Method of producing substituted pyrimidin-5-yl carboxylic acids

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

 

The invention relates to the field of organic chemistry, to a new method of obtaining substituted pyrimidine-5-ylcarbamate acids of the formula I, which can be used as plant growth stimulators.

Currently known method of producing esters of some pyrimidine-5-ylcarbamate acid interaction ethoxymethylenemalonic 1,3-ketoesters with derivatives of guanidine [Morfolinopyrimidine / Kristen H, Raddats M // Z. Chem. - 1981. - Vol.21, No. 3 - P.101, patent JP 61-243067]. However, in these works investigated esters (morpholine - N-benzylpiperazine-) substituted in the second position pyrimidinecarboxylic acids.

The closest is a method of obtaining 2-aryl-6-benzyl-pyrimidine-5-ylcarbamate acids, described by the authors of the patent KR 20070116876 (A). The synthesis of the desired products is carried out in 3 stages: the interaction of the corresponding 1,3-ketoesters with dimethylacetal of dimethylformamide get dimethylaminomethylphenol, cyclization of the latter with hydrochloride of arylamidine leads to the formation of esters of 2-aryl-6-benzylpyridine-5-ylcarbamate acid hydrolysis of the latter in aqueous solution sodium hydroxide obtain the corresponding acid. The proposed method of producing 2-aryl-6-benzyl-pyrimidine-5-ylcarbamate acids has several disadvantages: synthesis in three stages with the use of expensive and current the ranks of dimethylacetal N,N-dimethylformamide;

The present invention is to develop a method of producing substituted pyrimidine-5-ylcarbamate acids, which significantly expand the variable range of the substituents in the 2, 4 and 6 positions of the pyrimidine cycle, which can be used as plant growth stimulators.

The technical result is to obtain the substituted pyrimidine-5-ylcarbamate acids of the formula I, substituted in the 2, 4 and 6 positions of the pyrimidine cycle, reducing the consumption of expensive original components, increase the stimulating effect on plant height.

The technical result is achieved by conducting the reaction of various 1,3-ketoesters with orthoevra ant (acetic) acid, leading to the corresponding ethoxymethylenemalonic, cyclization of the latter with N-substituted guanidine and getirilemedigi proceeds with the formation of esters of pyrimidine-5-ylcarbamate acids, alkaline hydrolysis of which leads to the target pyrimidine-5-ylcarbonyl acids of formula I; retrieving a previously unstudied 2-aryl(hetaryl)aminopyrimidine-5-ylcarbamate acid; pyrimidine-5-ylcarbamate acids of the formula I as a growth stimulator

R1+R2=piperidine, pyrrolidine, morpholine, N-Alk(Ar)piperazine

R1=Alk, Ar; R2=Alk, Ar

R1=H, R2=H, Alk, Ar, Het:

R=H; 6-Me, 6-Et; 6-MeO; 6-EtO; 7-Me; 7-MeO; 8-Me; 8); 8-MeO; 8-EtO; 6,7-dime; 6,8-Dima; 6,8-DiMeo; 6-Cl

R3=Alk, Ar, CH2Cl; CH2SAr, CH2SHet:

;;;;;

;;

R4=H, Me

Pyrimidine-5-ylcarbamate acid of the formula I are formed by alkaline hydrolysis of the corresponding esters obtained by the interaction with the N-substituted guanidino and getreligion with ethoxymethylenemalonic 1,3-ketoesters.

Table 1 shows the results of the germination test seed treatment marigold rejected (Tagetes patula L.) 0.05% solution of 2-benzylamino-4-methylpyrimidin-5-icarbonell acid; table 2 shows the results of the germination test seed treatment marigold rejected (Tagetes patula L.) 0,01-0,05% solution of 4-methyl-2-(2-phenylethylamine)pyrimidine-5-icarbonell acid.

The following are examples of implementation of the invention.

EXAMPLE 1. 4-methyl-(2-piperidine-1-yl)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of acetoacetic ester 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle In the GRE 20 cm). After cooling, the mixture was added 0.1 mol piperidine-1-incorporatedin, 5 ml of ethanol and boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester 4-methyl-(2-piperidine-1-yl)-pyrimidine-5-icarbonell acid was filtered, washed with ethanol and recrystallized from ethanol.

