A new class of potent non-imidazole H3 antagonists: 2-Aminoethylbenzofurans

Article abstract of DOI:10.1016/j.bmcl.2003.11.032

2-Aminoethylbenzofurans constitute a new class of H₃ antagonists that are more rotationally constrained than most previously reported H₃ antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.

Full text of DOI:10.1016/j.bmcl.2003.11.032

Bioorganic & Medicinal Chemistry Letters 14 (2004) 689–693
A new class of potent non-imidazole H3 antagonists:
2-aminoethylbenzofurans
Marlon Cowart,* John K. Pratt, Andrew O. Stewart, Youssef L. Bennani,y
Timothy A. Esbenshade and Arthur A. Hancock
GPRD_R4MN, AP9a/216, Department of Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064-6123, USA
Received 3 October 2003; revised 8 November 2003; accepted 14 November 2003
Abstract—2-Aminoethylbenzofurans constitute a new class of H3 antagonists that are more rotationally constrained than most
previously reported H3 antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed
in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in
analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.
# 2003 Elsevier Ltd. All rights reserved.
Histamine (1) is an important modulator of human and
animal physiological processes.1 Four distinct histamine
receptor subtypes mediate the direct actions of hista-
mine. H1 receptors play a critical role in regulating
inflammatory responses and CNS activity, and H1
antagonists are used clinically to treat allergic asthma
and rhinitis. H2 receptors regulate gastric acid secretion,
and H2 antagonists are used clinically to treat excess
acid production.2 The newly discovered H4 receptor is
found in immune cells, suggesting a role in regulating
inflammatory responses.3
clinical approval, perhaps due to inadequate drug-like
properties.
The imidazole-based H3 antagonists such as ciproxifan
(2) and thioperamide (3) are useful tools and reference
standards for pharmacological research,1 but attention
has been drawn to the potential liability of imidazole-
containing compounds for clinical use, due to their
potential to inhibit cytochrome-P450 (CYP) drug meta-
bolizing enzymes.8 This could then lead to drug–drug
interactions by inhibiting the metabolism of co-admin-
istered drugs.9 For this reason, non-imidazoles have
been targeted as potential drug candidates, and several
distinct classes of non-imidazole H3 antagonists have
been produced (Fig. 1). Several of the most potent and
promising classes of non-imidazoles such as 410 (UCL-
1972), 511 (UCL-2190), 6,12 and 713 (A-349821) share
common structural features, namely, a basic amine
connected through an alkoxy chain to a lipophilic
group. Of these prototypes, the amino-propyloxy-aryl
combination seen in compounds 5–7 may represent a
privileged H3 antagonist pharmacophore.1d,g
The recent cloning of H3 receptors from several species4
and the molecular characterization of H3 receptors have
provided new tools, and a clearer rationale, for a role
for H3 antagonists in treating human disease. Found on
presynaptic nerve terminals, the H3 receptor is con-
stitutively active, and acts as a ‘brake’ on neuro-
transmitter release.5 H3 antagonists relieve this
inhibition, thereby elevating levels of histamine, acetyl-
choline, and other neurotransmitters. In animal mod-
els, H3 antagonists have demonstrated efficacy in
enhancing cognition and attention,6 regulating wake-
fulness and weight gain,7 and ameliorating allergic
rhinitis8 (when coadministered with H1 antagonists).
However, in spite of the likely medical utility of H3
antagonists, no agent in the class has yet received
A new class of H3 antagonists, the 2-aminoethylbenzo-
furans (9) shown in Figure 2, was designed to give
compounds more structurally rigidified than those
comprising the established pharmacophore (8). By con-
verting the proximal methylene in 8 to a sp2 carbon,
then connecting to the phenyl moiety through a newly
created sp2 carbon, the resulting benzofurans (9) remove
two rotatable bonds. One goal was to enhance the
* Corresponding author. Tel.: +1-847-938-8170; Fax: +1-847-937-
9195; e-mail: marlon.d.cowart@abbott.com
y
Present address: Athersys, Inc., Cleveland, OH.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.032

