Thiadiazole-based Thioglycosides as Sodium-glucose Co-transporter 2 (SGLT2) Inhibitors

Article abstract of DOI:10.1002/cjoc.201090120

A series of thiadiazole-based thioglycosides were synthesized as SGLT2 inhibitors from D-glucose, D-galactose and a variety of phenylacetic acids via a convenient protocol in 8 steps and evaluated in vivo with an oral glucose tolerance test (OGTT), and 5-benzyl-1,3,4-thiadiazol-2-yl 1-thio-β-D-glucopyranoside (1a) was the most efficacious to suppress the blood glucose excursion during OGTT.

Full text of DOI:10.1002/cjoc.201090120

FULL PAPER
Thiadiazole-based Thioglycosides as Sodium-glucose
Co-transporter 2 (SGLT2) Inhibitors
Gao, Yunlonga(高云龙)
Zhao, Guilong*,b(赵桂龙)
Liu, Weib(刘巍)
Wang, Yulib(王玉丽)
Xu, Weirenb(徐为人)
Wang, Jianwu*,a(王建武)
a School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China
b Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of
Pharmaceutical Research, Tianjin 300193, China
A series of thiadiazole-based thioglycosides were synthesized as SGLT2 inhibitors from D-glucose, D-galactose
and a variety of phenylacetic acids via a convenient protocol in 8 steps and evaluated in vivo with an oral glucose
tolerance test (OGTT), and 5-benzyl-1,3,4-thiadiazol-2-yl 1-thio-β-D-glucopyranoside (1a) was the most
efficacious to suppress the blood glucose excursion during OGTT.
Keywords sodium-glucose cotransporter 2 (SGLT2), thiadiazole, synthetic methods, oral glucose tolerance test
(OGTT), biological activity
Introduction
inhibitors designed by our group to discover novel
anti-diabetic agents.
Type 2 diabetes is characterized by hyperglycemia
resulting from impaired insulin secretion in pancreatic
β-cells combined with insulin resistance in peripheral
tissues, and the goal of the therapy for type 2 diabetic
patients is the strict control of blood glucose levels
within the normal range due to the so-called “glucose
toxicity”.1 Over 99% of plasma glucose is filtered in the
renal glomerulus and then reabsorbed in the proximal
tubules by a class of transporters known as sodium-
glucose cotransporters (SGLT), SGLT1 and SGLT2,
and it has been established that this reabsorption process
is mainly mediated by SGLT2.2 Thus, inhibition of
SGLT2 can lead to the excretion of plasma glucose into
urine, lowering the blood glucose levels in type 2 dia-
betic patients. In view of the fact that inhibition of
SGLT1 was associated with gastrointestinal side effect,2
the selective inhibition of SGLT2 became a novel ther-
apy for the treatment of type 2 diabetes.
The natural product phlorizin is a well-documented
glucosuric agent (Figure 1); however, phlorizin has
proved to be nonselective against SGLT2 versus SGLT1
and metabolically liable to β-glucosidase-mediated
cleavage in the small intestine.3 Several selective
SGLT2 inhibitors, such as T-1095,4 sergliflozin5 and
dagapliflozin,2 have been developed by the drug dis-
covery industry based on the structure of phlorizin after
exploration of the molecular structure6 and biological
screening7-9 of phlorizin derivatives (Figure 1), and
herein we perform the syntheses and in vivo evaluation
of a series of thiadiazole-based S-glucoside as SGLT2
Figure 1 Molecular structures of some well-established SGLT
inhibitors.
Experimental
Melting points were determined with an XT-4 mi-
*
E-mail: zhao_guilong@126.com; Tel.: 0086-0531-88362708; Fax: 0086-0531-88564464
Received July 6, 2009; revised September 2, 2009; accepted November 13, 2009.
Project supported by the Scientific and Technological Support Plan of State Ministry of Science and Technology of PRC (No. 2007BAI40B01).
Chin. J. Chem. 2010, 28, 605— 612
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
605

Gao et al.
FULL PAPER
croscopic melting point apparatus and are uncorrected.
IR spectra were taken on a Thermo Nicolet Avtar 370
FT-IR spectrophotometer as KBr discs. H NMR and
539.1149.
5-Benzyl-1,3,4-thiadiazol-2-yl 2,3,4,6-tetra-O-acet-
yl-1-thio-β-D-galactopyranoside (10b) Colorless
1
13C NMR spectra were recorded on a Bruker AC400
spectrometer at 400 MHz for 1H NMR and at 100 MHz
for 13C NMR, with DMSO-d6 as solvent and TMS as an
internal standard. The HR-MS data were taken on an
Agilent Q-TOF 6510 mass spectroscope using an elec-
trospray ionization (ESI) technique. All the reagents
employed were of analytical grade unless otherwise
stated.
The two intermediates, 2-substituted benzyl-5-mer-
capto-1,3,4-thiadiazoles 6a—6h10 and 2,3,4,6-tetra-O-
acetylglucopyranosyl bromide and 2,3,4,6-tetra-O-
acetylgalactopyranosyl bromide 9a—9b,11 were pre-
pared according to known procedures with some modi-
fications and employed without further purifications and
characterizations.
crystals, yield 90%, m.p. 181—183 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.27—7.37 (m, 5H), 5.50 (d,
J＝10.0 Hz, 1H), 5.35 (d, J＝3.2 Hz, 1H), 5.31 (dd, J＝
3.2, 9.6, Hz, 1H), 5.10 (t, J＝9.8 Hz, 1H), 4.49 (s, 2H),
4.38 (t, J＝6.0 Hz, 1H), 3.99—4.08 (m, 2H), 2.054 (s,
3H), 2.050 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ: 171.83, 169.77, 169.30,
160.61, 137.16, 128.79, 128.74, 127.19, 82.43, 74.17,
70.50, 67.40, 66.70, 61.59, 35.07, 20.40, 20.29, 20.26,
20.22; IR (KBr) ν: 3030 (w), 1748 (s), 1491 (w), 1256
－1
(s), 1224 (s) cm . HR-MS (ESI-Q-TOF) calcd for
C23H27N2O9S2 ([M＋H]＋) 539.1158, found 539.1152.
