Quinoline-indole derivative and application thereof in preparation of drug used for treating alzheimer disease

Abstract

The invention discloses a quinoline-indole derivative and application thereof in preparation of a drug used for treating, improving and / or preventing alzheimer disease. The quinoline-indole derivativedisclosed by the invention is a multi-target anti-alzheimer disease active molecule, has the effects of inducing increase of number of neure of nerve cells PC12, neuronal differentiation and antioxidation and inhibiting Abeta aggregation and depolymerization, can promote formation of cerebral hippocampal neuron of an adult mouse and can improve APP / PS1 cognitive capability and spatial memory of an alzheimer disease mouse.

Description

technical field

[0001] The invention relates to the field of medicine, in particular to a quinoline-indole derivative and its application in the preparation of medicines for treating, improving and / or preventing Alzheimer's disease. Background technique

[0002] Alzheimer's disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system with memory loss and cognitive dysfunction as the main clinical symptoms. The incidence of AD increases sharply with age. rise. According to statistics, there are more than 37 million AD patients in the world. With the acceleration of population aging, the number of AD patients will increase at an average rate of one case every 3 seconds. By 2030, the density of AD in the population will increase from 2015 to 2015. 1 / 155 of the year rises to 1 / 100. Currently, clinical drugs for the treatment of Alzheimer's disease are mainly acetylcholinesterase inhibitors, such as donepezil, rivastigmine, and huperzine ...

Examples

Embodiment 1

[0037] Example 1: 2-(5-Hydroxy-1-H-indole-2-substituted)-8-hydroxyquinoline

[0038]

[0039] (1) Step 1: Synthesis of (E)-2-(5-acetoxy-2-nitro)-8-acetoxyquinoline

[0040]

[0041]Add 1.59g (10mmol) 2-methyl-8-hydroxyquinoline and 1.67g (10mmol) 2-nitro-5-hydroxybenzaldehyde to a 100mL round bottom bottle, 16mL acetic anhydride, stir at 150°C for 12h, After cooling to room temperature, add 50 mL of water, stir at room temperature for 1 hour, filter with suction, wash with water, and dry in vacuo to obtain a yellow solid (E)-2-(5-Acetoxy-2-nitro)-8-Acetoxy Quinoline 3.12g, yield 81%. R f =0.36 (petroleum / EtOAc=2 / 1). 1 H NMR (400MHz, CDCl 3 )δ8.27(d, J=16.0Hz, 1H), 8.16(d, J=8.5Hz, 1H), 8.08(d, J=8.9Hz, 1H), 7.68(dd, J=8.0, 1.1Hz, 1H), 7.62(d, J=8.6Hz, 1H), 7.60(d, J=2.4Hz, 1H), 7.50(t, J=7.8Hz, 1H), 7.44(dd, J=7.4, 1.2Hz, 1H), 7.28(d, J=16.0Hz, 1H), 7.22(dd, J=8.9, 2.4Hz, 1H), 2.57(s, 3H), 2.37(s, 3H).LC / MS(ESI): 393.1[M+H] + .

[0042] (2) Step 2: Synthesis of ...

Embodiment 2

[0048] Example 2: 2-(1-H-indole-2-substituted)-8-hydroxyquinoline

[0049]

[0050] The specific implementation steps are similar to Example 1, add 2.9g 2-(1-H-indole-2-substituted)-8-acetoxyquinoline and 10mL anhydrous methanol to a 100mL round bottom bottle, add 1.0 times Equivalent K 2 CO 3 . Stir at room temperature for 1 h, add 60 mL of water after the reaction is complete, filter with suction, separate by silica gel column chromatography, and elute with ethyl acetate to obtain a light yellow oily substance, namely 2-(1-H-indole-2-substituted)-8-hydroxy quinoline. Concrete implementation steps are similar to Example 1, and the productive rate is 83%. R f =0.35 (petroleum / EtOAc=1 / 1), mp 241.5-242.3°C. 1 H NMR (400MHz, CDCl 3 )δ9.54(s,1H),8.13(d,J=8.7Hz,1H),7.91(d,J=8.6Hz,1H),7.69(d,J=8.0Hz,1H),7.47(dd, J=8.2,0.8Hz,1H),7.43–7.36(m,1H),7.34–7.25(m,2H),7.22–7.16(m,2H),7.16–7.09(m,1H). 13 C NMR (101MHz, CDCl 3 )δ151.76,148.17,137.48,137.06,136.73,136.23,128.99,127...

Embodiment 3

[0051] Example 3: 2-(5-fluoro-1-H-indole-2-substituted)-8-hydroxyquinoline

[0052]

[0053] The specific implementation steps are similar to Example 1, add 2.9g 2-(5-fluoro-1-H-indole-2-substituted)-8-acetoxyquinoline and 10mL anhydrous methanol in the round bottom bottle of 100mL , add 1.0 times the equivalent of K 2 CO 3 . Stir at room temperature for 1 h, add 60 mL of water after the reaction is complete, filter with suction, separate by silica gel column chromatography, and elute with ethyl acetate to obtain a light yellow oily substance, namely 2-(5-fluoro-1-H-indole-2-substituted) -8-Hydroxyquinoline. Yield 91%. R f =0.39 (petroleum / EtOAc=1 / 1), mp 257.2-257.8°C. 1 HNMR (400MHz, DMSO) δ8.36 (d, J = 8.6Hz, 1H), 8.13 (d, J = 8.6Hz, 1H), 7.53 (dd, J = 8.7, 4.4Hz, 1H), 7.49–7.38 ( m,3H),7.36(s,1H),7.16(d,J=7.1Hz,1H),7.10(td,J=9.3,2.5Hz,1H). 13 C NMR (101MHz, DMSO) δ158.80(s), 156.49(s), 153.47(s), 147.83(s), 139.31(s), 137.76(s), 137.32(s), 134.24(s), 129.19 (d, ...

