Synthesis and structure-activity relationships of novel histamine H 1 antagonists: Indolylpiperidinyl benzoic acid derivatives

Article abstract of DOI:10.1021/jm0498203

A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H₁ antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT₂ receptor. Extensive optimization was carried out within this series and a number of histamine H₁ antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48, 51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.

Full text of DOI:10.1021/jm0498203

6326
J. Med. Chem. 2004, 47, 6326-6337
Synthesis and Structure-Activity Relationships of Novel Histamine H1
Antagonists: Indolylpiperidinyl Benzoic Acid Derivatives
Silvia Fonquerna,*,† Montse Miralpeix,*,‡ Llu´ıs Page`s,† Carles Puig,† Arantxa Cardu´s,† Francisca Anto´n,‡
AÄ lvaro Ca´rdenas,‡ Dolors Vilella,‡ Mo´nica Aparici,‡ Elena Calaf,‡ Jose´ Prieto,† Jordi Gras,‡ Josep M. Huerta,§
Graham Warrellow,† Jorge Beleta,‡ and Hamish Ryder†,‡
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024-Barcelona, Spain
Received March 4, 2004
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as
histamine H1 antagonists. Structure-activity relationship studies were directed toward
improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of
fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of
histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT2
receptor. Extensive optimization was carried out within this series and a number of histamine
H1 antagonists showing potency and long duration of action in vivo and low brain penetration
or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,
51 and 52 exhibited a long half-life in rat and have been selected for further preclinical
evaluation.
Introduction
although the specific mechanisms underlying these
effects are not understood, it is not clear whether this
is a class effect or is confined to certain members of the
second-generation of these drugs. Nevertheless, it must
be emphasized that most of the available data result
from in vitro experiments performed at very high and
irrelevant concentrations.7
Histamine is one of the most important chemical
mediators and through its interaction with H1 receptors,
present in most tissues, is involved in the pathophysi-
ology of allergic rhinoconjuntivitis, urticaria and atopic
dermatitis. Among the broad range of allergic diseases,
allergic rhinitis is the most prevalent condition, affecting
10 to 30% of adults and up to 40% of children, with
increasing prevalence over the past decade.1 The eco-
nomic burden of this disease is enormous, as is the
impact on the quality of life.2
Allergic rhinitis is an IgE-mediated disease that is
provoked by either seasonal or perennial inhaled al-
lergens. The symptoms of allergic rhinitis result from
inflammation of the nasal mucosa, which is initiated by
the interaction of aeroallergens with specific IgE anti-
bodies attached primarily to mast cells, which ac-
cumulate in nasal epithelium in response to repeated
exposure to allergen.3 The interaction between mast cell-
released mediators of inflammation, including hista-
mine, leukotrienes, prostaglandins, tryptase and kinins,
and neural and vascular structures within the nose,
cause the allergic rhinitis symptoms of itch, sneeze,
rhinorrhea and obstruction.4
First-generation antihistamines are effective and
relatively inexpensive; however, they also cause seda-
tion and dry mouth at therapeutic doses, due to their
blood-brain barrier penetration and lack of receptor
specificity. Somnolence is experienced by a significant
percentage (10 to 40%) of patients using these drugs,
and may impair driving and other types of perfor-
mance.8 In contrast, most second-generation histamine
H1-receptor antagonists have a greatly improved benefit-
to-risk ratio compared to their predecessors, mainly
because their reduced potential to cross the blood-brain
barrier and higher receptor specificity.9 Unfortunately,
some of the second-generation antihistamines can pro-
duce fatal arrhythmogenic events, through impairing
cardiac muscle repolarization. This results in the pro-
longation of the QT interval and the possible provocation
of the specific polymorphic ventricular tachyarrhythmia,
torsades de pointes.10 Such toxic events may occur under
the following conditions: overdosage, hepatic failure,
concomitant use of CYP450 inhibitors and/or cardiotoxic
drugs and finally preexistence of rhythm disturbances
and more especially congenital long Q-T syndrome.
Indeed, several second-generation histamine H1-anti-
histamines are substrates and modulators of CYP450,
in particular the subtype CYP3A4. Thus, their plasma
and tissue levels may be increased and become toxic in
the case of polymedication as well as the plasma and
tissue levels of concomitantly administered drugs.11
This paper describes the synthesis and structure-
activity relationships of new indolylpiperidinyl benzoic
acid derivatives, a family of histamine H1 antagonists
with potent and long lasting activity in vivo, low liability
The histamine H1 antagonists are used as the first-
line treatment for patients with allergic rhinitis.5 They
prevent symptoms associated with histamine release
such as sneezing, rhinorrhea, nasal and conjunctival
itching and lacrimation, although they do not control
symptoms of nasal congestion.6 Additional antiinflam-
matory effects of antihistamines have been described,
Corresponding authors. For S. Fonquerna: Treball 2, 08960 St Just
Desvern, Spain. Phone: +34-93-291-3999. Fax: +34-93-312-8635.
E-mail: sfonquerna@almirall.es. For M. Miralpeix: Cardener 68-74,
08024 Barcelona, Spain. Phone: +34-93-291-3468. Fax: +34-93-2827.
E-mail: mmiralpe@almirall.es.
† Department of Medicinal Chemistry.
‡ Department of Biology.
§ Department of Structural Analysis of Drug Discovery Division.
10.1021/jm0498203 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/04/2004

Novel Histamine H1 Antagonists
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6327
Scheme 1a
a Reagents and conditions: (a) KOH, MeOH, 70 °C, 5 h; (b) H2, Pd-C (10%), 1 h; (c) K2CO3, methylisobutyl ketone, 100 °C, 18 h; (d)
polymer-supported-NCO, Cl2CH2, rt, 3 h; (e) NaH, R2X, rt, 15 h; (f) NaOH, EtOH, rt, 16 h.
Scheme 2a
a Reagents and conditions: (a) Et3N, ClCO2Et, DCM, 0 °C 1 h; (b) NaH, R3X, 60 °C 1 h; (c) KOH, iPrOH, rfx 18 h; (d) XACO2R2, K2CO3,
MIK, 90 °C, 15 h; (e) NaOH, EtOH, rt, 24 h.
to enter into the brain and lacking cardiotoxic potential.
In addition, the compounds described in this paper show
low metabolic clearance and absence of CYP450 inhibi-
tion that suggests a low potential for drug-drug inter-
actions and intersubject variability in drug response.
Overall, these characteristics may distinguish the an-
tihistamines described in this paper from the second-
generation antihistamines.
Chemistry. Two different strategies were designed
in order to synthesize indolylpiperidine derivatives
1-53. At the beginning of the optimization process,
libraries of compounds were prepared to achieve a
higher throughput. Combinatorial techniques,12 such as
the use of polymer-supported scavengers and automated
purification in parallel, were applied. Scheme 1 shows
the general synthetic approach used in a parallel
fashion. Sequential condensation of a substituted indole
with piperidone and further hydrogenation of the cor-
responding adducts gave indolylpiperidines 57. Alkyla-
tion of indolylpiperidines 57 with appropriate halides
58 provided intermediates 59. The unreacted excess of
indolylpiperidines 57 was removed by incubation with
a polymer-supported isocyanate, and the crude was
purified in parallel by anionic exchange chromatogra-
phy.13 Further alkylation of indolic nitrogen with R2X
using sodium hydride as base and saponification of
intermediates 59 followed by acidification provided
indolylpiperidines 1-53. Purification of final library
members was achieved by semipreparative C-18 HPLC-
MS.
Alternatively, when highly characterized compounds
were required for advanced SAR studies, the sequential
synthetic approach described in Scheme 2 was followed.
Protection of indolylpiperidine 57 with ethyl chlorofor-
mate followed by alkylation of the indole ring with the
appropriate alkyl or arylalkyl halide provided interme-
diates 61. Further treatment with potassium hydroxide
at 80 °C led to key derivatives 62. Alkylation of

6328 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Fonquerna et al.
Table 1. Effect of Aromatic Substitution on in Vitro and in
Vivo Activity
indolylpiperidines 62 with appropriately substituted
halides 58 and further saponification afforded indolylpi-
peridines 1-53.
Biology. Biological Evaluation. To determine struc-
ture-activity relationships, all compounds described
were evaluated for their affinity for the guinea-pig
cerebellum histamine H1 receptor in a radioligand
binding assay.14 Selectivity was assessed by testing their
binding affinity against the human 5-HT2 and the rat
alpha-1 receptors.15,16 High affinity compounds for the
histamine H1 receptor, with at least 10 times selectivity
versus the other two receptors, were evaluated for their
antihistamine activity in the rat histamine-induced
cutaneous vascular permeability model.17 Compounds
showing potent and stable oral antihistamine activity
after 8 h postadministration in this model were then
tested for their capacity to cross the blood-brain barrier
in the H1 ex vivo binding assay in mice.18 Finally, for
selected compounds, pharmacokinetics studies were
performed in rats in order to determine the half-life of
elimination. For the most promising compounds, the
effect on QT interval prolongation in anaesthetised
guinea-pigs19 and the inhibitory effect on CYP3A4
isoform were measured.
a
a
b
compd
R1
R2
H1
86 3272
5HT2
R1
10
HICVPc (4 h)d,
1
H
H
H
H
H
H
H
H
H
0.1
0.035
-
-
-
2
5-OMe
5-F
6-F
5-Br
7-Br
7-Me
6-CF3
H
155 6700 >10
100
76
150 1500
80 1397
500 3100
>500 2900
500
225
221
219
34
3
500
260
10
10
3.6
10
7.6
6.9
10
4
5
6
>3
-
7
8
-
9
6′-F
3′-5′-diBr
5′-Me
5′-acetyl
4′-OMe
850
500
225
950 >10
779 >10
-
10
11
12
13
H
6.9
8.6
-
H
-
H
-
H
0.17
a Data are indicated as IC50 (nM). b Data are indicated as IC50
(µM). c Histamine-induced cutaneous vascular permeability model.
d Data are indicated as ED50 (mg/kg).
Results and Discussion
Table 2. Effect of the Indole Substitution on in Vitro and in
One of our lead structures when we initiated a
histamine H1 antagonist program was compound 1
which was related to some previously known mixed
5-lipoxygenase inhibitor/H1 antagonist.20 Compound 1
was a selective histamine H1 antagonist able to inhibit
histamine induced cutaneous vascular permeability
increase in rats after 1 h of oral administration with
higher potency than some standard compounds (Table
6). However, oral activity suffered from a 10-fold
decrease after 8 h. This was in accordance with its
pharmacokinetic profile showing a fast onset but a short
half-life in vivo (Table 5). In terms of safety, compound
1 showed a lack of adverse side effects commonly related
to antihistamines such as sedation and cardiovascular
toxicity (Table 6). The aim of our work was to modify
the structure in order to improve the duration of action
and pharmacokinetic profile while maintaining the
nonsedative properties and absence of potential cardiac
toxicity.
Our initial synthetic efforts were directed toward
determining the effect of substitution on the aromatic
rings of compound 1 (Table 1) on antihistaminic activity.
The presence of a methoxy group in 5-position of the
indolyl ring (2) enhanced in vivo activity with respect
to unsubstituted analogue 1 while keeping a similar
pattern of in vitro antihistaminic affinity and selectivity.
Halogen derivatives in position 5 and 6 of the indolyl
ring (3, 4 and 5) were less selective than compound 1
whereas the 7-bromo derivative (6), although showing
similar potency in vitro, was 30-fold less active in vivo.
The methyl (7) and trifluoromethyl (8) derivatives had
lower potency. On the other hand, substitution on the
benzoic acid ring (9, 10, 11 and 12) generally led to
derivatives with lower selectivity. However, compound
13, with a methoxy group in position 4, met our
selectivity criteria and showed similar potency in vivo
to analogue 1 although selectivity toward the 5-HT2
receptor was slightly reduced.
Vivo Activity
HICVPc
compd R1
R2
2-ethoxyethyl
2-methoxyethyl
2-methoxyethyl
butyl
cyclopropylmethyl
cyclopropylmethyl
allyl
[1,3]-dioxolanethyl
1-furan-2-ylmethyl
1-furan-2-ylmethyl
1-thiophen-2-ylmethyl
H1 5HT2
86 3272 10
R1
(4 h)d,
a
a
b
1
H
H
F
0.1
1.1
0.29
0.74
0.6
0.11
3
0.46
3
0.32
14
15
16
17
18
19
20
21
22
23
24
25
26
27
83 >10000 >10
140
127
1185 >10
9105 >10
H
H
F
140 >10000 >10
121 10000 >10
97 >10000 >10
H
H
H
F
354
4517
6.5
98 10000 >10
37
98
870 >10
500
1858 >10
1025 >10
2100
2900 >10
H
H
F
3.7 - -
5-chlorothiophen-2-ylmethyl 120
5-chlorothiophen-2-ylmethyl 28
3
1
3
H
H
2-[1,4]-dioxan-2-ylethyl
2-pyridin-2-ylethyl
390
570
6.2
- -
a Data are indicated as IC50 (nM). b Data are indicated as IC50
(µM). c Histamine-induced cutaneous vascular permeability model.
d Data are indicated as ED50 (mg/kg).
We then focused on modifications to the of N-alkyl
chain on the indole (Table 2). As general trends, we
observed that derivatives with alkyl, alkoxyalkyl, cy-
clolalkyl, heterocyclolalkyl and heterocycloaryl chains
showed a range of affinity and selectivity similar to
analogue 1 whereas activity in vivo was slightly re-
duced. However, entries 20, 26 and 27 with dioxolanyl-
ethyl, dioxanylethyl and pyridinylethyl groups led to
derivatives with low antihistaminic activity and less
selectivity than compound 1. The presence of a fluorine

