Heterocyclylamide-substituted thaizoles, pyrroles and thiophenes

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

 

The present invention relates to substituted heterocyclisation triazolam, pyrrole and typenum, method of their production, to their use for the treatment and/or prevention of certain diseases and also to their use for the preparation of drugs intended for the treatment and/or prevention of certain diseases, especially for use as antiviral agents, mainly against cytomegaloviruses.

In WO 99/23091 described aromatic heterocyclic compounds as anti-inflammatory drugs, which inter alia may be used for the treatment of viral infections, and in WO 04/052852 described derivatives of 3-pyrrolizine as antiviral agents, bearing carbocycle as Deputy urea.

Despite the presence on the market with antiviral action means structurally different type used in modern therapy drugs, such as ganciclovir, valganciclovir, foscarnet and cidofovir have serious side effects, for example, cause nephrotoxins, neutropenia or thrombocytopenia. In addition to these drugs can often develop resistance. Thus, effective therapy requires new tools.

Based on the foregoing, the present invention was used ass the cha - to provide new compounds that would have the same as well-known means, or the best antiviral effect for the treatment of viral infectious diseases of humans and animals.

With the invention it has been unexpectedly found that its proposed and considered in more detail in the subsequent description of substituted heterocycles have high antiviral efficacy.

In accordance with this object of the present invention are the compounds of formula (I)

in which

R1represents a group of the formula

orwhere

* indicates the place of attachment to the carbonyl group,

R3denotes phenyl or 5 - or 6-membered heteroaryl, each of which may be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, oxoprop, a nitrogroup, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl, C1-C6alkoxygroup,hydroxycarbonyl, C1-C6alkoxycarbonyl, an amino group, a C1-C6alkylamino, aminocarbonyl and C1-C6alkylaminocarbonyl,

R4additional the em phenyl or 5 - or 6-membered heteroaryl, each of

which may be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, oxoprop, a nitrogroup, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl, C1-C6alkoxygroup, hydroxycarbonyl, C1-C6alkoxycarbonyl, an amino group, a C1-C6alkylamino, aminocarbonyl and C1-C6alkylaminocarbonyl, and

R5and R6independently of one another denote hydrogen, methyl or ethyl,

R2represents phenyl which may be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl and C1-C6alkoxygroup,

A represents a group of the formula

,,orwhere

* indicates the place of attachment to the carbonyl group,

# indicates the place of attachment to the nitrogen atom of the urea

R7represents C1-C6alkyl which can be substituted for what estealam, selected from the group comprising C3-C6cycloalkyl, C6-C10aryl and 5 - or 6-membered heteroaryl, each of which, in turn, can be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, oxoprop, a nitrogroup, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl, C1-C6alkoxygroup, hydroxycarbonyl, C1-C6alkoxycarbonyl, an amino group, a C1-C6alkylamino, aminocarbonyl and C1-C6alkylaminocarbonyl, and

R8and R9independently of one another denote hydrogen, halogen or C1-C6alkyl which may be substituted by the Deputy selected from the group comprising C3-C6cycloalkyl, C6-C10aryl and 5 - or 6-membered heteroaryl, each of which, in turn, can be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, oxoprop, a nitrogroup, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl, C1-C6alkoxygroup, hydroxycarbonyl, C1-C6al is oxycarbonyl, an amino group, a C1-C6alkylamino, aminocarbonyl and C1-C6alkylaminocarbonyl,

and also their salts, solvate, and a solvate of their salts.

Proposed in the invention the compounds are compounds of formula (I) and their salts, solvate, and a solvate of these salts, falling under formula (I) compounds of the following formula and their salts, solvate, and a solvate of these salts, as well as falling under formula (I)below as examples of the compounds, their salts, solvate, and a solvate of these salts, provided that under under formula (I) of the following compounds does not already exist in the form of a salt, solvate and solvate salts.

Proposed in the invention compounds depending on their structure may exist in stereochemical forms (enantiomers, diastereomers). Accordingly the scope of the invention also includes the corresponding enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers can be known by their separating components in the form of individual stereoisomers.

In the scope of the present invention also includes all possible tautomeric forms proposed in the invention compounds.

As the salts according to the present invention the preferred physiologically harmless salts of its proposed connection is on. However, the scope of the invention are those salts which as such are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the proposed in the invention compounds.

To physiologically harmless salts proposed in the invention compounds include acid additive salts formed with mineral acids, carboxylic acids and sulfonic acids, for example, salts formed with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, econsultancy acid, toluensulfonate acid, benzosulfimide acid, naphthalenedisulfonic acid, acetic acid, triperoxonane acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

To physiologically harmless salts proposed in the invention compounds also include salts formed with the usual bases, preferably such as salts with alkali metals (e.g. sodium and potassium salts), salts with alkaline earth metals (e.g. calcium and magnesium salts) and ammonium salt, a derivative of ammonia or organic amines with 1 to 16 and what Ohm carbon, preferably such as ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, Ethylenediamine and N-methylpiperidin.

Under the solvate according to the invention refers to such forms proposed therein compounds, which are in solid or liquid state, form a complex in the education coordination with solvent molecules. Hydrates are a special form of the solvate formed as a result of the formation of coordination with water molecules.

In the scope of the present invention also includes prodrugs of its proposed connections. The term "prodrug" refers to such compounds, which themselves may possess or not to possess biological activity, but when his presence in the body turn into offered in the invention compounds (e.g., metabolic or by hydrolytic).

According to the invention is used to denote substituents concepts are, unless otherwise specified, the following values.

Alkyl per se and fragments "ALK" and "alkyl" as part of alkoxygroup, alkylamino, alkoxycarbonyl and alkylaminocarbonyl represent a linear or did the run alkyl residue usually 1-6 carbon atoms (C 1-C6alkyl), preferably 1-4 carbon atoms, particularly preferably with 1-3 carbon atoms, preferably, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxygroup preferably represents, for example, methoxy, ethoxy-, n-propoxy, isopropoxy-, tert-butoxy, h-pentoxil - and n-hexachrome.

Alkylamino is alkylamidoamines with one or two (independently selected from each other) alkyl substituents, preferably, for example, methylamino, ethylamino, h-propylamino, isopropylamino-, tert-butylamino, h-pentylamine, h-hexylamino-, N,N-dimethylamino-N,N-diethylamino-, N-ethyl-N-methylamino-, N-methyl-N-n-propylamino-, N-isopropyl-N-n-propylamino-, N-tert-butyl-N-methylamino-, N-ethyl-N-n-pentylamine - and N-n-hexyl-N-methylaminopropyl. C1-C3alkylamino represents, for example, monoalkylamines with 1-3 carbon atoms or dialkylaminoalkyl having 1-3 carbon atoms in each alkyl substituent.

Alkoxycarbonyl preferably represents, for example, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-phenoxycarbonyl and n-hexoxyethanol.

Alkylaminocarbonyl is alkylaminocarbonyl residue with one or two(independently selected from each other) alkyl substituents, preferably, for example, methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, tert-butylaminoethyl, n-intramyocardial, n-mexiletineciclovir, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-n-propylaminosulfonyl, N-isopropyl-N-n-propylaminosulfonyl, N-tert-butyl-N-methylaminomethyl, N-ethyl-N-n-intramyocardial and N-n-hexyl-N-methylaminoethanol. With1-C3alkylaminocarbonyl represents, for example, monoacylglycerols residue with 1 to 3 carbon atoms or dialkylaminoalkyl residue having 1-3 carbon atoms in each alkyl substituent.

Aryl is a mono - or bicyclic aromatic carbocyclic residue usually with 6-10 carbon atoms, preferably, for example, phenyl and naphthyl.

5 - or 6-membered heteroaryl according to the invention in General represents a monocyclic aromatic residue with 5 or 6 ring atoms and from 1-4 heteroatoms from the group comprising S, O and/or n Heteroaryl residue may be attached via a carbon atom or heteroatom. As preferred examples of heteroaryl can be called thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl and pyridazinyl.

Cycloalkyl represents the FDS is th cycloalkyl group usually with 3-6 carbon atoms, as the preferred examples which may be called cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The halogen may be fluorine, chlorine, bromine or iodine.

