Phenylacetic acid derivative and its use

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

 

The present invention relates to a derivative of phenylacetic acid, useful for the treatment of hyperlipidemia and the like, to the preparations on their basis and their application.

Recently, great attention is paid to the study of transcription factors associated with marker genes, which are involved in the induction of gene expression during differentiation of adipocytes through activation of proliferation peroxisomal receptor (abbreviated further as PPAR), which is one of intranuclear receptors. cDNA for PPAR were cloned in different species of animals, and found many isoforms of genes, in particular there are three types of such isoforms in mammals (α, δ and γ) (see J.Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression, 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology, 6, 1634 (1992)). It is also known that γ-PPAR isoform is expressed predominantly in adipose tissue, immune cells, adrenal gland, spleen, small intestine, α-PPAR isoforms mainly expressed in adipose tissue, liver, retina, and δ-PPAR isoform is expressed everywhere without specific binding to any tissue (see Endocrinology, 137, 354 (1996)).

It should be noted in this connection that thiazolidinone derivatives, such as pioglitazone, ciglitazone, rosiglitazone, troglitazone etc. known as a treatment for non-insulin-dependent is Chernogo mellitus (NIDDM) and represent hypoglycemic agents, used to reduce hyperglycemia in patients with diabetes mellitus. They are also effective for the purpose of weakening or correction of hyperinsulinemia, the improvement caused by glucose tolerance, and to reduce the level of serum lipids, and therefore they can be considered as a potential tool that can improve the condition defined by the insulinrezistentnost.

In addition, one of the intracellular target proteins of this group thiazolidinone derivatives clearly represents γ-PPAR isoforms, and it is believed that they increase the transcriptional activity of PPAR-γ (see, Endocrynology,137, 4189 (1996); Cell83, 803 (1995); Cell83, 813 (1995); J. Biol. Chem.,270, 12953 (1995)). In this regard, the activator (agonist) PPAR-γthat will enhance its transcriptional activity can be regarded as a hypoglycemic agent and/or hypolipidemic agent. In addition, since it is known that agonist of PPAR-γ increases expression of the protein PPAR-γ (Genes & Development, 10, 974 (1996)), the agent that increases the expression of the protein PPAR-γand an agent that activates PPAR-γwill also be clinically useful. Intracellular receptor PPAR-γ associated with the process of differentiation of adipocytes (see J. Biol. Chem.,272, 5637 (1997) and Cell83, 803 (1995)). It is known that thiazolidinone derivatives, cotoneaster this receptor, enhance the differentiation of adipocytes. Recently it was reported that thiazolidinone derivatives increase the fat content in the body, leading to the fact that people are gaining weight and becoming fat (see Lancet, 349, 952 (1997)). On this basis, activators (agonists) PPAR-γ and regulators of the expression of PPAR-γthat can increase the level of expression of the protein, have a hypoglycemic effect, hypolipidemic effect, and it is expected that they can be useful as a means for the prevention and/or treatment of conditions, such as a disorder of glucose metabolism and lipid metabolism (e.g. diabetes, hyperlipidemia (hypercholesterolemia, Hypo-HDL (high-density lipoprotein)-cholesterolemia, Hyper-LDL (low-density lipoprotein)-cholesterolemia, hypertriglyceridemia, etc.), atherosclerosis, cardiovascular disease, hypertension, diseases associated with blood circulation, etc.

Additionally, fibrate connection (e.g., clofibrate) is a hypolipidemic agent. It is also believed that one of the intracellular target proteins fibrotic connections is a PPAR-α (see Nature,347, 645 (1990); J. Steroid Biochem. Molec. Biol.,51, 157 (1994); Biochemistry, 32, 5598 (1993)). From these facts it follows that the regulators of PPAR-α possess hypolipidemic effect, and the can is about to put, they will be useful as a means for the prevention and/or treatment of hyperlipidemia, etc.

In addition, recently it was reported that PPAR-α has activity against obesity (see WO97/36579). Additionally it is reported that the effect on lipid metabolic stimulation (cholesterol, HDL, LDL, triglycerides and the like) is induced by agonists of PPAR-α (see J. Lipid Res.,39, 17 (1998)). In this context, there are reports that they lead to high cholesterol, type of high density lipoprotein (HDL) and reduce cholesterol type of low density lipoprotein (LDL)cholesterol is a type of lipoprotein very low density (VLDL) and triglycerides. It is also reported that the state associated with the presence of fatty acids in the blood, hypertension and insulinrezistentnost, improved with the introduction of bezafibrat, one of fibrate compounds (see Diabetes,46, 348 (1979)). On this basis, since agonists that activate PPAR-αand regulators of PPAR-αthat enhance the expression of the protein PPAR-αpossess hypolipidemic effect, we can hope that they will be tools that are useful for the treatment and/or prevention of conditions associated with impaired lipid metabolism (e.g., hyperlipidemia (hypercholesterolemia, Hypo-HDL-cholesterolemia, Hyper-the PNP-cholesterolemia, hypertriglyceridemia and the like), arteriosclerosis, cardiovascular disease, obesity, metabolic syndrome, etc), hypertension, diseases associated with blood circulation, etc.

Sometimes PPAR-δ referred to as PPAR-β or as NUC1 people. In regards to the activity of PPAR-δto date, it has been shown that hNUC1B (PPAR subtype, the structure of which differs from human NUC1 one amino acid) inhibits the transcriptional activity of the human PPAR-α and receptor thyroid hormone (see WO9604130). Recently it was reported about the discovery of compounds that have high affinity to the protein PPAR-δ and which may materially to activate PPAR-δ (i.e., are agonists), and that they have activity increasing the level of HDL (high-density lipoprotein) cholesterol and lower cholesterol, non-high density lipoprotein (see WO9728149, WO0100603, Proc. Natl. Acad. Sci. USA98, 5306 (2001)). It turned out that with the introduction of oxidized LDL foaming of macrophages and deposition on the vascular endothelium, with subsequent disruption of lipid metabolism. In this regard, agonists that can activate PPAR-δreduce the number of foam cells by a mechanism involving increased levels of HDL-cholesterol and lowering levels of LDL-cholester is on, so you can expect that they will be useful as a prophylactic and/or therapeutic agent for disorders of lipid metabolism (for example, when hyperlipidemia (hypercholesterolemia, Hypo-HDL-cholesterolemia, Hyper-LDL-cholesterolemia, hypertriglyceridemia, etc.), atherosclerosis, cardiovascular disease, obesity, metabolic syndrome and the like), hypertension, diseases associated with blood circulation, etc.

Recently it was reported that the activation of PPAR-δ enhances fatty acid oxidation, especially in skeletal muscle (see Proc. Natl. Acad. Sci. USA, 100, 15924 (2003)). This fact also allows us to suppose that agonists of PPAR-δ may be useful for improvement of lipid metabolism and for the treatment of obesity.

Activation of PPAR-δ has the effect not only on the condition associated with impaired lipid metabolism, but also enhances cellular differentiation of keratinocytes and is involved in maintaining cell structure that performs a barrier function in the body. It is shown that the skin is deficient in PPAR-δ mice after treatment TPA (12-O-tetradecanoylphorbol-13-acetate) changes associated with enhanced proliferation (see Mol. Cell Biol., 20, 5119 (2000)). In addition, it was shown that it has anti-inflammatory activity inflammation of the dermis (see J. Inest. Dermatol., 122, 971 (2004)). In this regard, agonists of PPAR-δ will be useful as a prophylactic and/or therapeutic agents for inflammatory skin disease (for example, when dermatitis (atopic dermatitis and the like), erythromelalgia, itching etc) and it is expected that they will have an effect in the quality of medicines, facilitate wound healing (e.g., burn wounds, external wounds and the like). In addition, it was shown that scarce PPAR-δ mice are observed pathological changes in the myelin covering the corpus callosum (see Mol. Cell. Biol.,20, 5119 (2000)), and agonists of PPAR-δ may be useful as a prophylactic and/or therapeutic agents in some nervous diseases.

However, it was reported that some funds from a number of agonists of PPAR-γ have an adverse impact on the liver and requires careful when using them as medicines. In addition, it is believed that hepatotoxic side effects of this kind is determined thiazolidinones structure, but there are no reports on exactly what the structure of these compounds allows to avoid hepatotoxicity. Very useful in this regard, we are searching for patterns to avoid toxicity in the development of PPAR agonists.

It is shown that the compounds described by formula (A)

(where a1Adenotes C1-4 alkylene and the like; And2Arepresents-O-; And3Arepresents CH and the like; nA is 1-5; R1Adenotes a halogen atom, trihalomethyl, trihalomethane and the like; R2Adenotes a C1-4 alkyl, trihalomethyl etc.; Cyc1Adenotes 1,3-thiazolidin, 1,3-oxazolidin etc.; Cyc2Adenotes a carbocyclic ring, heterocyclic ring and the like; R3Adenotes a hydrogen atom, C1-8 alkyl and the like; R4Ameans-A4A-CR8AR9A-COOR7A(where A4Aindicates a single bond; R7A, R8A, R9Arepresent a hydrogen atom, C1-4 alkyl) and the like) are known compounds used as regulators of PPAR (see, WO9946232).

The present invention is to provide a secure PPAR agonists that would be useful as a prophylactic and/or therapeutic agents with hyperlipidemia and the like, and which would have reduced side effects.

As a result of the research the authors of the present invention showed that the compounds described by the following formula (I) from the compounds described by the above formula (A), have an extremely low toxicity and, in particular, to avoid hepatotoxicity, and that was the essence of the present invention.

Thus, the present from Britanie refers to the following:

1. The compound described by formula (I)

where R1and R2each independently represents a hydrogen atom, C1-8 alkyl, halogen atom, C1-4 alkoxy, nitro, trihalomethyl, trihalomethane, trigalogenmetany, cyano, C1-4 alkylthio or NR7R8where R7and R8each independently represents a hydrogen atom or C1-4 alkyl); R3denotes a C1-8 alkyl which may be substituted by 1 to 3 atom(s) halogen or phenyl; R4denotes a hydrogen atom or C1-8 alkyl; R5and R6each independently represents a hydrogen atom or C1-4 alkyl, or R5and R6together with the adjacent carbon atom may form a carbocyclic ring; X represents a sulfur atom, an oxygen atom or a nitrogen atom which may have a substituent(s); ring And represents a cyclic group which may have a substituent(s), its salt or its MES, or its prodrug.

2. Connection in accordance with the above claim 1, wherein the cyclic group represented by ring a is 4-(trifluoromethyl)phenyl, 4-(triptoreline)phenyl, 4-(trifluoromethyl)piperidine-1-yl, 2,2-debtor-1,3-benzodioxol-5-yl, 4-phenylpiperazin-1-yl, 4-phenylpiperazin-1-yl, 1,3-dihydro-2H-isoindole-2-yl, 4-(4-chlorophenyl)piperazine-1-yl or 3,4-dihydro-1H-isoquinoline-2-yl.

3. The connection under the above item 2, in which cyclic group denoted by the ring And represents a 4-(trifluoromethyl)piperidine-1-yl, 2,2-debtor-1,3-benzodioxol-5-yl or 3,4-dihydro-1H-isoquinoline-2-yl.

4. Connection in accordance with the above claim 1, where the specified connection is:

(1) [3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid,

(2) [3-(2-{5-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid,

(3) [3-(2-{5-ethyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)-4-were]acetic acid,

(4) [3-(2-{5-isopropyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid,

(5) (3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-isopropyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid,

(6) [3-(2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid,

(7) (3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid,

(8) [2-fluoro-3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid,

(9) (2-fluoro-3-{2-[5-methyl-2-(4-phenylpiperazin-1-yl)-1,3-thiazol-4-yl]ethoxy}phenyl)acetic acid,

(10) (3-{2-[5-methyl-2-(4-phenylpiperazin-1-yl)-1,3-thiazol-4-yl]ethoxy}phenyl)acetic acid,

(11) (3-{2-[2-(1,3-dihydro-2H-isoindole-2-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2-forfinal)of the criminal code of usnow acid,

(12) [3-(2-{2-[4-(4-chlorophenyl)piperazine-1-yl]-5-methyl-1,3-thiazol-4-yl}ethoxy)-2-forfinal]acetic acid, or

(13) (3-{2-[2-(3,4-dihydro-1H-isoquinoline-2-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-4-were)acetic acid.

5. Pharmaceutical composition comprising a compound described by formula (I) according to above item 1, and its salt, or its MES, or its prodrug.

6. The pharmaceutical composition according to the above item 5, characterized in that this composition is a preventive and/or therapeutic agent suitable for treatment of PPAR-mediated diseases.

7. The pharmaceutical composition according to the above item 6, wherein the PPAR is a PPAR-δ.

8. The pharmaceutical composition according to the above item 7, wherein the PPAR-δ-mediated disease is a hyperlipidemia or obesity.

9. Drug comprising the compound described by formula (I) according to the above claim 1, its salt, or its MES, or its prodrug, and one or more other agents selected from a MTP inhibitor, an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of squalene synthase, fibranova medicines, ACAT inhibitor, an inhibitor of 5-lipoxygenase, an inhibitor of cholesterol intake, inhibitor suction GLCN the th acid, inhibitor of the transport of Na+/bile acid activator receptor HDL, tools that enhance the expression of the HDL receptor, inhibitor of pancreatic lipase, song probucol, composition with nicotinic acid and inhibitor of the transport protein for cholesterolemia ether.

10. The method of prevention and/or treatment of PPAR-mediated disease in a mammal which comprises the administration to a mammal an effective amount of a compound described by formula (I) according to the above claim 1, its salt, or its MES, or its prodrug, and

11. The use of compounds described by formula (I) according to the above claim 1, its salt, or its MES, or its prodrugs in obtaining preventive and/or therapeutic agent for use in PPAR-mediated disease.

C1-8 alkyl, described R1, R2and R4, denotes a linear or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl etc.

The halogen atom described by R1and R2denotes fluorine, chlorine, bromine, iodine.

C1-4 alkoxy, described R1and R2, denotes a linear or branched alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, the pet-butoxy etc.

Trihalomethyl described R1and R2means trehzameshchenny, for example, the atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine methyl.

Trihalomethane described R1and R2means trehzameshchenny, for example, the atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine methoxy.

Trigalogenmetany described R1and R2means trehzameshchenny, for example, the atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine methylthio.

C1-4 alkylthio described R1and R2refers to linear and branched, alkylthio, for example methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio etc.

C1-4 alkyl, described R5, R6, R7and R8, denotes a linear or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

"C1-8 alkyl" in the "C1-8 alkyl which may be substituted by 1 to 3 atom(s), halogen, described R3, denotes a linear or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl etc.

The halogen atom in the expression "C1-8 alkyl which may be substituted by 1 to 3 atom(s) halogen"means a fluorine atom, the Laura, bromine, iodine.

Carbocyclic ring which R5and R6may form together with the adjacent carbon atom, denotes, for example, C3-10 saturated carbocyclic ring and the like, C3-10 saturated carbocyclic ring means, for example, cyclopropane, CYCLOBUTANE, Cycloheptane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.

