Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands

Article abstract of DOI:10.1021/jm049615n

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT₆ receptor ligands. Furthermore, based on a screening appr

Full text of DOI:10.1021/jm049615n

J. Med. Chem. 2005, 48, 1781-1795
1781
Medicinal Chemistry Driven Approaches Toward Novel and Selective Serotonin
5-HT6 Receptor Ligands
Jo¨rg Holenz,*,† Ramon Merce`,† Jose´ Luis D´ıaz,† Xavier Guitart,‡ Xavier Codony,‡ Alberto Dordal,‡
Gonzalo Romero,‡ Antoni Torrens,§ Josep Mas,§ Blas Andaluz,† Susana Herna´ndez,† Xavier Monroy,‡
Elisabeth Sa´nchez,‡ Enrique Herna´ndez,‡ Raquel Pe´rez,‡ Roger Cub´ı,‡ Olga Sanfeliu,§ and Helmut Buschmann
Departments of Medicinal Chemistry, Discovery Biology, and Discovery Chemistry, Laboratorios Dr. Esteve S.A.,
Av. Mare de De´u de Montserrat 221, 08041 Barcelona, Spain
Received May 26, 2004
Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of
indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin
5-HT6 receptor ligands. Furthermore, based on a screening approach of a discovery library, a
series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT6 ligands. Many
of the compounds described in this paper possess excellent affinities, displaying pKi values
greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS
relevant receptors. First, structure-affinity relationships of these ligands are discussed. In
terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists,
were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT6 agonists ever
reported in the literature. These valuable tool compounds should allow for the detailed study
of the role of the 5-HT6 receptor in relevant animal models of disorders such as cognition deficits,
depression, anxiety, or obesity.
Introduction
of the 5-HT6 receptor mRNA in the peripheral nervous
system of rats8a,8c,9 and in other rat organs and tis-
sues.7,10 Interestingly, Hirst et al.8g found that even
though there is a sequence homology between rat and
mouse 5-HT6 receptors, the mouse receptor has a much
lower level of expression as compared to rats or humans,
especially in the basal ganglia. Thus, the pharmacologi-
cal profile of mice is, with respect to the 5-HT6 receptor,
quite different from that of rats and humans. These
results should be kept in mind when analyzing data
obtained with different animal species.
Being positively coupled to adenylyl cyclase,6,7,11
5-HT6 receptor is a member of the G-protein family,
which also includes the 5-HT4 and 5-HT7 receptors. A
constitutive activity of the mouse receptor has been
proposed,12 and due to the high degree of conservation
of the sequence responsible for such activity in the rat
and human receptor, the same constitutive activity is
likely. In fact, a constitutively active mutant of the
human receptor has been created recently.13 The 5-HT6
receptor appears to regulate several neurotransmitter
systems including dopamine, noradrenaline, glutamate,
aspartate, or acetylcholine. This has been demonstrated
by microdialysis,14 in situ hybridization,15 or electro-
physiology.16 Its unique distribution in the brain and
high affinity for therapeutic antipsychotics17 and anti-
depressants4 suggests a possible role of the 5-HT6
receptor in CNS disorders. Along with this, several
studies have been published reporting an association
of 5-HT6 receptor variants with schizophrenia,18 bipolar
affective disorders,19 Parkinson’s disease,20 or Alzhe-
imer’s disease.18b,21 In 1995, the importance of the 5-HT6
receptor in memory and learning was postulated using
antisense oligonucleotides in rats.22 The behavioral
syndrome induced by this treatment suggests that one
function of the receptor could be the control of cholin-
It is estimated that about 90% of actual patent
applications citing CNS diseases claim serotonergic
agents.1 At least 14 distinct serotonin (5-HT) receptor
subclasses are expressed in the mammalian CNS.2
These receptors are assembled into seven main classes
(5-HT1-7)3 5-HT6 being the most recently discovered and
cloned member of the family. Rat4 and mouse5 5-HT6
receptors were described in 1993 and 1994, respectively,
and the human 5-HT6 (h5-HT6) receptor was first
reported in 1996.6 The cloned rat receptor was initially
found to consist of a polypeptide chain of 437 amino
acids with little homology to other 5-HT receptors.7
Afterward, the discovery of an additional guanine base
in the rat sequence led to a corrected sequence compris-
ing 438 amino acids.6 The cloned h5-HT6 receptor
contains 440 amino acids and shares 96% homology with
the rat receptor within the transmembrane region. The
cloned mouse 5-HT6 receptor is a 440 amino acid peptide
with a 97% and 89% identity as compared with the rat
and human receptor, respectively. Expression of the
5-HT6 receptor mRNA and the 5-HT6 receptor localiza-
tion and distribution has been described using several
methods in rat and human.4,7,8 The 5-HT6 receptor has
been mainly localized in olfactory tubercles, striatum,
nucleus accumbens, and hippocampus. Lower levels
have been found in amygdala, hypothalamus, substantia
nigra, cerebellum, or cerebral cortex. No 5-HT6 mRNA
has been detected in several human peripheral tissues,8g
whereas other authors have reported some expression
* To whom correspondence should be addressed. Phone: +34
934466283. Fax: +34 934501611. E-mail: jholenz@esteve.es.
† Department of Medicinal Chemistry.
‡ Department of Discovery Biology.
§ Department of Discovery Chemistry.
Head of Research.
10.1021/jm049615n CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/04/2004

1782 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Holenz et al.
conceptual framework model. These potent ligands of
5-HT6 were investigated in terms of their structure-
affinity relationships (SAFIR), as well as their func-
tionalities.31 Furthermore, as a result of a screening of
Esteve’s discovery library against the cloned h5-HT6
receptor, a series of benzoxazinepiperidinyl sulfonamide
derivatives was identified as selective 5-HT6 agents.32
In the following, these approaches will be discussed in
detail.
Chemistry
Novel series of sulfonamides of indoles with different
substitution patterns were developed as potential 5-HT6
ligands and can be grouped into four classes based on
their common scaffolds: N-aminoalkylindoles, 3-ami-
noalkylindoles, 3-glyoxamidoindoles, and 3-piperidinyl-
indoles. The synthesis of all these series was carried out
starting from the suitable commercial nitroindoles 1-3
(Schemes 1-3). These were reacted with â-chloroalkyl-
amines33 as depicted in Scheme 1 to afford N-ami-
noalkyl-nitroindoles 4-6. Tryptamine-like compounds
were prepared by previously reported procedures34 using
oxalyl chloride35,36 and a secondary amine, followed by
reduction of the glyoxamide intermediates 7a-f with
borane to afford 8a-f (Scheme 2). 3-Tetrahydropiperi-
dinyl-5-nitroindole 9 was synthesized by reaction of
5-nitroindole 2a with N-methyl-4-piperidone37 (Scheme
3). In the next step, all functionalized nitroindole
derivatives obtained before (4-9) were hydrogenated
over palladium to yield the corresponding amines 10,
11a-f and 12a-c (Scheme 1), 13a-f34 and 14a,b
(Scheme 2), and 15 (Scheme 3). These were treated with
the corresponding sulfonyl chloride to afford the final
compounds 16-20. Furthermore, a series of N-(3-
glyoxamidoindolyl)sulfonamide derivatives (21a-e) was
prepared starting from the 5-nitro-3-glyoxamidoindole
intermediates 7a-b (Scheme 2).
1-Piperidin-4-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one
22a was synthesized as shown in Scheme 4 according
to the method described by Bell et al.38 from 2-ami-
nobenzyl alcohol, by reductive amination with N-(tert-
butyloxycarbonyl)-4-piperidone, followed by cyclization
using triphosgene. The cleavage of the protective group
is carried out by treatment with acidic media. 8-Methyl-
1-piperidin-4-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one 22b
was obtained using the same procedure from com-
mercially available 2-amino-3-methylbenzyl alcohol. The
piperidine derivatives were treated with the appropriate
sulfonyl chlorides to afford the final compounds 23a-j.
Figure 1. Selection of 5-HT6 reference ligands.
ergic neurotransmission. Following studies using selec-
tive antagonists of the receptor, an involvement of the
cholinergic system in the role of the 5-HT6 receptor23
can be deduced, leading to the proposal of 5-HT6 as a
therapeutic target for those pathologies where the
cholinergic function is altered, such as Alzheimer’s
disease and other dementias. Since then, great effort
has been done trying to elucidate the role and thera-
peutic possibilities of this receptor in these pathologies.
Controversial results have been obtained with either
positive24 or negative25 conclusions. Much work has been
performed to elucidate the involvement of 5-HT6 recep-
tors in disorders such as anxiety, depression, psychosis,
obesity, or convulsions.26 Nevertheless, the exact (func-
tional) role of the receptor in these indications has yet
to be ascertained. The use of knockout mice for the
receptor27 should help to understand the receptor in
more detail.
Potent and selective ligands with defined functionality
are important tools to further elucidate the functional
role of the 5-HT6 receptor. During the past few years,
the synthesis of a series of novel ligands has been
reported, introducing various new classes of compounds
as potent and selective binders for this serotonin recep-
tor.1 Agents that bind at the h5-HT6 receptor with Ki
values <50 nM include 5-methoxytryptamine, bro-
mocriptine, octoclothepin, and the neuroleptics, cloza-
pine, olanzapine, loxapine, chlorpromazine, and fluphena-
zine.2-Ethyl-5-methoxy-N,N-dimethyltryptamine(EMDT)
represents the first selective 5-HT6 agonist. As selective
antagonists, the benzenesulfonamides Ro 04-6790 and
Ro 63-0563,23a the benzo[b]thiophenesulfonamide SB-
271046,28 and the sulfonylindoles ALX1161, ALX1175,29
and MS-24530 (Figure 1) have been reported among
others.
Results and Discussion
Analysis of the structures of different 5-HT6 reference
ligands (cf. Figure 1) allowed for the construction of a
hypothetical framework model, which is depicted in
Figure 2. In total, four important parts within the
molecules were identified for obtaining good affinities
against the 5-HT6 receptor: these structural require-
ments within the framework comprise two hydrophobic
regions separated by a double electron acceptor func-
tional group (commonly a sulfone amide) and a proton
donor area (represented by an amino group that is
protonated at physiological pH). This model could now
be used to find novel lead structures. Thus, by fitting
To further study the 5-HT6 receptor and its physi-
ological function, different series of indolyl sulfonamides
were prepared based on a medicinal chemistry guided

Novel, Selective Serotonin 5-HT6 Receptor Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1783
Scheme 1a
a (i) Cl(CH2)nNR1R2, NaH, DMF, 80 °C; (ii) H2, Pd/C, EtOH; (iii) R4SO2Cl, pyridine.
Scheme 2a
a (i) Oxalyl chloride, Et2O, phthalimide, rt, 72 h; (ii) NHR1R2, Et2O, rt, 1 h; (iii) BH3-THF, rt, 16 h; (iv) H2, Pd/C, EtOH, rt; (v) R3SO2Cl,
pyridine.
Scheme 3a
a (i) N-Methyl-4-piperidone, NaOMe, MeOH, 48 h, reflux; (ii) H2, Pd/C, EtOH; (iii) R1SO2Cl, pyridine.
different hypothetical structures in this framework, the
likeliness of obtaining good binding affinities could be
estimated.
Based on this approach, in total four novel indole-
based series were selected and their synthesis was de-
veloped, namely, N-aminoalkylindoles (16a-c, 17a-n,

1784 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Holenz et al.
Scheme 4a
a (i) (a) N-Boc-4-piperidone, AcOH, toluene, reflux; (b) NaBH3CN,
AcOH, toluene, THF; (ii) (a) triphosgene, DIEA, THF; (b) HCl,
EtOAc; (iii) ArSO2Cl, DIEA, CH2Cl2.
Figure 3. Stimulation of cyclic AMP accumulation in C6 cells
stably expressing the human 5-HT6 receptor by either 5-HT
alone or 5-HT in the presence of (A) 19e (0.003, 0.03, 0.1m or
0.3 µM) or (B) 23d (0.3, 1, 3, or 10 µM). Panel C shows the
effect of 5-HT and 19g on cyclic AMP accumulation in C6 cells.
All data points represent the means of at least three separate
experiments.
Figure 2. Hypothetical framework model for 5-HT6 ligands.
18a-k), 3-aminoalkylindoles (19a-x), 3-piperidinylin-
doles (20a-f), and 3-glyoxamidoindoles (21a-e). Fur-
thermore, as a result of a screening campaign of Esteve’s
proprietary compound library, a new series of selective
5-HT6 ligands (benzoxazinepiperidinyl sulfonamides
23a-j) has been identified and preliminarily investi-
gated in terms of its structure-affinity relationships.
The binding affinities at the human 5-HT6 receptor
were determined in a filter binding assay using [3H]-
LSD. The activity of the compounds as putative agonists
or antagonists was studied in an in vitro system using
C6 cells overexpressing the receptor. The 5-HT6 receptor
is known to be positively coupled to the adenylyl cyclase
system, so agonists of the receptor would increase in a
significant way the levels of intracellular cyclic AMP
(cAMP). Figure 3 shows two typical examples of con-
centration-response curves to 5-HT in the presence of
different concentrations of compounds 19e and 23d,
which behave as clear antagonists. In addition, the
agonistic activity of compound 19g is displayed. Besides,
compounds displaying agonist properties in some degree
have been found to antagonize the serotonin-induced
cAMP formation, being defined as partial agonists.
Selected compounds with high affinity were profiled in
a commercially available panel of more than 50 radio-
ligand binding assays (MSD, Taiwan). These comprise
the characterization of potential interactions at the
ligand binding site of a wide range of mainly G-protein-
coupled receptors (GPCRs) and ligand-gated ion chan-
nels, plus a limited number of modulatory sites on
voltage-gated ion channels.
The binding and functionality results of selected
compounds are illustrated in Tables 1-5. Within the
N-aminoalkylindole series (Table 1), in total 28 repre-
sentatives have been prepared covering a wide range
of affinities reaching down to the nanomolar level (e.g.,
17a, Ki ) 1.9 nM). In comparison, the reference com-
pounds SB-271046, Ro 04-6790, and Ro 63-0563 have
been reported23a,26b to possess binding affinities (Ki) of