It is preferred according to the present invention are proposed therein the compounds of formula (I), in which

R1represents a group of the formula

where

* indicates the place of attachment to the carbonyl group,

R3denotes phenyl or 5 - or 6-membered heteroaryl, each of which may be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, oxoprop, a nitrogroup, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl, C1-C6alkoxygroup, hydroxycarbonyl, C1-C6alkoxycarbonyl, an amino group, a C1-C6alkylamino, aminocarbonyl and C1-C6alkylaminocarbonyl,

R2represents phenyl which may be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptorelin is, C1-C6alkyl and C1-C6alkoxygroup,

A represents a group of the formula

,,orwhere

* indicates the place of attachment to the carbonyl group,

# indicates the place of attachment to the nitrogen atom of the urea

R7represents C1-C6alkyl which may be substituted by the Deputy selected from the group comprising C3-C6cycloalkyl, C6-C10aryl and 5 - or 6-membered heteroaryl, each of which, in turn, can be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a hydroxy-group, oxoprop, a nitrogroup, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, triptoreline, C1-C6alkyl, C1-C6alkoxygroup, hydroxycarbonyl, C1-C6alkoxycarbonyl, an amino group, a C1-C6alkylamino, aminocarbonyl and C1-C6alkylaminocarbonyl, and

R8and R9independently of one another denote hydrogen, halogen or C1-C6alkyl,

and also their salts, solvate, and a solvate of their salts.

It is preferred according to the invention are also offered in theit compounds of formula (I), in which

R1represents a group of the formula

where

* indicates the place of attachment to the carbonyl group,

R3denotes phenyl or pyridyl, each of which may be substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a nitro-group, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, C1-C4alkyl and C1-C4alkoxygroup,

R2represents phenyl which may be substituted by 1-3 substituents, independently from each other selected from the group comprising fluorine, chlorine, cryptometer, dipterocarp, triptoreline and methyl,

A represents a group of the formula

,,orwhere

* indicates the place of attachment to the carbonyl group,

# indicates the place of attachment to the nitrogen atom of the urea

R7denotes methyl, ethyl or n-butyl, each of which can be substituted by the Deputy selected from the group comprising cyclopropyl and phenyl, which, in turn, can be substituted by trifluoromethyl, and

R8and R9independently of one another denote hydrogen, bromine, chlorine, m is Teal or ethyl,

and also their salts, solvate, and a solvate of their salts.

It is preferred according to the invention are further proposed therein the compounds of formula (I), in which

R1represents a group of the formula

where

* indicates the place of attachment to the carbonyl group, and

R3denotes phenyl or pyridyl, each of which can be

substituted by 1-3 substituents, independently from each other selected from the group comprising halogen, a nitro-group, cyano, trifluoromethyl, deformity, cryptometer, dipterocarp, monitortype, C1-C4alkyl and C1-C4alkoxygroup.

It is preferred according to the invention are also proposed therein the compounds of formula (I)in which R2represents phenyl which may be substituted by 1-3 substituents, independently from each other selected from the group comprising fluorine, chlorine, cryptometer, dipterocarp, triptoreline and methyl.

It is preferred according to the invention are further proposed therein the compounds of formula (I), in which

A represents a group of the formula

,,orwhere

* indicates a place connec the deposits to a carbonyl group,

# indicates the place of attachment to the nitrogen atom of the urea

R7denotes methyl, ethyl or n-butyl, each of which can be substituted by the Deputy selected from the group comprising cyclopropyl and phenyl, which, in turn, can be substituted by trifluoromethyl,

R8denotes hydrogen, bromine, chlorine or methyl, and

R9denotes hydrogen.

The object of the invention is also a method of obtaining compounds of formula (I), namely, that

[And] the compounds of formula (II)

,

in which R1has the above values, the first stage is subjected to interaction with the reducing agent, and the second stage is subjected in the presence of a derivative of carbonic acid interaction with compounds of the formula (III)

,

in which R2has the above values, or

[B] compounds of the formula (II) in the first stage is subjected to interaction with the reducing agent, and the second stage is subjected to interaction with compounds of the formula (IV)

,

in which R2has the above values, or

[In] the compounds of formula (V)

,

in which R2has the above values, a R10denotes methyl or ethyl, in the first stage is subjected to interaction with testwuide base, and the second stage is subjected in the presence of dehydrating agents interact with the compounds of the formula (VI)

,

in which R1has the above values.

Compounds of formula (III), (IV) and (VI) in principle known or can be obtained by known methods from the corresponding doctow.

Explanation of options [A] and [B], stage 1

The reaction is carried out usually in an inert solvent, preferably at a temperature in the range from 0°C to temperature distillation of the solvent and at a pressure in the range from normal to 3 bar.

As reducing agents can be used, for example, palladium on charcoal and hydrogen, a mixture of formic acid, triethylamine and palladium on charcoal, zinc, a mixture of zinc and hydrochloric acid, iron, a mixture of iron and hydrochloric acid, a mixture of iron sulfate (II) and hydrochloric acid, sodium sulfide, sodium disulfide, dithionite sodium, ammonium polysulfide, a mixture of sodium borohydride and Nickel chloride, tin dichloride, trichloride titanium or Raney Nickel and an aqueous solution of hydrazine, the preferred of which the Raney-Nickel, an aqueous solution of hydrazine, palladium on charcoal and hydrogen or a mixture of formic acid, triethylamine and palladium on charcoal.

As inert solvents can be used, for example the EP, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, and in the case of mixing with the water solvent can also be used mixtures thereof with water, while preferred as solvents methanol, ethanol, isopropanol, and in the case of Raney Nickel and an aqueous solution of hydrazine - tetrahydrofuran.

Explanation of option [A], stage 2

The reaction is carried out usually in an inert solvent, preferably at a temperature in the range from room temperature up to 40°C and at normal pressure.

As an example, derivatives of carbonic acid can be called N,N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl ether of Harborview acid or 4-nitrophenyloctyl ether of Harborview acid, preferred among which N,N-carbonyldiimidazole.

As inert solvents can be used, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tet is floridan, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, and in the case of mixing with the water solvent can also be used mixtures thereof with water, in this preferred among these solvents dimethyl sulfoxide.

Notes to option [B], stage 2

The reaction is carried out usually in an inert solvent, optionally in the presence of a base, preferably at a temperature in the range from room temperature to the temperature of distillation and solvent at normal pressure.

As inert solvents can be used, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, xylene, toluene, GE is San, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, in this preferred among these solvents are tetrahydrofuran or methylene chloride.

As the bases can be used, for example, carbonates of alkali metals such as cesium carbonate, sodium carbonate or potassium or tert-butyl potassium, as well as other bases, such as sodium hydride, DBU (databaseconnect), triethylamine or diisopropylethylamine, preferred among which triethylamine.

Notes to option [V], stage 1

The reaction is carried out usually in an inert solvent, preferably at a temperature in the range from 0°C to temperature distillation of solvents and under normal pressure.

As the bases can be used, for example, hydroxides of alkali metals such as sodium hydroxide, lithium or potassium, or carbonates of alkali metals such as cesium carbonate, sodium carbonate or potassium, preferred among which sodium hydroxide.

As inert solvents can be used, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, ethers, such as on the ethyl ester, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, or mixtures of such solvents with water, is preferred as a solvent mixture of ethanol and water.

Notes to option [V], stage 2

The reaction is carried out usually in an inert solvent, optionally in the presence of a base, preferably at a temperature in the range from -70 to 40°C. and at normal pressure.

As dehydrating agents at this stage can be used, for example, carbodiimide, such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-aminobutiramida, N,N'-dicyclohexylcarbodiimide, hydrochloride N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide (HDAC), N-cyclohexylcarbodiimide-N'-propylacetate-polystyrene (PS-carbodiimide), carbonyl compounds, such as carbonyldiimidazole, 1,2-oxazolium compounds such as 3-sulfate 2-ethyl-5-phenyl-1,2-oxazole or perchlorate 2-thread-butyl-5-methylisoxazole, acylaminoacyl, such as 2-ethoxy-1-etox the carbonyl-1,2-dihydroquinoline, papapostolou anhydride, isobutylparaben, bis-(2-oxo-3-oxazolidinyl)phosphorylchloride or hexaphosphate benzothiazolinone(dimethylamino)phosphonium, hexaflurophosphate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (gbtu), tetrafluoroborate 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium (TPTU) or hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (GATA), 1-hydroxybenzotriazole (HOBT), hexaflurophosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (GBP) or mixtures of these compounds with bases.

