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Application of 8-substituted oxoisoaporphine derivatives

A technology of isoapofil and its derivatives, which is applied in the new application field of 8-substituted oxidized isoapofil derivatives, can solve the problems of anti-Aβ aggregation that have not yet been found, and achieve good application prospects and good anti-Aβ aggregation activity , low toxicity effect

Inactive Publication Date: 2016-10-12
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The applicant has found in previous research that the 8-substituted oxidized isoapofil derivatives with the structure shown in the following formula (A) have a good inhibitory effect on acetylcholinesterase in vitro (please refer to the publication number for details) CN103923009A invention patent), but there is no relevant report that this kind of derivative has anti-Aβ aggregation effect alone and also has anti-Aβ aggregation effect at the same time as acetylcholinesterase

Method used

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  • Application of 8-substituted oxoisoaporphine derivatives
  • Application of 8-substituted oxoisoaporphine derivatives
  • Application of 8-substituted oxoisoaporphine derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Example 1: Synthesis of 4-chloro-2-phenylisoindoline-1,3-dione (compound 1)

[0027] Add 57g (0.1mol) of 3-chlorophthalic anhydride and 45g (0.1mol) of phenethylamine into a 1L three-hole round bottom flask, then add 500ml of toluene, reflux for 6 hours, pour it out while it is hot, and cool it down. Crystals were precipitated and filtered with suction to obtain compound 1 (white flaky crystals) with a yield of about 98%.

[0028] Compound 1 is analyzed, and its spectral characteristics are as follows:

[0029] 1 H NMR (CDCl 3 ,500MHz): δ3.00~3.04(m,2H),3.94~3.97(m,2H),7.23~7.34(m,5H),7.65(d,J=1.7,1H),7.66(s,1H) ,7.78(dd,J 1 =5.0 and J 2 =3.2,1H); ESI-MS (m / z): 287[M+H] + .

[0030] Therefore, it can be determined that the above-mentioned compound 1 is 4-chloro-2-phenylisoindoline-1,3-dione, and its structural formula is as follows:

[0031]

Embodiment 2

[0032] Embodiment 2: the synthesis of 8-Cl-1-azabenzanthrone (compound 2)

[0033] Add 75g (0.56mol) of anhydrous aluminum trichloride and 15g of sodium chloride into a 1L three-hole round bottom flask, mix and heat to 140°C for melting, then slowly add 53g (0.2mol) of compound 1 in batches After the addition, the temperature was raised to 220°C, and the reaction was stirred for 3 hours, poured into a mortar while heating, cooled, and crushed to obtain a reddish-brown solid, which was placed in a dry vessel.

[0034] Take 600ml of concentrated sulfuric acid and add it to a 2L three-hole round bottom flask. When the temperature rises to 80°C, start adding the reddish-brown solid obtained above in batches. About 600g of ice water was used to adjust the pH value to about 2-3 with NaOH, and a large amount of solid was precipitated, filtered with suction and washed with water to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum e...

Embodiment 3

[0038] Example 3: Synthesis of 8-amino-7H-dibenzoquinolin-7-one (compound 3)

[0039] Take 1.5g of compound 2 into the liner of the autoclave, add 100ml of ammonia water, react at 180°C for 12h, and then stop the reaction. After cooling, adjust the pH to 7-8 with 3mol / L HCl, filter with suction, and dry. The crude product was purified by silica gel column chromatography (petroleum ether / chloroform=7:1) to obtain compound 3 (red solid) with a yield of 40%.

[0040] Compound 3 was analyzed, and its spectral characteristics were as follows:

[0041] 1 H NMR (500MHz, DMSO): δ8.73(d, J=5.5Hz, 1H), 8.45(d, J=7.2Hz, 1H), 8.29(d, J=8.2Hz, 1H), 8.06(d, J=8.4Hz, 1H), 8.02–7.97(m, 1H), 7.94(d, J=5.6Hz, 1H), 7.55–7.48(m, 1H), 7.00(d, J=7.3Hz, 1H), 2.51(t, J=2.8Hz, 2H); ESI-MS(m / z): 247[M+H] + .

[0042] Therefore, it can be determined that the above-mentioned compound 3 is 8-amino-7H-dibenzoquinolin-7-one, and its structural formula is as follows:

[0043]

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Abstract

The invention discloses application of a series of 8-substituted oxoisoaporphine derivatives, specifically application of 8-substituted oxoisoaporphine derivatives or pharmaceutically acceptable salts thereof in preparation of Abeta aggregation inhibitor drugs, as well as application in preparation of drugs inhibiting acetylcholin esterase and resisting Abeta aggregation at the same time. The inventor finds that the derivatives not only has very good inhibitory activity in vitro to acetylcholin esterase, but also has good anti-acetylcholin esterase in vivo, and the compounds have very good anti-Abeta aggregation activity both at the molecular level and at the cellular level. More rarely, most of the compounds can penetrate the blood-brain barrier and have low toxicity, and have good application prospects in treatment of Alzheimer disease, cerebrovascular dementia and other diseases. The structure of the8-substituted oxoisoaporphine derivatives is shown as the specification, wherein n=1-5.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to the new application of 8-substituted oxidized isoapofil derivatives. Background technique [0002] Alzheimer's disease (Alzheimer disease, AD) was first discovered by German neuropathologist Alois Alzheimer (Alois Alzheimer) in 1907, and a disease named after him, AD is a progressive A neurodegenerative disorder that manifests as comprehensive cognitive impairment, including memory, orientation, judgment, and reasoning. Its clinical features are latent venereal disease, and gradually appear memory loss, cognitive dysfunction, abnormal behavior and social impairment. Usually the disease is progressive and gradually loses the ability to live independently. Since AD ​​disease involves a variety of pathological processes, its pathogenesis is a very complex, multi-mechanism, and multi-factor process. [0003] Although the pathogenesis of AD is still not fully understood...

Claims

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Application Information

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IPC IPC(8): A61K31/473A61P25/28
Inventor 唐煌卫沈旗陈薇
Owner GUANGXI NORMAL UNIV
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