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Amide arylpiperazine derivative and preparation method and application thereof

A technology of arylpiperazine and derivatives, applied in the field of medicinal chemistry, can solve the problems of cardiovascular side effects, difficulty in distinguishing blood vessels and urinary tract α-adrenergic receptors, etc., achieve strong inhibitory activity, good inhibitory selectivity, and ensure drug The effect of curative effect

Active Publication Date: 2018-09-14
袁牧
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the currently used α1-AR antagonists are generally antagonistic to the three subtypes of α1-AR (Eur.J.Pharmacol.1999,374,495–502), and it is difficult to distinguish vascular and urinary tract α-adrenergic receptors , often lead to a series of cardiovascular side effects in patients while treating BPH

Method used

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  • Amide arylpiperazine derivative and preparation method and application thereof
  • Amide arylpiperazine derivative and preparation method and application thereof
  • Amide arylpiperazine derivative and preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example 1

[0038] Preparation Example 1 Preparation of Intermediate II

[0039]

[0040] Dissolve 5g of 4-bromo-n-butane-1-ammonia hydrobromide and 4.686g (1.5eq) of di-tert-butyl dicarbonate in dichloromethane solution, stir to dissolve, slowly dropwise add 193mg (0.1eq) 4-Dimethylaminopyridine and 8.688g (4eq) of triethylamine in dichloromethane were reacted at room temperature for 1.5h. Finally, the reaction solution was washed with 0.5N hydrochloric acid aqueous solution and saturated brine in a separating funnel, dried over anhydrous sodium sulfate, filtered, and the organic solvent was distilled off under reduced pressure to obtain 5.387 g of Intermediate II.

preparation example 2

[0041] Preparation Example 2 Preparation of Intermediate III

[0042]

[0043] Intermediate II (5.387g) (1.5eq) was dissolved in acetonitrile, and 5.923g (3eq) of potassium carbonate solid and 3.150g of 2-isopropoxyphenylpiperazine were added, and refluxed at 80°C overnight. After the reaction solution was filtered, the mixed sample was applied to a silica gel column, and gradient elution was performed with petroleum ether and ethyl acetate to obtain 4.502 g of Intermediate III.

preparation example 3

[0044] Preparation Example 3 Preparation of Intermediate IV

[0045]

[0046]Dissolve 4.502g of intermediate III in 120ml of dichloromethane, slowly dropwise add 30ml of trifluoroacetic acid and stir at room temperature, spot the plate to monitor the end of the reaction. After the reaction was complete, add 20% aqueous sodium hydroxide solution to adjust the reaction solution to be alkaline, then extract 3 times with dichloromethane, dry over anhydrous sodium sulfate, remove the organic solvent by distillation under reduced pressure to obtain 3.203g of intermediate IV, without further purified and used directly in the next reaction.

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, particularly relates to an amide arylpiperazine derivative and further discloses a preparation method and application of the amide arylpiperazine derivative to preparation of medicines for treating benign prostatic hyperplasia. According to primary pharmacological researches on the amide arylpiperazine derivative and pharmaceutically acceptable salts, the derivative shows high antagonistic activity and selectivity on alpha1A-AR and alpha1D-AR but weak alpha1B subtype antagonistic activity in biological functional tests of rat in-vitro tissues (such as spleen, thoracic aorta and sperm duct), and accordingly medicinal side effects can be effectively reduced while medicinal curative effects are guaranteed, and efficientand safe options can be provided for research and development of novel medicines for benign prostatic hyperplasia.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to an amide-type arylpiperazine derivative, and further discloses a preparation method thereof and an application for preparing a medicine for treating benign prostatic hyperplasia. Background technique [0002] Benign prostatic hyperplasia (BPH) is a common urinary disorder in elderly men. The main clinical manifestations of BPH are lower urinary tract symptoms (LUTS), including frequent urination, urgency, waiting for urination, increased nocturia, and urination. Weakness and other symptoms; severe cases can lead to complications, such as acute urinary retention, urinary incontinence, recurrent urinary tract infections, hematuria, kidney failure, bladder stones, etc. In recent years, with the improvement of national living standards, the prolongation of the average life expectancy of the population and the acceleration of population aging, its incidence has ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/13C07D213/56C07D307/79C07D319/20C07D233/26C07D223/10C07D209/18C07D295/15C07D277/30C07D213/80C07D213/803C07D495/04A61P13/08
CPCA61P13/08C07D209/18C07D213/56C07D213/80C07D213/803C07D223/10C07D233/26C07D277/30C07D295/13C07D295/15C07D307/79C07D319/20C07D495/04
Inventor 袁牧陈洪叶碧波邵斌豪黄珺珺刘夏雯
Owner 袁牧
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