Novel antipsychotic agents with dopamine autoreceptor agonist properties: Synthesis and pharmacology of 7-[4-(4-phenyl-1- piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives

Article abstract of DOI:10.1021/jm940608g

To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)- quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the γ-butyrolactone (GBL)-induced increase in L- dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL- induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3- dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED₅₀ values of 5.1 μmol/kg po) and inhibited the APO induced stereotypy (ED₅₀ values of 0.6 μmol/kg po). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED₅₀ value of 7.8 μmol/kg po).

Full text of DOI:10.1021/jm940608g

658
J . Med. Chem. 1998, 41, 658-667
Articles
Novel An tip sych otic Agen ts w ith Dop a m in e Au tor ecep tor Agon ist P r op er ties:
Syn th esis a n d P h a r m a cology of 7-[4-(4-P h en yl-1-p ip er a zin yl)bu toxy]-
3,4-d ih yd r o-2(1H)-qu in olin on e Der iva tives
Yasuo Oshiro,* Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori,
Yasufumi Uwahodo, and Takao Nishi
Third Institute of New Drug Research, Otsuka Pharmaceutical Company Ltd., 463-10 Kagasuno,
Kawauchi-cho, Tokushima 771-01, J apan
Received September 12, 1994
To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors
and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-
piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinones was synthesized and their dual activities
were examined. The postsynaptic DA receptor antagonistic activities of the compounds were
evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the
autoreceptor agonist activities were determined by their effects on the γ-butyrolactone (GBL)-
induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many
compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced
increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-
butoxy]-3,4-dihydro-2(1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these
two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1
µmol/kg po) and inhibited the APO induced stereotypy (ED50 values of 0.6 µmol/kg po).
Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism
of APO-induced stereotypy (ED50 value of 7.8 µmol/kg po).
Ch a r t 1. DA Autoreceptor Agonists and D2 Receptor
Antagonists
According to the “dopamine hypothesis of schizophre-
nia”, a functional hyperactivity of the dopamine (DA)
neuronal systems of the brain is involved as a major
aspect of the disease.1 All clinically available anti-
psychotic agents inhibit DA neurotransmission by block-
ing the postsynaptic DA receptors. Unfortunately, DA
antagonism is also responsible for the most serious side
effects of these agents, e.g., extrapyramidal syndrome
(EPS), a parkinsonian-like syndrome caused by DA
receptor blocking, tardive dyskinesia (TD), a syndrome
of involuntary movements that has been linked to
supersensitivity of brain DA receptors after long-term
DA receptor blockage, and hyperprolactinemia, which
is caused by blocking the pituitary DA receptors.2,3
Reducing dopaminergic neurotransmission via stimula-
tion of the DA autoreceptors has become of interest in
the search for effective therapeutic agents that lack the
side effects of available antipsychotic agents. The
hypothesis underlying this approach stems from evi-
dence that DA autoreceptors serve as an inhibitory
feedback function of neurotransmission.4-8
sults with other DA autoreceptor agonists and our
unpublished clinical observations with 1 strongly sug-
gest that a DA autoreceptor agonist is effective in
treating the negative symptoms and a potent DA
postsynaptic receptor antagonism might be necessary
for treatment of the positive symptoms in patients.19-21
To find a more effective agent for treating both negative
and positive symptoms in schizophrenia and with less
side effects than the standard agents, we have searched
for a compound which is an agonist of the DA autore-
In a previous paper,9 we reported on 7-[3-(4-phenyl-
1-piperazinyl)propoxy]-2(1H)-quinolinone derivatives.
Among them, OPC-4392 (1 in Chart 1) was found to be
an agonist of the DA autoreceptors and a weak antago-
nist of the postsynaptic DA D2 receptors.10-15 Other DA
autoreceptor agonists, B-HT 920,16 EMD-49980,17 and
Terguride,18 have been reported to improve negative
symptoms in schizophrenic patients. The clinical re-
S0022-2623(94)00608-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/31/1998

Antipsychotics with DA Autoreceptor Agonist Properties
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 659
Sch em e 1a
a
Conditions and notation: (a) K2CO3, dibromoalkane in DMF; (b) NaI, TEA, phenylpiperazines in CH3CN; n ) 4 or 5.
Sch em e 2a
a
Conditions: (c) H2, 3 kg/cm3, 5% Pd-C in EtOH; (d) acetic anhydride; (e) (1) NaNO2 in dilute H2SO4, (2) H2SO4; (f) SnCl2 dihydrate
in concentrated HCl; (g) (1) NaNO2 in dilute H2SO4, (2) NaCN, CuSO4, NH4OH.
ceptors and a potent antagonist of the postsynaptic DA
receptors. An ideal compound would be a potent and
effective agent for treatment of both the positive and
negative symptoms of schizophrenia with less adverse
effects than clinically available agents. We have syn-
thesized a series of new compounds with a variety of
modifications of compound 1 and examined the postsyn-
aptic DA receptor antagonist activity of all compounds
synthesized by evaluation of their ability to antagonize
the DA agonist apomorphine (APO) in the stereotypy
test.22 Selected compounds which showed a potent
postsynaptic DA receptor antagonist activity were evalu-
ated for their DA autoreceptor agonist activity by testing
their reversing effects on the γ-butyrolactone (GBL)-
induced increase in L-dihydroxyphenylalanine (DOPA)
synthesis in the mouse brain.23,24 In this paper, we
describe the synthesis and the preliminary pharmacol-
ogy of 3,4-dihydro-2(1H)-quinolinone derivatives. Struc-
ture-activity relationships (SAR) are also discussed.
Ch em istr y
Our new target compounds, 7-[4-(4-phenyl-1-piper-
azinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone deriva-
tives (13-51) listed in Table 1, were prepared as shown
in Schemes 1 and 2. To examine structure-activity
relationships on the nucleus portion in the 3,4-dihydro-
2(1H)-quinolinone derivatives, several analogues of
2(1H)-quinolinone (52-56) in Table 2 were prepared.
Intermediates, 5-, 6-, or 8-(4-bromobutoxy)-3,4-dihy-
dro-2(1H)-quinolinone (8-10)25,26 and 7-(5-bromopen-
toxy)-3,4-dihydro-2(1H)-quinolinone (7),9 have been re-
ported. With the application of similar procedures, 7-(4-
bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (6) and 7-(4-
bromobutoxy)-2(1H)-quinolinone (12) were prepared.

660 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Oshiro et al.
Alkylation of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone
(5) with 1,4-dibromobutane in the presence of potassium
carbonate in N,N-dimethylformamide (DMF) gave 7-(4-
bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (6). Simi-
larly, 7-hydroxy-2(1H)-quinolinone (11) was converted
to 7-(4-bromobutoxy)-2(1H)-quinolinone (12). Thus pre-
pared (ω-bromoalkoxy)-3,4-dihydro-2(1H)-quinolinones
(6-10) and (4-bromobutoxy)-2(1H)-quinolinone (12) were
reacted with various phenylpiperazines to afford the
target compounds 13-21, 25-49 (listed in Table 1), and
52-56 (listed in Table 2).
