C-Met/HDAC double-target inhibitor, synthesis method and application thereof

A synthesis method and technology of c-met are applied in the field of medicine and achieve the effects of mild conditions, improved utilization efficiency and therapeutic effect, and high yield

Inactive Publication Date: 2019-08-16
北京凯恩梅格医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibitors with dual targets of c-Met and HDAC have synergistic anti-cancer effects, but there is no research on a single drug with these two targets in the prior art

Method used

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  • C-Met/HDAC double-target inhibitor, synthesis method and application thereof
  • C-Met/HDAC double-target inhibitor, synthesis method and application thereof
  • C-Met/HDAC double-target inhibitor, synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The structural formula of the c-Met / HDAC dual-target inhibitor in this example is as follows:

[0041]

[0042] Among them, the linker is n=4.

[0043] The synthesis method of the dual-target inhibitor of this embodiment is as follows:

[0044] (1) at first synthetic intermediate (a) reaction equation is as follows:

[0045]

[0046] At room temperature, crizotinib (900.6mg, 2mmol), methyl 5-bromovalerate (468.0mg, 2.4mmol) and potassium carbonate (830.0mg, 6mmol) were added to 30ml of DMF, stirred at room temperature for 24h , TLC (thin layer chromatography) detection (volume ratio of dichloromethane and methanol 10:1) raw material reaction is complete. Add 30ml of water to the reaction solution, stir until clear liquid, then extract with ethyl acetate (100ml) in 2 equal portions, wash the extract with saturated brine (100ml) in 2 equal portions, dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure and purified by c...

Embodiment 2

[0059] In the structural formula of the c-Met / HDAC dual-target inhibitor in this example, the linker is n=5, synthesized according to the method of Example 1, replacing methyl 5-bromopentanoate with methyl 6-bromohexanoate, and routinely adjusted the test parameters to obtain the target product (I-2). The 1HNMR data is as follows:

[0060] 1H NMR (400MHz, DMSO-d6): ppm: 10.44(s, 1H, N-OH), 7.96(s, 1H), 7.75(d, J=1.68Hz, 1H), 7.56-7.59(dd, J= 4.76Hz, 5.04Hz, 1H), 7.52(s, 1H), 7.44(t, J=8.68Hz, 8.68Hz, 1H), 6.89(d, J=1.4Hz, 1H), 6.06-6.11(q, J =6.48Hz,6.72Hz,6.48Hz,1H),5.67(s,2H),4.06-4.13(m,1H),2.95(d,J=10.96Hz,2H),2.28-2.31(t,J=6.72 Hz, 7.56Hz, 2H), 1.89-2.08(m, 8H), 1.80(d, J=6.72Hz, 3H), 1.22-1.54(m, 6H).

Embodiment 3

[0062] In the structural formula of the c-Met / HDAC dual-target inhibitor in this example, the linker is n=6, synthesized according to the method of Example 1, replacing methyl 5-bromopentanoate with methyl 7-bromoheptanoate, and routinely adjusting the test parameters to obtain the target product (I-3), the 1HNMR data is as follows:

[0063] 1HNMR(400MHz,DMSO-d6):ppm:10.37(s,1H,),8.70(s,1H),7.96(s,1H),7.75(d,J=1.68Hz,1H),7.57(dd,J =4.76Hz, 5.04Hz, 1H), 7.52(s, 1H), 7.44(t, J=8.68Hz, 1H), 6.90(d, J=1.4Hz, 1H), 6.06-6.11(q, J=6.44 Hz,6.72Hz,6.44Hz,1H),5.66(s,2H),4.05-4.11(m,1H),2.94(d,J=11.48Hz,2H),2.29(t,J=7Hz,2H), 1.89-2.06 (m, 8H), 1.80 (d, J=6.72Hz, 3H), 1.23-1.50 (m, 8H).

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Abstract

The invention discloses a c-Met / HDAC double-target inhibitor as well as a synthesis method and application thereof. A c-Met inhibitor crizotinib and an HDAC inhibitor vorinostat are used as lead structures; a single-structure double-target inhibitor is designed, the structure of the crizotinib is used as a cap-shaped structure of an HDAC inhibitor, so that an aniline acyl group in a vorinostat structure is replaced, and a hydroximic acid structure in the vorinostat is reserved as a chelating group of metal zinc ions; the single-structure double-target inhibitor is designed by introducing linking groups with different structures between the two inhibitors and utilizing the principle of pharmacophore splicing. The obtained double-target inhibitor has a good inhibition effect on both c-Met and HDAC, and can synergistically inhibit c-Met and HDAC. The preparation method disclosed by the invention is simple, mild in condition and high in yield.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a c-Met / HDAC dual-target inhibitor and its synthesis method and application. Background technique [0002] In the HGF / MET signaling pathway, HGF activates c-Met, activates the downstream RAS–RAF–MEK–MAPK and PI3K–AKT signaling pathways, and makes the proto-oncogene (c-Myc) and G1 / S-specific cycle protein- The expression of D1 (cyclin D1) increases, and the activity of cell cycle inspection proteins p21 and p27 decreases, promoting cell cycle progression and survival. Histone deacetylase (HDAC) is also a key regulator of cell cycle progression. Inhibiting HDAC can promote the expression of cell cycle check proteins p21 and p27, block the cell cycle, reduce the transcription of cyclin D1, and accelerate the degradation of c-Myc . Therefore, c-Met inhibitors and HDAC inhibitors have a certain synergistic effect on the mechanism of action on cancer. [0003] The cryst...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D405/14A61P35/00A61K31/4545
CPCA61P35/00C07D401/14C07D405/14
Inventor 不公告发明人
Owner 北京凯恩梅格医药科技有限公司
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