Lipophilic macrocyclic ligands, complexes thereof, and uses of same
Inventors
Rousseaux, Olivier • FOUGERE, OLIVIER • Catoen, Sarah
Assignees
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Publication Number
US-11261166-B2
Publication Date
2022-03-01
Expiration Date
Abstract
The present invention relates to novel lipophilic macrocyclic ligands, the complexes thereof, in particular radioactive complexes, and the uses of same in medical imaging and/or in therapy, in particular in interventional radiology.
Core Innovation
The invention relates to compounds of general formula (I) and lipophilic cyclen-based macrocyclic ligands, including cyclen-based monoalkylated ligands and ligands with lipophilic phenyl-containing arms. The compounds are described in pharmaceutically acceptable salt, optical isomer, geometric isomer, tautomer, and solvate forms, with defined structural parameters A=(CH2)n, where n is 0 to 15, and m is 1 to 10, and with specified substituent definitions for R1, R3, R4, and R5.
The disclosed compounds form stable ligand-metal chelates with a chemical element M, including radiometals, and a related general formula (III) describes complexing ligands in which COO− complexation groups coordinate a metal element M (M3+). The document reports strong thermodynamic affinity, stated as log KA ≥ 16, good kinetic inertia characterized by slow dissociation, and radiolabeling yield embodiments in the range 10–100%, preferably 75–99%.
The document further describes preparation and use of compounds of formula (I), including a multi-step synthesis route and the preparation of radiolabeled compounds associated with the ligand/complexing system. It also describes pharmaceutical composition embodiments comprising formula (I) compounds or complexes together with buffers and an oily phase using iodinated oil, including iodinated ethyl esters of fatty acids derived from poppyseed oil (LIPIODOL®).
The disclosed chemistry includes monoalkylated cyclen-glyoxal intermediates and amine-containing ligands, deprotection of monoalkylated cyclen-glyoxal C to produce an amine-containing ligand D, stereospecific alkylation using a triflate alkylating agent E4, and subsequent transformation to carboxylic-acid ligands G.
Claims Coverage
The provided claim content identifies one independent compound claim and related downstream claims. Across the items, the inventive features are centered on the defined formula (I) compound structure, complex formation with a chemical element M, cancer treatment, and pharmaceutical composition embodiments including iodinated oil with poppyseed-derived iodinated ethyl esters.
Compound of formula (I) with defined substituent options
A compound of formula (I) in which R1 is methyl or a (C6-C10)aryl; R3, R4 and R5 are independently selected from specified groups with optional substitution by halogen and halo(C1-C20)alkyl and with optional chain inclusion of (C6-C10)arylene(s) and/or (C5-C10)cycloalkylene(s); A is —(CH2)n— where n is 0 to 15 and m is 1 to 10; and pharmaceutically acceptable salt/isomer/tautomer/solvate forms.
Complex of the formula (I) compound with chemical element M
A complex formed from a compound of formula (I) or a salt thereof together with a chemical element M.
Cancer treatment by administering the claimed complex
A method for treating cancer by administering to a mammal in need a therapeutically effective amount of the claimed complex.
Pharmaceutical composition with iodinated oil using poppyseed-derived iodinated ethyl esters
A pharmaceutical composition wherein the iodinated oil contains iodinated ethyl esters of fatty acids derived from poppyseed oil.
The claim coverage focuses on defined formula (I) compound structures, complex formation with a chemical element M, therapeutic administration for cancer, and pharmaceutical composition embodiments that include an oily phase using poppyseed-derived iodinated ethyl ester iodinated oil.
Stated Advantages
Strong thermodynamic affinity (log KA ≥ 16).
Good kinetic inertia characterized by slow dissociation.
Good radiochemical extraction/yield when dissolved in an iodinated oil.
Enables liver-targeted imaging/therapy via interventional radiology.
Improved safety/tolerability.
Radiolabeling yield is stated as 10–100% (preferably 75–99%).
Documented Applications
Cancer treatment, including use in a mammal by administering a therapeutically effective amount of the claimed complex.
Medical imaging described as radiopaque / X-ray visible.
Intraarterial hepatic injection.
Liver-targeted medical imaging and therapy via interventional radiology using the disclosed chelates and formulations with an iodinated oil such as Lipiodol®.
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