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

Novel inhibitors of organic cation transporters for the treatment of mood disorders FIELD OF THE INVENTION The present invention relates to novel abacacyanome derivatives and to the pharmaceutically acceptable salts, solvates and tautomers of same. 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. PRIOR ART Mood disorders represent widespread, invalidating affections with up to 16% of the world population affected to varying degrees by symptoms of depressive type. These disorders which affect mood, cognition, motivation and behaviour weigh heavily on quality of life. They are associated with excess mortality, high suicide risk and various underlying conditions and, in addition to their effects on the person individually, they have a considerable social and economic impact. The first-line antidepressants used to treat major depression are mostly monoamine reuptake Inhibitors, in particular serotonin (5-HT) and noradrenaline (NE). These conventional antidepressant treatments have major limitations, in particular long delayed onset of action and undesirable side effects. In addition, they do not always give positive results, and about one third of patients do not respond satisfactorily to treatment. There is therefore a pressing need for drugs combining better efficacy and quicker onset of action. Rapid action compounds targeting the 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 given rise to high hopes for management of depression associated with suicide risk, but there remain concerns as to their true efficacy in large cohorts, and their long-term and side effects still remain to be solved. The identification of novel therapeutic pathways for depressive disorders therefore amounts to a major challenge in mental health research. Preceding studies by the inventors of the present invention identified atypical organic cation transporters (OCTs) as novel pharmacological targets for the treatment of depressive disorders. OCTs are polyspecific transporters taking part in the absorption and clearance of various endogenic and xenobiotic compounds in the nervous system and peripheral organs. They can also, with low affinity, transport biogenic amines (serotonin,  dopamine, noradrenaline). Two OCT sub-types, 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). It has recently been proposed that brain OCTs form a monoamine clearance system in addition to conventional high-affinity reuptake transporters (Figure 1). Reuptake transporters of dopamine (DATs), serotonin (SERT) and noradrenaline (NET) are responsible for clearing monoamines released from the extracellular space and for recycling thereof in neurone endings, and are the chief targets of conventional antidepressants (SSRSs and NSRIs). OCTs differ from conventional reuptake transporters through their very extensive distribution in the brain in a large variety of neuronal types, and through the fact that they accept all monoamines as substrates (Courousse T et Gautron S (2015). Pharmacol Ther. 146C:94-103). The inventors have recently proven the concept that OCTs and in particular OCT2 and OCT3, are relevant therapeutic targets for depression, by developing a novel ligand inhibiting these transporters and having high antidepressant potential: cyanome a derivative of a known OCT inhibitor, disprocynium 24   (D24)   (WO2019012150; Orrico-Sanchez, 2020, doi: 10.1038 / s41380-019-0548-4). Cyanome was evaluated, using a molecular modelling approach, as having better selectivity for OCTs in particular OCT2 over alpha adrenergic receptors, compared to D24. The molecular modelling approach was validated by in vitro transport and binding experiments, respectively evaluating the affinity of cyanome for OCT2 and for the a-adrenergic receptors. Additionally, cyanome was then modified as a prodrug, H2-cyanome (Figure 2), to enable passive diffusion thereof in the cerebral parenchyma and activation thereof via a redox mechanism. This prodrug called H2-cyanome, at low dose, exhibited efficacy as good as that of the conventional antidepressant fluoxetine (Prozac) in a mouse chronic depression model, with more rapid action on anhedonia one of the key symptoms of depression. However, the selectivity for OCTs over the alpha-adrenergic receptors remains unsatisfactory: although the affinity of the H2-cyanome for the a2 adrenergic receptors is low, H2-cyanome maintains affinity for the al adrenergic receptor which could be the source of undesirable side effects, in particular on blood pressure, heart rate or contractility. There therefore remains a need for an OCT inhibitor compound, in particular of OCT2 and OCT3, that can be used in the treatment of mood disorders such as depressive disorders and anxiety disorders, which has greater selectivity toward OCTs, in particular over the alpha-adrenergic receptors, to improve efficacy and to limit side effects. SUMMARY OF THE INVENTION The subject of the present invention is a compound of following formula (I): (I), a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, where: L is a divalent radical derived from a C1-C12 aliphatic chain wherein 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 optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, aryl, OH, NH2 and COOH, R1, R2, R3 and R4 are each independently chosen from a group formed by H, a halogen, NR9R10, OR11, COOR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an aryl, heteroaryl, heterocycle and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and cycloalkyl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR13, NR14R15 and COOR16, or R1 and R2, or R2 and R3, or R3 and R4, together with the carbon atoms to which they are bound, form an aryl, heteroaryl, heterocycle or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR17, NR18R19 and COOR20, R5 is a C1-C6 alkyl optionally substituted by one or more substituents chosen from the group formed by a halogen, OH, NH2 and COOH, R6 is H, halogen, NR21R22, OR23, COOR24, C1-C6 alkyl, a cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR25, NR26R27 and COOR28, R7 and R8 are each independently chosen from the group formed by H, halogen, NR29R30, OR31, COOR32, C1-C6 alkyl, an aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6, alkyl, C1-C6 alkyl halide, OR33, NR34R35 and COOR36, R9 to R36 are each independently chosen from among H, C1-C6 alkyl, an aryl and cycloalkyl. A further subject of the present invention is a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate, tautomer thereof, and a pharmaceutically acceptable excipient. A further subject of the present invention is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use thereof as a drug. A further subject of the present invention is 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. A further subject of the invention is a compound of following formula (II): R7 (II) a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, where: X- is a pharmaceutically acceptable anion, chosen in particular from the group formed by PF6-, Cl-, Br-, I-, BF4-, (C1-C6alkyl)-C(O)O-, (C1-C6 alkyl halide)-C(O)O-, (C1-C6alkyl)-SO3-,(C1-C6 alkyl halide)-SO3-, SO42-and PO43-, and L and R1 to R8 are such as defined above. Other aspects of the invention are as described below. DESCRIPTION OF THE FIGURES Figure 1: (A) correlation curves between experimental pKi and the virtual affinity of compound (II-A1) obtained by molecular modelling and docking of the a-adrenergic receptors a1-AR (pKi abacacyanome>1mM): receptors a1a (diamond), a1b (square) and a1d (triangle); (B) correlation curves between experimental pKi and the virtual affinity of compound (II-A1) obtained by molecular modelling and docking of the transporters OCT2 and OCT3 (pki II-A1 6.9 and 7.3 respectively). Figure 2: (A) correlation curves between experimental pKi and the virtual affinity of compound (II-A1) and compound (II-A3-1) obtained by molecular modelling and docking of the a-adrenergic receptors a1-AR (pKi