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Pentacyclic triterpenoid TGR5 receptor stimulant, preparation method and application thereof

A heterocyclic and cycloalkyl technology, applied in the field of TGR5 agonists, can solve the problems of difficult preparation, insufficient permeability, harsh multi-step reaction conditions, etc., and achieve the effect of abundant natural sources, simple synthesis method, and excellent agonistic activity

Active Publication Date: 2021-04-23
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But compound INT777 has the shortcoming that preparation is difficult, with cholic acid as the starting point, the synthetic route reaches twelve steps, and the multi-step reaction conditions are extremely harsh, recent literature also shows that INT777 also has obvious gallbladder filling phenomenon (Finn, PD etc., Am J Physiol Gastrointest Liver Physiol, 2019, 316, 412–424)
[0006] Oleanolic acid, a natural product of pentacyclic triterpenoids, can stimulate TGR5 receptors. Oral administration of 100 mg / kg oleanolic acid can significantly reduce the body weight and blood sugar levels of mice fed a high-fat diet, but due to its low TGR5 receptor agonistic activity , so it cannot be ruled out that the drug effect is caused by off-target effects (inhibition of PTP1B receptors) (Biochem.Biophys.Res.Commun 2007,362,793-8)
Subsequent in-depth research found that although the above compounds can significantly promote the secretion of GLP-1 in NCI-H716 cells in vitro, their solubility is extremely poor due to their high fat solubility and cannot be dissolved in the intestinal tract, so they cannot be released in vivo after oral administration. take effect
The Caco-2 monolayer cell permeability experiment shows that the compound cannot penetrate the cell membrane, and the TGR5 receptor is located on the basement membrane side of the intestinal epidermal endocrine L cells, and the insufficient permeability also determines that the compound cannot penetrate the intestinal epidermal endocrine L cells basement membrane to exert drug effect

Method used

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  • Pentacyclic triterpenoid TGR5 receptor stimulant, preparation method and application thereof
  • Pentacyclic triterpenoid TGR5 receptor stimulant, preparation method and application thereof
  • Pentacyclic triterpenoid TGR5 receptor stimulant, preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0151]

[0152] (1) Dissolve the raw material betulinic acid S1 (1.2g, 2.63mmol) in methanol (50mL) at room temperature. After changing nitrogen, quickly add 10% Pd / C, change nitrogen and then hydrogen, and stir at room temperature. After 24 hours, TLC detected that the reaction was complete. After nitrogen exchange, Pd / C was filtered off, and the reaction solution was spin-dried and separated by column chromatography with petroleum ether / ethyl acetate as an eluent system of 10:1 to obtain 1.04 g (2.27 mmol) of compound S2 as a white solid. Yield: 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).

[0153] (2) Dissolve the product S2 (1.04g, 2.27mmol) from the previous step in DMF (20mL) at room temperature, add anhydrous potassium carbonate (0.626g, 4.54mmol), and slowly add benzyl chloride (0.313mL ,2.72mmol)....

Embodiment 2

[0159]

[0160] (1) Dissolve S5 (1.00g, 1.82mmol) in dry DCM (10mL), add pyridine (732μL, 9.10mmol) dropwise at 0°C, and add p-nitrophenyl chloroformate (1.10mL) dropwise after 0.5 hours g, 5.46 mmol) in dry DCM (10 mL), returned to room temperature and stirred for 5 hours, TLC showed that the reaction was complete. Spin out DCM, extract with ethyl acetate (3×100mL), wash the combined organic layers with deionized water and saturated brine, dry and concentrate over sodium sulfate, and separate by column chromatography to obtain 1.20g (1.69mmol) of product S7 , Yield: 92.2%. 1 H NMR (300MHz, CDCl 3 )δ8.30-8.27(m,2H),7.40-7.35(m,7H),5.15-5.06(m,2H),4.60(t,1H,J=3.0Hz),2.30-2.15(m,5H) ,2.04-1.05(m, other alicyclic protons),0.96(s,3H),0.95(s,3H),0.92(s,3H),0.86-0.84(m,6H),0.76-0.74(m,6H ).

[0161] (2) Intermediate S-7 (100 mg, 0.182 mmol), DMAP (66.7 mg, 0.546 mmol) and triethylamine (75.7 μL, 0.546 mmol) were dissolved in dry DCM (2 mL), and cyclopropylamine (63.0 μL, 0.9...

Embodiment 3

[0168]

[0169] (1) Preparation of intermediate S8: Sodium hydride (9.84 mg, 0.246 mmol, 60%) was suspended in dry DMF (1 mL), and 2 mL of dry DMF solution of intermediate S8 (76.0 mg, 0.123 mmol) was added dropwise at 0°C , and then kept at 0°C and added dropwise methyl iodide (38.3 μL, 0.615 mmol), returned to room temperature after 10 minutes, and stirred overnight. TLC monitoring the next day showed that the reaction was complete. Quenched by adding deionized water, extracted with ethyl acetate (3×50mL), the combined organic layer was washed with deionized water and saturated brine respectively, dried and concentrated over sodium sulfate, and separated by column chromatography to obtain 59.0 mg of product S9 ( 0.093 mmol), yield: 76.0%. 1 H NMR (300MHz, CDCl 3 )δ7.37-7.30(m,5H),5.15-5.06(m,2H),4.49(t,1H,J=2.7Hz),3.35-3.28(m,2H),2.90(s,3H),2.30 -2.15(m,3H),1.91-0.96(m,other alicyclic protons),0.93(s,3H),0.88-0.84(m,12H),0.76-0.73(m,6H).

[0170] (2) Compound T20 (32....

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Abstract

The invention discloses a pentacyclic triterpenoid TGR5 receptor stimulant, a preparation method and application of the pentacyclic triterpenoid TGR5 receptor stimulant. The structure of the pentacyclic triterpenoid TGR5 receptor stimulant is as shown in a formula I, and the definition of each substituent is as shown in the specification and claims. According to the pentacyclic triterpenoid compound, the solubility is increased, the permeability is improved, the TGR5 receptor agonist activity is remarkably improved, Caco-2 monolayer cells can be penetrated, and the in-vivo drug effect exertion of the compound after oral administration is guaranteed. The TGR5 receptor stimulant is expected to be further developed into a medicine for treating metabolic diseases represented by diabetes.

Description

technical field [0001] The present invention relates to a class of TGR5 (bile acid G protein-coupled receptor) agonists, specifically, to a class of pentacyclic triterpenoids, a preparation method thereof, and the TGR5 receptor agonist or its pharmaceutical Use of acceptable salts or pharmaceutical compositions containing any one of them in the preparation of medicines for treating diabetes, obesity, hyperlipidemia, liver damage and inflammatory diseases. Background technique [0002] TGR5 is a G protein-coupled receptor that can be activated by bile acids and is named membrane bile acid receptor (M-BAR) or TGR5. TGR5 is highly expressed in gallbladder, bile duct epithelial cells, brown adipose tissue, muscle, intestine, kidney, placenta and brain. When the ligand binds to TGR5, it will activate adenylate cyclase, which will increase the level of intracellular cAMP and show different physiological effects in different tissues. In the small intestine, the increase of cAMP l...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P3/00A61P3/04A61P3/10A61P3/06A61P1/16A61P29/00
CPCC07J63/008A61P3/00A61P3/04A61P3/10A61P3/06A61P1/16A61P29/00A61K31/56A61K31/58C07J63/00
Inventor 南发俊谢欣张晨露郭世猛卓宁梁晓影张仰明贠盈刘桦楠
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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