Benzo[e][1,2,4]triazine-1-oxo derivatives, compositions and applications thereof

A technology of derivatives and compositions, applied in the field of pharmacy, can solve the problem that the relationship between autophagy and tumor cell death is not very clear

Active Publication Date: 2021-08-24
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The relationship between autophagy and tumor cell death is still unclear

Method used

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  • Benzo[e][1,2,4]triazine-1-oxo derivatives, compositions and applications thereof
  • Benzo[e][1,2,4]triazine-1-oxo derivatives, compositions and applications thereof
  • Benzo[e][1,2,4]triazine-1-oxo derivatives, compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Preparation of 3-[(7-chloroquinoline-4-amino)butylamino]-benzo[e][1,2,4]triazine-1-oxygen (R 1 =H)

[0046] Weigh (1g, 5.05mmol) 4,7-dichloroquinoline into a 50mL three-neck flask, add 1.74g of butanediamine under the protection of argon, heat at 110°C for 6-8h, after the reaction is complete, drop To room temperature, dichloromethane was added, the solvent was spin-dried, then ethyl acetate was added, and suction filtration was obtained to obtain a light yellow solid, which was purified by column chromatography, DCM:Me=20:1 to obtain 1.13g of compound 4-(aminobutyl)amine Base-7-chloroquinoline, yield 86%. The NMR test results are as follows:

[0047] 1 H NMR (400MHz, DMSO-d6) δ = 8.40 (d, J = 5.4Hz, 1H), 8.35 (d, J = 9.0Hz, 1H), 7.78 (d, J = 2.0Hz, 1H), 7.44 (dd , J=9.0, 2.0Hz, 1H), 6.49(d, J=5.4Hz, 1H), 3.30(t, J=5.9Hz, 2H), 2.82(t, J=6.8Hz, 2H), 1.70(s , 4H).

[0048] Weigh (50 mg, 0.275 mmol) of 3-chloro-1,2,4-benzotriazole-1-oxide and (68 mg, 0.275 ...

Embodiment 2

[0051] Example 2 Preparation of 3-[(7-chloroquinoline-4-amino)butylamino]-7-methyl-benzo[e][1,2,4]triazine-1-oxygen (R 1 =CH 3 )

[0052] Weigh (1g, 5.05mmol) 4,7-dichloroquinoline into a 50mL three-neck flask, add 1.74g of butanediamine under the protection of argon, heat at 110°C for 6-8h, after the reaction is complete, drop To room temperature, dichloromethane was added, the solvent was spin-dried, then ethyl acetate was added, and suction filtration was obtained to obtain a light yellow solid, which was purified by column chromatography, DCM:Me=20:1 to obtain 1.13g of compound 4-(aminobutyl)amine Base-7-chloroquinoline.

[0053] Weigh 3-chloro-7-methyl-1,2,4-benzotriazole-1-oxide (50 mg, 0.275 mmol) and the above-mentioned 4-(aminobutyl) amino-7 chloroquinoline (68 mg, 0.275mmol) was placed in a 50mL single-necked bottle, 10mL of DME and 0.5mL of triethylamine were added, and heated to reflux at 80°C for 5h. After the reaction was completed, the solvent was spin-dried...

Embodiment 3

[0056] Example 3 Preparation of 3-[(7-chloroquinoline-4-amino)butylamino]-7-chloro-benzo[e][1,2,4]triazine-1-oxygen (R 1 =Cl)

[0057] Weigh (1g, 5.05mmol) 4,7-dichloroquinoline into a 50mL three-neck flask, add 1.74g of butanediamine under the protection of argon, heat at 110°C for 6-8h, after the reaction is complete, drop To room temperature, dichloromethane was added, the solvent was spin-dried, then ethyl acetate was added, and suction filtration was obtained to obtain a light yellow solid, which was purified by column chromatography, DCM:Me=20:1 to obtain 1.13g of compound 4-(aminobutyl)amine Base-7-chloroquinoline.

[0058] Weigh 3,7-dichloro-1,2,4-benzotriazole-1-oxide (50mg, 0.275mmol) and the above-mentioned 4-(aminobutyl)amino-7 chloroquinoline (68mg, 0.275mmol ) into a 50 mL single-necked bottle, add 10 mL of DME, and 0.5 mL of triethylamine, and heat to reflux at 80° C. for 5 h. After the reaction was completed, the solvent was spin-dried, extracted with dichlo...

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Abstract

The present invention relates to a kind of 3-[(7-chloroquinoline-4-amino)butylamino]-7-substituted-benzo[e][1,2,4]triazine- 1‑Oxygen derivatives, their pharmaceutically acceptable salts, esters, solvates: R 1 selected from hydrogen, hydroxyl, C 1 -C 6 Alkyl, fluorine, chlorine and bromine; R 2 selected from hydrogen, C 1 -C 12 Alkyl or hydroxyl; R 3 selected from hydrogen, C 1 -C 12 Alkyl or hydroxyl. The present invention also provides a composition comprising 3-[(7-chloroquinoline-4-amino)butylamino]-7-substituted-benzo[e][1,2, 4] Triazine‑1‑oxygen derivatives, their pharmaceutically acceptable salts, esters, solvates and pharmaceutically acceptable excipients: wherein, R 1 selected from hydrogen, hydroxyl, C 1 -C 6 Alkyl, fluorine, chlorine or bromine; R 2 selected from hydrogen, C 1 -C 12 Alkyl or hydroxyl; R 3 selected from hydrogen, C 1 -C 12 Alkyl or hydroxyl. The present invention also claims protection of 3-[(7-chloroquinoline-4-amino)butylamino]-7-substituted-benzo[e][1,2,4]triazine-1-oxygen derivatives, and its pharmaceutical The application of acceptable salts, esters and solvates in the preparation of tumor therapeutic drugs.

Description

technical field [0001] The present invention relates to the field of pharmacy, in particular to a benzo[e][1,2,4]triazine-1-oxygen derivative and its composition and application. Background technique [0002] Cancer seriously endangers human life and health, and is one of the largest public health problems in the world. There are more than 14 million new cancer patients in the world every year, and more than 8.2 million people die from cancer every year. The number of cancer incidence and death in my country exceeds 4.3 million and 2.8 million respectively every year. The situation is grim. Malignant tumors (also known as cancers) are mainly diseases that hinder normal cell functions due to the disorder of cell proliferation mechanism. They may infiltrate normal tissues locally and transfer to other parts through the lymphatic system and circulatory system in the body. It has the characteristics of insensitivity to inhibitory growth signals, infinite proliferation without ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/53A61P35/00
CPCC07D401/12
Inventor 郭子扬褚延军田新芳裴海龙聂晶吴安庆李冰燕张健马季陈卫强周光明
Owner SUZHOU UNIV
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