abacacyanome>1mM) : receptors ala (diamond), alb (square) and a1d (triangle); (B) correlation curves between experimental pKi and the virtual affinity of compound (II-A1) and compound (II-A3-1) obtained by molecular modelling and docking of the transporters OCT2 and OCT3 (pki II-A3-1 6.8 and 7.8, respectively). Figure 3: immobility time observed in the forced-swim test of mice having received an intraperitoneal injection of saline solution (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 given in the form of mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION The inventors have surprisingly developed novel, more selective OCT inhibitors, capable of easily passing through the blood-brain barrier. Definitions The term "stereoisomer" used in the present invention refers to configuration 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 or racemate mixture. The term “tautomer” designates structural isomers of the compound obtained by prototropy i.e. by migration of a hydrogen atom and a shift in location of at least one double bond. The different tautomers of a compound are generally interconvertible and are present in equilibrium in solution, in proportions which can vary according to the solvent used, temperature or pH. In the present invention, formula (II’) illustrated below is the tautomeric form of formula (II): The term "pharmaceutically acceptable" designates that which is useful for preparing a pharmaceutical composition and is generally safe and nontoxic, for pharmaceutical use. The expression "pharmaceutically acceptable salt and / or solvate" in the present invention designates a salt and / or solvate of a pharmaceutically acceptable compound as defined above, and which has the pharmacological action 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, benzene sulfonic, 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 acids, and the like, and 2) base addition salts formed when an acid proton contained in the compound is either replaced by a metal ion such as an alkaline metal ion, alkaline-earth metal ion or aluminium 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 aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Acceptable solvates for therapeutic use of the compounds of the present invention, comprise conventional solvates such as those formed at the last preparation step of the compounds of the invention, on account of the presence of solvents. For example, mention can be made of solvates due to the presence of water (these solvates are generally called hydrates) or ethanol. The term "prodrug" relates to a typically pharmacologically inactive or less active derivative of an active drug which undergoes in cellulo or in vivo biotransformation to release the active drug (oxidation, reduction, chemical or enzymatic cleaving). Prodrugs can have numerous advantages compared to the corresponding active forms, such as better stability or improved bioavailability and better entry in the body, in the present case in the brain, and therefore increased action in the brain for the corresponding active form. The term “(C1-C12) aliphatic chain" designates a linear or branched, saturated monovalent hydrocarbon chain having 1 to 12 and in particular 1 to 6 carbon atoms. In the invention, an aliphatic chain covers linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. The term “(C1-C6) alkyl”, designates a linear or branched, saturated monovalent hydrocarbon chain having 1 to 6 carbon atoms. For example, mention can be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups. The term “(C2-C6) alkenyl” designates a linear or branched, monovalent hydrocarbon chain comprising at least one double bond and having 2 to 6 carbon atoms. For example, mention can be made of ethenyl, propenyl, allyl, butenyl, pentenyl, or hexenyl groups. The term “(C2-C6) alkynyl” designates a linear or branched monovalent hydrocarbon chain comprising at least one triple bond and having 2 to 6 carbon atoms. For example, mention can be made of ethynyl, propynyl, butynyl, pentynyl, or hexynyl groups. The term “aryl” designates an aromatic hydrocarbon group preferably having 6 to 10 carbon atoms and comprising one or more adjoining rings e.g. a phenyl or naphthyl group. The term “heteroaryl” designates an aromatic group having 5 to 10 cyclic atoms including one or more heteroatoms advantageously 1 to 4, and more advantageously 1 or 2, e.g. sulfur, nitrogen or oxygen atoms, the other cyclic atoms being carbon atoms. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazole, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl or indyl groups. The term “halogen” designates fluorine, chlorine, bromine and iodine atoms. The term “heterocycle” designates a ring comprising 4 to 10 cyclic atoms, saturated or unsaturated, but not aromatic, monocyclic or polycyclic (including rings) of which one or more, advantageously 1 to 4, more advantageously 1 or 2 cyclic atoms are a heteroatom e.g. sulfur, nitrogen or oxygen atoms, the other cyclic atoms being carbon atoms. It can in particular be a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, imidazolidinyl, azepanyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, thiazepanyl, benzimidazolonyl group. The term “cycloalkyl” designates a cyclic saturated hydrocarbon chain having 3 to 7 cyclic carbon atoms. A cycloalkyl can be monocyclic or bicyclic. For example, mention can be made of cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl groups. The term “(Cx-Cy) alkyl halide” designates a (Cx-Cy) alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom, in particular a chlorine, bromine, iodine or fluorine atom. For example, mention can be made of the trifluoromethyl group (-CF3). The term "pharmaceutical composition" in the present invention is meant to indicate a composition having preventive and curative properties. Compounds of the invention The subject of the present invention is a compound of formula (I) and a compound of formula (II) as described above. The formula (I) compound corresponds to the reduced form of the formula (II) compound. The formula (II) compound corresponds the in vivo active form, and the formula (I) compound corresponds to the corresponding prodrug which is easily able to diffuse within the cerebral parenchyma and to be activated therein by oxidation. The prodrug itself has little or no inhibiting action of OCTs. On the other hand, it has better ability to enter into the cerebral parenchyma, better stability and bioavailability. The active forms (oxidized forms of formula (II)) have better affinity for OCTs and better selectivity for OCTs over the adrenergic receptors, compared to H2-cyanome. One subject of the present invention therefore concerns a compound of following formula (I): (I), a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, where: L is a divalent radical derived from a C1-C12 aliphatic chain wherein 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 optionally being substituted by one or more substituents chosen from the grouped formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, aryl, OH, NH2 and COOH, R1, R2, R3 and R4 are each independently chosen from a group formed by H, a halogen, NR9R10, OR11, COOR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an aryl, heteroaryl, heterocycle and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and cycloalkyl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR13, NR14R15 and COOR16, or R1 and R2, or R2 and R3, or R3 and R4, together with the carbon atoms to which they are bound, form an aryl, heteroaryl, heterocycle or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR17, NR18R19 and COOR20, R5 is a C1-C6 alkyl optionally substituted by one or more substituents chosen from the group formed by a halogen, OH, NH2 and COOH, R6 is H, halogen, NR21R22, OR23, COOR24, C1-C6 alkyl, a cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR25, NR26R27 and COOR28, R7 and R8 are each independently chosen from the group formed by