Novel acetylcholinesterase inhibitors and their use in the prevention and treatment of obsessive-compulsive disorder and neurodegenerative disorders

Abstract

The present disclosure provides a compound of formula (I): JPEG2026506861000048.jpg37170, or a pharmaceutically acceptable salt and / or solvate thereof. The present disclosure also relates to the use of the compounds of formula (I) as pharmaceuticals, in particular for the prevention or treatment of addictions, obsessive-compulsive disorders and related behaviors, including obsessive-compulsive disorders and eating disorders, and neurodegenerative disorders such as Parkinson's disease or Alzheimer's disease.

Description

[Technical Field]

[0001] The present disclosure relates to novel acetylcholinesterase inhibitors that are particularly useful for the prevention and / or treatment of acetylcholine-related disorders such as eating disorders, addictions, obsessive-compulsive disorders, including obsessive-compulsive disorder, and neurogenic generative disorders. [Background technology]

[0002] Acetylcholine (ACh) is the primary neuromodulator in the striatal network and the primary transmitter at the neuromuscular junction. After release by exocytosis, the action of ACh is rapidly terminated by hydrolysis catalyzed by an enzyme called acetylcholinesterase (AChE). AChE inhibitors (AChEIs) inhibit this reaction, preventing the breakdown of ACh into choline and acetate. In this way, AChEIs increase the extracellular concentration and duration of action of ACh both in the central nervous system and at the neuromuscular junction.

[0003] The present applicant recently discovered that striatal ACh plays a key role in obsessive-compulsive disorders, particularly eating disorders (Favier et al., The Journal of Clinical Investigation, 2020, 130, 12, pp. 6616-6630). Eating disorders, such as anorexia nervosa and bulimia nervosa, affect up to 10% of the population in both full-blown and subthreshold forms. Anorexia nervosa has the highest mortality rate of all psychiatric disorders (approximately 5% over 10 years). Our understanding of the neural basis of anorexia nervosa is currently very limited, and as a result, there are no specific biological or pharmacological treatments for this serious condition.

[0004] Cholinergic interneurons are key regulators of the striatum and habit formation. To investigate the role of ACh in addictive behavior, we specifically inhibited ACh signaling in the striatum of a mouse model (VAChTcKO mice) by deleting the acetylcholine vesicular transporter. We then demonstrated that ACh transmission was reduced in VAChTcKO mice, which predisposed them to excessive addictive behaviors. To understand whether these excessive addictive behaviors lead to dysfunctional eating behaviors, we used a pathological feeding model using VAChTcKO mice: activity-based anorexia (ABA), a model of anorexia nervosa (Klenotich and Dulawa, 2012). In the ABA model, mutant mice lacking ACh in the striatum were more prone to self-starvation than control mice.

[0005] Based on these unexpected findings, Applicants hypothesized that acetylcholinesterase inhibitors may be effective in the prevention and / or treatment of obsessive-compulsive disorder.

[0006] There are currently several acetylcholinesterase inhibitors on the market that specifically target Alzheimer's disease, but they often cause serious side effects (such as dizziness, nausea and vomiting, and heart problems).

[0007] Therefore, there is a constant need for new cetylcholinesterase inhibitors with improved affinity for AChE and limited peripheral effects. Summary of the Invention

[0008] In this context, the inventors have surprisingly designed and developed new acetylcholinesterase inhibitors (AChEIs) that are activated only in the brain (and not in the body). This mechanism of action reduces the neuromuscular effects and unwanted peripheral side effects of AChEIs. These novel compounds have been shown to be useful in the prevention and / or treatment of eating disorders such as obsessive-compulsive disorders, especially anorexia nervosa.

[0009] According to a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, below [ka] indicates a single or double bond, X is an oxygen atom or an N—OH group, R 1 and R 2 are each independently H, an optionally substituted nitrogen-containing heterocyclyl group, an optionally substituted C-C aliphatic chain, or an optionally substituted aryl, wherein up to four methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-C-C alkyl, with the proviso that R 1 and R 2 at least one of which is an optionally substituted nitrogen-containing heterocyclyl group; L 1 and L 2 are C1-C 12 a divalent group derived from an aliphatic chain, in which one or more, preferably 1 to 4, methylene units are optionally replaced by arylene, -O-, -S-, -C(=O)-, -SO2-, or -N(C1-C6 alkyl)-, and in which the aliphatic chain is optionally substituted; p and n are each independently 0 or 1, provided that R 1 is an optionally substituted nitrogen-containing heterocyclyl group, p is 1, and R 2is an optionally substituted nitrogen-containing heterocyclyl group, then n is 1, and R' is H, halogen, an optionally substituted C1-C6 aliphatic chain, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted C1-C6 alkyl-aryl, wherein up to four methylene units of the aliphatic chain are O, C(O), NH, or N-C1-C 6- (optionally substituted with alkyl) or a pharmaceutically acceptable salt and / or solvate thereof.

[0010] According to a second aspect, the present disclosure relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above, a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0011] According to a third aspect, the present disclosure also relates to a compound of formula (I), a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the disclosure, for use as a medicament.

[0012] The present disclosure also relates to the use of a compound of formula (I) according to the present disclosure, a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present disclosure as a medicament or for the manufacture of a medicament.

[0013] The present disclosure also relates to a method for preventing and / or treating addictions, eating disorders, and obsessive-compulsive disorders, including obsessive-compulsive disorder, and Alzheimer's disease, comprising administering to a person in need thereof an effective dose of a compound of formula (I), a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present disclosure.

[0014] definition The term "stereoisomer" as used in this disclosure refers to configurational stereoisomers, more specifically optical isomers. Thus, optical isomers that are not mirror images of one another are referred to as "diastereoisomers," and optical isomers that are non-superimposable mirror images are referred to as "enantiomers." An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture or racemate.

[0015] For the purposes of this disclosure, the term "pharmaceutically acceptable" is intended to mean something that is useful in the preparation of pharmaceutical compositions and that is generally safe and non-toxic for pharmaceutical use.

[0016] The term "pharmaceutically acceptable salts and / or solvates" is intended in the framework of the present disclosure to mean salts and / or solvates of compounds which are pharmaceutically acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0017] Pharmaceutically acceptable salts include the following: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L25 tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid, and (2) Base addition salts formed when an acidic proton present in a compound is replaced by a metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or when the compound coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide.

[0018] Solvates that are acceptable for therapeutic use of the compounds of the present disclosure include conventional solvates such as those formed in the final stage of the preparation of the compounds of the present disclosure due to the presence of a solvent. As an example, mention may be made of solvates due to the presence of water (these solvates are also called hydrates) or ethanol.

[0019] The term "halogen" as used in this disclosure refers to a fluorine, bromine, chlorine, or iodine atom.

[0020] The term “C x -C y An "aliphatic chain" refers to a straight or branched hydrocarbon chain containing x to y carbon atoms, in particular 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, that is fully saturated or contains one or more unsaturations, but is not aromatic. According to the present disclosure, the term "aliphatic chain" includes substituted or unsubstituted, straight or branched, alkyl, alkenyl, or alkynyl groups.

[0021] The term "C1-C6 alkyl" as used in this disclosure means a straight or branched monovalent saturated hydrocarbon chain containing from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0022] The term "C2-C6 alkenyl," as used in this disclosure, means a straight or branched, monovalent saturated hydrocarbon chain containing 2 to 6 carbon atoms and containing at least one double bond, including, but not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0023] The term "C2-C6 alkynyl" as used in this disclosure means a straight or branched, monovalent unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms and containing at least one triple bond, including, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0024] As used in this disclosure, the term “C1-C 12 "Alkanediyl" means a divalent saturated hydrocarbon chain, straight or branched, containing 1 to 12 carbon atoms, including, but not limited to, methanediyl (methylene), ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, and the like.

[0025] As used in this disclosure, the term "C1-C 12 "Alkenedyl" means a divalent unsaturated hydrocarbon chain, straight or branched, containing 1 to 12 carbon atoms and containing at least one double bond, including, but not limited to, ethenediyl, propenediyl, butenediyl, pentenediyl, hexenediyl, and the like.

