Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators

Article abstract of DOI:10.1016/j.bmcl.2017.08.030

We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identifica

Full text of DOI:10.1016/j.bmcl.2017.08.030

Accepted Manuscript
Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as po-
tent and orally-active metabotropic glutamate receptor 5 negative allosteric
modulators
Wataru Hirose, Yoshihiro Kato, Itaru Natsutani, Makoto Takata, Maiko
Kitaichi, Satoki Imai, Shun Hayashi, Yukiyo Arai, Kohei Hoshino, Kohzo
Yoshida
PII:
S0960-894X(17)30830-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.08.030
BMCL 25224
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
12 June 2017
8 August 2017
14 August 2017
Please cite this article as: Hirose, W., Kato, Y., Natsutani, I., Takata, M., Kitaichi, M., Imai, S., Hayashi, S., Arai,
Y., Hoshino, K., Yoshida, K., Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent
and orally-active metabotropic glutamate receptor 5 negative allosteric modulators, Bioorganic & Medicinal
Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.08.030
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Title
Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active
metabotropic glutamate receptor 5 negative allosteric modulators
Author
a *
a
b
a
a
b
Wataru Hirose , Yoshihiro Kato , Itaru Natsutani , Makoto Takata , Maiko Kitaichi , Satoki Imai ,
b
a
a
a, *
Shun Hayashi , Yukiyo Arai , Kohei Hoshino and Kohzo Yoshida
a
Drug Research Division, Sumitomo Dainippon Pharma, 3-1-98 Kasugade-naka, Konohana-ku,
Osaka, 554-0022, Japan
b
Drug Research Division, Sumitomo Dainippon Pharma, 33-94 Enoki-cho, Suita, Osaka 564-0053,
Japan
Abstract
We describe here the design, synthesis and characterization of a series of
4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative
allosteric modulators (NAMs). Optimization of the substituents led to the identification of several
compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability,
in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain
penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like
effect in the rat forced swimming test (MED: 0.3 mg/kg, q.d.).

L-glutamate, a major excitatory neurotransmitter in the mammalian brain, exerts its
neuromodulatory effect via both ionotropic and metabotropic glutamate receptors (mGluRs), which
belong to G protein-coupled receptor (GPCR) class C. Eight mGluRs (mGluR1-8) have been cloned
and sequenced to date and are classified into three groups (Group I: mGluR1 and mGluR5; Group II:
mGluR2 and mGluR3; Group III: mGluR4 and mGluR6-8) based on their sequence homology,
1
, 2
signaling mechanism and pharmacological output. The post-synaptically located mGluR5 is
linked via Gq to activation of the phospholipase C cascade, which leads to increase in intracellular
2
, 3
calcium ions and activation of protein kinase C.
Over the past two decades, a number of glutamatergic approaches have been investigated for the
4
treatment of various CNS conditions. Accordingly, recent preclinical and clinical studies have
shown that negative allosteric modulators (NAMs) of mGluR5 can be beneficial in the treatment of
various CNS disorders, including anxiety, depression, Parkinson’s disease levodopa-induced
5
dyskinesia, fragile X syndrome, and addiction. We have also shown that DSR-98776, a selective
mGluR5 NAM, has antidepressant and antimanic efficacy in rodent behavioral models, indicating
6
that this compound might be useful in the treatment of a broad range of mood disorders. We report
herein the design, synthesis, optimization, and pharmacological effects of a novel series of
4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine mGluR5 NAMs, including DSR-98776.
Like MPEP (Fig. 1), a prototypical compound that acts as a noncompetitive antagonist for the
7
mGluR5, most compounds in clinical trials, such as AFQ-056, ADX-48621 and RG-7090 (Fig. 1)
have a di-substituted alkyne as a key structure. Due to the toxicity potential of the alkyne moiety
which can be influenced by metabolic activation and a crowded intellectural property space around
the di-substituted alkyne chemotypes, medicinal chemists have recently been exploring alternative
8
, 9
non-alkyne chemotypes. We have also reported 4,5,6,7-tetrahydropyrazolopyrazines, as
10
represented by compound 1 (Fig. 2), as novel mGluR5 NAMs without the typical alkyne motif.
Although compound 1 showed excellent oral absorption (B/A = 95％) and long half-life (t1/2 = 9.2
hr) in rats, its mGluR5 inhibitory activity (IC = 75 nM) didn’t reach the levels of reported mGluR5
5
0
11
12
13
14
NAMs (e.g. basimglurant: 7.0 nM, CTEP: 11.4 nM, GRN-529: 7.6 nM, AZD-9272: 7.6 nM ).
To grow up our compounds to be better ones, we carried out further optimization study from
compound 1 focusing on the replacement of pyrazole moiety in the central core scaffold of 1.
Sepracor’s researchers have previously reported similar bicyclic azole-amine mGluR5 NAMs with
15
4
,5,6,7-tetrahydrooxazolo[4,5-c]azepine structure. A representative compound of this series of

