Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/18—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
  • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/121—Solutions, i.e. homogeneous liquid formulation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present invention relates to novel reinforced macrocyclic ligands and their complexes, especially radioactive complexes, and their respective uses.
• the present invention also relates to a process for preparing said ligands and complexes.
• Macrocyclic ligands and their corresponding metal complexes are useful in many fields such as medical imaging, therapy or even chemical catalysis. These ligands make it possible to complex the metals thanks to their structure forming a cavity for trapping and complexing the metal.
• an additional carbon bridge is added to the basic macrocycle: the ligands thus formed are called reinforced ligands.
• This addition allows access to highly pre-organized macrocycles, having a three-dimensional internal cavity whose nature depends on the size of the macrocycle and the length of the bridge.
• the additional carbon bridge When applied to tetraazamacrocycles, the additional carbon bridge may be located on adjacent ("side") or opposite ("cross") nitrogen atoms.
• azacages which are spherical macrotricycles having two carbon bridges located on the pairs of opposite nitrogen atoms
• the reinforced ones which are macrobicycles having an ethylene or propylene bridge.
• the reinforced structures only cyclene or cyclam type macrocycles are known.
• the present invention aims to provide new ligands based on the pyclene macrocycle and reinforced, for complexing chemical elements, in particular radioelements and / or elements with magnetic properties.
• the present invention also aims to provide new complexes of these ligands, in particular radioactive and / or magnetically active complexes.
• the present invention aims to provide ligands and / or complexes particularly useful in medical imaging and / or therapy, for example as contrast agents.
• the present invention also aims to provide a pharmaceutical composition comprising complexes with reinforced ligands.
• the present invention aims to provide ligands and / or complexes useful as chemical catalysts.
• the present invention aims to provide a process for preparing these ligands and complexes.
• the present invention relates to a compound of general formula (I) below:
• X, X 2 , X 3 , ⁇ 1, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from the group consisting of:
• Rc and Rd being independently of one another H or a group (CC 20 ) alkyl
• alkyl group being optionally substituted with one or more substituents selected from the group consisting of:
• Re and Rf being independently of each other H or a group (d-C 20 ) alkyl
• Z 2 are independently selected from the group consisting of:
• Rg and Rh being independently of each other, selected from the group consisting of:
• alkyl groups possibly being substituted by one or more substituents chosen from the group consisting of:
• R is selected from the group consisting of:
• alkyl (C 1 -C 20 ) alkyl, (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, (C 1 -C 20 ) alkylene-W, (C 2 -C 20 ) alkenylene-W and (C 2 -C 20 ) alkynylene-W; said alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups which may optionally comprise one or more heteroatoms and / or one or more (C 6 -C 10 ) arylene (s) and / or one or more biphenylene (s) in their chain;
• W being selected from the group consisting of:
• R 1 and R 1 are independently of each other H or a (C 1 -C 20 ) alkyl group; said alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl and heteroaryl groups being optionally substituted with one or more substituents selected from the group consisting of:
• Rk and RI being independently of each other, H or a group (CrC 20 ) alkyl, said alkyl may optionally be substituted by one or more substituent (s) selected (s) from the group consisting of:
• halogen -C (O) ORm, -ORm, -N (Rm) (Rn), -C (O) -N (Rm) (Rn), -SH, -SRm, -S0 2 OH, -S0 2 - N (Rm) (Rn), -SCN, (C 6 -C 10 ) aryl and a functional chemical group for grafting to a vector or a biomolecule;
• Rm and Rn being independently of one another are H or a (d- C 20) alkyl; or one of its pharmaceutically acceptable salts or one of its optical isomers or one of its geometric isomers or one of its tautomers or one of its solvates.
• the inventors have developed new ligand-metal complexes (complexes also called chelates) from the macrocycle pyclene (3,6,9,15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 1 1, 13- triene).
• the pyclene macrocycle is of the following formula and is thus distinguished from the cyclene or cyclam macrocycles:
• the reinforced structure of the ligands according to the invention is as follows, based on a substituted pyclene macrocycle and comprising an ethylene bridge between two adjacent and non-involved carbon atoms:
• the inventors have discovered that the ethylene bridge induces a structural stress on the pyclene ring by bringing the bridged nitrogen atoms closer together.
