A kind of naphthalimide derivative and its preparation method and application

A kind of technology of naphthalimide and derivative, applied in the field of naphthalimide derivative and preparation thereof

Active Publication Date: 2019-02-05
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of them were abandoned due to various side effects such as myelosuppression, dose limitation, etc.

Method used

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  • A kind of naphthalimide derivative and its preparation method and application
  • A kind of naphthalimide derivative and its preparation method and application
  • A kind of naphthalimide derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 2-{3-[3-(3-aminopropyl)-aminopropyl]-aminopropyl}-2-[(2-dimethylamino)-ethyl]1H-benzisoquinoline-1 , the preparation of 3(2H)-diketoneacetamide pentahydrochloride (17a):

[0022]

[0023] (1) Take 5mmol (1.04g) of compound 14, 7.5mmol (1.0g) of anhydrous potassium carbonate in 50ml of acetonitrile, slowly add 5ml of acetonitrile solution of chloroacetyl chloride (containing 6mmol of chloroacetyl chloride) dropwise under stirring at room temperature, and dropwise , stirred at room temperature overnight, the reaction was completed, vacuum filtration, the solid was collected, washed with acetonitrile, and dried to obtain compound 15a;

[0024] (2) Add 1mmol of compound 15a and 1.5mmol (0.2g) of anhydrous potassium carbonate to 15ml of dry acetonitrile, add 5ml of N,N-dimethylformamide to the mixed solution, stir at 45°C for 15min, then add 1mmol of 5a, Stir at 45°C, monitor by TLC, evaporate the solvent under reduced pressure after the reaction, extract with chloroform...

Embodiment 2

[0027] 2-{3-[4-(3-aminopropyl)-aminobutyl]-aminopropyl}-2-[(2-dimethylamino)-ethyl]1H-benzisoquinoline-1 , Preparation of 3(2H)-diketoneacetamide pentahydrochloride (17b):

[0028]

[0029] Except replacing 5a with 5b in step (2), other synthesis and purification methods are the same as in Example 1. Yield: 78%, white solid: 1 H NMR (400MHz,D 2 O)δ: 8.21(d, J=7.2Hz, 1H, Ar-H); 8.18(s, 2H, Ar-H); 8.07(d, J=7.6Hz, 1H, Ar-H); 7.65(t ,J=7.8Hz,1H,Ar-H); 4.38(t,J=6.2Hz,2H,1×CH 2 ); 4.20(s,2H,1×CH 2 ); 3.44(t, J=6.2Hz, 2H, 1×CH 2 ); 3.30(t,J=8.0Hz,2H,1×CH 2 ); 3.18(t, J=8.0Hz, 2H, 1×CH 2 ); 3.01~3.12(m,8H,4×CH 2 ); 2.96(s,6H,2×CH 3 ); 2.18~2.22(m,2H,1×CH 2 ); 2.01~2.05(m,2H,1×CH 2 ); 1.73~1.75(m,2H,1×CH 2 ).ESI-MI m / z:526.4[M+1-5HCl] + .Anal.calcd.for C 28 h 48 Cl 5 N 7 o 3 : C 47.50%, H 6.83%, N 13.85%; found: C 47.4%, H 6.78%, N 13.98%.

Embodiment 3

[0031]2-{4-[4-(4-aminobutyl)-aminobutyl]-aminobutyl}-2-[2-(dimethylamino)-ethyl]1H-benzisoquinoline-1 , Preparation of 3(2H)-diketoneacetamide pentahydrochloride (17c):

[0032]

[0033] Except that 5a is replaced by 5d in step (2), other synthesis and purification methods are the same as in Example 1. Yield: 75%, white solid: 1 HNMR (400MHz,D 2 O) δ: 8.09 (d, J = 7.2Hz, 1H, Ar-H); 8.0 (d, J = 2.0, 2H, Ar-H); 7.97 (d, J = 2.0Hz, 1H, Ar-H) ;7.94(d,J=8.0Hz,1H,Ar-H);7.58(t,J=7.8,1H,Ar-H);4.32(t,J=6.0Hz,2H,1×CH 2 ); 4.18(s,2H,1×CH 2 ); 3.43(t, J=6.4Hz, 2H, 1×CH 2 ); 3.26(t, J=7.6Hz, 2H, 1×CH 2 ); 3.03~3.13(m,8H,4×CH 2 ); 2.98(s,6H,3×CH 3 ); 1.79~1.93(m,4H,2×CH 2 ); 1.70~1.76(m,4H,2×CH 2 ).ESI-MI m / z:554.4[M+1-5HCl] + .Anal.calcd.forC 30 h 52 Cl 5 N 7 o 3 : C 48.95%, H 7.12%, N 13.32%; found: C 48.89%, H 7.23%, N 13.28%.

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Abstract

The invention relates to a naphthalimide derivative and an application thereof.The naphthalimide derivative is of the structure in the formula I or the formula II.The aphthalimide derivative shows obvious inhibitory activity for proliferation of multiple tumor cells such as HCT-116 cells, HepG2 cells, K562 cells and SMMC-7721 cells, and lung metastasis of tumors can be effectively inhibited in the body.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a naphthalimide derivative modified with a polyamine and an alkane chain to modify a naphthalene ring of naphthalene, a preparation method and an application thereof. Background technique [0002] Naphthalimides are a class of anticancer agents that have been proven to have broad application prospects. Many naphthalimide derivatives (such as DMP-840, Elinafide, Amonafide) have entered clinical phase I and phase II trials. But most of them were abandoned due to various side effects such as myelosuppression and dose limitation. The representative drug, Amonafide, is a drug combined with cytarabine that is undergoing clinical phase III trials in patients with acute myeloid leukemia. Its toxic and side effects include bone marrow suppression, vomiting, rash and moderate phlebitis, etc., and the cause of this toxic and side effect may be that naphthalene is easily acety...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/14A61K31/473A61P35/00
CPCC07D221/14
Inventor 王玉霞田志勇谢松强苏雷棚王超杰
Owner HENAN UNIVERSITY
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