1 h-imidazole derivatives as modulators of cannabinoid cb2 receptors

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

 

The present invention relates to a group of derivatives of 1H-imidazole, which are modulators of receptors cannabinoids CB2to methods of producing these compounds, to novel intermediate compounds useful in the synthesis of these derivatives of imidazole. The invention also relates to the use of compounds disclosed in the description to get drugs that have beneficial effects. Beneficial effects disclosed in the description or it is obvious to the expert in the art from the description and the overall level of technology. The invention also relates to the use of compounds of the invention for obtaining a medicinal product for the treatment or prevention of a disease or condition. More specifically, the invention relates to new methods of use for treatment of a disease or condition disclosed in the description or obvious to a person skilled in the art from the description and the overall level of technology. In versions of the invention, certain compounds disclosed in the description, are used for the manufacture of drugs suitable for treatment of disorders involving CB2receptors cannabinoids, or which can be treated via manipulation of these receptors.

Derivatives of 1H-imidazole as modulators CB1the recipe is RA is known from WO 03/027076, WO 03/063781, WO 03/040107 and WO 03/007887. Derivatives (morpholine-4-yl)alkyl-(1H)-imidazole were claimed as modulators of receptor CB2in WO 01/58869, revealing three specific imidazole (examples 64, 65 and 66), which included n L-phenylalaninamide carboxamido group in position 4 of them (1H)-imidazole fragment. Derivatives of 1-aryl-(1H)-imidazole were stated in US 4952698 as the Central nervous system-active compounds. Recent advances in the field of selective ligands CB2receptors were considered K.H. Raitio et al. (Curr. Med. Chem. 2005, 12, 1217-1237).

It has been unexpectedly found new derived 1H-imidazole, which binds to CB2receptor, including compounds having approximately a hundred times higher affinity to the receptor CB2compared with the compounds in the prior art that was cited in WO 01/58869. In addition, many of the compounds in the scope of the present invention are highly selective with respect to receptor subtype CB2that means that they are associated with much higher affinity to the receptor CB2than with the receptor CB1. Compounds within the present invention are either agonists of the receptor CB2partial agonists of the receptor CB2, antagonists of the receptor CB2or inverse agonists of the receptor CB2.

The invention relates to a connection is in the General formula (I)

in which

- R1represents a hydrogen or halogen atom, or a C1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom or a hydroxy or amino group, or R1represents a C2-3-alkylamino group, C2-3-alkenylphenol group, and C2-3-Alchemilla group or C2-3-Alchemilla group may contain 1-3 fluorine atom, or R1represents acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifloromethyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C2-4-heteroalkyl group,

- R2represents a phenyl group which may be substituted by 1, 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano, or R2represents a heteroaryl group, and heteroaryl group may be substituted by 1, 2 or 3 substituents Y, and Y has the meaning defined above, provided that R2is not 6-methyl-2-peredelnoj group, or

R2represents the MES is unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed carbocyclic ring system, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed heterocyclic ring system, and carbocyclic or heterocyclic ring system may be substituted by 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or

R2represents a group of the General formula CH2-R5in which R5represents a phenyl group which is substituted by 1, 2, 3, 4 or 5 substituents Y, as defined above, or R5is a heteroaryl group or a 1,2,3,4-tetrahydronaphthalene or indenolol group, with the specified heteroaryl group or 1,2,3,4-tetrahydronaphthalene or indayla group may be substituted by 1, 2 or 3 substituents Y, as defined above, or R5is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed carbocyclic ring system, or

R5is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or to generowania tricyclic heterocyclic ring system, moreover, carbocyclic or heterocyclic ring system optionally can be substituted by 1-5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or

R2represents methylsulfonylamino group, methylsulfonylamino or acetamidomethyl group,

- R3represents a hydrogen or halogen atom, or a formyl, C1-6-alkylsulfonyl, C1-6-alkylsulfonyl, C1-6-alkylsulfanyl, trifloromethyl, benzylaniline or cyano, or

R3represents a C1-8is an alkyl group, with the specified C1-8is an alkyl group may be substituted by 1-5 substituents selected from the group consisting of fluorine, hydroxy or amino, or R3represents a C2-6-alkylamino, C2-6-alkenylphenol, C1-6-alkanoyloxy, C3-8-cycloalkyl, C5-8-geterotsyklicescoe or C2-6-heteroalkyl group, and these groups optionally substituted by 1-3 methyl groups, ethyl, amino or hydroxy-group or 1 to 3 fluorine atoms, or R3represents a phenyl group which is substituted by 1-5 substituents Y, where Y has the meaning defined above, or R3represents a heteroaryl group, with the specified heteroaryl g is the SCP may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, or R3represents benzyl or heteroaromatic group, and a benzyl - or heteroaromatic group may be substituted by 1, 2 or 3 substituents Y,

- R4represents one of the groups (i) or (ii)

where R6represents a branched or linear C4-8is an alkyl group, a C3-8-cycloalkyl group, C3-8-cycloalkyl-C1-2is an alkyl group, a C5-7-heteroseksualci-C1-2is an alkyl group, a C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2is an alkyl group, a C5-10-heterobicyclic-C1-2is an alkyl group, a C6-10-tricyclohexyl group, C6-10-tricyclohexyl-C1-2is an alkyl group, a C6-10-heterotrinuclear-C1-2is an alkyl group, and these groups may be substituted by 1-5 substituents selected from methyl, hydroxy, ethyl, trifloromethyl or fluorine, or R6represents phenyl, benzyl, naftalina or fenetylline group which may be substituted on their aromatic ring system 1-3 substituents Y, as defined above, provided that R6is not 2-methylphenylene group, or R6represents pyridyloxy or thienyl group,

- R7is the Wallpaper a hydrogen atom or a linear C 1-6is an alkyl group, with the specified linear C1-6is an alkyl group may be substituted by 1-3 fluorine atoms, or R7represents an ISO-propyl group,

- R8represents a C2-6is an alkyl group, and the group of substituted hydroxy or amino group or 1 to 3 fluorine atoms, or R8represents a branched C7-10is an alkyl group, a C3-8-cycloalkyl group, C5-8-geterotsyklicescoe group, C3-8-cycloalkyl-C1-2is an alkyl group, a C5-7-heteroseksualci-C1-2is an alkyl group, a C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2is an alkyl group, a C5-10-heterobicyclic-C1-2is an alkyl group, a C6-10-tricyclohexyl group, C6-10-tricyclohexyl-C1-2is an alkyl group, a C6-10-heterotrinuclear-C1-2is an alkyl group, and these groups may be substituted by 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifloromethyl or fluorine, or R8represents a phenyl group, with this group substituted by 1-5 substituents Y, as defined above, or R8represents naftalina, 1,2,3,4-tetrahydronaphthalene or indenolol group, with the specified naftalina, 1,2,3,4-tetrahydronaphthalene or indayla group m which may be substituted by 1-3 substituents Y, or R8represents phenyl-C1-3is an alkyl group, a diphenyl-C1-3is an alkyl group, and these groups may be substituted on the phenyl ring 1-5 substituents Y, where Y has the above meaning, or R8represents a benzyl group, with the specified benzyl group substituted by 1-5 substituents Y, or R8represents heteroaryl, heteroaromatic, naphthylmethyl or heteroaromatic group, with the specified heteroaryl, heteroaromatic, naphthylethylene or heterogenisation group may be substituted by 1-3 substituents Y, where Y has the above meaning, or R8represents piperidinyloxy, sepanlou, morpholinyl, azabicyclo[3.3.0]octanediol, 4-hydroxypiperidine or pyrrolidinyloxy group, provided that R8neither 6-methoxybenzothiazole-2-ilen group, nor [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,

or R7and R8together with the nitrogen atom to which they are linked, form a saturated or unsaturated, non-aromatic or partially aromatic, monocyclic, bicyclic or tricyclic heterocyclic group containing 7-10 ring atoms, with the specified saturated or unsaturated, non-aromatic or partially aromatic, monocyclic, b is cyclic or tricyclic heterocyclic group may be substituted by 1-5 substituents, selected from the group consisting of C1-3-alkyl, hydroxy, methoxy, cyano, phenyl, trifloromethyl or halogen, or

R7and R8together with the nitrogen atom to which they are linked, form a saturated monocyclic heterocyclic group, optionally comprising another heteroatom (selected from N, O, S), having 5-6 ring atoms, and specified heterocyclic group substituted by 1-5 substituents selected from the group consisting of C1-3-alkyl, hydroxy, amino, phenyl, benzyl or fluorine,

provided that R7and R8together with the nitrogen atom to which they are bound, do not form trimethylsilanol azabicyclo[3.2.1]octanediol group,

and their tautomers, stereoisomers and N-oxides, as well as pharmacologically acceptable salts, hydrate and solvate of such compounds of formula (1) and their tautomers, stereoisomers and N-oxide.

The invention relates to racemates, mixtures of diastereomers, as well as to the individual stereoisomers of the compounds having formula (I).

In the description of the substituents, the term "alkyl" means a linear or branched alkyl group. For example, C1-3-alkyl means methyl, ethyl, n-propyl or isopropyl. The term "heteroaryl" means a monocyclic or condensed bicyclic heteroaromatic groups, which include, but without limitation the, the following groups: furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, indazoles, indolyl, indolizinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin, benzimidazolyl, benzothiazolyl, purinol, chinoline, ethanolic, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, hinely, phthalazine, hintline, honokalani, 1,8-naphthyridine, except quinoline-2-about the group. The term "halogen" means chlorine, fluorine, bromine or iodine. The term "C3-8-cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The term "C5-8-heteroseksualci" refers to a ring containing N, O, S) heteroatoms, including, but without limitation, the following: piperidinyl, morpholinyl, azepane, pyrrolidinyl, thiomorpholine, piperazinil, tetrahydrofuryl, tetrahydropyranyl. The term "C5-10-bicycloalkyl group" refers to carbobicyclic ring systems, including, but without limitation, the following groups: bicyclo[2.2.1]heptenyl, bicyclo[3.3.0]octenyl or bicyclo[3.1.1]heptenyl. The term "C6-10-critically group" refers to carbocations ring systems, such as 1-adamantinoma, nordmanniana or 2-adamantinoma gruppirovanie "C 2-4heteroalkyl" refers to (N, O, S) heteroatoms containing linear or branched C2-4is an alkyl group, including, but without limitation, the following groups: methoxymethyl, dimethylaminomethyl and ethylsulfinyl.

Prodrugs of the above-mentioned compounds included in the scope of the present invention. Prodrugs are therapeutic agents that are essentially inactive but is converted in one or more active metabolites. Prodrugs are biodiversityiii derived molecules medicines used to overcome some of the barriers that impede the use of the original molecule drugs. These barriers include, but without limitation, the following: solubility, permeability, stability, presystemic metabolism and limitations in orientation (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.D. King, p. 215; J. Stella, "Prodrugs as therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P. Ettmayer et al., "Lessons learned from marketed and investigational prodrugs", J. Med. Chem., 47, 2393-2404, 2004). Prodrugs, i.e. compounds that when administered to humans by any known metabolized into compounds having the formula (I), included in the scope of the invention. This applies in particular to compounds with primary or secondary amino or hydroxyl groups. Such connections may exceed the SQL with organic acids, which leads to compounds having formula (I), and in which there is an additional group that is easily removed after the introduction, for example, but without limitation, the following: amidon, enamine, the basis of manniche, hydroxymethylene derived, O-(acyloxymethyl)derivative, carbamate, ester, amide or enamine.

N-oxides of the aforementioned compounds are within the scope of the present invention. Tertiary amines can give or not give rise to metabolites in the form of N-oxides. The extent to which such N-oxidation takes place, varies from trace amounts to almost quantitative conversion. N-oxides can be more active than their corresponding tertiary amines or less active. As N-oxides are easily reduced to their corresponding tertiary amines by chemical methods, in the human body it happens to varying degrees. Some N-oxides are almost quantitative recovery of the conversion into the corresponding tertiary amines, in other cases, the conversion is only a trace reaction or even completely absent (M.H. Bickel: "The pharmacology and Biochemistry of N-oxides",Pharmacological Reviews, 21(4), 325-355, 1969).

The invention in particular relates to compounds of General formula (I)

in which

- R1present is employed, a halogen atom or C 1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom or a hydroxy or amino group, or R1represents a C2-3-alkylamino group, C2-3-alkenylphenol group, and C2-3-Alchemilla group or C2-3-Alchemilla group may contain 1-3 fluorine atom, or R1represents acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifloromethyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C2-4-heteroalkyl group, and R2, R3and R4have the meanings given above.

