Reinforced macrocyclic ligands, complexes thereof, and uses of same
Inventors
Tripier, Raphaël • Rousseaux, Olivier • LE FUR, Mariane • BEYLER, MARYLINE • FOUGÈRE, Olivier • NIZOU, Gwladys
Assignees
Guerbet SA • Centre National de la Recherche Scientifique CNRS • Univerdite de Bretagne Occidentale
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Publication Number
US-11155553-B2
Publication Date
2021-10-26
Expiration Date
Abstract
Ligands that are based on the pyclen macrocycle that are reinforced, which are useful for complexing elements such as radioelements and/or elements with magnetic properties.
Core Innovation
The invention relates to compounds of formula (I) in which X1, X2, X3, Y1, Y2, Y3, Y4, Y5 and Y6 are independently selected from hydrogen and multiple alkyl, alkenyl, alkynyl, aryl, halogen, azide, thio, oxy, and sulfonyl-containing groups, together with functional chemical groups allowing grafting to a vector or to a biomolecule. The functional chemical groups are selected from succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, and squarate, and R1 is selected from alkylene, thiol, azide, hydrazine, and isothiocyanate.
The structural variability is further defined by Z1 and Z2 selected from hydrogen, (C1–C4) alkyl, halogen, –ORg, –N(Rg)(Rh), –SH, and –SRg, where Rg and Rh are selected from H, (C1–C4) alkyl, 2-THP, tosyl, nosyl, TMS, and multiple carbonyl/oxygen-linked variants. Rt is selected from (C1–C4) alkyl, benzyl, allyl, and trifluoromethyl, and the molecule includes R selected from H, (C1–C20)alkyl, (C2–C20)alkenyl, (C2–C20)alkynyl, (C1–C20)alkylene-W, (C2–C20)alkenylene-W, and (C2–C20)alkynylene-W, with optional heteroatoms, arylene groups, and biphenylene(s) in the chain(s).
The invention also relates to reinforced pyclen macrocyclic ligands formed by adding an ethylene bridge between adjacent, non-aromatic nitrogen atoms. The ethylene bridge rigidifies and reduces the internal cavity, and the disclosure further relates to metal complexes comprising a metal center M and the ligands, including radioelements and magnetically active elements, as well as pharmaceutically acceptable salts and isomeric, tautomeric, and solvate forms.
The document additionally describes complexation of a metal or element M with a ligand according to the invention, including microwave-assisted complexation and radiolabeling, and it references structural figures including NMR, MS, and X-ray structures. This supports use of the invention as a platform that can be grafted to vectors or biomolecules and can form a metal-containing complex for radiolabeling.
Claims Coverage
The provided claim set contains independent coverage directed to a compound of formula (I), a complex comprising a central atom M and the compound, and a pharmaceutical composition. Across the excerpt, the inventive features are centered on the compound of formula (I) with graftable functional groups and defined variable substitution patterns, and on a central-atom complex and related downstream uses.
Compound of formula (I) with grafting-allowed functional chemical group
A compound of formula (I) wherein X1, X2, X3, Y1, Y2, Y3, Y4, Y5 and Y6 are independently selected from defined substituent groups including a functional chemical group that allows grafting to a vector or to a biomolecule, wherein said functional chemical group is selected from succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, and squarate; wherein R1 is selected from an alkylene, thiol, azide, hydrazine and isothiocyanate; wherein Z1 and Z2 are independently selected from H, (C1–C4)alkyl, halogen, –ORg, –N(Rg)(Rh), –SH, and –SRg; wherein R is selected from defined alkyl/alkenyl/alkynyl and alkylene/alkenylene/alkynylene-W groups; and wherein the compound includes optional substitution patterns and pharmaceutically relevant forms.
Complex comprising central atom M and the compound of formula (I)
A complex made by combining a central atom M with the compound of formula (I).
Central atom M is a metal
The complex has M that is a metal.
Pharmaceutical composition containing the compound of formula (I)
A pharmaceutical composition includes the compound of formula (I) and optionally one or more pharmaceutically acceptable excipients.
The provided excerpt is primarily directed to a structurally variable compound of formula (I) that includes graftable functional chemical groups and defined substituent patterns. Dependent coverage further includes metal-containing central-atom complexes of the claimed compound and pharmaceutical compositions.
Stated Advantages
The ethylene bridge rigidifies and reduces the internal cavity.
More thermodynamically stable metal complexes.
More kinetically inert metal complexes.
Option to form metal complexes including radioelements and magnetically active elements.
Documented Applications
Pharmaceutical compositions optionally including iodinated oil/Lipiodol.
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