Antituberculous therapeutic agent: composition of imidazo[1,2-b]tetrazine and pyrazinamide

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

EFFECT: there are prepared new antituberculous therapeutic agents.

2 cl, 2 tbl, 6 ex

 

The technical field to which the invention relates

The invention relates to medicine, in particular to the pharmacy, and relates to pharmaceutical compositions having anti-TB activity and containing as the active ingredient along with pyrazinamide new connection 6 benzylthio-3-(3,5-dimethylpyrazole-1-yl)imidazo[1,2-b][1,2,4,5]tetrazin or known derivatives of imidazo[1,2-b][1,2,4,5]tetrazine-containing tetrazepam cycle 3,5-dimethylpyrazole fragment and 6 phenylthio - or 6-isopropylthiazole imidazole in the loop with pyrazinamide.

The level of technology

From tuberculosis annually about 2-3 million people worldwide. [Corbett E. L, C. J. Watt, N. Walker et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic, / / Arch. Intern. Med. 2003. V. 163. No. 9. P. 1009-1021]. One of the reasons for the difficulties of treatment of tuberculosis is currently the mass emergence of multidrug resistance (MDR) Mycobacterium tuberculosis. To the emergence of MDR strains often leads untimely interrupted treatment or poorly-chosen course of chemotherapy. Among MDR strains are particularly dangerous strains with extensively drug-resistant (XDR), resistant 4-9 drugs [G. Sotgiu et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. // Eur. Respir. J. 2009. Vol.33, No. 4. Pp.871-88111 PP.]. Mortality among patients with tuberculosis caused by such strains, despite �dorogostoyashie and a long course of treatment, up to 50% [Shenoi S., Friedland G. Extensively drug-resistant tuberculosis: a new face to an old pathogen. // Annu. Rev. Med. 2009. Vol.60. Pp.307-32014 pp.].

In most cases, the emergence of drug resistance, including pyrazinamide, associated with the occurrence of point mutations in certain codons of the genes encoding the target of the antibiotic. However, in recent years, increasing numbers of cases of resistance of bacteria to antibiotics that are not associated with known mutations that cannot be detected with standard molecular genetic techniques. Sustainability can be achieved by switching of bacterial cells in a latent state, with persistent forms of education, characterized by hypometabolism [Parrish N. M., Dick, J. D., W. R. Bishai Mechanisms of latency in Mycobacterium tuberculosis // Trends in Microbiology. 1998. Vol.6, No. 3. Pp.107-1126 pp; W. Shi, Y. Zhang Pho Y2 but not Pho Y1 is the Pho U homologue involved in persisters in Mycobacterium tuberculosis // Journal of Antimicrobial Chemotherapy. 2010. Vol.65, No. 6. Pp.1237-12426 pp]. Latent state, in turn, gives the bacteria the ability to survive under adverse conditions, and then, with the weakening of the immune systems of the body, to start the reproduction with the subsequent emergence of drug resistance. Pyrazinamide is one of the drugs that are active against these latent forms [W. Shi et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. // Science. 2011. Vol.333, No. 6049. Pp.1630-16323 pp.].

To expand tera�efticiency strategies for the treatment of tuberculosis is possible to exploit the synergies known anti-TB drugs and drugs with a new mechanism of action. Compounds currently used in the pharmaceutical industry, can be used for the treatment of tuberculosis, including MDR - SHL-strains for which there are no effective methods of treatment. Currently work is underway to search for compositions of compounds having a synergistic effect. Their use significantly reduces the probability of formation of resistant forms, as well as reduces the toxic effects of the compounds against the human body [Ramón-García S, Ng C, Anderson H, Chao JD, Zheng X, Pfeifer T, Av-Gay Y, Roberge M, Thompson CJ. Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen. Antimicrob Agents Chemother. 2011 Aug; 55(8):3861-9]. The problem of overcoming drug resistance of mycobacteria is complicated by poor tolerability sick of these funds. Therefore, the creation of more effective anti-TB drugs, including on the basis of known drugs and new, with a synergistic effect, is a priority of chemistry and pharmacy.

Solved problem: the Search for anti-TB drugs, active against strains with multiple drug resistance.

