Synthesis and pharmacological evaluation of phenylethynyl[1,2,4] methyltriazines as analogues of 3-methyl-6-(phenylethynyl)pyridine

Article abstract of DOI:10.1021/jm070078r

Procedures were developed for the synthesis of 3-methyl-5-phenylethynyl[1, 2,4]triazine (4), 6-methyl-3-phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-phenylethynyl[1,2,4]triazine (6a) as analogues of 2-methyl-6-(phenylethynyl)pyridine (2). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The most potent of the three analogues was 6a. Twenty additional analogues of 6a were synthesized and evaluated for mGluR5 antagonist efficacy. The most potent compounds were 3-(3-methylphenylethynyl)-5-methyl[1,2, 4]triazine (6b), 5-(3-chlorophenylethynyl)-5-methyl[1,2,4]triazine (6c), and 3-(3-bromophenylethynyl)-5-methyl[1,2,4]triazine (6d).

Full text of DOI:10.1021/jm070078r

3
388
J. Med. Chem. 2007, 50, 3388-3391
Brief Articles
Synthesis and Pharmacological Evaluation of Phenylethynyl[1,2,4]methyltriazines as Analogues
of 3-Methyl-6-(phenylethynyl)pyridine
,
†
†
†
†
†
‡,§
F. Ivy Carroll,* Sharadsrikar V. Kotturi, Hern a´ n A. Navarro, S. Wayne Mascarella, Brian P. Gilmour, Forrest L. Smith,
‡
‡
Bichoy H. Gabra, and William L. Dewey
Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709,
and Department of Pharmacology and Toxicology, Virginia Commonwealth UniVersity Medical Center, Richmond, Virginia 23298
ReceiVed January 19, 2007
Procedures were developed for the synthesis of 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-3-
phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-phenylethynyl[1,2,4]triazine (6a) as analogues of 2-methyl-
6-(phenylethynyl)pyridine (2). The compounds were evaluated for antagonism of glutamate-mediated
mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The most potent of the three analogues
was 6a. Twenty additional analogues of 6a were synthesized and evaluated for mGluR5 antagonist efficacy.
The most potent compounds were 3-(3-methylphenylethynyl)-5-methyl[1,2,4]triazine (6b), 5-(3-chlorophe-
nylethynyl)-5-methyl[1,2,4]triazine (6c), and 3-(3-bromophenylethynyl)-5-methyl[1,2,4]triazine (6d).
Glutamate (1), the major excitatory transmitter in the central
nervous system, acts on ionotropic and metabotropic glutamate
receptors. Several studies have been reported that suggest that
a
metabotropic glutamate 5 receptors (mGluR5) play an important
role in regulating the reinforcing actions of drugs of abuse. The
selective noncompetitive mGluR5 antagonist MPEP (2) was
reported to decrease cocaine self-administration in wild-type
1
2
mice, decrease cocaine self-administration in rats, decrease
3
nicotine self-administration in rats and mice, attenuate cocaine-
4,5
and morphine-induced condition place preference in mice, and
decrease ethanol drinking and ethanol-seeking (a relapse model)
in rats. Iso et al.7 showed that the more potent mGluR5
antagonist MTEP (3) prevented reinstatement of cocaine self-
administration induced by environmental cues associated with
cocaine availability.
6
In this paper we present the synthesis and evaluation of
the 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-3-
phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-(substituted
phenylethynyl)[1,2,4]triazine (6a-u) for antagonism of glutamate-
mediated mobilization of internal calcium in an mGluR5 in vitro
efficacy assay.
Chemistry
Diazotization of 911 using isoamyl nitrite in diiodomethane
afforded 3-iodo-6-methyl[1,2,4]triazine (10). Coupling of 10
The addition of lithium phenylacetylide to 78 followed by
oxidation with alkaline potassium ferricyanide10 yielded the
desired 4 and trans-3-methyl-5-styryl[1,2,4]triazine (8), which
were separated by chromatography (Scheme 1).
,9
12
with phenylacetylene using bis(triphenylphosphine)palladium-
(II) chloride and triethylamine in refluxing tetrahydrofuran
1
3,14
yielded 5 (Scheme 2).
