2,5,7-substituted oxazolpyrimidine derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oxazolopyrimidine compounds of formula (I) , in which A is selected from NH, O and S; R1 is selected from (C1-C6)-alkyl, (C3-C7)-cycloalkyl-CtH2t and Het-CtH2t-, where t is selected from 0, 1, 2 and 3; R2 is selected from phenyl and residue of aromatic 5-member - 6-member monocyclic heterocycle, which includes 1, 2 similar or different ring heteroatoms, selected from N, O and S, in which one of ring nitrogen atoms can carry atom of hydrogen or substituent R21, and in which phenyl and aromatic heterocycle residue are optionally substituted in one or more ring carbon atoms with one or more similar or different substituent R22; R3 is selected from (C1-C6)-alkyl, or R3 represents residue of saturated or unsaturated 3-member - 10-member, monocyclic or bicyclic ring, which includes 0, 1, 2 or 3 similar or different ring nitrogen atoms can carry hydrogen atom or (C1-C4)-alkyl substituent and one or two ring sulphur atoms can carry one or two oxo groups, and in which ring residue is optionally substituted in one or more ring carbon atoms with similar or different substituents R31, on condition that R3 cannot be (C1-C6)-alkyl, if A represents S; other values of radicals are given in i.1 of formula.

EFFECT: compounds of formula (I) are suitable for wound healing.

16 cl, 2 tbl, 9 ex

 

This invention relates to a 2,5,7-substituted derivative of oxazolopyridine and their physiologically acceptable salts.

In the prior art (see WO 2009/154775) have already been described are structurally similar compounds that are suitable for the treatment of multiple sclerosis. The mechanism of action of these compounds is the induction of reducing the sensitivity of the EDG-1 signaling pathways by activation of EDG-1 receptor (so-called superiority), which is then equivalent to the functional antagonism EDG-1 signaling pathway. Systematically means that especially on lymphocytes EDG-1 signaling pathway is constantly suppressed, whereby these cells can no longer hemotoxicity to follow the S1P gradient between the blood and lymphatic fluid. This means that the affected lymphocytes can no longer leave secondary lymphatic tissue (finding increased home), and the number of freely circulating lymphocytes in the plasma is gradually reduced. This deficit of lymphocytes in plasma (lymphopenia) causes immunomodulant, which is required for the mechanism of action of modulators of EDG-1 receptor are described in WO 2009/154775.

The aim of the present invention was to provide compounds which are particularly suitable for wound healing and in particular for the treatment of disorders in connection with healing �EN in patients with diabetes. In addition, it is desirable to provide compounds that are suitable for the treatment of syndrome of diabetic foot (DFS). Furthermore, it is desirable to achieve reproducible activation of signaling pathways EDG-1 receptor, which thereby allows, speaking pharmacological terms, sustained activation of EDG-1 signaling pathway.

The present invention therefore relates to oxazolidinone compounds of formula I,

in which A, R1, R2and R3are defined as follows. The mechanism of action of the compounds of formula I, therefore, is not based on desensitization EDG-1 signaling pathway, and thus diametrically opposed to the mechanism of action described in WO 2009/154775. The invention furthermore relates to methods for obtaining compounds of formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

Compared to healthy adults in patients with diabetes delayed wound healing and increased rate of infection, especially in the case of long-term hyperglycemia caused by, for example, poor regulation of blood sugar. Causes include disorders of the circulation, especially in the area of thin vessels, which leads to a degraded fabric supply�th oxygen and nutrients. Furthermore, the reduced degree of cell division and cell migration of keratinocytes, dermal fibroblasts and endothelial cells. In addition, the reduced activity of defensive cells (granulocytes) with reduced phagocytosis and destruction of bacteria). The function of antibodies (immunoglobulins) against bacteria is also limited in the case of high blood sugar levels. Accordingly, wounds and infections in patients with diabetes need special care.

EDG-1 receptor is a member of the family gene (EDG) receptors of the endothelial differentiation of the eight identified currently class A GPCR (G-protein receptors combined). This family can be divided into subfamilies sphingosine-1-phosphate (S1P)-activated receptors (five members) and receptors activated lysophosphatidic acid (LPA; three members). The endogenous ligand S1P is a pluripotent lysophospholipids valid on EDG-1 in different cell types through activation of GPCR Edg family of receptors, namely EDG-1 (=S1P1), Edg-3 (=S1P3), Edg-5 (=S1P2), Edg-6 (=S1P4) and Edg-8 (S1P5). Although S1P is described as an intracellular messenger, numerous cellular responses S1P are mediated through the activation of Edg receptors. S1P is generated by a family of enzymes sphingosines (SPHK), and destroyed by different phosphatases or LiAZ.

The subject of this �of subramania is oxazolidinedione compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, or physiologically acceptable solvate of any of them,

in which

And selected from NH, O and S;

R1selected from (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-alkinyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1, 2 and 3;

R2selected from phenyl and residue of an aromatic, 5-membered to 6-membered monocyclic heterocycle which comprises 1, 2 or 3 identical or different ring heteroatom selected from N, O and S, where one of the ring nitrogen atoms can carry a hydrogen atom or a substituent R21and wherein the phenyl and residue of an aromatic heterocycle optionally substituted at one or more ring carbon atoms by one or more identical or different substituents R22;

R3selected from (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-alkinyl, (C3-C7-cycloalkyl-CuH2u-, and Het-CvH2v- where u and v are chosen from 1 and 2, or R3represents the residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroa�mA selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31provided that R3cannot be (C1-C6)-alkyl if A represents S;

R21selected from (C1-C4)-alkyl, (C3-C7-cycloalkyl-CwH2wand oxy, where w is selected from 0, 1 and 2;

R22selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, hydroxycarbonyl, (C1-C4)-allyloxycarbonyl, aminocarbonyl, aminosulfonyl, R23and R23-O-;

R23represents the residue of a saturated 3-membered to 7-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatom selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom, or (C1-C4)-alkyl substituent and one of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one�or more carbon atoms, equal or different substituents R 24;

R24selected from halogen, (C1-C4)-alkyl, hydroxy and oxo;

R31selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, nitro, cyano, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl;

Het is a residue of a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises 1 or 2 identical or different ring heteroatom selected from N, O and S, and which is linked via a ring carbon atom, wherein the residue of a heterocycle optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;

m is selected from 0, 1 and 2, wherein all numbers m are independent of each other;

where all cycloalkyl groups, independently of each other and independently of any other substituents optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;

where alkyl, CtH2t, C uH2u, CvH2v, CwH2w, alkenyl and Alchemilla groups independently from each other and independently of any other substituents optionally substituted by one or more forame as Deputy.

Structural elements such as groups, substituents, hetero ring members, numbers or other signs, for example, an alkyl group, group, R22or R31, the number, m, u and v, which take place several times in the compounds of formula I, can all independently of each other have any of the specified values can be in each case identical or different from each other. For example, the alkyl group in dialkylamino group may be the same or different.

Alkyl, alkenyl and Alchemilla group can be linear, i.e. straight-chain or branched. This also applies when they are part of other groups, for example, alkyloxy groups (= alkoxy groups, alkyl-O - groups), allyloxycarbonyl group or alkyl-substituted amino groups, or when they are substituted. Depending on the respective definition, the number of carbon atoms in the alkyl group may be 1, 2, 3, 4, 5 or 6 or 1, 2, 3, or 4, or 1, 2 or 3. Examples of alkyl are methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl, including�th n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexyl, including n-hexyl, 3,3-dimethylbutyl and isohexyl. Double and triple bonds in the alkenyl and etkinlik groups can be present in any positions. In accordance with one embodiment of the invention, the alkenyl groups contain one double bond, and alkyline groups contain one triple bond. In one of the embodiments of the invention, the alkenyl group, or Alchemilla group contains at least three carbon atoms and linked to the remainder of the molecule through a carbon atom that is not part of a double or triple bond. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (=allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-inyl (=propargyl), but-2-inyl, booth-3-inyl, hex-4-inyl or hex-5-inyl. Substituted alkyl, alkenyl and alkyline groups can be substituted in any positions, provided that the compound is sufficiently stable and suitable for the desired purpose, such as use as a medicinal substance. The prerequisite that a specific group and a compound of formula I were quite stable and suitable for the desired purpose, such as the use as a medicinal substance, applicable, in General, concerning the definitions of all groups in the compound of the Fort�uly I.

As applicable, the preceding explanations regarding alkyl groups apply correspondingly to divalent alkyl groups such as group CtH2t, CuH2u, CvH2vand CwH2wwho, therefore, can be similarly linear and branched. Examples of divalent alkyl groups are-CH2- (=methylene), -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-. If the number in the divalent group, such as the number of t in group CtH2tfor example , is 0 (=zero), two groups that are attached to the appropriate group, such as CtH2tdirectly connected to each other via a single bond.

The number of ring carbon atoms in cycloalkyl group can be 3, 4, 5, 6 or 7. In one of the embodiments of the invention, the number of ring carbon atoms in cycloalkyl group, regardless of the number of ring carbon atoms in any other cycloalkyl group is 3, 4, 5 or 6, in another embodiment 3, 4 or 5, in another embodiment 3 or 4, in another embodiment 3, in another embodiment 5, 6 or 7, in another embodiment 5 or 6, in another embodiment 6 or 7, in another embodiment 6. Examples cycloalkyl groups are cyclepro�Il, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Independently from each other, and independently of any other substituents, cycloalkyl group optionally substituted by one or more identical or different (C1-C4)-alkyl substituents which can be present in any positions, i.e. cycloalkyl groups can be unsubstituted by alkyl substituents, or substituted alkyl substituents, e.g., 1, 2, 3, or 4, or 1 or 2 -(C1-C4)-alkyl substituents, for example methyl groups. Examples of alkyl-substituted cycloalkyl groups are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclobutyl. Examples cycloalkenyl groups that may represent groups such as (C3-C7-cycloalkyl-CtH2tare, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylmethyl, 2-cyclobutylmethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, 2-cycloheptylmethyl.

Independently from each other, and independently of any other substituents, alkyl groups, divalent alkyl, alkenyl, alkyline and cycloalkyl group optionally substituted by one or more forame as Deputy, which can be in any position�, i.e. these groups may be unsubstituted forame as Deputy or replaced by Fermi as Deputy, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, or 1, 2, 3, 4, 5, 6, 7, 8 or 9, or 1, 2, 3, 4, 5, 6 or 7, or 1, 2, 3, 4, or 5, or 1, 2 or 3, or 1 or 2, forame as Deputy. Examples of these fluorine-substituted groups are 3-vermeil, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-cryptochromes, 2,2,3,3,3-pentafluoropropyl, 4,4,4-tripcomputer, heptafluoroisopropyl, -CHF -, - CF2-, -CF2-CH2-, -CH2-CF2-, -CF2-CF2-, -CF(CH3)-, -C(CF3)2- 1-forciblepoppy, 2,2-divorcecare, 3,3-diversilobum, 1-forcelogix, 4,4-dipterology, 3,3,4,4,5,5-hexaferrites. Examples of alkyloxy groups in which the alkyl fragment is fluorine-substituted, are triptoreline, 2,2,2-triptoreline, pentaborate and 3,3,3-cryptochromes. In accordance with one embodiment of the invention, the total number of fluorine substituents and (C1-C4)-alkyl substituents, which independently of any other substituents optionally present in cycloalkyl groups of formula I, is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, in accordance with another embodiment of 1, 2, 3, 4, 5, 6, 7, 8 or 9, in accordance with another embodiment 1, 2, 3, 4 or 5, in accordance with another embodiment of 1,2,3 or 4.

Group, the�s as phenyl, naphthyl (=naphthalenyl) and residues of aromatic heterocycles, which are optionally substituted by one or more substituents, can be unsubstituted or substituted, for example, 1, 2, 3, 4, or 5, or 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2, or 1, same or different substituents that may be located in any positions. In accordance with one embodiment of the invention, the total number of nitro substituents in the compound of formula I is at most two. Aromatic nitrogen heterocycles, in which the original ring system carry a hydrogen atom from any ring nitrogen atom a 5-membered ring, such as pyrrole, imidazole, indole or benzimidazole ring, for example, may be substituted at the ring carbon atoms and/or such ring nitrogen atoms. In accordance with one embodiment of the invention, such substituents at the ring nitrogen atoms is selected from (C1-C4)-alkyl groups, i.e. such ring nitrogen atoms in aromatic heterocycles are hydrogen atom or (C1-C4)-alkyl Deputy. When a ring nitrogen atoms in aromatic heterocycles and any other heterocycles indicates that they can carry a hydrogen atom or a Deputy, such ring nitrogen atoms or are hydrogen atom or a Deputy, or they do not carry a hydrogen atom or a substituent. To�Lavie nitrogen atoms, which carry a hydrogen atom or a Deputy, are nitrogen-containing aromatic 5-membered ring as present in pyrrole, imidazole, indole or benzimidazole, for example, and in non-aromatic ring including a saturated ring. Ring nitrogen atoms which do not carry a hydrogen atom or a Deputy, if they are not present in the positively charged form, including any additional ring nitrogen atoms, in addition to the ring nitrogen atoms which carry a hydrogen atom or a Deputy, are in the aromatic ring, as present in thiazoline, imidazole, pyridine or benzimidazole, for example, and in non-aromatic ring in which they are atoms in the head of the bridge or part of a double bond, and they are like a ring nitrogen atom through which the ring is associated. Suitable ring nitrogen atoms in aromatic heterocycles in the compounds of formula I, such as the ring nitrogen atom in the pyridine ring, especially a ring nitrogen atom in an aromatic heterocycle representing R2can also be hydroxy Deputy-O-and be present as N-oxide, and such ring nitrogen atoms may also be present in the form of a Quaternary salt, such as N-(C1-C4)-alkyl salt such as N-methyl salt, in which, in accordance with one in�proscenium of the invention, the counter anion in such a Quaternary salt is a physiologically acceptable anion which is derived from the acid that forms a physiologically acceptable salt. In monosubstituted phenyl groups Deputy may be in the 2-position, 3-position or 4-position. In di-substituted phenyl groups Deputy may be in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Three-substituted phenyl groups Deputy may be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. The naphthyl may be 1-naphthyl (=naphthalene-1-yl) or 2-naphthyl (=naphthalene-2-yl). In monosubstituted 1-naftalina groups Deputy may be in 2-, 3-, 4-, 5-, 6-, 7- or 8-position. In monosubstituted 2-naftalina groups Deputy may be in 1-, 3-, 4-, 5-, 6-, 7- or 8 - position. In disubstituted naftalina groups, the substituents can be in any position in the ring, through which binds naftalina group and/or in the other ring.

In the residues of aromatic heterocycles representing R2or R3that may be designated as heteroaryl groups, as well as in all other heterocyclic groups in the compounds of formula I, including the group Het and non-aromatic heterocyclic group, predstavlâûŝi� R 3ring heteroatoms typically selected from N, O and S, where N includes ring nitrogen atoms which carry a hydrogen atom or a substituent as well as ring nitrogen atoms which do not carry a hydrogen atom or a substituent. The ring heteroatoms can be present in any positions, provided that the heterocyclic system is known in the art and is suitable as a subgroup for the desired target compound of formula I such as use as a medicinal substance. In accordance with one embodiment of the invention, two ring oxygen atoms cannot be present in adjacent ring positions of the heterocycle, in accordance with another embodiment of two heteroatom ring selected from oxygen and sulfur cannot be present in adjacent ring positions of any heterocycle. Saturated rings do not contain double bonds in the ring. Unsaturated ring system may be aromatic or partially unsaturated, including partially aromatic, in which in the latter case one ring in the bicyclic ring system is aromatic, and the ring system is linked via an atom in non-aromatic ring. Depending on the respective group, the unsaturated ring may contain one, two, three, four or five double bonds in the ring. Aromatic groups� contain a cyclic system of six or ten delocalized pi electrons in the ring. Depending on the respective group, saturated or unsaturated non-aromatic heterocyclic ring, including Het and non-aromatic groups representing R3can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In accordance with one embodiment of the invention, an aromatic heterocyclic rings are 5-membered or 6-membered monocyclic rings or 8-membered, 9-membered or 10-membered bicyclic rings, in another embodiment 5-membered or 6-membered monocyclic rings or 9-membered or 10-membered bicyclic rings, in another embodiment 5-membered or 6-membered monocyclic rings, in which 8-membered, 9-membered or 10-membered bicyclic ring composed of two condensed 5-membered rings, 5-membered rings and 6-membered rings condensed with each other, and two condensed 6-membered rings, respectively. In bicyclic aromatic heterocyclic groups, one or both rings can contain heterokontae members, and one or both rings may be aromatic. Usually, the bicyclic ring system containing aromatic ring and non-aromatic ring, are regarded as aromatic when they are linked through the carbon atom in the aromatic co�ice, and as non-aromatic when they are linked through the carbon atom in the non-aromatic ring. Unless otherwise indicated, the heterocyclic group include aromatic heterocyclic groups can be bonded via any suitable ring carbon atom, and in the case of nitrogen heterocycles via any suitable ring nitrogen atom. In accordance with one embodiment of the invention, an aromatic heterocyclic group in the compound of formula I, independently of any other aromatic heterocyclic group, linked via a ring carbon atom, in another embodiment via a ring nitrogen atom. Depending on the definition of the corresponding heterocyclic group, in one embodiment of the invention, the number of ring heteroatoms which can be present in the heterocyclic group, regardless of the number of ring heteroatoms in another heterocyclic group, a is 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1, wherein the ring heteroatoms can be the same or different. Heterocyclic groups which are optionally substituted, independently of any other heterocyclic groups being unsubstituted or substituted by one or more identical or different substituents, for example, 1, 2, 3, 4, or 5, or 1, 2, 3 or 4 1 or 2 or 3, or 1 or 2, or 1 substituents, which are specified in the definition of the relevant group. The substituents in the heterocyclic groups can be in any positions. For example, pyridin-2-yl group substituents can be in the 3-position and/or 4-position and/or 5-position and/or 6-position of the pyridyl-3-yl group substituents can be located in the 2-position and/or 4-position and/or 5-position and/or 6-position, in pyridyl-4-yl group substituents can be located in the 2-position and/or 3-position and/or 5-position and/or 6-position.

