SGLT Inhibitors as Antidiabetic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5321
(d, 1H, J ) 1.5 Hz), 7.65 (s, 1H), 7.94 (d, 1H, J ) 2.0 Hz),
graphed on silica gel (hexane-AcOEt (25:1)) to give 33 (811
mg, 56%) as a pale yellow solid. IR (Nujol) 1735, 1630 cm-1
;
10.45 (s, 1H); ESI-MS m/z 535 (M + Na
+), 537 (M + 2 + Na+),
1H NMR (DMSO-d6) δ 2.27 (d, 3H, J ) 0.5 Hz), 2.57 (s, 3H),
6.59 (d, 1H, J ) 8.0 Hz), 7.35 (dd, 1H, J ) 0.5, 8.0 Hz), 7.56
(m, 2H), 7.69 (m, 1H), 8.23 (dd, 2H, J ) 1.5, 7.5 Hz), 13.07 (s,
1H); APCI-MS m/z 271 (M + H+).
539 (M + 4 + Na+). Anal. (C23H22Cl2O9‚1/2H2O) C, H.
3-(Ben zo[b]fu r a n -5-yl)-2′,6′-d ih yd r oxy-4′-m et h ylp r o-
p iop h en on e 2′-O-(4,6-O-Ben zylid en e-â-D-glu cop yr a n o-
sid e) (40). A mixture of 4 (10.00 g, 21.81 mmol), benzaldehyde
dimethylacetal (4.98 g, 32.72 mmol), p-TsOH‚H2O (415 mg,
2.18 mmol), and CH2Cl2 (200 mL) was stirred at room
temperature for 1.5 h. The reaction mixture was evaporated,
and the residue was dissolved in AcOEt, washed with satu-
rated NaHCO3 and brine, and dried over MgSO4. The solvent
was removed. The residue was purified by column chroma-
tography on silica gel (CHCl3) to give 40 (10.92 g, 92%) as a
pale yellow foam: IR (neat) 3450, 1630 cm-1; 1H NMR(DMSO-
d6) δ 2.09 (s, 3H), 3.00 (t, 2H, J ) 7.3 Hz), 3.38 (m, 2H), 3.40-
3.47 (m, 2H), 3.54-3.70 (m, 3H), 4.24 (dd, 1H, J ) 5.4, 10.4
Hz), 5.22 (d, 1H, J ) 7.7 Hz), 5.52 (d, 1H, J ) 7.7 Hz), 5.58 (s,
1H), 5.65 (d, 1H, J ) 5.7 Hz), 6.42 (s, 1H), 6.59 (s, 1H), 6.90
(dd, 1H, J ) 0.9, 2.2 Hz), 7.24 (dd, 1H, J ) 1.7, 8.4 Hz), 7.36-
7.53 (m, 7H), 7.95 (d, 1H, J ) 2.2 Hz), 11.70 (s, 1H); ESI-MS
m/z 569 (M + Na+).