H, halogen, NR29R30, OR31, COOR32, C1-C6 alkyl, an aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR33, NR34R35 and COOR36, and R9 to R36 are each independently chosen from among H, C1-C6 alkyl, an aryl and a cycloalkyl. The formula (I) compound used in the present invention can be in the form of a stereoisomer or mixture of stereoisomers, such as a mixture of enantiomers, diastereoisomers or tautomers, in particular a racemic mixture. In some embodiments, the formula (I) compound can be in the form of an enantiomer having 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 wherein one or more methylene units, preferably one or two, are optionally replaced by -O- or -C(=O)-, said aliphatic chain optionally being substituted by one or more substituents chosen from the group formed by a C1-C6 alkyl, C1-C6 alkyl halide, an aryl, OH, NH2 and COOH. Preferably, L is a C1-C6 alkylene wherein one or more methylene units, preferably one or two, are optionally replaced by -O- or C(=O)-, said aliphatic chain optionally being substituted by one or more substituents chosen from the group formed by a C1 -C6 alkyl, C1-C6 alkyl halide, an aryl, OH, NH2 and COOH. More preferably L is a C1-C6alkylene, in particular C2-C3, wherein a methylene group is optionally replaced by -O-. In some embodiments, R1, R2, R3 and R4 are each independently chosen from a group formed by H, a halogen, NR9R10, OR11, COOR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an aryl, heteroaryl, heterocycle and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and cycloalkyl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR13, NR14R15 and COOR16, R9 to R16 each being independently chosen from among H,C1-C6 alkyl, an aryl and cycloalkyl. Preferably, R1, R2, R3 and R4 are independently chosen from a group formed by H, C1-C6 alkyl, in particular methyl, ethyl or isopropyl, phenyl, cyclopropyl, OH, O-(C1-C6 alkyl), in particular OCH3, COOH, COO-(C1-C6 alkyl), in particular COOMe, Cl, F, NH2, NH-(C1-C6 alkyl), in particular NHMe, and N(C1-C6 alkyl)2, in particular NMe2. In some preferred embodiments, R1, R3 and R4 are H and R2 is chosen from a group formed by a halogen, NR9R10, OR11, COOR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an aryl, heteroaryl, heterocycle and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and cycloalkyl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR13, NR14R15 and COOR16, R9 to R16 each being independently chosen from among H, C1-C6 alkyl, an aryl and cycloalkyl. More preferably, R1, R3 and R4 are H and R2 is chosen from a group formed by C1-C6 alkyl, in particular methyl, ethyl or isopropyl, phenyl, cyclopropyl, OH, O-(C1-C6 alkyl), in particular OCH3, COOH, COO-(C1-C6 alkyl), in particular COOMe, Cl, F, NH2, NH-(C1-C6 alkyl), in particular NHMe, and N(C1-C6 alkyl)2, in particular NMe2. Further preferably, R1, R3 and R4 are H and R2 is chosen from a group formed by OH and O-(C1-C6 alkyl), in particular OCH3. In other embodiments, R1 and R2, or R2 and R3, or R3 and R4, together with the carbon atoms to which they are bound, form an aryl, heteroaryl, heterocycle or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR17, NR18R19 and COOR20, R17 to R20 each independently being chosen from among H, C1-C6 alkyl, an aryl and cycloalkyl. For example, R1 and R2, together with the carbon atoms to which they are bound, form an aryl, heteroaryl, heterocycle or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide OR17, NR18R19 and COOR20, R17 to R20 each independently being chosen from among H, C1-C6 alkyl, an aryl and cycloalkyl, and R3 and R4 are H. More specifically, R1 and R2 together with the carbon atoms to which they are bound, can form an aryl ring optionally substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR17, NR18R19 and COOR20, R17 to R20 each independently being chosen from among H and C1-C6 alkyl, and R3 and R4 are H. In some embodiments, R5 is an unsubstituted C1-C6 alkyl. In one preferred embodiment, R5 is an isopropyl group. In some embodiments, R6 is H, Cl, F, OH, O-(C1-C6 alkyl), in particular OCH3, COOH, COO-(C1-C6 alkyl), particularly COOMe, NH2, NH-(C1-C6 alkyl), in particular NHMe, N(C1-C6 alkyl)2, in particular NMe2, C1-C6 alkyl, in particular methyl, ethyl or isopropyl, a phenyl or cyclopropyl. Preferably, R6 is H. In some embodiments, R7 and R8 each independently are chosen from the group formed by H, halogen, NR29R30, OR31, COOR32, C1-C6 alkyl, R29 to R32 are each independently chosen from among H, C1-C6 alkyl in particular a methyl, an aryl, in particular phenyl, and a cycloalkyl, in particular a cyclopropyl. Preferably, R7 and R8 are each independently NR29R30, R29 and R30 each independently being chosen from among H, C1-C6 alkyl, in particular a methyl, and a cycloalkyl, in particular a cyclopropyl. More preferably R7 is NH2 or NH-cyclopropyl, and R8 is NH2. In some preferred embodiments, the compound of formula (I) meets following formula (I-A): R7 (I-A) where L, R2, R5, R7 and R8 are as defined above. The compound of formula (I) is preferably chosen from among the following compounds: and the pharmaceutically acceptable, salts, solvates, enantiomers or tautomers thereof. 5 In particular, the compound of formula (I-A3) can be the enantiomer (I-A3-1) of following formula: (I-A3-1). The present invention also relates to the compound of formula (II), corresponding to the 10 oxidized form of the formula (I) compound: (II) a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, where: X- is a pharmaceutically acceptable anion chosen in particular from the group formed by PF6-, Cl-, Br-, I-, BF4-, (C1-C6alkyl)-C(O)O-, (C1-C6 alkyl halide)-C(O)O-, (C1-C6 alkyl)-SO3-,(C1-C6alkyl halide)-SO3-, SO42- and PO43-, L is a divalent radical derived from a C1-C12 aliphatic chain wherein 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 optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, an aryl, OH, NH2 and COOH, R1, R2, R3 and R4 are each independently chosen from a group formed by H, a halogen, NR9R10, OR11, COOR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an aryl, heteroaryl, heterocycle and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and cycloalkyl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR13, NR14R15 and COOR16, or R1 and R2, or R2 and R3, or R3 and R4, together with the carbon atoms to which they are bound, form an aryl, heteroaryl, heterocycle or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide OR17, NR18R19 and COOR20, R5 is a C1-C6 alkyl optionally substituted by one or more substituents chosen from the group formed by a halogen, OH, NH2 and COOH, R6 is H, halogen, NR21R22, OR23, COOR24, C1-C6 alkyl, a cycloalkyl, an aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR25, NR26R27 and COOR28, R7 and R8 are each independently chosen from the group formed by H, halogen, NR29R30, OR31, COOR32, C1-C6 alkyl, an aryl or heteroaryl, said alkyl, aryl, and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR33, NR34R35 and COOR36, and R9 to R36 are each independently chosen from H, C1-C6 alkyl, an aryl and a cycloalkyl. The formula (II) compound used in the present invention can be in the form of a stereoisomer or mixture of stereoisomers such as a mixture of enantiomers, diastereoisomers or tautomers, in particular a racemic mixture. In some embodiments the formula (II) compound can be in the form of an enantiomer having 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 formula (II) compound. In particular, in some preferred embodiments, the formula (II) compound meets following formula (II-A): (II-A) where X-, L, R2, R5, R7 and R8 are as defined above. The formula (II) compound is preferably chosen from among the following compounds: (II-A1), (II-A2), 10 (II-A3), where X is preferably a halogen, in particular |, and the pharmaceutically acceptable salts, solvates, enantiomers or tautomers thereof. In particular, the compound of formula (II-A3) can be the enantiomer (II-A3-1) of following formula: where X is preferably a halogen, in particular I. (II-A3-1), Method for preparing the compound of formula (I) The compound of formula (I), and the pharmaceutically acceptable salts, solvates, enantiomers or tautomers thereof, can be prepared with conventional methods known to skilled persons. In particular the formula (I) compound, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, can be obtained by regioselective reduction of the formula (II) compound: In some embodiments, regioselective reduction is conducted in the presence of sodium dithionite (Na2S2O4). The reduction reaction is particularly implemented in the presence of one or more suitable solvents such as water, acetonitrile, methanol, ethanol or mixtures thereof. The reduction reaction is preferably conducted at room temperature i.e. between 15°C and 30°C, for the time needed to obtain a satisfactory conversion rate. The preparation method of the formula (I) compound may particularly comprise prior synthesis of the formula (II) compound. The formula (II) compound can be obtained with conventional methods known to skilled persons. In particular, it can be prepared by reaction of a formula (III) compound with a formula (IV) compound: where R1 to R8 and X are as defined above, Lx and Lv are each independently a divalent radical derived from a C1-C12 aliphatic chain wherein 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 optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6, alkyl halide, an aryl, OH, NH2 and COOH, m and n are each 0 or 1, and R is OH and R’ is a leaving group, or R is a leaving group and R’ is a methyl. The formula (III) and (IV) compounds can be obtained with methods well known to skilled persons. It is understood that the preferred embodiments described for the formula (I) and (II) compounds in the present disclosure apply to the formula (III) and (IV) compounds. It is understood that when the formula (III) compound reacts with the formula (IV) compound, when 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 are each a component of fragment L as defined above for the formula (II) compound. It is understood that for coupling to be obtained between the formula (III) and (IV) compounds, only one thereof comprises a leaving group and the other comprises a function able to act on this leaving group (in particular in the presence of a base) to form the bond between the two compounds. The leaving group is particularly chosen from the group formed by halogen, preferably I, and the sulfonate ester group such as the mesylate or tosylate group. The reaction between the formula (III) and (IV) compounds is preferably performed in the presence of a base such as triethylamine, to form a nucleophilic species which will act on the compound carrying the leaving group. The reaction is preferably performed in a suitable solvent such as dichloromethane, dimethylformamide or acetonitrile. Preferably, it is conducted at room temperature. In particular, the formula (III) compound is 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide (when R’ is a methyl) or 2-iodomethyl-1-isopropyl-6-methoxy-quinolin-1-ium iodide (when R’ is a leaving group, here an iodine atom). In particular, the formula (IV) compound is abacavir (with R = OH), or abacavir wherein the OH function is tosylated (R is a leaving group). In the method for preparing a formula (I) compound, an intermediate compound obtained at the end of a reaction step, or the end compound obtained at the end of the reaction, can be separated from the reaction medium with methods well known to skilled persons, such as extraction, solvent evaporation or precipitation or crystallization (followed by filtration). Said compound can also be purified, if necessary, with methods well known in the prior art, such as recrystallisation, distillation, column chromatography (e.g. on silica gel) or high-performance liquid chromatography (HPLC). Pharmaceutical composition A further subject of the present invention is a pharmaceutical composition comprising a formula (I) compound as defined above, or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition of the invention can be formulated for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration intended for mammals including man. Posology varies according to treatment and the disorder under consideration. For administration via oral route, the pharmaceutical composition can be in solid or liquid form (solution or suspension). A solid composition can be in the form of tablets, gelatine capsules, powders, granules, etc. In tablets, the active ingredient can be mixed with one or more pharmaceutical vehicles such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic and others before being compressed. The tablets can be coated, in particular with sucrose and other suitable materials, or they can be treated to obtain delayed or extended release. For powders and granules, the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and with taste enhancers or sweeteners. For gelatine capsules, the active ingredient can be inserted in soft or hard gelatine capsules in powder or granule form as previously mentioned, or in the form of a liquid composition as mentioned below. A liquid composition can contain the active ingredient and a suitable sweetener, taste enhancer or colouring agent in a solvent such as water. The liquid composition can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It can be a syrup or elixir for example. For parenteral administration, the composition can be in the form of an aqueous suspension or solution which can contain suspending agents and / or wetting agents. The composition is advantageously sterile. It can be in the form of an isotonic solution (relative to blood). Therapeutic uses The present invention relates to a drug comprising a compound of the invention of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof. In other words, the present invention concerns a compound of the invention or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or a pharmaceutical composition of the invention for use thereof as a drug. The compounds of the invention, including their pharmaceutically acceptable salts, solvates, enantiomers or tautomers, are useful as inhibitors of organic cation transporters (OCTs). The subject of the present invention is therefore 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 use as OCT inhibitor. In other words, the subject of the present invention is the use of a compound of formula (I) or (II), or the pharmaceutical composition described above, as OCT inhibitor. In other words, the subject of the present invention is the use of a compound of formula (I) or (II), or of the pharmaceutical composition described above to prepare a drug acting as OCT inhibitor. The present invention also relates to a method for modulating the activity of OCTs in a patient in need thereof, in particularly a mammal and preferably a human, comprising the administration to the patient of an effective dose of a compound of the invention, or of a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or of 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 of the pharmaceutical composition of the invention, to prepare a drug for modulating the activity of OCTs in a patient in need thereof, in particular a mammal, and preferably a human. In particular, the present invention concerns a compound of the invention or a pharmaceutically acceptable salt, solvate enantiomer or tautomer thereof, or a pharmaceutical composition of the invention, for use thereof in the treatment or prevention of mood disorders, such as depressive disorders or anxiety disorders. In other words, the subject of the present invention is the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate enantiomer or tautomer thereof, or of 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 the treatment or prevention of mood disorders, such as depressive disorders or anxiety disorders, in a patient in need thereof, in