RU1795971C - Method of pyrazolpyridine or its salt synthesis - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of a pyraeolopyridine compound of the general formula: CH CH-DH CH-ty-C (0) - 1 N, where R1 is phenyl, R2 is piperidine substituted with lower alkyl, hydroxy (lower) alkyl , or its salt, which has a diuretic and antihypertensive effect, which can be used in medicine. The goal is the creation of new, more active substances of the specified class. The synthesis is carried out by the reaction of the corresponding acid or reactive derivative with a compound followed by isolation of the target product in free form or in the form of a salt. The new compounds are of low toxicity and in activity are better known analogues. 2 tab.

Description

ate

with

magnesium and evaporated in vacuo. The residue was chromatographed over 40 g of silica gel using chloroform as an eluent. The fractions containing the target compound were combined and evaporated in vacuo to give 1.30 g of 1- / 3- (2-phenyl-pyrazolo / 1,5-е / pyridin-3-yl / -acryloyl / - 2-ethylpiperidine (trans isomer) as an oil-like product.

This compound is converted to hemi-fumarate to give 0.96 g of yellow crystals of 1- 3- (2-phenylpyrazolo / 1,5-е) - pyridin-3-yl / -acryloyl -2-ethylpiperidi n-semifumarate (trans isomer). Mp 121-122 ° C (from a mixture of n-hexane with diethyl ether).

IR spectrum (liquid paraffin), cm: 1705, 1635, 1580. 1530L510.

NMR spectrum (OMSO-о b) (5, ppm): 0.77 (ЗН, t, 7.0 Hz), 1.30-1.83 (8N.m.), 6.66 ( 1H, s.), 6.83 (1H, d., 16.0 Hz), 7.00-7.83 (8H, m.), 8.07 (1H, d. 9.0 Hz). 8.77 (1.H, d. 7.0 Hz).

Elemental analysis data for

C23H25N30-0.5C4H404.

Calculated: C 71.92; H 6.52; N, 10.06. Found: C, 72.01; H 6.60; N, 10.03. PRI me R 2.

sn sn-soon

hL4-N-N

and

Under ice cooling, 1.79 g of thionyl chloride was added dropwise to a stirred mixture of 2.0 g of 3- (2-phenylpyrazolo / 1,5-е / pyridin-3-yl) -acrylic acid (trans-isomer) with 4 drops of M, M-dimethylformamide in 10 ml of methylene chloride ..

After stirring at room temperature for 3 hours, the solvent was evaporated in vacuo to give the acid chloride derivative.

On the other hand, under ice cooling and 6.80 g of bis- (trimethylsilyl) -acetamide, 6.48 / R / -2- (2-hydroxyethyl) -piperidine was added dropwise. The mixture was warmed to room temperature for 20 minutes with stirring.

Then 1.53 g of triethylamine and 40 ml of methylene chloride were added to the mixture. The above acid chlorohydride derivative was added to this mixture while cooling with ice, and the whole mass was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and 10 ml of a 1N hydrochloric acid solution and 10 ml of ethyl acetate were added to the mixture.

The resulting mixture was stirred for 30 minutes, and then 12 ml of a 1N sodium oxide solution were added and 60 ml of methylene chloride was extracted. The extract was dried over magnesium sulfate and the solvent was evaporated. The residue was chromatographed over 40 g of silica gel using a mixture of methylene chloride and ethyl acetate in a ratio of 5: 1. The fractions containing the target compound are combined and evaporated in vacuo to give 1.83 t (2P) -1- / 3- (2-phenylpyrazolo / 1,5-a / pyridin-3-yl) -acrylo sludge / 2- (2-hydroxyethyl) -piperidine (trans isomer), mp 145-146.5 ° C.

   + 39.61 ° (s - 1.04, 95% ethanol).

IR spectrum (liquid paraffin), cm: 3350.1640.15.1575.1520 cm 1.

NMR spectrum (CDC 1 s) b, ppm: 1.23-2.20

(8H, m), 2.63-3.90 (4H, m.), 4.00-4.40 (1H. M).

4.67-5.10 (1H, m.), 6.63 (1H, d. 16.0 Hz), 8.50

(1 N, t. 7.0 Hz), 7.77 (7H, m.), 7.92 (1 H, d, 16.0

Hz), 8.47 (1 H, doublet, 7.0 Hz).