Yield 72%, TPL 50-52°C. Found (%): C, 62,74; H, 7,71; N, 18,59. C13H19N3O2. Calculated (%): C, 62,63; H, To 7.68; N, 18,65. An NMR spectrum1N 1.35 (3H, t, CH2CH3, J=8.0); 1.56-1.68 (6N, m, piperid.); 3.28 (3H, s, CH3); 4.41 (2H, q,CH2CH3, J=12.5); 8.65 (1H, s, CH-pyrimid.). Mass spectrum, m/z 249 [M]+.

0.06 mol of ethyl ether 4-methyl-(2-piperidine-1-yl)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-methyl-(2-piperidine-1-yl)-pyrimidine-5-icarbonell acid was filtered, washed with water.

Yield 92%, TPL >200°C is sublimated. Found (Percent):C, To 59.51; H, To 6.80; N, Of 19.03. C11H15N3O2. Calculated (%):C, 59,71; N, 6,83; N, 18,99. An NMR spectrum1N 1.57-1.68 (6N, m, piperid.); 3.29 (3H, s, CH3); 8.66 (1H, s, CH-pyrimid.); 13.12 (1H, USS, COOH). Mass spectrum, m/z 220 [M-1]+.

EXAMPLE 2. 4-methyl-2-(4-methylphenylimino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of acetoacetic ester 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mol of 4-methylvinylpyridine, 5 ml of ethanol and boiled for 1 hour. Precipitated upon cooling, the precipitated ethyl ester 4-methyl-2-(4-methylphenylimino)-pyrimidine-5-icarbonell acid was filtered, washed with ethanol and recrystallized from ethanol.

Yield 81%, TPL 114-116°C. Found (%):C, 62,58; H, 6,30; N, 15,53. C15H17N3O2. Calculated (%):C, 66,40; H, 6,32; N, 15,49. An NMR spectrum1N 1.38 (3H, t, CH2CH3, J=8.0); to 2.06 (3H, s, CH3); 3.29 (3H, s, CH3); 4.43 (2H, q,CH2CH3, J=12.5); 7.24 (2H, d, 2CH-aryl., J=7.8); 7.38 (2H, d, 2CH-aryl., J=7.8); 8.67 (1H, s, CH-pyrimid.); 9.93 (1H, s, NH). Mass spectrum, m/z 271 [M]+.

0.06 mol of ethyl ether 4-methyl-2-(4-methylphenylimino)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-methyl-2-(4-methylphenylimino)-pyrimidine-5-icarbonell acid was filtered, washed with water.

The output 96%, TPL >200°C is sublimated. Found (Percent):C, To 59.51; H, 6,0; N of 19.03. C13H13N3O2. Calculated (%):C, 59,71; H, 6,83; N, 18,99. An NMR spectrum1N of 2.06 (3H, s, CH3); 3.29 (3H, s, CH3); 7.25 (2H, d, 2CH-aryl, J=7.8); 7.38 (2H, d, 2CH-aryl., J=7.8); 8.67 (1H, s, CH-pyrimid.); 10.01 (1H, s, NH); 13.15 (1H, USS, COOH). Mass spectrum, m/z 242 [M-1]+.

EXAMPLE 3. 2 benzylamino-4-methylpyrimidin-5-inkarbaeva acid

A mixture of 0.11 mol of acetoacetic ester 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mol benzylguanine, 5 ml of ethanol and boiled for 1 hour. Precipitated upon cooling, the precipitated ethyl ester 2-benzylamino-4-methylpyrimidin-5-icarbonell acid was filtered, washed with ethanol and recrystallized from ethanol.

Yield 79%, TPL 105-107°C. Found (%):C, 62,21; H, 6,34; N, 15,49. C15H17N3O2. Calculated (%):C, 66,40; H, 6,32; N, 15,49. An NMR spectrum1N 1.34 (3H, t, CH2CH3, J=8.0); 3.25 (3H, s, CH3); 4.39 (2H, q,CH2CH3, J=12.5); to 4.62 (2H, s, CH2); 7.35 (3H, m, 3CH-aryl.); 8.14 (2H, m, 2CH-aryl.); 8.61 (1H, s, CH-pyrimid.); 9.54 (1H, s, NH). Mass spectrum, m/z 271 [M]+.

0.06 mol of ethyl ether 2-benzylamino-4-methyl-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mol solution of Hydra is xida sodium (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 2-benzylamino-4-methylpyrimidin-5-icarbonell acid was filtered, washed with water.