modulators (compound 2, Fig. 2) was characterized as having potent in vitro mGluR5 inhibitory
activity (IC = 16 nM) and short in vivo half-life, which makes it unsuitable for clinical
50
development. They analyzed that a major contributor to the short half-life was a high rate of hepatic
oxidatitive metabolism. The aniline structure of compound 2 was likely to cause the instability
against hepatic oxidation, therefore, we designed 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine
derivatives having a benzoyl amide instead of the aniline where the pyrazole was replaced with
oxazole (3, Fig. 2) with an expectation of good pharmacokinetic properties and high in vitro activity.
Figure 1. Structures of representative mGluR5 NAMs
Figure 2. Core structure replacement based on our previous compound 1 and Sepracor’s compound
2
One of the reported synthetic routes, where the benzyl 3,6-dihydropyridine-1(2H)-carboxylate (4)
is used as starting material to produce the 4,5,6,7-tetrahydrooxazolopyridine core structure, is
15, 16
illustrated in Scheme 1.
4-amino-3-hydroxypiperidine 6a and 3-amino-4-hydroxypiperidine 6b
give two regioisomers of 4,5,6,7-tetrahydrooxazolopyridine, [5,4-c] and [4,5-c] orientation,

respectively. Sepracor’s researchers reported that [4,5-c] orientation was more favorable for mGluR5
inhibitory activity than [5,4-c] orientation in comparison of the corresponding compounds bearing
15
the same subsituents. Since a similar tendency was obtained in our experiments, we conducted the
optimization study about tetrahydrooxazolo[4,5-c]pyridine derivatives.
Scheme 1. Synthetic route for the two isomers of 4,5,6,7-tetrahydrooxazolopyridine
It is known that compound 5 epoxide ring opening reaction by nucleophilic addition of ammonia
17
or sodium azide selectively proceeded at the C-4 position. In our experiments, reaction of
compound 5 with ammonia followed by Boc protection of the inserted amino group gave 6a as a
major product (yield: 41%) and 6b as a minor product (yield: 25%). To obtain 6b efficiently, we
explored the aziridine ring opening reaction as a selective synthetic method for the
1
8
3
-amino-4-hydroxypiperidine structure. Namely, we prepared the piperidine-aziridine tert-butyl
carbamate 7 from compound 6a, and attempted regioselective ring opening reaction with oxygen
sources (Scheme 2). After tosylation of 6a, aziridine ring formation with aqueous NaOH provided
the target intermediate 7. Next aziridine ring opening reaction with benzoic acid proceeded with
complete regioselectivity in the presense of a catalytic amount of BF ·OEt to afford compound 8.
3
2
Reaction of 7 with water or acetic acid as an oxygen source also proceeded, but didn’t result in good
regioselectivity (data not shown). This finding suggests that steric hindrance of the Bz group is
crucial for regioselectivity. Finally, after removal of the Bz group of 8, conversion of 6a to 6b was
achieved in a quite good chemical yield (total 88%). Noteworthily, we confirmed that the
piperidine-aziridine derivative 7 could be obtained from mixture of the two regioisomers 6a and 6b
under the same reaction conditions.

