Discovery of novel modulators of metabotropic glutamate receptor subtype-5

Article abstract of DOI:10.1016/j.bmc.2003.10.021

A series of potent and selective mGluR5 antagonists were synthesized and evaluated in vitro and in vivo. It was found that a pyridyl functionality is a potential replacement for acetonitrile in the lead structure, with 2-pyridyl being most favored. Additi

Full text of DOI:10.1016/j.bmc.2003.10.021

Bioorganic & Medicinal Chemistry 12 (2004) 17–21
Discovery of novel modulators of metabotropic glutamate receptor
subtype-5
Bowei Wang,a,* Jean-Michel Vernier,a Sara Rao,b Janice Chung,b Jeffery J. Anderson,b
Jesse D. Brodkin,b Xiaohui Jiang,a Michael F. Gardner,a Xiaoqing Yanga and
Benito Munoza,*
aDepartment of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
bDepartment of Neuropharmacology, Merck Research Laboratories, MRLSDB1, 3535 General Atomics Court, San Diego,
CA 92121, USA
Received 30 June 2003; revised 7 October 2003; accepted 11 November 2003
Abstract—A series of potent and selective mGluR5 antagonists were synthesized and evaluated in vitro and in vivo. It was found
that a pyridyl functionality is a potential replacement for acetonitrile in the lead structure, with 2-pyridyl being most favored.
Additionally, the benzoxazole moiety could also be replaced by other heterobicyclic rings such as imidazothiazole.
# 2003 Elsevier Ltd. All rights reserved.
1. Introduction
For example, mGluR5-selective compounds, such as 2-
methyl-6-(phenylethynyl)-pyridine, MPEP (1), are
effective in animal models of mood disorders, including
anxiety and depression.5 Gene expression data from
humans indicate that mGluR5 modulation may be use-
ful for the treatment of schizophrenia.6 Additional
studies have also shown the potential utility of
mGluR5-modulatory compounds for the treatment of
movement disorders such as Parkinson’s disease.7 Other
research supports a role for mGluR5 modulation in the
treatment of cognitive dysfunction,8 epilepsy9 and neu-
roprotection.10 Finally, studies with mGluR5 knockout
mice and 1 also suggest that modulation of these recep-
tors may be useful in the treatment of drug addiction,
drug abuse and drug withdrawal.11
Glutamate is the major excitatory neurotransmitter in
the mammalian nervous system, which binds to neurons
and thereby activates cell surface receptors. Such sur-
face receptors are characterized as either ionotropic or
metabotropic glutamate receptors (mGluRs). mGluRs
are G protein-coupled receptors that activate intracel-
lular secondary messenger systems when bound by glu-
tamate. Activation of mGluRs results in a variety of
cellular responses. In particular, mGluR1 and mGluR5
activate phospholipase C, which is followed by mobili-
zation of intracellular calcium. Modulation of mGluR5
represents a potential approach for the treatment of
diseases that affect the nervous system.1 For example,
recent reports have implicated the involvement of
mGluR5 in nociceptive processes and have shown that
modulation of mGluR5 by mGluR5-selective com-
pounds is useful in the treatment of various pain states,
including acute, persistent and chronic pain,2 inflam-
matory pain3 and neuropathic pain.4
As part of our ongoing drug discovery efforts5 the novel
mGluR5 antagonist [4-(1,3-benzoxazol-2-yl)2-chloro-
phenyl]-acetonitrile (2) was identified by high through-
put screening. Preliminary SAR around this structure
led to replacement of the chloro functional group with
methoxy, as in 7, an analogue that is twice as potent as
2 in vitro. Methoxy was therefore incorporated into the
core structure during subsequent SAR investigation.
Herein, we report on the optimization of this lead into a
novel series of potent and selective mGluR5 antagonists
with in vitro activity that are suitable for further eval-
uation of in vivo efficacy in rat (Fig. 1).
Further evidence supports the use of mGluR5 modulators
for the treatment of psychiatric and neurological disorders.
