Derivative of heterocyclic carbon acids, which contain 2,5,7-substituted oxazolopyrimidine ring

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

 

The present invention relates to a derivative of heterocyclic carboxylic acids containing a 2,5,7-substituted oxazolopyridine ring, and to their physiologically acceptable salts.

Structurally similar compounds which can be used for the treatment of multiple sclerosis, have already been disclosed in the prior art (see WO 2009/154775). The scheme of action of these compounds is to use desensitization EDG 1 signaling pathway through activation of EDG 1 receptor (so-called superagonist), which is then equivalent to the functional antagonism EDG 1 signaling pathway. Systemically this means that especially for lymphocytes, EDG 1 signalling pathway is constantly suppressed, whereby the cells can no longer hemotoxicity to follow the S1P gradient between the blood and the lymph. This means that subjected to the lymphocytes are not able to leave the secondary lymphatic tissue (increased homing) and the amount of freely circulating lymphocytes in plasma is significantly reduced. Such a deficit of lymphocytes in plasma (lymphopenia) leads to immunosuppression, which is required for the mechanism of action of modulators of receptor EDG 1 disclosed in WO 2009/154775.

The objective of the present invention is to provide compounds that can be used specifically for healing wounds and is especially �La treatment of complications in the treatment of wounds in patients with diabetes. In addition, it was desirable to obtain compounds which can be used for the treatment of diabetic foot syndrome (DFS).

In addition, it was desirable to achieve reproducible activation of signaling pathways EDG 1 receptor, thereby would, in pharmacological terms, sustained activation of signaling pathways EDG 1.

The present invention relates to oxazolopyridine compounds of formula I.

where A, R1, R2, R3, R4, X and Y have the following values. The mechanism of action of the compounds of formula I, thus, not based on desensitization of signaling pathways EDG 1, and therefore diametrically opposed to the mechanism of action, disclosed in WO 2009/154775. In addition, the present invention relates to methods for producing compounds of formula I, to their use, particularly as active ingredients in pharmaceutical drugs, containing their pharmaceutical compositions.

Compared with healthy people, patients with diabetes wound healing occurs over a long time and there is increased rate of infection, especially in the case of prolonged hyperglycemia caused by, for example, by poor regulation of blood sugar levels. Causes include disorders of the circulation, especially in the area of small blood vessels that�children to disruption of the supply of oxygen and nutrients into tissue. Moreover, reduced the rate of cell division and cell migration of keratinocytes, dermal fibroblasts and endothelial cells. Further restricted the protective activity of different cells (granulocytes), accompanied by a weakening of phagocytosis (seizure and destruction of bacteria). The action of antibodies (immunoglobulins) against bacteria with high levels of sugar in the blood is also limited. Accordingly, wounds and infections in patients with diabetes should be treated in a special way.

Receptor Edg 1 is a member of a family of receptors of endothelial gene differentiation (Edg) of the eight identified currently A class A GPCR (receptor associated with G-protein). Specified family can be divided into subfamilies sphingosine-1-phosphate (S1-re-activated receptors (five members) and receptors activated lysophosphatidic acid (LPA; three members). The endogenous ligand S1P is a pluripotent lysophospholipid acting on different cell types by activating GPCR family of receptors Edg, 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, numerous cellular responses mediated through S1P activation of Edg receptors. S1P is produced by a family of enzymes sphingosines (SPHK) and decompose of various phosphatase�and or LiAZ.

In the present invention proposed compounds of oxazolopyridine formula I in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or their physiologically acceptable salts or physiologically acceptable solvates of such compounds or such salts,

where

A is selected from the group consisting of NH, O and S;

X is selected from the group consisting of (C1-C6)-Alcantara, (C2-C8)-Alcantara, (C2-C6)-alcindoro, (C3-C7)-cycloalkenyl and (C1-C6)-alcadeias, all of which are optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine and hydroxyl, where the oxygen atom (C1-C6-altingiaceae attached to the group R2;

Y represents a 4-7-membered saturated or partially unsaturated monocyclic or bicyclic heterocycle, which, in addition to the nitrogen atom of the ring represented in the formula I, contains 0, 1, 2 or 3 identical or different heteroatoms in the ring selected from the group consisting of N, O and S, where one or two additional nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one of the sulfur atoms of the ring may be substituted with one or two �sogrape, and where heterocycle, optionally substituted by one or more of the nitrogen atoms of the ring are the same or different (C1-C4)-alkyl substituents;

R1selected from the group consisting of (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-alkinyl, (C3-C7-cycloalkyl-CtH2tand Het-CtH2twhere t is selected from the group consisting of 0, 1, 2 and 3;

R2selected from the group consisting of phenylene and a bivalent radical consisting of aromatic 5-membered or 6-membered monocyclic heterocycle which contains 1, 2 or 3 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one of the nitrogen atoms of the ring may be substituted by hydrogen atom or a substituent R21and where the phenylene and a divalent radical consisting of aromatic heterocycle, optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22;

R3selected from the group consisting of (C1-C6)-alkyl, (C2-C6-alkenyl, (C2-C6)-alkinyl, (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v- where u and v selected from the group consisting of 1 and 2, or R3represents a radical consisting of saturated or unsaturated-to 10-membered monocyclic or bicyclic ring, which contains 0, 1, 2, 3 or 4 identical or different heteroatoms in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one or two of the sulfur atoms of the ring may be substituted with one or two exography and where the radical of the ring, optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R31provided that R3can't imagine (C1-C6)-alkyl if A represents S;

R4selected from the group consisting of hydrogen, (C1-C4)-alkyl and (C3-C7-cycloalkyl-CzH2z-1 where z is selected from the group consisting of 0, 1 and 2;

R21selected from the group consisting of (C1-C4)-alkyl and (C3-C7-cycloalkyl-CwH2w"- and oxy, where w is selected from the group consisting of 0, 1 and 2;

R22selected from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, hydroxycarbonyl, (C1-C4)-allyloxycarbonyl, aminocarbonyl and aminosulfonyl;

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

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

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

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

where all alkyl, alkadiene, CtH2t, CuH2u, CVH2V, CwH2w, zH2z, alkenyl, Allendale, alkyline and akindeinde groups, independently of each other and independently of other substituents, are optionally substituted by one or more of fortuntately.

Structural elements such as groups, substituents, heterocyclic members, numbers or other features, for example, alkyl groups, such as R22or R31the numbers, such as m, u and v, which can occur more than once in the compounds of formula I, can all independently of one another, to take any of the values specified, and in each case may be identical or may differ from each other. For example, the alkyl group in dialkylamino may be identical or may differ from each other.

Alkyl, alkenyl and alkyline group can be linear, i.e. straight-chain or may be branched. This also applies if they are part of other groups, for example, alkyloxy (= alkoxygroup, O alkyl group), allyloxycarbonyl groups or alkyl-substituted amino groups, or if they are replaced. Depending on the respective definition, the number of carbon atoms in the alkyl group may be 1, 2, 3, 4, 5, or 6, or 1, 2, 3, or 4, or 1, 2 or 3. Examples of Akilov are methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, WTO�-butyl, isobutyl and tert-butyl, pentyl including 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 present in any of the positions. In one embodiment of the present invention, the alkenyl groups contain one double bond and alkyline groups contain one triple bond.

In one embodiment of the present invention, the alkenyl group, or Alchemilla group contains at least three carbon atoms and linked to the rest of the molecule through a carbon atom that is not part of a double bond or triple bond. Examples of alkenyl and alkynyl are ethinyl, prop-1-enyl, prop-2-enyl (= allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-inyl (= propargyl), but-2-inyl, booth-3-inyl, hex-4-inyl or hex-5-inyl. Substituted alkyl group, alkenyl group and alkyline groups can be substituted in any positions, provided that the corresponding connection is stable enough and suitable for the desired purpose, such as use as a medicinal substance. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable for the desired purpose, such kacisolomone as a medicinal substance, applicable generally in the definitions of all groups in the compounds of formula I.

To the extent applicable, the above explanations regarding alkyl, alkenyl and etkinlik groups refer to divalent alkyl groups such as group Alcantara, CtH2t, CuH2u. CvH2v, CwH2wand CzH2zand to divalent alkenyl groups and alkynylaryl groups, such as groups alcantera and alcindoro, which are also similarly can be unbranched or branched. Double bonds and triple bonds in elendilmir and akindeinde groups can be located in any of the positions. In one embodiment of the present invention, Allendale groups contain one double bond and akindeinde groups contain one triple bond. Examples of divalent alkyl groups are-CH2-(= methylene), -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -C(CH3)2-CH2-, -CH2-C(CH3)2-,examples of divalent alkenyl groups include-CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -C(CH3)=C(CH3and examples of the divalent etkinlik group� are-C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C(CH3)2-C≡C-, -C≡C-C(CH3)2-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-. If the number in the divalent group, such as the number of t in group CtH2tfor example , is 0 (= zero), two groups that are attached to the group, such as CtH2tdirectly connected to each other by a simple relationship.

The number of carbon atoms of the ring in cycloalkyl group can be 3, 4, 5, 6 or 7. In one embodiment of the present invention, the number of carbon atoms of the ring in cycloalkyl group, regardless of the number of carbon atoms of the ring in any other cycloalkyl group is 3, 4, 5 or 6, in another embodiment 3, 4 or 5, in another embodiment 3 or 4, in another embodiment 3, in another embodiment 5, 6 or 7, in another embodiment 5 or 6, in another embodiment 6 or 7, in another embodiment 6. This applies correspondingly to divalent cycloalkyl groups, i.e. cycloalkenyl groups that can be linked to the adjacent groups via one or two carbon atoms of the ring. Examples cycloalkyl groups are the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of divalent cycloalkyl groups are cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, CYCLOBUTANE-1,3-diyl, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,1-diyl, cycle�hexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, Cycloheptane-1,4-diyl.

Independently from each other and independently of any other substituents, cycloalkyl and cycloalkenyl group, optionally substituted by one or more identical or different (C1-C4)-alkyl substituents, which may be located in any of the positions, i.e., cycloalkyl groups can be unsubstituted by alkyl substituents, or substituted alkyl substituents, e.g., 1, 2, 3, or 4, or 1 or 2, (C1-C4)-alkyl substituents, for example methyl groups. Examples of alkyl-substituted cycloalkyl and cycloalkenyl groups are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclobutyl, 2,2-dimethylcyclopropane-1,1-diyl, 2,2-dimethylcyclopropane-1,2-diyl, 2,2-dimethylcyclopentane-1,3-diyl, 6,6-dimethylcyclohexane-1,4-diyl. Examples cycloalkenyl groups that may represent groups such as (C3-C7- cycloalkyl-CtH2tis, for example, are the cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylmethyl, 2-cyclobutylmethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, 2-cycloheptylmethyl.

Independently from each other and independently of any other substituents, alkyl groups, two-shaft�nye alkyl group, alkenyl group, a divalent alkenyl group, alkyline group, a divalent alkyline group, cycloalkyl groups and divalent cycloalkyl group, optionally substituted by one or more fortuntately, which may be located in any of the positions, i.e., these groups may be unsubstituted fortuntately or may be substituted by fortuntately, 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, fortuntately. Examples of such 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, 2,2-divorcecare-1,2-diyl. Examples of alkyloxy in which the alkyl fragment is a fluorine-substituted compound, serve triptoreline, 2,2,2-triptoreline, pentaborate and 3,3,3-cryptochromes. In one embodiment of the present invention, the total number of fortuntately and (C1-C4)-alkyl substituents, which independently of any other W�of mustiala, not necessarily present in cycloalkyl and cycloalkenyl groups in the compounds of formula I, is 1, 2, 3,4, 5, 6, 7, 8, 9, 10 or 11, in another embodiment 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.

With groups such as the phenyl, naphthyl (= naphthalenyl), and residues of aromatic heterocycles, which are optionally substituted by one or more substituents, can be unsubstituted or substituted, for example, 1, 2, 3, 4, or 5, or 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2, or 1, same or different substituents, which may be located in any of the positions. In one embodiment of the present invention the total number of nitrosomethylurea in the compound of the formula I not more than two. Aromatic nitrogen-containing heterocycles, in which the original ring system is substituted by a hydrogen atom at the nitrogen atom of ring a 5-membered ring, such as pyrrole, imidazole, indole or benzimidazole ring can be substituted on carbon atoms and/or on the nitrogen atoms of the ring. In one embodiment of the present invention, such substituents at nitrogen atoms in the ring selected from (C1-C4)-alkyl groups, i.e. the nitrogen atoms of the ring in aromatic heterocycles substituted by hydrogen atom or (C1-C4)-alkyl substituent. If specified in the ratio of nitrogen atoms Kohl�and in aromatic heterocycles and any other heterocycles, they can be substituted by hydrogen atom or a substituent such nitrogen atoms of the ring or substituted by hydrogen atom or a Deputy, or they are not replaced by a hydrogen atom or a substituent. The nitrogen atoms of the ring are substituted by hydrogen atom or a substituent found in nitrogen-containing aromatic 5-membered ring, as in the case of pyrrole, imidazole, indole or benzimidazole, for example, and in non-aromatic ring including a saturated ring. The nitrogen atoms of the ring are not substituted by hydrogen atom or a Deputy, unless they are present in positively charged form, including any further nitrogen atoms of the ring in addition to nitrogen atoms of the ring are substituted by hydrogen atom or a substituent are aromatic ring, as in the case of thiazole, imidazole, pyridine or benzimidazole, for example, and in non-aromatic ring, where they represent a bridging atoms, or are part of a double bond, and they are both nitrogen atoms of the ring through which the ring is connected. Suitable nitrogen atoms of the ring in aromatic heterocycles in the compounds of formula I, such as the nitrogen atoms of the pyridine ring in the ring, especially the nitrogen atoms of the ring in an aromatic heterocycle representing R2may also be substituted by oxazolidine O-and be made�as Lena N-oxide, and such nitrogen atoms of the ring may also be present as a Quaternary salt, such as N-(C1-C4)-alkyl salt such as N-methyl salt, where in one embodiment of the present invention counterion in such a Quaternary salt is a physiologically acceptable anion, which is obtained from the acid that forms a physiologically acceptable salt. In monosubstituted phenyl groups the Deputy may be located in the 2-position, 3-position or 4-position. In disubstituted phenyl groups, the substituents can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl groups, the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. Naphthyl may be 1-naphthyl (= naphthalene-1-yl) or 2-naphthyl (= naphthalene-2-yl). In monosubstituted 1-naftalina groups Deputy may be located in 2-, 3-, 4-, 5-, 6-, 7- or 8-position. In monosubstituted 2-naftalina groups Deputy may be located in 1-, 3-, 4-, 5-, 6-, 7- or 8-position. In disubstituted naftalina groups, the substituents may likewise be located in any of the positions and the rings through which naftalina group is associated, and/or in another ring. This statement concerning the monovalent ostatka�, applicable respectively to the corresponding divalent residues such as phenylene group representing R2for example , which can likewise be unsubstituted or substituted, for example, 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2, or 1, same or different substituents, which may be located in any of the positions.

