Synthesis and SAR of novel histamine H3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.04.004

The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H₃ receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H₃ receptors are reported.

Full text of DOI:10.1016/j.bmcl.2006.04.004

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3415–3418
Synthesis and SAR of novel histamine H3 receptor antagonists
Cynthia D. Jesudason,a,* Lisa S. Beavers,a Jeffrey W. Cramer,a Joelle Dill,a
Don R. Finley,a Craig W. Lindsley,a,ꢀ F. Craig Stevens,a Robert A. Gadski,a
Samuel W. Oldham,a R. Todd Pickard,a Christopher S. Siedem,b Dana K. Sindelar,a
Ajay Singh,b Brian M. Watsona and Philip A. Hipskinda
aLilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
bArray Biopharma, 3200 Walnut Street, Boulder, CO 80301, USA
Received 17 March 2006; revised 31 March 2006; accepted 3 April 2006
Available online 3 May 2006
Abstract—The synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine
antagonists of the human and rat H3 receptors are described. The substitution around these rings as well as the nature of the sub-
stituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H3 receptors are
reported.
Ó 2006 Elsevier Ltd. All rights reserved.
Histamine is known to play an important role in the hu-
man body, with actions spanning diverse physiological
roles, from acting as a neurotransmitter in the central
nervous system (CNS) to peripheral effects on gastric
acid secretion and smooth muscle contraction.1 The
action of histamine is mediated through four distinct
receptors known to date as histamine H1, H2, H3, and
H4 receptors.2 Centrally administered histamine H3
antagonists lead to increased histamine levels3 and
may consequently be useful for the treatment of a vari-
ety of CNS disorders such as attention deficit and hyper-
activity disorder, cognitive disorders, schizophrenia or
obesity.4
Attempts to identify selective non-imidazole containing
ligands for the H3 receptors have resulted in the identi-
fication of several potent antagonists (Fig. 1) such as
UCL 2190 (1)5, A-923 (2)6, JNJ-5205872 (3)7, ABT-
239 (4)8, and compounds 59 and 6.10
Initial efforts employing a medium throughput screen
identified a novel tetrahydroisoquinoline (7) as a potent
Figure 1. Structures of non-imidazole based histamine H3 antagonists.
Keywords: Histamine H3 receptor antagonist; Tetrahydroisoquinolines; Tetrahydroquinolines; Tetrahydroazepines.
*
Corresponding author. Tel.: +1 317 276 7984; fax: +1 317 277 7287; e-mail: jesudason_cynthia_d@lilly.com
Present address: Merck Research Laboratories, PA, USA.
ꢀ
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.004