The original examples of heterocycles that may occur heterocyclic group include aromatic heterocyclic groups, saturated heterocyclic groups and non-aromatic unsaturated heterocyclic group, are Aset, ocset, pyrrole, furan, thiophene, imidazole, pyrazole, [1,3]dioxol, oxazole (=[1,3]oxazol), isoxazole(=[1,2]oxazole), thiazole (=[1,3]thiazole), isothiazole (=[1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxidiazol, [1,3,4]oxidiazol, [1,2,4]thiadiazole, [1,3,4]thiadiazole, tetrazole, pyridine, PYRAN, thiopyran, pyridazine, pyrimidine, pyrazine, [1,3]oxazine Serie, [1,4]oxazine Serie, [1,3]thiazin, [1,4]thiazin, [1,2,3]triazine, [1,3]dithiin, [1,4]dithiin, [1,2,4]triazine, [1,3,5]triazine and [1,2,4,5]tetrazin, azepin, [1,3]diazepine, [1,4]diazepine, [1,3]oxazepine, [1,4]oxazepine, [1,3]diazepine, [1,4]diazepin, Asotin, Asarin, �of clopant[b]pyrrole, 2-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-ox-5-azabicyclo[2.2.1]heptane, indole, isoindole, benzothiophene, benzofuran, [1,3]benzodioxol (= 1,2-methylenedioxybenzene), [1,3]benzoxazol, [1,3]benzothiazol, benzoimidazol, thieno[3,2-C]pyridine, chrome, isochroman, [1,4]benzodioxin, [1,4]benzoxazine, [1,4]benzothiazine, quinoline, isoquinoline, cinnoline, chinazoline, quinoxaline, phthalazine, thienothiophene, [1,8]naphthiridine and other naphthyridine, pteridine, and the respective saturated and partially unsaturated heterocycles in which one or more, e.g. one, two, three, four or all double bonds in the ring system including double bonds in aromatic ring are replaced with single bonds, such as azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, oxazolidine, thiazolidine, dihydropyridine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, ASEAN, chroman, isochroman, [1,4]benzodioxan (= 1,2-atlantooccipital), 2,3-dihydrobenzofuran, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline,for example.

Examples of residues of aromatic heterocycles, which may be present in the compounds of formula I are thiophenyl (=thienyl) including thiophene-2-yl and thiophene-3-yl, pyridinyl (=pyridyl), including pyridin-2-yl (=2-pyridyl), pyridin-3-yl (=3-pyridyl) and pyridine-4-yl (=4-pyridyl), imidazolyl, including, for example, 1H-and�idazole-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl and 1H-imidazol-5-yl, [1,2,4]triazolyl including 1H-[1,2,4]triazole-1-yl and 4H-[1,2,4]triazole-3-yl, tetrazolyl including 1H-tetrazol-1-yl and 1H-tetrazol-5-yl, chinoline (=chinolin), including quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinoline-6-yl, quinolin-7-yl and quinolin-8-yl,which are all optionally substituted as indicated in the definition of the relevant group. Examples of residues of saturated and partially unsaturated heterocycles which may be present in the compounds of formula I are azetidinol, pyrrolidinyl, including pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, including piperidine-1-yl, piperidine-2-yl, piperidine-3-yl and piperidine-4-yl, 1,2,3,4-tetrahydropyridine, 1,2,5,6-tetrahydropyridine, 1,2-dihydropyridine, azepane, atenil, ascani, octahydrocyclopenta[b]pyrrolyl, 2,3-dihydrobenzofuranyl comprising 2,3-dihydrobenzofuran-7-yl, 2,3-dihydro-1H-indole, octahydro-1H-indole, 2,3-dihydro-1H-isoindolyl, octahydro-1H-isoindolyl, 1,2-dihydroquinoline, 1,2,3,4-tetrahydroquinoline, decahydroquinoline, 1,2-dihydroisoquinolines, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, decahydroquinoline, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, pyrazolidine, imidazolidinyl ureido, hexahydropyridine, 1,2-dihydropyrimidines, piperazinyl, [1,3]diazepan, [1,4]�of iazepine, oxazolidinyl, [1,3]oxazinyl, [1,3]oxazepan, morpholinyl comprising morpholine-2-yl, morpholine-3-yl and morpholine-4-yl, [1,4]oxazepan, diazolidinyl, [1,3]tiziani, thiomorpholine, including thiomorpholine-2-yl, thiomorpholine-3-yl and thiomorpholine-4-yl, 3,4-dihydro-2H-[1,4]triazinyl, [1,3]diazepan, [1,4]thiazepines, oxetanyl, tetrahydrofuranyl, tetrahydrofuryl, isoxazolidine, isothiazolinones, oxazolidinyl, [1,2,4]oxadiazolidine, [1,2,4]thiadiazolyl, [1,2,4]diazolidinyl, [1,3,4]oxadiazolyl, [1,3,4]thiadiazolyl, [1,3,4]thiazolidine, 2,3-dihydrofuran, 2,5-dihydrofuran, 2,3-dihydrothieno, 2,5-dihydrothieno, 2,3-dihydropyrrole, 2,3-dihydroisoxazole, 4,5-dihydroisoxazole, 2,5-dihydroisoxazole, 2,3-dihydroisoxazole, 4,5-dihydroisoxazole, 2,5-dihydroisoxazole, 2,3-dihydropyrazol, 4,5-dihydropyrazol, 2,5-dihydropyrazolo, 2,3-dihydrooxazolo, 4,5-dihydrooxazolo, 2,5-dihydrooxazolo, 2,3-dihydrothiazolo, 4,5-dihydrothiazolo, 2,5-dihydrothiazolo, 2,3-dihydroimidazole, 4,5-dihydroimidazole, 2,5-dihydroimidazole, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyranyl, tetrahydro[1,3,5]triazinyl, [1,3]ditional, tetrahydropyranyl, tetrahydropyranyl, [1,3]DIOXOLANYL, 3,4,5,6-tetrahydropyridine, 4H-[1,3]thiazines, 1,1-diokso-2,3,4,5-tetrahydrothieno, 2-azabicyclo[3.1.0]hexyl, including 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]g�KSIL, includes 3-azabicyclo[3.1.0]hex-3-yl, 2-ox-5-azabicyclo[2.2.1]heptyl, which includes 2-ox-5-azabicyclo[2.2.1]hept-5-yl,all linked via a suitable ring carbon atom or ring nitrogen atom, and all optionally substituted as indicated in the definition of the corresponding group.

Halogen is fluorine, chlorine, bromine or iodine. In accordance with one embodiment of the invention, any halogen in the compound of formula I is independent of any other halogen, selected from fluorine, chlorine and bromine, in another embodiment from fluorine and chlorine.

When the oxo group is linked to carbon atom, it replaces two hydrogen atoms at the carbon atom of the original system. So, if CH2group in the chain or ring is substituted by oxo group, i.e., an oxygen atom with a double bond, it becomes a group C(O) (=C(=O)). Obviously, oxo group may not be in as a Deputy at the carbon atom in the aromatic ring, such as, for example, phenyl group. When a ring sulfur atom in the heterocyclic group may bear one or two oxo groups, it is a non-oxidized sulfur atom S in the case if he does not carry any oxo group, or it is S(O) group (= sulfoxide group, S-oxide group) in case it carries one oxo group, or it is S(O)2group (= sulfonic group, S,S-dioxide group) in SL�tea if he bears two oxo groups.

The present invention encompasses all stereoisomeric forms of compounds of formula I and their salts and solvates. With regard to each chiral center, independently of any other chiral center, the compounds of formula I can be present in S configuration or substantially S configuration, or in R configuration or substantially R configuration, or as a mixture of the S isomer and the R isomer in any ratio. The invention covers all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, the compounds according to the invention which can exist as enantiomers can be present in enantiomerically pure form, as a left-rotating and right-rotating the antipodes, in the form of mixtures of the two enantiomers in all ratios including racemate. In the case of E/Z isomerism, or CIS/TRANS isomerism, for example, double bonds or rings, such as cycloalkyl rings, the invention envisages both the E form and Z form, or the CIS form and the TRANS form and mixtures of these forms in all ratios. In accordance with one embodiment of the invention, a compound which can be in two or more stereoisomeric forms, is pure or essentially pure, individual CTE�easemera. Individual stereoisomers can be carried out, for example, by separating a mixture of isomers by conventional methods, e.g., chromatography or crystallization, by using stereochemical homogeneous starting materials in the synthesis, or by using a stereo selective synthesis. Optionally, before separation of stereoisomers can be carried out by the derivatization. The separation of the mixture of stereoisomers can be carried out at the stage of a compound of formula I or at the stage of starting material or intermediate during the synthesis. The present invention also encompasses all tautomeric forms of compounds of formula I and their salts and solvates.

If compounds of formula I contain one or more acidic and/or basic groups, i.e. salt-forming groups, the invention also covers their corresponding physiologically or toxicologically acceptable salts, i.e. non-toxic salts, in particular their pharmaceutically acceptable salts. Thus, the compounds of formula I which contain an acid group, such as hydroxycarbonyl group (= carboxymethyl group = C(O)-Oh group), may be present on such groups and can be used in accordance with the invention, for example, in the form of salts of alkali metals, alkaline earth metals or ammonium salts. More specific examples �such salts include sodium salt, potassium, calcium, magnesium, Quaternary ammonium salts, such as salts of tetraalkylammonium, or acid-additive salts with ammonia or organic amines, such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula I contain a basic group, i.e. a group which can protonemata, such as an amino group or a nitrogen heterocycle, may be present on such groups and can be used according to the invention, in the form of additive salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, methanesulfonic acid, oxalic, acetic, trifluoroacetic, tartaric, lactic, benzoic, malonic, fumaric, maleic, citric and other acids known to specialists in this field. If the compound of the formula I simultaneously contain acidic group and basic group in the molecule, the invention also encompasses, in addition to the mentioned forms of salts, inner salts (= betaine, zwitterionic). Salts of compounds of formula I can be obtained by conventional methods known to experts in this field, for example, by contacting compounds of formula I with organic or inorganic acid or base in a solvent or diluent, or with momostenango or cation exchange from another salt. The invention also includes all salts of the compounds of formula I, which owing to low physiological compatibility of salt-forming acid or base are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or to obtain physiologically acceptable salts.

The present invention encompasses all solvates of compounds of formula I, for example hydrates or adducts with alcohols such as (C1-C4-alkanol, active metabolites of compounds of formula I, and also prodrugs and derivatives of the compounds of the formula I which in vitro do not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds, for example, esters or amides carbenoxolone groups.

In accordance with one embodiment of the invention, And is selected from NH and O, in another embodiment A is selected from NH and S, in another embodiment A is selected from O and S, in another embodiment a represents NH, in another embodiment A is O, in another embodiment A is S.

In accordance with another embodiment of the invention, the number t is selected from 0, 1 or 2, in another embodiment 0 or 1, in another embodiment from 1, 2 or 3, in another embodiment 1 or 2, in �sche one embodiment t is 0, in another embodiment t is 1. In accordance with one embodiment R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2t- and Het-CtH2t-, in another embodiment is selected from (C1-C6)-alkyl and (C3-C7-cycloalkyl-CtH2t-, in another embodiment R1represents (C1-C6)-alkyl, in another embodiment R1is (C3-C7-cycloalkyl-CtH2t- and in yet another embodiment R1represents Het-CtH2t-. In accordance with one embodiment R1represents (C3-C7-cycloalkyl-CtH2t- where t is selected from 0, 1 and 2, in another embodiment R1represents (C3-C7-cycloalkyl-CtH2t- where t is selected from 0 and 1, in another embodiment R1represents (C3-C7-cycloalkyl-CH2-, in another embodiment R1represents (C3-C7-cycloalkyl-, in another embodiment R1represents Het-CtH2t- where t is selected from 0, 1 and 2, in another embodiment R1represents Het-CtH2t- where t is selected from 0 and 1, in another embodiment R1is a Het-CH2-, in another embodiment R1is Het. In accordance with one embodiment� (C 1-C6)-alkyl group representing R1is (C2-C6)-alkyl, in another embodiment (C2-C5)-alkyl, in another embodiment (C3-C5)-alkyl. In accordance with one embodiment (C2-C6)-alkenyl group and (C2-C6)-Alchemilla group representing R1pose (C3-C6)-alkenyl and (C3-C6-alkynyl, in another embodiment (C3-C4)-alkenyl and (C3-C4-alkinyl, respectively. In accordance with one embodiment (C3-C7)-cycloalkyl group present in R1is (C3-C6-cycloalkyl, in another embodiment (C3-C5-cycloalkyl, in another embodiment (C3-C4-cycloalkyl, in another embodiment a cyclopropyl. In accordance with one embodiment of the invention the group Het representing R1represents a 4-membered to 6-membered, in another embodiment 4-membered to 5-membered, in another embodiment 4-membered, saturated monocyclic of heterocycl, linked via a ring carbon atom, which comprises 1 or 2 identical or different ring heteroatom, in another embodiment 1 ring heteroatom selected from N, O and S, in another embodiment from O and S, and in one embodiment are About atoms. In�testii with one embodiment the group Het, representing R1represents oxetanyl group, for example, oxetan-3-ilen group. In accordance with one embodiment the number of substituents which are optionally present in the group Het representing R1that is one, two, or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het is unsubstituted. In accordance with one embodiment (C1-C4)-alkyl Deputy, who is in the group Het representing R1is a methyl group.

In accordance with one embodiment of the invention, the number of ring heteroatoms in an aromatic heterocycle representing R2is 1 or 2, in another embodiment it is 1. In accordance with one embodiment of the invention R2selected from phenyl and residue of an aromatic, 6-membered monocyclic heterocycle which comprises 1, 2 or 3 ring nitrogen atom, in another embodiment 1 or 2 ring nitrogen atom, in another embodiment 1 ring nitrogen atom, where one of the ring nitrogen atoms can carry a substituent R21that represents hydroxy, i.e. where one of the ring nitrogen atoms can be oxidized to N-oxide, and where the phenyl and residue of an aromatic heterocycle optionally substituted at one or more ring carbon atoms�Yes identical or different substituents R 22. In accordance with another embodiment R2represents phenyl, where phenyl optionally substituted at one or more ring atoms by identical or different substituents R22in one embodiment, R2represents pyridinyl, where the ring nitrogen atom can carry a substituent R21which is oxy, i.e., where the ring nitrogen atom may be oxidized to N-oxide, and where is pyridinyl optionally substituted at one or more ring carbon atoms of identical or different substituents R22. In accordance with another embodiment R2represents the residue of an aromatic 5-membered heterocycle which comprises 1, 2 or 3 identical or different ring heteroatom selected from N, O and S, where one of the ring nitrogen atoms can carry a hydrogen atom or a substituent R21and where the residue of an aromatic heterocycle optionally substituted at one or more ring carbon atoms of identical or different substituents R22. In accordance with one embodiment of the residue of an aromatic heterocyclic group representing R2selected from furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, in another embodiment from furanyl, thiophenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl,in another embodiment from furanyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, in another embodiment from furanyl, thiophenyl, pyridinyl and pyrimidinyl, in another embodiment from furanyl, thiophenyl and pyridinyl, which are all optionally substituted as indicated with respect to R2. In yet another embodiment R2selected from one or more groups furan-2-yl, thiophene-2-yl, pyridyl-3-yl, pyridin-4-yl and pyrimidine-5-yl, in another embodiment from phenyl, furan-2-yl, thiophene-2-yl, pyridin-3-yl, pyridin-4-yl and pyrimidine-5-yl, in another embodiment from pyridin-3-yl and pyridin-4-yl, in another embodiment from phenyl, pyridin-3-yl and pyridin-4-yl, which are all optionally substituted as indicated with respect to R2. In accordance with one embodiment the number of substituents R22, which are optionally present on ring carbon atoms in R2is 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. Ring carbon atoms in R2that do not carry a substituent R22carry a hydrogen atom.

