Novel piperidine substituted indoles and heteroderivatives thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

 

The technical field to which the invention relates.

The present invention mainly relates to piperidinomethyl the indoles or heteroprotein, and to their use as modulators of the activity of chemokine receptors, to pharmaceutical compositions containing these compounds, and to methods of their use as agents for treatment and prevention of inflammatory diseases such as asthma and allergic diseases, as well as for treatment and prevention of autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

Prior art

Chemokines are chemotactic cytokines with molecular weight 6-15 kDa, which are released from many cells in order to attract and activate, in particular, these cells, like macrophages, T and b lymphocytes, eosinophils, basophils and neutrophils (see reviews: Luster, New Eng J. Med., t, s-445 (1998), Rollins, Blood, t, s-928 (1997)).

There are two basic classes of chemokines, CXC and CC, the name of which is determined by the fact whether the first two cysteine residue (S) in the amino acid sequences are separated by one amino acid residue (SHS) or are adjacent (CC). CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP2) and protein - stimulator activity of melanoma growth (MGSA) are x motocyclisme primarily in respect of neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1a, MIP-1 (3, monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4 and MCP-5) and eotaxin (-1, -2 and -3) cause chemotaxis of other cells, in particular cell types, such as macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There are also chemokines - lymphotactin-1, lymphotactin-2 (both With chemokines), fractalkine (SHHHS chemokine), which are not included in the basic subfamily of chemokines.

Chemokines bind to specific cell-surface receptors, which belong to the family of conjugated proteins with seven transmembrane domains and associated with G-protein (for an overview see: Horuk, Trends Pharm. Sci., t.15, SS-165 (1994)), which is called "chemokine receptors". By linking with their cognate ligands of chemokine receptors transmit extracellular signals via associated trimeric G proteins, leading, along with other responses to the rapid increase in calcium concentration inside the cell, changing the shape of the cells, increased secretions of cell adhesion molecules, degranulating and stimulate cell migration. There are at least ten chemokine receptors in humans that are associated with CC-chemokines or respond to CC chemokines, typical are the following: CCR1 (or"R-1 or SS-R-1") [MIP-1a, MCP-3, MCP-4, RANTES] (Ben-Barruch, et, Cell, t, SS-425 (199), Luster, New Eng. J. Med., t, s-445 (1998)); CCR-2A and CCR-2B (or "CKR-2A"/"CKR-2B"or"SS-R-2A"/"CC-CKR-2B") [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo and others, r.Natl. Acad. Sci. USA, v.91. s-2756 (1994), Luster, New Eng. J. Med., t, s-445 (1998)); CCR-3 (or "R-3 or SS-R-3") [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, etc., J. Biol. Chem., t, s-16494 (1995), Luster, New Eng. J. Med., t, s-445 (1998)); CCR-4 (or"R-4"or"CC-R-4") [TARC, MIP-la, RANTES, MCP-1] (Power and others, J. Biol. Chem., t, cc.19495-19500 (1995), Luster, New Eng. J. Med., t, s-445 (1998)); CCR-5 (or "R-5", or "CCCKR-5") [MIP-1a, RANTES, MIP-1p] (Sanson, and others, Biochemistry, t.35, SS-3367 (1996)); CCR-6 (or "CKR-6"or "CC-CKR-6") [LARC] (Baba and others, J. Biol. Chem., t, s-14898 (1997)); CCR-7 (or R-7", or"SS-R-7") [ELC] (Yoshie and others, J. Leukoc. Biol., t, s-644 (1997)); CCR-8 (or R-8", or "SS-R-8") [1-309, TARC, MIP-lp] (Napolitano and others, J. Immunol, t, cc.2759-2763 (1996), Bernardini and others, Eur. J. Immunol, V.28, cc. 582-588 (1998)); and CCR-10 (or "R-10", or "SS-R-10") [MCP-1, MCP-3] (Bonini and others, DNA and Cell Biol., t.16., cc.1249-1256 (1997)).

It was shown that in addition to chemokine receptors mammals cytomegalovirus, herpes viruses and poxviruses (virus group smallpox) Express in infected cells proteins with the ability to communicate in the same way as chemokine receptors (see review: Wells and Schwartz, Curr. Opin. Biotech., Vol.8, cc.741-748 (1997)). CC chemokines, such as RANTES and MCP-3, can cause rapid immobilization of calcium through such coded virus receptors. The infection may allow the synthesis of receptors, is of itiva change of control of the normal immune system response to infection. In addition, chemokine receptors, such as CXCR-4, CCR-2, CCR-3, CCR-5, CCR-8, can work as coreceptor in the case of infection of mammalian cells by microbes, such as human immunodeficiency virus (HIV).

Chemokine receptors are considered as important mediators of inflammatory, infectious, and immunoregulatory disorders, disorders and diseases, including asthma and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, chemokinesis receptor CCR-3 plays a Central role in attracting eosinophils in the area of allergic inflammation and subsequent activation of these cells. Chemokine ligands of the receptor CCR-3 induce a rapid increase in intracellular calcium concentration, increase the excretion of cell adhesion molecules, the degranulation of the cells and stimulate the migration of eosinophils. In accordance with these agents, which are modulators of chemokine receptors could be useful in these disorders, disorders and diseases. In addition, agents that are modulators of chemokine receptors could be useful in infectious diseases, for example, by blocking infection CCR-3 expressing cells by human immunodeficiency virus (HIV) or prevent osdate on the immune responses of cells such as viruses, as cytomegalovirus.

Prior art

In the patent US 5521197 described piperidine-substituted indoles as agonists of 5-HT1F.

In the published international patent application WO 98006402 disclosed the use of these compounds for the treatment of the common cold or allergic rhinitis.

In the published international patent application WO 98011895 described these compounds intended for the treatment of migraine.

Similar compounds are described in published international patent application WO 2001043740, these compounds are also used as modulators of 5-HT.

In the published international patent application WO 2002008223 described piperidinylidene indoles attached to aryl ring, substituted peptides, as D4- modulators, but also with a partial effect on the

5-HT2Aor 5-HT2Cthe receptors.

In the published international patent application WO 99037304 described substituted derivatives of piperidine and piperazine, designed for the inhibition of factor XA.

In the published international patent application WO 2000075130 described derivatives interpipeline as Antiasthmatic and antiallergic agents, which includes the treatment of bronchial asthma.

The problem to be solved by the present invention is directed, is to enable the development of new modulators of chemokine receptor CCR-3. Unexpectedly, it was found that some piperidinylidene indoles very suitable as modulators of chemokine receptor CCR-3.

A brief description of the invention

In accordance with the present invention are new piperidylidene derivatives of indole or heteropneustidae formula 1:

in which R1, R5, R6A , b, D-E, X-W-V, Y, i, j, and m are as described below.

Another objective of the present invention is the obtaining of agonists or antagonists of the receptor CCR-3, or pharmaceutically acceptable salts of these compounds, in particular obtaining pharmaceutical compositions comprising pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds according to the present invention or pharmaceutically acceptable salts of such compounds. These and other objectives will be more clear from the following detailed description of the present invention.

Detailed description of the invention

The present invention relates to compounds of formula 1,

in which

R1represents aryl, heterocyclyl or kannelirovannye fragments based on them, where heterocyclyl represents a heterocyclic fragment and annelia is installed fragments include annelirovannymi arylheteroacetic, annelirovannymi heterocyclisation or annelirovannymi heterocyclisation, each of these arrow or heterocyclyl may be substituted by one, two or three radicals R2;

R2each independently means (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)halogenoalkane, (C1-C6)aralkyl, halogen, CN, COOR3, COR3, CONR3R4, NR3R4, NR3SO2R4, OR3, NO2, SR3, SOR3, SO2R3or SO2NR3R4;

R3represents H, (C1-C6)alkyl, (C3-C8)cycloalkyl or (C3-8-cycloalkyl)-(C1-C6)alkyl;

R4represents H, (C1-C6)alkyl, (C3-C8)cycloalkyl or (C3-C8)cycloalkyl-(C1-C6)alkyl, or

R3and R4together with located between the nitrogen atom or the group N-SO2- form an optionally substituted nitrogen-containing heterocyclic 3-8-membered ring system,

R5is a (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, (C1-C6)aralkyl, (C3-C6)cycloalkyl, (C3-C6cycloalkyl)-(C1-C6)alkyl, (C1-C6)halogenoalkane, (C1-C6 )thioalkyl, halogen, NO2CN;

R6each independently means (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, (C1-C6)aralkyl, (C3-C6)cycloalkyl, (C1-C6)halogenoalkane, (C1-C6)thioalkyl, halogen, OR3, SR3, CN, NO2, COOR3, COR3, CONR3R4, NR3R4, NR3COR4, NR3SO2R4, SOR3, SO2R3, SO2NR3R4, aryl or heterocyclyl;

But a (C3-C6) cycloalkyl-(C2-C8)alkylene, (C2-C8)alkylen with a linear or branched chain, optionally substituted with halogen or the group HE;

In represents aryl or heterocyclyl;

D-E represents CH-CH2- or=CH;

X-W-V is a N-C=CR7or C=C-NR7;

R7represents H or (C1-C6)alkyl;

Y is CF2, NR4, O, S(O)n;

i, j each independently is 0, 1 or 2;

n means 0, 1 or 2;

m means 0, 1, 2, 3 or 4;

and their pharmaceutically acceptable salts.

Compounds described in the text of this application may contain asymmetric centers. Compounds according to the present invention, in which there is any asimmetricheskii substituted atom may be isolated in optically active or racemic form. From prior art it is well known how to obtain optically active forms, for example, by separation of racemates or by synthesis from optically active starting compounds. Geometric isomerism olefins and compounds of this type may also be present in the compounds that are described in the text of this application, and all such stable isomers are included in the scope of the present invention. CIS - and TRANS - geometric isomers of the compounds according to the present invention are described and may be isolated as a mixture of isomers and the individual isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomers of the proposed structure are included in the scope of the present invention, unless specifically indicated specific stereochemistry or isomeric form.

