New inhibitors of organic cation transporters 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 drug for the prevention and / or treatment of mood disorders, such as depressive or anxiety disorders.

Description

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

[0001] The present invention relates to novel abacacyanom derivatives, as well as their pharmaceutically acceptable solvated or tautomeric salts. 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 and anxiety disorders. STATE OF THE ART

[0002] Mood disorders are widespread and debilitating 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, significantly impact individuals' quality of life. They are associated with increased mortality, a high risk of suicide, and various comorbidities, and, in addition to their individual effects, have a considerable social and economic impact. The antidepressants used as first-line treatment for major depression are mostly monoamine reuptake inhibitors, particularly of serotonin (5-HT) and norepinephrine (NE). These conventional antidepressant treatments have significant limitations, particularly a long onset of action and undesirable side effects.Furthermore, they do not always produce positive results, and approximately one-third of patients do not respond satisfactorily to treatment. Therefore, there is a pressing need for medications that combine greater efficacy with a faster onset of action. Rapid-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 regarding their actual efficacy in large cohorts, the persistence of their effects over the long term, and their side effects still need to be addressed. Identifying new therapeutic approaches for depressive disorders is therefore 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, norepinephrine) 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 the efficacy of antidepressants (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 monoamine clearance system, complementing classical high-affinity reuptake transporters (Figure 1). Dopamine reuptake transporters (DAT), serotonin reuptake transporters (SERT) and norepinephrine reuptake transporters (NET) are responsible for clearing monoamines released from the extracellular space and recycling them into the terminals of neurons, and are the main targets of conventional antidepressants (SSRSs 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, particularly 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 using a molecular modeling approach as having greater selectivity for OCTs, particularly OCT2, at alpha-adrenergic receptors compared to D24. The molecular modeling approach was validated by in vitro transport and binding experiments, evaluating the affinity of cyanome for OCT2 and alpha-adrenergic receptors, respectively. In addition, cyanobacteria was subsequently modified into a prodrug, H2-cyanobacteria ([Fig.2]), to allow its passive diffusion into the brain parenchyma and its activation via a redox mechanism. This prodrug, called H2-cyanome, has shown at low doses to be as effective as the classic antidepressant fluoxetine (Prozac) in a mouse model of chronic depression, with a faster action on anhedonia, one of the key symptoms of depression. However, its selectivity for OCTs compared to alpha-adrenergic receptors remains unsatisfactory. Indeed, although the affinity of H2-cyanome for α2-adrenergic receptors is low, H2-cyanome retains an affinity for . adrenergic receptors al, which could be a source of undesirable side effects, particularly on blood pressure, heart rate or contractility.

[0006] A need therefore remains for an OCT inhibitor compound, in particular of OCT2 and OCT3, useful in the treatment of mood disorders, such as depressive disorders and anxiety disorders, which is more selective of OCTs, in particular with respect to alpha-adrenergic receptors, in order to improve its efficacy and to limit side effects. Description of the invention

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

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

[0009] in which

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

[0011] R1, R2, R3 and R4 are independently chosen from a group consisting of H, a halogen, NR9R10, OR11, COOR12, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, an aryl, a heteroaryl, a heterocyclyl and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a C1-C6 alkyl, a 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, optionally being substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18 R19 and COOR20,

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

[0014] R6 represents H, halogen, NR21R22, OR23, COOR24, a C1-C6 alkyl, a cycloalkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR25, NR26 R27 and COOR28,

[0015] R7 and R8 are independently chosen from the group consisting of H, halogen, NR29R, OR, COOR, a Ci-C6 alkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Cr C6 haloalkyl, OR33, NR34R35 and COOR36,

[0016] R9 to R36 are independently chosen from H, a Ci-C6 alkyl, an aryl and a 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 drug.

[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 present invention relates to a compound of the following formula (II): R? (H) <

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

[0022] in which

[0023] X represents a pharmaceutically acceptable union, in particular chosen from the group consisting of PF6, Cl, Br, I, BF4, (Ci-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 THE 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 α-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 (abacacyanome pki 6.9 and 7.2, respectively).