[0026] The term "aryl group" as used in this disclosure means an aromatic hydrocarbon group, preferably containing 6 to 12 carbon atoms and containing one or more fused rings, such as, but not limited to, a phenyl group or a naphthyl group. Advantageously, it is a phenyl group.

[0027] The term "heterocyclyl group" as used herein refers to a group consisting of aromatic or non-aromatic, saturated or unsaturated, monocyclic or polycyclic groups (including fused, bridged, or spiro rings), preferably containing 5 to 10, particularly 5, 6, 9, or 10, atoms in the ring, in which one or more, particularly 1 to 4, and advantageously one or two, of the ring carbon atoms are replaced by heteroatoms selected from sulfur, oxygen, and nitrogen. When a heterocyclyl group is referred to as a "nitrogen-containing heterocyclyl group," this means that at least one of the heteroatoms in the ring is a nitrogen atom. The "nitrogen-containing heterocyclyl group" according to the present disclosure does not exclude the inclusion of oxygen and / or sulfur atoms in the ring in addition to at least one nitrogen atom. When attached to the remainder of the molecule via a nitrogen atom, the nitrogen-containing heterocyclyl group according to the present disclosure may be in its cationic form, and therefore has a valence of four.

[0028] When the heterocyclyl group is an aromatic compound, it may also be referred to as "heteroaryl" in the present disclosure. Examples of "nitrogen-containing heteroaryl" include, but are not limited to, pyrrolyl, pyridyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, or indolyl. Preferably, in the context of the present disclosure, nitrogen-containing heteroaryl is not pyridyl.

[0029] If the heterocyclyl group is non-aromatic, it may also be referred to in the present disclosure as "heterocycloalkyl." Examples of "nitrogen-containing heterocycloalkyl" include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, indolinyl, and isoindolinyl.

[0030] The term "C1-C6-alkyl-aryl" as used in the present disclosure means an alkyl group as defined above substituted with an aryl group as defined above. Advantageously, "C1-C6-alkyl-aryl" is a benzyl group.

[0031] In the context of the present disclosure, an "optionally substituted" group means that the group is, in particular, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkene, C2-C6 alkyne, aryl, N3, oxo, NR a R b , C.O.R. c , CO2R d ,CONR e R f , OR g , N + R h R i R j , CN and NO2, wherein R a ~Rj are, independently of one another, H, C1-C6 alkyl or aryl, preferably H or C1-C6 alkyl. Advantageously, the "optionally substituted" group is selected from the group consisting of C1-C6 alkyl and OR g and wherein R is substituted with one or two substituents selected from the group consisting of g is H or C1-C6 alkyl.

[0032] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl chain as defined above in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine, bromine or iodine, preferably a fluorine atom. For example, it is a CF3 group.

[0033] In the context of the present disclosure, "unsaturated" means that the hydrocarbon chain may contain one or more, advantageously one, unsaturated bond, i.e. a double bond C=C or a triple bond C≡C.

[0034] The term "leaving group" refers to an atom or group of atoms that can easily separate from a molecule that has a lone pair of electrons, breaking the bond between the molecules.

[0035] The term "pharmaceutical composition" in the framework of the present disclosure is understood as a composition having preventive and curative properties.

[0036] The term "prodrug" refers to a drug derivative, typically a pharmacologically inactive or less active derivative of an active drug, that releases the active drug via biotransformation by chemical or enzymatic reactions within a cell or organism. By "pharmacologically inactive or less active derivative," in the context of this disclosure, it is understood that the prodrug does not have the relevant activity with respect to inhibiting the acetylcholinesterase active site under test conditions. However, the oxidized form exhibits activity in in cellulo and in vivo tests because, under such conditions, the necessary transformation to provide the active drug is possible. Prodrugs may offer many advantages over the parent drug, including improved brain penetration and therefore increased activity in the brain, improved stability, and improved bioavailability.

[0037] In the context of the present disclosure, the prodrug compounds defined herein have enhanced activity in the brain. After penetration into the brain, the prodrug compounds are oxidized to provide the corresponding active drugs, i.e., potent acetylcholinesterase inhibitors.

[0038] Compounds of formula (I) Compounds of formula (I) for use according to the present disclosure may be in the form of a stereoisomer or a mixture of stereoisomers, for example a mixture of enantiomers, diastereoisomers or tautomers, in particular a racemic mixture.

[0039] In the context of the present disclosure, the nitrogen atoms of the compounds of formula (I) may have a valence of 3 or a valence of 4. When the valence is 4, for example when protonated, the nitrogen atom is in cationic form.

[0040] In particular, R 1 and / or R 2With respect to the nitrogen-containing heterocyclyl group, it may be attached to the remainder of the molecule through a carbon atom or a nitrogen atom. When attached to the remainder of the molecule through a nitrogen atom, the nitrogen atom may have a valence of 3 or 4. When the nitrogen atom has a valence of 4, it is in cationic form, i.e., ammonium. This is particularly true when the heterocyclyl group is heteroaryl.

[0041] In particular, the nitrogen of the piperidine moiety bearing the benzyl group in the compound of formula (I) may have a valence of 3 or a valence of 4. When the nitrogen atom has a valence of 4, it is in cationic form, i.e., ammonium.

[0042] In the context of this disclosure, R 1 and / or R 2 Nitrogen-containing heterocyclyl groups related to typically contain no heteroatoms other than the nitrogen atom.

[0043] In the context of this disclosure, R 1 and / or R 2 The nitrogen-containing heterocyclyl group related to is selected from the group consisting of optionally substituted pyrrolyl, pyridyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, indolyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, and isoindolinyl.

[0044] In some embodiments, R 1 and R 2are each independently an optionally substituted nitrogen-containing heterocyclyl group or an optionally substituted C-C aliphatic chain, wherein up to four methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N-C-C alkyl, with the proviso that R 1 and R 2 At least one of is an optionally substituted nitrogen-containing heterocyclyl group.

[0045] In some embodiments, R 1 and R 2 are each independently the same or different and are optionally substituted nitrogen-containing heterocyclyl groups as defined below.

[0046] According to a preferred embodiment, R 1 and R 2 are different, and R 1 and R 2 one of which is an optionally substituted nitrogen-containing heterocyclyl group as defined below, and the other is H, an optionally substituted C1-C6 aliphatic chain, or an optionally substituted aryl, preferably H, an optionally substituted C1-C6 aliphatic chain (e.g., C1-C6 alkyl), or an optionally substituted aryl (e.g., phenyl), more preferably H, C1-C6 alkyl, or aryl (e.g., phenyl), more preferably C1-C6 alkyl, including methyl, ethyl, propyl, tert-butyl, and n-butyl, and especially methyl.

[0047] In a preferred embodiment, R 1 and / or R 2 , preferably R 1 and R 2 is an optionally substituted nitrogen-containing heterocyclyl group having 1 to 4, preferably 1 or 2, more preferably 1 nitrogen atom replacing a carbon atom in the ring.

[0048] In a preferred embodiment, R1 and / or R 2 , preferably R 1 and R 2 is an optionally substituted nitrogen-containing heterocyclyl group selected from the group consisting of optionally substituted pyrrolyl, pyridyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, indolyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, and isoindolinyl.

[0049] In certain embodiments, R 1 and / or R 2 , preferably R 1 and R 2 is an optionally substituted nitrogen-containing heteroaryl, in particular selected from the group consisting of pyrrolyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl or indolyl.

[0050] In other particular embodiments, R 1 and / or R 2 , preferably R 1 and R 2 is an optionally substituted nitrogen-containing heterocycloalkyl, particularly selected from the group consisting of piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, indolinyl and isoindolinyl.

[0051] Preferably, R 1 and / or R 2 is, when the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more substituents, preferably one or two, more preferably one, are selected from the group consisting of halogen, C-C alkyl, C-C haloalkyl, C-C alkene, C-C alkyne, aryl, N, oxo, NH, NH—C-C alkyl, N(C-C alkyl), C(O)H, CO—C-C alkyl, COH, CN and NO, preferably halogen such as Cl, OH, NH, C-C alkyl such as methyl, and O—C-C alkyl such as methoxy.

