Indomethacin DeriVatiVes as COX-2 Inhibiting NO Donors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 25 6379
1
triturated with Et2O (100 mL). The off-white solid was collected,
washed with Et2O, and then dried under vacuum (0.51 g, 57%
yield). mp: 165–167 °C. 1H NMR (300 MHz, CD3OD): δ 7.62 (d,
J ) 8.4 Hz, 2H), 7.52 (d, J ) 8.4 Hz, 2H), 7.01 (d, J ) 2.1 Hz,
1H), 6.92 (d, J ) 9.0 Hz, 1H), 6.64 (dd, J ) 9.0, 2.1 Hz, 1H), 3.81
(s, 3H), 2.95 (m, 2H), 2.27 (s, 3H), 1.99 (m, 2H). 13C NMR (75
MHz, CD3OD): δ 169.9, 157.7, 140.0, 135.9, 134.9, 132.4, 132.2,
131.8, 130.2, 120.5 (d, JCP ) 18 Hz), 116.1, 112.5, 102.1, 55.1,
28.4 (d, JCP ) 134.3 Hz), 18.5 (d, JCP ) 3.8 Hz), 13.4. MS (API-
TIS): m/z 408 (MH)+.
(2-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-3-
yl}ethoxy)-N-({[3-(nitrooxy)propyl]amino}sulfonyl)carboxamide
(51). Chlorosulfonyl isocyanate (115 µL, 1.3 mmol) and NEt3 (180
µL, 1.3 mmol) were added to an ice-cold solution of 45 (0.40 g,
1.2 mmol) in CH2Cl2 (15 mL) and stirred in the ice-bath for 30
min. Compound 2 (0.26 g, 1.4 mmol) and NEt3 (250 µL, 1.8 mmol)
were added to the reaction, and the temperature allowed to warm
slowly in the ice-bath to room temperature. After 3 h, the reaction
mixture was diluted with CH2Cl2 (80 mL), washed with 3 N HCl,
water, and brine, and dried over Na2SO4, filtered, and concentrated.
The products were separated by silica gel column chromatography
eluted with EtOAc/hexane (1:1, Rf ) 0.32) to obtain the title
compound (0.15 g, 23% yield). The product can be recrystallized
from CHCl3/hexane. mp: 127–129 °C. 1H NMR (300 MHz, DMSO-
d6): δ 7.66 (d, J ) 8.6 Hz, 2H), 7.60 (d, J ) 8.6 Hz, 2H), 7.09 (d,
J ) 2.4 Hz, 1H), 6.99 (d, J ) 9.0 Hz, 1H), 6.70 (dd, J ) 9.0, 2.4
Hz, 1H), 4.54 (t, J ) 6.3 Hz, 2H), 4.31 (t, J ) 6.9 Hz, 2H), 3.80
(s, 3H), 3.03–2.97 (m, 4H), 2.23 (s, 3H), 1.86 (m, 2H). 13C NMR
(75 MHz, 5% CDCl3/DMSO-d6): δ 168.0, 155.9, 151.8, 137.8,
135.2, 134.3, 131.3, 130.7, 130.6, 129.2, 115.0, 114.8, 111.5, 101.5,
71.0, 64.4, 55.5, 39.8, 26.2, 23.4, 13.2. MS (API-TIS): m/z 569
(MH)+.
recrystallized from CHCl3 /hexane. mp: 51–52 °C. H NMR (300
MHz, CDCl3): δ 7.61 (d, J ) 8.5 Hz, 2H), 7.43 (d, J ) 8.5 Hz,
2H), 6.96 (d, J ) 2.1 Hz, 1H), 6.87 (d, J ) 9.0 Hz, 1H), 6.64 (dd,
J ) 9.0, 2.1 Hz, 1H), 5.15 (br, 1H), 4.44 (t, J ) 5.9 Hz, 2H), 4.23
(t, J ) 6.7 Hz, 2H), 3.81 (s, 3H), 3.24 (br. q, 2H), 2.96 (t, J ) 6.7
Hz, 2H), 2.32 (s, 3H), 1.88 (m, 2H). 13C NMR (75 MHz, CDCl3):
δ 168.1, 156.4, 155.8, 138.9, 135.1, 133.9, 130.9, 130.7, 128.9,
115.3, 114.8, 111.0, 101.2, 70.6, 55.5, 37.3, 27.2, 23.9, 13.0. MS
(API-TIS): m/z 490 (MH)+.