[0028] [Fig. 2] represents the immobility time observed in the forced swim test of mice administered intraperitoneally with 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 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" used in the present invention refers to configurational stereoisomers and, more particularly, to optical isomers. Optical isomers that are not mirror images of each other are called "diastereoisomers," and optical isomers that are non-superimposable mirror images are called "enantiomers." An equimolar mixture of two enantiomers of a chiral compound is called a racemic or racemate mixture.

[0031] The term "tautomer" refers to constitutional isomers of the compound obtained by prototropy, that is, by migration of a hydrogen atom and a change in the location of at least one double bond. The different tautomers of a compound are generally interconvertible and present in equilibrium in solution, in proportions that may vary depending on the solvent used, the temperature, or the pH.

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

[0033] The term "pharmaceutically acceptable" means what is useful for the preparation of a pharmaceutical composition and what 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 similar acids, and

[0037] 2) the base addition salts formed when an acidic 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] Solvates acceptable 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. By way of example, solvates due to the presence of water (these solvates are also called hydrates) or ethanol may be cited.

[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 can offer numerous advantages over their corresponding active forms, such as improved stability, bioavailability, and penetration into the body, in this case into the brain, thus increasing brain activity for the corresponding active form.

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

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

[0042] The term "alkenyl (C2-C6)" refers to a monovalent, linear or branched hydrocarbon chain comprising at least one double bond and having 2 to 6 carbon atoms. Examples include ethenyl, propenyl, allyl, butenyl, pentenyl, and 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. Examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.

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

[0045] The term "heteroaryl" designates an aromatic group comprising 5 to 10 cyclic atoms, one or more of which are 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, and 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 4 to 10 cyclic atoms, saturated or unsaturated, but non-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. These may include, in particular, the pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, imidazolidinyl, azepanyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, thiazepanyl, and benzimidazolonyl groups.

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

[0049] The term “haloalkyl (Cx-Cy)” refers to an (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. An example is the trifluoromethyl (-CF3) group.

[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] Compound of formula (I) corresponds to the reduced form of compound of formula (II). Compound of formula (II) corresponds to the active form in vivo, and compound of formula (I) corresponds to the corresponding prodrug, which is capable of readily diffusing into the brain parenchyma and being activated there by oxidation. The prodrug itself has little or no inhibitory activity against OCTs. However, it possesses improved penetration into the brain parenchyma, as well as greater stability and bioavailability.

[0053] The active forms (oxidized forms of formula (II)) have a better affinity for OCTs and a better selectivity for OCTs compared to 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] in which

[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, -O-, -S-, -C(=O)-, -SO2- or -N(Ci-C6 alkyl)- group, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, an aryl, OH, NH2 and COOH,

[0058] R1, R2, R3 and R4 are independently chosen from a group consisting of H, a halogen, NR9R10, OR11, COOR12, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, an aryl, a heteroaryl, a heterocyclyl and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a C1-C6 alkyl, a 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, optionally being substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18 R19 and COOR20,

[0060] R5 represents a Ci-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, a Ci-C6 alkyl, a cycloalkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR25, NR26 R27 and COOR28,

[0062] R7 and R8 are independently selected from the group consisting of H, halogen, NR29R, OR, COOR, a Ci-C6 alkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more selected substituents in the group consisting of a halogen, a Ci-C6 alkyl, a Cr-C6 haloalkyl, OR33, NR34R35 and COOR36, and

[0063] R9 to R36 are independently chosen from H, a Ci-C6 alkyl, an aryl and a 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, diastereomers or tautomers, in particular a racemic mixture.

[0065] In some embodiments, L is a divalent radical derived from an aliphatic CrCi2 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 chosen from the group consisting of a Ci-C6 alkyl, a Ci-C6 haloalkyl, an 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 Ci-C6 alkyl, a Ci-C6 haloalkyl, an aryl, OH, NH2, and COOH. More preferably, L is a Ci-C6 alkylene, particularly in the C2-C3 position, in which a methylene group is optionally replaced by -O-.