Novel Histamine H1 Antagonists
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6329
atom in position 6 of the indolyl ring turned out to be
decisive in order to improve oral activity (15, 18, 22 and
25). We observed that comparing a different set of
compounds with the same substitution pattern, in vivo
activity was at least 3-fold higher in 6-fluoro-substituted
derivatives.
anaesthetised guinea-pigs at different prefixed doses (3,
10 and 30 mg/kg, iv). The data shown in Table 6
indicated that at 10 mg/kg (iv) compounds 1 and 51 and
even at 30 mg/kg (iv) compounds 15 and 48 did not
produce any significant increase in the QT interval. For
cetirizine and loratadine, the two most prescribed
second-generation antihistamines, the maximal dose
without effect were 3 and 10 mg/kg (iv), respectively. It
is noteworthy that none of these compounds were
inhibitors of CYP3A4 (Table 6), indicating low drug-
drug interaction potential.
The next area of exploration was the alkoxybenzoic
acid moiety (Table 3). Initial changes were directed
toward differences in relative regiochemistry (28 and
29) and the length of the alkoxy chain (30, 31 and 32).
The most promising compound was 31, which showed
a 9-fold improvement of in vivo activity compared to 1,
although with reduced selectivity versus 5-HT2. Other
variations such as elongating the distance between the
carboxylic acid and the phenyl group (33, 34 and 35)
led to derivatives with a good profile of affinity and
selectivity but with low in vivo potency. On the other
hand, substitution of the phenyl group by an heterocycle
afforded either low affinity (39) or low selectivity (40).
Since 3-methylenebenzoic acid (31) had been identified
as a good substitution pattern we decided to study in
more detail the effect of adding various functional
groups. Compound 36 with a methoxy group ortho to
the carboxylic acid showed a 5-fold enhanced in vivo
potency compared to compound 1 together with similar
selectivity.
Having established the best substitution around three
different areas of the indolylpiperidine scaffold in terms
of activity and selectivity, we then proceeded to syn-
thesize a combinatorial library using the optimized
fragments (Table 4). As a general trend, we observed
that they all were selective antihistamines in vitro vs
5HT2 and alpha-1 receptors with the main differences
based on their behavior in vivo depending on the nature
of benzoic acid chain. Derivatives containing 2-ethoxy-
benzoic acid showed high in vivo activity with some loss
of action after 8 h and low brain penetration, whereas
compounds with 3-methylbenzoic acid showed low oral
activity. Derivatives containing 2-methoxy-5-methyl-
benzoic acid showed high in vivo activity and longer
duration of action although some of them had low ED50
values (<5 mg/kg) in the H1 ex vivo model suggesting
that they may cross the blood-brain barrier. Cetirizine,
a second-generation antihistamine that has been shown
to cause some degree of somnolence21 and reduced
motivation to perform workday activities,22 had an ED50
of 5 mg/kg in this model.
Conclusions
We have identified a novel series of indolylpiperidinyl
benzoic acid derivatives as potent in vivo histamine H1
antagonists with long lasting activity, low brain pen-
etration and lacking cardiotoxic potential. In addition,
our compounds have absence of CYP3A4 inhibition
indicating low drug-drug interaction potential.
Relative to our initial lead compound (1), we have
improved in vivo activity and pharmacokinetic profile.
We have demonstrated that a 6-fluoro substituent on
the indolyl ring enhances in vivo activity albeit with a
slight loss of selectivity. We have also discovered that
derivatives containing the 2-methoxy-5-methylbenzoic
acid fragment have high in vivo activity and a longer
duration of action. A selected group of histamine H1
antagonists showing potent activity and long duration
of action in vivo with low capacity to cross the blood-
brain barrier has also been identified. Their overall
pharmacological profile suggests that these novel com-
pounds constitute a promising series of potent and safe
antihistamines with an improved therapeutic window
compared with some marketed antihistamines (Table
6). Compounds 15, 48 and 51 have been selected for
further preclinical profiling, based on their duration of
action in vivo, pharmacokinetic profile, low brain pen-
etration and lack of cardiotoxic potential. Results of
these studies will be reported in due course.
Experimental Section
Chemistry. General. Reagents, starting materials, and
solvents were purchased from commercial suppliers and used
as received. All organic solutions were dried over sodium
sulfate. Concentration refers to evaporation under vacuum
using a Bu¨chi rotatory evaporator. Reaction products were
purified, when necessary, by flash chromatography on silica
gel (40-63 µm) with the solvent system indicated. Spectro-
scopic data were recorded on a Varian Gemini 300 or a Varian
Gemini 200 spectrometer. Melting points were recorded on a
Bu¨chi 535 apparatus. Where analyses are indicated only by
symbols of the elements, results obtained were within 0.4% of
the theoretical values.
Procedure for the Preparation of Intermediates 57.
3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole (56a). Indole
(30.0 g, 0.26 mol) was dissolved in a solution of potassium
hydroxide (77.6 g, 1.38 mol) in methanol (690 mL). 4-Piperi-
done monohydrate hydrochloride (102.3 g, 0.66 mol) was added
in one portion, and the mixture was heated to reflux for 5 h.
Potassium chloride precipitated upon cooling to room temper-
ature, and it was filtered off. The liquid phase was concen-
trated until only one-third of the liquid remained in the round-
bottom flask. Water was added, and a solid precipitated, which
was filtered and washed with ethyl ether. 31.9 g (63% yield)
of the final product was obtained. Melting point:183-185 °C
(lit.23: 178-181 °C).
At this point of the study, we were interested in
identifying potent in vivo antihistamines with a stable
and long duration of action as well as low capacity to
cross the blood-brain barrier (with ED50 higher than
cetirizine). Pharmacokinetic profiles of compounds with
an ED50 greater than 8 mg/kg in the H1 ex vivo assay
and consistent oral potency after 8 h were evaluated in
rats (Table 5). In accordance with the longer duration
of oral activity observed in selected compounds, the half-
lives of 15, 20, 48, 51 and 52 compounds were longer
than that for compound 1. Moreover, the small volumes
of distribution suggest low affinity of all these com-
pounds for tissues components and reduced potential
for toxicity.
Finally, the potential to cause adverse cardiac effects
was also assessed for compounds 1, 15, 48 and 51. The
effect on QT prolongation interval was measured in
3-Piperidin-4-yl-1H-indole (57a). Compound 56a (3.08 g,
14.0 mmol) was hydrogenated in a Parr apparatus during 1 h

6330 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Fonquerna et al.
Table 3. Effect of Piperidine Substitution on in Vitro and in Vivo Activity
a Data are indicated as IC50 (nM). b Data are indicated as IC50 (µM).). c Histamine-induced cutaneous vascular permeability model.
d Data are indicated as ED50 (mg/kg).
at 3 bar with Pd/C 10% (0.31 g) in 60 mL of methanol and 60
mL of a saturated solution of hydrogen chloride in methanol.
The catalyst was filtered under inert atmosphere, and the
solvent was removed at reduced pressure. A solution of sodium
hydroxide (0.56 g; 14.0 mmol)) in methanol (45 mL) was added,
and after 2.5 h at room temperature, the solvent was removed

Novel Histamine H1 Antagonists
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6331
Table 4. Pharmacological Profile of Indolylpiperidinyl Benzoic Acid Derivatives
a Data are indicated as IC50 (nM). b Data are indicated as IC50 (µM). c Histamine-induced cutaneous vascular permeability model. d Data
are indicated as ED50 (mg/kg).
under reduced pressure. Sodium chloride was removed from
the crude mixture by precipitation with ethanol (18 mL) and
dichloromethane (18 mL). After filtration and removal of the
solvent under reduced pressure, 3.10 g (100% yield) of 57a was
obtained. 1H NMR (DMSO-d6, 200 MHz, δ[ppm]) 1.46-1.64
(m, 2H), 1.83-1.89 (m, 2H), 2.57-2.69 (dt, 2J ) 12.1 Hz, 3J )
2.3 Hz, 2H), 2.76-2.82 (tt, J ) 11.70, 3.51 Hz, 1H), 2.98-3.04
(d, J ) 12.1 Hz, 2H), 6.90-7.07 (m, 3H), 7.31-7.34 (d, J ) 7.8
Hz, 1H), 7.53-7.57 (d, J ) 7.4 Hz, 1H), 10.79 (s, 1H).
The following analogues were prepared using the procedure
outlined for 57a above.
3.78 (s, 3H), 6.70-6.76 (m, 1H), 7.05 (m, 2H), 7.20-7.23 (m,
1H), 10.64 (s, 1H).
5-Fluoro-3-piperidin-4-yl-1H-indole (57c). 1H NMR (DM-
SO-d6, 200 MHz, δ[ppm]) 1.42-1.63 (m, 2H), 1.81-1.87 (m,
2H), 2.56-2.69 (td, J ) 12.1, 2.3 Hz, 1H), 2.78 (tt, J ) 11.7, J
) 3.5 Hz, 2H), 2.98-3.04 (m, 2H), 6.83-6.94 (td, J ) 8.9, J )
2.3 Hz, 1H), 7.14-7.15 (m, 1H), 7.26-7.35 (m, 2H), 10.90 (s,
1H).
6-Fluoro-3-piperidin-4-yl-1H-indole (57d). 1H NMR (DM-
SO-d6, 200 MHz, δ[ppm]) 1.44-1.64 (m, 2H), 1.83-1.89 (d, J
) 12.5 Hz, 2H), 2.59-2.70 (m, 2H), 2.74-2.89 (m, 1H), 2.99-
3.05 (d, J ) 12.1 Hz, 2H), 6.75-6.86 (m, 1H), 7.07-7.13 (m,
2H), 7.50-7.57 (dd, J ) 8.6, J ) 5.5 Hz, 1H), 10.88 (s, 1H).
5-Methoxy-3-piperidin-4-yl-1H-indole (57b). 1H NMR
(DMSO-d6, 200 MHz, δ[ppm]) 1.49-1.62 (m, 2H), 1.83-1.95
(m, 2H), 2.62 (s, 1H), 2.60-2.85 (m, 3H), 2.95-3.08 (m, 2H),

