A c-met/hdac dual-target inhibitor based on the structure of crizotinib and its synthesis method and application

A technology of crizotinib and a synthesis method, which is applied in the field of medicine and achieves the effects of mild conditions, high yield and simple preparation method

Active Publication Date: 2020-08-28
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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  • A c-met/hdac dual-target inhibitor based on the structure of crizotinib and its synthesis method and application
  • A c-met/hdac dual-target inhibitor based on the structure of crizotinib and its synthesis method and application
  • A c-met/hdac dual-target inhibitor based on the structure of crizotinib and its synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The structural formula of the c-Met / HDAC dual-target inhibitor based on the structure of crizotinib 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] Dissolve monomethyl adipate (320.3mg, 2.0mmol) in 30ml DMF, then add HATU (912.6mg, 2.4mmol) and DIPEA (517.0mg, 4.0mmol), stir for 15min under ice bath conditions, then add Crizotinib (945.7mg, 2.1mmol) was stirred at room temperature for 4h, and TLC monitoring (volume ratio of dichloromethane to methanol: 10:1) showed that the reaction of the raw material was basically complete. Add 30ml of water and 80ml of ethyl acetate, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Column chromatography of the resi...

Embodiment 2

[0059] In the structural formula of the c-Met / HDAC dual-target inhibitor based on the structure of crizotinib in this example, the linker is n=5, synthesized according to the method of Example 1, monomethyl adipate was replaced by monomethyl pimelate, and the test parameters were routinely adjusted to obtain the target product (I-2). The 1HNMR data were as follows:

[0060] 1HNMR (400MHz, DMSO-d6):ppm: 10.39(s,1H,),8.78(s,1H),7.99(s,1H),7.76(d,J=1.68Hz,1H),7.54-7.59(m ,2H),7.45(t,J=8.68Hz,8.68Hz,1H),6.90(d,J=1.4Hz,1H),6.06-6.11(q,J=6.44Hz,6.72Hz,6.44Hz,1H) ,5.69(s,2H),4.46-4.49(d,J=12.36Hz,1H),4.36-4.42(m,1H),3.96(d,J=13.44Hz,1H),3.17(t,J=11.80 Hz,12.6Hz,1H),2.71(t,J=12.36Hz,11.2Hz,1H),2.33(t,J=7.6Hz,7.28Hz,2H),1.93-2.06(m,4H),1.69-1.86 (m,5H), 1.46-1.54(m,4H), 1.22-1.30(m,2H).

Embodiment 3

[0062] In the structural formula of the c-Met / HDAC dual-target inhibitor based on the structure of crizotinib in this example, the linker is n=6, synthesized according to the method of Example 1, monomethyl adipate was replaced by monomethyl suberate, and the test parameters were routinely adjusted to obtain the target product (I-3). The 1HNMR data were as follows:

[0063] 1H NMR (400MHz, DMSO-d6): ppm: 10.40(s, 1H), 8.78(s, 1H), 7.98(s, 1H), 7.75(d, J=1.52Hz, 1H), 7.54-7.59(m ,2H),7.45(t,J=6.86Hz,6.86Hz,1H),6.90(d,J=1.68Hz,1H),6.06-6.11(q,J=6.72Hz,6.76Hz,6.44Hz,1H) ,5.69(s,2H),4.47(d,J=12.6Hz,1H),4.35-4.43(m,1H),3.95(d,J=13.44Hz,1H),3.13-3.20(t,J=12.32 Hz, 2.04Hz, 1H), 2.68-2.74(t, J=11.36Hz, 11.92Hz, 1H), 2.31-2.35(t, J=7.56Hz, 7.28Hz, 2H), 1.92-2.06(m, 4H) ,1.68-1.86(m,5H),1.07-1.50(m,8H).

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Abstract

The invention discloses a c-Met / histone deacetylase (HDAC) double-target inhibitor based on a crizotinib structure, and a synthesis method and application of the double-target inhibitor. According tothe inhibitor disclosed by the invention, c-Met inhibitor crizotinib and HDAC inhibitor vorinostat are taken as a lead structure to design a double-target inhibitor with a single structure; the crizotinib structure is used as a hat-shaped structure of the HDAC inhibitor to replace aniline acyl in a vorinostat structure; a hydroximic acid structure in the vorinostat is retained as a chelating groupof metal zinc ions; connecting groups with different structures are introduced between the the crizotinib structure and the hydroximic acid structure; and the double-target inhibitor with a single structure is designed through the principle of pharmacophores combination, so that the obtained double-target inhibitor has good inhibition effects on c-Met and HDAC, and can be used for synergisticallyinhibiting the c-Met and HDAC.

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 based on the structure of crizotinib 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/4545A61P35/00
CPCA61P35/00C07D401/14
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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