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Phthalazinone derivatives and application thereof

A technology of use, medicine, applied in the field of biomedicine

Inactive Publication Date: 2013-01-30
JIANGSU SIMCERE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no chemical small molecule report that simultaneously inhibits PARP and HDAC activity, and the development of PARP / HDAC dual-target inhibitors has potential anti-tumor applications

Method used

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  • Phthalazinone derivatives and application thereof
  • Phthalazinone derivatives and application thereof
  • Phthalazinone derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: 2-fluoro-[N-(2-hydroxylamine-2-oxoethyl)]-5-(4-oxo-3,4-dihydrophthalazine-1-methyl)benzidine Preparation of amides (C1)

[0054] 1) Preparation of intermediate 2-fluoro-5-(4-oxo-3,4-dihydrophthalazine-1-methyl)benzoic acid (A)

[0055]

[0056] People such as Menear, KeithA reported a kind of intermediate 2-fluoro-5-(4-oxo-3,4-dihydrophthalazine-1-methyl) benzoic acid (A) [Journal of Medicinal Chemistry, 51( 20), 6581-6591; 2008], the compound A used in this patent is prepared according to this method.

[0057] 2) 2-fluoro-N-(2-hydroxyamino-2-oxoethyl)-5-(4-oxo-3,4-dihydrophthalazine-1-methyl)benzamide (C1) preparation of

[0058]

[0059] 2-Fluoro-5-(4-oxo-3,4-dihydrophthalazine-1-methyl)benzoic acid (A) (450mg, 1.51mmol), 2-amino-N-hydroxy-acetamide (136.1mg, 1.51mmol), HATU (689mg, 1.81mmol), DIPEA (584mg, 4.53mmol) were added to DMF 10ML, under nitrogen protection, stirred, reacted at room temperature for 12h, concentrated to dryness, added wate...

Embodiment 2

[0061] Example 2: 2-fluoro-[N-(3-hydroxyamino-3-oxopropyl)]-5-(4-oxo-3,4-dihydrophthalazine-1-methyl)benzidine Preparation of amides (C2)

[0062]

[0063] Compound 2 (197 mg, 34%) was prepared in a similar manner to compound 1. HPLC: 97.03%, MS: [M+H] + =385.0; [M+Na] + =406.8;[M-H] - =383.0.

[0064] 1 H-NMR (400M, DMSO-d 6 )δ12.59(s,1H),10.46(s,1H),8.75(s,1H),8.29(m,2H),7.96(d,1H),7.89(t,1H),7.83(t,1H ), 7.60 (d, 1H), 7.46 (m, 1H), 7.21 (t, 1H), 4.33 (s, 2H), 3.43 (td, 2H), 2.23 (t, 2H) ppm.

Embodiment 3

[0065] Example 3: 2-fluoro-[N-(4-hydroxylamine-4-oxo-n-butyl)]-5-(4-oxo-3,4-dihydrophthalazine-1-methyl)benzene Formamide (C3) Preparation

[0066]

[0067] Compound 3 (240 mg, 40%) was prepared in a similar manner to compound 1. HPLC: 98.7%, MS: [M-H] - =396.9.

[0068] 1 H-NMR (400M, DMSO-d 6 )δ12.60(s,1H),10.38(s,1H),8.71(s,1H),8.27(m,2H),7.97(d,1H),7.89(t,1H),7.83(t,1H ),7.57(d,1H),7.44(m,1H),7.20(t,1H),4.33(s,2H),3.20(td,2H),1.98(t,2H),1.71(td,2H) ppm.

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Abstract

The invention relates to phthalazinone derivatives and application of the phthalazinone derivatives in the aspect of inhibiting the activity of poly(ADP-ribose)polymerase and the activity of histone deacetylases. The phthalazinone derivatives have the structure of formula (I). The median inhibitory concentration of partial compounds as shown in the formula (I) on the activity of poly(ADP-ribose)polymerase and the activity of histone deacetylases is about 10-7oml.L<-1>. The series of compounds can be used for preventing and treating tumors, local ischemic diseases, diabetes and inflammatory diseases.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of phthalazinone derivatives with the structure of formula (I) and their application in inhibiting the activity of poly(ADP-ribose) polymerase and histone deacetylase. Background technique [0002] Polyadenosine diphosphate-ribose polymerase [poly(ADP-ribose) polymerase, PARP] is a protease present in eukaryotic cells that catalyzes polyadenosine diphosphate (poly ADP) ribosylation, poly ADP ribose Kylation is a post-translational modification in cells. This modification acts on many proteins and involves chromosome stability, DNA damage repair, gene transcription, cell growth, death and apoptosis, etc. It is related to inflammation in terms of physiology and pathology. Diseases such as tumors and aging are closely related. [0003] Under normal circumstances, cells can repair DNA damage through base excision or homologous recombination. PARP and BRCA are the main enzymes inv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/32C07D401/12C07D403/12A61K31/502A61K31/506A61P9/10A61P3/10A61P29/00A61P35/00
Inventor 金秋刘肇彧黄伟赵勇王梦妤尹引杨洁
Owner JIANGSU SIMCERE PHARMA
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