Derivatives of pyrazolo(3,4-b)pyridine

 

(57) Abstract:

The essence of the invention: 5-deoxyactein derivatives of pyrazolo [3,4-b] pyridine f-ly I listed in the description, where R1-R5Y and Z have the meanings given in the description text.

The invention relates to new derivatives of pyrazolo/3,4/ pyridine of the formula I

R1z (I) where R1-H1-8-alkyl, C3-6-cycloalkyl, or R6where R6Is h, CL, Br, Fr, R2- linked to the nitrogen in position 1 - or 2-pyrazolopyrimidine ring and means1-8-alkyl, phenyl, benzyl, 2, 3 - or 4 - pyridyl, or alkoxyphenyl, R3- fluorine, chlorine or bromine, R4-N, R5-C1-8-alkyl or C3-7-cycloalkyl. Y is-CH=CH- , Z - or a group-Q-CH2-W-CH2-CO2R12where Q is-CH/OH/, W-C(R)(OH), where R is H, R12Is H or alkyl part chemically or physiologically hydrolyzable alkyl ether complex or sodium, potassium or 1/2-calcium.

It is known that some of the metabolic products of fermentation such as compactin etc. are inhibitors NM-COA reductase which is an enzyme that limits the speed in the biosynthesis of cholesterol.

The purpose of the invention is the synthesis of new compounds having valuable properties of the-6-1/1-methyl-ethyl) -pyrazolo(3,4-b)pyridin-5-yl/-3,5-dihydroxide-6-ENOAT (connection 1-1-1).

This compound was obtained using synthesis, comprising the following stages of the reaction, example 1 and example 1-g.

P R I m e R 1-a. Ethyl 4-/4-forfinal/-1,3-dimethyl-6-/1-methylethyl/pyrazolo/3, 4-b/-pyridine-5-ylcarbonyl (compound VII-I).

Synthesis of Dihydrocodeine

2,22 g /0,02 mol/5-amino-1,3-dimethylpyrazole and 5.3 g /0,02 mol/ethyl 2-/4-formanilide /-4-methyl-3-oxo-pentanoate mixed and heated at a temperature of about 130aboutC for 1 h Substances with a low boiling point of distilled under reduced pressure using a rotary evaporator. Then the reaction mixture was dissolved in chloroform, was washed with a saturated aqueous solution of sodium carbonate and water and dried over anhydrous magnesium sulfate. The chloroform was evaporated and the residual oil was purified using chromatography on silicagel column and was dihydropyrazolo /3,4-b/pyridine/XI-I/.

PAMR/SDS3/ mln.: 0,81 /A. I=7 Hz, 3H/, 1,0-1,3/ m, 6N/, 1,97/ s , 3H/, 2,64 /m, IH/, 3,44/A. I=3 Hz, IH/, 3,81 /s, 3H/, 4,06/ sq I=7 Hz, 2H/, 4,48 /e, I= =3 Hz, IH/, 6,84 /m, 4H/

Method of oxidation -1.

rate of 7.54 g Dihydrocodeine obtained at the stage described above, were dissolved in 15 ml of glacial acetic acid and to the mixture was added 2.2 g chromium dioxide is x substances by thin-layer chromatography to the mixture was added 100 ml of water. The mixture was extracted with chloroform. The chloroform layer was shaken with saturated aqueous sodium carbonate and water and then dried over anhydrous magnesium sulfate.

The chloroform was distilled. The residual oil was purified using chromatography on silicagel column /eluent: 1% methanol (chloroform) and was obtained the desired compound in the form of white crystals.

Melting point: 60-64aboutC, yield: 52% (calculated on aminopyrazole).

Method -2 oxidation.

1 g Dihydrocodeine obtained at the stage described above, was dissolved in acetone containing a small amount of ethanol, and to the mixture was added potassium permanganate (to 1.5-fold mol amount). The mixture is stirred at room temperature for 1 day. After confirming the complete disappearance of unreacted Dihydrocodeine using thin-layer chromatography manganese dioxide was removed by filtration. The filtrate was concentrated and the residual oil was processed in the same manner as in the method of oxidation of -1, and it turned out the desired connection.

Yield: 60% /per aminopyrazole/.

P R I m e R 1-b. 4-/4-forfinal/-5-hydroxymethyl-1,3-dimethyl-6-/1-forfinal/-1,3-dimetane, 0,69 g of anhydrous sodium acetate and 3.8 g /12 mmol/ connections VI-I was suspendibility in 50 ml of dry dichloromethane at room temperature. The reaction solution was mixed for 1 h and then thereto was added 100 ml of diethyl ether. The mixture was thoroughly mixed. The reaction mixture was subjected to filtration through a layer of celite, and the extract was evaporated under reduced pressure to dryness. The residue was subjected to chromatography on silicagel column (eluent: chloroform) to obtain 2.9 g (yield: 78%) of the desired compound as a slightly yellow substance.

Melting point: 144-146aboutC.