In the radicals of aromatic heterocycles representing R2or R3that may be designated as heteroaryl and heteroarenes group, as well as in all other heterocyclic rings in the compounds of formula I, including the group Het and non-aromatic heterocyclic group representing R3these heteroatoms in the ring generally selected from the group consisting of N, O and S, where N includes the nitrogen atoms of the ring are substituted by hydrogen atom or a Deputy, as well as the nitrogen atoms of the ring are not substituted by hydrogen atom or a substituent. Heteroatoms in the ring can be located in any of the positions, provided that the heterocyclic system is known in the art and is stable and suitable as a subgroup for the desired purpose of the compound of formula I such as use as a medicinal substance. In one embodiment of the present invention, two oxygen atoms of the ring can't do things�exist in adjacent ring positions of any of the heterocycles, in another embodiment, the oxygen atoms can not be a two heteroatom in the ring selected from the group consisting of oxygen and sulfur, may exist in adjacent ring positions of any of the heterocycles. Saturated rings do not contain double bonds of the ring. Unsaturated ring system may be aromatic or partially unsaturated, including partially aromatic, when in the latter case one ring in the bicyclic ring system is aromatic and ring system is linked via an atom in non-aromatic ring. Depending on the respective group of the unsaturated ring may contain one, two, three, four or five double bonds in the ring. Aromatic groups contain a cyclic system of six or ten delocalized π-electrons of the ring. Depending on the respective group, saturated or unsaturated non-aromatic heterocyclic ring, including Het and non-aromatic groups representing R3can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In one embodiment of the present invention, an aromatic heterocyclic rings are 5-membered or 6-membered monocyclic ring or 8-membered, 9-membered or 10-membered bicyclic rings, in another embodiment 5-membered and�and 6-membered monocyclic ring or a 9-membered or 10-membered bicyclic ring, in another embodiment 5-membered or 6-membered monocyclic ring, where the specified 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 heterokontae members, and one or both rings may be aromatic. Usually bicyclic ring system containing aromatic ring and non-aromatic ring, considered aromatic if they are connected via a carbon atom in the aromatic ring, and consider non-aromatic, if they are linked through the carbon atom in the non-aromatic ring. Unless stated otherwise, the heterocyclic group including an aromatic heterocyclic group, can be linked via any suitable carbon atom of the ring, and, in the case of nitrogen heterocycles via any suitable nitrogen atom of the ring. In one embodiment of the present invention, an aromatic heterocyclic group in the compound of formula I, independently from any other aromatic heterocyclic groups, linked through a carbon atom of the ring, in another embodiment, through the nitrogen atom of the ring. Depending on the definition, the corresponding het�acyclically group, in one embodiment of the present invention, the number of heteroatoms in the ring which may be present in the heterocyclic group, regardless of the number of heteroatoms in the ring in any other heterocyclic group, a is 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1, where said heteroatoms in the ring may be the same or different. Heterocyclic group, which are optionally substituted, independently from any other heterocyclic groups can be unsubstituted or can be 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, or 1 substituents specified in the definition of protective groups. The substituents at the heterocyclic groups can be located in any of the positions. For example, pyridin-2-yl group substituents can be located 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 from which you can get a heterocyclic group including aroma�quarter 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]thiadiazole, tetrazole, pyridine, Piran, 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]pyrrol, 2-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 2-ox-5-azabicyclo[2.2.1]heptane, indole, isoindole, benzothiophene, benzofuran, [1,3]benzodioxol (= 1,2-methylenedioxybenzene), [1,3]benzoxazol, [1,3]benzothiazol, benzoimidazol, thieno[3,2-c]pyridine, chrome, isochroman, [1,4]benzodioxin, [1,4]benzoxazine, [1,4]benzothiazine, quinoline, isoquinoline, cinnoline, chinazoline, quinoxaline, phthalazine, thienothiophene, [1,8]naphthiridine and other naphthyridine, pteridine, and the respective saturated and partially saturated heterocycles in which one or more of, for example, one, two, three, four or all double bonds in the ring system including double bonds in aromatic ring are replaced with simple connections, the�them, for example, azetidine, 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 that may exist 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, all optionally substituted as indicated in the definition of protective groups. Examples of residues of saturated and partially unsaturated heterocycles that may exist 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 PI�uridin-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-dihydroisoquinolines, 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]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, The 2.5-d�hidroizolatii, 2,3-dihydroisoxazole, 4,5-dihydroisoxazole, 2,5-dihydroisoxazole, 2,3-dihydropyrazol, 4,5-dihydropyrazol, 2,5-dihydropyrazolo, 2,3-dihydrooxazolo, 4,5-dihydrooxazolo, 2,5-dihydrooxazolo, 2,3-dihydrothiazolo, 4,5-dihydrothiazolo, 2,5-dihydrothiazolo, 2,3-dihydroimidazole, 4,5-dihydroimidazole, 2,5-dihydroimidazole, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyranyl, tetrahydro[1,3,5]triazinyl, [1,3]ditional, tetrahydropyranyl, tetrahydropyranyl, [1,3]DIOXOLANYL, 3,4,5,6-tetrahydropyridine, 4H-[1,3]thiazines, 1,1-diokso-2,3,4,5-tetrahydrothieno, 2-azabicyclo[3.1.0]hexyl, including 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, including 3-azabicyclo[3.1.0]hex-3-yl, 2-ox-5-azabicyclo[2.2.1]heptyl, 2-ox-5-azabicyclo[2.2.1]hept-5-yl, and all are connected via any suitable carbon atom or ring nitrogen atom of the ring, and optionally substituted, as indicated in the definition of protective groups.

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

If oxoprop linked to the carbon atom, it replaces two hydrogen atoms at the carbon atom of the original system. Thus, if CH2 group in the chain or ring is substituted with oxo, i.e. the oxygen atom with a double bond, it becomes a C(O) (= C(=O)) group. It is obvious that oxoprop cannot exist as a Deputy at the carbon atom in the aromatic ring, e.g. phenyl group. If the sulfur atom ring in the heterocyclic group may be substituted with one or two exography, it is a non-oxidized sulfur atom S in the case that it is not substituted by any exography, or S(O) group (= sulfoxide group, S-oxide group) in case it is substituted with one exography, or S(O)2group (= sulfone, S,S-dioxide group) if he substituted two exography.

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 present in S configuration or substantially S configuration, or in R configuration or substantially R configuration, or as a mixture of the S isomer and the R isomer in any ratio. The present 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. So, link� in accordance with the present invention, which can exist as enantiomers can be present in enantiomerically pure form, both the levorotatory and dextrorotatory antipodes, in the form of a mixture of two enantiomers in all respects, including racemate. In the case of E/Z isomerism, or CIS/TRANS isomerism, for example, double bonds or rings, such as cycloalkyl ring, the present invention includes both forms (E-form and Z form), or CIS-form and TRANS-form, as well as mixtures of these forms in all respects. In one embodiment of the present invention, compounds that can exist in two or more stereoisomeric forms are pure, or substantially pure individual stereoisomers. Individual stereoisomers can be carried out, for example, separating a mixture of isomers by conventional methods, for example, using chromatography or crystallization, by the use in the synthesis stereochemical homogeneous starting materials or by using stereoselective synthesis. Not necessarily, obtaining derivatives can be carried out before separation of stereoisomers. The separation of the mixture of stereoisomers can be carried out at the stage of compounds of the formula I or at the stage of starting materials or intermediate compounds in the synthesis process. The present invention also includes all tautomeric forms of compounds of formula I and their �Olya and solvates.

In that case, if the compounds of formula I contain one or more acidic and/or basic groups, i.e. salebrosa groups, the present invention also comprises their corresponding physiologically or toxicologically acceptable salts, i.e. non-toxic salts, especially their pharmaceutically acceptable salts. Thus, compounds of formula I which contain an acid group, such as hydroxycarbonyl group= carboxyl group = C(O)-OH group), can be used in accordance with the present invention, for example, as salts of alkali metals, salts of alkaline earth metals or ammonium salts. More specific examples of such salts include sodium salt, potassium salt, calcium salts, magnesium salts, Quaternary ammonium salts, such as salts of tetraalkylammonium or salt accession acid to the ammonium 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 be protonated, such as amino group or nitrogen-containing heterocycle, can be used in accordance with the present invention in the form of their salts joining with inorganic and organic acids. Examples of suitable acids include hydrogen chloride, methyl hydrogen, phosphoric acid, sulfuric acid, methane�AlfaNova acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, benzoic acid, malonic acid, fumaric acid, maleic acid, citric acid and other acids, well known to specialists in this field. If the compound of the formula I simultaneously contain acidic group and basic group in the molecule, in addition to the already mentioned forms of salts, this compound also includes an inner salt (= betaine, zwitterionic). Salts of compounds of formula I can be obtained by conventional methods which are well known to specialists in this field, for example, by contacting compounds of formula I with organic or inorganic acid or base in a solvent or diluent, or as a result of anion exchange or cation exchange from another salt. The present invention also includes all salts of the compounds of formula I, which due to low physiological compatibility of salt-forming acid or base are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates in chemical reactions or to obtain physiologically acceptable salts.

The present invention includes all solvates of compounds of formula I, for example hydrates or adducts with with�Itami, such as (C1-C4-alkanol, active metabolites of compounds of formula I, and also of proletaria 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 amides of carboxylic acids group.

In one embodiment of the present invention, A is selected from the group consisting of NH and O, in another embodiment of the invention, A is selected from the group consisting of NH and S, in another embodiment of the invention, A is selected from the group consisting of O and S, in another embodiment of the invention, A represents NH, in another embodiment of the invention, A represents O, in another embodiment of the invention, A represents the S.

Alkadiene, Allendale and akindeinde group in the group X may be linear or branched, as indicated in respect of such groups, and these groups as well as cycloalkenyl group representing X, can be linked to the adjacent groups, i.e. the heterocycle Y and the group R2or, in the case of a group of alcadeias, with the oxygen atom of altingiaceae, in any position. Neighboring groups can be bound to the same carbon atom or with other carbon atoms in the group X. In one embodiment, the chain of carbon atoms in �llandeilo, allendales and ascendiendo the group in the group X, which directly connects heterocycl Y with a group R2or, in the case of a group of alcadeias, with the oxygen atom of alcadeias group consisting of 1, 2, 3 or 4 carbon atoms, in another embodiment from 1, 2 or 3 carbon atoms, in another embodiment 1 or 2 carbon atoms, in another embodiment from 1 carbon atom. In case cycloalkenyl group representing X, in one embodiment heterocycle Y and the group R2linked to two carbon atoms of rings that are in the 1,2-position, 1,3-position or 1,4-position relative to each other, in another embodiment, the 1,2-position or 1,3-position relative to each other, in another embodiment, the 1,2-position relative to each other, in another embodiment, the 1,4-position relative to each other. In one embodiment, X is selected from the group consisting of (C1-C6)-Alcantara, (C2-C6)-Alcantara, (C3-C7)-cycloalkenyl and (C1-C6)-alcadeias, in another embodiment from (C1-C6)-Alcantara, (C2-C6)-Alcantara and (C1-C6)-alcadeias, in another embodiment from (C1-C6)-Alcantara, (C3-C7)-cycloalkenyl and (C1-C6)-alcadeias, in another embodiment from (C1-C6)-Alcantara and (C1-C6)-alcadeias, in other�Ohm version of (C 1-C6)-Alcantara, (C2-C6)-Alcantara, (C2-C6)-alkerdeel and (C3-C7)-cycloalkenyl, in another embodiment from (C1-C6)-Alcantara, (C2-C6)-Alcantara and (C3-C7)-cycloalkenyl, in another embodiment from (C1-C6)-Alcantara and (C2-C6)-Alcantara, in another embodiment X is (C1-C6)-alcander, in another embodiment X is (C2-C6)-alcander, in another embodiment X is (C3-C7)-cycloalkenyl and in another embodiment X is (C1-C6)-alcadeias, all of which are optionally substituted as indicated. In one embodiment, (C1-C6)-alcantarilla group present in X, is a (C1-C4)-landiolol group, in another embodiment, (C1-C3)-landiolol group, in another embodiment, (C1-C2)-landiolol group. In one embodiment, (C2-C6)-alcantarilla and (C2-C6)-alcantarilla group, represent X represent (C2-C4)-ascendiendo and (C2-C4)-alcindoro group, in another embodiment, (C2-C3)-ascendiendo and (C2-C3)-alcindoro group. In one embodiment, (C3-C7)-cycloalkenyl group predstavlyaemoi X, represents (C3-C6)-cycloalkenyl group, in another embodiment, (C3-C4)-cycloalkenyl group, in another embodiment cyclopropylamino group, in another embodiment cyclohexanediyl group. Examples of groups X, of which the relevant group representing X, you can choose in the above embodiments, or from which X is chosen in another embodiment of the present invention, represent a methylene, -CH(CH3)-(ethane-1,1-diyl), -CH2-CH2-(ethane-1,2-diyl, 1,2-ethylene), -C(CH3)2-(1-mutilate-1,1-diyl), -CH2-CH2-CH2-(propane-1,3-diyl, 1,3-propylene), -CH2-CH(CH3)- and-CH(CH3)-CH2-(propane-1,2-diyl, 1,2-propylene), which is an example of the group (C1-C6)-Alcantara, -CH=CH-(Eten-1,2-diyl), -CH=CH-CH2- and-CH2-CH=CH-(prop-1-ene-1,3-diyl and prop-2-ene-1,3-diyl) and-CH=C(CH3)- and-C(CH3)=CH-(prop-1-ene-1,2-diyl), which is an example of the group (C2-C6)-Alcantara, -C≡C-(etender) and-CH2-C≡C - and-C≡C-CH2-(prop-1-yn-1,3-diyl and prop-2-yn-1,3-diyl), which is an example of the group (C2-C6)-alcindoro, cyclopropane-1,1-diyl, cyclopropane-1,2-diyl and cyclohexane-1,4-diyl, which is an example of the group (C3-C7)-cycloalkenyl, -CH2-O-(metalinox), -CH2-CH2-O-(ethane-1,2-deeluxe), -CH(CH3)-O-(ethane-1,1-deeluxe), -C(CH3)sub> 2-O-(1-mutilate-1,1-deeluxe), -CH2-CH2-CH2-O-(propane-1,3-direksi) and-CH2-CH2-CH2-CH2-O-(butane-1,4-deeluxe), which is an example of the group (C1-C6)-alcadeias, all of which are optionally substituted as indicated in the description. Thus, in one embodiment, X is selected from the group consisting of-CH2-O-, -CH2-CH2-O-, -CH(CH3)-O - and-C(CH3)3-O-, in another embodiment from-CH2-O-, -CH2-CH2-O - and-CH(CH3)-O-, in another embodiment from-CH2-O - and-CH(CH3)-O-, in another embodiment, X represents-CH2-O-, wherein all these groups optionally substituted as indicated in the description, and where the oxygen atom linked to the group R2. In one embodiment the number of substituents which are optionally present in X, is 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1, and in another embodiment the group X is not substituted by substituents selected from the group consisting of fluorine and hydroxyl. In one embodiment, the number of hydroxysultaine in X is not greater than 2, in another embodiment no more than 1. In one embodiment not more than one hydroxysultaine is present in an individual carbon atom in X. In one embodiment, hydroxysultaine not present on carbon atoms which are part of a double bond in the group (C2- 6)-Alcantara. In one embodiment, hydroxysultaine not present at the carbon atom in the group (C1-C6)-alcadeias that is linked to the oxygen atom, in another embodiment no alternates are not present at the carbon atom in the group (C1-C6)-alcadeias that is linked to the oxygen atom, i.e. specified in the latest version of all the carbon atoms that are not associated with the specified oxygen atom, optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine and hydroxyl. The double bond in the group (C2-C6)-Alcantara can have the E configuration or Z configuration. In one embodiment, it has E configuration, in another embodiment it has a Z configuration.

