Synthesis and biological evaluation of N3-alkyl-thienopyrimidin-4-ones as mGluR1 antagonists

Article abstract of DOI:10.1002/bkcs.10283

Metabotropic glutamate receptor subtype 1 (mGluR1) is a potential target for the treatment of neuropathic pain, and there has been much effort to discover mGluR1 antagonists. In this study, a series of N³-alkyl-thienopyrimidin-4-ones were prepared by introducing various alkyl and aryl groups to the N³- and 7-positions of the thienopyrimidin-4-one core structure, respectively, and their inhibitory activities against mGluR1 were biologically evaluated. Structure-activity relationship study revealed that the trans-4-methylcyclohexyl, cycloheptyl, and cyclooctyl groups at N³-position, and 2-fluorophenyl group at 7-position were most effective in potentiating the inhibitory activity of the thienopyrimidin-4-one derivatives against mGluR1. Among the synthesized compounds, 3-cyclooctyl-7-phenylthienopyrimidin-4-one and 3-cycloheptyl-7-(2-fluorophenyl)thienopyrimidin-4-one exhibited the most potent inhibitory activities with IC₅₀ values of 115 and 107 nM, respectively.

Full text of DOI:10.1002/bkcs.10283

Article
DOI: 10.1002/bkcs.10283
BULLETIN OF THE
M. Kim et al.
KOREAN CHEMICAL SOCIETY
Synthesis and Biological Evaluation of N3-Alkyl-Thienopyrimidin-4-Ones
as mGluR1 Antagonists
Minjoo Kim,†,‡ Youngjae Kim,†,§ Seon Hee Seo,† Du-Jong Baek,‡ Sun-Joon Min,†,¶
†,¶,
Gyochang Keum,†,¶, and Hyunah Choo
*
*
†Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 136-791, Korea.
*E-mail: gkeum@kist.re.kr; hchoo@kist.re.kr
‡Department of Chemistry, College of Natural Sciences, Sangmyung University, Seoul 110-743, Korea
§Department of Chemistry, Yonsei University, Seoul 120-749, Korea
¶Department of Biological Chemistry, University of Science and Technology, Daejeon 305-350, Korea
Received January 7, 2015, Accepted January 26, 2015, Published online April 28, 2015
Metabotropic glutamate receptor subtype 1 (mGluR1) is a potential target for the treatment of neuropathic pain,
and there has been much effort to discover mGluR1 antagonists. In this study, a series of N3-alkyl-thienopyr-
imidin-4-ones were prepared by introducing various alkyl and aryl groups to the N3- and 7-positions of the
thienopyrimidin-4-one core structure, respectively, and their inhibitory activities against mGluR1 were bio-
logically evaluated. Structure–activity relationship study revealed that the trans-4-methylcyclohexyl, cyclo-
heptyl, and cyclooctyl groups at N3-position, and 2-fluorophenyl group at 7-position were most effective
in potentiating the inhibitory activity of the thienopyrimidin-4-one derivatives against mGluR1. Among
the synthesized compounds, 3-cyclooctyl-7-phenylthienopyrimidin-4-one and 3-cycloheptyl-7-(2-fluorophe-
nyl)thienopyrimidin-4-one exhibited the most potent inhibitory activities with IC50 values of 115 and 107 nM,
respectively.
Keywords: mGluR1 Antagonist, N3-Alkyl-thienopyrimidin-4-one, CNS disease, Neuropathic pain,
Glutamate
Introduction
mGluR1 using antisense oligonucleotide.7 Thus, mGluR1
has been considered as a potential target for treating neuro-
pathic pain.
Metabotropic glutamate receptors (mGluRs) are members of
class C GPCRs (G protein-coupled receptors), which are com-
posed of a large hydrophilic extracellular agonist-binding
region and a seven-transmembrane domain along with N-
and C-terminal regions.1 The mGluRs are divided to three
main groups on the basis of structural homology, pharmacol-
ogy, and signal transduction mechanisms: group I (mGluR1
and mGluR5), group II (mGluR2 and mGluR3), and group
III (mGluR4, mGluR6, mGluR7, and mGluR8).2 Among
the eight subtypes of mGluRs, mGluR1 was the first receptor
to be cloned.3 mGluR1 is mainly coupled with Gq protein,
whichstimulates phospholipaseCleadingtophosphatidylino-
sitol hydrolysis and increased intracellualar Ca2+ levels.4
mGluR1 is widely expressed in the central nervous system
(CNS) including the hippocampus, hypothalamus, thalamus,
amygdale, basal ganglia, cerebellum, and spinal cord. It has
been reported that overexpression or activation of mGluR1
is related to CNS disorders, including pain, anxiety, depres-
sion, and Parkinson's disease.5 It has also been reported that
mGluR1 knockout mice exhibit reduced sensitivity to pain,
and potent mGluR1 antagonists are active in a spinal nerve
ligation (SNL) animal model, which is a well-known neuro-
pathic pain model.6 In addition, hyperalgesia and mechanical
allodynia in the chronic constrictive injury (CCI) animal
model have been reduced by the knockdown of spinal
Various selective mGluR1 antagonists have been
discovered, and some of them showed potency in the neuro-
pathic pain animal models (Figure 1).8 Compound 1
(JNJ16259685) was reported to be efficacious in the rat forma-
lin model of hyperalgesia (7.5 mg/kg intraperitoneal dose),8a
while compound 2 (LY456236) potently inhibited mGluR1
(IC50 = 96 nM) and reverted formalin-induced paw-licking
behavior as well as mechanical allodynia in the SNL model
at intraperitoneal dose of 30 mg/kg.8b Compound 3 reduced
mechanical allodynia in the SNL model with an ED50 of
6.4 mg/kg.8c,d We have also been involved in the discovery
of novel mGluR1 antagonists and recently reported a series
of N3-aryl-thienopyrimidin-4-ones, among which the most
active compound had an IC50 value of 45 nM.8e In this study,
we designed the title compounds 4 with a thienopyrimidin-4-
one core structure to which various substituents as R1 to the
phenyl group at 7-position and N3-alkyl substituents as R2
were introduced (Figure 2).
Experimental
Materials and Methods. All reactions were carried out under
dry nitrogen or argon unless otherwise indicated. Commer-
cially available reagents were used without further
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
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BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
constant (J) in hertz (Hz). 1H NMR chemical shifts are
reported relative to CDCl3 (7.26 ppm). 13C NMR was
recorded relative to the central line of CDCl3 (77.0 ppm). Liq-
uid chromatography-mass spectrometry (LC/MS) analyses
were performed on either a Micromass QUATTRO micro™
(Waters Inc, Milford, MA, USA) or an Agilent 6410 Triple
Quad system (Agilent Technologies, Santa Clara, CA,
USA). Purity was checked on a Waters HPLC e2695 instru-
ment (Waters Inc, Milford, MA, USA) equipped with a UV/
visible detector 2489 and a SunFire™ (Waters Inc, Milford,
MA, USA) C18, 4.6 × 150 mm, 5 μm, reversed-phase column.
Standard conditions were as follows: eluent system
A (MeCN), system B (water/0.1 M ammonium acetate); flow
rate 1 mL/min; gradient (30–100%) A over 20 min; detection
at 254 and 280 nm.
O
O
HN
N
O
N
O
N
O
1 JNJ-16259685
2 LY456236
NH
N
N
N
OMe
S
O
3
3-Hydroxy-2-phenylacrylonitrile (6–1). To a solution of
phenyl acetonitrile (10 g, 85.4 mmol) and methyl formate
(67 mL), THF (250 mL) was added. In anhydrous condition,
asolutionofNaH(2.6 g, 106.7 mmol)inTHFwasaddeddrop-
wise to the reaction mixture at 0 ꢀC and the resulting mixture
was stirred at room temperature overnight. After the reaction,
the mixture was quenched with H2O, and several drops of 1 N
HCl were added until the pH of the solution was lowered to
4–5. Then the mixture was extracted with MC and dried with
MgSO4. After filtrationandevaporation, theresultingsolution
was concentrated under vacuum to give the product 6–1
(12.3 g, 84.7 mmol, 99% yield): 1H NMR (300 MHz, CDCl3)
δ 7.44–7.32 (m, 5H).
Figure 1. mGluR1 antagonists.
R1
=
H, F, Cl, Me, and OMe
N
R1
7
N3
R2
R2
=
S
O
4
2-(3-Fluorophenyl)-3-hydroxyacrylonitrile (6–2). Fol-
lowing the same procedure as with compound 6–1, the reac-
tion of phenyl acetonitrile (50 mg, 0.37 mmol), methyl
formate (237 mg, 3.94 mmol), and NaH (23 mg, 0.98 mmol)
in DMF (3 mL) gave the title compound 6–2 (60 mg, 0.37
1
mmol, 100% yield): H NMR (300 MHz, CDCl3) δ 8.15 (s,
0.57H), 7.75 (s, 0.43H), 7.53–7.37 (m, 2H), 7.32–7.22 (m,
1H), 7.13–7.08 (m, 1H).
N
O
3-Methoxy-2-phenylacrylonitriles (7–1). To a solution of
3-hydroxy-2-phenylacrylonitrile (12.3 g, 84.7 mmol) and
THF (100 mL), NaH (24.1 g, 169.4 mmol) was added and
the reaction mixture was stirred at room temperature for 2 h.
Then dimethylsulfate (13.7 mL, 144.0 mmol) was added to
Figure 2. Designed compounds 4.
purification. Solvents and gases weredried according tostand-
ard procedures. Organic solvents were evaporated with
reduced pressure using a rotary evaporator. Analytical thin-
layerchromatography(TLC)wasperformed usingglassplates
precoated with silica gel (0.25 mm). TLC plates were visua-
lized by exposure to UV light (UV), and then with a KMnO4
stain followed by brief heating on a hot plate. Flash column
chromatography was performed using silica gel 60 (230-400
mesh, Merck Co, Kenilworth, NJ, USA) with the indicated
ꢀ
the mixture and the resulting solution was stirred at 40 C.
The progress of reaction was monitored using TLC. After
the reaction, the mixture was quenched with H2O and evapo-
rated. Then it was diluted with ether by extraction and washed
with H2O. After drying with MgSO4, the crude compound was
purified by column chromatography (SiO2, Hexane:EtOAc =
1
5:1) to give product 7–1 (17.9 g, 112.5 mmol, quant.): H
NMR (300 MHz, CDCl3) δ 7.40–7.28 (m, 5H), 4.00 (s, 3H).
2-(3-Fluorophenyl)-3-methoxyacrylonitrile (7–2). Fol-
lowing the same procedure as with compound 7–1, the reac-
tion of 2-(3-fluorophenyl)-3-hydroxyacrylonitrile (100 mg,
0.61 mmol), NaH (29 mg, 1.22 mmol), and dimethylsulfate
(0.1 mL, 1.04 mmol) in THF (5 mL) gave the title compound
solvents. H and 13C spectra were recorded on Bruker 300,
Bruker 400 (Bruker Co, Billerica, MA, USA) or Varian 300
NMR spectrometers (Varian Inc, Palo Alto, CA, USA). H
NMR spectra are represented as follows: chemical shift, mul-
tiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublet, td = triplet of doublet, brs
= broad singlet, brt = broad triplet), integration, and coupling
1
1
1
7–2 (103 mg, 0.58 mmol, 95% yield): H NMR (300 MHz,
CDCl3) δ 8.10 (s, 0.42H), 7.65 (s, 0.58H), 7.52–7.36 (m,
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N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
2H), 7.33–7.23 (m, 1H), 7.19–7.11 (m, 1H), 4.06 (s, 1.26H),
3.96 (s, 1.74H).
