Agent having cardioprotective action and 1,3-disubstituted 2-aminobenzimidazolium halides

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutics and medicine and use of tricyclic imidazo[1,2-a]benzimidazole derivatives of general formula I or 1,3-disubstituted 2-aminobenzimidazolium halides of general formula II as an agent having cardioprotective action with high efficiency.

EFFECT: high efficiency.

3 cl, 1 tbl, 2 ex

 

The invention relates to tools having a cardioprotective effect.

The basis of Genesis damaged cardiomyocytes of a number of diseases of the cardiovascular system is the acidification of the intracellular environment and development "calcium paradox". These changes are caused by various etiological factors have a major pathogenetic significance and are often decisive for the prognosis of the disease. In this regard, it is natural to desire to have a corrective effect on the disturbed metabolism of cardiomyocytes [main VP, Savelyev V.V. the Role of Cardioceratidae in the treatment of chronic heart failure of ischemic Genesis. /Russian cardiology journal. - 2009. No. 1 (75). R-56].

In recent years as a possible physiological and pathophysiological factor in the development mechanisms of such effects of ischemic and reperfusion stress, arrhythmia, disorders of contractile function and death of cells, consider sarcolemmal Na+/H+exchanger 1 isoform (NHE-1) [Pisarenko I. Inhibitors of Na+/H+exchange - a new class of cardioprotection. / Russian physiological journal. I.M. Sechenov. - 2004. No. 9 (90). - S-1110].

Its biological role is linked to processes such as the exchange of ions of Na+and H+; regulation of pH iobama cells; growth, hypertrophy, differentiation; cell damage during ischemia; in the organization of the cytoskeleton and cell migration [Slepkov E.R., J.K. Rainey, B.D. Sykes, Fliegel L. Structural and functional analysis of the Na+/H+exchanger. / Biochem. J. - 2007. No. 401 (3). - R-633].

Activation of NHE1 occurs during ischemia and reperfusion. During ischemia Na+/H+exchanger begins to withdraw from sarcoplasmic cells ions H+accumulated there due to the intensification of the process of glycolysis, in exchange for the entry of Na+. The increase in the intracellular content of Na+in turn, activates 3Na+/Sa2+-reversionary exchange (NCE-exchanger) through the sarcolemma, initiating the entry of CA2+in cardiomyocytes. There is a "Sa2+-overload". Reperfusion exacerbates the damage caused during ischemia. During reperfusion, the concentration of extracellular protons decays rapidly formed large gradient outside/intracellular protons, which leads to increased calcium levels. As a result, there occurs deterioration in contractile function, develop severe rhythm disturbances, which ultimately leads to the death of cardiomyocytes. The mechanism of action of NHE inhibitors bound in the end to avoid this calcium overload [Fliegel L. Regulation of the Na(+)/H(+) exchanger in the healthy and diseased myocardium. Expert. Opin. Ther. Targets. - 2009. No. 13 (1). - R-68].

The main positive effects of NHE is inhibitorof on itemizedoverlay myocardium in experimental and clinical studies associated with improved contractile recovery of left ventricular function after reperfusion; reduction of ischemia and necrosis; reduction of degree of disturbance of ion homeostasis accompanying ischemia/reperfusion; reducing apoptosis, decrease the incidence and severity of arrhythmias caused by ischemia/reperfusion.

