Synthesis, structure-activity relationship studies, and identification of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual orexin receptor antagonists. Part 1

Article abstract of DOI:10.1016/j.bmcl.2013.01.088

A novel series of non-peptidic OX₁R/OX₂R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX₁R and hOX₂R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.

Full text of DOI:10.1016/j.bmcl.2013.01.088

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2212–2216
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, structure–activity relationship studies, and identification
of novel 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as dual
orexin receptor antagonists. Part 1
Thierry Sifferlen, Ralf Koberstein, Emmanuelle Cottreel, Amandine Boller, Thomas Weller, John Gatfield,
⇑
Catherine Brisbare-Roch, Francois Jenck, Christoph Boss
Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic
replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of
almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antag-
onists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of
these novel orexin receptor antagonists and the outcome of preliminary structure–activity relationship
studies are described in this communication.
Received 3 December 2012
Revised 17 January 2013
Accepted 20 January 2013
Available online 29 January 2013
Keywords:
Orexin receptors
Ó 2013 Elsevier Ltd. All rights reserved.
Neuropeptides
G-protein-coupled-receptors
Sleep
5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazine
The neuropeptides orexin A and orexin B (also named hypocre-
tin-1 and hypocretin-2) were discovered in 1998 by two indepen-
dent research groups. Both peptides are produced exclusively by a
small population of neurons in the lateral hypothalamus.1,2 Two
orphan G-protein-coupled receptors (GPCRs) for these endogenous
ligands were as well identified and they are known as orexin 1
(OX1R) and orexin 2 (OX2R) receptors. Both receptors are highly
conserved across mammalian species. The OX1 receptor binds
orexin A with high affinity and selectivity over orexin B, whereas
the OX2 receptor binds both neuropeptides with comparably high
affinity.2 Since the discovery of the orexin neuropeptides, several
studies have highlighted their potential role in the regulation of
biological functions including feeding2 and the sleep/wake cycle.3,4
During the last decade, several groups within the pharmaceutical
industry have developed orexin receptor antagonists in order to
identify the physiological role of the orexin receptors and explore
the potential of orexin receptor antagonists as therapeutics.5 We
have reported that almorexant, a dual orexin receptor antagonist
(DORA),6 promoted somnolence without cataplexy in rats, dogs,
and humans.7 In the course of our investigations towards the
identification of further non-peptidic, low molecular weight orexin
receptor antagonists, we were interested in heterocyclic
replacements of the dimethoxyphenyl unit contained in the
tetrahydroisoquinoline skeleton of almorexant.8 We reported that
the replacement of this moiety by a substituted pyrazole afforded
pyrazolo-tetrahydropyridines as potent DORAs.9 Herein, we de-
scribe the synthesis and preliminary structure–activity relation-
ship studies of a novel series of DORAs related to almorexant
where the dimethoxyphenyl moiety was replaced by substituted
imidazoles (Fig. 1).10
For a convenient preparation of the planned 5,6,7,8-tetrahydro-
imidazo[1,5-a]-pyrazine derivatives 9, it was envisaged to develop a
selective synthesis of the key trisubstituted imidazoles 4 (Scheme 1)
with the goal to avoid isomeric mixtures due to the issue of tautom-
erism associated with imidazoles. The developed synthesis started
with the diiodination of 2-substituted imidazoles 111 affording
4,5-diiodoimidazoles 2.12 Deprotonation of pseudosymmetric 2,
and subsequent N-alkylation (NaH, Br(CH2)2NHBoc, DMF) furnished
the corresponding derivatives 3. The pivotal step for the selective
preparation of 4-iodoimidazoles 4 was a regioselective iodine/mag-
nesium exchange of the 5-iodo moiety in 3 (EtMgBr, THF, ꢀ40 °C)
followed by trapping of the intermediate carbanion with water.13,14
The application of this methodology allowed to obtain exclusively
the target 4-iodoimidazoles 4. Boc-deprotection of 4 (4 N HCl in
dioxane, CH2Cl2) provided quantitatively the corresponding pri-
mary amines that reacted with 3-(4-(trifluoromethyl)phenyl)prop-
anal 5 in a subsequent microwave assisted Pictet–Spengler-like
reaction (DIPEA, EtOH, microwave).15 Boc-protection delivered
the racemic 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines 6, and the
⇑
Corresponding author.