"Cyclic group" in "cyclic group which may have a substituent(s)"represented by ring A, denotes, for example, carbocyclic ring or heterocyclic ring and the like, Carbocyclic ring means, for example, C3-15 mono-, bi - or triaromatic carbocyclic ring and the carbocyclic ring with an internal bridge, etc. C3-15 mono-, bi - or triaromatic carbocyclic ring and the carbocyclic ring with an internal bridge means, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, inden, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydroanthracene, indan (dihydroindeno), palikonda, dihydronaphthalene, tetrahydronaphthalene, peridontal, pergerson, perperoglou the Wren, perhydrophenanthrene, perhydroanthracene, perhydrophenanthrene, perhydrogenized, bicyclopentyl, bicyclohexyl, bicycloheptane ([2.2.1])bicycloheptane), bicicletta, bicycleand, bellocan, adamantane and the like, Heterocyclic ring means, for example, 4-18 membered mono-, bi - or triaromatic heterocyclic ring which may be partially or fully saturated and which contains 1-4 nitrogen atom, 1-2 oxygen atom and/or sulfur atom. 4-18 membered mono-, bi - or triaromatic heterocyclic ring which may be partially or fully saturated and which contains 1-4 nitrogen atom, 1-2 oxygen atoms and/or 1 sulfur atom, denotes, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, thiopyran, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin diazepin, thiadiazin, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, pyrrolopyridine, benzoxazole, benzothiazole, benzimidazole, chrome, benzocain, benzoxazepin, benzodiazepin, benzothiophen, benzodiazepin, benzothiadiazin the pin, benzazepin, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, beta carboline, acridine, fenesin, dibenzofuran, xanthine, dibenzothiophen, phenothiazines, phenoxazin, phenoxathiin, phenanthridine, phenanthroline, pyrimidine, peridontitis, pyrazoloquinoline, personafied, periodontal, azetidin, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dehydroacetic, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, tieton, dihydrothiophene, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazol the Dean), dihydrooxazolo, tetrahydrooxazolo, Dihydrocodeine, tetrahydroimidazo, dihydrooxazoles, tetrahydroazepine, perhydroxyl, dihydroxyvitamin, tetrahydroazepine, perhydroanthracene, dihydroeugenol, tetrahydrocortisol (thiadiazolidin), dihydrotriazine, tetrahydrothiophene, dihydrokavain, tetrahydrolipstatin, dihydrothiazine, tetrahydroazepine, targetrotation, dihydrokavain, tetrahydroazepine, targetrotation, morpholine, thiomorpholine, Ossetian, indolin (dihydroindol), isoindoline (dihydroindol (for example, 1,3-dihydro-2H-isoindole etc.)), dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, dihydrobenzofuran, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline (for example, 3,4-dihydro-1H-isoquinoline and the like), perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, tetrahydropyrimidin, dihydroindole, tetrahydroindole, permitiendoles, benzocain, digitalen oxazin, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, digitalisation, tetrahydrobenzene, dihydrobenzofuran, tetrahydrolipstatin, benzodioxepin, dihydroisoxazole, tetrahydrobenzaldehyde, dihydrocarvone, tetrahydrocarbazol, perhydrogenized, dihydrouridine, tetrahydrouridine, perhydrosqualene, dihydrobenzofuran, dihydroisobenzofuran, tetrahydroxybenzophenone, tetrahydrolipstatin, perhydrophenanthrene, perhydrophenanthrene, retroperitoneally, tetrahydro-beta-carbolin, dihydroartemisinin, hexahydroazepin, tetrahydropyrazino, tetrahydropapaveroline, dihydrodipicolinate, hexahydroazepin, dihydropyrimidinase, hexahydropyridine, tetrahydropyrimidines, dihydrothebainone, tetrahydrocannabinol, dihydroxyindole, tetrahydrocannabinol, dioxolane, dioxane, benzodioxol (for example, 1,3-and benzodioxol the like), benzodioxan, chrome, Roman etc.

"Deputy" in "cyclic group which may have a substituent(s)"represented by ring A, denotes, for example, C1-8 alkyl (linear and branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-util, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), halogen atom (fluorine, chromium, bromine, iodine), C1-4 alkoxy (linear and branched alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), nitro, trihalomethyl (for example, trehzameshchenny, for example, the atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) and chlorine other methyl), trihalomethane (for example, trehzameshchenny, for example, the atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine etc. methoxy), trigalogenmetany (for example, trehzameshchenny, for example, the atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine etc. methylthio), a cyano, C1-4 alkylthio (for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio etc.), NR9R10(where R9and R10each independently represents a hydrogen atom or C1-4 alkyl (linear and branched alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like)), carbocyclic ring which may have a substituent(s), heterocyclic ring which may have a substituent(s), etc. These optional substituents may be further substituted by 1-5 of superseded provisions. Carbocyclic ring and heterocyclic ring in the "ka is basilicecm ring, which may have a substituent(s)"and "heterocyclic ring which may have a substituent(s)"include a Deputy with the same values, which carbocyclic ring and heterocyclic ring in the cyclic group, shown in the form of a ring A. the substituent in the "carbocyclic ring which may have a substituent(s)"and "heterocyclic ring which may have a substituent(s)"include as a substituent, for example, C1-8 alkyl (linear and branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like), halogen atom (fluorine, chromium, bromine, iodine), C1-4 alkoxy (linear and branched alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like), nitro, trihalomethyl (for example, trehzameshchenny atom(s) of the iodine atom(s) of bromine, atom(s) fluorine or atom(s) chlorine and the like, methyl), trihalomethane (for example, trehzameshchenny atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine etc. methoxy), trigalogenmetany (for example, trehzameshchenny atom(s) of the iodine atom(s) of the bromine atom(s) fluorine or atom(s) chlorine etc. methylthio), a cyano, C1-4 alkylthio (for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, the pet-butylthio and the like), NR11R12(where R11and R12each independently represents a hydrogen atom or C1-4 alkyl (linear and branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like)), etc. These optional substituents may be further substituted by 1-5 of superseded provisions.

The substituent in the "nitrogen atom which may have a substituent(s)"represented by the value X means, for example, C1-8 alkyl (linear and branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl etc.), arylalkyl (for example, benzyl, phenethyl, phenyl, alkoxycarbonyl (tert-butoxycarbonyl) etc.

Unless otherwise stated, all isomers are included in the scope of the present invention. For example, alkyl, Alchemilla, Alchemilla, alkoxy, alkylthio, Allenova, Alcanena and akinlana group includes both linear and branched group. In addition, the scope of the present invention also includes isomers on double bond, ring, fused ring (E-, Z -, CIS-, TRANS-isomer), isomers generated based on asymmetric(s) atom(s) C (R-, S-isomer, α-, β-configuration, enantiomer, diastereoisomer), optically active isomers (D-, L-, d-, l-isomer), polar compounds, obtained by chromatographies the m division (more polar compounds, the less polar compound), equilibrium compounds, optically active isomers, a mixture thereof in an arbitrary ratio, and a racemic mixture.

Salts of the compounds described by formula (I)include all pharmaceutically acceptable salts. As pharmaceutically acceptable salts of the preferred non-toxic water-soluble salt. Such salts include, for example, salts of alkali metals (e.g. potassium, sodium, lithium and the like), salts of alkaline-earth metals (e.g. calcium, magnesium and the like), ammonium salts (e.g., salt of Tetramethylammonium, tetrabutylammonium salt and the like), pharmaceutically acceptable salts of an organic amine (e.g. triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine etc.), additive acid salt (inorganic salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc. and organic acid salts (e.g. acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isetionate, glucuronate, gluconate and the like).

N-oxide compounds of formula (I) indicates that the nitrogen atom in the compound described by formula (I), oxidized N-oxide may additionally represent the above salts of alkali (alkaline earth) metals, ammonium salts, salts of organic amine and an additive salt of the acid.

Acceptable solvate of the compound described by formula (I)include, for example, hydrates, alcohol solvate (for example, ethanol and the like), etc. Solvate preferably are non-toxic and water soluble. In addition, MES compounds of the present invention includes a solvent for salts of alkali (alkaline earth) metals, ammonium salts, salts of organic amine, an additive acid salts and N-oxides and other compounds of the present invention.

Compounds of the present invention transform the above salt, the above N-oxide or above the MES by known methods.

The prodrug compounds described by formula (I), refers to a compound that is transformed into a compound of formula (I) in the reaction with enzymes, acids of the stomach and similar compounds in the body. Prodrugs of the compounds described by formula (I)include, in the case where the compounds of formula (I) have an amino group, such prodrugs, which are represented by the compounds in which the amino group alleroed, alkiliruya fosfauriliruetsa (for example, compounds of formula (I), in which the amino group is subjected to reaction with amazonienne, alanine, intramyocardial, (5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxycarbonyl the scrap, the tetrahydrofuran, pyrrolidinyl, pivaloyloxymethyl, acetoxymethyl, tert-bootrom and the like); in the case where the compounds of formula (I) have a hydroxyl group, a prodrug represented by the compounds in which the hydroxyl group alleroed, alkiliruya fosfauriliruetsa barrueta (for example, compounds of formula (I), in which the hydroxyl allyawan, palmitoleate, propanolamine, evalueserve, succinylcoa, famailiar, aloneleave, dimethylaminoethylacrylate and the like); in the case where the compounds of formula (I) have a carboxyl group, a prodrug represented by the compounds in which carboxyl tarifitsiruetsya, amidines (for example, compounds of formula (I), in which carboxyl subjected to the esterification reaction with the ethyl group, the esterification reaction with ISO-propyl group, the esterification reaction with the phenyl group, the esterification reaction with carboxymethyl group, the esterification reaction with dimethylaminomethylene group, the esterification reaction with pivaloyloxymethyl group, the esterification reaction with ethoxycarbonylmethylene group, the esterification reaction with italicising group, the esterification reaction with (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl group, the esterification reaction with cyclohexyloxycarbonyloxy group, metallizirovanaya etc.); etc. pointed to by the e the compound can be obtained in accordance with known techniques. In addition, the prodrug of the compounds of formula (I) may be a hydrate or connection other than hydrate. In addition, the prodrug of the compounds of formula (I) can be converted into a compound described by formula (I), in physiological conditions, which are described in the corresponding manual for drug development ("The Development of Medicine" vol. 7 "Molecular Design" published in 1991, Hirokawa shoten p.p.163-198). In addition, the compound of formula (I) may be labeled with isotopes (e.g.,3H,14C,35S125I and the like), etc.

In the context of the present invention, the agonist and antagonist of PPAR include all modes of action, namely the methods related to the action of the agonist and antagonist of PPAR α, γ, δ, α+γ, α+δ, γ+δ and α+γ+δ. In addition, the preferred method steps according to the present invention is the action of PPAR agonist-δ.

Formula (I) describes compounds of the present invention, where each definition is related to the ring A, X, R1, R2and R3, is preferred. The preferred group, and the preferred rings are listed below, all of the characters used in the listing are of the above values.

As R1or R2the preferred hydrogen atom, C1-8 alkyl or a halogen atom. Atom bodoro is a, methyl, ethyl or fluorine are preferred.

As R3preferred C1-5 alkyl, C1-2 alkyl substituted by 1 to 3 atom(s), halogen, or phenyl. More preferred methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, phenyl or 2,2,2-triptorelin.

As R4the preferred hydrogen atom or C1-4 alkyl. The preferred hydrogen atom, methyl or ethyl.

As R5or R6the preferred hydrogen atom or C1-4. A hydrogen atom, methyl or ethyl are more preferred. Particularly preferred hydrogen atom.

As a carbocyclic ring, in which R5and R6together with the neighboring carbon atom to form a saturated C3-7 carbocyclic ring. More preferred cyclopropane, CYCLOBUTANE or cyclopentane.

As X preferred sulfur atom or oxygen. The sulfur atom is more preferable.

As carbocyclic ring represented by ring A, C3-10 mono - or bikebicycle ring is preferable. More preferred cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane or benzene. The most preferred benzene.

As the heterocyclic ring represented by ring A, preferably 5-10-membered mono - or barometrically heterocyclic ring, the can is to be partially or fully saturated and which contains 1-2 atom(s) nitrogen, 1-2 atom(s) of oxygen and/or sulfur atom. Piperidine, piperazine, 1,3-benzodioxol, 1,3-dihydro-2H-isoindole, 3,4-dihydro-1H-isoquinoline or 3,6-dihydro-2H-pyridine is preferable. Particularly preferred piperidine and piperazine.

As the substituent in the "cyclic group which may have a substituent(s)"represented by ring A, the preferred halogen atom, trihalomethyl, trihalomethane, trigalogenmetany, phenyl which may have a substituent(s) (where the substituents can be halogen atom, C1-4 alkyl, C1-4 alkoxy), pyridyl which may have a substituent(s), thienyl or furyl. The preferred fluorine atom, trifluoromethyl, triptoreline, triptoreline, phenyl, pyridin-2-yl, 4-chlorophenyl, 4-forfinal, 3-forfinal, thiophene-2-yl, thiophene-3-yl, furan-2-yl, 4-were, 4-medociprin or 5-triptorelin-2-yl.

Methods for obtaining compounds of the present invention

The compound of the present invention described by formula (I)can be obtained by combination of known methods, for example in accordance with the methods described below or by using the methods shown in the examples, which constitute the improved method described in the corresponding manual ("Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndEdition, Richard C. Larock, Wiley & Sons Inc, 1999"), etc. in Addition, the ingredients in the criminal code is mentioned below sources can be used in the form of salts. As such salts are salts of the above formula (I).

The compound described by formula (I)can be obtained by reaction of Mitsunobu the compounds of formula (II)

where all the symbols have the above meanings, with a compound described by formula (III)

where R13denotes a C1-8 alkyl or a protective group for carboxyl, and other symbols have the above values,

and the compound of the formula (I-1)

where all the symbols have the above values,

with the removal, if necessary, the protective group from carboxyl after the reaction.

The reaction Mitsunobu is a known method. This reaction is carried out, for example, by reacting the corresponding alcohol in an organic solvent (e.g. dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene and the like) in the presence of azo-compounds (for example, diethylazodicarboxylate (DEAD), diisopropylcarbodiimide, 1,1'-(azodicarbon)dipiperidino (ADDP), 1,1'-azobis(N,N-dimethylformamide and the like) and a phosphine compound (such as triphenylphosphine, tributylphosphine, trimethylphosphine, triphenylphosphine on the polymeric substrate and the like) at a temperature of from 0 to 60°C.

The protective group for the of arbocel includes, for example, methyl, ethyl, allyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, 2-chlorotrityl or solid-phase carrier associated with the contained group, etc. of the Protective group for carboxyl not necessarily limited to the above groups, the main thing is that she could be easily and selectively removed. For example, can be used by the group are described in the corresponding manual (Protective Groups in Organic Synthesis (T.W. Greene, John Wiley & Sons Inc, 1999).

The reaction of removing the protective group for carboxyl known and includes

(1) alkaline hydrolysis,

(2) the reaction of removing the protective group under acidic conditions,

(3) the reaction of removing the protective group by hydrogenolysis,

(4) the reaction of removing the protective group using silyl group,

(5) the reaction of removing the protective group using metals,

(6) the reaction of removing the protective group using metal complexes

etc.

Below is a detailed description of these methods.

(1) the Reaction of removing the protective group by alkali hydrolysis is carried out, for example, in an organic solvent (e.g. methanol, tetrahydrofuran or dioxane and the like) using a hydroxide of an alkali metal (e.g. sodium hydroxide, potassium hydroxide and lithium hydroxide and the like), hydroxide of alkaline-earth metal (such as barium hydroxide or calcium hydroxide and the like), carbonate (e.g. sodium carbonate or potassium carbonate and the like) or an aqueous solution, or a mixture thereof at a temperature from 0 to 40°C.

(2) the Reaction of removing the protective group under acidic conditions is carried out, for example, in an organic solvent (e.g. dichloromethane, chloroform, dioxane, ethyl acetate, or anisole, and the like), organic acid (e.g. acetic acid, triperoxonane acid, methanesulfonic acid or p-tosylate and the like) or inorganic acid (e.g. hydrochloric acid or sulfuric acid and the like) or mixtures thereof (e.g., hydrogen bromide/acetic acid and the like) at a temperature of from 0 to 100°C.

(3) the Reaction of removing the protective group by hydrogenolysis is carried out, for example, in a solvent (for example, ethers (e.g. tetrahydrofuran, dioxane, dimethoxyethane (DME) or diethyl ether and the like), alcohols (e.g. methanol or ethanol and the like), benzenes (e.g., benzene or toluene and the like), ketones (e.g. acetone or methyl ethyl ketone and the like), NITRILES (e.g. acetonitrile and the like), amido (for example, DMF and the like)in water, ethyl acetate, acetic acid or a mixed solvent consisting of at least two of the above solvents and the like), in the presence of a catalyst (e.g. palladium-on-charcoal, palladium mobiles, palladium hydroxide-on-charcoal,platinum oxide or Raney Nickel and the like), in hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate at a temperature of from 0 to 200°C.

(4) the Reaction of removing the protective silyl group is carried out, for example, in an organic solvent miscible with water (for example, tetrahydrofuran or acetonitrile and the like)using tetrabutylammonium fluoride at a temperature from 0 to 40°C.

(5) the Reaction of removing the protective group using metals carried out, for example, in an acidic solvent (e.g. acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of solute and an organic solvent of tetrahydrofuran and the like)in the presence of zinc powder with scoring if necessary, at a temperature from 0 to 40°C.

(6) the Reaction of removing the protective group using metal complexes is carried out, for example, in an organic solvent (e.g. dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol and the like), water or mixtures thereof, in the presence of a capture reagent (e.g., anti-hydride, triethylsilane, dimedone, research, diethylamine, pyrrolidine and the like), organic acid (e.g. acetic acid, formic acid, 2-ethylhexanoic acid and the like) and/or salts of organic acids (for example, 2-ethylhexanoate sodium, 2-ethylhexanoate potassium and the like), n is outstay or in the absence of a phosphine reagent (for example, triphenylphosphine and the like), with the use of the metal complexes (for example, tetranitroaniline palladium(0), dichlorobis(triphenylphosphine)palladium(II)acetate, palladium(II)chloride, Tris(triphenylphosphine)rhodium(I) and the like) at a temperature of from 0 to 40°C.

