HETEROCYCLIC NMDA ANTAGONISTS

Abstract

A compound of formula (I), or a salt thereof that may have an antagonistic action against an NMDA receptor that includes an NR2B subunit and may be useful as a prophylactic or therapeutic agent for depression, bipolar disorder, migraine, pain, a symptom peripheral to dementia, or the like.

##STR00001##

Claims

1-14. (canceled)

15. A compound which is (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one, or a salt thereof.

16. The compound according to claim 15, which is crystalline (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° degrees two theta.

17. The compound according to claim 15, which is crystalline (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° degrees two theta.

18. The compound according to claim 15, which is crystalline (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° degrees two theta.

19. A pharmaceutical composition comprising (4S)-3-{[2-(4-chloro fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one or a salt thereof and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising crystalline (4S)-3-{[2-(4-chloro fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° degrees two theta and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, the pharmaceutical composition comprising crystalline (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° degrees two theta and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 20, the pharmaceutical composition comprising crystalline (4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidin-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2°, and 24.5°±0.2° degrees two theta and a pharmaceutically acceptable carrier.

Description

EXAMPLES

[0458] The present disclosure is explained in further detail using the following by referring Examples, Experimental Examples, and Formulation Examples. These examples do not limit the present disclosure in any way and may be changed so long as they do not deviate from the scope of the present disclosure.

[0459] “Room temperature” in the following Examples generally means about 10° C. to about 35° C. The ratios indicated for mixed solvents are volumetric ratios unless otherwise specified. % means the wt. % unless specifically noted otherwise.

[0460] Elution in column chromatography in the Examples was performed under observation using TLC (thin layer chromatography). For TLC observation, 60 F.sub.254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent in column chromatography was also used as a developing solvent. For detection, a UV detector was employed. In silica gel column chromatography, the recitation of NH refers to use of an aminopropylsilane-bound silica gel, and the recitation of diol refers to use of 3-(2,3-dihydroxypropoxy)propylsilane-bound silica gel. In preparative HPLC (high-performance liquid chromatography), the recitation of C18 refers to use of octadecyl-bounded silica gel. The ratio shown for elution solvents indicates a capacity ratio unless otherwise specified.

[0461] ACD/SpecManager (trade name) software or the like was used in .sup.1H NMR analysis. Extremely gradual proton peaks such as those of hydroxyl groups or amino groups are sometimes not described.

[0462] MS was measured by LC/MS. An ESI method or APCI method was used as an ionization method. Data indicate measured values (found). Generally, molecular ion peaks are observed but sometimes they may be observed as fragment ions. In the case of salts, a molecular ion peak or a fragment ion peak of a free form is generally observed.

[0463] The unit of sample concentration (c) for optical rotation ([α].sub.D) is g/100 mL.

[0464] The elemental analysis value (anal.) is indicated as a calculated value (calcd) and a measured value (found).

[0465] The peaks in the powder x-ray diffraction of the Examples mean peaks measured at room temperature using an Ultima IV (Rigaku Corporation, Japan) using the Cu Kα radiation as a radiation source.

[0466] The measurement conditions are as follows.

[0467] Electric pressure/Electric current: 40 kV/50 mA

[0468] Scan speed: 6 degrees/min

[0469] Scan range of 2 theta: 2 to 35 degrees

[0470] The crystallinity by the powder x-ray diffraction of the Examples was calculated by the Hermans method.

[0471] The abbreviations below are used in the following Examples.

[0472] mp: melting point

[0473] MS: mass spectrum

[0474] M: molar concentration

[0475] N: normality

[0476] CDCl.sub.3: deuterochloroform

[0477] DMSO-d.sub.6: deuterodimethyl sulfoxide

[0478] .sup.1H NMR: proton nuclear magnetic resonance

[0479] LC/MS: liquid chromatograph mass spectrometer

[0480] ESI: electrospray ionization

[0481] APCI: atmospheric pressure chemical ionization

[0482] IPE: diisopropylether

[0483] DMF: N,N-dimethylformamide

[0484] THF: tetrahydrofuran

[0485] MeOH: methanol

[0486] MeCN: acetonitrile

[0487] NMP: N-methylpyrrolidone

Example 13

(4S,5S)-4-hydroxy-5-methyl-1-{[6-(4-methylphenoxy)pyridine-3-yl]methyl}pyrrolidine-2-one

A) Methyl 6-(p-tolyloxy)nicotinate

[0488] Potassium carbonate (8.55 g) was added at room temperature to a suspension of methyl 6-fluoronicotinate (8.00 g) and p-cresol (5.96 mL) in DMF (80 mL), and the mixture was stirred for three hours at 80° C. After diluting with water, the resulting precipitate was filtered and washed with water to give the title compound (12.5 g).

[0489] MS: [M+H].sup.+ 244.1.

B) (6-(p-tolyloxy)pyridine-3-yl)methanol

[0490] Sodium borohydride (6.61 g) was added at room temperature to a suspension of methyl 6-(p-tolyloxy)nicotinate (11.5 g) in THF (100 mL)/MeOH (20 mL) and stirred overnight. Then, the mixture was stirred for three hours at 60° C. After diluting with an aqueous ammonium chloride solution and ethyl acetate, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue was powderized using hexane to give the title compound (9.46 g).

[0491] MS: [M+H].sup.+ 216.1.

C) 5-(bromomethyl)-2-(p-tolyloxy)pyridine

[0492] Phosphorus tribromide (0.389 mL) was added at 0° C. to a mixture of (6-(p-tolyloxy)pyridine-3-yl)methanol (740 mg) and THF (10 mL) and stirred for three hours at room temperature.

