WO2012115066A1 - Glycine transport inhibitor - Google Patents

Glycine transport inhibitor 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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PCT/JP2012/054032
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French (fr)
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
    • 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
    • A61P25/04—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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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

Abstract

The present invention relates to a novel compound represented by formula [I] or a pharmacologically-permitted salt thereof. This compound, on the basis of the glycine-uptake-inhibiting effect thereof, is useful in the prevention or therapy of disorders such as schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, specific phobias, acute stress disorder, and the like), depression, drug dependence, seizures, tremors, pain, Parkinson's disease, attention-deficit hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders.

Description

グリシントランスポーター阻害物質Glycine transporter inhibitor
　本発明は、グリシントランスポーター阻害作用を有する化合物に関する。 The present invention relates to a compound having a glycine transporter inhibitory action.
　グルタミン酸受容体の一つであるＮＭＤＡ受容体は脳内の神経細胞膜上に存在しており、神経の可塑性、認知、注意、記憶など様々な神経生理学的な現象に関わっている。ＮＭＤＡ受容体には複数のアロステリック結合部位が存在し、グリシン結合部位もその一つである（ＮＭＤＡ受容体複合体グリシン結合部位）。ＮＭＤＡ受容体複合体グリシン結合部位はＮＭＤＡ受容体の活性化に関与していることが報告されている（非特許文献１）。 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).
　グリシン作動性神経のシナプス前終末に活動電位が到達するとシナプス間隙へのグリシンの放出が開始される。放出されたグリシンはシナプス後部の受容体等と結合した後、トランスポーターによりシナプス間隙から取り除かれる。このことよりグリシンのトランスポーターは細胞外液にあるグリシン量を調節することでＮＭＤＡ受容体の機能を調節していると考えられている。 When the action potential reaches the presynaptic end of the glycinergic nerve, release of glycine into the synaptic cleft starts. The released glycine is removed from the synaptic cleft by the transporter after binding to a receptor or the like at the postsynaptic part. This suggests that the glycine transporter regulates the function of the NMDA receptor by regulating the amount of glycine in the extracellular fluid.
　グリシントランスポーター（ＧｌｙＴ）は細胞外グリシンの細胞内への再取り込みに関わっているタンパクであり、現在までにＧｌｙＴ１及びＧｌｙＴ２の二つのサブタイプの存在が明らかとなっている。ＧｌｙＴ１は主に大脳皮質、海馬及び視床等に発現しており、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、及び睡眠障害等の疾患との関連が報告されている（非特許文献２～４）。 Glycine transporter (GlyT) 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).
　ＧｌｙＴ１阻害作用を有し、イミダゾリジン－２－オン構造をもつ化合物は以下の文献において報告がされている（特許文献１，２）。これらの特許文献１，２に記載された化合物は、イミダゾリジンの一方の環内窒素原子に、アミド若しくはカルボニルを介してフェニル基が結合しており、イミダゾリジンの他方の環内窒素原子に、フェニル基が結合していることを特徴とする化合物である。 Compounds having GlyT1 inhibitory activity and having an imidazolidin-2-one structure have been reported in the following documents (Patent Documents 1 and 2). In the compounds described in 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.
WO2008092878WO2008092878 WO2009034062WO2009034062
　本発明は、グリシン取り込み阻害作用に基づいた統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害等の疾患の予防又は治療に有用な新規な化合物又はその医薬上許容される塩を提供することを目的とする。 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.
　本発明者らはＧｌｙＴ１に対し阻害作用を有する新規な骨格の化合物につき鋭意検討した結果、下記に示す式で表される化合物であって、イミダゾリジンの一方の環内窒素原子に、窒素含有芳香環基が結合していることを特徴とする化合物が優れたＧｌｙＴ１阻害物質であることを見出し、本発明を完成するに至った。 As a result of intensive studies on a novel skeletal compound having an inhibitory effect on GlyT1, 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.
　以下、本発明を詳細に説明する。本発明の態様（以下、「本発明化合物」という）は以下に示すものである。
（１）
式［Ｉ］ Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1)
Formula [I]
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
（式中、
Ｒ1は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ヘテロアリール基（該ヘテロアリール基は、Ｃ1-6アルキル基で置換されても良い）、又はハロＣ1-6アルキル基を示し、
Ｒ2は、水素原子、又はＣ1-6アルキル基を示し、
Ｒ3は、Ｃ1-6アルキル基（該Ｃ1-6アルキル基は、Ｃ1-6アルキル基で置換されても良いフェニル基で置換されても良い）、フェニル基（該フェニル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）、又はピリジル基（該ピリジル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）を示し、
ｎは、０～３の整数を示し、
Ａ1、Ａ2、Ａ3、及びＡ4は、同一又は異なって、式ＣＨ、又は窒素原子を示し、但し、Ａ1、Ａ2、Ａ3、及びＡ4の１又は２個は窒素原子を示す。）で表される化合物又はその医薬上許容される塩。
（２）
Ｒ1が、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ヘテロアリール基（該ヘテロアリール基は、Ｃ1-6アルキル基で置換されても良い）、又はハロＣ1-6アルキル基であり、
Ｒ2が、水素原子であり、
ｎが、１～３の整数である（１）に記載の化合物又はその医薬上許容される塩。
（３）
Ｒ1はパラ位に結合している（１）又は（２）に記載の化合物又はその医薬上許容される塩。
（４）
Ａ1、Ａ2、Ａ3及びＡ4のいずれか１個が窒素原子であるか、又はＡ１及びＡ３が共に窒素原子である（１）～（３）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（５）
Ａ1が、窒素原子であり、
Ａ2、及びＡ4が、共に式ＣＨであり、
Ａ3が、式ＣＨ、又は窒素原子である（１）～（３）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（６）
Ｒ3が、フェニル基（該フェニル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）、又はピリジル基（該ピリジル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）である、（１）～（５）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（７）
（１）～（６）のいずれか１つに記載の化合物又はその医薬上許容される塩を有効成分として含む、医薬組成物。
（８）
（１）～（６）に記載の化合物又はその医薬上許容される塩を有効成分として含む、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害の疾患の予防剤又は治療剤。 (Where
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 A C 1-6 alkyl group,
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). May be substituted with 1 to 3 selected substituents),
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.
(2)
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,
The compound or a pharmaceutically acceptable salt thereof according to (1), wherein n is an integer of 1 to 3.
(3)
The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R 1 is bonded to the para position.
(4)
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, according to any one of (1) to (3) A compound or a pharmaceutically acceptable salt thereof.
(5)
A 1 is a nitrogen atom,
A 2 and A 4 are both of the formula CH,
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein A 3 is formula CH or a nitrogen atom.
(6)
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.
(7)
(1) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (6) or a pharmaceutically acceptable salt thereof.
(8)
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 A preventive or therapeutic agent for diseases of tremor, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, or sleep disorder.
　本発明化合物はグリシントランスポーター（ＧｌｙＴ１）阻害活性を有する。 The compound of the present invention has glycine transporter (GlyT1) inhibitory activity.
　本明細書において用いる「Ｃx-y（ｘ、及びｙは自然数を示す）」とは、炭素原子の数が、ｘ個からｙ個であることを示す。 As used herein, “C xy (x and y are natural numbers)” indicates that the number of carbon atoms is from x to y.
　本明細書において用いる「Ｃ1-6アルキル基」とは直鎖状又は分岐鎖状の炭素数１～６個のアルキル基を意味し、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ヘキシル基を挙げることができる。 As used herein, “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.
　本明細書において用いる「Ｃ1-6アルコキシ基」とは直鎖状又は分岐鎖状の炭素数１～６個のアルコキシ基を意味し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ヘキシルオキシ基を挙げることができる。 As used herein, “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.
　本明細書において用いる「ハロゲン（ハロ）」とは、フッ素、塩素、臭素、ヨウ素である。 As used herein, “halogen” is fluorine, chlorine, bromine or iodine.
　本明細書において用いる「ハロＣ1-6アルキル基」とはハロゲン原子で置換された直鎖状又は分岐鎖状の炭素数１～６個のアルキル基を意味し、ハロゲン原子の好ましい置換数は１～３個であり、例えばフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、トリクロロメチル基を挙げることができる。 As used herein, the term “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.
