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10-alkoxy camptothecine derivative and its preparing method and use

A technology of alkyl and alkane groups, applied to 10-alkoxycamptothecin derivatives and the fields of preparation and application thereof, can solve the problems of difficulty in continuing clinical research, reduced activity in the open-ring form, severe bleeding and the like

Inactive Publication Date: 2005-03-02
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the 1970s, camptothecin entered clinical research in the form of water-soluble sodium salt with its ring-opening structure. As a result, side effects such as severe bone marrow suppression, vomiting, diarrhea, and severe bleeding occurred, and the activity of the ring-opening form was greatly reduced, making clinical research difficult. continue
Moreover, the physical and chemical properties of the two are extremely close, making separation difficult.

Method used

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  • 10-alkoxy camptothecine derivative and its preparing method and use
  • 10-alkoxy camptothecine derivative and its preparing method and use
  • 10-alkoxy camptothecine derivative and its preparing method and use

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preparation example Construction

[0012] The preparation method of above-mentioned general formula (I) compound has following two kinds:

[0013] method 1

[0014] The preparation method of general formula (I) compound, its step is as follows:

[0015] The hydroxycamptothecin represented by the following formula (1) is reacted with the corresponding RX in a solvent under base catalysis at a temperature of 0-160° C. for 1-50 hours to obtain the intermediate 10 represented by the following formula (2): position etherification, and then carry out nitration at a temperature of -20 to 50°C to obtain a compound of general formula (I), wherein the above-mentioned R is C 1～20 Alkyl, C 1～20 Alkenyl or C 1～20 Hydroxy-containing alkane group, X is Cl, Br and I and CH 3 SO 3 , CF 3 SO 3 ,p-CH 3 C 6 h 4 SO 3 ;

[0016]

[0017] where R represents C 1～20 Alkyl, C 1～20 Alkenyl or C 1～20 Hydroxyl-containing alkane group, X represents Cl, Br and I and CH 3 SO 3 , CF 3 SO 3 ,p-CH 3 C 6 h 4 SO 3 .

[0...

Embodiment 1

[0029] Example 1 10-methoxycamptothecin (MOCPT)

[0030] HCPT (140mg) was completely dissolved in anhydrous DMF (8mL) under heating, and anhydrous K 2 CO 3 (150mg) and CH 3 I (0.09mL), reacted at 80°C for 2.5h, filtered while it was hot, recovered the solvent, added water, neutralized with 10% hydrochloric acid, filtered, and dried to obtain 105mg of 10-methoxycamptothecin, a light yellow solid, with a yield of 75 %, mp248°C.

Embodiment 2

[0031] Example 2 10-methoxy-9-nitrocamptothecin (MONCPT)

[0032] Under ice cooling, 10-methoxycamptothecin (105 mg) was dissolved in concentrated sulfuric acid, and 63% HNO was added 3 (0.02mL), continue to stir for 1.5h, pour the reaction solution into ice water, neutralize with hydrochloric acid, precipitate a solid, filter and dry. Column chromatography gave a yellow product (52 mg), yield 42.1%, mp 245°C (dec.). 1HNMR (δ, ppm, DMSO-d6): 0.86(t, 3H), 1.85(m, 2H), 4.10(s, 3H), 5.25(s, 2H), 5.40(s, 2H), 7.31(s, 1H), 8.03(d, 1H, J=9.6Hz), 8.43(s, 1H), 8.44(d, 1H, J=9.6Hz).EIMS(M + ): 423 (base peak).

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Abstract

The present invention discloses 10-alkoxy camptothecinie derivatives and its preparation process and application in treating tumor. The compounds have extraneous antitumor activity in different degree to P388 human leukemia cell, A649 human lung cancer cell, PC-3 human prostate cancer cell, HO-8910 human oophoroma cell, and K562 and HL60 human leukemia cell. The experiment of inoculating naked mouse with transplanted PC-3 human prostate cancer cell and inoculating mouse with S180 malignant solid tumor shows that partial compounds possess powerful tumor inhibiting activity.

Description

technical field [0001] The present invention relates to 10-alkoxy camptothecin derivatives, their preparation methods and their application in tumor treatment. Background technique [0002] Camptothecin is an alkaloid isolated from Camptothecus endemic to China for the first time in 1966 by Wall et al. Because of its unique chemical structure and significant anti-tumor activity, it has attracted the attention of relevant personnel all over the world. In the 1970s, camptothecin entered clinical research in the form of water-soluble sodium salt with its ring-opening structure. As a result, side effects such as severe bone marrow suppression, vomiting, diarrhea, and severe bleeding occurred, and the activity of the ring-opening form was greatly reduced, making clinical research difficult. continue. In 1985, the research results of Hsiang et al. of John Hopkins University showed that camptothecin is a specific inhibitor of DNA topoisomerase I, and topoisomerase I is a ribozyme ...

Claims

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Application Information

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IPC IPC(8): A61K31/475A61P35/00C07D491/22
Inventor 杨波吕伟何俏军何训贵王莹
Owner ZHEJIANG UNIV
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