the compound represented by formula (II), were treated with Grignard reagent to protect the phenolic group, without separation, and were subjected to interaction with the ORGANOMETALLIC reagent and S or Se, Paladino, and in the end were subjected to the interaction between the human connection, represented by formula (III). This method comprises 4 sub-phases of reactions that carry out consistently.

These sub-phases of the reactions described in detail below.

Protection of the phenolic group of the Grignard reagent

Anhydrous solvent used in this method are selected from the group consisting of those of the individual solvents as simple diethyl ether, tetrahydrofuran, hexane and heptane, and mixed solvents comprising at least two of these solvents. More preferably, when you choose a simple diethyl ether, tetrahydrofuran or a mixed solvent including simple diethyl ether and tetrahydrofuran, as anhydrous solvent. Most preferably, when choosing a polar solvent, which may be a tetrahydrofuran.

The Grignard reagent used in the present invention may be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butylacrylamide (R2MgCl) and alkalinized (R2MgBr). Of them isopropylaniline ((CH3)2CHMgCl) is most preferred.

The reaction temperature depends on the solvent, but usually, it is set in the range of -20~40°C, and preferably from 0°C to about room temperature (25°C). The reaction time depends on the temperature the s reaction and solvent, but, as a rule, it is 10-60 minutes, preferably 10-30 minutes.

Halogen-lithium substitution and the introduction of S or Se

The ORGANOMETALLIC reagent used for the halogen-lithium substitution can be selected from the group consisting of n-utility, sec-utility and tert-utility. Of these compounds tert-utility is the most preferred.

S or Se is preferred in the form of fine particles, and it is added dissolved in anhydrous tetrahydrofuran or add directly.

The reaction temperature depends on the solvent, but usually, it is set in the range of -78~25°C. the reaction Temperature for the halogen-metal substitution is preferably -75°C and the temperature for introduction S or Se is from -75 to about room temperature (25°C). The reaction of substitution of the halogen-metal occurs within 10-30 minutes, and the reaction of the introduction of S or Se occurs within 30-120 minutes.

Adding the compounds represented by formula (III)

To obtain compounds represented by formula (III)used in this way induce the Suzuki reaction mix using conventional palladium catalyst with subsequent halogenoalkanes. The halogen in the compound represented by formula (III)are selected from the group consisting of chlorine, bromine and iodine. Among them, chlorine is preferred.

The reaction temperature depends on the solvent, but usually, it is set in the range of -78~25°C, more preferably in the range of 0~10°C. the reaction Time usually is 10-120 minutes, preferably 10-60 minutes.

Method B: in a compound represented by the formula (V)

To obtain compounds represented by formula (V), the compound represented by formula (IV), preferably, subjected to interaction with the connection, usually used as fanatasies group, in the presence of a base.

Examples fanatasies groups include C1-C4 lower alkyl, allyl, alkylsilane, such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl and tert-butyldimethylsilyl, alkylaryl and tetrahydropyranyl. Of these compounds tert-bucilina group, tetrahydropyranyl group and a silyl group are preferred.

Aprotic polar solvent used in this method are selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform and dichloromethane. Specified simple ether may be selected from the group consisting of tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether of diethylene glycol, and dimethyl ether of triethylene glycol. Examples of aromatica is anyone hydrocarbon include benzene, toluene and xylene. As solvent in the present invention, the aprotic polar solvent is preferable, and in particular, N,N-dimethylformamide, chloroform or dichloromethane is preferable.

The base in this way is an amine, including pyridine, triethylamine, imidazole, N,N-dimethylaminopyridine. For the reaction of alkyl or allyl-etherified protective groups use such bases as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. In particular, imidazole and potassium carbonate are preferred.

Tetrahydropyranyl protective group is obtained by catalytic reaction of 3,4-dihydro-2H-Piran with alkyl - or allyltrichlorosilane.

The reaction temperature depends on the solvent, but usually, it is set in the range of -10~80°C, more preferably from 0 to about room temperature (25°C). The reaction time depends on the reaction temperature and solvent, but usually it ranges from one hour to one day. More preferably, when the reaction is completed within 4 hours.

Method C: the connection is represented by the formula (VII)

To obtain compounds represented by formula (VII), α-proton thio - or selenoamino compounds represented by formula (V)is subjected to the contraction in ode strong alkali getting the nucleophile, which is subjected to interaction with various electrophiles.

Anhydrous solvent used in this method are selected from the group consisting of those of the individual solvents as simple diethyl ether, tetrahydrofuran, hexane and heptane, and mixed solvents comprising at least two of these solvents. More preferably, when the anhydrous solvent choose simple diethyl ether, tetrahydrofuran or a mixed solvent including simple diethyl ether and tetrahydrofuran.

Strong alkali used for extraction of α-proton, which are selected from the group consisting of tert-butoxide potassium (t-BuOK), diisopropylamide lithium (LDA), n-utility, sec-utility and tert-utility, and of these compounds diisopropylamide lithium (LDA) is the most preferred.

The electrophile interacting with the nucleophile thio - or selenoamino, is any compound that can be easily obtained in the traditional way, well-known specialists in the field, or can be easily obtained in accordance with methods described in the reference documents, and examples include compounds containing highly reactive group of halogen, aldehyde or ketone, and his or dissolved in an anhydrous solvent to add, either on billaut directly for the reaction.

The reaction temperature depends on the solvent, but is usually -78~25°C. More preferably, when the reaction extraction of the α-proton is carried out in the presence of a strong alkali at a temperature of -75°C, which is added to the electrophile. The temperature was then slowly increased to room temperature (25°C). The reaction time is different for each reaction stage. For example, extraction of the α-proton strong alkali occurs within 10-30 minutes, and the reaction with the electrophile occurs within 30-90 minutes.

Method D: Obtaining compounds represented by formula (VIII)

The compound represented by formula (VIII), obtained by deleting fanatasies group of compounds represented by formula (VII).

The polar solvent used in this method are selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform and dichloromethane. A simple ether in the present invention can be selected from the group consisting of tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol. The alcohol may be methanol or ethanol. Examples of the aromatic hydrocarbon is benzene, toluene and xylene. As solvent is preferred in the present invention is p the polar solvent, and, in particular, tetrahydrofuran is preferable.

To remove fanatasies groups, in particular for the removal of methyl-, ethyl-, tert-butyl, benzyl or allylamino protective group, use trimethylsilylmethyl, sodium salt of acanthisitta, lithium iodide, aluminum halide, boron halide or a Lewis acid, such as triptorelin, and to remove the silyl protective group such as trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl and tert-butyldimethylsilyl, use of fluoride, such as tetrabutylammonium (Bu4N+F-), halogenated acid (hydrofluoric acid, hydrochloric acid, Hydrobromic acid or yodiewonderdog acid) or potassium fluoride.

To remove the silyl protective group, preferably the use of fluoride, and more preferably use tetrabutylammonium.

The reaction temperature depends on the method and solvent, but as a rule, is 0~120°C and preferably 10~25°C.

The reaction time depends on the reaction temperature, but generally it ranges from 30 minutes to one day. More preferably, when the reaction is completed within 2 hours.

Method E: Obtaining compounds represented by formula (IX)

To obtain compounds represented by formula (IX), connect the s, represented by formula (VIII), preferably subjected to interaction with complex alkilany ether halogenases acid or with complex alkilany ether alkylhalogenide acid in the presence of a base.

Complex alkilany ether halogenases acid or complex alkilany ether alkylhalogenide acid is a commonly used compound, which can be easily obtained. From complex alilovic esters alkylhalogenide acid compound, which cannot be easily obtained, produced by the synthesized complex Olkiluoto ether alkyloxy acid. The halogen in this way presents a chlorine atom, bromine atom and iodine atom.

The solvent used in this method may be a separate soluble solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol and methanol, or a mixed solvent obtained by mixing these compounds with 1-10% water. The most preferred solvent is a mixed solvent obtained by mixing acetone or dimethyl sulfoxide with 1-5% water.

The base used in this way is not limited, provided that it does not adversely influence the reaction, regardless of is it strong or weak, an example of which is an alkali metal hydride such as sodium hydride and lithium hydride, the hydride alkaline earth metal, such as potassium hydride, alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide, and a carbonate of an alkali metal such as lithium carbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate. Of these compounds, carbonate of an alkali metal is preferred, and more preferred is potassium carbonate.

The reaction temperature is not limited to, up to the boiling point of the solvent. However, high temperature is not preferred for inhibition of side reactions. The preferred reaction temperature is 0~90°C. the reaction Time varies depending on the reaction temperature, but usually ranges from 30 minutes to 1 day, and preferably 30-120 minutes.

Method F-I: obtaining the compound represented by formula (X)

To obtain compounds represented by the formula (X), ester of carboxylic acid compounds represented by formula (IX), in hydrolyzing the mixed solution of the soluble inorganic salt and alcohol. Or the hydrolysis of ester is carried out in a mixed solution comprising the compound represented by formula (IX), 2,0M lithium hydroxide, THF and water.

The solvent used in this way, is a soluble solvent which can be mixed with water, for example alcohols, such as methanol and ethanol.

The base used in this way, it is an aqueous solution obtained by mixing alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide, with water in a concentration of 0.1-3 N., based on the type of alkali metal salt and a carboxylic acid. The acid used to obtain the compounds represented by formula (X)represents a carboxylic acid, preferably an aqueous solution of acetic acid, an aqueous solution of sodium bisulfate (NaHSO4) or 0.1-3 N. aqueous solution of hydrochloric acid, and more preferred is 0,5M NaHSO4.

The reaction is preferably carried out at low temperature to inhibit side reactions, which typically is in the range from 0°C to room temperature. The reaction time depends on the reaction temperature, but generally is from 10 minutes to 3 hours and more preferably from 30 minutes to 1 hour. When 2,0M lithium hydroxide is subjected to interaction in a mixed solution of THF and water, the preferred reaction temperature is 0°C, and the preferred reaction time is 1-2 hours.

Method F-2: obtain the compound represented by formula (X)

<> The compound represented by formula (X), is obtained by substitution of the salt complex allyl ether of the compound represented by formula (IX), using a salt of an alkali metal salt or alkaline earth metal 2-ethylhexanoate and metal catalyst in an organic solvent.

The solvent used in this method is an anhydrous organic solvent selected from the group consisting of chloroform, dichloromethane and ethyl acetate.

The metal catalyst used in this way is palladianatravertin, and the preferred content of the catalyst is 0.01 to 0.1 equivalent.

The reaction is preferably carried out at low temperature to inhibit side reactions, which typically is in the range from 0°C to room temperature. The reaction time depends on the reaction temperature, but generally is from 10 minutes to 3 hours and more preferably from 30 minutes to 1 hour.

This salt compound can be easily isolated by centrifugation or by using ion-exchange resin. The compound obtained metal salt of the formula (X) is much easier to allocate than salt compound obtained by the method of F-1 (hydrolysis).

The compound obtained γ-type formula (I) is a substance with a PTS is ery important as PPAR ligand protein. This compound contains a chiral carbon, and this suggests that it also includes a stereoisomer of the compound. The present invention includes aryl compound represented by formula (I)and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt.

