Amide arylpiperazine derivatives, their preparation method, and their application in benign prostatic hyperplasia resistance

The technology of a compound, triethylamine, is applied in the field of preparation of drugs for the treatment of benign prostatic hyperplasia, which can solve problems such as clinical use restrictions

Inactive Publication Date: 2013-11-13
广州医学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the current α 1 Receptor blockers prazosin, terazosin, and doxazosin belong to furancarbonylpiperazines in structure, and experiments show that they do not have alpha 1 Subtype receptor selectivity, none 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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  • Amide arylpiperazine derivatives, their preparation method, and their application in benign prostatic hyperplasia resistance
  • Amide arylpiperazine derivatives, their preparation method, and their application in benign prostatic hyperplasia resistance
  • Amide arylpiperazine derivatives, their preparation method, and their application in benign prostatic hyperplasia resistance

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Embodiment 1: the preparation of compound 1

[0098] Dissolve 3-bromopropylamine hydrobromide (0.01mol) in 10% sodium hydroxide solution (50mL), extract with dichloromethane (3×50mL), dry the organic layer with anhydrous sodium sulfate, filter and concentrate Finally, the obtained free base (1.2 g) and di-tert-butyl dicarbonate (0.011 mol) were mixed and stirred in dichloromethane for 5 hours, the reaction solution was washed with water, dilute hydrochloric acid, and saturated sodium bicarbonate solution successively, and the organic layers were combined. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain a colorless oily liquid (2.2 g, yield 92%).

[0099] React the colorless oily liquid obtained in the previous step with o-methoxyphenylpiperazine (molar ratio 1:2), use dichloromethane as solvent, stir at room temperature for 6-10 hours, add water to the reaction solution, and combine the organic layers , dried, recovered the solvent, and separated t...

Embodiment 2

[0102] Embodiment 2: the preparation of compound 2

[0103] The light yellow oil represented by formula (11) was prepared according to the method of Example 1.

[0104] Dissolve the light yellow oil obtained in the previous step (0.5g, 0.0020mol) in dichloromethane (50mL), add DIPEA (0.5mL), add HATU (0.76g) and mix with 3-indoleacetic acid (0.35g) A solution in DMF (20 mL) was protected with nitrogen and stirred at room temperature for 6-10 hours. The reaction solution was washed with water, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was recovered, and separated by silica gel column chromatography (100-200 mesh silica gel sample was mixed, 300-400 mesh silica gel column was packed), ethyl acetate was used as the eluent, and Thin-layer chromatography detection, collecting the ethyl acetate-triethylamine volume ratio of 40:1 on the thin-layer plate, the fraction with a ratio shift value of 0.4~0.6 was obtained, and 0.63g of a pink viscou...

Embodiment 3

[0105] Embodiment 3: the preparation of compound 3

[0106] The light yellow oil represented by formula (11) was prepared according to the method of Example 1.

[0107] Dissolve the light yellow oil obtained in the previous step (0.5g, 0.0020mol) in dichloromethane (50mL), add DIPEA (0.5mL), add HATU (0.76g) and 3-indolepropionic acid (0.38g) The solution mixed with DMF (20 mL) was protected with nitrogen and stirred at room temperature for 6-10 hours. The reaction solution was washed with water, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was recovered, and separated by silica gel column chromatography (100-200 mesh silica gel sample was mixed, 300-400 mesh silica gel column was packed), ethyl acetate was used as the eluent, and Thin-layer chromatography was used to collect the fraction with a ratio shift of 0.4-0.6 when the volume ratio of ethyl acetate-triethylamine was 40:1 on the thin-layer plate, and 0.60 g of the product was obtai...

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Abstract

The invention relates to ten amide arylpiperazine derivatives, their preparation method, and their use in the preparation of benign prostatic hyperplasia treatment medicines. The preparation method of the amide arylpiperazine derivatives comprises the following steps: reacting free alkali of 3-bromopropylamine hydrobromide with di-tert-butyl dicarbonate to obtain a colorless oily liquid, reacting the colorless oily liquid with o-methoxyphenylpiperazine to obtain a light yellow oily material, reacting the light yellow oily material with trifluoroacetic acid to obtain a product, and reacting the product with N,N-diisopropylethylaine, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, and 5-indoleacetic acid or 3-indoleacetic acid or 3-indolepropionic acid or 3-indolebutyric acid or 5-hydroxy-2-indoleacetic acid or 5-methoxy-2-indoleacetic acid or 1-methyl-3-indoleacetic acid or 6-bromo-2-indoleacetic acid or 5-chloro-2-indoleacetic acid or 7-nitro-2-indoleacetic acid to obtain final products. Experiments prove that the benign prostatic hyperplasia resistance activities of eight compounds in the amide arylpiperazine derivatives are stronger than a contrast drug prazosin.

Description

technical field [0001] The present invention relates to derivatives of piperazine, in particular to novel amidoaryl piperazine derivatives, and also to a preparation method of these compounds and their use in the preparation of drugs for treating hyperplasia of the prostate gland. Background technique [0002] At present, the drugs for the treatment of benign prostatic hyperplasia are basically divided into two categories: one class uses 5α-reductase inhibitors; the other class uses α-reductase inhibitors. 1 Receptor antagonists relax prostate smooth muscle cells to achieve the purpose of relieving urinary tract obstruction, and the effect of the latter is more significant. Pathological studies have confirmed that benign prostatic hyperplasia is mainly stromal (smooth muscle and connective tissue) hyperplasia, and it has been reported in the literature that the stroma of benign prostatic hyperplasia mainly contains α 1 -AR. A large number of in vitro studies have confirmed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42A61K31/496A61P13/08
Inventor 袁牧黄珺珺朱柳季红黄亚建黎枭
Owner 广州医学院
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