SU1077571A3 - Process for preparing derivatives of pyrazolo(1,5-a) pyrimidine - Google Patents

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Description

din, 7-f3-pyridyl) pyrazolo 1,5-a) -pyrimidine-pyridine-1-oxide, 2-methyl-7-- (3-pyridyl) pyrazolo (1, 5-a) -pyrimidine-3- carbonitrile, 2,6-dimethyl-7- (3-pyridyl) pyrazole (1,5-a) -pyrimidine-3-carbonitrile and the 2-methyl-7- (3-pyridyl) pyrazolo tv ester (1, 5- a.) pyrimidine-3f-carboxylic acid.

Another method was used to determine the tranquilizing effect, where the conflict state in rats was caused by a modification of this method. Groups of six Wistar rats weighing 200-230 g were deprived of water for 48 hours and food for 24 hours. The test compounds were administered in single or partial doses orally or intraperitoneally as a suspension in 2% starch carrier containing 0.5% by volume. % / vol, polyethylene glycol and one drop of polysorbate 80, Control animals received one carrier. After 30 or 60 minutes, each rat was placed in an individual black poly-anaglose chamber.

From the tap on the back wall of the chamber a 10% glucose solution was supplied. A constant current of 0.3 ml passed between the grated stainless steel floor and the tap. After 20 seconds, drinking without electrics was turned on.

an alternating cycle of 5 seconds with the electric pulse on and 5 seconds with the electric pulse off. This alternation of on and off lasted 5 minutes. The number of electrical pulses recorded by each rat for 5 min was recorded and compared with control animals. The test compounds are considered active, if in the test group the number of lesions by electric current that the rats withstood was greater than that in the control group.

The following are examples of compounds obtained by the proposed method, the activity of which was established during experiments using this method: 7- (3-pyridyl) piraoo (1,5-a) pyrimidine-3-carbonitrile. and

2-ethyl-7- (3-pyridyl) pyrazolo (-1,5-a) -pyrimidine-3-carbonitrile.

According to another way

used to determine the tranquilizing activity of the compounds obtained according to the proposed method, measure the ability of the test compound to suppress tritiated benzodiaepine receptor receptor headspace receptors in warm-blooded animals.

In the experiments we used male lins of Wistar -200 rats of 150-200 g, - N-methyldiaeeps1M

(79.9 Ci / mmol) and N-methylflunitrazepam (84.3 Cю / mmol). The test compounds were dissolved either in dimethylformamide, or in acetic acid, or ethanol, or hydrochloric acid.

The rat cerebral cortex was gently homogenized in 20 vol. ice-cold sucrose was centrifuged twice at 1000 rpm 0 for 10 minutes and then at

30,000 rpm for 20 minutes, charging the untreated B –naptozomol fraction, which was again suspended in two times volume 5 of a hypotonic 50 mM solution

Tris-NSSS (pH 7.4), or re-suspended in half of the initial volume of a hypotonic 10 NIM solution of Tris-HCI (pH 7.4) and 0 were frozen at up until use. The frozen formulations were thawed and suspended in four times the volume at the time of the experiment. 5 Associated sample contained

30 µl of the Cg Fraction Suspension (0.2-0.0 mg of protein), 100 µl of the test drug, and 100 µl of N-diazepam (1.5 nM final concentration) Qi or H-flunitrazepam (final

Concentration 1.0 nM), which added 1.5 ml of 50 mM Tris-NSb (pH 7.4). Control samples with non-specific binding and with half-binding were obtained by mixing, respectively, 100 µl of diazepam (final concentration 3 µM) and 100 µl of desalted water. Soak 30 minutes on ice and then incubation was stopped by filtration

0 under vacuum through the filters of the glass fiber company Watmann brand SG / S. The filters were washed twice with 5 ml of ice-cold 50 i Tris-HCl (pH 7.4) and placed in scintillic 5 test tubes. After drying at 50-60 ° C for 30 minutes, 10 ml of the Redi-Beckman HB salt was added and the radioactivity was determined using a Scintillation Beckman nutrient. Compounds capable of suppressing the binding of n-benzodiazepine at a concentration of 20% are considered active. Inhibition of binding was calculated from the difference between full binding and binding to

the presence of the test compound divided by the total binding and multiplied by 100.

