Dihydro-2(1H)-quinolinone as Antidepressant Drug
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 2 187
colorless needles (EtOH) in 12% yield: mp 169-171 °C; 1H
NMR (DMSO-d6) δ 2.05 (2H, m), 2.44 (2H, m), 2.82 (2H, t, J
) 7 Hz), 3.17 (6H, m), 3.52 (2H, m), 3.86 (2H, m), 3.89 (5H,
m), 6.86 (1H, d, J ) 8 Hz), 7.04 (4H, m), 10.83 (1H, br). Anal.
(C23H28N3O2Cl‚HCl) C, H, N.
δ 1.88 (2H, m), 2.46 (2H, t, J ) 7 Hz), 2.62 (8H, m), 2.88 (2H,
t, J ) 7 Hz), 3.21 (4H, m), 4.00 (2H, t, J ) 7 Hz), 6.45 (1H, d,
J ) 8 Hz), 6.65 (1H, d, J ) 8 Hz), 6.79 (2H, m), 6.87 (1H, d, J
) 3 Hz), 7.05 (1H, t, J ) 8 Hz), 7.16 (1H, t, J ) 8 Hz), 10.01
(1H, br). Anal. (C22H26N4O2Cl) C, H, N.
1-[2-[4-(3-Ch lor op h en yl)-1-p ip er a zin yl]eth yl]-3,4-d ih y-
d r o-5-m eth oxy-2(1H)-qu in olin on e (36). This compound was
prepared in a similar procedure to that for 34a from 16 (10
mmol), NaI (15 mmol), 1-(3-chlorophenyl)piperazine (20 mmol),
and Na2CO3 (20 mmol) and obtained as colorless needles
(EtOH) in 29% yield: mp 132-132.5 °C; 1H NMR (DMSO-d6)
δ 2.04 (2H, m), 2.52 (2H, m), 2.80 (2H, t, J ) 7 Hz), 3.20 (6H,
m), 3.51 (2H, m), 3.79 (3H, s), 4.11 (2H, t, J ) 7 Hz), 6.64 (1H,
d, J ) 8 Hz), 6.80 (4H, m), 7.20 (2H, m). Anal. (C22H26N3O2Cl)
C, H, N.
1-[4-[4-(3-Ch lor op h en yl)-1-p ip er a zin yl]bu tyl]-3,4-d ih y-
d r o-5-m eth oxy-2(1H)-qu in olin on e (37). This compound was
prepared in a similar procedure to that for 34a from 17 (10
mmol), NaI (15 mmol), 1-(3-chlorophenyl)piperazine (20 mmol),
and Na2CO3 (20 mmol) and obtained as a white powder (EtOH)
in 60% yield: mp 128-129 °C dec; 1H NMR (DMSO-d6) δ 1.70
(4H, m), 2.46 (2H, t, J ) 7 Hz), 2.60 (6H, m), 2.91 (2H, t, J )
7 Hz), 3.22 (4H, m), 3.87 (3H, s), 3.99 (2H, t, J ) 7 Hz), 6.66
(1H, d, J ) 8 Hz), 6.76 (1H, d, J ) 8 Hz), 6.83 (2H, m), 6.90
(1H, d, J ) 3 Hz), 7.18 (1H, t, J ) 8 Hz), 7.22 (1H, t, J ) 8
Hz). Anal. (C24H30N3O2Cl) C, H, N.
P r ep a r a tion of 1-[3-[4-(3-Am in op h en yl)-1-p ip er a zin yl]-
p r op yl]-3,4-d ih yd r o-5-m eth oxy-2(1H)-qu in olin on e (49). A
mixture of 3,4-dihydro-5-methoxy-1-[3-[4-(3-nitrophenyl)-1-
piperazinyl]propyl]-2(1H)-quinolinone (48) (2.5 g, 10 mmol)
and 5% Pd-C (200 mg) in EtOH (200 mL) was hydrogenated
with a Parr apparatus under 3 kg/cm2 hydrogen pressure at
room temperature. Catalyst was filtered off and the filtrate
was evaporated to dryness in vacuo. The residue was purified
by column chromatography (SiO2, 1% MeOH in CH2Cl2) and
recrystallized from EtOH to give 49 as a white powder (46%
yield): mp 132-133 °C; 1H NMR (CDCl3) δ 1.85 (2H, m), 2.45
(2H, t, J ) 7 Hz), 2.57 (6H, m), 2.86 (2H, t, J ) 7 Hz), 3.16
(2H, m), 3.63 (2H, br), 3.83 (3H, s), 3.99 (2H, m), 6.19 (1H, dd,
J ) 3, 8 Hz), 6.21 (1H, d, J ) 3 Hz), 6.34 (1H, dd, J ) 3, 8 H
z), 6.61 (1H, d, J ) 8 Hz), 6.75 (1H, d, J ) 8 Hz), 7.02 (1H, t,
J ) 8 Hz), 7.18 (1H, t, J ) 8 Hz). Anal. (C23H30N4O2) C, H, N.
