Derivative compounds of carboxylic acid and agents comprising thereof as active components

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

 

The present invention relates to derivatives of carboxylic acid compounds.

More specifically the present invention relates to

(1) the derived connection carboxylic acid represented by the formula (I)

(where all the symbols have the same meanings as described below), or its non-toxic salt,

(2) the method of obtaining the specified connection, and

(3) medium containing the indicated compound as an active ingredient.

Recently, in the study of transcription factors involved in the expression of marker genes during differentiation of adipocytes, attention was drawn to the receptor-activated peroxisome proliferation (abbreviated in the text labeled as PPAR), which is one of intranuclear receptors. cDNA of the receptor PPAR cloned from various species, and were found multiple isoforms of genes, in particular, in mammals, there are three types of isoforms (α, δ, γ) (seeJ. Steroid Biochem. Molec. Biol.,51, 157 (1994);Gene Expression., 4, 281 (1995);Biochem Biophys. Res. Commun.,224, 431 (1996);Mol. Endocrinology., 6, 1634 (1992)). Isoform of PPAR γ predominantly expressed in adipose tissue, immune cells, adrenal glands, spleen, small intestine. Isoform of PPAR α predominantly expressed in adipose tissue, liver,mesh shell and PPAR δ isoform is widely expressed, without specificity to any tissue (seeEndocrinology., 137, 354 (1996)).

On the other hand, the following thiazolidinone derivatives known as funds used for the treatment of non-insulin dependent diabetes mellitus (NIDDM), and they represent a hypoglycemic agents, which are used to reduce hyperglycemia in patients with diabetes. They are also an effective means for correcting hyperinsulinemia, glucose tolerance and lower levels of serum lipids, and therefore are largely pinning their hopes on drugs used for the treatment of insulin resistance.

One of the target proteins in the cells for the specified thiazolidinone derivatives is PPAR γ and, as I believe, these derivative enhance the transcriptional activity of PPAR γ (seeEndocrinology., 137, 4189 (1996);Cell, 83, 803 (1995);Cell,83, 813 (1995);J. Biol. Chem.,270, 12953 (1995)). So, I think that the activator (agonist) PPAR γ, which increases its transcriptional activity, is a hypoglycemic agent and/or a hypolipidemic agent. In addition, because the agonist of PPAR γis known to stimulate the expression of the protein PPAR γ (Genes & Development,10, 974 (1996)), the floor is shown, the tool, which increases the protein expression of PPAR γand means activating PPAR γmay be clinically applicable.

Protein PPAR γ associated with differentiation of adipocytes (seeJ. Biol. Chem., 272, 5637 (1997) andCell, 83, 803 (1995)). It is known that thiazolidinone derivatives that activate this receptor, stimulate the differentiation of adipocytes. It was recently reported that thiazolidinone derivatives increase fat mass, and people increases in weight and obese (seeLancet., 349, 952 (1997)). Therefore, I believe the antagonists, which inhibit the activity of PPAR γand agents that reduce the expression of the protein PPAR γthey are also clinically effective means. On the other hand, researchers report about the connection, which phosphorylates the protein PPAR γ and reduces its activity (Science, 274, 2100 (1996)). Suppose that the agent is not associated with the protein PPAR γ as a ligand, but inhibits its activity is clinically applicable.

Think of these compounds are activators (agonists) PPAR γ and regulators of the expression of PPAR γthat can increase the expression of the protein, can be used as hypoglycemic agents, hypolipidemic means and tools for the prevention and/or treatment of diseases associated with what Arsenium metabolism, such as diabetes, obesity, syndrome X, hypercholesterolemia and hyperlipoproteinemia, etc., hyperlipidemia, atherosclerosis, hypertension, disease, occurring with circulatory disorders, overeating, etc.

On the other hand, believe that the antagonists, which inhibit the transcriptional activity of PPAR γor regulators of PPAR γthat inhibit expression of the protein, can be used as hypoglycemic agents and tools for the prevention and/or treatment of diseases associated with metabolic disturbances such as diabetes, obesity and syndrome X, etc., hyperlipidemia, atherosclerosis, hypertension and obesity, etc.

The following derived connection fibrate (for example, clofibrate) is known as a lipid-lowering agent.

In addition, I believe that one of the target proteins in cells derived compounds fibrate is a protein PPAR α (seeNature, 347, 645 (1990);J. Steroid Biochem. Molec. Biol., 51, 157 (1994);Biochemistry,32, 5598 (1993)). On the basis of the obtained results suggest that regulators of PPAR αthat can be activated derivative compounds of fibrate have hypolipidemic effects, and they can also be used as a means for the prevention and/or treatment of hyperlipidemia, etc.

In addition, international publication WO 9736579 it was reported, that PPAR α active against obesity. In addition, researchers have reported that increased levels of cholesterol associated with high density lipoprotein (HLD), and reduction of cholesterol associated with low density lipoprotein (LDL), lower cholesterol levels, associated with very low density lipoprotein (VLDL), and triglycerides was caused by the activation of PPAR α (J. Lipid Res.,39, 17 (1998)). It was also reported that the introduction of bezafibrat, which is derived from one of the compounds of fibrate, has a positive effect on the composition of fatty acids in the blood, hypertension, and insulin resistance (Diabetes,46, 348 (1997)). Therefore, agonists that activate PPAR αand regulators of PPAR αthat stimulate the expression of the protein PPAR αcan be used as lipid-lowering means and means for the treatment of hyperlipidemia, and in this regard, researchers believe that they can contribute to high cholesterol in combination with HLD, reducing the level of cholesterol in complex with LDL and/or VLDL, inhibition of atherosclerosis, and can be an effective means of obesity. Based on the above, the researchers conclude that these compounds are promising hypoglycemic agents for the treatment and/or prevention is yabuta, to alleviate hypertension, to reduce the risk factor for syndrome X and for the prevention of coronary heart disease.

On the other hand, was published several reports on the ligands, which are largely activate PPAR δor biological activity associated with PPAR δ.

Sometimes protein PPAR δ referred to as the protein PPAR βor it is also called NUC1 in humans. What is known regarding the activity of PPAR δas disclosed in international publication WO 9601430 that hNUC1B (PPAR subtype, whose structure differs from the structure of NUC1 people of the same amino acid) inhibits the transcriptional activity of PPAR α man and receptor thyroid hormone. Recently, in international publication WO 9728149 it was reported that the found compounds that have high affinity for the protein PPAR δ and which can be activated to a significant extent (i.e. are agonists) PPAR δand to increase the level of cholesterol associated with HDL (high density lipoprotein). So, I think that agonists that can activate PPAR δhave activity aimed at raising the level of cholesterol associated with HDL, and therefore, they can be used for inhibiting the development of atherosclerosis and treatment of this disease as lipid and hypoglycemic cf the of funds, for the treatment of diabetes, to eliminate risk factor for syndrome X and for the prevention of coronary heart disease.

Prerequisites to the creation of inventions

In international publication WO 01/21602 describes oxa-derivatives and thiazole derivatives of formula (A)

where XAndis 1, 2, 3, or 4 mA is 1 or 2, n is 1 or 2, QArepresents C or N AndAndrepresents O or S, ZArepresents O or a bond, R1Arepresents a hydrogen atom or alkyl, XAndis CH or N, R2Ais H, alkyl, etc., R2A, R2bAand RSarepresent a hydrogen atom, alkyl, alkoxy, halogen atom, amine or substituted amine (substituted amine is an amine substituted by one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, cyclogeranyl, cyclohexanoltramadol, cycloalkyl, cycloalkenyl, halogenated, hydroxyalkyl, alkoxyalkyl, thioalkyl. In addition, the amino substituents may be taken together with the nitrogen atom to which they relate, with the formation of 1-pyrrolidinyl, 1-piperidinyl, 1-azepine, 4-morpholinyl, 4-thiomorpholine, 1-piperazinil, 4-alkyl-1-piperazinil, 4-arylalkyl-1-piperazinil, 4-diarrhoel the-1-piperazinil, 1-pyrrolidinyl, 1-piperidinyl or 1-azepine (optionally substituted by alkyl, alkoxy, alkylthio, halogen, trifluoromethyl, hydroxyl). R3Arepresents H, alkyl, arylalkyl etc., Y is the CO2R4A(R4Arepresents a hydrogen atom, alkyl etc), and their pharmaceutically acceptable salts are used as tools against diabetes and obesity.

In order to identify compounds with modulating activity in relation to PPAR, the authors of the present invention have conducted extensive studies and as a result have found that a specified activity can be achieved by using compounds represented by formula (I), and thus, the present invention is completed.

The present invention relates to

(1) the derived connection carboxylic acid represented by the formula (I)

(where X and Y each independently represent a1-4alkylen,

Z is-O - or-S-,

R1, R2, R3and R4each independently represents a hydrogen atom or a C1-8alkyl,

R5is2-8alkenyl,

A is-O - or-S-,

D is D1D2D3D4or D5,

D1is1-8the alkyl,

D2representsthe ring 1 is saturated 3-7-membered monogatarareba containing one nitrogen atom and optionally one heteroatom selected from oxygen atom, sulfur and nitrogen,

D3represents

the ring 2 is a

(1) optionally partially or completely saturated With3-10mono - or bikebicycle aryl or

(2) optionally partially or fully saturated 3-10 membered mono - or bilateral containing 1-4 heteroatoms selected from oxygen atom, nitrogen and sulphur,

D4represents

D5represents

R6represents (1) hydrogen atom, (2)1-8alkyl, (3)1-8alkoxy, (4) CF3, (5) OCF3, (6) halogen atom, (7) nitro or (8) NR7R8,

R7or R8is a hydrogen or C1-8the alkyl, or

R7and R8taken together with the nitrogen atom to which they are linked, form a saturated 3-7-membered Monogatari containing one nitrogen atom and possibly another one heteroatom selected from oxygen atom, sulfur and nitrogen, and rich heteroaryl is optionally saturated With1-8the alkyl,

E is CH or a nitrogen atom, and

m is an integer of 1-3),

or its non-toxic salt,

(2) the method of obtaining the specified connection, and

(3) medium containing the indicated compound as an active ingredient.

In the description of C1-8alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or their isomeric groups.

In the description of C2-8alkenyl means ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or their isomeric groups.

In the description of C1-8alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or their isomeric groups.

In the description of C1-4alkylene means methylene, ethylene, trimethylene, tetramethylene or their isomeric groups.

In the description of the halogen is chlorine, bromine, fluorine or iodine.

In the description of saturated 3-7-membered Monogatari containing one nitrogen atom and optionally another heteroatom selected from oxygen atom, sulfur and nitrogen, represented by ring 1 represents, for example, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, targetability, targetability, peligrosa, targetrotation, tetrahydrooxazolo (oxazolidine), tetrahydrocortisol (isoxazolidine), tetrahydrothieno (thiazolidin), tetrahydrocortisol (isothiazolin), tetrahydrooxazolo, perhydroxyl, tetrahydrothiophene, targetrotation, morpholine, tiomo the folin etc.

In the description of saturated 3-6-membered Monogatari containing one nitrogen atom and optionally another heteroatom selected from oxygen atom, sulfur and nitrogen, represented by R6and R7taken together with the nitrogen atom to which they are attached, represents, for example, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, targetability, targetability, tetrahydrooxazolo (oxazolidine), tetrahydrocortisol (isoxazolidine), tetrahydrothieno (thiazolidin), tetrahydrocortisol (isothiazolin), tetrahydrooxazolo, tetrahydrothiophene, morpholine, thiomorpholine etc.

In the description of partially or completely, optional saturated With3-10mono - or bikebicycle aryl is, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclonona, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, Bensen, pentalene, azulene, pergerson, perhydroanthracene, inden, palikonda, indan, naphthalene, tetrahydronaphthalene or peritonealis etc.

In the description of a partly or fully, optional saturated 3-10 membered mono - or bilaterally containing 1-4 heteroatoms selected from oxygen atom is, nitrogen or sulfur, represented by the ring 2, 3-10-membered mono - or bilateral containing 1-4 heteroatoms selected from oxygen atom, nitrogen or sulfur, means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, azepine, diazepine, furan, Piran, oxepin, thiophene, Tianjin, tiepin, oxazol, isoxazol, thiazole, isothiazol, furazan, oxadiazole, oxazin, oxadiazon, oxazepine, oxadiazon, thiadiazole, teasin, thiadiazin, diazepin, thiadiazin, indole, isoindole endolysin, benzofuran, isobenzofuran, benzothiophene, isobenzofuran, ditionally, indazole, quinoline, isoquinoline, hemolysin, purine, phthalazine, pteridine, naphthiridine, cinoxacin, hinzelin, cinnolin, benzoxazole, benzothiazole, benzimidazole, chrome, benzofurazan, benzothiadiazole, benzotriazole etc.

