Method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine, represented by the general formula : where X=O or S, Ar=3-nitrophenyl or 2-thienyl. The described method consists in the fact that at the first stage 5-brom-4-(2-thienyl)-2-(thio)morpholylpyrimidine is obtained by interaction with the excess of 2-thienyllithium in the absolute ether at first at a temperature from -20 to -25°C for not less than 1 hour, and then at room temperature for not less than 18 hours, a solution of a mixture of potassium hexacyonoferrate (III) and potassium hydroxide in water are added with further mixing for 4 hours at room temperature, the ether phase is separated and distilled and the obtained remaining part is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate-hexane, 1:3, with (het)arylboric acid and tetrakis(triphenyphosphine)palladium(0) in tetrahydrofurane, a water solution of potassium carbonate is added and the obtained mixture is irradiated by microwave radiation at 155°C for 20 minutes, the solvent is distilled under a reduced pressure, the obtained residual is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate - hexane, 1:2 with obtaining the target product.

EFFECT: claimed is the highly-efficient two-stage method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidines, which can have a wide spectrum of biological activity.

4 ex

 

Area of technology

The present invention relates to 2-thio(morpholyl)-4,5-di(het)arylamidine the pyrimidines which possess broad spectrum of biological activities such as herbicidal and antibacterial, regulate the activity of specific proteins, such as ATON-1 that affect transcription factors and is involved in the formation of neurons, effects on epidermal growth factor (Epidermal growth factor - EGF), stimulating cell growth and cellular differentiation of epithelial cover, can be used in the treatment neurodegerative diseases, cognitive disorders and Alzheimer's disease.

The prior art also:

The main method of obtaining 2-thio(morpholyl)-4,5-di(het)arylamidine pyrimidines (3) is the condensation of (thio)morpholinosydnonimine (1) with 1,2-(het)aryl-3-dimethylaminopropanol (2) (Scheme 1) [WO 2012/055942. Alpha-7 nicotinic receptor fort he trtreatment of pain, a psychotic disorder, cognitive impaiment or alzheimer's desease. / Dean D. A. Lightfoot, Roomans S.]

The disadvantages of this method are: 1) low availability of source (thio)morpholinosydnonimine (1) and 1,2-(het)aryl-3-dimethylaminopropane (2), so that the necessary preliminary laborious multistep synthesis; 2) low total output of 2-thio(morpholyl)-4,5-di(het)arylamidine pyrimidines (3) are�s on average 20-40%.

Also known a method of producing 2,4,5-three(het)arylamidine pyrimidines (4) by a direct modification of 2-chloro-4,5-di(het)arylamidine pyrimidines using palladium catalyzed reactions with secondary amines to form the corresponding 2-dialkylamides 4,5,6-tripalmitin (5), and with the help of cross-combinations with Suzuki (het)airborne acids, with formation of the corresponding 2,4,5,6-tetras(het)arylamidine pyrimidines (6) in an organic solvent (1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile) at 80-100°C (Scheme 2) [WO 2012/172043. Purine derivatives and their use as pharmaceuticals for prevention or treatment of bacterial infections. / Denis A., Gerusz V., Ledoussal B., Bonvin Y., Desroy N., Gold, J., Moreau F., Oxoby M.]. The main disadvantage of this method is the long time of reactions - 16-48 hours.

Thus, the existing methods are multi-stage, require complicated preliminary synthesis of the starting compounds and time of reactions.

Object of the invention is to synthesize compounds having biological activity, from readily available raw materials, mild conditions, high yield.

The problem is solved in that in the first stage receive 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl (10A, b) interfaced as�eating 5-bromo-2-(thio)morpholinomethyl (7a, (b) with excess 2-titillate (8) in absolute ether, first at -20÷-25°C for at least 1 hour and then at room temperature for 18 hours, the mixture was added a solution of hexacyanoferrate(III) potassium and potassium hydroxide in water and stirred for at least 4 hours at room temperature, the ether phase is separated and distilled off and the obtained residue was subjected to chromatographic separation on silica gel at a ratio in eluent ethyl acetate-hexane 1:3,

and in a second step the obtained 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl mixed with (het)kilborne acid and tetrakis(triphenylphosphine)palladium(0) in tetrahydrofuran, is added an aqueous solution of potassium carbonate and the resulting mixture was irradiated with microwave radiation at 155°C for 20 minutes, the solvent was distilled off under reduced pressure, the obtained residue is subjected to chromatographic separation on silica gel at a ratio in eluent ethyl acetate-hexane 1:2.