Aryl compound represented by formula (I)and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt of the present invention can be effectively used as a composition for PPAR activator. Aryl compound represented by formula (I)and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt of the present invention can activate PPAR, thus, they can effectively be used as pharmaceutical compositions for the prevention and treatment of arteriosclerosis, hyperlipidemia, obesity, diabetes, dementia or Parkinson's disease and to lower cholesterol, strengthen muscles, improve endurance and memory, and as a composition for functional food and beverages, food additives, functional cosmetics and animal feed.

Aryl compound represented by formula (I)and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt of the present invention can be used for functional beauty is a composition for the prevention and improvement of obesity and functional cosmetic compositions to strengthen muscles and increase endurance. Functional cosmetic composition to strengthen muscles and increase endurance can be formulated as an ointment, lotion or cream to be applied on the body before and after exercise, and it can be used for an extended period of time to obtain the desired effect. Aryl compound represented by formula (I)and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt of the present invention can be formulated in an ointment, and applied to an area of the body for the prevention or treatment of diabetes or diabetic foot ulcers, the so-called diabetic ulcers.

The present invention provides a pharmaceutical composition, functional excipients for food, functional beverage, food additive and feed composition for the prevention and treatment of arteriosclerosis, dementia and Parkinson's disease, to strengthen muscles, increase endurance or to improve memory containing a PPAR activator as an active ingredient.

The present invention also provides a method of screening activator for the prevention and treatment of arteriosclerosis, dementia and Parkinson's disease, strengthen muscles, increase endurance and improve memory, which includes the stage of adding funds candidate that represents and is Tivadar PPAR, to PPAR; and measuring the activity of PPAR.

Pharmaceutically acceptable salt in the present invention includes all pharmaceutically acceptable organic salts, which may form a salt with the carboxylic acid compounds of the formula (I), and inorganic salts such as alkali metal ions and alkaline earth metal ions, examples of which include Li+, Na+, K+Ca2+and Mg2+.

A therapeutically effective dose of a compound represented by the formula (I)and its hydrate, MES, stereoisomer, and a pharmaceutically acceptable salt of the present invention can be determined in accordance with the type of connection, by way of introduction, the target entity and the target disease, but she is determined in accordance with accepted medical standards. The preferred dose of a compound represented by the formula (I)is 1-100 mg/kg (body weight)/day. The frequency of injection may be one or several times a day, within the allowable daily dose. The composition of the present invention can be administered orally or parenterally and be used in the form of conventional pharmaceutical preparations. For example, the composition of the present invention can be formulated in the form of tablets, powders, dry syrups, chewable tablets, granules, capsules, soft capsules, pills, drinks, sublingual drugs the the ATA, etc. Tablets of the present invention it is possible to introduce the subject by a method or by delivery of effective dose tablets bioavailability, which is an oral way. And route of administration, or the path can be determined in accordance with characteristics, stages of the target disease and other conditions. When the composition of the present invention receive in the form of tablets, it may optionally include pharmaceutically acceptable excipients. The content and characteristics of excipient can be determined in accordance with the solubility and chemical properties of selected tablets route of administration and standard pharmaceutical practice.

The method of carrying out the invention

Practical and preferred described in this application variants embodiment of the present invention are illustrative as shown in the following examples.

However, it should be clear that the experts in this field, when considering the present disclosure, may make modifications and improvements without departure from the essence and scope of the present invention.

Example 1: Obtaining S1

Method And

468 mg (2 mmol) 4-iodine-2-METHYLPHENOL was dissolved in 20 ml of anhydrous tetrahydrofuran in the presence of nitrogen and at this point the temperature of the support is ivali at 0°C. To the mixture was slowly added 1.5 ml of isopropylacrylamide (2M), with subsequent interactions within 10 minutes. The reaction solution was cooled to -78°C. and slowly added thereto 2,00 ml of tert-utility (solution 1,7M in hexane, 1.0 equivalent). After stirring for 10 minutes, to the mixture was added 64 mg (2 mmol, 1.0 equivalent) S in the form of a solid substance at the same temperature in one step. The reaction continued for 40 minutes while raising the temperature to 15°C. 541 mg (2 mmol, 1.0 equivalent) of 4-chloromethyl-4'-trifluoromethyl-biphenyl of the formula (III) was dissolved in 10 ml of anhydrous THF at slow addition at the same temperature. After interaction within one hour the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel to obtain 630 mg (yield: 84%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,50 (d, 2H), δ7,28 (t, 2H), δ7,13 (c, 1H), δ7,07 (kV, 1H), δ6,68 (d, 1H), δ5,20 (c, 1H), δ4,02 (c, 2H), δ2,17 (c, 3H).

Example 2: Getting connection S2

Method In

748 mg (2 mmol) of S1 and 290 mg (,0 equivalents) of imidazole was completely dissolved in 20 ml of dimethylformamide. To the mixture was added 165 mg (1.1 equivalents) of tert-butyldimethylsilyloxy, followed by stirring at room temperature for 4 hours. After completion of the reaction, the organic solvent was extracted using a solution of ammonium chloride and ethyl acetate. Moisture from the organic layer was removed by drying over magnesium sulfate. For cleaning used a column of silica gel and the solvent drove under reduced pressure to obtain 928 mg (yield: 95%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,50 (d, 2H), δ7,27 (t, 2H), δ7,13 (c, 1H), δ7,05 (kV, 1H), δ6,66 (d, 1H), δ4,04 (c, 2H), δ2,15 (c, 3H), δ1,01 (c, 9H), δ 0,20 (c, 6H).

Example 3: Obtaining connection S3

Way

977 mg (2 mmol) of compound S2 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 274 μl (2.0 mmol) of benzylbromide and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the Finance solvent drove under reduced pressure and the residue was subjected to purification column chromatography on silica gel with getting 961 mg (yield: 83%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,47-7,05 (m, 11H), δ6,63 (d, 1H), δ4,30 (m, 1H), δ3,54 (m, 1H), δ3,24 (m, 1H), δ2,12 (c, 3H), δ1,01 (c, 9H), δ0,21 (c, 6H).

Example 4: Obtaining connection S4

Way

489 mg (1 mmol) of compound S2 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 1.8 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added to 270 μl (2.0 mmol) 2-chloro-5-ftorangidridy and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was subjected to purification column chromatography on silica gel with getting 523 mg (yield: 83%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (c, 4H), δ7,45 (d, 2H), δ7,31 (d, 2H), δ7,08 (m, 4H), δ6,85 (m, 1H), δ6,60 (d, 1H), δ4,50 (t, 1H), δ3,41 (d, 2H), δ2,11 (c, 3H), δ1,01 (c, 9H), δ 0,20 (c, 6H).

Example 5: Receiving connection S5

Way

489 mg (1 mmol) of compound S2 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature is anjali to -78°C. To the mixture was slowly added 1.8 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 282 μl (2.0 mmol) of 3,4,5-triterpenoid and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was subjected to purification column chromatography on silica gel with getting 518 mg (yield: 82%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,74 (kV, 2H), δ7,14 (m, 4H), δ7,03 (d, 1H), δ6,79 (t, 4H), δ6,61 (kV, 1H), δ6,41 (d, 1H), δ4,39 (t, 1H), δ3,26 (d, 2H), δ2,14 (c, 3H), δ1,01 (c, 9H), δ 0,20 (c, 6H).

Example 6: Getting connection S6

Way

489 mg (1 mmol) of compound S2 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 1.8 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 259 μl (2.0 mmol) of 2,5-diferenciada and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped using the astora ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was subjected to purification column chromatography on silica gel to obtain 503 mg (yield: 82%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,30 (d, 2H), δ7,09 (m, 4H), δ6,75 (m, 1H), δ6,54 (m, 1H), δ4,44 (t, 1H), δ3,35 (m, 2H), δ2,19 (c, 3H), 1,01 (c, 9H), δ 0,20 (c, 6H).

Example 7: Getting connection S7

Way

489 mg (1 mmol) of compound S2 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 1.8 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 300 μl (2.0 mmol) of 2,5-dichlorobenzamide and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 531 mg (yield: 82%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (c, 4H), δ7,45 (d, 2H), δ7,33 (d, 2H), δ7,08 (m, 2H), δ7,05 (m, 3H), δ6,52 (d, 1H), δ4,61 (kV, 1H), δ3,58 (m, 2H), δ2,19 (c, 3H), 1,01 (c, 9H) δ0,20 (c, 6H).

Example 8: Getting connection S8

Way

489 mg (1 mmol) of compound S2 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 1.8 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 514 mg (2.0 mmol) 2-chloro-5-triftormetilfosfinov and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 538 mg (yield: 81%) of target compound (EIMS: 665,2 [M+H]+).

Example 9: Getting connection S9

Way

1131 mg (2 mmol) of compound S3, obtained in example 3 was completely dissolved in 20 ml of tetrahydrofuran. To the mixture was slowly added 5 ml (1M solution in tetrahydrofuran, 2.5 equivalent) tetrabutylammonium (TBAF) at room temperature. After interaction within 30 minutes the organic solvent was extracted with the use of the a Finance solution of ammonium chloride and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 873 mg (yield: 94%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,47~7,05 (m, 11H), δ6,63 (d, 1H), δ4,30 (m, 1H), δ3,54 (m, 1H), δ3,24 (m, 1H), δ2,14 (c, 3H).

Example 10: the connection S10

Method E

465 mg (1 mmol) of the compound S9 obtained in example 9, was thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 134 μl (1.2 mmol, 1.2 equivalents) of a compound ethyl ester bromoxynil acid, followed by intensive stirring for 4 hours. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 512 mg (yield: 93%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,22 (m, 5H), δ7,05 (m, 4H), δ6,54 (d, 1H), δ4,59 (c, 2H), δ4,26 (m, 3H), δ3,24 (m, 2H), δ2,18 (c, 3H), δ1,27 (t, 3H).

Example 11: the connection S1l

Method E

465 mg (1 mmol) of the compound S9 obtained in example 9, was thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 210 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromo-2-methylpropanoate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 463 mg (yield: 80%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (c, 4H), δ7,43 (d, 2H), δ7,22 (m, 5H), δ7,03 (m, 4H), δ6,50 (d, 1H), δ4,28 (kV, 1H), δ4,19 (m, 2H), δ2,12 (c, 3H), δ1,54 (c, 6H), δ1,19 (t, 3H).

Example 12: the connection S12

Method E

465 mg (1 mmol) of the compound S9 obtained in example 9, was thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 146 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromobutyrate. A mixture of load, the Wali at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 470 mg (yield: 83%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,46 (d, 2H), δ7,23 (m, 5H), δ7,03 (m, 4H), δ6,51 (d, 1H), δ4,53 (t, 1H), δ4,21 (m, 3H), δ3,27 (m, 2H), δ2,19 (c, 3H), δ1,99 (m, 2H), δ1,28 (t, 3H), δ1,09 (t, 3H).

Example 13: Getting connection S13

Method E

465 mg (1 mmol) of the compound S9 obtained in example 9, was thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 193 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromo-2-methylbutyrate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept at low d is the pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 474 mg (yield: 80%) of target compound (EIMS: 593,2 [M+H]+).