[0493] After diluting with ethyl acetate and water, the mixture was extracted with ethyl acetate. After washing with an aqueous sodium hydrogen carbonate solution and saturated saline solution, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was powderized using hexane/ethyl acetate to give the title compound (842 mg).

[0494] MS: [M+H].sup.+ 278.0.

D) (4S,5S)-4-hydroxy-5-methyl-1-{[6-(4-methylphenoxy)pyridine-3-yl]methyl}pyrrolidine one

[0495] 0.5 M potassium hexamethyldisilazide toluene solution (19.2 mL) was added at 0° C. to a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidine-2-one (2.00 g), 5-(bromomethyl)-2-(p-tolyloxy)pyridine (3.64 g), and THF (20 mL), and stirred overnight at room temperature.

[0496] After diluting with ethyl acetate and water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then it was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to obtain (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methyl-1-((6-(p-tolyloxy)pyridine-3-yl)methyl)pyrrolidine-2-one (2.13 g). This was dissolved in THF (10 mL), then 4M hydrogen chloride cyclopentyl methyl ether solution (20 mL) was added at room temperature, and the mixture was stirred for three hours at 60° C.

[0497] After diluting with ethyl acetate and aqueous saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane, and ethyl acetate/methanol) and powderized using hexane/ethyl acetate to give the title compound (1.24 g).

[0498] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.05 (3H, d, J=6.8 Hz), 2.15 (1H, dd, J=16.6, 3.4 Hz), 2.31 (3H, s), 2.52-2.61 (1H, m), 3.43-3.55 (1H, m), 4.07 (1H, d, J=15.4 Hz), 4.11-4.21 (1H, m), 4.59 (1H, d, J=15.4 Hz), 5.06 (1H, d, J=4.9 Hz), 6.90-7.02 (3H, m), 7.20 (2H, d, J=7.9 Hz), 7.66 (1H, dd, J=8.5, 2.4 Hz), 8.01 (1H, d, J=1.9 Hz).

Example 17

(4 S, 5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one

[0499] After adding 2 M hydrogen chloride-ethanol solution (240 mL) dropwise to an ethanol (100 mL) solution of the (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2-fluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidine-2-one (140 g) obtained by steps A) to E) in example 38 at 0° C., 5% hydrogen chloride-methanol solution (218 mL) was added, the resultant mixture was slowly returned to room temperature and stirred overnight (using grained silica gel tube). The mixture was concentrated, ethyl acetate (500 mL) was then added to the residue and cooled to 0° C., then aqueous sodium carbonate solution (500 mL) was slowly added, and the organic layer and the aqueous layer were isolated. The aqueous layer was washed with ethyl acetate (1000 mL), and the organic layer was isolated. The obtained organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. After dissolving the residue in ethyl acetate (500 mL), it was then filtered through NH silica gel pad (eluted with ethyl acetate (2000 mL)) and concentrated under reduced pressure. Toluene/ethyl acetate (1:0.5) was added to the residue and heated to 50° C. while stirring, then filtered to obtain a crude product (90.5 g). After further concentrating the filtrate, the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6.37 g).

[0500] All steps to this point were repeated 7 times to finally obtain 525 g of the title compound.

[0501] Ethyl acetate (1630 mL) was added to the title compound (523 g) thus obtained, heated to 50° C., and stirred until dissolved. The solution was filtered and cooled to room temperature, then heptane (2120 mL) was added dropwise while stirring. After stirring the mixture for 1 hour, heptane (4230 mL) was added dropwise. Heptane (4230 mL) was added dropwise to the mixture, and the mixture was further stirred overnight. The precipitate was collected by filtration and washed with heptane, then dried under reduced pressure at 50° C. to obtain the title compound (500 g) as crystals.

[0502] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.04 (3H, d, J=6.6 Hz) 2.15 (1H, dd, J=16.7, 3.3 Hz) 2.52-2.60 (1H, m) 3.45-3.54 (1H, m) 4.07-4.19 (2H, m) 4.59 (1H, d, J=15.5 Hz) 5.07 (1H, d, J=4.5 Hz) 6.86-7.27 (2H, m) 7.47 (2H, d, J=4.1 Hz) 7.61 (1H, d, J=11.3 Hz) 7.74 (1H, dd, J=8.5, 2.5 Hz) 7.99 (1H, d, J=1.9 Hz).

[0503] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Copper K-alpha radiation.

[0504] The obtained crystal was characterized by having specific peaks at the two thetas of 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees in a powder X-ray diffraction pattern.

Example 37

(4S,5S)-1-{[6-(2,4-difluorophenoxy)pyridine-3-yl]methyl}-4-hydroxy-5-methylpyrrolidine-2-one

A) Methyl 6-(2,4-difluorophenoxy)nicotinate

[0505] A mixture of methyl 6-fluoronicotinate (4.31 g), 2,4-difluorophenol (3.80 g), potassium carbonate (5.76 g), and MeCN (30 mL) was stirred for 16 hours at 60° C. The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate solution and saturated saline solution, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure to give the title compound (7.37 g).

[0506] MS: [M+H].sup.+ 266.3.

B) Methyl (6-(2,4-difluorophenoxy)pyridine-3-yl)methanol

[0507] Sodium borohydride (4.21 g) was added at room temperature to a suspension of methyl 6-(2,4-difluorophenoxy)nicotinate (7.37 g) in THF (60 mL)/MeOH (15 mL), and the mixture was stirred for three hours at 60° C.

[0508] Then added sodium borohydride (4.21 g) at room temperature, and the mixture was stirred for an additional three hours at 60° C. The solvent was distilled off, and the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure to give the title compound (6.59 g).