3-(2-Azidoethyl)-5-methoxy-2-methylindolyl 4-chlorophenyl
Ketone (54). To the crude product 46 (1.51 g, 4.4 mmol), was
added NaN3 (0.58 g, 8.9 mmol), and the mixture was heated to 70
°C in DMSO (50 mL) for 2 h. After the mixture was cooled to
room temperature, the DMSO was evaporated under vacuum. The
residue was dissolved in CH2Cl2 (150 mL), washed with water and
brine, dried over Na2SO4, filtered, concentrated, and dried under
vacuum to obtain the title compound. The product, >95% purity
from NMR analysis, was used in the next step without purification.
An analytical sample was obtained by silica gel column chroma-
tography eluted with EtOAc/hexane (1:5, Rf ) 0.45). 1H NMR (300
MHz, CDCl3): δ 7.64 (d, J ) 8.5 Hz, 2H), 7.45 (d, J ) 8.5 Hz,
2H), 6.91 (d, J ) 2.5 Hz, 1H), 6.89 (d, J ) 9.0 Hz, 1H), 6.67 (dd,
J ) 9.0, 2.5 Hz, 1H), 3.83 (s, 3H), 3.49 (t, J ) 7.0 Hz, 2H), 2.94
(t, J ) 7.0 Hz, 2H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
168.2, 155.9, 139.1, 135.4, 133.9, 131.1, 130.9, 130.5, 129.0, 115.5,
115.0, 111.2, 101.0, 55.7, 50.7, 24.1, 13.1.
3-(2-Aminoethyl)-5-methoxy-2-methylindolyl 4-chlorophenyl
Ketone Hydrochloride (55). The crude product 54 was hydroge-
nated in EtOAc (30 mL) in the presence of 10% Pd/C (0.14 g) and
acetic acid (0.5 mL) at 30 psi for 2 h. The reaction mixture was
filtered through Celite, and the filter cake was washed with MeOH
(100 mL). The filtrate was concentrated, and the residue was
partitioned between CH2Cl2 (200 mL) and water (100 mL). The
organic layer was washed with saturated Na2CO3, water, and brine,
dried over Na2SO4, filtered, concentrated, and dried under vacuum.
The product was dissolved in Et2O and treated with HCl/Et2O. The
brown solid was collected, washed with Et2O, and then dried under
3-(Nitrooxy)propyl [(2-{1-[(4-chlorophenyl)carbonyl]-5-meth-
oxy-2-methylindol-3-yl}ethoxy)carbonylamino]sulfonate (52). Chlo-
rosulfonyl isocyanate (130 µL, 1.5 mmol) and NEt3 (210 µL, 1.5
mmol) were added to an ice-cold solution of 45 (0.52 g, 1.5 mmol)
in CH2Cl2 (20 mL) and stirred in the ice-bath for 30 min. Compound
8 (0.25 g, 2.1 mmol) and NEt3 (210 µL, 1.5 mmol) were added to
the reaction; the temperature allowed to increase slowly in the ice-
bath to room temperature, and the mixture was stirred overnight.
The reaction mixture was partitioned between 3 N HCl (20 mL)
and CH2Cl2 (50 mL). The organic extract was washed with water
and brine, dried over Na2SO4, filtered, and concentrated. The
products were separated by silica gel column chromatography eluted
with EtOAc/hexane (1:1, Rf ) 0.1) to obtain the title compound as
1
vacuum (1.21 g, 73% yield for 4 steps). mp: >200 °C. H NMR
(300 MHz, DMSO-d6): δ 8.30 (br, 3H), 7.71 (d, J ) 8.7 Hz, 2H),
7.63 (d, J ) 8.7 Hz, 2H), 7.26 (d, J ) 2.1 Hz, 1H), 6.96 (d, J )
9.0 Hz, 1H), 6.71 (dd, J ) 9.0, 2.1 Hz, 1H), 3.80 (s, 3H), 3.00 (m,
4H), 2.23 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 168.0, 155.7,
137.6, 134.9, 134.2, 131.2, 130.5, 130.3, 129.0, 114.7, 111.5, 101.5,
55.6, 38.5, 21.6, 13.1. MS (API): m/z 343 (M - Cl)+.
