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7-ethyl-10-hydroxycamptothecin prodrug and its preparation method and application

A technology of hydroxycamptothecin and ethyl, which is applied in the field of camptothecin drug precursors, can solve the problems that cannot be directly used in clinical practice, the preparation process is cumbersome, and the quality is not easy to control, so as to achieve good market prospects and clinical application value, The effect of low preparation cost and high stability

Inactive Publication Date: 2018-05-01
王杭祥
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

7-Ethyl-10-Hydroxycamptothecin (SN-38) is one of the derivatives. Although the antitumor effect of SN-38 is good, it is also insoluble in pharmaceutically acceptable solvents due to poor water solubility ( Such as Tween 80, polyoxyethylene castor oil, etc.), so it cannot be directly used in clinical
[0008] But there are some defects in the SN-38 drug of above-mentioned polyethylene glycol coupling, at first, drug load is low (about 4%), need a large amount of adjuvant; Secondly, generate required coupling drug, need multi-step organic The reaction and preparation process are cumbersome and the quality is not easy to control

Method used

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  • 7-ethyl-10-hydroxycamptothecin prodrug and its preparation method and application
  • 7-ethyl-10-hydroxycamptothecin prodrug and its preparation method and application
  • 7-ethyl-10-hydroxycamptothecin prodrug and its preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0060] The synthesis of the SN-38 prodrug 1 of embodiment 1 containing alkane chain compound

[0061] Add n-butyric acid (116 μL, 1.3 mmol) and SN-38 (500 mg, 1.3 mmol) into a 100 mL round bottom flask, dissolve in 28 mL of anhydrous DMF (dimethylformamide), and then add EDC·HCl (267 mg, 1.4 mmol), DMAP (4-dimethylaminopyridine) (172 mg, 1.4 mmol) and DIEA (N,N-diisopropylethylamine) (232 μL, 1.4 mmol). Stir overnight at 25°C, remove the reaction solvent, dissolve the solid in dichloromethane, and then wash with 5% citric acid, saturated sodium bicarbonate, and saturated brine; the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is collected to reduce The solvent was removed under pressure; the solid was separated and purified by column chromatography (DCM:MeOH=75:1) to obtain product 1 (350 mg, yield 59%).

[0062] product 1 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0063] 1 H NMR (400MHz, CDCl 3 ): δ1.02-...

Embodiment 2

[0065] The synthesis of the SN-38 prodrug 2 of embodiment 2 containing alkane chain compound

[0066] Add n-heptanoic acid (108μL, 0.76mmol) and SN-38 (300mg, 0.76mmol) into a 100mL round bottom flask, dissolve in 20mL of anhydrous DMF, then add EDC·HCl (160mg, 0.84mmol), DMAP (103mg , 0.84mmol) and DIEA (149mL, 0.84mmol); stirred overnight at 25°C, after removing the reaction solvent, the solid was dissolved in dichloromethane, and then washed with 5% citric acid, saturated sodium bicarbonate, and saturated brine; the organic phase Dry over anhydrous sodium sulfate, filter, collect the filtrate and remove the solvent under reduced pressure; the solid is separated and purified by column chromatography (DCM:MeOH=75:1) to obtain product 2 (157 mg, yield 41%).

[0067] product 2 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0068] 1 H NMR (400MHz, CDCl 3 ): δ0.91-0.94(t,3H),1.00-1.04(t,3H),1.35-1.41(m,6H),1.43-1.49(t,3H),1.80-1.91(m,4H),2.64 -2.6...

Embodiment 3

[0070] The synthesis of the SN-38 prodrug 3 of embodiment 3 containing alkane chain compound

[0071] Add dodecanoic acid (153mg, 0.76mmol) and SN-38 (300mg, 0.76mmol) in a 100mL round bottom flask, dissolve in 20mL anhydrous DMF, then add EDC·HCl (160mg, 0.84mmol), DMAP (103mg , 0.84mmol) and DIEA (149μL, 0.84mmol); stirred overnight at 25°C, after removing the reaction solvent, the solid was dissolved in dichloromethane, and then washed with 5% citric acid, saturated sodium bicarbonate, and saturated brine; the organic phase Dry over anhydrous sodium sulfate, filter, collect the filtrate and remove the solvent under reduced pressure; the solid is separated and purified by column chromatography (DCM:MeOH=100:1) to obtain product 3 (220mg, 50%).

[0072] product 3 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0073] 1 H NMR (400MHz, CDCl 3 ): δ0.86-0.90(t,3H),1.01-1.05(t,3H),1.25-1.35(m,16H),1.40-1.43(t,3H),1.78-1.91(m,4H),2.64 -2.68(t,2H),3.1...

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Abstract

The invention discloses a 7-ethyl-10-hydroxycamptothecine drug precursor, a preparation method and an application thereof. A structure formula of the drug precursor is represented as the formula I or II. The drug precursor is prepared through an esterification reaction between a C-10 hydroxyl group or a C-20 hydroxyl group of 7-ethyl-10-hydroxycamptothecine and a hydrophobic molecule. The drug precursor has excellent anti-tumor activity and can directly release active components in vivo in a hydrolysis manner without catalytic hydrolysis of carboxylesterase, thereby achieving a high bioavailability. The drug precursor not only has excellent solubility in water but also has great solubility in amphipathic surfactants, such as tween-80 and the like, wherein the solubility can reach more than 30 mg / ml, and a high stability is achieved even that the drug precursor is diluted in water. The drug precursor can be prepared just through a one-step esterification method, is high in yield and low in preparation cost, is high in stability and good in safety, satisfies requirements in clinical medication and in large-scale industrial production, and has excellent market prospect and clinical application value.

Description

technical field [0001] The invention relates to a camptothecin class drug precursor, in particular to a series of 7-ethyl-10-hydroxycamptothecin drug precursors and their preparation method and application. Background technique [0002] Camptothecin is a natural alkaloid extracted from camptotheca japonica, which mainly acts on DNA topoisomerase I and has a strong ability to inhibit tumor cell proliferation. 7-Ethyl-10-Hydroxycamptothecin (SN-38) is one of the derivatives. Although SN-38 has a good antitumor effect, it is not soluble in pharmaceutically acceptable solvents due to its poor water solubility ( Such as Tween 80, polyoxyethylene castor oil, etc.), so they cannot be directly used clinically. The structural formula of 7-ethyl-10-hydroxycamptothecin is as follows: [0003] [0004] Irinotecan (Irinotecan, CPT-11) and so on are currently clinically approved camptothecin anticancer drugs. Irinotecan is obtained by modifying the C10 hydroxyl group on 7-ethyl-10-h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCY02P20/55
Inventor 王杭祥
Owner 王杭祥
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