Novel, Selective Serotonin 5-HT6 Receptor Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1785
Table 1. 5-HT6 Binding Affinity and Functionality of N-Aminoalkylindolyl Sulfonamides
a ANT ) antagonist; pAGO ) partial agonist.
0.8, 44.7, and 14.8 nM against h5-HT6, respectively. In
terms of functionalities, the majority of compounds of
this series behave as antagonists, with the exception of
18b, being a partial agonist. SAFIR showed that the
methyl group is the most appropriate alkyl group for
R1 and R2 to obtain highest affinities: 17a (Ki ) 1.9 nM)

1786 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Holenz et al.
Table 2. 5-HT6 Binding Affinity and Functionality of
3-Aminoalkylindolyl Sulfonamides
Table 3. 5-HT6 Binding Affinity and Functionality of
N-(3-Glyoxamidoindolyl) Sulfonamides
a ANT ) antagonist.
Table 4. 5-HT6 Binding Affinity and Functionality of
3-Piperidinylindolyl Sulfonamides
a ANT ) antagonist.
homologue piperidine shows a decrease in affinity (17m,
Ki ) 31.4 nM, vs 17a, Ki ) 1.9 nM). Further homolo-
gation of the alkylamino chain from ethylenamine (17m,
Ki ) 31.4 nM) to propylenamine (17n, Ki > 1000 nM)
results in a loss of affinity. Although alkyl substitution
in position 2 of the indole with a methyl group is
tolerated, a tendency toward lower affinities is dis-
played: 17e (Ki ) 74.6 nM) < 17a (Ki ) 1.9 nM), 17f
(Ki ) 123.6 nM) e 17b (Ki ) 94.2 nM), 17g (Ki ) 85.8
nM) e 17c (Ki ) 57.7 nM), and 18f (Ki > 1000 nM) <
18b (Ki ) 90.2 nM). There is not a general (true for all
sulfonamides) correlation between the sulfonamide
position within the indole moiety and the corresponding
affinity: in naphthyl-substituted systems, for instance,
the affinity ranking is 6- (18c) > 4- (16b) > 5-substitu-
a ANT ) antagonist; AGO ) agonist; pAGO ) partial agonist.
b N-Methylindole derivative.
> 17h (Ki ) 97.3 nM) and 17c (Ki ) 57.7 nM) > 17j (Ki
) 140.5). Interestingly, replacement of the dimethyl-
amino group with pyrrolidine results in only slightly
weaker to similar affinities (cf. 17l, Ki ) 9.8 nM, with
17a, Ki ) 1.9 nM, or 18i, Ki ) 18.6 nM, with 18c, Ki )
19.8 nM), whereas replacement with the six-membered

Novel, Selective Serotonin 5-HT6 Receptor Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1787
Table 5. 5-HT6 Binding Affinity and Functionality of
Benzoxazinepiperidinyl Sulfonamides
decrease the affinity (19n, Ki ) 163.0 nM vs 19i, Ki )
5.3 nM). Especially aromatic sulfonamide substituents
bearing the 5-chloro-3-methylbenzothiazole motif (19c,
19g, 19o) lead to low Ki values. N-Methyl substitution
results in lower affinities (19m, Ki ) 40.8 nM).
Recently, a new series, the N-(3-glyoxamidoindolyl)-
sulfonamides (Table 3), has been prepared to make use
of synthetic opportunities along with the elaborated
chemical pathways (see Scheme 2). Five representatives
have been prepared so far to have a first insight into
the potential of this class. Interestingly, already two
compounds reached remarkable affinities (21b, Ki )
18.4 nM and 21c, Ki ) 224.4 nM) suggesting potential
for further optimization. Both compounds behave as
antagonists. As within the series described before, it
seems that the NMe2 substitution pattern and the
6-chloroimidazothiazol-5-sulfonamide are favorable for
good binding in this class as well. On the other side,
21b reaches a slightly weaker affinity as compared to
its “alkyl chain” analogue 19b (cf. Table 2).
Within the 3-piperidinylindoles series (Table 4), six
representatives have been synthesized, nearly all of
them displaying excellent affinities reaching into the
nanomolar range. The 5-sulfonamido-3-methyl-5-chlo-
robenzothiazole substituted compound 20a has a Ki
value of 1 nM. Other substitutions, for example, 5-chlo-
rothiophene (20d, Ki ) 24.3 nM) or 8-quinolyl (20e, Ki
) 21.2 nM), lead to slightly reduced affinities. Five
compounds have been proven to display antagonistic
properties. Formally, these compounds can be regarded
as cyclic analogues of 5-sulfonamido-3-aminoalkylin-
doles with n ) 3 (cf. Table 3). Even though only one
representative of the latter class has been prepared
(19n, Ki ) 163.0 nM), it can be concluded, that the cyclic
orientation of the proton donor group (i.e., the amino
function) has a beneficial influence on binding as
compared to the rotationally not hindered propyl group
in 19n.
As a result of a screening performed with a series
of more than 700 compounds containing a benz-
oxazinepiperidinyl sulfonamide scaffold, belonging to a
more general discovery library, several compounds
(depicted in Table 5) showed affinities for the 5-HT6
receptor with a high degree of selectivity. Among a large
number of aromatic group substituents at R2, 3-ben-
zothienyl (23a,b), 5-chloro-3-methyl-2-benzothienyl (23c),
1-naphthyl (23d,e), 8-quinolyl (23g,h), and 2,5-dimeth-
oxyphenyl (23j) displayed the best affinities (e.g., 23d
Ki ) 51.7 nM). Substitution on the phenyl ring of the
benzoxazinone moiety with a methyl group seems not
to affect affinity in a significant manner. Thus, methyl
substitution at R1 led to similar results for compounds
23a vs 23b and 23g vs 23h. A bigger difference was
observed for compound 23d (Ki ) 51.7 nM) vs 23e (Ki
) 246.2 nM). In terms of functionality, antagonist
behavior was observed within all tested compounds.
This series is currently undergoing a further lead
optimization phase.
a ANT ) antagonist.
tion (17b) for a 1-naphthyl substitution, whereas it is
4- (16c) > 6- (18d) > 5-substitution (17c) for 2-naphthyl
sulfonamides. There is a tendency toward higher affini-
ties achieved with 5-substitution pattern (5-sulfon-
amides) even though more representatives of the 4-sul-
fonamides need to be prepared to prove this trend. In
agreement to that, the 6-chloroimidazothiazol-5-sul-
fonamides 17a and 17l are the highest-affinity com-
pounds of the whole N-aminoalkylindole series. Alkyl-
aryl sulfonamides (18e or 18k) seem to possess less
pronounced binding affinity within this series.
Representatives of the 5-sulfonamidotryptamine se-
ries (Table 2) display the highest affinities of all series
described within this paper, reaching below the nano-
molar range (e.g., 19c 0.1 nM), thus being superior to
most compounds known in the literature. In terms of
functionality, this series comprises antagonists as well
as agonists and partial agonists. Affinities (Ki) under
0.5 nM were obtained by compounds 19c, 19e, 19f, 19g,
and 19o. Again, the NMe2 group has a beneficial
influence on affinity with longer alkyl substituents
having slightly decreased affinities (e.g., 19d vs 19h,
19q), but the introduction of heterocylic moieties such
as morpholine (19v, Ki ) 163.5 nM vs 19d, Ki ) 0.8 nM)
or pyrrolidine (19r, Ki ) 4.0 nM vs 19g, Ki ) 0.3 nM)
reduces the affinity significantly. The ideal length for
the alkyl chain that connects the indole moiety with the
NR1R2 group seems again to be two carbon atoms. The
gramine pattern (n ) 1) reduces the affinity (19a, Ki )
5.3 nM vs 19c, Ki ) 0.1 nM), and longer chains (n ) 3)
Conclusions
New series of 5-HT6 receptor ligands with high
affinity and selectivity have been synthesized. The
affinities for the 5-HT6 receptor are comparable or in
some cases even superior to 5-HT6 ligands reported in