[0052] Preferably, R 1 and / or R 2 , preferably R 1 and R 2 One of them is as follows: [ka] (In the formula, R 3 ~R 8 are each independently selected from the group consisting of H, halogen, OH, NH, NH—C1-C6 alkyl, C1-C6 aliphatic chain, aryl, heteroaryl, and C1-C6 alkyl-aryl, wherein up to four methylene units of the aliphatic chain are optionally replaced by O, C(O), NH, or N—C1-C6 alkyl, and the aliphatic chain, aryl, heteroaryl, or alkyl-aryl is optionally substituted; or R 3 -R 4 , R 4 -R 5 , R 5 -R 6 and R 6 -R 7 one or more of the combinations of: together with the carbon atoms to which they are attached, form an optionally substituted aromatic or non-aromatic five- or six-membered ring; R 9 and R10 are each independently one or more substituents selected from the group consisting of H, a C1-C6 aliphatic chain, aryl, heteroaryl, and C1-C6 alkyl-aryl, wherein up to four methylene units of the aliphatic chain are optionally replaced by O, (C)O, NH, or N-C1-C6 alkyl, and wherein the aliphatic chain, aryl, heteroaryl, or alkyl-aryl is optionally substituted; [ka] indicates a single or double bond, and [ka] is R 1 and the rest of the molecule.) is a group corresponding to

[0053] In (C) of formula (I), R 9 are one or more substituents attached to a carbon atom of the nitrogen-containing ring, and R 10 is understood to be one or more substituents attached to a carbon atom of the phenyl moiety that is attached to the rest of the molecule.

[0054] More preferably, R 3 ~R 8 are each independently selected from the group consisting of H, halogen, OH, NH, NH—C1-C6 alkyl, C1-C6 alkyl, and aryl, such as phenyl; or R 3 -R 4 , R 4 -R 5 , R 5 -R 6 and R 6 -R 7 one or more of the combinations together with the carbon atoms to which they are attached form an aromatic or non-aromatic 5- or 6-membered ring that is unsubstituted or substituted with one or more, preferably one, substituent selected from halogen, OH, NH, NH—C1-C6 alkyl, C1-C6 alkyl, and O—C1-C6 alkyl.

[0055] According to a preferred embodiment, R 8 is H or C1-C6 alkyl such as methyl, ethyl or isopropyl, especially methyl.

[0056] According to a preferred embodiment, R 3 -R 4 , R 4 -R 5 , R 5 -R 6 and R 6 -R 7 together with the carbon atoms to which they are attached form an aromatic six-membered ring such as phenyl which may be unsubstituted or substituted with substituents selected from halogen, OH, NH, NH-C1-C6 alkyl, C1-C6 alkyl and O-C1-C6 alkyl such as methoxy; R 3 ~R 7 The other groups up to are H.

[0057] According to a preferred embodiment, R 9 and R 10 are each independently one or more, preferably one, substituent selected from the group consisting of H, C1-C6 alkyl, halogen, OH, NH2, and NH-C1-C6 alkyl. More preferably, R 9 is one substituent selected from the group consisting of halogens such as OH and Cl, and R 10 is H.

[0058] R 1 or R 2 is formula (B) as defined above, the nitrogen to which the other moieties in the molecule are attached must be bonded to the following bond that said nitrogen forms in the ring: [ka] It can be neutral or cationic depending on the nitrogen atom, the bond being single or double, and the valence of the nitrogen not exceeding four.

[0059] In certain embodiments, R 1 and / or R 2 , preferably R 1 and R 2 is an optionally substituted 8-10 membered bicyclic nitrogen-containing heterocyclyl group, in particular selected from the group consisting of quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH, NH-C1-C6 alkyl, C1-C6 alkyl or O-C1-C6 alkyl such as methoxy.

[0060] Formula (I) as defined herein encompasses both the active compound, ie, the drug, and its prodrug.

[0061] According to certain embodiments, when the compound of formula (I) is a prodrug, R 1 and / or R 2 , preferably R 1 and R 2 In such embodiments, one of the R is an optionally substituted nitrogen-containing heterocycloalkyl, meaning that the ring is non-aromatic. 1 or R 2 is also an optionally substituted nitrogen-containing heterocycloalkyl group, it is preferably the same or a different nitrogen-containing heterocycloalkyl. According to such embodiments, the heterocycloalkyl may undergo an oxidation reaction once the prodrug penetrates the brain to provide the active drug.

[0062] Thus, according to a particular embodiment, when the compound of formula (I) is a pharmaceutical, R 1 or R 2 is a nitrogen-containing heterocyclyl group, it is an optionally substituted nitrogen-containing heteroaryl, meaning that the ring is aromatic. In such embodiments, if the other R 1 or R 2is also an optionally substituted nitrogen-containing heterocyclyl group, it is preferably the same or different nitrogen-containing heterocycloaryl.

[0063] Thus, in the prodrugs of the present disclosure, R 1 and / or R 2 The optionally substituted nitrogen-containing heterocycloalkyl for is preferably selected from the group consisting of pyrrolyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl and indolyl, preferably quinolinyl and isoquinolinyl.

[0064] In the pharmaceutical composition according to the present disclosure, R 1 and / or R 2 The optionally substituted nitrogen-containing heteroaryl for is preferably selected from the group consisting of piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl and isoindolinyl, preferably dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0065] In the context of this disclosure, a pharmaceutical compound is the oxidized form of the corresponding prodrug compound. For example, if a prodrug contains a heterocycloalkyl, it can be oxidized and thereby aromatized to the corresponding drug, thus providing the corresponding heteroaryl.

[0066] X is preferably an oxygen atom.

[0067] L1 and L2 are each independently C1-C 12A linker corresponding to a divalent group derived from an aliphatic chain, wherein one or more, preferably 1 to 4, more preferably 1 or 2 methylene units may be replaced by arylene, -O-, -S-, -C(=O)-, -SO2- or -N(C1-C6 alkyl)-, wherein the aliphatic chain may be replaced by one or more, preferably one, substituent selected from OH, halogen, C1-C6 alkyl or aryl, preferably OH or C1-C6 alkyl.

[0068] According to a preferred embodiment, L1 and L2 are each independently an unsubstituted C1-C 12 Aliphatic chain, preferably C1-C 12 Alkanediyl, C2-C 12 L1 and L2 are each independently a methylene group or a linker of the formula -CH=. When the linker is of the formula -CH=, the linker is connected to R via a double bond. 1 is understood to be directly bonded to the oxygen atom via a single bond.

[0069] In the compounds of formula (I), n and p are each independently 0 or 1, provided that R 1 is an optionally substituted nitrogen-containing heterocyclyl group, p is 1, and R 2 When R is an optionally substituted nitrogen-containing heterocyclyl group, n is 1. 1 is not an optionally substituted nitrogen-containing heterocyclyl group, p may be 0 or 1, and R 2 When R is not an optionally substituted nitrogen-containing heterocyclyl group, n can be 0 or 1. Preferably, R 1 is not an optionally substituted nitrogen-containing heterocyclyl group, p is 0, and R 2 is not an optionally substituted nitrogen-containing heterocyclyl group, then n is 0. In other words, R 1 or R 2is not an optionally substituted nitrogen-containing heterocyclyl group, the above R 1 or R 2 is preferably attached directly to the oxygen atom by the indanone group, rather than via a linker L1 or L2.

[0070] According to a preferred embodiment, R' is H, halogen, C1-C6 alkyl, aryl, heteroaryl, or C1-C6 alkyl-aryl, wherein said alkyl, aryl, heteroaryl, or alkyl-aryl is unsubstituted or substituted by one or more, preferably one, substituent selected from OH, halogen, C1-C6 alkyl, or aryl, in particular OH or C1-C6 alkyl. Preferably, R' is H, halogen, or C1-C6 alkyl, such as methyl or ethyl. More preferably, R' is H.

