Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists

Article abstract of DOI:10.1016/j.bmcl.2008.07.125

Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H₃ receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H₃ activity (IC₅₀ = 0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC₅₀ of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H₃ inverse agonists.

Full text of DOI:10.1016/j.bmcl.2008.07.125

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5101–5106
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3
receptor inverse agonists
Makoto Jitsuoka, Daisuke Tsukahara, Sayaka Ito, Takeshi Tanaka, Norihiro Takenaga, Shigeru Tokita,
*
Nagaaki Sato
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imid-
azole H3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead.
Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-
hand piperidine portion was carried out to yield the potent spiro-derivatives 2tꢀx. Spiro-isobenzofura-
none 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which
possessed dramatically improved H3 activity (IC50 = 0.72 nM; more than 20-fold improvement over
2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC50 of 0.54 nM.
Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3
inverse agonists.
Received 12 June 2008
Revised 28 July 2008
Accepted 30 July 2008
Available online 5 August 2008
Keywords:
Histamine H3 inverse agonist
Spiro-isobenzofuranone
PET tracer
Ó 2008 Elsevier Ltd. All rights reserved.
Brain permeability
Despite the pharmacological discovery of the H3 receptor in
1983,1 it was not until 1999, with its genetic identification,2 that
the H3 receptor gained widespread attention and redirected the de-
tailed pharmacological characterization of the receptor and drug
discovery efforts from academia and pharmaceutical industries.3
Studies have shown that signaling through the H3 receptor acti-
vates G-proteins that inhibit adenylate cyclase activity and reduces
intracellular cAMP levels.2,4 The H3 receptors, which are predomi-
nantly expressed in the CNS, are localized on the presynaptic mem-
brane as autoreceptors, and negatively regulate the release and
synthesis of histamine.1 The H3 receptor is also known to modulate
the release of other neurotransmitters such as norepinephrine,
dopamine, acetylcholine, serotonin, and GABA,5 and accordingly,
it has been suggested that H3 antagonists/inverse agonists could
serve as effective therapeutics for several CNS-related disorders.6
In animal models, H3 receptor antagonists/inverse agonists have
been shown to enhance wakefulness, improve attentive and cogni-
tive behaviors, and reduce feeding and body weight.7,8 It has re-
focused on non-imidazole classes of H3 receptor antagonists/in-
verse agonists. Since the identification of the H3 receptor genes,
various classes of non-imidazole H3 receptor antagonists have been
developed to target the CNS H3 receptors.3,7,11 Among them,
BF2.649,9,12 ABT-834,13 and GSK189254,14 as shown in Chart 1, tar-
get CNS disorders such as excessive daytime sleepiness, schizo-
phrenia, and cognitive dysfunctions, and have successfully
entered clinical trials.
Recently, our corporate chemical collection was screened
against the human H3 receptor, and resulted in the identification
of 2a. Subsequently, the substituted piperidine component (left-
hand portion of 2a) was extensively screened for H3 affinity, and
resulted in the identification of potent spiro-isobenzofuranones
1a and 1b. In this report, the discovery and characterization of
these potent, selective, and brain-penetrable H3 inverse agonists
are described.
The synthetic route for the derivatives reported herein is illus-
trated in Schemes 1–4. Carbamoylchloride 4, which was generated
in situ from N-methyl-2-(1-piperidinyl)ethanamine (3) and tri-
phosgene, was coupled with substituted piperidines and pipera-
cently been reported that BF2.649 (Chart 1),
a potent and
selective H3 receptor inverse agonist, can suppress excessive day-
time sleep among narcoleptic patients.9
zines
5
to afford 2aꢀy in 20–30% yield (Scheme 1). The
First-generation imidazole-based H3 antagonists, which possess
inhibitory actions on cytochrome P450 activity, may cause drug–
drug interactions against co-administered drugs by inhibiting he-
patic clearance.10 Because of these liabilities, current efforts have
substituted piperidines and piperazines 5 employed in the present
study were either commercially available or reported in the litera-
ture.15 The low yields for these coupling reactions can be improved
by reversing the reaction sequence. For instance, compound 2x was
prepared in 81% yield by the generation of the carbamoylchloride
from 3H-spiro[2-benzofuran-1,40-piperidin]-3-one followed by
coupling with amine 3. For the preparation of alcohol 8 (Scheme
* Corresponding author. Tel.: +81 29 877 2004; fax: +81 29 877 2029.
E-mail address: nagaaki_sato@merck.com (N. Sato).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.125

