A. Vidal et al. / European Journal of Medicinal Chemistry 45 (2010) 405–410
409
126.0, 127.9, 132.8, 133.5, 134.0, 156.1, 168.3; ESI-MS m/z 368
(Mþ); Anal. C17H26IN3O4S$0.8H2O (C, H, N).
1,5
1,25
1
+37%
+30%
+31%
+22%
4.1.4.4. [3-(4-Hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-
carboxamido)propyl] diethylmethyl ammonium iodide (11). Yield
75%; mp 169–171 ꢀC; Rf 0.36 (B); IR (cmꢁ1) 3500–3300, 1633, 1542,
0,75
0,5
1334, 1181; 1H NMR (DMSO-d6)
d
1.07 (t, J ¼ 6.7, 6H, CH2CH3), 1.84
(m, 2H, CH2CH2CH2), 2.62 (s, 3H, NCH3), 2.75 (s, 3H, NþCH3), 3.03–
3,27 (m, 8H, CH2CH2CH2, CH2CH3), 7.70–8.03 (m, 4H, Ph), 8.87
(broad s, 1H, NH), 14.32 (broad s, 1H, OH); 13C NMR (DMSO-d6)
0,25
0
d
7.4, 21.8, 36.0, 39.1, 46.6, 55.7, 57.2, 111.2, 124.2, 126.0, 127.9, 132.9,
IL-1 (10 ng/mL)
-
-
-
-
-
-
-
+ +
+
+
+
+
+
133.5, 134.0, 156.1, 168.3; ESI-MS m/z 382 (Mþ); Anal. C18H28IN3O4S
Conc.(M) 10-5 10-6 10-8 10-5 10-6 10-8 Ctrl
(C, H, N).
2
3
4.1.4.5. [3-(4-Hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-
carboxamido)propyl]triethyl ammonium iodide (12). Yield 63%; mp
204–206 ꢀC; Rf 0.53 (B); IR (cmꢁ1) 3400–3200, 1624, 1527, 1345,
+45%
2
1,5
1
+18%
1184; 1H NMR (CDCl3)
d
1.16 (t, J ¼ 6.4, 9H, CH2CH3), 1.88 (m, 2H,
CH2CH2CH2), 2.78 (s, 3H, NCH3), 3.13–3.35 (m, 10H, CH2CH2CH2,
CH2CH3), 7.87–7.96 (m, 4H, Ph), 8.86 (broad s, 1H, NH), 14.33 (s, 1H,
OH); 13C NMR (CDCl3)
d 7.1, 21.5, 35.9, 39.1, 52.1, 53.8, 111.2, 124.2,
126.0, 127.9, 132.9, 133.5, 134.0, 156.2, 168.3; ESI-MS m/z 396 (Mþ);
Anal. C19H30IN3O4S$0.9H2O (C, H, N).
0,5
4.1.5. N-(3-Hydroxypropyl)-4-hydroxy-2-methyl-2H-1,2-
benzothiazine-3-carboxamide 1,1-dioxide (13)
0
IL-1 (10 ng/mL)
-
-
-
-
-
-
-
+
+
+
+
+
+
+
10-5 10-6 10-8 10-5 10-6 10-8 Ctrl
To a suspension of methyl 4-hydroxy-2-methyl-2H-1,2-benzo-
thiazine-3-carboxylate 1,1-dioxide (4) (2.00 g; 7.43 mmol) in
xylene (200 mL) was added, under argon, 3-amino-1-propanol
(0.68 mL; 8.92 mmol). The reaction mixture was stirred 20 h at
140 ꢀC, and then evaporated under reduced pressure. The oily
residue was purified by silica gel column chromatography with
a stepwise gradient of EtOH in cyclohexane (0–50%) to give 13
(980 mg; 42%) as an oil; Rf 0.74 (C); IR (cmꢁ1) 3500–3300, 1621,
Conc.(M)
2
3
Fig. 3. Effects of propoxicam (2) and its QA derivative (3) on TGF-b2 and Tb-RII
expression in articular chondrocyte culture treated by IL-1 or not (percentage repre-
sents % increase relative to control).
acetone, and dried under vacuum. Recrystallization from the
appropriate solvent gave the desired product.
1540, 1343, 1184. 1H NMR (CDCl3)
d
1.85 (qt, J ¼ 5.3, 2H,
CH2CH2CH2), 2.88 (s, 3H, NCH3), 3.60 (m, 2H, NHCH2), 3.78
(t, J ¼ 5,3, 2H, NHCH2CH2CH2), 7,22 (broad s, 1H, CH2OH), 7.71–7.79
(m, 2H, Ph), 7.89 (d, J ¼ 7.3, 2H, Ph), 8.05 (d, J ¼ 7.3, 2H, Ph); 13C NMR
4.1.4.1. [3-(4-Hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-
3-carboxamido)butyl]trimethyl ammonium iodide (3). Yield 89%;
mp 249–251 ꢀC; Rf 0.15 (B); IR (cmꢁ1) 3500–3300, 1629, 1537, 1339,
(CDCl3)
d 34.6, 39.8, 41.2, 59.7, 117.5, 125.2, 127.1, 129.1, 132.7, 133.5,
134.6, 156.9, 168.9.