4-7-membered saturated or partially saturated, monocyclic or bicyclic heterocycle Y includes the nitrogen atom of the ring depicted in formula I which is substituted by a carbonyl group linked to the group X as a heteroatom in the ring, and in addition includes 0, 1, 2 or 3, in one embodiment of the present invention is 0, 1 or 2, in another embodiment 0 or 1, in another embodiment 1 or 2, in another embodiment 1, in another embodiment 0, identical or different other heteroatoms in the ring selected from the group, consisting of N, O and S, where one or two additional nitrogen atoms of the ring can b�th substituted by hydrogen atom or (C 1-C4)-alkyl substituent and one of the sulfur atoms of the ring may be substituted with one or two exography, and where the specified heterocycle, optionally substituted by one or more of the carbon atoms of the ring, the same or different (C1-C4)-alkyl substituents. In one embodiment, the additional heteroatoms that may be present in Y is selected from the group consisting of N and O, in another embodiment from the group consisting of N and S, in another embodiment from the group consisting of O and S, in another embodiment they are N atoms, in another embodiment they represent O atoms, and in another embodiment they represent S atoms. As applicable to compounds of formula I in General, the heteroatoms in the ring in Y can be located any of the provisions, provided that the heterocyclic system is well known to those skilled in the art and is stable and suitable as a subgroup for the desired goals of the compounds of formula I such as use as medicinal substances. In one embodiment of the present invention, two carbon atoms of the ring in Y cannot be present in adjacent ring positions, in another embodiment, two heteroatom in the ring Y is selected from the group consisting of oxygen and sulfur cannot be present in adjacent ring positions, in another embodiment, two heteroatom in Kohl�e in Y, including the nitrogen atom of the ring, which is depicted in formula I, can not be in adjacent ring positions. In that case, if Y is a saturated, specified heterocycl Y do not contain double bonds of the ring. In that case, if Y is partially unsaturated, i.e. the specified heterocycle Y contains one or more double bonds in the ring, but is non-aromatic, in one embodiment heterocycle contains one or two, in another embodiment one ring double bond, which can be located in any suitable positions. In one embodiment, Y is saturated, in another embodiment, Y is a partially unsaturated.

In one embodiment, Y is a 4-6-membered, in another embodiment, 4-5-membered, in another embodiment, the 5-6-membered, in another embodiment 4-membered, in another embodiment 5-membered, in another embodiment 6-membered heterocycle, which is saturated or partially unsaturated and a monocyclic or bicyclic, and which is otherwise defined as indicated with respect to Y at all, until such time as applicable. In one embodiment, the number of ring members in the monocyclic heterocycle, Y represents, matter, as indicated in the description in the General definition of Y, or in the above embodiments, the bicyclic heterocycle constituting Y is a 6-7-membered, in another embodiment 6-membered, in another embodiment 7-membered.In the bicyclic heterocycles, representing the Y atoms in the head of the bridge can be nitrogen atoms, which is any of the nitrogen atoms of the ring that may be present in addition to the nitrogen atom of the ring depicted in formula I, and/or the carbon atoms of the ring. In one embodiment, one of the atoms in the head of the bridge in the bicyclic heterocycle constituting Y is a carbon atom and the other is a carbon atom or a nitrogen atom, in another embodiment, both of the atom in the head of the bridge are carbon atoms. Examples of bicyclic ring systems from which to choose bicyclic heterocycles representing Y, in one embodiment, are bicyclo[3.1.0], bicyclo[3.2.0], bicyclo[4.1.0], bicyclo[2.2.1] and bicyclo[2.1.1] ring systems that include a nitrogen atom of the ring shown in the formula, and additional heteroatoms in the ring which are optionally present in Y, and which are saturated or partially unsaturated and otherwise defined as indicated with respect to Y at all, until such time as applicable. In one embodiment, the bicyclic heterocycle representing Y is saturated. In one embodiment, Y represents a monocyclic of heterocycle, in another embodiment, Y represents a bicyclic heterocycle. In one embodiment, the number (C1-C4)-alkyl substituents, which are optionally PR�absent the carbon atoms of the ring in Y, is one, two, three, or four, in another embodiment one or two, and in another embodiment, Y is not substituted at the carbon atoms of the ring (C1-C4)-alkyl substituents.

In one embodiment, Y represents a 4-7-membered saturated monocyclic or bicyclic heterocycle, which in addition to the nitrogen atom of the ring represented in the formula I, contains 0 or 1 heteroatoms in the ring selected from the group consisting of N, O and S, where the additional nitrogen atom in the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and the sulfur atom of the ring may be substituted with one or two exography, and where heterocycle, optionally substituted by one or more of the carbon atoms of the ring are identical or different (C1-C4)-alkyl substituents. In another embodiment, Y is a 4-6-membered, saturated, monocyclic of heterocycl that does not contain other heteroatoms in the ring in addition to the nitrogen atom of the ring depicted in formula I, where the specified ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different (C1-C4)-alkyl substituents. In another embodiment, Y is selected from one or more heterocycles of azetidine, pyrrolidine and piperidine nitrogen atom of the ring is a nitrogen atom Col�and Y, depicted in formula I which contains a carbonyl group associated with the group X, where said heterocycles, optionally substituted at the carbon atoms of the ring one or more identical or different (C1-C4)-alkyl substituents, and in another embodiment, these heterocycles have no alkyl substituents.

The group R4-O-C(O)- may be linked to the heterocycle Y in any suitable position. In one embodiment, the group R4-O-C(O)- linked to the carbon atom of the ring in Y in any position, in another embodiment it relates to a carbon atom of a ring in Y, which is located in the position of the ring adjacent to the nitrogen atom of the ring in Y, shown in the formula I, in another embodiment this group is linked to a carbon atom of a ring in Y, which is adjacent to the specified nitrogen atom of the ring or is separated from the nitrogen atom of the ring one or two ring members in another embodiment, it relates to a carbon atom of a ring, which is adjacent to the specified nitrogen atom of the ring or is separated from the nitrogen atom of the ring by at least one member of the ring, in another embodiment it relates to a carbon atom of a ring in Y, which is separated from the nitrogen atom of the ring one or two ring members, and in another embodiment it relates to a carbon atom of a ring, which is separated from the specified atom of the azo�ring and at least one member of the ring. For example, in the case of a heterocycle, Y, which contains no other heteroatoms in the ring in addition to the nitrogen atom depicted in formula I, and where the specified nitrogen atom of the ring, thus, is in the position of the heterocycle, in one embodiment, the group R4-O-C(O)- linked to the carbon atom of the ring in any position, in another embodiment it is linked in position 2, in another embodiment in position 3, in another embodiment in position 4, in another embodiment in position 2 or 3, in another embodiment in position 3 or 4, in another embodiment in position 2, 3 or 4. In one embodiment, in a partially unsaturated heterocycle Y group R4-O-C(O)- linked to the ring atom that is not part of a double bond. In one embodiment, in the case of the bicyclic heterocycle Y group R4-O-C(O)-linked to the ring atom that is not an atom in the head of the bridge. The group Y may be present in the heterocycle Y in any stereochemical position, for example, in the endo-position or in the Exo-position in the case or bicyclic ring Y, or in CIS-position or in the TRANS-position relative to the substituent in Y, or at the carbon atom having the S configuration, or a carbon atom having R-configuration. For example, in the case of the ring Y is selected from the group consisting of azetidine, pyrrolidine, piperidine and peligrosamente, the nitrogen atom of the ring which made�ing a nitrogen atom of the ring in Y, depicted in formula I, and which contains a group R4-O-C(O)- in position 2, in one embodiment, the carbon atom substituted by the group R4-O-C(O)- is present in S configuration. Examples of the groups R4-O-C(O)-Y-choose from a specified group in the compounds of formula I, in one embodiment are 2-hydroxycarbonylmethyl-1-yl, 2-((C1-C4-allyloxycarbonyl)azetidin-1-yl, (S)-2-hydroxycarbonylmethyl-1-yl, (S)-2-((C1-C4-allyloxycarbonyl)azetidin-1-yl, 3-hydroxycarbonylmethyl-1-yl, 3-((S1-C4-allyloxycarbonyl)azetidin-1-yl, 2-hydroxycarbonylmethyl-1-yl, 2-((C1-C4-allyloxycarbonyl)pyrrolidin-1-yl, (S)-2-hydroxycarbonylmethyl-1-yl, (S)-2-((C1-C4-allyloxycarbonyl)pyrrolidin-1-yl, 3-hydroxycarbonylmethyl-1-yl, 3-((S1-C4-allyloxycarbonyl)pyrrolidin-1-yl, 2-hydroxycarbonylmethyl-1-yl, 2-((C1-C4-allyloxycarbonyl)piperidine-1-yl, (S)-2-hydroxycarbonylmethyl-1-yl, (S)-2-((C1-C4-allyloxycarbonyl)piperidine-1-yl, 3-hydroxycarbonylmethyl-1-yl, 3-((S1-C4-allyloxycarbonyl)piperidine-1-yl, 4-hydroxycarbonylmethyl-1-yl, 4-((C1-C4-allyloxycarbonyl)piperidine-1-yl, 2-hydroxycarbonylmethyl-1-yl, 2-((C1-C4)-al�jocstarbunny)peligrosas-1-yl, (S)-2-hydroxycarbonylmethyl-1-yl, (S)-2-((C1-C4-allyloxycarbonyl)peligrosas-1-yl, 3-hydroxycarbonylmethyl-1-yl, 3-((S1-C4-allyloxycarbonyl)peligrosas-1-yl, 4-hydroxycarbonylmethyl-l-yl, 4-((C1-C4-allyloxycarbonyl)peligrosas-1-yl, 2-hydroxycarbonylmethyl-4-yl, 2-((C1-C4-allyloxycarbonyl)morpholine-4-yl, 3-hydroxycarbonylmethyl-4-yl, 3-((S1-C4-allyloxycarbonyl)morpholine-4-yl, 2-hydroxycarbonylmethyl-4-yl, 2-((C1-C4-allyloxycarbonyl)thiomorpholine-4-yl, 3-hydroxycarbonylmethyl-4-yl, 3-((S1-C4-allyloxycarbonyl)thiomorpholine-4-yl, 2-hydroxycarbonyl-1,1-diocletianopolis-4-yl, 2-((C1-C4-allyloxycarbonyl)-1,1-diocletianopolis-4-yl, 3-hydroxycarbonyl-1,1-diocletianopolis-4-yl, 3-((S1-C4-allyloxycarbonyl)-1,1-diocletianopolis-4-yl, 2-hydroxycarbonyl-4-methylpiperazin-1-yl, 2-((C1-C4-allyloxycarbonyl)-4-methylpiperazin-1-yl, 3-hydroxycarbonyl-4-methylpiperazin-1-yl, 3-((S1-C4-allyloxycarbonyl)-1-methylpiperazin-1-yl.

In one embodiment of the present invention, the number t is selected from the group consisting of 0, 1 or 2, in another embodiment 0 or 1, in another embodiment from 1, 2 or 3, in another embodiment from 1 or 2, in another embodiment, t is 0, in another embodiment t is 1. In one embodiment, R1selected from the group consisting of (C1-C6)-alkyl, (C3-C7-cycloalkyl-CtH2t- and Het-CtH2t-, in another embodiment from (C1-C6)-alkyl and (C3-C7-cycloalkyl-CtH2t-, in another embodiment, R1represents (C1-C6)-alkyl, in another embodiment, R1represents (C3-C7-cycloalkyl-CtH2t-, and in another embodiment, R1represents Het-CtH2t-. In one embodiment, R1represents (C3-C7-cycloalkyl-CtH2t- where t is selected from the group consisting of 0, 1 and 2, in another embodiment, R1represents (C3-C7-cycloalkyl-CtH2t- where t is selected from the group consisting of 0 and 1, in another embodiment, R1represents (C3-C7-cycloalkyl-CH2-, in another embodiment, R1represents (C3-C7-cycloalkyl, in another embodiment, R1represents Het-CtH2t- where t is selected from the group consisting of 0, 1 and 2, in another embodiment, R1represents Het-CtH2t- where t is selected from the group consisting of 0 and 1, in another embodiment, R1is a Het-CH2-, in another embodiment, R1represents Het. In one�m option (C 1-C6)-alkyl group, which is an R1is (C2-C6)-alkyl, in another embodiment, (C2-C5)-alkyl, in another embodiment, (C3-C5)-alkyl. In one embodiment, (C2-C6)-alkenyl group and (C2-C6)-Alchemilla group representing R1are (C3-C6)-alkenyl and (C3-C5)-ukinila, respectively, in another embodiment, (C3-C4)-alkenyl and (C3-C4)-ukinila, respectively. In one embodiment, (C3-C7)-cycloalkyl group, which is an R1is (C3-C6)-cycloalkyl, in another embodiment, (C3-C5)-cycloalkyl, in another embodiment, (C3-C4)-cycloalkyl, in another embodiment a cyclopropyl. In one embodiment, the group Het, which is an R1is a 4-6-membered, in another embodiment 4-membered or 5-membered, in another embodiment 4-membered, saturated monocyclic of heterocycle, which is attached through a carbon atom of the ring, and which contains 1 or 2 identical or different heteroatom in the ring, in another embodiment 1 heteroatom in the ring which is selected from the group consisting of N, O and S, in another embodiment from O and S, and which in another embodiment is an O atom. In one embodiment, the group Het, which presented�a splash zones R 1represents oxetanyl group, for example, oxetan-3-ilen group. In one embodiment the number of substituents, optionally present in the group Het representing R1that is one, two, or three, in another embodiment one or two, in another embodiment one, and in another embodiment such a group Het is unsubstituted. In one embodiment, (C1-C4)-alkyl Deputy, present the group Het representing R1is a methyl group.

In one embodiment of the present invention, the number of heteroatoms in the ring in an aromatic heterocycle representing R2is 1 or 2, in another embodiment it is 1. In one embodiment of the present invention, R2selected from the group consisting of phenylene and a bivalent residue of an aromatic, 6-membered monocyclic heterocycle which comprises 1, 2 or 3 nitrogen atom ring, in another embodiment 1 or 2 nitrogen atom of the ring, in another embodiment 1, the nitrogen atom of the ring, where one of the nitrogen atoms of the ring may have a substituent R21that represents hydroxy, i.e. where one of the nitrogen atoms of the ring mode to be oxidized to N-oxide, and where the phenylene and a divalent residue of an aromatic heterocycle optionally substituted by one or more of the carbon atoms of the ring are the same or different to replace�s R 22. In another embodiment, R2represents a phenylene, where the specified phenylene, optionally substituted by one or more of the ring atoms are identical or different substituents R22and in another embodiment, R2is pyridinyl, where the specified nitrogen atom of the ring may be substituted by R21that represents hydroxy, i.e., where the specified nitrogen atom ring mode to be oxidized to N-oxide, and where pyridinyl, optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22. In another embodiment, R2represents a divalent residue of an aromatic 5-membered heterocycle which comprises 1, 2 or 3 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one of the nitrogen atoms of the ring may be substituted by hydrogen atom or a substituent R21and where is the divalent residue of an aromatic heterocycle, 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 the group consisting of purandara, difendere, oxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, in another variation�those of purandara, difendere, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, in another embodiment from purandara, difendere, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, in another embodiment from purandara, difendere, peridiniella and pyrimidinyl, in another embodiment from purandara, difendere and pyridinyl, all of which are optionally substituted as indicated with respect to R2.

The carbon atoms of the ring through which the phenylene group and the divalent residue of an aromatic heterocycle representing R2associated with oxazolopyridine ring and the group X, can be in any of the positions. Phenylene group representing R2can be 1,2-phenylene, i.e. oxazolopyridine ring and the group X can be bonded in the 1,2-position, or in anthopology in relation to each other, it can be 1,3-phenylene, i.e. oxazolopyridine ring and the group X can be bonded in the 1,3-position or meta-position relative to each other, and it can be 1,4-phenylene, i.e. oxazolopyridine ring and the group X can be bonded in the 1,4-position or para-position relative to each other. In one embodiment, the phenylene group representing R2, selected from the group consisting of 1,3-phenylene and 1,4-phenylene, in another embodiment it is with�Oh 1,3-phenylene, and in another embodiment it represents 1,4-phenylene, all of these groups, optionally substituted as indicated with respect to R2. In one embodiment, R2choose one or more from the group of phenylene, furan-2,5-deila, thiophene-2,4-Diil, thiophene-2,5-deila, pyridine-2,4-Diil, pyridine-2,5-deila, pyridine-3,5-deila, pyridine-2,6-deila and pyrimidine-2,5-deila, in another embodiment from the group of furan-2,5-deila, thiophene-2,4-Diil, thiophene-2,5-deila, pyridine-2,4-Diil, pyridine-2,5-deila, pyridine-3,5-deila, pyridine-2,6-deila and pyrimidine-2,5-deila, in another embodiment from pyridine-2,4-Diil, pyridine-2,5-deila, pyridine-3,5-deila and pyridine-2,6-deila, in another embodiment from phenylene, pyridine-2,4-Diil, pyridine-2,5-deila, pyridine-3,5-deila and pyridine-2,6-deila, all of which are optionally substituted as indicated with respect to R2. In one embodiment the number of substituents R22that was not necessarily present at the carbon atoms of the ring in R2is 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. The nitrogen atoms of the ring in R2with no Deputy R22substituted by a hydrogen atom.