　本明細書において用いる「ヘテロアリール基」とは窒素原子、酸素原子、及び硫黄原子からなる群から選ばれる少なくとも１個の原子を環内に有する単環のヘテロアリール基を意味する。窒素原子を環内に有する場合、その窒素原子はＮオキシドであってもよい。 As used herein, “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. When a nitrogen atom is contained in the ring, the nitrogen atom may be an N oxide.
　ヘテロアリール基は、好ましくは５，又は６員のヘテロアリール基であり、例えばピリジル基、ピリダジル基、ピリミジル基、ピラジル基、ピラゾリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、イソオキサゾリル基、チエニル基、トリアゾリル基、オキサジアゾリル基、チアジアゾリル基を挙げることができる。 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.
　本明細書中における「医薬上許容される塩」とは、薬剤的に許容することのできる酸付加塩を意味し、用いられる酸としては、硫酸、塩酸、臭化水素酸、硝酸及びリン酸等の無機酸、或いは、酢酸、シュウ酸、乳酸、クエン酸、リンゴ酸、グルコン酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸及びｐ－トルエンスルホン酸等の有機酸を挙げることができる。遊離体から当該塩への変換は従来の方法で行うことができる。 In the present specification, 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.
　本発明化合物において、好ましい態様を以下にあげる。
Ｒ1が、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ヘテロアリール基（該ヘテロアリール基は、Ｃ1-6アルキル基で置換されても良い）、又はハロＣ1-6アルキル基である化合物が好ましい。ここで、ハロＣ1-6アルキル基は、トリフルオロメチル基がより好ましく、ハロゲン原子は、塩素原子がより好ましい。ヘテロアリール基が、Ｃ1-6アルキル基で置換される場合、ヘテロアリール基の結合位置と隣接しない位置で置換されることが好ましい。
Ｒ1はパラ位に結合している化合物が好ましい。
Ｒ2が、水素原子である化合物が好ましい。
ｎが１～３の整数である化合物が好ましい。
Ａ1、Ａ2、Ａ3及びＡ4のいずれか１個が窒素原子であるか、又はＡ１及びＡ３が共に窒素原子である化合物が好ましく、
Ａ1が、窒素原子であり、
Ａ2、及びＡ4が、共に式ＣＨであり、
Ａ3が、式ＣＨ、又は窒素原子である化合物がより好ましい。
Ｒ3が、フェニル基（該フェニル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）、又はピリジル基（該ピリジル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）である化合物が好ましい。ここで、フェニル基は、メタ位に置換基を有するフェニル基がさらに好ましく、ピリジル基は、４位に置換基を有するピリジン－２－イル基がさらに好ましい。フェニル基及びピリジル基の置換基であるハロＣ1-6アルキル基は、トリフルオロメチル基がより好ましい。 Preferred embodiments of the compound of the present invention are listed below.
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. Here, the halo C 1-6 alkyl group is more preferably a trifluoromethyl group, and the halogen atom is more preferably a chlorine atom. When 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. Here, the phenyl group is more preferably a phenyl group having a substituent at the meta position, and 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.
　本発明化合物は複数の不斉中心を含むことができる。従って前記化合物は光学活性体で存在するとともにそのラセミ体でも存在することができ、さらに複数のジアステレオマーも存在することができる。前記の全ての形態は本発明の範囲内に含まれる。個々の異性体は公知の方法、例えば光学活性な出発物質若しくは中間体の使用、中間体若しくは最終生成物の製造における光学選択的な反応又はジアステレオ選択的な反応、或いは中間体又は最終生成物の製造におけるクロマトグラフィーを用いた分離等により得ることが可能である。さらに、本発明化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。同様に、本発明化合物の水和物又は溶媒和物の医薬上許容される塩も本発明の範囲内に含まれる。 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.
　本発明に係る化合物は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術（例えば、第１５改正日本薬局方に規定する方法等）によって製造することができる。これらの投与剤型は、患者の症状、年齢及び治療の目的に応じて適宜選択することができる。 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.
　これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤（例えば、結晶セルロース、デンプン、乳糖、マンニトール）、結合剤（例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン）、滑沢剤（例えば、ステアリン酸マグネシウム、タルク）、崩壊剤（例えば、カルボキシメチルセルロースカルシウム）、その他薬理学的に許容される各種添加剤を配合し、製造することができる。 These formulations 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.
　また、本発明の化合物を１以上の他の治療薬、種々の抗精神病薬（antipsychotics）、抗うつ薬、例えば、５ＨＴ３アンタゴニスト、５ＨＴ２アンタゴニスト、セロトニンアゴニスト、ＮＫ－１アンタゴニスト、選択的セロトニン再取込阻害薬（ＳＳＲＩ）、セロトニンノルアドレナリン再取込阻害薬（ＳＮＲＩ）、三環系抗うつ薬、ドーパミン作動性抗うつ薬、Ｈ３アンタゴニスト、５ＨＴ１Ａアンタゴニスト、５ＨＴ１Ｂアンタゴニスト、５ＨＴ１Ｄアンタゴニスト、Ｄ１アゴニスト、Ｍ１アゴニスト、抗けいれん薬、認知機能増強薬、および、その他向精神薬（psychoactive drug）と共に使用してもよい。 In addition, 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.
　本発明の化合物と組み合わせて共に使用してもよい他の治療薬とは、例えばオンダンセトロン（ｏｎｄａｎｓｅｔｒｏｎ）、グラニセトロン（ｇｒａｎｉｓｅｔｒｏｎ）、メトクロプラミド（ｍｅｔｏｃｌｏｐｒａｍｉｄｅ）、スマトリプタン（ｓｕｍａｔｒｉｐｔａｎ）、ラウオルシン（ｒａｕｗｏｌｓｃｉｎｅ）、ヨヒムビン（ｙｏｈｉｍｂｉｎｅ）、フルオキセチン（ｆｌｕｏｘｅｔｉｎｅ）、シタロプラム（ｃｉｔａｌｏｐｒａｍ）、エスシタロプラム（ｅｓｃｉｔａｌｏｐｒａｍ）、フェモキセチン（ｆｅｍｏｘｅｔｉｎｅ）、フルボキサミン（ｆｌｕｖｏｘａｍｉｎｅ）、パロキセチン（ｐａｒｏｘｅｔｉｎｅ）、インダルピン（ｉｎｄａｌｐｉｎｅ）、サートラリン（ｓｅｒｔｒａｌｉｎｅ）（登録商標）、ジメルジン（ｚｉｍｅｌｄｉｎｅ）、ベンラファキシン（ｖｅｎｌａｆａｘｉｎｅ）、レボキセチン（ｒｅｂｏｘｅｔｉｎｅ）、ミルナシプラン（Ｍｉｌｎａｃｉｐｒａｎ）、デュロキセチン（ｄｕｌｏｘｅｔｉｎｅ）、イミプラミン（ｉｍｉｐｒａｍｉｎｅ）、アミトリプチリン（ａｍｉｔｒｉｐｔｉｌｉｎｅ）、クロミプラミン（ｃｈｌｏｍｉｐｒａｍｉｎｅ）、ノルトリプチリン（ｎｏｒｔｒｉｐｔｉｌｉｎｅ）、ブプロピオン（ｂｕｐｒｏｐｉｏｎ）、アミネプチン（ａｍｉｎｅｐｔｉｎｅ）、ジバルプロエクス（ｄｉｖａｌｐｒｏｅｘ）、カルバマゼピン（ｃａｒｂａｍａｚｅｐｉｎｅ）、ジアゼパム（ｄｉａｚｅｐａｍ）、リスペリドン（ｒｉｓｐｅｒｉｄｏｎｅ）、オランザピン（ｏｌａｎｚａｐｉｎｅ）、ジプラシドン（ｚｉｐｒａｓｉｄｏｎｅ）、アリピプラゾール（ａｒｉｐｉｐｒａｚｏｌｅ）、クエチアピン（ｑｕｅｔｉａｐｉｎｅ）、ペロスピロン（ｐｅｒｏｓｐｉｒｏｎｅ）、クロザピン（ｃｌｏｚａｐｉｎｅ）ハロペリドール（ｈａｌｏｐｅｒｉｄｏｌ）、ピモジド（ｐｉｍｏｚｉｄｅ）、ドロペリドール（ｄｒｏｐｅｒｉｄｏｌ）、クロルプロマジン（ｃｈｌｏｒｐｒｏｍａｚｉｎｅ）、チオリダジン（ｔｈｉｏｒｉｄａｚｉｎｅ）、メソリダジン（ｍｅｓｏｒｉｄａｚｉｎｅ）、トリフルオペラジン（ｔｒｉｆｌｕｏｐｅｒａｚｉｎｅ）、ペルフェナジン（ｐｅｒｐｈｅｎａｚｉｎｅ）、フルフェナジン（ｆｌｕｐｈｅｎａｚｉｎｅ）、チフルプロマジン（ｔｈｉｆｌｕｐｒｏｍａｚｉｎｅ）、プロクロルペラジン（ｐｒｏｃｈｌｏｒｐｅｒａｚｉｎｅ）、アセトフェナジン（ａｃｅｔｏｐｈｅｎａｚｉｎｅ）、チオチキセン（ｔｈｉｏｔｈｉｘｅｎｅ）、クロルプロチキセン（ｃｈｌｏｒｐｒｏｔｈｉｘｅｎｅ）、ラモトリジン（ｌａｍｏｔｒｉｇｉｎｅ）、ロキサピン（ｌｏｘａｐｉｎｅ）、モリンドン（ｍｏｌｉｎｄｏｎｅ）等を挙げることができる。これら組み合わせは、同時に（同一の医薬処方において、または異なる医薬処方において）、別々に、または連続的に投与されればよい。 Other 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, ), Trifluoperazine, perphenazine, fluphenazine, tiflupromazine, prochlorperazine, aceto Examples thereof include phenazine (acetophenazine), thiothixene, chlorprothixene, lamotrigine, loxapine, and molindone. These combinations may be administered simultaneously (in the same pharmaceutical formulation or in different pharmaceutical formulations), separately or sequentially.