In a more preferred embodiment, the invention relates to compounds of formula (I)

in which

- R3represents a hydrogen or halogen atom, or formyl, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifloromethyl, methylsulfanyl, ethylsulfanyl or cyano, or R3represents a C1-6is an alkyl group, with the specified C1-6is an alkyl group can contain 1-3 fluorine atom or a hydroxy or amino group, or R3represents a C2-6-alkylamino, C2-6-alkenylphenol, C1-6-alkanoyloxy, C3-8 -cycloalkyl, C5-8-geterotsyklicescoe or C2-6-heteroalkyl group, and these groups optionally substituted by 1-3 methyl groups, ethyl, amino or hydroxy-group or 1 to 3 fluorine atoms, or R3represents a phenyl group which is substituted by 1-5 substituents Y, where Y has the meaning defined above, or R3represents a heteroaryl group, with the specified heteroaryl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, or R3represents benzyl or heteroaromatic group, with the specified benzyl or heteroaromatic group may be substituted by 1, 2 or 3 substituents Y,

- R4is a subgroup of (ii)

in which

- R7represents a hydrogen atom, linear or C1-6is an alkyl group, or isopropyl group,

- R8represents a C2-6is an alkyl group, and the group of substituted hydroxy or amino group or 1 to 3 fluorine atoms, or R8represents a branched C7-10is an alkyl group, a C3-8-cycloalkyl group, C5-8-geterotsyklicescoe group, C3-8-cycloalkyl-C1-2is an alkyl group, a C5-7-heteroseksualci-C1-2is an alkyl group, 5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2is an alkyl group, a C5-10-heterobicyclic-C1-2is an alkyl group, a C6-10-tricyclohexyl group, C6-10-tricyclohexyl-C1-2is an alkyl group, a C6-10-heterotrinuclear-C1-2is an alkyl group, and these groups may be substituted by 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifloromethyl or fluorine, or R8represents a phenyl group, with this group substituted by 1-5 substituents Y, as defined above, or R8represents naftalina or 1,2,3,4-tetrahydronaphthalene or indenolol group, and these groups may be substituted by 1-3 substituents Y, or R8represents phenyl-C1-3is an alkyl group, a diphenyl-C1-3is an alkyl group, and these groups may be substituted on the phenyl ring 1-5 substituents Y, where Y has the meaning mentioned above, or R8represents a benzyl group, with the specified benzyl group substituted by 1-5 substituents Y, or R8represents heteroaryl, heteroaromatic or heteroaromatic group, with the specified heteroaryl, heteroaromatic or heterogenisation group may be substituted by 1-3 substituents Y, as defined enter the, or R8represents piperidinyloxy, sepanlou, morpholinyl, azabicyclo[3.3.0]octanediol, 4-hydroxypiperidine or pyrrolidinyloxy group, provided that R8neither 6-methoxybenzothiazole-2-ilen group, nor [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group, or

R7and R8together with the nitrogen atom to which they are linked, form a saturated or unsaturated, non-aromatic or partially aromatic, monocyclic, bicyclic or tricyclic heterocyclic group having 7-10 atoms in the ring, and the specified heterocyclic group may be substituted by one or two C1-3-alkyl groups, hydroxy groups, phenyl groups, trimethylfluorosilane groups, benzyl groups, diphenylmethylene groups or halogen atom, or R7and R8together with the nitrogen atom to which they are linked, form a saturated monocyclic heterocyclic group, optionally containing another heteroatom (selected from N, O, S), having 5-6 atoms in the ring, and the specified heterocyclic group substituted by 1-3 C1-3-alkyl groups, hydroxy-group or 1-2 fluorine atoms,

provided that R7and R8together with the nitrogen atom to which they are bound, do not form trimethylsilanol azabicyclo[3.2.1]octanediol group is, and R1and R2have the meanings given above.

Also in the preferred embodiment, the invention relates to compounds of formula (I)

in which

- R1represents a halogen atom or C1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom or a hydroxy-group, or R1represents a C2-3-alkylamino group, C2-3-alkenylphenol group, acetyl, cyclopropyl, cyano, methylsulfonyl, methylsulfinyl, methylsulfonyl or C2-4-heteroalkyl group,

- R2represents a phenyl group which may be substituted by 1, 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano, or R2represents a monocyclic heteroaryl group, with the specified heteroaryl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, provided that R2is not 6-methyl-2-peredelnoj group, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic the forge or condensed tricyclic carbocyclic ring system, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed heterocyclic ring system, with the specified carbocyclic or heterocyclic ring system may be substituted by 1-5 substituents selected from methyl, ethyl, amino, hydroxyl or fluorine, or

R2represents a group of the General formula CH2-R5where R5represents a phenyl group which is substituted by 1, 2, 3, 4 or 5 substituents Y, as defined above, or R5is a heteroaryl group or a 1,2,3,4-tetrahydronaphthalene or indenolol group, with the specified heteroaryl group or 1,2,3,4-tetrahydronaphthalene or indayla group may be substituted by 1, 2 or 3 substituents Y, as defined above, or R5is a mono-unsaturated or fully saturated monocyclic, condensed bicyclic or tricyclic condensed 4-10-membered carbocyclic ring system, or

R5is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed heterocyclic ring system, with the specified carbocyclic the Kai or heterocyclic ring system may be optionally substituted by 1-3 methyl groups, ethyl, amino or hydroxy-group or fluorine atom,

- R3represents a hydrogen or halogen atom, or methylsulfonyl or cyano, or R3represents a C1-6is an alkyl group, with the specified C1-6is an alkyl group can contain 1-3 fluorine atom or a hydroxy or amino group, or R3represents a C2-6-alkylamino or C2-6-alkenylphenol group, and these groups optionally substituted by 1-3 fluorine atoms,

- R4is a subgroup of (ii)

in which

- R7represents a hydrogen atom or a linear C1-3is an alkyl group,

- R8represents a C2-6is an alkyl group, with this group substituted hydroxy or amino group or 1 to 3 fluorine atoms, or R8represents a branched C7-10is an alkyl group, a C3-8-cycloalkyl group, C5-8-geterotsyklicescoe group, C3-8-cycloalkyl-C1-2is an alkyl group, a C5-7-heteroseksualci-C1-2is an alkyl group, a C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2is an alkyl group, a C5-10-heterobicyclic-C1-2is an alkyl group, a C6-10-tricyclohexyl group, C6-10-tricyclohexyl-C1-2is an alkyl group, a C6-10-hetero icelolly-C 1-2is an alkyl group, and these groups may be substituted by 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifloromethyl or fluorine, or R8represents a phenyl group, with this group substituted by 1-5 substituents Y, as defined above, or R8represents naphthyl or 1,2,3,4-tetrahydronaphthyl, or indanyl, and these groups may be substituted by 1-3 substituents Y, or R8represents phenyl-C1-3is an alkyl group, a diphenyl-C1-3is an alkyl group, and these groups may be substituted on the phenyl ring 1-5 substituents Y, where Y has the meaning mentioned above, or R8represents a benzyl group, with the specified benzyl group substituted by 1-5 substituents Y, or R8represents heteroaryl, heteroaromatic or heteroaromatic group, with the above heteroaryl, heteroaromatic or heterogenisation groups can be substituted by 1-3 substituents Y, as defined above, or R8represents piperidinyloxy, sepanlou, morpholinyl, azabicyclo[3.3.0]octanediol, 4-hydroxypiperidine or pyrrolidinyloxy group, provided that R8neither 6-methoxybenzothiazole-2-ilen group, nor [3-chloro-5-(trifluoromethyl)pyrid-2-yl]metalno the group.

In an even more preferred embodiment, the invention relates to compounds of formula (I)

in which

- R1represents a halogen atom or C1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom or a hydroxy-group, or R1represents cyano or methylsulfonyl group,

- R2is a mono-unsaturated or fully saturated 5 to 7-membered monocyclic carbocyclic ring system, which may be substituted by 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or R2represents a phenyl group which may be substituted by 1, 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano,

- R3represents a hydrogen or halogen atom, or methylsulfonyl or cyano, or R3represents a C1-6is an alkyl group, with the specified C1-6is an alkyl group may include 1-3 fluorine atom or a hydroxy or amino group,

- R4is a subgroup of (ii)

in which

- R7predstavljaet a hydrogen atom or methyl group,

- R8represents a C2-6is an alkyl group with the specified group substituted by 1-3 fluorine atoms, or R8represents a branched C7-10is an alkyl group, a C3-8-cycloalkyl group, C5-8-geterotsyklicescoe group, C3-8-cycloalkyl-C1-2is an alkyl group, a C5-7-heteroseksualci-C1-2is an alkyl group, a C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2is an alkyl group, a C5-10-heterobicyclic-C1-2is an alkyl group, a C6-10-tricyclohexyl group, C6-10-tricyclohexyl-C1-2is an alkyl group, a C6-10-heterotrinuclear-C1-2is an alkyl group, and these groups may be substituted by 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifloromethyl or fluorine, or R8represents a phenyl group, with this group substituted by 1-5 substituents Y, as defined above, or R8represents naftalina or 1,2,3,4-tetrahydronaphthalene or indenolol group, and these groups may be substituted by 1-3 substituents Y, or R8represents phenyl-C1-3is an alkyl group, a diphenyl-C1-3is an alkyl group, and these groups may be substituted on the phenyl ring 1-5 substituents Y, where Y has the above-mentioned knowledge is the group of or R8represents a substituted benzyl group, with the specified benzyl group substituted by 1-5 substituents Y, or R8represents heteroaryl, heteroaromatic or heteroaromatic group, with the above heteroaryl, heteroaromatic or heterogenisation groups can be substituted by 1-3 substituents Y, as defined above, provided that R8neither 6-methoxybenzothiazole-2-ilen, nor [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group.

In the most preferred embodiment, the invention relates to compounds of formula (I)

in which

- R1represents a halogen atom or C1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom, or R1represents cyano or methylsulfonyl group,

- R2represents a six-membered saturated monocyclic carbocyclic ring, or R2represents a phenyl group which may be substituted by 1, 2 or 3 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano,

- R3represents hydrogen, is whether halogen atom, or methylsulfonyl or cyano, or R3represents a C1-4is an alkyl group, with the specified C1-4is an alkyl group may include 1-3 fluorine atom,

- R4is a subgroup of (ii)

in which

- R7represents a hydrogen atom or methyl group,

- R8represents a C2-6is an alkyl group with the specified group substituted by 1-3 fluorine atoms, or R8represents a branched C7-10is an alkyl group, a C3-8-cycloalkyl group, C5-8-geterotsyklicescoe group, C3-8-cycloalkyl-C1-2is an alkyl group, a C5-7-heteroseksualci-C1-2is an alkyl group, a C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2is an alkyl group, a C5-10-heterobicyclic-C1-2is an alkyl group, a C6-10-tricyclohexyl group, C6-10-tricyclohexyl-C1-2is an alkyl group, a C6-10-heterotrinuclear-C1-2is an alkyl group, and these groups may be substituted by 1-5 substituents selected from methyl, hydroxy, ethyl, amino, hydroxymethyl, trifloromethyl or fluorine, or R8represents a phenyl group, with this group substituted by 1-3 substituents Y, as defined above, or R8represents nafti is inuu group, moreover, this group may be substituted by 1-3 substituents Y, or R8represents phenyl-C1-2is an alkyl group, and the group may be substituted on the phenyl ring, 1-3 substituents Y, where Y has the above meaning, or R8represents a substituted benzyl group, with the specified benzyl group substituted by 1-5 substituents y

The invention in a preferred embodiment, also relates to compounds having formula (I)in which R2represents a six-membered saturated monocyclic carbocyclic ring, or R2represents a phenyl group which may be substituted by 1, 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano, and all other symbols have the meanings described above.

In another embodiment, the invention relates to compounds of General formula (XIV)

in which

- R1represents a halogen atom or C1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom or a hydroxy or amino group, or R1represents a C2-3-alkyne is the function group, C2-3-alkenylphenol group, with the specified C2-3-Alchemilla group or C2-3-Alchemilla group may include 1-3 fluorine atom, or R1represents acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifloromethyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C2-4-heteroalkyl group,

- R2represents a phenyl group which may be substituted by 1, 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano, or R2represents a heteroaryl group, with the specified heteroaryl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, provided that R2is not 6-methyl-2-peredelnoj group, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed carbocyclic ring system, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered, monocyclic will stifle, condensed bicyclic or tricyclic condensed heterocyclic ring system, with the specified carbocyclic or heterocyclic ring system may be substituted by 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or

R2represents a group of the General formula CH2-R5where R5represents a phenyl group which is substituted by 1, 2, 3, 4 or 5 substituents Y, as defined above, or R5is a heteroaryl group or a 1,2,3,4-tetrahydronaphthalene or indenolol group, with the specified heteroaryl group or 1,2,3,4-tetrahydronaphthalene or indayla group may be substituted by 1, 2 or 3 substituents Y, as defined above, or R5is a mono-unsaturated or fully saturated monocyclic, condensed bicyclic or tricyclic condensed 4-10-membered carbocyclic ring system, or

R5is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed heterocyclic ring system, with the specified carbocyclic or heterocyclic ring system may be optionally substituted by 1-5 substituents selected and the group, consisting of methyl, ethyl, amino, hydroxy or fluorine, or

R2represents methylsulfonylamino group, methylsulfonylamino or acetamidomethyl group

provided that R2is not phenyl, 4-methylphenylene or 4-metoksifenilny group,

- R3represents a hydrogen or halogen atom, or a formyl, C1-6-alkylsulfonyl, C1-6-alkylsulfonyl, C1-6-alkylsulfanyl, trifloromethyl, benzylmethyl or cyano, or R3represents a C1-8is an alkyl group, with the specified C1-8is an alkyl group may be substituted by 1-5 substituents selected from the group consisting of fluorine, hydroxy or amino, or R3represents a C2-6-quinil, C2-6alkenyl, C1-6-alkanoyl, C3-8-cycloalkyl, C5-8-heteroseksualci or C2-6-heteroalkyl, and these groups optionally substituted by 1-3 methyl groups, ethyl, amino or hydroxy groups or 1-3 fluorine atoms, or R3represents a phenyl group which is substituted by 1-5 substituents Y, where Y has the meaning defined above, or R3represents a heteroaryl group, with the specified heteroaryl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, or R3 represents benzyl or heteroaromatic group, with the specified benzyl or heteroaromatic group may be substituted by 1, 2 or 3 substituents Y,

