Journal of Medicinal Chemistry
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61 was obtained as a dark purple solid (159 mg, 97%): mp 285 °C
added to the stirring suspension, which was then heated at reflux with
stirring for 22 h. The suspension was cooled to room temperature,
filtered, and the residue was washed with CHCl3 (10 mL) and dried in
vacuo to provide 65 as a yellow-brown solid (47 mg, 42%): mp 252−
254 °C (dec). IR 3282, 2928, 1710, 1671, 1648, 1547, 1322, 1203
(dec). IR 3525, 2975, 1703, 1570, 1512, 1465, 1398, 1346, 1250, 1066
1
cm−1; H NMR (DMSO-d6) δ 7.88 (s, 1 H), 7.80 (s, 1 H), 7.46 (s, 1
H), 7.00 (s, 1 H), 6.15 (d, J = 2.8 Hz, 2 H), 5.23 (d, J = 4.2 Hz, 1 H),
4.94 (d, J = 5.2 Hz, 1 H), 4.67 (d, J = 4.6, 1 H), 4.57−4.44 (m, 3 H),
4.13 (m, 1 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.60 (m, 3 H), 3.47 (m, 1
H); MALDI m/z (rel intensity) 516 (MH+, 100); HRESIMS m/z
calcd for C25H26NO11 516.1506 (MH+), found 516.1508 (MH+);
HPLC purity, 99.28% (90% MeOH, 10% H2O).
1
cm−1; H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 2.5 Hz, 1 H),
8.71 (d, J = 8.9 Hz, 1 H), 8.54 (dd, J = 9.0, 2.5 Hz, 1 H), 8.28 (d, J =
7.1 Hz, 1 H), 7.63−7.47 (m, 3 H), 4.99 (d, J = 7.4 Hz, 1 H), 4.89 (d, J
= 5.8 Hz, 1 H), 4.72−4.59 (m, 1 H), 4.55 (d, J = 5.4 Hz, 1 H), 4.50−
4.38 (m, 2 H), 4.38−4.27 (m, 1 H), 3.71−3.62 (m, 1 H), 3.60−3.41
(m, 2 H); negative ion ESIMS m/z (rel intensity) 461/463 (M + Cl¯,
69, 31); negative ion HRESIMS m/z calcd for C21H17N2O8 425.0985
[(M − H+)¯], found 425.0991 [(M − H+)¯]; HPLC purity, 98.85%
(MeOH−H2O, 90:10).
(2′S,3′S,4′R)-5,6-Dihydro-6-(2′,3′,4′,5′-tetrahydroxypentyl)-
3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (66). Indeno-
benzopyran 25 (38 mg, 0.13 mmol) was suspended with stirring in
MeOH (25 mL) at room temperature. A solution of D-ribitylamine
(34, 56 mg, 0.37 mmol) in H2O (0.25 mL) was added to the stirring
suspension, which was then heated at reflux with stirring for 72 h. The
suspension was cooled to room temperature, filtered, and the residue
was washed with MeOH (2 mL) and dried in vacuo to provide 66 as a
yellow-orange solid (16 mg, 29%): mp 260−262 °C (dec). IR 3395,
2928, 1669, 1553, 1622, 1507, 1432, 1353, 1262 cm−1; 1H NMR (300
MHz, DMSO-d6) δ 8.93−8.86 (m, 2 H), 8.76 (d, J = 9.5 Hz, 1 H),
8.63−8.52 (m, 1 H), 8.93−8.81 (m, 1 H), 8.34 (d, J = 7.0 Hz, 1 H),
7.70−7.49 (m, 2 H), 5.25 (d, J = 4.8 Hz, 1 H), 5.05 (d, J = 5.2 Hz, 1
H), 4.80 (d, J = 5.1 Hz, 1 H), 4.74−4.58 (m, 2 H), 4.56−4.41 (m, 1
H), 4.29−4.15 (m, 1 H), 3.74−3.54 (m, 3 H); negative ion ESIMS m/
z (rel intensity) 425 [(M − H+)¯, 100]; negative ion HRESIMS m/z
calcd for C21H17N2O8 425.0985 [(M − H+)¯], found 425.0991 [(M −
H+)¯]; HPLC purity, 99.83% (MeOH−H2O, 90:10).