* Corresponding authors. Tel.: +1-858-202-5272; fax: +1-858-202-
5752; e-mail: bowei_wang@merck.com
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.10.021

18
B. Wanget al. / Bioorg. Med. Chem. 12 (2004) 17–21
2. Chemistry
respectively (Table 1). However, these compounds were
not suitable for in vivo studies because of poor solubi-
lity and poor pharmacokinetic properties in rat. For
example, 2 has low oral bioavailability (F=0.7%) and a
short half-life (T1/2=0.6 h) in rat. Based on in vitro
human and rat liver microsomes metabolism studies, the
major metabolic pathway is proposed to be as follows:
the acetonitrile methylene undergoes metabolic oxida-
tion to release cyanide and afford the aldehyde 18, sub-
sequent oxidation then yeilds the corresponding
carboxylic acid 19 (Scheme 4) which was observed and
identified by LC/MS/MS.
The benzoxazole analogues were made either through a
stepwise amide-coupling reaction followed by dehy-
dration reaction or a one-pot reaction. The stepwise
procedure, as shown in Scheme 1, entails conversion of
3-methoxy-4-methylbenzoic acid to its corresponding
acyl chloride followed by coupling with 2-aminophenol
to give compound 4. PTSA catalyzed-dehydration of
compound 4 gave benzoxazole 5. NBS bromination of
compound 5 and subsequent substitution of the benzyl
bromide by sodium cyanide gave compound 7.
Alternatively, a one-pot procedure was utilized to pre-
pare compounds (11a, 11b, 11c) as shown in Scheme 2.
Treatment of 4-hydroxy-3-methoxybenzoic acid with 2-
aminophenol in the presence of trimethylsilylpolyphos-
phate gave benzoxazole 9.12 Conversion of the phenol
group in 9 to its triflate followed by palladium-catalyzed
coupling reactions with 2-pyridylzinc bromide, 3-pyr-
idylboronic acid or 4-pyridylboronic acid to give com-
pound 11a, or 11b, or 11c, respectively.
Consequently, our efforts were directed at optimization
of 2 and 7 with an emphasis on improving solubility,
oral bioavailability and half-life. In an attempt to
improve the metabolic stability, replacement for the
labile acetonitrile group were sought. Pyridyl groups
were chosen for initial studies because they may increase
The imidazole-fused analogues (16a, 16b, 16c) were
prepared as outlined in Scheme 3. Conversion of 4-ace-
tyl-2-methoxyphenol to its corresponding triflate fol-
lowed by palladium-catalyzed coupling reaction with 2-
pyridylzinc bromide gave compound 14. Bromination of
14 and subsequent cyclization reaction with either 2-
aminothiazole, 2-amino-2-thiazoline, or 2-aminopyr-
idine gave compounds 16a, or 16b, or 16c, respectively.
3. Results and discussion
Scheme 2. Reagents: (a) 2-aminophenol, trimethylsilylpolysphate; (b)
Cs2CO3, N-phenyltrifluoromethanesulfonimide, DMF; (c) 11a: 2-tri-n-
butylstannylpyridine, Pd(PPh3)4, DMF; 11b: 3-pyridylboronic acid,
Pd(PPh3)4, K2CO3, n-Bu4NBr, DMF/H2O; 11c: 4-pyridylboronic acid,
Pd(PPh3)4, K2CO3, n-Bu4NBr, DMF/H2O.
Aryl benzoxazoles 2 and 7 were discovered to be potent
mGluR5 antagonists with IC50 values of 6 and 3 nM,
Figure 1. mGluR5 antagonists.
Scheme 3. Reagents: (a) Cs2CO3, N-phenyltrifluoromethane-sulfoni-
mide, DMF; (b) 2-pyridyl zinc bromide, Pd(PPh3)4, THF; (c) Br2,
AcOH/HBr; (d) 16a: 2-aminopyridine, EtOH; 16b: 2-aminothiazole,
EtOH; 16c: 2-amino-2-thazoline, EtOH.
Scheme 1. Reagents: (a) SOCl2; (b) 2-aminophenol, diisopropylethyl-
amine, THF; (c) p-TsOH, toluene; (d) NBS, benzoyl peroxide, CCl4;
(e) NaCN, DMF.

