2,5-substituted oxazolopyrimidine derivatives

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

 

The present invention relates to 2,5-substituted oxazolopyridine compounds and their physiologically acceptable salts.

Structurally similar compounds have already been described (see WO 2009/154775) and are compounds applicable for the treatment of multiple sclerosis. The mechanism of action of these compounds is to initiate the loss of sensitivity of signaling pathways EDG-1 activation of the EDG-1 receptor (so-called severalones), which is then equivalent to the functional antagonism of signaling pathways EDG-1. Systemically this means that, mainly on lymphocytes signaling pathway EDG-1 is suppressed permanently, causing these cells can no longer chemotactic to follow the S1P gradient between the blood and lymphatic fluid. Damaged lymphocytes can no longer leave secondary lymphatic tissue (increased homing), and the amount of freely circulating in the plasma of lymphocytes is significantly reduced. This lack of lymphocytes in plasma (lymphopenia) causes immunosuppression, which is absolutely necessary for the mechanism of action of modulators of receptor EDG-1 as described in WO 2009/154775.

The object of the present invention are compounds which are specifically suitable for healing wounds and, in particular, for the treatment of disorders associated with wound healing in patients with art�adusa diabetes. In addition, it was desirable to obtain compounds which are suitable for the treatment of syndrome of diabetic foot (diabetic foot syndrome - DFS). Moreover, it was desirable to achieve reproducible activation of signaling pathways EDG-1 receptor that enables, speaking pharmacological terms, in persistently activate EDG-1 signaling pathway.

The present invention relates to a derivative of oxazolopyridine of the formula I

where A, R1and R2take the values specified below. Thus, the mechanism of action of the compounds of formula I is not based on loss sensitivity EDG-1 signaling pathway and, therefore, diametrically opposed to the mechanism of action described in WO 2009/154775. The invention also relates to methods for obtaining compounds of formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising these compounds.

Compared to healthy adults in patients with diabetes is slow healing of wounds and increased rate of infection, especially in the case of prolonged hyperglycemia caused by poor regulation of blood sugar. The reasons include poor circulation, especially in small vessels, which drive�t to oxygen deficiency and insufficient supply of nutrients to the tissues. In addition, reduced cell division and the rate of cell migration of keratocytes, fibroblasts and dermal endothelial cells. Moreover, the protective activity of different cells (granulocytes) with reduced phagocytosis and destruction of bacteria) limited. The function of antibodies (immunoglobulins) against bacteria are also limited in the case of high values of sugar content in blood. Therefore, wounds and infections in patients with diabetes should be treated in a special way.

EDG-1 receptor is a member of the receptor gene of endothelial differentiation (Edg), including eight identified at present receptor class A (G-protein-coupled receptors - GPCRs). This family can be subdivided into subfamilies sphingosine-1-phosphate-activated receptors (S1P) (five representatives) and receptors activated lysophosphatidic acid (LPA; three representatives). The endogenous ligand S1P is a pluripotent lysophospholipid that affect cells of various types of GPCR activation from the Edg family of receptors, namely Edg-1 (=S1P1), Edg-3 (=S1P3), Edg-5 (=S1P2), Edg-6 (=S1P4) and Edg-8 (S1P5). Although S1P is also described as an intracellular messenger, a number of cellular responses S1P is mediated via activation of Edg receptors. S1P is generated enzyme family sphingosine (sphingosine kinases - SPHK) and various�under various phosphatases or LiAZ.

The object of the present invention is oxazolopyridine compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and its physiologically acceptable salt or physiologically acceptable solvate of any of these compounds.

where

A is selected from NH, O and S;

R1selected 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 R1represents the residue of a saturated or unsaturated 3-10-membered monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different heteroatom selected from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two sulfur atom of the ring may bear one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11;

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

R11selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, nitro group, cyanide groups, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl;

R21selected from (C1-C4)-alkyl, (C3-C7-cycloalkyl-CwH2Wand actigraphy, where w is selected from 0, 1 and 2;

R22selected from a halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino group, nitro group, cyanide groups, hydroxycarbonyl, (C1-C4)-allyloxycarbonyl, aminocarbonyl, aminosulfonyl, R23and R23-O-;

R23represents the residue of a saturated 3-to 7-membered monocyclic�about or bicyclic ring, which includes 0, 1, 2, 3 or 4 identical or different heteroatom selected from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one of the sulfur atoms of the ring can bear one or two carbonyl group and where the residue of a ring is optionally substituted on one or more carbon atoms, equal or different substituents R24;

R24selected from halogen, (C1-C4)-alkyl, hydroxyl and the carbonyl group;

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

m is selected from 0, 1 and 2, where all numerical values for m are independent of each other;

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

where all alkyl, CuH2u, Cv/sub> H2v, CwH2w, alkenyl and alkyline groups, independently of each other and independently of any other substituents, are optionally substituted by one or more fluorine substituents.

Structural elements such as groups, substituents, heterocycle, numbers or other distinguishing features, for example alkyl groups, groups such as R22or R11the numbers, such as m, u and v, which can occur more than once in the compounds of formula I, independently from each other can have the same value and in any case may be the same or different. For example, the alkyl group in dialkylamino may be the same or different.

Alkyl, alkenyl and alkyline group can be linear, i.e. straight-chain or branched. This also applies when they are part of other groups, such as alkyloxy (=alkoxygroup, alkyl-O-group), allyloxycarbonyl groups or alkyl-substituted amino groups, or when they are substituted. Depending on the respective definition, the number of carbon atoms in the alkyl group can 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, 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 bonds and triple bonds in the alkenyl groups and etkinlik groups can be in any positions. In one embodiment, the alkenyl groups contain one double bond and alkyline groups contain one triple bond. In one embodiment, the alkenyl group, or Alchemilla group contains at least three carbon atoms and is attached to the remainder of the molecule through a carbon atom that is not involved in a double bond or triple bond. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, Pro-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 group, alkenyl group and alkyline groups can be substituted in any positions, provided that the compound is sufficiently stable and suitable for the desired purpose, such as the use as a medicament. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable for a desired purpose, such as the use as a drug, usually has effect and in respect�attachment to the definitions of all groups in the compounds of formula I.

When applicable, the above explanations relating to the alkyl groups have power, respectively, and in relation to divalent alkyl groups such as group CuH2u, CvH2vand CwH2wwho, therefore, can also be linear or 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 a numerical value in the divalent group, such as, for example, the value of u in group CuH2uthat is 0 (=zero), two groups that are attached to the specified group, such as CuH2uconnect directly via a single bond.

The number of carbon atoms in the ring cycloalkyl group may be 3, 4, 5, 6 or 7. In one embodiment, the number of carbon atoms in the ring cycloalkyl group, regardless of the number of carbon atoms in the ring any other cycloalkyl group is 3, 4, 5 or 6, in another embodiment the invention is 3, 4 or 5, in another embodiment equal to 3 or 4, in another embodiment 3, in another embodiment 5, 6 or 7, in another embodiment, osushestvlyaetsya is 5 or 6, in yet another embodiment, the invention is 6 or 7, in another embodiment equal to 6. Examples cycloalkyl groups are the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Regardless of any other and independently of any other substituents, cycloalkyl groups are optionally substituted by one or more identical or different (C1-C4)-alkyl substituents which can be present in any positions, i.e., cycloalkyl groups may be substituted by alkyl substituents, or substituted alkyl substituents, for example 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 for example (C3-C7-cycloalkyl are the cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylmethyl, 2-cyclobutylmethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, 2-cycloheptylmethyl.

Regardless of any other and independently of any other substituents, alkyl groups, dvuhvalenten�e alkyl group, alkenyl group, alkyline group and cycloalkyl groups are optionally substituted by one or more fluorine atoms, which can be in any positions, i.e., these groups can be groups which are not substituted by fluorine atoms, or a group substituted by fluorine atoms, 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 fluorine atoms. Examples of these fluorine-substituted groups are trifluoromethyl, 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-diverticulosis, 3,3,4,4,5,5-hexaferrites. Examples of alkyloxy in which the alkyl fragment is fluorine-substituted, are triptoreline, 2,2,2-triptoreline, pentaborate and 3,3,3-cryptochromes. In one embodiment, the total number of fluorine substituents and (C1-C4)-alkyl substituents, which independently of any other substituents optionally present on cycloalkyl groups in the compounds of formula I, as well 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, a friend in�the approach of the invention is 1, 2, 3, 4, 5, 6, 7, 8 or 9, in another embodiment 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3, or 4.

Groups such as phenyl, naftalina (=naphthalenyl), and residues of aromatic heterocycles which are optionally substituted by one or more substituents, can be unsubstituted or can be substituted, such as 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 one embodiment, the total number of nitro substituents in the compound of formula I is not more than two. Aromatic nitrogen-containing heterocycles, in which the original ring system, the nitrogen atom of the cycle bears a hydrogen atom in the 5-membered ring, such as, for example, pyrrole, imidazole, indole or benzimidazole ring can be substituted on carbon atoms and/or on nitrogen atoms in the cycle. In one embodiment, the substituents on the nitrogen atoms in the ring selected from (C1-C4)-alkyl groups, i.e. the nitrogen atoms in aromatic heterocycles carry a hydrogen atom or a (C1-C4)-alkyl Deputy. When the ratio of nitrogen atoms in the ring in aromatic heterocycles and any other GE�erotico stated, they carry a hydrogen atom or a Deputy, such nitrogen atoms bear a hydrogen atom or a Deputy, or they do not carry a hydrogen atom or a substituent. The nitrogen atoms of the ring, which bear a hydrogen atom or a Deputy, found in nitrogen-containing aromatic 5-membered ring, which is present, for example, pyrrole, imidazole, indole or benzimidazole, and in non-aromatic ring including a saturated ring. The nitrogen atoms of the ring that do not carry a hydrogen atom or a Deputy, if they are not in the positively charged form, including any additional nitrogen atoms in addition to nitrogen atoms of the ring, which carry a hydrogen atom or a Deputy, are found in the aromatic ring, which is present, for example, thiazole, imidazole, pyridine or benzimidazole, and in the non-aromatic ring in which they are atoms of the bridging connection (bridgehead atom) or are part of a double bond, and they occur as the nitrogen atoms of the ring through which the ring is attached. Suitable nitrogen atoms of the ring in aromatic heterocycles in the compounds of formula I, such as the nitrogen atom in the pyridine ring, in particular a nitrogen atom in the aromatic heterocycle represented as R2may also carry oxy-Deputy-O-and can be represented as N-AUX�d, and such nitrogen atoms of the ring may also be present in the form Quaternary salts, for example in the form of N-(C1-C4)-alkyl salt such as N-methyl salt, where in one embodiment the counterion in such a Quaternary salt is a physiologically acceptable anion derived from an acid that forms a physiologically acceptable salt. In monosubstituted phenyl groups Deputy may be in position 2, position 3 or position 4. In disubstituted phenyl groups, the substituents can be in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions. In trisubstituted phenyl groups, the substituents can be 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-positions. 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 may likewise be located in any positions of the ring, via which subscribes naftalina group, and/or the other ring.