　本発明の化合物の組み合わせによる使用および治療方法に関連する特に有利な点には、個々の成分の通常使用される投与量よりも少ない投与量での同等または改善された効果を挙げることができる。また、精神障害の陽性症状および／または陰性症状および／または認知機能障害に対する治療効果のさらなる増強も期待される。本発明の組み合わせによる使用および治療方法は、ある種の神経弛緩薬での治療に十分に応答しない、または該治療に耐性のある患者の治療においても利益を提供しうる。 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.
　本発明に係る化合物の投与量は、成人を治療する場合で１日１～２０００ｍｇであり、これを１日１回又は数回に分けて投与する。この投与量は、患者の年齢、体重及び症状によって適宜増減することができる。 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.
　式[Ｉ]の化合物は種々の合成方法によって製造することができる。以下の方法は、本発明化合物の製造法の例示であり、これに限定されるものではない。 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.
　一般的製造法中、「不活性溶媒」とは例えばメタノール、エタノール、イソプロパノール、ｎ－ブタノール、エチレングリコール等のアルコール類、ジエチルエーテル、ｔ－ブチルメチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル類、ペンタン、ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素類、酢酸エチル、ギ酸エチル等のエステル類、アセトン、メチルエチルケトン等のケトン類、クロロホルム、ジクロロメタン等のハロゲン化炭素系溶媒、ジメチルホルムアミド、N-メチルピロリドン等のアミド類、アセトニトリル、ジメチルスルホキシド、水又はこれらの混合溶媒等である。 In general production methods, “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 And amides such as dimethylformamide and N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, water or a mixed solvent thereof.
　「塩基」とは例えば、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウムなどのアルカリ金属又はアルカリ土類金属の水素化物；リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジドなどのアルカリ金属又はアルカリ土類金属のアミド；ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属又はアルカリ土類金属の低級アルコキシド；ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウムなどのアルキルリチウム；水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなどのアルカリ金属又はアルカリ土類金属の水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸セシウムなどのアルカリ金属又はアルカリ土類金属の炭酸塩；炭酸水素ナトリウム、炭酸水素カリウムなどのアルカリ金属又はアルカリ土類金属の炭酸水素塩；トリエチルアミン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノン－５－エン（ＤＢＮ）、Ｎ，Ｎ－ジメチルアニリンなどのアミン；ピリジン、イミダゾール、２，６－ルチジンなどの塩基性ヘテロ環化合物などである。これらの塩基は当業者に公知である種々の反応条件に応じて適宜選択される。 “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 carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; Alkali metals or alkalis such as sodium hydrogen carbonate and potassium hydrogen carbonate Earth metal bicarbonates; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4 .3.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
　「酸」とは例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などの無機酸及びｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、ギ酸、酢酸、クエン酸、シュウ酸などの有機酸である。これらの酸は当業者に公知である種々の反応条件に応じて適宜選択される。 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.
　一般的製造法中、Ｘ1はハロゲン原子又は水酸基を示し、Ｘ2は塩素原子、臭素原子、ヨウ素原子、又はトリフルオロメタンスルホニルオキシ基を示し、Ｐ1はメチル基、ベンジル基などのエステルの保護基（Ｔｈｅｏｄｏｒａ　Ｗ．Ｇｒｅｅｎ，Ｐｅｔｅｒ　Ｇ．Ｍ．Ｗｕｔｓ、「有機合成における保護基（Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，Ｆｏｒｔｈ　Ｅｄｉｔｉｏｎ）」；Ｗｉｌｅｙ　Ｉｎｔｅｒｓｃｉｅｎｃｅ参照）を示し、Ｐ2はｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基などの窒素原子の保護基（同上資料参照）を示し、その他は前記と同義である。
一般的製造法１ In general production methods, 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, and P 1 protects an ester such as a methyl group or a benzyl group. group (Theodora W.Green, Peter G.M.Wuts, "protecting group (Green's protective groups in organic synthesis in organic synthesis, Forth Edition)"; see Wiley Interscience) indicates, 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.
General manufacturing method 1
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
工程１：不活性溶媒中、塩基の存在下又は非存在下、化合物（１）とＸ1がハロゲン原子である化合物（２）を反応させることで化合物（３）を得ることができる。又は、不活性溶媒中、塩基の存在下又は非存在下、化合物（１）とＸ1が水酸基である化合物（２）を、有機リン化合物とアゾ化合物もしくはリンイリド試薬を用いた光延反応により、化合物（３）を得ることができる。ここで有機リン化合物としてはトリフェニルホスフィン、トリブチルホスフィン等が、アゾ化合物としてはアゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル、アゾジカルボン酸ジｔｅｒｔブチル等が、リンイリド試薬としてはシアノメチレントリブチルホスホラン等が挙げられる。
工程２：Ｔｈｅｏｄｏｒａ　Ｗ．Ｇｒｅｅｎ，Ｐｅｔｅｒ　Ｇ．Ｍ．Ｗｕｔｓ、「有機合成における保護基（Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，Ｆｏｒｔｈ　Ｅｄｉｔｉｏｎ）」に記載の脱保護反応により、化合物（４）を得ることができる。
工程３：不活性溶媒中、塩基の存在下又は非存在下、化合物（４）に対して化合物（５）を用いてアミド化反応を行うことにより本発明化合物［Ｉ］を得ることができる。ここでアミド化反応とは当業者に公知である多くの標準的な手順により実施することができ、例えばクロロ炭酸エチル、クロロ炭酸イソブチル、ピバロイルクロリド等を用いた混合酸無水物経由のアミド化、又は塩化オキサリル、塩化チオニル等を用いた酸塩化物経由のアミド化、或いは１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）、1，3－ジシクロヘキシルカルボジイミド（ＤＣＣ）、ジフェニルホスホリルアジド（ＤＰＰＡ）、シアノリン酸ジエチル、カルボニルジイミダゾール（ＣＤＩ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸（ＨＡＴＵ）、又はベンゾトリアゾール－1－イルオキシトリス（ジメチルアミノ）ホスホニウム　ヘキサフルオロホスフェート（ＢＯＰ試薬）等の縮合剤を用いたアミド化を挙げることができる。ここで縮合剤を用いたアミド化反応の際、必要に応じて１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、ヒドロキシスクシンイミド（ＨＯＳｕ）などの添加剤を使用することができる。
一般的製造法２ 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. Alternatively, 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. Here, triphenylphosphine, tributylphosphine, etc. are used as the organic phosphorus compound, diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditertbutyl azodicarboxylate, etc. as the azo compound, and cyanomethylene tributylphosphorane, etc. as the phosphorus ylide reagent. Can be mentioned.
