Novel inhibitors of organic cation transporters for the treatment of mood disorders

Abstract

The present invention relates to novel inhibitors of organic cation transporters (OCT), having formula (I) or (II): (I) (II), and a pharmaceutically acceptable salt, solvate, enantiomer or tautomer of same. The present invention also relates to the use of these compounds as a drug for the prevention and / or treatment of mood disorders, such as depressive disorders or anxiety disorders.

Description

[0001]DESCRIPTION Novel organic cation transporter inhibitors for the treatment of mood disorders FIELD OF THE INVENTION The present invention relates to novel abacacyanome derivatives, as well as their pharmaceutically acceptable salts, solvates or tautomers. The compounds of the invention are inhibitors of organic cation transporters (OCTs), particularly useful in the treatment and / or prevention of mood disorders, such as depressive disorders and anxiety disorders. STATE OF THE ART Mood disorders represent widespread and disabling conditions, with up to 16% of the world's population affected to varying degrees by depressive-like symptoms. These disorders, which affect mood, cognition, motivation and behavior, have a significant impact on the quality of life of individuals.They are associated with excess mortality, a high suicide risk, and various comorbidities and, in addition to their individual effects, have a considerable social and economic impact. The antidepressants used as first-line treatment for major depression are mostly monoamine reuptake inhibitors, particularly serotonin (5-HT) and norepinephrine (NE). These conventional antidepressant treatments have important limitations, particularly a too long onset of action and unwanted side effects. In addition, they do not always produce positive results, and approximately one-third of patients do not respond satisfactorily to treatment. There is therefore a pressing need for drugs combining better efficacy with a faster onset of action. Fast-acting compounds targeting glutamate receptors (NMDA or mGlu2 / 3) (Berman et al., 2000; doi.org / 10.1016 / S0006- 3223(99)00230-9) or serotonin (5-HT2A; Moliner et al., 2023; doi.org / 10.1038 / s41593- 023-01316-5) have recently raised great hopes for the management of depression associated with suicide risk, but concerns regarding their actual efficacy in large cohorts, the persistence of effects over the long term and their side effects still need to be addressed. Identifying new therapeutic avenues for depressive disorders therefore represents a major challenge for mental health research. Previous studies by the inventors of the present invention have identified atypical organic cation transporters (OCTs) as new pharmacological targets for the treatment of depressive disorders. OCTs are polyspecific transporters, which participate in the absorption and clearance of various endogenous and xenobiotic compounds in the nervous system and peripheral organs.They can also transport biogenic amines (serotonin, dopamine, noradrenaline) with low affinity. Two OCT subtypes, OCT2 and OCT3, are expressed in the central nervous system where they modulate mood-related functions such as anxiety, stress response, and antidepressant efficacy (Bacq et al., Mol. Psychiatry, 2012, 17, 926-939; Courousse et al., Pharmacol. Therapeutics, 2015, 146, 94-103). Recently, it has been proposed that brain OCTs constitute a clearance system for monoamines, in addition to classical high-affinity reuptake transporters (Figure 1). Dopamine (DAT), serotonin (SERT), and norepinephrine (NET) reuptake transporters are responsible for the clearance of monoamines released from the extracellular space and their recycling into neuronal terminals, and are the main targets of conventional antidepressants (SSRIs and NSRIs).OCTs differ from classical reuptake transporters by their widespread distribution in the brain, in a wide variety of neuronal types, and by the fact that they accept all monoamines as substrates (Couroussé T and Gautron S (2015). Pharmacol Ther.146C:94-103). The inventors recently demonstrated proof of concept that OCTs, especially OCT2 and OCT3, are relevant therapeutic targets for depression by developing a novel inhibitory ligand of these transporters with strong antidepressant potential, cyanome, a derivative of a known OCT inhibitor, disprocynium 24 (D24) (WO2019012150; Orrico-Sanchez, 2020, doi: 10.1038 / s41380-019-0548-4). Cyanoma was evaluated via a molecular modeling approach as having better selectivity for OCTs, especially OCT2, towards alpha adrenergic receptors compared to D24.The molecular modeling approach was validated by in vitro transport and binding experiments, evaluating the affinity of cyanome with OCT2 and β-adrenergic receptors, respectively. In addition, cyanome was then modified into a prodrug, H2-cyanome (Figure 2), to allow its passive diffusion into the brain parenchyma and its activation by a redox mechanism. This prodrug, named H2-cyanome, showed at low doses as good efficacy as the classic antidepressant fluoxetine (Prozac) in a mouse model of chronic depression, with a faster action on anhedonia, one of the key symptoms of depression. However, the selectivity for OCT over α-adrenergic receptors remains unsatisfactory.Indeed, although the affinity of H2-cyanome for α2 adrenergic receptors is low, H2-cyanome retains an affinity for α1 adrenergic receptors, which could be a source of undesirable side effects, in particular on blood pressure, heart rate or contractility. A need therefore remains for an OCT inhibitor compound, in particular OCT2 and OCT3, useful in the treatment of mood disorders, such as depressive disorders and anxiety disorders, which is more selective for OCT, in particular compared to alpha-adrenergic receptors, in order to improve its efficacy and to limit side effects. DISCLOSURE OF THE INVENTIONThe subject of the present invention is a compound of the following formula (I):. a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, wherein L is a divalent radical derived from a C1-C12 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)- group, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH, R 1 , R 2 , R 3 and R 4 are independently selected from a group consisting of H, halogen, NR 9 R 10 , GOLD 11 , COOR 12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 13 , NR 14 R 15 and COOR 16 , or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 17 , NR 18 R 19 and COOR 20 , R 5represents a C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, OH, NH2 and COOH, R 6 represents H, halogen, NR 21 R 22 , GOLD 23 , COOR 24 , C1-C6 alkyl, cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 25 , NR 26 R 27 and COOR 28 , R 7 and R 8 are independently selected from the group consisting of H, halogen, NR 29 R 30 , GOLD 31 , COOR 32, C1-C6 alkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 33 , NR 34 R 35 and COOR 36 , R 9 to R 36are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl.The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or tautomer thereof, and a pharmaceutically acceptable excipient. The present invention also relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use as a medicament. The present invention also relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use in the treatment and / or prevention of mood disorders, such as depressive disorders and anxiety disorders.The present invention also relates to a compound of the following formula (II): a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, wherein X- represents a pharmaceutically acceptable anion, especially selected from the group consisting of PF6-, Cl-, Br-, I-, BF4-, (C1-C6 alkyl)-C(O)O-, (C1-C6 haloalkyl)-C(O)O-, (C1-C6 alkyl)-SO3-, (C1-C6 haloalkyl)-SO3-, SO42- and PO43-, andL and R 1 to R 8are as defined above. Other aspects of the invention are as described below. DESCRIPTION OF THE FIGURES Figure 1: (A) correlation curves between the experimental pKi and the virtual affinity of the compound (II-A1) obtained by molecular modeling and docking of the α-adrenergic receptors α1-AR (pKi abacacyanome>1mM): receptors α1a (diamond), α1b (square) and α1d (triangle); (B) the correlation curves between the experimental pKi and the virtual affinity of the compound (II-A1) obtained by molecular modeling and docking of the transporters OCT2 and OCT3 (pki II-A16.9 and 7.3, respectively).Figure 2: (A) Correlation