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Nobiletin derivative or pharmaceutically acceptable salt thereof as well as preparation method and application thereof

A technology of nobiletin and derivatives, applied in organic chemistry, drug combination, antineoplastic drugs, etc., which can solve the problems of high toxicity and clinical use restrictions

Active Publication Date: 2019-11-26
广东克冠达医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The overexpression of P-glycoprotein (P-gp) is one of the main mechanisms leading to multidrug resistance in tumor cells. The existing research on P-gp protein inhibitors such as verapamil, cyclosporine and other chemical reversal agents Clinical use is limited due to high toxicity

Method used

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  • Nobiletin derivative or pharmaceutically acceptable salt thereof as well as preparation method and application thereof
  • Nobiletin derivative or pharmaceutically acceptable salt thereof as well as preparation method and application thereof
  • Nobiletin derivative or pharmaceutically acceptable salt thereof as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] In the compound shown in formula (I), when X is O, its specific synthetic route is as follows:

[0077]

[0078] (1) Synthesis of Compound 12

[0079]

[0080] At room temperature, compound 3,4,5-trimethoxyphenol and sodium acetate were sequentially added to acetic anhydride and mixed, and heated at 110°C for 2 hours. After the reaction was completed, the reaction system was concentrated under reduced pressure and extracted three times with ethyl acetate. Washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain phenyl acetate containing different substituents, namely compound 12.

[0081] (2) Synthesis of Compound 13

[0082]

[0083] Compound 12 was added to glacial acetic acid solution, and boron trifluoride ether solution (about 48%) was added. The reaction mixture was stirred at 70°C for 2 hours and was monitored for completion by TLC analysis. Then the reaction system was quenched with water, ex...

Embodiment 2

[0097] The preparation of embodiment 2 compound C1

[0098] (1) Synthesis of compound 13a

[0099]

[0100] At room temperature, 3,4,5-trimethoxyphenol, compound 11a (9.2g, 50mmol) and sodium acetate (8.2g, 100mmol) were sequentially added to acetic anhydride (47mL, 500mmol) and mixed, heated at 110°C for 2 hours . After the reaction was completed, the reaction system was concentrated under reduced pressure and extracted three times with ethyl acetate. Washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to obtain 3,4,5-trimethoxyphenethyl ester, namely compound 12a (11.2 g, 49.5 mmol). White solid, 99% yield. 1 H NMR (400MHz, CDCl 3 )δ6.34(s,2H), 3.83(s,9H), 2.29(s,3H).

[0101] Compound 12a (11.2 g, 49.5 mmol) was added to glacial acetic acid (37.5 mL), and boron trifluoride ether solution (48%, 250 mL) was added to the system. The reaction system was stirred at 70° C. for 4 hours, and the reaction effect was monit...

Embodiment 3

[0106] The preparation of embodiment 3 compound C2

[0107] (1) Synthesis of compound 13b

[0108]

[0109] The raw material is replaced by 2,3,4-trimethoxy-6-hydroxyacetophenone and nitric acid, and the product is obtained according to the method of step (2) in Example 2, that is, 2,3,4-trimethoxy 1-5-nitro-6-hydroxyacetophenone, yellow solid, yield: 79%. 1 H NMR (400MHz, CDCl 3 )δ13.56(s,1H), 4.10(s,3H), 4.07(s,3H), 3.81(s,3H), 2.69(s,3H).

[0110] (2) Synthesis of compound C2

[0111]

[0112] 5.0 mmol 2,3,4-trimethoxy-6-hydroxyacetophenone, 15 mmol triethylamine, 6.0 mmol 3,4-dimethoxybenzoyl chloride, dichloromethane (25 mL) solution. Obtain product 2-acetyl-3,4,5-trimethoxy-6-nitrophenyl-3,4-dimethoxy-methyl benzoate according to the method of step (4) in Example 1 , off-white solid, yield: 90%. 1 H NMR (500MHz, CDCl 3 )δ7.73(dd, J=8.5,2.0Hz,1H),7.52(d,J=2.0Hz,1H),6.92(d,J=8.5Hz,1H),4.06(s,3H),4.02( s,3H), 3.96(s,3H), 3.95(s,3H), 3.93(s,3H), 2.52(s,3H).

...

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Abstract

The invention discloses a nobiletin derivative or a pharmaceutically acceptable salt thereof as well as a preparation method and application thereof. The nobiletin derivative has a structural formula(I) shown in the description, in the formula, R1, R2, R3 and R4 are respectively selected from hydrogen, halogen, hydroxyl, amino, C1-6 substituted or non-substituted alkoxy, a C1-6 substituted or non-substituted ester group, C1-6 substituted or non-substituted alkamino and a C1-6 substituted or non-substituted amide group; R5 is selected from a C3-9 substituted or non-substituted aromatic ring and a C3-9 substituted or non-substituted aromatic heterocyclic ring; and X is selected from O or NR6. The nobiletin derivative or the pharmaceutically acceptable salt thereof, which is disclosed by theinvention, is novel in structure, and in addition, the compound has an excellent inhibition function on P-gp, can be prepared into a P-gp inhibitor, is capable of treating and / or preventing related diseases caused by P-gp, particularly diseases related to tumor drug resistance, or can be mixed and used with other medicines and used as a drug resistance reversal agent, has a high reversion multiple, and is capable of remarkably improving medicine effects of medicines.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, more specifically, to a class of nobiletin derivatives or pharmaceutically acceptable salts thereof and their preparation methods and applications. Background technique [0002] Tumor multidrug resistance (Multiple drug resistance, MDR) refers to a kind of cross-resistance in which tumor cells develop resistance to one antitumor drug and also develop resistance to other antitumor drugs with different structures and mechanisms of action. , is one of the important reasons leading to the failure of tumor chemotherapy. One of the main ways to overcome multidrug resistance is to search for reversal agents of multidrug resistance and combine them with anticancer drugs to restore the sensitivity of multidrug resistant tumor cells to anticancer drugs. [0003] The overexpression of P-glycoprotein (P-gp) is one of the main mechanisms leading to multidrug resistance in tumor cells. The existin...

Claims

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Application Information

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IPC IPC(8): C07D311/30C07D407/04C07D405/04C07D215/22A61P35/00
CPCC07D311/30C07D407/04C07D405/04C07D215/22A61P35/00
Inventor 吴德燕谢莹周慧芳
Owner 广东克冠达医药科技有限公司
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