JP2013249257A - Glycine transporter inhibitory substance - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound, and a pharmaceutically acceptable salt thereof, useful in the treatment or prevention of diseases caused by inhibitory activity on glycine intake, such as schizophrenia, Alzheimer's disease, cognitive impairment, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post traumatic stress disorder, specific phobias, acute stress disorder etc.), depression, substance abuse, convulsions, tremors, pain, or sleep disorders.SOLUTION: There is provided a compound represented by formula [I], or a pharmaceutically acceptable salt thereof.

Description

  The present invention relates to a compound having a glycine transporter inhibitory action.

  The NMDA receptor, which is one of glutamate receptors, exists on the nerve cell membrane 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).

  When the action potential reaches the presynaptic terminal of the glycinergic nerve, release of glycine into the synaptic cleft is started. The released glycine is removed from the synaptic cleft by the transporter after binding to a receptor or the like in the postsynaptic region. This suggests that the glycine transporter regulates the function of the NMDA receptor by regulating the amount of glycine in the extracellular fluid.

  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 to date. 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, and sleep disorders have been reported (Non-Patent Documents 2 to 4) ).

  Compounds having a GlyT1 inhibitory activity and having a 5-membered heteroarylamide structure have been reported in the following documents (Patent Documents 1 to 3, Non-Patent Documents 5 to 6).

WO2005 / 037216 WO2006 / 106425 WO2008 / 065500

Molecular Psychiatry (2004) 9, 984-997 Current Medicinal Chemistry, 2006, 13, 1017-1044 Neuropsychopharmacology (2005), 1-23 Expert Opinion on Therapeutic Patents (2004) 14 (2) 201-214 Bioorganic & Medicinal Chemistry Letters (2009) 19 2974-2976 Bioorganic & Medicinal Chemistry Letters (2010) 20 907-911

  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 A novel compound or a pharmaceutically acceptable salt thereof useful for the prevention or treatment of diseases such as depression, acute stress disorder, etc.), depression, drug dependence, convulsions, tremors, pain, or sleep disorders For the purpose.

  As a result of intensive studies on a compound having a novel skeleton having an inhibitory action on GlyT1, the present inventors have found that a compound represented by the following formula is an excellent GlyT1 inhibitor and complete the present invention. It came.

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]

Formula [I]

(Where
R ¹ represents a hydrogen atom or a C _1-6 alkyl group,
R ² is
a) substituted with 1 to 3 substituents selected from the group consisting of a phenyl group substituted with 1 to 5 halogen atoms, a C _1-6 alkoxy group, a halogen atom, and a C _3-6 cycloalkyl group A C _1-6 alkyl group, or
b) represents a C _3-6 cycloalkyl group,
Y represents a nitrogen atom or the formula CH;
Ar ¹ represents a structure selected from the following formula group [II],

R ^a is a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo C _1-6 alkoxy group optionally substituted with a pyrrolidinyl group, a fluorine atom, a chlorine atom, or A phenoxy group optionally substituted with a halo C _1-6 alkoxy group,
R ^f represents a halogen atom,
R ^b , R ^c , R ^d , R ^e , R ^g , R ^h , and R ⁱ are the same or different and each represents a hydrogen atom or a halogen atom) or a pharmaceutically acceptable salt thereof .

(2) R ² is
a) C _1-6 alkoxy groups, and 1-5 of 1-3 substituents which may be substituted with C _1-6 alkyl group selected from the group consisting of phenyl group substituted with a halogen atom, or ,
b) a C _3-6 cycloalkyl group,
Ar ¹ is a structure selected from the formula group [II],
R ^a is a halo C _1-6 alkyl group, a halo C _1-6 alkoxy group that may be substituted with a pyrrolidinyl group, or a phenoxy group that may be substituted with a halo C _1-6 alkoxy group,
R ^f is a halogen atom,
R ^c , R ^d , and R ^g are the same or different and are a hydrogen atom or a halogen atom,
The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R ^b , R ^e , R ^h , and R ⁱ are hydrogen atoms.

