HETEROCYCLIC COMPOUNDS FOR TREATING OR PREVENTING DISORERS CAUSED BY REDUCED NEUROTRANSMISSION OF SEROTONIN, NOREPHNEPHRINE OR DOPAMINE

Abstract

A heterocyclic compound represented by the general formula (1) or a salt thereof:

##STR00001## wherein m, l, and n respectively represent an integer of 1 or 2; X represents —O— or —CH.sub.2—; R.sup.1 represents hydrogen, a lower alkyl group, a hydroxy-lower alkyl group, a protecting group, or a tri-lower alkylsilyloxy-lower alkyl group; R.sup.2 and R.sup.3, which are the same or different, each independently represent hydrogen or a lower alkyl group; or R.sub.2 and R.sub.3 are bonded to form a cyclo-C3-C8 alkyl group; and R.sup.4 represents an aromatic group or a heterocyclic group, wherein the aromatic or heterocyclic group may have one or more arbitrary substituent(s).

Claims

1. A method for treating depression and/or depression status caused by adjustment disorder, comprising administering to a subject in need a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof: ##STR00093## wherein m=2, n=1; X represents CH.sub.2—; R.sup.1 represents hydrogen, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a protecting group selected from unsubstituted C1-C6 alkanoyl, phthalol, C1-C6 alkoxycarbonyl, unsubstituted aralkyloxycarbonyl, 9-fluorenylmethoxycarbonyl, nitrophenylsulfenyl, aralkyl and C1-C6 alkylsilyl groups, or a tri C1-C6 alkylsilyloxy C1-C6 alkyl group; R.sup.2 and R.sup.3, which are the same or different, each independently represent hydrogen or a C1-C6 alkyl group; or R.sub.2 and R.sub.3 are bonded to form a cyclo-C3-C8 alkyl group; and R.sup.4 represents any of (1) a phenyl group, (2) an indolyl group, (3) a benzothienyl group, (4) a naphthyl group, (5) a benzofuryl group, (6) a quinolyl group, (7) an isoquinolyl group, (8) a pyridyl group, (9) a thienyl group, (10) a dihydrobenzoxazinyl group, (11) a dihydrobenzodioxinyl group, (12) a dihydroquinolyl group, (13) a chromanyl group, (14) a quinoxalinyl group, (15) a dihydroindenyl group, (16) a dihydrobenzofuryl group, (17) a benzodioxolyl group, (18) an indazolyl group, (19) a benzothiazolyl group, (20) an indolinyl group, (21) a thienopyridyl group, (22) a tetrahydrobenzazepinyl group, (23) a tetrahydrobenzodiazepinyl group, (24) a dihydrobenzodioxinyl group, (25) a fluorenyl group, (26) a pyridazinyl group, (27) a tetrahydroquinolyl group, (28) a carbazolyl group, (29) a phenanthryl group, (30) a dihydroacenaphthylenyl group, (31) a pyrrolopyridyl group, (32) an anthryl group, (3) a benzodioxinyl group, (34) a pyrrolidinyl group, (35) a pyrazolyl group, (36) an oxadiazolyl group, (38) a tetrahydronaphthyl group, (39) a dihydroquinazolinyl group, (40) a benzoxazolyl group, (41) a thiazolyl group, (42) a quinazolinyl group, (43) a phthalazinyl group, (44) a pyrazinyl group, and (45) a chromenyl group, wherein these aromatic or heterocyclic groups may have one or more substituent(s) selected from (1-1) a halogen atom, (1-2) a C1-C6 alkyl group, (1-3) a C1-C6 alkanoyl group, (1-4) a halogen-substituted C1-C6 alkyl group, (1-5) a halogen-substituted C1-C6 alkoxy group, (1-6) a cyano group, (1-7) a C1-C6 alkoxy group, (1-8) a C1-C6 alkylthio group, (1-9) an imidazolyl group, (1-10) a tri C1-C6 alkylsilyl group, (1-11) an oxadiazolyl group which may have one or more C1-C6 alkyl group(s), (1-12) a pyrrolidinyl group which may have one or more oxo group(s), (1-13) a phenyl group which may have one or more C1-C6 alkoxy group(s), (1-14) a C1-C6 alkylamino C1-C6 alkyl group, (1-15) an oxo group, (1-16) a pyrazolyl group which may have one or more C1-C6 alkyl group(s), (1-17) a thienyl group, (1-18) a furyl group, (1-19) a thiazolyl group which may have one or more C1-C6 alkyl group(s), (1-20) a C1-C6 alkylamino group, (1-21) a pyrimidyl group which may have one or more C1-C6 alkyl group(s), (1-22) a phenyl C2-C6 alkenyl group, (1-23) a phenoxy group which may have one or more halogen atom(s), (1-24) a phenoxy C1-C6 alkyl group, (1-25) a pyrrolidinyl C1-C6 alkoxy group, (1-26) a C1-C6 alkylsulfamoyl group, (1-27) a pyridazinyloxy group which may have one or more C1-C6 alkyl group(s), (1-28) a phenyl C1-C6 alkyl group, (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, (1-30) an imidazolyl C1-C6 alkyl group, (1-31) a phenyl C1-C6 alkoxy group, (1-32) a hydroxy group, (1-33) a C1-C6 alkoxycarbonyl group, (1-34) a hydroxyl C1-C6 alkyl group, (1-35) an oxazolyl group, (1-36) a piperidyl group, (1-37) a pyrrolyl group, (1-38) a morpholinyl C1-C6 alkyl group, (1-39) a piperazinyl C1-C6 alkyl group which may have one or more C1-C6 alkyl group(s), (1-40) a piperidyl C1-C6 alkyl group, (1-41) a pyrrolidinyl C1-C6 alkyl group, (1-42) a morpholinyl group, and (1-43) a piperazinyl group which may have one or more C1-C6 alkyl group(s).

2. (canceled)

3. The method according to claim 1, wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof R.sup.4 represents any of (1) a phenyl group, (2) an indolyl group, (3) a benzothienyl group, (4) a naphthyl group, (5) a benzofuryl group, (6) a quinolyl group, (7) an isoquinolyl group, (8) a pyridyl group, (9) a thienyl group, (10) a dihydrobenzoxazinyl group, (11) a dihydrobenzodioxinyl group, (12) a dihydroquinolyl group, (13) a chromanyl group, (14) a quinoxalinyl group, (15) a dihydroindenyl group, (16) a dihydrobenzofuryl group, (17) a benzodioxolyl group, (18) an indazolyl group, (19) a benzothiazolyl group, (20) an indolinyl group, (21) a thienopyridyl group, (22) a tetrahydrobenzazepinyl group, (23) a tetrahydrobenzodiazepinyl group, (24) a dihydrobenzodioxepinyl group, (25) a fluorenyl group, (26) a pyridazinyl group, (27) a tetrahydroquinolyl group, (28) a carbazolyl group, (29) a phenanthryl group, (30) a dihydroacenaphthylenyl group, (31) a pyrrolopyridyl group, (32) an anthryl group, (33) a benzodioxinyl group, (34) a pyrrolidinyl group, (35) a pyrazolyl group, (36) an oxadiazolyl group, (38) a tetrahydronaphthyl group, (39) a dihydroquinazolinyl group, (40) a benzoxazolyl group, (41) a thiazolyl group, (42) a quinazolinyl group, (43) a phthalazinyl group, (44) a pyrazinyl group, and (45) a chromenyl group, wherein these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from (1-1) a halogen atom, (1-2) a C1-C6 alkyl group, (1-3) a C1-C6 alkanoyl group, (1-4) a halogen-substituted C1-C6 alkyl group, (1-5) a halogen-substituted lower C1-C6 alkoxy group, (1-6) a cyano group, (1-7) a C1-C6 alkoxy group, (1-8) a C1-C6 alkylthio group, (1-9) an imidazolyl group, (1-10) a tri C1-C6 alkylsilyl group, (1-11) an oxadiazolyl group which may have 1 C1-C6 alkyl group, (1-12) a pyrrolidinyl group which may have 1 oxo group, (1-13) a phenyl group which may have 1 C1-C6 alkoxy group, (1-14) a C1-C6 alkylamino C1-C6 alkyl group, (1-15) an oxo group, (1-16) a pyrazolyl group which may have 1 C1-C6 alkyl group, (1-17) a thienyl group, (1-18) a furyl group, (1-19) a thiazolyl group which may have 1 C1-C6 alkyl group, (1-20) a C1-C6 alkylamino group, (1-21) a pyrimidyl group which may have 1 C1-C6 alkyl group, (1-22) a phenyl C1-C6 alkenyl group, (1-23) a phenoxy group which may have 1 halogen atom, (1-24) a phenoxy C1-C6 alkyl group, (1-25) a pyrrolidinyl C1-C6 alkoxy group, (1-26) a C1-C6 alkylsulfamoyl group, (1-27) a pyridazinyloxy group which may have 1 C1-C6 alkyl group, (1-28) a phenyl C1-C6 alkyl group, (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, (1-30) an imidazolyl C1-C6 alkyl group, (1-31) a phenyl C1-C6 alkoxy group, (1-32) a hydroxy group, (1-33) a C1-C6 alkoxycarbonyl group, (1-34) a hydroxy C1-C6 alkyl group, (1-35) an oxazolyl group, (1-36) a piperidyl group, (1-37) a pyrrolyl group, (1-38) a morpholinyl C1-C6 alkyl group, (1-39) a piperazinyl C1-C6 alkyl group which may have 1 C1-C6 alkyl group, (1-40) a piperidyl C1-C6 alkyl group, (1-41) a pyrrolidinyl C1-C6 alkyl group, (1-42) a morpholinyl group, and (1-43) a piperazinyl group which may have 1 C1-C6 alkyl group.

4. The method according to claim 3, wherein in the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof m represents 2; l and n respectively represent 1; X represents —CH.sub.2—; R.sup.1 represents hydrogen, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a benzyl group, or a tri C1-C6 alkylsilyloxy C1-C6 alkyl group; and R.sup.4 represents any of (1) a phenyl group, (2) an indolyl group, (4) a naphthyl group, (5) a benzofuryl group, and (31) a pyrrolopyridyl group, wherein these aromatic or heterocyclic groups may have 1 to 4 substituent(s) selected from (1-1) a halogen atom, (1-2) a C1-C6 alkyl group, (1-3) a C1-C6 alkanoyl group, (1-4) a halogen-substituted C1-C6 alkyl group, (1-5) a halogen-substituted C1-C6 alkoxy group, (1-6) a cyano group, (1-7) a C1-C6 alkoxy group, (1-8) a C1-C6 alkylthio group, (1-9) an imidazolyl group, (1-10) a tri C1-C6 alkylsilyl group, (1-11) an oxadiazolyl group which may have 1 C1-C6 alkyl group, (1-12) a pyrrolidinyl group which may have 1 oxo group, (1-13) a phenyl group which may have 1 C1-C6 alkoxy group, (1-14) a C1-C6 alkylamino C1-C6 alkyl group, (1-15) an oxo group, (1-16) a pyrazolyl group which may have 1 C1-C6 alkyl group, (1-17) a thienyl group, (1-18) a furyl group, (1-19) a thiazolyl group which may have 1 C1-C6 alkyl group, (1-20) a C1-C6 alkylamino group, (1-21) a pyrimidyl group which may have 1 C1-C6 alkyl group, (1-22) a phenyl C1-C6 alkenyl group, (1-23) a phenoxy group which may have 1 halogen atom, (1-24) a phenoxy C1-C6 alkyl group, (1-25) a pyrrolidinyl C1-C6 alkoxy group, (1-26) a C1-C6 alkylsulfamoyl group, (1-27) a pyridazinyloxy group which may have 1 C1-C6 alkyl group, (1-28) a phenyl C1-C6 alkyl group, (1-29) a C1-C6 alkylamino C1-C6 alkoxy group, (1-30) an imidazolyl C1-C6 alkyl group, (1-31) a phenyl C1-C6 alkoxy group, (1-32) a hydroxy group, (1-34) a hydroxy C1-C6 alkyl group, (1-35) an oxazolyl group, (1-36) a piperidyl group, (1-37) a pyrrolyl group, (1-38) a morpholinyl C1-86 alkyl group, (1-39) a piperazinyl C1-C6 alkyl group which may have 1 C1-C6 alkyl group(s), (1-40) a piperidyl C1-C6 alkyl group, (1-41) a pyrrolidinyl C1-C6 alkyl group, (1-42) a morpholinyl group, and (1-43) a piperazinyl group which may have 1 C1-C6 lower alkyl group.