1788 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Holenz et al.
3.14 (m, 4H), 3.43 (m, 2H), 4.78 (t, 2H, J ) 7.3 Hz), 6.80 (d,
1H, J ) 3.2 Hz), 7.78 (d, 1H, J ) 3.2 Hz), 7.89 (d, 1H, J ) 9.1
Hz), 8.06 (dd, 1H, J ) 9.1, 2.3 Hz), 8.58 (d, 1H, J ) 2.3 Hz),
11.1 (br s, 1H).
the literature. In terms of functionality, high-affinity
antagonists, as well as agonists and even partial ago-
nists, were prepared and could function as potent and
selective tool compounds to further elucidate the role
of the 5-HT6 receptor in many possible indications, for
example, cognition enhancement, depression, anxiety,
or obesity. Compound 19e (Ki ) 0.2 nM) represents an
excellent tool compound for in vivo studies of 5-HT6
antagonist properties, whereas 19c (Ki ) 0.1 nM) and
19g (Ki ) 0.3 nM) represent the highest-affinity 5-HT6
agonists ever reported in the literature to our knowl-
edge. Having these valuable tools in hands, we are
currently performing in vivo studies to elucidate the role
of the 5-HT6 receptor in the above-mentioned therapeu-
tic indications. In addition, to further optimize and to
understand the structure-affinity relationships within
the different lead scaffolds in more detail as well as to
confirm the trends described above, more representa-
tives of the different classes are currently being syn-
thesized.
Compounds 4, 5a-f, and 6a-c were prepared analogously.
To a solution of 5c (4.15 g, 13.95 mmol) in EtOH/H2O (2:1),
1 g (5%) of Pd/C moistened with water (50%) was added. The
mixture was hydrogenated under 20 psi at room temperature
for 20 h and filtered through a pad of Celite. The EtOH was
evaporated, and the aqueous solution was treated with 20%
aqueous NaOH. After extraction with CHCl3, the organic phase
was dried with Na2SO4 and evaporated to afford a brown
colored oil. This oil was dissolved in EtOH (10 mL), cooled to
0 °C, and treated with a solution of 4.2 N HCl in EtOH (10
mL). The violet colored amorphous solid obtained was filtered
off, washed with precooled EtOH, and dried at 60 °C to afford
1
2.71 g (64%) of 11c. Mp 245-246 °C. H NMR (DMSO-d6) δ
1.17 (t, 6H, J ) 7.2 Hz), 3.13 (q, 4H, J ) 7.2 Hz), 3.41 (m,
2H), 4.67 (t, 2H, J ) 7.0 Hz), 6.59 (d, 1H, J ) 3.1 Hz), 7.16
(dd, 1H, J ) 8.8, 2.0 Hz), 7.58 (d, 1H, J ) 2.0 Hz), 7.60 (d, 1H,
J ) 3.1 Hz), 7.76 (d, 1H, J ) 8.8 Hz).
Compounds 10, 11a-f, and 12a-c were prepared analo-
gously.
General Procedure for the Preparation of (5-Amino-
1H-indol-3-yl)-2-oxoacetamides (14). 2-(5-Amino-1H-in-
dol-3-yl)-N,N-diethyl-2-oxoacetamide Hydrochloride (14b).
To a solution of 2-(5-Nitro-1H-indol-3-yl)-N,N-diethyl-2-oxo-
acetamide (7b)34 (4.0 g, 13.8 mmol) in DMF (100 mL), 800 mg
(5%) of Pd/C moistened with water (50%) were added. The
mixture was hydrogenated under 20 psi at room temperature
for 20 h. The resulting mixture was filtered through a pad of
Celite. The solvent was evaporated to afford an oil that was
dissolved in EtOH (25 mL), cooled to 0 °C, and treated with a
solution of 5 N HCl in EtOH (3 mL). The suspension was
filtered, and the yellow colored amorphous solid obtained was
washed with precooled Et2O and dried at 60 °C to afford 3.9 g
(98%) of 14b. Mp 210-213 °C. 1H NMR (DMSO-d6) δ 1.05 (m,
3H), 1.16 (m, 3H), 3.22 (m, 2H), 3.41 (m, 2H), 7.26 (dd, 1H, J
) 8.6, 1.9 Hz), 7.62 (d, 1H, J ) 8.6 Hz), 8.11 (d, 1H, J ) 1.9
Hz), 8.15 (d, 1H, J ) 3.3 Hz), 10.18 (br s, 2H), 12.57 (s, 1H).
Compound 14a was prepared analogously.
Preparation of 5-Amino-3-(1-methylpiperidin-4-yl)-1H-
indole (15). To a solution of 5-nitro-3-(1,2,3,6-tetrahydro-1-
methyl-4-pyridinyl)-1H-indole39 (9) (11.3 g, 44 mmol) in DMF
(500 mL), 4 g (5%) of Pd/C moistened with water (50%) were
added. The mixture was hydrogenated under 20 psi at room
temperature for 20 h. The resulting mixture was filtered
through a pad of Celite. The solvent was evaporated to afford
an oil that was triturated with Et2O (3 mL) to obtain a dark
colored amorphous solid. The solid was filtered off, washed
with cooled Et2O, and dried at 60 °C to afford 7.3 g (73%) of
15 as a brown colored amorphous solid. 1H NMR (CDCl3) δ
1.80-1.90 (m, 2H), 2.00-2.14 (m, 4H), 2.34 (m, 3H), 2.71 (m,
1H), 2.98 (d, 2H, J ) 11.9 Hz), 3.49 (m, 2H), 6.64 (dd, 1H, J )
8.4, 2.1 Hz), 6.90 (d, 1H, J ) 2.1 Hz), 6.95 (d, 1H, J ) 1.6 Hz),
7.15 (d, 1H, J ) 8.4 Hz), 7.86 (br s, 1H).
Experimental Section
General Methods. Melting points were determined in open
capillary tubes on a Bu¨chi 535 melting point apparatus and
are uncorrected. Proton NMR spectra were obtained on a
Varian Unity 300 spectrometer. Elemental analysis for carbon,
hydrogen, and nitrogen for target compounds that are critical
for the interpretation of the relationship between structure
and affinity (SAFIR) were performed by Servei de Microana`lisi
in the Consejo Superior de Investigaciones Cient´ıficas of
Barcelona (CSIC) and were within (0.4% of theory for the
formulas given unless otherwise indicated. Furthermore, for
critical compounds, the purity was determined by HPLC and
found to be >95% for all these compounds (see Supporting
Information), using the following conditions: Waters Alliance
2690 and 2695 (Software Millenium 3.20) and Agilent 1100
(software Chemstation A.06.03) equipment with Waters Sym-
metry C8 3.9 µm p.s. 150 mm × 3.9 mm eluted with a mixture
of acetonitrile and water containing 10 mM heptanesulfonate
and 25 mM K3PO4 at pH 2.5; Waters Xterra MS-C8 5 µm p.s.
150 mm × 3.9 mm or 100 mm × 3.5 mm eluted with a mixture
of acetonitrile containing 0.05% TFA and water containing
0.05% TFA; Waters Xterra MS-C8 3.5 µm p.s. 100 mm × 3
mm eluted with a mixture of acetonitrile and water containing
10 mM phosphate buffer at pH 7.0 and Waters Xterra RP8 5
µm p.s. 150 mm × 3.9 mm eluted with a mixture acetonitrile
and water containing 10 mM ammonium acetate buffer, pH
7.0. Analytical thin-layer chromatography (TLC) was con-
ducted on precoated silica gel 60 F254 plates (Merck). Silica
gel 60, 220-400 mesh was used for flash chromatography
purification. All starting materials were obtained from com-
mercial sources and used as received.
General Procedure for Preparation of N-Aminoalkyl-
aminoindoles (10, 11a-f, 12a-c). 5-Amino-1-(2-diethyl-
aminoethyl)-1H-indole Dihydrochloride (11c). A solution
of 5-nitroindole (2a) (6.5 g, 40 mmol) in anhydrous DMF (25
mL) was added dropwise to a solution of NaH (50%, suspension
in mineral oil, 4.0 g, 85.2 mmol) in anhydrous DMF (150 mL)
at room temperature. After being stirred for 30 min, the
mixture was cooled to 0 °C, and 2-chloro-N,N-diethyletha-
namine hydrochloride (10.8 g, 80 mmol) was added dropwise.
Then, the solution was heated at 80 °C for 3 h. After the
solution was cooled (0 °C), H2O (50 mL) was added slowly. The
mixture was extracted with CHCl3, and the organic extract
was washed with water, dried with Na2SO4, and evaporated
to give a brown colored oil. This oil was dissolved in EtOH (50
mL), cooled to 0 °C, and treated with a solution of 5 N HCl in
EtOH (10 mL). The yellow colored amorphous solid was filtered
off, washed with precooled EtOH, and dried at 60 °C to afford
9.87 g (83%) of 5-nitro-1-(2-diethylaminoethyl)-1H-indole hy-
drochloride 5c. 1H NMR (DMSO-d6) δ 1.20 (t, 6H, J ) 7.1 Hz),
General Procedure for the Synthesis of Indolylsul-
fonamido Compounds (16-21). To a solution of 1.5 mmol
of the corresponding amino-1H-indole in 10 mL of pyridine, a
solution of 1.5 mmol of the corresponding sulfonyl chloride in
2 mL of pyridine was added dropwise at room temperature.
The reaction mixture was monitored by TLC until completion,
then evaporated to dryness, dissolved in EtOAc, and slightly
alkalized with aqueous diluted NH3. The organic phase was
separated and washed with water and a saturated solution of
NaHCO3. The organic layer was separated, dried with anhy-
drous Na2SO4, and evaporated. The products were further
purified using SiO2 column chromatography with CHCl3/
MeOH mixtures as eluents.
The following compounds were prepared analogously from
the properly substitued aminoindoles.
N-[1-(2-Dimethylaminoethyl)-2-methyl-1H-indol-4-yl]-
5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide (16a).
Cream colored amorphous solid. Yield 41%. Mp 78-80 °C. 1H