6332 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Fonquerna et al.
Table 5. Pharmacological and ADME Profile of
ethyl bromide (0.060 g, 0.320 mmol) was added. The crude
mixture was stirred at room temperature for 15 h. The solvent
was removed under reduced pressure, and ethanol (1 mL) was
added. Aqueous NaOH (2 M, 0.20 mL) was added, and the
crude mixture was stirred at room temperature for 16 h. The
crude mixture was neutralized with a aqueous HCl (2 N, 0.2
mL) and the solvent was removed at reduced pressure. The
mixture was purified using a 500 mg Varian C18 chromatog-
raphy column affording 0.041 g (45% yield) of compound 1.
Indolylpiperidinyl Benzoic Acid Derivatives
HICVPb HICVPb
H1
Vss
Cl
a
compd H1
(4 h)c
(8 h)c ex vivoc t1/2 (h) (L/kg) (L/kg‚h)
1
2
86 0.1
0.22
0.08
0.13
0.8
8
>100
40
1.1
0.9
3.4
1.6
2.9
3.9
3.1
3.8
0.7
0.5
0.3
0.4
0.5
0.6
1.8
1.1
0.6
0.8
0.1
0.4
0.3
0.2
0.6
0.3
155 0.035
140 0.29
127 0.74
354 0.45
470 0.05
125 0.24
81 0.20
15
16
20
48
51
52
100
0.9
>100
General Procedure for Preparation of Intermediates
60. 4-(1H-Indol-3-yl)piperidine-1-carboxylic Acid Ethyl
Ester (60a). 57a (10.0 g, 50.0 mmol) was dissolved in
dichloromethane (100 mL), and triethylamine (7.7 mL, 55.0
mmol) was added. Once cooled in an ice-bath, a solution of
ethyl chloroformate (5.5 mL, 55.0 mmol) in dichloromethane
(3 mL) was added dropwise. After 1 h of stirring at 0 °C, the
reaction mixture was washed with water. The organic phase
was dried over magnesium sulfate and filtered and the solvent
removed under reduced pressure. The final product (12.7 g,
93% yield) was precipitated with a mixture of hexane/ethyl
0.14
0.56
0.66
9.5
11.5
29
a Data are indicated as IC50 (nM). b Histamine-induced cutane-
ous vascular permeability model. c Data are indicated as ED50 (mg/
kg). Vss: Volume of distribution at the steady state. Cl: Clearance.
Table 6. Efficacy and Safety Data for Selected Compounds and
Standards
HICVPa
(1 h)b
QTcc,d
(iv)
CYP3A4
1
ether 5:1. Melting point: 101-104 °C. H NMR (CDCl3, 200
compd
H1 ex vivob
inhibition,e %
MHz, δ[ppm]) 1.3 (t, 3H), 1.7 (qd, 2H), 2.1 (m, 2H), 2.8-3.1
(m, 3H), 4.2 (q, 2H), 4.3 (m, 2H), 6.9 (s, 1H), 7.0-7.3 (m, 2H),
7.4 (d, 1H), 7.7 (d, 1H), 8.1 (bs, 1H).
1
0.02
0.16
0.03
0.32
0.51
0.75
8
10
30
30
10
3
0
15
15
40
48
51
9.5
11.5
5
-9
-5
13
4-(5-Methoxy-1H-indol-3-yl)piperidine-1-carboxylic Acid
Ethyl Ester (60b). Compound 60b was synthesized in a
fashion analogous to that of compound 60a. 1H NMR (CDCl3,
200 MHz, δ[ppm]) 1.20-1.24 (t, 3H), 1.56-1.72 (m, 2H), 1.98-
2.12 (m, 2H), 2.80-3.08 (m, 3H), 3.80 (s, 3H), 4.15-4.40 (m,
4H), 6.80-6.95 (m, 2H), 7.05 (s, 1H), 7.20-7.28 (m, 1H), 8.17
(s, 1H).
4-(6-Fluoro-1H-indol-3-yl)piperidine-1-carboxylic Acid
Ethyl Ester (60c). Compound 60c was synthesized in a
fashion analogous to that of compound 60a. 1H NMR (CDCl3,
200 MHz, δ[ppm]) 0.95 (t, 3H), 1.3 (m, 6H), 1.5-1.8 (m, 4H),
1.9 (m, 1H), 2.0 (s, 1H), 2.9 (t, 2H), 3.9 (t, 2H), 4.1 (q, 2H), 4.2
(m, 2H), 6.7 (s, 1H), 6.7-6.9 (m, 2H), 7.5 (m, 1H).
General Procedure for Preparation of Intermediates
61. 4-[1-(2-Ethoxyethyl)-1H-indol-3-yl]piperidine-1-car-
boxylic Acid Ethyl Ester (61a). 60a (4.9 g, 18.0 mmol) was
dissolved in dimethylformamide (60 mL), and a dispersion of
60% NaH in mineral oil (0.9 g, 23.0 mmol) was added in
portions at room temperature. After 30 min of stirring,
1-bromo-2-ethoxyethane (2.48 mL, 20.0 mmol) was added
dropwise. The reaction mixture was heated at 60 °C for 1 h.
The solvent was removed under reduced pressure and the
residue suspended in water and extracted with ethyl acetate.
The organic phase was washed successively with water and
brine, dried over magnesium sulfate, filtered and evaporated
to dryness to provide 6.2 g (100% yield) of the final product as
a semisolid, pure enough to perform the next synthetic step.
1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.1 (t, 3H), 1.3 (t, 3H), 1.7
(qd, 2H), 2.1 (m, 2H), 2.8-3.1 (m, 3H), 3.4 (q, 2H), 3.7 (t, 2H),
4.2 (q, 2H), 4.3 (m, 4H), 6.9 (s, 1H), 7.0-7.3 (m, 2H), 7.35 (d,
1H), 7.6 (d, 1H).
cetirizine
loratadine
12.9
10
30
a Histamine-induced cutaneous vascular permeability model.
b Data are indicated as ED50 (mg/kg, po). c Data are indicated as
maximal dose without effect (mg/kg, iv). d Doses tested: 3, 10, and
30 mg/kg (iv). e Data correspond to the incubation performed with
25 µM compound concentration and without 15 min of preincu-
bation.
5-Bromo-3-piperidin-4-yl-1H-indole (57e). 1H NMR (DM-
SO-d6, 200 MHz, δ[ppm]) 1.80-2.10 (m, 4H), 2.90-3.20 (m,
5H), 7.15-7.21 (m, 2H), 7.27-7.30 (m, 1H), 7.85 (s, 1H), 11.18
(s, 1H).
7-Bromo-3-piperidin-4-yl-1H-indole (57f). 1H NMR (DM-
SO-d6, 200 MHz, δ[ppm]) 1.55-1.61 (m, 2H) 1.82-1.95 (m,
2H), 2.55-2.67 (m, 2H), 2.78-2.90 (m, 2H), 2.92-3.15 (m, 2H),
6.88-6.95 (m, 2H), 7.10 (s, 1H), 7.30-7.35 (m, 1H), 7.56-7.64
(m, 1H).
7-Methyl-3-piperidin-4-yl-1H-indole (57g). 1H NMR (DM-
SO-d6, 200 MHz, δ[ppm]) 1.52-1.66 (m, 2H), 1.83-1.90 (m,
2H), 2.42 (s, 3H), 2.52-2.71 (m, 2H), 2.74-2.89 (m, 1H), 2.99-
3.95 (m, 2H), 6.84-6.87 (m, 2H), 7.03-7.04 (m, 1H), 7.35-
7.40 (m, 1H), 10.72 (s, 1H).
3-Piperidin-4-yl-6-trifluoromethyl-1H-indole (57h). 1H
NMR (DMSO-d6, 200 MHz, δ[ppm]) 1.60-1.72 (m, 2H), 1.87-
1.90 (m, 2H), 2.58-3.15 (m, 5H), 7.22-7.26 (d, J ) 7.8 Hz,
1H), 7.35 (s, 1H), 7.68 (s, 1H), 7.75-7.80 (d, J ) 8.2 Hz, 1H),
11.30 (s, 1 H).
General Procedure for the Parallel Preparation of
Compounds 1-40. 2-(2-{4-[1-(2-Ethoxyethyl)-1H-indol-3-
yl]piperidin-1-yl}ethoxy)benzoic Acid (1). 2-(2-Chloro-
ethoxy)benzoic acid methyl ester (0.22 g, 0.50 mmol) was added
to a mixture of 57a (0.10 g, 0.50 mmol), potassium carbonate
(0.08 g, 0.60 mmol) and potassium iodide (0.04 g, 0.20 mmol)
in isobutylmethyl ketone (1.5 mL) under nitrogen atmosphere.
The mixture was heated at 90 °C for 18 h. After cooling to
room temperature, dichloromethane (1.5 mL) and polystyrene
methylisocyanate (0.08 g, 0.10 mmol) were added, and the
mixture was stirred at room temperature for 3 h. After
filtration, the solution was placed directly on a 500 mg Varian
SCX ion exchange column. The column was washed with
methanol (5 mL), and the product was eluted with 20:1
methanol/ammonia mixture (5 mL). The solvent was removed
under reduced pressure affording 0.11 g (60% yield) of 59a.
A 60% dispersion of NaH in mineral oil (0.016 g, 0.36 mmol)
was added to a solution of 59a (0.080 g, 0.2 mmol) in
anhydrous dimethylformamide (1 mL) under nitrogen atmo-
sphere. After stirring at room temperature for 30 min, ethoxy-
4-[1-(2-Methoxyethyl)-1H-indol-3-yl]piperidine-1-car-
boxylic Acid Ethyl Ester (61b). Compound 61b was syn-
1
thesized in a fashion analogous to that of compound 61a. H
NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.40 (m, 5H), 1.50-1.80
(m, 2H), 2.80-3.10 (m, 3H), 3.35 (s, 3H), 3.65 (t, 2H), 4.05-
4.38 (m, 6H), 6.89 (s, 1H), 7.00-7.38 (m, 3H), 7.57-7.63 (m,
1H).
4-(1-Butyl-1H-indol-3-yl)piperidine-1-carboxylic Acid
Ethyl Ester (61c). Compound 61c was synthesized in a
fashion analogous to that of compound 61a. 1H NMR (CDCl3,
200 MHz, δ[ppm]) 0.95 (t, 3H), 1.3 (m, 6H), 1.5-1.8 (m, 4H),
1.9 (m, 1H), 2.0 (s, 1H), 2.9 (t, 2H), 3.9 (t, 2H), 4.1 (q, 2H), 4.2
(m, 2H), 6.9 (s, 1H), 7.0-7.3 (m, 2H), 7.4 (d, 1H), 7.7 (d, 1H).
4-(1-Cyclopropylmethyl-1H-indol-3-yl)piperidine-1-car-
boxylic Acid Ethyl Ester (61d). Compound 61d was syn-
1
thesized in a fashion analogous to that of compound 61a. H
NMR (CDCl3, 200 MHz, δ[ppm]) 0.30-0.40 (m, 2H), 0.55-0.75
(m, 2H), 0.80-0.95 (m, 1H), 1.25 (t, 3H), 1.60-1.78 (m, 2H),

