Novel organic cation transporter inhibitors for the treatment of mood disorders

Abstract

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

Description

Title of the invention: Novel organic cation transporter inhibitors for the treatment of mood disorders FIELD OF THE INVENTION

[0001] 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

[0002] Mood disorders are 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 individuals' quality of life. They are associated with excess mortality, a high suicide risk and various comorbidities and, in addition to their effects on the individual level, have a considerable social and economic impact. The antidepressants used as first-line treatment for major depression are, for the most part, monoamine reuptake inhibitors, particularly serotonin (5-HT) and noradrenaline (NE). These conventional antidepressant treatments have important limitations, in particular a too long onset of action and unwanted side effects.Furthermore, they do not always yield 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 and a faster onset of action. Fast-acting compounds targeting glutamate (NMDA or mGlu2 / 3) receptors (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 about their actual efficacy in large cohorts, the persistence of effects over the long term, and their side effects still need to be addressed. The identification of new therapeutic avenues for depressive disorders therefore constitutes a major challenge for mental health research.

[0003] Previous studies by the inventors of the present invention have identified atypical organic cation transporters (OCTs) as novel 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.

[0004] 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 very 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).

[0005] The inventors recently demonstrated proof of concept that OCTs, including 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). Cyanome was evaluated via a molecular modeling approach as having better selectivity for OCTs, including OCT2, towards alpha adrenergic receptors compared to D24. The molecular modeling approach was validated by in vitro transport and binding experiments, assessing the affinity of cyanome to OCT2 and α-adrenergic receptors, respectively. In addition, cyanome was subsequently modified into a prodrug, H2-cyanome ([Fig.2]), to allow its passive diffusion in the brain parenchyma and its activation according to an oxidation-reduction mechanism. This prodrug, called H2-cyanome, has shown at low doses as good an efficacy as the classic antidepressant fluoxetine (Prozac) in a model of chronic depression in mice, with a more rapid action on anhedonia, one of the key symptoms of depression. However, the selectivity for OCTs compared to alpha-adrenergic receptors remains unsatisfactory. Indeed, although the affinity of H2-cyanome for a2 adrenergic receptors is low, H2-cyanome retains an affinity for . adrenergic receptors, which could be a source of unwanted side effects, particularly on blood pressure, heart rate or contractility.

[0006] 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 with respect to alpha-adrenergic receptors, in order to improve its efficacy and to limit side effects. Statement of the invention

[0007] The subject of the present invention is a compound of the following formula (I): R? (I),

[0008] a pharmaceutically acceptable salt, solvate or tautomer thereof,

[0009] wherein

[0010] L is a divalent radical derived from a CrCi2 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene group, -O-, -S-, -C(=O)-, -SO2- or -N(Ci-C6 alkyl)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, aryl, OH, NH2 and COOH,

[0011] R1, R2, R3 and R4 are independently selected from a group consisting of H, a halogen, NR9R10, OR11, COOR12, 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, OR13, NR14 R15 and COOR16,

[0012] or R1 and R2 or R2 and R3 or R3 and R4 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 selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR17, NR18 R19 and COOR20,

[0013] R5 represents C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH2 and COOH,

[0014] R6 represents H, halogen, NR21R22, OR23, COOR24, 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, OR25, NR26 R27 and COOR28,

[0015] R7 and R8 are independently selected from the group consisting of H, halogen, NR29R, OR, COOR, 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, OR33, NR34R35 and COOR36,

[0016] R9 to R36 are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] The subject of the present invention is a compound of the following formula (II): R? (H) <

[0021] a pharmaceutically acceptable salt, solvate or tautomer thereof,

[0022] wherein

[0023] X represents a pharmaceutically acceptable union, in particular chosen from the group consisting of PF6, Cl, Br, I, BF4, (C1-C6 alkyl)-C(O)O, (Cr-C6 haloalkyl)-C(O)O, (Cr-C6 alkyl)-SO3, (Cr-C6 haloalkyl)-SO3, SO42 and PO43, and

[0024] L and R1 to R8 are as defined above.

[0025] Other aspects of the invention are as described below. DESCRIPTION OF FIGURES

[0026] [Fig. 1 A] represents the correlation curves between the experimental pKi and the virtual affinity obtained by molecular modeling and docking of the a-adrenergic receptors al-AR (pKi abacacyanome>lmM): ala receptors (diamond), alb (square) and ald (triangle).