Partially or fully saturated 3-10 membered mono - or bilateral containing 1-4 heteroatoms selected from oxygen atom, nitrogen or sulfur, means aziridine, azetidine, pyrrolin, pyrrolidin, imidazolin, imidazolidine, triazoline, thiazolidin, tetrazolyl, tetrazolium, pyrazoline, pyrazolidine, dihydropyridines, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, targetability, dihydropyridin, tetrahydropyridine, targetability, dihydrazide is, tetrahydroazepine, peligrosa, dihydrovitamin, tetrahydroazepine, targetrotation, oxiran, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dehydroacetic, tetrahydroazepine, perhydroxyl, trilian, tieton, dihydrothiophene, tetrahydrothiophene, dehydration (dihydrothiophene), tetrahydrate (tetrahydrothiopyran), dihydrothiophene, tetrahydrothiophene, pengertian, dihydrooxazolo, tetrahydrooxazolo (oxazolidine), dihydroisoxazole, tetrahydrooxazolo (isoxazolidine), dihydrothiazolo, tetrahydrothieno (thiazolidin), dihydroisoxazole, tetrahydrocortisol (isothiazolin), dihydrofuran, tetrahydrofuran, dihydroimidazole, tetrahydrooxazolo (oxadiazolidine), 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, isoindoline, dihydrobenzofuran, perhydroanthracene, dihydroisobenzofuran, peligrosamente, digit benzothiophen, targetobjecttype, dihydroisobenzofuran, peligrosamente, dihydroindol, peritoneal, dihydroquinoline, tetrahydroquinoline, perhydroxyl, dihydroisoquinoline, tetrahydroisoquinoline, perhydrosqualene, dihydrophenazine, tetrahydrophthalate, PermitRootLogin, dihydronaphthalene, tetrahydronaphthalene, perhydroanthracene, dihydroquinoxaline, tetrahydroquinoxalin, perhydrophenanthrene, dihydroquinazolin, tetrahydroquinazolin, perhydrophenanthrene, dihydroindole, tetrahydroindole, permitiendoles, benzocain, dihydroisoxazole, dihydrobenzofuran, pyrazinamidase, dihydroisoxazole, perhydroanthracene, dihydrobenzofuran, perhydroanthracene, dehydrobenzperidol, perhydroanthracene, dioxolane, dioxane, ditiolan, Titian, dioksiinien, benzodioxan, chroman, benzodithiol, benzodithiol etc.

Unless otherwise noted, all isomers are included in the present invention. For example, an alkyl group, alkoxygroup and Allenova group consist of straight or branched hydrocarbon chains. In addition, the isomers in the presence of a double bond, ring, conjugate ring (E-, Z-, CIS-, TRANS-isomer), isomers formed in the presence of asymmetric atom(s) C (R-, S-, α-, β-isomer, enantiomer, diastereoisomer), optically active isomers (D-, L-, d-, l-isomer), polar travel is, obtained by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, rotamer, their mixtures with arbitrary relations and racemic mixtures are also included in the present invention.

According to the present invention, unless specifically and clearly qualified specialists in this field, the symbolindicates that the relationship is the reverse side of a plane (namely, α-configuration), symbolindicates that the link is on the front plane (namely, β-configuration), symbolindicates α-configuration β-configuration or a mixture thereof, and the symbolindicates the mixture αconfiguration β-configuration.

The connection according to the present invention can be converted into non-toxic salt by known methods.

Preferably, non-toxic salt is pharmaceutically acceptable and water-soluble.

Non-toxic salt means, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium etc), ammonium salts (Tetramethylammonium, tetrabutylammonium etc), salts of organic amines (triethylamine, methylamine, dimethylamine, cyclopenta the amine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, Tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine etc), acid additive salts (inorganic salts (hydrochloride, bromohydrin, loggedout, sulfate, phosphate, nitrate etc), salts of organic acids (acetate, triptorelin, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, aconsultant, bansilalpet, toluensulfonate, isetionate, glucuronate, gluconate, etc. and so on

In addition, the solvate of the compounds according to the present invention and the above alkali (alkaline earth) metals, ammonium, organic amines and acid additive salt is included in the present invention.

Preferably, the MES is non-toxic and water soluble. Corresponding solvate mean, for example, a solvate formed with such a solvent as water, alcohol (ethanol, etc. and so on

In the present invention, the regulator PPAR includes all of the regulators of PPAR α, γ, δ, α+γ, α+δ and α+γ+δ. The preferred type of regulators is the regulator of PPAR α, regulator of PPAR γ, regulator of PPAR δ, regulator of PPAR α+γ, regulator of PPAR α+δmore preferably the regulator PPAR α+γ.

The regulator PPAR also includes an agonist of PPAR and PPAR antagonist. The encoder PPR preferably is a PPAR agonist, more preferably, the agonist of PPAR α, agonist of PPAR γ, agonist of PPAR δ, agonist of PPAR α+γ or agonist of PPAR α+δand, most preferably, the agonist of PPAR α+γ.

In the description of R5preferably represents propenyl and more preferably allyl.

In the description of X preferably represents C1-2alkylene (methylene, ethylene), and more preferably methylene.

In the description of Y preferably represents C1-2alkylene (methylene, ethylene), and more preferably ethylene.

In the description of Z preferably represents-O - or-S - and more preferably-O-.

In the description And preferably represents-O - or-S - and more preferably-O-.

In the description of D preferably represents D1D2D3or D4and more preferably D3or D4and most preferably D4.

Among the compounds represented by formula (I), preferred compounds are compounds represented by formula (I-A)

(where all the symbols have the same meanings as described above),

compounds represented by formula (I-B)

(where all the symbols have the same meanings as described above),

compounds represented by formula (I-C)

(where all the symbols have the same meanings as described above),

compounds represented by formula (I-D)

(where all the symbols have the same meanings as described above),

and compounds represented by formula (I-E)

(where all the symbols have the same meanings as described above).

Specific compounds according to the present invention include compounds shown in tables 1-5, the compounds described in the examples, and their non-toxic salts.

In each table, Me means methyl group, Et means ethyl group, Pr means through the group, i-Pr means isopropyl group, t-Bu means tert-boutelou group, and other symbols have the same meanings as described above.

Table 1

Table 2

Table 3

Table 4

Table 5

Methods for producing compounds according to the present invention

Among the compounds according to the present invention, represented by formula (I), the compound in which R1represents a C1-8alkyl, i.e. the compound represented by formula (IA)/p>

(where R1-1represents a C1-8alkyl, and other symbols have the same meanings as described above) can be obtained by reacting compounds represented by formula (II)

(where R9represents a removable group (halogen atom, mesilate or tosyloxy etc.), D6has the same meaning as D, provided that the amine group represented by D6may be protected, if necessary, and other symbols have the same meanings as described above), with the compound represented by formula (III)

(where R10represents OH or SH, and other symbols have the same meanings as described above), if necessary, with subsequent reaction of removing the protective group.

This reaction is known. For example, it is conducted at a temperature of from 0 to 80°in an organic solvent (e.g. tetrahydrofuran (THF), diethyl ether, methylene chloride, chloroform, carbon tetrachloride, pentane, hexane, benzene, toluene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), etc) in the presence of a base (sodium hydride, potassium carbonate, triethylamine, pyridine, sodium iodide, cesium carbonate etc).

The reaction of removing the protective group can be the t can be performed in the following way.

The reaction of removing the protective group from the amino group are well known, and examples mentioned reaction include:

(1) the reaction of removing protection in acidic conditions, or

(2) the reaction of removing protection by hydrogenolysis, etc.

These methods are described below in more detail.

(1) the Reaction of removing the protection in acidic conditions can be carried out, for example, in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, methanol, ethanol, isopropyl alcohol etc) or in the absence of an organic solvent, or in aqueous solution using an organic acid (acetic acid, triperoxonane acid, methanesulfonate etc) or inorganic acid (hydrochloric acid, sulfuric acid, etc. or a mixture thereof (hydrogen bromide/acetic acid etc) at a temperature of from 0 to 100°C.

(2) the Reaction of removing the protection by hydrogenolysis can be carried out, for example, in a solvent such as the simple ether (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether etc), type of alcohol (e.g. methanol, ethanol etc), type of benzene (e.g., benzene, toluene etc), type of ketone (e.g. acetone, methyl ethyl ketone, etc.), type nitrile (e.g. acetonitrile etc), type of amide (e.g. dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent or in the MCA and two or more of these solvents, etc.), in the presence of a catalyst (e.g. palladium-on-charcoal, palladium black, palladium hydroxide, platinum oxide, Raney Nickel, etc.), with normal or forced pressure in the atmosphere of hydrogen or in the presence of ammonium formate at a temperature of from 0 to 200°C.

The protective group for protecting the amino group includes, for example, benzyloxycarbonyl, tert-butoxycarbonyl, TRIFLUOROACETYL, 9-fluorenylmethoxycarbonyl etc.

The protective group for protecting the amino group, is not very limited to the above protective groups, and other groups can also be used because they can be easily and selectively removed. For example, the groups described in the publication by T.W. Greene,Protective Groups in Organic Synthesis,3rdEd., Wiley, New York, 1999, can be applied.

The claimed compounds according to the invention can be easily obtained by selecting the reaction of removing protection, which can easily comprehend any specialist in this field.

(2) Among the compounds according to the present invention, represented by formula (I), the compound in which R1represents a C1-8alkyl and Z represents-O-, i.e. the compound represented by formula (IB)

(where all the symbols have the same meanings as described above), can be obtained by reacting compounds depict ablanovo formula (IV)

(where all the symbols have the same meanings as described above), with the compound represented by formula (III-1)

(where all the symbols have the same meanings as described above), if necessary, with subsequent reaction of removing the protective group.

This reaction is known. For example, it is conducted at a temperature from 0 to 60°by interacting with the corresponding alcohol compound in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc. in the presence of azo compounds (diethylazodicarboxylate, diisopropylcarbodiimide, 1,1'(azodicarbon)piperidine, 1,1'-azobis(N,N-dimethylformamide), etc).

The reaction of removing the protective group can be carried out by the methods described above.

(3) Among the compounds according to the present invention, represented by formula (I), the compound in which R1represents hydrogen, i.e. the compound represented by formula (IC)

(where all the symbols have the same meanings as described above), can be obtained by conducting hydrolysis of the above compound represented by formula (IA) or (IB).

The above hydrolysis reaction is known. It is performed, n is the sample, (1) in an organic solvent suitable for mixing with water (THF, dioxane, ethanol, methanol etc) or in a mixture of solvents, using an aqueous solution of alkali (potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and so on), or

(2) in alcohol (methanol, ethanol etc), using the above-mentioned alkali in anhydrous conditions. These reactions may be conducted at temperatures from 0 to 100°in normal conditions.

Compounds represented by formulas (II) and (IV)are known compounds or can be easily obtained by known methods described in the examples.

For example, among the compounds of formula (IV), 2-(5-methyl-2-phenyloxazol-4-yl)ethanol can be obtained by methods described in the publication ofJ. Med. Chem.,35, 1853-1864 (1992).

For example, among the compounds of formula (IV), 2-(5-methyl-2-(morpholine-4-yl)oxazol-4-yl)ethanol can be obtained by methods described in the publication ofJ. Med. Chem.,41, 5037-5054 (1998).

For example, the compound represented by formula (III)may be obtained by methods shown in the following reaction scheme 1.

In the reaction scheme 1, R11represents a protective group for protecting a hydroxy-group, X1represents a C1-3alkylen, and other symbols have the same meanings as described above.

The reaction scheme 1

In the reaction scheme 1 compounds that are used as starting materials represented by the formulas (V) and (VII)are known compounds or can be easily obtained by known methods.

When carrying out each reaction described in the description, the reaction product can be purified by usual purification methods such as distillation under normal or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or acid magnesium, washing and recrystallization. The treatment can be carried out when carrying out each reaction or after completion of several reactions.

The pharmacological activity

With the help of the following experiments, the researchers confirmed that the compounds according to the present invention of formula (I) regulate the activity of PPAR.

Measuring agonistic activity of compounds in relation to PPAR α and agonistic activity of compounds in relation to PPAR γ:

(1) preparation of materials for studies using luciferase using PPAR α or PPAR γ man.

All operations were performed basic methods used in genetic engineering, and methods that are typically used for yeast adenoviridae or twohybrid system.

As the expressing vector containing the gene luciferase under the control of the promoter timedancing (TC), structural gene luciferase "carving out" of PicaGene Basic Vector 2 (trade name, Toyo Ink Inc., catalogue No. 309-04821)to obtain the expression vector of gene luciferase pTK-Luc. under the control of the TK promoter (-105/+51), with minimum promoter activity from pTKβwith TK promoter (Chrontech Inc., catalogue No. 6179-1). In the opposite direction TK promoter was injected four times repeated sequence UAS, which is a response element of the Gal4 protein, the main transcription factor in yeast, to build a 4 X UAS-TK-Luc. as a reporter gene. Below used the enhancer sequence (SEQ ID NO.:1).

