EP3645534A1

EP3645534A1 - Reinforced macrocyclic ligands, complexes thereof, and uses of same

Info

Publication number: EP3645534A1
Application number: EP18733626.8A
Authority: EP
Inventors: Raphaël TRIPIER; Olivier Rousseaux; Mariane LE FUR; Maryline BEYLER; Olivier FOUGÈRE; Gwladys NIZOU
Original assignee: Guerbet SA; Centre National de la Recherche Scientifique CNRS; Univerdite de Bretagne Occidentale
Current assignee: Guerbet SA; Centre National de la Recherche Scientifique CNRS; Univerdite de Bretagne Occidentale
Priority date: 2017-06-28
Filing date: 2018-06-28
Publication date: 2020-05-06
Also published as: FR3068355A1; FR3068355B1; US11155553B2; WO2019002505A1; US20200157101A1

Abstract

The invention relates to new macrocyclic ligands of formula (I) and complexes thereof, particularly radioactive complexes, and to the uses thereof and a method for preparing same. The ligands have a reinforced pyclene core.

Description

Enhanced macrocyclic ligands, their complexes and their uses

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.

To limit the flexibility of these ligands and / or functionalize their structure, 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.

When applied to tetraazamacrocycles, the additional carbon bridge may be located on adjacent ("side") or opposite ("cross") nitrogen atoms.

To date, only three types of bridged tetraazamacrocycles exist:

- "ansamacrocycles", which are macrobicycles whose additional carbon bridge comprises at least four 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. Among the reinforced structures, only cyclene or cyclam type macrocycles are known.

There is therefore a need for new reinforced ligands, notably allowing the formation of thermodynamically and kinetically inert stable metal complexes. In particular, there is a need for new reinforced ligands based on a pyclene macrocycle and allowing the formation of stable metal complexes, in particular thermodynamically stable and kinetically inert.

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:

in which :

X, X ₂ , X ₃ , Υ 1, Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are independently selected from the group consisting of:

H, (C 1 -C ₂₀ ) alkyl, (C ₂ -C ₂ O) alkenyl, (C ₂ -C ₂ O) alkynyl, (C ₆ -C ₁₀ ) aryl, halogen, azide (-N ₃ ), -C (O) ORa, -ORa, -N (Ra) (Rb), -C (O) -N (Ra) (Rb), -SH, -SRa, -S0 ₂ OH, -SO ₂ -N (Ra) (Rb), -SCN and a functional chemical group for grafting to a vector or a biomolecule; Ra and Rb being independently of one another, H or a group (CrC ₂₀ ) alkyl; said 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 said alkyl, alkenyl, alkynyl and (C ₆ -C ₁₀ ) aryl groups possibly being substituted by one or more substituents chosen from the group consisting of:

halogen, -C (O) ORc, -ORc, -N (Rc) (Rd), -C (O) -N (Rc) (Rd), -SH, -SRc, -S0 ₂ OH, -S0 ₂ - N (Rc) (Rd) -SCN, (C ₆ -C ₁₀ ) 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;

said alkyl group being optionally substituted with one or more substituents selected from the group consisting of:

halogen, -C (O) ORe, -ORe, -N (Re) (Rf), -C (O) -N (Re) (Rf), -SH, -SRe, -S0 ₂ OH, -S0 ₂ - N (Re) (Rf) -SCN, (C ₆ -C ₁₀ ) aryl and a functional chemical group for grafting to a vector or a biomolecule;

Re and Rf being independently of each other H or a group (d-C ₂₀ ) alkyl;

and Z ₂ are independently selected from the group consisting of:

H, (CrC ₄ ) alkyl, halogen, -ORg, -N (Rg) (Rh), -SH and -SRg,

Rg and Rh being independently of each other, selected from the group consisting of:

H, (CrC ₄ ) alkyl, 2-THP (tetrahydropyranyl), tosyl, nosyl, TMS (trimethylsilyl), -O-C (O) Rt, -C (O) Rt, -OC (O) ORt, - NH-C (O) -ORt, -NH-C (O) Rt; Rt being selected from: (CrC ₄ ) alkyl such as methyl or tert-butyl, benzyl, allyl and trifluoromethyl;

said alkyl groups possibly being substituted by one or more substituents chosen from the group consisting of:

halogen, -C (O) ORp, -ORp, -N (Rp) (Rq), -C (O) -N (Rp) (Rq), -SH, -SRp, -S0 ₂ OH, -S0 ₂ - N (Rp) (Rq) and -SCN; Rp and Rq being independently of one another, H or a (CrC ₄ ) alkyl group;

R is selected from the group consisting of:

H, (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:

(C ₆ -C ₁₀ ) aryl, heteroaryl of 5 to 10 atoms, biphenyl, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1) ), - (Rj) P (O) (ORi), -O-P (O) (ORi) (ORj), -SH, -S0 ₂ OH, -S0 ₂ -N (Ri) (Rj) and -SCN ;

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:

(C 1 -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, halogen, -C (O) ORk, -ORk, -N (Rk) (RI), -C ( 0) -N (Rk) (RI), -SH, -SRk, -SO ₂ OH, -SO ₂ -N (Rk) (RI), -SCN, (C ₆ -C ₁₀ ) aryl and biphenyl;

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. Thus, 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.

These properties are important when using the compounds in particular in vivo since this reduces the risk of unwanted release of the complexed element in case of competition with the medium (other cations, metal or not), other chelating entities, or conditions harmful (reducing medium for example). In addition, the steric constraints and the reduced cavity size allow improved selectivity with respect to certain metals.

In particular, 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. Definitions

By "ligand" is meant a compound capable of complexing a chemical element such as a metal, preferably a radioelement. According to one embodiment, the ligands in the sense of the invention are in anionic form and can complex chemical elements in cationic form. According to the present invention, the compounds of formula (I) are ligands, more particularly reinforced ligands.

According to one embodiment, the term "reinforced ligand" means a pyclene macrocycle comprising an additional ethylenic bridge connecting two adjacent nitrogen atoms of said macrocycle.

The term "radioelement" means any known radioisotope of a chemical element, whether natural or artificially produced.

In particular, 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.

The term "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. The term "complex" is synonymous with "chelate".

In the context of the invention, 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. such 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. According to one embodiment, 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. Preferably, the medical imaging method is X-ray imaging. According to a particular embodiment, 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.

The term "(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.

The term "(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.

The term "(C ₂ -C ₂ o) alkenyl" denotes an alkyl as defined above, comprising at least one carbon-carbon double bond.

The term "(C ₂ -C ₂ O) alkenylene" denotes an alkyl as defined above, comprising at least one carbon-carbon and divalent double bond.

The term "(C ₂ -C ₂₀ ) alkynyl" denotes an alkyl as defined above, comprising at least one carbon-carbon triple bond.

The term "(C ₂ -C ₂₀ ) alkynylene" denotes an alkyl as defined above, comprising at least one carbon-carbon and divalent triple bond.

The term "(C ₆ -C ₁₀ ) aryl" refers to monocyclic, bicyclic or tricyclic hydrocarbon aromatic compounds, particularly phenyl and naphthyl.

According to one embodiment, the biphenyl radicals may be substituted identically to the aryls according to the invention.

The term "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.

The term "(C ₆ -C ₁₀ ) arylene" means an aryl as defined above and divalent, in particular phenylene and naphthylene.

According to one embodiment, "halogen" denotes F, Cl, Br, I, At and their isotopes, preferably F, Cl, Br, I and their isotopes. According to one embodiment, "halogen" denotes F, Cl, Br, I, At, preferably F, Cl, Br and I. Among the heteroatoms, mention may in particular be made of P, N, O and S, preferably N and O. According to one particular embodiment, the alkyl, alkenyl and alkynyl groups of the compounds of general formula (I) comprise 1 or 2 heteroatoms ( s).