curves between experimental pKi and virtual affinity of compound (II-A1) and compound (II-A3-1) obtained by molecular modeling and docking of α-adrenergic receptors α1-AR (pKi abacacyanome>1mM): receptors α1a (diamond), α1b (square) and α1d (triangle); (B) Correlation curves between experimental pKi and virtual affinity of compound (II-A1) and compound (II-A3-1) obtained by molecular modeling and docking of OCT2 and OCT3 transporters (pki II-A3-16.8 and 7.8, respectively). Figure 3: Immobility time observed in the forced swimming test of mice injected intraperitoneally with saline (SAL), fluoxetine (FLUOX, 18 mg / kg) or compound II-A2 (ACv2, 0.2 mg / kg). Statistics: FLUOX versus SAL: **P < 0.01, unpaired Mann-Whitney test; ACv2 versus SAL: *P < 0.05, unpaired Mann-Whitney test. Data are presented as mean ± SEM.DETAILED DESCRIPTION OF THE INVENTIONSurprisingly, the inventors have developed new, more selective OCT inhibitors capable of easily crossing the blood-brain barrier.Definitions The term "stereoisomer" as used in the present invention refers to configurational stereoisomers and more particularly to optical isomers. Optical isomers that are not mirror images of each other are called "diastereoisomers", and optical isomers that are non-superimposable mirror images are called "enantiomers". An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture or racemate. The term "tautomer" refers to constitutional isomers of the compound obtained by prototropy, i.e. by migration of a hydrogen atom and change of location of at least one double bond.The different tautomers of a compound are generally interconvertible and present in equilibrium in solution, in proportions which can vary according to the solvent used, the temperature or even the pH. In the context of the present invention, the formula (II') represented below is the tautomeric form of the formula (II):. The term "pharmaceutically acceptable" means that which is useful for the preparation of a pharmaceutical composition and that which is generally safe and non-toxic for pharmaceutical use. The expression "pharmaceutically acceptable salt and / or solvate" means, within the scope of the present invention, a salt and / or solvate of a pharmaceutically acceptable compound, as defined above, and which possesses the pharmacological activity of the corresponding compound.Pharmaceutically acceptable salts include:1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, etc.; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphthoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphthalenesulfonic, propionic, succinic, dibenzoyl-L25 tartaric, tartaric, p-toluenesulfonic, trimethylacetic, trifluoroacetic and the like, and2) base addition salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or coordinated with an organic or inorganic base.Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and others. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. Examples include solvates due to the presence of water (these solvates are also called hydrates) or ethanol. The term "prodrug" refers to a typically pharmacologically inactive or less active derivative of an active drug that undergoes biotransformation in cellulo or in vivo to release the active drug (oxidation, reduction, chemical or enzymatic cleavage).Prodrugs may have many advantages over the corresponding active forms, such as better stability and bioavailability and better penetration into the body, in this case into the brain, and thus increased activity in the brain for the corresponding active form. The term “(C1-C12) aliphatic chain” means a saturated, linear or branched monovalent hydrocarbon chain having 1 to 12, especially 1 to 6, carbon atoms. According to the invention, an aliphatic chain covers substituted or unsubstituted, linear or branched alkyl, alkenyl or alkynyl groups. The term “(C1-C6) alkyl” means a saturated, linear or branched monovalent hydrocarbon chain having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups.The term "(C2-C6) alkenyl" denotes a monovalent, linear or branched hydrocarbon chain, comprising at least one double bond and comprising 2 to 6 carbon atoms. Examples include ethenyl, propenyl, allyl, butenyl, pentenyl, or hexenyl groups. The term "(C2-C6) alkynyl" denotes a monovalent, linear or branched hydrocarbon chain, comprising at least one triple bond and comprising 2 to 6 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, or hexynyl groups. The term "aryl" denotes an aromatic hydrocarbon group, preferably comprising 6 to 10 carbon atoms, and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group.The term "heteroaryl" denotes an aromatic group comprising 5 to 10 ring atoms including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as for example sulfur, nitrogen or oxygen atoms, the other ring atoms being carbon atoms. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl or indyl. The term "halogen" denotes fluorine, chlorine, bromine and iodine atoms.The term "heterocycle" designates a cycle comprising from 4 to 10 cyclic atoms, saturated or unsaturated, but not aromatic, monocyclic or polycyclic, (including cycles), of which one or more, advantageously 1 to 4, even more advantageously 1 or 2, cyclic atom(s) is (are) a heteroatom, such as for example sulfur, nitrogen or oxygen atoms, the other cyclic atoms being carbon atoms. This may in particular be the pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, imidazolidinyl, azepanyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, thiazepanyl, benzimidazolonyl group. The term "cycloalkyl" designates a saturated cyclic hydrocarbon chain, comprising 3 to 7 cyclic carbon atoms. A cycloalkyl can be monocyclic or bicyclic. Examples include cyclopropyl, cyclopentyl, cyclohexyl, or cycloheptyl.The term "(Cx-Cy) haloalkyl" means a (Cx-Cy) alkyl group, as defined above, in which one or more hydrogen atoms are replaced by a halogen atom, in particular a chlorine, bromine, iodine or fluorine atom. By way of example, the trifluoromethyl group (-CF3) may be mentioned. The term "pharmaceutical composition" in the context of the present invention is understood to mean a composition having preventive and curative properties. Compounds of the inventionThe subject of the present invention is a compound of formula (I) and a compound of formula (II) as described above. The compound of formula (I) corresponds to the reduced form of the compound of formula (II). The compound of formula (II) corresponds to the active form in vivo and the compound of formula (I) corresponds to the corresponding prodrug which is capable of diffusing easily into the brain parenchyma and being activated there by oxidation.The prodrug itself has no inhibitory activity towards OCTs. However, it has a better capacity for penetration into the brain parenchyma, better stability and bioavailability. The active forms (oxidized forms of formula (II)) have a better affinity for OCTs and a better selectivity for OCTs over adrenergic receptors, over H2-cyanome. An object of the present invention therefore relates to a compound of the following formula (I):. a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, wherein L is a divalent radical derived from a C1-C12 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)- group, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH, R 1 , R 2 , R 3 and R 4 are independently selected from a group consisting of H, halogen, NR 9 R 10 , GOLD 11 , COOR 12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 13 , NR 14 R 15 and COOR 16 , or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 17 , NR 18 R 19 and COOR 20 , R 5represents a C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, OH, NH2 and COOH, R 6 represents H, halogen, NR 21 R 22 , GOLD 23 , COOR 24 , C1-C6 alkyl, cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 25 , NR 26 R 27 and COOR 28 , R 7 and R 8 are independently selected from the group consisting of H, halogen, NR 29 R 30 , GOLD 31 , COOR 32, C1-C6 alkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 33 , NR 34 R 35 and COOR 36 , and R 9 to R 36are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl. The compound of formula (I) used according to the present invention may be in the form of a stereoisomer or a mixture of stereoisomers, such as a mixture of enantiomers, diastereoisomers or tautomers, including a racemic mixture. In certain embodiments, the compound of