Structural simplification of natural product 4-O-methyl saucerneol of lignans, and preparation method, pharmaceutical composition and application thereof

A compound, methoxyl technology, applied in the field of medicine, can solve the problems of difficult extraction and separation, complex structure of natural products, limited sources, etc.

Active Publication Date: 2019-06-18
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But it is difficult to extract and separate, so the source is limited
In addition, the structure of natural products is complex, and it is difficult to prepare by synthetic methods.

Method used

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  • Structural simplification of natural product 4-O-methyl saucerneol of lignans, and preparation method, pharmaceutical composition and application thereof
  • Structural simplification of natural product 4-O-methyl saucerneol of lignans, and preparation method, pharmaceutical composition and application thereof
  • Structural simplification of natural product 4-O-methyl saucerneol of lignans, and preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] 500mL round bottom bottle contains (25g, 0.137mol) homovanillic acid, 150ml DMF is dissolved, (66g, 0.477 mol) anhydrous K 2 CO 3 Add, add BnBr (34mL, 0.286mol) dropwise at room temperature, TLC shows complete after 5h, add 500mL EA, 500mL water to the reaction solution, separate, take the organic phase, extract the aqueous phase with EA (100ml*2), combine the EA The phases were washed with 200 mL of water and saturated sodium chloride successively, dried with anhydrous sodium sulfate, filtered, concentrated, and column chromatography (PE:EA=20:1) to obtain 42 g of the product with a yield of 85%.

[0119] (34g, 90mmol) of the above product in anhydrous methanol, the suspension was stirred for 5 minutes and then (30g, 540mmol) KOH was added, the reaction solution was clear, and the TLC was completed by stirring at room temperature for 4 hours. Concentrate the reaction solution, remove methanol, add 300mL water and 200mL ether to the reaction solution, separate the water pha...

Embodiment 2

[0122] Step A: A 200ml round-bottomed bottle contains (9.6g, 35.3mmol) of the above product, 20mL SOCl 2 Add, react at 55°C for 1.5h, concentrate, and set aside -I.

[0123] Add (6.43g, 36.4mmol) (S)-benzyloxazolidinone to a 250mL two-necked flask, dissolve in 100mL anhydrous THF, and drop (2.5M, 14.5mL, 36.4mmol) under the protection of argon at -78℃n -BuLi, drip for about 15min, react at this temperature for 0.5h, then drip the prepared I 10mL anhydrous THF solution, warm to room temperature and react for 3h to complete the reaction. 20mL saturated ammonium chloride was slowly dropped into the reaction solution, concentrated to remove most of the THF, 300mL EA, 50mL water, 100mL EA aqueous phase extraction, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography (PE: EA=5:1) 15.7 g of the product was obtained, and the yield was 99%.

[0124]

[0125] 1 H NMR(400MHz, CDCl 3 )δ6.83-7.45(m,13H), 5.16(s,2H), 4.66-4.69(m,1H), 4.26-4....

Embodiment 3

[0127] Step B

[0128] (2.23g, 5mmol) Compound 18 was added dropwise (2.0M, 3mL, 6mmol) NaHMDS in 50mL THF under the protection of argon at -78°C. After 1.5h at -78°C, (0.9mL, 6mmol) tert bromide was added dropwise Butyl ester, 2h TLC shows complete at this temperature, 10mL saturated ammonium chloride is dripped, 200mL EA extraction, 50mL saturated sodium chloride washing, anhydrous sodium sulfate drying, filtration, concentration, column chromatography (PE:EA=15:1 ) The product was 2.3 g, and the yield was 85%.

[0129]

[0130] 1 H NMR(400MHz, CDCl 3 )δ 6.79-7.43 (m, 13H), 5.42 (dd, J = 4.4 Hz, 11.2 Hz, 1H), 5.12 (s, 2H), 4.55-4.60 (m, 1H), 4.02-4.11 (m, 2H) ), 3.88(s,3H),3.24-3.39(m,2H), 2.78-2.81(m,1H), 2.60(dd,J=4.4Hz,16.8Hz,1H),1.43(s,9H); 13 C NMR(100MHz, CDCl 3 )δ173.5, 171.0, 152.8, 149.6, 147.7, 137.1, 135.7, 129.9, 129.5, 128.9, 128.6, 127.8, 127.3, 120.7, 113.9, 112.2, 80.9, 71.0, 65.7, 56.0, 55.8, 44.2, 40.2, 37.6, 28.1 ; HR-MS(ESI)calcd for C 32 H 35 O 7 NNa(M+Na) ...

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Abstract

The invention discloses a structural simplification of a natural product 4-O-methyl saucerneol of lignans, and a preparation method, a pharmaceutical composition and application thereof. The inventionspecifically relates to a compound as shown in a formula (I) or an isomer thereof and a pharmaceutically acceptable salt thereof, and a preparation meathod of the compounds. The novel pharmaceuticalcomposition comprises an effective dose of the compound as shown in the formula (I) and a pharmaceutically acceptable carrier. The invention also discloses application of the compounds to prepare a medicament for the preparation, prevention and/or treatment of tumors, wherein the tumors includes neural glioblastoma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer,oral epidermal cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostatic cancer, colon cancer and rectal adenocarcinoma.

Description

Technical field [0001] The present invention relates to a novel 4-O-methylsauricol structure simplification, its preparation method, a pharmaceutical composition containing them, and its use as medicine, especially as an antitumor medicine, belonging to the technical field of medicine. Background technique [0002] Hypoxia inducible fac-tor-1 (HIF-1) is composed of hypoxia, CoCl 2 , Deferoxamine, etc. induce cells to produce a nuclear protein with transcriptional activity, composed of α and β subunits. HIF-1 is ubiquitous in human and mammalian cells. Although it is also expressed under normoxia, HIF-1 protein synthesized under normoxia is quickly degraded by the intracellular oxygen-dependent ubiquitin protease degradation pathway ; HIF-1 can be stably expressed only under hypoxic conditions, causing a series of cell responses to hypoxia, can promote red blood cell production, angiogenesis, regulate vasomotor and promote glycolysis, which has important pathophysiological signifi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08C07D207/26A61K31/40A61K31/4015A61P35/00
Inventor 李燕谢平刘晓宇焦晓臻杜倩倩李晓宇杨飞龙
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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