A compound for improving α-tubulin acetylation level and its preparation method and application

A compound and drug technology, applied in the field of medicine, can solve problems such as the burden on the patient's family, high cost of treatment and care, and inability to delay the progress of the disease

Active Publication Date: 2022-02-22
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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  • A compound for improving α-tubulin acetylation level and its preparation method and application
  • A compound for improving α-tubulin acetylation level and its preparation method and application
  • A compound for improving α-tubulin acetylation level and its preparation method and application

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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 α-tubulin and its preparation method and application, belonging to the technical field of medicine. The compound has a general structural formula as shown below: wherein, R 1 from R 2 independently selected from Me, Et, or n-Pr. Although the compound provided by the present invention cannot inhibit HDAC6 activity, it still increases the acetylation level of α-tubulin in SH-SY5Y cells in a dose-dependent manner, so it is expected to be used for Alzheimer's disease and related neurodegeneration The prevention and treatment of diseases, so it 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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Patent Type & Authority Patents(China)
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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