• the size of the internal cavity of the ligand is smaller and much more rigid than that of the unreinforced pylenes.
• the doublets of the nitrogen atoms point in constrained directions and involve a pre-organization of the ligand.
• This structural modification notably makes it possible to complex the metals stably and the complexes are thus inert. It is then possible to prepare more thermodynamically stable complexes but also more kinetically inert.
• the new reinforced ligands and their complexes can be vectorized by grafting biomolecules or vectors, which makes it possible to target their therapeutic use or in medical imaging.
• ligand is meant a compound capable of complexing a chemical element such as a metal, preferably a radioelement.
• the ligands in the sense of the invention are in anionic form and can complex chemical elements in cationic form.
• the compounds of formula (I) are ligands, more particularly reinforced ligands.
• the term "reinforced ligand” means a pyclene macrocycle comprising an additional ethylenic bridge connecting two adjacent nitrogen atoms of said macrocycle.
• radioelement means any known radioisotope of a chemical element, whether natural or artificially produced.
• the term "element with magnetic properties” means any element which, subjected to a magnetic induction, begins to produce itself, in the volume which it occupies and outside, a magnetic induction as well as any paramagnetic element. which, having no property of spontaneous magnetization, acquires, under the effect of an external magnetic field, a magnetization directed in the same direction as this field of excitation.
• complex means the combination of a ligand as defined above with a chemical element such as a metal, preferably a radioelement as defined above and / or an element with magnetic properties such that defined above.
• a chemical element such as a metal, preferably a radioelement as defined above and / or an element with magnetic properties such that defined above.
• complex is synonymous with "chelate”.
• the term “treat”, “treatment” or “therapeutic treatment” means to reverse, relieve, inhibit the progression of, disorder or condition to which this term is applicable, or one or more symptoms.
• a disorder preferably a pathological disorder.
• the term “medical imaging” refers to the means of acquiring and restoring images of the human or animal body from various physical phenomena such as X-ray absorption, nuclear magnetic resonance, ultrasonic wave reflection or radioactivity.
• the term “medical imaging” refers to X-ray imaging, MRI (Magnetic Resonance Imaging), single photon emission computed tomography (SPECT) or Single Photon Emission Computed Tomography (SPECT). ), positron emission tomoscintigraphy (PET) and luminescence.
• the medical imaging method is X-ray imaging.
• the medical imaging method is MRI if the complex according to the invention comprises Gd (III), SPECT if the complex according to the invention comprises a gamma and PET emitter if the complex according to the invention comprises a beta + emitter.
• (CrC 20 ) alkyl refers to saturated aliphatic hydrocarbons, which may be linear or branched and comprise from 1 to 20 carbon atoms. Preferably, the alkyls comprise from 1 to 10 carbon atoms, more preferably from 1 to 5 carbon atoms. By “branched” is meant that an alkyl group is substituted on the main alkyl chain.
• the preferred alkyls according to the invention are methyl, ethyl, propyl, isopropyl or tert-butyl.
• (C 1 -C 20 ) alkylene denotes an alkyl radical as defined above and divalent.
• the preferred alkylenes according to the invention are the (dC 3 ) alkylene is methylene, ethylene and propylene and more preferably methylene.
• (C 2 -C 2 o) alkenyl denotes an alkyl as defined above, comprising at least one carbon-carbon double bond.
• (C 2 -C 2 O) alkenylene denotes an alkyl as defined above, comprising at least one carbon-carbon and divalent double bond.
• (C 2 -C 20 ) alkynyl denotes an alkyl as defined above, comprising at least one carbon-carbon triple bond.
• (C 2 -C 20 ) alkynylene denotes an alkyl as defined above, comprising at least one carbon-carbon and divalent triple bond.
• (C 6 -C 10 ) aryl refers to monocyclic, bicyclic or tricyclic hydrocarbon aromatic compounds, particularly phenyl and naphthyl.
• the biphenyl radicals may be substituted identically to the aryls according to the invention.
• heteroaryl of 5 to 10 atoms refers to monocyclic, bicyclic or tricyclic hydrocarbon aromatic compounds having 5 to 10 carbon atoms and in which at least one of the carbon atoms is replaced by a heteroatom, preferably N According to one embodiment, the heteroaryl is a pyridinyl, thiazolyl or indazolyl group.