5. The method according to claim 4, wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof R.sup.1 represents hydrogen; R.sup.2 and R.sup.3, which are the same or different, each independently represent a C1-C6 alkyl group; or R.sup.2 and R.sup.3 are bonded to form a cyclo-C3-C8 alkyl group; and R.sup.4 represents any of (1) a phenyl group, (2) an indolyl group, (4) a naphthyl group, (5) a benzofuryl group, and (31) a pyrrolopyridyl group, wherein these aromatic or heterocyclic groups may have 1 to 2 substituent(s) selected from (1-1) a halogen atom, (1-2) a C1-C6 alkyl group, (1-5) a halogen-substituted C1-C6 alkoxy group, (1-6) a cyano group, and (1-7) a C1-C6 alkoxy group.

6. The method according to claim 5, wherein in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is selected from (4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline, 2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)benzonitrile, (4aS,8aR)-1-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline, (4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline, 5-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1 (2H)-yl)-1-methyl-1H-indole-2-carbonitrile, (4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline], (4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline, 5-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-1H-indole-2-carbonitrile, ((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-2-naphthonitrile, (4aS,8aS)-3,3-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline, and (4aS,8aS)-1-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline, (4aS,8aS)-1-(4-(difluoromethoxy)phenyl-3,3-dimethyldecahydroquinoxaline, and (4aR,8aR)-1-(4-difluoromethyoxy)-3-fluorophenyl-3,3-dimethyldecahydroquinoxaline.

7-16. (canceled)

17. The method according to any one of claims 1, and 3 to 5, wherein in the depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state bipolar disorder; dysthymic disorder; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; hypomelancholia; recurrent brief depressive disorder; refractory depression; chronic depression; double depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; depression caused by physical diseases, Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer; presenile depression; senile depression; depression in children and adolescents; and depression induced by drugs.

18. The method according to claim 17, wherein the depression is caused by physical disease caused by physical disease selected from Cushing('s) syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactorrhea syndrome, Parkinson's disease, Alzheimer's disease, cerebrovascular dementia, brain infarct, brain hemorrhage, subarachnoid hemorrhage, diabetes millitus, virus infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer.

Description

EXAMPLES

[0208] Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Pharmacological Tests. The chemical structures of racemic bodies and optically active forms are indicated, for example, as shown below.

Racemic Body

Relative Configuration

[0209] ##STR00010##

Optically Active Form

Absolute Configuration

[0210] ##STR00011##

Reference Example 1

Production of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one

Relative Configuration

[0211] ##STR00012##

[0212] 90%/o acetone cyanohydrin (9.79 g, 104 mmol) was added to an aqueous (100 mL) solution of cis-cyclopentane-1,2-diamine (9.88 g, 98.6 mmol) at room temperature, and the mixture was stirred under reflux for 16 hours. The solvent was removed from the reaction mixture under reduced pressure, followed by azeotropy with ethanol. The obtained residue was purified by silica gel column chromatography (methylene chloride/methanol=l/10) to obtain cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (5.00 g, 30%) in a white powder form.

[0213] .sup.1H-NMR (CDCl.sub.3) δppm: 1.20 (1H, brs),1.34 (3H, s),1.39 (3H, s),1.40-2.20 (6H, m),3.50-3.70 (2H, m),5.89 (1H, brs).

[0214] Compounds of Reference Examples 2 to 12 shown below were produced in the same way as in Reference Example 1 using appropriate starting materials.

Reference Example 2

[0215] Trans-3,3-dimethyloctahydrocyclopentapyrazin-2-one

Relative Configuration

[0216] ##STR00013##

[0217] .sup.1H-NMR (CDCl.sub.3) δppm: 1.26-1.55 (9H, m), 1.75-2.00 (4H, m), 2.85-3.02 (1H, m),3.05-3.20 (1H, m),6.02 (1H, brs).

Reference Example 3

Cis-3,3-dimethylhexahydrofuro[3,4-b]pyrazin-2-one

Relative Configuration

[0218] ##STR00014##

[0219] .sup.1H-NMR (CDCl.sub.3) δppm: 1.37 (3H, s), 1.40 (3H, s), 1.50-1.85 (1H, br),3.73-4.1 (6H, r),6.02-622 (1H, br).

Reference Example 4

Trans-3, 3-dimnethylhexahydrofuro[3,4-b]pyrazin-2-one

Relative Configuration

[0220] ##STR00015##

[0221] .sup.1H-NMR (CDCl.sub.3) δppm: 1.38-1.43 (1H, br), 1.44 (3H, s), 1.47 (3H, s), 3.38-3.52 (1H, m), 3.52-3.65 (3H, m), 4.00-4.14 (2H, m), 6.28-6.45 (1H, br).

Reference Example 5

(4aS,8aS)-3,3-dimethyloctahydroquinoxalin-2-one

Absolute Configuration

[0222] ##STR00016##

[0223] .sup.1H-NMR (CDCl.sub.3) δppm: 1.14-1.37 (6H, m), 1.38 (3H, s), 1.42 (3H, s) 1.69 (1H, brs), 1.74-1.84 (2H, m), 2.57-2.65 (1H, m), 2.96-3.04 (1H, m), 5.61 (1H, s)

Reference Example 6

(4aR,8aR)-3,3-dimethyloctahydroquinoxalin-2-one

Absolute Configuration

[0224] ##STR00017##

[0225] .sup.1H-NMR (CDCl.sub.3) δppm: 1.14-1.37 (6H, m), 1.38 (3H, s), 1.42 (3H, s), 1.63 (1H, brs), 1.73-1.83 (2H, m), 2.57-2.66 (1H, m), 2.95-3.04 (1H, m), 5.55 (1H, s)

Reference Example 7

Trans-3,3-diethyloctahydroquinoxalin-2-one

Relative Configuration

[0226] ##STR00018##

[0227] .sup.1H-NMR (CDCl.sub.3) δppm: 0.92 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.3 Hz), 1.13-1.49 (7H, m), 1.60-1.99 (6H, m), 2.55-2.60 (1H, m), 2.91-3.00 (1H, m), 5.69 (1H, brs)

Reference Example 8

Trans-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Relative Configuration

[0228] ##STR00019##

[0229] .sup.1H-NMR (CDCl.sub.3) δppm: 1.14-1.46 (4H, m), 1.70-2.17 (9H, m), 2.43-2.52 (1H, m), 2.55-2.66 (1H, m), 2.78-2.88 (1H, m), 2.97-3.06 (1H, m), 5.65 (1H, brs)

Reference Example 9

Cis-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Relative Configuration

[0230] ##STR00020##

[0231] .sup.1H-NMR (CDCl.sub.3) δppm: 1.1-1.3 (1H, m), 1.35-2.1 (12H, m), 2.5-2.6 (1H, m), 2.75-2.85 (1H, m), 3.15-3.3 (2H, m), 5.65 (1H, br).

Reference Example 10

6 Trans-octahydro-1′H-spiro[cyclohexane-1,2′-quinoxalin]-3′-one

Relative Configuration

[0232] ##STR00021##

[0233] 1H-NMR (CDCl.sub.3) δppm: 1.18-1.88 (18H, m), 2.03-2.13 (1H, m), 2.47-258 (1H, m), 2.92-3.00 (1H, m), 5.59 (1H, s)

Reference Example 11

Cis-3,3-dimethyldecahydrocyclobeptapyrazin-2-one

Relative Configuration

[0234] ##STR00022##

[0235] .sup.1H-NMR (CDCl.sub.3) δppm: 1.12-2.00 (16H, m), 2.03-2.20 (1H, m), 3.35-3.55 (2H, m), 5.88 (1H, brs).

Reference Example 12

Trans-3,3-dimethyldecahydrocycloheptapyrazin-2-one

Relative Configuration

[0236] ##STR00023##

[0237] .sup.1H-NMR (CDCl.sub.3) δppm: 1.35 (3H, s), 1.39 (3H, s), 1.42-1.9 (11H, m), 2.73-2.85 (1H, m), 3.13-3.26 (1H, m), 5.51 (1H, brs).

Reference Example 13

Production of cis-4,4-dimethyloctahydrocyclopenta[b][1,4]diazepin-2-one

Relative Configuration

[0238] ##STR00024##

[0239] A toluene (200 mL) suspension of cis-cyclopentane-1,2-diamine (19.7 g, 197 mmol) and 3-methyl-2-butenoic acid (19.7 g, 197 mmol) was stirred under reflux for 24 hours under azeotropic conditions using a Dean-Stark apparatus. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the deposited crystal was collected by filtration. The obtained crystal was washed with ether and then dried to obtain cis-4,4-dimethyloctahydrocyclopenta[b][1,4]diazepin-2-one (8.60 g, 24%) in a light brown powder form.

[0240] .sup.1H-NMR (CDCl.sub.3) δppm: 1.10-1.56 (10H, m), 1.65-1.80 (1H, m), 2.02-2.30 (3H, m), 2.60 (1H, d, J=12.8 Hz), 3.18-3.37 (1H, m), 3.68-3.85 (1H, m), 5.73 (1H, brs).

[0241] Compounds of Reference Examples 14 and 15 below were produced in the same way as in Reference Example 13 using appropriate starting materials.

Reference Example 14

(5aS,9aS)-4,4-dimethyldecahydro[b][1,4]diazepin-2-one

Absolute Configuration

[0242] ##STR00025##

[0243] .sup.1H-NMR (CDCl.sub.3) δppm: 1.00-1.45 (11H, m), 1.63-1.83 (3H, m), 1.83-2.00 (1H, m), 2.31-2.43 (1H, m), 2.65-2.81 (2H, m), 3.00-3.16 (1H, m), 5.54-5.90 (1H, br).

Reference Example 15

(5aR,9aR)-4,4-dimethyldecahydro[b][1,4]diazepin-2-one

[0244] ##STR00026##

[0245] .sup.1H-NMR (CDCl.sub.3) δppm: 1.02-1.36 (11H, m), 1.64-1.83 (3H, m), 1.83-1.97 (1H, m), 2.37 (1H, dd, J=2.4, 13.9 Hz), 2.66-2.81 (2H, m), 3.01-3.15 (1H, m), 5.75-5.92 (1H, brs).

Reference Example 16

Production of cis-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine

Relative Configuration

[0246] ##STR00027##

[0247] Lithium aluminum hydride (541 mg, 14.3 mmol) was added to an anhydrous dioxane (40 mL) solution of cis-3,3-dimethyloctahydrocyclopentapyrazin-2-one (2.00 g, 11.9 mmol) with stirring at room temperature, and the mixture was gradually heated and stirred for 10 minutes under reflux. The reaction mixture was cooled to ice temperature. Then, sodium sulfate decahydrate was added thereto in small portions until no hydrogen gas was generated. Then, the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=1/10) to obtain cis-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine (1.67 g, 91%) in a pale yellow oil form.