By "vector" is meant 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.

By "biomolecule" is meant 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.

By "functional chemical group allowing the grafting to a vector or to a biomolecule" is meant any chemical group or chemical function allowing, after reaction, the coupling of a ligand according to the invention with a vector or a biomolecule as defined above. .

According to one embodiment, 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).

The term "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. Compounds of general formula (I)

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).

According to one embodiment, the compounds of general formula (I) are in salt form, preferably in pharmaceutically acceptable salt form.

The term "pharmaceutically acceptable salt" denotes, in particular, non-toxic salts making it possible to retain the properties of the compounds according to the invention. Examples of pharmaceutically acceptable salts are found in Berge, et al. ((1977) J. Pharm Sd, vol.66, 1). By "pharmaceutically acceptable salts" is meant in particular salts of organic or inorganic acid or base. For example, the compounds of general formula (I) are in the form of hydrochloride, hydrobromide, sodium or meglumine salt.

Preferably, in formula (I) above,

- Xi, X ₂ , X ₃ , Υι, Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are chosen independently of each other from the group consisting of:

H, (Ci-C ₂ o) alkyl, (C ₂ -C ₂₀₎ alkenyl, (C ₂ -C ₂₀₎ alkynyl, (C ₆ -C ₁₀₎ aryl, halogen, azide (-N _3), -C (0) ORa, -ORa, -N (Ra) (Rb), -C (O) -N (Ra) (Rb), -SH, -SO ₂ OH, -SCN and a functional chemical group allowing the grafting to a vector or a biomolecule; Ra and Rb being independently of one another, H or a group (CrC ₂₀ ) alkyl; said 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; and said alkyl, alkenyl, alkynyl and (C ₆ -C ₁₀ ) aryl groups may optionally be substituted with one or more substituents selected 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;

halogen, -C (O) ORe, -ORe, -N (Re) (Rf), -C (O) -N (Re) (Rf), -SH, -SO ₂ OH, -SCN,

(C ₆ -C ₁₀ ) aryl and a functional chemical group for grafting to a vector or a biomolecule;

Re and Rf being independently of each other H or a group (CC ₂₀ ) alkyl;

- Σ _! and Z ₂ are independently selected from the group consisting of:

H, (CrC ₄ ) alkyl, halogen, -ORg, -N (Rg) (Rh) and -SH;

H, a group (dC ₄ ) alkyl, 2-THP (tetrahydropyranyl), tosyl, nosyl, TMS

(trimethylsilyl), -O-C (O) Rt, -C (O) Rt, -OC (O) ORt, -NH-C (O) -ORt, -NH-C (O) Rt; Rt being selected from: (CrC ₄ ) alkyl such as methyl or tert-butyl, benzyl, allyl and trifluoromethyl;

halogen, -C (O) ORp, -ORp, -N (Rp) (R q), -C (O) -N (Rp) (R q), -SH, -SO ₂ OH and -SCN; Rp and Rq being independently of each other H or a group (CC ₄ ) alkyl;

R is selected from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, (C ₁ -C ₂ ) 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 and / or one or more biphenylene (s) in their chain;

W being selected from the group consisting of:

(C ₆ -C 10) aryl, heteroaryl of 5 to 10 atoms, biphenyl, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1) , -P (O) (ORi), -O-P (O) (ORi) (ORj), -SH, -SO ₂ OH and -SCN;

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:

(C 1 -C ₂₀ ) alkyl, (C ₂ -C ₂ O) alkenyl, (C ₂ -C ₂ O) alkynyl, halogen, -C (O) ORk, -ORk, -N (Rk) (RI), - C (O) -N (Rk) (RI), -SH, -SO ₂ OH, -SCN, (C ₆ -C ₁₀ ) aryl and biphenyl;

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.

According to one embodiment, R is chosen from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C 1 -C ₂₀ ) alkylene-W;

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:

(C ₆ -C ₁₀ ) aryl, heteroaryl of 5 to 10 atoms, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1), (R 1) P (O) (OR 1), -O-P (O) (OR 1) (OR 1), -SH, -SR 1, -SO ₂ OH, -SO ₂ -N (R 1) (R 1), - SCN and a biphenyl group;

R 1 and R 1 being independently of one another H or a group (CrC ₂₀ ) alkyl;

said alkyl, alkylene, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from the group consisting of:

(CrC 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, -SO ₂ OH, -SO ₂ -N (Rk) (RI), -SCN, (C ₆ -C ₁₀ ) aryl and a biphenyl group;

Rk and RI being independently of each other H or a group (CrC ₂₀ ) alkyl.

According to a particular embodiment, R is chosen from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C 1 -C ₂₀ ) alkylene-W;

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:

(C 1 -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, halogen, -C (O) ORk, -ORk, -N (Rk) (RI), -C ( 0) -N (Rk) (RI), -SH, -SRk, -SO ₂ OH, -SO ₂ -N (Rk) (RI) -SCN, (C ₆ -C ₁₀ ) aryl and a biphenyl group;

Rk and RI being independently of each other H or a group (CrC ₂₀ ) alkyl.

According to one embodiment, R is chosen from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C ₁ -C 4 alkylene-W;

W being selected from the group consisting of:

(C ₆ -C 10) aryl, heteroaryl of 5 to 10 atoms, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1), - (R 1) P (O) (OR 1), -O-P (O) (OR 1) (OR 1), -SH, -SO ₂ OH, -SO ₂ -N (R 1) (R 1) and - SCN;

(CrC 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, -SO ₂ OH, -SO ₂ -N (Rk) (RI), -SCN and (C ₆ -C ₁₀ ) aryl;

Rk and RI being independently of each other H or a group (CrC ₂₀ ) alkyl.

According to a particular embodiment, R is chosen from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C ₁ -C ₂ O) alkylene-W;

W being selected from the group consisting of:

(C ₆ -C ₁₀ ) aryl, heteroaryl of 5 to 10 atoms, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1), -P (O) (ORi), -O-P (O) (ORi) (ORj), -SH, -SO ₂ OH and -SCN;

(CrC 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, -SO ₂ OH, -SCN and (C ₆ -C ₁₀ ) aryl;

Rk and RI being independently of each other H or a group (CrC ₂₀ ) alkyl.

According to a particular embodiment, 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.

According to one embodiment, R is selected from H, (CrC ₂₀ ) alkyl, (C ₂ -

C ₂₀₎ alkenyl, (C ₂ -C ₂₀₎ alkynyl, (Ci-C ₂ o) alkylene-W, (dC ^ alkenylene-W and (CC ₂₀₎ alkinylene-W;

W being selected from the group consisting of:

-COOH, -P (O) (OH) _2, - (R 1) P (O) -OH, -OH, -SH, -C (O) -N (R 1) (R 1) with R 1 and R 1 as defined above, and

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.

According to one embodiment, 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:

-COOH, -P (O) (OH) _2, -P (O) -OH, -OH, -SH, -C (O) -N (R 1) (R 1) with R 1 and R 1 as defined above , and

Q being selected from (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, halogen,

C (0) ork, -ORk, -N (Rk) (RI), -C (0) -N (Rk) (RI), -SH, -S0 ₂ OH and -SCN;

Rk and RI being independently of each other H or a group (CrC ₂₀ ) alkyl.

According to one embodiment, R is selected from H, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkylene-W; W being selected from the group consisting of:

- -P (0) (OH) _2, - (Q) P (O) -OH

with Q being as defined above,

and preferably W being selected from the group consisting of:

-COOH-P (O) (OH) _2, -P (O) -OH,

with Q being as defined above.

