Benzo[b]thiophene-2-carboxamides and benzo[b]furan-2-carboxamides are potent antagonists of the human H3-receptor

Article abstract of DOI:10.1016/j.bmcl.2006.03.074

Benzo[b]thiophene-2-carboxamides and benzo[b]furan-2-carboxamides have been found to be antagonists on the human histamine-3-receptor, showing a K_i value of as low as 4 nM.

Full text of DOI:10.1016/j.bmcl.2006.03.074

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3162–3165
Benzo[b]thiophene-2-carboxamides and benzo[b]furan-
2-carboxamides are potent antagonists of the human H3-receptor
Bernd Peschke,* Sonja Bak, Rolf Hohlweg, Rita Nielsen, Dorthe Viuff and Karin Rimvall
Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Received 3 March 2006; revised 15 March 2006; accepted 16 March 2006
Available online 17 April 2006
Abstract—Benzo[b]thiophene-2-carboxamides and benzo[b]furan-2-carboxamides have been found to be antagonists on the human
histamine-3-receptor, showing a Ki value of as low as 4 nM.
Ó 2006 Elsevier Ltd. All rights reserved.
The H3-receptor was first discovered in 1983 in rats.1
N
O
and subsequently a human variant (hH3) has been iden-
tified and cloned.2 It is a presynaptic receptor located on
histaminergic neurons, and it has been suggested that a
functional H3-antagonist could be beneficial for the
treatment of, for example, attention deficit hyperactivity
disorder, epilepsy, obesity, or Alzheimer’s disease.3 For
this reason a number of projects have been initiated in
several pharmaceutical companies to identify com-
pounds, which ultimately could be used as potential
drugs against these ailments.4
N
F
F
F
Figure 1. NNC 0038-0000-1202, Ki = 4.7 ( 0.4) nM.
types of substituents have proven to influence the hepat-
ic metabolic stability of compounds22–24 and have been
used successfully in NNC 0038-0000-1202 and its ana-
logues.20 Aldehydes 3a–c were used as key intermediates
in the preparation of this type of compounds. Employ-
ing the described synthesis strategy for aldehyde 3a.25
we prepared the other two aldehydes 3b and 3c as
depicted in Scheme 1. Starting with commercially avail-
able phenols 1b,c, tetrahydropyran moieties (THP) were
attached to the hydroxyl-groups. The THP moieties on
compounds 2a–c were utilized as directing groups in
directed metallation reactions with n-butyllithium in
the presence of N,N,N0,N0-tetramethylethylenediamine
(TMEDA). The intermediates were quenched with
DMF to provide the aldehydes 3a–c.25 It is noteworthy
that the reaction with THP-ether 2b yielded only small
amounts of the desired aldehyde because the lithiated
species was not stable at ꢀ10 °C. Interestingly, starting
with THP-ether 2c, only one of the two possible regio-
isomeric aldehydes was isolated. Cyclization with dieth-
yl bromomalonate26 furnished esters 4a–c and the
corresponding carboxylic acids 5a–c27 were obtained
after saponification employing standard conditions.
5-Cyanobenzo[b]furan-2-carboxylic acid was prepared
as described in the literature.28,29
In recent years, a number of non-imidazole-containing
H3-antagonists have been developed.5–19 One of them
was NNC 0038-0000-1202 (Fig. 1),20 which was studied
both in vitro and in vivo.21 In order to expand our
knowledge about the structure–activity relationship
(SAR) of compounds of this type, we wondered whether
a ring closure over the cinnamic double bond could lead
to equally potent H3-antagonists. In this context, we
considered
benzo[b]thiophene-2-carboxylic
acids,
benzo[b]furan-2-carboxylic acids, or quinoline-3-car-
boxylic acid to be ring-closed analogues of cinnamic
acids as used in NNC 0038-0000-1202.
Besides a number of commercially available benzo[b]-
thiophene-2-carboxylic acids and benzo[b]furan-2-
carboxylic acids, we also wanted to incorporate trifluo-
romethyl- and trifluoromethoxy-substituted acids. These
Keywords: Histamine-3 receptor; hH3-receptor; Benzo[b]furan;
Benzo[b]thiophene.
Having a number of acids available, we turned our
attention to the amine part of the possible H3-antago-
*
Corresponding author. Tel.: +45 44 43 47 19; fax: +45 44 66 34 50;
e-mail: bpes@novonordisk.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.074