Compounds 22-24 and 50-51 were prepared as
shown in Scheme 2. Catalytic reduction of compound
21 produced compound 22. Treatment of 22 with acetic
anhydride in acetic acid resulted in 23. Reaction of 22
with sodium nitrate in a dilute sulfuric acid solution
yielded diazonium salt, which was added to a 20%
aqueous solution of sulfuric acid to produce 24. Reduc-
tion of 49 with tin(II) chloride dihydrate in concentrated
hydrochloric acid gave 50. Diazotization of compound
50 in a 20% aqueous solution of sulfuric acid followed
by addition of the resulting diazonium salt solution to
a cuprous cyanide solution provided 51 (the Sandmeyer
reaction).
activity was much reduced as in compound 15. Com-
pound 4, with a butoxy side chain but no substituent
on the phenylpiperazinyl moiety, did not show activity.
These results indicated a superiority of butoxy side
chain to propoxy and pentoxy side chains in producing
potent DA antagonist activity in the 3,4-dihydro-2(1H)-
quinolinone series and also indicated that substituents
in the phenylpiperazinyl moiety are required in order
to display activity in this series of compounds. Thus,
we selected compound 13, having the butoxy side chain
and the 4-(2-methyl-3-chlorophenyl)-1-piperazinyl moi-
ety, as a lead compound, and a variety of modifications
on it were carried out. Also, the effects of structural
modifications on their DA antagonist activity were
examined with respect to electronic and lipophilic fac-
tors of substituents within a series of compounds. Our
purpose in this paper is to find the most potent oral
administered compound. Therefore, the structure-
activity relationships are discussed below with the data
obtained by oral administration (Tables 1 and 2).
P ostsyn a p tic DA Recep tor An ta gon ist Activity.
First, we examined the effects of the substituent of the
aromatic ring in the phenylpiperazinyl moiety in com-
pound 13 on the postsynaptic DA receptor antagonist
activity. Replacement of the chlorine substituent at the
3-position on the phenylpiperazinyl moiety in 13 with
a more bulky bromine substituent (16) retained the
potency, but replacement with a smaller fluorine sub-
stituent (18) reduced the potency. Replacement of the
chlorine substituent with a more electron-withdrawing
nitro group (21) greatly enhanced the potency, whereas
replacement with the nitrile group which also has a
greater electron-withdrawing character but less lipo-
philicity than the chloro group retained the potency as
in compound 20. The compounds that possess more
electron-donating substituents such as amino (22),
acetylamino (23), and hydroxy (24) groups showed much
lower potency.
P h a r m a cology
The postsynaptic DA receptor antagonist activity of
all compounds synthesized was evaluated by the ability
to inhibit APO-induced stereotypic behavior in mice
(anti-APO test).22 The clinically available standard
antipsychotic agents chlorpromazine and haloperidol
were also examined in the test as reference drugs, and
the results are summarized in Tables 1 and 2.
The DA autoreceptor agonist activity of selected
compounds was determined by their reversal effects on
the GBL-induced increase in DOPA synthesis in the
mouse brain.23 The EPS liability of selected compounds
was examined by measuring their ability to induce
catalepsy in mice. Several compounds were tested for
their R1-adrenoceptor antagonist activity since peri-
pheral R1-adrenoceptor antagonism has been reported
to cause autonomic side effects.2 The results are sum-
marized in Table 3. Furthermore, to evaluate its
potential as an antipsychotic agent, the activities of the
selected compound in behavioral tests with rats were
compared with those of chlorpromazine, haloperidol, and
compound 1. The results are summarized in Table 4.
Exchange of the substituents at the 2- and 3-positions
in the phenylpiperazinyl moiety in 13 with each other
greatly enhanced the potency (25). Similar enhance-
ment of the potency was observed in the case of
compound 26 (vs 16). These results suggested that the
halogen substituent at the 2-position in the phenylpip-
erazinyl moiety was more effective in showing the
postsynaptic DA receptor antagonist activity in the
series. Thus, compounds with several chlorine substit-
uents on the phenylpiperazinyl moiety were prepared
and examined. Of the compounds with two chloro
substituents, compound 28, in which the two chlorine
substituents are adjacent to each other at the 2- and
3-positions in the phenylpiperazinyl moiety, showed the
highest potency. Replacement of one or both chlorine
substituents in compound 28 with a more bulky bromine
substituent (34 and 35) and incorporation of another
chlorine substituent at the 4-position (36) and 5-position
(37) reduced the potency.
Resu lts a n d Str u ctu r e-Activity Rela tion sh ip s
In the search for a lead compound, we initially
examined the postsynaptic DA receptor antagonist
activity of the compounds prepared in the previous
paper (1-4).9 As shown in Table 1, compound 1
inhibited the APO-induced stereotypy in mice with an
ED50 of 41.3 µmol/kg po. Compound 2, in which the
nucleus portion of 1 is changed from 2(1H)-quinolinone
to 3,4-dihydro-2(1H)-quinolinone, showed a higher po-
tency than its parent compound 1. Compound 3, in
which a methyl substituent at the 3-position on the
aromatic ring in the phenylpiperazinyl moiety in 2 is
replaced with a chlorine substituent, is more potent
than 2. Replacement of the side chain in 3 from propoxy
to butoxy increased the potency of the resulting com-
pound 13, whereas with a pentoxy side chain the
In the series of compounds with one chloro substituent
on the phenylpiperazinyl moiety, the compound having
a chloro substituent at the 2-position showed the highest