3-(Ben zo[b]fu r a n -5-yl)-2′,6′-d ih yd r oxy-3′-m et h yla cr y-
lop h en on e 2′-O-â-D-Glu cop yr a n osid e (35). Compound 33
(805 mg, 2.98 mmol) was glycosylated by the same procedure
as described for the synthesis of 7. The crude glucoside 34 (1.23
g) was obtained. The crude 34 was condensed with benzofuran-
5-carboxaldehyde (353 mg, 2.41 mmol) by the same procedure
as described for the synthesis of 4. The reaction mixture was
acidified with 10% HCl and extracted with AcOEt. The organic
layer was washed with saturated NaHCO3, brine, dried over
Na2SO4, and evaporated. The residue was chromatographed
on silica gel (CHCl3-MeOH (20:1)) to give 35 (360 mg, 27%
from 33) as a yellow amorphous solid: IR (Nujol) 3350, 1730,
1705, 1635 cm-1 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.95-
;
3.00 (m, 2H), 3.10-3.15 (m, 2H), 3.29 (m, 1H), 3.55 (dd, 1H, J
) 6.0, 11.0 Hz), 4.05 (t, 1H, J ) 6.0 Hz), 4.50 (d, 1H, J ) 7.5
Hz), 4.91 (d, 1H, J ) 5.0 Hz), 4.97 (d, 1H, J ) 4.5 Hz), 5.32 (d,
1H, J ) 5.0 Hz), 6.65 (d, 1H, J ) 8.0 Hz), 6.98 (dd, 1H, J )
1.0, 2.0 Hz), 7.12 (d, 1H, J ) 8.0 Hz), 7.20 (d, 1H, J ) 16.0
Hz), 7.44 (d, 1H, J ) 16.0 Hz), 7.62 (d, 1H, J ) 8.5 Hz), 7.69
(dd, 1H, J ) 1.5, 8.5 Hz), 8.00 (d, 1H, J ) 1.5 Hz), 8.05 (d, 1H,
J ) 2.0 Hz), 9.88 (s, 1H); ESI-MS m/z 479 (M + Na+).
6′-Acetoxy-3-(ben zo[b]fu r a n -5-yl)-2′-h yd r oxy-4′-m eth -
ylp r op iop h en on e 2′-O-(2,3-O-Dia cetyl-4,6-O-ben zylid en e-
â-D-glu cop yr a n osid e) (41). A mixture of 40 (2.02 g, 3.70
mmol), Ac2O (2.1 mL), and pyridine (20 mL) was stirred at
room temperature for 4.5 h. The reaction mixture was poured
into 10% citric acid and extracted with AcOEt. The organic
layer was washed with saturated NaHCO3 and brine, dried
over MgSO4, and evaporated. The residue was triturated in
iso-Pr2O to give 41 (2.37 g, 95%) as colorless needles, mp 200-
3-(Ben zo[b]fu r a n -5-yl)-2′,6′-d ih yd r oxy-3′-m et h ylp r o-
p iop h en on e 2′-O-â-D-Glu cop yr a n osid e (36). Compound 35
(393 mg, 0.86 mmol) was hydrogenated over 10% Pd-C (40
mg) in the presence of piperazine (74 mg) in 50% aqueous KOH
(1 mL), EtOH (3 mL), and DMA (1.5 mL) for 2 h. The catalyst
was removed by filtration, and the filtrate was acidified with
10% HCl and extracted with AcOEt. The organic layer was
washed with saturated NaHCO3 and brine, dried over Na2-
SO4, and evaporated. The residue was chromatographed on
silica gel (CHCl3-MeOH (10:1)) to give 36 (322 mg, 82%) as a
1
203 °C: IR (Nujol) 1765, 1750, 1700 cm-1; H NMR (DMSO-
d6) δ 1.94 (s, 3H), 2.01 (s, 3H), 2.02 (s, 3H), 2.34 (s, 3H), 2.87-
3.03 (m, 4H), 3.76 (t, 1H, J ) 9.9 Hz), 3.90 (t, 1H, J ) 9.4 Hz),
3.97 (dd, 1H, J ) 4.5, 9.9 Hz), 4.44 (dd, 1H, J ) 4.6, 10.0 Hz),
5.07 (dd, 1H, J ) 7.9, 8.1 Hz), 5.40 (t, 1H, J ) 9.4 Hz), 5.63 (s,
1H), 5.68 (d, 1H, J ) 7.9 Hz), 6.74 (s, 1H), 6.91 (dd, 1H, J )
0.9, 2.2 Hz), 7.00 (s, 1H), 7.17 (dd, 1H, J ) 1.8, 8.6 Hz), 7.39
(s, 5H), 7.49 (d, 1H, J ) 1.3 Hz), 7.51 (d, 1H, J ) 8.4 Hz), 7.95
(d, 1H, J ) 2.2 Hz); ESI-MS m/z 690 (M + NH4+).