According to one embodiment, R is different from H.

According to one embodiment, 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.

According to a particular embodiment, W is a phenyl, a pyridinyl or a group -C (O) ORi with R 1 as defined above. According to a particular embodiment, Ζ _λ and Z ₂ , which are identical or different, are H, OH or Cl, preferably H. According to one embodiment, X _1; X ₂ , X ₃ , Υι, Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are independently selected from the group consisting of:

H, (CrC2o) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, halogen, azide (-N ₃ ),

said 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

said alkyl, alkenyl and alkynyl groups being optionally substituted with one or more substituents selected from the group consisting of:

halogen, -C (O) ORc, -ORc, -N (Rc) (Rd), -C (O) -N (Rc) (Rd), -SH, -SRc, -S0 ₂ OH, -S0 ₂ - N (Rc) (Rd) -SCN, (C ₆ -C ₁₀ ) aryl and a functional chemical group allowing the grafting to a vector or a biomolecule

(preferably from the group consisting of halogen, -C (O) ORc, -ORc, -N (Rc) (Rd), -

C (O) -N (Rc) (Rd), -SH, -SO ₂ OH, -SO ₂ -N (Rc) (Rd) -SCN, (C ₆ -C ₁₀ ) aryl and a functional chemical group allowing the grafting to a vector or a biomolecule);

Rc and Rd being independently of each other, H or a group (CrC ₂₀ ) alkyl.

According to one embodiment, 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.

According to one embodiment, Y _1; Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are independently selected from the group consisting of:

H, (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.

According to a particular embodiment, Y _1; Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are H.

According to a particular embodiment Y ₂ and Y ₃ are H or OH, preferably H. According to one embodiment, the compounds according to the invention have the following formula (II):

(II)

with 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:

in which Rk is H or a group (CrC ₂₀ ) alkyl, in particular H or a group CrC ₄ ) alkyl, preferably a methyl,

wherein Rk is H or a group (CrC ₂₀ ) alkyl, especially H or a group (CrC ₄ ) alkyl, preferably t-butyl. According to one embodiment, the alkyl groups of the radicals Ra, Rb, Rc and Rd are not substituted. According to one embodiment, the alkyl groups of the radicals Ζ _λ and Z ₂ are not substituted.

According to one embodiment, the compounds according to the invention have the following general formula (I):

in which :

- X _1; X ₂ , X ₃ , Υι, Y ₂ , 3 3, 4 4, Y 5 and Y ₆ are independently selected from the group consisting of:

H, (Ci-C ₂ o) alkyl, (C ₂ -C ₂₀₎ alkenyl, (C ₂ -C ₂₀₎ alkynyl, (C ₆ -C ₁₀₎ aryl, halogen, -C (0) ORa, -ORa, -N (Ra) (Rb), -C (O) -N (Ra) (Rb), -SH, -SRa, -S0 ₂ OH, S0 ₂ -N (Ra) (Rb), -SCN and a functional chemical group allowing the grafting to a vector or a biomolecule; Ra and Rb being independently of one another, H or a group (CrC ₂₀ ) alkyl;

said 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:

H, (CrC ₄ ) alkyl, halogen, -ORg, -N (Rg) (Rh), -SH and -SRg;

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:

(C ₆ -C ₁₀ ) aryl, heteroaryl of 5 to 10 atoms, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1), - (Rj) P (O) (ORi), -O-P (O) (ORi) (ORj), -SH, -S0 ₂ OH, -S0 ₂ -

N (R 1) (R 1), and -SCN;

(CrC 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, -SO ₂ OH, -SO ₂ -N (Rk) (RI), -SCN and (C ₆ -C ₁₀ ) aryl;

Rk and RI being independently of one another, H or a group (CrC ₂₀ ) alkyl.

complex

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. According to one embodiment, M is a metal cation. According to one embodiment, M is a natural metal cation or a radioelement, preferably a radioelement.

According to one embodiment, 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).

According to one embodiment, 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). According to one particular embodiment, 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).

According to a particular embodiment, M is chosen from lanthanides and is preferentially Gd, and in particular the Gd ³⁺ ion.

According to a particular embodiment, 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.

According to a particular embodiment, in the context of applications in imaging or in therapy as defined below, M is chosen from:

⁶⁸ Ga, ⁶⁷ Ga, ⁵² Mn, ^99m Tc, ⁹⁰ Y, ⁸⁶ Y, ⁵⁹ Fe, ^195m Pt, ¹⁰³ Pd, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁷ Cu, ⁶⁴ Cu, ²¹² Pb, ²¹² Bi, ²¹³ Bi and ¹¹¹ ln. .

According to another embodiment, in the context of industrial applications as catalysts, M is chosen from: Pd, Rh, Ru, Pt, Ag, Au and Re.

According to another embodiment, in the context of applications in in vitro diagnostic tools M is chosen from lanthanides, Fe, Rh and Ru.

Pharmaceutical composition

The invention also relates to 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.

The pharmaceutical composition may comprise an oily phase, especially an iodinated oil. According to a particular embodiment, the pharmaceutical composition further comprises ethyl esters of iodized fatty acids of the carnation oil.

According to one embodiment, the pharmaceutical composition according to the invention consists of an iodized oil and complexes according to the invention. Typically, 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.

Preferably, the pharmaceutical composition according to the invention is radio-opaque, and therefore visible by X-ray radiography.

According to a particular embodiment, the pharmaceutical composition is an injectable composition. According to one embodiment, 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.

According to one embodiment, the following imaging techniques will be usable depending on the nature of the chemical element M of the complex as defined above:

in the case where the chemical element M is a gamma ray emitter, the tomography or single photon emission tomoscintigraphy (TEMP) also called SPECT in English for "Single Photon Emission Computed Tomography" is usable,

in the case where the chemical element M is a positron emitter, positron emission tomography (PET), also called PET or PET scan for "Positron Emission Tomography" is usable.

in the case where the chemical element M is gadolinium or manganese, 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. In particular, 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.

By "cancer" is meant abnormal cell proliferation (also called tumor) within a normal tissue of the body. These 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.

Among the cancers, there may be mentioned liver cancers, in particular primary cancers of the liver, preferably hepatocarcinomas. According to a particular embodiment, mention may be made, among cancers, of hepatocarcinoma, epithelioid hemangioendothelioma, cholangiocarcinoma, neuroendocrine tumors and metastases of other cancers such as metastases of colorectal cancer.

According to a particular embodiment, the cancer is an intermediate stage hepatocellular carcinoma in adults. Process for the preparation of the compounds of general formula (I) and complexation

The invention relates to a method for preparing a compound of general formula (I) below:

X _1; X ₂ , X ₃ , Υι, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Z _1; Z ₂ and R being as defined above,

said process comprising a reduction step C of a compound of the following formula (XI I I):

in which 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;

to obtain a compound of formula (Γ) below:

Y ₃ ^Y 4 (Γ)

wherein Xi, Χ ₂ Χ3, Υι, Υ2, Υ3, Υ _4, Ys, Ye and R are as defined above.

The compounds of formula (Γ) correspond to compounds of formula (I) in which Z ₁ = Z ₂ = H.

Generally, the reduction step C leads to the formation of an intermediate compound of formula (XX):

wherein X1, _X2, X3, Y1, Y2, Y3, _Y4, Y5, Ye and R are as defined above.

In one embodiment, the reduction step C leads to the formation of at least one of the following intermediate compounds of formulas (XXI) and (XXII):

(XXI I) in which X _1; X ₂ , X ₃ , Υι, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Ye and R are as defined above.

According to a preferred embodiment, 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).