(400 MHz, CDCl3) δ 8.06 (s, 1H), 7.83–7.80 (m, 3H),
7.50–7.46 (m, 2H), 7.41–7.36 (m, 1H), 3.87 (d, J = 7.3 Hz,
2H), 2.31–2.17 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 157.7, 154.2, 145.0, 138.0, 133.8,
130.3, 128.7, 128.3, 128.0, 125.0, 53.9, 28.3, 19.9; LC/MS
(ESI+): m/z: calcd for C16H16N2OS: 284.38, [M + H]+; found:
285.10
Methyl
3-amino-4-phenylthiophene-2-carboxylates
(8–1). NaOMe (5 M in MeOH, 3.5 mL, 17.6 mmol) followed
by methylthioglycolate (1.8 mL, 20.1 mmol) was added to
3-methoxy-2-phenylacrylonitriles (2 g, 12.6 mmol). The reac-
tion mixture was stirred and refluxed at 65 ꢀC overnight. After
the reaction, the mixture was filtered using celite and washed
with methylene chloride. The crude compound was then pur-
ified by column chromatography (SiO2, hexane:EtOAc = 5:1)
to give the white solid product 8–1 (1.5 g, 6.6 mmol, 52%
yield in two steps): 1H NMR (300 MHz, CDCl3) δ
7.49–7.39 (m, 5H), 7.25 (s, 1H), 5.64 (br, 2H), 3.88 (s, 3H).
3-Neopentyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one
(4–4). Following the same procedure as with compound 4–1,
the reaction of methyl 3-amino-4-phenylthiophene-2-
carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL), neopen-
tylamine (0.117 mL, 0.99 mmol), and AcOH (0.1 mL) gave
1
the title compound 4–4 (46 mg, 0.15 mmol, 36% yield): H
Methyl
3-amino-4-(3-fluorophenyl)thiophene-2-
NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.83–7.80 (m, 3H),
7.50–7.45 (m, 2H), 7.40–7.36 (m, 1H), 3.94 (s, 2H), 1.04
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.0, 154.0,
148.5, 138.0, 133.8, 130.3, 128.7, 128.3, 128.0, 125.1,
56.1, 33.9, 27.7; LC/MS (ESI+): m/z: calcd for C17H18N2OS:
298.41, [M + H]+; found: 299.10
carboxylate (8–2). Following the same procedure as with
compound 8–1, the reaction of 2-(3-fluorophenyl)-3-
methoxyacrylonitrile (102.7 mg, 0.58 mmol), 0.5 M NaOMe
in MeOH (1.62 mL, 0.81 mmol), and methylthioglycolate
(0.08 mL, 0.91 mmol) gave the title compound 8–2 (56 mg,
0.22 mmol, 38% yield): 1H NMR (300 MHz, CDCl3) δ
7.46–7.38 (m, 1H), 7.26–7.04 (m, 4H), 5.61 (brs, 2H), 3.86
(s, 3H).
3-Allyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one(4–1).
To a pressure bottle containing methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL)
was added, followed by allylamine hydrochloride (93 mg,
0.99 mmol) andAcOH(0ꢀ.1 mL). The reaction mixturewas stir-
red and refluxed at 160 C overnight. After the reaction, the
mixture was evaporated then solidified with ether. The pro-
duced white crystals were filtered and dried in vacuo to give
3-Cyclobutyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one
(4–5). Following the same procedure as with compound 4–1,
the reaction of methyl 3-amino-4-phenylthiophene-2-
carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL), cyclo-
butylamine (0.084 mL, 0.99 mmol), and AcOH (0.1 mL) gave
1
the title compound 4–5 (84 mg, 0.30 mmol, 69% yield): H
NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.82–7.79 (m, 3H),
7.49–7.45 (m, 2H), 7.40–7.36 (m, 1H), 5.17–5.09 (m, 1H),
2.63–2.56 (m, 2H), 2.44–2.32 (m, 2H), 1.99–1.91 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 157.6, 153.9, 145.0, 137.8,
133.8, 130.3, 128.6, 128.3, 127.9, 124.6, 50.1, 30.1, 15.4;
LC/MS (ESI+): m/z: calcd for C16H14N2OS: 282.36, [M +
H]+; found: 283.05
3-Cyclopentyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one
(4–6). Following the same procedure as with compound 4–1,
the reaction of methyl 3-amino-4-phenylthiophene-2-
carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL), cyclo-
pentylamine (0.080 mL, 0.81 mmol), and AcOH (0.1 mL)
gave the title compound 4–6 (108 mg, 0.37 mmol, 85% yield):
1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.82–7.79 (m,
3H), 7.49–7.45 (m, 2H), 7.40–7.36 (m, 1H), 5.30–5.23 (m,
1H), 2.31–2.22 (m, 2H), 1.99–1.75 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 157.7, 153.6, 145.3, 137.8, 133.8,
130.2, 128.7, 128.3, 127.9, 124.7, 55.6, 32.6, 24.6; LC/MS
(ESI+): m/z: calcd for C17H16N2OS: 296.39, [M + H]+; found:
297.05
3-Cyclohexyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one
(4–7). Following the same procedure as with compound 4–1,
the reaction of methyl 3-amino-4-phenylthiophene-2-
carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL), cyclo-
hexylamine(0.113 mL, 0.99 mmol),andAcOH(0.1 mL)gave
the title compound 4–7 (110 mg, 0.35 mmol, 82% yield): 1H
NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.82–7.79 (m, 3H),
7.49–7.44 (m, 2H), 7.40–7.36 (m, 1H), 4.91–4.84 (m, 1H),
2.05 (d, J = 12.0 Hz, 2H), 1.95 (d, J = 13.2 Hz, 2H),
1.81–1.78 (m, 1H), 1.68–1.48 (m, 4H), 1.32–1.21 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 157.3, 153.5, 144.9, 137.8,
1
the title compound 4–1 (66 mg, 0.25 mmol, 58% yield): H
NMR (300 MHz, CDCl3) δ 8.11 (s, 1H), 7.84–7.79 (m, 3H),
7.50–7.44 (m, 2H), 7.41–7.36 (m, 1H), 6.08–5.95 (m, 1H),
5.34–5.24 (m, 2H), 4.72–4.67 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 157.3, 154.3, 147.3, 138.1, 133.7, 131.9, 130.5,
128.7, 128.3, 128.0, 124.9, 119.1, 48.0; LC/MS (ESI+): m/z:
calcd for C15H12N2OS: 268.34, [M + H]+; found: 269.05
3-Butyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one (4–2).
Following the same procedure as with compound 4–1, the
reaction of methyl 3-amino-4-phenylthiophene-2-carboxylate
(100 mg, 0.43 mmol), CH(OEt)3 (1 mL), n-butylamine
(0.097 mL, 0.99 mmol), and AcOH (0.1 mL) gave the title
1
compound 4–2 (92 mg, 0.32 mmol, 75% yield): H NMR
(400 MHz, CHCl3) δ 8.10 (s, 1H), 7.82–7.79 (m, 3H),
7.56–7.49 (m, 2H), 7.40–7.36 (m, 1H), 4.07 (t, J = 7.3 Hz,
2H), 1.84–1.76 (m, 2H), 1.42 (sextet, J = 7.5 Hz, 2H), 0.97
(t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.7,
154.2, 145.3, 137.9, 133.8, 130.4, 128.7, 128.3, 128.0,
124.9, 46.6, 31.6, 19.8, 13.6; LC/MS (ESI+): m/z: calcd for
C16H16N2OS: 284.38, [M + H]+; found: 285.10
3-Isobutyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one
(4–3). Following the same procedure as with compound 4–1,
the reaction of methyl 3-amino-4-phenylthiophene-2-
carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL), isobuty-
lamine (0.099 mL, 0.99 mmol), and AcOH (0.1 mL) gave the
title compound 4–3 (70 mg, 0.25 mmol, 57% yield): 1H NMR
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BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
133.8, 130.2, 128.7, 128.3, 127.9, 124.8, 53.2, 33.0, 25.9,
25.3; LC/MS (ESI+): m/z: calcd for C18H18N2OS: 310.42,
[M + H]+; found: 311.10
0.6H), 8.19 (s, 0.4H), 7.82–7.79 (m, 3H), 7.48–7.44 (m,
2H), 7.39–7.35 (m, 1H), 4.90–4.79 (m, 1H), 2.07–1.62 (m,
8H), 1.51–1.43 (m, 1H), 1.33–1.16 (m, 2H), 0.95–0.90 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 153.6, 145.1,
144.9, 137.8, 133.8, 130.2, 128.7, 128.3, 128.3, 128.0,
124.9, 124.8, 53.8, 53.4, 38.5, 33.5, 32.7, 31.9, 29.3, 29.0,
27.2, 23.7, 12.3, 11.6; LC/MS (ESI+): m/z: calcd for
C20H22N2OS: 338.47, [M + H]+; found: 339.10.