The output 96%, TPL >222°C sublimates. Found (Percent):C, To 59.51; H, To 6.80; N, Of 19.03. C13H13N3O2. Calculated (%):C, 59,71; H, 6,83; N, 18,99. An NMR spectrum13.24 (3H, s, CH3); to 4.62 (2H, s, CH3); 7.35 (3H, m, 3CH-aryl.); 8.14 (2H, m, 2CH-aryl.); 8.60 (1H, s, CH-pyrimid.); 9.53 (1H, s, NH); 13,10 (1H, USS, COOH). Mass spectrum, m/z 242 [M-1]+.

EXAMPLE 4. 4-methyl-2-(2-phenylethylamine)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of acetoacetic ester 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mol of 2-phenylethylamine, 5 ml of ethanol and boiled for 1 hour. Precipitated upon cooling, the precipitated ethyl ester 4-methyl-2-(2-phenylethylamine)-pyrimidine-5-icarbonell acid was filtered, washed with ethanol and recrystallized from ethanol.

Yield 71%, TPL 98-100°C. Found (%):C, 67,13; H, 6,69; N, 14,79. C16H19N3O2. Calculated (%):C, 67,35; N, Of 6.71; N, 14,73. An NMR spectrum1N 1.34 (3H, t, CH2CH3, J=8.0); 2.82 (2H, t, CH2, J=12.0); 3.25 (3H, s, CH3); 4.11 (2H, t, CH2, J=12.0); 4.39 (2H, q,CH2CH3, J12.5); 7.31 (3H, m, 3CH-aryl.); 8.13 (2H, m, 2CH-aryl.); 8.61 (1H, s, CH-pyrimid.); 9.53 (1H, s, NH). Mass spectrum, m/z 285 [M]+.

0.06 mol of ethyl ether 4-methyl-2-(2-phenylethylamine)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-methyl-2-(2-phenylethylamine)-pyrimidine-5-icarbonell acid was filtered, washed with water.

Yield 95%, TPL >232°C sublimates. Found (Percent):C, 65,19; H, Of 5.85; N, 16,23. C14H15N3O2. Calculated (%):C, 65,36; H, 5,88; N, 16,33. An NMR spectrum12.82 (2H, t, CH2, J=12.0); 3.24 (3H, s, CH3); 4.11 (2H, t, CH2, J=12.0); 7.34 (3H, m, 3CH-aryl.); 8.15 (2H, m, 2CH-aryl.); 8.61 (1H, s, CH-pyrimid.); 9.52 (1H, s, NH); to 13.09 (1H, USS, COOH). Mass spectrum, m/z 256 [M-1]+.

EXAMPLE 5. 4,6-dimethyl-2-phenylaminopyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of acetoacetic ester 0.12 mol triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, the mixture was added 0.1 mol phenylquinoline, 5 ml of ethanol and boiled for 1 hour. Precipitated upon cooling, the precipitated ethyl ester of 4,6-dimethyl-2-phenylaminopyrimidine-5-icarbonell acid hoteltravel the Lee, washed with ethanol and recrystallized from ethanol.

Yield 65%, TPL 92-94°C. Found (%):C, 62,20; H, of 6.31; N, 15,55. C15H17N3O2. Calculated (%):C, 66,40; H, 6,32; N, 15,49. An NMR spectrum1N 1.35 (3H, t, CH2CH3, J=8.0); 2,61 (3H, s, CH3); 3.24 (3H, s, CH3); 4.40 (2H, q,CH2CH3, J=12.5); 7.41 (3H, m, 3CH-aryl.); 8.19 (2H, m, 2CH-aryl.); 9.95 (1H, s, NH). Mass spectrum, m/z 271 [M]+.

0.06 mol of ethyl ether 4,6-dimethyl-2-phenylaminopyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation is 4,6-dimethyl-2-phenylaminopyrimidine-5-icarbonell acid was filtered, washed with water.

Yield 92%, TPL >218°C sublimates. Found (Percent):C, 59,48; H, PC 6.82; N, 18,95. C13H13N3O2. Calculated (%):C, 59,71; H, 6,83; N, 18,99. An NMR spectrum1H 2,60 (3H, s, CH3); 3.23 (3H, s, CH3); 7.41 (3H, m, 3CH-aryl.); 8.19 (2H, m, 2CH-aryl.); 10.00 (1H, s, NH); 13.14 (1H, USS, COOH). Mass spectrum, m/z 242 [M-1]+.

