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Optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same

a technology of pyranochromenyl phenol and phenol derivative, which is applied in the direction of drug composition, organic racemisation, metabolic disorder, etc., can solve the problems of difficult to develop a product actually utilizing glabridin, rapid increase in obesity ratio, etc., and achieve excellent anti-obesity efficacy, excellent anti-diabetic effect, and chemical stability. high

Inactive Publication Date: 2019-05-23
GLACEUM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The optically active pyranochromenylphenol derivatives described in this patent are more stable and have excellent effects on diabetes and obesity. The R-enantiomer is more stable and has good anti-diabetic effect, while the S-enantiomer is more stable and has good anti-obesity effect.

Problems solved by technology

Due to improvement in the standard of living resulting from the recent economic development, frequent ingestion of instant food products and dietary habits of consumption of large amounts of meat lead to a rapid increase in obesity ratio.
However, inspite of useful medicinal efficacy, glabridin is easily broken down by sunlight, moisture, acidity, basicity, oxygen, heat, and the like due to low chemical stability, so that it is very difficult to develop a product actually utilizing glabridin (Non-Patent Document 2).

Method used

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  • Optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same
  • Optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same
  • Optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of (R)-3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound 1a) and (S)-3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound 1b)

[0096]3-(2-hydroxy-4-ethoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene in the form of a racemic compound was synthesized in accordance with the method exemplified in Korean Patent Application Laid-Open No. 10-2015-0075030 (Patent Document 2).

1-1: Preparation of 2-(2-benzyloxy-4-ethoxyphenyl)-3-(2,2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl)-acrylic acid methyl ester

[0097]A three-neck round flask was cooled in a dry ice-acetone bath at −78° C. while being maintained under a nitrogen atmosphere, and 45 ml of a 1.0 M lithium diisopropyl amide (LDA)-THF solution was added thereto. Thereafter, 8.10 g (30.0 mmol) of (2-benzyloxy-4-ethoxyphenyl)acetic acid methyl ester was dissolved in 150 ml of THF, and then the resulting solution was slowly added ...

example 2

Preparation of (R)-3-(2-hydroxy-4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound 2a) and (S)-3-(2-hydroxy-4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound 2b)

[0115]3-(2-hydroxy-4-propoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene was synthesized in the form of a racemic compound by using the same method as in Example 1, except that in Example 1-1, (2-benzyloxy-4-propoxyphenyl) acetic acid methyl ester was used instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl ester. Daicel Chiral Technologies Co., Ltd. was requested for the separation and purification of the synthesized sample, 10 g of an R-enantiomer and 10 g of an S-enantiomer with >99% ee were provided, and the results of 1H-NMR, 13C-NMR, optical rotation, and M.P. for the enantiomers are shown as follows.

[0116]1H-NMR (CDCl3): 6.976 (d, 1H, J=8.4 Hz), 6.817 (d, 1H, J=8.0 Hz), 6.452 (dd, 1H, J=8.0, 2.0 Hz), 6.392 (d, 1H, J=8.4 Hz), ...

example 3

Preparation of (R)-3-(2-hydroxy-4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound 4a) and (S)-3-(2-hydroxy-4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene (Compound 4b)

[0124]3-(2-hydroxy-4-butoxyphenyl)-8,8-dimethyl-2,3,4,8,9,10-hexahydropyrano[2,3-f]chromene was synthesized in the form of a racemic compound by using the same method as in Example 1, except that in Example 1-1, (2-benzyloxy-4-butoxyphenyl) acetic acid methyl ester was used instead of (2-benzyloxy-4-ethoxyphenyl) acetic acid methyl ester. Daicel Chiral Technologies Co., Ltd. was requested for the separation and purification of the synthesized sample, 10 g of an R-enantiomer and 10 g of an S-enantiomer with >99% ee were provided, and the results of 1H-NMR, 13C-NMR, optical rotation, and M.P. for the enantiomers are shown as follows.

[0125]1H-NMR (CDCl3): 7.009 (d, 1H, J=8.4 Hz), 6.847 (d, 1H, J=8.0 Hz), 6.482 (dd, 1H, J=8.0, 2.0 Hz), 6.408 (d, 1H, J=8.4 Hz), 6.35...

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Abstract

The present invention relates to pyranochromenylphenol derivatives having different efficacies depending on the direction of optical activity and a pharmaceutical composition including the same, and in the pyranochromenylphenol derivatives, an R-enantiomer has excellent anti-diabetic efficacy by suppressing a rise in blood sugar and an S-enantiomer has excellent anti-obesity efficacy by suppressing an increase in body weight.

Description

TECHNICAL FIELD[0001]The present specification claims priority to and the benefit of Korean Patent Application No. 10-2016-0081674 filed in the Korean Intellectual Property Office on Jun. 29, 2016, the entire contents of which are incorporated herein by reference.[0002]The present invention relates to pyranochromenylphenol derivatives having different efficacies depending on the direction of optical activity and a pharmaceutical composition including the same, and to an R-enantiomer having excellent anti-diabetic efficacy and an S-enantiomer having excellent anti-obesity efficacy and a pharmaceutical composition including each of the enantiomers.BACKGROUND ART[0003]Obesity, which about 30 to 40% of modern people have, is defined as a state in which excessive fat tissues are accumulated in the body, and obesity occurs when excessive energy is accumulated due to imbalance of energy supply in the human body. Due to improvement in the standard of living resulting from the recent economi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D493/04C07B57/00A61P3/04
CPCC07D493/04C07B57/00A61P3/04C07B2200/07A61K31/352A61K31/353
Inventor YOO, SANG KUCHUNG, JIN WOOKJO, IN GEUNKIM, JL YOUNGIM, JEONG HOKANG, KU SUKKIM, JIN YOUNG
Owner GLACEUM INC