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Camptothecin derivatives

一种化合物、低级的技术，应用在药物组合、杂环化合物有效成分、有机化学等方向，能够解决抗癌活性微乎其微、毒性等问题

Inactive Publication Date: 2008-07-30
CALIFORNIA PACIFIC MEDICAL CT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This sodium salt produces severe toxicity and minimal anticancer activity in vivo

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0342] This example illustrates the preparation of camptothecin-20-O-esters of unsubstituted and substituted 4-fluorophenoxyacetic acid.

[0343] A. Camptothecin-20-O-ester of 4-fluorophenoxyacetic acid (000417)

[0344] A mixture of camptothecin (30mg, 0.086mmol), 4-fluorophenoxyacetic acid (30mg, 0.18mmol), EDCI (60mg, 0.31mmol), DMAP (5mg, 0.047mmol) and dichloromethane (5ml) was Stir at room temperature for 20 hours. Dichloromethane (20ml) was then added to the solution. The organic layer was washed with water (20ml), saturated NaHCO 3 Aqueous solution (10ml) and brine (20ml), then washed with MgSO 4 dry. After removing the solvent under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl 3 :CH 3 OH 9:1), to obtain 33mg camptothecin-20-O-4-fluorophenoxy acetate, yield 76.7%, mp 227-229°C (decomposition).

[0345] Chemical structure analysis: 1 HNMR (CDCl 3 , 600MHz): δ8.41(s, 1H, Ar-H), 8.25(d, 1H, Ar-H), 7.96(d, 1H, Ar-H), 7...

Embodiment 2

[0377] This example illustrates the preparation of camptothecin-20-O-esters of unsubstituted and substituted 4-bromophenoxyacetic acid.

[0378] A. Camptothecin-20-O-ester of 4-bromophenoxyacetic acid (000315)

[0379] A mixture of camptothecin (30mg, 0.086mmol), 4-bromophenoxyacetic acid (41mg, mmol), EDCI (60mg, 0.31mmol), DMAP (5mg, 0.047mmol) and dichloromethane (5ml) was at room temperature Stirring was continued for 20 hours. Dichloromethane (20ml) was then added to the solution. The organic layer was washed with water (20ml), saturated NaHCO 3 Aqueous solution (10ml) and brine (20ml), then washed with MgSO 4 dry. After removing the solvent under reduced pressure, the resulting solid was recrystallized from ethyl acetate to give 42 mg of camptothecin-20-O-4-bromophenoxyacetate, yield 87.1%, mp 232-234°C (decomposition ).

[0380] Chemical structure analysis: 1 HNMR (CDCl3 , 600MHz): δ8.67(s, 1H, Ar-H), 8.26(d, 1H, Ar-H), 8.10(d, 1H, Ar-H), 7.90(t, 1H, Ar-H), 7.73...

Embodiment 3

[0412] This example illustrates the preparation of unsubstituted and substituted camptothecin-20-O-esters of 4-iodophenoxyacetic acid.

[0413] A. Camptothecin-20-O-ester of 4-iodophenoxyacetic acid (000413)

[0414] A mixture of camptothecin (30mg, 0.086mmol), 4-iodophenoxyacetic acid (36mg, 0.18mmol), EDCI (60mg, 0.31mmol), DMAP (5mg, 0.047mmol) and dichloromethane (5ml) was Stir at room temperature for 20 hours. Dichloromethane (20ml) was then added to the solution. The organic layer was washed with water (20ml), saturated NaHCO 3 Aqueous solution (10ml) and brine (20ml), then washed with MgSO 4 dry. After removing the solvent under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl 3 :CH 3 OH 9:1), to obtain 46mg of camptothecin-20-O-4-iodophenoxyacetate, yield 88.0%, mp 228-230°C.

[0415] Chemical structure analysis: 1 HNMR (CDCl 3 , 600MHz): δ8.41(s, 1H, Ar-H), 8.29(d, 1H, Ar-H), 7.98(d, 1H, Ar-H), 7.88(t, 1H, Ar-H), 7.7...

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PUM

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Abstract

(20 S )esters of camptothecin analogs are provided. The compounds are (20 S ) esters of an oxyalkanoic acid and camptothecin, which is optionally substituted at the 7, 9, 10, 11, and 12 positions of the camptothecin ring. The compounds are useful for treating cancer.

Description

[0001] introduce field of invention [0002] The present invention relates to novel camptothecin derivatives which are useful in the treatment of various types of cancer. Background of the invention [0003] Camptothecin (often abbreviated as "CPT") is a phytotoxic alkaloid that was first isolated from the wood and bark of Camptotheca acuminata (Nyssaceae) by Wall and co-workers in 1966, It has anti-tumor activity against the mouse leukemia L1210 system. The compound has a pentacyclic ring system with an asymmetric center in ring E with a 20S configuration. Pentacyclic ring systems include pyrrolo[3,4-b]quinolines (rings A, B and C), conjugated pyridones (ring D) and six-membered lactones with a 20α-hydroxyl group (ring E). Camptothecin itself is insoluble in water. Therefore, the water-soluble sodium carboxylate salt of camptothecin was evaluated clinically early. It appears that carboxylates are actually compounds in which the E ring is opened to form the sodium salt. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/47C07D491/22A61P35/00C07D311/00C07D221/00C07D209/00A61K31/4745C07B61/00
CPCC07D491/22A61K31/4745A61P35/00
Inventor 杨立锡泮显道王慧娟
Owner CALIFORNIA PACIFIC MEDICAL CT
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