Design, synthesis, and discovery of 3-piperazinyl-3,4-dihydro-2(1H)-quinolinone derivatives: A novel series of mixed dopamine D2/D4 receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00421-2

3-Piperazinyl-3,4-dihydro-2(1H)-quinolinone derivatives (δ-lactams) were designed, synthesized, and identified as a new series of mixed dopamine D₂/D₄ receptor antagonists. To further the structure-activity relationship (SAR) study, 3-piperazinylindolin-2-ones (γ-lactams) and 3-piperazinyl-3H,4H,5H-benzo[f]azepin-2-ones (ε-lactams) were also prepared and examined. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00421-2

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2119±2122
Design, Synthesis, and Discovery of 3-Piperazinyl-3,4-
dihydro-2(1H)-quinolinone Derivatives:
A Novel Series of Mixed Dopamine D2/D4 Receptor Antagonists
He Zhao,* Andrew Thurkauf, Julia Braun, Robin Brodbeck and Andrzej Kieltyka
Neurogen Corporation, 35 Northeast Industrial Road, Branford, CT 06405, USA
Received 25 May 2000; accepted 14 July 2000
AbstractÐ3-Piperazinyl-3,4-dihydro-2(1H)-quinolinone derivatives (d-lactams) were designed, synthesized, and identi®ed as a new
series of mixed dopamine D2/D4 receptor antagonists. To further the structure±activity relationship (SAR) study, 3-piperazinyl-
indolin-2-ones (g-lactams) and 3-piperazinyl-3H,4H,5H-benzo[ f ]azepin-2-ones (e-lactams) were also prepared and examined.
# 2000 Elsevier Science Ltd. All rights reserved.
Introduction
it was also desirable to minimize a1 binding in order to
avert undesirable cardiovascular e€ects. In the course of
our studies, we identi®ed two series of compounds hav-
ing a combination of D2 and D4 receptor anities com-
parable to clozapine 5. They are trans-1-[2-(phenyl-
cyclopropyl)methyl]-4-aryl-piperazines (e.g., 6)29 and
benzylpiperazinyl ethanoindoline derivatives (e.g., 7).30
In this paper, we describe a new series of mixed dopa-
mine D2/D4 receptor antagonists, the 3-piperazinyl-3,4-
dihydro-2(1H)-quinolinones (e.g., 9, Fig. 2), and
demonstrate how they are genealogically related to the
previously mentioned indoline derivatives.
Schizophrenia is a debilitating disease for which
researchers believe that brain dopamine receptors are
the primary targets for medical treatment.1 Molecular
biology studies have identi®ed ®ve dopamine receptor
subtypes which can be classi®ed into two classes, D1-like
(D1 and D5)2,3 and D2-like (D2, D4, and D5),4 6 based
on their ability to stimulate or inhibit adenylate cyclase,
respectively. In the last several years, intense research
e€ort has been focused on the D4 receptor. These e€orts
led to the clinical trials of a number of D4 selective
antagonists7 18 including NGD94-1 (1),19 L-745,870
(2),20 U-101387 (3),21 and CP-293019 (4)22 in Figure 1.
However, these compounds have not proved to be e-
cacious as potential antipsychotic agents. For example,
compound 2 was found to be ine€ective in humans.23
Many laboratories have also identi®ed a number of D2
selective agonists24,25 or antagonists,26,27 but none of
them are ecacious in treating all schizophrenic patients.
Design and Synthesis
The indoline containing compound 7 was previously
evaluated as a lead with potent D4 binding activity and
weak D2 binding anity.30 Based on this lead com-
pound, compound 8 was designed at ®rst by removing
one carbon from the indoline part of compound 7 and
prepared starting from N-methylaniline.31 Biological
screening showed that this compound had not only lost
some activity for D4 binding, but it was totally inactive
at D2 receptors.
Clozapine (5)28 is the ®rst marketed antipsychotic agent
which binds with substantially greater anity to dopa-
mine D4 than to D2 receptor subtype. Although D4 may
play an important role in the actions of clozapine, the
association with D2 may be also required for e€ective
antipsychotic action. Therefore, we set out a research
program to obtain a compound that possessed a D2/D4
binding ratio similar to that of clozapine. Furthermore,
We reasoned that this decreasing anity resulted from
the loss of conformational restriction present in 7.
Molecular modeling studies indicated that the energeti-
cally most favorable presentation of the amide oxygen
of 7 is directed away from the indoline phenyl, as shown
in Figure 2. It seemed that an alternative conformational
*Corresponding author. Tel.: +1-203-488-8201; fax: +1-203-483-7027;
e-mail: hzhao@nrgn.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00421-2