[0248] .sup.1H-NMR (CDCl.sub.3) δppm: 1.04 (3H, s), 1.16 (3H, s), 1.28-2.02 (8H, m), 2.37 (1H, d, J=12.9 Hz), 2.70 (1H, d, J=12.9 Hz), 3.00-3.15 (1H, m), 3.15-3.32 (1H, m).

[0249] Compounds of Reference Examples 17 to 34 below were produced in the same way as in Reference Example 16 using appropriate starting materials.

Reference Example 17

Trans-2,2-dimethyloctahydro-1H-cyclopenta[b]pyrazine

Relative Configuration

[0250] ##STR00028##

[0251] .sup.1H-NMR (CDCl.sub.3) δppm: 1.08 (3H, s), 1.19-1.92 (11H, m), 2.15-2.30 (1H, m), 2.55-2.74 (21H, m), 2.77 (1H, d, J=12.2 Hz).

Reference Example 18

Cis-2,2-dimethyldecahydrocyclopenta[b][1,4]diazepine

Relative Configuration

[0252] ##STR00029##

[0253] .sup.1H-NMR (CDCl.sub.3) δppm: 1.11 (3H, s), 1.14 (3H, s), 1.15-1.45 (6H, m), 1.55-1.67 (1H, m), 1.67-1.77 (1H, m), 1.97-2.12 (2H, m), 2.68-2.80 (1H, m), 2.98-3.11 (2H, m), 3.16-3.28 (1H, m).

Reference Example 19

Cis-2,2-dimethyloctahydrofuro[3,4-b]pyrazine

Relative Configuration

[0254] ##STR00030##

[0255] .sup.1H-NMR (CDCl.sub.3) δppm: 1.08 (3H, s), 1.18 (3H, s), 1.40-1.80 (2H, br), 2.41 (1H, d, J=13.2 Hz), 2.69 (1H, d, J=13.2 Hz), 3.33-3.43 (1H, m), 3.43-3.55 (1H, m), 3.63-3.72 (1H, m), 3.75-3.96 (3H, m).

Reference Example 20

Trans-2,2-dimethyloctahydrofuro[3,4-b]pyrazine

Relative Configuration

[0256] ##STR00031##

[0257] .sup.1H-NMR (CDCl.sub.3) δppm: 1.13 (3H, s), 1.30 (3H, s), 1.44-1.65 (2H, m), 2.64-2.78 (2H, m), 2.83 (1H, d, J=12.2 Hz), 3.11-3.22 (1H, m), 3.46 (1H, dd, J=7.3, 10.5 Hz), 3.55 (1H, dd, J=7.4, 10.5 Hz), 3.94 (1H, t, J=7.1 Hz), 4.00 (1H, t, J=7.2 Hz).

Reference Example 21

Cis-2,2-dimethyldecahydro-1H-benzo[b][1,4]diazepine

Relative Configuration

[0258] ##STR00032##

[0259] .sup.1H-NMR (CDCl.sub.3) δppm: 1.08 (3H, s), 1.13 (3H, s), 1.18-1.84 (12H, m), 2.65-2.93 (3H, m), 3.14-3.22 (1H, m).

Reference Example 22

(5aS,9aS)-2,2-dimethyldecahydro-1H-benzo[b][1,4]diazepine

Absolute Configuration

[0260] ##STR00033##

[0261] .sup.1H-NMR (CDCl.sub.3) δppm: 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (1H, m), 2.31-2.43 (1H, m), 2.79-2.90 (1H, m), 2.90-3.04 (1H, m).

Reference Example 23

(5aR,9aR)-2, 2-dimethyldecahydro-1H-benzo[b][1,4]diazepine

Absolute Configuration

[0262] ##STR00034##

[0263] .sup.1H-NMR (CDCl.sub.3) δppm: 1.00-1.35 (11H, m), 1.50-1.85 (7H, m), 2.20-2.31 (1H, m), 2.31-2.43 (1H, m), 2.79-2.90 (1H, m), 2.90-3.04 (1H, m).

Reference Example 24

Cis-2,2-dimethyldecahydroquinoxaline

Relative Configuration

[0264] ##STR00035##

[0265] .sup.1H-NMR (CDCl.sub.3) δppm: 1.06 (3H, s), 1.19 (3H, s), 1.20-1.40 (5H, m), 1.53-1.60 (3H, m), 1.70-1.77 (1H, m), 1.92-2.15 (1H, m), 2.36 (1H, d, J=12.7 Hz), 2.66-2.72 (1H, m), 2.72 (1H, d, J=12.7 Hz), 3.16-3.28 (1H, m).

Reference Example 25

Trans-2,2-dimethyldecahydroquinoxaline

Relative Configuration

[0266] ##STR00036##

[0267] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05 (3H, s), 1.08-1.74 (10H, m), 1.23 (3H, s), 2.02-2.12 (1H, m), 2.40-2.50 (1H, m), 2.60 (1H, d, J=12.1 Hz), 2.73 (1H, d, J=12.1 Hz).

Reference Example 26

(4aS,8aS)-2,2-dimethyldecahydroquinoxaline

Absolute Configuration

[0268] ##STR00037##

[0269] .sup.1H-NMR (CDCl.sub.3) δppm: 1.01-1.43 (6H, m), 1.05 (3H, s), 1.23 (3H, s), 1.58-1.63 (1H, m), 1.68-1.74 (3H, m), 2.03-2.19 (1H, m), 2.40-2.49 (1H, m), 2.60 (1H, d, J=12.1 Hz), 2.73 (1H, d, J=12.1 Hz).

Reference Example 27

(4aR,8aR)-2,2-dimethyldecahydroquinoxaline

[0270] ##STR00038##

[0271] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05 (3H, s), 1.09-1.56 (6H, m), 1.23 (3H, s), 1.58-1.63 (1H, m), 1.66-1.75 (3H, m), 2.03-2.12 (1H, m), 2.41-2.50 (1H, m), 2.61 (1H, d, J=12.1 Hz), 2.75 (1H, d, J=12.1 Hz).

Reference Example 28

Trans-2,2-diethyldecahydroquinoxaline

Relative Configuration

[0272] ##STR00039##

[0273] .sup.1H-NMR (CDCl.sub.3) δppm: 0.79 (3H, t, J=7.5 Hz), 0.81 (3H, t, J=7.5 Hz), 0.86-1.02 (1H, m), 1.08-1.40 (8H, m), 1.47-1.60 (2H, m), 1.67-1.87 (3H, m), 2.06-2.15 (1H, m), 2.33-2.42 (1H, m), 2.57 (1H, d, J=12.1 Hz), 2.81 (1H, d, J=12.1 Hz).

Reference Example 29

Trans-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Relative Configuration

[0274] ##STR00040##

Reference Example 30

Cis-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Relative Configuration

[0275] ##STR00041##

Reference Example 31

Trans-octahydro-1′H-spiro[cyclopentane-1,2′-quinoxaline]

Relative Configuration

[0276] ##STR00042##

[0277] .sup.1H-NMR (CDCl.sub.3) δppm: 1.10-1.97 (18H, m), 2.10-2.21 (1H m), 2.29-2.38 (1H, m), 2.71 (1H, d, J=12.2 Hz), 2.76 (1H, d, J=12.2 Hz).

Reference Example 32

Trans-octahydro-1′H-spiro[cyclohexane-1,2′-quinoxaline]

Relative Configuration

[0278] ##STR00043##

[0279] .sup.1H-NMR (CDCl.sub.3) δppm: 1.12-1.76 (20H, m), 2.12-2.20 (1H, m), 2.44-2.53 (1H, m), 2.55 (1H, d, J=12.2 Hz), 2.98 (1H, d, J=12.2 Hz).

Reference Example 33

Cis-2,2-dimethyldecahydro-1H-cyclohepta[b]pyrazine

Relative Configuration

[0280] ##STR00044##

[0281] .sup.1H-NMR (CDCl.sub.3) δppm: 1.00-2.02 (18H, m), 2.42 (1H, d, J=12.4 Hz), 2.58 (1H, d, J=12.4 Hz), 2.75-2.86 (1H, m), 3.13-3.25 (1H, m).

Reference Example 34

Trans-2,2-dimethyldecahydro-1H-cyclohepta[b]pyrazine

Relative Configuration

[0282] ##STR00045##

[0283] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05 (3H, s), 1.21 (3H, s), 1.23-1.80 (12H, m), 2.09-2.20 (18, m), 2.46-2.60 (2H, m), 2.68 (1H, d, J=11.8 Hz).

Reference Example 35

Production of (2RS,4aSR,8aSR)-2-ethyldecahydroquinoxaline

Relative Configuration

[0284] ##STR00046##

[0285] Dichloro(pentamethylcyclopentadienyl)iridium (III) dimer (70 mg, 0.090 mmol) and sodium bicarbonate (73 mg, 0.87 mmol) were added to an aqueous (20 mL) solution of trans-cyclohexane-1,2-diamine (2.00 g, 17.5 mmol) and (±)-1,2-butanediol (1.69 mL, 18.4 mmol) with stirring at room temperature. Degassing and argon substitution were repeated 3 times, and the mixture was then stirred for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methylene chloride/methanol) to obtain (2R*,4aS*,8aS*)-2-ethyldecahydroquinoxaline (2.03 g, yield: 69%) in a yellow solid form.

[0286] .sup.1H-NMR (CDCl.sub.3) δppm: 0.92 (3H, t, J=7.5 Hz), 1.10-1.60 (7H, m), 1.64-1.83 (5H, m), 2.16-2.31 (2H, m), 2.44 (1H, dd, J=11.5, 10.4 Hz), 2.58-2.67 (1H, m), 3.02 (1H, dd, J=11.5, 2.7 Hz).

Reference Example 36

Production of (4aS,8aS)-1-benzyldecahydroquinoxaline

[0287] ##STR00047##

[0288] Benzaldehyde (3.05 mL, 30.0 mmol) was added to a methanol (300 mL) solution of (1S,2S)-cyclohexane-1,2-diamine (3.43 g, 30.0 mmol) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was cooled to 0° C. Sodium borohydride (2.27 g, 60.0 mmol) was added thereto, and the mixture was stirred at 0° C. for 2 hours. To the reaction mixture, water (30 mL) was added, and the product was extracted twice with methylene chloride (50 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to obtain (1S,2S)—N-benzylcyclohexane-1,2-diamine (cas no. 207450-11-1) (2.95 g, yield: 48%) in a pale yellow oil form.

[0289] The obtained (1S,2S)—N-benzylcyclohexane-1,2-diamine (2.90 g, 14.2 mmol) was dissolved in methylene chloride (284 nL). To the solution, 60% sodium hydride (1.99 g, 49.7 mmol) was added with ice-cooling and stirring in a nitrogen atmosphere. After 5 minutes, (2-1.5 bromoethyl)diphenylsulfonium trifluoromethanesulfonate (6.92 g, 15.6 mmol) was added to the reaction mixture with ice-cooling and stirring, and the mixture was stirred overnight at room temperature. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added dropwise in small portions, and the product was then extracted twice with methylene chloride (100 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane) to obtain (4aS,8aS)-1-benzyldecahydroquinoxaline (2.28 g, 70%) in a light brown solid form.

[0290] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.4 (4H, m), 1.50 (1H, br), 1.6-1.9 (4H, m), 2.05-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 2.65-2.75 (1H, m), 2.8-2.95 (2H, m), 3.14 (1H, d, J=13.4 Hz), 4.11 (1H, d, J=13.4 Hz), 7.15-7.4 (5H, m).