SEQ ID NO:1: enhancer Sequence, repeating the response element Gal4 four times in a row.

5'-T(CGACGGAGTACTGTCCTCCG)x4 AGCT-3'

The vector was received, as described below, which is expressed chimeric receptor protein, where carboxylic yeast Gal4 protein DNA binding domain was fused with the ligand-binding domain of PPAR α or γ man. That is, PicaGene Basic Vector 2 (trade name, Toyo Ink Inc., catalogue No. 309-04821) was used as the primary expressing vector, the structural gene was exchanged for gene chimeric receptor protein, while the domains of the promoter and enhe the sulfur remained, as we were.

DNA encoding a protein consisting of the DNA binding domain of Gal4 represented by a sequence of from 1 to 147-Oh amino acids associated with the ligand-binding domain of human PPAR α or γ in a frame, was introduced in the forward direction of the promoter/enhancer in PicaGene Basic Vector 2 (trade name, Toyo Ink Inc., catalogue No. 309-04821). In this case, DNA was built in the following way: in aminocore landscapebased domain of human PPAR α or γ added signal nuclear translocation produced from T-antigen of the virus SV-40, Ala Pro Lys Lys Lys Arg Lys Val Gly (SEQ ID NO:2)to obtain a protein localized in the nucleus. On the other hand, in carboxysomes the above domain was added to the 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 determine the downregulation of condensed protein-labeled epitope sequence.

According to the comparison of the structures of PPAR person described in the literature R. Mukherjeeet al. (seeJ. Steroid Biochem. Molec. Biol., 51, 157 (1994)), M.E. Greenet al., (seeGene Expression.,4, 281 (1995)), A. Elbrechtet al. (seeBiochem Biophys. Res. Commun.,224, 431 (1996)) or A. Schmidtet al. (seeMol. Endocrinology., 6, 1634 (1992)), part of the structural gene, used as landscapebased domain of human PPAR α or γis DNA, teruya the following peptide:

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

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

(each legendbase.ui domain of PPAR γ1 person and legendbase.ui domain of PPAR γ2 people is a sequence Ser204-Tyr506which is identical sequence).

In order to measure basal levels of transcription were received expressing a vector containing a DNA-binding domain of the Gal4 protein, absent in landscapebased domain of PPAR, which exclusively encodes the synthesis of the amino acid sequence from the 1st amino acid to 147-th amino acid in the protein Gal4.

(2) Analysis of luciferase using PPAR α or γ.

Cells CV-1 used as the host cell, cultivated in the usual way. That is, for the cultivation of CV-1 cells used a modified method Dulbecco Wednesday Needle (DMEM)with 10% fetal serum of bovine (GIBCO BRL Inc., catalogue No. 26140-061) and 50 units/ml penicillin G and 50 μg/ml of streptomycin sulfate in the gas atmosphere of 5% carbon dioxide at 37°C.

Cells in the number 2x106made in cups with a diameter of 10 cm and washed with medium without serum was then added to the medium (10 ml). Reporter gene (10 µg), Gal4-PPAR expressing vector (0.5 μg) and 50 μl LpofectAMINE (GIBCO BRL Inc., catalogue No. 18324-012) were thoroughly mixed and added to the culture to enter these DNA into the host cell. Cells were cultured at 37°C for 5 to 6 hours, and thereto was added 10 ml of medium containing 20% cialisbuynow fetal bovine serum (GIBCO BRL Inc., catalogue No. 26300-061) and then cultured at 37°With during the night. Cells "dispersed" by trypsin, and their newly sown in 96-well tablets at a density of 8000 cells/100 ml DMEM-10% cialisbuynow serum/well. A few hours after the completion of cultivation, when the cells were attached to a plastic surface, was added 100 μl of DMEM-10% cialisbuynow serum containing compounds according to the present invention, the concentration of which was two times higher than the final concentration. Culture cells were left at 37°C for 42 hours, and the cells were dissolved, to measure the luciferase activity according to the manufacturer's instructions.

As for the agonistic activity of PPAR αthe relative activity of the compounds according to the present invention (10 μm) shown in table 6, provided that the luciferase activity is 1.0 in the case of carbacyclin (10 μm)used as a positive control compounds, which can significantly activate the transcription of the luciferase gene in relation to the structure to PPAR α (seeEur. J. Biochem., 233, 242 (1996);Genes & Development, 10, 974 (1996)).

As for the agonistic activity of PPAR γthe relative activity of the compounds according to the present invention (10 μm) shown in table 7, assuming that the luciferase activity is 1.0 in the case of troglitazone (10 μm)used as a positive control compounds, which can significantly activate the transcription of the luciferase gene in relation to PPAR γ (seeCell, 83, 863 (1995);Endocrinology,137, 4189 (1996) andJ. Med. Chem.,39, 665 (1996)) and which was already released as a hypoglycemic agent.

In addition, the analysis of each compound was carried out three times to verify the reproducibility of the results obtained and confirmation of dose-dependent activity.

For example, hypoglycemic and hypolipidemic effects of the compounds according to the present invention can be measured in the following ways. Hypoglycemic and hypolipidemic effects (1):

Male 8-week-old mice of KKAy/Ta Jcl (five mice per group) previously fed individually in separate cages for approximately one week and the food was given in the form of granules and watered with tap water from a bottle with drinking water as much as you want. Mice were adapted to switch to powdered foods for three days. On the first day of the experiment (day 0) was determined by the body weight of mice. Blood samples were collected from the coccygeal vein using microcapillary for measuring the concentration of glucose in plasma. Based on the measured glucose concentration in the plasma of mice were divided into several groups (five mice per group), using stratified busbyberkly method. The body weight of mice was determined the next morning and the next day for six days they were given a connection with the food mixture containing 0.03% (wt./wt.), 0,01% (wt./wt.) or 0.003% (wt./wt.) compounds according to the present invention, or powdered foods only. On the morning of the fourth and seventh day in mice was determined by body weight and amount of food consumed to calculate the average injected dose. In the morning of the seventh day samples of blood of going to and from the coccygeal vein to measure levels of glucose and triglycerides (TG). On the seventh day after the determination of body weight blood samples were collected from the abdominal Vena cava under conditions of anesthesia with ether to determine the plasma insulin, neeterificirovannah fatty acids (NEFA), levels of GOT and GPT using commercially available kits. And then deleted the liver and weighed. Total RNA was obtained from the left lobe of the liver and measured the level of gene expression of a bifunctional protein by the method of the Northern blot. In fact, significant differences in food consumption between the control group (only powdered food) and the group treated with compounds (chopped food containing 0.03%, 0.01% or 0,003% of compounds)were observed. The calculated dose was approximately 40 mg/kg/day in the group receiving food containing 0.03% of the connection.

Based on the data, demonstrating the improvement in levels of plasma glucose, insulin in plasma NEFA or TG in fat KKAy/Ta mice, suggest that the test compound may be used as a means for preventing and/or treating diabetes mellitus, hyperlipidemia, atherosclerosis, etc. Specified action probably mediated through the activation of PPAR γin vivo.In addition, it is likely that the increase in weight of the liver and increase the level of expression of HD mPHK depends on activation of PPAR αin vivo.

Hypoglycemic and g is politicamente effects (2):

Male 8-week-old rats Zucker fa/fa (line: Crj-[FOR]-fa/fa)and healthy rats Zucker lean (line: Crj-[FOR]-lean), comparing pre-fed individually in separate cages for about two weeks and were given food pellets and tap water from automatic waterers as much as you want. Within five days of treatment, rats were adapted to oral introduction of food through the gastric tube. During this period the General condition of the rats was observed, and a healthy 10-week-old rats were used for the experiment. The body weight of each rat was determined in the morning of the first day of the experiment (day 0), and blood samples were collected from the coccygeal vein using the micro capillary to measure the concentrations of plasma glucose, TG, NEFA and HbA1c. On the basis of HbA1c and body weight of the rats were divided into groups consisting of five animals each, using stratified bezvybornost method. In addition, rats were replaced, it is possible to prevent deviation of the mean values of other parameters between groups. The body weight of each animal was determined every morning from the day after the division of animals into groups. The injected volume was calculated based on the measured body weight on the day of injection, and oral administration through a gastric tube connection according to the present invention or only media (in 0.5% methylcellulose) was the Dean once a day for 13 days. Healthy animals (lean rats) gave only the media.

The amount of food consumed was measured in the morning on 1, 4, 7, 10 and 13 day to calculate the average consumption of food. On the seventh day the blood samples were collected from the coccygeal vein using microcapillary to measure the concentrations of plasma glucose, TG, NEFA and HbA1c. And on the 14th day oral test glucose tolerance (OGTT), in order to assess the effect of improving the status of intolerance to glucose. Rats were kept hungry in the previous before the test day (day 13)to spend the OGTT. After the blood samples were collected the next day (day 14), rats were loaded with 40% glucose solution in the amount of 2 g/5 ml/kg by oral administration. After 60 and 120 minutes after exercise blood samples were collected from the coccygeal vein using microcapillary to determine the levels of glucose in plasma.

Animals were given food after OGTT and entered the compound according to the present invention on the 15th day. In the morning on the 16th day after the determination of body weight blood samples were collected from the coccygeal Vena cava under conditions of anesthesia with ether to determine the levels of plasma glucose, insulin in plasma TG, NEFA, GOT and GPT. And, finally, the liver was removed and weighed.

Based on the data, demonstrating the improvement in levels of plasma glucose, insulin in plasma TG, NEFA or HbA1c at adorble the s rats Zucker fa/fa, assume that the test compound may be used as a means for preventing and/or treating diabetes mellitus, hyperlipidemia, atherosclerosis, etc. in Addition, reduced levels of plasma glucose, measured on an empty stomach, and improvement of intolerance to glucose during OGTT suggests the possible existence of funds for the prevention and/or treatment of diabetes. The specified action is likely mediated through activation of PPAR γin vivo.In addition, I believe that the increase in weight of the liver depends on the activation of PPAR αin vivo.

Hypoglycemic and hypolipidemic effects (3):

Male cynomolgus monkeys from 3 to 4 years of age (average body weight of approximately 3 kg) was subjected to a medical examination and adapted to receive food once a day in the form of granules in the amount of 100 g and a tap water from automatic waterers as much as they were kept individually in separate cages for the monkeys for more than one month. Then the animals began to eat within one hour. In addition, animals previously fed for 14 days. On the 14th day and the 7th day prior to the processing in monkeys was determined by the weight of the body, and then collected samples of blood from the saphenous vein hindquarters to determine the haematological parameters (red blood cells, hematocrit, hemoglobin, is robotito and leukocyte count) and biochemical parameters (GOT, GPT, alkaline phosphatase, total protein, urea nitrogen, blood, creatinine, creatinekinase, total bilirubin, glucose, total cholesterol, HDL, LDL and TG). In addition, the General condition of the animals was monitored during acclimatization and pre-feeding, and healthy animals used for the experiment. The food intake was measured every day.

On the basis of determining the weight of the body on the last day of the acclimatization period, animals were divided into several groups (three animals per group) using stratified bezvybornost method. In the morning of days 1, 3, 7, 10 and 14 were determined by the weight of the body. The injected volume was calculated based on the last measurement of body weight, and was carried out by oral administration through a gastric tube connection according to the present invention (3-100 mg/kg/day) or media (diluted solution) once daily for 14 days. 1, 7 and 14 days after treatment blood samples were collected for measuring the above-mentioned hematological and biochemical parameters before the introduction of the compounds according to the present invention. The data obtained indicate that the level of glucose in the blood does not change with the intake of compounds according to the present invention. Three weeks before and 14 days after the start of treatment blood samples were collected from the saphenous vein in the hind limbs or brezplacni veins across the 1, 2 and 4 hours after oral administration through a gastric tube and 1, 2 and 3 hours after food, to measure the levels of glucose and TG in plasma.

Based on the data, indicating the improvement of TG levels in plasma from monkeys, which was kept on starvation diet, suggest that the test compound may be used as a tool for the prevention and/or treatment of hyperlipidemia and atherosclerosis, etc. Specified action probably mediated through the activation of PPAR αin vivo.The researchers also observed the effect of suppressing the afternoon increase in TG. In addition, you can assess, is it compound the risk of toxicity, based on other biochemical parameters.

Toxicity

The toxicity of the compounds represented by formula (I) according to the present invention, is so low that the connection is considered as safe enough for use as a pharmaceutical product.