5-(4-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-glucopyranoside
(10c)
1
Colorless crystals, yield 95%, m.p. 135—137 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.37 (d, J＝8.4 Hz, 2H),
7.42 (d, J＝8.0 Hz, 2H), 5.58 (d, J＝10.0 Hz, 1H), 5.41
(t, J＝9.4 Hz, 1H), 4.95—5.01 (m, 2H), 4.50 (s, 2H),
4.12—4.16 (m, 2H), 4.04—4.07 (m, 1H), 2.03 (s, 3H),
1.99 (s, 3H), 1.95 (s, 3H), 1.93 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ: 171.38, 169.82, 169.40,
169.18, 169.07, 160.56, 136.14, 131.89, 130.71, 128.70,
82.08, 74.75, 72.42, 69.28, 67.63, 61.56, 34.23, 20.37,
20.29, 20.20, 20.18; －IR (KBr) ν: 1748 (s), 1492 (w),
General procedure for the preparation of 5-substi-
tuted benzyl-1,3,4-thiadiazol-2-yl 2,3,4,6-tetra-O-
acetyl-1-thio-β-D-glucopyranosides and 5-substituted
benzyl-1,3,4-thiadiazol-2-yl 2,3,4,6-tetra-O-acetyl-1-
thio-β-D-galactopyranosides (10a—10p)
A 100 mL round-bottomed flask was charged with
10 mmol of 2-mercaptothiadiazoles 6a—6h, 10 mmol
of sodium hydroxide and 20 mL of water, and the slurry
thus obtained was stirred at room temperature, followed
by addition of 10 mmol of solid benzyltriethylammo-
nium bromide and 20 mmol of glucosyl bromide or ga-
lactosyl bromide 9a—9b dissolved in 30 mL of di-
chloromethane. The resultant mixture was stirred vig-
orously at room temperature for 10 h until all the
2-mercaptothiadiazole was consumed completely as
monitored by TLC analysis and during this process an-
other 10 mmol of sodium hydroxide was added when
necessary to keep the reaction mixture in pH 8—10.
The reaction mixture was diluted with 200 mL of
dichloromethane, washed sequentially with brine, 5%
aqueous sodium hydroxide and brine, and dried over
anhydrous sodium sulfate. The dried organic phase was
evaporated on a rotary evaporator to afford the crude
product as an oily residue, which was purified through
column chromatography to furnish the products 10a—
10p as colorless crystals.
1
1254 (s), 1230 (s) cm . HR-MS (ESI-Q-TOF) calcd for
C23H26ClN2O9S2 ([M＋H]＋) 573.0768, found 573.0755.
5-(4-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-galactopyranoside (10d)
1
Colorless crystals, yield 92%, m.p. 141 ℃; H NMR
(DMSO-d6, 400 MHz) δ: 7.36 (d, J＝8.4 Hz, 2H), 7.41
(d, J＝8.4 Hz, 2H), 5.49 (d, J＝10.0 Hz, 1H), 5.34 (d,
J＝3.2 Hz, 1H), 5.30 (dd, J＝3.2, 9.6 Hz, 1H), 5.09 (t, J
＝9.8 Hz, 1H), 4.49 (s, 2H), 4.37 (t, J＝6.0 Hz, 1H),
3.99—4.07 (m, 2H), 2.05 (s, 3H), 2.04 (s, 3H), 1.91 (s,
6H); 13C NMR (DMSO-d6, 100 MHz) δ: 171.31, 169.77,
169.32, 160.74, 136.16, 131.97, 130.70, 128.74, 82.46,
74.21, 70.53, 67.42, 66.71, 61.61, 34.27, 20.38, 20.30,
20.23; IR (KBr) ν: 1748 (s), 1491 (w), 1255 (s), 1232 (s)
－ 1
cm . HR-MS (ESI-Q-TOF) calcd for C23H25ClN2-
NaO9S2 ([M＋Na]＋) 595.0588, found 595.0582.
5-(4-Methylbenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-glucopyranoside (10e)
1
Colorless crystals, yield 84%, m.p. 120—122 ℃; H
5-Benzyl-1,3,4-thiadiazol-2-yl 2,3,4,6-tetra-O-acet-
yl-1-thio-β-D-glucopyranoside (10a) Colorless cryst-
als, yield 89%, m.p. 124—126 ℃; 1H NMR (DMSO-d6,
400 MHz) δ: 7.26—7.37 (m, 5H), 5.58 (d, J＝10.0 Hz,
1H), 5.41 (t, J＝9.4 Hz, 1H), 4.95—5.01 (m, 2H), 4.48
(s, 2H), 4.11—4.17 (m, 2H), 4.03—4.07 (m, 1H), 2.02
(s, 3H), 1.99 (s, 3H), 1.95 (s, 3H), 1.91 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) δ: 171.42, 169.32, 168.89,
168.68, 168.56, 159.95, 136.66, 128.28, 128.25, 126.67,
81.59, 74.24, 71.92, 68.81, 67.13, 61.05, 34.56, 19.90,
19.78, 19.70, 19.68; IR (KBr)－ν: 3032 (w), 1748 (s),
NMR (DMSO-d6, 400 MHz) δ: 7.15 (d, J＝7.6 Hz, 2H),
7.21 (d, J＝7.2 Hz, 2H), 5.57 (d, J＝10.0 Hz, 1H), 5.40
(t, J＝9.6 Hz, 1H), 4.94—5.00 (m, 2H), 4.42 (s, 2H),
4.11—4.15 (m, 2H), 4.02—4.05 (m, 1H), 2.27 (s, 3H),
2.02 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.91 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) δ: 172.31, 169.82, 169.39,
169.18, 169.06, 160.39, 136.36, 134.13, 129.33, 128.63,
82.11, 74.73, 72.41, 69.30, 67.63, 61.56, 34.73, 20.56,
20.34, 20.29, 20.20, 20.18; IR (KBr) ν: 3025 (w), 1746
－1
(s), 1515 (s), 1381 (s), 1222 (s) cm . HR-MS (ESI-
Q-TOF) calcd for C24H29N2O9S2 ([M＋H]＋) 553.1314,
1
1490 (w), 1257 (s), 1224 (s) cm . HR-MS (ESI-Q-TOF)
found 553.1313.
