Triptolide derivative, and preparation method and application thereof

A technology of triptolide and derivatives, which can be used in drug combinations, pharmaceutical formulations, steroids, etc., can solve problems such as poor water solubility and toxicity, and achieve strong inhibitory activity, good application prospects, strong inhibition of leukemia cells and resistance to leukemia cells. Influenced by leukemia cell activity

Inactive Publication Date: 2010-06-30
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0004] However, triptolide has its disadvantages as an anticancer drug: its toxicity is large and its water solubility is poor

Method used

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  • Triptolide derivative, and preparation method and application thereof
  • Triptolide derivative, and preparation method and application thereof
  • Triptolide derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of triptolide methyl chloroacetate

[0037] Weigh triptolide (50mg, 0.139mmol) and dissolve it in 5ml chloroform, add 4-dimethylaminopyridine (85mg, 0.696mol) at -5°C and shake it for 0.5 hours, then slowly add the chlorine dissolved in chloroform dropwise. Acetyl chloride (0.039ml, 0.490mmol), slowly return to room temperature and stir for 24 hours, wash the reaction product with 5% dilute hydrochloric acid (volume percentage) and water for 2 to 3 times, dry over anhydrous magnesium sulfate, and distill under reduced pressure , silica gel column chromatography, collecting the eluent as V 乙酸乙酯 :V 石油醚 = 10:90 of the eluted product obtained, concentrated under reduced pressure to obtain 45 mg of a colorless transparent solid, which is triptolide chloroacetate, with a yield of 74.2% and a melting point of 122-124°C.

[0038] 1 H NMR (CDCl 3 , 300M Hz) δ5.30(s, 1H), 5.10(s, 1H), 4.67(s, 2H), 4.19(d, J=6.6Hz, 2H), 3.84(d, J=3Hz, 1H), 3.56(d...

Embodiment 2 4

[0039] The synthesis of embodiment 2 triptolide tetrahydropyrrolidone acetate

[0040] Weigh 10mg (0.029mmol) triptolide chloroacetate prepared in Example 1 and dissolve it in 1ml N,N-dimethylformamide, add 3.0mg (0.0348mmol) tetrahydropyrrole at 0°C, and weigh 4.8mg (0.0348mmol) Anhydrous K 2 CO 3 Add it to the above solution, react at room temperature 25°C for 24h, concentrate under reduced pressure, perform silica gel column chromatography, and collect the eluent as V 甲醇 :V 氯仿 =100:1 The obtained eluted product, the eluted product was concentrated under reduced pressure to obtain 7.4 mg of a colorless solid, which is triptolide of tetrahydropyrrolidone acetate in this example, and the yield was 74%. mp 152-154°C.

[0041] 1 H NMR (CDCl 3 , 300M Hz) δ5.13(s, 1H), 4.68(s, 2H), 4.19(d, J=7.2Hz, 2H), 3.89(d, J=3.3Hz, 1H), 3.55(d, J= 3.3Hz, 1H), 3.48(d, J=5.4Hz, 1H), 2.75(m, 1H), 2.35(m, 2H), 2.35(m, 2H), 2,20(m, 2H), 1.93( m, 2H), 1.90(m, 2H), 1.90(m, 2H), 1.85(m, 1H), ...

Embodiment 4

[0045] The synthesis of embodiment 4 morphine morpholino acetate triptolide

[0046] The specific process is the same as in Example 2, and the molar ratio of each reaction substance is also the same as in Example 2, with a yield of 75%, a colorless solid. mp 98-99°C.

[0047] 1 H NMR (CDCl 3 , 300M Hz) δ5.13(s, 1H), 4.67(s, 2H), 3.83(d, J=3.0Hz, 1H), 3.76(t, J=4.5Hz, 2H), 3.76(t, J= 4.5Hz, 2H), 3.54(d, J=3.0Hz, 1H), 3.48(dd, J=5.7Hz, 1H), 3.35(q, J=16.5Hz, 28.2Hz, 2H), 2.68(m, 1H ), 2.64(m, 2H), 2.64(m, 2H), 2.17(m, 2H), 1.90(m, 2H), 1.56(m, 1H), 1.45(m, 2H), 1.26(s, 1H) , 1.21(m, 1H), 1.01(s, 3H), 0.98(d, J=6.9Hz, 3H), 0.86(d, J=6.9Hz, 3H). 13 C NMR (CDCl3, 75M Hz) δ173.0, 169.5, 159.7, 125.5, 71.2, 69.9, 66.9, 66.9, 63.6, 63.2, 61.3, 59.7, 59.6, 55.5, 55.1, 53.1, 53.1, 40.4, 35.8, 29.9, 28.3, 23.6, 17.6, 17.2, 16.8, 13.8. HREIMS m / z 487.2200 (calcd for C 26 h 33 o 8 N 1 , 487.2201).

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Abstract

The invention discloses triptolide derivative, and a preparation method and application thereof. The triptolide derivatives has the general formula as shown in Formula (I), wherein R is selected from chlorine, amine, fatty amine or aromatic amine. In the invention, triptolides, which are natural products in plants, are used as lead compounds to be modified in structure, thereby obtaining compounds capable of resisting chronic granulocytic leukemia activity in different degrees. The compounds have strong activity for inhibiting and resisting leukaemia cells, and have especially strong activity for inhibiting the chronic granulocytic leukemia cells resisting STI571. The invention lays foundation for the triptolide derivatives to develop into novel medicaments for treating the chronic granulocytic leukemia, can be used for preparing medicaments for treating the chronic granulocytic leukemia, and has good application prospects.

Description

technical field [0001] The invention relates to the technical field of organic compounds, in particular to a triptolide derivative and its preparation method and application. Background technique [0002] Chronic myeloid leukemia (CML) is a myeloid cell proliferation disorder. Bcr-Abl is a fusion protein that causes chronic myelogenous leukemia (CML), and belongs to non-receptor tyrosine kinases. The great success in clinical efficacy of targeted therapy with specific small molecule inhibitors against protein tyrosine kinases further confirmed the importance of protein tyrosine kinases in tumorigenesis. The world's first approved targeted therapy drug is Gleevec (STI-571, Chinese name "Gleevec"), which is a powerful targeted inhibitor. However, with the wide application of STI571 in clinical practice, the problem of drug resistance has become increasingly prominent. [0003] As early as the 1950s, domestic Chinese medicine used Tripterygium wilfordii to treat rheumatoid a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/585A61P35/02
Inventor 潘景轩
Owner SUN YAT SEN UNIV
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