Additionally, the reaction of removing the protective group other than the above methods, can be performed, for example, in accordance with the methods described in Greene (T.W. Green, Protective Groups in Organic Synthesis, Wiley & Sons, New York, 1999). As it is obvious to experts in this field, the target compounds of the present invention can be easily obtained with the selective use of these reactions to the removal of the protective group.

Compounds described by formulas (II) or (III)used as starting materials or reagents known in themselves or can be easily obtained according to the method described below in the example, or in accordance with known techniques, for example, by the method described in the corresponding manual ("Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndEdition, Richard C. Larock, Wiley & Sons Inc, 1999").

As it is obvious to experts in this field, in each reaction described in the present description, the reaction is performed under heating, it can be carried out using a water bath, oil bath, sand bath or a microwave oven

In each reaction in the present description, can be used reagent for solid-phase substrate, corresponding to the given polymer macromolecule (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol and the like).

In each reaction in the present description, the reaction product can be purified in the usual way, for example, at normal pressure or by distillation under reduced pressure, or when performing high-performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography using an ion-exchange resin, eskikaya resin, or by washing or recrystallization, etc. Cleaning can be carried out at each stage of the reaction or only after some reaction stages.

The pharmacological activity

Except as described in the example of the pharmacological test is performed, in particular, the in vivo test using animals, such as the following methods. Hypoglycemic effect and hypolipidemic effect of the compounds according to the present invention can be determined according to the following methods.

Hypoglycemic and hypolipidemic effects (I):

Determine the body weight and level of blood glucose in mice KKAy/Ta Jcl and distribute the bat is across multiple groups depending on the level of glucose in the blood. Within six days, starting from the next day, mice were fed with pellets or crushed balls, comprising the compound of the present invention. After the second treatment, the mice are weighed to determine the amount of consumed feed them, and then recalculate the average consumption of feed per administered dose. Additionally, measure the level of glucose in the blood, triglycerides (TG) in plasma insulin levels in the plasma level neeterificirovannah fatty acids (NEFA) and the level of GOT and GPT.

The connection can be considered as a possible prophylactic and/or therapeutic agent for diabetes mellitus, hyperlipidemia, atherosclerosis, etc. if it will have a lowering effect on plasma glucose, insulin levels in the plasma NEFA level or the level of triglycerides in plasma in mice KKAy/TA compared to the normal diet.

Hypoglycemic and hypolipidemic effects (2):

Determine the weight of the body, the glucose level in the blood, the level of NEFA, TG and HbA1c in rats Zucker fa/fa (strain: Crj-[FOR]-fa/fa) and in normal control animals line lean (strain: Crj-[FOR]-lean). Rats are placed into multiple groups based on the level of HbA1c and body weight. Starting from the next day, the animals spend re-introduction through the mouth of the compounds of the present invention. Whereas control animals injected carriers.

Since the beginning of the La re introduction calculate the average food intake and measure the blood levels of glucose, NEFA, TG and HbA1c. Additionally, determine glucose tolerance oral test (OGTT) to evaluate the effect of compounds to improve the state of intolerance to glucose. The day before the test OGTT rats survive without food. The next day the rats give glucose in the amount of 2 g/5 ml/kg, and after 60 and 120 minutes after glucose load was measured in the plasma level of insulin, NEFA, triglycerides, GOT, GPT, and fresh weight of the liver.

You can consider using this connection as a means for the prevention and/or treatment of diabetes, hyperlipidemia, atherosclerosis, etc. if it will have an effect on reduction in plasma glucose levels, insulin levels in plasma, as well as the level of NEFA, HbA1c plasma or level of triglycerides in the plasma of rats Zucker fa/fa compared to the normal diet. In addition, the effect of this agent in reducing fasting plasma glucose levels and improve the condition of intolerance to glucose in OGTT test will also indicate the possibility of its use as a tool for the prevention and/or treatment of diabetes.

Hypocholesterolemic and hypolipidemic effects (3):

The SD rats kept on vysokochastotnoi diet (solid balls CRF-1 in a mixture with a 5.5% peanut butter, 1.5% cholesterol, 0.5% of holeva acid, Oriental Bio Service), then a stomach who's weigh and measure different the following settings. These include the following: LDL, HDL, TG, NEFA and TC. Rats are placed into multiple groups in accordance with the level of HDL. Starting from the next day, for six days once a day animals injected through the mouth, the solution of the compounds, suspended in medium (0.5% aqueous solution of methylcellulose), and continue to feed animals vysokochastotnoi food. Upon completion of the last injection measure the levels of plasma lipids (triglycerides, HDL, LDL, NEFA, TC).

You can consider using this connection as a means for the prevention and/or treatment of hyperlipidemia, atherosclerosis, etc. if it's in SD rats on an empty stomach will have an effect on the decrease in the plasma level of TG, TC and LDL.

Hypoglycemic and hypolipidemic effects (4):

Conduct a medical examination of the apes, cynomolgus and put them in test devices. Animals are weighed, spread across multiple groups and repeated intranasal, intragastric administration of a solution of a medicinal product, including 3-100 mg/kg/day of the compounds of the present invention, with the use of catheters to force power and syringes for injection. After the introduction of selected blood samples and conduct the above hematological analysis (determination of the number of erythrocytes, pokazateljnaja, hemoglobin, platelet count, and leukocyte count) and biochemical blood analysis (determination of GOT, GPT, alkaline phosphatase, total protein, urea nitrogen, blood creatinine level creatinekinase, total bilirubin, blood glucose, total cholesterol, LDL, HDL and triglycerides). Additionally, before the introduction of the compounds of the present invention and 14 days after the beginning of the introduction of selected blood samples after 1, 2 and 4 hours after injection and 1, 2, and 3 h after feeding (meal one hour) to determine blood levels of glucose, total cholesterol, LDL, HDL and triglycerides.

Assume that the effect in reducing levels of plasma TG, TC and LDL in normal monkeys, cynomolgus fasting can be seen as an opportunity to use this connection as a preventive and/or drugs for hyperlipidemia and atherosclerosis, etc. were also Observed inhibitory effect with respect to the observed postprandial increase in triglycerides. In addition, it is assumed that the inhibitory effect of the compound on the level of glucose in the blood after food load may indicate its potential as a prophylactic and/or therapeutic agent for diabetes. Additionally, it should be ascertained on the basis of other biochemical, parametro is, do consider compounds toxic effect.

Toxicity:

The toxicity of the compounds described by formula (I)is very low, so it is quite safe to use as pharmaceuticals.

The use of pharmaceutical drugs:

Since the compound described by formula (I) according to the present invention, its salt, MES or its prodrug has agonistic activity against PPAR-δ, for example, has an effect on raising HDL-cholesterol, enhances the effect of the removal of LDL contributes to the transport of lipids, especially cholesterol, and reverse migration, inhibits the formation of foamy macrophages, inhibits the biosynthesis of cholesterol, it is expected that such compounds can be used as a means for the prevention and/or treatment of diseases associated with disorders of glucose metabolism/lipid (such as diabetes, hyperlipidemia (hypercholesterolemia, Hypo-HDL-cholesterolemia, Hyper-LDL-cholesterolemia, hypertriglyceridemia, and the like), arteriosclerosis, cardiovascular disease, obesity, metabolic syndrome and the like), hypertension, diseases associated with blood circulation disorders, inflammatory skin diseases, etc.

The compound of formula (I) or its salt, its MES or its prolic RSTO can be administered in combination with other drugs order

1) complement and/or enhance the preventive and/or therapeutic effect,

2) improvement of dynamics and absorption of the compound and dose reduction, and/or

3) weakening side effects connection.

The compound described by formula (I), its salt, its MES or its prodrug and other pharmaceutical preparations may be administered in the form of a composition comprising the specified connection consisting of one drug, or they may be administered as separate preparations. In the case when these pharmaceutical drugs are administered as separate preparations, they may be administered simultaneously or at different times. In the latter case, the compound described by formula (I)or its salt, its MES or its prodrug may be administered before administration of the other pharmaceutical preparations. Alternatively, other pharmaceutical preparations may be administered before administration of the compounds of formula (I), its salts, its MES or its prodrugs. Methods of administration of these pharmaceutical preparations may be the same or different.

Other pharmaceutical preparations may represent a low-molecular compounds. Additionally, they can be a macromolecular protein, polypeptide, polynucleotide (DNA, RNA, and gene), " antisense polynucleotide, trap, antibody or vaccine, etc. To the and other pharmaceutical preparations may be appropriately selected taking into account the standard clinical dose. Additionally, the ratio of the compounds introduced into the composition of the present invention, and other drugs can be appropriately selected depending on the age and body weight of the subject, which it is introduced, method of administration, time of administration, type of illness and its symptoms, combination of drugs, etc. for Example, other pharmaceutical preparations may be used from 0.01 to 100 weight parts per 1 weight part of the compound of the present invention. Other pharmaceutical preparations can be entered in the appropriate ratio, in combination with one or more optional agents.

The list of diseases for which it is noted prophylactic and/or therapeutic effect of the above combined preparations not specifically limited and may include all those diseases for which preventive and/or therapeutic effect of the compounds of formula (I), its salts, its MES or prodrugs via the mechanism of compensation and/or amplification.

Like other medicines used to compensate and/or enhance lipid-lowering effect of the compounds of formula (I), its salts, its MES or its prodrug, that is a way of improving lipid metabolism, applied in this case an additional among the CTB may include, for example, the inhibitor of MTP (microsomal transport protein for triglycerides), an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of squalene synthase, fibrin (derived fibrin acid), an inhibitor of ACAT (acyl-CoA: cholesterol-O-acyltransferase), an inhibitor of 5-lipoxygenase, an inhibitor of cholesterol absorption, absorption inhibitor of bile acid, an inhibitor of migration of Na+/bile acid in Powszechny intestine (IBAT), activator/enhancer of the expression of LDL receptor, an inhibitor of pancreatic lipase, a composition with probucol, composition with nicotinic acid, an inhibitor of the transport protein for cholesterolemia ether (CEPT), other anticholesterolemic therapeutic agent, etc.

Examples of MTP inhibitor include BMS-201038, BMS-212122, BMS-200150, GW-328713, R-103757, etc. are Examples of an inhibitor of HMG-CoA reductase inhibitor include atorvastatin, falastin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, etc. Examples of ACAT inhibitor include F-12511, F-1394, CI-1011, melinamide etc. are examples of the inhibitor of squalene synthase include TAK-475, etc. Examples of fibrate include gemfibrozil, clofibrate, bezafibrat, fenofibrate, clinofibrate, simfibrate etc. are Examples of ACAT inhibitor include CI-1101, FCE27677, RP73163 etc. are Examples of an inhibitor of cholesterol absorption include ezetimibe, soy sterols, etc. Examples inhibitor absorption of bile acids include cholestyramine, the wheel is Elam, colestimide etc. are examples of the activator/enhancer of the expression of the LDL receptor include MD-700, LY295427 etc. are examples of the lipase inhibitor of the pancreas include orlistat, etc. Know that sometimes in the case of a combination of fibrate and an inhibitor of HMG-CoA-reductase celebrated relationship with rhabdomyolysis, and this combination is contraindicated for patients with renal insufficiency and patients with impaired renal function. In the case of combinations of the compounds of the present invention, its salts, its MES or its prodrugs and the above medicines, improving lipid metabolism, you can correct abnormal lipid metabolism without the risk of rhabdomyolysis. As part of these consolidated funds, representing a combination with the compounds of the present invention, their salt, their MES or its prodrug, a preferred inhibitor of HMG-CoA-reductase, fibrin (derived fibrin acid), an inhibitor of cholesterol absorption, absorption inhibitor of bile acid, an inhibitor of pancreatic lipase and composition with nicotinic acid.

Like other medicines used to compensate and/or to enhance the hypoglycemic effect of the compounds of formula (I), its salts, its MES or its prodrugs, and to increase a therapeutic effect in the beam complications of diabetes, for example, therapeutic drugs used in diabetes, these include, for example, hypoglycemic agent on the basis of sulfonylureas, biguanides drug, an inhibitor of alpha-glucosidase, fast-acting activator of insulin secretion, insulin product inhibitor dipeptidylpeptidase (DPP)4, agonist GLP-1, activator receptor beta-3 adrenaline, as well as drugs used to treat complications of diabetes, etc.

Examples of hypoglycemic agents on the basis of sulfonylureas include acetohexamide, glibenclamide, gliclazide, glyclopyramide, hlorpropamid, tolazamide, tolbutamide, and glimepiride, etc. Examples biguanide drugs include the hydrochloride of buformin and Metformin hydrochloride etc. are Examples of alpha-glucosidase inhibitors include acarbose and voglibose. Examples of fast-acting activators of insulin secretion include nateglinide and Repaglinide etc. are Examples of DPP4 inhibitor include NVP-DPP728A etc. are Examples of agonists of GLP-1 include the basis 4 etc. are Examples of activators of the receptor beta-3 adrenaline include AJ-9677, BMS-210285, CP-331679, KUL-1248, LY-362884, L-750335, CP331648, etc. Examples of therapeutic agents used to treat complications of diabetes include epalrestat, zenarestat, fidarestat, zopolrestat, AS-3201, SG-210, etc.

Like other medicines used to compensate and/or enhance the action in the managing of reducing obesity, the compound of formula (I), its salt, its MES or its prodrug, for example, anti-obesity, they include, for example, means that the vast appetite, an inhibitor of pancreatic lipase, activator receptor beta-3 adrenaline, inhibitor re-absorption of serotonin-norepinephrine-dopamine, etc. are Examples of tools that suppresses appetite, include leptin, mazindol, amphetamine, methamphetamine, etc. are examples of the lipase inhibitor of the pancreas include orlistat, etc. Examples of activator receptor beta-3 adrenaline include AJ-9677, BMS-210285, CP-331679, KUL-1248, LY-362884, L-750335, CP-331648 etc. Examples inhibitor re-absorption of serotonin-norepinephrine-dopamine include sibutramine, etc.

The weight ratio of the compounds described by formula (I), its salt, its MES or its prodrug, and other drugs not specifically limited.

Can optionally be administered two or more other drugs in the combination.

Examples of other pharmaceutical drugs used to compensate and/or enhance the preventive and/or therapeutic effect of the compounds of formula (I), its salts, its MES or its prodrugs include compounds that have already been found but also those which will be found on the basis of the above mechanism.

When using the soedineniya of the present invention of formula (I), its salts, its MES or his or prodrugs of compounds of formula (I), its salts, its MES or its prodrugs in combination with other pharmaceutical preparations, these compounds is usually injected into the body systemically or locally, by mouth or parenterally.

The dose of these compounds depends on the age, weight and symptoms of the patient, the characteristics of the medicinal products, route of administration, time of administration, etc. But practically these compounds administered orally once or several times per day in number, each, from 1 mg to 1000 mg per adult human subject parenterally once or several times a day in number, each, from 1 mg to 100 mg per adult person, or continuously injected into a vein over 1 hour to 24 hours a day.

Needless to say that the dose of these compounds may be less than the above values, or there may be a need to increase the above range, because the dose will vary, depending on conditions, as described above.

Compounds of the present invention of formula (I), their salts, their MES, or prodrug compound of the formula (I), its salt, its MES, its prodrug in combination with other pharmaceutical preparations may be used for administration in the form of solid or liquid agent for ErrorLog introduction, injection of the agent for external application, suppository, eye drops or in the form of an inhaled drug for insertion through the mouth, etc.

Examples of the solid agent for oral administration include tablet, pill, capsule, powder and balls. Examples of capsules include hard capsule and soft capsule.

The above-described solid agent for internal reception includes one or more active materials in the form of the product obtained in the usual manner, by itself or in combination with a carrier (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch and the like), a binder (for example, hydroxypropylcellulose, polyvinylpyrrolidone, metasilicates magnesium and the like), a tool that promotes the decomposition (for example, fibrinogenolysis calcium and the like), means of supporting slide (for example, magnesium stearate and the like), a stabilizer, a tool that promotes dissolution (e.g., glutamic acid, aspartic acid and the like) or the like, a Solid agent may contain a coating of an agent (for example, on the basis of white sugar, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose and the like) or may include two or more layers. Alternatively, the solid agent may be encapsulated using absorbe the ith material, such as gelatin.