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M. Jitsuoka et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5101–5106
NC
O
N
N
Cl
BF2.649
O
ABT-239
O
H
N
N
N
O
GSK189254
Chart 1. Structures of non-imidazole H3 antagonists and inverse agonists.
O
b
a
N
N
N
N
N
N
N
H
R1
R2
X
NH
Cl
O
R1
R2
5 : X = N or C
X
3
2a−y (20−30%)
4
Scheme 1. Reagents and conditions: (a) triphosgene, N,N-diisopropylethylamine, CHCl3, 0 °C, 3 h; (b) N,N-diisopropylethylamine, CHCl3, 70 °C, 4 h.
O
OH
Br
O
a
b
OH
R3
R3
R3
O
O
O
O
6a: R3 = H
6b: R3 = OMe
7a: R3 = H (44%)
7b: R3 = OMe (65%)
8a: R3 = H (71%)
8b: R3 = OMe (90%)
Scheme 2. Reagents and conditions: (a) i—n-BuLi, THF, ꢀ78 °C, 1 h, then 4,4-ethylenedioxycyclohexanol, rt, 18 h; ii—concd HCl, acetone, H2O, reflux, 18 h; (b) NaBH4, H2O/
THF (v/v = 1/10), 0 °C, 1 h, diastereomeric ratio > 4:1.
O
O
R5
R5
O
R4
R4
O
R5
R4
a
b
c
N
O
O
N
O
OH
11a: R4 = OMe, R5 = H
11b: R4 = H, R5 = OMe
10a: R4 = OMe, R5 = H (48%)
10b: R4 = H, R5 = OMe (47%)
9a: R4 = OMe, R5 = H
9b: R4 = H, R5 = OMe
OH
R5
R4
O
O
12a: R4 = OMe, R5 = H (90% over 2 steps)
12b: R4 = H, R5 = OMe (74% over 2 steps)
Scheme 3. Reagents and conditions: (a) n-BuLi, THF, rt, 2 h then 4,4-ethylenedioxycyclohexanol, rt, 18 h; (b) 2 N H2SO4, acetone, 80 °C, 18 h; (c) NaBH4, H2O/THF (v/v = 1/10),
0 °C, 4 h, diastereomeric ratio > 4:1.

