Nitrogen-containing biaromatic ring compounds as well as preparation method and application thereof

A compound and aromatic ring technology, applied in the field of nitrogen-containing biaryl ring compounds, can solve the problems of insufficient inhibitory ability and low affinity of liver cancer cells, and achieve the effects of good anti-cancer effect, strong inhibitory effect and good development prospect.

Active Publication Date: 2021-07-09
YUNNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the affinity of enoxacin to TRBP is not high enough (KD~12.56μM), and the inhibitory ability to liver cancer cells is still not strong enough

Method used

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  • Nitrogen-containing biaromatic ring compounds as well as preparation method and application thereof
  • Nitrogen-containing biaromatic ring compounds as well as preparation method and application thereof
  • Nitrogen-containing biaromatic ring compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The preparation method of nitrogen-containing biaryl ring derivatives of the present invention can be summarized as follows:

[0042] (a) For compounds of formula (I):

[0043]

[0044] Take compound A (0.1mmol) in a 25mL round bottom flask, dissolve it with 10mL of dichloromethane, then add SOCl 2 (0.12mmol), reflux at 45°C for 3h, then add the primary amine R 1 H (0.12mmol), Et 3 N (0.12mmol) and pyridine (0.01mmol) were reacted at room temperature for 8h. After the reaction was completed, the reaction solution was poured into water and washed with 3×25mL CH 2 Cl 2After extraction, the combined organic phases were washed with brine 3×25mL, followed by anhydrous Na 2 SO 4 Dry, concentrate and mix the sample with a rotary evaporator, pass through a 100-200 mesh silica gel column to obtain the compound with the structure (I), that is, compound 1-5 of Example 2-6.

[0045] Primary amine R 1 H is a commercially available raw material, purchased from Adamas, Acro...

Embodiment 2

[0057]

[0058] Take the nitrogen-containing biaryl acid obtained in Example 1, that is, compound (A), in a 25mL round-bottomed flask, dissolve it with 10mL of dichloromethane, and then add SOCl 2 (0.12mmol), reflux at 45°C for 3h, then add diethylethylenediamine (CAS: 100-36-7) (0.12mmol), Et 3 N (0.12mmol) and pyridine (0.01mmol) were reacted at room temperature for 8h. After the reaction was completed, the reaction solution was poured into water and washed with 3×25mL CH 2 Cl 2 After extraction, the combined organic phases were washed with brine 3×25mL, followed by anhydrous Na 2 SO 4 Dry, concentrate and mix the sample with a rotary evaporator, pass through a 100-200 mesh silica gel column (PE:EA=4:1) to obtain compound 1 as a yellow solid. 1 H-NMR (300MHz, CDCl 3 ): δ7.18-7.15(2H, d, J=8.7Hz), 6.97(1H, s), 6.74-6.71(2H, d, J=8.7Hz), 6.00(2H, s), 5.60(1H, s), 3.76(3H, s), 3.13-3.10(2H, q, J=5.1Hz), 2.97(6H, s), 2.35-2.28(4H, q, J=7.2Hz), 2.18-2.14(2H , t, J=6.5Hz...

Embodiment 3

[0060]

[0061] Take the nitrogen-containing biaryl acid obtained in Example 1, that is, compound (A), in a 25mL round bottom flask, dissolve it with 10mL of dichloromethane, then add EDCI (0.12mmol) and HOBt (0.12mmol), and then add Benzylamine (CAS: 100-46-9) (0.12mmol) and DMAP (0.01mmol) were reacted at room temperature for 8h. After the reaction was completed, the reaction solution was poured into water and washed with 3×25mL CH 2 Cl 2 After extraction, the combined organic phases were washed with brine 3×25mL, followed by anhydrous Na 2 SO 4 After drying, it was concentrated and mixed with a rotary evaporator, and passed through a 100-200 mesh silica gel column (PE:EA=6:1) to obtain compound 2 as a white solid. 1 H-NMR (300MHz, CDCl 3 ): δ7.18-7.16(3H, m), 7.12(1H, s), 7.09-7.08(1H, m), 6.86-6.85(2H, m), 6.67-6.64(2H, d, J=8.7Hz ), 5.99(2H, s), 5.43(1H, s), 4.24-4.22(2H, d, J=5.1Hz), 3.74(3H, s), 3.97(6H, s). 13 C NMR (75MHz, CDCl 3 ):δ168.43,149.99, 148.29,141...

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Abstract

The invention relates to nitrogen-containing biaromatic ring compounds, a preparation method and an application, namely a pharmaceutical composition consisting of the compound as an effective component, a preparation method and an application of the compound in resisting liver cancer. A series of nitrogen-containing biaromatic ring compounds with novel structures are synthesized, generation of miRNA is induced by regulating TRBP, a good anti-liver cancer effect is shown, small molecules have a relatively strong inhibiting effect on proliferation of liver cancer cells, individual compounds even have a better curative effect than enoxacin, no similar structure has the effect before, and the compounds have good development prospects.

Description

technical field [0001] The application relates to nitrogen-containing biaryl ring compounds, derivatives, synthesis methods, applications, and medicines, and belongs to the field of chemistry and medicines. Background technique [0002] Liver cancer ranks fourth in cancer-related mortality and sixth in incidence of all cancers in the world. Patients with liver disease are prone to hepatocellular carcinoma, mainly due to hepatitis B or C virus infection or hepatitis B infection. Under these conditions, DNA mutations frequently occur. However, systemic small molecule drugs inhibit receptor tyrosine kinases and do not directly target these mutated genes or proteins. Multikinase inhibitors have been approved for the treatment of HCC, including first-line treatment sorafenib and lenvatinib; however, the 1-year median survival of patients remains low. Treatments currently in development include angiogenesis inhibitors and immune checkpoint inhibitors, which have a similar 1-yea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/68C07D495/04A61P31/18A61P1/16A61P35/00A61P35/04A61K31/36A61K31/4188
CPCC07D317/68C07D495/04A61P31/18A61P35/00A61P35/04A61P1/16C07B2200/07Y02P20/55
Inventor 肖伟烈王飞李一明周宗元曹碧云李晓莉张芮菡张兴杰
Owner YUNNAN UNIV
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