formula (I) may be in the form of an enantiomer having an enantiomeric purity of at least 70%, preferably at least 80%, more preferably at least 90%, for example between 95% and 99%.In some embodiments, L is a divalent radical derived from a C1-C12 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by -O- or -C(=O)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH. Preferably, L is C1-C6 alkylene in which one or more methylene units, preferably one or two, are optionally replaced by -O- or -C(=O)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH. More preferably, L is C1-C6, especially C2-C3, alkylene, in which a methylene group is optionally replaced by -O-. In some embodiments, R. 1 , R2 , R 3 and R 4 are independently selected from a group consisting of H, halogen, NR 9 R 10 , GOLD 11 , COOR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 13 , NR 14 R 15 and COOR 16 ,R9 to R16 being independently selected from H, C1-C6 alkyl, aryl and cycloalkyl.Preferably, R 1 , R 2 , R 3 and R 4are independently selected from a group consisting of H, C1-C6alkyl, including methyl, ethyl or isopropyl, phenyl, cyclopropyl, OH, O-(C1-C6alkyl), including OCH3, COOH, COO-(C1-C6alkyl), including COOMe, Cl, F, NH2, NH-(C1-C6alkyl), including NHMe, and N(C1-C6 alkyl)2, including NMe2. In certain preferred embodiments, R1, R3 and R4 are H and R2 is selected from a group consisting of halogen, NR 9 R 10 , GOLD 11 , COOR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 13 , NR 14 R 15 and COOR 16 , R 9 to R 16being independently selected from H, C1-C6 alkyl, aryl and cycloalkyl. More preferably, R1, R3 and R4 are H and R2 is selected from a group consisting of C1-C6 alkyl, including methyl, ethyl or isopropyl, phenyl, cyclopropyl, OH, O-(C1-C6 alkyl), including OCH3, COOH, COO-(C1-C6 alkyl), including COOMe, Cl, F, NH2, NH-(C1-C6 alkyl), including NHMe, and N(C1-C6 alkyl)2, including NMe2. Even more preferably, R1, R3 and R4 are H and R2 is selected from a group consisting of OH and O-(C1-C6 alkyl), including OCH3. In other embodiments, R 1 and R 2 or R 2 and R 3 or R 3 and R 4 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 17,NR18R19 and COOR20, wherein R17 to R20 are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl. For example, R 1 and R 2 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 17 , NR 18 R 19 and COOR 20,R17 to R20 being independently selected from H, C1-C6 alkyl, aryl and cycloalkyl, and R3 and R4 are H. More specifically, R1 and R2 may form together with the carbon atoms to which they are attached an aryl ring optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR17, NR18R19 and COOR20, R17 to R20 being independently selected from H and C1-C6 alkyl, and R3 and R4 are H. In some embodiments, R 5 represents a C1-C alkyl 6, unsubstituted. In a preferred embodiment, R 5 is an isopropyl group. In some embodiments, R 6represents H, Cl, F, OH, O-(C1-C6alkyl), in particular OCH3, COOH, COO-(C1-C6alkyl), in particular COOMe, NH2, NH-(C1-C6alkyl), in particular NHMe, N(C1-C6 alkyl)2, in particular NMe2, C1-C6 alkyl, in particular methyl, ethyl or isopropyl, a phenyl or a cyclopropyl. Preferably, R6 is H. In certain embodiments, R 7 and R 8 are independently selected from the group consisting of H, halogen, NR 29 R 30 , GOLD 31 , COOR 32 , a C1-C6 alkyl, R 29 to R 32 being independently chosen from H, a C1-C6 alkyl, in particular a methyl, an aryl, in particular a phenyl, and a cycloalkyl, in particular a cyclopropyl. Preferably, R7 and R8 independently represent NR29R30, R29 and R30 being independently chosen from H, a C1-C6 alkyl, in particular a methyl, and a cycloalkyl, in particular a cyclopropyl. More preferably, R 7 represents NH2 or NH-cyclopropyl and R 8represents NH2.In ​​certain preferred embodiments, the compound of formula (I) corresponds to the following formula (IA): in which L, R 2 , R 5 , R 7 and R 8 are as defined above.The compound of formula (I) is preferably selected from the following compounds:and the pharmaceutically acceptable salts, solvates, enantiomers or tautomers thereof. In particular, the compound of formula (I-A3) may be the enantiomer (I-A3-1) of the following formula: The present invention also relates to the compound of formula (II), corresponding to the oxidized form of the compound of formula (I): a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, wherein X- represents a pharmaceutically acceptable anion, in particular selected from the group consisting of PF6-, Cl-, Br-, I-, BF4-, (C1-C6 alkyl)-C(O)O-, (C1-C6 haloalkyl)-C(O)O-, (C1-C6 alkyl)-SO3-, (C1-C6 haloalkyl)-SO3-, SO42- and PO43-,L is a divalent radical derived from a C1-C aliphatic chain 12 wherein one or more methylene units, preferably one or two, are optionally replaced by an arylene group, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH, R 1 , R 2 , R 3 and R 4 are independently selected from a group consisting of H, halogen, NR 9 R 10, GOLD 11 , COOR 12 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 13 , NR 14 R 15 and COOR 16 , or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 17 , NR 18 R 19 and COOR 20 , R 5represents a C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, OH, NH2 and COOH, R 6 represents H, halogen, NR 21 R 22 , GOLD 23 , COOR 24 , C1-C6 alkyl, cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 25 , NR 26 R 27 and COOR 28 , R 7 and R 8 are independently selected from the group consisting of H, halogen, NR 29 R 30 , GOLD 31 , COOR 32, C1-C6 alkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 33 , NR 34 R 35 and COOR 36 , and R 9 to R 36are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl. The compound of formula (II) used according to the present invention may be in the form of a stereoisomer or a mixture of stereoisomers, such as a mixture of enantiomers, diastereoisomers or tautomers, in particular a racemic mixture. In certain embodiments, the compound of formula (II) may be in the form of an enantiomer having an enantiomeric purity of at least 70%, preferably at least 80%, more preferably at least 90%, for example between 95% and 99%, in particular 96%, 97%, 98% or 99%. The preferred embodiments defined above for formula (I) also apply to the compound of formula (II). In particular, in certain preferred embodiments, the compound of formula (II) corresponds to the following formula (II-A): in which X-, L, R 2 , R 5 , R 7 and R 8are as defined above. The compound of formula (II) is preferably chosen from the following compounds: in which X is preferably a halogen, especially I, and the pharmaceutically acceptable salts, solvates, enantiomers or tautomers thereof. In particular, the compound of formula (II-A3) may be the enantiomer (II-A3-1) of the following formula: which X is preferably a Method of compound of formula The compound of formula (I), as well as its pharmaceutically acceptable salts, solvates, enantiomers or tautomers, may be prepared according to conventional methods known to those skilled in the art. In particular, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, may be obtained by the regioselective reduction of the compound of formula (II): According to certain embodiments, the regioselective reduction is carried out in the presence of sodium dithionite (Na2S2O4). The reduction reaction is in particular carried out in the presence of one or more suitable solvents, such as water, acetonitrile, methanol, ethanol or mixtures thereof. The reduction reaction is preferably carried out at room temperature, i.e. between 15°C and 30°C, for the time necessary to obtain a satisfactory conversion rate. The method for preparing the compound of formula (I) may in particular comprise the prior synthesis of the compound of formula (II). The compound of formula (II) may be obtained according to conventional methods known to those skilled in the art. In particular, it may be prepared by reacting a compound of formula (III) with a compound of formula (IV): in which R 1 to R 8and X are as defined above,Lx and Lv independently represent a divalent radical derived from a C1-C aliphatic chain 12wherein one or more methylene units, preferably one or two, are optionally replaced by an arylene group, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH,m and n are each 0 or 1, andR represents OH and R' represents a leaving group or R represents a leaving group and R' represents methyl.The compounds of formula (III) and (IV) may be obtained according