Benzoylaminoheterocyclyl coumpounds as glucokinase (glk) activators

FIELD: chemistry.

SUBSTANCE: present invention refers to the compound 5-[3-[(2S)-1-(difluoromethoxy)-propane-2-yl]-oxy-5-[(5-methylpyrazin-2-yl)-carbamoyl]]phenoxy]-N,N-dimethyl-pyrazine-2-carboxamide. The invention also refers to a pharmaceutical composition, and also to application of the compound under cl.1.

EFFECT: making the new biologically active compounds showing GLK (glucokinase) activator activity.

5 cl, 6 ex, 2 tbl, 2 dwg

 

The present invention relates to a group benzylaminocarbonyl compounds useful in the treatment or prevention of diseases or conditions mediated glucokinase (GLK or GK), leading to a decrease in glucose threshold for insulin secretion. Additionally assume that the connection will be to reduce the level of glucose in the blood by increasing the absorption of glucose in the liver. Such compounds may be useful in the treatment of diabetes mellitus type 2 and obesity. The invention also relates to pharmaceutical compositions containing these compounds, and to methods of treatment of diseases mediated through GLK, using these compounds.

In β-cells of the pancreas and the cells of the liver parenchyma main transport of glucose through the cytoplasmic membrane is GLUT2. At physiological concentrations of glucose the rate at which GLUT2 transports glucose across the membrane, does not limit the overall rate of absorption of glucose by these cells. The absorption rate of glucose is limited by the rate of phosphorylation of glucose to glucose-6-phosphate (G6P), which is catalyzed by glucokinase (GLK) [1]. GLK has a high (6-10 mm) Km (the Michaelis constant) in relation to glucose and is not inhibited by physiological concentrations of G-6-P [1]. The GLK expression is restricted to certain tissues and cell types, in particular β-cells of the pancreas and liver cells (hepatocytes) [1]. In these cells the activity of GLK limits the rate of glucose utilization and thus controls the degree of induced glucose insulin secretion and glycogen synthesis in the liver. These processes are critical for the maintenance of glucose homeostasis throughout the body and both are broken in diabetes [2].

When one of the subtypes of diabetes, "diabetes Mature type young" second type (MODY-2), diabetes caused by mutations leading to loss of GLK [3, 4]. Hyperglycemia in patients suffering from MODY-2, occurs as a result of violations of glucose utilization in the pancreas and liver [5]. Violation of glucose utilization in the pancreas of patients suffering from MODY-2, leads to an increase in threshold caused by glucose insulin secretion. On the contrary, rare, causing activation of mutations GLK reduce the threshold, resulting in the family hyperinsulinemia [6, 6A, 7]. In addition to reduced activity of GLK found in diabetics suffering from MODY-2, the activity of hepatic glucokinase is also reduced in diabetic patients suffering from type 2 diabetes [8]. It is important that the total or selective for the liver GLK overexpression prevents or reverses the development of the diabetic phenotype in dietary and genetic models of the disease [9-12]. In addition, with the full treatment of diabetics, suffering from type 2 diabetes, fructose improves glucose tolerance by stimulating glucose utilization in the liver [13]. I believe that this action is mediated caused by fructose increased activity of GLK in the cytosol of hepatocytes using the mechanism described below [13].

The activity of hepatic GLK inhibited by Association with regulatory proteins GLK (GLKRP). Complex GLK/GLKRP stable binding of fructose-6-phosphate (F6P) GLKRP and destabilized by the replacement of the sugar phosphate to fructose-1-phosphate (F1P). F1P is formed by indirect fructokinase phosphorylation of dietary fructose. Therefore, the integrity of the complex GLK/GLKRP and the activity of hepatic GLK is regulated depending on food intake, because F6P prevails on stage after absorption, whereas F1P prevails in the state after a meal. In contrast to hepatocytes β-cells of the pancreas expresses GLK in the absence GLKRP. Thus, the GLK activity of β-cells is widely regulated by the availability of its substrate, which is a glucose. Small molecules can activate GLK directly or by destabilization of the complex GLK/GLKRP. Assume that the first class of compounds stimulates glucose utilization in the liver and pancreas, while the latter acts selectively in pecan is. Nevertheless suggest that compounds with any of the profiles, therapeutically useful in the treatment of diabetes mellitus type 2, as this disease is characterized by impaired glucose disposal in both tissues.

GLK, GLKRP and channel ToATPexpressed in neurons of the hypothalamus, an area of the brain that are important for the regulation of energy balance and control of food intake [14-18]. Demonstrated that these neurons Express arkticheskie and anorectics neuropeptides [15, 19, 20], and assume that they are sensitive to glucose neurons in the hypothalamus, which inhibited or excited by the changes of the concentrations of glucose in their environment[17, 19, 21, 22]. The ability of these neurons to sense changes in the levels of glucose is broken in many genetic and experimentally induced models of obesity [23-28]. Intracerebroventricularly (icv) infusion of glucose analogs representing competitive inhibitors, glucokinase, stimulates food intake hungry rats [29, 30]. Conversely, icv infusion of glucose suppresses food [31]. Thus, a small molecular activators GLK can reduce food consumption and growth of the mass of the body with centralized action on the GLK. Thus, the GLK activators can be used therapeutically when lechenia.patienta to diabetes eating disorders, including obesity. Hypothalamic actions are complementary or synergistic action of the same compounds existing in the liver and/or pancreas with normalization of glucose homeostasis, for the treatment of type 2 diabetes. Thus, the system GLK/GLKRP can be described as a potential target for "diazirine" (useful in diabetes and obesity.

GLK is also expressed in specific entero-endocrine cells, which is believed to control sensitive to glucose secretion ingreenwich peptides GIP (glucosidation insulinotropic polypeptide) and GLP-1 (like peptide-1), respectively K-cells and L-cells of the intestine (32, 33, 34). Thus, a small molecular activators GLK may have additional favorable action on insulin secretion, function, and survival of β-cells and the weight of the body due to stimulation of the secretion of GIP and GLP-1 these entero-endocrine cells.

In WO 00/58293 and WO 01/44216 (Roche) described a series benzylcarbamoyl compounds as glucokinase activators. The mechanism by which such compounds activate GLK, assessed by measuring the direct effect of such compounds in the analysis, in which the GLK activity is associated with the production of NADH (reduced form nicotinamide), which, in turn, change Aut optical (see details about the following in vitro assays). Compounds of the present invention can activate GLK directly or can aktivirovat GLK by inhibiting interaction GLKRP with the GLK.

Additional GLK activators described in WO 03/095438 (substituted phenylacetamide, Roche), WO 03/055482 (carboxamidine and sulfonamidnuyu derivatives, Novo Nordisk), WO 2004/002481 (arylcarboxylic derivatives, Novo Nordisk) and in WO 03/080585 (aminosilane benzylaminocarbonyl, Banyu).

In the international patent application authors present invention № WO 03/000267 described group benzylaminopurine carboxylic acids, which are activators of the enzyme glucokinase (GLK).

In the international patent application authors present invention № WO 03/015774 described compounds of the formula (A):

where R3represents phenyl or substituted heterocycle, non-substituted carboxylic acid pyridyl.

In the international patent application WO 2004/076420 (Banyu) described compounds, which in General are a subset of the compounds described in WO 03/015774, where, for example, R1represents a (substituted) alkilany ether and R2represents a (substituted) phenoxy.

The inventors have unexpectedly discovered a small group of compounds, a subgroup of compounds described in WO 03/015774, which has excellent performance in respect of the enzyme GLK and more favorable physical properties, including, for example, the greater the solubility, the greater penetrating power and/or less binding to plasma proteins. Accordingly, it can be expected that such compounds with the balance of these properties, will demonstrate higher levels of free drug in plasma and superior efficacy in vivo after administration of the oral dose that determine, for example, activity in tests of tolerance introduced to oral glucose (OGTT). Thus, it can be expected that this group of compounds will provide superior effects by oral administration of a smaller dose and that it is particularly suitable for use in the treatment or prevention of diseases or conditions mediated GLK. Compounds according to the invention may also have superior strength and/or favorable physical properties (as described above), and/or favorable toxicity profiles, and/or favorable metabolic profile compared with other GLK activators known in the art and described in WO 03/015774.

Thus, in accordance with the first aspect of the invention proposed compound of formula (I):

where R1selected from farmacocinetica, deformational and trifloromethyl;

R2 is a Deputy to the carbon atom of ring a and is selected from-C(O)NR4R5, -SO2NR4R5, -S(O)pR4and NO-2;

NO-1 is a 5 - or 6-membered attached to an atom of the heteroaryl ring containing the nitrogen atom in position 2 relative to the amide nitrogen atom is attached to this ring, and maybe 1 or 2 additional ring heteroatoms independently selected from O, N and S, where the ring may substituted on an available carbon atom or nitrogen atom ring, provided that it is thus not stereoselectivity, 1 or 2 substituents independently selected from R6;

NO-2 is a 4-, 5 - or 6-membered attached to an atom or N atom heterocyclyl ring containing 1, 2, 3 or 4 heteroatoms independently selected from O, N and S, where the group-CH2- may be replaced by a group-C(O)- and where the sulphur atom in the heterocyclic ring may possibly be oxidized to a group S(O) or S(O)2where this ring possibly substituted on an available carbon atom or nitrogen 1 or 2 substituents independently selected from R7;

R3is a Deputy to the carbon atom of ring a and is selected from halogeno;

R4selected from hydrogen, (1-4C)alkyl [substituted by 1 or 2 substituents, independently selected from NO 2, -OR5 , -SO2R5, (3-6C)cycloalkyl (possibly substituted by 1 group selected from R7and-C(O)NR5R5], (3-6C)cycloalkyl (possibly substituted by 1 group selected from R7and NO-2;

R5represents a hydrogen atom or (1-4C)alkyl;

R6independently selected from (1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkyl S(O)p(1-4C)alkyl, amino(1-4C)alkyl, (1-4C)alkylamino(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl and/or (R6as the substituent on carbon atom) halogeno;

R7selected from (1-4C)alkyl groups,- C(O)(1-4C)alkyl, -C(O)NR4R5, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, -S(O)pR5and/or (R7as the substituent on carbon atom) hydroxy and (1-4C)alkoxy;

ring a represents a 5 - or 6-membered heteroaryl ring containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, where the ring may optionally substituted on an available nitrogen atom (provided that it is thus not stereoselectivity) Deputy selected from R8;

R8selected from (1-4C)alkyl, (3-6C) cycloalkyl, hydroxy(1-4C)alkyl, (1-4C) alkoxy (1-4C) alkyl, group-C(O)(1-4C) alkyl, benzyl and (1-4C)alkylsulfonyl;

p is (independently in each case) 0, 1 or 2;

n is 0, 1 or 2;

or its salt.

It is clear that when R4depict is to place a (1-4C)alkyl, substituted-C(O)NR5R5each R5independently selected from hydrogen and (1-4C)alkyl, and thus this definition of R4includes (but not limited to) (1-4C)alkyl, substituted-CONH2, -CONHMe, -CONMe2or-CONMeEt.

It is clear that when the compound of formula (I) contains more than one ring NO-2, they may be the same or different.

It is clear that when the compound of formula (I) contains more than one group R4they may be the same or different.

It is clear that when the compound of formula (I) contains more than one group R5they may be the same or different.

It is clear that when the compound of formula (I) contains more than one group R3they may be the same or different.

A similar rule applies to all other groups and substituents of the compounds of formula (I)as defined previously.

The compounds of formula (I) can form salts that are in the scope of the invention. Pharmaceutically acceptable salts are preferred, although other salts may be useful, for example, when selecting or clearing the connection.

In another aspect the invention relates to compounds of formula (I), as defined previously, or to pharmaceutically acceptable salts.

In another aspect the invention relates to compounds of formula (I), as defined previously, or its prodrug. Under adamie examples of prodrugs of the compounds of formula (I) are hydrolyzable in vivo esters of compounds of formula (I). Thus, in another aspect the invention relates to compounds of formula (I), as defined previously, or hydrolyzable in vivo complex ether.

In this description, the term "alkyl" includes alkyl groups of straight and branched chain. However references to individual alkyl groups such as "propyl"are specific only for remotemachine option and references to individual alkyl groups branched chain, such as tert-butyl, are specific only for option branched chain. For example(1-4C)alkyl" includes methyl, ethyl, propyl, isopropyl and tert-butyl. The same rule applies to other General terms.

In order to avoid uncertainty, reference group NO-1, containing the nitrogen atom in position 2 belongs to the position 2 relative to the amide nitrogen atom is attached to this group. For example, the definition of formula (I) encompasses (but is not limited to) the following structures:

Suitable examples NO 1 as a 5 - or 6-membered ring attached With a heteroaryl ring, as defined previously, include thiazolyl, isothiazolin, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxides is a Lil and triazolyl.

It is clear that NO-2 may represent a saturated or partially or fully unsaturated ring.

Suitable examples of NO-2 include azetidine, furyl, thienyl, thiazolyl, isothiazolin, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, morpholino, morpholinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, pyrrolidinyl, pyrrolidinyl, 2.5-dioxopyrimidine, 1,1-dioxotetrahydrofuran, 2-Oxymetazoline, 2,4-dioxoimidazolidin, 2-oxo-1,3,4-(4-triazolyl), 2-oxazolidinone, 2-oxitetraciclina, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiazolidine, 1,3-DIOXOLANYL, 1,2,4-triazolyl, 1,2,3-triazolyl, pyranyl and 4-pyridinyl.

It is clear that NO-2 can be attached by any suitable available atom or N, thus, for example, NO-2 as "imidazolyl" includes 1-, 2-, 4 - and 5-imidazolyl.

Suitable examples of the ring As defined earlier, include thienyl, furyl, thiazolyl, isothiazolin, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl. Additional suitable examples of ring a include aromatic heterocycles, where the nitrogen atom or sulfur ring oxidized, but aromaticity is retained, for example pyridine N-oxide. Others on the walking examples of ring a include thiazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl.

It is clear that above with the appropriate values for NO-1, NO-2 and rings And may be substituted as defined previously.

It is clear that when determining heterocyclyl group NO-1, NO-2 and rings And covers heteroaryl or heterocyclyl ring which may be substituted on the nitrogen atom, such substitution may not result in a charged stereoselectivity nitrogen atoms or unstable structures (such as the connection of the N-th halogeno). It is clear that the definition of NO-1, NO-2 and ring And, as suggested, does not include any of the links O-O, O-S or S-S. it is Clear that the definition of NO-1, NO-2 and rings And do not include unstable structures.

Examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl; examples of (1-4C)alkoxy include methoxy, ethoxy, propoxy, isopropoxy and tert-butoxy; examples of (3-6C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of halogen include fluorescent, chloro, bromo and iodide; examples of hydroxy(1-4C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl and 4-hydroxybutyl; examples of (1-4C)alkoxy (1-4C) alkyl include methoxymethyl, ethoxymethyl, tert-butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, methoxypropyl, 2-methoxyp is alil and methoxybutyl; examples of group (1-4C)S(O)p(1-4C)alkyl include methylsulfonylmethyl, ethylsulfinyl, ethylsulfonyl, methylsulfinylpropyl, methylsulfinylbutyl, methylsulfonylmethyl, ethylsulfonyl, ethylsulfonyl, methylsulfinylpropyl, methylsulfinylbutyl, methylthiomethyl, ethylthiomethyl, ethylthioethyl, metaltipped and methylthiomethyl; examples of groups of amino(1-4C)alkyl include aminomethyl, aminoethyl, 2-aminopropyl, 3-aminopropyl, 1-linosopril and 4-aminobutyl; examples of (1-4C)alkylamino(1-4C)alkyl include (N-methyl)aminomethyl, (N-ethyl)aminomethyl, 1-((N-methyl)amino)ethyl, 2-((N-methyl)amino)ethyl, (N-ethyl)aminoethyl, (N-methyl)aminopropyl, and 4-((N-methyl)amino)butyl, examples of the group di(1-4C)alkylamino(1-4C)alkyl include dimethylaminomethyl, methyl(ethyl)aminomethyl, methyl(ethyl)aminoethyl, (N,N-diethyl)aminoethyl, (N,N-dimethyl)aminopropyl and (N,N-dimethyl)aminobutyl; examples of (1-4C)alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino and tert-butylamino; examples of the group di(1-4C)alkylamino include dimethylamino, methyl(ethyl)amino, diethylamino, dipropylamino, diisopropylamino, dibutylamino; examples of the group-C(O)(1-4C) alkyl include methylcarbamyl, ethylcarboxyl, propylmalonic and tert-butylcarbamoyl; examples of (1-4C) alkylsulfonyl include methylsulphonyl, ethylsulfonyl, isopropylphenyl and tert-BU is ylsulphonyl.