calcd for C23H27N2O9S2 ([M＋H]＋) 539.1158, found
606
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 605— 612

Thiadiazole-based Thioglycosides as Sodium-glucose Co-transporter 2 Inhibitors
5-(4-Methylbenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-galactopyranoside (10f)
White foam, yield 91%; 1H NMR (DMSO-d6, 400 MHz)
δ: 7.15 (d, J＝8.0 Hz, 2H), 7.22 (d, J＝8.0 Hz, 2H),
5.50 (d, J＝10.0 Hz, 1H), 5.35 (d, J＝3.2 Hz, 1H), 5.31
(dd, J＝3.4, 9.8 Hz, 1H), 5.09 (t, J＝10.0 Hz, 1H), 4.43
(s, 2H), 4.37 (t, J＝6.2 Hz, 1H), 4.00—4.05 (m, 2H),
2.28 (s, 3H), 2.05 (s, 6H), 1.92 (s, 3H), 1.91 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) δ: 172.23, 169.77, 169.30,
160.55, 136.41, 134.14, 129.36, 128.63, 82.45, 74.17,
70.52, 67.42, 66.70, 61.62, 34.76, 20.55, 20.36, 20.30,
20.22; IR (KBr) ν: 3025 (w), 1747 (s), 1517 (s), 1380
tetra-O-acetyl-1-thio-β-D-galactopyranoside
(10j)
1
Colorless crystals, yield 88%, m.p. 107—109 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.47—7.49 (m, 2H),
7.33—7.36 (m, 2H), 5.52 (d, J ＝10.0 Hz, 1H),
5.30—5.35 (m, 2H), 5.12 (t, J＝9.6 Hz, 1H), 4.58 (s,
2H), 4.39—4.40 (m, 1H), 4.02—4.05 (m, 2H), 2.07 (s,
3H), 2.04 (s, 3H), 1.93 (s, 6H); 13C NMR (DMSO-d6,
100 MHz) δ: 170.20, 169.77, 169.74, 169.29, 160.61,
134.68, 133.14, 131.53, 129.59, 129.46, 127.70, 82.44,
74.21, 70.53, 67.42, 66.72, 61.58, 33.36, 20.41, 20.28,
20.－21; IR (KBr) ν: 3028 (w), 1747 (s), 1499 (s), 1228 (s)
1
cm . HR-MS (ESI-Q-TOF) calcd for C23H26ClN2O9S2
－1
(s), 1224 (s) cm . HR-MS (ESI-Q-TOF) calcd for
([M＋H]＋) 573.0768, found 573.0759.
C24H29N2O9S2 ([M＋H]＋) 553.1314, found 553.1309.
5-(2,4-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,
5-(3-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
6-tetra-O-acetyl-1-thio-β-D-glucopyranoside
(10k)
1
tetra-O-acetyl-1-thio-β-D-glucopyranoside
(10g)
Colorless crystals, yield 83%, m.p. 193—195 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.67 (d, J＝2.0 Hz, 1H),
7.54 (d, J＝8.4 Hz, 1H), 7.46 (dd, J＝2.0, 8.4 Hz, 1H),
5.58 (d, J＝10.0 Hz, 1H), 5.41 (t, J＝9.6 Hz, 1H),
4.94—5.00 (m, 2H), 4.58 (s, 2H), 4.12—4.16 (m, 2H),
1
Colorless crystals, yield 87%, m.p. 112—114 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.30—7.44 (m, 4H),
5.59 (d, J＝10.0 Hz, 1H), 5.42 (t, J＝9.4 Hz, 1H),
4.96—5.02 (m, 2H), 4.52 (s, 2H), 4.13—4.18 (m, 2H),
4.05—4.08 (m, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.95 (s,
3H), 1.94 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ:
171.03, 169.81, 169.40, 169.18, 169.06, 160.63, 139.50,
133.23, 130.60, 128.70, 127.58, 127.17, 82.06, 74.76,
72.42, 69.29, 67.63, 61.55, 34.39, 20.38, 20.29, 20.20,
20.－18; IR (KBr) ν: 3030 (w), 1749 (s), 1507 (s), 1219 (s)
4.03—4.07 (m, 1H), 2.01 (s, 3H), 1.98 (s, 3H), 1.95 (s,
3H), 1.94 (s, 3H);－IR (KBr) ν: 3028 (w), 1750 (s), 1497
(s), 1223 (s) cm 1. HR-＋MS (ESI-Q-TOF) calcd for
C23H25Cl2N2O9S2 ([M＋H] ) 607.0379, found 607.0370.
5-(2,4-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,
6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (10l)
1
1
cm . HR-MS (ESI-Q-TOF) calcd for C23H26ClN2O9S2
Colorless crystals, yield 85%, m.p. 183—185 ℃; H
([M＋H]＋) 573.0768, found 573.0774.
NMR (DMSO-d6, 400 MHz) δ: 7.67 (d, J＝1.6 Hz, 1H),
7.54 (d, J＝8.4 Hz, 1H), 7.45—7.47 (m, 1H), 5.51 (d,
J＝10.0 Hz, 1H), 5.28—5.34 (m, 2H), 5.09 (t, J＝9.8
Hz, 1H), 4.58 (s, 2H), 4.38 (t, J ＝6.0 Hz, 1H),
3.99—4.08 (m, 2H), 2.08 (s, 3H), 2.04 (s, 3H), 1.94 (s,
3H), 1.92 (s, 3H);－IR (KBr) ν: 3030 (w), 1748 (s), 1491
(s), 1220 (s) cm 1. HR-MS (＋ESI-Q-TOF) calcd for
5-(3-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-galactopyranoside
(10h)
1
Colorless crystals, yield 85%, m.p. 188—190 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.30—7.44 (m, 4H),
5.52 (d, J＝10.0 Hz, 1H), 5.35 (d, J＝3.2 Hz, 1H), 5.31
(dd, J＝3.4, 9.8 Hz, 1H), 5.10 (t, J＝9.8 Hz, 1H), 4.52
(s, 2H), 4.39 (t, J＝6.2 Hz, 1H), 4.00—4.09 (m, 2H),
2.07 (s, 3H), 2.05 (s, 3H), 1.93 (s, 3H), 1.92 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) δ: 170.96, 169.77, 169.31,
160.78, 139.53, 133.27, 130.63, 128.68, 127.58, 127.21,
82.40, 74.19, 70.50, 67.41, 66.69, 61.60, 34.38, 20.39,
20.30, 20.25, 20.24; －IR (KBr) ν: 3032 (w), 1749 (s),
C23H25Cl2N2O9S2 ([M ＋ H]
) 607.0379, found
607.0373.