1-[3-[4-(3-Ch lor oph en yl)-1-piper azin yl]pr opyl]-5-eth oxy-
3,4-d ih yd r o-2(1H)-qu in olin on e Hyd r och lor id e (50). This
compound was prepared in a similar procedure to that for 34b
from 18 (10 mmol), NaI (15 mmol), 1-(3-chlorophenyl)piper-
azine (20 mmol), and Na2CO3 (20 mmol) and obtained as
colorless needles (EtOH) in 43% yield: mp 221-224 °C dec;
1H NMR (DMSO-d6) δ 1.34 (3H, t, J ) 7 Hz), 2.02 (2H, m),
2.51 (2H, m), 2.82 (2H, t, J ) 7 Hz), 3.14 (6H, m), 3.94 (4H,
m), 4.04 (2H, q, J ) 7 Hz), 6.75 (1H, d, J ) 8 Hz), 6.85 (2H,
m), 6.95 (1H, dd, J ) 3 and 8 Hz), 7.04 (1H, d, J ) 3 Hz), 7.22
(2H, m), 11.09 (1H, br). Anal. (C24H30N3O2Cl‚HCl) C, H, N.
1-[3-[4-(3-Ch lor op h en yl)-1-p ip er a zin yl]p r op yl]-3,4-d i-
h yd r o-5-(2-p r op oxy)-2(1H )-q u in olin on e H yd r och lor id e
(51). This compound was prepared in a similar procedure to
that for 34b from 19 (10 mmol), NaI (15 mmol), 1-(3-
chlorophenyl)piperazine (20 mmol), and Na2CO3 (20 mmol) and
obtained as colorless needles (EtOH) in 51% yield: mp 218-
229 °C dec; 1H NMR (DMSO-d6) δ 1.27 (6H, d, J ) 6 Hz), 2.03
(2H, m), 2.51 (2H, m), 2.81 (2H, t, J ) 7 Hz), 3.14 (6H, m),
3.49 (2H, m), 3.92 (4H, m), 4.59 (1H, m), 6.76 (1H, d, J ) 8
Hz), 6.81 (1H, d, J ) 8 Hz), 6.86 (1H, dd, J ) 3, 8 Hz), 6.95
(1H, dd, J ) 3, 8 Hz), 7.04 (1H, d, J ) 3 Hz), 7.20 (1H, t, J )
8 Hz), 7.26 (1H, t, J ) 8 Hz), 11.07 (1H, br). Anal. (C25H32N3O2-
Cl‚HCl) C, H, N.
P r ep a r a tion of 1-[3-[4-(3-Ch lor op h en yl)-1-p ip er a zin yl]-
p r op yl]-3,4-d ih yd r o-5-h yd r oxy-2(1H)-qu in olin on e (52). A
solution of the free base of 34a (4.1 g, 10 mmol) in 47% HBr
(50 mL) was refluxed for 4 h, concentrated in vacuo, and made
basic with a 37% NH4OH solution. The precipitated crystals
were filtered, washed, dried, dissolved in EtOH, and evapo-
rated to dryness. Recrystallization from EtOH gave 52 as a
white powder (74% yield): mp 200-201.5 °C; 1H NMR (CDCl3)
5-Ch lor o-1-[3-[4-(3-ch lor oph en yl)-1-piper azin yl]pr opyl]-
3,4-d ih yd r o-2(1H)-qu in olin on e Hyd r och lor id e (53). This
compound was prepared in a similar procedure to that for 34b
from 20 (10 mmol), NaI (15 mmol), 1-(3-chlorophenyl)piper-
azine (20 mmol), and Na2CO3 (20 mmol) and obtained as
colorless needles (EtOH) in 40% yield: mp 217 °C dec; 1H NMR
(DMSO-d6) δ 2.03 (2H, m), 2.60 (2H, m), 3.00 (2H, t, J ) 7
Hz), 3.14 (6H, m), 3.51 (2H, m), 3.86 (2H, m), 3.98 (2H, t, J )
7 Hz), 6.87 (1H, dd, J ) 3, 8 Hz), 6.95 (1H, d, J ) 3 Hz), 7.04
(1H, dd, J ) 3, 8 Hz), 7.26 (4H, m), 11.04 (1H, br). Anal.
(C22H29N3OCl2‚2HCl) C, H, N.
Analogously, compounds 54-57 were prepared from 20 (10
mmol) and 2 molar equiv of the corresponding phenylpiper-
azines and Na2CO3. Their yield, mp, and formulas are listed
in Table 2. 1H NMR spectra for these compounds are presented
in the Supporting Information.