6 Benzylthio-3-(3,5-dimethylpyrazole-1-yl)imidazo[1,1-b][1,2,4,5]tetrazin disclosed in the present invention is a new, previously undescribed connection. The method thereof is described [Thickness S. G., Ishmetova R. I., N. Ignatenko.To.,Coratina A. V., Ganebnyh I. N., Olszewski V. A. Kalinin, V. N., Rusyns G. L. Interaction 1,2,4,5-tetrazines with the S-nucleophile Izv. An. Ser. chem. 2011. No. 5. S. 961-967]. 6-R-3-(3,5-Dimethylpyrazole-1-yl)imidazo[1,2-b][1,2,4,5]tetrazine (R=SPh, SPri) as described previously [Izv. An. Ser. chem. 2011. No. 5. S. 961-967; RF Patent 2462466, 27.09.2012].

Known activity of derivatives imidazo[1,2-b][1,2,4,5]tetrazine against protein kinases PknA and PknB Mycobacterium tuberculosis [RF Patent 2462466, 27.09.2012]. Antitubercular activity of imidazo[1,2-b][1,2,4,5]tetrazines not known and is not described.

Used in the invention pyrazinamide is widely used in medical practice, drug. Amide pyrazinecarboxamide acid (pyrazinamide) has a bactericidal action against persistent forms of mycobacteria [W. Shi, Y. Zhang Pho Y2 but not Pho Y1 is the Pho U homologue involved in persisters in Mycobacterium tuberculosis // Journal of Antimicrobial Chemotherapy. 2010. Vol.65, No. 6. Pp.1237-12426 pp].

Identified empirically the ability of the announced imidazo[1,2-b][1,2,4,5]tetrazines in combination with pyrazinamide multiply the antibacterial action. The minimum inhibitory concentration of the claimed compositions of the present invention for MDR-strain MS office-115 amounted to 1.0 to 2.0 μg/ml. Minimum inhibitory concentration of pyrazinamide for these strains 200 μg/ml. Thus, the activity of the composition against Mycobacterium increased to 200 times. Sub-lethal concentration� imidazo[1,2-b][1,2,4,5]tetrazines and pyrazinamide in mice LD 50=499 mg/kg and 1680 mg/kg, respectively. Reduce the dose of each of the substances in the composition leads to a decrease in toxic effects used combinations of drugs.

Disclosure of invention

The object of the invention is the use as anti-TB medicines compositions in the composition used in the practice of medicine pyrazinamide acting on latent forms of mycobacteria and means of a new mechanism of action, derived imidazo[1,2-b][1,2,4,5]tetrazine formula I, where R = benzyl, as well as compositions known derivatives of imidazo[1,2-b][1,2,4,5]tetrazine General formula I, where R = isopropyl or phenyl with pyrazinamide, with a molar ratio of 1:1.

Imidazo[1,2-b][1,2,4,5]tetrazine provided in the present invention, can be obtained using known methods for the synthesis of [Thickness S. G., Ishmetova R. I., N. Ignatenko.To., Coratina A.V., Ganebnyh I. N., Olszewski V. A. Kalinin, V. N., Rusyns G. L. Interaction 1,2,4,5-tetrazines with the S-nucleophile Izv. Academy of Sciences, Ser. chem. 2011. No. 5. S. 961-967]. derivatives and 6-(alkylthio)imidazo[1,2-b][1,2,4,5]tetrazines [Izv. An. Ser. chem., 2011, 5].

Examples of specific performance:

Example 1: the Composition of pyrazinamide with 3-(3,5-dimethylpyrazole-1-yl)-6-(phenylthio)imidazo[1,2-b][1,2,4,5]tetrazin (1R)

323 mg of 3-(3,5-Dimethylpyrazole-1-yl)-6-(phenylthio)imidazo[12-b][1,2,4,5]tetrazine and 123 mg of pyrazinamide, placed in a round bottom flask with 5 ml of chloroform, and the solution was stirred for 5 minutes and the solvent was distilled off under reduced pressure on a rotary evaporator.

Example 2: the Composition of pyrazinamide with 3-(3,5-dimethylpyrazole-1-yl)-6-(isopropylthio)imidazo[1,2-b][1,2,4,5]tetrazin (2P)

Prepared analogously to example 1 from 289 mg of 3-(3,5-dimethylpyrazole-1-yl)-6-(isopropylthio)imidazo[1,2-b][1,2,4,5]tetrazine and 123 mg of pyrazinamide.

Example 3: 6-(Benzylthio)-3-(3,5-dimethylpyrazole-1-yl)imidazo[1,2-b][1,2,4,5]tetrazin(3)

The output is 57%. So a MP 139-140°C. Found (%): C, 56.96; H, 4.48; N, 29.06. C16H15N7S.

