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Novel dihydro pteridinone derivative, preparing method thereof and application to medicine

A technology of dihydropteridone and derivatives is applied in the directions of drug combination, antitumor drug, organic chemistry, etc., can solve the problem of no long-acting drug and the like, achieves reduction of toxic side effects and adverse reactions, simple preparation method, The effect of increasing selectivity

Inactive Publication Date: 2016-07-27
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although several Plk1 kinase inhibitors have been disclosed, their application is still limited by pharmacokinetics and pharmacokinetics, especially in the face of problems such as drug resistance of various types of tumors and selectivity within the kinase family , there is no long-acting drug yet, so there is an urgent need to develop Plk1 kinase inhibitors with improved properties such as high efficiency, low toxicity, and pharmacokinetics

Method used

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  • Novel dihydro pteridinone derivative, preparing method thereof and application to medicine
  • Novel dihydro pteridinone derivative, preparing method thereof and application to medicine
  • Novel dihydro pteridinone derivative, preparing method thereof and application to medicine

Examples

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Effect test

Embodiment 1

[0027] Example 1, (R)-N-cyclopentyl-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pterene Pyridin-2-ylamino)-3-hydroxyl-benzamide (compound 1), the reaction scheme is as follows figure 1 Shown:

[0028] The first step, (R)-2-amino-butyric acid methyl ester (compound 1b)

[0029] Under ice bath, take (R)-2-amino-butyric acid (compound 1a) (10g, 96.9mmol) and dissolve it in 120mL of methanol, slowly add thionyl chloride (16mL, 0.22mol) dropwise, reflux and stir for 2 hours , cooled to room temperature, concentrated the reaction solution under reduced pressure to obtain a light yellow oil, then added 100mL tert-butyl methyl ether and stirred for 0.5 hours, a white solid was precipitated, filtered by suction, and dried in vacuo overnight to obtain compound 1b (10.5g, white solid, yield 93%). 1 HNMR (600MHz, CDCl3) δ8.78(s, 2H), 4.15(d, J=5.2Hz, 1H), 3.82(s, 3H), 2.14(q, J=7.4Hz, 2H), 1.12(t, J=7.5Hz, 3H).

[0030] The second step, (R)-2-cyclopentyl-amino-butyric ...

Embodiment 2

[0046] Example 2, (R)-N-cyclopentyl-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pterene Pyridin-2-ylamino)-3-(2-hydroxyethoxy)benzamide (Compound 2)

[0047] Such as figure 2 As shown, compound 1 (100mg, 0.209mmol), 2-bromoethanol (26.7μl, 0.376mmol) and potassium carbonate (57.8mg, 0.418mmol) were dissolved in acetone, reacted at 60°C for 12 hours, and cooled to At room temperature, the reaction solution was concentrated under reduced pressure, distilled water was added, extracted with ethyl acetate (50mL×3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure by column chromatography (petroleum Ether: ethyl acetate = 1:2) separation and purification to obtain the target product (55 mg, light yellow solid, yield 47.6%). 1 HNMR (600MHz, CDCl 3 )δ8.39(d, J=8.5Hz, 1H), 7.54(s, 1H), 7.40(d, J=1.1Hz, 1H), 7.26(dd, J=8.5, 1.7Hz, 1H), 6.19( d,J=6.8Hz...

Embodiment 3

[0048] Example 3, (R)-N-cyclopentyl-4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pterene Pyridin-2-ylamino)-3-(2-methoxyethoxy)benzamide (Compound 3)

[0049] Such as image 3 , Dissolve compound 1 (100mg, 0.209mmol), 2-bromoethyl methyl ether (35.3μl, 0.376mmol) and potassium carbonate (57.8mg, 0.418mmol) in acetone, react at 60°C for 12 hours, after the reaction Cool to room temperature, concentrate the reaction solution under reduced pressure, add distilled water, extract with ethyl acetate (50mL×3), wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure with column chromatography (Petroleum ether:ethyl acetate=1:2) separation and purification gave the target product (45 mg, reddish-brown solid, yield 40%). 1HNMR (600MHz, CDCl 3 )δ8.54(d, J=8.4Hz, 1H), 7.74(s, 1H), 7.68(s, 1H), 7.45(s, 1H), 7.26(d, J=8.5Hz, 1H), 6.07( d,J=7.2Hz,1H),4.45–4.36(m,1H),4.29–4.26(m,1H)...

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Abstract

The invention discloses a novel dihydro pteridinone derivative, a preparing method thereof and application to medicine.The novel dihydro pteridinone derivative is characterized in that the structure general formula is shown in the formula (I) or (II) (see the formulas in the description).The dihydro pteridinone derivative can be used in a drug for treating cell proliferation diseases.The dihydro pteridinone derivative is simple in preparing method and greatly improves selectivity in Plk family while keeping good kinase inhibitory activity to Plk1 to improve selectivity to most kinds of kinase, targeting ability of the drug is improved, and toxic and side effects as well as untoward effects are reduced while the pharmacological effect is kept.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a class of novel dihydropteridinone derivatives, a preparation method thereof and a drug application as a Plks kinase inhibitor. Background technique [0002] Protein kinases are a class of enzymes that transfer phosphate groups from high-energy donor molecules (such as ATP) to specific target molecules. They are important signaling molecules in cell signal transduction pathways, and play a role in regulating cell DNA replication, cycle operation, energy metabolism and growth. and differentiation play a key role. Polo-like kinases (Polo-like kinases, Plks) are a class of serine / threonine kinases with highly conserved structure. There are five subtypes in human cells, namely Plk1-5. They play an important role in the regulation of cell growth and cell mitosis cycle (Journal of Cell Science. 2005, 118(21): 5101-5108.). Studies have shown that Plk1 regulates multiple key st...

Claims

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Application Information

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IPC IPC(8): C07D475/00A61P35/00A61P35/02
CPCC07D475/00
Inventor 廖晨钟杨洋涂正超张兴星倪勇郑敏许涵菲肖炫詹美苗
Owner HEFEI UNIV OF TECH
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