B. Wanget al. / Bioorg. Med. Chem. 12 (2004) 17–21
19
Table 1. In vitro data for mGlu5 receptor antagonists Table 2. Rat pharmacokinetic and RO data for mGluR5 antagonists
Compd
mGlu5 Ca2+ flux IC50 (nM)a
Ki (nM)b
Compd
F%a
T1/2
(iv)a
Cl
(mL/min/kg)a
RO
(%)b
Brain levels
(mM)b
2
7
6
3
41
416
IAc
22
23
325
30
3
159
254
IAc
91
2
0.7
100
73
0.6
1.5
0.77
2.6
74
70
6
NROc
33
27
BLQd
3.1
2.9
11a
11b
11c
16a
16b
16c
11a
16a
16b
91
7
52
6.8
a Dosed at 2 mg/kg iv and 10 mg/kg po.
b Dosed at 10 mg/kg ip.
94
IAc
c NRO denotes no receptor occupancy.
a Ca2+ flux assay using glutamate (10 mM) as agonist. Concentration-
response curves were performed using 12 concentrations, performed
in duplicate wells in two or more separate experiments.5
b Displacement by test compounds of [3H]-3-methoxy-PEPy bound to
rat cortical membranes.13
d BLQ denotes below low limit of quantitation (<20 nM).
4. Conclusion
c IA denotes inactive at 2 mM concentration.
In summary, a series of potent, bioavailable mGluR5
antagonists have been identified. Based on the in vitro
and in vivo data generated to date, compounds 11a and
16b are being evaluated in a panel of further investigation
in animal models of pain, anxiety and drug dependence.
5. Experimental
5.1. N-(2-Hydroxyphenyl)-3-methoxy-4-methylbenz-
amide (4)
3-Methoxy-4-methylbenzoic acid (3) (1.2 g, 7.2 mmol)
and thionyl chloride (10 mL) was heated to reflux under
Argon for 2 h. The cooled reaction mixture was con-
centrated in vacuo, and the resulting brown oil was dis-
solved in THF (15 mL) and slowly added to a cooled
mixture of 2-aminophenol (780 mg, 7.1 mmol), diiso-
propylethylamine (1.5 mL, 8.6 mmol) and THF (20 mL)
at 0 ꢀC. The resulting reaction mixture was allowed to
warm to rt, after 1 h the reaction mixture was con-
centrated in vacuo, and the resulting brown oil was
purified by flash chromatography on silica gel, using 1:4
EtOAc/hexane, to afford compound 4 as a yellow solid
(1.9 g, 100% yield). MS (ESI) 258 (M+H)+.
Scheme 4. Proposed major metabolite in rat PK study.
the solubility. Introduction of a 2-pyridyl group led to
compound 11a (Table 1) and this represents a sig-
nificant improvement over 2, with regard to the PK
profile: F=100% and T1/2=1.5 h. Further studies
showed that this compound, however, has poor receptor
occupancy (RO)14 about 33% (IP). In addition, there
were no observed in vivo effects in the Fear Potentiated
startle (FPS)15 rat model of anxiety, consistent with
poor RO.
Interestingly the 3- and 4-pyridyl analogues (11b and
11c, Table 1) were much less active than the 2-pyridyl
compound 11a. Further SAR studies showed that imi-
dazopyridine, as in 16a (IC50=22 nM) (Table 1), is an
acceptable isostere for the benzoxazole moiety. Unfor-
tunately, 16a had a poor rat PK profile, and was not
efficacious in the FPS rat model, again consistent with
the low RO (Table 2). However the imidazothiazole
derivative 16b, which is equipotent with 16a (Table 1),
showed good bioavailability (91%), half-life (2.6 h) and
acceptable RO (52%) (Table 2). Interestingly, com-
pound 16c, which has a saturated thiazole ring, is 10-
fold less potent than the parent Compound 16a (Table
1). Compounds 11a and 16b have been tested in a panel
of animal models most notably in the FPS rat models.
Although the compounds were potent against the
receptor, brain penetrant, they did not show any effi-
cacy. This is likely due to the poor receptor occupancy
for the compounds. Efforts are currently being directed
towards improving the RO for the series as well as
potency.
