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Tricyclic thiazolo[5,4-d]pyrimidone derivative and application thereof

A thiazolo, 4-d technology is applied in the field of tricyclic thiazolo[5,4-d]pyrimidinone derivatives, which can solve the problems of large toxic and side effects, single action target, short half-life and the like

Active Publication Date: 2021-12-14
XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In recent years, it has been found that many traditional Chinese medicines have significant curative effects in the treatment of AD, such as icariin, sinapine, salvia miltiorrhiza and kudzu root, etc., all have strong inhibitory effects on AChE; although these drugs have greatly improved the neurocognitive ability of patients, they have alleviated the symptoms of AD. AD symptoms, but in the clinical manifestations, the target is single, the toxic side effects are large, the half-life is short (the number of daily medications is high), drug resistance and adverse reactions are prone to occur, etc.

Method used

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  • Tricyclic thiazolo[5,4-d]pyrimidone derivative and application thereof
  • Tricyclic thiazolo[5,4-d]pyrimidone derivative and application thereof
  • Tricyclic thiazolo[5,4-d]pyrimidone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Preparation of Compound A:

[0125] At -10°C, dissolve 57.3ml, 0.83mol of sodium nitrite and 100g, 0.83mol of ethyl cyanoacetate in 700ml of pure water, then slowly add 36.6ml, 0.055mol of 85% concentrated phosphoric acid, dropwise After the time lasted for 3 hours, the temperature was raised to 45°C and stirred for 1 hour, then 74ml of concentrated hydrochloric acid, 0.88mol was added, and the stirring was continued at 0°C overnight, a large amount of white solids precipitated, filtered to obtain white compound A as 2-cyano -Ethyl 2 hydroxyiminoacetate, no purification is required for the next step reaction;

[0126] Preparation of compound B:

[0127] At room temperature, the obtained white compound A was 43 g of ethyl 2-cyano-2 hydroxyiminoacetate, 0.3 mol was dissolved in 500 ml of pure water, and 350 ml of saturated sodium bicarbonate solution was slowly added dropwise under stirring, Then add 156g of sodium dithionite, 0.9mol, heat up to 35°C, react for 1 hour, ...

Embodiment 2

[0145] Preparation of compound H1:

[0146] Dissolve 0.27 g 1 mmol of compound F obtained in Example 1 in 20 mL Add 0.98g 3mmol of cesium carbonate, 0.15g 1.2mmol of phenylboronic acid, and 0.015g 0.01mmol of tetrakistriphenylphosphine palladium to the anhydrous toluene, and under the protection of argon, reflux the reaction until all the raw materials disappear, and extract with dichloromethane , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used forward silica gel column chromatography gradient elution, and the eluent was ethyl acetate:methanol at a volume ratio of 10:1 to obtain compound H1 as 2-phenyl-6,7 -Dihydropyrrole[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, yield: 68%, light yellow solid, melting point: 276-277°C;

[0147] 1 H NMR (400MHz, CDCl 3 )δ8.06(dd, J=6.8,2.8Hz,2H),7.47(d,J=2.1Hz,2H),7.45(d,J=0.9Hz,1H),4.27(t,J=7.3Hz, 2H), 3.21(t, J=8.0Hz, 2H), 2.57–2.18(m, 2H).

Embodiment 3

[0149] Preparation of compound H2:

[0150] Dissolve 0.27 g 1 mmol of compound F obtained in Example 1 in 20 mL 0.98g 3mmol of cesium carbonate, 0.16g 1.2mmol of 2-methylphenylboronic acid, 0.015g 0.01mmol of tetrakistriphenylphosphine palladium were respectively added to anhydrous toluene, and under the protection of argon, the reaction was refluxed until all the raw materials disappeared. Extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used forward silica gel column chromatography gradient elution, the eluent is ethyl acetate:methanol with a volume ratio of 10:1, to obtain compound H2 as 2-(2 -Methylphenyl)-6,7-dihydropyrrole[1,2-a]thiazolo[5,4-d]pyrimidin-9(5H)-one, yield: 61%, pale yellow solid, melting point : 178-179°C;

[0151] 1 H NMR (400MHz, CDCl 3 )δ7.74(d, J=7.8Hz, 1H), 7.32(ddd, J=22.2, 14.9, 8.4Hz, 3H), 4.44(t, J=7.3Hz, 2H), 3.22(t, J=8.0 Hz, 2H), 2.65(s, 3H), 2.53–2.18(m, 2H).

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Abstract

The invention relates to a tricyclic thiazolo[5,4-d]pyrimidone derivative and application thereof. The derivative is prepared by the steps that ethyl cyanoacetate serves as an initial raw material, a hydroxylamine compound (A) is generated under the action of sodium nitrite and phosphoric acid, ethyl 2-aminocyanoacetate (B) is obtained through reduction of sodium hydrosulfite and reacts with acetic anhydride and a Lawesson's reagent separately to obtain5-amino-4-formate thiazole compounds (D), NBS (N-bromosuccinimide) bromination is conducted, a 2-bromo-dihydropyrrolo[1,2-a]thiazolo[5,4-d]pyrimidinone compound (F) and a 2-bromo-7,8-dihydro-5H-pyridino[1,2-a]thiazolo[5,4-d]pyrimidin-10(6H)-one derivative (G) are obtained under the action of phosphorus oxychloride, and finally Suzuki coupling reaction is conducted to obtain 64 differently-substituted tricyclic thiazolo[5,4-d]pyrimidone derivatives H1-H32 and I1-I32. The inhibitory activity of the 64 compounds on acetylcholinesterase / butyrylcholinesterase in Alzheimer's disease and the antibacterial activity of Candida albicans, and the result shows that 46 compounds have strong inhibitory activity on acetylcholinesterase / butyrylcholinesterase, and 27 compounds have inhibitory activity on candida albicans.

Description

technical field [0001] The invention relates to a tricyclic thiazolo[5,4-d]pyrimidinone derivative and its application. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD) is a neurodegenerative disease caused by damage to the memory, language and reasoning of the brain hemispheres. Name it. In recent years, the prevalence of AD has been increasing year by year, and it is showing a younger trend. It is estimated that by 2050, more than 130 million people worldwide will suffer from AD. Because of the lack of very effective prevention and treatment methods, it has become the fourth cause of death after heart disease, cancer and stroke. Since there is no effective drug applied clinically to prevent the onset of AD and to treat AD, it is urgent to find a drug that can effectively treat AD. [0003] In recent years, it has been found that many traditional Chinese medicines have significant curative effects in the treatment of AD, such as icariin, sinapi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/14A61P25/28A61P31/10
CPCC07D513/14A61P25/28A61P31/10Y02A50/30
Inventor 阿吉艾克拜尔·艾萨曾艳聂礼飞胡尔西地·博扎罗夫赵江瑜
Owner XINJIANG TECHN INST OF PHYSICS & CHEM CHINESE ACAD OF SCI
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