Application for a pharmacy

Since the compound represented by formula (I) according to the present invention, and its non-toxic salt have activity modulating PPAR, believe that they can be used as hypoglycemic agents, hypolipidemic funds, funds intended for the prevention and/or treatment is s disease, associated with metabolic disorders such as diabetes, obesity, syndrome X, hypercholesterolemia and hyperlipoproteinemia, etc., hyperlipidemia, atherosclerosis, hypertension, disease, occurring with circulatory disorders, obesity, coronary heart disease, etc., agents that increase the level of cholesterol associated with HDL, agents that lower cholesterol associated with LDL and/or VLDL, and agents intended to mitigate the risk of diabetes or syndrome X.

In addition, since the compound represented by formula (I) according to the present invention, and its non-toxic salt active agonist of PPAR α and/or activity of PPAR agonist γbelieve that they can be used as hypoglycemic agents, hypolipidemic funds, funds intended for the prevention and/or treatment of diseases associated with metabolic disorders such as diabetes, obesity, syndrome X, hypercholesterolemia and hyperlipoproteinemia and so on, as well as diseases such as hyperlipidemia, atherosclerosis, hypertension, diseases occurring disorder circulation, and overeating, etc., agents that increase the level of cholesterol associated with HDL, agents that lower cholesterol associated with LDL and/or VLDL, agents designed to inhibit the development of atherosclerose his treatment and anti-obesity. I believe that these tools can also be used to treat and/or prevent diabetes as hypoglycemic agents, for reducing hypertension, to eliminate the risk factors of syndrome X, and as a means for prevention of ischaemic heart disease.

In the present invention, the compound represented by formula (I)may be introduced in combination with other drugs to : 1) complement and/or enhance the preventive measures and/or treatment, 2) improving the dynamic parameters and the suction connection properties, and reduce the dose and/or 3) reduction of side effects connection.

The compound represented by formula (I)may be introduced in combination with other drugs in the form of a composition in one medicinal product containing these components, or may be introduced separately. In the case when the components are administered independently, they can be administered simultaneously or with time. Introduction with the period of time includes a method of introducing a compound represented by the formula (I), to other medicines, and Vice versa; you can enter them the same way or in different ways.

The above combination has an effect on any disease, treatment and/or prevention of it is done by a join represented by formula (I), supplemented and/or enhanced.

As other medicines that complement or enhance the effects of the compounds represented by formula (I), or which enhance the effects of treatment complications of diabetes, using, for example, hypoglycemic agent type sulfonylureas drugs group biguanide, inhibitor of alpha-glucosidase, rapid stimulator of insulin secretion, insulin product, a PPAR agonist, an insulin sensitizer without agonistic activity of PPAR, activator beta-3 adrenaline receptor, inhibitor alsoreported or inhibitor dipeptidylpeptidase IV etc.

Examples of sulfonylureas include acetohexamide, glibenclamide, gliclazide, glyclopyramide, hlorpropamid, tolazamide, tolbutamide, and glimepiride, etc.

Examples of drugs biguanide include the hydrochloride of buformin and Metformin hydrochloride etc.

Examples of alpha-glucosidase inhibitors include acarbose and voglibose etc.

Examples of rapid stimulators of insulin secretion include nateglinide and Repaglinide etc.

Examples of PPAR agonists include pioglitazone, troglitazone, rosiglitazone and JTT-501, etc.

Examples of insulin sensitizers, not having the activity of a PPAR agonist, include ONO-5816 and YM-440, etc.

Examples of activators beta 3 prescriptions the ora of adrenaline include AJ9677, L750355 and CP331648, etc.

Examples of inhibitors alsoreported include epalrestat, fidarestat and zenarestat etc.

The weight ratio of the compound represented by formula (I), and other drugs not very limited.

In combination arbitrarily can be entered two or more other medicines.

Examples of other drugs for compensation and/or to enhance the effect of prevention and/or treatment, due to the compound represented by formula (I)include not only those compounds that are found up to the present time, but also those compounds that will be found on the basis of the above mechanism.

In the case where the compound represented by formula (I) according to the present invention, or a combination of compounds represented by formula (I), with other medicines used for the above purpose, the connection or combination is usually administered systemically or topically, orally or parenterally.

Input dose determined, for example, the age, body weight, symptom, the desired therapeutic effect, the route of administration and duration of treatment. For an adult dose usually ranges from 1 ng to 100 mg, by oral administration, administered up to several times in the Yan, and from 0.1 ng to 10 mg when administered parenterally, administered up to several times a day, or by continuous introduction from 1 to 24 hours a day through a vein.

As mentioned above, the doses depend on various conditions. Therefore, there are cases when the use of doses that are higher or lower than the above fields.

In the case where the compound represented by formula (I) according to the present invention, or a combination of compounds represented by formula (I), with other medicines used for the above purpose, the connection or combination is usually administered systemically or topically, orally or parenterally. For the treatment it is advisable to choose the most effective way of introduction.

Input dose determined, for example, the age, body weight, symptom, the desired therapeutic effect, the route of administration and duration of treatment. For an adult dose usually ranges from 1 ng to 100 mg, by oral administration, administered up to several times a day, and from 0.1 ng to 10 mg when administered parenterally, administered up to several times a day, or by continuous introduction from 1 to 24 hours a day through a vein.

As mentioned above, the doses depend on various conditions. Therefore, there are cases when the use of doses that are the two who are below or above the above fields.

The compound represented by formula (I)according to the present invention, or a combination of compounds represented by formula (I), with other medicines, you can enter in the composition in the form of, for example, solid preparations for internal use and liquid preparations for internal use, each drug is intended for oral administration, or in the form of injection preparations for external use or suppositories, each drug is intended for parenteral administration.

Examples of solid oral preparations for internal use include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.

Such a solid preparation for internal use get the usual method of manufacture of a medicinal product containing one or more active substances either as such or in the form of a mixture with an excipient (lactose, mannitol, glucose, microcrystalline cellulose, starch etc), binder (hydroxypropylcellulose, polyvinylpyrrolidone, metasilicates magnesium etc), dezintegriraat reagent (calcium salt glycolate, cellulose, etc.), lubricating reagent (magnesium stearate etc), stabilizer and substance contributing to the solution is s (glutamic acid, aspartic acid and so on). If necessary, a solid preparation coated with a layer agent (sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose etc). The drug can be covered by two or more layers. In addition, capsules made of absorbable material such as gelatin, included in the scope of the invention.

Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. Such a liquid preparation obtained by dissolution, suspension or emulsion of one or more active substances in a solvent, usually used for such purposes (purified water, ethanol, a mixture thereof, etc.). In addition, such liquid formulations can also contain some additives, such as humectants, suspendresume agents, emulsifiers, sweeteners, flavouring substances, flavouring agents, preservatives or buffers reagents, etc.

Injectable preparations for parenteral administration include solutions, suspensions, emulsions and solids for injection, which is dissolved or suspended before use. Such injection drug use by dissolution, suspension or emulsion of one or more active substances in a solvent. In to the amount of solvent can be used, for example, distilled water for injection, physiological saline, vegetable oils, alcohols, such as propylene glycol, polyethylene glycol or ethanol, and mixtures thereof. In addition, the injectable preparation may contain a stabilizer, a substance that promotes dissolving (glutamic acid, aspartic acid, Polysorbate 80 (registered trade name), etc), suspendisse agent, emulsifying agent, a sedative agent, a buffer, a preservative, etc. of Such injectable preparation may be obtained by sterilization at the final stage or aseptic way. Alternatively, it is also possible aseptic solid product, such as a lyophilized product, receive and spayed or dissolved in aseptic distilled water for injection or other solvent before use.

Dosage forms of medicines for parenteral administration for external use include ointments, gels, creams, preparations for compresses, plasters, liniments, atomized liquid, inhalations, sprays, eye drops, nasal drops and the like. This product contains one or more active substances, and get a well known manner or in accordance with applicable generally by the method of preparation of the dosage form.

Ointments are prepared in accordance with the laws the AI with well-known methods of preparing dosage forms or ways, usually used in the manufacture of dosage forms. For example, they are obtained by grinding into powder or melting one or more active substances in a base. Materials choose among the well-known framework, commonly used for the preparation of ointments. For example, you can use one or a mixture of two or more bases selected from higher fatty acids or esters of higher fatty acids (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, esters of adipic acid, esters of myristic acid, esters palmitic acid, esters of stearic acid, esters of oleic acid, etc.), waxes (beeswax, whale wax, ceresin, etc.), surface-active substances (esters polyoxyethylenated esters and phosphoric acid etc), higher alcohols (cetanol, stearyl alcohol, cetosteatil alcohol etc), silicone oils (dimethylpolysiloxane etc), hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin etc), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol etc), vegetable oils (castor oil, olive oil, sesame oil, terpentine oil, etc.), animal oils (mink oil, yolk is aslo, squalane, squalene etc), water, substances that promote absorption, and substances against skin irritation. In addition, the ointment may contain a humectant, preservative, stabilizer, antioxidant, perfume, etc.

The gels are prepared in accordance with well-known methods of preparing dosage forms or methods which are usually used in the manufacture of dosage forms. For example, they are obtained by melting one or more active substances in a base. Gel Foundation choose among the well-known framework, commonly used for the preparation of gels. For example, you can use one or a mixture of two or more bases selected from lower alcohols (ethanol, isopropyl alcohol, etc.), agents of gelatinization (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose etc), neutralizing agents (triethanolamine, diisopropanolamine etc), surfactants (polyethylene glycol monostearate etc), gums, water, substances that promote absorption, and substances that protect against skin irritation. In addition, the gels may contain a preservative, a stabilizer, an antioxidant, a perfume, etc.

Creams are manufactured in accordance with well-known methods of preparing dosage forms or methods which are usually used in the manufacture of dosage forms. the example they are obtained by melting or emulsifying one or more active substances in a base. Based creams choose among the well-known framework, commonly used for the preparation of creams. For example, you can use one or a mixture of two or more bases selected from esters of higher fatty acids, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butyleneglycol etc), higher alcohols (2-hexyldecanol, cetanol etc), emulsifiers (polyoxyethylenesorbitan esters, esters of fatty acids and so on), water, substances that promote absorption, and substances against skin irritation. In addition, the creams may contain a preservative, an antioxidant, a perfume, etc.

Drugs to compress receive in accordance with well-known methods of preparing dosage forms or methods which are usually used in the manufacture of dosage forms. For example, they are obtained by melting one or more active substances in the base, mixing until a homogeneous mass and then applying the mixture on the substrate and its distribution over the surface of the substrate. The basis of drugs to compress choose among the well-known framework, commonly used for the preparation of drugs to compress. For example, you can use one or a mixture of two or more bases selected the s of thickeners (polyacrylic acid, polyvinylpyrrolidone, Arabian gum, starch, gelatin, methylcellulose, etc.), humectants (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium etc), water, additives, contributing to the dissolution of the reagents giving stickiness, and substances that protect against skin irritation. In addition, preparations for the compress may contain a preservative, an antioxidant, a perfume, etc.

The patches are manufactured in accordance with well-known methods of preparing dosage forms or methods which are usually used in the manufacture of dosage forms. For example, they are obtained by melting one or more active substances in a base and then applying them to the substrate and distribution over the surface of the substrate. A basis of plaster choose from well-known framework, commonly used for the manufacture of adhesives. For example, you can use one or a mixture of two or more bases selected from polymers, fats and oils, higher fatty acids, reagents, giving stickiness and substances, protects against skin irritation. In addition, the patch may include a preservative, an antioxidant, a perfume, etc.

Liniments are prepared in accordance with well-known methods of preparing dosage forms or methods which are usually used in the production of the dosage forms. For example, they are obtained by dissolution, suspension or emulsion of one or more active substances in one environment or in more than one medium selected from water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerine, Soaps, emulsifiers, suspendida reagents and the like. In addition, liniments may contain a preservative, an antioxidant, a perfume, etc.

Spray drugs, inhaled medicines and sprays can contain, in addition to usually used for such purposes diluent, a stabilizer such as sodium bisulfite, buffer, creating isotonicity, for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid. Ways of making spray described in detail, for example, in U.S. patent 2868691 and U.S. patent 3095355. In addition, you can apply the spray reagents.

In the case of the introduction of drugs into the nose in the form of drops, they are usually sprayed in a certain number of intranasally in the form of liquid or powder containing drugs, with the help of a special device for nasal drops or spray.

Eye drops for parenteral administration may be in the form of a liquid, suspension, emulsion, liquid, dissolved in a solvent when used, or ointments.