1-[3-[4-(3-Am in oph en yl)-1-piper azin yl]pr opyl]-5-ch lor o-
3,4-d ih yd r o-2(1H)-qu in olin on e (58). This compound was
prepared by catalytic hydrogenation of 5-chloro-3,4-dihydro-
1-[3-[4-(3-nitrophenyl)-1-piperazinyl]propyl]-2(1H)-quinolino-
ne (57) (10 mmol) in the presence of 5% Pd-C (200 mg) in
EtOH (200 mL) and obtained as a white powder in 89% yield:
mp 161-163 °C; 1H NMR (DMSO-d6) δ 1.72 (2H, m), 2.36 (2H,
t, J ) 7 Hz), 2.51 (6H, m), 2.59 (2H, t, J ) 7 Hz), 3.02 (6H, m),
3.95 (2H, t, J ) 7 Hz), 4.85 (2H, br), 6.04 (1H, dd, J ) 3, 8
Hz), 6.15 (2H, m), 6.85 (1H, t, J ) 8 Hz), 7.16 (1H, d, J ) 8
Hz), 7.23 (1H, d, J ) 8 Hz), 7.30 (1H, t, J ) 8 Hz). Anal.
(C22H27N4OCl) C, H, N.
P r ep a r a t ion of 1-[3-[4-(3-Acet yla m in op h en yl)-1-p i-
per azin yl]pr opyl]-5-ch lor o-3,4-dih ydr o-2(1H)-qu in olin on e
(59). A mixture of 58 (2.5 g, 10 mmol), acetic anhydride (50
mL), and a catalytic amount of 4-(dimethylamino)pyridine (100
mg) was stirred for 2 h and evaporated to dryness. Recrystal-
lization from EtOH afforded 59 as a white powder (75%
1
yield): mp 177-178 °C; H NMR (DMSO-d6) δ 1.72 (2H, m),
2.02 (3H, s), 2.34 (2H, t, J ) 7 Hz), 2.51 (6H, m), 2.59 (2H, t,
J ) 7 Hz), 3.09 (4H, m), 3.93 (2H, t, J ) 7 Hz), 6.62 (1H, dd,
J ) 3, 8 Hz), 7.01 (1H, dd, J ) 3, 8 Hz), 7.21 (5H, m), 9.78
(1H, br). Anal. (C24H29N4O2Cl) C, H, N.
P r ep a r a tion of 1-[3-[4-(3-Ch lor op h en yl)-1-p ip er a zin yl]-
p r op yl]-3,4-d ih yd r o-5-m eth ylth io-2(1H)-qu in olin on e Hy-
d r och lor id e (60). This compound was prepared in a similar
procedure to that for compound 34b by reacting 1-(3-chlo-
rophenyl)piperazine (2.5 g, 21 mmol), Et3N (3 mL, 21.5 mmol),
and NaI (2.5 g, 16.7 mmol) with 25 (2.7 g, 10 mmol) and
obtained as colorless leaflets (EtOH) in 51% yield: mp 221-
224 °C; 1H NMR (DMSO-d6) δ 2.01 (2H, m), 2.48 (3H, s), 2.57
(2H, m), 2.88 (2H, t, J ) 7 Hz), 3.14 (6H, m), 3.53 (2H, m),
3.88 (2H, m), 3.97 (2H, t, J ) 7 Hz), 6.87 (1H, dd, J ) 3, 8
Hz), 6.96 (1H, dd, J ) 3, 8 Hz), 7.04 (3H, m), 7.26 (1H, t, J )
8 Hz), 7.29 (1H, t, J ) 8 Hz), 10.65 (1H, br). Anal. (C23H28N3-
OSCl‚2HCl) H, N; C: calcd 54.93, found 59.93.
P r ep a r a tion of 5-Am in o-1-[3-[4-(3-ch lor op h en yl)-1-p i-
p er a zin yl]p r op yl]-3,4-d ih yd r o-2(1H)-qu in olin on e Dih y-
d r och lor id e (61). Crude 28 (3.3 g, 10 mmol) and NaI (2.5 g,
16.7 mmol) were dissolved in CH3CN (100 mL) and the solution
was refluxed for 30 min; then 1-(3-chlorophenyl)piperazine (3.0
g, 15 mmol) and Et3N (3 mL, 21.5 mmol) were added. The
resultant mixture was refluxed for a further 2 h and cooled to
room temperature. The precipitates were filtered off and the
filtrate was concentrated in vacuo. The residue was extracted
with AcOEt and the extract was washed, dried, concentrated
in vacuo, purified by column chromatography (SiO2, 2% MeOH
in CH2Cl2), and dissolved in 50% EtOH. The solution was
acidified with concentrated HCl. After being stirred for 1 h at
80 °C, the solution was evaporated to dryness in vacuo. The
residue was recrystallized from EtOH to give 61 as a white
powder (61% yield): mp 218-240 °C dec; 1H NMR (DMSO-
d6) δ 2.03 (2H, m), 2.56 (2H, m), 2.92 (2H, t, J ) 7 Hz), 3.21