EXAMPLE 6. 4,6-dimethyl-2-(4-methylpyrazol-2-ylamino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of acetoacetic ester 0.12 mol triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of atrovaginata (nozzle in the Game 20 cm). After cooling, was added 0.1 mol of 4-methylpyrazol-2-igualadina, 5 ml of dimethylformamide and boiled for 1 hour. Precipitated upon cooling, the precipitated ethyl ester of 4,6-dimethyl-2-(4-methylpyrazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with ethanol, dissolved in chloroform, filtered through a 2 cm layer of silica gel. Evacuated chloroform and recrystallized from a mixture of ethanol-dimethylformamide.

Yield 49%, TPL 213-215°C. Found (%):C, 64,22; H, 5,70; N, 20,72. C18H19N5O2. Calculated (%):C, 64,08; H, Of 5.68; N, 20,76. An NMR spectrum1N 1.43 (3H, t, CH2CH3, J=8.0); 2,69 (3H, s, CH3); was 2.76 (3H, s, CH3); 3.49 (3H, s, CH3); 4.48 (2H, kVCH2CH3, J=12.5); 7.14-7.61 (4H, m, 4CH-Benz.); 10.19 (1H, s, NH). Mass spectrum, m/z 337 [M]+.

0.06 mol of ethyl ether 4,6-dimethyl-2-(4-methylpyrazol-2-ylamino)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation is 4,6-dimethyl-2-(4-methylpyrazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with water.

Yield 92%, TPL >300°C. Found (%):C, 59,87; H, is 4.85; N, 22,58. C16H15N5O2. Calculated (%):C, 62,13; H, 4,89; N, 22,64. An NMR spectrum1N to 2.67 (3H, s, CH3); was 2.76 (3H, s,CH 3); 3.49 (3H, s, CH3); 7.14-7.61 (4H, m, 4CH-Benz.); 10.19 (1H, s, NH); 13.18 (1H, USS, COOH). Mass spectrum, m/z 308 [M-1]+.

EXAMPLE 7. 4-phenyl-(2-piperidine-1-yl)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol benzoyloxy ether 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mol piperidine-1-incorporatedin, 5 ml of ethanol and boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester of 4-phenyl-(2-piperidine-1-yl)-pyrimidine-5-icarbonell acid was filtered, washed with ethanol and recrystallized from ethanol.

Yield 77%, TPL 108-110°C. Found (%):C, 69,74; H, for 6.81; N, 13,42. C18H21N3O2. Calculated (%):C, 69,43; H, To 6.80; N, 13,49. An NMR spectrum1N 1.39 (3H, t, CH2CH3, J=8.0); 1.58-1.69 (6H, m, piperid.); 4.43 (2H, q,CH2CH3, J=12.5); 7.40 (3H, m, 3CH-aryl.); 8.16 (2H, m, 2CH-aryl.); 8.70 (1H, s, CH-pyrimid.). Mass spectrum, m/z 311 [M]+.

0.06 mol of ethyl ester of 4-phenyl-(2-piperidine-1-yl)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-phenyl-(2-PI is Eridan-1-yl)-pyrimidine-5-icarbonell acid was filtered, washed with water.

The output 96%, TPL >238°C sublimates. Found (Percent):C, 67,75; H, 6,03; N, 14,86. C16H17N3O2. Calculated (%):C, 67,83; H, Equal To 6.05; N, 14,83. An NMR spectrum1N 1.58-1.69 (6H, m, piperid.); 7.40 (3H, m, 3CH-aryl.); 8.16 (2H, m, 2CH-aryl.); 8.70 (1H, s, CH-pyrimid.); 13.04 (1H, USS, COOH). Mass spectrum, m/z 282[M-1]+.

EXAMPLE 8. 4-phenyl-6-methyl-2-(benzoxazol-2-ylamino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol benzoyloxy ether 0.12 mol triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mole benzoxazol-2-igualadina, 5 ml of dioxane and boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester of 4-phenyl-6-methyl-2-(benzoxazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with dioxane and recrystallized from dioxane.

