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Preparation method and application of antitumor drug X-TOA

A technology of X-TOA and compounds, applied in the general formula of X-TOA and its synthesis and application fields, can solve problems such as not yet developed

Active Publication Date: 2016-06-01
思路迪生物医药(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies to improve the water solubility of TOA and enhance the biological activity through chemical methods have not yet been carried out.

Method used

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  • Preparation method and application of antitumor drug X-TOA
  • Preparation method and application of antitumor drug X-TOA
  • Preparation method and application of antitumor drug X-TOA

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Preparation of Compound 2-Aomethyl-3,5,6-Trimethylpyrazine

[0085] According to "Optimization of the synthesis process of intermediate 2-Aomethyl-3,5,6-trimethylpyrazine". Xu Kuo, Wang Penglong, Han Qiujun, etc. Anhui Medicine, 2013, 17(9): 1467- 1470" method. Weigh 20.00g (0.15mol) anhydrous ligustrazine, 23.54g NBSN-bromosuccinimide (0.15mol, finely ground before use) into a 250mL three-necked flask, 100mLCCl 4 As the reaction solvent, 4 85W incandescent lamps were irradiated, and the reaction was refluxed at 95°C for 1 hour. TLC [V (petroleum ether): V (acetone) = 3:1] detected that the reaction was basically complete; after cooling, it was filtered, the filtrate was collected, and the solvent was recovered under reduced pressure to obtain a purple-red viscous liquid (content is 60%). HRMS(ESI)m / z: 216.00135[M+H] + , Theoretical calculation: C 8 H 11 BrN 2 : 216.00851.

Embodiment 2

[0086] Example 2 Preparation of compound G-TOA

[0087] Weigh 66.57mg (0.38mmol) Boc-L-glycine, 95.50mg (0.50mmol) EDCI, 3.05mg (0.025mmol) DMAP and 147.75mg (0.25mmol) TOA in a 50mL single-neck flask, and add an appropriate amount of dichloride Methane dissolved it and stirred overnight at room temperature. TLC [V(dichloromethane): V(methanol)=20:1] detects the reaction progress, the reaction solution is extracted with dichloromethane, the organic layer is collected, an appropriate amount of anhydrous sodium sulfate is removed from the water, evaporated under reduced pressure, and separated by silica gel column [V(dichloromethane):V(methanol)=20:1] to obtain a white solid; dissolve it in ethyl acetate containing 3M HCl, stir in an ice-salt bath for 1 h; evaporate the reaction solution under reduced pressure and use appropriate amount of ethyl acetate Reconstitute, adjust the pH to neutral with saturated sodium bicarbonate solution, collect the organic layer, remove water with a...

Embodiment 3

[0088] Example 3 Preparation of Compound A-TOA

[0089] Weigh 71.90mg (0.38mmol) Boc-L-alanine, 95.50mg (0.50mmol) EDCI, 3.05mg (0.025mmol) DMAP and 147.75mg (0.25mmol) TOA in a 50mL single-necked flask, and add an appropriate amount of Dissolve with dichloromethane and stir overnight at room temperature. According to the operation of Example 2, a white solid with a melting point of 89.7-92.1°C was obtained, (c1.0, methanol), yield: 56%. 1 H-NMR(CDCl 3 )δ(ppm): 0.54, 0.89, 1.11(s, each, 3H, 3×-C H 3 , The methyl group of oleanolic acid), 0.87 (brs, 6H, 2×-C H 3 , The methyl group of oleanolic acid), 0.91 (brs, 6H, 2×-C H 3 , The methyl group of oleanolic acid), 2.49, 2.51, 2.55 (s, each, 3H, 3×-C H 3 , The methyl group of ligustrazine), 2.74 (brs, 2H, -N H 2 ), 2.86(m, 1H, -CH=CC H -), 3.58(s, 1H, -NH 2 C H -), 4.53(m, 1H, -OCOC H -), 5.12, 5.19 (d, each, J=10Hz, 1H, -OC H 2 -), 5.24 (brs, 1H, -C H =C-), 1.00-2.50 (25H, methyl of alanine, methine and methylene of oleanolic acid);...

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PUM

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Abstract

The invention provides a preparation method of compounds with the structure represented by general formula 1, and an application of the compounds in the preparation of antitumor drugs. The compounds are prepared through ester bond condensation of a 3th hydroxyl group of an anticancer lead compound TOA (patent 201110055102.X) and a carboxyl group of amino acids; and the compounds have a more substantial inhibition effect on liver cancer, colorectal carcinoma, cervical carcinoma and stomach cancer cell lines than the TOA, have smaller toxicity to normal cells than cis-platinum, have obviously better water solubility than the TOA, and are especially suitable for preparing antitumor treatment drugs.

Description

Technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacology, in particular to the general structural formula of X-TOA and its synthesis and application. Pharmacological experiments have proved that this type of compound has obvious anti-tumor effects and is less toxic to normal cells; compared with precursor compounds TOA improves the toxicity of tumor cells and at the same time improves its hydrophilicity. It can be used to prepare the prevention and treatment of liver cancer and other cancers. [0002] X-TOA structure general formula [0003] [0004] Among them, R stands for glycine, alanine, proline, leucine, isoleucine, valine, lysine, phenylalanine, sarcosine, pyroglutamic acid, tryptophan and serine . Background technique [0005] Chinese patent ZL201110055102.X discloses the anti-cancer lead compound TOA. The pharmacodynamic experiment shows that the lead TOA can significantly inhibit the proliferation of a variety of tumor ce...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61P35/00
CPCY02P20/55
Inventor 雷海民王鹏龙褚福浩张宇忠刘伟
Owner 思路迪生物医药(上海)有限公司
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