It is clear that the extent to which some of the compounds of formula (I)defined above may exist in optically active or racemic forms due to one or more than one asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form that has the property to stimulate GLK directly or to inhibit the interaction GLK/GLKRP. Synthesis of optically active forms can be carried out using standard methods of organic chemistry well known in the field of technology, for example by synthesis from optically active starting compounds or by separation of the racemic form. In addition, it is clear that some compounds may exist in tautomeric forms, and that the invention also applies to any and all tautomeric forms of the compounds according to the invention, which can activate GLK.

In addition, it is clear that some of the compounds of formula (I) and their salts may exist in solvated, and resolutiony forms, such as, for example, hydrated forms. It is clear that the invention encompasses all such solvated forms that activates GLK.

In one of the embodiments of the proposed invention the compounds of formula (I), in an alternative embodiment of the proposed pharmaceutically acceptable salts of the compounds is of the formula (I), in yet another alternative embodiment of the proposed hydrolyzable in vivo esters of compounds of formula (I), and in yet another alternative embodiment of the proposed pharmaceutically acceptable salt hydrolyzable in vivo esters of compounds of formula (I).

Preferred values of each variable group are the following. These values can be used, when appropriate, with any of the values, definitions, claims, aspects or embodiments defined earlier or later. In particular, each may be used as an individual limitation of the broadest definition of formula (I). In addition, each of the following values can be used in combination with one or more than one of the other following values to limit the broadest definition of formula (I).

(1) R1is pharmacokinetic or diplomatically.

(2) R1is pharmacokinetic, and the configuration is preferably represent (S), that is, a side chain represents:

(3) R1is diplomatically, and the configuration is preferably represent (S), that is, a side chain represents:

(4) R2represents-C(O)NR4R5 .

(5) R2represents-SO2NR4R5.

(6) R2represents-S(O)pR4.

(7) R2is a NOT-2.

(8) R2represents-C(O)NR4R5or-SO2NR4R5.

(9) R2located in the para-position relatively simple essential connection.

(10) n is 0 or 1.

(11) n is equal to 0.

(12) n is 1, R2located in the para-position relatively simple essential communication, R2is in ortho-position relatively simple essential connection.

(13) n is 1, R2located in the para-position relatively simple essential communication, R3is in the meta position relative to the simple essential connection.

(14) n is equal to 1.

(15) n is equal to 2.

(16) n is 2 and both R3represent halogeno.

(17) n is equal to 2, and each R3independently represents a fluorescent or chloro.

(18) n is 2, R2located in the para-position relatively simple essential communication, R3is in ortho-position relatively simple essential connection.

(19) n is 2, both R3represent halogeno, R2located in the para-position relatively simple essential communication, R3is in ortho-position relatively simple essential connection.

(20) n is 2, both R3represent halogeno, R2is vapor-deposited and relatively simple essential communication and one R 3is in ortho-position relatively simple essential communication and the other R3is in the meta position relative to the simple essential connection.

(21) R3represents chloro or fluorescent.

(22) R3is fluorescent.

(23) R3represents chloro.

(24) n is 2 and both R3are fluorescent.

(25) n is 2 and one R3is fluorescent and the other represents chloro.

(26) p is equal to 0.

(27) p is equal to 1.

(28) p is equal to 2.

(29) NO-1 is a 5-membered heteroaryl ring.

(30) NO-1 is a 6-membered heteroaryl ring.

(31) NO-1 is substituted by 1 or 2 substituents independently selected from R6.

(32) NO 1 replaced by 1 Deputy selected from R6.

(33) NO-1 is not substituted.

(34) NO-1 is selected from thiazolyl, isothiazoline, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.

(35) NO-1 is selected from thiazolyl, isothiazoline, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl.

(36) NO-1 is selected from pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl.

(37) NO-1 represents a possibly substituted pyrazolyl, for example pyrazolyl or N-methylpyrazole.

(38) NO-1 represents a pyridyl Il is pyrazinyl.

(39) NO-1 is pyrazinyl.

(40) NO-1 is selected from pyrazolyl, N-methylpyrazole and methylpyrazine (such as 5-methylpyrazine-2-yl).

(41) NO-1 is pyrazolyl (possibly substituted by ethyl, isopropyl or 1 or 2 methyl groups), thiazolyl (possibly replaced by stands), pyrazinyl (possibly replaced by stands), pyridyl (possibly replaced with fluorescent), isoxazolyl (possibly replaced by stands) and thiadiazolyl (possibly replaced by stands).

(42) NO-1 is pyrazolyl (possibly substituted by ethyl, isopropyl, deformation or 1 or 2 methyl groups), thiazolyl (possibly replaced by stands), pyrazinyl (possibly replaced by stands), pyridyl (possibly replaced with fluorescent), isoxazolyl (possibly replaced by stands) and thiadiazolyl (possibly replaced by stands).

(43) NO-1 is selected from pyrazinyl (possibly replaced by stands), pyrazolyl (possibly substituted on the carbon atom in the stands), methylthiazolyl (in particular, 1,2,4-thiadiazole-5-yl, especially 3-methyl-1,2,4-thiadiazole-5-yl), thiazolyl (possibly replaced by stands), pyridyl (possibly replaced with fluorescent) and isoxazolyl.

(44) R6selected from (1-4C)alkyl, halogeno, hydroxy(1-4C)alkyl, di(1-4C)alkylamino(1-4C)alkyl.

(45) R6selected from methyl, ethyl, chloro, fluorescent, hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl is, dimethylaminomethyl.

(46) R6selected from methyl, ethyl, chloro, fluorescent, hydroxymethyl and methoxymethyl.

(47) R6selected from methyl or ethyl.

(48) R6represents methyl.

(49) R6selected from (1-4C)alkyl and (1-4C)alkoxy(1-4C)alkyl.

(50) R6selected from methyl, ethyl, isopropyl and methoxymethyl.

(51) when there are 2 Deputy R6they both selected from methyl, ethyl, bromo, chloro, fluorescent; preferably both are methyl and at least one is available on the nitrogen atom.

(52) R4represents a hydrogen atom.

(53) R4represents (1-4C)alkyl [substituted by 1 or 2 substituents, independently selected from NO 2, -OR5, -SO2R5, (3-6C)cycloalkyl (possibly substituted by 1 group selected from R7and-C(O)NR5R5].

(54) R4represents (1-4C)alkyl [substituted by 1 Deputy selected from NO 2, -OR5, -SO2R5, (3-6C) cycloalkyl and-C(O)NR5R5].

(55) R4represents (1-4C)alkyl.

(56)R4represents (1-4C)alkyl, substituted-OR5.

(57) R4represents (1-4C)alkyl, substituted NO-2.

(58) R4represents a (3-6C)cycloalkyl, in particular cyclopropyl or cyclobutyl.

(59) R4represents a (3-6C)cycloalkyl substituted group is, selected from R7.

(60) R4represents a (3-6C)cycloalkyl substituted by a group selected from-OR5and (1-4C)alkyl.

(61) R4selected from (1-4C)alkyl and (3-6C)cycloalkyl.

(62) R4selected from methyl, ethyl, cyclopropyl and cyclobutyl.

(63) R4is a NOT-2.

(64) R4selected from hydrogen, (1-4C)alkyl and (1-4C)alkyl, substituted-OR5.

(65) NO-2 is not substituted.

(66) NO-2 substituted by 1 or 2 substituents, independently selected from (1-4C)alkyl, hydroxy and (1-4C)alkoxy.

(67) NO-2 is a fully saturated ring system.

(68) NO-2 is a fully unsaturated ring system.

(69) NO-2 is selected from azetidine, morpholine, morpholine, piperidine, piperazinil, 3-oxopiperidine, thiomorpholine, pyrrolidine, pyrrolidone, 2,5-dioxopyrimidine, 1,1-dioxotetrahydrofuran, 2-oxazolidinone, 2-oxitetraciclina, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxothiazolidine, 1,3-DIOXOLANYL, 2-Oxymetazoline, 2,4-dioxoimidazolidin, pyranyl and 4-pyridinyl.

(70) NO-2 is selected from azetidine, morpholine, morpholine, piperidine, piperazinil, pyrrolidinyl, thiomorpholine, tetrahydrofuranyl and tetrahydropyranyl.

(71) NO-2 selected from Furie, teinila, thiazolyl, isothiazoline, thiadiazolyl, pyridyl, Piras the Nile, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, 1,2,4-triazolyl and 1,2,3-triazolyl.

(72) NO-2 selected from Furie, teinila, thiazolyl, isothiazoline, thiadiazolyl, pyridyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinil, 3-oxopiperidine, pyrrolidinyl, pyrrolidinyl, 2-oxazolidinone, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxotetrahydrofuran and 2-Oxymetazoline.

(73) NO-2 is selected from morpholino, furil, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinil, 3-oxopiperidine, pyrrolidinyl, 2-pyrrolidinyl, 2-oxazolidinone, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxotetrahydrofuran and 2-Oxymetazoline.

(74) NO-2 is selected from morpholino, furil, imidazolyl, isoxazolyl, oxadiazolyl, piperidinyl, piperazinil, 3-oxopiperidine, pyrrolidinyl, 2-pyrrolidinyl, tetrahydropyranyl, 1,1-dioxotetrahydrofuran and 2-Oxymetazoline.

(75) NO-2 is oxadiazolyl or pyrazolyl.

(76) R5represents hydrogen.

(77) R5is a (1-4)alkyl, preferably methyl.

(78) R3represents hydrogen or methyl.

(79) R7is a Deputy for the carbon atom and select the from hydroxy, (1-4C)alkoxy, (1-4C)alkyl groups,- C(O)(1-4C)alkyl, -C(O)NR4R5, (1-4C)alkoxy(1-4C)alkyl and hydroxy(1-4C)alkyl.

(80) R7is a Deputy for the carbon atom and is selected from hydroxy, (1-4C)alkoxy, (1-4C)alkyl groups,- C(O)(1-4C)alkyl, -C(O)NR4R5and hydroxy(1-4C)alkyl.

(81) R7is a Deputy for the carbon atom and is selected from hydroxy, methoxy, -Come, -CONH2, -CONHMe, -CONMe2and hydroxymethyl.

(82) R7is a Deputy for the carbon atom and is selected from (1-4C)alkyl, hydroxy and (1-4C)alkoxy.

(83) R7is a Deputy for the carbon atom and selected from methyl, ethyl, methoxy and hydroxy.

(84) R7is a Deputy on the nitrogen atom and is selected from (1-4C)alkyl groups,- C(O)(1-4C)alkyl, -C(O)NR4R5, (1-4C)alkoxy(1-4C)alkyl and hydroxy(1-4C)alkyl.

(85) R7is a Deputy on the nitrogen atom and is selected from (1-4C)alkyl, hydroxy and (1-4C)alkoxy.

(86) R7represents methyl.

(87) R8selected from methyl, hydroxy, methoxy, -CONH2, -CONHMe, -CONMe2, hydroxymethyl, hydroxyethyl, -NHMe and-NMe2.

(88) R8selected from methyl, -CONH2, hydroxyethyl and hydroxy.

(89) R8selected from (1-4C)alkyl and (1-4C)alkoxy.

(90) R8selected from methyl, methoxy, isopropoxy.

(91) R8represents ethyl.

(92) R9selected from methyl, hydroxy, methoxy, -CONH2, -CONHMe, -CONMe2, hydroxymethyl, hydroxyethyl, -NHMe and-NMe2.

(93) R9represents methyl.

(94) NO-2 is a 5-membered ring.

(95) NO-2 is a 6-membered ring.

(96) NO-2 is selected from tanila, furil, thiazolyl, isothiazoline, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl and oxadiazolyl.

(97) NO-2 is selected from tanila, furil, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl and oxadiazolyl.

(98) NO-2 is selected from pyridyl, pyrazinyl, thiazolyl and tanila.

(99) NO-2 is selected from pyridyl, pyrazinyl and thiazolyl.

(101) NO-2 is selected from pyridyl, pyrazinyl, pyridazinyl and thiazolyl.

(102) NO-2 is selected from pyridyl and pyrazinyl.

(103) NO-2 is pyrazinyl.

(104) NO-2 is not substituted on the nitrogen atom.

(105) NO-2 has one Deputy on the nitrogen atom, selected from R8.

(106) R8represents (1-4C)alkyl.

(107) R8represents a (3-6C)cycloalkyl.

(108) R8represents hydroxy(1-4C)alkyl or (1-4C)alkoxy(1-4C)alkyl.

(109) R8represents-C(O)(1-4C)alkyl.

(110) R8represents benzyl.

(111) R8represents (1-4C)al is ylsulphonyl.

(112) R8represents (1-4C)alkyl or benzyl.

In accordance with another embodiment of the invention, the following preferred group of compounds according to the invention.

In one aspect of the invention proposed compound of formula (I) or its salt, where

R1selected from farmacocinetica and deformational (in particular, deformational);

R2selected from-C(O)NR4R5, -SO2NR4R5and-SOpR4;

ring a is a pyridyl or pyrazinyl;

R3selected from fluorescent and chloro;

n is 0 or 1;

NO-1 is selected from pyrazolyl (possibly substituted by ethyl, isopropyl, deformation or 1 or 2 metelli), thiazolyl (possibly replaced by stands), pyrazinyl (possibly replaced by stands), pyridyl (possibly replaced with fluorescent), isoxazolyl (possibly replaced by stands) and thiadiazolyl (possibly replaced by stands);

R4represents hydrogen or (1-4C)alkyl;

R3represents hydrogen or (1-4C)alkyl;

p is 0,1 or 2, in particular 2.

In another aspect of isbreene proposed compound of formula (I) or its salt, where

R1selected from farmacocinetica and deformational (in particular, deformational);

R2selected from-C(O)NR4R5and-SOpR4;

the ring And made the focus of a pyridyl or pyrazinyl;

R3selected from fluorescent and chloro;

n is 0 or 1;

NO-1 is selected from pyrazolyl (possibly replaced by stands) and pyrazinyl (possibly replaced by stands);

R4represents (1-4C)alkyl;

R5represents hydrogen or (1-4C)alkyl;

p is 0,1 or 2, in particular 2.

In another aspect of isbreene proposed compound of formula (I) or its salt, where

R1selected from farmacocinetica and deformational (in particular, deformational);

R2selected from-C(O)NR4R5and-SOpR4;

ring a is a pyridyl or pyrazinyl;

R3selected from fluorescent and chloro;

n is 0 or 1;

NO-1 is selected from pyrazolyl (possibly replaced by stands) and pyrazinyl (possibly replaced by stands);

R4represents methyl;

R5represents hydrogen or methyl;

p is 0,1 or 2, in particular 2.