7-Phenyl-3-(4-propylcyclohexyl)thieno[3,2-d]pyrimidin-
4(3H)-one (4–12). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
4-propylcyclohexylamine (0.148 mL, 0.90 mmol), and AcOH
(0.1 mL) gave the title compound 4–12 (106 mg, 0.30 mmol,
70% yield, dr = 1:1): 1H NMR (400 MHz, CDCl3) δ 8.22 (s,
0.5H), 8.18 (s, 0.5H), 7.80–7.78 (m, 3H), 7.49–7.43 (m,
2H), 7.38–7.34 (m, 1H), 4.88–4.78 (m, 1H), 2.05–1.14 (m,
13H), 0.94–0.87 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
157.3, 153.5, 145.1, 144.9, 137.8, 137.8, 133.8, 130.2,
130.2, 128.7, 128.6, 128.3, 128.3, 128.0, 124.9, 124.8,
53.8, 53.4, 38.9, 36.5, 33.2, 32.7, 32.3, 31.3, 29.3, 27.3,
20.8, 20.1, 14.4, 14.3; LC/MS (ESI+): m/z: calcd for
C21H24N2OS: 352.50, [M + H]+; found: 353.10
3-(2-Methylcyclohexyl)-7-phenylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–8). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
2-methylcyclohexylamine (0.120 mL, 0.90 mmol), and
AcOH (0.1 mL) gave the title compound 4–8 (66 mg, 0.20
1
mmol, 47% yield, dr = 1:2): H NMR (400 MHz, CDCl3) δ
8.14 (m, 1H), 7.83–7.81 (m, 3H), 7.49–7.45 (m, 2H),
7.40–7.36 (m, 1H), 5.00 (dt, J = 3.8, 13.2 Hz, 0.3H), 4.67 (s,
0.7H), 2.49–1.23 (m, 9H), 0.88 (d, J = 7.2 Hz, 1H), 0.83 (d,
J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 157.7,
153.4, 145.5, 137.9, 133.8, 130.3, 128.7, 128.3, 128.0,
56.5, 34.8, 31.9, 31.0, 26.6, 26.0, 25.7, 25.4, 19.6, 18.2,
11.4; LC/MS (ESI+): m/z: calcd for C19H20N2OS: 324.45,
[M + H]+; found: 325.05
3-(3-Methylcyclohexyl)-7-phenylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–9). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
3-methylcyclohexylamine (0.120 mL, 0.90 mmol), and
AcOH (0.1 mL) gave the title compound 4–9 (98 mg, 0.30
3-(4-Isopropylcyclohexyl)-7-phenylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–13). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
4-isopropylcyclohexylamine (0.148 mL, 0.90 mmol), and
AcOH (0.1 mL) gave the title compound 4–13 (89 mg, 0.25
1
mmol, 71% yield, dr = 1:2): H NMR (400 MHz, CDCl3) δ
8.23 (s, 0.3H), 8.20 (s, 0.7H), 7.83–7.80 (m, 3H), 7.49–7.46
(m, 2H), 7.41–7.35 (m, 1H), 5.19–5.11 (m, 0.3H),
4.95–4.87 (m, 0.7H), 2.28–1.50 (m, 8H), 1.34–1.24 (m,
1H), 1.16 (d, J = 7.3 Hz, 1H), 1.02–0.92 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 157.3, 153.5, 145.0, 144.9, 137.8,
133.8, 130.3, 128.7, 128.3, 127.9, 124.8, 55.0, 41.3, 38.3,
34.0, 32.6, 32.3, 30.8, 28.5, 25.4, 22.3, 20.6, 17.9; LC/MS
(ESI+): m/z: calcd for C19H20N2OS: 324.45, [M + H]+; found:
325.05
3-(trans-4-Methylcyclohexyl)-7-phenylthieno[3,2-d]pyri-
midin-4(3H)-one (4–10). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-phe-
nylthiophene-2-carboxylate (76 mg, 0.33 mmol), CH(OEt)3
(1 mL), trans-4-methylcyclohexylamine (0.1 mL, 0.76
mmol), and AcOH (0.1 mL) gave the title compound 4–10
(54 mg, 0.17 mmol, 50% yield): 1H NMR (400 MHz, CDCl3)
δ 8.20 (s, 1H), 7.84–7.79 (m, 3H), 7.49–7.45 (m, 2H),
7.40–7.36 (m, 1H), 4.90–4.82 (m, 1H), 2.05–2.01 (m, 2H),
1.92–1.88 (m, 2H), 1.75–1.64 (m, 2H), 1.55–1.44 (m, 1H),
1.31–1.21 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 157.4, 153.5, 144.9, 137.8, 133.8, 130.2,
128.7, 128.3, 127.9, 124.8, 53.1, 34.3, 32.7, 31.9, 22.0; LC/
MS (ESI+): m/z: calcd for C19H20N2OS: 324.45, [M + H]+;
found: 325.05.
1
mmol, 58% yield, dr = 1:1): H NMR (400 MHz, CDCl3) δ
8.22 (s, 0.5H), 8.18 (s, 0.5H), 7.81–7.77 (m, 3H), 7.47–7.43
(m, 2H), 7.38–7.34 (m, 1H), 4.88–4.79 (m, 1H), 2.08–1.12
(m, 10H), 0.93 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 157.4, 157.4, 153.5, 145.2,
144.8, 137.9, 137.8, 133.8, 130.2, 130.2, 128.7, 128.6,
128.3, 127.9, 124.8, 53.7, 53.4, 43.1, 39.2, 32.8, 32.5, 29.0,
27.5, 27.4, 26.1, 21.0, 19.9; LC/MS (ESI+): m/z: calcd for
C21H24N2OS: 352.50, [M + H]+; found: 353.10.
3-(4-(tert-Butyl)cyclohexyl)-7-phenylthieno[3,2-d]pyri-
midin-4(3H)-one (4–14). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-phe-
nylthiophene-2-carboxylate
(100 mg,
0.43 mmol),
CH(OEt)3 (1 mL), 4-tert-butylcyclohexylamine (0.161 mL,
0.90 mmol), and AcOH (0.1 mL) gave the title compound
1
4–14 (103 mg, 0.28 mmol, 65% yield, dr = 1:1): H NMR
(400 MHz, CDCl3) δ 8.51 (s, 0.5H), 8.20 (s, 0.5H),
7.82–7.80 (m, 3H), 7.50–7.45 (m, 2H), 7.41–7.36 (m, 1H),
5.05–5.01 (m, 0.5H), 4.88–4.80 (m, 0.5H), 2.22–1.10 (m,
9H), 0.90 (d, 9H); 13C NMR (100 MHz, CDCl3) δ 157.8,
157.4, 153.7, 153.5, 145.7, 144.8, 137.9, 133.8, 130.2,
128.7, 128.7, 128.3, 127.9, 53.3, 49.5, 47.2, 46.1, 33.0,
32.8, 32.4, 29.3, 27.6, 27.6, 26.8, 22.7; LC/MS (ESI+): m/z:
calcd for C22H26N2OS: 366.53, [M + H]+; found: 367.10.
3-Cycloheptyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-
one (4–15). Following the same procedure as with compound
4–1, the reaction of methyl 3-amino-4-phenylthiophene-2-
3-(4-Ethylcyclohexyl)-7-phenylthieno[3,2-d]pyrimidin-
4(3H)-one (4–11). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
4-ethylcyclohexylamine (0.133 mL, 0.90 mmol), and AcOH
(0.1 mL) gave the title compound 4–11 (7 mg, 0.02 mmol,
1
5% yield, dr = 3:2): H NMR (400 MHz, CDCl3) δ 8.22 (s,
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
carboxylate (80 mg, 0.34 mmol), CH(OEt)3 (0.65 mL), cyclo-
heptylamine (0.08 mL, 0.63 mmol), and AcOH (0.08 mL)
gave the title compound 4–15 (103 mg, 0.32 mmol, 93%
yield): 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H),
7.86–7.83 (m, 3H), 7.51–7.46 (m, 2H), 7.38–7.35 (m, 1H),
5.06–4.97 (m, 1H), 2.11–1.65 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 157.0, 153.5, 145.4, 137.8, 133.8, 130.2,
128.6, 128.3, 127.9, 124.8, 55.4, 35.4, 27.4, 25.2; LC/MS
(ESI+): m/z: calcd for C19H20N2OS: 324.45, [M + H]+; found:
325.05.
3-Cyclooctyl-7-phenylthieno[3,2-d]pyrimidin-4(3H)-one
(4–16). Following the same procedure as with compound 4–1,
the reaction of methyl 3-amino-4-phenylthiophene-2-
carboxylate(100 mg, 0.43 mmol), CH(OEt)3 (1 mL), cyclooc-
tylamine (0.113 mL, 0.81 mmol), and AcOH (0.1 mL) gave
the title compound 4–16 (83 mg, 0.24 mmol, 57% yield): 1H
NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.82–7.79 (m, 3H),
7.49–7.44 (m, 2H), 7.40–7.36 (m, 1H), 5.17–5.10 (m, 1H),
2.04–1.94 (m, 4H), 1.87–1.83 (m, 2H), 1.74–1.60 (m, 8H);
13C NMR (100 MHz, CDCl3) δ 157.0, 153.5, 145.6, 137.8,
133.8, 130.2, 128.7, 128.3, 127.9, 124.8, 54.1, 34.1, 26.3,
26.0, 25.0; LC/MS (ESI+): m/z: calcd for C20H22N2OS:
338.47, [M + H]+; found: 339.05.
(77 mg, 0.25 mmol, 57% yield): 1H NMR (400 MHz, CDCl3)
δ 8.22 (s, 1H), 7.85 (s, 1H), 7.82–7.79 (m, 2H), 7.50–7.46 (m,
2H), 7.41–7.37 (m, 1H), 5.21–5.13 (m, 1H), 4.18–4.14 (m,
2H), 3.63 (td, J = 2.7, 11.4 Hz, 2H), 2.08–1.96 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 157.2, 153.5, 144.5, 138.0,
133.6, 130.6, 128.7, 128.3, 128.0, 124.6, 67.4, 50.3, 32.7;
LC/MS (ESI+): m/z: calcd for C17H16N2O2S: 312.39, [M +
H]+; found: 313.05.
3-(1-Methylpiperidin-4-yl)-7-phenylthieno[3,2-d]pyri-
midin-4(3H)-one (4–20). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-phe-
nylthiophene-2-carboxylate
(100 mg,
0.43 mmol),
CH(OEt)3 (1 mL), 1-methylpiperidine-4-amine (0.124 mL,
0.99 mmol), and AcOH (0.1 mL) gave the title compound
1
4–20 (47 mg, 0.15 mmol, 34% yield): H NMR (400 MHz,
CDCl3) δ 8.24 (s, 1H), 7.83–7.78 (m, 3H), 7.49–7.45 (m,
2H), 7.40–7.36 (m, 1H), 4.98–4.90 (m, 1H), 3.03 (d, J =
12.2 Hz, 2H), 2.36 (s, 3H), 2.27–2.20 (m, 2H), 2.03–1.98
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 157.3, 153.6,
144.6, 138.0, 133.7, 130.5, 128.7, 128.3, 128.0, 124.5,
54.8, 50.3, 45.4, 31.3; LC/MS (ESI+): m/z: calcd for
C18H19N3OS: 325.43, [M + H]+; found: 326.05.
7-(2-Fluorophenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–21). Following the same
procedure as with compound 4–1, the reaction of methyl 3-
amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg,
3-(Cyclopropylmethyl)-7-phenylthieno[3,2-d]pyrimidin-
4(3H)-one (4–17). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
cyclopropylmethanamine (0.086 mL, 0.99 mmol), and AcOH
(0.1 mL) gave the title compound 4–17 (76 mg, 0.27 mmol,
0.40 mmol),
CH(OEt)3
(1 mL),
trans-4-
methylcyclohexylamine (0.1 mL, 0.76 mmol), and AcOH
(0.1 mL) gave the title compound 4–21 (87 mg, 0.25 mmol,
1
1
63% yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H),
64% yield): H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H),
7.83–7.79 (m, 3H), 7.49–7.45 (m, 2H), 7.40–7.36 (m, 1H),
3.93 (d, J = 7.2 Hz, 2H), 1.37–1.25 (m, 1H), 0.71–0.59 (m,
2H), 0.50–0.39 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
157.7, 154.3, 147.3, 138.0, 133.8, 130.3, 128.7, 128.3,
128.0, 124.9, 50.9, 11.0, 4.2; LC/MS (ESI+): m/z: calcd for
C16H14N2OS: 282.36, [M + H]+; found: 283.00.
7.94 (d, J = 1.6 Hz, 1H), 7.83 (td, J = 1.8, 7.6 Hz, 1H),
7.39–7.33 (m, 1H), 7.27–7.16 (m, 2H), 4.89–4.81 (m, 1H),
2.05–2.01 (m, 2H), 1.91–1.87 (m, 2H), 1.73–1.63 (m, 2H),
1.55–1.43 (m, 1H), 1.30–1.20 (m, 2H), 0.97 (d, J = 6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 160.0 (d, JC-F = 246.8
Hz), 157.2, 154.0, 144.9, 133.1 (d, JC-F = 6.0 Hz), 131.3 (d,
JC-F = 2.8 Hz), 131.2, 129.6 (d, JC-F = 8.2 Hz), 124.1, 124.1
3-(Cyclohexylmethyl)-7-phenylthieno[3,2-d]pyrimidin-
4(3H)-one (4–18). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-phenylthio-
phene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3 (1 mL),
cyclohexylmethanamine (0.129 mL, 0.99 mmol), and AcOH
(0.1 mL) gave the title compound 4–18 (102 mg, 0.32 mmol,
(d, JC-F = 3.4 Hz), 121.4 (d, JC-F = 14.0 Hz), 116.0 (d, JC-F
=
22.4 Hz), 53.2, 34.3, 32.6, 31.9, 21.9; LC/MS (ESI+): m/z:
calcd for C19H19FN2OS: 342.44, [M + H]+; found: 343.00.
