Ether arylpiperazine derivatives and salts thereof, preparation method and use

An arylpiperazine, derivative technology, applied in the discovery of drug lead compounds, the field of medicinal chemistry, can solve the difficulty in distinguishing vascular and urinary tract α-adrenergic receptors, cardiovascular side effects, poor α1 receptor subtype selectivity, etc. question

Active Publication Date: 2017-04-12
GUANGZHOU MEDICAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this class of α1 receptor antagonists has poor selectivity for α1 receptor subtypes, so the clinically used α1 receptor antagonists for the treatment of BPH generally have cardiovascular system (CVS) adverse reactions
[0007] The third-generation drug for the treatment of BPH is a highly selective α1 receptor antagonist, such as tamsulosin, which is being used clinically and has a good effect. Clinical trials have shown that compared with non-subtype-selective α1-AR antagonists, Tamsulosin has little effect on blood pressure and orthostatic hypotension, but produces a series of side effects, such as abnormal ejaculation, cardiovascular symptoms, sexual dysfunction and dizziness (Eur. Urol, 1999, 36, 1–13).
[0008] However, the main difficulty of the currently used α1-AR antagonists is that most antagonists have general antagonism to the three subtypes of α1-AR (Eur.J.Pharmacol.1999,374,495–502), and it is difficult to distinguish between vascular and urinary tract α adrenergic receptor
Therefore, leading to a series of cardiovascular side effects in patients

Method used

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  • Ether arylpiperazine derivatives and salts thereof, preparation method and use
  • Ether arylpiperazine derivatives and salts thereof, preparation method and use
  • Ether arylpiperazine derivatives and salts thereof, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: the preparation of intermediate 2

[0066]

[0067] Add 5g (0.021mol) 4-(bromoethane) phenylacetic acid, 100mL tetrahydrofuran into a 250mL round bottom flask, slowly add 21.9mL borane dimethyl sulfide complex (BMS, 2M in THF) at 0°C . The reaction mixture was reacted at 0° C. for 1 h, and then gradually returned to normal temperature. After the reaction was completed, water was slowly added to terminate the reaction, extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was directly used in the next reaction without purification.

Embodiment 2

[0068] Embodiment 2: the preparation of intermediate 3

[0069]

[0070] Add 4g (18.7mmol) of intermediate 2, 2.58g (18.7mmol) of sesamol, 10.32g (74.8mmol) of potassium carbonate, and 150mL of acetone into a 250mL round bottom flask, and react at 60°C for 16h. TLC showed the starting material was completely reacted. The reaction was stopped, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluent: V (ethyl acetate): V (petroleum ether) = 1:10, to obtain 4.06 g of white solid, yield: 67% (using 4-(bromoethane as raw material) ) phenylacetic acid calculation). M.p.: 102-103°C; 1 H NMR (400MHz, DMSO-d 6 )δin ppm: 7.32(d, J=8.0Hz, 2H), 7.22(d, J=8.0Hz, 2H), 6.79(d, J=8.5Hz, 1H), 6.68(d, J=2.5Hz, 1H ),6.43(dd,J=8.5,2.5Hz,1H),5.94(s,2H),4.97(s,2H),4.60(t,J=5.2Hz,1H),3.60(td,J=7.0, 5.2Hz, 2H), 2.72(t, J=7.0Hz, 2H); 13 C NMR (101MHz, DMSO-d 6 )δinppm: 154.25, 148.34, 141.64, 139.65, 135.07, 129.33, 128.09, 108.46, 106.64, 101.4...

Embodiment 3

[0071] Embodiment 3: the preparation of intermediate 4

[0072]

[0073] Add 4g (14.7mmol) of intermediate 3, 5.94g (58.8mmol) of triethylamine, 0.18g of 4-(N,N-dimethyl)aminopyridine (catalytic amount), 100mL of dichloromethane into a 250mL round bottom flask, A dichloromethane solution of 4.19 g (22.1 mmol) p-toluenesulfonyl chloride (TsCl) was added slowly at 0°C. The reaction mixture was reacted at 0° C. for 16 h, and TLC showed that the starting material was completely reacted. Slowly add water to terminate the reaction, extract with dichloromethane (100 mL×3), combine the organic phases, wash with water and saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate. The crude product was purified by silica gel column chromatography, eluent: V (ethyl acetate): V (petroleum ether) = 1:15, to obtain 5.76 g of white solid, yield: 95%. M.p.:90-91℃; 1 H NMR (400MHz, DMSO-d 6 )δin ppm: 7.65(d, J=8.0Hz, 2H), 7.40(d, J=8.0Hz, 2H), 7.30(d, J=8.0Hz, 2H), ...

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Abstract

The invention discloses ether aryl piperazine derivatives and salt thereof as well as a preparation method and application of the ether aryl piperazine derivatives and in particular relates to an ether aryl piperazine derivative (I), wherein, the definitions of m, n, o, X, Y, Z, R and R1-R5 are described in the specification. The invention also discloses a preparation method of the ether aryl piperazine derivatives and application of the ether aryl piperazine derivatives in resistance to benign prostatic hyperplasia and tumour. Primary pharmacodynamic study on the ether aryl piperazine derivative compounds is carried out, a dual-luciferase reporter gene and an in-vitro anti-tumour experiment are carried out, and results show that some ether aryl piperazine derivative compounds have good alpha1-AR subtype selectivity and good antitumour activity and can be developed into a novel benign prostatic hyperplasia resistant and anti-tumour medicament.

Description

technical field [0001] The invention relates to the field of medicinal chemistry and the discovery of drug lead compounds, in particular to a novel ether aryl piperazine derivative, its preparation method and its use in the preparation of anti-benign prostatic hyperplasia drugs and anti-tumor drugs. 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): frequent urination, urgency, waiting for urination, increased nocturia, and urinary weakness. Severe cases can lead to complications such as acute urinary retention, urinary incontinence, recurrent urinary tract infections, hematuria, kidney failure, and bladder stones. As the disease progresses, complex complications are accompanied. Therefore, the therapeutic drug research of BPH has become a new focus of research on senile diseases (J.Med.Chem.1988,31,1087-1093; Br.J.Pharmacol.2000,129,65...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/64C07D405/12A61P13/08A61P35/00
CPCC07D317/64C07D405/12
Inventor 袁牧陈洪许芳叶碧波何雪兰梁雪黄碧云许冰冰黄珺珺朱柳
Owner GUANGZHOU MEDICAL UNIV
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