As the bases can be used, for example, carbonates of alkali metals such as sodium carbonate or sodium bicarbonate or potassium, and organic bases, such as trialkylamine, for example, triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine (DMAP) or diisopropylethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene) or pyridine, preferred among which triethylamine.

The condensation is preferably carried out with the use of TBTU (tetrafluoroborate O-benzotriazole-N,N,N',N'-tetramethylurea), DMAP.

As inert solvents can be used, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachlorethane, 1,2-dichloroethane or trichloroethylene, simple EF the market, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, and in the case of mixing with the water solvent can also be used mixtures thereof with water, in this preferred among these solvents are dimethylformamide.

In another embodiment, obtained in the first stage variant [In] the carboxylic acid can be in the second stage first interaction with the corresponding gloriouse agent, such as thionyl chloride into the acid chloride of carboxylic acid, and then the interaction with compounds of the formula (VI) in the presence of an appropriate base to turn in the compounds of formula (I).

The compounds of formula (II) are known or can be obtained from compounds of the formula

in which R10has the above value, the interaction in the first stage with an appropriate base and interaction in the second stage with compounds of the formula (VI) in the presence of dehydrating agents.

This reaction is carried out oppo is ichno variant [In].

The compounds of formula (VII) are known or can be obtained by the interaction of the compounds of the formula

in which R10has the above significance, with fuming nitric acid, concentrated nitric acid, nitrouse acid or a mixture of sulfuric acid and nitric acid in a different ratio between them, not necessarily in acetic anhydride as solvent, preferably at a temperature in the range from room temperature up to 60°C. and at normal pressure.

The compounds of formula (VIII) are known or can be synthesized by known methods from the corresponding doctow.

The compounds of formula (V) are known or can be obtained from compounds of formula (VIII) interaction in the first stage with an appropriate reducing agent and interaction in the second stage in the presence of an appropriate derivative of carbonic acid with the compounds of the formula (III) or interaction in the second stage with compounds of the formula (IV).

This reaction is carried out analogously options [A] and [B].

The scheme of synthesis 1

Scheme of synthesis of 2

Proposed in the invention compounds of General formula (I) possess an unexpected range of actions, which it was impossible to predict in advance. Proposed in the invention compounds is reavley antiviral activity against members of the group of viruses Herpes viridae (herpes viruses), first of all in relation to cytomegalovirus (CMV); mainly against human cytomegalovirus (HCMV). Thus proposed in the invention compound suitable for the treatment and prevention of certain diseases, primarily of viral infections, particularly infections, the pathogens which are the above-mentioned viruses, and the resulting infectious diseases. The term "viral infection" in the following description refers to herself excited by a specific virus infection, and due to this viral infection disease.

Compounds of General formula (I) due to their special properties can be used to make medicines that are suitable for the prophylaxis and/or treatment of relevant diseases, especially viral infections.

As an example of indications proposed in the invention compounds include the following:

1) treatment and prevention of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections);

2) treatment and prevention caused by cytomegalovirus infections in patients with transplantirovannam bone marrow and transplanted organs, frequent threatening their lives to diseases such as HCMV pneumonitis, encephalitis, as well as gastrointestinal and systemic HCMV infection have been the AI;

3) treatment and prevention of HCMV infection in infants and young children;

4) treatment of acute HCMV infection in pregnant women;

5) treatment of HCMV infections in patients with suppressed immune reactions, suffering from cancer and undergoing cancer treatment;

6) treatment of HCMV-positive cancer patients to reduce mediated HCMV virus progression of the tumor (see J. Cinatl, etc., FEMS Microbiology Reviews, 28, 2004, SS-77).

Proposed in the invention compounds preferably used for the preparation of pharmaceuticals for the prophylaxis and/or treatment of infections generated by one of the representatives of the group of herpes viruses, particularly cytomegalovirus, especially human cytomegalovirus.

Proposed in the invention compounds due to their pharmacological properties can be used for the treatment and/or prevention of viral infections, especially HCMV infections, individually and, if necessary, in combination with the active substances of other types, primarily with antiviral active substances, such as ganciclovir, valganciclovir or acyclovir.

Another object of the present invention is the application of its proposed compounds for the treatment and/or prevention of certain diseases, etc is doctitle viral infections, first of all infections caused by the human cytomegalovirus or other representative of the group of herpes viruses.

Another object of the present invention is the application of its proposed compounds for the treatment and/or prevention of certain diseases, especially of the aforementioned diseases.

Another object of the present invention is the application of its proposed compounds for the preparation of medicines intended for the treatment and/or prevention of certain diseases, especially of the aforementioned diseases.

Another object of the present invention is a method of treatment and/or prevention of certain diseases, especially of the aforementioned diseases, using offer in the invention compounds in an antiviral effective amount.

Proposed in the invention compounds may exert its effect systemically and/or topically. To this end, you can apply them accordingly, for example, oral, parenteral, pulmonale, intranasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival in the ears or in the form of the implant, respectively, of the stent.

For such applications proposed in the invention compounds can enter the body in the composition correspond to their dosage forms.

For oral administration, suitable pharmaceutical form known from the prior art principle of action and fast and/or modified release of them proposed in the invention compounds found in such dosage forms in crystalline and/or amorphous and/or dissolved form. As examples of such dosage forms include tablets (uncoated or coated, for example, with a coating resistant to gastric juice, or slowly soluble or insoluble coating, regulating or controlling the release proposed in the invention compounds), quickly disintegrating in the oral cavity of a tablet, a wafer with a film coating, lyophilizate film-coated, capsule (e.g., solid or megkozeliteni capsules), pills, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral application of the proposed invention compounds suggests the possibility of their introduction into the body without absorption (for example, intravenous, intraarterial, intracardiac, intraspinal or intraluminal introduction) or absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal injection). As suitable for parenteral use Lek is stannah forms can be called in addition to other dosage forms for injection or infusion in the form of solutions, suspensions, emulsions, liofilizatow or sterile powders.

For the application of the proposed invention compounds other suitable methods, for example, inhalation dosage forms (in particular, powder inhalers, nebulizers), nasal drops, solutions, sprays, lingual and sublingual tablets, or pills to slow dissolution in the buccal pocket, a wafer with a film coating or capsules, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, mash), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milk, pastes, foams, powders, implants or stents.

Proposed in the invention compounds can be converted to the above applications. For this we offer in the invention compounds can in a known manner by mixing with inert, non-toxic, pharmaceutically acceptable auxiliary substances. These excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers, dispersing agents or wetting (for example, sodium dodecylsulfate, polychiorinated), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilized the market (for example, antioxidants, such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) and korrigentami taste and/or smell.

Another object of the present invention are drugs, containing at least one proposed in the invention, the connection, usually together with one or more inert, non-toxic, pharmaceutically acceptable auxiliary substances, and their use for the purposes described above.

In General, to achieve effective results proposed in the invention compounds, it is preferable to introduce into the body at a dose that, when intravenous administration is from about 0.001 to 10 mg/kg body weight, preferably from about 0.01 to 5 mg/kg of body weight, and oral administration is from about 0.01 to 25 mg/kg body weight, preferably from 0.1 to 10 mg/kg of body weight. However, in some cases, namely depending on the body weight of the patient, the route of administration of the active substance into the body, the individual response to the active ingredient, type of dosage forms containing his time and, accordingly, the time interval of introducing medicines into the body may need to apply offer in the invention compounds at doses other than the above amounts. Thus, in particular, sometimes what may be sufficient to use proposed in the invention compounds at a dose least the above lower limit, while in other cases you may need to use proposed in the invention compounds in a dose exceeding the above upper limit. If necessary, the use proposed in the invention compounds in large doses, it may be appropriate to divide them into several smaller doses based on several sessions per day.

Shown in the following experimental part of the description and in the examples, percentage data are, unless otherwise stated, the mass percent, the parts are mass parts, and the ratio between the solvents, the ratio of dilution or dilution and concentration of liquid-liquid solutions in each case are indicated in terms of volume.

A. Examples

Abbreviations

BINAP2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
CD3CNdeuterocanonical
TCXthin-layer chromatography
PHIdirect chemical ionization
DHMdichloromethane
DIAN,N-diisopropylethylamine (base Chunga)
DMAP4-N,N-dimethylaminopyridine
DMFN,N-dimethylformamide
DMSOthe sulfoxide
EDCI·HClhydrochloride N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide
EAethyl acetate (ethyl ester of acetic acid)
EIionization by electron impact (MS)
ESIionization electrospray (MS)
tPLmelting point
hhour(s)
GATAhexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
Gbtuhexaphosphate O-(benzotriazol-1-yl)- N,N,N',N'-tetramethylurea
Ehudliquid chromatography high pressure or high performance liquid chromatography
LC-MSmass spectrometry in combination with liquid chromatography
GAVEdiisopropylamide lithium
MSmass spectroscopy
NMRnuclear magnetic resonance
OF ghvdJhud with reversed-phase CT room temperature
Rtretention time (when jhud)
TBTUtetrafluoroborate O-(benzotriazol-1-yl)- N,N,N',N'-tetramethylurea
THFtetrahydrofuran

Methods ghud - and LC-MS analysis

Method 1 (LC-MS): a type of mass spectrometer: Micromass ZQ; type ghud-chromatograph: Waters Alliance 2795; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm×4 mm; eluent A: 1 l water+0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 to min 90% eluent A→a 2.5 min 30% eluent A→a 3.0 min 5% eluent A→4.5 min 5% eluent A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV detection: 210 nm.

Method 2 (LC-MS): instrument: mass spectrometer Quattro LCZ with jhud-chromatograph Agilent 1100 Seri; column: Phenomenex Synergi 2µ Hydro-RP Mercury 20 mm×4 mm; eluent A: 1 l water+0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 to min 90% eluent A →a 2.5 min 30% eluent A→a 3.0 min 5% eluent A→4.5 min 5% eluent A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV detection: 208-400 nm.

Method 3 (LC-MS): a type of mass spectrometer: Micromass ZQ; type ghud-chromatograph: HP 1100 Series UV detector diode matrix; column: Phenomenex Synergi 2µ Hydro-RP Mercury, 20x4 mm; eluent A: 1 l water+0.5 ml 50%formic acid, eluent B: 1 l of acetonitrile+0.5 ml 50%formic acid; gradient: 0.0 to min 90% eluent A→a 2.5 min 30% eluent A→a 3.0 min 5% eluent And→4.5 min 5% eluent A; flow rate: 0,0 min 1 ml/min, 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; oven: 50°C.; UV detection: 210 nm.

The source connections

Example 1A

1-methyl-2-trichloroacetyl-1H-pyrrol

1,09 ml (12.3 mmole) of trichloroacetamide add in an atmosphere of argon in 5 ml DHM, then at RT for 30 min added dropwise a solution of N-methylimidazole in 3 ml DHM. The mixture is then left to mix overnight at RT, and the solution was concentrated and the residue purified by filtration through flash Frit (cyclohexane, cyclohexane/ethyl acetate in a ratio of 40:1). In this way receive the desired product in the form of a liquid.

Output: 2,12 g (76% of theory).

LC-the (method 1): R t=2,34 minutes

MS (EI+): m/z=225 (M+).

Example 2A

1-methyl-4-nitro-2-trichloroacetyl-1H-pyrrol

2,12 g (9,34 mmole) of 1-methyl-2-trichloroacetyl-1H-pyrrole dissolved in 9.5 liters of acetic anhydride, cooled to -20°C and mix from 0.43 ml (9,34 mol) of nitric acid. The mixture is allowed to rise slowly to CT and stirred for 1 h at RT. After that the reaction mixture is poured into 95 g of ice and within 2.5 h intensively mixed (first formed oily residue, and then crystallization occurs). The precipitate was separated by vacuum filtration, stirred with 20 ml of methanol, filtered and left to dry overnight under vacuum. To remove simultaneously formed regioisomer the mixture for 2 hours and stirred with 10 ml of a mixture of acetic acid and water in a ratio of 1:1, then the solid is separated by vacuum filtration and dried in vacuum. In this way receive the desired product as a solid.

Output: 1,71 g (67% of theory).

LC-MS (method 2): Rt=of 2.51 minutes

1H-NMR (400 MHz, DMSO-d6):δ=8,58 (d, 1H), 7,80 (d, 1H), 4.00 points (s, 3H).

Example 3A

Ethyl ester of 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid

0.50 g (of 1.84 mmole) of 1-methyl-4-nitro-2-trichloroacetyl-1H-pyrrol add 5 ml of ethanol, and then mixed with of 0.26 ml (of 1.84 mmole) of triethylamine and within 2 h and stirred at RT. Then the reaction mixture was mixed with 5 ml of water, stirred for 30 min at 0°C and finally the precipitate was separated by vacuum filtration and dried in vacuum.

Output: 321 mg (88% of theory).

LC-MS (method 3): Rt=2,25 minutes

MS (ESI+): m/z=199 (M+N)+.

1H-NMR (300 MHz, DMSO-d6):δ=8,29 (d, 1H), 7,31 (d, 1H), 4,27 (q, 2H), 3,92 (s, 3H), of 1.30 (t, 3H).

Example 4A

Ethyl ester of 1-methyl-4-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]-1H-pyrrole-2-carboxylic acid

304 mg (1,53 mmole) ethyl ester of 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid added to 6 ml of a mixture of ethyl acetate and ethanol in a ratio of 1:1, and then mixed with 163 mg (0.15 mmole) of palladium (10%on charcoal) and 580 mg (9,20 mmole) of ammonium formate and within 1 h and stirred at 80°C. After cooling, the mixture is filtered through kieselguhr, washed with ethanol and the filtrate under vacuum to remove the solvent. The residue is dissolved in 6 ml of THF, mixed with 374 mg (of 1.84 mmole) 4-cryptonetxdeviceevent and within 1 h and stirred at RT. Then the solution is concentrated and the residue purified by means OF ghvd (acetonitrile/water). In this way receive the desired product as a solid.

Output: 486 mg (85%" from theory).

LC-MS (method 3): Rt=2,61 minutes

MS (ESI+): m/z=372 (M+N)+.

1H-NMR (300 MHz, DMSO-d6):δ=8,80 (s, 1H, 8,39 (s, 1H), 7,53 (m, 2H), 7,26 (d, 2H), 7,20 (d, 1H), 6,72 (d, 1H), 4,20 (q, 2H), 3,82 (s, 3H), of 1.28 (t, 3H).

Example 5A

1-methyl-4-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]-1H-pyrrole-2-carboxylic acid

470 mg (1,27 mmole) ethyl ester of 1-methyl-4-[({[4-(triptoreline)-phenyl]amino}carbonyl)amino]-1H-pyrrole-2-carboxylic acid, add 5 ml of THF, and then added 152 mg (6,33 mmole) of lithium hydroxide in 1 ml of water and allowed to mix overnight at reflux. Then the reaction mixture was concentrated, the residue is acidified with 2-molar hydrochloric acid, the precipitate is separated by vacuum filtration and dried in vacuum. In this way receive the desired product as a solid.

Output: 429 mg (98% of theory).

LC-MS (method 2): Rt=2,09 minutes

MS (ESI+): m/z=344 (M+N)+.

1H-NMR (300 MHz, DMSO-d6):δ=12,16 (Shir. s, 1H), 9,01 (s, 1H), 8,58 (s; 1H), 7,53 (m, 2H), 7,25 (d, 2H), 7,18 (d, 1H), 6,63 (d, 1H), 3,80 (s, 3H).

