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Colchicine derivative containing histone deacetylase inhibitory activity, preparation method and application thereof

A technology of deacetylase and colchicine, applied in the field of novel colchicine derivatives, can solve the problems of complex administration mode, single action target, different half-life and the like, and achieve the effect of good anti-tumor activity

Inactive Publication Date: 2015-06-17
EAST CHINA NORMAL UNIV +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The former has a large number of clinical application examples, but it often brings inconvenience to clinical research due to factors such as drug distribution, different half-lives, and complex administration methods; while the latter can overcome the above-mentioned defects while maintaining synergy, Therefore, it has become an important branch of pharmaceutical chemists in the development of new anti-tumor drugs.
Due to blocking multiple pathways of tumor cell survival, such small molecule drugs can overcome the shortcomings of traditional drugs that are prone to drug resistance
For example, the first-generation tyrosine kinase inhibitor imatinib has a single target, mainly inhibiting the tyrosine kinase Bcr-Abl
Patients tend to develop drug resistance after taking imatinib for a period of time

Method used

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  • Colchicine derivative containing histone deacetylase inhibitory activity, preparation method and application thereof
  • Colchicine derivative containing histone deacetylase inhibitory activity, preparation method and application thereof
  • Colchicine derivative containing histone deacetylase inhibitory activity, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1.1 Preparation of compound 3

[0033] Dissolve 900 mg of monomethyl terephthalate in 10 mL of toluene, add 2.1 mL of thionyl chloride dropwise at room temperature, then raise the temperature to 60-70°C for 2 hours, remove the solvent and excess thionyl chloride under reduced pressure to obtain a colorless liquid . This liquid was dissolved in 5 mL of dichloromethane, and added dropwise to a dichloromethane solution in which 1.1 mL of triethylamine and 832 mg of tert-butyl 2-aminophenylcarbamate were dissolved, and the reaction was stopped after 30 minutes at room temperature. After extraction with dichloromethane, washing with 1N hydrochloric acid and saturated sodium carbonate, the organic phase was dried and spin-dried. The crude product was crystallized in petroleum ether-ethyl acetate to obtain 1.28 g of a white solid, with a yield of 86.5%. 1 H NMR (400MHz, DMSO) δ9.98(s,1H),8.71(s,1H),8.15–8.03(m,4H),7.55(dd,J=13.6,7.8Hz,2H),7.27–7.08( m,2H), 3.91(s,3H), 1.44(...

Embodiment 2

[0035] 1.2 Preparation of Compound 4

[0036] At room temperature, 50 mg of compound 3 and 11 mg of lithium hydroxide monohydrate were dissolved in a mixture of 3 mL of ethanol and 0.27 mL of water. After reacting for 1 hour, 1N hydrochloric acid was added to adjust the pH to weak acidity, and the solvent was removed under reduced pressure. The resulting solid, 53 mg deacetylcolchicine, 43 mg diisopropylethylamine, 44 mg 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro Phosphate ester was dissolved in 5mL of dichloromethane, reacted at room temperature for two hours, extracted with dichloromethane, washed with 1N hydrochloric acid, dried with water, and separated by column using dichloromethane-methanol as developing solvent to obtain 62 mg of light yellow solid , yield 81.1%. 1 H NMR (400MHz, CDCl 3 )δ9.38(s,1H),7.84–7.67(m,6H),7.63(s,1H),7.41–7.35(m,2H),7.23–7.13(m,3H),6.90(d,J= 10.9Hz,1H),6.58(s,1H),4.97–4.81(m,1H),4.00(d,J=12.6Hz,3H),3.98–3.87(m,6H),3.61(s...

Embodiment 3

[0038] 1.3 Preparation of Compound 5

[0039]Compound 4 was dissolved in 20 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and reacted at room temperature for 3 hours. Add saturated sodium carbonate solution to quench the reaction, extract with dichloromethane, wash the organic phase with water, wash with saturated brine, dry over anhydrous sodium sulfate and distill under reduced pressure. The obtained crude product was slurried with dichloromethane-petroleum ether to obtain 31 mg of white solid with a yield of 69.6%. 1 H NMR (400MHz, CDCl 3 )δ9.32(s,1H),8.50(d,J=6.3Hz,1H),7.78(s,1H),7.70(d,J=8.0Hz,2H),7.51(d,J=7.8Hz, 2H),7.37(d,J=10.8Hz,1H),7.26–7.23(m,1H),7.00(t,J=7.4Hz,1H),6.94(d,J=11.0Hz,1H),6.84– 6.68(m,2H),6.56(s,1H),4.98–4.83(m,1H),4.02(s,3H),3.92(s,3H),3.90(s,3H),3.55(s,3H) ,2.61–2.47(m,1H),2.42–2.25(m,2H),2.21–2.09(m,1H).HPLC:room temperature;t R =9.35min, UV 254 =95.6%;HRMS(ESI):m / z calcd for C 34 h 33 N 3 o 7 Na(M+Na + ):618.2216,found:61...

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Abstract

The invention provides a colchicine derivative that is shown as general formula I and contains histone deacetylase inhibitory activity, its pharmaceutically acceptable salts, a preparation method and application thereof. In the general formula I, X can be carbonyl, methylene, substituted methylene, ethylidene and substituted ethylidene; Y can be an aromatic ring, a substituted aromatic ring, a heteroaromatic ring and a substituted heteroaromatic ring; and Z can be hydrogen, an aromatic ring, a substituted aromatic ring, a heteroaromatic ring and a substituted heteroaromatic ring. The compounds have good anti-tumor activity, and can be applied by means of oral administration, intravenous injection, intramuscular injection and the like clinically.

Description

technical field [0001] The invention relates to a class of multi-target inhibitors acting on microtubules and histone deacetylases, as well as methods and applications for preparing these compounds. More specifically, it relates to novel colchicine derivatives (I) having the following structures, their preparation methods and the application of these compounds in the antitumor field. [0002] Background technique [0003] Microtubules are a polar cytoskeleton, an important factor in maintaining cell shape, and an important class of anti-tumor targets. Colchicine (1) is a representative compound with antitumor activity that acts on the microtubule colchicine binding site, but its application is limited due to its strong toxicity and side effects. [0004] [0005] Combined drug use and the development of single-molecule multi-target drugs are a direction in the field of anti-tumor drug research. The synergistic effect between different targets can increase drug efficac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/80C07C231/12C07C237/40C07D333/20A61K31/381A61K31/167A61P35/00
Inventor 吕伟张翾刘雅倩于秀华罗宇方艳芬章雄文陈奕丁健
Owner EAST CHINA NORMAL UNIV
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