Compounds 6a-u were synthesized as shown in Scheme 3.
1
5
*
To whom correspondence should be addressed. Telephone: 919-541-
Condensation of 11 with pyruvic aldehyde gave a mixture of
the desired 5-methyl-3-methylthio[1,2,4]triazine (12) and 6-meth-
yl-3-methylthio[1,2,4]triazine (13), which were separated by
fractional recrystallization from a 2-propanol and heptane
mixture (9:1). Oxidation of 12 with m-chloroperoxybenzoic acid
6
679. Fax: 919-541-8868. E-mail: fic@rti.org.
†
Research Triangle Institute.
Virginia Commonwealth University Medical Center.
Present address: Department of Pharmaceutics, Harding University
‡
§
College of Pharmacy, Searcy, AR 72194.
a
Abbreviations: CHO-K1, Chinese hamster ovary; mGluR1, metabo-
15
provided the sulfone 14. Displacement of the methylsulfonyl
tropic glutamate 1 receptor; mGluR5, metabotropic glutamate 5 receptor;
MPEP, 3-methyl-6-(phenylethynyl)pyridine; MTEP, (2-methyl-1,3-thiazol-
group with the appropriate lithium substituted phenylacetylide
4
-yl)ethynlpyrridine.
generated from butyllithium in tetrahydrofuran at -78 °C
1
0.1021/jm070078r CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/15/2007

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14 3389
Scheme 1a
nature of the inhibition caused by active test compounds was
determined by running glutamate concentration response curves
in the presence and absence of a single concentration of test
compound. Insurmountable antagonism of the effect of glutamate
indicated a noncompetitive mode of inhibition. The IC50 values
were calculated using Prism (GraphPad Software, San Diego,
CA). Compounds active at the mGluR5 were screened at the
human mGluR1 to determine selectivity. The specifics of how
the cell lines expressing the human mGluR5 and mGluR1 were
created and our calcium dye assay procedures are detailed in
the Supporting Information.
a
Reagents: (a) n-C4H9Li, C6H5CtCH, -78 to 0 °C (30 min); (b)
K3FeCN6, NaOH, H2O, 24 h.
Scheme 2a
Results and Discussion
a
The compounds were evaluated for antagonism of glutamate-
mediated mobilization of internal calcium in an mGluR5 in vitro
efficacy assay (Table 1). The 3-methyl-5-phenylethynyl-, 6-meth-
yl-3-phenylethynyl-, and 5-methyl-3-phenylethynyl[1,2,4]triazine
Reagents: (a) CH2I2, isoamyl nitrite, reflux, 2 h; (b) C6H5CtCH,
Pd[P(C6H5)3]4, CuI, Et3N, THF, reflux 3-4 h.
Scheme 3a
(4, 5, and 6a, respectively) were first synthesized and evaluated
to determine the effect of placing the methyl and phenylethynyl
groups at different positions on the [1,2,4]triazine ring. Com-
pound 6a had an IC50 of 140 nM. The other two compounds, 4
and 5, were totally inactive. On the basis of the assumption
that the addition of substituent to 6a might lead to compounds
with improved efficacy in their ability to antagonize the
mGluR5, the 5-methyl-3-(substituted phenylethynyl)[1,2,4]-
triazines (6b-u) were synthesized and evaluated. The most
interesting compounds were 3-methyl, 3-chloro, and 3-bro-
mophenylethynyl analogues 6b-d with IC50 values of 2.3, 4.2,
and 6 nM, respectively. The 3-methylphenylethynyl analogue
a
Reagents: (a) CH3COCOH, NaHCO3, 0-25 °C (4 h); (b) m-Cl-
C6H4CO3H, CH2Cl2, 0-25 °C (1-2 h); (c) n-C4H9Li, C6H5CtCH, -78
C, THF.
