Novel c-Met/HDAC double-target inhibitor, and synthetic method and application thereof

A synthesis method and technology of c-met are applied in the field of medicine to achieve the effects of improving utilization efficiency and therapeutic effect, simple preparation method and high yield

Active Publication Date: 2019-07-16
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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  • Novel c-Met/HDAC double-target inhibitor, and synthetic method and application thereof
  • Novel c-Met/HDAC double-target inhibitor, and synthetic method and application thereof
  • Novel c-Met/HDAC double-target inhibitor, and synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The structural formula of the novel c-Met / HDAC dual-target inhibitor in this example is as follows:

[0043]

[0044] Among them, the linker is n=2.

[0045] The synthesis method of the novel c-Met / HDAC dual-target inhibitor in this example is as follows:

[0046] (1) at first synthetic intermediate (a) reaction equation is as follows:

[0047]

[0048] At room temperature, 4-pyrazoleboronic acid pinacol ester (3.9g, 20.0mmol) was dissolved in 30.0mlDMF, potassium carbonate (5.5g, 40.0mmol) and 3-bromopropionate methyl ester (4.0g, 24.0mmol), after stirring at room temperature for 24 hours, TLC monitoring (the volume ratio of petroleum ether to ethyl acetate is 2:1) the reaction raw material still remains. Add 30ml of water to the reaction mixture, stir until clear liquid, then extract with ethyl acetate (50ml×2), wash the extract with saturated brine (50ml×2), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate After concentration, the r...

Embodiment 2

[0063] In the structural formula of the c-Met / HDAC dual-target inhibitor in this example, the linker is n=3, synthesized according to the method of Example 1, replacing methyl 3-bromopropionate with methyl 4-bromobutyrate, and adjusting other test parameters routinely to obtain the target product (I-2), the 1HNMR data is as follows :

[0064] 1HNMR (400MHz, DMSO-d6):ppm: 10.43(s,1H),7.88(s,1H),7.74(d,J=1.68Hz,1H),7.57(dd,J=4.76Hz,4.76Hz,1H ),7.53(s,1H),7.45(t,J=8.68Hz,8.68Hz 1H),6.89(s,1H),6.06-6.11(q,J=6.72Hz,1H),5.68(s,2H) , 4.06 (t, J = 6.72Hz, 5.92Hz, 2H), 1.92-1.99 (m, 4H), 1.79 (d, J = 6.44Hz, 3H).

Embodiment 3

[0066] In the structural formula of the c-Met / HDAC dual-target inhibitor in this example, the linker is n=4, synthesized according to the method of Example 1, replacing methyl 3-bromopropionate with methyl 5-bromovalerate, and routinely adjusting other test parameters to obtain the target product (I-3), the 1HNMR data is as follows :

[0067] 1 HNMR (400MHz, DMSO-d 6 ):ppm:10.38(s,1H),8.78(s,1H),7.87(s,1H),7.73(d,J=1.68Hz,1H),7.57(dd,J=4.76Hz,5.04Hz,1H ),7.52(s,1H),7.44(t,J=8.96Hz,8.86Hz,1H),6.88(d,J=1.44Hz,1H),6.06-6.11(q,J=6.88Hz,6.72Hz, 6.72Hz, 1H), 5.68(s, 2H), 4.06(t, J=6.72Hz, 7Hz, 2H), 1.97(t, J=7.32Hz, 7.28Hz, 2H), 1.80(d, J=6.72Hz ,3H), 1.69-1.76(m,2H), 1.40-1.47(m,2H).

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Abstract

The invention discloses a novel c-Met / HDAC double-target inhibitor, and a synthetic method and an application thereof. The inhibitor provided by the invention has the following advantages: with a c-Met inhibitor namely Crizotinib and an HDAC inhibitor namely Vorinostat as precursor structures, a double-target inhibitor with a single structure is designed; the Crizotinib is used to remove the structure except a piperidine ring as a cap-like structure of the HDAC inhibitor to replace an aniline acyl group in a Vorinostat structure; a hydroxamic acid structure in the Vorinostat is retained as a chelating group of a metal zinc ion; linking groups with different structures are introduced between the Crizotinib and the Vorinostat; by utilization of the principle of pharmacophore combination, thedouble-target inhibitor with the single structure is designed; and the obtained double-target inhibitor has good inhibitory effect on c-Met and HDAC, and can synergistically inhibit c-Met and HDAC.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a novel 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61P35/00
CPCA61P35/00C07D401/04
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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