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Ketorolac derivative as well as preparation method and application thereof

A technology of ketorolac and its derivatives, which is applied to the pharmaceutical composition containing the ketorolac derivatives, the field of ketorolac derivatives and its preparation, can solve the problems of short half-life and poor stability of ketorolac, and achieve The effect of high physical and chemical stability and good pharmacokinetic properties

Active Publication Date: 2022-04-22
NANJING HERON PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The present invention obtains a ketorolac derivative N23 and its left-handed pair by derivatizing the carboxyl group of racemic ketorolac or S-ketorolac Enantiomer N23(S), which overcomes the problems of short half-life, poor stability, irritation and compatibility of ketorolac

Method used

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  • Ketorolac derivative as well as preparation method and application thereof
  • Ketorolac derivative as well as preparation method and application thereof
  • Ketorolac derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The synthesis of embodiment 1 compound N23

[0039]

[0040]At room temperature, weigh ketorolac (5.0g, 19.6mmol), add DMF (10mL) and stir to dissolve, then add 4-chloromethyl-5-methyl-1,3-dioxole-2- Ketone (2.91g, 19.6mmo), and then the reaction bottle was moved to an ice bath for stirring, and sodium carbonate (1.46g, 15.7mmol) was added to the reaction bottle in 5 batches, and the addition was completed. The reaction was moved to room temperature and the reaction was stirred overnight. After TLC detects that the reaction is complete, add ethyl acetate 100mL and water 70ml to the reaction bottle, shake and separate the liquids, and the organic layer is washed with 5% sodium thiosulfate (30ml), washed with water (30ml), and dried over anhydrous sodium sulfate. , concentrated, made sand, and obtained 6.5 g of white solid by flash column chromatography, yield 90.4%.

[0041] 1 H NMR (400MHz, CDCl 3 )δ7.762-7.743(m,2H),7.620-7.584(m,1H),7.535-7.498(m.2H),6.7854(d,J...

Embodiment 2

[0043] Embodiment 2: the synthesis of compound N23 (S)

[0044]

[0045] The experimental method is the same as in Example 1, except that ketorolac is replaced by S-ketorolac.

[0046] 1 H NMR (400MHz, CDCl 3 )δ7.762-7.743(m,2H),7.620-7.584(m,1H),7.535-7.498(m.2H),6.7854(d,J=3.6Hz,1H),6.090(d,J=3.6Hz ,1H),4.920(s,2H),4.612-4.546(m,1H),4.483-4.416(m,1H),4.142-4.089(m,1H),2.973-2.776(m,2H),2.1769(s ,3H)

[0047] ESI-MS m / z=390.1,[M+Na] + .

Embodiment 3

[0048] The synthesis of embodiment 3 compound N23

[0049] At room temperature, weigh ketorolac (5.0g, 19.6mmol), add THF (10mL) and stir to dissolve, then add 4-chloromethyl-5-methyl-1,3-dioxole-2- Ketone (2.91g, 19.6mmol), and then the reaction flask was moved to an ice bath for stirring, and sodium carbonate (1.46g, 15.7mmol) was added to the reaction flask in 5 batches, and the addition was completed. The reaction was moved to room temperature and the reaction was stirred overnight. After TLC detects that the reaction is complete, add ethyl acetate 100mL and water 70ml to the reaction bottle, shake and separate the liquids, and the organic layer is washed with 5% sodium thiosulfate (30ml), washed with water (30ml), and dried over anhydrous sodium sulfate. , concentrated, made sand, and obtained 6.2 g of a white solid by flash column chromatography, with a yield of 86.2%.

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Abstract

The invention relates to a ketorolac derivative as well as a preparation method and application thereof. The ketorolac derivative N23 and the levorotatory enantiomer N23 (S) thereof are obtained by derivatizing carboxyl of ketorolac, and the problems of short half-life period, poor stability, irritation, compatibility and the like of ketorolac are solved. In-vivo rat tests show that the compound has good pharmacokinetic properties.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a ketorolac derivative, a preparation method and application thereof, and a pharmaceutical composition containing the ketorolac derivative. Background technique [0002] Ketorolac (Ketorolac), the chemical name is 5-benzoyl-2,3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, which is a derivative of pyrrolidine carboxylic acid, and its chemical structure and pharmacological effects are similar to those of Tome Indomethacin, zomeacin, and indomethacin are similar and belong to non-steroidal anti-inflammatory drugs. Mainly by inhibiting cyclooxygenase (COX), thereby reducing the synthesis and release of prostaglandins to produce anti-inflammatory effects. The reduction of prostaglandins can reduce the sensitivity of nerve fibers to noxious stimuli, thereby playing analgesic, anti-inflammatory and antipyretic effects. The analgesic activity of ketorolac is stronger, 0.4 times...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P19/02A61P29/00A61P25/04A61P25/06A61K31/407
CPCC07D487/04A61P19/02A61P29/00A61P25/04A61P25/06Y02P20/55
Inventor 苏钰文吕田陈星燃闵涛徐颖
Owner NANJING HERON PHARMA SCI & TECH CO LTD
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