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Limonin derivatives and preparation methods and medical applications thereof

A use and pharmaceutical technology, applied to water-soluble limonin derivatives for the treatment of pain and inflammation, can solve the problems of insufficient effect, low bioavailability, poor water solubility, etc., to eliminate inflammation, relieve pain, and relieve pain. pain effect

Active Publication Date: 2017-07-07
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have found that limonin compounds have effects in analgesia, anti-inflammation, anti-cancer, antibacterial, etc., but their clinical application is affected due to their insufficient effects, poor water solubility, and low bioavailability

Method used

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  • Limonin derivatives and preparation methods and medical applications thereof
  • Limonin derivatives and preparation methods and medical applications thereof
  • Limonin derivatives and preparation methods and medical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Preparation of 23-(2-(piperidin-1-yl)acetyl)limonoid (I-1)

[0109] 23-Chloroacetyllimonoid (IV-1)

[0110] Add limonin (8g, 17mmol) and dichloromethane (125mL) into a 250mL three-necked bottle, stir and cool down to 0°C, add aluminum trichloride (10.2g, 76.5mmol) in batches, after the addition is complete, keep stirring for 20 Minutes, dropwise added a mixed solution of chloroacetyl chloride (2.2g, 19.5mmol) and dichloromethane (5mL), after dropping, kept at 0~-5°C for 1 hour, then continued stirring at room temperature for 3 hours, then stopped the reaction. Slowly pour the reaction solution into 100 mL of ice water, separate the dichloromethane layer, extract the water layer twice with dichloromethane (100 mL×2), combine the organic layers, and wash three times with 1 mol / L sodium hydroxide aqueous solution (100 mL×2). 3), washed twice with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered with suction, and evaporated to remove the solvent un...

Embodiment 2

[0115] Preparation of 23-(2-(morpholin-4-yl)acetyl)limonoid (I-2)

[0116] Using compound IV-1 (2.0g, 3.65mmol) and morpholine (0.95g, 10.90mmol) as raw materials, the operation process was the same as I-1, and the crude product was purified by column chromatography (dichloromethane:methanol=90:1), 1.2 g of light yellow solid (I-2) was obtained, yield 54.9%, 146° C. (charring). 1 H NMR (300MHz, CDCl 3 )δ7.59(s,1H),7.26(s,1H),5.51(s,1H),4.79(d,J=13.1Hz,1H),4.49(d,J=13.2Hz,1H),4.06( s,2H),3.85–3.73(m,4H),3.70(s,2H),3.00(dd,J=16.8,3.7Hz,1H),2.95–2.79(m,1H),2.78–2.57(m, 5H),2.57–2.42(m,2H),2.24(dd,J=15.8,3.1Hz,1H),1.91–1.78(m,3H),1.62–1.46(m,1H),1.32(s,3H) ,1.20(s,3H),1.17(s,3H),1.10(s,3H).ESI-MS(m / z):598.3[M+H] +

[0117] Using compound I-2 (1.0g, 1.67mmol) as raw material, the operation process was the same as I-1·HCl to obtain 0.87g of light yellow solid (I-2·HCl), yield 83%, m.p.>200℃.

Embodiment 3

[0119] Preparation of 23-(2-(piperazin-1-yl)acetyl)limonoid (I-3)

[0120] Using compound IV-1 (2.0g, 3.65mmol) and N-tert-butoxycarbonylpiperazine (2.73g, 14.6mmol) as raw materials, the operation process was the same as I-1, and the crude product was subjected to column chromatography (dichloromethane:methanol = 150:1) purification to obtain 1.46g light yellow intermediate. Dissolve the intermediate in methanol (20mL), add saturated HCl in methanol (20mL) dropwise with stirring in an ice bath, after the dropwise reaction, react at room temperature for 2 hours, and detect by TLC (developing solvent: dichloromethane:methanol=25:1) After the reaction was complete, it was placed at 0-5°C for 1 hour, and 0.9 g of a light yellow solid (I-3) was obtained by suction filtration. The total yield of the two steps was 41.2%. 1 H NMR (300MHz, CDCl 3 )δ7.57(s,1H),7.25(s,1H),5.49(s,1H),4.77(d,J=12.7Hz,1H),4.47(d,J=13.4Hz,1H),4.03( s,2H),3.68(s,2H),3.06(s,4H),2.97(dd,J=16.8,3.9Hz,1H),2.9...

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Abstract

The invention relates to the field of pharmaceutical chemistry and in particular relates to a type of water-soluble limonin derivatives (I) and (II) and preparation methods thereof. Pharmacodynamic experiment results prove that the compound disclosed by the invention has the effects of treating inflammations, rheumatoid arthritis, pain and the like. The structural formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of water-soluble limonin derivatives, their preparation method, pharmaceutical composition containing these compounds and their application in treating pain and inflammation. Background technique [0002] Pain has been listed as the fifth vital sign after body temperature, pulse, respiration and blood pressure by modern medicine. If the pain is not treated in time and effectively, it will seriously affect the daily quality of life and social stability. Although great progress has been made in the research of analgesics, both non-steroidal antipyretic analgesic and anti-inflammatory drugs for mild and moderate pain, and analgesics for moderate and severe pain all have their own side effects and limitations, and some face potential abuse issues. [0003] Rheumatoid arthritis is a common joint inflammation. The cause of the disease is not very clear. It is a ...

Claims

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Application Information

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IPC IPC(8): C07J73/00A61K31/585A61P29/00
CPCC07J73/008
Inventor 徐云根何广卫贾成舒朱启华储昭兴嵇莹莹龚国清
Owner CHINA PHARM UNIV
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