- Z represents a chlorine atom or a C1-3is an alkyl group, a hydroxy-group, or-O-Na-O-K-O-Li, or-O-Cs group, or Z represents N-methoxy-N-methylaminopropyl,

moreover, these compounds are useful in the synthesis of compounds of General formula (I), in which

- R1represents a halogen atom or C1-3is an alkyl group, and C1-3is an alkyl group may include 1-3 fluorine atom or a hydroxy or amino group, or R1represents a C2-3-alkylamino group, C2-3-alkenylphenol group, with the specified C2-3-Alchemilla group or C2-3-Alchemilla group may include 1-3 fluorine atom, or R1represents acetyl, cyclopropyl, cyano, methylsulfonyl, ethylsulfonyl, methylsulfinyl, ethylsulfinyl, trifloromethyl, methylsulfanyl, ethylsulfanyl group, formyl group or a C2-4-heteroalkyl group,

- R2represents a phenyl group which may be substituted by 1, 2, 3, 4 or 5 substituents Y, which can be the same or different, selected from the group consisting of methyl, ethyl, propyl,methoxy, ethoxy, hydroxy, chlorine, iodine, bromine, fluorine, trifloromethyl, triptoreline, carbamoyl, phenyl and cyano, or R2represents a heteroaryl group, with the specified heteroaryl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, provided that R2is not 6-methyl-2-peredelnoj group, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed carbocyclic ring system, or

R2is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed heterocyclic ring system, with the specified carbocyclic or heterocyclic ring system may be substituted by 1-5 substituents selected from methyl, ethyl, amino, hydroxy or fluorine, or

R2represents a group of the General formula CH2-R5where R5represents a phenyl group which is substituted by 1, 2, 3, 4 or 5 substituents Y, as defined above, or R5is a heteroaryl group or a 1,2,3,4-tetrahydronaphthalene or indenolol group, with the specified heteroaryl group or 1,2,3,4-tetrahed naftalina or indayla group may be substituted by 1, 2 or 3 substituents Y, as defined above, or R5is a mono-unsaturated or fully saturated monocyclic, condensed bicyclic or tricyclic condensed 4-10-membered carbocyclic ring system, or

R5is a mono-unsaturated or fully saturated 4 to 10-membered monocyclic, condensed bicyclic or tricyclic condensed heterocyclic ring system, with the specified carbocyclic or heterocyclic ring system may be optionally substituted by 1-5 substituents selected from the group consisting of methyl, ethyl, amino, hydroxy or fluorine, or

R2represents methylsulfonylamino group, methylsulfonylamino or acetamidomethyl group,

- R3represents a hydrogen or halogen atom, or a formyl, C1-6-alkylsulfonyl, C1-6-alkylsulfonyl C1-6-alkylsulfanyl, trifloromethyl, benzylmethyl or cyano, or R3represents a C1-8is an alkyl group, with the specified C1-8is an alkyl group may be substituted by 1-5 substituents selected from the group consisting of fluorine, hydroxy or amino, or R3represents a C2-6-alkylamino, C2-6-alkenylphenol, C1-6-limoilou, C3-8-cycloalkyl, C5-8-geterotsyklicescoe or C2-6-heteroalkyl group, and these groups optionally substituted by 1-3 methyl groups, ethyl, amino or hydroxy groups or 1-3 fluorine atoms, or R3represents a phenyl group which is substituted by 1-5 substituents Y, where Y has the meaning defined above, or R3represents a heteroaryl group, with the specified heteroaryl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning defined above, or R3represents benzyl or heteroaromatic group, with the specified benzyl or heteroaromatic group may be substituted by 1, 2 or 3 substituents Y.

GENERAL ASPECTS of SYNTHESES

The compounds of formula (I) can be obtained by various methods. The choice of a specific method depends on a number of factors such as the compatibility of functional groups with the reagents, the use of protective groups, catalysts, activating and cross-linking reagents and final structural properties present in the final product.

Imidazole derivatives can be obtained according to known methods. The relevant articles are as follows:

a) Gomez-Sanchez et al.,J. Heterocyclic Chem.(1987), 24, 1757-1763;

b) Matsuura et al.,J. Chm. Soc. Perkin Trans. I(1991), 11, 2821-2826;

c) Ueda et al.,Tetrahedron Lett.(1988), 29, 4607-4610;

d) Gupta et al.,Eur. J. Med. Chem.(2004), 39, 805-814;

e) Van Berkel et al.,Tetrahedron Lett.(2004), 45, 7659-7662;

f) Haberhauer and Rominger,Tetrahedron Lett.(2002), 43, 6335-6338;

g) Dell Erba et al.,Tetrahedron(1997), 53, 2125-2136;

h) Lipshutz et al.,Tetrahedron Lett.(1992), 33, 5865-5868.

Compounds of General formula (I) can be obtained according to the procedures described in schemes 1-6.

Scheme 1: the symbols R1-R8have the meanings given above, R9and R10represent alkyl(C1-3)

Derivatives of nitroenamine General formula (II) can be obtained according to the procedure published Gomez-Sanchez et al.,J. Heterocyclic Chem.(1987), 24, 1757-1763. Derivatives of nitroenamine General formula (II) can react with ortho-esters of the General formula (III), forming the imidazole derivatives of General formula (IV) (scheme 1). Subsequent basic hydrolysis of ester, for example, using lithium hydroxide (LiOH), NaOH, KOH or CsOH can give an intermediate compound in the form of alkaline salts imidazolecarboxamide acids, which can be acidified with an acid, such as aqueous hydrogen chloride (HCl), forming derivative imidazolecarboxamide acids of General formula (V). Compounds of General formula (IV) can be lidirovali an amine of General formula R7R8NH in the compound of General formula (I), where X represents the FDS is th subgroup (ii), defined above. These amidation can kataliziruetsa by trimethylaluminum (CH3)3Al. (For more information on aluminiumveredelung conversion of esters to amides, see: Jose I. Levin, E. Turos, S.M. Weinreb,Synth. Commun.(1982), 12, 989-993). Derivatives imidazolecarboxamide acids of General formula (V) or their respective alkali metal salts can react with the amine of General formula R7R8NH with the formation of compounds of General formula (I), where X represents subgroup (ii)defined above. This specific reaction preferably takes place by the means of activation and crosslinking, such as the formation of the active ester, or in the presence of so-called cross-linking reagent, such as DCC, HBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea of hexaphosphate), TBTU, HOAt (N-hydroxy-7-isobenzofuranone), PyBOP (benzotriazol-1 yloxy-Tris(pyrrolidino)phosphonium hexaflurophosphate), BOP, CIP (2-chloro-1,3-dimethylimidazolidine of hexaphosphate), 2-chloro-1,3-dimethylimidazolium chloride, PyAOP (7-asobancaria-1 yloxy-Tris(pyrrolidino)phosphonium hexaflurophosphate) and so on (For more information about the methods of activation and crosslinking see a) M. Bodanszky, A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; (b) K. Akaji et al.,Tetrahedron Lett.(1994), 35, 3315-3318; c) F. Albericio et al.,Tetrahedron Lett.(1997), 38, 4853-4856); (d) C. Montalbetti and V. Falque,Tetrahedron(2005), 61, 10827-10852.

Alternatively, the compound having General formula (V), or the corresponding alkali metal salts can react with the so-called halogenation agent such as thionyl chloride (SOCl2or oxalylamino. This reaction gives the corresponding carbonylchloride (acid chloride) (Va), which can subsequently react with a compound having the formula R7R8NH in which R7and R8have the meanings described above, forming a compound of General formula (I), where X represents subgroup (ii)defined above. Such reactions can be catalyzed by pyridine or 4-dimethylaminopyridine (DMAP).

The compound having General formula (V), can react with N-methoxy-N-methylamine in the presence of a crosslinking reagent, which leads to the corresponding N-methoxy-N-methylamide General formula (VI), subsequently reacting with a lithium reagent of General formula R6-Li or a Grignard reagent to form compounds of General formula (I), where X represents subgroup (i), defined above.

Scheme 2: the symbols R1-R5have the meanings are the same as above, R9represents alkyl(C1-3). In the compounds of the General formula R2-B(OH)2R2represents phenyl which is optionally substituted, or heteroaryl group, in the " reagent Suzuki.

Alternatively, the compound having General formula (VII)may react with the compound of General formula (VIII), where L is a so-called leaving group, for example chlorine, bromine, iodine or mesilate (scheme 2). The compound having General formula (VII), may also react with methylsulfonylmethane or methylsulfonylmethane, forming methylsulfonylamino group or methylsulfonylamino group in position 1 of the imidazole nucleus. Such reactions are preferably carried out in the presence of bases, such as sodium hydride or potassium carbonate, in order to facilitate the nucleophilic attack of the compound (VII), to obtain the compounds of formula (IV), where R2represents a group-CH2R5and R5has the meaning mentioned above.

Alternatively, the compound having General formula (VII)may react with the compound of General formula R2-B(OH)2in which R2represents phenyl which is optionally substituted, or a heteroaryl group, i.e. with the so-called reagent Suzuki, forming a compound of General formula (IV). Compounds of General formula (IV) can be converted to compounds of General formula (I) according to scheme 1. Such reactions can kataliziruetsa metals.

Scheme 3: the symbols R1-R3have C is achene, same as above, R9represents alkyl(C1-3).

The compound having General formula (IX)may react with a derivative of nitrite, e.g. sodium nitrite (NaNO2), forming a compound of General formula (X). (Scheme 3). The compound having General formula (X), can react with the anhydride of General formula (R1CO)2O in the presence of a reducing agent, such as hydrogen, and a catalyst, such as Pd-on-coal (Pd/C) and the like, in an inert organic solvent, for example ethanol, to form the compound of General formula (XI). The compound having General formula (XI)may react with the amine of General formula R2NH2in an inert solvent, such as butyronitrile, forming a compound of General formula (IV). Compounds of General formula (IV) can be converted to compounds of General formula (I) according to scheme 1.

Alternatively, the compound of General formula (XI) can be obtained in two-stage reaction of compounds of General formula (XII). The compound of General formula (XII) can be deprotonirovannoi strong base such as tert-piperonyl potassium (KO-t-Bu), followed by reaction with allermuir compound of General formula R3COL, where L is a leaving group such as chloride, followed by treatment with an acid, for example hydrochloric, etc. of the target compound of General formula (XIII) may re herawati with the anhydride of General formula (R 1CO)2O, forming a compound of formula (XI). Alternatively, the compound having General formula (X)may react with a regenerating agent, such as hydrogen, and a catalyst, such as Pd-on-coal (Pd/C) and the like, in an inert organic solvent, for example ethanol, in the presence of acid, for example hydrochloric, resulting in a compound of General formula (XIII).

Figure 4: the symbols R1-R3have the meanings are the same as above, X represents subgroup (ii).

The compound having General formula (I)in which X represents subgroup (ii), and in which the position 5 of the imidazole molecules contains a hydrogen atom, can be deprotonirovannoi strong dinucleophiles base, such as diisopropylamide lithium (LDA), followed by treatment group, R3-L, where L is a leaving group, which leads to the formation of compounds of General formula (I)in which X is a subgroup of (ii), and in which the position 5 of the imidazole molecules contain substituent R3(scheme 4).

Figure 5: the symbols R2, R7, R8and R9have the meanings are the same as above, E is an electrophilic molecule, L is a leaving group.

Derived imidazole of the General formula (IV), where R1and R3presented Aut a hydrogen, and where R9has the meaning mentioned above, can be converted through hydrolysis of ester, for example, using lithium hydroxide (LiOH), NaOH, KOH or CsOH, which leads to the formation of intermediate compounds in the form of alkaline salts imidazolecarboxamide acids, and these salts can be acidified, for example, aqueous hydrogen chloride (HCl) to obtain the derivatives imidazolecarboxamide acids of General formula (V). Derivatives imidazolecarboxamide acids of General formula (V) can be lidirovali that leads to the formation of compounds of General formula (I), where R1and R3represent hydrogen, and R2, R7and R8have the meanings mentioned above. The connection specified General formula (I)in which R1and R3represent hydrogen, and R2, R7and R8have the meanings mentioned above, can be deprotonirovannoi strong dinucleophiles base, such as diisopropylamide lithium (LDA), or n-BuLi, followed by treatment group E-L in which L is a leaving group such as iodide, bromide, or S-alkyl, and E is an electrophilic group, including, but without limitation, the following: -S-alkyl, primary alkyl, chlorine, bromine, iodine or cyano, in order to obtain the compound of General formula (I), where X represents subgroup (ii and where 2/5-position of the imidazole molecules which contains Deputy E and/or a hydrogen atom, depending on the type of group E-L, applied in this reaction (scheme 5). The definition of group E is part of the definition of R1and R3and not beyond the scope of the definition of R1and R3the data above. A mixture of compounds, which may be formed in the last stages of the reaction in scheme 5, can be isolated and purified, for example, chromatographic or crystallization methods.