[0027] [Fig. IB] represents the correlation curves between the experimental pKi and the virtual affinity obtained by molecular modeling and docking of the OCT2 and OCT3 transporters (pki abacacyanome 6.9 and 7.2, respectively).

[0028] [Fig.2] represents the 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 INVENTION

[0029] Surprisingly, the inventors have developed new, more selective OCT inhibitors capable of easily crossing the blood-brain barrier. Definitions

[0030] The term "stereoisomer" as used herein 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.

[0031] The term "tautomer" designates constitutional isomers of the compound obtained by prototropy, that is to say 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.

[0032] In the context of the present invention, the formula (II') represented below is the tautomeric form of the formula (II):

[0033] The term "pharmaceutically acceptable" means that which is useful in the preparation of a pharmaceutical composition and that which is generally safe and non-toxic for pharmaceutical use.

[0034] The expression "pharmaceutically acceptable salt and / or solvate" designates, within the framework of the present invention, a salt and / or a solvate of a pharmaceutically acceptable compound, as defined above, and which possesses the pharmacological activity of the corresponding compound.

[0035] Pharmaceutically acceptable salts include:

[0036] 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, and

[0037] 2) base addition salts formed when an acid proton present in the 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.

[0038] Acceptable solvates for 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. For example, solvates due to the presence of water (these solvates are also called hydrates) or ethanol may be mentioned.

[0039] 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 the case present in the brain, and therefore increased activity in the brain for the corresponding active form.

[0040] The term “(CrCi2) aliphatic chain” denotes a saturated, linear or branched monovalent hydrocarbon chain comprising 1 to 12, in particular 1 to 6, carbon atoms. According to the invention, an aliphatic chain covers substituted or unsubstituted, linear or branched alkyl, alkenyl or alkynyl groups.

[0041] The term "(Ci-C6) alkyl" denotes a saturated, linear or branched monovalent hydrocarbon chain comprising 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups.

[0042] The term "(C2-C6) alkenyl" designates a monovalent, linear or branched hydrocarbon chain, comprising at least one double bond and comprising 2 to 6 carbon atoms. By way of example, mention may be made of ethenyl, propenyl, allyl, butenyl, pentenyl, or hexenyl groups.

[0043] The term "(C2-C6) alkynyl" designates a monovalent, linear or branched hydrocarbon chain, comprising at least one triple bond and comprising 2 to 6 carbon atoms. By way of example, mention may be made of ethynyl, propynyl, butynyl, pentynyl, or hexynyl groups.

[0044] The term “aryl” denotes an aromatic hydrocarbon group, preferably comprising from 6 to 10 carbon atoms, and comprising one or more fused rings, such as for example a phenyl or naphthyl group.

[0045] The term "heteroaryl" denotes an aromatic group comprising 5 to 10 cyclic 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 cyclic atoms being carbon atoms. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, imidazolyl groups, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl or even indyl.

[0046] The term "halogen" refers to the atoms of fluorine, chlorine, bromine and iodine.

[0047] The term “heterocycle” designates a cycle comprising from 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, 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.

[0048] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon chain, comprising 3 to 7 cyclic carbon atoms. A cycloalkyl may be monocyclic or bicyclic. Examples include cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl groups.

[0049] The term "(Cx-Cy) haloalkyl" denotes 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, mention may be made of the trifluoromethyl group (-CF3).

[0050] 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 invention

[0051] The present invention relates to a compound of formula (I) and a compound of formula (II) as described above.

[0052] 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 little or no inhibitory activity against OCTs. On the other hand, it has a better capacity for penetration into the brain parenchyma, better stability and bioavailability.

[0053] The active forms (oxidized forms of formula (II)) have a better affinity for OCT and a better selectivity for OCT over adrenergic receptors, compared to H2-cyanome.

