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Alantolactone derivative and salts thereof

A technology of inulin and derivatives, which can be applied in drug combinations, endocrine system diseases, digestive system, etc., can solve the problems of poor water solubility, low bioavailability, short half-life, etc., and achieve improved survival and high tumor inhibition rate , the effect of excellent performance

Active Publication Date: 2017-03-15
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this document only discloses the data of in vitro tumor inhibition experiments on tumor cells. In animal experiments, we found that the oral toxicity of this compound is relatively high, it is difficult to be used in clinical practice, and its water solubility is not ideal. The effects of tumor inhibition experiments in animals and in vivo are not satisfactory, and have no clinical application value
Therefore, on the basis of the existing technology, the structure of inulin is modified, and a new derivative of inulin is provided to significantly improve its effect when used for the treatment of diseases such as cancer, and reduce its cytotoxicity, and By preparing the derivative into a derivative salt as a prodrug, it overcomes the shortcomings of the original drug such as poor water solubility, short half-life, and low bioavailability, which has become an urgent problem to be solved in the prior art.

Method used

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  • Alantolactone derivative and salts thereof
  • Alantolactone derivative and salts thereof
  • Alantolactone derivative and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Preparation of compound (II)

[0025]

[0026] 1) Preparation of compound (I-II)

[0027]

[0028] Inulin (300.0mg, 1.29mmol) was dissolved in dichloromethane (50mL), and dimethylamine hydrochloride (1.6g, 19.4mmol) and potassium carbonate (5.2g, 37.4mmol) were successively added to the above mixed system ), the system was heated to reflux for 3 hours, the solid was removed by filtration, the filtrate was washed with water, dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound (I-II) (white solid, 236.0g, Yield: 50%).

[0029] 2) Preparation of compound (II), dissolving compound (I-II) (200.0mg, 0.72mmol) obtained in step 1) in methanol (7mL), adding fumaric acid (86.7mg, 0.74mmol ), stirring and reacting for 0.5 hour, spin off the solvent, add ethyl acetate to dissolve, and filter to obtain compound (II) (white solid, 246.4mg, yield: 87.3%)

[0030] Elemental analysis determines the molecular form...

Embodiment 2

[0033] Preparation of compound (III)

[0034]

[0035] 1) Preparation of compound (I-III)

[0036]

[0037]Inulin (2.0g, 8.6mmol) was dissolved in dichloromethane (10mL), and a solution of peroxybenzoic acid (2.1g, 10.3mmol) in dichloromethane (20mL) was slowly added dropwise to the above system. React for 3 hours, quench the reaction with saturated aqueous sodium thiosulfate solution, wash the organic layer with saturated aqueous sodium bicarbonate (20mL×3), dry and concentrate, and purify by column chromatography (petroleum ether: ethyl acetate = 5:2) to obtain the compound (I-III) (white solid, 2.0g, yield 94%)

[0038] 2) Preparation of compound (III)

[0039] The compound (I-III) (300.0mg, 1.29mmol) obtained in the previous step was dissolved in dichloromethane (50mL), and dimethylamine hydrochloride (1.6g, 19.4mmol) and carbonic acid were added to the above mixed system in turn. Potassium (5.2g, 37.4mmol), the system was heated to reflux for 3 hours, the solid w...

Embodiment 3

[0043] In vitro cancer cell inhibitory effect of inulin derivative salts

[0044] The inhibitory effect of inulin derivative salts on cancer cells was detected by tetramethylazolidine blue (MTT) colorimetric method.

[0045] MTT colorimetric method experimental steps: Inoculate cancer cells in the logarithmic growth phase into 96-well cell culture plates at a density of 5×104 cells per milliliter, and adjust the zero wells to normal culture medium without cells. After 12 hours, the medium containing inulin derivatives with different concentration gradients was replaced, and the normal medium was replaced in the zero-adjusted wells. Five replicate wells were set for each concentration gradient, and cultured in a 37°C, 5% CO2 incubator. After 24 hours, the cell state and growth changes were observed under a microscope. After 48 hours, add tetramethylazolazolium blue (KG Bio, 5 mg / mL) solution to each well, continue to cultivate at 37°C, 5% CO2 incubator, suck out the medium aft...

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Abstract

The invention provides an alantolactone derivative shown as formula (I). The acid for salt forming is inorganic acid or organic acid, the inorganic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, seleninic acid, phosphomolybdic acid, phosphorous acid and sulfurous acid, and the organic acid is selected from citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-acid, oxalic acid, methanesulfonic acid, pentanoic acid, oleic acid, lauric acid, p-toluene sulfonic acid, 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, phthalic acid, tartaric acid, malonic acid, succinic acid, fumaric acid, glycollic acid, mercaptan acid, glycine, sarcosine, sulfonic acid, nicotinic acid, methylpyridine acid, isonicotinic acid, benzoic acid or substituted benzoic acid.

Description

[0001] Technical field: [0002] The present invention relates to inulin derivatives and their salts and their application and preparation. [0003] Background technique: [0004] Inula helenium is a plant of the genus Inula in the family Compositae, a perennial herb whose roots are used for medicinal purposes. It has the functions of invigorating the spleen and harmonizing the stomach, regulating qi and relieving depression, relieving pain and preventing miscarriage. It is used for chest and flank, abdominal distension and pain, vomiting and diarrhea, chest and flank contusion, pain in the chest and flank, restless fetal movement and other diseases. Inulin volatile oil contains inulin, iso-inulin and other ingredients, its chemical structure is similar to Sandonian, it has anthelmintic effect on pigs, dogs, and cats, its curative effect is better than that of Sandonian, and its toxicity is lower. [0005] Inulin (CAS: 546-43-0,) belongs to sesquiterpenoids, and is also the ma...

Claims

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Application Information

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IPC IPC(8): C07D307/92C07D493/10A61K31/365A61P5/14A61P29/00A61P35/00A61P11/00A61P1/00A61P37/02A61P1/04
CPCC07D307/92C07D493/10
Inventor 杨诚杨光孙涛周红刚刘双伟盛彭真高险王常骅卢聘
Owner NANKAI UNIV
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