Scheme 6: the symbols R2, R7and R8have the meanings are the same as above.

The compound of General formula (I), where R1and R3represent hydrogen, and R2, R7and R8have the meanings mentioned above, can react with a halogenation agent such as N-chlorosuccinimide (NCS) or bromine (Br2), in an inert organic solvent, for example dichloromethane, to form the compound of General formula (I)in which R3represents Cl or Br, and R1is a hydrogen atom. The compound of General formula (I), where R3represents Cl or Br, and R1is a hydrogen atom can react with a halogenation agent such as N-chlorosuccinimide (NCS) or bromine (Br2) in an inert organic solvent, for example dichloromethane, to form the compound of General formula (I)in which R3represents Cl or Br, and R1represents Cl or Br (scheme 6).

For gaining the more detailed information about the nucleophiles, electrophiles and the concept of leaving groups, see: M.B. Smith and J. March: Advanced organic chemistry, p. 275, 5th ed., (2001) John Wiley & Sons, New York, ISBN: 0-471-58589-0).

More information on the introduction and subsequent removal of the protective groups in organic synthesis can be found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, Inc., New York, 1999.

Pharmaceutically acceptable salts may be obtained using standard techniques known in the prior art, for example, by mixing the compounds of the present invention with a suitable acid, for example an inorganic acid, such as hydrochloric, or with an organic acid, such as fumaric.

PHARMACEUTICAL

Compounds of the invention can be converted into a form suitable for administration by conventional methods using auxiliary substances such as liquid or solid carrier. The pharmaceutical compositions of the invention can enter enterline, orally, parenterally (intramuscularly or intravenously), rectally or locally (topically). You can enter them in the form of solutions, powders, tablets, capsules (including microcapsules), ointment (cream or gel), or suppositories. Suitable fillers for such compositions are standard pharmaceutically liquid or solid fillers and diluents, solvents, shall alligatory, lubricants, flavoring agents, dyes and/or buffer substances. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars or polyalcohols, xylytol, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as liver fat fish oil sunflower, peanut or sesame seeds, polyethylene glycol and solvents such as, for example, sterile water and mono - or polyhydric alcohols, such as glycerin.

Compounds of the present invention is usually introduced in the form of pharmaceutical compositions, which are important and new variants of the invention due to the presence of compounds, more preferable specific compounds disclosed in the description. Types of pharmaceutical compositions that may be used include, but without limitation, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, etc. disclosed herein or obvious to a person skilled in the art from the description and General knowledge in the art. In variants of the invention provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the pharmaceutical composition from which bretania. The container may include various written materials such as instructions for use, or notes in the form prescribed by a governmental Agency regulating the manufacture, use or sale of pharmaceutical products, and specified notice reflects approval by the Agency regarding the manufacture, use or sale for introducing a person or animal.

PHARMACOLOGICAL METHODS

In vivoandin vitropharmacological tests associated with neurotransmission cannabinoid CB2receptors have been described in the literature. Some examples:

• Ibrahim, M.M.et al. (2003)Proc. Natl. Acad. Sci.USA100, 10529-10533.

• Hanus, L.et al. (1999)Proc. Natl. Acad. Sci.USA96, 14228-14233.

• Zhang, J.et al. (2003)Eur. J. Neuroscience17, 2750-2754.

• Klein, T.W.et al. (2003)J. Leukoc. Biol. 74, 486-496.

• Shoemaker, J.L.et al.(2005),J. Pharmacol. Exp. Ther. 315, 828-838.

• Iwamura, H.et al. (2001),J. Pharmacol. Exp. Ther. 296, 420-425.

In vitrothe affinity to the cannabinoid CB1receptors

The affinity of compounds of the invention for cannabinoid receptors CB1can be determined using membrane preparations of cells of the Chinese hamster ovary (CHO), in which the human cannabinoid CB1the receptor is stably transfitsirovannykh together with [3H]CP-55,940 as radioligand. On the Le incubation of freshly prepared preparation of cell membranes with [ 3H]-ligand, with or without addition of compounds of the invention by filtration on glass fiber filters is the separation of bound and free ligand. The radioactivity on the filter is measured by liquid scintillation method.

In vitrothe affinity to the cannabinoid CB2receptors

The affinity of compounds of the invention for cannabinoid receptors CB2can be determined using membrane preparations of cells of the Chinese hamster ovary (CHO), in which the human cannabinoid CB2the receptor is stably transfitsirovannykh together with [3H]CP-55,940 as radioligand. After incubation of freshly prepared preparation of cell membranes with [3H]-ligand, with or without addition of compounds of the invention by filtration on glass fiber filters is the separation of bound and free ligand. The radioactivity on the filter is measured by liquid scintillation method.

Due to its modulating activity of cannabinoid CB2receptor compounds of the present invention are suitable for use in the treatment of disorders of the immune system, inflammatory disorders, allergies, pain, neuropathic pain, multiple sclerosis, neurodegenerative, Rastro the STV, dementia, dystonia, muscle spasticity, tremor, epilepsy, traumatic brain injuries, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, cerebral ischemia, apoplexy, craniocerebral trauma, wounds of the spinal cord, neuropeptidergic disorders, neurodegeneration brain system, atherosclerosis, viral encephalitis, disorders associated with demyelination and other neurological disorders, as well as in the treatment of cancers, diabetes, gastrointestinal diseases, lung diseases, asthma and cardiovascular diseases, as well as other diseases, in a process which involved CB2-receptor neuropterida.

Compounds of the invention can be converted into a form suitable for administration by conventional methods, with the use of auxiliary substances and/or liquid or solid materials carriers.

DOSE

The affinity of compounds of the invention for cannabinoid receptors CB2was determined as described above. On the affinity of binding measured for the compounds of formula (I), we can estimate theoretical minimum effective dose. When the concentration of the compound equal to twice the measured value of Ki, 100% cannabinoid CB2receptors will probably be busy connection. P is the education of the specified concentration to mg of compound per kg weight of the patient leads to a theoretical minimum effective dose, taking bioavailability perfect. Pharmacokinetic, pharmacodynamic and other studies may change the dose that is actually injected to higher or lower values. The dose, which preferably is 0.001 to 1000 mg/kg, preferably 0.1 to 100 mg/kg weight of the patient.

THERAPY

Used in the description, the term "treatment" refers to treatment of a condition or disease of a mammal, preferably a human, and includes: (1) preventing the disease or pathological condition in a patient who may be predisposed to the disease but has not yet been diagnosed with the disease, (2) slowing of a disease or pathological condition, i.e. stop its development, (3) exemption from disease or pathological condition, i.e. causing regression of the pathological condition, or (4) exemption from pathological conditions caused by the disease, i.e. stopping the symptoms of the disease.

EXAMPLES

EXAMPLE 1: MATERIALS AND METHODS

All reactions involving moisture-sensitive compounds or conditions, were carried out in an atmosphere of anhydrous nitrogen. The reactions were tested using thin layer chromatography (TLC) coated silica gel plastic films (Merck precoated silica gel 60 F254) with the indicated eluent. Spots Visualizer who were UV light (254 nm) or I 2. Flash chromatography refers to the cleaning with the indicated eluent and silica gel Acros (0,030-0.075 mm). Petroleum ether refers petroleum ether 40-60. The spectra of nuclear magnetic resonance (1H NMR and13C NMR) were determined in the indicated solvent with tetramethylsilane was as an internal standard. Chemical shifts are given in ppm (δ scale) fluctuations tetramethylsilane. The coupling constants J are given in Hertz (Hz). The shape of the peaks in the NMR spectra indicated by the symbol "square" (Quartet), "DQC." (double Quartet), t (triplet), dt (double triplet), d (doublet), DD (double doublet), "s (singlet), "users" (broadened singlet) and m (multiplet). Melting points were recorded on the apparatus to determine the melting points Bϋchi B-545 or determined by the method of differential scanning calorimetry (DSC). Outputs refer to the dedicated net products.

The equipment and procedure of preparative LC/MS

Sciex API 150 EX mass spectrometer with elektrorazpredelenie

2 Shimadzu LC8A LC pump

Shimadzu SCL-10A VP system controller

Shimadzu SPD-10A VP UV

Gilson 215 injector/collector

Column:Phenomenex Luna C18 (2)
150×21,2×5 µm
Eluent:A 100% water + 0.1% of formic acid at pH=3
B 100% acetonitrile + 0.1% of formic acid
Injection:2.5 ml
Separator:1-50000 flow of a mixture of 0.2 ml/min
(25% H2O/75% ACN with 0.25% HCOOH)
MS scan:Between 100 and 900'ail, step 1 Amu, scan time 1 s
Method:The velocity profiles of flow and gradient

Total time (min)The flow rate
(ml/min)
And,% (vol./about.)In,% (vol./about.)
05955
25955
2,120 955
12200100
14200100
14,520955
1520955

EXAMPLE 2: SYNTHESIS of SPECIFIC COMPOUNDS

Specific compounds, the synthesis of which is described below, are intended to further illustrate the invention in more detail, and thus, it is believed, do not limit the scope of the invention in any way. Other variants of the invention will be obvious to experts in the art from consideration of the description and practical application of the invention disclosed in the description. Thus, it is envisaged that the description and the connection will only be considered selectively, in accordance with the true scope and nature of the invention, indicated in the claims.

Synthesis of compounds 1

Part A:Stir magnetic stirrer, a mixture of ethyl 5-methyl-1H-imidazole-4-carboxylate (13,875 g 0,090 mo is b) phenylboronic acid (13,16 g to 0.108 mol) and CuI (0.85 grams, 0,0045 mol) in ethanol/water (900 ml, 1/1 (vol./about.)) was divided into 12 equal parts and reacted in parallel at 85°C for 60 hours. After cooling to room temperature, these 12 parts were combined and concentrated in vacuum. The residue was purified flash chromatography (ethyl acetate/petroleum ether 40-65=1/1 (vol./vol.), the result that was obtained ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (5,88 g, yield 26%).

1H-NMR (400 MHz, CDCl3): δ of 1.42 (t, J=7 Hz, 3H), 2,47 (s, 3H), 4,40 (sq, J=7 Hz, 2H), 7,26-7,31 (m, 2H), of 7.48-7,56 (m, 3H), to 7.59 (s, 1H).

Part B:(-)-CIS-mertaniemi (CAS 38235-68-6) (0.95 ml, 5.7 mmol) was dissolved in anhydrous dichloromethane (15 ml), then was added (CH3)3Al (2,9 ml of 2M solution in heptane, 5.8 mmol). The resulting mixture was stirred with a magnetic stirrer for 10 min at room temperature, after which was added ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (1.1 g, 4.8 mmol). The resulting mixture was stirred at 35°C for 16 h, poured into an aqueous solution of NaHCO3was stirred for 30 min and filtered on Hyflo. The filtrate was extracted twice with dichloromethane. The organic layers were dried over Na2SO4filtered and concentrated in vacuum. Subsequent purification with flash chromatography (ethyl acetate/petroleum ether 40-65=1/2 (about./about.)) gave N-[(1R,2S,5R)-rel-6,6-Dima is albicilla[3.1.1]heptane-2-methyl]-5-methyl-1-phenyl-1H-imidazol-4-carboxamid, connection 1 (of 1.05 g, yield 65%).

Melting point: 85-89°C.

Similarly, there were obtained the following compounds 2-7

Connection 2: melting Point: 214-219°C.

Connection 3: melting Point: 167-169°C.

Compound 4: from R-(+)-Binyamina (CAS 32511-34-5).

Melting point: 209-212°C.

Connection 5: endo-(1R)-1,3,3-trimethylbicyclo[2.2.1]heptane-2-amine.

Melting point: 149-152°C.

Compound 6: melting Point: 198-200°C.

Compound 7: melting Point: 232-234°C.

Synthesis of compound 8

Part A:Ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate (4.8 g, yield 21%) was obtained according to the described method (J. Heterocyclic Chem. 1987, 24, 1757-1763) of ethyl 3-aniline-2-nitroaniline (23,6 g, 0.01 mol) and triethylorthoformate (150 ml). Originally formed crude product was purified flash chromatography (eluent: diethyl ether), Rf (diethyl ether ~0,15), to obtain pure ethyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate in the form of oil.

Part BEthyl 2-methyl-1-phenyl-1H-imidazole-4-carboxylate (2.25 g, 0.012 mol) are subjected to interaction (similar to the procedure described above for compound 1) with AlMesub> 3(7.2 ml of a 2M solution in hexane, 0,0144 mol) and 1-adamantanamine·HCl (2.25 g, 0.012 mol). Originally formed crude product was purified flash chromatography (eluent: diethyl ether)to obtain N-substituted-2-methyl-1-phenyl-1H-imidazol-4-carboxamide (2.2 g, yield 55%). Melting point: 207-210°C.

Compound 9 was obtained similarly to compound 6 from (-)-CIS-mertaniemi (CAS 38235-68-6).

Melting point: 124-127°C.