Example 14: the connection S14

Method F

550 mg (1 mmol) of compound S10 obtained in example 10, was thoroughly mixed with 15 ml of THF and 10 ml of water, to the mixture was slowly added to 0.6 ml of 2,0M solution of lithium hydroxide at 0°C. After stirring at 0°C for 60 minutes, to the mixture was added 2.5 ml of 0,5M NaHSO4. The organic solvent was extracted using sodium chloride solution and ethyl acetate. After filtration the solvent is kept under reduced pressure and the residue was purified using LH-20 column chromatography to obtain 512 mg (yield: 98%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,22 (m, 5H), δ7,05 (m, 4H), δ6,54 (d, 1H), δ4,59 (c, 2H), δ4,24 (m, 1H), δ3,24 (m, 2H), δ2,18 (c, 3H).

Example 15: the connection S15

Method E

465 mg (1 mmol) of the compound S9 obtained in example 9, was thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 219 mg (1.2 mmol, 1.1 equivalent) complex allyl ether bromoxynil acid, followed by intensive stirring for 4 hours. After completion of the reaction, the organic solvent was extracted using the receiving solution of sodium chloride and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 529 mg (yield: 94%) of target compound (EIMS: 563,1 [M+H]+).

Example 16: the connection S16

Method F

504 mg (1 mmol) of compound S15 obtained in example 15, and 56 mg (0.05 mmol, 0.05 equivalent) of tetranitroaniline palladium was dissolved in 20 ml of anhydrous dichloromethane, followed by stirring at room temperature. 174 mg (1 mmol, 1.0 equivalent) of 2-ethylhexanoate potassium was dissolved in 2 ml of anhydrous dichloromethane and slowly added to the reaction solution. After stirring at room temperature for one hour was carried out by centrifugation to remove solvent. The resulting solid was washed with 20 ml dichloromethane and 20 ml of normal hexane, followed by drying to obtain 509 mg (yield: 91%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,22 (m, 5H), δ7,05 (m, 4H), δ6,54 (d, 1H), δ4,59 (c, 2H), δ4,24 (m, 1H), δ3,24 (m, 2H), δ2,18 (c, 3H).

Examples 17-150

Compounds shown in table 1, were obtained by means of examples 1-16, and NMR data for each compound are presented in table 2.

Table 1

Table 2
Example1H-NMR
17δ 7,66 (c, 4H), was 7.45 (d, 2H), 7,31 (d, 2H), was 7.08 (m, 4H), 6,55 (d, 1H), 6,85 (m, 1H), 4,58 (c, 2H), to 4.52 (t, 1H), 3,41 (kV, 2H), 2.05 is (c, 3H).
18δ 7,74 (kV, 2H), 7,16 (m, 4H), 7,02 (d, 1H), 6,80 (t, 4H), 6,61 (kV, 1H), 6,40 (d, 1H), with 4.64 (c, 2H), to 4.38 (t, 1H), 3,23 (kV, 2H), 2,14 (c, 3H).
19δ to 7.67 (c, 4H), was 7.45 (d, 2H), 7,30 (m, 2H), 7,10 (m, 4H), 6,74 (m, 1H), 4,59 (c, 2H), of 4.44 (t, 1H), and 3.31 (q, 2H), 3,41 (kV, 2H), 2,16 (c, 3H).
20δ 7,66 (c, 4H), was 7.45 (d, 2H), 7,33 (d, 2H), was 7.08 (m, 2H), 7,05 (m, 3H), of 6.50 (d, 1H), br4.61 (t, 1H), 4,56 (c, 2H), of 3.56 (m, 2H), 2,16 (c, 3H).
22δ 7,66 (c, 4H), 7,43 (d, 2H), 7,22 (m, 5H), 7,03 (m, 4H), of 6.50 (d, 1H), 4,19 (m, 2H), 2,14 (c, 3H), 1.55V (c, 6H).
23δ to 7.67 (c, 4H), was 7.45 (d, 2H), 7.23 percent (m, 5H), 7,03 (m, 4H), 6,51 (d, 1H), 4,54 (t, 1H), 4,30 (kV, 1H), 3.27 to (m, 2H),2,18 (c, 3H), of 1.98 (m, 2H), 1,10 (t, 3H).
25δ to 7.67 (c, 4H), was 7.45 (d, 2H), 7,22 (m, 5H), 7,05 (m, 4H), is 6.54 (d, 1H), 4,59 (c, 2H), 4,24 (m, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
26δ 7,66 (c, 4H), was 7.45 (d, 2H), 7,31 (d, 2H), was 7.08 (m, 4H), 6,55 (d, 1H), 6,85 (m, 1H), 4,58 (c, 2H), to 4.52 (t, 1H), 3,41 (kV, 2H), 2.05 is (c, 3H).
27δ 7,74 (kV, 2H), 7,16 (m, 4H), 7,02 (d, 1H), 6,80 (t, 4H), 6,61 (kV, 1H), 6,40 (d, 1H), with 4.64 (c, 2H), to 4.38 (t, 1H), 3,23 (kV, 2H), 2,14 (c, 3H).

28δ to 7.67 (c, 4H), was 7.45 (d, 2H), 7,30 (m, 2H), 7,10 (m, 4H), 6,74 (m, 1H), 4,59 (c, 2H), of 4.44 (t, 1H), and 3.31 (q, 2H), 3,41 (kV, 2H), 2,16 (c, 3H).
29δ 7,66 (c, 4H), was 7.45 (d, 2H), 7,33 (d, 2H), was 7.08 (m, 2H), 7,05 (m, 3H), of 6.50 (d, 1H), br4.61 (t, 1H), 4,56 (c, 2H), of 3.56 (m, 2H), 2,16 (c, 3H).
31δ 7,51 (m, 2H), 7,39 (d, 2H), 7,20~7,03 (m, 11H), to 6.57 (d, 1H), 4,63 (c, 2H), 3,25 (m,2H), 2,17 (c, 3H).
32δ 7,51 (m, 2H), 7,39 (d, 2H), 7,29 (d, 2H), 7,10 (m, 6H), at 6.84 (t, 1H), 6,55 (d, 1H), 4,57 (c, 2H), 4,51 (kV, 1H), 3,38 (m, 2H), 2,17 (c, 3H).
33δ 7,52 (t, 2H), 7,42 (d, 2H), 7,18 (d, 2H), 7,10 (m, 4H), 6,62 (m, 3H), 4,65 (c, 2H), 4,19 (kV, 1H), 3,17 (m, 2H), 2,19 (c, 3H).
34δ 7,51 (m, 2H), 7,39 (d, 2H), 7,27 (d, 2H), 7,10 (m, 5H), 6.75 in (t, 2H), return of 6.58 (d, 1H), with 4.64 (c, 2H), of 4.44 (q, 1H), 3,29 (m, 2H), 2,18 (c, 3H).
36δ 7,52 (m, 2H), 7,40 (m, 3H), 7,27~7,06 (m, 8H), 6,55 (d, 1H), 6,55 (d, 1H), 4,66 (c, 2H), 4,47 (kV, 1H), 3,44 (m, 2H), 2,17 (c, 3H).
40δ 7,51 (m, 2H), 7,39 (d, 2H), δ7,20~7,03 (m, 11H), to 6.57 (d, 1H), 4,63 (c, 2H), 3,25 (m, 2H), 2,17 (c, 3H).
41δ 7,51 (m, 2H), 7,39 (d, 2H), 7,29 (d, 2H), 7,10 (m, 6H), at 6.84 (t, 1H), 6,55 (d, 1H), 4,57 (c, 2H), 4,51 (kV, 1H), 3,38 (m, 2H), 2,17 (c, 3H).
42δ 7,52 (t, 2H), 7,42 (d, 2H), 7,18 (d, 2H), 7,10 (m, 4H), 6,62 (m, 3H), 4,65 (c, 2H), 4,19 (kV, 1H), 3,17 (m, 2H), 2,19 (c, 3H).
43δ 7,51 (m, 2H), 7,39 (d, 2H), 7,27 (d, 2H), 7,10 (m, 5H), 6.75 in (t, 2H), return of 6.58 (d, 1H), with 4.64 (c, 2H), of 4.44 (q, 1H), 3,29 (m, 2H), 2,18 (c, 3H).
45δ 7,52 (m, 2H), 7,40 (m, 3H), 7,27~7,06 (m, 8H), 6,55 (d, 1H), 6,55 (d, 1H), 4,66 (c, 2H), 4,47 (kV, 1H), 3,44 (m, 2H), 2,17 (c, 3H).
46δ 7,34 (d, 2H), 7,17 (m, 7H), 7,07 (m, 2H), 7,02 (d, 2H), 6,56 (d, 1H), 4,71 (c, 2H), 4,28 (kV, 1H), 3,18 (m, 2H), 2,17 (c, 3H).
47δ of 7.3 (d, 2H), 7,29 (d, 2H), 7,14 (m, 2H), was 7.08 (m, 4H), at 6.84 (m, 1H), 6,56 (d, 1H), with 4.64 (c, 2H), 4,50 (kV, 1H), 3,38 (m, 2H), 2,17 (c, 3H).
49δ 7,34 (d, 2H), 7,28 (d, 2H), 7,14 (m, H), was 7.08 (m, 3H), 6.75 in (t, 2H), to 6.57 (d, 1H), 4,65 (c, 2H), 4,43 (kV, 1H), 3,29 (m, 2H), 2,18 (c, 3H).
50δ 7,34 (kV, 4H), 7,21 (d, 2H), 7,15 (m, 2H), 7,07 (m, 3H), is 6.54 (d, 1H), 4,62 (c, 2H), 4,59 (kV, 1H), 3,54 (m, 2H), 2,16 (c, 3H).
55δ 7,34 (d, 2H), 7,17 (m, 7H), 7,07 (m, 2H), 7,02 (d, 2H), 6,56 (d, 1H), 4,71 (c, 2H), 4,28 (kV, 1H), 3,18 (m, 2H), 2,17 (c, 3H).