[0067] In certain embodiments, R1, R2, R3 and R4 are independently chosen from a group consisting of H, a halogen, NR9R10, OR11, COOR12, a Ci-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, an aryl, a heteroaryl, a heterocyclyl and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR13, NR14R15 and COOR16, R9 to R16 being independently chosen from H, a Ci-C6 alkyl, an aryl and a cycloalkyl. Preferably, R1, R2, R3 and R4 are independently selected from a group consisting of H, Ci-C6 alkyl, in particular methyl, ethyl or isopropyl, phenyl, cyclopropyl, OH, O-(Cr C6 alkyl), in particular OCH3, COOH, COO-(Ci-C6 alkyl), in particular COOMe, Cl, F, NH2, NH-(Ci-C6 alkyl), in particular NHMe, and N(Ci-C6 alkyl)2, in particular NMe2.

[0068] In some preferred embodiments, R1, R3 and R4 are H and R2 is selected from a group consisting of a halogen, NR9R10, OR11, COOR12, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, an aryl, a heteroaryl, a heterocyclyl and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR13, NR14R15 and COOR16, R9 to R16 being independently selected from H, a Ci-C6 alkyl, an aryl and a cycloalkyl. More preferably, R1, R3, and R4 are H, and R2 is chosen from a group consisting of Ci-C6 alkyls, in particular methyl, ethyl, or isopropyl, phenyl, cyclopropyl, OH, O-(Ci-C6 alkyl), in particular OCH3, COOH, COO-(Ci-C6 alkyl), in particular COOMe, Cl, F, NH2, NH-(Ci-C6 alkyl), in particular NHMe, and N(Ci-C6 alkyl)2, in particular NMe2. Even more preferably, R1, R3, and R4 are H, and R2 is chosen from a group consisting of OH and O-(Ci-C6 alkyl), in particular 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, optionally being substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18R19 and COOR20, R17 to R20 being independently chosen from H, a Ci-C6 alkyl, an aryl and a cycloalkyl. For example, R1 and R2 together with the carbon atoms to which they are bonded form an aryl, heteroaryl, heterocyclyl or cycloalkyl ring, optionally being substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18R19 and COOR20, R17 to R20 being independently chosen from H, a Ci-C6 alkyl, an aryl and a cycloalkyl, and R3 and R4 are H.More specifically, R1 and R2 can together with the carbon atoms to which they are bonded form an aryl ring optionally substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18R19 and COOR20, R17 to R20 being independently chosen from H and a Ci-C6 alkyl, and R3 and R4 are H.

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

[0071] In some 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, Ci-C6 alkyl, in particular methyl, ethyl or isopropyl, a phenyl or a cyclopropyl. Preferably, R6 is H.

[0072] In certain embodiments, R7 and R8 are independently selected from the group consisting of H, halogen, NR29R30, OR31, COOR32, a Ci-C6 alkyl, R29 to R32 being independently chosen from H, a C6-alkyl group, in particular a methyl group, an aryl group, in particular a phenyl group, and a cycloalkyl group, in particular a cyclopropyl group. Preferably, R and R represent independently of each other NR R, R and R30 being independently chosen from H, a C6-alkyl group, in particular a methyl group, and a cycloalkyl group, in particular a cyclopropyl group. More preferably, R7 represents NH2 or NH-cyclopropyl and R8 represents NH2.

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

[0074] in which 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 with formula (I): R? (H) 6 N- -^ N MJ 1.11 R* s'f" N" R4 R3 xe

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

[0079] in which

[0080] X- represents a pharmaceutically acceptable anion, in particular chosen from the group consisting of PF6, Cl, Br, I, BF4, (alkyl in Ci-C6)-C(O)O, (haloalkyl in Cr C6)-C(O)O, (alkyl in CrC6)-SO3, (haloalkyl in CrC6)-SO3, SO42 and PO43,

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

[0082] R1, R2, R3 and R4 are independently chosen from a group consisting of H, a halogen, NR9R10, OR11, COOR12, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, an aryl, a heteroaryl, a heterocyclyl and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a C1-C6 alkyl, a 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, optionally being substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18 R19 and COOR20,