[0509] MS: [M+H].sup.+ 238.3.

C) 5-(bromomethyl)-2-(2,4-difluorophenoxy)pyridine

[0510] Phosphorus tribromide (2.90 mL) was added at 0° C. to a mixture of (6-(2,4-difluorophenoxy)pyridine-3-yl)methanol (6.59 g) and THF (70 mL) and stirred for 16 hours at room temperature.

[0511] The mixture was diluted with ethyl acetate, and the solution was washed with aqueous sodium hydrogen carbonate solution and saturated saline solution, and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.07 g).

[0512] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 4.72 (2H, s), 7.10-7.20 (2H, m), 7.36-7.50 (2H, m), 7.96 (1H, dd, J=8.5, 2.4 Hz), 8.18 (1H, d, J=2.3 Hz).

D) (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(2,4-difluorophenoxy)pyridin-3-yl)methyl)-5-methylpyrrolidine-2-one

[0513] 1.6 M butyllithium hexane solution (6.16 mL) was added at −78° C. to a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidine-2-one (2.26 g) and THF (40 mL) and stirred for 30 minutes at 0° C. 5-(bromomethyl)-2-(2,4-difluorophenoxy)pyridine (2.96 g) was added to the mixture and stirred for 1 hour at room temperature then stirred for an additional 7.5 hours at 50° C. After diluting with ethyl acetate and water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give the title compound (2.30 g).

[0514] MS: [M+H].sup.+ 449.2.

E) (4S,5S)-1-{(6-(2,4-difluorophenoxy)pyridine-3-yl]methyl}-4-hydroxy-5-methylpyrrolidine one

[0515] A mixture of (4S,5S)-4((tert-butyldimethyl silyl)oxy)-1-((6-(2,4-difluorophenoxy)pyridine-3-yl)methyl)-5-methylpyrrolidine-2-one (2.29 g) and 2M hydrogen chloride-ethanol solution (40 mL) were stirred for one hour at room temperature.

[0516] The mixture was concentrated, then the residue was diluted with aqueous sodium hydrogen carbonate solution, then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and ethyl acetate/methanol) to give a crude product. This was dissolved in ethyl acetate at 80° C., heptane was added dropwise to the solution, and the resulting suspension was stirred for 18 hours at room temperature.

[0517] The precipitate was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (1.47 g).

[0518] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.04 (3H, d, J=6.8 Hz), 2.14 (1H, dd, J=16.6, 3.0 Hz), 2.52-2.63 (1H, m), 3.44-3.54 (1H, m), 4.04-4.21 (2H, m), 4.59 (1H, d, J=15.4 Hz), 5.05 (1H, d, J=4.9 Hz), 7.06-7.19 (2H, m), 7.32-7.48 (2H, m), 7.71 (1H, dd, J=8.5, 2.4 Hz), 7.97 (1H, d, J=1.9 Hz).

Example 38

(4 S, 5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one

A) Methyl 6-(2-fluoro-4-formylphenoxy)nicotinate

[0519] A mixture of methyl 6-fluoronicotinate (12.2 g), 3-fluoro-4-hydroxybenzaldehyde (11.0 g), potassium carbonate (16.3 g), and NMP (75 mL) was stirred for 16 hours at 90° C. in a nitrogen atmosphere.

[0520] The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate solution and saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from hexane to give the title compound (17.4 g).

[0521] MS: [M+H].sup.+ 276.0.

B) Methyl 6-(4-(difluoromethyl)-2-fluorophenoxy)nicotinate

[0522] (Diethylamino)sulfur trifluoride (11.5 mL) was added to a solution of methyl 6-(2-fluoro-4-formylphenoxy)nicotinate (8.00 g) in toluene (90 mL) at 0° C., and the mixture was stirred for one day at room temperature. After adding MeOH (10 mL) to stop the reaction, the mixture was diluted with 10% potassium carbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.14 g).

[0523] MS: [M+H].sup.+ 298.0.

C) (6-(4-(difluoromethyl)-2-fluorophenoxy)pyridine-3-yl)methanol

[0524] Sodium borohydride (4.14 g) was added to a THF (60 mL)/MeOH (15 mL) suspension of methyl 6-(4-(difluoromethyl)-2-fluorophenoxy)nicotinate (8.14 g) at room temperature, and the mixture was stirred for 1 hour at 60° C. Sodium borohydride (4.14 g) was added at room temperature, and the mixture was stirred for an additional hour at 60° C. The mixture was diluted with water, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.33 g).

[0525] MS: [M+H].sup.+ 270.0.

D) 5-(bromomethyl)-2-(4-(difluoromethyl)-2-fluorophenoxy)pyridine

[0526] Phosphorus tribromide (0.357 mL) was added to a mixture of (6-(4-difluoromethyl)-2-fluorophenoxy)pyridine-3-yl)methanol (920 mg) and THF (10 mL) at 0° C., and this was stirred for 16 hours at room temperature. After diluting the mixture with ethyl acetate, the solution was washed with sodium hydrogen carbonate aqueous solution and a saturated saline solution and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (977 mg).

[0527] MS: [M+H].sup.+ 332.0.

E) (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2-fluorophenoxy)pyridine-3-yl)methyl)-5-methylpyrrolidine-2-one

[0528] 1.6 M butyllithium-hexane solution (4.50 mL) was added dropwise to a mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-5-methylpyrrolidine-2-one (1.65 g) and THF (24 mL) at −78° C., and this was stirred for 30 minutes at 0° C. 5-(bromomethyl)-2-(4-(difluoromethyl) fluorophenoxy)pyridine (2.39 g) was added to the mixture, and this was stirred for 20 minutes at room temperature. Afterward, this was stirred for 22 hours at 50° C. and stirred for 48 hours at 40° C. The mixture was diluted with ethyl acetate and water and afterward it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), to give the title compound (2.15 g).

