COX-1 Inhibiting Analgesics without Gastric Damage
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 8 2407
Hz), 8.49–8.40 (m, 2H), 8.02 (d, 2H, J ) 8.7 Hz), 7.87 (t, 1H, J )
8.0 Hz), 7.76 (d, 2H, J ) 8.7 Hz). FAB-MS m/z: 311 [M + H]+.
Anal. (C14H9F3N2O3) C, H, N.
after recrystallization from EtOAc/n-hexane. Mp 149.0–150.0 °C.
IR (KBr) cm-1: 3466, 3363 (NH2), 3276 (NH), 1635 (CO). 1H
NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 7.62–7.57 (m, 3H),
7.21–7.11 (m, 3H), 6.74 (dd, 1H, J ) 8.2, 1.2 Hz), 6.58 (td, 1H, J
) 8.2, 1.2 Hz), 6.30 (s, 2H), 2.27 (s, 3H). FAB-MS m/z: 226 [M]+,
227 [M + H]+. Anal. (C14H14N2O) C, H, N.
4-Nitro-N-(2-trifluoromethylphenyl)benzamide (10o). Accord-
ing to the general procedure (GP-A), 10o was obtained in 58%
yield as white needles after recrystallization from EtOAc/n-hexane.
1
Mp 225.0–227.0 °C. IR (KBr) cm-1: 3114 (NH), 1683 (CO). H
2-Amino-N-(phenyl)benzamide (11g). According to the general
procedure (GP-B-1), 11g was obtained in 83% yield as white
granules after recrystallization from EtOAc/n-hexane. Mp 128.0–129.5
°C. IR (KBr) cm-1: 3470, 3420 (NH2), 3364 (NH), 1600 (CO). 1H
NMR (300 MHz, DMSO-d6) δ: 10.00 (s, 1H), 7.70 (d, 2H, J )
8.0 Hz), 7.66 (dd, 1H, J ) 8.0, 1.5 Hz), 7.26 (t, 2H, J ) 8.0 Hz),
7.24 (t, 1H, J ) 8.0 Hz), 7.21 (t, 1H, J ) 8.0 Hz), 6.75 (dd, 1H,
J ) 8.0, 1.2 Hz), 6.60 (t, 1H, J ) 8.0 Hz), 6.37 (br s, 2H). FAB-
MS m/z: 212 [M]+, 213 [M + H]+. Anal. (C13H12N2O) C, H, N.
2-Amino-N-(4-chlorophenyl)benzamide (11h). According to
the general procedure (GP-B-1), 11h was obtained in 88% yield
as a white powder after recrystallization from EtOAc/n-hexane. Mp
198.0–199.5 °C. IR (KBr) cm-1: 3412, 3329 (NH2), 3223 (NH),
NMR (300 MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.38 (d, 2H, J )
9.0 Hz), 8.24–8.15 (m, 4H), 8.17 (d, 2H, J ) 9.0 Hz). FAB-MS
m/z: 311 [M + H]+.
4-Nitro-N-(3-trifluoromethylphenyl)benzamide (10p). Accord-
ing to the general procedure (GP-A), 10p was obtained in 98%
yield as white needles after recrystallization from EtOAc/n-hexane.
1
Mp 209.0–211.0 °C. IR (KBr) cm-1: 3301 (NH), 1660 (CO). H
NMR (300 MHz, DMSO-d6) δ: 10.86 (s, 1H), 8.40 (dd, 2H, J )
7.0, 2.0 Hz), 8.25 (s, 1H), 8.21 (dd, 2H, J ) 7.0, 2.0 Hz), 8.06 (d,
1H, J ) 8.0 Hz), 7.64 (t, 1H, J ) 8.0 Hz), 7.50 (d, 1H, J ) 8.0
Hz). FAB-MS m/z: 311 [M + H]+.
4-Nitro-N-(4-trifluoromethylphenyl)benzamide (10q). Accord-
ing to the general procedure (GP-A), 10q was obtained in 71%
yield as white needles after column chromatography (eluent: EtOAc/
n-hexane ) 1/4). Mp 216.0–217.0 °C. IR (KBr) cm-1: 3416 (NH),
1669 (CO). 1H NMR (300 MHz, DMSO-d6) δ: 10.90 (s, 1H), 8.40
(dd, 2H, J ) 8.9, 2.0 Hz), 8.20 (dd, 2H, J ) 8.9, 2.0 Hz), 8.02 (d,
2H, J ) 8.6 Hz), 7.75 (d, 2H, J ) 8.6 Hz). FAB-MS m/z: 311 [M
+ H]+. Anal. (C14H9F3N2O3) C, H, N.