Yield 64%, TPL 255-257°C. Found (%):C, 63,54; H, 4,89; N, 14,85. C21H18N4O3. Calculated (%):C, 67,37; H, Is 4.85; N, 14,96. An NMR spectrum1N 1.41 (3H, t, CH2CH3, J=8.0); 2,60 (3H, s, CH3); 4.47 (2H, q,CH2CH3, J=12.5); 6.99-7,58 (9H, m, 9CH-arene.); 9,85 (1H, s, NH). Mass spectrum, m/z 374 [M]+.

0.06 mol of ethyl ester of 4-phenyl-6-methyl-2-(benzoxazol-2-ylamino)-pyrimidine-5-icarbonell acid was wet floor is gross with alcohol, added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-phenyl-6-methyl-2-(benzoxazol-2-yl)-pyrimidine-5-icarbonell acid was filtered, washed with water.

The output 96%, TPL >300°C With decomposition. Found (Percent):C, 65,73; H, A 4.03; N, Ls 16.80. C19H14N4O3. Calculated (%):C, 65,89; H, 4,07; N, 16,18. An NMR spectrum1H 2,60 (3H, s, CH3); 6.96-rate of 7.54 (9H, m, 9CH-arene.); 9,85 (1H, s, NH); 13.04 (1H, USS, COOH). Mass spectrum, m/z 345 [M-1]+.

EXAMPLE 9. 4-(5-methyl[1,3,4]thiadiazole-2-altimeter)-2-(benzothiazol-2-ylamino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of 4-(5-methyl[1,3,4]thiadiazole-2-ylthio)acetoacetic ester 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mole benzothiazol-2-igualadina, 5 ml of dioxane and boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester 4-(5-methyl [1,3,4]thiadiazole-2-altimeter)-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with dioxane and recrystallized from dioxane.

Yield 81%, TPL 240-242°C. Found (%):C, 48,81; H, of 3.60; N, 18,87. C18H16N6O2S3. Calculated (%):C, 48,63; H, 3,63; N, 18,90. An NMR spectrum1N 1.4 (3H, t, CH2CH3, J=8.0); 4.46 (2H, q,CH2CH3, J=12.5); 4.99 (2H, s, SCH2); 7.02 (1H, t, 1CH-Benz, J=7.8); 7.19 (1H, t, 1CH-Benz, J=7.8); 7.58 (2H, m, 2CH-Benz.); 8.73 (1H, s, CH-pyrimid.); 10.15 (1H, s, NH). Mass spectrum, m/z 444 [M]+.

0.06 mol of ethyl ester of 4-(5-methyl[1,3,4]thiadiazole-2-altimeter)-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-(5-methyl [1,3,4]thiadiazole-2-altimeter)-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with water.

The output 96%, TPL >300°C With decomposition. Found (Percent):C, 46,23; H, 2.91 In; N, 20,14. C16H12N6O2S3. Calculated (%):C, 46,14; H, 2,90; N, 20,18. An NMR spectrum1N 4.99 (2H, s, SCH2); 7.02 (1H, t, 1CH-Benz, J=7.8); 7.19 (1H, t, 1CH-Benz., J=7.8); 7.58 (2H, m, 2CH-Benz.); 8.71 (1H, s, CH-pyrimid.) 10,15 (1H, s, NH); 13.04 (1H, USS, COOH). Mass spectrum, m/z 415 [M-1]+.

EXAMPLE 10. 4-chloromethyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of 4-chloroacetoxy ether 0.12 mol of triethylorthoformate boiled for two hours with simultaneous distillation of the liberated in the reaction of ethyl alcohol (the nozzle in the Game 20 cm). After cooling, was added 0.1 mol of best the azole-2-igualadina, 5 ml of dioxane and boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester and 4-chloromethyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with dioxane and recrystallized from dioxane.

Yield 43%, TPL 286-288°C. Found (%):C, 51.89ˆ; H, 3,74; N, 16,01. C15H13ClN4O2S. Calculated (%):C, 51,65; H, 3,76; N, 16,06. An NMR spectrum1N 1.48 (3H, t, CH2CH3, J=8.0); 4.35 (2H, q,CH2CH3, J=12.5); 5.00 (2H, s, CH2); 7.11 (1H, t, 1CH-Benz, J=7.8); 7.23 (1H, t, 1CH-Benz, J=7.8); 7.59 (2H, m, 2CH-Benz.); 8.71 (1H, s, CH-pyrimid.); 9.54 (1H, s, NH). Mass spectrum, m/z 348 [M]+.