• (C 6 -C 10 ) arylene means an aryl as defined above and divalent, in particular phenylene and naphthylene.
• halogen denotes F, Cl, Br, I, At and their isotopes, preferably F, Cl, Br, I and their isotopes.
• halogen denotes F, Cl, Br, I, At, preferably F, Cl, Br and I.
• heteroatoms mention may in particular be made of P, N, O and S, preferably N and O.
• the alkyl, alkenyl and alkynyl groups of the compounds of general formula (I) comprise 1 or 2 heteroatoms ( s).
• vector in particular nanovectors, active ingredients, liposomes, micelles, microparticles, nanoparticles, particles of iron oxide (Ultra Small Particle of Iron Oxide (USPIO), Small Particle of Iron Oxide (SPIO)), polymersomes and aggregates of molecules.
• USPIO Ultra Small Particle of Iron Oxide
• SPIO Small Particle of Iron Oxide
• biomolecule in particular peptides such as cyclic peptides, pseudopeptides, polypeptides, proteins or functional domains of proteins, haptens, antibodies, antibody fragments, vitamins, hormones, nucleosides, nucleotides, DNA, RNA or DNA or RNA fragments, fatty acids or fatty acid derivatives, phospholipids or phospholipid derivatives, cholesterol or derivatives thereof cholesterol, monosaccharides, oligosaccharides, polysaccharides and polyamines.
• peptides such as cyclic peptides, pseudopeptides, polypeptides, proteins or functional domains of proteins, haptens, antibodies, antibody fragments, vitamins, hormones, nucleosides, nucleotides, DNA, RNA or DNA or RNA fragments, fatty acids or fatty acid derivatives, phospholipids or phospholipid derivatives, cholesterol or derivatives thereof cholesterol, monosaccharides, oligosaccharides, polysaccharides and polyamines.
• the term "functional chemical group allowing the grafting to a vector or a biomolecule” a group selected from the group consisting of: succinimidyl, N-hydroxysuccinimidyl, sulfosuccinimidyl, maleimidyl, biotinyl, squarate, alkynylene true (or an alkynylene of formula
• R 1 CH with R 1 being alkylene), thiol (-SH), azide (-N 3 ), hydrazine (-NH-NH 2 ) and isothiocyanate (-SCN).
• LIPIODOL refers to an iodized oil and preferably to the pharmaceutical specialty LIPIODOL ® injectable solution manufactured and marketed by Guerbet and consisting of ethyl esters of iodized fatty acids of carnation oil.
• LIPIODOL ® is a product especially used for visualization, localization and / or vectorization during transarterial chemoembolization of hepatocellular carcinoma at the intermediate stage, in adults, as well as for the diagnosis by hepatic arterial pathway of hepatic extension. malignant liver lesions or not.
• the compounds of general formula (I), or reinforced ligands according to the invention can have centers of chirality and be in different isomeric forms.
• the invention therefore also relates to optical isomers (enantiomers or racemic mixture), geometric (diastereomers, cis / trans or Z / E isomers), tautomers and solvates such as hydrates of the compounds of general formula (I).
• the compounds of general formula (I) are in salt form, preferably in pharmaceutically acceptable salt form.
• pharmaceutically acceptable salt denotes, in particular, non-toxic salts making it possible to retain the properties of the compounds according to the invention.
• pharmaceutically acceptable salts are found in Berge, et al. ((1977) J. Pharm Sd, vol.66, 1).
• pharmaceutically acceptable salts is meant in particular salts of organic or inorganic acid or base.
• the compounds of general formula (I) are in the form of hydrochloride, hydrobromide, sodium or meglumine salt.
