Discovery of a series of (4,5-dihydroimidazol-2-yl)-biphenylamine 5-HT7 agonists.

Article abstract of DOI:10.1016/S0960-894X(02)00925-3

A novel (4,5-dihydroimidazol-2-yl)-biphenylamine series of 5-HT(7) agonist compounds was developed from a structurally related lead compound 1. The newly discovered series is exemplified by compound 2 that possesses high affinity for 5-HT(7) receptors and

Full text of DOI:10.1016/S0960-894X(02)00925-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 269–271
Discovery of a Series of (4,5-Dihydroimidazol-2-yl)-biphenylamine
5-HT7 Agonists
Vinod Parikh,* Willard M. Welch* and Anne W. Schmidt
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
Received 28 May 2002; accepted 24 September 2002
Abstract—A novel (4,5-dihydroimidazol-2-yl)-biphenylamine series of 5-HT7 agonist compounds was developed from a structurally
related lead compound 1. The newly discovered series is exemplified by compound 2 that possesses high affinity for 5-HT7 receptors
and shows intrinsic agonist activity in functional assays. This new series has significant a1 and a2 activities perhaps due to the pre-
sence of the 2-aminoimidazoline moiety.
# 2002 Elsevier Science Ltd. All rights reserved.
The
neurotransmitter
serotonin
(5-hydroxy-
Stimulation of this receptor by standard agents such as
8-hydroxy-2-(N,N-dipropylamino)-1,2,3,4-tetrahydron-
aphthalene (8-OH-DPAT), a 5-HT7 agonist,4 has been
reported to cause a phase advance in peak circadian cell
firing rates in SCN cells in slices5 taken from rats con-
strained to a 12/12 light–dark cycle prior to test. We
sought compounds that would be selective and potent
agonists of this receptor.
tryptamine, 5-HT) has been implicated in a variety
of physiological and pathophysiological processes
such as cardiovascular regulation, memory, thermo-
regulation, sleep, feeding, depression, anxiety, drug
abuse and migraine. Fourteen subtypes of 5-HT
receptors organized into seven distinct receptor classes,
5-HT1–5-HT7, are now recognized.1 The 5HT7 receptor
has cloned from several species including rat, guinea
pig, human and shows a high degree of homology
(ꢀ95%). The 5-HT7 receptor is well represented in a
diversity of neuronal and non-neuronal tissue where, in
at least some tissues, its activation has been shown to
elevate intracellular cAMP.2
Compounds capable of binding to the 5-HT7 receptor
were identified by their ability to block binding of 3H-5-
carboxamidotryptamine (3H-5-CT), a potent 5-HT7
agonist, to 5-HT7 receptors. High-Throughput screen-
ing of the Pfizer compound library identified compound
1, which binds potently to the 5-HT7 receptor and which
was characterized as a full agonist at this receptor,
compound 1 at 10 uM increasing adenylate cyclase
activity to the same extent as 10 uM 5-HT.6 The subject
series of (4,5-dihydroimidazol-2-yl)-biphenylamine deri-
vatives was derived from compound 1 by elimination of
the pyridyl ring while adding a lipophilic aromatic ring
at the 6-position. Through overlap of these two mole-
cules, we reasoned that meta-substitution in this second
aromatic ring, as suggested by the presence of the iso-
propyl group in compound 1, might be favored for
agonist activity at the 5-HT7 receptor.
Functionally, the 5-HT7 receptor has been impli-
cated in regulation of circadian rhythms in mam-
mals.2 In the CNS, cells containing this receptor are
found in the superchiasmatic nucleus3 (SCN),
region long associated with circadian rhythm reg-
ulation. For a number of years, disruption of circa-
dian rhythms has been implicated in a variety of CNS
disorders including depression, seasonal affective dis-
order, shift worker syndrome and jet lag among others.
We reasoned that compounds that regulated the circa-
dian cycle in humans might be useful in alleviating these
conditions.
a
*Corresponding author. Fax: +1-860-686-0013; e-mail: vinod_d_
parikh@groton.pfizer.com
0960-894X/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00925-3

