Substituted [1,2,4]triazolo[4,3-a]pyridines, demonstrating properties of antagonists of adenosine a2a receptors, and their application

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

 

This invention relates to new compounds, substituted [1,2,4]triazolo[4,3-a]pyridinium showing antagonistic activity against adenosine A2A receptors, and to their use as a pharmaceutical substance, the pharmaceutical compositions, drugs and adjuvants. The invention relates also to methods for treating disorders of the Central nervous system (CNS) neurodegenerative, inflammatory, infectious and oncological diseases.

Adenosine regulates many physiological functions, in particular, acts as a cytoprotector in normal and pathophysiological conditions in response to stress in organs and tissues [Haskó G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008; 7: 759-770]. This protective response may manifest as increased blood supply (vasodilate or angiogenesis), ischemic preconditioning [Akaiwa K, Akashi H, Harada H, Sakashita H, Hiromatsu S, Kano T, Aoyagi S. Moderate cerebral venous congestion dosage rapid cerebral protection via adenosine A1 receptor activation. Brain Res. 2006; 1122: 47-55], and/or anti-inflammatory effect (activation and infiltration of inflammatory cells, production of cytokines and free radicals) [Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature. 2001; 41: 916-920]. Extracellular adenosine acts on cellular membranes of the receptors, activating the appropriate intracellular signaling cascades.

There are four subtypes of adenosine receptors, denoted as A1, A2A, AV and A3 (table 1), each of which has a unique pharmacological profile, tissue distribution and binding of effector molecules [Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001; 53: 527-552]. All adenosine receptors belong to the family of receptors associated with G-proteins (GPCRs), which are structurally similar to the receptors of biogenic amines.

The affinity of adenosine receptor (fu. testingb) ES, nM
Table 1
Properties of adenosine GPCR receptors
Subtype receptorsA1A2AA2BA3
G proteinGi, GoGs, GolfGs, GqGi, Gq
The signaling mechanismInhibition of adenylate cyclase (↓AC)
Activation of FOS is alipaz With (↑PLC) (↑AC) (↓chCa+2)(↑AC) (↑PLC)(↓AC) (↑PLC)
Blockade of calcium channels (↓chCa+2)
Activation of potassium channels (↑chK+)
Effector molecules (second messengers)↓cAMP↑cAMP↑cAMP↑cAMP
↑IP3↑IP3↑IP3↑IP3
↓chCa+2↑chCa+2↑chCa+2↑chCa+2
↑chK+
The affinity of adenosine receptor (radioligand bindingand) Kd, nM10 (rA1)30 (rA2A)>100000 (hA2B)1000 (hA3)
310 (hA1)700 (hA2A)24000 (hA2B)290 (hA3)

Table 1
Tissue distribution (high expression)CNS (cortex, hippocampus, mossack, spinal cord); the adrenal glands; the AtriaSpleen; thymus; leukocytes (lymphocytes, granulocytes); platelets; GABA-neurons, olfactory bulbBlind and thick intestine; urinary bladderFat cells; testes
a) [J Med Chem. 2000; 43: 2196]; b) [Bioorg Med Chem Lett. 2011; 21(7): 1933]

Activation of A1 receptors leads to inhibition of adenylate cyclase through related receptors A1 Gi/o - proteins [Londos C, Cooper DM, Wolff J. the Subclasses of external adenosine receptors. PNAS USA. 1980; 77: 2551-2554], and also increases the activity of phospholipase C PLC [Rogel A, Bromberg Y, Sperling O, Zoref-Shani, E. Phospholipase is involved in the adenosine activated signal transduction pathway conferring protection against iodoacetic acid-induced injury in primary rat neuronal cultures. Neurosci Lett. 2005; 373: 218 to 221]. The A1 receptors activate potassium channels, including channels QUATRE, the block Q-, The p - and N-type calcium Ca2+ channels.

Activation of A2A receptors increases the activity of adenylate cyclase. In the peripheral system, the major proteins associated with A2A receptors are Gs-proteins. In the striatum, where the content of A2A receptors maximum, they are associated with proteins Golf [Kull, Svenningsson P, Fredholm BB. Adenosine A2A receptors are colocalized with and activate Golf in the striatum of the rat. Mol Pharmacol. 2000; 58: 771-777], which is similar to Gs-proteins linked to adenylate cyclase. The A2A receptor is able to activate PLC-signaling cascade, induce the synthesis of intitolata and increase the intracellular concentration of calcium and activate protein kinase C.

The A2 receptors In positively coupled with adenylate cyclase and phospholipase C. Many of the functions of receptors AV determined by phospholipase C, which is activated by Gq proteins [Linden J, Thai T, Figler H, Jin X, Robeva AS. Characterization of human A2B adenosine receptors: radioligand binding, western blotting, and coupling to Gq in human embryonic kidney 293 cells and HMC-1 mast cells. Mol Pharmacol. 1999; 56: 705-713]. These receptors are involved in the signaling cascade of arachidonic acid [Donoso MV, Lopez R, Miranda R, Briones R, Huidobro-Toro JP. A2B adenosine receptor mediates human chorionic vasoconstriction and signals through the arachidonic acid cascade. Am J Physiol Heart Circ Physiol. 2005; 288: H2439-H2449].

The A3 receptors are involved in the classical signaling pathways, inhibition of adenylate cyclase, stimulating phospholipase C and causing the mobilization of calcium ions [Zhou QY, et al. Molecular cloning and characterization of an adenosine recepor: the A3 adenosine receptor. PNAS USA. 1992; 89: 7432-7436]. Agonists A3 receptors inhibit the growth of melanoma cells, participating in the WNT-signaling cascade [Fishman P, et al. Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene. 2002; 21: 4060-4064].

Small molecule modulators of adenosine receptors can find wide application in pharmacology and medicine. Currently there are a large number of substances with affinity for adenosine receptors, but most of them are not selective. Selective ligands of adenosine receptors (for example, some analogs of adenine and xantina) have a very complex pharmacological profile, so have very limited clinical use (except weakly selective affine caffeine). Therefore, the search for selective adenosine ligands is an important task. Of particular importance are selective antagonists of A2A receptors.

A large number of scientific papers and patents on the use of antagonists of A2A receptors as drug candidates for the treatment of CNS disorders, which include, in particular:

- Parkinson's disease [Pinna A. Novel investigational adenosine A2A receptor antagonists for PA's disease. Expert Opin Invest Drugs. 2009; 18(11): 1619-1631];

- Alzheimer's disease and other cognitive disorders [Takahashi RN, Pamlona FA, Prediger RD. Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies. Front Biosci. 2008; 13: 2614-32];

-brain ischemia and stroke [Monopoli A, Lozza G, Forlani A, Mattavelli A, Ongini E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport. 1998; 9(17): 3955-3959];

- mental disorder [Wardas J. Potential role of adenosine A2A receptors in the treatment of schizophrenia. Front Biosci., 2008; 13: 4071-4096];

- other neurodegenerative diseases and dependencies [Ribeiro JA, Sebastião AM, de Mendonça A. Adenosine receptors in the nervous system: pathophysiological implications. Prog Neurobiol. 2002; 68(6): 377-392].

The prospect of finding selective adenosine A2A-ligands is confirmed by a series of CNS drug candidates that are currently in various stages of clinical trials (table 2) [http://www.integrity.prous.com]:

Table 2.
Antagonists of A2A adenosine receptors in different stages of testing
ConnectionDeveloperStructurePhase I trialsPurposeLink
Istradefylline KW-6002Kyowa Hakko KirinPhase 3 registrationParkinson's diseaseKW-6002 Drugs of the Future 2001, 26(1): 21
Preladenant SCH-420814 MK-3814Schering-Plough (Merck & Co.)Phase 3Parkinson's diseaseJ Med Chem 2011, 54(13): 4312

Table 2.
Tozadenant RO-449351 SYN-115Roche Biotie Therapies NIDAPhase 2/3Parkinson's diseaseJ Neurosci 2010, 30(48): 16284
Phase 0/1Dependence on cocaine
Vipadenant BIIB-014 V-2006 VR-2006Biogen Idec VernalisPhase 2 Trials discontinuedParkinson's diseaseJ Med Chem 2009, 52(1): 33

Parkinson's disease
Table 2.
ST-1535Sigma-TauPhase 1Eur J Pharmacol 2008, 579(1-3): 149
V-81444VernalisThe structure is not disclosedPhase 1Parkinson's diseaseSuccessful outcome for V81444 in phase I study. Vernalis Press Release 2012, May 02
PBF-509PalobiofarmaThe structure is not disclosedPhase 1Parkinson's diseasePalobiofarma Web Site 2012, Novemb. 16

Table 2.
AlmirallAlmirall Neurocrine BiosciencesPreclinical trialsParkinson's diseaseJ Med Chem 2008, 51(22): 7099
DT-1133Domain TherapeuticsThe structure is not disclosedPreclinical trialsParkinson's diseaseDomain Therapeutics SA Web Site 2013, February 19

Table 2
SCH-442416Merck & Co.Preclinical trialsDiagnostic agentJ Med Chem 2000; 43(23): 4359

Previously it was shown that adenosine, which accumulates near the tumor tissue [BIay J, White TD, Oskin DW. The increasing interest among Fluid of Solid Carcinomas Contains immunosuppressive Concentrations of Adenosine. Cancer Research. 1997; 57: 2602-2605], significantly inhibits the ability of activated T-lymphocytes and natural killer cells to contact with tumor cells and kill them [Hoskin DW, Reynolds T, Blay J. Adenosine as a possible inhibitor of killer T-cell activation in the microenvironment of solid tumours. Int J Cancer. 1994; 59: 854-855]. Hypoxia, which has been developing in terms of solid tumors leads to increased concentrations of adenosine near the tumor tissue. Adenosine binding to the adenosine A2A receptor type, located on the cell membrane of lymphocytes, reports adenosine signal inside the cells, which reduces the ability of lymphocytes to attack the tumor tissue [Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia. Clin Cancer Res. 2008; 14(19): 5947-5952]. On this basis, a new approach is proposed to enhance the effectiveness of anticancer therapy (in particular, vaccines) using adjuvant, aplauses the camping antagonist of A2A receptors [Ohta A, Sitkovsky M. Methods and composition for improving immune responses. WO 2008/147482 04.12.2008].

Studies have shown that agonists of the adenosine receptor A2A are important regulators of inflammatory processes. It was shown that A2A agonists have anti-inflammatory properties in vitro and in vivo. Adenosine, engaging in interaction with surface receptors A1, A2A, AV and A3 has a different biological effect. From all four of A2A receptors is most common and is closely associated with inflammatory reaction. The conducted research allowed to reveal the ability of A2A to inhibit the phosphorylation of tyrosine kinase Zap-70, the secretion of eosinophils and monocytes, loosen perforin and cytotoxicity of lymphokine-activated killer cell Activation receptor adenosine A2A suppresses system inflammatory signaling in cytokine and accelerates the healing process. [M. A. Trevethick, S. J. Mantell, E. F. Stuart, A. Barnard, K. N. Wright, M Yeadon, Pfizer Global R&D, "the Treatment of inflammatory processes of the respiratory tract agonists of the adenosine receptor A2A", journal Pharmacist, 2009, issue No. 3, http://www.provisor.com.ua/].

Thus, the search for effective and selective antagonists of A2A receptors is extremely important and promising task.

With the aim of developing new high-performance A2A ligands by the authors of the present invention made an extensive screening vary the x low molecular weight compounds, determining the effectiveness of their interaction with adenosine receptors. Unexpectedly been found connection hits, some of which are derivatives of [1,2,4]triazolo[4,3-a]pyridines. We then conducted aimed modification of the detected structures and testing of new compounds, with a relationship "structure-activity" and selected the most promising lines and connections-leaders. In the synthesized a series of new derivatives of [1,2,4]triazolo[4,3-a]pyridines, not previously described in the literature, which are original and highly effective antagonists of A2A receptors.

The purpose of the present invention is to create a new selective antagonists of A2A receptors.

This goal is achieved by the new antagonists of adenosine A2A receptors represents a substituted [1,2,4]triazolo-[4,3-a]pyridine General formula I and their pharmaceutically acceptable salts.