In the residues of aromatic heterocycles represented by R1or R2that can be defined as a heteroaryl group, as well as in all other heterocyclic�fir rings in the compounds of formula I, including the group Het and non-aromatic heterocyclic groups represented by R1the ring heteroatoms typically selected from the atoms N, O and S, where the N atoms comprise nitrogen atoms of the ring, which carry a hydrogen atom or a substituent and the nitrogen atoms of the ring that 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, is stable and suitable as a subgroup for the desired purpose of application of the compounds of formula I such as use as a medicinal substance. In one embodiment the two oxygen atoms of the ring can not be in adjacent positions of any heterocycle, in another embodiment, two heteroatom ring atoms selected from oxygen and sulfur cannot be adjacent the provisions of any rings of the heterocycle. Saturated rings do not contain double bonds in the ring. Unsaturated ring system may be aromatic or partially unsaturated, including partially aromatic, where in the latter case one ring in the bicyclic ring system is an aromatic ring system attached through a non-aromatic atom in the ring. Depending on the respective group of unsaturated ring �might contain one, two, three, four or five double bonds in the ring. Aromatic groups include 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 represented by R1can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In one embodiment the aromatic heterocyclic rings are 5-membered or 6-membered monocyclic ring or 8-membered, 9-membered or 10-membered bicyclic rings, in another embodiment of the invention is 5-membered or 6-membered monocyclic ring or 9-membered or 10-membered bicyclic rings, in another embodiment, the invention is 5-membered or 6-membered monocyclic ring, where 8-membered, 9-membered or 10-membered bicyclic ring consists 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 heterocyclic group, and one or both rings may be aromatic. Usually bizik�algebraic ring system, containing an aromatic ring and non-aromatic ring, are regarded as aromatic when they are attached via a carbon atom in the non-aromatic ring, and as non-aromatic when they are attached via a carbon atom in the non-aromatic ring. Unless otherwise stated, heterocyclic the group including an aromatic heterocyclic group, can join through suitable carbon atom of the ring and, in the case of nitrogen heterocycles via any suitable nitrogen atom of the ring. In one embodiment the aromatic heterocyclic group in the compound of formula I, independently of any other aromatic heterocyclic group, attached through a carbon atom of the ring, in another embodiment of the invention is through the nitrogen atom of the ring. Depending on the definition of the corresponding heterocyclic group, in one embodiment, the number of ring heteroatoms which can be present in the heterocyclic group, regardless of the number of ring heteroatoms in any other heterocyclic group, a is 1, 2, 3 or 4, in another embodiment the invention is 1, 2 or 3, in another embodiment 1 or 2, in another embodiment equal to 1, where the ring heteroatoms can be the same�mi or different. Heterocyclic groups which are optionally substituted, independently of any other heterocyclic groups can be 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, or 1, 2 or 3, or 1 or 2 substituents, or 1 substituent specified in the definition of the relevant group. The substituents on 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, in a pyridin-3-yl group substituents can be located in the 2-position and/or 4-position and/or 5-position and/or 6-position, in pyridine-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 which can be derived heterocyclic group including an aromatic heterocyclic group, saturated heterocyclic group 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]thiad�Athol, 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, cyclopenta[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, benzimidazole, 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, respectively 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, for example, azetidin, oxetan, 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.

Examples of residues of aromatic heterocycles, which can occur 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-imidazol-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 optionally substituted as indicated in the definition of the relevant group. Examples of residues of saturated and partially unsaturated heterocycles, which can occur 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, including 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-dihydroiso�indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, decahydroquinoline, decahydroquinoline, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl, pyrazolidine, imidazolidinyl ureido, hexahydropyridine, 1,2-dihydropyrimidines, piperazinyl, [1,3]diazepan, [1,4]diazepan, oxazolidinyl, [1,3]oxazinyl, [1,3]oxazepan, morpholinyl, including 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]oxadiazolyl, [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, tetrahydro�retinyl, 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]hexyl, including 3-azabicyclo[3.1.0]hex-3-yl, 2-ox-5-azabicyclo[2.2.1]heptyl, including 2-ox-5-azabicyclo[2.2.1]hept-5-yl, which is attached via any suitable carbon atom or ring nitrogen atom of the ring and are optionally substituted as indicated in the definition of the corresponding group.

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

When oxoprop attached to the carbon atom, it replaces two hydrogen atoms on the carbon atom of the original system. Thus, if CH2group in the chain or ring is substituted by exography, i.e. the hydrogen atoms are substituted by oxygen atom with a double bond, it becomes C(O) (=C(=O)) group. It is clear that oxoprop cannot be a Deputy at the carbon atom in the aromatic ring, such as, for example, a ring of the phenyl group. When the sulphur atom in the heterocyclic ring group may bear one and�and two carbonyl group, it is a non-oxidized sulfur atom S in the event that if he's not responsible for what any of carbonyl group, or it is part of the S(O) group (=sulfoxide group, S-oxide group) in that case, if he carries one oxoprop, or it is part of the S(O)2group (=sulfonic group, S,S-dioxide group) in the case where it carries two of the carbonyl group.

The present invention includes 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 represented in the S configuration, or essentially S configuration, or in R configuration or substantively R configuration or as a mixture of e S isomer and the R isomer in any ratio. The invention includes 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 present invention which can exist as enantiomers, may be represented in enantiomerically pure form, in the form of the levorotatory and dextrorotatory antipodes, and 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 on dual�m bonds or rings, such as cycloalkyl rings, the invention includes the E form and Z-form or CIS-form and TRANS form and mixtures of these forms in all ratios. In one embodiment, the compound may exist in two or more isomeric forms, is pure or essentially pure individual isomers. Getting the individual stereoisomers can be carried out, for example, by separation of the mixture of isomers by conventional methods such as chromatography or crystallization, by the use of pure stereochemical forms of the starting materials in the synthesis or by stereoselective synthesis. Optional, (derivatization) obtaining can be carried out before separation of stereoisomers. The separation of the mixture of stereoisomers can be carried out at the stage of obtaining compounds of formula I, at the stage of starting material or intermediate product in the synthesis process. The present invention also includes all tautomeric forms of compounds of formula I and their salts and solvates.

In the case where compounds of formula I contain one or more acidic and/or basic groups, i.e. salt-forming groups, the invention also comprises their corresponding physiologically or toxicologically acceptable salts, i.e. non-toxic salts, in particular their pharmaceutically acceptable salts. Thus compounds of formula I, which contain an acid group, such as hydroxycarbonyl group=carboxyl group=C(O)-OH group), and can be used according to the invention, for example, in the form of salts of alkali metals, salts of alkaline-earth metals and ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, Quaternary ammonium salts such as tetraalkylammonium salts, or acid-additive salts with ammonia or organic amines, such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula I which contain a basic group, i.e. a group which can protonemata, such as an amino group or nitrogen-containing heterocycle, can be used according to the invention in the form of additive salts with inorganic and organic acids. Examples of suitable acids include hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, benzoic acid, malonic acid, fumaric acid, malic acid, citric acid and other acids, are known to those skilled the art. If the compound of the formula I simultaneously contain acidic group primary group in the molecule, the connection also includes in addition to the salt forms, inner salt (=betaine, zwitterionic). Salts of compounds of formula I can be obtained by conventional methods known to the specialist in the art, for example by contacting the compound of formula I with organic or inorganic acid or base in a solvent or diluent, or by anion exchange 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 salt-forming acid or base are not directly suitable for use in pharmaceuticals but which can be applied, for example, as intermediates for chemical reactions or to obtain physiologically acceptable salts.

The present invention further includes all solvates of compounds of formula I, for example hydrates or the reaction products of accession 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 may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds, for example esters or AMI�s of carboxylic acid groups.

In one embodiment, A 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 represents the S.

In one embodiment, R1selected from (C1-C6)-alkyl, (C2-C6-alkenyl and (C2-C6)-alkynyl, in another embodiment, R1represents (C1-C6)-alkyl, in another embodiment, R1represents (C2-C5)-alkyl, and in another embodiment, R1represents (C1-C4)-alkyl, provided that R1cannot be an alkyl group when A represents S. In another embodiment, R1selected from (C1-C6)-alkyl, (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v-, in another embodiment from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v-, in another embodiment, R1represents (C3- 7-cycloalkyl-CuH2u- and in yet another embodiment, R1represents Het-CvH2v- where in this embodiment, u and v independently from each other selected from 1 and 2. In one embodiment, u is 1, in another embodiment, u is 2. In one embodiment, v is 1, in another embodiment, v is 2. In one embodiment, the group (C3-C7-cycloalkyl-CuH2u- designated as R1selected from dihydro-CuH2u- cyclobutyl-CuH2uand cyclopentyl-CuH2u-.

In one embodiment, R1selected from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2vor R3represents the residue of a saturated or unsaturated 3-10-membered monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different heteroatoms in the ring selected from the atoms N, O and S, where one or two nitrogen atoms of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two sulfur atom of the ring may bear one or two carbonyl group and where the residue of a ring is optionally substituted on one or a few� the carbon atoms of the ring are the same or different substituents R 11and in another embodiment, R1represents the residue of a saturated or unsaturated 3-10-membered monocyclic or bicyclic ring which comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms selected from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two sulfur atom of the ring may bear one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11. In one embodiment, the number of heteroatoms in the ring, denoted by R1, 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. Thus, the residue of a ring, denoted as R1may be carbocyclic or heterocyclic. In one embodiment implemented�of tvline of the invention, the ring heteroatoms in R 1selected from N and O atoms, in another embodiment from N and S atoms, in another embodiment from O and S atoms, in another embodiment they are N atoms, where the nitrogen atoms of the ring can carry a hydrogen atom or a (C1-C4)-alkyl Deputy, when they are in a saturated or partially unsaturated heterocycles, or a 5-membered aromatic ring heterocycles, such as, for example, pyrrole or benzimidazole, or does not bear a hydrogen atom or (C1-C4) is an alkyl substituent in the aromatic heterocycles, such as imidazole or pyridine. In the rest of the heterocycle representing R1that includes in the ring one or more sulfur atoms, in one embodiment, one of the sulfur atoms is oxidized and bears one or two carbonyl group, and any other sulfur atoms in the ring are non-oxidized. The residue is monocyclic or bicyclic ring representing R1may join the group A via any suitable carbon atom in the ring or the nitrogen atom in the ring. In one embodiment of the invention it is attached via a carbon atom of the ring, in another embodiment of the invention it is attached via a carbon atom of the ring �Lee, in the case where A represents NH, via the nitrogen atom of the ring, and in another embodiment, it is attached via the nitrogen atom of the ring. The residue is monocyclic or bicyclic ring representing R1may be unsaturated and in this case contain in the ring 1, 2, 3, 4, or 5, or 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2 double bonds or 1 double bond and may, in either one or both rings can be aromatic or non-aromatic, or it can be rich and in this latest case does not contain a double bond in the ring. In one embodiment, the residue of a ring, representing R1is saturated or aromatic, in another embodiment it is saturated, in another embodiment, it is aromatic. In one embodiment, the remainder of the 3-membered or 4-membered ring representing R1is saturated. If R1includes nitrogen atoms in the ring, which can carry a hydrogen atom or a (C1-C4)-alkyl substituent may be present at one of the nitrogen atoms in the ring or two nitrogen atoms in the ring. In one embodiment, optional substituents of R11on the carbon atoms of the ring, predstavlyayushie� R 1is 1, 2, 3, 4, 5 or 6, in another embodiment the invention is 1, 2, 3, 4 or 5, in another embodiment, - 1, 2, 3 or 4, in another embodiment, - a 1, 2 or 3, in another embodiment 1 or 2, and in yet another embodiment, is 1.

