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Azulene derivatives and salts thereof

A technology of derivatives and compositions, applied in the field of azulene derivatives and their salts, can solve problems such as the disappearance of hypoglycemic effect

Inactive Publication Date: 2005-09-21
ASTELLAS PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, since any of these compounds are O-glycosides containing O-glucosidic bonds between glucose and aglycone moieties, there is a problem that O-glucosidases, etc. Hydrolysis of glucosidic bonds, so that the hypoglycemic effect disappears

Method used

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  • Azulene derivatives and salts thereof
  • Azulene derivatives and salts thereof
  • Azulene derivatives and salts thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0179] At -40°C, boron trifluoride-ether complex (0.39ml) and triisopropylsilane (1.23ml) were added dropwise to 2,3,4,6-tetra-O-benzyl-1-C- In a solution of [3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucopyranose (2.3 g) in acetonitrile (40 ml), the mixture was stirred for 2 hours. Saturated aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-[(3 -Methylazulen-1-yl)methyl]phenyl]-D-glucitol (1.47 g).

Embodiment 2

[0181] At -78°C, 1M boron tribromide in n-heptane (20ml) was added dropwise to (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[ 3-[(3-Methylazulen-1-yl)methyl]phenyl]-D-glucitol (0.76 g) was dissolved in dichloromethane (20 ml), and the mixture was stirred for 30 minutes. Dichloromethane-toluene (ratio: 2:1, 60ml) was added to the reaction mixture, and methanol (6ml) was further added to the mixture. The reaction mixture was cooled to room temperature and concentrated to half its volume, then methanol (25 ml) was added to the mixture, and concentrated. This operation was repeated three times. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[3-[(3-methylazulen-1-yl)methyl]phenyl ]-D-glucitol (0.068 g).

[0182] In the same manner as in Examples 1 and 2, the compounds of Examples 3 and 4 were obtained, respectively.

Embodiment 5

[0184] In an argon atmosphere, two drops of 1,2-dibromoethane were added dropwise to a suspension of zinc powder (0.17 g) in THF (5.0 ml), and the mixture was heated to reflux for 5 minutes. After cooling to room temperature, two drops of chlorotrimethylsilane were added to the reaction mixture. The mixture was stirred for 15 minutes. Next, (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxybenzene was added to the reaction mixture Base]-D-glucitol (1.4 g), the mixture was heated under reflux for 1 hour. After cooling to room temperature, tetrakis(triphenylphosphine)palladium(0) (0.27 g) and methyl 2-chloroazulen-1-carboxylate (0.28 g) were added to the reaction mixture. The mixture was heated to reflux for 6 hours. After cooling to room temperature, the reaction mixture was poured into 10% aqueous hydrochloric acid under ice cooling. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous so...

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Abstract

The present invention provides an azulene derivative and a salt thereof, wherein an azulene ring is bonded to a benzene ring directly or via a lower alkylene which may be substituted with a halogen atom and the benzene ring is directly bonded to the glucose residue, and it is usable as a Na<+>-glucose cotransporter inhibitor, especially for a therapeutic and / or preventive agent for diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes-related diseases such as insulin-resistant diseases and obesity.

Description

field of invention [0001] The present invention relates to azulene derivatives of specific chemical formulas and salts thereof. More specifically, the present invention relates to azulene derivatives and salts thereof that can effectively treat or prevent diabetes, such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as various diabetes-related Diseases such as insulin resistance disease and obesity, for example, as a drug, especially as Na + - Inhibitors of glucose cotransporters. Background of the invention [0002] In recent years, there has been a need for a way to suppress Na + - Glucose cotransporter (SGLT) drugs that reabsorb glucose in the gut and kidney (Na + - Glucose cotransporter inhibitors), as antidiabetic agents rapidly normalize hyperglycemia and improve energy balance in the body. expect such Na + -Glucose cotransporter inhibitors are excellent for the treatment or prevention of diabetes, such ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/04A61P3/10A61P43/00C07D309/10C07D309/12
CPCC07D309/10C07D309/12A61P3/10A61P3/04A61P43/00A61K31/351
Inventor 冨山泰野田淳橘田香代子小林义典今村雅一村上猛生贝和弘铃木贵之黑嵜英志
Owner ASTELLAS PHARMA INC
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