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Tricyclic diterpenoid derivative and preparation method as well as application of tricyclic diterpenoid derivative in preparation of neuroprotective drugs

A tricyclic diterpene and neuroprotective technology, which is applied in the field of medicine and its preparation and application, can solve the problems of limited compound resources and restricted development, and achieve the effect of simple synthesis method, environmental friendliness and mild reaction conditions

Inactive Publication Date: 2015-04-22
EAST CHINA NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, natural products are still an important source of drug discovery, however, the limited resources of these compounds limit their development

Method used

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  • Tricyclic diterpenoid derivative and preparation method as well as application of tricyclic diterpenoid derivative in preparation of neuroprotective drugs
  • Tricyclic diterpenoid derivative and preparation method as well as application of tricyclic diterpenoid derivative in preparation of neuroprotective drugs
  • Tricyclic diterpenoid derivative and preparation method as well as application of tricyclic diterpenoid derivative in preparation of neuroprotective drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the preparation of tricyclic diterpene derivative (leader) shown in formula (5)

[0038]

[0039] The preparation of tricyclic diterpene derivatives shown in formula (5), that is, compound 5: Dissolve compound 1 (8g, 29, 19mmol) in 50mlDCM, slowly add Br 2 (1.5ml, 29.19mmol) of DCM solution 50ml, after the dropwise addition, stir for 1h, TLC detects that the reaction of the raw materials is complete, add water, extract the aqueous phase with DCM (30ml×3), combine the organic phases, wash with water (30ml×2), saturated NaHCO3 Wash (30ml×2), wash with saturated NaCl (30ml×2), dry over anhydrous sodium sulfate, and concentrate to obtain compound 2 (yellow oil), which is directly used in the next step.

[0040] The previous step crude product compound 2 (10.2g, 29mmol), TBSCl (6.5g, 43.5mmol), imidazole (3.95g, 58mmol) were placed in a single-necked bottle, injected into DMF50ml, N 2 Replace and stir overnight at room temperature. TLC detects that the rea...

Embodiment 2

[0043] Embodiment 2: the preparation of tricyclic diterpene derivatives shown in formula (6), (7), (8), (9)

[0044]

[0045] The preparation of tricyclic diterpene derivatives shown in formula (6), namely compound 6: compound 5 (60mg, 0.19mmol) was placed in a single-necked bottle, N 2 For replacement, inject 10ml of methanol, add 5 drops of concentrated sulfuric acid dropwise, and stir at room temperature. TLC detected that the reaction of the raw materials was complete, added 10ml of water, extracted the aqueous phase with EA (10ml×3), combined the organic phases, washed with water (10ml×2), washed with saturated NaCl (10ml×2), dried over anhydrous sodium sulfate, concentrated, and silica gel Column chromatography (PE:EA=2:1) ​​and concentration gave product 6 (58 mg white solid, 91.8%). 1 H NMR (400MHz, CDCl 3 )δ7.49(s, 1H), 6.82(s, 1H), 3.85(s, 6H), 3.30(dd, J=11.1, 5.0Hz, 1H), 2.91(dd, J=16.8, 5.9Hz, 1H ), 2.82-2.71(m, 1H), 2.28(dt, J=12.9, 3.4Hz, 1H), 1.63-1.47(m,...

Embodiment 3

[0049] Embodiment 3: Preparation of tricyclic diterpene derivatives shown in formula (10), (11), (12), (13), (14), (15), (16), (17), (18)

[0050]

[0051] The preparation of tricyclic diterpene derivatives represented by formula (10), that is, compound 10: compound 5 (100 mg, 0.31 mmol), EDC.HCl (126 mg, 0.64 mmol), HOBt (86 mg, 0.64 mmol), DMAP (227 mg, 1.86mmol) and methylamine hydrochloride (64mg, 0.94mmol) were placed in a single-necked bottle, N 2 Replacement, inject 10ml of anhydrous DCM, stir overnight at room temperature. TLC detects that the reaction of the raw materials is complete, add 10ml of water, adjust the pH of the system to 1 H NMR (300MHz, CDCl 3 )δ7.89(s, 1H), 7.81(br.s, 1H), 6.80(s, 1H), 3.91(s, 3H), 3.31(dd, J=10.5, 5.5Hz, 1H), 3.10-2.60 (m, 5H), 2.28 (d, J=12.6Hz, 1H), 1.96-1.69 (m, 4H), 1.20 (s, 3H), 1.08 (s, 3H), 0.90 (s, 3H).

[0052] Preparation of tricyclic diterpene derivatives represented by formula (11), namely compound 11: Compound 5 (100...

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Abstract

The invention discloses a tricyclic diterpenoid derivative as shown in a formula (I) and a preparation method of the tricyclic diterpenoid derivative. A series of novel tricyclic diterpenoid derivatives as shown in the formula (I) can be prepared by taking the tricyclic diterpenoid derivative as shown in a formula (5) as a leading compound through such reactions as esterification, amidation, protection, acylation and deprotection. Furthermore, the invention also provides an application of the tricyclic diterpenoid derivative in preparation of neuroprotective drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a tricyclic diterpene derivative and its preparation method and its application in the preparation of neuroprotective medicine. Background technique [0002] Neurodegenerative diseases caused by loss of neurons, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), muscular atrophy side Amyotrophic lateral sclerosis (ALS), etc., seriously affect people's health and quality of life. Although the lesion sites and causes of different types of neurodegenerative diseases are not the same, all of these diseases cause neuronal cell damage. Excessive damage to nerve cells is irreversible and worsens over time to the point of dysfunction, leading to accelerated death. [0003] The mechanism of nerve cell injury is complex, involving oxidative stress, excitotoxicity, mitochondrial dysfunction, apoptosis and...

Claims

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Application Information

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IPC IPC(8): C07C51/347C07C65/26C07C67/08C07C69/76C07C231/02C07C235/66C07C231/12C07C45/61C07C49/84C07D295/192A61P25/00A61P25/28
CPCC07C41/22C07C43/23C07C45/64C07C49/84C07C51/367C07C65/26C07C67/08C07C67/29C07C69/16C07C69/94C07C231/02C07C231/12C07C235/66C07C2603/26C07D295/192C07F7/1804
Inventor 仇文卫庞涛汪滢滢
Owner EAST CHINA NORMAL UNIVERSITY
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