Oxabicycloheptanes and oxabicycloheptenes for the treatment of reperfusion injury

A technology of reperfusion injury and alkyl, applied in the direction of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, drug combinations, etc., can solve the problems of restricting patients with acute myocardial injury, delaying travel time, etc.

Active Publication Date: 2015-05-13
里克思特生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, administration of these treatments to patients with acute myocardial injury is severely limited by the delay in onset of reperfusion due to the travel time to the heartbeat center

Method used

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  • Oxabicycloheptanes and oxabicycloheptenes for the treatment of reperfusion injury
  • Oxabicycloheptanes and oxabicycloheptenes for the treatment of reperfusion injury
  • Oxabicycloheptanes and oxabicycloheptenes for the treatment of reperfusion injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0377] The synthesis of embodiment 1.LB-107

[0378] LB-107 (5) was prepared by reacting acid 3 with N-methylpiperazine (4) in the presence of EDC. To prepare 5 in better yield, three different approaches were tried. In the first approach, a one-pot reaction of LB-100 using thionyl chloride in ethanol was attempted, but no product was observed. In the second method, the acid chloride of LB-100 was reacted with methanol in the presence of triethylamine / DMAP to give the desired methyl ester. The resulting methyl esters are obtained in low yields and the separation of triethylamine from the product is also tedious. Therefore a two-step approach was used. In the third method, endoxal (1) was heated under reflux in methanol to afford the desired monoethyl ester 3 in 95% yield. When compound 3 was treated with N-methylpiperazine (4) in the presence of EDC and a catalytic amount of N-hydroxybenzotriazole, the desired methyl ester 5 was obtained in 39% yield after purification b...

Embodiment 2

[0385] Example 2. Protein Phosphatase 2A Inhibitors

[0386] Compounds used in the methods of the invention are protein phosphatase 2A (PP2A) inhibitors (Lu et al., 2009; US 7,998,957 B2). Compounds LB-100 and LB-102 are in vitro inhibitors of PP2A in human cancer cells and in xenografts of human tumor cells in mice when administered parenterally to mice. These compounds inhibit the growth of cancer cells in a mouse model system. Another structural analog of these compounds, LB-107, has been shown to be active when administered orally to mice.

[0387] LB100, LB102 or LB107 were tested in animal models of cardiac ischemia-reperfusion injury.

[0388] The structure of LB100 is:

[0389] The structure of LB102 is:

[0390] The structure of LB107 is:

Embodiment 3

[0391] Example 3. Increase in Akt Phosphorylation and Activation

[0392] Compounds LB-100, LB-102, LB-107, and other analogs of LB-100 disclosed herein increase phosphorylation of Akt in mammalian cells including, but not limited to, cardiomyocytes, brain cells, and endothelial cells cell. Compounds LB-100, LB-102, LB-107, and other analogs of LB-100 disclosed herein reduce dephosphorylation and inactivation of Akt by protein phosphatase 2A (PP2A) in mammalian cells, which Animal cells include, but are not limited to, cardiomyocytes, brain cells, and endothelial cells. Compounds LB-100, LB-102, LB-107, and other analogs of LB-100 disclosed herein increase activation of Akt by protein phosphatase 2A (PP2A) in mammalian cells including, but not limited to , cardiomyocytes, brain cells and endothelial cells.

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Abstract

A method of reducing reperfusion injury in mammalian tissue comprising contacting the tissue with a protein phosphatase 2A (PP2A) inhibitor having the structure.

Description

[0001] Various publications are cited throughout this application. The entire disclosures of these documents are incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Background technique [0002] Reperfusion is the reestablishment of blood flow and re-oxygentaion of the affected area after an ischemic event, and it is crucial to limit irreversible damage. However, the lack of oxygen and nutrients from the blood creates conditions under which reperfusion injury can occur. Restoration of blood flow after an ischemic event leads to inflammation and oxidative damage. Once blood flow is restored, white blood cells release inflammatory factors, such as interleukins, as well as free radicals. The restored blood flow reintroduces oxygen that has damaged cellular proteins, DNA, and plasma membranes into the cell. [0003] Since acute myocardial infarction (MI) remains the leading cause of death worldwide, the p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/08
CPCA61K31/34A61K31/4178A61K31/4525A61K31/496A61K31/341A61K31/443A61P17/02A61P41/00A61P43/00A61P9/10A61P9/14
Inventor 约翰·S·科瓦奇
Owner 里克思特生物技术有限公司
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