E-mail address: christoph.boss@actelion.com (C. Boss).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.088

T. Sifferlen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2212–2216
2213
R
O
N
O
O
N
O
N
N
N
N
N
O
N
H
N
H
N
H
R'
(reference 9)
this work
CF3
pyrazolo-tetrahydropyridines
CF3
CF3
almorexant
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines
(ACT-078573)
Figure 1. Almorexant, the related pyrazolo-tetrahydropyridines, and the investigated 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines.
R
R
R
R
HN
N
HN
I
N
N
N
N
N
BocHN
BocHN
a
b
c
I
I
I
I
3
1
2
4
CHO
F3C
d,e,f
5
R
N
R
R
N
O
N
N
N
N
N
NBoc
NBoc
N
H
R'
d,g
R'
I
O
introduction of
R' substituents
(Scheme 2)
TsO
N
H
CF3
CF3
CF3
9
7
6
8
Scheme 1. Preparation of 5,6,7,8-tetrahydroimidazo[1,5-a]-pyrazines. Reagents and conditions: (a) I2, Na2CO3, dioxane, H2O, rt (95–100%); (b) NaH, DMF, rt, then
Br(CH2)2NHBoc, 100 °C (42–77%); (c) (i) 3 M EtMgBr in Et2O, THF, ꢀ40 °C, (ii) H2O (82–95%); (d) 4 M HCl in dioxane, CH2Cl2, 0 °C to, rt (97–100%); (e) aldehyde 5, DIPEA, EtOH,
microwave (50 W; 140 °C; 6 bar; 10 min); (f) Boc2O, DIPEA, CH2Cl2, rt (58–87% over 2 steps); (g) tosylate 8, DIPEA, 3-methyl-2-butanone, 80 °C (25–60%).
versatility of the iodo-substituent allowed the preparation of a vari-
ety of derivatives 7 (Scheme 2). Boc-deprotection of 7 followed by
N-alkylation of the resulting secondary amines with the chiral (S)-
tosylate 8 delivered the target 5,6,7,8-tetrahydroimidazo[1,5-a]pyr-
azines 9 as diastereoisomeric mixtures that could be further sepa-
rated into the enantiomers via chromatography.
copper-mediated procedure (MeSNa, CuCl, NMP) allowed the
insertion of the thiomethyl residue (7k) that was oxidized (m-
CPBA, CH2Cl2) to the corresponding sulfone (7l). Stille cross-cou-
pling reaction with 6 (tributyl(vinyl)tin, Pd2dba3, PPh3, DMF)18
smoothly introduced the vinyl moiety (7h) that could be either
hydrogenated (H2, 10% Pd/C, MeOH) to the ethyl-substituted deriv-
ative (7i) or converted into the cyclopropyl moiety (7j) using mod-
ified cyclopropanation conditions (Et2Zn, CH2I2, CF3CO2H).19
The antagonistic activity of the 5,6,7,8-tetrahydroimidazo[1,5-
a]-pyrazines 9 with both orexin receptors was evaluated with a
cell-based FLIPR assay (fluorometric imaging plate reader) measur-
ing Ca2+ flux as a functional determinant of orexin binding.20 Pre-
liminary structure–activity relationship studies were devoted to
the exploration of the influence of substituent R0 on the potency to-
ward both orexin receptors (Table 1). These initial investigations
were performed with derivatives 9 containing the para-CF3-phenyl
ring from almorexant, and having ethyl as a fixed substituent R like
in the related dual pyrazolo-tetrahydropyridines.9 Limiting the
substituent R0 to hydrogen (diastereoisomers 10) led to moderate
potency toward hOX2R and absence of affinity for hOX1R. A methyl
group induced a substantial eightfold increase in hOX2R potency