[0084] R5 represents a Ci-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, a Ci-C6 alkyl, a cycloalkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group

[0086]

[0087]

[0088]

[0089] consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR25, NR26, R27 and COOR28, R7 and R8 are independently chosen from the group consisting of H, halogen, NR29R , OR , COOR , a Ci-C6 alkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Cr C6 haloalkyl, OR33, NR34R35 and COOR36, and R9 to R36 are independently chosen from H, a Ci-C6 alkyl, an aryl and a 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, diastereomers 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 some preferred embodiments, the compound of formula (II) corresponds to the following (ILA) formula: 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 solvated or tautomer salts, 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 solvated or tautomeric salt thereof, can be obtained by the regioselective reduction of the compound of formula (II):

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

[0096] The reduction reaction is carried out in particular 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 include the prior synthesis of the compound of formula (II). The compound of formula (II) may be obtained by 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, -O-, -S-, -C(=O)-, -SO2 or -N(Ci-C6 alkyl)- group, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, an 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 a methyl.

[0103] The compounds of formula (III) and (IV) can be obtained by 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 this 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=l or m=l 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 in order for the coupling to take place between the compounds of formula (III) and (IV), only one of them includes a leaving group and the other includes 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 the halogen, preferably I, and the sulfonate ester group such as the mesylate or tosylate group.

[0107] The reaction between 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 l-isopropyl-6-methoxy-2-methylquinolin-l-ium iodide (when R' is a methyl) or 2-iodomethyl-l-isopropyl-6-methoxy-quinolin-l-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 of 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, solvent evaporation 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 can be formulated for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local, or rectal administration in mammals, including humans. The dosage varies depending on the treatment and the condition involved.

[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 vehicles such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, and others before being Tablets. Tablets may be coated, in particular with sucrose or other suitable materials, or they may be treated to provide prolonged or delayed action. In powders or granules, the active ingredient may be mixed or granulated with dispersing agents, wetting agents, or suspending agents, and with flavor enhancers or sweeteners. In gelatin capsules, the active ingredient may be incorporated into soft or hard gelatin capsules in the form of a powder or granules as described above, or in the form of a liquid composition as described below.

[0116] A liquid composition may contain the active ingredient as well as a suitable sweetener, flavor enhancer, or color 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 a suspension or an aqueous 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 medicinal product comprising a compound of the invention, of formula (I) or (II), or a pharmaceutically acceptable solvated or tautomeric salt 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 solvated or tautomeric salt thereof, or a pharmaceutical composition of the invention, for use as a drug.

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

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

[0122] In other words, the present invention relates to the use of a compound of formula (I) or (II), or the pharmaceutical composition as described above, as an OCT inhibitor. In further terms, the present invention relates to the use of a compound of formula (I) or (II), or the pharmaceutical composition as described above, for the preparation of a drug acting as an OCT inhibitor.

[0123] The present invention also relates to a method of modulating OCT activity in a patient in need, in particular a mammal, and preferably a human, comprising administering to the patient an effective dose of a compound of the invention, or of a pharmaceutically acceptable solvated or tautomeric salt thereof, or of the pharmaceutical composition of the invention.

[0124] In other words, the present invention relates to the use of a compound of the invention, or of a pharmaceutically acceptable solvated or tautomeric salt thereof, or of the pharmaceutical composition of the invention, for the preparation of a drug to modulate the activity of OCTs in a patient in need of it, 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 solvated or tautomeric salt 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 present invention relates to the use of a compound of the invention or a pharmaceutically acceptable solvated or tautomeric salt 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 or anxiety disorders, in a patient in need, in particular a mammal, and preferably a human, comprising administering to the patient an effective dose of a compound of the invention, or of a pharmaceutically acceptable solvated or tautomeric salt thereof, or of the pharmaceutical composition of the invention.