Elemental analysis data for C2zH25Mz02:

Calculated: C 73.58; H 6.71; N, 11.19. Found: C, 73.98; H 6.76; N, 11.24. Mass spectrum: 375 (M + 4). In accordance with a procedure similar to that described above in Example 2, the following compounds were prepared (Examples 3-18).

Example 3,, -. CONQ J A

J C./

Mr. he

0

5

0

5

(25 / -1- / 3- (2-Phenylpyrazolo / 1,5-a) pyridin-3-yl) acryloyl / -2- (2-hydroxyethyl) piperidine / trans isomer). so pl. 98-99.5 ° C.

a D23 0 -41.20 ° (c- 1.0, 95% ethanol).

IR spectrum (chloroform), cm: 3330, 1635, 1570, 1520.

NMR spectrum (СОС1з) 5, ppm: 1.17-2.20 (8Н.m.), 2.67-4.00 (4Н, m.), 2.73 (1 Н, s) 4.67-5.10 (1 H, m), 6.70 (1 H, d, 16.0 Hz), 6.89 (1 N. t., 7.0 Hz), 7.25- 7.87 (7H, m.), 8.00 (1H, d, 16.0 Hz), 8.57 (1 H, d, 7.0 Hz).

Elemental analysis data for C23H25N302:

Calculated: C 73.58; H 6.71; N, 11.18.

Found: C, 73.68; H, 6.81; N, 11.21.

Mass spectrum: 375 (M4).

Example 4. CONQ

f he

Ag-O

N-n

Male SD rats weighing 200-300 g are killed by lowering their blood and the thoracic aorta is removed. In organ baths filled with 25 ml of Tyrode's solution, helical strips 2.0 x 15 mm in size are suspended. These strips are connected to a strain gauge and isometric tension is measured. A stream of bubbles of a mixture of 95% oxygen with 5% carbon dioxide is passed through a solution in the bath, and its temperature is maintained at 37 ° C. After adjusting the resting tension to 0.5 g, the arterial strips are contracted using a 3.2 x M norepinofrin solution.

The test substance is added cumulatively to the organ bath. At the end of each test, papaverine solution M was added to the organ bath to achieve maximum relaxation.

(II) Test compound.

(2P) -1 / 3- / 2-Phenylpyrazolo / 1,5-a / pyr idin-3-yl / acryloyl / 2- / 2-hydroxyethyl / piperidine (trans isomer) (compound of example

2).

(Iii) Test Results. The value of MKgo is 5.3 x g / ml. Test 2.

The action to enhance the flow of renal blood .;

(I) Test Procedure.

The test was carried out on adult dogs of the beagle breed of both sexes weighing 8-15 kg. Under anesthesia with 35 mg / kg sodium pentobarbital, administered intraperitoneally, the trachea is intubated for artificial respiration; Catheters are inserted into the femoral vein to deliver the drug to the body.

A short incision of the left renal artery is exposed by a side incision and adjacent tissue is removed to make room for the installation of an electromagnetic flow velocity sensor. Renal blood flow is measured by connecting a speed sensor to a flow meter.

(II) Test compound.

The same compound as used in test I.

() Test results,

Dose mg / kg increased renal blood flow,%

0.2 blood% + 19.7

Test 3. Diuretic effect. (I) Test Procedure.

The test is carried out on rats of the race FCLSD at the age of 6 weeks weighing 170-206 g after animals were kept on hunger for 18 hours. Directly

after oral administration of a test substance suspended in 0.5% methylcellulose (0.5% MC) to the body, 20 ml / kg saline is administered to the animals by mouth. Rats are seated three animals per cell to study metabolism. Urine is collected within 3 hours. Urine volume is measured with a graduated cylinder, and uric acid in urine is determined using a Determiner

5 UAKit (manufactured by Kiova Medex Co., Ltd.). Tests were carried out on 3 groups of animals, 3 animals each.

The test results are presented in Table 1.

0 1- / 3- (2-Methyl-b-phenylimidazo / 2,1-b / -1,3,4-thiadiazol-5-yl) acryloyl / -2-ethylpiperidine (trans isomer) (compound of example 35 of EP-0041215, class C 07 D 513/04, 1981). .

5 Test 4. Antihypertensive activity.

Test method.