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M. Cowart et al. / Bioorg. Med. Chem. Lett. 14 (2004) 689–693
selectivity of compounds for H3 over other receptors. It
has also recently been proposed that reductions in rota-
table bond count are associated with improved absorp-
tion in vivo,14 and with increased drug-likeness.15
The synthesis of the target benzofurans required phe-
nols 16–19 as starting materials (Fig. 3). While 19 is
commercially available, and 18 was easily produced by
amination of 17, the preparation of 16 required a multi-
step sequence. By trans-lithiation of 10, then quenching
with tri-isopropyl borate, the borate ester 11 was pro-
duced, which when treated acid produced the boronic
acid 12. Suzuki coupling of 12 with 14 gave 15, which
was deprotected with fluoride to give 16. By carefully
controlled selective iodination of 16, 18, and 19 with
sodium hypochlorite and sodium iodide at low tem-
perature, good yields of the monoiodides 20–22 were
produced. The palladium catalyzed Sonagashira–
Stevens coupling products were readily cyclized to the
2-hydroxyethylbenzofurans 23–25 in high yields. For
conversion to the final products (26–28), the alcohols
were converted to the mesylates, which could be isolated
in high yield, but typically were not purified, but reacted
directly with target amines in CH3CN at ambient tem-
perature. For the most highly hindered amines, (2R,5R)-
dimethylpyrrolidine and (cis-2,6)-dimethylpiperidine,
heating at 80 ꢀC for 2–48 h was required to induce
displacement of the mesylates, and was accompanied by
substantial amounts (50 and 90%, respectively) of the
Figure 1. Structures of H3 antagonists based on imidazoles (2, 3), and
non-imidazole H3 antagonists (4–7).
Figure 2. H3 antagonists based on 2-aminoethylbenzofurans (9) have
less conformational mobility than analogues (8) based on the 3-ami-
nopropyloxyphenyl skeleton.
Figure 3. Synthesis of the 2-aminoethylbenzofuran H3 antagonists.