Conducting the reaction of 5-bromo-2-(thio)morpholinomethyl (7a, b) with excess 2-titillate (8) in absolute ether is carried out in the temperature range -20÷-25°C for at least 1 hour, because the increase in temperature leads to the decomposition of the 2-titillate (8) and a sharp decline in the output of intermediate 5-bromo-4-(2-thienyl)-2-(thio)morpholin-1,2-dihydropyrimidine (9a, b), inturn reducing the temperature below -25°C leads to a significant increase in time of reaction. Reaction time 1 h -20÷-25°C and 18 hours at room temperature sufficient to complete the reaction of accession, whereas its reduction by any of the temperatures also leads to a reduction of output of intermediate 5-bromo-4-(2-thienyl)-2-(thio)morpholin-1,2-dihydropyrimidine (9a, b).

After the formation of 5-bromo-4-(2-thienyl)-2-(thio)morpholin-1,2-dihydropyrimidine (9a, b) in the reaction mixture was added a solution of the mixture of hexacyanoferrate(III) potassium and potassium hydroxide in water and stirred for at least 4 hours at room temperature, because the time of reaction less than 4 hours does not ensure complete oxidation of the intermediate 5-bromo-4-(2-thienyl)-2-(thio)morpholin-1,2-dihydropyrimidine (9a, b) to target 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl (10a, b), i.e. reduces its output.

The selection of the product (10a, b) is carried out by chromatographic separation on silica gel at a ratio in eluent ethyl acetate-hexane 1:3. The increase of this ratio in favor of hexane lead to unnecessary consumption of solvent, whereas the increase in the proportion of ethyl acetate in Buente not happening selective separation of the target product (10a, b) from the side of impurity.

After cleaning in the second stage, the reaction of 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl (10a, b) with (het)kilborne acid (11 or 12) occurs at 155°C for 20 �minutes. This temperature is optimal. Time 20 minutes is enough for the reaction, the increase in time does not significantly increase the yield of the desired 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholinomethyl (I), while reducing the time less than 20 minutes leads to a decrease in the yield of product (I).

The selection of the product (I) is carried out by chromatographic separation on silica gel at a ratio in eluent ethyl acetate-hexane 1:2. The increase of this ratio in favor of hexane lead to unnecessary consumption of solvent, whereas the increase in the proportion of ethyl acetate in Buente not happening selective separation of the target product (I) from incidental impurities.

The analysis of the intermediate and target compounds is carried out using NMR spectroscopy (NMR Spectra of1H and13C measured on a Bruker AVANCEIII-500 (500 and 126 MHz) in a solution of CDCl3, internal standard TMS). Full assignment of signals was1H and13C is made using a combination of 2D experiments1H-1H COSY,1N13C HSQC/NMS), gas chromatography/mass spectrometry (Gas chromatograph-mass spectrometer Agilent GC A MS C Inert XL EI/CI with quadrupole mass spectrometric detector) and elemental analysis on an automatic analyzer Perkin-Elmer PE-2400.

Example 1

To a solution of 5-bromo-2-morpholin�of rimidine (7a) 732 mg (3 mmol) in absolute ether at -30°C is added an excess of 2-titillate (2) 405 mg (4.5 mmol) in 20 ml of absolute ether. The reaction mixture was stirred at -20°C for 1 hour, then stop cooling and stirring continued for a further 18 hours at room temperature. Then to the reaction mixture was added a solution of the mixture of hexacyanoferrate(III) potassium 2 g (6 mmol) and potassium hydroxide (1 g (18 mmol) in 20 ml of water and stirred it for 4 hours at room temperature. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate-hexane, 1:3). The result is 5-bromo-4-(2-thienyl)-2-morpholinomethyl (10a) in the form of a beige powder.

The output of 499 mg (51%).

So a MP 122-124°C.

The NMR spectrum1H (δ, m. D., J/Hz): 3.77 (m, 4H, och2); 3.82 (m, 4H, NCH2); 7.15 (d. d, 1H, H(4'), J=5.1, 3.9); 7.52 (d. d, 1H, H(5'), J=5.1, 1.1); 8.33 (d. d, 1H, H(3'), J=3.9, 1.1); 8.40 (s, 1H, H(6)).