The following compounds are compounds capable of suppressing bonds of n-benzodiazepine-specific receptors in the rat brain: 7- (3-pyridyl) pyrazolo ethyl ester (1,5-a) pyrimidine-3-carboxylic acid, 5-ethyl ethyl ester -7- (3-pyridyl) pyrazolo (1,5-a) pyrimidine-3-carboxylic acid, 7- {3-thienyl) piraeolo (1,5-a) pyrimidine-3carboxylic acid ethyl ester and 7- (3- pyridyl) pyrazolo {1, 5-a) pyrimidine-3-carbonitrile.

Example 1. 7- (3-Pyridyl) pyrazole (1, 5-a) pyrimidine.

A mixture of 50.0 g of 3-acetylpyridine and 60 ml of N, N-dimethyl formamide dimethyl acetal was refluxed for 16 hours. The solvent was removed in vacuo and hexane was added to the crystallization. The resulting crystals are recrystallized from methylene chloride-hexane and get 36.5 g of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-it with so pl. 66-67 C.

A mixture of 8.81 g of the obtained compound and 4.15 g of 3-aminopyrazole in 50 ml of glacial acetic acid was heated under reflux for 8 hours. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The solution is washed with an aqueous saturated sodium bicarbonate solution, the organic layer is separated and concentrated. Hexane is added and the mixture is cooled to form a crystalline vein, the precipitate is filtered off and a product is obtained. 146-147 C.

Example 2. 7- {3-Pyridyl) pyrazolo (1,5-a) pyrimidine-3-carbonitrile.

A mixture of 17.61 g of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one and 10.8 g of 3-aminopyrazole-4-carbonitrile in 75 ml ice is boiled under reflux for 6 hours Noah yi hydrochloric acid. The mixture is treated analogously to example 1, resulting in a gain of tan crystals with so pl. 258-260 S.

Example 3. 3-Methyl-7- (3-pyridyl) pyrazolo (1,5-a) pyrimidine.

Following the procedure of Example 2, a mixture of 3-amino-4-methylpyrazole and 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one is boiled under reflux for 6 hours in glacial acetic acid.

PRI me R 4. 3-Chlor-7- (3-pyridyl) pyrazolo (1,5-a) pyrimidine.

Following the procedure of Example 2, a mixture of 3-amino-4-chloropyrazole and 3-methylamino-1- (3-pyridyl) -2-propen-1-one in glacial acetic acid is boiled under reflux for 6 hours, the result is the prichgiot of the target product with m. 225-226 ° C.

Example 5. 2-Ztil-7- (3-pyridyl) pyrazolo (1,5-a) pyrimidine-3-carbonitrile.

Following the procedure of Example 2, a mixture of 2.72 g of 3-amino-5-ethylpyrazole-4-carbonitrile and 3.52 g of 3-dimethylamino-1 .- {3-py5 readyl) - - is boiled under reflux for 16 hours. 2-propen-1-one in 25 ml of glacial acetic acid, the result is 2.65 g of the desired product in the form of colorless crystals with

T..PL. 170-1; 2rs.

0 Example 6. 7- (3-Pyridyl) pyrazolo (1,5-a) pyrimidine-3-carboxylic acid ethyl ester.

Following the procedure of Example 2, boil for 16 hours with reverse

5 cooler mixture of 1.04 g of 3-amino-4-carboethoxypyrazole and 1.18 g of 3-dimethylamino-1- (3-pyrch1) -2-propen-1-one in 25 ml of glacial acetic acid, as a result 1.30 g of the desired product in the form of colorless needle-like crystals with so pl. 170-17lc.