The object of the present invention are substituted [1,2,4]triazolo[4,3-a]pyridine General formula I and their pharmaceutically acceptable salts:

where a represents an optionally substituted aminocarbonyl group-N-C(O)-, in which the amino group may be substituted and the substituents can be selected from

hydrogen, C1-C5of alkyl, enabled the substituted C 1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which the heteroatoms are selected from oxygen or nitrogen;

aryl selected from phenyl, possibly substituted by hydroxy, C1-C5the alkyl, C1-C5alkoxy, halogen, C1-C5allmineral, or naphthyl;

or amino group is selected from C3-C7heterocyclyl containing 1-2 heteroatoms in the cycle selected from nitrogen, oxygen or sulfur, possibly substituted by hydroxy, C1-C5by alkyl, benzyl, phenyl which may be substituted with halogen, with the specified heterocyclyl may be condensed with a benzene ring;

allmenalp, in which acyl is selected from the

C1-C6alkylsulphonyl, where alkyl may be substituted by phenyl, substituted phenyl in which the substituents selected from C1-C5alkoxy; a 5-membered heteroaryl with a heteroatom selected from oxygen atom or sulfur;

benzoyl possibly substituted C1-C5the alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy;

geterotsiklicheskikh in which heterocyclyl selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, possibly condensed with a benzene ring and may substituted C1-C5 by alkyl, halogen;

or ureido-group, in which one of the substituents end aminogroup represents hydrogen, and the second Deputy is chosen from:

C1-C3of alkyl, substituted phenyl, 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur;

With2-C6alkenyl;

aryl selected from phenyl, substituted C1-C5the alkyl, C1-C5alkoxy, Ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarboxylic;

5-membered heterocyclyl, in which the heteroatoms are selected from sulfur atom or oxygen, and possibly substituted allyloxycarbonyl group;

Represents a non-aromatic cyclic Deputy, selected from C4-C6cycloalkyl;

aromatic cyclic Deputy selected from phenyl, which may be substituted with halogen, C1-C3alkoxy;

non-aromatic 5-6 membered heterocyclic Deputy to the nitrogen atom as a heteroatom, and possibly N-substituted C1-C3by alkyl;

aromatic 5-6 membered heterocyclic Deputy, in which the heteroatoms are selected from nitrogen, oxygen or sulfur, and which may be substituted C1-C6by alkyl;

or aromatic 5-6 membered heterocyclic Deputy, in the cat the rum heteroatom selected from nitrogen, condensed with a benzene ring;

R1a, R1b and R1c independently represent hydrogen, C1-C3alkoxy;

excluding the compounds presented in Table 3.

Below are definitions of terms used in the description of the present invention.

"Aminocarbonyl" means-C(=O)NR2group, each R independently of one another is hydrogen, alkyl, alkenyl (see alternates aminocarbonyl group, see "Deputy carbamoyl"). Preferably carbarnoyl, methylaminomethyl, ethylaminomethyl, propylaminoethyl or butylaminoethyl. Aminocarbonyl may have substituents, see "Deputy carbamoyl" defined in this section.

"Aminothiazolyl" means R-C(=S)NH2aminothiazolyl may have substituents, see "Deputy carbamoyl", "substituted iminodicarboxylate group" defined in this section.

"Substituted iminodicarboxylate group" (aminothiophenol) means R R N-C(=S)- group in which the substituents R' and R" can be represented optionally substituted by alkyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. Preferred aminocarbonyl g is uppada are optionally substituted C 1-C5alkyl, C1-C5cycloalkyl, optionally substituted aryl (see Deputy cyclic system), optionally substituted hetaryl (see Deputy cyclic system), optionally substituted heterocyclyl (see Deputy heterocyclyl) or amino group, R R"n

"Amino" means a radical of the formula-NR2in which each R independently of one another represents hydrogen, alkyl, alkenyl or cycloalkyl, for example, -NH2methylamino, diethylamino, cyclohexylamino, tert-butylamino or ethylamino.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Preferably piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, azocyclotin. Azaheterocycle may have substituents (see the substituents of the cyclic system).

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preimushestvenno from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents" which may be the same or different. Preferably phenyl or naphthyl.

"Alkenyl" means linear or branched hydrocarbon group containing 2 to 7 carbon atoms and including at least one carbon-carbon double bond.

Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylmethanol.

Alchemilla group can have one or more substituents, see "Alternate alkenylphenol group".

"Deputy alkenylphenol group can be a halogen, alkenylacyl, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroarylboronic, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, arelaxation, heteroarylboronic.

"Quinil" means linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including at least one carbon-carbon triple bond.

Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. Alchemilla group can have one or more substituents, see "Alternate alkenylphenol group". Preferred alkenylamine groups are ethinyl, PROPYNYL, n-butynyl, ISO-butenyl, 3-methylbut-2-inyl, n-pen is inil, buta-1,3-Dien and hexa-1,3,5-Triin.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-6 carbon atoms in the chain. Branched group indicates that the group C1-C6of alkyl, such as methyl, ethyl or propyl, are attached to a linear chain alkyl. Preferred straight or branched alkyl groups are groups that represent alkyl groups having from 1 to 10 carbon atoms. The most preferred group of the lower alkyl have from 1 to 8 carbon atoms. Preferred alkyl groups are C1-C6alkyl, more preferred are methyl, ethyl, n-propyl, 2-ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. The alkyl may have substituents, see "Substituted alkyl".

"Alkylsilanes" means cycloalkyl, substituted alkyl. Preferably 1-, 2-, 3 - or 4-methyl or ethylcyclohexyl.

"Alkylcyclohexanes" refers to alkyl substituted by alkylcyclohexanes. Preferably 2-, 3 - or 4-methyl - or ethylcyclohexylamine or 2-, 3 - or 4-methyl - or ethylcyclohexylamine.

"Aralkyl" refers to alkyl substituted by aryl. Preferred kalkilya groups include benzyl, naphthas-1-ylmethyl, naphthas-2-ilma is silt and phenethyl.

"Alkyloxy" or "Alkoxy" means C1-C6Alkyla - group in which alkyl is defined in this section. The preferred alkoxygroup are methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy and tert-butoxy.

"Aromatic cycle" (aromatic system) means a planar cyclic system in which all the atoms of the cycle involved in the formation of a unified system of conjugation, including, according to the hückel rule, (4n+2) π-electrons (n is a nonnegative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, etc., In the case of heteroaromatic cycles in the system of pairing involves π-electrons and the p-electrons of heteroatoms, their total number is also equal to (4n+2). Examples of such cycles include pyridine, thiophene, pyrrole, furan, thiazole, etc., Aromatic cycle can have one or more "cyclic system substituents" which may be anaeroven with non-aromatic cycle, heteroaromatic or heterocyclic system.

"Acyl group (Acyl) means R-C(=O) -, preferably C1-C6acyl), optionally substituted C1-C5alkyl-C(=O)-, C1-C5cycloalkyl-C(=O)-, (preferably cyclopropyl-C(=O)-, cyclobutyl-C(=O)-); heterocyclyl-C(=O)-, (preferably 2-methylfuran), aryl-C(=O)-(aroyl), aralkyl-C(=O) -, preferably 3-finalment the n-C(=O)-), heteroaryl-C(=O)-(heteroaryl), heteroallyl-C(=O)- group, in which C1-C6alkyl, C1-C5alkenyl-, C1-C6cycloalkyl-, heterocyclyl-, aryl-, aralkyl, heteroaryl, heteroaromatic, a methoxy group, these groups may have substituents, see "cyclic system substituents", "substituted alkyl", "substituted alkenyl, the substituents of the heterocyclic system" is defined in this section.

"α-aminoaniline group (α-aminoacyl) means C(=O)CH(R2k)NR2k+1R2k+2,

where R2k, R2k+1and R2k+2can take is hydrogen, C1-C5alkyl-, aryl, saturated or unsaturated heterocyclyl, or NR2kR2k+2is a 5-6 membered heterocycle, these groups may have substituents, see "cyclic system substituents", "substituted alkyl", "heterocyclic substituents system", "substituted aryl", as defined in this section.

"Alloctype" means R(=O)-O-group.

"Hydrazinecarboxamide group" means-C(=O)-NH-NH2group. Hydrazinecarboxamide group may have substituents, see "Deputy carbamoyl" defined in this section.

"Heteroaryl" (hetaryl) means an aromatic monocyclic or poly is clichesque system, comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms replaced by a heteroatom or heteroatoms, such as nitrogen, sulfur or oxygen. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. The nitrogen atom in heteroaryl can be oxidized to N-oxide. Heteroaryl may have one or more "cyclic system substituents" which may be the same or different. Preferably pyrrolyl, furanyl, thienyl, pyridinyl. Heteroaryl may have substituents (see the substituents of the cyclic system).

"Heterocycle" means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, predominantly from 4 to 6 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur, phosphorus. The prefix "Aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl can the be oxidized to N-oxide, S-oxide or S-dioxide. Representatives heterocyclyl are piperidinyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,4-dioxane-2-yl, tetrahydrofuryl, tetrahydrothieno and other Heterocyclyl may have substituents. The preferred connection: piperidinyl, replaced by stands; piperidinyl, substituted optionally substituted hydroxy-group; piperidinyl substituted phenyl; piperazinil, substituted C1-C5the alkyl.

"The hydroxy-group" (Hydroxyl group) refers to-Oh group.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine and chlorine.

"Cycloalkyl" denotes a saturated carbocyclic group having one or more rings having 3-10 carbon atoms. Preferred cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and decahydronaphthalene.

"Cycloalkenyl" refers to a group of alkyl, substituted cycloalkyl group. Preferred cycloalkenyl include cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, decahedron-1-ylmethyl and decahedron-2-ylmethyl.

"Cyano" denotes the group-C≡N.

"Substituted alkyl" substituted alkyl may have one or more identical or different substituents including halogen, alkenylacyl, cyclo is lcil, aryl, heteroaryl, heterocyclyl, the hydroxy-group. Preferred alkyl substituents are acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, quinil, amino, aryl, aryloxy, carbarnoyl, carbalkoxy, carboxy, carboxamido, carboxamido, cyano, disubstituted amino, formyl, guanidino, halogen, heteroaryl, heterocyclyl, hydroxy, minamino, nitro, oxo, hostnamen, sulfinil, sulfonamid, sulfonyl, thio, thiazolin, touraid or ureido.

"Substituted aryl" denotes phenyl or naphthyl, substituted by one or more substituents of aryl groups which may be the same or different, where "Deputy aryl group" includes alkyl, alkenyl, quinil, aryl, aralkyl, the hydroxy-group, alkoxygroup, alloctype, urlcategory, hydroxyalkyl, acyl, formyl, carboxylate, alkanoyl, aroyl, halogen, the nitro-group, trihalomethyl, cyano, alkoxycarbonyl, aryloxyalkyl, arelaxation, allmenalp, aroylamino, carbarnoyl, allylcarbamate, dialkylamino, arylcarbamoyl, aralkylamines, alkylsulfonyl, alkylsulfanyl, arylsulfonyl, arylsulfonyl, aralkylamines, aralkylamines or - NRaRbwhere Raand Rbdenote independently hydrogen, alkyl, aryl or aralkyl.

Preferably phenyl, substituted hydroxy-group; C 1-C5the alkyl (preferably stands); halogen (preferably chlorine, fluorine); aminocarbonyl group; sulfopropyl. Preferably naphthyl, substituted C1-C5the alkyl. The aryl may be anaeroven with non-aromatic cyclic system or heterocycle.

"The amino substituents of the" amino substituents R' and R" represent hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C5cycloalkyl (see Deputy cyclic system), optionally substituted aryl (see Deputy cyclic system), optionally substituted heteroaryl (see Deputy cyclic system), optionally substituted heterocyclyl (see Deputy cyclic system), alkoxycarbonyl substituted linear or nonlinear C1-C5by alkyl, halogen, heterocyclyl; alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclizations.

"Cyclic system substituents" can be representatives of the aryl groups are preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Preferably phenyl, substituted hydroxy-group; C1-C5by alkyl; halogen; aminocarbonyl group.