Additional preferred compounds according to the invention represent each of the compounds of Examples, each of which represents another independent aspect of the invention. In other aspects the present invention also includes any two or more than two compounds of Examples.

Specific compounds according to the invention include any one or more of:

3-[(2S)-1-(deformedarse)propan-2-yl]oxy-N-5-methylpyrazine-2-yl)-5-(6-methylsulfonylmethyl-3-yl)oxybenzoic;

5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide;

5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-(1H-pyrazole-3-elkarra-mail)phenoxy]-N,N-dimethylpyrazine-2-carboxamide;

3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oxy-N-(1H-pyrazole-3-yl)benzamide;

5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(1-methylpyrazole-3-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide;

3-[(2S)-1-(deformedarse)propan-2-yl]oxy-N-(1-methylpyrazole-3-yl)-5-(6-methylsulfonylmethyl-3-yl)oxybenzoic:

or its salt.

Compounds according to the invention can be introduced in the form of prodrugs. The prodrug is bioresistant or pharmaceutically acceptable compound, destroyed in the body to form compounds of the invention (such as ester or amide compounds according to the invention, in particular hydrolyzable in vivo ester). Various forms of prodrugs are known in the art. Examples of such derivatives, prodrugs, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. WIdder et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen;

in) H.Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H.Bundgaard p.113-191 (1991);

g) H.Bundgaard, Advanced Drug Delivery Reviews, 8,1-38 (1992);

d) H.Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N.Kakeya e al., Chem Pharm Bull, 32, 692 (1984).

The content of the above-cited documents are incorporated herein by reference.

Examples of prodrugs are the following. Hydrolyzable in vivo ester compounds according to the invention containing a carboxy or hydroxy group is, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal with obtaining the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include C1-C6alkoxymethyl esters, for example methoxymethyl, C1-C6alkanolamine esters, for example pivaloyloxymethyl, phthalidyl esters, With3-C8cycloalkylcarbonyl1-C6alkyl esters, for example 1-cyclohexanecarbonitrile; 1,3-dioxolan-2-animately esters, for example 5-methyl-1,3-dioxolan-2-animationy; and (C1-C6alkoxycarbonylmethyl esters.

Hydrology in vivo ester compounds according to the invention containing a hydroxy-group includes inorganic esters such as phosphate esters (including phosphoramidite cyclic esters) and α-aryloxyalkyl ethers and related compounds which as a result of hydrolysis in vivo of ester are split with the formation of the parent(s), hydroxyl(s) g is PI(groups). Examples of α-aryloxyalkyl ethers include acetoxymethyl and 2,2-dimethylphenylacetate. The choice of groups, forming hydrolyzable in vivo ester for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (obtaining alkalicarbonate esters), dialkylamino andN(dialkylaminomethyl)-N-allylcarbamate (obtaining carbamates), dialkylaminoalkyl and carboxyethyl.

Under certain conditions, the compounds of formula (I) can form pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salt of the compounds according to the invention is, for example, salt accession acid compounds according to the invention which is sufficiently basic, for example salt accession acid, for example, from inorganic or organic acid, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid. It is clear that salt accession acid can be formed from any sufficiently basic group, which, for example, can be in NO 1, or may, for example, represent a substituent R2. Additionally, a suitable pharmaceutically acceptable salt of the compounds according to the invention which is sufficiently acidic is an alkali salt is about metal, for example, sodium salt or potassium salt, alkaline earth metal, for example a salt of calcium or magnesium, ammonium salt or a salt with an organic base, which provides a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

Another aspect of the invention is a pharmaceutical composition containing defined above, the compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically-acceptable diluent or carrier.

In accordance with another aspect of the invention proposed defined above, the compound of formula (I) or its pharmaceutically acceptable salt for use as a medicine.

In accordance with another aspect of the invention proposed defined above, the compound of formula (I) or its pharmaceutically acceptable salt for use as a drug for the treatment of a disease mediated through GLK, in particular type 2 diabetes.

In addition, in accordance with the invention, the proposed use of the compounds of Formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment of a disease mediated through GLK, in particular type 2 diabetes.

The connection appropriately preparation, is in the form of a pharmaceutical composition for use in this way.

In accordance with another aspect of the present invention, a method for treating diseases mediated through GLK, in particular diabetes, by introducing an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt to a mammal in need of such treatment.

In accordance with another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts, for the treatment of a disease mediated through GLK.

In accordance with another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts for the treatment of type 2 diabetes.

Specific diseases that can be treated using compounds or compositions according to the invention include reducing the level of blood glucose in diabetes type 2 without serious risk of hypoglycemia (and potentially for the treatment of type 1), dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance.

As discussed above, thus, the system GLK/GLKRP can be described as a potential target for "diazirine" (favorably diabetes and obesity). Thus, in accordance with another aspect of the invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable the Oh salt in the manufacture of a medicinal product for use in the combined treatment or prevention, in particular the treatment of diabetes and obesity.

In accordance with another aspect of the invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salts in the manufacture of a medicinal product for use in the treatment or prevention of obesity.

In accordance with another aspect of the invention, a method of combined treatment of obesity and diabetes by introducing an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt to a mammal in need of such treatment.

In accordance with another aspect of the invention proposed defined above, the compound of formula (I) or its pharmaceutically acceptable salt for use as a drug for treatment or prevention, in particular treatment of obesity.

In accordance with another aspect of the invention, a method for treating obesity by introducing an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt to a mammal in need of such treatment.

Compounds according to the invention can be particularly suitable for use as a pharmaceutical, for example, due to favorable physical and/or pharmacokinetic properties and/or toxicity profile.

The composition of the invention can be in forms which, suitable for oral administration (for example, in the form of tablets, pellets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, in the form of fine powder or a liquid aerosol), for administration by insufflation (for example, in the form of a fine powder) or for parenteral administration (for example, in the form of a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular dose or in the form of a suppository for rectal dose). Preferred dosage forms suitable for oral administration.

The composition of the invention can be prepared using conventional methods using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more than one dye, sweetener, corrigent and/or preservative.

Suitable pharmaceutically acceptable excipients for the preparation of tablets include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate is or calcium carbonate, granulating agents and disintegrating agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc: preservatives, such as ethyl - or propyl-para-hydroxybenzoate, and antioxidants, such as ascorbic acid. Preparations in the form of tablets can be uncoated or coated to modify their raspadaemosti and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability, and/or symptoms, in any case, using conventional covering agents and methods that are well known in the field of technology.

Compositions for oral administration can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions generally contain the active ingredient in the form of fine powder together with one or more than one suspendium agent such as carboxymethylcellulose sodium, methylcellulose, hypromellose, sodium alginate, p is livingparrillas, tragacanth gum and Arabic gum; dispersing agent or a lubricant, such as lecithin or condensation products of accelerated with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids, and anhydrides of exit, for example polyethylene sorbitan monooleate. Aqueous suspensions can also contain one or more than one preservative (such as ethyl - or propyl-para-hydroxybenzoate, antioxidants (such as ascorbic acid), colorants, corrigentov and/or sweeteners (such as sucrose, saccharin or aspartame).

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil (such as Ara is isovue oil, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Oily suspensions may also contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Can be added sweeteners, such as described above, and corrigentov to getting good for oral administration of the drug. These compositions can be conserved by adding an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of the aqueous slurry by adding water, as a rule, contain the active ingredient together with a dispersing agent or a humectant, suspenders agent and one or more than one preservative. Examples of suitable dispersing agents or humectants and suspendida agents mentioned above. There may be additional excipients, such as sweeteners, corrigentov and dyes.

The pharmaceutical compositions according to the invention can also be in the form of emulsions of oil in water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil such as liquid paraffin or a mixture. Suitable emulsifying agents may represent, for example, resins of natural origin Taiwan is born, such as the Arabian gum or tragacanth gum, phosphatides of natural origin, such as soybean lecithin, esters or partial esters derived from fatty acids and anhydrides of exit (for example, sorbitan monooleate) and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitol monooleate. The emulsion may also contain sweeteners, corrigentov and preservatives.

Syrups and elixirs can be prepared with a sweetener, such as glycerin, propylene glycol, sorbitol, aspartame or sucrose and can also contain reducing irritation agent, preservative, corrigent and/or dye.

Pharmaceutical compositions can also be in the form of a sterile injectable aqueous or oily suspension which can be prepared according to known methods using one or more than one suitable dispersing agent or a humectant and a suspending agent, as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of obychno the aerosol under pressure, designed for spraying the active ingredient in the form of an aerosol containing fine solid or liquid drops. Can be used conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons, and a spray device for convenience, is intended for spraying a measured amount of the active ingredient.

Further information on the preparation reader can find in Chapter 25.2 in volume 5 in Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The amount of active ingredient that is combined with one or more than one excipient obtaining a single dosage form varies depending on the object being treated and the particular route of administration. For example, a drug intended for oral administration to humans, as a rule, contains, for example, from 0.5 mg to 2 g of active agent, prepared with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 wt.% by weight of the entire composition. Standard dosage forms generally contain from about 1 mg to about 500 mg of the active ingredient. For more information on routes of administration and schemes of medicine the reader can find in Chapter 25.3 in volume 5 in Comprehensiv Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The magnitude of the doses of the compounds of formula (I) for therapeutic or preventive tasks, as a rule, varies in accordance with the nature and severity of the condition, age and sex of the animal or patient and the route of administration in accordance with well known principles of medicine.

When using the compounds of formula (I) for therapeutic or preventive tasks it normally administered so that a daily dose is in the range, for example from 0.5 mg to 75 mg per 1 kg of weight of a body, if necessary, it can be entered in fractional doses. As a rule, smaller doses administered during the use of the parenteral route. Thus, for example, for intravenous administration, as a rule, use a dose in the range, for example from 0.5 mg to 30 mg 1 kg of body weight. Similarly, for administration by inhalation using a dose in the range, for example from 0.5 mg to 25 mg 1 kg of body weight. However, preferably oral administration.

This increased activity of GLK can be applied as a stand-alone therapy or in combination with one or more than one substance and/or method of treatment for the condition that is being treated. Such joint treatment may be accomplished by simultaneous, sequential or separate introduction the Oia individual components of the treatment. Simultaneous treatment may be performed via a single pill or in a separate tablets. For example, in the treatment of diabetes mellitus chemotherapy may include the following main categories of treatment:

1) insulin and insulin analogues;

2) substances that increase insulin secretion, including sulfonylureas (eg, glyburide, glipizide), regulators of glucose levels after a meal (for example, Repaglinide, nateglinide);

3) agents that improve the action of incretin (for example, inhibitors dipeptidylpeptidase IV and agonists of the GLP-1);

4) agents that increase insulin sensitivity, including PPAR agonists (receptors activation of peroxisome proliferation)gamma (for example pioglitazone and rosiglitazone), and agents with combined PPAR-alpha and-gamma activity;

5) agents that modulate the balance of glucose in the liver (e.g., Metformin, inhibitors of fructose-1,6-bisphosphatase, glycogen phosphorylase inhibitors, inhibitors of kinases glikogensintetazy);

6) agents designed to reduce the absorption of glucose from the intestine (for example acarbose);

7) agents that prevent the reabsorption of glucose by the kidney (SGLT inhibitors (sodium-dependent glucose carrier));

8) agents designed to treat the complications of prolonged hyperglycaemia (for example, inhibitors of the aldose reductase);

9) the agents shall Rotel obesity (for example, sibutramine and orlistat);

10) agents against dyslipidemia, such as inhibitors of HMG (3-hydroxy-3-methyl-glutaryl)-COA reductase inhibitor (e.g., statins); PPARα agonists (fibrates, eg gemfibrozil); substances that increase the excretion of bile acids (cholestyramine); inhibitors of cholesterol absorption (vegetable stanely, synthetic inhibitors); inhibitors of absorption of bile acids (IBATi) and nicotinic acid and analogues (Niacin and drugs with a slow release);

11) antihypertensive agents such as β-blockers (eg atenolol, inderal); ACE inhibitors (acetylcholinesterase) (eg, lisinopril); calcium antagonists (e.g. nifedipine); receptor antagonists angiotensin (eg candesartan), α antagonists and diuretic agents (eg, furosemide, benzothiazyl);

12) modulators of hemostasis, such as antithrombotic agents, activators of fibrinolysis and protivotrematodoznye agents; thrombin antagonists; inhibitors of factor XA; inhibitors of factor VIIa); protivotrematodoznye agents (e.g. aspirin, clopidogrel); anticoagulants (heparin and low molecular weight analogues, hirudin) and warfarin;

13) agents providing antagonistic activity against glucagon, and

14) anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (e.g. the measures aspirin) and steroidal anti-inflammatory drugs (such as cortisone).

In accordance with another aspect of the present invention proposed individual compounds obtained as the final products of the Examples set forth below, and their salts.

The connection according to the invention or its salt can be obtained using any of the methods, known as applicable for obtaining such compounds or structurally related compounds. Functional groups can be protected, and the protection can be removed using conventional methods. Examples of protective groups, such as the protective group of amino and carboxylic acids (as well as tools for education and possible removal of the protection) see T.W.Greene and P.G.M. Wins, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New York, 1991.

Methods of synthesis of compounds of formula (I) proposed as another aspect of the invention. Thus, in accordance with another aspect of the invention, a method for obtaining compounds of formula (I), including the method (a)-(e) (where, if not otherwise specified, variables are as defined previously for compounds of formula (I):

(a) the interaction of the acid of formula (III) or activated derivative with the compound of the formula (IV), where R1is as defined for formula (I), or preds the factory worker;

or (b) the interaction of the compounds of formula (V) with the compound of the formula (VI)

where X1represents a leaving group, and X2represents a hydroxyl group or X1represents a hydroxyl group, and X2represents a leaving group, and where R1is as defined for formula (I), or a predecessor;

method (b) can also be carried out with the use of ester intermediate of formula (VII)where R1represents a protective group described below, followed by hydrolysis of ester and amide formation by methods described elsewhere and well known to specialists in this field of technology;

or (C) the interaction of the compounds of formula (VIII) with the compound of the formula (IX)

where X3represents a leaving group or an ORGANOMETALLIC reagent and X4represents a hydroxyl group or X3represents a hydroxyl group and X4represents a leaving group or an ORGANOMETALLIC Rea is UNT, and where R1is as defined for formula (I), or a predecessor;

method (C) can also be carried out with the use of ester intermediate of formula (X) followed by hydrolysis of ester and amide formation by methods described elsewhere and well known to specialists in this field of technology;

or

(d) the interaction of the compounds of formula (XI) with the compound of the formula (XII)

where X5represents a leaving group, and where R1is as defined for formula (I), or a predecessor; or

e) the interaction of the compounds of formula (XIII)

where R2ais a predecessor to R2that is a-CONR4R5or-SO2R4R5such as carboxylic acid, ester or anhydride (for R2=-CONR4R3), or equivalents of sulfonic acid (R2representing-SO2NR4R5); with an amine of the formula-NR4R5;

and then, if necessary:

1) the conversion of compounds of formula (I) into another compound of formula (I);

2) conversion of the precursor to the R 1in R1;

3) remove any protective groups and/or

4) formation of its salts.

Suitable leaving groups X1-X3for methods (b)-(d) are any leaving group known in the field of machinery for these types of interactions, such as halogeno, alkoxy, tripterocalyx, methansulfonate or steam-toluensulfonate, or group (such as hydroxyl group), which can be converted into a leaving group (such as oxydiphenylene group) in situ.

