Costunolide derivative and pharmaceutical composition, preparation method and uses thereof

A technology of woody lactone and derivatives, applied in the field of medicine

Active Publication Date: 2015-06-03
ACCENDATECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are no reports about the compound of formula (I), its pharmaceutical composition, its preparation method, and its use in the preparation of medicines, especially its use in the preparation of medicines for the treatment of rheumatoid arthritis and cancer

Method used

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  • Costunolide derivative and pharmaceutical composition, preparation method and uses thereof
  • Costunolide derivative and pharmaceutical composition, preparation method and uses thereof
  • Costunolide derivative and pharmaceutical composition, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Structural formula is as follows the preparation route of formula II:

[0032]

[0033] Preparation of compound 1:

[0034] Under the protection of nitrogen, dissolving cosmolide (2.0g, 8.6mmol) in dried dichloromethane, cooled to zero, slowly added 1M diisobutylaluminum hydride dichloromethane solution (10.6mL, 10.6mmol ), continue stirring for two hours after adding, after TLC detects that the reaction is substantially complete, quench with saturated ammonium chloride solution (100mL), filter a layer of diatomaceous earth, extract the aqueous phase three times with dichloromethane, and combine the dichloromethane layers , washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and purification by concentration column chromatography, 1.37 g (68%) of the hemiacetal intermediate was obtained. Dissolve 1.27g of hemiacetal in 40mL of methanol, cool to zero, add sodium borohydride (427mg, 11.3mmol) in batches, stir for four hours, TLC sho...

Embodiment 2

[0048] The synthetic method of compound III:

[0049]

[0050] Take compound II (590mg, 2.4mmol), dimethylamine hydrochloride (2.94g, 36mmol) was dissolved in 120mL of dichloromethane, 9.95g of potassium carbonate was added, refluxed for 5 hours, filtered, spin-dried, and obtained by silica gel column chromatography Compound III (645 mg).

[0051] 1 H NMR (400MHz, CDCl 3 )δ 5.17 (br d, J = 10.2Hz, 1H), 3.76 (t, J = 7.9Hz, 1H), 2.71 (dd, J = 13.0, 5.2Hz, 1H), 2.55 (dd, J = 13.0, 5.2Hz, 1H), 2.46-2.36(m, 1H), 2.36-2.29(m, 1H), 2.25(m, 8H), 2.17-2.10(m, 1H), 2.07-1.95(m, 3H), 1.77 -1.69(m, 1H), 1.68(s, 3H), 0.98(s, 3H), 0.88-0.71(m, 2H), 0.53-0.49(m, 1H), 0.44(t, J=5.4Hz, 1H ); 13 C NMR (100MHz, CDCl 3 )δ177.6, 133.4, 127.7, 85.0, 58.6, 51.3, 47.9, 46.2, 41.2, 38.8, 32.4, 31.9, 25.4, 20.2, 18.2, 18.0, 16.7.

Embodiment 3

[0053] The synthetic method of compound IV:

[0054]

[0055] Take compound II (167 mg), deuterated dimethylamine hydrochloride (530 mg) was dissolved in 15 mL of dichloromethane, 1.8 g of potassium carbonate was added, stirred for 24 hours, filtered, spin-dried, and passed through the column to obtain compound IV (150 mg, 76% ).

[0056] 1 H NMR (400MHz, CDCl 3 )δ5.15(br d, J=11.4Hz, 1H), 3.74(t, J=7.9Hz, 1H), 2.69(d, J=12.8Hz, 1H), 2.53(d, J=12.8Hz, 1H ), 2.45-2.33(m, 1H), 2.32-2.17(m, 8H), 2.16-2.09(m, 1H), 2.06-1.93(m, 3H), 1.78-1.62(m, 4H), 0.97(s , 3H), 0.83-0.73(m, 2H), 0.50(dd, J=9.3, 4.9Hz, 1H), 0.43(t, J=5.3Hz, 1H).; 13 CNMR (100MHz, CDCl 3 )δ176.6, 132.3, 126.7, 84.0, 57.5, 50.2, 46.9, 45.2, 40.2, 37.8, 31.3, 30.9, 24.4, 19.2, 17.2, 17.0, 15.6.

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Abstract

The present invention relates to a compound as represented by formula (I), pharmaceutical composition thereof as well as preparation method and uses thereof, in particular to the uses of the compound as represented by formula (I) for treating rheumatoid arthritis and cancers.

Description

technical field [0001] The present invention belongs to the technical field of medicines, in particular, it relates to coynelide derivatives or their salts, a pharmaceutical composition for treating cancer or adjuvant treatment of tumors using it as an active ingredient, a preparation method thereof, and the pharmaceutical compound and combination The application of the drug in the preparation of anti-cancer, auxiliary anti-cancer or preparation of drugs for rheumatoid arthritis or auxiliary treatment of rheumatoid arthritis. Background technique [0002] Parthenolide, a sesquiterpene lactone compound, is a compound extracted from feverfew, which was originally used to treat skin infections, rheumatism and migraine. Recent studies have shown that parthenolide can inhibit the growth of cancer cells such as prostate cancer, breast cancer, gastric cancer, leukemia cancer, kidney cancer, lung cancer, colon adenocarcinoma, and medulloblastoma. Can treat skin cancer caused by ult...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/93A61K31/365A61P35/00A61P35/02A61P19/02A61P29/00
CPCA61P19/02A61P25/00A61P29/00A61P35/00A61P35/02C07D307/93
Inventor 陈悦张泉龙菁韩滨马小彦
Owner ACCENDATECH
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