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H. Zhao et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2119±2122
Figure 1.
Scheme 1. Reagents and conditions: (i) diethyl bromomalonate,
K2CO3, CH3CN, rt, 18 h, 98%; (ii) 2-nitrobenzyl chloride, NaOEt,
EtOH, re¯ux, 15 h, 54%; (iii) H2, 10% Pd/C, 1 atm, EtOAc, rt, 24 h,
91%; (iv) EtOH, re¯ux, 4 h, 85%; (v) 20% NaOH, MeOH, re¯ux,
18 h; then 6 N HCl, 82%; (vi) MeI or EtI, NaH, THF, argon, rt, 5 h,
85% or 78%, respectively.
benzo[ f ]azepin-2-ones (e-lactams) were also synthesized
by direct condensation of the substituted phenylpiper-
azines with the corresponding a-halogen lactams as
shown in Scheme 2. For example, when the substituted
piperazine 18 was stirred with 3-chloroindolin-2-one
1933 and potassium carbonate at room temperature for
15 h, compound 20 (g-lactam) was prepared. Although
many alkylation conditions were tried for the N-mono-
substitution of compound 20, the disubstituted com-
pounds (21, 2234±26) were always the major products.
No disubstituted compound was observed when com-
pound 28 (e-lactam), prepared from 3-iodo-1H,3H,
4H,5H-benzo[f]azepin-2-one 27,35 was treated under the
same reaction conditions. Only the monosubstituted
compounds (29, 3036±34) were produced. We were
unable to prepare 3-bromo-1,3,4-trihydroquinolin-2-
one due to rapid dehydrohalogenation. Thus, the direct
condensation strategy was not applicable to the synth-
esis of d-lactam series.
Figure 2.
restriction, which would hold the carbonyl in this
orientation, might provide a more favorable receptor
anity pro®le. Consequently, compound 9 was designed
by placing two carbons between the a position of the
amide and the corresponding carbon of the phenyl ring
to generate a new benzofused d-lactam system.
Scheme 1 depicts the synthesis used to prepare these
benzofused d-lactams. Alkylation of 1-[(4-chlorophenyl)-
methyl] piperazine 10 with diethyl bromomalonate and
potassium carbonate in acetonitrile provided compound
11, which was then treated with freshly prepared sodium
ethoxide and alkylated with 2-nitrobenzyl chloride to
give compound 12. Hydrogenation of 12 with 10% Pd/
C in ethyl acetate at atmospheric pressure generated the
amine 13, which could be cyclized to form the lactam 14.
Decarboxylation of 14 provided 15, which was alkylated
on the nitrogen with either iodomethane or iodoethane
to provide compounds 1632 and 17, respectively.
Results and Discussion
Table 1 shows the binding data for the target com-
pounds at D2, D4, and a1 receptors. Anities at D2 and
D4 receptors were determined via standard competitive
displacement assays using human D2 and D4 clones with
[3H]YM 09151 as the competitive ligands. Anity at the
a1 receptor was determined via standard competitive
displacement assays using rat brain homogenate with
[3H]prazosin as the competitive ligand.
In order to better understand the structure±activity
relationships of the lactam system, 3-indolin-2-one
derivatives (g-lactams) and 3-piperazinyl-3H,4H,5H-
Surprisingly, all ®ve- and seven-member ring lactams
are inactive to both D2 and D4 binding. Only the six-

H. Zhao et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2119±2122
2121
to the secondary lactam 15. The anity data of 16 for
dopamine receptors are very close to those of clozapine.
The N-ethyl compound 17 is 6-fold more potent than
compound 16 for D2 but equal for D4. As above, the
current d-lactams 16 and 17 have more potent D2 and
D4 anity binding and better a1 pro®le than clozapine 5
and another two series (6 and 7), which we identi®ed
earlier.
Compounds were also assessed as to their functional
activity both at the D2 and D4 receptors. D2 functional
activity was assessed via compound reversal of quinpir-
ole inhibited, forskolin stimulated cAMP production
from whole cells, while D4 functional activity was asses-
sed via inhibition of quinpirole stimulated GTPg35S
binding from cell membranes. Functional assessment of
compounds 16 and 17 at both the D2 and D4 receptors
indicates no agonist properties up to 10 mM, while
demonstrating functional Ki values of 4 nm and 1.5 nm,
respectively, at the D2 receptor, and 1 nm and 1.5 nm at
the D4 receptor.
In conclusion, the d-lactams 16 and 17 thus displayed a
D2 and D4 anity ratio similar to that of clozapine
while being free of the liabilities caused by high a1 a-
nity. Further structure±activity relationship investiga-
tions of this series of mixed dopamine D2/D4 receptor
antagonists are in progress.
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Scheme 2. Reagents and conditions: (i) K2CO3, CH3CN, re¯ux, 15 h,
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7.03±6.98 (m, 1H), 6.75±6.73 (m, 1H), 4.02 (s, 2H), 3.57 (t,
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7.32±7.13 (m, 8H), 3.45 (s, 2H), 3.35 (s, 3H), 3.04±2.98 (m, 1H),
2.71±2.59 (m, 4H), 2.47 (m, 2H), 2.30±2.16 (m, 2H), 1.75±1.64
(m, 2H), 1.53±1.43 (m, 2H); LC-MS (APCI, m/z) 384 (M+1).
35. Prepared from 1H,3H,4H,5H-benzo[ f ]azepin-2-one by
treatment with TMEDA (3 equiv) and iodotrimethyl silane (3
equiv) in anhydrous dichloromethane at 0 ꢀC under argon for
30 min, and subsequent treatment with solid iodine (1.5 equiv)
at the same temperature for an additional 1 h. The reaction
was quenched by addition of excess aqueous sodium sul®te
and worked up as usual. The residue was puri®ed by silica gel
column chromatography to give the product as a white solid in
84% yield.
36. Mp 145 ꢀC (2 HCl, dec.); H NMR (400 MHz, CDCl3) d
1
7.30±7.19 (m, 6H), 7.08±7.03 (m, 1H), 6.81 (d, J=8.1 Hz, 1H),
3.42 (s, 2H), 3.18 (s, 3H), 2.67±2.63 (m, 4H), 2.41 (m, 4H), 1.49
(s, 3H); LC-MS (APCI, m/z) 370 (M+1).