but this alkyl residue could not improve the affinity for hOX1R as
shown with diastereoisomers 11. Compared to methyl, ethyl affor-
ded an almost equipotent diastereoisomeric mixture (12) but
The versatility of the iodo-substituent in 5,6,7,8-tetrahydroimi-
dazo[1,5-a]pyrazines 6 allowed the straightforward introduction of
a variety of substituents R0 (Scheme 2). Several residues could be
conveniently introduced with one synthetic operation. Thus,
hydrogenolytic cleavage of the iodo-substituent (H2, 10% Pd/C,
K2CO3, MeOH) delivered 7a. Iodine/lithium exchange (n-BuLi,
THF, ꢀ78 °C) or iodine/magnesium exchange (EtMgBr, THF,
ꢀ30 °C) with 6 and subsequent trapping of the intermediate carb-
anion with diverse electrophiles proved to be a particularly
straightforward synthetic approach allowing the insertion of
methyl (7b), chloro (7c), isopropyl (7f), cyano (7g), n-propyl (7n),
and carboxylic acid (7o) residues. The latter was converted into
amides (7p) after additional coupling with amines (TBTU, HNR1R2,
DIPEA, DMF). In another approach, copper-mediated trifluorome-
thylation16 (FSO2CF2CO2Me, CuI, HMPA, DMF) allowed the intro-
duction of the trifluoromethyl moiety (7d). Alkoxy residues (7e)
could be incorporated by copper-mediated alkoxylations (MeOH
or EtOH, CuI, 1,10-phenanthroline, Cs2CO3, microwave).17 A related

2214
T. Sifferlen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2212–2216
R
R
R
N
7i
N
N
j
N
7j
N
i
N
N
N
NBoc
NBoc
NBoc
NBoc
NBoc
A
A
A
A
A
7h
h
R
R
R
R
N
N
a-g
l
k
N
N
N
N
NBoc
A
NBoc
R'
I
MeS
MeO2S
A
7a R' = H
7k
7l
7b R' = Me
7c R' = Cl
7d R' = CF3
7e R' = OMe/OEt
7f R' = i-Pr
7g R' = CN
CF3
6
o
m
R
N
R
R
N
R
N
N
N
N
n
p
N
N
NBoc
NBoc
NBoc
NBoc
HO2C
R1R2NOC
A
A
A
A
7n
7m
7o
7p
Scheme 2. Versatility of the iodo-substituent in 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines for the introduction of substituents R0. Reagents and conditions: (a) H2 (1 atm),
10% Pd/C (10% in weight), K2CO3, MeOH, rt (69–98%); (b) n-BuLi, MeI, THF, ꢀ78 °C (45–70%); (c) n-BuLi, hexachloroethane, THF, ꢀ78 °C (39–66%); (d) FSO2CF2CO2Me, CuI,
HMPA, DMF, 80 °C (30–84%); (e) MeOH (R0 = OMe) or EtOH (R0 = OEt), CuI, 1,10-phenanthroline, Cs2CO3, microwave (150 W; 150 °C; 13 bar; 90 min) (29–35%); (f) (i) n-BuLi,
THF, acetone, ꢀ78 °C, (ii) Burgess’ reagent, THF, 0 °C, (iii) H2 (1 atm), 10% Pd/C (20% in weight), MeOH, rt (18–20% over 3 steps); (g) n-BuLi, para-toluenesulfonyl cyanide, THF,
ꢀ78 °C (27–50%); (h) Pd2dba3, PPh3, tributyl(vinyl)tin, DMF, 90 °C (63–77%); (i) H2 (1 atm), 10% Pd/C (100% in weight), MeOH, rt (83–97%); (j) (i) Et2Zn, CH2I2, CF3CO2H,
CH2Cl2, 0 °C to rt, (ii) Boc2O, DIPEA, CH2Cl2, rt (34–40% over 2 steps); (k) MeSNa, CuCl, NMP, 140 °C (66–84%); (l) m-CPBA, CH2Cl2, rt (51–86%); (m) n-BuLi, allyl bromide, THF,
ꢀ78 °C (40–55%); (n) H2 (1 atm), 10% Pd/C (50% in weight), MeOH, rt (80–95%); (o) 3 M EtMgBr in Et2O, CO2, THF, ꢀ30 °C to rt (82%); (p) TBTU, HNR1R2, DIPEA, DMF, rt (35–
65%).