5.2. 2-(3-Methoxy-4-methylphenyl)-1,3-benzoxazole (5)
A solution of 4 (1.5 g, 5.8 mmol) and p-toluenesulfonic
acid monohydrate (7.6 g, 40 mmol) in toluene (30 mL)
was refluxed overnight. The mixture was cooled to rt,
filtered, washed with warm chloroform. The filtrate was
concentrated in vacuo. The resulting brown oil was
purified by flash chromatography on silica gel, using 1:4
EtOAc:hexane, to afford compound 5 as a colorless
solid (690 mg, 50% yield). MS (ESI) 240 (M+H)+.
5.3. 2-[4-(Bromomethyl)-3-methoxyphenyl]-1,3-benzox-
azole (6)
A solution of compound 5 (1.0 g, 4.1 mmol), benzoyl
peroxide (66 mg, 0.3 mmol) and N-bromosuccinimide
(970 mg, 5.4 mmol) in carbon tetrachloride (18 mL) was
heated to reflux conditions under argon and placed
under a UV light for 1 h. The reaction mixture was
cooled to rt, filtered, washed with dichoromethane.
After concentrating the filtrate in vacuo, the resulting

20
B. Wanget al. / Bioorg. Med. Chem. 12 (2004) 17–21
colorless solid was purified by flash chromatography,
using a gradient elution of 1:4 EtOAc/hexane to EtOAc,
to afford compound 6 as a colorless solid (1.3 g, 100%
yield). MS (ESI) 319 (M+H)+.
ether (200 mL) and precipitated as the hydrochloride
salt upon treatment with 1 M HCl in diethyl ether (20
mL). The resulting colorless solid was then treated with
EtOAc (1 L) and heated at refluxing. The reaction clear
solution was cooled to rt, and the solid was collected by
filtration to yield a colorless solid as the desired com-
5.4. 2-[4-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]acetoni-
trile (7)
pound 11a (3.3 g, 32% yield) (mp 215 ꢀC) H NMR
1
(CD3OD, 300MHz) d 8.88 (m, 1H), 8.69 (m, 1H), 8.41
(d, 1H), 8.09 (m, 3H), 7.91 (d, 1H), 7.82 (m, 1H), 7.45
(m, 1H), 7.48 (m, 2H), 4.10 (s, 3H). MS (ESI) 303
(M+H)+.
A solution of 6 (318 mg, 1 mmol) in DMF (7.5 mL) and
deionzed water (2.5 mL) was treated with sodium cya-
nide (150 mg, 3.0 mmol) at rt under argon for 3 h. DMF
(10 mL) was added to help dissolve the solids, and the
reaction mixture was stirred overnight at rt. Workup
was done by washing reaction with satd brine (3Â30
mL), extraction with EtOAc. The combined organic
extracts were dried (Na2SO4), filtered and concentrated
in vacuo. Flash chromatography of resulting orange
solid on silica gel, using a gradient elution of 1:9
EtOAc/hexane to 1:3 EtOAc/hexane, afforded the
desired product 7 as a yellow solid (264 mg, 100%
yield). 1H NMR (CDCl3, 300 MHz) d 7.86–7.36 (m,
7H), 3.99 (s, 3H), 3.74 (s, 2H), 2.59À1.91 (m, 8H). MS
(ESI) 265 (M+H)+.
5.8. 2-(3-Methoxy-4-pyridin-3-ylphenyl)-1,3-benzoxazole
(11b)
A solution of 10 (148 mg, 0.4 mmol) in 6mL of 2:1
DMF:H2O (5 mL) was degassed via argon for 10
min. K2CO3 (137 mg, 0.99 mmol), Pd(Ph3P)4 (23 mg,
0.02 mmol), n-Bu4NBr (128 g, 0.40 mmol) and 3-
pyridylboronic acid (73 mg, 0.60 mmol) were added
at rt. The resulting mixture was then heated at 75 ꢀC
for 1 h under argon. The reaction mixture was
cooled to rt and filtered through a pad of Celite. The
filtrate was concentrated in vacuo and purified by
flash chromatography on silica gel, using 1:3 EtOAc/
hexane, to afford compound 11b as a yellow solid (35
5.5. 4-(1,3-Benzoxazol-2-yl)-2-methoxyphenol (9)
1
3-Hydroperoxy-4-hydroxybenzoic acid (8) (25 g, 149
mmol) and 2-amino phenol (16.2 g, 149 mmol) were
combined in a round bottom flask. Trimethylsilyl poly-
phosphate (80 mL) was added neat. The mixture was
heated at 180 ꢀC for 30 min. The mixture was poured
over ice and allowed to stir overnight. The suspension
was filtered to afford compound 9 as a pale green solid
(31.4 g, 100% yield). MS (ESI) 242 (M+H)+.