In accordance with one embodiment of the invention R3selected from (C1-C6)-alkyl, (C2-C6-alkenyl and (C2-C6)-alkynyl, in another embodiment R3is (C1-C6)-alkyl, in another voploscheni� R 3is (C2-C5)-alkyl, and in another embodiment R3is (C1-C4)-alkyl, provided that R3cannot be an alkyl group, if A is S. In accordance with another embodiment R3selected from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v-, in another embodiment R3is (C3-C7-cycloalkyl-CuH2u-, in another embodiment R3is Het-CvH2v- where in this embodiment the u and v independently from each other selected from 1 and 2. In accordance with one embodiment u is 1. in another embodiment u is 2. In accordance with one embodiment v is 1. in another embodiment, v is 2. In accordance with one embodiment of group (C3-C7-cycloalkyl-CuH2u- representing R3selected from dihydro-CuH2u- cyclobutyl-CuH2uand cyclopentyl-CuH2u-.

In accordance with one embodiment R3selected (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v-, or R3represents the residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms selected from N, O and S, where one or two of to�licevyh nitrogen atoms can carry a hydrogen atom or (C 1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31and in yet another embodiment R3represents the residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31. In accordance with one embodiment, the number of ring heteroatoms in the ring, representing R3is 0, 1, 2 or 3, in another embodiment it is 0, 1 or 2, in another embodiment it is 0 or 1, in another embodiment it is 0, in another embodiment it is 1, 2, 3 or 4, in another embodiment it is 1, 2 or 3, in another embodiment it is 1 or 2, in another embodiment it is 1. The remainder of the ring representing R 3maybe so, carbocyclic or heterocyclic. In accordance with one embodiment of ring heteroatoms in R3selected from N and O, in another embodiment from N and S, in another embodiment from O and S, in another embodiment they are N, in which the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl Deputy, under saturated or partially unsaturated heterocycles, or a 5-membered aromatic ring heterocycles, such as pyrrole or benzimidazole, for example, or not carry a hydrogen atom or (C1-C4)-alkyl Deputy, as available in aromatic heterocycles such as imidazole or pyridine, for example. In the rest of the heterocycle representing R3that includes one or more sulfur atoms, in one embodiment one of the ring atoms of sulfur is not oxidized or bears one or two oxo groups, and any other ring sulfur atoms are not oxidized. The residue is monocyclic or bicyclic ring representing R3may be associated with a group And via any suitable ring carbon atom or ring nitrogen atom. In accordance with one embodiment it is linked via a ring carbon atom, in another embodiment it is linked via a ring carbon atom or, if A represents NH, via to�iceway the nitrogen atom, in another embodiment it is attached via a ring nitrogen atom. The residue is monocyclic or bicyclic ring representing R3may be unsaturated, and in this case contains 1, 2, 3, 4, or 5, or 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2, or 1 double bond in the ring and may be in any of the two groups, aromatic or non-aromatic, or it can be saturated, and in this case does not contain in the ring no double bonds. In accordance with one embodiment, the residue of a ring, representing R3is saturated or aromatic, in another embodiment it is saturated, and in another embodiment it is aromatic. In accordance with one embodiment of the residue 3-membered or 4-membered ring representing R3is saturated. If R3includes ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent may contain one ring nitrogen atom, or two of the ring nitrogen atom. In accordance with one embodiment of the number of optional substituents of R31the ring carbon atoms in the ring, representing R3is 1, 2, 3, 4, 5 or 6, in another embodiment 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1

The ring, which can represent R3can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In accordance with one embodiment R3is a 4-membered to 10-membered, in another embodiment 4-membered to 9-membered, in another embodiment 4-membered to 8-membered, in another embodiment 4-membered to 7-membered, in another embodiment 5 to 7 membered, in another embodiment 5 - or 6-membered, in another embodiment 6-membered, in another embodiment of 8-10-membered, in another embodiment 9-10-membered. In accordance with one embodiment of the 3-membered ring representing R3that does not include any ring heteroatoms. In accordance with one embodiment R3is a monocyclic, in yet another embodiment bicyclic. In accordance with one embodiment of the bicyclic group representing R3is at least 7-membered. Amongst the rest of the ring, representing R3may be cycloalkyl, phenyl, naftalina group, a residue of an unsaturated, aromatic or non-aromatic heterocyclic group or a residue of a saturated heterocyclic group, which are all optionally substituted at ring carbon atoms and ring nitrogen atoms, as indicated in the relation R3. With regard to applicability, all the explanations given above in otnosheniiakh groups applicable respectively to R3. Another example of groups which can represent R3are cycloalkenyl groups such as (C5-C7)-cycloalkenyl groups which can be bonded via any ring carbon atom and optionally substituted as indicated with respect to R3. In one embodiment, the optional substituents of R31I cycloalkenyl groups representing R3chosen from fluorine and (C1-C4)-alkyl. In accordance with one embodiment cycloalkenyl groups contain one double bond in the ring, which may be present in any position. Examples cycloalkenyl are cyclopentenyl, including cyclopent-1-enyl, cyclopent-2-enyl and cyclopent-3-enyl, cyclohexenyl, including cyclohex-1-enyl, cyclohex-2-enyl and cyclohex-3-enyl, and cycloheptenyl, including cyclohepta-1-enyl, cyclohepta-2-enyl, cyclohepta-3-enyl and cyclohepta-4-enyl. Examples of residues of rings, of which the selected R3in one embodiment of the invention, are cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxetanyl, including oxetan-3-yl, tetrahydrofuranyl, including tetrahydrofuran-3-yl, tetrahydrothiophene, including tetrahydrothiophene-3-yl, tetrahydropyranyl, including tetrahydropyran-4-yl, azetidine, including azetidin-1-yl, pyrrolidinyl, piperidinyl, imidazolidinyl ureido, piperazinyl, �morpholinyl, including morpholine-1-yl, thiomorpholine, furanyl, including furan-3-yl, thiophenyl, including thiophene-3-yl, pyrazolyl, including pyrazol-3-yl, imidazolyl, thiazolyl, including thiazol-2-yl, pyridinyl including pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, pyridazinyl, including pyridazin-3-yl, where all of them, if applicable, one or two ring nitrogen atom may carry a hydrogen atom or (C1-C4)-alkyl, and where all of them optionally substituted by one or more ring carbon atoms of identical or different substituents R31and where in all of them, if applicable, a ring sulphur atom may be non-oxidized, i.e. be present as a sulfur atoms or to carry one or two oxo groups, i.e. be present in the form of sulfoxide or sulfone.

In accordance with one embodiment R3selected from phenyl and a residue of a saturated or unsaturated 3-membered to 7-membered, monocyclic ring, in another embodiment from phenyl and a residue of a saturated or unsaturated 5-membered to 7-membered, monocyclic ring, in another embodiment from phenyl, pyridinyl and residue of a saturated 3-membered to 7-membered, monocyclic ring, in another embodiment from phenyl, pyridinyl and residue of a saturated 5-membered to 7-membered, monocyclic ring, in yet another embodiment from phenyl and a residue of a saturated 3-membered to 7-Glenn�, monocyclic ring, in another embodiment from phenyl and a residue of a saturated 5-membered to 7-membered, monocyclic ring, where in all these embodiments a monocyclic ring comprises 1 or 2 identical or different ring heteroatom selected from N, O and S, where one or two ring nitrogen atom may carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atom can carry one or two oxo groups and where the phenyl, pyridinyl, and the remainder of the ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31and where pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. In accordance with one embodiment R3selected from phenyl and pyridinyl, in another embodiment R3represents pyridinyl, and in another embodiment R3represents phenyl, where in these embodiments pyridinyl includes groups pyridin-2-yl, pyridin-3-yl and pyridin-4-yl in one embodiment selected from one or more data groups, and where in all these embodiments, the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms of identical or different substituents R31.

In accordance with one embodiment w is selected from 0 and 1, in another embodiment it is 0, in another�nom embodiment it is 1. In accordance with one embodiment (C3-C7)-cycloalkyl group present in R21is (C3-C6-cycloalkyl, in another embodiment (C3-C5-cycloalkyl, in another embodiment a cyclopropyl. In accordance with one embodiment R21selected from (C1-C4)-alkyl and hydroxy, in another embodiment R21represents (C1-C4)-alkyl, in another embodiment it is (C1-C3)-alkyl, in another embodiment it is methyl, and in another embodiment it represents hydroxy.

In accordance with one embodiment of the invention, the substituents R22which are not necessarily present in the group R2selected from halogen , hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, R23and R23-O-, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, amino, cyano, R23and R23-O-, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, R23and R23-O-, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl and (C1-C4)-alkyloxy-where in all embodiments of R23has the values defined here.

� accordance with one embodiment of the 1, 2 or 3 of the substituents R22in yet another embodiment 1 or 2 of the substituents R22and in yet another embodiment 1 of the substituents R22which are not necessarily present in the group R2have the meanings indicated in the General definition of R22and hereby are selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, hydroxycarbonyl, (C1-C4)-allyloxycarbonyl, aminocarbonyl, aminosulfonyl, R23and R23-O-, where R23has certain values here, and any additional substituents R22which are not necessarily present in the group R2for example , 1, 2 or 3 additional Deputy R22or 1 or 2 additional Deputy R22or 1 further substituent R22selected from halogen , hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, R23and R23-O-, where all alkyl groups independently of each other optionally substituted by one or more forame as Deputy, as generally applies to alkyl groups. In accordance with one embodiment of the substituents R22which are not necessarily present in the group R2and who in the aforementioned waples�research Institute determined as specified in the General definition of R22for example , 1 or 2 such Deputy R22or 1 such substituent R22selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, R23and R23-O-, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, R23and R23-O-, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, amino, R23and R23-O-, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino and cyano, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy - and cyano, where R23has the values defined here. In accordance with one embodiment of the substituents R22which are not necessarily present in the group R2and in which the above-mentioned embodiment have the meanings given in the General definition of R22for example , 1 or 2 such Deputy R22or 1 such substituent R22are not arranged at the annular carbon atoms in the group R2that are adjacent to the atom through which the group� R 2associated with oxazolidinedione ring depicted in formula I. In accordance with another embodiment in the case of the phenyl group representing R21 or 2 of such substituent R22or 1 such substituent R22not necessarily present in one of the positions 3, 4 and 5 of the phenyl group, and in another embodiment 1 such substituent R22is present in position 4 of the phenyl group. In accordance with one embodiment of the optional substituents of R22which are not necessarily present in the group R2for example , 1, 2 or 3 additional Deputy R22or 1 or 2 additional Deputy R22or 1 further substituent R22selected from halogen , hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino and cyano, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, amino and cyano, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy - and cyano, in another embodiment from halogen, (C1-C4)-alkyl and (C1-C4)-alkyloxy in another embodiment from halogen and (C1-C4)-alkyl-where in all these embodiments all alkyl groups independently of each other optionally substituted on�or more fluorine substituents.

In accordance with one embodiment of the invention R23is the remainder monocyclic ring, in another embodiment the remainder of the bicyclic ring. The remainder of the ring representing R23may be carbocyclic or heterocyclic. In accordance with one embodiment of the balance monocyclic ring representing R23is carbocyclic, in yet another embodiment heterocyclic. In accordance with one embodiment of the residue bicyclic ring representing R23is carbocyclic, in yet another embodiment heterocyclic. In accordance with one embodiment of the invention, the number of ring heteroatoms in R23is 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1, and in another embodiment it is 0, and in this latest incarnation, R23thus is (C3-C7)-cycloalkyl group. In accordance with one embodiment of the balance monocyclic ring representing R23is oxetanyl group, for example, oxetan-3-ilen.

In accordance with one embodiment of ring heteroatoms in R23selected from N and O, in another embodiment from O and S, in another� incarnation of them is N, and in yet another embodiment of them is O, where the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl Deputy. R23can be attached via any suitable ring carbon atom and the ring nitrogen atom. If R23connected to the oxygen atom, in one embodiment, R23attached via a ring carbon atom. In accordance with another embodiment, R23attached via a ring carbon atom, regardless of the atom attached to R23. In accordance with another embodiment, R23attached via a ring nitrogen atom. In accordance with another embodiment of the number of optional substituents of R24the ring of carbon atoms in R23is 1, 2, 3, or 4, or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. R23can be 3-, 4-, 5-, 6- or 7-membered. In accordance with one embodiment R23is a 4-7-membered, in another embodiment 4-6-membered, in another embodiment of the 5-6-membered, in another embodiment 4-5-membered. In accordance with one embodiment of the 3-membered ring representing R23not contain any ring heteroatoms. Examples of residues of rings, of which the selected R23in one embodiment of the invention, are oxetan-3-yl, azeti�in-1-yl, pyrrolidin-1-yl, piperidine-1-yl, piperidine-4-yl, morpholine-4-yl and piperazine-1-yl, which are all optionally substituted as indicated. In accordance with one embodiment R23selected from one or more residues of oxetan-3-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, morpholine-4-yl and piperazine-1-yl, in another embodiment of any one or more of the residues oxetan-3-yl, azetidin-1-yl, piperidine-1-yl, morpholine-4-yl and piperazine-1-yl, in another embodiment of any one or more residues of oxetan-3-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-Il, and in another embodiment R23is oxetan-3-yl, which are all optionally substituted as indicated.

In accordance with one embodiment of the invention R24selected from halogen, (C1-C4)-alkyl and hydroxy, in another embodiment from fluorine, (C1-C4)-alkyl and hydroxy, in another embodiment from fluorine, methyl and hydroxy, in another embodiment from fluorine and methyl, in another embodiment from methyl and hydroxy, in another embodiment from fluorine, (C1-C4)-alkyl, hydroxy and oxo.

In accordance with one embodiment of the invention R31selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1/sub> -C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyano, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, OK�about, amino, (C1-C4)-alkylamino and di((C1-C4)-alkyl)amino, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyloxy and di((C1-C4)-alkyl)amino, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy and (C1-C4)-alkyloxy, in another embodiment from halogen, (C1-C4)-alkyl and (C1-C4)-alkyloxy, in another embodiment from fluorine, chlorine, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy and (C1-C4)-alkyloxy, where in all these embodiments all alkyl groups, independently of each other, optionally substituted one or more fluorine substituents.

In accordance with one embodiment of the optional substituents of R31the aromatic ring residue representing R3for example , the phenyl group or pyridinoline groups representing R3selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyano, (C1-C4)-alkyl�of arbonil, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino and di((C1-C4)-alkyl)amino, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyloxy go((C 1-C4)-alkyl)amino, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy and (C1-C4)-alkyloxy, in another embodiment from halogen, (C1-C4)-alkyl and (C1-C4)-alkyloxy, in another embodiment from fluorine, chlorine, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy and (C1-C4)-alkyloxy, where in all these embodiments all alkyl groups, independently of each other, optionally substituted one or more fluorine substituents.

In accordance with one embodiment of the optional substituents of R31the residue of a saturated or unsaturated non-aromatic ring, representing R3selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl and cyano, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino and cyano, in another embodiment from halogen, (C1-C43-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy and oxo, in another embodiment from halogen, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyloxy and oxo, in another embodiment from fluorine, chlorine, (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyloxy and oxo, in another embodiment from (C1-C4)-alkyl, hydroxy and oxo, in another embodiment from alkyl and hydroxy, and in another embodiment they are (C1-C4)-alkyl, where in all these embodiments all alkyl groups independently of each other optionally substituted by one or more fluorine substituents. If the balance ring representing R3contains any oxo groups as substituents R31in one embodiment there are not more than two such oxo Deputy, and in yet another embodiment not more than one such oxo Deputy.