In one embodiment of the present invention, R3selected from the group consisting of (C1-C6)-alkyl, (C2-C6-alkenyl and (C2-C6)-alkynyl, in another embodiment, R3 represents (C1-C6)-alkyl, in another embodiment, R3represents (C2-C5)-alkyl, and in another embodiment, R3represents (C1-C4)-alkyl, provided that R3cannot be an alkyl group when A represents S. In another embodiment, R3selected from the group consisting of (C3-C7-cycloalkyl-CuH2U- and Het-CvH2v-. In another embodiment, R3represents (C3-C7-cycloalkyl-CuH2U-, and in another embodiment, R3represents Het-CvH2v- where in the specified embodiment, u and v independently from each other selected from the group consisting of 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, a group (C3-C7-cycloalkyl-CuH2U- that is an R3, selected from the group consisting of cyclopropyl-CuH2u- cyclobutyl-CuH2uand cyclopentyl-CuH2u- and the group Het-CvH2v- that is an R3,is tetrahydrofuranyl-CvH2v-. In one embodiment, R3selected from the group consisting of cyclopropyl-CuH2u- cyclobutyl-CuH2uand cyclopentyl-CuH2u-.

In one embodiment, R3/sup> selected from the group consisting of (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v-, or R3represents a radical consisting of saturated or unsaturated, 3-10-membered monocyclic or bicyclic ring which contains 0, 1, 2, 3 or 4 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)alkyl substituent and one or two of the sulfur atoms of the ring may be substituted with one or two exography, and where the radical of the ring, optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R31and in another embodiment, R3represents a radical consisting of saturated or unsaturated, 3-10-membered monocyclic or bicyclic ring which contains 0, 1, 2, 3 or 4 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one or two of the sulfur atoms of the ring may be substituted with one or two exography, and where the rest of the ring, optionally substituted by one or more of the carbon atoms of the ring are identical or once�ary substituents R 31. In one embodiment, the number of heteroatoms in the ring, representing R3,is 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, in another embodiment 0, in another embodiment it is 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. Thus, the radical of the ring, which is an R3may be carbocyclic or heterocyclic. In one embodiment, these heteroatoms in the ring in R3selected from the group consisting of N and O, in another embodiment from N and S, in another embodiment from O and S, in another embodiment they are N, where the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent in saturated or partially unsaturated heterocycles, or a 5-membered aromatic ring heterocycles, such as, for example, pyrrole or benzimidazole, or they can be substituted by hydrogen atom or (C1-C4)-alkyl substituent in the aromatic heterocycles, such as imidazole or pyridine. The heterocycle radical representing R3that contains one or more of the sulfur atoms of the ring, in one embodiment, one of the sulfur atoms of the ring is unoxidized or substituted with one or two exography, and all other �Toms sulfur rings are non-oxidized. The radical of a monocyclic or bicyclic ring representing R3may be associated with A group via any suitable carbon atom or ring nitrogen atom of the ring. In one embodiment, it is linked via a carbon atom of the ring, in another embodiment it is linked via a carbon atom of the ring or, in the case that a represents NH, via the nitrogen atom of the ring, and in another embodiment it is connected through the nitrogen atom of the ring. The radical of a monocyclic or bicyclic ring representing R3can be unsaturated and in this case may contain 1, 2, 3, 4, or 5, or 1, 2, 3, or 4, or 1, 2 or 3, or 1 or 2, or 1 double bonds and rings may be aromatic or non-aromatic in either of the two rings, or it may be unsaturated, and in this case it does not contain double bond of the ring. In one embodiment, the specified radical of a ring, representing R3,is saturated or aromatic, in another embodiment it is saturated, and in another embodiment it is aromatic. In one embodiment, the said radical comprising from 3-membered or 4-membered ring representing R3,is saturated. If R3includes the nitrogen atoms of the ring which may be substituted by hydrogen atom or (C1-C4)-alkyl substituent can then be od�n such nitrogen atoms of the ring or may attend two of these nitrogen atoms of the ring. In one embodiment, optional substituents of R31the carbon atoms of the ring, representing R3,is 1, 2, 3, 4, 5 or 6, in another embodiment 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1.

The ring, which may be an R3,can be 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In one embodiment, R3is a 4-10-membered, in another embodiment, 4-9-membered, in another embodiment, 4-8-membered, in another embodiment 4 to 7-membered, in another embodiment, 5-7-membered, in another embodiment, the 5-6-membered, in another embodiment 6-membered, in another embodiment, 8-10-membered, in another embodiment, 9-10-membered. In one embodiment, the 3-membered ring representing R3it does not contain any heteroatoms in the ring. In one embodiment, R3is a monocyclic, in another embodiment, the bicyclic. In one embodiment, the bicyclic group representing R3is at least 7-membered. Among other specified radical of a ring, representing R3,can be cycloalkyl group, phenyl group, naftalina group, a radical consisting of unsaturated, aromatic or non-aromatic heterocyclic group, or a radical consisting of us�saturated heterocyclic group, all of which are optionally substituted at the carbon atoms of the ring and the nitrogen atoms of the ring as defined in relation to R3. As long as possible, all the above explanations with respect to such group of the applicable respectively to R3. Other examples of groups which can represent R3,are cycloalkenyl groups such as (C5-C7)-cycloalkenyl groups, which may be connected through any carbon atom of the ring and optionally substituted as defined in relation to R3. In one embodiment, optional substituents of R31I cycloalkenyl group representing R3, selected from the group consisting of fluorine and (C1-C4)-alkyl. In one embodiment cycloalkenyl groups contain one double bond in the ring, and the specified double bond may be present in any position. Examples of cycloalkenyl are cyclopentenyl, including cyclopent-1-enyl, cyclopent-2-enyl and cyclopent-3-enyl, cyclohexenyl, including cyclohex-1-enyl, cyclohex-2-enyl and cyclohex-3-enyl, and cycloheptenyl, including cyclohepta-1-enyl, cyclohepta-2-enyl, cyclopent-3-enyl and cyclohepta-4-enyl. Examples of radicals of rings, choose from R3in one embodiment of the present invention represent cyclobutyl, cyclopentyl, cyclohexyl, phenyl,�Setenil, 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 morpholinyl-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 cycloalkenyl, if applicable, one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl, and where all of them optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R31and where in all of them, if applicable, the sulfur atom of the ring may be oxidized, i.e. be present as a sulfur atom, or may be substituted by one or two exography, i.e. be present in the form of sulfoxide or sulfone.

In one embodiment, R3selected from the group consisting of phenyl and a radical consisting of a saturated or unsaturated 3-to 7-membered, monocyclic ring, in another embodiment from phenyl and a radical consisting of a saturated or unsaturated 5-7-membered, m�and monocyclic, ring, in another embodiment from phenyl, pyridinyl and radical consisting of saturated 3-to 7-membered monocyclic ring, in another embodiment from phenyl, pyridinyl and radical consisting of a saturated 5-7-membered, monocyclic ring, in another embodiment from phenyl and pyridinyl, in another embodiment from phenyl and a radical consisting of saturated 3-to 7-membered, monocyclic ring, in another embodiment from phenyl and a radical consisting of a saturated 5-7-membered, monocyclic ring, in another embodiment, one or more of the group consisting of phenyl, cyclobutyl, cyclopentyl, cyclohexyl and pyridinyl, in another embodiment, one or more of the group consisting of phenyl, cyclopentyl and cyclohexyl, in another embodiment, one or both of the phenyl group and cyclohexyl, where in all these embodiments, the monocyclic ring contains 1 or 2 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one or two of the sulfur atoms of the ring may be substituted with one or two exography, and where said phenyl, pyridinyl, radical rings, cyclobutyl, cyclopentyl and cyclohexyl, optionally substituted by one or more of the carbon atoms of the ring odinakovymi different substituents R 31and where pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. In another embodiment, R3represents phenyl, which is optionally substituted by one or more identical or different substituents R31.

In one embodiment of the present invention, the number z is selected from the group consisting of 0 and 1, in another embodiment, z=0, in another embodiment, z=1. In one embodiment of the invention, the group R4selected from the group consisting of hydrogen and (C1-C4)-alkyl, in another embodiment, R4selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl and isopropyl, in another embodiment from hydrogen, methyl and ethyl, in another embodiment, R4represents hydrogen, in another embodiment, R4represents (C1-C4)-alkyl, in another embodiment, R4is methyl, and in another embodiment, R4represents ethyl. In one embodiment, (C3-C7)-cycloalkyl group present in R4represents (C3-C6-cycloalkyl, in another embodiment it represents cyclopropyl.

In one embodiment of the present invention, the number w is selected from the group consisting of 0 and 1, in another embodiment, w=0, in another embodiment, w=1. In one embodiment, (C3-C7)-cycloalkyl group which is present in R21represents (C3-Csub> 6}-cycloalkyl, in another embodiment, (C3-C5-cycloalkyl, in another embodiment a cyclopropyl. In one embodiment, R21selected from the group consisting of (C1-C4)-alkyl and hydroxy, 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 hydroxy.

In one embodiment of the present invention, the substituents R22optionally present in the group R2, selected from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro and cyano, in another embodiment from halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, amino and cyano, in another embodiment from halogen, hydroxyl, (C1-C4)-alkyl and (C1-C4)-alkyloxy-, in another embodiment from fluorine, chlorine, hydroxyl, (C1-C4)-alkyl and (C1-C4)- alkyloxy-, in another embodiment from fluorine, chlorine and (C1-C4)-alkyl-, and in another embodiment they are (C1-C4)-alkyl substituents.

In one embodiment, 1, 2 or 3 of the substituents R22in another embodiment, 1 or 2 of the substituents R22and in another embodiment 1, the substituents R 22which are not necessarily present in the group R2are defined as shown in the General definition of R22and, thus, they are chosen from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro, cyano, hydroxycarbonyl, (C1-C4)-allyloxycarbonyl, aminocarbonyl and aminosulfonyl, and any other substituents R22which are not necessarily present in the group R2for example , 1, 2 or 3 other substituent R22or 1 or 2 other substituent R22or 1 of the other substituent R22, selected from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, (C1-C4)-alkyl-S(O)m-, amino, nitro and cyano, where all alkyl groups independently of each other optionally substituted by one or more of fortuntately, as it usually applies to alkyl groups. In one embodiment, the substituents R22which are not necessarily present in the group R2and who in the aforementioned embodiment, determined as specified in the General definition of R22for example , 1 or 2 such Deputy R22or 1 such substituent R22, selected from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4and�Biloxi-, (C1-C4)-alkyl-S(O)m-, amino, nitro and cyano. In one embodiment, the substituents R22which are not necessarily present in the group R2and that in the above embodiment, determined as specified in the General definition of R22for example , 1 or 2 such Deputy R22or 1 such substituent R22not located at the carbon atoms of the ring within the group, R2located next to the atom through which the group R2attached to oxazolopyridine the ring represented in the formula I. In one embodiment, the other substituents R22which are not necessarily present in the group R2for example , 1, 2 or 3 other substituent R22or 1 or 2 other substituent R22or 1 of the other substituent R22, selected from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl, (C1-C4)-alkyloxy-, amino, cyano, in another embodiment from halogen, hydroxy, (C1-C4)-alkyl and (C1-C4)-alkyloxy-, in another embodiment from halogen, (C1-C4)-alkyl and (C1-C4)-alkyloxy-, in another embodiment from halogen and (C1-C4)-alkyl-where in all these embodiments all alkyl groups independently of each other optionally substituted by one or more of fortuntately.

In one embodiment of the present invention, R 31selected from the group consisting of halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyano, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, oxo, amino, (C1-C4)-alkylamino, d�((C 1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, oxo, 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 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 and (C1-C4)-alkyloxy, where in all these embodiments all alkyl groups independently of each other optionally substituted by one or more of fortuntately.

In one embodiment, optional substituents of R31the specified moiety consisting of saturated or unsaturated non-aromatic ring, representing R3, selected from the group consisting of halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4 )-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl, cyano, (C1-C4)-alkylcarboxylic, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)- alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano, aminosulfonyl, (C1-C4)-alkylaminocarbonyl and di((C1-C4)-alkyl)aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, cyano and aminosulfonyl, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, amino, (C1-C4)-alkylamino and di((C1 4)-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 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 and (C1-C4)-alkyloxy, where in all these embodiments all alkyl groups independently of each other optionally substituted by one or more of fortuntately.

In one embodiment, optional substituents of R31the specified moiety consisting of saturated or unsaturated non-aromatic ring, representing R3, selected from the group consisting of halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy, oxo, (C1-C4)-alkyl-S(O)m-, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino, (C1-C4)-alkylcarboxylic, (C1-C4)-alkylsulfonyl and cyano, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1 -C4)-alkyloxy, oxo, amino, (C1-C4)-alkylamino, di((C1-C4)-alkyl)amino and cyano, in another embodiment from halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl, (C1-C4)-alkyloxy and oxo, in another embodiment from halogen, (C1-C4)-alkyl, hydroxyl, (C1-C4)-alkyloxy and oxo, in another embodiment from fluorine, chlorine, (C1-C4)-alkyl, hydroxyl, (C1-C4)-alkyloxy and oxo, in another embodiment from (C1-C4)-alkyl, hydroxyl and oxo, in another embodiment from alkyl and hydroxyl, and in another embodiment they are (C1-C4)-alkyl, wherein in all these embodiments all alkyl groups independently of each other optionally substituted by one or more of fortuntately. If the radical of the ring, representing R3that contains any of the carbonyl group as the substituents R31in one embodiment, there are not more than two such oxazolidines, and in another embodiment not more than one such oxazolidine.

In one embodiment of the present invention, these heteroatoms in the ring in Het selected from the group consisting of N and O, in another embodiment from O and S, in another embodiment they represent O atoms. In another embodiment, the number of heteroatoms in the ring is in Het . In one embodiment, two oxygen atoms of the ring in Het are not in adjacent ring positions, in another embodiment, two heteroatom in the ring selected from the group consisting of O and S are not in adjacent ring positions, in another embodiment, two heteroatom in the ring are not in adjacent ring positions. The nitrogen atoms of the ring in Het substituted by hydrogen atom or a substituent as indicated in the description. In one embodiment, optional substituents at the nitrogen atoms of the ring in Het represents (C1-C4)-alkyl substituents. In one embodiment, optional substituents at the nitrogen atoms of the ring and the carbon atoms of the ring in Het represents (C1-C4)-alkyl substituents. In one embodiment, the number of optional substituents at Het is 1, 2, 3, 4 or 5, in another embodiment 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. Het can be attached 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 a heteroatom in the ring. 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 5-membered or 6-membered, in another embodiment 4-membered. Examples of Het, where it is chosen one option from are �xethanol, 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 Titan-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, all optionally substituted as indicated with respect to Het.

In the present invention all compounds of formula I in which one or more of the structural elements such as groups, & nbsp;� and number defined as in any of the specific options or definitions of the elements or one or more of the specific values listed here as examples of elements, where all combinations of one or more of specific options and/or definitions and/or specific values of the elements are the subject of the present invention. Also with respect to all such compounds of formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvates are the subject of the present invention.