The ring, which can represent R1can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In one embodiment, R1is a 4-10-membered, in another embodiment the invention is 4 to 9-membered, in another embodiment, - 4-8-membered, in another embodiment, the invention is 4 to 7-membered, in another embodiment, 5 to 7-membered, in another embodiment, the invention is 5-membered or 6-membered, in another embodiment, the invention is 6-membered, in another embodiment, - 8-10-membered, in another embodiment, - 9-10-membered. In one embodiment the 3-membered ring representing R1does not include heteroatoms. In one embodiment, R1is a monocyclic, in another embodiment of the invention is bicyclic. In one embodiment, the implementation and�gaining bicyclic group, representing R1is at least 7-membered. Among others, the residue of a ring, representing R1may be cycloalkyl group, phenyl group, naftalina group, the remainder of the unsaturated aromatic or non-aromatic heterocyclic group or a residue of a saturated heterocyclic group which are optionally substituted on the carbon atoms of the ring and the nitrogen atoms of the ring, as defined relative to R1. As applicable, all explanations given above with respect to such groups, shall apply accordingly with respect to R1. Another example of groups which can represent R1are cycloalkenyl groups such as (C5-C7)-cycloalkenyl group, which can then be connected through any carbon atom of the ring and are optionally substituted as defined relative to R1. In one embodiment, optional substituents of R11on cycloalkenyl group representing R1selected from a fluorine atom and (C1-C4)-alkyl. In one embodiment of the invention cycloalkenyl groups contain one double bond in the ring, which can be in any position. Examples cycloalkenyl are cyclopentenyl, including cyclopent-1-enyl, cycle�pent-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, cyclopent-3-enyl and cyclohepta-4-enyl. Examples of residues of rings, of which the selected R1in one embodiment of the invention, represent 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 these groups, if applicable, one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl, and all these groups are optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11and where in all these groups, if applicable, the sulfur atom of the ring may be oxidized, i.e. present as a sulfur atom, or carries �yourself and one or two carbonyl group, i.e. in the form of sulfoxide or sulfone.

In one embodiment, R1selected from phenyl and a residue of a saturated or unsaturated 3-to 7-membered monocyclic ring, in another embodiment from phenyl and a residue of a saturated or unsaturated 5-7-membered monocyclic ring, in another embodiment from phenyl, pyridinyl and residue of a saturated 3-to 7-membered monocyclic ring, in another embodiment from phenyl, pyridinyl and residue of a saturated 5-7-membered monocyclic ring, in another embodiment from phenyl and a residue saturated 3-to 7-membered monocyclic ring, in yet another embodiment from phenyl and a residue of a saturated 5-7-membered monocyclic ring, where in all these embodiments, the monocyclic ring comprises 1 or 2 identical or different heteroatom selected from the atoms N, O and S, where one or two nitrogen atom in the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two sulfur atom in the ring may bear one or two carbonyl group, where the phenyl, pyridinyl, and the remainder of the ring are optionally substituted by one or more of the carbon atoms of the ring �same or different substituents R 11and where pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. In yet another embodiment, R1selected from phenyl and pyridinyl, in another embodiment, R1represents pyridinyl, in another embodiment, R1represents phenyl, where in these embodiments, pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl in one embodiment of the invention is selected from any one or more of these groups and where in all these embodiments, the phenyl and pyridinyl are optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11.

In one embodiment, w is selected from 0 and 1, in another embodiment it is 0, in another embodiment it is 1. In one embodiment of the invention (C3-C7)-cycloalkyl group in R21represents (C3-C6-cycloalkyl, in another embodiment, - (C3-C5-cycloalkyl, in yet another embodiment, the cyclopropyl. In one embodiment, R21selected from (C1-C4)-alkyl � of actigraphy, in another embodiment, R21represents (C1-C4)-alkyl, in another embodiment it represents (C1-C3)-alkyl, in another embodiment it is methyl, and in another embodiment it represents a hydroxy group.

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

In one embodiment, R11selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, actigraphy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyanide groups, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyanide groups, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, (C1-C4)-alkyl-S(O)m -, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyanide groups and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, amino group, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyanide groups and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, amino group, (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, (C1-C7)-cycloalkyl, hydroxyl groups 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, hydroxyl groups and (C1-C4)-Alki�hydroxy, where in all these embodiments all alkyl groups independently of each other are optionally substituted by one or more fluorine substituents.

In one embodiment, optional substituents of R11on the aromatic ring residue representing R1, such as phenyl group or pyridinoline group representing R1selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C44)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyanide groups, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyanide groups, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in yet another embodiment, osushestvlenie� of the invention - from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyanide groups and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyanide groups and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (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 and di((C1-C4)-alkyl)amino, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl groups and (C1-C4)-alkyloxy, in another embodiment from halogen, (C1-C4)-alkyl and (C1-C4)-alkyloxy, in yet another embodiment, the implementation and�gaining - from fluorine, chlorine, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl groups and (C1-C4)-alkyloxy, where in all these embodiments, the alkyl groups independently of each other are optionally substituted by one or more fluorine substituents.

In one embodiment, optional substituents of R11on the residue of a saturated or unsaturated non-aromatic ring, representing R1selected from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonamides and cyanide groups, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy, carbonyl group, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino and cyano, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, a hydroxyl group, (C1-C4)-alkyloxy and the carbonyl group, in another embodiment, osushestvlenie� of the invention - from halogen, (C1-C4)-alkyl, a hydroxyl group, (C1-C4)-alkyloxy and the carbonyl group, in another embodiment from fluorine, chlorine, (C1-C4)-alkyl, a hydroxyl group, (C1-C4)-alkyloxy and the carbonyl group, in another embodiment from (C1-C4)-alkyl, hydroxyl and the carbonyl group, in another embodiment from alkyl and hydroxyl groups, and in another embodiment they are (C1-C4)-alkyl, where in all these embodiments all alkyl groups independently of each other are optionally substituted by one or more fluorine substituents. In the case where the residue of a ring, representing R1that contains any of the carbonyl group as the substituents R11in one embodiment, the present invention is not more than two such oxo-substituents, in another embodiment, the present invention is not more than one such oxo substituent.

In one embodiment, the substituents R22, which are optionally present on the group R2selected from a halogen , a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, AMI�of gruppi, nitro-group, cyanide groups, R23and R23-O-, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, amino, cyanide groups, R23and R23-O-, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, R23and R23-O-, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl and (C1-C4)-alkyloxy-where in all embodiments, R23takes the values defined in the invention.

In one embodiment, 1, 2 or 3 substituent R22in another embodiment, 1 or 2 substituent R22and in yet another embodiment the substituents R 122, which are optionally present on the group R2take the values defined in the General description of R22and, thus, selected from a halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino group, nitro group, cyanide groups, hydroxycarbonyl, (C1-C4)-allyloxycarbonyl, aminocarbonyl, aminosulfonyl, R23and R23-O-, where R23prin�took the values defined in the description, and any additional substituents R22, which are optionally present on the group R2such as 1 , 2 or 3 additional Deputy R22or 1 or 2 additional Deputy R22or 1 further substituent R22selected from a halogen , a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino group, nitro group, cyanide groups, R23and R23-O-, where all alkyl groups independently of each other are optionally substituted by one or more fluorine substituents, as it usually applies to alkyl groups. In one embodiment, the substituents R22, which are optionally present on the group R2and that in the above-described embodiment, the values defined in the description of R22, for example 1 or 2 such Deputy R22or 1 such substituent R22selected from a halogen , a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino group, nitro group, cyanide groups, R23and R23-O-, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C 1-C4)-alkyl-S(O)m-, amino group, R23and R23-O-, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, amino group, R23and R23-O-, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino and cyanide groups, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy - and cyanide groups, where R23takes the values defined in the description. In one embodiment, the substituents R22, which are optionally present on the group R2and that in the above-described embodiment, the values defined in the description of R22, for example 1 or 2 such Deputy R22or 1 such substituent R22not located on the carbon atoms of the ring in the group R2that are adjacent to the atom through which the group R2attached to oxazolopyridine ring depicted in formula I. In another embodiment of the invention in the case where the phenyl group is R21 or 2 such substituents R22 or 1 such substituent R22not necessarily in any of the positions 3, 4 and 5 of the phenyl group, and in another embodiment 1 such substituent R22is in position 4 of the phenyl group. In one embodiment, these additional substituents R22, which are optionally present on the group R2such as 1 , 2 or 3 additional Deputy R22or 1 or 2 additional Deputy R22or 1 further substituent R22selected from a halogen , a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino and cyanide groups, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy-, amino and cyanide groups, in another embodiment from halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C44)-alkyloxy - and cyanide groups, 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 I�are optionally substituted by one or more fluorine substituents.

In one embodiment, R23represents the balance of the monocyclic ring, in another embodiment the residue bicyclic ring. The remainder of the ring representing R23may be carbocyclic or heterocyclic. In one embodiment, the residue is monocyclic ring representing R23is carbocyclic, in another embodiment of the invention is heterocyclic. In one embodiment, the residue bicyclic ring representing R23is carbocyclic, in another embodiment of the invention is heterocyclic. In one embodiment, the number of ring heteroatoms in R23is 0, 1, 2 or 3, in another embodiment, is 0, 1 or 2, in another embodiment 0 or 1, in another embodiment, - 1, 2, 3 or 4, in another embodiment, - a 1, 2 or 3, in another embodiment 1 or 2, in another embodiment - 1, and in another embodiment it is 0, hence in this latter case, R23represents (C3-C7)-cycloalkyl group. In one embodiment, osushestvlenie� of the invention, the residue of a monocyclic ring, representing R23is oxetanyl group such as, for example, oxetan-3-yl.