• - Xi, X 2 , X 3 , ⁇ , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are chosen independently of each other from the group consisting of:
• halogen -C (O) ORc, -ORc, -N (Rc) (Rd), -C (O) -N (Rc) (Rd), -SH, -SO 2 OH, -SCN, (C 6 - C10) aryl and a functional chemical group for grafting to a vector or a biomolecule; Rc and Rd being independently of one another H or a group (CC 20 ) alkyl;
• alkyl group being optionally substituted with one or more substituents selected from the group consisting of:
• Re and Rf being independently of each other H or a group (CC 20 ) alkyl
• Z 2 are independently selected from the group consisting of:
• Rg and Rh being independently of each other, selected from the group consisting of:
• Rt being selected from: (CrC 4 ) alkyl such as methyl or tert-butyl, benzyl, allyl and trifluoromethyl;
• alkyl groups possibly being substituted by one or more substituents chosen from the group consisting of:
• R is selected from the group consisting of:
• alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups which may optionally comprise one or more heteroatoms and / or one or more C 6 -C 10 arylene and / or one or more biphenylene (s) in their chain;
• W being selected from the group consisting of:
• R 1 and R 1 are independently of each other H or a (C 1 -C 20 ) alkyl group; said alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl and heteroaryl groups being optionally substituted with one or more substituents selected from the group consisting of:
• Rk and RI being independently of each other, H or a group (CrC 20 ) alkyl, said alkyl may optionally be substituted by one or more substituent (s) selected (s) from the group consisting of:
• halogen -C (O) ORm, -ORm, -N (Rm) (Rn), -C (O) -N (Rm) (Rn), -SH, -SO 2 OH, -SCN, (C 6 - C10) aryl and a functional chemical group for grafting to a vector or a biomolecule;
• Rm and Rn being independently of one another are H or a (d- C 20) alkyl.
• R is chosen from the group consisting of:
• said alkyl and alkylene groups may optionally comprise one or more heteroatoms and / or one or more C 6 -C 10 arylene (s) and / or one or more biphenylene (s) in their chain, preferably a group biphenylene;
• W being selected from the group consisting of:
• R 1 and R 1 being independently of one another H or a group (CrC 20 ) alkyl
• alkyl, alkylene, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from the group consisting of:
• Rk and RI being independently of each other H or a group (CrC 20 ) alkyl.
• R is chosen from the group consisting of:
• W being a phenyl or pyridinyl group, said alkyl, alkylene, phenyl or pyridinyl groups being optionally substituted with one or more substituents selected from the group consisting of:
• Rk and RI being independently of each other H or a group (CrC 20 ) alkyl.
• R is chosen from the group consisting of:
• W being selected from the group consisting of:
• R 1 and R 1 being independently of one another H or a group (CrC 20 ) alkyl
• alkyl, alkylene, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from the group consisting of:
• Rk and RI being independently of each other H or a group (CrC 20 ) alkyl.
• R is chosen from the group consisting of:
• W being selected from the group consisting of:
• R 1 and R 1 being independently of one another H or a group (CrC 20 ) alkyl
• alkyl, alkylene, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from the group consisting of:
• Rk and RI being independently of each other H or a group (CrC 20 ) alkyl.
• R is chosen from H, (Cr 5 ) alkylene-C (O) ORk or has the following formula (i): Wherein Rz is selected from (C 1 -C 10 ) alkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) alkynyl, halogen, - C (O) ORk, -ORk, -N (Rk) (RI), - C (O) -N (Rk) (RI), -SH, -SRk, -S0 2 OH, -SO 2 -N (Rk) (RI) and - SCN;
• Rk and RI being independently of each other H or a group (CrC 10 ) alkyl.
• R is selected from H, (CrC 20 ) alkyl, (C 2 -
• W being selected from the group consisting of:
• Q being selected from (C 1 -C 20 ) alkyl, (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, halogen, - C (O) ORk, -ORk, -N (Rk) (RI), - C (O) -N (Rk) (RI), -SH, -SRk, -S0 2 OH, -SO 2 -N (Rk) (RI) and - SCN;
• Rk and RI being independently of each other H or a group (CrC 20 ) alkyl.
• R is selected from H, (CrC 20 ) alkyl, (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, (CrC 2 o) alkylene-W, (CrC 2 o) alkenylene-W and (CC 20 ) alkynylene-W;
• W being selected from the group consisting of:
• Q being selected from (C 1 -C 20 ) alkyl, (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, halogen,
• Rk and RI being independently of each other H or a group (CrC 20 ) alkyl.
• R is selected from H, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) alkylene-W; W being selected from the group consisting of:
• W being selected from the group consisting of:
• R is different from H.
• W is chosen from a (C 6 -C 10 ) aryl, a heteroaryl consisting of 5 to 10 atoms, or a group -C (O) ORi with R 1 as defined above.
• W is a phenyl, a pyridinyl or a group -C (O) ORi with R 1 as defined above.