Example 7. 2-ethyl-7- (3-pyridyl) pyrazolo (1,5-a) 5 pyrimidine-3-carboxylic acid ethyl ester.

Following the procedure of Example 2, a mixture of 1.83 g of 3-amino-4-carboethoxy-5-ethylpyrazole and 1.76 g of 3-dimethylamino-1- (3-pyridyl) -2- is boiled under reflux for 16 hours. propylene-l-one in 25 ml of glacial acetic acid, to obtain 1.20 g of the desired product in the form of colorless crystals with m.p. 119-120 C.

5 Example 8. 7- (3-Thienyl) pyrazolo (1,5-a) pyrimidine-3-carboxylic acid ethyl ester.

Following the procedure of Example 2, boil for 10 hours with reverse

0 by cooler a mixture of 3.10 g of 3-amino-4-carboethoxypyrazole and 3.62 g of 3-dimethylamino-1- (3-thienyl) -3-propen-1-one in 25 ml of glacial acetic acid j as a result

5 4.40 g of the desired product in the form of reddish-brown crystals with so pl. 129-130 ° C.

Example 9. 7- (3-Thienyl) pyrazolo (1,5-a) pyrimidine-3-carbonitrile.

0G Following the procedure of Example 1, a mixture of 35.0 g of 3-acetylthiophene and 50 ml of N, N-dimethylformamide dimethyl acetal is boiled under reflux for 12 hours.

5 get 43.5 g of crude product. 5.0 g of this product is recrystallized from methylene chloride-hexane, resulting in 3.85 g of 3-dimethylamino-1- {3-thienyl) -2-propen-1 .. -it with so pl. 89-90 ° C. and

