Preparation of a series of 5-methyl-3-(substituted)-[1,2,4]triazines

Article abstract of DOI:10.1016/j.tetlet.2011.04.075

Procedures for the synthesis of thirty-six 5-methyl-3-(substituted)-[1,2,4] triazines have been described. These compounds were evaluated for antagonism at metabotropic glutamate receptor subtype 5 (mGluR5). Two compounds, 5b and 3c, were determined to be

Full text of DOI:10.1016/j.tetlet.2011.04.075

Tetrahedron Letters 52 (2011) 3345–3346
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of a series of 5-methyl-3-(substituted)-[1,2,4]triazines
Moses G. Gichinga, Jeremy P. Olson, Elizabeth Butala, Brian P. Gilmour, Hernán H. Navarro,
⇑
F. Ivy Carroll
Center for Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Procedures for the synthesis of thirty-six 5-methyl-3-(substituted)-[1,2,4]triazines have been described.
These compounds were evaluated for antagonism at metabotropic glutamate receptor subtype 5
(mGluR5). Two compounds, 5b and 3c, were determined to be low micromolar inhibitors of mGluR5.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 11 March 2011
Revised 18 April 2011
Accepted 19 April 2011
Available online 29 April 2011
Keywords:
Triazine
mGluR5 antagonist
Addiction
Heterocyclic synthesis
There are several studies that show that metabotropic gluta-
mate receptor subtype 5 (mGluR5) plays a role in central nervous
system disorders including addiction, pain, fragile X syndrome,
and anxiety.1–5 In a previous study, we discovered that 3-(substi-
tuted phenylethynyl)-5-methy[1,2,4]triazines (1) were potent
antagonists of glutamate-mediated mobilization of internal cal-
cium in an mGluR5 in vitro efficacy assay.6
pared as described previously.6 The products 3a–f and 4a–f were
isolated in moderate yields after chromatographic separation.
The thio-linked compounds 5a–f and 6a–f were synthesized
after deprotonation of the corresponding thiols (12a–f) and benzyl
thiols (13a–f) with sodium hydride in THF followed by displace-
ment of the methylsulfonyl group in 11 (Scheme 2).
Preparation of either aniline derivatives or benzyl amines did
not require basic conditions to facilitate the displacement of the
methylsulfonyl group in 11 (Scheme 3). Benzyl amines (14a–f)
reacted rapidly in refluxing THF to provide the desired analogues
(7a–f) in good yields. Reaction of various substituted anilines
(15a–f) with 11 did not occur in refluxing THF but the desired
products (8a–f) could be isolated by heating the reactants without
solvent at 110 °C under N2 blanket after chromatographic separa-
tion. The low yields (13–20%) were a result of decomposition of
11 under heat.
CN
N
N
N
N
Cl
X
Y
O
1
2
In 2006, Buttelmann et al.7 reported that 2 had Ki of 1 nM in an
mGluR5 binding assay and was active in an anxiolytic test after
oral administration. We, therefore, considered it would be of inter-
est to synthesize and evaluate triazine analogues of compound 2
(3a–f and 4a–f) for antagonism at mGluR5. In addition, we pre-
pared analogues 5a–f, 6a–f, 7a–f, and 8a–f where the oxygen atom
was replaced by a sulfur or amino group.
N
N
N
N
N
X
O
NaH, THF
rt, 0.5 h
44-67%
OH
O
N
n
+
S
O
X
9/10
11
3a-f
The phenoxy and benzyloxy substituted methyl-[1,2,4]triazines
were synthesized from the corresponding phenols (9a–f) and ben-
zyl alcohols (10a–f), which were first deprotonated with sodium
hydride in THF and added to 5-methyl-3-sulfonyl[1,2,4]triazine
(11) (Scheme 1). 5-Methyl-3-sulfonyl[1,2,4]triazine (11) was pre-
NaH, THF
-78 oC, 2 h
7-39%
X = F, Cl, Br, CH3, CN, CF3
n = 0, 1
N
N
X
O
N
4a-f
⇑
Corresponding author. Tel.: +1 919 541 6679; fax: +1 919 541 8868.
E-mail address: fic@rti.org (F. Ivy Carroll).
Scheme 1. Synthesis of substituted phenoxy and benzyloxy methyl[1,2,4]triazines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.075

3346
M. G. Gichinga et al. / Tetrahedron Letters 52 (2011) 3345–3346
Table 1
N
N
N
SH
N
N
n
O
S
Selected inhibition of human mGluR5-mediated intracellular calcium mobilization for
heterocyclic-linked analogues
NaH, THF
rt, 0.5 h
+
X
S
N
X
O
52-65%
11
12/13
5a-f
NaH, THF
-78 oC, 2 h
41-88%
X = F, Cl, Br, CH3, CN, CF3
n = 0, 1
N
N
Compound
5b
5f
3c
X
S
6a-f
N
% Inhibition at 10
lV
44
13.4 2.3
35
n.d.
51
15.2 4.0
IC50
(
lM)
Scheme 2. Synthesis of thiophenol and benzylthiol substituted methyl[1,2,4]-
triazines.
Acknowledgment
This research was supported by the National Institute on Drug
Abuse Grant DA05477.
N
N
N
N
NH2
N
O
N
n
O
THF
X
+
S
Reflux, 3 h
75-96%
N
H
X
14/15
11
7a-f
Supplementary data
110 oC
15 min
Supplementary data (experimental details including 1H NMR,
13C NMR, MS, and elemental analysis data and calcium mobiliza-
tion assay procedure are provided) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2011.04.075.
X = F, Cl, Br, CH3, CN, CF3
n = 0, 1
13-20%
N
N
X
N
N
H
8a-f
Scheme 3. Synthesis of aniline and benzylamine substituted methyl[1,2,4]triazines.
References and notes
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