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Substituted benzene propenyl piperazinyl alkyl polyhydric benzamide compound and preparation method and application thereof

A compound and alkyl technology, which is applied in the field of preparation of HIV-1 integrase inhibitors, can solve the problems of drug resistance, central nervous disorder, multi-drug resistance, etc., and achieve the effect of mild reaction conditions and simple steps

Inactive Publication Date: 2011-05-11
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, some currently used drugs can cause side effects such as liver failure, central nervous disturbances (such as dizziness)
In addition, long-term use will cause problems such as serious drug resistance
To make matters worse, HIV-1 is known to exhibit multidrug resistance in multi-drug combination therapy

Method used

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  • Substituted benzene propenyl piperazinyl alkyl polyhydric benzamide compound and preparation method and application thereof
  • Substituted benzene propenyl piperazinyl alkyl polyhydric benzamide compound and preparation method and application thereof
  • Substituted benzene propenyl piperazinyl alkyl polyhydric benzamide compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of (E)-N-(3-(4-phenylacryloylpiperazin-1-yl)propanyl)-3,4,5-trihydroxybenzamide

[0042] (a) Add 0.03mol of 3-chloropropylamine hydrochloride into the three-necked flask, then add 30mL of anhydrous-treated dichloromethane, and add dropwise to the dichloromethane solution of 3-chloropropylamine hydrochloride 10mL of triethylamine solution, stirred and reacted for half an hour, then added dropwise 0.01mol of 3,4,5-trimethoxybenzoyl chloride in dichloromethane solution at 0°C, after the dropwise addition was completed, remove the ice bath, React overnight at room temperature. The reaction system was washed with 30mL saturated NaHCO 3 solution, 30mL of 2mol / L hydrochloric acid solution and 30mL of saturated saline solution, the organic phase was separated and dried with anhydrous sodium sulfate, and vacuum precipitation can obtain N-3-chloropropyl-3,4,5-trimethyl Oxybenzamide, yield: 88%.

[0043] (b) Preparation of N-3-(piperazin-1-yl)propyl-3,4,5-trimethoxy...

Embodiment 2

[0063] Preparation of (E)-N-(3-(4-p-methylbenzoylpiperazin-1-yl)propanyl)-3,4,5-trihydroxybenzamide

[0064] (a), (b) steps are with embodiment 1

[0065] (c) Preparation of (E)-N-(3-(4-p-toluacryloylpiperazin-1-yl)-propanyl)-3,4,5-trimethoxybenzamide

[0066]

[0067] Add 10 mL of thionyl chloride to 4.0 mmol of p-methylcinnamic acid, reflux for 4 to 5 hours, remove excess thionyl chloride under reduced pressure, and add 15 mL of dichloromethane after cooling for later use.

[0068] 3mmol of NaHCO 3 Add N-3-(piperazin-1-yl)propyl-3,4,5-trimethoxybenzamide (3mmol) in dichloromethane solution, and dichloride of p-toluacryloyl chloride The methane solution was slowly added dropwise to the stirred solution at 0°C, and after 1 hour, the ice bath was removed and left to stand overnight, and then 30 mL of saturated NaHCO 3 solution, 30mL of 2molL -1 Hydrochloric acid and 30 mL of saturated saline solution, the organic phase was separated with a separatory funnel, dried over a...

Embodiment 3

[0080] Preparation of (E)-N-(3-(4-p-chlorophenylacryloylpiperazin-1-yl)propanyl)-3,4,5-trihydroxybenzamide

[0081] (a), (b) steps are with embodiment 1

[0082] (c) Preparation of (E)-N-(3-(4-p-chlorophenylacryloylpiperazin-1-yl)-propanyl)-3,4,5-trimethoxybenzamide

[0083]

[0084] Add 10 mL of thionyl chloride to 3.8 mmol of p-chlorocinnamic acid, reflux for 4 to 5 hours, remove excess thionyl chloride under reduced pressure, and add 15 mL of dichloromethane after cooling for later use.

[0085] 3mmol of NaHCO 3 Add N-3-(piperazin-1-yl)propyl-3,4,5-trimethoxybenzamide (3mmol) in dichloromethane solution, and then add p-chlorophenylacryloyl chloride in dichloromethane The solution was slowly added dropwise to the stirred solution at 0°C, and after 1 hour, the ice bath was removed and left to stand overnight, and then 30 mL of saturated NaHCO 3 solution, 30mL of 2molL -1 Hydrochloric acid and 30 mL of saturated saline solution, the organic phase was separated with a se...

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Abstract

The invention relates to a (E)-N-3-(4-substituted benzene propenyl piperazine-1-base) alkyl benzamide compound shown in a formula (I) or a salt thereof, wherein R<1>, R<2> and R<3> express -H, -OH, -ONa, -OK or -ONH4, R<4> and R<5> express-H, halogen, C(1-3) linear or branched alkyl, -OH, -ONa, -OK, -ONH4, -NO2 or -CN, and n is an integer of 1-3. The invention also relates to a preparation methodof the compound, which comprises the following steps: synthesizing multi-alkoxy benzoyl chloride substituted alkylamine by using multi-substituted benzoyl chloride and hydrochloride of chlorinated alkyl amino as raw materials; carrying out reaction on the compound and piperazine to prepare N-piperazinyl alkyl multi-substituted benzamide; reacting with substituted benzene acryloyl chloride to prepare (E)-N-3-(4-substituted benzene propenyl piperazine-1-base) alkyl benzamide; acting with BBr3 or BF3 aether solution to be further hydrolyzed to generate the corresponding (E)-N-3-(4-substituted benzene propenyl piperazine-1-base) alkyl polyhydric benzamide compound, and then reacting with alkaline to generate the corresponding salt. The compound has inhibition function to HIV-1 integrase.

Description

technical field [0001] The invention relates to (E)-N-3-(4-substituted phenylpropenylpiperazin-1-yl)alkylbenzamide compounds and their salts, their preparation methods and their use in the preparation of HIV-1 integrase inhibitors in the application. Background technique [0002] AIDS is a major infectious disease that gradually destroys the human immune system and seriously threatens human health and survival. Since it was first discovered in 1981, it has spread rapidly around the world. By the end of 2008, there were 33.2 million surviving HIV-1 infections worldwide. In 2008, there were 2.5 million new infections and 2.1 million deaths. 70 million people. [0003] HIV-1 (Human Immunodeficiency Virus-I), which belongs to retroviruses, is a virus that causes AIDS (Acquired Immunodeficiency Syndrome, AIDS). [0004] HIV-1 targets CD4-positive cell populations such as helper T cells, macrophages, and dendritic cells, etc., and destroys these immunocompetent cells, resulting...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/182A61K31/445A61P31/18
Inventor 胡利明黄雅理徐雪梅曾程初何红秋王存新
Owner BEIJING UNIV OF TECH
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