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Pyrrolidone pyrazole compound and purposes thereof as drugs

A compound, pyrrolidone technology, applied in the field of medicine, can solve the problems of poor cell penetration ability and unsatisfactory anti-tumor activity of peptide compounds

Inactive Publication Date: 2014-05-28
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This discovery has made the research of anti-tumor drugs targeting p53-MDM2 binding a major field in recent years. The early studies of small molecule inhibitors mainly focused on peptides and their analogs, synthetic octapeptide AP and natural product loops. Nonapeptide chlorofusin has excellent inhibitory activity, but the antitumor activity is not ideal due to the poor cell penetration ability of peptide compounds (C.Garcia-Echeverria, P.Chene and M.JJ Blommers.Discovery of potent antagonists of the interaction between human double minute2 and tumor suppressor p53.Journal Medicinal Chemistry.2000,43:3205-3208)

Method used

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  • Pyrrolidone pyrazole compound and purposes thereof as drugs
  • Pyrrolidone pyrazole compound and purposes thereof as drugs
  • Pyrrolidone pyrazole compound and purposes thereof as drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: Preparation of 2-hydroxyl-4-phenyl-4-oxo-2-butenoic acid methyl ester

[0069]

[0070] Slowly drop 29.2g (0.2mol) of diethyl oxalate and 12.0g (0.1mol) of acetophenone mixture into 2mol / L sodium methoxide / methanol solution, the solution slowly turns yellow and solids precipitate out. After dropping, under mechanical stirring, heat at 70°C for 2-3 hours, stop heating, cool to room temperature, pour the reaction solution into 2L of water, fully dissolve and filter out the insoluble matter. The filtrate was adjusted to pH 3-4 with concentrated hydrochloric acid, stirred in an ice-water bath for 1-2 hours, a large amount of light yellow solid was precipitated, filtered with suction, washed with water to obtain a light yellow solid, and freeze-dried to obtain 15.0 g of pure product, yield 72.8% .

[0071] 1 H NMR (300MHz, DMSO-d 6 )δ:14.83(bar,1H),8.06(d,2H,J=7.5Hz),7.70(t,1H,J=7.1Hz),7.57(d,2H,J=7.5Hz),7.11(s, 1H),3.85(s,3H).ESI-MS(m / z):207.29[M+1]+ . ...

Embodiment 2

[0072] Example 2: Preparation of 2-(3-(1H-imidazole) propyl) isoindole-1,3-dione

[0073]

[0074] Put 2.0g of 60% sodium hydride and 2.7g of imidazole into a 25mL eggplant-shaped flask, add 50mL of DMF at 40°C and stir for 1.5 hours, then add 5.4g of 2-(3-bromopropyl)isoindole-1,3-dione into the reaction flask , stirred for 30 minutes, then heated to 80°C, reacted overnight, TLC showed that the reaction was complete, stopped the reaction, added water, extracted with ethyl acetate, and dried the organic phase with anhydrous sodium sulfate. Flash preparative chromatography (CH 2 Cl 2 :CH 3 OH=100:1) to obtain white solid 1.18g, yield 24.7%.

[0075] 1 H NMR (300MHz, DMSO-d 6 )δ:7.86(m,4H),7.62(s,1H),7.18(s,1H),6.86(s,1H),4.00(t,2H,J=7.1Hz),3.53(t,1H,J =6.8Hz),2.01(m,2H).ESI-MS(m / z):255.27[M+1] + .

Embodiment 3

[0076] Embodiment 3: the preparation of 3-(1H-imidazole) propylamine

[0077]

[0078] Add 1.0g of 2-(3-(1H-imidazole)propyl)isoindole-1,3-dione and 0.50g of 80% hydrazine hydrate into 60mL of ethanol, heat to reflux for 12 hours, cool, and filter off the precipitated white solid , then concentrate the filtrate to 20mL, add 10mL of 4mol / L hydrochloric acid, then heat to 50°C for 30 minutes, filter off the precipitated white solid, cool the filtrate to 0°C, add KOH solid to the pH of the solution to 10-12, and a solid precipitates , adding water to dissolve the precipitated solid, extracting it with dichloromethane, drying the organic phase, and evaporating to dryness to obtain 220 mg of a colorless liquid, with a yield of 44.8%.

[0079] 1 H NMR (300MHz, DMSO-d 6 )δ:7.48(s,1H),7.05(s,1H),6.92(s,1H),4.00(t,2H,J=6.9Hz),2.70(t,1H,J=6.8Hz),1.90( m,2H).ESI-MS(m / z):126.35[M+1] + .

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Abstract

The invention belongs to the technical field of medicines. The invention provides a pyrrolidone compound, its optical isomer, raceme and cis-trans-isomer and any combination thereof or its pharmaceutically acceptable salt which are shown as formula (I). The compounds of the invention can be used as small molecule inhibitors of p53-MDM2 (murine double minute2) / X protein interacting. The compounds of the invention can be used for preparing antitumor drugs or anti-inflammatory drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, specifically, pyrrolidone pyrazole compounds and their use as medicines, especially the application in preparing antitumor medicines. Background technique [0002] p53 protein is a tumor suppressor protein, and its inactivation is closely related to 50% to 60% of cancers. The reason may be that the transcriptional activation domain of the p53 tumor suppressor protein is linked to a cellular oncoprotein, such as a gene (murine double minute2, MDM2) that was first discovered in the double minichromosomal gene amplification of mouse cell lines, and is found in mice and humans. (The homologous gene is HDM2) is expressed in many tissues (Michael S C, et al. Regulation of p53 stability and activity in response to genotoxic stress [J]. Mvta Res, 2000, 462: 179-188.). [0003] In recent years, the discovery of the p53 tumor suppressor gene has greatly promoted the research on tumor pathogenesis and ant...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4178A61P35/00A61P29/00A61P35/02
CPCC07D487/04A61K31/4178A61P29/00A61P35/00A61P35/02
Inventor 张万年缪震元庄春林盛春泉姚建忠吴岳林郭子照李锦
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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