The aryl may be annylirovan with non-aromatic cyclic system or heterocycle is m Preferably zamestitelyami cyclic system are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5alkyl, hydroxygroups, C1-C5alkyloxy (methoxy, ethoxy, propoxy), carboxypropyl, aminocarbonyl (see "aminocarbonyl"), phenylenecarbonyl with a 5-7 membered saturated cycle containing 1-3 heteroatoms (atoms nitrogen, oxygen and sulfur, preferably).

"Deputy" means a chemical moiety that is attached to the molecular core (scaffold, fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Substituted aminocarbonyl group" (aminocarbonyl) means R R N-C(=O)- group in which the substituents R' and R" can be represented optionally substituted by alkyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. Preferred aminocarbonyl groups are optionally substituted C1-C5alkyl, C1-C5cycloalkyl, optionally substituted aryl (see Deputy cyclic system), optionally substituted hetaryl (see Deputy cyclic system), optionally substituted heterocyclyl (see mandated the tel heterocyclyl) or amino group, R R"n

"Deputy carbamoyl" means the Deputy attached to aminocarbonyl group, the value of which is defined in this section. Deputy carbamoyl represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-alkyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic-carbonylethyl or RkaRk+1aN-, RkaRk+1aNC(=O)-alkyl, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Substituents of the heterocycle can be representatives of the aryl groups are preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be anaeroven with non-aromatic cyclic system or heterocycle is. Preferably zamestitelyami cyclic system are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5alkyl, optionally substituted cyclo C1-C5alkyl, C1-C5alkene, hydroxygroups,1-C5alkyloxy (methoxy, ethoxy, propoxy, fluids, ethylene glycol fluids of methanediol), cyano, C1-C5allyloxycarbonyl (methyl, ethyl), allylthiourea (methylthio) carboxypropyl, aminocarbonyl (see "aminocarbonyl"), phenylenecarbonyl with a 5-7 membered saturated cycle containing 1-3 heteroatoms (atoms nitrogen, oxygen and sulfur, preferably).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other fabricated forms intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"The nitro-group" means the group-NO2.

"Trifluoromethyl" refers to the group R-CF3;

"Ureido" means the group of NH2-CO-NH-.

More preferred are a substituted [1,2,4]triazolo[4,3-a]pyridine represented by the General formulas (I-1, I-2, I-3, as well as their pharmaceutically acceptable salts:

where has the values defined above;

R2a, R2b and R2c are, independently represent H, C1-C3alkoxy; R3a and R3b independently represent hydrogen, C1-C5alkyl, possibly substituted C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which the heteroatoms are selected from oxygen or nitrogen; aryl selected from phenyl, possibly substituted by hydroxy, C1-C5the alkyl, C1-C5alkoxy, halogen, C1-C5allmineral, or naphthalene;

R3a and R3b may form together a cyclic substituents, the group R3a-N-R3b represents C3-C7heterocyclyl containing 1-2 heteroatoms in the cycle selected from nitrogen, oxygen or sulfur, possibly substituted by hydroxy, C1-C5by alkyl, benzyl, phenyl which may be substituted with halogen, with the specified heterocyclyl may be condensed with a benzene ring;

R4 represents a C1-C5alkyl, where alkyl may be substituted by phenyl, substituted phenyl in which the substituents selected from C1-C5alkoxy; a 5-membered heteroaryl with a heteroatom selected from oxygen atom or sulfur; aryl selected from phenyl, possibly substituted C1-C5the alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heteros CLIL, in which heterocyclyl selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, possibly condensed with a benzene ring and may substituted C1-C5by alkyl, halogen;

R5 represents hydrogen;

R6a and R6b independently represent hydrogen, C1-C3alkyl, substituted phenyl, 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur; With2-C6alkenyl, aryl selected from phenyl, substituted C1-C5the alkyl, C1-C5alkoxy, Ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarboxylic;

R6a and R6b may form together a cyclic substituents, the group R6a-N-R6b represents a 5-membered heterocycle, in which the heteroatoms are selected from sulfur atom or oxygen, and possibly substituted allyloxycarbonyl group;

The most preferred derivatives of [1,2,4]triazolo[4,3-a]pyridines are:

3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methoxybenzylamine (I-1-01);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methoxybenzylamine (I-1-02);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid naphthyl-1-amide (I-1-03);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-METI phenylamide (I-1-04);

3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I-1-05);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid phenylamide (I-1-06);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-propylamide (I-1-07);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 4-methylphenylamine (I-1-08);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 4-tortenelme (I-1-09);

3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (2-methoxyphenyl)methylamide (I-1-10);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (2-methoxyphenyl)methylamide (I-1-11);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-tortenelme (I-1-12);

3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-chlorpheniramine (I-1-13);

3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-chlorpheniramine (I-1-14);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-chlorpheniramine (I-1-15);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-16);

3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-17);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-hydroxy-6-methylphenylene (I-1-19);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic sour is s (cyclohexyl)methylamide (I-1 to 20);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2,3-dimethylaniline (I-1-21);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3,4-dimethylphenylamine (I-1-23);

3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3,5-dimethylphenylamine (I-1-24);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-ethylvanillin (I-1-25);

3-(pyrid-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I-1-26);

3-(pyrid-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-27);

3-(pyrid-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-28);

3-(pyrid-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-29);

3-(5-methylfuran-2)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-30);

3-(thienyl-2)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-31);

3-(indol-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-32);

3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-ethylvanillin (I-1-33);

3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-34);

3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-35);

3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (furan-yl)methylamide (I-1-36);

3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (furan-2-yl)methylamide (I-1-37);

3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid heptamethylnonane (I-1-38);

N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-3,5-dimethylpiperidin (I-1-39);

N-{3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-4-hydroxy-4-(4-chlorophenyl)-piperidine (I-1-40);

N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-4-benzylpiperidine (I-1-41);

N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-1,2,3,4-tetrahydroquinolin (I-1-42);

N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-4-hydroxy-4-(4-chlorophenyl)-piperidine (I-1-43);

3-phenyl-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methyl-chloro-phenylamide (I-1-44)

3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-naphthylamide (I-1-47);

3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-propylamide (I-1-48);

3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-49);

3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-tortenelme (I-1-50);

3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I-1-51);

3-(2-forfinal)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (furan-2-yl)methylamide (I-1-52);

N-{3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazo what about[4,3-a]pyridine-8-carbonyl}-piperazine (I-1-53);

N-{3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-N'-methylpiperazine (I-1-54);

N-{3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-2-hydroxyethylamine (I-1-55);

8-[(2-ethoxybenzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-01);

8-{[(2-methoxyphenyl)acetyl]-amino}-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-02);

8-[(Tien-3-yl)acetylamino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-03);

8-[(2-chloro-5-methylthio-benzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-04);

8-[(Tien-3-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-05);

8-[(3-methyltin-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-06);

8-[(indol-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-07);

8-[(3-fluoro-4-methoxy-benzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-08);

8-[(2,3-dihydrobenzo[1,4]dioxin-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo [4,3-a] pyridine (I-2-09);

8-[(5-chlortan-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-10);

8-[(3,4-methylendioxy-benzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-11);

8-[(5-methylisoxazol-3-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-12);

8-[(2-methoxybenzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-13);

8-[(2-methoxybenzoyl)amino]-3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-14);

8-[(2-ethoxybenzoyl) the Mino]-3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-15);

8-[(2-methoxybenzoyl)amino]-3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-16);

8-[(2-methoxybenzoyl)amino]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-17);

8-(benzoylamine]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-18);

8-(benzoylamine]-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-19);

8-(2-methoxybenzylamine]-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-20);

8-(2-ethoxybenzylidene]-3-phenyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-21);

8-[(2-perbenzoic)amino]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-22);

8-[(2-perbenzoic)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-23);

8-[(2-methoxybenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-24);

8-[(2-methoxybenzoyl)amino]-3-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-25);

8-[(2-methoxybenzoyl)amino]-3-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-26);

8-[(2-chlorobenzoyl)amino]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-27);

8-[(2-chlorobenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-28);

8-[(2,6-dichlorobenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-29);

8-[(2,6-dimethylbenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-30);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3,4-acid)-urea (I-3-01);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(2-methoxy-5-meth is fenil)-urea (I-3-02);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3,4-atlanticcity)-urea (I-3-03);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(2-phenylethyl)-urea (I-3-04);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3,4-methylenedioxyphenyl)-urea (I-3-05);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-06);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(tetrahydrofuran-2-methyl)-urea (I-3-07);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(2-methoxycarbonylmethyl-3)-urea (I-3-08);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3-acetylphenyl)-urea (I-3-09);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(4-methoxy-2-were)-urea (I-3-10);

1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(4-methoxy-3-forfinal)-urea (I-3-11);

1-(3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-12);

1-(3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-13);

1-{3-N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(furyl-2-methyl)-urea (I-3-14);

1-{3-N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(furyl-2-methyl)-urea (I-3-15);

1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(2-methoxyphenyl)-urea (I-3-16);

1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(3,4-acid)-urea (I-3-17);

1-{3-(N-methylpiperidin-3-yl)[1,2,4]three is gold[4,3-a]pyridine-8-yl}-3-(2-methoxyphenyl)-urea (I-3-18);

1-{3-(N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(3,4-acid)-urea (I-3-19);

1-(3-pyrid-4-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-20);

1-(3-pyrid-3-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-21);

1-(3-pyrid-4-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-22);

1-(3-pyrid-3-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-23);

1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-allylation (I-3-24);

1-{3-(N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-allylation (I-3-25);

The subject of this invention are pharmaceutically acceptable salts of the compounds of General formula I. the Part of the compounds of the present invention contains an ionic group (secondary, tertiary amines) and can form salts, which were obtained by methods known in the art.

The subject of this invention is a method of obtaining derivatives of [1,2,4]triazolo[4,3-a]pyridines of General formula I-2 and I-3 (Scheme 2):

From 2-chloro-3-nitropyridine b1 was obtained the corresponding 2-hydrazino-3-nitropyridine b2. Hydrazines b2 was cyclocondensation with a suitable acyl-derivatives, getting [1,2,4]triazolo[4,3-a]pyridine b3. Further nitropyridine b3 was reduced by hydrogen over palladium on coal and received a series of courtesans is cyclic amines b4. The acylation of amines b4 appropriate allelochemical (acylchlorides, allfreedom, Allbreed in neutral aprotic solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) under cooling led to a series of substances I-2. Interaction of amines b4 with isothioscyanates in a neutral solvent (ethanol, dichloromethane, dioxane, chloroform and the like) led to a series of substances I-3.

The substituents R2, R3a and R3b, R4, R6 and in Schemes 1 and 2 defined above, X=Cl.

The object of this invention is the active component has the properties of the antagonist of A2A receptors, representing (substance) for the preparation of pharmaceutical compositions and dosage forms for the prevention and treatment of disorders of the Central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases, which are the compounds of General formula I.

The subject of this invention are new compounds of General formula I represents a tool (adjuvant) to enhance the immune response or action of medicines in the combined treatment of disorders of the Central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases.

The subject of this invention is pharmaceutical to the position, having antagonistic activity against adenosine A2A receptor, comprising as an active ingredient (substance) or means (adjuvant) compounds of General formula I or their pharmaceutically acceptable salts in therapeutically effective amounts.

The subject of this invention is any of the above pharmaceutical compositions in the form of tablets, capsules and injections, ointments, gels and other ready-made forms, placed in pharmaceutically acceptable packing.

Pharmaceutical compositions can include pharmaceutically acceptable excipients, namely: applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. Pharmaceutical composition together with a compound of General formula I or its pharmaceutically acceptable salt according to the present invention may include other active substances, provided that they do not cause unwanted effects.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as R the alignments or suspension for injection, or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The subject of this invention is a method of obtaining a pharmaceutical composition by mixing with an inert filler, an auxiliary agent, a carrier and/or solvent, at least one active ingredient (substance) of General formula I or its pharmaceutically acceptable salt in a therapeutically effective amount.

The subject of this invention is a method of selective inhibition of the activity of the adenosine A2A receptor, which consists in the action of the active ingredient (substance) of General formula I on biological objects or clicks is sci, whose functions are regulated by adenosine A2A receptors.