(3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl.

(4) R ² is any of 1-3 C _1-6 alkoxy group substituted by an optionally C _1-6 alkyl group, or a C _3-6 cycloalkyl group (1) - (3) Or a pharmaceutically acceptable salt thereof.

(5) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein R ² is a branched C _3-6 alkyl group or a C _3-6 cycloalkyl group. Salt.

(6) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein Y is the formula CH.

(7) Ar ¹ is represented by the formula [III]

A group represented by
R ^a is a haloC _1-6 alkoxy group,
R ^c and R ^d are the same or different and are a hydrogen atom or a halogen atom;
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (6), wherein R ^b and ^Re are hydrogen atoms.

(8) Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient Preventive or therapeutic agent for depression, drug dependence, convulsions, tremor, pain, or sleep disorder.

  The compound of the present invention has glycine transporter (GlyT1) inhibitory activity.

As used herein, “C _xy (x and y are natural numbers)” indicates that the number of carbon atoms is from x to y.

As used herein, the “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, or butyl. Group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group.

As used herein, the “C _3-6 cycloalkyl group” means a cycloalkyl group having 3 to 6 carbon atoms, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

As used herein, the “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.

  As used herein, “halogen” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

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, and the preferred number of substitution of halogen atoms is 1 to 3, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group.

As used herein, the term “halo C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substitution of halogen atoms is 1 to 3, for example, a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.

  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. Or 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.

Preferred embodiments of the compound of the present invention are listed below.
A compound in which R ¹ is a C _1-6 alkyl group is preferred, and a compound in which a methyl group is preferred.
R ² is 1-3 C _1-6 optionally substituted C _1-6 alkyl group an alkoxy group, or a C _3-6 is preferable compound is a cycloalkyl group, branched C _3-6 A compound that is an alkyl group or a C _3-8 cycloalkyl group is more preferable.
Ar ¹ represents the formula [III]

And a compound represented by the following formula: R ^a is a halo C _1-6 alkoxy group, R ^c and R ^d are the same or different and are a hydrogen atom or a halogen atom, and R ^b And a compound in which R ^e is a hydrogen atom.
Compounds where Y is the formula CH are preferred.

  The compound of the present invention may 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.

  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.

  In addition, the compounds of the present invention may 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.

  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), metoclopramide (metoclopramide), fluoxetine (fluxetine), citalopram (citallopram), escitalopram (dal), feloxetine (fluxetine) rtraline, zimeldine, venlafaxine, reboxetine, milnacipran, duloxetine, imipramine, imitriprine, imitriprine, imipramine ), Bupropion, amineeptine, divalproex, carbamazepine, diazepam, risperidone, olanzapine ), Ziprasidone, aripiprazole, quetiapine, perospirone, clozapine, haloperidol, piperidone, piperidone, , Mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine Chlorperazine, acetophenazine, thiothixene, chlorprothixene, lamotrigine, loxapine, molindone, etc. can be mentioned. These combinations may be administered simultaneously (in the same pharmaceutical formulation or in different pharmaceutical formulations), separately or sequentially.

  Particularly advantageous in connection with the use and treatment methods by 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 per day. This dosage can be appropriately increased or decreased depending on the age, weight and symptoms of the patient.

  Compounds of formula [I] can be prepared 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.

  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 and 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.

  “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 metal or alkaline earth such as sodium methoxide, sodium ethoxide, potassium tert-butoxide Lower alkoxides of similar metals; alkyl lithium such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide Alkali metal or alkaline earth metal hydroxide such as barium; Alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate; Alkali metal or alkaline earth such as sodium hydrogen carbonate, potassium hydrogen carbonate Metal carbonates; 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.

  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.

  Examples of the “Lewis acid” include boron trifluoride, aluminum trichloride, titanium tetrachloride, iron trichloride, zinc chloride, tin tetrachloride and the like.

General manufacturing method 1

In the formula, X ¹ represents a halogen atom or a hydroxyl group, L ¹ represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group; It is synonymous with.