5-(2,6-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,
6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (10m)
1
Colorless crystals, yield 90%, m.p. 208 ℃; H NMR
(DMSO-d6, 400 MHz) δ: 7.54 (d, J＝8.0 Hz, 2H), 7.40
(t, J＝8.0 Hz, 1H), 5.61 (d, J＝10.4 Hz, 1H), 5.41 (t,
J＝9.4 Hz, 1H), 4.95—5.02 (m, 2H), 4.71 (s, 2H),
4.13—4.17 (m, 2H), 4.02—4.06 (m, 1H), 2.01 (s, 3H),
1.99 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H); I－R (KBr) ν:
1
1504 (s), 1211 (s) cm . HR-MS (ESI-Q-TOF) calcd for
C23H26ClN2O9S2 ([M＋H]＋) 573.0768, found 573.0764.
5-(2-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-glucopyranoside
(10i)
1
1
Colorless crystals, yield 90%, m.p. 141—143 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.48—7.50 (m, 2H),
7.34—7.36 (m, 2H), 5.59 (d, J＝10.0 Hz, 1H), 5.41 (t,
J＝9.4 Hz, 1H), 4.94—5.01 (m, 2H), 4.58 (s, 2H),
4.13—4.16 (m, 2H), 4.04 (d, J＝10.4 Hz, 1H), 2.01 (s,
3H), 1.98 (s, 3H), 1.94 (s, 3H), 1.93 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ: 170.31, 169.81, 169.40,
169.18, 169.05, 160.44, 134.66, 133.13, 131.54, 129.57,
129.44, 127.69, 82.14, 74.76, 72.43, 69.34, 67.64, 61.56,
33.35, 20.43, 20.28, 20.18; IR (KBr) ν: 3028 (w), 1748
3031 (w), 1749 (s), 1498 (s), 1221 (s) cm . HR-MS
(ESI-Q-TOF) calcd for C23H25Cl2N2O9S2 ([M＋H]＋)
607.0379, found 607.0367.
5-(2,6-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,
6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (10n)
1
Colorless crystals, yield 84%, m.p. 189—191 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 7.54 (d, J＝8.0 Hz, 2H),
7.40 (t, J＝8.2 Hz, 1H), 5.53 (d, J＝10.0 Hz, 1H), 5.35
(d, J＝3.2 Hz, 1H), 5.31 (dd, J＝3.2, 9.6 Hz, 1H), 5.09
(t, J＝9.8 Hz, 1H), 4.71 (s, 2H), 4.39 (t, J＝6.2 Hz, 1H),
4.03—4.05 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 1.95 (s,
3H), 1.92 (s, 3H);－IR (KBr) ν: 3024 (w), 1746 (s), 1501
(s), 1218 (s) cm 1. HR-MS (＋ESI-Q-TOF) calcd for
－1
(s), 1501 (s), 1224 (s) cm . HR-MS (ESI-Q-TOF)
calcd for C23H26ClN2O9S2 ([M＋H]＋) 573.0768, found
573.0767.
5-(2-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
C23H25Cl2N2O9S2 ([M ＋ H]
) 607.0379, found
Chin. J. Chem. 2010, 28, 605— 612
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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607

Gao et al.
FULL PAPER
607.0377.
5-(4-Methoxybenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
tetra-O-acetyl-1-thio-β-D-glucopyranoside
－1
3345 (s), 3255 (s), 1602 (w), 1482 (w) cm . HR-MS
(ESI-Q-TOF) calcd for C15H19N2O5S2 ([M ＋H] ＋ )
371.0735, found 371.0747.
(10o)
1
Colorless crystals, yield 82%, m.p. 167—169 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 6.90 (d, J＝8.4 Hz, 2H),
7.25 (d, J＝8.8 Hz, 2H), 5.57 (d, J＝10.0 Hz, 1H), 5.40
(t, J＝9.4 Hz, 1H), 4.94—5.00 (m, 2H), 4.40 (s, 2H),
4.11—4.16 (m, 2H), 4.02—4.06 (m, 1H), 3.73 (s, 3H),
2.02 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.91 (s, 3H); IR
(KBr) ν: 3030 (w), 1748 (s), 1503 (s), 1378 (s), 1226 (s)
5-Benzyl-1,3,4-thiadiazol-2-yl 1-thio-β-D-galacto-
pyranoside (1b) Colorless crystals, yield 93%, m.p.
200—202 ℃; 1H NMR (DMSO-d6, 400 MHz) δ:
7.26—7.37 (m, 5H), 5.52 (s, 1H), 5.11 (s, 1H), 4.81 (d,
J＝9.6 Hz, 1H), 4.66 (s, 2H), 4.43 (s, 3H), 3.74 (s, 1H),
3.36—3.52 (m, 5H); 13C NMR (DMSO-d6, 100 MHz) δ:
170.47, 163.48, 137.32, 128.75, 128.72, 127.07, 86.81,
79.62, 74.25, 69.51, 68.02, 59.97, 34.99; IR (KBr) ν:
3413 (s), 3340 (s), 3201 (s), 1600 (w), 1481 (w)
－1
cm . HR-MS (ESI-Q-TOF) calcd for C24H29N2O10S2
([M＋H]＋) 569.1264, found 569.1260.
－1
5-(4-Methoxybenzyl)-1,3,4-thiadiazol-2-yl 2,3,4,6-
cm . HR-MS (ESI-Q-TOF) calcd for C15H19N2O5S2
tetra-O-acetyl-1-thio-β-D-galactopyranoside
(10p)
([M＋H]＋) 371.0735, found 371.0742.