Examples of compounds in accordance with the present invention, which is defined with respect to any structural elements, as in specified embodiments of the present invention, the definitions of such elements, and which are a part of the subject of the present invention, are compounds of formula I in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvates of such compounds and such salts, where R3selected from the group consisting of (C1-C6)-alkyl, (C3-C7-cycloalkyl-CuH2u- and Het-CvH2v- where u and v selected from the group consisting of 1 and 2, or R3represents a radical consisting of �Assenova or unsaturated 3-10-membered monocyclic or bicyclic ring, which contains 0, 1 or 2 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one of the sulfur atoms of the ring may be substituted with one or two exography, and where the radical of the ring, optionally substituted by one or more of the carbon atoms of the ring are identical or different substituents R31provided that R3can't imagine (C1-C6)-alkyl if A represents S;

Het represents a radical consisting of a saturated 4-6-membered monocyclic heterocycle, which contains 1 heteroatom in the ring selected from the group consisting of N, O and S and which is attached via a carbon atom of the ring, where the heterocycle radical, optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C1-C4)-alkyl;

and all other groups and numbers are defined as in the General definition of the compounds of formula I or one of the variants of the present invention or definitions of structural elements.

Another such example are compounds of the formula I in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and afiniruyuschy acceptable salt, and physiologically acceptable solvates of such compounds or such salts, in which

A is selected from the group consisting of O and S;

X is selected from the group consisting of (C1-C6)-Alcantara, (C2-C6)-Alcantara and (C1-C6)-alcadeias;

Y represents a 4-7-membered saturated monocyclic or bicyclic heterocycle, which, in addition to the nitrogen atom of the ring represented in the formula I, contains 0 or 1 heteroatom in the ring selected from the group consisting of N, O and S, where the additional nitrogen atom in the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and the sulfur atom of the ring may be substituted with one or two exography, and where heterocycle, optionally substituted by one or more of the carbon atoms of the ring are the same or different (C1-C4)-alkyl substituents;

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

R2selected from the group consisting of phenylene and pyridinyl, where the phenylene and pyridinyl, optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22;

R3selected from the group consisting of (C1- 6)-alkyl, (C3-C7- cycloalkyl-CuH2u- and Het-CvH2v- where u and v selected from the group consisting of 1 and 2, or

R3represents a radical consisting of saturated or unsaturated 3-10-membered monocyclic or bicyclic ring which contains 0, 1 or 2 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one of the nitrogen atoms of the ring may be substituted with one or two exography and where the radical of the ring, optionally substituted by one or more of the nitrogen atoms of the ring are the same or different substituents R31provided that R3cannot be (C1-C6)-alkyl if A represents S;

Het represents a radical consisting of a saturated 4-6-membered monocyclic heterocycle, which contains 1 heteroatom in the ring selected from the group consisting of N, O and S and which is attached via a carbon atom of the ring, where the radical representing heterocycle, optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine and C1-C4)-alkyl;

and all other groups and numbers are defined �well as in the General definition of the compounds of formula I, or in one of the variants of the invention or definitions of structural elements.

Another such example are compounds of the formula I in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts and physiologically acceptable solvates of such compounds or such salts, where A represents O;

X is selected from the group consisting of (C1-C6)-Alcantara and (C1-C6)-alcadeias;

Y is a 4-6-membered saturated monocyclic of heterocycle, which, in addition to the nitrogen atom of the ring represented in the formula I contains no other heteroatoms in the ring, where the ring is optionally substituted by one or more of the carbon atoms of the ring are the same or different (C1-C4)-alkyl substituents;

R1selected from the group consisting of (C1-C6)-alkyl and (C3-C7-cycloalkyl-CtH2t- where t is selected from the group consisting of 0 and 1;

R2represents a phenylene, which is optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R22;

R3selected from the group consisting of (C3-C7-cycloalkyl-CuH2u- and Het-CVH2V- where u and v selected from the group consisting of 1 and 2,or R 3represents a radical consisting of a saturated or unsaturated 3-to 7-membered monocyclic or bicyclic ring which contains 0, 1 or 2 identical or different heteroatom in the ring selected from the group consisting of N, O and S, where one or two of the nitrogen atoms of the ring may be substituted by hydrogen atom or (C1-C4)-alkyl substituent and one of the sulfur atoms of the ring may be substituted with one or two exography, and where the radical of the ring, optionally substituted by one or more of the carbon atoms of the ring are the same or different substituents R31provided that R3cannot be (C1-C6)-alkyl if A represents S;

R4selected from the group consisting of hydrogen and (C1-C4)-alkyl;

R22selected from the group consisting of halogen, hydroxyl, (C1-C4)-alkyl and (C1-C4)-alkyloxy;

R31selected from the group consisting of halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl, hydroxyl and (C1-C4)-alkyloxy;

Het represents a radical consisting of a saturated 4-6-membered monocyclic heterocycle, which contains 1 heteroatom in the ring selected from the group consisting of O and S and which is attached via a carbon atom of the ring, where the radical of g�of teracycle, optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C1-C4)-alkyl;

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

where all alkyl, alkadiene, CtH2t, CuH2Uand CvH2vgroups independently of each other and independently of other substituents, are optionally substituted by one or more of fortuntately.

Similarly, also with respect to all of the disclosed here, the specific compounds, such as compounds of examples that are variants of the embodiment of the present invention, in which different groups and numbers in the General definition of the compounds of formula I are of particular value, are presented in the relevant specific compounds, suggesting that they are the subject of the present invention in any of their stereoisomeric forms and/or in a mixture of stereoisomeric forms in any ratio, and in the form of their physiologically acceptable salts and physiologically acceptable solvates of such compounds or such salts. Regardless of whether disclosed here the nodules�Noe coupling compound in the free form and/or connection in the form of specific salts, in the present invention proposed compounds in the form of free compounds or in the form of all their physiologically acceptable salts and, if disclosed to a specific salt, optionally in the form specified specific salt, and in the form of the physiologically acceptable solvates of such a compound or such a salt. Thus, the present invention also proposed a compound of formula I which is selected from one or more of the disclosed in the invention specific compounds of formula I, including the compounds presented herein, and their physiologically acceptable salts and physiologically acceptable solvates of such compounds or such salts, where in the present invention proposed a compound of formula I in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, if applicable. Examples that can be specified, are compounds of formula I or their physiologically acceptable salts or physiologically acceptable solvates of such compounds or such salts selected from the group consisting of

(S)-1-(2-{4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-(2-{4-[5-{2-pertenece)-7-ProPak�oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-(2-{4-[5-(5-fluoro-2-methylphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-(2-{4-[5-(3-fluoro-4-methylphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-(2-{2,6-dimethyl-4-[7-propoxy-5-(pyridin-3-yloxy)oxazolo[5,4-d]pyrimidine-2-yl]phenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-(2-{4-[5-(2,4-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(S)-1-{2-[2,6-dimethyl-4-(5-phenoxy-7-propoxyethanol[5,4-d]pyrimidine-2-yl)phenoxy]acetyl}pyrrolidin-2-carboxylic acid and

(S)-1-(2-{4-[5-(3-chlorphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid,

where TRANS-2-fertilisations group in the compound (S)-1-(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid can be present in S,S-configuration or R,R-configuration or mixtures of the two forms of grouping in any respect.

Another object of the present invention are methods of obtaining the compounds of formula I and their salts and solvates, which these compounds can be obtained, and which are presented next. In one method, the compound of formula II is subjected to mutually�deystviy with a compound of the formula III, receiving the compound of formula I,

where the groups A, X, Y, R1, R2, R3and R4in the compounds of formulas II and III are defined as in compounds of formula I and additionally functional groups can be present in protected form or in the form of group-predecessor, which is later converted into the final group. Group L1in the compounds of the formula II is a leaving group that can be substituted, using the reaction of nucleophilic aromatic substitutions such as a halogen atom, e.g. a chlorine or bromine atom, or sulphoxide group or sulfonyl group, for example, a group of the formula-S(O)-Alk or-S(O)2-Alk, where Alk is a (C1-C4)-alkyl group, e.g. methyl or ethyl.

The reaction of compounds of formulae II and III represent a reaction of nucleophilic aromatic substitution at the carbon atom in position 5 oxazolo[5,4-d]pyrimidine ring, i.e. pyrimidine group, and it can be carried out under conditions that are standard for such reactions which are well known to specialists in this field. Usually the reaction, depending on the specific conditions under consideration, are in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, CL�reform or dichloroethane, in ether, such as tetrahydrofuran (THF), dioxane, dibutyl ether, Diisobutyl ether or 1,2-dimethoxyethane (DME), in a ketone, such as acetone or butan-2-it, in an ester such as ethyl acetate or butyl acetate, a nitrile such as acetonitrile, amine, such as N,N-dimethylformamide (DMF) 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. Generally, it is desirable to add a base to increase the nucleophilicity of the compound of formula III, for example, tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as a hydride, hydroxide, carbonate or bicarbonate of an alkali metal such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or sitedisability. Before the reaction with the compound of formula II, the compound of the formula III can also separately be treated with base and turn into salt.

The starting materials of formulas II and III can be obtained using the methods disclosed in the literature or analogous to the methods disclosed in the literature, and in many cases they are commercially available. Connect�of formula IIa, i.e., the compound of formula II, where L1represents, for example, sulfoxide group of the formula Alk-S(O)- or sulfonyl group of the formula Alk-S(O)2-, can be obtained by subjecting bimodally aminomalonate ester of formula IV with an activated carboxylic acid derivative of the formula V, receiving the compound of formula VI, exposing the interaction of the latter compound with thiourea of the formula VII, receiving the compound of formula VIII, alkylating the thiol alkylating reagent of the formula IX, getting a thioether of the formula X, by cyclization of the latter compound with formation of the system oxazolo[5,4-d]pyrimidine ring, receiving the compound of formula XI, alkylating last connection on the oxygen atom of ketogroup or tautomeric hydroxyl group using an alkylating reagent of the formula XII by introducing the group R"O-C(O)-X - in the compound of formula XIII, using the reaction with a compound of the formula XIV, removing the protective group of the obtained compound of the formula XV, getting a carboxylic acid of the formula XVI by introducing the group R4O-C(O)-Y-, using a reaction with a compound of the formula XVII and oxidizing the thioether group in the resulting compound of formula XVIII, receiving the corresponding sulfoxide or sulfone of the formula IIa.

The order of introduction of the structural elements during the synthesis of compounds of formula I may also bitration; for example, in the compound of the formula XV thioether group can first be oxidized, yielding the corresponding sulfoxide or sulfone of the formula XIX, wherein L1represents-S(O)-Alk or-S(O)2-Alk, and the grouping-A-R3you can enter using the reaction with a compound of the formula III and the compounds of formula XX can remove the protective group, getting a carboxylic acid of the formula XXI, and the grouping R4O-C(O)-Y - you can enter using the reaction with the compound of formula XVII, receiving the compound of formula I.

Groups A, X, Y, R1, R2, R3and R4in the compounds of formulas IIa, V, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX and XXI are defined as for compounds of formula I and additionally functional groups can be present in protected form or in the form of group-predecessor, which is later converted into the final group. Group of Xain compounds of formula XIV has the same meaning as the group X in the compounds of formula I, or comprises part of the group X in the desired compound of formula II, such that after the reaction of compounds of formulas XIII and XIV of group Xaand any part of groups FG1and FG2,remaining in the compound of formula XV, together form the desired group X. for example, if the group X is alcantarillado, group Xain the compound of the formula IV may be desired alcadeias group and group FG 2may be a hydrogen atom attached to the oxygen atom, or a group of Xscan be elendilmir fragment, group FG2represents a leaving group and group FG1in the compound of the formula XIII represents a hydroxyl group, an oxygen atom, which, together with elendilmir fragment then, after the alkylation of a compound of formula XIII, compound of formula XIV, forms need alcadeias group.

Group FG1and FG2in the compounds of formulas V, VI, VIII, X, XI, XIII and XIV represent functional groups that can be used for the specified type of reaction combinations used to form the desired group X group Xaand any part group FG1and FG2remaining in the compound of formula XV. If, for example, group Xaattach the reaction of nucleophilic substitution to the group R2or to the atom in the group FG1such as the oxygen atom in the hydroxyl group, representing FG1as described above, FG2can be a leaving group such as a halogen atom such as chlorine, bromine or iodine, or sulfonyloxy, such as methansulfonate, triftormetilfullerenov or toluensulfonate. If the group Xaattached to the group R2the reaction catalyzed by a transition metal, FG2/sup> can be a leaving group, such as group Bronevoy acid, broowaha ether, dialkylamino or stannane, and in this case FG1can be a halogen. FG2it can also be a hydrogen atom or a carbon atom that is part of a double bond in allendales group representing Xaif they use the reaction Hyuk to bind Xawith R2and in this case FG1can be a halogen. If they use the reaction of Wittig or reaction Wittig-Horner to bind Xawith R2, FG2can be phosphonopropyl, such as triphenylphosphine or postonline group such as diethylphosphinic, and the compound of formula XIV can be salt or ester of phosphonic acid, and in this case FG1may be aldehyde group-C(O) H or ketone group-C(O)-alkyl, and Vice versa.In General, the group FG1located at the carbon atom in the phenylene group or a heterocyclic group, which is an R2that is, in the compounds of formulas XV, IIa and I, substituted by a group X. Group FG1in the compounds of formulas V, VI, VIII, X and XI can also be present in protected form or in the form of group-predecessor, which is later converted into the group which in the compound of the formula XIII is reacted with a compound of formula XIV. So, for example, hydroxyl group performance�et a FG 1in the compound of the formula XIII may be present in protected form in the compounds of formulas V, VI, VIII, X and XI, for example, in the form of esterified hydroxyl group, such as benzyl ether or alkyl ether such as methyl ether. Such esters can be split, using methods that are well known to specialists in this field. Review of methods for removing protective groups can be found in the literature, for example in P. J. Kocienski, Protecting Groups (Thieme Veriag, 1994), or T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis (John Wiley & Sons, 1999).

Group L1in the compounds of formulas IIa and XIX has the above values. Group L2in the compounds of the formula V is nucleophilic substitutable leaving group, and may be in particular a halogen atom such as chlorine or bromine, and the compound of the formula V can also be carbonylchloride. L2it can also be a group of the formula R2-C(O)-Oh, and the compound of formula V can thus be, for example, a carboxylic acid anhydride. Group L3and L4represent leaving groups which can be replaced using a nucleophilic substitution reaction, and can be in particular by halogen atoms such as chlorine, bromine or iodine, or sulfonyloxy, such as methansulfonate, triftormetilfullerenov or toluensulfonate, i.e. compounds of formulas IX and XII can be �of primer, organic halides or sulfonates. The group R' in the compounds of formulas IV and VI may be alkyl, such as, for example, (C1-C3)-alkyl, such as methyl or ethyl. The group R" in the compounds of formulas XIV, XV, XIX, and XX is a group that can be used to protect the carboxylic acid function as an ether, for example, (C1-C4)-alkyl group such as methyl, ethyl or tert-butyl, or benzyl group. As indicated, the compounds of formula XI may also be present in another tautomeric form, for example in the form of corresponding derivatives of 7-hydroxyanisole[5,4-d]pyrimidine, where the movable hydrogen atom, in formula XI is attached to the nitrogen atom of the ring in 6-position system oxazolopyridine ring attached to the oxygen atom linked to a carbon atom of the ring in position 7. If applicable, this applies to all compounds involved in the formation of compounds of formula I, which may be present in tautomeric form, different from that provided in their formulas. In the reactions of the process of producing compounds of the formula II, as in all other reactions involved in the formation of compounds of formula I, the starting materials can also be used in the form of salts and/or products can be obtained in the form of salts. So, for example, compounds of formula IV can be in the form of salt accession acid, such as hydrochloride.

The reaction of compounds of formulas IV and V can be carried out in standard conditions of acylation of an amine activated carboxylic acid derivative, such as galoyanized or anhydride. Usually the reactions are in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, an ether such as THF, dioxane, dibutyl ether, Diisobutyl ether or DME, in a ketone, such as acetone or butan-2-it, in an 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 of the lead, adding a base, e.g. a tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholin or inorganic base, such as hydroxide, carbonate or bicarbonate of an alkali metal, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate. The reaction of compounds of formulas VI and VII are usually run in an inert solvent, e.g. an alcohol, such as methanol, ethanol or isopropanol, or an ether, such as THF, dioxane or DME, or a mixture of solvents, at temperatures from about 20°C to about 80°C, for example at temperatures from about 40°C d� about 80°C, in the presence of base, for example, alkoxide, such as sodium methoxide, ethoxide sodium methoxide or potassium tert-butoxide potassium.