270
V. Parikh et al. / Bioorg. Med. Chem. Lett. 13 (2003) 269–271
Table 1.
Table 2.
Compda
R
Rat 5HT7
pKiÆSEM
Rat a1
pKiÆSEM
Rat a2
pKiÆSEM
Compda
R
Rat 5HT7
pKiÆSEM
Rat a1
pKiÆSEM
6.68c
6.78Æ0.09
6.56Æ0.15
7.36d
6.59Æ0.10
6.88Æ0.09
7.04Æ0.16
7.05Æ0.01
5.92c
Rat a2
pKiÆSEM
7.71c
7.75Æ0.11
7.58Æ0.20
8.00d
7.10Æ0.08
7.62Æ0.16
7.66Æ0.18
7.49Æ0.03
6.96Æ0.01
7.59Æ0.03
7.13Æ0.16
13
14
15
2-Thiophene
3-Thiophene
3-Pyridyl
7.78Æ0.05
6.99Æ0.07
8.21Æ0.09
2
3
4
5
6
7
8b
9b
10
11
12
H
3-CH3
3-F
3-OCH3
3-CF3
3-Cl
7.79Æ0.08
7.67Æ0.05
7.55Æ0.07
7.45c
7.34Æ0.05
7.58Æ0.09
6.77Æ0.04
6.81Æ0.04
6.74Æ0.09
7.56Æ0.11
7.39Æ0.08
7.50b
7.16c
7.96c
6.59Æ0.06
6.59Æ0.07
8.29Æ0.14
aAll compounds were characterized by H NMR, MS, and IR.
bn=2.
cn=1.
1
3-CN
3-COCH3
3-CH(CH3)2
4-OCH3
2,4-(OCH3)2
6.58Æ0.04
analogue 2 being most potent. Electron withdrawing or
donating groups has as marginally effects in the binding
affinity compare to the unsubstituted analogue. In the
case of the heterocyclic analogues presented in Table 2,
the 2-thiophene analogues 13 and 14 were active at the
5-HT7 receptor but demonstrated significant a2 binding
activity using rat cortical membranes. The 3-pyridyl
analogue 15 was much less active at 5-HT7 and a1
receptors but the potent a2 binding activity was
retained.
6.68Æ0.04
aAll compounds were characterized by H NMR, MS, and IR.
1
bTested as hydrochloride salt.
cn=2.
dn=1.
In this paper, we describe the synthesis of a series of
(4,5-dihydroimidazol-2-yl)-biphenylamine
and the 5-HT7 binding activity of the series.
derivatives
2-Anilinoimidazoline derivatives such as clonidine and
brimonidine10 have been shown to have clinical anti-
hypertensive activity attributable to the a2 activity
inherent in the 2-aminoimidazoline moiety. Unfortu-
nately, this antihypertensive property was also seen
within compounds of the present series, the most potent
5- HT7 binding derivative 2 causing pronounced hyper-
tension in rats.
The synthesis of the biaryl moiety of the series of (4,5-
dihydroimidazol-2-yl)-biphenylamine analogues shown
in Table 1 was carried out using straightforward Suzuki
coupling methodology. Thus, meta and para substituted
phenylboronic acids 2-thiophene boronic acid and
3-pyridyl boronic acid reacted with commercially avail-
able 2-bromo-6-nitrotoluene in the presence of the Pdꢁ
catalyst Pd (PPh3)4 and CsF in dimethoxyethane to give
the corresponding cross coupled intermediates in good
yields. The nitro group could be reduced quantitatively
to the desired aniline derivative with iron powder and
hydrochloric acid.7 The resulting aniline intermediate
was then converted to the thiourea in two steps with
carbon disulfide and the water-soluble carbodiimide
DEC8 followed by reaction with ethylenediamine. This
intermediate thiourea was then readily cyclized to the
2-aminoimidazoline derivative by refluxing in ethanol in
presence of mercury oxide (Scheme 1).9
Compounds from a series of (4,5-dihydroimidazol-2-yl)-
biphenylamine derivatives were shown to bind to 5-HT7
receptors with moderate to good potencies. A repre-
sentative compound from this series was shown to be a
full agonist in a 5-HT7 functional assay. Because of the
association of blood pressure changes related to a1 and
a2 activity, compound 2 was examined in a rat hyper-
tension model. Profound blood pressure and heart rate
changes were seen after iv Administration of com-
pound 2. These effects are likely due to the a2 activity
of compound 2, a discovery that greatly decreased
future interest in these analogues. As a result of this
finding, we have since terminated synthetic efforts in
this area.
Within the series of derivatives shown in Table 1, it will
be noted that binding to the 5-HT7 receptor was highly
dependant upon substituent with the unsubstituted
Scheme 1. Reagents and yields (range): (a) DME, CsF, Pd, 100 ꢁC, 4 h, 75–100%; (b) Fe powder, HCl, EtOH, 80 ꢁC, 2 h, 82–100%; (c) CS2, DEC,
THF, rt, 24 h, 11–82%; (d) NH2(CH2)2NH2, CH2Cl2, rt, 24 h, 85–100%; (e) HgO, EtOH, 80 ꢁC, 2 h, 70–100%.

V. Parikh et al. / Bioorg. Med. Chem. Lett. 13 (2003) 269–271
271
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