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Thiazole and pyrimidone compound and preparation method and application thereof

A technology of compound and pyrimidinone, which is applied in the field of thiazolopyrimidinone compound and its preparation, can solve the problems of lower learning and memory ability and increase learning and memory, and achieve the effect of high selectivity, strong activity and low risk of cardiotoxicity

Active Publication Date: 2017-01-04
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] According to literature reports, α7 nicotinic acetylcholine receptor positive allosteric modulators (PAM) have the effect of increasing learning and memory. Experiments show that mice lacking nAChRα7 subunit are compared with the control group containing α7nAChR subunit mice. Decreased learning and memory ability in water maze experiment

Method used

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  • Thiazole and pyrimidone compound and preparation method and application thereof
  • Thiazole and pyrimidone compound and preparation method and application thereof
  • Thiazole and pyrimidone compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of 6-(2-chloro-6-methylphenyl)-2-anilinothiazolo[4,5-d]pyrimidin-7(6H)-one (No. JWX-A0824)

[0037] 1. Synthesis of 2-chloro-N-(2-chloro-6-methylphenyl)acetamide (A2)

[0038]

[0039] Compound A1 (14.2g, 100mmol) was dissolved in 100ml of acetic acid and 80ml of saturated sodium acetate aqueous solution, and chloroacetyl chloride (17.0g, 150mmol) was added under ice-cooling, cloudiness soon appeared, slowly rose to room temperature, and stirred overnight. Add 100ml of water, filter with suction, wash with water, and dry to obtain 12.7g of white solid, denoted as A2, with a yield of 58.0%. The crude product was directly submitted to the next step without purification.

[0040] 2. Synthesis of 4-amino-N-(2-chloro-6-methylphenyl)-2-ethylthiothiazole-5-carboxamide (A3)

[0041]

[0042] Dissolve compound A2 (10.9g, 50mmol) in 100ml of acetone, add 100ml of aqueous solution of dipotassium cyanamide dithioformate (9.7g, 50mmol) into the syste...

Embodiment 2

[0050] Example 2: Preparation of 2-(6-chloro-2-methylpyrimidin-4-amino)-6-(2-chloro-6-methylphenyl)thiazolo[4,5-d]pyrimidin-7(6H)-one (No.: LD486)

[0051]

[0052] Compound A5 (370mg, 1.0mmol) and 2-methyl-4-amino-6-chloropyrimidine b1 (287mg, 2.0mmol) were dissolved in 3ml of anhydrous THF, NaH (48mg, 2.0mmol) was added, dried and condensed tube, with balloons on top. Heat to reflux for 0.5h. The reaction was stopped, cooled to room temperature, poured into ice water, and dilute hydrochloric acid was added dropwise to adjust the pH to neutral, and a large amount of solids were precipitated. Suction filtration, washing and drying gave 398 mg of yellow solid, yield 95.0%. Recrystallized from ethanol, m.p.>300°C, recorded as LD486.

[0053] 1 H-NMR (400MHz, DMSO-d 6 )δ8.44(s,1H),7.65–7.40(m,3H),6.99(s,1H),2.56(s,3H),2.15(s,3H). 13 C-NMR (101MHz, DMSO-d 6 )δ167.8, 164.0, 159.5, 158.1, 155.9, 150.9, 139.1, 134.0, 132.3, 131.4, 130.3, 128.1, 112.0, 104.6, 25.5, 18.2. ...

Embodiment 3

[0054] Example 3: Preparation of 6-(2-chloro-6-methylphenyl)-2-p-methylanilinothiazolo[4,5-d]pyrimidin-7(6H)-one (No. JWX-A1029)

[0055]

[0056] The synthesis method is the same as compound JWX-A0824. White solid, yield 88.8%, m.p. 241-246°C, denoted as JWX-A1029.

[0057] 1 H-NMR (400MHz, CDCl 3 )δ10.08(s,1H),7.81(s,1H),7.45(d,J=8.3Hz,2H),7.33(d,J=7.8Hz,1H),7.26(t,J=7.8Hz, 1H), 7.19(d, J=9.8Hz, 1H), 7.12(d, J=8.2Hz, 2H), 2.27(s, 3H), 2.13(s, 3H). 13 C-NMR (101MHz, CDCl 3 )δ171.41, 165.98, 155.47, 149.13, 138.64, 136.39, 135.17, 133.73, 132.90, 130.77, 130.08, 129.59, 128.03, 121.07, 108.21, 21.02, 18.35.

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Abstract

The invention provides a thiazole and pyrimidone compound shown in a chemical formula (I), a preparation method thereof and application of the compound in preparation of drugs for treating central nervous system diseases. X = O or S, Y = C or N, and when Y = C, R3 is selected from H, C1-C12 alkyls, phenyls and five-member or six-membered heterocycles, R2 is selected from H, C1-C12 alkyls, phenyl and five-member or six-membered heterocycles, R1 is selected from H, C1-C6 alkyls, C1-C6 alkoxy, C1-C6 alkyl sulphanyl, C1-C6 alkyl amino, phenyls, halogen, one or more substituted phenyls of C1-C4 alkyls and C1-C4 alkoxy, benzylthio, arylamine, halogen, C1-C4 alkyl, C1-C4 alkoxy, five-member or six-membered heterocycles and one or more C1-C4 alkyl or hydroxyl substituted arylamine and roylamino in five-member or six-membered heterocycles.

Description

technical field [0001] The invention relates to a thiazolopyrimidinone compound, a preparation method thereof, and an application thereof in preparing medicines for treating diseases of the central nervous system. Background technique [0002] Alzheimer's disease, also known as Alzheimer's disease, is a progressive and fatal neurodegenerative disease. Symptoms and behavioral disturbances. Many studies have clearly shown that acetylcholine deficiency and reduced expression of nicotinic acetylcholine receptors (nAChRs) in the brain of AD patients are common phenomena. [0003] According to literature reports, α7 nicotinic acetylcholine receptor positive allosteric modulators (PAM) have the effect of increasing learning and memory. Experiments show that mice lacking nAChRα7 subunit are compared with the control group containing α7nAChR subunit mice. The ability to learn and remember is reduced in the water maze experiment. The mode of action of α7 nicotinic acetylcholine rec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61P25/28
CPCC07D513/04A61P25/00A61P25/16A61P25/28
Inventor 王克威孙崎焦文宣唐婧姝
Owner PEKING UNIV