Novel, Selective Serotonin 5-HT6 Receptor Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1789
NMR (DMSO-d6) δ 2.10 (s, 6H), 2.28 (s, 3H), 2.50 (m, 2H), 4.14
(t, 2H, J ) 6.3 Hz), 6.43 (d, 1H, J ) 2.0 Hz), 6.92 (d, 1H, J )
7.5 Hz), 7.00 (t, 1H, J ) 7.7 Hz), 7.17 (d, 1H, J ) 2.2 Hz), 7.25
(d, 1H, J ) 7.5 Hz), 7.49 (d, 1H, J ) 8.4 Hz), 7.85 (s, 1H), 7.99
(d, 1H, J ) 8.5 Hz).
N-[1-(2-Dimethylaminoethyl)-1H-indol-4-yl]naphtha-
lene-1-sulfonamide (16b). Cream colored amorphous solid.
Yield 55%. Mp 169-172 °C. 1H NMR (DMSO-d6) δ 2.08 (s, 6H),
2.48 (m, 2H), 4.10 (t, 2H, J ) 6.6 Hz), 6.58 (d, 1H, J ) 3.1
Hz), 6.85-6.96 (m, 2H), 7.15 (d, 1H, J ) 7.8 Hz), 7.19 (d, 1H,
J ) 3.1 Hz), 7.54-7.68 (m, J ) 2 Hz), 7.83 (dd, 1H, J ) 8.6,
1.8 Hz), 7.94 (d, 1H, J ) 8.1 Hz). Anal. (C22H23N3O2S) C, H,
N.
N-[1-(2-Dimethylaminoethyl)-1H-indol-4-yl]naphtha-
lene-2-sulfonamide (16c). Cream colored amorphous solid.
Yield 51%. Mp 156-158 °C. 1H NMR (DMSO-d6) δ 2.08 (s, 6H),
2.48 (m, 2H), 4.10 (t, 2H, J ) 6.6 Hz), 6.58 (d, 1H, J ) 3.1
Hz), 6.85-6.96 (m, 2H), 7.15 (d, 1H, J ) 7.8 Hz), 7.19 (d, 1H,
J ) 3.1 Hz), 7.54-7.68 (m, J ) 2 Hz), 7.83 (dd, 1H, J ) 8.6,
1.8 Hz), 7.94 (d, 1H, J ) 8.1 Hz). Anal. (C22H23N3O2S) C, H,
N.
7.73 (dd, 1H, J ) 8.6, 1.8 Hz), 7.95 (d, 1H, J ) 7.9 Hz), 8.02
(d, 2H, J ) 8.6 Hz), 8.27 (d, 1H, J ) 1.5 Hz), 9.89 (s, 1H).
Anal. (C23H25N3O2S) C, H, N.
N-[1-(2-Diethylaminoethyl)-1H-indol-5-yl]-6-chloroimi-
dazo[2,1-b][1,3]thiazole-5-sulfonamide (17h). Beige colored
1
amorphous solid. Yield 44%. Mp 68-70 °C. H NMR (CDCl3)
δ 1.00 (t, 6H, J ) 7.0 Hz), 2.60 (q, 4H, J ) 7.0 Hz), 2.81 (t, 2H,
J ) 6.7 Hz), 4.21 (t, 2H, J ) 6.7 Hz), 6.38 (d, 1H, J ) 3.0 Hz),
6.79 (d, 1H, J ) 4.5 Hz), 6.96 (dd, 1H, J ) 8.6, 1.7 Hz), 7.14
(d, 1H, J ) 3.0 Hz), 7.19 (d, 1H, J ) 8.8 Hz), 7.40 (d, 1H, J )
1.5 Hz), 7.59 (d, 1H, J ) 4.4 Hz). Anal. (C19H22ClN5O2S2) C,
H, N.
N-[1-(2-Diethylaminoethyl)-1H-indol-5-yl]naphthalene-
1-sulfonamide (17i). Cream colored amorphous solid. Yield
63%. Mp 133-135 °C. 1H NMR (DMSO-d6) δ 0.87 (m, 6H), 2.58
(m, 4H), 2.76 (m, 2H), 4.14 (m, 2H), 6.24 (s, 1H), 6.73 (d, 1H,
J ) 8.8 Hz), 7.11 (s, 1H), 7.21 (d, 1H, J ) 8.0 Hz), 7.29 (s,
1H), 7.50 (t, 1H, J ) 7.8 Hz), 7.63-7.71 (m, 2H), 8.04 (d, 2H,
J ) 7.5 Hz), 8.13 (d, 1H, J ) 8.2 Hz), 8.76 (d, 1H, J ) 8.2 Hz),
10.21 (s, 1H).
N-[1-(2-Diethylaminoethyl)-1H-indol-5-yl]naphthalene-
2-sulfonamide (17j). Cream colored amorphous solid. Yield
N-[1-(2-Dimethylaminoethyl)-1H-indol-5-yl]-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (17a). Cream
1
46%. Mp 97-104 °C. H NMR (CDCl3) δ 0.95 (t, 6H, J ) 7.1
1
colored amorphous solid. Yield 24%. Mp 50-52 °C. H NMR
Hz), 2.54 (q, 4H, J ) 7.0 Hz), 2.76 (t, 2H, J ) 6.7 Hz), 4.07 (t,
2H, J ) 6.7 Hz), 6.66 (dd, 1H, J ) 8.5, 1.7 Hz), 6.91 (s, 1H),
6.97 (s, 1H), 7.01 (d, 1H, J ) 8.8 Hz), 7.22 (dd, 1H, J ) 8.6,
1.6 Hz), 7.26 (s, 1H), 7.42-7.55 (m, 3H), 7.63 (d, 1H, J ) 8.1
Hz), 7.70 (d, 1H, J ) 8.2 Hz), 8.03 (s, 1H), 9.95 (s, 1H). Anal.
(C24H27N3O2S) C, H, N.
(CDCl3) δ 2.26 (s, 6H), 2.64 (t, 2H, J ) 6.4 Hz), 4.16 (t, 2H, J
) 6.4 Hz), 6.39 (m, 1H), 6.78 (d, 1H, J ) 4.0 Hz), 6.94 (d, 1H,
J ) 8.4 Hz), 7.15 (m, 2H), 7.39 (s, 1H), 7.55 (d, 1H, J ) 4.0
Hz).
N-[1-(2-Dimethylaminoethyl)-1H-indol-5-yl]naphtha-
lene-1-sulfonamide (17b). Orange colored amorphous solid.
1
N-[1-(2-Dimethylaminoethyl)-1H-indol-5-yl]-4-phenyl-
benzenesulfonamide (17k). Yellow colored oil. Yield 68%.
1H NMR (DMSO-d6) δ 0.83 (m, 6H), 2.50 (m, 4H), 2.70 (m,
2H), 4.13 (m, 2H), 6.30 (d, 1H, J ) 2.6 Hz), 6.87 (d, 1H, J )
8.6 Hz), 7.24 (s, 1H), 7.30 (m, 2H), 7.44 (m, 3H), 7.66 (d, 2H,
J ) 7.2 Hz), 7.72 (AB sys, 2H, J ) 8.5 Hz), 7.78 (AB sys, 2H,
J ) 8.5 Hz), 9.91 (s, 1H).
Yield 54%. Mp 179-181 °C. H NMR (CDCl3) δ 2.25 (s, 6H),
2.63 (t, 2H, J ) 7.0 Hz), 4.11 (t, 2H, J ) 7.0 Hz), 6.28 (d, 1H,
J ) 3.1 Hz), 6.68 (dd, 1H, J ) 8.6, 2.0 Hz), 7.03-7.11 (m, 3H),
7.37 (m, 1H), 7.58-7.70 (m, 2H), 7.94 (d, 1H, J ) 8.7 Hz), 8.00
(d, 1H, J ) 7.9 Hz), 8.06 (d, 1H, J ) 7.3 Hz), 8.73 (d, 1H, J )
8.7 Hz). Anal. (C22H23N3O2S) H, N, C: calcd, 67.15; found,
66.71.
N-[1-(2-Dimethylaminoethyl)-1H-indol-5-yl]naphtha-
lene-2-sulfonamide (17c). Grey colored solid. Yield 48%. Mp
54-57 °C. 1H NMR (CDCl3) δ 2.26 (s, 6H), 2.63 (t, 2H, J ) 7.1
Hz), 4.14 (t, 2H, J ) 7.1 Hz), 6.35 (d, 1H, J ) 3.1 Hz), 6.88
(dd, 1H, J ) 8.6, 2.0 Hz), 7.10 (d, 1H, J ) 3.1 Hz), 7.15 (d, 1H,
J ) 8.6 Hz), 7.31 (d, 1H, J ) 2.0 Hz), 7.50-7.63 (m, 2H), 7.69
(dd, 1H, J ) 8.7, 1.8 Hz), 7.84 (m, 3H), 8.29 (s, 1H). Anal.
(C22H23N3O2S) H, N, C: calcd, 67.15; found, 66.73.
N-{1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (17l). Colorless
1
amorphous solid. Yield 54%. Mp 81-84 °C. H NMR (CDCl3)
δ 1.85 (m, 6H), 2.68 (m, 4H), 3.00 (m, 2H), 4.38 (m, 2H), 6.40
(d, 1H, J ) 3.1 Hz), 6.82 (d, 1H, J ) 4.5 Hz), 6.96 (d, 1H, J )
8.6 Hz), 7.19 (d, 1H, J ) 2.7 Hz), 7.22 (m, 1H), 7.41 (m, 1H),
7.64 (d, 1H, J ) 4.5 Hz). Anal. (C19H20ClN5O2S2‚1/3H2O) C, H,
N.
N-{1-[2-(Piperidin-1-yl)ethyl]-1H-indol-5-yl}-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (17m). Color-
less amorphous solid. Yield 61%. Mp 74-80 °C. 1H NMR
(DMSO-d6) δ 1.37-1.44 (m, 6H), 2.36 (m, 4H), 2.57 (m, 2H),
4.20 (t, 2H, J ) 6.6 Hz), 6.34 (d, 1H, J ) 2.7 Hz), 6.83 (d, 1H,
J ) 8.7 Hz), 7.24 (s, 1H), 7.35-7.38 (m, 2H), 7.57 (d, 1H, J )
4.2 Hz), 7.88 (d, 1H, J ) 4.5 Hz), 10.48 (br s, 1H). Anal. (C20H22-
ClN5O2S2) C, H, N.
N-{1-[3-(Piperidin-1-yl)propyl]-1H-indol-5-yl}-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (17n). Colorless
amorphous solid. Yield 30%. Mp 85-86 °C. 1H NMR (DMSO-
d6) δ 1.36 (m, 2H), 1.49 (m, 4H), 1.86 (m, 2H), 2.15-2.44 (m,
6H), 4.10 (t, 2H, J ) 6.7 Hz), 6.33 (d, 1H, J ) 3.1 Hz), 6.79
(dd, 1H, J ) 8.7, 2.0 Hz), 7.21 (d, 1H, J ) 2.0 Hz), 7.30-7.36
(m, 2H), 7.52 (d, 1H, J ) 4.4 Hz), 7.83 (d, 1H, J ) 4.4 Hz),
10.25 (br s, 1H). Anal. (C21H24ClN5O2S2‚2/3H2O) C, H, N.
N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (18a). Cream
colored amorphous solid. Yield 67%. 1H NMR (DMSO-d6) δ 2.28
(s, 6H), 2.61 (t, 2H, J ) 7.0 Hz), 4.14 (t, 2H, J ) 7.0 Hz), 6.41
(d, 1H, J ) 3.1 Hz), 6.81 (m, 2H), 7.12 (d, 1H, J ) 3.1 Hz),
7.19 (m, 1H), 7.42 (d, 1H, J ) 8.2 Hz,), 7.56 (d, 1H, J ) 4.6
Hz).
N-[1-(2-Dimethylaminoethyl)-1H-indol-5-yl]-1-phenyl-
methanesulfonamide (17d). Cream colored amorphous solid.
1
Yield 34%. Mp 163-166 °C. H NMR (CDCl3) δ 2.30 (s, 6H),
2.70 (t, 2H, J ) 7.1 Hz), 4.22 (t, 2H, J ) 7.1 Hz), 4.29 (s, 2H),
6.48 (d, 1H, J ) 3.1 Hz), 7.04 (dd, 1H, J ) 8.8, 2.2 Hz), 7.19
(d, 1H, J ) 3.1 Hz), 7.31 (d, 1H, J ) 8.8 Hz), 7.33-7.40 (m,
5H), 7.49 (d, 1H, J ) 2.2 Hz).
N-[1-(2-Dimethylaminoethyl)-2-methyl-1H-indol-5-yl]-
6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonamide (17e).
Colorless amorphous solid. Yield 24%. Mp 182-183 °C. 1H
NMR (DMSO-d6) δ 2.14 (s, 6H), 2.34 (s, 3H), 2.39 (m, 2H), 4.01
(m, 2H), 6.09 (s, 1H), 6.70 (dd, 1H, J ) 8.5, 1.8 Hz), 7.08 (d,
1H, J ) 1.8 Hz), 7.21 (d, 1H, J ) 8.5 Hz), 7.51 (d, 1H, J ) 4.5
Hz), 7.80 (d, 1H, J ) 4.5 Hz). Anal. (C18H20ClN5O2S2) C, H, N.
N-[1-(2-Dimethylaminoethyl)-2-methyl-1H-indol-5-yl]-
naphthalene-1-sulfonamide (17f). Colorless amorphous
solid. Yield 33%. Mp 183-184 °C. 1H NMR (DMSO-d6) δ 2.12
(s, 6H), 2.29 (s, 3H), 2.35 (t, 2H, J ) 7.0 Hz), 4.01 (t, 2H, J )
7.0 Hz), 5.98 (s, 1H), 6.62 (dd, 1H, J ) 8.7, 1.9 Hz), 6.98 (d,
1H, J ) 2.0 Hz), 7.07 (d, 1H, J ) 8.6 Hz), 7.49 (m, 1H), 7.63
(m, 1H), 7.70 (m, 1H), 8.02 (d, 2H, J ) 7.5 Hz), 8.12 (d, 1H, J
) 8.0 Hz), 8.75 (d, 1H, J ) 8.4 Hz), 10.15 (s, 1H). Anal.
(C23H25N3O2S) C, H, N.
N-[1-(2-Dimethylaminoethyl)-2-methyl-1H-indol-5-yl]-
naphthalene-2-sulfonamide (17g). Colorless amorphous
solid. Yield 58%. Mp 199-200 °C. 1H NMR (DMSO-d6) δ 2.11
(s, 6H), 2.30 (s, 3H), 2.35 (t, 2H, J ) 7.0 Hz), 4.03 (t, 2H, J )
7.0 Hz), 6.03 (s, 1H), 6.75 (dd, 1H, J ) 8.6, 2.0 Hz), 7.10 (d,
1H, J ) 2.0 Hz), 7.13 (d, 1H, J ) 8.6 Hz), 7.54-7.67 (m, 2H),
N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (18b). Color-
1
less amorphous solid. Yield 67%. H NMR (DMSO-d6) δ 2.19
(s, 9H), 2.55 (t, 2H, J ) 6.7 Hz), 4.13 (t, 2H, J ) 6.7 Hz), 6.42
(d, 1H, J ) 3.1 Hz), 6.69 (dd, 1H, J ) 8.3, 1.9 Hz), 7.13 (d, 1H,