P R I m e R s 1-d and 1-E. /E/-3-/4-/4-forfinal/-1,3-dimethyl-6 - 1-methyl-ethyl/pyrazolo/3,4-b/pyridine-5-yl/Pro - paraldehyde /compound III-I/

P R I m e R 1-d. 14.5 g /40 mmol/CIS-1-ethoxy-2/-tri-n-butylstannyl/ethylene was dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to -78aboutC in nitrogen atmosphere. To this solution, dropwise, was added 26 ml /40 mmol/ 15 wt.% solution n-utillity-n-hexane. The mixture was mixed for 20 min and then thereto was added dropwise a solution of 2.5 g /8 mmol/ connections V-I, dissolved in 20 ml of dry tetrahydrofuran. The reaction mixture was stirred at -78aboutC for 1 h, then was avowals diethyl ether. The ether extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, the residue was subjected to liquid separation between n-hexane and acetonitrile. The combined acetonitrile layer was subjected to distillation under reduced pressure and was essentially pure compound IV-I.

P R I m e R 1-that is, the Compound IV-I obtained in example 1-d was dissolved in 70 ml of tetrahydrofuran, and to the mixture was added 20 ml of water and 3 g of p-toluenesulfonic acid. The mixture is stirred at room temperature for 2 hours the Reaction solution was carefully kind of balanced out in an aqueous solution of gidrookisyei. Then thereto was added diethyl ether, and was several times performed the extraction. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then the solvent was distilled under reduced pressure. The residue was subjected to chromatography on silicagel column /eluent: ethyl acetate /n-hexane=1/9/volume/volume/, giving the desired compound as a yellow substance.

Quantity: 2.2 g /yield:79%/.

Melting point:133-134aboutWITH

P R I m e R 1-f. Ethyl-/E/-7-/4-/4 forfinal/-1,3 of Dima were washed with dry petroleum ether, were dried in a stream of nitrogen and then suspendibility in 200 ml of dry hydrofuran. The suspension was cooled to -15aboutIn nitrogen atmosphere, and thereto was dropwise added to 3.9 ml /30 mmol/ ethylacetoacetate. The mixture was mixed for 15 minutes Then, dropwise, was added 20 ml /30 mmol/ 15 wt. %. solution n-utillity-n-hexane, and the mixture is stirred for 30 minutes Then to the mixture was added a solution of 2.1 g /6.1 mmole/ connections III-I, dissolved in dry tetrahydrofuran, and the mixture was mixed for 1 h To the reaction mixture at -15aboutC, was added 10 ml of a saturated aqueous solution of ammonium chloride, the mixture was three times extracted with diethyl ether. The ether solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to dryness. The residue was subjected to chromatography on silicagel column/eluent: ethyl acetate/chloroform =1/9/the volume of/the amount of//, giving 2.5 g/ yield:89%/ desired compound in the form of a white substance.

Melting point: 95-98aboutC.

P R I m e R I-g. Recovery method 1. Ethyl/E/-7-/4-/4-forfinal/-1, 3-di - methyl-6-/1-methylethyl/pyrazolo /3,4-b/pyridine-5-yl/-3,5-dihydroxide-6 - ENOAT (connection 1-1-1).

Quantity: 1,81 g (yield:78%)

NMR / mln. in l3/ 1,28 /so, I=8 Hz, 3H/, 1,32/d, I=8 Hz, 6N/, 1,4-1,8/ m , IH/, 1,92 / c. 3H/, 2,2-2,6/ m, 3H/, 2,9-3,8/m, 2N/, 3,42/ heptane. , I= 8 Hz, IH/, 4,06/s, 3H/, 4,1-4,6 /m, 4H/, 5,1-5,5/ m, IH/, 6,6-6,7/m, IH/, 6,9-7,3/ m, 4H/

Recovery method 2.

Ethyl/E/-7-/6-cyclopropyl-4-/4 - forfinal/-1-methyl-31- phenylpyrazole/3,4-b/pyridine-5-yl/-3,5-dihydroxy - hept-6-ENOAT (connection 1-1-14).

200 ml of diethyl ether solution of approximately 0.15 mol/l of zinc borohydride were mixed in a nitrogen atmosphere while cooling the solution at -70aboutC. To the mixture, gradually, the wall of the reactor was added a solution of 3.75 g /7,12x10-3mol/ connections 11-14, dissolved in 40 ml of dry diethyl ether. Next is exist using thin-layer chromatography to the mixture at -70aboutWith added 40 ml of methanol and then 100 ml of water to complete the reaction. To the reaction solution to bring the pH to 4 was added diethyl ether and dilute acetic acid and the product was extracted in diethyl ether.

Dyatlovo-ether layers were washed with water up until Dyatlovo-ether layer became neutral, then it was washed with a saturated aqueous solution of sodium chloride. Dyatlovo-ether layers were dried over anhydrous magnesium sulfate and then the solvent was evaporated using an evaporator. The residue was subjected to chromatography on silicagel column /eluent: benzene/ethyl acetate/giving to 3.09 g (82,0%) of the desired compound as a slightly yellow powder.