[0071] In certain embodiments, R 1 is an optionally substituted nitrogen-containing heterocyclyl group as defined in this disclosure, R' is H or C1-C6 alkyl such as methyl or ethyl, p is 1, n is 0, and R 2 is C1-C6 alkyl, including methyl, ethyl, propyl, tert-butyl, and n-butyl. Preferably, R 1 is an optionally substituted nitrogen-containing heterocyclyl group as defined herein, p is 1, and L is C-C 12 is a divalent group derived from an aliphatic chain, preferably methylene or a linker of formula -CH=, R 2 is methyl, n is O, and R' is H.

[0072] According to a particular embodiment, in the compounds of formula (I), R 1is selected from the group consisting of quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, which may be unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH, NH—C1-C6 alkyl, C1-C6 alkyl, or O—C1-C6 alkyl, such as methoxy; R 2 is methyl, n is O, p is 1, and L1 is C1-C 12 is a divalent group derived from an aliphatic chain, preferably methylene or a linker of formula -CH=; and R' is H.

[0073] In other embodiments, R 2 is an optionally substituted nitrogen-containing heterocyclyl group as defined in this disclosure, R' is H or C1-C6 alkyl such as methyl or ethyl, p is 0, n is 1, and R 1 is C1-C6 alkyl, including methyl, ethyl, propyl, tert-butyl, and n-butyl. Preferably, R 2 is an optionally substituted nitrogen-containing heterocyclyl group as defined herein, p is 0, and L is C-C 12 is a divalent group derived from an aliphatic chain, preferably methylene or a linker of formula -CH=, R 1 is methyl, n is 1, and R' is H.

[0074] In other embodiments, in the compound of formula (I), R 2 is selected from the group consisting of quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, unsubstituted or substituted by one or more, preferably one, substituent selected from halogen, OH, NH, NH—C1-C6 alkyl, C1-C6 alkyl or O—C1-C6 alkyl such as methoxy; R 1 is methyl, n is 1, p is O, and L2 is C1-C 12 A divalent group derived from an aliphatic chain, preferably methylene or a linker of formula -CH=, where R' is H.

[0075] According to a preferred embodiment, the compound of formula (I) is [ka] JPEG2026506861000009.jpg230170 JPEG2026506861000010.jpg219170 JPEG2026506861000011.jpg250164 JPEG2026506861000012.jpg248164.

[0076] In some embodiments, the compound of formula (I) is selected from the group consisting of compounds 1'-76', where X is N-OH and the other substituents are as defined above for compounds 1-76, respectively. For example, in compound 1', X is N-OH and the other substituents are the same as in compound 1, i.e., R' is H, R 2 is CH3, L 1 is -CH2-, p is 1, n is 0, R 1 is dihydroquinolinyl.

[0077] In particular embodiments, the compounds of formula (I) according to the present disclosure are prodrugs as defined above, in particular: [ka] JPEG2026506861000014.jpg103170.

[0078] In certain embodiments, the compounds of formula (I) according to the present disclosure are pharmaceuticals as defined above, in particular: [ka] JPEG2026506861000016.jpg249170 JPEG2026506861000017.jpg246159 JPEG2026506861000018.jpg199170.

[0079] In certain preferred embodiments, the compounds of formula (I) according to the present disclosure are [ka] JPEG2026506861000020.jpg203161 and their hydrochloride salts.

[0080] In a more preferred embodiment, the compound of formula (I) according to the present disclosure is [ka] or its hydrochloride salt.

[0081] Methods for preparing compounds of formula (I) The compound of formula (I) above, or its pharmaceutically acceptable salt and / or solvate, can be obtained by conventional methods known in the art. In particular, the compound of formula (I) above, or its pharmaceutically acceptable salt and / or solvate, can be obtained by the following steps: (a) Formula (II): [ka] (In the formula, below, [ka] is a single or double bond, R x is an optionally substituted nitrogen-containing heterocyclyl group as defined above, Lx is the C1-C as defined above 12 is a divalent group derived from an aliphatic chain, v is 0 or 1, and LV is a leaving group) with a compound of formula (III) or (III'): [ka] (In the formula, X is an oxygen atom or a group N—OH, R i is R as defined above 2 -(L2) n where R 2 is not an optionally substituted nitrogen-containing heterocyclyl group, and in particular R i is a methyl group, R ii is R as defined above 1 -(L1) p where R 1 is not an optionally substituted nitrogen-containing heterocyclyl group, and in particular R ii is a methyl group, and R' is as defined above) with a compound of (b) optionally, reacting a compound of formula (III) or (III') with a compound of formula (IV): [ka] (In the formula, below [ka] is a single or double bond, R y is an optionally substituted nitrogen-containing heterocyclyl group as defined above, L y is the C1-C defined above. 12 is a divalent group derived from an aliphatic chain, w is 0 or 1, LV is a leaving group) reacting the compound of It can be obtained by a method comprising:

[0082] The compounds of formula (II), (III), (III') and (IV) can be obtained according to methods known to those skilled in the art. It is understood that the preferred embodiments described for the compound of formula (I) in this disclosure are applicable to compounds (II), (III), (III') and (IV).

[0083] When a compound of formula (II) reacts with a compound of formula (III), Rx is usually selected from the group represented by R 1 and L x is generally understood to be as defined above for L1, v is generally understood to be as defined above for p, and, where applicable, in compounds of formula (IV), R y is usually written as R above. 2 and L y is typically as defined above for L2, and n is typically as defined above for n.

[0084] Also, when a compound of formula (II) reacts with a compound of formula (III'), Rx is usually the same as R 2 and L x is typically as defined above for L2, v is typically as defined above for n, and, where applicable, in compounds of formula (IV), R y is usually R 1 and L y is generally understood to be as defined above for L1, and n is generally understood to be as defined above for p.

[0085] LV is in particular selected from the group consisting of halogens, preferably Cl, and sulfonate groups such as mesylate or tosylate.

[0086] In a preferred embodiment, in the compound of formula (III), R iis a methyl group and R′ is H. The synthesis of the above preferred compounds of formula (III) is described in particular in Wang, Wei; Guangdong Huagong, 2015, Vol. 42(17), p. 73-74 and in EP 296560 A1.

[0087] Optionally, additional steps of protection / deprotection / or functionalization known to those skilled in the art may be carried out before or after the reaction with compounds of formula (II) and formula (III) or (III'), to provide compounds of formula (I) with the appropriate substituents as described above.

[0088] In particular, after step (a) and before step (b), in the compound of formula (III) or (III′), R i or R ii Deprotection may be performed at the position where R is attached, i.e., i or R ii The -OH group is removed to give an OH group at the corresponding position, which reacts with the compound of formula (IV) to form R 1 and R 2 and R are both nitrogen-containing heterocyclyl groups.

[0089] According to a preferred embodiment, R 1 and R 2 is a nitrogen-containing heterocyclyl group. According to this embodiment, step (b) is not performed, and R in compound (III) is i group in the R 2 -(L2) n - group or R in compound (III') ii group in the R 1 -(L1) p -corresponding to the group.

[0090] According to a preferred embodiment, compounds of formula (III) or (III') can be obtained from donepezil by selectively deprotecting one of the two methoxy groups carried by the indanone moiety, for example using strongly basic conditions. In this embodiment, R i or R ii are each methyl groups.

[0091] In the process for preparing the compounds of formula (I), the 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 known to those skilled in the art, such as by extraction, evaporation of the solvent, precipitation or crystallization (followed by filtration).

[0092] The compounds can be purified, if necessary, by methods known in the art, such as by recrystallization, distillation, column chromatography (eg, silica gel), or high performance liquid chromatography (HPLC).

[0093] Pharmaceutical Composition The present disclosure also relates to pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and at least one compound of formula (I) above, or a pharmaceutically acceptable salt and / or solvate thereof.

[0094] According to some embodiments, the pharmaceutical composition of the present disclosure comprises 0.1 mg to 5 mg, preferably 0.1 mg to 2.5 mg, of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0095] The pharmaceutical compositions of the present disclosure may be intended for oral or parenteral (including, but not limited to, subcutaneous, intramuscular, or intravenous), intraperitoneal, intraocular, intravitreal, topical, or sublingual administration, preferably intraperitoneal, oral, or intravenous. The active ingredient may be mixed with a conventional pharmaceutical carrier and administered in a unit form for administration to animals, preferably mammals, including humans.