The NMR spectrum13C (δ, M. D.): 44.35 (NCH2); 66.73 (och2); IS AT 101.89 (C(5)); 127.99 (C(4')); 130.46 (C(5')); 131.00 (C(3')); 142.37 (C(2')); 155.72 (C(4)), 159.55 (C(2)); 161.38 (C(6)).

Elemental analysis for C12H12BrN3OS:

Calculated (%): C, 44.18; H, 3.71; N, 12.88.

Found (Percent): C, 44.11; H, 3.70; N, 12.63.

GLC: tR=26.01 min Mass spectrum: (EI, 70 eV), m/z (IRel, %): 325 [M]+(100)79Br, 327 [M]+(100)81Br.

5-Bromo-2-morpholinomethyl 326 mg (1 mmol) of (10a) is mixed with 3-nitrophenylarsonic acid (11) 200 mg (1.2 mmol) and tetrakis(triphe�ifopen)palladium(0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution was added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave radiation at 155°C (250 W) for 20 minutes. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate-hexane, 1:2). The result is 5-(3-nitrophenyl)-4-(2-thienyl)-2-morpholinomethyl (13a) as a yellow powder. The yield 258 mg (70%).

So a MP 172-174°C.

The NMR spectrum1H (δ, m. D., J/Hz): 3.82 (m, 4H, och2); 3.92 (m, 4H, NCH2); 6.71 (d. d, 1H, H(3'), J=3.8, 1.0); 6.85 (d of d, 1H, H(4'), J=5.0, 3.8); 7.38 (d. d, 1H, H(5'), J=5.0, 1.0); 7.61 (t, 1H, H(5"), J=7.9); 7.66 (D. t, 1H, H(6"), J=7.7, 1.5); 8.20 (s, 1H, H(4)); 8.21 (t, 1H, H(2"), J=1.9); 8.27 ((D. d, 1H, H(4"), J=8.1, 2.1, 1.2).

The NMR spectrum13C (δ, M. D.): is at 44.28 (NCH2); 66.85 (och2); 118.25 (C(5)); 122.76 (C(4")); 124.67 (C(2")); 127.80 (C(4')); 129.74 (C(5')); 128.82, 129.86 (C(5"), C(3')); 136.14 (C(6")); 139.42 (C(1")); 142.60 (C(2')); 148.63 (C(3")); 156.51 (C(6)); 159.30 (C(4)); 160.46 (C(2)).

Elemental analysis for C18H16N4O3S:

Calculated (%): C, 58.68; H, 4.38; N, 15.21.

Found (Percent): C, 58.75; H, 4.28; N, 15.41.

GLC: tR=33.99 min Mass spectrum: (EI, 70 eV), m/z (IRel, %): 368 [M]+(100).

Example 2

To a solution of 5-bromo-2-thiomorpholine (7b) 780 mg (3 mmol) in absolute ether� at -30°C is added an excess of 2-titillate (2) 405 mg (4.5 mmol) in 20 ml of absolute ether. The reaction mixture was stirred at -20°C for 1 hour, then stop cooling and stirring continued for a further 18 hours at room temperature. Then to the reaction mixture was added a solution of the mixture of hexacyanoferrate(III) potassium 2 g (6 mmol) and potassium hydroxide (1 g (18 mmol) in 20 ml of water and stirred it for 4 hours at room temperature. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate - hexane, 1:3). The result is 5-bromo-4-(2-thienyl)-2-thiomorpholine (10b) as a yellow powder.

Output 709 mg (69%).

So a MP 105-107°C.

The NMR spectrum1H (δ, m. D., J/Hz): 2.67 (m, 4H, SCH2); 4.16 (m, 4H, NCH2); 7.15 (d. d, 1H, H(4'), J=5.1, 3.9); 7.52 (d. d, 1H, H(5'), J=5.1, 1.1); 8.33 (d. d, 1H, H(3'), J=3.9, 1.1); 8.39 (s, 1H, H(6)).

The NMR spectrum13C (δ, M. D.): is at 26.84 (SCH2); 46.64 (NCH2); 101.47 (C(5)); 128.00 (C(4')); 130.43 (C(5')); 130.95 (C(3')); 142.45 (C(2')); 155.78 (C(4)), 159.05 (C(2)); 161.46 (C(6)).

Elemental analysis for C12H12BrN3S2:

Calculated (%): C, 42.11; H, 3.53; N, 12.28.

