WO2012115066A1 - Inhibiteur du transport de la glycine - Google Patents

Inhibiteur du transport de la glycine Download PDF

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WO2012115066A1
WO2012115066A1 PCT/JP2012/054032 JP2012054032W WO2012115066A1 WO 2012115066 A1 WO2012115066 A1 WO 2012115066A1 JP 2012054032 W JP2012054032 W JP 2012054032W WO 2012115066 A1 WO2012115066 A1 WO 2012115066A1
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group
compound
alkyl group
disorder
pharmaceutically acceptable
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Japanese (ja)
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実 守谷
裕之 太田
修資 山本
公美 阿部
裕子 荒木
相敏 孫
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大正製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a compound having a glycine transporter inhibitory action.
  • NMDA receptor which is one of glutamate receptors, exists on nerve cell membranes in the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory.
  • the NMDA receptor has a plurality of allosteric binding sites, one of which is the glycine binding site (NMDA receptor complex glycine binding site). It has been reported that the NMDA receptor complex glycine binding site is involved in the activation of the NMDA receptor (Non-patent Document 1).
  • Glycine transporter is a protein involved in the reuptake of extracellular glycine into cells, and the existence of two subtypes, GlyT1 and GlyT2, has been clarified so far.
  • GlyT1 is mainly expressed in cerebral cortex, hippocampus and thalamus, etc., and is schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, Post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, and sleep A relationship with a disease such as a disorder has been reported (Non-Patent Documents 2 to 4).
  • Patent Documents 1 and 2 Compounds having GlyT1 inhibitory activity and having an imidazolidin-2-one structure have been reported in the following documents (Patent Documents 1 and 2).
  • Patent Documents 1 and 2 a phenyl group is bonded to one ring nitrogen atom of imidazolidine through an amide or carbonyl, and the other ring nitrogen atom of imidazolidine is bonded to It is a compound characterized by having a phenyl group bonded thereto.
  • the present invention relates to schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders Alternatively, it is an object to provide a novel compound useful for treatment or a pharmaceutically acceptable salt thereof.
  • anxiety disorder general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders
  • the present inventors have obtained a compound represented by the following formula, which contains a nitrogen-containing aromatic group on one ring nitrogen atom of imidazolidine.
  • the inventors have found that a compound having a cyclic group bonded thereto is an excellent GlyT1 inhibitor and completed the present invention.
  • R 1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a heteroaryl group (the heteroaryl group may be substituted with a C 1-6 alkyl group), or halo
  • R 2 represents a hydrogen atom or a C 1-6 alkyl group
  • R 3 is a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a phenyl group which may be substituted with a C 1-6 alkyl group), a phenyl group (the phenyl group is A halogen atom and optionally substituted by 1 to 3 substituents selected from a halo C 1-6 alkyl group) or a pyridyl group (the pyridyl group is a halogen atom and a halo C 1-6 alkyl group).
  • n represents an integer of 0 to 3
  • a 1 , A 2 , A 3 , and A 4 are the same or different and represent the formula CH or a nitrogen atom, provided that one or two of A 1 , A 2 , A 3 , and A 4 are nitrogen atoms Indicates. Or a pharmaceutically acceptable salt thereof.
  • R 1 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a heteroaryl group (the heteroaryl group may be substituted with a C 1-6 alkyl group), or a haloC 1- 6 alkyl groups
  • R 2 is a hydrogen atom
  • a 1 , A 2 , A 3 and A 4 is a nitrogen atom, or A 1 and A 3 are both nitrogen atoms, according to any one of (1) to (3) A compound or a pharmaceutically acceptable salt thereof.
  • a 1 is a nitrogen atom
  • a 2 and A 4 are both of the formula CH
  • R 3 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from a halogen atom and a halo C 1-6 alkyl group), or a pyridyl group (the pyridyl group is A compound of any one of (1) to (5) or a pharmaceutical thereof, which may be substituted with 1 to 3 substituents selected from a halogen atom and a halo C 1-6 alkyl group Top acceptable salt.
  • (1) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (6) or a pharmaceutically acceptable salt thereof.
  • Schizophrenia Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, convulsions comprising the compound according to (1) to (6) or a pharmaceutically acceptable salt thereof as an active ingredient
  • the compound of the present invention has glycine transporter (GlyT1) inhibitory activity.
  • C xy (x and y are natural numbers) indicates that the number of carbon atoms is from x to y.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl Group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, A butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group can be exemplified.
  • halogen is fluorine, chlorine, bromine or iodine.
  • halo C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. There are 1 to 3, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group.
  • heteroaryl group means a monocyclic heteroaryl group having at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
  • the nitrogen atom may be an N oxide.
