Naphthalimide derivatives for the treatment of cancer

A technology of naphthalimide and derivatives, applied in the field of naphthalimide derivatives for treating cancer, can solve the problems of low cytotoxicity and the like

Inactive Publication Date: 2007-04-18
UNIBIOSCREEN SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] 3) The cytotoxic titer in normal cardiac cells is low;

Method used

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  • Naphthalimide derivatives for the treatment of cancer
  • Naphthalimide derivatives for the treatment of cancer
  • Naphthalimide derivatives for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0075] -n=0, and / or

[0076] -m=0, and / or

[0077] -m=2, two substituents R 3 Adjacent and together with the carbon atom to which they are attached form a phenyl group, and / or

[0078] -R 1 It is an alkylene group with 1 to 3 carbon atoms, and is selected from the group consisting of dimethylamino, diethylamino, pyrrolidinyl, piperidino, N-methylpiperazinyl, morpholino and ureylene Is connected to the nitrogen-containing group, more preferably, R 1 Is dimethylene linked to dimethylamino or diethylamino, and / or

[0079] -R’ is selected from: C 2-7 Alkylcarbonyl, amino-carbonyl, thioaminocarbonyl, alkylaminocarbonyl, alkylthioaminocarbonyl, alkylthiocarbonyl, and poly(aminoalkyl), where the number of aminoalkyl repeating units ranges from 2 to about 5 In the range.

[0080] In the second aspect, the present invention provides a class of substituted naphthalimide (isoquinolindione) derivatives represented by general formula (II), and / or pharmaceutically acceptable salts and / or solvat...

Embodiment 1

[0144] Example 1-Preparation of 2-chloro-N-[({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de ]Isoquinolin-5-yl}amino)carbonyl]acetamide

[0145] Under nitrogen, 100 mg of aminonafetil was dissolved in 2 mL of acetonitrile, and then a solution of 95 mg of 2-chloroacetyl isocyanate (2 equivalents) in 2.5 mL of acetonitrile was carefully added. The reaction was maintained at room temperature for 4 hours. Then, acetonitrile was evaporated under reduced pressure, and the residue was subjected to flash chromatography (SiO 2 , Eluent: CH 2 Cl 2 / MeOH 95:5), thus obtaining 25.5 mg (yield: 18%) of the desired product:

[0146]

[0147] Under 300MHz, in DMSO, it is characterized by proton nuclear magnetic resonance (hereinafter denoted as 1 H NMR), the results are as follows: 11.15 (H-17, bs); 10.30 (H-19, s); 8.57 (H-2, d, J=2.1); 8.53 (H-4, d, J=2.1) ; 8.34 (H-8, s); 8.32 (H-6, s); 7.79 (H-7, t, J = 7.8); 4.17 (H-13, t, J = 6.8), 3.76 (H-21 , S); 2.61 (H-14, t, J=6.6) and ...

Embodiment 2

[0148] Example 2-Preparation of 2,2,2-Trichloro-N-[({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H -Benzo[de]isoquinolin-5-yl}amino)carbonyl]acetamide

[0149]

[0150] Under nitrogen, 700 mg of aminonafetil was dissolved in 14 mL of acetonitrile. Carefully add a solution of 932 mg trichloroacetyl isocyanate (2 equivalents) in 14 mL acetonitrile. The reaction was maintained at room temperature for 4.5 hours. Then acetonitrile was evaporated under reduced pressure, and the residue was subjected to flash chromatography (SiO 2 , Eluent: CH 2 Cl 2 / MeOH 97:3), thus 540.5mg (yield: 46%) of the desired product is obtained, which is characterized by:

[0151] - 1 H NMR (300MHz, DMSO) is as follows: 11.18 (H-17 and H-19, bs); 8.76 (H-2, bs); 8.75 (H-4, bs); 8.43 (H-8, d, J= 6.6); 8.41 (H-6, d, J=6.0); 7.85 (H-7, t, J=7.5); 4.20 (H-13, t, J=6.6), 2.69 (H-14, t, J=6.3) and 2.35 (H-15 and H-16, s) (the same number of atoms as in Example 1), and

[0152] -300MHz, carbon nuclear magnet...

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Abstract

Novel substituted naphthalimide derivatives of formula (I) and (II), pharmaceutically acceptable salts thereof and solvates thereof, are useful for making pharmaceutical compositions for the treatment of cell proliferative diseases such as cancer. The invention also provides methods for making such derivatives.

Description

Technical field [0001] The present invention relates to new substituted naphthalimides and 1,2-dihydro-3H-dibenzisoquinoline-1,3-dione derivatives, their preparation methods and their use as antitumor agents Medicines, especially pharmaceutical compositions containing the above-mentioned compounds as effective ingredients for the prevention and / or treatment of various forms of cancer. Background of the invention [0002] Various forms of substituted naphthalimides are known in the art to have anti-tumor effects or other useful biological activities. [0003] For example, U.S. Patent Nos. 3,935,227 and 3,940,398 disclose compounds having the following general formula: [0004] [0005] Where R 2 And R 3 Each is independently selected from: hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro, cyano, amino and trifluoromethyl; A is a straight or branched chain of 1-8 carbon atoms Alkylene; and Z is an optionally substituted piperidinyl or piperazinyl; or a pharmac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/14C07D405/12A61K31/4375A61P35/00
Inventor E·范夸克比克G·西蒙L·范登霍夫R·基斯F·达罗
Owner UNIBIOSCREEN SA
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