for 16 hours under reflux 1 a mixture of 3.24 g of 3-gram No. 4-carbonitrile-4-carbonitrile and 5.44 g of the indicated recrystallized compound in 25 ml of glacial acetic acid is boiled, to give 3.25 g of the desired compound. product in the form of colorless crystals with so pl. 215-216 ° C. Example lOi b-Methyl-7- (3-pidyl) pyrazblo (l, 5-a) pyrimidine-3-carbonitrile. A mixture of 50.0 g of 3-propionylpyridine and 55 ml of methyl methylacetal H and i-dimethylformamide is heated under reflux for 15 hours. The solvent is stripped off in vacuo, and the residue crystallizes upon cooling. The solid is dissolved in methylene chloride, and the solution is passed through a column of magnesium silicate. Addition of hexane to ae: yields 34.4 g; 3-dimethylamino-2-methyl-1- (3-pyridyl) -2-Propen-1-it in the form of pale yellow crystals with so pl. 76-78 ° C. A mixture of 5.70 g of this product; And 3.24 g of 3-aminopyrazole-4-carbo: nitrile in 25 mp. glacial acetic acid was refluxed for 15 hours. The solvent was distilled off in vacuo. The residue was treated with a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic layer is dried with anhydrous sodium sulfate and passed through a column of magnesium silicate hydrate. Addition of hexane to the eluate gives 4.00 g of the desired product as colorless crystals with a mp. 193.5-194 ,. PRI me R 11. 3-Bromo-7- (3-pyridyl} pyrazolo (1,5-a) pyrimidine. A mixture of 0.01 mol of 3-dimethylamino-1- (3-pyridyl) -2-propene 1-she and 0.01 mol of 3-amino-4-bromopyrazap j in glacial acetic acid are heated under reflux for 8 hours, the solvent is distilled off and the desired product is obtained with mp 2432440 s. -Methyl-7- (3-pyridyl) pyrazolo (1,5-a) pyrimidine-3-carbonitrile, A mixture of 3.50 g of 3-dimethylamino- 1- (3-pyridyl) is refluxed for 6 hours. 2 -2 propen-1-one 25 ml of glacial acetic acid and 2.44 g of 3-amino-5-methylpyrazole-4-carbonitrile. The solvent is distilled under vacuum. The solvent was dissolved in dichloromethane, and the solution was washed with a saturated sodium bicarbonate solution. The dichloromethane layer was dried with anhydrous sodium sulfate and passed through a column of magnesium silicate hydrate. 245-246 0. Example 13. 2, b-Dimethyl-7- (3-pyridyl) pyrazolo (1,5-a) pyrimidine-3-carbonitrile. A mixture of 1.90 g of 3-dimethylamino-2- methyl 1- (3-pyridyl) -2-propen-1-one and 1.22 g of 3-amino-5-methylpyrazole-4-carbonitrile in 25 ml of glacial acetic acid are refluxed in t for 6 hours. The solvent is distilled off in vacuo, and the residue is extracted with a mixture of dichloromethane and a saturated aqueous solution of sodium bicarbonate. The dichloromethane layer was separated, dried with anhydrous sodium sulfate, and passed through a magnesium silicate column. The eluent is concentrated and hexane is added, to give 0.95 g of the desired product with so pl. 207-209 ° C. Example 14. 2-methyl-7- (3-pyridyl) pyrazolo (1,5-a) -pyrimidine-3-carboxylic acid ethyl ester. A mixture of 9.09 g of 3-dimethylamino-1- (3-pyridyl -2-propen-2-one and 2.54 g of ethyl ester 3-c. 5-methylpyrazole) is boiled under reflux for 16 hours. 4-carboxylic acid in 25 ml of acetic acid. The solvent is distilled off, and the residue in dichloromethane is washed with a saturated solution of sodium bicarbonate. The dichloromethane solution is passed through a column of magnesium silicate hydrate. The eluent is concentrated and hexane is added, to give 3.1 g of the desired product with a melting point of 145-14bs.Example 15. 2-methyl-7- (3-pyridyl) pyrazolo hydrochloride (1,5-a) pyrimidine-3-carboxylic acid In a water bath, a mixture of 3.0 g of ethyl 2-methyl-7- (3-pyridyl) -pyrazolo- (1,5-a) pyrimidine-3-carboxylic acid, 125 ml of ethyl alcohol is heated for 4 hours for 4 hours and 50 ml of 1N sodium hydroxide. The result is 2.92 g of 2-methyl-7- (3-pyridyl) pyrazolo (1,5-a) sodium pyrimidine-3-carboxylate with mp 375-380 ° C (with decomposition) 1.87 g of this salt is stirred for 16 hours with 30 ml of 1N hydrochloric acid and 1.6 g of the expected product are obtained with a mp. 280 C (with overlapping). Example 16. 7- (6-Methyl-2-pyridyl) pyrazolo (1,5-a) pyrimidine-3-carbonitrile. A mixture of 25.0 g of 2-acetyl-6-methylpyridine and 35 ml of N. is boiled for 16 hours. N, K-dimethylformamide cymetyl acetal. The mixture is cooled and filtered, the result is 3-dimethylg "CHO-1- {6-methyl-2-pyridyl) -2-propen-1-it in the form of crystals with so pl. 97-98 ° C.

Claims (1)

METHOD FOR PRODUCING PYRAZOLO (1,5-a) PYRIMIDINE DERIVATIVES - hydrogen or C <-Sualkyl; R. is hydrogen, chlorine, bromine, ' ⁴ CyC} -alkyl, cyano, carboxy or alkoxycarbonyl., Where CyCualkyl,' characterized by the fact that ⁰ 3-aminopyraeol of the general formula or C 4 -C γ -alkyl ⁴ , where Rj is hydrogen R. - unsubstituted pyridyl or “thienyl, or substituted with C (-Calkyl) where R ^ and R4 are as defined, are reacted with a compound of the general formula where R is CyCualkyl; R4 and R „have the indicated values *, followed by isolation of the target product.