  • the heteroaryl group is preferably a 5- or 6-membered heteroaryl group, for example, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, pyrazolyl group, thiazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thienyl group, A triazolyl group, an oxadiazolyl group, a thiadiazolyl group can be mentioned.
  • the “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid.
  • Inorganic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Mention may be made of organic acids. Conversion from the educt to the salt can be performed by conventional methods.
  • R 1 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a heteroaryl group (the heteroaryl group may be substituted with a C 1-6 alkyl group), or a haloC 1- Compounds that are 6 alkyl groups are preferred.
  • the halo C 1-6 alkyl group is more preferably a trifluoromethyl group, and the halogen atom is more preferably a chlorine atom.
  • the heteroaryl group is substituted with a C 1-6 alkyl group, it is preferably substituted at a position not adjacent to the bonding position of the heteroaryl group.
  • R 1 is preferably a compound bonded to the para position.
  • a compound in which R 2 is a hydrogen atom is preferred.
  • a compound in which n is an integer of 1 to 3 is preferred.
  • a compound in which any one of A 1 , A 2 , A 3 and A 4 is a nitrogen atom, or A 1 and A 3 are both nitrogen atoms is preferred, A 1 is a nitrogen atom, A 2 and A 4 are both of the formula CH, More preferred are compounds wherein A 3 is the formula CH or a nitrogen atom.
  • R 3 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from a halogen atom and a halo C 1-6 alkyl group), or a pyridyl group (the pyridyl group is A compound which may be substituted with 1 to 3 substituents selected from a halogen atom and a halo C 1-6 alkyl group is preferred.
  • the phenyl group is more preferably a phenyl group having a substituent at the meta position
  • the pyridyl group is more preferably a pyridin-2-yl group having a substituent at the 4-position.
  • the halo C 1-6 alkyl group which is a substituent of the phenyl group and the pyridyl group is more preferably a trifluoromethyl group.
  • the compound of the present invention can contain a plurality of asymmetric centers. Therefore, the compound can exist in an optically active form and also in a racemic form thereof, and a plurality of diastereomers can also exist. All of the above forms are included within the scope of the present invention.
  • the individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using chromatography in the production of Further, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
  • the compound according to the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, Etc.) according to the 15th revision Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age and purpose of treatment.
  • compositions containing the compounds of the invention are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
  • the compounds of the present invention can be combined with one or more other therapeutic agents, various antipsychotics, antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT1A antagonist, 5HT1B antagonist, 5HT1D antagonist, D1 agonist, M1 agonist, anti It may be used with anticonvulsants, cognitive enhancers, and other psychoactive drugs.
  • antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT
  • therapeutic agents that may be used in combination with the compounds of the present invention include, for example, ondansetron, granisetron, metoclopramide, sumatriptan, lauolsine, yohimbine (Yohimbine), fluoxetine (flu) xine, citalopram (ci), escitalopram (e), meloxetine (feloxetine), faloxetine (d) z Meldine, venlafaxine, reboxetine, milnacipran, duloxetine, lipramine, imipramine, mitripipline, mitripipline, ), Amineptine, divalproex, carbamazepine, diazepam, risperidone, olanzapine, ziprasid ne), aripiprazole, quetiapine, perospirone, clozapine, haloperidol, pimrodine, pdropizine, dropperidol,
  • Particularly advantageous points related to the use and treatment methods of the combination of compounds of the present invention may include the same or improved effect of individual components at doses less than those normally used. Furthermore, further enhancement of the therapeutic effect on positive and / or negative symptoms of mental disorders and / or cognitive dysfunction is also expected.
  • the use and method of treatment according to the combination of the present invention may also provide benefits in the treatment of patients who do not fully respond to or are resistant to treatment with certain neuroleptic drugs.
  • the dose of the compound according to the present invention is 1 to 2000 mg per day when treating an adult, and this is administered once or divided into several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and symptoms of the patient.
  • the compound of the formula [I] can be produced by various synthetic methods.
  • the following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.
  • inert solvent means, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, ethylene glycol, diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane.
  • Ethers such as 1,2-dimethoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene, xylene, esters such as ethyl acetate and ethyl formate, ketones such as acetone and methyl ethyl ketone, chloroform and dichloromethane
  • esters such as ethyl acetate and ethyl formate
  • ketones such as acetone and methyl ethyl ketone
  • amides such as dimethylformamide and N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, water or a mixed solvent thereof.
  • Base means, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower alkoxides of similar metals; alkyllithiums such as butyllithium, sec-butyllithium, tert-butyllithium, methyllithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, water Alkali metal or alkaline earth metal hydroxides such as barium fluoride; Alkali metal or alkaline earth metal hydro
  • Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, oxalic acid, etc. Organic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • X 1 represents a halogen atom or a hydroxyl group
  • X 2 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group
  • P 1 protects an ester such as a methyl group or a benzyl group.