Examples of liquid agent to receive through the mouth include pharmaceutically acceptable aqueous solution, suspension, emulsion, syrup and elixir. In such a liquid agent is one or more active agents are dissolved, suspended or emuleret using the usual solvent (for example, using purified water, ethanol, mixtures thereof and the like). Additionally, such a liquid agent may include a wetting agent, a means to suspendirovanie, emulsifier, sweetener, flavoring agent, preservative, buffer, etc.

The agent used for parenteral administration may be, for example, in the form of an ointment, gel, creams, wet compresses, paste, liniment, sprayed agent, inhalation agent, spray, aerosol, eye drops, solution for irrigation of the nasal cavity, etc. Each of these agents contain one or more active materials and can be obtained by a known method or based on a commonly used composition.

Ointment get by a known method or by using a commonly used composition. For example, one or more active materials are rubbed or dissolved in the basis of obtaining such materials. The basis for ointments selected from known or commonly used materials. In more detail, they can enable higher alifaticheskikh or ester of higher aliphatic acid (for example, such as adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, esters of adipic acid, an ester of myristic acid, an ester of palmitic acid, ester of stearic acid, ester of oleic acid and the like), waxes (e.g. beeswax, wax fatty tissues of the whale, ceresin, etc), surfactant (e.g., ester polyoxyethyleneglycol ether and phosphoric acid and the like), higher alcohol (for example, cetanol, stearyl alcohol, cetosteatil alcohol and the like), silicone oil (for example, dimethylpolysiloxane and the like), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin and the like), a glycol (e.g. ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol and the like), vegetable oils (e.g. castor oil, olive oil, sesame oil, turpentine oil), oils of animal origin (for example, mink oil, yolk oil, squalane, squalene), water, activator absorption and means preventing the development of rashes, which can be used singly or in mixture of two or more such means. The base may also include a humectant, preservative, stabilizer, antioxidant, perfume, etc.

Gel get by a known method or with the help of the commonly used compositions. For example, one or more active materials are dissolved in the basis of obtaining such a gel. Gel base selected from known or commonly used materials. For example, use a lower alcohol (e.g. ethanol, isopropyl alcohol and the like), gelling agent (e.g., carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose and the like), a neutralizer (e.g., triethanolamine, diisopropanolamine and the like), a surfactant (for example, polyethylene glycol monostearate and the like), gums, water, activator absorption and means preventing the development of rashes, which can be used singly or in mixture of two or more such agents. Gel base may also include a preservative, an antioxidant, a perfume, etc.

Cream get by any known method or by using a commonly used composition. For example, one or more active materials are dissolved in the basis of obtaining such a cream. A creamy base selected from known or commonly used materials. For example, use an ester of higher aliphatic acid, a lower alcohol, hydrocarbons, polyhydric alcohol (for example, propylene glycol, 1,3-butyleneglycol and the like), higher alcohol (for example, 2-hexyldecanol, cetanol etc.), emulsifier (for example, polyoxyethylenated esters, complex is haunted esters of aliphatic acids and the like), the water activator absorption and means preventing the development of rashes, which can be used singly or in mixture of two or more such agents. Cream base may also include a preservative, an antioxidant, a perfume, etc.

Compress receive any known method or by using a commonly used composition. For example, one or more active materials are dissolved in the base to obtain a pasty mixture, which is distributed on the basis of obtaining such a wet compress. The basis for wet compress selected from known or commonly used materials. For example, use a thickener (for example, polyacrylic acid, polyvinylpyrrolidone, Arabian gum, starch, gelatin, methylcellulose and the like), a humidifier (for example, urea, glycerin, propylene glycol and the like), a filler (for example, kaolin, zinc oxide, talc, calcium, magnesium and the like), water, a means of facilitating the dissolution of the agent, which imparts stickiness, and means preventing the development of rashes, which can be used singly or in mixture of two or more such means. The basis for wet compresses may also include a preservative, an antioxidant, a perfume, etc.

Pasty agent receive by any known method or by using a commonly used composition. For example, one or more AK is active materials dissolved in the base to obtain a pasty mixture, which are distributed on the basis of obtaining such a pasty agent. The basis for pasty agent selected from known or commonly used materials. For example, there may be used a polymer base, fat and oil, higher aliphatic acid, an agent that imparts stickiness, and means preventing the development of rashes, which can be used singly or in mixture of two or more such agents. The basis for pasty agent can also include a preservative, an antioxidant, a perfume, etc.

Liniment get by any known method or by using a commonly used composition. For example, one or more active materials are dissolved, suspended or emuleret in water, alcohol (e.g. ethanol, polyethylene glycol and the like), higher aliphatic acid, glycerin, soap, emulsifier, the means of supporting suspendirovanie, and the like, singly or in combination of two or more such agents with getting liniment. The liniment may optionally include a preservative, an antioxidant, a perfume, etc.

Sprayed agent, inhalation agent, spray, aerosol, each may include a commonly used diluent, and optionally a stabilizer, such as hydrosulfite sodium, and a buffer capable of maintaining isotonicity, such as an isotonic agent (e.g., chloride hydroxide is I, sodium citrate or citric acid and the like) way to get the spray and the corresponding references are listed in U.S. patent No. 2868691 and 3095355.

Injectable drug for parenteral administration consists of solid injectable drug, which is then dissolved or suspended from receiving solution, suspension, emulsion, and solvent used for dilution immediately before use. The injectable preparation is produced by dissolution, suspension or emulsion of one or more active materials in the solvent. As such a solvent can be used distilled water for injection, saline, vegetable oil, alcohol such as propylene glycol, polyethylene glycol and ethanol, and the like, singly or in combination. The injectable preparation may also contain a stabilizer, a tool that promotes dissolution (e.g., glutamic acid, aspartic acid, Polysorbate-80 (trade name) and the like), a means to suspendirovanie, emulsifying agent, soothing agent, a buffer, a preservative, etc. Injectable sterile drug at the final stage or receive in the course of the aseptic process. Alternatively, initially, there may be obtained a solid agent such as a freeze dried product, which subsequently makes the aseptic or dissolved in aseptic distilled water for injection or other solvent immediately before use.

Ingaliruyet agent for parenteral administration may be presented in the form of an aerosol spray powder for inhalation or liquid for inhalation. Liquid for inhalation may be dissolved or suspended in water or another appropriate medium before use.

These englishusa agents receive by a known method.

For example, a liquid for inhalation is obtained on the basis of the materials appropriately selected from preservatives (such as benzalkonium chloride, paraben and the like), dyes, sautereau means (e.g., sodium phosphate, sodium acetate and the like), means to maintain isotonicity (e.g., sodium chloride, concentrated glycerin and the like), thickeners (for example, carboxyvinyl polymer and the like), the promoters of absorption and the like, if necessary.

Powder for inhalation derived from materials appropriately selected from the funds contributing to the slide (for example, stearic acid and its salts and the like), binders (e.g. starch, dextrin and the like), media (e.g., lactose, cellulose and the like), coloring agents, preservatives (e.g. benzalkonium chloride, paraben and the like), the promoters of absorption and the like, if necessary.

In case of introduction of the liquid preparation for inhalation typically use a sprayer (e.g., atomizer, nebulizer and so on). In the case of the introduction of the powder for inhalation usually use powder inhaler.

Other examples of compositions used for parenteral administration include suppositories for rectal administration and pessaries for vaginal administration, obtained by a standard method using a composition comprising one or more active materials.

The effect of the present invention

Since the compound described by formula (I) according to the present invention, and its non-toxic salt have agonistic activity against PPAR-δsuch as raising HDL-cholesterol, increased removal of LDL, stimulation of the transport of lipids, especially cholesterol, and activation of reverse migration, as well as inhibitory effect on cholesterol biosynthesis, it is expected that they can be used as tools for the prevention and/or treatment of diseases associated with impaired glucose metabolism/lipid (such as diabetes, hyperlipidemia (hypercholesterolemia, Hypo-HDL-cholesterolemia, Hyper-LDL-cholesterolemia, hypertriglyceridemia, and the like), arteriosclerosis, cardiovascular disease, obesity, metabolic syndrome and the like), hypertension, diseases associated with circulatory disorders, inflammatory skin diseases, etc.

The BEST WAY for the IMPLEMENTATION of THE POPULATION of the PRESENT INVENTION

Below is a detailed description of the present invention with reference to examples, which do not limit its scope. The solvents in parentheses, are in the context of describing chromatographic separation methods based on TLC, refer to the solvents used for separation or elution, and the ratio of solvents used are given in volumetric units. These NMR relate to the measurement results1H-NMR, and given in parentheses solvents are solvents used in determining the NMR.

Used in the names of compounds are the names given in accordance with the system of ACD/name (brand, Advanced Chemistry Development Inc.) or ACD/name batch (brand, Advanced Chemistry Development Inc.), included in the computer program that assigns the appropriate name in the IUPAC rules or under the rules of the nomenclature of organic chemical compounds IUPAC.

Example 1

Methyl-[3-(2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetate

In an argon atmosphere to a solution of methyl-(3-hydroxy-4-were)acetate (1,00 g) in methylene chloride (22 ml) is added 2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethanol (2.00 g), triphenylphosphine (2,18 g) and 1,1'-(azodicarbon)di is hypericin (2.10 g) and the mixture is stirred over night at room temperature. The reaction mixture was concentrated and the resulting residue is purified column chromatography on silica gel (hexane:ethyl acetate = 4:1) to obtain the specified title compound (2.38 g)having the following physical parameters.

TLC: Rf and 0.62 (hexane:ethyl acetate = 2:1);

1H NMR (CDCl3): δ 8,05-to 7.99 (m, 2H), 7,30-7,24 (m, 2H), 7,05 (d, J=7.5 Hz, 1H), 6,77-6,72 (m, 2H), 4,24 (t, J=6.5 Hz, 2H), to 3.67 (s, 3H), of 3.56 (s, 2H), 3,00 (t, J=6.5 Hz, 2H), 2,75 (kV, J=7.5 Hz, 2H), of 2.15 (s, 3H), of 1.29 (t, J=7.5 Hz, 3H).

Example 2

[3-(2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

To a stirred solution of the compound obtained in example 1 (1.90 g)in tetrahydrofuran (10 ml) and methanol (10 ml) is added 2N aqueous sodium hydroxide solution (10 ml) and stirred for three minutes at room temperature. To the reaction mixture is added 1N hydrochloric acid (25 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and the filtrate concentrated to obtain specified in the connection header (3,66 g)having the following physical parameters.

TLC: Rf of 0.40 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 8,00 (m, 2H), 7,25 (d, J=8,1 Hz, 1H), 7,05 (d, J=8,1 Hz, 1H), 6,76-of 6.71 (m, 3H), 4,22 (t, J=6.6 Hz, 2H), to 3.58 (s, 2H), 2,99 (t, J=6.6 Hz, 2H), was 2.76 (q, J=7.5 Hz, 2H), and 2.14 (s, 3H), of 1.29 (t, J=7.5 Hz,3H).

Example 3 - example 27

According to the procedure described in examples 1 and 2, using methyl-(3-hydroxy-4-were)acetate or instead of the corresponding alcohol derivative and methyl-(3-hydroxy-4-were)acetate and the corresponding alcohol derivative instead of 2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethanol the following compounds of the present invention.

Example 3

[3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf is 0.49 (chloroform:methanol = 10:1);

1H NMR (CDCl3): δ 7,24-7,17 (m, 1H), 6.87 in-6,77 (m, 3H), of 4.16 (t, J=7,0 Hz, 2H), 4.00 points (userd, J=13,0 Hz, 2H)and 3.59 (s, 2H), 2,93 (t, J=7,0 Hz, 2H), 2,90 (dt, J=2.5 a, 13,0 Hz, 2H), 2,29-2,12 (m, 1H), 2,24 (s, 3H), 1.93 and (userd, J=13,0 Hz, 2H), 1,67 (DQC, J=4,5, 13,0 Hz, 2H).

Example 4

[3-(2-{5-propyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf value of 0.52 (chloroform:methanol = 10:1);

1H NMR (CDCl3): δ 8,08 (d, J=8.0 Hz, 2H), to 7.67 (d, J=8.0 Hz, 2H), 7,22 (TD, J=7,5, 1.0 Hz, 1H), PC 6.82 (m, 3H), 4,23 (t, J=6.5 Hz, 2H), 3,60 (s, 2H), 2,99 (t, J=6.5 Hz, 2H), 2,70 (t, J=7.5 Hz, 2H), 1,74 (sextet, J=7.5 Hz, 2H), and 1.00 (t, J=7.5 Hz, 3H).

Example 5

[3-(2-{5-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf is 0.49 (chloroform:methanol = 10:1);

1H NMR (CDCl3): δ 8,08 (d, J=8.0 Hz, 2H), to 7.67 (d, J=8.0 Hz, 2H), 7,21 (dt, J=7,5, 1.0 Hz, 1H), PC 6.82 (m, 3H), 4,22 (t, J=6.6 Hz, 2H), 3,60 (s, 2H), 3,17 (septa is, J=7,0 Hz, 1H), 3,00 (t, J=6.5 Hz, 2H), of 1.34 (d, J=7,0 Hz, 6H).

Example 6

[4-methyl-3-(2-{5-propyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.50 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 12,22 (users, 1H), of 8.09 (d, J=8,4 Hz, 2H), 7,83 (d, J=8,4 Hz, 2H), 7,00 (d, J=7.5 Hz, 1H), 6,84 (s, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,19 (t, J=6.3 Hz, 2H), 3,47 (s, 2H), 2,96 (t, J=6.3 Hz, 2H), 2,70 (t, J=7.2 Hz, 2H), 2,02 (s, 3H),1,66-to 1.59 (m, 2H), of 0.91 (t, J=7.2 Hz, 3H).

Example 7

[3-(2-{5-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.47 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 12,22 (users, 1H), 8,10 (d, J=8,4 Hz, 2H), to 7.84 (d, J=8,4 Hz, 2H), 7,00 (d, J=7.2 Hz, 1H), at 6.84 (d, J=1.2 Hz, 1H), of 6.68 (DD, J=7,2 Hz, 1.2 Hz, 1H), 4,20 (t, J=6.3 Hz, 2H), 3.46 in (s, 2H), 3.27 to-3,13 (m, 1H), 2,97 (t, J=6.3 Hz, 2H), 2,03 (s, 3H), of 1.26 (d, J=7.5 Hz, 6H).

Example 8

[3-(2-{5-ethyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.54 (chloroform:methanol = 8:1);

1H R (DMSO-d6): δ 12,22 (users, 1H), 7,01 (d, J=7.2 Hz, 1H), for 6.81 (s, 1H), 6,69 (d, J=7.2 Hz, 1H), 4,12 (t, J=6.3 Hz, 2H), 3,98-of 3.78 (m, 2H), 3,47 (s, 2H), 3,06 was 2.76 (m, 4H), 2.63 in (kV, J=7.2 Hz, 2H), 2,54 (m, 1H), 2,04 (s, 3H), 1,94 to 1.76 (m, 2H), 1.60-to the 1.44 (m, 2H), 1,12 (t, J=7.2 Hz, 3H).

Example 9

[3-(2-{5-isopropyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf to 0.39 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 12,23 (users, 1H), 8,04-to 7.99 (m, 2H), of 7.48 was 7.45 (m, 2H), 7,00 d, J=7.5 Hz, 1H), 6,84 (s, 1H), 6,70 is 6.67 (m, 1H), 4,19 (t, J=6.3 Hz, 2H), 3.46 in (s, 2H), 3,22-3,13 (m, 1H), 2.95 points (t, J=6.3 Hz, 2H), 2,03 (s, 3H), 1,25 (d, J=6.9 Hz, 6H).

Example 10

[4-methyl-3-(2-{5-pentyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.25 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 8,07 (d, J=8.1 Hz, 2H), 7,65 (d, J=8.1 Hz, 2H), 7,03 (d, J=7.5 Hz, 1H), 6.75 in (s, 1H), 6,74 (d, J=7.5 Hz, 1H), of 5.89 (users, 1H), 4,22 (t, J=6.6 Hz, 2H), 3,55 (s, 2H), 2,99 (t, J=6.6 Hz, 2H), 2,71 (t, J=7.5 Hz, 2H), 2.13 and (s, 3H), of 1.66 (quintet, J=7.5 Hz, 2H), 1,35 (m, 4H), of 0.90 (t, J=6.6 Hz, 3H).