particular a mammal and preferably a human, comprising the administration to the patient of an effective dose of a compound of the invention or of a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, or of the pharmaceutical composition of the invention. The invention also proposes 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 the administration to the patient of an effective dose of a compound of the invention or a pharmaceutically acceptable salt, solvate enantiomer or tautomer thereof, or a pharmaceutical composition of the invention. According to the disorder to be prevented or treated and the route of administration, the compound of the invention can in particular be administered in a single daily dose, in several daily doses or continuously administered e.g. by infusion. Examples 1) Synthesis 1.1) Material and methods The reagents used were supplied by Sigma-Aldrich (St. Louis, Missouri, United States) and used without any further purification, with the exception of 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide which was prepared in the laboratory following the method described in Orrico-Sanchez, 2020, doi: 10.1038 / s41380-019-0548-4. The chemical formulas, molecular formulas, calculations of molecular weight, monoisotopic mass (exact mass) were determined using ChemDraw Professional (PerkinElmer Informatics, Waltham, Massachusetts, USA). The software MestReNova (Mestrelab Research, S.L., Santiago de Compostela, Spain) was used to view, treat, analyze and report NMR spectra. The NMR spectra were recorded on Bruker Avance III NanoBay 300 and 400 spectrometers (using tetramethylsilane (TMS) as internal standard) at IPCM (Institut Parisien de Chimie Moleculaire). Chemical shifts 6 (ppm) were indirectly referenced against TMS via reference signals of the solvent. Silica gel plates, 60 F254 (Merck, Darmstadt, Germany) were used for Thin Layer Chromatography (TLC) of the products, monitoring of reactions and starting materials, with UV-VIS detection at 254 nm and 365 nm. A laboratory freeze dryer Christ Alpha 2-4 LD (Bioblock Scientific) was used for lyophilization. Data of mass spectrometry (MS) were measured at: Institut de biologie Paris-Seine (IBPS). 1.2) Synthesis of the compounds of the invention 1.2.1) Synthesis of abacacyanome (II-A1) a) Synthesis of the intermediate H2-QUIN Scheme 1. Synthesis of the intermediate H2-QUIN 6-methoxy-1-isopropylquinolin-1-ium iodide 6-methoxyquinolin (5 g, 31.40 mmol) was heated under reflux 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 the residue washed with Et2O to give the desired compound (9.4 g, 91%) in the form of a yellow solid; 1H-NMR (400 MHz, DMSO-d6) 6 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 (3M in DCM, 19.43 mL, 58.3 mmol) at 0 °C. The reaction mixture was left under agitation at this temperature for 1 h then 2 h at room temperature. Water was slowly added followed by a concentrated HCl solution until the formation of two layers, after which ammonium chloride was added and the solution made alkaline with ammonia. The organic layer was washed in water, dried over MgSO4 and vacuum concentrated to give dihydroquinoline (6.02 g), which was used directly at the following step without purification. The dihydroquinoline was heated under reflux 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-methylquinolin-1-ium iodide (9.2 g) with a yield of 88%; 1H-NMR (400 MHz, DMSO-d6) 5 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-methylquinolin-1-ium iodide 100 mg (0.29 mmol, 1 eq) was dissolved in 15 ml of dichloromethane (DCM), brown / yellow colour. After dissolution, the addition was made of about 90 pL (0.64 mmol, 2.2 eq) of triethylamine (TEA). The red / brown solution darkened and turned a brown / black colour. After five minutes, iodine was added at 74 mg (0.29 mmol, 1 eq). After 3 hours, 74 mg (0.29 mmol, 1 eq) of iodine were added. The reaction was left under agitation for 60 hours at room temperature. The mixture was purified as follows: the solvent was removed in vacuo (oily black / brown liquid). 5 ml of cyclohexane were added and the colour turned pink. The cyclohexane was removed after 1 hour and the remainder removed in vacuo. The reaction mixture was diluted with DCM (30 mL) and washed with NaCl sat. NaCl (2x20 mL). The solvent was removed in vacuo. TLC and the ninhydrin test revealed the presence of triethylammonium in water. The NMR spectrum still showed excess TEA. The reaction mixture was diluted with DCM (3 mL) and filtered on 1 cm silica gel, DCM / MeOH (1:0 ^ 95:5). In general, it is not necessary to purify the reaction product which is used for addition onto abacavir. b) Coupling to abacavir (II-A1) with X= I In a round-bottomed flask under argon fitted with a magnetic stir bar, abacavir (61 mg, 0.213 mmol), silver acetate (AgOAc) (2.13 mg, 12.8 pmol) and 1,2-bis(diphenylphosphino)ethane (dppe) (5.1 mg, 12.8 pmol) were added. Next, 0.64 mL of dimethylformamide (DMF) were added. The mixture was left under agitation at ambient temperature for 10 minutes then at -10°C. The addition was then made of H2-QUIN (0.1 g, 0.213 mmol) and LiHMDS (2.8 mg, 17 pmol). The reaction medium was left under these conditions for 8 hours until consuming of the reagents. Finally, according to thin layer chromatography, we performed separation of the fractions by column chromatography (Cyclohexane / EtOAc 7:3). 1H NMR (400 MHz, CDCI3,) 6 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). dissolved in 15 ml dichloromethane (DCM). After dissolution, about 41 pl (0.29 mmol, 1 eq) of triethylamine (TEA) were added. After five minutes, 70 mg (0.31 mmol, 1.1 eq) of N-iodosuccinimide (NIS) were added. The solution turned brown / black. After 10 minutes, the addition was made of 87 mg (0.25 mmol, 0.87 eq) abacavir sulfate. The reaction was left under agitation for 24 hours at ambient temperature. The reaction mixture was washed with saturated NaCl solution and saturated NH4Cl solution. The washed reaction mixture was vacuum concentrated and applied to a Preparative Layer Chromatography plate (PLC) (layer thickness 1 mm). The different layers were scraped. The silica gel powder was washed in DCM and MeOH (5%) and analysed by 1H NMR spectroscopy. The retention factor (Rf) of A2 was 0.26 on TLC with DCM / MeOH (95:5) The same reaction was then repeated with a greater amount (400 mg of 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide, 1.17 mmol). The reaction product was purified on silica gel column chromatography using the elution gradient: DCM / MeOH (1:0 ^ 95:5) to give 105 mg (yield 16%). 1H NMR (300 MHz, CD3CN) 5 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) 5 158.92, 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 1.2.3) Synthesis of compound (II-A3) (II-A3) with X=I, Tosylate chloride (51 mg, 0.27 mmol, 1 eq) was added dropwise under agitation at 0°C to a white suspension of abacavir sulfate (90 mg, 0.27 mmol, 1 eq) with TEA (about 75 pl, 0.54 mmol, 2.00 eq) in acetonitrile (ACN) (10 ml) since this solvent immediately dissolves TsCl contrary to DCM. The formed suspension was left under agitation at ambient temperature for 7 hours. Within three hours, the mixture was fully dissolved. 5 ml of cyclohexane and n-pentane were added. The solvents were removed after 1 hour to eliminate remaining tosylate chloride, and the remaining solvents were removed in vacuo. The product was analysed under 1HNMR spectroscopy which revealed the presence of abacavir tosylate. N, N-dimethylformamide (DMF) was added. The addition was then made of TEA (about 75 pl, 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). The reaction was left under agitation at 70°C for 17 hours. Toluene (20 ml) was added for easier removal of DMF, 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 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 vacuum concentrated then purified by silica gel chromatography. 