56δ 7,34 (d, 2H), 7,29 (d, 2H), 7,14 (m, 2H), was 7.08 (m, 4H), at 6.84 (m, 1H), 6,56 (d, 1H), with 4.64 (c, 2H), 4,50 (kV, 1H), 3,38 (m, 2H), 2,17 (c, 3H).
58δ 7,34 (d, 2H), 7,28 (d, 2H), 7,14 (m, 2H), was 7.08 (m, 3H), 6.75 in (t, 2H), to 6.57 (d, 1H), 4,65 (c, 2H), 4,43 (kV, 1H), 3,29 (m, 2H), 2,18 (c, 3H).
59δ 7,34 (kV, 4H), 7,21 (d, 2H), 7,15 (m, 2H), 7,07 (m, 3H), is 6.54 (d, 1H), 4,62 (c, 2H), 4,59 (kV, 1H), 3,54 (m, 2H), 2,16 (c, 3H).
61δ of 7.55 (q, 2H), 7,42 (m, 4H), 7,31 (m, 1H), 7,17 (m, 5H), 7,05 (m, 4H), is 6.54 (m, 1H), 4,60 (c, 2H), 4,28 (m, 2H), 3,21 (m, 2H), 2,17 (c, 3H).
62δ of 7.55 (q, 2H), 7,42 (m, 4H), 7,31 (m, 3H), was 7.08 (m, 4H), 6,85 (m, 1H), 6,54 (m, 1H), br4.61 (c, 2H), 4,50 (kV, 2H), 3,39 (m, 2H), 2,17 (c, 3H).
63δ EUR 7.57 (q, 2H), 7,47 (kV, 2H), 7,43 (m, 2H), 7,34 (m, 1H), 7,18 (d, 2H), to 7.09 (m, 2H), 6,63 (m, 3H), 4,65 (c, 2H), 4,19 (kV, 1H), and 3.16 (m, 2H), 2,18 (c, 3H).
66 δ 7,56 (kV, 2H), 7,41 (m, 5H), 7,33 (m, 1H), 7,27 (d, 2H), 7,12 (t, 1H), 7,06 (m, 2H), 6,55 (d, 1H), br4.61 (c, 2H), 4,48 (kV, 1H), of 3.45 (m, 2H), 2,17 (c, 3H).
70δ of 7.55 (q, 2H), 7,42 (m, 4H), 7,31 (m, 1H), 7,17 (m, 5H), 7,05 (m, 4H), is 6.54 (m, 1H), 4,60 (c, 2H), 4,28 (m, 2H), 3,21 (m, 2H), 2,17 (c, 3H).
71δ of 7.55 (q, 2H), 7,42 (m, 4H), 7,31 (m, 3H), was 7.08 (m, 4H), 6,85 (m, 1H), 6,54 (m, 1H), br4.61 (c, 2H), and 4.5 (q, 2H), 3,39 (m, 2H), 2,17 (c, 3H).
72δ EUR 7.57 (q, 2H), 7,47 (kV, 2H), 7,43 (m, 2H), 7,34 (m, 1H), 7,18 (d, 2H), to 7.09 (m, 2H), 6,63 (m, 3H), 4,65 (c, 2H), 4,19 (kV, 1H), and 3.16 (m, 2H), 2,18 (c, 3H).
75δ 7,56 (kV, 2H), 7,41 (m, 5H), 7,33 (m, 1H), 7,27 (d, 2H), 7,12 (t, 1H), 7,06 (m, 2H), 6,55 (d, 1H), br4.61 (c, 2H), 4,48 (kV, 1H), of 3.45 (m, 2H), 2,17 (c, 3H).
76δ 7,79 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,52 (t, 1H), 7,45 (d, 2H), 7.24 to~7,13 (m, 5H), was 7.08 (m, 2H), 7,03 (d, 2H), 6,56 (d, 1H), 4,63 (c, 2H), 4,29 (kV, 1H), 3,25 (m, 2H), 2,17 (c, 3H).
77δ 7,78 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,52 (t, 1H), 7,45 (d, 2H), 7,32 (kV, 2H), to 7.09 (m, 4H), at 6.84 (m, 1H), 6,54 (m, 1H), 4,63 (c, 2H), to 4.52 (q, 2H), 3,39 (m, 2H), 2,18 (c, 3H).
78δ 7,79 (c, 1H), 7,72 (d, 1H), 7,58 (d, 1H), 7,54 (t, 1H), 7,47 (d, 2H), 7,21 (d, 2H), to 7.09 (d, 2H), 6,63 (m, 2H), 6,59 (d, 1H), 4,65 (c, 2H), 4,20 (kV, 1H), 3,17 (m, 2H), 2,19 (c, 3H).
79δ 7,78 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,52 (t, 1H), 7,45 (d, 2H), 7,0 (d, 2H), to 7.09 (m, 3H), 6,76 (t, 2H), return of 6.58 (d, 1H), with 4.64 (c, 2H), 4,45 (kV, 1H), 3,30 (m, 2H), 2,19 (c, 3H).

81δ 7,79 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,44 (m, 3H), 7,12 (t, 1H), 7,07 (m, 2H), 6,56 (d, 1H), 4,68 (c, 2H), 4,49 (1, 1H), of 3.45 (m, 2H), 2,17 (c, 3H).
85δ 7,79 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,52 (t, 1H), 7,45 (d, 2H), 7.24 to~7,13 (m, 5H), was 7.08 (m, 2H), 7,03 (d, 2H), 6,56 (d, 1H), 4,63 (c, 2H), 4,29 (kV, 1H), 3,25 (m, 2H), 2,17 (c, 3H).
86δ 7,78 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,52 (t, 1H), 7,45 (d, 2H), 7,32 (kV, 2H), to 7.09 (m, 4H), at 6.84 (m, 1H), 6,54 (m, 1H), 4,63 (c, 2H), to 4.52 (q, 2H), 3,39 (m, 2H), 2,18 (c, 3H).
87δ 7,79 (c, 1H), 7,72 (d, 1H), 7,58 (d, 1H), 7,54 (t, 1H), 7,47 (d, 2H), 7,21 (d, 2H), to 7.09 (d, 2H), 6,63 (m, 2H), 6,59 (d, 1H), 4,65 (c, 2H), 4,20 (kV, 1H), 3,17 (m, 2H), 2,19 (3, 3H).
88δ 7,78 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,52 (t, 1H), 7,45 (d, 2H), 7,30 (m, 2H), to 7.09 (m, 3H), 6,76 (t, 2H), return of 6.58 (d, 1H), with 4.64 (c, 2H), 4,45 (kV, 1H), 3,30 (m, 2H), 2,19 (s, 3H).
90δ 7,79 (c, 1H), 7,72 (d, 1H), EUR 7.57 (d, 1H), 7,44 (m, 3H), 7,12 (t, 1H), 7,07 (m, 2H), 6,56 (d, 1H), 4,68 (c, 2H), 4,49 (1, 1H), of 3.45 (m, 2H), 2,17 (c, 3H).
106δ of 8.15 (d, 1H), 7,94 (d, 2H), 7,74 (kV, 1H), 7,68 (d, 2H), 7,63 (d, 1H), 7.23 percent (t, 2H), 7,16 (t, 1H), was 7.08 (d, 2H), 7,02 (d, 1H), 6,98 (kV, 1H), is 6.54 (d, 1H), 4,56 (c, 2H), 4,30 (kV, 1H), 3,37 (m, 1H), 2,15 (c, 3H).
108δ 8,10 (t, 3H), of 7.96 (d, 1H), 7,79 (m, 3H), 7,00 (c, 1H), 6,95 (d, 1H), 6.75 in (t, 2H), 6,60 (d, 1H), 4,62 (c, 2H), 4.26 deaths (kV, 1H), and 3.31 (m, 1H), 3.15 in (m, 1H), 2,15 (c, 3H).
109δ 8.17 and (c, 1H), 8,02 (d, 2H), to 7.84 (d, 1H), 7,69 (t, 3H), 7,12 (m, 2H),? 7.04 baby mortality (kV, 1H), 6,78 (t, 1H), to 6.57 (d, 1H), br4.61 (c, 2H), to 4.41 (q, 1H), 3,35 (m, 2H), 2,17 (c, 3H).
111δ 8,18 (c, 1H), 8,01 (d, 2H), of 7.90 (d, 1H), 7,70 (kV, 3H), 7,44 (t, 1H), 7,30 (m, 1H), 7,14 (t, 1H), 7,03 (m, 2H), 6,56 (d, 1H), 4,60 (c, 2H), of 4.44 (q, 1H), 3,53 (m, 1H), 3,41 (m, 1H), 2,16 (c, 3H).
115δ of 8.15 (d, 1H), 7,94 (d, 2H), 7,74 (kV, 1H), 7,68 (d, 2H), 7,63 (d, 1H), 7.23 percent (t, 2H), 7,16 (t, 1H), was 7.08 (d, 2H), 7,02 (d, 1H), 6,98 (kV, 1H), is 6.54 (d, 1H), 4,56 (c, 2H), 4,30 (kV, 1H), 3,37 (m, 1H), 2,15 (c, 3H).
117δ 8,10 (t, 3H), of 7.96 (d, 1H), 7,79 (m, 3H), 7,00 (c, 1H), 6,95 (d, 1H), 6.75 in (t, 2H), 6,60 (d, 1H), 4,62 (c, 2H), 4.26 deaths (kV, 1H), and 3.31 (m, 1H), 3.15 in (m, 1H), 2,15 (c, 3H).
118δ 8.17 and (c, 1H), 8,02 (d, 2H), to 7.84 (d, 1H), 7,69 (t, 3H), 7,12 (m, 2H),? 7.04 baby mortality (kV, 1H), 6,78 (t, 1H), to 6.57 (d, 1H), br4.61 (c, 2H), to 4.41 (q, 1H), 3,35 (m, 2H), 2,17 (c, 3H).

120δ 8,18 (c, 1H), 8,01 (d, 2H), of 7.90 (d, 1H), 7,70 (kV, 3H), 7,44 (t, 1H), 7,30 (m, 1H), 7,14 (t, 1H), 7,03 (m, 2H), 6,56 (d, 1H), 4,60 (c, 2H), of 4.44 (q, 1H), 3,53 (m, 1H), 3,41 (m, 1H), 2,16 (c, 3H).
121δ of 7.69 (m, 2H), to 7.15 (m, 9H), of 6.52 (d, 1H), 6,24 (c, 1H), and 58 (c, 2H), 4,23 (kV, 1H), 3,39 (m, 2H), 2,16 (c, 3H).
122δ 7,73 (m, 2H), 7,14 (m, 6H), 6.90 to (m, 1H), 6,56 (d, 2H)and 4.65 (q, 1H), 4,59 (c, 2H), 3,42 (m, 2H), 2,17 (c, 3H).
123δ of 7.69 (m, 2H), of 7.48 (d, 2H), 7,21 (d, 2H), 7,10 (d, 2H), 6,63 (m, 2H), 4,65 (c, 2H), 4,20 (t, 1H), 3,17 (m, 2H), 2,18 (c, 3H).
124δ 7,73 (m, 2H), δ7,14 (m, 6H), δ6,90 (m, 1H), δ6,56 (d, 2H), δ4,59 (c, 2H), δ4,26 (kV, 1H), δ3,39 (m, 2H), δ2,17 (c, 3H).
130δ of 7.69 (m, 2H), to 7.15 (m, 9H), of 6.52 (d, 1H), 6,24 (c, 1H), 4,58 (c, 2H), 4,23 (kV, 1H), 3,39 (m, 2H), 2,16 (c, 3H).
131δ 7,73 (m, 2H), 7,14 (m, 6H), 6.90 to (m, 1H), 6,56 (d, 2H)and 4.65 (q, 1H), 4,59 (c, 2H), 3,42 (m, 2H), 2,17 (c, 3H).
132δ 7,73 (m, 2H), 7,14 (m, 6H), 6.90 to (m, 1H), 6,56 (d, 2H)and 4.65 (q, 1H), 4,59 (c, 2H), 3,42 (m, 2H), 2,17 (c, 3H).
133δ 7,73 (m, 2H), 7,14 (m, 6H), 6.90 to (m, 1H), 6,56 (d, 2H), 4,59 (c, 2H), 4.26 deaths (kV, 1H), 3,39 (m, 2H), 2,17 (c, 3H).
136δ 7,30~to 6.57 (m, 16H), 6,55 (d, 1H), 4,59 (c, 2H), 4,18 (kV, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
137δ 7,30~to 6.57 (m, 14H), is 6.54 (d, 1H), δ4,58 (c, 2H), 4,34 (kV, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
139δ 7,30~6,55 (m, 14H), is 6.54 (d, 1H), 4,59 (c, 2H), 4,34 (kV, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
140δ 7,29~of 6.52 (m, 14H), of 6.52 (d, 1H), 4,57 (c, 2H), 4,50 (kV, 1H), 3,47 (m, 2H), 2,17 (c, 3H).
145δ 7,30~to 6.57 (m, 16H), 6,55 (d, 1H), 4,59 (c, 2H), 4,18 (kV, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
146δ 7,30~to 6.57 (m, 14H), is 6.54 (d, 1H), 4,58 (c, 2H), 4,34 (kV, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
148δ 7,30~6,55 (m, 14H), is 6.54 (d, 1H), 4,59 (c, 2H), 4,34 (kV, 1H), 3,24 (m, 2H), 2,18 (c, 3H).
149δ 7,29~of 6.52 (m, 14H), of 6.52 (d, 1H), 4,57 (c, 2H), 4,50 (kV, 1H), 3,47 (m, 2H), 2,17 (c, 3H).