Terms and definitions

The terms in the text of this application is not given a special definition, should be considered in this value, in which the specialist in the art considers this term, with due regard to the description of the present invention and context. However, when used in the text of this application, unless otherwise stated, the following terms are used in the specified value and the following symbols are used.

When specifying groups, radicals or fragments defined below, the number of carbon atoms is often specified before the name of the group, for example, (C1-C6)alkyl means an alkyl group or an alkyl radical containing from 1 to 6 carbon atoms. As a rule, in the case of groups that include two or more subgroups, the group that is specified last is the place of attachment of the moiety, for example, "thioalkyl" means a monovalent radical of the formula HS-Alk-. If not specifically indicated, specifying all of the formulas and groups are assumed to be generally accepted symbols and terms.

Normally, when specifying a chemical structure or compound include all tautomeric forms and isomeric forms and mixtures, such as individual geometric isomers or optical isomers or racemic, or nerezisca mixture of isomers, unless the specific stereochemistry or a specific isomeric form is specifically not included in the name or link structure.

The term "substituted" when used in the text of this application, means that one or more hydrogen atoms of the specified atom is replaced with a selection from the indicated group, provided that you do not exceed the normal valency of the specified atom and that the introduction of such substituent results in a stable structure.

The phrase "pharmaceutically acceptable" is used in Exte this application to refer to such compounds, substances, materials, compositions and/or dosage forms that are part of the medical report are suitable for use in contact with tissues of the human or animal and not have excessive toxicity, do not cause irritation, allergic reactions and do not create other problems or complications, commensurate with a reasonable balance of benefits and risks.

When used in the text of this application, the term "pharmaceutically acceptable salts" refers to derivatives of these compounds, where the original connection modify by obtaining its salts with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to specified mineral or organic salts with acids formed by the remnants of the main character, for example, involving amino groups; alkali or organic salts of acidic residues nature, such as including the group of carboxylic acids, and other Pharmaceutically acceptable salts include the well-known non-toxic salts or the Quaternary ammonium salts of the parent compounds formed, for example, from non-toxic inorganic or organic acids. For example, such well-known non-toxic salts include salts derived from inorganic acids, such as chloromethane sour is a, Hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; and salts derived from organic acids, such as acetic acid, propionic acid, succinic acid (butanedioate), glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, 4,4'-Methylenebis(3-hydroxy-2-naphthoic acid), maleic acid, hydroxymaleimide acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluensulfonate acid, methanesulfonate acid, ethicality acid, oxalic acid, sotynova acid, etc.

Pharmaceutically acceptable salts according to the present invention can be obtained by conventional chemical methods, based on compounds that contain a fragment of a basic or acidic nature. Generally, such salts can be obtained through the interaction of the compounds in the form of the free acid or free base with a stoichiometric amount of the appropriate base or acid in water or in a medium of an organic solvent, or a mixture of two normally non-aqueous media, preferably such as EF the R, the ethyl acetate, ethanol, isopropanol or acetonitrile. The list of suitable salts can be found in the manual Remington, such salts release the active parent compound in vivo, in the case when such prodrug is administered to the patient is a mammal. Prodrugs according to the present invention receive by modifying functional groups present in the compound, so that the modifying group useplease, either by regular manipulation or in vivo, with the formation of the target compounds. Prodrugs include compounds according to the present invention, in which the hydroxy-group, the amino or sulfhydryl group attached to any other group that in the case when the prodrug according to the present invention is administered to the patient is a mammal, cleaved with the formation of the free hydroxy-group, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to specified, acetate, formate and benzoylpropionate functional alcohol groups and amino groups of the compounds according to the present invention.

The term "aryl" when used in the text of this application or separately, or in combination with another Deputy, means either an aromatic monocyclic system or aromatic mu is Tellicherry system, containing carbon atoms. For example, aryl includes phenyl or naftalina ring system, where aryl means, typically an aromatic system, for example phenyl.

The term "heterocyclyl" when used in the text of this application or separately, or in combination with another Deputy means monovalent Deputy resulting from removal of a hydrogen from a five-, six - or semichasnoho saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four heteroatoms included in the ring selected from nitrogen, oxygen and sulfur. Examples of suitable heterocycles include tetrahydrofuran, thiophene, diazepine, isoxazol, piperidine, dioxane, morpholine, piperazine or

Although the term "heteroaryl" falls under the term "heterocyclyl", when used in the text of this application "heteroaryl" strictly means unsaturated heterocycle, in which the double bond to form an aromatic system. Suitable examples of heteroaromatic systems include pyridine, pyrimidine,

;;;;;or

The term "kannelirovannye fragments OS is ove aryl or heterocyclyl" when used in the text of this application or separately, or in combination with another Deputy, where there are kannelirovannye fragments in the form of aryl-heterocyclyl (a), heterocyclyl-aryl (b) or heterocyclyl-heterocyclyl (b),means a monovalent Deputy obtained by removing one hydrogen atom from:

(a) an aromatic monocyclic system or aromatic multicyclonic system containing carbon atoms, which is anilinophenol with five-, six - or semiclean saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four heteroatoms included in the ring selected from nitrogen, oxygen and sulfur, or

b) a five-, six - or semichasnoho saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four heteroatoms included in the ring selected from nitrogen, oxygen and sulfur, which is fused with a monocyclic aromatic system or aromatic multicyclone systems containing carbon atoms, or

in five-, six - or semichasnoho saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four heteroatoms included in the ring selected from nitrogen, oxygen and sulfur, which is a fused five-, six - or semicolon the m saturated or unsaturated (including aromatic) heterocycle, containing carbon atoms and one, two, three or four heteroatoms included in the ring selected from nitrogen, oxygen and sulphur.

Suitable examples of annelated fragments on the basis of the aryl or heterocyclyl include chinoline, 1-indoyl, 3-indoyl, 5-indoyl, 6-indoyl, indolizinyl, benzimidazolyl or purines.

The term "halogen" as used in this application means the Deputy - halogen selected from fluorine, chlorine, bromine or iodine.

The term "-(C1-C6)alkyl" when used in the text of this proposal, either individually or in combination with another Deputy, means acyclic, alkyl substituent with a linear or branched chain, containing from one to six carbon atoms, and includes, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

The term "-(C3-C8)cycloalkyl" when used in the text of this proposal, either individually or in combination with another Deputy means cycloalkenyl Deputy containing from three to six carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "-(C1-C6)halogenoalkane" when used in the text of this application or separately, or in combination with another Deputy, means acyclic, the alkyl is a " linear or branched chain, containing up to six carbon atoms, where one or more hydrogen atoms replaced by halogen atom selected from bromine, chlorine, fluorine or iodine. In accordance with this "-(C2-C6-halogenoalkane" has the same meaning, except that the chain contains from two to six carbon atoms. Preferably, the term (C1-C6)halogenoalkane means (C1-C6-foralkyl, such as trifluoromethyl, 2,2,2-triptorelin or perforated.

The term "-(C1-C6)alkoxy" as used in the text of this application or separately, or in combination with another Deputy means the Deputy (C1-C6)alkyl-O-, where alkyl is as defined above, and contains up to six carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy or 1,1-dimethylmethoxy. The last Deputy, as you know, usually referred to as tert-butoxy.

The term "-(C1-C6)acyloxy" when used in the text of this application or separately, or in combination with another Deputy means the Deputy (C1-C6)alkyl-(CO)O-, where alkyl is as defined above, and contains up to six carbon atoms. Acyloxy includes Masao-, EtCOO, h-Lsoo-from Lsoo, h-Video-, second-BuCOO - or tert-Video-.

The term "-(C1-C6)aralkyl" when using the selected authentication in the text of this application or separately, or in combination with another Deputy means the Deputy-aryl -(C1-C6)alkyl, where alkyl is as defined above, and contains up to six carbon atoms. Aralkyl includes benzyl, phenylethyl, phenylpropyl, 1-phenyl-1-methylethyl, phenylbutyl or 1-phenyl-1,1-dimethylmethoxy.

The term "-(C1-C6)thioalkyl" when used in the text of this application or separately, or in combination with another Deputy, means acyclic, alkyl substituent with a linear or branched chain containing up to six carbon atoms and Tilney (HS) group as a substituent. Example thioalkyl group is thiopropyl, such as HS-CH2CH2CH2-.

The term "-C2-C8-alkylen" when used in this application means a bivalent alkyl substituent obtained by removing one hydrogen atom from each end of aliphatic hydrocarbons with a linear or branched chain, containing from two to eight carbon atoms and includes, for example, CH2CH2C(CH3)2CH2CH2-. In accordance with this "-(C1-C3)alkylene" has the same meaning, except that the chain contains from one to three carbon atoms.

Preferred embodiments of the inventions

Preferred ablauts the compounds of formula 1, where Y represents S or S=O, and R1, R5, R6A , b, D-E, X-W-V, i, j, and m are as described above. Especially preferred are compounds of formula 1A or 1B:

where R1, R5, R6A , b, D-E, X-W-V and m are as described above. Also preferred are compounds of formula 1, 1A or 1B, where:

R1represents aryl or heterocyclyl, both of which

optionally substituted with one, two or three radicals R2and

In means phenyl.

Also preferred are compounds of formula 1, 1A or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2and

In means phenyl.

Also preferred are compounds of formula 1, 1A or 1B, where:

In means phenyl and

D-E represents CH-CH2-.