These eye drops are prepared by any known what major way. For example, one or more active substances are dissolved, suspended or emuleret in the solvent. As such a solvent for eye drops can be used sterilized purified water, saline and other aqueous or non-aqueous solvents (e.g., vegetable oil), separately or in combination of solvents. Eye drops may contain one or more solvents, optionally selected from isotonic reagent (for example, sodium chloride, concentrated glycerin), buffer reagent (e.g. sodium phosphate, sodium acetate), surfactants (for example, Polysorbate 80 (trade name), polyoxometalate 40, polyoxyethylene-hydrogenated castor oil), stabilizer (sodium citrate, edetate sodium), preservatives (such as benzalkonium chloride, paraben), etc. sterile Eye drops at the final stage or prepare aseptic way. Alternatively, aseptic solid reagent, such as freeze-dried product, which was previously received, may be aseptic or may be dissolved in aseptic distilled water for injection or other solvent prior to use.

Inhalation preparations for parenteral administration include aerosols, powders for inhalation and liquid Inga is acii. These inhaled medicines can be in the form of a solution or suspension in water or other adequate environment to use.

Inhaled medicines can be obtained in accordance with the well-known method.

For example, liquid preparations for inhalation can be prepared, if necessary, with addition of selected accordingly preservative (benzalkonium chloride, paraben and so on), dye, buffer (sodium phosphate, sodium acetate, etc.), isotonic reagent (sodium chloride, concentrated glycerin, etc.), thickener (carboxyquinolone etc), substances that contribute to the absorption, etc.

Powders for inhalation can be prepared, if necessary, with addition of selected appropriately lubricating reagent (stearic acid, its salt, etc.), binders (starch, dextrin, etc.), filler (lactose, cellulose, etc.), dye, preservative (benzalkonium chloride, paraben and so on), substances that contribute to the absorption, etc.

When injected liquid for inhalation, typically use a spray (aerosol inhaler, nebulizer). When using powders for inhalation, the introduction of an inhaled drug is usually performed using the device for inhalation of powder reagents.

Other compositions for parenteral the th introduction include suppositories and pessaries for vaginal administration, containing one or more active substances and are manufactured in accordance with commonly used methods of manufacture of dosage forms.

The present invention discloses in detail below on the basis of the reference examples and examples, but the present invention is not limited to these examples.

Solvents are presented in parentheses indicate manifesting solvent or an eluting solvent, and the ratio of the used solvent in the chromatographic separations or TLC presents volume. Solvents are presented in parentheses in the NMR indicate the solvents used for the measurement. MOMO means methoxyethoxy.

Reference example 1

3-Methoxysalicylaldehyde

To a solution of 3-hydroxybenzaldehyde (1.0 g) in tetrahydrofuran (25 ml) is added sodium hydride (374 mg) at 0°and the mixture is stirred at 0°C for 20 minutes. To the reaction mixture add methoxymethane (0,92 ml), the mixture is stirred for 30 minutes at room temperature. The reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (GE is San:ethyl acetate = 8:1→ 5:1) to obtain specified in the connection header (1,36 g)having the following physical characteristics.

TLC: Rf is 0.69 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ 9,98 (s, 1H), 7,62-7,40 (m, 3H), 7,30 (m, 1H), 5,24 (s, 2H), 3,50 (s, 3H).

Reference example 2

3-Methoxyethoxymethyl alcohol

To a suspension of lithium-aluminiumhydride (178 mg) in tetrahydrofuran (15 ml) added dropwise a solution of the compound obtained in reference example 1 (1,30 g) in tetrahydrofuran (24 ml) at 0°and the mixture is stirred at 0°C for 20 minutes. In the reaction mixture is added dropwise a saturated aqueous solution of sodium sulfate, and then added to the mixture of the ether. The reaction mixture was dried over anhydrous magnesium sulfate and concentrated to obtain crude specified in the title compound (1.39 g)having the following physical characteristics. The compound obtained is used in the next reaction without purification.

TLC: Rf 0.25 in (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ 7,28 (DD, J=7,8, and 7.8 Hz, 1H), 7,10-6,92 (m, 3H), 5,19 (s, 2H), 4,67 (sird, J=3.0 Hz, 2H), 3,48 (s, 3H).

Reference example 3

Ethyl ester of 2-(N-allyl-N-(3-methoxyethoxymethyl)amino)acetic acid

To a solution of the compound obtained in reference example 2 in tetrahydrofuran (16 ml) was added triethylamine (2.0 ml) and tozi the chloride (0,72 ml) at 0° C, and the mixture is stirred for 40 minutes at 0°C. To the reaction mixture are added ethanol (0,23 ml), the mixture is stirred for 20 minutes at 0°C. To the reaction mixture add a solution of acetonitrile (5.0 ml), potassium carbonate (2.16 g) and ethyl ester of N-allylglycine (1.68 g) in acetonitrile (18 ml), the mixture is stirred for 40 minutes at 75°C. the Reaction mixture is cooled to room temperature, then poured into cold water and extracted with the ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 8:1→6:1) to obtain the specified title compound (1.84 g)having the following physical characteristics.

TLC: Rf of 0.40 (hexane:ethyl acetate = 5:1);

NMR (CDCl3): δ of 7.23 (DD, J=7,8, and 7.8 Hz, 1H), 7,08-of 6.90 (m, 3H), 5,88 (DDT, J=16,8, to 10.2, 6.6 Hz, 1H), 5,28-5,10 (m, 2H), 5,17 (s, 2H), 4,16 (kV, J=7.2 Hz, 2H), of 3.77 (s, 2H), 3,48 (s, 3H), of 3.32 (s, 2H), 3,28 (d, J=6,6 Hz, 2H), 1.27mm (t, J=7.2 Hz, 3H).

Reference example 4

Ethyl ester of 2-(N-allyl-N-(3-hydroxybenzyl)amino)acetic acid

To a solution of the compound obtained in reference example 3 (1.80 g)in ethanol (6,1 ml) is added 4n. a solution of hydrogen chloride-dioxane (3.1 ml), and the mixture is stirred over night at room temperature. The reaction mixture is poured into cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (1,61 g)having the following physical characteristics.

TLC: Rf to 0.39 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ 7,17 (DD, J=7,8, and 7.8 Hz, 1H), 6,94-6,84 (m, 2H), 6.73 x (m, 1H), by 5.87 (DDT, J=16,8, to 10.2, 6.6 Hz, 1H), 5,28-5,10 (m, 2H), 4,15 (kV, J=6,9 Hz, 2H), of 3.73 (s, 2H), and 3.31 (s, 2H), 3,26 (d, J=6.6 Hz, 2H), 1.26 in (t, J=6.9 Hz, 3H).

Reference example 5

6-(Peligrosas-1-yl)nicotinic acid

A suspension of 6-chloronicotinic acid (5.0 g) and perhydroanthracene (7,16 ml) in xylene (20 ml) was stirred at 140°C for 30 hours in an argon atmosphere. The reaction mixture is cooled to room temperature, diluted with hexane and filtered. Insoluble material was dissolved in ethyl acetate. The organic layer is washed with water and saturated saline solution successively, dried over anhydrous magnesium sulfate and concentrated to obtain specified in the connection header (3,19 g)having the following physical characteristics.

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

Reference example 6

Benzyl ester 3-methoxycarbonyl-2-(6-peligrosas-1-yl)pyridine-3-ylcarbonyl)propionic acid

To a solution of the compound obtained in reference the example 5 (3,19 g), and methyl ester hydrochloride 3-amino-3-benzyloxycarbonylamino acid (to 4.38 g) in anhydrous dimethylformamide (40 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (3,34 g) and triethylamine (4,45 ml), and the mixture is stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution successively, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 3:1) to obtain specified in the connection header (2,94 g)having the following physical characteristics.

TLC: Rf 0,77 (chloroform:methanol = 9:1).

Reference example 7

3-Methoxycarbonyl-2-(6-(peligrosas-1-yl)pyridine-3-ylcarbonyl)propionic acid

To a suspension of 10% palladium-on-coal (300 mg, 50% water) in ethanol (10 ml) add a solution of the compound obtained in reference example 6 (2,94 g), in ethanol (15 ml), and the mixture is stirred at room temperature for 2 hours in hydrogen atmosphere. The reaction mixture was filtered and concentrated to obtain specified in the title compound having the following physical characteristics.

TLC: Rf of 0.20 (hexane:methanol = 9:1).

Reference example 8

Methyl ether 3-is cetyl-3-(6-(peligrosas-1-yl)peridinin-3-ylcarbonyl)propionic acid

To a solution of the compound obtained in reference example 7 and 4-dimethylaminopyridine (40 mg) in anhydrous pyridine (10 ml) is added acetic anhydride (1,26 ml) and the mixture was stirred at 80°C for 15 hours. The reaction mixture is cooled to room temperature and concentrate to obtain specified in the title compound having the following physical characteristics.

TLC: Rf of 0.20 (hexane:ethyl acetate = 1:1).

Reference example 9

Methyl ester 2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-methoxazole-4-yl)acetic acid

To a solution of the compound obtained in reference example 8, acetic anhydride (20 ml) is added concentrated sulfuric acid (2 ml), and the mixture was stirred at 90°C for 2 hours. The reaction mixture is cooled to room temperature, neutralized with saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution successively, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 2:1) to obtain the specified title compound (1.44 g)having the following physical characteristics.

TLC: Rf of 0.44 (hexane:ethyl acetate = 1:1);

NMR (CDCl3

Reference example 10

2-(2-(6-(Peligrosas-1-yl)pyridine-3-yl)-5-methoxazole-4-yl)ethanol

In the suspension sociallyengaged (166 mg) in anhydrous tetrahydrofuran (10 ml) in an atmosphere of argon is added dropwise a solution of the compound obtained in reference example 9 (1.44 g)in anhydrous tetrahydrofuran (10 ml) at 0°C, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is cooled at 0°C. In the reaction mixture was added dropwise methanol (1.0 ml), the mixture is stirred for 15 minutes. The reaction mixture was diluted with diisopropyl ether. To the diluted reaction mixture is added saturated aqueous solution of sodium carbonate (10 ml), the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered through a filter with layered on top of the sodium sulfate. Insoluble material was washed with diisopropyl ether. The combined organic layers concentrated to obtain specified in the title compound (1.20 g)having the following physical characteristics.

TLC: Rf of 0.45 (ethyl acetate);

NMR (CDCl3): δ 8,72 (d, J=2.4 Hz, 1H), 7,94 (DD, J=9,0, 2.4 Hz, 1H), 6,51 (d, J=9.0 Hz, 1H), 3,94-a 3.87 (m, 2H), 3,68 (DD, J=6,3, 5.7 Hz, 4H), 3,47-3,40 (who, 1H), 2,69 (t, 6.0 Hz, 2H), 2,30 (s, 3H)and 1.83-1.77 in (m, 4H), 1,62-of 1.52 (m, 4H).

Example 1

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

To a solution of the compound obtained in referential example 10 (500 mg)and the compound obtained in reference example 4 (623 mg)in anhydrous methylene chloride (30 ml) in an argon atmosphere, add triphenylphosphine (656 mg) and 1,1'-(azodicarbon)dipiperidino (631 mg) at room temperature, and the mixture is stirred for 18 hours. The reaction mixture was concentrated, and the residue was diluted with diethyl ether and filtered. The filtrate was washed with 2n. aqueous solution of sodium hydroxide, water and saturated saline solution successively, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate = 4:1) to give the compounds according to the present invention (777 mg)having the following physical characteristics.

TLC: Rf of 0.47 (hexane:ethyl acetate = 1:1);

NMR (CDCl3): δ 8,71 (d, J=2.4 Hz, 1H), of 7.96 (DD, J=9,0, 2.4 Hz, 1H), 7,20 (DD, J=7,8, 7.5 Hz, 1H), 6,92-to 6.88 (m, 2H), 6,82-6,77 (m, 1H), 6,50 (d, J=9.0 Hz, 1H), 5,94-5,80 (m, 1H), 5,23-5,12 (m, 2H), 4,22 (t, J=6,9 Hz, 2H), 4,14 (kV, J=6,9 Hz, 2H), 3,76 (s, 2H), 3,68 (DD, J=6,3, 5.7 Hz, 4H), 3,30 (s, 2H), 3.27 to (d, J=6.6 Hz, 2H), 2.95 points (t, J=6.9 Hz, 2H), 2,34 (s, 3H)and 1.83-1.77 in (m, 4H), 1,58-of 1.52 (m, 4H), 1,24 (t, J=6,9 Hz, 3H).

The use of the 1(1) - example 1(17)

By the same procedure described in example 1 using the corresponding alcohol derivatives instead of the compound obtained in reference example 11, and the compound obtained in reference example 5, or the corresponding phenol derivatives were obtained the following compounds according to the present invention.

Example 1(1)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-isopropyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.35 (hexane:ethyl acetate = 4:1).

