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A kind of camptothecin phosphate compound, its preparation method and application

A technology of camptothecin phosphate and alkali phosphate, applied in the field of biomedicine, can solve the problems of large toxic and side effects, low activity, etc., and achieve the effects of facilitating absorption and transport, high product purity, and reduced antitumor activity

Active Publication Date: 2018-11-30
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Aiming at the above defects or improvement needs of the prior art, the present invention provides a camptothecin phosphate compound, its preparation method and application, and its purpose is to combine camptothecin The 20-position hydroxyl group is modified to form an ester bond to improve the stability of the lactone ring, thereby solving the technical problems of low activity and large toxic and side effects of existing camptothecin derivatives as antitumor drugs

Method used

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  • A kind of camptothecin phosphate compound, its preparation method and application
  • A kind of camptothecin phosphate compound, its preparation method and application
  • A kind of camptothecin phosphate compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the synthesis of target compound Ia

[0036]

[0037]Synthesis of raw material camptothecin 20-O-L-glycine ester: Take N-Boc-glycine (3.13mmol) in a round-bottomed flask, add dry dichloromethane (200mL) to dissolve it, and then add xi Dentine (3.13 mmol), N,N'-diisopropylcarbodiimide (DIPC, 3.13 mmol) and 4-dimethylaminopyridine (DMAP, 3.13 mmol). The reaction was stirred at room temperature for 16 hours. After the thin-layer chromatography detection reaction was completed, the solid impurities were removed by suction filtration, and then the organic phase was washed with 0.1N hydrochloric acid, dried, and concentrated under reduced pressure to obtain a white solid, which was separated by column chromatography (chloroform-methanol) to obtain the intermediate camptothecin -20-O-(N'-tert-butoxycarbonyl)-L-glycinate. Take camptothecin-20-O-(N'-tert-butoxycarbonyl)-L-glycine ester (2mmol) in a round bottom flask, add CH 2 Cl 2 (2 mL) and TFA (2 mL), sti...

Embodiment 2

[0044] Embodiment 2: the synthesis of target compound Ib

[0045]

[0046] Same as Example 1, only alanine is used instead of glycine. The detection data of the product obtained from the reaction are as follows: yield: 81%; melting point: 275-276°C; 1 H-NMR (400MHz, CDCl 3 )δ:8.40(s,1H,C7-H),8.23(m,2H,C9-H,C12-H),7.82(t,1H,C10-H,J=4Hz),7.67(t,1H, C11-H, J=4Hz),7.20(s,1H,C14-H),5.72(d,1H,C17-H,J=20Hz),5.42(d,1H,C17-H,J=20Hz), 5.30(s,2H,C5-H),4.24-4.30(m,1H,alanine-H),3.97-4.13(m,4H,S CH 2 CH 3 -H),2.14-2.32(m,2H,C18-H),1.14-1.56(m,9H,alanine-H,SCH 2 CH 3 -H) 1.01 (t, 3H, C19-H, J=8Hz); MS-ESI m / z: 594.2 [M+Na] + , confirmed to be compound Ib.

Embodiment 3

[0047] Embodiment 3: the synthesis of target compound Ic

[0048]

[0049] Same as Example 1, only valine is used instead of glycine. The detection data of the product obtained from the reaction are as follows: yield: 82%; melting point: 279-281°C; 1 H-NMR (400MHz, CDCl 3 )δ:8.40(s,1H,C7-H),8.23(m,2H,C9-H,C12-H),7.83(t,1H,C10-H,J=4Hz),7.66(t,1H, C11-H, J=4Hz), 7.21(s, 1H, C14-H), 5.72(m, 1H, C17-H), 5.41(m, 1H, C17-H), 5.30(s, 2H, C5- H),3.94-4.17(m,4H,S CH 2 CH 3 -H),3.18-3.22(m,1H,Valine-H),2.80-3.95(m,1H,Valine-H),2.11-2.31(m,2H,C18-H),1.12-1.62 (m,12H,valine-H,SCH 2 CH 3 -H), 0.97(t, 3H, J=8Hz, C19-H); MS-ESI m / z: 622.1[M+Na] + , confirmed to be compound Ic.

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Abstract

The invention discloses camptothecin phosphate compounds, a preparation method of the compounds and application of the compounds in preparation of anti-tumor drugs. Cytotoxic activity tests prove that the compounds have the good cytotoxic activity, the anti-tumor activity of all the compounds is higher than that of a clinical control drug-irinotecan, and the compounds can be used for preparing the anti-tumor drugs. Accordingly, the preparation process is simple, the raw materials are cheap and easy to obtain, and the product purity is high.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically relates to a camptothecin phosphate compound, its preparation method and application. Background technique [0002] Camptothecin is a quinoline alkaloid with significant cytotoxic activity that Wall et al. first isolated from the Chinese dove tree (camptotheca acuminata) in 1966 (J.Nat.Prod.2004,67,129- 135), showed a good inhibitory effect on various malignant tumors such as bone cancer, liver cancer, bladder cancer and leukemia, but it was found in clinical use that camptothecin would produce myelosuppression, vomiting and Serious side effects such as diarrhea, and poor water solubility due to the special basicity of the nitrogen on the quinoline ring in the molecular structure, so it cannot be directly administered parenterally to the human body. In order to further improve its water solubility and reduce its toxic and side effects, phase I clinical trials were carried out on ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61P35/00
CPCC07F9/6561
Inventor 徐传瑞刘映前李斌赵晓博陈玉媛张娜张健成丕乐尤佳薛慧颖
Owner HUAZHONG UNIV OF SCI & TECH