°
6
b was almost as potent as MPEP, which had an IC50 of
Table 1. Inhibition of Human mGluR5-Mediated Intracellular Calcium
Mobilization for Phenylethylnyl[1,2,4]methyltriazinesa
1.5 nM. The smaller, stronger electron-withdrawing 3-fluo-
compd IC50 (nM) LogD(7.4) b compd
LogD(7.4) b
rophenylethynyl analogue 6e was 22 times less potent than the
IC50 (nM)
IA
3-chlorophenylethynyl analogue 6c. Similarly, the 3-trifluorom-
2
4
5
6
6
6
6
6
6
6
6
6
1.5 ( 0.4
IA
IA
3.75
2.01
2.69
2.69
3.15
2.42
3.46
2.74
3.26
2.60
2.13
3.15
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
2.60
3.26
4.45
4.68
3.20
3.61
3.06
2.83
4.11
3.92
3.92
2.55
ethylmethyl- and 3-cyanophenylethynyl analogues 6f and 6h
were 24 and 20 times less potent than the 3-methylphenylethynyl
analogue 6b. The least favored of the 3-substituted analogues
was the electron-releasing 3-methoxyphenylethynylphenyl ana-
logue 6g, which was almost 200 times less potent than the
IA
510 ( 40
80 ( 20
132 ( 20
1890 ( 530
IA
a
b
c
d
e
f
g
h
i
140 ( 20
2.3 ( 0.1
4.2 ( 1.0
6.0 ( 1.0
96 ( 20
85 ( 20
312 ( 120
52 ( 20
IA
3
-methylphenylethynyl analogue 6b. Surprisingly, the 4-phe-
IA
IA
noxyphenylethynyl analogue 6m with an IC50 of 80 nM was
the most potent of the 4-substituted analogues studied. The only
disubstituted phenylethynyl analogue to show any efficacy was
the 4-fluoro-3-methylphenylethynyl analogue 6n, which had an
IC50 of 132 nM. Compound 6n results from the addition of a
8900 ( 3700
IA
IA
6t
6u
a
IA, inactive. b Calculated at pH 7.4 with ACD/LogD.
4
-fluoro substituent to the 3-methylphenylethynyl analogue (6b).
yielded the desired 5-methyl-3-(substituted phenylethynyl)[1,2,4]-
triazines (6a-u).
When viewed from this prospective, the addition of the 4-fluoro
substituent to 6b reduces its efficacy 60-fold.
The LogD for 4, 5, and 6a-u along with the standard
compound 2 were calculated using ACD/LogD (ACD/Labs,
Toronto, Canada), and the results are listed in Table 1. With
the exception of compounds 6l, 6m, and 6r-t, all com-
pounds possessed lower calculated LogD(7.4) compared with
MPEP.
Compounds 6a-h,l-o,s were also evaluated for antagonism
of glutamate-mediated mobilization of internal calcium in an
mGluR1 in vitro efficacy assay. None of the compounds tested
possessed any efficacy at mGluR1.
MTEP showed a LogD of 2.1 and was more potent than
MPEP (LogD ) 3.75) in an in vivo binding assay and in the
1
3
fear-potentiated startle model of anxiety. It is interesting to
note that the 3-methyl-, 3-chloro-, and 3-bromophenyl com-
pounds 6b-d, which have IC50 values of less than 6 nM in the
mGluR5 assay, have LogD values of 3.15, 2.42, and 3.46,
respectively.