Example 151 connection S151

Method And

590 mg of 4-iodine-2-METHYLPHENOL was dissolved in 20 ml of anhydrous tetrahydrofuran in the presence of nitrogen and at this point the temperature was maintained at 0°C. To the mixture was slowly added 1.5 ml of isopropylacrylamide (2M), with subsequent interactions within 10 minutes. The reaction solution was cooled to -78°C and slowly added 2.00 ml of tert-utility (solution 1,7M in hexane, 1.0 equivalent). After stirring for 10 minutes, to the mixture was added 158 mg Se in the form of solids (2 mmol, 1.0 equivalent) at the same temperature in one step. The reaction continued for 40 minutes while raising the temperature to 15°C. 541 mg (2 mmol, 1.0 equivalent) of 4-chloromethyl-4'-triptoreline astoral in 10 ml of anhydrous THF and slowly added to the reaction mixture at the specified temperature. After interaction within one hour the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 712 mg (yield: 84%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,50 (d, 2H), δ7,28 (t, 2H), δ7,13 (c, 1H), δ7,07 (kV, 1H), δ6,68 (d, 1H) δ5,20 (c, 1H), δ4,02 (c, 2H), δ2,17 (c, 3H).

Example 152: Getting connection S152

Method In

842 mg (2 mmol) of the compound S151 and 290 mg (2.0 equivalents) of imidazole was completely dissolved in 20 ml of dimethylformamide. To the mixture was slowly added 165 mg (1.1 equivalents) of tert-butyldimethylsilyloxy, followed by stirring at room temperature for 4 hours. After completion of the reaction, the organic solvent was extracted using a solution of ammonium chloride and ethyl acetate. Moisture from the organic layer was removed by drying over magnesium sulfate. For cleaning used a column of silica gel and the solvent drove under reduced pressure to obtain 1018 mg (yield: 95%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,7 (c, 4H), δ7,50 (d, 2H), δ7,27 (t, 2H), δ7,13 (c, 1H), δ7,05 (kV, 1H), δ6,66 (d, 1H), δ4,04 (c, 2H), δ2,15 (c, 3H), δ1,01 (c, 9H), δ 0,20 (c, 6H).

Example 153: connection S153

Way

1071 mg (2 mmol) of the compound S152 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 301 μl (2.2 mmol) of benzylbromide and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 938 mg (yield: 75%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,47~7,05 (m, 11H), δ6,63 (d, 1H), δ4,30 (m, 1H), δ3,54 (m, 1H), δ3,24 (m, 1H), δ2,12 (c, 3H), δ1,01 (c, 9H), δ0,21 (c, 6H).

Example 154: Getting connection S154

Way

1071 mg (2 mmol) of the compound S152 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) d is Isopropylamine lithium (LDA). Then to the reaction solution was added 297 μl (2.2 mmol) of 2-chloro-5-ftorangidridy and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 1017 mg (yield: 75%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (c, 4H), δ7,45 (d, 2H), δ7,31 (d, 2H), δ7,08 (m, 4H), δ6,85 (m, 1H), δ6,60 (d, 1H), δ4,50 (t, 1H), δ3,41 (d, 2H), δ2,11 (c, 3H), δ1,01 (c, 9H), δ 0,20 (c, 6H).

Example 155: Getting connection S155

Way

1071 mg (2 mmol) of the compound S152 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 310 μl (2.2 mmol) of 3,4,5-triterpenoid and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted with the use of the ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 1020 mg (yield: 75%) of target compound (EIMS: 681,1 [M+H]+).

Example 156: Getting connection S156

Way

1071 mg (2 mmol) of the compound S152 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 285 μl (2.2 mmol) of 2,5-diferenciada and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 992 mg (yield: 75%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,30 (d, 2H), δ7,09 (m, 4H), δ6,75 (m, 1H), δ6,54 (m, 1H), δ4,44 (t, 1H), δ3,35 (m, 2H), δ2,19 (c, 3H), 1,01 (c, 9H), δ 0,20 (c, 6H).

Example 157: Getting connection S157

Way

1071 mg (2 mmol) connect the deposits S152 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 330 μl (2.2 mmol) of 2, 5-dichlorobenzamide and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with a solution of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 1042 mg (yield: 75%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (c, 4H), δ7,45 (d, 2H), δ7,33 (d, 2H), δ7,08 (m, 2H), δ7,05 (m, 3H), δ6,52 (d, 1H), δ4,61 (kV, 1H), δ3,58 (m, 2H), δ2,19 (c, 3H), 1,01 (c, 9H), δ 0,20 (c, 6H).

Example 158: Getting connection S158

Way

1071 mg (2 mmol) of the compound S152 was dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature was lowered to -78°C. To the mixture was slowly added 3.6 ml (1,8M, 2.0 equivalent) of diisopropylamide lithium (LDA). Then to the reaction solution was added 561 mg (2.2 mmol) of 2-chloro-5-triftormetilfosfinov and the temperature was slowly raised to room temperature. After interaction within 30 minutes the reaction was stopped with the help of p is the target of ammonium chloride and the organic solvent was extracted using ethyl acetate and sodium chloride solution and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 1068 mg (yield: 75%) of target compound (EIMS: 713,1 [M+H]+).

Example 159: Getting connection S159

Method D

1251 mg (2 mmol) of the compound S153, obtained in example 153, was completely dissolved in 20 ml of tetrahydrofuran. To the mixture was slowly added 5 ml (1M solution in tetrahydrofuran, 2.5 equivalent) tetrabutylammonium (TBAF) at room temperature. After interaction within 30 minutes the organic solvent was extracted using a solution of ammonium chloride and ethyl acetate, then dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel with getting 940 mg (yield: 92%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,47~7,05 (m, 11H), δ6,63 (d, 1H), δ4,30 (m, 1H), δ3,54 (m, 1H), δ3,24 (m, 1H), δ2,14 (c, 3H).

Example 160: Getting connection S160

Method In

511 mg (1 mmol) of the compound S159 obtained in example 159, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture add the Yali 134 μl (1.2 mmol, 1.2 equivalent) complex ethyl ester bromoxynil acid, followed by intensive stirring for 4 hours. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to obtain 556 mg (yield: 93%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,22 (m, 5H), δ7,05 (m, 4H), δ6,54 (d, 1H), δ4,59 (c, 2H), δ4,26 (m, 3H), δ3,24 (m, 2H), δ2,18 (c, 3H), δ1,27 (t, 3H).

Example 161: Getting connection S161

Method E

511 mg (1 mmol) of the compound S159 obtained in example 159, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 210 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromo-2-methylpropanoate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over sulfate is Agnes to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to obtain 500 mg (yield: 80%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (c, 4H), δ7,43 (d, 2H), δ7,22 (m, 5H), δ7,03 (m, 4H), δ6,50 (d, 1H), δ4,28 (kV, 1H), δ4,19 (m, 2H), δ2,12 (c, 3H), δ1,54 (c, 6H), δ1,19 (t, 3H).

Example 162: Getting connection S162

Method E

511 mg (1 mmol) of the compound S159 obtained in example 159, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 146 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromobutyrate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 519 mg (yield: 83%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,46 (d, 2H), who of 7.23 (m, 5H), δ7,03 (m, 4H), δ6,51 (d, 1H), δ4,53 (t, 1H), δ4,21 (m, 3H), δ3,27 (m, 2H), δ2,19 (c, 3H), δ1,99 (m, 2H), δ1,28 (t, 3H), δ1,09 (t, 3H).

Example 163: Getting connection S163

Method E

511 mg (1 mmol) of the compound S159 obtained in example 159, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 193 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromo-2-methylbutyrate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure, and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 512 mg (yield: 80%) of target compound (EIMS: 641,1 [M+H]+).

Example 164: Getting connection S164

Method F

597 mg (1 mmol) of the compound S160 obtained in example 160, thoroughly mixed with 15 ml of THF and 10 ml of water, then slowly added to 0.6 ml of 2,0M solution of lithium hydroxide at 0°C. After stirring at 0°C for 60 the minutes to the mixture was added 2.5 ml of a solution of 0,5M NaHSO 4. The organic solvent was extracted using sodium chloride solution and ethyl acetate. After filtration the solvent is kept under reduced pressure and the residue was purified using LH-20 column chromatography with getting 517 mg (yield: 93%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,22 (m, 5H), δ7,05 (m, 4H), δ6,54 (d, 1H), δ4,59 (c, 2H), δ4,24 (m, 1H), δ3,24 (m, 2H), δ2,18 (c, 3H).

Example 165: Getting connection S165

Method E

511 mg (1 mmol) of the compound S159 obtained in example 159, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 219 mg (1.2 mmol, 1.1 equivalent) complex allyl ether bromoxynil acid, followed by intensive stirring for 4 hours. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure, and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 572 mg (yield: 94%) of target compound (EIMS: 611,1 [M+H]+).

Example 166: Getting connection S16

Method F

504 mg (1 mmol) of the compound S165, obtained in example 165, and 56 mg (0.05 mmol, 0.05 equivalent) of tetranitroaniline palladium was dissolved in 20 ml of anhydrous dichloromethane, followed by stirring at room temperature. 174 mg (1 mmol, 1.0 equivalent) of 2-ethylhexanoate potassium was dissolved in 2 ml of anhydrous dichloromethane and slowly added to the reaction solution. After stirring at room temperature for one hour was carried out by centrifugation to remove solvent. The resulting solid was washed with 20 ml dichloromethane and 20 ml of normal hexane, followed by drying to obtain 547 mg (yield: 90%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,67 (c, 4H), δ7,45 (d, 2H), δ7,22 (m, 5H), δ7,05 (m, 4H), δ6,54 (d, 1H), δ4,59 (c, 2H), δ4,24 (m, 1H), δ3,24 (m, 2H), δ2,18 (c, 3H).

Examples 167-301

Compounds shown in table 3, were obtained by means of examples 151-166, and NMR data of compounds similar to the compounds of examples 17-149.

Table 3

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Example 302: Receive connection W302

Method E

421 mg (1 mmol) of the compound S151 obtained in example 151, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 134 μl (1.2 mmol, 1.2 equivalents) of a compound ethyl ester bromoxynil acid, followed by intensive stirring for 4 hours. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to obtain 472 mg (yield: 93%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (d, 4H), δ7,46 (d, 2H), δ7,23 (m, 4H), δ6,57 (d, 1H), δ4,61 (c, 2H), δ4,25 (kV, 2H), δ4,04 (c, 2H), δ2,23 (c, 3H), δ1,28 (c, 3H).