[0529] MS: [M+H].sup.+ 481.2.

F) (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridine-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one

[0530] A mixture of (4S,5S)-4-((tert-butyldimethylsilyl)oxy)-1-((6-(4-(difluoromethyl)-2-fluorophenoxy)pyridine-3-yl)methyl)-5-methylpyrrolidine-2-one (2.14 g) and 2 M hydrogen chloride-ethanol solution (40 mL) was stirred for 18 hours at room temperature. The mixture was concentrated, then the residue was diluted with sodium hydrogen carbonate aqueous solution. Afterward, this was extracted with ethyl acetate. The organic layer was washed with saturated saline solution. Afterward, this was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and ethyl acetate/methanol), and a crude product (1.61 g) was obtained. The crude product was dissolved in warm ethyl acetate (5 mL), to the solution was added heptane (8 mL) dropwise at room temperature, and the mixture was stirred for 15 minutes. Heptane (16 mL) was added dropwise to the obtained mixture at room temperature, and the mixture was stirred for an additional 30 minutes. Heptane (16 mL) was added dropwise to the obtained mixture at room temperature, and the mixture was stirred for an additional 72 hours. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (1.52 g) as crystals.

[0531] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.04 (3H, d, J=6.8 Hz), 2.15 (1H, dd, J=16.6, 3.4 Hz), 2.52-2.61 (1H, m), 3.45-3.55 (1H, m), 4.06-4.21 (2H, m), 4.59 (1H, d, J=15.4 Hz), 5.07 (1H, d, J=4.9 Hz), 7.07 (1H, t, J=57.0 Hz), 7.15 (1H, d, J=8.7 Hz), 7.47 (2H, d, J=4.1 Hz), 7.61 (1H, d, J=10.9 Hz), 7.74 (1H, dd, J=8.5, 2.4 Hz), 7.99 (1H, d, J=1.9 Hz).

[0532] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Copper K-alpha radiation.

[0533] The obtained crystal was characterized by having specific peaks at the two thetas of 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees in a powder X-ray diffraction pattern.

Example 45

(5S)-1-{[2-(2,4-difluorophenoxy)pyrimidine-5-yl]methyl}-5-methylpyrrolidine-2-one

A) methyl 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylate

[0534] A mixture of methyl 2-chloropyrimidine-5-carboxylate (5.00 g), 2,4-difluorophenol (2.77 mL), potassium carbonate (6.01 g), and MeCN (60 mL) was stirred for 16 hours at room temperature in a nitrogen atmosphere. The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with 10% potassium carbonate aqueous solution and saturated saline solution, dried over sodium sulfate, passed through NH silica gel pad, and concentrated under reduced pressure. The residue was crystallized from hexane to give the title compound (7.18 g).

[0535] MS: [M+H].sup.+ 267.0.

B) 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylic Acid

[0536] 2 M sodium hydroxide aqueous solution (20.2 mL) was added to a mixture of methyl 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylate (7.18 g) and THF (80 mL) at room temperature, and the mixture was stirred for 5 hours. The mixture was concentrated under reduced pressure, and this was diluted with water (40 mL) and then neutralized with 1 M hydrochloric acid (40 mL). The obtained precipitate was collected and washed with water to give the title compound (4.98 g).

[0537] MS: [M−H].sup.+ 250.9.

C) (2-(2,4-difluorophenoxy)pyrimidine-5-yl)methanol

[0538] Isobutyl chloroformate (3.07 mL) and 4-methylmorpholine (3.25 mL) were added to a mixture of 2-(2,4-difluorophenoxy)pyrimidine-5-carboxylic acid (4.97 g) and THF (80 mL) at 0° C., and the mixture was stirred for 1 hour at the same temperature. Sodium borohydride (1.86 g) and water (20 mL) were added dropwise at 0° C., and the mixture was stirred for an additional 16 hours at room temperature. The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with 10% potassium carbonate aqueous solution and saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.93 g).

[0539] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 4.50 (2H, d, J=5.7 Hz), 5.38 (1H, t, J=5.7 Hz), 7.11-7.21 (1H, m), 7.41-7.53 (2H, m), 8.59 (2H, s).

D) 5-(bromomethyl)-2-(2,4-difluorophenoxy)pyrimidine

[0540] Phosphorus tribromide (1.29 mL) was added to a mixture of (2-(2,4-difluorophenoxy)pyrimidine-5-yl)methanol (2.93 g) and THF (30 mL) at 0° C., and this was stirred for 16 hours at room temperature. The mixture was diluted with ethyl acetate, and the solution was washed with sodium hydrogen carbonate aqueous solution and saturated saline solution and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g).

[0541] MS: [M+H].sup.+ 300.9.

E) (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidine-5-yl]methyl}-5-methylpyrrolidine-2-one

[0542] 1.6 M butyllithium-hexane solution (2.30 mL) was added dropwise to a mixture of (S)-5-methylpyrrolidine-2-one (0.364 g) and THF (12 mL) at −78° C., and this was stirred for 30 minutes at 0° C. 5-(bromomethyl)-2-(2,4-difluorophenoxy)pyrimidine (1.11 g) was added to the mixture, and this was stirred for 1.5 hours at room temperature. The mixture was diluted with ethyl acetate and ammonium chloride aqueous solution and then it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate, passed through a silica gel/NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (0.621 g) as crystals.

