1,3,4-Thiadiazol-2-amine Derivatives as Urotensin-II Receptor (UT) Antagonists

Full text of DOI:10.1002/bkcs.10475

Note
DOI: 10.1002/bkcs.10475
BULLETIN OF THE
C. J. Lim et al.
KOREAN CHEMICAL SOCIETY
1,3,4-Thiadiazol-2-amine Derivatives as Urotensin-II Receptor (UT)
Antagonists
Chae Jo Lim,†,‡ Ju Young Jang,†,‡ Sung Hwan Kim,†,‡ Byung Ho Lee,†
Kwang-Seok Oh,†,‡ and Kyu Yang Yi†,‡,
*
†Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.
*E-mail: kyyi@krict.re.kr
‡Department of Medicinal Chemistry and Pharmacology, University of Science and Technology,
Daejeon 34113, Korea
Received May 18, 2015, Accepted June 12, 2015, Published online September 1, 2015
Keywords: Urotensin-II receptor (UT), UT antagonists, 1,3,4-Thiadiazol-2-amine, Cardiovascular disease
Because urotensin-II (U-II), the most potent of all vasocon-
strictors, is involved in the regulation of cardiovascular func-
tions, it has received great attention as a potential therapeutic
target.1 U-II, a cysteine-linked cyclic peptide, is expressed in a
variety of tissues, including blood vessels, heart, liver, kidney,
skeletal muscle, and lung.2 The effects of this peptide are
mediated through its interaction with a G protein-coupled
receptor known as GPR14 or the urotensin-II receptor
(UT).3 Upon binding of U-II to UT, complex signal transduc-
tion pathways are activated to control a wide range of physi-
ological effects associated with cardiovascular activities
including vasoconstriction, vasodilation, cell proliferation,
and hypertrophy.4 Furthermore, the results of several studies
demonstrate that elevated U-II plasma levels and increased
levels of UT expression are associated with numerous cardior-
enal and metabolic diseases, including hypertension,5 heart
failure,6 atherosclerosis,7 diabetes,8 and renal failure.9 There-
fore, UT has become one of the most promising therapeutic
targets forthe treatment of heart failure as well asa broadrange
of other cardiovascular maladies.10
Although scientists in a number of pharmaceutical compa-
nies have expended a great of effort to develop a variety of
pharmacophore derivatives of UT antagonists,11 a significant
need still exists for potent and selective UT antagonists. In our
continuing efforts,12 we utilized a virtual screening approach
using LigandScout 3.0 (inte:ligand) to uncover new chemical
scaffolds that could serve as UT antagonists. This study led to
theidentificationof1,3,4-thiadiazoleureaspossessing theary-
loxymethyl group at C-5 as hit compounds. In an experimental
investigation, we observed that the 2,4-dimethylphenoxy-
methyl derivative 1 exhibits a low UT binding affinity, which
corresponds to 6.6% inhibition at 10 μM (Figure 1). With the
aim of enhancing the binding activity, several substances were
tested in which the phenylurea group attached to 1,3,4-thiadia-
zole moiety of 1 is altered. In particular, replacement of the
phenylurea group with aminobenzyl group and further intro-
duction of piperidin-4-yloxy group, which was expected to
provide an additional interaction with U-II receptor, at the
para position of aminobenzyl group resulted in a large
increase in binding affinity. Based on these preliminary obser-
vations, we carried out the synthesis, biological evaluation,
and structure–activity relationship (SAR) study of several
1,3,4-thiadiazol-2-amine derivatives. The results of this effort,
in which a highly potent UT antagonist with a 0.13 μM of IC50
value was uncovered, are described below.
The general routes employed for the preparation of 1,3,4-
thiadiazol-2-amine derivatives 2 are outlined in Scheme 1.
Commercially available phenols 3 were treated with ethyl bro-
moacetate in the presence of potassium carbonate to produce
the corresponding 2-aryloxy ethyl acetates 4, which were then
subjected tohydrolysis with3NNaOH inmethanoltoyieldthe
respective 2-aryloxy acetic acids 5. Condensation reactions of
5 with thiosemicarbazide in phosphorus oxychloride gave
1,3,4-thiadiazol-2-amines 6,13 which then were protected with
Boc (tert-butoxycarbonyl) group to afford 7 as key intermedi-
ates. In parallel sequences, 2-substituted phenols 9 were
coupled with 1-Boc-4-hydroxypiperidine under Mitsunobu
conditions to form the corresponding ethers 10, which upon
treatment with NBS (N-bromosuccinimide) and AIBN (2,20-
azobis(2-methylpropionitrile)) in carbon tetrachloride gener-
ated benzylic bromides 11. The target compounds 2 were then
produced by simple N-alkylation reactions of 7 with 11 in the
presence of potassium carbonate followed by deprotection of
N-Boc groups of the formed products 8 with 4M HCl in
dioxane.
The binding affinities of the 1,3,4-thiadiazol-2-amine deri-
vatives 2 to membranes of HEK293 cells expressing the
human UT receptor were determined by conducting a compet-
itive binding assay with Eu-labeled U-II and a time-resolved
fluorometric (TRF) assay.14 The initial SAR study focused
on an exploration of substances containing a variety of substi-
tuents on the aryloxymethyl group at C-5 of the 1,3,4-thiadia-
zol-2-amine moiety. The results, summarized in Table 1, show
that, while the unsubstituted member of this group 2a has a
moderate binding affinity toward UT (IC50 = 1.44 μM), an
analog possessing a m-chloro group (2c) has a 1.3-fold
increasedUTbindingactivitycomparedto2a. However, repo-
sitioning the chloro substituent from the meta (2c) to the ortho
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KOREAN CHEMICAL SOCIETY
(2b) or para (2d) positions resulted in a slight reduction in the
UT binding activity. In addition, binding affinities of fluoro
substituted analogs 2e and 2f also displayed similar trends.
The results of additional studies showed that, in general, the
disubstituted analogs 2g–j and 2n–p had higher binding affi-
nities than monosubstituted derivatives 2a–f, except for the
2,4- (2k), 3,5- (2l), and 2,6- (2m) dichloro derivatives. The
3,4-dimethoxy derivative 2g displayed an enhanced UT bind-
ingactivity(IC50 = 0.87 μM)comparedtothatof2a. Whilethe
3,4-difluoro analog 2i exhibited a similar UT binding activity
asthat of2g, incorporation oftwomethylgroups attheC-3and
C-4 position (2h) led to a 2.1-fold increase in binding affinity.
Importantly, the 3,4-dichloro analog 2j was observed to have
the most potent UT binding activity (IC50 = 0.13 μM) among
all of the substances tested. In addition, other disubstituted
derivatives such as 3-Me–4-Cl (2n), 3-Cl–4-F (2o), and 3-
CF3–4-F (2p) were found to have comparatively low binding
affinities than 2j. Finally, studies were carried out to probe the
effects of substituents (Z) in place of chloro group at the meta
position of 4-(piperidin-4-yloxy)benzyl moiety. The results
demonstrate that removal (Z = H, 2q) or replacing it with
fluoro (2r) or methyl (2s) leads to large decreases in binding
affinities compared to that of the chloro analog 2j. These
Table 1. Substituents effects on the UT binding affinity of 1,3,4-
thiadiazol-2-amines.
N
N
Z
O
N
H
NH
S
X
O
Y
2
Compound
X
Y
Z
UT IC50a,b (μM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
H
2-Cl
3-Cl
4-Cl
3-F
H
H
H
H
H
H
4-OMe
4-Me
4-F
4-Cl
4-Cl
5-Cl
6-Cl
4-Cl
4-F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
1.44
1.12
1.09
1.31
1.21
1.49
0.87
0.41
0.78
0.13
1.46
2.17
3.26
0.67
0.64
0.55
2.53
3.57
4.64
4-F
3-OMe
3-Me
3-F
O
N
N
O
N
N
H
S
H
3-Cl
2-Cl
3-Cl
2-Cl
3-Me
3-Cl
3-CF3
3-Cl
3-Cl
3-Cl
1
UT IC50 = 6.6~ (10 ꢀM)
N
N
4-F
Z
O
4-Cl
4-Cl
4-Cl
N
H
NH
S
X
F
Me
O
Y
2
a UT binding affinities of compounds were determined by using a
competitive binding with Eu-U-II and a TRF assay.
b Values are means of at least two measurements.
Figure 1. Structural modification of 1,3,4-thiadiazole based UT
antagonists.
N
N
O
O
H
O
a
c
d
b
O
O
O
NH
Et
H
O
O
X
S
2
X
X
X
Y
3
Y
Y
Y
4
5
6
N
N
N
N
N
N
e
f
Z
Boc
Z
O
O
O
N
Boc
N
N
NH
NH
S
S
S
H
X
X
X
Boc
O
O
Y
Y
Y
7
2
8
Z
Z
Boc
Z
Boc
h
g
N
Br
N
OH
O
O
9
10
11
Scheme 1. (a) Ethyl bromoacetate, K2CO3, DMF, 100 ꢀC, 2 h;(b) 3N NaOH, MeOH, rt, 1 h;(c) POCl3, NH2CSNHNH2, reflux, 4 h; (d) (Boc)2O,
DMAP, THF, 50 ꢀC, 20 h; (e) 11, K2CO3, DMF, rt, 5 h; (f ) 4 M HCl in 1,4-dioxane, rt, 1 h; (g) 1-Boc-4-hydroxypiperidine, DEAD, PPh3, THF,
rt, 5 h; (h) NBS, AIBN, CCl4, reflux, 3 h.
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results indicate that the property of substituents at the meta
position of 4-(piperidin-4-yloxy)benzyl moiety might play a
critical role in determining binding to UT.
added di-tert-butyl dicarbonate (550 mg, 2.52 mmol) and
DMAP (17 mg, 0.14 mmol). The mixture was stirred at 50 ꢀ
C for 20 h. After cooling, water (50 mL) was added, and the
mixture was extracted with ethyl acetate (50 mL × 2). The
organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure.
The resulting residue was subjected to silica gel column chro-
matography (ethyl acetate/n-hexane = 1/2, v/v) to obtain the
In summary, the SAR studies described above led to the
finding that of 1,3,4-thiadiazol-2-amine derivatives, contain-
ing N-(3-chloro-4-(piperidin-4-yloxy)benzyl) group, serve
as potent UT antagonists. The results of this extensive optimi-
zation effort, probing the effects of aryloxymethyl group at C-
5 on the 1,3,4-thiadiazol-2-amine moiety, led to the identifica-
tion of the 3,4-dichloro analog 2j, a highly potent UT antago-
nist with an IC50 value of 0.13 μM. Further studies are being
carried out with the aim of improving the pharmacokinetic
properties of the 1,3,4-thiadiazol-2-amine derivatives.
1
title compound (168 mg, 63% yield). H NMR (300 MHz,
CDCl3) δ 7.33 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.85 (d, J =
8.8 Hz, 1H), 5.36 (s, 2H), 1.56 (s, 9H).
Synthesis of tert-butyl 4-(4-(((tert-butoxycarbonyl)(5-
((3,4-dichlorophenoxy)methyl)-1,3,4-thiadiazol-2-yl)
amino)methyl)-2-chlorophenoxy)piperidine-1-carboxyl-
ate (8j). To a stirred solution of 7j (100 mg, 0.27 mmol) in
N,N-dimethylformamide (1.0 mL) were added 11 (130 mg,
0.32 mmol) and K2CO3 (75 mg, 0.54 mmol). The mixture
was stirred at room temperature for 5 h. After cooling, water
(50 mL) was added, and the mixture was extracted with ethyl
acetate (50 mL × 2). The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The resulting residue was subjected to silica
gel column chromatography (ethyl acetate/n-hexane = 1/3,
Experimental
Synthesis of ethyl 2-(3,4-dichlorophenoxy)acetate (4j). To
a stirred solution of 3,4-dichlorophenol (3j, 2.0 g, 12.3 mmol)
in N,N-dimethylformamide (50 mL) were added ethyl bro-
moacetate (2.0 mL, 18.4 mmol) and K2CO3 (3.4 g, 24.5
mmol). The reaction mixture was stirred at 100 ꢀC for 2 h.
After cooling, water (100 mL) was added, and the mixture
was extracted with ethyl acetate (100 mL × 2). The organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The result-
ingresiduewassubjectedtosilicagelcolumnchromatography
(ethyl acetate/n-hexane = 1/20, v/v) to obtain the title com-
1
v/v) to obtain the title compound (98 mg, 55% yield). H
NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.29–7.36 (m,
2H), 7.11 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 5.36 (s, 2H),
5.25 (s, 2H), 4.46–4.53 (m, 1H), 3.58–3.69 (m, 2H),
3.37–3.48 (m, 2H), 1.78–1.89 (m, 4H), 1.54 (s, 9H), 1.46
(s, 9H).
1
pound (2.7 g, 89% yield). H NMR (300 MHz, CDCl3) δ
7.32 (d, J = 9.1 Hz, 1H), 7.00 (s, 1H), 6.76 (d, J = 9.1 Hz,
1H), 4.59 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2
Hz, 3H).
Synthesis of N-(3-chloro-4-(piperidin-4-yloxy)benzyl)-
5-((3,4-dichlorophenoxy)methyl)-1,3,4-thiadiazol-2-
amine (2j). A solution of 8j (50 mg, 0.08 mmol) in 1.0 mL of
HCl solution (4M in 1,4-dioxane) was stirred at room temper-
ature for 1 h. The mixture was concentrated in vacuo to give
the title compound (34 mg, 94% yield). 1H NMR (500
MHz, DMSO-d6) δ 7.36 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H),
7.18 (d, J = 8.3 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J = 8.3 Hz,
1H), 6.76 (d, J = 8.0 Hz, 1H), 5.13 (s, 2H), 4.62 (s, 2H),
4.54 (m, 1H), 3.60 (m, 2H), 3.44 (m, 2H), 1.84–1.87 (m,
4H); 13C NMR (125 MHz, DMSO-d6) δ 169.7, 157.2,
154.0, 151.6, 132.6, 132.1, 131.6, 129.9, 128.2, 123.9,
123.0, 117.5, 116.7, 116.5, 71.0, 65.2, 63.5, 47.5, 27.3; HR-
MS (EI): Calcd. for C21H21Cl3N4O2S [M]+ 498.0451, Found
498.0451.