Also preferred are compounds of formula 1, 1A or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2and

In means phenyl,

D-E is CH-CH2-.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E who appoints CH-CH 2and

And means CH2-CH2-CH2-.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E is CH-CH2and

And means(CH3)2-CH2-CH2-.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2and

In means phenyl,

D-E is CH-CH2-,

A means.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E is CH-CH2-,

And is aand

R7means N.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E is CH-CH2-,

A meansand

R7means Me.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, neobyazatel is substituted by one, two or three radicals R2,

In means phenyl, and

D-E means C=CH-.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three

the radicals R2,

In means phenyl,

D-E means C=CH - and

And means CH2-CH2-CH2-.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E means C=CH - and

And means(CH3)2-CH2-CH2-.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E means C=CH - and

A means

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three radicals R2,

In means phenyl,

D-E means C=CH-

A meansand

R7means N.

Also preferred are compounds of formula 1, 1a or 1B, where:

R1means phenyl, optionally substituted one, two or three what adically R 2,

In means phenyl,

D-E is=CH-,

And is aand

R7represents Me.

Also preferred are compounds of formula 1, 1a or 1B, where

R1means phenyl, optionally substituted one, two or three radicals R2and

R2each independently means COOR3, COR3, NR3R4, NR3SO2R4, SOR3, SO2R3or SO2NR3R4; in particular COOR3or SO2R3;

R3represents H or (C1-C6)alkyl; in particular H or methyl;

R4represents H or (C1-C6)alkyl; in particular H or methyl.

Also preferred are compounds of formula 1, 1a or 1B, where

R1means phenyl, optionally substituted by one radical R2and R2represents a

COOR3or SO2R3;

R3represents H or methyl;

R4means H or methyl.

Also preferred are compounds of formula 1, 1a or 1B, where:

R5is a (C1-C6)alkyl, (C3-C6)cycloalkyl or (C2-C6)halogenoalkane; or

R2is a CF3or halogen, in particular fluorine; or

R6predpochtite is correctly represents halogen, in particular fluorine. Also preferred is a method of obtaining compounds of formula 1 or 1A, wherein the compound of formula 2:

subjected to interaction with the compound of the formula 3:

where R1, R5, R6But, X-W-V, i, j, and m are as described above, and

LG represents a suitable tsepliaeva group, in particular halogen, mesilate, triplet, toilet or brasilit.

The compounds of formula 1 or 1A can be obtained by using the reactions and techniques described below. The interaction is carried out in a solvent environment, which is suitable for the substances and reagents and suitable for the effective implementation of the transformation. Specialist in the field of organic synthesis will be understood that the functional groups present in the molecule must be compatible with the terms of the proposed transformation. This can sometimes require a change of procedure stages of the synthesis, or the choice of the specific circuit implementation of the method, in order to obtain the target compound according to the present invention. It should also be noted that another important condition for the planning of the synthesis is a reasonable choice of protective groups used to protect reactive functional the social groups, present in the compounds described in the text of this application. Authoritative source that describes many alternatives for professionals in the field of organic chemistry is the guide: Greene, Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

Compounds according to the present invention suitable for the production of pharmaceuticals for the prophylaxis and/or treatment of diseases mediated by the activity of CCR-3 receptor.

It is preferable for obtaining a medicinal product for the prevention and/or treatment of a wide range of inflammatory, infectious, and immunoregulatory disorders, disorders and diseases, including asthma and allergic diseases, infection by pathogenic microbes (which, by definition, include viruses), as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

Most preferred is getting medicines for the prevention and/or treatment, for example, inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, diseases associated with hypersensitivity lung, allergic pneumonitis, eosinophilic cellulitis (eosinophilic inflammation of the loose fiber) (e.g., syndrome Vella), eosinophilic pneumonia (n is an example, syndrome Loeffler (Loeffler), chronic eosinophilic pneumonia), atonic (eosinophilic) fasciitis (e.g., Shulman syndrome), allergies, delayed-type, interstitial pulmonary process (Lai) (e.g., idiopathic (of unknown origin) pulmonary fibrosis) or Lai associated with rheumatoid arthritis, systemic red (systemic erythematous) lupus, ankylosing spondylitis, systemic sclerosis, Sjogren syndrome, polymyositis or dermatomyositis; General anaphylactic reaction or allergic reactions, drug allergies (e.g., to penicillin, cephalosporins), eosinophilic-myalgic syndrome due to eating contaminated tryptophan, an allergic reaction to an insect sting; autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic red (systemic erythematous) lupus, asthenic bulbar palsy (bulbospinal paralysis), juvenile diabetes; glomerulonephritis, autoimmune thyroiditis syndrome behceta; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host; inflammatory bowel disease such as Crohn's disease (granulomatous disease) and ulcerative colitis; spondylitis; scleroderma; psoriasis (including psoriasis, OPOS adowanie T-cells) and inflammatory diseases of the skin, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (inflammation of blood vessels) (for example, nekrotizirovannye, skin and allergic vasculitis); eosinophilic myositis, atonic (eosinophilic) fasciitis; with leukocyte infiltration of the skin or organs.

Synthesis

Asutamiseni the compounds of formula 2A get through reductive condensation ring structure, substituted by at least one functional amino group and containing hydrogen in the ortho-position, with functional geography protected azazil:

After condensation of the hydrogen atom is replaced by acylation according to the Friedel-Crafts using the derived α-halogen-acetylchloride or substituted α-halogen-acetonitrile and then subjected to hydrolysis with the formation of a α-catasetinae:

(Hal denotes CL or Br). After acylation conducting ring closure in the presence of acid:

where the values of R5, R6In, i, j, and m at all stages of the method are as described above, and

PG represents a protective group for the nitrogen, preferably benzyl group.

Substituted on carbon compounds of formula 2B or 2R get pose the STV-With condensation under the reaction conditions Buchwald (Buchwald) ring structure, substituted by at least one functional nitrogroup and halogen ortho-position with an α-C-atom of the functional ketogroup:

(Hal denotes Cl or Br). After the condensation reaction is conducted ring closure under the reduction conditions:

Then carry out the condensation of the newly formed ring with functional geography of azazil in the presence of acid:

followed, in the case of compound 2 g, hydrogenation of the double bond of azazil:

where at all stages of method R5, R6In, D-E, i, j, and m are as described above.

Compounds of formula 1B-g can be obtained by the interaction of compounds 2B-d with a compound of formula 3:

where R1, R5, R6And, In, Y, i, j, and m are as described above; and

LG represents a suitable tsepliaeva group, in particular halogen, mesilate, triplet, toilet or brasilit.

N-Methylated compounds of formula 1D or 1E can be obtained by the exploits of methylation of compounds 1B or h

where R1, R5, R6And, In, Y, i, j and m are the two who are such as specified above.

As will be clear to a person skilled in the technical field, there are numerous modifications and variations of the present invention, carried out in accordance with the above. Thus, it is necessary to understand that, in the scope defined by the attached claims, the present invention can also be carried out otherwise than, in particular, described in the text of this application.

Example 1

1-(3-Bromopropionyl)-4-torbenson

To a solution of n-portifino (20,8 ml) and 1-3-dibromopropane (60 ml) in acetonitrile (250 ml) is added To a2CO3(55,0 g) in small portions and the resulting mixture is refluxed for 3 hours. Then the salt and the solvent is removed, the product is distilled. So Kip. 112-115°C./1 mbar.

Example 2

(1-Benzylpiperidine-4-yl)-(4-forfinal)Amin

A solution of 4-foronline (32,7 g), N-benzylpiperidine (to 106.0 g) and acetic acid (to 106.0 g) in 1,2-dichloroethane (1200 ml) is cooled to a temperature below 15°C. To stir the solution slowly added a suspension of acetic acid (495,0 g) and sodium borohydride (31,2 g). After 2 hours stirring at 15°C and an additional 2 hours at room temperature the solvent is removed in vacuum. Add ethyl acetate (500 ml) and water (700 ml) with stirring and the reaction is th mixture is neutralized with sodium carbonate (approximately 250 g). The organic phase is separated, washed with 2 m solution of NaHCO3(100 ml) and water (100 ml) and dried using sodium sulfate. After removal of the solvent and recrystallization from ether/petroleum ether get a 53.8 g of the product as orange crystals, TPL-92°C.

Example 3

1-[2-(1-Benzylpiperidine-4-ylamino)phenyl]-2-chlorobutane-1-he

(1-Benzylpiperidine-4-yl)-(4-forfinal)Amin (a 51.2 g) was dissolved in 180 ml of benzene and cooled in an ice bath. Added dropwise to trichloride boron (180 ml, 1 M solution in hexane) in 30 minutes. Add 2-chlorobutyronitrile (18.6 g) and aluminiumchlorid (24,0 g) and the resulting mixture is refluxed for 15 hours and Then the mixture is cooled, add 180 ml of 2 n Hcl solution and the resulting mixture was additionally refluxed. Add 200 ml water and 200 ml of CH2CL2and then the resulting mixture is brought to a value rn, adding portions of sodium carbonate. The phases are separated, the organic phase is dried using sodium sulfate and then the solvent is removed. The obtained oily substance is purified column Express chromatography (CH2Cl2:MeOH in a ratio of 96:4). The output is 20.7 g of a colorless oily substance.

1H NMR (300 MHz, CDCl3): of 1.10 (3H, t), 1,62-to 1.79 (3H, m), 2,01-of 2.36 (6H, m), 2,80 of 2.92 (2H, m), 3.43 points is 3.57 (1H, m)and 3.59 (2, s)of 5.03 (1H, dd), to 6.75 (1H, dd), 7,16-7,22 (1H, m), 7.23 percent-7,42 (4H, m), the 7.43 (1H, dd), of 8.92 (1H, br d).