Novel Histamine H1 Antagonists
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6333
2.00-2.10 (m, 2H), 2.85-3.09 (m, 3H), 3.90 (d, 2H), 4.19 (q,
2H), 4.20-4.30 (m, 2H), 6.90 (s, 1H), 7.10-7.39 (m, 3H), 7.63
(d, 1H).
4-(6-Fluoro-1-furan-3-ylmethyl-1H-indol-3-yl)piperidine-
1-carboxylic Acid Ethyl Ester (61o). Compound 61o was
synthesized in a fashion analogous to that of compound 61a.
1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.23 (t, 3H), 1.51-
1.76 (m, 2H), 1.95-2.08 (m, 2H), 2.79-3.08 (m, 3H), 4.07-
4.38 (m, 4H), 5.00 (s, 2H), 6.20 (s, 1H), 6.79-7.00 (m, 3H),
7.23-7.39 (m, 2H), 7.54-7.59 (m, 2H).
4-(1-Furan-2-ylmethyl-1H-indol-3-yl)piperidine-1-car-
boxylic Acid Ethyl Ester (61e). Compound 61e was syn-
1
thesized in a fashion analogous to that of compound 61a. H
NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.24 (t, 3H), 1.55-1.74
(m, 2H), 1.98-2.14 (m, 2H), 2.80-3.06 (m, 3H), 4.10-4.37 (m,
4H), 5.20 (s, 2H), 6.20-6.38 (m, 2H), 6.89 (s, 1H), 7.14-7.43
(m, 2H), 7.36-7.42 (m, 2H), 7.60-7.72 (m, 1H).
General Procedure for Preparation of Intermediates
62. 1-(2-Ethoxyethyl)-3-piperidin-4-yl-1H-indole (62a).
61a (6.2 g, 18.0 mmol) was dissolved in a 2-propanol (120 mL),
and potassium hydroxide (12.0 g, 0.18 mol) was added. The
reaction mixture was refluxed for18 h. The solvent was
removed under reduced pressure, and ice-water was added
to the residue. Concentrated hydrochloric acid was added
dropwise with stirring until acidic pH value. Then sodium
hydroxide (8 N) was added dropwise until basic pH value. After
30 min of stirring under these conditions, the mixture was
extracted with dichloromethane, washed successively with
water and brine, dried over magnesium sulfate, filtered and
evaporated to dryness. 4.8 g (97%) of the desired final product
4-(1-Thiophen-2-ylmethyl-1H-indol-3-yl)piperidine-1-
carboxylic Acid Ethyl Ester (61f). Compound 61f was
synthesized in a fashion analogous to that of compound 61a.
1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.23 (t, 3H), 1.56-
1.78 (m, 2H), 1.96-2.10 (m, 2H), 2.80-3.05 (m, 3H), 4.06-
4.40 (m, 4H), 5.40 (s, 2H), 6.83-6.94 (m, 3H), 7.10-7.20 (m,
3H), 7.35-7.39 (m, 1H), 7.58-7.64 (m, 1H).
4-[1-(5-Chlorothiophen-2-ylmethyl)-1H-indol-3-yl]pi-
peridine-1-carboxylic Acid Ethyl Ester (61g). Compound
61g was synthesized in a fashion analogous to that of
compound 61a. 1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.25
(t, 3H), 1.56-1.72 (m, 2H), 1.98-2.14 (m, 2H), 2.80-3.16 (m,
3H), 4.03-4.39 (m, 4H), 5.30 (s, 2H), 6.60-6.78 (m, 2H), 7.14-
7.30 (m, 3H), 7.60-7.72 (m, 1H).
1
was obtained as a yellowish oil. H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.2 (t, 3H), 1.7 (qd, 2H), 2.1 (m, 4H), 2.9 (t, 2H), 3.0
(tt, 1H), 3.2 (m, 2H), 3.4 (q, 2H), 3.7 (t, 2H), 4.3 (t, 2H) 6.9 (s,
1H), 7.0-7.4 (m, 3H), 7.7 (d, 1H).
4-[1-(2-Ethoxyethyl)-5-methoxy-1H-indol-3-yl]piperi-
dine-1-carboxylic Acid Ethyl Ester (61h). Compound 61h
was synthesized in a fashion analogous to that of compound
1-(2-Methoxyethyl)-3-piperidin-4-yl-1H-indole (62b).
Compound 62b was synthesized in a fashion analogous to that
1
of compound 62a. H NMR (CDCl3, 200 MHz, δ[ppm]) 1.55-
1
61a. H NMR (CDCl3, 200 MHz, δ[ppm]) 1.02-1.25 (m, 6H),
2.15 (m, 5H), 2.78-3.05 (m, 3H), 3.10-3.24 (m, 2H), 3.30 (s,
3H), 3.64-3.78 (m, 2H), 4.19-4.33 (m, 2H), 6.89 (s, 1H), 7.00-
7.38 (m, 3H), 7.57-7.63 (m, 1H).
1.55-1.74 (m, 2H), 1.95-2.07 (m, 2H), 2.80-3.04 (m, 3H),
3.38-3.43 (m, 2H), 3.60-3.68 (m, 2H), 3.80 (s, 3H), 4.10-4.40
(m, 6H), 6.80-6.96 (m, 2H), 7.10 (s, 1H), 7.22-7.30 (m, 1H).
4-[6-Fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piperidine-
1-carboxylic Acid Ethyl Ester (61i). Compound 61i was
synthesized in a fashion analogous to that of compound 61a.
1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.40 (m, 5H), 1.50-
1.80 (m, 2H), 2.80-3.10 (m, 3H), 3.35 (s, 3H), 3.65 (t, 2H),
4.05-4.38 (m, 6H), 6.77-6.83 (m, 2H), 6.90-7.07 (m, 1H),
7.43-7.55 (m, 1H).
4-(1-Butyl-6-fluoro-1H-indol-3-yl)piperidine-1-carbox-
ylic Acid Ethyl Ester (61j). Compound 61j was synthesized
in a fashion analogous to that of compound 61a. 1H NMR
(CDCl3, 200 MHz, δ[ppm]) 0.95 (t, 3H), 1.3 (m, 6H), 1.5-1.8
(m, 4H), 1.9 (m, 1H), 2.0 (s, 1H), 2.9 (t, 2H), 3.9 (t, 2H), 4.1 (q,
2H), 4.2 (m, 2H), 6.7 (s, 1H), 6.7-6.9 (m, 2H), 7.5 (m, 1H).
1-Butyl-3-piperidin-4-yl-1H-indole (62c). Compound 62c
was synthesized in a fashion analogous to that of compound
1
62a. H NMR (CDCl3, 200 MHz, δ[ppm]) 0.9 (t, 3H), 1.2-1.4
(m, 2H), 1.5-1.9 (m, 3H), 1.9 (m, 1H), 2.0 (s, 1H), 2.6-2.9 (m,
3H), 3.1-3.2 (m, 2H), 3.9 (t, 2H), 4.1 (q, 2H), 6.9 (s, 1H), 7.0-
7.3 (m, 2H), 7.4 (d, 1H), 7.7 (d, 1H).
1-Cyclopropylmethyl-3-piperidin-4-yl-1H-indole (62d).
Compound 62d was synthesized in a fashion analogous to that
1
of compound 62a. H NMR (CDCl3, 200 MHz, δ[ppm]) 0.30-
0.40 (m, 2H), 0.55-0.65 (m, 2H), 0.80-0.93 (m, 1H), 1.60-
1.75 (m, 2H), 2.00-2.13 (m, 2H), 2.78-2.88 (t, 2H), 2.90-3.12
(m, 1H), 3.16-3.24 (m, 2H), 3.86-3.98 (d, 2H), 6.99 (s, 1H),
7.11-7.39 (m, 3H), 7.65 (d, 1H).
1-Furan-2-ylmethyl-3-piperidin-4-yl-1H-indole (62e).
Compound 62e was synthesized in a fashion analogous to that
4-(1-Cyclopropylmethyl-6-fluoro-1H-indol-3-yl)piperi-
dine-1-carboxylic Acid Ethyl Ester (61k). Compound 61k
was synthesized in a fashion analogous to that of compound
1
of compound 62a. H NMR (CDCl3, 200 MHz, δ[ppm]) 1.60-
1.81 (m, 2H), 1.92-2.10 (m, 3H), 2.76-2.98 (m, 3H), 3.20 (d,
2H), 5.20 (s, 2H), 6.20-6.38 (m, 2H), 6.89 (s, 1H), 7.14-7.43
(m, 2H), 7.36-7.42 (m, 2H), 7.60-7.72 (m, 1H).
1
61a. H NMR (CDCl3, 200 MHz, δ[ppm]) 0.30-0.40 (m, 2H),
0.55-0.75 (m, 2H), 0.80-0.95 (m, 1H), 1.25 (t, 3H), 1.60-1.78
(m, 2H), 2.00-2.10 (m, 2H), 2.85-3.09 (m, 3H), 3.90 (d, 2H),
4.19 (q, 2H), 4.20-4.30 (m, 2H), 6.70 (s, 1H), 6.70-6.90 (m,
2H), 7.5 (m, 1H).
3-Piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole (62f).
Compound 62f was synthesized in a fashion analogous to that
1
of compound 62a. H NMR (CDCl3, 200 MHz, δ[ppm]) 1.60-
4-(6-Fluoro-1-furan-2-ylmethyl-1H-indol-3-yl)piperidine-
1-carboxylic Acid Ethyl Ester (61l). Compound 61l was
synthesized in a fashion analogous to that of compound 61a.
1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.20 (t, 3H), 1.52-1.66
(m, 2H), 1.90-2.05 (m, 2H), 2.89-3.06 (m, 3H), 4.12-4.37 (m,
4H), 5.10 (s, 2H), 6.18-6.25 (m, 2H), 6.90-7.00 (m, 2H), 7.05-
7.12 (m, 1H), 7.35 (s, 1H), 7.45-7.58 (m, 1H).
4-(6-Fluoro-1-thiophen-2-ylmethyl-1H-indol-3-yl)pi-
peridine-1-carboxylic Acid Ethyl Ester (61m). Compound
61m was synthesized in a fashion analogous to that of
compound 61a. 1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.20-1.32
(t, 3H), 1.56-1.78 (m, 2H), 1.96-2.12 (d, 2H), 2.78-3.06 (m,
3H), 4.12-4.39 (m, 4H), 5.30 (s, 2H), 6.73-7.03 (m, 5H), 7.20-
7.24 (m, 1H), 7.40-7.46 (m, 1H).
4-[1-(5-Chlorothiophen-2-ylmethyl)-6-fluoro-1H-indol-
3-yl]piperidine-1-carboxylic Acid Ethyl Ester (61n). Com-
pound 61n was synthesized in a fashion analogous to that of
compound 61a. 1H NMR (CDCl3, 200 MHz, δ[ppm]) 1.18-1.24
(t, 3H), 1.40-1.56 (m, 2H), 1.95-2.08 (m, 2H), 2.76-3.05 (m,
3H), 4.12-4.38 (m, 4H), 5.20 (s, 2H), 6.60-6.97 (m, 5H), 7.43-
7.56 (m, 1H).
1.81 (m, 2H), 1.92-2.10 (m, 3H), 2.76-2.98 (m, 3H), 3.20 (d,
2H), 5.40 (s, 2H), 6.83-6.94 (m, 3H), 7.10-7.20 (m, 3H), 7.35-
7.39 (m, 1H), 7.58-7.64 (m, 1H).
1-(5-Chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-
indole (62 g). Compound 62g was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.56-1.78 (m, 2H), 1.98-2.15 (m, 2H), 2.76-3.02 (m,
3H), 3.14-3.26 (d, 2H), 5.30 (s, 2H), 6.60-6.78 (m, 2H), 7.14-
7.30 (m, 3H), 7.60-7.72 (m, 1H).
1-(2-Ethoxyethyl)-5-methoxy-3-piperidin-4-yl-1H-in-
dole (62h). Compound 62h was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.05-1.20 (t, 3H), 1.57-2.05 (m, 5H), 2.75-2.88 (m,
3H), 3.17-3.22 (m, 2H), 3.38-3.50 (m, 2H), 3.62-3.72 (m, 2H),
3.80 (s, 3H), 4.16-4.25 (m, 2H), 6.80-6.96 (m, 2H), 7.10 (s,
1H), 7.22-7.30 (m, 1H).
6-Fluoro-1-(2-methoxyethyl)-3-piperidin-4-yl-1H-in-
dole (62i). Compound 62i was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.55-1.78 (m, 2H), 1.92-2.16 (m, 1H), 2.70-2.96 (m,