Synthesis of tert-butyl 4-(2-chloro-4-methylphenoxy)
piperidine-1-carboxylate (10, Z = Cl). To a solution of 2-
chloro-4-methylphenol 9 (Z = Cl) (500 mg, 3.50 mmol) and
1-Boc-4-hydroxypiperidine (1.1 g, 5.25 mmol) in THF (20
mL) were added diethyl azodicarboxylate (DEAD) (2.39
mL, 5.25 mmol, 40 wt % in toluene), and triphenylphosphine
(1.38 g, 5.25 mmol). After being stirred at room temperature
for 5 h, the mixture was diluted with water (50 mL) and
extracted with ethyl acetate (50 mL × 2). The organic layer
was washed with brine, dried over anhydrous sodium sulfate,
and concentrated in vacuo. The resulting residue was sub-
jected to silica gel column chromatography (ethyl acetate/n-
Synthesis of 2-(3,4-dichlorophenoxy)acetic acid (5j). To
a stirred solution of 4j (2.5 g, 9.8 mmol) in MeOH (30 mL)
was added 3N NaOH solution (13.1 mL, 39.3 mmol). After
being stirred at room temperature for 1 h, the mixture was
diluted with water (100 mL), acidified with 3N HCl, and
extracted with dichloromethane (100 mL × 2). The organic
layer was washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo to give the title compound
(2.12 g, 97% yield) . 1H NMR (300 MHz, DMSO-d6) δ 7.49
(d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H),
4.73 (s, 2H).
Synthesis of 5-((3,4-dichlorophenoxy)methyl)-1,3,4-
thiadiazol-2-amine (6j). A solution of 5j (2.4 g, 11.0 mmol)
and thiosemicarbazide (2.0 g, 22.0 mmol) in phosphorus oxy-
chloride (30 mL) was stirred at reflux for 4 h. After cooling,
water (50 mL) was added. After being stirred at reflux for
12 h, the mixture was cooled to room temperature and neutra-
lized with 5N NaOH. The resulting solid was separated by fil-
tration, washed with water, and dried in vacuo to give the title
1
compound (2.9 g, 95% yield). H NMR (300 MHz, DMSO-
d6) δ 7.52 (d, J = 9.0 Hz, 1H), 7.36 (s, 1H), 7.03 (d, J = 9.0
Hz, 1H), 5.31 (s, 2H).
Synthesis of tert-butyl (5-((3,4-dichlorophenoxy)
methyl)-1,3,4-thiadiazol-2-yl) carbamate (7j). To a stirred
solution of 6j (200 mg, 0.72 mmol) in THF (6.0 mL) were
Bull. Korean Chem. Soc. 2015, Vol. 36, 2549–2552
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BULLETIN OF THE
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hexane = 1/20, v/v) to give the title compound (1.0 g, 88%
yield). H NMR (300 MHz, CDCl3) δ 7.20 (s, 1H), 7.00 (d,
J = 8.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.43–4.51 (m,
1H), 3.63–3.75 (m, 2H), 3.36–3.48 (m, 2H), 2.29 (s, 3H),
1.76–1.95 (m, 4H), 1.49 (s, 9H).
1
Synthesis of tert-butyl 4-(4-(bromomethyl)-2-chloro-
phenoxy)piperidine-1-carboxylate (11, Z = Cl). A carbon
tetrachloride (10 mL) solution of 10 (Z = Cl) (420 mg, 1.28
mmol), N-bromosuccinimide (251 mg, 1.41 mmol, NBS),
and azobisisobutyronitrile (21 mg, 0.13 mmol, AIBN) was
stirred at reflux for 3 h. The mixture was concentrated under
reduced pressure, giving a residue that was subjected to silica
gel column chromatography (ethyl acetate/n-hexane = 1/20,
1
v/v) to afford the title compound (350 mg, 67% yield). H
NMR (500 MHz, CDCl3) δ 7.45 (s, 1H), 7.25 (d, J = 8.4 Hz,
1H), 6.93 (d, J = 8.4 Hz, 1H), 4.58 (m, 1H), 4.45 (s, 2H),
3.68 (m, 2H), 3.50 (m, 2H), 1.89–1.91 (m, 4H), 1.49 (s, 9H).
Acknowledgments. This research was supported financially
by a grant from the Ministry of Science, ICT & Future Pla-
nning (2011-0019397) and the R&D program of MKE/KEIT
(10038744), Korea.
Supporting Information. Experimental procedures and
spectral data of compounds 2a–2s. This material can be found
in the online version.
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Bull. Korean Chem. Soc. 2015, Vol. 36, 2549–2552
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