3,5-disubsitutued 2-amino-pyrazine compound and preparation technology and application thereof

A preparation process and compound technology, applied in organic chemistry, drug combination, antitumor drugs, etc., can solve the problem of no Aurora kinase inhibitor, etc., and achieve the effect of good proliferation inhibitory activity, strong inhibitory activity, and obvious inhibitory activity

Active Publication Date: 2018-07-06
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently multiple Aurora kinase inhibitors in clinical trials, such as VX-680, PHA-739358, AZD-1152, MLN8054, SNS-314, ENMD-2076, AMG900, etc. (Pharmaceutical Progress 2008, 32, 337; Chinese Journal of Antibiotics 2010, 35,641), but so far no Aurora kinase inhibitors have been used clinically
However, there is no report on the inhibitory activity of this type of compound for Aurora kinase

Method used

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  • 3,5-disubsitutued 2-amino-pyrazine compound and preparation technology and application thereof
  • 3,5-disubsitutued 2-amino-pyrazine compound and preparation technology and application thereof
  • 3,5-disubsitutued 2-amino-pyrazine compound and preparation technology and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: the preparation of p-hydroxybenzoic acid n-propionamide

[0024] Stir and dissolve p-hydroxybenzoic acid (690mg, 5.0mmol) in 15mL of acetone, then add n-propylamine (6.0mmol), and after complete dissolution, add 1-(3-dimethylaminopropyl)-3-ethylcarbodi Imine hydrochloride was refluxed at 70°C for 12h. After the reaction was finished, the acetone was distilled off, and the residue was diluted with ethyl acetate, and then washed with 1mol / L hydrochloric acid and 10wt% Na 2 CO 3 After washing, the organic phase was dried and the solvent was evaporated, and a white powder was obtained by column chromatography. The product detection data are as follows:

[0025] Yield: 71%; 1 H NMR (600MHz, DMSO-d 6 )δ10.08(s,1H),9.97(s,1H),7.85(d,J=9.0Hz,2H),7.75(d,J=7.2Hz,2H),7.32(t,J=7.8Hz, 2H), 7.07-7.06 (m, 1H), 6.86 (d, J=9.0Hz, 2H).

[0026] Use cyclopropylamine, cyclopentylamine, cyclohexylamine, morpholine, 4-methylpiperazine, aniline, p-chloroaniline or m-chlor...

Embodiment 2

[0027] Example 2: Preparation of 4-O-(3-amino-6-bromo-pyrazinyl-2)-benzoic acid n-propylamide

[0028] Synthetic general method: Dissolve 2-amino-3,5-dibromo-pyrazine (253mg, 1.0mmol) in 10mL N-methylpyrrolidone (or N-ethylpyrrolidone, or N-cyclohexylpyrrolidone), and then Add the p-hydroxybenzoic acid n-propionamide (1.2mmol) prepared above, and add K after completely dissolving 2 CO 3 (276mg, 2.0mmol), in N 2 Under protection, react at 100°C for 6h. After the reaction was completed, it was diluted with 30 mL of ethyl acetate, the organic layer was washed with saturated brine, dried, the solvent was evaporated and the column chromatography was used to obtain the intermediate 4-O-(3-amino-6-bromo-pyrazinyl-2)- N-Propylamide Benzoate. Bright brown liquid. The product detection data are as follows:

[0029] Yield: 90%; 1 H NMR (600MHz, DMSO-d 6 )δ9.94(s,1H),8.20(s,1H),7.70(d,J=8.4Hz,2H),6.78(d,J=8.4Hz,2H),3.19-3.15(m,2H), 1.52-1.48 (m, 2H), 0.87 (t, J = 7.2Hz, 3H).

[...

Embodiment 3

[0031] Example 3: Preparation of 4-O-(3-amino-6-(3,5-dimethylisoxazolyl-4)pyrazinyl-2)-benzoic acid n-propylamide

[0032] Get the 4-O-(3-amino-6-bromo-pyrazinyl-2)-benzoic acid n-propylamide (0.5mmol) and 3,5-dimethylisoxazole-4-boronic acid ( 84.6mg, 0.6mmol) was dissolved in 10mL 1,4-dioxane, and then the catalyst Pd(dppf)Cl was added 2 ·CH 2 Cl 2 (40.8mg, 0.05mmol), 2mol / L Na 2 CO 3 solution (0.05mL, 0.1mmol), in N 2 Reflux at 100°C under protection until the reaction is complete, evaporate the solvent under reduced pressure, and dilute the residue with 15 mL of ethyl acetate, wash with saturated brine, dry, and evaporate the solvent to obtain a white solid by column chromatography. The product detection data are as follows:

[0033] Yield: 72%; Purity: 95% (HPLC:MeOH:H 2 O=70:30,0.5mL / min,t R =7.60min); 1 HNMR (600MHz, DMSO-d 6 )δ8.44(t, J=5.4,1H),7.89(d,J=7.2Hz,2H),7.79(s,1H),7.31(d,J=7.2Hz,2H),6.78(s,2H ),3.21-3.18(m,2H),2.29(s,3H),2.07(s,3H),1.53-1.49(m,2H),...

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Abstract

The invention discloses a 3,5-disubsitutued 2-amino-pyrazine compound. The compound has the structure shown in the formula I; in the formula I, NR1R2 is n-propylamino, cyclopropylamino, cyclopentylamino, cyclohexylamino, morpholinyl, 4-methyl piperazine, anilino, 4-chloroaniline or 3-chloroaniline; Ar is 3,5-dimethyl-isoxazolyl-4 or 1-methyl-1H-pyrazolyl-4; and the invention further provides the preparation technology and application thereof. The compound has the outstanding inhibiting effect on growth of four kinds of cancer cells including a human cervical cancer cell HeLa, a human brain glioma cell U87, a human hepatoma cancer cell HepG2 and a human colon cancer cell LoVo, wherein a large part of the compound has an obviously higher inhibiting effect on proliferation of the cancer cellsthan positive control VX-680, particularly the compound Ih and Ii have relatively high activity on the four kinds of cancer cells, and have prominent activity inhibiting effect on aurora kinase A andaurora kinase B, and therefore the compound can be applied to preparation of anti-cancer drugs.

Description

technical field [0001] The invention relates to a 3,5-disubstituted 2-amino-pyrazine compound and its preparation process and application. Background technique [0002] Aurora kinases (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 completely different and non-overlapping functions. Aurora A affects the separation and maturation of centrosome...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D403/04A61P35/00
CPCC07D403/04C07D413/04
Inventor 陈世武孛永鑫
Owner LANZHOU UNIVERSITY
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