Diaphragm-free electrosynthesis of substituted pyrido[1,2-a]benzimidazoles

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to method of obtaining 7-R-pyrido[1,2-a]benzimidazoles of general formula, , where a) R=CF3, R'=H; b) R=CN, R'=H; c) R=COOH, R'=H; d) R=COOCH3, R'=H; e) R=COOC2H5, R'=H; f) R=COOPh, R'=H; g) R=CF3, R'=CH3; h) R=CN, R'=CH3, which consists in the fact that reduction of N-(2-nitro-4-R-phenyl)-3,5-R'-pyridinium chlorides is carried out in mixture of alcohol and 4% hydrochloric acid, taken in ratio 1:1, by means of electric current in electrolyser without diaphragm in galvanostatic mode at temperature 40°C on lead cathode, with passing charge in 4 F for 0.5 h, current power 0.4 A through electrolytic cell, with application of platinum anode, target products are extracted by filtration of precipitated sediment after processing reaction mixture with ammonium hydroxide.

EFFECT: method of obtaining derivatives of pyrido[1,2-a]benzimidazoles, which can be applied as semi-products for synthesis of biologically active substances, demonstrating antioxidant activity, which finds application in field of optoelectronics, for example non-linear optics, has been elaborated.

8 ex

 

The invention relates to a method for synthesis of nitrogen containing heterocyclic compounds, in particular to the preparation of the substituted pyrido[1,2-a]benzimidazoles of the General formula

where (a) R=CF3, R'=H; b) R=CN, R'=H; R=COOH, R'=H; g) R=SOON3, R'=H; d) R=SOOS2N5, R'=H; (e) R=COOPh, R'=H; W) R=CF3, R'=CH3; W) R=CN, R'=CH3that can be used as intermediates for the synthesis of biologically active substances exhibiting antioxidant activity [N. G. Kathrotiya, Μ.P. Patel // J. Chem. Sci, 125, 5, 993-1001 (2013), as medicines against malaria [A. J. Ndakala, R. K. Gessner, P. W. Gitari, N. October, K. L. White, A. Hudson, F. Fakorede, M. D. Shackleford, M. Kaiser, C. Yeates, S. A. Charman, K. Chibale // J Med Chem, 54, 4581-4589 (2011)], antibacterial agents [B. S. Chetan, Hardik H. J., P. P. Manish, G. P. Ranjan // Med Chem Res, 22, 3035-3047 (2013)], antifungal agents [Η. Takeshita, J. Watanabe, Y. Kimura, K. Kawakami, H. Takahashi, M. Takemura, A. Kitamura, K. Someya, R. Nakajima // Bioorg. Med. Chem. Lett, 20, 3893-3896 (2010)] inhibitors of perforin [D. M. Lyons, K. M. Huttunen, K. A. Browne, et al // Bioorg. Med. Chem., 19, 4091-4100 (2011)]. In addition pyrido[1,2-α]benzimidazoles possess fluorescent properties [X. Chen, Η. Yang, Υ. Ge, L. Feng, J. Jia, J. Wang // Luminescence, 27, 382-389 (2012)], which finds application in optoelectronics, such as in nonlinear optics.

The closest in content is a method of producing substituted pyrido[1,2-a]benzimidazoles, based on the reduction of chloride� N-(2-nitro-4-R-phenyl)pyridinium in a diaphragm cell in galvanostatic mode at a lead cathode, at a current of 0.6 A. the Anolyte is 15% sulfuric acid solution, the anode is made of platinum. The substrate was dissolved in a mixture of ethanol and 4% hydrochloric acid, taken in the ratio 1:1. The electrolysis is carried out with stirring at a temperature of 40-45°C, passing through an electrolytic cell in charge 4 Φ for 0.5 h. the Yield of the target products 88-96% (Pat. No. 2522549 of the Russian Federation (2014)).