Calculated (%): C, 56.93; H, 4.78; N, 28.82. The NMR spectrum1H (CDCl3, δ, M. D.): 2.40, 2.72 (both with, 3H, 2Me in pyrazoline); 4.26 (s, 2H, CH2); 6.18 (s, 1H, H(4) in pyrazoline); 7.17-7.26 (m, 5H, 5C in SPh); 8.16 (s, 1H, CH).

Example 4: the Composition of pyrazinamide with 6-(benzylthio)-3-(3,5-dimethylpyrazole-1-yl)imidazo[1,2-b][1,2,4,5]tetrazin(3P)

Prepared analogously to example 1 from 337 mg of 6-(benzylthio)-3-(3,5-dimethylpyrazole-1-yl)imidazo[1,2-b][1,2,4,5]tetrazine and 123 mg of pyrazinamide.

Example 5: Activity of the compositions of the substances in the test system of Mycobacterium smegmatis mc2155

To determine the activity of the compositions in the test system of Mycobacterium smegmatis mc2155 method was used paper discs. The methodology was to determine the minimum concentration of a substance at which the disk appears a zone of inhibition of growth of the strain, susianna�about lawns on agar medium.

Minimum inhibitory concentration for 1P - 2,23 μg/disc (5 nmol), 2P - 6.18 of μg/disk (15 nmol), 3P - a 46.1 ág/disc (50 nmol).

Table 1
Minimum inhibitory concentration of the compositions against M. smegmatis mc2
CipherStructure molecular weightM. smegmatis mc2
MICK, nmol/disk
1p5
110
2P15
210
3P50
350

Example 6. Activity of agents against Mycobacterium tuberculosis �LOU-strain MS-115.

Antimycobacterial activity of the tested compounds was studied by the dynamics of growth of strain MS-115 enriched in the liquid medium Middlebrook 7H9 in the presence of various concentrations of the compounds in comparison with the growth of the strain on the environment, containing no drugs, and a medium containing a control drugs. The MDR strain MS-115 rifampicin resistant (1 μg/ml), isoniazid (0.1 μg/ml), streptomycin (0.1 mg/ml), ethambutol (5 μg/ml), pyrazinamide (100 μg/ml) [Matyugina E, Khandazhinskaya A, Chernousova L, Andreevskaya S, Smirnova T, A Chizhov, I Karpenko, Kochetkov S, L. Alexandrova The synthesis and antituberculosis activity of 5'-nor carbocyclic uracil derivatives. Bioorg Med Chem. Nov 2012 15; 20(22):6680-6686].

Detection of growth of a culture of mycobacteria was performed using the automated system of crop growth Bactec MGIT 960 (BD, USA) every hour with Epicenter software (BD, USA). The experiment duration is 42 days. Minimum inhibitory concentration of the compositions shown in table 2.

Table 2
Minimum inhibitory concentration of the compositions against M. tuberculosis MDR-strain MS-115.
CipherM. tuberculosis MS-115
MIC, mcg/ml
1p<1
11
2p2
21
31

1. Individual chemical compound described by formula I, where R=benzyl.

2. Anti-TB drug, which is a composition derived imidazo[1,2-b][1,2,4,5]tetrazine General formula I, where R=benzyl, isopropyl or phenyl and known antituberculous drug pyrazinamide in a molar ratio of 1:1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining cyclic guanidine, which can be applied in coating compositions, in particular in electrically precipitated coating compositions. Method includes reaction of (i) cyanamide, (ii) polyamine and (iii) weak acid with 5.0<pKa<13.5. Invention also relates to method of obtaining polymer resin and method of obtaining cyclic guanidine, containing 6-membered ring.

EFFECT: claimed method makes it possible to reduce amount of wastes in production of cyclic guanidines.