In male Wistar rats aged 11 weeks, one kidney was removed under anesthesia. Deoxycorticosterone acetate (DOSA), subsidized in peanut butter, is administered subcutaneously in an amount of 30 mg / kg 2 times a week / Drinking water is replaced with 1% saline,

5 For the experiment, animals with an average blood pressure of ISO-200 mmHg are used for 5 to 11 weeks after surgery.

Test compound (dosage

0 10 mg / kg) is given for oral administration daily for 5 days to rats whose blood pressure is elevated by DOS.

Blood pressure is measured at the femoral artery using a pressure transducer

5 and recorded as electrically integrated mean blood pressure values.

The test results are presented in Table 2.

0 Test 5 ,. . . . Inhibition of platelet aggregation. (I) Test Procedure. Blood is collected from the carotid artery of male Japanese white rabbits weighing 2.5-3.0 kg and mixed in a 1:10 volume ratio with a 3.8% sodium citrate solution. After centrifugation of the mixture at 150 g for 15. min, a plate-rich plasma (CPP) was obtained.

The ability of the plates to aggregate is measured using an aggregometer (nikohklzal NKK NEMA TRACER model PAT-4A). 0.24 ml of CPR containing 6.5-7.5 x 108 plates / ml and 5 μl of the test solution or a mixture of polyethylene glycol 200 with ethanol and water in a 1: 1: 2 ratio are successively added to the cuvette. The whole mixture was stirred for 2 minutes at 37 ° C and 125 µg / ml of collagen was added to initiate the aggregation process. The test was conducted using PPC obtained from 3 other rabbits.

(II) Test compound. The same compound as used in test I.

(Iii) Test Results. Inhibitory effect on plate aggregation. The ICbo value is 7.9 x g / ml. Test 6. Cardiotonic action.

(I) Test Procedure.

Hartley male guinea pigs are weighed 500-600 g each by lowering the blood, after which the heart is removed from each animal. The arterial strip is removed and suspended in an organ bath containing 50 ml of Tyrode solution, the temperature of which is maintained at 30 ° when aerated with a gas mixture containing 95% oxygen and 5% carbon dioxide. The atrium is connected to a tension sensor with an initial tension of 0.4-0.6 g. After achieving constant mobility, a drug agent is added to the bath solution, and the effect on compression force and pulsation rate are observed for 30 minutes. Efficacy is expressed as percentages before and after drug administration. For each concentration, 3 separate preparations are used.

(II) Test compound, The same compound as that used in test I.

() Test results are shown below.

Test compound concentration 10 g / ml Percentage increase in compressive force 10.0 Percentage increase in cardiac pulsation -10.7 Test 7. Antihypertensive effect .;

(I) Test Procedure.

Under anesthesia in Wistar rats, one kidney was removed at eleven weeks of age. Twice a week, animals were given OOMg / kg of deoxycardiosticosterone acetate (DOSA) suspended in peanut butter, and 1% saline was given as drinking water. . .

Animals with an average blood pressure of 150-200 mm Hg are used to determine the experiment. within 5 to 13 weeks after surgery.

The test compound (at a dose of 3.2 mg / kg) was administered orally daily for 5 days to animals suffering from hypertension caused by the use of DOS.

Blood pressure is measured on the femoral artery using a pressure sensor, which is recorded as electrically integrated values of mean arterial pressure.

(II) Test compound.

1- / 3- (2-Phenylpyrazolo / 1,5-a / pyridi n-3-yl) acryloyl / -2-ethylpiperidine polufuram (trans-isomer) (compound of example

1).

(Ill) Test Results.

The maximum degree of decrease in blood pressure is 32%.

The data presented prove the advantage of Compound I over known compounds EP No. 0041215, useful as diuretics for lowering blood pressure.

In terms of toxicity, the compound of formula I is low toxic.

SUMMARY OF THE INVENTION Method for the preparation of a pyrazolopyridine compound of the formula

CH CH-COR2

v TRi N-N

SI

where Ri is phenyl;

R2 is piperidine substituted with lower alkyl, hydroxy (lower) alkyl, lower alkanoyloxy (lower) alkyl or lower alkoxy (lower) alkyl, or a salt thereof, characterized in that

compound of the formula

sn sn-soon

.QsVv

where the Rt values are indicated above.

or its reactive derivative by a formula wherein R values are indicated

mine on the carboxyl group, or its salt above, or its salt with the allocation of the target

reacting with the product compound in free or salt form.

Table. Urine and uric acid excretion (control 100%) (dose 10 mg / kg)

Compound (A)

Antihypertensive activity

Table 2.