1
Colorless crystals, yield 87%, m.p. 183—185 ℃; H
NMR (DMSO-d6, 400 MHz) δ: 6.91 (d, J＝8.4 Hz, 2H),
7.25 (d, J＝8.4 Hz, 2H), 5.49 (d, J＝10.0 Hz, 1H), 5.34
(d, J＝3.2 Hz, 1H), 5.31 (dd, J＝3.4, 9.8 Hz, 1H), 5.09
(t, J＝10.0 Hz, 1H), 4.40 (s, 2H), 4.37 (t, J＝6.0 Hz,
1H), 3.98—4.08 (m, 2H), 3.73 (s, 3H), 2.06 (s, 3H),
2.05 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H); IR (KBr)－ν:
5-(4-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-glucopyranoside (1c) Colorless crystals, yield 93%,
1
m.p. 230—232 ℃; H NMR (DMSO-d6, 400 MHz) δ:
7.34 (d, J＝8.4 Hz, 2H), 7.39 (d, J＝8.4 Hz, 2H), 5.57
(d, J＝6.0 Hz, 1H), 5.18 (d, J＝4.8 Hz, 1H), 5.03 (d,
J＝5.2 Hz, 1H), 4.85 (d, J＝9.6 Hz, 1H), 4.52 (t, J＝5.6
Hz, 1H), 4.43 (s, 2H), 3.64—3.65 (m, 1H), 3.44—3.47
(m, 1H), 3.14—3.25 (m, 4H); 13C NMR (DMSO-d6, 100
MHz) δ: 169.97, 163.33, 136.29, 131.76, 130.67, 128.66,
86.18, 81.46, 77.71, 72.58, 69.37, 60.60, 34.17; IR (KBr)
1
3031 (w), 1749 (s), 1504 (s), 1379 (s), 1224 (s) cm .
HR-MS (ESI-Q-TOF) calcd for C24H29N2O10S2 ([M＋
H]＋) 569.1264, found 569.1249.
－1
General procedure for the preparation of
5-substituted benzyl-1,3,4-thiadiazol-2-yl 1-thio-β-D-
glucopyranosides and 5-substituted benzyl-1,3,4-
thiadiazol-2-yl 1-thio-β-D-galactopyranosides (1a—
1p)
ν: 3471 (s), 3339 (s), 3248 (s), 1479 (m) cm . HR-MS
(ESI-Q-TOF) calcd for C15H18ClN2O5S2 ([M＋H]＋ )
405.0346, found 405.0340.
5-(4-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-galactopyranoside (1d) Colorless crystals, yield
1
A 250 mL round-bottomed flask was charged with
100 mL of absolute methanol followed by 0.115 g (5
mmol) of sodium, and the mixture was stirred at room
temperature until all the sodium disappeared. Subse-
quently, 5 mmol of acetate 10a—10p was added, and
the clear solution thus obtained was stirred at room tem-
perature for 5 h until both the starting acetates 10a—
10p and the intermediates formed by partial deacetyla-
tion disappeared completely as monitored by TLC
analysis.
90%, m.p. 169—171 ℃; H NMR (DMSO-d6, 400
MHz) δ: 7.34 (d, J＝8.4 Hz, 2H), 7.39 (d, J＝8.4 Hz,
2H), 5.44 (d, J＝6.0 Hz, 1H), 4.99 (d, J＝4.4 Hz, 1H),
4.80 (d, J＝9.6 Hz, 1H), 4.61 (d, J＝5.2 Hz, 1H), 4.57
(d, J＝4.4 Hz, 1H), 4.43 (s, 2H), 3.73 (t, J＝3.4 Hz, 1H),
3.44—3.51 (m, 4H), 3.36—3.37 (m, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ: 169.97, 163.59, 136.31,
131.78, 130.68, 128.68, 86.80, 79.67, 74.26, 69.49,
68.11, 60.07, 34.19; IR (KBr) ν: 3473 (s), 3332 (s),
－1
3240 (s), 1490 (m) cm . HR-M＋S (ESI-Q-TOF) calcd
Around 10 mg of dried strongly acidic resin (H＋
form) was added, and the resulting mixture was stirred
at room temperature until it turned neutral as judged by
pH test paper.
for C15H18ClN2O5S2 ([M ＋H] ) 405.0346, found
405.0339.
5-(4-Methylbenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-glucopyranoside (1e) Colorless crystals, yield 90%,
1
The resin was filtered off, and the filtrate was
evaporated on a rotary evaporator to afford the crude
product as a pale yellow solid, which was triturated with
ethyl acetate/petroleum ether at room temperature to
yield the desired products 1a—1p as colorless crystals.
5-Benzyl-1,3,4-thiadiazol-2-yl 1-thio-β-D-glucopy-
ranoside (1a) Colorless crystals, yield 90%, m.p.
169—171 ℃; 1H NMR (DMSO-d6, 400 MHz) δ:
7.26—7.35 (m, 5H), 5.57 (d, J＝6.0 Hz, 1H), 5.18 (d,
J＝4.4 Hz, 1H), 5.03 (d, J＝4.8 Hz, 1H), 4.85 (d, J＝
9.6 Hz, 1H), 4.52 (t, J＝5.4 Hz, 1H), 4.42 (s, 2H),
3.63—3.68 (m, 1H), 3.44—3.49 (m, 1H), 3.14—3.16
(m, 4H); 13C NMR (DMSO-d6, 100 MHz) δ: 170.53,
163.19, 137.30, 128.76, 128.74, 127.09, 86.22, 81.45,
77.73, 72.59, 69.37, 60.61, 35.02; IR (KBr) ν: 3410 (s),
m.p. 240—242 ℃; H NMR (DMSO-d6, 400 MHz) δ:
7.14 (d, J＝8.0 Hz, 2H), 7.19 (d, J＝8.0 Hz, 2H), 5.58
(d, J＝6.0 Hz, 1H), 5.20 (d, J＝2.8 Hz, 1H), 5.04 (d,
J＝4.8 Hz, 1H), 4.85 (d, J＝9.6 Hz, 1H), 4.53 (t, J＝5.4
Hz, 1H), 4.36 (s, 2H), 3.64—3.68 (m, 1H), 3.44—3.49
(m, 1H), 3.12—3.26 (m, 4H), 2.26 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) δ: 170.86, 163.14, 136.23,
134.28, 129.32, 128.61, 86.26, 81.45, 77.74, 72.60,
69.38, 60.62, 34.69, 20.63; IR (KBr) ν: 3345 (s), 3253
－1
(s), 1514 (w), 1474 (w) cm . HR-MS (ESI-Q-TOF)
calcd for C16H21N2O5S2 ([M＋H]＋) 385.0892, found
385.0890.