[0054] An object of the present invention therefore relates to a compound of the following formula (I): A? (I), r NSÂ , R6-* Tr 'N Rs J R? X / N" XHS tyin R3 Y 'hT ''C' R4 Rs

[0055] a pharmaceutically acceptable salt, solvate or tautomer thereof,

[0056] wherein

[0057] 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 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,

[0058] R1, R2, R3 and R4 are independently selected from a group consisting of H, a halogen, NR9R10, OR11, COOR12, 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, OR13, NR14 R15 and COOR16,

[0059] or R1 and R2 or R2 and R3 or R3 and R4 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 selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR17, NR18 R19 and COOR20,

[0060] R5 represents a C1-C6 alkyl optionally substituted by one or more substituents chosen from the group consisting of a halogen, OH, NH2 and COOH,

[0061] R6 represents H, halogen, NR21R22, OR23, COOR24, 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, OR25, NR26 R27 and COOR28,

[0062] R7 and R8 are independently selected from the group consisting of H, halogen, NR29R, OR, COOR, 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, OR33, NR34R35 and COOR36, and

[0063] R9 to R36 are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl.

[0064] 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, in particular a racemic mixture.

[0065] In some embodiments, L is a divalent radical derived from a CrCi2 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.

[0066] Preferably, L is a 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 a C1-C6 alkyl, a C1-C6 haloalkyl, an aryl, OH, NH2 and COOH. More preferably, L is a C1-C6 alkylene, especially a C2-C3 alkylene, in which a methylene group is optionally replaced by -O-.

[0067] In some embodiments, R1, R2, R3 and R4 are independently selected from a group consisting of H, halogen, NR9R10, OR11, COOR12, 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, OR13, NR14R15 and COOR16, wherein R9 to R16 are independently selected from H, C1-C6 alkyl, aryl and cycloalkyl. Preferably, R1, R2, R3 and R4 are independently selected from a group consisting of H, C1-C6 alkyl, especially methyl, ethyl or isopropyl, phenyl, cyclopropyl, OH, O-(CrC6 alkyl), especially OCH3, COOH, COO-(C1-C6alkyl), especially COOMe, Cl, F, NH2, NH-(C1-C6alkyl), especially NHMe, and N(C1-C6alkyl)2, especially NMe2.

[0068] In certain preferred embodiments, R1, R3 and R4 are H and R2 is selected from a group consisting of halogen, NR9R10, OR11, COOR12, 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, OR13, NR14R15 and COOR16, wherein R9 to R16 are 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.

[0069] In other embodiments, R1 and R2 or R2 and R3 or R3 and R4 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being 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, C1-C6 alkyl, aryl and cycloalkyl. For example, R1 and R2 together with the carbon atoms to which they are attached form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being 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, 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 bonded an aryl ring optionally substituted by 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.

[0070] In some embodiments, R5 represents unsubstituted C1-C6 alkyl. In a preferred embodiment, R5 is isopropyl.

[0071] In certain embodiments, R6 represents H, Cl, F, OH, O-(Ci-C6 alkyl), in particular OCH3, COOH, COO-(Ci-C6 alkyl), in particular COOMe, NH2, NH-(Ci-C6 alkyl), in particular NHMe, N(CrC6 alkyl)2, in particular NMe2, C1-C6 alkyl, in particular methyl, ethyl or isopropyl, a phenyl or a cyclopropyl. Preferably, R6 is H.

[0072] In some embodiments, R7 and R8 are independently selected from the group consisting of H, halogen, NR29R30, OR31, COOR32, C1-C6 alkyl, R29 to R32 being independently selected from H, C1-C6 alkyl, especially methyl, aryl, especially phenyl, and cycloalkyl, especially cyclopropyl. Preferably, R and R independently represent NR R, R and R30 being independently selected from H, C1-C6 alkyl, especially methyl, and cycloalkyl, especially cyclopropyl. More preferably, R7 represents NH2 or NH-cyclopropyl and R8 represents NH2.

[0073] In certain preferred embodiments, the compound of formula (I) corresponds to the following formula (IA): R7 (IA)

[0074] wherein L, R2, R5, R7 and R8 are as defined above.

[0075] The compound of formula (I) is preferably chosen from the following compounds: (I-Al) NH

[0076] and pharmaceutically acceptable solvated salts or tautomers thereof.

