1-(Arylsulfonyl)-2,3-dihydro-1H-quinolin-4-one derivatives as 5-HT 6 serotonin receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2010.12.007

Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with high binding affinities for 5-HT₆ receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)- 2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT₆ (IC₅₀ = 8 nM) receptor with good selectivity over other serotonin and dopamine receptors.

Full text of DOI:10.1016/j.bmcl.2010.12.007

Bioorganic & Medicinal Chemistry Letters 21 (2011) 698–703
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1-(Arylsulfonyl)-2,3-dihydro-1H-quinolin-4-one derivatives as 5-HT6
serotonin receptor ligands
Chul Min Park a, , Jin Il Choi b, Jung Hwan Choi a, So Young Kim a, Woo Kyu Park c, Churl Min Seong a
⇑
a Medicinal Chemistry Research Center, Bio-Organic Division, Korea Research Institute of Chemical Technology, Sinseongno 19, Yuseong-gu, Daejeon 305-600, South Korea
b Energy Materials Research Center, Advanced Materials Division, Korea Research Institute of Chemical Technology, Sinseongno 19, Yuseong-gu, Daejeon 305-600, South Korea
c Pharmacology Research Center, Bio-Organic Division, Korea Research Institute of Chemical Technology, Sinseongno 19, Yuseong-gu, Daejeon 305-600, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with
high binding affinities for 5-HT6 receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naph-
thalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT6
(IC50 = 8 nM) receptor with good selectivity over other serotonin and dopamine receptors.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 October 2010
Revised 25 November 2010
Accepted 1 December 2010
Available online 8 December 2010
Keywords:
5-HT6 receptor
Antagonist
Memory dysfunction
Brain penetrant
The 5-HT6 receptor, one of the most recently identified seroto-
nin receptors, consists of 440 amino acids with seven transmem-
brane domains and is positively coupled to the adenylate cyclase
secondary messenger system.1 It is almost exclusively expressed
within the brain and located in areas important for memory forma-
tion and habituation.2 Binding studies have disclosed that certain
tricyclic antipsychotic drugs and antidepressants have significant
affinities for 5-HT6 receptor.3 Initial in vivo experiments showed
that administration of antisense oligonucleotides (AOs), directed
at 5-HT6 receptor mRNA, elicited a behavioral syndrome in rats
consisting of yawning, stretching, and chewing, which could be
dose dependently blocked by the muscarinic antagonist atro-
pine.4,5 This study implies that 5-HT6 receptors modulate choliner-
gic neurotransmission and hence 5-HT6 receptor antagonists may
be useful for the treatment of memory dysfunction.
has a tryptamine derivative. Compounds 1a (Ro 04-6790) and 1b
(Ro 63-0563) have only moderate potency at the rat 5-HT6 receptor
and were found to be poorly brain penetrant. Compound 2a (SB-
271046), a potentand selective 5-HT6 receptorantagonistwhich later
entered into clinical trials, has excellent bioavailability, but its brain
penetration is a little low (B/P = 0.1). As a trial to improve brain pen-
etration, Roche researchers afforded 4,9,12 lacking the sulfonamide
NHhydrogen bond donorsof 1a–2b. Wealsopostulated that aninser-
tion of an additional ring system to piperazinyl aromatic ring of 2a
would increase rigidity and lipophilicity to enhance its brain penetra-
tion, and found thatquinolin-4-one moiety showed the improvement
of the brain penetration (Fig. 2). This paper describes the synthesis
and structure–activity relationship of piperazinyl derivatives of
1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-one derivatives for
5-HT6 receptor antagonists.
As the result of recent researches, several selective 5-HT6 receptor
antagonists have been reported including RO-04-6790 (1a, pKi = 7.3),
RO-63-0563 (1b, pKi = 7.8),6 SB-271046 (2a, pKi = 8.9), 2b (pKi = 9.2),7
MS-245(3, pKi = 8.6),8 and RO-65-7674(4, pKi = 8.6)9 asshown inFig-
ure 1. According to the published pharmacophore models,10,11 four
common features were identified: two hydrophobic aromatic scaf-
folds, double electron acceptor functional group (commonly a sulfon-
amide), and basic side chain (protonated at physiological pH).