Step 1: Compound (3) can be obtained by reacting compound (1) with compound (2) wherein X1 is a halogen atom in an inert solvent in the presence or absence of a base. Alternatively, compound (3) can be obtained by subjecting compound (1) and compound (2) wherein X1 is a hydroxyl group to various amidation reactions known to those skilled in the art. Here, the amidation reaction is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium in an inert solvent in the presence or absence of a base. Hexafluorophosphoric acid (HATU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide (DCC) ), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmol Amidation reaction using a condensing agent such as folinium chloride (DMT-MM), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI); An amidation reaction via a mixed acid anhydride using ethyl borocarbonate, isobutyl chlorocarbonate or trimethylacetyl chloride. Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.

Step 2: The compound (I) of the present invention can be obtained by reacting the compound (3) with the compound (4) in an inert solvent in the presence or absence of a base.

General manufacturing method 2

Step 3: Compound (7) can be obtained by subjecting Compound (5) and Compound (6) 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 4: The compound (I) of the present invention can be obtained by the method of the general production method 1, step 1 using the compound (7) and the compound (2).

General manufacturing method 3

In the formula, R ^a and R ^b are independently selected from a hydrogen atom, a C _1-6 alkoxy group, a halogen atom, a C _3-6 cycloalkyl group, and a phenyl group substituted with 1 to 5 halogen atoms. Represents a C _1-5 alkyl group, a C _3-6 cycloalkyl group, or a phenyl group substituted with 1 to 5 halogen atoms which may be substituted with 1 to 3 substituents, or R ^a and R ^b may form a C _3-6 cycloalkyl ring together with the carbon atom to which it is bonded.

Step 5: Compound (7a) can be obtained by the method of Step 3 of General Production Method 2 using Compound (8) and Compound (1). The compound (7a) is included in the compound represented by the above compound (7).

General manufacturing method 4

In the formula, R ^1a represents a C _1-6 alkyl group, and other symbols are as defined above.

Step 6: Compound (I-2) of the present invention by reacting compound (I-1) of the present invention wherein R ¹ is a hydrogen atom with compound (9) in an inert solvent in the presence or absence of a base. Can be obtained.

General manufacturing method 5

In the formula, X ² represents boric acid, a boric acid ester or a halogen atom, Ar ² represents a phenyl group which may be substituted with a halo C _1-6 alkoxy group, and other symbols are as defined above.

Step 7: Compound of the present invention by reacting Compound (11) with Compound (11) in the presence of a copper catalyst and optionally an amine ligand in an inert solvent in the presence or absence of a base (I-3) can be obtained. Here, examples of the copper catalyst include copper oxide (I), copper iodide (I), copper bromide (I), copper bromide (II), copper acetate (I), copper acetate (II) and the like. Examples of the amine ligand include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, and phenanthroline.

  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.

  In the following production examples and examples, the microwave reactor used was Biotage Initiator.

  In the following preparation examples and examples, “NH silica gel cartridge” when purified using column chromatography is Biotage® SNAPPartridge KP-NH, and “silica gel cartridge” is Biotage® SNAPPartridge KP. -Sil was used. As the “reverse phase silica gel cartridge”, MORITEX (registered trademark) Purif-Pack ODS was used.

  In the following production examples and examples, “NH silica” 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.

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
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 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, 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 or micromass Platform LC

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 1-Methyl-N- [3- (trifluoromethoxy) benzyl] -1H-imidazole-4-carboxamide

To a mixture of 1-methyl-1H-imidazole-4-carboxylic acid (500 mg), EDC · HCl (920 mg), HOBt · H 2 O (735 mg) and acetonitrile (10 mL) was added 3-trifluoromethoxybenzylamine (841 mg) in acetonitrile (841 mg). 10 mL) solution was added and stirred overnight at room temperature. Acetonitrile was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform / methanol = 1: 0 to 9: 1) to give the title compound (1.18 g). .
1H NMR (600 MHz, CHLOROFORM-d) d ppm 3.73 (s, 3 H), 4.62 (d, J = 6.0 Hz, 2 H), 7.08-7.14 (m, 1 H), 7.18 (s, 1 H) , 7.26-7.30 (m, 1 H), 7.31-7.37 (m, 2 H), 7.47 (br. S., 1 H), 7.52-7.57 (m, 1 H)
(ESI pos.) M / z: 300 ([M + H] ⁺ )