[0291] Compounds of Reference Examples 37 to 39 below were produced in the same way as in Reference Example 36 using appropriate starting materials.

Reference Example 37

(4aS,8aS)-1-benzyldecahydroquinoxaline

Absolute Configuration

[0292] ##STR00048##

[0293] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.4 (4H, m) 1.50 (1H, br), 1.6-1.9 (4H, m) 205-2.2 (1H, m), 2.2-2.3 (1H, m), 2.4-2.5 (1H, m), 2.65-2.75 (1H, m), 2.8-2.95 (2H, m), 3.13 (1H, d, J=13.4 Hz), 4.11 (1H, d, J=13.4 Hz), 7.15-7.4 (5H, m).

Reference Example 38

Cis-decahydroquinoxaline-1-carboxylic acid tert-butyl ester

Relative Configuration

[0294] ##STR00049##

[0295] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.15 (1H, m), 1.2-1.75 (19H, m), 1.75-1.85 (1H, m), 1.85-2.2 (1H, m), 3.70 (1H, br),4.83 (1H, br).

Reference Example 39

Cis-1-benzyldecahydroquinoxaline

Relative Configuration

[0296] ##STR00050##

[0297] .sup.1H-NMR (CDCl.sub.3) δppm: 1.0-2.0 (10H, m), 2.2-2.4 (1H, m), 2.45-2.7 (2H, m), 2.75-3.1 (2H, m), 3.63 (2H, br), 7.05-7.45 (5H, m).

Reference Example 40

Production of (4aR,8aS)-2,2-dimethyldecahydecahydroquinoxaline

Absolute Configuration

[0298] ##STR00051##

Reference Example 41

(4aS,8aR)-2,2-dimethyidecahydroquinoxaline

Absolute Configuration

[0299] ##STR00052##

[0300] (−)-dibenzoyl-L-tartaric acid monohydrate (13.8 g, 36.7 mmol) in ethanol (140 mL) was added to an ethanol (140 mL) solution of cis-2,2-dimethyldecahydroquinoxaline (13.7 g, 81.4 mmol) with stirring at room temperature. The reaction mixture was stirred for 30 minutes under reflux and cooled to room temperature, and the deposited white crystal was then collected by filtration. The obtained crystal was washed with ethanol (20 mL) and then dried to obtain a white solid <1> (13.1 g). The filtrate and washes obtained in obtaining the solid <1> were concentrated under reduced pressure. The obtained residue was dissolved in ethanol (100 mL). To the solution, an ethanol (130 mL) solution of (+)-dibenzoyl-D-tartaric acid (13.1 g, 36.6 mmol) was added with stirring at room temperature, and the deposited crystal was collected by filtration. The obtained crystal was washed with ethanol (20 mL) and then dried to obtain a light brown solid <2> (16.6 g).

[0301] A methanol (130 mL)/water (10 mL) suspension of the solid <1> was stirred for 30 minutes under reflux. Then, the reaction mixture was cooled to room temperature, and the deposited crystal was collected by filtration. The deposited crystal was washed with methanol (10 mL) and then dried to obtain (4aR,8aS)-2,2-dimethyldecahydroquinoxaline dibenzoyl-L-tartrate (11.4 g, 21.6 mmol) in a white solid form (the absolute configuration of cis-2.2-dimethyldecahydroquinoxaline was determined by the X-ray crystallographic analysis of the white solid). This solid was dissolved in a 1 N aqueous sodium hydroxide solution (44 mL), and the product was extracted with ether (100 mL) three times and with methylene chloride (100 mL) three times. The extracted organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (3.44 g, yield: 25%) in a white solid form.

[0302] .sup.1H-NMR (CDCl.sub.3) δppm: 1.06 (3H, s), 1.20 (3H, s), 1.2-1.4 (4H, m), 1.45-1.95 (5H, m), 1.95-2.15 (1H, m), 2.36 (1H, d, J=12.7 Hz), 2.65-2.75 (21, m), 3.15-3.25 (1H, m).

[0303] A methanol (130 mL)/water (10 mL) suspension of the solid <2> was stirred for 1 hour under reflux. Then, the reaction mixture was cooled to room temperature, and the deposited crystal was collected by filtration. The deposited crystal was washed with methanol (10 mL) and then dried to obtain (4aS,8aR)-2,2-dimethyldecahydroquinoxaline dibenzoyl-D-tartrate (16.0 g, 30.4 mmol) in a white solid form. This solid was dissolved in a 1 N aqueous sodium hydroxide solution (65 mL), and the product was extracted with methylene chloride (100 mL) three times. The extracted organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (4.63 g, yield: 34%) in a light brown solid form.

[0304] .sup.1H-NMR (CDCl.sub.3) δppm: 1.06 (3H, s), 1.19 (3H, s), 1.2-1.45 (5H, m), 1.45-1.65 (3H, m), 1.65-1.8 (1H, m), 1.95-2.15 (1H, m), 2.36 (1H, d, J=12.7 Hz), 2.6-2.8 (2H, m), 3.15-3.25 (1H, m).

[0305] Compounds of Reference Examples 42 to 45 below were produced in the same way as in Reference Examples 40 and 41 using appropriate starting materials.

Reference Example 42

(4a′R,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

[0306] Absolute Configuration

##STR00053##

[0307] .sup.1H-NMR (CDCl.sub.3) δppm: 1.20-2.20 (16H, m), 2.69 (1H, d, J=12.4 Hz), 2.72-2.82 (1H, m), 2.87-3.02 (2H, m).

Reference Example 43

(4a′S,8a′R)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

[0308] ##STR00054##

[0309] .sup.1H-NMR (CDCl.sub.3) δppm: 1.20-2.20 (16H, m), 2.68 (1H, d, J=12.5 Hz), 2.72-2.82 (1H, m), 2.87-3.02 (21, m).

Reference Example 44

(4aR,8aS)-1-benzyldecahydroquinoxaline

Absolute Configuration

[0310] ##STR00055##

[0311] .sup.1H-NMR (CDCl.sub.3) δppm: 1.0-1.25 (1H, m), 1.25-1.65 (5H, m), 1.65-2.05 (3H, m), 2.2-2.4 (1H, m), 2.45-2.7 (2H, m), 2.75-3.1 (3H, m), 3.63 (2H, br), 7.15-7.4 (5H, m).

Reference Example 45

(4aS,8aR)-1-benzyldecahydroquinoxaline

Absolute Configuration

[0312] ##STR00056##

[0313] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.25 (1H, m), 1.25-1.65 (5H, m), 1.65-2.05 (3H, m), 2.2-2.4 (1H, m), 2.5-2.7 (2H, m), 2.75-3.1 (3H, m), 3.63 (2H, br), 7.15-7.4 (5H, m).

Reference Example 46

Production of (trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester

Relative Configuration

[0314] ##STR00057##

[0315] Trans-cyclohexane-1,2-diamine (3.00 g, 26.3 mmol) was diluted with ethanol (15 ml). To the solution, bromoethyl acetate (6.12 mL, 55.2 mmol) was added dropwise with ice-cooling, and the mixture was then stirred overnight at room temperature.

[0316] To the reaction solution, water was added, and the mixture was stirred. The product was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methylene chloride/methanol) to obtain (trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester (2.35 g, yield: 74.4%) in an orange particulate solid form.

[0317] .sup.1H-NMR (CDCl.sub.3) δppm: 1.13-1.41 (4H, m), 1.28 (3H, t, J=7.1 Hz), 1.72-1.97 (41H, m), 2.59-2.67 (1H, m), 3.06-3.13 (1H, m), 3.35 (1H, d, J=17.4 Hz), 3.48 (1H, d, J=16.8 Hz), 3.52 (1H, d, J=17.4 Hz), 3.60 (1H, d, J=16.8 Hz), 4.17 (2H, q, J=7.1 Hz), 6.79 (1H, brs).

[Reference Example 47] Production of 2-(trans-decahydroquinoxalin-1-yl)ethanol

Relative Configuration

[0318] ##STR00058##

[0319] Lithium aluminum hydride (1.00 g, 26.4 mmol) was suspended in anhydrous dioxane (40 ml). To the suspension, an anhydrous dioxane (10 ml) solution of (trans-3-oxodecahydroquinoxalin-1-yl)acetic acid ethyl ester (2.35 g, 9.78 mmol) was added dropwise with stirring at room temperature, and the mixture was then stirred under reflux for 10 minutes. The reaction mixture was cooled on ice, and sodium sulfate decahydrate was added thereto in small portions until no gas was generated. This mixture was filtered through celite and washed with methylene chloride, and the filtrate was then concentrated under reduced pressure to obtain 2-(trans-decahydroquinoxalin-1-yl)ethanol (1.74 g, yield: 97%) in a brown oil form.

[0320] .sup.1H-NMR (CDCl.sub.3) δppm: 0.95-1.1 (1H, m), 1.15-1.44 (3H, m), 1.68-1.80 (5H, m), 1.85-1.94 (1H, m), 2.05-2.44 (4H, m), 2.87-2.97 (3H, m), 3.04-3.16 (1H, m), 3.46-3.54 (1H, m), 3.60-3.69 (1H, m).

Reference Example 48

Production of trans-1-[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline

Relative Configuration

[0321] ##STR00059##

[0322] Triethylamine (4.61 mL, 33.0 mmol) and subsequently tert-butyldimethylsilyl chloride (4.27 g, 28.3 mmol) were added to a methylene chloride (40 mL) solution of 2-(trans-decahydroquinoxalin-1-yl)ethanol (1.74 g, 9.44 mmol) with ice-cooling and stirring, and the mixture was stirred overnight at room temperature. To the reaction mixture, water (100 mL) was added to terminate the reaction. The product was extracted with methylene chloride (100 mL). The organic layer was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain trans-1-[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline (2.00 g, yield: 71%) in a light brown oil form.

[0323] .sup.1H-NMR (CDCl.sub.3) δppm: 0.06 (6H, s), 0.89 (9H, s), 0.98-1.36 (4H, m), 1.65-1.79 (4H, m), 1.85-1.95 (1H, m), 2.08-2.14 (1H, m), 2.24-2.39 (1H, m), 2.45-2.61 (2H, m), 2.79-3.03 (4H, m), 3.62-3.80 (2H, m).

[0324] Compounds of Reference Examples 50 and 51 below were produced in the same way as in Reference Example 1 using appropriate starting materials.

Reference Example 50

(4a′S,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Absolute Configuration

[0325] ##STR00060##

[0326] .sup.1H-NMR (CDCl.sub.3) δppm: 0.99-1.38 (4H, m), 1.55-1.78 (5H, m), 1.78-1.94 (3H, m), 2.21-2.33 (2H, m), 2.48-2.59 (1H, m), 2.63 (1H, brs), 2.76-2.87 (1H, m), 7.36 (1H, s).

Reference Example 51

[0327] (4a′R,8a′R)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxalin]-3′-one

Absolute Configuration

[0328] ##STR00061##

[0329] .sup.1H-NMR (CDCl.sub.3) δppm: 0.97-1.36 (4H, m), 1.55-1.77 (5H, m), 1.77-1.92 (3H, m), 2.20-2.32 (2H, m), 2.47-2.57 (1H, m), 2.63 (1H, brs), 2.76-2.86 (1H, m), 7.36 (1H, s).

[0330] Compounds of Reference Examples 52 and 53 below were produced in the same way as in Reference Example 16 using appropriate starting materials.

Reference Example 52

(4a′S,8a′S)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

[0331] ##STR00062##

[0332] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.90 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, dd, J=1.5, 12.2 Hz), 3.01 (1H, d, J=12.2 Hz).