According to one embodiment, the organic acid is selected from acetic acid, trifluoroacetic acid, and mixtures thereof. According to one embodiment, acetic acid is used in admixture with NaBH ₄ or (Me) ₄ NBH ₄ . According to another embodiment, trifluoroacetic acid is used in admixture with NaBH ₄ .

The organic acids and borohydrides (A-BH ₄ ) 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).

According to one embodiment, the ratio A-BH ₄ / organic acid, preferably the ratio NaBH ₄ / TFA, is 1/1. According to one embodiment, 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).

According to one embodiment, 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.

According to one embodiment, 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.

According to one embodiment, the process according to the invention comprises, prior to said reduction step C, a condensation step A of a compound of formula (X) below:

Y ₃ Y ₄ (X)

Χι, Χ2, Χ3, Υι, 2, Υ3, Υ4, Υ5 and Υ ₆ being as defined above,

with a compound of formula (XI) below:

with E being a (dC ₄ ) alkyl, preferably ethyl or methyl;

According to one embodiment, the compound of formula (XI) is chosen from the following compounds:

to obtain a compound of formula (XI I) below

Xi, 2, 3, Υι, Y 2, Y ₃ , Y ₄ , Y ₅ and Y ₆ being as defined above.

According to one embodiment, 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.

According to one embodiment and when R is different from H, 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,

to obtain a compound of formula (XIII) below:

X _1; X ₂ , X ₃ , Υι, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ and R being as defined above. By functionalization B is meant the addition of the group R when it is different from H on a compound of formula (XI I).

According to one embodiment, the process for preparing a compound of formula (I) according to the invention comprises after step C and when at least one of group _λ and Z _{2 groups} is different from H, a step of functionalization D 'of a compound of formula (Γ) below:

in which X _1; X ₂ , X ₃ , Y 1, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y and R are as defined above, to obtain a compound of formula (I) as according to the invention in which one of least groupings Ζ and Z ₂ is different from H.

According to one embodiment, 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:

wherein Xi, X _2, X3, Y1, Y2, Y3, _Y4, Y5, Ye and R are as defined above,

to obtain a compound of formula (I) as according to the invention in which at least one of groups Ζ _λ and Z ₂ is different from H.

By functionalization D or D 'is meant the addition or the modification of a group Ζ _λ and / or Z ₂ to obtain, at the end of the process, a compound of formula (I) in which at least one of groups Ζ _λ and Z ₂ is different from H.

The functionalization steps B and D may be performed according to methods known to those skilled in the art.

According to one embodiment, the steps A, B, C and D as defined above can be chained according to one of the following diagrams:

A = Condensation

B = Fo ncti o nnali satio n

C = reduction

D = Z conversion

D D

Possible sequence of steps A, B, C, D According to one embodiment, the reduction C of the compound of the following formula

leads to the formation of at least one of the intermediate compounds of the following formulas

According to one embodiment, the reduction C of the compound of the following formula:

in which R is as defined above.

According to one embodiment, the functionalization of the compound of the following formula:

leads to the formation of at least one of the intermediate compounds of the following formulas:

According to one embodiment, the process for preparing a compound of formula (I) according to the invention comprises the following steps:

condensation step A as defined above; then

optionally step B of functionalization as defined above; then step C reduction as defined above; then

optionally 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.

Description of the Figures

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 3: Mass spectrometry of compound 3a.

Figure 4: Mass spectrometry of compound 4.

Figure 5: ¹³ C NMR Spectrum of Compound 4 (CDCl ₃ , 75.45 MHz, 298K)

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.

The examples below are given for illustrative purposes and are not limiting of the present invention.

EXAMPLES

The acronyms used in the text below will have the following meanings:

ACN: acetonitrile

DCM: dichloromethane

DIPEA: diisopropylethyl amine

EtOH: ethanol

MeOH: methanol

NaOH: soda

TA: room temperature

TFA: trifluoroacetic acid

THF: Tetrahydrofuran

EXAMPLE 1 Preparation of the Reinforced Ligands of Formula (I) According to the Invention 1- Condensation Step A According to the Invention

A solution of diethyloxalate (2.02 g, 13.8 mmol) in EtOH (100 mL) was added to a solution of 1 "pyclene (2.37 g, 1 1, 5 mmol) in EtOH (200 mL). It was stirred at room temperature overnight then concentrated The resulting residue was purified by alumina column chromatography (CH ₂ Cl ₂ / MeOH 98/2) The final product 2 "was obtained as a solid white (0.548 g, 19%) and corresponds to a compound of formula (XII) according to the invention.

¹ H NMR (300 MHz, CDCl ₃ ): 7.52 (t, 1H, ³ J = 7.7 Hz), 7.02 (d, 1H, ³ J = 7.9 Hz), 6.93 (d, 1H, ³ J = 7.5 Hz), 5.59 (d, 1 H, ² J = 16.2 Hz), 4.62 (ddd, 1 H, ² J = 13.9 Hz, ³ J = 1 1 .1 Hz, ³ J = 2.5 Hz), 4.08 (d, 1H, ² J = 16.6 Hz), 3.95 (dd, 1H, ² J = 17.3 Hz), 3.77 (ddd, 1H, ² J = 13.9 Hz, ³ J = 10.6 Hz, ³ J = 4.52 Hz), 3.70 (d, 1H, ² J = 17.3 Hz), 3.5 (ddd, 1H, ² J = 12.4 Hz, ³ J = 10.6 Hz, ³ J = 4.5 Hz), 3.24 (dt, 1H, ² J = 13.9 Hz, ³ J = 4.4 Hz), 3.13 (dt, 1H, ² J = 12.4 Hz, ³ J = 4.1 Hz), 3.01 (dt, 1H, ² J = 12.2 Hz, ³ J = 3.2 Hz), 2.83 (dt, 1H, ² J = 13.9 Hz, ³ J = 3.0 Hz), 2.74 (td, 1H, ² J = 1.17 Hz, ³ J = 2.3 Hz).

¹³ C NMR (75.47 MHz, CISC ₃ ): 162.96, 161.23, 159.10, 153.42, 136.83, 120.58, 1 19.44, 55.40, 52.53, 47.89, 47.66, 44.61, 44.20

Another embodiment:

A solution of diethyloxalate (4.21 g, 28.49 mmol) in MeOH (100 mL) was added to a solution of 1 "pyclene (5.88 g, 28.49 mmol) in MeOH (200 mL). The mixture was stirred at room temperature overnight then concentrated, the resulting residue was taken up in dichloromethane and the solution was filtered and concentrated to remove the unreacted p1-rene. The solid was solubilized in methanol (5 mL) and then ethyl acetate was added (150 mL). The crystals formed were filtered and dried under vacuum. The final product 2 "was obtained in the form of white crystals (6.28 g, 85%) and corresponds to a compound of formula (XII) according to the invention.

2- Next steps according to the invention:

The synthesis of the compounds of formula (I) is carried out according to the following scheme:



Compound 1 a - functionalization step B

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%).

¹ H NMR (300 MHz, CDCl ₃ ): 7.90-7.80 (m, 2H), 7.72 (t, 1H, ³ J = 7.91 Hz), 7.38 (t, 1H, ³ J = 7.72 Hz), 6.97 ( d, 1H, ³ J = 7.91 Hz), 6.65 (d, 1H, ³ J = 7.54 Hz), 5.59 (d, 1H, ² J = 16.20 Hz), 4.70 (m, 1H), 4.19 ( d, 1H, ² J = 14.3 Hz), 4.12, 3.92 (m, 2H), 3.93 (s, 3H), 3.86 (d, 1H, ² J = 14.3 Hz), 3.77-3.54 (m, 3H). , 3.20 (m, 1H), 2.99-2.76 (m, 3H), 2.72 (m, 1H).