5-(4-Methylbenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-galactopyranoside (1f) Colorless crystals, yield
1
85%, m.p. 193—195 ℃; H NMR (DMSO-d6, 400
608
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 605— 612

Thiadiazole-based Thioglycosides as Sodium-glucose Co-transporter 2 Inhibitors
MHz) δ: 7.15 (d, J＝8.0 Hz, 2H), 7.20 (d, J＝7.6 Hz,
2H), 5.46 (d, J＝6.0 Hz, 1H), 5.02 (d, J＝5.6 Hz, 1H),
4.81 (d, J＝9.6 Hz, 1H), 4.64—4.65 (m, 1H), 4.60 (d,
J＝4.8 Hz, 1H), 4.37 (s, 2H), 3.72—3.73 (m, 1H),
3.45—3.54 (m, 4H), 3.36—3.39 (m, 1H), 2.27 (s, 3H);
13C NMR (DMSO-d6, 100 MHz) δ: 170.83, 163.42,
136.24, 134.30, 129.34, 128.61, 86.87, 79.64, 74.28,
69.51, 68.11, 60.06, 34.70, 20.64; I－R (KBr) ν: 3340 (s),
129.34, 127.68, 86.73, 79.60, 74.22, 69.50, 68.04, 59.95,
33.22; IR (KBr) ν: 3440 (s), 3339 (s), 1503 (w), 1483
－1
(w) cm . HR-MS (ESI-Q-TOF) calcd for C15H18ClN2-
O5S2 ([M＋H]＋) 405.0346, found 405.0337.
5-(2,4-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-
β-D-glucopyranoside (1k) Colorless crystals, yield
1
88%, m.p. 183—185 ℃; H NMR (DMSO-d6, 400
MHz) δ: 7.65 (d, J＝2.4 Hz, 1H), 7.50 (d, J＝8.4 Hz,
1H), 7.44 (dd, J＝2.4, 8.4 Hz, 1H), 5.57 (bs, 1H), 5.03
(bs, 3H), 4.85 (d, J＝9.6 Hz, 1H), 4.52 (s, 2H), 3.66 (d,
J＝12.0 Hz, 1H), 3.47 (dd, J＝5.2, 12.0 Hz, 1H),
3.20—3.26 (m, 2H), 3.12—3.18 (m, 2H); 13C NMR
(DMSO-d6, 100 MHz) δ: 168.44, 163.30, 134.13,
134.03, 132.92, 132.78, 128.96, 127.77, 86.12, 81.47,
77.70, 72.57, 69.35, 60.58, 32.65; I－R (KBr) ν: 3465 (s),
1
3257 (s), 1510 (w), 1477 (w) cm . HR＋-MS (ESI-Q-
TOF) calcd for C16H21N2O5S2 ([M＋H] ) 385.0892,
found 385.0883.
5-(3-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-glucopyranoside (1g) Colorless crystals, yield 83%,
1
m.p. 166—168 ℃; H NMR (DMSO-d6, 400 MHz) δ:
7.27—7.42 (m, 4H), 5.58 (d, J＝6.0 Hz, 1H), 5.19 (d,
J＝4.8 Hz, 1H), 5.03 (d, J＝5.2 Hz, 1H), 4.86 (d, J＝
9.6 Hz, 1H), 4.52 (t, J＝5.8 Hz, 1H), 4.45 (s, 2H),
3.64—3.68 (m, 1H), 3.44—3.50 (m, 1H), 3.12—3.27
(m, 4H); 13C NMR (DMSO-d6, 100 MHz) δ: 169.64,
163.38, 139.66, 133.18, 130.57, 128.66, 127.55, 127.07,
86.17, 81.45, 77.71, 72.57, 69.34, 60.58, 34.31; IR (KBr)
1
3345 (s), 1514 (w), 1479 (w) cm . HR-＋MS (ESI-Q-
TOF) calcd for C15H17Cl2N2O5S2 ([M＋H] ) 438.9956,
found 438.9955.
5-(2,4-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-
β-D-galactopyranoside (1l) Colorless crystals, yield
1
91%, m.p. 233—235 ℃; H NMR (DMSO-d6, 400
－1
ν: 3401 (s), 3325 (s), 1503 (w), 1471 (w) cm . HR-MS
MHz) δ: 7.65 (d, J＝2.0 Hz, 1H), 7.50 (d, J＝8.4 Hz,
1H), 7.44 (dd, J＝2.0, 8.0 Hz, 1H), 5.43 (d, J＝6.0 Hz,
1H), 4.96 (d, J＝5.6 Hz, 1H), 4.81 (d, J＝9.6 Hz, 1H),
4.60 (t, J＝5.0 Hz, 1H), 4.56 (d, J＝4.8 Hz, 1H), 4.51 (s,
2H), 3.73 (t, J＝3.8 Hz, 1H), 3.44—3.54 (m, 4H),
3.34—3.39 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) δ:
168.41, 163.57, 134.14, 134.05, 132.92, 132.78, 128.97,
127.79, 86.72, 79.66, 74.23, 69.50, 68.08, 60.02, 32.6－6;
(ESI-Q-TOF) calcd for C15H18ClN2O5S2 ([M＋H]＋ )
405.0346, found 405.0341.
5-(3-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-galactopyranoside (1h) Colorless crystals, yield
1
87%, m.p. 231—232 ℃; H NMR (DMSO-d6, 400
MHz) δ: 7.27—7.41 (m, 4H), 5.43 (d, J＝5.6 Hz, 1H),
4.82 (d, J＝9.6 Hz, 1H), 4.60 (d, J＝5.6 Hz, 1H), 4.56
(d, J ＝4.4 Hz, 1H), 4.45 (s, 2H), 3.73 (s, 1H),
3.46—3.56 (m, 4H), 3.35—3.39 (m, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ: 169.61, 163.64, 139.67,
133.18, 130.58, 128.65, 127.54, 127.07, 86.76, 79.62,
74.23, 69.48, 68.06, 60.00, 34.30; I－R (KBr) ν: 3408 (s),
1
IR (KBr) ν: 3447 (s), 3323 (s), 1511 (w), 1498 (w) cm .