The subject of this invention is a medicinal product, which has antagonistic activity against adenosine A2A receptor, in the form of tablets, capsules or injections, placed in pharmaceutically acceptable packing intended for the prevention and treatment of disorders of the Central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases in humans and warm-blooded animals, including a new active ingredient (substance) of General formula I or pharmaceutical composition in a therapeutically effective amount.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). Clinical dosage means the General formula I in patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient. At the same daily dose in adults is usually 10~500 mg, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during certain periods of the straps (preferably from one to six times per day).

The object of the present invention is a method for the prevention and treatment of disorders of the Central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases in animals and humans, which is the introduction in an effective amount to a patient a drug or pharmaceutical composition that includes a new active ingredient (substance) of General formula I, in therapeutically effective amounts.

The invention is illustrated by, but is not limited to the following examples.

Source reagents and physico-chemical methods of proof of the structure of the synthesized substances and their purity.

All solvents and reagents were obtained from commercial sources, such as Acros (Belgium), Sigma-Aldrich (USA), Lancaster (England) and ChemDiv (USA). Solvents and reagents were used without additional purification.1H-NMR spectra were recorded on a spectrometer Bruker DPX-400 (400 MHz, 27°C). Chemical shifts are given in δ scale (M. D.), the internal standard tetramethylsilane was.

LC-MS characterization of the claimed compounds (Tables 5-7) was determined on the installation Shimadzu HPLC equipped with a column Waters XBridge C183.5 mm (4.6 mm × 150 mm), detector, PE SCIEX API 150 EX mass detector, or by a spectrophotometric detector Shimadzu detector (λ, 220 and 254 nm). In accordance with the data of LC-MS is the CE of the synthesized compounds had a basic substance content above 95%.

Analytical TLC was performed on silica gel on aluminium plates Silufol UV254(5 cm × 15 cm) (Kavalier, Czech Republic) or on glass plates with 0.25 mm layer of silica gel 60 F254(Merck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For chromatographic purification of used silica gel 5-40 µm (Chemapol, Czech Republic) and 63 µm (EM Science, USA).

Methods of obtaining and NMR characteristics of the claimed compounds

Example 1. Synthesis of ethyl ester of 2-hydrazine-nicotinic acid A2-1

A solution of ethyl-2-chloronicotinate A1-1 (10 g, 53.9 mmol) and anhydrous hydrazine (4.08 g, 127.6 mmol) in 200 ml of dioxane was stirred at 60°C for 12 hours. The mixture was cooled, concentrated in vacuo and dissolved in 35 ml of absolute methanol, removing the precipitate. The methanol was evaporated, the product A2-1 was led under absolute ether. Yield: 5.4 g (55%). MB 181; LC-MS m/z 182 (M+H).

Example 2. General method for the synthesis of ethyl esters of 2-[(2-acyl-substituted)hydrazine]-nicotinic acid.

A suspension of carboxylic acid (45.8 mmol), hydroxybenzotriazole HOBt (6.25 g, 46 mmol) and N-ethyl-N'-3-dimethylaminopropylamine EDC (8.74 g, 46 mmol) in dry dichloromethane (200 ml) was stirred at room temperature for 10 minutes, then the mixture solution was added hydrazine A2-1 (9.5 g, 52.4 mmol) in 150 ml of dichloromethane. The reaction mixture was stirred at room te is the temperature from 2.0 to 16 hours, remove the precipitate, and then washed with water (3×100 ml). The organic layer was dried over MgSO4and was evaporated. The obtained solid residue was used further without additional purification. Output: 50-85%.

Example 3. General method for the synthesis of ethyl ester of 3-substituted [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid A3 (see Scheme 1).

To a solution of 3.0 mmol of ethyl ester 2-[(2-acyl-substituted)hydrazine]-nicotinic acid in 150 ml of dichloromethane was added 15 ml of POCI3, the mixture is then boiled 2.5 to 20 hours, monitoring the reaction by TLC. The mixture was cooled and concentrated in vacuum. The residue was dissolved in 200 ml of ethyl acetate, the mixture was treated with aqueous solution of NaHCO3and dried over magnesium sulfate. After evaporation of ethyl acetate was received heterocyclic esters A3 outputs of 70-90%.

Scheme 1

where R2, R3a and R3b have the above meanings, X=IT.

Example 4. General method for the synthesis of 3-substituted [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid A4 (see Scheme 1).

To a cooled (0°C.) solution of 1.5 mmol of the ester A3 in 10 ml of ethanol was added with stirring, 1.5 ml of 2.5 n aqueous NaOH solution. The mixture was heated to room temperature within 3 hours, the reaction was stopped by adding concentrated hydrochloric acid (to pH=2-3). CME is ü evaporated, the residue was washed with water and dried. Output acids A4: 70-95%.

Example 5. General method for the synthesis of amides of 3-substituted [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid I-1/

The synthesis was carried out according to Scheme 1.

The mixture of acid A4 (1.0 mmol), amine (1.1 mmol), carbodiimide EDC (1.0 mmol) and 1-hydroxybenzotriazole (1.0 mmol) in 10 ml DMF was stirred 2-20 hours at room temperature, monitoring the reaction by using LS-MS. After the reaction mixture was diluted with 30 ml water and was extracted with methylene chloride (3×30 ml). The organic layer was dried over magnesium sulfate and evaporated. The product was purified chromatographically on silica gel (eluent CH2Cl2/Meon 19:1). The outputs of the amides (I-1 25-85%.

Thus were obtained the compounds of General formula I-1-01-I-1-55, shown in Table 4.

Below is the NMR spectral data of some of the resulting amides of compounds of General formula I-1:

I-1-01. 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 6.74 (dt, J=7.6, 2.1 Hz, 1H), 7.25-7.36 (m, 3H), 7.47 (, J=8.8 Hz, 2H), 7.56 (t, J=2.1 Hz, 1H), 8.00 (dd, J=8.8, 5.4 Hz, 2H), 8.27 (d, J=7.0 Hz, 1H), 8.76 (d, J=6.9 Hz, 1H), 11.71 (s, 1H)

I-1-02. 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 6.74 (dt, J=7.1, 2.4 Hz, 1H), 7.30 (m, 3H), 7.51 (m, 2H), 7.57 (m, 1H), 7.75 (m, 1H), 7.84 (td, J=7.4, 2.0 Hz, 1H), 8.31 (d, J=7.0 Hz, 1H), 8.48 (dd, J=7.0,3.1 Hz, 1H), 11.65 (s, 1H)

I-1-03. 1H NMR (400 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.25 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.60 (m, 2H), 7.70 (m, 3H), 7.79 (d, J=8.2 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 8.33 (d, J=6.9 Hz, 1H), 8.38 (d, J=7.0 Hz, 1H), 8.50 (d, J=7.5 Hz, 1H), 8.58 (d, J=8.5 Hz, 1H), 12.27 (s, 1H)

I-1-04. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 3.86 (s, 3H), 6.99 (d, J=7.6 Hz, 1H), 7.21 (m, 2H), 7.30 (m, 2H), 7.65 (m, 4H), 8.27 (m, 2H), 11.68 (s, 1H)

I-1-05. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 3.91 (s, 3H), 6.98 (d, J=7.8 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 7.24 (t, J=7.0 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.63 (bs, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.7 Hz, 2H), 8.25 (d, J=7.0 Hz, 1H), 8.72 (d, J=7.0 Hz, 1H), 11.71 (s, 1H)

I-1-06. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=7.6 Hz, 1H), 7.30 (t, J=7.0 Hz, 1H), 7.42 (t, J=7.6 Hz, 2H), 7.52 (m, 2H), 7.75 (m, 1H), 7.84 (m, 3H), 8.31 (d, J=7.0 Hz, 1H), 8.48 (dd, J=6.9, 3.1 Hz, 1H), 11.67 (s, 1H)

I-1-07. 1H NMR (400 MHz, DMSO-d6) δ 1.34 (d, J=6.5 Hz, 6H), 4.24 (m, 1H), 7.14 (t, J=7.0 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.64 (t, J=8.3 Hz, 1H), 8.15 (m, 2H), 9.51 (d, J=7.6 Hz, 1H)

I-1-08. 1H NMR (400 MHz, DMSO-d6) δ 2.35 (s, 3H), 7.22 (d, J=8.1 Hz, 2H), 7.29 (t, J=7.0 Hz, 1H), 7.51 (m, 2H), 7.72 (m, 3H), 7.84 (td, J=7.4, 1.7 Hz, 1H), 8.30 (d, J=7.0 Hz, 1H), 8.46 (dd, J=7.0, 3.1 Hz, 1H), 11.59 (s, 1H)

I-1-09. 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.21 (m, 4H), 7.31 (d, J=8.5 Hz, 1H), 7.65 (m, 2H), 7.86 (m, 2H), 8.27 (m, 2H), 11.72 (s, 1H)

I-1-10. 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 3.93 (s, 3H), 4.66 (d, J=5.8 Hz, 2H), 6.91 (t, J=7.4 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.17 (m, 3H), 7.27 (t, J=7.4 Hz, 1H), 7.31 (d, J=7.4 Hz, 1H), 7.81 (d, J=8.6 Hz, 2H), 8.14 (d, J=7.0 Hz, 1H), 8.65 (d, J=7.0 Hz, 1H), 10.04 (t, J=5.8 Hz, 1H)

I-1-11. 1H NMR (400 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.67 (d, J=5.9 Hz, 2H), 6.91 (t, J=7.3 Hz, 1H), 7.01 (d, J=8.1 Hz,1H), 7.25 (m, 2H), 7.32 (d, J=7.4 Hz, 1H), 7.49 (m, 2H), 7.73 (m, 1H), 7.80 (t, J=7.4 Hz, 1H), 8.20 (d, J=6.9 Hz. 1H), 8.39 (dd, J=7.1, 3.2 Hz, 1H), 9.99 (t, J=5.9 Hz, 1H)

I-1-12. 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 6.95 (m, 1H), 7.21 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.46 (m, 2H), 7.65 (m, 2H), 7.89 (dt, J=11.4,2.2 Hz, 1H), 8.28 (d, J=7.0 Hz, 2H), 11.86 (s, 1H)

I-1-13. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.18 (m, 3H), 7.24 (t, J=7.0 Hz, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 8.06 (t, J=2.1 Hz, 1H), 8.25 (d, J=7.0 Hz, 1H), 8.73 (d, J=7.0 Hz, 1H), 11.85 (s, 1H)

I-1-14. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (dd, J=7.9, 2.1 Hz, 1H), 7.27 (t, J=7.0 Hz, 1H), 7.45 (m, 3H), 7.63 (d, J=8.3 Hz, 1H), 7.99 (dd, J=8.7, 5.3 Hz, 2H), 8.06 (t, J=2.1 Hz, 1H), 8.27 (d, J=7.0 Hz, 1H), 8.77 (d, J=7.0 Hz, 1H), 11.81 (s, 1H)

I-1-15. 1H NMR (400 MHz, DMSO-d6) δ 7.20 (dd, J=8.0, 2.0 Hz, 1H), 7.30 (t, J=7.0 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.52 (m, 2H), 7.66 (d, J=8.2 Hz, 0H), 7.75 (m, 1H), 7.84 (t, J=7.4 Hz, 1H), 8.08 (t, J=2.0 Hz, 1H), 8.31 (d, J=7.0 Hz, 1H), 8.49 (dd, J=7.0, 3.1 Hz, 1H), 11.75 (s, 1H)

I-1-16. 1H NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.86 (s, 3H), 7.10 (t, J=7.4 Hz, 1H), 7.22 (m, 3H), 7.30 (m, 2H), 7.65 (m, 2H), 8.27 (m, 2H), 8.31 (d, J=7.0 Hz, 1H), 11.54 (s, 1H)

I-1-17. 1H NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.91 (s, 3H), 7.09 (t, J=7.4 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 7.26 (m, 3H), 7.86 (d, J=8.7 Hz, 2H), 8.29 (d, J=7.5 Hz, 2H), 8.74 (d, J=7.0 Hz, 1H), 11.56 (s, 1H)

I-1-19. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.87 (s, 3H), 6.76 (d, J=7.5 Hz, 1H), 6.80 (d, J=7.7 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.21 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.65 (m, 2H), 8.26 (m, 2H), 9.37 (s, 1H), 10.99 (s, 1H)