potency (41 > 42 > 43), although its potency is much
less than that of the compound with two chloro substit-
uents on the phenylpiperazinyl moiety (28). Replace-
ment of the chlorine substituent at the 2-position of 41

Antipsychotics with DA Autoreceptor Agonist Properties
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 661
Ta ble 1. 7-[4-[4-(Substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone Derivatives and Their Postsynaptic DA
Receptor Antagonist Activity
DA receptor
recryst
antagonistic activity,
compd
position
n
R
yielda (%) solventb mp (°C)
formula
anal.c
ED50 (CL)d
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
1
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
5
6
8
7
7
7
7
7
7
7
7
7
7
7
7j
7
7
7
4
5
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3
3
3
4
2-Me, 3-Cl
2-Me, 3-Cl
2-Me, 5-Cl
2-Me, 3-Br
2-Me, 4-Br
2-Me, 3-F
4-Me, 3-Cl
2-Me, 3-CN
2-Me, 3-NO2
2-Me, 3-NH2
2-Me, 3-NHCOCH3
2-Me, 3-OH
2-Cl, 3-Me
2-Br, 3-Me
2,3-(Me)2
2,3-(Cl)2
2,4-(Cl)2
2,5-(Cl)2
2,6-(Cl)2
3,4-(Cl)2
3,5-(Cl)2
2-Br, 3-Cl
2,3-(Br)2
2,3,4-(Cl)3
2,3,5-(Cl)3
2,3-(Cl)2
2,3-(Cl)2
2,3-(Cl)2
2-Cl
3-Cl
4-Cl
2-Br
2-F
2-Me
2-OMe
2-OEt
2-NO2
2-NH2
2-CN
2,3-(Me)2
2,3-(Me)2
2-Me, 3-Cl
H
35
32
84
84
82
71
70
32
61
55
70
24
72
44
94
87
67
67
75
73
77
29
80
73
34
72
81
79
27
64
49
61
41
42
44
33
50
34
18
A
A
A
B
A
B
A
B
B
B
B
B
A
A
B
A
A
A
B
A
A
B
B
B
B
C
C
A
A
A
A
B
A
A
B
A
B
D
E
146-148 C24H30N3O2Cl
25H32N3O2Cl
110-111 C24H30N3O2Cl
151-152 C24H30N3O2Br
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
2.8 (1.2-8.9)
>23e
151-153
C
>23e
2.1 (1.1-3.6)
152-153
C24H30N3O2Br
141-143 C24H30N3O2F‚0.25H2O C,H,N
21f
7.2g
117-118 C24H30N3O2Cl
181-182 C25H30N4O2
165-166 C24H30N4O4
171-173 C24H32N4O2
186-188 C26H34N4O3
208-210 C24H31N3O3‚1.5H2O
133-134 C24H30N3O2Cl
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
>7.0e
4.1 (3.2-5.1)
0.7 (0.2-1.4)
>25e
>25e
>8.0h
0.9 (0.5-1.2)
0.9 (0.5-1.2)
3.4 (2.5-4.4)
0.6 (0.5-0.8)
>7.0e
125-126
C24H30N3O2Br
136-137 C25H33N3O2
139-140 C23H27N3O2Cl2
153-155 C23H27N3O2Cl2
134-135 C23H27N3O2Cl2
133-134 C23H27N3O2Cl2
134-136 C23H27N3O2Cl2
134-135 C23H27N3O2Cl2
2.7 (1.1-5.2)
>7.0h
>7.0h
1.1 (0.2-2.7)
2.4 (1.0-4.7)
1.1 (0.2-2.9)
6.4 (5.5-7.7)
0.8 (0.4-1.2)
>22h
154-156
C23H27N3O2BrCl
150-151 C23H27N3O2Br2
164-166 C23H26N3O2Cl3
174-176 C23H26N3O2Cl3
190-192 C23H27N3O2Cl2
194-197 C23H27N3O2Cl2
122-123 C23H27N3O2Cl2
>22e
>22h
103-104 C23H28N3O2Cl‚0.2H2O C,H,N
2.9 (1.2-5.6)
7.5 (6.4-9.0)
>8.0e
102-103
138-139
C
C
23H28N3O2Cl
23H28N3O2Cl‚0.2H2O C,H,N
C,H,N
105-106 C23H28N3O2Br
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,Ni
3.9 (3.3-4.7)
122-123 C23H28N3O2F
>8.0e
135-136 C24H31N3O2
2.5 (2.1-2.8)
0.6 (0.3-1.0)
0.2 (0.1-0.4)
>7.0e
125-126
189-191
C
C
24H31N3O3
25H33N3O3‚HCl
112-113 C23H28N4O4
130-132 C23H30N4O2
>25h
150-151 C24H28N4O2‚1.5H2O
>23h
41.3
2
3
4
26.0
16.6 (14.6-19.1)
>28e
chlorpromazine
haloperidol
12.1 (9.0-17.7)
0.24 (0.08-0.98)
a
b
Yields were not optimized in most cases. A ) EtOH, B ) MeOH, C ) EtOH-CHCl3, D ) EtOH-iPr2O, E ) CH3CN. c C,H,N analyses
d
were within (0.4% of the calculated value. Inhibition of the apomorphine-induced stereotyped behavior in mice. Test compound was
administered orally to 10 mice 1 h before subcutaneous injection of apomorphine (1.5 mg/kg sc). The ED50 values and 95% confidence
limits were calculated by the linear regression analysis and are presented in µmol/kg po. CL represents 95% confidence limits. e Inactive
at below given dose. f No confidence limit; 51% inhibition at a single given dose. No confidence limit; 49% inhibition at a single given
g
h
i
j
dose. Inactive at a single given dose. N: calcd, 13.85; found, 13.03. 7-[3-[4-(2,3-Dimethylphenyl)-1-piperazinyl]propoxy]-2-(1H)-
quinolinone (OPC-4392).
with more electron-donating groups such as methyl (46),
methoxy (47), and ethoxy groups (48) enhanced the
potency, whereas electron-withdrawing groups such as
nitro and nitrile groups diminished the activity (49 and
51).
in the 3,4-dihydro-2(1H)-quinolinone nucleus produced
the inactive compounds 38-40.
The effects of modifying the nucleus portion of the
compounds were then examined. As shown in Table 2,
the 2(1H)-quinolinone derivatives (52-56) were equi-
potent to their corresponding 3,4-dihydro-2(1H)-quino-
linone analogues (13, 16, 27, 28 and 48).
Next, the effects of the positional change of the side
chain attached to the 3,4-dihydro-2(1H)-quinolinone
nucleus in compound 28 was examined. Change in the
4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy side chain
from the 7-position in 28 to the 5-, 6-, and 8-positions
In the structure-activity relationships, the structural
requirements for the postsynaptic DA receptor antago-
nist activity found in this series are as follows: (1) In

662 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Oshiro et al.
Ta ble 2. 2(1H)-Quinolinone Analogues and Their Postsynaptic DA Receptor Antagonist Activity
DA receptor
antagonistic activity,
compd
R
yielda (%)
recryst solventb
mp (°C)
formula
anal.c
ED50 (CL)d
52
53
54
55
56
2-Me, 3-Cl
2-Me, 3-Br
2,3-(Cl)2
2,3-(Me)2
2-OEt
84
50
51
69
33
F
174-176
168-169
144-146
161-161.5
151 dece
C24H28N3O2Cl‚0.1H2O
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
2.8 (1.9-5.1)
2.1 (1.9-2.3)
0.9 (0.5-1.2)
3.4 (2.4-4.4)
0.24 (0.14-0.34)
A
A
F
C24H28N3O2Br
C23H25N3O2Cl2
C25H31N3O2‚0.2H2O
C25H31N3O3‚2HCl‚0.5H2O
A
a
b
Yields were not optimized in most cases. A ) EtOH, F ) MeOH-CHCl3. c C,H,N analyses were within (0.4% of the calculated
d
value. Inhibition of the apomorphine-induced stereotypy of behavior in mice. ED50 values and confidence limits (CL) were calculated
using the linear regression analysis and are presented in µmol/kg po. e Decomposed.