In accordance with one embodiment of the invention, the ring heteroatoms in Het selected from N and O, in another embodiment from O and S, in another embodiment they are About atoms. In accordance with another embodiment, the number of ring heteroatoms in Het is 1. In accordance with one embodiment two ring oxygen atom in Het is not present in adjacent ring positions, in another embodiment two ring heteroa�mA selected from O and S, not present in adjacent ring positions, in another embodiment two ring heteroatom are not present in adjacent ring positions. Ring nitrogen atoms in Het are a hydrogen atom or a Deputy, as defined here. In accordance with one embodiment of optional substituents at the ring nitrogen atoms in Het are (C1-C4)-alkyl substituents. In accordance with one embodiment of optional substituents at the ring nitrogen atoms and ring carbon atoms in Het are (C1-C4)-alkyl substituents. In accordance with one embodiment, the number of optional substituents at Het is 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. Het may be bonded via any suitable ring carbon atom. In accordance with one embodiment Het is attached via a ring carbon atom that is not adjacent to a ring heteroatom. Het can be 4-, 5-, 6 - or 7-membered. In accordance with one embodiment Het is a 4 - or 5-membered, in another embodiment 5- - 7-membered, in another embodiment 5 - or 6-membered, in another embodiment 4-membered. Examples of Het, where Het is selected in one embodiment, are oxetanyl, including oxetan-2-yl and oxetan--Il, tetrahydrofuranyl, including tetrahydrofuran-2-yl and tetrahydrofuran-3-yl, tetrahydropyranyl, including tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl, oxetanyl, including oxepin-2-yl, oxepin-3-yl and oxepin-4-yl, [1,3]DIOXOLANYL, including [1,3]dioxolan-2-yl and [1,3]dioxolan-4-yl, [1,4]dioxane, including [1,4]dioxan-2-yl, titanyl, including teetan-2-yl and tietan-3-yl, tetrahydrothiophene, including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, tetrahydrothiopyran, including tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl, [1,4]ditional, including [1,4]dition-2-yl, azetidine, including azetidin-2-yl and azetidin-3-yl, pyrrolidinyl, including pyrrolidinyl-2-yl and pyrrolidinyl-3-yl, piperidinyl, including piperidinyl-2-yl, piperidinyl-3-yl and piperidinyl-4-yl, azepane, including azepin-2-yl, azepin-3-yl and azepin-4-yl, oxazolidinyl, including oxazolidin-2-yl, oxazolidin-4-yl and oxazolidin-5-yl, thiazolidine, including thiazolidin-2-yl, thiazolidin-4-yl and thiazolidin-5-yl, morpholinyl, including morpholine-2-yl and morpholine-3-yl, thiomorpholine, including thiomorpholine-2-yl and thiomorpholine-3-yl, which are all optionally substituted as indicated with respect to Het.

The subject of the invention are all compounds of formula I, where any one or more structural elements such as groups, substituents and numbers have the values defined in any�m of the specified embodiments or definitions of the elements or have any one or more specific values, which are mentioned herein as examples of elements, where all combinations of one or more specified embodiments and/or definitions and/or specific values of the elements are the subject of the present invention. With respect to all such compounds of formula I, object of the present invention are also all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvates of any of them.

Example compounds of the invention which with respect to any structural elements have the values defined in the specific embodiments of the invention or definitions of such elements, and which are the subject of the invention are compounds of formula I, in which

R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1, and 2;

the group Het, available in R1represents a residue of a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises 1 ring heteroatom selected from O and S, and which is linked via a ring carbon atom, where the residue of a heterocycle optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl; and

all other groups and numbers them�Ute values specified in the General definition of the compounds of formula I or in any specified embodiments of the invention or definitions of structural elements, in any of their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvates of any of them.

Another such example are compounds of the formula I, in which

R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1 and 2;

R2selected from phenyl and pyridinyl, where the ring nitrogen atom of pyridine may bear a hydroxy substituent, and where the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms by one or more identical or different substituents R22;

R3selected from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v- where u and v are chosen from 1 and 2, or R3represents the residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatom selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atom can carry one silt� two oxo groups, and where the rest of the ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31; and

all other groups and numbers have the meanings given in the General definition of the compounds of formula I or in any specified embodiments of the invention or definitions of structural elements, in any of their stereoisomeric forms or mixtures of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvates of any of them.

Another such example are compounds of the formula I, in which

And selected from NH, O and S;

R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1 and 2;

R2selected from phenyl and pyridinyl, where the ring nitrogen atom of pyridine may bear a hydroxy substituent, and where the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms by one or more identical or different substituents R22;

R3selected from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v- where u and v are chosen from 1 and 2, or R3represents the residue of a saturated or unsaturated, 3-membered to 7-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatom, in�selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atom can carry one or two oxo groups and where the rest of the ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31;

R22selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, cyano, aminocarbonyl, aminosulfonyl, R23and R23-O-;

R23represents the residue of a saturated 3-membered to 6-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatom selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one of the ring sulfur atoms can carry one or two oxo groups and where the rest of the ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R24;

R24selected from fluorine, (C1-C4)-alkyl and hydroxy;

R31selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-� 4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl;

Het is a residue of a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises 1 or 2 identical or different ring heteroatom selected from N, O and S, and which is linked via a ring carbon atom, wherein the residue of a heterocycle optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;

m is selected from 0, 1 and 2, wherein all numbers m are independent of each other;

where all cycloalkyl groups, independently of each other and independently of any other substituents optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;

where alkyl, CtH2t, CuH2uand CvH2vthe group, all independent from each other and independently of any other substituents optionally substituted by one or more fluorine substituents,

in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically PR�acceptable solvates of any of them.

Similarly, also with respect to all specific compounds described herein, such as compounds of examples that represent embodiments of the invention, in which different groups and numbers in the General definition of the compounds of formula I are of particular value present in the relevant specific connection, it is assumed that they are the subject of the present invention in any of their stereoisomeric forms and/or mixtures of stereoisomeric forms in any ratio, and in the form of their physiologically acceptable salts and in the form of their physiologically acceptable solvates of any of them. Regardless, there is disclosed a specific compound in the form of a free compound and/or as a specific salt, they are the object of the invention, and in the form of the free compounds and in the form of all its physiologically acceptable salts, and, if disclosed specific salt, optionally in the form of this specific salt, and in the form of a physiologically acceptable solvate of any of them. Thus, the subject invention is also the compound of the formula I which is selected from any one or more specific compounds of formula I described herein, including compounds of the examples listed below, and their physiologically acceptable salts and physiologically acceptable solvates of any of them, where the compound of formula I is �the subject of the invention in any of the stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, if applicable.

Another object of the present invention are methods of obtaining the compounds of formula I and their salts and solvates, which compounds can be obtained and which are as follows. In accordance with one method, the compound of formula II is subjected to reaction with a compound of formula III, giving the compound of formula I,

where the groups A, R1, R2and R3in the compounds of formulas II and III have the meanings given in the definition of compounds of the formula I and additionally functional groups can be present in protected form or in the form of a preceding group which is later converted into the final group. The group Alk in compounds of the formula IIa is (C1-C4)-alkyl group, e.g. methyl or ethyl.

The reaction of compounds of formulae II and III is the reaction of nucleophilic aromatic substitution on the carbon atom at the 5-position of oxazole[5,4-d]pyrimidine ring, i.e. in the pyrimidine fragment, and can be carried out under standard conditions for such reactions which are well known to specialists in this field. Usually the reaction is carried out in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichlorid�n, simple ether, such as tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether or 1,2-dimethoxyethane (DME), a ketone, such as acetone or butan-2-he, ester such as ethyl acetate or butyl acetate, a nitrile such as acetonitrile, amide such as N,N-dimethylformamide (DMF) or N-methylpyrrolidine-2-he (NMP), or mixtures of solvents, at temperatures ranging from about 20C to about 160C, for example, at temperatures of from about 40 to about 100C, depending on the characteristics of the case. Usually to enhance the nucleophilicity of the compound of formula III is favorable to add a base, e.g. a tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as alkaline earth metal hydride, hydroxide, carbonate or bicarbonate, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or diisopropylamide lithium. The compound of formula III may also be processed by the base and turn into a salt separately before the reaction with the compound of formula II.

The starting compounds of formulas II and III can be obtained by using the procedures described in the literature or analogous processes�am described in the literature, and in many cases are industrially available. Compounds of formula II can be obtained by reaction of the ester of aminomalonate acid of formula IV with an activated carboxylic acid derivative of the formula V to produce a compound of formula VI, the reaction of the latter compound with thiourea of the formula VII to produce a compound of formula VIII, alkylation of thiol alkylation reagent of formula IX to obtain the thioether of the formula X, cyclization of the latter compound with formation of oxazol[5,4-d]pyrimidine ring system to produce a compound of formula XI, alkylation of the latter compound by an oxygen atom of ketogroup or tautomeric hydroxy group, respectively, with an alkylating reagent of the formula XII, and simple oxidation of thioether fragment in the resulting compound of formula XIII with getting sulfone of the formula II.

Group, R1and R2in the compounds of formulas V, VI, VIII, X, XI, XII and XIII have the meanings given in the definition of compounds of formula I, and additionally can functional groups present in protected form or in the form of a preceding group which is later converted into the final group. The group Alk in compounds of formulas IX, X, XI and XIII has the values listed in the definition of compounds of formula II. The group R' in the compounds �of oral IV and VI may be alkyl, as (C1-C3)-alkyl, such as methyl or ethyl. Group L1in the compounds of the formula V is nucleophilic substitutable leaving group and may be in particular a halogen atom such as chlorine or bromine, and the compound of the formula V may, therefore, be halogenerator carboxylic acid. L1can also be a group of the formula R2-C(O)-Oh, and the compound of formula V can be thus, for example, a carboxylic acid anhydride. Group L2and L3represent leaving groups which may be substituted in the reaction of nucleophilic substitution and can be in particular a halogen atom such as chlorine, bromine or iodine, or sulfonyloxy group such as methanesulfonate, triftormetilfullerenov or toluensulfonate, i.e. compounds of formulas IX and XII may be, for example, organic halides or sulfonates. As mentioned, the compounds of formula XI may also be present in tautomeric form, for example in the form of derivatives of 7-hydroxy-oxazol[5,4-d]pyrimidine, in which the mobile hydrogen atom, in formula XI is associated with an annular nitrogen atom in 6-position oxazolidinedione ring system, is connected to the oxygen atom adjacent to the ring carbon atom at the 7-position. With regard to the applicability, applicable to all compounds having months�about when obtaining compounds of formula I, they can be present in any particular tautomeric form than the form that is shown in their formulas. In reactions of this process of producing compounds of formula II, as in all the other reactions involved in the formation of compounds of formula I, can also be used starting compounds and/or products obtained in salt form. For example, compounds of formula IV can be applied in the form of additive salts of acids, such as hydrochloride.

The reaction of compounds of formulas IV and V can be carried out in standard conditions of acylation of an amine activated carboxylic acid derivative, such as galoyanized or acid anhydride. Usually the reaction is carried out in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, a simple ether, such as THF, dioxane, dibutyl ether, diisopropyl ether or DME, a ketone, such as acetone or butan-2-he, ester such as ethyl acetate or butyl acetate, or in water, or mixture of solvents, at temperatures from about-10C to about 40C, for example, at temperatures from about 0C to about 30C. Usually the reaction is carried out with addition of a base, e.g. a tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholin, or reorgan�ical grounds, such as the hydroxide, carbonate or bicarbonate of an alkali metal as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate. The reaction of compounds of formulas VI and VII is usually carried out in an inert solvent, e.g. an alcohol, such as methanol, ethanol or isopropanol, or in a simple ether, such as THF, dioxane or DME, or a mixture of solvents, at temperatures ranging from about 20C to about 80C, for example, at temperatures of from about 40C to about 80C in the presence of base, for example, alkoxide, such as sodium methoxide, ethoxide sodium methoxide or potassium tert-butoxide potassium.

The reaction of compounds of formulae VIII and IX is a reaction of nucleophilic substitution on the terminal carbon atom in the alkyl group, the carrier group L2and can be carried out under standard conditions for such reactions which are well known to specialists in this field. Usually, the reaction is carried out in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, a simple ether, such as THF, dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone or butan-2-he, ester such as ethyl acetate or butyl acetate, n�tile, such as acetonitrile, amide, such as DMF or NMP, or a mixture of solvents, including two-phase mixture with the aqueous solutions, at temperatures of from about-20C to about 100C, for example at temperatures from about-10C to about 30C, depending on the characteristics of the case. Usually to enhance the nucleophilicity of the compound of formula VIII and/or bind the acid which is liberated during the reaction, it is favorable to add a base, e.g. a tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as a hydride, hydroxide, carbonate or bicarbonate of an alkali metal as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or diisopropylamide lithium. The compound of formula VIII may also be processed by the base and turn into a salt separately before the reaction with the compound of formula IX.

Cyclization of a compound of formula X to the compound of formula XI may favorably be carried out in the presence of a phosphorus halide such as phosphorus pentachloride or phosphorus oxychloride or mixtures thereof, in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon, �ACOM as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, at temperatures ranging from about 20C to about 100C, for example at temperatures from about 50C to about 80C.

The reaction of compounds of formulae XI and XII is another nucleophilic substitution reaction at the carbon atom in the group R1, carrier group L3and can be carried out in standard reaction conditions that are well known to specialists in this field. Usually the reaction is carried out in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, a simple ether, such as THF, dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone or butan-2-he, ester such as ethyl acetate or butyl acetate, a nitrile such as acetonitrile, amide, such as DMF or NMP, or a mixture of solvents, at temperatures ranging from about 20C to about 100C, for example, at temperatures of from about 40C to about 80C, depending on the characteristics of the case. Usually to enhance the nucleophilicity of the compound of formula XI and/or bind the acid which is liberated during the reaction, it is favorable to add a base, e.g. a tertiary amine, such contritely, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as a hydride, hydroxide, carbonate or bicarbonate of an alkali metal as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or diisopropylamide lithium. The compound of the formula XI may also be processed by the base and turn into a salt separately before the reaction with the compound of formula XII. In addition, obtained by the reaction with a compound of formula XII, a compound of formula XI can turn into a compound of formula XIII by reaction with a suitable alcohol of the formula R1-HE, where R1has the meanings given for compounds of formula I, and additionally can functional groups present in protected form or in the form of group-predecessor, under the reaction conditions of Mitsunobu in the presence of azodicarboxylate, such as diethylazodicarboxylate or diisopropylcarbodiimide, and phosphine, such as triphenylphosphine or tributylphosphine, in an inert aprotic solvent, for example, a simple ether, such as THF or dioxane (cf. O. Mitsunobu, Synthesis (1981), 1-28).

Oxidation of Alk-S - group in compounds of formula XIII as a sulfonic group in the compounds of formula II can osushestvlya�Xia using hydrogen peroxide or percolate, such as 3-chloroperbenzoic acid or monoperoxyphthalic acid, in an inert solvent such as chlorinated hydrocarbon, such as dichloro methane or chloroform or ester, such as ethyl acetate or butyl acetate, at temperatures from about 0 C to about 40 C, for example, at about 20C.

The sequence of the stages in the formation of compounds of formula X can also be changed first and the ester aminomalonate acid of formula IV, such as diethyl ether complex is introduced into the reaction with thiourea in presence of alkali metal alkoxide, such as ethoxide sodium, then the sulfur atom alkiliruya, for example, metiliruetsa iodomethane, and the product allerede compound of the formula V (cf. M. H. Holschbach et al., Eur. J. Med. Chem. 41 (2006), 7-15).

Additional compounds of formula I can be derived from suitable compounds obtained in accordance with the above-described processes using the functionalization or modification of contained functional groups according to standard procedures, for example, a complex esterification, amidation, hydrolysis, simple esterification, alkylation, acylation, sulfonylamine, recovery, oxidation, conversion into salts, and others. For example, a hydroxy group, which can be freed from the ethyl group by splitting �easiest ether, for example, using tribromide boron, or a protected hydroxy group using unprotect, maybe hard to tarifitsirovatsja, giving ether carboxylic acids or ether sulfonic acids, or transform in a simple ether. The esterification reaction of hydroxy groups can favorably be carried out by alkylation of the corresponding compound of halogen, such as bromide or iodide, in the presence of base, e.g. an alkali metal carbonate such as potassium carbonate or cesium carbonate. In an inert solvent, for example, amide like DMF or NMP or a ketone like acetone or butan-2-he, or the corresponding alcohol under the reaction conditions of Mitsunobu, you make reference to above. Hydroxy group can turn into a halide by treatment halogenous agent. A halogen atom can be replaced by many groups in substitution reactions, which can also be a reaction catalyzed by a transition metal. The nitro group can be restored to the amino group, for example, using catalytic hydrogenation. The amino group can be modified in the standard conditions for alkylation, for example, by reaction with a halogen compound, or by using the reductive amination of a carbonyl compound, or for acylation or sulfonylurea, for example, by reaction with a reactive derivative of carbon�howling acid, as the acid chloride or acid anhydride or acid chloride sulfonic acid, or with an activated carboxylic acid, which can be obtained from the carboxylic acid by handling agent combinations as, for example, N,N'-carbonyldiimidazole (CDI), carbodiimide as 1,3-dicyclohexylcarbodiimide (DCC) or hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N'n'-tetramethylurea (HATU), tetrafluoroborate O-(cyano (ethoxycarbonyl)methylamino)-N,N,N',N'-tetramethylurea (TOTU), or tetrafluoroborate [(benzotriazole-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium (TBTU). Carboxylic ester group can be hydrolyzed in acidic or basic conditions, yielding the carboxylic acid. Carbon-acid group can be activated or transform into a reactive derivative, as mentioned above, and subjected to reaction with an alcohol or an amine or ammonia, giving an ester or amide. Primary amide may degidratirutego, giving the nitrile. A sulfur atom, for example, in the group alkyl-S - or heterocyclic ring can be oxidized by the peroxide, such as hydrogen peroxide, or percolate, giving sulfoxide fragment S(O) or a fragment sulfone S(O)2. The carboxylic acid group, ester group, carboxylic acid and ketone group can be restored to the JV�RT for example, using a complex hydride such as a hydride, lithium borohydride or sodium borohydride.