[0077] The present invention also relates to the compound of formula (II), corresponding to the oxidized form of the compound of formula (I): R? (H) 6 N- -^ N MJ 1 .1 1 R* s'f" N" R4 R3 xe

[0078] a pharmaceutically acceptable salt, solvate or tautomer thereof,

[0079] wherein

[0080] X- represents a pharmaceutically acceptable anion, in particular chosen from the group consisting of PF6, Cl, Br, I, BF4, (C1-C6 alkyl)-C(O)O, (Cr-C6 haloalkyl)-C(O)O, (Cr-C6 alkyl)-SO3, (Cr-C6 haloalkyl)-SO3, SO42 and PO43,

[0081] L is a divalent radical derived from a CrCi2 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene group, -O-, -S-, -C(=O)-, -SO2 or -N(Ci-C6 alkyl)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, aryl, OH, NH2 and COOH,

[0082] R1, R2, R3 and R4 are independently selected from a group consisting of H, a halogen, NR9R10, OR11, COOR12, 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, OR13, NR14 R15 and COOR16,

[0083] or R1 and R2 or R2 and R3 or R3 and R4 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 selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR17, NR18 R19 and COOR20,

[0084] R5 represents a C1-C6 alkyl optionally substituted by one or more substituents chosen from the group consisting of a halogen, OH, NH2 and COOH,

[0085] R6 represents H, halogen, NR21R22, OR23, COOR24, C1-C6 alkyl, cycloalkyl, aryl or heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group

[0086]

[0087]

[0088]

[0089] consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR25, NR26 R27 and COOR28, R7 and R8 are independently selected from the group consisting of H, halogen, NR29R , OR , COOR , 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, OR33, NR34R35 and COOR36, and R9 to R36 are 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. 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) has the following formula (ILA): R? (II-A)

[0090]

[0091] in which X, L, R2, R5, R7 and R8 are as defined above. The compound of formula (II) is preferably chosen from the following compounds: (II-A1), 'NH HAS ' •• M (II-A2), (II-A3),

[0092] and pharmaceutically acceptable solvated salts or tautomers thereof. Method for preparing the compound of formula (I)

[0093] The compound of formula (I), as well as its pharmaceutically acceptable salts, solvates or tautomers, can be prepared according to conventional methods known to those skilled in the art.

[0094] In particular, the compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, may be obtained by the regioselective reduction of the compound of formula (II):

[0095] According to certain embodiments, the regioselective reduction is carried out in the presence of sodium dithionite (Na2S2O4).

[0096] The reduction reaction is notably carried out in the presence of one or more suitable solvents, such as water, acetonitrile, methanol, ethanol or mixtures thereof.

[0097] 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.

[0098] 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):

[0099] in which R1 to R8 and X are as defined above,

[0100] Lx and Lv independently represent 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 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,

[0101] m and n are each equal to 0 or 1, and

[0102] R represents OH and R' represents a leaving group or R represents a leaving group and R' represents methyl.

[0103] The compounds of formula (III) and (IV) can be obtained according to methods well known to those skilled in the art. It is understood that the preferred embodiments described for the compounds of formula (I) and (II) in the present disclosure apply to the compounds of formula (III) and (IV).

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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).

[0109] 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.

[0110] 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).

[0111] 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

[0112] 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.

[0113] 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.

[0114] For oral administration, the pharmaceutical composition may be in solid or liquid form (solution or suspension).

[0115] 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 tablet. 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 flavorings 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.

[0116] A liquid composition may contain the active ingredient together with a suitable sweetener, flavor enhancer or colorant 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.

[0117] 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

[0118] The present invention relates to a medicament comprising a compound of the invention, of formula (I) or (II), or a pharmaceutically acceptable salt, solvate or tautomer thereof, or a pharmaceutical composition of the invention.

[0119] In other words, the present invention relates to a compound of the invention or a pharmaceutically acceptable salt, solvate or tautomer thereof, or a pharmaceutical composition of the invention, for use as a medicament.

[0120] The compounds of the invention, including their pharmaceutically acceptable salts, solvates or tautomers, are useful as inhibitors of organic cation transporters (OCT).

[0121] The subject of the present invention is therefore a compound of the invention, of formula (I) or (II), or a pharmaceutically acceptable salt, solvate or tautomer thereof, or the pharmaceutical composition as described above, for its use as an OCT inhibitor.

[0122] In other words, the subject of the present invention is 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 subject of the present invention is 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.

[0123] The present invention also relates to a method of 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 or tautomer thereof, or the pharmaceutical composition of the invention.

[0124] In other words, the present invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, solvate 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.

[0125] In particular, the present invention relates to a compound of the invention or a pharmaceutically acceptable salt, solvate 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.

[0126] In other words, the subject of the present invention is the use of a compound of the invention or a pharmaceutically acceptable salt, solvate 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.

[0127] The present invention also relates to a method of 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 or tautomer thereof, or the pharmaceutical composition of the invention.