The reaction of compounds of formulae VIII and IX is a reaction of nucleophilic substitution at the carbon atom in the group Alk, which contains the group L3and the reaction can be carried out under standard conditions for such reactions which are well known to specialists in this field. Usually the reaction, depending on the specific conditions under consideration, are in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, an ether such as THF, dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone or butan-2-it, in an ester such as ethyl acetate or butyl acetate, a nitrile such as acetonitrile, in amide, such as DMF or NMP, or mixtures of solvents, including a two-phase mixture with the aqueous solutions, at temperatures from about -20°C to about 100°C, for example at temperatures from about -10°C to about 30°C. Generally, it is desirable to add a base to increase the nucleophilicity of the compounds of the formula VII and/or to bind the acid liberated during the reaction, for example, a tertiary amine, such as Tr�ethylamine, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as a hydride, hydroxide, carbonate or bicarbonate of an alkali metal such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or sitedisability. Before the reaction with the compound of formula IX, compound of formula VIII can also separately be treated with a base, turning it into salt.

The cyclization of compounds of formula X to compounds of the formula XI conduct in the presence of a halide of phosphorus compounds such as phosphorus pentachloride or phosphorus oxychloride or mixtures thereof, in an inert solvent, e.g., hydrocarbon or chlorinated 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.

The reaction of compounds of formulas XI and XII represents a different reaction of nucleophilic substitution at the carbon atom in the group R1that contains the group L4and this reaction can be carried out under conditions that are standard for such reactions which are well known to specialists in this field. Usually the reaction depending on the specific conditions under consideration, lead in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, an ether such as THF, dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone or butan-2-it, in an ester such as ethyl acetate or butyl acetate, a nitrile such as acetonitrile, amide, such as DMF or NMP, or in a mixture of solvents, at temperatures from about 20°C to about 100°C, for example at temperatures from about 40°C to about 80°C. Generally, it is desirable to add a base to increase the nucleophilicity of the compound of formula XI and/or to bind the acid liberated during the reaction, for example, tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as a hydride, hydroxide, carbonate or bicarbonate of an alkali metal such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or sitedisability. Before the reaction with the compound of the formula XII, the compound of formula XI can also separately be treated with a base, turning e�about in salt. The compound of formula XI can be obtained not only by using a reaction with a compound of the formula XII, but it is also possible to carry out the transformation using the reaction with the corresponding alcohol of formula R1-OH, where R1has the values defined for compounds of formula I, functional groups can optionally be present in protected form or in the form of group-predecessor, under the reaction conditions Mitsunobu in the presence of azodicarboxylate, such as diethylazodicarboxylate or diisopropylcarbodiimide, and phosphine, such as triphenylphosphine or tributylphosphine in an inert aprotic solvent, e.g. an ether, such as THF or dioxane, in the compound of the formula XIII (see O. Mitsunobu, Synthesis (1981), 1-28).

The reaction of a combination of a compound of formula XIII with compounds of formula XIV can be carried out by using the reaction of various types, as already mentioned above, for example, using the alkylation reaction. Thus, the group R2for example, if it contains a hydroxyl group, which is an FG1, to alkylate using a compound of the formula XIV, where FG2represents a leaving group, which can be used in the reaction of nucleophilic substitution, such as a halogen atom such as chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonate or toluensulfonate. Response, which will�Yu nucleophilic substitution at the carbon atom of the group XIV, which contains the group FG2can be carried out under conditions that are standard for such reactions which are well known to specialists in this field. Usually a specified reaction, depending on the specific conditions under consideration, are in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon, such as benzene, toluene, xylene, chlorobenzene, dichloro methane, chloroform or dichloroethane, an ether such as THF, dioxane, dibutyl ether, Diisobutyl ether or DME, an alcohol such as methanol, ethanol or isopropanol, a ketone such as acetone or butan-2-it, in an ester such as ethyl acetate or butyl acetate, a nitrile such as acetonitrile, in amide, such as N,N-dimethylformamide or N-methylpyrrolidine-2-it, or in a mixture of solvents, at temperatures from about 20°C to about 100°C, for example at temperatures from about 40°C to about 80°C. Generally, it is desirable to add a base to increase the nucleophilicity of the compound of formula XIII and/or to bind the acid liberated during the reaction, for example, tertiary amine such as triethylamine, ethyldiethanolamine or N-methylmorpholine, or an inorganic base such as a hydride, hydroxide, the carbonate or bicarbonate of an alkali metal such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate �whether sodium bicarbonate, or an alkoxide or amide such as sodium methoxide, ethoxide sodium, potassium methoxide, tert-butoxide potassium, sodium amide or sitedisability. Before the reaction with the compound of formula XIV, compound of formula XIII, where FG1represents hydroxyl, can also separately be treated with a base and turn it into a salt. The compound of the formula XIV, where FG1represents hydroxyl, can be converted into a compound of formula XV, using not only the reaction with the compound of the formula XIV, where FG2represents a leaving group, as indicated in the description, but also, using the reaction with the corresponding alcohol, i.e. a compound of the formula XIV, where FG1represents a hydroxyl, in the conditions of the above reaction Mitsunobu. The reaction of a combination of a compound of formula XIII with compounds of formula XIV, using a reaction catalyzed by a transition metal, can also lead in terms of the reaction cross-combination, catalyzed by palladium, such as the reaction of a combination of Hake, Steele or Suzuki (see A. de Meijere and F. Diederich (Ed.), Metal-Catalyzed Cross-Coupling Reactions (Wiley-VCH, 2004)).

The removal of protective groups, R"is a protected carboxylic acid group in the compounds of formula XV to obtain the compounds of formula XVI can be done by standard methods that are well known to specialists in this field and summarized in the above-mentioned books by P. J. Kocenski and T. W. Greene and P. G. M. Wuts, for example, in the basic conditions by treatment with an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide, in the case of compounds in which R" represents an alkyl group such as methyl or ethyl, by treatment with trifluoroacetic acid, in the case of compounds in which R" is a tert-butyl group, or by hydrogenation in the presence of a catalyst is a transition metal such as palladium-on-charcoal, in the case of compounds in which R" is a benzyl group.

For insertion of the fragment R4O-C(O)-Y-, group, carboxylic acid HO-C(O)- in compounds of the formula XVI is typically activated in situ using conventional amide linking reagent, or into a reactive carboxylic acid derivative, which can be obtained in situ or highlight. For example, the compound of formula XVI can be converted into gelegenheid by processing thionylchloride, with phosphorus pentachloride, tribromide phosphorus or oxaliplatin, or handle alkylchlorosilanes, such as ethylchloride or isobutylbarbituric to obtain the mixed anhydride. Normal linking reagents that can be used are: papapostolou anhydride, N,N'-carbonyldiimidazole, such as N,N'-carbonyldiimidazole (CDI), carbodiimide, such as 1,3-diisopropylcarbodiimide(DIC), 1,3-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbodiimides together with additives like 1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-asobancaria (HOAT), binding agents based on Urania, such as O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HATU), O-(benzotriazole-1-yl)-N,N,N '-tetramethylpropylenediamine (HBTU) or O-(cyano(ethoxycarbonyl)methylamino)-N,N,N',N'-tetramethylethylenediamine (TOTU), and binding agents on the basis of phosphonium, such as (benzotriazole-1-yloxy)Tris(dimethylamino)fosfodiesterasa (BOP), benzotriazole-1-yloxy) (PyBOP) or (PyBroP).

Conditions of reactions to obtain the compounds of formula XVIII from compounds of formulas XVI and XVII depend on the specific context under consideration, for example, the reagent used, and they are well known to specialists in this field. For example, in case of activation of a compound of formula XVI using acid chloride or bromohydrin, the combination reaction with a cyclic amine of the formula XVII are usually run in an inert solvent, e.g., hydrocarbon or chlorinated hydrocarbon or ether similar to the above, in an ester such as ethyl acetate or butyl acetate, a nitrile such as �clonicel, in water, or in a mixture of solvents including a mixture of water and miscible or immiscible with water, an organic solvent, at temperatures from about -10°C to about 100°C, especially at temperatures from about 0°C to about 80°C, e.g. at room temperature. Appropriate response allhelgona derived from carboxylic acids of formula XVI with a compound of formula XVII to conduct in the presence of base such as a tertiary amine, such as triethylamine, ethyldiethanolamine, N-methylmorpholine or pyridine, or inorganic bases such as hydroxide, carbonate or bicarbonate of an alkali metal, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate. In case of activation of the carboxylic acid group in the compounds of formula XVI using amide linking agent, such as, for example, carbodiimide or TOTU, the reaction is usually run in an anhydrous conditions in an inert aprotic solvent, e.g. an ether, such as THF, dioxane or DME, or amide, such as DMF or NMP, at temperatures ranging from about -10°C to about 80°C, especially at temperatures from about 0°C to about 60°C in the presence of base such as a tertiary amine, such as triethylamine, ethyldiethanolamine or N-methylmorpholin. If the compound of formula XVII is used in the form of salt accession acid, for the reaction with the compound of formula� XVI, usually add the amount of base sufficient for the isolation of a compound of formula XVII in a free form.

Oxidation of Alk-S group in the compounds of formula XVIII to a sulfoxide group or sulfone in the compounds of formula IIa can be done by using hydrogen peroxide or percolate, such as 3-chloroperbenzoic acid or monoperoxyphthalic acid, in an inert solvent, e.g. in a chlorinated hydrocarbon such as dichloro methane or chloroform, or ester, such as ethyl acetate or butyl acetate, at temperatures from about 0°C to about 40°C, for example, at a temperature of about 20°C.

The above explanation of the oxidation of compounds of formula XVIII to compounds of formula IIa are applicable, respectively, to the oxidation of compounds of formula XV to compounds of the formula XIX, and similarly, the explanations given for the reaction of compounds of formulas II and III, to remove the protective groups at the carboxylic acid group in the compounds of formula XV and for the reaction of compounds of formulas XVI and XVII, respectively applicable to the reaction of the compounds of formulas XIX and III, to the removal of the protective groups of carboxylic acid groups in the compounds of the formula XX by reaction of compounds of formulas XXI and XVII.

Other stage of obtaining compounds of formula X can also be changed, and aminomalonate ester of formula IV, such as diethyl ether complex, you can first put�ü interaction in the presence of alkali metal alkoxide, such as ethoxide sodium, thiourea, and the sulfur atom can then alkylate, for example, to metilirovanie iodomethane, and the resulting product can be allievate compound of formula V (see M. H. Holschbach et al., Eur. J. Med. Chem. 41 (2006), 7-15).

Other compounds of formula I can be obtained from the corresponding compounds obtained in accordance with the disclosures above processes by functionalization or modification of any existing functional groups in accordance with standard procedures, for example, by conversion to an ester, by amidation, hydrolysis, etherification, alkylation, acylation, sulfonylamine, recovery, oxidation, conversion into salts, and other ways. For example, a hydroxyl group, which can be extracted from the ether groups in the ether cleavage, for example, using trichromate boron, or a protected hydroxyl group by removing the protective group, can be converted into an ester, getting ether carboxylic acids or ether sulfonic acids, or atrificial. The esterification of the hydroxyl group can be successfully accomplished by alkylation with the respective halogen compound, e.g., bromide or iodide, in the presence of base, e.g. an alkali metal carbonate such as potassium carbonate or cesium carbonate, in an inert� solvent, for example, in an amide such as DMF or NMP or a ketone like acetone or butan-2-he, or the corresponding alcohol under the reaction conditions Mitsunobu mentioned above. Hydroxyl group can be converted into a halide by treatment with halogenous agent. A halogen atom can be replaced by different groups in substitution reactions, which can also be a reaction catalyzed by a transition metal. The nitro group can be restored to the amino group, for example, using catalytic hydrogenation. An amino group can be modified under standard conditions for alkylation, for example using the reaction with the halogen compound, or using reductive amination of a carbonyl compound, or for acylation or sulfonylurea, for example, using a reaction with a reactive carboxylic acid derivative such as acid chloride or acid anhydride or sulfonic acid chloride, or with an activated carboxylic acid, which can be obtained from the carboxylic acids as a result of processing a bonding agent such as CDI, carbodiimides, such as DCC or EDC, HATU, TOTU, TBTU. The ester group of carboxylic acid to hydrolyze in acidic or alkaline conditions, yielding the carboxylic acid. The carboxylic acid group can be activated or turned into a reactive derivative, �AK stated above, and to carry out the reaction with an alcohol or an amine or ammonia to obtain ester or amide. Primary amide can be degidratiruth to obtain the nitrile. A sulfur atom, for example, alkyl-S group or a heterocyclic ring may be oxidized by the peroxide, such as hydrogen peroxide, or percolate to obtain sulfoxide fragment S(O) or sulfonic fragment S(Oh)2. The carboxylic acid group, ester group of carboxylic acid and a ketone group can be restored to the alcohol, for example, using a complex hydride such as a hydride, litebrite or detribalized. The compound of formula I or an intermediate connection, such as a compound of the formula II, which contains a double bond or triple bond in the group X, which can be easily obtained using the combination reaction catalyzed by a transition metal, a compound of formula XIV, which contains a double or triple bond in the group Xaand the compound of formula XIII in accordance with the above description can be converted by hydrogenation in the presence of a hydrogenation catalyst such as palladium catalyst, the compound wherein X is a saturated group.

All reactions used in the above methods of synthesis of compounds of formula I, by themselves, well known in the art, and can implement�yield at standard conditions in accordance with the procedures described in the literature, or in similar conditions, for example, see Houben-Weyl, Methoden der Organischen Chemie (Mewthods of Organic Chemistry), Thieme-Veriag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York. If desired, the obtained compounds of formula I, as well as any intermediate compounds, can be cleaned using normal cleaning methods, for example, by recrystallization or by chromatography. As already mentioned, the starting compounds and intermediate compounds used in the above-described methods of synthesis which contain an acidic or basic group, can also be used in the form of salts, and all the intermediate and final target compound can also be obtained in the form of salts. Similarly, as indicated above, depending on the conditions of the specific options to avoid unwanted course of the reaction or side reactions during the synthesis of the compounds, it is usually necessary or advantageous to temporarily block functional groups by introducing protective groups and deleting them at a later stage of the synthesis, or by introducing functional groups in the form of groups of precursors which are later converted into the desired functional groups. As examples of protective groups you can specify aminosidine group, acyl group or allyloxycarbonyl group, e.g., tert-butyloxycarbonyl group (= Boc), Kotor�Yu can be removed by treatment with trifluoroacetic acid (= TFA), benzyloxycarbonyl group that can be removed using catalytic hydrogenation, fluoren-9-yl-methoxycarbonyl group, which can be removed by treatment with piperidine, and the protective group of carboxylic acid groups which can be protected as an ester group, such as tert-butyl esters, and such protective groups can be removed by treatment with trifluoroacetic acid, or benzyl esters, and such a protective group can be removed using catalytic hydrogenation. As an example, the group's predecessor, you can specify the nitro group which can be converted into an amino group by restoring, for example, using catalytic hydrogenation. Such strategies of synthesis and protecting groups and groups of precursors that can be used in the specific case, well known to specialists in this field.

Another object of the present invention are the new starting compounds and intermediate compounds, which occur during the synthesis of compounds of formula I, including compounds of formulas II, IIa, III, IV, V, VI, VIII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX and XXI, where A, X, Xa, Y, R1, R2, R3, R4, R', Alk, FG1, FG2, L1, L2and L4I have the values defined above, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any� respect, and their salts and solvates of such compounds or such salts, and their use as intermediates. The present invention also includes all tautomeric forms of these intermediate compounds and parent compounds. All the above explanations and the above variations in relation to compounds of formula I also apply respectively to said intermediate compounds, and source materials. The object of the present invention are particularly disclosed in the description of a new specific starting compounds and intermediate compounds. Regardless of whether they are opened as free compounds or as a specific salt, they are the subject of the present invention, in the form of free compounds or in the form of their salts, and if disclosed to a specific salt, in addition to form of this specific salt, and in the form of solvates of such compounds or such salts.