Example 6A

1-(5-methylpyridin-2-yl)piperazine

Stage 1

1-(tert-butyloxycarbonyl)-4-(5-methylpyridin-2-yl)piperazine

In an argon atmosphere 2.50 g (19.6 mmole) of 2-methyl-5-chloropyridine and of 4.38 g (23.5 mmole) of N-(tert-butyloxycarbonyl)piperazine are dissolved in 50 ml of absolute toluene. Then add of 2.26 g (23.5 mmole) of tert-butyl sodium, and 0.37 g (a 0.59 mmole)BINAP and 0.36 g (of 0.39 mmole) of Tris-(dibenzylideneacetone)diplodia and heated to 70°C with a dwell time at this temperature for 12 hours After cooling, the reaction mixture is mixed with diethyl ether, washed three times with a saturated solution of sodium chloride, dried over sodium sulfate and vacuum to remove the solvent. The residue is purified Express chromatography (mixture of cyclohexane and ethyl acetate in the ratio 9:1).

Output: 5,27 g (97% of theory).

LC-MS (method 1): Rt=1,26 minutes

MS (ESI+): m/z=278 (M+N)+.

1H-NMR (300 MHz, CDCl3):δ=8,02 (d, 1H), 7,34 (dd, 1H), 6,59 (d, 1H), 3,55 (m, 4H), of 3.45 (m, 4H), of 2.21 (s, 3H), 1,49 (s, 9H).

Stage 2

1-(5-methylpyridin-2-yl)piperazine

3,47 g (12.5 mmole) of 1-(tert-butyloxycarbonyl)-4-(5-methylpyridin-2-yl)piperazine dissolved in 10 ml of dioxane and mixed with 31 ml (125 mmol) of hydrogen chloride in dioxane (4-molar). The mixture is then stirred for 2 h at RT. The mixture is concentrated, the residue is alkalinized 1-molar sodium hydroxide solution and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and dried in vacuum.

Output: 2,18 g (98% of theory).

LC-MS (method 3): Rt=0,38 minutes

MS (ESI+): m/z=177 (M+N)+.

1H-NMR (300 MHz, CDCl3): δ=8,02 (d, 1H), 7,32 (dd, 1H), 6,59 (d, 1H), of 3.45 (m, 4H), to 3.00 (m, 4H), of 2.20 (s, 3H).

Example 7A

1-ethyl-4-[({[4-(triptoreline)phenyl]amino)carbonyl)amino]-1H-pyrrole-2-carboxylic acid

At asanee connection receive analogously to example 5A.

LC-MS (method 2): Rt=2,10 minutes

MS (ESI+): m/z=358 (M+N)+.

Example 8A

1-butyl-4-[({[4-(triptoreline)phenyl]amino)carbonyl)amino]-1H-pyrrole-2-carboxylic acid

The specified connection receive analogously to example 5A.

LC-MS (method 3): Rt=2,47 minutes

MS (ESI+): m/z=386 (M+N)+.

1H-NMR (300 MHz, CMOS-d6): δ=8,90 (Shir. s, 1H), 8,48 (Shir. s, 1H), 7,54 (d, 2H), 7,26 (d, 2H), 7,24 (d, 1H), 6.73 x (d, 1H), is 4.21 (t, 2H), 1,62 (quint., 2H), 1,25 (sext., 2H), from 0.88 (t, 3H).

Example 9A

1-(cyclopropylmethyl)-4-[({[4-triptoreline)phenyl]amino}carbonyl)-amino]-1H-pyrrole-2-carboxylic acid

The specified connection receive analogously to example 5A.

LC-MS (method 2): Rt=2,33 minutes

MS (ESI+): m/z=384 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=8,86 (Shir. s, 1H), 8,45 (Shir. s, 1H), 7,55 (m, 2H), 7.23 percent-to 7.32 (m, 3H), of 6.68 (d, 1H), 4,11 (d, 2H), 1,21 (m, 1H), 0,45 (m, 2H), 0,32 (m, 2H).

Example 10A

4-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]thiophene-2-carboxylic acid

The specified connection receive similar examples 4A and 5A on the basis of methyl ester 4-aminothiophene-2-carboxylic acid (synthesized according to the method described in A.A.Kiryano and others in Tetrahedron Lett., 42, 2001, s-8800).

Yield: 72 mg (27% of theory, 2-stage).

LC-MS (method 2): Rt=2,25 minutes

MS (ESI+): m/z=347 (M+N)+.

1NAMR (400 MHz, DMSO-d6): δ=13,1 (Shir. s, 1H), 9,10 (Shir. s, 1H), 8,98 (Shir. s, 1H), 7,69 (s, 1H), 7,53-of 7.60 (m, 3H), 7,29 (d, 2H).

Example 11A

2-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]-1,3-thiazole-4-carboxylic acid

The specified connection receive similar examples 4A and 5A on the basis of the ethyl ester of 2-amino-1,3-thiazole-4-carboxylic acid (commercially available product, manufactured by ACROS).

Yield: 290 mg (61% of theory, 2 stages).

LC-MS (method 2): Rt=2,05 minutes

MS (ESI+): m/z=348 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=12,8 (Shir. s, 1H), 10,9 (Shir. s, 1H), which 9.22 (Shir. s, 1H), to $ 7.91 (s, 1H), 7,60 (d, 2H), 7,32 (d, 2H).

Example 12A

5-methyl-2-[({[4-(triptoreline)phenyl]aminocarbonyl)amino]-1,3-thiazole-4-carboxylic acid

The specified connection receive similar examples 4A and 5A on the basis of the methyl ester 2-amino-5-methyl-1,3-thiazole-4-carboxylic acid (commercially available product supplied by the company Tyger Scientific).

Yield: 148 mg (40% of theory, 2-stage).

LC-MS (method 3): Rt=2,47 minutes

MS (ESI+): m/z=362 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=12,7 (Shir. s, 1H), 10,7 (Shir. s, 1H), 9,18 (Shir. s, 1H), to 7.59 (d, 2H), 7,32 (d, 2H), 3,34 (s, 3H).

Example 13A

5-chloro-2-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]-1,3-thiazole-4-carboxylic acid

The connection specified floor is up analogously to examples 4A and 5A on the basis of the ethyl ester of 2-amino-5-chloro-1,3-thiazole-4-carboxylic acid (synthesis of this compound is described in K.J.Hodgetts and other in Org. Lett., 4, 2002, s-1366).

Output: 365 mg (89% of theory, 2-m stages).

LC-MS (method 3): Rt=of 2.51 minutes

MS (ESI+): m/z=382 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=13,2 (Shir. s, 1H), and 11.2 (Shir. s, 1H), 9.28 are (Shir. s, 1H), 7,58 (m, 2H), 7,33 (m, 2H).

Example 14A

5-bromo-2-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]-1,3-thiazole-4-carboxylic acid

The specified connection receive similar examples 4A and 5A on the basis of the ethyl ester of 2-amino-5-bromo-1,3-thiazole-4-carboxylic acid (synthesis of this compound is described in J.F. Okonya and others in Tetrahedron Lett., 43, 2002, SS-7054).

Output: 343 mg (74% of theory, 2 stages).

LC-MS (method 2): Rt=2,22 minutes

MS (ESI+): m/z=426 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=13,1 (Shir. s, 1H), and 11.2 (Shir. s, 1H), 9.28 are (Shir. s, 1H), 7,58 (m, 2H), 7,32 (m, 2H).

Example 15A

2-[({[4-(triptoreline)phenyl]amino}carbonyl)amino]-1,3-thiazole-5-carboxylic acid

The specified connection receive similar examples 4A and 5A on the basis of the ethyl ester of 2-amino-1,3-thiazole-5-carboxylic acid (commercially available product manufactured by RareChem).

Yield: 200 mg (55% of theory, 2-m stages).

LC-MS (method 3): Rt=2,36 minutes

MS (ESI+): m/z=348 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=12,8 (Shir. s, 1H), 10,9 (Shir. s, 1H), of 9.21 (Shir. s, 1H), 7,92 (s, 1H), 7,60 (d, 2H), 7,33 (d, 2H).