mg, 29% yield). H NMR (CDCl3, 300 MHz) d 8.83 (d,
1H), 8.60 (dd, 1H), 7.92 (m, 3H), 7.81 (m, 1H), 7.62 (m,
1H), 7.48 (d, 1H), 7.39 (m, 3H), 3.98 (s, 3H). MS (ESI)
303 (M+H)+.
5.9. 2-(3-Methoxy-4-pyridin-3-ylphenyl)-1,3-benzoxazole
(11c)
1
See 11b. H NMR (CDCl3, 300 MHz) d 8.68 (m, 2H),
7.95 (dd, 1H), 7.90 (m, 1H), 7.81 (m, 1H), 7.62 (m, 1H),
7.52 (m, 3H), 7.41 (m, 2H), 4.00 (s, 3H). MS (ESI) 303
(M++H).
5.6. 4-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl trifluoro-
methanesulfonate (10)
A solution of 9 (7.1 g, 29.4 mmol) in anhydrous DMF
(100 mL) was treated with Cs2CO3 (9.6 g, 29.4 mmol)
and N-phenyl trifluoromethanesulfonimide (10.5 g, 29.4
mmol) at rt. After 30 min the reaction mixture was
quenched with sat. NaHCO3 (50 mL) and the product
was extracted with EtOAc (500 mL). The EtOAc solu-
tion was washed with sat. brine (3Â100 mL), dried
(MgSO4), filtered and concentrated in vacuo. The resi-
due was chromatographed on silica gel, using 1:4
EtOAc/hexane, to afford compound 10 as a colorless oil
(10.8 g, 100% yield). MS (ESI) 374 (M+H)+.
5.10. 4-Acetyl-2-methoxyphenyl trifluoromethanesulfonate
acetovanillone (13)
Acetovanillone 12 (10 g, 0.06 mol), N-phenyltri-
fluoromethanesulfonimide (21.5 g, 0.06 mol) and
Cs2CO3 (19.5 g, 0.06 mol) were dissolved in acetonitrile
(90 mL) and DMF (10 mL). The resulting solution was
then stirred at rt for 12 h, diluted with diethyl ether (100
mL) and was washed successively with satd Na2CO3
(100 mL) and sat. brine (100 mL). The organic layer was
dried (MgSO4), concentrated and purified by flash col-
umn chromatography on silica gel, using a gradient
elution of 1:9 EtOAc/hexane to 3:7 EtOAc/hexane, to
afford compound 13 as a colorless oil (17.9 g, 100%
yield). MS (ESI) 299 (M+H)+.