Found (%): 42.01; H, 3.60; N, 12.09.

GLC: tR=27.87 min. Mass spectrum: (EI, 70 eV), m/z (IRel, %): 341 [M]+(100)79Br, 343 [M]+(100)81Br.

5-Bromo-2-thiomorpholine 342 mg (1 mmol) of (10b) is mixed with 3-nitrophenylarsonic acid (11) 200 mg (1.2 mmol) and tetracy�(triphenylphosphine)palladium(0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution was added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave radiation at 155°C (250 W) for 20 minutes. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate-hexane, 1:2). The result is 5-(3-nitrophenyl)-4-(2-thienyl)-2-thiomorpholine (13b) as a light yellow powder. The yield 258 mg (67%).

So a MP 163-164°C.

The NMR spectrum1H (δ, m. D., J/Hz): 2.72 (m, 4H, SCH2); 4.25 (m, 4H, NCH2); 6.70 (d. d, 1H, H(3'), J=3.9, 1.1); 6.85 (d of d, 1H, H(4'), J=5.1, 3.9); 7.37 (d of d, 1H, H(5'), J=5.1, 1.1); 7.60 (t, 1H, H(5"), J=7.9); 7.66 (D. t, 1H, H(6"), J=7.7, 1.5); 8.18 (s, 1H, H(6)); 8.21 (t, 1H, H(2"), J=1.9); 8.27 (D. D. d, 1H, H(4"), J=8.1, 2.2, 1.2).

The NMR spectrum13C (δ, M. D.): 27.00 (SCH2); 46.52 (NCH2); 117.90 (C(5)); 122.73 (C(4")); 124.68 (C(2")); 127.80 (C(4')); 129.70 (C(5')); 129.79, 129.80 (C(3'), C(5")); 136.14 (C(6")); 139.43 (C(1")); 142.69 (C(2')); 148.63 (C(3")); 156.57 (C(4)); 159.35 (C(6)); 160.28 (C(2)).

Elemental analysis for C18H16N4O3S:

Calculated (%): C, 58.68; H, 4.38; N, 15.21.

Found (Percent): C, 58.75; H, 4.28; N, 15.41.

GLC: tR=39.13 min. Mass spectrum: (EI, 70 eV), m/z (IRel, %): 384 [M]+(100).

Example 3

To a solution of 5-bromo-2-morpholinomethyl (7a) 732 mg (3 mmol) in absolute e�Ira at -30°C is added an excess of 2-titillate (2) 405 mg (4.5 mmol) in 20 ml of absolute ether. The reaction mixture was stirred at -20°C for 1.2 hours and then stop cooling and stirring continued for a further 19 hours at room temperature. Then to the reaction mixture was added a solution of the mixture of hexacyanoferrate(III) potassium 2 g (6 mmol) and potassium hydroxide (1 g (18 mmol) in 20 ml of water and stirred for 5 hours at room temperature. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent: ethyl acetate-hexane, 1:3). The result is 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl (10a) in the form of a beige powder. The yield 514 mg (53%).

So a MP 122-124°C.

The NMR spectrum1H (δ, m. D., J/Hz): 3.77 (m, 4H, och2); 3.82 (m, 4H, NCH2); 7.15 (d. d, 1H, H(4'), J=5.1, 3.9); 7.52 (d. d, 1H, H(5'), J=5.1, 1.1); 8.33 (d. d, 1H, H(3'), J=3.9, 1.1); 8.40 (s, 1H, H(6)).

The NMR spectrum13C (δ, M. D.): 44.35 (NCH2); 66.73 (och2); IS AT 101.89 (C(5)); 127.99 (C(4')); 130.46 (C(5')); 131.00 (C(3')); 142.37 (C(2')); 155.72 (C(4)), 159.55 (C(2)); 161.38 (C(6)).

Elemental analysis for C12H12BrN3OS:

Calculated (%): C, 44.18; H, 3.71; N, 12.88.

Found (Percent): C, 44.11; H, 3.70; N, 12.63.

GLC: tR=26.01 min Mass spectrum: (EI, 70 eV), m/z (IRel, %): 325 [M]+(100)79Br, 327 [M]+(100)81Br.