1790 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Holenz et al.
J ) 3.1 Hz), 7.23 (m, 1H), 7.45-7.37 (m, 2H), 7.63 (d, 1H, J )
2.0 Hz), 7.69 (d, 1H, J ) 8.6 Hz). Anal. (C21H22ClN3O2S2) C,
H, N.
8.4, 1.8 Hz), 7.13 (m, 1H), 7.33-7.44 (m, 5H), 7.48 (d, 1H, J )
8.6 Hz), 7.52 (d, 1H, J ) 8.4 Hz), 7.75 (t, 1H, J ) 4.8 Hz), 7.85
(d, 1H, J ) 8.1 Hz), 9.84 (s, 1H). Anal. (C26H29N3O2S‚1.75 H2O)
C, H, N.
N-[3-Dimethylaminomethyl-1H-indol-5-yl]-5-chloro-3-
methyl-benzo[b]thiophene-2-sulfonamide (19a). Cream
colored amorphous solid. Yield 33%. Mp 148-152 °C. 1H NMR
(DMSO-d6) δ 1.89 (m, 6H), 2.29 (s, 3H), 2.48 (s, 2H), 6.83 (m,
1H), 7.18 (m, 3H), 7.50 (m, 1H), 7.91 (m, 1H), 8.00 (m, 1H),
10.13 (br s, 1H), 10.92 (s, 1H). Anal. (C20H20ClN3O2S2) C, H,
N.
N-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (19b). Cream
colored amorphous solid. Yield 36%. Mp 215 °C (dec). 1H NMR
(DMSO-d6) δ 2.17 (s, 6H), 2.36 (m, 2H), 2.65 (m, 2H), 6.77 (dd,
1H, J ) 8.6, 1.7 Hz), 7.07 (s, 1H), 7.09 (s, 1H), 7.18 (d, 1H, J
) 8.6 Hz), 7.51 (d, 1H, J ) 4.5 Hz), 7.81 (d, 1H, J ) 4.5 Hz),
10.80 (s, 1H).
N-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (19c). Cream
colored amorphous solid. Yield 82%. Mp 226-227 °C. 1H NMR
(DMSO-d6) δ 2.04 (s, 6H), 2.23 (m, 2H), 2.28 (s, 3H), 2.59 (m,
2H), 6.83 (dd, 1H, J ) 8.4, 1.5 Hz), 7.09 (s, 2H), 7.19 (d, 1H, J
) 8.4 Hz), 7.49 (dd, 1H, J ) 8.7, 1.6 Hz), 7.91 (d, 1H, J ) 1.6
Hz), 7.99 (d, 1H, J ) 8.7 Hz), 10.13 (br s, 1H), 10.79 (s, 1H).
Anal. (C21H22ClN3O2S2‚1/4H2O) C, H, N.
N-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]naphtha-
lene-1-sulfonamide (19d). Cream colored amorphous solid.
Yield 66%. Mp 203-205 °C. 1H NMR (DMSO-d6) δ 2.09 (s, 6H),
2.21 (m, 2H), 2.54 (m, 2H), 6.69 (dd, 1H, J ) 8.6, 1.7 Hz), 6.94
(s, 1H), 7.03 (s, 1H), 7.06 (d, 1H, J ) 8.1 Hz), 7.49 (t, 1H, J )
7.8 Hz), 7.64 (m, 1H), 7.71 (m, 1H), 8.02 (m, 2H), 8.13 (d, 1H,
J ) 8.1 Hz), 8.79 (d, 1H, J ) 8.4 Hz), 10.10 (br s, 1H), 10.68
(s, 1H). Anal. (C22H23N3O2S) H, N, C: calcd, 67.15; found,
66.71.
N-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-
naphthalene-2-sulfonamide (19e). Cream colored amor-
phous solid. Yield 55%. Mp 230-240 °C (dec). 1H NMR (DMSO-
d6) δ 2.01 (s, 6H), 2.18 (m, 2H), 2.57 (m, 2H), 6.81 (dd, 1H, J
) 8.6, 1.7 Hz), 7.02 (s, 1H), 7.05 (d, 1H, J ) 1.7 Hz), 7.15 (d,
1H, J ) 8.6 Hz), 7.57 (m, 1H), 7.82 (d, 1H, J ) 7.5 Hz), 7.91
(d, 1H, J ) 8.9 Hz), 8.06 (d, 1H, J ) 8.2 Hz), 8.29 (d, 1H, J )
8.9 Hz), 8.35 (s, 1H), 9.94 (br s, 1H), 10.74 (s, 1H). Anal.
(C22H22ClN3O2S‚1/4H2O) C, H, N.
N-[3-(2-Dimethylaminoethyl)-1H-indol-5-yl]-4-phenyl-
benzenesulfonamide (19f). Colorless amorphous solid. Yield
69%. Mp 184-186 °C. 1H NMR (DMSO-d6) δ 2.08 (s, 6H), 2.32
(m, 2H), 2.64 (m, 2H), 6.83 (dd, 1H, J ) 8.6, 1.9 Hz), 7.08 (d,
1H, J ) 2.0 Hz), 7.11 (d, 1H, J ) 1.9 Hz), 7.17 (d, 1H, J ) 8.6
Hz), 7.34-7.50 (m, 3H), 7.66 (d, 2H, J ) 7.5 Hz), 7.72 (AB
sys, 2H, J ) 8.6 Hz), 7.79 (AB sys, 2H, J ) 8.6 Hz), 9.79 (s,
1H), 10.75 (s, 1H). Anal. (C24H25N3O2S) C, H, N.
N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]naphtha-
lene-1-sulfonamide (18c). Cream colored amorphous solid.
Yield 67%. Mp 139-142 °C. 1H NMR (DMSO-d6) δ 2.21 (s, 6H),
2.50 (t, 2H, J ) 7.0 Hz), 4.03 (t, 2H, J ) 7.0 Hz), 6.35 (d, 1H,
J ) 3.1 Hz), 6.48 (dd, 1H, J ) 8.4, 1.7 Hz), 7.00 (s, 1H), 7.05
(d, 1H, J ) 3.1 Hz), 7.29 (m, 1H), 7.37 (t, 1H, J ) 7.8 Hz),
7.60 (m, 1H), 7.67 (m, 1H), 7.92 (d, 1H, J ) 8.1 Hz), 7.98 (d,
1H, J ) 8.1 Hz), 8.10 (d, 1H, J ) 7.3 Hz), 8.73 (d, 1H, J ) 8.8
Hz). Anal. (C22H23N3O2S) C, H, N: calcd, 10.68; found, 11.30.
N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]naphtha-
lene-2-sulfonamide (18d). Cream colored amorphous solid.
Yield 80%. Mp 140-143 °C. 1H NMR (DMSO-d6) δ 2.19 (s, 6H),
2.55 (t, 2H, J ) 7.0 Hz), 4.11 (t, 2H, J ) 7.0 Hz), 6.39 (d, 1H,
J ) 3.1 Hz), 6.67 (dd, 1H, J ) 8.3, 1.4 Hz), 7.10 (d, 1H, J )
3.1 Hz), 7.19 (s, 1H), 7.39 (d, 1H, J ) 8.4 Hz), 7.49-7.65 (m,
2H), 7.69 (dd, 1H, J ) 8.9, 1.6 Hz), 7.81-7.88 (m, 3H), 8.29 (s,
1H). Anal. (C22H23N3O2S) C, H, N.
N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-2-(naph-
thalen-1-yl)-ethanesulfonamide (18e). Yellow colored amor-
phous solid. Yield 40%. 1H NMR (DMSO-d6) δ 2.15 (s, 6H),
2.62 (t, 2H, J ) 7.1 Hz), 3.38 (m, 2H), 3.49 (m, 2H), 4.22 (t,
2H, J ) 7.1 Hz), 6.47 (d, 1H, J ) 2.8 Hz), 7.04 (m, 2H), 7.23
(d, 1H, J ) 3.1 Hz), 7.26-7.45 (m, 5H), 7.56 (d, 1H, J ) 8.4
Hz), 7.68 (dd, 1H, J ) 7.5, 1.5 Hz), 7.77 (d, 1H, J ) 8.3 Hz).
Anal. (C24H27N3O2S) C, H, N.
N-[1-(2-Dimethylaminoethyl)-2-methyl-1H-indol-5-yl]-
5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide (18f).
Colorless amorphous solid. Yield 46%. Mp 203-205 °C. 1H
NMR (DMSO-d6) δ 2.13 (s, 6H), 2.33 (s, 6H), 2.39 (t, 2H, J )
7.0 Hz), 4.07 (t, 2H, J ) 6.8 Hz), 6.08 (s, 1H), 6.76 (dd, 1H, J
) 8.6, 2.0 Hz), 7.13 (d, 1H, J ) 2.0 Hz), 7.20 (d, 1H, J ) 8.6
Hz), 7.51 (dd, 1H, J ) 8.7, 2.0 Hz), 7.93 (d, 1H, J ) 2.0 Hz),
8.00 (d, 1H, J ) 8.8 Hz), 10.20 (s, 1H). Anal. (C22H24ClN3O2S2)
C, H, N.
N-{1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl}-6-chloro-
imidazo[2,1-b][1,3]thiazole-5-sulfonamide (18g). Yellow
1
colored amorphous solid. Yield 59%. Mp 53-57 °C. H NMR
(DMSO-d6) δ 1.64 (m, 4H), 2.50 (m, 4H), 2.70 (m, 2H), 4.14
(m, 2H), 6.31 (d, 1H, J ) 2.8 Hz), 6.71 (d, 1H, J ) 8.8 Hz),
7.11 (s, 1H), 7.31 (d, 1H, J ) 2.9 Hz), 7.37 (d, 1H, J ) 8.6 Hz),
7.56 (d, 1H, J ) 4.4 Hz), 7.91 (d, 1H, J ) 4.5 Hz), 10.63 (br s,
1H).
N-{1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl}-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (18h). Yellow
1
colored amorphous solid. Yield 58%. Mp 69-71 °C. H NMR
(DMSO-d6) δ 1.58 (m, 4H), 2.31 (m, 4H), 2.36 (s, 3H), 2.59 (m,
2H), 4,11 (m, 2H), 6.31 (s, 1H), 6.79 (d, 1H, J ) 8.4 Hz), 7.09
(s, 1H), 7,29 (d, 1H, J ) 2.3 Hz), 7.38 (d, 1H, J ) 8.5 Hz), 7.51
(d, 1H, J ) 8.6 Hz), 7.94 (d, 1H, J ) 1.0 Hz), 8.00 (d, 1H, J )
8.35 Hz), 10.39 (br s, 1H).
N-[3-(2-Diethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-
methyl-benzo[b]thiophene-2-sulfonamide (19 g). Cream
colored amorphous solid. Yield 62%. Mp 170-173 °C. 1H NMR
(DMSO-d6) δ 0.88 (t, 6H, J ) 7.1 Hz), 2.28 (s, 3H), 2.30-2.46
(m, 6H), 2.58 (m, 2H), 6.85 (dd, 1H, J ) 8.6, 2.0 Hz), 7.10 (m,
2H), 7.20 (d, 1H, J ) 8.6 Hz), 7.50 (dd, 1H, J ) 8.7, 2.0 Hz),
7.90 (d, 1H, J ) 2.0 Hz), 7.98 (d, 1H, J ) 8.7 Hz), 10.10 (br s,
1H), 10.80 (s, 1H). Anal. (C23H26ClN3O2S2) C, H, N.
N-[3-(2-Diethylaminoethyl)-1H-indol-5-yl]naphthalene-
1-sulfonamide (19h). Cream colored amorphous solid. Yield
N-{1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl}naph-
thalene-1-sulfonamide (18i). Cream colored amorphous
solid. Yield 66%. Mp 160-165 °C. 1H NMR (DMSO-d6) δ 1.74
(m, 4H), 2.71 (m, 4H), 2.94 (m, 2H), 4.24 (m, 2H), 6.27 (d, 1H,
J ) 2.8 Hz), 6.61 (d, 1H, J ) 8.6 Hz), 7.09 (s, 1H), 7.24 (d, 1H,
J ) 8.5 Hz), 7.28 (d, 1H, J ) 2.8 Hz), 7.54 (t, 1H, J ) 7.9 Hz),
7.63 (m, 1H), 7.71 (m 1H), 8.03 (d, 1H, J ) 7.6 Hz), 8.11-8.23
(m. 2H), 8.77 (d, 1H, J ) 8.2 Hz), 10.46 (br s, 1H). Anal.
(C24H25N3O2S‚1/3CHCl3) C, H, N.
1
N-{1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl}naph-
thalene-2-sulfonamide (18j). Beige colored amorphous solid.
Yield 57%. Mp 54-60 °C. 1H NMR (DMSO-d6) δ 1.54 (m, 4H),
2.24 (m, 4H), 2.50 (m, 2H), 4.06 (m, 2H), 6.25 (s, 1H), 6.77 (d,
1H, J ) 8.4 Hz), 7.07 (s, 1H), 7.23 (m, 1H), 7.32 (d, 1H, J )
8.1 Hz), 7.61 (m, 2H), 7.75 (d, 1H, J ) 8.8 Hz), 7.95 (d, 1H, J
) 7.6 Hz), 8.03 (m, 2H), 8.34 (s, 1H), 10.11 (br s, 1H).
N-{1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl}-2-(naph-
thalen-1-yl)-ethanesulfonamide (18k). Yellow colored amor-
67%. Mp 174-175.5 °C. H NMR (DMSO-d6) δ 0.90 (t, 6H, J
) 6.9 Hz), 2.35-2.43 (m, 8H), 6.69 (dd, 1H, J ) 8.4, 1.8 Hz),
6.95 (d, 1H, J ) 1.8 Hz), 7.02 (d, 1H, J ) 2.4 Hz), 7.05 (d, 1H,
J ) 8.7 Hz), 7.47 (t, 1H, J ) 8.1 Hz), 7.66 (m, 2H), 8.01 (m,
2H), 8.12 (d, 1H, J ) 8.4 Hz), 8.78 (d, 1H, J ) 7.8 Hz), 10.10
(br s, 1H), 10.67 (s, 1H). Anal. (C24H27N3O2S) C, H, N: calcd,
9.97; found, 10.40.
N-[3-(2-Diethylaminoethyl)-1H-indol-5-yl]naphthalene-
2-sulfonamide (19i). Cream colored amorphous solid. Yield
1
1
phous solid. Yield 68%. H NMR (DMSO-d6) δ 1.49 (m, 4H),
70%. Mp 172-173 °C. H NMR (DMSO-d6) δ 0.87 (t, 6H, J )
2.31 (m, 4H), 2.66 (t, 2H, J ) 6.5 Hz), 3.3 (m, 4H), 4.16 (t, 2H,
J ) 6.5 Hz), 6.40 (dd, 1H, J ) 3.1, 0.7 Hz), 7.04 (dd, 1H, J )
7.1 Hz), 2.39 (m, 6H), 2.55 (m, 2H), 6.82 (d, 1H, J ) 8.6 Hz),
7.05 (s, 1H), 7.09 (s, 1H), 7.13 (d, 1H, J ) 8.6 Hz), 7.60 (m,