Example 11

[4-methyl-3-(2-{5-phenyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.51 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ of 8.25 (d, J=8,4 Hz, 2H), 7,89 (d, J=8,4 Hz, 2H), a 7.85 (d, J=7.5 Hz, 2H), 7,53 (d, J=7.5 Hz, 2H), 7,43 (m, 1H), 6,97 (d, J=7.5 Hz, 1H), 6.89 in (s, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,35 (t, J=6.0 Hz, 2H), 3,48 (s, 2H), 3,30 (users, 1H), 3,29 (t, J=6.0 Hz, 2H), 1.91 a (s, 3H).

Example 12

[3-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.45 (chloroform:methanol = 8:1);

1H R (DMSO-d6): δ 12,27 (users, 1H), with 8.05 (d, J=8,4 Hz, 2H), 7,81 (d, J=8,4 Hz, 2H), 7,19 (DD, J=8,4, 7.5 Hz, 1H), 6,88-6,74 (m, 3H), 4,28 (t, J=6.6 Hz, 2H), 3,50 (s, 2H), 3,14 (t, J=6.6 Hz, 2H), 2,46 (s, 3H).

Example 13

[4-methyl-3-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.47 (chloroform:methanol = 8:1);

1H R (DMSO-d6): δ 12,23 (users, 1H), with 8.05 (d, J=7.8 Hz, 2H), 7,81 d, J=7.8 Hz, 2H), 7,01 (d, J=7.2 Hz, 1H), 6,86 (s, 1H), 6,70 (d, J=7.2 Hz, 1H), 4,27 (t, J=6.3 Hz, 2H), 3,48 (s, 2H), and 3.16 (t, J=6.3 Hz, 2H), 2,46 (s, 3H), 2,02 (s, 3H).

Example 14

[4-methyl-3-(2-{5-methyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.20 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 7,98 (d, J=9.0 Hz, 2H), 7,24 (d, J=9.0 Hz, 2H),? 7.04 baby mortality (d, J=8,1 Hz, 1H), 6,74 (m, 2H), 4,21 (d, J=6.3 Hz, 2H), of 3.56 (s, 2H), 2,98 (d, J=6.3 Hz, 2H), a 2.36 (s, 3H), and 2.14 (s, 3H).

Example 15

[3-(2-{5-isopropyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf 0.21 in (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 8,00 (m, 2H), 7,25 (d, J=8.1 Hz, 2H), 7,19 (t, J=8,1 Hz, 1H), to 6.80 (m, 3H), 4,18 (t, J=6.6 Hz, 2H), of 3.56 (s, 2H), 3,14 (septet, J=6.9 Hz, 1H), 2,97 (t, J=6.6 Hz, 2H), 1,32 (d, J=6.9 Hz, 6H).

Example 16

[3-(2-{5-(2,2,2-triptorelin)-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.30 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 12,29 (users, 1H), 8,13 (d, J=8,4 Hz, 2H), of 7.90 (d, J=8,4 Hz, 2H), 7,19 (t, J=7.2 Hz, 1H), 6,82-6,79 (m, 3H), 4,23-Android 4.04 (m, 4H), 3,50 (s, 2H), 3,06 (t, J=6.3 Hz, 2H).

Example 17

[3-(2-{5-propyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.27 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 8,00 (m, 2H), 7,27-to 7.18 (m, 3H), 6,86-of 6.78 (m, 3H), is 4.21 (t, J=6.6 Hz, 2H)and 3.59 (s, 2H), 2,97 (t, J=6.6 Hz, 2H), 2,68 (t, J=7.5 Hz, 2H), 1,74 (sextet, J=7.5 Hz, 2H), 0,99 (t, J=7.5 Hz, 3H).

Example 18

[4-methyl-3-(2-{5-propyl-2-4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf 0.21 in (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 8,00 (m, 2H), 7,24 (m, 2H), 7,05 (d, J=7.5 Hz, 1H), 6,77 (c, 1H), 6.75 in (d, J=7.5 Hz, 1H), 4,23 (t, J=6.3 Hz, 2H), to 3.58 (c, 2H), 2,99 (t, J=6.3 Hz, 2H), 2,69 (t, J=7.2 Hz, 2H), 2,14 (c, 3H), 1,71 (sextet, J=7.2 Hz, 2H), 0,99 (t, J=7.5 Hz, 3H).

Example 19

[3-(2-{5-butyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf 0.31 in (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 8,00 (m, 2H), 7,27-7,19 (m, 3H), 6,86-of 6.78 (m, 3H), is 4.21 (t, J=6.6 Hz, 2H), 3,59 (c, 2H), 2,97 (t, J=6.6 Hz, 2H), 2,70 (t, J=7.5 Hz, 2H), of 1.66 (quintet, J=7.5 Hz, 2H), of 1.40 (sextet, J=7.5 Hz, 2H), 0,95 (t, J=7.5 Hz, 3H).

Example 20

[3-(2-{5-butyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.35 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ to 7.93 (d, J=8.7 Hz, 2H), 7,17 (d, J=8.7 Hz, 2H), 6.89 in (d, J=7.5 Hz, 1H), 6,68 (c, 1H), is 6.61 (d, J=7.5 Hz, 1H), 4,54 (users, 1H), 4,11 (t, J=6.3 Hz, 2H), 3.43 points (c, 2H), 2,88 (t, J=6.3 Hz, 2H), 2,66 (t, J=7.2 Hz, 2H), 2.06 to (s, 3H), 1,60 (quintet, J=7.2 Hz, 2H), of 1.36 (sextet, J=7.2 Hz, 2H), to 0.92 (t, J=7.2 Hz, 3H).

Example 21

[4-ethyl-3-(2-{5-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.41 (chloroform:methanol = 8:1);

1H R (DMSO-d6): δ 12,24 (users, 1H), of 8.09 (d, J=8.1 Hz, 2H), to 7.84 (d, J=8.1 Hz, 2H), 7,00 (d, J=7.5 Hz, 1H), 6,85 (c, 1H), 6,72 (d, J=7.5 Hz, 1H), 4,19 (t, J=6.3 Hz, 2H), 3,48 (c, 2H), 2,96 (t, J=6.3 Hz, 2H), 2,44 (kV, J=7.5 Hz, 2H), 2,38 (c, 3H), and 0.98 (t, J=7.5 Hz, 3H).

Example 22

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-methyl-,3-oxazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf 0.31 in (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 7,84 (c, 1H), 7,76 (d, J=8,4 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,00 (d, J=7.5 Hz, 1H), 6,83 (c, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,16 (t, J=6.3 Hz, 2H), 3.46 in (c, 2H), 2,92 (t, J=6.3 Hz, 2H), 2,34 (c, 3H), 2,04 (c, 3H).

Example 23

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-propyl-1,3-oxazol-4-yl]ethoxy}phenyl)acetic acid

TLC: Rf of 0.30 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ a 7.85 (c, 1H), to 7.77 (DD, J=8,1, 0.9 Hz, 1H), 7,51 (DD, J=8,1, 0.9 Hz, 1H), 7,18 (DD, J=7,5, 7.5 Hz, 1H), 6,79 (m, 3H), 4,18 (t, J=6.6 Hz, 2H), 3,49 (c, 2H), 2,92 (t, J=6.6 Hz, 2H), 2,69 (t, J=7,2 Hz, 2H), of 1.65 (sextet, J=7.2 Hz, 2H), of 0.93 (t, J=7.2 Hz, 3H).

Example 24

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-propyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf of 0.33 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ to 7.84 (d, J=1.5 Hz, 1H), to 7.77 (DD, J=8,4, 1.5 Hz, 1H), 7,51 (d, J=8,4 Hz, 1H), 7,01 (d, J=7.5 Hz, 1H), 6,85 (c, 1H), 6,70 (d, J=7.5 Hz, 1H), 4,19 (t, J=6.3 Hz, 2H), 3,48 (c, 2H), equal to 2.94 (t, J=6.3 Hz, 2H), 2,68 (t, J=7.2 Hz, 2H), 2,30 (c, 3H), 1,64 (sextet, J=7.2 Hz, 2H), to 0.92 (t, J=7.2 Hz, 3H).

Example 25

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-isopropyl-1,3-oxazol-4-yl]ethoxy}phenyl)acetic acid

TLC: Rf of 0.25 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 7,87 (d, J=0.9 Hz, 1H), 7,78 (DD, J=8,4, 0.9 Hz, 1H), 7,52 (d, J=8,4 Hz, 1H), 7,18 (DD, J=7,8, and 7.8 Hz, 1H), 6,79 (m, 3H), 4,17 (t, J=6.6 Hz, 2H), 3,50 (c, 2H), 3,18 (septet, J=6.9 Hz, 2H), 2,93 (t, J=6,6 Hz, 2H), 1.27mm (d, J=6,9 Hz, 2H).

Example 26

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-isopropyl-1,3-is xazal-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf of 0.37 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 7,87 (d, J=1.8 Hz, 1H), 7,78 (DD, J=8,4, 1.8 Hz, 1H), 7,52 (d, J=8,4 Hz, 1H), 7,01 (d, J=7.5 Hz, 1H), 6,84 (c, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,19 (t, J=6.3 Hz, 2H), 3,48 (c, 2H), 3,18 (septet, J=6,9 Hz, 1H), 2.95 points (t, J=6.3 Hz, 2H), 2,04 (c, 3H), of 1.26 (d, J=6.9 Hz, 6H).

Example 27

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-ethyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf 0.26 (chloroform:methanol = 9:1);

1H R (DMSO-d6): δ 7,86 (d, J=1.8 Hz, 1H), 7,78 (DD, J=8,4, 1.8 Hz, 1H), 7,52 (d, J=8,4 Hz, 1H), 7,01 (d, J=7.5 Hz, 1H), 6,84 (c, 1H), 6,69 (d, J=7.5 Hz, 1H), 4,18 (t, J=6.3 Hz, 2H), 3,48 (c, 2H), equal to 2.94 (t, J=6.3 Hz, 2H), 2,73 (kV, J=7.5 Hz, 2H), 2,04 (c, 3H), 1,21 (t, J=7.5 Hz, 3H).

Example 28

Hydrochloride 4-(trifluoromethyl)piperidine

In an argon atmosphere to a solution of 4-(trifluoromethyl)pyridine (was 9.33 g) in methanol (80 ml) is added concentrated hydrochloric acid (16 ml) and platinum oxide (510 mg) and everything is stirred for three days at room temperature under hydrogen pressure. The reaction mixture was filtered through celite (trade name) and the filtrate concentrated. To the residue is added saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then filtered. To the filtrate add a 4N solution of hydrogen chloride/ethyl acetate (50 ml) and then concentrated to obtain from asanoha in the connection header (13,0 g), having the following physical parameters.

TLC: Rf 0,13 (chloroform:methanol = 10:1);

1H NMR (CDCl3): δ 1,72 (DD, J=13,0, 4.0 Hz, 1H), 1,81 (DD, J=13,0, 4.0 Hz, 1H), 2,05-of 2.20 (m, 2H), 2,41 is 2.80 (m, 1H), 3,06 (dt, J=13,0, 3.0 Hz, 2H), 3,40-of 3.60 (m, 2H).

Example 29

4-(trifluoromethyl)-1-piperidinecarboxylic

To a suspended solution of the compound obtained in example 28 (3.80 g)in tetrahydrofuran (25 ml), add triethylamine (2.9 ml) and thiocarbonyldiimidazole (3.80 g) and stirred over night at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated to obtain a brown oily substance. Mixed mortar of the specified oil substances in ethanol (30 ml) and tetrahydrofuran (15 ml) cooled in ice water, saturated by ozonation with ammonia gas and then stirred over night at room temperature. Next, the reaction mixture is concentrated and the obtained yellow solid was washed with diethyl ether and dried to obtain specified in the connection header (2,19 g)having the following physical parameters.

TLC: Rf of 0.47 (chloroform:methanol = 10:1);

1H NMR (CDCl3): δ 1,76-to 1.61 (m, 2H), 2,03-of 1.93 (m, 2H), 2,44-of 2.24 (m, 1H), 3,15-3,03 (m, 2H)and 4.65 (userd, J=13,0 Hz, 2H), of 5.83 (users, 2H).

Note the R 30

Methyl-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}acetate

To a solution of the compound obtained in example 29 (2,18 g)in ethanol (10 ml) is added methyl 4-bromo-3-oxopentanoate (2.37 g) and stirred all night at room temperature. To the reaction mixture are added water and saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 4:2 to 2:1) to obtain the specified title compound (2.86 g)having the following physical indicators (2.86 g).

TLC: Rf of 0.51 (hexane:ethyl acetate=2:1);

1H NMR (CDCl3): δ 1,67 (DQC, J=5,0, 13,0 Hz, 2H), 1.93 and (userd, J=13,0 Hz, 2H), 2,23 (c, 3H), 2,31-2,11 (m, 1H), 2,89 (dt, J=2.5 a, 13,0 Hz, 2H), 3,53 (c, 2H), 3,70 (c, 3H), 4.00 points (userd, J=13,0 Hz, 2H).

Example 31

2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethanol

A solution of lithium aluminum hydride (336 mg) in anhydrous tetrahydrofuran (35 ml) cooled in ice water and add dropwise a solution of the compound obtained in example 30 (2.85 g)in anhydrous tetrahydrofuran (5 ml) and stirred for 15 minutes at room temperature. The reaction mixture is maintained within the conditions cooling with ice water, add to it until the NML saturated solution of sodium sulfate (1.8 ml) and stirred for one hour at room temperature. To the reaction mixture is added diethyl ether (20 ml), all mix, dried over anhydrous magnesium sulfate and then filtered through celite. The filtrate is concentrated to obtain specified in the connection header (2,46 g)having the following physical indicators:

TLC: Rf is 0.24 (hexane:ethyl acetate=2:1);

1H NMR (CDCl3): δ 1,68 (DQC, J=4,5, 13,0 Hz, 2H), 2.00 in 1,90 (m, 2H), 2,21 (c, 3H), 2,33 and 2.13 (m, 1H), to 2.67 (t, J=5.5 Hz, 2H), 2,92 (dt, J=3.0 a, 13,0 Hz, 2H), 3,85 (t, J=5.5 Hz, 2H), 3,98 (userd, J=13,2 Hz, 2H), 4,29 (user., 1H).

Example 32

Methyl-[2-fluoro-3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetate

In an argon atmosphere to a solution of the compound obtained in example 31 (227 mg), methyl-(2-fluoro-3-hydroxyphenyl)acetate (184 mg) and triphenylphosphine (262 mg) in anhydrous dichloromethane (5 ml) is added dropwise diethylazodicarboxylate (435 mg) and stirred for 4 hours at room temperature. The reaction mixture was concentrated and the resulting residue is purified column chromatography on silica gel (hexane:ethyl acetate=9:1 to 7:3) to obtain the specified title compound (306 mg)having the following physical parameters.

TLC: Rf of 0.64 (hexane:ethyl acetate=1:2);

1H NMR (CDCl3): δ 1,68 (CVD, J=12,7, 4,4 Hz, 2H), 1,94 (d, J=a 12.7 Hz, 2H), 2,13-of 2.28 (m, 1H), 2.26 and (c, 3H), 2,89 (TD, J=12,7, 2.7 Hz, 2H), 2,98 (t, J=6.9 Hz, 2H), 3,65-3,68 (m, 2H), 3,70 (c, 3H), 4,01 (d, J=12.7 G is, 2H), 4,25 (t, J=6.9 Hz, 2H), 6,74-6,83 (m, 1H), 6,85-7,02 (m, 2H).

Example 33

[2-fluoro-3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid

To a stirred solution of the compound obtained in example 32 (306 mg)in methanol (5 ml) and tetrahydrofuran (5 ml) is added 5N aqueous sodium hydroxide solution (2.00 ml) at room temperature and stirred for 2 hours. The reaction mixture is brought to pH 4 with 2N hydrochloric acid, diluted with water and the resulting crystals are separated by filtration. The crystalline substance is washed with water and dried to obtain specified in the title compound (226 mg)having the following physical parameters.

TLC: Rf of 0.60 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ 1,47 (CVD, J=12,7, 4,4 Hz, 2H), 1,86 (d, J=11.5 Hz, 2H), 2,19 (c, 3H), 2,47-2,63 (m, 1H), 2,86 (t, J=6,7 Hz, 2H), equal to 2.94 (dt, J=12,7, 2.7 Hz, 2H), 3,57 (d, J=1.5 Hz, 2H), 3,86 (d, J=a 12.7 Hz, 2H), 4,20 (t, J=6,7 Hz, 2H), to 6.80-6.87 in (m, 1H), 6,97-to 7.09 (m, 2H), 12,20-12,70 (users, 1H).