Suitable precursors for R1include a hydroxyl group or a protected hydroxyl group, such as any suitably protected hydroxyl group, known in the technical field, for example ethers such as methyl ether, or Silovye esters, such as-OSi[(1-4C)alkyl]3(where each of (1-4C)alkyl group is independently selected from methyl, ethyl, propyl, isopropyl and tert-butyl). Examples of such trialkylsilyl groups are trimethylsilyl, triethylsilyl, triisopropylsilyl and tert-butyldimethylsilyl. Additional suitable silyl ethers are ethers containing phenyl and substituted phenyl groups such as-Si(PhMe2and-Si(ToIMe2) (where ToI = methylbenzol). More appropriate values protective groups for hydrox the following. Himself R1can then be obtained by removal of the protective group for hydroxy, if it is present, and then by reacting with, for example, 2-(persulfonic)DIPEROXY acid in the presence of copper iodide (I) to obtain the compound where R1is diplomatically. This interaction is illustrated in figure 1. Other values of R1can be obtained by analogy or by using methods that are well known in the art see, for example, Bull. Chem. Soc. Japan, 73 (2000), 471-484, 471-484, international patent application WO 2002/050003 and Bioorganic and Medicinal Chemistry Letters, (2001), 11, 407.

Compounds of formulas (III)-(XII) are commercially available or known in the art or can be obtained using methods known in the technical field, such as presented in the accompanying Examples. For more information about how to obtain such compounds can be found in the publications of PCT applications of inventors WO 03/000267, WO 03/015774, WO 03/000262, WO 2004/076420, WO 2005/054200, WO 2005/054233, WO 2005/044801 and WO 2005/056530 and found in them the links. In General it is clear that any communication aryl-O or alkyl-O can be formed by nucleophilic substitution or by using catalyzed by metals ways, possibly in the presence of a suitable base.

The compounds of formula (XIII) can be obtained using such methods as presented in ways the Oh (a)-(d), and/or using the methods mentioned above for the compounds of formulas (III)-(XII).

Compounds of formula (III), (IX), (X), (XI) and (XIII) can be obtained by reacting the appropriate precursors to compounds of the formula (V) or their derivatives, depending on the nature of the group R1or its predecessor, for example, by nucleophilic substitution of the leaving group X1in the compound of formula (V). The compounds of formula (V), as a rule, are commercially available or can be obtained by simple interconversion of functional groups from commercially available compounds, or by means described in the literature methods. When the compound of the formula (V) contains the predecessor of R1the group R1can be converted into a compound of formula (III), (IX), (X), (XI) or (XIII) appropriate use of such interactions as well as interactions, illustrated in Schemes 1 and 2 below. Illustrative examples depicted in Schemes 1 and 2 below, and/or in the accompanying examples.

where PG is a protective group and R2, R3, A, n and NO-1 are as defined for formula (I).

where R2, R3And n are as defined for formula (I), R1and R2represents a suitable protective group, for example (1-4C)alkyl, the X 3represents a leaving group, for example chloro. Appropriate interaction terms for Stages (i)to(v) in Scheme 2 are as follows.

Stage (i) involves reacting a compound of formula (XIV) with the compound of the formula (VIII), for example 5-chloro-N,N-dimethylpyrazine-2-carboxamide, in the presence of a suitable base such as cesium carbonate, in a suitable solvent, for example DMSO, at a suitable temperature, for example from 0 to 60°C., more suitably at about 50°C.

Stage (ii) involves reacting a compound of formula (VII) with an R-alcohol, for example (2R)-1-[(2-methylpropan-2-yl)oxy]propan-2-I, in the presence of a suitable phosphine such as triphenylphosphine, and azodicarboxylate, such as diethylazodicarboxylate, in a suitable solvent, for example THF, and at a suitable temperature, for example from 0 to 10°C., more suitably about 0°C.

Stage (iii) involves the heating of a solution of the compounds of formula (XV) in a suitable acid, for example formic acid, at a suitable temperature, for example from 0 to 50 to 100°C., preferably at approximately 90°C.

Stage (iv) involves reacting a compound of formula (XVI) with 2,2-debtor-2-persulfonic acid in the presence of a suitable catalyst, for example copper iodide (I), in a suitable solvent, for example acetonitrile, and if appropriate the temperature, for example from 0 to 100°C., more preferably at about 55°C.

Stage (v) involves reacting the compounds of formula (XVIIa) with a suitable base, such as NaOH, in a suitable solvent, such as NMP and water, and at a suitable temperature, for example from 0 to 25°C., preferably at approximately 0°C.

Alternative compounds of formula (IIIa), where R1is deformational can be obtained in accordance with Scheme 3, as shown below.

where R2, R3And n are as defined for formula (I), R1and R2represents a suitable protective group, for example (1-4C)alkyl and TIPS, respectively, and X3represents a leaving group, for example chloro. Suitable reaction conditions for Steps (i)to(v) in Scheme 2 are as follows.

Stage (i) involves reacting a compound of formula (XVIII) with hydrogen in the presence of a suitable catalyst such as 10% palladium on activated carbon, and at a suitable temperature, for example from 0 to 25°C., more preferably at approximately 21°C.

Stage (ii) involves reacting the compounds of formula (XIX) with a compound of Formula (VIII), for example 5-chloro-N,N-dimethylpyrazine-2-carboxamide, in the presence of a suitable base, for example potassium carbonate, suitably the solvent, for example acetonitrile, and at a suitable temperature, for example from 0 to 200°C, more preferably approximately at the temperature of reflux distilled.

Stage (iii) involves reacting the compounds of formula (XV) with hydrogen fluoride in a suitable solvent, for example THF, and at a suitable temperature, for example from 0 to 25°C., more preferably at approximately 21°C.

Stage (iv) involves reacting a compound of formula (XVI) with 2,2-debtor-2-persulfonic acid in the presence of a suitable catalyst, for example copper iodide (I), in a suitable solvent, for example acetonitrile, and at a suitable temperature, for example from 0 to 100°C., more preferably at about 55°C.

Stage (v) involves reacting the compounds of formula (XVIIa) with a suitable base, such as LiOH, in a suitable solvent, such as THF and methanol, and at a suitable temperature, for example from 0 to 25°C., more preferably at approximately 21°C.

Examples of transformations of the compounds of formula (I) into another compound of Formula (I), is well known to specialists in this field of technology include interconversion of functional groups, such as hydrolysis, hydrogenation, hydrogenolysis, oxidation or repair, and/or other functionalization using standard interactions, such as amide or metal catalyzed the combination, or nucleophilic substitution. An example would be the removal of the substituent R3= chloro, for example, by reacting with hydrogen at atmospheric or elevated pressure in a suitable solvent, such as THF/methanol or ethanol.

It is clear that the substituents R2, R3and/or R6can be introduced into the molecule in any convenient place in the sequence of synthesis or may be present in the original substances. The predecessor to one of these substituents can be present in the molecule in the implementation of the method in the stages (a)to(e) above, and then transformed into the desired Deputy at the final stage with the formation of the compounds of formula (I), followed, if necessary,

1) converting the compounds of formula (I) into another compound of formula (I);

2) transformation of a precursor of R1in R1;

3) removing any protective groups and/or

4) the formation of its salts.

Specific reaction conditions for the above interactions are the following: when R1represents a protective group, R1preferably represents (1-4C)alkyl, for example methyl or ethyl.

Method (a) reaction of a combination of amino groups with carboxylic acids with amide formation is well known in the art. For example,

(i) using the m appropriate response combinations, such as the reaction of the carbodiimide combinations carried out with EDAC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in the presence of dimethylaminopyridine (DMAP) in a suitable solvent, such as dichloromethane (DCM), chloroform, or dimethylformamide (DMF)at room temperature, or

(ii) through the interaction, in which the carboxyl group is activated before carboxylic acid by reaction with oxalylamino or 1-chloro-N,N,2-trimethyl-1-Propylamine in the presence of a suitable solvent, such as DCM or DMF. The acid chloride of the acid can then be subjected to interaction with the compound of the formula (IV) in the presence of a base such as triethylamine or pyridine, in a suitable solvent, such as chloroform or DCM, at a temperature from 0°C to 80°C.

Method (b) is a compound of formula (V) and (VI) can interact with each other in a suitable solvent, such as DMF or tetrahydrofuran (THF), with a base such as sodium hydride or tert-piperonyl potassium, at a temperature in the range from 0 to 200°C, possibly with the use of heating in a microwave oven or a catalyst based on a metal such as palladium (II)acetate, palladium on carbon, copper acetate (II) or copper iodide (I); alternatively, the compounds of formulas (V) and (VI) can interact with each other in a suitable process is the, such as THF or DCM, with a suitable phosphine such as triphenylphosphine, and azodicarboxylate, such as diethylazodicarboxylate; method (b) can also be performed using the predecessor of ester of the formula (VII), such as arylnitrenes or triptoreline derivative, followed by conversion to carboxylic acid and amide formation as previously described;

Method (s) - compound of formula (VIII) and (IX) can interact with each other in a suitable solvent, such as DMF or THF, with a base such as sodium hydride or tert-piperonyl potassium, at a temperature in the range from 0 to 200°C, possibly with the use of heating in a microwave oven or a catalyst based on a metal such as palladium (II)acetate, palladium on carbon, copper acetate (II), copper iodide (I) or bromotris(triphenylphosphine)copper (I); method (C) can also be performed using the predecessor of ester of the formula (X), such as arylnitrenes or triptoreline derivative, followed by conversion to carboxylic acid and amide formation as previously described;

Method (d) the interaction of the compounds of formula (XI) with the compound of the formula (XII) can be carried out in a polar solvent such as DMF, or non-polar solvent such as THF with a strong base such as a hydride in the rija or tert-piperonyl potassium, at a temperature of from 0 to 200°C, possibly with the use of heating in a microwave oven or a catalyst based on a metal such as palladium (II)acetate, palladium on carbon, copper acetate (II) or copper iodide (I);

Method (e) reaction of a combination of amino groups with carboxylic or sulfonic acids or acid derivatives with amide formation is well known in the field of technology and described above for the Method (a).

I believe that some of the intermediate compounds of Formula (III), (VI), (VII), (IX) and/or (XI) are novel and comprise an independent aspect of the invention.

I think that some of the intermediate compounds of Formula (III), (IX) and/or (XI), where R1is the same as here defined, are novel and comprise an independent aspect of the invention.

I think that some of the intermediate compounds of Formula (XIII) are novel and comprise an independent aspect of the invention.

In the process of obtaining it may be beneficial to use a protective group for the functional group in the molecule. The protective group may be removed by any convenient method, described in the literature or known to experts-chemists as appropriate to remove interest of the protective group, such as the methods chosen to carry out the removal of the protective group with minimal disruption to other group is in the molecule.

Specific examples of protective groups for convenience below, where "low" indicates that the group to which it is applied, preferably has 1-4 carbon atoms. It is clear that these examples are not exhaustive. When the following are specific examples of methods for removing protective groups, they likewise are not exhaustive. The use of protective groups and methods for removing protection, not specifically mentioned, is certainly in the scope of the invention.

The protective group for carboxy may be a residue forming an ester of an aliphatic or analiticheskogo alcohol or forming ester of silanol (specified alcohol or silanol combined with caffeine preferably contains 1-20 carbon atoms). Examples of protective groups for carboxy include remotemachine or having a branched chain (1-12C)alkyl groups (for example, isopropyl, tert-butyl)group, a lower alkoxy-lower alkyl (for example, methoxymethyl, ethoxymethyl, isobutoxide; group (the lower aliphatic acyloxy)-(lower alkyl) (for example, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl); group (lower alkoxycarbonyl)-(lower alkyl) (for example 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); group aryl-(lower alkyl) (for example para-methoxybenzyl, ortho-nitrobenzyl, para-nitrobenzyl, benched the silt and phthalidyl); group three(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl); group three(lower alkyl)silyl-(lower alkyl) (for example, trimethylsilylmethyl); and (2-6C)alkeneamine group (for example, allyl and vinylaryl).

The methods are particularly suitable for removal of carboxyl protective groups include, for example, hydrolysis, catalyzed by acids, metals or fermentate.

Examples of protective groups for hydroxy include methyl, tert-butyl, lower alkeneamine group (e.g. allyl); lower alcoholnye groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower altneratively group (for example, allyloxycarbonyl); group aryl-(lower alkoxycarbonyl) (for example, benzyloxycarbonyl, para-methoxybenzeneboronic, ortho-nitrobenzenesulfonyl, para-nitrobenzenesulfonyl); group three(lower alkyl/aryl)silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl); tetrahydropyran-2-Il; group aryl-(lower alkyl) (e.g., benzyl); and group Triaryl-(lower alkyl) (for example, triphenylmethyl).

Examples of protective groups for amino include formyl, kalkilya groups (e.g. benzyl and substituted benzyl, for example para-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl and triphenylmethyl); di-para-untilmately and furylmethyl groups is; lowest alkoxycarbonyl (for example, tert-butoxycarbonyl); lower alkenylbenzenes (for example, allyloxycarbonyl); group aryl-(lower alkoxycarbonyl) (for example, benzyloxycarbonyl, para-methoxybenzeneboronic, ortho-nitrobenzenesulfonyl, para-nitrobenzenesulfonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example, methylidene); benzylidene and substituted benzylidene group.

Methods appropriate for removal of the protective groups for hydroxy and amino include, for example, nucleophilic substitution, hydrolysis, catalyzed by acid, base, metal or enzyme, catalytic hydrogenolysis/hydrogenation or photolytic destruction of groups, such as ortho-nitrobenzenesulfonyl, or with fluoride ions for silyl groups. For example, methylamine protective groups for hydroxyl groups can be removed using trimethylsilylmethyl, tert-butylamine protective group for a hydroxyl group may be removed by hydrolysis, for example by use of hydrochloric acid in methanol.

Examples of protective groups for amide groups include Alcoceber (for example, benzyloxyethyl and substituted benzyloxyethyl); alkoxymethyl (for example, methoxymethyl and trimethylsilylethynyl); three(alkyl/aryl)silyl (e.g., trimethylsilyl, tert-butylimide silyl, tert-butyldiphenylsilyl); three(alkyl/aryl)similarilty (for example, tert-butyldimethylsilyloxy, tert-butyldiphenylchlorosilane); 4-alkoxyphenyl (e.g., a 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g., 2,4-acid); 4-alkoxybenzyl (for example, 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl) and ALK-1-enyl (for example, allyl, but-1-enyl and substituted vinyl, for example 2-phenylphenyl).

Arelaxation group can be entered amide group by reacting the latter group with the corresponding oralmaxillofacial, and removed using catalytic hydrogenation. Alkoxymethyl, three(alkyl/aryl)silyl and trialkyl/similarieties groups can be introduced by reacting the amide with the corresponding chloride and removed by acid or in the case of groups containing silyl, fluoride ions. Alkoxyphenyl and alkoxybenzyl group usually imposed by arilirovaniya or alkylation with an appropriate halide and is removed by oxidation of the ammonium cerium nitrate. Finally, ALK-1-aniline groups can be introduced by reacting the amide with the appropriate aldehyde and removed by acid.

The above also applies to other pharmaceutical composition, method, method, application, and particularly the manufacture of medicines, Altern is effective and preferred aspects and embodiments described herein the compounds according to the invention.

The following examples are given for illustrative purposes and are not intended to restrict the scope of the invention. Each privedennoe in the examples, the connection is specific and independent aspect of the invention. In the following, not limiting the scope of invention Examples, unless otherwise noted:

(1) evaporation was carried out using a rotary evaporator under reduced pressure, and the procedure was carried out after removal of residual solids such as drying agents by filtration;

(2) procedures were carried out at room temperature, i.e. in the range of 18-25°C. and in an atmosphere of inert gas such as argon or nitrogen;

(3) the outputs are given for illustration only and are not necessarily fully achievable;

(4) the structure of the final products of formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; the values of chemical shifts of proton magnetic resonance was measured on a scale Delta and megasthenese peaks presented in accordance with the following: s - singlet; d - doublet; t - triplet; m - multiplet; br, broad; q, Quartet; quin quintet; sextet;

(5) the intermediate, generally not completely okharakterizovali and purity was assessed by thin layer chromatography chromatog is the her (TLC), high-performance liquid chromatography (HPLC), infrared analysis (IR) or NMR;

(6) flash chromatography, unless otherwise stated, were carried out on the silicon dioxide.