Step 2: Theodora W. Green, Peter G. et al. M.M. The deprotection reaction described in Wuts, “Protecting Groups in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)” can give compound (4).
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. Or amidation via acid chloride using oxalyl chloride, thionyl chloride or the like, or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), 1,3-dicyclohexylcarbodiimide ( DCC), diphenylphosphoryl azide (DPPA), diethyl cyanophosphate, carbonyldiimidazole (CDI), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphoric acid (HATU) or benzotriazol-1-yloxytris (dimethylamino) ) Can be mentioned amidation using a condensing agent such as phosphonium hexafluorophosphate (BOP reagent). Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.
General manufacturing method 2
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
工程４：一般的製造法１中の工程１と同様の方法により、化合物（１）と化合物（６）から本発明化合物［Ｉ］を得ることができる。
前述の化合物（１）は以下の方法に従って製造することができる。
一般的製造法３ 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
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
工程５：不活性溶媒中、酸化剤を用いたアルコールからアルデヒドへの一般的な酸化反応により、化合物（８）を得ることができる。ここで酸化反応とはＩＢＸ、ＴＥＭＰＯ、ＰＣＣ、ＰＤＣなどの酸化剤を用いた方法やスワーン酸化などが挙げられる。
工程６：不活性溶媒中、酸存在下又は非存在下、還元剤を用いて化合物（８）と化合物（９）を還元的アミノ化反応に供することで、化合物（１０）を得ることができる。ここで還元剤として水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化ホウ素ナトリウムなどが挙げられる。
工程７：Ｔｈｅｏｄｏｒａ　Ｗ．Ｇｒｅｅｎ，Ｐｅｔｅｒ　Ｇ．Ｍ．Ｗｕｔｓ、「有機合成における保護基（Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，Ｆｏｒｔｈ　Ｅｄｉｔｉｏｎ）」に記載の脱保護反応により、化合物（１１）を得ることができる。
工程８：不活性溶媒中、塩基の存在下又は非存在下、化合物（１１）をトリホスゲン、ホスゲン、カルボニルジイミダゾール等の試薬を用いて環化し、化合物（１）を得ることができる。
前述の化合物（１）は以下の方法に従っても製造することができる。
一般的製造法４ 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. Here, examples of 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. . Examples of 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.
General manufacturing method 4
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
工程９：不活性溶媒中、塩基の存在下又は非存在下、化合物（１２）とアンモニウムカーボネート、及びシアン化カリウムやシアン化トリメチルケイ素などシアノ化試薬を、必要に応じて加熱して、反応させることで化合物（１３）を得ることができる。
工程１０：不活性溶媒中、化合物（１３）を還元剤と反応させることで化合物（１４）を得ることができる。ここで還元剤とは水素化アルミニウムリチウムや水素化ビス（２－メトキシエトキシ）アルミニウムナトリウムなどが挙げられ、また必要に応じて加熱撹拌や三塩化アルミニウムの使用が好ましい。 
工程１１：不活性溶媒中、塩基の存在下又は非存在下、パラジウム触媒もしくは銅触媒および必要に応じて金属触媒の配位子を使用することで、化合物（１４）と化合物（１５）を反応させ、化合物（１）を得ることができる。ここでパラジウム触媒としてはＰｄ（ＯＡｃ）2、Ｐｄ2（ｄｂａ）3、Ｐｄ（ＰＰｈ3）4等が挙げられ、銅触媒としてはＣｕＩ、ＣｕＢｒ等が挙げられる。パラジウム触媒の配位子としては、トリフェニルホスフィン、Ｘａｎｔｐｈｏｓ、ＢＩＮＡＰ等が挙げられ、また銅触媒の配位子としては、Ｎ，Ｎ’－ジメチルエチレンジアミン、１，２－シクロヘキサンジアミン、フェナントロリン、プロリン等が挙げられる。 
前述の化合物（１）は以下の方法に従っても製造することができる。
一般的製造法５ 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. Examples of 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. To obtain compound (1). Here, examples of the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4 , and 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
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
工程１２：不活性溶媒中、塩基の存在下又は非存在下、例えば化合物（１７）のようなイソシアネートを化合物（１６）に反応させることでウレア構造を形成し、化合物（１８）を得ることができる。
工程１３：不活性溶媒中、塩基の存在下又は非存在下、化合物（１８）を加熱撹拌することで、化合物（１９）を得ることができる。
工程１４：一般的製造法４中の工程１０と同様の方法により、化合物（１９）から化合物（１）を得ることができる。 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.
次に、製造例、実施例及び試験例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Next, the present invention will be described in more detail with reference to production examples, examples and test examples, but the present invention is not limited to these examples.
　以下の製造例および実施例において、使用したマイクロウエーブ反応装置はＢｉｏｔａｇｅ社Ｉｎｉｔｉａｔｏｒである。 In the following production examples and examples, the microwave reactor used was Biotage Initiator.
　以下の製造例および実施例において、カラムクロマトグラフィーを使用して精製した際の「ＮＨシリカゲルカートリッジ」にはＢｉｏｔａｇｅ　ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－ＮＨ、「シリカゲルカートリッジ」にはＢｉｏｔａｇｅ　ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－ＳｉｌもしくはＨＰ－Ｓｉｌを使用した。 In the following production examples and examples, Biotage SNAPPartridge KP-NH is used for the “NH silica gel cartridge” when purified using column chromatography, and Biotage SNAPPartridge KP-Sil or HP-Sil is used for the “silica gel cartridge”. did.
　以下の製造例および実施例において、分取薄層クロマトグラフィー（ＰＴＬＣ）を使用して精製した際の「ＮＨシリカゲル」には和光、ＮＨ２シリカゲル６０Ｆ２５４プレート－ワコー　２０ｃｍ×２０ｃｍ、「シリカゲル」にはメルク、シリカゲル６０Ｆ２５４、２０ｃｍ×２０ｃｍを使用した。 In the following production examples and examples, “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.