enlarging the alkyl residue to n-propyl (13) proved to be detrimen-
tal for hOX2R affinity with an almost 10-fold loss in potency. Cyclo-
propyl was similarly tolerated regarding potency towards hOX2R
(15) but this substituent remained ineffective for the interaction
with hOX1R. Compared to ethyl, the unsaturated vinyl moiety trig-
gered an outstanding increase of potency towards hOX1R while
maintaining potency towards hOX2R (diastereoisomers 16). We
observed a similar trend with the iodo-substituent but to a lower
extent regarding the affinity for hOX1R (diastereoisomers 17). Fur-
ther evaluation of halogen atoms indicated the superiority of the
chloro moiety that allowed an outstanding improvement of po-
tency towards hOX1R as shown with the dual orexin receptor
antagonist 18. Previous investigations in the related tetrahydroiso-
quinoline and pyrazolo-tetrahydropyridine series have shown that
the (S,R)-stereoisomer was the most active isomer in both series
(Fig. 1).9 The influence of the stereochemistry for 5,6,7,8-tetrahy-
droimidazo[1,5-a]-pyrazines was investigated with the chloro-
containing derivatives (18/19). In this new series the (R,R) isomer
19 was also significantly less potent against both receptors com-
pared to the corresponding (S,R) stereoisomer 18 (7- and 12-fold
decrease, respectively, in hOX1R and hOX2R potency with 19).
The additional (R,S) and (S,S) isomers were essentially inactive
(stereoisomer 20). The electron-donating methoxy group afforded
appreciable potency towards both orexin receptors but the diaste-
reoisomers 21 remained clearly less potent than the chloro-con-
taining DORA 18. Lengthening of the alkoxy moiety to ethoxy
(diastereoisomers 22) proved to be highly detrimental for the po-
tency towards both orexin receptors. The influence of a related
thiomethyl group was also evaluated (stereoisomer 23). This moi-
ety induced a twofold decrease in hOX1R potency compared to the
chloro-derivative 18. Oxidation of the thiomethyl residue to the
corresponding sulfone (stereoisomer 24) resulted in a substantial
loss of potency towards hOX1R while keeping the affinity for
hOX2R almost unaffected. The electron-withdrawing cyano group
(diastereoisomers 25) and amide residues (diastereoisomers 26–
28) were detrimental for the potency towards hOX1R while the
affinity for hOX2R remained high with a secondary amide (27)
and especially with the cyano group (25).
The evaluation of substituents R0 clearly emphasized the supe-
riority of the chloro moiety for the identification of potent dual
orexin receptor antagonists. In an attempt to further improve
potency in this series of DORAs, we evaluated the influence of addi-
tional substituents R. With this aim in view, specific 2-substituted
imidazoles 1 had to be prepared in order to synthesize the corre-
sponding 5,6,7,8-tetrahydroimidazo[1,5-a]-pyrazines 9 according
to Scheme 1. A variety of 2-substituted imidazoles 1 were conve-
(IC50 >1 lM with both orexin receptors), and the importance of
the (R)-configuration for the phenylglycine moiety was already
established with the related tetrahydroisoquinoline and
pyrazolo-tetrahydropyridine series. The evaluation of additional
substituents R0 indicated that the electron-withdrawing trifluoro-
methyl moiety was detrimental for the potency toward hOX1R
niently prepared from commercially available nitriles and
a-ami-
no-acetaldehyde acetals.21 Thus, copper(I)-induced addition of
2,2-dimethoxyethanamine 30 to nitriles 29 (CuCl, neat, 85 °C)
delivered the corresponding amidines 31 (Scheme 3). After elimi-

T. Sifferlen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2212–2216
2215
Table 1
SAR studies of 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines: influence of R0
Table 2
SAR studies of 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines: influence of R
R
R
N
N
O
O
N
N
O
O
N
N
N
N
(R)
(R)
N
N
*
(R)
(R)
N
N
*
*
*
N
H
N
H
N
H
N
H
R'
R'
Cl
Cl
Ph
Ph
Ph
Ph
CF3
CF3
CF3
CF3
(S;R)-stereoisomer
(R;R)-stereoisomer
(S;R)-stereoisomer
Stereochemistry
(R;R)-stereoisomer
hOX1Ra
hOX1Ra
hOX2Ra
Compound
Stereochemistry
R0
hOX2Ra
Compound
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
(S,R) + (R,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R)
(R,R)
(S,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R)
H
Me
Et
n-Pr
i-Pr
c-Pr
CH@CH2
I
Cl
Cl
CF3
OMe
OEt
SMe
SO2Me
CN
CONH2
CONHMe
CONMe2
10,000
10,000
10,000
10,000
10,000
4171
150
717
40
283
1066
134
3980
85
1677
537
10,000
492
344
194
24
20
225
2904
29
23
23
9
107
11
73
2746
14
25
10
194
38
111
18
37
38
39
40
41
42
(S,R)
(S,R)
(S,R)
(S,R) + (R,R)
(S,R)
Et
Me
n-Pr
CH2OMe
i-Pr
c-Pr
40
90
459
1645
313
31
9
13
60
25
11
9
(S,R)
(S,R)
c-PrCH2
1426
35
a
IC50 values in nM (FLIPR assay).
potency towards both orexin receptors, but mainly for hOX1R with
an 11-fold loss in potency. The isosteric methoxymethyl was not
better tolerated and induced an even more pronounced loss of po-
tency for hOX1R (diastereoisomers 39). Compared to ethyl the
branched isopropyl moiety also induced a substantial eightfold de-
crease of potency towards hOX1R while keeping similar potency for
hOX2R (40). The sterically less demanding cyclopropyl group was
however better tolerated (stereoisomer 41) and similar to ethyl
regarding the affinities for both orexin receptors. The enlargement
to cyclopropylmethyl (stereoisomer 42) proved to be highly detri-
mental for hOX1R affinity with a 46-fold loss in potency compared
to cyclopropyl.
We measured the concentrations of the dual orexin receptor
antagonists 18 and 41 in brain and plasma sampled 3 h following
oral administration to male Wistar rats (100 mg/kg, po). Total con-
centrations of the DORA 18 reached 303 nM (153 ng/g) in the brain
and 4210 nM (2127 ng/ml) in plasma (brain/plasma ratio = 0.07).
When the dual orexin receptor antagonist 41 was orally adminis-
tered to rats, brain and plasma levels reached 385 nM (199 ng/g)
and 6398 nM (3308 ng/ml), respectively (brain/plasma ratio = 0.06).
Considering a plasma protein binding of 99% measured for 18 and 41
in human plasma, the concentrations of free 18 and 41 available in
the brain at 3 h can be estimated at 3.0 and 3.8 nM, respectively.
For a direct comparison with the related tetrahydroisoquinoline ser-
ies, a similar experiment afforded a five to sixfold higher concentra-
tion of free almorexant in brain (20 nM, brain/plasma ratio = 0.32).7
(S,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R) + (R,R)
(S,R) + (R,R)
a
IC50 values in nM (FLIPR assay).
nation of copper salts (thioacetamide, MeOH, filtration), cyclisation
under acidic conditions (12 M HCl, MeOH, 80 °C) led to the desired
2-substituted imidazoles 1. In another approach, deprotonation of
1-tritylimidazole 32 (n-BuLi, THF, ꢀ78 °C) afforded selectively the
carbanion at C-2 that could be trapped with a variety of electro-
philes.22 For example, quenching with DMF afforded 33 (Scheme
3) that could be converted to the methyl ether 36 after reduction
(NaBH4, MeOH), O-alkylation (NaH, MeI, THF), and cleavage of
the trityl group (AcOH, MeOH).
The structure–activity relationship studies to investigate the
influence of additional substituents R were performed with deriv-
atives 9 containing the para-CF3-phenyl ring from almorexant and
a chloro residue as substituent R0 (Table 2). Compared to ethyl
(DORA 18), methyl resulted in an almost twofold loss of potency
towards hOX1R (stereoisomer 37). Enlargement of the alkyl group
to n-propyl (stereoisomer 38) was even more detrimental for the
NH
R
O
a
O
b,c
H2N
R
CN
29
+
R
N
H
HN
N
O
O
30
31
1
HO
N
O
O
N
CHO
N
CPh3
CPh3
CPh3
CPh3
N
N
N
N
NH
N
N
d
f
g
e
32
33
34
35
36
Scheme 3. Synthesis of 2-substituted imidazoles. Reagents and conditions: (a) CuCl, neat, 0–85 °C; (b) thioacetamide, MeOH, 0–45 °C; (c) 12 M HCl, MeOH, 0–80 °C (overall
yield: 26–35%); (d) n-BuLi, DMF, THF, ꢀ78 °C (76%); (e) NaBH4, MeOH, 45 °C (99%); (f) NaH, MeI, THF, 0 °C to rt (51%); (g) AcOH, MeOH, 75 °C (99%).