Production Example 2 N- [4-Fluoro-3- (trifluoromethoxy) benzyl] propan-2-amine

2-Aminopropane (140 mg) was added to a solution of 4-fluoro-3-trifluoromethoxybenzaldehyde (500 mg) in chloroform (5 mL), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (610 mg) was added and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (NH cartridge, hexane / ethyl acetate = 9: 1 to 3: 1) to obtain the title compound (660 mg).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.09 (d, J = 6.2 Hz, 6 H), 2.74-2.91 (m, 1 H), 3.76 (s, 2 H), 7.07-7.35 (m, 3 H)
(ESI pos.) M / z: 252 ([M + H] ⁺ )

The following compounds were synthesized in the same manner.
(1-{[3- (trifluoromethoxy) benzyl] amino} cyclopentyl) methanol
(ESI pos.) M / z: 290 ([M + H] ⁺ )
N- (3-bromo-4-fluorobenzyl) propan-2-amine
(ESI pos.) M / z: 246, 248 ([M + H] ⁺ )
N- (3-bromo-4-fluorobenzyl) cyclohexaneamine
(ESI pos.) M / z: 286, 288 ([M + H] ⁺ )
N- [3-Chloro-5- (trifluoromethoxy) benzyl] cyclohexaneamine
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.96-1.99 (m, 10 H), 2.36-2.53 (m, 1 H), 3.81 (s, 2 H), 7.07-7.16 (m, 2 H), 7.27-7.34 (m, 1 H)
N- [3-Chloro-5- (trifluoromethoxy) benzyl] propan-2-amine
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.09 (d, J = 6.2 Hz, 6 H), 2.75-2.91 (m, 1 H), 3.78 (s, 2 H), 7.07-7.15 (m, 2 H), 7.28-7.32 (m, 1 H)
N- [3-Chloro-5- (trifluoromethoxy) benzyl] cyclopentanamine
(ESI pos.) M / z: 294 ([M + H] ⁺ )
N-[(2-Bromopyridin-4-yl) methyl] propan-2-amine
(ESI pos.) M / z: 229, 231 ([M + H] ⁺ )
N-[(6-Bromopyridin-2-yl) methyl] propan-2-amine
(ESI pos.) M / z: 229, 231 ([M + H] ⁺ )
N-[(6-Bromo-5-fluoropyridin-2-yl) methyl] propan-2-amine
(ESI pos.) M / z: 247, 249 ([M + H] ⁺ )
N-[(2-bromopyridin-4-yl) methyl] cyclobutanamine
(ESI pos.) M / z: 241, 243 ([M + H] ⁺ )
N- [4-Fluoro-3- (trifluoromethoxy) benzyl] cyclobutanamine
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.56-1.82 (m, 4 H), 2.12-2.31 (m, 2 H), 3.18-3.33 (m, 1 H), 3.68 (s, 2 H), 7.05-7.33 (m, 3 H)
(ESI pos.) M / z: 264 ([M + H] ⁺ )
N- [4-Fluoro-3- (trifluoromethoxy) benzyl] tetrahydro-2H-pyran-4-amine
(ESI pos.) M / z: 294 ([M + H] ⁺ )
N- (4-Fluorobenzyl) propan-2-amine
(ESI pos.) M / z: 168 ([M + H] ⁺ )
1- (4-Fluorophenyl) -N- [3- (trifluoromethyl) benzyl] methanamine