[0543] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.13 (3H, d, J=6.4 Hz), 1.44-1.59 (1H, m), 2.06-2.34 (3H, m), 3.52-3.64 (1H, m), 4.17 (1H, d, J=15.8 Hz), 4.56 (1H, d, J=15.4 Hz), 7.11-7.21 (1H, m), 7.41-7.53 (2H, m), 8.55 (2H, s).

[0544] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Copper K-alpha radiation.

[0545] The obtained crystal was characterized by having specific peaks at the two thetas of 7.4°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 20.6°±0.2° and 21.3°±0.2° degrees in a powder X-ray diffraction pattern.

Example 49

(4S)-3-{[2-(4-chloro-2-fluorophenoxy)pyrimidine-5-yl]methyl}-4-methyl-1,3-oxazolidine-2-one

A) Methyl 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylate

[0546] A mixture of methyl 2-chloropyrimidine-5-carboxylate (5.00 g), 4-chloro-2-fluorophenol (3.08 mL), potassium carbonate (6.01 g), and MeCN (60 mL) was stirred for 16 hours under a nitrogen atmosphere at room temperature. The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over sodium sulfate, passed through NH silica gel pad, and concentrated under reduced pressure. The residue was crystallized from hexane to give the title compound (7.39 g).

[0547] MS: [M+H].sup.+ 283.0.

B) 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylic Acid

[0548] 2 M sodium hydroxide aqueous solution (14.4 mL) was added to a mixture of methyl 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylate (7.39 g) and THF (50 mL) at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, then diluted with water (30 mL) and neutralized with 1 M hydrochloric acid (29 mL). The obtained precipitate was collected by filtration and washed with water to give the title compound (6.35 g).

[0549] MS: [M−H].sup.+ 266.8.

C) (2-(4-chloro-2-fluorophenoxy)pyrimidine-5-yl)methanol

[0550] Isobutyl chloroformate (3.67 mL) and 4-methylmorpholine (3.89 mL) were added to a mixture of 2-(4-chloro-2-fluorophenoxy)pyrimidine-5-carboxylic acid (6.33 g) and THF (100 mL) at 0° C., and the mixture was stirred for 1 hour at the same temperature. Sodium borohydride (2.23 g) and water (25 mL) were added dropwise at 0° C., and the mixture was stirred for an additional 16 hours at room temperature. The mixture was diluted with ethyl acetate and water, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over sodium sulfate, passed through NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the generated solid was washed with IPE to give the title compound (2.80 g).

[0551] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 4.50 (2H, d, J=5.3 Hz), 5.39 (1H, t, J=5.7 Hz), 7.33-7.40 (1H, m), 7.42-7.51 (1H, m), 7.65 (1H, dd, J=10.5, 2.3 Hz), 8.59 (2H, s).

D) 5-(bromomethyl)-2-(4-chloro-2-fluorophenoxy)pyrimidine

[0552] Phosphorous tribromide (1.15 mL) was added to a mixture of (2-(4-chloro-2-fluorophenoxy)pyrimidine-5-yl)methanol (2.80 g) and THF (25 mL) at 0° C., and this was stirred for 16 hours at room temperature. The mixture was diluted with ethyl acetate, and this solution was washed with sodium hydrogen carbonate aqueous solution and dried over sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from hexane to give the title compound (2.22 g).

[0553] MS: [M+H].sup.+ 316.9.

E) (4S)-3-[2-(4-chloro-2-fluorophenoxy)pyrimidine-5-yl]methyl-4-methyl-1,3-oxazolidine-2-one

[0554] 1.6 M butyllithium-hexane solution (0.637 mL) was added to a mixture of (S) methyloxazolidine-2-one (0.103 g) and THF (8 mL) at −78° C., and this was stirred for 30 minutes at 0° C. 5-(bromomethyl)-2-(4-chloro-2-fluorophenoxy)pyrimidine (0.323 g) was added to the mixture, and this was stirred for 60 hours at room temperature. The mixture was diluted with ethyl acetate and water and afterward it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (0.233 g) as crystals.

[0555] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.18 (3H, d, J=6.0 Hz), 3.77-3.87 (2H, m), 4.27 (1H, d, J=15.0 Hz), 4.35-4.50 (2H, m), 7.34-7.41 (1H, m), 7.43-7.51 (1H, m), 7.66 (1H, dd, J=10.4, 2.4 Hz), 8.63 (2H, s).

[0556] X-ray powder diffraction patterns were generated using a Rigaku Ultima IV (Rigaku, Tokyo, Japan) with Copper K-alpha radiation.

[0557] The obtained crystal was characterized by having specific peaks at the two thetas of 5.4°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 20.3°±0.2°, 21.0°±0.2°, 21.8°±0.2° and 24.5°±0.2° degrees in a powder X-ray diffraction pattern.

[0558] The Example compounds are shown in the following Tables. In the Tables, MS indicates a measured value. The compounds of examples 1 to 12, 14 to 16, 18 to 36, 39 to 44, 46 to 48, and 50 were produced according to the methods given in the above Examples or methods equivalent thereto.