0.06 mol of ethyl ester of 4-chloromethyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-chloromethyl-2-(benzothiazol-2-yl)-pyrimidine-5-icarbonell acid was filtered, washed with water and recrystallized from dimethylformamide.

Yield 62%, TPL >300°C With decomposition. Found (Percent):C, 48,53; H, 2,84; N, 17,52. C13H9ClN4O2S. Calculated (%):C, 48,68; H, And 2.83; N, 17,47. An NMR spectrum1N 5.00 (2H, s, CH2); 7.11 (1H, t, 1CH-Benz., J=7.8); 7.23 (1H, t, 1CH-Benz., J=7.8); 7.59 (2H, m, 2CH-Benz.); 8.69 (1H, s, CH-pyrimid.); 10,11 (1H, s, NH); 13.07 (1H, USS, COOH). Mass spectrum, mz 319 [M-1] +.

EXAMPLE 11. 4-phenyl-6-methyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol benzoyloxy ether 0.12 mol triethylorthoformate, 0.1 mole benzothiazol-2-igualadina and 5 ml of dioxane is boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester of 4-phenyl-6-methyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with dioxane and recrystallized from dioxane.

Yield 69%, TPL 254-256°C. Found (%):C, 64,83; H, 4,69; N, 14,42. C21H18N4O2S. Calculated (%):C, 64,60; H And 4.65; N, 14,35. An NMR spectrum1N 1.40 (3H, t, CH2CH3, J=8.0); at 2.59 (3H, s, CH3); 4.45 (2H, q,CH2CH3, J=12.5); 6.97-7,56 (9H, m, 9CH-arene.); 9,84 (1H, s, NH). Mass spectrum, m/z 390 [M]+.

0.06 mol of ethyl ester of 4-phenyl-6-methyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-phenyl-6-methyl-2-(benzothiazol-2-yl)-pyrimidine-5-icarbonell acid was filtered, washed with water.

Exit 98%, TPL >300°C With decomposition. Found (Percent):C, 65,73; H, A 4.03; N, Ls 16.80. C19H14N4O2S. Calculated (%):C, 65,89; H, 4,07; N, 16,18. An NMR spectrum1N at 2.59 (3H, CH3); 6.97-7,56 (9H, m, 9CH-arene.); 9,84 (1H, s, NH); 13.01 (1H, USS, COOH). Mass spectrum, m/z 360 [M-1]+.

EXAMPLE 12. 4-phenylthiomethyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-inkarbaeva acid

A mixture of 0.11 mol of 4-fenildiazoetanom ether 0.12 mol of triethylorthoformate, 0.1 mole benzothiazol-2-igualadina and 5 ml of dioxane is boiled for 1 hour. Precipitated after cooling, the precipitate ethyl ester 4-phenylthiomethyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with dioxane and recrystallized from dioxane.

Yield 86%, TPL 200-202°C. Found (%):C, 59,47; H, 4,32; N, of 13.27. C21H18N4O2S2. Calculated (%):C, 59,70; H, The 4.29; N, 13,26. An NMR spectrum1N 1.41 (3H, t, CH2CH3, J=8.0); 4.40 (2H, q,CH2CH3, J=12.5); 4.97 (2H, s, SCH2); 6.91-7,52 (9H, m, 9CH-arene.); 8.68 (1H, s, CH-pyrimid.); 10.14 (1H, s, NH). Mass spectrum, m/z 422 [M]+.

0.06 mol of ethyl ether 4-phenylthiomethyl-2-(benzothiazol-2-yl)-pyrimidine-5-icarbonell acid moistened with ethyl alcohol, was added 0.15 mole of sodium hydroxide solution (7%) and boiled for 1 hour. After cooling, to the mixture was added 0.15 mol hydrochloric acid solution (5%). The precipitation of 4-phenylthiomethyl-2-(benzothiazol-2-ylamino)-pyrimidine-5-icarbonell acid was filtered, washed with water.

Yield 88%, TPL >300°C with Razlog the tion. Found (Percent):C, 58,03; H, 3,61; N, 14,16. C19H14N4O2S2. Calculated (%):C, 57,85; H, To 3.58; N, 14,20. An NMR spectrum1N 4.97 (2H, s, SCH2); 6.88-of 7.48 (9H, m, 9CH-arene.); 8.67 (1H, s, CH-pyrimid.); 10.12 (1H, s, NH); 13.01 (1H, USS, COOH). Mass spectrum, m/z 393 [M-1]+.

