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Pentacyclic triterpenoids, preparation method, pharmaceutical composition and use thereof

A compound and drug technology, applied in the field of TGR5 agonists, can solve problems such as preparation difficulties

Active Publication Date: 2018-12-07
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compound INT777 has the disadvantage of being difficult to prepare. Starting from cholic acid, the synthetic route has as many as twelve steps, and extremely harsh reaction conditions are used many times.

Method used

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  • Pentacyclic triterpenoids, preparation method, pharmaceutical composition and use thereof
  • Pentacyclic triterpenoids, preparation method, pharmaceutical composition and use thereof
  • Pentacyclic triterpenoids, preparation method, pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0069] Preparation Example 1 (Compound No.: C33)

[0070]

[0071] (1) Benzyl betulinate

[0072] Dissolve the raw material betulinic acid (4g, 8.76mmol) (purchased from Xi'an Haoxuan Biotechnology Co., Ltd.) in DMF (50mL) at room temperature, add anhydrous potassium carbonate (2.4g, 17.37mmol), and slowly drop it under stirring After adding benzyl chloride (1.2 mL, 10.52 mmol) dropwise, the reaction solution was moved to 50° C. and stirred overnight. The next day, the mixture was cooled to room temperature, diluted with 100 mL of deionized water, extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with deionized water and saturated brine, dried over sodium sulfate and reduced Pressure distillation gave the desired white solid compound benzyl betulinate (4.62 g), molar yield: 97%. 1 H NMR (300MHz, CDCl 3 )δ7.34(m,5H),5.09(d,1H,J=11.7Hz),5.17(d,1H,J=11.7Hz),4.75(s,1H),4.62(s,1H),3.21- 3.15(m,1H),2.92-2.80(m,1H),2.10-1.90(m,2H),1.87-1.69(m...

preparation Embodiment 2

[0079] Preparation example two (compound number: C34)

[0080]

[0081] Betulinic acid (1.2g, 2.63mmol) was dissolved in methanol / ethyl acetate (40mL / 10mL). After changing the nitrogen, add a catalytic amount of Pd / C, and then change the nitrogen and hydrogen. Stir at room temperature for 2 days, and detect the reaction by TLC completely. After changing the nitrogen gas, the reaction solution was filtered, spin-dried, and separated by column chromatography with petroleum ether:ethyl acetate at a polarity of 10:1. The product C34 was obtained as a white solid (1.04 g, 2.27 mmol) with a molar yield of 86%. 1 H NMR (300MHz, CDCl 3 )δ3.13(t, 1H, J=9.0, 6.9Hz), 2.28-2.16(m, 2H), 1.98-1.78(m, 4H), 1.64-0.96(m, other alicyclic protons), 0.96(s ,3H),0.93(s,3H),0.92(s,3H),0.90(s,3H),0.89(s,3H),0.87(s,3H),0.78(s,3H); ESI-MS( m / z):481.3(M+Na) + (C 30 h 50 o 3 Theoretical value: 458.38).

[0082] Using the same method, using different natural products or compounds as raw mater...

preparation Embodiment 3

[0085] Preparation Example 3 3-α-Acetoxy Betulinic Acid (Compound No.: C97)

[0086]

[0087] (1) Benzyl 3-α-acetoxybetulinate

[0088] 3-α-Hydroxybetulinate benzyl ester (107mg, 0.20mmol) and a catalytic amount of DMAP (10mg, 0.08mmol) were dissolved in dichloromethane (10mL), triethylamine (82mL, 0.60mmol) was added, and ice-water bath Acetic anhydride (42 mL, 0.60 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC showed that the reaction was complete. After concentrating to remove the solvent, diluting with ethyl acetate, washing with water and saturated aqueous sodium chloride solution respectively, drying and concentrating the organic phase, and purifying the residue by column chromatography with petroleum ether / ethyl acetate as the eluent of 20:1 The compound 3-α-acetoxy betulinate benzyl ester was obtained as white solid (77 mg, 0.13 mmol), molar yield: 65%. 1 H NMR (300MHz, CDCl 3 )δ7.34(m,5H),5.09(d,1H,J=11.7Hz),5.17(d,1H,J=11.7Hz),4.62(...

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Abstract

The present invention relates to a pentacyclic triterpenoid compound represented by general formula (I) and a preparation method thereof, a pharmaceutical composition containing the compound, the application of the compound in the preparation of a drug for treating type 2 diabetes, and the The application of said compound in the treatment of type 2 diabetes.

Description

technical field [0001] The present invention relates to a class of TGR5 (G protein-coupled bile acid membrane receptor) agonists, in particular to a class of pentacyclic triterpenoids, a preparation method thereof, and a pharmaceutical composition comprising the compound, and Said compounds can act as TGR5 agonists. Background technique [0002] Diabetes is caused by different etiologies (such as genetic factors, immune dysfunction, microbial infection and its toxins, free radicals, mental factors, etc.) that lead to hypofunction of pancreatic β cells and / or resistance of body cells to insulin. A characteristic metabolic disorder syndrome. According to the statistics of the International Diabetes Federation (IDF), in 2010, there were more than 43 million people with diabetes among the people aged 20-79 in China, and the prevalence rate reached 4.5%. Diabetes has become a disease that endangers human safety and health. [0003] At present, the drugs for the treatment of di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P3/10
CPCC07J63/008A61K31/56A61K31/58A61P3/10
Inventor 南发俊谢欣王霄音张书永李静
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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