Novel, Selective Serotonin 5-HT6 Receptor Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1791
2H), 7.73 (d, 1H, J ) 8.6 Hz), 7.95 (d, 1H, J ) 7.9 Hz), 8.01
(m, 2H), 8.26 (s, 1H), 9.86 (br s, 1H), 10.71 (s, 1H). Anal.
(C24H27N3O2S) C, H, N.
N-{3-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naph-
thalene-2-sulfonamide (19t). Cream colored amorphous
solid. Yield 52%. Mp 180-182 °C. 1H NMR (DMSO-d6) δ 1.60
(m, 4H), 2.26 (m, 4H), 2.35 (m, 2H), 2.61 (m, 2H), 6.82 (dd,
1H, J ) 8.6, 2.0 Hz), 7.05 (m, 2H), 7.14 (d, 1H, J ) 8.6 Hz),
7.61 (m, 2H), 7.74 (dd, 1H, J ) 8.6, 1.8 Hz), 7.95 (d, 1H, J )
7.9 Hz), 8.02 (m, 2H), 8.27 (s, 1H), 9.86 (br s, 1H), 10.72 (s,
1H).
N-{3-[2-(Morpholin-4-yl)ethyl]-1H-indol-5-yl}-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (19u). Cream
colored amorphous solid. Yield 91%. Mp 200-201 °C. 1H NMR
(DMSO-d6) δ 2.25 (m, 6H), 2.27 (s, 3H), 2.62 (t, 2H, J ) 7.9
Hz), 3.52 (m, 4H), 6.84 (d, 1H, J ) 8.2 Hz), 7.06 (s, 1H), 7.10
(s, 1H), 7.20 (d, 1H, J ) 8.6 Hz), 7.50 (d, 1H, J ) 8.6 Hz), 7.92
(s, 1H), 8.00 (d, 1H, J ) 8.6 Hz), 10.13 (s, 1H), 10.80 (s, 1H).
N-{3-[2-(Morpholin-4-yl)ethyl]-1H-indol-5-yl}naph-
thalene-1-sulfonamide (19v). Cream colored amorphous
solid. Yield 94%. Mp 218-220 °C. 1H NMR (DMSO-d6) δ 2.30
(m, 6H), 2.56 (m, 2H), 3.56 (m, 4H), 6.69 (d, 1H, J ) 8.4 Hz),
6.93 (s, 1H), 7.06 (m, 2H), 7.48 (t, 1H, J ) 7.3 Hz), 7.67 (m,
2H), 8.02 (m, 2H), 8.13 (d, 1H, J ) 8.1 Hz), 8.78 (d, 1H, J )
8.1 Hz), 10.10 (s, 1H), 10.68 (s, 1H). Anal. (C24H25N3O3S‚2/3-
HCl) C, H, N.
N-{3-[2-(Morpholin-4-yl)ethyl]-1H-indol-5-yl}naph-
thalene-2-sulfonamide (19w). Cream colored amorphous
solid. Yield 92%. Mp 85-90 °C. 1H NMR (DMSO-d6) δ 2.27
(m, 6H), 2.61 (t, 2H, J ) 7.9 Hz), 3.52 (t, 4H, J ) 4.6 Hz), 6.82
(dd, 1H, J ) 8.6, 2.0 Hz), 7.06 (s, 1H), 7.07 (s, 1H), 7.15 (d,
1H, J ) 8.6 Hz), 7.61 (m, 2H), 7.74 (dd, 1H, J ) 8.8, 1.8 Hz),
7.96 (d, 1H, J ) 8.1 Hz), 8.03 (m, 2H), 8.27 (s, 1H), 9.87 (s,
1H), 10.74 (s, 1H).
N-{3-[2-(Morpholin-4-yl)ethyl]-1H-indol-5-yl}quinolyl-
8-sulfonamide (19x). Brown colored amorphous solid. Yield
48%. Mp 234-235 °C. 1H NMR (DMSO-d6) δ 2.29 (m, 6H), 2.66
(m, 2H), 3.47 (m, 4H), 6.84 (d, 1H, J ) 8.6 Hz), 7.07 (s, 1H),
7.09 (s, 1H), 7.18 (d, 1H, J ) 8.4 Hz), 7.45 (m, 3H), 7.70 (m,
4H), 7.79 (m, 2H), 9.79 (s, 1H), 10.77 (s, 1H).
N-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (20a). Color-
less amorphous solid. Yield 51%. Mp 239-241 °C (dec). 1H
NMR (DMSO-d6) δ 1.53-1.80 (m, 4H), 2.26 (s, 3H), 2.39-2.71
(m, 6H), 3.02 (d, 2H, J ) 8.8 Hz), 6.76 (d, 1H, J ) 8.8 Hz),
7.05 (s, 1H), 7.11 (s, 1H), 7.19 (d, 1H, J ) 8.8 Hz), 7.51 (d, 1H,
J ) 8.7 Hz), 7.91 (s, 1H), 8.00 (d, 1H, J ) 8.7 Hz), 10.10 (br s,
1H), 10.90 (s, 1H). Anal. (C23H24ClN3O2S2) C, H, N.
N-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]naphtha-
lene-1-sulfonamide Hydrochloride (20b). Colorless amor-
phous solid. Yield 69%. Mp 212 °C (dec). 1H NMR (DMSO-d6)
δ 1.80 (m, 4H), 2.74 (m, 4H), 3.04 (m, 2H), 3.39 (m, 2H), 6.63
(d, J ) 8.6 Hz, 1H), 7.00 (s, 2H), 7.08 (d, J ) 8.6 Hz, 1H), 7.49
(t, J ) 7.7 Hz, 1H), 7.60-7.77 (m, 2H), 8.04 (d, J ) 7.5 Hz,
2H), 8.13 (d, J ) 8.2 Hz, 1H), 8.79 (d, J ) 8.2 Hz, 1H), 10.16
(s, 1H), 10.66 (br s, 1H), 10.88 (s, 1H).
N-[3-(2-Diethylaminoethyl)-1H-indol-5-yl]-5-chloronaph-
thalene-1-sulfonamide (19j). Cream colored amorphous
solid. Yield 56%. Mp 154-156 °C. 1H NMR (DMSO-d6) δ 0.88
(t, 6H, J ) 6.7 Hz), 2.41 (m, 6H), 2.49 (m, 2H), 6.71 (d, 1H, J
) 8.1 Hz), 6.88 (s, 1H), 7.07 (m, 2H), 7.66 (m, 2H), 7.84 (d,
1H, J ) 7.0 Hz), 8.09 (d, 1H, J ) 7.0 Hz), 8.41 (d, 1H, J ) 8.2
Hz), 8.79 (d, 1H, J ) 8.6 Hz), 10.17 (br s, 1H), 10.71 (s, 1H).
N-[3-(2-Diethylaminoethyl)-1H-indol-5-yl]-3,5-dichlo-
robenzenesulfonamide (19k). Cream colored amorphous
solid. Yield 67%. Mp 168-170 °C. 1H NMR (DMSO-d6) δ 0.95
(t, 6H, J ) 7.1 Hz), 2.44-2.58 (m, 6H), 2.66 (m, 2H), 6.79 (dd,
1H, J ) 8.6, 1.7 Hz), 7.08 (d, 1H, J ) 0.9 Hz), 7.13 (d, 1H, J
) 1.7 Hz), 7.23 (d, 1H, J ) 8.6 Hz), 7.58 (m, 2H), 7.87 (m, 1H),
9.95 (br s, 1H), 10.82 (s, 1H).
N-[3-(2-Diethylaminoethyl)-1H-indol-5-yl]-4-phenyl-
benzenesulfonamide (19l). Cream colored amorphous solid.
Yield 68%. Mp 161-163 °C. 1H NMR (DMSO-d6) δ 0.89 (t, 6H,
J ) 7.1 Hz), 2.32-2.55 (m, 6H), 2.62 (m, 2H), 6.85 (d, 1H, J )
8.6 Hz), 7.08 (d, 1H, J ) 2.0 Hz), 7.13 (s, 1H), 7.18 (d, 1H, J
) 8.6 Hz), 7.33-7.50 (m, 3H), 7.64 (d, 2H, J ) 7.5 Hz), 7.72
(sys AB, 2H, J ) 8.6 Hz), 7.78 (sys AB, 2H, J ) 8.6 Hz), 9.80
(br s, 1H), 10.75 (s, 1H).
N-[3-(2-Diethylaminoethyl)-1-methyl-1H-indol-5-yl]-
naphthalene-2-sulfonamide (19m). Cream colored amor-
phous solid. Yield 13%. Mp 134-136 °C. 1H NMR (DMSO-d6)
δ 0.98 (t, 6H, J ) 7.1 Hz), 2.55 (m, 6H), 2.70 (m, 2H), 3.67 (s,
3H), 6.84 (s, 1H), 6.93 (dd, 1H, J ) 8.6, 2.0 Hz), 7.10 (d, 1H, J
) 8.7 Hz), 7.18 (d, 1H, J ) 1.7 Hz), 7.26 (s, 1H), 7.57 (m, 2H),
7.67 (dd, 1H, J ) 8.7, 1.8 Hz), 7.84 (m, 3H), 8.27 (d, 1H, J )
1.7 Hz). Anal. (C25H29N3O2S‚1/4H2O) C, H, N.
N-[3-(2-Dipropylaminoethyl)-1H-indol-5-yl]-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (19o). Yellow
1
colored amorphous solid. Yield 82%. Mp 90-95 °C. H NMR
(DMSO-d6) δ 0.80 (t, 6H, J ) 7.3 Hz), 1.31 (q, 4H, J ) 7.3 Hz),
2.26 (m, 7H), 2.38 (m, 2H), 2.56 (m, 2H), 6.83 (dd, 1H, J )
8.4, 1.8 Hz), 7.08 (s, 2H), 7.20 (d, 1H, J ) 8.6 Hz), 7.50 (dd,
1H, J ) 8.6, 2.0 Hz), 7.90 (d, 1H, J ) 2.0 Hz), 7.99 (d, 1H, J
) 8.6 Hz), 10.12 (br s, 1H), 10.79 (s, 1H). Anal. (C25H30-
ClN3O2S2‚1/2H2O) C, H, N.
N-[3-(2-Dipropylaminoethyl)-1H-indol-5-yl]naphtha-
lene-2-sulfonamide (19p). Cream colored amorphous solid.
Yield 50%. Mp 58-64 °C (dec). 1H NMR (DMSO-d6) δ 0.79 (t,
6H, J ) 7.3 Hz), 1.31 (q, 4H, J ) 7.3 Hz), 2.28 (t, 4H, J ) 7.3
Hz), 2.42 (m, 2H), 2.57 (m, 2H), 6.80 (dd, 1H, J ) 8.6, 1.7 Hz),
7.04 (d, 1H, J ) 1.7 Hz), 7.12 (m 2H), 7.60 (m, 2H), 7.72 (dd,
1H, J ) 8.6, 1.7 Hz), 7.98 (m, 3H), 8.25 (s, 1H), 9.87 (br s,
1H), 10.70 (s, 1H).
N-[3-(2-Dibutylaminoethyl)-1H-indol-5-yl]naphthalene-
1-sulfonamide (19q). Cream colored amorphous solid. Yield
1
71%. Mp 111-113 °C. H NMR (DMSO-d6) δ 0.86 (t, 6H, J )
7.0 Hz), 1.29 (m, 8H), 2.35 (m, 4H), 2.41 (m, 2H), 2.53 (m, 2H),
6.67 (dd, 1H, J ) 8.5, 1.9 Hz), 7.09 (m, 3H), 7.48 (t, 1H, J )
7.9 Hz), 7.68 (m, 2H), 8.01 (s, 1H), 8.04 (s, 1H), 8.12 (d, 1H, J
) 8.2 Hz), 8.78 (d, 1H, J ) 8.2 Hz), 10.13 (s, 1H), 10.67 (s,
1H). Anal. (C28H35N3O2S‚1/4H2O) C, H, N.
N-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlo-
rothiophene-1-sulfonamide (20c). Cream colored amor-
phous solid. Yield 59%. Mp 246-249 °C. 1H NMR (DMSO-d6)
δ 1.35-1.47 (m, 4H), 1.86 (m, 2H), 2.17 (s, 3H), 2.28 (m, 1H),
2.76 (d, 2H, J ) 10.6 Hz), 6.68 (d, 1H, J ) 8.8 Hz), 6.75 (s,
1H), 6.94 (s, 1H), 7.08 (d, 1H, J ) 9.0 Hz), 7.60-7.73 (m, 2H),
7.85 (d, 1H, J ) 7.1 Hz), 8.06 (d, 1H, J ) 7.1 Hz), 8.40 (d, 1H,
J ) 7.9 Hz), 8.79 (d, 1H, J ) 9.0 Hz), 10.20 (br s, 1H), 10.68
(s, 1H).
N-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlo-
rothiophene-2-sulfonamide (20d). Cream colored amor-
phous solid. Yield 18%. Mp 284 °C (dec). 1H NMR (DMSO-d6)
δ 1.62 (m, 2H), 1.78 (d, 2H, J ) 11.7 Hz), 1.99 (m, 2H), 2.18
(s, 3H), 2.55 (m, 1H), 2.84 (d, 2H, J ) 10.6 Hz), 6.81 (d, 1H, J
) 8.6 Hz), 7.07 (s, 1H), 7.13 (m 1H), 7.16 (s, 1H), 7.20-7.26
(m, 1H), 9.90 (br s, 1H), 10.83 (s, 1H).
N-{3-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}-5-chloro-
3-methyl-benzo[b]thiophene-2-sulfonamide (19r). Color-
less amorphous solid. Yield 35%. Mp 201-203 °C. 1H NMR
(DMSO-d6) δ 1.62 (m, 4H), 2.29 (s, 3H), 2.30 (m, 4H), 2.36 (m,
2H), 2.63 (m, 2H), 6.86 (d, 1H, J ) 8.6 Hz), 7.05 (s, 1H), 7.09
(s, 1H), 7.21 (dd, 1H, J ) 8.6, 2.2 Hz), 7.50 (dd, 1H, J ) 8.7,
2.0 Hz), 7.92 (s, 1H), 7.99 (dd, 1H, J ) 8.7, 2.2 Hz), 10.10 (br
s, 1H), 10.81 (s, 1H). Anal. (C23H24ClN3O2S2‚1/2H2O) C, H, N.
N-{3-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naph-
thalene-1-sulfonamide (19s). Cream colored amorphous
solid. Yield 66%. Mp 212-214 °C. 1H NMR (DMSO-d6) δ 1.66
(m, 4H), 2.36 (m, 6H), 2.58 (m, 2H), 6.71 (d, 1H, J ) 8.6 Hz),
6.93 (s, 1H), 7.02 (s, 1H), 7.07 (d, 1H, J ) 8.6 Hz), 7.48 (m,
1H), 7.68 (m, 2H), 8.02 (dd, 2H, J ) 7.2, 1.2 Hz), 8.12 (d, 1H,
J ) 8.2 Hz), 8.79 (d, 1H, J ) 8.6 Hz), 10.10 (br s, 1H), 10.68
(s, 1H).
N-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]quinolyl-2-
sulfonamide (20e). Cream colored amorphous solid. Yield
1
71%. Mp 280 °C (dec). H NMR (DMSO-d6) δ 1.25-1.52 (m,
4H), 1.85 (m, 2H), 2.18 (s, 3H), 2.27 (m, 1H), 2.74 (d, 2H, J )
11.4 Hz), 6.72 (dd, 1H, J ) 8.6, 2.0 Hz), 6.83 (d, 1H, J ) 1.5