5-Bromo-2-morpholinomethyl 326 mg (1 mmol) of (10A) is mixed with 2-thienylboronic boric acid (12) 154 mg (1.2 mmol) and tetrakis(triph�netspin)palladium(0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution was added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave radiation at 155°C (250 W) for 20 minutes. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate-hexane, 1:2). The result is a 4,5-di(2-thienyl)-2-morpholinomethyl (14a) in the form of light yellow powder. The yield 264 mg (80%).

T. PL. 158 to 160°C.

The NMR spectrum1N (δ, M. D., J/Hz): 3.81 (m, 4H, och2); 3.90 (m, 4H, NCH2); 6.89 (d. d, 1H, H(4'), J=4.9, 3.8); 6.91 (d. d, 1H, H(3'), J=3.8, 1.3); 7.02 (d. d, 1H, H(3"), J=3.5, 1.2); 7.12 (d. d, 1H, H(4"), J=5.2, 3.5); 7.36 (d. d, 1H, H(5'), J=4.9, 1.3); 7.43 (d. d, 1H, H(5"), J=5.2, 1.2); 8.27 (s, 1H, H(6)).

The NMR spectrum13C (δ, M. D.): is at 44.28 (NCH2); 66.86 (och2); 112.82 (C(5)); 126.85 (C(5")); 127.58 (C(4")); 127.84 (C(4')); 128.14 (C(3")); 129.58 (C(5')); 129.95 (C(3')); 138.20 (C(2")); 142.83 (C(2')); 157.53 (C(4)); 160.31 (C(6)); 160.72 (C(2)).

Elemental analysis for C16H15N3OS2:

Calculated (%): C, Is At 58.33; H, 4.59; N, 12.75.

Found (Percent): C, 58.45; H, 4.44; N, 12.79.

GLC: tR=28.72 min. Mass spectrum: (EI, 70 eV), m/z (IRel, %): 329 [M]+(100).

Example 4

To a solution of 5-bromo-2-thiomorpholine (7b) 780 mg (3 mmol) in absolute ether at -30°C is added an excess of 2-titillate� (2) 405 mg (4.5 mmol) in 20 ml of absolute ether. The reaction mixture was stirred at -20°C for 1.5 hours, then stop cooling and stirring was continued for 18.5 hours at room temperature. Then to the reaction mixture was added a solution of the mixture of hexacyanoferrate(III) potassium 2 g (6 mmol) and potassium hydroxide (1 g (18 mmol) in 20 ml of water and stirred it for 4.5 hours at room temperature. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate-hexane, 1:3). The result is 5-bromo-4-(2-thienyl)-2-thiomorpholine (10b) as a yellow powder. The output of 739 mg (72%).

So a MP 105-107°C.

The NMR spectrum1H (δ, m. D., J/Hz): 2.67 (m, 4H, SCH2); 4.16 (m, 4H, NCH2); 7.15 (d. d, 1H, H(4'), J=5.1, 3.9); 7.52 (d. d, 1H, H(5'), J=5.1, 1.1); 8.33 (d. d, 1H, H(3'), J=3.9, 1.1); 8.39 (s, 1H, H(6)).

The NMR spectrum13C (δ, M. D.): is at 26.84 (SCH2); 46.64 (NCH2); 101.47 (C(5)); 128.00 (C(4')); 130.43 (C(5')); 130.95 (C(3')); 142.45 (C(2')); 155.78 (C(4)), 159.05 (C(2)); 161.46 (C(6)).

Elemental analysis for C12H12BrN3S2:

Calculated (%): C, 42.11; H, 3.53; N, 12.28.

Found (%): 42.01; H, 3.60; N, 12.09.

GLC: tR=27.87 min. Mass spectrum: (EI, 70 eV), m/z (IRel, %): 341 [M]+(100)79Br, 343 [M]+(100)81Br.

5-Bromo-2-thiomorpholine 342 mg (1 mmol) of (10b) is mixed with 2-thienylboronic boric acid (12) 154 mg (1.2 mmol) and tetracy�(triphenylphosphine)palladium(0) 58 mg (0.05 mmol). The resulting mixture was dissolved in 4 ml of degassed tetrahydrofuran. To the resulting solution was added a solution of potassium carbonate 346 mg (2.5 mmol) in 4 ml of degassed water. The resulting mixture was irradiated with microwave radiation at 155°C (250 W) for 20 minutes. Thereafter, the solvent is distilled off on a rotary evaporator under reduced pressure, the obtained residue is subjected to chromatographic separation on a column of silica gel (eluent : ethyl acetate-hexane, 1:2). The result is a 4,5-di(2-thienyl)-2-thiomorpholine (14b) in the form of light yellow powder. The yield 252 mg (73%).