M. Cowart et al. / Bioorg. Med. Chem. Lett. 14 (2004) 689–693
691
styrene side product produced by E2 elimination. Com-
mercially available optically pure amines were used to
prepare 30–34 and 37 in >96% e.e. Products were pur-
ified to >95% purity by reversed phase HPLC, eluting
with acetonitrile/aqueous CF3CO2H.
matic benzofuran ring substituents are compared in the
compounds bearing identical amines in Table 1 (29 ver-
sus 43; 33 versus 39; 37 versus 44), there appears to be
little effect of the aromatic ring on H3 potency. Among
chiral compounds, the (3R)-dimethylaminopyrrolidine 31
was slightly more potent than the (3S)-dimethylamino-
pyrrolidine 30. The (2S)-hydroxymethylpyrrolidines (33,
39) were much more potent than the (2R)-hydro-
xymethylpyrrolidines (32, 44). It might be anticipated
that the potency of racemic 35 still could be increased
further with the synthesis of the appropriate pure enan-
tiomer. Since the absolute configuration of the most
potent enantiomer of 2-hydroxymethylpyrrolidine (2S)
As our ultimate goal was to find CNS drug candidates,
we sought compounds with an ability to achieve selec-
tively high brain concentrations, features associated with
relatively high lipophilicity and low molecular weight.
We also sought compounds combining comparable and
high potency at both human and rat H3 receptors
(Ki<10 nM), since this would enhance the likelihood
that agents found potent and effective in the rat beha-
vioral models would have similar effects in humans.
An assessment of the SAR of the basic amine moiety
from the data in Table 1 shows that for compounds
29–38, all bearing the 4-cyanophenyl aromatic group, the
pyrrolidine 29, the racemic 2-methylpyrrolidine 35 and
2-methylpiperidine 37, and (2S)-hydroxymethyl pyrroli-
dine 33 possessed the greatest potency (<10 nM) at the
human receptor, while only compound 35 possessed a
similar degree of high potency at the rat receptor. Ana-
logues bearing pyrrolidine rings with other polar sub-
stituents (30–32, 34), and polar heterocycles (36, 42, 45)
all had lower H3 potency. When the effects of the aro-
Figure 4. Synthesis of R-2-methylpyrrolidine.
Table 1. SAR of compounds of general structure 9, varying the aromatic substituent R, and the amine moiety
Compd
Human H3
pKiÆSEM
Rat H3
Ki nM
Ki nM
pKiÆSEM
Ar substituent R !
Ph(4-CN)
Amine #
Pyrrolidine
29
30
31
32
33
34
35
36
37
38
4.2
49
16
18
2.2
320
0.95
600
5.8
10
8.37Æ0.07
7.31Æ0.03
7.80Æ0.09
7.75Æ0.19
8.65Æ0.04
6.50Æ0.20
9.02Æ0.06
6.22Æ0.12
8.23Æ0.10
7.99Æ0.17
47
140
63
160
26
1600
6.5
2200
45
7.33Æ0.04
6.86Æ0.07
7.20Æ0.16
6.78Æ0.13
7.59Æ0.08
5.79Æ0.20
8.19Æ0.11
5.66Æ0.14
7.35Æ0.09
7.30Æ0.20
(3S)-Dimethylaminopyrrolidine
(3R)-Dimethylaminopyrrolidine
(2R)-Hydroxymethylpyrrolidine
(2S)-Hydroxymethylpyrrolidine
(2R)-Carboxymethylpyrrolidine
(Æ2)-Methylpyrrolidine
N-Imidazolyl
(Æ2)-Methylpiperidine
(Á3,4)-Tetrahydropyridine
50
Ph(4-CO
morpholine)
39
(2S)-Hydroxymethylpyrrolidine
1.9
8.72Æ0.04
6.9
8.16Æ0.06
(Æ2)-Methylpiperidine
(Á3,4)-Tetrahydropyridine
Morpholine
40
41
42
3
5.9
45
8.52Æ0.19
8.23Æ0.25
7.35Æ0.20
14
17
160
7.87Æ0.20
7.77Æ0.16
6.79Æ0.22
Pyridine(4-CO
morpholine)
Pyrrolidine
(2R)-Hydroxymethylpyrrolidine
Morpholine
43
44
45
3.9
36
150
8.4Æ0.25
7.44Æ0.32
6.83Æ0.17
29
110
260
7.53Æ0.24
6.96Æ0.24
6.59Æ0.08
3
Binding potencies were assessed by displacement of H–N-a-methyl histamine. The human H3 values were from cloned human H3 expressed in C6
cells, while rat H3 values were from rat cortical membranes. pKi=ꢁlogKi. The number of independent pKi determinations was ꢂ3 for all compounds.

