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Dihydroartemisinin/neurotransmitter conjugate as well as synthesis method and application thereof

A technology of dihydroartemisinin and neurotransmitters, which is applied in nervous system diseases, organic chemical methods, medical preparations containing active ingredients, etc., to achieve the effect of easy industrialization and simple preparation process

Inactive Publication Date: 2020-10-09
广州药本君安医药科技股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the SSRI drugs can produce nausea, vomiting and other gastrointestinal reactions and adverse reactions such as dizziness and headache during treatment.
Therefore, research on the pathogenesis of depression and the development of new therapeutic drugs still need to be further studied.

Method used

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  • Dihydroartemisinin/neurotransmitter conjugate as well as synthesis method and application thereof
  • Dihydroartemisinin/neurotransmitter conjugate as well as synthesis method and application thereof
  • Dihydroartemisinin/neurotransmitter conjugate as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The synthesis of 12-β-O-(N-(β-aminopropionyl))aminoethyldihydroartemisinin (CTL-B-1) comprises the following five steps:

[0053] (1) Preparation of 12-β-O-(2-bromoethyl) dihydroartemisinin: Dissolve (310mg, 1.1mmol) dihydroartemisinin in 20mL dry DCM, add a small amount of activated Molecular sieves, after precooling in ice bath for 5min, add phosphotungstic acid (160mg, 0.05equiv), after activation for 10min, add 2-bromoethanol (206.2mg, 1.65mmol), react in ice bath for 0.5h, room temperature ( 15°C) for 26 hours, followed by TLC. After the reaction, water was added, extracted with DCM, dried, and separated by column chromatography [V (petroleum ether): V (ethyl acetate) = 40:1] to obtain 274.6 mg of a white solid, Yield 63.8%.

[0054] The structural data of the product are as follows: 1 H NMR (CDCl 3 ,300MHz)δ:0.87(d,J=7.5Hz,3H), 0.92(d,J=6.3Hz,3H),1.17-1.26(m,2H),1.40(s,3H),1.57-1.63(m ,1H), 1.66-1.75(m,2H),1.79-1.90(m,1H),1.95-2.02(m,1H),2.02-2.11(m,2H),2.33(...

Embodiment 2

[0064] The synthesis of 12-β-O-(N-(γ-aminobutyryl))aminoethyldihydroartemisinin (CTL-B-2) comprises the following five steps:

[0065] (1) Preparation of 12-β-O-(2-bromoethyl)dihydroartemisinin: the steps are the same as in Example 1 step (1);

[0066] (2) Preparation of 12-β-O-(2-azidoethyl)dihydroartemisinin: the steps are the same as step (2) in Example 1;

[0067] (3) Preparation of 12-β-O-(2-aminoethyl)dihydroartemisinin: the steps are the same as step (3) in Example 1;

[0068] (4) Preparation of 12-β-O-(N-(N-Fmoc-γ-aminobutyryl)aminoethyl)dihydroartemisinin: Weigh Fmoc-γ-butyric acid (325.4mg, 1.0mmol ), implemented according to Example 1 step (4), to obtain 483.7 mg of light yellow oil, yield 76.2%.

[0069] The structural data of the product are as follows: 1 H NMR (300HMz, CDCl 3 )δ:7.76-7.73(m,2H,H-29,H-29a),7.59-7.57(m,2H,H-26,H-26a),7.41-7.36(m,2H,H-28,H -28a),7.31-7.27(m,2H,H-27,H-27a),5.37(d,2H,H-12,H-5),4.77-4.36(m,4H,H-23,H- 24),4.19 (m,1H,H-24),3.79-3.6...

Embodiment 3

[0074] The synthesis of 12-beta-O-(N-(4-(1H-imidazolyl)) aminoethyl dihydroartemisinin (CTL-B-3) comprises the following two steps:

[0075] (1) Preparation of 12-β-O-(2-bromoethyl)dihydroartemisinin: the steps are the same as in Example 1 step (1);

[0076] (2) Preparation of 12-β-O-(N-(4-(1H-imidazolethyl))aminoethyldihydroartemisinin: take 12-β-(O-2-bromoethyl)dihydro Artemisinin (391.3mg, 1.0mmol) was dissolved in 30ml of DMF, histamine (221.4mg, 1.5mmol) and potassium carbonate (414.6mg, 3.0mmol) were added, stirred at 78°C for 3 hours, TLC (DCM: Methanol=10:1, V:V, R f =0.42) monitoring, the reaction was completed, moved to room temperature, extracted with DCM (3×50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated by distillation under reduced pressure to obtain a mixture. Column chromatography separation (DCM:methanol=50:1, V:V,R f =0.15), to obtain 279.1 mg of a yellow oily substance, with a yield of 66.2%.

[0077] The structural data of the pr...

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Abstract

The invention discloses a dihydroartemisinin / neurotransmitter conjugate as well as a synthesis method and application thereof, the structure of the dihydroartemisinin / neurotransmitter conjugate is shown as a formula I, wherein the symbol * refers to a beta-configuration, and R is a beta-aminopropionyl group, a gamma-aminobutyryl group or a 2-(1H-imidazole-4-yl)ethyl group. The compound disclosed by the invention is reported for the first time, has a treatment effect on neurodegenerative diseases, can be used for preparing medicines for treating neurodegenerative diseases, and particularly canbe used for preparing medicines for treating depression. Compared with other prior art, the preparation process of the compound is simple and is easy to industrialize.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a dihydroartemisinin / neurotransmitter complex and its synthesis method and its application in the preparation of medicines for treating neurodegenerative diseases, especially in the preparation of medicines for treating depression Applications. Background technique [0002] Depression is a relatively common disease among mental system diseases, with a relatively high clinical incidence rate. The main clinical manifestations are depression, sadness, depression, despair and other emotional symptoms. Severe cases have a high suicidal tendency, which seriously affects daily life and career development. Depression is complex and easy to relapse, and severe cases may frequently appear suicidal manifestations or be admitted to hospital for treatment multiple times. Depression can occur alone or in combination with other diseases. [0003] Traditionally, antidepressants ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/20A61K31/357A61K31/4178A61P25/00A61P25/24
CPCA61P25/00A61P25/24C07B2200/07C07D493/20
Inventor 陈河如唐银莹李艳冰刘志军
Owner 广州药本君安医药科技股份有限公司
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