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5- or 6-substited naphthoyl imines compounds and antineoplastic application

A technology of naphthalene imide and compound, applied in the field of naphthalimide compound and anti-tumor application, can solve the problems of toxic and side effects, unpredictable and serious toxic and side effects, and achieve the effects of strong cytotoxicity and avoiding toxic and side effects

Inactive Publication Date: 2008-12-17
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, in clinical application, it was found that mitonafide (mitonafide) has serious central nervous system toxicity; amonafide (amonafide) forms N-acetylaminonaphtamide (amonafide) under the action of N-acetyltransferase in vivo, and other Unlike most drugs, amonafide tends to cause greater toxic and side effects in fast-metabolizing humans, and the toxic and side effects caused by individual genetic differences are unpredictable

Method used

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  • 5- or 6-substited naphthoyl imines compounds and antineoplastic application
  • 5- or 6-substited naphthoyl imines compounds and antineoplastic application
  • 5- or 6-substited naphthoyl imines compounds and antineoplastic application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of 3-bromo-1,8-naphthalene anhydride (2):

[0033] Liquid bromine (8.2g, 51.3mmol) was added dropwise to a mixed solution of 1,8-naphthalene anhydride (10g, 50.5mmol) and 70% nitric acid (200mL) at 25°C. After the mixture was stirred at 70°C for 2 hours, it was cooled, filtered, washed with water, and dried to obtain the target compound as a solid.

Embodiment 2

[0035] Preparation of 5-bromo-[2-(dimethylamino)ethyl]-1hydro-benzo[de]isoquinoline-1,3(2hydro)-dione (3):

[0036] A mixture of 3-bromo-1,8-naphthalene anhydride (2) (277mg, 1mmol) and N,N-dimethylethylenediamine (1.2mmol) was heated to reflux in ethanol (20mL) for 2 hours, and the solvent was removed, Obtain the target product.

[0037] Yield 92%, light brown solid, mp 77.2-78.6°C; 1 H NMR (400MHz CDCl 3 )δ (ppm) 8.65 (s, 1H) 8.59 (dd, 1H, J = 1.0 and 7.2Hz) 8.35 (s, 1H) 8.11 (dd, 1H, J = 0.7 and 8.3Hz) 7.77 (t, 1H, J =7.8Hz) 4.34(t, 2H, J=6.9Hz) 2.70(t, 2H, J=6.9Hz) 2.39(s, 6H)

Embodiment 3

[0039] 5-(dimethylamino-ethylamine)-2-[2-(dimethylamino)ethyl]-1 hydrogen-benzo[de]isoquinoline-1,3(2 hydrogen)-dione ( 4a) Preparation:

[0040] Compound 3 (174mg, 0.5mmol), CuI (9.6mg, 0.05mmol), Proline (11.5mg, 0.1mmol), Cs 2 CO 3 (247.5mg, 0.6mmol) and N,N-dimethylethylenediamine (0.75mmol) in DMSO (2mL), stirred at 110°C for 8 hours under nitrogen protection. The crude product was purified by column chromatography using dichloromethane: methanol as the developing solvent to obtain the pure target compound.

[0041] Yield 52%, orange solid, mp 97.2-98.6°C; 1 H NMR (400MHz CDCl 3 )δ (ppm) 8.265 (dd, 1H, J = 0.8 and 7.2Hz) 8.02 (s, 1H) 7.93 (d, 1H, J = 7.6Hz) 7.58 (t, 1H, J = 7.2Hz) 7.11 (s, 1H) 4.94 (t, 1H, J = 4.4Hz) 4.32 (t, 2H, J = 7.2Hz) 3.32-3.28 (m, 2H) 2.67-2.64 (m, 4H) 2.37 (s, 6H) 2.30 (s, 6H); 13 C NMR (100MHz CDCl 3 )δ (ppm) 164.6, 164.4, 147.1, 133.8, 131.6, 127.1, 126.6, 123.3, 122.4, 122.0, 121.9, 110.0, 57.4, 57.0, 45.7, 45.1, 41.0, 38.1; IR (KBr cm -...

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Abstract

The invention relates to a 5-site or 6-site substituent naphthalimide compound and antitumor applications thereof, which belongs to the fine chemical field. The compound is characterized in that various aliphatic amidogen, heterocyclic amidogen, aryl and Ar aryl are respectively introduced into the 5-site or 6-site of the naphthalimide by a nucleophilic substitution reaction to obtain small molecule compound similar to a lead compound amonafide structure. The small molecule compound has obvious inhibiting activity in vitro test on Hela and P388D1, and wherein, some compounds have stronger cytotoxicity than the amonafide under the same test conditions. In addition, the structures of the compounds take on diversity; the compounds without acetylation sites can be prevented from having the side effect similar to the amonafide; the other compounds with the acetylation sites can be prevented from having the side effect by personalized administration, therefore, the compound has medical application prospect in curing diseases related to tumors.

Description

technical field [0001] The invention relates to a class of 5- or 6-substituted naphthalimide compounds and anti-tumor applications, belonging to the field of fine chemicals. Background technique [0002] Cancer is a serious threat to human health and life safety, and the development of highly effective and low-toxic antitumor drugs is a very active research direction in the field of medical chemistry. Naphthalimide compounds are a class of compounds with good anticancer activity, among which amonafide (N-(β-dimethylaminoethyl)-3-amino-1,8-naphthoyl imine)] and mitonafide (N-(β-dimethylaminoethyl)-3-nitro-1,8-naphthalimide)] have entered phase II clinical trials (Brana M.F. , Santos A., Roldan C.M., et al. Eur. J. Med. Chem. Chim. Ther., 1981, 16, 207). Such compounds can intercalate between base pairs of DNA, inhibit the synthesis of DNA and RNA, and inhibit topoisomerase II, thereby achieving the purpose of inhibiting tumors. [0003] However, in clinical application, it...

Claims

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Application Information

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IPC IPC(8): C07D221/12C07D409/12A61K31/473A61K31/496A61K31/5377A61P35/00
Inventor 钱旭红解丽娟崔京南肖义徐玉芳
Owner DALIAN UNIV OF TECH
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