B. Peschke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3162–3165
3163
O
O
OH
R3
OH H
R3
a)
b)
O
R4
R4
R4
R3
b: 17%
c: 51%
b: 85%
c: 89%
2
1
3
R3
R4
d)
c)
R3
R4
O
O
O
HO
O
EtO
a: 86%
b: 15%
c: 57%
a: 86%
b: 40%
c: 97%
5
4
R3
R4
a
b
c
CF3
H
OCF3
H
CF3
H
Scheme 1. Reagents and conditions: (a) 3,4-dihydro-2H-pyrane, anhydrous HCl, CH2Cl2; (b) i—n-BuLi, TMEDA; ii—DMF; (c) EtOOCCHBr-
COOEt, K2CO3, MEK, D; (d) LiOH dioxane/H2O.
nists. We selected the (S)-2-aminomethylpyrrolidines,30
which already had been used for the series of cinnamic
amides, and which were prepared as described in the lit-
erature20 from proline. The coupling of acids and
amines was easily accomplished by reaction with 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDAC) in the presence of 3,4-dihydro-3-hy-
droxy-1,2,3-benzotriazin-4-one (DHOBt) and DIPEA,
as depicted in Scheme 2. Hence in a few steps, the com-
pounds 5–16 were isolated and subsequently screened
11 nM.20 Generally, all compounds which were substi-
tuted at the 5-position with trifluoromethyl (compounds
8–10), trifluromethoxy (compound 11) or cyano (com-
pound 12) were highly potent hH3-antagonists with Ki
values between 4 and 14 nM. On the other hand, com-
pounds substituted at the 6-position were less potent
than the corresponding 5-substituted analogues. This
becomes obvious when the potency of the respective
pairs of amides 8/13, 9/14, and 10/15 is compared to
each other. The 7-ethoxy-substituted benzo[b]furan-2-
carboxamide 16 exhibits, with a Ki of 17 nM, a similar
potency to the 5-trifluoromethyl-substituted compound
13.
for antagonism at the hH3-receptor, utilizing
a
[35S]GTPcS-assay.2,31
As indicated in Table 1, all prepared benzo[b]thiophene
and benzo[b]furan derivatives proved to be highly po-
tent antagonists at the hH3 receptor. Benzo[b]thiophene
carboxamides, for example, compound 5, which com-
prises the unsubstituted benzo[b]thiophene carboxamide
scaffold, exhibited a Ki value of 4 nM. Substitution with
chlorine in the 3-position reduced the potency only very
slightly, as can be seen from the results of compound 6.
However, somewhat surprising was the influence of the
amine moiety on the potency of the compounds. A com-
parison of potency within the series of compounds 8–10
which differ only in the amino moiety and all bear a tri-
fluoromethyl group in the 5-position of the benzo[b]fu-
ran moiety, and within the regioisomerical series of
compounds 13–15 reveals that in both series the amides
of (pyrrolidinomethyl)pyrrolidine are the most potent
ones, but with rather little difference between the poten-
cy of all tested compounds. In part, this had been
expected: in the cinnamic amide series, no significant
Also, several benzo[b]furan-2-carboxamides prepared in
the series were at least equipotent to the lead compound
NNC 0038-0000-1202 that showed a Ki value of
R1'
R1
N
R1'
N
R2
O
R2
O
a)
R1
HO
N
+
X
R3
R3
NH
X
R5
R5
R4
R4
III
I
II
Scheme 2. –X– = –O–, –S–, and –CH@N–. Reagents: (a) EDAC, DHOBt, DIPEA.

3164
B. Peschke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3162–3165
Table 1. hH3-potency of compounds 5–16
R1'
N
R1
R2
O
N
X
R3
R5
R4
0
Compound
R1
R1
R2
R3
R4
R5
X
Kia (nM)
5
6
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)5–
Et
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
OEt
S
4 ( 0.44)
12 ( 0.88)
5 ( 0.64)
4 ( 0.81)
7 ( 1.1)
H
S
7
H
O
O
O
O
O
O
O
O
O
O
8
CF3
CF3
CF3
H
9
H
10
11
12
13
14
15
16
Et
Et
H
14 ( 0.58)
11 ( 0.70)
5 ( 0.50)
15 ( 1.5)
22 ( 2.9)
46 ( 12)
7 ( 1.1)
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)5–
Et
OCF3
CN
H
H
H
CF3
CF3
CF3
H
H
H
–(CH2)4–
H
a
[
35S]GTPcS-assay, mean of three experiments.
compound NNC 0038-0000-1202, or in the ring-closed
benzo[b]thiophene or benzo[b]furan analogues 5–16.
Table 2. hH3-potency of quinoline-3-carboxamides
N
O
N
O
We have synthesized new substituted benzo[b]furan-2-
carboxylic acids, which were incorporated in the amide
template as ring-closed analogues of the cinnamic amide
lead compound NNC 0038-0000-1202. The compounds
exhibited competitive potencies as antagonists on the
hH3-receptor. Substitutions with electron-withdrawing
groups such as trifluoromethyl or a trifluoromethoxy
group were tolerated at positions 5 and 6 of the
benzo[b]furan-scaffold. In contrast to what had been
predicted from the results of the cinnamic amides, com-
pound 10, which is an amide of (R)-2-((diethylami-
no)methyl)pyrrolidine exhibited with a Ki of 14 nM a
quite interesting potency on the hH3-receptor in the
[35S]GTPcS-assay. However, amides of quinoline-3-car-
boxylic acid did not yield potent hH3-antagonists.
N
N
N
N
17
18
Entry
17
18
>150
Kia (nM)
>150
a
[
35S]GTPcS-assay, mean of three experiments.
difference was found between (pyrrolidinomethyl)pyrr-
olidino- and the (piperidinomethyl)pyrrolidino-ana-
logues either. However, the strong potency of the
amides of ((diethylamino)methyl)pyrrolidine 10 and 15
would not have been predicted from the rather weakly
potent analogues in the cinnamic amide series.
Acknowledgments
In general, we concluded that the compounds in the
benzo[b]thiophene and in the benzo[b]furan series all
showed quite interesting potency, independently of the
nature of the substitutent, acknowledging, that only a
very narrow variety of substituents were investigated.
We thank Dr. Claus Bekker Jeppesen, Bent Kolling,
Charlotte Fjordager, and Sine L. Rosenfalck for excel-
lent technical support.
References and notes
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larged the ring from a five-membered ring in compounds
5–16 to a six-membered ring in compounds 17 and 18.
Another possibility could be the added polarity of the
nitrogen in the quinoline ring, which was not present in
compounds of the cinnamic amide series, such as in lead
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