Example 4

1-(1-Benzylpiperidine-4-yl)-2-ethyl-5-fluoro-1H-indol

1-[2-(1-Benzylpiperidine-4-ylamino)phenyl]-2-chlorobutane-1-he (20.7 g) is mixed with 250 ml of dioxane, 27 ml of water and 2.3 g of sodium borohydride and then heated to 120°C. for 12 hours boiling under reflux add additional 3.3 g of sodium borohydride and the mixture is refluxed an additional 16 hours and Then remove the solvent, add 200 ml of water and extracted with the mixture, using 150 ml of CH2Cl2, then dried over sodium sulfate and concentrated in vacuo. The obtained oily substance is purified column Express chromatography (CH2Cl2:MeOH in a ratio of 96:4). The output is 11.9 g of pale yellow oily substance.

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), 1,72 (2H, br d), 2,19 (2H, br t), 2,39-2,48 (2H, m), and 2.79 (2H, q), 2,98 (2H, br d)and 3.59 (2H, s), 4,12-of 4.25 (1H, m), to 6.19 (1H, s), to 6.88 (1H, td), 7,19 (1H, dd), 7,21-7,31 (1H, m,), 7,31-7,39 (4H, m), 7,49-7,52 (1H, m).

Example 5

1-(piperidine-4-yl)-2-ethyl-5-fluoro-1H-indol

A solution of 1-(1-benzylpiperidine-4-yl)-2-ethyl-5-fluoro-1H-indole (11.9 g) and acetic acid (4,1 ml) in methanol (250 ml) hydronaut within 8 hours (50°C/1013 mbar). The resulting mixture was then filtered and concentrated in vacuo. Add CH2Cl2(250 ml), NaHCO 3(100 ml) and water (300 ml) and then the resulting mixture is stirred for 10 minutes. The organic layer is extracted using l3and then dried (MgSO4) and concentrated in vacuo. By recrystallization from ether/petroleum ether obtain 6.4 g of pure product (yield 73%) as colorless crystals.

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), of 1.65 (2H, br d)and 1.83 (1H, s), 2,22-is 2.37 (2H, m), 2,62 (2H, td), and 2.79 (2H, q), 3,10 (2H, br d), 4,20-or 4.31 (1H, m), 6,18 (1H, s), 6,83 (1H, td), 7,19 (1H, dd), to 7.59-7,14 (1H, m).

Example 6

2-Ethyl-5-fluoro-1-{1-[3-(4-perpenicular)propyl] piperidine-4-yl}-

A mixture of 1-(1-benzylpiperidine-4-yl)-2-ethyl-5-fluoro-1H-indole (2.4 g), 1-(3-bromopropionyl)-4-fervently (2.4 g), acetonitrile and potassium carbonate are heated at the boil under reflux for 5 hours the Solvent is removed and the resulting oily substance is purified column Express chromatography (ethyl acetate : petroleum ether in the ratio 1:1). The fraction containing the product, raids!! from the solvent and then the resulting oily substance is recrystallized from ethanol. Yield 1.2 g (30%) of colorless crystals.

TPL: 82-84°C;1H NMR (300 MHz, CDCl3): of 1.33 (3H, t, J 7,5), 1,77-TO 1.87 (4H, m), 2,10 (2H, td, J 12,5, J 2,5), 2.48-2.66 (4H, m), a 2.75 (2H, q, J 7,5), 2,94-IS 3.08 (4H, m), as 4.02-to 4.15 (1H, m), of 6.20 (1H, s), 6,83 (1H, td, J 9,5, J 2,5), 6,98? 7.04 baby mortality (2H, m), 7,16 (1H, dd, J 9,5, J 2,5), WAS 7.36-7,40 (2H, m), 7,47 (1H, dd, J 9,0, J 4,0).13 C NMR (75 MHz, CDCl3): 13,23, 21,12, 26,95, 30,62, 33,10, 53,88, 54,11, 57,10, 98,85, 104,70, 105,00, 108,12, 108,46, 112,07, 115,98. 116,27, 129,30, 132,22, 132,33, 144,20, 156,05, 159,15, 160,21, 163,48.

Example 7

1-(2-Nitro-4-forfinal)butane-2-he

To a solution of 1-bromo-2-nitro-4-ftoheia (6.2 g), Pd2dba3(260 mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (455 mg), K3RHO4(13,7 g) and 4-methoxyphenol (700 mg) in toluene (60 ml) is added 2-butanone (5.6 ml) and the resulting mixture heated to 60°C for 24 hours in an argon atmosphere. Then the resulting mixture is extracted with water and ethyl acetate (ratio 1:1) and washed with 2 M NaOH solution and water. The solvent is removed and the remaining product is distilled Express chromatography (cyclohexane : ethyl acetate in the ratio 9:1), thus obtaining 2.6 g (yield 44%) of pure product as light yellow crystals.

1H NMR (400 MHz, DMSO): and 0.98 (3H, t), of 2.56 (2H, q), 4,22 (2H, s), 7,51 (1H, dd), 7,63 (1H, td), 7,98 (1H, dd).

Example 8

2-Ethyl-6-fluoro-1H-indol

A solution of 1-(2-nitro-3-forfinal)butane-2-she (2.5 g) in ethanol (25 ml) is heated to 70°C. Add Na2S2O4(10.7 g) in water (30 ml) and the resulting mixture is heated to boiling under reflux for 1 hour. The ethanol is removed by distillation, the resulting residue is extracted twice with ethyl acetate, then the organic layer is washed with water and dried, the Solvent is removed and the remaining product was then purified from impurities Express chromatography (cyclohexane : ethyl acetate in the ratio 9:1). Obtain 1.3 g (yield 67%) of pure product as a white crystalline solid.

1H NMR (400 MHz, DMSO): of 1.26 (3H, t), of 2.72 (2H, q), 6,12 (1H, s), 6.73 x-to 6.80 (1H, m), 7,02 (1H, br d), 7,37 (1H, dd), 10,98 (1H, br s).

Example 9

2-Ethyl-6-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole

To a suspension of 2-ethyl-5-fluoro-1H-indole (1.2 g) in acetic acid (21 ml) at 90°C, add a mixture of 4-piperidone (3.4 g) and 2 N. phosphoric acid (7 ml). The reaction mixture was stirred at 95°C for 4 h, then add water (50 ml) and the reaction mixture is allowed to cool to room temperature. The pH value was adjusted to 11 with concentrated NaOH solution and then the resulting mixture was extracted with ethyl acetate. Washed with water, dried over magnesium sulfate and concentrated in vacuo. The obtained residue is washed (ether) and dried on the vacuum filter, thus obtaining 1.5 g (yield 84%) of product as a white crystalline solid. So pl. 194-6°C.

Example 10

2-Ethyl-6-fluoro-3-[1-(4-torpedoshaped)-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole

A solution of 2-ethyl-6-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (1.5 g), 1-(3-bromopropionyl)-4-fervently (1.7 g), potassium iodide (20 mg) and potassium carbonate (1.1 g) in DMF (10 ml) is heated at 95°C for 1 h and Then added ethyl acetate (80 ml) and water (35 ml) and the organic phase is additionally extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and concentrated in vacuo. The crude product is purified Express chromatography (CH2CL2:Meon in the ratio of 100:2) and get his g - hydrochloride interaction in acetone with a suitable quantity of ether solution of Hcl, thus obtaining 1.7 g of pure product (yield 55%) as white crystals. TPL°C.

Example 11

2-Ethyl-6-fluoro-3-piperidine-4-yl-1H-indole

3-(1-Benzyl-1,2,3,6-tetrahydropyridine-4-yl)-2-ethyl-6-fluoro-1H-indole (1.4 g) hydronaut for 1 hour at room temperature and a pressure of 1013 mbar) in the presence of catalyst (10% Pd/C (0.3 g) and methanol (25 ml). The catalyst was removed by filtration, the solvent evaporated and the obtained residue was washed with small portions of ether. Obtain 1.2 g (yield 85%) of pure product.

1H NMR (400 MHz, DMSO): of 1.20 (3H, t), of 1.52 (2H, br d), 1,90-2,04 (2H, m), 2,59-a 2.71 (4H, m), 2.71 to and 2.83 (1H, m), of 3.07 (2H, br d), 6,74 (1H, t), of 6.99 (1H, d), 7,52-of 7.60 (1H, m), of 10.72 (1H, br s).

Example 12

2-Ethyl-6-fluoro-3-{1-[3-(4-perpenicular)propyl]piperidine-4-yl}-1H-indole

A mixture of 2-ethyl-6-fluoro-3-piperidine-4-yl-1H-indole (0.9 g), 1-(3-bromo-propylsulfonyl)-4-fervently (1.0 g), potassium iodide (20 mg) and potassium carbonate (0.7 g) in DMF (10 ml) is heated at 100°C for 3 h and then allowed to cool to room temperature over but the I. Add ethyl acetate (50 ml) and water (25 ml) and then the organic phase is washed with water, dried and concentrated in vacuo. The crude product is purified Express chromatography (CH2Cl2:MeOH in a ratio of 95:5) and get his g - hydrochloride interaction in acetone with a suitable quantity of ether solution of Hcl with getting at the same time, after recrystallization from ether, 1.1 g of pure product (yield 70%) as white crystals.

1H NMR (400 MHz, DMSO): to 1.19 (3H, t), of 1.75 (2H, br d), 1,92-2,02 (2H, m), 2,35 (2H, br q), at 2.59 (2H, q), 2,92-3,09 (5H, m), of 3.10-3.20 (2H, m), 3,47 (2H, br d), of 6.71-6,79 (1H, m), 7,01 (1H, dd), 7,22 (2H, br t), 7,44-7,49 (2H, m), 7,58 to 7.62 (1H, m), 10,87 (1H, br s).