Known among NHE inhibitors tool that has cardioprotective effect, Zoniporide (CF-597396) - [1-(quinoline-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine hydrochloride monohydrate [A Guzman-Perez et al. Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility./ Bioorganic & Medicinal Chemistry Letters. - 2001. No. 11(6). - R-807]. In vitro studies on rabbit platelets shown that this drug inhibits NHE-1-dependent swelling of platelets (maximum inhibition of 93%) [Tracey W.R. et al. Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1) // Cardiovasc. Drug Rev. - 2003. - No. 21. - 17-32]. In studies on isolated heart Langendorff zoniporide causes a dose-dependent reduction in infarct size (EU50=0,25 nm). At a dose of 50 nm, the drug reduces the size of myocardial infarction 83%than 2.5 times higher than eniporide or cariporide (EC500,69 and 5,11 nm, respectively). On the model of myocardial ischemic injury in vivo it was shown that zoniporide has cardioprotective effect [Knight D.R. et al. A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic myocardial injury in vitro and in vivo // J.PharmacoI.Exp.Ther. - 2001. - №297 (1). - .254-259]. Zoniporide significantly reduced the size of infarction without hemodynamic and contractile function of the heart, weakened postreperfusion contractile dysfunction, and decreased the frequency and duration of ventricular fibrillyatsy [Tracey WR et al. Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1) // Cardiovasc Drug Rev. - No. 21. - 2003. - 17-32]. He essentially had no effect on coronary blood flow, and the main effect was associated with changes in metabolism [Ayoub IM, et al. Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes the postresuscitation myocardial dysfunction through benefits on energy metabolism // Crit Care Med. - 2007. No. 35(10). - P. 2329-2336].

Clinical trials of the drug was carried out by the firm "Pfazer patients with myocardial infarction, diseases of the coronary arteries, atherosclerosis. The most frequent side effects in patients receiving zoniporide were drowsiness and orthostatic hypotension. Also watched nausea, vomiting, and headache [Dalvie, D. et al. Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences/ Drug Metab. Dispos. 2010 - №38(4). - R-654]. Therefore, it was studied the neurotoxic effect zoniporide in rats. Identified as clinical and electrophysiological and microscopic properties of peripheral sensory axonopathy [Pettersen JC et al. Neurotoxic effects of zoniporide: a selective inhibitor of the Na+/H+exchanger isoform 1 // Toxicol Pathol. - 2008. No. 36(4). - P.608-619]. Risk p is uridine peripheral nervous system may limit the dose and duration of therapy of cardiovascular diseases [Liu CN, Somps CJ 1Na+/H+Exchanger-1 Inhibitors Reduce Neuronal Excitability and Alter Na+Channel Inactivation Properties in Rat Primary Sensory Neurons./ TOXICOLOGICAL SCIENCES. - 2008. No. 103(2). - P.346-353].

The technical result is to increase the efficiency cardioprotective actions.

The technical result is achieved by using as a cardioprotective means tricyclic derivatives of imidazo[1,2-a]benzimidazole of General formula I:

where Ar=C6H4OCH3-R, C6H4OH-p

NR2=N(CH2CH2)2O,

including

Ia Ar=C6H4OCH3-R; NR2=N(CH2CH2)2O

IB Ar=C6H4OH-R; NR2=N(CH2CH2)2O

or halides of 1,3-disubstituted 2-aminobenzimidazole General formula I:

where Ar=C6H4F-4, C6H3(O2CH2)-3,4

NR2=N(C2H5)2N(CH2CH2)O; X=Cl, Br,

including

IIa Ar=C6H4F-4; NR2=N(CH2CH2)2O, X=Cl

IIb Ar=C6H3(O2CH2)-3,4; NR2=N(C2H5)2X=Br.

Connections may be used, including, for making money, having a cardioprotective effect, as well as to restore and improve cardioprotective functions in living organisms.

Compound Ia is izvestno as having the ability to inhibit PDE camp and reduce the excitability of atrial (VA Anisimov, A. A. Spasov, VA Kosolapov, A.F. Kucheryavenko, O. Ostrovski, I.E. Larionov, R.E., Libenson. Pharmacological activity of 2-methoxyphenylalanine 9 dialkylaminoalkyl[1,2-a]benzimidazole. Chem.-Pharm. journal, 2005, t, No. 9, p.26-32), as well as exhibiting the properties of purine antagonist P2Y1receptors and antithrombotic activity [RF patent №2377990, IPC A61K 31/5377, 2006).

Compound IB is antioxidant and antiplatelet activity, as well as weak antiserotonin and antipsoriaticescoe action (VA Anisimov, A. A. Spasov, VA Kosolapov, Chernikov MV, A. Stukalina, L.V. Alcova, I.E. Larionov, R.E., Libenson, O.E. Vatolina. Synthesis and biological activity of 9-dialkylaminomethyl-2-hydroxy(deoxy)phenylimidazo[1,2-a]benzimidazole. Chem.-Pharm. journal, 2006, t, No. 10, p.23-26).