Production Example 3 N- [3- (trifluoromethoxy) benzyl] propan-2-amine

To a solution of acetone (0.38 mL) and 3-trifluoromethoxybenzylamine (1.0 g) in chloroform (10 mL) was added sodium triacetoxyborohydride (2.2 g), and the mixture was stirred at room temperature for 45 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform / methanol = 1: 0 to 9: 1) to give the title compound (0.68 g). .
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.10 (d, J = 6.4 Hz, 6 H), 2.84 (spt, J = 6.3 Hz, 1 H), 3.80 (s, 2 H), 7.09 (d, J = 7.3 Hz, 1 H), 7.20 (s, 1 H), 7.30-7.36 (m, 1 H)
(ESI pos.) M / z: 234 ([M + H] ⁺ )

The following compounds were synthesized in the same manner.
N- [3- (trifluoromethoxy) benzyl] cyclohexaneamine
(ESI pos.) M / z: 274 ([M + H] ⁺ )

Production Example 4 N- (propan-2-yl) -N- [3- (trifluoromethoxy) benzyl] -1H-1,2,4-triazole-3-carboxamide

N- [3- (trifluoromethoxy) benzyl] isopropylamine (450 mg), 1H-1,3,4-triazole-5-carboxylic acid (220 mg), HATU (1.1 g), diisopropylethylamine (750 mg) and acetonitrile (5 mL) was stirred at room temperature overnight. After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (NH cartridge, hexane / ethyl acetate = 1: 1 to 0/1, chloroform / methanol = 1: 0 to 19: 1) to obtain the title compound (500 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.19-1.30 (m, 6 H), 4.57-6.01 (m, 3 H), 7.08-7.13 (m, 2 H), 7.15-7.22 (m, 1 H ), 7.30-7.38 (m, 1 H), 7.97-8.21 (m, 1 H)
(ESI pos.) M / z: 329 ([M + H] ⁺ )

The following compounds were synthesized in the same manner.
N- (3-bromo-4-fluorobenzyl) -N- (propan-2-yl) -1H-1,2,4-triazole-3-carboxamide
(ESI pos.) M / z: 339, 341 ([M + H] ^- )
N- (3-bromo-4-fluorobenzyl) -N-cyclohexyl-1H-1,2,4-triazole-3-carboxamide
(ESI pos.) M / z: 379, 381 ([M + H] ^- )
N- [3-Chloro-5- (trifluoromethoxy) benzyl] -N- (propan-2-yl) -1H-1,2,4-triazole-3-carboxamide
(ESI pos.) M / z: 363 ([M + H] ⁺ )
N- [3-Chloro-5- (trifluoromethoxy) benzyl] -N-cyclopentyl-1H-1,2,4-triazole-3-carboxamide
(ESI pos.) M / z: 389 ([M + H] ⁺ )
N- [4-Fluoro-3- (trifluoromethoxy) benzyl] -N- (propan-2-yl) -1H-1,2,4-triazole-3-carboxamide
(ESI pos.) M / z: 347 ([M + H] ⁺ )

Production Example 5 N- (4-Fluoro-3-hydroxybenzyl) -1-methyl-N- (propan-2-yl) -1H-imidazole-4-carboxamide

(1) A solution of 4-fluoro-3-hydroxybenzoic acid methyl ester (5 g), tert-butyldimethylsilyl chloride (13.2 g), and imidazole (10 g) in dimethylformamide (50 mL) was stirred at room temperature for 1 hour. Water was added, extracted with diethyl ether, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 1: 0 to 19: 1), and methyl 3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzoate (7. 2 g) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.21 (s, 6 H), 1.01 (s, 9 H), 3.89 (s, 3 H), 7.03-7.16 (m, 1 H), 7.54-7.69 ( m, 2 H)

(2) To a solution of methyl 3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzoate (2 g) in tetrahydrofuran (20 mL) cooled in a dry ice-acetone bath, diisobutylaluminum hydride (1.0 M Hexane solution (7.7 mL) was added dropwise and stirred for 1 hour. Diisobutylaluminum hydride (7.7 mL) was further added, and the mixture was further stirred for 1 hour. Aqueous potassium sodium tartrate solution was added and stirred for 1 hour, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain (3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorophenyl) methanol (1.7 g).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.19 (s, 6 H), 1.00 (s, 9 H), 4.60 (s, 2 H), 6.82-7.08 (m, 3 H)

(3) Manganese dioxide (9.2 g) was added to a solution of (3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorophenyl) methanol (900 mg) in chloroform (20 mL) and stirred overnight at room temperature. did. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzaldehyde (935 mg).