The final connection is possible

Example 1

N-{1-methyl-5-[(4-pyridine-2-reparation-1-yl)carbonyl]-1H-pyrrol-3-yl}-N'-[4-(triptoreline)phenyl]urea

50 mg (0.15 mmole) of 1-methyl-4-[({[4-(triptoreline)phenyl]amino}-carbonyl)amino]-1H-pyrrole-2-carboxylic acid (example 5A) add 1 ml of DMF, and then mixed with 56 mg (of 0.18 mmole) of tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (TBTU) and 8.9 mg (0.07 mmole) of 4-(dimethylamino)pyridine (DMAP). Then added 29 mg (0,18 mmole) 1-(2-pyridyl)piperazine and stirred for 8 h at RT. In conclusion, the reaction mixture is purified by means OF ghvd (acetonitrile/water). In this way receive specified in the title compound in the form of solids.

Yield: 54 mg (76% of theory).

LC-MS (method 1): Rt=1,61 minutes

MS (ESI+): m/z=489 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=rate of 8.75 (s, 1H), 8,32 (s, 1H), 8,13 (dd, 1H), 7,50-to 7.59 (m, 3H), 7,25 (d, 2H), 7,02 (d, 1H), 6,86 (d, 1H), of 6.68 (dd, 1H), 6,28 (d, 1H), and 3.72 (m, 4H), to 3.64 (s, 3H), 3,55 (m, 4H).

Example 2

N-(1-methyl-5-([4-(5-methylpyridin-2-yl)piperazine-1-yl]carbonyl) -1H-pyrrol-3-yl)-N'-[4-(triptoreline)phenyl]urea

The specified connection receive analogously to example 1 from compounds of examples 5A and 6A.

Yield: 50 mg (68% of theory).

LC-MS (method 1): Rt=1,66 minutes

MS (ESI+): m/z=503 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=8,7 (Shir. s, 1H), 8,32 (Shir. s, 1H), 7,98 (d, 1H), 7,53 (m, 2H), 7,42 (dd, 1H), 7,25 (d, 2H), 7,02 (d, 1H), 6,80 (d, 1H), 6,28 (d, 1H), 3,68 is 3.76 (m, 4H), 3,63 (s, 3H), 3.45 points-of 3.53 (m, 4H), 2,17 (s, 3H).

Example 3

N-{1-ethyl-5-[(4-pyridine-2-reparation-1-yl)carbonyl]-1H-pyrrol-3-yl}-N'-[4-(triptoreline)phenyl] urea

The specified connection receive analogously to example 1 from compounds of examples 7A and 6A.

Yield: 29 mg (43% of theory).

LC-MS (method 2): Rt=1,79 minutes

MS (ESI+): m/z=503 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=a total of 8.74 (Shir. s, 1H), 8,32 (Shir. s, 1H), 8,13 (d, 1H), 7,49-of 7.60 (m, 3H), 7,22-7,28 (m, 2H), was 7.08 (s, 1H), 6.87 in (d, 1H), of 6.68 (dd, 1H), of 6.26 (s, 1H), Android 4.04 (q, 2H), 3,68-of 3.77 (m, 4H), 3,50-to 3.58 (m, 4H), of 1.26 (t, 3H).

Example 4

N-(1-ethyl-5-{[4-(5-methylpyridin-2-yl)piperazine-1-yl]carbonyl)-1H-pyrrol-3-yl)-N'-[4-(triptoreline)phenyl] urea

The specified connection receive analogously to example 1 from compounds of examples 7A and 6A.

Yield: 26 mg (39% of theory).

LC-MS (method 2): Rt=1,80 minutes

MS (ESI+): m/z=517 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=8,75 (Shir. s, 1H), 8,32 (Shir. s, 1H), 7,98 (m, 1H), 7,54 (m, 2H), 7,42 (m, 1H), 7,26 (m, 2H), was 7.08 (m, 1H), 6,80 (d, 1H), and 6.25 (s, 1H), a 4.03 (q, 2H), 3,68 is 3.76 (m, 4H), 3,44-to 3.52 (m, 4H), to 2.18 (s, 3H), 1,25 (t, 3H).

N-{1-butyl-5-[(4-pyridine-2-reparation-1-yl)carbonyl]-1H-pyrrol-3-yl}-N'-[4-(triptoreline)phenyl] urea

The specified connection receive analogously to example 1 and the walking of the compound from example 8A.

Yield: 41 mg (69% of theory).

LC-MS (method 2): Rt=2,11 minutes

MS (ESI+): m/z=531 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=8,75 (Shir. s, 1H), 8,33 (Shir. s, 1H), 8,12 (d, 1H), 7,58 (m, H), 7,54 (d, 2H), 7,26 (d, 2H), 7,07 (d, 1H), 6.87 in (d, 1H), of 6.68 (dd, 1H), of 6.26 (d, 1H), was 4.02 (t, 2H), and 3.72 (m, 4H), 3,53 (m, 4H), to 1.59 (quint., 2H), 1,18 (sext, 2H), from 0.84 (t, 3H).

Example 6

N-(1-butyl-5-{[4-(5-methylpyridin-2-yl)piperazine-1-yl] carbonyl}-1H-pyrrol-3-yl)-N'-[4-(triptoreline)phenyl]urea

The specified connection receive analogously to example 1 from compounds of examples 8A and 6A.

Yield: 19 mg (20% of theory).

LC-MS (method 2): Rt=1,97 minutes

MS (ESI+): m/z=545 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=a total of 8.74 (Shir. s, 1H), 8,32 (Shir. s, 1H), 7,98 (d, 1H), 7,53 (d, 2H), 7,41 (dd, 1H), 7,25 (d, 2H), 7,07 (d, 1H), 6,80 (d, 1H), and 6.25 (d, 1H), was 4.02 (t, 2H), and 3.72 (m, 4H), 3,47 (m, 4H), of 2.16 (s, 3H), of 1.59 (quint., 2H), 1,18 (sext., 2H), or 0.83 (t, 3H).

Example 7

N-{1-(cyclopropylmethyl)-5-[(4-pyridine-2-reparation-1-yl)carbonyl]-1H-pyrrol-3-yl)-N'-[4-(triptoreline)phenyl] urea

The specified connection receive analogously to example 1 from the compound from example 9A.

Yield: 51 mg (86% of theory).

LC-MS (method 1): Rt=1,84 minutes

MS (ESI+): m/z=529 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=8,75 (Shir. s, 1H), 8,33 (Shir. s, 1H), 8,13 (dt, 1H), 7,51-to 7.61 (m, 3H), 7,27 (d, 2H), 7,13 (d, 1H), to 6.88 (d, 1H), 6,69 (dd, 1H), 6,28 (d, 1H), 3,90 (d, 2H), to 3.73 (m, 4H), 3,53 (m, 4H), of 1.12 (m, 1H), 0,45 (m, 2H),and 0.28 (m, 2H).

Example 8

N-(1-(cyclopropylmethyl)-5-{[4-(5-methylpyridin-2-yl)piperazine-1-yl]carbonyl}-1H-peopel-3-yl)-N'-[4-(triptoreline)phenyl]urea

The specified connection receive analogously to example 1 from compounds of examples 9A and 6A.

Yield: 52 mg (85% of theory).

LC-MS (method 1): Rt=1,86 minutes

MS (ESI+): m/z=543 (M+N)+.

1H-NMR (300 MHz, DMSO-d6): δ=8,77 (Shir. s, 1H), 8.34 per (Shir. s, 1H), 7,98 (d, 1H), 7,54 (d, 2H), 7,41 (dd, 1H), 7,25 (d, 2H), 7,12 (d, 1H), 6,80 (d, 1H), 6,27 (d, 1H), 3,89 (d, 2H), and 3.72 (m, 4H), of 3.48 (m, 4H), of 2.16 (s, 3H), of 1.12 (m, 1H), 0,45 (m, 2H), and 0.28 (m, 2H).

Example 9

N-(5-{[4-(5-methylpyridin-2-yl)piperazine-1-yl]carbonyl}-3-thienyl)-N'-[4-(triptoreline)phenyl]urea

The specified connection receive analogously to example 1 from compounds of examples 10A and 6A.

