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Poly(ADP-ribose) polymerase inhibitor as well as preparation method and application thereof

A technology of compounds and hydrates, applied in chemical instruments and methods, anti-inflammatory agents, drug combinations, etc.

Inactive Publication Date: 2015-03-04
HANGZHOU XIPAN BIOMEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical efficacy of existing PARP inhibitors against tumors needs to be further improved.

Method used

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  • Poly(ADP-ribose) polymerase inhibitor as well as preparation method and application thereof
  • Poly(ADP-ribose) polymerase inhibitor as well as preparation method and application thereof
  • Poly(ADP-ribose) polymerase inhibitor as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0033] The preparation steps of the compound of the present invention are as follows:

[0034]

Embodiment 1

[0035] Example 1: Preparation of 4-[3-(4-(dimethylphosphono)-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one

[0036]

[0037] According to the preparation method disclosed in WO2004080976, DMAP (14 mg, 0.06 mmol) and TEA (0.6 mmol) were added to compound A (110 mg, 0.3 mmol) in dichloromethane (5 mL). The reaction solution was cooled to 0°C, and dimethylphosphonyl chloride (40mg, 0.36mmol) was added under nitrogen protection. The reaction solution was stirred overnight at room temperature and spin-dried. The crude product was separated and purified by chromatography to obtain the target compound (42mg, 32%).

[0038] m / z(M+H) + 443; 1 H NMR: (DMSO-D6: 12.61 (s, 1H), 8.25 (dd, J 7.7, 1.0Hz, 1H), 7.93 (d, J 7.7Hz, 1H), 7.90-7.76 (m, 2H), 7.50- 7.29(m,2H),7.21(t,J9.0Hz,1H),4.31(s,2H),3.70-3.40(m,5H),3.23-3.04(m,3H),1.40-1.43(m,6H ).

Embodiment 2-4

[0040] Referring to the preparation method disclosed in Example 1 and WO2004080976, the intermediate 4-[3-(piperazine-1-carbonyl)benzyl]-2H-phthalazin-1-one (compound B), 4-[3- ([1,4]diazepane-1-carbonyl)benzyl]-2H-phthalazin-1-one (compound C), 4-[3-([1,4]diazepane Alkane-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (compound D) was prepared (compounds B, C and D were prepared with reference to WO2004080976).

[0041]

[0042]

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Abstract

The invention provides a poly(ADP-ribose) polymerase inhibitor as well as a preparation method and application thereof. The poly(ADP-ribose) polymerase inhibitor is a compound shown in a formula I in the specification or pharmaceutically acceptable salts, hydrates or solvates of the compound, wherein R1 is selected from hydrogen and halogens such as F, Cl, Br or I; R2 and R3 are respectively and independently selected from methyl, ethyl or naphthenic bases with 3-6 carbon atoms; and n is 1 or 2. By adopting the poly(ADP-ribose) polymerase inhibitor provided by the invention, poly(ADP-ribose) polymerases can be effectively inhibited, so that the poly(ADP-ribose) polymerase inhibitor can be used for preparing medicines for preventing and / or treating inflammations or cancers such as colon cancer, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, uterus cancer, liver cancer, gastric cancer, skin cancer, blood cancer or prostatic cancer.

Description

technical field [0001] The invention belongs to the technical field of pharmaceuticals, and relates to a polyadenosine diphosphate-ribose polymerase inhibitor and its preparation method and application, in particular to a heteroaromatic polyadenosine diphosphate-ribose polymerase inhibitor and its preparation method and application It is used in the preparation of medicines for preventing and / or treating inflammation or cancer. Background technique [0002] Poly(ADP-ribose) polymerase (PARP) is a kind of protein closely related to single-strand DNA damage repair. Among the PARP protein families discovered so far, PARP-1 is the most abundant and the most important member. When single-strand damage occurs in DNA due to chemical or radioactive factors, PARP-1 is rapidly activated and cleaves the substrate nicotinamide adenine dinucleotide to produce nicotine and ADP ribose, which is further polymerized into poly ADP ribose (PAR). PAR binds to receptor proteins and initiates t...

Claims

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Application Information

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IPC IPC(8): C07F9/6558A61K31/675A61P35/00A61P29/00
Inventor 李剑张波单波
Owner HANGZHOU XIPAN BIOMEDICAL TECH
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