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Meldrum's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors

A technology of substituents and compounds, applied in the field of hydroxylamine-substituted Michaelis acid, barbituric acid and pyrazolone derivatives as HNO donors, can solve the problems of less HNO donors and the like

Active Publication Date: 2018-08-17
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, apart from Angeli's salt, derivatives of Piloty's acid, and acyloxynitroso compounds, there are very few physiologically applicable HNO donors

Method used

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  • Meldrum's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors
  • Meldrum's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors
  • Meldrum's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors

Examples

Experimental program
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example

[0160] The following examples are presented for illustrative purposes and should not be used to limit the scope of the disclosed subject matter.

example 1

[0161] Example 1: Synthetic Compounds

[0162] Compounds described herein can be prepared according to the general methods described in Schemes 1 to 3 or by procedures known in the art. Starting materials for the reactions are either commercially available or may be prepared by known procedures or obvious modifications thereof. For example, 5-bromo-5-methyl Michaelis acid is obtained by bromination of 5-methyl-Miners acid (sodium bicarbonate, bromine, water) 1 . 5-Acetyl-Milleis acid was obtained by acylation of Michaelis acid (acetic acid, N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, dichloromethane) 2 . 5-Acetyl-N,N-dimethylbarbituric acid obtained by acylation of N,N-dimethylbarbituric acid (acetyl chloride, pyridine, dichloromethane) 2,3 . 5-Ethyl-barbituric acid is obtained by reduction of 5-acetyl-Meeter's acid (sodium cyanoborohydride, acetic acid) 4 . 4-Acetyl-N-phenyl-5-methyl-pyrazolone obtained by acylation of N-phenyl-5-methyl-pyrazolone (acetyl c...

example 2

[0209] Example 2: HNO production

[0210] The compounds described herein are believed to donate HNO based on the general strategy shown in Scheme 4, where X is a leaving group. Piloty's acid and its derivatives with a sulfinate leaving group are typical examples of this strategy. The compounds described herein employ a carbon-based leaving group to allow the release of HNO at neutral pH along with a stabilizing carbanion.

[0211] Process 4. HNO release

[0212] General process:

[0213]

[0214] specific instance:

[0215] (a) HNO release from Michaelis acid derivatives 1a and 2a at pH 7.4 at 37°C

[0216]

[0217] (b) HNO release from barbituric acid 3a and 4a at pH 7.4 at 37 °C

[0218]

[0219] (c) HNO release from pyrazolones 6a-12a at pH 7.4 at 37 °C

[0220]

[0221] Nitrous oxide is prepared by dimerization and dehydration of HNO and is the most common marker of HNO production (Fukuto, J.M. et al., Chem. Res. Toxicol. 2005, 18, 790-801 ). However, HNO...

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PUM

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Abstract

The invention relates to meldrum's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors. The disclosed subject matter provides certain N-substituted hydroxylamine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the disclosed subject matter provides methods of using such compounds or pharmaceutical compositions for treating, preventing, or delaying the onset and / or development of a disease or condition. In some embodiments, the diseaseor condition is selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy.

Description

[0001] This application is an application date of October 16, 2012, application number 201280051009.4, and a branch of an invention patent application titled "Michael's acid, barbituric acid and pyrazolone derivatives substituted by hydroxylamine as HNO donors". case application. [0002] This application requires the title of "N-Substituted Hydroxylamine Derivativeswith Carbon-Based Leaving as Physiologically Applicable Nitroxyl (HNO) Donors" submitted on October 17, 2011. Groups as Physiologically Useful Nitroxyl (HNO) Donors), the entire contents of which are incorporated herein by reference. [0003] This invention was made in part with government support under Grant No. CHE-0911305 awarded by the National Science Foundation (NSF). The government may have certain rights in this invention. technical field [0004] The present application relates to hydroxylamine-substituted Michaelis acid, barbituric acid and pyrazolone derivatives as HNO donors. Background technique ...

Claims

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Application Information

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IPC IPC(8): C07D231/22C07D231/20A61K31/4152A61P9/00A61P9/10A61P9/04A61P9/12A61P35/00
CPCC07D231/22C07D231/46C07D239/62C07D319/06C07D231/08A61P35/00A61P43/00A61P9/00A61P9/04A61P9/10A61P9/12
Inventor 约翰·P·托斯卡诺达里尔·A·格思里
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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