Example 1(2)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.43 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 7,19 (DD, J=8,0, 8.0 Hz, 1H), 6,93-6,86 (m, 2H), 6,78 (m, 1H), by 5.87 (DDT, J=16.5, and of 10.0, 6.4 Hz, 1H), total of 5.21 (m, 1H), 5,15 (m, 1H), 4,19 (t, J=7,0 Hz, 2H), 4,15 (kV, J=7,0 Hz, 2H, in), 3.75 (s, 2H), 3.46 in-3,37 (m, 4H), 3,30 (s, 2H), 3.27 to (d, J=6,5 Hz, 2H), 2.95 points (t, J=7,0 Hz, 2H), 2,56-2,48 (m, 4H), of 2.33 (s, 3H), of 2.25 (s, 3H), of 1.26 (t, J=7.0 Hz, 3H).

Example 1(3)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-(1,2,3-thiadiazole-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0,66 (hexane:ethyl acetate = 1:1);

NMR (CDCl3): δ 8,71 (s, 1H), 8,13 (s, 4H), 7,21 (DD, J=7,9, 7.9 Hz, 1H), 6,98 to 6.75 (m, 3H), by 5.87 (m, 1H), 5,30-5,08 (m, 2H), 4.26 deaths (t, J=6.6 Hz, 2H), 4,14 (kV J=7.2 Hz, 2H, in), 3.75 (s, 2H), 3,38-3,20 (m, 4H), of 3.00 (t, J=6.6 Hz, 2H), 2,41 (s, 3H), 1,25 (t, J=7.2 Hz, 3H).

Example 1(4)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-cyclohexylphenol)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.65 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ 7,94-to 7.84 (m, 2H), 7,32-of 7.23 (m, 2H), 7,19 (DD, J=7,8, and 7.8 Hz, 1H), of 6.96-6,86 (m, 2H), 6,79 (m, 1H), by 5.87 (DDT, J=17.1 to, to 10.2, 6.6 Hz, 1H), 5,28-5,10 (m, 2H), 4,23 (t, J=6.6 Hz, 2H), 4,14 (kV, J=7.2 Hz, 2H), 3,74 (s, 2H), 3,29 (s, 2H), 3,26 (d, J=6.6 Hz, 2H), 2,97 (t, J=6.6 Hz, 2H), 2,53 (m, 1H), a 2.36 (s, 3H), 1,96 of 1.28 (m, 10H), 1,25 (t, J=7.2 Hz, 3H).

Example 1(5)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-(tetrahydropyran-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.20 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ of 7.96-7,88 (m, 2H), 7,34-7,24 (m, 2H), 7,20 (DD, J=8,1, 8,1 Hz, 1H), of 6.96-6,86 (m, 2H), 6,79 (m, 1H), by 5.87 (DDT, J=17.1 to, to 10.2, 6.6 Hz, 1H), 5,28-5,10 (m, 2H), 4,23 (t, J=6.6 Hz, 2H), 4,20-Android 4.04 (m, 4H), 3,74 (s, 2H), 3,60-of 3.48 (m, 2H), 3,30 (s, 2H), 3,26 (d, J=6.6 Hz, 2H), 2,97 (t, J=6.6 Hz, 2H), and 2.79 (m, 1H), is 2.37 (s, 3H), 1,94 is 1.70 (m, 4H), 1,25 (t, J=7.2 Hz, 3H).

Example 1(6)

Ethyl ester of 2-(N-allyl-N-(3-(2-(5-methyl-2-piperidinomethyl-4-yl)ethoxy)benzyl)amino)acetic acid

NMR (CDCl3): δ 7,19 (t, J=8,1 Hz, 1H), 6,92-6,87 (m, 2H), 6,69 (m, 1H), by 5.87 (m, 1H), 5,26-5,12 (m, 2H), 4,19 (t, J=7.2 Hz, 2H), 4,14 (kV, J=7.2 Hz, 2H, in), 3.75 (s, 2H), 3,40-of 3.32 (m, 4H), 3,30 (s, 2H), 3.27 to (d, J=6.3 Hz, 2H), equal to 2.94 (t, J=7.2 Hz, 2H), 1,71-and 1.54 (m, 6H), of 1.26 (t, J=7.2 for the C, 3H).

Example 1(7)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-phenyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf and 0.46 (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ 8,03-to 7.93 (m, 2H), 7,49 and 7.36 (m, 3H), 7,20 (DD, J=7,8, and 7.8 Hz, 1H), of 6.96-6.87 in (m, 2H), to 6.80 (m, 1H), by 5.87 (m, 1H), 5,28-5,10 (m, 2H), 4,24 (t, J=6,8 Hz, 2H), 4,14 (kV, J=7,0 Hz, 2H, in), 3.75 (s, 2H), 3,30 (s, 2H), or 3.28 (m, 2H), 2,98 (t, J=6,8 Hz, 2H), of 2.38 (s, 3H), 1,25 (t, J=7.0 Hz, 3H).

Example 1(8)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-dimethylaminopyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.28 in (hexane:ethyl acetate = 2:1);

NMR (CDCl3): δ a total of 8.74 (m, 1H), to 7.99 (DD, J=9,0, 2.4 Hz, 1H), 7,20 (DD, J=8,0 8,0 Hz, 1H), 6,94-6,86 (m, 2H), 6,79 (m, 1H), 6,53 (m, 1H), by 5.87 (DDT, J=16,8, of 10.0, 6.5 Hz, 1H), total of 5.21 (m, 1H), 5,14 (m, 1H), 4,22 (t, J=7,0 Hz, 2H), 4,14 (kV, J=7,0 Hz, 2H, in), 3.75 (s, 2H), 3,30 (s, 2H), 3.27 to (d, J=6,5 Hz, 2H), 3,14 (s, 6H), 2.95 points (t, J=7,0 Hz, 2H), 2,34 (s, 3H), 1,25 (t, J=7.0 Hz, 3H).

Example 1(9)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-dimethylaminophenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.26(hexane:ethyl acetate = 4:1).

Example 1(10)

Methyl ester of 2-(N-allyl-N-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)-2-methylpropionic acid

TLC: Rf of 0.48 (hexane:ethyl acetate = 4:1);

NMR (CDCl3): δ 8,02-7,94 (m, 2H), of 7.48-7,37 (m, 3H), and 7.7 (DD, J=8,0, 8.0 Hz, 1H), 6,98-to 6.88 (m, 2H), 6.73 x (m, 1H), 5,78 (DDT, J=16.5, and of 10.0, 6.5 Hz, 1H), 5,00 (m, 1H), 4,90 (m, 1H), 4,24 (t, J=6.5 Hz, 2H), of 3.77 (s, 2H), 3,69 (s, 3H), of 3.28 (d, J=6,5 Hz, 2H), 2,98 (t, J=a 6.5 Hz, 2H), of 2.38 (s, 3H), of 1.38 (s, 6H).

Example 1(11)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-morpholinopropan-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.44 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,76 (d, J=2.4 Hz, 1H), 8,04 (DD, J=9,0, 2.4 Hz, 1H), 7,19 (t, J=9,2 Hz, 1H), of 6.96-6,85 (m, 2H), 6,83-6,74 (m, 1H), only 6.64 (d, J=9.0 Hz, 1H), 5,98-5,74 (m, 1H), 5,27-5,04 (m, 2H), 4,28-4,06 (m, 4H), a 3.87-of 3.78 (m, 4H), 3,74 (s, 2H), 3,65-3,55 (m, 4H), 3,32-up 3.22 (m, 4H), 2.95 points (t, J=7,0 Hz, 2H), 2,35 (s, 3H), 1,25 (m, 3H).

Example 1(12)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-piperidinomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.33 (chloroform:methanol =10:1);

NMR (CDCl3): δ 8,72 (d, J=2.4 Hz, 1H), of 7.97 (DD, J=9,0, 2.4 Hz, 1H), 7,19 (t, J=8.0 Hz, 1H), of 6.96-6,85 (m, 2H), 6,79 (m, 1H), only 6.64 (d, J=9.0 Hz, 1H), 5,98-5,73 (m, 1H), 5,27-5,04 (m, 2H), 4,28-a 4.03 (m, 4H), 3,74 (s, 2H), 3,61 (Sirs, 4H), 3,32-up 3.22 (m, 4H), to 2.94 (t, J=6.6 Hz, 2H), 2,34 (s, 3H), 1,65 (Sirs, 6H), 1,25 (m, 3H).

Example 1(13)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-diethylaminomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.48 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,71 (d, J=2.6 Hz, 1H), 7,95 (DD, J=9,2, 2.6 Hz, 1H), 7,19 (t, J=6,8 Hz, 1H), 6,95 to 6.75 (m, 3H), 6,47 (d, J=9,2 Hz,1H), to 5.85 (m, 1H), total of 5.21 (d, J=and 17.2 Hz, 1H), 5,14 (d, J=10.3 Hz, 1H), 4,22 (t, J=6,8 Hz, 2H), 4,14 (kV, J=7.2 Hz, 2H), 3,74 (s, 2H), 3,55 (kV, J=7,0 Hz, 4H), 3,29 (s, 2H), 3.27 to (d, J=6,4 Hz, 2H), only 2.91 (t, J=6,8 Hz, 2H), 2,34 (s, 3H), 1,35-of 1.15 (m, 9H).

Example 1(14)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-pyrrolidinone-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf to 0.80 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,73 (d, J=2.4 Hz, 1H), 7,98 (DD, J=8,8, 2.4 Hz, 1H), 7,19 (t, J=7.2 Hz, 1H), 6,93 to 6.75 (m, 2H), 6,91 (s, 1H), 6,37 (d, J=8,8 Hz, 1H), 5,98-5,74 (m, 1H), from 5.29-5,09 (m, 2H), 4,22 (t, J=6.6 Hz, 2H,), to 4.16 (q, J=7.2 Hz, 2H), 3,74 (s, 2H), 3,50 (m, 4H), 3,29 (s, 2H), 3,26 (d, J=6.6 Hz, 2H), equal to 2.94 (t, J=6.6 Hz, 2H), 2,34 (s, 3H), 2,02 (m, 4H), 1,24 (t, J=7.2 Hz, 3H).

Example 1(15)

Ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-morpholinomethyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

NMR (CDCl3): δ 7,87 (d, J=9.0 Hz, 2H), 7,20 (t, J=8,1 Hz, 1H), 6,95-6,87 (m, 4H), 6,79 (m, 1H), 5,86 (m, 1H), 5.25-inch-5,11 (m, 2H), 4,23 (t, J=6.6 Hz, 2H), 4,14 (kV, J=6,9 Hz, 2H), a 3.87 (t, J=4.5 Hz, 4H), 3,74 (s, 2H), 3,32-3,20 (m, 8H), 2,96 (t, J=6.6 Hz, 2H), 2,35 (s, 3H), 1,25 (t, J=6.9 Hz, 3H).

Example 1(16)

Tert-butyl ester 2-(N-allyl-N-(3-(2-(2-morpholino-5-methylthiazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0,85 (chloroform:methanol = 9:1);

NMR (CDCl3): δ 7,19 (t, J=8,4 Hz, 1H), 6,94-6,87 (m, 2H), 6,77 (m, 1H), 5,86 (m, 1H), 5,26-5,10 (m, 2H), 4,19 (t, J=6.9 Hz, 2H), 3,79 (t, J=4.5 Hz, 4H), of 3.75 (s, 2H), 3,37 (t, J=4.5 Hz, 4H), 3,26 (d,J=6,6 Hz, 2H), 3,21 (s, 2H), 2.95 points (t, J=6.9 Hz, 2H), 2.05 is (s, 3H), of 1.46 (s, 9H).

Example 1(17)

Ethyl ester of 2-(N-allyl-N-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)acetic acid

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

NMR (CDCl3): δ 8,00-to 7.95 (m, 2H), 7,44-7,39 (m, 3H), of 7.23 (d, J=8.7 Hz, 2H), 6,85 (d, J=8.7 Hz, 2H), 5,94-5,80 (m, 1H), 5,23-5,11 (m, 2H), 4,23 (t, J=6.6 Hz, 2H), 4,14 (kV, J=7.2 Hz, 2H), 3,70 (s, 2H), 3.27 to (with, 2H), 3,24 (d, J=6.6 Hz, 2H), 2,97 (t, J=6.6 Hz, 2H), is 2.37 (s, 3H), 1,25 (t, J=7.2 Hz, 3H).

Example 2

2-(N-Allyl-N-(3-(2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

To a solution of the compound obtained in example 1 (777 mg)in ethanol and tetrahydrofuran (20 ml, 1:1) add 2 N. aqueous sodium hydroxide solution (3.0 ml) at room temperature, and the mixture is stirred for 15 hours. The reaction mixture was adjusted to a pH of approximately pH 5 with 2 N. hydrochloric acid and extracted with ethyl acetate. The extract is successively washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to obtain compound according to the present invention (546 mg)having the following physical characteristics.