[0128] 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 or tautomer thereof, or the pharmaceutical composition of the invention.

[0129] 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) Synthesis 1.1) Materials and methods

[0130] The reagents used were supplied by Sigma-Aldrich (St. Louis, Missouri, USA) and used without further purification, except for l-isopropyl-6-methoxy-2-methylquinolin-l-ium iodide which was prepared in the laboratory according to the method described in Orrico-Sanchez, 2020, doi: 10.1038 / s41380-019-0548-4

[0131] Chemical formulas, summary formulas, molecular mass calculations, monoisotopic mass (exact mass) were determined using ChemDraw Professional (PerkinElmer Informatics, Waltham, Massachusetts, USA). MestReNova software (Mestrelab Research, SL, Santiago de Compostela, Spain) was used to visualize, process, analyze and report the NMR spectra.

[0132] NMR spectra were recorded on Bruker Avance III NanoBay 300 and 400 spectrometers (using trimethylsilane (TMS) as internal standard) at IPCM (Institut Parisien de Chimie Moléculaire). 5 chemical shifts (ppm) are related to TMS indirectly via the solvent reference signals.

[0133] 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 Institut de biologie Paris-Seine (IBPS). 1.2) Synthesis of the compounds of the invention 1.2.1) Synthesis of abacacyanome (II-A1)

[0134] a) Synthesis of the H2-QUIN intermediate

[0135] Diagram 1. S y nthesis of the H2-QUIN intermediate 6-methoxy-l-isopropylquinolin-l-ium odide

[0136] 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) ô 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. 6.5 Hz, CHCH3).

[0137] 1-isopropyl-6-methoxy-2-methylquinolin-l-ium odide PI

[0138] l-Isopropyl-6-methoxyquinolin-l-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 the dihydroquinoline (6.02 g), which was directly used for the next step without purification. Dihydroquinoline was refluxed in EtOH (40 mL) with iodine (9.6 g) for 15 minutes and then cooled to room temperature.The resulting residue was filtered and washed with EtOH and Et2O to obtain l-isopropyl-6-methoxy-2-methylquinoline-l-ium iodide (9.2 g) in 88% yield; 1H-NMR (400 MHz, DMSO-d6) ô 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). .

[0139] 2-(iodomethyl)-l-isopropyl-6-methoxyquinolin-l-ium iodide (H2-QUIN).

[0140] l-Isopropyl-6-methoxy-2-methylquinoline-l-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 the ninhydrin test revealed the presence of triethylammonium in water.The NMR spectrum always 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 that is used for addition to abacavir.

[0141] b) Coupling with abacavir .HAS •THERE. XNH I

[0142] 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 pmol) and 1,2-bis(diphenylphosphino)ethane (dppe) (5.1 mg, 12.8 pmol) 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 pmol) were added. The reaction medium is left under these conditions for 8 hours until the reagents are consumed. Finally, according to thin layer chromatography, we carried out a separation of the fractions by column chromatography (Cyclohexane / EtOAc 7:3).

[0143] 1 H NMR (400 MHz, CDC13,) ô 7.30-7.20 (m, 6H, aromatic), 6.82 (s, 1H, aromatique), 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). 1.2.2) Synthesis of composition (II-A2)

[0144] MeG.. (ILA2) A KAA "N M 7

[0145] 100 mg (0.29 mmol, 1 eq) d'iodure of l-isopropyl-6-méthoxy-2-méthylquinolin-l- ium were 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 in color. 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 in vacuo and applied to a preparative chromatography (PLC) plate (layer thickness 1 mm). The individual layers were scraped off. The silica gel powder was washed with DCM and MeOH (5%) and analyzed by 'H NMR spectroscopy. The retention factor (Rf) of A2 was 0.26 on TLC with DCM / MeOH (95:5)

[0146] The same reaction was then repeated with a larger amount (400 mg of l-isopropyl-6-methoxy-2-methylquinolin-l-ium iodide, 1.17 mmol). The crude product was purified by silica gel column chromatography using an elution gradient: DCM / MeOH (1:0 95:5) to give 105 mg (16% yield).

[0147] 1 H 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).

[0148] 13 C NMR (101 MHz, CDC13) ô 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.