Compounds IIa, IIB is not described.

The technical result is also new connections in a number of halogenides 1,3-disubstituted 2-aminobenzimidazole with cardioprotective effect.

The technical result is achieved halides 1-dialkylaminomethyl-3-[substituted(disubstituted)phenacyl]-2-aminobenzo-imidazole General formula II:

where IIA Ar=C6H4F-4; NR2=N(CH2CH2)2O, X=Cl

IIb Ar=C6H3(O2CH2)-3,4; NR2=N(C2H5) 2X=Br.

Below are examples of the preparation of compounds IIA and IIB.

Example 1. Synthesis of chloride 1-morpholinomethyl-3-(4-florfenicol)-2-aminobenzimidazole (IIA).

A mixture of 1.23 g (5 mmol) 1-morpholinoethyl-2-aminobenzimidazole, 0.87 g (5 mmol) of ω-chloro-4-fortetienne and 15 ml of dry acetonitrile is boiled until complete reaction of quaternization (~8-10 hours, control - TLC). Then, the acetonitrile evaporated to small volume, the residue that represents the desired chloride, filtered and washed with acetone. The yield of 92.5%. TPL 198-199°C.

Found, %: C 60,15; H 5,68; Cl 8,54; F 4,60; N 13,45. C21H24ClFN4O2.

Calculated, %: C 60,21; H 5,77; Cl 8,46; F Of 4.54; N 13,37.

The IR spectrum v cm-1: 3206, 3168, 3022 (N+H2), 1693 (C=O), 1663 (C=N), 1599 (C=C), 1226 (C-N), 1118 (C-O).

An NMR spectrum1H (DMSO-d6), δ, ppm (J, Hz): 2.40-2.60 m [4H, N(CH2)2], 2.67 t (2H, J=5.7 Hz, NCH2), 3.48 t [4H, J=3.9 Hz, O(CH2)2], 4.39 t (2H, J=5.7 Hz, NCH2), equal to 6.05 (2H, CH2), 7.24-7.62 m (6H, HAr), 8.14-8.21 (m 2H, HAr), 9.22 USS (2H, N+H2).

Example 2. Bromide 1-diethylaminoethyl-2-amino-3-(3,4-methylendioxyphenyl)benzimidazole (IIB).

In a hot solution of 1.16 g (5 mmol) 1-diethylaminoethyl-2-aminobenzimidazole in acetone contribute 1.22 g (5 mmol) of 3,4-methylenedioxyphenethylamine, the mixture is stirred and leave for 3-4 hours at 20-25°C. the precipitation bromide is separated and washed with acetone. Output is 97,3%. TPL 235-236°C (decomposition).

IR-spectrum (solid state), v, cm-1: 3310, 3236,3090, 1681, 1652, 1449, 1255, 1033,751.

An NMR spectrum1H (DMSO-d6), δ, ppm: 0.81 t (6H, J 6.9 Hz, 2CH3); 2.73 t (2H, J 6.2 Hz, CH2); 4.29 t (2H, J 6.2 Hz, CH2); 5.88 (2H, CH2CO); 6.20 (2H, OCH2O); 7.15-7.40 (m, 3H, HAr), 7.48-7.65 (m, 3H, HAr), 7.75 (1H, J 8.1 Hz, HAr), N+H2in the exchange.

Below are the results of testing the cardioprotective properties of compounds.

1. Materials and methods.

1.1. Materials.

The compounds I and II, zoniporide (SIGMA, USA).

Reagents: sodium chloride "chemically pure" NaCl ("NPO ECROS", Russia), a set of reagents for immunoassay analysis of Rat cardiac troponin I (cTn-I) (cat. the number CSB-E08420r) company CUSABIO BIOTECH CO.,LTD. (China), Evans blue, triphenyltetrazolium, Evans blue (SIGMA, USA), 2,3,5-triphenyltetrazolium chloride (SIGMA, USA).

1.2. Animals.

In experiments were used 57 female rats, weighing 260-300 g, which were kept in a vivarium conditions with natural light regime on a standard diet of laboratory animals in accordance with GOST P 50258-92 [1993]. Studies were performed in accordance with the applicable requirements of GOST ISO/IEC 17025-2009, GOST P ISO 5725-2002 and "good laboratory practice", approved by order of the health Ministry of the Russian Federation dated 23 August 2010 No. 708n, in compliance with the "European Convention for the protection of vertebrate animals used for the experiment the clients or other scientific purposes" [Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes Official Journal L 276, 20.10.2010, p.33-79 (revising Directive 86/609/EEC)].

Animals were divided into 11 groups:

1-3 control:

1 - "control-linopirdine" - the animals were held all complex operations, in addition to ligation of the left coronary artery;

2 - "control-ischemia/reperfusion" - animals was performed by ligation of the left coronary artery followed by reperfusion, was injected with saline;

3 - "control-zoniporide" - animals with ligation of the left coronary artery was introduced zoniporide 10 minutes before reperfusion.

4-7 experienced (animals with ligation of the left coronary artery was introduced, operating connections for 10 minutes before reperfusion):

4 - "IIa"; 5 - "Ia"; 6 - "IIC"; 7 - "IB".

1.3. Methods.

The experiments were performed on anesthetized rats females (chloral hydrate, 400 mg/kg) in conditions of artificial ventilation, thoracotomy, pericardiotomy. Ischemia/reperfusion was modeled by a 60-minute ligation of the left coronary artery, with subsequent 60-min reperfusion. Saline zoniporide studied compounds were administered intravenously in an equivalent volume of 1 mg/kg 10 min before reperfusion. The development of myocardial ischemia followed by electrocardiogram in II standard lead (computerized electrocardiograph "Poly-Spectrum-8/", Russia); the size of the anatomic area at risk and necrosis of the myocardium, myocardial marker surface is idene - the troponin I in rats.

Evaluation of the anatomical dimensions of risk zones and zones of infarction was produced using the method of double staining blue Evans and triphenyltetrazolium with subsequent processing program Image J.

The content of troponin I in the blood plasma of rats as a marker of myocardial damage was determined by immunohistochemistry set of reagents for immunoassay analysis of Rat cardiac troponin I (cTn-I) firms CUSABIO BIOTECH CO., LTD. (China) universal microplate reader ELX 800 manufactured by Bio-Tek Instruments, Inc. (USA). The content of troponin I expressed in PCG/ml of plasma.

1.4. Methods of statistical processing

All statistical calculations were performed using the software package Statistica for Windows 6.0, company StatSoft, Inc. (USA). Conducted a pairwise comparison of samples using U-test, Mann-Whitney. The hypothesis of the existence of differences between samples were taken at the level of p<0,05.

2. The results of the study

When studying the effect of compounds on the size of the area at risk and myocardial infarction ischemia/reperfusion have been shown the following results. Animals 2-7 group when carrying out ligation of the left coronary artery and ischemic damage to the myocardium of the left ventricle, which is confirmed by ST segment elevation on the ECG in the second standard lead and staining of Evans blue. In control and op is the shaft sections area of risk amounted in all groups on average 42-55% (table 1). This confirms the uniformity of the surgical intervention.

Subsequent staining with triphenyltetrazolium under control-ischemia/reperfusion" zone of necrosis was 44,36%. With the introduction of zoniporide, IIA, IIB, Ia, IB, there is a significant decrease in the zone of infarction compared with "control-ischemia/reperfusion". Thus the studied compounds were surpassed zoniporide on their activity (table 1). Compound IIA statistically 1.4 times higher than the comparator drug.

When analyzing changes in the level of troponin I in the blood plasma of animals group "control-ischemia/reperfusion have shown a significant increase compared to linearizovannykh (table 1.). In experimental groups, a statistically significant reduction in a marker of damage to the group "control-ischemia/reperfusion was observed with the introduction of zoniporide, compounds IIA, Ia, IIB, IB 2.1, 2,5; 1,7; 1.9 and 1.5 times, respectively.