pale yellow foam: IR (Nujol) 3400, 1635 cm-1 1H NMR
;
(DMSO-d6) δ 2.22 (s, 3H), 2.95 (t, 1H, J ) 7.5 Hz), 3.00-3.10
(m, 2H), 3.15-3.25 (m, 2H), 3.28 (t, 1H, J ) 7.5 Hz), 3.37 (m,
1H), 3.63 (dd, 1H, J ) 5.5, 11.0 Hz), 4.14 (t, 1H, J ) 5.5 Hz),
4.46 (d, 1H, J ) 7.5 Hz), 4.97 (d, 1H, J ) 5.0 Hz), 5.06 (d, 1H,
J ) 4.5 Hz), 5.48 (d, 1H, J ) 4.5 Hz), 6.61 (d, 1H, J ) 8.5 Hz),
6.88 (dd, 1H, J ) 1.0, 2.0 Hz), 7.06 (d, 1H, J ) 8.5 Hz), 7.20
(dd, 1H, J ) 1.5, 8.5 Hz), 7.46 (d, 1H, J ) 8.5 Hz), 7.52 (d, 1H,
J ) 1.5 Hz), 7.93 (d, 1H, J ) 2.0 Hz), 9.87 (s, 1H); ESI-MS
m/z 476 (M + NH4+); HR-FABMS calcd for C24H26NaO9 (M +
Na+) m/z 481.1475, found 481.1488.
6′-Acetoxy-3-(ben zo[b]fu r a n -5-yl)-2′-h yd r oxy-4′-m eth -
ylp r op iop h en on e 2′-O-(2,3-O-Dia cetyl-â-D-glu cop yr a n o-
sid e) (42). A mixture of 41 (2.04 g, 3.03 mmol), p-TsOH‚H2O
(58 mg, 0.30 mmol), AcOH (60 mL), and H2O (6 mL) was
stirred at room temperature for 20 h. The reaction mixture
was poured into ice-water and extracted with AcOEt. The
organic layer was washed with saturated NaHCO3 and brine,
dried over MgSO4, and evaporated. The residue was chromato-
graphed on silica gel (CHCl3-MeOH (10:1)) to give 42 (1.58
3′,5′-Dich lor o-2′,6′-dih ydr oxyacetoph en on e 2′-O-(2,3,4,6-
O-Tetr a a cetyl-â-D-glu cop yr a n osid e (38). A mixture of 2′,6′-
dihydroxyacetophenone 2′-O-(2,3,4,6-O-tetraacetyl-â-D-glu-
copyranoside (37) (4.84 g, 10 mmol), NCS (3.47 g, 26 mmol),
and DMF (50 mL) was stirred at 50 °C for 10 h. After cooling,
the reaction mixture was diluted with AcOEt and washed with
water and brine. The organic layer was dried over MgSO4 and
evaporated. The residue was chromatographed on silica gel
(AcOEt-hexane (1:2)) to give 38 (3.46 g, 63%) as pale yellow
1
g, 89%) as a colorless foam: IR (Nujol) 3405, 1750 cm-1; H
NMR (DMSO-d6) δ 1.87 (s, 3H), 2.00 (s, 6H), 2.31 (s, 3H), 2.84-
3.11 (m, 4H), 3.48-3.57 (m, 2H), 3.64-3.77 (m, 2H), 4.77 (t,
1H, J ) 5.8 Hz), 4.89 (dd, 1H, J ) 8.1, 9.7 Hz), 5.10 (t, 1H, J
) 9.7 Hz), 5.50 (d, 1H, J ) 8.1 Hz), 5.59 (d, 1H, J ) 5.7 Hz),
6.70 (s, 1H), 6.89 (dd, 1H, J ) 0.9, 2.2 Hz), 7.00 (s, 1H), 7.16
(dd, 1H, J ) 1.5, 8.5 Hz), 7.47-7.50 (m, 2H), 7.94 (d, 1H, J )
2.2 Hz); ESI-MS m/z 602 (M + NH4+); HR-FABMS calcd for
C
30H32NaO12 (M + Na+) m/z 607.1791, found 607.1782.