In Vitro Pharmacology
CHO-K1 cells were stably transfected with the human
mGluR5, and these cells were used to determine the effects of
MPEP and test compounds on glutamate-stimulated mobilization
of internal calcium (Table 1). Changes in internal calcium levels
were measured using the Calcium 3 dye kit (Molecular Devices
Corporation, Sunnyvale, CA) at one-half the recommended dye
concentration. The IC50 values were determined by measuring
the effect of 10 different concentrations of test compound on
internal calcium flux caused by 3 µM glutamate (∼EC80). The
In summary, synthetic procedures were developed for prepa-
ration of 3-methyl-5-phenylethynyl[1,2,4]triazine (4), 6-methyl-
3-phenylethynyl[1,2,4]triazine (5), and 5-methyl-3-(substituted
phenylethynyl)[1,2,4]triazines (6a-u). The meta-substituted
3-methyl-, 3-chloro-, and 3-bromophenyl analogues 6b-d, all
possessed low nanomolar IC50 values in an mGluR5 efficacy

3
390 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14
Brief Articles
Table 2. 5-Methyl-3-(substituted phenylethynyl)[1,2,4]triazine Analogues, Yields, and Analytical Dataa
compd
yield (%)
mp (°C)
recrystallization solvent
molecular formula
analysis
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
45
31
15
14
23
3
20
16
16
35
9
154-156
115-116
119-120
124-126
141-143
73-74
133-135
142-144
99-100
112-113
115-116
170-172
167-169
123-124
105-106
123-124
170-172
108-110
141-143
138-139
163-164
(CH3)2CHOH
EtOAc
(CH3)2CHOH
(CH3)2CHOH-C7H16
EtOAc
EtOAc-C7H16
EtOAc
(CH3)2CHOH-C7H16
(CH3)2CHOH
(CH3)2CHOH
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
(CH3)2CHOH
EtOAc
(CH3)2CHOH
(CH3)2CHOH
C12H9N3
C13H11N3
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C12H8ClN3
C12H8BrN3‚0.5H2O
C13H8F3N
C13H8F3N3
C13H11N3O
C13H8N4‚0.5H2O
C13H11N3
C13H11N3O
C13H8F3N3
C18H13N3
C18H13N3O
C13H10FN3
C14H13N3
C14H13N3O
C12H7F2N3
C14H7F6N3
C16H11N3
C16H11N3
C13H9N3O2
8
30
20
30
40
8
1
23
15
14
t
u
2 H, J ) 1.4 Hz), 7.46-7.42 (m, 3 H), 2.91 (s, 3 H); 13C NMR
(CDCl ) δ 167.0, 148.3, 144.2, 132.7, 130.8, 129.1, 128.7, 128.0,
20.3, 98.9, 84.6, 23.9. Anal. (C12 ) C, H, N.
The second fraction was obtained as an oil and had a complex
spectra. The third fraction on concentration yielded a golden-yellow
solid, which was recrystallized from (CH CHOH to give 3.20 g
33%) of trans-3-methyl-5-styryl[1,2,4]triazine (8): mp 98-99 °C;
assay. The compounds were selective for the mGluR5 relative
to the mGluR1 and possessed LogD values less than that of
MPEP.
3
1
9 3
H N
Experimental Section
3 2
)
Commercial reagents and solvents were used as received. All
(
reactions were run under dry N
2
in oven-dried glassware. The
Cl (saturated) used
1
H NMR (CDCl
3
) δ 9.12 (s, 1 H), 8.03 (d, 1 H, J ) 16.1 Hz),
NaHCO (saturated), NaCl (saturated), and NH
3
4
7
1
1
.64-7.61 (m, 2 H), 7.43-7.41 (m, 3 H), 7.03 (d, 1 H, J )
in various procedures refer to saturated aqueous solutions. Unless
otherwise specified, all organic solvents were anhydrous and used
as received. Reactions were monitored by TLC on silica gel GF
plates. Preparative separations were performed using flash column
chromatography on silica gel (grade 62, 60-200 mesh) or prep-
erative thin layer chromatography (PTLC) on 20 cm × 20 cm silica
gel GF plates. Fraction elution was monitored using a hand-held
13
6.1 Hz), 2.87 (s, 3 H); C NMR (CDCl
3
) δ 167.3, 154.4, 145.7,
41.3, 135.4, 130.7, 129.4, 128.4, 122.9, 24.3. Anal. (C12
11 3
H N )
C, H, N.
3
-Iodo-6-methyl[1,2,4]triazine (10). The general procedure of
12
Nair and Richardson was followed. To a well-stirred mixture of
.50 g (0.005 mol) of 9 in 25 mL of CH was added 8.13 g
0
2 2
I
1
13
(0.07 mol, 9.3 mL) of isoamyl nitrite. The mixture was refluxed
for 2 h when TLC indicated absence of starting material. Column
chromatography eluting with hexanes enabled the recovery of
UV lamp. Melting points were uncorrected. H NMR and C NMR
spectra were measured using a Bruker Advance DPX-300 MHz
spectrometer in CDCl
tively, and were referenced to internal (CH )
3
or DMSO-d
6
at 300 and 75 MHz, respec-
Si. Elemental analysis
2 2
CH I . This was followed by elution with increasing concentrations
3 4
of EtOAc in hexanes to give 0.20 g (20%) of 10: mp 59-60 °C;
was conducted by Atlantic Microlab, Norcross, GA. Results were
within (0.4% of calculated values.