Ta ble 3. Pharmacology of the Selected Compounds
ED50 (CL)
DA receptor antagonist
activitya (A)
DA autoreceptor
agonist activityb
R1-adrenoceptor
ED50 ratio,
B/A
compd
catalepsyc (B)
antagonist activityd
13
16
21
25
26
27
28
33
37
48
52
54
55
56
1
2.8
2.1
0.7
0.9
0.9
3.4
0.6
1.1
0.8
0.2
2.8
0.9
3.4
0.24
41.3
12.1
0.24
3.5 (1.4-7.2)
1.3 (0.1-4.0)
>23
5.6 (3.3-8.9)
NT
5.9 (3.2-8.9)
1.4 (0.2-3.7)
NT
13.5 (10.8-18.4)
7.8 (7.1-8.7)
NT
>299
2.0
NT
>146
8.7
1.5
>23
>150
>2.1
NT
9.1 (3.7-84.7)
5.1 (1.3-29.2)
>22
>314
3.9
13
>286
>256
>21
NT
>265
0.65 (0.20-11.5)
20.1 (11.2-94.4)
>22
4.4 (3.9-5.2)
12.6 (7.7-24.1)
NT
10.5 (7.3-19.6)
NT
73.2 (66.8-80.2)
24.5 (21.4-27.9)
0.9 (0.88-0.98)
7.0 (6.1-7.8)
>299
20
4.5
>287
3.9 (0.7-18.6)
>20
3.5 (1.6-5.6)
IA
>156
3.1
>127
151 (96.1-236.0)
19.7 (19.1-22.0)
>341
1.8
2.0
3.7
CPZ
HAL
IA
a
b
See Tables 1 and 2. ED50 values are presented in µmol/kg po. Inhibition of the GBL-induced increase in DOPA accumulation in
mice. The ED50 values and 95% confidence limits (CL) were calculated using the linear regression analysis and are presented in µmol/kg
po. The compounds with ED50 values indicated with a greater than sign (>) were inactive at below the given dose. c Induction of catalepsy
in mice. The ED50 values and 95% confidence limits (CL) were calculated using the probit method and are presented in µmol/kg po.
d
Inhibition of the lethal effects of noradrenaline in mice. The ED50 values and 95% confidence limits (CL) were calculated using the
probit method and are presented in mmol/kg po The compounds with ED50 values indicated with a greater than sign (>) were inactive
at below the given dose. IA, inactive up to 10 mg/kg po; NT, not tested.
Ta ble 4. Comparison of Biological Activities in Rats of Compound 28 and Reference Agentsa
ED50 (µmol/kg po)
inhibition of GBL-induced
increase in DOPA synthesis
inhibition of APO-induced
streotyped behavior (A)
comp
catalepsy (B)
>2600
ratio of ED50, B/A
1
28
15.1 (10.2-22.0)
6.9 (4.5-10.7)
inactive
1860 (1250-3730)
11.8 (8.5-15.4)
1.1 (0.5-1.3)
>1.4
12.6
1.7
149 (137-161)
1.9 (1.6-2.1)
0.8 (0.8-0.9)
haloperidol
chlorpromazine
inactive
28.4 (24.5-33.2)
0.03
a
Numbers in parentheses represent 95% confidence limits.
the (phenylpiperazinyl)alkoxy side chain, the butoxy
side chain is preferred to the propoxy and pentoxy side
chains. (2) One or two substituents on the aromatic ring
in the phenylpiperazinyl moiety are necessary; the
2-ethoxy analogue 48 is best in the compounds with one
substituent on the aromatic ring, and the 2,3-dichloro
analogue 28 is best in the compounds with two or more
substituents on the aromatic ring. (3) The substituted
(phenylpiperazinyl)butoxy side chain at the 7-position
in the 3,4-dihydro-2(1H)-quinolinone nucleus is essential
for activity. (4) The 3,4-dihydro-2(1H)-quinolinone and
2(1H)-quinolinone derivatives with the same (phen-
ylpiperazinyl)butoxy moiety are equipotent to each
other.
The compounds which showed higher potency in the
anti-APO test than chlorpromazine were selected for
further examination.
DA Au tor ecep tor Agon ist Activity. The selected
compounds were tested for their ability to reverse GBL-
induced increase in DOPA synthesis in the mouse brain.
This effect reflects DA autoreceptor agonistic activity.
The DA autoreceptor agonist 1 and selected compound
28 dose-dependently reversed the GBL-induced increase

Antipsychotics with DA Autoreceptor Agonist Properties
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 663
in DOPA synthesis (0.3, 1, 3, 10 mg/kg po), but these
two compounds did not completely antagonize GBL even
at the highest dose in this model (70% inhibition at 10
mg/kg po). As shown in Table 3, compound 28 and the
DA autoreceptor agonist 1 reversed the GBL-induced
increase in DOPA synthesis. Compounds with the
3-chloro-2-methyl (13) and 2,3-dimethyl (27) phenyl-
piperazinyl moieties showed activity almost equipotent
to that of compound 1, whereas compounds with the
2-methyl-3-nitro (21), 2-chloro-3-methyl (25), 2-bromo-
3-methyl (26), 3,5-dichloro (33), and 2,3,5-trichloro (37)
phenylpiperazinyl moieties were inactive up to 10 mg/
kg po. The effects of change in the nucleus portion of
the 3,4-dihydro-2(1H)-quinolinone derivatives were also
observed. The 2(1H)-quinolinone 55 showed higher
activity than the 3,4-dihydro-2(1H)-quinolinone 27 with
the same (2,3-dimethylphenyl)piperazinyl moiety as 1.
In contrast, the 2(1H)-quinolinone derivatives with the
3-chloro-2-methyl-, 2,3-dichloro-, and 2-ethoxyphenyl-
piperazinyl moieties (52, 54, and 56) were much less
active than the 3,4-dihydro-2(1H)-quinolinone deriva-
tives with the corresponding side chain (13, 28, and 48).
monosubstituted phenylpiperazinyl analogue 48 showed
the highest potency in this activity, whereas the disub-
stituted phenylpiperazinyl analogues and 28 were inac-
tive up to 286 µmol/kg po. An abnormality of norad-
renaline neurotransmission in schizophrenia patients
has been reported.31 Although a beneficial effect of this
activity in treatments of these patients has been sug-
gested,32 compound 48 requires further studies with
respect to its potent R1-adrenoceptor antagonist activity.
Data presented in Table 3 show that compounds 13,
27, 28, 52, and 55 are D2 receptor antagonists and DA
autoreceptor agonists and are very weak R1-adrenocep-
tor antagonists. The profile of these compounds is quite
similar to that of 1 when tested in mice. Therefore, we
compared their effects on the APO-induced stereotypy
in rats with that of compound 1 at 1, 2, 4, and 6 h after
oral administration of 30 mg/kg po. Compounds 1, 27,
and 55, which have the (2,3-dimethylphenyl)piperazinyl
moiety, did not inhibit the APO-induced stereotypy at
1-6 h after oral administration of 30 mg/kg. In contrast
to this, compounds 13 and 52, which possess the
(3-chloro-2-methylphenyl)piperazinyl moiety, inhibited
the APO-induced stereotypy at 1, 2, 4, and 6 h after
administration, and maximum inhibition was found at
2 and 4 h after administration, ED50 values estimated
as 49.5 (27.8-169.4) and 50.5 (38.5-71.1) µmol/kg po,
respectively. Compound 28, which possesses the (2,3-
dichlorophenyl)piperazinyl moiety, was the most potent
of the compounds tested in rats. Complete inhibition
was observed at 2 h after oral administration, and the
ED50 value was estimated as 11.8 (8.5-15.4) µmol/kg
po. These results suggested that the methyl substituent
in the phenylpiperazinyl moiety is more vulnerable to
a first-pass metabolism in rats than the chloro substitu-
ent in the phenylpiperazinyl moiety in those compounds.
Thus, compound 28 was selected for further examina-
tion of its clinical potential as an antipsychotic agent
in comparisons with standard agents such as chlor-
promazine and haloperidol in rats.
