O-carbonyl phosphoramidate prodrugs for aqueous solubility
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Solution Overview
Problem
Current pharmaceutical agents, such as oxazolidinones, face challenges with modest aqueous solubility, particularly for the antibacterial agent MRX-I, which limits their administration in liquid forms like injections or infusions due to their pH-independent solubility and the non-basic nature of the (isoxazole-3-yl)amino group, making it difficult to form stable pharmaceutical salts and incorporate typical NH-prodrug groups.
Innovation Solution
Development of O-carbonyl phosphoramidate prodrug derivatives that enhance water solubility and stability, allowing for convenient administration in liquid, solid, or powder forms, with a nitrogen-phosphorus bond cleavage in vivo to release the active drug entity, providing improved solubility, stability, and controlled release profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If typical NH-prodrug groups are incorporated to improve solubility, then solubility may be enhanced, but the non-basic nature of the (isoxazole-3-yl)amino group prevents stable salt formation and effective prodrug incorporation
Solution Approach 1:
The patent introduces an O-carbonyl phosphoramidate group as an intermediary structure that bridges the (isoxazole-3-yl)amino group and the desired prodrug functionality. This intermediary enables stable attachment of solubility-enhancing groups despite the non-basic nature of the amino group, resolving the contradiction between solubility improvement and stable prodrug incorporation
Solution Approach 2:
The patent changes the chemical parameters of the prodrug group by using O-carbonyl phosphoramidate derivatives with specific carbonyl groups (acetyl, benzoyl, pivaloyl, etc.). These parameter changes in the prodrug structure enable stable attachment and enhanced solubility where conventional NH-prodrug groups failed
2Ease of operation
If liquid form administration is pursued to improve convenience, then ease of operation is enhanced, but modest solubility requires large volumes and slow infusion rates
Solution Approach 1:
The patent changes the solubility parameter of the drug by converting it to an O-carbonyl phosphoramidate prodrug derivative. This parameter change enables the drug to be formulated in liquid form at clinically relevant concentrations, reducing the required volume from 300 cc to much smaller volumes while maintaining the same dose
3Quantity of substance
If prodrug derivatives are developed to improve solubility, then aqueous solubility is enhanced, but the structure must maintain stability for therapeutic administration
Solution Approach 1:
The O-carbonyl phosphoramidate group serves as a stable intermediary structure that enhances solubility while maintaining chemical stability. The carbonyl group (acetyl, benzoyl, pivaloyl, etc.) provides steric and electronic stabilization that prevents premature hydrolysis, allowing the prodrug to remain stable during storage and administration
Solution Approach 2:
The patent creates composite molecular structures by combining the (isoxazole-3-yl)amino group with O-carbonyl phosphoramidate moieties. This composite structure integrates solubility-enhancing features with stability-providing elements, achieving both enhanced aqueous solubility and sufficient chemical stability for therapeutic use
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
The O-carbonyl phosphoramidate prodrugs offer superior therapeutic outcomes by improving solubility, tolerability, and distribution of the active agent, enabling more effective and convenient administration compared to the parent form, with high aqueous solubility and stability suitable for various therapeutic applications.
Implementation Method 1
with a nitrogen-phosphorus bond cleavage in vivo to release the active drug entity
Data Source
AI summary
The present invention provides certain water-soluble O-carbonyl phosphoramidate prodrugs of the following formula (I), or pharmaceutically acceptable salts thereof that are therapeutic or antibacterial agents, pharmaceutical compositions containing them, methods for their use, and reagents and methods for preparing these compounds.