3-Cycloheptyl-7-(2-fluorophenyl)thieno[3,2-d]pyrimi-
din-4(3H)-one (4–22). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-(2-
fluorophenyl)thiophene-2-carboxylate (70 mg, 0.28 mmol),
CH(OEt)3 (1 mL), cycloheptylamine (0.066 mL, 0.52 mmol),
and AcOH (0.1 mL) gave the title compound 4–22
(45 mg, 0.13 mmol, 47% yield): 1H NMR (300 MHz, CDCl3)
δ 8.22 (s, 1H), 7.98 (s, 1H), 7.98–7.84 (m, 1H), 7.41–7.38
(m, 1H), 7.31–7.19 (m, 2H), 5.03 (m, 1H), 2.13–1.66 (m,
1
73% yield): H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H),
7.82–7.79 (m, 3H), 7.49–7.45 (m, 2H), 7.40–7.36 (m, 1H),
3.77 (d, J = 7.3 Hz, 2H), 1.95–1.84 (m, 1H), 1.74–1.67 (m,
5H), 1.29–1.12 (m, 3H), 1.07–0.98 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 157.8, 154.2, 148.0, 138.0, 133.8,
130.3, 128.7, 128.3, 128.0, 125.0, 52.8, 37.3, 30.6, 26.2,
25.6; LC/MS (ESI+): m/z: calcd for C19H20N2OS: 324.45,
[M + H]+; found: 325.05.
12H); 13C NMR (100 MHz, CDCl3) δ 160.0 (d, JC-F
=
7-Phenyl-3-(tetrahydro-2H-pyran-4-yl)thieno[3,2-d]pyr-
imidin-4(3H)-one (4–19). Following the same procedure
as with compound 4–1, the reaction of methyl 3-amino-4-phe-
nylthiophene-2-carboxylate (100 mg, 0.43 mmol), CH(OEt)3
(1 mL), tetrahydro-2H-pyran-4-amine (0.102 mL, 0.99
mmol), and AcOH (0.1 mL) gave the title compound 4–19
247.0 Hz), 156.9, 154.0, 145.5, 133.1 (d, JC-F = 5.9 Hz),
131.3 (d, JC-F = 2.9 Hz), 131.2, 129.6 (d, JC-F = 8.2 Hz),
124.1, 124.1 (d, JC-F = 3.4 Hz), 121.4 (d, JC-F = 13.8 Hz),
116.0 (d, JC-F = 22.1 Hz), 55.4, 35.4, 27.4, 25.2; LC/MS
(ESI+): m/z: calcd for C19H19FN2OS: 342.44, [M + H]+;
found: 343.00.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
3-Cyclooctyl-7-(2-fluorophenyl)thieno[3,2-d]pyrimidin-
4(3H)-one(4–23). Following the same procedure as with com-
pound 4–1, the reaction of methyl 3-amino-4-(2-fluorophe-
0.23 mmol, 58% yield): 1H NMR (400 MHz, CDCl3) δ 8.19
(s, 1H), 7.85 (s, 1H), 7.64–7.59 (m, 2H), 7.45–7.40 (m,
1H), 7.10–7.05 (m, 1H), 5.13 (m, 1H), 1.99–1.62 (m, 14H);
13C NMR (100 MHz, CDCl3) δ 162.9 (d, JC-F = 244.0 Hz),
156.9, 153.3, 145.7, 136.3 (d, JC-F = 3.0 Hz), 135.8 (d, JC-F
= 8.0 Hz), 130.7, 130.1 (d, JC-F = 9.0 Hz), 124.9, 123.8 (d,
nyl)thiophene-2-carboxylate
(100 mg,
0.40 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.128 mL, 0.92 mmol),
and AcOH (0.1 mL) gave the title compound 4–23 (90 mg,
0.25 mmol, 63% yield): 1H NMR (400 MHz, CDCl3) δ 8.18
(s, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.83 (td, J = 1.8, 7.6 Hz,
1H), 7.41–7.34 (m, 1H), 7.28–7.17 (m, 2H), 5.17–5.10 (m,
1H), 2.05–1.60 (m, 14H); 13C NMR (100 MHz, CDCl3) δ
160.0 (d, JC-F = 247.0 Hz), 156.9, 154.0, 145.7, 133.0 (d,
JC-F = 6.1 Hz), 131.3 (d, JC-F = 2.8 Hz), 131.1, 129.6 (d, JC-
JC-F = 3.0 Hz), 115.2 (d, JC-F = 22.0 Hz), 114.8 (d, JC-F
=
21.0 Hz), 54.2, 34.1, 26.3, 26.0, 25.0; LC/MS (ESI+): m/z:
calcd for C20H21FN2OS: 356.46, [M + H]+; found: 357.10.
7-(4-Fluorophenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–27). Following the same
procedure with compound 4–1, the reaction of methyl
3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate (100
F = 8.3 Hz), 124.1, 124.1 (d, JC-F = 3.8 Hz), 121.4 (d, JC-F
=
13.8 Hz), 115.9 (d, JC-F = 22.3 Hz), 54.3, 34.0, 26.3, 26.0,
25.0; LC/MS (ESI+): m/z: calcd for C20H21FN2OS: 356.46,
[M + H]+; found: 357.05.
7-(3-Fluorophenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–24). Following the same
procedure as with compound 4–1, the reaction of methyl 3-
amino-4-(3-fluorophenyl)thiophene-2-carboxylate (100 mg,
mg,
0.40 mmol),
CH(OEt)3
(1 mL),
trans-4-
methylcyclohexylamine (0.1 mL, 0.76 mmol), and AcOH
(0.1 mL) gave the title compound 4–27 (113 mg, 0.33 mmol,
83% yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H),
1
7.83–7.78 (m, 3H), 7.19–7.13 (m, 2H), 4.86 (tt, J = 3.7,
12.4, 1H), 2.05–2.01 (m, 2H), 1.92–1.88 (m, 2H),
1.75–1.64 (m, 2H), 1.56–1.44 (m, 1H), 1.31–1.21 (m, 2H),
0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
162.6 (d, JC-F = 245.0 Hz), 157.3, 153.4, 144.9, 136.7,
130.0 (d, JC-F = 8.0 Hz), 130.0, 129.9 (d, JC-F = 3.0 Hz),
124.8, 115.6 (d, JC-F = 22.0 Hz), 53.2, 34.3, 32.7, 31.9,
22.0; LC/MS (ESI+): m/z: calcd for C19H19FN2OS: 342.44,
[M + H]+; found: 343.05.
3-Cycloheptyl-7-(4-fluorophenyl)thieno[3,2-d]pyrimidin-
4(3H)-one (4–28). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(4-fluoro-
phenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol),
CH(OEt)3 (1 mL), cycloheptylamine (0.096 mL, 0.76 mmol),
and AcOH (0.1 mL) gave the title compound 4–28 (126 mg,
0.37 mmol, 92% yield): 1H NMR (400 MHz, CDCl3) δ 8.19
(s, 1H), 7.82–7.76 (m, 3H), 7.18–7.12 (m, 2H), 5.03–4.96
(m, 1H), 2.11–1.58 (m, 12H); 13C NMR (100 MHz, CDCl3)
δ 162.6 (d, JC-F = 246.0 Hz), 156.9, 153.3, 145.4, 136.7,
130.0 (d, JC-F = 8.0 Hz), 129.9, 129.9 (d, JC-F = 3.0 Hz),
124.8, 115.6 (d, JC-F = 22.0 Hz), 55.4, 35.4, 27.3, 25.2; LC/
MS (ESI+): m/z: calcd for C19H19FN2OS: 342.44, [M + H]+;
found: 343.00.
3-Cyclooctyl-7-(4-fluorophenyl)thieno[3,2-d]pyrimidin-
4(3H)-one (4–29). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(4-fluoro-
phenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.105 mL, 0.76 mmol),
and AcOH (0.1 mL) gave the title compound 4–29 (45 mg,
0.13 mmol, 39% yield): 1H NMR (400 MHz, CDCl3) δ 8.18
(s, 1H), 7.82–7.78 (m, 3H), 7.18–7.13 (m, 2H), 5.17–5.10
(m, 1H), 2.03–1.61 (m, 14H); 13C NMR (100 MHz, CDCl3)
δ 162.6 (d, JC-F = 246.0 Hz), 157.0, 153.3, 145.7, 136.7,
130.0 (d, JC-F = 8.0 Hz), 130.0, 129.9 (d, JC-F = 3.0 Hz),
124.8, 115.6 (d, JC-F = 21.0 Hz), 54.2, 34.1, 26.3, 26.0,
25.0; LC/MS (ESI+): m/z: calcd for C20H21FN2OS: 356.46,
[M + H]+; found: 357.05.
0.40 mmol),
CH(OEt)3
(1 mL),
trans-4-
methylcyclohexylamine (0.1 mL, 0.76 mmol), and AcOH
(0.1 mL) gave the title compound 4–24 (74 mg, 0.21 mmol,
1
54% yield): H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H),
7.86 (s, 1H), 7.65–7.59 (m, 2H), 7.45–7.40 (m, 1H),
7.10–7.05 (m, 1H), 4.86 (tt, J = 3.7, 12.4 Hz, 1H),
2.06–2.02 (m, 2H), 1.92–1.88 (m, 2H), 1.75–1.65 (m, 2H),
1.56–1.44 (m, 1H), 1.31–1.21 (m, 2H), 0.98 (d, J = 6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, JC-F = 243.0
Hz), 157.3, 153.3, 145.0, 136.3 (d, JC-F = 3.0 Hz), 135.7 (d,
JC-F = 8.0 Hz), 130.8, 130.1 (d, JC-F = 9.0 Hz), 124.9, 123.8
(d, JC-F = 3.0 Hz), 115.2 (d, JC-F = 23.0 Hz), 114.8 (d, JC-F
=
21.0 Hz), 53.2, 34.3, 32.7, 31.9, 22.0; LC/MS (ESI+): m/z:
calcd for C19H19FN2OS: 342.44, [M + H]+; found: 343.00.
3-Cycloheptyl-7-(3-fluorophenyl)thieno[3,2-d]pyrimi-
din-4(3H)-one (4–25). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(3-fluoro-
phenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol),
CH(OEt)3 (1 mL), cycloheptylamine (0.096 mL, 0.76 mmol),
and AcOH (0.1 mL) gave the title compound 4–25 (32 mg,
0.09 mmol, 23% yield): 1H NMR (400 MHz, CDCl3) δ 8.21
(s, 1H), 7.86 (s, 1H), 7.65–7.60 (m, 2H), 7.46–7.40 (m,
1H), 7.11–7.06 (m, 1H), 5.03–4.98 (m, 1H), 2.10–1.65 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, JC-F
=
244.0 Hz), 156.9, 153.3, 145.5, 136.3 (d, JC-F = 2.2 Hz),
135.7 (d, JC-F = 9.0 Hz), 130.7, 130.1 (d, JC-F = 8.0 Hz),
124.9, 123.8 (d, JC-F = 3.0 Hz), 115.2 (d, JC-F = 23.0 Hz),
114.8 (d, JC-F = 21.0 Hz), 55.4, 35.5, 27.3, 25.2; LC/MS
(ESI+): m/z: calcd for C19H19FN2OS: 342.44, [M + H]+;
found: 343.05.