Example 13

2-Ethyl-6-fluoro-3-{1-[3-(4-perpenicular)propyl]piperidine-4-yl}-1-methyl-1H-indol

To a solution of 2-ethyl-6-fluoro-3-{1-[3-(4-fluoro-phenylsulfanyl)-propyl]piperidine-4-yl}-1H-indole (0.4 g) in DMF (5 ml) at 5°C. add sodium hydride (0.1 g) and the resulting mixture stirred for 15 min at room temperature. Then the mixture is cooled to 5°C, add Me (0.1 ml) and stirred the mixture for 30 minutes at room temperature. Add ethyl acetate (50 ml) and water (50 ml), the organic layer washed with water, dried over MgSO4and concentrated in vacuo. The hydrochloride salt is obtained by interaction of acetone with a suitable quantity of ethereal Hcl to obtain after which recristallization from the ether, 0.2 g of pure product (yield 46%) as white crystals.

1H NMR (400 MHz, DMSO): of 1.12 (3H, t), of 1.74 (2H, br d), 1,92 is 2.01 (2H, m), 2,29-to 2.42 (2H, m), 2,78 (2H, q), 2,92-is 3.08 (5H, m), 3,10-3,17 (2H, m), of 3.46 (2H, br d), 3,62 (3H, s), 6,79 (1H, br t), 7,18-7,27 (3H, m), 7,47 (2H, dd), 7,66 (1H, dd).

Examples 14-17

2-Ethyl-6-fluoro-3-{1-[3-(4-perpenicular)propyl]-1,2,3,6-tetrahydropyridine-4-yl}-1-methyl-1H-indol

1H NMR (400 MHz, DMSO): to 1.19 (3H, t), 1,19 is 2.10 (2H, m), 2,50-2,62 (1H, m), 2,75-2,90 (3H, m), 3,05 (2H, t), 3,31-3,39 (3H, m), 3,56-3,63 (1H, m), 3,68 (3H, s), 3,70-3,81 (1H, m), 3,93-was 4.02 (1H, m), 5,62 (1H, br s), 6,86 (1H, br t), 7,22 (2H, t), 7,29 (1H, dd), 7,45 is 7.50 (3H, m).

2-Ethyl-5-fluoro-1-1-(3-n-triftormetilfullerenov)piperidine-4-yl]-1H-indole

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), 1,90 (2H, br d), 2,00-2,12 (2H, m), 2,66-and 2.83 (4H, m), 2,99 is 3.23 (6H, m), 3,51 (2H, br d), 4,47-4,60 (1H, m), 6.20 (1H, s), 6,83 (1H, td), 7,21 (1H, dd), 7,54 (2H, dd), 7,62-7,70 (3H, m).

2-Ethyl-5-fluoro-1-{1-[3-(4-perpenicular)-3-methyl-butyl]piperidine-4-yl}-1H-indole

2-Ethyl-5-fluoro-1-(1-{2-[1-(4-perpenicular)cyclopropyl]ethyl}-piperidine-4-yl)-1H-indole

Examples 18-20

2-Ethyl-6-fluoro-3-[1-(3-n-triftormetilfullerenov)piperidine-4-yl]-1H-indole

2-Ethyl-6-fluoro-3-{1-[3-(4-fluoro-phenylsulfanyl)-3-methyl-butyl]piperidine-4-yl}-1H-indole

2-Ethyl-6-fluoro-3-(1-{2-[1-(4-fluoro-phenylsulfanyl)cyclopropyl-ethyl}-piperidine-4-yl)-1H-indole

Examples 21-23

2-Ethyl-6-fluoro-1-methyl-3-[1-(3-n-triftormetilfullerenov)-piperidine-4-yl]-1H-indole

2-Ethyl-6-fluoro-3-{1-[3-(4-perpenicular)-3-methylbutyl]piperidine-4-yl}-1-methyl-1H-indol

2-Ethyl-6-fluoro-3-(1-{2-[1-(4-fluoro-phenylsulfanyl)cyclopropyl]ethyl}-piperidine-4-yl)-1-methyl-1H-indol

Examples 24-26

2-Ethyl-6-fluoro-3-[1-(3-n-triftormetilfullerenov)-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole

2-Ethyl-6-fluoro-3-{1-[3-(4-fluoro-phenylsulfanyl)-3-methyl-butyl]-1,2,3,6-tetrahydropyridine-4-yl}-1H-indole

2-Ethyl-6-fluoro-3-(1-{2-[1-(4-perpenicular)cyclopropyl]ethyl}-1,2,3,6-tetrahydropyridine-4-yl)-1H-indole

Examples 27-29

2-Ethyl-6-fluoro-1-methyl-3-[1-(3-n-triftormetilfullerenov)-1,2,3,6-tetrahydropyridine-4-yl]-1H-indole

2-Ethyl-6-fluoro-3-{1-[3-(4-fluoro-phenylsulfanyl)-3-methyl-butyl]-1,2,3,6-tetrahydropyridine-4-yl}-1-methyl-1H-indol

2-Ethyl-6-fluoro-3-(1-{2-[1-(4-fluoro-phenylsulfanyl)cyclopropyl]ethyl}-1,2,3,6-tetrahydropyridine-4-yl)-1-methyl-1H-indol

Examples 30-37

3-{3-[4-(2-Ethyl-5-Florinda-1-yl)-3,6-dihydro-2H-pyridine-1-yl]propulsor the Anil}-[1,2,4]triazolo[4,3-a] pyridine

1H NMR (400 MHz, DMSO): 1,22 (3H, t), and 1.63 (2H, br d), 1,73 of-1.83 (2H, m), 1,98-2,11 (2H, m), 2,19-of 2.34 (2H, m), 2,43 (2H, t), by 2.73 (2H, q), and 2.83 (2H, br d)and 3.15 (1H, t), 3.25 to and 3.31 (1H, m), 4,08-4,19 (1H, m), 6,18 (1H, s), 6,86 (1H, td), 7,12 (1H, t), 7,17 (1H, dd), 7,37 (1H, dd), 7,42 (1H, dd), 7,82 (1H, d), 8,48 (1H, d).

2-{3-[4-(2-Ethyl-5-Florinda-1-yl)-3,6-dihydro-2H-pyridine-1-yl]propylsulfonyl}thiazolo[5,4-b]pyridine

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), of 1.75 (2H, br d), 1,97-of 2.08 (2H, m), 2,20-of 2.33 (2H, m), 2,41 is 2.51 (2H, m), 2,56-to 2.65 (2H, m), 2,78 (2H, q), of 3.12 (2H, br d), to 3.49 (2H, t), 4,18-4,30 (1H, m), of 6.20 (1H, s), 6.87 in (1H, td), 7,19 (1H, dd), of 7.48-7,53 (2H, m), 8,21 (1H, dd), and 8.50 (1H, dd).

5-Chloro-2-{3-[4-(2-ethyl-5-Florinda-1-yl)-piperidine-1-yl]propylsulfonyl}benzothiazole

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), of 1.93 (2H, br d), 2,30-to 2.42 (2H, m), of 2.81 (2H, q)to 2.99 (2H, br q), 3,13-of 3.32 (4H, m), of 3.56 (2H, t), 3,60-3,81 (2H, m), 4.53-in-the 4.65 (1H, m), 6.22 (1H, m), PC 6.82 (1H, br t), 7,21 (1H, dd), the 7.43 (1H, dd), to $ 7.91-8,02 (2H, m), 8,08 (1H, dd).

2-{3-[4-(2-Ethyl-5-Florinda-1-yl)-3,6-dihydro-2H-pyridine-1-yl] propylsulfonyl} benzooxazol

1H NMR (400 MHz, DMSO): of 1.27 (3H, t), of 1.76 (2H, br d), 1,99-of 2.09 (2H, m), 2,19-of 2.27 (2H, m), 2.40 a of $ 2.53 (2H, m), 2,59 (2H, t), 2,77 (2H, q), 3,11 (2H, br d), of 3.43 (2H, t), 4,17-to 4.28 (1H, m), of 6.20 (1H, s), 6,85 (1H, td), 7,18-7,22 (2H, m), 7,30-to 7.35 (2H, m), 7,47-of 7.55 (1H, m), 7,62-to 7.67 (1H, m).

2-Ethyl-5-fluoro-1-{1-[3-(5-triptorelin-2-ylsulphonyl)propyl]-1,2,3,6-tetrahydropyridine-4-yl}-1H-indole

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), is 1.73 (2H, br d), 1,73-to 1.82 (2H, m), 2,12 (2H, br t), 2,32 is 2.44 (3H,m), 2,78 (2H, q), to 3.02 (2H, br d), 3,24-of 3.32 (3H, m), 4,13-to 4.23 (1H, m), of 6.20 (1H, s), 6,85 (1H, td), 7,20 (1H, dd), 7,46-7,51 (1H, m), 7,53 (1H, m), to 7.99 (1H, dd), 8,81 (1H, s).

2-Ethyl-6-fluoro-3-{1-[3-(4-perpenicular)propyl]piperidine-3-yl}-1H-indole

1H NMR (400 MHz, DMSO): to 1.19 (3H, t), 1,51-1,85 (6N, m)a 1.96 (1H, br. t), 2,30 is 2.44 (3H, m), 2,64-of 2.72 (3H, m), 2,83-2,90 (2H, m), with 2.93 (2H, t)6,70-of 6.78 (1H, m), of 6.99 (1H, dd), 7,13 (2H, t), 7,35-7,41 (2H, m), 7,49-rate of 7.54 (1H, m), 10,77 (1H, s).

Ethyl ester of 3-{3-[4-(2-ethyl-5-Florinda-1-yl)piperidine-1-yl]propylsulfonyl}benzoic acid

TPL-181°C.

