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Antidiabetic bicyclic compounds

A compound and heterocyclic technology, applied in the field of bicyclic compounds, can solve the problems of lipid distribution with side effects and failure to significantly improve lipid metabolism, etc.

Inactive Publication Date: 2008-01-16
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compounds currently on the market fail to significantly improve lipid metabolism and may actually have side effects on lipid profile

Method used

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  • Antidiabetic bicyclic compounds
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220]

[0221] To Intermediate 5-3 (0.1 mmol, 36 mg), CuI (0.02 mmol, 4 mg), N,N-dimethylglycine HCl salt (0.06 mmol, 8.4 mg), 2-methyl-4-fluoro-phenol ( 0.15mmol, 19mg) and Cs 2 CO 3 (0.47 mmol, 153 mg) was added dioxane (1 mL). The reaction was heated at 95°C overnight, then filtered. The filtrate was neutralized with TFA (0.5 mL), then concentrated. The residue was subjected to reverse phase HPLC (YMC-Pack Pro C185 micron, 20%-80% CH 3 CN / H 2 O / 0.1% TFA) to give pure product as a solid. LC-MS determination of C 18 h 16 FN 2 o 3 S[M+H + ]: theoretical value 359.1, measured value 359.0.

Embodiment 2

[0223]

[0224] To intermediate 5-3 (0.1mmol, 36mg), CuI (0.02mmol, 4mg), N,N-dimethylglycine HCl salt (0.06mmol, 8.4mg), 2,4-dichloro-phenol (0.15mmol , 25mg) and Cs 2 CO 3 (0.47 mmol, 153 mg) was added dioxane (1 mL). The reaction was heated at 95°C overnight, then filtered. The filtrate was acidified with TFA (0.5 mL), then concentrated. The residue was subjected to reverse phase HPLC (YMC-Pack Pro C185 micron, 20%-80% CH 3 CN / H 2 O / 0.1% TFA) to give pure product as a solid. LC-MS determination of C 17 h 13 Cl 2 N 2 o 3 S[M+H + ]: theoretical value 395.0, measured value 394.9.

Embodiment 3

[0226]

[0227] To a solution of Intermediate 5-5 (25 mg, 0.1 mmol) in DMF (0.5 mL) was added Cs sequentially 2 CO 3 (0.3mmol, 98mg), 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (0.15mmol). The reaction was heated at 50 °C for 1 h with CH 3 CN (1 mL) was diluted, then acidified with trifluoroacetic acid (0.4 mL). The mixture was subjected to reverse phase HPLC (YMC-Pack Pro C185 microns, 20%-80% CH 3 CN / H 2 O / 0.1% TFA) to give pure product as a solid. LC-MS determination of C 17 h 12 CIF 3 N 3 o 3 S[M+H + ]: theoretical value 430.0, measured value 430.0.

[0228] Intermediate 6-1

[0229]

[0230] This intermediate was prepared from cyclohexanone ethyl acetate according to the method of Intermediate 5-1. LC-MS determination of C 13 h 17 INO 2 [M+H + ]: theoretical value 346.0, measured value 346.0.

[0231] Intermediate 6-2

[0232]

[0233] This intermediate was prepared from Intermediate 6-1 by converting Intermediate 5-1 to 5-2.

[0234] P...

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Abstract

Bicyclic compounds containing a fused pyridine ring, including pharmaceutically acceptable salts and prodrugs thereof, are agonists of G-protein coupled receptor 40 (GPR40) and are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Description

field of invention [0001] The present invention relates to bicyclic compounds containing fused pyridine rings, including pharmaceutically acceptable salts and prodrugs thereof, which are G protein-coupled receptor 40 (GPR40) agonists and are therefore useful as therapeutic compounds, especially for the treatment of 2 Type 2 diabetes and conditions frequently associated with the disease, including obesity and lipid metabolism disturbances. Background of the invention [0002] Diabetes mellitus is characterized by high plasma glucose levels (hyperglycemia) in the fasting state or following administration of glucose during an oral glucose tolerance test from a variety of etiologies. There are two recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), the patient produces little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes, or non-insulin-dependent diabetes (NDDM), the body still produces insulin. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44A61K31/47C07D215/16C07D215/20C07D413/00
CPCC07D413/04C07D417/04C07D215/20C07D417/12C07D413/12A61P3/04A61P3/06A61P43/00A61P5/50A61P3/10
Inventor 葛敏杨立虎周昌友林松年E·D·克莱恩
Owner MERCK & CO INC
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