Compounds of formula I, optionally in combination with other pharmacologically active compounds, can introduce animals, especially mammals, including humans, as pharmaceuticals

means, in mixtures with one another or in the form of pharmaceutical compositions. Such administration can be done orally, for example in the form of tablets, film-coated tablets, sugar-coated, granules, hard and soft �latinovich capsules fluids, including water, alcohol and oily solutions, juices, drops, syrups, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of solutions for subcutaneous, intramuscular or intravenous injection or infusion, especially aqueous solutions. Compounds of formula I can optionally be used for local drug delivery, for example, stents coated to prevent or reduce in-stent restenosis, or entering their premises by means of a catheter. Suitable forms of administration depend, among others, be treated from the disease and its severity.

Specific amount of a compound of formula I and/or physiologically acceptable salts and/or solvates present in the pharmaceutical compositions is usually in the range from about 0.2 to about 800 mg, e.g., from about 0.5 to about 500 mg, e.g., from about 1 to about 200 mg, in single dose, but depending on the type of pharmaceutical composition, it may also be higher. Pharmaceutical compositions generally include from about 0.5 to about 90% by weight. compounds of the formula I and/or physiologically acceptable salts and/or solvates. Obtaining pharmaceutical compositions can be effected by methods known in themselves. For this purpose, one or more compounds �of ormula I and/or physiologically acceptable salts and/or solvates together with one or more solid or liquid pharmaceutical substances carriers or means of delivery and/or additives or excipients and, if necessary a combination of medicines and other pharmacologically active compounds having therapeutic or prophylactic action, are prepared in a suitable introduction to the form, and in doses that can be used in medicine or veterinary medicine. As substances carriers and additives can be used suitable organic and inorganic substances which do not react in an undesirable way with the compounds of the formula I or their physiologically acceptable salts or solvates. As examples of the types of additives that may be contained in the pharmaceutical compositions and medicines, you can specify lubricants, preservatives, thickeners, stabilizers, disintegrant, wetting agents, agents for achieving a depot effect, emulsifiers, salts, for example, to change the osmotic pressure, buffer substances, colorants, flavoring agents and fragrances. Examples of substances carriers and additives include water, physiological saline, vegetable oils, waxes, alcohols such as ethanol, isopropanol, 1,2-PROPANEDIOL, benzyl alcohol or glycerol, polyols, mannitol, polyethylene glycols, polypropylenglycol, glyceryltrinitrate, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose, glucose, sugar�rose, or starch, such as corn starch, stearic acid and its salts, such as magnesium stearate, talc, lanolin, petrolatum, or mixtures thereof, e.g. mixtures of water with one or more organic solvents, such as mixtures of water with alcohols. Compounds of formula I and their physiologically acceptable salts and solvates can also be liofilizirovanny and the resulting freeze-dried products to use to get, for example, compositions for injection.

Doses of the compounds of the formula I and/or their physiologically acceptable salts and/or solvates varies from case to case and usually adapts their physician in accordance with accepted rules and procedures for specific circumstances, to achieve an optimal effect. Doses depend, for example, the nature and severity of the subject to treatment of the disease, gender, age, weight and individual responsiveness of the patient, human or animal, the effectiveness and duration of action of the compounds used, on whether the treatment the treatment of acute or chronic disease or prophylactic, or on whether other active ingredients in addition to the compound of formula I. the daily dose is from about 0.01 mg/kg to about 100 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg, or from about 0.3 mg/kg to about 5 mg/kg (in each case per kg of body weight), nab�emer, it corresponds to the dose for administration to an adult weighing about 75 kg to achieve the desired results. Daily dose can be administered in a single dose, or, especially if injected large quantities, divided into several doses, for example two, three or four separate doses.

The introduction can also be performed continuously, for example, by continuous infusion or injection. Depending on individual behavior in a particular case, it may be necessary to increase or decrease the indicated dosages.

The following are examples which illustrate the invention.

If illustrative compounds containing main group, purified by high performance liquid chromatography (HPLC) on a column with reversed phase (RP) and, as usual, carry out gradient elution with a mixture of water and acetonitrile containing trifluoroacetic acid (TFA), and some of them get in the form of their salts accession trifluoroacetic acid, depending on the details of the processing conditions such as evaporation or lyophilization. In the title compounds of examples and in their structural formulas no so obtained, trifluoroacetic acid is not specified.

The obtained compound is usually characterized by spectral data and chromatographic data, especially mass spectra (M�) and HPLC retention times (R tin minutes, receiving, combining analytical HPLC/MS characterization (LC/MS), and/or using the spectra of nuclear magnetic resonance (NMR). Features of the NMR spectra contain information about the chemical shifts δ (in M. D.), the number of atoms of hydrogen and multiplestore (s = s = singlet, d = d = doublet, dd = DD = doublet of doublets, t = t = triplet, dt =dt = doublet of triplets, q = kV = Quartet, m = m = multiplet; br = width = extended) signals. Based on the MS spectrum usually result in mass number (m/z molecular ion peak M, e.g. M+, or ion source, such as the ion M+1, for example, [M+1]+, i.e. the protonated molecular ion [M+H]+, which is formed depending on the ionization method. Usually use the method of ionization by electrospray (ESI). Use the following conditions LC/MS.

Method IH

Column: UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow 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 in 1.1 min, then from 95% B to 95% A + 5% B within of 0.6 min; MS ionization method: ESI+

Method IH

Column: UPLC BEH C18, 50×2.1 mm, 1.7 μm; flow rate: 0.9 ml/min; eluent A: acetonitrile + 0.035% for formic acid; eluent B: water + 0.05% of formic acid; gradient: from 5% A + 95% B to 95% A + 5% B in 1.1 min, then 95% A + 5% B within of 0.6 min; MS ionization method: ESI+

Method IH

Example 1

(S)-1-(2-{4-[5-(2,5-Divergence)-7-propoxyethanol[5.4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(a) Diethyl 2-(4-methoxy-3,5-dimethylbenzylamine)malonate

Of 116.8 g of diethylaminoethylcellulose dissolved in 700 ml of dichloromethane, and 231 ml of triethylamine are added while cooling on an ice bath. Then slowly added dropwise a solution of 109,6 g of 4-methoxy-3,5-dimethylbenzonitrile in 400 ml of dichloromethane. After 2 h at 0°C, slowly add 200 ml of water. After phase separation, the aqueous phase twice extracted using 200 ml of dichloromethane. The combined organic phases were washed with 2M hydrochloric acid and then with water, dried over sodium sulfate, filtered and evaporated. The obtained residue was treated with methyl tertiary butyl ether, after which the resulting precipitate is filtered off, getting as a result of 178.7 g specified in the header connection.

(b) Sodium 4,6-dihydroxy-5-(4-methoxy-3,5-dimethylbenzylamine)pyrimidine-2-tiolet

1.5 equivalent of sodium methoxide solution 30% fortress in methanol) is added to 20,6 g of thiourea in 900 ml �no comment. no comment of ethanol. After adding 91 g of diethyl 2-(4-methoxy-3,5-dimethylbenzylamine)malonate small portions, the mixture was stirred at 60°C for 3 hours. The resulting mixture was then cooled to room temperature, and the precipitate is filtered off with suction, washed with 100 ml of ethanol and 100 ml of diethyl ether and dried under reduced pressure. Get up 78.2 g of crude specified in the header connection.

(c) N-(4,6-Dihydroxy-2-methylsulfonylamino-5-yl)-4-methoxy-3,5-dimethylbenzamide

To 19.1 g of sodium 4,6-dihydroxy-5-(4-methoxy-3,5-dimethylbenzylamine)pyrimidine-2-thiolate in 190 ml of water and 80 ml of N-methylpyrrolidine 2-butanone were cooled to 0°C. When cooling is added 5.9 g of sodium hydroxide, after which the resulting mixture was stirred at 0°C for 30 min Then added a solution of 3.7 ml iodomethane 4.3 ml of N-methylpyrrolidine-2-one. After completion of the reaction (2 hours), the mixture was acidified with concentrated hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and dried under reduced pressure. Get a 10.1 g specified in the header connection.

LC/MS (Method IH): Rt=1,03 min; m/z=336,1 [M+H]+

(d) 2-(4-Methoxy-3,5-dimethylphenyl)-5-methylsulfonylamino[5,4-d]pyrimidine-7-ol

To 10.1 g of N-(4,6-dihydroxy-2-methylsulfonylamino-5-yl)-4-methoxy-3,5-dimethylbenzamide in 55 ml of phosphorus oxychloride was heated at 60°C in t�within 3 hours. After cooling, the resulting solid portion was filtered off with suction and washed with methyl tert-butyl ether. Then the solid is dissolved in a mixture of dichloromethane and tetrahydrofuran, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated under reduced pressure. Get 5.9 g specified in the header connection.

LC/MS (Method IH): Rt=1,24 min; m/z=318,08 [M+H]+

(e) 2-(4-Methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-7-propoxyethanol[5,4-d]pyrimidine

5.9 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfonylamino[5,4-d]pyrimidine-7-ol are dissolved in 150 ml of N,N-dimethylformamide, and added 7.7 g of potassium carbonate and then 2.7 g of 1-bromopropane. The resulting solution was stirred at 60°C for 5 hours, and then, after cooling, was poured into 150 ml of water. The resulting precipitate is filtered off with suction. The resulting mixture of stereoisomers purified using chromatographic processing on a column of silica gel (Isolute cartridge with 50 g silica, heptane/ethyl acetate 9/1). In addition to 1.4 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-6-propyl-6H-oxazolo[5,4-d]pyrimidine-7-she (LC/MS (Method IH): Rt=1,43 min; m/z=360,13 [M+H]+), you get 2.5 g specified in the header connection.

LC/MS (Method IH): Rt=1,51 min; m/z=360,13 [M+H]+

(f) 2,6-Dimethyl-4-(5-methylsulfanyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)φ�Nol

At -20°C 0,70 ml trichromate Bora slowly added to a solution of 2.5 g of 2-(4-methoxy-3,5-dimethylphenyl)-5-methylsulfanyl-7-propoxyethanol[5,4-d]pyrimidine in 50 ml of dichloromethane. After 1 hour at -20°C and 2 hours at room temperature, the resulting mixture was quenched by adding saturated aqueous sodium bicarbonate solution, while the temperature was maintained below 5°C. After phase separation, the aqueous phase twice extracted with dichloromethane. The combined organic phases are dried and concentrated under reduced pressure. Get 2.0 g specified in the header connection.

LC/MS (Method IH): Rt=1,41 min; m/z=346,11 [M+H]+

(g)Tert-butyl [2,6-dimethyl-4-(5-methylsulfanyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)phenoxy]acetate

3.20 g of potassium carbonate and then with 0.93 ml of tert-butylbromide added to a solution of 2.00 g of 2,6-dimethyl-4-(5-methylsulfanyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)phenol in 20 ml of N,N-dimethylformamide. The resulting mixture was left to react at 60°C for 1 hour, and then allowed to cool and poured into water.

The resulting precipitate is filtered off with suction and dried under reduced pressure. Get 2,45 g specified in the header connection.

LC/MS (Method IH): Rt=1,52 min; m/z=460,18 [M+H]+

(h) Tert-butyl [4-(5-methanesulfonyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)-2,6-dimethylphenoxy]acetate

250 mg of tert-butyl[2,6-dimethyl-4-(5-methylsulfanyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)phenoxy]acetate are dissolved in 5 ml of dichloromethane. Then at 0°C is added 268 mg of 3-chloroperbenzoic acid, and the resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was treated with 1M aqueous sodium hydroxide solution, the layers were separated, and the organic layer successively twice extracted with dichloromethane. The combined organic phases were washed with an aqueous solution of sodium bisulfite 10% of the fortress, dried over sodium sulfate, filtered and evaporated under reduced pressure. Get 268 mg specified in the header connection. LC/MS (Method IH): Rt=1,38 min; m/z=492,17 [M+H]+

(i) Tert-butyl {4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetate

62 mg of potassium carbonate and 32 mg of 2,5-dipthera is added to a solution of 100 mg of tert-butyl [4-(5-methanesulfonyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)-2,6-dimethylphenoxy]acetate in 1.5 ml N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was then poured into water, neutralized by adding an aqueous solution of sodium bisulfate 10% of the fortress, and twice extracted with ethyl acetate. The combined organic layers dried and concentrated under reduced pressure. After filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified using preparative HPLC, yielding 69 mg specified�about in the header of the connection.

LC/MS (Method IH): Rt=1,47 min; m/z=542,20 [M+H]+

(j) {4-[5-(2,5 Divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy]acetic acid

69 mg of tert-butyl {4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetate was dissolved in 1.6 ml of dichloromethane, and add 0.8 ml of trifluoroacetic acid. After 16 hours the mixture was concentrated and dried by freezing. Get 71 mg specified in the header connection.

LC/MS (Method GH): Rt=1.35 V min; m/z=486,33 [M+H]+

(k) Tert-butyl (S)-1-(2-{4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylate

60 mg of {4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetic acid dissolved in 1 ml N,N-dimethylformamide, and add 35 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimides, 7 mg of 1-hydroxy-7-isobenzofuranone and 139 μl N,N-diisopropylethylamine, and after 5 minutes, was added 17 mg of tert-butyl L-polinate. After 16 hours at room temperature, add 10 ml of water, whereupon the pH of the resulting mixture was adjusted to 3 by adding 2M aqueous hydrochloric acid and twice extracted with ethyl acetate. The combined organic layers washed with saturated sodium bicarbonate solution and sodium chloride solution, dried and concentrated under reduced �the force. Get 61 mg specified in the header connection.

LC/MS (Method IH): Rt=1,46 min; m/z=639,26 [M+H]+

(i)(S)-1-(2-{4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

59 mg of tert-butyl (S)-1-(2-{4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylate was dissolved in 1.2 ml of dichloromethane, and added 0.5 ml of trifluoroacetic acid. After 16 hours at room temperature, the resulting mixture was concentrated under reduced pressure and dried by freezing. Get 53 mg specified in the header connection.

LC/MS (Method IH): Rt=To 1.36 min; m/z=583,19 [M+H]+

Example 2

(S)-1-(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

(a) Tert-butyl {4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetate

In an argon atmosphere and at 0°C, 26 mg of TRANS-2-forceclosure was added to a suspension of 10 mg of sodium hydride (60% in mineral oil) in 2 ml of N,N-dimethylformamide. After 15 minutes, slowly add a solution of 100 mg of tert-butyl [4-(5-methanesulfonyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)-2,6-dimethylphenoxy]acetate in 1 ml of N,N-dimethylformamide. After 12 hours at room�a combined temperature the mixture was quenched, adding water and twice extracted with ethyl acetate. The combined organic layers dried and concentrated under reduced pressure. Get 101 mg specified in the header connection.

LC/MS (Method IH): Rt=1,49 min; m/z=530,26 [M+H]+and 552,26 [M+Na]+

(b) {4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetic acid

98 mg of tert-butyl {4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetate was dissolved in 3.5 ml of dichloromethane, and treated with 1.5 ml of trifluoroacetic acid. After 16 hours the mixture was concentrated and dried by freezing. Get 96 mg specified in the header connection. LC/MS (Method IH): Rt=1,35 min; m/z=474,20 [M+H]+

(c) Tert-butyl (S)-1-(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylate

82 mg of {4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetic acid was added to 1.5 ml of N,N-dimethylformamide, and 48 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimides, and add 10 mg of 1-hydroxy-7-isobenzofuranone and 195 μl of N,N-diisopropylethylamine, and after 5 minutes, was added 24 mg of tert-butyl L-polinate. After 16 hours at room temperature, add 10 ml of water, whereupon the pH of the resulting mixture was adjusted �about 3, adding 2M aqueous hydrochloric acid and twice extracted with ethyl acetate. The combined organic layers washed with saturated sodium bicarbonate solution and sodium chloride solution, dried and concentrated under reduced pressure. Get 79 mg specified in the header connection.