Scheme 2. Reagents and conditions: (a) TsCl, DMAP, Et N, CH Cl , rt, 93%; (b) aq. NaOH, DMF,
3
2
2
5
9
0 °C, quant.; (c) BzOH, cat. BF ·OEt , CH Cl , 0 °C, quant.; (d) aq. NaOH, MeOH, THF, 50 °C,
3 2 2 2
5%.
In accordance with this selective synthetic method of 6b from 5, the
tetrahydrooxazolo[4,5-c]pyridine derivatives 12-24 (Table 1) were prepared (Scheme 3). After
deprotection of the Boc group of 6b, amide condensation with 5-substituted picolinic acid gave
compounds 10a-d. Oxidation of the hydroxy group of 10a-d by Dess-Martin periodinane followed
1
by cyclization with Burgess’ reagent afforded compounds 11a-d. Compound 11e (R = CN) was
1
synthesized via cross coupling reaction of 11d (R = Br) with Zn(CN) . Deprotection of the Cbz
2
group of compounds 11a-e was performed with TMSI or HBr, and finally amidation of the resulting
amines with appropriate carboxylic acids or acyl chlorides provided compounds 12-24.
Scheme 3. Reagents and conditions: (a) aq. NH , EtOH, 70 °C; (b) Boc O, Et N, CH Cl , rt; (c)
3
2
3
2
2
TsCl, DMAP, Et N, CH Cl , rt, 74% in 3 steps; (d) aq. NaOH, DMF, 50 °C, quant.; (e) BzOH, cat.
3
2
2
BF ·OEt , CH Cl , 0 °C, quant.; (f) aq. NaOH, MeOH, THF, 50 °C, 95%; (g) HCl, dioxane, rt, 94%;
3
2
2
2
(
h) 5-substituted picolinic acid, WSC, HOBt, Et N, DMF, rt, 51-98%; (i) Dess-Martin periodinane,
3
CH Cl , 0 °C, 76-91%; (j) Burgess' reagent, THF, 40 °C, 81-95%,; (k) Zn(CN) , Zn, Pd (dba) , dppf,
2
2
2
2
3
DMA, 120 °C, 95%,; (l) TMSI, CH Cl , 0 °C, 19-93% for 11a-11c and 11e; (m) HBr, AcOH, reflux,
2
2
9
0% for 11d; (n) (substituted) benzoic acid, WSC, HOBt, Et N, DMF, rt, 20-98%.
3

We first determined compound 12 IC value for inhibition of human mGluR5 and its in vitro
50
metabolic stability in human and rat hepatic microsomes. Compound 12 has the same substituents
3-CN, 5-F) on the right-hand phenyl group as Sepracor’s compound 2. Compounds functional IC50
(
values for inhibition of human mGluR5 were determined according to a previously reported method
using calcium mobilization assay with HEK293 cells expressing recombinant human receptor and
10
EC concentration of L-glutamate. Although compound 12 showed lower mGluR5 inhibitory
9
0
activity (IC = 403 nM) than compound 2, it was, as expected, highly stable after 30 min incubation
50
1
9
at 37 ºC with human or rat hepatic microsomes (human: >97%, rat: >97%). This finding allowed us
to start optimization of the substituents on the pyridyl and phenyl groups in order to improve
mGluR5 inhibitory activity.
First, we expected substitutions at the 5′-position on the left pyridyl group and at the meta-
10
-
position on the right phenyl group to be favorable for mGluR5 inhibitory activity. Indeed, the 5-F
(13) and 5-Cl (14) derivatives showed well-improved inhibitory activity (54 nM and 32 nM,
respectively). However, the 5-Cl derivative 14 possessed poor aquaous solubility, while the 5-F
derivative 13 had acceptable one (16 g/mL at pH 7.4). Fixing the 5-F substitution, we turned our
attention to optimization of the substituents on the right phenyl group (18-24). Only small
substituents such as F, Cl and Me were tolerated. The substituents optimization provided a little
improved inhibitory activity compared with compound 1, but not as much as compound 2 or
reoported other highly potent modulators, however, compounds 13 and 18-24 maintained a high
metabolic stability in both human and rat hepatic microsomes (all >91%). Considering potency, in
vitro ADMET profile, and other physicochemical properties (Table 2), compounds 13, 19 and 24
were selected for in vivo pharmacokinetic and pharmacodynamic studies in rats.
Table 1. In vitro mGluR5 inhibitory activity of the synthesized compounds
1
2
Compound
R
F
F
R
IC (nM)
50
1
1
2
3
3-CN, 5-F
H
403
54