2216
T. Sifferlen et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2212–2216
7. Brisbare-Roch, C.; Dingemanse, J.; Koberstein, R.; Hoever, P.; Aissaoui, H.;
Flores, S.; Mueller, C.; Nayler, O.; van Gerven, J.; de Haas, S. L.; Hess, P.; Qiu, C.;
Buchmann, S.; Scherz, M.; Weller, T.; Fischli, W.; Clozel, M.; Jenck, F. Nat. Med.
2007, 13, 150.
8. Koberstein, R.; Aissaoui, H.; Bur, D.; Clozel, M.; Fischli, W.; Jenck, F.; Mueller, C.;
Nayler, O.; Sifferlen, T.; Treiber, A.; Weller, T. Chimia 2003, 57, 270.
9. Sifferlen, T.; Boss, C.; Cottreel, E.; Koberstein, R.; Gude, M.; Aissaoui, H.; Weller,
T.; Gatfield, J.; Brisbare-Roch, C.; Jenck, F. Bioorg. Med. Chem. Lett. 2010, 20,
1539.
10. Previous structure–activity relationship studies in the tetrahydroisoquinoline
and pyrazolo-tetrahydropyridine series have indicated that two substituents
are mandatory for the aryl or heterocycle moiety in order to reach potent
affinities with both orexin receptors. Imidazoles were considered as a valuable
heterocyclic replacement for the dimethoxyphenyl moiety due to the fact that
they can be conveniently disubstituted, and the versatile chemistry of
imidazoles allows the introduction of diverse substituents having different
electronic properties.
11. 2-Substituted imidazoles 1 used for the investigations are either commercially
available or specifically synthesized (Scheme 3). Substituents R corresponding
to these 2-substituted imidazoles 1 are listed in Table 2.
12. Wittenberger, S. J.; Tasker, A.; Sorensen, B. K.; Donner, B. G. Synth. Commun.
1993, 23, 3231.
13. For recent reviews on halogen/magnesium exchange: (a) Abarbri, M.;
Thibonnet, J.; Berillon, L.; Dehmel, F.; Rottlaender, M.; Knochel, P. J. Org.
Chem. 2000, 65, 4618; (b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.
F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302.
14. Polyhalogenated imidazoles undergo halogen/magnesium or halogen/lithium
exchange in a specific sequence (C2 > C5 > C4), under the appropriate reaction
conditions: (a) Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans. 1 1983, 4, 735; (b)
Groziak, M. P.; Wei, L. J. Org. Chem. 1991, 56, 4296; (c) Carver, D. S.; Lindell, S.
D.; Saville-Stones, E. A. Tetrahedron 1997, 53, 14481; (d) Butz, R. H.-J.; Lindell, S.
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2003, 60, 1.
Previous investigations of the corresponding tetrahydroisoquino-
line and pyrazolo-tetrahydropyridine series have outlinedthat brain
penetration can be substantially influenced by the substitution of
the phenethyl motif and further evaluation of this moiety was envis-
aged for 5,6,7,8-tetrahydroimidazo[1,5-a]-pyrazines.
In summary, we have described the synthesis and the identifi-
cation of a novel series of dual orexin receptor antagonists based
on the heterocyclic replacement of the dimethoxyphenyl moiety,
present in the tetrahydroisoquinoline series, by a disubstituted
imidazole. Investigations of the imidazole allowed to discover
appropriate substituents affording potent dual orexin receptor
antagonists 18 and 41 with low nanomolar potency for hOX1R
and hOX2R. Efforts to further optimize potency and mainly brain
penetration by fine-tuning of the pivotal phenethyl motif, and
the sleep-promoting activity of leading 5,6,7,8-tetrahydroimi-
dazo[1,5-a]-pyrazines with a rat EEG model will be disclosed in
due course.
Acknowledgments
The authors would like to thank Katalin Menyhart, Celia Müller
and Ronny Haenner for expert technical support and Professor
Henri Ramuz for continuous stimulating discussions.
References and notes
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6. For the purposes of this communication, a dual orexin receptor antagonist
(DORA) is defined as having less than 20-fold selectivity for either OX1R or
OX2R.