8-Substituted 3,4-dihydroquinolinones as a novel scaffold for atypical antipsychotic activity

Article abstract of DOI:10.1016/j.bmcl.2005.06.097

Several new, potent dopamine subtype 2 (DA D₂) active compounds with serotonin subtype 2A (5-HT_2A) pharmacology are presented. 8-Substituted 3,4-dihydroquinolinones, tetrahydroquinolines, and N-acyl tetrahydroquinolines were evaluated in primary assays. Subtle changes on this novel scaffold translated to large changes in potency and selectivity in vitro. These compounds show promise as novel atypical antipsychotics for the treatment of schizophrenia.

Full text of DOI:10.1016/j.bmcl.2005.06.097

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4560–4563
8-Substituted 3,4-dihydroquinolinones as a novel scaffold
for atypical antipsychotic activity
Jamie M. Singer,* Bridget M. Barr, Linda L. Coughenour,
Tracy F. Gregory and Michael A. Walters
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 31 May 2005; revised 22 June 2005; accepted 29 June 2005
Available online 8 August 2005
Abstract—Several new, potent dopamine subtype 2 (DA D2) active compounds with serotonin subtype 2A (5-HT2A) pharmacology
are presented. 8-Substituted 3,4-dihydroquinolinones, tetrahydroquinolines, and N-acyl tetrahydroquinolines were evaluated in pri-
mary assays. Subtle changes on this novel scaffold translated to large changes in potency and selectivity in vitro. These compounds
show promise as novel atypical antipsychotics for the treatment of schizophrenia.
Ó 2005 Elsevier Ltd. All rights reserved.
Nearly 24 million people worldwide are afflicted with
schizophrenia, a chronic debilitating mental disorder.1
It is thought that excess dopamine in the brain underlies
the positive symptoms of schizophrenia and that block-
ade of dopamine receptors is a prerequisite for antipsy-
chotic activity. There is a clearly established relationship
between the dose that is adequate to treat positive symp-
toms and the drugÕs affinity for the DA D2 receptor.2
Older standards of treatment such as haloperidol, a
non-subtype selective dopamine antagonist without sig-
nificant serotonergic pharmacology, have little effect on
negative symptoms and are implicated in the develop-
ment of extra-pyramidal side effects (EPS).3
The newer generation of treatments, referred to as atyp-
ical antipsychotics, incorporate potent activity at seroto-
nin (5-HT) receptors. It is thought that 5-HT2A
antagonism together with relatively weaker dopamine
antagonism are principal features that differentiate the
side-effect profile of atypical antipsychotics, such as clo-
zapine, from the first generation of treatments.4
Although the newer atypical antipsychotics olanzapine,
risperidone, and quetiapine have brought about
improvements in toleration and negative symptomolo-
gy, chronic treatment may lead to unwanted weight
gain, blood dycrasias, and motor dysfunctions, such as
EPS and tardive dyskinesia (TD).5 These side effects
may be linked to drug-dependent affinity for other
receptors.6 The search continues for new atypical anti-
psychotics that are more efficacious and have fewer side
effects than currently available treatments. In this paper,
we describe our recent efforts to discover novel tem-
plates in the area of selective dual 5-HT2A/D2 antago-
nists for potential use as treatments for schizophrenia.
N
N
OH
N
Cl
Cl
O
N
N
H
F
Haloperidol
Clozapine
The compounds prepared in this program include a un-
ique 8-linked 3,4-dihydroquinolinone scaffold (Scheme
1). The chemistry affording aniline 1 was readily scale-
able and amenable to rapid diversification.7 Nitration
of commercially available phenylacetic acids proceeded
smoothly to provide a coupling substrate for benziso-
thiazole and benzisoxazole piperazines.8 The piperazine
was efficiently coupled to the acid using BOP-Cl. Bor-
ane-methyl sulfide complex was utilized to reduce the
amide and treatment with Raney Ni afforded 1. From
F
N
N
N
O
N
O
Risperidone
Keywords: Atypical Antipsychotics; Dopamine; Serotonin.
*
Corresponding author. Tel.: +1 734 622 53 94; fax: +1 73 46 223
171; e-mail: jamie.singer@pfizer.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.097