1
13
H NMR (DMSO-d
DMSO-d ) δ 158.0, 151.9, 133.4, 18.6.
-Methyl-3-phenylethynyl[1,2,4]triazine (5). The general pro-
6
) δ 8.55 (s, 1 H), 2.56 (s, 3 H); C NMR
(
6
3
-Methyl-5-phenylethynyl[1,2,4]triazine (4) and trans-3-
6
Methyl-5-styryl[1,2,4]triazine (8). To a well-stirred and cooled
solution of 5.00 g (0.05 mol) of phenylacetylene in anhydrous THF
at -78 °C was added 30.60 mL of 1.6 M solution of BuLi in
hexanes, and the mixture was stirred for 30 min. The mixture was
1
3
14
cedure of Cosford and Lautens was followed. To a stirred
solution of 280 mg (1.27 mmol) of 10 in 10 mL of dry anhydrous
2
THF under a steady stream of dry N was added 18 mg
(
0.016 mmol) of Pd(PPh . After a few minutes, 1 mL of TEA
3 4
)
2
transferred by cannulation under N to a well-stirred and cooled
and 10 mg (0.05 mmol) of CuI were added, and the mixture was
stirred for 5 min. This was followed by a dropwise addition of
phenylacetylene (0.14 mL, 1.27 mmol) over 5 min, and the mixture
was gently refluxed for 4 h. TLC using 75:25 hexanes/EtOAc as
eluent indicated the absence of 10. Concentration of the mixture
under reduced pressure was followed by column chromatography.
Elution with hexanes and increasing concentrations of EtOAc
resulted in 5 being eluted as the third fraction, which was
solution of 4.60 g (0.05 mol) of 7 in 50 mL of anhydrous THF
maintained at -78 °C. After the addition was complete, the mixture
was stirred at -78 °C for 30 min, allowed to warm to 0 °C in an
ice bath, and stirred for another 30 min. Addition of 0.7 mL of
H
2
O was followed by 0.3 mL of NH
were separated while still cold. The cold organic layer was dried
over anhydrous Na SO , filtered over Celite, and used directly for
the next step. The organic layer was stirred with 4.55 g of K
FeCN , 65 mL of 3 N NaOH, and 100 mL of water for 24 h
according to the procedure of Konno and co-workers. The organic
layer was separated, and the aqueous layer was extracted with Et
2 × 100 mL). The organic layers were collected, washed with
NaCl solution, dried over anhydrous Na SO , filtered over Celite,
4
Cl solution, and the layers
2
4
3
-
recrystallized from EtOAc and heptane to give 200 mg (80%) of
6
1
10
5: mp 144-146 °C; H NMR (DMSO-d ) δ 8.50 (s, 1 H), 7.70 (d,
6
1
2
1
H, J ) 1.5 Hz), 7.68 (d, 1 H, J ) 1.8 Hz), 7.45-7.37 (m, 3 H),
.77 (s, 3 H); 13C NMR (DMSO-d
) δ 156.5, 153.2, 149.2, 133.0,
30.5, 128.9, 121.3, 92.2, 86.0, 20.0. Anal. (C12 ) C, H, N.
5-Methyl-3-methylthio[1,2,4]triazine (13) and 6-Methyl-3-
2
O
(
6
9 3
H N
2
4
and concentrated to yield a thick brown oil. Chromatographic
separation of this oil on silica gel, eluting with hexanes and
increasing concentrations of EtOAc, resulted in three fractions. The
first fraction on concentration yielded a yellow solid, which was
methylthio[1,2,4]triazine (12). To a well-stirred, ice-cold suspen-
sion of 10.8 g (0.06 mol) of 40% solution of commercially available
pyruvic aldehyde and 5.00 g (0.06 mol) of solid NaHCO
3
in
recrystallized from (CH
of 3-methyl-5-phenylethynyl[1,2,4]triazine (4): mp 88-90 °C; H
NMR (CDCl ) δ 9.15 (s, 1 H), 7.67 (d, 2 H, J ) 1.2 Hz), 7.64 (d,
3 2
) CHOH and heptane to give 1.6 g (17%)
60 mL of anhydrous EtOH was added dropwise a solution of
1
15
2
14.0 g (0.06 mol) 11 in 60 mL of H O over a period of 45 min.
