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Benzamide derivative resisting proliferative activity and pharmaceutical preparation thereof

A benzamide and pharmacy technology, applied in the field of new benzamide derivatives and preparation thereof, can solve the problems of unsuitability for large-scale preparation, large side effects and high production cost

Inactive Publication Date: 2013-05-08
INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] But these drugs have the following disadvantages: (1) low curative effect, short-chain fatty acids, such as butyric acid and other anti-tumor effects are poor; (2) side effects are large, and hydroxamic acid compounds are based on Zn 2+ In order to bind the target, it is known that there are many Zn-containing 2+ protein, so the side effects of hydroxamic acid compounds are relatively large; (3) the cost is high, and the cyclotetraphthalein structure containing epoxyketone group and the cyclotetrapeptide structure without epoxyketone group need to be prepared by biological methods. Separation and purification by high-performance liquid chromatography is not suitable for large-scale preparation, and the production cost is high; if it is prepared by chemical method, the cost will be higher
(4) Stability is poor, because benzamides contain phenylenediamine structure, their physical and chemical properties are unstable

Method used

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  • Benzamide derivative resisting proliferative activity and pharmaceutical preparation thereof
  • Benzamide derivative resisting proliferative activity and pharmaceutical preparation thereof
  • Benzamide derivative resisting proliferative activity and pharmaceutical preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0205] Example 1. Synthesis of N-(2-amino-5-fluorophenyl)-4((4-(pyridin-3-yl)pyrimidine-2-amino)methyl)benzamide (compound 1)

[0206] Step 1. Synthesis of 3,3-Dimethylamino-1-pyridin-3-yl-propenone

[0207] Dissolve 2g of 3-acetylpyridine in 5ml of anhydrous N,N-dimethylformamide, then add 5ml of N,N-dimethylformamide diacetal to the solution, and heat to 110°C for reaction 3 Hours, thin-layer chromatography showed that the reaction was complete, N,N-dimethylformamide was recovered under reduced pressure, the residual liquid was placed in the refrigerator overnight, a yellow solid was precipitated, filtered by suction, washed with ethyl acetate / petroleum ether 1:1, to obtain Yellow solid 2.05g.

[0208] The melting point of the product is m.p.82-83°C;

[0209] Step 2. Synthesis of 4-guanidinomethyl-benzoic acid

[0210] Dissolve 2g of methylisothiourea sulfate in 10ml of 1mol / L sodium hydroxide aqueous solution, slowly add 2.15g of 4-aminomethylbenzoic acid dropwise under ...

Embodiment 2

[0260] Example 2. Synthesis of N-(2-amino-5-fluorophenyl)-4-((4-methoxyphenylamino)methyl)benzamide (compound 5)

[0261] Step 1. Synthesis of methyl p-aldehyde benzoate

[0262] Dissolve 2.0 g of p-aldehyde benzoic acid in 20 ml of methanol, slowly add 1.81 ml of thionyl chloride dropwise under ice bath, after the addition is completed, after heating and refluxing for 3 hours, thin layer chromatography shows that the reaction is complete, and the solvent is recovered under reduced pressure. Cool and filter to obtain 2.13 g of light yellow solid.

[0263] The melting point of the product is m.p.59-61°C;

[0264] Step 2. Synthesis of methyl 4-((4-methoxyphenylamino)methyl)benzoate hydrochloride

[0265] Dissolve 1.59g of p-aminoanisole and 2.13g of the product of step 1 in 15ml of methanol, and add 3.07g of NaBH in batches under ice-cooling 4 , and dropwise added glacial acetic acid to keep the pH of the reaction solution at 5-6, thin-layer chromatography showed that the rea...

Embodiment 3

[0304] Example 3. Synthesis of 4-(((phenylethyl)(2-hydroxyethyl)amino)methyl)-N-(2-amino-5-fluorophenyl)benzamide (compound 8)

[0305] Step 1. Synthesis of methyl 4-((phenethylamino)methyl)benzoate hydrochloride

[0306] Dissolve 1.43ml of phenethylamine and 1.46g of methyl p-aldehyde benzoate in 10ml of methanol, add 2.5g of sodium borohydride in batches under ice bath, and add dropwise glacial acetic acid to keep the pH of the reaction solution at 5-6, thin layer Chromatography showed that the reaction was complete, and the solvent was removed under reduced pressure. The residue was distributed in ethyl acetate / water and made acidic with 2N hydrochloric acid. A large amount of white solid was precipitated, which was filtered and dried to obtain 2.06 g of white solid.

[0307] Step 2. Synthesis of methyl 4-(((2-(tert-butyldimethylsilyloxy)ethyl)(phenethyl)amino)methyl)benzoate

[0308] Take a 100ml dry three-necked bottle, under the protection of dry nitrogen, dissolve 2.06...

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Abstract

The invention discloses a novel benzamide derivative represented by the formula (I), wherein various substituent groups Het, G1, G2, G3, Y, X1, X2, X3 and X4 are defined in the specification. Furthermore, the invention further discloses preparation methods of the compounds, pharmaceutical compositions containing the compounds, and the purposes of the compounds as active components of medicines for treating diseases related to proliferation, such as leukemia and solid tumours.

Description

[0001] This application is a divisional application of the application number 200880015929.4 and the title of the invention "benzamide derivatives with antiproliferative activity and their pharmaceutical preparations" submitted on March 14, 2008. technical field [0002] The present invention relates to a kind of compound that is used for the treatment of diseases related to proliferation, more specifically, relates to a kind of new benzamide derivative and its preparation method, the salt of the derivative and the compound or its salt Drugs that are active ingredients. Background technique [0003] Malignant tumors seriously threaten human life and health. According to the statistics of the World Health Organization, about 6.3 million people die of malignant tumors in the world every year, and about 1.5 million people die of cancer every year in my country. At present, there are more than 1.8 million new cancer patients in China every year. Due to factors such as environme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D405/04C07D239/42C07D403/04C07D409/04A61K31/506A61K31/5377A61P17/06A61P35/00A61P35/02
CPCC07D307/85C07D239/96C07D417/04C07D239/42C07D403/04C07D241/20C07D405/12C07D317/58C07D405/04C07D407/12C07D317/66C07D401/04C07D401/12C07D407/04C07D409/04C07D239/94C07D239/38A61P17/06A61P35/00A61P35/02
Inventor 李庶心刘永学赵砚瑾韩春光匡先照黄琳仪肖文松孙小梅邓晓东薛阳叶清泉
Owner INST OF RADIATION MEDICINE ACAD OF MILITARY MEDICAL SCI OF THE PLA
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