J. M. Singer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4560–4563
4561
R4
O2N
O
R4
O
b
a
OH
R4
OH
N
N
50%
87%
X
N
N
O
NO2
N
NH
X
N
H2N
O2N
d
c
N
R4
Cl
R4
N
N
X
66%
49%
X
N
N
1
O
e
97%
e
R3
43%
Cl
O
R2'
R2
R3'
Cl
R3
R3'
Cl
R2'
R2
O
O
HN
HN
or
R4
R4
N
N
N
N
X
X
N
N
f
42%
O
2
3
R2
R2'
R3
R1
N
R3'
R4
N
N
X
N
4a-l
Scheme 1. Reagents: (a) TFAA, NH4NO3, CHCl3; (b) BOP-Cl, Et3N, CH2Cl2; (c) BMS complex, toluene, reflux; (d) Raney Ni, H2, cat. Et3N; (e)
Et3N, THF; (f) AlCl3, chlorobenzene, reflux.
R2'
R3
R2'
R2
R2
R3
O
N
HN
R3'
R3'
R1
g
h
4
R4
R4
N
N
N
N
75%
64%
X
X
N
N
5
6a-k
Scheme 2. Reagents: (g) BH3 THF; (h) R1COCl, Et3N, THF.
this common intermediate, appropriate acid chlorides
were employed to yield 2. Alternatively, chloropropio-
nyl chlorides may be used to afford cyclization sub-
strates (amide 3). Friedel–Crafts cyclization to the
lactam yielded the first targets 4a–l, which were then fur-
ther derivatized via a reduction–acylation procedure
(Scheme 2). In selected cases, borane was again used
to reduce the amide of the 3,4-dihydroquinolinone (5a
and 5b). N-Acyl tetrahydroquinolines were prepared
via acylation of 5 with the appropriate acid chlorides
to furnish compounds 6a–k.
Table 1. 3,4-Dihydroquinolinones
R2
R2'
R3
R3'
O
N
R1
R4
N
N
X
N
4
0
0
Entry
X
R1
R2, R2 R3, R3 R4
D2 Ki 5HT2A
(nM)a Ki (nM)a
4a
4b
4c
4d
4e
4f
S
H
H
H
H
H
H
H
H
>100
21
15
0.28
0.22
0.17
1.06
0.17
0.18
The affinities of target compounds for DA D2 and 5-
HT2A receptors were evaluated in in vitro binding assays
using the radioligands [3H]spiperone or [3H]ketanserin,
respectively.9
S
H
CH3
CH3
H
S
H
6-F
H
S
CH3
H
73
81
S
CH3
H
CH3
H, Ph
CH3
CH3
CH3
CH3
CH3
CH3
H
S
H
H
15
>100
4g
4h
4i
O
S
H
H
H
190
The in vitro results for 4a–l are given in Table 1. Substi-
0
H
H
5-CH3 11
6-F 92
5-CH3 35
0.13
2.23
0.28
0.05
0.28
tutions at R3,R3 are required for potency in DA D2.
While fluoro is tolerated at the 6-position, chloro substi-
tution is not (entries 4c and 4k). Methyl groups at the
5-position seem to enhance affinity in DA D2 (see 4j
vs. 4g). When the lactam nitrogen is substituted with
a methyl group, (4e) a fourfold reduction in DA D2
SO
O
S
H
H
4j
H
H
4k
4l
H
H
6-Cl
6-F
>100
>100
O
H
H
a Values are means of at least three experiments, see Ref. 8.

4562
J. M. Singer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4560–4563
potency takes place. Replacement of benzisothiazole with
benzisoxazole results in compounds with conserved 5-
HT2A affinity, except in the case of 4g, which shows a sig-
nificant reduction of affinity for both receptors. Oxidation
of the benzisothiazole is detrimental both to DA D2 and 5-
HT2A potency. In general, these compounds retain the de-
sired 10-fold ratio of DA D2 to 5-HT2A affinity.
In general, the lactam scaffold is useful for modulating
DA D2 affinity and the N-acyl scaffold reveals robust
5-HT2A potency. This trend can be seen more clearly
in the plot (Fig. 1).
In summary, a series of novel 8-substituted 3,4-dihydro-
quinolinones, tetrahydroquinolines, and N-acyltetrahy-
droquinolines were synthesized and evaluated in vitro
for affinity to DA D2 and 5-HT2A receptors. This flexi-
ble scaffold proves useful for promoting atypical anti-
psychotic activity.10 Additionally, this series of
compounds provides options for the development of
SAR in either DA D2 or 5-HT2A. The optimal separa-
tion of at least 10-fold ratio of DA D2/5-HT2A binding
translates to a lack of EPS in a rat model.11 Although
the SAR for both receptors does not track together,
small changes on this scaffold can have a large impact
in tuning DA D2 or 5-HT2A affinities or both.
To determine whether the lactam carbonyl was essential
for binding, selected compounds were reduced. The
resultant tetrahydroquinolines given in Table 2 retain
5-HT2A potency, but with a threefold decrease in affinity
for the DA D2 receptor when compared to analogs from
Table 1. Owing to this characteristic drop in D2 affinity,
these intermediates were not routinely screened.
Table 3 (compounds 6a–k) shows that the potency is
recovered by introduction of acyl groups on the tetrahy-
droquinoline. Again, 6-chloro substitutions adversely
affect DA D2 affinity for these compounds, as seen in
6h. Although tolerated in DA D2, large acyl groups
(6c, 6d) result in reduced affinity for 5-HT2A. Interest-
ingly, the cyclohexyl group (6e) does not cause this
change. When comparing 6j to 4f from Table 1, it seems
that the large phenyl group at R3 has a deleterious effect
on 5-HT2A potency in the N-acyl series.
100
80
60
40
20
0
4i
4d
Table 2. Tetrahydroquinolines
HN
R4
N
N
4f
6j
X
N
0
0.5
1
1.5
2
5
5HT2A Ki, nM
Entry
X
R4
D2 Ki (nM)a
5HT2A Ki (nM)a
Figure 1. Plot DA D2 vs. 5-HT2A for N-acyl and lactam analogs. Blue
dots represent tetrahydroquinoline analogs from Tables 2 and 3, while
green squares represent 3,4-dihydroquinolinone analogs from Table 1.
Four compounds are shown with their Table reference.
5a
5b
S
S
H
6-F
59
55
0.18
0.28
a Values are means of at least three experiments see Ref. 8.
Table 3. N-Acyl tetrahydroquinolines
R3
O
N
R3'
R1
R4
N
N
X
N
6
0
Entry
X
R1
R3, R3
R4
D2 Ki (nM)a
5HT2A Ki (nM)a
6a
6b
6c
6d
6e
6f
S
S
S
S
S
S
O
S
O
S
S
Phenyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
16
17
11
4
0.61
0.30
1.24
1.07
0.59
0.44
0.32
0.31
0.29
2.15
0.75
H
2,5-Dimethyoxy benzyl
3-Methoxy benzyl
H
H
Cyclohexyl
CH3
CH3
H
25
18
17
>50
29
12
12
6-F
5-CH3
6-Cl
6-F
H
6g
6h
6i
CH3
CH3
6j
6k
CH3
CH3
H, phenyl
CH3
5-CH3
a Values are means of at least three experiments see Ref. 8.