1 ³ C NMR (75.47 MHz, CDCl ₃ ): £ 165.71, 163.43, 160.97, 159.82, 158.63, 154.21, 146.15, 137.69, 136.67, 127.42, 123.44, 120.45, 1 19.28, 59.90, 59.47, 56.75, 53.02, 52.51, 46.19, 44.97, 44.68.

ESI-MS (CH ₃ CN / H ₂ O, 50/50): m / z 410.15 [M + H] ⁺ , 432.10 [M + Na] ⁺ .

Compound 1 c - functionalization step B

A solution of tert-butyl bromoacetate (0.668 g, 3.42 mmol) in acetonitrile (100 mL) is added to a solution composed of pyclene oxalate (0.890 g, 3.42 mmol), K ₂ CO ₃ (1.42 g, 10.3 mmol) in acetonitrile (150 mL). The reaction medium is stirred at ambient temperature for 24 hours. The solvent is evaporated and the residue obtained is taken up in dichloromethane. The product is then filtered and concentrated. The product obtained is a yellow oil which will be used in the next step without further purification (1.25 g).

¹ H NMR (300 MHz, CDCl ₃ ): 7.28 (t, 1H, ³ J = 7.7 Hz), 6.8 (d, 1H, ³ J = 7.5 Hz), 6.63 (d, 1H, ³ J = 7.5 Hz), 5.26 (d, 1 H, ² J = 16.6 Hz), 4.08 (m, 1 H), 3.89 (d, 1 H, ² J = 16.6 Hz), 3.68 (m, 4H), 3.0 (m , 4H), 2.77 (m, 2H), 2.52 (m, 1H), 1.18 (m, 9H).

¹³ C NMR (75.47 MHz, CISC ₃ ): £ 170.65, 162.42, 159.73, 158.43, 153.60, 136.48, 1 19.67, 1 19.1 1, 80.37, 61 .08, 56.45, 52.59, 52.07, 46.64, 46.07, 44.76, 27.61 .

ESI-HR-MS (positive, H ₂ O) m / z calcd for [C ₁₉ H ₂₇ N ₄ O ₄ ] ⁺ , 375.2027; obtained 375.2027 [M + H] ⁺ , calculated for [C ₉ H ₂₆ N ₄ O ₄ Na] ⁺ , 397.1846; obtained 397.1846 [M + Na] ⁺ , calculated for [C ₁₅ H ₁₉ N ₄ O ₄ ] ⁺ , 319.1400; obtained 319.1400 [M - tBu + 2H] ⁺ . Compound 1 c '- functionalization step B

A solution of methyl bromoacetate (587 mg, 3.38 mmol) in acetonitrile (13 mL) is added to a solution composed of pylene oxalate (1.0017 g, 3.38 mmol) and K ₂ CO ₃ (796 mg). mg, 5.76 mmol) in acetonitrile (13 mL). The reaction medium is stirred at room temperature for 4 h. After evaporation, the foam obtained is taken up in ethyl acetate (100 mL) and washed with the minimum amount of water (3 mL). The organic phase is dried over MgSO ₄ , filtered and evaporated to give the product 1 c 'as a white foam (1.093 g, 97%)

¹ H NMR (300 MHz, CDCl ₃ ): 7.48 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 5.55 (d, J = 16.5Hz, 1H), 4.46-4.27 (m, 1H), 4.14-3.80 (m, 4H), 3.62 (s, 3H), 3.45 (d, J = 18.0Hz, 1H). ), 3.34 - 3.20 (m, 2H), 3.15 (d, J = 11.9 Hz, 1H), 2.96 (d, J = 10.2 Hz, 2H), 2.77 - 2.56 (m, 1H).

¹³ C NMR (75.47 MHz, CISC ₃ ): £ 172.33, 162.83, 160.22, 158.84, 154.07, 136.87, 120.1 1, 1 19.48, 61.46, 57.08, 52.34, 52.13, 51.19, 46.82, 46.38, 45.33.

Compound 2a - obtaining an unreinforced pyclene not belonging to the invention

Hydrochloric acid (20 mL, 3M) is added to compound 1a (0.200 g, 0.49 mmol). The reaction medium is refluxed for 24 hours and is concentrated. The desired compound 2a is a colored oil (190 mg, 86% calculated for the hydrochloride salt).

1H NMR (300 MHz, D ₂ O): δ 8.19 (t, 1H), 8.01 (d, 1H), 7.88 (d, 1H), 7.61 (t, 1H), 7.23 (d, 1H); H), 6.95 (d, 1H), 4.54 (s, 2H), 4.52 (s, 2H), 4.18 (s, 2H), 3.57 (m, 2H), 3.42-3.30 (m, 6H). ¹³ C NMR (75.47 MHz, D ₂ 0): £ 166.48, 163.95, 157.07, 154.55, 153.60, 147.50, 146.03, 142.48, 132.14, 128.92, 125.91, 125.67, 61.36, 60.27, 54.61, 52.09, 46.73, 45.76 .

ESI-HR-MS (positive, H ₂ O) m / z calcd for [C ₁₈ H ₂₄ N ₅ O ₂ ] ⁺ 342.192451, obtained: 342.192738 [M + H] ⁺ ; calcd for C ₁₈ H ₂₃ N ₅ Na0 ₂ ] ⁺ 364.174396, obtained 364.174089 [M + Na] ⁺ ; calculated for [C ₁₈ H ₂₃ N ₅ O] 2 ⁺ : 162.594582, obtained: 162.594105 [M + 2H-H ₂ O] ²⁺ ; calcd for [C ₁₈ H ₂₅ N ₅ O ₂ ] ₂ ⁺ 171.599864, obtained: 171.599371 [M + 2H] ²⁺

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.

7 ^~ _R = 8 min: m / z Calcd for [C ₁₃ H ₁₉ N ₄ 0] ^+: 247.15, obtained: 247.20 [M + H] ⁺

7 ^~ _R = 12.5 min: m / z: calculated for [C ₁₃ H ₂₁ N ₄ O ₂ ] ⁺ : 265.16, obtained: 265.20 [M + H] ⁺ Compound 10a - reduction step C

Under an inert atmosphere, a solution of trifluoroacetic acid (1.984 g, 17.4 mmol) in anhydrous THF (5 mL) is slowly added to a suspension of NaBH ₄ (693 mg, 18.3 mmol) in THF anhydrous (5 mL) cooled to 0 ° C. The reaction mixture is stirred at the same temperature for 5 minutes. Then, compound 1a (452.8 mg, 1.11 mmol) solubilized in a 1: 1 THF / DCM mixture (10 mL) is slowly added to the reaction medium. The mixture is stirred at the same temperature for 10 minutes and then overnight at room temperature. Water and sodium hydroxide 10 M were added to neutralize the excess of NaBH ₃ OCOCF _3. The borane is then extracted with DCM (3 × 20 mL), the combined organic phases are dried over MgSO ₄ , sintered and evaporated. Compound 10a is thus obtained without further purification (white foam, 227.5 mg, 54%)

¹³ C NMR (75.47 MHz, D ₂ 0): 165.34, 159.02, 158.67, 153.76, 147.27, 138.50, 137.81, 125.61, 124.54, 124.36, 123.73, 69.58, 67.54, 60.53, 60.19, 60.06, 55.30, 47.66

ESI-MS (CH ₃ CN / H ₂ O, 50/50): m / z calcd for [C ₂₁ H ₂₈ N ₅ O ₂ ] ⁺ 382.22, obtained 382.15 [M + H-2BH ₃ ] ⁺

Compound 10c - reduction step C

In a 50 mL flask, under argon, a solution of trifluoroacetic acid (1. 559 g; 13.68 mmol) in anhydrous THF (6 mL) is added dropwise to a suspension of NaBH ₄ (545.3 mg). 14.4 mmol) in anhydrous THF (6 mL) cooled to 0 ° C. The reaction mixture is stirred at the same temperature for 5 minutes and then a solution of compound 1 (321.2 mg, 0.96 mmol) in dichloromethane (4 mL) is added dropwise to the reducing agent at 0 ° C. . The reaction mixture is stirred for 10 min at the same temperature and then at 30 ° C overnight.