Compounds 1a–2b possess a sulfonamide moiety, and compound 3
Scheme1 outlinessyntheticroutes toward2,3-dihydro-1H-quin-
olin-4-one derivatives substituted at 5- or 7-position with pipera-
zine analogues. 3-Phenylamino-propionic acid analogues 5 were
required using three different methods. First, coupling with methyl
acrylate, followed by hydrolysis of the resulting ester, produced the
intermediate 5 (Method A). Second, direct coupling with acrylic acid
under refluxcondition was used (Method B). Third, reductiveamina-
tion with methyl acetoacetates using NaBH3CN in MeOH, followed
by hydrolysis, afforded propionic acid analogues 5 (Method C).
Treatment of 5 with polyphosphoric acid provided quinolin-4-one
6, which was substituted with piperazine derivatives to afford
(piperazin-1-yl)-quinolin-4-one 7. Sulfonamide substituted quino-
⇑
Corresponding author.
E-mail address: parkcm@krict.re.kr (C.M. Park).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.007

C. M. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 698–703
699
NH2
Cl
H
H
Me
N
N
R
Me
S
N
H
O O
N
X
N
N
S
S
O O
HN
Me
MeO
2a, R = H, SB-271046 (pKi = 8.9; B/P = 0.10)
2b, R = Me, (pKi = 9.2; B/P = 0.18)
1a, X = N, RO-04-6790 (pKi = 7.3)
1b, X = CH, RO-63-0563 (pKi = 7.8)
Me
H
N
Me
N
N
MeO
Me
S
N
N
N
O
S
N
O
O
S
O
3, MS-245
4, RO-65-7674
(pKi = 8.6)
(pKi = 8.6; B/P = 0.10)
Figure 1. Structures of 5-HT6 receptor antagonists.
H
N
MeO
N
MeO
N
N
S
O
HN
S
N
S
O
O
S
Cl
O
Me
Cl
2a, SB-271046
Me
rigidify
Hydrophobic
Basic side
chain
site
O
R2
N
N
N
S
O
R1
Ar
O
Hydrophobic
site
Double
acceptor
Figure 2. Design of 2,3-dihydro-1H-quinolin-4-one derivatives as a 5-HT6 ligand.
lin-4-one 8 was provided by sulfonylation of 7 with arylsulfonyl
chloride in pyridine.
of 10 could then be done with 2-naphthalenesulfonyl chloride to af-
ford sulfonamide substituted quinolin-4-one 8a.
The synthetic approach to 2,3-dihydro-1H-quinolin-4-one deriv-
atives substituted at 6-position with N-methylpiperazine is de-
scribed in Scheme 2. 4-(N-Methyl-piperazin-1-yl)-phenylamine 9
was synthesized from 1-bromo-4-nitrobenzene by reacting with ex-
cess N-methylpiperazine at 80 °C, followed by reduction of the nitro
functionality with catalytic hydrogenation. Phenylamine 9 was cou-
pled with ethyl acrylate in the presence of acetic acid, hydrolyzed
with NaOH in MeOH, and then cyclized to afford quinolin-4-one 10
by treatment with polyphosphoric acid at 120 °C. Functionalization
The affinities of the compounds for the 5-HT6 receptor were
measured by means of radioligand binding studies conducted with
a human recombinant 5-HT6 receptor, expressed by HEK293 cell
line using [3H]-lysergic acid diethylamide (LSD) as radioligand.13
Thebindingaffinities of thesynthesized compoundsare shown in
Table 1. Initially, the effects of N-methylpiperazin-1-yl groups
substituted at position 5, 6, or 7 of 1-(2-naphthalenesulfonyl)-2,
3-dihydro-1H-quinoline-4-one (8a–c) were investigated. Gratify-
ingly, quinolone nucleus 8b and 8c substituted at 5-or 7-position

700
C. M. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 698–703
COOMe
(a), (b)
R1
R1
O
(Method A)
O
X
Y
X
X
Y
COOH
COOH
R1
(c)
(e)
+
N
H
R1
(Method B)
NH2
N
Y
H
COOMe
R1
5
6
(d), (b)
(Method C)
R2
R2
N
N
O
O
N
N
N
X = F, Cl, Br
(f) or (g)
(h)
Y = Cl, Br, OMe
N
H
R1
R1
Y
Y
O
S
O
Ar
7
8
Scheme 1. Reagents and conditions: (a) R1CH@CHCOOMe, AcOH, 80 °C; (b) NaOH, MeOH, rt; (c) R1CH@CHCOOH, 110 °C; (d) R1C(@O)CH2COOMe, NaBH3CN, MeOH, rt;
(e) polyphosphoric acid, 120 °C; (f) N-methylpiperazine, 80 °C; (g) piperazine or N-methylpiperazine, CH3CN, 80 °C; (h) ArSO2Cl, pyridine, rt.
