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Quinazoline derivatives with selective aurora A kinase inhibitory activity, preparation method and application thereof

A kinase and drug technology, applied in the field of quinazoline derivatives, can solve the problem of insufficient development of selective AuroraA kinase inhibitors, and achieve the effects of enhancing tumor killing effect, improving inhibitory activity and selectivity, and improving quality of life

Active Publication Date: 2019-06-04
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Most of the lead compounds existing in the prior art are Aurora kinase inhibitors, but the development of selective Aurora A kinase inhibitors is far from enough. For this, the present invention provides a series of high-efficiency selective Aurora A kinase inhibitors, It is of great significance for tumor targeted therapy

Method used

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  • Quinazoline derivatives with selective aurora A kinase inhibitory activity, preparation method and application thereof
  • Quinazoline derivatives with selective aurora A kinase inhibitory activity, preparation method and application thereof
  • Quinazoline derivatives with selective aurora A kinase inhibitory activity, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] N-(5-methyl-1H-pyrazol-3-yl)-7-(4-ethyl piperidinecarboxylate-1-yl)-4-amino-2-phenylquinazoline (A-1)

[0086]

[0087] Step 1: 7-Chloro-2-phenylquinazolin-4(3H)-one

[0088]

[0089] To 2-amino-4-chlorobenzoic acid (1.716g, 10mmol) at room temperature, K 2 CO 3 (4.146g, 30mmol) and dry acetonitrile (20mL) was added dropwise to benzoyl chloride (1.6mL, 12mmol). After the addition was complete, it was heated to 95°C and stirred overnight. The reaction was quenched with 2N aqueous HCl and a brown solid precipitated out. Suction filtration, washing 3 times with water, and drying to obtain the condensate. The condensate was dissolved in acetic anhydride (25 mL) and heated to reflux for 2 h. After the acetic acid and acetic anhydride in the reaction were removed under reduced pressure, ammonium acetate was added, and the reaction was carried out at 170°C for 6h. The reaction system was cooled from 170°C to about 80°C and then poured into water, a large amount of sol...

Embodiment 2

[0100] N-(5-methyl-1H-pyrazol-3-yl)-7-(4-piperidinecarboxylic acid-1-yl)-4-amino-2-phenylquinazoline (A-2)

[0101]

[0102] Steps 1, 2 and 3 are the same as Steps 1, 2 and 3 of Example 1, respectively.

[0103] Step 4: N-(5-Methyl-1H-pyrazol-3-yl)-7-(4-piperidinecarboxylic acid-1-yl)-4-amino-2-phenylquinazoline

[0104]

[0105] N-(5-methyl-1H-pyrazol-3-yl)-7-(4-piperidinecarboxylic acid-1-yl)-4-amino-2-phenylquinazoline (125mg, 0.26mmol) Soluble in TFA / CH 2 Cl 2 (V:V=1:1) was stirred in a mixed solvent for 4 hours, and after removing the solvent under reduced pressure, the solution was washed with saturated NaHCO 3 The pH value of the solution was adjusted to be neutral, and silica gel column chromatography (CH 2 Cl 2 / MeOH, V:V=20:1~10:1) to obtain a yellow solid (122 mg, yield 99%). 1 H NMR (400MHz, DMSO-d 6 )δ:12.36(s,1H),10.83(s,1H),8.52(d,J=9.6Hz,1H),8.38-8.35(m,2H),7.62-7.60(m,4H),7.39(d ,J=7.2Hz,1H),7.19(s,1H),6.66(s,1H),3.98(d,J=13.2Hz,2H),3.11(t,J=11.2...

Embodiment 3

[0107]N-(5-methyl-1H-pyrazol-3-yl)-7-(4-tert-butyl piperidinecarboxylate-1-yl)-4-amino-2-(2,6-methoxybenzene Formyl) quinazoline (A-3)

[0108]

[0109] Step 1: 2-(2,6-Methoxybenzoyl)quinazolin-4(3H)-one

[0110]

[0111] The synthesis method of compound 2-(2,6-methoxybenzoyl)quinazolin-4(3H)-one is the same as step 1 of Example 5, and the yield is 49.4%. 1 H NMR (400MHz, DMSO-d 6 )δ: 12.83(s, 1H), 8.18(d, J=8.8Hz, 1H), 7.72(d, J=2.0Hz, 1H), 7.65(dd, J=2.0, 2.0Hz, 1H), 7.48( t,J=8.4Hz,1H),6.79(d,J=8.8Hz,2H),3.68(s,6H). 13 C NMR (101MHz, DMSO-d 6 )δ: 189.1, 161.0, 158.9, 150.8, 149.0, 139.9, 133.5, 129.4, 128.6, 127.9, 122.2, 115.4, 105.2, 56.6, 55.3ppm. MS (ESI+APCI) m / z 345.1[M+H] + .

[0112] Step 2: 7-(4-tert-butyl-piperidinecarboxylate-1-yl)-2-(2,6-methoxybenzoyl)quinazolin-4(3H)-one

[0113]

[0114] The synthetic method of 7-(4-tert-butyl piperidinecarboxylate-1-yl)-2-(2,6-methoxybenzoyl)quinazolin-4(3H)-one and the steps of Example 1 2 is the same, the ...

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Abstract

The invention discloses a quinazoline derivative with activity of selectively inhibiting Aurora A kinase, a preparation method and an application thereof. The invention discloses a compound shown in a formula (I) or (II), or a pharmaceutically-acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug, and simultaneously discloses applications of the compound shown in the formula (I) or (II), or the pharmaceutically-acceptable salt, the hydrate, the solvate, the polymorph, the tautomer or the prodrug in preparing a medicine for inhibiting the Aurora A kinase, and in preparing a medicine for treatment and / or prevention and / or delay and / or auxiliary treatment and / or managing proliferative diseases. The quinazoline derivative disclosed by the invention has better activity and selectivity of inhibiting the Aurora A, simultaneously has obvious inhibiting action for proliferation of tumor cells. The medicine is expected to be combined with the traditional chemotherapeutic drug for use, and has the advantages that the tumor killing effect is enhanced, the recurrence interval is prolonged and the live quality of patients is improved.

Description

technical field [0001] The invention relates to a quinazoline derivative with selective Aurora A kinase inhibitory activity, a preparation method and application thereof. Background technique [0002] Mitosis is a very complex and finely regulated process that results in the production of two identical daughter cells. Three highly homologous serine-threonine protein kinases of Aurora kinases (Aurora A, B, C) play important roles in regulating many key steps of mitosis. Since the discovery of Aurora kinases from Drosophila in 1995, the lack of these kinases has been shown to lead to severe mitotic abnormalities. [0003] The expression and activity of Aurora A peak in the G2 / M phase of the cell cycle and play a key role in the maturation and differentiation of centrosomes. Aurora B is also highly expressed during mitosis, peaking in kinase activity slightly later than Aurora A. The role of Aurora C is similar to that of Aurora B. It is generally expressed at a high level i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D403/12C07D403/14A61K31/517A61K31/5377A61P35/00
CPCC07D401/14C07D403/12C07D403/14
Inventor 鲁桂龙亮彭伟
Owner SUN YAT SEN UNIV