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10-substitution homocamptothecin compounds and uses

A technology of homocamptothecin and compound, applied in the field of medicine, can solve the problems of large toxic and side effects, poor water solubility and the like

Inactive Publication Date: 2008-07-16
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

However, at present, camptothecin drugs still have the disadvantages of poor water solubility and high toxicity and side effects. It is necessary to continue to modify their structures to achieve the purpose of enhancing water solubility and reducing toxicity.

Method used

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  • 10-substitution homocamptothecin compounds and uses
  • 10-substitution homocamptothecin compounds and uses
  • 10-substitution homocamptothecin compounds and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The synthesis of embodiment 1 7-methyl-10-hydroxyl homocamptothecin

[0064] 0.50g of 9-ethyl-9-hydroxyl-2,3,8,9-tetrahydro-5H-6-oxa-3a-aza-cycloheptane-1,4,7-trione and 0.50g 5-Hydroxy-2-aminoketone was dissolved in 500 mL of toluene, refluxed to separate water, after 30 minutes, 0.10 g of p-toluenesulfonic acid was added, the reflux was continued for 4 h, the solvent was evaporated, washed with acetone and methanol, and 0.5 g of yellow solid 7- Methyl-10-hydroxyhomamptothecin (70.7%).

[0065] 1 HNMR(DMSO), δ: 0.87(t, 3H), 1.86(q, 2H), 2.76(s, 3H), 3.06(d, 1H), 3.49(d, 1H), 5.28(s, 2H), 5.39 (d, 1H), 5.53(d, 1H), 6.03(s, 1H), 7.42(s, 1H), 7.72(t, 1H), 7.87(t, 1H), 8.15(q, 2H), 8.69( s, 1H), 10.32 (s, 1H).

Embodiment 2

[0066] Example 2 Synthesis of 7-methyl-10-tert-butoxycarbonyl phenylalanine ester-based homocamptothecin

[0067] Dissolve 50mg of tert-butoxycarbonylphenylalanine and 50mg of N, N cyclohexyl carboximide in 10ml of dichloromethane, stir at room temperature for 10min, add 50mg of p-dimethylaminopyridine, continue stirring for 10min, then add 50mg of 7-methyl- 10-Hydroxyhomocamptothecin, after reacting for 6 hours, evaporate the solvent to dryness, add 10ml ether, filter, and the filter cake is purified on a silica gel chromatographic column (eluent: CH 2 Cl 2 / CH 3 OH 100:5), to obtain 21 mg of yellow solid 7-methyl-10-tert-butoxycarbonylphenylalanine ester homocamptothecin (25.8%).

[0068] 1 HNMR(DMSO), δ: 0.87(t, 3H), 1.40(s, 9H), 1.86(q, 2H), 2.73(s, 3H), 3.14(d, 2H), 3.27(d, 2H), 4.50 (q, 1H), 5.30(s, 2H), 5.47(d, 2H), 6.04(s, 1H), 7.29(s, 1H), 7.37-7.40(m, 5H), 7.51(d, 1H), 7.69 (d, 1H), 7.72 (s, 1H), 8.20 (d, 1H).

Embodiment 3

[0069] Example 3 Synthesis of 7-methyl-10-tert-butoxycarbonyl glycinate-based homocamptothecin

[0070] According to the method of Example 2, tert-butoxycarbonylglycine was used instead of tert-butoxycarbonylphenylalanine to obtain 22 mg of yellow solid 7-methyl-10-tert-butoxycarbonylglycinyl homocamptothecin (31.4%).

[0071] 1 HNMR(DMSO), δ: 0.87(t, 3H), 1.42(s, 9H), 1.87(q, 2H), 2.75(s, 3H), 3.27(d, 2H), 4.08(d, 2H), 5.30 (s, 2H), 5.47(d, 2H), 6.04(s, 1H), 7.40(s, 1H), 7.49(t, 1H), 7.65(d, 1H), 7.97(s, 1H), 8.20( d, 1H).

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Abstract

The invention relates to the technical field of medicines and is a new utilization of 10-bit substituting camplotheca acumiate fruit alkaline compound and the usage as a medicine. The compound structure of the invention is as indicated by a general formulation (I), which comprises the racemic mixture of the compound and an enantiomer of every compound. The compound of the invention has the function of inhibiting topoisomerase, has antitumor activity, antifungal activity and antibacterial activity, can be used as a topoisomerase inhibiter and can be used for preparing antitumor medicine, antifungal medicine and antibacterial medicine.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to a novel homocamptothecin compound with antitumor activity and its application as medicine. Background technique [0002] Camptothecin (camptothecin, CPT) is a natural alkaloid extracted from camptotheca, with a fused five-ring rigid structure, as shown below: [0003] [0004] Camptothecin is the most important inhibitor of topoisomerase I and exhibits antitumor activity against a variety of human tumor cell lines. Years of structure-activity studies have resulted in a large number of derivatives with development value, among which Irinotecan (CPT-11) and Topotecan (Topotecan, TPT) have been approved by the FDA for marketing, and Benonotecan was approved by the FDA in 2004. Approved for listing in South Korea. [0005] The E ring of the six-membered lactone ring of camptothecin is easily hydrolyzed in vivo to form an inactive carboxylate, which significantly reduces its in vi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00A61P31/00
Inventor 张万年游亮缪震元姚建忠盛春泉张晶车晓颖郭巍王文雅
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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