4-Amino-N-(phenyl)benzamide (11a). According to the general
procedure (GP-B-1), 11a was obtained in 93% yield as white
granules after recrystallization from EtOAc/n-hexane. Mp 136.0–138.0
°C. IR (KBr) cm-1: 3488, 3394 (NH2), 3350 (NH), 1647 (CO).1H
NMR (300 MHz, DMSO-d6) δ: 9.80 (s, 1H), 7.74 (dd, 2H, J )
7.8, 1.9 Hz), 7.71 (dd, 2H, J ) 8.7, 2.0 Hz), 7.30 (tt, 2H, J ) 7.8,
2.0 Hz), 7.03 (tt, 1H, J ) 7.8, 2.0 Hz), 6.59 (dd, 2H, J ) 7.4, 2.0
Hz), 5.70 (s, 2H). FAB-MS m/z: 213 [M + H]+. Anal. (C13H12N2O·
1/5H2O) C, H, N.
1
1651 (CO). H NMR (300 MHz, DMSO-d6) δ: 9.85 (s, 1H), 7.77
(dd, 2H, J ) 8.9, 2.0 Hz), 7.72 (dd, 2H, J ) 8.7, 2.0 Hz), 7.36 (dd,
2H, J ) 8.9, 2.0 Hz), 6.59 (dd, 2H, J ) 8.7, 2.0 Hz), 5.80 (s, 2H).
FAB-MS m/z: 246 [M]+, 247 [M + H]+, 248 [M + 2]+, 249 [M
+ 2 + H]+. Anal. (C13H11ClN2O·1/12H2O) C, H, N.
2-Amino-N-(2-trifluoromethylphenyl)benzamide (11i). Ac-
cording to the general procedure (GP-B-1), 11i was obtained in
99% yield as a white solid after recrystallization from EtOAc/n-
hexane. Mp 123.0–125.0 °C. IR (KBr) cm-1: 3420, 3288 (NH2),
1
3250 (NH), 1648 (CO). H NMR (300 MHz, DMSO-d6) δ: 9.90
(s, 1H), 7.79–7.52 (m, 5H), 7.21 (td, 1H, J ) 8.5, 1.0 Hz), 6.75
(dd, 1H, J ) 8.5, 1.0 Hz), 6.58 (td, 1H, J ) 8.5, 1.0 Hz), 6.40 (s,
2H). FAB-MS m/z: 280 [M]+, 281 [M + H]+. Anal. (C14H11F3N2O)
C, H, N.
2-Amino-N-(3-trifluoromethylphenyl)benzamide (11j). Ac-
cording to the general procedure (GP-B-1), 11j was obtained in
94% yield as brown plates after recrystallization from EtOAc/n-
hexane. Mp 132.0–134.0 °C. IR (KBr) cm-1: 3476, 3371 (NH2),
4-Amino-N-(4-chlorophenyl)benzamide (11b). According to
the general procedure (GP-B-2), 11b was obtained in 86% yield
as white granules after recrystallization from EtOAc/n-hexane. Mp
197.0–198.0 °C. IR (KBr) cm-1: 3412, 3330 (NH2), 3223 (NH),
1
3296 (NH), 1581 (CO). H NMR (300 MHz, DMSO-d6) δ: 10.27
(s, 1H), 8.21 (s, 1H), 7.99 (d, 1H, J ) 8.0 Hz), 7.63–7.22 (m, 4H),
6.77 (dd, 1H, J ) 8.0, 1.0 Hz), 6.60 (m, 1H), 6.40 (s, 2H). FAB-
MS m/z: 280 [M]+, 281 [M + H]+. Anal. (C14H11F3N2O) C, H, N.
2-Amino-N-(4-trifluoromethylphenyl)benzamide (11k). Ac-
cording to the general procedure (GP-B-1), 11k was obtained in
90% yield as brown granules after recrystallization from EtOAc/
n-hexane. Mp 160.0–162.0 °C. IR (KBr) cm-1: 3464, 3360 (NH2),
1
1651 (CO). H NMR (300 MHz, DMSO-d6) δ: 9.87 (s, 1H), 7.79
(dd, 2H, J ) 9.0, 2.1 Hz), 7.70 (dd, 2H, J ) 8.7, 1.8 Hz), 7.35 (dd,
2H, J ) 9.0, 2.1 Hz), 6.59 (dd, 2H, J ) 8.7, 1.8 Hz), 5.78 (s, 2H).
FAB-MS m/z: 246 [M]+, 247 [M + H]+, 248 [M + 2]+, 249 [M
+ 2 + H]+. Anal. (C13H11ClN2O·1/9H2O) C, H, N.
4-Amino-N-(4-tolyl)benzamide (11c). According to the general
procedure (GP-B-1), 11c was obtained in 91% yield as a white
powder after recrystallization from EtOAc/n-hexane. Mp 165.0–167.0
°C. IR (KBr) cm-1: 3468, 3359 (NH2), 3214 (NH), 1650 (CO).1H
NMR (300 MHz, DMSO-d6) δ: 9.70 (s, 1H), 7.96 (d, 2H, J ) 8.7
Hz), 7.61 (d, 2H, J ) 8.0 Hz), 7.10 (d, 2H, J ) 8.0 Hz), 6.58 (d,
2H, J ) 8.7 Hz), 5.72 (s, 2H), 2.26 (s, 3H). FAB-MS m/z: 227 [M
+ H]+. Anal. (C14H14N2O·1/10H2O) C, H, N.