P R I m m e R 2. Sodium /E/-7-/4-/4-forfinal/-1,3-dimethyl-6-/1-methylethyl/pyrazolo/3,4-b/pyridine-5-yl/-3.5 digidoc - silent-6-ENOAT (connection 1-5-1).

200 mg (0.43 mmol) of the compound 1-1-1 was dissolved in 2 ml of ethanol, and to the mixture was added dropwise to 0.85 ml of 0.5 N. aqueous solution of sodium hydroxide. The mixture is stirred at room temperature for 1 h Then the ethanol was distilled under reduced pressure, to the mixture was added 2 ml of water and the mixture was extracted with diethyl ether. The water layer was dried by freezing, giving the eat).

In the same way as in example 1 were obtained compound VII-2 VII-18. The physical properties of the compounds obtained are shown in table. 1. PAMR compound VII-4 /l3/ mln.: 0,96 /so, I=8 Hz, 3H/, 1,42 /e , I=7 Hz, 6N/, 3,27 /heptane, I=7 Hz, IH/, was 4.02 per square, I=8 Hz, 2H/, 4,18 /m , 3H/, 6,6-7,3/ m, N/ PAMR compound VII-8 /l3/ mln.: 1,07 /so, I= 8 Hz, 3H/, 1,42/e, I=7 Hz, 6N/, 1,59/so, I=8 Hz, 3H 3,41 /heptane, I=7 Hz, IH/, 4,20 /sq, I=8 Hz, 2H/, 4,70 /sq, I=8 Hz, 2H/, 7,1-8,0/m, 5H/

In the same manner as in example 1-b were obtained compound VI-2-VI-17.

The physical properties of the obtained compounds are shown in table. 2.

In the same manner as in example 1, were obtained compound V-2-V-18. The physical properties of the compounds obtained are shown in table. 3.

In the same way as in examples 1-d and 1-e, were obtained compound (III-2 III-18. The physical properties of the obtained compounds are shown in table. 4.

In the same manner as in example 1-f, the compounds II-2-II-18. The physical properties of the obtained compounds are shown in table. 5.

PAMR of compound II-4 /Cl3/ mln.:

1,24 /so, I=9 Hz, 3H/, 1,32 /e, I=8 Hz, 6N/, 2,1-2,5 /m, 2N/, 2,6-2,9 m , 1H/, 3,2-3,7/ m,, 3H/, 3,9-4,7/ m, 3H/. 4,11 /c. 3H/, 4,9-5,4/ m, 1H/,6,3-7,2/m, 1/HE,

PAMR of compound II-5-/CCl3/ mln.:3/ mln.:

1,26 /so, I=7 Hz, 3H/, 1,33/e, I=7 Hz, 6N/, 1,92/c. 3H/, 2,2-2,6/m, 1H/, 2,45/e,I=6 Hz, 2H/, 3,41/s 2N/, 3,43/heptane I=7 Hz, 1H/, 4,22/sq , I=7 Hz, 2H/, 4,4-4,8/m, 1H/, 4,8-5,6/m, 1H/, 5,65/ c. 2H/, 6,4-6,8/m, 1H/, 7,0-7,7/m, N/. PAMR of compound II-14 /l3/ mln.:

0,9-1,5/m, 4H/, 1,24/so, I=8 Hz, 3H/, 2,1-2,5/m,1H/,

2,5-2,7/m, 2H/, 3,31/s 2N/, 4,05/c. 3H/, 4,12/sq, I=8 Hz, 2H/

4,4-4,8 /m , 1H/, 5,35/doctor, doctor, I=17 Hz, j=6 Hz, 1H/, 6,4-7,2/m, 10H/ PAMR of compound II-15 /Cl3/ mln.:

0,9-1,4 (m, 4H/, 1,26-/so, I=8 Hz, 3H/, 1,74/c. 9H/,

1,88/c. 3H/, 2,2-2,4-/m, 1H/, 2,4-2,6/m, 2N/, 3,35/c. 2H/, 4,14/sq , I=8 Hz, 2H/, 4,3-4,7/m, 1H/, 5,40/doctor, doctor, I=17 Hz, j=6 Hz, 1H/, 6,50/e, I= 17 Hz, 1H/, 6,9-7,4/m , 4H/ PAMR of compound II-16 /l3/ mln.: 0,4-1,4/m , 8H/, 1,28/so , I= 8 Hz, 3H/, 1,75/c. 9H/, 2,1-2,5/m, 2H/, 2,4-2,6/m , 2H/, 3,43/c/. , 2H/, 4,23/sq, I=8 Hz, 2H/, 4,4-4,7/m, 1H/, 6,52/ doctor , doctor I=17 Hz, j=6 Hz, 1H/,6,64/ d, 1H, j=6 Hz/, 6,9-7,6/m, 4H/, PAMR of compound II-17 /l3/ mln.:

0,8-1,5/m , 4H/, 1,20/so, I=8 Hz, 3H/, 1,80/c. 9H/,2,0-2,7/m, 1H/, 2,3-2,5/m , 2N/, 3,30/c. , 2H/, 4,10/sq, I=8 Hz, 2H/, 4,3-4,7/m, 1H/, 5,35/doctor,doctor, I=17 Hz, j=6 Hz, 1H/, 6,3-7,3/m, 10H/,

In this way, as in the example 1-0 received connection 1-1-2-1-1-18. The physical properties of the compounds obtained are shown in table. 6.