In one embodiment, the ring heteroatoms in R23selected from N and O atoms, in another embodiment of the invention is made of atoms O and S, in another embodiment they are N atoms, and in yet another embodiment, they are About atoms, where the nitrogen atoms of the ring can carry a hydrogen atom or a (C1-C4)-alkyl Deputy. R23can join via any suitable carbon atom ring and the nitrogen atom of the ring. In the case where R23attached to the oxygen atom, in one embodiment, R23attached via a carbon atom of the ring. In another embodiment, R23attached via a carbon atom of the ring, regardless of the atom to which R23attached. In yet another embodiment, R23attached through the nitrogen atom of the ring. In one embodiment, optional substituents of R24on the carbon atoms of the ring in R23is 1, 2, 3 or 4 or 5, in another embodiment the invention is 1, 2, 3 or 4, in another embodiment, - a 1, 2 or 3, in another embodiment, the implementation and�gaining - 1 or 2, in another embodiment - 1. R23can be 3-membered, 4-membered, 5-membered, 6-membered or 7-membered. In one embodiment, R23is a 4-7-membered, in another embodiment, 4 to 6-membered, in another embodiment, the invention is 5 to 6-membered, in another embodiment, - 4-5-membered. In one embodiment the 3-membered ring representing R23that does not include any heteroatoms. Examples of residues of rings, of which the selected R23in one embodiment of the invention are oxetan-3-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, piperidine-4-yl, morpholine-4-yl and piperazine-1-yl, which are optionally substituted as defined above. In one embodiment, R23selected from any one or more of the residues oxetan-3-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl, morpholine-4-yl and piperazine-1-yl, in another embodiment, any one or more residues of oxetan-3-yl, azetidin-1-yl, piperidine-1-yl, morpholine-4-yl and piperazine-1-Il in another embodiment, any one or more of the residues oxetan-3-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-Il, and in yet another �the Ariant of the invention R 23is oxetan-3-yl, where all these residues are optionally substituted as indicated.

In one embodiment, R24selected from halogen, (C1-C4)-alkyl and hydroxyl group, in another embodiment from fluorine, (C1-C4)-alkyl and hydroxyl group, in another embodiment from fluorine, methyl and hydroxyl groups, in another embodiment from fluorine and methyl, in another embodiment from methyl and hydroxyl groups, in another embodiment from fluorine, (C1-C4)-alkyl, hydroxyl and the carbonyl group.

In one embodiment, the heteroatoms in the ring Het is selected from N and O atoms, in another embodiment from O and S atoms, in another embodiment, they are atoms of O. In yet another embodiment, the number of ring heteroatoms in Het is 1. In one embodiment the two oxygens in the ring in Het are not in adjacent positions, in another embodiment, two heteroatom ring atoms selected from O and S, are not in adjacent positions, in another embodiment, the implementation of izobreteny� two heteroatom ring are not in adjacent positions in the ring. The nitrogen atoms of the ring in Het carry a hydrogen atom or a Deputy, as defined. In one embodiment, optional substituents on the nitrogen atoms of the ring in Het represents (C1-C4)-alkyl substituents. In one embodiment, optional substituents on the nitrogen atoms of the ring and the carbon atoms of the ring in Het represents (C1-C4)-alkyl substituents. In one embodiment, optional substituents on Het is 1, 2, 3, 4 or 5, in another embodiment the invention is 1, 2, 3 or 4, in another embodiment, - a 1, 2 or 3, in another embodiment 1 or 2, in another embodiment - 1. Het can join via any suitable carbon atom of the ring. In one embodiment, Het attached through a carbon atom of the ring which is not adjacent to the heteroatom. Het can be 4-membered, 5-membered, 6-membered or 7-membered. In one embodiment, Het is a 4-membered or 5-membered, in another embodiment, 5-7-membered, in another embodiment of the invention is 5-membered or 6-membered, in another embodiment, the invention is 4-membered. Examples of Het, of which about selected�in or some Het, in one embodiment of the invention are oxetanyl, including oxetan-2-yl and oxetan-3-yl, 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 all are optionally substituted as defined relative to Het.

The subject of the invention are all compounds of formula I where l�fight one or more structural elements, such as groups, substituents and numbers are defined in any one of specific embodiments of the invention or definitions of the elements or accepts any one or more specific values that are specified in the description as examples of elements, where all combinations of one or more specific embodiments of the invention or definitions and/or specific values of the elements are the subject of the present invention. Moreover, with respect to all such compounds of formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, as well as all physiologically acceptable salts and physiologically acceptable solvates of any of them are the subject of the present invention.

Examples of compounds according to the present invention, with respect to any structural elements are defined in the described embodiments of the invention or definitions of such elements, and which are the subject of the present invention, are compounds of formula I, where

A is selected from O and S;

R1selected from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v- where u and v are chosen from 1 and 2, or R1represents the residue of a saturated or unsaturated 3-10-membered monocyclic or bicyclic ring which comprises 0, 1, 2, 3or 4 identical or different heteroatom, chosen from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two sulfur atom of the ring may bear one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11;

R2selected from phenyl and pyridinyl, where the nitrogen atom of pyridine can bear hydroxy-Deputy and where the phenyl and pyridinyl are optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22;

and all other groups and numbers take the values defined in the General definition of the compounds of formula I or in any specific embodiments of the invention or definitions of structural elements in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvate of any of these compounds.

Another such example are compounds of the formula I, where A represents O;

R1selected from (C3-C7-cycloalkyl-CuH2u- and Het-CvH2vwhere u and v are chosen from 1 and 2, or R1represents the residue of a saturated or nanasawa�tion, 3-10-membered monocyclic ring which comprises 0, 1 or 2 identical or different heteroatom selected from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one or two sulfur atom in the ring may bear one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11;

R2selected from phenyl and pyridinyl, where the nitrogen atom of pyridine can bear oxo-Deputy and where the phenyl and pyridinyl are optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22;

R11selected from halogen, (C1-C4)-alkyl, (C1-C4)-alkyloxy and cyanide groups;

R22selected from a halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy, cyanide groups, R23and R23-O-;

R23represents the residue of a saturated 3-6-membered monocyclic ring which includes 0 or 1 hetero-atom selected from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one of the sulfur atoms of the ring can carry on with�the be one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R 24;

R24selected from a fluorine atom, (C1-C4)-alkyl and hydroxyl groups;

Het is a residue of a saturated 4-7-membered monocyclic heterocycle, which contain in the ring 1 hetero-atom selected from the atoms N, O and S and which is attached via a carbon atom of the ring, where the residue of a heterocycle is optionally substituted by one or more identical or different substituents selected from a fluorine atom and (C1-C4)-alkyl;

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

where all alkyl, CuH2uand CvH2vgroups, independently of each other and independently of any other substituents, are optionally substituted by one or more fluorine substituents,

in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and physiologically acceptable salts and physiologically acceptable solvates of any of these compounds.

Another such example are compounds of the formula I, where A represents O;

R1represents the residue of a saturated or unsaturated 3-to 7-member�steering monocyclic ring, which includes 0 or 1 hetero-atom selected from the atoms N, O and S, where the nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and the sulfur atom of the ring may carry one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R11;

R2selected from phenyl and pyridinyl, where the nitrogen atom of pyridine can bear hydroxy-Deputy and where the phenyl and pyridinyl are optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22;

R11selected from halogen, (C1-C4)-alkyl and (C1-C4)-alkyloxy;

R22selected from a halogen, a hydroxyl group, (C1-C4)-alkyl-, (C1-C4)-alkyloxy, R23and R23-O-;

R23represents the residue of a saturated 3-6-membered monocyclic ring which includes 0 or 1 hetero-atom selected from the atoms N, O and S, where one or two nitrogen atom of the ring can carry a hydrogen atom or a (C1-C4)-alkyl substituent and one of the sulfur atoms of the ring may carry one or two carbonyl group and where the residue of a ring is optionally substituted by one or more of the carbon atoms of the ring about�inculami or different substituents R 24;

R24selected from a fluorine atom, (C1-C4)-alkyl and hydroxyl groups;

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

where all alkyl groups, independently of each other and independently of any other substituents, are optionally substituted by one or more fluorine substituents,

in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and physiologically acceptable salts and physiologically acceptable solvates of any of these compounds.

Similarly, with regard to all specific compounds disclosed herein, such as, for example, compounds that are embodiments of the invention, where different groups and numbers in the General definition of the compounds of formula I are taking specific values presented in the relevant specific connection, it is stated that they are the subject of the present invention in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and physiologically acceptable salts and physiologically acceptable solvates of any of the�azannyh compounds. Regardless, reveals whether a particular connection in the description in the form of a free compound and/or in the form of the specific salt, the specified connection is the subject of this invention in the form of the free compounds and in the form of all its physiologically acceptable salts, and if disclosed to a specific salt, in the form of this specific salt, and in the form of physiologically acceptable solvates of any of these compounds. Thus, the subject invention also is a compound of formula I, which is selected from any one or more specific compounds of formula I disclosed in this specification, including examples of the compounds presented below, and their physiologically acceptable salts and physiologically acceptable solvates of any of these compounds, where the compound of formula I is a subject of the present invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, if applicable. An example of the compound is a compound of formula I or its physiologically acceptable salt or physiologically acceptable solvate of any of them, which are selected from compounds

5-(2-pertenece)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine,

4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenol,

5-(2-PIF�phenoxy)-2-(3-methoxyphenyl)oxazolo[5,4-d]pyrimidine,

4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]phenol,

5-(2-pertenece)-2-(4-methoxy-3-methylphenyl)oxazolo[5,4-d]pyrimidine,

5-(2-pertenece)-2-(4-methoxy-3-triptoreline)oxazolo[5,4-d]pyrimidine,

4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-METHYLPHENOL,

2-(4-methoxy-3,5-dimethylphenyl)-5-phenoxyacetate[5,4-d]pyrimidine,

2-(4-methoxy-3,5-dimethylphenyl)-5-(pyridin-3-yloxy)oxazolo[5,4-d]pyrimidine, and

4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-triptoreline.

Another object of the present invention are methods of obtaining the compounds of formula I and their salts and solvates, whereby can be obtained the compounds and which are presented below. In one method, the compound of formula II is subjected to interaction with the compound of formula III to obtain compounds of the formula I

where the groups A, R1and R2in the compounds of formulas II and III take the values defined for compounds of formula I and additionally functional groups can be represented in protected form or in the form of a precursor group, which then undergoes transformation into the final group. Group L1in compounds of formula II represents a group to delete, which can be substituted in the reaction of aromatic nucleophilic substitution, such as sulfonyloxy groups�, for example, methansulfonate or triftormetilfullerenov, a halogen atom, for example chlorine or bromine, sulfoxide group or sulfonic group, for example a group of formula-S(O)-Alk or-S(O)2-Alk, where Alk is a (C1-C4)-alkyl group, for example methyl or ethyl.

