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Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof

A technology of artemisinin and nitrogen atoms, applied to medical preparations containing active ingredients, pharmaceutical formulas, organic active ingredients, etc., can solve problems such as serious side effects and poor quality of life of patients

Active Publication Date: 2011-08-17
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these anti-cancer drugs have relatively serious side effects, and the quality of life of patients is poor. There is a great need for the birth of new anti-cancer drugs with high efficiency and safety.

Method used

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  • Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof
  • Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof
  • Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Embodiment 1 (method A)

[0080]

[0081] First condense dihydroartemisinin and ethylene glycol in the presence of boron trifluoride ether complex to generate β-hydroxyarteether, and then react it with p-toluenesulfonyl chloride to obtain p-toluenesulfonate of β-hydroxyarteether Ester (compound 2, Y=C 2 h 4 ), white crystals, melting point 96-98°C.

[0082] Compound 2 (Y=C 2 h 4 , 1.54g) was dissolved in dimethylformamide (10mL), then ammonia water (0.5mL) was added, stirred and heated to 40-50°C, and reacted for about 20h. After TLC detected that the raw material spots basically disappeared, the reaction solution was poured into ice water, extracted repeatedly with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, the eluent was a mixed solvent of ethyl acetate / petroleum ether...

Embodiment 2

[0090] Embodiment 2 (method A)

[0091]

[0092] First, dihydroartemisinin and propylene glycol are condensed in the presence of boron trifluoride ether complex to generate β-hydroxyartemisin, and then it is reacted with p-toluenesulfonyl chloride to obtain p-toluenesulfonate of β-hydroxyartemisinin Ester (compound 2, Y=C 3 h 6 ).

[0093] The p-toluenesulfonate (compound 2, Y=C 3 h 6 , 2.05g) and ammonia water (3.4mL) as raw materials, the reaction conditions and post-treatment method were the same as in Example 1 to obtain 0.9g of yellow oil, with a yield of 67%.

[0094] Using a method similar to that of Example 1, the melting point of the maleate salt (code name SM 1046) of the above yellow oil was 143-145°C; the melting point of succinate (code name SM 1048) was 136-138°C. Citrate (code SM 1047) melting point: 132-134°C.

[0095] 1 HNMR (free base, 300MHz, CDCl 3 )δ: 5.38(s, 2H), 4.77(d, J=4.2Hz, 2H), 3.90(m, 2H), 3.45(m, 2H), 2.72(t, J=7.2Hz, 4H), 1.43( s, 6H...

Embodiment 3

[0099] Embodiment 3 (method D)

[0100]

[0101] The p-toluenesulfonate of β-hydroxyarteether (compound 2, Y=C 2 h 4 , 4.8g) was reacted with methylamine ethanol solution, stirred and heated to 40-50°C, and reacted for about 20h. After TLC detected that the raw material spots basically disappeared, the reaction solution was concentrated, the residue was extracted with ethyl acetate several times, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel, the eluent was a mixed solvent of ethyl acetate / petroleum ether / triethylamine) to obtain 2.6 g of a light yellow oil, which was 7, Y=C 2 h 4 , R=CH 3 ).

[0102] The above product is then combined with p-toluenesulfonate of hydroxyarteether (compound 11, Z=C 2 h 4 , 1.9g) was dissolved in dimethylformamide (20mL), stirred and heated to 50°C in the prese...

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Abstract

The invention relates to nitrogen-atom-containing arteannuin dimers disclosed as Formula (1) and pharmaceutically acceptable salts thereof, wherein X is NR, NR(CH2)nNR or a formula disclosed in the specification; R is H or C14 alkyl group; Y and Z are respectively (CH2)m, (CH2)n(OCH2CH2)m, OC(CH2)nCO or COAr; Ar is phenyl group, naphthyl group or heterocyclic group; N is a 2-8 whole number, and mis a 1-11 whole number; and the heterocyclic group is quinary or sexenary, and contains 1-2 heteroatoms selected from N, O and S. The invention also provides a preparation method of the nitrogen-atom-containing arteannuin dimers, a pharmaceutical composition of the nitrogen-atom-containing arteannuin dimers, and application of the nitrogen-atom-containing arteannuin dimers in preparing drugs for treating cancers, especially endometrial carcinoma, oophoroma, cervical carcinoma, breast cancer, colon cancer, lung cancer, prostatic cancer, liver cancer and / or stomach cancer.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a nitrogen atom-containing artemisinin dimer and its pharmaceutically acceptable salt, its preparation method, and its application in the preparation of anticancer drugs. Background technique [0002] In the 1970s, Chinese researchers extracted artemisinin from Artemisia annua L., and confirmed that it has a strong antimalarial effect in the laboratory and clinically. Research. Since 1986, artemisinin, artesunate, artemether, dihydroartemisinin and their compound preparations have been approved as new antimalarial drugs in China (Zhang Jianfang, "Late Report" Yangcheng Evening News Publishing House, 2006 ; Li Ying et al. Front Chem China 2010, 5: 357-422). These antimalarials are now widely used around the world. [0003] After the antimalarial effect of artemisinin was confirmed, research on other biological activities such as anti-parasite, anti-cancer and immunosuppressio...

Claims

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Application Information

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IPC IPC(8): C07D493/18A61K31/496A61K31/357A61P35/00
CPCA61K31/357C07D493/18A61K31/496A61P35/00
Inventor 李英朱焰张瑜周洁芸曹霖谢淑武
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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