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Biaryl pyridine deubiquitinating enzyme inhibitor as well as preparation method and application thereof

A pyridine and aryl technology, applied in the application field of preparing anti-tumor drugs, can solve the problems of low efficiency, unsatisfactory micromolar level specificity, etc.

Active Publication Date: 2018-04-13
杭州市西溪医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] DUBs as an anti-tumor drug target is a current research hotspot, but the inhibitors targeting DUBs have low efficacy and the IC of most inhibitors 50 At the micromolar level and unsatisfactory specificity, there is currently no highly specific DUBs inhibitor that has been officially approved for marketing in clinical practice

Method used

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  • Biaryl pyridine deubiquitinating enzyme inhibitor as well as preparation method and application thereof
  • Biaryl pyridine deubiquitinating enzyme inhibitor as well as preparation method and application thereof
  • Biaryl pyridine deubiquitinating enzyme inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1 3-bromo-5-(4-methoxybenzylthio)pyridine

[0104]

[0105] 4-Methoxybenzylthiol (32.55g, 211.07mmol) was dissolved in 500mL dimethylformamide, NaH (9.29g, 232.18mmol) was added, and reacted at 20°C for 30min, then, 3,5-dibromopyridine ( 1,50.00g, 211.07mmol), react at 20°C for 16 hours, add 100mL of water to terminate the reaction, extract with ethyl acetate (100mL x 3), wash the organic layer with water (200mL x 3), dry over anhydrous sodium sulfate, and recover under reduced pressure The solvent was separated by column chromatography to obtain 48.0 g of white solid (compound 2), with a yield of 73%. 1 HNMR (400MHz, CDCl 3 ): δ=8.38(d, J=2.1Hz, 1H), 8.31(d, J=1.9Hz, 1H), 7.60(t, J=2.0Hz, 1H), 7.13-7.08(m, 2H, Ar- H),6.79-6.73(m,2H,Ar-H),4.00(s,2H,CH 2 ),3.71(s,3H,CH 3 ).ESI-MS: m / z=311[M+H] + .

Embodiment 2

[0106] Example 2 3-(2-isopropylphenyl)-5-(4-methoxybenzylthio)pyridine

[0107]

[0108] Compound 2 (15.00g, 48.35mmol), 2-isopropylphenylboronic acid (8.72g, 53.19mmol), Pd(dppf)Cl 2 (3.54g, 4.84mmol) and sodium carbonate (10.25g, 96.71mmol) were added to dioxane / water (10 / 1) 150mL, stirred and reacted at 100°C for 16 hours, after the reaction was completed, the solvent was recovered under reduced pressure, and 20mL of water was added , extracted with dichloromethane (50mL x 3), dried over anhydrous sodium sulfate, recovered the solvent under reduced pressure, and obtained 13.6g of yellow oil (compound 3) by column chromatography, with a yield of 78%. 1 H NMR (400MHz, CDCl 3 ): δ=8.52(d, J=2.2Hz, 1H, pyridine-H), 8.36(d, J=1.9Hz, 1H, pyridine-H), 7.48(t, J=2.1Hz, 1H, pyridine-H ),7.42-7.35(m,2H,Ar-H),7.25-7.16(m,2H,Ar-H),7.11-7.02(m,1H,Ar-H),6.81(d,J=8.6Hz, 2H,Ar-H),4.10(s,2H,CH 2 ),3.78(s,3H,CH 3 ),2.86(q,J=13.7,6.8Hz,1H,CH),1.15(t,J=10.8Hz,6H,CH 3 ).ESI-MS: m / z=359...

Embodiment 3

[0109] Example 3 3-benzyl-5-(4-methoxybenzylthio)pyridine

[0110]

[0111] Synthesis of Compound 4: Using Compound 2 and 2-ethylphenylboronic acid as raw materials, the synthesis and post-treatment were the same as in Example 2. 11.7 g of a yellow oil (compound 4) was obtained, yield 72%. 1 H NMR (400MHz, CDCl 3): δ=8.52(d, J=2.1Hz, 1H, pyridine-H), 8.38(d, J=1.8Hz, 1H, pyridine-H), 7.50(t, J=2.0Hz, 1H, pyridine-H ),7.39–7.15(m,5H,Ar-H),7.10(d,J=7.7Hz,1H,Ar-H),6.81(d,J=8.6Hz,2H,Ar-H),4.11(d ,J=7.4Hz,2H,CH2),3.78(s,3H,CH3),2.50(q,J=7.5Hz,2H,CH2),1.07(t,J=7.5Hz,3H,CH3).ESI- MS:m / z=336.5[M+H] + .

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Abstract

The invention designs and synthesizes a biaryl pyridine deubiquitinating enzyme inhibitor. The biaryl pyridine deubiquitinating enzyme inhibitor has the structure which is shown as a general formula (I). The biaryl pyridine deubiquitinating enzyme inhibitor provided by the invention has good inhibiting activity on deubiquitinating enzyme, and has a good in-vitro proliferation inhibiting effect ontumour cells, such as K562 cells, Hep-G2 cells, HCT-116 cells, WSD-DLCL cells and A549 cells. According to the compound disclosed by the invention, raw materials required for synthesis are easily obtained; a route design is reasonable; reaction conditions are mild; the yield in each step is high; the operation is simple and convenient; the biaryl pyridine deubiquitinating enzyme inhibitor is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine, in particular, the invention relates to a new class of biarylpyridine deubiquitinase inhibitors, its preparation method and application, and the application of the compound in the preparation of antitumor drugs. Background technique [0002] Malignant tumor is one of the major diseases that seriously endanger human health. The prevention and treatment of tumors has become a subject of widespread attention worldwide, and the research and development of antitumor drugs is also in an extremely urgent need. The morbidity and mortality of various tumors continue to rise, and the treatment of tumors is facing great challenges (CA-Cancer.J.Clin.2016,66,115-132). The high morbidity and mortality of tumors also provides a broad market space for tumor therapeutic drugs. In 2014, the global anti-tumor drug market has reached 60 billion US dollars. Therefore, it is imminent to find new drug targets for tumor treatm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/70C07D417/12C07D333/42C07D333/44C07D409/12C07D417/14C07D409/14C07D405/14C07D401/14C07D413/12C07D405/06C07D413/14A61K31/44A61K31/4439A61K31/381A61K31/4436A61K31/4545A61K31/444A61K31/495A61K31/496A61K31/443A61K31/454A61P35/00A61P35/02
CPCC07D213/70C07D333/42C07D333/44C07D401/14C07D405/06C07D405/14C07D409/12C07D409/14C07D413/12C07D413/14C07D417/12C07D417/14Y02P20/55
Inventor 蔡兆斌张建康席建军邵益丹潘旭旺赵艳梅何若愚刘寿荣茅维嘉方红英俞哲黄斌朱元东柯云玲史婷婷琚立萍庄让笑
Owner 杭州市西溪医院
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