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Serial water-soluble hydroxycamptothecine naphthenic amino alcohol derivative and preparation method and use thereof

A technology of alkali cycloalkanol and hydroxycamptotheca, applied in the field of new camptothecin derivative antitumor drugs, can solve the problems of normal cell damage, increase cytotoxicity, adverse reactions, etc., and achieve the protection of normal cells and inhibition of cells. Proliferation and selectivity enhancing effects

Inactive Publication Date: 2013-05-22
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main problem of the existing camptothecin derivatives is still to pursue the purpose of increasing cytotoxicity, while ignoring the selectivity to tumor cells, thus causing damage to normal cells and causing serious adverse reactions

Method used

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  • Serial water-soluble hydroxycamptothecine naphthenic amino alcohol derivative and preparation method and use thereof
  • Serial water-soluble hydroxycamptothecine naphthenic amino alcohol derivative and preparation method and use thereof
  • Serial water-soluble hydroxycamptothecine naphthenic amino alcohol derivative and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 10-Hydroxy-9-L-prolinol methylene camptothecin (PRPT): Add HCPT1.0g, glacial acetic acid 60ml, formaldehyde solution 0.90g, L-prolinol 1.12g in the reaction vessel, Stir at 82°C until the solution is clear. After 10 minutes, pour it into 200ml of ether immediately, filter out the precipitated flocculent precipitate, wash with a small amount of 1% glacial acetic ether solution, and dry to obtain 1.40g of a light yellow solid. The yield 92.1%, purity 88.5% (HPLC-UV), acetone recrystallized purity 99.2% (HPLC-UV).

[0025] MS: 478[M+H] + . 1 H-NMR (DMSO-d6): 0.86 (3H, t, 18-CH 3 ), 1.70 (2H, 4'-CH 2 ), 1.83 (5H, m, 19-CH 2 , 3'-CH 2 ), 1.91 (3H, s, CH 3 COOH), 3.36 (H 2 O), 5.43 (2H, s, 17-CH 2 ), 6.53 (20-OH), 7.26 (1H, s, 14-CH), 7.52 (1H, d, 11-CH), 8.07 (1H, d, 12-CH), 8.84 (1H, s, 7- CH). 1 H-NMR (D 2 O): 0.90 (3H,t,18-CH 3 ), 1.88 (2H, m, 19-CH 2 ), 2.50 (3H, s, CH 3 COOH), 2.07 (2H, m, 4'-CH 2 ), 2.31 (2H, m, 3'-CH2 ), 3.14, 3.27 (2H, m, 6'-CH 2 ), 3...

Embodiment 2

[0028] 10-Hydroxy-9-(4`-hydroxyl)-piperidinol methylene camptothecin (PPPT): add HCPT100mg, glacial acetic acid 10ml, formaldehyde solution 220mg, 4-piperidinol 280mg in the reaction vessel, Stir at ℃ until the solution is clear. After 10 minutes, pour it into 50ml of ether, filter out the precipitated flocculent precipitate, wash with a small amount of 1% glacial acetic ether solution, and dry to obtain 102mg of a light yellow solid with a purity of 88.8% (HPLC -UV), recrystallized from acetone with a purity of 98.4% (HPLC-UV).

[0029] MS: 478[M+H] + . 1 H-NMR (DMSO-d6): 0.88 (3H,t,18-CH 3 ), 1.44, 1.76 (2H, t, t, 3', 5'-CH 2 ), 1.84 (2H, m, 19-CH 2 ), 1.88 (3H, s, CH 3 COOH), 2.37 (2H,t,t,2',6'-CH 2 ), 3.58 (1H, m, 4'-CH 2 ), 4.13 (2H, s, ArCH 2 N), 5.24 (2H, s, 5-CH 2 ), 5.42 (2H, s, 17-CH 2 ), 6.51 (20-OH), 7.52 (1H, s, 14-CH), 7.40 (1H, d, 11-CH), 7.98 (1H, d, 12-CH), 8.72 (1H, s, 7- CH). IR(KBr,cm -1 ):3423, 2938, 1749, 1655 (ν C=O ), 1594, 1506, 1469, 138...

Embodiment 3

[0032] 10-Hydroxy-9-(4`-hydroxyethyl)-piperazinemethylene camptothecin (QPPT): add 100mg of HCPT, 10ml of glacial acetic acid, 90mg of formaldehyde solution, and 144mg of 4-hydroxyethylpiperazine into the reaction vessel , stirred at 45°C until the solution was clear, poured into 70ml of diethyl ether, filtered out the precipitated flocculent precipitate, washed with a small amount of 1% glacial acetic ether ether solution, and dried to obtain 111 mg of a light yellow solid with a purity of 91.7% (HPLC- UV), recrystallized from acetone with a purity of 98.5% (HPLC-UV).

[0033] MS: 507[M+H] + . 1 H-NMR (DMSO-d6): 0.86 (3H,t,18-CH 3 ), 1.84 (2H, m, 19-CH 2 ), 2.50 (3H, s, CH 3 COOH), 2.61 (10H, m, 2', 3', 5', 6', 7'-CH 2 ), 3.50 (2H,t,8'-CH 2 ), 4.09 (2H, s, ArCH2N), 5.24 (2H, s, 5-CH 2 ), 5.42 (2H, s, 17-CH 2 ), 6.52 (20-OH), 7.26 (1H, s, 14-CH), 7.41, 7.43 (1H, d, 11-CH), 7.98 (1H, d, 12-CH), 8.73 (1H, s, 7-CH). IR(KBr,cm -1 ): 3423, 1746, 1655 (ν C=O ), 1589, 150...

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Abstract

The invention discloses serial water-soluble hydroxycamptothecine naphthenic amino alcoholderivative. The serial water-soluble hydroxycamptothecine naphthenic amino alcohol derivative is synthesized by leading naphthenic amino alcohol methylene into a hydroxycamptothecine structure for the first time; and the hydroxycamptothecine with strong cell toxicity is decorated into the hydroxycamptothecine naphthenic amino alcohol derivative with medium cell toxicity. Therefore, the selectivity of induction of tumor cell apoptosis is improved; the situation that the hydroxycamptothecine prolinol has special hydrogenation reduction metabolic pathway in the body is found out for the first time; existing camptothecin derivatives do not have special hydrogenation reduction metabolic pathway; and active oxygen in the cell can be controlled, so as to inhibit cell proliferation, selectively induce cancer cell apoptosis, and inhibit cell inflammatory necrosis. Normal cell function is not affected.

Description

technical field [0001] The present invention relates to a novel camptothecin derivative antitumor drug, as well as a preparation method and application. More specifically, it relates to 9-cycloalkanol methylene-10-hydroxyl substituted camptothecin derivatives, a preparation method and the application of these compounds in the preparation of antitumor drugs. Background technique [0002] In 1966, Wall et al. first discovered camptothecin (CPT) from the endemic plant camptotheca japonica in China. 10-Hydroxycamptothecin (HCPT) was discovered in 1985 and has been used clinically in China. Due to unsatisfactory solubility, severe adverse reactions such as myelosuppression, diarrhea and nephrotoxicity limit the clinical use. In 1985, Redinob and Stewart discovered that the anti-tumor mechanism of camptothecin is to inhibit DNA topoisomerase I, which led to large-scale chemical structure modification and structure-activity relationship research in the medical field. In 1998, th...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61P35/00
Inventor 张世轩耿涛姜波孙晨光哈莉莎覃华栋宋歌钱媛范庆宇
Owner DALIAN UNIV OF TECH
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