Example 303: Getting connection S303

Method E

421 mg (1 mmol) of the compound S151 obtained in example 151, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2 mmol, 2.5 equivalent) of potassium carbonate at room temperature. To the mixture was added 210 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromo-2-methylpropanoate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 428 mg (yield: 80%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (d, 4H), δ7,46 (d, 2H), δ7,23 (m, 4H), δ6,57 (d, 1H), δ4,25 (kV, 2H), δ4,04 (c, 2H), δ2,23 (c, 3H), δ1,56 (c, 6H), δ1,28 (c, 3H).

Example 304: Receive connection S304

Method E

421 mg (1 mmol) of the compound S151 obtained in example 151, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 146 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromobutyrate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After conclusion of the Oia reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 444 mg (yield: 83%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (d, 4H), δ7,46 (d, 2H), δ7,23 (m, 4H), δ6,57 (d, 1H), δ4,33 (t, 1H), δ4,25 (kV, 2H), δ4,04 (c, 2H), δ2,23 (c, 3H), δ2,00 (m, 2H), δ1,56 (c, 6H), δ1,28 (c, 3H), δ1,25 (m, 3H).

Example 305: Getting connection S305

Method E

421 mg (1 mmol) of the compound S151 obtained in example 151, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 193 μl (1.2 mmol, 1.2 equivalent) ethyl-2-bromo-2-methylbutyrate. The mixture was heated at a temperature of 60~90°C when adding an additional amount of acetone for 4 hours under vigorous stirring. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. After filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 440 mg (yield: 80%) of target compound (EIMS: 551,1 [M+H]+).

Por the measures 306: Getting connection S306

Method F

460 mg (1 mmol) of the compound W302 obtained in example 302, thoroughly mixed with 15 ml of THF and 10 ml of water, to the mixture was slowly added to 0.6 ml of 2,0M solution of lithium hydroxide at 0°C. After stirring at 0°C for 60 minutes, to the mixture was added 2.5 ml of a solution of 0,5M NaHSO4. The organic solvent was extracted using sodium chloride solution and ethyl acetate. After filtration the solvent is kept under reduced pressure and the residue was purified using LH-20 column chromatography with getting 472 mg (yield: 93%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (d, 4H), δ7,46 (d, 2H), δ7,23 (m, 4H), δ6,57 (d, 1H), δ4,61 (c, 2H), δ4,04 (c, 2H), δ2,22 (c, 3H).

Example 307: Getting connection S307

Method E

421 mg (1 mmol) of the compound S151 obtained in example 151, thoroughly mixed with 10 ml of acetone containing 5% water, and 346 mg (2.5 mmol, 2.5 equivalents) of potassium carbonate at room temperature. To the mixture was added 219 mg (1.2 mmol, 1.2 equivalents) of a compound allyl ether bromoxynil acid, followed by intensive stirring for 4 hours. After completion of the reaction, the organic solvent was extracted using sodium chloride solution and ethyl acetate and dried over magnesium sulfate to remove moisture from the organic layer. On the Le filtration the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel using hexane/ethyl acetate (vol./about. = 5:1) to give 467 mg (yield: 90%) of target compound (EIMS: 521,1 [M+H]+).

Example 308: connection S308

Method F

519 mg (1 mmol) of the compound S307 obtained in example 307, and 56 mg (0.05 mmol, 0.05 equivalent) of tetranitroaniline palladium was dissolved in 20 ml of anhydrous dichloromethane, followed by stirring at room temperature. 174 mg (1 mmol, 1.0 equivalent) of 2-ethylhexanoate potassium was dissolved in 2 ml of anhydrous dichloromethane and slowly added to the reaction solution. After stirring at room temperature for one hour was carried out by centrifugation to remove solvent. The resulting solid was washed with 20 ml dichloromethane and 20 ml of normal hexane, followed by drying to obtain 471 mg (yield: 91%) of target compound.

1H NMR (300 MHz, CDCl3) δ7,66 (d, 4H), δ7,46 (d, 2H), δ7,23 (m, 4H), δ6,57 (d, 1H), δ4,61 (c, 2H), δ4,04 (c, 2H), δ2,22 (c, 3H).

Examples 309-348

Compounds shown in Table 4, were obtained by means of examples 302-308, and NMR data for each compound are presented in table 5.

Table 4

Table 5
Etc.1H-NMR
309δ 7,52 (m, 2H), 7,40 (d, 2H), 7,24 (d, 2H), 7,18 (d, 2H), to 7.09 (t, 2H), to 6.57 (d, 1H), br4.61 (c, 2H), 4.04 the (c, 2H), 2,22 (c, 3H).
313δ 7,52 (m, 2H), 7,40 (d, 2H), 7,24 (d, 2H), 7,18 (d, 2H), to 7.09 (t, 2H), to 6.57 (d, 1H), br4.61 (c, 2H), 4.04 the (c, 2H), 2,22 (c, 3H).
314δ 7,34 (d, 2H), 7.24 to~7,13 (m, 6H), to 6.57 (d, 1H), br4.61 (c, 2H), was 4.02 (c, 2H), 2,23 (c, 3H).
318δ 7,34 (d, 2H), 7.24 to~7,13 (m, 6H), to 6.57 (d, 1H), br4.61 (c, 2H), was 4.02 (c, 2H), 2,23 (c, 3H).
319δ 7,56 (d, 2H), 7,43 (m, 4H), 7,32 (m, 1H), 7,22 (m, 4H), 6,56 (d, 1H), br4.61 (c, 2H), 4.04 the (c, 2H), 2,23 (c, 3H).
323δ 7,56 (d, 2H), 7,43 (m, 4H), 7,32 (m, 1H), 7,22 (m, 4H), 6,56 (d, 1H), br4.61 (c, 2H), 4.04 the (c, 2H), 2,23 (c, 3H).
324δ 7,72 (m, 2H), to 7.59~7,42 (m, 7H), 7,21 (d, 1H), 6,59 (d, 1H), br4.61 (c, 2H), 4.04 the (c, 2H), 2,23 (c, 3H).
328δ 7,72 (m, 2H), to 7.59~7,42 (m, 7H), 7,21 (d, 1H), 6,59 (d, 1H), br4.61 (c, 2H), 4.04 the (c, 2H), 2,23 (c, 3H).
329δ 8,94 (c, 1H), 8,04 (kV, 1H), to 7.77 (d, 1H), to 7.59 (d, 2H), 7,25 (d, 1H), was 7.08 (d, 1H), 6,69 (kV, 1H), 6,34 (d, 1H), with 4.64 (c, 2H), 3,97 (c, 2H), 2,24 (c, 3H).
333δ 8,94 (c, 1H), ,04 (kV, 1H), to 7.77 (d, 1H), to 7.59 (d, 2H), 7,25 (d, 1H), was 7.08 (d, 1H), 6,69 (kV, 1H), 6,34 (d, 1H), with 4.64 (c, 2H), 3,97 (c, 2H), 2,24 (c, 3H).
339δ 7,71 (m, 2H), 7,34 (c, 1H), 7,27 (m, 1H), 7,13 (t, 2H), 6,59 (d, 1H), 6,28 (c, 1H), 4,62 (c, 2H), 3,97 (c, 2H), 2,25 (c, 3H).
343δ 7,71 (m, 2H), 7,34 (c, 1H), 7,27 (m, 1H), 7,13 (t, 2H), 6,59 (d, 1H), 6,28 (c, 1H), 4,62 (c, 2H), 3,97 (c, 2H), 2,25 (c, 3H).
344δ 7,31 (m, 2H), 7,24 (d, 2H), 7,18 (m, 2H), was 7.08 (t, 1H), 6,93 (d, 2H), 6.89 in (d, 1H), 6,82 (kV, 1H), 6,76 (c, 1H), is 6.54 (d, 1H), 4,60 (c, 2H), 3,95 (c, 2H), 2,22 (c, 3H).
348δ 7,31 (m, 2H), 7,24 (d, 2H), 7,18 (m, 2H), was 7.08 (t, 1H), 6,93 (d, 2H), 6.89 in (d, 1H), 6,82 (kV, 1H), 6,76 (c, 1H), is 6.54 (d, 1H), 4,60 (c, 2H), δ3,95 (c, 2H), 2,22 (c, 3H).

Experimental example 1

The test activity and cytotoxicity

The potency of the compound represented by formula (I)according to the present invention in respect of PPARδ was confirmed by analysis of transfection. In addition, we examined the selectivity for subtypes of PPAR, such as PPARα and PPARγ. Cytotoxicity was tested using MTT analysis and in vivo activity was investigated in the experiment on animals.

Analysis of transfection

This analysis used the CV-1 cells. Cells were planted in 96-well plate containing DMEM, supplemented with 10% FBS, DBS (delipidation) and 1% penicillin/streptomycin, and coltivirus is whether at 37°C, 5% CO 2the incubator. The experiment was carried out in accordance with the stages of inoculation, transfection, sample processing and confirmation. In particular, CV-1 cells were planted in 96-well plates (5000 cells/well), followed by transfection in 24 hours. For transfection used a full-sized plasmid DNA PPAR, reporter DNA, confirming the activity of PPAR, thanks to its luciferase activity, DNA β-galactosidase, providing information on the effectiveness of transfection, and the reagent for transfection. The samples were dissolved in dimethyl sulfoxide (DMSO) and this solution was treated cells through a medium at various concentrations. After cultivation of the cells in the incubator for 24 hours the cells were literally using lisanova buffer. Activity luciferase and activity of β-galactosidase was measured using a luminometer and a reader for microplates. The obtained values for luciferase modified using the values for β-galactosidase. These values were used to plot and calculated EC50.

Table 6
Data EC50
Connection # hPPARδhPARα hPPARγ
S142,6 nmiaia
S229,3 nmiaia
S2312 nmiaia
S463,7 nmiaia
S6633 nmiaia
S1063,2 nmiaia
S1644,5 nmiaia
S30653 nmiaia
ia = not active

As shown in table 6, the compounds of the present invention are highly selective in respect of PPARδ. The active compounds according to the present invention in respect of PPARδ was 2 nm-200 nm.

MTT analysis

MTT analysis is carried out to test the cytotoxicity of the compounds, represented by formula (I)according to the present invention. MTT is a yellow substance, soluble in water, but when it is introduced into the living cell, it is transformed into insoluble crystal purple color under the action of dehydrogenase in the mitochondria. Cytotoxicity can be confirmed by measuring OD550after dissolving MTT in dimethyl sulfoxide. The experiment was carried out as follows.

CV-1 cells were planted in 96-well plates (5000 cells/well). Cells were cultured at 37°C, 5% CO2incubator for 24 hours and treated samples at various concentrations. Then the cells were again cultured for 24 hours and added MTT reagent. After culturing for 15 minutes the resulting purple crystals were dissolved in dimethyl sulfoxide. The optical density was measured using a reader for microplates for confirmation of cytotoxicity.

As a result, it was confirmed that the compound represented by formula (I), has no cytotoxicity even at concentrations 100-1000 times higher than the value EC50in relation to PPAR.