I-1-20. 1H NMR (400 MHz, DMSO-d6) δ 1.00-1.35 (m, 5H), 1.57-1.89 (m, 6H), 3.37 (t, J=6.3 Hz, 2H), 7.23 (t, J=7.0 Hz, 1H), 7.49 (m, 2H), 7.72 (m, 1H), 7.80 (t, J=7.4 Hz, 1H), 8.18 (d, J=7.0 Hz, 1H), 8.39 (dd, J=7.0, 3.3 Hz, 1H), 9.59 (t, J=5.9 Hz, 1H)

I-1-21. 1H NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3H), 2.43 (s, 3H), 7.03 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.30 (t, J=7.0 Hz, 1H), 7.51 (m, 2H), 7.75 (m, 1H), 7.85 (t, J=7.3 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 8.34 (d, J=7.0 Hz, 1H), 8.48 (dd, J=7.0, 3.3 Hz, 1H), 11.42 (s, 1H)

I-1-23. H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.30 (s, 3H), 7.15 (d, J=8.0 Hz, 1H), 7.29 (t, J=7.0 Hz, 1H), 7.51 (m, 2H), 7.58 (m, 2H), 7.75 (m, 1H), 7.84 (t, J=7.4 Hz, 1H), 8.29 (d, J=7.0 Hz, 1H), 8.46 (dd, J=7.0, 3.2 Hz, 1H), 11.54 (s, 1H)

I-1-24. 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 6H), 3.86 (s, 3H), 6.81 (s, 1H), 7.21 (m, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.46 (s, 2H), 7.65 (m, 2H), 8.26 (m, 2H), 11.63 (s, 1H)

I-1-25. 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=7.5 Hz, 3H), 2.94 (q, J=7.5 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H), 7.29 (m, 3H), 7.52 (m, 2H), 7.75 (m, 1H), 7.86 (t, J=7.4 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.35 (d, J=7.0 Hz, 1H), 8.49 (dd, J=6.9,3.2 Hz, 1H), 11.53 (s, 1H)

I-1-36. 1H NMR (400 MHz, DMSO-d6) δ 4.71 (d, J=5.5 Hz, 2H), 6.38 (m, 2H), 7.20 (t, J=6.9 Hz, 1H), 7.44 (t, J=8.5 Hz, 2H), 7.55 (s, 1H), 7.95 (dd, J=8.5, 5.3 Hz, 2H), 8.18 (d, J=6.9 Hz, 1H), 8.69 (d, J=6.9 Hz, 1H), 9.91 (t, J=5.5 Hz, 1H)

I-1-37. 1H NMR (400 MHz, DMSO-d6) δ 4.72 (d, J=5.8 Hz, 2H), 6.39 (m, 2H), 7.23 (t, J=7.0 Hz, 1H), 7.49 (m, 2H), 7.55 (d, J=1.8 Hz, 1H), 7.73 (m, 1H), 7.79 (t, J=7.4 Hz, 1H), 8.22 (d, J=7.0 Hz, 1H), 8.41 (dd, J=7.0, 3.2 Hz, 1H), 9.88 (t, J=5.8 Hz, 1H)

I-1-38. 1H NMR (400 MHz, DMSO-d6) δ 1.57 (m, 4H), 1.68 (m, 4H), 1.85 (m, 2H), 3.28 (m, 2H), 3.65 (t, J=6.2 Hz, 2H), 7.07 (t, J=6.8 Hz, 1H), 7.33 (d, J=6.7 Hz, 1H), 7.43 (t, J=8.8 Hz, 2H), 7.96 (dd, J=8.8, 5.3 Hz, 2H), 8.55 (d, J=7.1 Hz, 1H)

I-1-39. 1H NMR (400 MHz, DMSO-d6) δ 0.74 (d, J=6.5 Hz, 3H), 0.86 (m, 1H), 0.99 (d, J=6.5 Hz, 3H), 1.42-2.09 (m, 3H), 2.31 (m, 1H), 2.55-2.91 (m, 1H), 3.24-3.69 (m, 1H), 4.59 (m, 1H), 7.06 (t, J=6.9 Hz, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.43 (t, J=8.8 Hz, 2H), 7.97 (m, 2H), 8.56 (d, J=7.1 Hz, 1H)

I-1-40. 1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, J=13.7 Hz, 2H), 2.32 (m, 2H), 3.30 (m, 4H), 3.89 (s, 3H), 5.43 (s, 1H), 7.04 (t, J=6.9 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.91 (m, 1H), 8.48 (d, J=6.9 Hz, 1H), 9.43 (s, 1H)

I-1.41. 1H NMR (400 MHz, DMSO-d6) δ 1.31 (m, 2H), 1.52 (m, 1H), 1.77 (d, J=14.3 Hz, 1H), 1.84 (m, 1H), 2.58 (d, J=7.1 Hz, 2H), 2.81 (t, J=12.5 Hz, 1H), 3.03 (t, J=12.6 Hz, 1H), 3.42 (d, J=13.1 Hz, 1H), 4.60 (d, J=12.9 Hz, 1H), 7.06 (t, J=6.9 Hz, 1H), 7.16 (m, 3H), 7.25 (m, 2H), 7.36 (d, J=6.7 Hz, 1H), 7.42 (t, J8.7 Hz, 2H), 7.95 (dd, J=8.7, 5.5 Hz, 2H), 8.54 (d, J=7.1 Hz, 1H)

I-1-42. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 2H), 2.90 (t, J=6.7 Hz, 2H), 3.78 (s, 2H), 7.02 (m, 4H), 7.17 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.8 Hz, 2H), 7.45 (m, 1H), 7.94 (dd, J=8.8, 5.4 Hz, 2H), 8.55 (d, J=7.0 Hz, 1H)

I-1-43. 1H NMR (400 MHz, DMSO-d6) δ 1.50 (d, J=13.0 Hz, 1H), 1.78 (d, J=13.8 Hz, 1H), 2.04 (m, 2H), 3.30 (m, 2H), 3.53 (t, J=13.0 Hz, 1H), 4.58 (d, J=12.7 Hz, 1H), 5.22 (s, 1H), 7.08 (t, J=6.9 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.43 (m, 3H), 7.53 (d, J=8.6 Hz, 2H), 7.96 (dd, J=8.8, 5.3 Hz, 2H), 8.55 (d, J=7.1 Hz, 1H)

I-1-44. 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 7.01 (t, J=7.0 Hz, 1H), 7.15 (dd, J=8.6, 2.4 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.60 (m, 3H), 7.84 (d, J=7.1 Hz, 2H), 7.89 (d, J=6.7 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.48 (d, J=6.9 Hz, 1H), 9.93 (s, 1H)

Example 6. Synthesis of 3-nitropyridine-2-hydrazine b2-1 (scheme 2, b2, R2=H).

(see Diagram 2)

In the conical flask was placed a solution of 0.6 mol of chloropyridine b1in 2 liters of ethanol and was added in portions to 2.5 mole of hydrazine hydrate is added. The mixture was stirred at room temperature for two hours. The precipitation was filtered, washed with water and cold ethanol, dried in the air. The product yield b2-1: 95%.

Example 7. General method for the synthesis of 3-substituted 8-nitro[1,2,4]triazolo[4,3-a]pyridines b3 (see Diagram 2)

To a suspension of 5 mmol of hydrazine b2-1 in 50 ml of ethanol dobelli 5.5 mmol of the corresponding orthoevra and boiled with stirring for 1-2 hours. The mixture was cooled, precipitated precipitate was filtered, washed with ether and dried. The output b3: 50-80%.

Example 8. General IU the od of the synthesis of 3-substituted 8-amino[1,2,4]triazolo[4,3-a]pyridines b4 (Scheme 2)

In a 250 ml autoclave were placed 0.05 mol of compound b3 in 100 ml of methanol, 1 g of 10% Pd/C and was first made at room temperature until complete absorption of the calculated amount of hydrogen. The mixture was filtered, the organic was evaporated, precipitated precipitate was washed with acetonitrile, and dried. The output b4: 50-70%.

Example 9. General method for the synthesis of 3-substituted 8-acylamino[1,2,4]triazolo[4,3-a]pyridines I-2

The synthesis was carried out in accordance with Scheme 2.

Amin b4 (0.001 mol) was dissolved in 3 ml of dichloromethane, was added triethylamine (0.002 mol, 0.202 g) and cooled to 0°C. With vigorous stirring gently added 0.0012 mol of the acid chloride R4C(O)X, and the mixture was heated to room temperature. After three hours the reaction mass was diluted with dichloromethane (30 ml), washed with 2.0 n hydrochloric acid (2×15 ml), dried over sodium sulfate and chromatographically a mixture of CH2Cl2/EtOH (height of the column of 5 cm, width 1 cm). Received net products with 1-2 outputs 60-90%.

Thus were obtained the compounds I-2-01-I-2-30, are presented in Table 5.

Below the por is dstanley NMR spectral data of some of the resulting amides I-2:

I-2-04. 1H NMR (400 MHz, DMSO-d6) δ 1.75 (t, J=7.0 Hz, 3H), 2.06 (m, 1H), 2.19 (m, 1H), 2.54 (m, 4H), 4.02 (p, J=8.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 6.90 (t, J=7.1 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.58 (td, J=7.2, 1.9 Hz, 1H), 7.94 (d, J=7.1 Hz, 1H), 8.13 (dd, J=7.9, 1.9 Hz, 1H), 8.25 (d, J=7.1 Hz, 1H), 11.09 (s, 1H)

I-2-07. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 1H), 2.21 (m, 1H), 2.55 (m, 4H), 4.05 (d, J=8.0 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.48 (m, 2H), 7.67 (d, J=8.1 Hz, 1H), 8.02 (m, 2H), 9.99 (s, 1H), 11.92 (s, 1H)

I-2-10. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.19 (m, 1H), 2.52 (m, 4H), 4.04 (p, J=8.4 Hz, 1H), 6.93 (t, J=7.1 Hz, 1H), 7.18 (m, 1H), 7.83 (d, J=7.1 Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 8.11 (d, J=4.1 Hz, 1H), 10.43 (s, 1H).

Example 10. General method for the synthesis of 3-substituted 8-ureido[1,2,4]triazolo[4,2-a]pyridines 1-3

The synthesis was carried out in accordance with Scheme 2.

Amin b4 (0.001 mol) was dissolved in 3 ml of dichloromethane, was added triethylamine (0.002 mol, 0.202 g) and cooled to 0°C. Under vigorous stirring was added 0.0012 mol of isothiocyanate R6NCO and the mixture was heated to room temperature. 1-3 hours the reaction mass was diluted with dichloromethane (30 ml), washed with 2.0 n hydrochloric acid (2×15 ml), dried over sodium sulfate and chromatographically a mixture of CH2Cl2/EtOH (height of the column of 5 cm, width 1 cm). Received net products with 1-3 outputs 60-90%.

Thus were obtained the compounds I-3-01-I-3-25 are presented in Table 6.

Below is the NMR spectral data of some of the obtained urea 1-3:

I-3.03. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.18 (m, 1H), 2.53 (m, 4H), 4.00 (p, J=8.3 Hz, 1H), 4.20 (m, 4H), 6.74 (m, 2H), 6.84 (t, J=7.1 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.79 (d, J=6.8 Hz, 1H), 7.88 (d, J=7.3 Hz, 1H), 9.13 (s, 1H), 9.26 (s, 1H)

I-3-06. 1H NMR (400 MHz, DMSO-d6) δ 2.03 (m, 1H), 2.17 (m, 1H), 2.50 (m, 4H), 3.98 (p, J=8.4 Hz, 1H), 4.33 (d, J=5.5 Hz, 2H), 6.25 (d, J=3.1 Hz, 1H), 6.36 (dd, J=3.1, 1.8 Hz, 1H), 6.80 (t, J=7.1 Hz, 1H), 7.46 (t, J=5.5 Hz, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.75 (d, J=6.9 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H), 9.07 (s, 1H)

I-3-08. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 1H), 2.18 (m, 1H), 2.54 (m, 4H), 3.86 (s, 3H), 4.01 (p, J=8.2 Hz, 1H), 6.85 (t, J=7.1 Hz, 1H), 7.73 (d, J=5.5 Hz, 1H), 7.84 (d, J=6.9 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.97 (d, J=5.5 Hz, 1H), 10.11 (s, 1H), 10.74 (s, 1H)

I-3-10. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.19 (m, 1H), 2.24 (s, 3H), 2.51 (m, 4H), 3.74 (s, 3H), 4.00 (p, J=8.4 Hz, 1H), 6.70 (m, 2H), 6.82 (t, J=7.1 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 8.61 (s, 1H), 9.52 (s, 1H).