to methods well known to those skilled in the art. It is understood that the preferred embodiments described for compounds of formula (I) and (II) in the present disclosure apply to compounds of formula (III) and (IV).It is understood that when the compound of formula (III) reacts with the compound of formula (IV), in the case where m=0 and n=1 or m=1 and n=0, Lx or Ly is typically as defined above for L. In another alternative, when m = n = 1, Lx and Ly each represent a component of the fragment L as defined in the compound of formula (II) above. It is understood that for the coupling to take place between the compounds of formula (III) and (IV), only one of them comprises a leaving group and the other comprises a function capable of acting on this leaving group (in particular in the presence of a base) to form the bond between the two compounds. The leaving group is in particular chosen from the group consisting of halogen, preferably I, and the sulfonate ester group such as the mesylate or tosylate group.The reaction between the compounds of formula (III) and (IV) is preferably carried out in the presence of a base, such as triethylamine, so as to form a nucleophilic species, which will act on the compound bearing the leaving group. The reaction is preferably carried out in a suitable solvent such as dichloromethane, dimethylformamide or acetonitrile. Preferably, it is carried out at room temperature. In particular, the compound of formula (III) is 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide (when R' is methyl) or 2-iodomethyl-1-isopropyl-6-methoxy-quinolin-1-ium iodide (when R' is a leaving group, in this case an iodine atom). In particular, the compound of formula (IV) is abacavir (with R = OH) or abacavir in which the OH function is tosylated (R is a leaving group.In the method for preparing a compound of formula (I), an intermediate compound obtained at the end of a reaction step or the final compound obtained at the end of the reaction can be separated from the reaction medium by methods well known to those skilled in the art, such as extraction, evaporation of the solvent or precipitation or crystallization (followed by filtration). Said compound can also be purified if necessary by methods well known in the art, such as recrystallization, distillation, column chromatography (for example on silica gel) or high performance liquid chromatography (HPLC). Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, and a pharmaceutically acceptable excipient.The pharmaceutical composition according to the invention may be formulated for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, intended for mammals, including humans. The dosage varies according to the treatment and the condition in question. For oral administration, the pharmaceutical composition may be in solid or liquid form (solution or suspension). A solid composition may be in the form of tablets, gelatin capsules, powders, granules, etc. In tablets, the active ingredient may be mixed with one or more pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like before being compressed. The tablets may be coated, especially with sucrose or other suitable materials, or they may be treated so as to have prolonged or delayed activity.In powders or granules, the active ingredient may be mixed or granulated with dispersing agents, wetting agents, or suspending agents and with flavor correctors or sweeteners. In gelatin capsules, the active ingredient may be filled into soft or hard gelatin capsules in the form of a powder or granules as mentioned above or in the form of a liquid composition as mentioned below. A liquid composition may contain the active ingredient together with a suitable sweetener, flavor enhancer, or coloring agent in a solvent such as water. The liquid composition may also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It may be, for example, a syrup or an elixir.For parenteral administration, the composition may be in the form of an aqueous suspension or solution which may contain suspending agents and / or wetting agents. The composition is advantageously sterile. It may be in the form of an isotonic solution (with respect to blood). Therapeutic uses The present invention relates to a medicament comprising a compound of the invention, of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or a pharmaceutical composition of the invention. In other words, the present invention relates to a compound of the invention or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or a pharmaceutical composition of the invention, for use as a medicament.The compounds of the invention, including their pharmaceutically acceptable salts, solvates, enantiomers or tautomers, are useful as inhibitors of organic cation transporters (OCT). The present invention therefore relates to a compound of the invention, of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or the pharmaceutical composition as described above, for its use as an OCT inhibitor. In other words, the present invention relates to the use of a compound of formula (I) or (II), or the pharmaceutical composition as described above, as an OCT inhibitor. In still other words, the present invention relates to the use of a compound of formula (I) or (II), or the pharmaceutical composition as described above, for the preparation of a medicament acting as an OCT inhibitor.The present invention also relates to a method for modulating OCT activity in a patient in need thereof, in particular a mammal, and preferably a human, comprising administering to the patient an effective dose of a compound of the invention, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or the pharmaceutical composition of the invention. In other words, the present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or the pharmaceutical composition of the invention, for the preparation of a medicament for modulating OCT activity in a patient in need thereof, in particular a mammal, and preferably a human.In particular, the present invention relates to a compound of the invention or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or a pharmaceutical composition of the invention, for use in the treatment or prevention of mood disorders, such as depressive disorders or anxiety disorders. In other words, the present invention relates to the use of a compound of the invention or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or a pharmaceutical composition of the invention, for the treatment or prevention of mood disorders, such as depressive disorders or anxiety disorders.The present invention also relates to a method for treating or preventing mood disorders, such as depressive disorders or anxiety disorders, in a patient in need thereof, in particular a mammal, and preferably a human, comprising administering to the patient an effective dose of a compound of the invention, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or the pharmaceutical composition of the invention. The invention also provides a method for delaying the onset of mood-related disorders, such as depressive disorders and anxiety disorders, in a patient in need thereof, in particular a mammal, and preferably a human, comprising administering to the patient an effective dose of a compound of the invention, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or the pharmaceutical composition of the invention.Depending on the disorder to be prevented or treated and the route of administration, the compound of the invention may in particular be administered in a single daily dose, in several daily doses or administered continuously, for example by means of an infusion.Examples 1) Synthesis1.1) Materials and methodsThe reagents used were supplied by Sigma-Aldrich (St. Louis, Missouri, USA) and used without further purification, with the exception of 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide which was prepared in the laboratory according to the method described in Orrico-Sanchez, 2020, doi: 10.1038 / s41380-019-0548-4Chemical formulas, summary formulas, molecular mass calculations, monoisotopic mass (exact mass) were determined using ChemDrawProfessional (PerkinElmer Informatics, Waltham, Massachusetts, USA). The MestReNova software (Mestrelab Research, SL, Santiago de Compostela, Spain) was used to visualize, process, analyze, and report the NMR spectra. NMR spectra were recorded on Bruker Avance III NanoBay 300 and 400 spectrometers (using trimethylsilane (TMS) as an internal standard) at IPCM (Institut Parisien de Chimie Moléculaire). Chemical shifts ^ (ppm) are related to TMS indirectly via the solvent reference signals. Silica gel 60 F254 plates (Merck, Darmstadt, Germany) were used for thin-layer chromatography (TLC) of products, reaction monitoring, and starting materials with UV-VIS detection at 254 nm and 365 nm. A Christ Alpha 2-4 LD laboratory freeze dryer (Bioblock Scientific) was used for freeze-drying. Mass spectrometry (MS) data were measured at the Paris-Seine Institute of Biology (IBPS). 