TLC: Rf of 0.18 (chloroform:methanol = 9:1);

NMR (CDCl3): δ 8,71 (d, J=2.4 Hz, 1H), of 7.96 (DD, J=9,0, 2.4 Hz, 1H), 7,24 (DD, J=7,8, 7.5 Hz, 1H), 6,93-PC 6.82 (m, 3H), 6,51 (d, J=9,0 Hz, 1H), 5,96-5,80 (m, 1H), 5,35-of 5.26 (m, 2H), 4,23 (t, J=6.9 Hz, 2H), 3,81 (s, 2H), to 3.67 (DD, J=6,0, 6.0 Hz, 4H), to 3.34 (d, J=6,9 Hz, 2H), 3,29 (s, 2H), 3.00 and-2,70 (width, 1H), equal to 2.94 (t, J=6.9 Hz, 2H), 2,34 (s, 3H), 1,84-1,72 (m, 4H), 1,59 of 1.50 (m, 4H).

Example 2(1) - example 2(17)

By the same procedure described in example 2, using the compounds obtained in example 1(1)-example 1(17), instead of the compound obtained in example 1 and, if necessary, with subsequent transformation into the corresponding salt by the standard method were obtained the following compounds according to the present invention.

Example 2(1)

2-(N-Allyl-N-(3-(2-(2-isopropyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.32 (chloroform:methanol:acetic acid=100:10:1);

NMR (CDCl3): δ then 7.20 (DD, J=8,0, 8.0 Hz, 1H), 6,94-of 6.78 (m, 3H), of 5.92 (m, 1H), and 5.30 (d, J=11,4 Hz, 1H), from 5.29 (d, J=to 15.0 Hz, 1H), 4,15 (t, J=7,0 Hz, 2H), 3,88 (s, 2H), 3,38 (d, J=7,0 Hz, 2H), and 3.31 (s, 2H), 2,99 (Sept, J=7,0 Hz, 1H), 2,86 (t, J=7,0 Hz, 2H), 2,24 (s, 3H), of 1.30 (d, J=7,0 Hz, 6H).

Example 2(2)

2-(N-Allyl-N-(3-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0,69 (chloroform:methanol:water= 50:20:1);

NMR (CDCl3): δ then 7.20 (DD, J=8,0, 8.0 Hz, 1H), 6,95-6,87 (m, 2H), for 6.81 (DD, J=8,0, 2.0 Hz, 1H), to 5.93 (m, 1H), 5,28 (d, J=16,8 Hz, 1H), 5,27 (d, J=10.5 Hz, 1H), 4,19 (t, J=7,0 Hz, 2H), 3,88 (s, 2H), of 3.45 (DD, J=5,0, 5.0 Hz, 4H), to 3.38 (d, J=6,5 Hz, 2H), and 3.31 (s, 2H), 2,92 (t, J=7,0 Hz, 2H), 2,59 (DD, J=5,0 5,0 Hz, 4H), is 2.37 (s, 3H), 2,24 (s, 3H).

Example 2(3)

Sodium salt of 2-(N-allyl-N-(3-(2-(2-(4-(1,2,3-thiadiazole-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.36 (chloroform:methanol = 8:1);

NMR (DMSO-d6): δ 9,74 (s, 1H), 8,28 (d, J=8.6 Hz, 2H), 8,07 (d, J=8.6 Hz, 2H), 7,16 (DD, J=7,8, and 7.8 Hz, 1H), 6,95-6,70 (m, 3H), 5,80 (m, 1H), 5,19-4,96 (m, 2H), 4,20 (t, J=6.5 Hz, 2H), to 3.67 (s, 2H), 3,19 (d, J=6,0 Hz, 2H), equal to 2.94 (t, J=6.5 Hz, 2H), 2,77 (s, 2H), of 2.38 (s, 3H).

Example 2(4)

2-(N-Allyl-N-(3-(2-(2-(4-cyclohexylphenol)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf of 0.32 (chloroform:methanol = 8:1);

NMR (CDCl3): δ 7,86 (d, J=8,4 Hz, 2H), 7,30-to 7.18 (m, 3H), 7,12-7,00 (m, 2H), to 6.88 (m, 1H), 6,03 (m, 1H), 5.56mm (Sirs, 1H), 5,48-and 5.30 (m, 2H), 4,36-Android 4.04 (m, 4H), 3,68 (d, J=6.3 Hz, 2H), 3,52 (s, 2H), 2,93 (t, J=6,6 Hz, 2H), of 2.51 (m, 1H), 2,34 (s, 3H), 1,96 by 1.68 (m, 5H), 1,52-to 1.14 (m, 5H).

Example 2(5)

2-(N-Allyl-N-(3-(2-(2-(4-(tetrahydropyran-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf to 0.39 (chloroform:methanol = 4:1);

NMR (CDCl3): δ to $ 7.91 (d, J=8.1 Hz, 2H), was 7.36-7,24 (m, 3H), 7,16 (m, 1H), 7,05 (m, 1H), 6,92 (m, 1H), 6,14 (m, 1H), 5,54 is 5.38 (m, 2H), 5,08 (Sirs, 1H), 4,34-was 4.02 (m, 6H), 3,76 (d, J=6.3 Hz, 2H), 3,62-of 3.54 (m, 4H ), to 2.94 (t, J=6.6 Hz, 2H), 2,80 (m, 1H), of 2.38 (s, 3H), 1,92 is 1.70 (m, 4H).

Example 2(6)

1/2 Calcium salt of 2-(N-allyl-N-(3-(2-(5-methyl-2-piperidinomethyl-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: 0,55 (chloroform:methanol = 5:1);

NMR (CDCl3): δ 7,13 (t, J=8,1 Hz, 1H), 6.89 in-to 6.80 (m, 2H), 6,72 (m, 1H), 5,80 (m, 1H), 5,16-to 4.98 (m, 2H), 4.09 to (t, J=6.9 Hz, 2H), to 3.67 (s, 2H), 3,36-of 3.12 (m, 6H), of 2.92 (s, 2H), 2,80 (t, J=6.9 Hz, 2H), 2,16 (, 3H), 1,58 is 1.48 (m, 6H).

Example 2(7)

2-(N-Allyl-N-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)acetic acid

Free form

TLC: Rf 0.21 in (chloroform:methanol = 8:1);

NMR (CDCl3): δ 8,02-of 7.90 (m, 2H), of 7.48-7,35 (m, 3H), of 7.23 (m, 1H), 7,05-6,83 (m, 3H), 5,96 (m, 1H), 5,44 is 5.28 (m, 2H), 4,22 (t, J=6.6 Hz, 2H), 4,12 (s, 2H), 3,60 (m, 2H), 3,47 (s, 2H), equal to 2.94 (t, J=6.6 Hz, 2H), to 2.35 (s, 3H).

Sodium salt

TLC: Rf and 0.61 (chloroform:methanol = 4:1);

NMR (DMSO-d6): δ 7,95-of 7.90 (m, 2H), 7,55 was 7.45 (m, 3H), 7,15 (DD, J=8, 8 Hz, 1H), 6,95-6,70 (m, 3H), 5,80 (m, 1H), 5,20-5,00 (m, 2H), 4,20 (t, J=6.5 Hz, 2H), 3,70 (s, 2H), 3,20 (d, J=7 Hz, 2H), 2.95 points (t, J=a 6.5 Hz, 2H), 2,80 (s, 2H), 2,35 (s, 3H).

Example 2(8)

2-(N-Allyl-N-(3-(2-(2-(6-dimethylaminopyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.26 (chloroform:methanol:acetic acid=100:10:1);

NMR (CDCl3): δ 8,73 (d, J=2.4 Hz, 1H), to 7.99 (DD, J=2,4, 9,0, 1.5 Hz, 1H), 7,24 (DD, J=8,0, 8.0 Hz, 1H), 6,94-for 6.81 (m, 3H), of 6.52 (d, J=9.0 Hz, 1H), 5,90 (m, 1H), 5,31 (d, J=11.2 Hz, 1H), and 5.30 (d, J=15,8 Hz, 1H), 4,22 (t, J=7,0 Hz, 2H), 3,85 (s, 2H), 3,36 (d, J=7,0 Hz, 2H), and 3.31 (s, 2H), 3,14 (s, 6H), of 2.93 (t, J=7,0 Hz, 2H), 2,34 (s, 3H).

Example 2(9)

2-(N-Allyl-N-(3-(2-(2-(4-dimethylaminophenyl)-5-methoxazole-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.31 in (chloroform:methanol:acetic acid=100:10:1);

NMR (CDCl3): δ 7,83 (m, 2H), 7,22 (DD, J=8,0, 8.0 Hz, 1H), 6,94-to 6.80 (m, 3H), 6,70 (m, 2H), of 5.89 (m, 1H), from 5.29 (d, J=11.8 Hz, 1H), 5,28 (d, J=15.2 Hz, 1H), 4,22 (t, J=7,0 Hz, 2H), 3,84 (s, 2H), 3,35 (d, J=7,0 Hz, 2H), 3,29 (s, 2H), 3.00 and (s, 6H), of 2.93 (t, J=7,0 Hz, 2H), 2,32 (s, 3H).

Example 2(10)

2-(N-Allyl-N-(3-(2-(2-phenyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)-2-methylpropionate acid

Free form

TLC: Rf of 0.32 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,02-to 7.95 (m, 2H), 7,47-7,39 (m, 3H), 7,25 (m, 1H), of 6.96-6.89 in (m, 2H), 6,85 (m, 1H), to 5.85 (DDT, J=16,8, to 10.2, 6.6 Hz, 1H), total of 5.21 (m, 1H), 5,18 (m, 1H), 4,25 (t, J=7,0 Hz, 2H), 3,74 (s, 2H), 3,32 (d, J=6,6 Hz, 2H), 2,98 (t, J=7,0 Hz, 2H), of 2.38 (s, 3H), 1,45 (s, 6H).

Sodium salt

TLC: Rf is 0.42 (chloroform:methanol = 10:1);

NMR (DMSO-d6): δ of 7.96-7,86 (m, 2H), 7,56-the 7.43 (m, 3H), 7,12 (DD, J=8,0, 8.0 Hz, 1H), 6,99 (Sirs, 1H), 6.89 in (d, J=8.0 Hz, 1H), 6,69 (DD, J=8,0, 2.0 Hz, 1H), of 5.75 (DDT, J=17,0, 10,5, 6.0 Hz, 1H), 4.92 in (m, 1H), amounts to 4.76 (m, 1H), 4,18 (t, J=7,0 Hz, 2H), 3,76 (s, 2H), 3,29 (d, J=6.0 Hz, 2H), 2,92 (t, J=7,0 Hz, 2H), a 2.36 (s, 3H), of 1.17 (s, 6H).

Example 2(11)

2-(N-Allyl-N-(3-(2-(2-(6-morpholinopropan-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf is 0.22 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,76 (d, J=2.2 Hz, 1H), 8,04 (DD, J=9,0, 2.2 Hz, 1H), 7,24 (t, J=8.0 Hz, 1H), of 6.96-PC 6.82 (m, 3H), only 6.64 (d, J=9.0 Hz, 1H), 6,01-5,78 (m, 1H), 5,32 (d, J=10,8 Hz, 1H), 5,31 (d, J=to 15.4 Hz, 1H), 4,22 (t, J=6,8 Hz, 2H), 3,84 (2H), is 3.82 (t, J=5.0 Hz, 4H)and 3.59 (t, J=5.0 Hz, 4H), 3,37 (d, J=6,8 Hz, 2H), and 3.31 (s, 2H), equal to 2.94 (t, J=6,8 Hz, 2H), 2,35 (s, 3H).

Example 2(12)

2-(N-Allyl-N-(3-(2-(2-(6-piperidinomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.28 in (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,72 (d, J=2.2 Hz, 1H), of 7.97 (DD, J=9,0, 2.2 Hz, 1H), 7.23 percent (t, J=8.0 Hz, 1H), 6,97-6,79 (m, 3H), only 6.64 (d, J=9.0 Hz, 1H), 6,02 is 5.77 (m, 1H), 5,31 (d, J=9.8 Hz, 1H), from 5.29 (d, J=16.0 Hz, 1H), 4,21 (t, J=6,8 Hz, 2H), 3,85 (s, 2H), 3,60 (Sirs, 4H), to 3.36 (d, J=7,0 Hz, 2H), 3,30 (s, 2H), 2,92 (t, J=6,8 Hz, 2H), 2,33 (s, 3H), 1,65 (Sirs, 6H).

