[1,2,4] triazolo [1,5-c] pyrimidine derivatives

A technology of pyrimidine derivatives and triazolo, which is applied in the fields of drug combination, organic active ingredients, nervous system diseases, etc.

Inactive Publication Date: 2001-12-26
KYOWA HAKKO KOGYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the adenosine receptor antagonism of [1,2,4]triazolo[1,5-c]pyrimi

Method used

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  • [1,2,4] triazolo [1,5-c] pyrimidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0160] N-(4-Chloro-2-methylthiopyrimidin-6-yl)-N’-(2-furoyl)hydrazine (Compound A)

[0161] 2-Furohydrazide 65g (515mmol) and DBU70ml (510mmol) were dissolved in 150ml of DMF, at room temperature to which the DMF solution of 4,6-dichloro-2-methylthiopyrimidine was slowly added dropwise [50.0g (256mmol ) / 100mL] (control the internal temperature below 45°C). The reaction solution was stirred at room temperature for about 2 hours, then poured into ice water, adjusted to pH 6-7 with 2 mol / L hydrochloric acid aqueous solution, and the resulting solid was collected by filtration. The obtained solid was dissolved in an organic solvent (chloroform / methanol=10 / 1), washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue was triturated with chloroform (twice) to obtain 56.9 g of Compound A as white cotton-like crystals (yield 78%). The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatograp...

reference example 2

[0163] 7-Chloro-3-(2-furyl)-5-methylthio[1,2,4]triazolo[4,3-c]pyrimidine (Compound B)

[0164] In an argon atmosphere, 225 g (1.58 mol) of phosphorus pentoxide was suspended in 320 mL of xylene, 340 mL (256 g, 1.58 mol) of hexamethyldisiloxane was added thereto, and the mixture was heated at 90° C. for about 1.5 hours. After the contents were almost dissolved, 90 g (316 mmol) of Compound A was added, followed by further heating at 160° C. for 2 hours. After the reaction was completed, the reaction solution was cooled, then ice water was added, ammonia water was added under cooling (inner temperature 5° C. or less) to make it alkaline, and the mixture was extracted with chloroform. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate=1 / 1) to obtain 66.1 g of Compound B as a white solid (yield 78%). 1 H NMR (δppm, CDCl 3 ): 7.75(dd, J=0.7, 1.7Hz, 1H), 7.44(s, 1H), 6.97(dd, J=0.7, 3.3Hz, 1H), 6.66(dd, J=1.7, 3...

reference example 3

[0166] 7-Chloro-2-(2-furyl)-5-methylthio[1,2,4]triazolo[1,5-c]pyrimidine (Compound C)

[0167] Compound B2.7g (10mmol) was dissolved in THF8.5mL, DBU1.5mL (10mmol) was added under ice-cooling, and stirred at room temperature for about 1 hour. During this period, crystals were precipitated from the reaction solution. After the reaction, the precipitated solid was washed with THF to obtain 2.1 g of Compound C (yield 81%) as a white solid. 1 H NMR (δppm, CDCl 3 ): 7.65(dd, J=0.7, 1.7Hz, 1H), 7.36(s, 1H), 7.28(dd, J=0.7, 3.3Hz, 1H), 6.60(dd, J=1.7, 3.3Hz, 1H) , 2.78(s, 3H) Mass(m / z): 266, 268(M + )IR (KBr): 3745, 1596, 1508, 1452 cm -1 Melting point: 230°C

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Abstract

The present invention relates to a [1,2,4]triazolo[1,5-c]pyrimidine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 represents a substituted or unsubstituted aryl group Or substituted or unsubstituted aromatic heterocyclic group, R2 represents hydrogen atom, halogen, substituted or unsubstituted lower alkyl group, substituted or unsubstituted aryl group or substituted or unsubstituted aromatic heterocyclic group, na and nb are the same or different, represent an integer of 0-4, Q represents a hydrogen atom or 3,4-dimethoxybenzyl, R6 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a halogen atom or a hydroxyl group, R3 Represents: ①hydroxyl, ②hydroxyl lower alkyl, ③substituted or unsubstituted lower alkoxy, or ④selected from substituted or unsubstituted imidazo[1,2-a]pyridyl, imidazo[1,2- a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzothiazolyl, benzo-2,1,3-thiadiazolyl, isoxazolyl and 3-oxo Substituted-3,4-dihydro-2H-benzo[1,4]oxazine group, when R3 represents hydroxyl, hydroxyl lower alkyl or substituted or unsubstituted lower alkoxy, R4 and R5 are The same or different, represent substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl, or R4 and R5 together with adjacent carbon atoms form a substituted or unsubstituted saturated carbocyclic ring, R3 represents selected from substituted or Unsubstituted imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzothiazolyl, In the case of benzo-2,1,3-thiadiazolyl, isoxazolyl and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, R4 The same as or different from R5, represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group, or R4 and R5 together with adjacent carbon atoms form a substituted or unsubstituted saturated carbocyclic ring.

Description

field of invention [0001] The present invention is about showing that adenosine A 2A Receptor antagonism, can be used in the treatment and prevention of adenosine A 2A [1,2,4]triazolo[1,5-c]pyrimidine derivatives for various diseases caused by receptor hyperactivity (for example, Parkinson's disease, Alzheimer's disease and depression). Background of the invention [0002] Adenosine A 2A It is known that the receptor exhibits a neurotransmitter attenuating effect ("European Journal of Pharmacology", Vol. 168, p. 258, 1989). Therefore, adenosine A 2A Receptor antagonists are expected to be used as drugs for Parkinson's disease, antidementia, or depression, etc. 2A Drugs for the treatment or prevention of various diseases caused by hyperactivity of receptors. In addition, the antagonist is expected to be effective in Alzheimer's disease, progressive supranuclear palsy, AIDS encephalopathy, disseminated spongiform encephalopathy, multiple sclerosis, amyotrophic lateral scl...

Claims

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Application Information

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IPC IPC(8): A61P25/24A61P25/28C07D487/04
CPCC07D487/04A61P25/24A61P25/28
Inventor 岛田纯一因间宽哲小坂田直人盐崎静男神田知之桑名良寿
Owner KYOWA HAKKO KOGYO CO LTD
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