Example 34 example 34(15)

According to the procedure described in example 32 and example 33 using the compound obtained in example 31, or the corresponding alcohol derivative instead and methyl-(2-fluoro-3-hydroxyphenyl)acetate or its corresponding alcohol derivative will receive the following compounds of the present invention.

Example 34

(3-{2-[2-(1,1'-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf of 0.57 (dichloromethane:methanol = 9:1);

1H NMR (DMSO-d6): δ to 2.06 (c, 3H), 2,35 (c, 3H), equal to 2.94 (t, J=6,23 Hz, 2H), 3,49 (c, 2H), 4,19 (t, J=6,23 Hz, 2H), of 6.71 (d, J=EUR 7.57 Hz, 1H), 6,86 (c, 1H), 7,02 (d, J=EUR 7.57 Hz, 1H), 7,38 (t, J=EUR 7.57 Hz, 1H), 7,47 (t, J=EUR 7.57 Hz, 2H), of 7.70 (d, J=EUR 7.57 Hz, 2H), 7,78 (d, J=8,30 Hz, 2H), 7,98 (d, J=8,30 Hz, 2H), 12,25 (c, 1H).

Example 34(1)

(4-methyl-3-{2-[5-methyl-2-(4-phenylpiperazin-1-yl)-1,3-thiazol-4-yl]phenyl)acetic acid

TLC: Rf of 0.65 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,23 (users, 1H), 7,34-7,13 (m, 5H), 7,02 (d, J=7.5 Hz, 1H), PC 6.82 (d, J=1.2 Hz, 1H), 6,79 (DD, J=7,5, 1.2 Hz, 1H), 4,12 (t, J=6.3 Hz, 2H), 3.96 points-a 3.83 (m, 2H), 3,48 (c, 2H), 2,99 (dt, J=12,3, 2.7 Hz, 2H,), of 2.86 (t, J=6.3 Hz, 2H), 2,78-2,62 (m, 1H), 2,20 (c, 3H), 2.05 is (c, 3H), 1,87 to 1.76 (m, 2H), 1,67 (DQC, J=12,3, 3,9 Hz, 2H).

Example 34(2)

(3-{2-[2-(4-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf 0.31 in (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ 2,04 (c, 3H), 2,34 (c, 3H), of 2.93 (t, J=6.3 Hz, 2H), 3,48 (c, 2H), 4,17 (t, J=6.3 Hz, 2H), 6,70 (DD, J=7,5, 1.5 Hz, 1H), at 6.84 (d, J=1.5 Hz, 1H), 7,01 (DD, J=7,5, 0.7 Hz, 1H), 7,54 (d, J=9.0 Hz, 2H), of 7.90 (d, J=9.0 Hz, 2H), 12,22 (c, 1H).

Example 34(3)

(2-fluoro-3-{2-[5-methyl-2-(4-phenylpiperazin-1-yl)-1,3-thiazol-4-yl]ethoxy}phenyl)acetic acid

TLC: Rf of 0.54 (chloroform:methanol:=9:1);

1H NMR (DMSO-d6): δ 1,67 (CVD, J=12,3, 4,2 Hz, 2H), 1,81 (t, J=12.3 Hz, 2H), 2,20 (c, 3H), 2,71 (TT, J=8,4, 3.6 Hz, 1H), 2,87 (t, J=6.6 Hz, 2H), 3.00 and (TD, J=12,3, 2,1 Hz, 2H), to 3.58 (c, 2H), 3,90 (d, J=12.3 Hz, 2H), 4,21 (t, J=6.6 Hz, 2H), 6.73 x-6,89 (m, 1H), 6,93-7,13 (m, 2H), 7,13-to 7.35 (m, 5H), 12,37 (c, 1H).

Example 34(4)

(3-{2-[5-methyl-2-(4-phenylpiperazin-1-yl)-1,3-thiazol-4-yl]ethoxy}phenyl)acetic acid

TLC: Rf 0,54 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,25 (users, 1H), 7,28-7,13 (m, 3H), of 6.96 (d, J=9.0 Hz, 2H), 6,86 to 6.75 (m, 4H), 4,14 (t, J=6.9 Hz, 2H), 3,51 (c, 2H), 3,48-3,39 (m, 4H), 3,26 is 3.15 (m, 4H), of 2.86 (t, J=6.9 Hz, 2H), 2,21 (c, 3H).

Example 34(5)

[3-(2-{2-[4-(4-chlorophenyl)piperazine-1-yl]-5-methyl-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf 0,51 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,25 (users, 1H), 7,24 (d, J=9.0 Hz, 2H), 7,19 (t, J=8,1 Hz, 1H), 6,97 (d, J=9.0 Hz, 2H), 6,84 to 6.75 (m, 3H), 4,14 (t, J=6.9 Hz, 2H), 3,51 (c, 2H), 3,48-3,39 (m, 4H), 3.27 to 3.15 in (m, 4H), of 2.86 (t, J=6,9 Hz, 2H), 2,21 (c, 3H).

Example 34(6)

[3-(2-{5-methyl-2-[4-(4-were)piperazine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.48 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ of 12.26 (users, 1H), 7,18 (t, J=8,1 Hz, 1H),? 7.04 baby mortality (d, J=8,4 Hz, 2H), 6,86 (d, J=8,4 Hz, 2H), 6,84 to 6.75 (m, 3H), 4,14 (t, J=6.9 Hz, 2H), 3,51 (c, 2H), 3,48-to 3.38 (m, 4H), 3,21-is 3.08 (m, 4H), of 2.86 (t, J=6,9 Hz, 2H), 2,21 (c, 3H), 2,20 (c, 3H).

Example 34(7)

(3-{2-[2-(1,3-dihydro-2H-isoindole-2-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-2-forfinal)acetic acid

TLC: Rf value of 0.52 (chloroform:methanol:=9:1);

1H NMR (DMSO-d6): δ 2,23 (c, 3H), only 2.91 (t, J=6.6 Hz, 2H), to 3.58 (d, J=0.9 Hz, 2H), 4,24 (t, J=6.6 Hz, 2H), 4,66 (c, 4H), to 6.80-6.87 in (m, 1H), 6,98-7,10 (m, 2H), 7,27-7,34 (m, 2H), 7,35-7,41 (m, 2H), 12,41 (users, 1H).

Example 34(8)

[3-(2-{2-[4-(4-chlorophenyl)piperazine-1-yl]-5-methyl-1,3-thiazol-4-yl}ethoxy)-2-torfin the l] acetic acid

TLC: Rf 0.56 to (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,41 (users, 1H), 7,24 (d, J=9.0 Hz, 2H), 7,09-6,92 (m, 4H), 6,88-of 6.78 (m, 1H), 4,21 (t, J=6.6 Hz, 2H), 3,57 (d, J=1.5 Hz, 2H), 3,48-3,37 (m, 4H), 3,28-and 3.16 (m, 4H), 2,88 (t, J=6.6 Hz, 2H), 2,21 (c, 3H).

Example 34(9)

[3-(2-{2-[4-(4-chlorophenyl)piperazine-1-yl]-5-methyl-1,3-thiazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.48 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,21 (users, 1H), 7,24 (d, J=9.0 Hz, 2H), 7,01 (d, J=7.5 Hz, 1H), 6,97 (d, J=9.0 Hz, 2H), for 6.81-of 6.78 (d, J=1.2 Hz, 1H), 6,69 (DD, J=7,5, 1.2 Hz, 1H), 4,13 (t, J=6.6 Hz, 2H), 3,48 (c, 2H), 3.46 in-3,37 (m, 4H), 3,26 is 3.15 (m, 4H), 2,87 (t, J=6.6 Hz, 2H), 2,21 (c, 3H), 2.05 is (c, 3H).

Example 34(10)

[3-(2-{2-[4-(4-chlorophenyl)piperidine-1-yl]-5-methyl-1,3-thiazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.40 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ 1,55-of 1.64 (m, J=12,5, 4.0 Hz, 1H), 1,68 (DD, J=12,5, 4.0 Hz, 1H), 1,74-to 1.87 (m, 2H), 2.05 is (c, 3H), 2,20 (c, 3H), 2,73 (TT, J=12,5, 3.5 Hz, 1H), 2,85 (t, J=6.5 Hz, 2H), 2,99 (dt, J=12,5, 2.5 Hz, 2H), 3,48 (c, 2H), 3,89 (userd, J=12,5 Hz, 2H), 4,12 (t, J=6.5 Hz, 2H), 6,69 (DD, J=7,0, 1.1 Hz, 1H), PC 6.82 (d, J=1.1 Hz, 1H), 7,02 (d, J=7.5 Hz, 1H), 7,27 (d, J=8.5 Hz, 2H), 7,34 (d, J=8.5 Hz, 2H), 12,20 (users, 1H).

Example 34(11)

(3-{2-[2-(3,4-dihydro-1H-isoquinoline-2-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf of 0.55 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,20 (users, 1H), 7,26 for 7.12 (m, 4H), 7,02 (d, J=7.5 Hz, 1H), PC 6.82 (d, J=1.5 Hz, 1H), 6,69 (DD, J=7,5, 1.5 Hz, 1H), 4,51 (c, 2H), 4,14 (t, J=6.6 Hz, 2H), 3,61 (t, J=6.0 Hz, 2H), 3,48 (c, 2H), 2.95 and-2,82 (m, 4), 2,22 (c, 3H), 2.05 is (c, 3H).

Example 34(12)

(4-methyl-3-{2-[5-methyl-2-(4-phenyl-3,6-dihydro-2H-pyridine-1-yl)-1,3-thiazol-4-yl]ethoxy}phenyl)acetic acid

TLC: Rf value of 0.52 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 2,15 (c, 3H), and 2.27 (c, 3H), 2,61 of 2.68 (m, 2H), 2,98 (t, J=6.6 Hz, 2H), to 3.58 (c, 2H), 3,68 (t, J=5.8 Hz, 2H), was 4.02-4,07 (m, 2H), 4,20 (t, J=6.6 Hz, 2H), 6,06-6,11 (m, 1H), 6,72-6,79 (m, 2H), 7,05 (d, J=7.5 Hz, 1H), 7,21-the 7.43 (m, 5H).

Example 34(13)

[3-(2-{2-[4-(4-forfinal)piperidine-1-yl]-5-methyl-1,3-thiazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.38 (methanol:dichloromethane = 1:9);

1H NMR (DMCO-d6): δ 12,21 (users, 1H), 7,27 (DD, J=8,7, 5.7 Hz, 2H), 7,10 (t, J=8.7 Hz, 2H), 7,02 (d, J=7.5 Hz, 1H), PC 6.82 (d, J=1.2 Hz, 1H), 6,70 (DD, J=7,5, 1.2 Hz, 1H), 4,12 (t, J=6.6 Hz, 2H), 3.96 points-is 3.82 (m, 2H), 3,48 (c, 2H), 2,98 (t, J=dt, 12,3, 2.4 Hz, 2H), 2,86 (t, J=6.6 Hz, 2H), 2,72 (TT, J=12,3, 3.3 Hz, 1H), 2,20 (c, 3H), 2.05 is (c, 3H), 1,87-of 1.73 (m, 2H), 1,64 (DQC, J=12,3, 4,2 Hz, 2H).

Example 34(14)

(4-methyl-3-{2-[5-methyl-2-(4-phenylpiperazin-1-yl]-1,3-thiazol-4-yl]ethoxy}phenyl)acetic acid

TLC: Rf of 0.54 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ 2,14 (c, 3H), 2.26 and (c, 3H), 2,96 (t, J=6.6 Hz, 2H), 3,21-of 3.27 (m, 4H), 3,49-to 3.58 (m, 6H), 4,17 (t, J=6.6 Hz, 2H), 6,72-6,76 (m, 2H), 6,86-6,97 (m, 3H),? 7.04 baby mortality (DD, J=8,1, 0.7 Hz, 1H), 7.24 to 7,31 (m, 2H).

Example 34(15)

{4-methyl-3-[2-(5-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-yl}-1,3-thiazol-4-yl)ethoxy]phenyl}acetic acid

TLC: Rf of 0.47 (methanol:dichloromethane = 1:9);

1H NMR (CDCl3): δ 8,44 is 8.38 (m, 1H), 7,65 (DD, J=9,0, 2.4 Hz, 1H),? 7.04 baby mortality (d, J=7.2 Hz, 1H), 6,0-of 6.71 (m, 2H), 6,65 (d, J=9.0 Hz, 1H), 4,19 (t, J=6.6 Hz, 2H), 3,79 at 3.69 (m, 4H), 3,57 (c, 2H), 3,54-of 3.46 (m, 4H), 2,96 (t, J=6.6 Hz, 2H), and 2.27 (c, 3H), 2,14 (c, 3H).

Example 35

Methyl-(3-{2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetate

According to the procedure described in example 31 and example 32, using [2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetate instead of the compound obtained in example 30, and methyl-(3-hydroxy-4-were)acetate instead of methyl-(2-fluoro-3-hydroxyphenyl)acetate receive specified in the title compound having the following physical parameters.

TLC: Rf of 0.48 (ethyl acetate:hexane=1:2);

1H NMR (CDCl3): δ 2,15 (c, 3H), 2,37 (c, 3H), 2,98 (t, J=6.3 Hz, 2H), 3,56 (c, 2H), 3,67 (c, 3H), 4,23 (t, J=6.3 Hz, 2H), 6,78-of 6.71 (m, 2H), 7,05 (d, J=7.8 Hz, 1H), 7,56 (d, J=8.7 Hz, 2H), to 7.84 (d, J=8.7 Hz, 2H).

Example 36

Methyl-[4-methyl-3-(2-{5-methyl-2-[4-(pyridin-2-yl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetate

In an argon atmosphere a solution of the compound obtained in example 35 (300 mg), tri-n-butyl-(2-pyridyl)tin (273 mg), lithium chloride (85 mg) and tetrakis(triphenylphosphine)palladium (39 mg) in dioxane (3 ml) is stirred for 5 hours at a temperature of 115°C. the Reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate, and then the end of tryout. The residue is purified column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (240 mg)having the following physical parameters.

TLC: Rf 0,09 (hexane:ethyl acetate=2:1).

Example 37

Methyl-[3-(2-{2-[4-(furan-3-yl)phenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-4-were]acetate

The mixed solution of the compound obtained in example 35 (300 mg), 3-Puilboreau acid (97 mg), sodium carbonate (92 mg) and tetrakis(triphenylphosphine)palladium (39 mg) in dimethoxyethane (6 ml) and water (2 ml) is stirred for 2 hours at a temperature of 90°C. the Reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 9:1 to 4:1) to obtain the specified title compound (260 mg)having the following physical parameters.

TLC: Rf is 0.24 (hexane:ethyl acetate=2:1).

Example 38 Example 38(1)

According to the procedure described in example 33 using the compound obtained in example 36 and example 37 instead of the compound obtained in example 32, receive the following compounds according to the present invention.

Example 38

[4-methyl-3-(2-{5-meth is l-2-[4-(pyridin-2-yl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.38 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ 2,05 (c, 3H), 2,37 (c, 3H), 2.95 points (t, J=6,32 Hz, 2H), 3.45 points (c, 2H), 4,18 (t, J=6,32 Hz, 2H), 6,69 (d, J=7,51 Hz, 1H), 6,86 (c, 1H), 7,01 (d, J=7,51 Hz, 1H), 7,38 (DDD, J=7,50, 4,76, 1,10 Hz, 1H), of 7.90 (DDD, J=8,06, 7,50, 1,74 Hz, 1H), 8,01 (d, J=8,24 Hz, 2H), 8,01-with 8.05 (m, 1H), they were 8.22 (d, J=8,24 Hz, 2H), 8,68 (DDD, J=4,76, 1,74, of 0.91 Hz, 1H).

Example 38(1)

[3-(2-{2-[4-(furan-3-yl)phenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.33 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ to 2.06 (c, 3H), 2,35 (c, 3H), of 2.93 (t, J=6,32 Hz, 2H), 3,49 (c, 2H), 4,17 (t, J=6,32 Hz, 2H), 6,70 (d, J=7,51 Hz, 1H), 6,85 (c, 1H), 7,02 (d, J=7,51 Hz, 1H), 7,01-7,02 (m, 1H), 7,73 (d, J=8,24 Hz, 2H), 7,75 for 7.78 (m, 1H), of 7.90 (d, J=8,24 Hz, 2H), 8,28 (c, 1H), 12,25 (users, 1H).

Example 39 example 39(8)

According to the procedure described in example 37 and example 33 using the compound obtained in example 35, or instead of corresponding to its derivative and the corresponding boranova acid instead of 3-Puilboreau acid will receive the following compounds according to the present invention.