All reactions used in the above-described syntheses of the compounds of formula I, by themselves, well known in the art and can be carried out under standard conditions according to or analogously to procedures described in the literature, for example, in Houben-Weyl, Methoden der Organischen Chemie (Methods of organic chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Willey & Sons, new York. If desired, the obtained compounds of formula I, as well as any intermediate compounds, can be purified using conventional purification procedures, for example, recrystallization or chromatography. As already mentioned, the starting compounds and intermediate compounds used in the above-described synthesis which contain an acidic or basic group can also be used in the formation of salts, and all intermediate and final target compound can also be obtained in the form of salts. As similarly mentioned above, depending on the circumstances of the case, to avoid unwanted course of the reaction or side reactions during the synthesis of compounds typically may be necessary or advantageous to temporarily block functional groups by introducing protective groups at a later stage of the synthesis of multi-angles filming again� their protection, or introduce functional groups in the form of groups of precursors which are later converted into the desired functional groups. As examples of protective groups can be mentioned amino-protecting groups which may be the acyl group or allyloxycarbonyl group, e.g., tert-butyloxycarbonyl group (=BOC), which can be removed by treatment with trifluoroacetic acid (=TFA), benzyloxycarbonyl group which can be removed by catalytic hydrogenation, or fluoro-9-ylmethoxycarbonyl group which can be removed by treatment with piperidine, and the protective group of carboxylic acid groups which can be protected in the form of ester groups, such as tert-butyl esters, which can be subjected to release treatment with trifluoroacetic acid, or benzyl esters, which can be removed protection by catalytic hydrogenation. As an example of the preceding groups may be mentioned a nitro group, which can be transformed into the amino group with, for example, by catalytic hydrogenation. Such strategies of synthesis and protective and prior groups that are appropriate in a particular case, known qualified specialists.

Another object of the present invention are new source �couplers and intermediate products, used in the synthesis of compounds of formula I, including compounds of formulas II, III, IV, V, VI, VIII, IX, X, XI, XII and XIII, in which A, R1, R2, R3, R', L1, L2and L3have the meaning defined above, in any of their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their salts and solvates of any of them, and their use as intermediates. The invention also encompasses all tautomeric forms of the intermediate and source connections. All explanations and embodiments of the invention described above in relation to compounds of formula I also apply respectively to the intermediate and parent compounds. The subject of the invention, in particular, are the new specific starting compounds and intermediate compounds described herein. Regardless, describes whether they as a free compound and/or as a specific salt, they are the subject of the invention and in the form of free compounds and in the form of their salts, and, if disclosed specific salt, optionally in the form of this specific salt, and the form of the solvates of any of them.

Compounds of formula I, optionally in combination with other pharmacologically active compounds may be administered to animals, particularly mammals, including humans, as pharmaceuticals by themselves, in mixtures with one nor�UDI others or in the form of pharmaceutical compositions. The introduction can be carried out orally, for example in the form of tablets, film-coated tablets, pills, sugar-coated, granules, hard and soft gelatine capsules, solutions, including water, alcohol and oily solutions, juices, drops, syrups, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of solutions for subcutaneous, intramuscular or intravenous injection or infusion, in particular, aqueous solutions. Compounds of formula I may optionally be used in the methods of local drug delivery, for example, coated stents for the prevention or reduction of restenosis in the stent, or by applying them locally with the help of a catheter. The proper form of introduction depends, among other factors, from the disease being treated or its severity.

The amount of a compound of formula I and/or physiologically acceptable salts and/or solvates present in the pharmaceutical compositions is typically in the range of from about 0.2 to about 800 mg, e.g., about 0.5 to about 500 mg, e.g., from about 1 to about 200 mg, per unit dose, but depending on the type of the pharmaceutical composition it may also be higher. Pharmaceutical compositions typically contain at�Erno 0.5 to about 90 percent by weight of a compound of formula I and/or physiologically acceptable salts and/or solvates. Obtaining pharmaceutical compositions can be known in itself. For this purpose, one or more compounds of the formula I and/or their physiologically acceptable salts and/or solvates together with one or more solid or liquid pharmaceutical carriers or excipients and/or additives or excipients and, if desired combinational medication, other pharmacologically active compounds having therapeutic or prophylactic action, are converted into a suitable form for administration and dosage, which can then be used in humans or in veterinary medicine. As the suitable substances carriers and additives can be used suitable organic and inorganic substances that do not react in an undesirable way with the compounds of the formula I or their physiologically acceptable salts or solvates. As examples of the types of additives that may be contained in the pharmaceutical compositions and medicaments that may be mentioned lubricating agents, preservatives, thickeners, stabilizers, dezintegriruetsja agents, wetting agents, agents to achieve the effect of storage, emulsifiers, salts, for example for influencing the osmotic pressure, buffer substances, coloring agents, flavoring and aromatic� substances. Examples of carriers and additives include water, physiological saline, vegetable oils, waxes, alcohols such as ethanol, isopropanol, 1,2-PROPANEDIOL, benzyl alcohol or glycerol, polyols, mannitol, polyethylene glycols, polypropylenglycol, triacetate of glycerol, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose, glucose, sucrose or starch, like corn starch, stearic acid and its salts, such as magnesium stearate, talc, lanolin, vaseline or petrolatum, or mixtures thereof, e.g. mixtures of water with one or more organic solvents, such as mixtures of water with alcohols. Compounds of formula I and their physiologically acceptable salts and solvates can also be lyophilisates and the resulting freeze-dried be used to obtain, for example, injectable compositions.

The dose administered of a compound of formula I and/or its physiologically acceptable salt and/or solvate depends on the specific case, and as usual, be determined by the physician in accordance with the usual rules and procedures according to the individual circumstances to achieve an optimal effect. It depends on the nature and severity of the disorder to be treated, sex, age, weight and individual response of the patient, human or animal, the effectiveness and duration d�istia the compounds used, from the fact, whether the treatment is intended for the treatment of acute or chronic disease or prophylactic, or entered any other active compound in addition to the compound of formula I. Typically, in order to get the desired results, for administration to an adult weighing about 75 kg is appropriate, for example, a daily dose from about 0.01 mg/kg to about 100 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg, or from about 0.3 mg/kg to about 5 mg/kg (in each case mg per kg of body weight). The daily dose may be administered as a single dose or, in particular, when injected large quantities be divided into several, e.g. two, three or four separate doses. The introduction can also be carried out continuously, for example, continuous infusion or injection. Depending on individual behaviour, in each case, it may be necessary to deviate in the upper or lower side from the indicated doses.

The following examples illustrate the invention.

When compounds of examples containing a basic group were purified using preparative liquid chromatography high pressure (HPLC) on the material of the column with reversed phase (RP) and as usual eluent was a gradient mixture of water and acetonitrile containing trifluoroacetic acid (TFA), they were received partly in the form of their additive �Oli with trifluoroacetic acid, depending on the details of processing, such as the conditions of evaporation or lyophilization. In naming compounds of the examples and their structural formulas contained any such trifluoroacetic acid is not specified.

The compounds were characterized usually by spectroscopic data and chromatographic method, in particular, mass spectrum (MS) and HPLC retention time (Rt; in min) which were given the combined analytical HPLC/MS characterization (LC/MS), and/or spectra, nuclear magnetic resonance (NMR or MRI). In the NMR characterization is given by the chemical shift δ (in frequent. per million ppm), the number of hydrogen atoms and the multiplicity of the signals (s = singlet, d = doublet, dd = double doublet, t = triplet, dt = double triplet, q = Quartet, m = multiplet, br = broad) signals. In the MS mainlygiven the mass number (m/z molecular ion peak M, such as M+orcollateral ion such as the ion M+1,for example [M+1]+, i.e. the protonated molecular ion [M+H]+that is formed depending on the ionization method used. Basically, the method of ionization was elektrorazpredelenie ionization (ESI). Used conditions LC/MS were as follows.

Method LC1

Column: Waters XBridge C18, 50 x 4.6 mm, 2.5 µm; flow: 1.3 ml/min; eluent A: acetonitrile + 0.08% of formic acid; eluent B: water + 0.1% formic acid; g�adient: from 3% A + 97% to 60% A + 40% b for 3.5 minutes, then from 60% A + 40% to 98% A + 2% b for 0.5 min, then 98% A + 2% b for 1 min; MS ionization method: ESI+

Method LC2

Column: Waters XBridge C18, 50 x 4.6 mm, 2.5 µm; flow: 1.7 ml/min; eluent A: acetonitrile + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: 5% A + 95% b for 0.3 minutes, then 5% A + 95% up to 95% A + 5% b for 3.2 minutes, then 95% A + 5% b for 0.5 min; MS ionization method: ESI+

Method LC3

Column: YMC-PAC J sphere H80, 33 x 2.1 mm, 4 µm; flow: 1.3 ml/min; eluent A: acetonitrile + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 5% A + 95% up to 95% A + 5% b for 2.5 min; MS ionization method: ESI+

Method LC4

Column: YMC-PAC J sphere H80, 33 x 2.1 mm, 4 µm; flow: 1.0 ml/min; eluent A: acetonitrile + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 5% A + 95% up to 95% A + 5% b for 3.7 min; MS ionization method: ESI+

Method LC5

Column: YMC-PAC J sphere H80, 33 x 2.1 mm, 4 µm; flow: 1.0 ml/min; eluent A: acetonitrile + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 2% A + 98% a to 95% A + 5% b for 5 min, then 95% A + 5% b for 1.25 min; MS ionization method: ESI+

Method LC6

Column: YMC-PAC J sphere H80, 33 x 2.1 mm, 4 µm; flow: 1.3 ml/min; eluent A: acetonitrile + 0.08% of formic acid; eluent B: water + 0.1% formic acid; gradient: from 5% A + 95% up to 95% A + 5% b for 2.5 min; MS ionization method: ESI+

Method LC7

Column: YMC-PAC J sphere H80, 33 x 2.1 mm, 4 µm; flow: 1.0 ml/min; eluent A: acetone�Rhyl + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 5% A + 95% up to 95% A + 5% b for 3,4 minutes, then 95% A + 5% b for 1.0 min; MS ionization method: ESI+

Method LC8

Column: YMC-PAC J sphere H80, 33 x 2.1 mm, 4 µm; flow: 1.3 ml/min; eluent A: acetonitrile + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: from 5% A + 95% In up gradient from 5% A + 95% b for 0.5 min, then gradient from 5% A + 95% up to 95% A + 5% b for 3 min, then 95% A + 5% In for 0.5 min; MS ionization method: ESI+

Method LC9

Column: Waters XBridge C18, 50 x 4.6 mm, 2.5 µm; flow: 1.3 ml/min; eluent A: acetonitrile + 0.1% formic acid; eluent B: water + 0.1% formic acid; gradient: from 2% A + 98% a to 60% A + 40% b for 3.5 min, then from 60% A + 40% to 98% A + 2% b for 1 min; MS ionization method: ESI+

Method LC10

Column: Waters XBridge C18, 50 x 4.6 mm, 2.5 µm; flow: 1.7 ml/min; eluent A: acetonitrile + 0.05% of TFA; eluent B: water + 0.05% of TFA; gradient: 5% A + 95% b for 0.2 minutes, then 5% A + 95% up to 95% A + 5% within 2.2 min, then 95% A + 5% for a 1.1 min; MS ionization method: ESI+

Example 1

5-(3,4-Dihydro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine

(a) Diethyl ether 2-(3-methyl-benzoylamino)malonic acid

Of 41.1 g of the hydrochloride of diethyl ether aminomalonate acid was dissolved in 200 ml of dichloromethane, and added 80,7 ml of triethylamine under cooling � ice bath. A solution of 30 g of 3-methyl-benzoyl chloride is slowly added dropwise in 200 ml of dichloromethane. After 2 hours at 0°C, was added dropwise 100 ml of water. The phases were separated, and the aqueous phase was extracted with 100 ml dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated, yielding 54 g of crude unpurified connection specified in the header.

(b) N-(4,6-Dihydroxy-2-merkapto-pyrimidine-5-yl)-3-methyl-benzamide

1.5 equivalent of sodium methoxide (30% in methanol) was added to 7,79 g of thiourea in 150 ml of absolute ethanol. Dropwise added a solution of 30 g of diethyl ether 2-(3-methyl-benzoylamino)of malonic acid in 100 ml of absolute ethanol, and the mixture was stirred at 60°C for 2 hours. Then the mixture was cooled to 0°C for 30 minutes, and the residue was filtered by pumping, washed and dried. Received 28.6 g of a crude unrefined connection specified in the header.

(C) N-(4,6-Dihydroxy-2-methylsulfanyl-pyrimidine-5-yl)-3-methyl-benzamide

28.6 g of N-(4,6-dihydroxy-2-merkapto-pyrimidine-5-yl)-3-methyl-benzamide derivative in 280 ml of water was cooled to 0 °C. Under cooling was added 10.3 g of sodium hydroxide, and the mixture was stirred at 0°C for 30 minutes. Then was added a solution of 6.4 ml iodomethane in 108 ml of N-methylpyrrolidine-2-one. After completion of the reaction (6 hours), the mixture was acidified with 6 rules. hydrochloric acid, and the precipitate was filtered and dried. P�was lucali 21,3 g specified in the header connection.

(d) 5-Methylsulfanyl-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-7-ol

21 g of N-(4,6-Dihydroxy-2-methylsulfanyl-pyrimidine-5-yl)-3-methyl-benzamide derivative in 100 ml of chloroquine phosphorus was heated to 70°C for 3 hours. After cooling, the mixture was poured into 500 ml of diethyl ether. The residue was filtered and washed with diethyl ether. Received 7.6 g specified in the header connection.

LC/MS (method LC3): Rt(reaction time)=1,62 min; m/z=274,10 [M+H]+

(e) 5-Methylsulfanyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine

7.1 g of 5-methylsulfanyl-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-7-ol was dissolved in 50 ml of dimethylformamide, and added to 14.4 g of potassium carbonate and then 3.2 g of 1-bromo-propane. The suspension was stirred at 60°C for 5 hours, and then, after cooling, poured into 150 ml of water. The precipitate was filtered by pumping. The resulting mixture of regioisomers were separated using chromatography on silica gel (gradient heptane/ethyl acetate). Except 2.3 g 5-methylsulfanyl-6-propyl-2-(3-methyl-phenyl)-6H-oxazolo[5,4-d]pyrimidine-7-she (LC/MS (method LC1): Rt(reaction time)=2,16 min; m/z=316,14 [M+H]+), obtained 3.4 g specified in the header connection.

LC/MS (method LC3): Rt(reaction time)=to 2.54 min; m/z=316,14 [M+H]+

(f) 5-Methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine

3.9 g of 5-methylsulfanyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine was dissolved in 100 ml love�armitana, added 6.4 g of 3-chloroperbenzoic acid, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered and washed with dichloromethane. The combined filtrates were washed twice, each time with 100 ml aqueous solution of 0.1 per norms. sodium hydroxide, dried over sodium sulfate, filtered and evaporated in vacuum. Received 4.1 g specified in the header connection.

LC/MS (method LC3): Rt(reaction time)=1,96 min; m/z=348,07 [M+H]+

(g) 5-(3,4-Dichloro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine

103 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine was added to a solution of 49 mg of 3,4-dichlorophenol in 3 ml of DMF. The mixture was stirred at room temperature for 2 hours. After filtration, the solvent was distilled in vacuo, the product was isolated using preparative HPLC, receiving 54 mg specified in the header connection.

LC/MS (method LC3): Rt(reaction time)=2,76 min; m/z=430,06 [M+H]+

Example 2

5 Cyclohexyloxy-7-propoxy-2-(3-methyl-phenyl)oxazolo[5,4-d]pyrimidine

113 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)oxazolo[5,4-d]pyrimidine was added to a solution of 29 mg of cyclohexanol in 3 ml of DMF. The mixture was stirred at room temperature for 18 hours. After filtration, the solvent of othona�and vacuum the product was isolated using preparative HPLC, receiving 10 mg specified in the header connection.

LC/MS (method LC3): Rt(reaction time)=2,75 min; m/z=368,20 [M+H]+

Example 3

(7 Propoxy-2-(3-methyl-phenyl)oxazolo[5,4-d]pyrimidine-5-yl)-(tetrahydro-Piran-4-yl)-amine

A mixture of 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)oxazolo[5,4-d]pyrimidine, 40 mg of the hydrochloride of 4-aminotetrahydrofuran and 39 μl of triethylamine in 3 ml of DMF was heated for 8 hours at 50°C. After filtration, the solvent was distilled in vacuo, the product was isolated using preparative HPLC, yielding 22 mg specified in the header connection.

