A class of naphthalimide compounds containing 2-mercaptobenzothiazole and triazole heterocycle, its preparation method and application

A technology of mercaptobenzothiazole and naphthalimide, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve problems such as toxic and side effects, achieve the effect of improving biological activity and antitumor performance

Inactive Publication Date: 2017-01-04
DALIAN UNIV OF TECH
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  • Description
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Problems solved by technology

Although Costanza et al. reported that Amonafide has a therapeutic effect on advanced breast cancer, its further research had to be discontinued due to its strong toxic side effects

Method used

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  • A class of naphthalimide compounds containing 2-mercaptobenzothiazole and triazole heterocycle, its preparation method and application
  • A class of naphthalimide compounds containing 2-mercaptobenzothiazole and triazole heterocycle, its preparation method and application
  • A class of naphthalimide compounds containing 2-mercaptobenzothiazole and triazole heterocycle, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] N-(N',N'-dimethylaminoethyl)-6-(4-((benzothiazole-2-mercapto)methyl)-[1,2,3]-triazole)naphthoyl Synthesis of imine (compound M1):

[0036] (1) 4-Azide-1.8-naphthalimide (Intermediate 2)

[0037]

[0038] Add 2.5g (9mmol) 4-bromo-1,8 naphthalene anhydride into a 50mL two-necked flask, stir and dissolve with 35mL DMF, slowly add 0.87g (13.5mmol) sodium azide to the reaction system, heat to 55°C, and reflux Magnetically stirred for 1 h, cooled, and the reaction solution was poured into water, a large amount of yellow precipitate was precipitated, filtered and dried to obtain 2.04 g of yellow solid, yield: 95.1%.

[0039] (2) 2-(2-Alkyne-1-propylthio)benzo[d]thiazole (Intermediate 3)

[0040]

[0041] Weigh 4.02g (24mmol) of 2-mercaptobenzothiazole, dissolve it with 40mL of acetone, add 3.34mL (24mmol) of triethylamine, and the reaction solution is an orange transparent liquid, add 1.88mL (24mmol) of propyl bromide alkyne, ultrasonically oscillated for 10 minutes, st...

Embodiment 2

[0051] N-(N',N'-diethylaminoethyl)-6-(4-((benzothiazole-2-mercapto)methyl)-[1,2,3]-triazole)naphthoyl Synthesis of imine (compound M2):

[0052] Except that N,N-diethylethylenediamine was used instead of N,N-dimethylethylenediamine in (4), other synthesis and experimental treatment methods were the same as in Example 1. Separation by silica gel column chromatography (column chromatography eluent is CH 2 Cl 2 :CH 3 OH=12:1), the target product M2 was obtained as light brown solid with a yield of 70.6%. Melting point: 114.3-115.9°C.

[0053] 1 H NMR (400MHz, CDCl 3 )δ8.66(dd, J=7.4,4.1Hz,2H),8.16(s,1H),8.11(d,J=8.6Hz,1H),7.88(d,J=8.1Hz,1H),7.79( t,J=7.8Hz,2H),7.69(t,J=7.9Hz,1H),7.43(t,J=7.6Hz,1H),7.33(t,J=7.6Hz,1H),4.85(s, 2H), 4.35(t, J=6.6Hz, 2H), 2.90(s, 2H), 2.77(s, 4H), 1.14(s, 6H).

[0054] +ESI MS(M+H):C 28 h 26 N 6 o 2 S 2 , calculated value: 543.1559, measured value: 543.1635.

Embodiment 3

[0056] N-(N',N'-dimethylaminopropyl)-6-(4-((benzothiazole-2-mercapto)methyl)-[1,2,3]-triazole)naphthoyl Synthesis of imine (compound M3):

[0057] Except that N,N-dimethylpropylenediamine was used instead of N,N-dimethylethylenediamine in (4), other synthesis and experimental treatment methods were the same as in Example 1. Separation by silica gel column chromatography (column chromatography eluent is CH 2 Cl 2 :CH 3 OH=12:1), the target product M3 was obtained as light brown solid with a yield of 80.3%. Melting point: 116.0-118.2°C.

[0058] 1 H NMR (400MHz, CDCl 3 )δ8.66(dd, J=7.4,4.7Hz,2H),8.16(s,1H),8.12(d,J=8.5Hz,1H),7.88(d,J=8.1Hz,1H),7.80( t,J=8.5Hz,2H),7.74–7.62(m,1H),7.43(t,J=7.6Hz,1H),7.33(t,J=7.6Hz,1H),4.86(s,2H), 4.27(t, J=6.9Hz, 2H), 2.65(s, 2H), 2.42(s, 6H), 2.05(s, 2H).

[0059] +ESI MS(M+H):C 27 h 24 N 6 o 2 S 2 , calculated value: 529.1402, measured value: 529.1462.

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Abstract

The invention relates to a naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, and application of the naphthalimide compound. The compound has a structure as shown in the general formula Y. According to the compound, five-membered triazolecycle is introduced in a non-naphtho mode to increase a conjugate area of a naphthalimide parent and simultaneously is connected with an active group which is mercaptobenzothiazole so as to design and synthetize a compound with wide antineoplastic activity. The compound takes good suppression effect on normal growth of tumor cells based on different tissue sources such as cervical cancer, liver cancer and breast cancer.

Description

technical field [0001] The invention relates to a class of naphthalimide compounds containing 2-mercaptobenzothiazole and triazole heterocycles in the field of bioorganic synthesis, its preparation method and its application. Background technique [0002] In the early 1970s, For the first time, the research team designed and synthesized a series of 3-nitronaphthimide derivatives, and tested these compounds against tumors in vitro and in vivo. Among them, Amonafide and Mitonafide are two very famous compounds. Amonafide is one of the earliest naphthalimide derivatives in clinical research. It has good inhibitory effect on human cervical cancer Hela, human nasopharyngeal carcinoma KB and leukemia P388 and HL-60. Mitonafide has a strong inhibitory effect on human cervical cancer Hela and human nasopharyngeal carcinoma KB cells. The mechanism of action of Mitonafide and Amonafide is relatively similar. They are also DNA intercalating agents, which induce DNA strand breaks un...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/14A61K31/473A61K31/496A61P35/00
CPCC07D417/14
Inventor 李晓莲尹方敏张英利刘馨月赵赫门泽宇
Owner DALIAN UNIV OF TECH
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