PAMR connection 1-1-2 /l3/ mln.:

1,29/so , I=8 Hz, 3H/, 1,36/e, I=8 Hz, 6N/, 1,5-1,8/m, 1H/, 1,988,6/m, 2N/- PAMR connection 1-1-3 /l3/ mln.:

1,1-1,5/m , N/, 1,6-1,7/m , 1H/, 1,9-2,0/m, 3H/,2,3-2,5/m, 2N/, 2,8-3,2/m , 1H/, 3,3-3,7/m, 3H/, 3,8-4,5/m, 4H/, 5,2-5,6/m, 1H/, 6,4-6,7/m , 1H/, 7,0-7,6/m , 7H/, 8,3-8,5/m , 2H/, PAMR connection 1-2-4 /l3/ mln.:

1,25/so, I=8 Hz, 3H/, 1,33/e, I=8 Hz, 6H/, 1,7-2,0/m, 1H/,

2,2-2,6/m , 3H/, 2,9-3,8/m, 3H/, 3,8-4,6/m, 2H/, 4,10/sq, I=8 Hz, 2H/, 4,12/c. 3H/, 4,9-5,4/m, 1H/, 6,3-7,2/m, 10H/, PAMR connection 1-1-5 /l3/ mln.:

0,8-11, /m , 4H/, 1,28/so, I=7 Hz, 3H/, 1,4-1,8/m, 2N/, 1,89/c. 3H/, 2,1-2,6/m, 4H/, 3,0-3,8/s 2N/, 3,98/c. 3H/,

4,18/sq , I= 7 Hz, 2H/ 4,3-4,6/m, 1H/, 5,3-5,7/m, 1H/, 6,4-6,8/m, 1H/, 6,9-7,3/m, 4H/, PAMR connection 1-1-6 /l3/ mln.:

1,29 /so, I=7 Hz, 3H/, 1,37/e, I=7 Hz, 6H/, 1,4-1,9/m, 2H/,

2,2-4,7/m , 2H/, 3,0-3,9/m, 3H/, 3,9-4,7/m, 2H/, 4,19/sq, I=7 Hz, 2H/, 5,1-5,5/m , 1H/, 6,6-6,9/m, 1H/, 7,0-8,6/m, 10H/, PAMR connection 1-1-7 /l3/ mln.:

1,28/so , I=7 Hz, 3H/, 1,32.D., I=7 Hz, 6H/, 1,4-1,8/m, 2H/, 1,84/c. 9H/, 1,89/c. , 3H/2,3-2,6/m , 3H/3,1-3,7/m, 1H/, 3,41/heptane, I=7 Hz, 1H/, 3,9-4,7/m , 2H/, 4,17/sq, I=7 Hz, 2H/, 5,1-5,5/m, 1H/, 6,4-6,7/m, 1H/, 6,9-7,3/m, 4H/, PAMR connection 1-1-10 /l3/ mln.:

1,29/so, I=7 Hz, 3H/, 1,33/e, I=7 Hz, 6H/, 1,4-1,9/m, 2H/,

1,90/c. 3H/, 2,2-2,6/m, 3H/, 3,1-3,7-/m, 1H/, 3,43/heptane, I=7 Hz, 1H/, 3,8-4,5/m, 2N/, 4,19/kV, I=7 Hz, 2H/, 5,1-5,5/m, 1H/, 5,62/c. 2H/, 7,3-7,7/m, 1H/, 6,9-7,6/m, N/, PAMR connection 1-1-14 /l3/ mln.:

0,9-1,3/m , 4H/, 1,4-1,8/m , 2H/, 1,28/so, I=8 Hz, 3H/, 2,3-2,5/m, 3H/, 4,1-4,2/m , 1H/, 4,3-4,5/m, 1H/,4,18/square I=8 Hz, 28 Hz, 3H/, 1,4-1,8/m, 2H/,1,78/c. 9H/, 1,87/c. , 3H/, 2,3-2,5/m, 1H/, 2,4-2,5/m, 2H/,4,0-4,1/m, 1H/, 4,18/sq, I= 8 Hz, 2H/, 4,3-4,4/m, 1H/, 5,50/doctor,doctor,I=17 Hz, j=6 Hz, 1H/, 6,55/e, I= 17 Hz, 1H/, 7,0-7,3/m, 4H/, PAMR connection 1-1-16 (l3) million dollars.:

0,4-0,9/m , 4H/, 0,9-1,5/m, 6H/, 1,29/so, I=8 Hz, 3H/, 1,74/c. 9H/, 2,2-2,5/m , 2H/, 2,4-2,5/m, 2H/, 3,9-4,5/m, 2H/, 4,19/sq, I=8 Hz, 2H/, 5,50/doctor , doctor , I=17 Hz, j=6 Hz, 1H/, 6,58/e, I=17 Hz, 1H/, 6,9-7,4/m, 4H/ PAMR connection 1-1-17 (l3) million dollars.:

0,9-1,5/m , 6H/, 1,28/so, I=8 Hz, 3H/, 1,86/c. 9H/,2,2-2,6/m, 1H/, 2,3-2,5/m , 2H/, 3,9-4,5/m, 2H/, 4,18/sq, I=8 Hz, 2H/, the 5.45/doctor,doctor, I=17 Hz, j=6 Hz, 1H/,

6,63/e, I=17 Hz, 1H/, 6,8-7,3/m, 9H/,

In the same way as in example 2, were obtained compound 1-5-2-1-5-18. The physical properties of the compounds obtained are shown in table. 7. PAMR connection 1-5-8 (l3) million dollars.:

1,0-1,7/m, 2H/, 1,29/e, I=7 Hz, 6H/, 1,47/so, I=7 Hz, 3H/,

1.7 to 2.3/m , 3H/, 3,1-3,3/m, 1H/, 3,3-3,9/m, 1H/, 3,53/heptane, I=7 Hz, 1H/, 4,0-4,3/m , 1H/, 4,49/sq, I=7 Hz, 2H/, 5,2-5,5/m, 1H/, 6,4-6,7/m, 1H/, 7,0-7,7/m, 5H/, PAMR connection 1-5-14 (l3) million dollars.:

0,9-1,3/m , 4H/, 1,3-1,8/m , 2H/, 1,9-2,0/m, 1H/, 2,4-2,6/m, 2H/, 3,5-3,7/m , 1H/, 4,04/c. 3H/, 4,1-4,2/m, 1H/, 5,51/doctor,doctor, I=17 Hz, j=6 Hz, 1H/, 6,44/e , I=17 Hz, 1H/, 6,8-7,2/m, N/, PAMR connection 1-5-15 (l3) million dollars.:

1,0-1,2/m, 4H/, 1,3-1,8/m, 2H/, 1,71/c. 9H/, 1,77/c. 3H/,1,9-2,1/m , 1H/, 2,4-2,5/m, 2H/, 3,5-3,6/m, 1H/,4,1-4,2/m, 1H/, 5,52/doctor,doctor, I=17 Hz, j= 6 Hz, 1H/, 6,38/e, I=17 Hz, 1H/, 7,1-7,3/m, 4H/, PAMR connection 1-5-16 (l3) million $ I=6 Hz, 1H/, 6,40/e, I=17 Hz, 1H/, 7,2-7,4/m, 4H/. PAMR connection 1-5-17 (l3) mln.;

1,0-1,2/m , 4H/, 1,3-1,8/m, 2H/, 1,80/c. 9H/, 1,9-2,1/m, 1H/, 2,5-2,6/m, 2H/, 3,5-3,6/m, 1H/,4,1-4,2/m, 1H/, 5,51/doctor, doctor, I=17 Hz, j=6 Hz, 1H/, 6.42 per/e, I=17 Hz, 1H/, 6,8-7,2/m, 9H/.

P R I m e R 3. /E/-7-/4-/4-forfinal/-1,3-dimethyl-6-/1-methylethyl/pyrazolo /3,4-b/pyridine-5-yl/-3,5-dihydroxide - 6-ANOVA acid (compound 1-2-1).

0.25 g (of 0.53 mmole) connection 1-1-1 was dissolved in 3 ml of ethanol, to the solution was added dropwise 1,06 ml of 0.5 N. aqueous solution of sodium hydroxide. The ethanol was distilled under reduced pressure, and then to the mixture was added 3 ml of distilled water. The solution was washed with diethyl ether. The aqueous layer was carefully kind of balanced out 1% hydrochloric acid and was extracted with diethyl ether. The ether layer was dried over anhydrous magnesium sulfate and was supariwala under reduced pressure, giving the desired compound.

Quantity: 0.21 g/yield:90%/,

PAMR (DMSO-d6/ mln.: 1,29/e, I=7 Hz, 6N/, 1,83/c. 3H/, 2,1-2,3/m , 2H/, 2,4-2,6/m, 1H/, 3,0-3,6/m, 4H/, 3,96/c. 3H/, 4,3-4,8/m, 2N/, 5,2-5,6/m, 1H/, 6,3-6,6/m, 1H/, 7,2-7,4/m, 4H/, 11,5-12,0/Shir. C., 1H/.

The compounds of this invention exhibit high inhibitory activity against cholesterol biosynthesis, in which G-COA reductase acts as an enzyme, limit theine. Thus, the compounds of the present invention are useful as therapeutic agents against hyperlipidemia, hyperlipoproteinemia and atherosclerosis.

They can be transformed into a variety of suitable prom or ready forms of drugs depending on the assignment method. Compounds of the present invention may be administered in the form of free acids or in the form physiologically hydrolyzable and acceptable esters or lactones, or pharmaceutically acceptable salts.