1H NMR (300 MHz, MeOD) 5 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) h2n            (II-A3-1) with X = I Synthesis of the 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) were added PPh3 (207 mg, 0.79 mmol, 2.25 eq) and imidazole (48 mg, 0.7 mmol, 2 eq) at room temperature. After an agitation time of 5 minutes, I2 (170 mg, 0.67 mmol, 1.9 eq) was added. The reaction was left under agitation for 4h at room temperature after which NaHCO3 (84 mg, 1 mmol, 3 eq) and water were added to halt the reaction. The solvent was evaporated under reduced pressure and the reaction product was purified by flash chromatography (DCM / MeOH 9:1 to 6:4). The resulting compound was washed with toluene and the filtrate evaporated to give a pale yellow solid (yield <10%) 1H NMR (300 MHz, CDCI3) 5 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 the intermediate LP83: 1-isopropyl-6-methoxy-2-methylquinolin-1-ium An argon-purged round-bottomed flask was charged with methylmagnesium bromide solution (3M in ether, 600 pL, 2 mmol, 2 eq) cooled to 0°C, and a solution of 1-isopropyl-6-methoxyquinolin-1-ium iodide (330 mg, 1 mmol, 1 eq) was added in DCM (1 mL) for 5 min. The mixture was left under agitation at 0°C for 1h and then at room temperature for 2h. The reaction was cooled with water and DCM added. A 1N HCl solution (about 0.2 mL) was added followed by saturated NH4Cl and NH4OH solution until the pH reached about 10.5. The organic phase was separated, dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The resulting product was used without further purification, dissolved in EtOH (5 mL) with I2 (365 mg, 1.44 mmol, 1.5 eq) and heated under reflux for 15min. After leaving the reaction to cool to room temperature, Et2O was added and a brown solid was formed and washed with Et2O and EtOH. (yield = 83%) 1HNMR (300 MHz, DMSO) 5 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 round-bottomed flask, a solution of LP83 (34.3 mg, 0.1 mmol, 1 eq) in THF (1 mL) was cooled to -78°C. nBuLi (1.6 M in hexane, 63 pL, 0.1 mmol, 1 eq) was added dropwise to the solution. After 30 minutes, LP70 (50 mg, 0.13 mmol, 1.3 eq) dissolved in THF was added dropwise and the reaction mixture was left at room temperature overnight. The reaction was cooled with saturated NH4Cl solution. The solvent was evaporated and the resulting solid was dissolved in DCM; the organic phase was washed with water and brine, dried over MgSO4 and evaporated under reduced pressure. The compound was recrystallized from DCM / Et2O to give a black solid (yield = 4.6%) 1H NMR (300 MHz, CDCl3) 5 8.43 (s, 1H), 8.23 (s, 1H), 7.55 (d, J = 1.7 Hz, 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 modelling 2.1) Material and methods 3D modelling was performed on Discovery Studio software. The theoretical affinities of the compounds of the invention (II-A1) and (II-A3-1) for OCTs and alpha-adrenergic receptors were evaluated using a set of calibrations composed of ligands for which the affinity is described in the literature. Modelling was carried out with the following steps: 1. Search for models The models for the studied targets (adrenergic receptors and OCTs) were searched in the database of the National Center for Biotechnology Information (NCBI) using BLAST (“Basic local alignment search tool”). The models were classified according to 3 parameters: Query cover (percent sequence coverage), E-value (probability of relevant matching between sequences) and Per.ident (percent identity), the objective being to select those with the highest cover percentage, minimum E-value and best percent identity with the protein sequence to be modelled. Several models can be used simultaneously for optimal aligning of the sequence of a target protein. 2. Initial aligning and optimisation Discovery Studio directly displays the elements of the protein structure, including cocrystallized ligands. For the a-adrenergic receptors, it happens that the receptors are cocrystallized with agonists or antagonists. These crystals must be cleaned of the different nonrelevant molecules contained in the structures such as residual water molecules or stabilizers used for crystallization. Initially, the primary sequence of the model was directly compared in Discovery Studio software with the sequence of the target receptor obtained on NCBI. The option “Align Sequence and Structure” allowed the aligning of 2 or more sequences to obtain better percent identity. This step has to be performed manually for OCTs using models of D-xylose / proton symporters and the method for predicting transmembrane helices available on-line on TMHMM software, since the structuring of the membrane helices is better conserved than that of sequences. This method is effectively necessary having regard to the low percentages and coverage between OCTs and the potential models. The OCT helices which must be conserved when aligning were therefore aligned with the corresponding regions of the model. The alignment was optimised so that it could be used for homology modelling. The last step for optimising alignment comprises conservation of the disulfide brides between the model and the protein to be modelled. 3. Homology generation of models The models must be « prepared » before being used for homology generation of models. Preparation allows cleaning of the protein and correction of uncertainties and errors in selected structures: inserting missing atoms in incomplete residues, modelling missing loops, deleting alternative conformations and removing H2O molecules, verifying and correcting the protonation states of residues at desired pH. The prerequisites for homology-based generation of models are alignment of the primary sequence of the target protein with its model(s), and structuring of the « prepared » model with or without co-crystallized ligands. The protocol “Create Homology Models” available in Discovery Studio allows the generation of up to 50 different 3D models of the protein of interest, and the association with each model of an energy value representing the stability thereof. Their quality is therefore expressed by their PDF total energy (homology-derived pseudo-energy and stereochemical pseudo-energy) and their DOPE score (Discrete Optimized Protein Energy). The optimal model (having the lowest PDF energies and best DOPE score) is used for the anchoring step of the ligand in the receptor (docking). 4. Minimization For OCTs in particular, an additional minimization step is necessary to obtain an optimal 3D model, since it minimizes the energy of the ligand derived from the template. The positioning and orientation of the new 3D structure of the protein relative to an implicit membrane were optimised with the protocol “Add membrane and orient molecule” in Discovery Studio. Harmonic restraint was also applied to the backbone of the modelled protein. When prepared, the protein was minimized in 3 steps. First minimization used the tool “Smart Minimizer” at an RMS gradient (Root Mean Square) of 0.05. Next, a second minimization with the Newton-Raphson algorithm (NR) “Adopter Basis NR” was performed at an RMS gradient of 0.0001. Finally, minimization with NR was repeated without harmonic restraint. 5. Creation of the 3D structure, preparation et generation of ligand conformations The ligands were obtained in 2D with the software ChemDraw Professional, then transferred into Discovery Studio to generate their 3D structure. They were prepared following a protocol dedicated to small molecules, which allows consideration to be given to the different protonation states of the molecules at the given pH, deletion of duplicates, counting of isomers and tautomers, and generation of the 3D coordinates of the structures. The following step entailed 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 increased conformational coverage of the studied molecules. The maximum number of these conformers is limited to 225 conformations and these structures were used as such for the docking step i.e. anchoring of the ligands in the target proteins. 