6334 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Fonquerna et al.
3H), 3.10-3.30 (m, 2H), 3.31 (s, 3H), 3.60-3.74 (t, 2H), 4.15-
4.21 (t, 1H), 6.79-7.05 (m, 2H), 7.10-7.28 (m, 1H), 7.44-7.58
(m, 1H).
1-Butyl-6-fluoro-3-piperidin-4-yl-1H-indole (62j). Com-
pound 62j was synthesized in a fashion analogous to that of
compound 62a. 1H NMR (CDCl3, 200 MHz, δ[ppm]) 0.9 (t, 3H),
1.2-1.4 (m, 2H), 1.5-1.9 (m, 4H), 1.9 (m, 1H), 2.0 (s, 1H), 2.6-
2.9 (m, 3H), 3.1-3.2 (m, 2H), 3.9 (t, 2H), 4.1 (q, 2H), 6.7-6.9
(m, 2H), 7.5 (m, 1H).
1-Cyclopropylmethyl-6-fluoro-3-piperidin-4-yl-1H-in-
dole (62k). Compound 62k was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 0.30-0.40 (m, 2H), 0.55-0.65 (m, 2H), 0.80-0.93 (m,
1H), 1.60-1.75 (m, 2H), 2.00-2.13 (m, 2H), 2.78-2.88 (t, 2H),
2.90-3.12 (m, 1H), 3.16-3.24 (m, 2H), 3.86-3.98 (d, 2H), 6.70
(s, 1H), 6.70-6.90 (m, 2H), 7.5 (m, 1H).
6-Fluoro-1-furan-2-ylmethyl-3-piperidin-4-yl-1H-in-
dole (62l). Compound 62l was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.57-1.64 (m, 2H), 1.92-2.17 (m, 3H), 2.62-2.85 (m,
3H), 3.06-3.20 (m, 2H), 5.10 (s, 2H), 6.18-6.25 (m, 2H), 6.90-
7.00 (m, 2H), 7.05-7.12 (m, 1H), 7.35 (s, 1H), 7.45-7.58 (m,
1H).
6-Fluoro-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-
indole (62m). Compound 62m was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.56-1.78 (m, 2H), 1.98-2.10 (m, 2H), 2.72-3.02 (m,
4H), 3.18-3.29 (m, 2H), 5.30 (s, 2H), 6.78-7.08 (m, 5H), 7.20-
7.28 (m, 1H), 7.51-7.60 (m, 1H).
1-(5-Chlorothiophen-2-ylmethyl)-6-fluoro-3-piperidin-
4-yl-1H-indole (62n). Compound 62n was synthesized in a
fashion analogous to that of compound 62a. 1H NMR (CDCl3,
200 MHz, δ[ppm]) 1.56-1.78 (m, 2H), 1.98-2.10 (m, 2H),
2.72-3.02 (m, 4H), 3.18-3.29 (m, 2H), 5.20 (s, 2H), 6.60-6.97
(m, 5H), 7.43-7.56 (m, 1H).
6-Fluoro-1-furan-3-ylmethyl-3-piperidin-4-yl-1H-in-
dole (62o). Compound 62o was synthesized in a fashion
analogous to that of compound 62a. 1H NMR (CDCl3, 200 MHz,
δ[ppm]) 1.55-1.72 (m, 2H), 1.93-2.10 (m, 2H), 2.62-2.90 (m,
3H), 3.15-3.22 (m, 2H), 5.00 (s, 2H), 6.20 (s, 1H), 6.79-7.00
(m, 3H), 7.23-7.39 (m, 2H), 7.54-7.59 (m, 2H).
General Procedure for Preparation of Compounds
1-53 for Confirmation of Structure. 2-(2-{4-[1-(2-Ethoxy-
ethyl)-1H-indol-3-yl]piperidin-1-yl}ethoxy)-4-methoxy-
benzoic Acid (13). To a solution of 62a (1.94 g, 7.13 mmol)
in methylisobutyl ketone (35 mL) were added triethylamine
(2.10 mL, 12.12 mmol), 2-(2-chloroethoxy)-4-methoxybenzoic
acid methyl ester (2.26 g, 9.72 mmol) and potassium iodide
(0.12 g, 0.7 mmol). The crude mixture was heated at 90 °C for
15 h. The solvent was removed under reduced pressure, and
the residue was partitioned between ethyl acetate and water.
The organic phase was dried over sodium sulfate and filtered
and the solvent evaporated to afford 4 g of a crude mixture
which was used without further purification in the next
synthetic step. The crude material was dissolved in ethanol
(20 mL) and aqueous NaOH (2 N, 7.13 mL) was added. After
stirring for 24 h at room temperature, the solvent was removed
at reduced temperature, and water (20 mL) was added. The
solution was neutralized with aqueous hydrochloric acid (6 N)
and extracted with chloroform. The organic phase was dried
over sodium sulfate and filtered and the solvent was removed
under reduced pressure. The crude mixture was purified by
column chromatography over silica gel affording 1.4 g (42%)
of 13. Melting point: 66.6-67.9 °C. 1H NMR (CDCl3, 300 MHz,
δ[ppm]) 1.14-1.18 (t, J ) 7.0 Hz, 3H), 1.88-2.09 (m, 4H),
2.31-2.39 (m, 2H), 2.82-2.86 (m, 3H), 3.09-3.13 (d, J ) 11.3
Hz, 2H), 3.42-3.49 (q, J ) 7.0, 2H), 3.71-3.75 (t, J ) 6.1 Hz,
2H), 3.84 (s, 3H), 4.22-4.26 (t, J ) 6.1 Hz, 2H), 4.35-4.39 (t,
J ) 5.2 Hz, 2H), 6.54-6.55 (m, 1H), 6.61-6.65 (dd, J ) 8.9
Hz, J ) 2.1 Hz, 1H), 6.97 (s, 1H), 7.05-7.10 (t, J ) 7.5 Hz,
1H), 7.16-7.21 (t, J ) 7.6 Hz, 1H), 7.33-7.35 (d, J ) 8.2 Hz,
1H), 7.57-7.60 (d, J ) 8.0 Hz, 1H), 7.93-7.96 (d, J ) 8.6 Hz,
1H). Anal. (C27H34N2O5) C, H, N.
2-(2-{4-[1-(2-Ethoxyethyl)-5-methoxy-1H-indol-3-yl]pi-
peridin-1-yl}ethoxy)benzoic Acid (2). Compound 2 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 156.1-159.2 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.02-1.07 (t, J ) 7.0 Hz, 3H), 1.86-2.09 (m, 4H),
2.62-2.71 (m, 2H), 2.82-2.94 (m, 1H), 2.96-2.99 (m, 2H),
3.22-3.26 (m, 2H), 3.34-3.41 (q, J ) 7.0 Hz, 2H), 3.62-3.65
(t, J ) 5.34 Hz, 2H), 3.80 (s, 3H), 4.19-4.23 (t, J ) 6.6 Hz,
2H), 4.44-4.47 (m, 2H), 6.73-6.76 (dd, J ) 8.9 Hz, 2.1 Hz,
1H), 6.99-7.04 (t, J ) 7.5 HZ, 1H), 7.09 (s, 1H), 7.14-7.15
(m, 1H), 7.22-7.25 (m, 1H), 7.32-7.41 (m, 2H), 7.50-7.53 (dd,
J ) 7.5 Hz, J ) 1.4 Hz, 1H). Anal. (C27H34N2O5) C, H, N.
2-(2-{4-[6-Fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]pi-
peridin-1-yl}ethoxy)benzoic Acid (15). Compound 15 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 119.6.-120.1 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.89-1.96 (m, 4H), 2.60-2.66 (m, 3H), 2.87-3.10 (m,
4H), 3.22 (s, 3H), 3.60-3.64 (t, J ) 5.2 Hz, 2H), 4.23-4.26 (t,
J ) 5.1 Hz, 2H), 4.39-4.46 (m, 2H), 6.81-6.88 (m, 1H), 6.99-
7.04 (t, J ) 7.3 Hz, 1H), 7.13 (s, 1H), 7.20-7.40 (m, 3H), 7.5-
7.54 (m, 1H), 7.62-7.67 (dd, J ) 8.6 Hz, J ) 5.5 Hz, 1H). Anal.
(C25H29FN2O4) C, H, N.
2-{2-[4-(1-Butyl-1H-indol-3-yl)piperidin-1-yl]ethoxy}-
benzoic Acid (16). Compound 16 was synthesized in a fashion
analogous to that of compound 13. Melting point: 158.7-159.9
1
°C. H NMR (DMSO-d6, 300 MHz, δ[ppm]) 0.87-0.90 (t, J )
7.2 Hz, 3H), 1.21-1.31 (m, 2H), 1.67-1.76 (m, 2H), 1.87-2.02
(m, 4H), 2.60-2.67 (m, 2H), 2.85-2.97 (m, 3H), 3.20-3.23 (d,
J ) 12.1 Hz, 2H), 4.09-4.13 (t, J ) 7.0 Hz, 2H), 4.42-4.45 (t,
J ) 5.3 Hz, 2H), 6.96-7.03 (m, 2H), 7.09-7.13 (m, 1H), 7.22-
7.24 (d, J ) 8.2 Hz, 1H), 7.37-7.42 (m, 2H), 7.52-7.55 (m,
1H), 7.63-7.65 (d, J ) 7.8 Hz, 1H). Anal. (C26H32N2O3) C, H,
N.
2-{2-[4-(1-Cyclopropylmethyl-1H-indol-3-yl)piperidin-
1-yl]ethoxy}benzoic Acid (17). Compound 17 was synthe-
sized in a fashion analogous to that of compound 13. Melting
point: 158.6-160.3 °C. 1H NMR (DMSO-d6, 300 MHz, δ[ppm])
0.32-0.39 (m, 2H), 0.47-0.53 (m, 2H), 1.10-1.31 (m, 1H),
1.85-2.05 (m, 4H), 2.60-2.69 (m, 2H), 2.85-2.98 (3H), 3.20-
3.24 (d, J ) 11.6 Hz, 2H), 3.97-4.00 (d, J ) 7.0 Hz, 2H), 4.42-
4.45 (t, J ) 4.9 Hz, 2H), 6.97-7.04 (m, 2H), 7.09-7.14 (m, 1H),
7.20-7.24 (m, 2H), 7.36-7.41 (m, 1H), 7.44-7.47 (d, J ) 7.9
Hz, 1H), 7.52-7.55 (dd, J ) 7.6 Hz, J ) 1.8 Hz, 1H), 7.64-
7.67 (d, J ) 7.9 Hz, 1H). Anal. (C26H30N2O3) C, H, N
2-{2-[4-(1-Cyclopropylmethyl-6-fluoro-1H-indol-3-yl)pi-
peridin-1-yl]ethoxy}benzoic Acid (18). Compound 18 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 97 °C. 1H NMR (DMSO-d6, 300 MHz, δ[ppm])
0.33-0.35 (m, 2H), 0.54-0.67 (m, 2H), 1.20-1.25 (m, 1H),
1.98-2.01 (m, 4H), 2.32-2.41 (m, 2H), 2.82-2.85 (m, 3H),
3.13-3.17 (d, 2H), 3.84-3.86 (m, 2H), 4.41-4.45 (m, 2H),
6.80-6.87 (m, 2H), 6.99-7.12 (m, 4H), 7.41-7.50 (m, 2H),
7.89-7.93 (dd, 1H).
2-{2-[4-(1-Allyl-1H-indol-3-yl)piperidin-1-yl]ethoxy}-
benzoic Acid (19). Compound 19 was synthesized in a fashion
analogous to that of compound 13. Melting point: 123.1-125.3
°C. 1H NMR (Cl3CD, 300 MHz, δ[ppm]) 1.96-2.03 (m, 4H),
2.33-2.41 (m, 2H), 2.82-2.91 (m, 3H), 3.13 (d, 2H), 4.40-4.44
(m, 2H), 4.66-4.68 (m,2H), 5.08-5.22 (m, 2H), 5.91-6.04 (m,
1H); 6.10 (bs, 1H), 6.92 (s, 1H), 7.04-7.11 (m. 3H), 7.18 (t,
1H), 7.21-7.31 (m, 1H), 7.41 (t, 1H), 7.57 (d, 1H), 7.89 (d, 1H).
2-(2-{4-[1-(2-[1,3]Dioxolan-2-yl-ethyl)-1H-indol-3-yl]pi-
1
peridin-1-yl}ethoxy)benzoic Acid (20). H NMR (DMSO-
d6, 300 MHz, δ[ppm]) 1.85-2.10 (m, 6H), 2.59-2.72 (m, 2H),
2.84-3.01 (m, 3H), 3.20-3.24 (m, 2H), 3.76-3.81 (m, 2H),
3.91-3.96 (m, 2H), 4.18-4,23 (t, J ) 7.2 Hz, 2H), 4.39-4.49
(m, 2H), 4.77-4.80 (t, J ) 4.6 Hz, 2H), 6.97-7.04 (m, 2H),
7.10-7.15 (m, 2H), 7.21-7.24 (d, J ) 8.2 Hz, 1H), 7.26-7.40
(m, 2H), 7.52-7.54 (m, 1H), 7.64-7.67 (d, J ) 7.9 Hz, 1H).
Anal. (C27H32N2O5) C, H, N
2-{2-[4-(6-Fluoro-1-furan-2-ylmethyl-1H-indol-3-yl)pi-
peridin-1-yl]ethoxy}benzoic Acid (22). Compound 22 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 173.5-174.5 °C. 1H NMR (DMSO-d6, 300 MHz,