The pharmaceutical composition of the invention preferably is prescribed orally in the form of compounds of the present invention by itself, or in the form of powders, granules, tablets or capsules formulated by mixing the compounds of the present invention with a suitable pharmaceutically acceptable carrier, comprising a binder such as hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, gum tragakant, polyvinylpyrrolidone or SMS-Sa, excipient, such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine or powder, crystalline cellulose, a lubricating agent such as magnesium stearate, talc, the polyethylene glycol or silica, Armenia is not limited to such a oral appointment, it is applicable for parenteral purposes. For example, it may be administered in the form of a suppository formed using an oil base material, such as cocoa butter, polyethylene glycol, lanolin or triglyceride of fatty acids, transdermal therapeutic base formed with a liquid paraffin, white vaseline, higher alcohols, ointment Macrogol, hydrophilic ointment or gidrogennogo base material, injectable formulation prepared using one or more materials selected from the group consisting of polyethylene glycol, gidrogennogo base material, distilled water, distilled water for injection and excipient, such as lactose or corn starch, or preparative forms for appointment through the mucous membrane, such as mucous membrane of the eyes, nasal mucosa and the mucosa of the mouth.

In addition, the compounds of the present invention can be combined with the basic ion exchange resins, which are capable of binding bile acids and still not absorbed by the gastrointestinal tract.

Daily dose of the compounds of formula I is 0,. the oz can of course vary depending on the return, weight and condition of the patient.

Compounds of formulas II-VII are new, they are important intermediate compounds for preparing compounds of formula I. Accordingly, the present invention relates also to compounds of formulas II-VII and to the processes of their production.

Examples of pharmacological tests.

Test A: Inhibition of cholesterol biosynthesis from acetate in vitro.

The enzyme solution was prepared from the liver of male rats Wistar, which was inserted cannula and output of bile within 24 h, the Liver was cut in twilight and microsome assay and the fraction floating on top, can precipitate 40-80% solution of ammonium sulfate (soup fraction) were prepared from liver homogenate according to the modified method Knauss et al, Kuroda, M., et. al., Biochim. Biophys. Acta,: 489, 119/1977/. For analysis of the biosynthesis of cholesterol, microsome assay (0.1 mg protein) and soup fraction (1.0 mg protein) were incubated for 2 h at 37aboutWith 200 µl reaction mixture containing ATP, 1 mm Glutathione, 6 mm Glucose-1-phosphate, 10 mm NAD; 0.25 mm, 0.25 mm NADP, SOA, 0.04 mm and 0.2 mm (2-14C) sodium acetate (0; 2 CI) with 4 μl of a solution of the test compounds, dissolved-CON and the mixture was heated at 75aboutC for 1 h is Not capable of saponification of the lipids were extracted with petroleum ether and were counted introduced radioactivity 14C. Inhibiting activity of the compounds expressed by the indicator IC50.

Test: Inhibition of cholesterol biosynthesis in cell culture.

Cells ner G2 was sown on 12 mesh plates and were incubated with the modified bagle environment Duibecco (DME) containing 10% of bovine embryo serum (IBS) at 37aboutC, 5% CO2up until the cells became confluent within approximately 7 days. Cells were exposed to DME medium containing 5% serum with a lack of content lipoprotein (LpDS), obtained by the method of ultracentrifugation for almost 24 hours the Medium was replaced with 0.5 ml of fresh 5% LpDS containing DME prior to analysis, and were added 10 μl of a solution of the test compounds dissolved in water or DMSO. After 0 hours (B-1) or 4 h (b-2) after adding the compounds were added to 0.2 CI (214C) sodium acetate (20 µl). After additional incubation for 4 h with (214C) sodium acetate medium was removed, cells were washed with saline, buferizovannyiy phosphate (S), cooled at 4aboutC. The UP>C. a healthy dose of liquid from the stage of thererofre was used for analysis of protein, and the rest of malalas 1 ml of 15% Et-CON at the 75aboutC for 1 h Unsaponifiable lipids were extracted with petroleum ether, were counted14With radioactivity. The results of the count were tested in cellular protein designated by the value of the use of frm/mg (disintegrations per minute/mg protein. Inhibitory activity of compounds expressed by the value of the IC50.

Test: Inhibition of cholesterol biosynthesis in vivo. The male rats Spragne-Dawley weighing about 150 g were given food in the form of conventional food Ourina and water needs, and before using to test for inhibition of in vivo biosynthesis of cholesterol in rats subjected to the impact of the lighting scheme 12 h light /12 h darkness (2:00 after noon - 2:00 until noon in a dark time). Animals were divided into groups of five rats, so that the average body mass was present in each group. Compound in a dose of 0.02-0.2 mg/kg of body weight (0.4 ml/100 g body weight) was dissolved in water or suspendibility in 0.5% methylcellulose and administered orally for 2-3 hours before dusk (8:00 in the afternoon) when cholesterol biosynthesis in rats reached a maximum. As the counter is itonline 10 MK CI (2-14C) sodium acetate in a volume of 0.2 ml each after 2 h took samples of blood, immediately separated serum. Total lipids were extracted according to the method of Folch and others and amylases a mixture Eton-CON. Unsaponifiable lipids were extracted with petroleum ether, counted the radioactivity, the introduction of unsaponifiable lipids.

