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23-hydroxybetulinic acid 3-site modified derivative, and preparation method and application thereof

A derivative, betulinic acid technology, applied in the field of preparation, 3-position modified derivatives of 23-hydroxy betulinic acid, can solve rare problems

Active Publication Date: 2021-08-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies on the C3 locus are quite rare

Method used

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  • 23-hydroxybetulinic acid 3-site modified derivative, and preparation method and application thereof
  • 23-hydroxybetulinic acid 3-site modified derivative, and preparation method and application thereof
  • 23-hydroxybetulinic acid 3-site modified derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] 3-Pyridylamide-23-acetyl-lupine-20(29)-en-28-oic acid benzyl ester

[0049] 23-HBA (10.0g, 21.0mmol) was dissolved in DMF (120mL), and potassium carbonate (10.0g, 72mmol) and benzyl bromide (3mL, 25.0mmol) were gradually added thereto. After reacting at room temperature for 2h, 2 Double the volume of water (240mL), the product precipitated, and the crude product was obtained by suction filtration (it can be directly injected into the next step), and column chromatography (petroleum ether: ethyl acetate = 2:1-1:1) gave a white solid 28-benzyl protected 23-HBA Derivatives 1.

[0050] Compound 1 (1.00g, 2.05mmol) was dissolved in dichloromethane (40mL), DMAP (0.052g, 0.41mmol) was added, acetic anhydride (211.7μL, 2.26mmol) was added dropwise under stirring, and the reaction was monitored at room temperature to The raw materials disappeared, the reaction solution was concentrated, extracted with ethyl acetate (50mL×3), the organic layers were combined, washed ...

Embodiment 2

[0054]

[0055] 3-Pyrazinamide-23-acetyl-lupine-20(29)-en-28-oic acid benzyl ester

[0056] The synthetic method refers to the synthesis of Example 1, 48.9%. 1 H NMR (500MHz, Chloroform-d) δ9.34(d, J=3.8Hz, 1H), 8.74(q, J=2.6Hz, 2H), 7.37-7.29(m, 5H), 5.16-5.01(m, 2H), 4.72(d, J=2.4Hz, 1H), 4.60(s, 1H), 4.25-4.11(m, 2H), 3.97(dd, J=16.3, 11.5Hz, 1H), 3.01(td, J =10.8, 4.7Hz, 1H), 2.30-2.12(m, 2H), 2.08-1.99(m, 1H), 1.95(d, J=4.2Hz, 3H), 1.93-1.81(m, 3H), 1.76- 1.68(m, 3H), 1.64-1.53(m, 2H), 1.43(d, J=8.0Hz, 2H), 1.42-1.39(m, 2H), 1.38(d, J=6.4Hz, 2H), 1.35 -1.32(m, 2H), 1.29(d, J=4.9Hz, 2H), 1.27-1.24(m, 2H), 1.04(ddd, J=17.4, 8.0, 4.4Hz, 3H), 0.96(d, J =17.7Hz, 2H), 0.92(d, J=4.8Hz, 1H), 0.89(d, J=2.8Hz, 3H), 0.86(s, 3H), 0.83(s, 1H), 0.77(s, 3H ). 13 C NMR (125MHz, Chloroform-d) δ175.8, 169.6, 163.7, 150.5, 147.3, 146.2, 144.7, 143.9, 136.5, 128.5, 128.2, 128.0, 109.7, 67.9, 65.7, 56.5, 51.0, 50.9, 49.4, 49 ESI-MS m / z: 710.5 [M+H] + ; HR-MS (ESI) m / z: calculated ...

Embodiment 3

[0058]

[0059] 3-Cyclohexaneamide-23-acetyl-lupine-20(29)-en-28-oic acid benzyl ester

[0060] The synthetic method refers to the synthesis of Example 1, 45.7%. 1 H NMR (300MHz, Chloroform-d) δ7.37-7.32(m, 5H), 5.17-5.08(m, 3H), 4.72(s, 1H), 4.60(s, 1H), 4.09-4.01(m, 2H ), 3.90(d, J=11.4Hz, 1H), 3.47(d, J=11.5Hz, 1H), 3.05-2.99(m, 1H), 2.40-2.26(m, 2H), 2.19(t, J= 10.6Hz, 1H), 1.95(s, 3H), 1.68(s, 3H), 0.93(s, 3H), 0.82(s, 3H), 0.75(s, 3H), 0.70(s, 3H); ESI- MS m / z: 714.5[M+H] + ; HR-MS (ESI) m / z: calculated for C 46 h 68 NO 5 [M+H] + :714.5092, found: 714.5089.

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Abstract

The invention discloses a 23-hydroxybetulinic acid 3-site modified derivative, and a preparation method and application thereof. According to the invention, new drug molecules are found based on structural modification of natural products, and aliphatic side chains with different sizes, benzene rings substituted by different groups at different positions and nitrogen-containing heterocyclic ring substituents are introduced through derivatization of C3-site hydroxyl, so that a novel antitumor compound with relatively good activity is obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to 3-position modified derivatives of 23-hydroxybetulinic acid, a preparation method and application. Background technique [0002] The traditional Chinese medicine Pulsatilla chinensis (Bunge) Regel is a medicinal plant, and its root is widely used in the adjuvant treatment of intestinal amoebiasis, malaria, vaginal trichomoniasis, bacterial infection and malignant tumor. 23-hydroxybetulinic acid (23-HBA) is a pentacyclic triterpenoid compound extracted and isolated from its root, which is the main active ingredient of Pulsatilla radix. RosMarinus, Oplopanax and Glycyrrhiza and other plants. [0003] 23-HBA can be regarded as a hydroxylated derivative of betulinic acid, which belongs to the lupin-type triterpenes, similar to betulinic acid, and has significant antitumor activity. Studies have shown that 23-HBA has effects on B16 (mouse melanoma cell line), SGC-7901 (human gastr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61P35/00A61K31/58
CPCC07J63/008A61P35/00
Inventor 徐进宜朱华健徐盛涛刘洁鲁丽雪姚鸿陈哲生杨冬华叶文才
Owner CHINA PHARM UNIV