Testing on animals

The effect of inhibition of obesity

The test animals with the use of mice was performed to confirm the in vivo effect of the compounds of the present invention. Used C7BL/6 (SLC Co.) mice aged 8 weeks. To induce obesity, the animals were given feed containing 35% fat. When animal feeding this food with a high content of fat in 60 days they are orally administered the media, S14, S46 and S106 (10 mg/kg/day). As a result, only 31% of a group of mice that were treated S14, showed weight gain, compared with the group handling the media, and 43% and 37% of group processing of S46 and group processing S106, respectively, showed a weight gain.

The effect of an improvement in diabetes

GTT (test for glucose tolerance) was carried out to confirm the improving effect of the compounds of the present invention for diabetes. Glucose (1.5 g/kg) intraabdominal were injected into mice, which was pre-treated for 57 days by oral administration samples. The level of blood glucose was measured every hour. Fasting glucose was lower in the treatment groups S14, S46 and S106 (10 mg/kg/day) compared with the control group. The group that was treated with the compound of the present invention, showed a rapid decrease in the level of glucose in the blood after 20-40 minutes and clearance of glucose in 100 minutes. At the same time, the group handling the media the level of glucose in the blood is not restored to normal even after 120 minutes. The presented results show that the compounds S14, S46 and S106 have the effect of improving diabetes.

Effectively the gain muscular endurance and improve muscle function

Testing on animals was carried out to confirm this effect of the composition of the present invention, as increased muscle endurance and improve muscle function. A large part of the muscle is formed in the stage of development. Thus, compounds S14, S46 and S106 (10 mg/kg/day) treated pregnant mice during either pregnancy or lactation, or both during pregnancy and during lactation. Weight gain and growth rate did not differ significantly in fetuses of the control group and group processing. Muscles were visually examined after removal of the skin. As a result the muscles in the group treatment were red, in contrast to the control group. Was carried out by ATPase staining and immunoablative. As a result, in the processing group observed an increase in muscle fiber type I. the Role of changes in muscle fiber to increase muscle endurance and muscle function were investigated in the test on the treadmill. As a result, the time begonia animals in the group treatment was much greater compared with the control group.

Table 7
The results of tests of muscular endurance
The growth rate of group (treatment/control group is (a) PregnancyLactationPregnancy + lactation
TimeLengthTimeLengthTimeLength
S142.4 times2.5 times2.12,2
times
3.6 times3.9
S461.91.91.5 times1.5 times2.8 times3.0 times
S1062.12.21.81.83.2 times3.4 times

When the compound of the present invention was treated adults, muscle endurance and muscle function was also improved. In particular, S14, S46 and S106 oral was administered to C57BL/6 mice aged 10 weeks in to the ncentratio 10 mg/kg, during the introduction of the mice I was forced to move. The test was carried out using a treadmill for 30 minutes every day for 30 days, specifically at a speed of 2 m/min for the first 5 minutes, 5 m/min for 5 minutes, 8 m/min for 5 minutes and 20 m/min in the last 5 minutes. At the end of the test the effect of increasing muscle endurance and muscle function was tested on the treadmill. As a result, the movement (increase in the processing group compound S14: 1.5 times, in the processing group connection S46: 1.3 times, in the processing group connection S106: 1.4 times) and the distance (the increase in the processing group compound S14: 1.5 times, in the processing group connection S46: 1.3 times, in the processing group connection S106: 1.4 times) was increased in group treatment compared with the control group.

Improve memory

Testing on animals was carried out to study therapeutic effect of the compounds of the present invention for dementia and Parkinson's disease, based on the action of this compound, aimed at improving memory. To confirm the effect of the compounds of the present invention during brain development connection orally was administered to pregnant mice at a concentration of 10 mg/kg during pregnancy and lactation. Performed test method is orrisa using a water maze to determine any changes in brain function in the processing group and the control group. In this test examined the assimilation of spatial skills and memory, mainly dependent on the hippocampus in the brain. As a result, the average time spent on discovery platform, was much shorter in group treatment compared with the control group; specifically, the processing group took 5.2 sec to find the platform (group processing connection S14: 5.2 sec, group processing S46: 7.8 seconds, group processing S106: 6,1 s)and the control group required on average 24,2 sec, which indicates a significant improvement of memory in the processing group.

therapeutic effect of the compounds of the present invention for dementia and Parkinson's disease, based on the action of this compound, aimed at improving memory, investigated using models of brain disease in animal (mouse C57BL/6 10 weeks of age). First, in the brain of mice were injected with LPS to create models of brain disease in the animal. The mice were divided into four groups in accordance with the introduction and exercises. For exercises used treadmill at a speed of 2 m/min for the first 5 minutes, 5 m/min for 5 minutes, 8 m/min for 5 minutes and 20 m/min in the last 5 minutes. After carried out the test according to the method of Morris water maze, and the results of predstavlenij table 8. As a result, it was confirmed therapeutic effect of the compounds of the present invention for dementia and Parkinson's disease, achieved through the improvement of memory by using connections and exercises.

Table 8
Experimental groupThe results of tests using water maze
MediaExercise (X)32 seconds
Exercise (About)24 seconds
S14Exercise (X)21 second
Exercise (About)12 seconds
S46Exercise (X)27 seconds
Exercise (About)18 seconds
S106Exercise (X)23 seconds
Exercise (About)15 seconds

Industrial note nimoth

A new connection according to the present invention acts as a ligand of activiator PPAR, and, thus, is a highly promising candidate for pharmaceutical compositions for the prevention and treatment of cardiovascular disease, diabetes, obesity, dementia and Parkinson's disease, lower cholesterol, strengthen muscles or to improve memory; functional food adjuvant, functional beverage, food additives, functional cosmetic composition and the composition of the feed.

1. Aryl compound represented by formula (I)or its hydrate, MES, stereoisomer or pharmaceutically acceptable salt:

where a represents S or Se; represents N or
; R1is an aryl selected from the following structures:

R2represents H or
R3represents H or C1-C8 alkyl;
R4and R5independently represent H or C1-C8 alkyl;
R6represents H, C1-C8 alkyl, C2-C7 of alkenyl, alkali metal or alkaline earth metal;
R11and R12independently represent H, C1-C8 alkyl or halogen;
R21represents H, halogen or C1-C7 alkyl;
m and n independently to provide the amount integers, having a value of 1-4;
p is an integer having a value of 1-5;
q is an integer having a value of 1-4;
r is an integer having a value of 1-3;
s is an integer having a value of 1-5; and alkyl radicals R2, R3, R4, R5, R6, R11, R12and R21may be substituted by one or more halogen atoms, provided that the case where R2represents N and a represents S, is excluded.

2. Aryl compound or its hydrate, MES, stereoisomer or pharmaceutically acceptable salt according to claim 1, where R1is an aryl selected from the following structures:

R2represents; R3represents a C1-C5 alkyl, substituted or not substituted with halogen; R4and R5independently represent H or C1-C5 alkyl, substituted or not substituted with halogen; R6represents H, C1-C7 alkyl, alkali metal or alkaline earth metal; R11and R12independently represent H, C1-C5 alkyl substituted by one or more fluorine atoms, or fluorine; R21represents H, halogen or C1-C5 alkyl, substituted or not substituted by halogen atoms; p is an integer having a value of 1-5; q is an integer having a value of from 1 to 4; and s is an integer having a value of from 1-5.

3. Aryl compound or its hydrate, MES, stereoisomer or pharmaceutically acceptable salt according to claim 1, where the aryl compound is a compound represented by the formula (IV), and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt:

where A, R1, R3and m have the meanings defined for formula 1 in claim 1.

4. Aryl compound or its hydrate, MES, stereoisomer or pharmaceutically acceptable salt according to claim 1, where the aryl compound is a compound represented by the formula (VIII), and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt:

where A, R1, R3, R21m and s have the meanings defined for formula 1 in claim 1.

5. The method of obtaining aryl compounds represented by formula (I) in claim 1, comprising the following stages:
a) interaction of the compounds represented by formula (II)with a Grignard reagent and then the interaction with the organic compound of lithium, Paladino;
b) adding S or Se in the form of a powder to the mixture from step a); and
c) interaction of the mixture with the compound represented by formula (III), to obtain the compound represented by formula (I):

where A, R1, R3and m have the meanings defined for formula 1 in claim 1, X1represents a bromine atom or an iodine atom, and X2represents a chlorine atom, a bromine atom, an iodine atom or a removable group having reactivity with nucleophilic substitution.

6. The method of obtaining aryl compounds according to claim 5, comprising the additional step in which the compound represented by formula (IV)is subjected to interaction with alkylhalogenide or complex alkilany ether alkylhalogenide acid with obtaining ester compound represented by formula (XI):

where A, R1, R3, R4, R5and m have the meanings defined for formula 1 in claim 1, and R6Arepresents a protective group of carboxylic acid containing C1-C4 alkyl or allyl.

7. The method of obtaining aryl compounds according to claim 6, comprising the additional step in which the compound represented by formula (XI), hydrolyzing to obtain the compound represented by formula (XII):


where A, R1, R3, R4, R5and m have the meanings defined for formula 1 in claim 1, R6Arepresents a protective group of carboxylic acid containing C1-C4 alkyl or Allie who, and R6brepresents H, alkali metal or alkaline earth metal.

8. The method of obtaining aryl compounds according to claim 5, comprising the additional step, in which the alpha-hydrogen, thio - or selenoamino compounds represented by formula (IV), processed by strong alkali and then subjected to interaction with the compound represented by formula (VI), to obtain the compound represented by formula (VIII):

where A, R1, R3, R21m and s have the meanings defined for formula 1 in claim 1, and X3represents a chlorine atom, a bromine atom, an iodine atom or a group to delete.

9. The method of obtaining aryl compounds of claim 8, where the phenolic group of compounds represented by formula (IV)protect alkylsilane group and then treated with a strong alkali and add the compound represented by formula (VI), and then phenol-protective group is removed:

where A, R1, R3, R21m and s have the meanings defined for formula 1 in claim 1, and X3represents a chlorine atom, a bromine atom, an iodine atom or a group to delete.

10. The method of obtaining aryl compounds of claim 8, comprising the additional step in which the compound represented by formula (VIII)is subjected to interaction with alkylhalogenide or complex the m alkilany ether alkylhalogenide acid with obtaining ester compounds, represented by formula (IX):


where A, R1, R3, R4, R5, R21m and s have the meanings defined for formula 1 in claim 1, and R6Arepresents a protective group of carboxylic acid containing C1-C4 alkyl or allyl.

11. The method of obtaining aryl compound of claim 10, comprising the additional step, in which the ester compound represented by formula (IX), hydrolyzing to obtain the compound represented by formula (X):

where A, R1, R3, R4, R5, R21m and s have the meanings defined for formula 1 in claim 1, R6arepresents a protective group of carboxylic acid containing C1-C4 alkyl or allyl, and R6brepresents H, alkali metal or alkaline earth metal.

12. Pharmaceutical composition for the prevention and treatment of arteriosclerosis, hyperlipidemia, diabetes, obesity, dementia and Parkinson's disease, lower cholesterol, strengthen muscles, increase endurance or to improve memory containing aryl compound represented by formula (I)or its hydrate, MES, stereoisomer or pharmaceutically acceptable salt according to claim 1 as an active ingredient and pharmaceutically acceptable excipient.