Example 2(13)

2-(N-Allyl-N-(3-(2-(2-(6-diethylaminomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf is 0.22 (chloroform:methanol = 10:1);

NMR (CDCl3): δ 8,71 (d, J=2.4 Hz, 1H), 7,95 (DD, J=9,0, 2.4 Hz, 1H), 7.23 percent (t, J=7.8 Hz, 1H), 6,97-for 6.81 (m, 3H), 6,47 (d, J=9.0 Hz, 1H), 6,00-5,78 (m, 1H), 5,31 (d, J=10,8 Hz, 1H), and 5.30 (d, J=15,8 Hz, 1H), 4,22 (t, J=7,0 Hz, 2H), 3,84 (s, 2H), 3,55 (kV, J=7.2 Hz, 4H), to 3.36 (d, J=7,4 Hz, 2H), 3,30 (s, 2H), 2,93 (t, J=7,0 Hz, 2H), 2,33 (s, 3H), 1,99 (t, J=7.2 Hz, 6H).

Example 2(14)

2-(N-Allyl-N-(3-(2-(2-(6-pyrrolidinone-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf is 0.49 (chloroform:methanol = 6:1);

NMR (CDCl3): δ 8,73 (d, J=2.2 Hz, 1H), 7,98 (DD, J=8,8, 2.2 Hz, 1H), 7.23 percent (t, J=8.0 Hz, 1H), 6,97-for 6.81 (m, 3H), 6,38 (d, J=8,8 Hz, 1H), 6,04 is 5.77 (m, 1H), and 5.30 (d, J=10.4 Hz, 1H), from 5.29 (d, J=15.6 Hz, 1H), 4,22 (t, J=7,0 Hz, 2H), 3,80 (s, 2H), 3,5 (m, 4H), to 3.33 (d, J=6.6 Hz, 2H), or 3.28 (s, 2H), 2,93 (t, J=7,0 Hz, 2H), 2,34 (s, 3H), 2,02 (m, 4H).

Example 2(15)

Hydrochloride of 2-(N-allyl-N-(3-(2-(2-(4-morpholinomethyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid

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

NMR (DMSO-d6): δ 7,74 (d, J=9.0 Hz, 2H), 7,20 (t, J=8,1 Hz, 1H), 7,01 (d, J=9.0 Hz, 2H), 6,91-6,77 (m, 3H), of 5.81 (m, 1H), 5,22-5,09 (m, 2H), 4,17 (t, J=6.3 Hz, 2H), of 3.73 (t, J=4,2 Hz, 4H), 3,68 (s, 2H), 3,52-is 3.08 (m, 9H), 2,87 (t, J=6.3 Hz, 2H), 2,31 (s, 3H).

Example 2(16)

Dichlorhydrate 2-(N-allyl-N-(3-(2-(5-methyl-2-morpholinomethyl-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.28 in (chloroform:methanol = 9:1);

NMR (DMSO-d6): δ 10,96 (width, 1H), 7,34 (t, J=8,1 Hz, 1H), 7,24 (m, 1H), to 7.09 (d, J=8,1 Hz, 1H), 6,99 (DD, J=8,1, 2.1 Hz, 1H), 6,03 (m, 1H), 5,56-vs. 5.47 (m, 2H), 4,35 (s, 2H), 4,24 (t, J=6.3 Hz, 2H), with 3.89 (s, 2H), 3,82 (d, J=6,9 Hz, 2H,), 3,76-of 3.54 (m, 8H), of 3.07 (t, J=6.3 Hz, 2H), 2,34 (s, 3H).

Example 2(17)

2-(N-Allyl-N-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)acetic acid

TLC: Rf 0.14 (chloroform:methanol = 9:1);

NMR (CDCl3): δ 8,00-to 7.95 (m, 2H), 7,43-7,39 (m, 3H), of 7.23 (d, J=8,4 Hz, 2H), 6.89 in (d, J=8,4 Hz, 2H), 5,95-5,80 (m, 1H), lower than the 5.37 is 5.28 (m, 2H), 4,24 (t, J=6.6 Hz, 2H), 3,84 (s, 2H), 3,35 (d, J=7.2 Hz, 2H), 3,29 (, 2H), 2,98 (t, J=6.6 Hz, 2H), 2,60-2,20 (Sirs, 1H), of 2.38 (s, 3H).

Preparative example 1

The following components were mixed in a standard way, extruded with getting 100 tablet is, containing each 50 mg of the active ingredient.

Table 6
Connection No.Relative activity to the positive control compound (carbacyclin=1)
Example 20,9
Table 7
Connection No.Relative activity to the positive control compound (troglitazone=1)
Example 211,5
2-(N-allyl-N-(3-(2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-
methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid5.0 g
Calcium carboxymethylcellulose (disintegrator)0.2 g
Magnesium stearate (lubricating agent)0.1 g
Microcrystalline cellulose4.7 grams

Preparative example 2

After mixing the following components in a standard way prepared solution was sterilized in the usual way and in portions of 5 ml were poured into vials, respectively, and liofilizirovanny standard way to obtain 100 ampoules of injectable preparation containing each 20 mg of the active ingredient.

2-(N-allyl-N-(3-(2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-
methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid2.0 g
Mannitol20 g
Distilled water1000 ml

1. Derived compounds carboxylic acids represented by the formula (I)

RG the X and Y each independently represents a C 1-4alkylen;

Z denotes-O-;

R1, R2, R3and R4each independently means a hydrogen atom or a C1-8alkyl;

R5means C2-8alkenyl;

A represents-O - or-S-;

D is D1D2D3D4or D5;

D1means C1-8alkyl;

D2is

the ring 1 is a saturated 6-membered monogatarareba containing one nitrogen atom and optionally another heteroatom selected from oxygen atom, sulfur and nitrogen;

D3is

the ring 2 is

(1) a fully saturated C3-10monocarbocyclic the aryl or

(2) optional saturated 5-membered monogatarareba containing 3 heteroatoms selected from nitrogen atoms, and sulfur, or a fully saturated 6-membered monogatarareba containing 1 heteroatom represents oxygen;

D4is

D5is

R6represents (1) hydrogen atom, (2) C1-8alkyl, (3) NR7R8;

R7or R8represents a hydrogen atom or a C1-8alkyl or

R7and R8taken in the natural with the nitrogen atom, to which they are attached, form a saturated 5-6-membered Monogatari containing one nitrogen atom and optionally another heteroatom represents an oxygen atom;

E denotes CH or a nitrogen atom, and

m is an integer 1-3,

or its non-toxic salt.

2. The compound according to claim 1 where Z is-O -, and D is the D1D2D3or D4or its non-toxic salt.

3. The compound according to claim 1, where D is the D1or its non-toxic salt.

4. The compound according to claim 1, where D is the D2or its non-toxic salt.

5. The compound according to claim 1, where D is the D3or its non-toxic salt.

6. The compound according to claim 1, where D is the D4or its non-toxic salt.

7. The compound according to claim 1, where D is the D5or its non-toxic salt.

8. The compound according to claim 3, which is a

(1) ethyl ester of 2-(N-allyl-N-(3-(2-(2-isopropyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid, or

(2) 2-(N-allyl-N-(3-(2-(2-isopropyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid, or its non-toxic salt.

9. The compound according to claim 4, which is a

(1) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(2) ethyl ester of 2-(N-allyl-N-(3-(2-(5-methyl-2-piperidinomethyl-4-yl)ethoxy)benzyl)am the but)acetic acid,

(3) tert-butyl ether 2-(N-allyl-N-(3-(2-(2-morpholino-5-methylthiazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(4) 2-(N-allyl-N-(3-(2-(2-(4-methylpiperazin-1-yl)-5-methylthiazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(5) 2-(N-allyl-N-(3-(2-(5-methyl-2-piperidinomethyl-4-yl)ethoxy)benzyl)amino)acetic acid, or

(6) 2-(N-allyl-N-(3-(2-(5-methyl-2-morpholinomethyl-4-yl)ethoxy)benzyl)amino)acetic acid,

or its non-toxic salt.

10. The compound according to claim 5, which is a

(1) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-(1,2,3-thiadiazole-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(2) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-cyclohexylphenol)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(3) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-(tetrahydropyran-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(4) 2-(N-allyl-N-(3-(2-(2-(4-(1,2,3-thiadiazole-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(5) 2-(N-allyl-N-(3-(2-(2-(4-cyclohexylphenol)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid, or

(6) 2-(N-allyl-N-(3-(2-(2-(4-(tetrahydropyran-4-yl)phenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

or its non-toxic salt.

11. The connection according to claim 6, which is a

(1) ethyl ester of 2-(N-al the Il-N-(3-(2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid, or

(2) 2-(N-allyl-N-(3-(2-(2-(6-(peligrosas-1-yl)pyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

or its non-toxic salt.

12. The connection according to claim 7, which is a

(1) ethyl ester of 2-(N-allyl-N-(3-(2-(2-phenyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(2) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-dimethylaminopyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(3) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-dimethylaminophenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(4) methyl ester of 2-(N-allyl-N-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)-2-methylpropionic acid,

(5) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-morpholinopropan-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(6) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-piperidinomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(7) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-diethylaminomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(8) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(6-pyrrolidinone-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(9) ethyl ester of 2-(N-allyl-N-(3-(2-(2-(4-morpholinomethyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(10) ethyl ester of 2-(N-allyl--(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)acetic acid,

(11) 2-(N-allyl-N-(3-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)acetic acid,

(12) 2-(N-allyl-N-(3-(2-(2-(6-dimethylaminopyridine-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(13) 2-(N-allyl-N-(3-(2-(2-(4-dimethylaminophenyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(14) 2-(N-allyl-N-(3-(2-(2-phenyl-5-methoxazole-4-yl)ethoxy)benzyl)amino)-2-methylpropionic acid,

(15) 2-(N-allyl-N-(3-(2-(2-(6-morpholinopropan-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(16) 2-(N-allyl-N-(3-(2-(2-(6-piperidinomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(17) 2-(N-allyl-N-(3-(2-(2-(6-diethylaminomethyl-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(18) 2-(N-allyl-N-(3-(2-(2-(6-pyrrolidinone-3-yl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid,

(19) 2-(N-allyl-N-(3-(2-(2-(4-morpholinomethyl)-5-methoxazole-4-yl)ethoxy)benzyl)amino)acetic acid, or

(20) 2-(N-allyl-N-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzyl)amino)acetic acid,

or its non-toxic salt.

13. The regulator activated peroxisome proliferation receptor, comprising as active ingredient a compound represented by the formula (I) according to claim 1, or its non-toxic salt, and optionally a carrier, order the tel or the solvent.

14. The remedy for the prevention and/or treatment of diseases associated with metabolic disorders such as diabetes, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, disease, occurring with circulatory disorders, overeating, or ischemic heart disease, which contains as active ingredient a compound represented by the formula (I) according to claim 1, or its non-toxic salt, and optionally a carrier, excipient or solvent.

15. A tool that increases the level of cholesterol associated with HDL, lowers cholesterol associated with LDL and/or VLDL, eliminates the risk factor for the occurrence of diabetes mellitus and/or syndrome X, containing as active ingredient a compound represented by the formula (I) according to claim 1, or its non-toxic salt, and optionally a carrier, excipient or solvent.



 

Same patents:

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, technology of organic compounds.

SUBSTANCE: invention relates to heterocyclic o-dicarbonitriles. Invention describes heterocyclic o-dicarbonitriles of the general formula: wherein R means the following compounds: . Heterocyclic o-dicarbonitriles can be used for preparing hexazocyclanes-fluorophores as a donor-fragment used for preparing hexazocyclanes-bifluorophores and hexazocyclanes-trifluorophores. Invention provides preparing new compounds possessing valuable properties.

EFFECT: valuable properties of compounds.

2 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to a derivative of 1,2,4-thiadiazole, substituted in the 5-position of General formula I, in which X Is N; R1- C1-6alkyl; R2is hydrogen, R3, R4and R5each independently selected from hydrogen; trifloromethyl;is Ar2, Ar2CH2or Het2; AG2is phenyl; Het2is a monocyclic heterocycle selected from thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl, their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

Benzothiazoles // 2293736

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3- or 4-yl, cyclohex-1-enyl, cyclohexyl, or it represents 1,2,3,6-tetrahydropyridin-4-yl or piperidin-4-yl that are optionally substituted with -C(O)CH3 or -C(O)OCH3 in position 1 at nitrogen atom (N); R2 represents lower alkyl, piperidin-1-yl substituted with hydroxy-group optionally, or it represents phenyl optionally substituted with -(CH2)n-N(R')-C(O)-(CH2)n-NR'2, -(CH2)n-halogen, lower alkyl or -(CH2)n-N(R')-(CH2)n-O-lower alkyl, or it represents morpholinyl or pyridinyl that is substituted optionally with halogen atom, -N(R')-(CH2)n-O-lower alkyl, lower alkyl, lower alkoxy-group, morpholinyl or -(CH)n-pyrrolidinyl; n = 0, 1 or 2; R' represents hydrogen atom or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicament possessing affinity to adenosine A2A-receptors and containing one or some compounds of the general formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds.

17 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 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 novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

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