Synthesis and structure-activity relationships of piperidinylpyrrolopyridine derivatives as potent and selective H1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.12.008

The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H₁ antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.

Full text of DOI:10.1016/j.bmcl.2004.12.008

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1165–1167
Synthesis and structure–activity relationships of
piperidinylpyrrolopyridine derivatives as potent and selective
H1 antagonists
*
Silvia Fonquerna, Montse Miralpeix, Lluıs Pages, Carles Puig, Arantxa Cardus,
*
´
Francisca Anton, Dolors Vilella, Monica Aparici, Jose Prieto, Graham Warrellow,
`
´
´
´
´
Jorge Beleta and Hamish Ryder
Almirall Prodesfarma, Research Center, Cardener 68-74, 08024 Barcelona, Spain
Received 25 October 2004; revised 29 November 2004; accepted 2 December 2004
Available online 13 January 2005
Abstract—The synthesis and structure–activity relationships of piperidinylpyrrolopyridines as potent and selective H1 antagonists
are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the dura-
tion of action in vivo and lack of sedative properties.
Ó 2004 Elsevier Ltd. All rights reserved.
H1 antagonists are used as the first-line treatment of
allergic rhinitis.1 First-generation antihistamines are
O
N
effective but they cause sedation and dry mouth due to
blood–brain barrier and lack of specificity,2 respectively.
Second-generation H1 antagonists have low sedative po-
tential although most of them present cardiotoxic side
effects.3 New compounds being characterised and re-
cently launched to market have much reduced risk of
causing cardiac adverse effects and should also have
no sedative effects.
O
OH
N
O
Compound 1
The piperidinylpyrrolopyridinyl derivatives were typi-
cally synthesised according to a procedure described
in Scheme 1. Pyrrolopyridine was condensed with
4-oxo-piperidine-1-carboxylic acid ethyl ester and fur-
ther hydrogenation led to the core intermediate 22.
Alkylation of azaindolylpiperidine derivative 22 with
appropriate alkyl and arylalkyl halides provided inter-
mediates 23. Deprotection of the ethyl carbamate
moiety was achieved by heating in the presence of potas-
sium hydroxide leading to derivatives 24. Alkylation of
piperidinylpyrrolopyridinyl derivatives 24 with appro-
priately substituted halides and further saponification
afforded azaindolylpipepiridinyl derivatives 2–21.
We have recently reported4 the identification of a new
series of indolylpiperidine derivatives as potent, selective
and nonsedative H1 antagonists. SAR studies on this
series showed the relevance of the nature of the acidic
chain on the in vivo duration of action. In this paper
we describe our efforts in developing a new series of
H1 antagonists in which the indole ring has been re-
placed by a pyrrolopyridine group. We wished to inves-
tigate the effect of this substitution on the in vivo H1
activity and on sedative potential.
In order to determine structure–activity relationships,
all compounds described herein were evaluated for their
affinity for the guinea-pig cerebellum H1 receptor in a
radioligand binding assay.5 Selectivity was assessed by
testing their binding affinity against the human 5-HT2
and the rat a1 receptors.6,7 High affinity compounds
Keywords: H1 antagonists; Antihistamine; Piperidinylpyrrolopyridines.
*
Corresponding authors. Tel.: +34 932913999; fax: +34 3128635
(S.F.); tel.: +34 291 3468; fax: +34 93 2912827 (M.M.);
e-mail addresses: sfonquerna@almirall.es; mmiralpe@almirall.es
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.008

1166
S. Fonquerna et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1165–1167
O
O
O
O
O
N
N
a,b
c
+
N
N
H
N
O
O
N
R1
N
N
H
N
22
23
O
H
N
Y
N
OH
d
e,f
23
N
R1
N
N
R1
N
24
2-21
Scheme 1. Reagents and conditions: (a) KOH, MeOH, 60 °C, 15 h; (b) H2, PtO2, MeOH, 1 h, 30 psi; (c) R1–X, NaH, DMF, 25 °C; (d) KOH, i-
PrOH, 60 °C, 15h; (e) X–Y–CO2 R2, MEK, 90 °C, 15 h; (f) NaOH, THF–MeOH, 60 °C, 1 h.
for the H1 receptor, with at least 10 times selectivity
versus the other two receptors, were evaluated for
their antihistamine activity in the rat histamine-induced
skin vascular permeability model. Compounds showing
potent and stable oral antihistamine activity after 8h
post-administration in this model, were then tested for
their capacity to cross the blood–brain barrier in the
H1 ex vivo binding assay in mice.8 For the most prom-
ising compounds, the effect on QT prolongation inter-
val9 was measured.
Compound 1 was the lead structure in the previous re-
ported series, the indolylpiperidines. It was a potent
and selective H1 antagonist in vitro and in vivo with
Table 1. Pharmacological profile of piperidinepyrrolopyridinyl derivatives 2–21
R1
N
N
R2
N
HISVPe (4 h)f
HISVPe (8 h)f
H1 ex vivoh
a
a
c
Compd
R1
R2
H1
5HT2
a1
1
—
A
A
A
A
B
—
2-Ethoxyethyl
Butyl
86
190
235
225
295
185
215
170
240
3272
>10,000
>10,000
10,000
>10,000
3900
10
>10
0.1
0.08
1
0.22
0.20
—
8
34
—
—
—
18
—
—
—
—
—
—
—
16
—
—
—
5.4
69
15
57
2
3
4.9
4
3-Furanylmethyl
5-Chloro-2-thiophenylmethyl
2-Ethoxyethyl
10
>10
>10
>10
>10
>10
83 (10)d
>10
2.6
35 (1)g
1
—
—
5
6
0.21
11 (1)g
24 (1)g
24 (1)g
—
5 (1)g
3 (1)g
20 (1)g
0.07
1
0.20
—
7
B
Butyl
10,000
7600
>10,000
8
B
3-Furanylmethyl
5-Chloro-2-thiophenylmethyl
2-Ethoxyethyl
—
—
9
B
10
11
12
13
14
15
16
17
18
19
20
21
C
C
C
C
D
D
D
D
E
90 (500)b
13 (500)b
—
—
Butyl
120
70
>10,000
>10,000
>10,000
4950
3-Furanylmethyl
5-Chloro-2-thiophenylmethyl
2-Ethoxyethyl
—
—
135
403
275
560
330
690
475
205
365
>10
>10
>10
>10
>10
>10
>10
>10
>10
0.45
—
Butyl
>10,000
10,000
3-Furanylmethyl
5-Chloro-2-thiophenylmethyl
2-Ethoxyethyl
1
—
—
>10,000
10,000
7 (1)g
0.05
0.08
0.20
0.5
—
E
Butyl
3-Furanylmethyl
5-Chloro-2-thiophenylmethyl
>10,000
10,000
10,000
0.13
0.20
0.7
E
E
a Data correspond to the average of IC50 (nM) obtained from at least two independent experiments.
b Data correspond to the average of % of inhibition (nM dose) obtained from at least two independent experiments.
c Data correspond to the average of IC50 (lM dose) obtained from at least two independent experiments.
d Data correspond to the average of % of inhibition (lM dose) obtained from at least two independent experiments.
e Histamine-induced skin vascular permeability model.
f Data are indicated as ED50 (mg/kg); five animals were used for each tested dose.
g Data correspond to the average of % of inhibition (mg/kg) obtained from five animals.
h Data are indicated as ED50 (mg/kg); three animals were used for each tested dose.