HR-MS (ESI-Q-TOF) calcd for C15H17Cl2N2O5S2
([M＋H]＋) 438.9956, found 438.9962.
5-(2,6-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-
β-D-glucopyranoside (1m) Colorless crystals, yield
1
1
3335 (s), 1505 (w), 1474 (w) cm . HR-＋MS (ESI-Q-
85%, m.p. 219 ℃; H NMR (DMSO-d6, 400 MHz) δ:
TOF) calcd for C15H18ClN2O5S2 ([M＋H] ) 405.0346,
found 405.0337.
7.53 (d, J＝8.0 Hz, 2H), 7.39 (t, J＝8.2 Hz, 1H), 5.57 (d,
J＝6.0 Hz, 1H), 5.18 (d, J＝4.8 Hz, 1H), 5.03 (d, J＝
5.2 Hz, 1H), 4.86 (d, J＝9.6 Hz, 1H), 4.66 (s, 2H), 4.51
(t, J＝5.6 Hz, 1H), 3.67 (dd, J＝5.0, 11.4 Hz, 1H),
3.44—3.49 (m, 1H), 3.12—3.27 (m, 4H); 13C NMR
(DMSO-d6, 100 MHz) δ: 166.98, 163.26, 135.00,
132.77, 130.22, 128.68, 86.02, 81.47, 77.69, 72.54,
69.33, 60.55, 31.56; IR (KBr) ν: 3402 (s), 3321 (s),
5-(2-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-glucopyranoside (1i) Colorless crystals, yield 86%,
1
m.p. 189—191 ℃; H NMR (DMSO-d6, 400 MHz) δ:
7.33—7.46 (m, 4H), 5.59 (d, J＝4.0 Hz, 1H), 5.21 (s,
1H), 5.04 (s, 1H), 4.86 (d, J＝9.6 Hz, 1H), 4.51 (s, 3H),
3.65—3.68 (m, 1H), 3.46—3.49 (m, 1H), 3.18—3.25
(m, 4H); 13C NMR (DMSO-d6, 100 MHz) δ: 169.07,
163.24, 134.87, 133.15, 131.55, 129.58, 129.41, 127.73,
86.22, 81.49, 77.78, 72.64, 69.41, 60.64, 33.33; IR (KBr)
－1
1504 (w), 1465 (w) cm . HR-MS (ESI-Q-TOF) calcd
for C15H17Cl2N2O5S2 ([M ＋H] ＋ ) 438.9956, found
438.9949.
－1
ν: 3445 (s), 3336 (s), 1500 (w), 1475 (w) cm . HR-MS
5-(2,6-Dichlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-
β-D-galactopyranoside (1n) Colorless crystals, yield
(ESI-Q-TOF) calcd for C15H18ClN2O5S2 ([M＋H]＋ )
1
405.0346, found 405.0351.
87%, m.p. 175 ℃; H NMR (DMSO-d6, 400 MHz) δ:
5-(2-Chlorobenzyl)-1,3,4-thiadiazol-2-yl 1-thio-β-
D-galactopyranoside (1j) Colorless crystals, yield
7.53 (d, J＝8.4 Hz, 2H), 7.39 (t, J＝8.0 Hz, 1H), 5.42 (d,
J＝6.0 Hz, 1H), 4.96 (d, J＝6.0 Hz, 1H), 4.82 (d, J＝
9.6 Hz, 1H), 4.65 (s, 2H), 4.61 (t, J＝5.2 Hz, 1H), 4.55
(d, J＝4.8 Hz, 1H), 3.73 (t, J＝3.8 Hz, 1H), 3.45—3.54
(m, 4H), 3.34—3.39 (m, 1H); 13C NMR (DMSO-d6, 100
MHz) δ: 166.96, 163.52, 135.00, 132.78, 130.22, 128.68,
86.61, 79.63, 74.22, 69.48, 68.07, 59.98, 31.56; IR (KBr)
1
88%, m.p. 246—247 ℃; H NMR (DMSO-d6, 400
MHz) δ: 7.45—7.49 (m, 2H), 7.33—7.35 (m, 2H), 5.42
(d, J＝6.0 Hz, 1H), 4.95 (d, J＝5.6 Hz, 1H), 4.81 (d,
J＝9.6 Hz, 1H), 4.58—4.60 (m, 1H), 4.55 (d, J＝4.8 Hz,
1H), 4.52 (s, 2H), 3.72 (t, J＝3.8 Hz, 1H), 3.43—3.53
(m, 4H), 3.36—3.38 (m, 1H); 13C NMR (DMSO-d6, 100
MHz) δ: 168.93, 163.44, 134.86, 133.08, 131.49, 129.53,
－1
ν: 3422 (s), 3325 (s), 1502 (w), 1469 (w) cm . HR-MS
(ESI-Q-TOF) calcd for C15H17Cl2N2O5S2 ([M＋H]＋)
Chin. J. Chem. 2010, 28, 605— 612
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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609

Gao et al.
FULL PAPER
438.9956, found 438.9950.
5-(4-Methoxybenzyl)-1,3,4-thiadiazol-2-yl 1-thio-
β-D-glucopyranoside (1o) Colorless crystals, yield
glucose levels were determined using commercially
available kits based on a well-established glucose oxi-
dase method.
The blood glucose concentration-time plot for each
compound was thus obtained, and the inhibition rate
was calculated as follows: inhibition rate＝[AUC(ve-
hicle) －AUC(compounds 1a—1p)]/[AUC(vehicle) －
AUC(control)]×100%, wherein the AUC represents the
area under curve for the plot of each compound, vehicle
or control.