5.7. 2-(3-Methoxy-4-pyridin-2-ylphenyl)-1,3-benzoxazole
hydrochloride salt (11a)
A solution of 10 (11.7 g, 31.3 mmol) in anhydrous DMF
(150 mL) was degassed via argon for 10 min. Then 2-tri-
n-butylstannylpyridine (11.5 g, 31.3 mmol) and
Pd(Ph3P)4 (3.6 g, 3.1 mmol) were added at rt. The
resulting mixture was then heated at 100 ꢀC for 1 h
under Argon, cooled to rt and filtered through a pad of
Celite. The filtrate was concentrated in vacuo after
purification by flash chromatography on silica gel, using
1:3 EtOAc/hexane, to afford the desired compound as
an off-colorless solid which was then dissolved in diethyl
5.11. 1-(3-Methoxy-4-pyridin-2-ylphenyl)ethanone (14)
A solution of 13 (5.8 g, 19.5 mmol) in THF (100 mL)
was degassed by bubbling Argon through the solution
for 15 min, then treated with 2-pyridyl zinc bromide (3
mL of 0.5 M in THF, 19.5 mmol) and Pd(PPh3)4 (1.1 g,
0.97 mmol). The resulting reaction mixture was degas-
sed for further 5 min and heated to reflux for 12 h under

B. Wanget al. / Bioorg. Med. Chem. 12 (2004) 17–21
21
Argon. The reaction mixture was cooled to rt and fil-
Acknowledgements
tered through a pad of Celite. The filtrate was con-
centrated in vacuo, purified by flash chromatography
on silica gel, using a gradient elution of 1:9 EtOAc/
hexane to 2:3 EtOAc/hexane, to afford compound 14
as a white solid (4 g, 90.5% yield). MS (ESI) 228
(M+H)+.
The authors would like to thank Merryl Cramer for
providing PK support. In addition, the authors are
grateful to Dr. John Hutchinson, Dr. Peppi Prasit, Dr.
NickCosford and Dr. Janet Gunzner for ikndly
reviewing this manuscript and providing suggestions.
5.12. 2-Bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)etha-
none (15)
References and notes
A solution of 14 (400 mg, 1.7 mmol) in benzene (6 mL)
and 30% HBr/Acetic acid (6 mL) was cooled to 0 ꢀC
and was treated with a solution of bromine (0.086 mL,
1.67 mmol) in benzene (1 mL) over 1 h via syringe
pump. The reaction was stirred for an additional 30
min, then poured into an iced solution of satd
NaHCO3 (100 mL), and the product was extracted into
EtOAc (3Â50 mL). The combined organic layers were
dried (MgSO4) and concentrated to afford compound
15 as a brownish oil (470 mg, 87.2% yield). MS (ESI)
307 (M+H)+.
1. Spooren, W. P. J. M.; Gasparini, F.; Salt, T. E.; Kuhn, R.
Trends Pharmacol. Sci. 2001, 22, 331.
2. Walker, K.; Bowes, M.; Panesar, M.; Davis, A.; Gentry,
C.; Kesingland, A.; Gasparini, F.; Spooren, W. P. J. M.;
Stoehr, N.; Pagano, A.; Flor, P. I.; Varanesic, I.; Lingen-
hoehl, K.; Johnson, E. C.; Varney, M.; Urban, L.; Kuhn,
R. Neuropharmacology 2001, 40, 1. Bordi, F.; Ugolini, A
Brain Res. 2001, 871, 223.
3. Walker, K.; Reeve, A.; Bowes, M.; Winter, J.; Wother-
spoon, G.; Davis, A.; Schmid, P.; Gasparini, F.; Kuhn,
R.; Urban, L. Neuropharmacology 2001, 40, 10. Bhave,
G.; Karim, F.; Carlton, S. M.; Gereau, R. W. Nat. Neu-
rosci. 2001, 4, 417.
4. Dogrul, A.; Ossipov, M. H.; Lai, J.; Malan, T. P., Jr.;
Porreca, P. Neurosci. Lett. 2000, 292, 115.
5. Cosford, N. D.; Tehrani, L.; Roppe, J.; Schweiger, E.;
Smith, N. D.; Anderson, J. J.; Bristow, L.; Brodkin, J.;
Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney,
M. A. J. Med. Chem. 2003, 46, 204.
6. Ohnuma, T.; Augood, S. J.; Arai, H.; McKenna, P. J.;
Emson, P. C. Mol. Brain. Res. 1998, 56, 207.
7. Spooren, W. P. J. M.; Gasparini, F.; Bergmann, R.;
Kuhn, R. Europ. J. Pharmacol. 2000, 406, 403. Awad, H.;
Hubert, G. W.; Smith, Y.; Levey, A. I.; Conn, P. I. J.
Neurosci. 2000, 20, 7871.
8. Riedel, G.; Casabona, G.; Platt, B.; Macphail, E. M.;
Nicoletti, F. Neuropharmacology 2000, 39, 1943. Chap-
man, A. G.; Nanan, K.; Williams, M.; Meldrum, B. S.