　以下の製造例および実施例において、分取高速液体クロマトグラフィー（ＨＰＬＣ）による精製は以下の条件により行った。ただし、塩基性官能基を有する化合物の場合、本操作でトリフルオロ酢酸を用いたときには、フリー体を得るための中和操作等を行う場合がある。
機械：Ｇｉｌｓｏｎ社　ｐｒｅｐａｒａｔｉｖｅ　ＨＰＬＣ　ｓｙｓｔｅｍ
カラム：資生堂　Ｃａｐｃｅｌｐａｋ　Ｃ１８　ＭＧII　５μｍ　２０×１５０ｍｍ又はＷａｔｅｒｓ　ＳｕｎＦｉｒｅ　Ｐｒｅｐ　Ｃ１８　ＯＢＤ　５μｍ　３０×５０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジエント条件１：０分（Ａ液／Ｂ液＝９０／１０）、２２分（Ａ液／Ｂ液＝２０／８０）、２５分（Ａ液／Ｂ液＝１０／９０）、流速２０ｍＬ／ｍｉｎ
グラジエント条件２：０分（Ａ液／Ｂ液＝８０／２０）、２０分（Ａ液／Ｂ液＝５／９５）、２５分（Ａ液／Ｂ液＝１／９９）、流速２０ｍＬ／ｍｉｎ
グラジエント条件３：０分（Ａ液／Ｂ液＝９０／１０）、１１分（Ａ液／Ｂ液＝２０／８０）、１２分（Ａ液／Ｂ液＝５／９５）、流速４０ｍＬ／ｍｉｎ
グラジエント条件４：０分（Ａ液／Ｂ液＝８０／２０）、１０分（Ａ液／Ｂ液＝５／９５）、１１分（Ａ液／Ｂ液＝１／９９）、流速４０ｍＬ／ｍｉｎ
検出法：ＵＶ　２５４ｎｍ
　以下の製造例および実施例において、マススペクトル（ＭＳ）は、以下の条件により測定した。
ＭＳスペクトル：島津ＬＣＭＳ－２０１０ＥＶ、ｍｉｃｒｏｍａｓｓ　Ｐｌａｔｆｏｒｍ　ＬＣ、又は島津ＬＣＭＳ－ＩＴ－ＴＯＦ
　以下の製造例および実施例において、核磁気共鳴スペクトル（ＮＭＲ）は以下の条件により測定した。
ＮＭＲスペクトル：［１Ｈ－ＮＭＲ］６００ＭＨｚ：ＪＮＭ－ＥＣＡ６００（日本電子）、５００ＭＨｚ：ＪＮＭ－ＥＣＡ５００（日本電子）、３００ＭＨｚ：ＵＮＩＴＹＮＯＶＡ３００（Ｖａｒｉａｎ　Ｉｎｃ．）、２００ＭＨｚ：ＧＥＭＩＮＩ２０００／２００（Ｖａｒｉａｎ　Ｉｎｃ．）
　以下の製造例および実施例において、化合物名はＡＣＤ／Ｎａｍｅ　（ＡＣＤ／Ｌａｂｓ　１２．０１，　Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．）により命名した。
製造例１　３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン In the following production examples and examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson preparative HPLC system
Column: Shiseido Capcelpak C18 MGII 5 μm 20 × 150 mm or Waters SunFire Prep C18 OBD 5 μm 30 × 50 mm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile gradient 1: 0 minutes (A solution / B solution = 90/10), 22 minutes (A solution / B liquid = 20/80), 25 minutes (A liquid / B liquid = 10/90), flow rate 20 mL / min
Gradient condition 2: 0 minutes (A liquid / B liquid = 80/20), 20 minutes (A liquid / B liquid = 5/95), 25 minutes (A liquid / B liquid = 1/99), flow rate 20 mL / min
Gradient condition 3: 0 minute (A liquid / B liquid = 90/10), 11 minutes (A liquid / B liquid = 20/80), 12 minutes (A liquid / B liquid = 5/95), flow rate 40 mL / min
Gradient condition 4: 0 minutes (A liquid / B liquid = 80/20), 10 minutes (A liquid / B liquid = 5/95), 11 minutes (A liquid / B liquid = 1/99), flow rate 40 mL / min
Detection method: UV 254 nm
In the following production examples and examples, mass spectra (MS) were measured under the following conditions.
MS spectrum: Shimadzu LCMS-2010EV, micromass platform LC, or Shimadzu LCMS-IT-TOF
In the following production examples and examples, nuclear magnetic resonance spectra (NMR) were measured under the following conditions.
NMR spectrum: [1H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL), 300 MHz: UNITYNOVA300 (Varian Inc.), 200 MHz: GEMINI 2000/200 (Varian Inc.)
In the following production examples and examples, the compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).
Production Example 1 3- [6- (Trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（１）［１－（ヒドロキシメチル）シクロヘキシル］カルバミン酸　ｔｅｒｔ－ブチル（０．８２ｇ）のＤＭＳＯ（１０ｍＬ）溶液に２－ヨードキシ安息香酸（１．２ｇ）を加え、室温で一晩撹拌した。水、酢酸エチルを加え、不溶物をセライト（登録商標）でろ去し、ろ液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤をろ去した。ろ液を減圧下濃縮した後、残渣をクロロホルム（１０ｍＬ）に溶かし、２－トリフルオロメチル－５－アミノピリジン（０．７ｇ）および水素化トリアセトキシホウ素ナトリウム（１．１ｇ）を加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出の後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、［１－（｛［６－（トリフルオロメチル）ピリジン－３－イル］アミノ｝メチル）シクロヘキシル］カルバミン酸　ｔｅｒｔ－ブチル（０．６３ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.17 - 2.11 (m, 19 H), 3.66 (s, 1 H), 4.28 - 4.64 (m, 2 H), 6.86 - 6.95 (m, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 8.04 (d, J=3.2 Hz, 1 H)
(ESI pos.) m/z : 396（［Ｍ+Na］+）
（２）［１－（｛［６－（トリフルオロメチル）ピリジン－３－イル］アミノ｝メチル）シクロヘキシル］カルバミン酸　ｔｅｒｔ－ブチル（６００ｍｇ）のエタノール（８ｍＬ）溶液に４Ｍ塩酸／酢酸エチル（４ｍＬ）を加え、一晩撹拌した。反応液を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥し、乾燥剤をろ別後、ろ液を減圧下濃縮した。Ｎ－［（１－アミノシクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（３００ｍｇ）を得た。
(ESI pos.) m/z : 274（［Ｍ+H］+）
（３）Ｎ－［（１－アミノシクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（３００ｍｇ）のＴＨＦ（１０ｍＬ）溶液に、トリエチルアミン（０．７ｍＬ）を加え、氷冷し、トリホスゲン（１３０ｍｇ）を加えた。室温で２時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をイソプロピルエーテルで洗浄し、標題化合物（２３０ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.50 (d, J=5.0 Hz, 2 H), 1.57 - 1.67 (m, 3 H), 1.67 - 1.79 (m, 5 H), 3.69 (s, 2 H), 5.52 (br. s., 1 H), 7.64 (d, J=8.7 Hz, 1 H), 8.36 (s, 1 H), 8.69 (d, J=2.8 Hz, 1 H)
(ESI pos.) m/z : 300（［Ｍ+H］+）
(ESI neg.) m/z : 298（［Ｍ-H］-）
同様の方法により、以下の化合物を合成した。
３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 262（［Ｍ+H］+）
３－（５－クロロピリジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 266（［Ｍ+H］+）
３－（５－フルオロピリジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 250（［Ｍ+H］+）
３－（６－クロロピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 266（［Ｍ+H］+）
３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．４］ノナン－２－オン
(ESI pos.) m/z : 248（［Ｍ+H］+）
３－（６－ブロモピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 310（［Ｍ+H］+）
製造例２　３－（５－クロロピリミジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン (1) 2-iodoxybenzoic acid (1.2 g) was added to a solution of tert-butyl [1- (hydroxymethyl) cyclohexyl] carbamate in DMSO (10 mL) and stirred at room temperature overnight. Water and ethyl acetate were added, the insoluble material was removed by filtration through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was dissolved in chloroform (10 mL), 2-trifluoromethyl-5-aminopyridine (0.7 g) and sodium triacetoxyborohydride (1.1 g) were added, and Stir overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) and tert-butyl [1-({[6- (trifluoromethyl) pyridin-3-yl] amino} methyl) cyclohexyl] carbamate (0 0.63 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.17-2.11 (m, 19 H), 3.66 (s, 1 H), 4.28-4.64 (m, 2 H), 6.86-6.95 (m, 1 H), 7.41 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 3.2 Hz, 1 H)
(ESI pos.) M / z: 396 ([M + Na] +)
(2) [1-({[6- (Trifluoromethyl) pyridin-3-yl] amino} methyl) cyclohexyl] carbamate tert-butyl (600 mg) in ethanol (8 mL) solution in 4M hydrochloric acid / ethyl acetate (4 mL ) And stirred overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. N-[(1-aminocyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (300 mg) was obtained.
(ESI pos.) M / z: 274 ([M + H] +)
(3) To a solution of N-[(1-aminocyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (300 mg) in THF (10 mL) was added triethylamine (0.7 mL), and the mixture was ice-cooled. , Triphosgene (130 mg) was added. After stirring at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with isopropyl ether to give the title compound (230 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.50 (d, J = 5.0 Hz, 2 H), 1.57-1.67 (m, 3 H), 1.67-1.79 (m, 5 H), 3.69 (s, 2 H), 5.52 (br. S., 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 8.36 (s, 1 H), 8.69 (d, J = 2.8 Hz, 1 H)
(ESI pos.) M / z: 300 ([M + H] +)
(ESI neg.) M / z: 298 ([M-H]-)
The following compounds were synthesized by the same method.
