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Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof

A compound, imidazo technology, applied in the field of medicinal chemistry, can solve problems such as blocking tumor cell growth

Active Publication Date: 2014-04-09
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, if PTK activity can be inhibited, it is possible to block the growth of tumor cells

Method used

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  • Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof
  • Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof
  • Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 2

[0064] Preparation Example 2 3-Hydroxymethyl-pyridine-2-carboxylic acid isopropyl ester (4)

[0065]

[0066] Compound 2 (52.7 g, 0.25 mol) was dissolved in 400 mL of thionyl chloride and heated to reflux until the solution became homogeneous, and then the solvent was spin-dried. Add 2 × 50mL anhydrous THF and rotary steam to remove residual thionyl chloride. The obtained red liquid was dissolved in 400 mL of anhydrous THF and cooled to 0° C., sodium borohydride (28.6 g, 0.76 mol) was added in batches, stirred at 0° C. for 4 hours, and the reaction solution was carefully poured into ice water. 3×200mL dichloromethane extraction, add anhydrous Na 2 SO 4 dry. Column chromatography (petroleum ether: ethyl acetate = 3:2) gave compound 4 (18.8 g, 38%) as a yellow solid. 1 H NMR (CDC1 3 ,300MHz):δ8.69(dd,J=1.5,4.7Hz,1H),7.88(dd,J=1.5,7.7Hz,1H),7.46(dd,J=4.7,7.8Hz,1H),5.35( septet,J=6.4Hz,1H),4.81(m,2H),1.45(d,J=6.3Hz,6H);EI-MS m / z:195(M) + .

preparation Embodiment 3

[0067] Preparation Example 3 3-{[Methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-pyridine-2-carboxylic acid isopropyl ester (5)

[0068]

[0069] Compound 4 (1.734g, 8.89mmol), methyl 2-p-toluenesulfonamidoacetate (TsNHCH 2 COOCH 3 ) (2.163g, 8.89mmol), and triphenylphosphine (3.499g, 13.338mmol) were dissolved in 100mL of anhydrous THF, cooled to 0°C, and protected with nitrogen. DEAD (2.165 mL, 13.338 mmol) was dissolved in 10 mL of anhydrous THF, and DEAD was added dropwise. The ice bath was removed, stirred for two hours and then spin-dried to obtain red oily liquid compound 5, which was directly used in the next reaction.

[0070] Methyl 8-hydroxy-1,6-naphthalene-7-carboxylate (6)

[0071]

[0072] The compound 5 (8.89mmol) obtained in the previous step reaction was dissolved in 50mL of anhydrous methanol and cooled to 0°C. Sodium methoxide (1.681 g, 31.123 mmol) was added slowly. Remove the ice bath and stir for 3 hours. Spin off the solvent, add 20...

preparation Embodiment 4

[0073] Preparation Example 4 5-Bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (7)

[0074]

[0075] NBS (30mg, 0.167mmol) was added to 1mLCH of compound 6 (34mg, 0.167mmol) at room temperature 2 Cl 2 solution, stirred for 1 hour. Filtration and drying gave white solid compound 7 (30mg, yield 85%); 1 HNMR(d 6 -DMSO,300MHz):δ9.26(dd,J=1.5,4.2Hz,1H),8.59(dd,J=1.6,8.4Hz,1H),8.00(dd,J=4.2,8.4Hz,1H), 3.94(s,3H).

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Abstract

The invention relates to 1,3,5-tri-substituted-1H-imidazo[4,5-h]1,6-diazanaphthalene-2(3H)-one compounds shown as the general formula I, isomers thereof and pharmaceutically acceptable salts thereof, a preparation method and applications thereof, and compositions comprising the compounds. The invention also relates to applications of the compounds, the isomers thereof, the pharmaceutically acceptable salts thereof and the compositions comprising the compounds, as protein multi-target kinase inhibitors, in preparation of medicines used for treating protein kinase related disease, especially c-Met related disease, such as neoplastic disease.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to 1,3,5-trisubstituted-1H-imidazo[4,5-h]1,6-phthalazin-2(3H)-one compounds and their isomers And pharmaceutically acceptable salts, preparation methods and uses thereof, and compositions comprising said compounds. The present invention also relates to the compound, its isomer and pharmaceutically acceptable salt and the composition containing it as a multi-target protein kinase inhibitor in the preparation for the treatment of tumor diseases related to protein kinases, especially c-Met use in medicines for diseases. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. It is characterized by abnormal proliferation and metastasis of cells or mutant cells to surrounding tissues. Second to cardiovascular and cerebrovascular diseases. Tumor treatment methods include surgery, radiotherapy, and drug therapy ...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61K31/4375A61K31/444A61K31/4545A61K31/5377A61K31/496A61P35/00
CPCC07D471/14
Inventor 龙亚秋耿美玉许忠良王勇艾菁
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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