[0128] The invention also proposes a method for delaying the onset of mood-related disorders, such as depressive and anxiety disorders, in a patient in need, in particular a mammal, and preferably a human, comprising administering to the patient an effective dose of a compound of the invention, or of a pharmaceutically acceptable solvated or tautomeric salt thereof, or of 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 can in particular be administered as a single daily dose, in several daily doses or administered continuously, for example by means of an infusion. Examples 1) Summary 1.1) Materials and methods

[0130] The reagents used were supplied by Sigma-Aldrich (St. Louis, Missouri, USA) and used without further purification, with the exception of 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, and 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] The NMR spectra were recorded on the Bruker Avance III NanoBay 300 and 400 spectrometers (using trimethylsilane (TMS) as an internal standard) at the IPCM (Institut Parisien de Chimie Moléculaire). The chemical shifts (ppm) are related to TMS indirectly via the solvent reference signals.

[0133] Silica gel plates 60 F254 (Merck, Darmstadt, Germany) were used for thin-layer chromatography (TLC) of the products, reaction control, 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 iodide

[0136] 6-Methoxyquinoline (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 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 iodide

[0138] I-isopropyl-6-methoxyquinolin-1-ium iodide (10 g, 29.15 mmol) was added for 5 min to a MeMgBr solution (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 for 2 h at room temperature. Water was added slowly, followed by concentrated HCl until two layers formed. Ammonium chloride was then added, and the solution was made alkaline with ammonia. The organic layer was washed with water, dried over MgSO4, and concentrated under vacuum to give dihydroquinoline (6.02 g), which was used directly for the next step without purification. 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 l-isopropyl-6-methoxy-2-methylquinoline-l-ium iodide (9.2 g) with a yield of 88%; 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 (H2-QUIN) odide.

[0140] 100 mg (0.29 mmol, 1 eq) of l-isopropyl-6-methoxy-2-methylquinoline iodide was dissolved in 15 mL of yellow-brown dichloromethane (DCM). After dissolution, approximately 90 µL (0.64 mmol, 2.2 eq) of triethylamine (TEA) were added. The reddish-brown solution darkened to a brownish-black color. After five minutes, 74 mg (0.29 mmol, 1 eq) of iodine was added. After three hours, another 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 under vacuum (black-brown oily liquid). Five mL of cyclohexane was added, which turned pink. The cyclohexane was removed after one hour, and the remaining solution was removed under vacuum. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaCl (2 x 20 mL). The solvent was removed under vacuum. TLC and the ninhydrin test revealed the presence of triethylammonium in the water.The NMR spectrum still shows an excess of TEA. The reaction mixture was diluted with DCM (3 mL) and filtered through a 1 cm DCM / MeOH silica gel (1:0 → 95:5). Generally, it is not necessary to purify the crude product used for the addition to abacavir.

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

[0142] In an argon-filled flask 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. Next, H2-QUIN (0.1 g, 0.213 mmol) and LiHMDS (2.8 mg, 17 pmol) were added. The reaction mixture was left under these conditions for 8 hours until the reactants were 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 was dissolved in 15 mL of dichloromethane (DCM). After dissolution, approximately 41 µL (0.29 mmol, 1 eq) of triethylamine (TEA) was added. After five minutes, 70 mg (0.31 mmol, 1.1 eq) of N-iodosuccinimide (NIS) was added. The solution turned a dark brown 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 and saturated NH4Cl solutions. The washed reaction mixture was concentrated under vacuum and applied to a preparative chromatography (PLC) plate (1 mm layer thickness). The individual layers were scraped off. The silica gel powder was washed with DCM and MeOH (5%) and analyzed by ¹H 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 quantity (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 a gradient elution: DCM / MeOH (1:0 95:5) to give 105 mg (yield 16%).

[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 = 9.3Hz, 1H), 7.67 (d, J = 3.0Hz, 1H), 7.45 (d, J = 4.2Hz, 1H), 7.41 (d, J = 2.9Hz, 1H), 7.38 (d, J = 2.9Hz, 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 under 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 resulting 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 eliminate the remaining tosylate chloride, and the remaining solvents were removed under vacuum. The product was analyzed by 1H NMR spectroscopy, which revealed the presence of abacavir tosylate.

