A class of benzopyran-4-one substituted naphthalimide-polyamine conjugates and their preparation methods and uses

A technology of benzopyran and naphthalimide, which is applied in the field of "naphthalimide-polyamine" conjugate and its preparation, can solve the problems of toxic and side effects, limited clinical activity, central nervous system toxicity and the like

Active Publication Date: 2018-06-26
HENAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, severe central nervous system (NCS) toxicity, hematological toxicity, and bone marrow suppression have also been found in clinical trials, and the clinical activity is limited

Method used

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  • A class of benzopyran-4-one substituted naphthalimide-polyamine conjugates and their preparation methods and uses
  • A class of benzopyran-4-one substituted naphthalimide-polyamine conjugates and their preparation methods and uses
  • A class of benzopyran-4-one substituted naphthalimide-polyamine conjugates and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 6-(2-4H-1-benzopyran-4-one)-{2-[(2-dimethylamino)-ethyl]}-1H-benzoisoquinoline-1,3(2H )-diketone} hydrochloride (18a) preparation:

[0034]

[0035] (1) Dissolve 1,3-propanediamine (50mmol) in 30mL of 10v% methanol solution of triethylamine, and dissolve 4.3g of Boc 2 O (20mmol) methanol solution 20mL was slowly dropped into the above solution, and the drop was completed and raised to room temperature and stirred for 12h; 2 CO 3 Washed with solution, collected organic layer, anhydrous Na 2 SO 4 Dried and concentrated to give compound 1;

[0036] (2) Dissolve 4.50g (23.9mmol) of compound 1 in 100mL of acetonitrile, add 4.5g (32mmol) of anhydrous potassium carbonate, stir at room temperature for 15min, then raise the temperature to 45°C, and add 5.45g (20.4mmol) of N-( 3-bromopropyl) phthalimide, reacted at 45°C for 12h. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was first extracted with dichloromethane, a...

Embodiment 2

[0045] 6-(2-4H-1-benzopyran-4-one)-{2-[3-(3-aminopropyl)-aminopropyl]1H-benzoisoquinoline-1,3(2H )-keto} dihydrochloride (18b) preparation:

[0046]

[0047] Except that N,N-dimethylethylenediamine was replaced by 3a in step (8), add 2mL of 4M HCl ethanol dropwise (V 4M盐酸 :V 乙醇 =1:2) solution, other synthesis and purification methods are the same as in Example 1. Yield: 86%, 1 HNMR (400MHz,D 2 O)δ: 8.15~8.26(m, 3H, Ar-H); 7.82(d, 1H, J=8.8Hz, Ar-H); 7.63~7.67(m, 1H, Ar-H); 7.51~7.56( m, 2H, Ar-H); 7.29(t, J=7.78Hz, 1H, Ar-H), 7.12(d, J=4.28Hz, 1H, Ar-H); 6.26(s, 1H, Ar-H ); 4.18(t, J=6.96Hz, 2H, 1×N-CH 2 ); 3.21~3.26(m,4H,2×N-CH 2 ); 3.15(t, J=7.82Hz, 2H, 1×N-CH 2 ); 2.12~2.20(m,4H,2×CH 2 ); ESI-MS m / z: 456.2[M+1–2HCl] + .Anal.calcd for C 27 h 27 Cl 2 N 3 o 4 1.85H 2 O: C 57.73%, H 5.51%, N 7.48%; found C 57.64%, H 5.50%, N7.42%.

Embodiment 3

[0049] 6-(2-4H-1-benzopyran-4-one)-{2-[3-(4-aminobutyl)-aminopropyl]1H-benzoisoquinoline-1,3(2H )-keto} dihydrochloride (18c) preparation:

[0050]

[0051] Except that 3b was used instead of N,N-dimethylethylenediamine in step (8), add 2mL of 4M HCl ethanol solution dropwise (V 4M盐酸 :V 乙醇 =1:2), other synthesis and purification methods are the same as in Example 1. Yield: 86%, white solid 1 H NMR (400MHz,D 2 O)δ: 7.74~7.78(m, 3H, Ar-H); 7.42(t, 1H, J=3.70Hz, Ar-H); 7.26~7.29(m, 2H, Ar-H); 7.05(s, 2H, Ar-H); 6.74(t, J=4.08Hz, 1H, Ar-H), 5.64(d, 1H, J=4.68Hz, Ar-H); 3.98(t, J=6.78Hz, 2H, 1×N-CH 2 ); 3.16~3.22(m,4H,2×N-CH 2 ); 3.10(t,2H,J=7.12Hz 1×N-CH 2 ); 2.06(t,2H,J=7.02Hz 1×CH 2 ); 1.78-1.89 (4H,2×CH 2 ).ESI-MI m / z:470.21[M+H-2HCl] + .Anal.calcd for C 28 h 29 Cl 2 N 3 o 4 1.6H 2 O: C 58.87%, H 5.68%, N 7.36%; found C 58.97%, H 5.57%, N 7.45%.

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Abstract

The invention relates to a benzopyran-4-one substituted naphthalimide-polyamine conjugate and a preparing method and usage thereof. The naphthalimide-polyamine conjugate has a structure as shown in a formula I. The benzopyran-4-one substituted naphthalimide-polyamine conjugate has obvious inhibition activity for cell proliferation of multiple tumor cells such as HCT-116 (human colon cancer cell), HepG2 (human hepatoma carcinoma cell), K562 (human chronic myeloid leukemia cells) and SMMC7721 (human hepatoma carcinoma cell); the conjugate can also serve as a targeting mitochondria fluorescence probe and can effectively inhibit pulmonary metastasis of the tumor, wherein a is 0, 1 or 2, m is 1, 2 or 3, n is 1, 2, 3, or 4, R is H or CH3, and R1 is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of "naphthalimide-polyamine" conjugates containing benzopyran-4-one, a preparation method and application thereof. Background technique [0002] Polyamine is a kind of biological endogenous small molecule with complex physiological functions. Most eukaryotic cells have a polyamine transport system on their cell membranes, which can adjust the concentration of polyamines in cells as needed. Based on these characteristics of polyamines, it has attracted much attention in the design of anti-tumor and neuroprotective drugs. And recent studies have shown that natural polyamines or synthetic polyamines have the potential to develop into a targeting carrier that can effectively utilize polyamine transporters on cell membranes. [0003] In recent years, naphthalimide compounds have attracted much attention as antitumor agents, and a variety of naphthalimide derivati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04A61P35/00C09K11/06
CPCC07D405/04C09K11/06C09K2211/1029C09K2211/1033C09K2211/1044C09K2211/1088
Inventor 王超杰王玉霞谢松强代付军李骞
Owner HENAN UNIVERSITY
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