Compound 10: N-substituted-2-methyl-1-phenyl-1H-imidazol-4-carboxamide (0.33 g, 0.001 mol) was dissolved in anhydrous tetrahydrofuran (25 ml). The resulting solution was slowly added to a solution of Diisopropylamine lithium (1.25 ml 2M solution in heptane/THF, 0,0025 mol LDA) under N2at -70°C. Then added to the solution under the conditions (0.14 g, 0.001 mol) in anhydrous THF, and the resulting solution was stirred for 1 hour at -70°C. the Solution was allowed to reach room temperature and was stirred for another 2 h, then neutralized aqueous acetic acid. After concentration in vacuo the resulting residue was purified flash chromatography (diethyl ether/petroleum ether (40-60)=3/1 (vol./vol.), to obtain compound 10 and compound 11, respectively.

The melting point of compound (10: 180-183°C.

Compound 11: Compound 11 was obtained more than the effectively, the reaction of ethyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (compare the corresponding methyl ester 3j in J. Heterocyclic Chem. 1987, 24, 1757-1763) AlMe31-adamantanamine·HCl, in accordance with the methods of amidation Weinrebe (Weinreb)described above for compounds 1,part B.

Melting point: 201-204°C.

The synthesis of compounds 12

Part A:Ethyl 2,5-dimethyl-1-(3-methoxyphenyl)-1H-imidazole-4-carboxylate was obtained analogously to the procedure described in J. Heterocyclic Chem. 1987, 24, 1757-1763, from ethyl 3-(3-methoxybenzylamine)-3-methyl-2-nitroaniline and triethylorthoformate.

Part B:Ethyl 2,5-dimethyl-1-(3-methoxyphenyl)-1H-imidazole-4-carboxylate was amitirova (similar to the procedure described above for compound 1) (under stirring at 70°C for 16 h) with AlMe3and (-)-CIS-mertaniemi (CAS 38235-68-6), forming a connection 12. Melting point: 153 to 155°C.

Similarly, there were obtained compounds 13-20.

other: 156-158°Cother: 214-216°Cother: 190-193°C

so what.: 217-223°C other: 216-218°Cother: 137-140°C

other: 119-121°Cother: 186-188°C

Synthesis of compound 21

Part A:To stir magnetic stirrer, a suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (15,42 g, 0,100 mol) in anhydrous THF was slowly added sodium hydride (NaH) (4,88 g of 60%suspension, 0,120 mol) and the resulting mixture was stirred at room temperature for 30 min Benzylbromide (13,8 ml, 0,120 mol) was slowly added, and the resulting mixture was reacted for 16 hours. Then to the mixture was added water. The organic layer was separated from the aqueous layer. The aqueous layer was extracted 3 times with ethyl acetate. The organic layer was dried over MgSO4filtered and fully concentrated in the form of oil. The obtained residue was purified (to separate the two formed regioisomer) flash chromatography (gradient of diethyl ether/ethyl acetate) to obtain ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (11.4 g, yield 47%).

1H-NMR (400 MHz, CDCl3): δ of 1.40 (t, J=7 Hz, 3H), of 2.45 (s, 3H), 4,37 (sq, J=7 Hz, 2H), 5,10 (s, 2H), 7.03 is-was 7.08 (m, 2H), 7,28-7,38 (m, 3H), of 7.48 (s, 1H).

Part B:Ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (1.5 g, 0,0061 mol) of p will gorhaut interaction with the substituted-1-amine·HCl (1,72 g, 0,0092 mol) and Al(CH3)3(4.6 ml, 2M in hexane, 0,0092 mol) in 1,2-dichloroethane (20 ml) at 70°C for 40 h according to the procedure described for compound 1,part B. Purification with flash chromatography (ethyl acetate/petroleum ether = 1/1 (vol./about.)) gave compound 21 (1.24 g, 58%).

Melting point: 182-184°C.

Similarly, there were obtained compounds 22, 23 and 23A:

Synthesis of compound 22

Compound 22 was obtained by reaction of 3-(methylsulfonylamino)propylchloride with ethyl 4-methyl-1H-imidazole-5-carboxylate, using the K2CO3as the base in DMF at 90°C for 20 h, followed by separation of the two regioisomers formed flash chromatography (ethyl acetate/methanol = 9/1 (about./vol.), followed by catalyzed Al(CH3)3the amidation with (-)-CIS-mertaniemi.

The connection 22. Melting point: 84-108°C. Rfof 0.35 (EtOAc/MeOH = 4/1 (about./vol.)).

Compound 23 (from endo-(1R)-1,3,3-trimethylbicyclo[2.2.1]heptane-2-amine). Melting point: 149-156°C. Rfof 0.4 (EtOAc/MeOH = 4/1 (about./vol.)).

The synthesis of compounds 23A

Compound 23A was obtained by the interaction of 1-methylpiperidin-2-ylmethyl·HCl ether methanesulfonate acid with ethyl 4-methyl-1H-imidazole-5-carboxylate, used the eat KOH as base in dimethyl sulfoxide at 60°C for 40 h, with the subsequent separation of the regioisomers formed flash chromatography (dichloromethane/methanol = 95/5 (about./vol.), with the subsequent conversion of the resulting ester to the corresponding carboxylic acid (lithium hydroxide/THF/water at 60°C for 20 h) and the interaction of the formed carboxylic acid with (-)-CIS-mertaniemi using PyBOP (benzotriazol-1-yloxytris(pyrrolidino)-phosphonium hexaflurophosphate) as cross-linking reagent in the presence of diisopropylethylamine in dichloromethane. The crude compound 23A was further purified flash chromatography (dichloromethane/methanol = 95/5 (about./vol.), followed by conversion of the selected free base to the hydrochloride. Compound 23A. Melting point: 148-153°C.

Synthesis of compound 24

Part A:To stir magnetic stirrer, a solution of ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (8,4 g, 0,0345 mol) in methanol (200 ml) was slowly added a solution of KOH (7,3 g, purity 85%, 0,110 mol) and the resulting mixture was heated at 80°C for 2 hours. The solution was cooled to room temperature and concentrated, then added HCl (9,2 ml). The precipitate was collected by filtration to obtain N-benzyl-5-methyl-1H-imidazole-4-carboxylic acid (6,77 g, yield 91%).

Melting point: 292°C (decomposition).

Part B:To stir magnetic stirrer, a solution of N-benzyl-5-methyl-1H and idazole-4-carboxylic acid (6,77 g, 0,031 mol) in anhydrous acetonitrile (35 ml) was sequentially added diisopropylethylamine (DIPEA) (17,2 ml, 0,0992 mol), HBTU (14,098 g, 0,0372 mol) and methoxyethylamine (3,63 g, 0,0372 mol). The resulting mixture was reacted at 20°C for 16 h and was subsequently concentrated in a vacuum. The obtained residue was collected with ethyl acetate and sequentially washed with 5%aqueous solution of NaHCO3and water. The organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The resulting oil residue (of 18.45 g) was purified flash chromatography (ethyl acetate/acetone = 7/3 (about./about.)) obtaining N-methoxy-N-methyl-5-methyl-1-benzyl-1H-imidazole-4-carboxamide (10,77 g, yield 82%).

MN+= 260.

1H-NMR (400 MHz, CDCl3): δ was 2.34 (s, 3H), 3,47 (s, 3H), of 3.77 (s, 3H), 5,09 (s, 2H), 7,05-7,10 (m, 2H), 7.18 in-7,28 (m, 3H), of 7.48 (s, 1H).

Part C:To stir magnetic stirrer, a solution of 1-naphthylacetamide (49 ml, 0.25 M in THF, 0,00123 mol) was added a solution of N-methoxy-N-methyl-5-methyl-1-benzyl-1H-imidazole-4-carboxamide (2,69 g, 0,0104 mol) in anhydrous THF (10 ml) and the resulting solution was stirred for 1 hour. The reaction mixture was neutralized 1N HCl (21 ml), then was extracted with ethyl acetate (EtOAc). The EtOAc layer was twice washed with water, dried over MgSO4that was filtered and concentrated in vacuum. The crude residue was purified flash chromatography (utilized the t/petroleum ether = 1/1 (vol./vol.), followed by another flash chromatographic purification (dichloromethane/methanol = 99/1 (about./vol.), the resulting net connection 24 (1.35 g, yield 66%) as oil.

1H-NMR (400 MHz, CDCl3): δ of 2.58 (s, 3H), 5,12 (s, 2H), 7,08-7,13 (m, 2H), 7,31-7,40 (m, 3H), 7,44-7,56 (m, 4H), 7,78-of 7.82 (m, 1H), 7,84-7,89 (m, 1H), 7,92-of 7.96 (m, 1H), 8,16 is 8.22 (m, 1H).

The synthesis of compounds 25

Similarly, there was obtained compound 25 (N-methoxy-N-methyl-5-methyl-1-phenyl-1H-imidazole-4-carboxamide and n-hexalite in anhydrous diethyl ether). Flash chromatographic purification (methyl tert-butyl ether/petroleum ether = 1/3 (about./about.)) the initial allocation of the crude product gave compound 25 (yield 24%) as oil pale yellow color.

The connection 25.1H-NMR (400 MHz, CDCl3): δ 0,86-of 0.94 (m, 3H), of 1.25 to 1.47 (m, 6H), 1,70-1,80 (m, 2H), 2,50 (s, 3H), 3.04 from-3,11 (m, 2H), 7,26-to 7.32 (m, 2H), 7,50-to 7.59 (m, 4H).

Similarly, there was obtained compound 26

The connection 26; Rf(methanol/dichloromethane = 3/97 (about./vol.), silica gel) = 0,65.

Synthesis of compound 27

To stir magnetic stirrer, a solution of N-(adamant-1-yl)-1-phenyl-1H-imidazole-4-carboxylate (1,61 g of 0.005 mol) in dichloromethane (20 ml) was added a solution of Br2(0,52 ml 0,010 mmol) in dichloromethane (5 ml). The resulting mixture was reacted at room temperature for 4 hours. Dichloromethane and 5%aqueous solution of NaHCO3was added to the reaction mixture. The separated organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (dichloromethane/acetone = 19/1 (about./vol.)). Subsequent recrystallization from acetonitrile gave N-(adamant-1-yl)-5-bromo-1-phenyl-1H-imidazol-4-carboxamide (0.51 g, yield 26%). Melting point: 229-232°C.

Similarly, there was obtained compound 28 with 17%yield using N-chlorosuccinimide (NCS) as gloriously agent, for 40 hours at room temperature. Flash chromatography (dichloromethane/acetone = 19/1 (about./vol.)). Melting point: 209-213°C.

Synthesis of compound 29

To stir magnetic stirrer, a solution of N-(adamant-1-yl)-5-bromo-1-phenyl-1H-imidazole-4-carboxylate (0,60 g) in dichloromethane (20 ml) was added a solution of Br2(0,30 ml) in dichloromethane (5 ml) and triethylamine (0.21 in ml). The resulting mixture was reacted at room temperature for 50 hours. Dichloromethane and 5%aqueous solution of NaHCO3was added to the reaction mixture. The separated organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (dichloromethane). Subsequent stirring in diethyl ether, followed Phi is Tricia, gave N-(adamant-1-yl)-2,5-dibromo-1-phenyl-1H-imidazol-4-carboxamide (0.29 grams). Melting point: 228-231°C.

Similarly, there was obtained compound 30 with a 32%yield of N-(adamant-1-yl)-5-chloro-1-phenyl-1H-imidazole-4-carboxylate using N-chlorosuccinimide (NCS) as glorieuses agent. Melting point: 193-195°C.

Synthesis of compound 31

To stir magnetic stirrer suspension of N-(adamant-1-yl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate (2,01 g 0,006 mol) in anhydrous THF (20 ml) under N2at -70°C was slowly added a solution of diisopropylamide lithium (LDA) (9,0 ml of 2M solution in heptane/THF, 0.018 mol LDA) and the resulting solution was stirred for 1 hour under N2at -70°C. Then was added a solution of para-toluensulfonate (1.63 g, 0,009 mol) in anhydrous THF (10 ml) and the resulting solution was stirred for 1 hour at -70°C. the Solution was brought to room temperature and was stirred for another 12 h, after which the reaction was stopped with water. The mixture was extracted with diethyl ether. The organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (dichloromethane/acetone = 19/1 (about./about.)) and subsequently recrystallized from acetonitrile, resulting in the received connection 31 (0,23 g, yield 11%). That is ka melting compounds 31: 246-248°C.

Similarly, the received connection 32 of N-(adamant-1-yl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate using dimethyl disulfide (CH3SSCH3with 31%yield. Melting point: 172-173°C.

Similarly, there was obtained compound 33 of N-(adamant-1-yl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate using a pair of tolylaldehyde with 28%yield. Melting point: 216-218°C.

Similarly, there was obtained compound 33A of N-(adamant-1-yl)-2-methyl-1-phenyl-1H-imidazole-4-carboxylate using a pair of tolylsulfochloride. Melting point: 242-244°C.

Similarly, the received connection 34 of N-(adamant-1-yl)-1-phenyl-1H-imidazole-4-carboxylate using a pair of thailandthailand with a 7%yield.

Melting point: 237-239°C.

Similarly, there was obtained compound 35 of N-(adamant-1-yl)-1-phenyl-1H-imidazole-4-carboxylate using dimethyl disulfide (CH3SSCH3with 12% yield.

Melting point: 166-168°C.