Example 39

(3-{2-[2-(4'-fluoro-1,1'-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid

TLC: Rf 0,54 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,24 (users, 1H), of 7.97 (d, J=8,4 Hz, 2H), to 7.77 (d, J=8,4 Hz, 2H), 7,76 (DD, J=8,7, 5.7 Hz, 2H), 7,30 (t, J=8.7 Hz, 2H), 7,02 (d, J=7.5 Hz, 1H), 6,85 (d, J=1.2 Hz, 1H), 6,70 (DD, J=7,5, 1.2 Hz, 1H), 4,18 (t, J=6.3 Hz, 2H), 3,49 (c, 2H), equal to 2.94 (t, J=6.3 Hz, 2H), 2,35 (c, 3H), 2.05 is (c, 3H).

Por the measures 39(1)

(3-{2-[2-(3'-fluoro-1,1'-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were]acetic acid

TLC: Rf 0,54 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,25 (users, 1H), 7,98 (d, J=8.7 Hz, 2H), 7,83 (d, J=8.7 Hz, 2H), 7,62-7,44 (m, 3H), 7,26-7,17 (m, 1H), 7,02 (d, J=7.8 Hz, 1H), 6,85 (d, J=1.2 Hz, 1H), 6,70 (DD, J=7,8, 1.2 Hz, 1H), 4,18 (t, J=6,3 Hz, 2H), 3,49 (c, 2H), equal to 2.94 (t, J=6.3 Hz, 2H), 2,36 (c, 3H), 2.06 to (c, 3H).

Example 39(2)

[4-methyl-3-(2-{5-methyl-2-[4-thiophene-2-yl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.37 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ 2,05 (c, 3H), 2,35 (c, 3H), of 2.93 (t, J=6,32 Hz, 2H), 3,47 (c, 2H), 4,17 (t, J=6,32 Hz, 2H), 6,70 (DD, J=7,51, of 1.28 Hz, 1H), 6,85 (DD, J=1,28, to 0.73 Hz, 1H), 7,01 (DD, J=7,51, to 0.73 Hz, 1H), 7,16 (DD, J=4,94, 3,66 Hz, 1H), 7,60 (DD, J=4,94, 1,10 Hz, 1H), to 7.61 (DD, J=3,66, 1,10 Hz, 1H), to 7.77 (d, J=at 8.60 Hz, 2H), 7,92 (d, J=at 8.60 Hz, 2H).

Example 39(3)

[4-methyl-3-(2-{5-methyl-2-[4-(thiophene-3-yl)phenyl]-1,3-oxazol-4-yl}ethoxy)phenyl]acetic acid

TLC: Rf of 0.37 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ to 2.06 (c, 3H), 2,36 (c, 3H), equal to 2.94 (t, J=6,32 Hz, 2H), 3,48 (c, 2H), 4,18 (t, J=6,32 Hz, 2H), 6,70 (DD, J=7,51, to 0.92 Hz, 1H), 6,85 (d, J=0,92 Hz, 1H), 7,02 (d, J=7,51 Hz, 1H), to 7.61 (DD, J=5,13, 1,46 Hz, 1H), 7,66 (DD, J=5,13, with 2.93 Hz, 1H), to 7.84 (d, J=8,61 Hz, 2H), to 7.93 (d, J=8,61 Hz, 2H), to 7.99 (DD, J=2,93, 1,46 Hz, 1H).

Example 39(4)

[3-(2-{2-[4-(furan-2-yl)phenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.33 (chloroform:methanol = 9:1);

1H NMR (DMSO-d6): δ 2,05 (c, 3H), 2,35 (c, 3H), of 2.93 (t, J=6,32 Hz, 2H), 3,48 (c, 2H), 4,18 (t, J=6,32 is C, 2H), 6,62 (DD, J=3,48 and 1.83 Hz, 1H), 6,70 (DD, J=7,69, 1,10 Hz, 1H), 6,85 (d, J=1,10 Hz, 1H), 7,02 (d, J=of 7.69 Hz, 1H), 7,06 (d, J=3,48 Hz, 1H), 7,80 (d, J=at 8.60 Hz, 2H), 7,79 (d, J=1,83 Hz, 1H), 7,94 (d, J=at 8.60 Hz, 2H), 12,24 (users, 1H).

Example 39(5)

[3-(2-{2-[4-(furan-2-yl)phenyl]-5-isopropyl-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.35 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ of 1.33 (d, J=of 6.96 Hz, 6H), 2,13-to 2.18 (m, 3H), to 3.02 (t, J=6,50 Hz, 2H), 3.15 in (septet, J=of 6.96 Hz, 1H), to 3.58 (c, 2H), 4,24 (t, J=6,50 Hz, 2H), of 6.49 (DD, J=3,30 and 1.83 Hz, 1H), 6,72 (d, J=3,30 Hz, 1H), 6,76 (d, J=7,51 Hz, 1H), 6,78 (c, 1H), 7,05 (d, J=7,51 Hz, 1H), 7,49 (d, J=1,83 Hz, 1H), 7,71 (d, J=8,42 Hz, 2H), 7,98 (d, J=8,42 Hz, 2H).

Example 39(6)

[3-(2-{5-isopropyl-2-[4-(thiophene-2-yl)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid

TLC: Rf of 0.35 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ of 1.33 (d, J=7,0 Hz, 6H), 2,16 (c, 3H), to 3.02 (t, J=6.6 Hz, 2H), 3.15 in (septet, J=7,0 Hz, 1H), to 3.58 (c, 2H), 4,24 (t, J=6.6 Hz, 2H), 6,74-of 6.78 (m, 2H), 7,05 (d, J=7.5 Hz, 1H), to 7.09 (DD, J=4,8, and 3.3 Hz, 1H), 7,31 (DD, J=4,8, 1.2 Hz, 1H), 7,37 (DD, J=3.3V, 1.2 Hz, 1H), 7,65 (d, J=8.7 Hz, 2H), of 7.97 (d, J=8.7 Hz, 2H).

Example 39(7)

(3-{2-[5-isopropyl-2-(4'-methoxy-1,1'-biphenyl-4-yl)-1,3-oxazol-4-yl]ethoxy}-4-were]acetic acid

TLC: Rf of 0.41 (chloroform:methanol = 9:1);

1H NMR (CDCl3): δ to 1.32 (d, J=6.9 Hz, 6H), 2,16 (c, 3H), to 3.02 (t, J=6.5 Hz, 2H), 3.15 in (septet, J=6.9 Hz, 1H), to 3.58 (c, 2H), 3,85 (c, 3H), 4,24 (t, J=6.5 Hz, 2H), 6,74-of 6.78 (m, 2H), 6,98 (d, J=6,9 Hz, 2H),? 7.04 baby mortality (d, J=7.5 Hz, 1H), 7,56 (d, J=6,9 Hz, 2H), 7,60 (d, J=8.7 Hz, 2H), 8,01 (d, J=8.7 Hz, 2H).

Example 39(8)

(3-{2-[5-isopropyl-2-(4'-is ethyl-1,1'-biphenyl-4-yl)-1,3-oxazol-4-yl]ethoxy}-4-were]acetic acid

TLC: Rf 0,61 (methanol:dichloromethane = 1:9);

1H NMR (DMSO-d6): δ 12,23 (users, 1H), of 7.97 (d, J=8,4 Hz, 2H), 7,76 (d, J=8,4 Hz, 2H), to 7.61 (d, J=7.8 Hz, 2H), 7,28 (d, J=7.8 Hz, 2H), 7,01 (d, J=7.5 Hz, 1H), 6.87 in (d, J=1.2 Hz, 1H), 6,70 (DD, J=7,5, 1.2 Hz, 1H), 4,21 (t, J=6.3 Hz, 2H), 3,49 (c, 2H), 3,19 (septet, J=7.2 Hz, 1H), 2,97 (t, J=6.3 Hz, 2H), 2,34 (c, 3H), 2.06 to (c, 3H), 1.27mm (d, J=7.2 Hz, 6H).

Biological examples

In volume the following experiments it was shown that the compounds of the present invention described by formula (I)have agonistic activity against PPAR.

The definition of agonistic activity against PPAR:

(1) Obtaining materials in luciferase test using human PPAR

To evaluate the compounds of the present invention carry out the determination by the method described below, which has been improved from the point of view of accuracy of measurement and from the point of view of the sensitivity of the measurement.

In this test to obtain the expression vector of gene luciferase, operating under the control of the promoter timedancing (TK), structural gene luciferase cut out from the vector PicaGene Basic Vector 2 (trade name, Tokyo Ink Inc., No. catalog 309-04821) to obtain the vector of gene expression of luciferase pTK-Luc. under control of the TK promoter (-105/+51), with the necessary minimal promoter activity of pTKβincluding the TK promoter (Chrontech Inc., No. catalog 6179-1). At the top of the hour is ü promoter TK embed repeated four UAS sequence, which are reactive sequence of the Gal4 protein, the main transcription factor in yeast, to construct a 4 X UAS-TK-Luc. as a reporter gene. Shown below is used enhancer sequence (SEQ ID NO:1). SEQ ID NO: 1: enhancer sequence with repetitive reactive protein Gal4

5'-T(CGACGGAGTACTGTCCTCCG)C AGCT-3'

By the above method receive vector, on the basis of which is expressed protein, so that at the carboxyl end of the yeast protein Gal4 DNA-binding domain merge with the binding domain of the ligand in human PPAR α, γ or δ. In other words, the vector PicaGene Basic Vector 2 (trade name, Tokyo Ink Inc., No catalog 309-04821) is used as a basic expression vector, the structural gene is replaced by a chimeric receptor protein, and promoter and enhancer domains left unchanged.

DNA encoding legendbase.ui domain of human PPAR α, γ or δ, merge with DNA that encodes a DNA-binding domain in the protein Gal4, in the course of reading the information of the DNA coding sequence from 1 to 147 amino acids, for fixation of a reading frames, followed by embedding in the course of reading the promoter/enhancer in the vector PicaGene Basic Vector 2 (trade name, Tokyo Ink Inc., No. catalog 309-04821). Next, perform a comparison of the consequences of the successive DNA by the following procedure, aminocore landscapebased domain of human PPAR α, γ or δ is a sequenced nuclear translocation signal, obtained from the T antigen of SV-40: Ala Pro Lys Lys Lys Arg Lys Val Gly (SEQ ID NO: 2), what is being done to obtain the expressed chimeric protein, localized to intranuclear. On the other hand, carboxysomes is a sequenced epitope of the hemagglutinin of influenza virus: Tyr Pro Tyr Asp Val Pro Asp Tyr Ala (SEQ ID NO: 3) and the stop codon for translation in order to identify the expressed fused protein, labeled epitope sequence.

In accordance with the results of the comparison of the structures of the human PPAR described in the literature (R. Mukherjee et al. (see J. Steroid Biochem. Molec. Biol.,51, 157 (1994)), M.E. Green et al. (see Gene Expression.,4, 281 (1995)), A. Elbrecht et al. (see Biochem. Biophys. Res. Commun.,224, 431 (1996)) or A. Schmidt et al. (see Mol. Endocrinology, 6, 1634 (1992)), the portion of the structural gene, used as landscapebased domain of human PPAR α, γ or δrepresents the DNA encoding the following peptide:

legendbase.ui domain of human PPAR α: Ser167-Tyr468

legendbase.ui domain of human PPAR γ: Ser176-Tyr478

legendbase.ui domain of human PPAR δ: Ser139-Tyr441

(each legendbase.ui domain of human PPAR γ 1 and legendbase.ui D. the Maine human PPAR γ 2 is a Ser204-Tyr506i.e. the same sequence). To determine the basal level of transcription get the expression vector containing the DNA-binding domain of the Gal4 protein, which is absent in landscapebased domain of PPAR and which exclusively encodes a sequence from 1 to 147 amino acid in the protein Gal4.

(2) the Luciferase test using human PPAR α, γ or δ

CV-1 cells used as host cells are cultivated in accordance with conventional method. Specified cultivation involves the use of Dulbecco modified eagle medium (DMEM) with the addition of 10% fetal calf serum (GIBCO BRL Inc., No. catalog 26140-061), 50 IU/ml penicillin G and 50 μg/ml of streptomycin sulfate, specified the cultivation of CV-1 cells is carried out in an atmosphere of 5% gas carbon dioxide at 37°C.

In the case of transfection for the introduction of DNA transfer and reporter gene and expression vector Gal4-PPAR in the host cell, C6cells plated on Cup size of 10 cm and washed once with serum-free medium with the addition of subsequently thereto environment (10 ml). Reporter gene (10 µg), the expression vector Gal4-PPAR (0.5 μg) and 50 μl of LipofectAMINE (GIBCO BRL Inc., No. catalog 18324-012) after thorough mixing, add to the culture cups. Spend cultivation Avenue is 37° C for 5-6 hours and then add 10 ml of medium containing 20% cialisbuynow fetal calf serum (GIBCO BRL Inc., No. catalog 26300-061), and then hold culturing overnight at 37 ° °C. the Cells are dispersed by tripsinova processing and then re-plated on 96-well tablets with a density of 8000 cells/100 μl of DMEM-10% cialisbuynow serum/well. Several hours after the start of cultivation, when the cells will stick to the plastic grid, add 100 ál of DMEM-10% cialisbuynow serum containing compounds of the present invention, the concentration of which is twice the final concentration. The culture was incubated for 42 hours at a temperature of 37°and the cells are then diluted to determine the luciferase activity in accordance with the manufacturer's instructions.

Carbacyclin activates PPAR δwhile the relative activity of the compounds of the present invention is measured in the conditions under which fold amplification/activation transcription is defined as 1 for the case of a final concentration of 30 μm carbacyclin. Based on this, calculate the indicator of the ratio of amplification/activation of transcription of PPAR δ compounds obtained in example 33, as shown in table 1.

tr>
Table 1
The final concentration (ám)The multiplicity of amplification/activation transcription
0,10,47
0,31,08
1,01,23

In the result, it was shown that the compounds of the present invention exhibit better agonistic activity against PPAR δ.

The effect that lowers the level of cholesterol in the blood

and the level of lipids

7-week-old male mice for six days contain vysokochastotnoi diet (solid balls CRF-1, mixed with 5.5% peanut butter, 1.5% cholesterol, 0.5% of holeva acid, Oriental Bio Service) and then weighed mice, and measured various the following settings. Measure the following parameters: LDL, HDL, levels of TG, NEFA and TC. Mice are placed into five groups depending on the level of TC, spending division without taking into account the average values of other parameters. Starting from the next day and continuously for six days animals injected forcefully through the mouth once daily suspended solution of the compounds in the medium (0.5% aqueous solution of methylcellulose), continuing to stand on their vysokochastotnoi diet. The next day after the last injection (day 7 from the beginning of the introduction) measures the level of lipids in the plasma level of triglycerides, LDL, HDL, NEFA,TC).

Calculate the relative activity of the compounds of the present invention under conditions in which the index of the group introduction the media is 100%. Then, as shown in table 2, for the compounds obtained in example 33, calculate the indicators characterizing its effect on raising HDL-cholesterol and the effect on reduction of LDL-cholesterol.

Table 2
Dose (mg/kg)Effect on raising HDL-cholesterolThe effect is to reduce LDL cholesterol
3150,082,5
10162,775,7
30157,372,3

In the result, it was shown that the compound of the present invention increases the level of HDL, depending on the dose and reduces the level of LDL. In this regard, the compounds of the present invention is useful as a therapeutic agent for hyperlipidemia.

An example of obtaining the drug, using the method according to the present invention are described below.

Example of getting 1:

The following components are mixed in accordance with the usual technique, tabletirujut to obtain 10,000 tablets each containing 10 mg of ActionEvent.

[3-(2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid (100 g);

calcium carboxymethylcellulose (medium conducive to decomposition) (20 g);

magnesium stearate (lubricant) (10 g);

microcrystalline cellulose (870 g).

Example of getting a 2:

After mixing the following components by a standard method, the obtained solution is filtered through a dust filter and fill the capsules in portions of 5 ml, respectively, sterilized by heating in an autoclave to obtain 10,000 ampoules for injection, each of which contains 20 mg of the active ingredient.

[3-(2-{5-ethyl-2-[4-(triptoreline)phenyl]-1,3-oxazol-4-yl}ethoxy)-4-were]acetic acid (200 g);

mannitol (2 kg);

distilled water (50 l).

INDUSTRIAL APPLICABILITY

The toxicity of the compounds of formula (I), its salts or its MES, or its prodrug very low, so that they are reasonably safe for their use as pharmaceutical agents. In addition, since this compound is a PPAR agonist, it is useful as a prophylactic and/or therapeutic agent for hyperlipidemia, etc.