TABLE-US-00001 TABLE 1-1 EXAMPLE IUPACNAME Structure ADDITIVE MS 1 5-methyl-1-{[4-(4- methylphenoxy)phenyl]methyl} pyrrolidin-2-one [00025] 296.3 2 5-methyl-1-{[4-(4- methylphenoxy)pheny]methyl} pyrrolidin-2-one (optical isomer) [00026] 296.2 3 5-methyl-1-{[4-(4- methylphenoxy)phenyl]methyl} pyrrolidin-2-one (optical isomer) [00027] 296.2 4 5-methyl-1-{[5-(4- methylphenoxy)pyrazin-2- yl]methyl}yrrolidin-2-one [00028] 298.2 5 5-methyl-1-{[2-(4- methylphenoxy)pyrimidin-5- yl]methyl}pyrrolidin-2-one [00029] 298.2 6 (4S,5S)-4-hydroxy-5-methyl-1- {[4-(4- methylphenoxy)phenyl]methyl} pyrrolidin-2-one [00030] 312.2 7 (4S,5S)-5-ethyl-4-hydroxy-1-{[4- (4-methylphenoxy) phenyl]methyl}pyrrolidin-2-one [00031] 326.2 8 5-methyl-1{[5-(4- methylphenoxy)pyrimidin-2- yl]methyl}pyrrolidin-2-one [00032] 298.1 9 (4S,5S)-1-{[4-(4- fluorophenoxy)phenyl]methyl}-4- hydroxy-5-methylpyrrolidin-2-one [00033] 316.1 10 (4R,5S)-4-hydroxy-5-methyl-1- {[4-(4- methylphenoxy)phenyl]methyl} pyrrolidin-2-one [00034] 312.2

TABLE-US-00002 TABLE 1-2 EXAMPLE IUPACNAME Structure ADDITIVE MS 11 (4S,5R)-4-hydroxy-5-methyl-1- {[4-(4- methylphenoxy)pheny]methyl} pyrrolidin-2-one [00035] 312.2 12 (4R,5R)-4-hydroxy-5-methyl-1- {[4-(4- methylphenoxy)pheny]methyl} pyrrolidin-2-one [00036] 312.2 13 (4S,5S)-4-hydroxy-5-methyl-1- {[6-(4-methylphenoxy)pyridin-3- yl]methyl}pyrrolidin-2-one [00037] 313.2 14 (4S,5S)-4-hydroxy-5-methyl-1- {[6-(4-methylphenoxy)pyridin-3- yl]methyl}pyrrolidin-2-one [00038] 313.2 15 (4S,5S)-4-hydroxy-5-methyl-1- {[2-(4-methylphenoxy)pyrimidin-5- yl]methyl}pyrrolidin-2-one [00039] 314.2 16 (4S,5S)-4-hydroxy-5-methyl-1- {[5-(4-methylphenoxy)pyridin-2- yl]methyl}pyrrolidin-2-one [00040] 313.2 17 (4S,5S)-1-({6-[4-(difluoromethyl)- 2-fluorophenoxy]pyridin-3- yl}methyl)-4-hydroxy-5- methylpyrrolidin-2-one [00041] 367.1 18 (4S)-4-methy-3-{[4-(4- methylphenoxy)phenyl]methyl} 1,3-oxazolidin-2-one [00042] 298.2 19 (4S,5S)-4-hydroxy-5-methyl-1- {[5-(4-methylphenoxy)pyrazin-2- yl]methyl}pyrrolidin-2-one [00043] 314.2 20 (4S)-4-methyl-3-{[6-(4- methylphenoxy)pyridin-3- yl]methyl}-1,3-oxazolidin-2-one [00044] 299.2

TABLE-US-00003 TABLE 1-3 EXAMPLE IUPACNAME Structure ADDITIVE MS 21 (5S)-5-methyl-1-{[6-(4- methylphenoxy)pyridin-3- yl]methyl}pyrrolidin-2-one [00045] 297.2 22 (5S)-5-methyl-1-{[2-(4- methylphenoxy)pyrimidin-5- yl]methyl}pyrrolidin-2-one [00046] 298.2 23 (4S)-3-{[2-(2-fluoro-4- methylphenoxy)pyrimidin-5- yl]methyl}-4-methyl-1,3- oxazolidin-2-one [00047] 318.2 24 (4S)-4-methyl-3-{[2-(2,4,6- trifluorophenoxy)pyrimidin-5- yl]methyl}-1,3-oxazolidin-2-one [00048] 340.1 25 (4S)-3-{[6-(2-fluoro-4- methylphenoxy)pyridin-3- y]methyl}-4-methyl-1,3- oxazolidin-2-one [00049] 317.2 26 (4S,5S)-1-{[6-(2-fluoro-4- methylphenoxy)pyridin-3- yl]methyl}-4-hydroxy-5- methylpyrrolidin-2-one [00050] 331.2 27 (4S,5S)-4-hydroxy-5-methyl-1- {[6-(2,4,6-trifluorophenoxy)pyridin- 3-yl]methyl}pyrrolidin-2-one [00051] 353.1 28 (4S)-4-methyl-3-{[6-(2,4,6- trifluorophenoxy)pyridin-3- yl]methyl}-1,3-oxazolidin-2-one [00052] 339.2 29 1-{[6-(4-methylphenoxy) pyridin-3-yl]methyl}-5- (trifluoromethyl)pyrrolidin-2-one [00053] 351.2 30 (4S)-4-methyl-3-{[2-(4- methylphenoxy)pyrimidin-5- yl]methyl}-1,3-oxazolidin-2-one [00054] 300.2