3-{3-[4-(2-Ethyl-5-Florinda-1-yl)piperidine-1-yl]propylsulfonyl}-benzoic acid

1H NMR (400 MHz, DMSO): a 1.25 (3H, t), 1,90 (2H, br. d)1,98 is 2.10 (2H, m), 2,72-is 2.88 (4H, m), to 3.02 3.21-in (7H, m), 3,44-of 3.60 (2H, m), a 4.53 (1H, br.s), 6,21 (1H, s), to 6.88 (1H, td), 7,22 (1H, dd), 7,49 (1H, t), to 7.68 (1H, br. d), 7,70-7,80 (2H, m), 7,88 (1H, s).

The method of treatment

Thus, the present invention relates to compounds that can be used in the treatment and/or prevention of a wide range of inflammatory, infectious, and immunoregulatory diseases, including asthma and allergic diseases, infection by pathogenic microbes (which, by definition, include viruses), as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

For example, the compounds according to the present invention, which inhibit one or several flats which are functions of the chemokine receptor in a mammal (for example, chemokine receptor human), can be introduced in order to inhibit (i.e. reduce or prevent) inflammation or infectious disease. In the inhibited one or more inflammatory processes, such as the emigration of leukocytes, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or the release of inflammatory mediators. For example, the infiltration of eosinophils in the zone of inflammation (e.g. asthma or allergic rhinitis) can be weakened in accordance with the method according to the present invention. In particular, the compound described in the example below, has activity against blocking the migration of cells synthesizing CCR-3 receptor, using appropriate chemokines, according to the above research.

Similarly, the compounds according to the present invention, which are promoters of one or more functions of the chemokine receptor in a mammal (e.g., chemokines person), due to the introduction stimulate (induce or enhance the immune or inflammatory response, such as the emigration of leukocytes, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or the release of inflammatory mediators, resulting in the beneficial stimulation of inflammatory processes. For example, the R, eosinophils may be involved to suppress parasitic infections. In addition, can also be considered the treatment of the above mentioned inflammatory, allergic and autoimmune diseases using the compounds according to the present invention, which promotirovat one or more functions of the chemokine receptor in a mammal, if the delivery of a sufficient number of connections that causes according to the present invention the reduction of the synthesis of the receptor cell by inducing internalization (in a cage) chemokine receptor or through the delivery connection in such a way that it changes the direction of cell migration.

In addition to primates, for example, in addition to person, treatment in accordance with the method according to the present invention can be subjected to many other mammals. For example, can be subjected to the treatment of mammals, including, but not limited to, cows, sheep, goats, horses, dogs, Guinea pigs, rats or other representatives of the families of cattle, sheep, horse, dog, cat, representatives of rodent or mouse, or rat. However, the method can be used for other representatives, for example for the treatment of birds. The patient to be treated according to the above-described method, is a mammal, male or female who is in need of modulation of activity chemokine receptor. The term "modulation" as used in the text of this application, as expected, indicates antagonism, agonism, partial antagonism and/or partial agonism.

Diseases or conditions of humans or other mammals, which need treatment with inhibitors of the functioning of the chemokine receptors include, but are not limited to specified: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, allergic lung disease, allergic pneumonitis, eosinophilic cellulitis (eosinophilic inflammation of the loose fiber) (e.g., syndrome Vella), eosinophilic pneumonias (e.g., syndrome Loeffler (Loeffler), chronic eosinophilic pneumonia), atonic (eosinophilic) fasciitis (e.g., Shulman syndrome), allergies, delayed-type, interstitial pulmonary process (Lai) (e.g., idiopathic pulmonary fibrosis, or Lai associated with rheumatoid arthritis, systemic red (systemic erythematous) lupus, ankylosing spondylitis, systemic sclerosis, Sjogren syndrome, polymyositis or dermatomyositis); General anaphylactic reaction or Allergy is a mini reactions drug allergies (e.g., to penicillin, cephalosporins), eosinophilic-myalgic syndrome due to eating contaminated tryptophan, an allergic reaction to an insect bite, autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic red (systemic erythematous) lupus, asthenic bulbar palsy (bulbospinal paralysis), juvenile diabetes; glomerulonephritis, autoimmune thyroiditis syndrome behceta; graft rejection (e.g., in transplantation), including aleocharinae graft or graft-versus-host; inflammatory bowel disease such as Crohn's disease (granulomatous disease) and ulcerative colitis; spondylitis; scleroderma; psoriasis (including psoriasis, mediated by T-cells) and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (inflammation of blood vessels) (for example, nekrotizirovannye, skin) and hypersensitive vasculitis (inflammation of blood vessels); eosinophilic myositis, atonic (eosinophilic) fasciitis; malignant tumor with leukocyte infiltration of the skin or organs. It is also possible to treat other diseases or conditions, etc which can be suspended undesirable inflammatory condition, including, but not limited to, reperfusion disorders, atherosclerosis, some malignant hematological diseases, cytokine-induzirovanna toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis. Infectious diseases or conditions of humans or other organisms that can be treated with inhibitors of the functioning of the chemokine receptor include, but are not limited to the above, the human immunodeficiency virus (HIV).

Diseases or conditions of humans or other organisms that can be treated with promoters of the functioning of the chemokine receptor include, but are not limited to specified: immunosuppression (immune suppression), for example, in patients with the syndrome of immunodeficiency, such as acquired immunodeficiency syndrome (AIDS) or other viral infections, treatment of patients undergoing radiotherapy (radiation therapy), chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression (immune suppression); immunosuppression due to congenital deficiency of function of the receptor or due to other reasons; and infectious diseases, such as diseases caused by parasites, including, n is not limited to, infection with nematodes (round worms); (trichiurus, enterobiasis, ascariasis, hookworm, Strongyloides, trichinosis, filariasis); trematodes (paragonimus) (schistosomiasis, clonorchis), infection with cestodes (tape worms) (echinococcosis, tanios - infection Taeniasis saginata, cysticercosis); infection of visceral worms-parasites, visceral form of the syndrome "wandering larvae" (larva migrans), (for example, takaros), eosinophilic gastroenteritis (e.g., when the infection Anisaki sp., Phocanema sp.), the cutaneous form of the syndrome "wandering larvae" (larva migrans) (infection Ancylostona braziliense, Ancylostoma caninum). In accordance with this connection according to the present invention can be used in the prevention and treatment of many inflammatory, infectious, and immunoregulatory disorders, disorders and diseases. In addition, the above treatment of inflammatory, allergic and autoimmune diseases can also be considered in relation to the promoters of the functioning of the chemokine receptor, if you expect to deliver such a large number of connections, which is sufficient to cause the weakening of the allocation of the receptor cell by inducing internalization (in a cage) chemokine receptor or delivery connection in such a way that it leads to change of the direction of migration to ATOC.

In accordance with another aspect of the present invention can be used for assessment of suspected specific agonists or antagonists of receptors associated with G-protein. The present invention relates to the use of these compounds in the acquisition and holding of screening compounds that modulate the activity of chemokine receptors. In addition, the compounds according to the present invention can be used for establishing or determining the binding sites of other compounds with chemokine receptors, e.g., through competitive inhibition or as a basic connection with the conduct of a study involving the comparison of compounds with known activity and compounds with unknown activity. In the case when developing a new method or technique of research, the compounds according to the present invention can be used to test their effectiveness.

In particular, such compounds can be represented for sale as a set, for example, for use in pharmacological studies associated with the above diseases. Compounds according to the present invention can also be used to assess the alleged specific modulators of chemokine receptors. In updat is out, you can use the compounds according to the present invention for testing the specificity of the receptors associated with G-protein, which, as I believe, are not the chemokine receptors, or using as example of compounds that do not bind to these receptors, or by using the compounds according to the present invention as a structural variants of compounds active against these receptors, which may help to identify specific areas of cooperation.

Pharmaceutical form

The compounds of formula 1 is administered to the mammal in a therapeutically effective amount. The term "therapeutically effective amount" means such amount of the compounds of formula 1, the introduction of which to the mammal alone or in combination with another therapeutic agent is effective to prevent or ameliorate symptoms of a disease mediated by the activity of CCR-3 receptor, or the development of this disease.

Compounds according to the present invention can be introduced into such dosage forms for oral administration such as tablets, capsules (each of which includes compositions with delayed release or timed release), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emuls is I. Compounds according to the present invention can also be entered using a form for intravenous (bolus or infusion), forms for intraperitoneal administration, forms for subcutaneous injection or form for intramuscular injection, all using dosage forms well known to the specialist in the field of pharmaceutics. Compounds according to the present invention can be introduced separately, but as a rule, they are administered together with a pharmaceutically acceptable carrier, selected depending on the intended route of administration, taking into account conventional pharmaceutical practices.

The dosage of the compounds according to the present invention will, of course, largely depend on known factors such as the pharmacodynamic characteristics of the particular agent and the manner and method of its introduction, and the specific input connection on age, sex, state of health of the patient and medical indications, as well as the body weight of the patient; the nature and extent of symptoms; kind of concurrent treatment; the frequency of reception; the method of administration, the condition of the kidneys and liver of the patient and the required effect. The attending physician or veterinarian will be able to determine and prescribe the effective amount of the drug required to prevent, to the of ntrolle or stop the progression of the disease.

As a General guidance, the daily dose in oral administration of each active ingredient, when used to achieve the specified action will vary in the range from about 0.001 to 1000 mg/kg body weight, preferably approximately from 0.01 to 100 mg/kg of body weight per day and most preferably approximately 1.0 to 20 mg/kg/day. When administered intravenously, the most preferred doses are in the range from approximately 1 to approximately 10 mg/kg/minute infusion at a constant speed. Compounds according to the present invention can be entered as a single dose per day or the total daily dose may be entered divided into several doses, for example two, three or four times a day.

