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Dihydroisoquinoline compounds and their use in the preparation of neuroprotective or antidepressant drugs

A technology of dihydroisoquinoline and neuroprotection, which is applied in the field of medicine, can solve the problems of poor patient compliance and no expected treatment response, and achieve good acute and chronic treatment of depression, good clinical application prospects, obvious neuroprotection and The effect of the repair function

Inactive Publication Date: 2016-08-17
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are many kinds of antidepressant drugs currently available clinically, but there are still quite a few patients who do not have the expected therapeutic response to some classic antidepressant drugs, even imipramine, fluoxetine, citalopram, and venlaxine” blockbuster drug
In addition, the long treatment cycle of these drugs often leads to poor patient compliance, and how to avoid or reduce the side effects of antidepressant drugs is also one of the main goals of current antidepressant drug research

Method used

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  • Dihydroisoquinoline compounds and their use in the preparation of neuroprotective or antidepressant drugs
  • Dihydroisoquinoline compounds and their use in the preparation of neuroprotective or antidepressant drugs
  • Dihydroisoquinoline compounds and their use in the preparation of neuroprotective or antidepressant drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Preparation of 2-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)isoindole-1,3-dione (2)

[0030]

[0031] Weigh 70 g (0.20 mol) of 3-(1,3-dioxoisoquinolin-2-yl)-N-(4-methoxyphenethyl)propylamine (1) into a 2L reaction flask, followed by adding P 2 o 5 36g (0.25mol), xylene 400mL and POCl 3 110 mL (1.2mol), heated to 125 o C, stop the reaction after 3 hours, pour off the xylene, adjust the pH to 10 with hydrochloric acid, extract with DCM (500 mL×3), evaporate the solvent, separate by column chromatography, and elute with DCM / MeOH=100:1, Obtained 33.5 g of yellow solid 2-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)isoindole-1,3-dione (2), yield : 50.8%. 1 H-NMR (DMSO-d 6 ):7.86-7.81 (m, 4H), 7.15-7.10 (m, 2H), 6.94-6.91 (m, 1H), 3.87 (t, J = 8 Hz,2H), 3.76 (s, 3H), 3.48 ( t, J = 8 Hz, 2H), 3.01 (t, J = 8 Hz, 2H), 2.52 (t, J = 8 Hz, 2H); 13 C-NMR (DMSO-d 6 ): δ 167.72, 163.61, 158.12, 134.27, 131.61, 129.13, 128.97, 128.29, 122.87, 116.11, 110....

Embodiment 2

[0032] Example 2 Preparation of 2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethylamine hydrochloride (3)

[0033]

[0034] Weigh 33.5 g (100.2 mmol) of 2-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)ethyl)isoindole-1,3-dione (2) In a round-bottomed flask, add 500 mL of concentrated hydrochloric acid, heat to reflux, and after 8 h, spot the plate to complete the reaction, stop the reaction, evaporate the solvent, add an appropriate amount of acetone, immediately a solid precipitates, and filter with suction to obtain a gray solid 2-( 7-methoxy-3,4-dihydroisoquinolin-1-yl)ethylamine hydrochloride (3) 20.9 g, yield: 86.7%. 1 H-NMR (DMSO-d 6 ): 7.58 (s, 1H),7.45-7.37 (m, 2H), 3.89 (s, 3H), 3.80 (t, J = 8 Hz, 2H), 3.61 (t, J = 8 Hz,2H), 3.46 (br, s, 2H), 3.23-3.22 (m, 2H), 3.03 (t, J = 8 Hz, 2H).

Embodiment 3

[0035] Example 3 Preparation of N-(2-(7-methoxy-3,4-dihydroisoquinolin-1-yl)acetamide oxalate (4)

[0036]

[0037] Weigh 20.9 g (75.4 mmol) of 2-(7-methoxy-3,4-dihydroisoquinolin-1-yl) ethylamine hydrochloride (3) into the reaction flask, and then add potassium carbonate 22.9 g (165.88 mmol), DMF 120 mL, and finally add 7.8 mL (82.94 mmol) of acetic anhydride dropwise under ice bath, naturally warm to room temperature, stop the reaction for 10 h, add 200 mL of water and 300 mL of DCM, separate the liquid, evaporate the solvent , to obtain a brown oil, separated by column chromatography, and eluted with DCM / MeOH=80:1 to obtain a light yellow oil. After dissolving an appropriate amount of acetone, acetone solution of oxalic acid was added dropwise thereto, and a large amount of white solids were precipitated immediately. Filtered, 8.5 g of white powdery solid can be obtained, yield: 39.9%. 1 H-NMR (D 2 O): 7.34-7.30 (m, 2H), 7.27-7.24 (m, 1H),3.78 (s, 3H), 3.73 (t, J = 8 Hz,...

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Abstract

The invention belongs to the field of medicines and relates to a dihydro isoquinoline compound and application thereof in treatment of mental disorder, related to emotion, especially depressive disorder. Shown in a structural formula I, the dihydro isoquinoline compound has good protection activity on PC12 cells damaged under the induction action of corticosterone in an in vitro experiment, which suggests that the dihydro isoquinoline compound has a function of protecting nerve cells, further experiments verify that the dihydro isoquinoline compound can effectively improve level of BNDF (brain-derived neurotrophic factor) in nerve cells, the oxidation resistance of the nerve cells can also be effectively enhanced, and growth of the nerve cells is promoted; the dihydro isoquinoline compound has potential of treating mental disorder owning to repairing and protective effect on the nerve cells, is preferable for treating emotion and cognitive mental disorders, such as depressive disorder, senile dementia, anxiety, obsession and schizophrenia and is especially preferable for treatment of depression. In vivo experiments, including forced swimming and open field experiment, the dihydro isoquinoline compound shows obvious effect of alleviating depressive state of experimental animals respectively. The formula (I) is described in the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to the use of a class of dihydroisoquinoline compounds in nerve restoration and antidepressant treatment. Background technique [0002] Mental diseases are mainly a group of nervous system diseases mainly manifested in disorders of behavior and psychological activities. Among them, depression is a common mental disorder, with approximately 350 million patients worldwide. Depression differs from the usual mood swings and short-lived emotional responses to the challenges of everyday life. In particular, long-term moderate or severe depression can become a serious disorder. Patients may be greatly affected, performing poorly at work as well as at school and at home. At its worst, depression can lead to suicide. Suicide deaths are estimated to be as high as 1 million people each year. [0003] There are many kinds of antidepressant drugs currently available clinically, but there are still qui...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/14A61K31/472A61P25/18A61P25/24A61P25/00
CPCC07D217/14
Inventor 罗有福魏于全
Owner SICHUAN UNIV
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