[0096] For oral administration, the pharmaceutical composition may be in solid or liquid form (solution or suspension).

[0097] Solid compositions may be in the form of tablets, gelatin capsules, powders, granules, etc. For tablets, the active ingredient may be mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc., and then compressed. Tablets may be further coated, particularly with sucrose or other suitable materials, or may be treated to extend or delay activity. For powders or granules, the active ingredient may be mixed or granulated with dispersing agents, wetting agents, suspending agents, and may also be mixed with flavorings or sweeteners. For gelatin capsules, the active ingredient may be introduced into soft or hard gelatin capsules in the form of powder or granules as described above, or in the form of a liquid composition as described below.

[0098] The liquid composition can contain the active ingredient in a solvent such as water together with a sweetener, a flavor enhancer, or a suitable colorant. Alternatively, the liquid composition can be obtained by suspending or dissolving the above powder or granules in a liquid such as water, juice, milk, etc. It can also be, for example, a syrup or elixir.

[0099] 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 preferably sterile. It may also be in the form of an isotonic solution (compared to blood).

[0100] therapeutic use The compounds of formula (I), pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutical compositions according to the present disclosure can act as acetylcholinesterase inhibitors and inhibit the hydrolysis of acetylcholine to choline and acetic acid, thus prolonging the duration of action of acetylcholine in the central nervous system.

[0101] The present disclosure relates to a compound of formula (I) according to the present disclosure or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present disclosure, particularly to use as a pharmaceutical in the prevention and / or treatment of acetylcholinesterase-related diseases.

[0102] In other words, the present disclosure relates to the use of a compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present disclosure, for the manufacture of a medicament, particularly for the prevention and / or treatment of an acetylcholinesterase-associated disorder.

[0103] In other words, the present disclosure relates to the use of a compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present disclosure, for the prevention and / or treatment of an acetylcholinesterase-associated disorder.

[0104] In other words, the present disclosure relates to a method for preventing and / or treating an acetylcholinesterase-associated disorder, comprising administering to a person in need thereof an effective dose of a compound of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present disclosure.

[0105] According to some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention and / or treatment of an acetylcholinesterase-associated disorder is administered to a subject in need thereof at a daily dose ranging from 0.005 mg / kg to 0.5 mg / kg, preferably from 0.01 mg / kg to 0.1 mg / kg, more preferably from 0.01 mg / kg to 0.05 mg / kg, and even more preferably from 0.01 mg / kg to 0.03 mg / kg.

[0106] The acetylcholine-related disorder is preferably selected from the group consisting of addiction, obsessive-compulsive disorder and eating disorder, and related behaviors, and neurodegenerative disorders such as Parkinson's disease or Alzheimer's disease.In the context of the present disclosure, the term "eating disorder" includes anorexia, particularly anorexia nervosa, bulimia, particularly bulimia nervosa, and the compulsive aspects of obesity.By "compulsive aspects of obesity" in the framework of the present disclosure, it is understood that overweight and obese patients often exhibit compulsive eating behaviors (see Houben et al., Journal of Health Psychology, 2019 Volume 24, p.1145-1152).

[0107] In particular, the compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof according to the present disclosure are useful for the prevention or treatment of addictions, obsessive-compulsive disorders and associated behaviors, including eating disorders, particularly eating disorders such as anorexia nervosa and bulimia nervosa. [Brief explanation of the drawings]

[0108] [Figure 1]Experiment #1: Effects of daily administration of donquin (compound 56) and donepezil at 0.03 mg / kg on VGLUT3T8I / T8I mice in an activity-induced anorexia nervosa (ABA) model, compared with saline-treated VGLUT3T8I / T8I mice. Saline-treated wild-type (WT) mice were used as controls. (A) Food intake (% of baseline) during the food restriction period (7 or 8 days) was measured in WT mice (n = 8, circles), VGLUT3T8I / T8I mice administered 0.03 mg / kg donquin daily (n = 7, triangles), and VGLUT3T8I / T8I mice administered saline daily (n = 8, squares). (B) Body weight was measured daily, and mice that fell below 75% of their baseline weight were considered anorexic. Percentage of mice that maintained ≥75% of baseline body weight during the food restriction period of the ABA test for WT mice (n = 8, solid line), VGLUT3T8I / T8I mice administered 0.03 mg / kg of donquin daily (n = 7, dotted line), and VGLUT3T8I / T8I mice administered saline (n = 8, dashed line). Experiment #2: Effects of daily administration of donquin (compound 56, 0.01 mg / kg), donepezil (0.03 mg / kg), and saline on VGLUT3T8I / T8I mice in an activity-induced anorexia (ABA) model. (C) Measurement of food intake (% of baseline) during the food restriction period (7 or 8 days) in VGLUT3T8I / T8I mice receiving 0.01 mg / kg donquin daily (n = 7, triangles), VGLUT3T8I / T8I mice receiving 0.03 mg / kg donepezil daily (n = 8, squares), and VGLUT3T8I / T8I mice receiving saline (n = 8, circles). (D) During the food restriction period of the ABA test: Percentage of mice that maintained ≥75% of their baseline body weight in VGLUT3T8I / T8I mice receiving saline (n = 8, solid line), VGLUT3T8I / T8I mice receiving 0.01 mg / kg donquin daily (n = 7, dotted line), and VGLUT3T8I / T8I mice receiving 0.03 mg / kg donepezil daily (n = 8, dashed line). [Example]

[0109] 1 Synthesis 1.1 Materials Air- and moisture-sensitive manipulations were performed under nitrogen or reduced pressure using standard Schlenk techniques. Anhydrous solvents (EtO, EtOH, DCM, MeOH, CHCN, THF, toluene, and hexane) were purchased from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). Other chemicals were purchased from Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich, and TCI Europe (Boerenveldseweg, Belgium) and used without purification unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed using Merck SIL G / UV254 plates. Compounds were visualized by UV light irradiation or by immersion of the plates in solutions of phosphomolybdic acid, ninhydrin, and potassium permanganate followed by heating. Flash column chromatography was performed using silica gel 60 (Sigma-Aldrich, St. Louis, USA). NMR spectra were recorded on a Brucker Avance III nanobay 300 MHz or 400 MHz spectrometer. 1 H and 13C NMR chemical shifts (δ) are given in ppm relative to the TMS scale. The following abbreviations are used for proton spectral multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, qt: quintet, sp: septet, m: multiplet, br.: broad, dd: double doublet, and dt: double triplet. Coupling constants (J) are given in Hz. Mass spectrometry was performed at the Mass Spectroscopy Service of Paris Descartes University using a Shimadzu Nexera X2 HPLC system (Kyoto, Japan) in perfusion mode or a High Resolution Orbitrap Exactive Mass Spectrometer (Thermo Fisher, San Jose, USA). HPLC purification was performed using a Gilson analytical instrument (Villiers-le-Bel, France).