Compounds according to the present invention can be introduced in the form of intranasal form the local application with the use of suitable intranasal filler or can be introduced using transdermal transdermal patch to the skin. In the case when the compound is administered in the form of transdermal delivery, injected dose, of course, more will be introduced continuously, than periodically.

The compounds of formula 1 are typically administered in the form of a mixture with pharmaceutically acceptable diluents, fillers, excipient the AMI or carriers (collectively referred to in the text of this application pharmaceutically acceptable carriers), appropriately selected in accordance with the intended method of administration, that is, to obtain tablets for oral administration, capsules, elixirs, syrups and the like, and subject to accepted pharmaceutical practice.

For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be used in conjunction with any suitable for oral administration non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and similar holders; for oral administration in liquid form drug component for oral administration can be used in conjunction with any suitable for oral administration non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. In addition, when appropriate or necessary, the composition may also be introduced suitable binder, sliding substances (excipients in the manufacture of tablets), the agents contributing to the disintegration of the dosage form, and tint the agents. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sugar ve is estvo from corn (sweetener), natural and synthetic gums such as acacia, tragacanth gum or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and other substances. Lubricants used in the preparation of such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and other substances that contribute to the disintegration of the dosage form include, in particular, starch, methylcellulose, agar, bentonite, xanthan resin, etc.

Compounds according to the present invention can also be introduced in the form of liposomal delivery, such as small single-layer liposomes, large single-layer liposomes multilayer liposomes. Liposomes can be obtained from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds according to the present invention can also be used in combination with soluble polymers, such as carriers for delivering drugs to the target. Such polymers can include polyvinylpyrrolidone, pernovae copolymers, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted palmitoleate remains.

In addition, the compounds according to the present invention can also be is used in conjunction with a number of biodegradable polymers, which can be used to produce forms with controlled release of drugs, such as polylactic (α-oxopropionate) acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, poly-Epsilon-caprolactone, polyhydroxyalkane acid, poly-ortho-esters, Polyacetals, policyidreference, polycyanoacrylate and sewn or amphipatic block copolymers - hydrogels.

Dosage forms (pharmaceutical compositions)suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient in a unit dosage form.

In these pharmaceutical compositions the active ingredient will usually be present in amounts of about 0.5-95% by weight calculated on the total weight of the composition.

Gelatin capsules can contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. To obtain a CT can be used such diluents. As tablets and capsules can be prepared in the form of products with slow release to ensure a constant release of the drug within a few hours. Compressed t is blacki may have a coating of sugar or can be covered with a film, to mask the unpleasant taste and protect the tablet from atmospheric conditions, or may have intersolubility coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain tinted agents and agents that improve the taste and smell to increase the attractiveness for the patient.

Generally, suitable carriers for solutions for parenteral administration are water, a suitable oil, saline, aqueous dextrose (glucose) and similar solutions of sugars and glycols, such as propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents include sodium bisulfite, sodium sulfite or ascorbic acid or separately, or in combination. Also use citric acid and its salt and sodium salt add (ethylenediaminetetraacetic acid). In addition, solutions for parenteral administration may contain preservatives, such as benzalconi chloride, methyl - or propylparaben and chlorbutanol.

Suitable pharmaceutical carriers are described in Reminqton's Pharmaceutical Sciences, Mack Publishing Comany - the conventional guidance in the field.

In that case, when the compound of formula 1 is administered two or more of the above other therapeutic agent, as a rule, the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when it is administered separately, due to the additive or synergistic effect of therapeutic agent when it is administered in combination.

In particular, when receiving a single dosage form, the potential exists for interaction between the combined active ingredients. For this reason, in the case where the compound of formula 1 and the second therapeutic agent are combined in a single unit dosage forms, composition prepared in such a way that, although the active ingredients and combine in a single dosage form, physical contact between the active ingredients is minimized (i.e. reduced). For example, one active ingredient may be intersolubility floor. Using intersolubility coverage for a single active ingredient, it is possible not only to minimize the contact between the associated combination of active ingredients, but it is also possible to control the release of one of these components in W is lubochna-intestinal tract thus to one active ingredient is not released in the stomach, but was mainly released in the intestine. One of the active ingredients may also be covered with a substance that is used to achieve a slow release in the gastrointestinal tract and also helps to minimize physical contact between the associated combination of active ingredients.

In addition, a component designed for slow release, can optionally have intersolubility floor, so that the release of this component occurs only in the intestine. Another option involves the preparation of a combination product in which one component is covered with a polymer for sustained release or cover intersolubility polymer coating and the other component is also coated with a polymer of low viscosity, such as hypromellose (receiver array), or use other suitable substances known from the prior art, in order to further separate from each other active ingredients. A polymer coating is used to receive an additional barrier to interaction with another component.

These and other ways to minimize contact between the components of the combined product in accordance with the present and the gain with the introduction in the form of a single dosage form, and with the introduction of separate forms, but at the same time and in the same manner as will be well understood by a person skilled in the art in accordance with the description of the present invention.

1. The compound of formula 1

where R1represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo[5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, each of these phenyl or heterocyclyl may be substituted by one, two or three radicals R2;
R2each independently means (C1-C6)halogenated, halogen, COOR3; CONR3R4;
R3represents H or (C1-C6)alkyl;
R4represents H or (C1-C6)alkyl;
R5is a (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)microalgal;
R6each independently means (C1-C6)alkoxy, (C1-C6)halogenated, halogen, OR3, CN, CONR3R4;
And represents C(CH3)2-CH2-CH2-CH2-CH2-CH2-or, optionally substituted with halogen or the group HE;
Represents a phenyl;
D-E represents CH-CH2- or=CH-;
X-W-V is a N-C=CR7or C=C-NR7;
R7represents H or (C1-C6 )alkyl;
Y represents NR4, O, S(O)n;
i, j, m each represent 1;
n means 0 or 2;
and its pharmaceutically acceptable salts.

2. The compound of formula 1a

and R1, R5, R6, A, B, D-E, X-W-V, i, j, and m are as stated in claim 1.

3. The compound according to claim 1 or 2, where R1represents phenyl, optional substitutions of one, two or three radicals R2.

4. The compound according to any one of claims 1 to 3, where D E denotes CH-CH2-.

5. The compound according to any one of claims 1 to 4, where a represents CH2-CH2-CH2-.

6. The compound according to any one of claims 1 to 4, where a represents C(CH3)2-CH2-CH2-.

7. The compound according to any one of claims 1 to 4, where a means

8. The compound according to any one of claims 1 to 7, where X-W-V is a N-C=CR7.

9. The compound according to any one of claims 1 to 8,
where R1means phenyl, optionally substituted one, two or three radicals R2and
R2each independently means COOR3or CONR3R4;
R3represents H or (C1-C6)alkyl;
R4represents H or (C1-C6)alkyl;

10. The method of obtaining compounds of formula 1 or 1A, which consists in the fact that the compound of formula 2

subjected to interaction with compounds is receiving formula 3

where R1, R5, R6, A, B, D-E, X-W-V, i, j, and m are as defined in claim 1, and
LG represents a suitable tsepliaeva group selected from halogen, mutilates group, triflate group, tosylate group or brasilito group.

11. Pharmaceutical composition having the properties of a modulator of the activity of the chemokine receptor CCR3, characterized in that it contains one or more compounds of formula 1 or 1A according to one of claims 1 to 9.

12. The compound of formula 1 or 1A according to any one of claims 1 to 9 as a drug that modulates the activity of the chemokine receptor CCR3.

13. The use of compounds of formula 1 or 1A according to one of claims 1 to 9 for obtaining a medicinal product intended for the prevention and/or treatment of diseases in which a therapeutically useful is the use of a modulator of the activity of the chemokine receptor CCR3.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention is related to derivatives of isothiourea of formula I, including their pharmaceutically acceptable salts, which possess properties of antagonist CXCR4. In compounds of formula I , where R1 means remainder of formula (a) , (b) or (c) , R2 means -(CR22R23)1-3-, R3 and R8 each means S, R4 and R5 each independently means C3-C12cycloalkyl, C1-C12alkyl or saturated C8-C12 polycyclic hydrocarbon remainder, such as adamantine, non-substituted phenyl or non-substituted benzyl unnecessarily substituted with group R25, R6 means H or C1-C6alkyl, R7 means CH, R9 means direct connection or -(CR22R23)1-2-, R10-R15 each means H, R16-R23 each independently means H, C1-C6alkyl, or R20 and R21 together with carbon atoms, to which they are connected, create a benzene ring, and R25 has one of values given above for R16-R23.

EFFECT: improved method for production of derivatives of isothiourea.

5 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to mono-sodium salt 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]thiazole[4,5-d]pyrimidine-2(3H)-on as a modulator of the activeness of chemokine receptors, method of obtaining it and pharmaceutical composition on its basis, and also its application in production of medicinal agents.

EFFECT: obtaining compounds, which can find application in treatment of diseases mediated by chemokine receptors, such as asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), inflammatory bowel disease, osteoarthritis, and rheumatoid arthritis.