1
1
1
1
1
1
2
2
2
2
2
4
Cl
Me
Br
CN
F
H
32
5
H
177
174
237
58
6
H
7
H
8
2-F
3-F
4-F
3-Cl
3-OMe
9 (DSR-98776)
F
63
0
1
2
3
4
F
90
F
50
F
157
F
3-Cl, 5-Me 46
3-Cl, 5-F 38
F
Table 2. Physicochemical properties and in vitro ADMET profiles of compound 1, 13, 19 and 24
19
1
7
4
13
54
16
24
38
6
(
DSR-98776)
IC for
5
0
5
63
23
human mGluR5 (nM)
aqueous solubility
(pH 7.4, g/mL)
microsomal stability
(remaining %)
>
>
97%
97%
>97%
>97%
>97%
>97%
>97%
>97%
human
rat
a
CYP inhibition (IC )
All >40 M
All >50 M
All >50 M
All >50 M
5
0
CYP induction
Negative
Negative
Negative
Negative

-6
-6
-6
-6
PAMPA (pH 7.4)
37.0 x 10 cm/s
34.5 x 10 cm/s
31.7 x 10 cm/s
37.1 x 10 cm/s
P-gp net flux ratio
hERG inhibition (IC )
1.2
1.1
1.1
0.9
50
15 M
64 M
Negative
74 M
Negative
19 M
Negative
in vitro AMES test
No data
a
IC values for inhibition of CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4 isoforms were
5
0
determined.
The pharmacokinetc parameters of compounds 13, 19 and 24 are summarized in Table 3. All 3
compounds showed similar pharmacokinetic profiles in rats characterized by high bioavailability
(102% 168% and 80%, respectively) and low in vivo clearance (4.6, 10.8 and 3.8 mL/min/kg,
respectively). Half-life after i.v. administration was 2.1, 2.0 and 8.9 hr respectively. In monkeys,
clearance and half-life were improved (CL: 4.2, 2.8 and 1.7 mL/min/kg, t : 4.8, 9.5 and 16.1 hr,
1
/2
respectively) compared to those in rats, and the high bioavailability was retained (B/A: 139, 114 and
61%, respectively). Encouraged by these good results, we decided to evaluate the 3 compounds
3
occupancy of mGluR5 using ex vivo inhibition of [ H]-MPEPy binding to this receptor (Fig. 3). In
the rat cortex, compounds 13 and 24 produced dose-dependent receptor occupancy after daily oral
administration for 4 days (See ref. 6 for data of compound 19). Compound 13 achieved 50% receptor
occupancy at the low dose of 0.3 mg/kg, p.o. compared to compound 24, which had lower
occupancy (48% at 1 mg/kg, p.o.).
Table 3. Pharmacokinetic parameters of compounds 13, 19 and 24 in rats and monkeys following
a
single administration
b
c
t1/2
hr)
CL
Vdss
AUC
Cmax
B/A
compd.
species dose
(
(mL/min/kg)
(L/kg) (hr·ng/mL)
(ng/mL) (%)
1
3
rat
0.35 mpk, i.v. 2.1
0 mpk, p.o.
monkey 0.5 mpk, i.v.
0 mpk, p.o.
4.6
4.2
10.8
2.8
0.73
1,289
37,413
2058
N/A
102
N/A
139
N/A
168
N/A
1
2,750
3,905
2,070
4.8
2.0
9.5
1.6
1
57,101
1,549
26,073
3,046
19
rat
1 mpk, i.v.
1.6
2.2
(DSR-98776)
10 mpk, p.o.
monkey 0.5 mpk, i.v.