It was also studied the catalytic effect of solutions of pyrimidine-5-ylcarbamate acids on the growth of annual plants marigolds rejected (Tagetes patula L.), which is widely used for the greening of urban areas.

EXAMPLE 13.

It is established that during the processing of seeds of marigolds rejected {Tagetes patula L.) 0.05% solution of 2-benzylamino-4-methylpyrimidin-5-icarbonell acid the average height of the plants compared to the control increased by 7.9 see the Processing solution has a positive effect on seed germination (table 1).

EXAMPLE 14.

It is established that during the processing of seeds of marigolds rejected {Tagetes patula L.) 0,01-0,05% solution of 4-methyl-2-(2-phenylethylamine)pyrimidine-5-icarbonell acid medium plant height, compared with the control, increased by 7.7-9.2 cm, while the higher the concentration, the higher the positive effect. Germination of seeds also depends on the concentration, in this case, the optimal result is achieved when using a 0.01% solution (table 2).

The method of obtaining substituted pyramid is n-5-ylcarbamate acids of formula I by the interaction of the N-substituted guanidino and getreligion with ethoxymethylenemalonic 1,3-ketoesters, wherein upon receipt of the esters of pyrimidine-5-ylcarbamate acids are used ethoxymethyleneamino 1,3-ketoesters and various N-substituted guanidine and getirilemedigi:

R1+R2=piperidine, pyrrolidine, morpholine, N-Alk(Ar)piperazine
R1=Alk, Ar; R2=Alk, Ar
R1=H, R2=H, Alk, Ar, Het:

R=H; 6-Me, 6-Et; 6-MeO; 6-EtO; 7-Me; 7-MeO; 8-Me; 8); 8-MeO; 8-EtO; 6,7-dime; 6,8-Dima; 6,8-DiMeo; 6-C1
R3=Alk, Ar, CH2Cl; CH2SAr, CH2SHet:


R4=H, Me,
which can be used as plant growth stimulators.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2-aza-bicyclo[3.3.0]octane derivative of formula , with stereogenic centres in a (1S,3S,5S)-configuration, where A is a thiazolyl which is unsubstituted or monosubstituted, where the substitute is independently selected from a group comprising C1-4alkyl, C3-6cycloalkyl and NH2; B is phenyl which is unsubstituted or mono- or disubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl, trifluoromethyl, NHC(O)CH3 and halogen; and R1 is an imidazo[2,1·b]thiazolyl or benzoisoxazolyl group, where said groups are independently unsubstituted or monosubstituted, where the substitutes are independently selected from a group comprising C1-4alkyl; or R1 is a 2,3-dihydrobenzofuranyl group; or a pharmaceutically acceptable salt. The 2-aza-bicyclo[3.3.0]octane derivative of formula (I) is as a medicinal agent having the activity of orexin receptor antagonists.

EFFECT: obtaining novel 2-aza-bicyclo[3,3,0]octane derivatives as orexin receptor antagonists.

8 cl, 1 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylbipyrrolidine carboxamides of formula , where values of R, R1, R2, R3 and R4 are given in claim 1.

EFFECT: compounds have activity which binds to the H3 ligand, which allows use thereof in pharmaceutical compositions for treating sleep disorder.

10 cl, 1 tbl, 4 dwg, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

wherein the cycle A represents a carbocyclic group or a heterocyclic group; R1 means (i) lower alkyl optionally substituted by halogen, (ii) lower alkenyl, (iii) lower alkynyl or (iv) a carbocyclic group; each of R3a, R3b, R3c and R3d independently means hydrogen, halogen, lower alkyl optionally substituted by halogen, lower alkenyl, carbocyclyl - lower alkoxy or a carbocyclic group, or R3a and R3b or R3c and R3d can form C3-C10 cycloalkane ring together with an adjoining carbon atoms and can form oxo; a pharmaceutically acceptable salt or solvate of said compound effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

EFFECT: preparing the pharmaceutically acceptable salt or solvate effective in treating the diseases caused by β-amyloid protein production, secretion and/or fixation.

18 cl, 139 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to particular compounds, which demonstrate inhibiting activity with respect to ERK, whose structure formula is given in description, to their pharmaceutically acceptable salts, based on them pharmaceutical composition and their application for treatment of cancer, mediated by ERK activity.

EFFECT: obtaining compounds, which demonstrate inhibiting activity with respect to ERK.