After 18 hours, the precipitate is filtered on sintered porosity of 4, then a solution of NaOH (10 M, 4 mL) was added to the filtrate, and ultrapure H ₂ 0 (15 mL) and DCM (20 mL). The desired product is then extracted with DCM (3 x 20 mL), the combined organic phases are dried over MgSO ₄ , sintered and evaporated. Compound 10c is thus obtained without further purification (white foam, 250.4 mg, 82%) ¹³ C NMR (75.47 MHz, CISC ₃ ): 170.94, 158.77, 153.42, 138.41, 124.45, 124.21, 69.33, 67.44, 60.07, 59.04, 53.57, 51.16, 45.09.

ESI-MS (CH ₃ CN / H ₂ 0, 50/50): m / z calcd for [C ₁₆ H ₂ 5 N ₄ 0 _2] ⁺ 305.19, 305.15 obtained Compounds 3a and 13a - hydrolysis step

Compound 10a (204.9 mg, 0.53 mmol) is solubilized in ultrapure HCl (3M, 2.6 mL). The reaction mixture is stirred at 40 ° C. for 4 days and then at reflux for 2 days. The water is evaporated. An oil is obtained. This oil is then purified by HPLC-C 18 chromatography (H ₂ 0 0.1% HCl / acetonitrile: 90/10 to 5/95). The product 3a is then obtained in the form of a beige oil (45 mg, 20% calculated for the trifluoroacetate salt).

¹ H NMR (500 MHz, D ₂ 0): £ 8.56-8.53 (t, 1H), 8.29-8.28 (d, 1H), 8.13-8.1 1 (d, 1H), 7.96-

7.93 (t, 1H), 7.60-7.58 (d, 1H), 7.45-7.44 (d, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 4.57 (s, 2H); ,

4.15 (s, 2H), 3.87-3.84 (m, 4H), 3.40 (br s, 4H), 3.20-3.18 (t, 2H)

1 ³ C NMR (125 MHz, D ₂ 0): £ 166.68, 160.01, 156.08, 152.05, 149.33, 148.24, 143.26,

130.80, 129.02, 128.23, 128.13, 63.22, 61.62, 59.12, 56.66, 51.68, 46.08

ESI-HR-MS (positive, H ₂ O): m / z calcd for [C ₂₀ H ₂₆ N ₅ O ₂ ] ⁺ 368.2081, obtained 368.2078;

[M + H] ⁺ , calcd for [C ₂₀ H ₂₆ N ₅ O ₂ ] ₂ ⁺ 184.6076, obtained 184.6078 [M + 2H] ²⁺ .

Analytical HPLC C-18 (H ₂ 0.1% TFA / ACN 0.1% TFA 98/2> 20/80): t _R : 18.42 min m / z calculated for [C ₂ H ₂₆ N ₅ O ₂ ] ⁺ 368.21; obtained 368.25 [M + H] ⁺ ; purity: 91%

Upon purification of compound 3a, compound 13a is also obtained as a beige oil (9.8 mg).

¹ H NMR (500 MHz, D ₂ 0): £ 8.51 (t, J = 8.0 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H ), 7.90 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 5.03 (s, 2H), 4.90 ( s, 2H), 4.46 (s, 2H), 4.07 (s, 2H), 3.91-3.74 (m, 4H), 3.44 (s, 4H), 3.10 (t, J = 4.7 Hz, 2H).

¹³ C NMR (125 MHz, D ₂ 0): £ 161.14, 158.42, 155.42, 151.94, 149.29, 143.29, 128.99, 128.56, 127.54, 126.15, 63.51, 62.32, 61.60, 57.74, 56.68, 50.65.

ESI-HR-MS (positive, H ₂ O): m / z calcd for [C ₂₀ H ₂₈ N ₅ O] ⁺ 354.228837, obtained 354.228823 [M + H] ⁺ ; calcd for [C ₂₀ H ₂₉ N ₅ O] 2 ⁺ 177.618057, obtained 177.618215 [M + 2H] ²⁺ ; calculated for [Ci ₃ H ₁₉ N ₄ ] ⁺ 231 .160423, obtained 231 .160338 [M-fragmentation] ⁺ ; calcd for [C ₂₀ H ₂₇ N ₅ ] ²⁺ 168.612774, obtained 168.612527 [M + 2H-H ₂ O] ²⁺ ; calculated for [C ₇ H ₈ N] ⁺ 106.065126, obtained 106.06501 1 [Fragment] *. Compound 3c - hydrolysis step

Compound 10c (250.4 mg, 0.78 mmol) is solubilized in ultrapure HCl (3M, 4.8 mL). The reaction mixture is stirred under reflux for 20 hours. After evaporation, an orange oil is obtained. This oil is then purified by HPLC-C18 chromatography (H ₂ 0 0.1% TFA / 0.1% acetonitrile TFA: 98/2> 20/80). The product 3c is then obtained in the form of a beige oil (97 9 mg, 25% calculated for the trifluoroacetate salt).

1 H NMR (500 MHz, D ₂ 0): 7.95-7.92 (t, 1H), 7.52-7.47 (2d, 2H), 4.80 (s, 2H), 4.28 (s, 2H), 3.89 - 3.84 (m.p. , 6H), 3.57 (br s, 2H), 3.35 (m, 2H), 3.26 - 3.25 (m, 2H), 3.12 - 3.10 (m, 2H)

1 ³ C NMR (125 MHz, D ₂ 0): £ 177.08, 160.30, 151 .45, 143.16, 129.30, 127.70, 63.06, 62.91, 62.81, 58.04, 57.92, 57.25, 52.15, 49.98, 46.49.

ESI-HR-MS (positive, H ₂ O): m / z calcd for [C ₁₅ H ₂₃ N ₄ O ₂ ] ⁺ 291 .181552, obtained 291 .181585 [M + H] ⁺ ; calculated for [C ₁₅ H ₂₄ N ₄ O ₂ ] ²⁺ 146.094414, obtained 146.094221 [M + 2H] ²⁺ .

Analytical HPLC C-18 (H ₂ 0.1% TFA / ACN 0.1% TFA 98/2> 20/80): t _R : 16.57 min m / z calculated for [C ₁₅ H ₂₃ N ₄ O ₂ ] ⁺ 291 .18 ; obtained 291.25 [M + H] ⁺ ; purity: 98%

Compound 11 - reduction step C

Under an inert atmosphere, a solution of trifluoroacetic acid (6.2713 g, 55 mmol) in anhydrous THF (10 mL) is slowly added to a suspension of NaBH ₄ (2.196 g, 58 mmol) in dry THF (30 mL). ) cooled to 0 ° C. Then, the pyclene oxalate (1 g, 3.84 mmol) solubilized in a mixture CH ₂ Cl ₂ / MeOH (10 mL / 50 μί) anhydrous is added slowly to the reaction medium at 0 ° C with vigorous stirring. The mixture is stirred at 0 ° C for 30 min and then for two days at room temperature.