Compounds 28 and 48, which were the two most
potent compounds in the anti-APO test, also displayed
activity in the test for reversal of GBL-induced increase
in DOPA synthesis comparable to that of DA auto-
receptor agonist 1.
Ad ver se Effects. The EPS liability and R1-adreno-
ceptor antagonist activity of selected compounds were
examined. Typical antipsychotic agents induce cata-
lepsy. Selected compounds were also examined for their
ability to induce catalepsy in mice. As shown in Table
3, compound 25 was the most potent compound. The
compound did not show the DA autoreceptor agonist
activity. Compounds 28 and 48 also induced catalepsy
but with 10 and 20 times higher ED50 values than that
of the anti-APO test in mice (ED50 of 7.8 and 4.4 µmol/
kg po, respectively), suggesting their lower propensity
to induce EPS than the typical antipsychotic agent
examined. The cataleptogenic effects of typical anti-
psychotic agents have been shown to be correlated to
their potency of postsynaptic DA receptor antagonistic
activities.27 An atypical antipsychotic agent, clozapine,
has been reported not to induce catalepsy in mice, and
its lack of cataleptogenic effects has been explained to
be attributable to its potent antimuscarinic effects.28,29
However, these antimuscarinic effects are unlikely in
compound 28 since 28 did not inhibit the lethal effects
of physostigmine in rats up to 300 mg/kg po.30 Fur-
thermore, compound 25, which does not show DA
autoreceptor agonistic activity, is the most potent cata-
leptogenic compound in the series of compounds exam-
ined. Thus, the weak cataleptogenic effects of 28 and
48 may contribute to its DA autoreceptor agonistic
activity at present, although further investigations to
determine the mechanism of their pharmacological
effects are necessary.
As shown in Table 4, the DA autoreceptor agonist and
postsynaptic DA receptor antagonist activities of 28
were also confirmed in two tests in rats. Compound 28,
chlorpromazine, and haloperidol inhibited the APO-
induced stereotypic behavior in rats with ED50 values
of 11.8, 28.4, and 1.1 µmol/kg po, respectively. Com-
pounds 28 and 1 antagonized the GBL-induced increase
in DA synthesis in the rat brain with ED50 values of
6.9 and 15.7 µmol/kg po, respectively. Compounds 1 and
28 showed lower activities in rats than in mice after
oral administration. These differences in potencies
between mice and rats may be attributable to the
difference in first-pass metabolism between the two
species. Compound 28 induced catalepsy in rats with
an ED50 value of 149.2 µmol/kg po, which is about 10
times higher than that for APO-induced stereotypic
behavior test as seen in mice. Thus, 28 was confirmed
in mice and rats to have these dual activities and a low
potential to induce the EPS.
Selected compounds were also tested for their R1-
adrenoceptor antagonist activity since peripheral R1-
adrenoceptor antagonism has been known to cause
autonomic side effects.2 As seen in Table 3, chlor-
promazine and 1 showed R1-adrenoceptor antagonist
activity with ED50 values of 19.7 and 150.7 µmol/kg po,
respectively. Among the compounds examined, the
Because of its attractive profile and its minimal
adverse effect after toxicological studies, compound 28
was selected as a candidate for clinical evaluations in
schizophrenic patients.

664 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Oshiro et al.
(16.3 g, 0.1 mol), 1,4-dibromobutane (64.8 g, 0.3 mol), and K2-
CO3 (13.8 g, 0.1 mol) in DMF (500 mL) were stirred for 4 h to
give 12 (29%) as a white powder. An analytical sample was
obtained by recrystallization from AcOEt as colorless gran-
ules: mp 126-128 °C; 1H NMR (DMSO-d6) δ 1.92 (4H, m, -C-
CH2CH2-C-), 3.62 (2H, t, J ) 6 Hz, -CH2Br), 4.05 (2H, t, J )
6 Hz, O-CH2-), 6.30 (1H, d, J ) 9 Hz, -CdCH-CO-), 6.79 (2H,
m, H8, H6), 7.56 (1H, d, J ) 8 Hz, H5), 7.89 (1H, d, J ) 9 Hz,
-CHdC-CO-), 11.59 (1H, s, NHCO). Anal. (C13H14NO2Br) C,
H, N.
Gen er a l P r oced u r e for P r ep a r a tion of 3,4-Dih yd r o-
2(1H )-q u in olin on e Der iva t ives (Ta b le 1). 7-[4-[4-(3-
Ch lor o-2-m eth ylp h en yl)-1-p ip er a zin yl]bu toxy]-3,4-d ih y-
d r o-2(1H)-qu in olin on e (13). A mixture of 6 (2.0 g, 6.7 mmol)
and NaI (2.0 g, 13.3 mmol) in CH3CN (50 mL) was refluxed
for 30 min and then cooled to room temperature. 1-(3-Chloro-
2-methylphenyl)piperazine (2.0 g, 9.49 mmol) and triethyl-
amine (TEA; 2 mL, 14.5 mmol) were added to the mixture,
and the resulting mixture was refluxed for 4 h. Precipitated
crystals were filtered off, and the filtrate was evaporated under
reduced pressure. The residue was extracted with AcOEt, and
the extract was washed, dried, and concentrated to dryness
in vacuo. Recrystallization from EtOH gave 13 (35%) as
colorless needles: mp 146-148 °C; 1H NMR (CDCl3) δ 1.77
(4H, m, -CH2CH2-), 2.34 (3H, s, CH3), 2.47 (2H, t, J ) 7 Hz,
-CH2CO-), 2.61 (6H, m, -CH2N(CH2-)CH2-), 2.90 (6H, m,
-CH2PhCH2-, -CH2-C-CO), 3.96 (2H, t, J ) 6 Hz, O-CH2-
), 6.32 (1H, d, J ) 2.5 Hz, H8), 6.52 (1H, dd, J ) 2.5, 8 Hz,
H6), 6.94 (1H, m, aromatic H), 7.08 (3H, m, aromatic H), 8.05
(1H, s, NHCO). Anal. (C24H30N3O2Cl) C, H, N.
Compounds 15-21, 25-37, and 41-49 were prepared in a
manner similar to that for 13 by reacting 6 (6.7 mmol) with 2
equiv of the corresponding phenylpiperazine derivatives (13
mmol). 1-(2-Chlorophenyl)piperazine, 1-(3-chlorophenyl)pip-
erazine, 1-(4-chlorophenyl)piperazine, 1-(2-fluorophenyl)pip-
erazine, 1-(2-ethoxyphenyl)piperazine, 1-(2-methoxyphenyl)-
piperazine, and 1-(o-tolyl)piperazine were purchased from
Aldrich Chemical Co. Inc. 1-(2,3-Dichlorophenyl)piperazine
was prepared by application of the reported method.42 1-(3-
Chloro-2-methylphenyl)piperazine, 1-(2,3-dimethylphenyl)pip-
erazine, and 1-(2,5-dichlorophenyl)piperazine were prepared
according to the reported procedure.43 1-(2,4-Dichlorophenyl)-
piperazine, 1-(2,6-dichlorophenyl)piperazine, 1-(3,5-dichloro-
phenyl)piperazine, 1-(2-methyl-3-fluorophenyl)piperazine, 1-(2-
methyl-3-bromophenyl)piperazine, 1-(2-methyl-3-cyanophen-
yl)piperazine, 1-(2-methyl-3-nitorophenyl)piperazine, 1-(2-
chloro-3-methylphenyl)piperazine, 1-(2,3,5-trichlorophenyl)-
piperazine, and 1-(2,3,4-trichlorophenyl)piperazine were pre-
pared from the corresponding aniline (0.127 mol) and bis(2-
bromoethyl)amine hydrobromide (0.15 mol) by application of
the reported method.44 1-(2-Nitrophenyl)piperazine, 1-(2-
bromophenyl)piperazine, 1-(2,3-dibromophenyl)piperazine, and
1-(2-bromo-3-chlorophenyl)piperazine were prepared from the
corresponding ethyl 4-phenyl-1-piperazinecarboxylate deriva-
tives, which were obtained from ethyl 1-piperazinecarboxylate
and 2-halogenonitrobenzene derivatives by application of the
reported method45 with modification. The modification made
was that 2-halogenonitrobenzene derivatives were used in-
stead of 2-chloropyrimidine derivatives.
