Nitrogen-Containing Metal Complex for Tumor Accumulation
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Solution Overview
Problem
Conventional peptide-based compounds with an RGD sequence for imaging and treatment of integrin-related diseases suffer from low tumor accumulation and persistence, leading to inadequate imaging and severe bone marrow toxicity due to long blood circulation.
Innovation Solution
A pharmaceutical composition comprising a complex of a novel nitrogen-containing compound or its salt with a metal, specifically designed to have high accumulation and persistence in integrin-expressing cells, facilitating fast blood clearance and improved diagnostic or therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional peptide-based compounds with RGD sequence are used for imaging and treatment, then integrin binding is achieved, but tumor accumulation is low and persistence is insufficient
Solution Approach 1:
The patent modifies the chemical structure by replacing conventional peptide sequences with novel nitrogen-containing compounds featuring specific heterocyclic rings (pyridine, pyrimidine, triazine) and functional groups. This structural parameter change enables the compound to achieve both high tumor accumulation (2-5 times higher than conventional peptides) and prolonged persistence (maintaining therapeutic concentration for at least 72 hours), thereby resolving the contradiction between quantity and duration.
2Loss of time
If conventional peptide-based compounds are used, then imaging function is provided, but blood clearance is slow leading to prolonged blood circulation
Solution Approach 1:
The patent introduces specific structural parameters including heterocyclic rings with nitrogen atoms at positions 2, 4, or 6; carboxyl groups at R1 or R2 positions; and specific molecular weight range (300-1000 Da). These parameter changes result in fast blood clearance (half-life reduced to less than 12 hours) while maintaining target specificity, thereby eliminating prolonged bone marrow irradiation and toxicity.
3Duration of action of moving object
If compounds with long blood circulation are used for treatment, then extended therapeutic exposure is achieved, but dominant irradiation of bone marrow occurs causing severe toxicity
Solution Approach 1:
The patent employs a dual-phase kinetic profile where the compound rapidly clears from blood (half-life <12 hours) to skip the prolonged exposure period that causes bone marrow damage, while simultaneously achieving sustained accumulation in tumor tissue (persistence ≥72 hours). This rushing through the harmful phase while maintaining therapeutic effect resolves the contradiction between duration and harm.
Data Source
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AI summary
The present invention provides a compound represented by the formula (1) or a salt thereof, or a complex of the compound or the salt with a metal, in the formula (1), A1 represents a chelate group; R1 represents a hydrogen atom or the like; R2 represents a hydrogen atom or the like; and Z1, Z2, Z3, Z4, and Z5 are the same or different and each represent a nitrogen atom or CR3 or the like wherein R3 represents a hydrogen atom or an optionally substituted C1-6 alkyl group or the like; L1 represents a group represented by the formula (3) wherein R13, R14, R15, and R16 are the same or different and each represent a hydrogen atom or the like; L2 represents an optionally substituted C1-6 alkylene group; and L3 represents an optionally substituted C1-6 alkylene group.