(2′S,3′R,4′R,5′S,6’R)-5,6-Dihydro-6-[(3′,4′,5′-trihydroxy-6′-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)methyl)]-2,3-dime-
thoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]-
isoquinoline (62). β-D-Glucopyranosylmethylamine (51, 59 mg, 0.31
mmol) was added to a stirring solution of indenobenzopyran 20 (75
mg, 0.21 mmol) in CHCl3 (20 mL) and MeOH (10 mL). The
reaction mixture was stirred and heated at reflux for 20 h, cooled to
room temperature, and concentrated in vacuo. The residue was
suspended in CHCl3 (20 mL) and filtered and then suspended in
MeOH (20 mL), filtered, and dried by evaporation of solvents in
vacuo to provide 62 as a purple solid (70 mg, 63%): mp 324 °C (dec).
1
IR 3374, 2913, 1686, 1527, 1495, 1420, 1384, 1245, 1109 cm−1; H
NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1 H), 7.58 (s, 1 H), 7.46 (s, 1
H), 7.01 (s, 1 H), 6.15 (s, 2 H), 5.44−5.37 (m, 1 H), 5.05 (d, J = 4.2
Hz, 1 H), 4.89 (d, J = 5.1 Hz, 1 H), 4.78−4.67 (m, 1 H), 4.53 (s, 1 H),
4.00−3.93 (m, 1 H), 3.89 (s, 3 H), 3.84 (s, 3 H); MALDI m/z (rel
intensity) 528 (MH+, 100); HRCIMS m/z calcd for C26H26NO11
528.1506 (MH+), found 528.1484 (MH+); HPLC purity, 98.80%
(90% MeOH, 10% H2O).
(2′RS)-5,6-Dihydro-6-(2′,3′-dihydroxypropyl)-3-nitro-5,11-
dioxo-11H-indeno[1,2-c]isoquinoline (63). Indenobenzopyran 25
(71 mg, 0.24 mmol) was suspended with stirring in MeOH (20 mL) at
room temperature. A solution of racemic 3-aminopropane-1,2-diol
(26, 56 mg, 0.62 mmol) in MeOH (2 mL) was added to the stirring
suspension, which was then heated at reflux with stirring for 23 h. The
suspension was cooled to room temperature, filtered, and dried in
vacuo to provide 63 as a red solid (55 mg, 63%): mp 272−273 °C. IR
3419, 2923, 1751, 1701, 1648, 1609, 1541, 1420, 1041 cm−1; 1H NMR
(300 MHz, DMSO-d6) δ 8.87 (d, J = 2.5 Hz, 1 H), 8.73 (d, J = 9.0 Hz,
1 H), 8.56 (dd, J = 9.0 Hz, 2.5 Hz, 1 H), 8.15 (d, J = 7.3 Hz, 1 H),
7.66−7.49 (m, 4 H), 5.16 (d, J = 5.0 Hz, 1 H), 5.02 (t, J = 5.5 Hz, 1
H), 4.63−4.53 (m, 2 H), 4.05−3.96 (m, 1 H), 3.61 (t, J = 5.3 Hz, 2
H); negative ion ESIMS m/z (rel intensity) 401/403 (M + Cl¯, 100/
30); negative ion HRESIMS m/z calcd for C19H13N2O6 365.0774 [(M
− H+)¯], found 365.0777 [(M − H+)¯]; HPLC purity, 99.71%
(MeOH−H2O, 90:10).
(2′R,3′R,4′R)-5,6-Dihydro-6-(2′,3′,4′,5′-tetrahydroxypentyl)-
3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (67). Indeno-
benzopyran 25 (70 mg, 0.24 mmol) was suspended with stirring in
MeOH (30 mL) at room temperature. A solution of D-lyxitylamine
(37, 75 mg, 0.50 mmol) in H2O (1 mL) was added to the stirring
suspension, which was then heated at reflux with stirring for 21 h. The
suspension was cooled to room temperature, filtered, and dried in
vacuo to provide 67 as an orange solid (38 mg, 37%): mp 245 °C
1
(dec). IR 3282, 2929, 1697, 1612, 1561, 1507, 1344, 1121 cm−1; H
NMR (300 MHz, DMSO-d6) δ 8.90 (d, J = 2.5 Hz, 1 H), 8.76 (d, J =
9.0 Hz, 1 H), 8.58 (dd, J = 9.0, 2.5 Hz, 1 H), 8.17 (d, J = 7.3 Hz, 1 H),
7.68−7.48 (m, 3 H), 4.84−4.55 (m, 2 H), 4.09 (s, 1 H), 3.67 (t, J = 6.3
Hz, 2 H); negative ion ESIMS m/z (rel intensity) 461/463 (M + Cl¯,
100, 50); negative ion HRESIMS m/z calcd for C21H18N2O8Cl
461.0751 (M + Cl¯), found 461.0761 (M + Cl¯); HPLC purity,
99.65% (MeOH−H2O, 90:10).
