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9-amino substituted pyrido acridine derivative, preparation method and uses thereof

A technology of acridine and derivatives, applied in the field of medicine, can solve the problems of short half-life, side effects of peripheral cholinergic system, unfavorable long-term use of patients, etc., and achieve the effect of good effect, simple preparation method, and easy-to-obtain raw materials

Active Publication Date: 2015-02-04
SHANGHAI RONA THERAPEUTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, most of the above four clinically applied cholinesterase inhibitors have short half-lives and serious side effects of the peripheral cholinergic system, which are not conducive to long-term use by patients.

Method used

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  • 9-amino substituted pyrido acridine derivative, preparation method and uses thereof
  • 9-amino substituted pyrido acridine derivative, preparation method and uses thereof
  • 9-amino substituted pyrido acridine derivative, preparation method and uses thereof

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Experimental program
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Effect test

Embodiment 19

[0018] The preparation of embodiment 19-benzylaminopyridoacridine

[0019] 1) In a 250ml three-necked flask, add 5.20g (26mmol) of o-bromobenzoic acid (26mmol), 8-aminoquinoline (34mmol), 7.5g (36.2mmol) of potassium carbonate and 0.3g (4.7mmol) of copper powder, and then add 30ml Isoamyl alcohol was used as a solvent, and stirred under reflux at 140°C for 2h. After the reaction, evaporate the solvent under reduced pressure, add 600ml of water to the obtained residue, react at 80°C for 20 minutes, filter while hot, wash the filter cake, combine the water layer, acidify the water layer with concentrated hydrochloric acid to pH=2, and precipitate a large amount of light green Precipitate, filter with suction, and recrystallize the obtained solid with chloroform to obtain compound N-(quinolyl)anthranilic acid (formula II), with a yield of 51%;

[0020] 2) In a 100ml round bottom flask, add the compound represented by formula II (18mol) and 14.37ml of phosphorus oxychloride, and ...

Embodiment 2

[0022] Embodiment 2 Identification and analysis of compounds of the present invention

[0023] The 9-amino-substituted pyridoacridine derivatives obtained by the method described above 1 After H NMR nuclear magnetic resonance spectrum, fast atom bombardment mass spectrometry, melting point and other tests, its chemical structure was confirmed by analysis.

[0024] The physical and chemical properties are as follows:

[0025] 1) Appearance: light yellow powder

[0026] 2) Melting point: 201~204℃

[0027] 3) Molecular weight: 335.4

[0028] 4) Molecular formula: C 23 h 17 N 3 , the structural formula is as follows:

[0029]

[0030] 5) Fast atom bombardment mass spectrometry (FAB-MS): m / z: 336[M+H] + .

[0031] 6) 1H NMR nuclear magnetic resonance spectrum: the sample is dissolved in deuterated dimethyl sulfoxide (DMSO-d6), and measured at 400MHz, the obtained spectral data is: δ: 8.81 (d, 1H, J=8.4, - ArH), 8.34(d, 1H, J=8.4, -ArH), 8.24(t, J=9.3Hz, 2H, ArH), 8.02(...

Embodiment 3

[0032] The determination of embodiment 3 in vitro acetylcholinesterase inhibitory activity

[0033] Application of Ellman (Ellman, G.L.; Courtney, K.D.; Andres, V.; et al.Biochem.Pharmacol.1961, 7, 88.) method test compound for acetylcholinesterase inhibition IC 50 value. All tests were carried out with a Microplate reader ELX808TM microplate reader (BioTek, USA) at 37°C. The data analysis software used Origin software for data processing, and galantamine hydrobromide was used as the reference substance.

[0034] experimental method:

[0035] 1) Preparation of inhibitor stock solutions: the tested inhibitors were formulated into 10 mM DMSO solutions.

[0036] 2) Preparation of enzyme stock solution: Acetylcholinesterase (extracted from electric eel) was purchased from Sigma Company; 0.1 mg / mL and 2 mg / mL were prepared respectively with phosphate buffer solution of pH=8.0.

[0037] 3) Preparation of substrate stock solution: Acetylmercaptocholine (acetylcholinesterase subst...

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Abstract

The present invention relates to a 9-amino substituted pyrido acridine derivative, a preparation method and uses thereof, wherein the structure formula of the derivative is represented in the instruction. The preparation method comprises that 2-bromobenzoic acid and 8-amino quinoline are adopted to prepare N-(quinolyl)anthranilic acid, the product is subjected to cyclization with phosphorus oxychloride to obtain 9-chloro pyrido acridine, the 9-chloro pyrido acridine is dissolved in ethanol, and benzylamine is added to carry out a nucleophilic substitution reaction so as to prepare the target product. The derivative can be used as an acetylcholinesterase inhibitor so as to be used for the treatment of Alzheimer's disease, cerebrovascular dementia and other diseases.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a 9-amino-substituted pyridoacridine derivative with acetylcholinesterase inhibitory activity and a preparation method and application thereof. Background technique [0002] Alzheimer's disease (AD), also known as Alzheimer's disease, is a progressive neurodegenerative disease characterized by comprehensive cognitive impairment, including memory, positioning, judgment and reasoning. The patient has abnormal behavior and social barriers. As the condition worsens, the patient even loses the ability to live independently. Since AD ​​disease involves a variety of pathological processes, its etiology has not yet been definitively stated, and its pathogenesis is a very complex, multi-mechanism, and multi-factor process. And acetylcholinesterase (AchE), also known as acetylcholine hydrolase (acetylcholine hydrolase), its main biological function is to rapidly hydrolyze the neurotransm...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P25/28A61P9/00A61P27/06A61P21/04
CPCC07D471/04
Inventor 霍丽妮陈睿李培源苏炜
Owner SHANGHAI RONA THERAPEUTICS CO LTD
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