[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) were added. The reaction was stirred at 70°C for 17 hours.

[0156] Toluene (20 mL) was added to facilitate the removal of DMF, and the solvents were removed under vacuum. 5 mL of cyclohexane and n-pentane were added. The solvents were removed after 4 hours, and the remainder was removed under vacuum. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaCl and saturated NH4Cl solutions (2 x 20 mL). During extraction, some of the product precipitated onto the walls of the separatory 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 using Discovery Studio software. The theoretical affinities of the compounds of the invention with OCTs and alpha-adrenergic receptors were evaluated using a standard curve consisting of ligands whose affinity is described in the literature.

[0159] The modeling was carried out according to the following steps: 1. Model search

[0160] The models for the targets studied (adrenergic receptors and OCT) were searched in the database of the National Center for Biotechnology Information (NCBI) by BLAST (“Basic local alignment search tool”).

[0161] The models were ranked according to three parameters: Query cover (percentage of sequence coverage), E-value (probability of relevant sequence matching), and Per.ident (percentage of identity). The objective was to select those with the highest percentage of coverage, the lowest 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 target protein sequence. 2. Initial alignment and optimization

[0162] Discovery Studio directly displays the elements of the protein structure, including co-crystallized ligands. In the case of α-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] Initially, the primary sequence of the model was directly compared in Discovery Studio software to the target receptor sequence obtained from NCBI. The “Align Sequence and Structure” option allowed for the alignment of two or more sequences to obtain a higher percentage of identity. This step must be performed manually for OCTs using D-xylose / proton symporter models and the transmembrane helix prediction method available online in the TMHMM software, as the structures of membrane helices are better conserved than sequences. Indeed, this method is necessary given the low percentages and overlap between the OCTs and the potential models. The OCT helices that must be preserved during alignment were therefore aligned to the corresponding regions of the model.

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

[0165] The models must be "prepared" before being used for model generation by homology. Preparation allows the protein to be cleaned up and uncertainties and errors in the selected structures to be corrected: inserting missing atoms into incomplete residues, modeling missing loops, removing alternative conformations and eliminating H2O molecules, and verifying and correcting the protonation states of the residues at the desired pH.

[0166] The prerequisites for generating homology models are the alignment of the primary sequence of the target protein with its model(s), as well as the structure of the "prepared" model with or without co-crystallized ligands. The "Create Homology Models" protocol available in Discovery Studio allows the generation of up to 50 different 3D models of the protein of interest and the association of each model with an energy value representing its stability. Their quality is thus expressed by their PDF energies (pseudo-homology-derived energy and stereochemical pseudo-energy) and their DOPEscore (Discrete Optimized Protein Energy). The optimal model (with the lowest PDF energies and the best DOPEscore) will be used for the ligand docking step. 4. Minimization

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

[0168] The positioning and orientation of the new 3D protein structure relative to an implicit membrane were optimized using the “Add membrane and orient molecule” protocol in Discovery Studio. A harmonic constraint on the modeled protein backbone was also applied. Once prepared, the protein was minimized in three steps. First, minimization was performed using the “Smart Minimizer” tool at an RMS (Root Mean Square) gradient of 0.05. Second, minimization was performed using the Newton-Raphson (NR) algorithm “Adopter Basis NR” at an RMS gradient of 0.0001. Finally, the NR minimization was repeated without 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 using ChemDraw Professional software, then transferred to Discovery Studio to generate their 3D structure. They were prepared according to a protocol dedicated to small molecules, which takes into account the different protonation states of the molecules at the pH considered, removes duplicates, enumerates isomers and tautomers, and generates the 3D coordinates of the structures.

[0171] The next step consisted of generating conformers using the BEST protocol (see Nouri, K et al. Int. J. Mol. Sci. 2022 Nov 23;23(23): 14615 doi: 10.3390 / ijms232314615), which increases the conformational coverage of the molecules under study. 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 ligands to target proteins.