5 cl

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing M-(1,5,3-dithiazepan-3-yl)amides of general formula (1) where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which involves reaction of N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of a samarium nitrate crystalline hydrate Sm(NO3)3·6H2O catalyst with molar ratio N1,N1,N6,N6-tetramethyl-2,5-dithiahexane-1,6-diamine:RC(O)NHNH2:Sm(NO3)3·6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure in the mixture of solvents - ethyl alcohol and chloroform for 20-28 hours.

EFFECT: method of producing N-(1,5,3-dithiazepan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds for treating cell-proliferative disorders having formula (II): wherein the values R1,R2, X, A, B, R6, R7, R9 are specified in cl. 1 of the patent claim with the exception of the compound of formula: .

EFFECT: there are presented compounds possessing anticancer activity.

95 cl, 27 dwg, 11 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing N-(1,5,3-dithiazepinan-3-yl)amides of general formula (1): where R = p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c) which involves reaction of t-butyl-1,5,3-dithiazepinane with a hydrazide of general formula RC(O)NHNH2 [R is as described above] in the presence of an iron chloride crystalline hydrate catalyst FeCl3-6H2O in molar ratio t-butyl-1,5,3-dithiazepinane:RC(O)NHNH2:FeCl3-6H2O=10:10:(0.3-0.7) at temperature of 65-75°C and atmospheric pressure of a mixture of solvents - ethyl alcohol-chloroform for 40-48 hours.

EFFECT: novel method of producing N-(1,5,3-dithiazepinan-3-yl)amides with high selectivity and output, which can be used as biologically active compounds, selective sorbents and extractants of noble and precious metals.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound selected from a group consisting of: 4-[(2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-[(5-chlor-2-{[(2S)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl](pyridin-2-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2S)-3-fluor-2- methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-{[(6-{[(2R)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid, 4-{[(6-{[(2S)-2-fluorobutyl](pyridin-2-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, 4-[(5-chlor-2-{[(2R)-2-fluoropropyl] (pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl]benzoic acid, 4-[(5-chlor- 2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4-methylphenoxy)methyl] benzoic acid, 4-[(2-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoic acid, 4-[(2-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl] benzoic acid, 4-{[(6-{[(2S)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl} benzoic acid and 4-{[(6-{[(2R)-2-fluoropropyl](pyridin-3-ylsulfonyl)amino}-2,3-dihydro-1H-inden-5-yl)oxy)methyl}benzoic acid, or a pharmaceutically acceptable salt thereof. These compounds have an EP1 receptor antagonist effect and may be used for treating the dysfunction pollakiuria.

EFFECT: preparing the sulfonamide compounds with a strong EP1 receptor antagonist effect.

23 cl, 24 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine derivatives and their pharmaceutically acceptable salts possessing the properties of a HIV replication inhibitor. In formula (I'): , R1 means a hydrogen atom; R7 means a hydrogen atom; C1-6alkyl; R8 means a hydrogen atom; C1-6alkyl; R4 means cyano; R9 means -CH=CH-CN; R5 means C3-7cycloalkyl; C1-6alkyloxy; aryl; Het; C1-6alkyl substituted by a radical specified in hydroxy, C1-6alkyloxy, cyano, amino, mono- and di-C1-6alkylamino, C1-6alkylcarbonylamino, aryl, Het, dioxoalanine optionally substituted by one or two C1-6alkyl radicals, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl optionally substituted by C1-6alkyl or C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, aryl C1-6alkyloxycarbonyl and C3-7cycloalkyl; or R5 means C1-6alkyl substituted by two C1-6alkyloxy radicals; R6 means a hydrogen atom or C1-6alkyl; X means -NR1- or -O; the values of Het are presented in the patent claim. The invention also refers to a pharmaceutical composition containing said compounds.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of a HIV replication inhibitor.

9 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,2'-dibenzthiazolyl-disulphide via electrochemical oxidation of an alkaline solution of 2-mercaptobenzthiazole at temperature of 70°C and current density of 1 A/cm2, wherein the process is carried out on alternating current with frequency of 55…575 Hz, preferably 100…120 Hz and more preferably 105…115 Hz. The highest current output is achieved using alternating current with frequency of 110 Hz.

EFFECT: high efficiency of the electrolysis cell, reduced electric power consumption, avoiding use of toxic and expensive reagents.

2 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

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