1. The compound of formula (I)

where R1and R2each independently represents a hydrogen atom, C1-8 alkyl or at the m halogen;

R3denotes a C1-8 alkyl which may be substituted by 1 to 3 atom(s) halogen or phenyl;

R4denotes a hydrogen atom or C1-8 alkyl;

R5and R6each independently represents a hydrogen atom;

X denotes a sulfur atom or an oxygen atom;

ring a represents a 4-(trifluoromethyl)piperidine-1-yl, 2,2-debtor-1,3-benzodioxol-5-yl or 3,4-dihydro-1H-isoquinoline-2-yl; its salt, or its MES.

2. The compound according to claim 1, where the connection specified is a

(1) [3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid,

(3) [3-(2-{5-ethyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)-4-were]acetic acid,

(5) (3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-isopropyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid,

(7) (3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)5-methyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid,

(8) [2-fluoro-3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid, or

(13) (3-{2-[2-(3,4-dihydro-1H-isoquinoline-2-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-4-were)acetic acid.

3. Pharmaceutical composition for prevention and/or treatment of diseases mediated PPARδcomprising the compound of formula (I) according to claim 1, its salt, or with ivat and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, wherein the disease mediated by PPARδrepresents hyperlipidemia or obesity.

5. Drug for preventing and/or treating diseases mediated by PPARδcomprising the compound of formula (I) according to claim 1, its salt, or its MES and one or more agents selected from the group consisting of an MTP inhibitor, an inhibitor of HMG-CoA reductase inhibitor, an inhibitor of squalene synthase, fibranova medicines, ACAT inhibitor, an inhibitor of 5-lipoxygenase, an inhibitor of cholesterol absorption, absorption inhibitor of bile acid transport inhibitor of Na+/bile acid activator receptor LDL, enhancer in the expression of LDL receptor, inhibitor of pancreatic lipase, song probucol, composition with nicotinic acid and inhibitor of protein-carrier complex ester of cholesterol.

6. The method of prevention and/or treatment of diseases mediated by PPAR, in a mammal which comprises the administration to a mammal an effective amount of the compounds of formula (I), its salts or its MES.

7. The use of the compounds of formula (I) according to claim 1, its salt, or its MES to obtain preventive and/or therapeutic agent suitable for treatment of diseases mediated by PPAR.

8. A compound selected from the GRU is dust, consisting of

(1)

(3-{2-[2-(3,4-dihydro-1H-isoquinoline-2-yl)-5-methyl-1,3-thiazol-4-yl]ethoxy}-4-were)acetic acid;

(2)

[2-fluoro-3-(2-{5-methyl-2-[4-(trifluoromethyl)piperidine-1-yl]-1,3-thiazol-4-yl}ethoxy)phenyl]acetic acid;

(3)

(3-{2-[2-(2,2-debtor-1,3-benzodioxol-5-yl)-5-isopropyl-1,3-oxazol-4-yl]ethoxy}-4-were)acetic acid.



 

Same patents:

The invention relates to new thiazole derivative of the formula I, where R1denotes a group of formula (a), (b), (C), R2denotes a group of formula (d), where Het represents a five - or six-membered heterocyclic group which is substituted by9and in the loop which, in addition to the nitrogen atom, can optionally contain an oxygen atom, R3denotes hydrogen, alkyl, cycloalkyl, phenyl, R4denotes hydrogen, phenyl, R5- R8independently of one another denotes hydrogen, R9denotes a group of formula (e) and (f), R10denotes phenyl, a-i denotes 0 or a positive integer, i.e

The invention relates to substituted imidazolidin-2,4-donovin compounds, method of their production and to the use of these compounds in medicine

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, chemical technology, biology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (11): wherein X2 represents a leaving group; R3 and R4 represent substitutes chosen independently from group consisting of hydrogen atom, aromatic group and aliphatic group, or taken in common -NR3R4 form 4-11-membered aliphatic ring, but R3 and R4 can't means hydrogen atom simultaneously. Method involves interaction of compound of the formula (10): wherein X1 represents a leaving group with amine of the formula (3): (HNR3R4) in the presence of Lewis acid and a non-nucleophilic base and wherein groups X1 and X2 are similar. Compounds of the formula (11) can be used in treatment of anomalous growth of cells.

EFFECT: improved method of synthesis, valuable biological property of compound.

14 cl, 5 sch, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formulae (I) and (II) and their pharmaceutically acceptable salts and esters wherein each Z1, Z2 and Z3 is chosen from series of (C1-C6)-alkoxy-group, -CH2OCH3 and -CH2OCH2CH3, or one Z1, Z2 or Z3 means hydrogen atom, and each of two others is chosen independently from series (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2CH2R1, -CH2-morpholino, -OR2, -OCH2CF3, -OCH(CH3)CH2OH and -COOQ wherein Q is chosen from series hydrogen atom and (C1-C6)-alkyl, or one of Z1, Z2 or Z3 means hydrogen atom, and two others in common with carbon atoms and in combination with bonds between them and benzene cycle to which they are bound for a cycle chosen from 5- and 6-membered unsaturated cycles and 5- and 6-membered saturated cycles that comprise at least one oxygen atom as heteroatom, and wherein R1 is chosen from series -F, -OCH3, -N(CH3)2 and unsaturated 5-membered cycles comprising at least one nitrogen or oxygen atom as heteroatom, and wherein R2 means 3-6-membered saturated cycle, and each Y1 and Y2 is chosen independently from series -Cl, -Br, -NO2, -C≡N and -C≡CH, and their pharmaceutically acceptable salts and esters and wherein Z4 is chosen from series (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -OH, -SCH3, -CF3, -NO2, -COOQ2, -N(CH3)2, -OCH2-phenyl, -Cl, -Br, -F, -OCH2COQ1, saturated 5- and 6-membered cycles comprising at least one heteroatom wherein heteroatom is chosen from nitrogen (N) and oxygen (O) atom, and wherein Q1 is chosen from series, -OH, -NH2 and -O(C1-C6)-alkyl; Q2 is chosen from series hydrogen atom and (C1-C6)-alkyl; Y1 and Y2 are chosen independently from series -Cl, -Br, -NO2, -C≡N and -C≡CH under condition that if both Y1 and Y2 means -Cl then Z4 doesn't means -Cl, and if both Y1 and Y2 mean -NO2 then Z4 doesn't mean -NO2, and if both Y1 and Y2 mean -CN then Z4 doesn't mean -CN. Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to MDM2. Invention provides synthesis of novel biologically active compounds and preparing pharmaceutical compositions based on thereof possessing inhibitory activity with respect to MDM2.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

14 cl, 50 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): their pharmaceutically acceptable salts or solvates, or stereoisomers possessing properties of agonists of β2-adrenoreceptors, to pharmaceutical composition based on thereof, using the claimed compounds in manufacturing a medicinal agent, and to a method for modulation of β2-adrenergic receptors. In the formula (I) each among R1-R5 is chosen independently from group comprising hydrogen atom, (C1-C4)-alkyl and Ra wherein alkyl is substituted optionally with substituted chosen from Rb; or R4 and R5 are combined to form group of the formula: -NRdC(=O)C(Rd)=C(Rd)-; R6, R7 and R8 represent hydrogen atom; R9 represents (C1-C4)-alkyl; R10 represents hydrogen atom or (C1-C4)-alkyl; each among R11, R12 and R13 is chosen independently from group including hydrogen atom, (C1-C4)-alkyl, vinyl, cyclohexyl, phenyl, halogen atom, -CO2Rd, -ORd, -S(O)mRd, -N(NRdRe)Rd or -S(O)2NRdRe, 5-6-membered monocyclic heteroaryl comprising 1 or 2 heteroatoms chosen from nitrogen (N), sulfur (S) atoms, 9-membered bicyclic heteroaryl comprising N as a heteroatom and 5-membered heterocycle comprising N as a heteroatom; or R11 and R12 in common with atoms to which they are bound form 6- or 7-membered heterocyclic ring comprising oxygen (O) atom as a heteroatom and wherein for R11-R13 each phenyl or heteroaryl is substituted optionally with 1 or 2 substitutes chosen independently from Rc, and each heterocyclyl is substituted optionally with 1 or 2 substitutes chosen from Rb and Rc; alkyl is substituted optionally with substitute chosen from Rb, and vinyl is substituted optionally with substitute chosen from Rm; w = 0, 1, 2, 3 or 4. Values Ra, Rb, Rc, Rd, Rm and m are given in the invention claim.

EFFECT: improved method for modulation, valuable medicinal properties of compounds and pharmaceutical composition.

22 cl, 225 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (1): wherein Y means -O-, -S- or -N(R2)- wherein R2 means hydrogen atom, (C1-C10)-alkyl or aralkyl; Z means 2,5-furanyl, 2,5-thiophenyl, 4,4'-stilbenyl or 1,2-ethyleneyl residue; R1 means hydrogen or halogen atom, (C1-C10)-alkyl, (C1-C10)-alkoxy-group, cyano-group, -COOM or -SO3M wherein M means hydrogen atom or alkaline or alkaline-earth metal atom. Method for synthesis involves carrying out the reaction of compound of the formula (2): with dicarboxylic acid of the formula: HOOC-Z-COOH (3) or with it ester wherein Y, Z and R1 have values given above in N-methylpyrrolidone or N,N-dimethylacetamide medium in the presence of an acid catalyst and optionally in the presence of an accessory solvent able to remove water from the reaction mixture.

EFFECT: improved method of synthesis.

11 cl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (1): wherein R1 means (C1-C6)-alkyl that can be substituted with phenyl; R2, R3, R4 and R5 represent independently each of other hydrogen halogen atom, nitro-group, (C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-, (C6-C10)-aryloxy-group, (C6-C10)-aryl that can be mono-, di- or tri-substituted with halogen atom; 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 under condition that R2, R3, R4 and R5 can't mean simultaneously hydrogen atom and at least one residue among R2, R3, R4 and R5 represents 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 at value R6 - hydrogen atom, (C1-C4)-alkyl or (C6-C10)-aryl-(C1-C4)-alkyl wherein aryl can be substituted with halogen atom; A means a simple bond, -COn, -SOn or -CONH; n = 1 or 2; R7 means hydrogen atom; (C1-C18)-alkyl or (C2-C18)-alkenyl that can be substituted from one to three times with (C1-C4)-alkyl, (C1-C4)-alkyloxy-group, -N-((C1-C4)-alkyl)2-group, -COOH, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl, (C6-C12)-aryloxy-group, (C6-C12)-arylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxy-group, halogen atom, -CF3 or oxo-group wherein aryl, in turn, can be substituted with halogen atom, (C1-C)-alkyl, aminosulfonyl- or methylmercapto-group; (C6-C10)-aryl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl, (C6-C10)-aryl-(C2-C6)-alkenyl, (C6-C10)-aryl, diphenyl, diphenyl-(C1-C4)-alkyl, indanyl that can be mono- or di-substituted with (C1-C18)-alkyl, (C1-C18)-alkyloxy-group, (C3-C8)-cycloalkyl, hydroxy-group, (C1-C4)-alkylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-group, (C6-C10)-aryloxy-group, nitro-, cyano-group, (C6-C10)-aryl, fluorosulfonyl, (C1-C6)-alkyloxycarbonyl, (C6-C10)-arylsulfonyloxy-group, pyridyl, -NHSO2-(C6-C10)-aryl, halogen atom, -CF3 or -OCF3 wherein alkyl can be substituted once again with halogen atom, -CF3 or (C1-C4)-alkyloxy-group; or group Het-(CH2)r wherein r = 0, 1, 2 or 3 wherein Het means saturated or unsaturated 5-7-membered heterocycle comprising atoms nitrogen (N), oxygen (O) or sulfur (S) and can be condensed with benzene and substituted with (C1-C4)-alkyl, (C6-C10)-aryl, halogen atom, (C1-C4)-alkyloxy-group, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C)-alkylmercapto- or nitro-group and wherein aryl condensed with benzene can be, in turn, substituted with halogen atom, (C1-C4)-alkyloxy-group; and to their pharmacologically acceptable salts and additive salts of acids, and to a method for their preparing. Proposed compounds show inhibitory effect on activity of hormone-sensitive lipase.

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

14 cl, 199 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and pharmaceutically acceptable salts. Claimed compounds have modulation effect on CB cannabinoid receptor. In the general formula (I) , R and R1 are the same or different and are phenyl optionally substituted by 1-3 substitutes Y, where Y is substitute selected out of group including chlorine, iodine, bromine, fluorine, on condition that X is not a sub-group (ii); or one of R and R1 radicals is phenyl group, while the other radical is formed or linear C2-8-alkyl group or benzyl group; X is one of the sub-groups (i) or (ii). Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim.

EFFECT: enhanced efficiency of composition and treatment method.

5 cl, 1 tbl, 25 ex

FIELD: chemistry; oxa-and thiazole derivatives.

SUBSTANCE: oxa- and thiazole derivatives have general formula . Their stereoisomers and pharmaceutical salts have PPARα and PPARγ activity. The compounds can be used for treating diseases, eg. diabetes and anomaly of lipoproteins through PPARα and PPARγ activity. In the general formula, x has value of 1, 2, 3 or 4; m has value of 1 or 2; n has value of 1 or 2; Q represents C or N; A represents O or S; Z represents O or a bond; R1 represents H or C1-8alkyl; X represents CH; R2 represents H; R2a, R2b and R2c can be the same or different and they are chosen from H, alkoxy, halogen; R3 represents aryloxycarbonyl, alkyloxycarbonyl, alkyl(halogen)aryloxycarbonyl, cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, arylcarbonylamino, alkylsulphonyl, cycloheteroalkyloxycarbonyl, heteroarylalkenyl, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, halogenalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenylsulphonyl, heteroarylsulphonyl, arylsulphonyl, arylalkenylarylalkyl, arylalkoxycarbonyl-heteroarylalkyl, heteroaryloxyarylalkyl, where alkyl is in form of C1-8alkyl; Y represents CO2R4, where R4 represents H or C1-8alkyl; including all their stereoisomers and pharmaceutical salts, under the condition that, if A is O, then R3 is not aryloxycarbonyl or alkoxyaryloxycarbonyl.

EFFECT: the compounds can be used in curing such diseases as diabetes and lipoprotein anomalies.

10 cl, 30 dwg, 12 tbl, 584 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: Disclosed are compound of formula I wherein Het represents group of formula 2 (m = 0 or 1; X is hydrogen or C1-C12-alkyl or C1-C4-haloalkyl; Y is group of formula 3 and 4 wherein substitutes have meanings described in specification); A represents hydrogen, unsubstituted C1-C12-alkyl; C3-C8-cycloalkyl, or aryl; B represents hydrogen or C1-C6-alkyl; or A and B with carbon atom to which they are attached form saturated C3-C10-alkyl; A and Q1 together represent unsubstituted C3-C6-alkanediyl, wherein two non-adjacent carbon atoms optionally form further unsubstituted cycle; meanings of the rest substitutes are as described in specification.

EFFECT: new agents for controlling of agriculture pests.

4 cl, 28 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the following formulae:

and , and to a pharmaceutical composition possessing the PPAR-ligand binding activity and comprising the indicated compound, and a pharmaceutically acceptable vehicle. Also, invention relates to a method for treatment of patient suffering with physiological disorder that can be modulated with the compound possessing the PPAR-ligand binding activity. Method involves administration to the patient the pharmaceutically effective dose of indicated compound or its pharmaceutically acceptable salt.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

The invention relates to a method for producing 4-methyl-5-formyl-thiazol by oxidation of 4-methyl-5-(2-hydroxyethyl)-thiazole using an aqueous solution of chromium oxide or inorganic bichromate in the presence of sulfuric acid and the oxidation is carried out in a two-phase system water-organic solvent, at a temperature of 20-50°C., the organic solvent used diethyl ether, benzene, chloroform, and methylene chloride

The invention relates to a method for producing 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] methoxy] benzyl] thiazolidin-2,4-dione of formula (1), including the restoration of the compounds of formula (2'), where R is a (C1-C4)alkyl group, with the use of Raney Nickel or magnesium and, optionally, re-esterification using sulfuric acid in the temperature range from 0 to 60oWith obtaining the compounds of formula (3'), which is subjected to hydrolysis to obtain the acid of formula (4), the condensation of the acid of formula (4) with N-methyl-anthranilamide formula (7) without any pre-activation of the acid to obtain the compounds of formula (1), which is optionally transformed into a pharmaceutically acceptable salt
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