Me
Me
N
O
N
Br
N
N
(a), (b)
(c), (d), (e)
NO2
N
H
NH2
9
10
Me
N
O
N
(f)
N
S
O
O
8a
Scheme 2. Reagents and conditions: (a) N-methylpiperazine, 80 °C; (b) H2, Pd/C, EtOH, rt; (c) ethyl acrylate, AcOH, reflux; (d) NaOH, MeOH, rt; (e) polyphosphoric acid,
120 °C; (f) 2-naphthalenesulfonyl chloride, pyridine, rt.
Table 1
5-HT6 receptor binding properties of 2,3-dihydro-l/f-quinolin-4-one derivativesa
R5
O
R6
R7
N
S
R2
O
Ar
O
8a n
R2
R5
R6
R7
IC50 (nM)
b
Compound
Ar
8a
8b
8c
8d
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
H
H
H
Me
H
H
MeN(CH2CH2)2N–
H
311
26
61
H
H
H
MeN(CH2CH2)2N–
H
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
H
28

C. M. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 698–703
701
Table 1 (continued)
b
Compound
8e
Ar
R2
H
R5
H
R6
R7
IC50 (nM)
165
2-Naphthyl
OMe
MeN(CH2CH2)2N–
Me
Cl
8f
H
H
H
MeN(CH2CH2)2N–
419
S
8g
8h
8i
8j
8k
8l
2-Naphthyl
2-Naphthy
2-Naphthy
2-Naphthy
4-Me-Ph
2-Naphthy
2-Naphthy
2-Naphthy
Me
Et
Me
Me
H
H
H
Me
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
MeN(CH2CH2)2N–
HN(CH2CH2)2N–
H
H
C
H
H
H
H
H
H
H
H
C
H
C
8
9
15
11
129
47
58
42
8m
8n
Br
H
a
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors expressed in HEK293 cell line.
All values are means of three separate competition experiments.
b
gave moderate binding affinities (IC50 = 26 nM and 61 nM, respec-
showed similar binding affinity to 8b. Introduction of OMe substi-
tute on C6 position in compound 8e (IC50 = 165 nM) or substitution
of 3-methyl-2-benzothiophenesulfonyl group in compound 8f
(IC50 = 419 nM) reduced binding affinities.
Next, the effects of substituents of 5-(N-methylpiperazin-1-yl)-
substituted quinolone series 8c were also observed. Replacement
tively) for 5-HT6 receptor, which provided consistent results to sup-
port our rational design of potent 5-HT6 receptor ligands. Further
optimizations of 8b were carried out by substitution at various posi-
tions. Compound 8d (IC50 = 28 nM) containing methyl group at C2
position of 7-(N-methylpiperazin-1-yl)-substituted quinolone 8b
O
Me
Ph
H
N
N
N
H
O
O
F
O
Me
Ph
F
H
N
S
Me
13a, 5-F
13b, 7-F
N
H
Me
Me
N
O
O
N
N
H
O
6a, 5-F
6b, 7-F
F
(a)
(b)
N
H
Me
+
+
O
Me
Ph
O
H
N
H
12a, 5-F
12b, 7-F
N
N
N
H
H2N
N
Ph
H
O
O
F
11
14a, 5-F
14b, 7-F
N
S
Me
O
O
O
O
(c)
(d)
Me
N
N
F
13a, b
N
S
Me
N
S
Me
O
O
O
O
15a-(
R
), 5-F
8g-(
R
), 5-substituted
), 7-substituted
15b-(
R
), 7-F
8d-(
R
O
O
(c)
(d)
F
14a, b
Me
N
N
N
S
N
S
Me
Me
O
O
O
O
16a-(
S
), 5-F
8g-(
S
), 5-substituted
), 7-substituted
16b-(
S
), 7-F
8d-(
S
Scheme 3. Reagents and conditions: (a) p-TsOH, cyclohexane, Dean–Stark, reflux; (b) 2-naphthalenesulfonyl chloride, pyridine, 80 °C; chromatographic separation; (c) 25%
H2SO4, EtOH, rt; (d) N-methylpipeazine, CH3CN, reflux.