3-Cyclooctyl-7-(3-fluorophenyl)thieno[3,2-d]pyrimidin-
4(3H)-one(4–26). Following the same procedure as with com-
pound 4–1, the reaction of methyl 3-amino-4-(3-fluorophe-
nyl)thiophene-2-carboxylate
(100 mg,
0.40 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.105 mL, 0.76 mmol),
and AcOH (0.1 mL) gave the title compound 4–26 (83 mg,
7-(2-Chlorophenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–30). Following the same
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
procedure as with compound 4–1, the reaction of methyl 3-
amino-4-(2-chlorophenyl)thiophene-2-carboxylate (100 mg,
7-(3-Chlorophenyl)-3-cycloheptylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–34). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(3-chloro-
phenyl)thiophene-2-carboxylate (100 mg, 0.37 mmol),
CH(OEt)3 (1 mL), cycloheptylamine (0.09 mL, 0.71 mmol),
and AcOH (0.1 mL) gave the title compound 4–34 (58 mg,
0.16 mmol, 44% yield): 1H NMR (400 MHz, CDCl3) δ 8.21
(s, 1H), 7.88–7.87 (m, 1H), 7.85 (s, 1H), 7.72 (dt, J = 1.5,
7.5 Hz, 1H), 7.43–7.33 (m, 2H), 5.04–4.97 (m, 1H),
2.12–1.61 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 156.9,
153.3, 145.5, 136.1, 135.4, 134.5, 130.8, 129.8, 128.3,
127.9, 126.3, 124.9, 55.4, 35.4, 27.3, 25.2; LC/MS (ESI+):
m/z: calcd for C19H19ClN2OS: 358.89, [M + H]+;
found: 359.00.
0.37 mmol),
CH(OEt)3
(1 mL),
trans-4-
methylcyclohexylamine (0.093 mL, 0.71 mmol), and AcOH
(0.1 mL) gave the title compound 4–30 (118 mg, 0.33 mmol,
89% yield): 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.86
(s, 1H), 7.54–7.46 (m, 2H), 7.39–7.32 (m, 2H), 4.85 (tt, J =
3.7, 12.4, 1H), 2.05–2.01 (m, 2H), 1.90–1.87 (m, 2H),
1.72–1.62 (m, 2H), 1.55–1.41 (m, 1H), 1.30–1.20 (m, 2H),
0.97 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
157.3, 154.2, 145.1, 135.2, 133.6, 133.2, 132.5, 132.0,
130.1, 129.5, 126.7, 123.8, 53.2, 34.3, 32.7, 31.9, 22.0; LC/
MS (ESI+): m/z: calcd for C19H19ClN2OS: 358.89, [M +
H]+; found: 359.05.
7-(2-Chlorophenyl)-3-cycloheptylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–31). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(2-chloro-
phenyl)thiophene-2-carboxylate (100 mg, 0.37 mmol),
CH(OEt)3 (1 mL), cycloheptylamine (0.09 mL, 0.71 mmol),
and AcOH (0.1 mL) gave the title compound 4–31 (42 mg,
0.12 mmol, 31% yield): 1H NMR (400 MHz, CDCl3) δ 8.16
(s, 1H), 7.86 (s, 1H), 7.55–7.45 (m, 2H), 7.39–7.32 (m,
2H), 5.02–4.96 (m, 1H), 2.11–1.61 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 156.9, 154.2, 145.6, 135.2, 133.6,
133.1, 132.5, 132.0, 130.1, 129.5, 126.7, 123.8, 55.4, 35.4,
27.4, 25.2; LC/MS (ESI+): m/z: calcd for C19H19ClN2OS:
358.89, [M + H]+; found: 359.00.
7-(2-Chlorophenyl)-3-cyclooctylthieno[3,2-d]pyrimidin-
4(3H)-one (4–32). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(2-chloro-
phenyl)thiophene-2-carboxylate (100 mg, 0.37 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.099 mL, 0.71 mmol),
and AcOH (0.1 mL) gave the title compound 4–32 (111 mg,
0.30 mmol, 80% yield): 1H NMR (400 MHz, CDCl3) δ 8.14
(s, 1H), 7.86 (s, 1H), 7.53–7.46 (m, 2H), 7.39–7.32 (m,
2H), 5.14–5.11 (m, 1H), 2.00–1.59 (m, 14H); 13C NMR
(100 MHz, CDCl3) δ 157.0, 154.2, 145.9, 135.2, 133.6,
133.1, 132.5, 132.0, 130.1, 129.5, 126.7, 123.8, 54.2, 34.1,
26.3, 26.0, 25.0; LC/MS (ESI+): m/z: calcd for
C20H21ClN2OS: 372.92, [M + H]+; found: 373.00.
7-(3-Chlorophenyl)-3-cyclooctylthieno[3,2-d]pyrimidin-
4(3H)-one (4–35). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(3-chloro-
phenyl)thiophene-2-carboxylate (100 mg, 0.37 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.099 mL, 0.71 mmol),
and AcOH (0.1 mL) gave the title compound 4–35 (95 mg,
0.25 mmol, 69% yield): 1H NMR (400 MHz, CDCl3) δ 8.19
(s, 1H), 7.88 (t, J = 1.8 Hz, 1H), 7.71 (dt, J = 1.4, 7.4 Hz,
1H), 7.40–7.32 (m, 2H), 5.16–5.11 (m, 1H), 2.04–1.61 (m,
14H); 13C NMR (100 MHz, CDCl3) δ 156.9, 153.3, 145.8,
136.1, 135.4, 134.5, 130.8, 129.8, 128.3, 127.9, 126.3,
124.9, 54.2, 34.1, 26.3, 26.0, 25.0; LC/MS (ESI+): m/z: calcd
for C20H21ClN2OS: 372.92, [M + H]+; found: 373.00.
7-(4-Chlorophenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–36). Following the same
procedure as with compound 4–1, the reaction of
methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate
(100 mg, 0.37 mmol), CH(OEt)3 (1 mL), trans-4-
methylcyclohexylamine (0.093 mL, 0.71 mmol), and AcOH
(0.1 mL) gave the title compound 4–36 (89 mg, 0.25 mmol,
1
67% yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H),
7.82 (s, 1H), 7.80–7.76 (m, 2H), 7.45–7.42 (m, 2H), 4.86
(tt, J = 3.7, 12.4, 1H), 2.05–2.01 (m, 2H), 1.92–1.88 (m,
2H), 1.74–1.64 (m, 2H), 1.56–1.44 (m, 1H), 1.31–1.20 (m,
2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 157.3, 153.3, 145.0, 136.5, 134.0, 132.2, 130.3, 129.5,
128.8, 124.9, 53.2, 34.3, 32.7, 31.9, 22.0; LC/MS (ESI+):
m/z: calcd for C19H19ClN2OS: 358.89, [M + H]+;
found: 359.00.
7-(3-Chlorophenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–33). Following the same pro-
cedure aswith compound4–1, thereaction ofmethyl 3-amino-
4-(3-chlorophenyl)thiophene-2-carboxylate (100 mg, 0.37
mmol), CH(OEt)3 (1 mL), trans-4-methylcyclohexylamine
(0.093 mL, 0.71 mmol), and AcOH (0.1 mL) gave the title
7-(4-Chlorophenyl)-3-cycloheptylthieno[3,2-d]pyrimi-
din-4(3H)-one (4–37). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(4-chloro-
phenyl)thiophene-2-carboxylate (100 mg, 0.37 mmol),
CH(OEt)3 (1 mL), cycloheptylamine (0.09 mL, 0.71 mmol),
and AcOH (0.1 mL) gave the title compound 4–37 (97 mg,
0.27 mmol, 73% yield): 1H NMR (400 MHz, CDCl3) δ 8.19
(s, 1H), 7.82 (s, 1H), 7.79–7.76 (m, 2H), 7.46–7.42 (m,
2H), 5.04–4.96 (m, 1H), 2.12–1.61 (m, 12H).
1
compound 4–33 (93 mg, 0.26 mmol, 70% yield): H NMR
(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.88–7.87 (m, 1H), 7.86
(s, 1H), 7.72 (dt, J = 1.5, 7.5 Hz, 1H), 7.42–7.34 (m, 2H),
4.86 (tt, J = 3.7, 12.4, 1H), 2.06–2.02 (m, 2H), 1.92–1.89
(m, 2H), 1.75–1.65 (m, 2H), 1.55–1.44 (m, 1H), 1.31–1.21
(m, 2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.3, 153.3, 145.0, 136.2, 135.4, 134.5, 130.8,
129.9, 128.3, 128.0, 126.3, 124.9, 53.2, 34.3, 32.7, 31.9,
22.0; LC/MS (ESI+): m/z: calcd for C19H19ClN2OS: 358.89,
[M + H]+; found: 359.00.
13C NMR (100 MHz, CDCl3) δ 156.9, 153.3, 145.5, 136.5,
133.9, 132.2, 130.3, 129.5, 128.8, 124.9, 55.4, 35.5, 25.2; LC/
MS (ESI+): m/z: calcd for C19H19ClN2OS: 358.89, [M + H]+;
found: 359.05.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1445

BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
7-(4-Chlorophenyl)-3-cyclooctylthieno[3,2-d]pyrimidin-
4(3H)-one(4–38). Following the same procedure as with com-
pound 4–1, the reaction of methyl 3-amino-4-(4-chlorophe-
as with compound 4–1, the reaction of methyl 3-amino-4-(m-
tolyl)thiophene-2-carboxylate (100 mg, 0.40 mmol),
CH(OEt)3 (1 mL), trans-4-methylcyclohexylamine (0.101
nyl)thiophene-2-carboxylate
(100 mg,
0.37 mmol),
mL, 0.77 mmol), and AcOH (0.1 mL) gave the title compound
4–42 (43 mg, 0.13 mmol, 32% yield): H NMR (400 MHz,
1
CH(OEt)3 (1 mL), cyclooctylamine (0.099 mL, 0.71 mmol),
and AcOH (0.1 mL) gave the title compound 4–38 (37 mg,
0.10 mmol, 27% yield): 1H NMR (400 MHz, CDCl3) δ 8.18
(s, 1H), 7.83–7.76 (m, 3H), 7.45–7.42 (m, 2H), 5.16–5.10
(m, 1H), 2.05–1.61 (m, 14H); 13C NMR (100 MHz, CDCl3)
δ 156.9, 153.3, 145.7, 136.5, 133.9, 132.2, 130.2, 129.5,
128.8, 124.9, 54.2, 34.1, 26.3, 26.0, 25.0; LC/MS (ESI+):
m/z: calcd for C20H21ClN2OS: 372.92, [M + H]+;
found: 373.05.
