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Bibenzimidazole derivative with PPARgamma exciting agent activity and application thereof

A technology of benzimidazole and biphenyl is applied to bisbenzimidazole derivatives with PPARγ agonist activity and their application fields, which can solve the problems of adipose tissue surge, bone marrow fatty acid change, and patient weight gain.

Inactive Publication Date: 2008-01-09
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although TZD compounds have been proven to be very effective anti-type II diabetes drugs in clinical practice, because these two drugs can cause side effects such as weight gain, edema, adipose tissue surge, and changes in bone marrow fatty acids, it is necessary to find a class Novel PPARγ agonists

Method used

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  • Bibenzimidazole derivative with PPARgamma exciting agent activity and application thereof
  • Bibenzimidazole derivative with PPARgamma exciting agent activity and application thereof
  • Bibenzimidazole derivative with PPARgamma exciting agent activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: 4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]- Biphenyl-2-methanol

[0050]

[0051] Dissolve 608 mg of bisimidazole, 2 mmol, in 30 ml of anhydrous DMF, add 88 mg of 60% NaH under stirring at room temperature, and then add 610 mg of biphenyl raw material. After reacting for 6 h, TLC monitored that the reaction was complete. Dilute the system with a large amount of ethyl acetate, wash with cold water, dry the organic phase, and purify the product. Yield 100%.

[0052] 1H NMR (400Mz, CDCl3): δ7.82-7.78 (2H, m), 7.54-7.45 (2H, m), 7.44-7.33 (3H, m), 7.32-7.21 (5H, m), 7.09 (2H, d, J=8.05Hz), 5.45(2H,s), 3.81(3H,s), 3.57(3H,s), 2.94(2H,t, J=7.78Hz), 2.77(3H,s), 1.95- 1.80(2H, m), 1.05(3H, t, J=7.41Hz).

[0053] Dissolve the above product in anhydrous THF and add 100mg LiAlH 4 Powder, the reaction was completely converted after 1h. Add a certain amount of ethyl acetate, wash with brine, dry the organic phase, concentr...

Embodiment 2

[0055] Example 2: 4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]- Biphenyl-4-methoxy

[0056]

[0057] Dissolve 3.04 g of bis-imidazole in 30 ml of DMF, add 410 mg of 60% NaH with stirring at room temperature, add 2.50 g of p-bromobenzyl bromide solid, and react overnight at 60°C. The system was diluted with water, extracted three times with ethyl acetate, the organic phases were combined, and washed once with water. Purify by dry chromatography (developing solvent: dichloromethane / methanol=10:1). A viscous product was obtained, which was recrystallized from ethyl acetate to obtain a white granular crystalline product.

[0058] Take 237mg, 0.5mmol of the above crystals, p-methoxyphenylboronic acid 88mg K 2 CO 3 Dissolve the solid powder together in 15ml of THF / EtOH (1:1) mixed solution, add catalyst Pd (PPh 3 ) 4 60mg, stirred and heated to 60°C for reaction. The color change of the system is first yellow, then indigo, and then in...

Embodiment 3

[0060] Example 3: 4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]- Methyl biphenyl-4-carboxylate

[0061]

[0062] Take 480mg, 1.01mmol of bisimidazole protected by bromobenzyl group, 200mg of methyl p-formate phenylboronic acid, and K2CO3 solid powder 276mg, dissolve in 30ml of THF / EtOH (1:1) mixed solution, slowly add catalyst Pd (PPh3 ) 4116mg, stirred and heated to 60°C for reaction. The color of the system gradually darkened, and the reaction was terminated after 1 h. The solvent was removed by concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed with NaHCO3 and NaCl solution, dried and purified by chromatography to obtain a white solid product. (Developer: dichloromethane / methanol=20:1)

[0063] 1H NMR (400Mz, CDCl3): δ8.07 (2H, d, J=8.43Hz), 7.80-7.77 (1H, m), 7.61-7.52 (4H, m), 7.41-7.26 (5H, m), 7.14 (2H, d, J=7.88Hz), 5.46(2H, s), 3.92(3H, s), 3.80(3H, s), 2.93(2H, t, J=7.79Hz), 2.78(3H, s)...

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Abstract

A compound or its salt, their preparations and uses in treatment of PPAR gamma acceptor related diseases are disclosed. The compound is selective PPAR gamma agonist and has specific excitation activity. It can be used to treat diabetes mellitus or metabolic syndrome.

Description

technical field [0001] The invention relates to a compound with PPARγ agonist activity, a preparation method and its clinical application in treating PPARγ receptor-related diseases, such as diabetes or related complications. Background technique [0002] Diabetes is a disease caused by a variety of genetic disorders, which plagues a considerable part of the world's population. Divided into two types: (1) type I diabetes or insulin-dependent diabetes mellitus (IDDM), in which patients secrete little or no insulin; (2) type II diabetes or non-insulin-dependent diabetes (MDDM), in which type II diabetes The concentration of plasma insulin in patients is basically the same as that of normal people. However, the patient's body is resistant to insulin, which will further affect the metabolism of sugar and fat in insulin-sensitive tissues, namely muscle, liver and adipose tissue, and the concentration of insulin in the plasma of patients with type II diabetes is not enough to ove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/18A61K31/4184A61P3/10A61P9/12A61P9/00A61P3/04A61P3/06
CPCC07D235/20A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12
Inventor 郭建辉王猛姜勇
Owner SHANGHAI ALLIST PHARM CO LTD
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