The interaction of the compounds of formulas II and III is a reaction of aromatic nucleophilic substitution at the carbon atom in position 5 oxazolo[5,4-d]pyrimidine ring, i.e. in the pyrimidine fragment, and can be performed under standard conditions for such reactions which are well known to those skilled the art. Usually, the reaction is carried out in an inert solvent, such as hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, in a simple ether, such as tetrahydrofuran (THF), dioxane, simple dibutyl ether, simple 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), N,N-dimethylacetamide (DMA) or N-methylpyrrolidine-2-he (NMP), or mixtures of solvents, at temperatures from about 20°C to about 160°C, for example at temperatures from about 40°C to about 100°C, depending�spine from the characteristics of the case. Usually it is favorable for enhancing the nucleophilicity of the compound of formula III 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 alkaline-earth metal, such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydrogen carbonate, 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 III can also be machined base with obtaining a salt separately before the interaction with the compound of formula II.

The starting compounds of formulas II and III can be obtained in accordance with the methods described in the scientific literature or analogously to methods described in the scientific literature, and in many cases are commercially available. For example, compounds of formula II can be obtained by the interaction of 5-aminopyrimidine-derivative of formula IV with an activated carboxylic acid derivative of the formula V to produce a compound of formula VI, cyclization of the latter compound through education oxazolo[5,4-d]pyrimidine cyclic system to produce a compound of formula VII, which can p�establet a compound of formula II, depending on the values of R' and L 1and optional modification of the group R' in the compound of formula VII to produce a compound of formula II.

The group R2in the compounds of formulas V, VI and VII takes the values defined for compounds of formula I, functional groups can also be in protected form or in the form of precursor groups which are then converted into the final group. The group R' in the compounds of formulas IV, VI and VII may represent a hydroxyl group or a halogen atom, such as chlorine or bromine. Group L2in the compounds of the formula V is nucleophile is being replaced, remove the group and, in particular, can be a halogen atom such as chlorine or bromine, and, thus, the compound of formula V can represent gelegenheid carboxylic acid. L2can also represent a group of the formula R2-C(O)-Oh, and thus, the compound of formula V may be, for example, a carboxylic acid anhydride. Compounds involved in the synthesis of compounds of formula I, such as compound of the formula IV may also be represented in another tautomeric form, for example in the keto-form, in the case where R1in the compound of formula IV represents a hydroxyl group. Compounds involved in the synthesis of compounds forms�ly I, including starting compounds, intermediates and products, also can be applied or can be obtained in salt form.

Compounds of formula IV are commercially available or can be obtained in accordance with the methods described in the scientific literature. For example, the compound of formula IV, where R' represents a hydroxyl group, which is a 5-aminouratsil, in its tautomeric hydroxy-form can be obtained from uracil nitration with getting 5-nitrouracil and restoration of the nitro group, for example as described in the publication B. Johnson et al., J. Am. Chem. Soc. 41 (1919), 782-789. The compound of formula IV, where R1represents chlorine, i.e. 5-amino-2,4-dichloropyrimidine, can be obtained from 5-nitrouracil chlorination, for example by treatment with phosphorus oxychloride, and the restoration of the nitro group in the resulting 2,4-dichloro-5-nitropyrimidine, for example as described in the publication N. Whittaker, J. Chem. Soc. (1951), 1565-1570.

The interaction of the compounds of formula IV and V may be carried out in standard conditions of acylation of an amine activated carboxylic acid derivative such as acid chloride or anhydride. Usually, the reaction is carried out in an inert solvent, such as hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, in a simple EF�re, such as THF, dioxane, simple dibutyl ether, simple diisopropyl ether or DME, in a ketone, such as acetone or butan-2-he, ester such as ethyl acetate or butyl acetate, or in water or in a mixture of solvents, at temperatures from about -10°C to about 40°C, for example at temperatures from about 0°C to about 30°C. Usually the reaction is carried out with addition of a base, e.g. a tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholin, or inorganic bases, such as the hydroxide, carbonate or bicarbonate of an alkali metal, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogen carbonate.

In the case where the group R' in the compound of formula VI represents a hydroxyl group, cyclization of a compound of formula VI to the compound of formula VII is conveniently carried out in the presence halogenides agent such as a phosphorus halide, e.g. phosphorus pentachloride or phosphorus oxychloride or a mixture thereof, in an inert solvent, such as hydrocarbon or chlorophana the hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, at temperatures from about 20°C to about 100°C, for example at temperatures from about 50°C to about 80°C.

In the case where the group R' in the compound form�s VI represents a halogen atom, such as chlorine, cyclization of a compound of formula VI to the compound of formula VII can be carried out thermally, for example by heating the compound of formula VI in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon, for example toluene, xylene or chlorobenzene, an amide, for example DMF, DMA or NMP, or a nitrile, for example acetonitrile, to temperatures from about 1000C to about 200°C, for example to temperatures from about 120°C to about 180°C, optionally under pressure and optionally in the presence of base such as a tertiary amine, for example triethylamine, ethyldiethanolamine or N-methylmorpholin, or inorganic bases, such as hydroxide, carbonate or bicarbonate of an alkaline metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate. Thermal cyclization can be successfully performed in a microwave reactor.

Compound of formula VII may already be a compound of the formula II used in the reaction with the compound of the formula III, if it was obtained from the compound of formula VI, where R represents a halogen atom, such as chlorine, and a halogen atom in the cyclization product was not replaced, for example during processing, or if it was obtained from the compound of formula VI, where R' represents a hydroxyl group, and one�temporarily cyclization with the second hydroxyl group in the compound of the formula VII halogenides, for example through substitution of the chlorine atom that can be done during cyclization using phosphorus halide. If the compound of formula VII, where R' represents a hydroxyl group, obtained as the product of the cyclization, the hydroxyl group may be subjected to conversion to the deleted group under standard conditions, for example a halogen atom such as a chlorine atom, processing halogenous agent such as a phosphorus halide, or sulfonyloxy, as shown above, by treatment with sulphonylchloride or a sulfonic acid anhydride. Depending on the characteristics of the case, such as the reactivity of a specific compound of formula III, which should be subjected to interaction with the compound of formula II may also be useful to modify the group R' in the compound of the formula VII, even if it is already deleted group. For example, the compound of formula VII, where R1is a halogen, such as chlorine, may be subjected to conversion to the compound of formula II, where L1is a group-S(O)2-Alk, which is then subjected to interaction with the compound of formula III by treatment alkanesulphonic acid of the formula Alk-S(O)-OH, where Alk is a (C1-C4)-alkyl. Such transformation is usually carried out in the presence of base, such to�to the hydride, the hydroxide, carbonate or bicarbonate of an alkali metal, e.g. sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, in an inert solvent such as a hydrocarbon or chlorinated hydrocarbon, for example benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, ether, for example THF, dioxane, simple dibutyl ether, simple diisopropyl ether or DME, an amide like DMF or NMP, or mixtures of solvents, at temperatures from about 20°C to about 150°C, for example at temperatures from about 50°C to about 120°C. Alkanesulfonyl acid may also be machined, ground and turn into a salt prior to interaction with the compound of formula VII.

Furthermore, compounds of formula I can be derived from suitable compounds obtained in accordance with the above-described methods of introducing functional groups or modification of contained functional groups according to standard methods, for example by esterification, amidation, hydrolysis, etherification, alkylation, acylation, sulfonylamine, recovery, oxidation, conversion into salts, and others. for Example, a hydroxyl group, which may be released from the group of simple ester through cleavage of Pro�that ether, for example using tribromide boron, or a protected hydroxyl group by removing the protection, can tarifitsirovatsja with the receipt of ester carboxylic acids or of ester sulfonic acids, or tarifitsirovatsja with simple ether. Reaction tarifitsirovana hydroxyl group with simple ether can successfully be carried out by alkylation of the corresponding halogenated compounds, such as bromide or iodide, in the presence of base, such as alkali metal carbonate such as potassium carbonate or cesium carbonate, in an inert solvent, such as in an amide, such as DMF or NMP or a ketone like acetone or butan-2-it, or with the respective alcohol under the reaction conditions Mitsunobu (Mitsunobu), i.e. in the presence of azodicarboxylate, such as diethylazodicarboxylate or diisopropylcarbodiimide, and phosphine, such as triphenylphosphine or tributylphosphine, in an inert aprotic solvent, for example in a simple ether, such as THF or dioxane (Ref. O. Mitsunobu, Synthesis (1981), 1-28).

The hydroxyl group may be subjected to conversion into a halide by treatment halogenous agent. A halogen atom may be substituted with various groups as a result of the substitution reaction, crotona could also be a reaction catalyzed by a transition metal�ohms. The nitro group can be reduced to the amino group, for example by catalytic hydrogenation. The amino group can be modified under standard conditions for alkylation, for example by interaction with the halogen-containing compound or by reductive amination of carbonyl compounds or by acylation or sulfonylamine, such as the interaction with reactive carboxylic acid derivative such as acid chloride or acid anhydride, or with an activated carboxylic acid, which can be obtained by treating a bonding agent such as N,N'-carbonyldiimidazole (CDI), carbodiimides, for example 1,3-dicyclohexylcarbodiimide (DCC), or the 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',N1-tetramethylurea (TOTU) or tetrafluoroborate [(benzotriazole-1-yloxy)-dimethylamino-methylene]-dimethylamine (TBTU). The group of ester carboxylic acid may be subjected to hydrolysis in acidic or basic conditions with obtaining carboxylic acids. The carboxylic acid group can be activated and turn into a reactive derivative, as described above, and subjected to interaction with alcohol, amine or ammonia with obtaining� ester or amide. Primary amide may be digidrirovanny with obtaining nitrile. A sulfur atom, such as alkyl-S-group or a heterocyclic ring, may be subjected to oxidation by peroxide, such as hydrogen peroxide and a superacid with getting sulfoxide fragment S(O) or sulfonic fragment S(O)2. The carboxylic acid group, an ester group of carboxylic acid and ketogroup may be reduced to the alcohol, for example a complex hydride, such as alumalite lithium, lithium borohydride or sodium borohydride.