3-(trans-4-Methylcyclohexyl)-7-(o-tolyl)thieno[3,2-d]pyr-
imidin-4(3H)-one (4–39). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-(o-
tolyl)thiophene-2-carboxylate
CH(OEt)3 (1 mL), trans-4-methylcyclohexylamine (0.101
CDCl3) δ 8.20 (s, 1H), 7.80 (s, 1H), 7.61–7.59 (m, 2H),
7.38–7.34 (m, 1H), 7.21–7.19 (m, 1H), 4.86 (tt, J = 3.7,
12.4 Hz, 1H), 2.43 (s, 3H), 2.05–2.01 (m, 2H), 1.91–1.88
(m, 2H), 1.75–1.64 (m, 2H), 1.55–1.44 (m, 1H), 1.31–1.21
(m, 2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.4, 153.6, 144.8, 138.2, 138.0, 133.7, 130.2,
129.0, 128.7, 128.5, 125.4, 124.7, 53.1, 34.3, 32.7, 31.9,
22.0, 21.6; LC/MS (ESI+): m/z: calcd for C20H22N2OS:
338.47, [M + H]+; found: 339.05.
3-Cycloheptyl-7-(m-tolyl)thieno[3,2-d]pyrimidin-4(3H)-
one (4–43). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(m-tolyl)
thiophene-2-carboxylate (100 mg, 0.40 mmol), CH(OEt)3
(1 mL), cycloheptylamine (0.098 mL, 0.77 mmol), and AcOH
(0.1 mL) gave the title compound 4–43 (79 mg, 0.23 mmol,
(100 mg,
0.40 mmol),
mL, 0.77 mmol), and AcOH (0.1 mL) gave the title compound
4–39 (86 mg, 0.25 mmol, 64% yield): H NMR (400 MHz,
1
1
CDCl3) δ 8.12 (s, 1H), 7.63 (s, 1H), 7.32–7.24 (m, 4H),
4.84 (tt, J = 3.7, 12.4 Hz, 1H), 2.24 (s, 3H), 2.04–2.00 (m,
2H), 1.90–1.86 (m, 2H), 1.71–1.62 (m, 2H), 1.55–1.42 (m,
1H), 1.30–1.19 (m, 2H), 0.96 (d, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.4, 154.4, 145.0, 138.6, 137.0,
133.5, 131.5, 130.5, 130.4, 128.4, 125.8, 123.8, 53.2, 34.3,
32.6, 31.9, 22.0, 20.5; LC/MS (ESI+): m/z: calcd for
C20H22N2OS: 338.47, [M + H]+; found: 339.10.
58% yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H),
7.79 (s, 1H), 7.61–7.59 (m, 2H), 7.37–7.33 (m, 1H),
7.20–7.18 (m, 1H), 5.03–4.97 (m, 1H), 2.43 (s, 3H),
2.10–1.62 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 157.0,
153.6, 145.3, 138.2, 138.0, 133.7, 130.1, 129.0, 128.7,
128.5, 125.4, 124.7, 55.3, 35.5, 27.4, 25.2, 21.6; LC/MS
(ESI+): m/z: calcd for C20H22N2OS: 338.47, [M + H]+; found:
339.10.
3-Cycloheptyl-7-(o-tolyl)thieno[3,2-d]pyrimidin-4(3H)-
one (4–40). Following the same procedure as with compound
4–1, the reaction of methyl 3-amino-4-(o-tolyl)thiophene-2-
carboxylate (100 mg, 0.40 mmol), CH(OEt)3 (1 mL), cyclo-
heptylamine (0.098 mL, 0.77 mmol), and AcOH (0.1 mL)
gave the title compound 4–40 (44 mg, 0.13 mmol, 33% yield):
1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.63 (s, 1H),
7.34–7.24 (m, 4H), 5.01–4.96 (m, 1H), 2.24 (s, 3H),
2.11–2.06 (m, 2H), 1.90–1.59 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 157.1, 154.4, 145.5, 138.6, 137.0, 133.5,
131.4, 130.5, 130.4, 128.4, 125.8, 123.8, 55.4, 35.4, 27.4,
25.2, 20.5; LC/MS (ESI+): m/z: calcd for C20H22N2OS:
338.47, [M + H]+; found: 339.10.
3-Cyclooctyl-7-(m-tolyl)thieno[3,2-d]pyrimidin-4(3H)-
one (4–44). Following the same procedure as with compound
4–1, the reaction of methyl 3-amino-4-(m-tolyl)thiophene-2-
carboxylate(100 mg, 0.37 mmol), CH(OEt)3 (1 mL), cyclooc-
tylamine (0.107 mL, 0.77 mmol), and AcOH (0.1 mL) gave
the title compound 4–44 (98 mg, 0.28 mmol, 69% yield): 1H
NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.78 (s, 1H),
7.61–7.59 (m, 2H), 7.37–7.33 (m, 1H), 7.20–7.18 (m, 1H),
5.16–5.10 (m, 1H), 2.42 (s, 3H), 2.04–1.60 (m, 14H); 13C
NMR (100 MHz, CDCl3) δ 157.0 153.6, 145.6, 138.2,
138.0, 133.7, 130.1, 129.0, 128.7, 128.5, 125.4, 124.7,
54.1, 34.1, 26.4, 26.0, 25.0, 21.6; LC/MS (ESI+): m/z: calcd
for C21H24N2OS: 352.50, [M + H]+; found: 353.10.
3-Cyclooctyl-7-(o-tolyl)thieno[3,2-d]pyrimidin-4(3H)-
one (4–41). Following the same procedure as with compound
4–1, the reaction of methyl 3-amino-4-(o-tolyl)thiophene-2-
carboxylate(100 mg, 0.37 mmol), CH(OEt)3 (1 mL), cyclooc-
tylamine (0.107 mL, 0.77 mmol), and AcOH (0.1 mL) gave
the title compound 4–41 (85 mg, 0.24 mmol, 61% yield): 1H
NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.63 (brd, J = 0.8
Hz, 1H), 7.30–7.23 (m, 4H), 5.16–5.07 (m, 1H), 2.24 (s,
3H), 2.04–1.59 (m, 14H); 13C NMR (75 MHz, CDCl3) δ
157.1, 154.4, 145.8, 138.6, 137.0, 133.5, 131.5, 130.5,
130.4, 128.4, 125.8, 123.8, 54.2, 34.1, 26.3, 26.1, 25.0,
20.5; LC/MS (ESI+): m/z: calcd for C21H24N2OS: 352.50,
[M + H]+; found: 353.05.
3-(trans-4-Methylcyclohexyl)-7-(p-tolyl)thieno[3,2-d]pyr-
imidin-4(3H)-one (4–45). Following the same procedure as
with compound 4–1, the reaction of methyl 3-amino-4-(p-
tolyl)thiophene-2-carboxylate
(100 mg,
0.40 mmol),
CH(OEt)3 (1 mL), trans-4-methylcyclohexylamine (0.101
mL, 0.77 mmol), and AcOH (0.1 mL) gave the title compound
4–45 (116 mg, 0.34 mmol, 86% yield): 1H NMR (400 MHz,
CDCl3) δ 8.19 (s, 1H), 7.78 (s, 1H), 7.71–7.69 (m, 2H),
7.29–7.27 (m, 2H), 4.86 (tt, J = 3.7, 12.4 Hz, 1H), 2.40 (s,
3H), 2.05–2.01 (m, 2H), 1.91–1.88 (m, 2H), 1.74–1.64 (m,
2H), 1.55–1.44 (m, 1H), 1.31–1.21 (m, 2H), 0.98 (d, J = 6.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 153.6,
144.8, 137.9, 137.8, 130.9, 129.7, 129.4, 128.2, 124.7,
53.1, 34.3, 32.7, 31.9, 22.0, 21.3; LC/MS (ESI+): m/z: calcd
for C20H22N2OS: 338.47, [M + H]+; found: 339.10.
3-(trans-4-Methylcyclohexyl)-7-(m-tolyl)thieno[3,2-d]
pyrimidin-4(3H)-one (4–42). Following the same procedure
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1446

BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
3-Cycloheptyl-7-(p-tolyl)thieno[3,2-d]pyrimidin-4(3H)-
3-Cyclooctyl-7-(2-methoxyphenyl)thieno[3,2-d]pyrimi-
din-4(3H)-one (4–50). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-(2-methox-
yphenyl)thiophene-2-carboxylate (100 mg, 0.38 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.101 mL, 0.72 mmol),
and AcOH (0.1 mL) gave the title compound 4–50 (97 mg,
0.26 mmol, 69% yield): 1H NMR (400 MHz, CDCl3) δ 8.14
(s, 1H), 7.93 (s, 1H), 7.63 (dd, J = 1.7, 7.5 Hz, 1H), 7.36
(ddd, J = 1.8, 7.5, 8.3 Hz, 1H), 7.07 (td, J = 1.1, 7.5 Hz,
1H), 7.02 (dd, J = 0.9, 8.3 Hz, 1H), 5.16–5.09 (m, 1H), 3.82
(s, 3H), 2.00–1.59 (m, 14H); 13C NMR (100 MHz, CDCl3)
δ 157.1, 157.1, 154.5, 145.4, 133.7, 132.9, 131.4, 129.4,
123.6, 122.5, 120.6, 111.4, 55.7, 54.0, 34.1, 26.4, 26.0,
25.0; LC/MS (ESI+): m/z: calcd for C21H24N2O2S: 368.50,
[M + H]+; found: 369.05.
one (4–46). Following the same procedure as with
compound 4–1, the reaction of methyl 3-amino-4-(p-tolyl)
thiophene-2-carboxylate (100 mg, 0.40 mmol), CH(OEt)3
(1 mL), cycloheptylamine (0.098 mL, 0.77 mmol), and AcOH
(0.1 mL) gave the title compound 4–46 (41 mg, 0.12 mmol,
30% yield): 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.78
(s, 1H), 7.70–7.68 (m, 2H), 7.29–7.27 (m, 2H), 5.03–4.98
(m, 1H), 2.40 (s, 3H), 2.10–1.62 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 157.0, 153.6, 145.3, 137.9, 137.8, 130.9,
129.6, 129.3, 128.2, 124.7, 55.3, 35.5, 27.4, 25.2, 21.3; LC/
MS (ESI+): m/z: calcd for C20H22N2OS: 338.47, [M + H]+;
found: 339.05.
