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A class of phthalazinone derivatives and uses thereof

A technology of phthalazine and pyrazine, which is applied in the field of 2,3-phthalazinone derivatives and their use as drugs, and can solve problems such as energy exhaustion

Active Publication Date: 2016-01-20
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this ribosylation process is based on the consumption of cellular energy. The activation of PARP-1 caused by an appropriate amount of DNA damage plays a role in repairing and restoring the cells; while a large amount of DNA damage causes the excessive activation of PARP, through this ribosylation can cause cellular NAD + and ATP energy depletion and death

Method used

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  • A class of phthalazinone derivatives and uses thereof
  • A class of phthalazinone derivatives and uses thereof
  • A class of phthalazinone derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Example 1: Preparation of 4-(3-(4-pyridineformylpiperazine-1-carbonyl)phenylamino)phthalazin-1(2H)-one (001)

[0179] Dissolve tert-butoxycarbonylpiperazine (4.28g, 0.023mol), triethylamine (6.98g, 0.069mol), m-aminobenzoic acid (7.01g, 0.023mol) in N,N-dimethylformamide ( 100ml), add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.72g, 0.023mol), stir at room temperature, after the reaction is over, add water to quench the reaction and precipitate The solid product was filtered and dried to give tert-butyl 4-(3-aminobenzoyl)piperazine-1-carboxylate.

[0180] Add trifluoroacetic acid (0.25ml) to a solution of triethylamine (0.3ml) in ethanol (50ml) in an ice bath (0°C), and add 4-(3-aminobenzoyl)piperene obtained in the previous step after 15 minutes tert-butyl oxazine-1-carboxylate (1.65g, 0.0054mol) and 1,4-dichlorophthalazine (1.07g, 0.0054mol), heated to reflux, after the reaction (about 30min), add ethyl acetate (100ml ), washed with water (3*50...

Embodiment 2

[0185] Example 2: Preparation of 4-(3-(4-(2-propylpentanoylpiperazine-1-carbonyl)phenylamino)phthalazin-1(2H)-one (003)

[0186] Preparation Method Reference Example 1: The target compound was obtained with a melting point of 204-205°C.

[0187] ESI-MSm / z: 475.7(m+H) + , calculated value: 475.3.

Embodiment 3

[0188] Example 3: Preparation of 4-(3-(4-(cyclopropylformyl)piperazine-1-carbonyl)phenylamino)phthalazin-1(2H)-one (007)

[0189] The preparation method refers to Example 1, and the melting point is >230°C.

[0190] ESI-MS m / z: 415.9 (m-H) - , calculated value: 416.2.

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Abstract

The present invention provides novel phthalazinone compounds and isomer thereof, pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs; which can be used as PARP inhibitor and pharmaceutical compositions containing the novel phthalazinone compounds; wherein A, R1 and X are defined as shown. The medicine is used for the treatment of: vascular diseases, neurotoxicity, or diseases improved through the inhibition of PARP activity; or used as adjuvants for the treatment of cancers, or used for enhancing the therapeutic effect of radiation or chemotherapeutic agents on tumor cells, wherein the cancers includes breast cancer, ovarian cancer, colon cancer, melanoma, lung cancer, gastrointestinal stromal tumor, brain cancer, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic myeloid leukocytes hypercytosis, liver canser, lymphoma, peritoneal cancer, soft tissue sarcoma, neuroendocrine tumors, advanced solid tumors, and glioblastoma.

Description

technical field [0001] The present invention relates to a class of phthalazinone derivatives and pharmaceutical compositions containing such derivatives, and mainly relates to 2,3-phthalazinone derivatives and their use as medicines. In particular, the present invention relates to the use of these compounds for inhibiting the activity of poly(ADP-ribose) polymerase (also known as poly(ADP-ribose) synthase and poly ADP-ribosyltransferase, commonly referred to as PARP) . Background technique [0002] The mammalian enzyme PARP, a 113 kDa multi-domain protein, is involved in DNA damage signaling through its ability to recognize and rapidly bind DNA single- or double-strand breaks (D'Amours et al., Biochem. J. 342:249 -268 (1999)). [0003] The polyadenosine diphosphate (ADP-ribose) ribose synthetase family now includes about 18 proteins, which are divided into 3 types. Type Ⅰ mainly exists in the nucleus, including PARP-1, PARP-2, PARP-3, etc.; Ⅱ Type III mainly exists in org...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D237/32C07D237/34C07D413/12C07D487/04A61K31/502A61K31/5377A61P35/00A61P35/02
Inventor 王勇张仓纪剑峰张景忠王小伟张文萍
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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