Table 1 shows the main indicators of the cardioprotective action of compounds Ia, IB and IIA, IIB model of ischemia/reparatii intravenous dose of 1 mg/kg

27,78±4,23*
Table 1
Key indicators cardioprotective actions in models of ischemia/reparatii when in trevenna the dose of 1 mg/kg
No.GroupnThe size of the area at risk (% in relation to the left ventricle)The size of the zone of necrosis (% relative to risk)The level of troponin I (PCG/ml)
1.Control-linopirdine60,00±0,000,00±0,00136,65±38,03
2.Control-ischemia/reperfusion753,20±4,9944,36±3,79528,32±81,32#
3.Control-zoniporide747,25±3,8234,87±2.57 m*252,76±72,05*
4.IIa546,33±3,224,10±1,47*$211,88±60,14*
5.Ia845,01±1,77316,55±62,34*
6.IIb451,09±between 6.0829,92±4,84*287,46±60,14*
7.IB546,04±5,2830,04±2,58*346,78±of 99.75*
#- value is statistically significant in regard to the group "control-linopirdine";
* - value is statistically significant in regard to the group "control-ischemia/reperfusion";
$- value is statistically significant in regard to the group "control-zoniporide".

3. Conclusions

Thus, in vivo studies in models of ischemia/reperfusion is shown in the cardioprotective effect of the studied derivatives of benzimidazole compounds Ia, IB and IIA, IIB.

It is shown that the compounds Ia, IB, IIB intravenous dose of 1 mg/kg statistically significantly in relation to the group "control-ischemia/reperfusion" reduce the size of the zone of necrosis of the myocardium and the level of troponin I in the blood on the model ish is MIA/reperfusion in rats providing an effect similar zoniporide.

Compound IIA with intravenous dose of 1 mg/kg statistically significantly superior to zoniporide influence on the size of the zone of necrosis of the myocardium and largely reduced the level of troponin I in the blood on the model of ischemia/reperfusion in rats.

1. Use as a cardioprotective means tricyclic derivatives of imidazo[1,2-a]benzimidazole of General formula I:

where Ar=C6H4OCH3-R, C6H4OH-p
NR2=N(CH2CH2)2O,
including
Ia Ar=C6H4OCH3-R; NR2=N(CH2CH2)2O
IB Ar=C6H4OH-R; NR2=N(CH2CH2)2O
or halides of 1,3-disubstituted 2-aminobenzimidazole General formula II:

where Ar=C6H4F-p, C6H3(O2CH2)-3,4
NR2=N(C2H5)2N(CH2CH2)O X=Cl, Br,
including
IIa Ar=C6H4F-R, NR2=N(CH2CH2)2O, X=Cl
IIb Ar=C6H3(O2CH2)-3,4, NR2=N(C2H5)2X=Br.

2. The use according to claim 1 for the manufacture of tools have cardioprotective effects, as well as to restore and improve cardioprotective functions in living organisms.

3. The halides of 1,3-disubstituted 2-iminobis imidazole General formula II:

where Ar=C6H4F-R6H3(O2CH2)-3,4
NR2=N(C2H5)2N(CH2CH2)O X=Cl, Br,
including
IIa Ar=C6H4F-p, NR2=N(CH2CH2)2O, X=Cl
IIb Ar=C6H3(O2CH2)-3,4, NR2=N(C2H5)2X=Br.



 