General information: All connections 36-114 were obtained according to the General method shown in scheme 3, above. The compounds of General formula (IV) were transformed (see diagram 1 above) through according to the corresponding carboxylic acid of the General structure (V) into compounds of General formula (I), where X represents subgroup (ii)

Synthesis of compound 36

Part A:NaNO2(13.8 g) was dissolved in water (48 ml) at 4°C. the resulting solution was slowly added to stir magnetic stirrer, a solution of methyl ester 3-oxomalonate acid (17,4 g, 0.15 mol), keeping the temperature <5°C. After stirring the mixture for 2 hours was added water (120 ml) and the resulting mixture was twice extracted with diethyl ether. The combined organic layers are then washed with water and 5%aqueous solution of NaHCO3. The organic layer was dried over MgSO4, was filtered and was fully concentrated to obtain crude methyl ester 2-hydroxyimino-3-oxomalonate acid (24 g) as a colorless oil without further purification.

1H-NMR (400 MHz, CDCl3): δ to 2.42 (s, 3H), 3,91 (s, 3H), 9,90 (users, 1H).

Part B:The crude methyl ester 2-hydroxyimino-3-oxomalonate acid (24 g, ~0.15 mol)dissolved in stir magnetic stirrer, a mixture of acetic acid (293 ml), acetic anhydride (110 ml) and Pd/C (4 g)was hydrogenosomal for 20 h at room temperature at a pressure of H21 ATM. After filtration on Hyflo acetic acid and acetic anhydride were removed by concentration in vacuo. The crude mixture was purified flash chromatography (dichloromethane/methanol = 95/5 (about./vol.), the resulting received the methyl ester of 2-acetylamino-3-oxomalonate acid (16.7 g, yield 60%) as a white solid. Rf(dichloromethane/methanol = 95/5 (about./about.)) = 0,4.

1H-NMR (400 MHz, CDCl3): δ of 2.08 (s, 3H), 2.40 a (s, 3H), 3,83 (s, 3H), from 5.29 (d, J~7 Hz, 1H), of 6.71 (user., 1H).

Part C:To stir magnetic stirrer, a solution of methyl ester of 2-acetylamino-3-oxomalonate acid (5 g, of 28.9 mmol) in butyronitrile was added aniline (3.42 ml) and triperoxonane acid (2,89 ml), after which the resulting mixture was heated under reflux for 45 min Butyronitrile was removed in vacuum at room temperature and the obtained residues were collected dichloromethane and washed twice with an aqueous solution of potassium carbonate. The organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (diethyl ether/acetone = 4/1 (about./about.)) with the receipt of methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (3.0 g, yield 46%).

1H-NMR (400 MHz, CDCl3): δ 2,22 (s, 3H), of 2.33 (s, 3H), 3,91 (s, 3H), 7.18 in-7,22 (m, 2H), 7,51-to 7.59 (m, 3H).

Part D:To stir magnetic stirrer, a solution of methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (8.0 g, 0.035 mol) in THF (100 ml) was added LiOH solution (1.68 g) in water (100 ml). The resulting mixture was heated at 70°C for 16 h, then cooled to room temperature and acidified with 2 molar equivalents of 1 n HCl solution. Formed precipitate was collected with p is the receiving of the crude 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (7.0 g, yield 93%).

1H-NMR (400 MHz, DMSO-d6): δ 2,31 (s, 3H), 2,43 (s, 3H), 7,56-to 7.61 (m, 2H), 7,66-7,71 (m, 3H).

Part E:To stir magnetic stirrer, a solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.6 g, 0,0028 mol) in acetonitrile (35 ml) was sequentially added diisopropylethylamine (DIPEA, base Chunga) (1.27 g), hexaflurophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU) (1.27 g) and (-)-CIS-mertaniemi (1,05 ml, 0,0028 mol). The resulting mixture was reacted at 20°C for 16 h and was subsequently concentrated in a vacuum. The obtained residue was collected dichloromethane and washed with 5%aqueous solution of NaHCO3. The organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (dichloromethane/methanol = 95/5 (about./about.)) obtaining N-[(1R,2S,5R)-rel-6,6-dimethylbicyclo[3.1.1]heptane-2-methyl]-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (compound 36) (0,70 g, yield 72%). Rf(silica gel/dichloromethane/methanol = 95/5 (about./about.)) ~0,6.

Similarly, there were obtained compounds 37-47:

Compound 37:1H-NMR (400 MHz, CDCl3): δ 1.26 in (t, J=7 Hz, 3H), 2,41 (s, 3H), 2,56 (sq, J=7 Hz, 2H), 7.23 percent-7,28 (m, 2H), 7,49-of 7.60 (m, 6H), 7,66 (d, J=8 Hz, 1H), 7,88 (d, J=8 Hz, 1H), 8,11 (d, J=8 Hz, 1H), 8,28 (d, J=8 Hz, 1H), 9,85 (s, 1H).

Compound 38: the Point of the melt is to be placed: 177-179°C.

Compound 39: endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptane-2-amine.

Melting point: 130-132°C (DSC).

The connection 40: endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptane-2-amine.

1H-NMR (300 MHz, CDCl3): δ 0,89 (s, 3H), of 0.96 (t, J=7 Hz, 3H), of 1.12 (s, 3H), 1,17-of 1.27 (m, 5H), 1,40-1,60 (m, 2H), 1,67-of 1.81 (m, 3H), of 2.15 (s, 3H), 2,70-2,95 (m, 2H), 3,78 (DD, J~10 and 2 Hz, 1H), 7.18 in-of 7.23 (m, 2H), 7,34 (userd, J~10 Hz, 1H), of 7.48-EUR 7.57 (m, 3H).

Compound 41: melting Point: 117,5-120°C (DSC).

The connection 42: melting Point: 193-196°C (DSC).

Compound 43: melting Point: 157-159°C (DSC).

Compound 44: melting Point: 76-79°C (DSC).

Compound 45: R-(+)-phenethylamine.

1H-NMR (300 MHz, CDCl3): δ 1,58-to 1.61 (m, 3H), 2,17 (s, 3H), of 2.33 (s, 3H), 5.25 to 5.35 (m, 1H), 7,15-rate of 7.54 (m, 11H).

The connection 46: melting Point: 139-141°C (DSC).

Compound 47:1H-NMR (400 MHz, CDCl3): δ 1,10 (s, 9H), 1.69 in (s, 3H), 2,24 (s, 3H), 7,00-7,06 (m, 2H), 7,46-of 7.55 (m, 3H), peak NH invisible and probably merged with the peak of the H2O at δ 1,60.

Synthesis of compound 48

To stir magnetic stirrer, a solution of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.66 g, 0,00306 mol) in dichloromethane (35 ml) is sledovatelno added diisopropylethylamine (DIPEA) (3.1 ml), CIP (hexaphosphate 2-chloro-1,3-dimethylimidazolidine) (2.55 g) and 3-hydroxyadamantane (0,612 g, 0,00366 mol). The resulting mixture was reacted at 20°C for 16 h, then was concentrated in vacuum. The obtained residue was collected dichloromethane and washed with 5%aqueous solution of NaHCO3. The organic layer was dried over MgSO4that was filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (dichloromethane/methanol = 98/2 (about./about.)) obtaining N-(3-gidroksilamin-1-yl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.75 g, yield 67%). Rf(silica gel/dichloromethane/methanol = 98/2 (about./about.)) ~0,6. Melting point: 215-220°C.

Similarly, there were obtained compounds 49-85:

Compound 49: melting Point: 245-247°C.

Compound 50: melting Point: 251-253°C.

Compound 51: (from racemic endo-2-aminobutyl[2.2.1]heptane:

1H-NMR (400 MHz, DMSO-d6): δ 0,85-of 1.64 (m, 8H), to 2.13 (s, 3H), 2,21 (users, 1H), 2,24 (s, 3H), 2.40 a (users, 1H), 4,07-4,16 (m, 1H), 7,34 (userd, J~8 Hz, 2H), 7,40 (userd, J~7 Hz, 1H), 7,52-to 7.61 (m, 3H).

Compound 52: (from nordmanniana): melting Point: 147-150°C.

Compound 53: melting Point: 111-113°C.

/p>

The connection 54: melting Point: 204-207°C.

Compound 55: melting Point: 115-117°C.

The connection 56: melting Point: 208-210°C.

Compound 57: melting Point: 243-245°C.

The connection 58: melting Point: 178-181°C.

Compound 59:1H-NMR (300 MHz, CDCl3): δ of 2.28 (s, 3H), 2,43 (s, 3H), 7.23 percent-7,27 (m, 2H), 7,55-of 7.60 (m, 3H), 7,79 (DD, J=9 and 2 Hz, 1H), they were 8.22 (d, J=9 Hz, 1H), 8,42 (s, 1H), to 8.62 (d, J~5 Hz, 1H), to 8.94 (d, J=5 Hz, 1H), of 10.25 (users, 1H).

Melting point: 198,5°C (DSC).

Compound 60:1H-NMR (300 MHz, CDCl3): δ to 2.29 (s, 3H), 2,43 (s, 3H), 7.23 percent-7,27 (m, 2H), 7,54-of 7.60 (m, 3H), 7,70-7,76 (m, 2H), 7,95 (d, J=8 Hz, 1H), 8.17-a 8,21 (m, 1H), 8,27-8,29 (m, 1H), 8,63 (d, J=8 Hz, 1H), 10,20 (users, 1H).

Melting point: 241,5°C (DSC).

Compound 61: melting Point: 171-172°C.

Compound 62: melting Point: ~113°C. Rf(diethyl ether/petroleum ether = 1/1 (vol./about.)) ~0,15.

1H-NMR (400 MHz, CDCl3): δ 1,66-of 1.78 (m, 6H), 2,08-to 2.18 (m, 9H), are 2.19 (s, 3H), up 3.22 (s, 3H), 4,59 (s, 3H), 7,06 (users, 1H), 7,25-7,30 (m, 2H), 7,47-of 7.55 (m, 3H).

Compound 63: melting Point: 221-223°C.

Compound 64: melting Point: 170-172°C.

The connection 65 melting Point: 168-170°C.

Compound 66: (from endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptane-2-amine).

Melting point: 102-107°C.

Compound 67: melting Point: 166-168°C.

Compound 68: melting Point: 208-210°C.

Compound 69: melting Point: 154-156°C.

Compound 70: (from racemic endo-2-aminobutyl[2.2.1]heptane).

Melting point: 165-167°C.

Compound 71: melting Point: 69-72°C.

Compound 72:1H-NMR (400 MHz, CDCl3): δ 1,66-of 1.78 (m, 6H), 2,08-2,17 (m, 9H), 2,32 (s, 3H), of 2.51 (s, 3H), 6,95 (users, 1H), 7,51 (d, J=4 Hz, 1H), 7,83 (d, J=4 Hz, 1H).

Melting point: 130-133°C.

Compound 73: (from endo-(1S)-1,3,3-trimethylbicyclo[2.2.1]heptane-2-amine).

Melting point: 146-148°C.

Compound 74:1H-NMR (400 MHz, CDCl3): δ 1,65-of 1.78 (m, 6H), 2,08-2,19 (m, 12H), and 2.27 (s, 3H), of 3.78 (s, 3H), 6,97 (users, 1H), 7.03 is for 7.12 (m, 3H), 7,43-7,49 (m, 1H).

Compound 75:1H-NMR (400 MHz, CDCl3): δ of 2.21 (s, 3H), is 2.37 (s, 3H), 3,82 (s, 3H), 7,07-7,13 (m, 2H), 7,16-7,21 (m, 1H), 7,46-to 7.59 (m, 4H), 7,66 (d, J=8 Hz, 1H), 7,87 (d, J=8 Hz, 1H), 8,13 (d, J=8 Hz, 1H), 8,28 (d, J=8 Hz, 1H), 9,70 (users, 1H).

Compound 76: melting Point: 217-219°C.

Compound 77: melting Point: 217-218°C. In the synthesis of this particular connection in the last stages of the reaction as a cross-linking reagent used chloride of 2-chloro-1,3-dimethylimidazolidine instead CIP.

Compound 78: melting Point: 186-187°C. In the synthesis of this particular connection in the last stages of the reaction as a cross-linking reagent used chloride of 2-chloro-1,3-dimethylimidazolidine instead CIP.

Compound 79: melting Point: 123-125°C.

Compound 80: melting Point: 214-217°C.

Compound 81: melting Point: 149-150°C.

Compound 82:1H-NMR (400 MHz, CDCl3): δ 0,75-0,80 (m, 2H), 0,97-1,03 (m, 2H), 1,45-of 1.52 (m, 1H), 1,65-of 1.78 (m, 6H), 2,08-to 2.18 (m, 9H), was 2.34 (s, 3H), 6,98 (users, 1H), 7.23 percent-7,28 (m, 2H), 7,45-7,56 (m, 3H).

In the synthesis of this particular connection in the last stages of the reaction as a cross-linking reagent used chloride of 2-chloro-1,3-dimethylimidazolidine instead CIP.

Compound 83:1H-NMR (400 MHz, CDCl3): δ 0,75-0,80 (m, 2H), 0,97-1,02 (m, 2H), 1,45-of 1.52 (m, 1H), of 2.38 (s, 3H), 4,80 (userd, J=7 Hz, 2H), 7,25-7,30 (m, 2H), 7,35 (ushort, J=7 Hz, 1H), 7,47-to 7.68 (m, 7H).

Compound 84: melting Point: 136-137°C.

