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Compound with multi-target inhibition effect, composition, functional molecule and application of compound

A compound and ring atom technology, applied in the field of multi-target inhibitory compounds, can solve problems such as poor therapeutic effect

Active Publication Date: 2021-07-16
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the reported dual-target inhibitors of BET and kinases were found accidentally, or were further modified from these known inhibitors, and the therapeutic effect was poor, which limited their application.

Method used

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  • Compound with multi-target inhibition effect, composition, functional molecule and application of compound
  • Compound with multi-target inhibition effect, composition, functional molecule and application of compound
  • Compound with multi-target inhibition effect, composition, functional molecule and application of compound

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preparation example Construction

[0133] The present invention also provides a preparation method of the above-mentioned compound, comprising the following steps:

[0134] S101: providing a compound of the structure shown in formula (I-1);

[0135]

[0136] Wherein, P represents halogen;

[0137] Wherein, the definition of each group in the structural compound shown in formula (I-1) is as above, and will not be repeated here.

[0138] S102: providing a compound of structure shown in formula (I-2);

[0139]

[0140] The definition of each group in the structural compound shown in formula (I-2) is as above, and will not be repeated here.

[0141] Further, step S102 includes the following steps:

[0142] S1021: making compound A and amino acid NH 2 R 1 CHCOOH is reacted to obtain compound B;

[0143] S1022: Compound B is subjected to reduction and ring closure with hydrosulfite to obtain compound C;

[0144] S1023: Reductive amination of compound C with the corresponding ketone to obtain compound D; ...

Embodiment 1

[0195]

[0196] (a) Compound 1A (25g, 113.64mmol), D-alanine (11.12g, 125.0mmol), potassium carbonate (17.25g, 125.0mmol) were dissolved in 500ml of ethanol: water = 3: 1 mixed solvent, 80 Heat to reflux at ℃ for 8 hours, monitor the reaction with a TLC plate, cool to room temperature after the reaction, evaporate the solvent, dissolve in water, adjust the pH to 1-2 with 1N HCl, a large amount of yellow solid precipitates, filter, and wash with 200ml petroleum ether The solid was dried in a vacuum oven to obtain 28.7 g of a yellow solid, that is, compound 1B, with a yield of 88%.

[0197] 1 H NMR (400MHz, CDCl 3 )δ8.35(d, J=6.9Hz, 1H), 8.06(d, J=9.1Hz, 1H), 6.90(s, 1H), 6.85(d, J=9.2Hz, 1H), 4.33(p, J=7.0Hz, 1H), 1.67 (d, J=7.0Hz, 3H).

[0198] (b) Compound 1B (28.7g, 99.31mmol), potassium carbonate (27.41g, 198.62mmol) was dissolved in 500ml of water, sodium dithionite (86.45g, 496.55mmol) was slowly added in batches, and reacted at 60°C for 8h to obtain colorless The ...

Embodiment 2

[0217]

[0218] The compound of Example 2 was prepared in the same manner as in Example 1, except that pyridine-3-boronic acid was used instead of phenylboronic acid in step (j) of Example 1.

[0219] 1 H NMR (400MHz, DMSO-d 6 )δ9.67(s, 1H), 9.35(d, J=2.2Hz, 1H), 8.74(dd, J=4.8, 1.6Hz, 1H), 8.59(d, J=5.2Hz, 1H), 8.49( dt, J=8.0, 2.0Hz, 1H), 7.63–7.54(m, 2H), 7.47(d, J=5.1Hz, 1H), 7.30(dd, J=8.7, 2.1Hz, 1H), 7.03(d ,J=8.7Hz,1H),4.11(q,J=6.7Hz,1H),3.89(p,J=6.6Hz,1H),3.26(s,3H),1.28(d,J=6.6Hz,3H ), 1.21(d, J=6.5Hz, 3H), 0.99(d, J=6.7Hz, 3H).LC-MS(ESI)[M+H] + :388.22.

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Abstract

The invention relates to a compound with a multi-target inhibition effect, a composition, a functional molecule and application of the compound. The compound has a structure shown in a formula (I), wherein K in the formula is as shown in the specification. The compound has an inhibition effect on BET and kinase double targets and can simultaneously act on different signal channels of tumor cell growth to achieve a better treatment effect.

Description

[0001] This application claims the priority of the Chinese patent application submitted to the China Patent Office on January 15, 2020, with the application number 2020100400404, and the title of the invention is "multi-target inhibitory compound, composition, functional molecule and its application", all of which The contents are incorporated by reference in this application. technical field [0002] The invention relates to the technical field of medicinal chemistry, in particular to multi-target inhibitory compounds, compositions, functional molecules and applications thereof. Background technique [0003] Complex diseases can often be attributed to the dysregulation of multiple signaling pathways and physiological processes, which are difficult to be cured by the specific modulation of a single target. Multidrug inhibition, as an effective strategy, has received extensive attention in current anticancer drug development. Compared with single-target or combination therap...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D403/12C07D487/04C07D403/14C07D401/12C07D401/14C07D413/12C07D413/14A61K31/506A61K31/498A61P35/00A61P43/00
CPCC07D471/04C07D403/12C07D487/04C07D403/14C07D401/12C07D401/14C07D413/12C07D413/14A61P35/00A61P43/00A61K31/498A61K31/506A61K31/497A61K31/422A61P35/04
Inventor 熊兵沈竞康缪泽鸿陈丹琦吕铠铠曹丹燕李艳莲王昕陈驎
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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