(2′R)-5,6-Dihydro-6-(2′,3′-dihydroxypropyl)-3-nitro-5,11-
dioxo-11H-indeno[1,2-c]isoquinoline (64). Indenobenzopyran 25
(71 mg, 0.24 mmol) was suspended with stirring in MeOH (20 mL) at
room temperature. (R)-3-Aminopropane-1,2-diol (28, 52 mg, 0.57
mmol) was added to the stirring suspension, which was then heated at
reflux with stirring for 23 h. The product mixture was absorbed onto
silica gel (2 g) and purified by flash chromatography (SiO2, 100%
CHCl3 to 95:5 CHCl3−MeOH, 11 cm × 2 cm, 10 mL fractions). The
impure, product-containing fractions were pooled and concentrated.
The residue was suspended in CHCl3 (15 mL), filtered, and dried in
vacuo to provide 64 as a yellow-orange solid (31 mg, 35%): mp 226−
229 °C (dec). IR 3303, 2929, 1707, 1657, 1624, 1583, 1542, 1497,
(2′S,3′R,4′R)-5,6-Dihydro-6-(2′,3′,4′,5′-tetrahydroxypentyl)-
3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (68). Indeno-
benzopyran 25 (71 mg, 0.24 mmol) was suspended with stirring in
CHCl3 (20 mL) and MeOH (15 mL) at room temperature. A solution
of D-xylitylamine (40, 116 mg, 0.77 mmol) in H2O (0.5 mL) was
added to the stirring suspension, which was then heated at reflux with
stirring for 22 h. The suspension was cooled to room temperature,
filtered, and the residue was washed with CHCl3 (15 mL) until the
filtrate that drained was nearly colorless. The residue was dried in
vacuo to provide 68 as a red-orange solid (48 mg, 47%): mp 205 °C
1
1456, 1328, 1034 cm−1; H NMR (300 MHz, DMSO-d6) δ 8.89 (d, J
1
(dec). IR 3467, 2942, 1717, 1655, 1638, 1541, 1329, 1106 cm−1; H
= 2.5 Hz, 1 H), 8.76 (d, J = 9.0 Hz, 1 H), 8.58 (dd, J = 8.9, 2.5 Hz, 1
H), 8.17 (d, J = 7.3 Hz, 1 H), 7.67−7.52 (m, 3 H), 5.17 (d, J = 5.0 Hz,
1 H), 5.02 (t, J = 5.5 Hz, 1H), 4.62−4.56 (m, 2 H), 4.05−3.99 (m, 1
H), 3.61 (t, J = 5.3 Hz, 2 H); negative ion ESIMS m/z (rel intensity)
401/403 (M + Cl¯, 100/33); negative ion HRESIMS m/z calcd for
C19H13N2O6 365.0774 [(M − H+)¯], found 365.0777 [(M − H+)¯];
HPLC purity, 99.71% (MeOH−H2O, 90:10).
(2′R,3′S,4′R)-5,6-Dihydro-6-(2′,3′,4′,5′-tetrahydroxypentyl)-
3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (65). Indeno-
benzopyran 25 (77 mg, 0.26 mmol) was suspended with stirring in
CHCl3 (20 mL) and MeOH (15 mL) at room temperature. A solution
of D-arabitylamine (31, 97 mg, 0.64 mmol) in H2O (0.5 mL) was
NMR (300 MHz, DMSO-d6) δ 8.90 (d, J = 2.5 Hz, 1 H), 8.77 (d, J =
9.0 Hz, 1 H), 8.59 (dd, J = 9.0, 2.5 Hz, 1 H), 8.32 (d, J = 7.4 Hz, 1 H),
7.68−7.52 (m, 3 H), 5.08 (d, J = 5.1 Hz, 1 H), 4.91 (d, J = 6.2 Hz, 1
H), 4.68 (d, J = 5.3 Hz, 1 H), 4.59 (s, 2 H), 4.14 (s, 1 H), 3.67 (s, 2
H); negative ion ESIMS m/z (rel intensity) 461/463 (M + Cl¯, 100/
30); negative ion HRESIMS m/z calcd for C21H18N2O8Cl 461.0751
(M + Cl¯), found 461.0760 (M + Cl¯); HPLC purity, 95.09%
(MeOH−H2O, 90:10).
(2′S,3′R,4′S,5′R)-5,6-Dihydro-6-(2′,3′,4′,5′,6′-pentahydroxy-
hexyl)-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (69).
Indenobenzopyran 25 (70 mg, 0.24 mmol) was partially dissolved
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dx.doi.org/10.1021/jm401814y | J. Med. Chem. 2014, 57, 1495−1512