Compound 85: Rf (dichloromethane/methanol = 98/2 (about./about.))=0,2

Compound 86: melting Point: 242-244°C. MH+(free base) = 368. Compound 86 was obtained from racemic Exo-2-aminobutyl[2.2.1]heptane and methyl ester of 2-acetylamino-3-oxomalonate acid, analogously to the synthesis of compound 36 as described in the above description,part C.

Compound 87: melting Point: 181-183°C. MH+= 410. Compound 87 was obtained from (-)-CIS-mertaniemi (CAS 38235-68-6) and methyl ester of 2-acetylamino-3-oxomalonate acid, analogously to synthesis, as described in the description above for compounds 36,part C.

Compound 88: Rf(dichloromethane/methanol = 97/3 (about./about.)) = 0,2. In the synthesis of this particular connection in the last stages of the reaction as a crosslinking reagent was used chloride of 2-chloro-1,3-dimethylimidazolidine instead CIP.

Synthesis of compound 89

Part A:To stir magnetic stirrer, a suspension of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.4 g, of 1.85 mmol) in CHCl3(4 ml) was added oxalicacid (0.34 g, 2,685 mmol)and the resulting mixture is reacted at 58°C for 2 h, then was concentrated in vacuum. The obtained residue was collected dichloromethane followed by the addition of diisopropylethylamine (0.28 g, 2,148 mmol). For the eat to the reaction mixture was slowly added a solution of 2,3-dichloraniline (0.35 g, 2,146 mmol) in dichloromethane (5 ml), and the mixture was reacted for 2 hours at room temperature, then was concentrated in vacuum. The obtained residue was purified flash chromatography (dichloromethane) to give N-(2,3-dichlorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (compound 89) (0.24 g, yield 36%).

Melting point: 127-129°C.

Similarly, there were obtained compounds 90-114:

Compound 90:1H-NMR (400 MHz, CDCl3): δ 1,50-of 1.78 (m, 12H), 1,88-to 1.98 (m, 2H), 2,18 (s, 3H), of 2.34 (s, 3H), 4,12-to 4.23 (m, 1H), 7,10-7,20 (m, 3H), of 7.48-EUR 7.57 (m, 3H).

LC/MS: retention time: 2,88 min; MH+= 326.

Compound 91:1H-NMR (400 MHz, CDCl3): δ 1,65-2,07 (m, 9H), 2,17 (s, 3H), 2,32 (s, 3H), of 3.73 (s, 2H), 7,16-7,20 (m, 2H), 7,41 (users, 1H), 7,49-EUR 7.57 (m, 3H).

LC/MS: retention time: 2,22 min; MH+= 314.

Compound 92:1H-NMR (400 MHz, CDCl3): δ 1.56 to of 1.66 (m, 4H), 1,73-to 1.87 (m, 4H), 2,18 (users, 6H), of 3.65 (t, J=7 Hz, 2H), 3,91 (t, J=7 Hz, 2H), 7,19-of 7.23 (m, 2H), 7,47-7,56 (m, 3H).

LC/MS: retention time: 2,12 min; MH+= 297.

Compound 93: Rf(dichloromethane/methanol = 95/5 (about./about.)) = 0,65.

Compound 94: LC/MS: retention time: 1,88 min; MH+= 307.

Compound 95: melting Point: 134-135°C.

Compound 96: melting Point: 119-121°C.

Compound 97: Rf(dichloromethane/methanol = 97/3 (about./about.)) = 0,6.

Compound 98: melting Point: 125-127°C.

Compound 99:1H-NMR (400 MHz, CDCl3): δ 1,60 (d, J=7 Hz, 3H), 2,17 (s, 3H), of 2.33 (s, 3H), and 5.30 (quintet, J=7 Hz, 1H), 7,15-rate of 7.54 (m, 11H).

LC/MS: retention time: 2,60 min; MH+= 320.

Compound 100:1H-NMR (400 MHz, CDCl3): δ of 2.15 (s, 3H), of 2.36 (s, 3H), of 2.97 (DD, J~15 and 6 Hz, 2H), 3,40 (DD, J~15 and 8 Hz, 2H), 4,88-to 4.98 (m, 1H), 7,16-7,27 (m, 6H), 7,37 (userd, J~8 Hz, 1H), of 7.48-EUR 7.57 (m, 3H).

LC/MS: retention time: 2,63 min; MH+= 332.

Compound 101:1H-NMR (400 MHz, CDCl3): δ to 2.18 (s, 3H), of 2.34 (s, 3H), 6,44 (d, J=8 Hz, 1H), 7,15-7,38 (m, 12H), of 7.48-EUR 7.57 (m, 3H), 7,92 (userd, J~8 Hz, 1H).

LC/MS: retention time: 3,59 min; MH+= 382.

Compound 102: LC/MS: retention time: 1,30 min; MH+= 338.

Compound 103: LC/MS: retention time: 2,81 min; MH+= 356.

Compound 104: LC/MS: retention time: 2,98 min; MH+= 396.

Compound 105: LC/MS: retention time: 2,17 min; MH+= 300.

Compound 106: LC/MS: retention time: 2,08 min; MH+= 346.

Compound 107: melting Point: 117-118°C.

Compound 108: melting Point: 123-125°C.

Compound 109: melting Point: 130-132°C.

Compound 110:1H-NMR (400 MHz, CDCl3): δ 2,17 (s, 3H), is 2.37 (s, 3H), 3,86 (s, 3H), 3,88 (s, 3H), 4,55 (d, J~6 Hz, 2H), PC 6.82 (d, J=8 Hz, 1H), 6.90 to-to 6.95 (m, 2H), 7,17-7,21 (m, 2H), 7,45 (users, 1H), 7,50-EUR 7.57 (m, 3H).

Compound 111: Rf(dichloromethane/methanol = 95/5 (about./about.)) = 0,65.

Compound 112:1H-NMR (400 MHz, CDCl3): δ of 2.16 (s, 3H), of 2.35 (s, 3H), of 2.93 (t, J=7 Hz, 2H), 3,66 (sq, J~7 Hz, 2H), 7,16-7,34 (m, 8H), of 7.48-7,56 (m, 3H).

LC/MS: retention time: 3,13 min; MH+= 320.

Compound 113: LC/MS: retention time: to 2.67 min; MH+= 352.

Compound 114:1H-NMR (400 MHz, CDCl3): δ 0,94-of 1.05 (m, 2H), 1,11-to 1.31 (m, 3H), 1,52-to 1.87 (m, 6H), to 2.18 (s, 3H), of 2.35 (s, 3H), of 3.25 (t, J=7 Hz, 2H), 7,16-7,21 (m, 2H), 7,22-7,29 (m, 1H), of 7.48-EUR 7.57 (m, 3H).

LC/MS: retention time: was 2.76 min; MH+= 312.

EXAMPLE 3: a PHARMACEUTICAL FORM of CONNECTION 1

For oral (p.o.) introduction:To the required amount (0.5 to 5 mg) of solid compound 1 in a glass test tube was added a certain amount of glass beads and the solid is crushed by shaking for 2 minutes After adding 1 ml of 1%solution of methylcellulose is in the water and 2% (vol./about.) Poloxamer 188 (Lutrol F68) connection suspended by shaking for 10 minutes Then the pH was brought to 7 with a few drops of aqueous NaOH (0.1 N.). Remaining in suspension particles are then suspended in the ultrasonic bath.

For vnutriarterialnah (I.P. Pavlova.) introduction:To the required amount (0.5 to 15 mg) solid connections 1 in the glass tube was added a certain amount of glass beads and the solid is crushed by shaking for 2 minutes After adding 1 ml of 1%solution of methylcellulose and 5%mannitol in water, the connection is suspended by shaking for 10 minutes the pH was brought to 7.

EXAMPLE 4: the results of the PHARMACOLOGICAL TEST

Data on the affinity cannabinoid receptor, obtained according to the methods described above, are shown in the table below. BMS-I, BMS-II, BMS-III represent the three imidazole given as examples in WO 01/58869 (there examples 64, 65 and 66, respectively). All three of these certain imidazole derivatives contain L-phenylalaninamide carboxamido group in position 4 of them (1H)-imidazole group, as shown below. The present invention includes new derivatives of 1H-imidazole, in which there is no specified L-phenylalaninamide carboxamidine group, but which are approximately 100 times higher affinity for the receptor CB2compared with the compounds of the prior art shown is suspended in the examples of WO 01/58869, as becomes apparent from the data presented in table 1.

Table 1
Cannabinoid SV1-
receptor human
Cannabinoid SV2-
receptor human
ConnectionThe affinity ofIn vitro- pKiThe affinity ofIn vitro- pKi
BMS-I-6,4
BMS-II-<6,0
BMS-III-7,2
Connection 1<6,07,3
Connection 11<6,09,0
The connection 14<6,08,2
The connection 156,2>9,0
The connection 206,68,0
The connection 26-6,8
The connection 33-8,1
Compound 33A6,18,2
The connection 44-8,8
The connection 49<6,08,6
Connection 90-8,3

- = Not determined.

1. The compounds of formula (I)

in which R1represents a hydrogen or halogen atom or C1-3is an alkyl group, with the specified1-3is an alkyl group may include 1-3 fluorine atom, or R1represents cyclopropyl, cyano or methylsulfonyl group,
R2p is ecstasy a phenyl group, which may be substituted by 1 Deputy Y is selected from methoxy, chlorine, fluorine, trifloromethyl and cyano, or
R2represents pyridyloxy group,
provided that R2is not 6-methyl-2-peredelnoj group, or
R2is a fully saturated 6 to 7 membered monocyclic, condensed bicyclic ring system, or
R2represents benzothiazolyl, benzodioxolyl or thiazole group, and these groups may be substituted by 1 fluorine atom, or
R2represents a group of the General formula CH2-R5in which R5represents a phenyl group, or R5is a fully saturated 7-membered condensed bicyclic carbocyclic ring system, or R5represents piperidino tertrahydrofuran ring or ring system, which may be substituted stands, or
R2represents methylsulfonylamino (C3) alkyl group,
R3represents a hydrogen or halogen atom, or a C1-6-alkylsulfonyl or cyano, or
R3represents a C1-8is an alkyl group, with the specified C1-8is an alkyl group may be substituted by 1-3 fluorine atoms, or R3represents a phenyl group, which is esena Deputy Y, where Y has the meaning defined above, or R3represents fornillo group,
R4represents one of the groups (i) or (ii)

where R6represents a C4-8branched or linear alkyl group
or R6represents naftalina group,
R7represents a hydrogen atom or a linear C1-6is an alkyl group,
R8represents a C3-6is an alkyl group substituted by 1-3 fluorine atoms, or
R8represents a C3-8-cycloalkyl group, piperidino group3-8-cycloalkyl-C1-2is an alkyl group, tetrahydrofuranyl-C1-2is an alkyl group, a C5-10-bicycloalkyl group5-10-bicycloalkyl-C1-2is an alkyl group, a C6-10-tricyclohexyl group6-10-tricyclohexyl-C1-2is an alkyl group, and these groups may be substituted by 1-3 substituents selected from methyl or hydroxy, or
R8represents a phenyl group substituted by 1-2 substituents Y as defined above, or
R8represents naftalina, 1,2,3,4-tetrahydronaphthalene or indenolol group, and these groups may be substituted by 1 Deputy Y, or
R8represents phenyl-C1-3-Alki is inuu group, diphenyl-C1-3is an alkyl group, and these groups may be substituted on their phenyl ring 1 Deputy Y, where Y has the meaning mentioned above, or
R8represents a benzyl group substituted by 2 substituents Y, or
R8represents hyalinella, pyridinoline, benzimidazole or naphthylmethyl group which may be substituted by the Deputy Y, where Y has the meaning mentioned above, or
R8represents azabicyclo[3.3.0]octanediol group,
provided that R8neither 6-methoxybenzothiazole-2-ilen group, nor [3-chloro-5-(trifluoromethyl)pyrid-2-yl]methyl group,
or R7and R8together with the nitrogen atom to which they are linked, form a saturated, non-aromatic, monocyclic or bicyclic heterocyclic group containing only one nitrogen atom having 7-10 ring atoms that may be substituted 3 C1-3-alkyl groups,
or R7and R8together with the nitrogen atom to which they are linked, form a saturated monocyclic heterocyclic group, optionally comprising another N atom having 6 ring atoms, and specified heterocyclic group substituted C1-3-alkyl groups,
provided that R7and R8together with the nitrogen atom to which they relate, not about atout trimethylsilanol azabicyclo[3.2.1]octanediol group,
as well as their stereoisomers and pharmaceutically acceptable salts of these compounds of formula (1) and their stereoisomers.

2. Compounds according to claim 1, where R4represents subgroup (ii)

where R1, R2, R3, R7and R8have the meanings as given in claim 1.

3. The compound of formula (XIV)

in which Z represents a C1-3-alkoxygroup, in which R1, R2and R3have the meanings as given in claim 1,
provided that R2is not phenyl, 4-methylphenylene or 4-metoksifenilny group,
moreover, these compounds are useful in the synthesis of compounds of General formula (I).

4. Pharmaceutical composition having modulating receptors cannabinoids ST2activity, comprising a pharmacologically active amount of the compound according to one of claims 1 and 2, or its salt as an active ingredient, and a pharmaceutically acceptable carrier and/or pharmaceutically acceptable auxiliary substance.