13. To notice activator receptor, activated proliferation peroxisome (PPAR)containing aryl compound represented by formula (I)and its hydrate, MES, a stereoisomer and a pharmaceutically acceptable salt according to claim 1 as an active ingredient.

14. Pharmaceutical composition for the prevention and treatment of arteriosclerosis, dementia and Parkinson's disease, to strengthen muscles, increase endurance or to improve memory containing activator receptor-activated proliferation peroxisome (PPAR)containing aryl compound represented by formula (I)or its hydrate, MES, stereoisomer or pharmaceutically acceptable salt according to claim 1 as an active ingredient.

15. The way to study the effects of compounds according to any one of claims 1 to 4 on the receptor that is activated by proliferation peroxisome intended for the prevention and treatment of arteriosclerosis, dementia and Parkinson's disease, to strengthen muscles, increase endurance or to improve memory, which includes the stage of adding funds candidate, representing an activator of PPAR, PPAR; and measuring the activity of PPAR.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to new thiophene derivatives of formula (I) where A is represented by *-CO-CH2CH2-, *-CO-CH=CH, where the asterisks indicate the link through which the formula (I) thiophene group is bound; R1 is represented by C2-5alkyl; R2 is represented by hydrogen, methyl or ethyl; R3 is represented by hydrogen; R4 is represented by C1-4alkyl; R5 is represented by a hydroxy group, 2,3-di-hydroxypropoxygroup or -OCH2-CH(OH)-CH2-NHCOR52; R52 is represented by hydroxymethyl, and R6 is represented by C1-4alkyl; and to its salt. The invention also refers to the pharmaceutical composition that is agonistic in relation to S1P1/EDG1 receptor on the basis of the mentioned compounds.

EFFECT: new compounds and a composition based on them that may find their application in medicine as immunomodulating agents.

17 cl, 2 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I) where A denotes *-CO-CN=CH-, *-CO-CH2CH2-, or where the sign * indicates the thiophene bonding site in formula (I), R1 denotes hydrogen or methyl, R2 denotes n-propyl or isobutyl, R3 denotes hydrogen, methyl, ethyl, n-propyl, isopropyl or isobutyl, R4 denotes hydrogen or methoxy, R5 denotes hydrogen, C1-C4alkyl, C1-C4alkoxy or hydrogen, R6 denotes -(CH2)k-(CHR65)p-CHR66-CONR61R62 hydroxy, hydroxy(C2-C4)alkoxy, di(hydroxy(C1-C4)alkyl)(C1-C4)alkoxy, 2,3-dihydroxypropoxy, -OCH2-(CH2)m-NHCOR64, -OCH2-CH(OH)-CH2-NR61R62, -OCH2- CH(OH)-CH2-NHCOR64 or -OCH2-CH(OH)-CH2-NHSO2R63, R61 denotes hydrogen, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, carboxymethyl or C1-C4alkylcarboxymethyl, R62 denotes hydrogen, R63 denotes methyl or ethyl, R64 denotes hydroxymethyl, methyl aminomethyl or 2-methyl aminoethyl, R65 denotes hydrogen, R66 denotes hydrogen, m equals 1 or 2, k equals 0, p equals 1, R67 denotes hydrogen, C1-C4alkyl or halogen, and to a salt thereof. The invention also relates to a pharmaceutical composition for preventing or treating diseases or disorders associated with an activated immune system based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as immunodepressants.

31 cl, 2 tbl, 114 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an isoxazoline-substituted benzamide derivative of formula or salt thereof, where A1 denotes a carbon or nitrogen atom, A2 and A3 independently denote a carbon atom, G denotes a benzene ring, W denotes an oxygen or sulphur atom, X denotes a halogen atom or C1-C6alkyl, arbitrarily substituted with a radical R4, Y denotes a halogen atom, cyano, nitro, C1-C6alkyl, C1-C6alkyl arbitrarily substituted with radical R4, -OR5, -N(R7)R6, phenyl, D-41, when n equals 2, each Y can be identical or different from each other, R1 denotes -C(R1b)=NOR1a, M-5, -C(O)OR1c, -C(O)SR1c, -C(S)OR1c, -C(S)SR1c, -C(O)N(R1e)R1d, -C(S)N(R1e)R1d, -C(R1d)=NN(R1e)R1lf, phenyl, phehnyl substituted with (Z)p1, or D-3, D-8, D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59, R2 denotes C1-C6alkyl, -CH2R14a, E-5, C3-C6alkynyl, -C(O)R15, -C(O)OR15, -C(O)C(O)OR15 or -SR15, where, when R1 denotes -C(R1b)=NOR1a, M-5, or -C(R1b)=NN(R1e)R1f, R2 can denote a hydrogen atom, when R1 denotes -C(O)OR1c, -C(O)SR1c, -C(S)OR1c or -C(S)SR1c, R2 can denote hydrogen, when R denotes -C(O)N(R1e)R1d or -C(S)N(R1c)R1d, R2 can denote a hydrogen atom, when R1 denotes phenyl, phenyl substituted with (Z)p1, or D-3, D-8, -D-13-D-15, D-21, D-35, D-52-D-55 or D-57-D-59 R2 can denote C1-C6halogenalkyl, C1-C6alkyl arbitrarily substituted with a radical R14a, C3-C6alkenyl, -C(O)NH2, -C(O)N(R16)R15, or R2 together with R1 can form =C(R2b)R2a, R3 denotes C1-C6alkyl arbitrarily substituted with radical R4, D-1, D-3, D-8, D-13-D-15, D-21, D-35, D-41, D-52-D-55, D-57-D-59 denote aromatic heterocyclic rings, m equals an integer from 2 to 3, n equals an integer from 0 to 2.

EFFECT: isoxazoline-substituted benzamide derivative and salt thereof are used in pest control, against harmful arthropods in agriculture and horticulture or in livestock farming and in the field of hygiene.

12 cl, 18 tbl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 1H-quinazoline-2,4-diones of formula and to their pharmaceutically acceptable salts where R1 and R2 have the values specified in cl. 1 of the patent claim. The specified compounds exhibit antagonistic activity with respect to the AMPA receptor.

EFFECT: reception of a pharmaceutical composition for preparing a preparation used for treating a condition mediated by the AMPA receptor and first of all for treating epilepsy or schizophrenia.

8 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (1), where A1, A2, A3, A4, A5 ad A6 are independently selected from a group comprising CR3 and N; provided that the biggest one of A1, A2, A , A4, A5 and A6 denotes N; B1, B2 and B3 are independently selected from a group comprising CR2 and N; each R3 independently denotes H or C1-C6 alkyl; and R1, R2, R4, R5, W and n are as given in the description, or salts thereof which are suitable for use in agriculture. The invention also relates to compositions containing compounds of formula (1), and insect-pest control methods which involve contact between the pest or habitat thereof with a biologically effective amount of the compound or composition according to the present invention, as well as to methods of protecting seeds and animals from insects-pests.

EFFECT: high effectiveness of the obtained compounds in insect-pest control.

29 cl, 12 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a composition for ceratic fibre colouring, including colouring of human hair. The composition includes at least one diamino-N,N-dihydropyrizolone derivative as an oxidised base. Also the invention describes a method of keratic fibre colouring with application of the said composition, amino-N,N-dihydropyrizolone derivatives or one of its additive salts, diamino-N,N-dihydropyrizolone derivatives or one of its additive salts, and a method of thir obtaining.

EFFECT: obtaining a colourant for keratic fibre with high light and wet wash resistance.

34 cl, 6 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 represents halogen atom; R2 represents halogen atom; R3 represents (C1-C4)-alkyl; X represents nitrogen atom (N) or -CH; n = 0-3 under condition that when X represents -CH then n= 1 at least. Also, invention relates to novel compounds of the formula (II): wherein R1 represents halogen atom; R2 represents halogen atom; R3 represents hydrogen atom (H) or (C1-C4)-alkyl; X represents N or -CH; n = 0-3 under condition that when X represents -CH then n = 1 at least. Also, invention relates to a method for synthesis of compound of the formula (I), a method for synthesis of compound of the formula (II) and to a method for synthesis of compound of the formula (III) given in the invention description. Also, invention describes intermediate compounds of the formula (4) given in the invention description. Invention provides synthesis of novel biologically active compounds that can be used as insecticides, and a method for their synthesis.

EFFECT: valuable properties of compounds.

24 cl, 3 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing 1-phenyl-4-methyl-4-hydroxyethylpyrrolidine-3 (dimezone S), which is a developer for photographic materials by reacting an excess of phenylhydrazine with 2,2-dihydroxyphenylpropionic acid

The invention relates to 2-[(dihydro)pyrazolyl-3'-oxymethylene] anilides formula I

< / BR>
in whichmeans simple or double bond, and the index and the substituents have the following meanings:

n means 0, 1 or 2;

m means 0, 1 or 2 and the substituents R2may be different if m is greater than 1;

X represents a direct bond, O or NRa;

Rameans hydrogen;

R1means halogen or C1-C4alkyl, or, if n is 2, represents optionally associated with two adjacent ring atoms of the hydrocarbon bridge containing 3 or 4 carbon atoms;

R2means nitro, halogen, C1-C4alkyl, C1-C4halogenated or1-C4alkoxycarbonyl;

R3means optionally substituted alkyl, optionally substituted saturated cycle or optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms;

R4means hydrogen, optionally substituted alkyl;
The invention relates to a method for producing 1-phenylpyrrolidine-3 or 4-methyl-1-phenylpyrrolidine-3, which are used as components manifestations of black-and-white photographs

The invention relates to the production of developers for photographic materials

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and to their pharmaceutically acceptable salts or esters, where X1 is O, S, CH2; R1 is hydrogen; R2 is hydrogen or C1-C7alkyl, R3 is hydrogen or C1-C7alkyl; R4 and R8 are independently hydrogen, C1-C7alkyl, C1-C7alkoxy-C1-C7alkyl, fluoroC1-C7alkyl; R5, R6 and R7 are independently hydrogen, C1-C7alkyl, halogen, fluoroC1-C7alkyl; and one or R5, R6 and R7 represents , where X2 is S, O, NR9, (CH2)PNR9CO or (CH2)PCONR9, R9 is hydrogen, C1-C7alkyl; one or two of Y1, Y 2, Y3 and Y4 is N, and the rest represent C-R12 R10 is C1-C7alkyl, C3-C7 cycloalkyl; R11 is hydrogen; R12 in each case is independently selected from hydrogen, C1-C7alkyl, C3-C7 cycloalkyl, fluoroC1-C7 alkyl, C1-C7alkoxy-C1-C7alkyl, hydroxyC1-C7alkyl, di-C1-C7alkylamino-C1-C7alkyl; R13 is phenyl or heteroaryl, which is a 6-member aromatic ring, containing nitrogen as a heteroatom, which can be substituted with a CF3 group, lower fluroalkoxy group or halogen; m=0 or 1, n=0, 1, 2, and p=0, 1 or 2, and the sum of m, n and p=1, 2, 3 or 4; under the condition that, there are no formula I compounds, where X1 is O, R2 and R3 are hydrogen; R6 is , X2 is O or S, and m=0. The invention also relates to pharmaceutical compositions containing such compounds, with agonistic activity towards PPARδ and/or PPARα.

EFFECT: obtaining compounds for pharmaceutical compositions, with agonistic activity towards PPARδ and/or PPARα.

28 cl, 155 ex

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