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1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer, derivative and salt thereof and preparation and application of optical isomer

A technology of methoxyphenyl and optical isomers, applied in 1--3-piperazine)-2-propanol optical isomers, optical isomers of aryl piperazine compounds, for the preparation and treatment of hypertension and benign prostatic hyperplasia, which can solve problems such as clinical use restrictions

Inactive Publication Date: 2012-12-05
广州医学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since the currently used drugs are not alpha 1 - Receptor subtype selective antagonists, their effect on cardiovascular tissue alpha 1 -Receptors all have significant antagonistic effects at the same time, thus showing side effects such as orthostatic hypotension and reflex tachycardia, which greatly restricts clinical use

Method used

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  • 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer, derivative and salt thereof and preparation and application of optical isomer
  • 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer, derivative and salt thereof and preparation and application of optical isomer
  • 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer, derivative and salt thereof and preparation and application of optical isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of (R)-IV-1

[0042] Step 1: Preparation of R-3-(4-indoxyl)-1,2-propylene oxide

[0043] Add NaH (2.4g) and DMF into a dry four-neck flask, and stir well to make NaH a uniformly dispersed suspension. Slowly drop into the DMF solution of 6.65g (0.05mol) 4-oxindole at normal temperature, then slowly drop into the DMF solution of 13.68g (0.06mol) R-glycidyl p-toluenesulfonate after one hour, and continue the reaction at room temperature for 8 hour, water was added to remove excess NaH, the reaction was also extracted three times with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, filtered to obtain a yellow oil, column chromatography (petroleum ether: ethyl acetate 7: 1) After further purification, 7.88 g of light yellow liquid was obtained, with a yield of 84%.

[0044] Step 2: Synthesis of o-methoxyphenylpiperazine hydrochloride

[0045] Add 8.925g (0.05mol) of dichlorodiethanolamin...

Embodiment 2

[0052] Embodiment 2: the preparation of (S)-IV-1

[0053] Step 1: Preparation of S-3-(4-indoxyl)-1,2-propylene oxide

[0054] Add NaH (2.4g) and DMF into a dry four-neck flask, and stir well to make NaH a uniformly dispersed suspension. Slowly drop into the DMF solution of 6.65g (0.05mol) 4-oxindole at normal temperature, then slowly drop into the DMF solution of 13.68g (0.06mol) S-glycidyl p-toluenesulfonate after one hour, and continue the reaction at room temperature for 8 hour, water was added to remove excess NaH, the reaction was also extracted three times with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, filtered to obtain a yellow oil, column chromatography (petroleum ether: ethyl acetate 7: 1) After further purification, 7.01 g of light yellow liquid was obtained, with a yield of 74.6%.

[0055] Step 2: Synthesis of S-1-(2-methoxyphenyl)-4-[3-(4-indyloxy)-2-hydroxypropyl]piperazine

[0056] 3.84g (0.02m...

Embodiment 3

[0059] Embodiment 3: Preparation of (R)-IV-2

[0060] Step 1: Preparation of R-3-(4-indoxyl)-1,2-propylene oxide

[0061] Add NaH (2.4g) and DMF into a dry four-neck flask, and stir well to make NaH a uniformly dispersed suspension. Slowly drop into the DMF solution of 6.65g (0.05mol) 4-oxindole at normal temperature, then slowly drop into the DMF solution of 13.68g (0.06mol) R-glycidyl p-toluenesulfonate after one hour, and continue the reaction at room temperature for 8 hour, water was added to remove excess NaH, the reaction was also extracted three times with ethyl acetate, the organic phases were combined, washed with water, dried over anhydrous magnesium sulfate, filtered to obtain a yellow oil, column chromatography (petroleum ether: ethyl acetate 7: 1) After further purification, 8.44 g of light yellow liquid was obtained, with a yield of 90%.

[0062] Step 2: Synthesis of o-chlorophenylpiperazine hydrochloride

[0063]Add 8.925g (0.05mol) of dichlorodiethanolamine ...

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Abstract

The invention relates to a 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer, a derivative and a salt thereof and a preparation method and an application of the optical isomer. The 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer is characterized by being an optical isomer shown as a structural general formula (R)-I or formula (S)-I, wherein the substituents of R1' and R2' are hydrogen; or the optical isomer is a free alkali or salt shown as a structural general formula (R)-I or formula (S)-I, wherein the substituents of R1' and R2' are alkyl, alkoxyl, aryl, substituted aryl, aryloxy, substituted aryloxy or halogen, and the substituent of R in the formula is halogen, alkoxy or alkyl. The 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazidine)-2-propanol optical isomer is suitable for preparing a medicament for treating hypertension and benign prostatic hyperplasia; the conventional medicament excipients can be added for preparing oral dosage forms such as syrup, capsules, tablets and particles; and the medicament excipients can include solid carriers such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate and mannite, or oral excipients such as ethanol, glycerol and water, or adjuvants such as flavoring agents and sweeteners, or the conventional technical mixtures known by technological personnel in other preparation fields.

Description

technical field [0001] The present invention relates to optical isomers of arylpiperazine compounds, in particular to 1-(4-indoxyl)-3-(4-(2-methoxyphenyl)piperazine)-2- Propanol optical isomers, their derivatives and salts and their preparation methods and uses are suitable for the preparation of medicines for treating hypertension and benign prostatic hyperplasia. It belongs to the technical field of chemical pharmacy. Background technique [0002] Hypertension is a common chronic disease and frequently-occurring disease, and its incidence rate is increasing year by year and tends to be younger. It can lead to serious cardiovascular complications, such as hemorrhagic stroke, myocardial infarction, heart failure, cerebrovascular embolism and other organ damage. main expenditure point. The total number of hypertensive patients in my country ranks first in the world. According to data reports in 2010, the total number of hypertensive patients in my country exceeds 160 milli...

Claims

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Application Information

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IPC IPC(8): A61K31/496A61P9/12C07D209/43A61P13/08A61P13/02
Inventor 袁牧陈敏生朱柳季红黄碧云黄珺珺刘夏雯姜清芳赵鑫余清声纪缓缓
Owner 广州医学院
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