12
N. Leleu-Chavain et al. / European Journal of Medicinal Chemistry xxx (xxxx) xxx
(IVC), 123.1 (CH), 110.2 (CH), 45.5 (CH2), 43.1 (CH), 29.5 (2CH2), 28.8
(CH2), 27.3 (CH2), 26.3 (CH2), 25.9 (2CH2), 22.3 (CH2), 13.9 (CH3); LC-
MS (ESI) m/z 332.1 (MHþ), tr 5.06 min, lmax 237 nm, purity 96.5%.
7.67 (dd, J ¼ 1.7; 8.6 Hz, 1H), 7.20 (d, J ¼ 8.6 Hz, 1H), 4.82 (hept.,
J ¼ 7.0 Hz, 1H), 2.09 (m, 3H), 2.04 (m, 6H), 1.90 (m, 6H), 1.57 (d,
J ¼ 7.0 Hz, 6H); 13C NMR (CDCl3)
d
207.1 (IVC), 184.1 (IVC), 169.8 (IVC),
138.6 (IVC), 133.2 (CH), 126.5 (CH), 122.7 (IVC), 110.7 (CH), 47.1 (IVC),
40.5 (CH), 39.5 (3CH2), 36.6 (3CH2), 28.3 (3CH), 19.5 (2CH3); LC-MS
(ESI) m/z 356.1 (MHþ), tr 4.91 min, lmax 255 nm, purity 97.2%.
4.31. 6-Benzoyl-3-pentylbenzo[d]thiazol-2(3H)-one (6)
The product was purified by silica gel column chromatography
(CH2Cl2/MeOH 99:1, v/v). A yellow powder was obtained: yield
89%; mp 65 1 ꢀC; 1H NMR (CDCl3)
d
8.13 (d, J ¼ 1.7 Hz,1H), 7.70 (m,
4.36. 6-(1-Adamantanecarbonyl)-3-butylbenzo[d]thiazol-2(3H)-
one (11)
7H), 3.85 (t, J ¼ 7.3 Hz, 2H), 1.65 (m, 2H), 1.30 (m, 4H), 0.85 (t,
J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3)
d
194.9 (IVC), 170.0 (IVC), 140.5 (IVC),
137.6 (IVC), 132.4 (IVC), 132.4 (CH), 129.8 (2CH), 129.1 (CH), 128.4
(2CH),125.0 (CH), 122.9 (IVC),110.0 (CH), 43.2 (CH2), 28.9 (CH2), 27.4
(CH2), 22.3 (CH2), 13.9 (CH3); LC-MS (ESI) m/z 326.1 (MHþ), tr
4.64 min, lmax 237 nm, purity 95.6%.
The product was purified by preparative TLC (petroleum ether/
EtOAc 99:1, v/v). A white powder was obtained: yield 17%; mp
98 1 ꢀC; 1H NMR (CDCl3)
d
7.79 (d, J ¼ 1.7 Hz, 1H), 7.70 (dd, J ¼ 1.7;
8.5 Hz, 1H), 7.04 (d, J ¼ 8.5 Hz, 1H), 3.96 (t, J ¼ 7.4 Hz, 2H), 2.10 (s,
3H), 2.05 (s, 6H), 1.82 (s, 6H), 1.75 (quint., J ¼ 7.6 Hz, 2H), 1.44 (sext.,
J ¼ 7.5 Hz, 2H), 0.97 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3)
d
207.2 (IVC),
4.32. 3-Pentyl-6-(2,2,3,3-tetramethylcyclopropanecarbonyl)benzo
[d]thiazol-2(3H)-one (7)
170.0 (IVC),139.1 (IVC), 133.7 (IVC),126.8 (CH), 122.8 (CH), 122.7 (IVC),
109.8 (CH), 47.1 (IVC), 43.0 (CH2), 39.5 (3CH2), 36.6 (3CH2), 29.8
(CH2), 28.3 (3CH), 20.2 (CH2), 13.8 (CH3); LC-MS (ESI) m/z 370.1
(MHþ), tr 4.99 min, lmax 245 nm, purity 99.6%.
The product was purified by silica gel column chromatography
(cyclohexane/EtOAc 9:1, v/v). A white powder was obtained: yield
50%; mp 95 1 ꢀC; 1H NMR (CDCl3)
d
7.62 (d, J ¼ 1.8 Hz, 1H), 7.49
(dd, J ¼ 1.8; 8.8 Hz, 1H), 7.12 (d, J ¼ 8.8 Hz, 1H), 3.98 (t, J ¼ 7.3 Hz,
4.37. 6-(1-Adamantanecarbonyl)-3-hexylbenzo[d]thiazol-2(3H)-
one (12)
2H), 1.78 (quint., J ¼ 7.3 Hz, 2H), 1.44 (m, 1H), 1.41 (m, 4H), 1.26 (m,
6H), 1.21 (m, 6H), 0.93 (t, J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3)
d 178.2
(IVC), 169.9 (IVC), 136.7 (IVC), 135.7 (IVC), 125.2 (CH), 123.9 (CH), 121.1
(IVC), 111.0 (CH), 43.2 (CH2), 35.7 (CH), 31.4 (CH2), 29.0 (CH2), 27.5
(2IVC), 23.7 (CH2), 22.5 (2CH3), 16.7 (2CH3), 14.1 (CH3); LC-MS
(APCIþ) m/z 346.2 (MHþ), tr 5.50 min, lmax 235 nm, purity 97.2%.