  • P 2 is tert- butoxycarbonyl group , Represents a protecting group for a nitrogen atom such as a benzyloxycarbonyl group (see the above-mentioned document), and the others are as defined above.
  • Step 1 Compound (3) can be obtained by reacting compound (1) with compound (2) wherein X 1 is a halogen atom in an inert solvent in the presence or absence of a base.
  • compound (1) and compound (2) in which X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base are subjected to Mitsunobu reaction using an organic phosphorus compound and an azo compound or a phosphorus ylide reagent.
  • (3) can be obtained.
  • Step 2 Theodora W. Green, Peter G. et al. M.M.
  • Step 3 The compound [I] of the present invention can be obtained by subjecting compound (4) to an amidation reaction in an inert solvent in the presence or absence of a base using compound (5).
  • the amidation reaction here can be carried out by a number of standard procedures known to those skilled in the art, for example amides via mixed acid anhydrides using ethyl chlorocarbonate, isobutyl chlorocarbonate, pivaloyl chloride, etc.
  • a condensing agent such as phosphonium hexafluorophosphate (BOP reagent).
  • additives such as 1-hydroxybenzotriazole (HO)
  • Step 4 Compound [I] of the present invention can be obtained from Compound (1) and Compound (6) by the same method as in Step 1 in General Production Method 1.
  • the aforementioned compound (1) can be produced according to the following method.
  • General manufacturing method 3
  • Step 5 Compound (8) can be obtained by a general oxidation reaction from an alcohol to an aldehyde using an oxidizing agent in an inert solvent.
  • the oxidation reaction include a method using an oxidizing agent such as IBX, TEMPO, PCC, and PDC, and swallowing.
  • Step 6 Compound (10) can be obtained by subjecting compound (8) and compound (9) to a reductive amination reaction using an reducing agent in an inert solvent in the presence or absence of an acid.
  • the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • Step 7 Theodora W. Green, Peter G. et al. M.M.
  • the compound (11) can be obtained by the deprotection reaction described in Wuts, “Protective Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
  • Step 8 Compound (1) can be obtained by cyclization of compound (11) with an agent such as triphosgene, phosgene, or carbonyldiimidazole in an inert solvent in the presence or absence of a base.
  • the aforementioned compound (1) can also be produced according to the following method.
  • Step 9 In an inert solvent, in the presence or absence of a base, the compound (12), ammonium carbonate, and a cyanation reagent such as potassium cyanide and trimethyl silicon cyanide are reacted by heating as necessary.
  • Compound (13) can be obtained.
  • Step 10 Compound (14) can be obtained by reacting compound (13) with a reducing agent in an inert solvent.
  • the reducing agent include lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride, and heating and stirring and use of aluminum trichloride are preferable if necessary.
  • Step 11 Compound (14) and Compound (15) are reacted in an inert solvent in the presence or absence of a base by using a palladium catalyst or a copper catalyst and optionally a metal catalyst ligand.
  • a palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4
  • examples of the copper catalyst include CuI and CuBr.
  • Examples of the ligand for the palladium catalyst include triphenylphosphine, Xantphos, BINAP and the like, and examples of the ligand for the copper catalyst include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, phenanthroline, proline and the like. Is mentioned.
  • the aforementioned compound (1) can also be produced according to the following method. General manufacturing method 5
  • Step 12 A urea structure is formed by reacting, for example, an isocyanate such as compound (17) with compound (16) in an inert solvent in the presence or absence of a base to obtain compound (18). it can.
  • Step 13 Compound (19) can be obtained by heating and stirring compound (18) in an inert solvent in the presence or absence of a base.
  • Step 14 Compound (1) can be obtained from compound (19) by the same method as in Step 10 in General Production Method 4.
  • microwave reactor used was Biotage Initiator.
  • Biotage SNAPPartridge KP-NH is used for the “NH silica gel cartridge” when purified using column chromatography
  • Biotage SNAPPartridge KP-Sil or HP-Sil is used for the “silica gel cartridge”. did.
  • NH silica gel when purified using preparative thin layer chromatography (PTLC) is Wako, NH 2 silica gel 60F254 plate-Wako 20 cm ⁇ 20 cm, “silica gel” is Merck Silica gel 60F254, 20 cm ⁇ 20 cm was used.
  • PTLC preparative thin layer chromatography
  • Tris (2,4-pentanedionato) iron (III) 103 mg
  • ethylmagnesium bromide 0.39 mL
  • a saturated aqueous ammonium chloride solution was added, the mixture was extracted with chloroform, and the organic layer was concentrated under reduced pressure.
  • the residue was purified by preparative HPLC and PTLC (silica gel, ethyl acetate only) to give the title compound (3.0 mg).