Antagonistic activity of the new compounds of General formula I and their pharmaceutically acceptable salts relative to the adenosine A2A receptor was performed ex vitro functional test cells. The experiment used a cell line ValiScreen cell line (PerkinElmer, USA) expressing recombinant human adenosine receptor type A2A.

In Tables 4-6 presents data on the activity of some of the compounds of General formula I, confirming their high antagonistic activity against adenosine A2A receptor: A means inhibition of the A2A receptor the compound at a concentration of 10 μm represent more than 75%, In more than 50%, With more than 25%, D - 10%.

Example 11. General method for the synthesis of salts of compounds of General formula I.

Part of the compounds of the present invention contains an ionic group (secondary, tertiary amines) and can form salts, which were obtained by methods known in the art.

For this purpose, for example, to a solution of a base in an inert solvent (alcohol, acetone, chloroform, ether, ethyl acetate) solution was added an equivalent amount (sometimes excess) organic or inorganic acid in an inert solvent and sought precipitation of the desired salt. The inorganic acid may be chloroethanol acid, phosphoric acid, sulfuric acid, nitric acid, Hydrobromic acid or iodomethane acid. The organic acid may be methanesulfonate, p-toluensulfonate, acetic acid, triperoxonane acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, almond acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, but not the Ogre is nicias them. Table 7 presents examples obtained pharmaceutically acceptable salts and some of their properties.

Biological tests and activity of the synthesized compounds.

Example 11. The study of the antagonistic activity of the compounds of General formula I and their pharmaceutically acceptable salts relative to the adenosine A2A receptor.

Antagonistic activity of the new compounds of General formula I and their pharmaceutically acceptable salts relative to the adenosine A2A receptor was performed ex vitro functional test cells. The experiment used a cell line ValiScreen cell line (PerkinElmer, USA) expressing recombinant human adenosine receptor type A2A. Stimulation of receptors in these cells agonist CGS-21680 (Tocris) activates adenylate cyclase, resulting in increased synthesis of intracellular cyclic adenosine monophosphate (cyclic amp or camp). The amount of camp was determined using technologies LANCE (LANCE Ultra camp kit, PerkinElmer). The ability of test compounds to reduce the number of camp synthesized in the presence of CGS-21680, were evaluated for their antagonistic activity. As standard (connection comparison) used are described in the literature antagonist KW-6002 (Axon Medchem, Netherlands).

Cells were cultured in the DMEM (Paneco, Russia) with the addition of 10% FBS (Biological Industries), a mixture of penicillin/streptomycin (Paneco) and G418 (Sigma) at 37°C in an atmosphere of 5% CO2. Before the experiment, cells were removed from the culture bottle with a solution of Versene (Paneco) and suspended in buffer SB2 (Wednesday Hanks+5 mm HEPES (pH 7.4)+0.1% of BSA+200 uM Ro-20-1734+2U/mL ADA (adenosine deaminase)) to a density of 0.2 million cells per milliliter. To the cell suspension were added to 1:150 (by volume) ULight™-anti-cAMP Antibody (PerkinElmer) and the mixture is poured into white 384-well plates (PerkinElmer) 5 µl (1000 cells) in each well.

Test compounds were dissolved in DMSO to a concentration of 6.32 mm and prepared 3.16-fold serial dilution in DMSO. Prepared serial dilution was diluted 50-fold with buffer SB1 (Wednesday Hanks+5 mm HEPES (pH 7.4)+0.1% of BSA). The obtained solutions of the compounds in SB1 buffer were mixed in a 1:1 ratio with a solution of CGS-21680 (12.64 nm), pre-cooked in the buffer SB3 (SB1+0.1% Pluronic F127). The mixture of the tested compounds with agonist was added (5 μl in duplicate into the wells of the plate containing 5 μl of the cells (as described above) and the plates incubated for 30 minutes at room temperature. Each plate also contained 16 holes for each controle (MAX and MIN). MAX - cells with 3.16 nm CGS 21680 (concentration of agonist, the corresponding EU90, i.e. the concentration that causes 90% aktivnosti cells); signal otati holes were used in the calculations as 100% activity (0% inhibition). MIN - cells with a mixture of 3.16 nm CGS-21680 and 2 μm KW-6002 (the concentration of the antagonist, the corresponding IC100i.e. concentration causing 100% inhibition of aktivnosti cells); the signal from these holes were used in the calculations as 0% activity (100% inhibition). In addition, each plate contained wells (4 repeats), where cells were treated with agonist (CGS-21680) at different concentrations. The final concentration of DMSO in all wells was equal to 1%.

Formed in the cells of camp was determined quantitatively using a set of LANCE Ultra cAMP kit (PerkinElmer, USA), in accordance with the methodology recommended by the manufacturer. Fluorescent signal was measured on the device Victor3V (PerkinElmer) with an integrated program for measuring LANCE High Count.

The apparent affinity of the test compounds was determined by the formula:

Ki=IC50/(1+L/KD),

where IC50the concentration of antagonist, in which the activity of adenylate cyclase accounts for 50% of the maximum, L is the concentration of CGS-21680, in which measurements are made (3.16 nM) and KD- the apparent affinity constant CGS-21680, quantitatively corresponds to the value of EC50(concentration premaxillae stimulation of cells) for CGS-21680 and some curves to stimulate accumulation of camp in the cells at various concentrations of agonist. In tables 5-7 presents data on the activity link the General formula I.

Example 12. Radioligand analysis of the interaction of compounds of General formula I with adenosine A1, A2A, AV and A3 receptors.

Radioligand analysis of the interaction of compounds of General formula I with adenosine A1, A2A, AV and A3 receptors was performed to determine the selectivity of the interaction of compounds of General formula I with adenosine A2A receptor. When determining the interaction of these compounds with adenosine A2A receptor used membrane preparations derived from embryonic human kidney cells expressing recombinant human A2A receptor. The receptor expression was 7 pmol/mg protein. As radioligand used [3H]CGS 21680 at a concentration of 0.05 μm. Solutions of test compounds were prepared as described in the procedure for the functional test with the difference that instead of the environment SB1 used a buffer of the following composition: 50 mM Tris-HCl, pH 7.4, 10 TM MgCl2, I mM EDTA, 2 U/mL Adenosine Deaminase. Membrane preparations were incubated in the presence of a mixture of test compounds and [3H]CGS 21680 for 90 min at 25°C and the mixture was filtered on steklofibrobetonnykh filters GF (Millipor, USA). Radioactivity on the filters was determined using gidrostimulyatsionnye MicroBeta counter (PerkinElmer, USA). Nonspecific binding was measured in the presence of 50 μm NECA, which was not more than 15 per cent of the associate. The affinity of the test compounds was determined by the formula:

Ki=IC50/(1+L/KD),

where IC50the concentration of antagonist, in which the binding of [3H]CGS-21680 is reduced to 50% of the maximum, L is the concentration of [3H]CGS-21680, in which measurements are made (50 nM) and KD- constant affinity of [3H]CGS-21680, quantitatively corresponds to the value of EC50(concentration premaxillae binding) [3H]CGS-21680, and some curves radioactive binding at different concentrations of [3H]CGS-21680 (KD=64 nm).

Similarly investigated the interaction of the new compounds of General formula I with adenosine A1, A2B and A3 receptors.

Radioligand analysis of the interaction of some compounds of General formula I with adenosine A1, A2A, A2B and A3 receptors showed high selectivity for adenosine A2Athe receptor (table 8).

Example 13. Obtaining pharmaceutical compositions.

The pharmaceutical composition according to the invention is prepared using generally accepted engineering techniques and includes a pharmacologically effective amount of the drug substance, representing a compound of formula I or its pharmaceutically acceptable salt, which typically ranges from 5 to 30 wt.%, in combination with one or b is more pharmaceutically acceptable auxiliary additives, such as diluents, binders, loosening agents, absorbents, fragrances, flavoring agents. In accordance with known methods of the pharmaceutical compositions can be presented in various solid or liquid forms.

Examples of solid dosage forms include, for example, tablets, pills, gelatin capsules, etc.

Examples of liquid dosage forms for injection and parenteral administration include solutions, emulsions, suspensions, etc.

Composition, as a rule, obtained using standard procedures involving mixing the active compound with a liquid or finely powdered solid carrier.

Example. 100 mg of the composition containing 15.0 mg of the compound 3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (compound I-1-16)

Compound I-1-1615.0 mg
Lactose40.0 mg
Alginic acid20.0 mg
Citric acid5.0 mg
Tragakant20.0 mg

According to the invention likewise get a pharmaceutically what song containing a medicinal substance other compounds of General formula I.

1. Substituted [1,2,4]triazolo[4,3-a]pyridine General formula I and their pharmaceutically acceptable salts

where a represents an optionally substituted aminocarbonyl group-N-C(O)-, in which the amino group may be substituted and the substituents can be selected from
hydrogen, C1-C5of alkyl, possibly substituted C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which the heteroatoms are selected from oxygen or nitrogen;
aryl selected from phenyl, possibly substituted by hydroxy, C1-C5the alkyl, C1-C5alkoxy, halogen, C1-C5allmineral, or naphthyl;
or amino group is selected from C3-C7heterocyclyl containing 1-2 heteroatoms in the cycle selected from nitrogen, oxygen or sulfur, possibly substituted by hydroxy, C1-C3by alkyl, benzyl, phenyl which may be substituted with halogen, with the specified heterocyclyl may be condensed with a benzene ring;
allmenalp, in which acyl is selected from
C1-C6alkylsulphonyl, where alkyl may be substituted by phenyl, substituted phenyl in which the substituents selected from C1-C5alkoxy; a 5-membered hetero is a reel with a heteroatom, selected from oxygen atom or sulfur;
benzoyl possibly substituted C1-C5the alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy;
geterotsiklicheskikh in which heterocyclyl selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, possibly condensed with a benzene ring and may substituted C1-C5by alkyl, halogen;
or raidgroup, in which one of the substituents end aminogroup represents hydrogen, and the second Deputy is chosen from:
C1-C3of alkyl, substituted phenyl, 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur;
With2-C6alkenyl;
aryl selected from phenyl, substituted C1-C5the alkyl, C1-C5alkoxy, Ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarboxylic;
5-membered heterocyclyl, in which the heteroatoms are selected from sulfur atom or oxygen, and possibly substituted allyloxycarbonyl group;
Represents a non-aromatic cyclic Deputy, selected from C4-C6cycloalkyl;
aromatic cyclic Deputy selected from phenyl, which may be substituted with halogen, C1-C3is laksi;
non-aromatic 5-6 membered heterocyclic Deputy to the nitrogen atom as a heteroatom, and possibly N-substituted C1-C3by alkyl;
aromatic 5-6 membered heterocyclic Deputy, in which the heteroatoms are selected from nitrogen, oxygen or sulfur, and which may be substituted With1-C6by alkyl;
or aromatic 5-6 membered heterocyclic Deputy, in which the heteroatom is selected from nitrogen, condensed with a benzene ring;
R1a, R1b and R1c independently represent H, C1-C3alkoxy, excluding connection:





n=1,2; R=H, Hal, Me, MeO, CMe3, CF3

n=1,2; R=H, Hal, Me, MeO, CMe3, CF3

n=1,2; R=H, Hal, Me, MeO, CMe3, CF3






2. Substituted [1,2,4]triazolo[4,3-a]pyridine under item 1 of the General formula I-1, I-2, I-3, as well as their pharmaceutically acceptable salts:

where:
In the matter specified in paragraph 1;
R2a, R2b and R2c, together with the IMO represent H, With1-C3alkoxy;
R3a and R3b independently represent hydrogen, C1-C5alkyl, possibly substituted C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which the heteroatoms are selected from oxygen or nitrogen; aryl selected from phenyl, possibly substituted by hydroxy, C1-C5the alkyl, C1-C5alkoxy, halogen, C1-C5allmineral, or naphthalene;
R3a and R3b may form together a cyclic substituents, the group R3a-N-R3b represents C3-C7heterocyclyl containing 1-2 heteroatoms in the cycle selected from nitrogen, oxygen or sulfur, possibly substituted by hydroxy, C1-C5by alkyl, benzyl, phenyl which may be substituted with halogen, with the specified heterocyclyl may be condensed with a benzene ring;
R4 represents a C1-C5alkyl, where alkyl may be substituted by phenyl, substituted phenyl in which the substituents selected from C1-C5alkoxy; a 5-membered heteroaryl with a heteroatom selected from oxygen atom or sulfur; aryl selected from phenyl, possibly substituted C1-C5salkola, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclyl in which heterocyclyl selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms and, selected from nitrogen, oxygen or sulfur, possibly condensed with a benzene ring and may substituted C1-C5by alkyl, halogen;
R5 represents hydrogen;
R6a and R6b independently represent hydrogen, C1-C3alkyl, substituted phenyl, 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur; With2-C6alkenyl, aryl selected from phenyl, substituted C1-C5the alkyl, C1-C5alkoxy, Ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarboxylic;
R6a and R6b may form together a cyclic substituents, the group R6a-N-R6b represents a 5-membered heterocycle, in which the heteroatoms are selected from sulfur atom or oxygen, and possibly substituted allyloxycarbonyl group;