N-(2-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-
3-yl}ethyl){4-[(nitrooxy)methyl]phenyl}carboxamide (56). A mix-
ture of 55 (1.01 g, 2.7 mmol), 10 (0.59 g, 3.0 mmol), DMAP (0.4
g, 3.3 mmol), EDAC (0.67 g, 3.5 mmol), and NEt3 (1.6 mL, 11.5
mmol) in CH2Cl2 (30 mL) and THF (20 mL) was stirred at room
temperature for 2 days. The reaction mixture was partitioned
between 3 N HCl (30 mL) and EtOAc (50 mL × 2). The combined
organic extracts were washed with water and brine, dried over
Na2SO4, filtered, and concentrated. The product was separated by
silica gel column chromatography eluted with EtOAc/hexane (2:3,
Rf ) 0.25 in 1:1) to obtain the title compound (0.28 g, 20% yield).
The product can be recrystallized from Et2O and hexane. mp:
141–144 °C. 1H NMR (300 MHz, CDCl3): δ 7.70 (d, J ) 8.2 Hz,
2H), 7.61 (d, J ) 8.5 Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H), 7.41 (d,
J ) 8.2 Hz, 2H), 6.98 (d, J ) 2.5 Hz, 2H), 6.89 (d, J ) 9.0 Hz,
1H), 6.67 (dd, J ) 9.0, 2.5 Hz, 1H), 6.4 (br. t, 1H), 5.43 (s, 2H),
3.74 (s, 3H), 3.67 (br. q, 2H), 3.00 (t, J ) 6.6 Hz, 2H), 2.30 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 168.2, 166.8, 156.0, 139.1,
136.0, 135.3, 135.0, 133.8, 131.0, 130.88, 130.85, 129.0, 128.8,
127.4, 116.6, 115.0, 111.5, 101.0, 55.6, 39.9, 23.9, 13.2. MS (API-
TIS): m/z 522 (MH)+. Anal. (C27H24ClN3O6) C, H, N.
1
a solid (0.143 g, 17% yield). mp: 44–46 °C. H NMR (300 MHz,
CDCl3): δ 7.61 (d, J ) 8.5 Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H), 6.94
(d, J ) 2.3 Hz, 1H), 6.89 (d, J ) 9.0 Hz, 1H), 6.65 (dd, J ) 9.0,
2.3 Hz, 1H), 4.48 (t, J ) 6.0 Hz, 2H), 4.36 (t, J ) 6.9 Hz, 2H),
4.31 (t, J ) 6.0 Hz, 2H), 3.82 (s, 3H), 3.02 (br. t, 2H), 2.31 (s,
3H), 2.07 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 168.5, 156.0,
150.9, 139.2, 135.6, 133.6, 131.1, 130.9, 130.6, 129.0, 115.0, 114.5,
111.3, 101.2, 69.0, 68.5, 66.1, 55.7, 26.3, 23.4, 13.1. MS (API-
TIS): m/z 570 (MH)+.
(2-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-
3-yl}ethoxy)-N-[3-(nitrooxy)propyl]carboxamide (53). A solution
of 45 (0.39 g, 1.1 mmol) in THF (5 mL) was added to a mixture
of phosgene (20% in toluene, 10 mL) and K2CO3 (0.16 g, 1.2
mmol). The reaction was stirred at room temperature for 1 h then
heated to 50 °C for an additional 0.5 h. The reaction was cooled
down to room temperature. The excess phosgene was removed by
evaporation of the reaction mixture to half the volume under reduced
pressure. The resulting crude intermediate was dissolved in THF
(20 mL), and 2 (0.20 g, 1.1 mmol) and DMAP (0.44 g, 3.6 mmol)
were added and stirred at room temperature for 1.5 h. The reaction
was quenched with 3 N HCl (100 mL) and extracted with EtOAc
(50 mL × 2). The combined organic layers were washed with 3 N
HCl, water, and brine, dried over Na2SO4, filtered, and concentrated.
The product was separated by silica gel column chromatography
eluted with EtOAc/hexane (2:3, Rf ) 0.25) to obtain the title
compound as a solid (0.47 g, 83% yield). The product can be
N-(2-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methylindol-
3-yl}ethyl){[3-(nitrooxy)propyl]amino}carboxamide (57). N,N′-
Carbonyldiimidazole (79 mg, 0.49 mmol) and 55 (0.16 g, 0.46
mmol) in CH2Cl2 (10 mL) were stirred at room temperature for
45 min. Compound 2 (85 mg, 0.46 mmol) and NEt3 (0.07 mL,
0.5 mmol) in THF (5 mL) was added to the resulting solution, and