TABLE-US-00004 TABLE 1-4 EXAMPLE IUPACNAME Structure ADDITIVE MS 31 (4S,5S)-1{[-6-(2,6-difluoro-4- methylphenoxy)pyridin-3- yl]methyl}4-hydroxy-5- methylpyrrolidin-2-one [00055] 349.2 32 (4S)-3-{[2-(2,6-difluoro-4- methylphenoxy)pyrimidin-5- yl]methyl}-4-methyl-1,3- oxazolidin-2-one [00056] 336.2 33 (5S)-5-methyl-1-{[6-(2,4,6- trifluorophenoxy)pyridin-3- yl]methyl}imidazolidin-2-one [00057] 338.1 34 (4R,5S)-3,3-difluoro-4-hydroxy-5- methyl-1-{[6-(2,4,6- trifluorophenoxy)pyridin-3- yl]methyl}pyrrolidin-2-one [00058] 389.1 35 (5S)-1-{[6-(2,4- difluorophenoxy)pyridin-3- yl]methyl}5-methylimidazolidin-2- one [00059] 320.2 36 (4R,5S)-1-{[6-(2,4- difluorophenoxy)pyridin-3- yl]methyl}-3,3-difluoro-4-hydroxy- 5-methylpyrrolidin-2-one [00060] 371.1 37 (4S,5S)-1{[-6-(2,4- difluorophenoxy)pyridin-3- yl]methyl}-4-hydroxy-5- methylpyrrolidin-2-one [00061] 335.2 38 (4S,5S)-1-({6-[4-(difluoromethyl)- 2-fluorophenoxy]pyridin-3- yl}methyl)-4-hydroxy-5- methylpyrrolidin-2-one [00062] 367.1 39 4-(fluoromethyl)-3-{[6-(2-fluoro- 4-methylphenoxy)pyridin-3- yl]methyl}-1,3-oxazolidin-2-one [00063] 335.1 40 4-(difluoromethyl)-3-{[6-(2- fluoro-4-methylphenoxy)pyridin-3- yl]methyl}-1,3-oxazolidin-2-one [00064] 353.1

TABLE-US-00005 TABLE 1-5 EXAMPLE IUPACNAME Structure ADDITIVE MS 41 (4S,5S)-1-({6-[2-fluoro-4- (trifluoromethyl)phenoxy]pyridin- 3-yl}methyl)-4-hydroxy-5- methylpyrrolidin-2-one [00065] 385.1 42 (5S)-1-({2-[4-(difluoromethyl)-2- fluorophenoxy]pyrimidin-5- yl}methyl)-5-methylpyrrolidin-2- one [00066] 352.2 43 (4S,5S)-1-{[6-(4-chloro-2- fluorophenoxy)pyridin-3- yl]methyl}4-hydroxy-5- methylpyrrolidin-2-one [00067] 351.1 44 (5S)-1-{[2-(2-fluoro-4- methylphenoxy)pyrimidin-5- yl]methyl}-5-methylpyrrolidin-2- one [00068] 316.1 45 (5S)-1-2-{[2,4- difluorophenoxy)pyrimidin-5- yl]methyl}-methylpyrrolidin-2- one [00069] 320.1 46 (5S)-1-{[2-(4-chloro-2- fluorophenoxy)pyrimidin-5- yl]methyl}-5-methylpyrrolidin-2- one [00070] 336.1 47 (5S)-1-({6-[4-(difluoromethy)-2- fluorophenoxy]pyridin-3- yl}methyl)-5-methylpyrrolidin-2- one [00071] 351.1 48 (5S)-1-{[6-(2,4- difluorophenoxy)pyridin-3- yl]methyl}-5-methylpyrrolidin-2- one [00072] 319.1 49 (4S)-3-{[2-(4-chloro-2- fluorophenoxy)pyrimidin-5- yl]methyl}-4-methyl-1,3- oxazolidin-2-one [00073] 338.1 50 (4S)-3-({6-[4-(difluoromethyl)-2- fluorophenoxy]pyridin-3- yl}methyl)-4-methyl-1,3- oxazolidin-2-one [00074] 353.1

Experimental Example 1: NR2B Ca.SUP.2+ Influx Assay

[0559] To confirm that compounds of the present disclosure exhibit antagonistic action on an NMDA receptor containing an NR2B subunit, human embryonic kidney cells expressing an NMDA receptor composed of four subunits including two sets of heterodimers of NR1 and NR2B—specifically, HEK 293 cells expressing human glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) and human glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B)—were used to measure an activation suppression effect on this receptor.

[0560] The HEK 293 cells that express GRIN1 and GRIN2B were purchased from ChanTest (human NMDA (NR1/NR2B) receptor-expressing, stable replicating cell line (HEK 293) catalog no. CT6121).

[0561] Intracellular calcium-ion (Ca.sup.2+) influx caused by glycine and glutamic acid respectively binding to NR1 and NR2B was used as an index of NMDA receptor activation.

[0562] The HEK 293 cells expressing GRIN1 and GRIN2B were cultured in a cell culture flask in an incubator (37° C., in 5% CO.sub.2) using a DMEM/F-12 (Cosmo Bio, 10-092-CM) medium supplemented with 10% FBS (fetal bovine serum, AusGene), 100 units/mL penicillin, 100 μg/mL streptomycin, 500 μg/mL neomycin, 100 μg/mL Zeocin (registered trademark of Invitrogen), and 5 μg/mL blasticidin.