LC/MS (method LC4): Rt(reaction time)=2,75 min; m/z=369,27 [M+H]+

Example 4

7 Propoxy-5-(thiazol-2-ylsulphonyl)-2-(3-methyl-phenyl)oxazolo[5,4-d]pyrimidine

113 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)oxazolo[5,4-d]pyrimidine was added to a solution of 34 mg of 2-mercaptothiazole in 3 ml of DMF. The mixture was heated to 100°C in a microwave reactor for 15 minutes. After cooling and filtration, the solvent was distilled in vacuo, the product was isolated using preparative HPLC, yielding 14 mg specified in the header connection.

LC/MS (method LC3): Rt(reaction time)=2,44 min; m/z=385,09 [M+H]+

Example 5

5-(2-Fluoro-phenoxy)-2-(4-methoxy-3,5-dime�yl-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine

Specified in the header connection received in accordance with the procedure described in example 1 using 4-methoxy-3,5-dimethylbenzonitrile in stage (a) and 2-forfinal in stage (g).

LC/MS (method LC5): Rt(reaction time)=4,72 min; m/z=424,25 [M+H]+

Example 6

5-(2-Fluoro-phenoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine

1.0 ml of 1M solution trichromate boron in dichloromethane was slowly added to a cooled with ice to a solution of 145 mg of 5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine in 8 ml of dichloromethane. The mixture was stirred for 2 hours under cooling with ice, and further 1 hour at room temperature. Then carefully added to a saturated solution of sodium bicarbonate. After extraction with dichloromethane, drying over sodium sulfate, filtration and removal of solvent under vacuum, there was obtained 126 mg specified in the header connection.

LC/MS (method LC2): Rt(reaction time)=of 3.91 min; m/z=410,02 [M+H]+

Example 7

7-Ethoxy-5-(2-fluoro-phenoxy)-2-(1-oxy-pyridin-3-yl)-oxazolo[5,4-d]pyrimidine

(a) 7-Ethoxy-5-methylsulfanyl-2-pyridin-3-yl)-oxazolo[5,4-d]pyrimidine

7-Ethoxy-5-methylsulfanyl-2-pyridin-3-yl-oxazolo[5,4-d]pyrimidine obtained in accordance � procedure described in example 1, using nicotinanilide in stage (a) and brometane in stage (e).

(b) 7-Ethoxy-5-methanesulfonyl-2-(1-oxy-pyridin-3-yl)-oxazolo[5,4-d]pyrimidine

21 μl of 30% aqueous hydrogen peroxide solution was added to a solution of 20 mg of 7-ethoxy-5-methylsulfanyl-2-pyridin-3-yl-oxazolo[5,4-d]pyrimidine in 1 ml of acetic acid. The solution was heated to 80°C for 1 hour. After adding 21 μl of 30% aqueous hydrogen peroxide solution and heating to a temperature of reflux for another two hours, the reaction was completed. After cooling, was added 5 ml of toluene, and the solvent was removed under vacuum. Crude crude product is used in stage (C) without further purification.

(C) 7-Ethoxy-5-(2-fluoro-phenoxy)-2-(1-oxy-pyridin-3-yl)-oxazolo[5,4-d]pyrimidine

21 mg of potassium carbonate and 23 mg of 7-ethoxy-5-methanesulfonyl-2-(1-oxy-pyridin-3-yl)-oxazolo[5,4-d]pyrimidine was added to a solution of 9 mg of 2-forfinal in 2 ml of DMF. The mixture was stirred at room temperature for 18 hours. After filtration, the solvent was distilled in vacuo, the product was isolated using preparative HPLC, receiving 6 mg specified in the header connection.

LC/MS (method LC10): Rt(reaction time)=2,07 min; m/z=369,09 [M+H]+

Example 8

5-(2-Fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine

(a) 2-(4-Methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-oxazolo[5,4-d]pyrimidine-7-ol

2-(4-Methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-oxazolo[5,4-d]pyrimidine-7-ol were obtained in accordance with the procedure described in example 1, stage (a) to(d) using 4-methoxy-3,5-dimethylbenzonitrile in stage (a).

(b) 2-(4-Methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine

A solution of 793 mg of triphenylphosphine and 527 mg of diethylazodicarboxylate in 50 ml of tetrahydrofuran was stirred for 15 minutes at 0°C. was Then added 800 mg of 2-(4-methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-oxazolo[5,4-d]pyrimidine-7-ol, 224 mg oxetan-3-ol and 770 μl of triethylamine. The mixture was stirred at room temperature for 1.5 hours. Then was added 120 mg oxetan-3-ol, 793 mg of triphenylphosphine and 527 mg of diethylazodicarboxylate, and the mixture was stirred for 18 hours. The precipitate was filtered and washed with tetrahydrofuran. The solvent was removed in vacuo and the specified in the title compound was isolated via chromatography on silica gel (gradient heptane/etoac) as a white solid. Yield: 580 mg.

(C) 5-Methanesulfonyl-2-(4-methoxy-3,5-dimethyl-phenyl)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine

1.1 g of 3-chloroperbenzoic acid was added to a solution of 580 mg of 2-(4-methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-7-(oxetan-3-yloxy)-�casolo[5,4-d]pyrimidine in 30 ml of dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. Then the solvent was extracted with twice 30 ml of water 1 standards. the sodium hydroxide solution. The combined aqueous layers were extracted with twice 30 ml of dichloromethane. Then the combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed under vacuum to give 547 mg specified in the header connection in the form of a pale yellow oil.

(d) 5-(2-Fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine

410 mg of potassium carbonate and 547 mg of 5-methanesulfonyl-2-(4-methoxy-3,5-dimethyl-phenyl)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine was added to a solution of 49 mg of 2-forfinal in 8 ml DMF. The mixture was stirred at room temperature for 2 hours. After filtration, the solvent was distilled in vacuum, and the product was isolated via chromatography on silica gel (gradient heptane/ethyl acetate) to give 275 mg specified in the header connection.

LC/MS (method LC2): Rt(reaction time)=3,87 min; m/z=438,03 [M+H]+

Example 9

5-pent-4-enyloxy-7-propoxy-2-(3-methylphenyl)-oxazolo[5,4-d]pyrimidine

50 mg of 1,2-dibromoethane was added to a suspension of 500 mg of tetrahydrofurfurylamine and 73 mg of magnesium shavings in 10 ml of THF. The mixture was stirred for 5 hours, and then divided into several portions. 1.5 ml dissolve�and THF was added to a solution of 130 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine and 16 mg of lithium chloride in 7 ml of THF. The mixture was stirred at room temperature for 16 hours. After removal of the solvent in vacuo, the product was isolated via chromatography on silica gel (gradient heptane/ethyl acetate) to give 78 mg specified in the header connection.

LC/MS (method LC1): Rt(reaction time)=5,50 min; m/z=354,25 [M+H]+

By analogy with the formation of compounds of the examples described above, the obtained compound examples of formula I listed in Table 1. In part, they were received in the form of their salts of trifluoroacetic acid.

Table 1
Examples of compounds of the formula I
ExampleNameLC/MSm/z [M+H]+BP. response, which will. [min]
102-(2-chloro-5-fluoro-phenyl)-5-(2,5-dimethyl-2H-pyrazol-3-yloxy)-7-ethoxy-oxazolo[5,4-d]pyrimidineLC1445,36 (1)4,93
112-(2-chloro-5-fluoro-phenyl)-7-cyclopropylmethoxy-5-(2,5-dimethyl-2H-pyrazol-3-yloxy)-oxazolo[5,4-d]pyrimidineLC1430,355,04
125-(3,4-debtor-phenylsulfanyl)-7-ethoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC1400,335,42
132-(2-chloro-5-fluoro-phenyl)-7-cyclopropylmethoxy-5-(1,1-diokso-tetrahydro-lambda-thiophene-3-ylsulphonyl)-oxazolo[5,4-d]pyrimidineLC1470,125,01
145-(1,1-diokso-tetrahydro-lambda-thiophene-3-ylsulphonyl)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC1424,174,99
152-(3,4-dichloro-phenyl)-5-(2-fluoro-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC1434,115,53
167 cyclopropylmethoxy-5-pent-4-enyloxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC1366,35,44
173-(7-ethoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-N,N-dimethyl-benzolsulfonat LC2455,043,8

182-(3-fluoro-phenyl)-5-(6-methyl-pyridazin-3-yloxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC2382,12,97
195-(6-methyl-pyridazin-3-yloxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2378,113,09
203-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-benzolsulfonatLC2441,083,55
213-[2-(2-chloro-5-fluoro-phenyl)-7-ethoxy-oxazolo[5,4-d]pyrimidine-5-yloxy]-benzolsulfonatLC2465,043,34
223-(7-ethoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-benzolsulfonatLC2427,063,4
233-[2-(-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yloxy]-benzolsulfonat LC2445,13,42
245-(2,5-dimethyl-2H-pyrazol-3-yloxy)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC2384,193,62
255-(2,5-dimethyl-2H-pyrazol-3-yloxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2380,133,74
265-(2,5-dimethyl-2H-pyrazol-3-yloxy)-7-ethoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2366,09Of 3.69
275-(1,1-diokso-tetrahydro-lambda-thiophene-3-ylsulphonyl)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2420,17A 3.78
287 cyclopropylmethoxy-5-(1,1-diokso-tetrahydro-lambda-thiophene-3-ylsulphonyl)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2432,16Of 3.75

297 cyclopropylmethoxy-5-(2-fluoro-phenoxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2392,054,17
302-(2-chloro-5-fluoro-phenyl)-7-ethoxy-5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidineLC2403,99Of 3.98
315-(2-fluoro-phenoxy)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC2384,044,08
327 cyclopropylmethoxy-5-(2-fluoro-phenoxy)-2-(3-fluoro-phenyl)-oxazolo[5,4-d]pyrimidineLC2396,054,05
332-(2-fluoro-5-methyl-phenyl)-5-phenoxy-7-propoxy-oxazolo[5,4-d]pyrimidineLC2380,114,17
342-(2-chloro-5-fluoro-phenyl)-7-cyclopropylmethoxy-5-(2,2-dimethyl-[1,3]dioxolan-4-ylethoxy)-oxazolo[5,4-d]pyrimidineLC2450,11 3,96
357 cyclopropylmethoxy-5-(2,2-dimethyl-[1,3]dioxolan-4-ylethoxy)-2-(3-fluoro-phenyl)-oxazolo[5,4-d]pyrimidineLC2416,183,86
367 cyclopropylmethoxy-5-(2,2-dimethyl-[1,3]dioxolan-4-ylethoxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2412,24
375-(2,2-dimethyl-[1,3]dioxolan-4-ylethoxy)-7-ethoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2386,173,86
385-(oxetan-3-yloxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2342,13,74

397 cyclopropylmethoxy-5-(oxetan-3-yloxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC2354,123,72
405-(2-ft�p-phenoxy)-2-(3-methoxy-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine LC2396,124,08
412-(3-methoxy-phenyl)-7-propoxy-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidineLC2379,123,14
423-[5-(2-fluoro-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidine-2-yl]-phenolLC2382,07Of 3.64
433-[7-propoxy-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidine-2-yl]-phenolLC2365,11To 2.74
442-(3,4-dichloro-phenyl)-7-propoxy-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidineLC2417,053,7
452-(3,4-dichloro-phenyl)-5-(2,2-dimethyl-[1,3]dioxolan-4-ylethoxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC2454,094,36
467-ethoxy-5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4 d]pyrimidine LC2410,074,15
474-[7-ethoxy-5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethyl-phenolLC2396,053,73
485-((1S,2S)-2-fluoro-cyclohexyloxy)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC2390,094,15

492-[3,5-dimethyl-4-(oxetan-3-yloxy)-phenyl]-5-(2-fluoro-phenoxy)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidineLC2480,083,63
505-(5-fluoro-2-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3394,23Of 2.58
515-phenoxy-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3362,22,47
52 5-(3-chloro-4-triptoreline-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3480,142,76
535-(2,4-dimethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3390,222,67
545-(3-fluoro-4-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3394,122,57
555-(4-methyl-thiazol-2-ylsulphonyl)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3399,092,52
562-methyl-6-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-2H-pyridazin-3-oneLC3435,16 (1)Of 1.91
57[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yl]-(tetrahydro-Piran-4-yl)-amineLC3407,172,14
582-(2-chloro-5-fluoro-phenyl)-5-(4-methyl-thiazol-2-ylsulphonyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC3436,982,44
592-(2-chloro-5-fluoro-phenyl)-7-propoxy-5-(thiazol-2-ylsulphonyl)-oxazolo[5,4-d]pyrimidineLC3423,07Of 2.35

605-(4-chloro-2-methoxy-phenoxy)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC3430,132,44
612-(3-fluoro-phenyl)-5-phenoxy-7-propoxy-oxazolo[5,4-d]pyrimidineLC3366,172,36
625 cyclohexyloxy-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC3372,152,65
632-(2-chloro-5-fluoro-phenyl)-5-(4-chloro-2-methoxy-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidine464,212,54
64[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yl]-(4,4-debtor-cyclohexyl)-amineLC3441,282,45
65The morpholine-4-yl-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yl)-amineLC3370,181,83
662-(2-chloro-5-fluoro-phenyl)-5-(5-chloro-2-methyl-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC3448,062,67
675-(5-chloro-2-methyl-phenoxy)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC3414,12,64
682-(2-chloro-5-fluoro-phenyl)-7-propoxy-5-(3-triftormetilfullerenov-phenoxy)-oxazolo[5,4-d]pyrimidineLC3500,072,71
692-(3-fluoro-phenyl)-7-propoxy-5-(3-cryptomaterial�Neal-phenoxy)-oxazolo[5,4-d]pyrimidine LC3466,092,68
705-(4-methyl-cyclohexyloxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3382,182,88

717 propoxy-5-(tetrahydro-Piran-4-yloxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC3370,182,22
722-(2-chloro-5-fluoro-phenyl)-5-(5-fluoro-pyridin-3-yloxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC3460,11 (1)2,17
737 propoxy-2-(3-methyl-phenyl)-5-p-tolyloxy-oxazolo[5,4-d]pyrimidineLC4376,273,32
745-(4-chloro-3-fluoro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC4414,233,42
755-(2-fluoro-4-methoxy-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine LC4410,283,17
767 propoxy-5-(pyridin-2-yloxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC4363,232,68
777 propoxy-5-(pyridin-3-yloxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC4363,242,23
782-(2-chloro-5-fluoro-phenyl)-5-phenoxy-7-propoxy-oxazolo[5,4-d]pyrimidineLC4400,073,1
792-(2-chloro-5-fluoro-phenyl)-5-(5-fluoro-2-methyl-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC4432,123,22
802-(2-chloro-5-fluoro-phenyl)-5-cyclohexyloxy-7-propoxy-oxazolo[5,4-d]pyrimidineLC4406,153,47
815-(3-fluoro-4-methyl-phenoxy)-2-(3-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimide� LC5398,144,69

822-(3-fluoro-phenyl)-7-propoxy-5-(4-triftormetilfullerenov-phenoxy)-oxazolo[5,4-d]pyrimidineLC5466,172,72
835-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5432,264,84
842-(2-chloro-5-fluoro-phenyl)-5-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC5470,214,8
852-(2-chloro-5-fluoro-phenyl)-5-(4-methyl-cyclohexyloxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC5420,245,09
865-(2,6-dichloro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5430,114,89
873-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-benzonitrileLC5387,164,45
885-(4-chloro-2-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5410,18Of 4.95
895-(3-chloro-4-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5410,184,97
905-(2-chloro-4-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5410,184,82
915-(2-chloro-6-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5410,174,84
923-methoxy-4-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-benzonitrileLC5417,17 4,4

935-(3-ethoxy-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5406,174,82
945-(2,5-debtor-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5398,114,6
955-(2,4-debtor-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5398,124,59
965-(2-tert-butyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5418,225,14
975-(2,6-debtor-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5398,154,65
987 propoxy-2-(3-methyl-phenyl)-5-(3-methyl-phenyl) - hydroxy-oxazolo[5,4-d]pyrimidineLC5 376,164,75
995-(4-fluoro-2-methoxy-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5410,144,6
1005-(2-chloro-3,5-debtor-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5432,134,85
1015-(2-chloro-5-fluoro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5414,154,79
1027 cyclopropylmethoxy-5-(2,5-dimethyl-2H-pyrazol-3-yloxy)-2-(3-fluoro-phenyl)-oxazolo[5,4-d]pyrimidineLC5396,07At 3.97
1035-(2-fluoro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC5380,11Is 4.57