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

[0173] The CDOCKER function of Discovery Studio allows for the anchoring of a number of ligands to a protein. The protein is kept rigid, while the ligand can be flexible. The ligand-binding region (i.e., the ligand's active site) is determined using the co-crystallized ligands, if present, 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 literature 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 docking has been performed, 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 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)) were identified. The “Analyze ligand poses” function of Discovery Studio made it possible to identify these interactions and enumerate the type of bond present between the ligand and the proteins for each complex.

[0176] The ligand poses were then re-evaluated and re-scored using scoring functions other than interaction energy by applying the “Ligaton pose score” 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 free-rotating, polar, or lipophilic contact surfaces. 2.2) Results

[0177] The results obtained are illustrated in [Fig.1A] and [Fig.1B] 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.1A]) 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 al-adrenergic receptors in refined 3D models of OCTs and al-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, in accordance with 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 Table 1 below:

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

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

[0186] Method: The forced swim test is used to evaluate the potential efficacy of antidepressants in rodents. The animal is placed in a water tank Ih 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 immobility time will be. Conversely, if an animal struggles longer than the control animal, this indicates antidepressant activity of the administered compound.

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

[0188] Discussion: These preliminary experiments indicate a significant effect of a low dose of the compound (ILA2) in the forced swim test, a classic acute test for evaluating the activity of antidepressants. Since almost all conventional antidepressants exhibit a significant effect in this acute test, these results demonstrate an antidepressant effect of abacacyanomy and its derivatives.

Claims

1. Demands Composed 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, in which L is a divalent radical derived from an aliphatic CrCi2 chain in which one or more methylene units, preferably one or two, are optionally replaced by an arylene, -O-, -S-, -C(=O)-, -SO2 or -N(Ci-C6 alkyl)- group, said aliphatic chain being optionally substituted by one or more substituents selected from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, an aryl, OH, NH2 and COOH, R1, R2, R3, and R4 are independently selected from a group consisting of H, a halogen, NR9R10, OR11, COOR12, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, an aryl, a heteroaryl, a heterocyclyl, and a cycloalkyl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl being optionally substituted by one or more substituents selected from the group consisting of a halogen, a C1-C6 alkyl, a CrC6 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 bonded, forming an aryl, heteroaryl, heterocyclyl, or cycloalkyl ring, being optionally substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR17, NR18R19 and COOR20, R5 represents a Ci-C6 alkyl optionally substituted by one or more substituents chosen from the group consisting of a halogen, OH, NH2 and COOH, R6 represents H, halogen, NR21R22, OR23, COOR24, a Ci-C6 alkyl, a cycloalkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a Ci-C6 haloalkyl, OR25, NR26R27 and COOR28, R7 and R8 are independently chosen from the group consisting of H, halogen, NR29R30, OR31, COOR32, a Ci-C6 alkyl, an aryl or a heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted by one or more substituents chosen from the group consisting of a halogen, a Ci-C6 alkyl, a CrC6 haloalkyl, OR33, NR34R35 and COOR36, R9 to R36 are independently chosen from H, a Ci-C6 alkyl, an aryl and a cycloalkyl.

2. A 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 Ci-C6 alkylene, in particular a C2-C3, 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 selected 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 Ci-C6 alkyl, in particular an isopropyl.

6. A 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, an alkyl in CrC6, especially a methyl, and a cycloalkyl, especially a cyclopropyl. A compound of formula (I) according to any one of claims 1 to 6, selected from the following compounds: A (i-ad (I-A3).

8.

9. 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, notably chosen from the group consisting of PF6, Cl, Br, I, BF4, (C1-C6 alkyl)-C(O)O, (Ci-C6 haloalkyl)-C(O)O, (CrC6 alkyl)-SO3, (Ci-C6 haloalkyl)-SO3, SO42 and PO43, and L and R1 to R8 are as defined in any one of claims 1 to 7.

10. A compound of formula (II) according to claim 9, selected from the The 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, 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 medicinal product. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or tautomer thereof, pharmaceutical composition according to the claim 8 or 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 or anxiety disorders.

Images