(4) From 3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzaldehyde (1.7 g) and 2-aminopropane (435 mg) in the same manner as in Production Example 2, N- (3- {[Tert-Butyl (dimethyl) silyl] oxy} -4-fluorobenzyl) propan-2-amine (2.0 g) was obtained.
(ESI pos.) M / z: 298 ([M + H] ⁺ )

(5) In the same manner as in Production Example 4, N- (3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzyl) propan-2-amine (2.0 g) and 1-methyl- From 1H-imidazole-4-carboxylic acid (840 mg), N- (3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzyl) -1-methyl-N- (propan-2-yl) -1H-imidazole-4-carboxamide (1.19 g) was obtained.
(ESI pos.) M / z: 406 ([M + H] ⁺ )

(6) N- (3-{[tert-butyl (dimethyl) silyl] oxy} -4-fluorobenzyl) -1-methyl-N- (propan-2-yl) -1H-imidazole-4-carboxamide (1 .19 g) in THF (20 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 2.9 mL), and the mixture was stirred at room temperature for 10 minutes. Water was added and extracted with chloroform. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, chloroform / methanol = 1: 0 to 19: 1) to obtain the title compound (750 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.11-1.23 (m, 6 H), 3.70 (br. S., 3 H), 4.47-5.75 (m, 3 H), 6.70-7.55 (m, 5 H)
(ESI pos.) M / z: 292 ([M + H] ⁺ )

Production Example 6 6-Bromo-5-fluoropyridine-2-carbaldehyde

(1) N-bromosuccinimide (940 mg) and benzoyl peroxide (102 mg) were added to a solution of 2-bromo-3-fluoro-6-picoline (500 mg) in carbon tetrachloride (10 mL), and the mixture was heated and stirred at 80 ° C. for 5 hours. did. After stirring at room temperature for 16.5 hours, N-bromosuccinimide (90 mg) and benzoyl peroxide (20 mg) were added, and the mixture was heated and stirred at 80 ° C. for 5 hours. After stirring at room temperature for 18 hours, the insoluble material was filtered off and washed with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel cartridge, hexane: ethyl acetate = 98: 2-82: 18) and (silica gel cartridge and NH silica gel cartridge, hexane: ethyl acetate = 98: 2). To 82:18) to give 2-bromo-6- (dibromomethyl) -3-fluoropyridine (663 mg).
(ESI pos.) M / z: 346, 348, 350, 352 ([M + H] ⁺ )

(2) A solution of 2-bromo-6- (dibromomethyl) -3-fluoropyridine (615 mg) and calcium carbonate (391 mg) in dimethyl sulfoxide (6.5 mL) was heated and stirred at 150 ° C. for 4.5 hours and then returned to room temperature. For 15.5 hours. Water was added and the mixture was stirred and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel cartridge, hexane: ethyl acetate = 98: 2-82: 18) to give the title compound (240 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 7.55-7.64 (m, 1 H), 7.95-8.03 (m, 1 H), 9.99 (s, 1 H)
(ESI pos.) M / z: 204, 206 ([M + H] ⁺ )

Example 1 N, 1-Dimethyl-N- [3- (trifluoromethoxy) benzyl] -1H-imidazole-4-carboxamide

Under a nitrogen atmosphere, sodium hydride (8 mg) was added to a solution of 1-methyl-N- [3- (trifluoromethoxy) benzyl] -1H-imidazole-4-carboxamide in dimethylformamide (1 mL) and stirred at room temperature for 10 minutes. did. Methyl iodide (12 μL) was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform / methanol = 1: 0 to 49: 1) to give the title compound (42 mg).