3- (6-Methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 262 ([M + H] +)
3- (5-Chloropyridin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 266 ([M + H] +)
3- (5-Fluoropyridin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 250 ([M + H] +)
3- (6-Chloropyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 266 ([M + H] +)
3- (6-Methoxypyridin-3-yl) -1,3-diazaspiro [4.4] nonan-2-one
(ESI pos.) M / z: 248 ([M + H] +)
3- (6-Bromopyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 310 ([M + H] +)
Production Example 2 3- (5-Chloropyrimidin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　窒素雰囲気下、１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）、５－クロロ－２－ヨードピリミジン、Ｐｄ2（ｄｂａ）3（３４ｍｇ）、Ｘａｎｔｐｈｏｓ（３８ｍｇ）、およびｔｅｒｔ－ブトキシナトリウム（９４ｍｇ）のトルエン（４ｍＬ）溶液を１００℃で２時間撹拌した。反応液をクロロホルムで希釈し、ＮＨシリカゲルを加え、減圧下濃縮した。これをカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム／メタノール）で精製し、標題化合物（１２３ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.37 - 1.76 (m, 10 H), 3.85 (s, 2 H), 5.13 (br. s., 1 H), 8.55 (s, 2 H)
(ESI pos.) m/z : 267（［Ｍ+H］+）
同様の方法により、以下の化合物を合成した。
３－［５－（トリフルオロメチル）ピリミジン－２－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 301（［Ｍ+H］+）
製造例３　［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸 Under a nitrogen atmosphere, 1,3-diazaspiro [4.5] decan-2-one (100 mg), 5-chloro-2-iodopyrimidine, Pd 2 (dba) 3 (34 mg), Xantphos (38 mg), and tert- A solution of butoxy sodium (94 mg) in toluene (4 mL) was stirred at 100 ° C. for 2 hours. The reaction mixture was diluted with chloroform, NH silica gel was added, and the mixture was concentrated under reduced pressure. This was purified by column chromatography (silica gel cartridge, chloroform / methanol) to obtain the title compound (123 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.37-1.76 (m, 10 H), 3.85 (s, 2 H), 5.13 (br. S., 1 H), 8.55 (s, 2 H)
(ESI pos.) M / z: 267 ([M + H] +)
The following compounds were synthesized by the same method.
3- [5- (Trifluoromethyl) pyrimidin-2-yl] -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 301 ([M + H] +)
Production Example 3 [3- (6-Methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（１）３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（１．４５ｇ）のＤＭＦ（２０ｍＬ）溶液を氷冷し、水素化ナトリウム（２６６ｍｇ）を加え、３０分撹拌した。ブロモ酢酸エチル（０．７４ｍＬ）を加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝７５：２５～６０：４０）で精製し、［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸エチル（１．０５ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.01 - 1.92 (m, 10 H), 1.24 - 1.37 (m, 3 H), 3.68 (s, 2 H), 3.93 (s, 3 H), 3.97 (s, 2 H), 4.22 (q, J=7.0 Hz, 2 H), 6.64 - 6.82 (m, 1 H), 8.06 (d, J=3.1 Hz, 1 H), 8.15 - 8.26 (m, 1 H)
(ESI pos.) m/z : 348（［Ｍ+H］+）
（２）［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸エチル（１．００ｇ）のメタノール（１０ｍＬ）溶液に水（５ｍＬ）、水酸化ナトリウム（１４０ｍｇ）を加え、室温で一晩撹拌した。減圧下溶媒を留去した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで洗浄した。水層を１Ｍ塩酸で中性にした後、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮し、標題化合物（０．９９ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 - 1.20 (m, 1 H), 1.30 - 1.41 (m, 2 H), 1.47 - 1.60 (m, 2 H), 1.66 - 1.90 (m, 5 H), 3.68 (s, 2 H), 3.91 (s, 3 H), 3.97 (s, 2 H), 6.74 (d, J=9.6 Hz, 1 H), 8.02 - 8.17 (m, 2 H)
(ESI pos.) m/z : 320（［Ｍ+H］+）
同様の方法により、以下の化合物を合成した。
｛２－オキソ－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝酢酸
(ESI pos.) m/z : 358（［Ｍ+H］+）
［３－（５－クロロピリミジン－２－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸
(ESI pos.) m/z : 325（［Ｍ+H］+）
｛２－オキソ－３－［５－（トリフルオロメチル）ピリミジン－２－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝酢酸
(ESI pos.) m/z : 359（［Ｍ+H］+）
［３－（６－クロロピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸
(ESI pos.) m/z : 324（［Ｍ+H］+）
［３－（６－ブロモピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸
(ESI pos.) m/z : 368（［Ｍ+H］+）
実施例１　Ｎ－（３，５－ジフルオロフェニル）－２－［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］アセトアミド (1) A solution of 3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (1.45 g) in DMF (20 mL) was ice-cooled and sodium hydride was added. (266 mg) was added and stirred for 30 minutes. Ethyl bromoacetate (0.74 mL) was added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 75: 25 to 60:40), and [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [ 4.5] Dec-1-yl] ethyl acetate (1.05 g) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.01-1.92 (m, 10 H), 1.24-1.37 (m, 3 H), 3.68 (s, 2 H), 3.93 (s, 3 H), 3.97 ( s, 2 H), 4.22 (q, J = 7.0 Hz, 2 H), 6.64-6.82 (m, 1 H), 8.06 (d, J = 3.1 Hz, 1 H), 8.15-8.26 (m, 1 H )
(ESI pos.) M / z: 348 ([M + H] +)
(2) A solution of [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] ethyl acetate (1.00 g) in methanol (10 mL) To the mixture were added water (5 mL) and sodium hydroxide (140 mg), and the mixture was stirred overnight at room temperature. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.99 g).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09-1.20 (m, 1 H), 1.30-1.41 (m, 2 H), 1.47-1.60 (m, 2 H), 1.66-1.90 (m, 5 H ), 3.68 (s, 2 H), 3.91 (s, 3 H), 3.97 (s, 2 H), 6.74 (d, J = 9.6 Hz, 1 H), 8.02-8.17 (m, 2 H)
(ESI pos.) M / z: 320 ([M + H] +)
The following compounds were synthesized by the same method.
{2-Oxo-3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] dec-1-yl} acetic acid
(ESI pos.) M / z: 358 ([M + H] +)
[3- (5-Chloropyrimidin-2-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid
(ESI pos.) M / z: 325 ([M + H] +)
{2-Oxo-3- [5- (trifluoromethyl) pyrimidin-2-yl] -1,3-diazaspiro [4.5] dec-1-yl} acetic acid
(ESI pos.) M / z: 359 ([M + H] +)
[3- (6-Chloropyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid
(ESI pos.) M / z: 324 ([M + H] +)
[3- (6-Bromopyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid
(ESI pos.) M / z: 368 ([M + H] +)
Example 1 N- (3,5-difluorophenyl) -2- [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] Acetamide
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸（９０ｍｇ）のクロロホルム（２ｍL）溶液にジイソプロピルエチルアミン（０．０５ｍL）、ＨＡＴＵ（１１７ｍｇ）、および３，５－ジフルオロアニリン（４０ｍｇ）を加え、室温で２日間撹拌した。クロロホルムで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝２：１～１：１、およびNHシリカゲルカートリッジ、ヘキサン／酢酸エチル＝３：１～２：１）で精製し、標題化合物（６９ｍｇ）を得た。
実施例２　２－｛２－オキソ－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝－Ｎ－［３－（トリフルオロメチル）フェニル］アセトアミド To a solution of [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid (90 mg) in chloroform (2 mL) was added diisopropylethylamine (0. 05 mL), HATU (117 mg), and 3,5-difluoroaniline (40 mg) were added, and the mixture was stirred at room temperature for 2 days. The mixture was diluted with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 2: 1 to 1: 1, and NH silica gel cartridge, hexane / ethyl acetate = 3: 1 to 2: 1) to give the title compound (69 mg). Obtained.