Reference Example 53

(4a′R,8a′R)-octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

[0333] ##STR00063##

[0334] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.91 (15H, m), 2.15-2.30 (3H, m), 2.69 (1H, d, J=12.2 Hz), 3.01 (1H, d J=12.2 Hz).

Reference Example 54

Production of (4aS,8aR)-tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate

Absolute Configuration

[0335] ##STR00064##

[0336] Di-tert-butyl dicarbonate (1.70 g, 7.79 mmol) was added to a MeOH (16 ml) solution of (4aR,8aS)-1-benzyldecahydroquinoxaline (1.63 g, 7.08 mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was then purified by basic silica gel column chromatography (Hex-AcOEt) to obtain (4aS,8aR)-tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.38 g, yield: quantitative) in a colorless oil form.

[0337] .sup.1H-NMR (CDCl.sub.3) δppm: 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.66 (1H, brs), 2.86 (1H, d, J=13.2 Hz), 3.03 (1H, brs), 3.50-4.10 (2H, br), 4.16 (1H, d, J=13.2 Hz), 7.21-7.36 (5H, m).

[0338] A compound of Reference Example 55 below was produced in the same way as in Reference Example 54 using appropriate starting materials

Reference Example 55

(4aR,8aS)-tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate

Absolute Configuration

[0339] ##STR00065##

[0340] .sup.1H-NMR (CDCl.sub.3) δppm: 1.26-1.66 (14H, m), 1.79-1.96 (2H, m), 2.14-2.33 (2H, m), 2.40-2.45 (1H, m), 2.65 (1H, brs), 2.86 (1H, d, J=13.2 Hz), 3.03 (1H, brs), 3.51-4.10 (2H, br), 4.16 (1H, d, J=13.2 Hz), 7.21-7.36 (5H, m).

Reference Example 56

Production process of (4aS,8aR)-tert-butyl decahydroquinoxaline-1-carboxylate

Absolute Configuration

[0341] ##STR00066##

[0342] Pearlman's catalyst (0.24 g) was added to an EtOH (25 ml) solution of (4aS,8aR)-tert-butyl 4-benzyldecahydroquinoxaline-1-carboxylate (2.4 g, 7.26 mmol). This suspension was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered through celite, and the residue was washed with EtOH. Then, the filtrate was concentrated 1.5 under reduced pressure to obtain (4aS,8aR)-tert-butyl decahydroquinoxaline-1-carboxylate (1.67 g, yield: 96%) in a colorless oil form.

[0343] .sup.1H-NMR (CDCl.sub.3) δppm: 1.16-1.53 (14H, m), 1.53-1.82 (3H, m), 1.83-2.00 (1H, m), 2.68-2.83 (1H, m), 2.85-3.10 (3H, m), 3.65-4.06 (21H, m).

[0344] A compound of Reference Example 57 below was produced in the same way as in Reference Example 56 using appropriate starting materials.

Reference Example 57

(4aR,8aS)-tert-butyl decahydroquinoxaline-1-carboxylate

Absolute Configuration

[0345] ##STR00067##

[0346] .sup.1H-NMR (CDCl.sub.3) δppm: 1.18-1.55 (14H, m), 1.55-1.82 (3H, m), 1.85-2.00 (1H, m), 2.68-2.82 (1H, m), 2.85-3.10 (3H, m), 3.65-4.04 (2H, m).

Reference Example 58

Production process of cis tert-butyl 4-(4-chlorophenyl)decahydroquinoxaline-1-carboxylate

Relative Configuration

[0347] ##STR00068##

[0348] A toluene (4 ml) suspension of cis tert-butyl decahydroquinoxaline-1-carboxylate (240 mg, 0.999 mmol), 1-bromo-4-chlorobenzene (211 mg, 1.10 mmol), Pd(OAc).sub.2 (11.2 mg, 0.0499 mmol), t-Bu.sub.3P.HBF.sub.4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the celite layer was washed with AcOEt (5 ml×2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a white solid (87 mg, yield: 25%).

[0349] .sup.1H-NMR (CDCl.sub.3) δppm: 1.10-1.40 (4H, m), 1.40-1.52 (10H, m), 1.63-1.71 (1H, m), 1.73-1.82 (1H, m), 2.15-2.28 (1H, m), 2.74 (1H, dt, J=3.6, 11.8 Hz), 2.90-2.97 (1H, m), 3.05-3.11 (1H, m), 3.27 (1H, dr, J=3.4, 12.6 Hz), 3.77-3.86 (1H, m), 4.01-4.10 (1H, m), 7.08-7.13 (2H, m), 7.25-7.30 (2H, m).

[0350] Compounds of Reference Examples 59 to 63 below were produced in the same way as in Reference Example 35 using appropriate starting materials.

Reference Example 59

(4aS,8aS)-decahydroquinoxaline

Absolute Configuration

[0351] ##STR00069##

[0352] .sup.1H-NMR (CDCl.sub.3) δppm: 1.12-1.58 (6H, m), 1.62-1.78 (4H, m), 2.20-2.29 (2H, m), 2.82-3.02 (4H, m).

Reference Example 60

(4aR,8aR)-decahydroquinoxaline

Absolute Configuration

[0353] ##STR00070##

[0354] .sup.1H-NMR (CDCl.sub.3) δppm: 1.14-1.27 (2H, m), 1.27-1.57 (4H, m), 1.62-1.79 (4H, m), 2.19-2.30 (2H, m), 2.83-3.03 (4H, m).

Reference Example 61

(2R,4aS,8aS)-2-methyldecahydroquinoxaline

Absolute Configuration

[0355] ##STR00071##

[0356] .sup.1H-NMR (CDCl.sub.3) δppm: 1.02 (3H, d, J=6.3 Hz), 1.11-1.51 (6H, m), 1.62-1.79 (4H, m), 2.14-2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd, J=10.2, 11.7 Hz), 2.81-2.91 (1H, m), 2.94 (1H, dd, J=2.9, 11.7 Hz).

Reference Example 62

(2S,4aR,8aR)-2-methyldecahydroquinoxaline

Absolute Configuration

[0357] ##STR00072##

[0358] .sup.1H-NMR (CDCl.sub.3) δppm: 1.02 (3H, d, J=6.3 Hz), 1.10-1.49 (6H, m), 1.62-1.80 (4H, m), 2.14-2.22 (1H, m), 2.24-2.33 (1H, m), 2.44 (1H, dd, J=10.3, 11.7 Hz), 2.80-2.91 (1H, m), 2.94 (1H, dd, J=2.9, 11.7 Hz).

Reference Example 63

(2R,4aS,8aS)-2-ethyldecahydroquinoxaline

Absolute Configuration

[0359] ##STR00073##

[0360] .sup.1H-NMR (CDCl.sub.3) δppm: 0.92 (3H, t, J=7.5 Hz), 1.1-1.55 (8H, m), 1.6-1.8 (4H, m), 2.14-2.32 (2H, m), 2.39-2.5 (1H, m), 2.57-2.68 (1H, m), 3.01 (1H, dd, J=2.6, 11.6 Hz).

Example 1

Production of (4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline

Absolute Configuration

[0361] ##STR00074##

[0362] A toluene (8 mL) suspension of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (337 mg, 2.00 mmol), 6-bromo-1-(triisopropylsilyl)-1H-indole (846 mg, 2.40 mmol), sodium tert-butoxide (269 mg, 2.80 mmol), palladium (II) acetate (22.5 mg, 0.0902 mmol), and tri-tert-butylphosphine tetrafluoroborate (29.1 mg, 0.101 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature. Then, water (0.5 mL) and ethyl acetate (10 mL) were added thereto, and the mixture was stirred, followed by addition of magnesium sulfate. Insoluble matter was filtered through celite, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (n-hexane:ethyl acetate) to obtain colorless, amorphous (4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline (0.75 g, yield: 85%).

[0363] .sup.1H-NMR (CDCl.sub.3) δppm: 1.1-1.2 (18H, m), 1.21 (3H, s), 1.29 (3H, s), 1.3-1.55 (5H, m), 1.55-1.8 (7H, m), 2.79 (1H, d, J=11.6 Hz), 2.91 (1H, d, J=11.6 Hz), 3.45-3.6 (2H, m), 6.49 (1H, dd, J=0.7, 3.2 Hz), 6.82 (1H, dd, J=2.0, 8.6 Hz), 693 (II, s), 7.08 (1H, d, J=3.2 Hz), 7.45 (1H, d, J=8.6 Hz).

Example 2

Production of (4aR,8aS)-1-(1H-indol-6-yl)-3,3-dimethyldecahydroquinoxaline

Absolute Configuration

[0364] ##STR00075##

[0365] Tetra-n-butyl ammonium fluoride (1 M in THF) (3.41 mL, 3.41 mol) was added to a tetrahydrofuran (15 mL) solution of (4aR,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-indol-6-yl)decahydroquinoxaline (0.750 g, 1.71 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane) to obtain a white solid. The obtained solid was recrystallized from diisopropyl ether/hexane to obtain (4aR,8aS)-1-(1H-indol-6-yl)-3,3-dimethyldecahydroquinoxaline (305 mg, yield: 63%).

[0366] .sup.1H-NMR (CDCl.sub.3) δppm: 1.0-1.55 (1H, m), 1.55-1.85 (4H, m), 2.79 (1H, d, J=11.6 Hz), 2.94 (1H, d, J=11.6 Hz), 3.45-3.55 (1H, m), 3.6-3.75 (1H, m), 6.35-6.5 (1H, m), 6.79 (1H, s), 6.86 (1H, dd, J=2.1, 8.7 Hz), 7.03 (1H, dd, J=2.7, 2.7 Hz), 7.47 (1H, d, J=8.6 Hz), 7.92 (1H, br).

Example 3

Production of (4aS,8aS)-1-(4-chlorophenyl)decahydroquinoxaline

Absolute Configuration

[0367] ##STR00076##

[0368] 1-chloroethyl chloroformate (229 μL, 2.10 mmol) was added to a methylene chloride (6.5 mL) solution of (4aS,8aS)-1-benzyl-4-(4-chlorophenyl)decahydroquinoxaline (0.650 g, 1.91 mmol) with ice-cooling and stirring. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was then concentrated under reduced pressure. The obtained residue was dissolved in methanol (6.5 mL), and this solution was stirred for 1 hour under reflux. The solvent was distilled off from the reaction mixture. To the obtained residue, acetone (5 mL) was added, and the mixture was stirred. The deposited crystal was collected by filtration. The obtained crystal was washed with acetone (1 mL) and then dried to obtain (4aS,8aS)-1-(4-chlorophenyl)decahydroquinoxaline (253 mg, yield: 53%) in a white powder form.

[0369] .sup.1H-NMR (DMSO-d.sub.6) δppm: 0.85-1.05 (1H, m), 1.1-1.4 (2H, m), 1.4-1.65 (3H, m), 1.65-1.8 (1H, m), 1.9-2.05 (1H, m), 2.8-3.0 (2H, m), 3.05-3.2 (3H, m), 3.2-3.5 (1H, m), 7.1-7.2 (2H, m), 7.35-7.45 (2H, m), 9.2-9.65 (2H, m).

