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Glaucocalyxin A thiazole derivative, preparation method and application thereof

A technology of calyxine and derivatives, applied in the field of medical invention, can solve the problems of low polarity, poor water solubility, drug administration and the like, and achieve the effects of improving water solubility, excellent activity and improving bioavailability

Active Publication Date: 2015-02-18
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, indigosin has low polarity and poor water solubility, so it is not suitable for direct administration as a drug; it has strong anti-tumor effect in vitro, but it needs a large dose for a long time to produce drug effect in vivo [Zhang Chong, Shang Xiaojun , Ma Suying, Bai Suping. Medical Herald, 2013,32,1399-1402]
[0008] In addition, there are also patents [CN101993359A, open date 2011.03.30; CN101993370A, open date 2011.03.30; CN101993373A, open date 2011.03.30; CN102584780A, open date 2012.01.16] reported the fatty acid and aromatic acid of its 7-position and 14-position hydroxyl Esters, dibasic acid esters, polypeptides and acetals are structurally modified, but these derivatives still have water solubility problems

Method used

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  • Glaucocalyxin A thiazole derivative, preparation method and application thereof
  • Glaucocalyxin A thiazole derivative, preparation method and application thereof
  • Glaucocalyxin A thiazole derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the preparation of 2-bromocalyxin

[0071] Weigh 166mg (0.5mmol) cylindrin and dissolve it in 5mL THF, put it in an ice bath, then dissolve 160mg (0.5mmol) tribromopyridinium in 1mL THF, slowly add it to the reaction system dropwise after ice bathing, add 30mL distilled water after 30min Quench the reaction, extract with dichloromethane, 30 mL each time, extract 3 times, combine the extracts, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate by silica gel column chromatography, petroleum ether-ethyl acetate (2:1) was eluted to obtain 145.5 mg of white solid (C-2 epimer) with a yield of 70.8%. mp.203-205℃

[0072] Isomer 1: 1 H NMR (400MHz, CDCl 3 )δ6.15(s,1H),5.42(s,1H),4.90(dd,J=12.2,6.8Hz,1H),4.84(s,1H),4.33(dd,J=11.9,3.9Hz,1H ),3.07(br s,1H),2.65(dd,J=13.4,6.8Hz,1H),2.09(dd,J=13.4,9.3Hz,1H),1.98–1.86(m,2H),1.83–1.66 (m,2H),1.60–1.38(m,4H),1.27(s,3H),1.16(s,3H),1.12(s,3H); 13 C NMR (100MHz, C...

Embodiment 2

[0074] Embodiment 2: the preparation of the thiazole derivative of cyanine A

[0075] The reaction formula is as follows:

[0076]

Embodiment 21

[0077] Example 2.1: Preparation of 2-aminothiazole derivative II a of cerulein A

[0078] Weigh 82mg (0.2mmol) of the obtained 2-bromocyanin and 15mg (0.2mmol) of thiourea prepared in Example 1 and dissolve them in 2mL of ethanol, heat and reflux for 5h and then cool naturally, add 10mL of saturated NaHCO 3 Add 18 mL of distilled water after the solution was alkalized, extract 3 times with dichloromethane, 30 mL each time, combine the extracts, wash 2 times with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform silica gel column chromatography Separation and purification, eluting with petroleum ether / ethyl acetate 2 / 1, yielded 28.6 mg of a white solid, which is the 2-aminothiazole derivative II a of cyanine A in this example, with a yield of 36.8%. mp.254-256℃.

[0079] 1 H NMR (400MHz, C 5 D. 5 N)δ7.59(s,1H),7.26(s,1H),6.36(s,1H),5.42(s,1H),5.15(s,1H),4.90(s,1H),4.82(dt, J=11.9,4.0Hz,1H),3.29(br s,1H),2.61(d,J=15....

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Abstract

The invention relates to a glaucocalyxin A (GLA) thiazole derivative. The structure II of the derivative is shown in the description, wherein R is hydrogen, alkyl, alkylene and aromatic hydrocarbon. Based on cytotoxic activity evaluation experiment, the GLA thiazole derivative disclosed by the invention has very strong human tumor cell proliferation inhibitory activity which is better than that of parent compound GLA.

Description

technical field [0001] The invention relates to the field of medical inventions, in particular to a thiazole derivative of glaucocalyxin A (GLA), a preparation method and application thereof. Background technique [0002] Glaucocalyxin A (GLA), chemical name: (5β,7α,9β,10α)-7,14-dihydroxykauri-16-ene-3,15-dione; also known as leukamenin F, Molecular formula is C 20 h 28 o 4 , molecular weight: 332.43, CAS registration number: 79498-31-0, density: 1.22g / cm 3 , melting point: 513.4°C, easily soluble in methanol and ethanol, and its structural formula is shown in formula Ⅰ. [0003] [0004] Glaucocalyx is the main medicinal ingredient of Isodon japonica var. glaucocalyx, a medicinal plant of the genus Isodon japonica var. glaucocalyx. Yunnan Botanical Research. 1981,3(03):1-3) was the first to isolate cyanine from the calyx calyx, and its structure was identified by spectral methods. Its content is as high as 1.03% in the dried leaves of Saccharomyces indigo. [0005...

Claims

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Application Information

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IPC IPC(8): C07D277/60A61K31/428A61P35/00A61P35/02
CPCC07D277/60
Inventor 白素平陈亮辉黄锋刘巍海广范李婷任茜周慧超
Owner XINXIANG MEDICAL UNIV
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