Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs

A technology of dihydropyrazole piperazine and derivatives, which is applied in the preparation of dihydropyrazole piperazine derivatives and the application field of anticancer drugs, can solve the problems of poor water solubility and limited clinical application, and achieve low toxicity, High reproducibility and good yield

Inactive Publication Date: 2015-10-07
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of these drugs have poor water solubility, which

Method used

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  • Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs
  • Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs
  • Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs

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Experimental program
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Embodiment approach

[0027] A detailed embodiment of the present invention is as follows:

[0028] Step 1: Under the action of stirring at 0±5°C, dissolve the compound represented by formula I in anhydrous methanol in a round bottom flask, and add SOCl dropwise 2 , after 10±5min, transfer to 20±10°C and continue to stir for 6±3h, filter and dry, dissolve the obtained solid crude product in absolute ethanol and recrystallize to obtain the compound shown in formula II.

[0029] Step 2: Under stirring at 20±10°C, sequentially add the compound shown in formula III, the compound shown in formula IV and absolute ethanol to the round bottom flask, and add 5-50% NaOH aqueous solution drop by drop , after reacting for 4±2h, filter, and the obtained solid was washed with distilled water, cold ethanol, and distilled water successively, and dried. The obtained solid crude product was dissolved in absolute ethanol for recrystallization to obtain a compound with the structure shown in Formula V.

[0030] Step ...

Embodiment 1

[0034] Preparation of N-methylpiperazino(4-(5-(α-naphthyl)-3-phenyl-4,5-dihydropyrazole)phenyl)methanone (Compound 80)

[0035]

[0036] Under stirring at 0°C, sequentially add the intermediate 55, 4-dimethylaminopyridine, 1-hydroxybenzotriazole and anhydrous dichloromethane into the reaction vessel, and after 10±5 minutes, add 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stirred and refluxed, TLC tracking reaction (developing agent V AcOEt :V 正己 烷 =2:1), after 8±3h, the reaction solution was sequentially washed with saturated KHSO 4 Aqueous solution, saturated Na 2 CO 3 , washed with saturated brine, and then rotary evaporated, and the obtained solid crude product was dissolved in absolute ethanol for recrystallization to obtain the target compound 80.

[0037] Crystals were obtained with a yield of 86.9%. 1 H NMR (DMSO-d 6 , 400MHz) δ: 8.33(s, 1H, ArH), 8.02(d, J=7.9Hz, 1H, ArH), 7.87(d, J=8.3Hz, 1H, ArH), 7.78(d, J=6.8Hz , 2H, ArH), 7.70~7.58(m, ...

Embodiment 2

[0039] N-Methylpiperazino(4-(5-(α-naphthyl)-3-(4-methyl-phenyl)-4,5-dihydropyrazole)phenyl)methanone (Compound 81) preparation of

[0040]

[0041] The preparation method refers to Example 1. Crystals were obtained with a yield of 88.3%. 1 H NMR (DMSO-d 6 , 400MHz) δ: 8.31(s, 1H, ArH), 8.01(d, J=7.9Hz, 1H, ArH), 7.86(d, J=8.2Hz, 1H, ArH), 7.68~7.59(m, 4H, ArH), 7.40(t, J=7.5Hz, 1H, ArH), 7.27~7.20(m, 5H, ArH), 6.94(d, J=8.3Hz, 2H, ArH), 6.22(s, 1H, CH) , 4.19 (dd, J 1 =12.6,J 2 =12.4Hz, 1H, CH), 3.54(s, 4H, CH 2 ), 3.45(s, 4H, CH 2 ), 3.36(s, 3H, CH 3 ), 3.08 (d, J=13.9Hz, 1H, CH 2 ), 2.18 (s, 3H, CH 3 ).ESI-MS: 489.6[M+H] + , C 32 h 32 N 4 O.

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Abstract

The invention discloses dihydropyrazol piperazine derivatives containing a naphthalene ring skeleton and related preparation method and application in preparation of anti-cancer drugs. The preparation method is characterized by providing the general formula shown in the specification. The dihydropyrazol piperazine derivatives disclosed by the invention have an obvious inhibition effect on human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung cancer cell (A549) and liver cancer cell (HepG2), and the action effect is approximately equivalent to that of a positive control drug Celecoxib; some of the dihydropyrazol piperazine derivatives containing a naphthalene ring skeleton perform better than the positive control drug; and meanwhile, the derivatives show equivalent or better cytotoxicity to the human renal epithelial cell (293T) than the positive control drug Celecoxib. Therefore, the dihydropyrazol piperazine derivatives containing a naphthalene ring skeleton, disclosed by the invention, have better bioactivity, higher selectivity and lower toxicity.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, and relates to a preparation method of a class of dihydropyrazole piperazine derivatives containing a naphthalene ring skeleton and an application in anticancer drugs. Background technique [0002] There are many reports on the naphthalene ring skeleton in various international journals, and it can be said to be a hot spot in the field of compound structure modification. In addition to having excellent antibacterial activity, it also has excellent antitumor activity. With the gradual in-depth study of the mechanism of tumorigenesis and development, naphthalene ring compounds are gradually and more widely used in the development of anti-tumor lead compounds. [0003] Pyrazoles are an important class of heterocyclic compounds widely distributed in nature. Since the antipyridine containing pyrazole ring was found to have analgesic, anti-inflammatory and antipyretic effects, this type o...

Claims

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Application Information

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IPC IPC(8): C07D231/06A61K31/496A61P35/00
CPCC07D231/06
Inventor 朱海亮严晓强晏天龙王忠长
Owner NANJING UNIV
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