3-Cyclooctyl-7-(p-tolyl)thieno[3,2-d]pyrimidin-4(3H)-
one (4–47). Following the same procedure as with compound
4–1, the reaction of methyl 3-amino-4-(p-tolyl)thiophene-2-
carboxylate (100 mg, 0.37 mmol), CH(OEt)3 (1 mL), cyclooc-
tylamine (0.107 mL, 0.77 mmol), and AcOH (0.1 mL) gave the
title compound 4–47 (75 mg, 0.21 mmol, 53% yield): 1H NMR
(400 MHz, CDCl3) δ 8.18 (s, 1H), 7.77 (s, 1H), 7.71–7.69 (m,
2H), 7.28–7.26 (m, 2H), 5.16–5.10 (m, 1H), 2.40 (s, 3H),
2.04–1.61 (m, 14H); 13C NMR (100 MHz, CDCl3) δ 157.1,
153.6, 145.5, 137.9, 137.8, 131.0, 129.6, 129.3, 128.2, 124.7,
54.1, 34.1, 26.1, 26.0, 25.0, 21.3; LC/MS (ESI+): m/z: calcd
for C21H24N2OS: 352.50, [M + H]+; found: 353.05
7-(3-Methoxyphenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–51). Following the same
procedure as with compound 4–1, the reaction of methyl
3-amino-4-(3-methoxyphenyl)thiophene-2-carboxylate (100
mg,
0.38 mmol),
CH(OEt)3
(1 mL),
trans-4-
methylcyclohexylamine (0.095 mL, 0.72 mmol), and AcOH
(0.1 mL) gave the title compound 4–51 (102 mg, 0.29 mmol,
76% yield): 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.83
(s, 1H), 7.42–7.35 (m, 3H), 6.96–6.91 (m, 1H), 4.86 (tt, J =
3.7, 12.4 Hz, 1H), 3.87 (s, 3H), 2.05–2.01 (m, 2H),
1.91–1.88 (m, 2H), 1.75–1.65 (m, 2H), 1.55–1.44 (m, 1H),
1.31–1.20 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 159.7, 157.3, 153.5, 144.8, 137.6, 135.0,
130.4, 129.6, 124.8, 120.7, 114.1, 113.4, 55.3, 53.1, 34.3,
32.6, 31.9, 22.0; LC/MS (ESI+): m/z: calcd for C20H22N2O2S:
354.47, [M + H]+; found: 355.05.
7-(2-Methoxyphenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–48). Following the same
procedure with compound 4–1, the reaction of methyl 3-
amino-4-(2-methoxyphenyl)thiophene-2-carboxylate (100
mg,
0.38 mmol),
CH(OEt)3
(1 mL),
trans-4-
methylcyclohexylamine (0.095 mL, 0.72 mmol), and AcOH
(0.1 mL) gave the title compound 4–48 (86 mg, 0.24 mmol,
64% yield): H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H),
3-Cycloheptyl-7-(3-methoxyphenyl)thieno[3,2-d]pyrimi-
din-4(3H)-one (4–52). Following the same procedure
with compound 4–1, the reaction of methyl 3-amino-4-(3-
methoxyphenyl)thiophene-2-carboxylate (100 mg, 0.38
mmol), CH(OEt)3 (1 mL), cycloheptylamine (0.092 mL,
0.72 mmol), and AcOH (0.1 mL) gave the title compound
1
7.94 (s, 1H), 7.63 (dd, J = 1.8, 7.5 Hz, 1H), 7.36 (ddd, J =
1.8, 7.5, 8.3 Hz, 1H), 7.07 (td, J = 1.0, 7.5 Hz, 1H),
7.04–7.02 (m, 1H), 4.85 (tt, J = 3.6, 12.3 Hz, 1H), 3.82 (s,
3H), 2.04–2.00 (m, 2H), 1.90–1.87 (m, 2H), 1.72–1.62 (m,
2H), 1.52–1.43 (m, 1H), 1.30–1.20 (m, 2H), 0.97 (d, J = 6.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 157.1,
154.5, 144.7, 133.7, 132.9, 131.4, 129.4, 123.6, 122.5, 120.6,
111.4, 55.7, 53.0, 34.3, 32.7, 31.9, 22.0; LC/MS (ESI+): m/z:
calcd for C20H22N2O2S: 354.47, [M + H]+; found: 355.05
3-Cycloheptyl-7-(2-methoxyphenyl)thieno[3,2-d]pyri-
midin-4(3H)-one (4–49). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-(2-methoxy-
1
4–52 (91 mg, 0.26 mmol, 68% yield): H NMR (400 MHz,
CDCl3) δ 8.19 (s, 1H), 7.82 (s, 1H), 7.42–7.35 (m, 3H),
6.95–6.90 (m, 1H), 5.03–4.96 (m, 1H), 3.86 (s, 3H),
2.09–1.61 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 159.6,
156.8, 153.3, 145.2, 137.4, 134.8, 130.2, 129.4, 124.6,
120.5, 113.9, 113.2, 55.1, 35.3, 27.2, 25.0; LC/MS (ESI+):
m/z: calcd for C20H22N2O2S: 354.47, [M + H]+;
found: 355.05.
phenyl)thiophene-2-carboxylate
CH(OEt)3 (1 mL), cycloheptylamine (0.092 mL, 0.72 mmol),
(100 mg,
0.38 mmol),
3-Cyclooctyl-7-(3-methoxyphenyl)thieno[3,2-d]pyrimi-
din-4(3H)-one (4–53). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-(3-methox-
yphenyl)thiophene-2-carboxylate (100 mg, 0.38 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.101 mL, 0.72 mmol),
and AcOH (0.1 mL) gave the title compound 4–53 (102 mg,
0.28 mmol, 73% yield): 1H NMR (400 MHz, CDCl3) δ 8.18
(s, 1H), 7.82 (s, 1H), 7.42–7.35 (m, 3H), 6.95–6.90 (m,
1H), 5.16–5.09 (m, 1H), 3.86 (s, 3H), 2.04–1.60 (m, 14H);
13C NMR (100 MHz, CDCl3) δ 159.8, 157.0, 153.5, 145.6,
137.6, 135.1, 130.3, 129.6, 124.8, 120.7, 114.1, 113.4,
and AcOH (0.1 mL) gave the title compound 4–49 (110 mg,
1
0.31 mmol, 81% yield): H NMR (400 MHz, CDCl3) δ 8.15
(s, 1H), 7.94 (s, 1H), 7.63 (dd, J = 1.8, 7.6 Hz, 1H), 7.36 (ddd,
J = 1.8, 7.5, 8.3 Hz, 1H), 7.07 (td, J = 1.1, 7.5 Hz, 1H), 7.02
(dd, J = 0.8, 8.3 Hz, 1H), 5.03–4.96 (m, 1H), 3.82 (s, 3H),
2.10–1.61 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 157.1,
157.1, 154.5, 145.2, 133.7, 132.9, 131.4, 129.4, 123.6, 122.5,
120.6, 111.4, 55.7, 55.3, 35.5, 27.4, 25.2; LC/MS (ESI+): m/z:
calcd for C20H22N2O2S: 354.47, [M + H]+; found: 355.05
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1447

BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
55.3, 54.2, 34.1, 26.3, 26.0, 25.0; LC/MS (ESI+): m/z: calcd
for C21H24N2O2S: 368.50, [M + H]+; found: 369.05.
7-(4-Methoxyphenyl)-3-(trans-4-methylcyclohexyl)thieno
[3,2-d]pyrimidin-4(3H)-one (4–54). Following the same
procedure as with compound 4–1, the reaction of methyl 3-
were treated to cells 75 s before mGluR activation. All data
were collected andanalyzed usingFDSS6000andrelated soft-
ware (Hamamatsu, Japan).
Results and Discussion
amino-4-(4-methoxyphenyl)thiophene-2-carboxylate
mg, 0.38 mmol), CH(OEt)3 (1 mL),
methylcyclohexylamine (0.095 mL, 0.72 mmol), and AcOH
(100
trans-4-
The designed N3-alkyl-thienopyrimidin-4-ones 4 were pre-
pared in four steps from various arylacetonitriles 5 (R1 = H,
F, Cl, Me, or OMe) (Scheme 1). The arylacetonitriles 5 were
formylated by treatment with methyl formate and NaH in THF
to give the acrylonitriles 6 as enol forms (72–100% yields).9
The enols 6 underwent methylation by methyl sulfate and
NaH in THF to afford 7 (19–100% yields), which were con-
verted to thiophenes 8 in 17–70% yields by treatment with
methyl thioglycolate and NaOMe. The thiophenes 8 thus
obtained were reacted with various alkylamines 9 in the pres-
ence of triethyl orthoformate under acidic conditions to afford
the target compounds 4 in 23–93% yields (Scheme 1). The ref-
erence compound, pyridothienopyrimidinone 3, was synthe-
sized by a known method.8c
(0.1 mL) gave the title compound 4–54 (75 mg, 0.21 mmol,
1
56% yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H),
7.77–7.74 (m, 3H), 7.02–6.98 (m, 2H), 4.85 (tt, J = 3.7, 12.4
Hz, 1H), 3.85 (s, 3H), 2.05–2.01 (m, 2H), 1.91–1.88 (m,
2H), 1.74–1.64 (m, 2H), 1.54–1.45 (m, 1H), 1.31–1.20 (m,
2H), 0.97 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
159.4, 157.4, 153.5, 144.7, 137.5, 129.5, 129.0, 126.4, 124.7,
114.1, 55.4, 53.1, 34.3, 32.7, 31.9, 22.0; LC/MS (ESI+): m/z:
calcd for C20H22N2O2S: 354.47, [M + H]+; found: 355.05.
3-Cycloheptyl-7-(4-methoxyphenyl)thieno[3,2-d]pyri-
midin-4(3H)-one (4–55). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-(4-methoxy-
phenyl)thiophene-2-carboxylate
CH(OEt)3 (1 mL), cycloheptylamine (0.092 mL, 0.72 mmol),
(100 mg,
0.38 mmol),
The synthesized compounds were biologically evaluated
against Chem-3 cells with stably expressing mGluR1. Intra-
cellular calcium ion levels are increased by glutamate-
mediated mGluR1 activation and decreased by mGluR1
antagonists. Thus, mGluR1 antagonistic effects of the title
compounds were evaluated by measuring the changes of intra-
cellular calcium levels using FDSS6000, an imaging-based
plate reader for cellular assays.10 Percent inhibitions (% inhi-
bitions) for all the synthesized compounds were measured at
10 and 1 μM, and IC50 values were also obtained for the
selected compounds with potent inhibitory activities at these
concentrations. The inhibitory activities of the compounds
4–1 to 4–20 with R1 fixed as hydrogen and various R2 groups
are shown in Table 1. For inhibitory activities against
mGluR1, the size of the R2 group seemed very important.
The compounds 4–1 to 4–3 with small substituents such as
and AcOH (0.1 mL) gave the title compound 4–55 (115 mg,
1
0.32 mmol, 85% yield): H NMR (400 MHz, CDCl3) δ 8.19
(s, 1H), 7.77–7.73 (m, 3H), 7.02–6.98 (m, 2H), 5.03–4.96 (m,
1H), 3.85 (s, 3H), 2.10–1.58 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 159.4, 157.0, 153.5, 145.2, 137.5, 129.5, 129.0,
126.5, 124.7, 114.1, 55.4, 35.5, 27.4, 25.2; LC/MS (ESI+):
m/z: calcd for C20H22N2O2S: 354.47, [M + H]+; found: 355.05.
3-Cyclooctyl-7-(4-methoxyphenyl)thieno[3,2-d]pyrimi-
din-4(3H)-one (4–56). Following the same procedure with
compound 4–1, the reaction of methyl 3-amino-4-(4-methox-
yphenyl)thiophene-2-carboxylate (100 mg, 0.38 mmol),
CH(OEt)3 (1 mL), cyclooctylamine (0.101 mL, 0.72 mmol),
and AcOH (0.1 mL) gave the title compound 4–56 (130 mg,
0.35 mmol, 93% yield): 1H NMR (400 MHz, CDCl3) δ 8.18
(s, 1H), 7.77–7.73 (m, 3H), 7.02–6.99 (m, 2H), 5.17–5.10
(m, 1H), 3.86 (s, 3H), 2.04–1.60 (m, 14H); 13C NMR (100
MHz, CDCl3) δ 159.4, 157.1, 153.5, 145.5, 137.5, 129.4,
129.0, 126.5, 124.7, 114.1, 55.4, 53.1, 34.1, 26.3, 26.0,
25.0; LC/MS (ESI+): m/z: calcd for C21H24N2O2S: 368.50,
[M + H]+; found: 369.05.