1
0 mpk, p.o.
1 mpk, i.v.
0 mpk, p.o.
monkey 0.5 mpk, i.v.
0 mpk, p.o.
69,184
4,339
4,065
1,727
2,875
114
N/A
80
24
rat
8.9
3.8
1.7
2.4
2.1
1
34,508
5,090
16.1
N/A
61
1
6,2417
a
b
c
Data are presented as the mean of 2 (i.v.) or 3 (p.o.) rats and 2 monkeys (i.v. and p.o.) per cohort.
AUC from 0 to infinity after test compound administration.
Estimated because i.v. and p.o. doses were not identical. >100% BA was observed probably due to
saturation of metabolic or excretion pathway.

1
00
Compund 13
Compound 24
8
6
4
2
0
0
0
0
0
7
7
8
5
0
4
20
1
8
0
0
.1
1
10
mg/kg p.o.
Figure 3. Ex vivo mGluR5 occupancy of compounds 13 and 24. Effect of compound 13 or 24 on ex
3
vivo binding of [ H]-MPEPy in the rat frontal cortex. Occupancy rate is expressed as percentage of
receptor labeling in the cortex of the vehicle-treated animals. Each symbol represents the mean±S.E.
(n = 4).
Finally, the in vivo therapeutic efficacy of compound 13 was evaluated in a rat model of
depression. In the forced swimming test, compound 13, given orally at 0.3 and 1 mg/kg for 7
consecutive days, significantly decreased rats immobility time with mGluR5 receptor occupancy
expected to be over of 50% (Fig. 4).

Forced swimming test
1
1
1
1
1
80
60
40
20
00
**
**
##
8
6
4
2
0
0
0
0
0
Vehicle
30
0.1
0.3
1
imipramine Compd. 13 Compd. 13 Compd. 13
mg/kg, p.o.
Figure 4. Effects of compound 13 and imipramine on immobility time in the rat forced swimming
test. Each bar represents the mean±S.E. of immobility time during a 6 min test session (n = 10 for
imipramine-treated group, 6 for compound 13-0.1 mg/kg treated group or 12 for other groups).
#
#
P<0.01, Differences between imipramine-treated group and the vehicle-treated group were
assessed using Student's t-test. **P<0.01, Differences between compound 13-treated group and the
vehicle-treated group were determined using parametric Dunnett's multiple comparison test,
following significant results of one-way ANOVA.
In summary, using the scaffolds of our previously reported compound 1 and Sepracor’s compound
2, we succeeded in synthesizing a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as novel
mGluR5 NAMs. The representative compounds 13, 19 and 24 inherited the benefits of compound 1
and 2 with improved in vitro activity and excellent pharmacokinetic profiles. Compound 13, given
orally at 0.3 mg/kg, showed potent antidepressant-like efficacy in the rat forced swimming test, a
preclinical tool for evaluation of potential compounds efficacy on depression. In addition, potential
toxicity of compounds 13 and 19 were studied in male rats by oral gavage for 14 days. Overall, these
compounds were both well tolerated at dose levels up to 100 mg/kg/day. These findings indicate that
the novel mGluR5 NAMs 13 and 19 have good potential as therapeutic agents for the treatment of
depression and other CNS disorders. The results of further evaluation of these compounds will be
presented in due course.

Acknowledgments
We thank Ms. Keiko Bando for elemental anlysis of compounds, Ms. Maki Yamaguchi for HRMS
measurement and Dr. Norio Fujiwara for useful discussions.
Supplementary data
Supplementary data (compound data and experimental procedure of biological tests) associated with
this article can be found, in the online version, at xxx.
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9. Microsomal stability is presented as the remaining amount (%) of the test compound following
incubation with human or rat hepatic microsomes for 30 min at 37 ºC. See supplementary material
for detailed experimental procedure.

Synthesis and optimization of
,5,6,7-tetrahydrooxazolo[4,5-c
pyridines as potent and
4
]
orally-active metabotropic
glutamate receptor 5 negative
allosteric modulators
Wataru Hirose, Yoshihiro Kato, Itaru Natsutani, Makoto Takata, Maiko Kitaichi, Satoki Imai,
Shun Hayashi, Yukiyo Arai, Kohei Hoshino, Kohzo Yoshida