[0149] MS and HRMS analyses were performed in MeOH:

[0150] MS (ESI+): m / z predicted for C25H30N7O: 445.25; found 445.24

[0151] HRMS (ESI+): m / z predicted for C25H30N7O: 445.2585; found 445.2484

[0152] HRMS (APCI): m / z predicted for C25H30N7O: 445.25; found 445.2475 1.2.3) Synthesis of compound (II-A3)

[0154] 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 in vacuo. The product was analyzed by 1H NMR spectroscopy, which revealed the presence of abacavir tosylate.

[0155] N,N-Dimethylformamide (DMF) was added. TEA (approximately 75 μl, 0.54 mmol, 2.00 eq), l-isopropyl-6-methoxy-2-methylquinolin-l-ium iodide (92 mg, 0.27 mmol, 1 eq) with DMF (3 mL) was added. The reaction was stirred at 70°C for 17 hours.

[0156] Toluene (20 ml) was added to more easily remove 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 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). During extraction, some of the product precipitated on the walls of the separating funnel. The precipitated product was dissolved in MeOH.

[0157] 1 H 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). 2) Molecular modeling 2.1) Materials and methods

[0158] The 3D modeling was carried out on the Discovery Studio software. The theoretical affinities of the compounds of the invention with OCTs and alpha-adrenergic receptors were evaluated using a standard range consisting of ligands whose affinity is described in the literature.

[0159] The modeling was carried out according to the following steps: 1. Search for models

[0160] 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”).

[0161] The models were classified according to 3 parameters: Query cover (percentage of sequence coverage), E-value (probability of relevant correspondence 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

[0162] Discovery Studio directly displays the elements of the protein structure, including co-crystallized ligands. In the case of a-adrenergic receptors, the receptors are sometimes co-crystallized with agonists or antagonists. These crystals must be cleaned of various irrelevant molecules present in structures such as residual water molecules or stabilizers used during crystallization.

[0163] First, the primary sequence of the model was compared directly in the Discovery Studio software to the target receptor sequence obtained on NCBI. The “Align Sequence 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 the alignment were therefore aligned to the corresponding regions of the model.

[0164] The alignment was then optimized for use in homology modeling. The final step in alignment optimization involves preserving disulfide bonds between the template and the protein to be modeled. 3. Generation of homology models

[0165] Models must be "prepared" before being used for homology model generation. Preparation allows cleaning the protein and correcting uncertainties and errors in the 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 the residues at the desired pH.

[0166] The prerequisites for the generation of 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 the 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 (pseudo-energy derived from homology and pseudo-stereochemical 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

[0167] For OCTs in particular, an additional minimization step is necessary to obtain an optimal 3D model because it allows the energy of the ligand from the template to be minimized.

[0168] The positioning and orientation of the new 3D protein structure relative to an implicit membrane were optimized by the “Add membrane and orient molecule” protocol in Discovery Studio. A harmonic constraint on the modeled protein backbone 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 (“Root Mean 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.

[0169] 5. Creation of the 3D structure, preparation and generation of the conformations of the ligand

[0170] The 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 the isomers and tautomers, to generate the 3D coordinates of the structures.

[0171] The next step consisted of generating 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.

[0172] 6. Anchoring of the ligand in the receptor (or Docking step)

[0173] Discovery Studio's CDOCKER function allows the anchoring of a 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 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.

[0174] 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 binding to specific ligands makes it possible to define the positioning of the binding site sphere.

[0175] Once the docking is carried out, 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 list the type of bond present between the ligand and the proteins for each complex.

[0176] Ligand poses were then re-evaluated and re-scored by other scoring functions than interaction energy through 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

[0177] The results obtained are illustrated in [Fig.lA] and IB which describe correlation curves between the experimental pKi and the virtual affinity of the derivative (ILA1) for the adrenergic receptors ala (diamonds) alb (squares) and ald (triangles) ([Fig.lA]) and OCT2 and 3 (Fig.b).

[0178] Observations:

[0179] According to this predictive method, the abacacyanome hybrid derivative (ILA1) exhibits improved selectivity for OCTs and low affinity for α1-adrenergic receptors in refined 3D models of OCTs and α1-adrenergic receptors. 3) Biological results 3.1) In vitro results

[0180] The affinity of the compound (ILA2) for various adrenergic receptors (ala / b / d and a2a / b / c) was evaluated by displacement of radioactive ligands in membrane preparations of CHO cells expressing recombinant human adrenergic receptors, according to established methodologies (Amphoux et al., Eur J Pharmacol. 2010;634(l-3):l-9).