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. After vigorous stirring of the biphasic mixture for 5 min at RT, 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:

ESI-HR-MS (positive, H ₂ O): m / z calcd for [C ₁₃ H ₂ N ₄ ] ⁺ : 233.176073 m / z; found: 233.175875 [M + H] ⁺

1H NMR (500 MHz, CDCl ₃ ): 7.72 (t, J = 7.7 Hz, 1H), 7.27 (2d, J = 7.0, 3.1 Hz, 2H), 5.71 (s, 1H), 4.49 (td, J = 11.4). , 4.7 Hz, 1H), 4.35 (dd, J = 14.5, 8.4 Hz, 2H), 4.20 (d, J = 14.5 Hz, 1H), 3.69 (dd, J = 14.5, 10.4 Hz, 2H), 3.55-3.41 (m, 1H), 3.41-3.30 (m, 1H), 3.22-3.10 (m, 1H), 2.82 (dd, J = 14.7, 6.7 Hz, 2H), 2.61 (dd, J = 14.8, 5.3 Hz, 1H). ), 2.47 (d, J = 14.2 Hz, 1H), 2.25 (td, J = 12.4, 2.6 Hz, 1H), 2.03 (dd, J = 19.4, 11.1 Hz, 2H), 0.86 (td, J = 11.3, 7.3 Hz, 1H).

¹ H NMR (125 MHz, CDCl ₃ ): 154.56, 153.19, 138.09, 125.13, 123.95, 69.37, 62.67, 62.48, 61.14, 60.79, 60.52, 53.55, 52.23, 50.78, 47.04, 44.76.

Compound 4 - hydrolysis step

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%).

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.57 (t, J = 7.6 Hz, 1H), 7.10 (dd, J = 7.3, 5.3 Hz, 2H), 4.19 (s, 2H), 3.97 (s, 2H); ), 3.35 - 3.25 (m, 2H), 3.07 (d, J = 10.7 Hz, 2H), 2.87 (d, J = 4.4 Hz, 2H), 2.73 (d, J = 2.6 Hz, 2H), 2.37 (s). , 2H).

¹³ C NMR (125 MHz, CISC ₃ ): £ 160.98, 160.00, 137.12, 122.42, 122.31, 61.97, 55.80, 54.57, 49.61, 45.87, 43.15. Example 2 Preparation of Complexes According to the Invention

Preparation of the complex [Mn (2a)] (ClO ₄ )

Compound 3a.3HCl (20 mg, 0.044 mmol) is dissolved in water (5 mL) and the pH of the solution is adjusted to 5 with 1M KOH solution. A solution of Mn (ClO ₄ ) ₂ .6H ₂ O (16 mg, 0.044 mmol) in water (2 mL) is added to the ligand solution. The reaction medium is refluxed for 1 h and then concentrated.

Figure 8 provides the structure obtained by X-ray diffraction of the [Mn (2a)] (IC0 ₄ ) complex.

ESI-HR-MS (positive, H ₂ 0): m / z calcd for [Ci ₈ H ₂₂ MnN ₅ 0 _2] ⁺ 395.1 14 846, 395.1 14 156 obtained; calcd for [Ci ₈ H ₂₃ MnN ₅ 0 _2] ²⁺ 198.061061, 198.061026 obtained.

Preparation of the complex [Zn (2a)] (ClO ₄ )

Compound 3a.3HCl (20 mg, 0.044 mmol) is dissolved in water (5 mL) and the pH of the solution is adjusted to 5 with 1M KOH solution. A solution of Zn (ClO ₄ ) ₂ .6H ₂ O (16.5 mg, 0.044 mmol) in water (2 mL) is added to the ligand solution. The reaction medium is refluxed for 1 h and then concentrated.

ESI-HR-MS (positive, H ₂ O): m / z calcd for [C ₁₈ H ₂₂ ZnN ₅ O ₂ ] ⁺ 404.105944, obtained 404.106289; calculated for [C ₁₈ H ₂₃ ZnN ₅ O ₂ ] ²⁺ 202.556610, obtained 202.557059.

Preparation of the complex [Cu (2a)] (ClO ₄ )

Compound 3a.3HCl (20 mg, 0.044 mmol) is dissolved in water (5 mL) and the pH of the solution is adjusted to 5 with 1M KOH solution. A solution of Cu (ClO ₄ ) ₂ .6H ₂ O (16.4 mg, 0.044 mmol) in water (2 mL) is added to the ligand solution. The reaction medium is refluxed for 1 h and then concentrated.

ESI-HR-MS (positive, H ₂ 0): m / z calcd for [C ₁₈ H ₂₂ CuN ₅ 0 _2] ⁺ 403.106399, 403.106320 obtained; calcd for [Ci ₈ H ₂₃ CuN ₅ 0 _2] ²⁺ 202.056838, 202.056983 obtained.

Preparation of the complex [Zn (3a)] (CI)

In a G10 glass vessel, under an argon stream, a solution of ZnCl ₂ (11.88 mg, 0.085 mmol) in anhydrous 1-butanol (1 mL) is added to a solution of the compound 3a (8.2 mg, 0.017 mmol) in the same solvent (1 mL) in the presence of DIPEA (5.9 μM - 0.034 mmol). The mixture is then stirred in the microwaves at 130 ° C. for 8 hours. After returning to RT, the whole reaction medium is transferred to a 50 mL Falcon ™ and centrifuged at 4000 g for 12 min. The supernatant is removed and the precipitate is rinsed with THF (2 x 5 mL) by centrifugation. The precipitate is solubilized in water and evaporated to give the expected complex as a beige powder (4.5 mg, 57%).

Maldi-MS (ditranol, HCCA / H ₂ O 1: 1): for C ₂ H 24 N ₅ O ₂ Zn ⁺ m / z obtained: 430.30, m / z calculated: 430.12 [M] ⁺ ; for C ₂ oH ₂₆ N ₅ 0 ₃ Zn ⁺ m / z obtained 448.30, m / z: Calculated: 448.13 [M + H ₂ 0] ⁺

Preparation of the complex [Cu (3a)] (ClO ₄ )

In a G10 glass vessel, under argon flow, a solution of Cu (ClO ₄ ) ₂ .6H ₂ O (50 mg, 0.12 mmol) in anhydrous 1-butanol (1.3 mL) is added to a solution of compound 3a (13.3 mg, 0.027 mmol) in the same solvent (1.4 mL) in the presence of DIPEA (9.4 μM - 0.054 mmol). The mixture is then stirred in the microwaves at 130 ° C. for 8 hours. After returning to RT, the whole reaction medium is transferred to a 50 mL Falcon ™ and centrifuged at 4000 g for 12 min. The supernatant is removed and the precipitate is rinsed with THF (2 x 5 mL) by centrifugation. The precipitate is solubilized in water and evaporated slowly to give the expected complex as blue needles (12.8 mg, 89%)

ESI-MS (positive, H ₂ O / ACN 50/50 0.1% TFA): for C ₂ oH ₂₄ N ₅ 0 ₂ Cu ⁺ m / z obtained: 429.05, m / z calculated: 429.12 [M] ⁺ ; for C ₂ H ₂₅ N ₅ 0 ₂ Cu ²⁺ m / z obtained: 215.10, m / z calcd: 215.06 [M + H] ²⁺ ; for C ₂₂ H ₂ ₅ F ₃ N ₅ 0 ₄ Cu ⁺

UV: UV analysis shows a characteristic absorbance of a transition d → d from Cu ²⁺ of the complex to A _max = 650 nm with a molar absorption coefficient ε = 103 L.mor ¹ .cm ^{~ 1} .