The disadvantages of this method of synthesis of substituted pyrido[1,2-a]benzimidazoles are use a diaphragm to separate the anode and cathode spaces in the electrolysis, which leads to an increase of the resistance of charge transfer and consequently increase the operating voltage on the electrode and the growth of electricity consumed, as well as a decrease in the rate of conversion of the substrate and the yields of target products. In addition, the use of the diaphragm, which is made of mechanically strong, chemically inert electrical insulator, thus having a small resistance, significantly complicates the design and cost of the cell.

The purpose of the invention is the creation bezdiafragmennoi electrochemical method of obtaining substituted pyrido[1,2-a]benzimidazoles, which allows to reduce the cost of synthesis and increase the yield of target products.

This object is achieved in that for the electroreduction of chloride 1-(2-nitro-4-R-phenyl)-3,5-R'-pyridinium and�uses the electrolytic cell without diaphragm. This reduces the strength of the current from 0.6 A to 0.4 A at the same temperature and the process time, as in the above method. As a result, also eliminates the need for the use of sulfuric acid serving as the anolyte in the diaphragm cell electrosynthesis, which increases the life of the equipment, due to the absence of corrosion, and decrease the amount of harmful waste. Moreover, the recovery is carried out in galvanostatic mode at a lead cathode at a current of 0.4 A, using a platinum anode. The substrate was dissolved in a mixture of ethanol and 4% hydrochloric acid, taken in the ratio 1:1. The electrolysis is carried out with stirring at a temperature of 40°C, passing through an electrolytic cell in charge 4 f for 0.5 h. the desired products excreted by filtration precipitated sludge after treatment of the reaction mixture of ammonium hydroxide.

Implementation of the proposed method of synthesis of substituted pyrido[1,2-a]benzimidazoles can reduce the strength of the current from 0.6 A to 0.4 A, to simplify the design of the cell and to obtain the desired products with the release of 91-98%.

The structure and purity of the intermediates and target products pyrido[1,2-a]benzimidazoles were analyzed by NMR1N-spectroscopy and mass spectrometry, mass spectrometry, high-definition, determination of melting point and elemental SOS�ava.

The invention is illustrated by the following examples.

Example 1. 7-(Trifluoromethyl)pyrido[1,2-a]benzimidazole (a). Electrochemical synthesis was carried out in bezdiafragmennoi cell in galvanostatic mode at a lead cathode with an area of 85 cm2the current is 0.4 A, the current density 4.71 mA/cm2. The anode is made of platinum. 1 g (3.34 mmol) of the chloride of 1-(2-nitro-4-(trifluoromethyl)phenyl)pyridinium was dissolved in 20 ml of ethanol was added 20 ml of 4% hydrochloric acid. The electrolysis is conducted with stirring at 40°C. having passed through an electrolytic cell in charge 4 Φ for 0.5 hours, the electrolysis was stopped, the electrolyte was podslushivaet 25% ammonia solution to pH=7-8, and the precipitate was filtered, yielding 0.74 g (96% of theory) of 7-(trifluoromethyl)pyrido[1,2-a]benzimidazole. So a MP 233-235°C.

The NMR spectrum1H (DMSO-d6) δ, MD: 7.09 t (1N, H2, J 7.0 Hz), 7.66 t (1N, H3, J 8.0 Hz), 7.68 (1H, H9, J 8.0 Hz), 7.75 (1H, H4, J 9.0 Hz), 8.16 (1H, H6, J 1.5 Hz), 8.53 DD, 1H, H8, J 2 Hz, J 8 Hz), 9.15 (1H, H1, J 7.5 Hz).

MS, m/z: 236 (100) [M]+, 217 (20), 186 (12), 167 (4), 118 (5), 69 (5), 63 (11), 51 (17), 39 (20).

Found, %: C 60.79; Η 2.96; N, 12.01.

Calculated, %: C 61.02; Η 2.97; Ν 11.86. C12H7N2

Examples 2-8. Other substituted pyrido[1,2-a]benzimidazoles prepared analogously to example 1.

Pyrido[1,2-a]benzimidazol-7-carbonitrile (b). The yield 0.69 g (94%). So a MP 242-244°C.