Reduction
DCMdichloromethane;
DEADdiethylazodicarboxylate;
DIADdiisopropylsalicylic;
DIPEAN,N-diisopropylethylamine;
DMAdimethylacetamide;
DMSOdimethyl sulfoxide;
DMFdimethylformamide;
EDAC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate;
Ehudliquid chromatography high pressure;
A receiver arraythe hypromellose;
LC/the liquid chromatography/mass spectroscopy;
NMIPN-methyl-2-pyrrolidone;
NMRnuclear magnetic resonance spectroscopy;
CTroom temperature;
THFtetrahydrofuran;
TFAtriperoxonane acid;
CDCl3deuterochloroform;
MgSO4magnesium sulfate;
PTFEpolytetrafluoroethylene;
TIPStriisopropylsilyl.

Example 1 -[(2S)-1-(deformedarse)propan-2-yl]oxy-N-(5-methylpyrazine-2-yl)-5-(6-methylsulfonylmethyl-3-yl)oxybenzoic

A mixture of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazine-2-yl)benzamide (190 mg, 0.54 mmol), 5-bromo-2-methylsulfonylamino (CAS No..98626-95-0) (140 mg, 0.59 mmol), cesium carbonate (350 mg, at 1.08 mmol) and bromotris(triphenylphosphine) copper (I) - (101 mg, 0.11 mmol) in DMA (5 ml) was stirred in a microwave reactor at 160°C for 6 Chabal ethyl acetate (50 ml) and the mixture was washed with water (50 ml), brine (50 ml), dried (MgSO4) and was evaporated in vacuum.

The crude residue was subjected to chromatography on silica, elwira 10-100% ethyl acetate in isohexane, to give the desired compound (19 mg).

1H NMR δ (CDCl3): 1.40 (d, 3H), 2.56 (s, 3H), 3.23 (s, 3H), 3.96-4.05 (m, 2H), 4.65-4.72 (m, 1H), 6.26 (t, 1H), 6.86 (t, 1H), 7.21 (t, 1H), 7.36 (t, 1H), 7.46-7.49 (m, 1H), 8.08 (d, 1H), 8.15 (s, 1H), 8.30 (s, 1H), 8.49 (d, 1H), 9.52 (d, 1H); m/z 509 (M+H)+.

Obtain 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazine-2-yl)benzamide is described below.

3-[(2S)-1-(Deformedarse)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazine-2-yl)benzamid

3-[(2S)-1-(Deformedarse)propan-2-yl]oxy-N-(5-methylpyrazine-2-yl)-5-phenylmethanone (0,48 g at 1.08 mmol) was dissolved in ethanol (10 ml) and THF (10 ml) and the flask was evacuated and purged with argon (3 times). Was added 10% palladium on carbon (48 mg) and the flask additionally was evacuated and finally blew gaseous hydrogen. The reaction mixture was stirred at RT for 20 hours. The reaction mixture was removed and purged with argon (3 times) and the catalyst was removed by filtration through celite®. The filtrate was concentrated in vacuum to give the desired compound (0,38 g).

1H NMR δ (d6-DMSO): 1.19 (d, 3H), 2.39 (s, 3H), 3.85-3.95 (m, 2H), 4.65-4.72 (m, 1H), 6.46 (s, 1H), 6.65 (t, 1H), 6.93 (s, 1H), 7.06 (s, 1H), 8.27 (s, 1H), 9.16 (s, 1H), 9.74 (s, 1H), at 10.82 (s, 1H); m/z 354 (M+H)+.

3-[(2S)-1-(Difftime is hydroxy)propane-2-yl]oxy-N-(5-methylpyrazine-2-yl)-5-phenylmethanone

1-Chloro-N,N,2-trimethylpropyl-1-EN-1-amine (of 0.26 ml, 2.0 mmol) was added to a solution of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-phenylmethanone acid (0.54 g, 1.5 mmol) in DCM (20 ml) and was stirred for 1 hour. Added 5-methylpyrazine-2-amine (CAS no. 5521-58-4) (335 mg, 3.1 mmol), then pyridine (0.25 ml, 3.1 mmol) and the reaction mixture was stirred for another 30 minutes, then evaporated in vacuum and distributed between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was additionally extracted into ethyl acetate (50 ml) and the combined organic substance was washed with water (50 ml), brine (50 ml), dried (MgSO4) and was evaporated in vacuum. The crude residue was subjected to chromatography on silica, elwira 40-100% ethyl acetate in isohexane to give the desired compound (0,48 g).

1H NMR δ (CDCl3): 1.39 (d, 3H), 2.58 (s, 3H), 3.96-4.05 (m, 2H), 4.63-4.70 (m, 1H), 5.13 (s, 2H), 6.30 (t, 1H), 6.78 (t, 1H), 7.09 (t, 1H), 7.16 (t, 1H), 7.35-7.48 (m, 5H), 8.17 (s, 1H), 8.39 (s, 1H), 9.58 (d, 1H); m/z 444 (M+H)+.

3-[(2S)-1-Deformedarse)propan-2-yl]oxy-5-phenylmethanone acid

The monohydrate of lithium hydroxide (19 mg, 0.45 mmol) in water (2 ml) was added to methyl 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-fenilmetilketenom (0.11 g, 0.3 mmol) in THF (4 ml) and the mixture was stirred at RT for 20 hours. THF was removed in vacuum and the aqueous layer was brought to pH 3 citric Ki is lotay, then was extracted into ethyl acetate (2×30 ml). Organic matter was washed with water (30 ml), brine (30 ml), dried (MgSO4), filtered and the solvent was removed in vacuum to give the desired compound (0.1 g).

1H NMR δ (d6-DMSO): 1.27 (d, 3H), 4.00 (m, 2H), 4.75 (sextet, 1H), 5.15 (s, 2H), 6.72 (t, 1H), 6.87 (t, 1H), 7.08 (t, 1H), 7.16 (t, 1H), 7.41 (m, 5H), 12.95 (s, 1H); m/z 351 (M+H)+.

Methyl-3-[2S)-1-(deformedarse)propan-2-yl]oxy-5-(fenilmetilketenom

2.2-Debtor-2-persulfonic acid (GAS No..1717-59-5) (0,239 ml, 2,31 mmol) was added dropwise with stirring to a degassed mixture of methyl-3-[(2S)-1-hydroxypropan-2-yl]oxy-5-fenilmetilketenom (0.73 g, 2,31 mmol) and copper iodide (I) (88 mg, 0.46 mmol) in acetonitrile (10 ml) at 45°C. the Reaction mixture was stirred at 45°C for 24 hours. The solvent was removed in vacuo and added ethyl acetate (30 ml). Organic matter was washed with water (30 ml), brine (30 ml), dried (MgSO4), filtered and the solvent was removed in vacuum. The residue was subjected to chromatography on silica, elwira gradient of 0-30% ethyl acetate in isohexane, to give the desired compound (0.11 g).

1H NMR δ (CDCl3): 1.37 (d, 3H), 3.93 (s, 3H), 4.00 (m, 2H), 4.63 (sextet, 1H), 5.10 (s, 2H), 6.28 (t, 1H), 6.77 (t, 1H), 7.28 (t, 1H), 7.41 (m, 6H); m/z 367 (M+N)+.

Methyl-3-[(2S)-1-hydroxypropan-2-yl]oxy-5-(fenilmetilketenom

Bromeilles (1.89 g, 7.20 mmol) was added to a mixture of methyl-3-hydroxy-5-[(2S)-1-hydroxypropan-2-yl]oxybenzoyl (1.55 g, 6,86 mmol) and potassium carbonate (1.89 g, 0.014 mol) in DMF (16 ml) and the reaction mixture was stirred at RT for 20 hours. Added ethyl acetate (40 ml) and the mixture was washed with water (40 ml), saturated sodium bicarbonate solution (40 ml), brine (40 ml), dried (MgSO4), filtered and the solvent was removed in vacuum. The residue was subjected to chromatography on silica, elwira gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (1.7 g).

1H NMR δ (CDCl3): 1.30 (d, 3H), 1.95 (m, 1H), 3.76 (m, 2H), 3.92 (s, 3H), 4.53 (m, 1H), 5.11 (s, 2H), 6.78 (t, 1H), 7.25 (m, 1H), 7.32 (m, 1H), 7.45 (m, 5H); m/z 317 (M+N)+.

Methyl-3-hydroxy-5-[(2S)-1-hydroxypropan-2-yl]oxybenzoyl

Attributively (GAS No..16029-98-4) (115 ml of 0.79 mol) was added to a solution of methyl-3-hydroxy-5-[(2S)-1-methoxypropan-2-yl]oxybenzoyl (CAS No..863504-77-2) (38,01 g, 0,158 mol) in acetonitrile (500 ml) and was stirred for 24 hours. Was added methanol (300 ml) and the reaction mixture was stirred for 10 minutes. To the mixture was added 10% wt./about. water pentahydrate sodium thiosulfate (100 ml) and was stirred for 20 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, the organic solvents were removed in vacuum and the product extragear the Wali in ethyl acetate (4×100 ml). The combined organic layers were dried (MgSO4), filtered and the solvents were removed in vacuum. The crude substance was recrystallized from ethyl acetate to give the desired compound (16,8 g).

1H NMR δ (d6-DMSO): 1.18 (d, 3H), 3.40-3.55 (m, 2H), 3.80 (8, 3H), 4.35 (sextet, 1H), 4.80 (t, 1H), 6.57 (m, 1H), 6.90 (m, 2H), 9.75 (s, 1H); m/z 304 (M+H)+.

Methyl-3-hydroxy-5-[(2S)-1-methoxypropan-2-yl]oxybenzoyl

Methyl-3-[(2S)-1-methoxypropan-2-yl]oxy-5-fenilmetilketenom (CAS No..851885-42-2) (50.0 g, 0,152 mmol) was dissolved in a mixture TNR : ethanol (600 ml) and the flask was evacuated and purged with nitrogen (3 times). Was added 10% palladium on carbon (5.0 g), the flask additionally was evacuated and finally blew gaseous hydrogen. The reaction mixture was stirred at ambient temperature for 20 hours to complete the reaction. The reaction mixture was removed and purged with nitrogen (3 times). The catalyst was filtered and the filtrate was concentrated in vacuum to give the desired compound (36,7 g).

1H NMR δ (d6-DMSO): 1.2 (d, 3H), 3.25 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.55 (m, 1H), 6.6 (s, 1H), 6.9 (s, 1H), 6.95 (s, 1H), 9.8 (s, 1H).

Example 2: 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide

A mixture of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazine-2-yl)who insipida (0,19 g, 0.54 mmol), 5-chloro-N,N-dimethyl-pyrazin-2-carboxamide (100 mg, 0.54 mmol) and potassium carbonate (149 mg, of 1.08 mmol) in acetonitrile (5 ml) was stirred in a microwave reactor at 140°C for 5 hours and the mixture was evaporated in vacuum. Added ethyl acetate (50 ml) and the mixture was washed with water (50 ml), brine (50 ml), dried (MgSO4) and was evaporated in vacuum. The crude residue was subjected to chromatography on silica, elwira 0-5% methanol in DCM to give the desired compound (150 mg).

1H NMR δ (CDCl3): 1.40 (d. 3H), 2.55 (s, 3H). 3.15 (s. 311), 3.18 (s, 3H), 3.95-4.05 (m, 2H), 4.64-4.71 (m, 1H), 6.26 (t, 1H), 6.97 (t, 1H), 7.32 (t, 1H), 7.40 (t, 1H). 8.13 (s. 1H), 8.38 (d, 1H). 8.41 (s, 1 H), 8.53 (d, 1H), 9.53 (d, 1H); m/z 503 (M+N)+.

Obtain 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazine-2-yl)benzamide was described earlier.

Getting 5-chloro-N,N-dimethylpyrazine-2-carboxamide is described below.

5-Chloro-N,N-dimethylpyrazine-2-carboxamide

Oxalicacid (1.7 ml, 19 mmol) was added to a suspension of 5-chloropyrazine-2-carboxylic acid (GAS No..36070-80-1) (2,53 g, 16.0 mmol) in dichloromethane (25 ml) and DMF (4 drops) at RT and in argon atmosphere. The mixture was allowed to mix for 1.5 h, concentrated in vacuo and the residue pererestorani in dichloromethane (25 ml). Then dropwise added dimethylamine (2 M in THF, 8,77 ml, 17.6 mmol), then triethylamine (4.9 ml, 35 mmol) and gave the opportunity to premesis is the promise for another 5.5 hours. The reaction mixture was concentrated in vacuo and the residue pererestorani in dichloromethane and filtered. The filtrate was subjected to chromatography on silica, elwira gradient of 50-100% ethyl acetate in isohexane to give the desired compound (1.88 g).

1H NMR δ (CD3OD): 3.34 (s, 3H), 3.38 (s, 3H), 8.90 (s, 1H), 8.92 (s, 1H); m/z 186 (M+N)+.

An alternative way to obtain 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide below.

1-Chloro-N,N,2-trimethyl-1-Propylamine (6.9 ml, 52,3 mmol) was added to a solution of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)-pyrazin-2-yl]oksibenzoynoy acid (17,2 g of 41.8 mmol) in DCM (250 ml) and stirred at ambient temperature for 30 minutes. Added 5-methylpyrazine-2-amine (9.1 g, with 83.6 mmol) and pyridine (6.8 ml, with 83.6 mmol) and the reaction mixture was stirred over night. The solvent is evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), washed with water (2×100 ml), citric acid (1 N., 100 ml), saturated sodium bicarbonate solution (2×100 ml) and saturated brine (10 ml), dried (NgSO4), filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica, elwira gradient 25-100% ethyl acetate in isohexane with the teachings of the product as a colourless foam (11.2 g). To a 200 mg sample of this substance was added diethyl ether (1 ml) and the resulting suspension suspended overnight with vigorous stirring. The resulting white solid was isolated by filtration and dried in vacuum. The x-ray diffraction on the powder confirmed that this substance contains a significant degree of crystallinity. The remaining substance (9.2 grams) were divided into two parties (3.5 g, 5.7 g). For smaller parties (3.5 g) was added diethyl ether (12.5 ml) and to the majority party (5.7 g) was added diethyl ether (20 ml). In a large party entered the seed previously obtained a crystalline substance (50 mg). Both parties was stirred for 16 hours at room temperature. The resulting colorless solid was isolated by filtration were combined and dried in vacuum. The resulting substance (6,1 g, 29%) had a picture of the x-ray diffraction on the powder, consistent with previously obtained crystalline substance and is described to Form a 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)-carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide described below.

Data1H NMR and mass spectrometry were consistent with those obtained using a previously described method.

Form a 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-METI pyrazin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide characterized by obtaining at least one of the following 2θ values, measured using CuKa radiation: 20,3 and 15.6. Form a 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide characterized as giving a picture of the x-ray diffraction on the powder, essentially as shown in Figa Ten most prominent peaks are presented in Table A.

25,707
Table a
Ten most prominent peaks of the diffraction of x-rays on the powder to Form a 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide
Angle 2-Theta (2θ)Intensity, %The relative intensity
20,325100OS
15,64694,3OS
23,1546,2OS
22,42443,8OS
9,26639,1OS
34,8OS
26,2132,9OS
18,7228,5OS
26,48528,5OS
8,42528,5OS

OS = very strong.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1 -(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction by the powder of at least one specific peak at about 2-theta = 20,3°.