1.2) Synthesis of the compounds of the invention1.2.1) Synthesis of abacacyanome (II-A1) a) Synthesis of the H2-QUIN intermediate. Scheme 1. Synthesis of 6-Methoxy-1-isopropylquinolin-1-ium H2-QUINIodide Intermediate 6-Methoxyquinoline (5 g, 31.40 mmol) was refluxed with iodopropane (15.6 mL, 157 mmol) for 48 h. The reaction mixture was cooled to room temperature and Et2O was added. The mixture was triturated and then the residue was washed with Et2O to give the desired compound (9.4 g, 91%) as a yellow solid; 1H-NMR (400 MHz, DMSO-d6)δ 9.44 (dd, 1 H, J = 1.5, 6.0 Hz, ArH), 9.11 (d, 1 H, J = 8.4 Hz, ArH), 8. 67 (d, 1 H, J = 9.9 Hz, ArH), 8.14 (dd, 1 H, J = 6.0, 8.3 Hz, ArH), 7.94 (d, 1 H, J = 3.0 Hz, ArH), 7.90 (dd, 1 H, J = 7.3, 9.0 Hz, ArH), 5.86 (h, 1 H, J = 6.5 Hz, CHCH3), 4 (s, 3 H, OCH3), 1.70 (d, 6 H, J = 6.5 Hz, CHCH3). 1-Isopropyl-6-methoxy-2-methylquinolin-1-ium iodide P1 1-Isopropyl-6-methoxyquinolin-1-ium iodide (10 g, 29.15 mmol) was added for 5 min to a solution of MeMgBr (3 M in DCM, 19.43 mL, 58.3 mmol) at 0 °C.The reaction mixture was stirred at this temperature for 1 h and then 2 h at room temperature. Water was added slowly, followed by concentrated HCl solution until two layers formed, then the addition of ammonium chloride, and the solution was made alkaline with ammonia. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give dihydroquinoline (6.02 g), which was directly used for the next step without purification. The dihydroquinoline was refluxed in EtOH (40 mL) with iodine (9.6 g) for 15 minutes, then cooled to room temperature. The resulting residue was filtered and washed with EtOH and Et2O to obtain 1-isopropyl-6-methoxy-2-methylquinoline-1-ium iodide (9.2 g) in 88% yield; 1H-NMR (400 MHz, DMSO-d6) δ 8.93 (d, 1 H, J = 8.6 Hz, ArH), 8.65 (d, 1 H, J = 9.9 Hz, ArH), 8.04 (d, 1 H, J = 8.5 Hz, ArH), 7.85 (d, 1 H, J = 3.1 Hz, ArH), 7.74 (d, 1 H, J = 8.5 Hz, ArH), 5.65 (sp, 1 H, J = 6.5 Hz, CHCH3),3.99 (s, 3 H, CH3), 1.85 (d, 6 H, J = 6.5 Hz, CHCH3).2-(Iodomethyl)-1-isopropyl-6-methoxyquinolin-1-ium iodide (H2-QUIN).1-Isopropyl-6-methoxy-2-methylquinoline-1-ium iodide 100 mg (0.29 mmol, 1 eq) was dissolved in 15 mL of dichloromethane (DCM), yellow-brown color. After dissolution, approximately 90 µL (0.64 mmol, 2.2 eq) of triethylamine (TEA) was added. The red-brown solution darkened to a brown-black color. After five minutes, 74 mg (0.29 mmol, 1 eq) of iodine was added. After 3 hours, 74 mg (0.29 mmol, 1 eq) of iodine was added. The reaction was stirred for 60 hours at room temperature. The mixture was purified as follows: The solvent was removed in vacuo (black-brown oily liquid). 5 ml of cyclohexane was added, which turned pink. The cyclohexane was removed after 1 hour and the remainder was removed in vacuo.The reaction mixture was diluted with DCM (30 mL) and washed with sat. NaCl (2x20 mL). The solvent was removed in vacuo. TLC and ninhydrin test revealed the presence of triethylammonium in water. The NMR spectrum still shows an excess of TEA. The reaction mixture was diluted with DCM (3 mL) and filtered through 1 cm silica gel DCM / MeOH (1:0 → 95:5). In general, it is not necessary to purify the crude product which is used for the addition to abacavir. b) Coupling with abacavir. In a flask under argon equipped with a magnetic stir bar, abacavir (61 mg, 0.213 mmol), silver acetate (AgOAc) (2.13 mg, 12.8 µmol) and 1,2-bis(diphenylphosphino)ethane (dppe) (5.1 mg, 12.8 µmol) were added. 0.64 mL of dimethylformamide (DMF) was then added. The mixture was stirred at room temperature for 10 minutes and then at -10°C. Then, H2-QUIN (0.1 g, 0.213 mmol) and LiHMDS (2.8 mg, 17 µmol) were added. The reaction medium was left under these conditions for 8 hours until the reagents were consumed. Finally, according to thin layer chromatography, we carried out a separation of the fractions by column chromatography (Cyclohexane / EtOAc 7:3).RMN 1H (400 MHz, CDCl3,) δ 7.30–7.20 (m, 6H, aromatic), 6.82 (s, 1H, aromatic), 3.96 (s, 3H, OCH3), 3.49 (s, 2H, NCH2Ph), 3.20 (dd, J1 = 18.0 Hz, J2 = 7.6 Hz, 1H), 2.87 (m, 2H), 2.66 (dt, J1 = 13.6 Hz, J2 = 3.6 Hz, 2H), 1.98–1.82 (m, 3H), 1.72–1.63 (m, 2H), 1.48 (m, 1H), 1.39–1.24 (m, 3H). 100 mg (0.29 mmol, 1 eq) of 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide was dissolved in 15 mL of dichloromethane (DCM). After dissolution, approximately 41 μL (0.29 mmol, 1 eq) of triethylamine (TEA) was added. After five minutes, 70 mg (0.31 mmol, 1.1 eq) of N-iodosuccinimide (NIS) was added. The solution turned brown-black. After 10 minutes, 87 mg (0.25 mmol, 0.87 eq) of abacavir sulfate was added. The reaction was stirred for 24 hours at room temperature. The reaction mixture was washed with saturated NaCl solution and saturated NH4Cl solution. The washed reaction mixture was concentrated under vacuum and applied to a preparative chromatography (PLC) plate (layer thickness 1 mm). The different layers were scraped. The silica gel powder was washed with DCM and MeOH (5%) and analyzed by NMR spectroscopy. 1H. The retention factor (Rf) of A2 was 0.26 on TLC with DCM / MeOH (95:5). The same reaction was then repeated with a larger amount (400 mg of 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide, 1.17 mmol). The crude product was purified by silica gel column chromatography using a gradient elution: DCM / MeOH (1:0 → 95:5) to give 105 mg (16% yield). 1H NMR (300 MHz, CD3CN) δ 8.82 (d, J = 8.8 Hz, 1H), 8.73 (dd, J = 4.3, 1.7 Hz, 1H), 8.54 (dd, J = 13.4, 9.3 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.45 (d, J = 4.2 Hz, 1H), 7.41 (d, J = 2.9 Hz, 1H), 7.38 (d, J = 2.9 Hz, 1H), 7.29 (d, J = 2.9 Hz, 1H), 7.20 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 3.0 Hz, 1H), 6.90 (dd, J = 8.8, 3.1 Hz, 1H),6.07 - 5.96 (m, 1H), 5.62 (t, J = 6.3 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 158.92, 157.71, 155.79, 147.24, 145.92, 143.57, 141.90, 135.35, 130.05, 129.29, 127.57, 122.46, 121.35, 121.30, 117.04, 114.09, 109.16, 105.15, 77.37, 60.01, 58.50, 56.65, 55.80, 55.57, 53.49, 51.52, 29.60, 22.32, 21.75, 19.72. MS and HRMS analyses were performed in MeOH:MS (ESI. + ): m / z predicted for C25H30N7O: 445.25; found 445.24 HRMS (ESI + ): m / z predicted for C25H30N7O: 445.2585; found 445.2484 HRMS (APCI): m / z predicted for C25H30N7O: 445.25; found 445.2475 Tosylate chloride (51 mg, 0.27 mmol, 1 eq) was added dropwise with stirring at 0°C to a white suspension of abacavir sulfate (90 mg, 0.27 mmol, 1 eq) with TEA (approximately 75 μl, 0.54 mmol, 2.00 eq) in acetonitrile (ACN) (10 ml) because this solvent immediately dissolves TsCl unlike DCM. The formed suspension was stirred at room temperature for 7 hours. Within three hours, the mixture was completely dissolved. 5 ml of cyclohexane and n-pentane were added. The solvents were removed after 1 hour to remove the remaining tosylate chloride and the remaining solvents were removed under vacuum. The product was analyzed by 1H NMR spectroscopy, which revealed the presence of abacavir tosylate. N,N-Dimethylformamide (DMF) was added. TEA (approximately 75 μL, 0.54 mmol, 2.00 eq), 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide (92 mg, 0.27 mmol, 1 eq) with DMF (3 mL) were added.The reaction was stirred at 70°C for 17 hours. Toluene (20 mL) was added to facilitate DMF removal, and the solvents were removed in vacuo. 5 mL of cyclohexane and n-pentane were added. The solvents were removed after 4 hours, and the remainder was removed in vacuo. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaCl solution and saturated NH4Cl solution (2x20 mL). The washed reaction mixture was concentrated in vacuo and then purified by silica gel chromatography. 1H NMR (300 MHz, MeOD) δ 7.89 (s, 1H), 7.75 - 7.66 (m, 2H), 7.28 - 7.19 (m, 2H), 6.18 (dd, J = 5.2, 2.4 Hz, 1H), 5.94 - 5.84 (m, 1H), 5.60 - 5.50 (m, 1H), 4.14 - 4.04 (m, 1H), 3. 