1
3297 (NH), 1641 (CO). H NMR (300 MHz, DMSO-d6) δ: 10.30
(s, 1H), 7.95 (d, 2H, J ) 8.5 Hz), 7.69 (d, 2H, J ) 8.5 Hz), 7.64
(dd, 1H, J ) 8.0, 1.5 Hz), 7.22 (td, 1H, J ) 8.0, 1.3 Hz), 6.76 (dd,
1H, J ) 8.0, 1.3 Hz), 6.60 (td, 1H, J ) 8.0, 1.3 Hz), 6.37 (s, 2H).
FAB-MS m/z: 280 [M]+, 281 [M + H]+. Anal. (C14H11F3N2O·
1/10H2O) C, H, N.
3-Amino-N-(2-trifluoromethylphenyl)benzamide (11l). Ac-
cording to the general procedure (GP-B-1), 11l was obtained in
60% yield as white needles after recrystallization from EtOAc/n-
hexane. Mp 83.0–85.0 °C. IR (KBr) cm-1: 3449, 3358 (NH2), 3225
(NH), 1648 (CO). 1H NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H),
8.33 (s, 1H), 8.30 (d, 1H, J ) 8.0 Hz), 7.95 (d, 1H, J ) 7.5 Hz),
7.76 (t, 1H, J ) 8.0 Hz), 7.14 (d, 1H, J ) 7.5 Hz), 6.99 (td, 1H,
J ) 7.5, 1.4 Hz), 6.79 (dd, 1H, J ) 7.5, 1.3 Hz), 6.60 (t, 1H, J )
7.5 Hz), 4.97 (s, 2H). FAB-MS m/z: 289 [M + H]+. Anal.
(C14H11F3N2O·1/20H2O) C, H, N.
3-Amino-N-(3-trifluoromethylphenyl)benzamide (11m). Ac-
cording to the general procedure (GP-B-1), 11m was obtained in
98% yield as white needles after recrystallization from EtOAc/n-
hexane. Mp 83.0–84.0 °C. IR (KBr) cm-1: 3384, 3277 (NH2), 3083
(NH), 1653 (CO). 1H NMR (300 MHz, DMSO-d6) δ: 10.38 (s,
1H), 8.24 (s, 1H), 8.03 (d, 1H, J ) 8.5 Hz), 7.57 (t, 1H, J ) 8.0
Hz), 7.42 (d, 1H, J ) 8.0 Hz), 7.17 (t, 1H, J ) 8.0 Hz), 7.10–7.06
(m, 2H), 6.77 (dd, 1H, J ) 8.0, 1.5 Hz), 5.36 (s, 2H). FAB-MS
m/z: 280 [M]+, 281 [M + H]+. Anal. (C14H11F3N2O·1/10H2O) C,
H, N.
2-Amino-N-(2-tolyl)benzamide (11d). According to the general
procedure (GP-B-1), 11d was obtained in 87% yield as white plates
after recrystallization from EtOAc/n-hexane. Mp 101.0–102.0 °C.
IR (KBr) cm-1: 3485, 3378 (NH2), 3265 (NH), 1605 (CO). 1H
NMR (300 MHz, DMSO-d6) δ: 9.60 (s, 1H), 7.68 (dd, 1H, J )
8.0, 1.5 Hz), 7.30–7.13 (m, 5H), 6.72 (dd, 1H, J ) 8.0, 1.2 Hz),
6.56 (td, 1H, J ) 8.0, 1.0 Hz), 6.37 (s, 2H), 2.20 (s, 3H). FAB-MS
m/z: 226 [M]+, 227 [M + H]+. Anal. (C14H14N2O) C, H, N.
2-Amino-N-(3-tolyl)benzamide (11e). According to the general
procedure (GP-B-1), 11e was obtained in 78% yield as white
needles after recrystallization from EtOAc/n-hexane. Mp 115.0–117.0
°C. IR (KBr) cm-1: 3470, 3365 (NH2), 3277 (NH), 1635 (CO). 1H
NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 7.60 (td, 2H, J )
8.2, 1.5 Hz), 7.50 (d, 1H, J ) 8.0 Hz), 7.22–7.16 (m, 2H), 6.90 (d,
1H, J ) 8.0 Hz), 6.74 (dd, 1H, J ) 8.0, 1.0 Hz), 6.57 (td, 1H, J )
8.0, 1.0 Hz), 6.30 (s, 2H), 2.30 (s, 3H). FAB-MS m/z: 226 [M]+,
227 [M + H]+. Anal. (C14H14N2O) C, H, N.
2-Amino-N-(4-tolyl)benzamide (11f). According to the general
procedure (GP-B-1), 11f was obtained in 87% yield as white needles