Yield: 60 mg (63%) of theory).

LC-MS (method 3): Rt=2,05 minutes

MS (ESI+): m/z=506 (M+N)+.

1H-NMR (400 MHz, DMSO-d6): δ=9,05 (Shir. s, 1H), 8,95 (Shir. s, 1H), 7,98 (d, 1H), 7,56 (d, 2H), 7,47 (s, 1H), 7,39-7,44 (m, 2H), 7,29 (d, 2H), 6,80 (d, 1H, in), 3.75 (m, 4H), 3,51 (m, 4H), of 2.16 (s, 3H).

See the table below for the compounds synthesized analogously to example 1 from the appropriate starting compounds:

B. assessment of the physiological effectiveness of the proposed in the invention compounds

The proposed action is s in the invention compounds in vitro can be demonstrated by the following experiments.

Experiments on suppression of cytopathogenicity HCMV virus (human cytomegalovirus) proposed in the invention compounds

The test compounds used in the form of 50 millimolar (50 mm) solutions in dimethyl sulfoxide (DMSO). As comparative compounds used ganciclovir, foscarnet and cidofovir. After adding 2 μl of 50-, 5-, of 0.5 and 0.05-millimolar initial solutions in DMSO to each 98 μl of culture medium for growing the cells in row 2 And-N in two replications spend dilution in a ratio of 1:2 culture medium, 50 μl of which add up to the number 11 96-well plate. The wells in rows 1 and 12 contain only 50 ál of culture medium. Then in the wells of row 1 pipette add 150 ál of a suspension of 1×104cells (human foreskin fibroblasts [NHDF]) (cells in the wells of row 1 are the control), respectively, into the wells of rows 2 through 12 of the pipette add 150 ál of a suspension of 1×104cells in the form of a mixture of positive HCMV virus and uninfected cells (multiplicity of infection equal to 0,001-0,002, i.e. for every 1000 uninfected cells have 1-2 infected cells). Hole number 12 (without test compounds) only contain the virus, which serves as the control. The final concentration of test compounds is from 250 to 0.0005 microns. Tablets incubi the Ute for 6 days at 37°C in an atmosphere with 5%content of CO 2i.e. all cells, including in the wells with the control virus are infected with them (100%cytopathogenic effect [of the centre e]). After that, the cells in the wells fixed and stained by addition of a mixture of formalin and dyes Institute (30 min), then washed twice with distilled water and dried in a drying Cabinet at 50°C. Next, the cells in the tablets visually assessed through a microscope of the type "overhead" (Plaque multiplier firm Technomara).

In the analysis experienced tablets you can get the following information:

figure CC50(NHDF): the maximum concentration of the test compound in μm, at which it has no cells no noticeable cytotoxic action in comparison with untreated control cells;

indicator EC50(HCMV): the concentration of the test compound in μm, at which it inhibits the cytopathic effect by 50% compared to untreated control virus;

SI (index selectivity): CC50(NHDF)/EC50(HCMV).

Representative data about the action proposed in the invention compounds in vitro is shown below in table A.

Table a
Compound of example No.NHDF cells, SS50[µm]HCMV virus, EU [µm]index SI, HCMV
4210,000728767
9210,00593559
14110,00167333 stations
23110,00542637

The suitability of the proposed invention compounds for the treatment caused by HCMV virus infections can be demonstrated in the following experiment on animal models.

The xenograft model with Gelfoam®infected with HCMV virus

Animals

For experiments using 3-4-week-old female immunodeficient mice (16-18 g) line Fox Chase SCID, Fox Chase SCID-NOD or SCID-beige, which are purchased from commercial producers, their suppliers (Bomholtgaard, Jackson). Animals are insulators in sterile conditions (including the use of sterile bedding and feed).

The replication of the virus

Human cytomegalovirus (HCMV)strain Davis, propagated in vitro on human embryonic foreskin fibroblasts (NHDF cells). After being infected NHDF cells with the plurality for which Azania, equal to 0.01, virus-infected cells are harvested after 5-7 days and stored at -40°C in the presence of a minimum maintenance medium (MEM), supplemented with 10% fetal calf serum (FCS) with 10% DMSO. After serial dilution of the virus-infected cell with a decimal step determine the titer at 24-hole tablets confluent NHDF cells after their preliminary vital neutral red staining or fixation and staining with a mixture of formalin with dye from the Institute (see above).

Preparation of sponges, transplantation, processing and analysis of results

Collagen sponge size 1×1×1 cm (Gelfoam®the firm Peasel & Lorey, cat. No. 407534; ..Chong and others, Abstracts of the 39thInterscience Conference on Antimicrobial Agents and Chemotherapy, 1999, c. 439; P.M.Kraemer and others, Cancer Research, 43, 1983, cc. 4822-4827) first moistened with phosphate buffered saline (SFR)by vacuum remove the included air bubbles and then stored in MEM medium, supplemented with 10% FCS. Next, 1×106virus infected NHDF cells (infection with strain Davis HCMV virus with a multiplicity of infection of 0.01) is separated after 3 h after infection, and 20 μl of MEM-medium with 10% FCS dotted on a damp sponge. If necessary, after 12-13 hours on infected sponges put basic fibroblast growth factor (bFGF) at a concentration of 5 ng/μl in 25 μl SFR with 0.1% BSA and 1 mm is TT (dithiothreitol) and incubated for 1 h For transplantation sponges immunodeficient mice their narcoticyou aventinum or with a mixture of acepromazine with xylazine and ketamine, the hair on the back removed with a shaver, in the epidermis, make an incision 1-2 cm, weaken and under the skin transplanted back a damp sponge. Surgical wound is closed with glue for gluing fabrics. At 24 h after transplantation to mice for 8 days three times a day (7.00, 14.00 and 19.00 hours), twice a day (8.00 and 17.00 hours), either once a day (14.00 hours) orally administered the test compound. Test the connection, use a dose of 3, 10, 30 or 100 mg/kg of body weight when injected volume of 10 ml/kg body weight. The test compound is administered to mice in a 0.5%suspension in tylose, optionally with the addition of 2% DMSO. 9 days after transplantation and after 16 h after the last injection of test compounds animals are painless killing and remove the sponge. Virus-infected cells isolated from the sponge by its degradation by collagenase (330 units/1.5 ml) and stored at -140°C in the presence of MEM, supplemented with 10% FCS with 10% DMSO. The efficacy of test compounds evaluated after serial dilution of the virus-infected cell with a decimal step, determining the titer at 24-hole tablets confluent NHDF cells after their preliminary vital the aqueous neutral red staining or fixation and staining with a mixture of formalin with dye from the Institute (see above). Thus to determine the number of infectious viral particles after application of the test compounds in comparison with the control group of animals who were given a placebo.

C. Examples of pharmaceutical compositions

Proposed in the invention compounds can be processed in the following pharmaceutical compositions.

Tablet

Composition: 100 mg of the compound from example 1,50 mg lactose (as monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25, a product of BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

The weight of one tablet 212 mg, a diameter of 8 mm, the radius of convexity 12 mm

Getting

The mixture of active ingredient with lactose and starch granularit in water using a 5%by weight solution of polyvinylpyrrolidone. After drying, the granulate for 5 min, mixed with magnesium stearate. From this mixture on a conventional tablet press press press tablet (settings tablets see above). Estimated value of the effort of pressing is 15 kN.

Suspension for oral use

Ingredients: 1000 mg of the compound from example 1, 1000 mg of ethanol (96%), 400 mg xanthan gum Rhodigel (product company FMC, Pennsylvania, USA) and 99 g of water.

Single dose containing 100 mg offered in the invention compounds correspond to the 10 ml oral suspension.

P is torching

Gum Rhodigel is suspended in ethanol and then to the resulting suspension type active substance. Further, when the mixing water is added. The mixture is stirred for about 6 h until complete swelling of the gums Rhodigel.

Solution for intravenous injection

Ingredients: 1 mg of the compound from example of 1.15 g of polyethylene glycol 400 and 250 g of water for injection.

