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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
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the existing phthalazinones have many defects, such as poor solubility and low bioavailability in vivo.

Method used

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  • 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...

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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

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Application Information

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