Pyrimidotriazole-indole compound and preparation method and application thereof

A technology for compounds, indoles, applied in the field of medicinal chemistry

Active Publication Date: 2018-12-18
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no relevant literature report on the combination of new compounds combining pyrimidotriazole and indole structures with the anti-tumor effect based on the BRD4 protein target. Therefore, this research is of great value

Method used

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  • Pyrimidotriazole-indole compound and preparation method and application thereof
  • Pyrimidotriazole-indole compound and preparation method and application thereof
  • Pyrimidotriazole-indole compound and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0065] This embodiment provides a compound e1, the structural formula of the compound e1 is as follows:

[0066]

[0067] The preparation method of the compound e1 comprises the following steps:

[0068] (1) Preparation of 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one: Take 5g (about 1eq) of 3-amino-1,2,4 - Triazole and 9mL (about 1.2eq) of ethyl acetoacetate were added to a 250mL round-bottomed flask, then 30mL of acetic acid solvent was added, and refluxed at 120°C for 6-8h, and the reaction system was monitored by TLC until the reaction was complete , then use the rotary evaporation method to remove excess acetic acid solution, then add ethyl acetate for suction filtration to obtain a filter cake, wash the filter cake with ethyl acetate, and dry in vacuo to obtain 8.0 g of pure 5-methyl-[1,2 ,4]triazolo[1,5-a]pyrimidin-7(4H)-one, the 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H )-ketone as a white solid in about 90% yield.

[0069] (2) Preparation of 7-chloro-5-...

Embodiment 2

[0072] This embodiment provides a kind of compound e2, and the structural formula of this compound e2 is as follows:

[0073]

[0074] The preparation method of the compound e2 comprises the following steps: take about 1mmol of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine and about 3mmol of 1-(3-nitro Add benzyl)-1H-indole to a 10mL microwave reaction tube, then add 2mL of hexafluoroisopropanol solvent and about 0.1mmol of bistrifluoromethanesulfonimide catalyst, seal and stir, heat to 100°C and react for about 6h . Then adopt TLC to monitor the reaction system, after the reaction system is lowered to room temperature, column chromatography obtains a yellow intermediate, which is added to a 50mL round bottom flask, and then 10mL of methanol and about 0.1mmol of Pd / C reducing agent are added , reacted for 6-10 h under the protection of hydrogen, and separated and purified by column chromatography to obtain pure compound e2. The compound e2 is a yellow solid with a yi...

Embodiment 3

[0076] This embodiment provides a compound e3, the structural formula of the compound e3 is as follows:

[0077]

[0078] The preparation method of this compound e3 comprises the following steps: Take about 1mmol of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine and about 3mmol of 1-(4-methoxy Add benzyl)-1H-indole to a 10mL microwave reaction tube, then add 2mL of hexafluoroisopropanol solvent and about 0.1mmol of bistrifluoromethanesulfonimide catalyst, seal and stir, heat to 100°C and react for about 6h. Then the reaction system was monitored by TLC, and the pure compound e3 was obtained by separation and purification by column chromatography after the reaction system dropped to room temperature. The compound e3 is a light yellow solid with a yield of 87% and a melting point of 164°C to 165°C; 1H NMR (400MHz, DMSO-d6) δ9.23(s,1H),8.70(s,1H),8.38–8.19(m,1H),7.90–7.69(m,2H),7.45-7.32(m,2H ), 7.30(d, J=8.6Hz, 2H), 6.90(d, J=8.6Hz, 2H), 5.60(s, 2H), 3.70(s, 3H), 2.72(...

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Abstract

The invention discloses a pyrimidotriazole-indole compound having a general formula as shown in I (shown in the description). The invention also provides a preparation method and application of the above compound. An in vitro BRD4 enzymatic activity inhibition test proves that the pyrimidotriazole-indole compound has potential inhibition effects on various tumor cells by inhibiting the enzymatic activity of BRD4, and can be used as a lead compound for antitumor drug preparation. In addition, a preparation method of the compound, provided by the present invention, has the advantages of mild reaction conditions, simple operation and high yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a pyrimidotriazole-indole compound, a preparation method thereof, and an application thereof as a BRD4 protein inhibitor in antitumor drugs. Background technique [0002] BET proteins are bromodomain-containing proteins that selectively bind to histone acetylated lysine residues to regulate a series of important biological processes. In the BET family, the overexpression of bromodomain protein 4 (BRD4) is closely related to the formation of various cancers such as breast cancer and colon cancer. By targeting BRD4, it can induce tumor cell apoptosis, etc., so as to achieve anti-tumor effect. Therefore, BRD4 is an important epigenetic regulatory protein that is closely related to tumors. The development of its inhibitors has received extensive attention in recent years. At present, 13 BRD4 inhibitors such as Apabetalone and CPI-0610 have entered the clinical developme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00
CPCA61P35/00C07D487/04
Inventor 刘宏民余斌郑一超袁硕申丹丹
Owner ZHENGZHOU UNIV
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