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A kind of aromatic heterocyclic modified naphthalimide derivative and preparation method and use thereof

A naphthalene imide and aromatic heterocycle technology, applied in the field of medicinal chemistry, can solve the problems such as dose toxicity and side effects failed to be successfully marketed, and achieve the effects of good development potential, good inhibitory activity, and novel skeleton

Active Publication Date: 2021-12-07
HENAN UNIVERSITY
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AI Technical Summary

Problems solved by technology

[0003] Naphthalimide compounds have a wide range of biological activities, and many naphthalimide derivatives have anti-tumor activity. Representative drugs such as naphfet and mitonaftide have entered the clinical research stage, but all of them are due to bone marrow Inhibition, dose limitation, hematological toxicity, and its unpredictable toxic side effects ultimately failed to market

Method used

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  • A kind of aromatic heterocyclic modified naphthalimide derivative and preparation method and use thereof
  • A kind of aromatic heterocyclic modified naphthalimide derivative and preparation method and use thereof
  • A kind of aromatic heterocyclic modified naphthalimide derivative and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 6-[1-(imidazo[1,2-a]pyridine)]-2-{4-[4-(4-aminobutyl)-aminobutyl]-aminobutyl}-1H-benzoiso Synthesis of quinoline-1,3(2H)-dione tetrahydrochloride (16a)

[0046]

[0047] (1) Take 1.0g (6.5mmol) compound 10 and anhydrous AlCl 3 1.29g (9.7mmol) was placed in a 100mL round-bottomed flask, and dry dichloromethane was added as a reaction solvent. After stirring at room temperature for 15 minutes, a dichloromethane solution of 0.48mL (6.8mmol) of acetyl chloride was slowly added dropwise under ice-bath conditions. After dropping, react at room temperature for 30 minutes. After 2 hours, it was poured into ice water, the organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, petroleum ether: ethyl acetate = 10:1 column separation and purification to obtain compound 11;

[0048] (2) Take 2.2g (7.5mmol) of compound 11 obtained in step (1), K 2 Cr 2 o 7 2H 2 O 6.6g (22.0mmol) was refluxed in 20mL glacia...

Embodiment 2

[0055] 6-[1-(imidazo[1,2-a]pyridine)]-2-[4-(4-aminobutyl)-aminobutyl]-1H-benzisoquinoline-1,3(2H )-Synthesis of diketone trihydrochloride (16b)

[0056]

[0057] Except replacing 5a with 3b in step (5), other synthesis and purification methods are the same as in Example 1. Yield 52%.

[0058] 1 H NMR (300MHz, Deuterium Oxide) δ: 8.60 (d, J = 6.0Hz, 1H), 8.31 (s, 1H), 8.24 (dd, J = 12.0, 6.0Hz, 3H), 7.96–7.84 (m, 1H ),7.75(t,J=7.5Hz,2H),7.63(t,J=7.5Hz,1H),7.42(s,1H),3.95(t,J=6.0Hz,2H),3.25–3.05(m ,6H),2.06-2.16(m,2H),1.86–1.63(m,4H). 13 C NMR(75MHz,Deuterium Oxide)δ164.55,164.19,140.54,134.10,132.10,131.79,131.22,130.60,130.46,128.50,128.37,127.66,127.08,121.95,121.09,117.46,114.72,112.01,47.31,44.47,39.78, 36.52, 24.17, 23.73, 23.16. ESI-MS m / z: 442.45[M-3HCl+1] + .Elemental analysis for C 26 h 30 Cl 3 N 5 o 2 2.9H 2 O: C, 51.78; H, 5.98; N, 11.61; Found: C, 51.89; H, 6.09; N, 11.45.

Embodiment 3

[0060] 6-[1-(imidazo[1,2-a]pyridine)]-2-[3-(3-aminopropyl)-aminopropyl]-1H-benzisoquinoline-1,3(2H )-Diketone Trihydrochloride (16c) Synthesis

[0061]

[0062] Except replacing 5a with 3a in step (5), other synthesis and purification methods are the same as in Example 1. Yield 59%.

[0063] 1 H NMR (300MHz, Deuterium Oxide) δ8.70(d, J=6.0Hz, 1H), 8.43(s, 1H), 8.35-8.24(m, 3H), 8.03-7.94(m, 1H), 7.84(dd ,J=9.0,3.0Hz,2H),7.68(t,J=9.0Hz,1H),7.50(t,J=6.0Hz,1H),4.07(t,J=7.5Hz,2H),3.22-3.13 (m,6H),2.29-1.90(m,4H). 13 C NMR(75MHz,Deuterium Oxide)δ164.60,164.25,140.43,134.56,131.92,131.67,131.38,130.57,130.50,128.78,128.70,128.48,127.86,127.17,122.04,121.04,117.73,114.88,111.88,45.44,44.63, 37.46,36.51,24.22,23.73.ESI-MS m / z:428.41[M-3HCl+1] + .Elemental analysis for C 25 h 28 Cl 3 N 5 o 2 3.2H 2 O: C, 50.51; H, 5.83; N, 11.78; Found: C, 50.56; H, 5.92; N, 11.62.

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Abstract

The invention discloses a naphthalimide derivative modified by an aromatic heterocycle. The general structural formula is shown in I. It has a novel skeleton, high efficiency and low toxicity, and has good inhibitory activity on tumor cells. The invention also discloses a preparation method of the above-mentioned compound, using naphthalimide as a raw material, respectively introducing active groups imidazopyridine and aminothiazole into the parent naphthalene ring, and synthesizing new naphthalimides modified by aromatic heterocycles Pharmacophore, and modified with polyamine chains, designed and synthesized a class of naphthalimide derivatives modified by imidazopyridine and aminothiazole aromatic heterocycles. While the compound retains the antitumor activity of naphthalimide, it also has the characteristics of imidazopyridine and aminothiazole, improves the biological activity of the original molecule, and improves the antitumor activity of the target molecule. The present invention also provides the application of the above compound in the preparation of antitumor drugs, which shows good development potential.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a naphthalimide derivative modified by an aromatic heterocycle, a preparation method and application thereof. Background technique [0002] Cancer is the disease with the highest mortality rate in the world. The World Cancer Report predicts that the number of cancer cases worldwide will reach 19 million by 2025. Cancer treatments generally include surgery, radiation therapy, chemotherapy, and biological therapy. Chemotherapy currently plays one of the most important roles in cancer treatment. [0003] Naphthalimide compounds have a wide range of biological activities, and many naphthalimide derivatives have anti-tumor activity. Representative drugs such as naphfeter and mitonaftide have entered the clinical research stage, but all of them are due to bone marrow Inhibition, dose limitation, blood toxicity, and its unpredictable side effects ultimately failed to market. [0004]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D417/04A61P35/00
CPCA61P35/00C07D417/04C07D471/04
Inventor 王玉霞苌聪聪代付军谢松强
Owner HENAN UNIVERSITY
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