[0181] The results indicate a very low affinity of ILA2, compared to classical ligands (Docherty, 2019, Eur J Pharmacol, 855:305-320), for all the receptors tested, as shown in the following Table 1:

[0182] [Tables 1] Targeted receptor IC50 (qM) Ki (qM) alpha lA(h) (radioligand) 200 99 alpha 1B (h) (radioligand) 100 28 alpha ID(h) (radioligand) 440 190 alpha2A(h) (radioligand) 280 130 alpha2B(h) (radioligand) 190 130 alpha2C(h) (radioligand) 290 94

[0183] IC50 and inhibition constant Ki of compound (II-A2) for alpha adrenergic receptors

[0184] Determination of the affinity of compound II-A2 for a panel of adrenergic receptors indicates that it does not bind or binds little to the a receptors, an important condition for avoiding possible cardiovascular side effects. 3.2) In vivo results

[0185] The compound (ILA2) was tested in a mouse resignation model, the forced swimming test, to evaluate its activity as an antidepressant in comparison with a known antidepressant, fluoxetine (Prozac®) and saline solution.

[0186] Method: The forced swimming test allows the potential efficacy of antidepressants in rodents to be assessed. The animal is placed in a tank of water for 1 hour after receiving an injection of the product (control: saline solution, fluoxetine (18 mg / kg) or ILA2 derivative (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.

[0187] Results: The results of the forced swimming test are illustrated in [Fig.2]. The immobility time observed for the compound (ILA2) 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 the compound (II-A2).

[0188] Discussion: These preliminary experiments indicate a significant effect of a low dose of the compound (ILA2) in the forced swimming 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

1. Claims Compound of the following formula (I): R* (I), , N ■ -À 7f 'N R! nA 4 „4 H' 'R8 R1 Rs a pharmaceutically acceptable salt, solvate or tautomer thereof, wherein L is a divalent radical derived from a CrCi2 aliphatic chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene group, -O-, -S-, -C(=O)-, -SO2 or -N(Ci-C6 alkyl)-, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, aryl, OH, NH2 and COOH, R1, R2, R3 and R4 are independently selected from a group consisting of H, halogen, NR9R10, OR11, COOR12, 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, OR13, NR14R15 and COOR16, or R and R or R and R or R and R together with the carbon atoms to which they are attached form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, being optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, OR17, NR18R19 and COOR20, R5 represents a C1-C6 alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, OH, NH2 and COOH, R6 represents H, halogen, NR21R22, OR23, COOR24, 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, OR25, NR26R27 and COOR28, R7 and R8 are independently selected from the group consisting of H, halogen, NR29R30, OR31, COOR32, 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, OR33, NR34R35 and COOR36, R9 to R36 are independently selected 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): (IA) N. N Rs U 1 O R5 in which L, R2, R5, R7 and R8 are as defined in claim 1.

3. Compound of formula (I) according to claim 1 or 2, characterized in that L is a C1-C6, in particular 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-(Ci-C6 alkyl), in particular OCH3.

5. Compound of formula (I) according to any one of claims 1 to 4, characterized in that R5 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 represent NR R , R and R being independently chosen from

7. H, a Cr-C6 alkyl, in particular a methyl, and a cycloalkyl, in particular a cyclopropyl. Compound of formula (I) according to any one of claims 1 to 6, chosen from the following compounds: A (i-ad (I-A3).

8.

9. 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 or tautomer thereof, and a pharmaceutically acceptable excipient. Compound of the following formula (II): A (il) a pharmaceutically acceptable salt, solvate or tautomer thereof, in which X- represents a pharmaceutically acceptable anion, in particular chosen 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, and L and R1 to R8 are as defined in any one of claims 1 to 7.

10. Compound of formula (II) according to claim 9, chosen from following compounds:

11.

12. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or tautomer thereof, a pharmaceutical composition according to claim 8 or a compound of formula (II) according to claim 9 or 10, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use as a medicament. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or tautomer thereof, a pharmaceutical composition according to claim 8 or a compound of formula (II) according to claim 9 or 10, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use as a medicament. claim 8 or a compound of formula (II) according to claim 9 or 10, or a pharmaceutically acceptable salt, solvate or tautomer thereof, for use in the prevention or treatment of mood disorders, such as depressive disorders or anxiety disorders.

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