The NMR spectrum1H (DMSO-d6) δ, MD: 7.10 � (1H, N2, J 6.5 Hz), 7.67 t (1N, H3, J 7 Hz), 7.74 (1H, H4, J 9.5 Hz), 7.75 (1H, H9, J 8.5 Hz), 8.35 (1H, H6, J 1.5 Hz), 8.51 DD, 1H, H8, J 2.0 Hz, J 8.5 Hz), 9.15 (1H, H1, J 6.5 Hz).

MS, m/z: 193 (100) [M]+, 167 (6), 165 (4), 154 (4), 139 (9), 97 (9), 78 (8), 63 (7), 51 (12), 39 (15).

Found, %: C Is At 74.64; Η 3.60; N, 21.87.

Calculated, %: C Is At 74.61; Η 3.63; N, 21.76. C12H7N3.

Pyrido[1,2-a]benzimidazol-7-carboxylic acid (in). The yield 0.69 g (91%). T. PL. >300°C.

The NMR spectrum1H (DMSO-d6) δ, MD: 7.05 m (1H, H2), 7.60 t (1N, H3, J 8.5 Hz), 7.70 (1H, H4, J 9.0 Hz), 7.95 DD (1H, H8, J 2.0 Hz, J 8.0 Hz), 8.35 (1H, H9, J 8.0 Hz), 8.40 (1H, H6J 1.0 Hz), 9.10 (1H, H1, J 7.5), 12.85 (1H, COOH).

MS, m/z: 212 (100) [M]+, 167 (38), 140 (15), 78 (10), 51 (6).

Found, %: C Is At 68.21; Η 3.72; N, 13.24.

Calculated, %: C 67.92; Η 3.77; N, 13.21. C12H8N2.

Methyl pyrido[1,2-a]benzimidazol-7-carboxylate (g). The yield 0.71 g (92%). So a MP 226-228°C.

The NMR spectrum1H (DMSO-d6) δ, MD: 3.9 (3H, CH3), 7.03 t (1N, H2, J 7.5 Hz), 7.55 t (1N, H3, J 8.5 Hz), 7.68 (1H, H4, J 8.0 Hz), 7.94 DD (1H, H8, J 1.5, J 7.5 Hz), 8.37 (1H, H9, J 8.0 Hz), 8.39 (1H, H6, J 1.0 Hz), 9.08 (1H, H1, J 7.5 Hz).

MS, m/z: 226 (100) [M]+, 195 (86), 167 (74), 140 (31), 78 (34), 63 (29), 51 (37), 39 (22).

Found, %: C 68.97; Η 4.34; Ν 12.42.

Calculated, %: C 69.02; Η 4.42; Ν 12.39. C13H10N4O2.

Ethyl pyrido[1,2-a]benzimidazol-7-carboxylate (e). The yield 0.71 g (91%). So a MP 179-182°C.

JV�KTR NMR 1H (DMSO-d6) δ, MD: 1.38 m (3H, CH3), 4.35 m (2H, CH2), 7.02 t (1N, H2, J 7.5 Hz), 7.57 tons (1H, H3, J 8.5 Hz), 7.67 (1H, H4, J 8.5 Hz), 7.95 DD (1H, H8, J 1.5, J 8.0 Hz), 8.35 (1H, H9, J 8.0 Hz), 8.38 (1H, H6, J 1.0 Hz), 9.07 (1H, H1, J 8.0 Hz).

MS, m/z: 240 (100) [M]+, 195 (58), 167 (56), 140 (26), 78 (41), 63 (32), 51 (34), 39 (26).

Found, %: C 69.85; Η 4.98; Ν 11.72.

Calculated, %: 70.00; Η 5.00; Ν 11.67. C14H12N2O2.

Phenyl pyrido[1,2-a]benzimidazol-7-carboxylate (e). The yield 0.74 g (91%).T. PL 257 to 260°C.

Range HRMS, found: m/z 289.0963 [M+H]+; C18H13N2O2+; calculated: M=289.0972.