In accordance with the present invention proposed a crystalline form, Form A, which has a picture of the x-ray diffraction by the powder of at least one specific peak at about 2-theta = 15.6°C.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction on the powder p is at least two specific peaks at about 2-theta = 20,3° and 15.6°.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction by the powder with specific peaks at about 2-theta=20,3, 15,6, 23,2, 22,4, 9,3, 25,7, 26,2, 18,7, 26,5 and 8.4°.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction on the powder is essentially the same as the picture of the x-ray diffraction on the powder presented on Figa

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction by the powder of at least one specific peak at 2-theta = 20,3° plus or minus 0.5° 2-theta.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1 -(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form a, which has the diffraction pattern of the x-ray beam is on the powder with at least one specific peak at 2-theta = 15.6° C plus or minus 0.5° 2-theta.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction on the powder at least two specific peaks at 2-theta = 20,3° and 15.6°, where these values may be plus or minus 0.5° 2-theta.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction by the powder with specific peaks at 2-theta= 20,3, 15,6, 23,2, 22,4, 9,3, 25,7, 26,2, 18,7, 26,5 and 8.4°, where these values may be plus or minus 0.5° 2-theta.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction by the powder of at least one specific peak at 2-theta = 20,3°.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form a, Kotor which has a picture of the x-ray diffraction by the powder of at least one specific peak at 2-theta = 15.6°C.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction on the powder at least two specific peaks at 2-theta = 20,3° and 15.6°.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction by the powder with specific peaks at 2-theta= 20,3, 15,6, 23,2, 22,4, 9,3, 25,7, 26,2, 18,7, 26,5 and 8.4°.

In accordance with the present invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form A, which has a picture of the x-ray diffraction on the powder presented on Figa

Analysis by DSC (differential scanning calorimetry) showed that the Shape And 5-[3-[(2S)-1-(deformedarse)propan-2-yl]-hydroxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide is a fusible solid substance with the beginning of melting at 75,0°C and a maximum at 83,1°C (Figb).

Thus, in accordance with the crust is Asim invention proposed a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]-hydroxy-5-[(5-methylpyridin-2-yl)carbamoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form And, with the onset of melting at about 75,0°C and a maximum at approximately 83,1°C.

Thus, in accordance with the present invention, a method for obtaining a crystalline form of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, comprising crystallization of 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide from a solution of 5-[3-[(2S)-1-(deformedarse)prolan-2-yl]-hydroxy-5-[(5-methylpyridin-2-yl)carbarnoyl|phenoxy]-N,N-dimethylpyrazine-2-carboxamide in diethyl ether.

When it is argued that the present invention relates to a crystalline form of 5-[3-[(2S)-1 -(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide, Form And degree of crystallinity for convenience is more than about 60%, more convenient, more than about 80%, preferably more than about 90% and even more preferably more than about 95%.

Form a 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide gives a picture of the x-ray diffraction on the powder is essentially the same as picture x-ray diffraction on the powder presented on Figa, and have about the merits of the ten most prominent peaks (angle 2-theta), presented in Table A. it is Clear that the values of the 2-theta in the film x-ray diffraction on the powder may differ slightly depending on the device or sample and, thus, the above values should not be regarded as absolute.

It is known that can be obtained picture of the x-ray diffraction on the powder, which has one or more than one measurement error depending on the measurement conditions (such as equipment or apparatus used). In particular, as a rule, it is known that the intensity in the film x-ray diffraction on the powder may vary depending on the measurement conditions. Thus, it is clear that the Form And 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide according to the present invention is not limited to the crystals, giving a picture of the x-ray diffraction on the powder, identical to the picture of the x-ray diffraction on the powder presented on Figa, and any crystals, giving a picture of the x-ray diffraction on the powder essentially the same as shown in Figa, are within the scope of the present invention. Specialist in the field of x-ray diffraction on the powder is able to judge the substantial identity of the paintings of the x-ray diffraction by far is the Cabinet.

Specialist in the field of x-ray diffraction on powder understands that the relative intensity of the peaks can be affected, for example, with a grain size greater than 30 microns, and the non-unitary aspect ratio of the image, which may affect the analysis of samples. Specialist in the art will also understand that the position of the reflections can influence the exact height at which the sample is fixed in the diffractometer, and the zero calibration of the diffractometer. Playmost the sample surface can also have a significant effect. Therefore, the data pattern of diffraction should not be understood as absolute values. (Jenkins. R & Snyder. R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H.P. & Alexander, LE (1974), X-Ray Diffraction Procedures).

Typically, the measurement error of a diffraction angle in an x-ray powder diffraction pattern is approximately 5% or less, in particular plus or minus 0.5° 2-theta, and such degree of a measurement error should be taken into account when considering the pattern of x-ray diffraction on powder on Figa and when reading Table A. in Addition, it is clear that the intensity can fluctuate depending on experimental conditions and sample preparation (preferred orientation).

Detailed information about the used method is

Diffraction of x-rays powder

Table B
The relative intensity, %*Definition
25-100OS (very strong)
10-25with (strong)
3-10cf (average)
1-3SL (weak)
* The relative intensities are derived from diffractograms measured with the use of analytical equipment with fixed slits: Siemens D5000.

Spectra of x-ray diffraction on the powder was determined by observing a sample of a crystalline substance on a substrate silicon single crystal Siemens (SSC) and rolling out the sample into a thin layer using the object-glass of the microscope. The sample was rotated at a speed of 30 revolutions per minute (to improve counting statistics) and were irradiated by x-rays generated by a copper long astrosociology tube operating at 40 kV and 40 mA with a wavelength of 1,5406 angstroms. A collimated x-ray source was passed cher the C automatic grid with different divergence, installed on V20, and the reflected radiation is directed through a 2 mm non-reflective slit and 0.2 mm slit of detecor. The sample was subjected to exposure for 1 second with an increase of 0.02 angle 2-theta (continuous scan mode) in the range from 2 degrees to 40 degrees 2-theta in theta-theta. The analysis time was 31 minutes and 41 seconds. The device is equipped with a scintillation counter as a detector. Registration control values and the data was carried out using the workstation Dell Optiplex 686 NT 4.0 operating software Diffract+. Specialists in the field of x-ray diffraction on the powder, it is clear that the relative intensity of the peaks can be affected, for example, with a grain size greater than 30 microns, and the non-unitary aspect ratio of the image, which may affect the analysis of samples. Specialist in the art will also understand that the position of the reflections can influence the exact height at which the sample is fixed in the diffractometer, and the zero calibration of the diffractometer. Playmost the sample surface can also have a significant effect. Therefore, the data pattern of diffraction should not be understood as absolute values.

Differential scanning calorimetry

Analysis instrument: Mettler DSC820e.

Typically, less than 5 mg of substance containing the of egasa in an aluminum vessel with a volume of 40 μl, equipped with a lid with a hole, was heated in the temperature range from 25°C to 325°C at a constant heating rate of 10°C per minute. The purge gas is nitrogen was used at a flow rate of 100 ml per minute.

The suspension of 5-(3-[(2S)-1-(deformedarse)propan-2-yl)-hydroxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy)-N,N-dimethylpyrazine-2-carboxamide

Spectra of x-ray diffraction on the powder (DLP) for 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide showed that starting material was amorphous. To obtain the crystalline form, Form a, approximately 500 mg of the substance was placed in a vessel with a magnetic stirrer and add approximately 2 ml of diethyl ether, the vessel is then tightly closed with a lid. The suspension is then left to mix on a magnetic stirrer at ambient temperature (25°C). After 2 hours the sample was removed from the mixer, the cover was removed and the suspension was left to dry in ambient conditions up to its analysis using DLP and DSC. Using DLP was determined that the resulting substance (Form A) is crystalline and differs from the original amorphous substance. This substance (Form) had a melting temperature of 75.0°C (onset).

3[(2S)-1-(Deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxib sauna acid

Methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzoyl (19,8 g and 46.6 mmol) was dissolved in THF (300 ml) and methanol (100 ml) was added LiOH (1 N., 51,3 ml)and then water is added dropwise to the dimness. The resulting solution was stirred for 16 hours at room temperature. Organic matter was removed by evaporation under reduced pressure. The aqueous suspension was diluted with water (100 ml), washed with ethyl acetate (200 ml), then acidified by adding hydrochloric acid (2 BC) prior to the deposition of solids. The resulting suspension was extracted with ethyl acetate (2×200 ml). The combined organic extracts were washed with water (200 ml) and brine (200 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain the product (17,2 g, 90%).

1H NMR δ (CDCl3): 1.39 (d, 3H), 3.17 (s, 3H), 3.19 (s, 3H), 3.93-4.05 (m, 2H), 4.60-4.69 (m, 1H), 6.26 (t, 1H), 6.99 (t, 1H), 7.50-7.55 (m, 2H), 6.38 (d, 1H), 8.55 (d, 1H), 10.17 (s, 1H); m/z 412 (M+H)+.

Methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethyl-carbarnoyl)pyrazin-2-yl]oxybenzoyl

2.2-Debtor-2-persulfonic acid (CAS No..1717-59-5) (0,84 ml, with 8.05 mmol) in acetonitrile (20 ml) was added via syringe pump dropwise over 90 minutes to a degassed stirred mixture of methyl 3-[5-(dimetic rebamol)pyrazin-2-yl]oxy-5-[(2S)-1-hydroxypropan-2-yl]oxy-benzoate (1.5 g, 22,0 mmol) and copper iodide (I) (154 mg, 4,55 mmol) in acetonitrile (300 ml) at 55°C. Volatiles were removed under reduced pressure and the residue was transferred to a DCM. The mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica, elwira gradient from 25%-100% ethyl acetate in isohexane with obtaining product (16.5 g, 62%).

1H NMR δ (CDCl3): 1.38 (3H, d), 3.15 (3H, s), 3.16 (3H, s), 3.91 (3H, s), 3.93-4.05 (2H, m), 4.62-4.68 (1H, m), 6.27 (1H, t), 6.95 (1H, t), 7.44-7.45 (1H. m), 7.49-7.51 (1H, m), 8.36 (1H, 8), 8.53 (1H, s); m/z 404 (M+H+).

Methyl-3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-hydroxypropan-2-yl]oxybenzoyl

A solution of hydrogen fluoride (70% in pyridine at 3.25 ml) was added to methyl-3[5-(dimethylcarbamoyl)pyrazin-yl]oxy-5-[(2S)-1-tryptophan-2-insulinotherapy-2-yl]oxybenzoyl in THF (300 ml) in a vessel made of PTFE (polytetrafluoroethylene) and the resulting solution was stirred for 18 hours at room temperature. Added additional quantity of a solution of hydrogen fluoride (70% in pyridine at 3.25 ml) and the reaction mixture was stirred for 66 hours. The reaction was suppressed by very careful addition of saturated aqueous sodium bicarbonate solution until the solution pH 8. The aqueous layer was extracted with ethyl acetate (2×500 ml) and the combined organic substance was dried (MgSO4

1H NMR δ (CDCl3) 1.32 (3H, d), 1.93 (1H, d), 3.17 (6H, d), 3.74-3.79 (1H, m), 3.91 (3H, s), 4.54-4.60 (1H, m), 6.96 (1H, t), 7.43 (1H, d), 7.51 (1H, d), 8.36 (1H, d), 8.53 (1H, d); m/z 376 (M+H+).

Methyl-3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-tryptophan-2-insulinotherapy-2-yl]oxybenzoyl

A mixture of methyl-3-hydroxy-5-[(2S)-1-tryptophan-2-insulinotherapy-2-yl]-oxybenzoates (40,2 g, 105 mmol), 5-chloro-N,N-dimethylpyrazine-2-carboxamide (20.5 g, 110 mmol) and potassium carbonate (36,3 g, 263 mmol) in acetonitrile (500 ml) was stirred while boiling under reflux for 6 hours. Volatiles were removed under reduced pressure and added ethyl acetate (500 ml) and water (500 ml). The organic layer was separated, the aqueous layer was re-extracted into ethyl acetate (250 ml) and the combined organic substance was washed with water (500 ml), brine (500 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain the product (55,6 g, 100%).

1H NMR δ (CDCl3) 1.01-1.07 (N, m), 1.34 (3H, d), 3.14-3.16 (3H, s), 3.17(3H, s), 3.72-3.77 (1H, m), 3.87-3.92 (4H, m), 4.51 (1H, m), 6.95 (1H, t), 7.39-7.40 (1H, m), 7.50-7.51 (1H, m), 8.34 (1H, d), 8.53 (1H, d); m/z 532 (M+H+)

Getting 5-chloro-N,N-dimethylpyrazine-2-carboxamide which was written earlier.

Methyl-3-hydroxy-5-[(2S)-1-tryptophan-2-insulinotherapy-2-yl]oxybenzoyl

To a solution of methyl-3-phenylmethoxy-5-[(2S)-1-tryptophan-2-insulinotherapy-2-yl]oxybenzoyl (CAS No..871657-71-5) (47,3 g, 0.1 mol) in ethanol (500 ml) was added 10% palladium on charcoal (5 g) under nitrogen. The reaction mixture was stirred in an atmosphere of hydrogen for 16 hours. Thereafter, the catalyst was filtered and the solvent was evaporated under reduced pressure to obtain the product (38,1 g, 100%).

1H NMR δ (CDCl3) 1.01-1.12 (22N, m), 1.32 (3H, d), 3.69-3.77 (2H, m), 3.89 (3H, 8), 4.48 (1H, q), 6.62 (1H, t), 7.10 (1H, d). 7.18 (1H, t): m/z 381 (M-H-).

Another alternative way to obtain 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide below.

To 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oksibenzoynoy acid (74,2 g, 180 mmol) was added DMF (1.4 ml, 18 mmol). Download dichloromethane (810 ml) and oxalicacid of 25.2 ml, 289 mmol) and the reaction mixture was allowed to mix at ambient temperature for 2 hours. The solvent was evaporated under reduced pressure, subjected to azeotropic distillation with toluene (2×600 ml) and the resulting oil was dissolved in pyridine (392 ml) and dichloromethane (500 ml).

4) and evaporated under reduced pressure. The residue was purified by flash chromatography to obtain specified in the connection header (66 g).

The sample of this substance (64 g, 127 mmol) was added diethyl ether (640 ml) and the resulting suspension was stirred over night.

The solid was filtered off, washed with diethyl ether (320 ml) and dried in vacuum at ambient temperature overnight to obtain a white crystalline solid (56 g).

This substance had a picture of the x-ray diffraction by the powder that is consistent with that described for the previously described Form And 5-[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[(5-methylpyridin-2-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide.

Data1H NMR and mass spectrometry were consistent with previously described.

Obtain 3-[(2S)-1-(deformedarse)propan-2-yl]-hydroxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oksibenzoynoy acid described neither the E.

3-[(2S)-1-Deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzone acid

To methyl 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzoyl (76,3 g, 179 mmol) was added NMP (534 ml), water (305 ml) and the solution was stirred at 0°C. was added dropwise 2 n sodium hydroxide (152 ml, 305 mmol) and the reaction mixture was stirred for 4 hours. Was added dropwise acetic acid (41 ml, 718 mmol), then water (1068 ml), and 1 N. HCl (400 ml) was added to achieve a pH of 3 and a number of substances vymalovani. The aqueous layer was extracted with toluene (3×988 ml) and combined with vymylenny substance, which was dissolved in ethyl acetate (988 ml)and the combined organic layers were washed with water (988 ml), saturated aqueous brine (988 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography elwira 5% Meon in dichloromethane to obtain specified in the title compound (64 g).

