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3-substituted coumarin derivative and use thereof

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

Inactive Publication Date: 2013-08-28
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 phase II clinical studies as an analgesic drug, but the drug effect is not satisfactory (Giblin, G. M. P.; et al. Discovery of 2-[(2,4-Dichlorophenyl)amino] -N-[(tetrahydro-2H-pyran-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide, a Selective CB2 Receptor Agonist for the Treatment of Inflammatory Pain. J. Med. Chem.2007, 50, 2597-2600); CB2 agonist S-777469 as a candidate drug for the treatment of atopic dermatitis has also completed phase II clinical research (Odan, M., et al., Discovery of S- 777469: an orally available CB2 agonist as an antipruritic agent. 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 derivative and use thereof
  • 3-substituted coumarin derivative and use thereof
  • 3-substituted coumarin derivative and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: N-Benzyl-8-ethoxy-2-oxo-2H-chromene-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 added dropwise in 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. Quenched with water, extracted with dichloromethane, the aqueous layer was adjusted to PH = 2 with 1M HCl and then extracted with dichloromethane, the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a crude product. Separation and purification by column chromatography, the elution condition is petroleum ether: ethyl acetate = 10:1 ~ 6:1, 1a was obtained as a yellow solid 441.2mg, yield 53.1%, melting point 65.3-66.8°C.

[0090] 1 H NMR (CDCl 3 , 500...

Embodiment 2

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

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

[0102] 1 H NMR (CDCl 3 , 500 Hz): 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-chromene-3-carboxamide (CHA03)

[0104] The preparation of compound CHA03 was the same as that of compound CHA01 in Example 1, except that benzylamine was replaced by cyclohexylamine (0.12 mmol, 11.9 mg), and CHA03 was obtained as a white solid 4.3 mg with a yield of 13.7% and a melting point of 150.8- 151.6°C.

[0105] 1 H NMR (CDCl 3 , 500 Hz): 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=7.0Hz), 1.41 (m, 4H), 1.27 (m, 1H).

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Abstract

The invention provides a 3-substituted coumarin derivative, and pharmaceutically acceptable salts, solvates, hydrates or crystal forms thereof. The above compound has a high calcium flow activity and a very good selectivity on a human derived cannabinoid receptor CB2, and is a specific agonist or inverse agonist of the cannabinoid receptor CB2. The compound is an active ligand of a novel cannabinoid II receptor CB2, and compounds of the above kind and pharmaceutically acceptable salts, solvates, hydrates or crystal forms thereof have high calcium flow activities and a very good selectivity on the human derived cannabinoid receptor CB2. The compound is the specific agonist or inverse agonist of the cannabinoid receptor CB2, and can be applied to the preparation of medicines for treating, preventing and inhibiting CB2 receptor mediated diseases. The structure of the derivative is represented by a general formula A shown in the specification.

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 Applications(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