All reactions used in the above-described syntheses of the compounds of formula I, by themselves, are known to those skilled in the art and may be carried out under standard conditions according to or analogously to methods described in the scientific literature, for example in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley&Sons, New York. If necessary, the obtained compound of formula I, as well as any intermediate products may be cleaned in accordance with standard techniques, for example by recrystallization or chromatography. As already mentioned, the starting compounds and intermediates used in the syntheses described above, which contain an acidic or basic group, can also be applied in the form of salts. And as already mentioned�subscribe above depending on the characteristics of the case in order to avoid undesirable direction reaction or side reactions during the synthesis of the compounds generally may be required or useful to temporarily block functional groups by introducing protective groups and their removal at a later stage of the synthesis, or introduce functional groups in the form of precursors which are later subjected to transformation into the desired functional groups. As examples of protective groups can be referred to protective groups of amino groups, which can represent an acyl group or allyloxycarbonyl group, for example tert-butyloxycarbonyl group (=Boc), which can be removed by treatment with trifluoroacetic acid (=TFUC), benzyloxycarbonyl group which can be removed by catalytic hydrogenation, or fluoren-9-ylmethoxycarbonyl group which can be removed by treatment with piperidine, and the protective group of carboxylic acid which may be protected by conversion to the ester group, such as a complex tert-butyl esters, which can be removed by treatment with trifluoroacetic acid, or a complex benzyl ester, which can be removed by catalytic hydrogenation. As an example of group-predecessor may be referred to the nitro group, which can develop concept design�to request an amino group recovery for example by catalytic hydrogenation. Such strategies of synthesis and protective groups and precursor, which is appropriate in a particular case, known to specialists in this field of technology.

Another object of the present invention are the new starting compounds and intermediates involved in the synthesis of compounds of formula I, including compounds of formulas II, III, IV, V, VI and VII, where A, R1, R2, R', L1and L2take the values defined above, in any stereometric forms or as a mixture of stereoisomeric forms in any ratio, and the salts and solvates of any of these compounds and their use as intermediates. The invention also includes all tautomeric forms of such intermediates and compounds. All explanations and embodiments of the invention described above and related to compounds of formula I also apply respectively to the intermediate products and parent compounds. The object of the present invention are, in particular, the new specific starting compounds and intermediates disclosed in this description. Regardless of whether a disclosed compound in the form of a free compound and/or a specific salt, they are the subject of the invention in the form of free compounds and in the form of their�her and if disclosed to a specific salt, optionally in the form of this specific salt, and in the form of the solvates of any of them.

Compounds of formula I, optionally in combination with other pharmaceutically active compounds may be administered to animals, in particular mammals, including humans, as pharmaceuticals by themselves, in mixtures with one another pharmaceutical agent or in the form of pharmaceutical compositions. The introduction can be administered 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 malanie solutions, juices, drops, syrups, emulsions or suspensions, rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for subcutaneous, intramuscular or intravenous injection or injection or infusion, in particular in the form of aqueous solutions. Compounds of formula I can additionally be used in methods of local drug delivery, e.g. stents with coatings to prevent or reduce re-stenosis, or local application using a catheter. A suitable form of administration depends on, among other things, on the disease being treated and its severity.

The amount of a compound of formula I and/or governecological acceptable salts and/or solvates, present in the pharmaceutical compositions is usually in the range from about 0.2 to about 800 mg, for example from about 0.5 to about 500 mg, for example 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 generally include from about 0.5 to about 90 percent by weight of a compound of formula I and/or pharmaceutically acceptable salts and/or solvates. Obtaining pharmaceutical compositions can be carried out in a manner known in the art. For this purpose, one or more compounds of the formula I and/or their pharmaceutically acceptable salts and/or solvates together with one or more solid or liquid pharmaceutical carriers and/or excipients and/or additives or excipients and, if necessary, combined drug, other pharmacologically active compounds having therapeutic or prophylactic action, are brought into a suitable form for administration and dosing, which can be used to treat humans or in veterinary medicine. As 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 pharmaceutical�logically acceptable salts or solvates. As examples of the types of additives that may be contained in the pharmaceutical compositions and medicinal products may be mentioned are lubricants, preservatives, thickeners, stabilizers, dezintegriruetsja substances, wetting agents, additives for achieving a depot effect, emulsifiers, salts, for example for regulating the osmotic pressure, buffer substances, colorants, flavorings and fragrances. Examples of carriers and additives include water, physiological saline, vegetable oils, waxes, alcohols such as ethanol, isopropanol, 1,2-PROPANEDIOL, benzyl alcohols or glycerol, polyols, mannitol, polyethylene glycols, polypropylenglycol, triacetate of glycerol, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose, glucose, sucrose or starch, such as corn starch, stearic acid and its salts, such as magnesium stearate, talc, lanolin, petrolatum, or mixtures thereof, for example 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 may also be subjected to lyophilization and the lyophilization can be used to obtain, for example, compositions for injection.

The dosage of a compound of formula I and/or its fiziologicheskii acceptable salt �/or solvate, subject to the introduction, depends on the individual case and usually adapts the attending physician in accordance with the usual rules and methods to specific circumstances to achieve the optimal effect. It depends on the nature and severity of the disorder to be treated, sex, age, weight and individual responsiveness of the human or animal, the effectiveness and duration of action of the compounds used, on whether the treatment is therapeutic treatment of acute or chronic disease or prophylactic, and whether entered in addition to the compound of formula I, other active compounds or not. Usually, to achieve the desired results when administered to the adult patient weighing 75 kg suitable, for example, is a daily dose from about 0.01 mg/kg to about 100 mg/kg, 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 in a single dose or, in particular, when injected large quantities, can be divided into several doses, for example two, three or four separate doses. The introduction can also be carried out continuously, for example by continuous infusion or injection. Depending on individual behavior in each case may be necessary for�isit and reduce the dosage.

The below examples illustrate the invention.

When compounds of examples containing basic groups, purified preparative liquid chromatography high pressure (HPLC) on the material of the column reversed phase (CP) and, as a rule, the eluent is a gradient mixture of water and acetonitrile containing trifluoroacetic acid (TFUC), these compounds get partially in the form of their acid-additive salts with trifluoroacetic acid, depending on the processing conditions, such as the conditions of evaporation or lyophilization. In the title compounds of the examples and their structural formulas contained any such trifluoroacetic acid is not specified.

The obtained compounds are usually characterized by spectroscopic data and chromatographic data, in particular data of mass spectrum (MS)and retention time of HPLC (Rt; min) which were obtained in a combined analytical HPLC/MS (LC/MS), and/or spectrum of nuclear magnetic resonance (NMR). In the NMR characterization presents the chemical shift δ (in M. D.), the number of hydrogen atoms and the multiplicity (s=singlet, d=doublet, DD=doublet of doublets, t=triplet, dt=double triplet, q=Quartet, m=multiplet; br.=widening) signals. In MS, the characteristic is usually represented by the mass number (m/z molecular ion peak M, such as M+or the hol�ƈ ion, such as the ion M+1, for example [M+1]+, i.e. the protonated molecular ion [M+H]+that can be obtained depending on the ionization method used. Usually by the method of ionization is elektrorazpredelenie ionization (ESI). The following conditions LC/MS:

Method IH

Column: UPLC BEH C18, 50×2.1 mm, 1.7 μm; the expiration rate: 0.9 ml/min; eluent A: acetonitrile+0.08% of formic acid; eluent B: water+0.1% formic acid; gradient: from 5% A+95% B to 95% A+5% B for for 1.1 min, then 95% A+5% B within of 0.6 min; MS ionization: ESI+.

Method IH

Column: YMC-Pack J sphere H80, 33 x 2.1 mm, 4 µm, expiration rate: 1.0 ml/min; eluent A: acetonitrile+0.05% TFUC; eluent B: water+0.05% TFUC; gradient: from 2% A+98% B to 95% A+5% B for 5 min, then 95% A+5% B within a 1.25 min; MS ionization: ESI+.

Method IH

Column: Waters XBridge C18, 50×4.6 mm, 2.5 μm; the expiration rate: 1.3 ml/min; eluent A: acetonitrile+0.05% TFUC; eluent B: water+0.05% TFUC; gradient: 5% A+95% B within 0.3 min, then 5% A+95% B to 95% A+5% B within 3,2 min and then 95% A+5% B for 0.5 min; MS ionization: ESI+.

Example 1

5-(2-Pertenece)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine

(a) N-(2,4-Dichloropyrimidine-5-yl)-4-methoxy-3,5-dimethylbenzamide

A solution of 3.2 g of 5-amino-2,4-dichloropyrimidine in 50 ml of ethyl acetate was added to a mixture of 25 ml of n�over-enriched aqueous sodium bicarbonate solution and 25 ml of water. Then to the resulting mixture at room temperature for 15 minutes was added a solution of 4.9 g of 3,5-dimethyl-4-methoxybenzonitrile. The mixture is intensively stirred for 4 hours. Then the layers were separated and the aqueous layer twice extracted with ethyl acetate. After drying over sodium sulfate and filtration the solvent was removed under vacuum to give 7,54 g of crude product. The crude product is triturated with 25 ml of isopropanol. The mixture was filtered and washed with 10 ml of isopropanol, getting to 2.74 g specified in the header of the product in the form of a solid white substance.

(b) 5-Chloro-2-(4-methoxy-3,5-dimethyl-phenyl)oxazolo[5,4-d]pyrimidine

A solution of 2.74 g of N-(2,4-dichloropyrimidine-5-yl)-4-methoxy-3,5-dimethylbenzamide and 3.2 ml of N,N-diisopropylethylamine in 17 ml of acetonitrile is divided into two parts, which are kept in a microwave reactor for 1 hour at 160°C. Both solutions were combined and the precipitate is isolated by filtration, receiving 600 mg specified in the header connection in the form of dark, but it is a pure solid (600 mg). The mother liquid solvents removed under vacuum and the resulting residue purified by chromatography (silica gel; elution with a gradient of heptane/ethyl acetate) to obtain additional 600 mg specified in the title compound in the form of a solid pale yellow color.

(c) 5-(2-Pertenece)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine

149 nghitila sodium is added in an argon atmosphere to a solution of 418 mg of 2-forfinal in 15 ml of dimethylacetamide. The mixture was stirred for 30 minutes at room temperature, and then to the mixture was slowly added a solution of 900 mg of 5-chloro-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine in 20 ml of dimethylacetamide. The mixture was stirred for 1.5 hours at room temperature. After the disappearance of the original oxazolo[5,4-d]pyrimidine to the reaction mixture is added aqueous citric acid solution (100 g/l) until neutral pH. The aqueous layer twice extracted with 15 ml of ethyl acetate, the combined organic layers dried over sodium sulfate, filtered and solvents removed under vacuum. Specified in the title compound is isolated by chromatography (silica gel; elution with a gradient of heptane/ethyl acetate) to give 820 mg of product as a white solid substance.

LC/MS (method GH): Rt=3,56 min; m/z=366,0 [M+H]+.