• ⁇ ⁇ and Z 2 which are identical or different, are H, OH or Cl, preferably H.
• X 1; X 2 , X 3 , ⁇ , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from the group consisting of:
• alkyl, alkenyl and alkynyl groups possibly comprising one or more heteroatoms and / or one or more (C 6 -C 10 ) arylene (s) and / or one or more biphenylene (s) in their chain; and
• alkyl, alkenyl and alkynyl groups being optionally substituted with one or more substituents selected from the group consisting of:
• Rc and Rd being independently of each other, H or a group (CrC 20 ) alkyl.
• X 1; X 2 and X 3 are independently selected from the group consisting of: H, halogen, (C 2 -C 20 ) alkynyl, (C 6 -C 10 ) aryl or azide, more preferably H.
• Y 1; Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are independently selected from the group consisting of:
• alkyl (C 1 -C 20 ) alkyl, (C 2 -C 20 ) alkenyl and (C 2 -C 20 ) alkynyl, said alkyl, alkenyl and alkynyl groups possibly comprising one or more heteroatoms (s) and / or one or more ( C 6 -C 10 ) arylene (s) and / or one or more biphenylene (s) in their chain.
• Y 1; Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are H.
• Y 2 and Y 3 are H or OH, preferably H.
• the compounds according to the invention have the following formula (II):
• X 2 and R being as defined above, preferably X 2 is H, halogen, (C 2 -C 20 ) alkynyl, (C 6 -C 10 ) aryl or azide, more preferably H.
• the invention also relates to a compound selected from the group consisting of the following compounds:
• Rk is H or a group (CrC 20 ) alkyl, in particular H or a group CrC 4 ) alkyl, preferably a methyl,
• Rk is H or a group (CrC 20 ) alkyl, especially H or a group (CrC 4 ) alkyl, preferably t-butyl.
• the alkyl groups of the radicals Ra, Rb, Rc and Rd are not substituted.
• the alkyl groups of the radicals ⁇ ⁇ and Z 2 are not substituted.
• the compounds according to the invention have the following general formula (I):
• X 2 , X 3 , ⁇ , Y 2 , 3 3, 4 4, Y 5 and Y 6 are independently selected from the group consisting of:
• alkyl, alkenyl and alkynyl groups optionally comprising one or more heteroatoms and / or one or more (C 6 -C 10 ) arylene (s) and / or one or more biphenylene (s) in their chain;
• Z 1 and Z 2 are chosen independently of one another from the group consisting of:
• Rg and Rh being independently of one another, H or a group (C
• C 4 ) alkyl chosen from the group consisting of H, (C 1 -C 20 ) alkyl, (C 2 -C 2 O) alkenyl, (C 2 -C 2 O) alkynyl, (C 1 -C 20 ) alkylene-W, (C 2 -C 20 ) alkenylene- W and (C 2 -C 20 ) alkynylene-W;
• W being selected from the group consisting of:
• R 1 and R 1 are independently of each other H or a (C 1 -C 20 ) alkyl group; said alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl and heteroaryl groups being optionally substituted with one or more substituents selected from the group consisting of:
• Rk and RI being independently of one another, H or a group (CrC 20 ) alkyl.
• the invention also relates to a complex of a compound of formula (I) or a salt thereof, as defined above, with a chemical element M, preferably a metal.
• M is a metal cation.
• M is a natural metal cation or a radioelement, preferably a radioelement.
• M is selected from transition metals (Se, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Y, Zr, Nb, Mo, Te, Ru, Rh, Pd, Ag , Hf, Ta, W, Re, Os, Ir, Pt, Au, Rf, Db, Sg, Bh, Hs, Cn), rare earths (Se, Y, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu), strontium (Sr), magnesium (Mg), rubidium (Rb), gallium (Ga), zinc (Zn), arsenic (As), aluminum (Al), lead (Pb), bismuth (Bi) and indium (In).
• transition metals Si, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Y, Zr, Nb, Mo, Te, Ru, Rh, Pd, Ag , Hf, Ta, W, Re, O
• M is selected from transition metals (Se, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Y, Zr, Nb, Mo, Te, Ru, Rh, Pd, Ag , Hf, Ta, W, Re, Os, Ir, Pt, Au, Rf, Db, Sg, Bh, Hs, Cn), strontium (Sr), magnesium (Mg), rubidium (Rb), gallium (Ga), zinc (Zn), arsenic (As), aluminum (Al), lead (Pb), bismuth (Bi) and indium (In).