The NMR spectrum1H (DMSO-d6, δ, M. D., J/Hz): 7.08 (t, 1Η, N(4'), J=8); 7.34 (m, 3H, N(2), Η(2'), N(6')); 7.48 (t, 2H, N(3), N(5')); 7.64 (t, 1H, H(3)); 7.75 (d, 1H, H(4)); 8.12 (d, 1H, N(9), J=8.5); 8.48 (d. d, 1H, H(8), J=2.0, J=8.5); 8.60 (d, 1Η, N(6), J=1.5); 9.12 (d, 1Η, H(1), J=8.5).

2,4-Dimethyl-7-(trifluoromethyl)pyrido[1,2-a]benzimidazol (g). The yield 0.78 g (98%). So a MP 125-128°C.

Range HRMS, found: m/z 265.0952 [M+H]+; C14H12N2F3+; calculated: M=265.0947.

The NMR spectrum1H (DMSO-d6, δ, M. D., J/Hz): 2.32 (s, 3H, 2CH3); 2.53 (s, 3H, SN3); 7.29 (s, 1H, H(3), J=0.5); 7.60 (d. d, 1H, H(8), J=1.5, J=8); 8.13 (s, 1Η, N(6),J=1.5); 8.38 (d, 1H, N(9), J=8.5); 8.77 (s, 1H, H(1), J=0.5)

2,4-Dimethylpyridin[1,2-a]benzimidazol-7-carbonitrile (h). The yield 0.69 g (90%). So a MP 216-219°C.

Range HRMS, found: m/z 222.1037 [M+H]+; C14H12N3+; calculated: M=222.1026.

p> The NMR spectrum1H (DMSO-d6, δ, M. D., J/Hz): 2.32 (s, 3H, 2CH3); 2.53 (s, 3H, SN3); 7.32 (d, 1H, H(3), J=0.5); 7.64 (d. d, 1H, H(8), J=1.5, J=8); 8.24 (d, 1Η, N(6), J=1.5); 8.38 (d, 1Η, N(9), J=8.5); 8.77 (d, 1Η, H(1), J=0.5).

The method of obtaining substituted pyrido[1,2-a]benzimidazoles of the General formula

where (a) R=CF3, R'=H; b) R=CN, R'=H; R=COOH, R'=H; g) R=COOCH3, R'=H; d) R=COOC2H5, R'=H; (e) R=COOPh, R'=H; W) R=CF3, R'=CH3; W) R=CN, R'=CH3
namely, that the restoration of chlorides N-(2-nitro-4-R-phenyl)-3,5-R'-pyridinium carried out in a mixture of ethanol and 4% hydrochloric acid, in the ratio 1:1, with the help of electric current in an electrolytic cell without diaphragm in a galvanostatic mode at a temperature of 40°C in the cathode lead, while passing through an electrolytic cell in charge 4 Φ for 0.5 h, a current of 0.4 A, using a platinum anode, target products are distinguished by filtration precipitated sludge after treatment of the reaction mixture of ammonium hydroxide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula

,

having Aβ42 secretion inhibiting activity. In formula I , hetaryl I is a five- or six-member heteroaryl group containing 1-3 heteroatoms selected from O, S or N, hetaryl II is a five- or six-member heteroaryl group containing 1-3 heteroatoms as defined above for hetaryl I, or is a bicyclic ring system containing 1-4 heteroatoms selected from S, O or N, where at least one ring is aromatic by nature, R1 is C1-7-alkyl, C1-7-alkoxy, C1-7-alkyl substituted with a halogen, or a halogen; R2 is a halogen, C1-7-alkyl, C1-7-alkoxy, hydroxy, C1-7-alkyl substituted with a halogen, C1-7-alkyl substituted with a hydroxy, or benzo[1,3]dioxolyl or is -(CHR)p-phenyl, optionally substituted with a halogen, C1-7-alkyl, C1-7-alkoxy, S(O)2-C1-7-alkyl, cyano, nitro, C1-7-alkoxy substituted with a halogen, dimethylamino, -(CH2)p-NHC(O)O-C1-7-alkyl or C1-7-alkyl, substituted with a halogen. The values of radicals R, R3, R4,p, n, m, o are given in the claim.