So a MP 149-152°C.

The NMR spectrum1H (δ, m. D., J/Hz): 2.71 (m, 4H, SCH2); 4.24 (m, 4H, NCH2); 6.88-6.90 (m, 2H, H(3'), H(4')); 7.02 (d. d, 1H, H(3"), J=3.5, 1.1); 7.12 (d. d, 1H, H(4"), J=5.1, 3.5); 7.36 (m, 1H, H(5')); 7.43 (d. d, 1H, H(5"), J=5.1,1.1); 8.25 (s, 1H, H(6)).

The NMR spectrum13C (δ, M. D.): 26.98 (SCH2); 46.53 (NCH2); 112.45 (C(5)); 126.84 (C(5")); 127.59 (C(4")); 127.86 (C(4')); 128.15 (C(3")); 129.57 (C(5')); 129.91 (C(3')); 138.24 (C(2")); 142.93 (C(2')); 157.59 (C(4)); 160.26 (C(2)); 160.39 (C(6)).

Elemental analysis for C16H15N3S3:

Calculated (%): C, 55.62; H, 4.38; N, 12.16.

Found (Percent): C, Is At 55.41; H, 4.45; N, 12.27.

GLC: tR=31.03 min. Mass spectrum: (EI, 70 eV), m/z (IRel, %): 345 [M]+(100).

Thus, we propose a new efficient method for producing 4,5-di(het)aryl-2-(thio)morpholinomethyl, which may be useful as an antibacterial with�organisations, and also for the treatment neurodegerative diseases, cognitive disorders and Alzheimer's disease.

The advantages of this method are:

1. The ease of varying the substituents due to the high availability of commercially available (het)arylboronic acids and the ease of obtaining organolithium compounds.

2. The flexible reactions and speed of their implementation, including through the use of microwave radiation.

3. Two stage and high yields of target products, in contrast to multi-stage (at least 3 stages) described in the literature methods of obtaining similar products to the outputs of not more than 50%.

The method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholinomethyl of the General formula (I)

where X=O or S, Ar=3-nitrophenyl, or 2-thienyl,
namely that the first stage to get 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl the interaction of 5-bromo-2-(thio)morpholinomethyl with excess 2-titillate in absolute ether, first at -20÷-25°C for at least 1 hour and then at room temperature for 18 hours, the mixture was added a solution of hexacyanoferrate(III) potassium and potassium hydroxide in water and stirred for at least 4 hours at room temperature, the ether phase is separated and distilled, and the resulting residue is subjected to chromatography time�the same silica gel at a ratio in eluent ethyl acetate - hexane 1:3, and the second stage is obtained 5-bromo-4-(2-thienyl)-2-(thio)morpholinomethyl mixed with (het)kilborne acid and tetrakis(triphenylphosphine)palladium(0) in tetrahydrofuran, is added an aqueous solution of potassium carbonate and the resulting mixture was irradiated with microwave radiation at 155°C for 20 minutes, the solvent was distilled off under reduced pressure, the obtained residue is subjected to chromatographic separation on silica gel at a ratio in eluent ethyl acetate - hexane 1:2.



 