• M is selected from transition metals (Se, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Y, Zr, Nb, Mo, Te, Ru, Rh, Pd, Ag, Hf, Ta, W, Re, Os, Ir, Pt, Au, Rf, Db, Sg, Bh, Hs, Cn).
• M is chosen from lanthanides and is preferentially Gd, and in particular the Gd 3+ ion.
• M is chosen from Mn, Fe, Co, Ni, Cu, Zn, Ga, As, Se, Al, Te, Pd and Pt.
• M is even more preferably chosen from Mn, Fe, Co, Ni, Cu, Zn and Ga.
• the stable or radioactive forms of these elements can be: 68 Ga, 67 Ga, 52 Mn, 52m Mn, 99m Tc, "Te, 91 Y, 91m Y, 90 Y, 88 Y, 55 Fe, 59 Fe, 195m Pt, 103 Pd, 186 Re, 188 Re, 67 Cu, 64 Cu, 212 Pb, 212 Bi, 213 Bi, 111 In, 26 Al, 82 Sr, 28 Mg, 44 Ti, 47 Sc, 51 Cr, 57 Co, 81 Rb. , 82 Rb, 192 lr, 117m Sn.
• M is chosen from:
• M is chosen from: Pd, Rh, Ru, Pt, Ag, Au and Re.
• M is chosen from lanthanides, Fe, Rh and Ru.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as defined above or a complex as defined above, and optionally one or more pharmaceutically acceptable excipient (s).
• the composition may furthermore comprise a buffer chosen from the buffers of established use, for example the buffers lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, tris ((hydroxymethyl) aminomethane), HEPES (2- [4-acid - (2-hydroxyethyl) -1-piperazine] ethanesulfonic acid), MES (2-morpholino ethanesulfonic acid), phosphate buffered saline (often abbreviated as PBS) and mixtures thereof.
• a buffer chosen from the buffers of established use, for example the buffers lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, tris ((hydroxymethyl) aminomethane), HEPES (2- [4-acid - (2-hydroxyethyl) -1-piperazine] ethanesulfonic acid), MES (2-morpholino ethanesulfonic acid), phosphate buffered s
• the pharmaceutical composition may comprise an oily phase, especially an iodinated oil.
• the pharmaceutical composition further comprises ethyl esters of iodized fatty acids of the carnation oil.
• the pharmaceutical composition according to the invention consists of an iodized oil and complexes according to the invention.
• the pharmaceutical composition according to the invention consists of LIPIODOL® and complexes according to the invention.
• LIPIODOL® is composed of ethyl esters of iodized fatty acids of carnation oil.
• the pharmaceutical composition according to the invention is radio-opaque, and therefore visible by X-ray radiography.
• the pharmaceutical composition is an injectable composition.
• the pharmaceutical composition according to the invention is administered by intra-arterial hepatic injection.
• the present invention also relates to a method for imaging the whole body or part of the body of an individual comprising a step of obtaining one or more images of the whole body or part of the body of an individual. by a medical imaging technique, wherein said whole body or said body part of the individual comprises the complex or the pharmaceutical composition as defined above.
• the invention also relates to a contrast product comprising the complex of a compound of formula (I) or a salt thereof as defined above.
• the invention also relates to a complex or a pharmaceutical composition as defined above, for its use in medical imaging.
• the invention also relates to the use of a complex or a pharmaceutical composition as defined above in medical imaging.
• the tomography or single photon emission tomoscintigraphy also called SPECT in English for "Single Photon Emission Computed Tomography” is usable
• PET positron emission tomography
• Magnetic Resonance Imaging MRI is usable.
• the invention relates to a complex of a compound of formula (I) or a salt thereof as defined above for its use for in vivo diagnostic purposes.
• the invention also relates to the use of a complex according to the invention as a catalyst, in particular in stereospecific, stereoselective, diastereospecific, stereospecific diastereoselective reactions and coupling reactions.
• the invention relates to a complex or a pharmaceutical composition as defined above, for its use in the treatment of cancers.
• the invention relates to the use of a complex as defined above for the preparation of a medicament for the treatment of cancers.