62 (qd, J= 10.9, 5.2 Hz, 1H), 2.87 - 2.71 (m, 1H), 2.46 - 2.36 (m, 1H), 2.37 (s, 3H), 2.04 (m, 2H), 1.77(dd, J = 37.1, 13.9, 5.8 Hz, 1H), 1.01 - 0.84 (m, 2H), 0.76 - 0.64 (m, 2H).1.2.4) Synthesis of compound (II-A3-1). Synthesis of intermediate LP70: N6-cyclopropyl-9-((1R,4S)-4-(iodomethyl)cyclopent-2-en-1-yl)-9H-purine-2,6-diamine To a solution of abacavir (100 mg, 0.35 mmol, 1 eq) in THF (3 mL) are added PPh3 (207 mg, 0.79 mmol, 2.25 eq) and imidazole (48 mg, 0.7 mmol, 2 eq) at room temperature. After 5 minutes of stirring, I2 (170 mg, 0.67 mmol, 1.9 eq) is added. The reaction is stirred for 4 h at room temperature after which NaHCO3 (84 mg, 1 mmol, 3 eq) and water are added to stop the reaction. The solvent is evaporated under reduced pressure and the crude product is purified by flash chromatography (DCM / MeOH 9 / 1 to 6 / 4). The resulting compound is washed with toluene and the filtrate is evaporated to give a light yellow solid. (yield <10%)1H NMR (300 MHz, CDCl3) δ 7.68 – 7.63 (m, 1H), 6.15 (s, 1H), 6.06 (dt, J = 5.6, 2.1 Hz, 1H), 5.97 (dt, J = 5.6, 2.1 Hz, 1H), 5.55 (ddq, J = 8.8, 6.6, 2.1 Hz, 1H), 5.15 (s, 2H), 3.40 (dd, J =9.9, 6.1 Hz, 1H), 3.29 (dd, J = 9.9, 5.3 Hz, 1H), 2.90 (dt, J = 13.7, 8.3 Hz, 1H), 1.59 (dt, J =13.6, 6.7 Hz, 1H), 0.88 – 0.83 (m, 2H), 0.70 – 0.63 (m, 2H).HRMS (ESI) m / z: [M+H]+ Calculated for C14H17IN6H 397.0632. Found 397.0636; (Error: 1.0 ppm)Synthesis of intermediate LP83: 1-isopropyl-6-methoxy-2-methylquinolin-1-ium. Into an argon-purged flask is added a solution of methyl magnesium bromide (3M in ether, 600 µL, 2 mmol, 2 eq) is cooled to 0°C and a solution of 1-isopropyl-6-methoxyquinolin-1-ium iodide (330 mg, 1 mmol, 1 eq) in DCM (1 mL) is added for 5 min. The mixture is stirred at 0°C for 1 h and then at room temperature for 2 h. The reaction is quenched with water and DCM is added. A 1N HCl solution (approximately 0.2 mL) is added followed by a saturated solution of NH4Cl and NH4OH until the pH is approximately 10.5. The organic phase is separated and dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The resulting product was used without further purification and was dissolved in EtOH (5 mL) with I2 (365 mg, 1.44 mmol, 1.5 eq) and heated at reflux for 15 min. After allowing the reaction to cool to room temperature, Et2O was added and the brown solid formed was washed with Et2O and EtOH.(yield = 83%) 1H NMR (300 MHz, DMSO) δ 8.90 (d, J = 8.6 Hz, 1H), 8.64 (d, J = 9.8 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.85 – 7.68 (m, 2H), 5.70 – 5.55 (m, 1H), 3.98 (s, 3H), 3.09 (s, 3H), 1.84 (d, J = 7.0 Hz, 6H). Synthesis of compound (II-A3-1): In an argon-purged flask, a solution of LP83 (34.3 mg, 0.1 mmol, 1 eq) in THF (1 mL) is cooled to -78°C. nBuLi (1.6M in hexane, 63 µL, 0.1 mmol, 1 eq) is added dropwise to the solution. After 30 minutes, LP70 (50 mg, 0.13 mmol, 1.3 eq) dissolved in THF is added dropwise, and then the reaction mixture is left at room temperature overnight. The reaction is quenched with saturated NH4Cl solution. The solvent is evaporated and the resulting solid is dissolved in DCM and the organic phase is washed with water and brine, dried over MgSO4 and evaporated under reduced pressure. The compound is then recrystallized from DCM / Et2O to give a black solid (yield = 4.6%) NMR. 1H (300 MHz, CDCl3) δ 8.43 (s, 1H), 8.23 ​​(s, 1H), 7.55 (d, J = 1.7Hz, 1H), 6.44 (s, 1H), 6.10 (s, 1H), 4.03 (s, 3H), 2.00 (d, J = 7.1 Hz, 6H), 0.69 (d, J = 7.6 Hz, 2H), 0.61 (s, 2H).2) Molecular modeling2.1) Materials and methods 3D modeling was performed on Discovery Studio software. The theoretical affinities of the compounds of the invention (II-A1) and (II-A3-1) with OCT and alpha-adrenergic receptors were evaluated using a standard range consisting of ligands whose affinity is described in the literature. The modeling was carried out according to the following steps: 1. Search for models The models for the targets studied (adrenergic receptors and OCT) were searched in the National Center for Biotechnology Information (NCBI) database by BLAST (“Basic local alignment search tool”).The models were ranked according to 3 parameters: Query cover (percentage of sequence coverage), E-value (probability of relevant match between sequences) and Per.ident (percentage of identity), the objective being to select those with the highest percentage of coverage, the minimum E-value and the best percentage of identity with the protein sequence to be modeled. Several models can be used simultaneously for optimal alignment of the sequence of a target protein. 2. Initial alignment and optimization Discovery Studio directly displays the elements of the protein structure, including co-crystallized ligands. In the case of α-adrenergic receptors, it happens that the receptors are co-crystallized with agonists or antagonists.These crystals must be cleaned of various irrelevant molecules present in the structures such as residual water molecules or stabilizers used during crystallization. First, the primary sequence of the model was compared directly in the Discovery Studio software to the target receptor sequence obtained on NCBI. The “AlignSequence and Structure” option allowed to align 2 or more sequences in order to obtain a better percentage of identity. This step must be done manually for OCTs using the D-xylose / proton symporter models and the transmembrane helix prediction method available online on the TMHMM software because the structures of the membrane helices are better preserved than the sequences. Indeed, this method is necessary given the low percentages and overlap between the OCTS and the potential models.The OCT helices that must be preserved during alignment were therefore aligned to the corresponding regions of the model. The alignment was then optimized for use in homology modeling. The final step in alignment optimization involves preserving disulfide bonds between the model and the protein to be modeled. 3. Homology Model Generation Models must be "prepared" before being used for homology model generation. Preparation cleans the protein and corrects uncertainties and errors in selected structures: inserting missing atoms into incomplete residues, modeling missing loops, removing alternative conformations and eliminating H2O molecules, and checking and correcting the protonation states of residues at the desired pH.The prerequisites for generating homology models are the alignment of the primary sequence of the target protein with its model(s) as well as the structure of the “prepared” model with or without co-crystallized ligands. The “Create Homology Models” protocol available in Discovery Studio allows the generation of up to 50 different 3D models of the protein of interest and the association of an energy value representing its stability with each model. Their quality is therefore expressed by their PDF energies (homology-derived pseudo-energy and stereochemical pseudo-energy) and their DOPEscore (Discrete optimized protein energy). The optimal model (with the lowest PDF energies and the best DOPEscore) will be used for the ligand docking step in the receptor (docking). 4.Minimization For OCTs in particular, an additional minimization step is necessary to obtain an optimal 3D model because it allows minimizing the energy of the ligand from the template. The positioning and orientation of the new 3D structure of the protein with respect to an implicit membrane were optimized by the “Add membrane and orient molecule” protocol in Discovery Studio. A harmonic constraint on the backbone of the modeled protein is also applied. Once prepared, the protein was minimized by 3 steps. A first minimization was done by the “Smart Minimizer” tool at a RMS (“RootMean Square”) gradient of 0.05. Then, a second minimization by the Newton-Raphson (NR) algorithm “Adopter Basis NR” is performed at a RMS gradient of 0.0001. Finally, the NR minimization was redone in the absence of the harmonic constraint. 5.Creation of the 3D structure, preparation and generation of ligand conformationsThe ligands were obtained in 2D with the ChemDraw Professional software, then transferred to Discovery Studio in order to generate their 3D structure. They were prepared according to a protocol dedicated to small molecules, which allows to take into account the different protonation states of the molecules at the pH considered, to remove duplicates, to list isomers and tautomers, to generate the 3D coordinates of the structures. The next step consisted of the generation of conformers via the BEST protocol (see Nouri, K et al. Int. J. Mol. Sci. 2022 Nov 23;23(23):14615 doi: 10.3390 / ijms232314615) which allows to increase the conformational coverage of the molecules studied. The maximum number of these conformers is limited to 225 conformations and these structures were used as is for the “docking” step, i.e. the anchoring of the ligands in the target proteins. 