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Novel triazolopyrazine derivative and use thereof

A technology of azolopyrazine and derivatives, applied in the field of pharmaceutical compositions for the prevention and treatment of abnormal proliferative diseases

Active Publication Date: 2015-06-10
KOREA RES INST OF CHEM TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Also, it has been reported that hepatocyte growth factor receptor (c-Met) is directly related to cancers such as pancreatic cancer, glioma, and hepatocellular carcinoma, which have not been successfully treated, and in, it is reported that hepatocyte growth In the process of overexpression of factor receptor (c-Met), lung cancer caused by the activation of ERBB3 signal transduction system is resistant to gefitinib (Gefitinib; Iressa (trade name: Irresa)) Sex (J.A. Engelman, K. Zejnullahu et. al. Science, 316:1039-1043 (2007))

Method used

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  • Novel triazolopyrazine derivative and use thereof
  • Novel triazolopyrazine derivative and use thereof
  • Novel triazolopyrazine derivative and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0073] The preparation method of each compound

[0074]

[0075] (S)-(4-Benzylmorpholin-2-yl)methanol

[0076] Dissolve 38.3ml (270.22mmnol) of 2-(benzylamino)ethanol and 25g (270.22mmnol) of (R)-2-(chloromethyl)oxirane in H 2 After O / IPA (26ml+26ml), it was stirred overnight at room temperature. After that, slowly drop 130ml of Et dissolved in water over 1 hour 3 After NOH (35%), it was stirred at room temperature for 3 hours. After the reaction is over, adjust the pH to 9 with 1N HCl, and then use H 2 O and EA for extraction, drying (Na 2 SO 4 ), filtered, concentrated under reduced pressure, and the residue was purified by chromatography (EA:Hex=1:1), so as to obtain (S)-(4-benzylmorpholin-2-ylmethanol as a colorless oil (50%).

[0077] 1 H-NMR (300MHz, CDCl 3 ) δ 7.36-7.22 (m, 5H), 3.94-3.85 (m, 1H), 3.76-3.42 (m, 6H), 2.68 (d, J=11.2Hz, 2H), 2.19 (dt, J=3.1Hz , 11.2Hz, 1H), 2.00(t, J=10.9Hz, 1H)

[0078] (S)-(4-Benzylmorpholin-2-yl)methyl 4-toluenesulfonate ...

preparation example 1

[0379] Formulation Example 1: Tablet (direct compression)

[0380] After screening 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and made into tablets by compression.

preparation example 2

[0381] Formulation example 2: tablet (wet assembly)

[0382] After screening 5.0 mg of active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving polysorbate 80 (0.3 mg) in purified water, an appropriate amount of the above solution was added, followed by micronization. After drying, the granules were screened and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. Tablets are made by compressing the granules.

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PUM

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Abstract

The present invention relates to a novel triazolopyrazine derivative or a pharmaceutically acceptable salt thereof; to a pharmaceutical composition containing the same as an active ingredient for inhibiting c-Met tyrosine kinase activity; and to a pharmaceutical composition for preventing or alleviating a hyper-proliferative disorder. The present invention efficiently inhibits c-Met tyrosine kinase activity, and thus can be useful as a therapeutic agent against various hyper-proliferative disorders associated with excessive cellular proliferation and growth due to abnormal kinase activity, for example, cancer, psoriasis, rheumatoid arthritis, or diabetic retinopathy.

Description

technical field [0001] The present invention relates to novel triazolopyrazine derivatives having tyrosine kinase inhibitory activity and use for the prevention and treatment of various hyperproliferative disorders comprising the triazolopyrazine derivatives as active ingredients Pharmaceutical composition. Background technique [0002] Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The above-mentioned protein kinases play an important role in the signal transduction of growth factors leading to cell growth, differentiation and proliferation, therefore, the activity of protein kinases affects almost all modes of cell life. [0003] Abnormalities in cell signal transduction systems based on mutations or overexpression of protein kinases are initiated in non-life-threatening diseases such as psoriasis, and are closely related to stroma diseases with toxic (pathogenic) diseases suc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P35/00A61P3/00A61P9/00A61P29/00
CPCC07D487/04A61K31/4985A61P1/00A61P1/04A61P1/16A61P3/00A61P7/02A61P9/00A61P9/10A61P13/12A61P17/06A61P19/02A61P27/02A61P27/06A61P29/00A61P35/00A61P37/06A61P43/00A61K31/5377
Inventor 郑熙静河在斗赵成伦金亨来李光浩李廷玉催祥云朴志勳
Owner KOREA RES INST OF CHEM TECH
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