Example 4

Production of cis-4-(benzo[b]thiophen-5-yl)-1,2,2-trimethyldecahydroquinoxaline hydrochloride

Relative Configuration

[0370] ##STR00077##

[0371] A 37% aqueous formaldehyde solution (0.81 mL, 9.9 mmol) was added to a methanol (10 mL) solution of cis-1-(benzo[b]thiophen-5-yl)-3,3-dimethyldecahydroquinoxaline (298 mg, 0.992 mmol) with stirring at room temperature. After 30 minutes, sodium cyanoborohydride (311 mg, 4.96 mmol) and acetic acid (0.30 mL) were added to the reaction solution at room temperature, and the mixture was stirred overnight. The solvent was distilled off from the reaction mixture under reduced pressure. Then, a saturated aqueous solution of sodium bicarbonate (50 mL) was added thereto, followed by extraction with ethyl acetate (50 mL) twice. The organic layer was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to obtain a brown oil. 4 N hydrochloric acid/ethyl acetate (0.6 mL) was added to an ethanol solution of the obtained oil with stirring at room temperature, and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain cis-4-(benzo[b]thiophen-5-yl)-1,2,2-trimethyldecahydroquinoxaline hydrochloride (258 mg, yield: 74%) in a white powder form.

[0372] .sup.1H-NMR (CDCl.sub.3) δppm: 1.17-1.34 (1H, m), 1.37-1.74 (2H, m), 1.47 (3H, s), 1.87-2.04 (1H, m), 1.90 (3H, s), 2.20-2.30 (1H, m), 2.39-2.54 (1H, m), 2.64-2.88 (2H, m), 2.75 (3H, d, J=4.9 Hz), 3.12 (1H, d, J=13.2 Hz), 3.69-3.74 (1H, m), 3.85-3.93 (1H, m), 3.87 (1H, d, J=13.2 Hz), 7.01 (1H, dd, J=8.8, 2.3 Hz), 7.21-7.32 (2H, m), 7.44 (1H, d, J=5.4 Hz), 7.75 (1H, d, J=8.8 Hz), 11.20 (1H, brs).

Example 5

Production of 2-(trans-4-(naphthalen-2-yl)decahydroquinoxalin-1-yl)ethanol dihydrochloride

Relative Configuration

[0373] ##STR00078##

[0374] Tetra-n-butyl ammonium fluoride (1 M in THF) (2.1 mL, 2.1 mmol) was added to a THF (10 mL) solution of trans-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-(naphthalen-2-yl)decahydroquinoxaline (820 mg, 1.93 mmol) with stirring at room temperature, and the mixture was stirred overnight. To the reaction mixture, ethyl acetate was added, and the resultant mixture was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to obtain a colorless, amorphous solid (534 mg). A 319 mg aliquot of the obtained solid was dissolved in ethanol. To the solution, 4 N hydrochloric acid/ethyl acetate (1.0 mL) was added with stirring at room temperature, and the deposited crystal was collected by filtration. The obtained crystal was washed with ethyl acetate and then dried under reduced pressure to obtain 2-(trans-4-(naphthalen-2-yl)decahydroquinoxalin-1-yl)ethanol dihydrochloride (365 mg, yield: 49%) in a white powder form.

[0375] .sup.1H-NMR (CDCl.sub.3) δppm: 1.23-1.76 (4H, m), 1.86-2.08 (3H, m), 2.43-2.48 (1H, m), 3.18-3.25 (1H, m), 3.72-3.77 (2H, m), 3.93-3.98 (1H, m), 3.93-4.78 (1H, br), 4.08-4.20 (2H, m), 4.39-4.55 (1H, m), 4.57-4.78 (2H, m), 4.97-5.06 (1H, m), 7.61-7.68 (3H, m), 7.81-8.07 (3H, m), 8.17-8.69 (1H, br), 12.73 (1H, brs), 14.91 (1H, brs).

Example 77

Production of (4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline

Absolute Configuration

[0376] ##STR00079##

[0377] A toluene (4 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-fluorobenzofuran (258 mg, 1.20 mmol), Pd(OAc).sub.2 (11.2 mg, 0.0499 mmol), t-Bu.sub.3P.HBF.sub.4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered, and the residue was washed with AcOEt (5 ml×2) Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless oil (167 mg). This oil was crystallized from hexane (1 mL) to obtain (4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline (107 mg, yield: 35%) in a white powder form.

[0378] .sup.1H-NMR(CDCl.sub.3) δppm: 1.0-1.45 (11H, m), 1.6-1.8 (3H, m), 1.8-1.95 (1H, m), 2.70 (1H, d, J=11.3 Hz), 3.04 (1H, d, J=11.3 Hz), 3.50 (1H, ddd, J=3.8, 3.8, 12.1 Hz), 3.55-3.65 (1H, m), 6.47 (1H, dd, J=3.4, 8.6 Hz), 6.84 (1H, dd, J=2.5, 2.5 Hz), 6.89 (1H, dd, J=8.6, 10.4 Hz), 7.60 (1H, J=2.2 Hz).

Example 106

Production of (4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride

Absolute Configuration

[0379] ##STR00080##

[0380] A toluene (10 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol), 1-bromo-4-chlorobenzene (345 mg, 1.80 mmol), Pd(OAc).sub.2 (16.8 mg, 0.0748 mmol), t-Bu.sub.3P.HBF.sub.4 (21.8 mg, 0.0751 mmol), and NaOt-Bu (202 mg, 2.10 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Then, insoluble matter was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt). The obtained oil was dissolved in 1 N HCl-EtOH (3 mL), and the solvent was distilled off under reduced pressure. The deposited crystal was recrystallized from ethanol/acetone to obtain (4aS,8aR)-1-(4-chlorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride (262 mg, yield: 55%) in a white powder form.

[0381] .sup.1H-NMR (DMSO-d.sub.6) δppm: 1.2-1.45 (6H, m), 1.51 (3H, s), 1.6-2.1 (5H, m), 2.93 (1H, d, J=13.6 Hz), 3.40 (1H, d, J=13.8 Hz), 3.65-3.85 (1H, m), 3.9-4.1 (1H, m), 6.8-7.05 (2H, m), 7.1-7.35 (2H, m), 8.14 (1H, br), 9.77 (1H, br).

Example 112

Production of (4aS,8aR)-1(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride

Absolute Configuration

[0382] ##STR00081##

[0383] A toluene (10 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-2-chloro-1-fluorobenzene (251 mg, 1.20 mmol), Pd(OAc).sub.2 (11.2 mg, 0.0500 mmol), t-Bu.sub.3P.HBF.sub.4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Then, insoluble matter was filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt). The obtained oil was dissolved in 1 N HCl-EtOH (3 mL), and ethanol was distilled off under reduced pressure. The deposited crystal was recrystallized from ethanol/acetone to obtain (4aS,8aR)-1-(3-chloro-4-fluorophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride (153 mg, yield: 46%) in a white powder form.

[0384] .sup.1H-NMR (DMSO-d.sub.6) δppm: 1.15-1.45 (6H, m), 1.51 (3H, s), 1.6-1.9 (4H, m), 1.9-2.05 (1H, m), 2.94 (1H, d, J=13.5 Hz), 3.3-3.45 (1H, m), 3.65-3.8 (1H, m), 3.95-4.1 (1H, m), 6.85-7.0 (1H, m), 7.12 (1H, dd, J=3.0, 6.2 Hz), 7.25 (1H, dd, J=9.1, 9.1 Hz), 8.13 (1H, br), 9.86 (1H, br).

Example 150

Production of 5-((4aR,8aS)-3,3-dimethyldecahydroquinoxalin-1-yl)-1-methyl-1H-indole-2-carbonitrile

Absolute Configuration

[0385] ##STR00082##

[0386] A toluene (4 ml) suspension of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 5-bromo-1-methyl-1H-indole-2-carbonitrile (259 mg, 1.10 mmol), Pd(OAc).sub.2 (11.2 mg, 0.0499 mmol), t-Bu.sub.3P.HBF.sub.4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the residue was washed with CH.sub.2Cl.sub.2:MeOH (3:1) (5 mL×2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless oil. This oil was crystallized from hexane (I mL) to obtain (4aS,8aR)-1-(7-fluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline (148 mg, yield: 46%) in a pale yellow powder form.

[0387] .sup.1H-NMR (CDCl.sub.3) δppm: 0.7-2.3 (15H, m), 2.7-3.2 (2H, m), 3.5-3.8 (2H, m), 3.85 (3H, s), 6.95-7.05 (2H, m), 7.15-7.3 (2H, m).

Example 237

Production of (4aS,8aS)-1-(3-chloro-4-cyanophenyl)-3,3-dimethyldecahydroquinoxaline hydrochloride

Absolute Configuration

[0388] ##STR00083##

[0389] A toluene (10 ml) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (400 mg, 2.38 mmol), 4-bromo-2-chlorobenzonitrile (669 mg, 3.09 mmol), Pd(OAc).sub.2 (53 mg, 0.24 mmol), t-Bu.sub.3P.HBF.sub.4 (70 mg, 0.24 mmol), and t-BuONa (320 mg, 3.33 mmol) was stirred for 5 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled. Then, insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (CH.sub.2Cl.sub.2/MeOH) to obtain an orange amorphous solid. This amorphous solid was dissolved in ethyl acetate (5 mL). A crystal deposited by the addition of 4 N HCl/AcOEt (0.6 mL) was collected by filtration and dried under reduced pressure to obtain (4aS,8aS)-1-(3-chloro-4-cyanophenyl)-3,3-dimethyldecahydroquinoxaline (304 mgm, 48%) in a pale orange powder form.

[0390] .sup.1H-NMR (CDCl.sub.3) δppm: 1.05-1.20 (1H, m), 1.23-1.44 (21H, m), 1.54-2.10 (4H, m), 1.63 (3H, s), 1.68 (3H, s), 2.35-2.40 (1H, m), 2.89 (1H, d, J=12.7 Hz), 3.19 (2H, br), 3.34 (1H, d, J=12.7 Hz), 7.06 (1H, dd, J=8.4, 2.0 Hz), 7.20 (1H, d, J=2.0 Hz), 7.61 (1H, d, J=8.4 Hz), 9.62 (1H, brs), 9.90 (1H, br)

Example 579

Production of (4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline]

Absolute Configuration

[0391] ##STR00084##

[0392] A toluene (4 ml) suspension of (4a′R,8a′S)-octahydro-1.sup.1H-spiro[cyclobutane-1,2′-quinoxaline] (180 mg, 0.998 mmol), 4-bromo-7-methoxybenzofuran (250 mg, 1.10 mmol), Pd(OAc).sub.2 (11.2 mg, 0.0499 mmol), t-Bu.sub.3P.HBF.sub.4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered, and the residue was washed with AcOEt (5 mL×2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless amorphous solid. This solid was crystallized from hexane (1 mL) to obtain (4a′R,8a′S)-4′-(7-methoxybenzofuran-4-yl)octahydro-1′H-spiro[cyclobutane-1,2′-quinoxaline] (107 mg, yield: 35%) in a white powder form.

[0393] .sup.1H-NMR (CDCl.sub.3) δppm: 0.95-11 (2H, m), 1.3-1.4 (1H, m), 1.4-2.1 (1H, m), 2.25-2.4 (1H, m), 3.01 (1H, d, J=11.0 Hz), 3.17 (1H, d, J=11.1 Hz), 3.40 (1H, br), 3.45-3.5 (1H, m), 3.97 (3H, s), 6.58 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.4 Hz), 6.80 (1H, d, J=2.1 Hz), 7.58 (1H, d, J=2.1 Hz).