  • Tables 1-1 to 1-3 show the structural formulas of the compounds shown in Examples 1 to 5 and the compounds synthesized by the same method and their instrument data.
  • the numbers described in the column of the examples in the table indicate which of the above Examples 1 to 5 was synthesized by the same method as in the above Examples.
  • Test Example 1 Glycine uptake inhibition experiment. Glycine uptake experiments were performed according to the method described in Neuron, 8, 927-935, 1992. T98G cells that are gliomas expressing human type 1 glycine transporter (GlyT1) were used. T98G cells were seeded in a 96-well plate at 2.0 ⁇ 10 4 cells / well and cultured overnight in a carbon dioxide incubator. A test substance is dissolved in a 100% DMSO solution, and then dissolved in 10 mM HEPES buffer (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin. Dissolved.
  • the test substance was pretreated for 10 minutes. Thereafter, a test substance and [ 3 H] glycine (final concentration 250 nM) were added to the cells and allowed to react at room temperature for 15 minutes. After completion of the reaction, the extracellular fluid was aspirated with a manifold, the excess labeled glycine present outside the cells was removed, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells was determined by measuring the radioactivity in the cell lysate with a liquid scintillation counter.
  • the glycine uptake in the presence of 10 ⁇ M ALX5407 was defined as nonspecific uptake, and the total uptake in the absence of 10 ⁇ M ALX5407 minus the nonspecific uptake was defined as the specific uptake. Further, the glycine uptake inhibitory activity (IC 50 value) was calculated from the suppression curve of the test substance at 10 ⁇ 9 to 10 ⁇ 5 M concentration.
  • ALX5407 is N-[(3R) -3-([1,1'-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt.
  • the IC 50 values of the example compounds in the present invention were all less than 10 ⁇ M.
  • an IC 50 value of Compound 1 0.020MyuM the IC 50 values for compounds 2 1.9 ⁇ M
  • IC 50 values of the compounds 3 are 2.2 uM
  • the IC 50 values for compounds 4 0.30 ⁇ M compound IC 50 value 5 4.5 uM
  • an IC 50 value of compound 6 2.3MyuM an IC 50 value of compound 7 0.026MyuM
  • an IC 50 value of compound 8 0.023MyuM an IC 50 value of compound 9 Is 0.079 ⁇ M
  • Compound 10 has an IC 50 value of 0.097 ⁇ M
  • Compound 11 has an IC 50 value of 0.055 ⁇ M
  • Compound 12 has an IC 50 value of 0.020 ⁇ M
  • Compound 13 has an IC 50 value of 0.058 ⁇ M
  • Compound 14 IC 50 values are 0.036MyuM, an IC 50 value of compound 15 0.14Myu
  • the compound of the present invention has glycine transporter (GlyT1) inhibitory activity, and therefore, diseases related to the glycine transporter, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generality) Anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / many It is effective for the prevention or treatment of dyskinesia, bipolar disorder, eating disorder, or sleep disorder.
  • GlyT1 glycine transporter

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Abstract

La présente invention concerne un nouveau composé représenté par la formule [I] ou l'un de ses sels pharmacologiquement permis. Ce composé, sur la base de son effet inhibiteur de l'absorption de la glycine, est utile dans la prévention ou le traitement de troubles tels que la schizophrénie, la maladie d'Alzheimer, une altération de la cognition, une démence, des troubles anxiogènes (un trouble d'anxiété généralisée, un trouble panique, un trouble obsessionnel compulsif, un trouble d'anxiété sociale, un trouble de stress posttraumatique, des phobies spécifiques, un trouble de stress aigu, et analogues), une dépression, une toxicodépendance, des crises épileptiques, des tremblements, la douleur, la maladie de Parkinson, le trouble de l'hyperactivité et du déficit de l'attention, un trouble bipolaire, des troubles de l'alimentation ou des troubles du sommeil.
PCT/JP2012/054032 2011-02-21 2012-02-21 Inhibiteur du transport de la glycine WO2012115066A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092878A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur de glyt1 et leurs utilisations pour le traitement de troubles neurologiques et neuropsychiatriques
WO2009034062A1 (fr) * 2007-09-11 2009-03-19 Glaxo Group Limited Composés qui inhibent le transporteur de glycine et ses utilisations en médecine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092878A1 (fr) * 2007-02-01 2008-08-07 Glaxo Group Limited Inhibiteurs du transporteur de glyt1 et leurs utilisations pour le traitement de troubles neurologiques et neuropsychiatriques
WO2009034062A1 (fr) * 2007-09-11 2009-03-19 Glaxo Group Limited Composés qui inhibent le transporteur de glycine et ses utilisations en médecine

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