6. Anchoring of the ligand in the receptor (Docking step) With the CDOCKER function of Discovery Studio, it is possible to obtain docking of a certain number of ligands with a protein. The protein is held rigid while the ligand can be flexible. The ligand binding site (i.e. active ligand site) is determined by means of the co-crystallized ligands if any, as is the case for the adrenergic receptors via a sphere surrounding the binding site. The co-crystallized ligand is then replaced by the ligands to be examined. If there is no co-crystallized ligand in the model, a bibliographic search on the binding site is carried out. This is the case for OCT2 and OCT3. The search for residues involved in binding to specific ligands allows the position of the sphere of the binding site to be determined. Once docking is completed, the result of this step gives interaction poses between the ligand and the protein of interest, with interaction energy scoring. The most stable protein / ligand complexes were selected as a function of the interaction energy of each pose (the most negative) and the positioning of the ligands according to binding mode (interaction with key residues of the binding site: ionic bonds between the N+ atom of the ligands and negatively charged residues of the protein (Asp or Glu). The function “Analyze ligand poses” in Discovery Studio allowed identifying of these interactions and analysis of binding mode between the ligand and proteins for each complex. The ligand poses were subsequently re-evaluated and re-scored using scoring functions other than interaction energy by applying the function “Score ligand poses”. Functions such as LUDI, PLP, Ligscore, Jain and PMF take into account steric configuration, weak interactions (hydrogen bonds, Van der Waals), as well as free rotation bonds, polar bonds or lipophilic contact surfaces. 2.2) Results The results obtained are given in Figures 1A and 1B illustrating correlation curves between experimental pKi and virtual affinity of derivative (II-A1) for the adrenergic receptors ala (diamonds), alb (square) and aid (triangles) (Fig.lA) and for OCT2 and OCT3 (Fig.1B); and Figures 2A and 2B illustrating correlation curves between experimental pKi and virtual affinity of derivative (II-A3-1) for the adrenergic receptors a1a (diamonds), a1b (squares) and a1d (triangles) (Fig.2A), and for OCT2 and OCT3 (Fig.2B). Observations: With this predictive method, the hybrid abacacyanome derivatives (II-A1) and (II-A3-1) exhibit improved selectivity for OCTs and low affinity for the a1-adrenergic receptors in refined 3D models of OCTs and a1-adrenergic receptors. 3) Biological results 3.1) In vitro results The affinity of compound (II-A2) for various adrenergic receptors (ala / b / d and a2a / b / c) was evaluated by moving radioactive ligands into membrane preparations of CHO cells expressing recombinant human adrenergic receptors conforming to established methodologies (Amphoux et al., Eur J Pharmacol. 2010 ;634(1-3):1-9). The results indicate very low affinity of II-A2, compared to conventional ligands (Docherty, 2019, Eur J Pharmacol, 855:305-320), for all assayed receptors, as indicated in following Table 1: [Table 1] Targeted receptor IC50 (pM) Ki (pM) alpha1A(h) (radioligand) 200 99 alpha1B (h) (radioligand 100 28 alpha1D(h) (radioligand) 440 190 alpha2A(h) (radioligand) 280 130 alpha2B(h) (radioligand) 190 130 alpha2C(h) (radioligand) 290 94 IC50 and inhibition constant Ki of compound (II-A2) for alpha adrenergic receptors Determination of the affinity of compound II-A2 for a panel of adrenergic receptors indicates that it does not or only scarcely binds to a receptors, an important condition to prevent possible cardiovascular side effects. 3.2) In vitro results Method Inhibition of hOCT-mediated absorption and determination of IC50 For the inhibition assay of OCT absorption, CHO cells stably transfected with human OCT2 were incubated with the OCT2 substrate, fluorescent ASP+ (50 pM ASP+) at 37 °C. For determination of IC50, 8 concentrations of the assayed compounds ranging from 30pM to 3nM were added during pre-incubation and incubation. Accumulated fluorescent ASP+ in the cells was measured with an EnVision plate reader. To confirm specificity, the same dosage was also used after 15 minute pre-incubation time with a reference OCT2 inhibitor. Evaluation of the affinity of the compounds for human alpha1A, 2A and 2C adrenergic receptors, determined with a radioligand binding assay in transfected CHO cells For the human alpha lA-adrenergic receptor, homogenates of cell membranes (20 pg proteins) were incubated for 60 min at 22°C with 0.1 nM [3H]prazosin in the absence or presence of the compound to be assayed in a buffer containing 50 mM Tris-HCl (pH 7.4), 0.5 mM EDTA, 20 mg / l aprotinin and 0.01 % bacitracin. Non-specific binding was determined in the presence of 0.1 mM epinephrine. For the human alpha 2A-adrenergic receptor, homogenates of cell membranes (48 pg proteins) were incubated for 60 minutes at 22°C with 1 nM [3H]RX 821002 in the absence or presence of the compound to be assayed in a buffer containing 50 mM Tris-HCl (pH 7.4), 2 mM MgCl2 and 1 mM EDTA. Non-specific binding was determined in the presence of 100 pM (-)epinephrine. For the human alpha 2C-adrenergic receptor, homogenates of cell membranes (12 pg proteins) were incubated for 60 minutes at 22°C with 2 nM [3H]RX821002 in the absence or presence of the assayed compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 2 mM MgCl2 and 1 mM EDTA. For all the receptors, after incubation, the samples were quickly vacuum filtered on glass fibre filters (GF / B, Packard) pre-impregnated with 0.3 % PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-well cell harvester (Unifilter, Packard). The filters were dried and counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed in percent inhibition of specific binding of the control radioligand. The standard reference compound was WB 4101 (for the alpha 1A receptor) or yohimbine (for the alpha 2A and 2C receptors), which were assayed in each experiment at several concentrations to obtain a competitive curve from which IC50 was calculated. Results: assayed compound: II-A3-1 Targeted receptor Compound concentration (M) % inhibition alpha1A(h) (radioligand) 1.0E-06 20.2567 5.0E-06 68,0706 1.6.0E-05 95.8283 alpha2A(h) (radioligand) 1.0E-06 -1.54E+01 5.0E-06 12.3165 1.6.0E-05 28.639 alpha2C(h) (radioligand) 1.0E-06 11.2852 5.0E-06 44.7548 1.60E-05 88.4877 (II-A3-1) does not therefore have any relevant affinity for the adrenergic receptors 3.3) In vivo results Compound (II-A2) was assayed in a mouse behavioural despair model, the forced-swim test, to evaluate antidepressant action in comparison with a known antidepressant, fluoxetine (Prozac®) and a saline solution. Method: The forced-swim test allows evaluation of the potential efficacy of antidepressants in rodents. The animal is placed in a water vessel 1h 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 followed by the immobility time (indicating « despair behaviour ») were measured. The sooner the animal adopts despair behaviour, the longer the immobilization time. On the contrary, if the animal struggles longer than the control animal, this indicates antidepressant action of the received compound. Results: The results of the forced-swim test are given in Figure 2. The immobility time observed for compound (II-A2) is shorter than that observed in the control animal. It is slightly longer than that obtained with fluoxetine. However, the amount of fluoxetine injected was 90 times higher than that of compound (II-A2). Discussion: These preliminary experiments indicate a significant effect of a low dose of 5      compound (II-A2) in the forced-swim test, a conventional acute test for evaluating the action of antidepressants. Insofar as almost all conventional antidepressants display a significant effect in this acute test, these results demonstrate an antidepressant effect of abacacyanome and derivatives thereof.

