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Flavonoid derivatives and their use in the preparation of pharmaceutical compositions

A technology of derivatives and flavonoids, applied in the field of preparation of dopamine transporter agonists, can solve the problems of weight loss and inability to receive effective treatment for patients

Inactive Publication Date: 2011-12-21
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although some progress has been made in the treatment of psychiatric and neurological diseases in recent years, many patients cannot be effectively treated because the drugs are ineffective for them or the drugs have serious side effects such as anti-parasympathetic nerve effects, myocardial toxicity, weight loss, etc. ( Edited by Hao Wei. Psychiatry, Fourth Edition, Beijing: People's Health Publishing House, 2001; Kapur, Shitij et al, Current Opinion in Psychiatry.17(2):115-121, March 2004.)

Method used

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  • Flavonoid derivatives and their use in the preparation of pharmaceutical compositions
  • Flavonoid derivatives and their use in the preparation of pharmaceutical compositions
  • Flavonoid derivatives and their use in the preparation of pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Synthesis of 5-O-acetylluteolin (1a)

[0048] 7-Benzyloxy-2-(3,4-dibenzyloxy)phenyl-5-hydroxy-4H-chromen-4-one (9)

[0049] Add luteolin (8) 100mg (0.35mmol) and anhydrous K to a 50ml three-necked bottle 2 CO 3 145mg (1.05mmol), DMF10ml and BnBr125μl (1.05mmol) were added under the protection of Ar, stirred and reacted for 4h under ice-bath conditions, then rose to room temperature and reacted overnight. The reaction solution was diluted with ethyl acetate, washed three times with distilled water and saturated NaCl solution. Anhydrous MgSO 4 dry. After filtration and concentration, a yellow solid was precipitated. Column chromatography (petroleum ether / CH 2 Cl 2 =2:1 to 1:1) to obtain 109 mg of light yellow solid, yield 56%. 1 HNMR (300MHz, CDCl 3 ): δ5.084 (s, 2H, OCH 2 Ph), 5.202(s, 4H, OCH2Ph), 6.391-6.399(d, 1H, J=2.4Hz, PhH), 6.450(s, 1H, C 3 -H), 6.475-6.481(d, 1H, J=1.8Hz, PhH), 6.949-6.978(d, 1H, J=8.7Hz, PhH), 7.312-7.485(m, 17H, PhH), 12.787(s , 1H...

Embodiment 2

[0055] Synthesis of 5-O-benzoylluteolin (1b)

[0056] Synthesis of 7-benzyloxy-2-(3,4-dibenzyloxy)phenyl-5-O-benzoyl-4H-chromen-4-one (12b)

[0057] Add compound 9100mg (0.18mmol) of dry CH in a 50ml three-necked flask 2 Cl 2 20ml and 60% NaH 15mg, reacted at room temperature for 30min under the protection of Ar, added 42μl (0.36mmol) of benzoyl chloride, stirred at room temperature for 1h, and the product spot showed bright blue fluorescence under ultraviolet light. The reaction system uses CH 2 Cl 2 Dilute, wash with distilled water and saturated NaCl solution twice. Anhydrous Na for organic phase 2 SO 4 Dry, filter and concentrate. Column chromatography (petroleum ether / ethyl acetate = 15:1 to 3:1 to ethyl acetate) yielded 118 mg of a light yellow solid with a yield greater than 99%. 1 HNMR (300MHz, CDCl 3 )δ5.146(s, 2H, OCH 2 Ph), 5.211 (s, 4H, OCH 2 Ph), 6.366-6.368 (d, 1H, J=0.6Hz, C 3 -H), 6.794-6.802(d, 1H, J=2.4Hz, PhH), 6.918-6.926(d, 1H, J=2.4Hz, PhH), 6...

Embodiment 3

[0061] 5-O-propionyl luteolin (1c)

[0062] Similar to the operation method of Example 2, 7-benzyloxy-2-(3,4-dibenzyloxy)phenyl-5-O-propionyl-4H-benzopyran-4-one (12c) can be obtained 286 mg, yield 86.5%. 1 HNMR (300MHz, CDCl 3 ): δ1.285-1.336 (t, 3H, CH 3 , J=7.5Hz), 2.730-2.806 (q, 2H, COCH 2 , J=7.5Hz), 5.149(s, 2H, OCH 2 Ph), 5.231(s, 2H, OCH 2 Ph), 5.243(s, 2H, OCH 2Ph), 6.426(s, 1H, C 3 -H), 6.670-6.678(d, 1H, J=2.4Hz, PhH), 6.882-6.890(d, 1H, J=2.4Hz, PhH), 6.978-7.006(d, 1H, J=8.4Hz, PhH ), 7.325-7.487 (m, 17H, PhH). MALDI-MS: 612.8 (M+H) + , 634.9 (M+Na) + , 650.8(M+K) + .

[0063] 5-O-propionyl luteolin (1c) 57 mg, yield 89.5%. 1 HNMR (300MHz, [d 6 ]DMSO): δ1.103-1.150 (t, 3H, J=7.2Hz, CH 3 ), 2.580-2.652 (q, 2H, J=7.2Hz, COCH 2 ), 6.438(s, 1H, C 3 -H), 6.506(s, 1H, PhH), 6.843(s, 1H, PhH), 6.875(s, 1H, PhH), 7.331(s, 2H, PhH), 9.393(s, 1H, OH), 9.806 (s, 1H, OH), 11.034 (s, 1H, OH). ESI-MS: 341.0 (M-H) - , 284.9 (M-C 2 h 5 CO) - .FT-IR (KBr, cm ...

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to flavonoid derivatives and their application in the preparation of pharmaceutical compositions for treating diseases related to dopamine transporters. The flavonoid derivatives of the present invention have the structure of general formula (I). The results of biological evaluation show that the compound of the present invention shows better stimulant effect on dopamine transporter than the prior art, can regulate the transport of dopamine by promoting the transport function of dopamine transporter, maintain the balance of extracellular dopamine concentration, and can prepare A dopamine transporter agonist for the treatment of psychiatric and neurological disorders. R1 is selected from hydroxyl, C1-C8 alkoxy, C1-C8 ester, glycoside, halogen; R2 is selected from hydrogen, C7 hydroxyl, C7 alkoxy, C7 ester, C7 halogen; R3 They are respectively selected from hydrogen, or contain one or more substituents on the benzene ring, and the substituents are respectively selected from hydroxyl, alkoxy, ester, aryl (hetero) group, halogen, and glycoside.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to flavonoid derivatives and their application in the preparation of pharmaceutical compositions, especially the application in the preparation of dopamine transport protein agonists. Background technique [0002] Mental and neurological disorders seriously affect the health of millions of people around the world. It has been reported that some common mental and / or neurological diseases such as anxiety disorders, mood disorders, schizophrenia, personality disorders, psychosexual disorders , drug abuse and dependence (drug abuse and dependence) affect people of all ages, and the duration of these diseases varies from weeks to decades. [0003] Studies have found that important neurotransmitters such as dopamine (DA), norepinephrine (norepinephrine), and serotonin (serotonin) play key physiological roles in mental and neurological diseases. Dopamine is the main catecholamine neurotr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61P25/22A61P1/08A61K31/352A61P25/00A61P25/28A61P25/20C07D311/30A61P43/00A61P25/18A61P25/30
Inventor 雷新胜林国强张建革刘宪波张培
Owner FUDAN UNIV
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