702
C. M. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 698–703
Figure 3. ORTEP representation of 13a.
Table 2
8g with piperazin-1-yl group decreased affinity (i.e., 8n; IC50
42 nM).
=
5-HT6 receptor binding properties of stereoisomers of 8d
and 8ga
To elucidate the optimal configuration in binding for 5-HT6
-phenyl-
b
Compound
IC50 (nM)
receptor, chiral separation method using (S)-(À)-5-(
a
ethyl)-semioxamazide 11 was employed as shown in Scheme
8d
28
43
17
8
8d-(R)
8d-(S)
8g
3.14–16 Fluoro-2-methyl-quinolin-4-ones (6a and 6b) were con-
densed under Dean–Stark condition with (S)-(À)-5-(
a-phenyl-
ethyl)-semioxamazide 11 to afford semioxamazones 12a and 12b,
which were sulfonylated with 2-naphthylsulfonyl chloride in pyri-
dine to give sulfonamide-substituted quinolin-4-ones (13a and
14a) and (13b and 14b). Diastereomeric mixture (13a and 14a)
was separated by column chromatography to provide 13a and 14a,
which were hydrolyzed to afford optically pure enantiomer 15a-
(R) and 16a-(S), respectively. The absolute configuration of 13a
was determined by X-ray analysis as shown in Figure 3. In the same
way, chiral resolution of mixture (13b and 14b) was also carried out.
(S)-Isomer 8d-(S) (IC50 = 17 nM) showed higher binding affinity
than (R)-isomer 8d-(R) (IC50 = 43 nM) and its racemate 8d
(IC50 = 28 nM). (S)-Isomer of 8g also showed higher binding affinity,
which implies that (S)-configuration on C2 in the quinolin-4-onenu-
cleus is preferable in binding for 5-HT6 receptor as shown in Table 2.
8g-(R)
8g-(S)
353
7
Displacement of [3H]-LSD binding to cloned human
5-HT6 receptors expressed in HEK293 cell line.
All values are means of three separate competition
experiments.
a
b
of 2-naphthalenesulfonyl group with p-toluenesulfonyl group (8k)
gave lower binding affinity (IC50 = 129 nM). Substitution of aro-
matic ring of quinolone core by chlorine or bromine in 7-position
(8l and 8m) had little effect (IC50 = 47 and 58 nM). Alkyl substitu-
tion at 2- positions (i.e., 8g–j; IC50 = 8–15 nM) gave higher binding
affinity than 8c. Replacement of N-methylpiperazin-1-yl group of
Table 3
Binding affinity at serotonin (5-HT1A–5-HT7) and dopamine (D2–D4) receptor subtypesa
b
Compound
IC50 (nM)
5-HT6
5-HT1A
5-HT2A
5-HT2C
5-HT7
143
620
>10,000
2007
D2
D3
D4
8b
8c
8d
8g
8h
8j
26
61
28
8
9
11
672
333
1598
1210
999
366
760
1462
48
455
704
5187
438
558
30
4
19
>10,000
>10,000
136
>10,000
>1000
1784
1300
2922
1520
482
623
180
3613
1789
>10,000
5522
>10,000
>10,000
>10,000
>10,000
1226
a
Receptors were all cloned human receptors expressed in CHO, HEK293, or SF9 cells, and [3H] radioligands were as follows: 8-OH-DPAT (5-HT1A), ketanserin (5-HT2A),
mesulergine (5-HT2C), LSD (5-HT6 and 5-HT7), and spiperone (D2–D4).
b
All values are means of two or three separate competition experiments.