[0110] 1.2 Synthesis and characterization General Procedure A Step 1: Synthesis of iodo-1-alkylquinolinium derivatives Optionally substituted quinoline (5 g, 31.40 mmol) was refluxed with the appropriate alkyl iodochloride (15.6 mL, 157 mmol) for 48 hours. The reaction mixture was cooled to room temperature, and EtO (diethyl ether) was added. After trituration of the mixture, the residue was washed with EtO to afford the desired 1-alkylquinolinium iodide as a solid. This compound was used without further purification. Next, the optionally substituted 1-alkylquinolinium iodide was added to a MeMgBr solution (3 M in DCM, 19.43 mL, 58.3 mmol) over 5 minutes at 0 °C. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. Water was slowly added, followed by a solution of 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 MgSO, and concentrated under vacuum to afford the appropriate dihydroquinoline, which was used directly in the next step without further purification. The dihydroquinoline was refluxed with iodine (9.6 g) in EtOH (40 mL) for 15 min and cooled to room temperature. The resulting residue was filtered and washed with EtOH and Et2O to give the corresponding 1-alkyl-methylquinoline-1-iodide. 100 mg (0.29 mmol, 1 eq) of optionally substituted 1-alkyl-methylquinoline-1-iodide was dissolved in 15 mL of dichloromethane (DCM) to give a brownish-yellow color. After dissolution, approximately 90 μL (0.64 mmol, 2.2 eq) of triethylamine (TEA) was added. The reddish-brown solution darkened to a brownish-black color. After 5 minutes, iodine (0.29 mmol, 1 eq) was added. After 3 hours, iodine was added again (0.29 mmol, 1 eq). The reaction was stirred at room temperature for 60 hours. The mixture was purified as follows: the solvent was removed under reduced pressure (a dark-brown oily liquid). 5 mL of cyclohexane was added, causing the color to change to pink. The cyclohexane was removed after 1 hour, and the remainder was removed under reduced pressure. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaCl (2 x 20 mL). The solvent was removed under reduced pressure. TLC and ninhydrin tests indicated the presence of triethylammonium (TEA) in water. NMR spectra also confirmed the presence of excess TEA. The reaction mixture was diluted with DCM (3 mL) and filtered through a 1 cm silica gel column with a solvent system of DCM / MeOH (1:0 to 95:5). Purification was usually not necessary, and the crude product was used for the addition to abacavir or was formed in situ.

[0111] Example: Synthesis of intermediate H2-QUIN [ka]

[0112] 6-Methoxy-1-isopropylquinolin-1-ium iodide 6-Methoxyquinoline (5 g, 31.40 mmol) was refluxed in iodopropane (15.6 mL, 157 mmol) for 48 hours. The reaction mixture was cooled to room temperature, and EtO was added. The mixture was triturated, and the residue was washed with EtO (diethyl ether) to obtain the target compound, 6-methoxy-1-isopropylquinolinium iodide, as a yellow solid (9.4 g, 91% yield). 1H-NMR (400MHz, DMSO-d6) δ9.44 (dd, 1H, J=1.5, 6.0Hz, ArH), 9.11 (d, 1H, J=8.4Hz, ArH), 8.67 (d, 1H, J=9.9Hz, ArH), 8.14 (dd, 1H, J=6.0, 8.3Hz, ArH), 7.94(d, 1H, J=3.0Hz, ArH), 7.90(dd, 1H, J=7.3, 9.0Hz, ArH), 5.86(h, 1H, J=6.5Hz, CHCH3), 4(s, 3H, OCH3), 1.70(d, 6H, J=6.5Hz, CHCH3).

[0113] 1-Isopropyl-6-methoxy-2-methylquinolin-1-ium iodide P1 1-Isopropyl-6-methoxyquinoline-1-iodide (10 g, 29.15 mmol) was added to a MeMgBr solution (3 M in DCM, 19.43 mL, 58.3 mmol) over 5 minutes at 0 °C. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. Water was slowly added, followed by a solution of 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 reduced pressure to yield the dihydroquinoline (6.02 g), which was used directly in the next step without purification. The dihydroquinoline was refluxed with iodine (9.6 g) in EtOH (40 mL) for 15 minutes and cooled to room temperature. The resulting residue was filtered and washed with EtOH and Et2O to give 1-isopropyl-6-methoxy-2-methylquinolin-1-iodide (9.2 g) in 88% yield. 1 H-NMR (400MHz, DMSO-d6) δ8.93 (d, 1H, J=8.6Hz, ArH), 8.65 (d, 1H, J=9.9Hz, ArH), 8.04 (d, 1H, J=8.5Hz, ArH), 7.85 (d, 1H, J=3.1Hz, ArH), 7.74(d, 1H, J=8.5Hz, ArH), 5.65(sp, 1H, J=6.5Hz, CHCH3), 3.99(s, 3H, CH3), 1.85(d, 6H, J=6.5Hz, CHCH3).

[0114] Synthesis of 2-(iodomethyl)-1-isopropyl-6-methoxyquinolin-1-ium iodide (H2-QUIN) 100 mg (0.29 mmol, 1 eq) of 1-isopropyl-6-methoxy-2-methylquinolin-1-ium iodide was dissolved in 15 mL of dichloromethane (DCM) to give a brownish-yellow color. After 5 min, 74 mg (0.29 mmol, 1 eq) of iodine was added. After 3 h, 74 mg (0.29 mmol, 1 eq) of iodine was added. The reaction was stirred at room temperature for 60 h. The mixture was purified as follows: The solvent was removed under reduced pressure (a dark brown oil). 5 mL of cyclohexane was added, causing the color to turn pink. The cyclohexane was removed after 1 h, and the remainder was removed under reduced pressure. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaCl (2 x 20 mL). The solvent was removed under reduced pressure. TLC and ninhydrin test indicated the presence of triethylammonium (TEA) in water. NMR spectroscopy also confirmed the presence of excess TEA. The reaction mixture was diluted with DCM (3 mL) and filtered through a 1 cm silica gel column with a solvent system of DCM / MeOH (1:0 to 95:5). Purification was usually not necessary, and the crude product was used for addition to abacavir or formed in situ.

[0115] Step 2: Coupling with donepezil Donepezil (1 g, 2.6 mmol) was demethylated at the 5-position by reacting with NaCN (1.25 g, 26 mmol) in DMSO (10 mL). The reaction was stirred at 100 °C for 2 days, cooled, diluted with water, and extracted with dichloromethane. The aqueous solution was acidified with concentrated HCl and extracted with dichloromethane. The organic layer was dried over MgSO and, after evaporation, gave the corresponding intermediate (500 mg).

[0116] A flask equipped with a magnetic stir bar under argon was charged with the intermediate (61 mg, 0.164 mmol), silver acetate (AgOAc) (2.13 mg, 12.8 μmol), and 1,2-bis(diphenylphosphino)ethane (dppe) (5.1 mg, 12.8 μmol). 0.64 mL of DMF was then added. The mixture was stirred at room temperature for 10 minutes and then at -10°C. Next, the reaction mixture of step 1 was stirred. Iodo-1-alkylquinolinium derivatives(0.1 g, 0.213 mmol) and LiHMDS (2.8 mg, 17 μmol) were added. The reaction mixture was left under these conditions for 8 hours until the reagents were consumed. Finally, fraction separation was carried out by column chromatography (cyclohexane / EtOAc 7:3) according to thin layer chromatography. The compounds were obtained in 3-10% yield.

[0117] Example: Synthesis of Compound 56 [ka]

[0118] Intermediate A7: 1 H-NMR (400 MHz, CDCl3) δ 7.30-7.20 (m, 3H, aromatic), 7.19-7.15 (m, 2H, aromatic), 7.10 (s, 1H, aromatic), 6.85 (s, 1H, aromatic), 3.85 (s, 3H, OCH3), 3.43 (s, 2H, NCH2Ph), 3.15 (dd, 1H), 2.90-2.80 (m, 2H), 2.66 (m, 2H), 1.93-1.83 (m, 3H), 1.69-1.55 (m, 2H), 1.40 (m, 1H), 1.35-1.15 (m, 3H).

[0119] Compound 56: (yield=10%), 1H-NMR (400 MHz, CDCl3) δδ 9.34 (d, 1H, NH), 8.80 (d, 1H, aromatic), 8.47 (d, 1H, aromatic), 8.41 (d, 1H, aromatic), 8.56 (s, 1H, aromatic), 8.26 (s, 1H, aromatic), 7.94 (d, 1H, aromatic), 7.50-7.45 (m, 2H, aromatic), 7.40-7.35 (m, 2H, aromatic). , 7.15 (s, 1H, aromatic), 6.92 (s, 1H, aromatic), 4.05 (s, 3H, OCH3); 3.96 (s, 3H, OCH3), 3.13 (s, 2H, NCH2Ph), 3.05 (s, 1H); 3.01 (m, 1H), 2.90-2.80 (m, 2H), 2.67 (m, 2H), 2.05-1.80 (m, 3H), 1.69-1.55 (m, 2H), 1.40 (m, 1H), 1.35-1.20 (m, 3H).