18 cl, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula (I), which possesses phosphodiesterase 10 inhibitory activity. In formula (I), R1 represents hydrogen, halogen or lower alkyl; the ring A represents optionally substituted 6-10-merous monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as heteroatoms, or a group containing a cycloaliphatic 6-merous ring condensed with the above heteroaryl, which is specified in 6-merous cycloalkane and aliphatic 6-merous heterocyclic ring containing an oxygen atom; the ring B represents optionally substituted 4-6-merous monocyclic nitrogen-containing group, which can additionally contain an oxygen atom or a 3-6-merous monocyclic hydrocarbonic group, which can be optionally saturated; R3 represents hydrogen; lower alkyl optionally substituted by a substitute specified in lower alkoxy; or lower cycloalky. The R2,Y radicals, as well as substitutes of the rings A and B are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compound, to a method of treating or preventing schizophrenia, anxiety disorders, drug addiction, disorders with a symptom of cognition deficiency, affective disorder or mood episode, each of which is mediated by phosphodiesterase 10 activity.

20 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in general formula , fragment A is specified in a group consisting of , or , R1, R3, R4 and R5 mean hydrogen or alkyl; each of R4a and R5a represents hydrogen; G1 represents aryl or heteroaryl, which can by unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl, halogen, cyano, -OR1b, -S(O)R2b, -C(O)R1b, -C(O)OR1b, -OC(O)N(Rb)(R3b), -(CR4bR5b)m-OR1b, -C(OH)[(CR4bR5b)m-R4b]2, and halogenalkyl; G2 means cycloalkyl, cycloalkenyl or heterocycle unsubstituted or substituted by 1, 2, 3, 4 or 5 substitutes specified in a group consisting of alkyl; Rb represents hydrogen or alkyl; R1b and R3b represents hydrogen, alkyl or halogenalkyl; R2b represents alkyl; R4b and R5b represents hydrogen, halogen, alkyl or halogenalkyl; m represents 1, 2, 3, 4 or 5; R2 is specified in a group consisting of hydrogen, alkyl, -(CR4aR5a)m-G1 and -S(O)2R6, R6 represents G1, X1 means N or CR9; X2 means N or CR10; X3 means CR11; X4 means N or CR12; provided one fragment of X1, X2 or X4 can represent N; each of R9, R10, R11, R12, R13 and R14 independently represents hydrogen, alkyl, alkenyl, halogen, -G1, -G2, -OR1a, -C(O)G3, -C(O)OR1a, -C(O)N(Rb)(R3a), -N(Rb)(R3a), -(CR4aR5a)m-G1, -CR4a=CR5a-G1, -(CR4aR5a)m-G2, -CR6a=C(R7a)2, halogenalkyl and fragment ; R1a and R3a represents hydrogen, alkyl, haloalkyl, G1, -(CR4aR5a)m-G1, G2 or -(CR4aR5a)m-G2; R6a is alkyl or halogenalkyl; R7a represents hydrogen, alkyl or helogenalkyl; G3 represents heterocycle attached to an adjoining carbonyl fragment through a nitrogen atom being a part of heterocycle; or R10 and R11 or R13 and R14 together with carbon atoms which they are attached to, form unsubstituted phenyl or cycloalkyl; Y1 means NR17, CR18R19, C(O), S(O)n or O; Y2 means NR20, CR18R19 or C(O); Y3 means NR17, CR18R19 or C(O); or Y1 and Y2 together represent CR18=CR19, n means 2; R17 represents hydrogen; R18 and R19 represents hydrogen; and R20 is specified in a group consisting of hydrogen, alkyl and -S(O)n-G1.

EFFECT: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a 5-HT2C and/or 5-HT6 receptor modulator, to a based pharmaceutical composition and to methods for preparing them.

33 cl, 7 tbl, 20 dwg, 278 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.