Novel Histamine H1 Antagonists
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6335
δ[ppm]) 1.82-2.01 (m, 4H), 2.56-2.70 (m, 2H), 2.82-2.97 (m,
3H), 3.19-3.23 (d, 11.9 Hz, 2H), 4.41-4.45 (t, J ) 5.2 Hz, 1H),
5.34 (s, 2H), 6.39-6.41 (dd, J ) 3.4 Hz, J ) 1.8 HZ, 1H), 6.49-
6.50 (m, 1H), 6.83-6.90 (m, 1H), 6.99-7.04 (m, 1H), 7.18-
7.24 (m, 2H), 7.36-7.42 (m, 2H), 7.52-7.55 (dd, J ) 7.63 Hz,
J ) 1.83 Hz, 1H), 7.58-7.59 (m, 1H), 7.64-7.69 (dd, J ) 8.70
Hz, J ) 5.34 Hz, 1H). Anal. (C27H27FN2O4) C, H, N.
4-{4-[1-(2-Ethoxyethyl)-1H-indol-3-yl]piperidin-1-
ylmethyl}benzoic Acid (31). Compound 31 was synthesized
in a fashion analogous to that of compound 13. Melting point:
143.9-145.4 °C. 1H NMR (DMSO-d6, 300 MHz, δ[ppm]) 1.01-
1.06 (m, 3H), 1.61-1.77 (m, 2H), 1.91-1.95 (m, 2H), 2.14-
2.21 (t, J ) 11 Hz, 2H), 2.73-2.81 (m, 1H), 2.91-2.94 (m, 2H),
3.34-3.41 (q, J ) 7.0 Hz, 2H), 3.60-3.67 (m, 4H), 4.22-4.26
(t, J ) 5.3 Hz, 2H), 6.95-7.00 (t, J ) 7.0 Hz, 1H), 7.07-7.13
(m, 2H), 7.40-7.48 (m, 2H), 7.53-7.59 (m, 2H), 7.83-7.86 (d,
J ) 7.6 Hz, 1H), 7.94 (s, 1H).
3-{4-[1-(2-Ethoxyethyl)-1H-indol-3-yl]piperidin-1-
ylmethyl}benzoic Acid (32). Compound 32 was synthesized
in a fashion analogous to that of compound 13. Melting point:
°C.143.9-145.4 1H NMR (DMSO-d6, 300 MHz, δ[ppm]) 1.01-
1.06 (t, J ) 7 Hz, 3H), 1.60-1.78 (m, 2H), 1.91-1.95 (m, 2H),
2.14-2.21 (t, J ) 11 Hz, 2H), 2.70-2.83 (m, 1H), 2.91-2.94
(d, J ) 11.3 Hz, 2H), 3.34-3.41 (q, J ) 7 Hz, 2H), 3.60 (s,
2H), 3.63-3.67 (t, J ) 5.5 Hz, 2H), 4.22-4.26 (m, 2H), 6.95-
7.00 (t, J ) 7.3 Hz, 1H), 7.07-7.13 (m, 2H), 7.40-7.48 (m, 2H),
7.53-7.59 (m, 2H), 7.83-7.86 (d, 7.6 Hz, 1H), 7.94 (s, 1H).
Anal. (C25H30N2O3) C, H, N.
5-{4-[1-(2-Ethoxyethyl)-1H-indol-3-yl]piperidin-1-yl-
methyl}-2-methoxybenzoic Acid (36). Compound 36 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 232.7-233.7 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.01-1.06 (t, J ) 6.9 Hz, 3H), 1.55-1.71 (m, 2H),
1.88-1.96 (m, 2H), 2.07-2.14 (m, 2H), 2.64-2.79 (m, 1H),
2.87-2.91 (m, 2H). 3.37-3.41 (m, 2H), 3.47 (s, 2H), 3.62-3.65
(t, J ) 5.3 Hz, 2H), 3.80 (s, 3H), 4.19-4.23 (t, J ) 5.5 Hz, 2H),
6.78-6.85 (m, 2H), 7.06-7.12 (m, 2H), 7.27-7.31 (dd, J ) 10.1,
J ) 2.3 Hz, 1H), 7.41-7.45 (dd, J ) 8.4 Hz, J ) 2.3 Hz, 1H),
7.50-7.57 (m, 2H). Anal. (C26H32N2O4) C, H, N.
5-{4-[1-(2-Ethoxyethyl)-1H-indol-3-yl]piperidin-1-yl-
methyl}-2-fluorobenzoic Acid (37). Compound 37 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 225.8-226.5 °C.1H NMR (DMSO-d6, 200 MHz,
δ[ppm]) 1.0 (t, J ) 7.0 Hz, 3 H) 1.7 (m, 2 H) 1.9 (m, 2 H) 2.1
(m, 2 H) 2.7 (m, 1 H) 2.9 (d, J ) 10.1 Hz, 2 H) 3.3 (m, 2H) 3.4
(s, 2H) 3.7 (m, 2 H) 4.2 (m, 2 H) 7.0 (m, 1 H) 7.1 (m, 2 H) 7.4
(m, 2 H) 7.5 (m, 3 H).
2-{2-[4-(1-Butyl-6-fluoro-1H-indol-3-yl)piperidin-1-yl]-
ethoxy}benzoic Acid (41). Compound 41 was synthesized
in a fashion analogous to that of compound 13. Melting point:
149.4-150.9 °C. 1H NMR (DMSO-d6, 300 MHz, δ[ppm]) 0.86-
0.91 (t, J ) 7.3 Hz, 3H), 1.18-1.32 (m, 2H), 1.62-1.75 (m, 2H),
1.83-2.03 (m, 4H), 2.61-2.69 (m, 2H), 2.83-2.99 (m, 3H),
3.20-3.24 (m, 2H), 4.05-4.10 (t, J ) 6.9 Hz, 2H), 4.42-4.46
(m, 2H), 6.80-6.87 (m, 1H), 6.99-7.04 (t, J ) 7.5 Hz, 1H),
7.15 (s, 1H), 7.21-7.41 (m, 3H), 7.52-7.55 (m, 1H), 7.62-7.67
(dd, J ) 8.9, 5.5 Hz, 1H).
2-{2-[4-(6-Fluoro-1-furan-3-ylmethyl-1H-indol-3-yl)pi-
peridin-1-yl]ethoxy}benzoic Acid (42). Compound 42 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 153.3-154.5 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.82-2.02 (m, 4H), 2.56-2.71 (m, 2H), 2.81-3.01 (m,
3H), 3.19-3.23 (d, J ) 11.9 Hz, 2H), 4.42-4.44 (m, 2H), 5.14
(s, 2H), 6.82-6.88 (m, 1H), 6.99-7.04 (t, J ) 7.5 Hz, 1H), 7.21-
7.24 (m, 2H), 7.35-7.42 (m, 2H), 7.52-7.57 (m, 2H), 7.63-
7.68 (dd, J ) 8.7 Hz, J ) 5.3 Hz, 1H), 7.75 (s, 1H).
1H), 7.27-7.32 (m, 1H), 7.44-7.59 (m, 3H). 7.83-7.86 (d, J )
7.6 Hz, 1H), 7.94 (s, 1H).
3-{4-[1-(2-Ethoxyethyl)-5-methoxy-1H-indol-3-yl]piper-
idin-1-ylmethyl}benzoic Acid (44). Compound 44 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 139.8-141.6 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.01-1.06 (t, J ) 7.0 Hz, 3H). 1.59-1.76 (m, 2H),
1.91-1.95 (m, 2H), 2.16-2.23 (t, J ) 10.8 Hz, 2H), 2.66-2.81
(m, 1H), 2.92-2.95 (d, J ) 11.0 Hz, 2H), 3.33-3.40 (q, J ) 7.9
Hz, 2H), 3.60-3.64 (m, 4H), 3.75 (s, 3H), 4.17-4.21 (t, J ) 5.5
Hz, 2H), 6.72-6.75 (dd, J ) 8.7 Hz, J ) 2.3 Hz, 1H), 7.00-
7.01 (m, 1H), 7.08 (s, 1H), 7.30-7.33 (d, J ) 8.9 Hz, 1H), 7.43-
7.48 (t, J ) 7.6 Hz, 1H), 7.56-7.58 (d, J ) 7.6 Hz, 1H), 7.84-
7.86 (d, J ) 7.6 Hz, 1H), 7.95 (s, 1H).
3-[4-(1-Furan-2-ylmethyl-1H-indol-3-yl)piperidin-1-yl-
methyl]benzoic Acid (45). Compound 45 was synthesized
in a fashion analogous to that of compound 13. Melting point:
153.9-155.1 °C. 1H NMR (DMSO-d6, 300 MHz, δ[ppm]) 1.57-
1.76 (m, 2H), 1.87-1.98 (m, 2H), 2.12-2.19 (t, J ) 10.7 Hz,
2H), 2.69-2.82 (m, 1H), 2.89-2.93 (m, 2H), 3.59 (s, 2H), 6.37-
6.44 (m, 2H), 6.96-7.01 (t, J ) 7.3 Hz, 1H). 7.08-7.13 (t, J )
7.3 Hz, 1H), 7.17 (s, 1H), 7.44-7.60 (m, 4H), 7.83-7.85 (m,
1H), 7.92 (s, 1H).
3-[4-(1-Thiophen-2-ylmethyl-1H-indol-3-yl)piperidin-1-
ylmethyl]benzoic Acid (46). Compound 46 was synthesized
in a fashion analogous to that of compound 13. Melting point:
228.7-229.2 °C. 1H NMR (DMSO-d6, 300 MHz, δ[ppm]) 1.60-
1.78 (m, 2H), 1.91-1.95 (d, J ) 11.6 Hz, 2H), 2.2 (t, J ) 11.0
Hz, 2H), 2.69-2.83 (m, 1H), 2.90-2.94 (d, J ) 11.0 Hz, 2H),
3.60 (s, 2H), 5.52 (s, 2H), 6.93-7.01 (m, 2H), 7.08-7.13 (m,
2H), 7.24 (s, 1H), 7.36.7.38 (m, 1H), 7.42-7.57 (m, 4H), 7.84-
7.86 (d, J ) 7.6 Hz, 1H), 7.94 (s, 1H).
3-{4-[1-(5-Chlorothiophen-2-ylmethyl)-1H-indol-3-yl]-
piperidin-1-ylmethyl}benzoic Acid (47). Compound 47 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 232.0-233.8 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.86-2.01 (m, 4H), 2.85-3.10 (m, 3H), 3.21-3.47 (m,
4H), 5.49 (s, 2H), 6.93-7.03 (m, 3H), 7.10-7.15 (t, J ) 7.5 Hz,
1H), 7.25 (s, 1H), 7.50-7.66 (m, 2H), 7.84-7.87 (m, 1H), 7.99-
8.01 (d, J ) 7.6 Hz, 1H), 8.15 (s, 1H).
2-Methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]pi-
peridin-1-ylmethyl}benzoic Acid (48). Compound 48 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 241.9-242.2 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.59-1.77 (m, 2H), 1.90-1.94 (m, 2H), 2.11-2.19 (m,
2H), 2.68-2.81 (m, 1H), 2.90-2.93 (d, J ) 11 Hz, 2H), 3.20 (s,
3H), 3.50 (s, 2H), 3.59-3.63 (t, J ) 5.2 Hz, 2H), 3.79 (s, 3H),
4.22-4.25 (t, J ) 5.3 Hz, 2H), 6.92-7.00 (m, 1H), 7.05-7.10
(m, 3H), 7.39-7.44 (m, 2H), 7.52-7.58 (m, 2H). Anal.
(C25H30N2O4) C, H, N.
5-{4-[6-Fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piper-
idin-1-ylmethyl}-2-methoxybenzoic Acid (49). Compound
49 was synthesized in a fashion analogous to that of compound
1
13. Melting point: 244.1-245.2 °C. H NMR (DMSO-d6, 300
MHz, δ[ppm]) 1.52-1.70 (m, 2H), 1.87-1.92 (m, 2H), 2.05-
2.14 (m, 2H), 2.65-2.77 (m, 1H), 2.86-2.90 (m, 2H), 3.19 (s,
3H), 3.46 (s, 2H), 3.58-3.61 (t, J ) 5.2 Hz, 2H), 3.79 (s, 3H),
4.19-4.22 (t, J ) 5.3 Hz, 2H), 6.77-6.84 (m, 1H), 7.05-7.10
(m, 2H), 7.25-7.30 (dd, J ) 8.5 Hz, J ) 2.1 Hz, 1H), 7.40-
7.44 (dd, J ) 8.5 Hz, J ) 2.1 Hz, 1H), 7.49-7.53 (dd, J ) 8.7
Hz, J ) 5.3 Hz, 1H), 7.56-7.57 (d, J ) 2.1 Hz, 1H). Anal.
(C25H29FN2O4) C, H, N.
5-[4-(6-Fluoro-1-furan-3-ylmethyl-1H-indol-3-yl)piperi-
din-1-ylmethyl]-2-methoxybenzoic Acid (50). Compound
50 was synthesized in a fashion analogous to that of compound
13. Melting point: 249.7-252.4 °C.
1H NMR (DMSO-d6, 300
MHz, δ[ppm]) 1.55-1.67 (m, 2H), 1.86-2.96 (m, 2H), 2.07-
2.22 (m, 2H), 2.67-2.81 (m, 1H), 2.90-2.94 (m, 2H), 3.51 (s,
2H), 3.81 (s, 3H), 5.11 (s, 2H), 6.40 (s, 1H), 6.78-6.88 (m, 1H),
7.07-7.10 (d, J ) 8.5 Hz, 1H), 7.21 (s, 1H), 7.36-7.46 (m, 3H),
7.50-7.59 (m, 3H), 7.72 (s, 1H).
2-Methoxy-5-[4-(1-thiophen-2-ylmethyl-1H-indol-3-yl)-
piperidin-1-ylmethyl]benzoic Acid (51). Compound 51 was
synthesized in a fashion analogous to that of compound 13.
3-{4-[6-Fluoro-1-(2-methoxyethyl)-1H-indol-3-yl]piper-
idin-1-ylmethyl}benzoic Acid (43). Compound 43 was
synthesized in a fashion analogous to that of compound 13.
Melting point: 184.3-184.9 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.58-1.75 (m, 2H), 1.90-1.93 (d, J ) 11 Hz, 2H),
2.13-2.20 (t, J ) 11 Hz, 2H), 2.68-2.81 (m, 1H), 2.80-2.93
(d, J ) 10.7 Hz, 2H), 3.21 (s, 3H), 3.60 (s, 2H), 3.61-3.63 (m,
2H), 4.20-4.24 (t, J ) 5.2 Hz, 2H), 6.79-6.86 (m, 1H), 7.12 (s,