Example 2 N- [3-Chloro-5- (trifluoromethoxy) benzyl] -1-methyl-N- (propan-2-yl) -1H-1,2,4-triazole-3-carboxamide hydrochloride

N- [3-Chloro-5- (trifluoromethoxy) benzyl] propan-2-amine (232 mg), 1-methyl-1H-imidazole-4-carboxylic acid (99 mg), EDC · HCl (196 mg), HOBT · A mixture of H2O (144 mg) and dimethylformamide (6 mL) was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue for extraction. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH cartridge, hexane / ethyl acetate = 9: 1 to 1: 1). 135 mg of the product was dissolved in ethyl acetate, 4M hydrochloric acid / ethyl acetate was added and stirred for 5 minutes, and then the solvent was distilled off under reduced pressure. Ethyl acetate and hexane were added to the residue, and the precipitated solid was collected by filtration to give the title compound (89 mg).

Example 3 1-Methyl-N- (propan-2-yl) -N- [3- (trifluoromethoxy) benzyl] -1H-1,2,4-triazole-3-carboxamide

N- (propan-2-yl) -N- [3- (trifluoromethoxy) benzyl] -1H-1,2,4-triazole-3-carboxamide (400 mg) in dimethylformamide (5 mL) in sodium hydride (60 mg) was added and stirred at room temperature for 10 minutes. Methyl iodide (430 mg) was added and stirred at room temperature for 2 hours. After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure. The residue was purified by PTLC (silica gel) (chloroform / methanol = 18: 1) to obtain the title compound (200 mg).

Example 4 N- {4-Fluoro-3- [4- (trifluoromethoxy) phenoxy] benzyl} -1-methyl-N- (propan-2-yl) -1H-imidazole-4-carboxamide

N- (4-fluoro-3-hydroxybenzyl) -1-methyl-N- (propan-2-yl) -1H-imidazole-4-carboxamide (100 mg), 4-trifluoromethoxyphenylboronic acid (140 mg), A mixture of copper (II) acetate monohydrate (68 mg), triethylamine (171 mg), 4A molecular sieves and chloroform (3 mL) was stirred at room temperature overnight. Chloroform and water were added for liquid separation, and then the organic layer was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (20 mg).

Example 5 N- {3- [1,1-Difluoro-2- (pyrrolidin-1-yl) ethoxy] -4-fluorobenzyl} -1-methyl-N- (propan-2-yl) -1H-imidazole -4-carboxamide

(1) N- (4-Fluoro-3-hydroxybenzyl) -1-methyl-N- (propan-2-yl) -1H-imidazole-4-carboxamide (150 mg), 4-methylbenzenesulfonic acid 2,2 -A mixture of difluoroethenyl (145 mg), potassium hydroxide (70 mg) and acetonitrile (6 mL) was stirred at room temperature for 30 minutes. Water and chloroform were added and the phases were separated, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform / methanol = 1: 0 to 19: 1), and 4-methylbenzenesulfonic acid 2,2-difluoro-2- [2-fluoro-5-({[( 1-methyl-1H-imidazol-4-yl) carbonyl] (propan-2-yl) amino} methyl) phenoxy] ethyl (260 mg) was obtained.
(ESI pos.) M / z: 526 ([M + H] ⁺ )

(2) 4-methylbenzenesulfonic acid 2,2-difluoro-2- [2-fluoro-5-({[(1-methyl-1H-imidazol-4-yl) carbonyl] (propan-2-yl) amino } Methyl) phenoxy] ethyl (100 mg) was dissolved in pyrrolidine (3 mL) and heated at 150 ° C. for 1 hour under microwave irradiation. The reaction solution was purified by PTLC (chloroform / methanol = 18: 1) to obtain the title compound (19 mg).