3-(Ben zo[b]fu r a n -5-yl)-2′,6′-d ih yd r oxy-4′-m et h ylp r o-
needles, mp 164.5-165.5 °C: IR (Nujol) 1750, 1630 cm-1; H
1
NMR (DMSO-d6) δ 1.97 (s, 3H), 1.98 (s, 6H), 2.06 (s, 3H), 2.50
(s, 3H), 3.87 (m, 1H), 4.00-4.12 (m, 2H), 4.99 (dd, 1H, J )
9.2, 9.5 Hz), 5.05 (dd, 1H, J ) 7.9, 9.9 Hz), 5.26 (d, 1H, J )
7.9 Hz), 5.38 (dd, 1H, J ) 9.5, 9.7 Hz), 7.80 (s, 1H), 10.86 (s,
1H); ESI-MS m/z 573 (M + Na+), 575 (M + 2 + Na+), 577 (M
+ 4 + Na+).
p iop h en on e 2′-O-(2,3-O-Dia cetyl-4,6-O-ben zylid en e-â-D-
glu cop yr a n osid e) (43). A mixture of 41 (671 mg, 1.00 mmol),
NaHCO3 (419 mg, 5.00 mmol), MeOH (5 mL), THF (5 mL),
and H2O (0.1 mL) was stirred at room temperature for 30 h.
The reaction mixture was diluted with AcOEt, washed with
water, and dried over MgSO4. The solvent was removed, and
the residue was chromatographed on silica gel (hexane-AcOEt
(2:1)) to give 43 (410 mg, 65%) as colorless needles, mp 187-
3-(Ben zo[b]fu r an -5-yl)-3′,5′-dich lor o-2′,6′-dih ydr oxypr o-
p iop h en on e 2′-O-â-D-Glu cop yr a n osid e (39). Compound 39
was prepared from 38 by the same procedure as described for
the synthesis of 4, with a yield of 54%, as a pale yellow solid,
189 °C: IR (Nujol) 1755, 1635 cm-1 1H NMR (DMSO-d6) δ
;
mp 107-110 °C: IR (Nujol) 3520, 3310, 1630 cm-1; H NMR
1
1.97 (s, 3H), 2.01 (s, 3H), 2.25 (s, 3H), 2.90-2.98 (m, 2H), 3.01-
3.09 (m, 2H), 3.76 (t, 1H, J ) 9.9 Hz), 3.88 (t, 1H, J ) 9.4 Hz),
3.95 (dd, 1H, J ) 4.6, 9.5 Hz), 4.32 (dd, 1H, J ) 4.6, 10.1 Hz),
5.05 (dd, 1H, J ) 7.9, 9.3 Hz), 5.40 (t, 1H, J ) 9.3 Hz), 5.63 (s,
1H), 5.63 (d, 1H, J ) 7.9 Hz), 6.43 (s, 1H), 6.53 (s, 1H), 6.90
(dd, 1H, J ) 0.9, 2.2 Hz), 7.19 (dd, 1H, J ) 1.7, 8.6 Hz), 7.39
(DMSO-d6) δ 3.00 (m, 2H), 3.06 (m, 2H), 3.20 (m, 2H), 3.25-
3.50 (m, 3H), 3.60 (m, 1H), 4.20 (t, 1H, J ) 5.5 Hz), 4.79 (d,
1H, J ) 7.3 Hz), 4.99 (d, 1H, J ) 5.1 Hz), 5.10 (d, 1H, J ) 4.4
Hz), 5.45 (d, 1H, J ) 4.7 Hz), 6.89 (dd, 1H, J ) 0.9, 2.2 Hz),
7.21 (dd, 1H, J ) 1.8, 8.6 Hz), 7.47 (d, 1H, J ) 8.6 Hz), 7.53