6336 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Fonquerna et al.
Melting point: 241.8-242.9 °C. 1H NMR (DMSO-d6, 300 MHz,
δ[ppm]) 1.59-1.73 (m, 2H), 1.91-1.95 (m, 2H), 2.09-2.17 (t,
J ) 11.0 Hz, 2H), 2.72-2.80 (m, 1H), 2.89-2.92 (d, J ) 11.0
Hz, 2H), 3.49 (s, 2H), 3.80 (s, 3H), 5.62 (s, 2H), 6.93-7.01 (m,
2H), 7.06-7.12 (m, 3H), 7.23 (s, 1H), 7.36-7.38 (dd, J ) 5.2
Hz, J ) 1.2 Hz, 1H), 7.42-7.46 (dd, J ) 8.4 Hz, J ) 2.3 Hz,
1H), 7.48-7.58 (m, 3H). Anal. (C27H28N2O3S) C, H, N, S.
5-[4-(6-Fluoro-1-thiophen-2-ylmethyl-1H-indol-3-yl)pi-
peridin-1-ylmethyl]-2-methoxybenzoic Acid (52). Com-
pound 52 was synthesized in a fashion analogous to that of
compound 13. Melting point: 244.8-246.4 °C. 1H NMR
(DMSO-d6, 300 MHz, δ[ppm]) 1.59-1.70 (m, 2H), 1.89-1.93
(m, 2H), 2.10-2.18 (t, J ) 11 Hz, 2H), 2.71-2.78 (m, 1H),
2.89-2.93 (d, J ) 11.3 Hz, 2H), 3.50 (s, 2H), 3.80 (s, 3H), 5.50
(s, 2H), 6.80-6.87 (m, 1H), 6.94-6.96 (dd, J ) 8.7 Hz, J ) 5.0
Hz, 1H), 7.06-7.13 (m, 2H), 7.23 (s, 1H), 7.36-7.45 (m, 3H),
7.52-7.58 (m, 2H). Anal. (C27H27FN2O3S) C, H, N, S.
5-{4-[1-(5-Chlorothiophen-2-ylmethyl)-6-fluoro-1H-in-
dol-3-yl]piperidin-1-ylmethyl}-2-methoxybenzoic Acid
(53). Compound 53 was synthesized in a fashion analogous to
that of compound 13. Melting point: 232.5-233.4 °C. 1H NMR
(DMSO-d6, 300 MHz, δ[ppm]) 1.62-1.73 (m, 2H), 1.90-1.94
(m, 2H), 2.15-2.22 (t, J ) 10.7 Hz, 2H), 2.72-2.80 (m, 1H),
2.92-2.95 (d, J ) 10.7 Hz, 2H), 3.53 (s, 2H), 3.80 (s, 3H), 5.45
(s, 2H), 6.83-6.89 (m, 1H), 6.95-7.08 (m, 3H), 7.24 (s, 1H),
7.39-7.43 (m, 2H), 7.54-7.59 (m, 2H). Anal. (C27H26ClFN2O3S)
C, H, N, S.
Biology. In Vitro Assays: Preparation of Compound
Solutions. Stock solutions (10-2 M) of the tested compounds
were prepared in 100% DMSO. Further dilutions were per-
formed in 50% DMSO.
six different concentrations run in duplicate. IC50 values were
obtained by nonlinear regression by use of SAS on a DEC AXP
computer.
In Vivo Assays: General Procedures. The animals were
fasted from the 16 h prior to the experiments, with water ad
libitum. Test compounds were dissolved in a solution contain-
ing 0.5% methylcellulose and 0.1% Tween 80 in distilled water
and administered in a volume of 10 mL/kg. All the experi-
mental protocols used in this paper have been approved by
the appropriate animal ethics committees.
Histamine-Induced Cutaneous Vascular Permeability
in Rats. Determination of Compound’s Duration of
Action. Overnight starved male Wistar rats weighing between
150 and 175 g were used. One, 4, 8 or 24 h after the oral
administration of the test compounds, the animals (n ) 5 per
condition) were slightly anaesthetised with ethyl ether in order
to shave the back and carry out four intradermal injections of
5 µg of histamine administered in a volume of 0.05 mL (100
µg/mL of histamine were dissolved in 0.9% saline solution).
0.5 mL of a solution of 0.5% Evans Blue dissolved in 0.9%
saline solution was immediately inoculated via the caudal vein.
All the animals were sacrificed by cervical dislocation 1 h after
administration of histamine. The surface skin containing the
four papules caused by the histamine was then sectioned. The
papules were evaluated by taking two measurements corre-
sponding to the maximum and minimum diameters of the
papule and applying the formula for calculating the area of
an ellipse. Results were calculated as the inhibitory effect of
each drug on the area of the papule caused by intradermal
injection of histamine.17
H1 ex Vivo Binding Assay in Mice. The objective of this
assay was to evaluate the capacity of the compounds to cross
the blood-brain barrier. The assay was performed essentially
as described by Leysen et al.18 with the following modifications.
Overnight starved male Swiss albino mice (20-25 g) were
treated orally with different doses of the test compounds, 90
min later they were killed, and the whole brain was dissected
out and homogenized in 10 mL of ice-cold 0.05 M Na+/K+
phosphate buffer (pH 7.4). One mL aliquot of the homogenate
was incubated, per triplicate, with 0.1 mL [3H]-mepyramine
(2 nM final concentration, 27 Ci/mmol, Amersham) during 40
min at 30 °C. The [3H]-mepyramine bound to the membranes
was determined by immediately filtration of the homogenates
under vacuum onto the glass fiber filters (Whatman GF/B),
followed by three rapid rinses with 5 mL of cold buffer
containing 10 µM cold mepyramine. The radioactivity bound
in the filters was determined by liquid scintillation spectrom-
etry. The nonspecific binding was determined by treating the
animals with 30 mg/kg po D-chlorpheniramine maleate. Mice
treated with vehicle (methylcellulose 0.5% and tween 0.1%)
were used to determine the total binding. Three animals were
used for each tested dose.
Measurement of Electrocardiographic (EGC; Espe-
cially QT Interval Prolongation) Effects in Guinea Pigs.
Male Dunkin-Hartley guinea pigs weighing between 500 and
600 g were anesthetised with urethane at the dose of 1.5 g/kg.
The trachea was cannulated and connected to a respiration
pump (Ugo Basile model 7025, tidal volume 10 mL/kg, fre-
cuency 60 cycles/min). The left jugular vein was cannulated
to administer the drugs. Surface electrodes were implanted
to pick up the ECG signal which was recorded in a Hewlett-
Packard cardiograph. Readings of the ECG were taken every
15 min during the stabilization period, which was no less than
30 min. The drugs were administered by intravenous perfusion
for 3 min. ECG records were taken on completion of perfusion
and at 15, 30, 45 and 60 min after administration of three
different doses: 3, 10 and 30 mg/kg (iv). The control animals
received vehicle only. The increase in the QTc interval was
corrected for the heart rate according to Bazett formula.
Compound effects on the QTc interval were calculated as the
change in ms from baseline values.
The specific radioligand binding to the receptors is defined
as the difference between the total binding and nonspecific
binding determined in the presence of an excess of unlabeled
ligand.
Histamine H1 Receptor Binding Assay. Binding to the
histamine H1 receptors was performed in guinea pig cerebel-
lum membranes as described by Chang et al.14 Briefly, the
membrane suspensions (160 µg/mL) were incubated at 30 °C
with 0.7 nM [3H]-mepyramine and different concentrations of
the test compounds in a final volume of 0.5 mL. Binding
reactions were terminated by filtration after 30 min of incuba-
tion, and the bound radioactivity was determined. Nonspecific
binding was measured in the presence of 10 µM of pro-
methazine. The affinity of each compound to the receptor was
determined by using at least six different concentrations run
in duplicate. IC50 values were obtained by nonlinear regression
by use of SAS on a DEC AXP computer.
5-HT2 Receptor Binding Assay. Binding of [3H]-ke-
tanserine to 5-HT2 receptors in human cortex membranes was
measured according to Pazos et al.15 Assays were carried out
at 37 °C in tubes containing an aliquot of cortex membranes
(170 µg of protein per mL) in incubation buffer (50 mM Tris-
HCl, pH 7.7) with 1 nM [3H]-ketanserine in a final volume of
1 mL. Nonspecific binding was defined in the presence of 10
µM mianserine. Binding reactions were terminated after 30
min of incubation by filtration, and the bound radioactivity
was determined. The affinity of each compound to the receptor
was determined by using at least six different concentrations
run in duplicate. IC50 values were obtained by nonlinear
regression by use of SAS on a DEC AXP computer.
Alpha-1 Receptor Binding Assay. Binding of [3H]-pra-
zosin to alpha-1 receptors in rat brain membranes was
measured according to Greengrass et al.16 Assays were carried
out at room temperature in 96-well plates containing an
aliquot of brain membranes (340 µg of protein per mL) in
incubation buffer (50 mM Tris-HCl, pH 7.7) with 0.25 nM [3H]-
prazosin in a final volume of 0.25 mL. Nonspecific binding was
defined in the presence of 100 µM prazosin. Binding reactions
were terminated after 60 min of incubation by filtration, and
the bound radioactivity was determined. The affinity of each
compound to the receptor was determined by using at least
HPLC Analysis for Pharmacokinetic Studies. Com-
pounds were administered intravenously (1 mg/kg) to male
Wistar rats. Animals were fasted overnight before administra-

