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5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and preparation method and use of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds

A technology of naphthalene and compound, which is applied to 5,8-disubstituted-1,6-naphthalene-7-carbonamide compound and dimer compound thereof. Block tumor cell growth and other issues

Inactive Publication Date: 2012-07-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and preparation method and use of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds
  • 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and preparation method and use of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds
  • 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and preparation method and use of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds

Examples

Experimental program
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Effect test

preparation example Construction

[0102] The preparation method of compound S2-1 is similar to that of compound 8-1, except that p-3-chlorobenzylamine is used instead of 2-chlorobenzylamine. Yellow solid, yield: 75-85%. 1 H NMR (300MHz, CDCl 3 ): δ9.20(d, J=4.2Hz, 1H), 8.55(d, J=8.4Hz, 1H), 8.20(m, 1H), 7.73(dd, J=4.2, 8.4Hz, 1H), 7.38 (s, 1H), 7.30 (m, 1H), 7.22 (m, 3H), 4.68 (d, J=6.3Hz, 2H).

[0103] Toluene-4-sulfonic acid 5-bromo-7-(3-chloro-benzylcarbamoyl)-1,6-naphthalene-8-carboxylate (S2-2)

[0104]

[0105] The preparation method of compound S2-2 is similar to that of compound 9-1, except that compound S2-1 is used instead of compound 8-1. White solid, yield: 85-95%. 1 H NMR (CDCl 3 ): δ9.04(d, 1H, J=4.2Hz), 8.57(d, 1H, J=8.4Hz), 8.01(m, 1H), 7.92(d, 2H, J=8.4Hz), 7.69(dd , 1H, J=4.2, 8.4Hz), 7.36-7.28(m, 6H), 4.61(d, 2H, J=6.6Hz), 2.46(s, 3H).

[0106] 8-((1r,4r)-4-aminocyclohexylamino)-N-(3-chloro-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S2)

[0107]

[0108] The pre...

experiment Embodiment 1

[0437] Experimental example 1: Inhibitory effect of 5,8-disubstituted-1,6-naphthyridine-7-carbonamide compounds and their dimer compounds on the proliferation of human cancer cell lines in vitro

[0438] Cell lines: human breast cancer cell line MDA-MB-435, human ovarian cancer cell line SK-BR-3, human malignant melanoma cell line A375, human skin squamous cell line A431, human colon cancer cell line HT-29, Human lung cancer cell line A-549, human liver cancer cell line BEL-7402, human pancreatic cancer cell line BXPC3, human acute myeloid leukemia cell line HL-60, and human prostate cancer cell line PC-3 were purchased from American Standard Biological Collection .

[0439] Method: sulforhodamine B (SRB) method, specifically as follows: a certain number of different types of tumor cells in the logarithmic growth phase were inoculated in 96-well culture plates, and after 24 hours of cell attachment, different concentrations of For the test compound of the present invention, t...

Embodiment 2

[0466] Example 2: Inhibition of 5,8-disubstituted-1,6-naphthyridine-7-carbonylamides and their dimer compounds on five protein tyrosine kinases

[0467] Protein tyrosine kinase: c-Src and EGFR are expressed by the insect baculovirus expression system in our laboratory, and the active intracellular kinase domain tyrosine kinase protein obtained by affinity purification with Ni-NTA column has been detected Meet the experimental requirements, subpackage at -70°C, and store. KDR, Flt-1 were purchased from Upstate Company (Waltham, MA, USA); ErbB2 was purchased from Calbiochem Company (Darmstadt, Germany).

[0468] Experimental method: The enzyme-linked immunosorbent assay (ELISA) method was used for the test of tyrosine kinase activity, as follows: first, the enzyme reaction substrate Poly(Glu, Tyr) 4:1 (20 μg / mL, overnight at 37°C) was coated with the enzyme Standard plates, washed and dried for later use. When performing the reaction, add 80 μL of ATP solution diluted with rea...

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Abstract

The invention discloses 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, a preparation method and use of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and pharmaceutical compositions containing the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds. More specifically, the invention discloses the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds expressed by structural formulae I and II or III, the dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the preparation method of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and provides the use of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the pharmaceutical compositions containing the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds in the treatment of diseases related to protein tyrosine kinase, in particular to c-Src, such as tumor diseases, by serving as a multi-target spot protein tyrosine kinase inhibitor.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to 5,8-disubstituted-1,6-naphthyridine-7-carbonamide compounds and their dimer compounds and their preparation methods. The present invention also relates to 5,8 -Disubstituted-1,6-naphthyridine-7-carbonamide compounds and their dimer compounds and pharmaceutical compositions containing the compounds are used as multi-target tyrosine protein kinase inhibitors for breast cancer, ovary Cancer, malignant melanoma, skin squamous cell carcinoma, colon cancer, lung cancer, liver cancer, pancreatic cancer, acute myeloid leukemia, prostate cancer and other diseases related to tyrosine kinase, especially c-Src. 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 cerebr...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61K31/4375A61K31/496A61P35/00A61P35/02
Inventor 龙亚秋丁健王勇谢华曾立凡
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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