LC/MS (Method IH): Rt=To 1.44 min; m/z=627,31 [M+H]+

(d) (S)-1-(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid

76 mg of tert-butyl (S)-1-(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylate was dissolved in 1.6 ml of dichloromethane and 0.8 ml of trifluoroacetic acid. After 16 hours at room temperature, the resulting mixture was concentrated under reduced pressure and dried by freezing. Get 83 mg specified in the header connection.

LC/MS (Method IH): Rt=1,33 min; m/z=571,25 [M+H]+

Exemplary compounds of formula I listed in Table 1, prepared in a manner similar to the method of producing the exemplary compounds described above. Some of them get in the form of their trifenatate salts.

Table 1
Exemplary compounds formula
ExampleNameLC/MSm/z [M+H]+Rt[min]
3(S)-1-(2-{4-[5-(2-pertenece)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1565,381,32
4(S)-1-(2-{4-[5-(5-fluoro-2-methylphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1579,401,36
5(S)-1-(2-{4-[5-(3-fluoro-4-methylphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1579,421,36
6(S)-1-(2-{2,6-dimethyl-4-[7-propoxy-5-(pyridin-3-yloxy)oxazolo[5,4-d]pyrimidine-2-yl]phenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1546,561,24
7(S)-1-(2-{4-[5-(2,4-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1583,381,36
8(S)-1-{2-[2,6-dimethyl-4-(5-phenoxy-7-propoxyethanol[5,4-d]pyrimidine-2-yl)phenoxy]acetyl}pyrrolidin-2-carboxylic acidLC1547,401,36
9(S)-1-(2-{4-[5-(3-chlorphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1581,121,40
10(S)-1-(2-{4-[5-(3-chlorphenoxy)-7-atoxicity[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC2567,151,37
11(S)-1-(2-{4-[7-ethoxy-5-(3-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC2551,151,33
12(S)-1-(2-{4-[7-ethoxy-5-(2-pertenece)oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC2551,161,32
13(S)-1-(2-{4-[5-(2,5-divergence)-7-atoxicity[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC2569,161,33
14(S)-1-(2-{4-[7-ethoxy-5-(5-fluoro-2-methylphenoxy)oxazolo[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acidLC1565,261,23
15(S)-1-[2-(2,6-dimethyl-4-{5-[methyl-(3,3,3-cryptochromes)amino]-7-propoxyethanol[5,4-d]pyrimidine-2-yl}phenoxy)acetyl]pyrrolidin-2-carboxylic acidLC3580,250,80
16(S)-1-{2-[4-(5-cyclobutylmethyl-7-propoxyethanol[5,4-d]pyrimidine-2-yl)-2,6-dimethylphenoxy]acetyl}pyrrolidin-2-carboxylic acidLC3539,25 0,81

Definition of pharmacological activity

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

To determine Edg 1 receptor activation by the compounds of the present invention uses GTP-γ-S ((GTP-γ-S = guanosine 5'-[thio]triphosphate) analysis of binding to a conjugate with G-protein receptor on the basis of the principle of scintillation analysis of convergence, using a preparation of cell membranes from cell lines CHO FIp-In which constitutive sverkhekspressiya human Edg 1 receptor.

(a) Establishment of cell lines

FIp-In™ expression system (Invitrogen, cat. no. K6010-01) allows you to create a stable mammalian cell lines in which the gene of interest is integrated in the result of a homologous recombination at a specific position in the genome, called Milenium site FIp recombination (FRT) using FIp recombinases encoded by the expression plasmid pOG44. Integration of gene-expression constructs pcDNA5/FRT into the genome of the cell line host FIp-In leads to transcription of the gene of interest. Consistently transfetsirovannyh cells become resistant to hygromycin.

One day before transfection, 200 000 FIp-In CHO cells seeded in Ham F-12 medium (Invitrogen, cat. no. 31765) supplemented with 10% fetal calf serum (FCS; Perbio Science, cat. no. SH30068.03) in 6-well plates and incubated in �conditions 37°C/5% CO 2in the course of the night. Using FuGENE® 6 transfection reagent (Roche, cat. no. 11988387001) cells together transferout with the expression plasmid FIp recombinases pOG44 and a modified plasmid, further comprising edg 1 gene (registration number no. NM_001400) called pcDNA5-FRT-TO_nFLAG_DEST-EDG 1, in the ratio of 9:1. To obtain the modified pcDNA5-FRT-TO_nFLAG_DEST Invitrogen plasmids the plasmid pcDNA5/FRT/TO (Invitrogen, cat. no. V6520-20) adapted for Gateway® (Invitrogen) cloning system, embedded Gateway cassette containing attR recombination sites flanking ccdB gene, and the gene for resistance to chloramphenicol (Gateway conversion system, Invitrogen, cat. no. 11828-029). In addition, a FLAG epitope tag is added prior to 5' att recombination site to provide recombinant expression of FLAG-tagged N-Terminus of proteins.

For transfection of one of the wells 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 μl of transfection reagent FuGENE® 6. After 20 minutes of incubation, the complex of transfection reagent/DNA distribute dropwise on the wells. The plates were incubated for 24 hours at 37°C. Then, cells from three wells is transferred to a T75 flask (Greiner Cellstar®, cat. no. 658175) containing Ham F-12 medium, supplemented with 10% FCS but without antibiotics, and incubated an additional 24 hours. 48 hours after transfection, the medium is replaced selection medium (Ham F-12 supplemented with 10% FCS and 300 µg/ml GI�of romycin B (Invitrogen, cat. no. 10687-010)). The medium is replaced every 2-3 days up until grow a sustainable population of cells. Cells break down several times and seeded into a new flask so that the cells did not reach more than 25% of confluently. After 2 weeks of selection, the cells are transferred into T175 flasks (Greiner Cellstar®, cat. no. 660175) and cultured to obtain party. Cells are harvested from culture flasks, using a short treatment (2-5 minutes) accurate (PAA, cat. no. L11-007), again suspended in selection medium (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) Preparation of membranes

Membrane preparations get by standard methods from the above Cho FIp-In cell lines, constitutive sverkhekspressiya human Edg 1 receptor. In short, cryopreserved cells are placed in culture and grown until confluently in T175 flasks for cell culture (Becton Dickinson, cat. no. 35 5001). Cell culture stop washing it does not contain calcium buferizovannyiy phosphate saline solution (PBS; Gibco, cat. no. 14190), and the cells are harvested with a rubber scraper when cooled to 4°C and not containing calcium PBS supplemented with a cocktail of protease inhibitor (complete protease inhibitor; Roche, cat. no. 1697498; 1 tablet per 50 ml) and then centrifuged at 4°C in the Techa�their 15 minutes at 1100×g (Heraeus Minifuge T). For cell lysis, the precipitate is again suspended in chilled to 4°C in hypotonic buffer consisting of 5 mm HEPES (Sigma-Aldrich, cat. no. H-0981), 1 mm EDTA (disodium salt; Merck, cat. No. 8418), supplemented with a cocktail of protease inhibitors (see above), and the cells kept on ice for another 15 minutes. After lysis of the cells was centrifuged at 4°C for 10 minutes at 400×g (Heraeus Minifuge T). The precipitate ruin in a Dounce homogenizer, diluted with the supernatant from the previous centrifugation and then centrifuged at 4°C for 10 minutes at 500×g (Heraeus Minifuge T) to separate the kernel and still intact cell membranes, which are mainly present in the supernatant. Then the supernatant is diluted with hypotonic buffer and centrifuged (Beckmann, Avanti J251) around 18600×g for 2 hours at 4°C. the membrane After centrifugation the precipitate is again suspended in a storage buffer consisting of 20 mm HEPES; 150 mm NaCl (Merck, cat. no. 6400), 1 mm EDTA (see above), supplemented with a cocktail of protease inhibitors (see above). Selected aliquots of the membrane preparation and stored at -80°C. the protein Concentration in the membrane preparation is determined in the sample, using a commercial protein analysis (Bio-Rad, DC Protein Assay, cat. nos. 500-0113, 500-0114, 500-0115).

(c) GTP-γ-S analysis

Edg 1 membrane preparation obtained in (b) is used in the commercially available kit for the scintillation analysis of sbli�access (SPA) conjugate for binding with G-protein receptor from Amersham Biosciences/GE Healthcare (code RPNQ0210), where is induced by ligand binding35S-radiochango GTP-γ-S with the receptor-containing membranes, which are related to scintillation beads, stimulates the emission of light, and allows us to quantitatively determine the agonistic activity for Edg 1 connection. The analysis is carried out using 96-well plates almost in accordance with the manufacturer's instructions. Before beginning experiments, scintillation beads suspended in revitalising the buffer consisting of Tris-HCl (pH of 7.4) supplemented with 0.1% (mass/volume) sodium azide, and then diluted with ice-analytical buffer (consisting of 20 mm HEPES, 100 mm NaCI, 1 mm EDTA (see above), 1 mm dithiothreitol (DTT), and at pH brought to 7.4) to a final concentration of beads in 30 mg/ml.

In the hole put 10 µl of specific analytical buffer, 10 μl of 100 μm solution of guanozintrifosfata (GDP), and 10 μl of a solution of tested compound in the analytical buffer/dimethylsulfoxide, yielding a final concentration of the tested compound (10 ám. For high concentrations, 10 μl of a solution of sphingosine-1-phosphate (S1P; Sigma, cat. no. S-9666) received in final S1P concentration of 10 μm, and for monitoring low concentrations of 10 ál analytical buffer is added to appropriate wells instead of the resulting solution of the tested compounds. All wells contain the same amount of dimethyl�of sulfoxide. Then 10 μl of a solution of [35S]GTP-γ-S (4 nm) and Edg 1 membrane preparation obtained in (b), (15 μg membrane protein in 100 ál analytical buffer) was added to each well. After incubation tablets at room temperature for 5 minutes, was added 50 µl of specific suspension scintillation beads (30 mg/ml). After an additional incubation period of 45 minutes at room temperature, the plates centrifuged for 10 minutes at 500×g. The quantitative value of [35S]GTP-γ-S binding, and thus the activation of the receptors is measured, the emission of beta particles (MicroBeta, Wallac) for 1 minute. The values correct for the background by subtracting the corresponding values for the control of low concentration. All measurements performed in triplicate. Activation of receptors with a test compound expressed as a percentage of the corresponding high concentration (10 μm S1P; accept as 100% activation). Table 2 lists the observed activation for exemplary compounds at 10 µm.

Table 2
Activation of the receptor Edg 1 compounds of the examples at concentrations of 10 μm at a percentage of the activation with 10 μm S1P
Example% activation
1101
297
396
4110
579
6112
790
8108
9128
1069
11100
1270
1395
1499
1542
1685

From the above results it is seen that the compounds can be successfully used for the treatment of wounds, and particularly for the treatment of impaired wound healing in patients with diabetes.

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

where
A represents O;
X is a (C1-C6)-alcander or (C1-C6)-alcadeias, where the oxygen atom (C1-C6)-alcadeias group attached to the group R2;
Y represents pyrrolidinyl;
R1represents (C1-C4)-alkyl;
R2represents a phenylene, optionally substituted by one or two carbon atoms in the ring are the same or different substituents R22;
R3selected from the group consisting of cycloalkyl-CuH2u- where u = 1; radical of a saturated 3-10-membered monocyclic ring, the phenyl or pyridyl, where the radical of a ring optionally substituted by one or two carbon atoms of the ring substituents R31;
R4represents hydrogen;
R22represents (C1-C4)-alkyl;
R31selected from the group consisting of halogen and (C1-C4)-alkyl.

2. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where X is a (C1-C6)-alcander.

3. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where
R3selected from the group consisting of cycloalkyl-CuH2u- where u = 1, phenyl, or pyridyl, �de radical ring optionally substituted by one or 2 carbon atoms of the ring substituents R 31.

4. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where R3selected from the group consisting of cycloalkyl-CuH2uwhere u is 1, or a radical of a saturated 3-10-membered monocyclic ring, where the radical of a ring optionally substituted by one or two carbon atoms of the ring substituents R31.

5. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where X is a (C1-C6)-alcadeias;
R3selected from the group consisting of cycloalkyl-CuH2u- where u = 1, phenyl, or pyridyl, where the radical of a ring optionally substituted by one or two carbon atoms of the ring substituents R31.

6. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where R31is a halogen.

7. The compound of formula I in any of its stereoisomeric form or its physiologically acceptable salt according to claim 1, where R31represents (C1-C4)-alkyl.

8. The compound of formula I or its physiologically acceptable salt of claim 1 selected from the group consisting of
(S)-1-(2-{4-[5-(2,5-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,b-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1(2-{4-[5-(TRANS-2-forcelogix)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1-(2-{4-[5-(2-pertenece)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1-(2-{4-[5-(5-fluoro-2-methylphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1-(2-{4-[5-(3-fluoro-4-methylphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1-(2-{2,6-dimethyl-4-[7-propoxy-5-(pyridin-3-yloxy)oxazolo[5,4-d]pyrimidine-2-yl]phenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1-(2-{4-[5-(2,4-divergence)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,b-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid
(S)-1-{2-[2,6-dimethyl-4-(5-phenoxy-7-propoxyethanol[5,4-d]pyrimidine-2-yl)phenoxy]acetyl}pyrrolidin-2-carboxylic acid
and
(S)-1-(2-{4-[5-(3-chlorphenoxy)-7-propoxyethanol[5,4-d]pyrimidine-2-yl]-2,b-dimethylphenoxy}acetyl)pyrrolidin-2-carboxylic acid.

9. (S)-l-[2-(2,6-dimethyl-4-{5-[methyl-(3,3,3-cryptochromes)amino]-7-propoxyethanol[5,4-d]pyrimidine-2-yl}phenoxy)acetyl]pyrrolidin-2-carboxylic acid.

10. The method of obtaining compounds of formula I according to any one of claims. 1-8, where the compound of formula II is subjected to interaction with the compound of formula III,

where the groups A, X, Y, R1, R2, R3and R4in compounds II and III are defined as in compounds of formula I, and, moreover, the functionality of�official group can be present in protected form or in the form of group-predecessor, 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.

11. Pharmaceutical composition for the activation of the receptor EDG-1, containing from 0.5 to 90 wt. % of compound according to any one of claims. 1-9 or its physiologically acceptable salt and a pharmaceutically acceptable carrier.

12. The compound according to any one of claims. 1-9 or its physiologically acceptable salt for use as drugs having an activating activity against receptor EDG-1.

13. The compound according to any one of claims. 1-9 or its physiologically acceptable salt for the treatment of complications in the treatment of wounds.

14. The compound according to any one of claims. 1-9 or its physiologically acceptable salt for wound healing.

15. The compound according to any one of claims. 1-9 or its physiologically acceptable salt for wound healing in diabetes.

16. The compound according to any one of claims. 1-9 or its physiologically acceptable salt for the treatment of diabetic foot.



 

Same patents:

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: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 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: chemistry.

SUBSTANCE: invention refers to thiacalixarene derivatives of general formula I , which can be used as agents for DNA delivery into eukaryotic cells.

EFFECT: there are produced new heterocyclic compounds possessing the effective biological properties.

2 dwg, 8 ex

FIELD: veterinary medicine.

SUBSTANCE: wound is preliminary treated with antiseptics. Then the preparation is injected drug directly under the base of the lesion. The preparation is used as the extract from the reindeer velvet antlers at a dose of 5-10 ml per one wound three times, once every 5 days.

EFFECT: use of the preparation Pantoin, the extract of reindeer velvet antlers, enables to speed up significantly the healing process of tear-contused wounds in horses and facilitates significantly the process of wound healing, particularly in the pasture period of maintenance.

2 tbl, 5 ex

Up!