Preparation of the complex [Mn (3a)] (ClO ₄ )

In a G10 glass vessel, under an argon stream, a solution of Mn (ClO ₄ ) ₂ .6H ₂ O (44.4 mg, 0.175 mmol) in anhydrous 1-butanol (1.7 mL) is added to a solution of compound 3a (14.6 mg, 0.035 mmol) in the same solvent (1.8 ml) in the presence of DIPEA (12.2 μl - 0.07 mmol). The mixture is then stirred in the microwaves at 130 ° C. for 8 hours. After returning to RT, the whole reaction medium is transferred to a 50 mL Falcon ™ and centrifuged at 4000 g for 12 min. The supernatant is removed and the precipitate is rinsed with THF (2 x 5 mL) by centrifugation. The precipitate is solubilized in water and evaporated to give the expected complex in the form of orange powder (4.5 mg, 25%)

Maldi-MS (ditranol, HCCA / H ₂ 0 1: 1): for C ₂ oH ₂₆ MnN ₅ 0 ₃ ⁺ m / z obtained 439 506, m / z: Calculated: 439 141 [M + H ₂ 0] ⁺

Claims

1. Compound of general formula (I) below:

in which :

H, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, (C ₆ -C ₁₀ ) aryl, halogen, azide (-N ₃ ), -C ( 0) ORa, -ORa, -N (Ra) (Rb), -C (O) -N (Ra) (Rb), -SH, -SRa, -S0 ₂ OH, -SO ₂ -N (Ra) ( Rb), -SCN and a functional chemical group for grafting to a vector or a biomolecule; Ra and Rb being independently of one another, H or a group (CrC ₂₀ ) alkyl; said 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; and said alkyl, alkenyl, alkynyl and (C ₆ -C ₁₀ ) aryl groups may optionally be substituted with one or more substituents selected from the group consisting of:

halogen, -C (O) ORc, -ORc, -N (Rc) (Rd), -C (O) -N (Rc) (Rd), -SH, -SRc, -S0 ₂ OH, -S0 ₂ - N (Rc) (Rd), -SCN, (C ₆ -C ₁₀ ) 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; said alkyl group being optionally substituted with one or more substituents selected from the group consisting of:

halogen, -C (O) ORe, -ORe, -N (Re) (Rf), -C (O) -N (Re) (Rf), -SH, -SRe, -S0 ₂ OH, -S0 ₂ - N (Re) (Rf), -SCN, (C ₆ -C ₁₀ ) aryl and a functional chemical group for grafting to a vector or a biomolecule;

Re and Rf being independently of each other H or a group (CC ₂₀ ) alkyl;

and Z ₂ are independently selected from the group consisting of:

H, (CrC ₄ ) alkyl, halogen, -ORg, -N (Rg) (Rh), -SH and -SRg;

H, (dC ₄ ) alkyl, 2-THP (tetrahydropyranyl), tosyl, nosyl, TMS (trimethylsilyl), -O-C (O) Rt, -C (O) Rt, -OC (O) ORt, - NH-C (O) -ORt, -NH-C (O) Rt;

Rt being selected from: (CrC ₄ ) alkyl, benzyl, allyl, and trifluoromethyl;

halogen, -C (O) ORp, -ORp, -N (Rp) (Rq), -C (O) -N (Rp) (Rq), -SH, -SRp -S0 ₂ OH -S0 ₂ -N ( Rp) (Rq) and -SCN; Rp and Rq being independently of one another, H or a (CrC ₄ ) alkyl group;

R is selected from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) alkenyl, (C ₂ -C ₂₀ ) alkynyl, (C ₁ -C ₂ ) alkylene-W, (C ₂ -C ₂₀ ) alkenylene-W and (C ₂ - C ₂₀ ) alkynylene-W;

said alkyl, alkenyl, alkynyl, alkylene, alkynylene 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:

(C ₆ -C 10) aryl, heteroaryl of 5 to 10 atoms, biphenyl, -C (O) OR 1, -C (O) -N (R 1) (R 1), -P (O) (OR 1) (OR 1) - (R 1) P (O) (OR 1), -O-P (O) (OR 1) (OR 1), -SH, -SO ₂ OH, -SO ₂ -N (R 1) (R 1) and -SCN;

(C 1 -C ₂₀ ) alkyl, (C ₂ -C ₂ O) alkenyl, (C ₂ -C ₂ O) alkynyl, halogen, -C (O) ORk, -ORk,

-N (Rk) (RI), -C (O) -N (Rk) (RI), -SH, -SRk, -SO ₂ OH, -SO ₂ -N (Rk) (RI), -SCN, ( C ₆ -C ₁₀ ) aryl and biphenyl;

The compound of claim 1, wherein R is selected from the group consisting of:

H, (C ₁ -C ₂₀ ) alkyl, (C 1 -C ₂₀ ) alkylene-W;

W being selected from the group consisting of:

(C ₆ -C ₁₀ ) aryl, heteroaryl of 5 to 10 atoms, -C (O) OR 1, -C (O) -N (R 1) (R 1),

-P (0) (OR 1) (OR 1), - (R 1) P (O) (OR 1), -O-P (O) (OR 1) (OR 1), -SH, -SO ₂ OH, -SO ₂ N (R 1) (R 1) and -SCN;

R 1 and R 1 being independently of one another H or a group (CrC ₂₀ ) alkyl; said alkyl, alkylene, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from the group consisting of:

(CrC 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, -SO ₂ OH, -SO ₂ -N (Rk) (RI), -SCN and (C ₆ -C ₁₀ ) aryl; Rk and RI being independently of each other H or a group (C _r C ₂₀ ) alkyl.

3. Compound according to the following dream (II)

(II)

with X ₂ and R being as defined in claim 1, preferably X ₂ is H.

The compound of claim 1 selected from the group consisting of the following compounds:

in which Rk is H or a group (CC ₂ o) alkyl, in particular H or a group (CrC ₄ ) alkyl, preferably a methyl,

wherein Rk is H or a (C 1 -C ₂₀ ) alkyl group, especially H or a (C ₁ -C ₄ ) alkyl group, preferably a t-butyl group.

5. Complex of a compound of formula (I) or a salt thereof according to any one of claims 1 to 4, with a chemical element M; M being preferably a metal. 6. Complex of a compound of formula (I) or a salt thereof according to

claim 5 for use as a medicament.

7. Contrast medium comprising the complex of a compound of formula (I) or a salt thereof according to claim 5.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a complex according to claim 5, and optionally one or more pharmaceutically acceptable excipient (s).

Process for preparing a compound of general formula (I) below:

X _1; X ₂ , X ₃ , Υι, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Ye, Z _1; Z ₂ and R being as defined in claim 1, said process comprising a reduction step C of a compound of following formula (XIII):

wherein Xi, X _2, X3, Y1, Y2, Y3, _Y4, Y5, Ye and R are as defined in claim 1,

in the presence of a mixture of A-BH reducing agent ₄ and an organic acid, with A being selected from the group consisting of Li, Na, K, Zn and (Me ₃ ) N;

to obtain a compound of formula (Γ) below:

in which X _1; X ₂ , X ₃ , Y 1, Y ₂ , Y ₃ , Y ₄ , Y ₅ , Ye and R are as defined above. 10. Preparation process according to claim 9, wherein the reduction step C is carried out in the presence of the mixture of NaBH ₄ reducing agent with trifluoroacetic acid.

11. Preparation process according to claim 9, comprising before said reduction step C, a condensation step A of a compound of formula (X) below:

Xi, X2, X3, Υι, Y2, Y3, Y4, Y5 and Y ₆ are as defined in claim 1. with a compound of formula (XI) below:

with E being a (C ₁ -C ₄ ) alkyl, preferably E is methyl or ethyl; to obtain a compound of formula (XII) below:

Xi, X2, X3, Υι, Y2, Y3, Y4, Y5 and Y ₆ are as defined in claim 1.