Example 2 2- {2-oxo-3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] dec-1-yl} -N- [3- ( Trifluoromethyl) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（５０ｍｇ）のＤＭＦ（１ｍＬ）溶液に水素化ナトリウム（８ｍｇ）を加え、室温で１０分撹拌した。２－クロロ－Ｎ－［３－（トリフルオロメチル）フェニル］アセトアミド（６０ｍｇ）を加え、２日間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した後、溶媒を減圧下留去した。残渣を分取ＨＰＬＣにて精製し、標題化合物（５６ｍｇ）を得た。
実施例３　２－｛２－オキソ－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝－Ｎ－［６－（トリフルオロメチル）ピリジン－２－イル］アセトアミド Sodium hydride (8 mg) was added to a solution of 3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (50 mg) in DMF (1 mL). And stirred at room temperature for 10 minutes. 2-Chloro-N- [3- (trifluoromethyl) phenyl] acetamide (60 mg) was added and stirred for 2 days. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (56 mg).
Example 3 2- {2-oxo-3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] dec-1-yl} -N- [6- ( Trifluoromethyl) pyridin-2-yl] acetamide
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　｛２－オキソ－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝酢酸（１００ｍｇ）のクロロホルム（３ｍＬ）溶液に塩化オキサリル（０．０５ｍＬ）およびＤＭＦ（１滴）を加え、９０℃で１時間撹拌した。反応液を減圧下濃縮した後、残渣をクロロホルム（２ｍＬ）に溶かし、トリエチルアミン（６０ｍｇ）および2－アミノ－６－トリフルオロメチルピリジン（７０ｍｇ）を加え、室温で一晩撹拌した。反応液を減圧下濃縮した後、残渣を分取ＨＰＬＣで精製し、標題化合物（２５ｍｇ）を得た。
実施例４　２－［３－（６－エチルピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド Chlorination of {2-oxo-3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] dec-1-yl} acetic acid (100 mg) in chloroform (3 mL) Oxalyl (0.05 mL) and DMF (1 drop) were added and stirred at 90 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform (2 mL), triethylamine (60 mg) and 2-amino-6-trifluoromethylpyridine (70 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (25 mg).
Example 4 2- [3- (6-Ethylpyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] -N- [4- (trifluoromethyl) Pyridin-2-yl] acetamide
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
（１）実施例１と同様の操作により、［３－（６－ブロモピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸（１．２９ｍｍｏｌ）より２－［３－（６－ブロモピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド（８２５ｍｇ）を得た。
（２）２－［３－（６－ブロモピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド（１２５ｍｇ）およびトリス（２，４－ペンタンジオナト）鉄（ＩＩＩ）（１０３ｍｇ）のＴＨＦ（２ｍＬ）およびＮＭＰ（０．２ｍＬ）溶液に臭化エチルマグネシウム（３Ｍ／ジエチルエーテル、０．３９ｍＬ）を滴下し、室温で2時間撹拌した。トリス（２，４－ペンタンジオナト）鉄（ＩＩＩ）（１０３ｍｇ）および臭化エチルマグネシウム（０．３９ｍＬ）を追加し、室温で一晩撹拌した。飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出し、有機層を減圧下濃縮した。残渣を分取ＨＰＬＣおよびＰＴＬＣ（シリカゲル、酢酸エチルのみ）で精製し、標題化合物（３．０ｍｇ）を得た。
実施例５　２－｛３－［６－（４－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル｝－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミドおよび２－｛３－［６－（５－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル｝－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド (1) In the same manner as in Example 1, [3- (6-bromopyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid (1. 29 mmol) from 2- [3- (6-bromopyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] -N- [4- (trifluoromethyl) Pyridin-2-yl] acetamide (825 mg) was obtained.
(2) 2- [3- (6-Bromopyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] -N- [4- (trifluoromethyl) Pyridin-2-yl] acetamide (125 mg) and tris (2,4-pentanedionato) iron (III) (103 mg) in THF (2 mL) and NMP (0.2 mL) in ethyl magnesium bromide (3 M / diethyl) Ether (0.39 mL) was added dropwise and stirred at room temperature for 2 hours. Tris (2,4-pentanedionato) iron (III) (103 mg) and ethylmagnesium bromide (0.39 mL) were added, and the mixture was stirred at room temperature overnight. 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).
Example 5 2- {3- [6- (4-Methyl-1H-imidazol-1-yl) pyridin-3-yl] -2-oxo-1,3-diazaspiro [4.5] dec-1-yl } -N- [4- (trifluoromethyl) pyridin-2-yl] acetamide and 2- {3- [6- (5-methyl-1H-imidazol-1-yl) pyridin-3-yl] -2- Oxo-1,3-diazaspiro [4.5] dec-1-yl} -N- [4- (trifluoromethyl) pyridin-2-yl] acetamide
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　２－［３－（６－ブロモピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド（１８８ｍｇ）、４－メチルイミダゾール（１１９ｍｇ）、トランス－１，２－ビス（メチルアミノ）シクロヘキサン（１７ｍｇ）、ヨウ化銅（Ｉ）（１１ｍｇ）、および炭酸セシウム（２８６ｍｇ）の１，４－ジオキサン（３ｍＬ）溶液を、封管中、１２０℃で２時間撹拌した。４－メチルイミダゾール（１１９ｍｇ）、トランス－１，２－ビス（メチルアミノ）シクロヘキサン（１７ｍｇ）、およびヨウ化銅（Ｉ）（１１ｍｇ）を追加し、さらに１２０℃で３時間撹拌した。セライトろ過の後、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣおよびＰＴＬＣ（シリカゲル、クロロホルム／メタノール＝１９：１）で精製し、２－｛３－［６－（４－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル｝－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド（３１ｍｇ）および２－｛３－［６－（５－メチル－１Ｈ－イミダゾール－１－イル）ピリジン－３－イル］－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル｝－Ｎ－［４－（トリフルオロメチル）ピリジン－２－イル］アセトアミド（２．７ｍｇ）を得た。 2- [3- (6-Bromopyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] -N- [4- (trifluoromethyl) pyridine-2 1 of -yl] acetamide (188 mg), 4-methylimidazole (119 mg), trans-1,2-bis (methylamino) cyclohexane (17 mg), copper (I) iodide (11 mg), and cesium carbonate (286 mg) , 4-Dioxane (3 mL) solution was stirred in a sealed tube at 120 ° C. for 2 hours. 4-Methylimidazole (119 mg), trans-1,2-bis (methylamino) cyclohexane (17 mg), and copper (I) iodide (11 mg) were added, and the mixture was further stirred at 120 ° C. for 3 hours. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and PTLC (silica gel, chloroform / methanol = 19: 1) to give 2- {3- [6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl]- 2-Oxo-1,3-diazaspiro [4.5] dec-1-yl} -N- [4- (trifluoromethyl) pyridin-2-yl] acetamide (31 mg) and 2- {3- [6- (5-Methyl-1H-imidazol-1-yl) pyridin-3-yl] -2-oxo-1,3-diazaspiro [4.5] dec-1-yl} -N- [4- (trifluoromethyl ) Pyridin-2-yl] acetamide (2.7 mg) was obtained.