C. M. Park et al. / Bioorg. Med. Chem. Lett. 21 (2011) 698–703
703
The functional efficacy of compound 8b was evaluated by mea-
References and notes
suring 5-HT-stimulated cAMP accumulation using HeLa cell line
expressing the cloned human 5-HT6 receptor.17 Compound 8b
significantly inhibited 5-HT-stimulated cAMP accumulation
(IC50 = 188 nM), indicating that compound 8b is a potent 5-HT6
receptor antagonist.
Pharmacokinetic studies demonstrated that 8d and 8g were
more brain penetrant (B/P = 0.41 and 0.50, respectively) than 2b
(B/P = 0.18). This improvement may be due to the reduction of
the number of H-donors of 8d and 8g, and also due to the higher
lipophilicity of 8d (log D = 3.2; polar surface area (PSA) = 69.3)
and 8g (log D = 3.6; PSA = 69.3) than 2b (log D = 2.99;
PSA = 100.6).18
Compounds 8b–d, 8g, 8h, and 8j were examined further for
binding affinity toward several serotonergic and dopaminergic
receptors (Table 3). All compounds displayed higher affinity for
the serotonin 5-HT6 receptor than for the serotonin 5-HT1A or
dopamine (D2–D4) receptors. Compound 8g produced moderate
binding affinity for the 5-HT2A and 5-HT2C receptors showing 48
and 30 nM of IC50 values, respectively. Meanwhile, compounds
8h and 8j expressed potent binding affinities for the 5-HT2C
receptor, with a severe decrease of the affinity for the 5-HT2A
receptor.
In conclusion, we report the synthesis and biological profiles of
a series of piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-
1H-quinolin-4-ones. Compounds 8d and 8g showed improved
brain penetration, which indicated quinolone core is a suitable
scaffold for the further development for serotonin 5-HT6 receptor
ligands. Compounds 8h and 8j showed high binding affinity
toward both 5-HT6 and 5-HT2C receptors and good selectivity over
other related serotonergic and dopaminergic receptor subtypes.
Additional SAR and pharmacological investigation of such com-
pounds are now in progress.
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15. Data for 13a: 1H NMR (200 MHz, CDCl3) d 1.18 (d, J = 6.9 Hz, 3H, NHCHCH3),
1.58 (d, J = 6.9 Hz, 3H, PhCHCH3), 2.21–2.43 (m, 2H, CH2), 4.81 (m, 1H, NCH),
4.99 (m, 1H, PhCH), 7.07 (m, 1H, ArH), 7.26–7.62 (m, 11H, ArH), 7.83–7.92 (m,
3H, ArH + NH), 8.27 (d, J = 2.0 Hz, 1H, ArH), 9.45 (br s, 1H, NNH); mp 183–
186 °C; MS (EI) m/e 410 (M+À148), 191, 127, 105; Crystallographic data
(excluding structure factors) for the structure in this paper have been
deposited with Cambridge Crystallographic Data Center (CCDC) as
supplementary publication numbers CCDC 796561.
16. Data for 8g-(R): 1H NMR (200 MHz, CDCl3) d 1.29 (d, J = 6.9 Hz, 3H, CH3), 2.17
(dd, J = 17.7 Hz, 1.6 Hz, 1H, COCHH), 2.31 (s, 3H, NCH3), 2.40–2.57 (m, 5H,
COCHH and 2NCH2), 2.93 (m, 4H, 2NCH2), 4.87 (m, 1H, CH), 6.94 (dd, J = 7.7 Hz,
1.8 Hz, 1H, ArH), 7.38–7.66 (m, 5H, ArH), 7.81–7.85 (m, 3H, ArH), 8.18 (d,
J = 1.6 Hz, 1H, ArH); mp 65–70 °C; MS (EI) m/e 449 (M+), 434, 405; HRMS m/e
calcd for C25H27N3O3S 449.1773; found 449.1771.
Supplementary data
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D. N. Br. J. Pharmacol. 2000, 130, 1606.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.007.
18. Pardridge, W. M. Adv. Drug Delivery Rev. 1995, 15, 5.