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Limonin-7-amino derivatives and preparation method and medicine application thereof

A pharmaceutical and alkyl technology, applied in the field of water-soluble limonin-7-amino and deoxylimonin-7-amino derivatives, can solve the problems of poor water solubility, low bioavailability, and impact on clinical use, and achieve Good analgesic and pain relief effect

Active Publication Date: 2015-07-01
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its insufficient effect, poor water solubility and low bioavailability, it affects its clinical use.

Method used

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  • Limonin-7-amino derivatives and preparation method and medicine application thereof
  • Limonin-7-amino derivatives and preparation method and medicine application thereof
  • Limonin-7-amino derivatives and preparation method and medicine application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of Compound IV

[0055]Add 1.0 g (0.002 mol) of limonin (III), 1.1 g (0.016 mol) of hydroxylamine hydrochloride, 45 ml of absolute ethanol, and 15 ml of pyridine into a 100 ml eggplant-shaped bottle, and heat to reflux for 2.5 hours. Thin-layer chromatography (TLC) detects, and after the reaction is complete, the reaction solution is cooled to room temperature, poured into 125 ml of 5% dilute hydrochloric acid configured in advance, adjusted its pH to be acidic, and cooled with ice water. The aqueous layer was extracted three times with 50 ml of dichloromethane, the combined extracts were washed three times with saturated brine, and dried over anhydrous sodium sulfate. Filter and distill off the solvent under reduced pressure. The crude product was subjected to column chromatography with dichloromethane:methanol (125:1) to obtain 0.98 g of a white solid with a yield of 95%. mp>250℃; 1 HNMR (CDCl 3 ,500MHz),δ(ppm):7.70(1H,brs),7.39(2H,d,J=1.7Hz),6.34(1H,s...

Embodiment 2

[0057] Preparation of compound V

[0058] In a 250mL eggplant-shaped flask, mix 1g (2.06mmol) of compound IV with 70mL of methanol, add 0.39g (6.19mmol) of NaBH under ice-cooling 3 CN and 1.91 g (24.74 mmol) ammonium acetate. Add 15mL TiCl dropwise under ice bath condition 3 Hydrochloric acid solution, remove the ice bath after dropping, and react at room temperature for 12 hours. TLC detected that the reaction was complete, poured into 300mL water, extracted the water layer with 100mL dichloromethane three times, and discarded the dichloromethane layer. The pH of the aqueous layer was adjusted to 8.5-9 with NaOH, extracted three times with 100 mL of dichloromethane, the combined extracts were washed three times with saturated brine, and dried over anhydrous sodium sulfate. Filter and distill off the solvent under reduced pressure. The crude product was subjected to column chromatography with dichloromethane:methanol (75:1) to obtain 0.61 g of compound V as a white solid, ...

Embodiment 3

[0061] Preparation of compound VI-1

[0062] 1 g (2.12 mmol) of compound V was dissolved in 50 mL of dichloromethane, and a catalytic amount of DMAP was added. Under the condition of ice bath, slowly drop 176 μL (2.34 mmol) of chloroacetyl chloride, after the drop, remove the ice bath, and react at room temperature. It was detected by TLC that the reaction was complete, and the reaction solution was diluted with 150 mL of dichloromethane, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Filter and distill off the solvent under reduced pressure. The crude product was subjected to column chromatography with dichloromethane:methanol (80:1) to obtain 0.98 g of compound VI-1 as a white solid, with a yield of 84%, m.p.>250°C. 1 H NMR (500MHz, CDCl 3 ),δ(ppm):7.41(s,1H),7.41(s,1H),6.72(d,J=8.3Hz,1H),6.31(s,1H),5.54(s,1H),4.48(dd ,J 1 =34.5Hz,J 2 =13.1Hz,2H),4.11(dd,J 1 =42.1Hz,J 2 =15.4Hz, 2H), 4.15-4.20(m, 1H), 4.00(brs, 1H), 3.83(s, 1H), 2.9...

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Abstract

The invention relates to the field of pharmaceutical chemistry and particularly relates to water-soluble limonin-7-amino derivatives (I) and (II) shown in the specification, and a preparation method and medicine application thereof. Pharmacological experiments prove that the compounds disclosed by the invention have the analgesic and anti-inflammatory effects and can be clinically used for relieving pain and inflammatory diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of water-soluble limonin-7-amino and deoxylimonin-7-amino derivatives, their preparation methods, and their analgesic and anti-inflammatory effects. Background technique [0002] There are at least 100 million pain patients in my country. If the pain is not treated in time and effectively, it will seriously affect the daily quality of life and social stability. Analgesia has become an important task for medical workers. At present, the mainstream analgesics on the market can be mainly divided into opioid receptor agonists, non-steroidal anti-inflammatory drugs, and anticonvulsants according to their mechanism of action and structure. 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 effec...

Claims

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Application Information

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IPC IPC(8): C07J73/00A61K31/585A61P29/00
CPCC07J73/008
Inventor 徐云根杨芸蒋艾豆朱启华龚国清
Owner CHINA PHARM UNIV
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