Macrocylic 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
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Publication Number
US-10711001-B2
Publication Date
2020-07-14
Expiration Date
Abstract
The present invention relates to compounds, ligands, and/or complexes that are useful in medical imaging and/or in therapy, especially in cancer treatment. The present invention also relates to a pharmaceutical composition comprising said compounds, ligands, and/or complexes that are useful for medical imaging, targeting, and/or treatment of cancers. The present invention also relates to a process for preparing these compounds, ligands, and/or complexes.
Core Innovation
The invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof, with substituents R1 to R6, X1 to X3, and Y1 to Y3 defined by selected classes of hydrogen, alkyl, alkylene, alkenyl, alkynyl, aryl, carbonylamido-type options, and C(O)OH group or a group of formula (II). The disclosure also relates to pyclene-derived macrocyclic ligands of general formula (I), including substituents comprising acetate and/or groups of formula (II) (picolinate groups), for chelating metal ions, including radioelements, by forming ligand-metal complexes/chelates.
The disclosure includes preparation routes to the ligands and complexes of general formula (I), including substituted-picolinate intermediates and an oxalate-route synthesis sequence from pyclene oxalate intermediate 2 through intermediates 3, 4, 5, and 6, and onward to ligand analogs 7 through 12. The document also presents optimization and improved yields for synthesis of the pyclene oxalate intermediate 2, with a reported yield of at least 90% for methanol (MeOH).
The document further includes radiolabeling related process conditions, preparation and characterization of yttrium and lanthanide complexes, including Y and Gd, Eu, Tb, Yb, and Lu, and examples of yttrium complexes, including 90Y. It also describes thermodynamic stability and kinetic inertness of the resulting chelates, radiolabeling optimization with yttrium-90, extraction into Lipiodol, stability in human physiological saline, and spectroscopic and thermodynamic characterization including NMR, UV-visible analysis, relaxivity, complexation kinetics, dissociation half-lives in HCl competitive medium, potentiometry-determined protonation constants, stability constants, and x-ray diffraction coordination described as a coordination sphere N6O3 racemic mixture.
Claims Coverage
The provided claims cover one independent claim family centered on a compound of general formula (I) or a pharmaceutically acceptable salt thereof, together with dependent coverage for refined structural variants, example compounds, radioisotope-containing complexes, and iodinated oil pharmaceutical compositions. Overall, the inventive features center on the general formula (I) scaffold, its defined substituent set, and downstream use in complexes and compositions.
General formula (I) compound or salt with defined substituents
A compound of general formula (I) or a pharmaceutically acceptable salt of general formula (I), wherein R1, R2, R3, R4, R5 and R6 represent, independently of each other, one of H, a (C1–C20)alkyl group or a (C1–C20)alkylene-(C6–C10)aryl group optionally substituted with one or more organic acid functions; X1, X2 and X3 represent, independently of each other, one of H, —C(O)N(Re)(Rd), a (C1–C20)alkyl, a (C2–C20)alkenyl, a (C2–C20)alkynyl, or a (C6–C10)aryl, with optional heteroatoms and/or arylene and optional aryl and organic acid substitutions; and Y1, Y2 and Y3 represent, independently of each other, a C(O)OH group or a group of formula (II), with at least one Y being a group of formula (II).
Specific substituent refinements within general formula (I)
The compound of general formula (I) is further defined with tighter substituent patterns, including H at selected R positions and restrictions on heteroatoms in the radicals Ri to N, O, and S.
Enumerated example compounds corresponding to general formula (I)
Specific compounds corresponding to general formula (I), including Pc-2a1pa sym, Pc-2a1pa asym, Pc-1a2pa sym, Pc-1a2pa asym, Pc-1a2pa asym C8, Pc-1a2pa asym C12, and Pc-3p2a.
Radioisotope metal-containing complex for therapeutic cancer treatment
A method of therapeutic treatment for a cancer patient that involves administering a complex in which the metal atom M is a radioisotope.
Iodinated oil pharmaceutical composition
A pharmaceutical composition in which the iodinated oil consists of ethyl esters of iodinated fatty acids derived from poppy oil.
Claim coverage centers on the general formula (I) compound scaffold with defined R1–R6, X1–X3, and Y1–Y3 substituents, and extends to refined structural variants, enumerated example compounds, radioisotope-containing complexes for therapeutic cancer treatment, and iodinated oil pharmaceutical compositions.
Stated Advantages
Strong thermodynamic stability of the ligand-metal chelates.
Kinetic inertness, including a dissociation half-life, for stable metal binding.
Liver-targeted vectorization enabled by dissolving chelates in iodinated oils such as Lipiodol®.
Cancer visualization and/or cancer treatment enabled by medical-imaging methods and therapeutic administration using the described compositions.
Documented Applications
Medical imaging using the described ligand-metal chelates and pharmaceutical compositions.
Cancer visualization using liver-targeted vectorization via iodinated oil such as Lipiodol®.
Therapeutic cancer treatment by administering a complex where the metal atom M is a radioisotope.
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