Pyridazinone derivative prodrugs or pharmaceutically acceptable salt thereof as well as pharmaceutical composition and application of prodrugs

A derivative, the technology of phthalazinone, applied in the field of medicinal chemistry, can solve the problems of poor solubility and low bioavailability

Active Publication Date: 2018-08-10
SHANGHAI BIOBOND PHARMA
View PDF32 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the existing phthalazinones have many defec

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
  • Pyridazinone derivative prodrugs or pharmaceutically acceptable salt thereof as well as pharmaceutical composition and application of prodrugs
  • Pyridazinone derivative prodrugs or pharmaceutically acceptable salt thereof as well as pharmaceutical composition and application of prodrugs
  • Pyridazinone derivative prodrugs or pharmaceutically acceptable salt thereof as well as pharmaceutical composition and application of prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: Synthesis of 4-(4-fluoro-3-(1-acryloylpiperazin-4-yl-carbonyl)-benzyl)phthalazin-1(2H)ketone (compound 7)

[0072] Scheme 1:

[0073]

[0074] Add 4-(4-fluoro-3-(piperazin-1-yl-carbonyl)-benzyl)phthalazin-1(2H)ketone (5) (0.78g, 2.13mmol) into a 25ml three-necked flask, and Add dichloromethane (6.5ml) and triethylamine (0.52g, 5.14mmol), stir to dissolve, cool down to 1-10°C, add acryloyl chloride (230mg, 2.56mmol) dropwise, raise to room temperature after dropwise, stir 1h. TLC showed that the reaction was complete; the reaction solution was directly concentrated to dryness, the residue was slurried with water, stirred for 1 h and then filtered to obtain an off-white solid, which was purified by a silica gel column to obtain a white solid product (330 mg), with a yield of 37%. 1 HNNR (400MHz, CDCl 3 )δ:10.98(1H,bs),8.49(1H,s),7.80-7.75(3H,m),7.36(2H,d,J=4.4Hz),7.06(1H,t,J=8.8Hz), 6.59-6.52(1H,m),6.34(1H,d,J=16.4),5.76(1H,m),4.32(2H,s),3.82-3.35(8H,m)....

Embodiment 2

[0075] Example 2: Synthesis of 4-(4-fluoro-3-(1-(2-butenoyl)piperazin-4-yl-carbonyl)-benzyl)phthalazin-1(2H)ketone (Compound 9)

[0076] Scheme 2:

[0077]

[0078] Add 4-(4-fluoro-3-(piperazin-1-yl-carbonyl)-benzyl)phthalazin-1(2H)ketone (5) (0.78g, 2.13mmol) into a 25ml three-necked flask, and Add dichloromethane (6.5ml) and triethylamine (0.52g, 5.14mmol), stir to dissolve, cool down to 1-10°C, then add 2-butenyl chloride (268mg, 2.56mmol) dropwise, dropwise To room temperature, stirred for 1h. TLC showed that the reaction was complete; the reaction solution was directly concentrated to dryness, the residue was slurried with water, stirred for 1 hour and then filtered to obtain an off-white solid, which was purified by a silica gel column to obtain a white solid product

[0079] (450 mg), yield 37%. 1 HNNR (400MHz, CDCl 3 )δ:11.07(1H,bs),8.49(1H,m),7.81-7.73(3H,m),7.36-7.33(2H,m),7.06(1H,t,J=8.8Hz),6.96-6.90 (1H,m),6.26(1H,s),5.21(1H,m),4.31(2H,s),3.80-3.21(8H,m),1....

Embodiment 3

[0080] Example 3: 4-(4-fluoro-3-(1-(3-methyl-2-butenoyl)piperazin-4-yl-carbonyl)-benzyl)phthalazin-1(2H)ketone ( Compound 11) Synthesis

[0081] Scheme 3:

[0082]

[0083] Add 4-(4-fluoro-3-(piperazin-1-yl-carbonyl)-benzyl)phthalazin-1(2H)ketone (5) (0.78g, 2.13mmol) into a 25ml three-necked flask, and Add dichloromethane (6.5ml) and triethylamine (0.52g, 5.14mmol), stir to dissolve, cool down to 1-10°C, then add 3-methylcrotonyl chloride (304mg, 2.56mmol) dropwise, dropwise To room temperature, stirred for 1h. TLC showed that the reaction was complete; the reaction solution was directly concentrated to dryness, the residue was slurried with water, stirred for 1 hour and then filtered to obtain an off-white solid, which was purified by a silica gel column to obtain a white solid product

[0084] (600 mg), yield 63%. 1 HNNR (400MHz, CDCl 3 )δ:11.01(1H,m),8.49(1H,m),7.80-7.73(3H,m),7.34(2H,m),7.08-7.04(1H,m),5.77(1H,s),4.31 (2H,s),3.78-3.11(8H,m),1.92-1.79(6H,m).MS(ESI...

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 belongs to the technical field of medicinal chemistry, in particular relates to pyridazinone derivative prodrugs or a pharmaceutically acceptable salt thereof, and relates to a pharmaceutical composition of the prodrugs and an application in preparing an antitumor medicine. The pyridazinone derivative prodrugs having a structural formula (I) shown in the description provided by the invention have good in-vivo solubility, after the prodrugs enter a body, pyridazinone medicine molecules are released by metabolism, so that in-vivo bioavailability of the pyridazinone medicine molecules is greatly improved, and the pyridazinone medicine molecules bind to an in-vivo PARP enzyme in an irreversible manner to play pharmacological effects, and the antitumor activity is remarkable.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a prodrug of a phthalazinone derivative or a pharmaceutically acceptable salt thereof, and also relates to its pharmaceutical composition and its application in the preparation of antitumor drugs. Background technique [0002] Studies have found that PARPs (Poly (ADP-ribose) polymerases, polyadenosine diphosphate (ADP-ribose) ribose synthetase) characterized by polyadenosine diphosphate-ribosylation activity are 18 kinds of nuclear enzymes and The superfamily of cytoplasmic enzymes is mainly divided into three types: type I mainly exists in the nucleus, including PARP-1, PARP-2, PARP-3, etc.; type II mainly exists in organelles, including V-PARP, etc.; III The type is mainly related to the telomere of the cell, including Tankyrasel and Tankyrase2. This polyadenosine diphosphate-ribosylation can regulate the catalytic activity and protein-protein interacti...

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
IPC IPC(8): C07D237/32A61K31/502A61P35/00
CPCA61P35/00C07D237/32
Inventor 高河勇刘振德张文生
Owner SHANGHAI BIOBOND PHARMA
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
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap