Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure–Activity Relationships, and Sleep-Promoting Properties in Rats

Article abstract of DOI:10.1002/cmdc.201900242

The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexin 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with in vivo efficacy similar to that of suvorexant in rats.

Full text of DOI:10.1002/cmdc.201900242

Accepted Article
Title: Oxadiazole Derivatives as Dual Orexin Receptor Antagonists:
Synthesis, Structure-Activity-Relationship, and Sleep-Promoting
Properties in the Rat
Authors: Christine Brotschi, Catherine Roch, John Gatfield, Alexander
Treiber, Jodi T. Williams, Thierry Sifferlen, Bibia Heidmann,
Francois Jenck, Martin H. Bolli, and Christoph Boss
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To be cited as: ChemMedChem 10.1002/cmdc.201900242
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10.1002/cmdc.201900242
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Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure-
Activity-Relationship, and Sleep-Promoting Properties in the Rat.
Christine Brotschi,* Catherine Roch, John Gatfield, Alexander Treiber, Jodi T. Williams, Thierry
Sifferlen, Bibia Heidmann, Francois Jenck, Martin H. Bolli, and Christoph Boss[a]
[a]
Dr. C. Brotschi, Dr. C. Roch, Dr. J. Gatfield, Dr. A. Treiber, Dr. J. T. Williams, Dr. T. Sifferlen, Dr. B. Heidmann, Dr. F. Jenck, Dr. M. H. Bolli, Dr. C. Boss.
Drug Discovery and Preclinical Research & Development
Idorsia Pharmaceuticals Ltd.
Hegenheimermattweg 91, 4123 Allschwil/BL (Switzerland)
E-mail: christine.brotschi@idorsia.com
Corresponding author
[*]
Supporting information for this article is given via a link at the end of the document.
Abstract: The orexin system plays an important role in the regulation
of wakefulness. Suvorexant, a dual orexin receptor antagonist
(DORA) is approved for the treatment of primary insomnia. Herein, we
outline our optimization efforts towards a novel DORA. We started our
investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)-piperidin-
1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone (3), a struc-
tural hybrid of suvorexant and a piperidine-containing DORA. During
the optimization, we resolved liabilities such as chemical instability,
CYP-3A4 inhibition, and low brain penetration potential. Furthermore,
structural modification of the piperidine-scaffold was essential to
improve potency on the orexin 2 receptor. This work led to the
identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-
{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-
1-yl}-methanone (51), a potent, brain penetrating DORA with in vivo
efficacy comparable to suvorexant in the rat.
OX2R alone is sufficient for promoting sleep in humans was under
debate[22-26] until recently when Merck published their results of
MK-1064, a SO2RA promoting sleep in mouse, dog and human in
a similar manner to DORAs.[27] SO1RAs are investigated mainly
for the treatment of addiction, stress, anxiety, and panic
disorders.[28-29] Here, we describe our efforts towards the
discovery of an orally active, brain penetrating DORA, with the
goal of improving OX2R-potency of our starting point, hybrid 3.
Results and Discussion
The following assays served to characterize and advance our
compounds as well as to establish the SARs with respect to
potency, safety, and efficacy. Compound potency on the orexin 1
receptor (OX1R) and orexin 2 receptor (OX2R) was assessed
using a calcium release assay (FLIPR) where inhibition of orexin
A-induced Ca2+ flux was determined as a functional readout of
orexin receptor antagonism. Values are reported as IC50 in nM
and are reported as the geomean of at least three measurements.
Earlier studies in our DORA program revealed CYP3A4 inhibition
Introduction
Insomnia is a common disorder where difficulty to fall or stay
asleep are the main symptoms. The cause of this phenomenon
can be manifold. Until 2014, insomnia patients were
predominantly treated with GABA-A potentiators, however the risk
of dependence, or reduced next day performance are well
described side effects emphasizing the need for further
therapeutic options. In 2014, the FDA approved the first dual
orexin receptor antagonist (DORA) for the treatment of insomnia
under the trade name Belsomra® (suvorexant).[1-3] The underlying
mechanism of DORA’s are the inhibition of orexin 1 (OX1R) and
orexin 2 receptors (OX2R) to promote sleep by reducing
wakefulness. The first proof of concept for this novel mechanism
was obtained with almorexant in 2007,[4] almost a decade after
the orexin neuropeptides (orexin A and orexin B) had been
discovered independently by two research groups,[5-6] Orexins,
also known as hypocretins originate from the common precursor
prepo-orexin which is produced by neurons located in the
hypothalamus. Orexin A binds to the G-protein-coupled receptors
OX1R and OX2R, whereas orexin B binds mainly to OX2R. Intense
research[7-11] resulted in the discovery of DORA’s, selective orexin
1 receptor antagonists (SO1RAs) and selective orexin 2 receptor
antagonists (SO2RAs). Almorexant was the first DORA on which
clinical data were published.[12-13] Currently, several additional
DORAs (e.g., lemborexant from Eisai,[14] compound from
Idorsia[15] and SO2RAs (MIN-202)[16-17] are evaluated in clinical
studies for the treatment of insomnia.[18-21] Whether blocking the
as
a potential liability of our compounds and we thus
systematically measured CYP3A4 inhibition using testosterone as
substrate. Metabolic stability of our compounds was assessed by
measuring intrinsic clearance in the presence of human liver
microsomes (HLM). To assess the compound's potential to
penetrate the brain, the human multidrug resistant protein
transporter (MDR1) assay was used to determine the substrate
susceptibility for the P-glycoprotein transporter. In addition, brain
penetration was measured in vivo in the rat and compound
concentrations in brain and plasma are expressed in ng/g and
ng/mL, respectively. Finally, efficacy of our compounds was
assessed using electroencephalography/ electromyography
(EEG/EMG) recording in male Wistar rats.
Figure 1: Competitor compounds 1 and 2, and our starting point hybrid 3.
1
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The starting point of our optimization work relied on published
structures of DORAs, such as compound 1[30] and Merck’s
suvorexant (MK-4305) 2.[31] In house, hybrid 3[32] was synthesized
and its racemate was determined to have an activity in the FLIPR
assay of 6 nM and 42 nM for OX1R and OX2R, respectively (Figure
1). The optimization route that was triggered by this promising
starting point is summarized in Figure 2..
Figure 2. The optimization route via O-linked benzoxazole 4, carbamate 5, and oxadiazole 8 and 27, resulted in compound 51.
Replacing the exocyclic nitrogen-atom in 3 by an oxygen-atom in
4 had no impact on OX1R and/or OX2R potency, however the O-
benzoxazole was chemically unstable, resulting in carbamate 5.
The carbamate analogs were equally potent, however they
showed significant CYP3A4 inhibition. Converting the carbamate
function into an oxadiazole moiety resolved this liability, but the
OX2R potency was diminished. Potency on Ox2R could be
restored by replacing the piperidine-core by a pyrrolidine (see
compound 27). Further optimization work included the analysis of
the different oxadiazole isomers and the fine tuning of the
substituent on the periphery to optimize on brain penetration. The
“fine tuning” also resulted in an increase in Ox1R potency.
Combining these efforts resulted in compound 51, a highly potent,
brain penetrating, and dual orexin receptor antagonist that
showed efficacy in a rat EEG/EMG experiment.
In detail, a close analog of the O-linked benzoxazole-ring-analog
4 was shown to be chemically unstable under acidic conditions
and hydrolyzed to the corresponding carbamate. Interestingly,
carbamate 5 was similar in potency to its benzoxazole analog 4.
Changing the substitution pattern to 2,5-dimethyl (6) increased
potency on OX2R, when compared to 5, and 3,5-dimethyl analog
7 showed potencies of 2 nM on both OXRs (Table 1).
Table 1. Carbamates vs. Oxadiazoles.
CYP3A4[b]
6
CYP3A4[b]
34
R
Cpd
OX1R[a]
OX2R[a]
19
Cpd
OX1R[a]
48
OX2R[a]
239
5
6
8
6
7
21
2
6
2
4
5
9
13
60
27
28
24
10
1.5
[a] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three independent experiments and were determined by FLIPR assay (see Supporting Information
for assay details); [b] IC50 in M, values are from single measurements with testosterone used as substrate; nd = not determined.
2
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Unfortunately, carbamates 5, 6, and 7 showed inhibitory activity
towards CYP3A4 in the range of 3 to 6 M. Furthermore, all
carbamates tested in vivo for brain penetration in rat (measured 3
h after oral dosing of 100 mg/kg) showed low plasma and brain
concentrations. The most potent compound 7 had plasma and
brain concentrations of 189 ng/mL and 49 ng/g, respectively. Our
task therefore was to replace the carbamate moiety to alter the
overall physicochemical properties to reduce CYP3A4 inhibition
and to increase plasma and brain concentrations, without
diminishing OX2R potency.
Our attempt to replace the carbamate moiety by an oxadiazole
was encouraging. The antagonistic activity of the oxadiazole
derivative 8 showed a profile with a 5-fold preference for OX1R
(48 nM and 239 nM on OX1R and OX2R, respectively) and the
CYP 3A4 inhibition of compound 8 was markedly reduced with an
IC50 value of 34 M compared to 6 M for 5. The oxadiazole
analogs 9 and 10 showed as well weaker CYP 3A4 inhibition
when compared to their carbamate analogs (see 9 vs. 6 and 10
vs. 7). However, no oxadiazole analog reached sufficient potency
on the OX2R. Furthermore, plasma and brain concentrations (3 h
after oral dosing of 100 mg/kg to rats) of 10 (45 ng/mL and 81
ng/g, respectively) were as low as for carbamate analog 7. In
contrast to SAR investigations performed by Merck,[33] substituent
alterations on the peripheral part such as on the oxadiazole-
moiety as well as on the biaryl-carboxamide-motif in our hands
did not lead to the desired increase in potency on OX2R,.
Furthermore, Merck published on 5-oxazole-2-methyl-
piperidiene[34] and 5-thiazole-2-methyl-piperidine analogs[35] with
profiles ranging from dual to OX2R selective antagonists.
We turned our attention to modifying the core, since we knew from
in house data, that core modifications can influence the selectivity
profile of a class of compounds.[36] For our SAR studies, we kept
the aryl-triazolyl-carboxamide and the unsubstituted phenyl-
oxadiazole constant, and investigated the impact of replacing the
piperidine-core on potency and selectivity (see Table 2). Ideally,
the core-replacement would lead to compounds with increased
potency on OX2R and therefore to compounds with a DORA
profile. Introduction of a methyl-group at the 6-position of the
piperidine-ring (trans-racemate 12) improved the potency on both
receptors equally. Interestingly, the less constrained compound
13 was more potent on both OXR when compared to piperidine-
analog 11. The selectivity profile of the ring opened analog 13 was
even more OX1R preferential than 11 (20-fold) and therefore of no
interest to us. Analog 14 showed a major drop in potency,
indicating that a tertiary carboxamide is preferred. When the linker
was shortened by one C-atom (15) the potency on both OXRs
was reduced dramatically. Compound 16, with an exit vector
shifted to position C-2, resulted in a potency loss of more than 10-
fold on both receptors when compared to 11. Similarly, when the
exit vector was kept at C-3 but elongated by one C-atom (17), a
drop in potency was observed. The potency of the 3-pyrrolidine
(18) and the 3-azetidine (21) was also markedly reduced. On the
other hand, the 2-substituted pyrrolidine (19) and azetidine
derivative (22) were identified as DORA’s with preference for
OX2R (6-fold and 16-fold, respectively). Besides potency, we
were also interested in core modifications that led to metabolically
more stable compounds in HLM when compared to those
containing the piperidine core.
Table 2: Core-replacements
X
12
trans-rac
Cpd
11
13
14
15
16
OX1R[a]
OX2R[a]
HLM[b]
40
334
85
4
1005
2463
nd
2758
690
nd
640
3510
nd
6
85
66
177
153
X
Cpd
17
1128
652
nd
18
1113
1021
nd
19
486
76
20
3167
2887
nd
21
2117
3883
nd
22
4150
262
19
OX1R[a]
OX2R[a]
HLM[b]
50
[a] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three independent experiments and were determined by FLIPR assay (see Supporting Information
for assay details); [b] Intrinsic metabolic clearance [L min-1 mg-1] with human liver microsomes, at 1 M; nd = not determined
Overall, compound 19 was the most potent compound on OX2R
and, compared to other core modifications, its rather low intrinsic
clearance of 50 L min-1 mg-1 in HLM, made the pyrrolidine the
most attractive core-replacement for further SAR studies. The R-
enantiomer 20 was substantially less potent on both receptors,
therefore the following SAR was performed on the more potent S-
enantiomer only. We also performed optimization work on
azetidine-analogs. These efforts resulted in potent OX2R
preferential compounds, but none of the azetidine analogs tested
in vivo reached reasonable plasma and brain concentrations
(data not shown).
3
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Table 3: SAR studies of oxadiazole-pyrrolidine-analogs with different R moieties
R
Cpd
19
486
76
23
128
16
24
352
36
25
26
64
37
27
339
19
28
72
9
OX1R[a]
OX2R[a]
1034
194
R
Cpd
29
123
8
30
40
7
31
13
8
32
92
11
33
92
19
34
22
4
35
22
7
OX1R[a]
OX2R[a]
MDR1
effluxb]
1.3
1.3
2.2
nd
nd
nd
nd
nd
nd
2.5
Papp
A-B[c]
24.5
36.3
30.7
17.8
[a] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three independent experiments and were determined by FLIPR assay (see Supporting Information
for assay details); [b] multidrug resistance protein 1 (MDR1) efflux ratio (Papp B-A/Papp A-B); [c] passive permeability Papp A-B (10-6 cms-1); nd = not determined.
In a next step, the R moiety attached to the oxadiazole and its
substitution pattern were investigated (Table 3). A 2-methyl (23),
a 2-methoxy (26) and a 2-chloro substituent (27) showed
improved potency compared to the unsubstituted analog 19. A 2-
methyl substituent (23) was preferred when compared to a 3-
methyl (24), and a 4-methyl group was substantially less potent
(25). A 2-trifluoromethoxy-substituent (31) led to the most potent
mono-substituted compound on both OX1R and OX2R. A di-
substituted compound with a 2-chloro, 3-methyl substitution (29)
improved potency in comparison to mono-substituted 27. Its 2-
methyl-3-chloro isomer 30 showed similar OX2R potency and a
threefold improved OX1R potency. The 2-methoxy-3-fluoro
substitution (28) showed an improved potency on OX2R when
compared to mono-substituted 26. Additional substitution patterns
such as 2,5-dimethyl (32) or 3,5-dimethyl (33) improved potency
on both OXRs indicating that a variety of modifications are
tolerated by the receptors. Compound 33 showed that an ortho
substituent is not mandatory, however, for most analogs an ortho
substituent was beneficial. Increasing the length of the substituent
to 2-ethoxy (34) improved the potency further (threefold on OX1R
and 9-fold on OX2R) when compared to 2-methoxy (26). The more
polar pyridine analog 35 was tolerated by both OXRs, showing
similar potency when compared to phenyl analog 34. A few
analogs were tested in a permeability assay containing the human
Next, we explored the SAR of the o-biaryl benzamide, keeping the
(S)-5-(pyrrolidin-2-yl)-3-(2-(trifluoromethoxy)
phenyl)-1,2,4-
oxadiazole scaffold constant (Table 4).
Table 4: Optimization of the biaryl carboxamide of oxadiazole-pyrrolidine-
analogs
R
Cpd
36
59
31
13
8
37
47
34
89
38
31
39
56
OX1R[a]
OX2R[a]
HLM[b]
29
15
18
187
170
266
189
multidrug resistance protein
1 (MDR1, P-gp) to evaluate
R
transmembrane permeability and P-gp substrate potential. A
MDR1 efflux ratio of 1.3 to 2.5 indicated that these compounds
are not, or weak substrates of the MDR1 efflux pump. The
Papp(A-B) values were in the range of 18 - 36 x 10-6 cm s-1
suggesting that all compounds are highly permeable.
In an attempt to reduce lipophilicity, heterocyles replacing the R-
phenyl ring were investigated (Table 3). Pyridine analog 35
showed high affinity for both OXRs and represents a compound
with higher brain free fraction when compared to the phenyl
analogs 29 to 31.
Cpd
40
65
18
nd
41
37
4
42
364
72
43
33
24
nd
44
5
OX1R[a]
OX2R[a]
HLM[b]
5
424
72
335
[a] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three
independent experiments and were determined by FLIPR assay (see
Supporting Information for assay details); [b] Intrinsic metabolic clearance [L
min-1 mg-1] with human liver microsomes, at 1 M; nd = not determined
4
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In comparison to 31, the unsubstituted triazolyl benzamide 36 and
the 5-chloro analog 37 were weaker in affinity at both OXRs.
Shifting the substituent from position 5 to position 4 was tolerated
in the case of 38 and 39. Replacing the triazole by a pyrimidine
(40) led to a loss in potency on both OXRs. All di-substituted
benzamides had a higher OX2R affinity than their mono-
substituted analogs, see 41 and 44. In addition to the potency,
human microsomal stability was measured. We observed that the
di-substituted analogs had lower microsomal stability than the
mono-substituted analogs. Metabolite identification studies
revealed that the methyl at the 4 position of the 4-methyl-5-
methoxybenzamide was metabolically labile (data not shown),
therefore we replaced this metabolic hotspot by a fluorine and
indeed, 42 showed an improved stability in HLM (CLint = 72 L
min-1 mg-1 compared to 424 L min-1 mg-1 for 41). Unfortunately,
this modification resulted in an unacceptable drop in potency on
both OXRs.
Table 5. Oxadiazole isomers A, B, and C
X
isomer A
isomer B
isomer C
Cpd
31
45
46
OX1R[a]
OX2R[a]
HLM[b]
13
8
14
4
184
118
96
170
148
[a] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three
independent experiments and were determined by FLIPR assay (see
Supporting Information for assay details); [b] Intrinsic metabolic clearance [L
min-1 mg-1] with human liver microsomes, at 1 M.
The potency loss on the OXRs caused by the symmetrical
Next, we investigated the various oxadiazole-isomers with
respect to their impact on potency and microsomal stability (see
Table 5). Asymmetric 1,2,4-oxadiazoles 31 (isomer A) and 45
(isomer B) were similar in potency, whereas the symmetric 1,3,4-
oxadiazole analog 46 (isomer C) showed a reduced potency on
both OXRs, indicating that the position of the heteroatoms (dipole
moment) does play a role for receptor binding affinity.[37]
Oxadiazole isomer C (46) was slightly more stable than isomers
A and B (CLint = 96 vs. 170 and 148 L min-1 mg-1 for 31 and 45)
in HLM. The slight improvement in in vitro stability was in line with
reported data for symmetric oxadiazole analogs compared to the
NO-bond comprising asymmetric oxadiazoles.[38]
oxadiazole
C
could be compensated by introducing
a
disubstituted ortho-triazolyl benzamide (e.g. 49, Table 6).
Unfortunately, compound 49 (isomer C) was less stable in HLM
than 47 or 48 (isomer A or B) suggesting that peripheral
substituents influence the microsomal clearance of the
compounds to a greater extent than the arrangement of the atoms
in the oxadiazole ring.
To assess whether our compounds penetrate into brain tissue, a
series of in vivo experiments were performed in male Wistar rats.
Absolute brain- and plasma concentrations were determined 3 h
after oral dosing (100 mg/kg) and the results of a selection of
compounds are summarized in Table 6.
Table 6. Oxadiazole isomers A, B, and C
MDR1
SF[a]
Cpd
Isomer
X
OX1R[b]
OX2R[b]
HLM[c]
[P][d]
[B][d]
[B/P][e]
[CSF][f]
efflux[g]
47
48
49
A
B
C
13
7
3
1
5
192
258
364
309
893
121
483
351
96
1.56
0.39
0.79
5.2
2.1
3
1.4
nd
nd
30
35
50
A
B
22
5
7
2
71
140
259
53
0.38
0.64
4.7
2.5
6.2
151
165
17.4
41
51
A
B
37
28
4
4
424
282
2237
1763
3253
1585
1.45
1.62
31.5
19.8
1.8
2.1
[a] SF = scaffold; [b] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three independent experiments and were determined by FLIPR assay (see
Supporting Information for assay details); [c] Intrinsic metabolic clearance [L min-1 mg-1] with human liver microsomes, at 1 M; [d] brain penetration experiment
was performed in rat (n=3) by sampling plasma and brain, 3 h following administration of 100 mg/kg po; [e] brain/plasma ratios were calculated assuming a brain
density around 1 g/mL; [f] CSF = cerebral spinal fluid [ng/mL]; [g] multidrug resistant protein 1 (MDR1) efflux ratio of (Papp B-A/Papp A-B); nd = not determined.
5
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By comparing plasma and brain concentrations of oxadiazole-
isomer A with those of isomer B, we could not find a trend for
increased concentrations for one of the two isomers (comparison
of 47 with 48, 35 with 50, and 41 with 51). However, the
symmetrical [1,3,4]-oxadiazole isomer C (see 49) showed lower
concentrations in plasma and brain when compared to the
the relative proportion of the time spent in non-REM and REM
sleep over the total sleep time remained unchanged (~ 82 % and
~18%, respectively for all groups, compared to matched-vehicle
treated rats; p = 0.1697 for 51 and p = 0.7385 for suvorexant,
paired t-test). Under the same conditions (Figure 3), compounds
41 and 47 showed a less pronounced sleep promoting effect
asymmetrical oxadiazole analogs (47, 48). Compounds 35 and 50, compared to compound 51. Both decreased significantly the time
both bearing a 2-ethoxypyridine, exhibited low plasma and brain
concentrations. Plasma and brain concentrations of pyridine
analogs appeared to be inferior to the more lipophilic analogs
either due to lower absorption and/or due to a higher efflux by P-
gp (see 50). Of all compounds investigated, 41, 47, and 51
reached the highest plasma and, in particular, brain
concentrations in the rat. These compounds were tested for their
human MDR1 susceptibility and their efflux ratios were in an
acceptable range between 1.4 and 2.5, confirming earlier
measurements suggesting that these compounds are not
substrates of the human MDR1 transporter protein and are
therefore viable candidates for further characterization.
spent in active wake compared to vehicle treated rats (-13.9% and
-7.3% vs. vehicle for 41 and 47; respectively; p<0.05 for 41 and
47). However, a significant increase was only observed for the
time spent in non-REM sleep (+7.3% (p<0.05) and +11.2%
(p<0.01) vs. vehicle for 41 and 47, respectively). The time spent
in REM sleep was marginally increased compared to vehicle
treated rats (+0.9% (p=0.7403) and +7.8% (p=0.2570) vs. vehicle
for 41 and 47, respectively). In contrast to compound 47,
compound 41 significantly increased the time spent in quiet wake
compared to vehicle treated rats (+19.2 % vs. vehicle, p<0.05).
For both, the relative proportion of the time spent in non-REM and
REM sleep over the total sleep time remained unchanged (~82%
non-REM sleep and ~18% REM sleep for 41 and matched vehicle
treated group (p=0.0549) and ~85% non-REM sleep and ~15%
REM sleep for 47 and matched vehicle treated group (p=0.8272)).
Due to its promising sleep promoting effect at 100 mg/kg and to
fully evaluate the potential of 51, we tested 51 at a lower dose of
30 mg/kg. At this dose, over the 12 h night period following
administration, 51 still significantly decreased the time spent in
active wake (-9.7% vs. vehicle, p<0.05) and increased the time
spent in non-REM sleep (+8% vs. vehicle, p<0.05). The increase
of the time spent in REM sleep was no longer significant (+11%
vs. vehicle, p=0.1084). In this experiment, compound 51
increased slightly but significantly the time spent in quiet wake
compared to vehicle treated rats (+8.3% vs. vehicle, p<0.05).The
same pattern of pharmacological activity was observed with
suvorexant at 30 mg/kg (-8.7% vs. vehicle (p<0.05) for the time
spent in active wake, +12.5% vs. vehicle (p<0.001) for the time
spent in non-REM sleep, and +11.1% (p=0.0815) for the time
spent in REM sleep.
We thus chose to advance 41, 47 and 51 and to test them in vivo
for their effect on the sleep/wake stages. We used freely moving
male Wistar rats implanted with radiotelemetric transmitters for
continuous recording of EEG/EMG signals. In a first step, 41, 47,
and 51 were tested at 100 mg/kg po administered at the beginning
of the nocturnal active phase, when endogenous orexin levels
increase. Over the 12 h night period following administration,
compound 51 showed a similar sleep promoting effect as
suvorexant when tested under the same experimental conditions
(Figure 3). Compared to vehicle treated rats, 51 significantly
decreased the time spent in active wake (-24% and -17% vs.
matched vehicle for 51 and suvorexant, respectively; p<0.001 for
51 and suvorexant, paired t-test), and significantly increased both
the time spent in non-REM (rapid eye movement) sleep (+14.3%
and +21.6% for 51 and suvorexant, respectively; p<0.001 for 51
and suvorexant, paired t-test) and the time spent in REM sleep
(+35.2% and +21.6% for 51 and suvorexant; respectively; p <
0.05 for 51 and not statistically significant for suvorexant with p =
0.0714, paired t-test). As is usually observed with DORAs,[31, 39-45]
Figure 3. Effect of suvorexant, 51, 41, and 47 on the
time spent in sleep and wake stages (% of total time)
during the 12 h night active period post administration
in male Wistar rats. Rats were administered a single
oral dose of vehicle (PEG 400) or compound. Data
are expressed as mean ± SEM. *p<0.05, **p<0.01,
***p<0.001 (n=14 for suvorexant, n=8 for 51, 41, and
47).
6
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10.1002/cmdc.201900242
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Table 7. IC50 and Ki values at human, rat, and dog orexin receptors.
[a]
[a]
[b]
[b]
[b]
[b]
[b]
Cpd
IC50
IC50
Ki
Ki
Ki
Ki
Ki[b]
Ki
hOX1R
hOX2R
hOX1R
hOX2R
rOX1R
rOX2R
dOX1R
dOX2R
47
41
51
13
2
6.8
2.4
14
1.6
4.7
32
9
1.1
1.6
1.1
29
27
3
3
13
17
1.0
1.3
11
10
1.6
1.3
[a] IC50 in nM. Values are the geometric mean (± 2-fold) of at least three independent experiments and were determined by FLIPR assay (see Supporting Information
for assay details); [b] Ki values are in nM and calculated via the Cheng-Prusoff equation from single FLIPR experiments run in duplicates.
Orexin receptors are conserved across species and compounds
were assessed in human, rat, and dog Ki measurements and
shown to be equipotent across species (Table 7).
potential species differences, we compared the pharmacokinetic
profiles in the rat and the dog (Table 8). Compound 51 showed
plasma clearance of 96 mL min-1 kg-1 in the rat, and of 17 mL min-
1 kg-1 in the dog. Considering blood-to-plasma partitioning and the
respective liver blood flows; compound 51 was classified as a
high clearance compound in the rat and a moderate-to-high
clearance compound in the dog. This correlated with the observed
differences in intrinsic clearance in dog liver microsomes (DLM)
(CLint = 543 L min-1 mg-1) when compared to RLM (CLint >1250
L min-1 mg-1).
For all compounds measured, CLint in rat liver microsomes (RLM)
was above 1250 L min-1 mg-1. We therefore performed brain
penetration experiments and in vivo EEG-experiments in rats at
the high dose of 100 mg/kg with the intention of saturating
metabolic processes. To further evaluate the potential of
compound 51, we assessed pharmacokinetic properties at lower
doses where less or no saturation was expected. To evaluate
Table 8. Pharmacokinetics of 51 in rat and dog
iv [a]
po [b]
Dose
CL
Vss
T1/2
[h]
Dose
AUC
Cmax
Tmax
[h]
F
[%]
Species
[mg kg-1]
[mL min-1 kg-1]
[L kg-1]
[mg kg-1]
[ng h mL-1]
[ng mL-1]
rat
0.1
0.1
96
17
1.2
1.3
0.2
1.3
10[c]
168
896
69.8
576
1
10
43
dog
2.2[d]
0.5
[a] iv = intravenous, formulation: HPbCD/DMSO 95%/ 5% in 30% H2O; [b] oral; [c] formulation: 0.5% methylcellulose (MC); [d] formulation: Cremophor
RH40/Lauroglycol 90; HPbCD = Hydroxypropyl Beta Cyclodextrin.
As volume of distribution was similar between both species, the
difference in clearance translated into a shorter half-life of 0.2 h in
rat compared to 1.3 h in the dog. Also, the bioavailability in dog
was higher compared to rat, i.e. 43 % vs. 10 %, respectively. With
this encouraging data in hand further profiling was performed and
the data are summarized in Table 9. Compound 51 showed no
relevant competitive or time-dependent inhibition of CYP3A4,
CYP2D6, and CYP2C9, no formation of reactive metabolites in a
glutathione trapping assay, and no inhibition of the hERG channel
was observed at the highest concentration measured (IC50 >20
M).
IC50 of 0.34 M). For compound 51 no significant inhibitory
activities were detected for these two off-targets (IC50 of 16 M
and greater than 30 M on serotonin 5-HT2B and DAT,
respectively).
In summary, our structural optimization started with hybrid 3, the
instability of the ether-linked analog 4 resulted in carbamate
analogs which revealed inhibitory activities on CYP 3A4.
Converting the carbamate function into an oxadiazole moiety
resolved this liability, however OX2R potency was diminished.
Changing the core structure from a piperidine to a pyrrolidine
restored potency on the OX2R and resulted in the discovery of a
novel pyrrolidine-oxadiazole series. Among these compounds,
the 1,2,4-oxadiazole 51 was found to be a potent, orally available,
brain penetrating dual orexin receptor antagonist, which showed
sleep-promoting effects comparable to suvorexant in rats.
Table 9. Profile of 51
time dependent inhibition
IC50 [M]
(IC50 shift assay)
P450 inhibition
CYP3A4
CYP2D6
CYP2C9
8.1
29
3
2
1
1
Chemistry
dGSH Trapping
[pmol mg-1 h1]
<100
>20
The synthesis[46] of compounds 4 to 51 are summarized in
Schemes 1-6. The oxygen linked benzoxazole 4 was prepared
starting from commercially available (R)-3-hydroxypiperidine HCl
(52) (Scheme 1). Amide coupling of 52 and 53a[31-32] afforded
intermediate 54, which upon nucleophilic substitution with 2,5-
dichlorobenzo[d]oxazole, yielded 4. Carbamate 5 was prepared
from 54 and commercially available 3-chlorophenyl isocyanate
hERG
In a panel of 50 ion channel, receptor and transporter assays,
compound 47 showed interactions with the serotonin 5-HT2B
receptor (IC50 of 0.67 M) and the dopamine transporter (DAT,
7
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cylcolpropylcarboxaldehyde), TEA, MeOH, NaBH4, rt, 18 h; b) 53a, TBTU,
DIPEA, DMF, rt, 18 h.
under basic conditions. Compounds 6 and 7 were synthesized
accordingly, using the corresponding isocyanates (see supporting
information).
The pyrolidine-oxadiazole analogs of isomer A (19, 23-25, 31, and
36-44) were synthesized via one of the two approaches outlined
in Scheme 4, approach A or B.
For Approach A, commercially available L-proline methyl ester
HCl (62) was coupled with 53a in an amide coupling to
intermediate 63. After ester hydrolysis under basic conditions,
carboxylic acid 64 and corresponding hydroxyamidine 58 were
coupled, followed by thermal cyclization to yield compounds 19
and 23-35. The substituted hydroxyamidines 58 were either
commercially available or synthesized from the corresponding
carboxylic acid (see supporting information).
Scheme 1: Synthesis of O-linked benzoxazole 4 and carbamates 5-7. Reagents
and conditions: a) TBTU, DIPEA, DCM, rt, 3 h; b) (i) NaH, THF, rt, 30 min; (ii)
2,5-dichlorobenzo[d]oxazole, THF, rt, 18 h; c) (i) NaH, THF, 0 °C to rt, 20 min;
(ii) corresponding isocyanate, THF, rt, 2.5 h.
Compounds containing a cyclic core structure (8 to 11,12,16-22)
were synthesized in analogy to Scheme 2, using corresponding
starting materials. For simplicity, only piperidine analogs are
outlined in Scheme 2.
Scheme 2: Synthesis of oxadiazole-piperidine analogs. Reagents and
conditions: a) TBTU, DIPEA, DCM, rt, 18 h; b) 2 N aq. NaOH, EtOH/THF, rt, 1.5
h; c) (i) PyBOP, DIPEA, DCM, rt, 16 h; (ii) dioxane, 90 °C, 16 h.
Scheme 4: General synthesis of pyrolidine-oxadiazole analogs of isomer A, and
compound 41 as a specific example. Reagents and conditions: a) TBTU,
DIPEA, DCM, rt, 18 h; b) 2 N aq. NaOH, EtOH/THF, rt, 1.5 h; c) (i) PyBOP,
DIPEA, DCM, rt, 16 h; (ii) dioxane, 90 °C, 16 h; d) TFA, DCM, 0 °C to rt, 5 h; e)
Br2, acetic acid/H2O, 60 °C, 2 h; f) CuI, DMCDA, Cs2CO3, 1H-1,2,3-triazole,
DMF, 120 °C, 1 h.
Compound 8 to 11 were synthesized starting from commercially
available methyl (R)-piperidine-3-carboxylate HCl 55, which upon
amide coupling with 53a yielded intermediate 56. Saponification
of the ester function under basic conditions yielded carboxylic acid
57, which was converted to oxadiazoles in a two-step procedure;
amide coupling with corresponding hydroxyamidine 58, followed
by thermal cyclization.
For Approach B, commercially available (tert-butoxycarbonyl)-L-
proline (65) and hydroxyamidine 58a were converted in a two-step
procedure into intermediate 66, boc-deprotection with TFA,
followed by amide coupling of 67 and ortho-biaryl carboxylic acid
53, led to compound 31 and 36-44. The synthesis of compound
41 is outlined as a representative for compounds 36 to 44,
following Approach B.
The synthesis of ring opened-analogs 13 to 15 is outlined in
Scheme 3. Commercially available amines 59 and 60 were
submitted to reductive amination conditions followed by amide
coupling.
The synthesis of the ortho-biaryl carboxylic acid 53b was
synthesized from commercially available benzoic acid 68.
Selective bromination with Br2 in acetic acid/H2O mixture led to
compound 69, which was converted via a copper mediated
coupling reaction to 53b. Amide coupling of 53b and amine 67
yielded compound 41. Syntheses of other biaryl acids 53 are
described in the literature[46] or in the supporting information.
The pyrrolidine-oxadiazole analogs of isomer B were synthesized
according to Scheme 5. Commercially available boc-protected
nitrile 70 was converted to the hydroxyamidine 71. Amide
coupling with the corresponding carboxylic acid 72, followed by
thermal cyclization yielded 73. Boc-deprotection yielded the
Scheme 3: Synthesis of oxadiazole-analogs with open form core-structures.
Reagents and conditions: a) corresponding aldehyde (acetaldehyde or
8
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corresponding amine 74 which was converted via amide coupling
to final compounds 45, 48, 50, and 51.
Conditions: MeCN [eluent A]; 13 mmol/L NH3 in H2O [eluent B]. Gradient: 95%
B → 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis + MS.
LC−HRMS parameters were the following: analytical pump
Waters Acquity binary, Solvent Manager, MS, SYNAPT G2 MS,
source temperature of 150 °C, desolvation temperature of 400 °C,
desolvation gas flow of 400 L/h; cone gas flow of 10 L/h, extraction
cone of 4 RF; lens 0.1 V; sampling cone 30; capillary 1.5 kV; high
resolution mode; gain of 1.0, MS function of 0.2 s per scan,
120−1000 amu in full scan, centroid mode. Lock spray: keucine
enkephalin, 2 ng/mL (556.2771 Da), scan time of 0.2 s with
interval of 10 s and average of 5 scans; DAD: Acquity UPLC PDA
detector. Column was an Acquity UPLC BEH C18 1.7 μm, 2.1 mm
x 50 mm from Waters, thermostated in the Acquity UPLC column
manager at 60 °C. Eluents were the following: H2O + 0.05% formic
acid; B, acetonitrile + 0.05% formic acid. Gradient was 2% to 98%
B over 3.0 min. Flow was 0.6 mL/min. Detection was at UV 214
nm. In cases where final compounds appear as a mixture of
conformational isomers, visible in their LC-MS spectra, the
retention time of the most abundant conformer is given.
Scheme 5: Synthesis of oxadiazoles, isomer B. Reagents and conditions: a)
hydroxylamine HCl, Na2CO3, MeOH, 70 °, 1 h; b) (i) TBTU, DIPEA, DCM, rt,
1.5 h; (ii) dioxane 80 °C, 2 d; c) TFA, DCM, rt, 1.5 h; d) corresponding 53,
TBTU, DIPEA, DCM, rt, 1.5 h.
The synthesis of symmetrical oxadiazoles 46 and 49 is outlined in
Scheme 6. Commercially available 75 and 76 were converted to
intermediate 77 in a two-step procedure. First, coupling of
hydrazine 76, followed by cyclization in the presence of the
Burgess reagent at elevated temperature resulted in 77. After
boc-deprotection with TFA, amide coupling of amine 78 with the
corresponding ortho-biaryl carboxylic acid 53 yielded 46 and 49.
Preparative HPLC with acidic conditions
Method D: Column: Waters XBridge (10 um, 75 x 30 mm). Conditions: MeCN
[eluent A]; H2O+ 0.5% HCOOH [eluent B]; Gradient: 90% B → 5% B over 6.4
min (flow: 75 mL/min). Detection: UV/Vis + MS.
Method E: Column: Waters Atlantis (10 um, 75 x 30 mm). Conditions: MeCN
[eluent A]; H2O + 0.5% HCOOH [eluent B]; Gradient: 90% B → 5% B over 6.4
min (flow: 75 mL/min). Detection: UV/Vis + MS.
Preparative HPLC with basic conditions
Scheme 6: Synthesis of symmetrical oxadiazole analog 46 and 49. Reagents
and conditions: a) (i) PyBOP, DIPEA, DCM, rt, 16 h; (ii) Burgess reagent,
dioxane, microwave irradiation,110°C, 30 min; b) TFA, DCM, rt, 16 h; c) TBTU,
DIPEA, DMF, rt, 18 h.
Method F: Column: Waters XBridge (10 um, 75 x 30 mm). Conditions: MeCN
[eluent A]; H2O + 0.5% NH4OH (25% aq.) [eluent B]; Gradient: 90% B → 5% B
over 6.5 min (flow: 75 mL/min). Detection: UV/Vis + MS
Flash column chromatography (FC) was performed either
conventional or by using Biotage SNAP cartridges (10−340 g) and
elution was with a Biotage Isolera system. Merck pre-coated thin
layer chromatography (TLC) plates were used for TLC analysis.
Experimental Section
Commercially available starting materials were used as received
without further purification. All reactions were carried out under an
atmosphere of nitrogen or argon. Compounds were purified by
flash chromatography on silica gel, or by preparative HPLC.
Compounds described below are characterized by LC-MS data
(retention time tR is given in min, molecular weight obtained from
the mass spectrum is given in g/mol using the conditions below.
In cases where compounds appeared as
conformational isomers, as visible in their LC-MS spectra, the
retention time of the most abundant conformer was given.
1H NMR and 13C NMR spectra were recorded on a Bruker (400 or
500 MHz) spectrometer in the indicated deuterated solvent.
Chemical shifts are reported in ppm relative to solvent peaks as
the internal reference. Due to hindered rotation, our compounds
exist in multiple conformations on the NMR time-scale, similar to
the diazepane series reported by Merck[31], therefore 1H NMR and
13C NMR spectra are reported in pictorial format, rather than in
numeric form (see Supporting Information).
a mixture of
Abbreviations used: AcOH, acetic acid; aq., aqueous; Burgess
reagent, methyl N-(triethylammoniumsulfonyl)carbamate; DCM,
dichloromethane; DIPEA, diisopropylethylamine; DMCDA, trans-
Mass spectrometry data were recorded by one of the following
methods:
LC-MS with acidic conditions
N,N’-dimethylcyclohexane-1,2-diamine;
dimethylformamide; DMSO, dimethylsulfoxide; EtOAc, ethyl
acetate; HCl, hydrochloric acid; FC, flash chromatography; H O,
water; hex., hexane; hept., heptane; HPLC, high performance
liquid chromatography; inorg., inorganic; MeCN, acetonitrile;
MeOH, methanol; min, minutes; NaHCO , sodium bicarbonate;
NaOH, sodium hydroxide; org. organi3c; prep., preparative;
DMF,
Method A: Agilent 1100 series with mass spectrometry detection (MS: Finnigan
single quadrupole). Column: Zorbax SB-aq (3.5 m, 4.6 x 50 mm). Conditions:
MeCN [eluent A]; H2O + 0.04% TFA [eluent B]. Gradient: 95% B → 5% B over
1.5 min (flow: 4.5 mL/min). Detection: UV/Vis + MS.
2
Method B: Agilent 1100 series with mass spectrometry detection (MS: Finnigan
single quadrupole). Column: Waters XBridge C18 (2.5 m, 4.6 x 30 mm).
Conditions: MeCN [eluent A]; H2O + 0.04% TFA [eluent B]. Gradient: 95% B →
5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis + MS.
LC-MS with basic conditions
PyBOP,
hexafluoro-phosphate;reaction; rt, room temperature; sat.,
saturated; TBTU, 2-(1H-benzotriazole-1-yl)-1,2,3,3-
benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium-
Method C: Agilent 1100 series with mass spectrometry detection (MS: Finnigan
single quadrupole). Column: Waters XBridge C18 (5 m, 4.6 x 50 mm).
9
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10.1002/cmdc.201900242
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tetramethyluronium tetrafluoroborate; THF, tetrahydrofuran; tR,
retention time.
organic solvents, then acidified to pH 4 with aq. 1 N HCl and
extracted with EtOAc (4x). The combined org. layers were dried
(MgSO4), filtered and concentrated to yield 57 (4.33 g, 73%) as a
white solid.
((R)-3-Hydroxy-piperidin-1-yl)-(5-methyl-2-[1,2,3]triazol-2-yl-
phenyl)-methanone (54). TBTU (13.1 g, 40.8 mmol) was added
to a rt solution of the 53a[31] (7.50 g, 36.9 mmol) and DIPEA (16.3
mL, 95.3 mmol) in DCM (85 mL) and after stirring for 30 min,
commercially available (R)-3-hydroxypiperidine HCl 52 (5.08 g,
36.9 mmol) was added. The reaction mixture was stirred at rt for
3 h, then the mixture was washed with water and the inorg. layer
extracted with DCM. The combined org. layers were dried
(MgSO4), filtered, concentrated, and the residue was purified on
a Biotage (EtOAc/hex. 1:1 to 4:1, Rf = 0.28 (100% EtOAc) yielding
54 (10.3 g, 97%) as a white foam. LC-MS A: tR = 0.64 min; [M+H]+
= 287.24.
Step 3. PyBOP (249 mg, 0.48 mmol) was added to a 0 °C solution
of 57 (100 mg, 0.32 mmol) and DIPEA (0.163 mL, 0.95 mmol) in
DCM (2.5 mL). The reaction mixture was stirred at 0 °C for 20 min,
then N-hydroxy-3-chloro-benzamidine (60 mg, 0.35 mmol) was
added and stirred for 20 min at 0 °C before the reaction mixture
was allowed to reach rt overnight. The mixture was quenched with
water and extracted with DCM (2x), the combined org. layers were
dried (MgSO4), filtered, and concentrated. To the crude was
added dioxane (5 mL) and the reaction mixture was stirred at
90 °C overnight. The mixture was concentrated in vacuo and the
crude oil was purified by prep. HPLC (Method F) to obtain 8 (6.2
mg, 14%) as a yellowish solid. LC-MS A: tR = 0.98 min; [M+H]+ =
449.00; LC-HRMS: tR = 1.23 min; [M+H]/z = 449.1487, found =
449.1500.
[(R)-3-(5-Chloro-benzooxazol-2-yloxy)-piperidin-1-yl]-(5-
methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone (4). NaH (47
mg, 1.16 mmol) was added to a 0 °C solution of 54 (225 mg, 0.73
mmol) in THF (3.6 mL) and the suspension was stirred at rt for 30
min before 2,5-dichlorobenzo[d]oxazole was added and the
resulting mixture stirred for 18 h. The reaction mixture was
quenched with water, the inorg. solvent was removed in vacuo
and the residue was extracted with DCM (2x). The combined org.
layers were dried (MgSO4), filtered and concentrated. The product
was purified by prep. HPLC (Method E) to obtain 4 (7.8 mg) as a
white solid. LC-MS A: tR = 1.01 min; [M+H]+ = 438.01; LC-HRMS:
tR = 1.15 min; [M+Na]/z = 460.1152, found = 460.1160.
N-Ethyl-5-methyl-N-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-ethyl]-
2-[1,2,3]triazol-2-yl-benzamide (13).
NaBH4 (15.3 mg, 0.41 mmol) was added to a rt solution of
commercially
available
2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-
ethylamine 62 (61 mg, 0.27 mmol), acetaldehyde (0.015 mL, 0.27
mmol ), and TEA (0.08 mL, 0.54 mmol) in MeOH (2 mL) and
stirred at rt for 18 h. The reaction mixture was quenched with H2O
and the org. solvent was removed in vacuo. The residue was
taken up in H2O and DCM, the org. layer separated and the inorg.
layer extracted with DCM (2x). The combined org. layers were
dried (MgSO4), filtered, and concentrated. The crude containing
product and remaining starting material was used as such in the
next step. TBTU (86.8 mg, 0.27 mmol) was added to a rt solution
of the crude 53 (45.8 mg, 0.23 mmol) and DIPEA (0.12 mL, 0.68
mmol) in DMF (2 mL) and the mixture was stirred at rt overnight.
Purification by prep. HPLC (Method F) yielded 13 (31 mg, 34%)
as a white solid and also 14 (15 mg, 18%, as a side product) was
isolated as a white solid. LC-MS B: tR = 0.87 min; [M+H]+ = 403.09;
LC-HRMS: tR = 1.11 min; [M+H]/z = 403.1877, found = 403.1883.
(3-Chloro-phenyl)-carbamic
acid
(R)-1-(5-methyl-2-
[1,2,3]triazol-2-yl-benzoyl)-piperidin-3-yl ester (5). NaH (366
mg, 8.38 mmol) was added to a 0 °C solution of 54 (1.29 g, 4.19
mmol) in THF (23 mL) and the resulting mixture was stirred at rt
for 20 min, before 3-chlorophenyl isocyanate (1.02 mL, 8.38
mmol) was added and stirred at rt for 2.5 h. The reaction was
quenched with sat. aq. NH4Cl-solution and the product extracted
with EtOAc. The inorg. layer was acidified (1 N HCl) and the
product was extracted with EtOAc. The combined org. layers were
washed with brine, dried (MgSO4), filtered, and concentrated.
Purification by prep. HPLC (Method F) yielded 5 (1.5 g, 60%) as
a white solid. LC-MS A: tR = 0.90 min; [M+H]+ = 440.45; LC-
HRMS: tR = 1.09 min; [M+H]/z = 440.1484, found = 440.1499.
5-Methyl-N-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-ethyl]-2-
[1,2,3]triazol-2-yl-benzamide (14). The title compound was
isolated as a side product from 13. LC-MS C: tR = 0.84 min;
[M+H]+ = 375.02; LC-HRMS: tR = 0.95 min; [M+H]/z = 375.1564,
found = 375.1574.
{(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-
yl}-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone (8)
Step
1.
(R)-1-(5-methyl-2-[1,2,3]triazol-2-yl-benzoyl)-
N-Cyclopropylmethyl-5-methyl-N-(3-phenyl-[1,2,4]oxadiazol-
piperidine-3-carboxylic acid ethyl ester (56). TBTU (13.1 g,
40.8 mmol) was added to a rt solution of 53a (7.50 g, 36.9 mmol)
and DIPEA (16.3 mL, 95.3 mmol) in DCM (85 mL), after stirring
for 30 min methyl (R)-piperidine-3-carboxylate HCl (55) was
added (5.8 g, 36.9 mmol) and the resulting mixture was stirred at
rt overnight. The reaction mixture was washed with water, the
inorg. layer was extracted with DCM and the combined org. layers
were dried (MgSO4), filtered, and concentrated. The product was
purified by Biotage (EtOAc/hex. 3:7, Rf = 0.23) yielding 56 (12.14
g, 96%) as a white foam.
5-ylmethyl)-2-[1,2,3]triazol-2-yl-benzamide (15)
Step 1.
Cyclopropylmethyl-(3-phenyl-[1,2,4]oxadiazol-5-
ylmethyl)-amine (64) was synthesized using procedure
described for 13, using commercially available (3-phenyl-1,2,4-
oxadiazol-5-yl)methylamine 63 and cyclopropanecarbox-
aldehyde, yielding 64 (60%) as a yellow oil. LC-MS B: tR = 0.47
1
min; [M+H]+ = 230.18. H NMR (400 MHz, CDCl3) δ: 8.11 (m, 2
H), 7.51 (m, 3 H), 4.18 (s, 2 H), 2.62 (d, J = 6.9 Hz, 2 H), 1.00 (m,
1 H), 0.54 (m, 2 H), 0.18 (m, 2 H).
Step 2. Amid coupling as described for compound 13, using 64
and 53a to yield 15 (69%) as a yellowish oil. LC-MS B: tR = 0.93
min; [M+H]+ = 414.94; LC-HRMS: tR = 1.18 min; [M+H]/z =
415.1877, found = 415.1886.
Step
2.
(R)-1-(5-methyl-2-[1,2,3]triazol-2-yl-benzoyl)-
piperidine-3-carboxylic acid (57). 2 N aq. NaOH solution (12.5
mL, 25 mmol) was added at rt to a suspension of 56 (6.48 g, 18.9
mmol) in EtOH (20 mL) and THF (20 mL) and the mixture was
stirred at rt for 1.5 h. The mixture was concentrated to remove the
10
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(5-Methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(S)-2-(3-phenyl-
[1,2,4]oxadiazol-5-yl)-pyrrolidin-1-yl]-methanone (19)
combined org. extracts were dried (MgSO4), filtered, and
concentrated. Purification and separation of the two isomers were
obtained by Biotage (EtOAc/hex. + 0.1 % AcOH 1:9 to 1:1; Rf of
product = 0.64 and Rf of undesired isomer = 0.24 in EtOAc (+
0.1 % AcOH). The product 53b was isolated as a beige solid (2.15
g, 80%). 1H NMR (400 MHz, DMSO) δ: 12.96 (s, 1 H), 8.01 (s, 2
H), 7.51 (s, 1 H), 7.28 (s, 1 H), 3.92 (s, 3 H), 2.26 (s, 3 H).
Step
1.
(S)-1-(5-Methyl-2-[1,2,3]triazol-2-yl-benzoyl)-
pyrrolidine-2-carboxylic acid methyl ester (63). TBTU (7.11 g,
22.1 mmol) was added to a rt solution of 53a (3.00 g, 14.8 mmol)
and DIPEA (10.1 mL, 59.1 mmol) in DCM (30 mL), after stirring
for 10 min L-proline methylester HCl (62) (3.19 g, 15.4 mmol) was
added and stirred at rt overnight. The reaction mixture was
washed with water, the inorg. layer was extracted with DCM and
the combined org. layers were dried (MgSO4), filtered and
concentrated. The product was purified by FC (EtOAc/hept. 7:3)
yielding 63 (4.36 g, 94%) as a white solid. LC-MS A: tR = 0.74 min;
[M+H]+ = 315.12.
Step 3. (S)-2-[3-(2-Trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-
5-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (66).
PyBOP (33.41 g, 64.1 mmol) was added to a rt solution of
commercially available (tert-butoxycarbonyl)-L-proline 65 (11.49
g, 53.4 mmol, and N'-hydroxy-2-(trifluoromethoxy) benzimid-
amide 58b (12.78 g, 53.4 mmol) and DIPEA (27.4 mL, 160 mmol)
in DCM (250 mL) and the mixture was stirred at rt for 1 h. The
reaction mixture was diluted with DCM and water, the org. layer
was separated and the inorg. layer was extracted with DCM. The
combined org. layers were washed with brine, dried (MgSO4),
filtered, and concentrated. To the residue was added dioxane
(300 mL) and the mixture was stirred at 90 °C for 18 h. The
reaction mixture was concentrated, the residue dissolved in
EtOAc and washed with aq. sat NaHCO3 (3x), dried (MgSO4),
filtered, and concentrated. Purification by Biotage (EtOAc/hex. 1:9
to 3:7, Rf = 0.64 EtOAc/hept. 1:1) yielded 66 (13.34 g, 63%) as a
yellow oil. LC-MS A: tR = 0.98 min; [M+H]+ = 400.08.
Step
2.
(S)-1-(5-Methyl-2-[1,2,3]triazol-2-yl-benzoyl)-
pyrrolidine-2-carboxylic acid (64). 2 N aq. NaOH solution (6.3
mL, 12.6 mmol,) was added at rt to a suspension of 63 (2.2 g, 7
mmol) in MeOH (9 mL) and THF (9 mL) and the mixture was
stirred at rt for 1.5 h. The mixture was concentrated to remove the
org. solvents. The residue was acidified to pH 4 with aq.1 N HCl
and extracted with EtOAc (4x). The combined org. layers were
dried (MgSO4), filtered and concentrated to yield 64 (2.0 g, 100%)
as a white solid. LC-MS B: tR = 0.57 min; [M+H]+ = 301.03.
Step 3. PyBOP (260 mg, 0.50 mmol) was added to a rt solution of
64 (100 mg, 0.32 mmol) and DIPEA (0.17 mL, 1.00 mmol) in DCM
(3 mL), the reaction mixture was stirred for another 10 min, then
N-hydroxy-benzamidine (58a) (60 mg, 0.35 mmol) was added and
the mixture was stirred at rt overnight. The mixture was quenched
with H2O and extracted with DCM (2x). The combined org. layers
were dried (MgSO4), filtered, and concentrated. To the crude was
added dioxane (4 mL) and the reaction mixture was stirred at 90
°C for 48 h. The mixture was concentrated and purification by
prep. HPLC (Method E) yielded 19 (54 mg, 41%) as a beige solid.
LC-MS A: tR = 0.96 min; [M+H]+ = 415.25; LC-HRMS: tR = 1.10
min; [M+H]/z = 401.1721, found = 401.1729.
Step 4. 5-(S)-Pyrrolidin-2-yl-3-(2-trifluoromethoxy-phenyl)-
[1,2,4]oxadiazole (67). TFA (32.1 mL, 419 mmol) was added to
a 0 °C solution of 66 in DCM (150 mL) and the mixture was stirred
at rt for 5 h. The mixture was concentrated, and the residue
dissolved in DCM, and basified with 1 N aq. NaOH until pH 12.
The layers were separated and the inorg. layer was extracted with
DCM (2x). The combined org. layers were dried (MgSO4), filtered,
and concentrated to yield 67 (9.4 g, 94%) as a yellow oil which
was used as such in the next step. 1H NMR (400 MHz, DMSO) δ:
8.07-8.11 (m, 1 H), 7.69-7.76 (m, 1 H), 7.59-7.66 (m, 2 H), 4.57
(dd, J1 = 5.2 Hz, J2 = 8.3 Hz, 1 H), 2.88-2.99 (m, 2 H), 2.19 (m, 1
H), 1.99-2.08 (m, 1 H), 1.71-1.92 (m, 2 H). LC-MS A: tR = 0.62
min; [M+H]+ = 300.12.
Compound 36 to 44 were synthesized in analogy to the
procedures described for compound 41.
(5-Methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[3-(2-
trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrrolidin-1-
yl}-methanone (41)
Step 5. TBTU (2.64 g, 8.23 mmol) was added to a rt solution of
53b (1.6 g, 6.86 mmol) and DIPEA (3.5 mL, 20.6 mmol) in DCM
(20 mL), after stirring for 15 min a solution of 67 (2.05 g, 6.86
mmol) in DCM (10.0 mL) was added and the resulting mixture was
stirred at rt for 1 h. The reaction mixture was washed with sat. aq.
NaHCO3 and the org. layer was dried (MgSO4), filtered and
concentrated. The product was purified by Biotage (EtOAc/hex.
1:9 to 3:7, Rf = 0.30 in EtOAc/hept. 1:1) yielding 41 (2.7 g, 77%)
as a white foam. LC-MS A: tR = 1.01 min; [M+H]+ = 515.10; LC-
HRMS: tR = 1.22 min; [M+H]/z = 515.1650, found = 515.1665.
Step 1. 2-Bromo-5-methoxy-4-methyl-benzoic acid (69). Br2
(0.79 mL, 15.3 mmol) was added to a rt suspension of 3-methoxy-
4-methylbenzoic acid (68) (2.12 g, 12.7 mmol) in AcOH (25 mL)
and H2O (25 mL), and the reaction mixture was stirred at 60 °C
for 2 h. The mixture was allowed to reach rt and the product which
crashed out as a white solid was filtered off and rinsed with cold
water to yield 69 (2.81 g, 90%) as a white solid which was used
as such in the next step. 1H NMR (400 MHz, DMSO) δ: 13.30 (s,
1 H), 7.50 (d, J = 0.6 Hz, 1 H), 7.29 (s, 1 H), 3.83 (s, 3 H), 2.18 (s,
3 H).
(5-Methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-
trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-
yl}-methanone (51)
Step 2. 5-Methoxy-4-methyl-2-[1,2,3]triazol-2-yl-benzoic acid
(53b). CuI (130 mg, 0.68 mmol) was added in portions to a rt
solution of 69 (2.81 g, 11.5 g), 1H-1,2,3-triazole (1 mL, 17.3 mmol),
DMCDA (0.3 mL, 1.85 mmol). and Cs2CO3 (7.47 g, 22.9 mmol) in
DMF (20.0 mL) were added and the resulting blue suspension
was stirred at 120°C for 1 h. The mixture was allowed to reach rt,
then EtOAc and H2O was added. The org. layer was separated
and the aq. layer was acidified with aq. HCl (24%). The brown-
greenish solution was extracted with EtOAc (2x), then the
Step
1.
(S)-2-(N-Hydroxycarbamimidoyl)-pyrrolidine-1-
carboxylic acid tert-butyl ester (71). Hydroxylamine HCl (1.70
g, 24.2 mmol) was added to a rt solution of commercially available
(S)-1-boc-2-cyanopyrrolidine (70) (3.0 g, 15.3 mmol) and Na2CO3
(1.98 g, 23.6 mmol) in MeOH (30 mL) and the resulting
suspension was stirred at 70 °C for 1 h. The reaction mixture was
filtered, the filter cake washed with MeOH and the filtrate
concentrated. The residue was dissolved in EtOAc and H2O, the
org. layer separated and the inorg. layer extracted with EtOAc
11
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900242
ChemMedChem
FULL PAPER
(1x). The combined org. layers were dried (MgSO4), filtered and
concentrated to yield 3.2 g of 71 (91%) as a white solid, which
was used as such in the next step. LC-MS A: tR = 0.45 min; [M+H]+
= 230.23.
concentrated. The product was purified by Biotage (EtOAc/hex.
1:9 to 3:7, Rf = 0.25 in EtOAc/hept. 1:1) yielding 77a (840 mg,
81% over 2 steps) as a white foam.
Step 2. (S)-2-[5-(2-Trifluoromethoxy-phenyl)-[1,3,4]oxadiazol-
2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (78a). TFA
(2 mL, 26.1 mmol) was added to a rt solution of 77a (840 mg, 2.1
mmol) in DCM (5.0 mL) and the reaction mixture was stirred at rt
overnight. The reaction mixture was concentrated, and the
residue taken up in DCM, then basified with 4 N aq. NaOH. The
org. layer was separated and the inorg. layer extracted with DCM.
The combined org. layers were dried (MgSO4), filtered, and
Step 2. (S)-2-[5-(2-Trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-
3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (73a).
TBTU (10.02 g, 31.2 mmol) was added to a rt solution of 2-
(trifluoromethoxy)benzoic acid (72a) (5.10 g, 24 mmol) and
DIPEA (10.3 mL, 60 mmol) in DCM (50 mL). The resulting
reaction mixture was stirred at rt for 10 min, then 71 (7.93 g, 32.2
mmol) was added and stirring was continued for 1.5 h at rt. The
reaction mixture was concentrated and to the residue was added
dioxane (30 mL) and the reaction-mixture was stirred at 80 °C for
2 days. The reaction mixture was concentrated, DCM was added,
and the org. layer was washed with aq. sat. NaHCO3 solution. The
org. layer was dried (MgSO4), filtered, and concentrated.
Purification by Biotage (EtOAc/hex. 1:9 to 3:7; Rf = 0.38 in
EtOAc/hept. 3:7) yielded 73a (8.27 g, 86%) as a yellow oil. LC-
MS A: tR = 0.99 min; [M+H]+ = 400.12.
1
concentrated to yield 78 (quantitatively) as a yellow oil. H NMR
(400 MHz, DMSO) δ: 9.82-10.14 (m, 1 H), 8.16 (dd, J1 = 1.9 Hz,
J2 = 8.3 Hz, 1 H), 7.82-7.94 (m, 1 H), 7.65-7.75 (m, 2 H), 5.18 (t,
J = 7.7 Hz, 1 H), 3.40 (m, 2 H), 2.45-2.57 (m, 1 H), 2.37 (m, 1 H),
2.03-2.21 (m, 2 H).
Step 3. TBTU (50.1 mg, 0.16 mmol) was added to a rt solution of
53a (24.3 mg, 0.12 mmol), DIPEA (61 L, 0.36 mmol) in DMF (0.5
mL) and after stirring for 10 min at rt, a solution of 78a (27.5 mg,
0.12 mmol) in DMF (0.5 mL) was added and the reaction mixture
was stirred at rt overnight. Purification by prep. HPLC (Method F)
yielded 46 (32 mg, 58%) as a slightly yellow solid. LC-MS A: tR =
0.93 min; [M+H]+ = 485.06; LC-HRMS: tR = 1.08 min; [M+H]/z =
485.1544, found = 485.1551.
Step 3. 3-(S)-Pyrrolidin-2-yl-5-(2-trifluoromethoxy-phenyl)-
[1,2,4]oxadiazole (74a). TFA (16 mL, 209 mmol) was added to a
rt solution of 73a (8.27 g, 20.7 mmol) in DCM (100 mL) and the
resulting mixture was stirred at rt for 1.5 h. The reaction mixture
was concentrated (to remove the excess TFA) and the residue
was dissolved in DCM and aq. 4 N NaOH solution was added until
pH 12. The layers were separated, and the aq. layer was
extracted with DCM (1x). The comb. org. layers were dried
(MgSO4), filtered, and concentrated to yield 74a (5.45 g, 90%) as
a yellowish oil, which was used as such in the next step. LC-MS
A: tR = 0.63 min; [M+H]+ = 300.12.
Acknowledgements
The authors gratefully thank Stephanie Bazire, Jeanine Thanner,
Markus Gude, Celia Müller-Grandjean, Katalin Menyhart, Thomas
Sasse, Cedric Fischer, Stephane Delahaye, Isabelle Weber,
Fabienne Drouet, Eric Soubieux, Rolf Wuest, Julia Khobzaoui and
Sandrine Chopinet.
Step 4. TBTU (4.47 g, 13.9 mmol) was added to a rt solution of
53b (2.50 g, 10.7 mmol) and DIPEA (4.59 mL, 26.8 mmol) in DCM
(20 mL) and the reaction mixture was stirred for 20 min at this
temperature before 74a (3.53 g, 11.8 mmol) dissolved in DCM (5
mL) was added and the resulting mixture was stirred at rt for 70
min. The reaction mixture was diluted with DCM and water. The
layers were separated, and the org. layer was dried (MgSO4),
filtered, and concentrated. Purification by FC (EtOAc/hept. 1:1)
yielded 51 (4.89 g, 89%) as a white solid. LC-MS A: tR = 1.0 min;
[M+H]+ = 515.12; LC-HRMS: tR = 1.21 min; [M+H]/z = 515.1650,
found = 515.1662.
Keywords: drug design • dual orexin receptor antagonists •
insomnia • sleep disorder • structure-activity relationship
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10.1002/cmdc.201900242
ChemMedChem
FULL PAPER
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The orexin system plays an important role in the regulation of wakefulness. Herein, we outline our optimization efforts towards a novel
dual orexin receptor antagonist (DORA). Our starting point was compound 3, a hybrid of Merck’s suvorexant and another published
DORA containing a piperidine as a core structure. Our work led to the identification of compound 51, a potent, brain penetrating DORA
with in vivo efficacy comparable to suvorexant in the rat.
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This article is protected by copyright. All rights reserved.