J. M. Singer et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4560–4563
4563
8. Lowe III, J. A.; Nagel, A. A. U.S. Patent 4,831,031, 1988;
Chem. Abstr. 1988, 111, 153842.
Acknowledgments
9. Standard filtration receptor binding techniques were
used to evaluate the affinity of compounds for
recombinant receptors. The DA D2 receptor binding
assay utilized cell membranes prepared from CHO cells
expressing human DA D2 receptors. The 5-HT2A
receptor binding assay utilized cell membranes prepared
from Swiss 3T3 cells expressing human 5-HT2A recep-
tors. Membrane and radioligand were incubated in the
presence, or absence, of varying concentrations of the
compound of interest for 120 min. Nonspecific binding
was determined by addition of high concentrations of
haloperidol or unlabeled ketanserin for the DA D2 or
5-HT2A assays respectively. Unbound radiolabel was
separated from bound radiolabel by vacuum filtration.
The amount of bound radiolabel was determined by
liquid scintillation spectrophotometry. The relationship
between concentration and percent inhibition of specific
binding was fit using nonlinear regression to determine
IC50 concentration. IC50 concentrations were converted
to Ki affinity constants using the Cheng–Prusoff
equation.
The authors acknowledge Susan Borosky, John Cordon,
and Kevin Serpa for generation of in vitro and in vivo
data.
References and notes
1. WHO Fact Sheet Number 265; The World Health Orga-
nization: Geneva, Switzerland, 2001.
2. Seeman, P.; Chau-Wong, M.; Tedesco, J.; Wong, K. Proc.
Natl. Acad. Sci. U.S.A. 1975, 11, 4376.
3. Martin, A. R. In BurgerÕs Medicinal Chemistry and Drug
Discovery, 5th ed.; Wolff, M. E., Ed.; Wiley-Interscience:
New York, 1997; Vol. 5, p 195.
4. Meltzer, H. Y.; Matsubara, S.; Lee, J. J. Pharm. Exp.
Ther. 1989, 251, 238.
5. Cunningham Owens, D. G. Drugs 1996, 51, 895; Wirshing,
D. A.; Wirshing, W. C.; Kysar, L.; Berisford, M.;
Goldstein, D.; Pashdag, M. A.; Mintz, J.; Marder, S. J.
Clin. Psychiatry 1999, 60, 358.
6. Cunningham Owens, D. G. Drugs 1996, 51, 895; Wirshing,
D. A.; Wirshing, W. C.; Kysar, L.; Berisford, M.;
Goldstein, D.; Pashdag, M. A.; Mintz, J.; Marder, S. J.
Clin. Psychiatry 1999, 60, 358; Green, B. Curr. Med. Res.
Opin. 1999, 15, 79.
10. Compounds 4b and 4c were determined to be active in the
d-amphetamine-stimulated locomotor activity (LMA)
in vivo model.
11. None of the compounds tested from this series produced a
minimally effective dose (MED) below 30 mg/kg in an
in vivo catalepsy test.
7. Davis, J. M.; Gregory, T. F.; Walters, M. A. PCT Int.
Appl. WO 2004/029048; Chem. Abstr. 2004, 140, 321381.