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A kind of heterocyclic compound for treating Alzheimer's disease and its preparation method

A technology of heterocyclic compounds and heterocycloalkyl, which is applied in the field of medicine, can solve the problems of few clinical and severe adverse reactions of liver toxicity, achieve the effect of inhibiting acetylcholinesterase activity, good acetylcholinesterase activity, and improving memory function

Active Publication Date: 2019-04-09
佳木斯大学附属第一医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tacrine is rarely used clinically because of its hepatotoxicity and serious adverse reactions
Donepezil, rivastigmine, and galantamine are three widely used second-generation AChE inhibitors for the treatment of AD, all of which exhibit high acetylcholinesterase inhibitory activity and mild toxicity, but these AChE inhibitors only It can alleviate the symptoms of AD but cannot reverse its pathological process, that is, it cannot fundamentally cure AD

Method used

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  • A kind of heterocyclic compound for treating Alzheimer's disease and its preparation method
  • A kind of heterocyclic compound for treating Alzheimer's disease and its preparation method
  • A kind of heterocyclic compound for treating Alzheimer's disease and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: 1-(4-((5-(2-hydroxyethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)phenyl)guanidine (compound 1)

[0054]

[0055] 5-(2-hydroxyethoxy)benzo[d]oxazol-2(3H)-one (3.9g), 1-(4-(bromomethyl)phenyl)guanidine (5.0g), carbonic acid A mixture of potassium (5.6g) in acetonitrile (400mL) was stirred and refluxed for 12h, the solvent was removed in vacuo, and the residue was eluted by gradient chromatography on a silica gel column. The mobile phase was petroleum ether / ethyl acetate 10:1 to 1:1, and the collected According to the corresponding components, 6.1 g of the title compound was obtained as a white solid, with a yield of 89.6% and a content of 99.1%.

[0056] ESI-MS: 343.13[M+H] +

[0057] Elemental analysis: theoretical value / measured value, C(59.64 / 59.54), H(5.30 / 5.38), N(16.37 / 16.48), O(18.69 / 18.71)

[0058] 1 H NMR (400MHz, CDCl 3 )δ8.99(s,1H),7.86(s,1H),7.34(s,1H),7.15(d,1H),6.91(d,2H),6.74(d,1H),6.64(s,2H ), 6.32(d,2H), 4.93(s,1H), 4.74(s,2H), 4.31(t,2...

Embodiment 2

[0059] Example 2: 1-(6-((5-(2-hydroxyethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)pyridin-3-yl) Guanidine (compound 2)

[0060]

[0061] 5-(2-hydroxyethoxy)benzo[d]oxazol-2(3H)-one (3.9g), 1-(6-(bromomethyl)pyridin-3-yl)guanidine (5.0g ), a mixture of potassium carbonate (5.6g) in acetonitrile (400mL) was stirred and refluxed for 12h, the solvent was removed in vacuo, and the residue was eluted by gradient chromatography on a silica gel column, and the mobile phase was petroleum ether / ethyl acetate 8:1 to 1: 1. Collect the corresponding components to obtain 5.9 g of the title compound as a white solid, with a yield of 85.4% and a content of 99.2%.

[0062] ESI-MS: 344.13[M+H] +

[0063] Elemental analysis: theoretical value / measured value, C(55.97 / 55.84), H(4.99 / 4.88), N(20.40 / 20.52), O(18.64 / 18.76)

[0064] 1 H NMR (400MHz, CDCl 3 )δ8.98(s,1H),7.86(s,1H),7.72(d,1H),7.56(d,1H),7.34(s,1H),7.26(d,1H),7.13(d,1H ), 6.74(d,1H), 6.64(s,2H), 4.93(s,1H), 4.54(s,2H), 4.31(t,2H...

Embodiment 3

[0065] Example 3: 1-(6-((5,6-bis(2-methoxyethoxy)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)pyridine -3-yl)guanidine (Compound 3)

[0066]

[0067] 5,6-bis(2-methoxyethoxy)benzo[d]oxazol-2(3H)-one (5.7g), 1-(6-(bromomethyl)pyridin-3-yl ) The mixture of guanidine (5.0g), potassium carbonate (5.6g) in acetonitrile (400mL) was stirred and refluxed for 16h, the solvent was removed in vacuo, and the residue was eluted by silica gel column chromatography gradient, and the mobile phase was ether / ethyl acetate 5: From 1 to 1:1, the corresponding components were collected to obtain 7.0 g of the title compound as a light yellow solid, with a yield of 81.4% and a content of 98.9%.

[0068] ESI-MS: 432.18[M+H] +

[0069] Elemental analysis: theoretical value / measured value, C(55.68 / 55.75), H(5.84 / 5.88), N(16.23 / 16.14), O(22.25 / 22.23)

[0070] 1 H NMR (400MHz, CDCl 3 )δ8.98(s,1H),7.86(s,1H),7.73(d,1H),7.54(d,1H),7.22(s,1H),7.13(d,1H),6.74(s,1H ), 6.64(s,2H), 4.50(s,2H), 4.31(t,4H), 3.7...

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Abstract

The invention relates to a heterocyclic compound for treating Alzheimer disease and a preparation method thereof. The heterocyclic compound has a good effect of inhibiting the activity of acetyl cholinesterase; as proved by a behavioral experiment research of a senescence-accelerated mouse (SAM-P / 8), the heterocyclic compound can effectively improve the memory function of the SAM-P / 8 mouse, so that the heterocyclic compound can be used for treating cognitive dysfunction and / or neural degeneration dementia with abnormal protein aggregation, particularly the Alzheimer disease.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a benzoxazolone heterocyclic compound for treating Alzheimer's disease, and also relates to a preparation method of the heterocyclic compound. Background technique [0002] Alzheimer's disease (AD) is a neurodegenerative disease that occurs in old age and is characterized by dementia. Its main clinical manifestations are progressive cognitive dysfunction and memory decline, personality and behavior changes, decreased judgment, social impairment, loss of self-care ability, and eventually death, which seriously endangers the health and quality of life of the elderly. With the aging of the population, Alzheimer's disease, mainly AD, has become the third major disease that threatens the lives of the elderly after cardiovascular and cerebrovascular diseases and malignant tumors. AD not only seriously endangers the health of the elderly, but also brings a heavy mental burden to the f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/58C07D413/06A61K31/421A61K31/4439A61K31/5377A61P25/28
CPCC07D263/58C07D413/06
Inventor 李欣罗海龙宋广福于佳楠程鹏飞盛宝英王丽华
Owner 佳木斯大学附属第一医院
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