15 cl, 4 tbl, 452 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

Jak inhibitors // 2538204

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I wherein R means C1-6alkyl, C1-6halogenalkyl, hydroxy-C1-6alkyl, hydroxygroup or halogen; m, n is equal to 0 or 1; Z1 means CH or NH; Z2 means CH or N; Z3 means CR1, N or NR2; R1 means H, C1-6alkyl, C3-7cycloalkyl, cyanogroup, cyano-C1-6alkyl or halogen; R2 means H or C1-6alkyl; X means CH, CR' or N; X' means CH, CR' or N; r is equal to 1; Y means CH or CR'; R' means R'a or R'b; R'a means a halogen or cyanogroup; R'b means C1-6alkyl, heterocycloalkyl specified in piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, OR", SR", S(=O)2R" or NR"R", optionally substituted by one or more R'c; R'c means a hydroxygroup, oxogroup, cyanogroup, C1-6alkyl, pyridinyl, carboxy-C1-6alkyl, aminocarbonyl-C1-6alkylaminogroup, C1-6alkylaminogroup, C1-6dialkylaminogroup or C1-6alkoxygroup; R" means H, C1-6alkyl, hydroxy-C1-6alkyl, piperidinyl, C3-7cycloalkyl or pyridinyl; Q means S(=O)2Q1, C(=O)Q2, C(=O)OQ3 or Q4; Q1 means C1-6alkyl, C3-7cycloalkyl-C1-6alkyl, C1-6alkylaminogroup or C1-6dialkylaminogroup optionally substituted by one or more Q1'; each Q1' independently means C1-6alkyl or cyanogroup; Q2 means C1-6alkyl optionally substituted by one or more Q2'; each Q2' independently means a cyanogroup; Q3 means C1-6alkyl; Q4 means C1-6alkyl, oxetanyl optionally substituted by one or more Q4'; each Q4' independently means a halogen, cyanogroup, cyano-C1-6alkyl; p is equal to 0, 1 or 2; q is equal to 1 or 2; each means a single bond or a double bond; provided one of Z1 and Z2, and Z3 and Z3 bonds are double and single.

EFFECT: compounds of formula I as JAK inhibitors.

23 cl, 2 tbl, 121 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically 4-((2-hydroxyethoxy)methyl)-5-methyl-2-methylmercapto-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one of formula (I) . The invention also relates to a method of producing and using said compound to treat West Nile fever.

EFFECT: obtaining a novel compound with useful biological activity.

3 cl, 2 tbl, 4 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A represents CRaRb or -CH2-CH2-; R1 represents hydrogen or alkyl; R2 represents hydrogen or alkyl; R3 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, 1H-pyrazolyl or substituted 1H-pyrazolyl, wherein substituted aryl represents aryl substituted by 1-3 substitutes independently specified in alkyl, halogen and halogenalkyl, and wherein substituted 1H-pyrazolyl represents 1H-pyrazolyl substituted by 1-3 substitutes independently specified in alkyl and aryl; Ra represents hydrogen or methyl; Rb represents hydrogen or methyl; or Ra and Rb together with a carbon atom, to which they are attached, form cyclopropyl, cyclobutyl or cyclopentyl; provided Ra and Rb both represent hydrogen, or both represent methyl simultaneously, R3 represents (1-methylcyclopropyl)methyl, which possess the inhibitory action on 11b-HSD1.

EFFECT: preparing the compounds, which possess the inhibitory action on 11b-HSD1.

15 cl, 1 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to application of 2-R1-4-R2-6-polynitromethyl-1,3,5-triazines of general formula: , where n=0, X=NO2, Cl, Br, R1=R2=OR3, OAr (R3=CH3, C2H5, CH2(CH2)6CH3, CH2CH2Cl, Ar=metha-C6H4CH3), R1=OR3, OAr, R2=N(C2H5)2; n=1, X=Cl, R1=OR3, R2=NH(CH2)2NH2, N(CH2CH2)2NCH3 as compounds, which possess antibacterial activity.

EFFECT: identification of compounds based on 1,3,5-triazine derivatives, which possess high antibacterial activity.

3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to mixture of E- and Z-isomers of (4-bromophenyl)ethylidene hydrazide of 2-[6-methyl-1-(thiethan-3-yl)uracyl-3-yl]acetic acid in molar ratio 3.5:1 of general formula: .

EFFECT: obtained is novel mixture of isomers, demonstrating hypotensive activity.

2 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to nitroimidazooxazine derivatives of general formula I, where n equals 1, V and W independently denote H or CH3, and one of X and Y is H and the other is one of the formulae and , where formula IIa includes a single ring labelled at position 3 and position 4 and containing R1 as a substitute, and formula IIb includes a first ring labelled at position 3 and position 4 and containing as substitutes both R2 and a terminal ring, labelled at position 4 and containing R1 as a substitute, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb include C, CH, or N at each ring position, where the single ring of formula IIa and the first ring and the terminal ring of formula IIb independently contain no more than two nitrogen atoms; Z in formulae IIa and IIb is CH2 or a direct bond, R1 is independently any one or two of H, F, C1, CF3, OCF3 or OCH2Ph, and R2 is H. The invention also relates to a pharmaceutical composition based on the compound of formula I, a method of preventing and treating a microbial infection based on use of the compound of formula , and specific nitroimidazooxazine derivatives.

EFFECT: obtaining novel compounds with useful biological activity.

7 cl, 21 dwg, 3 tbl

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