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7-Substituted camptothecin and camptothecin analogs and methods for producing the same

a technology of camptothecin and substituted camptothecin, which is applied in the field of preparing 7substituted camptothecin compounds and 7substituted camptothecin analogs, can solve the problems of poor yield of csub>4/sub>, csub>5/sub>, and achieve excellent yield

Inactive Publication Date: 2005-09-22
RES TRIANGLE INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] Accordingly, one object of the present invention is to provide a method of preparing 7-substituted camptothecin compounds in excellent yield and which cannot be prepared by Sawada et al. procedure (Sawada et al., Chem. Pharm. Bull. 39, 2574-2580 (1991)) which will be widely applicable to a large number of 7-substituents.

Problems solved by technology

The procedure of Sawada et al., Chem. Pharm. Bull. 39, 2574-2580 (1991) for preparing 7-alkyl compounds gives adequate yields for C1-3 alkyl compounds; however, the yields for C4, C5, C6-alkyl rapidly become poor.

Method used

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  • 7-Substituted camptothecin and camptothecin analogs and methods for producing the same
  • 7-Substituted camptothecin and camptothecin analogs and methods for producing the same
  • 7-Substituted camptothecin and camptothecin analogs and methods for producing the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-Amino-4,5-methylenedioxy-phenylbenzylmethanone

[0080] To a stirred solution of 1.5 g (10.0 mmol) of 2-amino-4,5-methylenedioxy-benzonitrile in THF (40 mL) was added CuBr (50 mg, 0.34 mmol) and benzylmagnesium chloride (40 mL, 1.0 M solution in Et2O). The reaction mixture was refluxed for 12 h. After cooling to 25° C., H2O (5 mL) was added followed by 15% H2SO4 (15 mL). After stirring for 14 h, ether (50 mL) was added. Organic layer was separated. Aqueous layer was extracted with ether (2×50 mL). The combined organic layer was dried and evaporated. Following chromatography (silica gel, CHCl3), 1.2 g (52%) of the title compound was obtained. IR (CHCl3) 1675 cm−1 MS m / z 255 (M+).

example 2

7-Benzyl-10, 11-MD-20(S)-Camptothecin

[0081] A mixture of S-tricyclic ketone (1.0 g, 4.2 mmol), 2-amino-4,5-methylenedioxy-phenylbenzylmethanone (1.1 g, 4.3 mmol) acetic acid (1 mL), p-TsOH (50 mg) in toluene (100 mL) was refluxed for 15 h. After removing the solvent, the crude product was purified by column chromatography (silica gel, CHCl3) to yield the product as a cream powder (1.33 g, 66%)1H-NMR (DMSO-d6) δ 0.89 (t, 3H), 1.91 (m, 2H), 4.62 (s, 2H), 5.22 (s, 2H), 5.41 (s, 2H), 6.10 (s, 2H), 6.50 (s, 1H), 6.90-7.10 (m, 5H), 7.21 (s, 1H), 8.07 (s, 1H), 8.22 (s, 1H); MS: m / z 483 (M+1)+.

example 3

7- Trimethylsilylmethyl-10,11 -MD-20(S)-Camptothecin

[0082] The title compound was prepared following analogous procedures as described in Examples 1 and 2 and involving the use of trimethylsilyl magnesium chloride as the Grignard reagent. 1H-NMR (DMSO-d6+CDCl3) δ 0.87 (t, 3H), 1.83 (m, 2H), 2.28 (s, 2H), 5.11 (s, 2H), 5.37 (s, 2H), 6.25 (s, 2H), 6.47 (s, 1H), 7.20 (s, 1H), 7.43 (s, 1H), 7.48 (s, 1H). MS m / z 478 (M+).

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Abstract

Methods of forming camptothecin compounds which are effective anti-tumor compounds are disclosed. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I-DNA cleavable complex.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to methods of preparing 7-substituted camptothecin compounds and 7-substituted camptothecin analogs. Camptothecin (CPT) and CPT analogs have been reported to inhibit the enzyme topoisomerase I and have in vitro and in vivo anticancer activity. It has been shown that a large number of substituents can be placed at C7 of CPT without loss of activity (Redinbo et al., Science 279, 1504-1513, 1998). [0003] 2. Background of the Invention [0004] Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid which is known to inhibit the enzyme topoisomerase I and is a potent anti-tumor agent. Camptothecin compounds have the general ring structure shown below. Camptothecin was isolated from the wood and bark of Camptotheca acuminata by Wall et al. (Wall et al., 1966, J. Am. Chem. Soc., 88:3888). [0005] Major synthetic efforts have been directed to derivatizing the B-ring at C7 to improve cytotoxic a...

Claims

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Application Information

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IPC IPC(8): C07D491/22
CPCC07D491/22A61P35/00
Inventor WANI, MANSUKH C.MANIKUMAR, GOVINDARAJANWALL, MONROE E.WALL, MICHAEL A.
Owner RES TRIANGLE INST
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