10 cl, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel deazapurines of formula (I): and pharmaceutically acceptable salts thereof, where n = 0; R1 is H, -NH2, -NHCH3, -NH-Ac, -OH, F, -OCH3, -CN, -NH(C=O)OC2H5; R2 is H, -NRARB, -ORA, C1-20alkyl, C1-20halogenalkyl, C6-10aryl, where RA and RB each independently represents H, C1-20alkyl, where C6-10aryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of C1-20alkyl, C1-20alkoxy and C1-20thioalkyl; each R3 independently represents H, halogen, CN, C1-20alkyl, C1-20alkoxy, C1-20thioalkyl, a -G-RC group, where G is absent or represents CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -OC-, -O- or (C=O) and where RC is H, -NRF-RG , -ORF, -SRF, -S(=O)RF, -S(=O)2RF, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, tert-butyl dimethyl silyloxy, heterocycle, C6-10aryl, C5-14heteroaryl with one N atom as a heteroatom, where RF and RG each independently represents H, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, 6-member heterocycle with one O atom as a heteroatom, where RF and RG together form a 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl, cycloalkenyl, where the said heterocycle relates to a non-aromatic 5-, 6-, 7-member ring or bi- or tri-cyclic group containing condensed 6-member rings with 1-2 heteroatoms independently selected from O, S, N; where each of the said alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of O, halogen, OH, -CN, C1-20halogenalkyl, -CH2CF3, C1-20alkyl, C1-20alkoxy, C3-6cycloalkyl, C6-10aryl, 5- or 6-member heterocycle with one or two N atoms as heteroatoms, NHRh, NRhRi, N-ORh, ORh, C(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, =NR4, where Rh and Rj present C1-20alkyl, C6-10aryl, and each of R4, R5 independently represents H, OH, ORx or C1-6alkyl, where Rx is C1-6alkyl, where the said aryl can be independently further unsubstituted or substituted with one or more substitutes selected from a group consisting of halogen, C1-20alkyl or C1-20alkoxy.

EFFECT: compounds can inhibit cytokine induced expression of adhesion molecules with endothelial cells, which enables their use in pharmaceutical compositions.

54 cl

Organic compounds // 2379309

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (I) in free or salt form, where Q is a bond, R1 and R2 independently represent H or C1-C8alkyl, or R3 is C1-C8alkyl, R4 and R5 independently represent halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C15carbocyclic group, nitro group, cyano-group, C1-C8alkylsulphonyl group, R6 is H or C1-C8alkyl; W is a group of formula (Wa1) or (Wa2), where A independently represents C or N, or W represents a group of formula (Wb); where Y independently represents C or N; and Z represents N, O or S, or W represents a group of formula (Wc), where Y independently represents C or N; and Z represents O or S; X represents -SO2-, -CH2-, -CH(C1-C8alkyl)- or a bond; m and n each independently represents an integer from 0 to 3; and p is 1, to a pharmaceutical composition with CRTh2 antagonist activity, as well as to use thereof as a medicinal agent and production method thereof.

EFFECT: new compounds which can be used in medicine are obtained and described.

10 cl, 153 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula I or to their pharmaceutically acceptable salts, where X1 - CH; X2 - N or CH; Q1 represents ,

where X11 - CH or C-halogen; X12 - CH, C-halogen or C-CF3; X13 - CH; X14 - C-E11, and E11 represents C0-10alkyl or C0-10alkoxy; X15 - CH or N; X16 - N or N+ -0; G1 - phenyl or 5-6-members unsaturated ring containing one heteroatom N or S; R1 - C0-10alkyl, cycloC3-10alkyl or piperidinyl, any of which is optionally substituted with 1-2 independent substitutes G11, or R1 represents phenyl; G11 is chosen from: OR21 where R21 represents C0-10alkyl; -oxo; -cycloC3-8alkyl; -C0-10alkyl optionally substituted with group N(C0-10alkyl)(C0-10alkyl) wherein C0-10alkyl is optionally substituted with group N(C0-10alkyl)C(O)C0-10alkyl; group OR2221, where R2221 - C0-10alkyl; group N(C0-10alkyl)C(O)C0-10alkyl; group N(C0-10alkyl)SO2(C0-10alkyl); group -N(C0-10alkyl)C(O)N(C0-10alkyl)(C0-10alkyl); group -N(C0-10alkyl)C(=O)R3331, where R3331 - C1-10alkoxy C1-10alkyl or tetrahydrofuranyl; -N(R21)R31 where R21 and R31 independently represent C0-10alkyl optionally substituted with thiophenyl, morphlinyl, furanyl; cycloC3-8alkyl; C1-10alkoxyC1-10alkyl; tetrahydropyranyl; piperidylC0-10alkyl; or piperidyl optionally substituted with C0-10alkyl; or R21 and R31 optionally taken together with nitrogen atom whereto attached, form 3-10-members saturated ring optionally substituted with one or more independent substitutes G1111, and optionally including one or more heteroatoms different from nitrogen whereto R21 and R31 are attached; where G1111 - C0-10alkyl optionally substituted with group OR77 where R77 - C0-10alkyl, or G1111 represents C1-10alkoxyC1-10alkyl, pirimidinyl, pyrazinyl, imidazolylmethyl; C(O)N(R21)R31 where R21 and R31 independently represent C0-10alkyl; -C(O)O(C0-10alkyl); -C(O) C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or halogen; -heterocyclylC0-10alkyl where heterocyclyl represents 4-6-members saturated ring containing 1 or 2 heteroatoms, independently chosen from N, O or S optionally substituted with a substitute chosen from: 1) OR2221, where R2221 - pyrimidinyl or C0-10lkyl; 2) C(O)OR2221, where R2221 - C0-10alkyl or phenyl-C0-10alkyl; 3) C(O)C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or C1-10alkoxy C1-10alkyl; 4) C(O)N(C0-10alkyl)(C0-10alkyl); 5) S(O)2C0-10alkyl; 6) SO2N(C0-10alkyl)(C0-10alkyl); 7) -NR2221R3331, where R2221 and R3331 taken together with nitrogen atom whereto attached, form pyrrolidinyl; or G11 represents C, which taken together with carbon whereto attached, forms C=C double bond substituted with R5 and G111 where R5 and G111 are hydrogens. The invention also specifically concerns cys-3-[8-amino-1-(2-phenylquinoline-7-yl)-imidazo[1,5-α]pyrazine-3-yl]-1-methl-cyclobutanole or its pharmaceutically acceptable salt. The specified compounds and their pharmaceutically acceptable salts are applicable in treatment of conditions mediated by activity IGF-1R proteinkinase, particularly angiogenesis, vascular permeability, immune response, cell apoptosis, tumour growth or inflammation. The invention also concerns a pharmaceutical composition.

EFFECT: improved efficiency of the composition and method of treatment.

14 cl, 3 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrrolo[3,2-c]pyridine derivatives of formula (I) or their pharmaceutically acceptable salts in which R1 is hydrogen; straight or branched C1-C6alkyl group optionally substituted with one or more substitutes selected from a group consisting of C1-C5alkoxy, hydroxyl, C3-C7 cycloalkyl, C1-C3 alkylthiazolyl and 1,3-dioxolanyl; straight or branched C2-C6 alkenyl group; straight or branched C2-C6 alkynyl group; C3-C7cycloalkyl group; or benzyl group optionally substituted with one or more substitutes selected from a group consisting of halogen, C1-C3alkyl and C1-C3alkoxy, R2 is a straight or branched C1-C6 alkyl group, R3 is hydrogen; straight or branched C1-C6 alkyl group; straight or branched C2-C6alkenyl group; or a benzyl group optionally substituted with one or more halogens, and R4 is 1,2,3,4-tetrahydroisoquinolinyl group; a benzyloxy group optionally substituted with one or more halogens; or an amine group substituted with one or two substitutes selected from a group consisting of hydrogen, straight or branched C1-C5alkylcarbonyl, phenoxycarbonyl, benzyl, optionally substituted with one or more halogens, and benzoyl, optionally substituted with one or more halogens, as well as to method of producing said compounds and a pharmaceutical composition with inhibitory effect on a proton pump containing these compounds.

EFFECT: new compounds are obtained and described, which exhibit excellent inhibitory effect on a proton pump and can provide reversible inhibitory effect on a proton pump.

7 cl, 82 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-H-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazole[3,4-b]pyridine-5-carboxamide, which is a compound of formula or its pharmaceutically acceptable salt, as well as to a method of producing said compounds. The invention also relates to use of the said compound or its pharmaceutically acceptable salt as phosphodiesterase IV (PDE4) inhibitor, for example in treatment and/or prevention of inflammatory and/or allergic disease, cognitive impairment or depression in mammals. The invention particularly pertains to use of the compound or its pharmaceutically acceptable salt in treating and/or preventing atopic dermatitis in mammals, for example via external local administration to a mammal, for example a human being.

EFFECT: pharmaceutical compositions are also provided, which contain the said compound or its pharmaceutically acceptable salt, particularly suitable for external local administration.

35 cl, 1 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: present invention is related to new crystalline forms of salt of mesylate2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidaso[1,2-a]pyridine-6-carboxamide and to their mixture. Besides the present invention is also related to methods of their preparation, application and pharmaceutical composition for inhibition of gastric acid secretion, which contains them. Production of new salt of 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidaso[1,2-a]pyridine-6-carboxamide and its crystalline forms for production of medicinal agent for use in treatment or prophylaxis of gastrointestinal disorders such as gastritis, gastric ulcer, duodenal ulcer, peptic ulcerous diseases, reflux-esophagitis, Zollinger-Ellison syndrome, ulcerogenic adenomas of pancreas, acute bleeding from upper compartments of gastrointestinal tract.

EFFECT: wider area of compounds application.

33 cl, 1 tbl, 12 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazole derivatives with general formula (I) and their pharmaceutically acceptable acid addition salts, optically pure enantiomers, racemates and diastereomer mixtures as adenosine receptor ligands and to a pharmaceutical preparation based on said compounds. In general formula (I), R1 represents C3-7cycloalkyl substituted with a OR group, or 2-(7-oxa-bicyclo[2.2.1]hept-1-yl)-ethyl; R represents hydrogen or C(O)-lower alkyl; X represents -CHR'-; and R' represents hydrogen or lower alkyl.

EFFECT: compounds can be used for treating or preventing diseases mediated by adenosine A2A receptors, for example Alzheimer's disease, certain depressive conditions, toxicomania and Parkinson's disease.

8 cl, 8 ex

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