OH
CN
OMe
CN
a
b
CN
R1
R1
R1
5
6
7
mGluR1 Assay Using FDSS6000. Chem-3 cells, which sta-
bly express mGluR1, were purchased from Milipore Co. The
cells were grown in DMEM medium supplemented with 10%
(v/v) fetal bovine serum, penicillin (100 U/mL), streptomycin
(100 μg/mL), and puromycin (10 μg/mL) at 37 ꢀC in a humid
atmosphere of 5% CO2 and 95% air. For calcium assay, cells
were harvested and dispensed into 96-well, black-walled,
clear-bottom plates at a density of 40 000 cells per well. After
18 h of incubation, cells were treated with Calcium-5 assay
reagent, which was prepared as per manufacture's instruction
(Molecular Devices Corporation, Sunnyvale, CA, USA). Dur-
ing fluorescence-based FDSS6000 assay, mGluR1 was acti-
vated using a high concentration of L-glutamate (10 μM) in
HBSS, and various concentrations of synthesized compounds
c
d
N
NH2
OMe
R1
R1
R2
N
various alkyl amines 9
S
S
O
O
4
8
Scheme 1. Synthesis of the thienopyrimidin-4-one derivatives 4a.
aReagents and conditions: (a) HCO2Me, NaH, DMF, 0 ꢀC ! rt,
72% ~ quant.; (b) (MeO)2SO2, NaH, THF, rt, 19% ~ quant; (c)
methyl thioglycolate, NaOMe in MeOH, 65 ꢀC, 17–70%; (d) alkyla-
mines 9, AcOH, CH(OEt)3, 160 ꢀC, 23–93%.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
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BULLETIN OF THE
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N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
Table 1. Inhibitory activities of the thienopyrimidin-4-ones 4 with hydrogen as R1 against mGluR1.
N
R1
R2
N
S
O
4
% Inhibitiona
Entry
Compd
R1
R2
at 10 μM
at 1 μM
IC50b in nM
1
2
3
4
5
6
7
8
4-1
4-2
4-3
4-4
4-5
4-6
4-7
4-8
4-9
4-10
4-11
4-12
4-13
4-14
4-15
4-16
4-17
4-18
4-19
4-20
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Allyl
Butyl
Isobutyl
29.85
86.88
41.82
88.02
27.98
91.17
94.91
87.67
89.86
97.31
45.44
3.57
30.10
20.62
28.31
42.07
19.53
53.99
71.66
57.40
46.09
81.60
16.11
13.17
16.14
6.56
82.12
82.36
13.32
47.77
16.92
11.35
93.37
NDc
NDc
NDc
Neopentyl
Cyclobutyl
Cyclopentyl
Cyclohexyl
2-Methylcylcohexyl
3-Methylcyclohexyl
trans-4-Methylcyclohexyl
4-Ethylcyclohexyl
4-Propylcyclohexyl
4-Isopropylcyclohexyl
4-tert-Butylcyclohexyl
Cycloheptyl
1727 38
NDc
612 44
265 59
1058 221
1205 170
197 13
NDc
9
10
11
12
13
14
15
16
17
18
19
20
21
NDc
−5.89
1.43
NDc
NDc
98.00
96.23
33.09
88.32
55.28
32.73
92.03
205 6
115 13
NDc
1155 65
NDc
NDc
Cyclooctyl
Cyclopropylmethyl
Cyclohexylmethyl
Tetrahydropyran-4-yl
1-Methylpiperidin-4-yl
Reference compound 3
6.7 1.8
a % Inhibition of increased intracellular calcium ion levels by treating L-glutamate by each tested compound at each concentration.
b Values are the mean SEM of triplicate experiments.
c Not determined.
allyl, butyl, and isobutyl showed only minimal inhibitory
activities against mGluR1, while the compound 4–4 with a
bulky neopentyl group showed moderate inhibitory activity
with an IC50 value of 1727 nM. Among the compounds 4–5
to 4–7 with cyclobutyl, cyclopentyl, and cyclohexyl groups,
the compound 4–7 showed potent activity with an IC50 value
of265 nM. Inthe case ofthecompounds4–8to 4–14 withsub-
stituted cyclohexane functionalities, the compounds 4–8 and
4–9 with 2-methyl and 3-methylcyclohexyl groups showed
only moderate inhibitory activities with IC50 values of 1058
and 1205 nM, respectively, while the compound 4–10 with
trans-4-methylcyclohexyl group showed significantly
enhanced inhibitory activity against mGluR1 (IC50 = 197 nM)
compared to the compound 4–7. However, the bulkier cyclo-
hexylsubstituentssuchasethyl,propyl,isopropylandtert-butyl
gave negative effects on inhibitory activities against mGluR1,
and the compounds 4–11 to 4–14 were barely active. The com-
pounds 4–15 and 4–16 with larger cyclic substituents such as
cycloheptyl and cyclooctyl groups showed potent inhibitory
activities with IC50 values of 205 and 115 nM, respectively.
Introduction of a methylene linker between the thienopyrimi-
din-4-one core and the cycloalkyl substituents did not improve
the inhibitory activity of the resulting derivatives (4–17 and
4–18). In the case of heterocyclic groups such as tetrahydropyr-
anyl and 1-methylpiperidinyl, the inhibitory activities of the
compounds 4–19 and 4–20 were weak. In summary, among
the7-phenylthienopyrimidin-4-ones withvariousN3-alkyl sub-
stituents, the compounds 4–10, 4–15, and 4–16 with trans-4-
methylcyclohexyl, cycloheptyl, and cyclooctyl groups, respec-
tively, showed the best inhibitory activity against mGluR1.
To further improve the inhibitory activity against mGluR1,
we fixed R2 as trans-4-methylcyclohexyl, cycloheptyl, and
cyclooctylgroups andmodifiedthe substituent R1 onthephenyl
ring attached to the thiophene. The mGluR1-overexpressing
cell-based assay results are shown in Table 2. Among the com-
pounds 4–21 to 4–29 with a fluorine substituent, the compound
4–22 showed the best inhibitory activity with an IC50 value of
107 nM. Other compounds 4–21 and 4–22 to 4–26 showed
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
Table 2. Inhibitory activities of the thienopyrimidin-4-ones 4 with various R1 groups against mGluR1.
%Inhibitiona
Entry
Compd
R1
R2
at 10 μM
at 1 μM
IC50b in nM
1
2
3
4
5
6
7
8
4-21
4-22
4-23
4-24
4-25
4-26
4-27
4-28
4-29
4-30
4-31
4-32
4-33
4-34
4-35
4-36
4-37
4-38
4-39
4-40
4-41
4-42
4-43
4-44
4-45
4-46
4-47
4-48
4-49
4-50
4-51
4-52
4-53
4-54
4-55
4-56
2-F
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
Cyclooctyl
trans-4-Methylcyclohexyl
Cycloheptyl
93.03
98.05
95.17
98.91
98.41
95.44
89.00
95.12
89.250
92.86
93.95
95.43
90.94
89.16
79.14
62.33
69.43
57.09
98.41
95.25
94.08
96.89
96.76
92.90
85.73
86.21
82.56
88.28
85.76
91.34
91.69
94.73
94.10
94.61
96.05
95.21
92.03
86.86
87.32
82.92
81.61
84.82
79.35
46.78
42.78
42.50
51.57
65.56
63.20
58.94
49.13
40.92
5.56
178 23
107 23
267 45
271 21
225 15
253 32
NDc
3-F
4-F
NDc
9
NDc
NDc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
2-Cl
494 42
353 54
620 95
NDc
3-Cl
NDc
4-Cl
NDc
15.39
7.67
NDc
NDc
2-Me
3-Me
4-Me
2-OMe
3-OMe
4-OMe
86.99
82.54
74.89
61.36
91.20
67.74
35.70
29.32
31.53
37.98
38.91
54.99
42.55
53.06
59.42
68.54
77.72
64.78
93.37
262 28
291 25
435 29
440 116
615 144
288 29
NDc
NDc
NDc
NDc
NDc
NDc
NDc
NDc
871 208
487 92
369 34
246 30
6.7 1.8
Cyclooctyl
Reference compound 3
a % Inhibition of increased intracellular calcium ion levels by treating L-glutamate by each tested compound at each concentration.
b Values are the mean SEM of triplicate binding experiments.
c Not determined.
mGluR1-inhibitoryactivities withIC50 values between 178and
271 nM, and the compounds 4–27 to 4–29 with a 4-F substitu-
ent exhibited only marginal activities. In the case of chlorine
substituent, only three compounds (4–31to 4–33) were moder-
ately active with IC50 values between 353 and 620 nM. The
compounds 4–39 to 4–44 with 2-Me or 3-Me substituent
showed high to moderate activities with IC50 values between
262 and 615 nM, while the compounds 4–45 to 4–47 with 4-
Me substituent were barely active. The compounds 4–54 to
4–56 with 4-OMe substituent were more active than the
compounds 4–48 ~ 4–53 with 2-OMe or 3-OMe substituent,
for which the inhibitory results are different from those of the
compounds with other substituents. Most compounds with
ortho substituents such as F, Cl, and Me are more active than
the compounds with meta and para substituents.
Atotal of56 N3-alkyl-thienopyrimidin-4-onesweresynthe-
sized and biologically evaluated against mGluR1 and, among
those synthesized compounds, the compounds 4–16 and 4–22
were the most active with IC50 values of 115 and 107 nM,
respectively.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1450

BULLETIN OF THE
Article
N3-Alkyl-Thienopyrimidin-4-Ones as mGluR1 Antagonists
KOREAN CHEMICAL SOCIETY
2004, 46, 609; (c) L. J. Martin, C. D. Blackstone, R. L.
Huganir, D. L. Price, Neuron 1992, 9, 259; (d) A. Simonyi,
R. T. Ngomba, M. Storto, M. V. Catania, L. A. Miller, B.
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Conclusion
Various alkyl groups and aryl groups were introduced into
the thienopyrimidin-4-one core structure, resulting in the
synthesis of a total of 56 N3-alkyl-thienopyrimidin-4-one deri-
vatives, which were biologically evaluated against mGluR1.
Structure–activity relationship study revealed that, in the case
of the alkyl groups bonded to the thienopyrimidin-4-one ring,
trans-4-methylcyclohexyl, cycloheptyl, and cyclooctyl
groups were most effective for inhibitory activities against
mGluR1, while among the aryl groups substituted at the 7-
position, 2-fluorophenyl group was the best to enhance the
inhibitory activities. Taken together, the compounds 4–16
and 4–22 exhibited the most potent inhibitory activities with
IC50 values of 115 and 107 nM, respectively. Further struc-
ture–activity relationship studies on these thienopyrimidin-
4-one compounds are in progress and will be reported in
due course.
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Acknowledgments. This research was supported by the
Basic
Science
Research
Program
(NRF-2013-
R1A1A2A10009907) funded by the National Research Foun-
dation of Korea (NRF). Additional funding was provided by
the Korea Institute of Science and Technology (KIST) Institu-
tional Program (2E25580, 2E25240, and 2E25473).
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Bull. Korean Chem. Soc. 2015, Vol. 36, 1439–1451
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1451