M. Jitsuoka et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5101–5106
5103
OH
OMs
CN
R5
R5
R5
R4
R3
R4
R3
R4
R3
a
b
O
O
O
O
O
O
14a (58% over 2 steps)
14b (70% over 2 steps)
14c (30% over 2 steps)
14d (62% over 2 steps)
8a
8b
12a
12b
13a
13b
13c
13d
COOH
R5
R4
R3
c
8a, 13−15a: R3 = R4 = R5 = H
8b, 13−15b: R3 = OMe, R4 = R5 = H
12−15c: R4 = OMe, R3 = R5 = H
12−15d: R5 = OMe, R3 = R4 = H
O
O
15a (84%)
15b (95%)
15c (88%)
15d (92%)
Scheme 4. Reagents and conditions: (a) methanesulfonyl chloride, Et3N, THF, 0 °C, 30 min; (b) Et4NCN, DMF, 100 °C, 18 h; (c) 30% H2SO4, dioxane, 100 °C, 48 h.
2), 2-bromobenzoic acid 6 was reacted with n-butyllithium, then
treated with 4,4-ethylenedioxycyclohexanol, followed by hydroly-
sis of the ketal group under acidic conditions to afford 7 (7a, 44%;
7b, 65%). Ketone 7 was reduced using sodium borohydride to give
the corresponding alcohol 8 in good yields. For the preparation of
alcohols 12 (Scheme 3), substituted 2-phenyloxazole 9 was reacted
with n-butyllithium followed by treatment with 4,4-ethylenedi-
oxycyclohexanol to afford 10 (10a, 48%; 10b, 47%). The imidate
and ketal groups of 10 were hydrolyzed under acidic conditions
to give ketone 11, which was reduced using sodium borohydride
to give the corresponding alcohol 12 in good yields. It is important
to note that the reduction of ketones 7 and 11 using sodium boro-
hydride was diastereoselective—the desired cis-isomers 8 and 12
were obtained with a diastereomeric ratio of greater than 4:1.
The hydroxy group of 8 and 12 was mesylated and displaced by
a cyanide ion to give 14, which was converted to the spiro-iso-
benzofuranone carboxylic acids 15aꢀd by subsequent treatment
with 30% sulfuric acid in dioxane (Scheme 4). The minor diastereo-
mer in 15 was separated by silica gel chromatography without dif-
ficulty. Finally, 15aꢀd were coupled with amine 3 in the presence
of 2-chloro-1,3-dimethylimidazolinium chloride and triethylamine
to afford 1aꢀd (Scheme 5).
ported herein reduced basal GTPcS binding, indicating that they
are inverse agonists. Selected compounds were evaluated for hERG
K+ channel inhibitory activity using the [35S]N-[(4R)-10-[(2R)-6-cy-
ano-1,2,3,4-tetrahydro-2-naphthalenyl]-3,4-dihydro-4-hydroxy-
spiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfonamide
binding assay to assess QTc prolongation liability.17 Screening of
Merck sample collection led to the identification of lead 2a, which
possessed an IC50 value of 110 nM (Table 1). Based on previous SAR
studies,3,7,11 the structure of 2a can be defined as a basic piperidine
pharmacophore with an ethylene linker and a lipophilic left-hand
pharmacophore tethered by a urea linkage. Consequently, our
studies focused on modifying the lipophilic left-hand component,
and by taking advantage of the urea linkage, a variety of 4-substi-
tuted piperidine and piperazine analogs were prepared and evalu-
ated (Table 1). Compared to compound 2a, the 1-naphthyl
derivative 2b was less potent, while replacement of the naphthyl
with a phenyl group as in 2c resulted in marked loss of potency.
The tetrahydroquinoline derivative 2d showed weak activity.
Introduction of spacers between the piperidine and phenyl rings
as in 2eꢀg proved to be ineffective. Inclusion of another 4-substit-
utent, in addition to the phenyl group, showed mixed results—the
4,4-diphenyl and 4-cyano-4-phenyl derivatives 2i and 2h dis-
played similar activities as that of lead 2a, whereas the 4-hydro-
xy-4-phenyl derivative 2j exhibited a complete loss of potency.
The 4-phenyl piperazine derivative 2k showed weak activity
The compounds described herein were tested in the [35S]GTP
cS
binding assay in membranes isolated from cells transfected with
cloned human H3 receptors.16 All the quinazolinone derivatives re-
O
N
COOH
R5
R5
R4
R3
R4
R3
a
N
N
+
N
H
O
O
O
O
15a
1a: R3 = R4 = R5 = H (87%)
1b: R3 = OMe, R4 = R5 = H (64%)
1c: R4 = OMe, R3 = R5 = H (95%)
1d: R5 = OMe, R3 = R4 = H (67%)
3
15b
15c
15d
Scheme 5. Reagents and conditions: (a) 2-chloro-1,3-dimethylimidazolinium chloride, Et3N, CHCl3, rt, 1 h.