[0120] Characterization of the compounds of the present disclosure Compound 62: (Yield=3.5%) [ka] 1 H-NMR (400 MHz, CDCl3) δ 9.77 (d, 1H, NH), 8.91 (d, 1H, aromatic), 8.23-8.09 (m, 1H, aromatic), 7.86 (d, 2H, aromatic), 7.70 (m, 2H, aromatic), 7.40-7.35 (m, 2H, aromatic), 7.17 (s, 1H, aromatic), 6 0.89 (s, 2H, aromatic), 5.92 (s, 2H, CH2); 4.68 (s, 3H, OCH3), 3.13 (s, 2H, NCH2Ph), 3.05 (s, 1H); 3.01 (m, 1H), 2.90-2.80 (m, 2H), 2.67 (m, 2H), 2.05-1.80 (m, 3H), 1.69-1.55 (m, 2H), 1.45 (m, 3H).

[0121] Compound 64: (Yield=4.20%) [ka] 1H-NMR (400MHz, CDCl3) δ8.95 (d, 1H), 8.41-8.16 (m, 3H, アロマティック), 8.0 8(m,1H)7.85(m,1H),7.75(m,1H),7.62(m,1H);-7.30(m,5H),7.13(d ,1H),6.94(s,1H);5.00(s,2H);3.86(s,3H);3.75(s,3H);3.16(s,2H );3.22(3H);2.84-2.51(m,4H);2.05-1.85(m,2H);1.59-1.25(m,5H).

[0122] Compound 63: (Yield=3.26%)

change

[0123] Compound 75: (Yield=9.15%)

change

[0124] Compound 76: (Yield=6.48%) [ka] 1 H-NMR (400MHz, CDCl3) δ8.92(s, 2H), 8.13(m, 3H), 7.85(m, 1H), 7.71(m, 1H), 7.52-7.30(m, 5H), 7.13(d, 1H), 6.82(s, 1) H);5.23(s, 3H);3.92(s, 3H);3.48(m, 3H);3.12(1H);2.86(m, 1H);2.63-2.30(m, 4H);2.25(m, 2H), 1.37-1.20(m, 11H).

[0125] General Procedure B Donepezil (1 g, 2.6 mmol) was demethylated at the 5-position by reacting with NaCN (1.25 g, 26 mmol) in DMSO (10 mL). The reaction was stirred at 100 °C for 2 days, cooled, diluted with water, and extracted with dichloromethane. The aqueous solution was acidified with concentrated HCl and extracted with dichloromethane. The organic layer was dried over MgSO and evaporated to give the corresponding intermediate (500 mg). In a flask equipped with a magnetic stir bar under argon, the intermediate (61 mg, 0.164 mmol) was stirred with K2CO3 (25 mg, 0.25 mmol, 1.5 equiv.), iodomethyl bromide (4 equiv.), and DMF (2 mL) at room temperature for 3 h. The mixture was then extracted with dichloromethane, and after evaporation, the crude product was used without purification with the quinoline derivative. The quinoline derivative (3.14 mmol, 2 equiv.) was refluxed with the crude iododonepezil derivative (15, 7 mmol, 5 equiv.) in anhydrous THF for 48 h. The reaction mixture was cooled to room temperature, and Et2O was added. The mixture was triturated, and the residue was washed with Et2O to afford the title compound as a brown solid in 2.45-10.3% yield.

[0126] Compound 59 (yield = 5.43%) [ka] 1H-NMR (400MHz, CDCl3): δ7.65(m, 3H), 7.49(m, 5H), 7.21-7.09(m, 2H), 6.92(s, 1H), 5.38(s, 2H), 5.31(s, 1H), 4.19(s, 3H) , 3.49(s, 2H), 3.22(m, 1H), 2.90-2.40(m, 4H), 2.60-2.45(m, 4H), 2.05-1.80(m, 2H), 1.57-1.35(m, 2H), 1.30-1.10(m, 3H).

[0127] Compound 58 (yield = 2.45%) [ka] 1 H-NMR (400 MHz, CDCl) δ 8.94 (d, 1H), 8.78 (d, 1H, aromatic), 8.18 (m, 2H, aromatic), 7.75 (d, 1H, aromatic), 7.65-7.35 (m, 6H, aromatic), 7.19 (s, 1H, aromatic), 7.13 (s, 1H, aromatic), 5.65 (s, 2H, CH); 3.91 (s, 3H); 3.71 (s, 2H), 3.55 (m, 1H); 2.95 (s, 2H); 2.60-2.22 (m, 6H), 1.80-1.54 (m, 5H).

[0128] Compound 57 (yield = 10.3%) [ka] 1 H-NMR (400MHz, CDCl3) δ8.95(d, 1H), 8.19(d, 2H, aromatic), 8.08(m, 2H) 7.85(m, 2H), 7.62(m, 2H), 7.52-7.30(m, 5H), 7.13(d, 1H), 6 .98(s, 1H);5.44(s, 2H);4.10(s, 2H);3.92(s, 3H);3.48(m, 1H);3.24(2H);2.6-2.34(m, 4H);2.01-1.82(m, 2H);1.61-1.28(m, 5H).

[0129] 2) Efficacy of Donquin (compound 56) in Ach-deficient mutant mice in the ABA model Self-starvation behavior is modeled in the activity-induced anorexia (ABA) test (Klenotich, SJ, Dulawa, 2012 Methods Mol Biol 829, 377-93). In this test, animals are housed in the presence of a running wheel. Food access is gradually restricted over an 8-day period. These animal studies used a hypocholinergic mouse model. The atypical vesicular transporter type 3 (VGLUT3) is expressed by all cholinergic striatal interneurons (El Mestikawy et al. 2011, Nat Rev Neurosci 12(4), 204-16).

[0130] In 2015, El Mestikawy's team discovered the p.T8I variant of VGLUT3, which is expressed in patients with substance use disorders and eating disorders (Sakae et al. Mol Psychiatry, 2015, 20(11), 1448-59). Mice expressing this variant (VGLUT3 T8I / T8I Mice) have reduced striatal cholinergic tone and are more vulnerable to self-starvation in the ABA model. T8I / T8I Mice exhibit the same cardinal symptoms as anorexic patients and are considered the best model of anorexia nervosa.

[0131] Anorexia Nervosa (ABA) model The ABA model was performed as described by Klenotich and Dulawa (Klenotich, SJ, Dulawa, 2012 Methods Mol Biol 829, 377-93) and previously reported (Favier, M., et al., J Clin Invest 130, 6616-6630 (2020)). For acclimatization, all mice were individually housed in cages with running wheels for 7 days with unlimited access to food, water, and the running wheel. After the acclimatization period, all mice were housed in the same running wheel cage for an additional 8 days. Food access was gradually restricted from 8 h (day 1) to 2 h (day 8) per day. Body weight and food intake were measured daily before and after food access, respectively. Mice that lost more than 25% of their initial (baseline) body weight were considered "anorexic." The number of days until mice reached 75% or less of their baseline body weight was used as a measure of survival. For pharmacological treatment experiments, donquin (i.e., compound 56 at 0.03 or 0.01 mg / kg, diluted in NaCl 0.9%), donepezil (reference compound, 0.03 mg / kg -1 Mice were intraperitoneally injected daily with either 0.9% NaCl (diluted with 0.9% NaCl) or 0.9% NaCl (control) solution. Mice were treated daily 30 min before the start of food access during both the baseline and food-restriction phases.

[0132] Figure 1(A) shows the effect of dongquin (i.e., compound 56) on VGLUT3 T8I / T8I We show that administering 0.03 mg / kg of VGLUT3 to mice daily for 7 days leads to levels of food intake similar to those of saline-treated wild-type mice. T8I / T8I Mice tend to eat less and exhibit self-starvation / anorexia-like behavior.