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C. D. Jesudason et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3415–3418
antagonist11 (Ki = 2.4 nM, IC50 = 6.6 nM) at human his-
tamine H3 receptor in vitro (Fig. 2). We were intrigued
by this water-soluble compound and sought to further
explore this structure type. This paper reports the
SAR of a number of tetrahydroisoquinolines, tetrahy-
droquinolines, and tetrahydroazepines.
The synthesis of 6-hydroxy tetrahydroisoquinoline com-
pounds is outlined in Scheme 1. 6-Hydroxy-3,4-dihydro-
1H-isoquinoline-2-carboxylic acid tert-butyl ester 812
was alkylated with 1-(3-chloro-propyl)-piperidine, fol-
lowed by removal of the Boc group, and further elabo-
ration of the newly unmasked nitrogen by reaction
with aldehydes, ketones, acid chlorides, sulfonyl chlo-
rides, and isocyanates to give the final products (11).
Scheme 2. Reagents and conditions: (a) H2, 10% Pd/C, NaOAcÆ3H2O,
EtOH, 60 psi, 4 h, 72%; (b) NaN3, H2SO4, toluene, 4 h, 79%; (c) LAH,
THF, 5 h, 70%; (d) BBr3, CH2Cl2, À78 °C, 3.5 h; (e) Boc2O, NaOH,
dioxane, 18 h, 89% (two steps).
The other tetrahydroisoquinoline regioisomers were
prepared as described in Scheme 1 from the corre-
sponding hydroxy-3,4-dihydro-1H-isoquinoline-2-car-
boxylic acid tert-butyl ester intermediates.13 The 8-
hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid
tert-butyl ester 12 was prepared as detailed in Scheme
2. The indanone 13 was prepared in two steps from
3-(3-methoxyphenyl)propanoic acid.14 The bromo sub-
stituent, whose role was to assure the desired regio-
chemistry, was removed by hydrogenation. Curtius
rearrangement of the resulting ketone 14 provided the
isoquinolinone 15, which was reduced to the corre-
sponding isoquinoline 16,15 demethylated, and protect-
ed with a Boc group.
Scheme 3. Reagents and conditions: (a) H2, PtO2, MeOH, 60 psi, 12 h,
100%; (b) BBr3, CH2Cl2, 4 h, À78 °C; (c) Boc2O, NaOH, dioxane, 77%
(two steps).
Table 1. Binding affinities (nM) of tetrahydroisoquinolines at the
human H3 receptora
In a similar manner, the tetrahydroquinoline com-
pounds were synthesized from the corresponding
hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic
acid
tert-butyl esters which were obtained by reduction of the
substituted quinolines (17) as illustrated in Scheme 3.16
The 7-hydroxy-1,3,4,5-tetrahydro-benzo[c]azepine-2-
carboxylic acid tert-butyl ester was prepared in an
R
Kib, nM SEM
analogous manner as that described in Scheme 2
6-methoxy-3,4-dihydro-2H-naphthalen-1-one.17
20
21
22
23
154 32
from
The
benzo[d]azepine-3-carboxylic acid tert-butyl ester was
a
b
c
d
e
>300
2.4 0.7
0.60 0.10
0.34 0.07
0.35 0.09
0.53 0.19
8.1 0.81
corresponding
7-hydroxy-1,2,4,5-tetrahydro-
84.2 13.7
15.4 1.3
>300
0.54 0.13
1.01 0.43
7.4 0.92
2.1 0.6
95.2 2.9
59 20
>300
prepared as described in the literature.18
>300
>300
a Binding potencies were assessed by displacement of [3H]N-a-meth-
ylhistamine using cloned human H3 receptors.
b Values are means of at least three experiments.
A representative subset of compounds based on the
tetrahydroisoquinoline core is shown in Table 1.
The receptor shows a preference for the orientation
Figure 2. Initial Screen Hit.
Scheme 1. Reagents and conditions: (a) 1-(3-chloro-propyl)-piperidine, Cs2CO3, KI, DMF, 90 °C, 18 h, 67%; (b) 4 M HCl in dioxane, CH2Cl2, rt,
4 h, 87%; (c) aldehyde, MP-CNBH3, CH2Cl2/MeOH (9:1), rt, 18 h; (d) acid chloride, Et3N, CH2Cl2, rt, 18 h; (e) sulfonyl chloride, Et3N, CH2Cl2, rt,
18 h; (f) isocyanate, Et3N, CH2Cl2, rt, 18 h.

C. D. Jesudason et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3415–3418
3417
Table 3. Binding affinities (nM) of tetrahydroisoquinolines and
tetrahydroazepines at the human and rat H3 receptorsa
provided by the 6- and 7-substituted tetrahydroiso-
quinolines (21 a–e and 22 a–e). The dibasic com-
pounds (22a–c) have subnanomolar affinity for the
human H3 receptor as does the monobasic compound
22d.
The data on a representative set of tetrahydroquinoline
compounds are shown in Table 2. In general, these com-
pounds were less active than the most closely homolo-
gous tetrahydroisoquinoline regioisomers shown in
Table 1.
Encouraged by the data on the 6- and 7-hydroxy tet-
rahydroisoquinolines, tetrahydrobenzazepines were
prepared and evaluated at both the human and rat
histamine H3 receptors (Table 3). Reports in the liter-
ature19 (for different chemical series) have described
significant potency differences between the human
and rat receptors. Likewise, we also saw a species dif-
ference with all the compounds being less potent at
the rat receptor. We selected compounds 22b and
28f based on their high affinity for human H3 recep-
tors for further evaluation.20 These compounds
potently inhibited the ex vivo binding of [3H]R-a-
methylhistamine in rat brain homogenates (IC50 = 1.1
and 5.3 mg/kg, po, for 22b and 28f, respectively).
The oral bioavailability of compounds 22b and 28f
in rat after a dose of 10 mg/kg was found to be
69% and P100%, respectively.
R
Kib (nM)
22
28
29
hH3
0.34
rH3
0.64
hH3
0.34
rH3
0.56
hH3
0.26
rH3
1.1
b
c
f
0.28
0.17
4.9
0.46
0.89
0.20
0.20
0.80
1.29
0.53
0.72
0.97
1.6
h
i
39.6
17.1
2.9
32.5
42.3
—
23.8
19.4
74.5
36.7
70.1
—
12.1
11.6
38.1
48.8
j
—
a Binding potencies were assessed by displacement of [3H]N-a-meth-
ylhistamine using cloned human H3 and rat H3 receptors.
b Values are means of at least three experiments.
Acknowledgments
The authors thank Mr. Michael Prunier and Mr. El-
don Van Meter for all the catalytic hydrogenation
chemistry.
In conclusion, we have discovered highly potent ligands
for both the human and rat H3 receptors. The full
biological profile of these compounds will be published
in due course.
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11. Binding potencies were assessed by displacement of [3H]-
N-a-methylhistamine using cloned human H3 receptors.
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[35S]GTPc [S] binding in CHO membranes expressing
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