6.Docking the ligand in the receptor (or Docking step) The CDOCKER function of Discovery studio allows the docking of a certain number of ligands to a protein. The latter is kept rigid, while the ligand can be flexible. The ligand binding region (i.e. the active site of the ligands) is determined using the co-crystallized ligands if they exist, as in the case of adrenergic receptors by means of a sphere surrounding the binding site. The co-crystallized ligand is then replaced by the ligands to be studied. In cases where the co-crystallized ligand is absent from the model, a bibliographic search concerning the binding site is carried out. This is the case for OCT2 and OCT3. The search for residues involved in the binding to specific ligands makes it possible to define the positioning of the sphere of the binding site.Once the docking is done, the result of this step consists of interaction poses between the ligand and the protein of interest indexed by an interaction energy. The most stable protein / ligand complexes were selected based on the interaction energy of each pose (the most negative) as well as the positioning of the ligands according to their binding mode (interaction with the key residues of the binding site: ionic bonds between the N+ atom of the ligands and the negatively charged residues of the protein (Asp or Glu). The “Analyze ligand poses” function of Discovery Studio made it possible to identify these interactions and to enumerate the type of bond present between the ligand and the proteins for each complex. The ligand poses were then re-evaluated and re-scored by other scoring functions than the interaction energy thanks to the application of the “Score ligand poses” function.Functions such as LUDI, PLP, Ligscore, Jain and PMF take into account steric configuration, weak interactions (hydrogen bonds, Van der Waals), as well as freely rotating, polar bonds or lipophilic contact surfaces. 2.2) Results The results obtained are illustrated in Figure 1A and 1B which describe correlation curves between the experimental pKi and the virtual affinity of the derivative (II-A1) for the adrenergic receptors α1a (diamonds), α1b (squares) and α1d (triangles) (Fig.1A) and OCT2 and 3 (Fig.1B), and in Figure 2A and 2B which describe correlation curves between the experimental pKi and the virtual affinity of the derivative (II-A3-1) for the adrenergic receptors α1a (diamonds), α1b (squares) and α1d (triangles) (Fig.2A) and OCT2 and 3 (Fig.2B).Observations:According to this predictive method, the abacacyanome hybrid derivatives (II-A1) and (II-A3-1) exhibit improved selectivity for OCTs and low affinity for ^1-adrenergic receptors in refined 3D models of OCTs and ^1-adrenergic receptors.3) Biological results3.1) In vitro resultsThe affinity of the compound (II-A2) for various adrenergic receptors (α1a / b / d and α2a / b / c) was evaluated by radioactive ligand displacement in membrane preparations of CHO cells expressing recombinant human adrenergic receptors, according to established methodologies (Amphoux et al., Eur J Pharmacol. 2010;634(1-3):1-9). The results indicate a very low affinity of II-A2, compared to classical ligands (Docherty, 2019, Eur J Pharmacol, 855:305-320), for all receptors tested, as shown in the following Table 1: [Table 1] Targeted receptor IC50 (μM) Ki (μM)alpha1A(h) (radioligand) 200 99 alpha1B (h). 100 28(radioligand alpha1D(h) 440 190 (radioligand) alpha2A(h) 280 130 (radioligand) alpha2B(h) 190 130 (radioligand) alpha2C(h) 290 94 (radioligand) IC 50and inhibition constant Ki of compound (II-A2) for alpha adrenergic receptors The determination of the affinity of compound II-A2 for a panel of adrenergic receptors indicates that it does not bind or binds weakly to α receptors, an important condition to avoid possible cardiovascular side effects. 3.2) In vitro results Methods hOCT-mediated uptake inhibition and IC50 determination For the OCT uptake inhibition assay, CHO cells stably transfected with human OCT2 are incubated with the fluorescent OCT2 substrate ASP+ (50 µM ASP+) at 37 °C. For IC50 determination, 8 concentrations of the test compounds ranging from 30μM to 3nM are added during pre-incubation and incubation. The fluorescent ASP+ accumulated in the cells is then measured using an EnVision plate reader.To confirm specificity, the same assay is also performed after 15 minutes of pre-incubation with a reference OCT2 inhibitor. Evaluation of the affinity of compounds for human alpha1A, 2A and 2C adrenergic receptors, determined in a radioligand binding assay in transfected CHO cells For the human alpha 1A-adrenergic receptor, cell membrane homogenates (20 μg of protein) are incubated for 60 min at 22°C with 0.1 nM [3H]prazosin in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 0.5 mM EDTA, 20 mg / L aprotinin and 0.01% bacitracin. Nonspecific binding is determined in the presence of 0.1 mM epinephrine.For the human alpha 2A-adrenergic receptor, cell membrane homogenates (48 μg of protein) are incubated for 60 minutes at 22°C with 1 nM [3H]RX 821002 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 2 mM MgCl2 and 1 mM EDTA. Nonspecific binding is determined in the presence of 100 μM (-)epinephrine. For the human alpha 2C-adrenergic receptor, cell membrane homogenates (12 μg of protein) were incubated for 60 minutes at 22°C with 2 nM [3H]RX821002 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 2 mM MgCl2 and 1 mM EDTA. For all receptors, after incubation, samples were rapidly vacuum filtered through glass fiber filters (GF / B, Packard) pre-impregnated with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard).The filters are dried and then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as the percentage inhibition of the specific binding of the control radioligand. The standard reference compound is WB 4101 (for alpha 1A receptor) or yohimbine (for alpha 2A and 2C receptors), which are tested in each experiment at several concentrations to obtain a competition curve from which the IC50 is calculated. Results: Test compound: II-A3-1 Targeted receptor Concentration % inhibition of compound (M) alpha1A(h) 1.0E-06 20.2567 (radioligand ). 5,0E-06 68,0706 1 ,6.0E-05 95,8283 alpha2A(h) 1.0E-06 -1.54E+01 (radioligand) 5,0E-06 12,3165 1.6.0E-05 28,639 alpha2C(h) 1.0E-06 11.2852 (radioligand) 5,0E-06 44,7548 1 ,6.0E-05 88,4877(II-A3-1) therefore has no relevant affinity for adrenergic receptors. 3.3) In vivo results The compound (II-A2) was tested in a mouse model of resignation, the forced swimming test, to evaluate its activity as an antidepressant in comparison with a known antidepressant, fluoxetine (Prozac®) and saline solution. Method: The forced swimming test allows the potential efficacy of antidepressants in rodents to be evaluated. The animal is placed in a tank of water 1 hour after receiving an injection of the product (control: saline solution, fluoxetine (18 mg / kg) or derivative II-A2 (0.2 mg / kg). The agitation time and then the immobility time (indicative of "desperate" behavior) are then measured. The faster the animal adopts desperate behavior, the longer the immobilization time will be. On the contrary, if an animal struggles longer than the control animal, this indicates antidepressant activity of the compound received.Results: The results of the forced swim test are shown in Figure 2. The immobility time observed for compound (II-A2) is lower than that observed for the control animal. It is slightly higher than that obtained with fluoxetine. However, the amount of fluoxetine injected is 90 times higher than that of compound (II-A2).Discussion: These preliminary experiments indicate a significant effect of a low dose of compound (II-A2) in the forced swim test, a classic acute test for evaluating the activity of antidepressants. Since almost all conventional antidepressants show a significant effect in this acute test, these results demonstrate an antidepressant effect of abacacyanome and its derivatives.

