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Agrarabine dimethylamine fumarate and its use in medicine preparation

A drug and application technology, applied in the field of agrarabine dimethylamine fumarate and its drug preparation, can solve the problems of large oral therapeutic window, low toxicity, small therapeutic window of Arglabin-DMA, etc., and achieve oral therapeutic window Large, low toxicity effect

Active Publication Date: 2016-12-21
ACCENDATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the therapeutic window of Arglabin-DMA is small, which brings inconvenience to the clinical use of the drug, and Arglabin-DMA has a strong hygroscopicity, which limits the range of its dosage form selection. Currently, it is used as an injection in clinical practice.
[0005] At present, there are no bibliographical reports about arglabine dimethylamine fumarate and its application in pharmaceutical preparation. The hygroscopicity of dimethylamine fumarate provided by the invention is lower than that of Arglabin-DMA, and its A range of dosage forms, low toxicity, and a large oral therapeutic window, used for the preparation of drugs for the treatment of cancer or auxiliary drugs for the treatment of cancer

Method used

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  • Agrarabine dimethylamine fumarate and its use in medicine preparation
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  • Agrarabine dimethylamine fumarate and its use in medicine preparation

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1: Preparation of agrarabine dimethylamine fumarate

[0021] In the 50mL round bottom flask that is equipped with magnetic stirring, thermometer, reflux condenser, add fumaric acid (1.98g, 17mmol), agrarabine dimethylamine (4.95g, 17mmol), ethanol (20ml), mix homogeneously; Heat to 78°C and stir for 1 hour; concentrate under vacuum and remove the solvent to obtain a light yellow solid; mix the light yellow solid with ethyl acetate (150mL) evenly, heat from room temperature to 77°C, stir for beating, and cool naturally. After filtering, washing with ethyl acetate, and vacuum drying for 24 hours, 5.9 g of white solid powder was obtained with a yield of 85%. 1 H NMR (D 2 O, 400MHz) δ6.58(s, 2H), 5.57(br s, 1H), 2.66(m, 2H), 2.27(s, 6H), 2.24-2.03(m, 4H), 1.97(br s, 3H ), 1.84-1.48(m, 5H), 1.35(s, 3H).

Embodiment 2

[0022] Embodiment 2: Agrabine dimethylamine fumarate anticancer activity test

[0023] Match various cancer cells into 2×10 5 / mL cell suspension, add to 24-well round-bottomed cell culture plate, add woody hydrocarbon lactone derivatives or their salts respectively, 5 wells for each test concentration, place at 37°C, 5% CO 2 Cultivate under saturated humidity conditions for 18 hours, use MTT method to measure the absorbance (A) value at the wavelength of 570nm of the enzyme-linked detector, and calculate the inhibitory effect of the compound of the present invention on the test cancer cells.

[0024] Table 1 Inhibitory activity of coynelide and its derivatives on various cancer cells (IC 50 , μM)

[0025] cell

[0026] MCF-7

[0027] Among them, HL-60, HL-60 / A, K562, MCF-7, CNE-1, CNE-2, Du145, HT-29, A549, HepG-2, Ec9706, SGC7901, SW1116, A498, ASPC-1, HT -29, HeLa, GL15, B16F1, T24, SKOV3, SW579, and PC-3 represent acute leukemia cell lines, doxorubic...

Embodiment 3

[0028] Embodiment 3: Humidity comparison

[0029] Table 2 Humidity Comparison

[0030]

[0031] Referring to the Pharmacopoeia method, take 1.0g of each test sample, spread it on a glass watch glass with a thickness of about 1mm; place it in an environment with a temperature of 25°C and a relative humidity of 85% for 24 hours, and calculate the percentage of weight gain.

[0032] Agrabine dimethylamine fumarate is compared with Agrabine dimethylamine hydrochloride, and hygroscopicity is significantly improved, and is reduced to 0.25% (as shown in table 2) by 20.75%, has increased its stability scope , Broaden the scope of dosage form selection. Compared with the preparation process of agrabine dimethylamine fumarate and agrabine dimethylamine hydrochloride, the fumarate process is easy to operate, has low requirements for instruments and equipment, and relatively low cost. General experimental conditions It can meet the experimental scale from hundreds of grams to kilogra...

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Abstract

The invention relates to a compound of arglabin dimethylamine fumarate with a structure shown as a formula (I) and application thereof to medicament preparation.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular, the invention relates to agrabine dimethylamine fumarate and its application in medicine preparation. Background technique [0002] Arglabin belongs to the guaiac sesquiterpene lactone compound, which is isolated and extracted from the aerial part of the wormwood (Artemisia) plant Artemisia glabella Kar.et Kir. growing in Kazakhstan. Its anticancer effect principle It inhibits farnesyltransferase, an enzyme that determines the function of oncogene fragments. Scientists believe that this enzyme accounts for 20%-30% of the pathogenesis of human tumors, and Arglabin also shows good anti-tumor effects Cell line activity and toxicity (human tumor cell line IC 50 =0.9-5.0 μg mL -1 ). In order to solve the water solubility problem of Arglabin, it is modified with dimethylamine at the C(13) position. Arglabin-DMA has been registered and marketed in the Republic of Kazakhstan for the t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/10C07C57/15C07C51/41A61K31/365A61P35/00A61P35/02
CPCC07D493/10
Inventor 薛志杰邱传将
Owner ACCENDATECH
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