Getting

The proposed invention in connection together with polyethylene glycol 400 with stirring dissolved in water. The resulting solution was sterilized by filtering through a filter with a pore diameter of 0.22 μm) and aseptically poured into subjected to heat sterilization of bottles for infusion. At the end of their sealed peelable stoppers and tear-off caps.

1. The compound of formula (I)

in which R1represents a group of the formula

where * indicates the place of attachment to the carbonyl group,
R3represents pyridyl which may be substituted by the Deputy, is independently selected from the group comprising C1-C6alkyl and cyano,
R5and R6independently of one another denote hydrogen,
R2represents phenyl which can be substituted by the Deputy selected from the group comprising cryptometer, deformation is a group and monitorsetup,
A represents a group of the formula
,,or
where * indicates the place of attachment to the carbonyl group,
# indicates the place of attachment to the nitrogen atom of the urea
R7represents C1-C6alkyl which may be substituted by the Deputy selected from the group comprising From3-C6cycloalkyl,
R8and R9independently of one another denote hydrogen, halogen or C1-C6alkyl, or one of its pharmaceutically active salts.

2. The compound according to claim 1, characterized in that
R1represents a group of the formula

where * indicates the place of attachment to the carbonyl group,
R3represents pyridyl which may be substituted by the Deputy, is independently selected from the group comprising From1-C4alkyl and cyano,
R2represents phenyl which can be substituted by the Deputy selected from the group comprising cryptometer, dipterocarp and monitorsetup,
A represents a group of the formula
,,or
where * indicates the place of attachment to CARBONYLS the nd group,
# indicates the place of attachment to the nitrogen atom of the urea
R7denotes methyl, ethyl or n-butyl, each of which can be substituted by the Deputy selected from the group comprising cyclopropyl, and
R8and R9independently of one another denote hydrogen, bromine, chlorine, methyl or ethyl,
or one of its pharmaceutically active salts.

3. The method of obtaining the compounds of formula (I) according to claim 1, characterized in that the compound of formula (V)

in which R2has specified in claim 1 values, a R10denotes methyl or ethyl, in the first stage is subjected to interaction with the corresponding base, and the second stage in the presence of dehydrating agents are interacting with the compound of the formula (VI)

in which R1has specified in claim 1 values.

4. The method of obtaining the compounds of formula (V), as defined in claim 3, characterized in that the compound of formula (II)

in which R1has specified in claim 1 value, the first stage is subjected to interaction with the reducing agent, and the second stage is subjected to interaction with the compound of the formula (IV)

in which R2has specified in claim 1 values.

5. The connection according to one of claims 1 or 2, which has antiviral activity the capacity of human cytomegalovirus (HCMV) or another representative of the group of Herpes viridae.

6. The drug, which has antiviral activity against human cytomegalovirus (HCMV) or another representative of the group of Herpes viridae containing compound according to one of claims 1 or 2 in combination with at least one inert, non-toxic, pharmaceutically acceptable auxiliary substance.

7. The drug according to claim 6, intended for the treatment and/or prevention of these viral infections.

8. The use of compounds according to one of claims 1 or 2 for the preparation of a medicinal product, which has antiviral activity against human cytomegalovirus (HCMV) or another representative of the group of Herpes viridae.

9. The way to fight viral infections selected from the human cytomegalovirus (HCMV) or another representative of the group of Herpes viridae, namely, that enter in antiviral effective amount of at least one compound according to one of claims 1 or 2, or a drug according to claim 6.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: formula (I) compound has antibacterial activity and can be used as a medicinal agent. In formula ,

R1 is hydrogen, halogen, C1-4alkyl; R2 is selected from hydrogen, halogen, C1-4alkyl; R3 is selected from hydrogen, halogen, cyano, C1-4alkyl; W is -N(R6)-; X is a single bond; ring A is an unsaturated or partially saturated ring containing 5-6 atoms, one or two of which are independently selected from nitrogen and sulphur; or an unsaturated or partially saturated bicyclic ring containing 9-10 atoms, one, two or three of which are selected from nitrogen and sulphur; R4 and R5 are substitutes on a carbon atom and are independently selected from a halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, formyl, hydroxy iminomethyl, C1-4alkoxyminomethyl, C1-4alkyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkoxy)carbamoyl, N-(C1-4alkyl)-N-(C1-4alkoxy)carbamoyl, C1-4alkylS(O)a, where a equals 0-2, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, C1-4alkylsulphonylamino, (saturated or unsaturated carbocycle containing 3-7 atoms)-R10- or (saturated, partially saturated or unsaturated ring containing 5-6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R11-; where R4 and R5 can independently and optionally substituted at the carbon atom with one or more R12; R6 is hydrogen; n equals 1-4; where values of R4 can be identical or different; m equals 0-4; where values of R5 can be identical or different; R12 is selected from azido, halogen, cyano, hydroxy, amino, carboxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkylS(O)a, where a equals 0-2, (saturated or unsaturated cabocycle containing 3-7 atoms)-R14- or (saturated, partially saturated or unsaturated ring containing 5 or 6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R15-; where R12 can independently and optionally be substituted at the carbon atom with one or more R9; R10, R11, R14 and R15 are independently selected from a single bond, -C(O)-, -N(R19)C(O)- or -C(O)N(R20)-; where R19 and R20 are independently selected from hydrogen or C1-4alkyl; R16 is selected from halogen, cyano, hydroxy, carboxy, methyl and methoxy. The invention also relates to a pharmaceutical composition, having antibacterial activity, containing the disclosed compound as an active ingredient, use of the disclosed compound to prepare a medicinal agent and a method of producing the compound of formula (I).

EFFECT: high activity of the compounds.

22 cl, 52 tbl, 721 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole derivatives of general formula I

and pharmaceutically acceptable salts thereof, where n equals 1 or 2, m equals 0, 1 or 2, A contains in the ring a group selected from -CR1=, -CR2=, -CR3=, -CR4= and -CR5=, where 0 or 1 in these groups is replaced with N, R1, R2, R3, R4 and R5 are independently selected from a group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6 heterocycloalkyl-C0-alkyl, where the said heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, C5heteroaryl-(C0-C4)alkyl, where the said heteroaryl contains 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12; -XN(XOR12)2, -XNR11XC(O)OR12 -XNR11XNR11C(O)R12 -XNR11XNR11R12, -XNR11C(O)R12, where each X is independently selected from a group comprising a chemical bond and C1-C4alkylene, each R11 is selected from a group comprising hydrogen and C1-C6alkyl, and R12 is selected from a group comprising hydrogen, C1-C6alkyl and phenyl, or R11 and R12 together with a nitrogen atom to which R11 and R12 are bonded form C6heterocycloalkyl. Said heteroaryl or heterocycloalkyl in R1, R2, R3, R4 or R5 optionally contains one substitute selected from a group comprising hydroxyl, cyano, C1-C6alkyl, hydroxyl(C1-C6)alkyl and carboxy, R6 and R7 independently denote hydrogen, R8 is selected from a group comprising C1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8a and -COOR8a or two R8 groups bonded to different carbon atoms, together form a (C1-C2)alkyl bridge, or two R8a groups bonded to one carbon atom form a (C3-C8)cycloalkyl group, where R8a is selected from a group comprising hydrogen and C1-C6alkyl, R9 is selected from a group comprising phenyl and C6heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, where the said phenyl or heteroaryl in R9 is optionally substituted with 1-2 substitutes independently selected from a group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14, where each of R13 and R14 is independently selected from a group comprising hydrogen and C1-C6alkyl, R10 denotes hydrogen, Y and Z are independently selected from a group comprising CR20 and N, where R20 denotes hydrogen, provided that compounds of formula I do not include compounds of formula II, which are described in claim 1, and provided that compounds of formula I do not include compounds which are: 1-(4-fluorophenyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)piperazine, 1- ((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridin-2- yl)piperazine, 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridin-2-yl)piperazine and 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-fluoropyridin-2-yl)piperazine. The invention also relates to specific compounds obtained.

EFFECT: novel pyrazole derivatives which can be used in treating diseases or disorders which are mediated by disrupted activation of the said compound are obtained.

8 cl, 1 tbl, 4 ex

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