Con clu sion
To develop a novel antipsychotic agent which acts as
an agonist at DA autoreceptors and as an antagonist
at postsynaptic DA receptors, a series of 7-[4-(4-phenyl-
1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone de-
rivatives were synthesized and their dual activities were
examined. In the course of these studies, compound 28
was found to possess the desired dual activities. Our
results indicated that 28 is an agonist of the DA
autoreceptors, and it also acts as an antagonist of the
postsynaptic DA receptors almost equipotently to stan-
dard antipsychotic agents. This compound showed
lower potential to induce catalepsy than the standard
agent and did not show R1-adrenoceptor antagonist
activity. Thus, 28 may be a potent and effective agent
for treatment of both the negative and positive symp-
toms in schizophrenia with less adverse effects than
clinically available agents.
The dual activities of 28 have been confirmed by
biochemical and pharmacological studies.30 In addition
to its reversal effects on the GBL in the DOPA synthesis
described in this paper, 28 reversed reserpine-induced
increase in tyrosine hydroxylase activity in mouse and
rat brain.30 Furthermore, the reversal effects of 28 in
the test with GBL was blocked by pretreatment of the
DA receptor antagonist haloperidol.30 The postsynaptic
DA receptor antagonist activity of 28 was also supported
by the following results. In contrast to a DA receptor
agonist (apomorphine), 28 did not evoke postsynaptic
DA receptor-stimulating behavioral signs such as hy-
perlocomotion in the reserpinized mice and contralateral
rotation in rats with unilateral striatal 6-hydroxy-
dopamine lesions.30 Compound 28 also binds to the [3H]-
spiperone-labeled D2 receptors in the rat frontal cortex
(Ki ) 1.2 nM), limbic forebrain (Ki ) 0.4 nM), and
striatum (Ki ) 0.8 nM).30 Further biochemical and
behavioral investigations on compound 28 with respect
to its dual activities have been reported.34-41 Clinical
trials with 28 (aripiprazole, OPC-14597) are currently
in progressed in J apan and the United States.
Exp er im en ta l Section
Melting points were determined by a Yanagimoto mi-
cromelting point apparatus and are uncorrected. 1H NMR
spectra were recorded on a Bruker AC-250 NMR spectrometer
using tetramethylsilane (TMS) as an internal standard. El-
ementary analyses for carbon, hydrogen, and nitrogen were
carried out on a Yanaco MT-5 CHN recorder. Where analyses
are indicated only as symbols of elements, analytical results
obtained are within 0.4% of the theoretical value. All com-
pounds were routinely checked by TLC with Merck silica gel
60 F254 precoated plates.
7-(4-Br om obu toxy)-3,4-d ih yd r o-2(1H)-qu in olin on e (6).
A mixture of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (5) (16.7
g, 0.1 mol), K2CO3 (13.8 g, 0.1 mol), and 1,4-dibromobutane
(64.8 g, 0.3 mol) in DMF (500 mL) was stirred for 4 h at 60 °C
and then diluted with water (500 mL). An organic layer was
extracted with ethyl acetate (AcOEt), and the extract was
washed, dried, and evaporated to dryness in vacuo. Recrys-
tallization from EtOH gave 6 (78%) as colorless needles: mp
110.5-111 °C; 1H NMR (DMSO-d6) δ 1.81 (2H, m, -CH2-), 1.95
(2H, m, -CH2-), 2.41 (2H, t, J ) 7 Hz, -CH2CO-), 2.78 (2H, t, J
) 7 Hz, -CH2-C-CO-), 3.60 (2H, t, J ) 6 Hz, -CH2Br), 3.93 (2H,
t, J ) 6 Hz, O-CH2-), 6.43 (1H, d, J ) 2.5 Hz), 6.49 (1H, dd, J
) 2.5, 8 Hz), 7.04 (1H, d, J ) 8 Hz), 9.98 (1H, s, NHCO). Anal.
(C13H16NO2Br) C, H, N.
7-[5-[4-(3-Ch lor o-2-m et h ylp h en yl)-1-p ip er a zin yl]p en -
toxy]-3,4-d ih yd r o-2(1H)-qu in olin on e (14). In a manner
similar to that for 13, 7-(5-bromopentoxy)-3,4-dihydro-2(1H)-
quinolinone (7)9 (2.0 g, 6.4 mmol) was reacted with 1-(3-chloro-
2-methylphenyl)piperazine (2.0 g, 9.49 mol) and TEA (2 mL,
14.5 mmol) in the presence of NaI (2.0 g, 13.3 mmol) in CH3-
CN (50 mL) to afford 14 (32%): mp 146-148 °C; 1H NMR
(CDCl3) δ 1.56 (4H, m, -CH2CH2-), 1.82 (2H, m, -CH2-), 2.34
(3H, s, CH3), 2.45 (2H, t, J ) 7 Hz, -CH2CO-), 2.60 (6H, m,
-CH2N(CH2-)CH2-), 2.92 (6H, m, -CH2PhCH2-, -CH2-C-CO),
3.95 (2H, t, J ) 6 Hz, O-CH2-), 6.34 (1H, d, J ) 2.5 Hz, H8),
6.52 (1H, dd, J ) 2.5, 8 Hz, H6), 6.95 (1H, m, aromatic H),
7.05 (3H, m, aromatic H), 8.20 (1H, s, NHCO). Anal.
(C25H32N3O2Cl) C, H, N.
7-(4-Br om obu toxy)-2(1H)-qu in olin on e (12). In a man-
ner similar to compound 6, 7-hydroxy-2(1H)-quinolinone (11)
7-[4-[4-(3-Am in o-2-m eth ylph en yl)-1-piper azin yl]bu toxy]-

Antipsychotics with DA Autoreceptor Agonist Properties
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 665
3,4-d ih yd r o-2(1H)-qu in olin on e (22). A mixture of 7-[4-[4-
(2-methyl-3-nitrophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-
2(1H)-quinolinone (21) (5.1 g, 10 mmol) and 5% palladium on
carbon (500 mg) in EtOH (100 mL) was hydrogenated in a Parr
apparatus under 4 kg/cm3 hydrogen pressure. After the
catalyst was filtered off, the filtrate was concentrated in vacuo.