Example 580

Production of (4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline hydrochloride

Absolute Configuration

[0394] ##STR00085##

[0395] A toluene (6 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (252 mg, 1.50 mmol), 4-bromo-6,7-difluorobenzofuran (384 mg, 1.65 mmol), Pd(OAc).sub.2 (16.8 mg, 0.0748 mmol), t-Bu.sub.3P.HBF.sub.4 (21.8 mg, 0.0751 mmol), and NaOt-Bu (202 mg, 2.10 mmol) was stirred for 3 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Then, insoluble matter was filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a pale yellow oil (193 mg). This oil was dissolved in ethanol (2 mL). To the solution, 1 N HCl-EtOH (1.2 mL) was added, and the mixture was stirred. The deposited crystal was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain (4aS,8aR)-1-(6,7-difluorobenzofuran-4-yl)-3,3-dimethyldecahydroquinoxaline hydrochloride (167 mg, yield: 31%) in a white powder form.

[0396] .sup.1H-NMR (DMSO-d.sub.6) δppm: 1.01-1.17 (2H, m), 1.34-1.44 (1H, m), 1.48 (3H, s), 1.52 (3H, s), 1.59-2.07 (5H, m), 3.00 (1H, d, J=13.0 Hz), 3.28 (1H, d, J=13.2 Hz), 3.75-3.9 (1H, m), 4.0-4.15 (1H, m), 6.83 (1H, dd, J=5.9, 13.5 Hz), 7.36 (1H, dd, J=2.6, 2.6 Hz), 8.0-8.2 (2H, m), 9.7-9.9 (1H, m).

Example 581

Production of (4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline

Absolute Configuration

[0397] ##STR00086##

[0398] A toluene (5 ml) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 5-bromo-1-(triisopropylsilyl)-1H-indole-2-carbonitrile (493 mg, 1.31 mmol), Pd(OAc).sub.2 (13.3 mg, 0.0594 mmol), tBu.sub.3P.HBF.sub.4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours in a nitrogen atmosphere. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane) to obtain (4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (430 mg, 78%) in a white amorphous solid form.

[0399] .sup.1H-NMR (CDCl.sub.3) δppm: 0.75-1.38 (26H, m), 1.41 (3H, s), 1.54-1.77 (4H, m), 2.01 (3H, quintet, J=7.5 Hz), 2.25-2.32 (1H, m), 2.65 (1H, d, =11.2 Hz), 2.75-2.85 (2H, m), 7.11 (1H, dd, J=2.0, 9.1 Hz), 7.32 (1H, d, J=2.0 Hz), 7.33 (1H, d, J=0.5 Hz), 7.50 (1H, d, J=9.1 Hz).

Example 582

Production of (4aS,8aS)-1-(2-cyano-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline

Absolute Configuration

[0400] ##STR00087##

[0401] Tetrabutylammonium fluoride (1 M THF solution, 0.73 mL, 0.73 mmol) was 1.5 added to an anhydrous tetrahydrofuran (5 mL) solution of (4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (170 mg, 0.366 mmol) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane=1/10.fwdarw.1/1). The solvent was removed under reduced pressure. The obtained residue was recrystallized from ethyl acetate/n-hexane to obtain (4aS,8aS)-1-(2-cyano-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (30 mg, yield: 27%) in a white powder form.

[0402] .sup.1H-NMR (DMSO-d.sub.6) δppm: 0.82-1.00 (4H, m), 1.08-1.34 (6H, m), 1.42-1.67 (5H, m), 2.19-2.27 (1H, m), 2.55 (1H, d, J=10.9 Hz), 2.59-2.69 (2H, m), 7.11 (1H, dd, J=1.8, 8.8 Hz), 7.26 (1H, d, J=0.8 Hz), 7.32 (1H, d, J=1.8 Hz), 7.36 (1H, d, J=8.8 Hz) 12.25 (1H, brs).

Example 583

Production of (4aS,8aR)-1-(7-chloro-2,3-dihydro-1H-inden-4-yl)-3,3-dimethyldecahydroquinoxaline

Absolute Configuration

[0403] ##STR00088##

[0404] A toluene (1 mL) solution of bis(tri-tert-butylphosphine)palladium (25.6 mg, 0.0501 mmol) was added to a toluene (4 ml) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 4-bromo-7-chloro-2,3-dihydro-1H-indene (255 mg, 1.10 mmol), and NaOt-Bu (135 mg, 1.40 mmol), and the mixture was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO.sub.4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the residue was washed with AcOEt (5 mL'2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a white solid (167 mg). This solid was recrystallized from ethanol/water to obtain (4aS,8aR)-1-(7-chloro-2,3-dihydro-1H-inden-4-yl)-3,3-dimethyldecahydroquinoxaline (136 mg, yield: 43%) in a white powder form.

[0405] .sup.1H-NMR (CDCl.sub.3) δppm: 0.97-1.12 (3H, m), 1.16 (3H, s), 1.27 (3H, s), 1.31-1.44 (2H, m), 1.45-1.76 (3H, m), 1.78-1.92 (1H, m), 1.94-2.06 (1H, m), 2.12-2.23 (1H, m), 2.51 (1H, d, J=11.2 Hz), 2.85-3.05 (5H, m), 3.1-3.2 (1H, m), 3.45-3.55 (1H, m), 6.58 (1H, d, J=8.4 Hz), 7.03 (1H, d, J=8.4 Hz).

Example 584

Production of (4aS,8aS)-1-(6-cyanonaphthalen-2-yl)-3,3-dimethyldecahydroquinoxaline dihydrochloride

Absolute Configuration

[0406] ##STR00089##

[0407] A toluene (5 mL) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 6-bromo-2-naphthonitrile (303 mg, 1.31 mmol), Pd(OAc).sub.2 (13.3 mg, 0.0594 mmol), tBu.sub.3P.HBF.sub.4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane). The solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate. To this solution, 1 N hydrochloric acid-ethanol was added, and the deposited crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain (4aS,8aS)-1-(6-cyanonaphthalen-2-yl)-3,3-dimethyldecahydroquinoxaline dihydrochloride (303 mg, yield: 65%) in a white powder form.

[0408] .sup.1H-NMR (DMSO-d.sub.6) δppm: 1.10-1.50 (6H, m), 1.56-1.90 (1H, m), 2.00-2.14 (1H, m), 3.08-3.45 (4H, m), 4.68-5.32 (1H, br), 7.45 (1H, dd, J=2.0, 8.9 Hz), 7.64 (1H, d, J=1.8 Hz), 7.73 (1H, dd, J=1.6, 8.6 Hz), 8.00 (1H, d, J=8.6 Hz), 8.04 (1H, d, J=8.6 Hz), 8.49 (1H, s), 9.10-9.28 (1H, br), 10.04-10.28 (1H, br).

Example 585

Production of (4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline

Absolute Configuration

[0409] ##STR00090##

[0410] A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (462 mg, 1.31 mmol), Pd(OAc).sub.2 (13.3 mg, 0.0594 mmol), tBu.sub.3P.HBF.sub.4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours in a nitrogen atmosphere. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane) to obtain (4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline (439 mg, 84%) in a white amorphous solid form.

[0411] .sup.1H-NMR (CDCl.sub.3) δppm: 0.95-1.20 (22H, m), 1.36-1.45 (3H, m), 1.52 (3H, s), 1.65-1.92 (7H, m), 2.11-2.20 (1H, m), 2.57-2.67 (2H, m), 2.83-2.95 (1H, m), 3.26-(1H, d, J=11.7 Hz), 6.55 (1H, d, J=3.5 Hz), 6.63 (1H, d, J=5.3 Hz), 7.18 (1H, d, J=3.5 Hz), 8.12 (1H, d, J=5.3 Hz).

Example 586

Production of (4aS,8aS)-3,3-dimethyl-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline fumarate

Absolute Configuration

[0412] ##STR00091##

[0413] Tetrabutylammonium fluoride (1 M THF solution, 1.95 mL, 1.95 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution of (4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline (430 mg, 0.976 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane=1/10.fwdarw.1/1) to obtain a product (370 mg, 1.30 mmol) in an oil form. This oil was dissolved in ethanol (5 mL). To this solution, an ethanol (5 mL) solution of fumaric acid (151 mg) was added, and ethanol was removed under reduced pressure. The obtained solid was recrystallized from ethanol/ethyl acetate to obtain 5-((4aS,8aS)-3,3-dimethyldecahydroquinoxalin-1-yl)-1H-indole-2-carbonitrile (246 mg, yield: 63%) in a white powder form.

[0414] .sup.1H-NMR (DMSO-d.sub.6) δppm: 0.94-1.09 (1H, m), 1.20 (3H, s), 1.26-1.55 (7H, m), 1.68-1.78 (1H, m), 1.85-2.04 (2H, m), 2.81-2.93 (1H, m), 2.95-3.23 (3H, m), 6.36-6.42 (1H, m), 6.49 (2H, s), 6.71 (1H, d, J=5.2 Hz), 7.32-7.38 (1H, m), 8.09 (1H, d, J=5.2 Hz), 8.50-11.20 (1H, br), 11.59 (1H, s).

Example 587

Production of (4aS,8aS)-1-(4-(difluoromethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline dihydrochloride

Absolute Configuration

[0415] ##STR00092##

[0416] A toluene (5 mL) suspension of (4aR,8aS)-2,2-dimethyldecahydroquinoxaline 1.5 (200 mg, 1.19 mmol), 4-bromo-1-difluoromethoxy-2-fluorobenzene (315 mg, 1.31 mmol), Pd(OAc).sub.2 (13.3 mg, 0.0594 mmol), tBu.sub.3P.HBF.sub.4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane). The solvent was removed under reduced pressure. The obtained residue was dissolved in ethyl acetate. To this solution, 1 N hydrochloric acid-ethanol was added, and the deposited crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain (4aS,8aS)-1-(4-difluoromethoxy-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline dihydrochloride (193 mg, yield: 40%) in a white powder form.

[0417] .sup.1H-NMR (DMSO-d.sub.6) δppm: 1.01-1.39 (6H, m), 1.49-1.67 (6H, m), 1.67-1.77 (1H, m), 1.96-2.05 (1H, m), 2.81-2.95 (2H, m), 3.02 (1H, d, J=12.5 Hz), 3.10-3.23 (1H, m), 4.30-4.80 (1H, br), 6.96-7.01 (1H, m), 7.02 (0.25H, s), 7.17 (1H, dd, J=2.5, 12.1 Hz), 7.20 (0.5H, s), 7.33 (1H, t, J=8.9 Hz), 7.39 (0.25H, s), 9.04-9.21 (1H, m), 9.70-9.85 (1H, m).

[0418] Compounds of Examples 6 to 76, 78 to 105, 107 to 111, 113 to 149, 151 to 236, 238 to 578, 588 to 1656 shown in tables below were produced in the same way as in the Examples using corresponding appropriate starting materials. In these tables, for example, the produced compounds have physical properties such as a crystalline form, m.p. (melting point), salt, .sup.1H-NMR, and MS (mass spectrum).

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[0419] Pharmacological Study 1

Measurement of Serotonin (5-HT) Uptake Inhibitory Activity of Test Compound Using Rat Brain Synaptosome

[0420] Male Wistar rats were decapitated, and their brains were removed and dissected to remove the frontal cortex. The separated frontal cortex was placed in a 20-fold weight of a 0.32 molarity (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4° C. for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction.

[0421] Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml).

[0422] Specifically, a solvent, unlabeled 5-HT, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and preincubated at 37° C. for 10 minutes. Then, a tritium-labeled 5-HT solution (final concentration: 8 μM) was added thereto to initiate uptake reaction at 37° C. 10 minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-O (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured.

[0423] An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled 5-HT (final concentration: 10 μM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 60.

