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High-camptothecin compounds and use thereof as medicaments

A technology of homocamptothecin and compound, applied in the field of medicine, can solve the problems of unstable camptothecin metabolism, toxic side effects, toxic effects and the like

Inactive Publication Date: 2011-04-13
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] A large number of studies have shown that camptothecin compounds have many advantages such as high efficiency, broad spectrum, and good selectivity. However, camptothecin still has disadvantages such as unstable metabolism in the body, low water solubility, toxicity, and species differences.
At first, researchers prepared camptothecin E ring ring-opening into carboxylate form to improve water solubility, however, this change significantly reduced the activity of camptothecin, and caused its serious toxic side effects (CancerChemother.Rpt. 1972, 56, 95)

Method used

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  • High-camptothecin compounds and use thereof as medicaments
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  • High-camptothecin compounds and use thereof as medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Example 1 7-{4-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

[0119]Will contain 100mg 7-formyl homocamptothecin, 10mg Yb(OTf) 3 , 100mg of 4-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline and 30mL of chloroform were reacted at room temperature, and the solvent was evaporated after TLC monitoring that the reaction was complete. Purified on a silica gel column (eluent: CH 2 Cl 2 / CH 3 OH 100:2), to obtain 70 mg of yellow solid 7-{4-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

[0120] 1 H-NMR (DMSO):

[0121] 0.88(t, 3H), 1.18(t, 3H), 1.88(q, 2H), 2.29(s, 6H), 3.06-3.48(q, 2H), 4.03(q, 4H), 4.94(s, 1H) , 5.39-5.53(q, 2H), 5.55(s, 2H), 6.04(s, 1H), 7.29-7.44(dd, 4H), 7.42(s, 1H), 7.80(t, 1H), 7.93(t , 1H), 8.25(d, 1H), 8.87(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Embodiment 2

[0122] Example 2 7-{4-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

[0123] According to the method of Example 1, replace 4-[6-(4 -Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 85 mg of yellow solid 7-{4-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxy Carbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

[0124] 1 H-NMR (DMSO):

[0125] 0.88(t, 3H), 1.87(q, 2H), 2.29(s, 6H,), 3.06-3.48(q, 2H), 3.58(s, 6H), 4.96(s, 1H), 5.39-5.54(q , 2H), 5.55(s, 2H), 6.03(s, 1H), 7.28-7.42(dd, 4H), 7.44(s, 1H), 7.81(t, 1H), 7.94(t, 1H), 8.25( d, 1H), 8.93(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Embodiment 3

[0126] Example 3 7-{3-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

[0127] According to the method of Example 1, replace 4-[6-(4-methyl-5- Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 56 mg of yellow solid 7-{3-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl] Phenyl}methyleneamino homocamptothecin.

[0128] 1 H-NMR (DMSO):

[0129] 0.89(t, 3H), 1.15(t, 3H), 2.28(q, 2H), 2.36(s, 3H), 3.04-3.48(q, 2H), 4.03(q, 2H), 5.28(s, 1H) , 5.53-5.58(q, 2H), 5.58(s, 2H), 6.04(s, 1H), 7.35(1H), 7.39(1H), 7.46(s, 1H), 7.48-7.50(2H), 7.84( s, 1H), 7.85(t, 1H), 8.03(t, 1H), 8.27(d, 1H), 8.96(d, 1H), 9.25(s, 1H), 9.67(s, 1H).

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Abstract

The invention relates to the technical field of medicaments, in particular to novel high-camptothecin compounds and use thereof as anti-tumor medicaments. The compounds have the structure shown in a general formula (I) and comprise optical isomers, racemes, trans-isomers and any mixture or pharmaceutical salts thereof in the forms. The compounds have the function of inhibiting the activity of topoisomerase and can be used for preparing the anti-tumor medicaments.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a homocamptothecin compound and its application as an antitumor drug. Background technique [0002] Camptothecin (Camptothecin) is an alkaloid extracted from the Chinese Davidiaceae plant Camptotheca acuminata by American chemist Wall et al. Camptothecin is a five-ring rigid structure composed of indolizine[1,2-b]quinoline fragments fused with six-membered-hydroxylactone. The 20th carbon with-hydroxyl is asymmetrical, which endows the molecule with Optical properties. Its structure is as follows: [0003] [0004] Camptothecin is the earliest discovered, most studied, and most widely used specific topoisomerase I inhibitor (Topo I), and is also the most classic Topo I specific inhibitor. exhibited good antitumor activity. After years of research on the structure-activity relationship, a large number of camptothecin derivatives with application value have been developed, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61K31/513A61P35/00
Inventor 张万年刘文锋缪震元祝令建盛春泉姚建忠郭巍程鹏飞庄春林
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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