　実施例１から５で示した化合物と、同様の方法で合成した化合物の構造式とそれらの機器データを表１－１から１－３に示した。表中の実施例の欄に記載された数字は、その化合物が上記実施例１から５の内、どの実施例と同様な方法で合成されたかを示したものである。 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.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
試験例１　[グリシン取り込み阻害実験]
　グリシン取り込み実験はＮｅｕｒｏｎ，８，９２７－９３５，１９９２に掲載された方法に従って行った。ヒト１型グリシントランスポーター（ＧｌｙＴ１）を発現した神経膠腫であるＴ９８Ｇ細胞を用いた。Ｔ９８Ｇ細胞を９６ウェルプレートに２．０×１０4個／ウェルにて播種し、炭酸ガスインキュベーター内にて一晩培養した。被検物質は１００％ＤＭＳＯ溶液に溶解したのち、１５０ｍＭ塩化ナトリウム、１ｍＭ塩化カルシウム、５ｍＭ塩化カリウム、１ｍＭ塩化マグネシウム、１０ｍＭグルコースおよび０．２％ウシ血清アルブミンを含む１０ｍＭＨＥＰＥＳ緩衝液（ｐＨ７．４）に溶解させた。細胞培養用培地を除去した後、被検物質を１０分間前処置した。その後、被検物質および［3Ｈ］グリシン（最終濃度　２５０ｎＭ）を細胞に添加し、室温にて１５分間反応させた。反応終了後、マニーホールドにて細胞外液を吸引し、細胞外に存在する余分な標識グリシンを除去したのち、０．５Ｍの水酸化ナトリウム水溶液にて細胞を溶解した。細胞内に存在するグリシン量は、細胞溶解液中の放射活性を液体シンチレーションカウンターで測定することにより求めた。１０μＭのＡＬＸ５４０７存在下におけるグリシン取り込み量を非特異的取り込みとし、１０μＭのＡＬＸ５４０７非存在下の総取り込み量から非特異的取り込み量を差し引いたものを特異的取り込み量とした。また、被検物質の１０-9～１０-5Ｍ濃度での抑制曲線からグリシン取り込み阻害活性（ＩＣ50値）を算出した。 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. After removing the cell culture medium, 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 μM ALX5407 was defined as nonspecific uptake, and the total uptake in the absence of 10 μM 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.
　なおＡＬＸ５４０７はＮ－［（３Ｒ）－３－（［１，１’－ビフェニル］－４－イルオキシ）－３－（４－フルオロフェニル）プロピル］－Ｎ－メチルグリシンＨＣｌ塩である。 ALX5407 is N-[(3R) -3-([1,1'-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt.
　本発明における実施例化合物のＩＣ50値はすべて１０μＭ未満であった。具体的に例示すると、化合物１のＩＣ50値は０．０２０μＭ、化合物２のＩＣ50値は１．９μＭ、化合物３のＩＣ50値は２．２μＭ、化合物４のＩＣ50値は０．３０μＭ、化合物５のＩＣ50値は４．５μＭ、化合物６のＩＣ50値は２．３μＭ、化合物７のＩＣ50値は０．０２６μＭ、化合物８のＩＣ50値は０．０２３μＭ、化合物９のＩＣ50値は０．０７９μＭ、化合物１０のＩＣ50値は０．０９７μＭ、化合物１１のＩＣ50値は０．０５５μＭ、化合物１２のＩＣ50値は０．０２０μＭ、化合物１３のＩＣ50値は０．０５８μＭ、化合物１４のＩＣ50値は０．０３６μＭ、化合物１５のＩＣ50値は０．１４μＭ、化合物１６のＩＣ50値は０．０３８μＭ、化合物１７のＩＣ50値は０．０７３μＭ、化合物１８のＩＣ50値は０．２０μＭ、化合物１９のＩＣ50値は０．２３μＭ、化合物２０のＩＣ50値は０．２７μＭ、また化合物２１のＩＣ50値は１．３μＭ、であった。 The IC 50 values of the example compounds in the present invention were all less than 10 μM. Specific examples, an IC 50 value of Compound 1 0.020MyuM, the IC 50 values for compounds 2 1.9μM, IC 50 values of the compounds 3 are 2.2 uM, the IC 50 values for compounds 4 0.30μM, 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 μM, Compound 10 has an IC 50 value of 0.097 μM, Compound 11 has an IC 50 value of 0.055 μM, Compound 12 has an IC 50 value of 0.020 μM, Compound 13 has an IC 50 value of 0.058 μM, Compound 14 IC 50 values are 0.036MyuM, an IC 50 value of compound 15 0.14MyuM, an IC 50 value of compound 16 0.038MyuM, an IC 50 value of compound 17 0.073MyuM, the IC 50 value of compound 18 0.20 μM, Compound 19 I 50 value 0.23MyuM, an IC 50 value of Compound 20 0.27MyuM, also an IC 50 value of Compound 21 was 1.3 [mu] M,.
　本発明化合物はグリシントランスポーター（ＧｌｙＴ１）阻害活性を有し、従って、グリシントランスポーターに関連する疾患、具体的には、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害等の予防又は治療に有効である。 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.

Claims (8)

  1. 式［Ｉ］
    Figure JPOXMLDOC01-appb-C000001
      　 
    （式中、
    Ｒ1は、水素原子、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ヘテロアリール基（該ヘテロアリール基は、Ｃ1-6アルキル基で置換されても良い）、又はハロＣ1-6アルキル基を示し、
    Ｒ2は、水素原子、又はＣ1-6アルキル基を示し、
    Ｒ3は、Ｃ1-6アルキル基（該Ｃ1-6アルキル基は、Ｃ1-6アルキル基で置換されても良いフェニル基で置換されても良い）、フェニル基（該フェニル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）、又はピリジル基（該ピリジル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）を示し、
    ｎは、０～３の整数を示し、
    Ａ1、Ａ2、Ａ3、及びＡ4は、同一又は異なって、式ＣＨ、又は窒素原子を示し、但し、Ａ1、Ａ2、Ａ3、及びＡ4の１又は２個は窒素原子を示す。）で表される化合物又はその医薬上許容される塩。     Formula [I]
    Figure JPOXMLDOC01-appb-C000001

    (Where
    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 A C 1-6 alkyl group,
    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). May be substituted with 1 to 3 selected substituents),
    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.
  2. Ｒ1が、ハロゲン原子、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、ヘテロアリール基（該ヘテロアリール基は、Ｃ1-6アルキル基で置換されても良い）、又はハロＣ1-6アルキル基であり、
    Ｒ2が、水素原子であり、
    ｎが、１～３の整数である請求項１に記載の化合物又はその医薬上許容される塩。     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,
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of 1 to 3.
  3. Ｒ1はパラ位に結合している請求項１又は２に記載の化合物又はその医薬上許容される塩。 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is bonded to the para position.
  4. Ａ1、Ａ2、Ａ3及びＡ4のいずれか１個が窒素原子であるか、又はＡ１及びＡ３が共に窒素原子である請求項１～３のいずれか１項に記載の化合物又はその医薬上許容される塩。 The compound according to any one of claims 1 to 3, wherein 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. Its pharmaceutically acceptable salt.
  5. Ａ1が、窒素原子であり、
    Ａ2、及びＡ4が、共に式ＣＨであり、
    Ａ3が、式ＣＨ、又は窒素原子である請求項１～３のいずれか１項に記載の化合物又はその医薬上許容される塩。     A 1 is a nitrogen atom,
    A 2 and A 4 are both of the formula CH,
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein A 3 is formula CH or a nitrogen atom.
  6. Ｒ3が、フェニル基（該フェニル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）、又はピリジル基（該ピリジル基は、ハロゲン原子、及びハロＣ1-6アルキル基から選ばれる１～３個の置換基で置換されても良い）である、請求項１～５のいずれか１項に記載の化合物又はその医薬上許容される塩。 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 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 3 substituents selected from a halogen atom and a halo C 1-6 alkyl group. Salt.
  7. 請求項１～６のいずれか１項に記載の化合物又はその医薬上許容される塩を有効成分として含む、医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
  8. 請求項１～６のいずれか１項に記載の化合物又はその医薬上許容される塩を有効成分として含む、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害の疾患の予防剤又は治療剤。 A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, comprising as an active ingredient the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. , Convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, or sleep disorder preventive or therapeutic agent.
PCT/JP2012/054032 2011-02-21 2012-02-21 Glycine transport inhibitor WO2012115066A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092878A1 (en) * 2007-02-01 2008-08-07 Glaxo Group Limited Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders
WO2009034062A1 (en) * 2007-09-11 2009-03-19 Glaxo Group Limited Compounds which inhibit the glycine transporter and uses thereof in medicine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008092878A1 (en) * 2007-02-01 2008-08-07 Glaxo Group Limited Glyt1 transporter inhibitors and uses thereof in treatment of neurological and neuropsychiatric disorders
WO2009034062A1 (en) * 2007-09-11 2009-03-19 Glaxo Group Limited Compounds which inhibit the glycine transporter and uses thereof in medicine

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