Inhibitory activity was observed as the percentage decrease in the number of counts (a measure background radiation) in the test groups (disintegrations per minute/2 ml serum (2 h) compared to the control group.

As for the compounds of the present invention indices of inhibitory activity against cholesterol biosynthesis, in which G-COA reductase serves as a limiting speed of the enzyme was measured using the above tests a and B. the Results are shown in table. 2, 2-2, 3, 3-2, and 3-3. Additionally presents the results of measurements using test With.

Indicators inhibitory activity of the reference compound using tests As below:

Reference compound IC50(molar concentration)

CS - 514 1.1 x 10-8< / BR>
In table. 8 presents indicators of the relative activity per BR>< / BR>
Inhibitory activity of the test In-1 below: Reference IC50 (molar connection Naya concentration) CS-514 1,1x106< / BR>
In table. 9 shows the relative activity based on the activity of the compounds of CS-514 testing In-1, estimated equal to 1.

Additionally, the test results In-1 table. 10 shows data inhibitory activity of the compounds of the present invention in a concentration of 1.H-7mol/L.

The results of measurement of inhibitory activity according to the test With.

The percentage decline starting after oral destination 0.2 mg/kg connection 1-5-4, 1-5-5 and 1-5-7 were, respectively, 53, 49, and 52% relative to the measured values of the control group. Percent reduction calculations after oral destination 0.2 mg/kg compound CS-514 in the same conditions was 39%.

Compounds of the present invention showed activity higher than the reference compounds CS-514 in tests a, b and C.

Test D: Acute toxicity.

a 0.5% suspension in CMC, the test compounds were administered orally to male ICR mice (a group of three mice). Acute toxicity was determined on the basis of mortality after seven days. Sony was administered orally in the amount of 1000 mg/kg, respectively.

1. DERIVATIVES of PYRAZOLO(3,4-B)PYRIDINE of General formula

R1Z

where R1is hydrogen, C1- C8-alkyl, C3- C6-cycloalkyl

or

< / BR>
where R6is hydrogen, chlorine, bromine or fluorine;

R2linked to the nitrogen of the nitrogen in position 1 or 2, pyrazolo-pyridine ring, and means C1- C8- alkyl, phenyl, benzyl, 2,3-or 4-pyridyl or alkoxyphenyl;

R3- fluorine, chlorine or bromine;

R4is hydrogen;

R5- C1- C8-alkyl or C3- C7-cycloalkyl;

Y - CH=CH-;

Z is a group of the formula

< / BR>
or a group of the formula - Q-CH2-W-CH2-CO2R12,

where Q is-CH(OH), W-C(R11)(OH), where R11is hydrogen, R12is hydrogen or alkyl part chemically or physiologically hydrolyzable alkyl ether complex or sodium, potassium or 1 - 2 calcium.

 

Same patents:

The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bis-(4-alkylaminopiridinium-1)alkanes of formula (1) where X stands for lipophilic anion from the following group: triiodide I3, iodate IO3, perchlorate ClO4; Y stands for either linear or branched alkylene group, which contains 4 to 18 carbon atoms; R stands for either linear or branched alkyl, cycloalkyl or arylalkyl group, which contains 5 to 18 carbon atoms, to methods of preparation thereof and application thereof as antibacterial and antiviral substances.

EFFECT: new substances show useful biological properties.

10 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of bis(4-alkylaminopyridine-1) alkanes of formula I where R1 -s linear or branched alkyl, cycloalkyl or arylalkyl groups having from 4 to 18 carbons, preferably from 8 to 12 carbons, ideally - normal octyl, R2 - linear or branched alkylene groups having from 4 to 18 carbons, preferably from 8 to 14 carbons, ideally - 1,10 decandyl, X1, X2 - halogenanions (identical or diverse): fluoride-, chloride-, bromide-, iodideanions, ideally - chlorideanions through interreacting of 4-alkylaminopyridine of formula II with disubstituted alkylene of formula III X1-R2-X2 in a solvent at increased temperature with mole ratio of formula II compound to formula III compound equals 2:1, the process is carried out in anoxic environment, acetic acid or its mixture with water is used as a solvent, meanwhile the compound of formula II is treated with the compound of formula III in gradual and continuous way or portionwise, ensuring the reaction at temperature ranging from 90° to 130°C, ideally from 100 to 105°C.

EFFECT: preparation of bis(4-alkylaminopyridine-1) alkanes of high quality with higher yield at essential saving of expandable materials.

6 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing HIV protease inhibitor atazanavir sulphate in form of Form A crystals, which involves reacting a solution of a free base of atazanavir in an organic solvent in which atazanavir sulphate is virtually insoluble, at temperature ranging from 35°C to 55°C with a first portion of concentrated sulphuric acid in an amount sufficient for reaction with less than approximately 15 wt % free base of atazanavir, addition of nucleating centres of Form A atazanavir sulphate crystals, addition of an additional amount of concentrated sulphuric acid in several steps, where the acid is added at increasing rate to form atazanavir sulphate crystals and drying the atazanavir sulphate to form Form A crystals. A method of producing atazanavir sulphate in form of Form C crystals is also proposed.

