Aryl piperazine derivatives (III), salt thereof, preparation method, and application

A technology of arylpiperazine and its derivatives, which is applied in the discovery of drug lead compounds and in the field of medicinal chemistry, which can solve the problems that prostate cancer cannot be cured, and the treatment result or survival rate cannot be improved.

Inactive Publication Date: 2015-11-18
广州市广金创展投资有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, metastatic prostate cancer is not curable and androgen ablation therapy becomes standard therapy
None of the conventional cancer treatments for prostate cancer have been very successful, although various chemotherapeutic drugs alone or in combination with radiation therapy are used to treat patients with advanced disease
Other studies have shown that once tumor cells become hormone-resistant, standard cytotoxic agents do little to improve treatment outcomes or survival in hormone-insensitive prostate cancer, although they do provide some pain relief for patients

Method used

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  • Aryl piperazine derivatives (III), salt thereof, preparation method, and application
  • Aryl piperazine derivatives (III), salt thereof, preparation method, and application
  • Aryl piperazine derivatives (III), salt thereof, preparation method, and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the preparation of intermediate 2

[0046]

[0047] Add 5 g (0.021 mol) of 4-(bromoethane) phenylacetic acid and 100 mL of tetrahydrofuran into a 250 mL round bottom flask, and slowly add 21.9 mL of borane dimethyl sulfide complex (BMS, 2MinTHF) 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

[0048] Embodiment 2: the preparation of intermediate 3

[0049]

[0050] Add 4g (18.7mmol) of intermediate 2, 3.85g (18.7mmol) of sodium saccharin, 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) = 1:6, to obtain 5.90 g of white solid, yield: 85% (using raw material 4-(bromoethane ) phenylacetic acid calculation). M.p.:97-98℃; MS(ESI,m / z):318.07[M+H] + ; 1 HNMR (500MHz, DMSO-d 6 )δinppm: 8.33 (d, J = 7.7Hz, 1H, Ar-H), 8.15–7.98 (m, 3H, Ar-H), 7.33 (d, J = 8.0Hz, 2H, Ar-H), 7.20 ( d,J=8.0Hz,2H,Ar-H),4.87(s,2H,CH 2 ), 3.58 (td, J=7.0, 5.4Hz, 2H, CH 2 ),2.70(t,J=7.0Hz,2H,CH 2 ),2.23(t,J=5.2Hz,1H,OH); 13 CNMR (126MHz, DMSO-d 6 )δinppm: 158.58, 139.19, 136.82, 135.87, 135.3...

Embodiment 3

[0051] Embodiment 3: the preparation of intermediate 4

[0052]

[0053]Add 4g (12.62mmol) of intermediate 3, 5.09g (50.48mmol) of triethylamine, 0.15g of 4-(N,N-dimethyl)aminopyridine (catalytic amount), 100mL of dichloromethane into a 250mL round bottom flask, A dichloromethane solution of 3.59 g (18.93 mmol) p-toluenesulfonyl chloride (TsCl) was slowly added 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) = 1:8, to obtain 4.75 g of white solid, yield: 80%. M.p.:119-120℃; MS(ESI,m / z):472.08[M+H] + ; 1 HNMR (400MHz, CDCl 3 )δinppm: 8.33 (d, J = 7.7Hz, 1H, Ar-H), 8.15–7....

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PUM

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Abstract

The invention relates to the fields of pharmaceutical chemistry and pharmaceutical lead compound research, and specifically relates to aryl piperazine derivatives (I); wherein the definitions of R1 to R5 are defined in the description. The invention also discloses a preparation method of the aryl piperazine derivatives and an antitumor application of the novel derivatives. The compounds have been subjected to primary pharmacodynamics research and in-vitro antitumor experiments, and the results show that some compounds have good antitumor activity and can be used to develop novel antitumor drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry and discovery of drug lead compounds, in particular to a class of novel arylpiperazine derivatives, their preparation method and application in antitumor drugs. Background technique [0002] Prostate cancer (PCa) is a very common disease in men, ranking second among male lethal cancers, and its morbidity and mortality are second only to lung cancer (CancerMetast.Rev, 2005, 12, 631; CA-CancerJ.Clin , 2012.62, 10). The incidence of PCa in European and American countries is much higher than that in China, Japan and other East Asian countries, and now the incidence of prostate cancer in my country is also showing an increasing trend (Journal of Clinical Oncology, 2013, 18, 330), prostate cancer has become a global problem ( Int. J. Cancer, 1984, 33, 223). [0003] Clinically, localized disease can be cured by surgery or radiation therapy to remove or destroy cancer cells. However, metastatic prost...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D275/06A61K31/496A61P35/00
CPCC07D275/06
Inventor 袁牧陈洪许芳叶碧波郭洁文许冰冰梁雪邵斌豪杨宗琳黄珺珺朱柳
Owner 广州市广金创展投资有限公司
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