TABLE-US-00164 50% Inhibitory concentration Test Compound (nM) Compound of Example 2 7.1 Compound of Example 7 1.0 Compound of Example 8 2.4 Compound of Example 10 6.2 Compound of Example 13 5.1 Compound of Example 15 12.5 Compound of Example 27 5.8 Compound of Example 33 2.6 Compound of Example 72 2.6 Compound of Example 77 0.8 Compound of Example 85 7.2 Compound of Example 106 9.7 Compound of Example 112 7.1 Compound of Example 118 13.7 Compound of Example 120 9.2 Compound of Example 124 8.5 Compound of Example 125 4.7 Compound of Example 130 5.3 Compound of Example 131 6.1 Compound of Example 132 8.8 Compound of Example 136 1.3 Compound of Example 150 5.4 Compound of Example 165 2.0 Compound of Example 186 5.2 Compound of Example 187 5.8 Compound of Example 188 6.0 Compound of Example 191 3.2 Compound of Example 192 2.9 Compound of Example 193 3.4 Compound of Example 196 4.4 Compound of Example 233 7.4 Compound of Example 246 6.8 Compound of Example 247 42.8 Compound of Example 273 44.0 Compound of Example 276 7.2 Compound of Example 281 5.8 Compound of Example 285 19.7 Compound of Example 288 56.1 Compound of Example 300 89.1 Compound of Example 307 19.3 Compound of Example 322 9.6 Compound of Example 344 6.8 Compound of Example 346 10.0 Compound of Example 348 6.4 Compound of Example 405 6.4 Compound of Example 409 35.6 Compound of Example 468 3.8 Compound of Example 577 5.2 Compound of Example 579 4.5 Compound of Example 580 2.5 Compound of Example 582 4.1 Compound of Example 586 5.2 Compound of Example 587 0.9 Compound of Example 593 4.9 Compound of Example 610 4.6 Compound of Example 621 7.0 Compound of Example 641 2.2 Compound of Example 654 1.5 Compound of Example 717 4.2 Compound of Example 778 87.5 Compound of Example 780 6.5 Compound of Example 781 6.2 Compound of Example 791 1.4 Compound of Example 717 42.6 Compound of Example 805 28.1 Compound of Example 841 7.3 Compound of Example 867 4.7 Compound of Example 884 7.3 Compound of Example 895 5.4 Compound of Example 918 10.0 Compound of Example 962 18.7 Compound of Example 983 6.5 Compound of Example 993 4.8 Compound of Example 1026 2.4 Compound of Example 1047 0.7 Compound of Example 1083 5.1 Compound of Example 1113 5.4 Compound of Example 1121 8.5 Compound of Example 1124 7.1 Compound of Example 1318 40.7 Compound of Example 1326 37.8 Compound of Example 1333 84.2 Compound of Example 1341 6.8 Compound of Example 1534 38.1

[0424] Pharmacological Study 2

Measurement of Norepinephrine (NE) Uptake Inhibitory Activity of Test Compound Using Rat Brain Synaptosome

[0425] Male Wistar rats were decapitated, and their brains were removed and dissected to remove the hippocampus. The separated hippocampus was placed in a 20-fold weight of a 0.32 molarity (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4° C. for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction.

[0426] Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μd volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml).

[0427] Specifically, a solvent, unlabeled NE, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and preincubated at 37° C. for 10 minutes. Then, a tritium-labeled NE solution (final concentration: 12 nM) was added thereto to initiate uptake reaction at 37° C. Ten minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-O (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured.

[0428] An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled NE (final concentration: 10 μM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 61.

TABLE-US-00165 50% Inhibitory concentration Test Compound (nM) Compound of Example 2 4.6 Compound of Example 7 9.5 Compound of Example 8 60.9 Compound of Example 10 8.8 Compound of Example 13 14.3 Compound of Example 15 11.0 Compound of Example 27 0.9 Compound of Example 33 0.7 Compound of Example 72 1.0 Compound of Example 77 3.9 Compound of Example 85 4.9 Compound of Example 106 37.2 Compound of Example 112 87.3 Compound of Example 118 3.7 Compound of Example 120 9.2 Compound of Example 124 0.8 Compound of Example 125 1.9 Compound of Example 130 0.5 Compound of Example 131 0.7 Compound of Example 132 3.1 Compound of Example 136 0.5 Compound of Example 150 23.6 Compound of Example 165 2.4 Compound of Example 186 3.8 Compound of Example 187 6.0 Compound of Example 188 0.8 Compound of Example 191 2.1 Compound of Example 192 3.6 Compound of Example 193 4.4 Compound of Example 196 1.7 Compound of Example 233 3.2 Compound of Example 246 3.8 Compound of Example 247 6.6 Compound of Example 273 6.8 Compound of Example 276 4.5 Compound of Example 281 2.0 Compound of Example 285 1.4 Compound of Example 288 22.0 Compound of Example 300 9.9 Compound of Example 307 40.4 Compound of Example 322 40.1 Compound of Example 344 7.5 Compound of Example 346 8.8 Compound of Example 348 4.6 Compound of Example 405 4.4 Compound of Example 409 9.1 Compound of Example 468 7.5 Compound of Example 577 5.9 Compound of Example 579 5.1 Compound of Example 580 5.4 Compound of Example 582 6.0 Compound of Example 586 4.0 Compound of Example 587 1.9 Compound of Example 593 3.3 Compound of Example 610 5.9 Compound of Example 621 0.7 Compound of Example 641 76.0 Compound of Example 654 1.0 Compound of Example 717 4.8 Compound of Example 778 4.2 Compound of Example 780 0.6 Compound of Example 781 3.0 Compound of Example 791 0.7 Compound of Example 717 30.4 Compound of Example 805 0.9 Compound of Example 841 1.0 Compound of Example 867 11.7 Compound of Example 884 4.8 Compound of Example 895 3.0 Compound of Example 918 0.8 Compound of Example 962 31.9 Compound of Example 983 47.6 Compound of Example 993 8.7 Compound of Example 1026 4.2 Compound of Example 1047 0.7 Compound of Example 1083 2.5 Compound of Example 1113 1.7 Compound of Example 1121 0.7 Compound of Example 1124 0.8 Compound of Example 1318 6.6 Compound of Example 1326 1.8 Compound of Example 1333 39.6 Compound of Example 1341 42.7 Compound of Example 1534 4.0

[0429] Pharmacological Study 3

Measurement of Dopamine (DA) Uptake Inhibitory Activity of Test Compound Using Rat Brain Synaptosome

[0430] Male Wistar rats were decapitated, and their brains were removed and dissected to remove the corpus striatum. The separated corpus striatum was placed in a 20-fold weight of a 0.32 molarity (M) sucrose solution and homogenized with a potter homogenizer. The homogenate was centrifuged at 1000 g at 4° C. for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4° C. for 20 minutes. The pellet was suspended in an incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride). The suspension was used as a crude synaptosome fraction.

[0431] Uptake reaction was performed using each well of a 96-well round-bottom plate and a 200 μl volume in total of a solution containing pargyline (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg/ml).

[0432] Specifically, a solvent, unlabeled DA, and serially diluted test compounds were separately added to the wells, and the synaptosome fraction was added in an amount 1/10 of the final volume to each well and preincubated at 37° C. for 10 minutes. Then, a tritium-labeled DA solution (final concentration: 2 nM) was added thereto to initiate uptake reaction at 37° C. Ten minutes later, the uptake reaction was terminated by suction filtration through a 96-well glass fiber filter plate. Furthermore, the filter was washed with a cold saline and then sufficiently dried. MicroScint-O (PerkinElmer Co., Ltd.) was added thereto, and the residual radioactivity on the filter was measured.

[0433] An uptake value obtained by the addition of only the solvent was defined as 100%, and an uptake value (nonspecific uptake value) obtained by the addition of the unlabeled DA (final concentration: 10 μM) was defined as 0%. A 50% inhibitory concentration was calculated from the test compound concentrations and inhibitory activities thereat. The results are shown in Table 62.

TABLE-US-00166 50% Inhibitory concentration Test Compound (nM) Compound of Example 2 85.9 Compound of Example 7 78.9 Compound of Example 8 377.8 Compound of Example 10 64.8 Compound of Example 13 85.4 Compound of Example 15 68.4 Compound of Example 27 31.9 Compound of Example 33 15.1 Compound of Example 72 47.9 Compound of Example 77 41.2 Compound of Example 85 95.7 Compound of Example 106 336.8 Compound of Example 112 263.7 Compound of Example 118 8.3 Compound of Example 120 187.2 Compound of Example 124 9.1 Compound of Example 125 5.2 Compound of Example 130 3.9 Compound of Example 131 8.3 Compound of Example 132 3.9 Compound of Example 136 7.7 Compound of Example 150 200.5 Compound of Example 165 6.8 Compound of Example 186 29.8 Compound of Example 187 12.1 Compound of Example 188 7.9 Compound of Example 191 13.5 Compound of Example 192 8.6 Compound of Example 193 5.7 Compound of Example 196 18.3 Compound of Example 233 38.8 Compound of Example 246 8.8 Compound of Example 247 8.7 Compound of Example 273 8.7 Compound of Example 276 10.9 Compound of Example 281 6.6 Compound of Example 285 43.9 Compound of Example 288 74.7 Compound of Example 300 81.3 Compound of Example 307 68.2 Compound of Example 322 67.7 Compound of Example 344 9.8 Compound of Example 346 7.8 Compound of Example 348 27.3 Compound of Example 405 74.8 Compound of Example 409 165.3 Compound of Example 468 54.0 Compound of Example 577 47.9 Compound of Example 579 46.5 Compound of Example 580 202.0 Compound of Example 582 68.8 Compound of Example 586 93.0 Compound of Example 587 76.1 Compound of Example 593 9.7 Compound of Example 610 13.2 Compound of Example 621 128.5 Compound of Example 641 9.7 Compound of Example 654 9.0 Compound of Example 717 60.1 Compound of Example 778 4.9 Compound of Example 780 4.3 Compound of Example 781 5.2 Compound of Example 791 160.9 Compound of Example 717 83.8 Compound of Example 805 5.1 Compound of Example 841 7.0 Compound of Example 867 85.7 Compound of Example 884 52.8 Compound of Example 895 19.9 Compound of Example 918 42.0 Compound of Example 962 69.5 Compound of Example 983 172.6 Compound of Example 993 39.6 Compound of Example 1026 12.3 Compound of Example 1047 1.1 Compound of Example 1083 53.7 Compound of Example 1113 26.0 Compound of Example 1121 29.9 Compound of Example 1124 49.3 Compound of Example 1318 83.5 Compound of Example 1326 91.8 Compound of Example 1333 73.0 Compound of Example 1341 113.3 Compound of Example 1534 214.8

[0434] Pharmacological Study 4

Forced Swimming Test

[0435] This test was conducted according to the method of Porsolt et al. (Porsolt, R. D., et al., Behavioural despair in mice: A primary screening test for antidepressants. Arch int Pharmacodyn. Ther., 229, pp 327-336 (1977)).

[0436] A test compound was suspended in a 5% gum arabic/saline (w/v), and this suspension was orally administered to male ICR mice (CLEA Japan, Inc. (JCL), 5 to 6 week old). One hour later, the mice were placed in a water tank having a water depth of 9.5 cm and a water temperature of 21 to 25° C. and immediately thereafter allowed to try to swim for 6 minutes. Then, a time during which the mouse was immobile (immobility time) was measured for the last 4 minutes. A SCANET MV-20 AQ system manufactured by Melquest Ltd. was used in the measurement and analysis of the immobility time.

[0437] In this experiment, the animals treated with the test compounds exhibited a reduction in immobility time. This demonstrates that the test compounds are useful as antidepressants.

TABLE-US-LTS-00001 LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).