3. Derivatives of [1,2,4]triazolo[4,3-a]pyridines under item 1, representing
3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methoxybenzylamine (I-1-01);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methoxybenzylamine (I-1-02);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid naphthyl-1-amide (I-1-03);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I-1-04);
3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I1-05);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid phenylamide (I-1-06);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-propylamide (I-1-07);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 4-methylphenylamine (I-1-08);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 4-tortenelme (I-1-09);
3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (2-methoxyphenyl)methylamide (I-1-10);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (2-methoxyphenyl)methylamide (I-1-11);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-tortenelme (I-1-12);
3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-chlorpheniramine (I-1-13);
3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-chlorpheniramine (I-1-14);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-chlorpheniramine (I-1-15);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-16);
3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-17);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-hydroxy-6-methylphenylene (I-1-19);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (cyclohexyl)methylamide (I-1-20);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2,3-dimethylphenyl the (I-1-21);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3,4-dimethylphenylamine (I-1-23);
3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3,5-dimethylphenylamine (I-1-24);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-ethylvanillin (I-1-25);
3-(pyrid-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I-1-26);
3-(pyrid-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-27);
3-(pyrid-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-28);
3-(pyrid-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-29);
3-(5-methylfuran-2)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-30);
3-(thienyl-2)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-31);
3-(indol-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-32);
3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-ethylvanillin (I-1-33);
3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-34);
3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methoxybenzylamine (I-1-35);
3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (furan-2-yl)methylamide (I-1-36);
3-(2-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (furan-2-yl)methylamide (I-1-37);
3-4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid heptamethylnonane (I-1-38);
N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-3,5-dimethylpiperidin (I-1-39);
N-{3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-4-hydroxy-4-(4-chlorophenyl)-piperidine (I-1-40);
N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-4-benzylpiperidine (I-1-41);
N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-1,2,3,4-tetrahydroquinolin (I-1-42);
N-{3-(4-forfinal)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-4-hydroxy-4-(4-chlorophenyl)-piperidine (I-1-43);
3-phenyl-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methyl-4-chloro-phenylamide (I-1-44)
3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-naphthylamide (I-1-47);
3-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-propylamide (I-1-48);
3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-methylphenylamine (I-1-49);
3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 2-tortenelme (I-1-50);
3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid 3-methylphenylamine (I-1-51);
3-(2-forfinal)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid (furan-2-yl)methylamide (I-1-52);
N-{3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-piperazine (I-1-53);
N-{3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-N'-methylpiperazine (I-1-54);
N-{3-(2-methoxyphenyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridine-8-carbonyl}-hydroxyethylamine (I-1-55);
8-[(2-ethoxybenzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-01);
8-{[(2-methoxyphenyl)acetyl]-amino}-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-02);
8-[(Tien-3-yl)acetylamino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-03);
8-[(2-chloro-5-methylthio-benzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-04);
8-[(Tien-3-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-05);
8-[(3-methyltin-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-06);
8-[(indol-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-07);
8-[(3-fluoro-4-methoxy-benzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-08);
8-[(2,3-dihydrobenzo[1,4]dioxin-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-09);
8-[(5-chlortan-2-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-10);
8-[(3,4-methylendioxy-benzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-11);
8-[(5-methylisoxazol-3-yl)carbylamine]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-12);
8-[(2-methoxybenzoyl)amino]-3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-13);
8-[(2-methoxybenzoyl)amino]-3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-14);
8-[(2-ethoxybenzoyl)amino]-3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-15);
8-[(2-methoxybenzoyl)amino]-3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-16);
8-[(2-methoxybenzoyl)amino]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-17);
8-(b is solumina]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-18);
8-(benzoylamine]-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-19);
8-(2-methoxybenzylamine]-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-20);
8-(2-ethoxybenzylidene]-3-phenyl-[1,2,4]triazolo[4,3-a]pyridine (I-2-21);
8-[(2-perbenzoic)amino]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-22);
8-[(2-perbenzoic)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-23);
8-[(2-methoxybenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-24);
8-[(2-methoxybenzoyl)amino]-3-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-25);
8-[(2-methoxybenzoyl)amino]-3-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-26);
8-[(2-chlorobenzoyl)amino]-3-(N-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-27);
8-[(2-chlorobenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-28);
8-[(2,6-dichlorobenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-29);
8-[(2,6-dimethylbenzoyl)amino]-3-(N-methylpiperidin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine (I-2-30);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3,4-acid)-urea (I-3-01);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(2-methoxy-5-were)-urea (I-3-02);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3,4-atlanticcity)-urea (I-3-03);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(2-phenylethyl)-urea (1-3-04);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3,4-methylenedioxyphenyl)-Icewine (I-3-05);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-06);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(tetrahydrofuran-2-methyl)-urea (I-3-07);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(2-methoxycarbonylmethyl-3)-urea (I-3-08);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(3-acetylphenyl)-urea (I-3-09);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(4-methoxy-2-were)-urea (I-3-10);
1-(3-cyclobutyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(4-methoxy-3-forfinal)-urea (I-3-11);
1-(3-cyclopentyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-12);
1-(3-cyclohexyl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-13);
1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(furyl-2-methyl)-urea (I-3-14);
1-{3-(N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(furyl-2-methyl)-urea (I-3-15);
1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(2-methoxyphenyl)-urea (I-3-16);
1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(3,4-acid)-urea (I-3-17);
1-{3-(N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(2-methoxyphenyl)-urea (I-3-18);
1-{3-(N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-(3,4-acid)-urea (I-3-19);
1-(3-pyrid-4-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-20);
1-(3-pyrid-4-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(FSD is l-2-methyl)-urea (I-3-22);
1-(3-pyrid-3-yl-[1,2,4]triazolo[4,3-a]pyridine-8-yl)-3-(furyl-2-methyl)-urea (I-3-23);
1-{3-(N-methylpiperidin-4-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-allylation (I-3-24);
1-{3-(N-methylpiperidin-3-yl)[1,2,4]triazolo[4,3-a]pyridine-8-yl}-3-allylation (I-3-25).

4. The method of obtaining [1,2,4]triazolo[4,3-a]pyridines of General formula I-2 and I-3:

where R2, R4, R6 and a have the above meanings, X=Cl,
consisting in successive cyclocondensation of artefiera In-C(OMe)3connection b2, obtained by the reaction of 2-chloro-3-nitropyridine b1 with hydrazine; restoring nitropyridine b3 hydrogen over palladium on coal; acylation of the resulting amine b4 appropriate allelochemical in the presence of a strong base to obtain compound I-2, or the interaction of amine b4 with the appropriate isocyanate in a neutral solvent to obtain compounds I-3.

5. Active component that has the property antagonist of A2A receptors, which are compounds of General formula I according to any one of paragraphs.1-3.

6. The active ingredient, having the properties of a selective antagonist of A2A receptors to receive medicines that are suitable for the prophylaxis and treatment of disorders of the Central nervous system, neurodegenerative, inflammatory and cancer diseases, which are compounds of General formula I on mu is mu PP.1-3.

7. Pharmaceutical composition having antagonistic activity against adenosine A2A receptor, comprising as an active ingredient or compound of General formula I according to any one of paragraphs.1-3 or their pharmaceutically acceptable salts in therapeutically effective amounts.

8. The pharmaceutical composition under item 7 in the form of tablets, capsules and injections, ointments, gels and other ready-made forms, placed in pharmaceutically acceptable packing.

9. A method of obtaining a pharmaceutical composition according to any one of paragraphs 7-8 by mixing with an inert filler, an auxiliary agent, a carrier and/or solvent, at least one active ingredient (substance) of General formula I on PP.1-3 or its pharmaceutically acceptable salt in a therapeutically effective amount.

10. The method of selective inhibition of the activity of the adenosine A2A receptor, which consists in the action of the active ingredient (substance) of General formula I on PP.1-3 or its pharmaceutically acceptable salt on biological objects or samples, whose functions are regulated by adenosine A2A receptors.

11. The drug is suitable for the prevention and treatment of disorders of the Central nervous system, neurodegenerative, inflammatory and cancer diseases, which contains the active ingredient under item 6 on the formula I or a pharmaceutical composition according to p. 7 in therapeutically effective amounts.

12. Drug under item 11 in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

FIELD: medicine, pharmaceutics.

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

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

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazolopyridine derivatives of formula (I), a pharmaceutical composition based thereon, use for treating and/or preventing disorders or conditions associated with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and an intermediate of formula (VIII). In general formula (I) G1 denotes H; G2 is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted phenyl; optionally substituted C1-C6-alkylaryl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted-C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G3 is selected from -(CH2)n-R1 and -(CH2)p-R5; G4 is selected from H; optionally substituted acyl; optionally substituted acylamino; optionally substituted acyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G5 dentes H.

EFFECT: high effectiveness of compounds.

15 cl, 2 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention refers to new phenoxymethyl compounds of formula (I) or its pharmaceutically acceptable salts, wherein: HET represents a heterocyclic ring having formula A29 or A31, wherein the far left part is connected to the group X of formula (I); X represents substituted phenyl or optionally substituted pyridinyl, wherein the substitutes are specified in C1-C4alkoxy and cyano; Z represents imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[1,2-b]pyridazin-6-yl each of which can be substituted, wherein the substitutes are specified in C1-C4alkyl and a halogen atom; and each R2 are independently specified in C1-C4 alkyl inhibiting at least one phosphodiesterase 10, as well as to pharmaceutical compositions containing these compounds, and methods of treating various CNS disorders.

EFFECT: preparing the new compounds.

23 cl, 2 tbl, 732 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,2,3,4-tetrahydropyrido[4,3-b]indole-containing phenothiazines of general formula 1 as inhibitors of cholinestrerases and blockers of serotonin receptors 5-HT6, a pharmaceutical preparation on their base, in particular for treatment of neurodegenerative diseases. In general formula 1, in which R1=H, (C1-C6) alkyl; R2, R3, R4, R5=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, R6, R7=H, F, Cl, Br, (C1-C6) alkyl, (C1-C6) alkoxy, NH2, NHAlkyl, NAlkyl2; A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2; CH2CH[(C1-C6)alkyl]C(O)N[(C1-C6)alkyl]CH2CH2, CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: increased efficiency of the application of compounds.