5. A method of obtaining a pharmaceutical composition according to claim 4, characterized in that the compound according to one of claims 1 and 2, or its salt are mixed with a pharmaceutically acceptable carrier and/or pharmaceutically acceptable auxiliary substance.

6. The compound according to any one of claims 1 and 2, or its salt to use the training as a drug for the treatment of disorders involving cannabinoid neurotransmission ST2-receptors.

7. The use of compounds according to claims 1 and 2 for preparing a pharmaceutical composition for the treatment of disorders involving cannabinoid neurotransmission ST2-receptors.

8. The use according to claim 7, where these disorders are selected from disorders of the immune system, inflammatory disorders, Huntington's disease, multiple sclerosis, allergies, cancer and pain, including neuropathic pain.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel anhydrous tetomilast type A crystalline form, having powder X-ray diffraction spectrum essentially the same as the powder X-ray diffraction spectrum having characteristic peaks at 2θ = 10.5°, 13.1°, 18.4°, 21.9° and 25.8°, pharmaceutical compositions based thereon and synthesis methods thereof.

EFFECT: considerable advantages in terms of industrial production owing to significantly better filterability.

8 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.

EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.

25 cl, 1 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I): where: X denotes -CH2-, -CH2CH2-; R1 denotes H; R2 and R3 denote H; or one of them denotes H and the other denotes a branched or straight C1-6alkyl, C3-6cycloalkyl or phenyl; where the said C1-6alkyl is possibly substituted with one OH, NH2, C3-6cycloalkyl, phenyl; where any phenyl is possibly substituted with one or two substitutes selected from halogen or C1-6alkyl; R4 denotes H; R5 denotes H, halogen, C1-6alkyl; or a pharmaceutically acceptable salt thereof.

EFFECT: compounds inhibit cholesterol absorption, which enables their use in treating and preventing atherosclerosis.

14 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I): where: X denotes CH2-, -CH2CH2- ; Y denotes -CH2- or O; Y1 denotes -CH2- or O; where at least on of Y and Y1 denote -CH2-; R1 denotes H; R2 and R3 independently denote hydrogen; or one of them denotes H2 and the other denotes a branched or straight C1-6alkyl; where the said C1-6alkyl is possibly substituted with one amino, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C3-6cycloalkyl, phenyl; where any phenyl is possibly substituted with one CN; R4 denotes H; R5 denotes halogen; or its pharmaceutically acceptable salt.

EFFECT: compounds inhibit cholesterol absorption, which enables their use in treating and preventing atherosclerosis.

12 cl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I:

, where: U, V and W independently represent CR5 where R5 stands for H, C1-C6alkyl; Q stands for NR5, NNR5, NO, CR5, where R5 stands for H, C1-C6alkyl; L1 stands for -NR5C(O)-, -NR5C(O)NR5-, -C(O)NR5-, -NR5- and C5heteroaryl, containing 2 N atoms and 1 O atom, where R5 stands for H, C1-C6alkyl; L2 represents bond, -O-, -NR5C(O)-, -NR5C(O)NR5-, -C(O)NR5- ,-NR5-, where R5 stands for H, C1-C6alkyl; n = 0 or 1; m = 0, 1, 2, 3 or 4; R1 stands for C6-C10aryl and C5heteroaryl, containing 1 N atom, condensed with benzene; where any aryl, heteroaryl, contained in R1, can be optionally substituted with 1-3 radicals, which represent halogen, NH2, NO2, CN, C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, C6-C10aryl-C0-C4alkyl, C5-C6heteroaryl-C0-C4alkyl, containing 1 or 2 N, C5-C6heterocycloalkyl-C0-C4alkyl, containing 1 or 2 N and/or O atoms; where methylene fragment of any alkyl group can be optionally substituted with O; where any aryl, heteroaryl or heterocycloalkyl substituent, contained in R1, can be optionally substituted with 1-3 radicals, which independently represent C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup and hydroxy-substituted C1-C6alkyl; R2 represents halogen, NH2, NO2, CN, C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, C6-C10aryl-C0-C4alkyl, C5heteroaryl-C0-C4alkyl, containing 1 or 2 N, C6heterocycloalkyl-C0-C4alkyl, containing 1 or 2 N atoms and/or O; where any aryl, heteroaryl or heterocycloalkyl, contained in R2, is optionally substituted with 1-3 radicals, which independently represent halogen, NH2, NO2, CN, C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxygroup; R3 represents H, C1-C6alkyl; R4 represents H, -XR6, -XNR5XR6, -XOXR6 and -XNR5XNR5R6; where each X independently represents bond and C1-C4alkylene; where any alkylene, contained in X can be optionally substituted with OH; R5 represents H, C1-C6alkyl; R6 represents C6-C10aryl and C5heteroaryl, containing 1 or 2 N and/or O, optionally condensed with benzene; where any aryl, heteroaryl, contained in R6, can be optionally substituted with 1-3 radicals, which independently represent C1-C6alkyl, OH, CN, -NR5S(O)0-2R5, -S(O)0-2NR5R5, - NR5S(O)0-2NR5R5, -C(O)NR5XNR5R5, -XNR5XNR5R5, -C(O)R7, -C(O)NR5XOR5, -C(O)NR5R5, -C(O)NR5R7, -C(O)NR5XR7 and -XC(O)OR5; where each X independently represent bond and C1-C4alkylene; where any alkylene, contained in X, is optionally substituted with OH; where each; R5 represents H, C1-C6alkyl; R7 represents C5-C6heterocycloalkyl-C0-C4alkyl, containing 1 or 2 N and/or O, where any heterocycloalkyl, contained in R7, is optionally substituted with radical, which represents diethylaminoethyl, dimethylaminogroup, aminogroup, C1-C6alkyl, pyrimidinyl, pyrazinyl, halogen-substituted C1-C6alkyl and -C(O)OR5; and its pharmaceutically acceptable salts, hydrates, solvates.

EFFECT: compounds possess inhibiting activity with respect to series of kinases, which allows to use them in pharmaceutical composition.

10 cl, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to derivatives of 2-pyridylmethylenecarboxamide of formula (I), where: -A represents a substituted or unsubstituted 5-member heterocyclyl group bound with carbonyl through carbon atom; -Z1 and Z2 which can be equal or different, represent hydrogen atom; C1-C5-alkyl; C5-alkoxycarbonyl; -Z3 represents substituted or unsubstituted C3-C7cycloalkyl; -Y represents C1-C5-halogenalkyl, containing to 5 halogen atoms which can be equal or different; X which can be equal or different, represents halogen atom, - n=0, 1, 2 or 3; and to their salts. Besides the invention describes a method of plant pathogenic fungi control with the use of such compounds.

EFFECT: there are prepared and described new derivatives of 2-pyridylmethylenecarboxamide which can be effective as fungicidal active agents.

8 cl, 96 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds exhibiting antiproliferative activity of formula (1) where W means N or C-R2; X means -NH-; Y means CH; Z means halogen, -NO2, C2-C3alkynyl-, halogen-C1-C3alkyl- and -C(=O)-C1-C3alkyl, A means a group of formula (i), (ii) or (iii) Q1 means phenyl; B1, B2, B3 and B4 independently mean C-RgRh, N-Ri or O; R1 means hydrogen; R2 means a residue specified from the group including hydrogen, halogen and -OR4; Ra, Rb, Rc, Rd, Re and Rf independently mean hydrogen; Rg and Rh independently mean a residue specified from the group including hydrogen, =O, -OR4 and -NR4C(=O)R5; or mean optionally a residue monosubstituted or twice-substituted with equal or different substitutes and specified from the group including C1-C6alkyl and phenyl, the substitute/substitutes is/are specified from the group including R8/, -OR4, -C(=O)R4, -C(=O)OR4 and -C(=O)NR4R5 where R8/ and other values of radicals are specified in the patent claim, optionally in the form of their pharmacologically noncontaminating acid addition salts. The invention also concerns a pharmaceutical composition.

EFFECT: new compounds have effective biological properties.

8 cl, 6 dwg, 1086 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 2,4-di(hetero)arylaminopyrimidine of general formula I or its pharmaceutically acceptable salt, possessing properties of ZAP-70 inhibitors. In compounds of formula I: Z stands for =CR2-; each of radicals R0 and R1 represents hydrogen; R2 represents (C1-C4)alkoxy; R3 represents -SO2NH2; or R1 and R2 form together with C-atoms, to which they are bound, 5-7-member non-aromatic carbocyclic or heterocyclic residue, where said heterocyclic residue includes 1 or 2 heteroatoms, selected from N and O, and heterocyclic residue, containing 1-2 atoms of oxygen can be substituted with fluorine atoms; R4 and R6 represent hydrogen, R5 represents hudrogen, halogen, (C1-C4)alkyl or CF3; one of R7, R8 and R9 represents NR10R11, and one or two others represent hydrogen, halogen, COOH, CF3 or (C1-C4)alkyl; R10 and R11 independently represents hydrogen or (C1-C4)alkyl. Invention also relates to methods of obtaining compounds.

EFFECT: compounds can be applied, for instance in case of acute or chronic rejection of organ or tissue, in treatment of atherosclerosis and other diseases, when inhibition of ZAP-70 is of importance.

9 cl, 7 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess properties inhibiting HIV replication, of general formula (I) , in form of E-isomer, in which -a1=a2-a3=a4- represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4. Represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n equals 0; m equals 2; each of R1 radicals independently on each other stands for hydrogen atom; C1-6alkyl; R2a stands for cyanogroup; X1 stands for -NR1-; R3 represents C2-6alkenyl, substituted with cyanogroup; R4 stands for C1-6alkyl; R5 represents radical of formula -Y-Alk-L, -Alk'-Y-L or -Alk'-Y-Alk-L; each of radicals Alk or Alk' independently represents bivalent C1-6alkyl or C2-6 alkenyl group; L stands for aryl or Het; Y stands for NR1; -CH=N-O-; Het stands for 5- or 6-member fully saturated ring system, in which one, two or three ring elements represent heteroatoms, each of which is independently selected from group, including nitrogen, oxygen and sulphur, and in which other ring elements represent carbon atoms; and, if possible, any nitrogen ring element can be optionally substituted with C1-6alkyl; and ring system can be optionally bound with benzene ring; and in which any carbon atom of ring, including any carbon atom of optionally bound benzene ring, each independently can be substituted with substituent selected from such groups as halogen atom, C1-6alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, C1-4 alkylcarbonyloxyC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, aryloxy, morpholinyl, aryl, Het1; Het1 stands for thienyl, isoxazolyl, thiadiazolyl, each of which can be optionally substituted with one or two C1-4alkyl radicals; Q stands for hydrogen atom; each aryl represents phenyl or phenyl, substituted with one, two substituents, each of which is independently selected from such groups as halogen atom, C1-6alkyl, C2-6alkinyl, cyano, polyhalogen C1-6alkyl or Het1, as well as to its pharmaceutically acceptable additive salts Invention also relates to pharmaceutical composition.

EFFECT: creation of novel compounds, which possess properties inhibiting HIV replication

5 cl, 7 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinoline, represented by formula , where R1 represents (1-6C)alkyl; R2 represents halogen, (1-4C)alcoxy; R3 represents OH, NO2, CN, fluoridated with (1-4C)alkoxy, (1-4C)alkoxy(2-4C)alkoxy. hydroxy(2-4C)alkoxy, (1-4C)alkoxycarbonyl, R7, R8-amino, R9, R10-amino, R9, R10-aminocarbonyl, R9, R10-aminosulfonyl or phenyl(1-4C)alkoxy, where phenyl ring in composition phenyl(1-4C)alkoxy is optionally substituted with one or several substituents, selected from (1-4C)alkoxy; R4 represents R11-phenyl or R11-(4-5C)heteroaryl, which represents heteroaromatic group, containing 4-5 carbon atoms and at least one heteroatom, selected from N and S, where phenyl or heteroaryl group is optionally additionally substituted with one or several substituents, selected from nitro, (1-4C)alkyl, (1-4C)alkoxy; R7 represents H, (1-4C)alkyl; R8 represents (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (1-4C)alkoxy(1-4C)alkylcarbonyl, furylcarbonyl; phenyl(1-4C)alkylcarbonyl, where phenyl ring is optionally substituted with one or several substituents, selected from (1-4C)alkoxy; R9 and R10 are not necessarily selected from H, (1-6C)alkyl and (1-4C)alkoxy(2-4C)alkyl; or R9 and R10 can be bound together with formation of morpholinyl ring; R11 represents H, R12, R13-amino, R14, R15-aminocarbonyl or R14, R15-aminosulfonyl; R12 represents H; R13 represents (1-4C)alkylsulfonyl, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl or pyperazinyl(1-4C)alkylcarbonyl; R14 and R15 are independently selected from H, (1-6C)alkyl, (1-4C)alkoxy(2-4C)alkyl and imidazolyl(1-4C)alkyl; X represents O or R16-N; Y represents CH2 or C(O);Z represents CN; R16 represents H, (1-4C)alkyl, (1-4C)alkylcarbonyl; or their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition, as well as to application of 4-phenyl-5-oxo-1,4,5,6,7,8-hexahydrochinoline derivatives by any of i.i. 1-10.

EFFECT: obtaining novel biologically active compounds, which possess agonistic activity with respect to FSH receptor.

13 cl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

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