1173; 1H NMR (DMSO-d6)
d 1.97 (m, 2H, CH2CH2CH2), 2.79 (s, 3H,
NCH3), 3.06 (s, 9H, Nþ(CH3)3), 3.30 (m, 4H, CH2CH2CH2), 7.88–7.96
4.1.6. N-(3-Iodopropyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-
3-carboxamide 1,1-dioxide (14)
(m, 4H, Ph), 8.86 (broad s, 1H, NH), 14,32 (broad s, 1H, OH); 13C NMR
(DMSO-d6)
d
22.7, 36.1, 39.2, 52,3, 63.3, 111.2, 124.1, 126.0, 127.9,
To a stirred solution of triphenylphosphine (0.907 g; 3.46 mmol)
and imidazole (0.236 g; 3.46 mmol) in anhydrous dichloromethane
(10 mL) was added dropwise diiode (0.878 g; 3.46 mmol). After
10 min, a solution of 13 (0.900 g, 2.88 mmol) in dichloromethane
(5 mL) was added. The reaction mixture was stirred 24 h at room
temperature, and then evaporated under reduced pressure. The
residue was purified by silica gel column chromatography with
a stepwise gradient of EtOH in CH2Cl2 (0–10%) to give 14 (949 mg;
78%) as a white solid; mp 162–164 ꢀC; Rf 0.48 (C); IR (cmꢁ1) 3500–
132.8, 133.5, 133.9, 156.1, 168.3; ESI-MS m/z 354 (Mþ); Anal.
C16H24IN3O4S$0.6H2O (C, H, N).
4.1.4.2. [3-(4-Hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-
3-carboxamido)butyl]trimethyl ammonium iodide (9). Yield 72%;
mp 240–242 ꢀC; Rf 0.19 (B); IR (cmꢁ1) 3500–3300, 1627, 1535, 1345,
1184; 1H NMR (DMSO-d6)
d 1.56–1.71 (m, 4H, CH2CH2CH2CH2), 2.49
(s, 3H, NCH3), 3.04 (s, 9H, Nþ(CH3)3), 3.33 (m, 4H, CH2CH2CH2CH2),
7.87–7.96 (m, 4H, Ph), 8.82 (broad s, 1H, NH), 14,45 (broad s, 1H,
3300, 1630, 1531, 1343, 1181; 1H NMR (CDCl3)
d
2.17 (qt, J ¼ 6.7, 2H,
OH); 13C NMR (DMSO-d6)
d
19.6, 25.6, 38.1, 39.2, 52,2, 64.8, 111.2,
CH2CH2CH2), 2.87 (s, 3H, NCH3), 3.24 (t, J ¼ 6.7, 2H, NHCH2CH2CH2),
3.78 (q, J ¼ 6.5, 2H, NHCH2), 6.75 (broad s, 1H, NH), 7.71–7.78 (m,
2H, Ph), 7.88 (d, J ¼ 6.7, 2H, Ph), 8.06 (d, J ¼ 6.7, 2H, Ph); 13C NMR
124.1, 126.0, 128.0, 132.8, 133.5, 133.9, 156.1, 168.1; ESI-MS m/z 368
(Mþ); Anal. C17H26IN3O4S$0.8H2O (C, H, N).
(CDCl3)
d 2.6, 33.0, 40.1, 40.5, 117.7, 125.1, 127.0, 129.0, 132.6, 133.5,
4.1.4.3. [3-(4-Hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-
3-carboxamido)propyl] dimethylethyl ammonium iodide (10). Yield
69%; mp 204–206 ꢀC; Rf 0.23 (B); IR (cmꢁ1) 3500–3300, 1621,
134.6, 157.4, 169.0.
4.1.7. [3-(4-Hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-
3-carboxamido)propyl] pyridinium iodide (15)
A mixture of 14 (900 mg; 2.13 mmol) in pyridine (10 mL) was
refluxed under argon for 20 h, and then evaporated under reduced
pressure. The residue was triturated with ether to precipitate 15
(860 mg; 81%), which was collected as a white solid; mp 194–
1534, 1345, 1181; 1H NMR (DMSO-d6)
d
1.21 (t, J ¼ 6.8, 3H,
CH2CH3), 1.89 (m, 2H, CH2CH2CH2), 2.78 (s, 3H, NCH3), 2.98 (s, 6H,
Nþ(CH3)2), 3.21–3,32 (m, 6H, CH2CH3, CH2CH2CH2), 7.87–7.97
(m, 4H, Ph), 8.85 (broad s, 1H, NH), 14.32 (s, 1H, OH); 13C NMR
(DMSO-d6)
d 7.8, 22.2, 36.0, 39.2, 49.6, 58.6, 60.2, 111.2, 124.1