[0563] On the day before the assay, the cells were detached from the flask by trypsinization, suspended in a seeding medium (DMEM (Invitrogen, 31053) supplemented with 10% FBS, 100 units/mL penicillin, and 100 μg/mL streptomycin) so as to be 8×10.sup.5 cells/mL, seeded at 25 μL per well in a 384-well plate (Falcon, 356663) so as to be 20,000 cells/well, and cultured overnight using the incubator. On the day of the assay, tetracycline (Wako Pure Chemical, 209-16561) was diluted with the seeding medium at 2 μg/mL, and added at 25 μL/well to the plate into which the cells were seeded, and this was cultured for 2 hours in the incubator. Afterward, the medium was removed and washed with an assay buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl.sub.2), 10 mM HEPES (pH 7.2), 10 mM glucose, 0.1% BSA) at 50 μL/well. Next, a loading buffer (buffer wherein 2.5 μM Fluo-4 AM, 2 mM amaranth, and 1 mM tartrazine are added to the assay buffer) was added at 25 μL/well, and this was incubated in the incubator for 30 minutes and for 15 minutes at room temperature. Solutions wherein the Example compounds were diluted with the above-mentioned assay buffer so as to be 30 μM (final concentration 10 μM) were added at 25 μL/well, and these were left standing for 15 minutes at room temperature. Using FDSS7000EX/μCELL (Hamamatsu Photonics), an assay buffer including 30 μM glutamic acid and 30 μM glycine was added at 25 μL/well, and a fluorescence signal of an Excitation wavelength of 480 nm and an Emission wavelength of 540 nm was measured every 3 seconds for 5 minutes. The inhibitory activity was calculated as a relative activity value (inhibitory rate) wherein relative to an integrated value of florescence values of each well, an integrated value of fluorescence values of a well into which an assay buffer without glutamic acid and glycine was defined as 100% inhibition. The results are shown in Table 2.

TABLE-US-00006 TABLE 2 Example % inhibited(10 μM) 1 99 2 98 3 99 4 93 5 91 6 97 7 98 8 53 9 96 10 94 11 91 12 93 13 97 14 96 15 90 16 95 18 98 19 82 20 97 21 98 22 95 23 94 24 93 25 96 26 97 27 97 28 96 29 93 30 90 31 97 32 92 33 97 34 97 35 96 36 97 37 97 38 95 39 92 40 95 41 95 42 97 43 98 44 97 45 96 46 97 47 99 48 98 49 97 50 98

[0564] As indicated in Table 2 above, compounds of the present disclosure suppressed intracellular calcium-ion (Ca.sup.2+) influx in an NMDA receptor containing an NR2B subunit. That is, it was confirmed that compounds of the present disclosure exert an antagonistic action on an NMDA receptor containing an NR2B subunit.

Experimental Example 2: [.SUP.3.H]MK-801 Binding Test In Vivo

[0565] In order to confirm that compounds of the present disclosure exert functional antagonistic action on an NMDA receptor containing the NR2B subunit in vivo, a binding test was performed using tritium-labeled form of MK-801 ((5R,10S)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene) ([.sup.3H]MK-801), which is a compound capable of binding to the opening site of the NMDA receptor.

[0566] The example compound (3 mg/kg/2 mL, 0.5% MC water) or vehicle (0.5% MC water 2 ml) was orally administered (p.o.) to Sprague Dawley rats (body weight 180-260 g). After a certain time (around after time-to maximum blood concentration), [.sup.3H]MK-801 (20 μCi/kg/mL, Muromachi Kikai) was intravenously administered. After 10 min, the rats were euthanized by decapitation, and subjected to craniotomy, and the hippocampus was collected. The collected hippocampus was homogenized in 30 volumes (30 mL per 1 g tissue) ice-cooled 20 mM HEPES (pH7.5, Hampton Research) using a homogenizer (T10 basic Ultra-Turrax) for 10 sec. Then, 600 μL of the homogenate was immediately filtered through GF/B Whatman glass filter (GE Health Care), which were presoaked in 0.5% polyethyleneimine (FUJIFILM Wako Pure Chemical Corporation) and set on Manifold Filtration System (Millipore) by suction. The filter was washed four times with ice-cooled saline (5 mL, Otsuka Pharmaceutical), put into a scintillation vial, and then 10 mL of liquid scintillator A (FUJIFILM Wako Pure Chemical Corporation) was added thereto, and the residual radioactivity was counted using liquid scintillation counter (ALOKA LSC-6100).

[0567] Separately, the residual radioactivity in 100 μL of the homogenate before the filtration was counted in the same way. The value of [the residual radioactivity in the filter/the residual radioactivity in the 100 μL of the homogenate] was calculated as a [.sup.3H]MK-801 binding rate to the NMDA receptor expressing in each individual hippocampus tissue. Then, the [.sup.3H]MK-801 binding rate in the vehicle control group was regarded as 100%, and the [.sup.3H]MK-801 binding rate in the group subcutaneously administered with excess amount of MK-801 maleate (2 mg/kg/2 mL, 0.5% MC water) was regarded as 0%. The difference between the percentage of [.sup.3H]MK-801 binding rate in the group orally administered with the example compound and that in the vehicle control group (100%) was analyzed as [.sup.3H]MK-801 binding inhibitory rate by the example compound. The results are shown in Table 3.

TABLE-US-00007 TABLE 3 Inhibitory Rate Example No. (3 mg/kg, p.o.) 38 22% 45 13% 49 19%

[0568] As shown in the above-mentioned Table 3, compounds of the present disclosure inhibited the binding of [.sup.3H]MK-801, which is a compound capable of binding to the opening site of the NMDA receptor containing the NR2B subunit. That is, compounds of the present disclosure were confirmed to have a functional antagonistic action on an NMDA receptor containing the NR2B subunit in vivo.

Formulation Example 1 (Production of Capsule)

[0569]

TABLE-US-00008 1) Compound of Example 1 30 mg 2) Fine cellulose powder 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg

[0570] 1), 2), 3), and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

[0571]

TABLE-US-00009 1) Compound of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1,000 tablets Total 140 g

[0572] The entirety of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum-dried, and sieved. 14 g of 4) and 1 g of 5) are mixed into the sieved powder, and the mixture is punched by a tableting machine. In this manner, 1,000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.