3
After completion of addition, the ice bath was removed, and the

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 14 3391
mixture was allowed to warm to room temperature and stirred for
elemental analysis data for 4, 5, 6a-u, and 9. This material is
4
h. Removal of EtOH under reduced pressure was followed by
extraction of the aqueous residue with CH Cl
(3 × 100 mL). The
organic layers were separated, dried over anhydrous Na SO , and
available free of charge via the Internet at http://pubs.acs.org.
2
2
2
4
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3 2
) CHOH/heptane (9:1) resulted in
1
5-methyl-3-methylthio[1,2,4]triazine (12) containing 3% of 13: H
13
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NMR (CDCl
5
3
) δ 8.81 (s, 1 H), 2.67 (s, 3 H), 2.50 (s, 3 H);
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C
3
-Methyl-3-methylsulfonyl[1,2,4]triazine (14).15 To a well-
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1
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) δ 166.7,
63.3, 152.5, 40.0, 22.5.
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3
) δ 9.34
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(
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the synthesis of 6a is given below. Compounds 6b-u were prepared
by a similar procedure. The percent yields, recrystallization solvents,
and analytical data for each compound are given in Table 2.
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5-Methyl-3-phenylethynyl[1,2,4]triazine (6a). To a well-stirred
and cooled solution of 1.30 g (0.013 mol) of phenylacetylene in
anhydrous THF at -78 °C was added 8.73 mL of 1.6 M solution
of BuLi in hexanes, and the mixture was stirred for 30 min. A
white suspension formed after 25 min of stirring. This mixture was
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derivatives. X. Addition reaction of phenylmagnesium bromide with
(
2
transferred by cannulation under N pressure to a well-stirred and
cooled solution of 2.00 g (0.012 mol) of 14 in 50 mL of anhydrous
THF at -78 °C. The mixture was stirred at -78 °C and was slowly
allowed to warm to room temperature. After the mixture was stirred
1
,2,4-triazines. Heterocycles 1987, 26, 3111-3114.
11) Erickson, J. G. 3-Amino-as-triazines. J. Am. Chem. Soc. 1952, 74,
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for 6 h at room temperature, 25 mL of NaHCO
and the organic layers were separated, collected, dried over
anhydrous Na SO , and concentrated to obtain a reddish-yellow
3
solution was added,
(
(
4
2
4
12) Nair, V.; Richardson, S. G. Modification of nucleic acid bases via
radical intermediates: synthesis of dihalogenated purine nucleosides.
Synthesis 1982, 670-672.
(13) Cosford, N. D.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.;
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S.; Washburn, M.; Varney, M. A. 3-[(2-Methyl-1,3-thiazol-4-yl)-
ethynyl]-pyridine: a potent and highly selective metabotropic
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solid. Column chromatography on silica gel, eluting with hexanes
and increasing concentrations of EtOAc, afforded 1.00 g (45%) of
6
a as a yellow solid, which was recrystallized from (CH
3
)
2
CHOH
) δ 9.05 (s, 1 H),
.71 (d, 1 H, J ) 1.44 Hz), 7.69 (d, 1 H, J ) 1.81 Hz), 7.43-7.40
1
and heptane: mp 154-156 °C; H NMR (CDCl
3
7
(
m, 3 H), 2.61 (s, 3 H); 1 C NMR (CDCl
3
3
) δ 159.2, 154.2, 147.6,
32.7, 130.2, 129.9, 128.8, 128.5, 120.8, 92.1, 85.7, 21.8. Anal.
) C, H, N.
1
(C
H N
12 9 3
(
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Acknowledgment. This research was supported by the
National Institute on Drug Abuse, Grants DA05477, DA016472,
K05-DA00480.
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reactions of 1,2,4-triazines: a general synthesis of furo[2,3-b]-
pyridines, 2,3-dihydropyrano[2,3-b]pyridines, and pyrrolo[2,3-b]-
pyridines. Tetrahedron 1987, 43, 5145-5158.
Supporting Information Available: Experimental details for
development of cells expressing human mGluR5 and mGluR1;
JM070078R