1042-(2-chloro-5-fluoro-phenyl)-7-cyclopropylmethoxy-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidine LC5430,044,45
1052-(3,4-dichloro-phenyl)-5-phenoxy-7-propoxy-oxazolo[5,4-d]pyrimidineLC5416,114,94
1067 cyclopropylmethoxy-2-(3,4-dichloro-phenyl)-5-(pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidineLC5429,1At 3.97
1075-(2-fluoro-phenoxy)-7-propoxy-2-pyridin-3-yl-oxazolo[5,4-d]pyrimidineLC5367,123,7
1087 cyclopropylmethoxy-2-(3,4-dichloro-phenyl)-5-(5-fluoro-pyridin-3-yloxy)-oxazolo[5,4-d]pyrimidineLC5447,064,6
1095-(2-fluoro-phenoxy)-2-(1-oxy-pyridin-3-yl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC5383,153,2
1107 cyclopropylmethoxy-2-(3,4-dichloro-phenyl)-5-phenoxy-oxazo�about[5,4-d]pyrimidine LC5428,134,85
1115-(2-fluoro-4-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC6394,213,01
1127 propoxy-2-(3-methyl-phenyl)-5-(4-triftormetilfullerenov-phenoxy)-oxazolo[5,4-d]pyrimidineLC6462,193,18
113[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yl]-(4-methyl-cyclohexyl)-amineLC6419,363,24
1146-[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yloxy]-2-methyl-2H-pyridazin-3-oneLC7432,1 (1)2,29

1155-(5-chloro-2-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8410,08Of 3.64
1167 propoxy-2-(3-methyl-phenyl)-5-(3-triftormetilfullerenov-phenoxy)-oxazolo[5,4-d]pyrimidineLC8462,043,71
1172-(2-chloro-5-fluoro-phenyl)-7-propoxy-5-(tetrahydro-Piran-4-yloxy)-oxazolo[5,4-d]pyrimidineLC8408,042,96
1185-(3-methoxy-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8392,123,33
1195-(2,4-dichloro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8430,033,67
1205-(2,5-dichloro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8430,033,65
1215-(3-chloro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8396,083,55
1225-(4-ethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8390,133,62
1237 propoxy-2-(3-methyl-phenyl)-5-(2,3,5-trimethyl-phenoxy)-oxazolo[5,4-d]pyrimidineLC8404,153,7
1245-(2-isopropyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8404,153,68
1255-(3-tert-butyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8418,163,79

1267 propoxy-5-(2-propyl-phenoxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8404,153,7
1275-(3,5-debtor-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8 398,093,46
1282-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-benzonitrileLC8387,153,12
1295-(4-fluoro-3-trifluoromethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8448,123,52
1305-(4-fluoro-3-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8394,153,47
131dimethyl-[3-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-phenyl]-amineLC8405,192,87
1325-(2,6-dimethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8390,18It was 3.54
1335-(2,5-dimethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine LC8390,18It was 3.54
1342-fluoro-4-(7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine-5-yloxy)-benzonitrileLC8405,143,24
1355-(2-methoxy-4-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8406,183,36
1365-(3,4-dimethoxy-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8422,183,12

1375-(2-chloro-5-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8410,093,57
1385-(3-chloro-5-fluoro-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8414,063,62
1395-(2-methylsulfanyl�-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine LC8408,093,38
1405-(4-chloro-3-methyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8410,083,67
1417 propoxy-2-(3-methyl-phenyl)-5-(2-trifluoromethyl-phenoxy)-oxazolo[5,4-d]pyrimidineLC8430,083,44
1427 propoxy-2-(3-methyl-phenyl)-5-(2,4,6-trimethyl-phenoxy)-oxazolo[5,4-d]pyrimidineLC8404,153,7
1435-(2-chloro-5-trifluoromethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8464,04Of 3.64
1445-(3-fluoro-5-trifluoromethyl-phenoxy)-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8448,073,61
1455-(2-chloro-4-trifluoromethyl-phenoxy)-7-Pro�hydroxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine LC8464,043,67
1467 propoxy-5-(2-propoxy-phenoxy)-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidineLC8420,183,48
147[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yl]-((1S,3S)-3-methyl-cyclohexyl)-amineLC8419,13,7

148[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yl]-(4-methyl-cyclohexyl)-amineLC8419,13,71
149[2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine-5-yl]-cyclohexyl-amineLC8405,083,53
1502-(2-chloro-5-fluoro-phenyl)-5-phenylsulfanyl-7-propoxy-oxazolo[5,4-d]pyrimidineLC8416,073,39
151 2-(2-chloro-5-fluoro-phenyl)-5-(2,5-dimethyl-furan-3-ylsulphonyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC8434,063,47
1522-(2-chloro-5-fluoro-phenyl)-5-(3-methyl-oxetan-3-ylethoxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC8407,992,82
1532-(2-chloro-5-fluoro-phenyl)-5-(5-fluoro-2-methyl-phenylsulfanyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC8448,073,5
1542-(2-chloro-5-fluoro-phenyl)-7-propoxy-5-(4-trifluoromethyl-cyclohexyloxy)-oxazolo[5,4-d]pyrimidineLC8474,123,4
1552-(2-chloro-5-fluoro-phenyl)-5-(5-methyl-pyridine-2-ylsulphonyl)-7-propoxy-oxazolo[5,4-d]pyrimidineLC8431,052,97
1562-(3,4-dichloro-phenyl)-5-phenylsulfanyl-7-propoxy-oxazolo[5,4-d]pyrimidineLC9 432,085,74

1572-(3,4-dichloro-phenyl)-5-(5-fluoro-2-methyl-phenoxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC9448,115,49
1587 cyclopropylmethoxy-2-(3,4-dichloro-phenyl)-5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidineLC9446,075,28
1597 cyclopropylmethoxy-2-(3,4-dichloro-phenyl)-5-(5-fluoro-2-methyl-phenoxy)-oxazolo[5,4-d]pyrimidineLC9460,125,38
1602-(3,4-dichloro-phenyl)-5-(5-fluoro-pyridin-3-yloxy)-7-propoxy-oxazolo[5,4-d]pyrimidineLC9435,185,13
(1) [M+CH3CN+H]+
(2) [M-H]+

Definition of pharmacological activity

(A) GTP-γ-S analysis using Edg-1 of human receptors

In order to determine the activation of receptor Edg-1 compounds of the invention, used as�Aliz GTP-γ-S (guanosine 5'-[γ-thio]triphosphate) for binding combined with the G-protein receptor, based on the principle of scintillation analysis approximations, with the drug of the cell membrane of CHO Flp-ln cell line, which over-expresses Edg-1 receptor.

(a) Generation of cell lines

Gene-expression system Flp-lnTM(Invitrogen, cat. no. C-01) provides for the generation of stable cell lines of mammals, which integrated a gene of interest using homologous recombination into a specific genomic location, called site Flp Recombination target (FRT) by Flp recombinases, coded pOG44 the expression plasmid. Integration of gene-expression constructs pcDNA5/FRT in Flp-ln cell line genome of the host results in the transcription of the gene of interest. Stable transfetsirovannyh cells become hygromycin-resistant.

One day before transfection, 200000 Flp-ln CHO cells were plated in Ham's F-12 medium (Invitrogen, cat. no. 31765) by adding 10% fetal bovine serum (FCS; Perbio Science, cat. no. SH30068.03) 6-hole tablet and incubated at 37°C/5% CO2during the following night. Using the transfection reagent FuGENE®6 (Roche, cat. no. 11988387001), cells were cotransfection with Flp recombinant gene expression by plasmid pOG44 and a modified plasmid, further comprising edg-1 gene (accession no. NM001400), called pcDNA5-FT-TO_nFLAG DEST-EDG-1 with a ratio of 9:1. To obtain the modified pcDNA5-FRT-TO(Invitrogen, cat. no. V6520-20) adapted for Gateway®cloning the system by bookmark Gateway cassette containing attR sites of recombination adjacent ccdB gene and a chloramphenicol-resistant gene (Gateway conversion system, Invitrogen, cat. no. 11828-029). In addition before 5' att recombination site added a FLAG epitope tag, to allow recombinant expression of N-terminal FLAG-associated proteins.

For transfection of one of the wells of 1.08 μg of pOG44 and 0.12 μg of pcDNA5-FRT-TOnFLAGDEST-EDG-1 were mixed with 100 μg of serum-free Ham F-12 medium containing 6 ál FuGENE®6 transfection reagent. After 20 min incubation, the complex of transfection reagent/DNA distribute dropwise on the cells. Cells were incubated for 24 hours. at 37°C. Then, from each of the 3 wells was transferred into a T75 flask (Greiner Cellstar®cat. no. 658175) containing Ham F-12 medium with addition of 10% FCS but without antibiotics, and incubated for another 24 hours. 48 hours after transfection the medium was replaced with selection medium (Ham F-12 with 10% FCS and 300 μg/ml of hygromycin (Invitrogen, cat. no. 10687-010). The medium was replaced every 2-3 days until, until you have grown resistant population of cells. Cells divided several times and seeded into a new vessel so that the cells have not reached more than 25% of the merger. After 2 weeks of selection, the cells were transferred in T vessels (Griner Cellstar ®cat. no. 660175) and were cultured for receiving parties. Cells were collected from culture vessels with a brief treatment (2-5 min) accurate (Accutase) (PAA, cat. No. L11-007), re-suspended in selection medium (see above) and centrifuged at 200 x g for 5 minutes. Cells re-suspended in a mixture of 90% FCS and 10% dimethylsulfoxide and stored frozen in liquid nitrogen.

(b) the Preparation of membranes

The preparation of the membrane was obtained by standard methods described above CHO Flp-ln cell lines, constitutive over-expressing human Edg-1 receptor.
Briefly, cryopreserved cells were taken in culture and were grown to confluence in T175 vessels for cell culture (Becton Dickinson, cat. No. 35 5001). The cell culture was stopped by washing with phosphate buffered free from calcium phosphate saline solution (PBS; Gibco, cat. No. 14190), and the cells were collected using a special rubber sticks (for elimination of adhesive cells) at 4°C cool free calcium PBS with the addition of a cocktail of protease inhibitor (complete protease inhibitor, Roche, cat. no. 1697498; 1 tablet per 50 ml) and subsequently centrifuged at 4°C for 15 min at 1100 x g (Heraeus Minifuge T). For cell lysis, the tablet re-suspended in 4°C cold hypotonic buffer consisting of 5 mm HEPES (Sigma-Aldrich, cat. no. H-0981), 1 mm EDTA (disodium salt; Merck, cat. no. 8418) with the addition of a cocktail of inhibit�RA protease (as above) in which the cells were kept for 15 minutes on ice. After lysis the cells were centrifuged at 4°C for 10 minutes at 400 x g (Heraes Minifuge T). The tablet was destroyed in a Dounce homogenizer, diluted with the supernatant from the previous centrifugation and subsequently centrifuged at 4°C for 10 minutes at 500 x g (Heraes Minifuge T) to separate the nuclei and intact cells from membranes that are present mainly in the supernatant. The supernatant was then diluted with hypotonic buffer and centrifuged (Beckmann, Avanti J251) at approximately 18600 x g for 2 hours at 4°C. After centrifugation the tablet membrane re-stored suspended in a buffer consisting of 20 mm HEPES; 150 mm NaCl (Merck, cat. no. 6400), 1 mm EDTA (as above) with the addition of a cocktail of protease inhibitors (as above). Selected aliquot of the preparation of the membrane and stored at -80°C. Determined the concentration of protein in the membrane preparation in the sample using a commercial protein analysis (Bio-Rad, DC Protein Assay, cat. no. 500-0113, 500-0114, 500-0115).

(c) GTP-γ-S Analysis

Membrane drug Edg-1 obtained in (b) were applied in an industrial set available for the analysis of scintillation proximity (SPA) for binding combined with G-protein receptor from Amersham Biosciences/GE Healthcare (code RPNQ0210), in which ligand-induced binding35S-radiochango GTP-γ-S with the receptor-containing racket.�Ana, which is bound to scintillation beads, stimulates the emission of light and allows to quantify the activity in vitro Edg-1 agonist compounds. The analysis was performed on 96-well plate on the merits in accordance with the manufacturer's instructions. Before beginning experiments scintillation beads suspended in a redox buffer consisting of Tris-HCl (pH 7.4) with addition of 0.1% (V/o) of sodium azide, and subsequently diluted with ice buffer for analysis (consisting of 20 mm HEPES, 100 mm NaCl, 1 mm EDTA (as above), 1 mm dithiothreitol (DTT), brought to pH 7.4) to a final concentration of beads in 30 mg/ml.

The wells were loaded 10 µl of special analytical buffer, 10 μl of 100 μm solution of guanozintrifosfata (GDP) and 10 μl of a solution of the test compound in a mixture of analytical buffer/dimethylsulfoxide, producing a final concentration of the test compound (10 μm. For higher controls into appropriate wells instead of the solution of the test compounds were added 10 μl of a solution of sphingosine-1-phosphate (S1P; Sigma, cat. no. S-9666), producing a final concentration of 10 μm S1P, and low controls - 10 ál analytical buffer. All wells contained an equivalent amount of dimethyl sulfoxide. Then to each well was added 10 μl of a solution of [35S]GTP-γ-S (4 nm) and Edg-1 membrane preparation obtained in (b) (15 µg Bel�s membrane in 100 ál analytical buffer). After incubation the tablet at room temperature for 5 minutes was added 50 µl of a certain suspension scintillation beads (30 mg/ml). After 45 min incubation period at room temperature, the plates were centrifuged for 10 min at 500 x g. A quantitative index of [35S]GTP-γ-S binding and thus receptor activation was measured by a beta counter (MicroBeta, Wallac) for 1 min Values were compensated for the background subtraction of the corresponding lower control. All measurements were done in triplicate. Activating receptor of the test compound was expressed as a percentage of the high control (10 μm S1P; was considered as 100% activation). Table 2 lists the observed activation by the compounds of examples when 10 mm.

From these measurements it is obvious that the compounds are highly suitable for wound healing and in particular for the treatment of disorders in connection with the healing of wounds in patients with diabetes.

1. The compound of formula I in any stereoisomeric form, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt

in which
And selected from NH, O and S;
R1selected from ( 1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1, 2 and 3;
R2selected from phenyl and residue of an aromatic, 5-membered to 6-membered monocyclic heterocycle which comprises 1, 2 identical or different ring heteroatoms selected from N, O and S, where one of the ring nitrogen atoms can carry a hydrogen atom or a substituent R21and wherein the phenyl and residue of an aromatic heterocycle optionally substituted at one or more ring carbon atoms by one or more identical or different substituents R22;
R3selected from (C1-C6) -alkyl, or R3represents the residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31provided that R3cannot be (C1-C6)-alkyl if A represents S;
R21in�bran from (C 1-C4)-alkyl, and actigraphy,
R22selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy and R23;
R23represents the residue of a saturated 3-membered to 7-membered, monocyclic, which includes 0, 1 or 2 identical or different ring heteroatoms selected from O and S, where one of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more carbon atoms, equal or different substituents R24;
R24selected from (C1-C4)-alkyl;
R31selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, oxo, amino, (C1-C4)-alkylamino, di ((C1-C4)-alkyl) amino, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl;
Het is a residue of a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises 1 or 2 identical or different ring heteroatom selected from O and S, and which is linked via a ring carbon atom, wherein the residue of a heterocycle optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;
where �CE cycloalkyl group, independently from each other and independently of any other substituents optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;
where the alkyl, the alkenyl groups are independently from each other and independently of any other substituents optionally substituted by one or more forame.

2. The compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or its physiologically acceptable salt according to claim 1, in which R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1 and 2.

3. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, as claimed in claim 1, in which R2selected from phenyl and pyridinyl, where the ring nitrogen atom of pyridine can carry oxo Deputy, and where the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms of identical or different substituents R22.

4. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, as claimed in claim 1, in which R3represents the residue is saturated�wow or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31.

5. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, as claimed in claim 1, in which
R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1 and 2;
R2selected from phenyl and pyridinyl, where the ring nitrogen atom of pyridine may bear a hydroxy substituent, and where the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms of identical or different substituents R22;
R3represents the residue of a saturated or unsaturated, 3-membered to 10-membered, monocyclic or bicyclic ring which comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from N, O and S, in which� one or two of the ring nitrogen atoms can carry a hydrogen atom or a (C 1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R31.

6. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, as claimed in claim 1, in which
And selected from NH, O and S;
R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1 and 2;
R2selected from phenyl and pyridinyl, where the ring nitrogen atom of pyridine may bear a hydroxy substituent, and where the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms of identical or different substituents R22;
R3represents the residue of a saturated or unsaturated, 3-membered to 7-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatom selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the remaining ring optionally substituted with one or �or more ring carbon atoms of identical or different substituents R 31;
R22selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy and R23;
R23represents the residue of a saturated 3-membered to 6-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from O and S, where one of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R24;
R24selected from (C1-C4)-alkyl;
R31selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl) amino, cyano, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl;
Het is a residue of a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises 1 or 2 identical or different ring heteroatom selected from O and S, and which is linked via a ring carbon atom, wherein the residue of a heterocycle optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;
where all cycloalkyl group, independent�about each other and independently of any other substituents optionally substituted by one or more identical or different substituents, chosen from fluorine and (C1-C4)-alkyl;
where all alkyl group is independently from each other and independently of any other substituents optionally substituted by one or more forame.

7. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt claimed in one or more paragraphs. 2-5, in which
And selected from NH, O and S;
R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2t- where t is selected from 0, 1 and 2;
R2selected from phenyl and pyridinyl, where the ring nitrogen atom of pyridine may bear a hydroxy substituent, and where the phenyl and pyridinyl optionally substituted at one or more ring carbon atoms of identical or different substituents R22;
R3represents the residue of a saturated or unsaturated, 3-membered to 7-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatom selected from N, O and S, where one or two of the ring nitrogen atoms can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of odinakovymi different substituents R 31;
R22selected from halogen, hydroxy, (C1-C4)-alkyl, (C1-C4)-alkyloxy, R23;
R23represents the residue of a saturated 3-membered to 6-membered, monocyclic ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from O and S, where one of the ring sulfur atoms can carry one or two oxo groups, and wherein the balance ring is optionally substituted at one or more ring carbon atoms of identical or different substituents R24;
R24selected from (C1-C4)-alkyl;
R31selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxy, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di ((C3-C4)-alkyl) aminosulfonyl;
Het is a residue of a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises 1 or 2 identical or different ring heteroatom selected from O and S, and which is linked via a ring carbon atom, wherein the residue of a heterocycle optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;
where all cycloalkyl g�uppy, independently from each other and independently of any other substituents optionally substituted by one or more identical or different substituents chosen from fluorine and (C1-C4)-alkyl;
where all alkyl group is independently from each other and independently of any other substituents optionally substituted by one or more forame.

8. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, as claimed in claim 1, in which A is O.

9. The compound of formula I in any of its stereoisomeric forms, or mixtures of stereoisomeric forms in any ratio, or its physiologically acceptable salt, as claimed in any one of claims. 2-6, in which A is O.

10. The method of obtaining compounds of formula I, as claimed in any one of claims. 1-9, including the interaction of a compound of formula II with a compound of formula III,

where the groups A, R1, R2and R3in the compounds of formulas II and III have the meanings given for compounds of the formula I and additionally functional groups can be present in protected form or in the form of a preceding group, and the group Alk is a (C1-C4)-alkyl.

11. Pharmaceutical composition intended for wound healing, including, for �ENISA least one compound of formula I, as claimed in any one of claims. 1-9, or its physiologically acceptable salt, and pharmaceutically acceptable carrier.

12. The compound of formula I, as claimed in any one of claims. 1-6 and 8, or a physiologically acceptable salt, pharmaceutical remedies intended for healing wounds.

13. The compound of formula I, as claimed in any one of claims. 1-6 and 8, or its physiologically acceptable salt for the treatment of disorders in connection with the healing of wounds.

14. The compound of formula I, as claimed in any one of claims. 1-6 and 8, or a physiologically acceptable salt intended for wound healing.

15. The compound of formula I, as claimed in any one of claims. 1-6 and 8, or its physiologically acceptable salt for wound healing in diabetics.

16. The compound of formula I, as claimed in any one of claims. 1-6 and 8, or its physiologically acceptable salt for the treatment of diabetic foot.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oxazolopyramidine compounds of formula I, where A represents O; R1 is selected from phenyl or pyrimidine, which are optionally substituted with R11; R2 represents phenyl, which is optionally substituted wby 1-3 ring carbon atoms with similar or different substituents R22, R11 represents halogen; R22 is selected from hydroxy group, (C1-C4)-alkyl, which is optionallysubstituted with 1-3 atoms of fluorine, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-; m equals 2. Invention also relates to pharmaceutical composition, which contains formula I compounds, and to method of obtaining formula I compounds.

EFFECT: formula I compounds, intended for activation of EDG-1 receptor and applied for wound healing.

15 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oxazolopyramidine compounds of formula (I), where A represents O; X represents (C1-C6)-alkanediyl or (C1-C6)-alkanediyloxy, where oxygen atom of (C1-C6)-alkanediyloxy is bound to group R2; Y represents pyrrolidinyl; R1 represents (C1-C4)-alkyl; R2 represents phenylene, optionally substituted by one or two carbon atoms in ring with similar or different substituent R22; R3 is selected from group, which consists of cycloalkyl-CuH2u-, where u equals 1; radical of saturated 3-10-member monocyclic ring, phenyl or pyridyl, where ring radical is optionally substituted by one or two carbon atoms of ring with substituent R31; R4 represents hydrogen; R22 represents (C1-C4)-alkyl; R31 is selected from group, which consists of halogen and (C1-C4)-alkyl. Invention also relates to (S)-l-[2-(2,6-dimethyl-4-{5-[methyl-(3,3,3-trifluoropropyl)amino]-7-propoxyoxazolo[5,4-d]pyrimidine-2-yl}phenoxy)acetyl]pyrrolidine-2-carboxylic acid, pharmaceutical composition and to method of obtaining compounds of formula (I) .

EFFECT: compounds of formula (I), intended for activation of EDG-1 receptor and applied for wound healing.

16 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula

,

having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4,p, n, m, o are given in the claim.

EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.

21 cl, 283 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 5,5-condensed heteroarylene compounds IIIB, where U2, V1, V2 and W1 are selected from O, N, NH, S or CR3a; U1, W2, X1 and X2 represent C or N; R1 and R2 represents hydrogen, -C(O)CH(NR1bR1c)R1a, -C(O)CH(N(R1c)C(O)OR1b)R1a or -C(O)OR1a; R3a represents hydrogen or R3; R3 represents halogen or -C(O)OR1a; L1 and L2 are such as given in invention formula, each Z1 and Z2 represents bond or -O-; each Rla, R1b and R1c represents hydrogen, C1-6 alkyl or C6-14 aryl; or Rlb and Rlc together with N atom, which they are bound to, form 5-6-membered heterocyclyl; q, r, s, t and u equal 1. Invention also relates to pharmaceutical compositions, containing 5,5-condensed heteroarylene compounds, and methods of treating or preventing HCV infection.

EFFECT: 5,5-condensed heteroarylene derivatives, possessing inhibiting activity with respect to hepatitis C virus.

43 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of obtaining fluorescent catecholamines selected from dopamine and adrenalin, and their metabolites, selected from homovanillic and vanillin-mandelic acids, by a method of derivation. The compounds can be used as highly sensitive and selective markers for the determination of various diseases. The method of derivation includes oxidation of the initial compounds and their interaction with amines that form condensed structures in a medium of the CAPS-buffer solution or glycin - KOH 0.2 mM hydrogen peroxide in the presence of horseradish peroxidase as a catalyst. The process in preferably carried out in a 0.1 M buffer solution with the concentration of horseradish peroxidase 0.01-1 mcM; concentration of hydrogen peroxide - 100 mcM, amine concentration - 0.1-33 mM; concentration of catecholamines and metabolites - 0.03-1 mcM.

EFFECT: method is simple and producible as it does not require higher temperature and is realised in a water solution.

2 cl, 2 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a number of substituted dihydrobenzocycloalkyloxymethyl oxazolpyrimidinone of formula

wherein n represents 1, 2 or 3; R1 represents hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl and propyl; R2 is specified in a group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, 1,1-difluoropropyl, methoxymethyl and 2-fluoroethoxymethyl; R3 and R4 represent (C1-C4)alkyl; and R5 and R6 are identical or different and are independently specified in a group consisting of hydrogen, halogen, (C1-C4)alkyl and (C1-C4)alkoxy. The invention also refers to specific compounds specified in cl.8 of the patent claim, to compounds of formula

a pharmaceutical composition and the use of the declared compounds.

EFFECT: dihydrobenzocycloalkyl-oxymethyloxazolpyrimidinone as metabotropic glutamate receptor mGluR2 modulators.

14 cl, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to nitroimidazoxazine derivatives of formula , wherein X represents O, OCH2, OCH2CH=CH or OCH2C≡C; Y represents a group of any of formulas IIa-IIc, wherein means an attachment point to X, and Z in formulas

represents CH2, CH=CH, C≡C or a direct bond; the numbers 2, 3 and 4 are positions of a terminal ring having R1 as a substitute; the terminal ring of formula I comprises C, CH or one nitrogen atom in each position, and each of R1 and R2 in formulas I and IIa represents one or two substitutes found in any accessible position of the ring and independently represents H, F, Cl, CF3, OCF2H, OCF3 or combinations thereof. Besides, the invention refers to a pharmaceutical compound based on a compound of formula I, a method of treating a microbial infection, specific compounds.

EFFECT: there are prepared new compound effective in treating the microbial infections, including in treating the diseases caused by Mycobacterium tuberculosis.

8 cl, 28 dwg, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to nitroimidazooxazine derivatives of general formula I, where n equals 1, V and W independently denote H or CH3, and one of X and Y is H and the other is one of the formulae and , where formula IIa includes a single ring labelled at position 3 and position 4 and containing R1 as a substitute, and formula IIb includes a first ring labelled at position 3 and position 4 and containing as substitutes both R2 and a terminal ring, labelled at position 4 and containing R1 as a substitute, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb include C, CH, or N at each ring position, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb independently contain no more than two nitrogen atoms; Z in formulae IIa and IIb is CH2 or a direct bond, R1 is independently any one or two of H, F, C1, CF3, OCF3 or OCH2Ph, and R2 is H. The invention also relates to a pharmaceutical composition based on the compound of formula I, a method of preventing and treating a microbial infection based on use of the compound of formula , and specific nitroimidazooxazine derivatives.

EFFECT: obtaining novel compounds with useful biological activity.

7 cl, 21 dwg, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of immunology. Claimed is application of monoclonal antibody against human Fas ligand protein (CD95L, or Apo1L, or FasL) or its antigen-binding fragment for manufacturing medication for prevention and/or treatment of skin diseases, associated with acantholysis of keratinocytes, in particular for prevention and/or treatment of pemphigus, where antibody contains amino acid sequences CDR of 3E1 antibody or is produced by hybridoma ATCC PTA-4017.

EFFECT: application of antibody in accordance with invention or its antigen-binding fragment provides more effective prevention of desmoglein (dsg3) cleavage in comparison with application of other antibodies.

11 cl, 16 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a suspension for treating psoriasis, containing calcipotriol monohydrate in the form of nanocrystals having the particle size distribution within the range of 200-600 nm; the particles are dispersed in an aqueous phase containing a non-ionic polymer surfactant specified in a group consisting of a surfactant in the form of poloxamers or polysorbates, in the amount of 0.01-5 wt % calculated using a suspension for preventing development of aggregation and/or calcipotriol monohydrate nanocrystal growth; the calcipotriol monohydrate nanocrystals are produced in the suspension by processing the suspension by a method involving the stages of reduction in crystalline calcipotriol monohydrate particle size in an aqueous phase to form microparticles having the particle size distribution within the approximate range of 5-20 mcm and the average approximate particle size of 10 mcm; the suspension is exposed to three high-pressure homogenisation cycles for 7-15 minutes each; in the first, second and third cycles, the pressure makes 300-800 bars, 800-1,200 bars and 1,200-1,700 bars respectively.

EFFECT: invention provides creating the local composition containing calcipotriol as an active agent, however being free from propylene glycol as a solvent.

34 cl, 8 ex, 5 tbl, 9 dwg

FIELD: medicine.

SUBSTANCE: to improve functional-aesthetic results of the plastic surgery of post-traumatic eyelid deformations, starting from 7-8 day from the moment of carrying out blepharoplasty of the post-traumatic cicatrical eyelid deformation, immediately after the removal of operational sutures, on the operated zone of the eyelid performed is a procedure of magnetic-photophoresis of a medical solution, made from 3000 ME of longidaze, 3 ml 25% solution of dimethylsulphoxide and 1 ml 0.25% solution of derinate, with 2 ml of the prepared solution being applied on an autodermal transplant and healthy skin surrounding it, with up to 1 cm indent from the wound edge, after 3-5 minutes a gauze pad, soaked with 2 ml of the remaining prepared solution, is applied on the processed surface of skin with the further 10 minute impact by a contact method by a travelling pulsed magnetic field of the apparatus "AMO-ATOS" with the frequency of pulse consecution of 5-10 Hz. Then, after the pad is removed, without the time interval, borders of the autodermal transplant and healthy skin closing are processed by infrared laser irradiation of a range of 0.89 mcm of the apparatus UZOR-2K with the frequency of the pulse repetition rate of 1500 Hz, in accordance with a contact labile method, 1 minute on each field, with carrying out 1 procedure daily for 10 days.

EFFECT: improvement of the quality of skin transplant engraftment, absence of secondary eyelid deformations, and reduction of the post-operational treatment duration.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology, namely represents a composition containing minoxidil and/or minoxidil sulphate combined with additives containing at least one antioxidant, at least one organic acid and selected fatty acids mixture. Besides, the invention refers to using the compounds for hair growth enhancement/recovery and/or hair loss prevention in mammals, particularly in a human.

EFFECT: using the invention provides faster anagen phase in mammalian hair growth and/or enhanced terminal hair above the skin surface by local application the declared compositions.

19 cl, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely to dermatology, and can be used for preventing and/or treating skin itching. It involves using L-serine as a therapeutic agent, a pharmaceutical composition containing L-serine, as well as a dermato-cosmetic composition containing L-serine as a single active agent, Avene Thermal Spring Water, glycerine and a cosmetically acceptable carrier. The L-serine concentration in the composition makes from 0.01 wt % to 10 wt % in relation to the total weight of the composition. More preferentially, the concentration makes 0.5 wt % to 3 wt % in relation to the total weight of the composition.

EFFECT: group of inventions provides the effectiveness of application.

8 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, namely to dermatology and mycology, and can be applied in the treatment of skin and its appendages. A pharmaceutical composition for external application contains nanoparticles for the laser thermotherapy of infectious affections of the skin and its appendages. The nanoparticles are characterised by, at least, one localised surface Plasmon resonance in the range of a wavelength from 400 to 1100 nm. The nanoparticles are dispersed in a physiologically acceptable carrier, which is characterised by the absence of the absorption or weak absorption and/or weak dispersion of light radiation in the said range of wavelengths and possessing biocidal properties. The pharmaceutical composition is applied on an affected area and irradiated by laser radiation with a wavelength close to the wavelength of the localised surface Plasmon resonance of the nanoparticles, contained in the composition, or equal to it. The irradiation is continued until the desirable temperature of heating of the said area is achieved.

EFFECT: group of inventions ensures an increased treatment efficiency, reduction of a risk of development of side effects, reduction of the number of recurrences due to the application of the pharmaceutical composition, capable of absorbing energy of the light radiation and transforming it into heat energy with the achievement of the specified temperature with laser irradiation at the specified wavelength with the lower intensity of laser radiation and possessing biocidal properties.

63 cl, 3 dwg, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry and represents a pharmaceutical composition for the external application for the treatment of skin diseases in the form of a cream, which includes as an active substance methylprednisolone aceponate in a therapeutically effective amount and a lipophilic base, characterised by the fact that as the lipophilic base it contains petrolatum, liquid paraffin and oil of castor oil plant seeds and additionally white bee wax, with the components of the composition being in a specified ratio in g/100 g of the composition.

EFFECT: invention provides the creation of the stable composition, improved pharmacological properties and absence of an irritating effect.

1 tbl

Antiallergic agent // 2553354

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents an anti-allergic agent containing polysaccharide containing galactose, glucose and rhamnose as ingredients, wherein polysaccharide contains galactose, glucose and rhamnose in molar ratio 3-5:1-3:1, and polysaccharide has certain structure.

EFFECT: invention provides extending the range of antiallergic agents.

12 cl, 6 ex, 6 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition in the form of a tablet with an erodible matrix, which contains one or more fumaric acid ethers, as well as a rate-controlling agent, representing hydroxypropylcellulose and a binding agent, representing lactose, with the decomposition of the said degradable matrix providing the controlled release of the said fumaric acid ether (ethers).

EFFECT: provision of the controlled release of fumaric acid ether (ethers).

19 cl, 43 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the beauty industry, representing a gel-like composition for topical application, containing salicylic acid with the concentration of ca. 17 wt %, elastic collodion in the amount of 5 to 10 wt % and ethyl lactate in the amount of 20 to 25 wt %, where the elastic collodion contains 65.8 wt % diethyl ether, 24.3 wt % ethanol, 2 wt % camphor, 3 wt % castor oil and 4.9 wt % nitro-cellulose.

EFFECT: invention provides excellent stability, even drying and the formation of a uniform film.

5 cl, 1 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11.8.0.01,10.02,7.014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones (IIa-d), which includes reacting 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones (Ia-d) with 3,4-dihydro-2H-pyran in a medium of an inert aprotic solvent, followed by separation of the end products. In general formula (I) Ar=Ph (a, d), C6H4Br-4 (b), C6H4OMe-4 (c), R=H (a-c), Cl (d).

EFFECT: obtaining 9-aryl-6,8,20-trioxa-13-azapentacyclo-[11,8,0,01,10,02,7,014,19]heneicosa-9,14,16,18-tetraene-11,12,21-triones.

2 cl, 1 tbl, 5 ex

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