Claims

CLAIMS1. Compound of the following formula (I): a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, wherein L is a divalent radical derived from a C1-C12 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)- group, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, OH, NH2 and COOH, R 1 , R 2 , R 3 and R 4 are independently selected from a group consisting of H, halogen, NR 9 R 10 , GOLD 11 , COOR 12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 13 , NR 14 R 15 and COOR 16 , or R 1 and R 2 or R 2 and R 3 or R 3 and R 4 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 17 , NR 18 R 19 and COOR 20 , R 5represents a C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, OH, NH2 and COOH, R 6 represents H, halogen, NR 21 R 22 , GOLD 23 , COOR 24 , C1-C6 alkyl, cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 25 , NR 26 R 27 and COOR 28 , R 7 and R 8 are independently selected from the group consisting of H, halogen, NR 29 R 30 , GOLD 31 , COOR 32, C1-C6 alkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR 33 , NR 34 R 35 and COOR 36 , R 9 to R 36 are independently chosen from H, C1-C6 alkyl, aryl and cycloalkyl.

2. Compound of formula (I) according to claim 1, characterized in that it corresponds to the following formula (IA): in which L, R 2 , R 5 , R 7 and R 8are as defined in claim 1.

3. Compound of formula (I) according to claim 1 or 2, characterized in that L is a C1-C6, especially C2-C3, alkylene, in which a methylene is optionally replaced by -O-.

4. Compound of formula (I) according to any one of claims 1 to 3, characterized in that R2 is chosen from a group consisting of OH and O-(C1-C6 alkyl), especially OCH3.

5. Compound of formula (I) according to any one of claims 1 to 4, characterized in that R 5 represents a C1-C6 alkyl, in particular an isopropyl.

6. Compound of formula (I) according to any one of claims 1 to 5, characterized in that R7 and R8 independently of each other represent NR29R30, R29 and R30 being independently chosen from H, a C1-C6 alkyl, in particular a methyl, and a cycloalkyl, in particular a cyclopropyl.

7. Compound of formula (I) according to any one of claims 1 to 6, chosen from the following compounds:

8. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, and a pharmaceutically acceptable excipient.

9. A compound of the following formula (II): a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, whereinX- represents a pharmaceutically acceptable anion, especially selected from the group consisting of PF6-, Cl-, Br-, I-, BF4-, (C1-C6 alkyl)-C(O)O-, (C1-C6 haloalkyl)-C(O)O-, (C1-C6 alkyl)-SO3-, (C1-C6 haloalkyl)-SO3-, SO42- and PO43-, andL and R 1 to R 8 are as defined in any one of claims 1 to 7.

10. Compound of formula (II) according to claim 9, chosen from the following compounds: in which X is a11. Compound of formula (II) according to claim 9, corresponding to the following formula: wherein X is preferably halogen, especially I.

12. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, A pharmaceutical composition according to claim 8 or a compound of formula (II) according to any one of claims 9 to 11, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, for use as a medicament.

13. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof,a pharmaceutical composition according to claim 8 or a compound of formula (II) according to any one of claims 9 to 11, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, for use in the prevention or treatment of mood disorders, such as depressive disorders or anxiety disorders.

Images