1
89%, m.p. 168—170 ℃; H NMR (DMSO-d6, 400
MHz) δ: 6.90 (d, J＝8.8 Hz, 2H), 7.24 (d, J＝8.8 Hz,
2H), 5.57 (d, J＝6.0 Hz, 1H), 5.19 (d, J＝4.8 Hz, 1H),
5.03 (d, J＝5.2 Hz, 1H), 4.85 (d, J＝9.6 Hz, 1H), 4.52 (t,
J＝5.6 Hz, 1H), 4.34 (s, 2H), 3.73 (s, 3H), 3.66 (dd, J＝
5.6, 10.8 Hz, 1H), 3.43—3.49 (m, 1H), 3.12—3.26 (m,
4H); 13C NMR (DMSO-d6, 100 MHz) δ: 171.23, 163.06,
158.30, 129.84, 129.23, 114.15, 86.24, 81.44, 77.71,
72.57, 69.35, 60.58, 55.04, 34.21; IR (KBr) ν: 3420 (s),
Results and discussion
－
3321 (s), 1500 (w), 1448 (w) cm 1. HR-MS
(ESI-Q-TOF) calcd for C16H21N2O6S2 ([M ＋H] ＋ )
The natural product phlorizin has been used for a
glucosuric agent for a long time; this O-glucoside,
however, is metabolically liable and suffers from
β-glucosidase-mediated cleavage in the small intestine
to almost inactive metabolites.3 We are interested in the
development of SGLT2 inhibitors as anti-diabetic
agents and designed a series of thiadiazole-based
S-glucosides, which are envisioned to be robust to the
metabolic cleavage by β-glucosidase (Scheme 1). In
view of the similarity of D-galactose with D-glucose
and the prevalence of D-galactose in the human body,
we also designed a series of thiadiazole-based
S-galactosides corresponding to the aforementioned
S-glucosides (Scheme 1).
Mercaptothiadiazoles 6a—6h were prepared starting
from substituted phenylacetic acids 2a—2h, which un-
derwent successively esterification, hydrazinolysis,
xanthatation and concentrated sulfuric acid-mediated
cyclization to furnish mercaptothiadiazoles 6a—6h ac-
cording to a known procedure (Scheme 2).10 Glucosyl
bromide and galactosyl bromide 9a—9b were prepared
from D-glucose and D-galactose in two steps according
to well-established procedures (Scheme 3).11
401.0841, found 401.0853.
5-(4-Methoxybenzyl)-1,3,4-thiadiazol-2-yl 1-thio-
β-D-galactopyranoside (1p) Colorless crystals, yield
1
82%, m.p. 185—187 ℃; H NMR (DMSO-d6, 400
MHz) δ: 6.90 (d, J＝8.4 Hz, 2H), 7.24 (d, J＝8.0 Hz,
2H), 5.43 (d, J＝6.0 Hz, 1H), 4.97 (d, J＝5.6 Hz, 1H),
4.81 (d, J＝9.6 Hz, 1H), 4.62 (d, J＝5.6 Hz, 1H), 4.57
(d, J＝4.4 Hz, 1H), 4.34 (s, 2H), 3.73 (s, 4H), 3.44—
3.54 (m, 4H), 3.34—3.38 (m, 1H); IR (KBr) ν: 3413 (s),
－1
3325 (s), 1503 (w), 1449 (w) cm . HR＋-MS (ESI-Q-
TOF) calcd for C16H21N2O6S2 ([M＋H] ) 401.0841,
found 401.0847.
Oral glucose tolerance test (OGTT)
Mice (20—22 g, 6/group) were fasted overnight and
the test compounds 1a—1p (1% CMC-Na; 100 mg/kg
and 20 mL/kg) or just vehicle (1% CMC-Na; 20 mL/kg)
was orally administered. After 2 h, the mice were chal-
lenged with glucose at 2 g/kg intraperitoneally and at a
volume of 10 mL/kg. The control mice received water
only. Blood samples were collected from the orbital
vein 0.5, 1, 2, 3 and 4 h after the glucose challenge for
the determination of blood glucose levels. The blood
Scheme 1 Synthetic route to the title compounds 1a— 1p from 6a— 6h and 9a— 9b
610
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Chin. J. Chem. 2010, 28, 605— 612

Thiadiazole-based Thioglycosides as Sodium-glucose Co-transporter 2 Inhibitors
Scheme 2 Synthetic route to 2-mercaptothiazoles 6a— 6h
The coupling of 6a—6h and 9a—9b gave rise to
sixteen thioglucoside and thiogalactoside tetraacetates
10a—10p, which underwent deacetylation on succes-
sive treatment＋with sodium methoxide and strongly
acidic resin (H form) in absolute methanol to furnish
the desired products 1a—1p (Scheme 1).
Compounds 1a—1p were screened in vivo with an
oral glucose tolerance test (OGTT), and the inhibition
rates of blood glucose levels for compounds 1a—1p
were summarized in Table 1. Obviously, compounds 1a,
1b, 1f and 1l were efficacious to suppress the blood
glucose excursion during the OGTT with 1a being the
most powerful, and the others were markedly less active
or almost inactive. Although the SGLT2 inhibitors dis-
closed so far were all glucosides,2-5 three corresponding
galactosides, 1b, 1f and 1l, also exhibit satisfactory in-
hibition rates even though they are less efficacious than
the glucoside 1a. Careful examination of the bioactivi-
ties and molecular structures of 1a, 1b, 1f and 1l did not
reveal apparent structure-activity relationship (SAR),
but the following conclusions could also be tentatively
drawn: (1) un-substituted (1a and 1b), p-substituted (1f)
and 2,4-disubstituted (1l) phenyl rings were preferred,
although the 1o and 1p with p-OMe substituents did not
showed any antihyperglycermic activity, and (2) various
mono- and di-substitution patterns of chloride were not
tolerated, except that the 2,4-dichlorophenyl was toler-
ated. Noteworthy is that it should be careful to draw a
conclusion that some compounds (li and 1m—1p) could
raise blood glucose levels only through OGTT.
Scheme 3 Synthetic route to glucosyl and galactosyl bromides
9a— 9b
Table 1 Inhibition rates of blood glucose levels of compounds 1a—1p in OGTT
Compd
Gliclazide
27.52
1a
1b
1c
1d
1e
1f
1g
1h
Inhibition rate/%
74.85
41.01
9.67
16.77
8.00
51.59
1.12
1.58
Compd
1i
1j
1k
1l
1m
1n
1o
1p
Inhibition rate/%
－
17.66
－
9.23
－
8.71
23.81
－
18.31
－
18.96
－
27.29
－
15.67
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