Aurora kinase A inhibitor and preparation and application thereof

A Aurora kinase and inhibitor technology, applied in the field of 2,4-diaminopyrimidine Aurora kinase A inhibitors, can solve the problems of loss, low anti-tumor activity, and poor solubility membrane penetration ability

Inactive Publication Date: 2017-05-17
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, American scholars Cochran and Lwerence respectively reported a class of 2,4-diphenyl ring-substituted monopyrimidine ring compounds. Some compounds have a selectivity of Aurora-A as high as 1000 times compared with Aurora-B, but due to their solubility And / or poor membrane penetration ability, resulting in low anti-tumor activity, lost the value of further development (J.Med.Chem.2012,55,7392)
In addition, a new class of pyrazole-substituted phthalazinone compounds reported by Norwegian scholar Prime M.E. has a selectivity of more than 1000 for Aurora-A kinase inhibition. It is not clear whether it has entered preclinical research (J.Med.Chem.2011 ,54,312)

Method used

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  • Aurora kinase A inhibitor and preparation and application thereof
  • Aurora kinase A inhibitor and preparation and application thereof
  • Aurora kinase A inhibitor and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: Preparation of 2-chloro-4-o-chloroaniline-5-nitropyrimidine

[0024] Dissolve 2,4-dichloro-5-nitropyrimidine (205mg, 1.05mmol) in dry dichloromethane, add o-chloroaniline (125mg, 1.0mmol) at room temperature and continue the reaction for 8h, evaporate the solvent after the reaction , The residue was directly chromatographed to obtain the product 2-chloro-4-o-chloroaniline-5-nitropyrimidine. Yield: 89%; Yellow solid; 1 H-NMR (600MHz, CDCl 3 )δ10.68 (s, 1H), 9.22 (s, 1H), 8.34-8.32 (m, 1H), 7.51-7.21 (m, 3H).

[0025]Use m-chloroaniline, or p-chloroaniline, or o-hydroxyaniline, or m-hydroxyaniline, or p-hydroxyaniline to replace o-chloroaniline respectively to prepare 2-chloro-4-m-chloroaniline-5-nitropyrimidine, or 2- Chloro-4-p-chloroaniline-5-nitropyrimidine, or 2-chloro-4-o-hydroxyaniline-5-nitropyrimidine, or 2-chloro-4-m-hydroxyaniline-5-nitropyrimidine, or 2 -Chloro-4-p-hydroxyaniline-5-nitropyrimidine.

[0026] Reaction with 2,4-dichloro-5-fluor...

Embodiment 2

[0027] Example 2: Preparation of p-aminobenzoic acid 4-amino-2,2,6,6-tetramethylpiperidine nitrogen oxide amide

[0028] Dissolve 1.8g of Boc-protected p-aminobenzoic acid in dry dichloromethane, and add 1.8g of EDC, 1.22g of HOBt and 1.53g of compound TMPO in sequence. Stir at room temperature until the reaction is complete. The organic phase was washed with water, and dried over anhydrous magnesium sulfate; the solvent was evaporated and column chromatography was performed to obtain 2.52 g of pink solid, with a yield of 90%. MS(ESI)392.15[M+2H] + .

[0029] Weighed 2.5 g of the product obtained from the above reaction and dissolved it in 15 ml of dichloromethane, added 6 ml of trifluoroacetic acid dropwise, stirred and reacted at room temperature for 0.5 h, evaporated the solvent under reduced pressure, and obtained 1.74 g of white solid by column chromatography of the obtained solid, yield 94%. MS(ESI)292.15[M+2H] + .

Embodiment 3

[0030] Example 3: Preparation of N-(5-nitro-4-o-chloroaniline-pyrimidine-2)-aminobenzoic acid 4-amino-2,2,6,6-tetramethylpiperidine nitrogen oxide amide

[0031] 2-Chloro-4-o-chloroaniline-5-nitropyrimidine (280 mg, 1 mmol) and p-aminobenzoyl 4-amino-2,2,6,6-tetramethylpiperidine nitrogen oxide (430 mg, 1.5mmol) was dissolved in ethanol, then 2ml of hydrochloric acid in dioxane was added, and heated to reflux. After the reaction was almost complete, the reaction was stopped, the solvent was evaporated, and a yellow solid was obtained by direct column chromatography, yield: 62%.

[0032]

[0033] m.p.:208-210℃;HPLC:MeOH:H 2 O(0.1%TFA)=65:35, 0.8ml / min, t=21.23min, 95.0%; IR(KBr,cm -1 ) 3362, 3015, 1629, 1536, 1506, 1422, 1332, 1195, 1025, 836, 726; ESR (DMSO): g = 2.006, An (G) = 15.96, △ H (G) = 2.95; HRMS (ESI) 540.2111 for[M+2H] + (calcd 540.2121 for C 26 h 31 N 7 o 4 Cl).

[0034] In the cell proliferation inhibition experiment described later, the sample number...

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Abstract

The invention discloses a novel stable nitroxide radical-marked aurora kinase A inhibitor and a preparation method and application thereof. The aurora kinase A inhibitor is N-(5-fluoro-4-o-chloroaniline-pyrimidin-2)-aminobenzoic acid 4-amino-2, 2, 6, 6-tetramethylpiperidyl oxynitride amide, or N-{5-fluoro-4-amino-(benzoyl o-chloroaniline)-pyrimidin-2}-aminobenzoic acid 4-amino-2, 2, 6, 6-tetramethylpiperidyl oxynitride amide. According to the preparation method, a target compound is prepared by performing a substitution reaction on 2, 4-dichloro-5-substituted-pyrimidine and aniline or p-aminobenzanilide and then 4-amino-2, 2, 6, 6-tetramethylpiperidyl nitrogen oxide. The aurora kinase A inhibitor is applied to preparation of anticancer medicines.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a stable nitroxide free radical labeled 2,4-diaminopyrimidine Aurora kinase A inhibitor, a preparation method and application of the inhibitor. Background technique [0002] Aurora kinases are a novel class of threonine / serine protein kinases that play crucial roles in important mitotic processes such as centrosome duplication, bipolar spindle formation, chromosome rearrangement, and chromosome checkpoint monitoring (Cancer Metastasis Rev. 2003, 22, 451). The Aurora kinase family has three structurally and functionally highly related subgroups: Aurora-A, Aurora-B and Aurora-C. Their protein primary structures all contain an N-terminal regulatory region and a C-terminal catalytic region, and the sequence similarity of the enzyme domain reaches 71%, and the residues of the ATP adenine ring binding site are also the same; but in cell division They have com...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61P35/00
CPCC07D401/12
Inventor 陈世武惠玲秦雯雯关霄文
Owner LANZHOU UNIVERSITY
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