[0133] Figure 1(B) shows the VGLUT3 T8I / T8I All mice (100%) showed less than 75% of their baseline body weight after 8 days of ABA testing. In contrast, daily administration of donquin at 0.03 mg / kg significantly reduced VGLUT3T8I / T8I ABA treatment prevented weight loss in mice, with 60% of mice maintaining at least 75% of their baseline weight after 8 days of ABA testing, similar to saline-treated wild-type controls. Similarly, Figure 1(C) shows that daily administration of donquin at 0.01 mg / kg rescued mice from self-starvation, with approximately 90% of mice still weighing at least 75% of their baseline weight after 8 days. Overall, this data demonstrates that donquin is an appropriate and effective treatment for anorexic behavior.

[0134] For comparison, we performed the same experiment using donepezil, a known acetylcholinesterase inhibitor (see Figure 1(C) and Figure 1(D)). Figure 1(C) shows that a low dose (0.01 mg / kg) of donepezil significantly increased VGLUT3 activity compared with 0.03 mg / kg of donepezil. T8I / T8I Figure 1(D) shows that daily administration of 0.03 mg / kg of donepezil effectively reduces body weight to less than 75% of baseline body weight. T8I / T8I This indicates that the effect of reducing the mouse population is low or even lower than that of daily administration of donquin at 0.01 mg / kg.

[0135] 3) Inhibition of acetylcholinesterase (AChE) 3.1 Procedure A solution of each compound tested is prepared by dissolving the compound in DMSO at a 1 mM stock solution and diluting with water to the following concentrations: 100 nM, 10 nM, and 1 nM.

[0136] The assay procedure for the MAK119 kit (colorimetric test) from Sigma Aldrich is carried out as follows: Prepare the working reagent (MAK119C) from the kit freshly and use within 30 minutes. Prepare solution A by dissolving the working reagent (192 mg) in 19.2 ml of the assay buffer (MAK119A) from the kit. Dispense Solution B, made with 200 mL of water and 200 mL of calibrator (MAK119B from the kit), into each well of a 96-well plate. Add 10 mL of the solution of the tested compound to the well, then add 190 mL of Solution A to all sample wells. Negative control wells are prepared by adding only solutions A and B without adding any test compound solution, and positive control wells are prepared by adding solutions A, B, and 1 μM donepezil.

[0137] Incubate the plate at room temperature for 2 min and measure the initial absorbance at 412 nm (A 412 ) _ini After further incubation at room temperature for 10 minutes, the final absorbance (A 412 ) _final ) was measured.

[0138] Then, perform the following calculation: (A 412 ) _blank The percentage of inhibition was calculated by comparing the absorbance at 412 nm (A412) of the samples containing the test compound with that of the negative and positive controls after 12 minutes of incubation.

[0139] 3.2) Results [Table 1]

[0140] These results indicate that the compounds of the present disclosure are at least as effective, and in some cases more effective, than donepezil in inhibiting acetylcholinesterase.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, below 【Chemistry 2】 represents a single or double bond, X is an oxygen atom or an N—OH group; R １ and R ２ are each independently H, an optionally substituted nitrogen-containing heterocyclyl group, an optionally substituted C １ -C ６ an aliphatic chain, or an optionally substituted aryl, wherein up to four methylene units of said aliphatic chain are O, C(O), NH, or N—C １ -C ６ may be substituted by alkyl, provided that R １ and R ２ at least one of which is an optionally substituted nitrogen-containing heterocyclyl group; L １ and L ２ are each independently C １ -C １２ A divalent group derived from an aliphatic chain, in which one or more, preferably 1 to 4, methylene units are arylene, —O—, —S—, —C(═O)—, —SO ２ -, or -N(C １ -C ６ alkyl)-, wherein the aliphatic chain is optionally substituted; p and n are each independently 0 or 1, provided that R １ is an optionally substituted nitrogen-containing heterocyclyl group, p is 1, and R ２ is an optionally substituted nitrogen-containing heterocyclyl group, then n is 1, and R' is H, halogen, optionally substituted C １ -C ６ an aliphatic chain, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted C １ -C ６ alkyl-aryl, wherein up to four methylene units of the aliphatic chain are O, C(O), NH, or N—C １ -C ６ may be substituted with alkyl) or a pharmaceutically acceptable salt and / or solvate thereof.

2. 2. The compound of claim 1, wherein the optionally substituted nitrogen-containing heterocyclyl group is selected from the group consisting of pyrrolyl, pyridyl, thiazinyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, purinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, isoindolyl, indolyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, and isoindolinyl.

3. R １ and / or R ２ , preferably R １ and R ２ One of the following formulas 【Transformation 3】 (In the formula, R ３ ~R ８ are each independently H, halogen, OH, or NH ２ , NH-C １ -C ６ Alkyl, C １ -C ６ Aliphatic chains, aryl, heteroaryl, and C １ -C ６ alkyl-aryl, wherein up to four methylene units of said aliphatic chain are selected from the group consisting of O, C(O), NH or N—C １ -C ６ may be substituted by alkyl, wherein the aliphatic chain, aryl, heteroaryl, or alkyl-aryl may be substituted, or R ３ -R ４ , R ４ -R ５ , R ５ -R ６ , and R ６ -R ７ one or more pairs of these, together with the carbon atoms to which they are attached, form an optionally substituted aromatic or non-aromatic 5- or 6-membered ring, R ９ and R １０ are each independently H, C １ -C ６ Aliphatic chains, aryl, heteroaryl, and C １ -C ６ one or more substituents selected from the group consisting of alkyl-aryl, wherein up to four methylene units of said aliphatic chain are O, C(O), NH, or N—C １ -C ６ optionally substituted by alkyl, wherein said aliphatic chain, aryl, heteroaryl, or alkyl-aryl is optionally substituted; below: 【Chemistry 4】 indicates a single or double bond, below: 【Transformation 5】 is R １ and the rest of the molecule) 3. The compound of claim 1 or 2, wherein the group corresponds to:

4. R ８ is H or C such as methyl １ -C ６ The compound of claim 3, wherein the aryl group is alkyl.

5. R ３ -R ４ , R ４ -R ５ , R ５ -R ６ , and R ６ -R ７ one pair of these, together with the carbon atom to which they are attached, is unsubstituted or is substituted with a halogen, OH, NH ２ , NH-C １ -C ６ Alkyl, C １ -C ６ Alkyl, O-C １ -C ６ alkyl, R ３ ~R ７ 5. The compound of claim 3 or 4, wherein the other group is H.

6. R ９ is a substituent selected from the group consisting of OH and halogen; R １０ The compound of claim 3 or 4, wherein is H.

7. R １ and / or R ２ , preferably R １ and R ２ is unsubstituted or OH, C １ -C ６ Alkyl or O-C １ -C ６ The compound according to any one of claims 1 to 6, wherein the compound is selected from the group consisting of quinolinyl, isoquinolinyl, dihydroquinolinyl, and dihydroisoquinolinyl, each of which is substituted with one or more substituents selected from the group consisting of alkyl.

8. R １ and R ２ and either one of the groups is an optionally substituted nitrogen-containing heterocyclyl group as defined in any one of claims 1 to 7, and the other is H, an optionally substituted C １ -C ６ an aliphatic chain or an optionally substituted aryl, preferably H, C １ -C ６ C including alkyl or phenyl, more preferably methyl, ethyl, propyl, tert-butyl, n-butyl, especially methyl １ -C ６ The compound of any one of claims 1 to 7, which is alkyl.

9. L １ and L ２ The compound according to any one of claims 1 to 8, wherein each of the groups independently represents a methylene group or a linker represented by the formula -CH=.

10. The compound of any one of claims 1 to 9, wherein R' is H.

11. The compound according to any one of claims 1 to 10, wherein X is an oxygen atom.

12. The following compounds: 【Transformation 6】 【change】 【change】 【change】 【change】 The compound of any one of claims 1 to 11, independently selected from the group consisting of:

13. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

14. A compound according to any one of claims 1 to 12 or a composition according to claim 13 for use as a medicament.

15. A compound according to any one of claims 1 to 12 or a composition according to claim 13 for use in the prevention and / or treatment of addictions, obsessive-compulsive disorders and related behaviours, including obsessive-compulsive disorders and eating disorders, and neurodegenerative disorders such as Parkinson's disease or Alzheimer's disease, in particular eating disorders, including anorexia nervosa, bulimia and obesity.

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