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27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to thieno[3,2-d]pyrimidine derivative of formula (I) or to its pharmaceutically acceptable salt: (I), where Y stands for -CH=CR1-, -C≡C- or -C(=O)NR1-; L stands for -C(=O)NR2-, -NR2C(=O)- or -NR2C(=O)NR2-; R1 and R2, each independently stands for H; R stands for H, a halogen atom, methyl or methoxy; E stands for phenyl or C3-10heteroaryl, which is non-substituted or substituted with 1-2 substituents, consisting of a group, which includes a halogen atom, -CF3, C1-6alkyl, hydroxy-C1-6alkyl, C3-8cycloalkyl, -(CH2)n-C1-6alkylamino, -(CH2)n-diC1-6alkylamino, -(CH2)nC1-6alkoxy, -(CH2)n-OS(=O)2-C1-6-alkyl, -(CH2)n-phenyl, -(CH2)n-C2-5heteroaryl and -(CH2)n-C4-6heterocycloalkyl, where C3-10heteroaryl represents pyridine, isoquinoline, indole or isoxazole, C2-5heteroaryl of radical -(CH2)n-C2-5heteroaryl represents imidazole or pyrrol, C4-6heterocycloalkyl of radical -(CH2)n-C4-6heterocycloalkyl represents piperazine, morpholine, diazepam, pyrrolidine or piperidine, and phenyl, heteroaryl and heterocycloalkyl each independently, is non-substituted or substituted with substituent selected from a group, which consists of C1-6alkyl, hydroxy-C1-6alkyl, a halogen atom and diC1-6alkylamino, n is equal to 0 or 1; and Z stands for H, -C(=O)R3, C1-6alkyl, hydroxyC1-6alkyl, C3-8cycloalkyl, piperidine, phenyl or pyridine, where piperidine, phenyl and pyridine, each independently, is non-substituted or substituted with C1-6alkyl, C1-6alkoxy or R3-piperazinyl and R3 represents C1-6alkyl or phenyl. The invention also relates to an intermediate compound for obtaining the claimed final compound of formula (I).

EFFECT: novel compound, which can be applied in medicine for the prevention or treatment of diseases, characterised by an anomalous growth of cells as a result of an excessive expression of proteinkinase, is obtained.

8 cl, 2 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is a group of inventions, which includes a method of treating a hyperproliferative disorder by introduction to a mammal of a therapeutic combination in the form of a combined composition or by alternation, and the therapeutic combination contains a therapeutically effective quantity of formula compound 4-(2-(1H-indasol-4-yl)-6-((4-(methylsulphonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine, or formula (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, or their stereoisomers, geometrical isomers, tautomers, or their salts and a therapeutically effective quantity of a chemiotherapeutic agent, selected from erlotinib, docetaxel, 5-FU, gemcitabine, PD-0325901, cisplatin, carboplatin, paclitaxel, bevacizumab, trastuzumab, pertuzumab, temozolomide, tamoxifen, doxorubicin, Akti-1/2, HPPD, rapamycin and lapatinib; a pharmaceutical composition of the same purpose and composition, application of the said therapeutic combination for manufacturing of medication for treatment of cancer, selected from breast cancer, cervical cancer, cancer of large intestine, endometrium, glioma, lung cancer, melanoma, ovarian cancer, cancer of pancreas and prostate, a product for treatment of a hyperproliferative disorder, including the said composition and an instruction and the product, containing the said combination for separate, simultaneous or successive application in treatment of a hyperproliferative disorder.

EFFECT: synergism of suppression of cell proliferation and regression of forms of cancer mentioned above.

45 cl, 52 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a compound having a structure according to formula I:

,

compositions containing the compounds of the above formula applicable to stimulate neurogenesis and/or inhibition of neuron degeneration.

EFFECT: invention may be used in treating diseases and conditions characterised by neuron loss and lower neurogenesis, including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury and depression.

8 cl, 2 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: a pharmaceutical combination for treatment of proliferative disease, which contains Hsp90 inhibitor ethamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid (AUY922) and mTOR inhibitor, representing everolimus (RAD001), a respective method of treating proliferative disease and a set for the same purpose.

EFFECT: synergic antiproliferative effect of the combination on cells of different types of cancer is demonstrated.

5 cl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the chemical-pharmaceutical industry and represents a method of obtaining a complex preparation for the application in veterinary, possessing immunomodulating and antiseptic properties, which includes mixing succinic acid, levamisole and formalin in distilled water with the following component ratio, wt %: levamisole - 3.0%-3.5%; succinic acid - 2.0%-2.5%; formalin - 0.3%-0.5%, distilled water - the remaining part; sterilisation of the solution by autoclaving is performed in a mode of 1 atm for 20 minutes.

EFFECT: elaboration of the method of obtaining the complex preparation for the application in veterinary, possessing immunomodulating and antiseptic properties.

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