Neuropharmacology 2000, 39, 1567.
9. Chapman, A. G.; Nanan, K.; Williams, M.; Meldrum,
B. S. Neuropharmacology 2000, 39, 1567.
5.13. 2-(3-Methoxy-4-pyridin-2-ylphenyl)imidazo[1,2-a]-
pyridine (16a)
Compound 15 (520 mg, 1.7 mmol) and 2-aminopyridine
(160 mg, 1.7 mmol) in ethanol (10 mL) was heated to
reflux for 12 h, then concentrated. The residue was dis-
solved in EtOAc (25 mL), washed with a solution of
satd NaHCO3 (25 mL), dried (MgSO4) and con-
centrated. The residue was purified by flash column
chromatography on silica gel, using EtOAc to MeOH/
EtOAc (1:19), to afford compound 16a as a yellow solid
1
(160 mg, 31.3% yield). H NMR (CDCl3, 300 MHz) d
8.72 (d, 1H), 8.13 (d, 1H), 7.75 (s, 1H), 7.91 (d, 1H),
7.87 (d, 1H), 7.75 (s, 1H), 7.70 (dd, 1H), 7.66 (d, 1H),
7.57 (dd, 1H), 7.20 (m, 2H), 6.79 (dd, 1H), 4.00 (s, 3H)
ppm. MS (ESI) 302 (M)+.
10. Bruno, V.; Ksiazek, I.; Battaglia, G.; Lukic, S.; Leon-
hardt, T.; Sauer, D.; Gasparini, F.; Kuhn, R.; Nicoletti,
F.; Flor, P. I. Neuropharmacology 2000, 39, 2223.
11. Chiamulera, C.; Epping-Jordan, M. P.; Zocchi, A.; Mar-
con, C.; Cottiny, C.; Tacconi, S.; Corsi, M.; Orzi, F.
Conquet. Nat. Neurosci. 2001, 4, 873.
12. Cho, C. S.; Kim, D. T.; Zhang, J. Q.; Ho, S.-L.; Kim, T.-
J.; Shim, S. C. J. Heterocycl. Chem. 2002, 39, 421.
13. Cosford, N. D.; Roppe, J.; Tehrani, L.; Schweiger, E. J.;
Seiders, T. J.; Chaudary, A.; Rao, S.; Varney, M. A.
Bioorg. Med. Chem. Lett. 2003, 13, 351.
14. Anderson, J. J.; Bradbury, M. J.; Giracello, D. R.; Chap-
man, D. F.; Holtz, G.; Roppe, J.; King, C.; Cosford,
N. D.; Varney, M. A. Eur. J. Pharmacol. 2003, 473, 34.
15. Brodkin, J.; Busse, C.; Sukoff, S. J.; Varney, M. A. Phar-
macol. Biochem. Behavior 2002, 73, 359.
5.14. 6-(3-Methoxy-4-pyridin-2-ylphenyl)imidazo[2,1-b]-
[1,3]thiazole (16b)
See 16a. 24.7%. 1H NMR (CDCl3, 300 MHz) d 8.73 (m,
1H), 7.92 (d, 1H), 7.89 (d, 1H), 7.86 (s, 1H), 7.73 (dt, 1H),
7.64 (s, 1H), 7.48 (s, 1H), 7.46 (d, 1H), 7.22 (m, 1H), 6.87
(d, 1H), 4.04 (s, 3H) ppm. MS (ESI) 308 (M)+.
5.14.1. 6-(3-methoxy-4-pyridin-2-ylphenyl)-2,3-dihydro-
1
imidazo[2,1-b][1,3]thiazole (16c). See 16a. 30% yield. H
NMR (CD3OD, 300 MHz) d 8.86 (d, 1H), 8.67 (t, 1H),
8.35 (d, 1H), 8.17 (s, 1H), 8.04 (m, 1H), 7.84 (m, 1H),
7.62 (s, 1H), 7.54 (m, 1H), 4.60 (m, 2H), 4.26 (m, 2H),
4.07 (s, 3H) ppm. MS (ESI) 310 (M)+.