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M. Cowart et al. / Bioorg. Med. Chem. Lett. 14 (2004) 689–693
Table 2. SAR of compounds of general structure 9, varying the aromatic R substituent, and the amine moiety
R!
Ph(4-CN)
Human H3
Ph(4-COmorpholine)
Human H3 Rat H3
Pyridine(4-COmorpholine)
Human H3 Rat H3
Rat H3
Amine #
#
Ki pKiÆSEM Ki pKiÆSEM
nM nM
#
Ki pKiÆSEM Ki pKiÆSEM
#
Ki pKiÆSEM Ki pKiÆSEM
nM nM
nM
nM
2
(2)-Methyl
pyrrolidine
(2R,5R)-Dimethyl 47
46 0.45 9.35Æ0.04 3.22 8.49Æ0.04 53 0.7 9.15Æ0.06
8.71Æ0.04 60 0.55 9.26Æ0.06 1.6 8.79Æ0.08
(R)*
(R)
5.1 8.29Æ0.00 42 7.38Æ0.04 54 2.2 8.65Æ0.22 6.9 8.16Æ0.17 61 5.9 8.23Æ0.23 26 7.59Æ0.16
pyrrolidine
(3R)-Hydroxy
pyrrolidine
Piperidine
(cis-2,6)-Dimethyl 50
piperidine
48
8.8 8.05Æ0.03 95 7.02Æ0.08 55 6.2 8.21Æ0.15 35 7.46Æ0.20 62 12 7.93Æ0.21 67 7.17Æ0.14
49
8.8 8.06Æ0.02 59 7.23Æ0.13 56 2.3 8.64Æ0.20 6.2 8.21Æ0.18 63 12
7.9Æ0.25 49 7.31Æ0.21
45 7.35Æ0.05
2.4 8.62Æ0.06 22 7.67Æ0.08 57 1.2 8.92Æ0.23 6.6 8.18Æ0.21 64 5.6 8.25Æ0.2
4-Methyl
piperidine
Hexahydro
azapine
51
52
15 7.82Æ0.14 16 7.79Æ0.20 58 17 7.76Æ0.25 43 7.37Æ0.17 65 87 7.06Æ0.26 151 6.82Æ0.21
7.8 8.11Æ0.14 44 7.36Æ0.25 59 3.5 8.46Æ0.24 10 8.0Æ0.18 66 16 7.8Æ0.26 33 7.48Æ0.52
*Compound determined to be 99.9% e.e. by chiral HPLC analysis of the l-tartrate salt.
corresponds to the (2R) configuration of 2-methylpyr-
rolidine, the reported16 synthesis of (2R)-methylpyrroli-
dine from (2S)-prolinol (>99% e.e.) was completed on
a large scale as shown in Figure 4. High yields were
obtained even when conducted on a 40 gram scale. This
amine was then used to prepare 46 and 60, bearing the
2R-methylpyrrolidine as the basic amine.
desirable balance of affinity to both receptors (ÁpKi
<1), analogue 35 and its pure enantiomer 46 were
judged most likely to penetrate the BBB efficiently and
achieve high CNS concentrations, compared to blood
levels. This assessment was based on the higher lipo-
philicity of 35 (CLogP=5.2), compared to benzene-
amide analogues like 53 (CLogP=4.3), or pyridineamide
analogues like 60 (CLogP=2.1). Indeed, racemic com-
pound 35 was found to efficiently penetrate CNS tissues,
with brain:plasma ratios >30ꢃ, and very high brain
concentrations were achieved (15,000 ng/gm) after iv
dosing of 35 at 5 mg/kg.
A comparison of the SAR of amine substituents in three
different aromatic substituted series (26–28) is shown in
Table 2. The amines in Table 2 were selected based on
the characteristics likely to induce the highest potency
among the compounds (29–45), that is, cyclic 5, 6, or
7-membered amines, especially ortho-methyl substituted
amines. The targeted compounds were indeed potent; for
example, incorporation of the (2R)-methylpyrrolidine in
the 4-cyanophenylbenzofuran series gave the highly potent
analogue 46 with Ki values of 0.45 nM at the human H3
receptor, and 3.2 nM at the cortical rat H3 receptor
(1.35 nM at cloned rat H3R). Thus 2-methylpyrrolidine
induced high potency in all series (analogues 46, 53, 60),
as did (2R,5R)-dimethylpyrrolidine (analogues 47, 54,
61). Similarly, (cis-2,6)-dimethylpiperidine (analogues
50, 57, 64) induced high potency in all series, as did
unsubstituted piperidine (49, 56, 63). Piperidine itself has
long been known to induce high H3 potency in disparate
H3 antagonist series.10ꢁ13
The in vitro, metabolic, pharmacokinetic, and in vivo
behavioral pharmacological profile of compounds in
this series will be fully described elsewhere, but the data
described here show that the new series of benzofuran-
based H3 antagonists contains compounds that achieve
high CNS concentrations, as well as balanced nanomo-
lar potency at both human and rat H3 receptors.
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