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2 cl, 3 tbl, 558 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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to an imine derivative, represented by formula , where "Ar" stands for pyridine, containing a chlorine atom on a ring or thiazole, which can contain the chlorine atom on a ring; "X" stands for a sulphur atom or CH2; when "Y" represents COR1, "R1" stands for a hydrogen atom or a C1-C5alkyl group, halogenated methyl group, except trifluoromethyl group, halogenated C2-C5alkyl group, C2-C5alkenyl group, halogenated C2-C5alkenyl group, C3-C5alkinyl group, non-substituted or substituted with an atom of chlorine, fluorine, methyl group or acetamide phenyl group, non-substituted (C6) aryl(C1-C3)alkyl group, (C1-C4)alkoxy (C1-C5)alkyl group, C1-C3alkoxycarbonyl group, (C1-C3) alkylsulphonyl (C1-C3)alkyl group, (C1-C3)alkylthio (C1-C3)alkyl group, non-substituted or substituted with a methyl group or a fluorine atom C3-C7cycloalkyl group, cyano(C1-C3) alkyl group, non-substituted phenoxy(C1-C3) alkyl group, non-substituted pyridylmethyl group, non-substituted imidazolylmethyl group, furanyl group, morpholine group, adamantly group, isothiocyanate group or a heterocyclic ring selected from quinoline, indole, pyridine, pyrazine, pyridazine or tetrahydrofurane, substituted with one, two or five substituents, selected from chlorine, bromine, trifluoromethane or fluorine, and a non-substituted heterocyclic ring, selected from quinoline, indole, pyridine, pyrazine, pyridazine or tetrahydrofurane, when "Y" represents CONR3R4 "R3" and "R4" stands for a hydrogen atom or C1-C5alkyl group, C1-C3alkoxygroup, non-substituted phenyl group, (C1-C3)alkoxy(C1-C3)alkyl group, C1-C3alkoxycarbonylmethyl group, non-substituted C3-C7cycloalkyl group, non-substituted benzenesulphonyl group; except the cases, when "R3" and "R4" simultaneously stand for hydrogen; when "Y" represents CONHCOR5, "R5" stands for a halogenated C1-C5alkyl group, non-substituted phenyl group; when "Y" represents CO2R9, "R9" stands for C1-C7alkyl group, halogenated C1-C5alkyl group, C2-C5alkenyl group, halogenated C2-C5alkenyl group, C3-C5alkinyl group, non-substituted or substituted with chlorine, fluorine or a nitro group naphthyl or a phenyl group, non-substituted (C6)aryl(C1-C3)alkyl group, (C1-C3)alkoxy (C1-C3) alkyl group, (C1-C3)alkylthio (C1-C3)alkyl group, tri(C1-C3alkyl)silyl(C1-C3)alkyl group, non-substituted C3-C7cycloalkyl group, 3-6-membered non-substituted heterocycloalkyl group, containing an oxygen atom as the heteroatom, non-substituted or substituted with methoxygroup phenylmethyl group, non-substituted furanylmethyl group, non-substituted thienylmethyl group, non-substituted pyridylmethyl group, succinimide group. The group of inventions also relates to methods of obtaining imine derivative of formula (1) (versions). The compound by the invention can be obtained from compounds, selected from the group, consisting of compounds, represented by formulas ACO-B (5), ACOOCOA (6), ACOOH (7), D-N=C=O (8) or HCO2Et(10) in the interaction with the compound of formula .

EFFECT: imine derivative, used as an insecticide, possessing the prolonged effect and wide spectrum of action.

5 cl, 22 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), possessing an activity with respect to cytokines, versions of based on them pharmaceutical compositions and their application. Formula (I) compounds can be applied for treatment or prevention asthma, COPD, ARDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or gouty arthritis. In general formula (I) L is selected from the group, consisting of -C(O)-, -CH2-, Ar1 represents a mono-, di- or trisubstituted phenyl ring, where substituents are independently selected from the group, consisting of a halogen and -C1-4alkyl; Ar2 represents an optionally substituted thiadiazolyl ring, where the substituent represents -C1-4alkyl, -C3-5cycloalkyl, -methylcyclopropyl, phenyl or a 5- or 6-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring with 9 or 10 atoms, with the said heteroaromatic ring containing 1, 2 or 3 heteroatoms, selected from the group, consisting of S, O and N, where the said phenyl or heteroaromatic ring is optionally mono- or disubstituted with substituents, independently selected from the group, consisting of a halogen, -C1-6alkyl, optionally substituted with 1-4 fluorine atoms, -O-C1-6alkyl, -CF3 and oxo.

EFFECT: increased efficiency of the application of the compounds.

16 cl, 1 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, denoted by Form B, characterised by X-ray powder diffraction at reflected angles of 2θ: 14.902, 18.123, 18.87, 20.204, 20.883, 21.79, 24.186, 26.947. The invention relates to a fungicidal composition containing a crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, denoted by Form B, in an effective amount and at least one additional component selected from a group consisting of a surfactant and a liquid carrier. The invention relates to a method of controlling plant diseases caused by fungal plant pathogens, which includes applying a fungicidally effective amount of said polymorph on a plant or part thereof or seeds. The invention also relates to methods of obtaining said crystalline polymorph.

EFFECT: crystalline polymorph of 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, having a higher melting point and which is less soluble.

12 cl, 13 tbl, 2 dwg, 25 ex

FIELD: medicine, pharmaceutics.

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

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

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to fluorinated aminotriazole derivatives of formula

,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 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 refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

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