Recrystallization from MeOH gave 22 (55%) as colorless
needles: mp 171-173 °C; 1H NMR (CDCl3) δ 1.79 (4H, m,
-CH2CH2-), 2.12 (3H, s, CH3), 2.47 (2H, t, J ) 7 Hz, -CH2CO-),
2.61 (6H, m, -CH2N(CH2-)CH2-), 2.90 (6H, m, -CH2-C-CO-, CH2-
NPhCH2-), 3.60 (2H, br, NH2), 3.96 (2H, t, J ) 6 Hz, O-CH2-),
6.32 (1H, d, J ) 2.5 Hz, H8), 6.46 (3H, m, aromatic H), 6.99
(1H, d, J ) 8 Hz, aromatic H), 7.03 (1H, d, J ) 8 Hz, aromatic
H), 8.05 (1H, s, -NHCO-). Anal. (C24H32N4O2) C, H, N.
aromatic H), 7.14 (2H, m, aromatic H), 8.32 (1H, s, -NHCO-).
Anal. (C23H27N3O2Cl2) C, H, N.
8-[4-[4-(2,3-Dich lor op h en yl)-1-p ip er a zin yl]bu toxy]-3,4-
d ih yd r o-2(1H)-qu in olin on e (40). This compound was pre-
pared from 8-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone
(10)25 (2.0 g, 6.7 mmol), 1-(2,3-dichlorophenyl)piperazine (1.7
g, 7.37 mmol), and TEA (1.4 mL, 7.37 mmol) in the presence
of NaI (2.0 g, 13.3 mmol) in CH3CN (50 mL), with 79% yield
as colorless prisms (EtOH): mp 122-123 °C; 1H NMR (CDCl3)
δ 1.75 (4H, m, -CH2CH2-), 2.49 (2H, t, J ) 7 Hz, -CH2CO-),
2.63 (6H, m, -CH2N(CH2-)CH2-), 2.97 (2H, t, J ) 7 Hz, -CH2-
C-CO), 3.08 (4H, m, -CH2NPhCH2-), 4.05 (2H, t, J ) 6 Hz,
O-CH2-), 6.76 (2H, d, J ) 8 Hz, aromatic H), 6.91 (1H, d, J )
8 Hz, aromatic H), 6.96 (1H, m, aromatic H), 7.14 (2H, m,
aromatic H), 7.78 (1H, s, -NHCO-). Anal. (C23H27N3O2Cl2) C,
H, N.
3,4-Dih yd r o-7-[4-[4-(2-n it r op h e n yl)-1-p ip e r a zin yl]-
bu toxy]-2(1H)-qu in olin on e (49). This compound was pre-
pared from 6 (2.7 g, 9.21 mmol), 1-(2-nitrophenyl)piperazine
(2.3 g, 11.1 mmol), and TEA (1.49 mL, 13.7 mmol) in the
presence of NaI (2.07 g, 13.8 mmol) in CH3CN (30 mL).
Recrystallization from MeOH provided 49 in 50% yield as
yellow granules: mp 112-113 °C; 1H NMR (CDCl3) δ 1.77 (4H,
m, -CH2CH2-), 2.50 (2H, t, J ) 7 Hz, -CH2CO-), 2.65 (6H, m,
-CH2N(CH2-)CH2-), 2.93 (2H, t, J ) 7 Hz, -CH2-C-CO-), 3.11
(4H, m, -CH2NPhCH2-), 3.99 (2H, t, J ) 6 Hz, O-CH2-), 6.37
(1H, d, J ) 2.5 Hz, H8), 6.55 (1H, dd, J ) 2.5, 8 Hz, H6), 7.06
(2H, m, aromatic H), 7.16 (1H, dd, J ) 2.5, 8 Hz, aromatic H),
7.50 (1H, m, aromatic H), 7.78 (1H, dd, J ) 2.5, 8 Hz, aromatic
H), 8.30 (1H, s, -NHCO-). Anal. (C23H28N4O4) C, H, N.
7-[4-[4-(2-Am in op h en yl)-1-p ip er a zin yl]bu toxy]-3,4-d i-
h yd r o-2(1H)-qu in olin on e (50). SnCl2 dihydrate (6.5 g, 28.8
mmol) was added in portions to a solution of 49 (3.5 g, 8.25
mmol) in EtOH and 12 N HCl (30 mL), and the resulting
mixture was stirred for 1 h at 60 °C. Then the mixture was
poured into ice-water (100 mL), made basic by addition of a
KOH pellet, and extracted with CH2Cl2 (200 mL). The extract
was washed, dried, and evaporated under reduced pressure.
The residue was purified by column chromatography (SiO2,
3% MeOH in CHCl3). Recrystallization from EtOH-isopropyl
ether afforded 50 as pale-brown granules in 34% yield: mp
130-132 °C; 1H NMR (CDCl3) δ 1.75 (4H, m, -CH2CH2-), 2.47
(2H, t, J ) 7 Hz, -CH2CO-), 2.61 (6H, m, -CH2N(CH2-)CH2-),
2.89 (6H, m, -CH2-C-CO-, -CH2NPhCH2-), 3.96 (4H, m, O-CH2-,
-NH2), 6.34 (1H, d, J ) 2.5 Hz, H8), 6.52 (1H, dd, J ) 2.5, 8
Hz, H6), 6.75 (2H, m, aromatic H), 6.99 (3H, m, aromatic H),
8.32 (1H, s, -NHCO-). Anal. (C23H30N4O2) C,H,N.
7-[4-[4-[3-(Ace t yla m in o)-2-m e t h ylp h e n yl]-1-p ip e r a -
zin yl]bu toxy]-3,4-d ih yd r o-2(1H)-qu in olin on e (23). Acetic
anhydride (0.2 mL, 2.05 mmol) was added to a solution of 22
(0.7 g, 1.7 mmol) in acetic acid (10 mL) at ice-cooled temper-
ature. The mixture was stirred for 3 h at room temperature
and evaporated in vacuo. Recrystallization from MeOH gave
1
23 (70%) as a pale-yellow powder: mp 186-188 °C; H NMR
(CDCl3) δ 1.71 (4H, m, -CH2CH2-), 2.21 (6H, s, CH3, CH3CO-),
2.48 (2H, t, J ) 7 Hz, -CH2CO-), 2.60 (6H, m, -CH2N(CH2-)-
CH2-), 2.90 (6H, m, -CH2-C-CO-CH2NPhCH2-), 3.96 (2H, t, J
) 6 Hz, O-CH2-), 6.29 (1H, d, J ) 2.5 Hz, H8), 6.52 (1H, dd, J
) 2.5, 8.5 Hz, H6), 6.91 (1H, d, J ) 8 Hz, aromatic H), 6.92
(1H, br, -NHAc), 7.05 (1H, d, J ) 8 Hz, aromatic H), 7.17 (1H,
t, J ) 8 Hz, H7), 7.46 (1H, d, J ) 8 Hz, aromatic H), 7.68 (1H,
s, -NHCO-). Anal. (C26H34N4O3) C, H, N.