1H NMR δ (DMSO-d6) 1.27 (3H, d), 3.03 (6H, 8), 3.99-4.04 (2H, m), 4.76-4.80 (1H, m), 6.52-6.91 (1H, t), 7.21 (1H, t), 7.34-7.38 (2H, m), 8.42 (1H, d), 8.56 (1H, d).

Methyl-3-[(2S)-1-deformedarse)propan-2-yl]oxy-5-[5-dimethylcarbamoyl-yl)pyrazin-2-yl]oxybenzoyl

A solution of methyl-3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-hydroxypropan-2-yl]oxybenzoyl (94 g, 250 mmol) in azet the nitrile (1130 ml) was degirolami nitrogen, then downloaded the copper iodide (I) (9,54 g, 50 mmol) and the solution was heated to 55°C. was added dropwise a solution of 2,2-debtor-2-persulfonic-acetic acid (CAS No..1717-59-5) (46.6 ml, 450 mmol) in acetonitrile (188 ml). After 3 hours, the solvent evaporated under reduced pressure at 25°C. the Residue was transferred into dichloromethane (500 ml) and filtered. The solid was further washed with dichloromethane until then, until the washing became transparent. The solvent is evaporated under reduced pressure at 25°C and the residue was purified by flash chromatography elwira 100%ethyl acetate to obtain specified in the title compound (54 g).

1H NMR δ (DMSO-d6) 1.28 (3H, d), 2.99-3.08 (6H, m), 3.86 (3H, s), 3.98-4.07 (2H, m), 4.78-4.82 (1H, m), 8.50-6.90 (1H, t), 7.25 (1H, t), 7.38-7.40 (2H, m), 8.42 (1H, d), 8.55 (1H, d)/

Methyl-3-[5-(dimethylcarbamoyl)Perrin-2-yl]oxy-5-[(2S)-1-hydroxypropan-2-yl]oxybenzoyl

A solution of methyl-3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-[(2-methylpropan-2-yl)oxy]propan-2-yl]oxybenzoyl (170 g, to 0.39 mol) in formic acid (850 ml) was heated to 90°C for 3 hours. Added ethyl acetate (1700 ml), water (1700 ml) and saturated aqueous brine (850 ml), the aqueous layer was separated and was extracted with ethyl acetate (850 ml) and the combined organic layers were washed with saturated aqueous brine (850 ml), dried (MgSO4) and evaporated under reduced pressure. The remainder R which was storyli in ethyl acetate (1500 ml), water (1500 ml) and methanol (150 ml). Was added sodium carbonate (170 g) and the biphasic solution was heated to the temperature of reflux distilled for 2 hours. The aqueous layer was separated and the organic layer was washed with water (1700 ml). The combined water phases were extracted with ethyl acetate (850 ml) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography elwira 100%ethyl acetate, to obtain specified in the connection header (148 g).

1H NMR δ (DMSO-d6) 1.23 (3H, d), 3.04 (6H, s), 3.47-3.56 (2H, m), 3.86 (3H, s), 4.49-4.53 (1H, m), 4.86 (1H, t), 7.19 (1H, t), 7.34-7.35 (1H, m), 7.38-7.39 (1H, m), 8.42 (1H, d), 8.55 (1H, d).

Methyl-3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-[(2-methylpropan-2-yl)oxy]propan-2-yl]oxybenzoyl

To methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-hydroxybenzoate (10 g, 32 mmol) was added triphenylphosphine (10.3 g, to 39.4 mmol), THF (100 ml) and (2R)-1-[(2-methylpropan-2-yl)oxy]propan-2-ol (CAS No..136656-73-0) (total of 5.21 g, to 39.4 mmol). The resulting suspension was cooled to 0°C. and was added dropwise diethylazodicarboxylate (50% wt./about. in toluene, of 13.7 ml, to 39.4 mmol), keeping the temperature below 10°C. After 2 hours the solvent is evaporated under reduced pressure and transferred into ethyl acetate (23 ml). The filtered solid was separated, and the mother solution was evaporated under reduced pressure, the shift is and ethyl acetate (23 ml) and isohexane (53 ml), the resulting solid was filtered, the mother solution was evaporated under reduced pressure and the resulting residue was purified by flash chromatography elwira a mixture of 80% ethyl acetate/20% isohexane with obtaining product (13.5 g).

1H NMR δ (DMSO-d6) 1.12 (N, s), 1.25 (3H, d), 3.03 (6H, s), 3.41-3.45 (1H, m), 3.47-3.51 (1H, m), 3.85 (3H, 8), 4.55-4.57 (1H, in), 7.20 (1H, t), 7.34-7.35 (1H, m), 7.40-7.41 (1H, m), 8.41 (1H, d), 8.54 (1H, d).

Methyl-3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-hydroxybenzoate

To methyl-3,5-dihydroxybenzoate (GAS No..2150-44-9) (85 g, 0.49 mol) was added 5-chloro-N,N-dimethylpyrazine-2-carboxamide (88.9 g, 0.48 mol), DMSO (1000 ml) and cesium carbonate (418 g, 1.2 mol) and the mixture was heated to 50°C for 3 hours. Was added water (1577 ml), then diethyl ether (540 ml). To the aqueous layer was added a 5 M solution of hydrochloric acid (395 ml, 1.97 mol) and the resulting white solid was filtered, washed with water (2×311 ml) and dried in vacuum at 40°C above the P2O5during the night to give the desired compound (143 g).

1H NMR δ (DMSO-d6) 3.03 (6N, s), 3.84 (3H, s), 6.92 (1 H, t), 7.21-7.22 (1H, m), 7.28-7.29 (1H, m), 8.41 (1H, d), 8.53 (1H, d), 10.20 (1H, s).

Getting 5-chloro-N,N-dimethylpyrazine-2-carboxamide described previously.

Example 3: 5-[3-[(2S)-1-deformedarse)propan-2-yl]oxy-5-(1H-pyrazole-3-yl-carbarnoyl)phenoxy]-N,N-dimethylpyrazine-2-carboxamide

Triperoxonane acid (2 ml) was added to a solution of tert-butyl 3-[[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzoyl]amino]pyrazole-1-carboxylate (150 mg, 0.26 mmol) in DCM (16 ml) and stirred at RT for 2 hours. The solvent was removed under vacuum, was added DCM (20 ml) and the mixture was washed with water (20 ml), saturated sodium bicarbonate solution (20 ml), brine (20 ml), dried (MgSO4) and evaporated in vacuo to give the desired compound (94 mg).

1H NMR δ (CDCl3): 1.38 (d, 3H), 3.15 (s, 3H), 3.18 (s, 3H), 3.95-4.03 (m, 2H), 4.62-4.69 (m, 1H), 6.25 (t, 1H), 6.84 (s, 1H), 6.92 (t, 1H), 7.31 (s, 1H), 7.37 (s, 1H), 7.44 (d, 1H), 8.39 (d, 1H), 8.49 (d, 1H), 9.71 (s, 1H), 10.04 (s, 1H); m/z 477 (M+N)+.

Example 4: 3-[(2S)-1-deformedarse)propan-2-yl]oxy-5-6-methylsulfonylmethyl-3-yl)oxy-N-(1H-pyrazole-3-yl)benzamid

The following compound was obtained in analogy to example 3 from tert-butyl 3-[[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oxy benzoyl]amino]pyrazole-1-carboxylate.

1H NMR δ (CDCl3): 1.39 (d, 3H), 3.23 (s, 3H), 3.95-4.04 (m, 2H), 4.64-4.71 (m, 1H), 6.26 (t, 1H), 6.83-6.86 (m, 2H), 7.19 (s, 1H), 7.35 (s, 1H), 7.45-7.48 (m, 1H), 7.52 (s, 1H), 8.07 (d, 1H), 8.48 (d, 1H), 8.65 (s, 1H); m/z 483 (M+H)+.

tert-Butyl-3-[[3-[2S)-1-(deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oxybenzoyl]amino]pyrazole-1-carboxylate

1-Chloro-N,N,2-trimethylpropyl-1-EN-1-the min (or 0.11 ml, 0.80 mmol) was added to a solution of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oksibenzoynoy acid (0,22 g, of 0.53 mmol) in DCM (5 ml) and was stirred for 1 hour. Added tert-butyl 3-aminopyrazole-1-carboxylate (CAS No..863504-94-1) (147 mg, 0.80 mmol), then pyridine (0,09 ml, 1.07 mmol) and the reaction mixture was stirred for another 45 minutes, then was evaporated in vacuum and distributed between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was additionally extracted in ethyl acetate (50 ml) and the combined organic substance was washed with water (50 ml), brine (50 ml), dried (MgSO4) and was evaporated in vacuum. The crude residue was subjected to chromatography on silica, elwira 20-50% ethyl acetate in isohexane to give the desired compound (0.15 g).

1H NMR δ (CDCl3): 1.38 (d, 3H), 1.60 (s, 9H), 3.16 (s, 3H), 3.19 (s, 3H), 3.93-4.04 (m, 2H), 4.60-4.64 (m, 1 H), 6.26 (t, 1H), 6.95 (t, 1H), 7.09 (d, 1H), 7.27-7.28 (m, 1H), 7.34 (t, 1H), 8.01 (d, 1H), 8.37 (d, 1H), 8.53 (d, 1H), 8.97 (8,1H); m/z 577 (M+H)+.

tert-Butyl-3-[[3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oxybenzoyl]amino]pyrazole-1-carboxylate used in obtaining according to Example 4 was obtained similarly from 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oksibenzoynoy acid.

Structure m/zNMR
583 (M+N)+1H NMR δ (CDCl3): 1.39 (d, 3H), 1.64 (s, N), 3.24 (s, 3H), 3.95-4.04 (m, 2H), 4.64-4.68 (m, 1H), 6.26 (t, 1H), 6.85 (t, 1H), 7.07 (d, 1H), 7.14 (t, 1H), 7.30 (t, 1H), 7.46-7.48 (m, 1H), 8.01 (d, 1H), 8.09 (d, 1H), 8.48 (d, 1H), 8.67 (s, 1H)

3-[(2S)-1-(Deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzone acid

The monohydrate of lithium hydroxide (45 mg, 1.06 mol) in water (5 ml) was added to a solution of methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzoyl (0.3 g, 0.71 mmol) in THF (10 ml) and stirred at RT for 20 hours. THF was removed in vacuum and the aqueous layer washed with ethyl acetate (50 ml) to remove any impurities. The aqueous layer was acidified and extracted with ethyl acetate (2×50 ml)then the combined organic phases were washed with brine (50 ml), dried (MgSO4) and the solvent was removed in vacuum to give the desired compound (0,22 g).

1H NMR δ (CDCl3): 1.39 (d, 3H), 3.17 (s, 3H), 3.19 (s. 3H), 3.93-4.05 (m, 2H), 4.60-4.69 (m, 1H), 6.26 (t, 1H), 6.99 (t, 1H), 7.50-7.55 (m, 2H), 8.38 (d, 1H),8.55 (d, 1H), 10.17 (s, 1H); m/z 412 (M+H)+.

Methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxybenzoyl

A mixture of methyl-3-[(2S)-1-(deformedarse)propane-2-the l]oxy-5-hydroxybenzoate (0.25 g, of 0.91 mmol), 5-chloro-N,N-dimethylpyrazine-2-carboxamide (168 mg, of 0.91 mmol) and potassium carbonate (250 mg, is 1.81 mmol) in acetonitrile (5 ml) was stirred in a microwave reactor at 140°C for 5 hours. The mixture was evaporated in vacuo and added ethyl acetate (50 ml). The mixture was washed with water (50 ml), brine (50 ml), dried (MgSO4) and was evaporated in vacuum. The residue was subjected to chromatography on silica, elwira from 20 to 70% ethyl acetate in isohexane to give the desired compound (0.3 g).

1H NMR δ (CDCl3): 1.38 (d, 3H), 3.15 (s, 3H), 3.18 (s, 3H), 3.91 (s, 3H), 3.93-4.04 (m, 2H), 4.61-4.69 (in, 1H), 6.26 (t, 1H), 6.96 (t, 1H), 7.44-7.45 (m, 1H), 7.50-7.51 (m, 1H), 8.36 (d, 1H), 8.53 (d, 1H); m/z 426 (M+H)+.

Getting 5-chloro-N,N-dimethylpyrazine-2-carboxamide described previously.

Methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxybenzoate

Methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-fenilmetilketenom (of 0.48 g, 1.1 mmol) was dissolved in ethanol (10 ml) and THF (10 ml) and the flask was evacuated and purged with argon (3 times). 10% palladium on carbon (140 mg) was added, the flask additionally was evacuated and finally blew gaseous hydrogen. The reaction mixture was stirred at RT for 20 hours to complete the interaction. The reaction mixture was evacuated and purged with argon (3 times), then the catalyst was removed by filtration through celite®. The filtrate was concentrated in vacuum is obtaining the desired compound (1,05 g).

1H NMR δ (CDCl3): 1.35 (d, 3H), 3.90 (s, 3H), 3.90-4.02 (m, 2H), 4.57-4.64 (m, 1H), 5.20 (s, 1H), 6.26 (t, 1H), 6.63 (t, 1H), 7.14-7.15 (m, 1H), 7.17-7.18 (m, 1H); m/z 275 (M-H)-.

Obtaining methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-fenilmetilketenom described previously.

Obtain 3-[(2S)-1 -(deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oksibenzoynoy acid described below.

3-(2S)-1-(Deformedarse)propan-2-yl]oxy-5-(6-methylsulfonylmethyl-3-yl)oxybenzone acid

A mixture of methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxybenzoate (233 mg, 0.84 mmol), 5-bromo-2-methylsulfonylamino (GAS No..98626-95-0) (200 mg, 0.84 mmol), cesium carbonate (549 mg, was 1.69 mmol) and bromotris(triphenylphosphine)copper (I) (157 mg, 0,17 mmol) in DMA (5 ml) was stirred in a microwave reactor at 160°C for 6 hours. Added ethyl acetate (50 ml) and water and the aqueous layer was acidified and extracted with ethyl acetate (2×50 ml). The combined organic substances were washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired compound (0.16 g).

1H NMR δ (d6-DMSO): 1.28 (d, 3H), 3.27 (s, 3H), 3.95-4.04 (m, 2H), 4.78-4.85 (m, 1 H), 6.71 (t, 1 H), 7.14-7.16 (m, 1 H), 7.22-7.23 (m, 1 H), 7.37-7.40 (m, 1H), 7.66-7.70 (m, 1H), 8.06 (d, 1H), 8.61 (d, 1H), 12.85 (s, 1H); m/z 418 (M+N)+.

Obtaining methyl-3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxybenzoate described previously.

Example 5: 5-[3-[2S)-1-(deformedarse)propan-2-yl]the xylose-5-[(1-methylpyrazole-3-yl)carbarnoyl]phenoxy]-N,N-dimethylpyrazine-2-carboxamide

A mixture of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazole-3-yl)benzamide (0.1 g, 0.29 mmol), 5-chloro-N,N-dimethylpyrazine-2-carboxamide (66 mg, 0.35 mmol) and potassium carbonate (81 mg, 0.59 mmol) in acetonitrile (5 ml) was stirred in a microwave reactor at 160°C for 6 hours. The resulting mixture was concentrated in vacuo and added ethyl acetate (50 ml). Organic matter was washed with water (50 ml), brine (50 ml), dried (MgSO4), filtered and concentrated in vacuum. The residue was subjected to chromatography on silica, elwira 10-100% ethyl acetate in isohexane, to give the desired compound (52 mg).

