Organic Acid Salts of CPR-PMEDAP Bisamidate Compounds
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Solution Overview
Problem
Current treatments for hematological malignancies, such as leukemias and lymphomas, face limitations in safety, efficacy, and drug resistance, with a need for novel nucleosides/nucleotides that can concentrate in blood cells to widen the therapeutic window and reduce exposure to other tissues.
Innovation Solution
The development of organic acid salts of cpr-PMEDAP bisamidate compounds, particularly the bis(ethyl) ester form, which preferentially distributes into PBMCs and is less hygroscopic, facilitating manufacturing and stability, including the use of carbohydrates to enhance storage stability in parenteral formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cpr-PMEDAP and N6-substituted PMEDAP compounds are used to treat hematological malignancies, then antiproliferative and differentiation-inducing effects are achieved, but high toxicity occurs
Solution Approach 1:
The patent modifies the chemical structure of PMEDAP compounds by introducing specific substitutions at the 6-position of the purine ring and using particular amino acid esters (bisamidates). These structural parameter changes result in compounds that maintain antiproliferative activity while reducing toxicity, as evidenced by the selective distribution into PBMCs and improved therapeutic window.
Solution Approach 2:
The invention creates compounds with localized properties through the use of specific amino acid ester substitutions that confer selective distribution characteristics. The bisamidate structures with particular alkyl esters (such as ethyl esters) exhibit preferential accumulation in blood cells, creating local high concentration at the target site while maintaining lower systemic exposure, thereby improving the therapeutic index.
2Reliability
If novel nucleosides/nucleotides are developed to concentrate in blood cells, then therapeutic window is widened and exposure to other tissues is reduced, but drug development complexity increases
Solution Approach 1:
The patent achieves selective blood cell concentration by modifying specific parameters of the nucleoside structure, particularly the amino acid ester substituents. The bisamidate configuration with specific alkyl groups (e.g., ethyl esters) creates molecules with inherent affinity for blood cells, achieving the desired distribution profile through rational structural modification rather than complex formulation approaches.
Solution Approach 2:
The amino acid ester moieties act as intermediary structures that mediate between the nucleoside core and the blood cell target. These ester groups serve as recognition elements or transport facilitators that enable selective accumulation in PBMCs, effectively acting as molecular mediators that guide the drug to its target without requiring complex delivery systems.
3Reliability
If organic acid salts of cpr-PMEDAP bisamidate compounds are used, then distribution into PBMCs is improved and hygroscopicity is reduced, but formulation complexity increases
Solution Approach 1:
The patent converts the cpr-PMEDAP bisamidate compounds into organic acid salts, which fundamentally changes their physical and chemical parameters. This salt formation reduces hygroscopicity (water absorption) and enhances stability, while simultaneously improving the distribution profile into PBMCs. The salt form provides better solubility and handling characteristics for formulation purposes.
Solution Approach 2:
The invention creates composite molecular structures by combining the cpr-PMEDAP bisamidate core with organic acid counterions. This composite approach, forming salt complexes, integrates the pharmacologically active nucleoside with organic acid moieties that provide desirable formulation properties, including reduced hygroscopicity and improved stability, while maintaining or enhancing the desired distribution characteristics.
Data Source
AI summary
A compound of formula 1and/or its salts, tautomers or solvates is used to treat hematological malignancies. In an embodiment, an organic acid salt of compound 1 is provided for general use in treatment of neoplasms, and in a further embodiment the salt is stabilized with carbohydrate.