Claims

1. A compound of following formula (I):(I),a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof,where:L is a divalent radical derived from a C1-C12 aliphatic chain wherein 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 optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, an aryl, OH, NH2 and COOH,R1, R2, R3 and R4 are each independently chosen from a group formed by H, a halogen, NR9R10, OR11, COOR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an aryl, heteroaryl, heterocycle and cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and cycloalkyl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR13, NR14R15 and COOR16,or R1 and R2, or R2 and R3, or R3 and R4, together with the carbon atoms to which they are bound, form an aryl, heteroaryl, heterocycle or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR17, NR18R19 and COOR20,R5 is a C1-C6 alkyl optionally substituted by one or more substituents chosen from the group formed by a halogen, OH, NH2 and COOH,R6 is H, halogen, NR21R22, OR23, COOR24, C1-C6 alkyl, a cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally being substituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR25, NR26R27 and COOR28,R7 and R8 are each independently chosen from the group formed by H, halogen, NR29R30, OR31, COOR32, C1-C6 alkyl, an aryl or heteroaryl, said alkyl, aryl and heteroaryl optionally beingsubstituted by one or more substituents chosen from the group formed by a halogen, C1-C6 alkyl, C1-C6 alkyl halide, OR33, NR34R35 and COOR36,R9 to R36 are each independently chosen from among H, C1-C6 alkyl, an aryl and cycloalkyl.

2. The compound of formula (I) according to claim 1, characterized in that it meets following formula (I-A):(I-A)where L, R2, R5, R7 and R8 are as defined in claim 1.

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

4. The compound of formula (I) according to any of claims 1 to 3, characterized in that R2 is chosen from a group formed by OH and O-(C1-C6 alkyl), in particular OCH3.

5. The compound of formula (I) according to any of claims 1 to 4, characterized in that R5 is a C1-C6 alkyl, in particular an isopropyl.

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

7. The compound of formula (I) according to any of claims 1 to 6, chosen from among the following compounds:(I-A2), and(I-A3).

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

9. A compound of following formula (II):(II)10a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof,where:X- is a pharmaceutically acceptable anion, chosen in particular from the group formed by PF6-, Cl-, Br-, I-, BF4-, (C1-C6 alkyl)-C(O)O-, (C1-C6 alkyl halide)-C(O)O-, (C1-C6 alkyl)-SO3-, (C1-C6 alkyl halide)-SO3-, SO42- and PO43-, andL and R1 to R8 are as defined in any of claims 1 to 7.

10. The compound of formula (II) according to claim 9, chosen from among the following compounds:(II-A1),(II-A2),(II-A3),10wherein X is preferably a halogen, in particular I.

11. The compound of formula (II) according to claim 9, meeting the following formula:(II-A3-1)wherein X is preferably a halogen, in particular I.1512. The compound of formula (I) according to any 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 of claims 9 to 11 or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, for use as a drug.

513. The compound of formula (I) according to any 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 of claims 9 to 11 or a pharmaceutically acceptable salt, solvate, enantiomer or tautomer thereof, for use in the 10 prevention or treatment of mood disorders such as depressive disorders or anxiety disorders.

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