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Pyrrylketone compound and application thereof as drug

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: 2012-07-25
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

(P.H.Kussie, S.Gorina, V.Marechal, and et al.Structure of the MDM2oncoprotein bound to the p53 tumor suppressor transactivation domain.Science.1996, 274:948-953) This discovery made it possible to target p53-MDM2 binding Antitumor drug research has become a major field in recent years. The early studies of small molecule inhibitors mainly focused on peptides and their analogs. Both the synthetic octapeptide AP and the natural product cyclic nonapeptide chlorofusin have excellent inhibitory activity, but Suboptimal antitumor activity due to poor cell penetration of peptides

Method used

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  • Pyrrylketone compound and application thereof as drug
  • Pyrrylketone compound and application thereof as drug
  • Pyrrylketone compound and application thereof as drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Embodiment 1: Preparation of 2-hydroxyl-4-phenyl-4-oxo-2-butenoic acid methyl ester

[0135]

[0136] 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 with a yield of 72.8% .

[0137] 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...

Embodiment 2

[0138] Example 2: Preparation of 2-(3-(1H-imidazole) propyl) isoindole-1,3-dione

[0139]

[0140] Put 2.0g of 60% sodium hydride and 2.7g of imidazole into a 25mL eggplant-shaped bottle, add 50mL of DMF and stir at 40°C for 1.5 hours, then add 5.4g of 2-(3-bromopropyl)isoindole-1,3-dione In the reaction bottle, stir for 30 minutes and then heat to 80°C, react overnight, TLC shows that the reaction is complete, stop the reaction, add water, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Flash preparative chromatography (CH 2 Cl 2 :CH 3 OH=100:1) to obtain 1.18 g of white solid with a yield of 24.7%.

[0141] 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

[0142] Embodiment 3: the preparation of 3-(1H-imidazole) propylamine

[0143]

[0144] Add 1.0 g of 2-(3-(1H-imidazole) propyl) isoindole-1,3-dione and 0.50 g of 80% hydrazine hydrate into 60 mL 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 solution pH 10-12, A solid was precipitated, and the precipitated solid was dissolved with water and extracted with dichloromethane. The organic phase was dried and evaporated to dryness to obtain 220 mg of a colorless liquid, with a yield of 44.8%.

[0145] 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 relates to the technical field of medicines, particularly a pyrrylketone compound and application thereof as a drug. The structure of the compound is disclosed as Formula (I), comprising optical isomer, raceme, cis-trans-isomer and any combination or medicinal salts thereof. The compound provided by the invention can be used as a micromolecular inhibitor for p53-MDM2 / X protein interactions, and can be used for preparing the antineoplastic drug.

Description

technical field [0001] The invention belongs to the technical field of medicine, specifically, pyrrolone 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%-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 minute 2, MDM2) that was first discovered in the double minichromosomal gene amplification of mouse cell lines, in mice and It is expressed in many tissues of human (homologous gene is HDM2). (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 anti-tumor drugs. A large nu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D401/14C07D409/14C07D405/14C07D207/38C07D401/06A61K31/4178A61K31/4439A61K31/5377A61P35/00
Inventor 张万年缪震元庄春林盛春泉姚建忠郭子照
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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