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Synthesis method and application of multi-target A beta oligomerization inhibitor

An inhibitor, multi-target technology, applied in the field of synthesis of multi-target Aβ oligomerization inhibitors, can solve the problems of product performance to be improved, complex synthesis method, etc., and achieve the effect of simple and reliable route and high yield

Active Publication Date: 2017-06-13
SHENZHEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In view of the above deficiencies in the prior art, the purpose of the present invention is to provide a synthesis method and application of a multi-target Aβ oligomerization inhibitor, aiming to solve the problem that the existing synthesis method is complex and cumbersome, and the performance of the synthesized product needs to be improved. question

Method used

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  • Synthesis method and application of multi-target A beta oligomerization inhibitor
  • Synthesis method and application of multi-target A beta oligomerization inhibitor
  • Synthesis method and application of multi-target A beta oligomerization inhibitor

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Example 1: Synthesis of N1-(3-(1H-imidazol-1-yl)propyl)-N2-((1-benzyl-4-yl)methyl)benzene-1,2-diamine, which The synthetic route is as follows:

[0046]

[0047] a, 3N1-((1-benzyl-4-yl)methyl)benzene-1,2-diamine (II) synthesis: bromoaniline (5.81mmol, 1equiv), (1-benzylpiperidine- 4-yl)methylamine (6.98mmol, 1.2equiv) was dissolved in dioxane (10ml) and 2mol / L potassium carbonate (10ml) mixed solution, adding catalyst [1,1'-bis(diphenylphosphine) Ferrocene] dichloropalladium (II) dichloromethane complex (0.3486mmol, 0.06equiv); ventilation, so that the whole device is filled with argon; the mixed system was refluxed at 100°C for 3h, and extracted 3 times with ethyl acetate , combined organic phase, washed once with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 90%.

[0048] b. Synthesis of N1-((1-benzyl-4-yl)methyl)-N2-(3-bromopropyl)benzene-1,2-diamine (Ⅲ): 3N1-((1-benzy...

Embodiment 2

[0050] Example 2: Synthesis of N2-(3-(1H-imidazol-1-yl)propyl)-N3-((1-benzyl-4-yl)methyl)naphthalene-2,3-diamine, which The synthetic route is as follows:

[0051]

[0052]

[0053] a, N2-((1-benzyl-4-yl)methyl)naphthalene-2,3-diamine (II) synthesis: 3-bromo-2-naphthylamine (5.81mmol, 1equiv), (1 -benzylpiperidin-4-yl)methanamine (6.98mmol, 1.2equiv) was dissolved in dioxane (15ml) and 2mol / L potassium carbonate (10ml) mixture, and catalyst [1,1′-bis (Diphenylphosphine) ferrocene] dichloropalladium (II) dichloromethane complex (0.3486mmol, 0.06equiv); ventilation, so that the whole device is filled with argon; the mixed system was refluxed at 100°C for 4h, Extracted three times with ethyl acetate, combined organic phase, washed once with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 88%.

[0054] b. Synthesis of N2-((1-benzyl-4-yl)methyl)-N3-(3-bromopropyl)naphthalene-2,3-dia...

Embodiment 3

[0056] Example 3: N1-(3-(1H-imidazol-1-yl)propyl)-N2-((1-benzyl-4-yl)methyl)benzene-1,2-diamine on Aβ oligomerization Chemical inhibition:

[0057] like figure 2 As shown, it is N1-(3-(1H-imidazol-1-yl)propyl)-N2-((1-benzyl-4-yl)methyl)benzene-1,2-diamine to Aβ42 oligo Comparison diagram of polymerization inhibition, in which, 1 is the protein marker; 2-3 is the control group; 4-5 is the sample addition group.

[0058] Prepare the DMSO monomer stock solution (1mM) of Aβ42 immediately before use, and prepare N1-(3-(1H-imidazol-1-yl)propyl)-N2-((1-benzyl-4-yl)methyl)benzene -1,2-diamine in DMSO stock solution (1 mM), take 4 μL Aβ42 stock solution and 4 μL N1-(3-(1H-imidazol-1-yl)propyl)-N2-((1-benzyl-4-yl )Methyl)benzene-1,2-diamine mother solution was mixed, 2 μL of 1% SDS solution was added, the total volume was adjusted to 15 μL with PBS buffer solution, incubated at 37°C for 6 and 12 hours, and SDS-PAGE analysis was carried out after sampling (15% separating gel). The ...

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Abstract

The invention discloses a synthesis method and application of a multi-target A beta oligomerization inhibitor. The synthesis method comprises the following steps: (1) taking bromaniline or derivatives thereof and (1-benzylpiperidine-4-yl)methylamine or derivatives thereof as starting raw materials, and carrying out Suzuki coupling reaction for preparing an intermediate II; (2) taking the intermediate II and 1,3-dibromopropane or other analogues as raw materials, and carrying out SN2 reaction for preparing an intermediate III with an alkyl chain; and (3) taking the intermediate III with the alkyl chain and imidazole or derivatives thereof as raw materials, and carrying out SN2 reaction for preparing the target product multi-target A beta oligomerization inhibitor. The synthesis method disclosed by the invention is simple and reliable in route, high in yield and more suitable for large-scale preparation. The multi-target A beta oligomerization inhibitor is applied to preparation of an A beta oligomerization inhibitor anti-AD medicine, a glutaminyl cyclase inhibitor anti-AD medicine and an acetylcholin esterase inhibitor anti-AD medicine and can be applied to kits of A beta oligomerization, glutaminyl cyclase and acetylcholin esterase.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a synthesis method and application of a multi-target Aβ oligomerization inhibitor. Background technique [0002] Alzheimer's disease (AD) is a common neurodegenerative disease, the main symptoms include progressive memory and cognitive dysfunction, and it is characterized by irreversibility and high mortality. AD is the main form of senile dementia, and AD patients account for more than 65% of the total number of senile dementia patients. With the development of global population aging, the incidence of AD and the number of patients are increasing rapidly. However, there is no specific drug for clinical treatment. AD has become the third largest worldwide health problem after cardiovascular and cerebrovascular diseases and tumors. A global economic and social issue. The large population base and the rapid development of aging are the basic national conditions of our country, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P25/28
CPCC07D401/12
Inventor 吴海强王丽邹永东郑易之贺震旦刘志刚余熙李玥吴序栎刘立忠
Owner SHENZHEN UNIV
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