O-Substituted Hydroxamic Acids for Efficient HNO Generation
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Solution Overview
Problem
Current nitroxyl (HNO) donors for therapeutic applications face challenges in generating HNO efficiently under physiological conditions without producing toxic byproducts, particularly cyanide, and have limited reactivity at neutral pH.
Innovation Solution
Development of O-substituted hydroxamic acids that generate nitrosocarbonyl intermediates under physiological conditions, which can be hydrolyzed to HNO, offering improved reactivity and reduced toxicity through specific structural modifications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If traditional HNO donors (Angeli's salt, Piloty's acid, acyloxy nitroso compounds) are used, then HNO can be generated, but toxic byproducts are produced and reactivity is limited at neutral pH
Solution Approach 1:
The patent modifies the molecular structure of hydroxamic acid donors by changing the leaving group parameters and substituent patterns. Specifically, it uses O-acylated hydroxamic acids with modified carbonyl groups that alter the hydrolysis kinetics and HNO release profile, enabling efficient generation at physiological pH while producing non-toxic byproducts
Solution Approach 2:
The patent converts the previously harmful cyanide byproduct into a beneficial non-toxic leaving group. By replacing the cyanide moiety with modified hydroxamic acid structures that release benign byproducts (such as substituted hydroxylamines), the system maintains HNO generation capability while eliminating toxicity
2Ease of operation
If N,O-bis-acylated hydroxylamine derivatives with arenesulfonyl leaving groups are used, then HNO can be generated under physiological conditions, but amide hydrolysis and acyl migration compete with HNO generation
Solution Approach 1:
The patent applies local quality by introducing specific substituents at particular positions on the hydroxamic acid molecule. The R1 and R2 substituents on the carbonyl group are carefully selected to modulate the electrophilicity and steric properties locally, enhancing HNO release while suppressing competing hydrolysis and migration reactions
Solution Approach 2:
The patent creates composite molecular structures by combining hydroxamic acid cores with specific acyl groups and substituents. This composite approach integrates multiple functional elements that work synergistically: the hydroxamic acid provides HNO donor capability, while the modified acyl groups with specific substituents control reaction selectivity and stability
3Object-affected harmful factors
If O-acylated hydroxamic acids with arenesulfonyl leaving groups are used, then HNO can be generated upon hydrolysis, but less than 5% HNO is generated at neutral pH
Solution Approach 1:
The patent systematically varies key molecular parameters including the acyl group composition, substituent types (R1 and R2), and leaving group structures. These parameter changes optimize the pH-dependent hydrolysis kinetics, shifting the reaction equilibrium toward HNO generation at physiological pH while maintaining non-toxic byproduct formation
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds achieve efficient HNO generation with enhanced yield and reduced toxicity, making them suitable for treating conditions like cardiovascular diseases and heart failure without the drawbacks of existing donors.
Implementation Method 1
Following deprotonation and loss of HX (e.g., a pyrazolone), the nitrosocarbonyl intermediate is subsequently hydrolyzed to HNO
Data Source
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AI summary
O-substituted hydroxamic acids with carbon-based leaving groups as HNO donors are disclosed. Pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions also are disclosed.