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Camptothecin derivatives

a technology of camptothecin and derivatives, applied in the field of new drugs, can solve the problems of severe toxicity of sodium salt and very little in vivo anticancer activity

Inactive Publication Date: 2007-06-26
SUTTER WEST BAY HOSPITALS +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[1289]This example provides guidance for determining the inhibition of topoisomerase I. This procedure is an intact cell assay and is a modification of a published procedure found at Cancer Res. 1986, 46, 2021-2026. A more recent publication can be found at J. Med. Chem. 1993, 36 2689-2700 at 2699. Here the modification of the previous procedure was used to quantitate the amount of topiosmerase I mediated DNA cleavage in intact cells. The DNA of HL-60 cells growing in culture in labeled by [3H] thymidine incorporation. The cells are exposed to compounds to be tested and lysed, and the protein is precipitated. Radioactive DNA in cleavable complex formation with topisomerase I co precipitates with the protein. The amount of cleavable complex formation is quantitated by counting the pellet with a liquid scintillation counter.

Problems solved by technology

This sodium salt produced severe toxicity and had very little in vivo anticancer activity.

Method used

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Examples

Experimental program
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Effect test

example 1

[0317]This example explains how to prepare non-substituted and substituted camptothecin-20-O-esters of 4-fluorophenoxyacetic acid.

A. Camptothecin-2-Oester of 4-fluorophenoxyacetic acid (000417)

[0318]The mixture of camptothecin (30 mg, 0.086 mmol), 4-fluorophenoxyacetic acid (30 mg, 0.18 mmol), EDCI (60 mg, 0.31 mmol), DMAP (5 mg, 0.047 mmol) and dichloromethane (5 ml) was stirred at room temperature for 20 hours (h), then dichloromethane (20 ml) was added to the solution. The organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl3:CH3OH 9:1) to afford 33 mg camptothecin-20-O-4-fluorophenoxyacetate, yield: 76.7%, mp 227-229° C. (dec.).

[0319]The chemical structure analysis was performed by 1H NMR (CDCl3, 600 MHz): δ 8.41 (s, 1H, Ar—H), 8.25 (d, 1H, Ar—H), 7.96 (d, 1H, Ar—H), 7.86 (t,...

example 2

[0350]This example explains how to prepare non-substituted and substituted camptothecin-20-O-esters of 4-bromophenoxyacetic acid.

A. Camptothecin-20-Oester of 4-bromophenoxyacetic acid (000315)

[0351]The mixture of camptothecin (30 mg, 0.086 mmol), 4-bromophenoxyacetic acid (41 mg, mmol), EDCI (60 mg, 0.31 mmol), DMAP (5 mg, 0.047 mmol) and dichloromethane (5 ml) was stirred at room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was recrystallized from ethyl acetate to afford 42 mg camptothecin-20-O-bromopbenoxyacetate, yield: 87.1%, mp 232-234° C. (dec.).

[0352]The chemical structure analysis was performed by 1H NMR (CDCl3, 600 MHz): δ 8.67 (s, 1H, Ar—H), 8.26 (d, 1H, Ar—H), 8.10 (d, 1H, Ar—H), 7.90 (t, 1H, Ar—H), 7.73 (t, 1H, Ar—H), 7.43 (d, 2H, Ar—H...

example 3

[0383]This example explains how to prepare non-substituted and substituted camptothecin-20-O-esters of 4-iodophenoxyacetic acid.

A. Camptothecin-20-Oester of 4-iodophenoxyacetic acid (000413)

[0384]The mixture of camptothecin (30 mg, 0.086 mmol), 4-iodophenoxyacetic acid (36 mg, 0.18 mmol), EDCI (60 mg, 0.31 mmol), DMAP (5 mg, 0.047 mmol) and dichloromethane (5 ml) was stirred at room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl3:CH3OH 9:1) to afford 46 mg camptothecin-20-O-4-fluorophenoxyacetate, yield: 88.0%, mp 228-230° C.

[0385]The chemical structure analysis was performed by 1H NMR (CDCl3, 600 MHz): δ 8.41 (s, 1H, Ar—H), 8.29 (d, 1H, Ar—H), 7.98 (d, 1H, Ar—H), 7.88 (t, 1H, Ar—H), 7.70 (t, 1H, ...

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Abstract

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

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a reissue of U.S. Pat. No. 6,350,756-B1 which claims priority to U.S. Provisional Application 60 / 263,040, filed Jan. 18, 2001, and is continuation-in-part thereof. This Provisional Application is incorporated herein reference.REFERENCE TO SOURCES OF FUNDING [0002]Work regarding the invention described and claimed in this application was funded at least in part by a funding agreement with a Federal agency under chapter 18 of 35 U.S.C., namely Department of Defense grant DAMD 17-99-9018.<?insert-end id="INS-S-00004" ?>INTRODUCTION[0003]1. Field of the Invention[0004]This invention relates to novel camptothecin derivatives that are useful for treating various types of cancer.[0005]2. Background of the Invention[0006]Camptothecin (often abbreviated as “CPT”), a phytotoxic alkaloid first isolated from the wood and bark of Camptotheca acuminata (Nyssaceae) by Wall and coworkers in 1966, was shown to have antitumor activ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/435C07D491/22A61K31/4745A61P35/00C07B61/00
CPCA61K31/4745C07D491/22A61P35/00
Inventor YANG, LI-XIPAN, XIANDOWANG, HUIJAN
Owner SUTTER WEST BAY HOSPITALS
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