Example 2

4-[5-(2-Pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenol

A solution of 510 mg of 5-(2-pertenece)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine in 20 ml of dichloromethane was cooled to 0°C. To the resulting mixture for 10 minutes, was added to 4.2 ml of 1M solution of tribromide boron in dichloromethane. The mixture was stirred at 0°C for 1 hour, then add another 2 ml of a 1M solution of tribromide boron in dichloromethane. The mixture was stirred for another hour and then slowly add 10 ml�sennoga aqueous sodium bicarbonate solution. The aqueous layer was extracted with twice 15 ml of dichloromethane and the combined organic layers dried over sodium sulfate and filtered. The solvents were removed under vacuum to give 445 mg specified in the title compound in the form of a solid white substance. LC/MS (method GH): Rt=3,62 min; m/z=352,13 [M+H]+

Similarly obtaining compounds of the examples described above, are compounds of formula I are presented in table 1. Some of them are obtained in the form of salts of trifluoroacetic acid.

Table 1
Examples of compounds of the formula I
ExampleConnection nameLC/MSm/z [M+H]+Rt [min]
35-(2-Pertenece)-2-(3-methoxy-phenyl)oxazolo[5,4-d]pyrimidineGH338,21,29
44-[5-(2-Pertenece)oxazolo[5,4-d]pyrimidine-2-yl]phenolGH324,211,23
55-(2-Pertenece)-2-(4-methoxy-3-methylphenyl)oxazole
[5,4-d]Piri�idin
GH352,221,27
65-(2-Pertenece)-2-(4-methoxy-3 - triptoreline)oxazol
[5,4-d]pyrimidine
GH406,161,38
74-[5-(2-Pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-METHYLPHENOLGH338,151,28
82-(4-Methoxy-3,5-dimethylphenyl)-5-phenoxyacetyl
[5,4-d]pyrimidine
GH348,033,55

92-(4-Methoxy-3,5-dimethylphenyl)-5-(pyridin-3-yloxy)oxazole
[5,4-d]pyrimidine
GH349,012,78
104-[5-(2-Pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-triptorelineGH392,111,31
112,6-Dimethyl-4-[5-(pyridin-3-yloxy)ACS�zolo[5,4-d]pyrimidine-2-yl]phenol GH335,141,15
124-[5-(3-Pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-isopropyl-6-METHYLPHENOLGH380,151,38
135-(2-Pertenece)-2-(4-methanesulfonyl-3-methylphenyl)oxazole
[5,4-d]pyrimidine
GH400,11,27
145-(2-pertenece)-2-(4-methanesulfonyl-2-methylphenyl)oxazole
[5,4-d]pyrimidine
GH400,121,26

Definition of pharmacological activity

(A) GTP-y-S biological test using Edg-1 receptors human

To determine the activation of Edg-1 receptors by the compounds according to the invention using GTP-y-S (guanosine-5'-[thio]triphosphate) biological test for G-protein-linked receptor binding based on the principle of scintillation proximity, applying a membrane preparation from Cho cell line Flp-ln, which steadfastly value produces Edg-1 receptor.

(a) Generation of cell lines

Flp-lnTMExpress�nnaya system (Invitrogen, cat. no. K6010-01) provides the ability to generate stable mammalian cell lines in which the target gene was integrated via homologous recombination at a specific genomic location, called site targets Flp recombination (Flp Recombination Target - FRT), by Flp recombination, indiragandhi the plasmid pOG44 expression. The integration of the pcDNA5/FRT expression construct into the Flp-ln cell line genome of the host leads to the transcription of a target gene. Consistently transfetsirovannyh cells become resistant to hygromycin.

One day before transfetsirovannyh 200000 cells Flp-ln-SSS seeded in Ham F-12 medium (Invitrogen, cat. no. 31765) with 10% fetal calf serum (fetal calf serum - FCS; Perbio Science, cat. no. SH30068.03) on 6-well plate and incubated at 37°C/5% CO2in the course of the night. Using FuGENE® 6 reagent transfetsirovannyh (Roche, cat. no. 11988387001) cells together transfection with Flp recombinase the expression plasmid pOG44 and a modified plasmid, further comprising edg-1 gene (accession number NM_001400) called pcDNA5-FRT-TO_nFLAG_DEST-EDG-1, in a ratio of 9:1. To obtain the modified pcDNA5-FRT-TO_nFLAG_DEST Invitrogen plasmids-plasmid pcDNA5/FRT/TO (Invitrogen, cat. no. V6520-20) adapted for Gateway® (Invitrogen) cloning system by inserting a Gateway cassette containing attR recombination sites flanking ccdB gene and a gene resistant to chloramphenicol (Gateway conversionsystem, Invitrogen, cat. no. 11828-029). In addition, some determinants FLAG label before site 5' att recombination to allow recombinant expression of N-terminal FLAG-tagged proteins.

For transfetsirovannyh one hole of 1.08 μg of pOG44 and 0.12 μg of pcDNA5-FRT-TO_nFLAG_DEST-EDG-1 was mixed with 100 µl containing serum Ham's F-12 medium containing 6 ál of reagent transfetsirovannyh FuGENE® 6. The mixture was incubated for 20 minutes, after which the complex of a reagent of transfective/DNA distribute dropwise on the cells. The cells are incubated for 24 hours at 37°C. Then the cells from 3 wells is transferred to a T75 flask (Greiner Cellstar®, cat. no. 658175) containing Ham F-12 medium containing 10% FCS but without antibiotics, and incubated in the indicated conditions for 24 hours. 48 hours after transfetsirovannyh environment replace selection medium (Ham F-12 containing 10% FCS and 300 μg/ml of hygromycin B (Invitrogen, cat. no. 10687-010)). The medium is replaced every 2-3 days until, until you get a stable population of cells. Cells share several times and seeded into a new flask so that not to get more than 25% of cell fusion. After two weeks of selection, the cells are transferred into T175 flasks (Greiner Cellstar®, cat. no. 660175) and grown for batches of cells. Cells are harvested from culture flasks short-term treatment (2 to 5 min.) Accutase (PAA, cat. no. L11-007), re-suspendirovanie in celek�ionic environment (see above) and centrifuged at 200×g for 5 minutes. The cells are again suspended in a mixture of 90% FCS and 10% dimethylsulfoxide and stored frozen in liquid nitrogen.

(b) Membrane preparation

Membrane the drug is produced by standard methods from the above cell line CHO Flp-ln, steadfastly producing value added Edg-1 receptor human. Briefly, cryopreserved cells are put into culture and grown to confluence in T175 flasks cell culture (Becton Dickinson, cat. no. 35 5001). Cell culture stopped by washing with phosphate-buffered saline, containing no calcium (PBS; Gibco, cat. no. 14190), cells are harvested with a rubber scraper (rubber policeman) cooled to 4°C, containing calcium PBS, supplied with a cocktail of protease inhibitor (complete protease inhibitor; Roche, cat. no. 1697498; 1 tablet per 50 ml), and sequentially centrifuged at 4°C for 15 minutes at 1100 g (Heraeus Minifuge T). For cell lysis, the pellet is again suspended in chilled to 4°C in hypotonic buffer containing 5 mm HEPES (Sigma-Aldrich, cat. no. H-0981), 1 mm EDTA (disodium salt; Merck, cat. No. 8418) with a cocktail of protease inhibitor (described above), in which the cells are stored for an additional 15 minutes on ice. After lysis of the cells was centrifuged at 4°C for 10 minutes at 400×g (Heraeus Minifuge T). Pellets are destroying in a Dounce homogenizer, diluted with supernatant obtained by �Ravadinovo previously centrifugation, and then again centrifuged at 4°C for 10 minutes at 500×g (Heraeus Minifuge T) to separate the nuclei and intact cells from membranes that are present mainly in the supernatant. After that, the supernatant is diluted with hypotonic buffer and centrifuged (Beckmann, Avanti J251) at approximately 18600×g for 2 hours at 4°C. After centrifugation, the membrane pellet is again suspended in a storage buffer consisting of 20 mM HEPES; 150 mm NaCl (Merck, cat. no. 6400), 1 mm EDTA (as described above) containing a cocktail of protease inhibitor (as described above). The membrane preparation is divided into aliquots and stored at -80°C. the protein Concentration of the membrane preparation is determined in the sample by means of a commercial biological analysis of protein (Bio-Rad, DC Protein Assay, cat. nos. 500-0113, 500-0114, 500-0115).

(c) GTP-y-S biological test

Edg-1 membrane preparation obtained in (b), use commercially available analytical kit scintillation proximity (scintillation proximity assay SPA) for G-protein-linked receptor binding from Amersham Biosciences/GE Healthcare (code RPNQ0210), in which ligand-induced binding35S-labeled radiolabeled GTP-y-S with the receptor-containing membrane, which is bound to scintillation beads that stimulates the emission of light and allows to quantitatively determine the in vitro activity of the Edg-1 agonist compounds. Bi�logical analysis is carried out on a 96-well plate on the merits in accordance with the manufacturer's instructions. Before beginning experiments scintillation granules suspended in the buffer recovery containing Tris-HCl (pH 7,4) with a 0.1% (wt./about.) sodium azide and serially diluted on ice in analytical buffer (consisting of 20 mm HEPES, 100 mm NaCl, 1 mm EDTA (as above), 1 mm dithiothreitol (DTT), pH of 7.4) to a final concentration of granules of 30 mg/ml.

To the wells of the load 10 µl of specific analytical buffer, 10 μl of 100 μm solution of guanozintrifosfata (GDP) and 10 μl of a solution of the test compounds in the analytical buffer/dimethylsulfoxide, yielding a final concentration of the test compound (10 μm. In appropriate wells instead of test compounds for high control, add 10 ál of a solution of sphingosine-1-phosphate (S1P; Sigma, cat. no. S-9666), receiving end S1P concentration of 10 μm, and for low control - 10 ál analytical buffer. All wells contain an equivalent amount of dimethyl sulfoxide. Then to each well add 10 ál of [35S]GTP-y-S solution (4 nm) and Edg-1 membrane preparation obtained in (b) (15 μg membrane protein in 100 ál analytical buffer). The plates were incubated at room temperature for 5 minutes, then add 50 ál of the suspension of the specific scintillation granules (30 mg/ml). Tablets incubated for 45 minutes at room temperature, then centrifuge for 0 minutes at 500×g. Quantitative determination of [35S]GTP-y-S binding and thus receptor activation is performed using a counter of beta-particles (MicroBeta, Wallac) for 1 minute. Values are adjusted taking into account the background subtraction of the appropriate value of low control. All the measurements were carried out three times. Activation of the receptor of the test compound expressed as a percentage of the corresponding high control (10 μm S1P; is regarded as 100% activation). Table 2 presents the values of the activations of the compounds obtained in examples 10 microns.

Table 2
Activation of the Edg-1 receptor compounds of examples when 10 μm in percent activation 10 μm S1p
ExampleActivation, %
1102
2115
395
483
542
687
7115
894
987
10107
11103
12112
13120

1469

From these data we can see that the compounds are excellent for healing wounds and, in particular, for the treatment of disorders associated with wound healing in patients with diabetes mellitus.