1792 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Holenz et al.
Hz), 6.90 (d, 1H, J ) 2.0 Hz), 7.02 (d, 1H, J ) 8.6 Hz), 7.57
(m, 1H), 7.74 (dd, 1H, J ) 8.4, 4.3 Hz), 8.12 (dd, 1H, J ) 7.3,
1.3 Hz), 8.19 (dd, 1H, J ) 8.2, 1.3 Hz), 8.52 (dd, 1H, J ) 8.4,
1.7 Hz), 9.21 (dd, 1H, J ) 4.3, 1.7 Hz), 9.36 (s, 1H), 10.64 (s,
1H). Anal. (C23H24N4O2S‚1/2H2O) C, H, N.
N-[3-(1-Methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenyl-
benzenesulfonamide (20f). Cream colored amorphous solid.
Yield 70%. Mp 247-248 °C. 1H NMR (DMSO-d6) δ 1.52 (s, 2H),
1.67 (m, 2H), 1.85 (m, 2H), 2.08 (s, 3H), 2.44 (m, 1H), 2.67 (d,
2H, J ) 10.25 Hz), 6.83 (d, 1H, J ) 8.4 Hz), 7.01 (s, 1H), 7.03
(s, 1H), 7.19 (d, 1H, J ) 8.4 Hz), 7.35-7.50 (m, 3H), 7.63-
7.73 (m, 4H), 7.79 (sys AB, 2H, J ) 7.6 Hz), 9.71 (br s, 1H),
10.76 (s, 1H).
2-[5-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl-
amino)-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetamide (21a).
Cream colored amorphous solid. Yield 42%. Mp 272 °C. 1H
NMR (DMSO-d6) δ 2.40 (s, 3H), 2.80 (s, 3H), 2.93 (s, 3H), 7.06
(dd, 1H, J ) 8.7, 1.9 Hz), 7.39 (d, 1H, J ) 8.8 Hz), 7.50 (dd,
1H, J ) 8.8, 2.0 Hz), 7.85 (s, 1H), 7.94 (d, 1H, J ) 1.7 Hz),
8.00 (d, 1H, J ) 8.5 Hz), 8.05 (d, 1H, J ) 3.1 Hz), 10.53 (s,
1H), 12.30 (s, 1H).
2-[5-(6-Chloroimidazo[2,1-b][1,3]thiazole-5-sulfonylami-
no)-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetamide (21b).
Cream colored amorphous solid. Yield 41%. Mp 161-164 °C.
1H NMR (DMSO-d6) δ 2.84 (s, 3H), 2.94 (s, 3H), 7.02 (d, 1H, J
) 7.6 Hz), 7.39 (d, 1H, J ) 8.5 Hz), 7.56 (d, 1H, J ) 4.4 Hz),
7.79 (s, 1H), 7.88 (d, 1H, J ) 4.4 Hz), 8.06 (s, 1H), 10.68 (s,
1H), 12.29 (s, 1H). Anal. (C17H14ClN5O4S2‚1/2H2O) C, H, N.
2-[5-(6-Chloroimidazo[2,1-b][1,3]thiazole-5-sulfonylami-
no)-1H-indol-3-yl]-N,N-diethyl-2-oxoacetamide (21c). Col-
orless amorphous solid. Yield 37%. Mp 249-251 °C. 1H NMR
(DMSO-d6) δ 1.02 (t, 3H, J ) 7.0 Hz), 1.14 (t, 3H, J ) 7.0 Hz),
3.17 (m, 2H), 3.39 (m, 2H), 7.02 (dd, 1H, J ) 8.8, 2.0 Hz), 7.39
(d, 1H, J ) 8.8 Hz), 7.56 (d, 1H, J ) 4.4 Hz), 7.79 (d, 1H, J )
1.6 Hz), 7.87 (d, 1H, J ) 4.4 Hz), 7.99 (d, 1H, J ) 2.5 Hz),
10.67 (s, 1H), 12.24 (s, 1H). Anal. (C19H18ClN5O4S2) C, H, N.
N,N-Diethyl-2-[5-(naphthalene-1-sulfonylamino)-1H-
indol-3-yl]-2-oxoacetamide (21d). Cream colored amorphous
solid. Yield 56%. Mp 275-277 °C. 1H NMR (DMSO-d6) δ 0.99
(t, 3H, J ) 7.0 Hz), 1.12 (t, 3H, J ) 7.0 Hz), 3.14 (m, 2H), 3.36
(m, 2H), 6.94 (dd, 1H, J ) 8.6, 2.0 Hz), 7.27 (d, 1H, J ) 9.0
Hz), 7.54 (t, 1H, J ) 7.7 Hz), 7.63 (m, 1H), 7.70 (m, 2H), 7.92
(s, 1H), 8.03 (d, 1H, J ) 7.3 Hz), 8.13 (m, 2H), 8.76 (d, 1H, J
) 8.8 Hz), 10.49 (s, 1H), 12.14 (s, 1H).
N,N-Diethyl-2-oxo-2-[5-(quinoline-8-sulfonylamino)-
1H-indol-3-yl]-acetamide (21e). Cream colored amorphous
solid. Yield 42%. Mp 227-232 °C. 1H NMR (DMSO-d6) δ 0.99
(t, 3H, J ) 6.9 Hz), 1.13 (t, 3H, J ) 6.9 Hz), 3.13 (m, 2H), 3.36
(m, 2H), 6.92 (dd, 1H, J ) 8.8, 1.8 Hz), 7.21 (d, 1H, J ) 8.6
Hz), 7.63 (t, 1H, J ) 7.6 Hz), 7.72 (m, 2H), 7.88 (s, 1H), 8.23
(m, 2H), 8.49 (d, 1H, J ) 7.4 Hz), 9.18 (dd, 1H, J ) 7.4, 1.4
Hz), 9.9 (s, 1H), 12.10 (s, 1H).
N-[3-(3-Diethylaminopropyl)-1H-indol-5-yl]naphtha-
lene-2-sulfonamide (19n). To a stirred mixture of 2a (6.7 g,
41.3 mmol) and phthalimide (2.7 g, 18.4 mmol) in anhydrous
Et2O (150 mL), malonyldichloride (18.1 g, 128 mmol) was
added dropwise. The reaction mixture was stirred at room
temperature under nitrogen for 72 h. The resulting reaction
mixture was cooled to 4 °C, and dimethylamine (67 mL) was
added. The resulting mixture was stirred at room temperature
for 1 h. Water (100 mL) was added, and the pH was adjusted
to pH 3 using concentrated aqueous HCl. The mixture was
extracted with EtOAc. The organic layer was separated, dried,
and evaporated to obtain an orange colored amorphous solid
that was purified using SiO2 flash chromatography with
CHCl3/MeOH (9:1) as solvent to yield 3.0 g (24%) of N,N-
diethyl-3-(5-nitro-1H-indol-3-yl)-3-oxopropanamide as a yellow
colored amorphous solid. 1H NMR (DMSO-d6) δ 1.02 (t, 3H, J
) 7.1 Hz), 1.11 (t, 3H, J ) 7.1 Hz), 3.20-3.40 (m, 4H), 4.02 (s,
2H), 7.68 (d, 1H, J ) 9.0 Hz), 8.11 (dd, 1H, J ) 9.0, 2.3 Hz),
8.59 (d, 1H, J ) 2.0 Hz), 9.00 (d, 1H, J ) 2.3 Hz), 12.59 (br s,
1H).
mL), borane in THF (12.5 mL, 1.0 M, 12.5 mmol, 3.8 equiv)
was added dropwise. The reaction mixture was stirred at room
temperature under N2 atmosphere for 20 h. A saturated
aqueous solution of NaHCO3 was added, and the mixture was
extracted with Et2O. The organic extracts were combined,
dried, and evaporated to dryness to afford 1.8 g of the borane
complex as an orange colored amorphous solid that was treated
with CsF (1.8 g) and Na2CO3 (1.8 g) in absolute EtOH (50 mL).
The mixture was heated at reflux under N2 atmosphere for
16 h. The resulting reaction mixture was filtered through
Decalite, and the filtrate was dried with Na2SO4 and evapo-
rated to dryness. The obtained solid was purified using SiO2
flash chromatography with CH2Cl2/MeOH/NH4OH (9:1:0.01)
as solvent to afford 0.5 g (55%) of N,N-diethyl-3-(5-nitro-1H-
indol-3-yl)propanamine as an orange colored oil. 1H NMR
(DMSO-d6) δ 0.91 (t, 6H, J ) 7.1 Hz), 1.74 (m, 2H), 2.40-2.50
(m, 6H), 2.73 (m, 2H), 7.38 (s, 1H), 7.47 (d, 1H, J ) 9.0 Hz),
7.95 (dd, 1H, J ) 9.0, 2.0 Hz), 8.47 (d, 1H, J ) 2.0 Hz), 11.54
(br s, 1H).
To a solution of N,N-diethyl-3-(5-nitro-1H-indol-3-yl)pro-
panamine (0.5 g, 1.8 mmol) in absolute EtOH (20 mL), 100
mg (5%) of Pd/C moistened with water (50%) were added. The
mixture was hydrogenated under 20 psi at room temperature
for 20 h. The resulting mixture was filtered through a pad of
Celite, and the filtrate was evaporated to dryness to afford
0.44 g (98%) of 3-[3-(diethylamino)propyl]-1H-indol-5-amine as
1
a red colored oil. H NMR (CDCl3) δ 1.02 (t, 6H, J ) 7.1 Hz),
1.86 (m, 2H), 2.50-2.60 (m, 6H), 2.67 (m, 2H), 6.64 (dd, 1H, J
) 8.4, 2.1 Hz), 6.90 (m, 2H), 7.16 (d, 1H, J ) 8.4 Hz), 7.78 (br
s, 1H).
From 3-[3-(diethylamino)propyl]-1H-indol-5-amine, follow-
ing the general methodology for the synthesis of indolylsul-
fonamido compounds, 19n was obtained as a colorless amor-
phous solid. Yield 47%. Mp 128-130 °C. 1H NMR (DMSO-d6)
δ 0.86 (t, 6H, J ) 7.0 Hz), 1.51 (t, 2H, J ) 6.9 Hz), 2.27 (t, J
) 6.9 Hz), 2.35 (q, 4H, J ) 7.0 Hz), 2.46 (m, 2H), 6.77 (d, 1H,
J ) 8.6 Hz), 7.00 (s, 1H), 7.10 (m, 2H), 7.60 (m, 2H), 7.72 (d,
1H, J ) 8.8 Hz), 7.95 (d, 1H, J ) 7.9 Hz), 8.02 (m, 2H), 8.26
(s, 1H), 9.86 (br s, 1H), 10.67 (s, 1H). Anal. (C25H29N3O2S) C,
H, N.
8-Methyl-1-piperidin-4-yl-1,4-dihydro-benzo[d][1,3]-
oxazin-2-one Hydrochloride (22b). 1-(tert-Butyloxycarbo-
nyl)-4-piperidone (9.96 g, 50 mmol), 2-amino-3-methyl-benzyl
alcohol (7.54 g, 55 mmol), and AcOH (6.3 mL, 110 mmol) were
dissolved in dry toluene (200 mL). The solution was refluxed
with azeotropic removal of water for 6 h, then evaporated to
half of the original volume. To the solution, NaBH3CN (10.37
g, 165 mmol) in dry THF (150 mL) was added. Then, AcOH
(4.9 mL, 85 mmol) was added dropwise. The reaction was
stirred at room temperature for 24 h and concentrated under
reduced pressure, and the residue was dissolved in EtOAc (350
mL). The solution was washed with saturated aqueous NaH-
CO3 (4 × 125 mL) and brine (125 mL). The combined EtOAc
layers were separated and dried with Na2SO4, and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography using 30% EtOAc in hexane. 1-(tert-
Butyloxycarbonyl)-4-(2-hydroxymethyl-6-methyl-phenylamine)-
piperidine was obtained as a brown viscuous oil (14.70 g, 92%).
1H NMR (CDCl3) δ 1.33 (m, 2H), 1.45 (s, 9H), 1.87 (d, 2H, J )
12.4 Hz), 2.26 (s, 3H), 2.69 (t, 2H, J ) 12.4 Hz), 3.08 (m, 1H),
3.59 (br s, 2H), 4.10 (m, 2H), 4.67 (s, 2H), 6.87 (m, 1H), 7.00
(d, 1H, J ) 7.3 Hz), 7.07 (d, 1H, J ) 7.5 Hz). This intermediate
(14.60 g, 47 mmol) was dissolved in dry THF (150 mL) and
cooled to 0 °C. To the solution, N,N-diisopropylethylamine (26
mL, 150 mmol) and triphosgene (5.04 g, 17 mmol) were added.
The reaction was stirred at 0 °C for 1 h and then at room
temperature for 72 h. Et2O (150 mL) was added, the mixture
was cooled to 0 °C for 2 h, and the hydrochloride salt of N,N-
diisopropylethylamine was removed by filtration. The filtrates
were evaporated to dryness, and the residue was dissolved in
EtOAc (300 mL). The EtOAc solution was washed with 5%
aqueous citric acid (2 × 250 mL), water (100 mL), and
saturated aqueous NaHCO3 (2 × 200 mL). The EtOAc layer
was dried with Na2SO4, and the solvent was removed under
To a stirred solution of N,N-diethyl-3-(5-nitro-1H-indol-3-
yl)-3-oxopropanamide (1.0 g, 3.3 mmol) in anhydrous THF (30

