1148 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5
Table 2. Pharmacokinetic Profile of 6 in Rats
Meng et al.
MHz, CD3OD) δ 7.33 (d, J ) 6.0, 1H), 7.31 (d, J ) 2.2, 1H), 7.31
(dd, J ) 2.2, 6.0, 1H), 7.07 (d, J ) 8.8, 2H), 6.78 (d, J ) 8.8, 2H),
4.07–3.90 (m, 7H), 3.85 (d, J ) 10.6, 1H), 3.69 (dd, J ) 5.3, 10.6,
1H), 3.42–3.25 (m, 4H), 1.34 (t, J ) 7.0, 3H); 13C NMR (125
MHz, CD3OD) δ 158.8, 140.0, 139.9, 134.4, 132.9, 131.9, 130.8,
130.1, 128.2, 115.5, 82.9, 82.2, 79.7, 76.4, 71.9, 64.5, 63.1, 39.2,
15.2; HRMS calcd for C21H25ClNaO6 (M + Na)+ 431.1237, found
431.1234. Anal. Calcd for C21H25ClO6: C, 61.68; H, 6.16. Found:
C, 61.16; H, 6.58.
dose (mg/kg)
1
Cmax (PO dose, µg/mL)
Tmax (PO dose, h)
T1/2 (h)
0.6
1.7
4.6
F (%)
84
Vss (L/kg)
Cl (mL/min/kg)
1.6
4.8
Supporting Information Available: Descriptions of hSGLT1
and hSGLT2 binding assays, in vivo pharmacology including
glucosuria and blood glucose-lowering experiments. Detailed
experimental procedures, physical state, and characterization for
compounds 5, 8, 10, and 11.
For the major anomer: HPLC tR ) 3.45 min, purity 100%; 1H NMR
(400 MHz, CD3OD) δ 7.54 (d, J ) 2.2, 1H), 7.45 (dd, J ) 2.2,
8.4, 1H), 7.35 (d, J ) 8.4, 1H), 7.08 (d, J ) 8.8, 2H), 6.79 (d, J )
8.8, 2H), 4.08 (d, J ) 15.0, 1H), 3.99 (d, J ) 15.0, 1H), 3.98 (q,
J ) 7.0, 2H), 3.92 (dd, J ) 2.2, 11.8, 1H), 3.80 (dd, J ) 5.3, 11.9,
1H), 3.74 (t, J ) 9.2, 1H), 3.57 (m, 1H), 3.41 (d, J ) 8.8, 1H),
3.08 (d, J ) 9.7, 1H), 3.06 (s, 3H), 1.35 (t, J ) 7.0, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.2, 139.0, 138.5, 134.2, 132.4, 131.2,
130.1, 129.2, 127.6, 114.8, 101.8, 78.0, 75.3, 74.5, 71.1, 63.8, 62.1,
49.0, 38.7, 14.5. Anal. Calcd for C22H27ClO7: C, 60.20; H, 6.20;
Cl, 8.07. Found: C, 60.05; H, 6.21; Cl, 8.01.
References
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tetra-Acetylated ꢀ-C-glucoside (13). To a stirred -10 °C
solution of O-methylglucoside 12 (123 g, 0.3 mol) in 1:1 CH2Cl2/
MeCN (1.1 L) was added Et3SiH (65 g, 0.6 mol) followed by
BF3 ·OEt2 (60 g, 0.4 mol) at a rate such that the reaction temperature
was maintained between -5 and -10 °C. The solution was allowed
to warm to 0 °C over 5 h prior to quenching with saturated aqueous
NaHCO3 (310 mL). After removal of organic volatiles under
reduced pressure, the residue was partitioned between 2 L each of
EtOAc and H2O. Following extraction of the aqueous layer with
EtOAc (2 × 2 L), the combined organic layers were washed with
H2O (2 L) and brine (2 L) prior to drying over MgSO4. Filtration
and concentration under reduced pressure yielded a yellow foam
(105 g). Peracetylation was achieved by addition of Ac2O (261 g,
2.6 mol) and DMAP (1.6 g, 13.1 mmol) to a solution of this residue
in CH2Cl2 (750 mL) and pyridine (200 g, 2.5 mol). After 1.5 h, the
reaction was quenched by addition of H2O (1.8 L), whereupon the
resulting mixture was extracted with CH2Cl2 (2×). The combined
organic layers were washed with 1 N HCl (2 × 1.8 L) and brine (2
× 1.8 L) prior to drying over MgSO4. After filtration and
concentration under reduced pressure, the residue was recrystallized
from absolute EtOH to yield the desired tetra-acetylated ꢀ-C-
glucoside 13 (90 g, 55% for two steps) as a white solid (the
stereochemistry for the anomeric position of 13 was established
according to ref 51). The mother liquors contained the correspond-
ing R-C-glucoside as well as a more polar furanose isomer: HPLC
1
tR ) 3.98 min, purity 100%; H NMR (400 MHz, CDCl3) δ 7.35
(d, J ) 8.4, 1H), 7.19 (dd, J ) 1.8, 8.4, 1H), 7.07 (d, J ) 1.8, 1H),
7.05 (d, J ) 8.8, 2H), 6.82 (d, J ) 8.8, 2H), 5.28 (t, J ) 9.2, 1H),
5.20 (t, J ) 9.2, 1H), 5.05 (t, J ) 9.2, 1H), 4.31 (d, J ) 9.7, 1H),
4.26 (dd, J ) 4.8, 12.8, 1H), 4.14 (dd, J ) 2.2, 12.4, 1H), 3.95–4.07
(m, 4H), 3.80 (m, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H),
1.71 (s, 3H), 1.40 (t, J ) 7.0, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.7, 170.3, 169.45, 168.7, 157.5, 139.1, 135.1, 134.6, 131.0,
129.79, 126.0, 114.5, 79.5, 76.1, 74.1, 72.5, 68.5, 63.4, 62.3, 38.2,
20.7, 20.6, 20.3, 14.8; mp 120 °C (uncorrected); HRMS calcd for
C29H33ClNaO10 (M + Na)+ 599.1660, found 599.1649. Anal. Calcd
for C29H33ClO10: C, 60.36; H, 5.76. Found: C, 60.43; H, 5.56.
(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-
hydroxymethyltetrahydro-2H-pyran-3,4,5-triol (6). To a stirred
solution of tetra-acetylated ꢀ-C-glucoside 13 (27 g, 47 mmol) in
2:3:1 THF/MeOH/H2O (480 mL) was added LiOH·H2O (2.3 g,
55 mmol). After the mixture was stirred overnight, the volatiles
were removed under reduced pressure. The residue, after dissolution
in EtOAc (300 mL), was subsequently washed with brine (150 mL),
brine containing 10 mL of 5% aq KHSO4 (50 mL) and brine (50
mL) prior to drying over Na2SO4. Filtration and removal of the
volatiles under reduced pressure yielded desired (2S,3R,4R,5S,6R)-
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-
2H-pyran-3,4,5-triol 6 (20.4 g, 100%) as a glassy off-white
amorphous solid: HPLC tR ) 3.26 min, purity 99%; 1H NMR (500
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