1H NMR δ (CDCl3): 1.30 (d, 3H), 3.08 (s, 3H), 3.11 (s, 3H), 3.69 (s, 3H), 3.85-3.97 (m, 2H), 4.56 (sextet, 1H), 6.18 (t, 1H), 6.73 (d, 1H), 6.85 (t, 1H), 7.19-7.21 (m, 2H), 7.27-7.29 (m, 1H), 8.29 (d, 1H), 8.45 (d, 1H), 8.76 (s, 1H): m/z 491 (M+H)+.

Synthesis of 5-chloro-N,N-dimethylpyrazine-2-carboxamide described previously.

3-[(2S)-1-(Deformedarse)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazole-3-yl)benzamid

3[(2S)-1-(Deformedarse)propan-2-yl]oxy-N-(1-methylpyrazole-3-yl)-5-phenylmethanone (0.1 g, 0.23 mmol) was dissolved in ethanol (3 ml) and THF (3 ml) and the flask was evacuated and purged with argon (3 times). Was added 10% palladium on carbon (0.01 g), the flask additionally was evacuated and finally blew gaseous hydrogen. The reactions is nnow the mixture was stirred at KG over 20 hours to complete the interaction. The reaction mixture was evacuated, purged with nitrogen (3 times). The catalyst was filtered through celite and the filtrate was concentrated in vacuum to give the desired compound (70 mg).

1H NMR δ (CDCl3): 1.28 (d, 3H), 3.71 (s, 3H), 3.80-3.96 (m, 2H), 4.51 (sextet, 1H), 5.96-6.38 (t, 1H), 6.53 (s, 1H), 6.73 (s, 1H), 6.91 (s, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 8.83(s, 1H); m/z 342 (M+N)+.

3-[(2S)-1-(Deformedarse)propan-2-yl]oxy-N-(1-methylpyrazole-3-yl)-5-phenylmethanone

DIPEA (0,198 ml, to 1.14 mmol) was added to a mixture of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-phenylmethanone acid (0.10 g, 0.28 mmol), 1-methylpyrazole-3-amine (CAS no. 1904-31-0) (39 mg, 0.4 mmol) and HATU (0,227 g, 0.6 mmol) in DMF (3 ml) and stirred at RT for 20 hours. Added ethyl acetate (30 ml) and the mixture was washed with water (30 ml), brine (30 ml), dried (MgSO4), filtered and concentrated in vacuum. The residue was subjected to chromatography on silica, elwira gradient of 0-100% ethyl acetate in isohexane to give the desired compound (0.1 g).

1H NMR δ (CDCl3): 1.36 (d, 3H), 3.68 (s, 3H), 3.82-3.95 (m, 2H), 4.48 (sextet, 1H), 5.00(s, 2H), 6.19 (t, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 6.93 (s, 1H), 7.03 (s, 1H), 7.28 (m, 1H), 7.35 (m, 5H), 8.59 (s, 1H); m/z 432 (M+H)+.

Synthesis of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-phenylmethanone acid described earlier.

Example 6: 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-N-(1-methylpyrazole-3-yl)-5-(6-methylsulphonyl is iridin-3-yl)oxybenzoic

A mixture of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazole-3-yl)benzamide (100 mg, 0.29 mmol), 5-bromo-2-methylsulfonylamino (CAS No.. 98626-95-0) (77 mg, 0.32 mmol), cesium carbonate (191 mg, 0.59 mmol) and bromotris(triphenylphosphine)copper(1) (55 mg, 0.06 mmol) in DMA (5 ml) was stirred in a microwave reactor at 160°C for 6 hours. Added ethyl acetate (50 ml) and washed with water (50 ml), brine (50 ml), dried (MgSO4), filtered and evaporated in vacuum. The residue was subjected to chromatography on silica, elwira 10-80% ethyl acetate in isohexane to give the desired compound (31 mg).

1H NMR δ (CDCl3):1.30 (d, 3H), 3.16 (s, 3H), 3.72 (s, 3H), 3.85-3.95 (m, 2H), 4.53-4.59 (m, 1H), 6.18 (t, 1H), 6.71 (d, 1H), 6.75 (t, 1H), 7.09 (t, 1H), 7.22 (d, 1H), 7.25 (t, 1H), 7.37-7.39 (m, 1H), 7.99 (d, 1H), 8.39 (d, 1H), at 8.62 (s, 1H): m/z 495 (M-H)-.

Synthesis of 3-[(2S)-1-(deformedarse)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazole-3-yl)benzamide was described earlier.

Biological tests

The biological effects of the compounds of formula (I) can be tested as follows.

(1) Enzymatic activity

Enzymatic activity of recombinant human pancreatic GLK can be measured by incubation GLK, ATP and glucose. The rate of formation of product can be determined by linking the analysis of glucose-6-phosphate-dehydrogenase, system NADP (nicotinamide nucleotides oxidized)/NADPH (nicotinamide adenine dinucleotide phosphate restored), and measure the linear increase in time of the optical density at 340 nm according to Brocklehurst et al. (Diabetes 2004, 53, 535-541). Activation GLK compounds can be assessed using this assay in the presence or absence of GLKRP, as described in Brocklehurst et al. (Diabetes 2004, 53, 535-541).

Compounds according to the invention was evaluated in the absence of GLKRP, as described by Brocklehurst et al. and activated glucokinase with values EC50shown below.

Table
Example No.Is EU50(µm)
10,069
20,056
30,065
40,033
50,079
60,077

Production of recombinant GLK and GLKRP

cDNA of human GLK and GLKRP obtained using PCR (polymerase chain reaction) from human mRNA pancreas and liver, respectively, using conventional methods as described in Sambrook J, Fritsch EF &Maniatis T, 1989. The primers for PCR are designed with the availa able scientific C with sequences of cDNA GLK and GLKRP, presented in Tanizawa et al., Proc NatlAcad Sci 1991 Aug 15:88(16):7294-7, and Warner et al., Mamm Genome. 1995 Aug; 6(8):532-6.

Cloning into the vector Bluescript II

cDNA GLK and GLKRP cloned in E. colic by using pBluescript II

Transformation

Transformation of E. coli, as a rule, was carried out by electroporation. 400 ml cultures of strains DH5a or BL21(DE3) were grown in L-broth to an OD (optical density) at 600 nm of 0.5 and collected by centrifugation at 2000 g. Cells are washed twice in ice-cold deionized water, resuspendable in 1 ml of 10%glycerol and kept the aliquot at -70°C. Ligerie mixture was absoluely using membranes Millipore V series™ (pore size 0,0025 mm). 40 ml of cells were incubated with 1 ml ligiously mixture or plasmid DNA on ice for 10 minutes in cuvettes for electroporation of 0.2 cm and then subjected to pulse using the apparatus Gene Pulser™ (BioRad) at 0.5 kV/cm, 250 MT. Transformants were selected on L-agar supplemented with tetracycline at a concentration of 10 mg/ml or ampicillin at 100 mg/ml

The expression

GLK expressed from the vector pTB375NBSE in cells of E. coli BL21 producing a recombinant protein containing a 6-His tag directly adjacent to the N-terminal methionine. Another alternative suitable vector is a pET21(+)DNA, Novagen, cat. No. 697703. 6-His tag was used to allow the cleaning recombining the protein on the column, Packed with agarose Nickel-nitrilotriacetate acid, purchased in Qiagen (cat. No. 30250).

GLKRP expressed from the vector pFLAG CTC (IBI Kodak) in BL21 E.coli cells producing recombinant protein containing the C-terminal tag FLAG. The protein was purified first by using ion-exchange chromatography on DEAE-sepharose with subsequent use of the label FLAG for the final cleaning on immunoaffinity column M2 with antibodies against FLAG, purchased at Sigma-Aldrich (cat. No. A1205).

(2) the Test for tolerance to oral input glucose (OGTI)

Tests for tolerance to oral input glucose (G.J Coope et al., British Journal of Pharmacology, (2006) 149, 328-335) can be carried out on in the minds of those suffering from obesity rats Zucker fa/fa (age 12-13 weeks or older)receiving a diet with a high fat diet (45% kcal fat) for at least two weeks before the experiment. Animals were not fed for 2 hours before use in experiments. Test the connection, or the media administered orally for 120 minutes before oral glucose solution at a dose of 2 g/kg of body weight. The levels of glucose in the blood is measured using Accucheck glucometer in samples taken from the tail vein at different time points before and after administration of glucose (time 60 minutes). Build a dependency graph of the glucose levels from time to time and RA is citybeat area under the curve (AUC) for 120 minutes (during the administration of glucose is taken as zero). Percentage reduction in the shift of the glucose level determined using the AUC for the group with medium as control as zero percent reduction.

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1. The compound 5-[3-[(2S)-1-(deformedarse)-propan-2-yl]-hydroxy-5-[(5-methylpyridin-2-yl)-carbarnoyl]phenoxy]-N,N-dimethyl-pyrazin-2-carboxamide or its pharmaceutically acceptable salt.

2. Pharmaceutical composition having activity of GLK activator (glucokinase), containing an effective amount of the compound 5-[3-[(2S)-1-(deformedarse)-propan-2-yl]-hydroxy-5-[(5-methylpyridin-2-yl)-carbarnoyl]phenoxy]-N,N-dimethyl-pyrazin-2-carboxamide or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

3. The compound according to claim 1 or its pharmaceutically acceptable salt for use as a medicinal product with the activity of GLK activator.

4. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment of a disease mediated through GLK.

5. The use of compounds according to claim 1 or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment of type 2 diabetes.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel amide derivatives of formula (I), isomers and pharmaceutically acceptable salt thereof, which have cancer cell selective inhibiting properties, caused by an epidermal growth factor receptor (EGFR), selected from EGFR or caused by EGFR mutation. In formula (I): (I) (a) or (b), A denotes a group (a) or (b), R4, R5, R6 and R7, each independently denote hydrogen, halogen, N-C1-6alkyl or N-hydroxyamido or inverse C-C1-6alkylamido (-NHCOC1-6alkyl), hydroxycarbonyl(-COOH), C1-6 alkyloxycarbonyl(-COOC1-6), C1-6alkyl or C1-6alkyl, substituted with a hydroxy group, C1-6dialkylamino or a saturated 5-6-member heterocyclic group with 1-2 heteroatoms and selected from nitrogen and oxygen atoms; R1 denotes a phenyl or a 6-member heteroaryl group with a nitrogen atom as a heteroatom, each of which is substituted with 1-3 X, or C1-6alkyl, substituted with a phenyl, which can be substituted with halogen atoms; R2 denotes hydrogen, hydroxy, C1-6alkoxy or C1-6alkoxy, substituted C1-6alkoxy or 5-6-member saturated heterocyclic group; R3 denotes hydrogen, -COOH, C1-6alkyloxycarbonyl or amido, N-unsubstituted or N-substituted Y; na and nb each is a whole number ranging from 1 to 3; where: X denotes hydrogen, halogen, hydroxy, cyano, nitro, (mono-, di- or trihalogen)methyl, mercapto, C1-6alkylthio, acrylamido, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, phenyloxy, C1-6dialkylamino or C1-6alkyl or C1-6alkoxy, substituted with Z, provided that when the number of substitutes X equals two or more, groups X can be condensed with each other to form a 5-member cyclic structure, possibly containing 2 nitrogen atoms in the ring as heteroatoms; Y denotes hydroxy, C1-6alkyl or C1-6alkyl substituted with Z, C1-6alkyl has 1-4 fragments selected from a group consisting of N, O, S, SO and SO2; and Z denotes C1-6alkyl, phenyl or a 6-member heterocyclic group containing one or more heteroatoms selected from N or O. Said phenyl or heterocyclic group is unsubstituted or substituted with a halogen.

EFFECT: improved properties of the derivatives.

4 cl, 7 tbl, 144 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula I or their pharmaceutically acceptable salts exhibiting the properties of voltage-dependent sodium channel inhibitors, such as NaV1.8. The latter play a central role in generating the action potentials in all excitable cells such as neurons and myocytes, and can be used for treating such diseases as epilepsy, irritable bowel syndrome, chronic pain, etc. In the compounds of formula I: R1 and R2 together with nitrogen atom a substituted ring selected from: (A),(B),(C),(D) or (E), which are specified in the patent claim, where in the ring (A): each of m1 and n1 is independently equal to 0-3, provided m1+n1 is equal to 3-4; z1 is equal to 0-4; Sp1 represents -O-, -S-, -NR'- or C1-C4alkylidene linker in which one methylene ring is optionally or independently substituted by -O-, provided Sp1 is bound with carbonyl group through an atom different from carbon; the ring B1 represents a 5-6-members saturated or aromatic, monocyclic or heterocyclic ring containing 1-4 heteroatoms selected from O or N with the ring B1 is optionally substituted by w1 independent variants -R11 with w1 being equal to 0-1; where in the ring (B): G2 represents CH; each of m2 and n2 is independently equal to 0-3, provided m2+n2 is equal to 2-4; p2 is equal to 0-2; q2 is equal to 0 or 1; z2 is equal to 0-4; Sp2 represents a bond or C1-C6alkylidene linker in which up to two methylene links are optionally or independently substituted by -O-. The other radical values are specified in the patent claim.

EFFECT: making new compounds of formula I or to their pharmaceutically acceptable salts showing the properties of voltage-dependent sodium channel inhibitors.

67 cl, 4 tbl, 503 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pharmaceutical composition having activity for stimulating formation of nerve tissue and (or) inhibiting neuron degeneration, containing a compound of formula , where each R1 is independently selected from a group consisting of H, F, CI, Br, R7 and -O-R7, where R7 denotes substituted alkyl containing 1-6 carbon atoms or an aralkyl or aryl group containing 6-14 carbon atoms; R2 is selected from O or S; R3 is selected from alkyl containing 1-6 carbon atoms or an ether containing 1-6 carbon atoms and R4 is selected from an aryl containing 6-14 carbon atoms, an aralkyl substituted with an aromatic group, substituted with a heteroatomatic group or substituted with a heteroaromatic-alkyl group, or R4 is selected from a substituted 3-quinolinylmethyl, 2-pyridyl, 2-pyridylmethyl, 2- or 4-pyrimidinyl, benzo[1,3]dioxol-5-yl or benzoxazolyl. The invention also relates to methods of stimulating formation of nerve tissue and/or inhibiting neuron degeneration, based on use of said compounds and specific compounds.

EFFECT: novel compositions and methods containing compounds which are useful for stimulating formation of nerve tissue.

23 cl, 5 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a N-(2-oxo-2-propoxyethyl)-β-phenyl-D- phenylalanyl-N-[(1-amino-6-isoquinolinyl)-methyl]-L-proline amide compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing said compound, as well as use of the compound to produce a medicinal agent for treating or preventing thrombin-mediated diseases. The invention also relates to a N-(carboxymethyl)-β-phenyl-D-phenylalanyl-N-[(1-amino-6-isoquinolinyl)methyl]-L-proline amide compound of pharmaceutically acceptable salt thereof.

EFFECT: obtaining novel compounds possessing useful biological properties.

5 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds of general formula

:, where X denotes halogen or (C1-C3)alkyl possibly substituted with a halogen; Y denotes hydrogen; R denotes hydrogen, halogen, cyano, (C1-C6)alkyl or (C2-C6)alkenyl possibly substituted with a halogen, (C2-C6)alkynyl possibly substituted with a halogen or hydroxy, (C1 -C6)alkoxy or (C2-C6)alkenyloxy, possibly substituted with a halogen, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxyamino(C1-C3)alkyl, phenyl, phenoxy, pyridyloxy or pyrimidyloxy, possibly substituted; n is an integer from 1 to 5; a plant disease control agent and a plant disease control method.

EFFECT: obtaining compounds with a wider suppressing spectrum at low doses of chemical processing, thus facilitating use as a plant disease control agent for agricultural and horticultural use, as well as reduced harmful effect on the environment.

4 cl, 6 tbl, 10 ex

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