Macrocyclic ligands with picolinate group(s), complexes thereof and also medical uses thereof
Inventors
LE FUR, Mariane • Tripier, Raphaël • Rousseaux, Olivier • BEYLER, MARYLINE
Assignees
Guerbet SA • Centre National de la Recherche Scientifique CNRS • Univerdite de Bretagne Occidentale
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10981912-B2
Publication Date
2021-04-20
Expiration Date
Abstract
A macrocycle compound of general formula (X) in which Y1 represents a C(O)OH group or a group of formula (II)
Core Innovation
The disclosure relates to macrocyclic pyclene ligands bearing picolinate group(s) defined by general formula (I), with Y1 and Y2 and Y3 as C(O)OH, a protected form of C(O)OH, or a defined group of formula (II). The ligand framework is based on the pyclene macrocycle (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) with variable substituents R1–R6 and X1–X3 that may include optional substituted organic acid functions.
The invention relates to preparing and regenerating general-formula (I) compounds by functionalizing an NH-containing precursor of general formula (IX) to form an intermediate (X) bearing distinct substituent groups on a nitrogen atom. The functionalization installs the group —C(R1)(R2)Y1, and the intermediate (X) can be optionally converted by a deprotection step to an NH-containing intermediate (XI) before functionalization to regenerate formula (I).
The document states a need for radiometal chelates with good thermodynamic stability and kinetic inertia, and for radiochemical yield/extraction and stable radioactive formulations for medical imaging and therapy. It emphasizes use with radioelements, including lanthanides such as Y(III), and defines imaging modalities including x-ray, MRI, SPECT and PET, together with cancer treatment, including intermediate-stage hepatocellular carcinoma.
A further aspect is the ability to form ligand-metal chelates that are dissolved in the iodinated oil Lipiodol® for liver-directed vectorization. The disclosure reports improved radiochemical yield/extraction into Lipiodol® and radiochemical stability of radioactive Lipiodol® in vitro, and includes preparation concepts for symmetrical and dissymmetrical compounds, including macrocycle synthesis from pyclene, selective N functionalization, and dissymmetrical picolinate intermediate installation using defined derivatives and coupling steps.
Claims Coverage
The provided content identifies one independent claim, clm-00001, directed to a compound of general formula (X) with variable R1/R2 substituents, variable X1/X2/X3 substituent options, and a Y1 group defined as a C(O)OH group, a protected C(O)OH form, or a group of formula (II). The inventive features focus on the allowed structural variability of R1/R2, X1/X2/X3, and Y1, including the defined radicals Ri and optional organic acid functions.
General formula (X) with variable R1 and R2 substituents
A compound of general formula (X) in which R1 and R2 represent, independently of each other, H or a (C1-C20)alkyl group or a (C1-C20)alkylene-(C6-C10)aryl group, wherein said alkyl, alkylene and aryl groups optionally are substituted with one or more organic acid functions.
Variable X1, X2, X3 group types with Re/Rd-defined substituents
X1, X2 and X3 represent, independently of each other, H, —C(O)N(Re)(Rd), a (C1-C20)alkyl, a (C2-C20)alkenyl, a (C2-C20)alkynyl and a (C6-C10)aryl, with Re and Rd being, independently of each other, H or a (C1-C20) alkyl group, wherein said alkyl, alkenyl and alkynyl groups optionally comprise one or more heteroatoms and/or one or more (C6-C10)arylenes in their chains, and wherein said alkyl, alkenyl and alkynyl groups optionally are substituted with a (C6-C10) aryl; and wherein said alkyl, alkenyl, alkynyl and aryl groups optionally are substituted with one or more organic acid functions.
Terminal/linked group Y1 as carboxylic acid, protected carboxylic acid, or formula (II) group
Y1 represents a C(O)OH group, a protected form of the C(O)OH group in which the hydrogen is replaced with an alkyl, or a group of formula (II) in which the radicals Ri represent, independently of each other, H, halogen, N3, (C1-C20)alkyl, (C2-C20)alkenyl, (C2-C20)alkynyl and (C6-C10)aryl, wherein said alkyl, alkenyl and alkynyl groups optionally comprise one or more heteroatoms and/or one or more (C6-C10)arylenes in their chains and, wherein said alkyl, alkenyl, and alkynyl groups optionally are substituted with a (C6-C10) aryl; and wherein said alkyl, alkenyl, alkynyl and aryl groups optionally are substituted with one or more organic acid functions.
Based on clm-00001, the claims cover a broad structural space defined by general formula (X) with independently variable R1/R2 substituents, independently variable X1/X2/X3 group types including —C(O)N(Re)(Rd), and a terminal/linked Y1 group defined as C(O)OH, a protected C(O)OH, or a group of formula (II) with radicals Ri selected from H, halogen, N3, alkyl, alkenyl, alkynyl, and aryl variants, optionally substituted with organic acid functions.
Stated Advantages
Good thermodynamic stability and kinetic inertia of ligand-metal chelates.
Improved radiochemical yield/extraction into Lipiodol®.
Radiochemical stability of radioactive Lipiodol® in vitro.
Supports safer, easier interventional-radiology cancer imaging/therapy, notably intermediate-stage hepatocellular carcinoma.
High yields in MeOH for the cyclene oxalate intermediate route.
Documented Applications
Liver-directed vectorization for cancer imaging and therapy by dissolving ligand-metal chelates in Lipiodol® (iodinated fatty-acid ethyl esters).
Medical imaging modalities including x-ray, MRI, SPECT and PET and cancer treatment for intermediate-stage hepatocellular carcinoma.
Radiolabeling of formula (I) compounds.
Synthesis of specific Pc ligands and intermediates.
Characterization of Pc ligands and yttrium complexes.
Interested in licensing this patent?