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3-substituted coumarin derivatives and uses thereof

A technology of coumarins and derivatives, which is applied in the field of medicine and can solve problems such as unsatisfactory drug efficacy

Inactive Publication Date: 2016-01-13
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The CB2 agonist GW842166X reported by GSK has completed three clinical phase II studies as an analgesic drug, but the drug effect is not satisfactory (Giblin, G.M.P.; etal. Discovery of 2-[(2,4-Dichlorophenyl)amino]-N- CB2 The agonist S-777469 has also completed clinical phase II studies as a candidate drug for the treatment of atopic dermatitis (Odan, M., et al., Discovery of S-777469: anorally available CB2 agonist as an antipruriticagent.Bioorg.Med.Chem.Lett.,2012,22,2803-2806)
At present, the research on CB2 selective ligands is mostly concentrated in the preclinical stage and clinical research stage, and there is no marketed drug

Method used

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  • 3-substituted coumarin derivatives and uses thereof
  • 3-substituted coumarin derivatives and uses thereof
  • 3-substituted coumarin derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: N-benzyl-8-ethoxy-2-oxo-2H-benzopyran-3-carboxamide (CHA01)

[0088] a) Preparation of 3-ethoxy-2-hydroxybenzaldehyde 1a

[0089] 60% sodium hydride (12.50mmol, 500mg) was suspended in 12.5mL of anhydrous DMSO, 2,3-dihydroxybenzaldehyde (5.00mmol, 690.6mg) was dropped into 2.5mL of anhydrous DMSO, and added after 1 hour at room temperature Bromoethane (5.00mmol, 544.9mg). React at room temperature for 24 hours. It was quenched with water and extracted with dichloromethane. The aqueous layer was adjusted to PH=2 with 1M HCl and then extracted with dichloromethane. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a crude product. After separation and purification by column chromatography, the elution condition is petroleum ether: ethyl acetate=10:1~6:1, and 1a is obtained as a yellow solid 441.2mg, the yield is 53.1%, and the melting point is 65.3-66.8°C.

[0090...

Embodiment 2

[0100] Example 2: 8-Ethoxy-2-oxo-N-(pyridine-3-methylene)-2H-benzopyran-3-carboxamide (CHA02)

[0101] The preparation of compound CHA02 is the same as that of compound CHA01 in Example 1, except that 3-aminomethylpyridine (0.12mmol, 13.0mg) is used instead of benzylamine to obtain CHA02 as a yellow solid, 17.7mg, with a yield of 54.7%. Melting point 213.5-214.8°C.

[0102] 1 HNMR(CDCl 3 ,500Hz): δ9.30(s,1H), 8.92(s,1H), 8.63(d,1H,J=1.0Hz), 8.54(d,1H,J=3.5Hz), 7.71(d,1H, J=7.5Hz), 7.28(m,3H), 7.20(dd,1H,J=1.5Hz,J=7.5Hz), 4.68(d,2H,J=6.0Hz),4.21(q,2H,J= 7.0Hz), 1.52(t, 3H, J=7.0Hz).

Embodiment 3

[0103] Example 3: N-cyclohexyl-8-ethoxy-2-oxo-2H-benzopyran-3-carboxamide (CHA03)

[0104] The preparation of compound CHA03 is the same as that of compound CHA01 in Example 1, except that cyclohexylamine (0.12mmol, 11.9mg) is used instead of benzylamine to obtain CHA03 as a white solid 4.3mg, yield 13.7%, melting point 150.8- 151.6°C.

[0105] 1 HNMR(CDCl 3 ,500Hz):δ8.88(s,1H),8.80(d,1H,J=7.0Hz), 7.28(d,1H,J=3.0Hz), 7.26(d,1H,J=2.0Hz), 7.18 (dd,1H,J=7.5Hz,J=2.0Hz),4.22(dd,2H,J=7.0Hz,J=14.0Hz),3.99(m,1H),2.00(m,2H),1.77(m , 2H), 1.64 (m, 1H), 1.53 (t, 3H, J=7.0 Hz), 1.41 (m, 4H), 1.27 (m, 1H).

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Abstract

The invention provides a 3-substituted coumarin derivative and its pharmaceutically acceptable salt, solvate, hydrate or crystal form. The compound of the invention generally exhibits higher calcium flow activity and good selectivity to human cannabinoid receptor CB2, and is a specific agonist or inverse agonist of the cannabinoid receptor CB2. The compounds provided by the present invention are active ligands of the novel cannabinoid type II receptor CB2, and the compounds and their pharmaceutically acceptable salts, solvates, hydrates or crystal forms generally exhibit relatively high High calcium flux activity and good selectivity. The compound of the invention is a specific agonist or an inverse agonist of the cannabinoid receptor CB2, and can be used in the preparation of medicines for treating, preventing and inhibiting diseases mediated by the CB2 receptor. The general formula A of the derivative is as follows:.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to a class of 3-substituted coumarin CB2 active ligands, in particular to 3-substituted coumarin compounds and their pharmaceutically acceptable salts, solvates, hydrates or crystal forms in Use in the preparation of medicaments for the treatment of diseases mediated by the cannabinoid type II receptor CB2. Background technique [0002] As early as several centuries ago, people have realized that plant cannabis has medicinal effects such as pain relief, anti-vomiting, anti-convulsion, and anti-inflammation. Cannabinoids are also one of the earliest addictive substances recognized by humans. Studies have proved that there are at least two subtypes of cannabinoid receptors: CB1 receptors and CB2 receptors, both of which belong to the rhodopsin-like family of G protein-coupled receptors (GPCRs) and have a 7-segment α-helix transmembrane structure , its complete amino acid sequence has 44% ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/18C07D405/12C07D413/04A61K31/37A61K31/4433A61K31/453A61K31/4245A61K31/5377A61P35/00A61P29/00A61P31/18A61P37/02A61P37/08A61P1/16A61P19/10A61P9/10A61P25/00A61P25/28A61P25/16A61P25/14
Inventor 陈建忠谢欣韩爽张菲菲
Owner ZHEJIANG UNIV
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