Apogossypol derivatives and preparation method thereof, and application of apogossypol derivatives in antitumor and immunoregulation

A technology of apogossypol and its derivatives, which is applied in the field of organic synthesis and medicine, and can solve the problems of less research

Active Publication Date: 2017-05-10
江苏度未生物工程科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no effective small molecule inhibitors acting on the IL-17A-IL-17RA signaling pathway, and there are very few related studies. As of 2016, there are only two compounds reported in the literature that can inhibit IL-17A Therefore, it is urgent to develop small molecule inhibitors of IL-17A to broaden the clinical drug options

Method used

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  • Apogossypol derivatives and preparation method thereof, and application of apogossypol derivatives in antitumor and immunoregulation
  • Apogossypol derivatives and preparation method thereof, and application of apogossypol derivatives in antitumor and immunoregulation
  • Apogossypol derivatives and preparation method thereof, and application of apogossypol derivatives in antitumor and immunoregulation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 5,5'-bis{3-(cyclohexylamine)imidazo[1,2-a]pyridyl}-3,3'-dimethyl-[2,2'-binaphthyl]-1,1 Preparation of ',6,6',7,7'-hexahydroxyl (LYZ-1)

[0028]

[0029] Weigh compound 1 (103mg, 0.2mmol, 1.0eq), 2-aminopyridine (45mg, 0.48mmol, 2.4eq), scandium trifluoromethanesulfonate (Sc(OTf) 3) (10mg, 0.02mmol, 0.1eq) in a round bottom flask was dissolved by adding 0.5mL of anhydrous DCM / MeOH (v / v=2:1) ​​solution. After 30min, cyclohexaneisonitrile (52mg, 0.48mmol, 2.4eq) was added and stirred at room temperature. The reaction was monitored by TLC, and the product was separated by column chromatography as the raw material for the next reaction. Under anhydrous and oxygen-free conditions, ethanethiol 2mL was added to anhydrous aluminum chloride (667mg, 5.0mmol, 25.0eq). After cooling to 0°C, the product obtained in the previous step (180mg, 0.2mmol, 1.0eq) was dissolved in anhydrous dichloromethane and added dropwise to the above solution. After 3 hours, add water to quench th...

Embodiment 2

[0032] 5,5'-bis{3-(cyclohexylamine)-7-methylimidazo[1,2-a]pyridyl}-3,3'-dimethyl-[2,2'-binaphthyl Preparation of ]-1,1',6,6',7,7'-hexahydroxyl (LYZ-2)

[0033]

[0034] The preparation method is as in Example 1, from compound 1 (103mg, 0.2mmol, 1.0eq), 4-methyl-2-aminopyridine (52mg, 0.48mmol, 2.4eq), scandium trifluoromethanesulfonate (Sc(OTf) 3 ) (10mg, 0.02mmol, 0.1eq), cyclohexane isonitrile (52mg, 0.48mmol, 2.4eq) prepared. Yellow-brown solid, yield 95%.

[0035] 1 H NMR (400MHz, DMSO-d 6 )δ14.19(s,1H),14.11(s,1H),10.23(s,1H),10.18(s,1H),9.58(s,1H),9.52(s,1H),8.83–8.61(m ,2H),8.45–8.08(m,2H),7.71(d,J=4.0,2H),7.69(s,1H),7.66(s,1H),7.38(t,J=7.6,2H),6.83 (s,1H),6.82(s,1H),2.92–2.79(m,1H),2.68–2.61(m,1H),2.56(s,6H),1.83(s,3H),1.78(s,3H ),1.71–1.64(m,2H),1.59–1.47(m,4H),1.45–1.20(m,6H),1.09–0.91(m,6H),0.64–0.52(m,2H). 13 C NMR (100MHz, DMSO-d 6 )δ149.12,149.08,149.01,146.99,146.95,146.86,144.09,144.02,142.98,136.01,133.95,133.86,128.96,128.93,128.79,128.75,128.67,12...

Embodiment 3

[0037] 5,5'-bis{3-(cyclohexylamine)-7-ethylimidazo[1,2-a]pyridyl}-3,3'-dimethyl-[2,2'-binaphthyl Preparation of ]-1,1',6,6',7,7'-hexahydroxyl (LYZ-3)

[0038]

[0039] The preparation method is as in Example 1, from compound 1 (103mg, 0.2mmol, 1.0eq), 4-ethyl-2-aminopyridine (59mg, 0.48mmol, 2.4eq), scandium trifluoromethanesulfonate (Sc(OTf) 3 ) (10mg, 0.02mmol, 0.1eq), cyclohexane isonitrile (52mg, 0.48mmol, 2.4eq) prepared. Reddish-brown solid, yield 96%. 1 H NMR (400MHz, DMSO-d 6 )δ14.26(s,1H),14.16(s,1H),10.26(s,1H),10.22(s,1H),9.60(s,1H),9.54(s,1H),8.76(s,1H ),8.75(s,1H),8.35–8.24(m,1H),8.19–8.05(m,1H),7.72(t,J=4.3,4H),7.69(s,1H),7.65(s,1H ),7.45(t,J=6.6,2H),6.84(d,J=4.6,2H),2.87(dd,J=14.6,7.2,4H),2.74–2.57(m,2H),1.84(s, 3H),1.80(s,3H),1.75–1.62(m,4H),1.58–1.50(m,4H),1.42–1.36(m,2H),1.30(t,J=7.4,6H),1.06– 0.90(m,7H),0.69–0.49(m,2H)

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Abstract

The invention belongs to the technical field of organic synthesis, particularly discloses a preparation method and application of apogossypol derivatives. The preparation method comprises the following steps: stirring apogossypol and isonitrile used as raw materials in a polar solvent at room temperature, and carrying out column chromatography separation to obtain a reaction product which is used as the raw material for the next reaction; under waterless oxygen-free conditions, adding ethanethiol into anhydrous aluminum chloride, cooling to 0 DEG C, dissolving the reaction product in the first step in anhydrous dichloromethane, and dropwisely adding into the solution; and after the reaction finishes, adding water to quench the reaction, regulating the pH value to 3-5, standing, carrying out vacuum filtration, washing the filter residue with dichloromethane, and carrying out vacuum drying, thereby obtaining the solid which is the target product. The multicomponent synthesis process centrally modifies the isopropyl of the apogossypol, thereby constructing series derivatives of apogossypol. The derivatives have favorable antitumor activity, have favorable inhibiting actions on IL-17A, and have wide application prospects.

Description

technical field [0001] The invention belongs to the field of organic synthesis and medicine, and relates to an apogossypol derivative, a preparation method thereof and the application of antitumor and immune regulation. Background technique [0002] Gossypol is a yellow polyphenolic compound that occurs naturally in certain plants in the Malvaceae family. Gossypol is a very promising natural compound with a wide range of biological activities. For example, it has anti-tumor and anti-fertility effects. Recent studies have shown that gossypol also has various biological activities such as anti-malarial, anti-parasite and anti-virus. In particular, it shows a strong inhibitory or killing effect on HIV, influenza virus, herpes virus and other membrane viruses. At the same time, gossypol is also the first plant-derived and very valuable interferon inducer. A potential broad-spectrum antiviral compound. Gossypol is a chiral hindered optical isomer, which is divided into (+)-goss...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/437A61P35/00
CPCC07D519/00
Inventor 王巍卢育智李俊周海兵
Owner 江苏度未生物工程科技有限公司
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