Antitumor drug (hydroxyl morpholine) and derivative thereof as well as preparation method and application thereof

An anti-tumor drug and pharmaceutical technology, applied in the field of medicine, can solve the problems of insignificant tumor cell inhibition, poor safety, and narrow therapeutic window, and achieve excellent anti-tumor activity and safety, wide therapeutic window, and broad anti-cancer spectrum Effect

Inactive Publication Date: 2011-11-09
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] But when the intraperitoneal dose of nidimoline exceeds 0.05mg / kg, toxic reactions occur, indicating that its active dose is relatively close to the toxic dose, the therapeutic window is very narrow, the safety of clinical application is relatively poor, and it has an inhibitory effect on other tumor cells. not obvious

Method used

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  • Antitumor drug (hydroxyl morpholine) and derivative thereof as well as preparation method and application thereof
  • Antitumor drug (hydroxyl morpholine) and derivative thereof as well as preparation method and application thereof
  • Antitumor drug (hydroxyl morpholine) and derivative thereof as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1 compound 1 and preparation method thereof, the structural formula of compound 1 is shown in (1)

[0058]

[0059] Take a dry 50ml eggplant-shaped bottle, add a magnetic stirring bar, 1.548g (2mmol) of nidimorph, add methanol: triethylamine: water (v: v: v) = 5: 1: 1 to dissolve a total of 21 ml of the solution , the reaction system was placed on a collector-type constant temperature heating magnetic stirrer to stir vigorously, the reaction system was sealed, and under the protection of dry nitrogen, the reaction was stopped after reflux at 70°C for 20 hours, and the reaction system was concentrated under reduced pressure at 50°C. Dried to obtain a brownish-yellow primary product, which was separated by silica gel column chromatography to obtain compound 1, a total of 0.46g, a yield of 40.6%, mp 150-152°C.

[0060] Elemental analysis found values: C, 63.54; H, 8.19.

[0061] Molecular formula (C 30 h 46 o 10 ) calculated: C, 63.58; H: 8.18.

[0062] ...

Embodiment 2

[0066] Embodiment 2 compound 6 (that is, oxydimorph) and preparation method thereof

[0067] (1) The preparation of intermediate 1, the structural formula of intermediate 1 is as follows:

[0068]

[0069] Take a dry 50ml eggplant-shaped bottle, add a magnetic stirring bar, 0.452g (0.8mmol) of compound 1, add 10ml of tetrahydrofuran solvent, 1ml of acetic anhydride, and 1ml of pyridine, and place the reaction system in a collector type constant temperature heating magnetic stirrer The reaction was stopped after 8 hours of closed and vigorous stirring at room temperature. Under reduced pressure at 45°C, spin out THF from the reaction bottle, add 20ml of anhydrous diethyl ether, stir vigorously at room temperature, a large amount of white solid precipitates, filter and dry to obtain intermediate 1, a total of 0.62g, yield 95.1%, mp 156~158°C .

[0070] Elemental analysis found values: C, 61.56; H, 7.16.

[0071] Molecular formula (C 42 h 58 o 16 ) calculated: C, 61.60; ...

Embodiment 3

[0109] Embodiment 3 compound 7 and preparation method thereof

[0110] use Figure 4 Represent the preparation technology of compound 7, the structural formula of compound 7 is as shown in (7),

[0111]

[0112] Take a dry 25ml eggplant-shaped bottle, add a magnetic stirring bar, 0.14g (0.16mmol) of intermediate 4, 0.12g of zinc acetate, add 15ml of anhydrous methanol, and seal the reaction system. Under the protection of dry nitrogen, the reaction system Stir vigorously on a collector-type constant-temperature heating magnetic stirrer, and stop the reaction after reflux at 70°C for 8 hours. The reaction solution is concentrated under reduced pressure at 50°C, and separated by column chromatography on silica gel to obtain a total of 0.03g of compound 7, with a yield of 25.8%, mp 176-179°C.

[0113] Elemental analysis found values: C, 60.06; H, 7.81; N, 8.95.

[0114] Molecular formula (C 31 h 48 N 4 o 9 ) calcd: C, 59.98; H, 7.79; N, 9.03.

[0115] Mass spectrum MS ...

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Abstract

The present invention relates to antitumor drug (hydroxyl morpholine) and derivative thereof as well as preparation method and application thereof. The antitumor drug (hydroxyl morpholine) and the derivative thereof have structures shown in general formula I. In the formula I, R1 represents hydroxyl, carbonyl, amide, low-level alkyl, benzyloxy methyl, arakyl or unsaturated alkyl of =CH2 or C2-5; R2 represents tetrazole, halogen atoms, halohydrocarbon, cyanogen, cyanomethy, low-level alkyl, benzyloxy methyl, arakyl or unsaturated alkyl of C2-5; and R3 represents hydroxyl, carbonyl or amide. The antitumor drug(hydroxyl morpholine) and the derivative thereof have more excellent antitumor activity and safety, and can be applied to treating tumors of liver cancer, lung cancer, breast cancer, leukemia, colon cancer, ovarian cancer, gastric cancer, nerve cancer and the like, thereby having wide treatment range; and the antitumor drug (hydroxyl morpholine) and the derivative thereof as an antitumor agent have application values in the medicine filed.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to oxydimorph and derivatives thereof, which inhibit tumor cell growth and exert antitumor effects, as well as their preparation method and application. Background technique [0002] In the anticancer screening of traditional Chinese medicines conducted by Feng Weijian et al., the methanol extract of Stellera chamaejasme L. showed strong anticancer activity (Chinese Journal of Oncology, Volume 17, Issue 1, January 1995). Daphne chamaejasme can be used to treat tumor diseases, and its crude extract is clinically reported to be effective in the treatment of lung cancer and liver cancer. Feng Weijian et al. used mouse leukemia as an active indicator to separate and extract Daphne chamaejasme, and obtained a diterpene active ingredient, of which nidimorphine has a strong anticancer effect, and its structure is: [0003] [0004] Nidimoline showed strong anticancer activity agains...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/22A61K31/357A61K31/41A61P35/00
Inventor 陈烨王洋徐利锋邹广辉卢红
Owner LIAONING UNIVERSITY
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