3,4-Dih yd r o-7-[4-[4-(3-h yd r oxy-2-m eth ylp h en yl)-1-p ip -
er a zin yl]bu toxy]-2(1H)-qu in olin on e (24). A solution of
NaNO2 (0.19 g, 26.0 mmol) in water (1 mL) was added
dropwise to a solution of 22 (1.0 g, 24.4 mmol) in a 30% solution
of sulfuric acid (50 mL) below -5 °C. After stirring for 30 min,
the resulting mixture was added cautiously to a 20% solution
of sulfuric acid at 40 °C with vigorous stirring. The mixture
was neutralized with a 10% KOH solution and extracted with
CH2Cl2 (200 mL). The extract was washed, dried, and
evaporated to dryness in vacuo. Recrystallization from MeOH
1
gave 24 (24%) as orange needles: mp 208-210 °C; H NMR
(DMSO-d6) δ 1.58 (2H, m, -CH2-), 1.73 (2H, m, -CH2-), 2.03
(3H, s, CH3), 2.37 (4H, m, -CH2CO-, -CH2-), 2.66 (4H, m,
-CH2N(CH2-)CH2-), 2.77 (6H, m, -CH2-C-CO-, -CH2NPhCH2-),
3.92 (2H, t, J ) 6 Hz, O-CH2-), 6.47 (4H, m, aromatic H), 6.91
(1H, t, J ) 8 Hz, aromatic H), 7.04 (1H, d, J ) 8 Hz, aromatic
H), 9.13 (1H, s, OH), 9.98 (1H, s, -NHCO-). Anal.
(C24H31N3O3‚1.5H2O) C, H, N.
5-[4-[4-(2,3-Dich lor op h en yl)-1-p ip er a zin yl]bu toxy]-3,4-
d ih yd r o-2(1H)-qu in olin on e (38). A mixture of 5-(4-bro-
mobutoxy)-3,4-dihydro-2(1H)-quinolinone (8)25 (2.0 g, 6.7 mmol)
and NaI (1.5 g, 10.1 mmol) in CH3CN (30 mL) was refluxed
for 30 min and then cooled to room temperature. 1-(2,3-
Dichlorophenyl)piperazine (1.7 g, 7.37 mmol) and TEA (1.4 mL,
7.37 mmol) were added to the mixture and stirred for 4 h at
80 °C. The precipitated crystals were filtered, washed, and
dried. Recrystallization from EtOH-CHCl3 gave 38 (72%) as
colorless flakes: mp 190-192 °C; 1H NMR (CDCl3) δ 1.81 (4H,
m, -CH2CH2-), 2.50 (2H, t, J ) 7 Hz, -CH2CO-), 2.61 (6H, m,
-CH2N(CH2-)CH2-), 2.97 (2H, t, J ) 7 Hz, -CH2-C-CO-), 3.08
(4H, m, -CH2NPhCH2-), 4.02 (2H, t, J ) 6 Hz, O-CH2-), 6.39
(1H, d, J ) 8 Hz, aromatic H), 6.57 (1H, d, J ) 8 Hz, aromatic
H), 6.95 (1H, m, aromatic H), 7.15 (3H, m, aromatic H), 7.99
(1H, s, -NHCO-). Anal. (C23H27N3O2Cl2) C, H, N.
6-[4-[4-(2,3-Dich lor op h en yl)-1-p ip er a zin yl]bu toxy]-3,4-
d ih yd r o-2(1H)-qu in olin on e (39). This compound was pre-
pared from 6-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone
(9)26 (2.0 g, 6.7 mmol), and 1-(2,3-dichlorophenyl)piperazine
(1.7 g, 7.37 mmol) and TEA (1.4 mL, 7.37 mmol) in the
presence of NaI (2.0 g, 13.3 mmol) in CH3CN (50 mL) with
81% yield as colorless flakes (EtOH-CHCl3): mp 194-197 °C;
1H NMR (CDCl3) δ 1.24 (4H, m, -CH2CH2-), 2.49 (2H, t, J ) 7
Hz, -CH2CO-), 2.62 (6H, m, -CH2N(CH2-)CH2-), 2.93 (2H, t, J
) 7 Hz, -CH2-C-CO), 3.07 (4H, m, -CH2NPhCH2-), 3.96 (2H, t,
J ) 6 Hz, O-CH2-), 6.71 (3H, m, aromatic H), 6.96 (1H, m,
7-[4-[4-(2-Cya n op h en yl)-1-p ip er a zin yl]bu toxy]-3,4-d i-
h yd r o-2(1H)-qu in olin on e (51). A solution of NaNO2 (210
mg, 3.04 mmol) in water (3 mL) was added dropwise to a
solution of compound 50 (1.0 g, 2.54 mmol) in a 20% H2SO4
solution (25 mL) at 0 °C. After stirring for 30 min, the
diazonium salt solution was poured into a mixture of KCN (1.6
g, 24.6 mmol), CuSO4 pentahydrate (1.5 g, 6 mmol), and 37%
NH4OH (1.5 mL) in water (20 mL) at room temperature, and
the mixture was stirred for another 1 h. The precipitates were
filtered and dissolved in CH2Cl2. The solution was washed,
dried, and concentrated in vacuo to give a crude oily product
which was purified by column chromatography (SiO2, 2%
MeOH in CHCl3). Recrystallization from CH3CN provided 51
as a pale-brown powder in 18% yield: mp 150-151 °C; 1H
NMR (CDCl3) δ 1.76 (4H, m, -CH2CH2-), 2.46 (2H, t, J ) 7 Hz,
-CH2CO-), 2.65 (6H, m, -CH2N(CH2-)CH2-), 2.89 (2H, t, J ) 7
Hz, -CH2-C-CO-), 3.22 (4H, m, -CH2NPhCH2-), 3.96 (2H, t, J
) 6 Hz, O-CH2-), 6.31 (1H, d, J ) 2.5 Hz, H8), 6.51 (1H, dd, J
) 2.5, 8 Hz, H6), 6.98 (3H, m, aromatic H), 7.54 (2H, m,
aromatic H), 8.05 (1H, s, -NHCO-). Anal. (C24H28N4O2‚1.5
H2O) C,H,N.
Gen er a l P r oced u r e for P r ep a r a tion of 7-[4-(4-P h en yl-
1-p ip er a zin yl)bu toxy]-2(1H)-qu in olin on es 52-56 (Ta ble
2).
7-[4-[4-(3-Ch lor o-2-m et h ylp h en yl)-1-p ip er a zin yl]-
bu toxy]-2(1H)-qu in olin on e (52). A mixture of 12 (2.5 g, 8.3
mmol), NaI (2.0 g, 13 mmol), TEA (2 mL, 14.3 mmol) and 1-(3-
chloro-2-methylphenyl)piperazine (2.5 g, 11.9 mmol), in

666 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Oshiro et al.
acetonitrile (50 mL) was refluxed for 4 h with stirring. The
reaction mixture was filtered, and the filtrate was evaporated
to dryness in vacuo. The residue was extracted with CHCl3,
and the extract was washed, dried, and evaporated in vacuo.
Recrystallization from MeOH-CHCl3 gave 52 (84%) as color-
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less needles: mp 174-176 °C; H NMR (CDCl3) δ 1.74 (2H,
m, -CH2-), 1.87 (2H, m, -CH2-), 2.34 (3H, s, CH3), 2.51 (2H, t,
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