technical field

[0001] The invention relates to the field of medicine, in particular to a quinoline-indole derivative and its application in the preparation of medicines for treating, improving and / or preventing Alzheimer's disease. Background technique

[0002] Alzheimer's disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system with memory loss and cognitive dysfunction as the main clinical symptoms. The incidence of AD increases sharply with age. rise. According to statistics, there are more than 37 million AD patients in the world. With the acceleration of population aging, the number of AD patients will increase at an average rate of one case every 3 seconds. By 2030, the density of AD in the population will increase from 2015 to 2015. 1 / 155 of the year rises to 1 / 100. Currently, clinical drugs for the treatment of Alzheimer's disease are mainly acetylcholinesterase inhibitors, such as donepezil, rivastigmine, and huperzine ...

Examples

Embodiment 1

[0037] Example 1: 2-(5-Hydroxy-1-H-indole-2-substituted)-8-hydroxyquinoline

[0038]

[0039] (1) Step 1: Synthesis of (E)-2-(5-acetoxy-2-nitro)-8-acetoxyquinoline

[0040]

[0041]Add 1.59g (10mmol) 2-methyl-8-hydroxyquinoline and 1.67g (10mmol) 2-nitro-5-hydroxybenzaldehyde to a 100mL round bottom bottle, 16mL acetic anhydride, stir at 150°C for 12h, After cooling to room temperature, add 50 mL of water, stir at room temperature for 1 hour, filter with suction, wash with water, and dry in vacuo to obtain a yellow solid (E)-2-(5-Acetoxy-2-nitro)-8-Acetoxy Quinoline 3.12g, yield 81%. R f =0.36 (petroleum / EtOAc=2 / 1). 1 H NMR (400MHz, CDCl 3 )δ8.27(d, J=16.0Hz, 1H), 8.16(d, J=8.5Hz, 1H), 8.08(d, J=8.9Hz, 1H), 7.68(dd, J=8.0, 1.1Hz, 1H), 7.62(d, J=8.6Hz, 1H), 7.60(d, J=2.4Hz, 1H), 7.50(t, J=7.8Hz, 1H), 7.44(dd, J=7.4, 1.2Hz, 1H), 7.28(d, J=16.0Hz, 1H), 7.22(dd, J=8.9, 2.4Hz, 1H), 2.57(s, 3H), 2.37(s, 3H).LC / MS(ESI): 393.1[M+H] + .

[0042] (2) Step 2: Synthesis of ...

Embodiment 2

[0048] Example 2: 2-(1-H-indole-2-substituted)-8-hydroxyquinoline

[0049]

[0050] The specific implementation steps are similar to Example 1, add 2.9g 2-(1-H-indole-2-substituted)-8-acetoxyquinoline and 10mL anhydrous methanol to a 100mL round bottom bottle, add 1.0 times Equivalent K 2 CO 3 . Stir at room temperature for 1 h, add 60 mL of water after the reaction is complete, filter with suction, separate by silica gel column chromatography, and elute with ethyl acetate to obtain a light yellow oily substance, namely 2-(1-H-indole-2-substituted)-8-hydroxy quinoline. Concrete implementation steps are similar to Example 1, and the productive rate is 83%. R f =0.35 (petroleum / EtOAc=1 / 1), mp 241.5-242.3°C. 1 H NMR (400MHz, CDCl 3 )δ9.54(s,1H),8.13(d,J=8.7Hz,1H),7.91(d,J=8.6Hz,1H),7.69(d,J=8.0Hz,1H),7.47(dd, J=8.2,0.8Hz,1H),7.43–7.36(m,1H),7.34–7.25(m,2H),7.22–7.16(m,2H),7.16–7.09(m,1H). 13 C NMR (101MHz, CDCl 3 )δ151.76,148.17,137.48,137.06,136.73,136.23,128.99,127...

Embodiment 3

[0051] Example 3: 2-(5-fluoro-1-H-indole-2-substituted)-8-hydroxyquinoline

[0052]

[0053] The specific implementation steps are similar to Example 1, add 2.9g 2-(5-fluoro-1-H-indole-2-substituted)-8-acetoxyquinoline and 10mL anhydrous methanol in the round bottom bottle of 100mL , add 1.0 times the equivalent of K 2 CO 3 . Stir at room temperature for 1 h, add 60 mL of water after the reaction is complete, filter with suction, separate by silica gel column chromatography, and elute with ethyl acetate to obtain a light yellow oily substance, namely 2-(5-fluoro-1-H-indole-2-substituted) -8-Hydroxyquinoline. Yield 91%. R f =0.39 (petroleum / EtOAc=1 / 1), mp 257.2-257.8°C. 1 HNMR (400MHz, DMSO) δ8.36 (d, J = 8.6Hz, 1H), 8.13 (d, J = 8.6Hz, 1H), 7.53 (dd, J = 8.7, 4.4Hz, 1H), 7.49–7.38 ( m,3H),7.36(s,1H),7.16(d,J=7.1Hz,1H),7.10(td,J=9.3,2.5Hz,1H). 13 C NMR (101MHz, DMSO) δ158.80(s), 156.49(s), 153.47(s), 147.83(s), 139.31(s), 137.76(s), 137.32(s), 134.24(s), 129.19 (d, ...

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