• the invention relates to a method of therapeutic treatment of a patient suffering from a cancer, comprising the administration to said patient of a complex or a pharmaceutical composition as defined above.
• said method of treatment does not include a surgical treatment step.
• the therapeutic treatment method, the complex or the pharmaceutical composition for its use in the treatment of cancers as defined above are based in particular on the fact that the chemical element M of the complex or of a pharmaceutical composition as defined herein above emits radiation that destroys cancer cells.
• the complex as defined above used for the preparation of a medicament for the treatment of cancers comprises in particular a chemical element M which emits beta (minus) radiation, Auger electrons or alpha particles.
• cancer abnormal cell proliferation (also called tumor) within a normal tissue of the body.
• cancerous cells are all derived from a single clone, a cancer-initiating cell that has acquired certain characteristics that allow it to divide indefinitely. During the evolution of the tumor, some cancer cells can migrate out of their place of production and form metastases.
• liver cancers in particular primary cancers of the liver, preferably hepatocarcinomas.
• hepatocarcinoma preferably epithelioid hemangioendothelioma
• cholangiocarcinoma cholangiocarcinoma
• neuroendocrine tumors preferably metastases of other cancers such as metastases of colorectal cancer.
• the cancer is an intermediate stage hepatocellular carcinoma in adults.
• the invention relates to a method for preparing a compound of general formula (I) below:
• X 1; X 2 , X 3 , Y 1, Y 2 , Y 3 , Y 4 , Y 5 , Y and R are as defined above, in the presence of a mixture of a reducing agent A-BH 4 and an organic acid, with A being selected from the group consisting of Li, Na, K, Zn and (Me 3 ) N;
• the reduction step C leads to the formation of at least one of the following intermediate compounds of formulas (XXI) and (XXII):
• the reduction step C is carried out in the presence of a mixture of the NaBH 4 reducing agent with trifluoroacetic acid (NaBH 4 / TFA mixture).
• the organic acid is selected from acetic acid, trifluoroacetic acid, and mixtures thereof.
• acetic acid is used in admixture with NaBH 4 or (Me) 4 NBH 4 .
• trifluoroacetic acid is used in admixture with NaBH 4 .
• organic acids and borohydrides that can be used according to the invention are described in particular in John Wiley's Encyclopedia of Reagents for Organic Synthesis (Leo A. Paquette Editor).
• the ratio A-BH 4 / organic acid preferably the ratio NaBH 4 / TFA, is 1/1.
• the number of equivalents of the mixture A-BH 4 / organic acid is between 2 and 10, preferably 5, by amide function of the compounds of formula (XIII) (or by amide function carried by the atoms of nitrogen belonging to the cycle pyclene).
• the reduction step C is carried out in the presence of an organic solvent, preferably chosen from tetrahydrofuran, dichloromethane (also called DCM or CH 2 CI 2 below), acetonitrile, methanol, ethanol, chloroform or their mixtures.
• an organic solvent preferably chosen from tetrahydrofuran, dichloromethane (also called DCM or CH 2 CI 2 below), acetonitrile, methanol, ethanol, chloroform or their mixtures.
• the reduction step C is carried out under an inert atmosphere. According to one embodiment, the reduction step C is carried out at ambient temperature, that is to say preferably between 15 ° C. and 25 ° C. According to one embodiment, the mixture of the reducing agent A-BH 4 and the organic acid is produced at a temperature of between 0 ° C. and 25 ° C., preferably around 0 ° C.
• the process according to the invention comprises, prior to said reduction step C, a condensation step A of a compound of formula (X) below:
• E being a (dC 4 ) alkyl, preferably ethyl or methyl;
• the compound of formula (XI) is chosen from the following compounds:
• Xi, 2, 3, ⁇ , Y 2, Y 3 , Y 4 , Y 5 and Y 6 being as defined above.
• the condensation step A is carried out in the presence of a polar solvent such as methanol, ethanol or their mixtures. According to one embodiment, the condensation step A is carried out at ambient temperature, ie between 15 ° C and 25 ° C.
