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Fused-ring derivative and preparation method thereof as well as application of fused-ring derivative in medicine

A technology of compounds and mixtures, applied in the field of fused ring derivatives, its preparation and its application in medicine, can solve the problems of sulfonylurea drugs loss of response, edema, weight gain, etc.

Active Publication Date: 2013-04-03
SHANGHAI HENGRUI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, over time, the body of patients often loses response to sulfonylurea drugs and develops tolerance
Metformin and alpha-glucosidase inhibitors often cause gastrointestinal problems, PPAR-gamma agonists are prone to weight gain and edema

Method used

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  • Fused-ring derivative and preparation method thereof as well as application of fused-ring derivative in medicine
  • Fused-ring derivative and preparation method thereof as well as application of fused-ring derivative in medicine
  • Fused-ring derivative and preparation method thereof as well as application of fused-ring derivative in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] 4-[4'-(3-Methylsulfonylpropoxy)-2',6'-dimethyl-biphenyl-3-yl-methoxy]-1a,6a-dihydro-1H-cyclopropyl [b]benzofuran-1-carboxylic acid

[0147]

[0148] first step

[0149] 3'-(chloromethyl)-2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)biphenyl

[0150] Under an ice bath, (2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)methanol 1a (348mg, 1mmol, using a known method" Patented CN101616913" prepared) was dissolved in 10 mL of dichloromethane, triethylamine (303 mg, 3 mmol) and methanesulfonyl chloride (172 mg, 1.50 mmol) were added, the temperature was raised to room temperature, and the reaction was stirred for 2 hours. Add 100 mL of water, extract with dichloromethane (100 mL×3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry with anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, and wash with silica gel column chromatography The residue obtained was purified by the removal system B to obtain t...

Embodiment 2

[0166] 4-[4'-(3-Methylsulfonylpropoxy)-2',6'-dimethyl-biphenyl-3-yl-methoxy]-1aR,6aR-dihydro-1H-cyclopropyl [b] Benzofuran-1R-carboxylic acid

[0167]

[0168] The 4-[4'-(3-methylsulfonylpropoxy)-2',6'-dimethyl-biphenyl-3-yl-methoxy]-1a,6a-dihydro-1H-ring Propyl[b]benzofuran-1-carboxylic acid 1 (0.11g, 0.21mmol) was subjected to chiral resolution, and the chiral isomers were separated by HPLC using preparation equipment and chiral column (separation conditions: chiral column AD-H Chiralpak 4.6, mobile phase: (ethanol: acetic acid = 1000:1), flow rate: 0.5 mL / min), collect the corresponding components, and remove the solvent by rotary evaporation to obtain the title product 4-[4'-(3- (Methylsulfonylpropoxy)-2',6'-Dimethyl-biphenyl-3-yl-methoxy]-1aR,6aR-dihydro-1H-cyclopropyl[b]benzofuran-1R- Formic acid 2 (38.90 mg, white solid).

[0169] 1 H NMR(400MHz, CDCl 3 )δ7.43-7.35(m,2H),7.31-7.26(m,2H),7.15(d,1H),6.65-6.59(m,,2H),6.57-6.55(m,2H),5.12(d ,1H),5.05(s,2H),4.14(t,2H),3.31-3....

Embodiment 3

[0171] 4-[4'-(3-Methylsulfonylpropoxy)-2',6'-dimethyl-biphenyl-3-yl-methoxy]-1aS,6aS-dihydro-1H-cyclopropyl [b] Benzofuran-1S-carboxylic acid

[0172]

[0173] The 4-[4'-(3-methylsulfonylpropoxy)-2',6'-dimethyl-biphenyl-3-yl-methoxy]-1a,6a-dihydro-1H-ring Propyl[b]benzofuran-1-carboxylic acid 1 (0.11g, 0.21mmol) was subjected to chiral resolution, and the chiral isomers were separated by HPLC using preparation equipment and chiral column (separation conditions: chiral column AD-H Chiralpak 4.6, mobile phase: (ethanol: acetic acid = 1000:1), flow rate: 0.5 mL / min), collect the corresponding components, and remove the solvent by rotary evaporation to obtain the title product 4-[4'-(3- (Methylsulfonylpropoxy)-2',6'-Dimethyl-biphenyl-3-yl-methoxy]-1aS,6aS-dihydro-1H-cyclopropyl[b]benzofuran-1S- Formic acid 3 (44.50 mg, white solid).

[0174] 1 H NMR(400MHz, CDCl 3 )δ7.43-7.35(m,2H),7.31-7.26(m,2H),7.15(d,1H),6.65-6.59(m,,2H),6.57-6.55(m,2H),5.12(d ,1H),5.05(s,2H),4.14(t,2H),3.31-3....

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Abstract

The invention relates to a fused-ring derivative and a preparation method thereof as well as application of the fused-ring derivative in medicine. Specifically, the invention relates to a novel fused-ring derivative as shown in a general formula (I), the preparation method of the derivative and a medicine composition containing the derivative as well as the application of the derivative serving as a therapeutic agent, particularly a GPR 40 agonist in preparation of the medicines for treating diseases such as diabetes mellitus and metabolic symptoms. The definitions of substituent groups in the general formula (I) are identical to those in the specification.

Description

Technical field [0001] The present invention relates to a new condensed ring derivative, its preparation method and pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a GPR40 agonist and in the preparation of drugs for the treatment of diseases such as diabetes and metabolic disorders the use of. Background technique [0002] Type II diabetes, also known as non-insulin-dependent diabetes or adult-type diabetes, is mainly manifested in the patient's body with too little insulin secretion or the body cannot effectively use insulin (insulin resistance). At present, there are about 185 million diabetic patients in the world, of which type II diabetic patients account for about 90-95% of the total number of diabetic patients, and at the same time continue to increase at a growth rate of 6%. In 2010, the overall prevalence of type II diabetes among people over 20 years old in my country has reached 9.7%. [0003] At present, the trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/93A61K31/343A61P3/10A61P3/00
Inventor 杨方龙范江董正董庆
Owner SHANGHAI HENGRUI PHARM CO LTD
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