6 cl, 1 dwg, 1 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (I)

,

in which R1 stands for a phenyl group, optionally substituted with one or several halogen atoms; R2 stands for hydrogen or a halogen atom or a cyanogroup; group -C(=O)Y, in which Y stands for a hydrogen atom or the group -NH2 or -OR3; group -C(=S)NH2; group -C(=NH)NH-OH; group -CH2OH or -CH2F; group -CH=N-OH; group -CH=CH2 or -C≡C-Ra; group (II) or (III); and Ra stands for the hydrogen atom or the (C1-C4)alkyl group; R3 stands for thehydrogen atom or the (C1-C4)alkyl group; and R4 stands for -NH2, (C1-C4)alkyl, (C1-C4)fluoroalkyl or (C3-C7)cycloalkyl group. The invention also relates to methods of obtaining compounds of formula (I), a medical preparation, a pharmaceutical composition, intermediate compounds for obtaining the formula (I) compound and the application of the formula (I) compound and intermediate compounds.

EFFECT: claimed compounds have anti-cancer activity.

21 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to phenothiazine-containing 1,2,3,4-tetrahydropyrido[4,3-b]indole derivatives of general formula 1 and hydrochlorides thereof as an agent for reducing uncontrolled protein aggregation in the nervous system, methods for production thereof, a pharmacological agent based thereon and a method of reducing uncontrolled protein aggregation in the nervous system. In general formula 1: R1=H, (C1-C6)alkyl; R2, R3, R4, R5=H, F, O, Br, (C1-C6)alkyl, (C1-C6)alkoxy, R6, R7= H, F, Cl, Br, (C1-C6)alkyl, (C1-C6)alkoxy, NH2, NHAlkyl, NAlkyl2, A=CH2CH2, CH=CHCH2, CH2CH2CH2, CH2CH[(C1-C6)alkyl]C(O), CH2CH2C(O)NHCH2CH2); CH2CH[((C1-C6)alkyl]C(O)N[(C1-C6))alkyl]CH2CH2), CH2CH(OH)CH2, CH2CH(OH)CH2NHCH2CH2, CH2CH(OH)CH2N[(C1-C6)alkyl]CH2CH2, CH2CHFCH2NHCH2CH2, CH2CHFCH2N[(C1-C6)alkyl]CH2CH2.

EFFECT: improved properties of derivatives.

9 cl, 2 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel indolizine derivatives of formula , to their pharmaceutically acceptable salts or prodrugs, which represent C1-6alkyl ethers, where values U, R1, R2, R3 are given in item one of the formula.

EFFECT: compounds possess an inhibiting activity with respect to xanthine oxidase, which makes it possible to use them in a pharmaceutical composition for the prevention or treatment of a disease, selected from the group, consisting of hyperurecemia, gout nodule, gout arthritis with hyperurecemia of the renal disorder and urine concrements.

18 cl, 17 tbl, 76 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts specified in a group consisting of phosphate salt, hydrochloride salt, sulphate salt, mesylate salt, maleate salt or malate salt. Also, the invention refers to a method for preparing the above salts, using them and a pharmaceutical composition on the basis of the above salts.

EFFECT: there are prepared new pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts effective in treating diabetes.

5 cl, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, anti-cancer therapy, and concerns a method of treating lymphoma specified in diffuse large B-cell lymphoma, marginal zone lymphoma and nodular sclerosis Hodgkin lymphoma by means of an organic derivative of arsenic, such as darinaparsin (S-dimethylarsinoglutathione, SGLU-1):

or its pharmaceutically acceptable salt. The administration is performed once a day for five days every four weeks in a dose of 200-420 mg/m2, in particular intravenously. The invention also concerns using the above compound or its pharmaceutically acceptable salt for preparing the respective drug and pharmaceutical compositions.

EFFECT: group of inventions provides the effective treatment of the above group of diseases with similar or higher activity or lower toxicity as compared to arsenic oxide.

8 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new macrocyclic compounds of formula

or their tautomer, pharmaceutically acceptable salt, solvate or ester, wherein: X represents O or NR; Y represents -O-(CH2)mCOOR or -O-(CH2)mCON(R)2, wherein groups related to a nitrogen atom, can be in a Z- or E-configuration; R1 and R2 independently represent hydrogen or halogen; R3, R4, R5, R6, R7, R8, R9 and R10 independently represent hydrogen, alkyl, OR, -O(CH2)mC(O)(CH2)pN(R)2, -O(CH2)mN(R)C(O)(CH2)pOR, -(CH2)mN3 or -O(CH2)mN3; and each R independently represents R11, hydrogen, alkyl, alkylamino, dialkylamino, alkoxycarbonyl, phenyl or a protective group; or two R on the same nitrogen are taken together with nitrogen for producing a 5-6-merous heterocyclic or heteroaryl ring; wherein the group contains more than one substitute R; wherein R is optionally substituted, and each R can be identical or different, and wherein the protective group is specified in ethoxymethyl, methoxymethyl, tert-butyldimethylsilyl (TBS), phenylmethylsilyl, trimethylsilyl (TMS), 2-trimethylsilyl ethoxymethyl (SEM), 2-trimethylsilylethyl, benzyl and substituted benzyl; R11 represents a group

,

wherein Z represents an inorganic or organic counter-ion specified in a halogen, -O-alkyl, toluene sulphonate, methylsulphonate, sulphonate, phosphate, formiate or carboxylate; n represents 0, 1 or 2; m and p independently represent 0, 1 or 2; and dashed lines mean either a single, or a double bond, wherein the necessary conditions of the valence are observed by additional hydrogen atoms; and wherein in formula I′, when n represents 1, and X represents O, and the double bond is present between the carbon atoms having R9 and R10, then at least one of R5, R6, R7, R8, R9 or R10 are other than hydrogen; and wherein in formula I′, when n represents 1, and X represents O, and the bond between the carbon atoms having R9 and R10, represents the single bond, then at least one of R5, R6, R7 or R8 is other than hydrogen. The invention also refers to pharmaceutical compositions containing these compounds, using them and methods of treating diseases mediated by kinases and a heat-shock protein 90 HSP90.

EFFECT: preparing the new macrocyclic compounds.

28 cl, 5 dwg, 3 tbl, 9 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to glycosidic derivatives of 1,2-dithiole-3-thione or 1,2-dithiol-3-one of formula 1 , where R1=S or O; R2 is a residue of per-O-acetyl D-glucose, per-O-acetyl D-galactose, per-O-acetyl D-mannose, per-O-acetyl D-xylose, per-O-acetyl L-arabinose, per-O-acetyl-D-maltose or D-glucose, which can be used against cancerous diseases.

EFFECT: new bioactive compounds with cancerous preventive action and pharmaceutical products based on them are proposed, which display the cancerous preventive effect in non-cytotoxic concentrations.

2 cl, 4 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a compound of formula and to its pharmaceutically acceptable salt and its enantiomers, wherein D means pyridyl, which is substituted by 1-2 independently specified groups R38; M means , wherein * means an attachment position to D; and † means an attachment position to Z; Z means -O-; Ar means phenyl, which is optionally substituted by 0-4 groups R2; and G means ; wherein each R38 means -C0-C6-alkyl-(substituted by one group containing heterocyclyl, which means a monocyclic structure, and contains 5 to 7 atoms, wherein 1 or 2 atoms are independently specified in a group containing N, O and S optionally substituted by one or more oxo groups); in each specific case R2 is independently specified in -H and halogen; each R13 means -H; Q means cyclopropyl. The invention also refers to a pharmaceutical composition based on the composition of formula (I), a method for inhibiting the activity of protein kinase of the growth factor receptors and a method of treating choroidal neovascularisation.

EFFECT: there are prepared new compounds possessing the activity on protein kinase inhibitors.

7 cl, 8 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula I and its pharmaceutically acceptable salt, wherein if a chemical valency permits, i represents 1 or 2, R1 represents H; a linear (C1-C4) alkyl group, R2 represents H, Cl or F, X represents either N, or CR3, R3 represents H; halogen; a linear (C1-C4) alkyl or (C1-C4) alkoxyl group, Y represents Z represents O or NRx, Rx represents H or a linear or branched (C1-C4) alkyl, k is equal to 2, 3 or 4, n and p independently represents 2, and a sum of n+p cannot exceed 4, T represents H or a linear (C1-C4) alkyl group; T′ represents a linear C1-C3 alkyl chain substituted by either (C1-C6)-dialkylaminogroup, or a 5-6-merous saturated heterocycle containing one nitrogen atom and optionally containing the second heteroatom specified in O, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; or a 5-merous saturated heterocycle containing one nitrogen atom, such a heterocyclic ring is optionally substituted by a (C1-C4) alkyl chain at nitrogen atoms; r represents zero, 1; R′ represents di(C1-C4)alkylamino, (C1-C4)alkoxy; except for the compounds specified in the clause. The invention also refers to a pharmaceutical composition based on the compound of formula (I), using the compound of formula (I) and to a method of treating diseases, in which the hedgehog signalling pathway modulation is effective.

EFFECT: there are prepared new heterocyclic compounds possessing t effective biological properties.

20 cl, 193 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel derivative of ferrocene 1-(1,1,1,3,3,3-hexafluoro-2-ferrocenylprop-2-yl)-imidazole of formula

which shows an antitumour activity. Also claimed is a method of its obtaining (versions).

EFFECT: invention makes it possible to obtain the novel derivative of ferrocene, which can be applied in medicine for chemotherapy of oncologic diseases.

4 cl, 1 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to molecular biology, in particular to short interfering RNA (siRNA), and can be used in antitumor therapy. On the basis of genome analysis the sequences of siRNA against the human gene HIF1A with SEQ ID NO:1-2 are designed, siRNA against the human gene HSP8A with SEQ ID NO:3-4, siRNA against the human gene APEX1 with SEQ ID NO:5-6, and siRNA against the human gene CCND3 with SEQ ID NO:7-8, associated with cell proliferation of human pancreatic adenocarcinoma. Using the obtained siRNA, including as part of a lentiviral vector, results in suppression of cell proliferation of human pancreatic adenocarcinoma and tumor destruction. The invention enables to achieve the level of suppression of proliferation up to 65% using siRNA to genes HIF1A and HSP8A associated with stress and responsible for the major proliferative (CCND3) and reparative (APEX-1) ways of cell division.

EFFECT: improving level of suppression of proliferation.

3 cl, 10 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: what is presented is a fused protein that is a Notch1 antagonist, which consists of a human Fc region fused with the EGF-like repeat 1-13 of Notch1 or the EGF-like repeat 1-24 of Notch1. Fc-portion is localised on a carboxy-terminal portion of the EGF-repeat. There are described a pharmaceutical composition for the protein-based Notch signal transmission inhibition and using it for preparing the pharmaceutical composition for treating an individual suffering from: tumour; ovarian cancer; metabolic disorder; vascular proliferative retinopathy. What is presented is using the fused protein for producing the pharmaceutical composition for inhibition: angiogenesis in the individual; physiological lymphangiogenesis or pathological lymphangiogenesis in the individual; tumour deposits in the individual.

EFFECT: using the invention provides the proteins expressed in a supernatant at a level by several times more than the fused protein containing the EGF-like repeats 1-36 of Notch1; they penetrate into the tumour better, maintain a ligand-binding ability with the fused protein containing the repeats 1-24, binds to DLL4 and JAG1, whereas the fused protein containing the repeats 1-13 only binds to DLL4, but not to JAG1 that can find application in therapy of various diseases related to the Notch1 activity.

18 cl, 124 dwg, 10 ex

FIELD: medicine.

SUBSTANCE: invention represents a combination for treating breast cancer, containing the HSP90 inhibitor and HER2 inhibitor, wherein the HSP90 inhibitor represents ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid or its pharmaceutically acceptable salt, as well as a method of treating breast cancer, which involves administering an effective amount of this combination in a patient in need thereof.

EFFECT: combination possesses the higher effectiveness as compared to its individual ingredients.

6 cl, 1 ex, 1 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new crystalline forms of acid addition salts of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, wherein the acid is specified in methanesulphonic, maleic, fumaric, citric, orotic, 10-camphor sulphonic acids and fencifose. The salts possess the agonist properties of neuronal nicotine receptor (NNR) and can be used for managing or preventing pain, an inflammation or a CNS disorder. Each of the crystalline salts is characterised by an X-ray powder diffraction diagram. The invention also involves an amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate and polymorphic forms of the above crystalline salts.

EFFECT: invention refers to a pharmaceutical composition containing an effective amount of the presented salts.

19 cl, 8 dwg, 33 ex

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