EFFECT: invention relates to a method of producing said compounds, a medicinal agent containing said compounds and a method of treating Alzheimer's disease, cerebral amyloid angiopathy, Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), vascular dementia, dementia pugilistica or Down syndrome, associated with β amyloid activity.

21 cl, 283 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds, which possess an inhibiting activity with respect to anti-apoptotic Bcl-2 proteins. The invention also relates to a pharmaceutical composition, containing the said compounds, and to a method of treating urinary bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukaemia, colorectal cancer, oesophageal cancer, hepatocellular cancer, lymphoblast leukosis, follicular lymphoma, lymphoid malignant diseases of a T-cell or B-cell origin, melanoma, myelogenous leukaemia, myeloma, oral cavity cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small-cell lung cancer or spleen cancer.

EFFECT: obtaining the compounds, possessing the inhibiting activity with respect to anti-apoptotic Bcl-2 proteins.

4 cl, 5 tbl, 405 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

Ethinyl derivatives // 2553461

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives 1-4 having the general structural formula: , where 1 - R=CH3, 2 - R=CH2CH3, 3 - R=CH2CF3, 4 - R=CH(CH3)2, characterised by that 6,7-diethoxy-3,4-dihydro-1-(3,4-diethoxybenzoyl)isoquinoline is mixed with methyl propiolate and methane, or ethanol, or 2,2,2-trifluoroethanol, or isopropanol and stirred at temperature of +50°C, the precipitate obtained at the end of the reaction and after removing reagents, is crystallised in ether.

EFFECT: method of producing derivatives which can be used as intermediate compounds when producing biologically active compounds.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to dihydroazol compounds of formula (I) wherein R1 means a C1-C6alkyl or C1-C6haloalkyl; X means a phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C12alkyls, C3-C10cycloalkyls, C1-C12haloalkyls, C2-C12alkenyls, C2-C12haloalkenyls, C1-C12alkinyls or C1-C12haloalkynyls; A1 means hydrogen, and A2 means CR7R8; G means G-1 or G-2; B1, B2, B3, B4 and B5 independently mean N or C-R9; Y means Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8 or Y-9 (as it is presented in the patent claim); R2, R3 independently mean hydrogen, C1-C12alkyl, C1-C12haloalkyl, thio-C1-C12alkyl, C1-C12alkylthio-C1-C12alkyl, hydroxy-C1-C12alkyl, C1-C12alkoxy-C1-C12alkyl, C2-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl, C3-C10cycloalkyl; R4 independently means hydrogen, C1-C12alkyl, C1-C12haloalkyl, thio-C1-C12alkyl, C1-C12alkylthio-C1-C12alkyl, hydroxy-C1-C12alkyl, C1-C12alkoxy-C1-C12alkyl, C2-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl or C3-C10cycloalkyl; R7 and R8 independently mean hydrogen, C1-C12alkyl or C1-C12haloalkyl; R9 means hydrogen, halogen, C1-C12alkyl, C1-C12haloalkyl, C1-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl or C2-C12haloalkynyl; each R10, R11, R12 and R13 independently means hydrogen, C1-C12alkyl or C1-C12haloalkyl; or R10 together with R11 form =O, =S or =NR2; or R12 together with R13 form =O, =S or =NR2; n=1. The invention also refers to compositions for treating or preventing endoparasitic infections or ectoparasitic invasions in animals and for protecting crops, plants, planting stock or timber against pests, to a method of treating or preventing endoparasitic infections or ectoparasitic invasions in animals, to a method for protecting crops and growing plants against pest attacks or invasions, to a method for preventing or controlling a pest invasion on site, and to using the compounds of formula (I).

EFFECT: compounds of formula (I) applicable for preventing or treating endoparasitic infections or ectoparasitic invasions in animals, and also as pesticides

30 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

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

5 cl, 7 tbl, 35 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

Up!