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Coumarin esterified derivative with effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as preparation method and application of coumarin esterified derivative

A technology of derivatives and coumarin, applied in the field of coumarin esterification derivatives and preparation thereof, achieves the effects of short reaction time, less environmental pollution, and inhibition of RXRα transcriptional activity

Inactive Publication Date: 2017-08-25
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there are no related reports on coumarin esterified derivatives with RXRα transcriptional activity

Method used

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  • Coumarin esterified derivative with effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as preparation method and application of coumarin esterified derivative
  • Coumarin esterified derivative with effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as preparation method and application of coumarin esterified derivative
  • Coumarin esterified derivative with effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as preparation method and application of coumarin esterified derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: Preparation of 4-chloromethyl-7-hydroxycoumarin

[0032] Mix resorcinol (5.5g, 0.05mol), ethyl 4-chloroacetoacetate (9.9g, 0.06mol), anhydrous bismuth chloride (0.8g, 2.5mmol) in a 100mL round bottom flask, and Under solvent conditions, heat and stir at 65°C for 5 hours. After the reaction, add 16 mL of 50% ethanol aqueous solution, continue heating and stirring at 65°C for 10 minutes, cool to room temperature, filter with suction, wash the solid part with water until neutral, and dry to obtain a white solid 7.45 g, namely 4-chloromethyl-7-hydroxycoumarin, the yield is 70%.

[0033] NMR data of 4-chloromethyl-7-hydroxycoumarin:

[0034] 1 H NMR (400MHz, DMSO-d 6 ):δ4.95(s,2H,CH 2 Cl),6.42(s,1H,3-H),6.76(d,1H,J=2.4Hz,8-H),6.83,6.85(dd,1H,J=2.4Hz,J=8.7Hz,6- H),7.67(d,1H,J=8.7Hz,5-H),10.66(s,1H,OH)ppm

Embodiment 2

[0035] Embodiment 2: Preparation of 4-chloromethyl-7-sorboyloxycoumarin (compound K1)

[0036] At 0°C, put sorbic acid (0.224g, 2.0mmol) in a 25mL two-neck round bottom flask, drop 2 drops of DMF, add 10mL of anhydrous dichloromethane (CH 2 Cl 2 ) was dissolved, and oxalyl chloride (0.2mL, 4.0mmol) was added with a disposable syringe; one mouth of the two-necked round-bottomed flask was tightly closed with a rubber stopper, and the other mouth was connected to an exhaust gas absorption device; after 30 minutes in an ice bath, it gradually returned to room temperature, and at room temperature Stir the reaction for 2h, after the reaction is over, distill to dryness under reduced pressure to remove unreacted oxalyl chloride; the product is washed with 2mL CH 2 Cl 2 After dissolving, it was added to 10 mL of CH containing 4-chloromethyl-7-hydroxycoumarin (0.315 g, 1.5 mmol) and triethylamine (0.208 g, 1.8 mmol) with a syringe 2 Cl 2 In the mixed solution, react at room tempera...

Embodiment 3

[0039] Embodiment 3: Preparation of 4-chloromethyl-7-hexanoyloxycoumarin (compound K2)

[0040] At 0°C, put hexanoic acid (0.232g, 2.0mmol) in a 25mL two-neck round bottom flask, drop 2 drops of DMF, add 10mL of CH 2 Cl 2 Dissolve, add oxalyl chloride (0.2mL, 4.0mmol) with a disposable syringe; one mouth of the two-neck round bottom flask is tightly closed with a rubber stopper, and the other mouth is connected to an exhaust gas absorption device; after 30 minutes in ice bath, gradually return to room temperature, and stir at room temperature Reacted for 2h, after the reaction was over, distilled to dryness under reduced pressure to remove unreacted oxalyl chloride; the product was washed with 2mL CH 2 Cl 2 After dissolving, it was added to 10 mL of CH containing 4-chloromethyl-7-hydroxycoumarin (0.315 g, 1.5 mmol) and triethylamine (0.208 g, 1.8 mmol) with a syringe 2 Cl 2 In the mixed solution, react at room temperature for 3 h; after the reaction, adjust the pH value of t...

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Abstract

The invention discloses a coumarin esterified derivative with an effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as a preparation method and application of the coumarin esterified derivative. The coumarin esterified derivative is a 4-chloromethyl-7-hydroxy coumarin esterified derivative shown by the following general formula. The invention also discloses a preparation method of the 4-chloromethyl-7-hydroxy coumarin esterified derivatives. The preparation method comprises the following steps: preparing 4-chloromethyl-7-hydroxy coumarin under solvent-free conditions by taking anhydrous bismuth chloride as a catalyst; preparing corresponding acyl chloride through different side chain acids; and reacting with the 4-chloromethyl-7-hydroxy coumarin, thereby obtaining the corresponding compound. The coumarin esterified derivative disclosed by the invention has a certain effect of inhibiting the transcriptional activity of RXRalpha and provides a thought for developing medicines taking the RXRalpha as a target. The structural formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a coumarin esterified derivative capable of inhibiting RXRα transcription activity, a preparation method and application thereof. Background technique [0002] Retinoid X Receptor (RXR) belongs to the superfamily of nonsteroidal hormone receptors and is a unique member of the nuclear receptor family with multiple biological functions, mediating many hormones, vitamin A and other drugs biological function. RXR is involved in the process of the body from embryonic development to organ formation, as well as the physiological regulation of various metabolisms in adults. In recent years, it has also been found that under the regulation of different ligands, RXR can perform nucleoplasmic shuttling and perform different biological functions, such as cell apoptosis, proliferation and differentiation. RXR includes three isoforms according to the promoter used and splicing ...

Claims

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Application Information

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IPC IPC(8): C07D311/16C07D405/12C07D407/12A61P35/00
CPCC07D311/16C07D405/12C07D407/12
Inventor 韩大雄王碧燕陈国旦王海燕
Owner XIAMEN UNIV
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