Example 6 N-cyclobutyl-N- [4-fluoro-3- (trifluoromethoxy) benzyl] -1-methyl-1H-imidazole-4-carboxamide hydrochloride

To a solution of 1-methyl-1H-imidazole-4-carboxylic acid (256 mg) in methanol (10 mL) was added diisopropylethylamine (391 μL), DMT-MM (655 mg), and N- [4-fluoro-3- (trifluoromethoxy). [Benzyl] cyclobutanamine (445 mg) was added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform, and then the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC, dissolved in 1.0 M hydrochloric acid and lyophilized to give the title compound (68 mg).

  The structural formulas of the compounds shown in Examples 1 to 6 and the compounds synthesized by the same method and the instrument data thereof are shown in Tables 1-1 to 1-4. The numbers described in the column of the examples in the table indicate which of the above Examples 1 to 6 was synthesized by the same method as in the above Examples.

Test Example 1 [Glycine uptake inhibition experiment]
The glycine uptake experiment was 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.

  ALX5407 is N-[(3R) -3-([1,1'-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt.

IC ₅₀ values of all the compounds of the present invention were 1 μM or less. Among the compounds of the present invention, the IC ₅₀ values of compounds 1 to 7, 9 to 11, 13, 15, 16, 18, 20, 21, 24 to 26, 29, and 31 were 0.1 μM or less. Among them, the IC ₅₀ values of the compounds 1, 5 to 7, 11, 15, 16, 18, 25, and 29 were 0.01 μM or less.

  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) Prevention of 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, sleep disorder, etc. It is effective for treatment.

Claims (8)

Formula [I]

(Where
R ¹ represents a hydrogen atom or a C _1-6 alkyl group,
R ² is
a) substituted with 1 to 3 substituents selected from the group consisting of a phenyl group substituted with 1 to 5 halogen atoms, a C _1-6 alkoxy group, a halogen atom, and a C _3-6 cycloalkyl group A C _1-6 alkyl group, or
b) represents a C _3-6 cycloalkyl group,
Y represents a nitrogen atom or the formula CH;
Ar ¹ represents a structure selected from the following formula group [II],

R ^a is a C _1-6 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a halo C _1-6 alkoxy group optionally substituted with a pyrrolidinyl group, a fluorine atom, a chlorine atom, or A phenoxy group optionally substituted with a halo C _1-6 alkoxy group,
R ^f represents a halogen atom,
R ^b , R ^c , R ^d , R ^e , R ^g , R ^h , and R ⁱ are the same or different and each represents a hydrogen atom or a halogen atom) or a pharmaceutically acceptable salt thereof . R ² is
a) C _1-6 alkoxy groups, and 1-5 of 1-3 substituents which may be substituted with C _1-6 alkyl group selected from the group consisting of phenyl group substituted with a halogen atom, or ,
b) a C _3-6 cycloalkyl group,
Ar ¹ is a structure selected from the formula group [II],
R ^a is a halo C _1-6 alkyl group, a halo C _1-6 alkoxy group that may be substituted with a pyrrolidinyl group, or a phenoxy group that may be substituted with a halo C _1-6 alkoxy group,
R ^f is a halogen atom,
R ^c , R ^d , and R ^g are the same or different and are a hydrogen atom or a halogen atom,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^b , R ^e , R ^h , and R ⁱ are hydrogen atoms. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C _1-6 alkyl. R ² is 1-3 C _1-6 is a C _1-6 alkyl group optionally substituted with an alkoxy group, or a C _3-6 according to any one of claims 1 to 3 is a cycloalkyl group Or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ² is a branched C _3-6 alkyl group or a C _3-6 cycloalkyl group. Y is Formula CH, The compound or its pharmaceutically acceptable salt of any one of Claims 1-5. Ar ¹ represents the formula [III]

A group represented by
R ^a is a haloC _1-6 alkoxy group,
R ^c and R ^d are the same or different and are a hydrogen atom or a halogen atom;
^Rb and ^Re are a hydrogen atom, The compound or its pharmaceutically acceptable salt of any one of Claims 1-6. 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 7 or a pharmaceutically acceptable salt thereof. Preventive or therapeutic agent for diseases of convulsions, tremors, pain, or sleep disorders.