Novel, Selective Serotonin 5-HT6 Receptor Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1793
1
reduced pressure to give 1-(tert-butyloxycarbonyl)-4-(piperidi-
nyl)-8-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one (15.63 g,
96%) of a crude yellow colored oil. 1H NMR (CDCl3) δ 1.33 (m,
2H), 1.45 (s, 9H), 1.87 (d, 2H, J ) 12.4 Hz), 2.26 (s, 3H), 2.69
(t, 2H, J ) 12.4 Hz), 3.08 (m, 1H), 3.59 (br s, 2H), 4.10 (m,
2H), 4.67 (s, 2H), 6.87 (m, 1H), 7.00 (d, 1H, J ) 7.3 Hz), 7.07
(d, 1H, J ) 7.5 Hz).
°C. H NMR (CDCl3) δ 1.9 (d, 2H, J ) 12.5 Hz), 2.3 (s, 3H),
2.7 (m, 4H), 3.3 (m, 1H), 4.0 (d, 2H, J ) 11.2 Hz), 4.9 (s, 2H),
7.0 (m, 2H), 7.1 (d, 1H, J ) 7.0 Hz), 7.6 (m, 3H), 7.9 (m, 1H),
8.1 (d, 1H, J ) 8.2 Hz), 8.2 (dd, 1H, J ) 7.3, 1.1 Hz), 8.7 (d,
1H, J ) 8.8 Hz). Anal. (C24H24N2O4S) C, H, N.
1-[1-(5-Dimethylaminonaphthalene-1-sulfonyl)-piperi-
din-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one
(23f). The reaction product was purified by crystallization with
EtOH to provide 23f in 72% yield as a colorless amorphous
solid. Mp 202-203 °C. 1H NMR (CDCl3) δ 1.9 (d, 2H, J ) 11.9
Hz), 2.3 (s, 3H), 2.7 (m, 4H), 2.9 (s, 6H), 3.3 (m, 1H), 4.0 (d,
2H, J ) 9.9 Hz), 4.9 (s, 2H), 7.0 (m, 2H), 7.2 (m, 2H, J ) 7.3
Hz), 7.5 (m, 2H), 8.2 (dd, 1H, J ) 7.3, 1.1 Hz), 8.4 (d, 1H, J )
8.6 Hz,), 8.6 (d, 1H, J ) 8.4 Hz). Anal. (C26H29N3O4S) C, H, N.
1-[1-(Quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-
benzo[d][1,3]oxazin-2-one (23g). The reaction product was
purified by crystallization with EtOH to provide 23g in 96%
yield as a colorless amorphous solid. Mp 169-171 °C. 1H NMR
(CDCl3) δ 1.8 (d, 2H, J ) 9.5 Hz), 2.6 (qd, 2H, J ) 12.6, 4.4
Hz), 3.0 (td, 2H, J ) 12.8, 2.5 Hz), 4.1 (tt, 1H, J ) 12.5, 3.8
Hz), 4.3 (ddd, 2H, J ) 13.0, 2.3 Hz), 5.0 (s, 2H), 7.1 (m, 3H),
7.3 (m, 1H), 7.6 (dd, 1H, J ) 8.4, 4.2 Hz), 7.6 (m, 1H), 8.1 (dd,
1H, J ) 8.2, 1.3 Hz), 8.3 (dd, 1H, J ) 8.3, 1.7 Hz), 8.5 (dd, 1H,
J ) 7.3, 1.5 Hz), 9.1 (dd, 1H, J ) 4.2, 1.8 Hz). Anal.
(C22H21N3O4S) C, H, N.
To a stirred solution of the crude 1-(tert-butyloxycarbonyl)-
4-(piperidinyl)-8-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one
(15.25 g, 44 mmol) in EtOAc (200 mL), a 5 M solution of HCl
in Et2O (500 mL) was added at 0 °C, and the resulting mixture
was stirred for 4 h at 0 °C. The precipitate formed was collected
by filtration, washed with Et2O, and dried, giving 22b as a
1
colorless amorphous solid (9.58 g, 77%). Mp 257-262 °C. H
NMR (DMSO-d6) δ 2.04 (d, 2H, J ) 13.6 Hz), 2.38 (s, 3H), 2.65
(m, 2H, J ) 12.9, 3.5 Hz), 2.98 (m, 2H), 3.28 (d, 2H, J ) 12.1
Hz), 3.76 (ddd, 1H, J ) 11.5, 8.3, 3.5 Hz), 5.06 (s, 2H), 7.11
(m, 2H), 7.23 (dd, 1H, J ) 7.2, 1.4 Hz), 8.50 (s, 1H), 9.48 (s,
1H).
General Procedure for the Synthesis of Piperidin-4-
yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Sulfonamides
(23a-j). The corresponding benzoxazinone hydrochloride (0.1
mmol) was suspended in dry CH2Cl2 (10 mL). N,N-Diisopro-
pylethylamine (0.25 mmol) was added, and the reaction
mixture was stirred at room temperature for 15 min. The
appropriate sulfonyl chloride (0.11 mmol) was then added, and
the mixture was stirred at room temperature until complete
conversion (TLC). The solution was washed with water, dried
with Na2SO4, evaporated, and crystallized as described for each
compound.
8-Methyl-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-
1,4-dihydro-benzo[d][1,3]oxazin-2-one (23h). The reaction
product was purified by crystallization with EtOH to provide
23h in 71% yield as a colorless amorphous solid. Mp 202-207
1
°C. H NMR (CDCl3) δ 1.9 (d, 2H, J ) 12.6 Hz), 2.3 (s, 3H),
The following compounds were prepared according to the
procedures described above from the corresponding substituted
benzoxazinones.
2.7 (qd, 2H, J ) 12.2, 3.9 Hz), 2.9 (m, 2H), 3.3 (tt, 1H, J )
11.7, 3.4 Hz), 4.3 (d, 2H, J ) 12.8 Hz), 4.9 (s, 2H), 7.0 (m, 2H),
7.1 (d, 1H, J ) 7.3 Hz), 7.5 (dd, 1H, J ) 8.3, 4.1 Hz), 7.6 (m,
1H), 8.0 (dd, 1H, J ) 8.2, 1.3 Hz), 8.2 (dd, 1H, J ) 8.3, 1.7
Hz), 8.5 (dd, 1H, J ) 7.3, 1.5 Hz), 9.1 (dd, 1H, J ) 4.2, 1.8
Hz). Anal. (C23H23N3O4S) C, H, N.
1-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-
1,4-dihydro-benzo[d][1,3]oxazin-2-one (23a). The reaction
product was purified by crystallization with EtOH to provide
23a in 76% yield as a colorless amorphous solid. Mp 166-168
1-[1-(5-Bromo-2-methoxybenzenesulfonyl)-piperidin-
4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (23i).
The reaction product was purified by crystallization with EtOH
to provide 23i in 68% yield as a colorless amorphous solid. Mp
213-216 °C. 1H NMR (CDCl3) δ 1.90 (d, 2H, J ) 11.9 Hz), 2.36
(s, 3H), 2.64 (m, 2H), 2.80 (m, 2H), 3.97 (s, 3H), 4.01 (m, 3H),
4.95 (s, 2H), 6.93 (d, 1H, J ) 8.8 Hz), 7.02 (m, 2H), 7.17 (d,
1H, J ) 7.3 Hz), 7.62 (dd, 1H, J ) 8.9, 2.5 Hz), 8.04 (d, 1H, J
) 2.6 Hz). Anal. (C21H23BrN2O5S) C, H, N.
1-[1-(2,5-Dimethoxybenzenesulfonyl)-piperidin-4-yl]-
8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (23j). The
reaction product was purified by crystallization with 2-pro-
panol to provide 23j in 68% yield as a colorless amorphous
solid. Mp 100-102 °C. 1H NMR (CDCl3) δ 1.89 (d, 2H, J )
12.45 Hz), 2.35 (s, 3H), 2.72 (m, 4H), 3.37 (m, 1H), 3.80 (s,
3H), 3.92 (s, 3H), 4.01 (d, 2H, J ) 10.6 Hz), 4.95 (s, 2H), 7.02
(m, 4H), 7.17 (d, 1H, J ) 7.8 Hz), 7.46 (d, 1H, J ) 3.1 Hz).
Anal. (C22H26N2O6S) C, H, N.
In Vitro 5-HT6 Membrane Binding Assays. Membranes
from HEK-293 with human 5-HT6 serotonin receptor expressed
were supplied by Receptor Biology. The binding assays were
performed as described by Roth et al.17 with slight modifica-
tions. The radioligand used was [3H]-LSD at 2.7 nM, and the
final volume was 200 µL. The incubation was initiated by
addition of 100 µL of membrane (22.9 µg of protein), and the
incubation time was 60 min at 37 °C. After incubation, the
membranes were collected onto polyethylenimine-pretreated
glass fiber filters (Schleicher & Schnell 3362). The filters were
washed with buffer (50 mM Tris Cl, pH ) 7.4). Then, filter
sections were transferred to vials, and liquid scintillation
cocktail was added to each vial. Nonspecific binding was
determined with 100 µM serotonin. Competition binding data
were analyzed by using the LIGAND program,40 and assays
were performed in triplicate determinations for each point.
Adenylyl Cyclase Activity Assay. The activation or
inhibition of adenylyl cyclase activity was studied by measur-
ing levels of cAMP in 96-well plates by the FlashPlate method
(PerkinElmer). C6 cells overexpressing the 5-HT6 receptor
1
°C. H NMR (DMSO-d6) δ 1.81 (d, 2H, J ) 11.1 Hz), 2.48 (m,
2H), 2.64 (t, 2H, J ) 11.6 Hz), 3.83-3.95 (m, 3H), 5.08 (s, 2H),
7.01-7.12 (m, 2H), 7.20-7.25 (m, 2H), 7.49-7.58 (m, 2H),
8.15-8.23 (m, 2H), 8.60 (s, 1H). Anal. (C21H20N2O4S2) C, H,
N.
1-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-8-
methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (23b). The
reaction product was purified by crystallization with EtOH to
provide 23b in 70% yield as a colorless amorphous solid. Mp
1
179-181 °C. H NMR (DMSO-d6) δ 1.93 (d, 2H, J ) 12 Hz),
2.23 (s, 3H), 2.43 (m, 2H), 2.59 (t, 2H, J ) 12 Hz), 3.49 (t, 1H,
J ) 10.9 Hz), 3.82 (d, 2H, J ) 10.8 Hz), 4.99 (s, 2H), 7.06 (m,
3H), 7.51 (m, 2H), 8.15 (m, 2H), 8.56 (s, 1H). Anal. (C22H22N2-
O4S2) C, H, N.
1-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-
piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one(23c).
The reaction product was purified by crystallization with EtOH
to provide 23c in 84% yield as a colorless amorphous solid.
1
Mp 204-206 °C. H NMR (DMSO-d6) δ 1.8 (d, 2H, J ) 10.8
Hz), 2.5 (m, 2H), 2.7 (s, 3H), 2.8 (t, 2H, J ) 11.4 Hz), 3.8 (d,
2H, J ) 11.4 Hz), 3.9 (m, 1H), 5.1 (s, 2H), 7.0 (t, 1H, J ) 7.2
Hz), 7.2 (d, 1H, J ) 8.1 Hz), 7.2 (m, 2H), 7.6 (dd, 1H, J ) 8.6,
2.0 Hz), 8.1 (d, 1H, J ) 2.0 Hz), 8.2 (d, 1H, J ) 8.6 Hz). Anal.
(C22H21ClN2O4S2) C, H, N.
1-[1-(Naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihy-
dro-benzo[d][1,3]oxazin-2-one (23d) The reaction product
was purified by crystallization with EtOH to provide 23d in
82% yield as a colorless amorphous solid. Mp 147-149 °C. 1H
NMR (DMSO-d6) δ 1.8 (d, 2H, J ) 10.5 Hz), 2.4 (m, 2H), 2.7
(t, 2H, J ) 11.6 Hz), 3.9 (n, 3H), 5.1 (s, 2H), 7.1 (m, 2H), 7.2
(m, 2H), 7.7 (m, 3H), 8.1 (d, 1H, J ) 8.1 Hz), 8.2 (d, 1H, J )
7.8 Hz), 8.3 (d, 1H, J ) 8.1 Hz), 8.7 (d, 1H, J ) 8.3 Hz). Anal.
(C23H22N2O4S) C, H, N.
8-Methyl-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-
1,4-dihydro-benzo[d][1,3]oxazin-2-one (23e). The reaction
product was purified by crystallization with EtOH to provide
23e in 72% yield as a colorless amorphous solid. Mp 203-204

1794 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
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Acknowledgment. The authors thank Prof. Jose´
Elguero, Dr. Jordi Frigola, and Dr. Jordi Quintana for
thoughtful contributions and critical reading of the
manuscript and Dr. Adriana Port and Mrs. Angeles
Go´mez for NMR and HPLC analyses.
Supporting Information Available: Two HPLC-system
charts for key target compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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