• the process for preparing a compound of formula (I) according to the invention comprises, between step A and step C, a step of functionalization B of a compound of formula (XII) below:
• X 1; X 2 , X 3 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 being as defined above,
• the process for preparing a compound of formula (I) according to the invention comprises after step C and when at least one of group ⁇ and Z 2 groups is different from H, a step of functionalization D 'of a compound of formula ( ⁇ ) below:
• the process for preparing a compound of formula (I) according to the invention comprises, before step C, and when at least one of groups Z 1 and Z 2 is different from H, a step of D functionalization of a compound of formula (XI II) below:
• the functionalization steps B and D may be performed according to methods known to those skilled in the art.
• steps A, B, C and D as defined above can be chained according to one of the following diagrams:
• the process for preparing a compound of formula (I) according to the invention comprises the following steps:
• step B of functionalization as defined above; then step C reduction as defined above; then
• step D of functionalization as defined above.
• the invention also relates to a process for preparing a complex such as according to the invention comprising a step of complexing a chemical element M as defined above with a ligand according to the invention, said step preferably being a radiolabeling step.
• the complexation is preferably carried out by microwaves.
• Figure 1 1 H NMR spectra and 13 C of the compound 2a.
• Figure 2 1 H and 13 C NMR spectra of the complex [Zn (2a)] (ClO 4 ).
• Figure 6 Spectrum obtained in HPLC-MS during the analysis of the precipitate containing the compound 2c and the corresponding lactam.
• Figure 7 Structure of the compound 1 1 obtained by X-ray diffraction.
• Figure 8 Structure of the complex [Mn (2a)] (IC0 4 ) obtained by X-ray diffraction.
• DIPEA diisopropylethyl amine
• the methyl ester of 6-chloromethylpyridine-2-carboxylic acid (71 lmg, 3.85 mmol) is added to a solution of pyclene oxalate (1.0 g, 3.85 mmol) in acetonitrile (300 mL) in the presence of K 2 CO 3 (1.5 g, 12 mmol).
• the reaction mixture is refluxed for four days and then filtered.
• the filtrate is concentrated and then purified by column chromatography using neutral alumina as support (eluent: CH 2 Cl 2 / MeOH 98/2). After evaporation, the product 1 obtained is a yellow oil (1.56 g, 99%).
• Compound 2c - Obtaining an unreinforced pyclene not belonging to the invention
• Compound 1 c '(336.9 mg, 1.01 mmol) is solubilized in ultrapure hydrochloric acid (10 ml, 3 M) .
• the reaction mixture is heated at 70 ° C for 2.5 days and then evaporated.
• the brown oil is taken up in the minimum amount of HCl and the product is precipitated with acetone (20 ml).
• the precipitate is analyzed on C-18 HPLC (0.1% H 2 TFA / 0.1% TFA ACFA, 98/2> 10/90) to give a separable mixture of the expected product 2c and the corresponding lactam.
• Figure 6 provides the spectrum obtained in HPLC-MS.
• the reaction medium is then filtered on sintered glass of porosity 4, and a solution of NaOH (10 M, 10 mL) is added to the filtrate.
• a solution of NaOH (10 M, 10 mL) is added to the filtrate.
• 40 mL of ultrapure water and 100 mL of DCM are added, the desired product is extracted into the organic phase with 3 x 100 mL of DCM.
• the organic phases are combined, dried over MgSO 4 , filtered and evaporated to give the crude product (white foam, 875.6 mg).
• the crude product (642.3 mg) is purified on a short column of basic alumina (0 3 cm; t 5 cm) with a DCM / MeOH gradient (100/0 ⁇ 85/15) to yield compound 11 in the form of of boron salt (white crystals, 208.7 mg, 21% (calculated for 2 BH 3 )).
• Figure 7 provides the structure obtained by X-ray diffraction of compound 11, and proves that its formula is as follows:
• a solution of ultrapure hydrochloric acid (3M, 2.2 mL) is added to compound 11 to hydrolyze amino-borane linkages.
• the acid mixture obtained is heated at 40 ° C. for 3 days.
• NaOH pellets are added to adjust the pH to 12-14.
• the aqueous phase is extracted with dichloromethane (3 ⁇ 25 mL) and the organic phase is dried over filtered MgSO 4 and concentrated.
• the resulting compound 4 is a yellow solid (90 mg, 100%).
• Figure 8 provides the structure obtained by X-ray diffraction of the [Mn (2a)] (IC0 4 ) complex.

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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2017
  • 2017-06-28 FR FR1755933A patent/FR3068355B1/fr active Active
• 2018
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