S. Fonquerna et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1165–1167
1167
O
O
cross blood–brain barrier compared to compound 1
and therefore less sedative properties should be ex-
pected. Finally, the potential to cause adverse cardiac
adverse effects was also assessed for compounds 19, 20
and 21. The effect in the QT prolongation interval was
measured in anesthetised guinea-pigs at a prefixed dose
of 10 mg/kg and compounds 19, 20 and 21 did not pro-
duce any significant increase.
*
OH
OH
*
R3
O
R4
A
B
C
R3 = H
3 = OMe
R3 = Cl
D
E
R3 = H
3 = OMe
R
R
Figure 1. Substituents for R1 in Table 1.
Regarding solubility in water, compounds from the pyr-
rolopyridinepiperidine series showed typically at least a
2-fold increase when comparing to structural equivalent
ones from the previous series. The range of solubility
moved from 1224 lg/mL (compound 2) to 115 lg/mL
(compound 20) whereas in the previous series the values
of solubility obtained ranged between 100 lg/mL (com-
pound 1) and 22 lg/mL.
low sedative potential. From the extensive optimisation
work carried out within this series, other promising
candidates with long duration of action in vivo and
better pharmacokinetic profile were identified.4
In order to evaluate the impact of the substitution of the
indole group by a pyrrolopyridine moiety a selected set
of compounds were synthesised and their pharmacolog-
ical profiles are reported in Table 1.
In conclusion, we have identified a new series of potent
and selective H1 antagonists. We also have discovered
that the nature of the acid chain bond to piperidine is
a key feature for maintaining both the duration of ac-
tion in vivo and lack of sedative properties. Further
work is underway and will be reported in due course.
Compound 2, with identical pattern of substitution as
compound 1, showed similar in vitro and in vivo H1
activities with enhanced selectivity versus 5HT2.
Encouragingly, compound 2 had a 4-fold reduced seda-
tive potential measured in the H1 ex vivo assay. This
interesting result prompted us to synthesise other deriva-
tives with selected substitution in R2 previously known
to provide long duration of action in the indolylpiper-
idine series. Maintaining the ethoxyethyl chain in R2,
we then proceeded to explore several substituents on
the piperidine. As a general trend, we obtained com-
pounds (6, 14 and 18) with high in vivo potencies similar
to compound 1 in spite of the fact that 14 and 18 showed
lower in vitro H1 activity. Moreover, compounds 6 and
14 showed an interesting 2-fold reduction of sedative
potential compared to 1.
References and notes
1. Bousquet, J.; Van Cauwenberge, P.; Khaltaev, N. J. Allergy
Clin. Immunol. 2001, 108, S147–S334.
2. Kay, G. G. J. Allergy Clin. Immunol. 2000, 105, S622–S627.
3. Dubuske, L. M. Clin. Ther. 1999, 21, 281–295.
4. Fonquerna, S.; Miralpeix, M. J. Med. Chem. 2004, 47,
6326–6337.
5. Chang, R. S.; Tran, V. T. J. Neurochem. 1979, 32, 1653–
1663.
6. Pazos, A.; Hoyer, D.; Palacios, J. M. Eur. J. Pharmacol.
1985, 106, 531–538.
7. Greengrass, P.; Bremner, R. Eur. J. Pharmacol. 1979, 55,
323–326.
8. Leysen, J. E.; Gommeren, W.; Janssen, P. F. M.; Janssen,
P. A. J. Drug Dev. Res. 1991, 22, 165–178.
9. Llenas, J.; Gras, J.; Palacios, J. M.; Roberts, D. J. Allergy
Clin. Immunol. 1999, 103, S256.
The most promising benzoic acid chain was E (Fig. 1) as
all the compounds containing this group showed high in
vivo potencies after 4 h and in particular compounds 19,
20 and 21 showed long duration of action keeping activ-
ity after 8 h. Furthermore, compound 20 and particu-
larly 19 and 21 proved to have a reduced capacity to