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M. Jitsuoka et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5101–5106
Table 1 (continued)
Table 1
Human H3 activities of the urea derivatives 2aꢀya
b
Compound
Human H3 (IC50, nM)
N
O
R1
R2
X
N
N
N
R1
R2
X
N
N
b
Cl
Cl
N
2m
2n
297 55
160 31
Compound
Human H3 (IC50, nM)
N
R1
R2
X
N
N
2a
2b
110 10
343 97
N
2o
2p
2q
2r
>1000
N
N
783 213
NH
O
N
O
O
2c
2d
2e
893 47
680 61
393 26
N
>1000
HN
N
H
N
N
N
N
560 195
380 95
68 27
NH
O
N
N
O
2s
2f
237 27
530 65
98 19
O
O
O
N
2t
2g
2h
O
N
N
N
N
N
2u
2v
2w
43
53
4
6
O
O
O
O
N
N
NH
2i
267 81
>1000
N
45 12
2j
N
O
HO
N
N
2k
506 147
2x
2y
21
1
Cl
N
N
N
387 34
2l
>1000
O
a
The values represent the mean SE for n P 3.
Inhibition of R-a-methylhistamine-induced binding of [35S]GTPcS at human H3
b
receptor.

M. Jitsuoka et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5101–5106
5105
Table 2
Table 4
In vitro profiles of 1aꢀda
Pharmacokinetic parameters of 1b in SD ratsa
O
iv (1 mg/kg)
po (3 mg/kg)
t1/2 = 1.4 h
Vdss = 7.2 L/kg
CLp = 74 mL/min/kg
N
7
N
t1/2 = 1.4 h
Tmax = 0.3 h
6
R6
5
Cmax = 0.06
F = 7%
lM
O
4
a
O
The values represent the mean for n = 3.
R6
H
5-MeO
6-MeO
7-MeO
Human H3 IC50 (nM)
hERGc IC50 (nM)
b
Compound
1a
1b
1c
1d
0.72 0.03
0.54 0.06
>10,000
>10,000
d
d
brain, and cerebrospinal fluid levels were 1.5
lM, 2.4 nmol/g, and
0.36 M, respectively (Table 3), and therefore, it is reasonable to
l
18
2
consider 1a as brain-penetrable in rats. Moreover, 1a is neither a
human nor a mouse P-gp substrate, and therefore the effects of
P-gp-mediated efflux in humans and mice should be negligible (Ta-
ble 3).19 Based on these data, the development of 1a as an oral drug
would be challenging; in contrast, however, development as an iv
tool such as a positron emission tomography (PET) tracer may be
feasible.
3.6 0.8
a
The values represent the mean SE for n P 3.
b
Inhibition of R-
receptor.
a cS at human H3
-methylhistamine-induced binding of [35S]GTP
c
Inhibition of [35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl]-
3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesul-
fonamide binding to hERG in HEK293 cells.
d
Not tested.
As a potential candidate for carbon isotope labeling, a methoxy
group was introduced into various positions in the phenyl ring of
the spiro-isobenzofuranone moiety of 1a (Table 2). Although the
6-methoxy and 7-methoxy derivatives 1c and 1d displayed signif-
icant losses in potency, the 5-methoxy derivative 1b showed en-
hanced activity (IC50 = 0.54 nM). The profiles of 1b and 1a were
comparable, where 1b showed good selectivity over other hista-
(IC50 = 506 nM). Slight improvements in potency were observed for
the para-chloro and meta-chloro derivatives 2n and 2m, whereas
the ortho-chloro derivative 2l was devoid of potency. Introduction
of a bulky alkyl group such as a tert-butyl group as in 2o was
ineffective.
mine receptor subtypes, such as H1, H2, and H4 (IC50 > 10
lM),
Next, we turned our attention to various spiro-derivatives.
Among the 3-azaspiro[5,5]undecane-based derivatives 2pꢀt,
spiro-benzopyranone 2t displayed the highest IC50 value (68 nM).
Several more potent derivatives were identified among the 8-aza-
spiro[4,5]decane-based derivatives 2uꢀy. The indanone and iso-
indolinone derivatives 2u and 2v possessed IC50 values of 43 and
53 nM, respectively. Methylation of 2v resulted in the slightly
more potent derivative 2w. Within our urea screening study,
spiro-isobenzofuranone 2x was found to be the most potent deriv-
