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Aryl heterocycle micromolecule compounds, derivatives thereof, and preparing methods and uses of the compounds and the derivatives

A technology of small molecular compounds and compounds, applied in the field of medicine, can solve problems such as hindering development, narrow therapeutic window, and poor solubility of natural products

Inactive Publication Date: 2015-02-11
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

Since the typical compound paclitaxel was used clinically in the 1990s, drug resistance caused by tumor cell mutations has been severe, and the poor solubility and narrow therapeutic window of natural products such as paclitaxel have hindered their development. It is urgent to find new molecules Entity [Miao ze-Hong, Ding Jian, Research advances on Circumventing Tumor Multidrug Resistance; Chin J Cancer, 2003, 22(8): 886-892.]

Method used

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  • Aryl heterocycle micromolecule compounds, derivatives thereof, and preparing methods and uses of the compounds and the derivatives
  • Aryl heterocycle micromolecule compounds, derivatives thereof, and preparing methods and uses of the compounds and the derivatives
  • Aryl heterocycle micromolecule compounds, derivatives thereof, and preparing methods and uses of the compounds and the derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: Preparation of compounds HYH11 and HYH57 (refer to the scheme shown in the following reaction formula)

[0109]

[0110] Step a: 2-Amino-6-chloropyridine (20g, 0.155mol, 1eq) was dissolved in DMF (300ml), at 0℃, N-bromosuccinimide (30.5g, 0.171mol, 1.1eq) Slowly add to the above mixture, react at room temperature for 2 hours, the reaction is complete. A large amount of water was added to precipitate a solid, filtered, washed with water, ethyl acetate / petroleum ether (V:V=1:4 (volume ratio)), and dried to obtain the crude product 2-amino-5-bromo-6-chloropyridine.

[0111] Step b: 2-Amino 5-bromo-6-chloropyridine (5.6g, 27mmol, 1eq) and N-ethylindole-5-boronic acid (5.36g, 28.3mmol, 1.05eq) were dissolved in toluene / ethanol (V :V=2:1) ​​In the mixed solvent (75ml), add potassium carbonate (5.6g, 40.5mmol, 1.5eq) aqueous solution (56ml, 100mg potassium carbonate per ml of water) and protect with nitrogen, add tetrakistriphenylphosphonium palladium ( 1.6g, 1.35mmol,...

Embodiment 2

[0118] Example 2 Preparation of compound HYH1

[0119] It was prepared in the same manner as in Example 1, except that phenylboronic acid was substituted for 2-benzyloxy-5-fluorophenylboronic acid pinacol ester.

[0120]

[0121] 1 H NMR(300MHz, CDCl 3 )δ7.57(d,J=8.3Hz,1H),7.46(s,1H),7.36(d,J=3.0Hz,2H),7.21-7.13(m,4H),7.13-7.07(m,2H) ), 6.86(d,J=8.6Hz,1H),6.56(d,J=8.3Hz,1H),6.43(d,J=3.1Hz,1H),4.52(s,2H),4.12(q,J =7.3Hz,2H),1.45(t,J=7.3Hz,3H).

Embodiment 3

[0122] Example 3 Preparation of compound HYH2

[0123] It was prepared in the same manner as in Example 1 except that 2-benzyloxyphenylboronic acid was substituted for 2-benzyloxy-5-fluorophenylboronic acid pinacol ester.

[0124]

[0125] 1 H NMR(300MHz, CDCl 3 )δ7.61(d,J=8.4Hz,1H), 7.55(d,J=1.2Hz,1H), 7.25(dd,J=8.0,4.5Hz,2H), 7.14(d,J=3.1Hz, 1H), 7.06(dd,J=7.1,1.6Hz,1H), 6.99(dd,J=7.1,5.7Hz,2H), 6.91(dd,J=7.9,1.4Hz,1H), 6.50(dd,J =9.6,5.8Hz,2H),6.42-6.30(m,1H),4.54(s,1H),4.16(dd,J=14.5,7.2Hz,2H),1.48(t,J=7.3Hz,3H) .

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Abstract

The invention discloses aryl heterocycle micromolecule compounds shown as a general structure formula I, derivatives or pharmaceutically acceptable salts and prodrugs thereof, and preparing methods and uses of the compounds, the derivatives, the pharmaceutically acceptable salts and the prodrugs of the compounds. The compounds have good physicochemical properties, and have antitumor activity. Research on mechanisms of action shows that: the compounds act on tubulin and are novel tubulin inhibitors. The general structure formula I is shown in the specification.

Description

Technical field [0001] The present invention relates to the field of medicine, in particular to a multi-substituted aryl heterocyclic small molecule compound, its derivative or pharmaceutically acceptable salt, prodrug molecule, and its preparation method and application. More specifically, the present invention relates to a class of polysubstituted aryl heterocyclic compounds, which are synthesized by the transition of the basic nucleus and the design of different substituents. This class of compounds has anti-tumor activity. The study of the mechanism of action shows that The compound acts on tubulin and is a new type of tubulin inhibitor. Background technique [0002] Tumor is one of the major diseases that affect human health. In recent years, the incidence of tumors is on the rise due to the influence of living environment, living habits and other factors. The National Cancer Institute (NCI) estimates that in 2013 there were more than 1.6 million new cancer patients in the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D403/04C07D403/14C07D409/14C07D213/73C07D413/04A61K31/4439A61K31/497A61K31/506A61K31/53A61K31/5377A61K31/4418A61K31/538A61P35/00
CPCC07D401/04C07D213/73C07D241/20C07D401/14C07D403/04C07D403/14C07D409/14C07D413/04
Inventor 胡有洪楼丽广陈红全海天李德文谢成英
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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