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Compound for improving acetylation level of alpha-tubulin as well as preparation method and application of compound

A compound and solvate technology, which is applied in the field of compounds that improve alpha-tubulin acetylation level and the preparation thereof, can solve the problems of inability to delay disease progression, burden on patients' families, expensive treatment and nursing costs, etc.

Active Publication Date: 2021-07-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

AD, cardiovascular disease, and cancer are known as the "three major killers" of the health of the elderly, but unlike heart disease and cancer, the clinical effects of existing Alzheimer's disease drugs are not satisfactory, and can only be temporarily and minimally Improving the patient's memory and the ability to carry out daily activities, and relieving some symptoms, can not delay the progress of the disease. Not only the treatment and nursing costs are expensive, but also cause serious mental burden to the nurses and the patient's family members.

Method used

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  • Compound for improving acetylation level of alpha-tubulin as well as preparation method and application of compound
  • Compound for improving acetylation level of alpha-tubulin as well as preparation method and application of compound
  • Compound for improving acetylation level of alpha-tubulin as well as preparation method and application of compound

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preparation example Construction

[0048] In yet another specific embodiment of the present invention, a preparation method of the above-mentioned compound is provided, the preparation method comprising:

[0049] a) When the compound is compound 3, its synthetic route is as follows:

[0050]

[0051] Those skilled in the art can obtain better reaction conditions through experimentation according to the above-mentioned route. As an illustration, the present invention further provides some specific implementation modes. The synthetic method of described compound 3 comprises:

[0052] (1) Dissolve phenothiazine in N,N-dimethylformamide, under low temperature conditions, add lithium bistrimethylsilylamide for reaction, then add 4-chloromethylpyrazole-1-ethyl acetate Ester, reaction under low temperature conditions; separation and purification, to obtain compound 2, the structural formula of compound 2 is

[0053] (2) dissolving the compound 2 obtained in step (1) in the fatty amine solution, stirring and reac...

Embodiment 1

[0078] Embodiment 1: the preparation of compound 2

[0079] (1) Dissolve phenothiazine (Formula 1) (125mg, 0.61mmol) in 2mL of N,N-dimethylformamide, and drop lithium bistrimethylsilylamide (0.8mL , 0.82mmol), stirred for 30min. Afterwards, ethyl 4-chloromethylpyrazole-1-acetate (190 mg, 0.94 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and then dropped into the reaction solution. Stir at -20°C for 3h. Extract with ethyl acetate, combine organic phase, wash with saturated NaCl, anhydrous NaCl 2 SO 4 Dry, filter and concentrate. Silica gel column chromatography gave ethyl 2-[4-((10H-phenothiazin-10-yl)methyl)-1H-pyrazol-1-yl]acetate (2), yellow oil, 100mg, yield rate 56%. 1 H NMR (400MHz, CDCl 3 )δ7.45(s,1H),7.25(s,1H),7.04–6.93(m,4H),6.84–6.68(m,4H),4.91(s,2H),4.76(s,2H),4.12 (q, J=7.1Hz, 2H), 1.17(t, J=6.0Hz, 3H); ESI-MSm / z: 388.06[M+Na] + .

Embodiment 2

[0080] Embodiment 2: the preparation of compound 3

[0081] (1) Dissolve ethyl 2-[4-((10H-phenothiazin-10-yl)methyl)-1H-pyrazol-1-yl]acetate (2) (50mg, 0.14mmol) in 2mL formaldehyde In aqueous amine solution, react at room temperature for 5h. Quenched with water, extracted with ethyl acetate, combined organic phases, washed with saturated NaCl, anhydrous NaCl 2 SO 4 Dry, filter and concentrate. Silica gel column chromatography gave N-methyl-2-[4-((10H-phenothiazin-10-yl)methyl)-1H-pyrazol-1-yl]amide (3a), white solid, 32mg , yield 78%. Melting point: 150–152°C; 1 H NMR (400MHz, CDCl 3 )δ7.51(s,1H),7.27(s,1H),7.04(d,J=7.6,Hz,2H),7.01–6.93(m,2H),6.82(t,J=7.5Hz,2H) ,6.68(d,J=7.9Hz,2H),6.02(s,1H),4.90(s,2H),4.64(s,2H),2.66(d,J=4.8Hz,3H); ESI-MS m / z:373.05[M+Na] + .

[0082] (2) Dissolve ethyl 2-[4-((10H-phenothiazin-10-yl)methyl)-1H-pyrazol-1-yl]acetate (2) (50mg, 0.14mmol) in 2mL ethyl alcohol In aqueous amine solution, react at room temperature for 5h. Quenched with...

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Abstract

The invention provides a compound for improving the acetylation level of alpha-tubulin as well as a preparation method and application of the compound, and belongs to the technical field of medicines. The compound has a structural general formula shown in the specification, wherein R1 is selected from R2 and is independently selected from Me, Et or n-Pr. Although the compound provided by the invention cannot inhibit HDAC6 activity, the acetylation level of SH-SY5Y cell alpha-tubulin is still increased in a dose-dependent manner, so that the compound is expected to be used for preventing and treating Alzheimer's disease and related neurological degeneration diseases, and has good practical application value.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound for improving the acetylation level of α-tubulin and its preparation method and application. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Alzheimer's disease (AD) is a common chronic neurodegenerative disease, clinically manifested as memory impairment, aphasia, apraxia, agnosia, impairment of visuospatial skills, executive dysfunction, personality and behavioral changes, etc. , is also the most common type of dementia, accounting for 5% -10% of the population over the age of 65. AD, cardiovascular disease, and cancer are known as the "three major k...

Claims

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Application Information

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IPC IPC(8): C07D417/06C07D471/04A61K31/5415A61K31/437A61P25/28
CPCC07D417/06C07D471/04A61P25/28
Inventor 刘兆鹏贾聪聪孙天雪吴琪孙硕
Owner SHANDONG UNIV
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