ative (IC50 = 21 nM). The carbonyl group of 2x is pivotal for potency
since the isobenzofuran derivative 2y showed a 10-fold loss in po-
tency. Consequently, in hopes of further enhancing the potency,
the corresponding amide derivative of 2x was synthesized and
evaluated. The active trans-isomer 1a showed a dramatic 30-fold
increase in potency (IC50 = 0.72 nM), relative to the corresponding
urea derivative 2x. Furthermore, 1a displayed excellent selectivity
over other histamine receptor subtypes, such as H1, H2, and H4
and 115 diverse, unrelated binding sites (IC50 > 10 M for all the
l
binding sites tested). Again, using the serum incubation method,
the hepatic clearance of 1b was found to be very poor (18 and
54 mL/min/kg for human and rat hepatocytes, respectively).18
The pharmacokinetic profile of 1b in rats was indeed poor (Table
4). As in the case of 1a, good brain permeability in rats was ob-
served for 1b (Table 3)—upon oral administration of 10 mg/kg of
1b in rats, the plasma, brain, and cerebrospinal fluid levels at 2 h
were 0.27 lM, 0.48 nmol/g, and 0.058 lM, respectively. Although
1b was a significant mouse P-gp substrate, the P-gp-mediated ef-
flux should not be an issue in humans based on the transcellular
transport ratio for human MDR1 (Table 3).19
In summary, spiro-isobenzofuranones 1a and 1b were deter-
mined as potent and selective non-imidazole H3 receptor inverse
agonists. Our studies showed that 1b is brain-penetrable in rats,
and is not a human P-gp substrate. Moreover, the structure of 1b,
which is amenable to carbon isotope labeling, is distinctly different
from the current quinazolinone class of clinical development can-
didates.20 On the basis of these features, we believe 1b to be an
ideal clinical PET tracer candidate. The synthesis and preclinical
characterization of tracers based on 1b for imaging H3 receptors
are currently in progress. Additionally, efforts to optimize the
structure of 1 to improve its metabolic stability are underway to
develop a candidate from this class of spiro-isobenzofuranone H3
receptor inverse agonists for clinical development.
(IC50 > 10
an absence of any significant hERG inhibitory activities
(IC50 > 10 M). Using the serum incubation method, the hepatic
lM) and 60 CNS receptors (IC50 > 10 lM), along with
l
clearance of 1a was found to be very poor (18 and 59 mL/min/kg
for human and rat hepatocytes, respectively).18 Based on a phar-
macokinetic study involving iv administration of 1 mg/kg of 1a in
rats, the plasma clearance in rats was determined as 97 mL/min/
kg. Upon iv administration of 1 mg/kg of 1a in rats, the plasma,
Table 3
Brain-penetration and P-gp susceptibility of 1a and 1b
Compound
Brain-penetration in SD ratsa
P-gp transporter assayb
Transcellular transport ratio (B-to-A)/(A-to-B)
Plasma (
l
M)
Brain (nmol/g)
CSF (l
M)
MDR1
mdr1a
1a
1b
1.5
0.27
2.4
0.48
0.37
0.058
1.2
2.3
2.0
7.0
a
The values represent the mean for n = 3. The concentrations were determined at 10 min after 1 mg/kg iv for 1a and at 2 h after 10 mg/kg po for 1b.
Transcellular transport ratio ((B-to-A)/(A-to-B)) was obtained from human MDR1- and mouse mdr1a-transfected LLC-PK1 cell monolayers. The values represent the mean
b
for n P 3. The value above 3.0 indicates that a compound is a P-gp substrate.

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M. Jitsuoka et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5101–5106
Drescher, K. U.; Wetter, J.; Marsh, K.; Lemaire, M.; Porsolt, R. D.; Bennani, Y. L.;
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