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

where
A represents O;
R1selected from phenyl or pyridinyl, which are optionally substituted with R11;
R2represents phenyl, which is optionally substituted by 1-3 carbon atoms of the ring are the same or different substituents R22;
R11is a halogen;
R22selected from a hydroxyl group, (C1-C4)-alkyl, which is optionally substituted with 1-3 fluorine atoms, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-;
m is equal to 2.

2. The compound of formula I in any of its stereoisomeric forms or physical�logicheskie acceptable salt according to claim 1, where R1represents phenyl, optionally substituted with R11.

3. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where R2represents phenyl, optionally substituted one carbon atom of the ring a substituent R22.

4. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where
R1represents pyridinyl, optionally substituted with R11;
R2represents phenyl, which is optionally substituted on one carbon atom of the ring a substituent R22.

5. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where
R22selected from a hydroxyl group, (C1-C4)-alkyl and (C1-C4)-alkyloxy.

6. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where
R22selected from a hydroxyl group, (C1-C4)-alkyl, (C1-C4)-alkyloxy and (C1-C4)-alkyl-S(O)m-.

7. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to one or more of claims. 1-5, where
R22selected from a hydroxyl group and (C1-C4)-alkyl.

8. Link� formula I or its physiologically acceptable salt according to one or more of claims. 1-6, selected from compounds
5-(2-pertenece)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine,
4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenol,
5-(2-pertenece)-2-(3-methoxyphenyl)oxazolo[5,4-d]pyrimidine,
4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]phenol,
5-(2-pertenece)-2-(4-methoxy-3-methylphenyl)oxazolo[5,4-d]pyrimidine,
5-(2-pertenece)-2-(4-methoxy-3-triptoreline)oxazolo[5,4-d]pyrimidine,
4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-METHYLPHENOL,
2-(4-methoxy-3,5-dimethylphenyl)-5-phenoxyacetate[5,4-d]pyrimidine,
2-(4-methoxy-3,5-dimethylphenyl)-5-(pyridin-3-yloxy)oxazolo[5,4-d]pyrimidine, and
4-[5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2-triptoreline.

9. The method of obtaining compounds of formula I according to any one of claims. 1-8, including the interaction of a compound of formula II with a compound of the formula III

where the groups A, R1and R2in the compounds of formulas II and III take the values defined for compounds of formula I and additionally functional groups can be represented in protected form or in the form of a precursor group, and the group L1represents a halogen atom or a group of the formula-S(O)-Alk or-S(O)2-Alk, where Alk is a (C1-C4)-alkyl.

10. Pharmaceutical composition for the activation of the receptor EDG-1, containing from 0.5 to 90% W� weight of a compound of formula I according to any one of claims. 1-8, or its physiologically acceptable salts, and pharmaceutically acceptable carrier.

11. The compound of formula I according to any one of claims. 1-8, or its physiologically acceptable salt for use as pharmaceutical agents that have an activating activity against receptor EDG-1.

12. The compound of formula I according to any one of claims. 1-8, or its physiologically acceptable salt for the treatment of disorders associated with wound healing.

13. The compound of formula I according to any one of claims. 1-8, or its physiologically acceptable salt for wound healing.

14. The compound of formula I according to any one of claims. 1-8, or its physiologically acceptable salt for wound healing in patients with diabetes mellitus.

15. The compound of formula I according to any one of claims. 1-8, or its physiologically acceptable salt for the treatment of diabetic foot syndrome.



 

Same patents:

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: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 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: medicine.

SUBSTANCE: invention relates to veterinary and can be applied in animal-breeding for stimulation of metabolic processes, and growth activity of calves. Medication for stimulation of metabolic processes and growth activity of calves includes succinic acid as energetic stimulator, with application of citric acid as activator of succinic acid, beetroot molasses as carbon component, and methionine and sodium chloride as stimulators of digestion system.

EFFECT: application of invention makes it possible to ensure expressed acceleration of growth energy in early postnatal period.

3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: cytoflavin is administered into laboratory animals (rats) daily immediately before overheating in an air laboratory thermostat at +40±1-2°C for 45 minutes. The preparation is administered intraperitoneally in a dose of 100 mg/kg of body weight for 14 days.

EFFECT: higher body adaptability by increasing antioxidant activity and reducing a rate of lipid peroxidation products accumulation with underlying thermal exposure.

4 tbl

FIELD: medicine.

SUBSTANCE: minor amputation of the foot with the further necrectomy is performed. After the application of an antimicrobial bandage and drainage, the wound is hermetised from the environment by the creation of a negative pressure above the wound in a combination with drug treatment. The reatment is performed in two steps. At the first step the wound with the antimicrobial bandage and drainage is first hermetised from above with an adhesive film, with the creation and support of the negative pressure not lower than 80 mm Hg. Urokinase 500000 U is additionally introduced daily intravenously by drop infusion per 100 ml of physiological solution, Vessel-Due-F in a dose of 600 LU per 100 ml of physiological solution and VAP 20 - alprostadil in a dose of 40 mcg per 100 ml of physiological solution. In addition Antistax in capsules is introduced to the patient. At the second stage active 24-hour vacuum aspiration with the change of the negative pressure from 10 to 80 mm Hg within a day is carried out. Additionally introduced is Vessel-Due-F in a dose of 1 capsule with 250 LU 2 times per day between meals and Antistax. At the first and second stages Antistax is introduced in a dose of 2 capsules in the morning 30-40 minutes before meal, daily. Duration of each stage constitutes not less than 7 days.

EFFECT: increase of the treatment efficiency due to the complete and timely purification of the wound from pathological exudates, elimination of the progression of the purulent-necrotic process, increase of the regenerative activity of tissues, activation of local immunity, recovery of microcirculation and oxygenation of the affected tissues.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves professional oral hygiene is carried out consisting in ultrasonic removal of supra- and subgingival dental deposits and polishing of supragingival teeth. Bite splinting and recovery of dentition integrity may be required. After dissecting a mucoperiosteal flap according to the known technique, an incision area is sanitated by means of a photodynamic therapy (PDT). The PDT is conducted with the use of a diode laser at wave length 660±5 nm and emitting power 0.5-1.0 Wt. The photosensitiser "Photoditasin" in the form of 0.5% gel is introduced by means of a cannula into dental gaps, under the dissected segments of the flap and onto the mucosal tissue for 5 minutes. The photosensitiser is washed out, and the gingival pockets are repeatedly exposed to laser light for 2-3 min in the same environment. Sterile osteoplastic material is introduced into bone defects, and the flap is sutured together.

EFFECT: effective cleansing of the surgical area, eliminating the periodontal inflammation, stimulating tissue osteogenesis and regeneration, stabilising the processes of bone tissue absorption of alveolar interdental septa and preserving the tissues.

2 cl, 1 ex

FIELD: medicine.

SUBSTANCE: to correct pathologic changes in the condition of viable offspring under a cytostatic impact the medication glutoxim is introduced to female rats in a dose of 50 mcg/kg 5 days before and 5 days after the introduction of the cytostatic medication vepesid. The latter is introduced once intravenously in a maximal tolerable dose, equal to 30 mg/kg. It has been established that glutoxim can be applied as means for the correction of pathologic changes in the viable offspring of rats, obtained from coupling 3 months after the cytostatic impact.

EFFECT: application of glutoxim as the means of corrective therapy makes it possible to increase efficiency and reduce its side effects.

6 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a polymeric carrier molecule, a complex of a polymeric carrier with a load, a method of producing a polymeric carrier molecule, a pharmaceutical composition and a vaccine. In one of the versions, the polymeric carrier molecule has the following formula (I): L-P1-S-[S-P2-S]n-S-P3-L and additionally contains in the structure at least one amino acid component (AA)x, wherein AA is an amino acid, x is an integer selected in the range of 1 to 100. If the amino acid component (AA)x is present in the structure, then it is a linker between P1 or P3 and component L. If component L is absent, then at least one amino acid component (AA)x is part of P1 or P3. Components P1 and P3 are different or identical and are a linear or branched chain of a hydrophilic polymer of polyethylene glycol (PEG); P2 is a cationic or polycationic peptide or a protein with length of 3 to 100 amino acids, or a cationic or polycationic polymer with molecular weight of 0.5 kDa to 30 kDa; -S-S is a disulphide bond; L is an optional ligand, n denotes an integer selected from 1 to 50. According to the second version, the polymeric carrier molecule has the formula (Ia) l-P1-S-{[S-P2-S]a[S-(AA)X-S]b}-S-P3-L, where a+b=n, where n equals 1, 2, 3, 4 or 5 to 10; a is an integer selected independent of integer b in the range of 1 to 50, b is an integer selected independent of integer a in the range of 1 to 50. Separate components [S-P2-S] and [S-(AA)x-S] are present in any order in the subformula {[S-P2-S]a[S-(AA)x-S]b}. The complex of the polymeric carrier with a load is formed by the polymeric carrier molecule and a nucleic acid. A pharmaceutical composition and a vaccine include the complex of the polymeric carrier with a load and optionally a pharmaceutically acceptable carrier and/or solvent. Polymeric carrier molecules and the complex of the polymeric carrier with a load are used as a medicinal agent for treating various diseases.

EFFECT: invention enables to obtain a stable polymeric carrier which enables efficient transfection of nucleic acids in cells in vivo and in vitro.

20 cl, 16 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to dermatology and can be used in treating sclerodermia. Versions of the invention provide using naltrexone in treating sclerodermia.

EFFECT: using the inventions enables reducing manifestations of sclerodermia, such as gratuitous synthesis and collagen deposits and fibrosis.

18 cl, 13 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method is realised by the intravenous allogeneic transplantation of multipotent mesenchymal stromal cells (MMSC) and hematopoietic stem cells (HSC) to laboratory mice one hour after irradiation. HSC are obtained from the placenta of female mice at the 14-day gestation term. MMSC are introduced in a dose of 6.5 mln cells/kg, with HSC being introduced in a dose of 400 thousand cells/kg.

EFFECT: invention makes it possible to extend the arsenal of means, capable of providing the regeneration potential of the spleen tissues, as well as to increase the regeneration of main morphometric spleen indices after exposure to a radiation load.

2 tbl

FIELD: medicine.

SUBSTANCE: introduction of endoscope into duodenum is realised. After that, "tight" filling of choledoch is performed through cholecystostoma with sterile solution, for instance, 0.25% Novocain. After that major duodenal papilla is catheterised and endoscopic papillosphincterotomy is carried out.

EFFECT: method makes it possible to provide effective surgical treatment of cholelithiasis with simultaneous reduction of probability of development of complications due to provision of possibility of fast identification and good visualisation of major duodenal papilla.

1 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

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