Novel Histamine H1 Antagonists
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6337
tion. Blood samples were collected at different time points from
0.1 to 24 h postadministration. Plasma was separated by
centrifugation and stored at -20 °C until analysis. Plasma
concentrations were determined by HPLC as described below.
Pharmacokinetic parameters were determined by noncom-
partmental analysis using WinNonlin (Pharsight, Inc. Moun-
tain, CA). Plasma levels (for compounds 1, 2, 15, 16, 20, 51
and 52) were determined by an isocratic HPLC (515 pump,
Waters) and UV detection (λ ) 225 nm, UV2487 Waters)
method using an on-line solid-phase system (PROSPEKT,
Spark-Holland) assisted by a sampling injector (ASPEC XL,
Gilson). Briefly, 1 mL of acidic solution (20 mM, pH 4, sodium
acetate buffer for compounds 2, 15, 51, 52; or 5 mM trifluo-
roacetic acid for compounds 1, 16, 20) was added to 5 mL
disposable conical tubes containing 100 µL of plasma (200 µL
for compound 1). The mixture was shaken for 15 s with a
vortex and centrifuged at 4000 rpm for 10 min (Megafuge 1.0R,
Heraeus). Samples were then loaded into a Gilson sample
processor. The on-line solid-phase extraction was carried out
by the PROSPEKT system connected to a Gilson sample
injector, using C2 and C2-end capped (for compounds 51 and
52) cartridges (Baker). The passage of the fluids through the
cartridges was carried out by the ASPEC sampling injector,
using the following sample preparation steps: (1) activate the
cartridge with 1.5 mL of acetonitrile (methanol for compound
1), (2) condition the cartridge with 1.5 mL of 0.2 M acetic acid
(10 mM trifluoracetic for compound 1), (3) load the sample,
(4) wash out the sample with 2 mL of water and 1 mL of
acetonitrile:water (30:70 v/v for compounds 1, 2, 51, 52; 40:60
v/v for compounds 15 and 16, and 35:65 v/v for compound 20).
Finally the elution into the analytical column (C18, 150 × 4
mm, Kromasil 100, Teknokroma) was carried out by passing
through the cartridge mobile phase during 1 min at a flow rate
of 1 mL/min. The mobile phase was a mixture of acetonitrile
(methanol for compound 2) and 20 mM sodium phosphate
containing 0.2% of triethylamine. The corresponding isocratic
method were:28% of organic for compound 20, 30% of organic
for compounds 1, 15, 52, 32% of organic for compound 51, 35%
of organic for compound 16 and 48% of organic for compound
2. The column temperature was kept at 40 °C. With these
conditions all compounds had a retention time in the range
between 9 and 12 min. Plasma levels of compound 48 were
determined by a HPLC-MS system (HPLC Alliance HT2790
and a ZMD mass spectrometer Micromass-Waters). Briefly 150
µl of acetonitrile containing 0.2% of trifluoroacetic acid were
added to a 5 mL disposable conical tubes containing 50 µL of
plasma. The mixture was shaken for 15 s with a vortex and
centrifuged at 4000 rpm for 10 min (Megafuge 1.0R, Heraeus).
100 µL of supernatant were transferred to a vial and 10 µl
were injected on the HPLC/MS system. Isocratic conditions
at a flow of 250 µL/min were applied to the chromatographic
system using a column of 100 × 2.1 mm, C18, 5 µM (Tekno-
kroma) kept at 40 °C. The mobile phase was a mixture of
acetonitrile and 10 mM formic acid contining 2.5 mM of NH3
(75:25, v/v). The mass spectrometer was working in ESI + mode
at m/z 423 (30 kV cone voltage, desolvation temperature 250°
C).
concentration in the incubation mixture. Final acetonitrile
concentration was 2%.
Acknowledgment. We are grateful to M. Rosa
Ortiz, Enric Vilanova, Ester Sent´ıs, Isabel Paga´n, Manel
Aznar, Josep M. Oliva and Rafael Lo´pez for their
dedicated work in the lab.
Supporting Information Available: Table of elemental
analyses data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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