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20 cl, 11 dwg, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , where R2 is selected from a group consisting of (1) phenyl, which is substituted with R2a, R2b and R2c, (2) furanyl, (3) C3-6 cycloalkyl; R2a, R2b and R2c are independently selected from a group consisting of (1) hydrogen, (2) halogen, (3) C1-6 alkyl, which is unsubstituted or substituted with (a) 1-6 halogen atoms, (4) -NR10R11, where R10 and R11 are hydrogen; R3 is C1-6 alkyl or C3-6 cycloalkyl, which is independently unsubstituted or substituted with 1-6 halogen atoms; R4 and R5 are hydrogen and m equals zero, R2 is directly bonded to a carbonyl; and to pharmaceutically acceptable salts thereof. The invention also pertains to compounds which are selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter GlyT1 inhibitors.

10 cl, 14 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 2,6-diazido-3,5-dicyanopyridine of formula (I), as well as synthesis method thereof, which involves reaction of a chloro-substituted derivative of 3,5-dicyanopyridine with an azidation agent in the medium of aqueous acetone, followed by extraction of the end product.

EFFECT: novel compound which can be used in synthesis of high-energy compounds is obtained and described.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing N-methyl-4-benzylcarbamidopyridinium iodide (MBI), which is used as substance in medicinal agents, involving reaction of isonicotinic acid with benzylamine at temperature 160-185°C and molar ratio 1.0:1.2 and alkylation of the obtained benzylamide of isonicotinic acid with methyl iodide at 40-50°C and molar ratio 1.0:1.2.

EFFECT: high output of the end product and low solvent consumption.

2 cl, 2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I), including any stereochemical isomer forms thereof, or a pharmaceutically acceptable salt thereof, , wherein A is phenyl or 6-member aromatic heterocycle containing 1 or 2 nitrogen atom; wherein said phenyl or 6-member aromatic heterocycle may be optionally condensed with phenyl; Z is CH2 or O; R1 is halogen, hydroxyl, C1-4alkyl, C1-4alkyloxy, or provided A is phenyl, then two neighbour substitutes R1 may be taken together to produce a radical of formula: -O-CH2-O- (a-1) or -O-CH2-CH2-O- (a-2); R2 is hydrogen or C1-4alkyl; each R3 and R4 independently is hydrogen, C1-6alkyl, C1-4alklyloxyC1-6alkyl or phenylC1-4alkyl; or R3 and R4 taken together with a nitrogen atom whereto attached form a radical of formula or , wherein X1 is CH2 or CHOH; and X2 is CH2, O or NR6; R5 is hydrogen, halogen, C1-4alkyl or C1-4alkyloxy; R6 is hydrogen, C1-4alkyl, C1-4alkylcarbonyl; n is equal to an integer 0, 1 or 2; provided the compound is other than , or a pharmaceutically acceptable salt thereof.

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22 cl, 10 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of preparative obtaining 5-methoxypyridine amine-2, which is realised by substitution of bromine in 5-bromopyridine amine-2 by means of sodium methoxide under conditions of microwave initiation, with reaction proceeding in methanol with catalysis by microdisperse powder of copper (I) oxide at 120-150°C for 3-4 h.

EFFECT: elaboration of method of preparating obtaining 5-methoxypyridine amine-2 preparative obtaining.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3,4,5-triazidopyridine-2,6-dicarbonitrile of formula (I) and the method of its production. 3,4,5- triazidopyridine-2,6-dicarbonitrile of formula (I) was produced by azidation of 3,4,5-trichloropyridine-2,6-dicarbonitrile with sodium azide in aqueous acetone.

EFFECT: invention can be used to produce new energy-intensive materials.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

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48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: invention relates to composition for dying keratin fibres, including 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1on as first oxidised base, 6-chlor-2-methyl-5-aminophenol as first component of condensation and substituted m-aminophenol as second component of condensation. Molar ratio of first oxidised base and first component of condensation is lower than 1.5, molar ratio of first oxidised base and second component of condensation is higher than 1, and molar amount of first oxidised base is higher or equals 2.5·10-3 mole per 100 g of composition.

EFFECT: claimed composition ensures obtaining intensive, chromatic, esthetically attractive low-selective and stable with respect to different aggressive impacts dying of keratin fibres with copper-red shades and, in addition, with neutral pH value.

16 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: medicine.

SUBSTANCE: invention refers to new compounds with pharmacological activity to sigma-receptor, and more specifically to pyrazole derivatives of formula (I) in which radicals and symbols have the values defined in cl. 1 of the patent claim; to a method for preparing such compounds; to a pharmaceutical composition containing them and to their application for manufacturing a medicinal agent for treatment and prevention of a sigma-receptor mediated disease or a condition, particularly for treatment of psychotic illness, such as depression, anxiety or schizophrenia, and neuropathic or inflammatory pain, including allodynia and/or hyperalgesia.

EFFECT: improved clinical effectiveness.

11 cl, 2 dwg, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

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