Eureka AIR delivers breakthrough ideas for toughest innovation challenges, trusted by R&D personnel around the world.

4-piperidone compound as well as preparation method and application thereof

A technology of piperidone and compounds, which is applied in the field of preparation of antineoplastic drugs, can solve the problems of short action time and half-life, low bioavailability, etc., and achieve the effects of reducing dosage, enhancing drug efficacy, and strongly inhibiting activity

Active Publication Date: 2018-11-02
FUJIAN MEDICAL UNIV
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Short duration of action and half-life in vivo (<1 hour), and low bioavailability (<15%)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 4-piperidone compound as well as preparation method and application thereof
  • 4-piperidone compound as well as preparation method and application thereof
  • 4-piperidone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of N-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperidin-4-one

[0022] Dissolve olaparib acid intermediate (50mg, M=297.6, 0.168mmol), HBTU (82mg, M=379.24, 0.2184mmol), HOBT (6.8mg, M=135.12, 0.05mmol) in 5ml anhydrous THF (add 2ml DMF co-solvent), stir at room temperature for half an hour, DIPEA (0.86ml, 65.14mg, 0.504mmol, M=129.24, ), and 22.32 mg of 4-piperidone (M=148.05 hydrochloric acid form 0.1508 mmol), and stirred overnight at 50°C. Extracted with dichloromethane, washed 3 times with water and once with brine to obtain intermediate 1, namely N-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2- Fluorobenzoyl]piperidin-4-one.

[0023] Ethyl acetate:petroleum ether=3:1 column chromatography yielded 25.79mg. Yield 40%. Mp: 230.8-233.8℃.1HNMR(400MHz,Chloroform-d)δ10.94(s,1H),8.51(s,1H),7.81-7.76(m,3H),7.39(d,2H),7.09(m ,1H),4.33(s,2H),4.20-3.92(m,2H),3.63(s,2H),2.61(m,2H),2.46(s,2H).LC-MS(ESI)m / z :380.1[M + H] + .

Embodiment 2

[0025] 3,5-(E)-bis(2-pyridylmethenyl)-N-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluoro Preparation of Benzoyl]piperidin-4-one

[0026] Mix intermediate 1 55.28mg (0.146mmol, M=379.13), sodium hydroxide 1.67mg (0.02mmol, M=84.01), absolute ethanol 10ml, stir at room temperature, add 2-pyridinecarbaldehyde 44.6mg (0.4166 mmol, M=107.11), react at room temperature. Dichloromethane extraction, washed 3 times with water, washed with brine once. That is, 3,5-(E)-bis(2-pyridinemethenyl)-N-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2 -Fluorobenzoyl]piperidin-4-one. Ethyl acetate:petroleum ether=3:1 column chromatography yielded 20.79mg. Yield: 37%. Mp: 156.3-158.0°C. 1H NMR (400MHz, Chloroform-d) δ10.99(s,1H),8.79(s,1H),8.46(s,1H),8.18(s,1H),7.63(m,9H),7.38(d, 1H), 7.10(d, 3H), 6.81(s, 1H), 5.52(s, 2H), 5.24(s, 2H), 4.08(s, 2H). LC-MS (ESI) m / z: 558.2[ m + H] + .

Embodiment 3

[0028] 3,5-(E)-bis(3-pyridylmethenyl)-N-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluoro Preparation of Benzoyl]piperidin-4-one

[0029] This product was prepared from 55.28mg (0.146mmol, M=379.13) of intermediate 1 and 44.6mg (0.4166mmol, M=107.11) of 3-pyridinecarbaldehyde. The preparation method was the same as in Experimental Example 2, and 29.6mg of yellow solid was obtained. Yield 52%. Mp: 147.39°C-149.7°C. .1H NMR (400MHz, Chloroform-d) δ11.52(s,1H),8.78(s,1H),8.66(d,1H),8.62–8.52(m,1H),8.49(s,1H),8.41 (s,1H),7.88(s,2H),7.80(s,3H),7.72(s,2H),7.54(s,1H),7.44(s,1H),7.17(d,2H),6.80( s,1H),5.09(s,2H),4.63(s,2H),4.17(s,2H).LC-MS(ESI)m / z:556.21[M + H] + .

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a 4-piperidone compound as well as preparation method and application thereof. The compound has a structural general formula as shown in the description, wherein Ar is a substituted benzene ring or a heteroaromatic ring. The preparation method comprises the following steps of enabling 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid to be firstly condensedwith 4-piperidone hydrochloride and then condensed with aromatic aldehyde under an alkaline condition to obtain the compound. The compound or medicinal salt thereof has high PARP1 inhibitory activity,and can be used in drugs for treating diseases or cancer so as to prevent and / or treat PARP1-related diseases.

Description

technical field [0001] The invention belongs to the field of preparation of antitumor drugs, and in particular relates to a 4-piperidone compound and a preparation method and application thereof. Background technique [0002] In 1946, Dobzhansky first proposed the concept of "synthetic lethality", that is, when two genes are mutated alone, there will be no effect, but mutations at the same time will lead to cell death. Based on the theory of synthetic lethality, PARP1 inhibitors are mainly used in patients with BRCA1 / 2-mutated ovarian or breast cancer. However, with the increase of clinical use, the resistance of tumor cells to PARP-1 inhibitors appears, so that the efficacy of the drug is reduced or even lost. The occurrence of resistance to PARP-1 inhibitors is mainly due to: ①The recovery of HR function in tumor cells with BRCA1 / 2 gene mutations, resulting in cell survival; concentration, leading to poor therapeutic effect. Olaparib (AZD2281 / KU-59436) developed by Astr...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/10A61K31/502A61P35/00A61P25/00A61P9/10A61P25/16A61P25/28A61P21/00A61P27/02A61P1/00
CPCA61P1/00A61P9/10A61P21/00A61P25/00A61P25/16A61P25/28A61P27/02A61P35/00C07D401/10C07D401/14
Inventor 吴丽贤刘洋林珊珊张灵玉张潇黄秀旺许建华
Owner FUJIAN MEDICAL UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com