The product was purified by silica gel column chromatography
(petroleum ether/EtOAc 9:1, v/v). A white powder was obtained:
yield 16%; mp 106 1 ꢀC; 1H NMR (CDCl3)
d
7.79 (d, J ¼ 1.5 Hz, 1H),
7.70 (dd, J ¼ 1.5; 8.5 Hz, 1H), 7.04 (d, J ¼ 8.5 Hz, 1H), 3.95 (t,
J ¼ 7.4 Hz, 2H), 2.10 (s, 3H), 2.04 (s, 6H), 1.92 (s, 6H), 1.76 (m, 2H),
4.33. 6-(Cyclopentanecarbonyl)-3-pentylbenzo[d]thiazol-2(3H)-
one (8)
1.34 (m, 6H), 0.93 (m, 3H); 13C NMR (CDCl3) 207.2 (IVC), 170.0 (IVC),
d
139.0 (IVC),133.7 (IVC),126.8 (CH),122.7 (CH),122.7 (IVC),109.8 (CH),
47.1 (IVC), 43.2 (CH2), 39.5 (3CH2), 36.6 (3CH2), 31.5 (CH2), 27.9
(3CH), 27.7 (CH2), 26.5 (CH2), 22.6 (CH2),13.8 (CH3); LC-MS (ESI) m/z
398.2 (MHþ), tr 5.78 min, lmax 240 nm, purity 99.7%.
The product was purified by silica gel column chromatography
(cyclohexane/EtOAc 95:5, v/v). A yellow oil was obtained: yield 6%;
1H NMR (CDCl3)
d
8.08 (d, J ¼ 1.7 Hz, 1H), 7.97 (dd, J ¼ 1.7; 8.5 Hz,
1H), 7.09 (d, J ¼ 8.5 Hz, 1H), 3.97 (t, J ¼ 7.4 Hz, 2H), 3.69 (quint.,
J ¼ 7.8 Hz, 1H), 1.92 (m, 4H), 1.72 (m, 6H), 1.36 (m, 4H), 0.90 (m, 3H);
4.38. 6-(1-Adamantanecarbonyl)-3-(2-dimethylaminopropyl)
benzo[d]thiazol-2(3H)-one (13)
13C NMR (CDCl3)
d
201.0 (IVC), 170.1 (IVC), 140.7 (IVC), 132.2 (IVC),
127.4 (CH), 123.4 (CH), 123.2 (IVC), 110.2 (CH), 46.3 (CH), 43.3 (CH2),
30.2 (2CH2), 29.0 (CH2), 27.5 (CH2), 26.4 (2CH2), 22.4 (CH2), 14.0
(CH3); LC-MS (APCIþ) m/z 318.1 (MHþ), tr 4.60 min, lmax 245 nm,
purity 98.7%.
The product was purified by silica gel column chromatography
(dichloromethane/MeOH 9:1, v/v). A white powder was obtained:
yield 25%; mp 114 1 ꢀC; 1H NMR (CDCl3)
d
7.79 (d, J ¼ 1.5 Hz, 1H),
7.70 (dd, J ¼ 1.5; 8.5 Hz, 1H), 7.04 (d, J ¼ 8.5 Hz, 1H), 3.95 (t,
J ¼ 7.4 Hz, 2H), 2.10 (s, 3H), 2.04 (s, 6H), 1.92 (s, 6H), 1.76 (m, 2H),
4.34. 6-(Adamantane-1-carbonyl)-3-pentyl-benzo[d]thiazol-
2(3H)-one (9)
1.24 (m, 5H), 0.93 (m, 3H); 13C NMR (CDCl3) 207.2 (IVC), 170.0 (IVC),
d
139.1 (IVC),133.7 (IVC),126.8 (CH),122.8 (CH),122.7 (IVC),109.8 (CH),
47.1 (IVC), 43.0 (CH2), 39.5 (3CH2), 36.6 (3CH2), 29.8 (2CH2), 28.3
(3CH), 20.2 (CH3), 13.8 (CH3); LC-MS (APCIþ) m/z 399.2 (MHþ), tr
5.78 min, lmax 235 nm, purity 99.7%.
The product was purified by silica gel column chromatography
(petroleum ether/EtOAc/ammoniac saturated MeOH 94:5.5:0.5, v/
v/v). A white powder was obtained: yield 68%; mp 119 1 ꢀC; 1H
NMR (CDCl3)
d
7.82 (d, J ¼ 1.3 Hz, 1H), 7.70 (dd, J ¼ 1.3; 8.4 Hz, 1H),
7.05 (d, J ¼ 8.4 Hz, 1H), 3.96 (t, J ¼ 7.3 Hz, 2H), 2.11 (m, 3H), 2.06 (m,
6H), 1.78 (m, 6H), 1.73 (m, 2H), 1.38 (quint., J ¼ 3.7 Hz, 4H), 0.92 (t,
4.39. 5-(1-Adamantanecarbonyl)-3-pentylbenzo[d]thiazol-2(3H)-
one (14)
J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3)
d
207.2 (IVC), 184.4 (IVC), 139.1 (IVC),
133.7 (IVC),126.8 (2CH),122.8 (IVC),109.9 (CH), 47.2 (IVC), 43.2 (CH2),
39.5 (3CH2), 36.7 (3CH2), 29.8 (CH2), 29.0 (CH2), 28.3 (3CH), 22.5
(CH2), 14.1 (CH3); LC-MS (ESI) m/z 384.2 (MHþ), tr 5.77 min, lmax
237 nm, purity 99.6%.
The product was purified by silica gel column chromatography
(petroleum ether/EtOAc 9:1, v/v). A yellow oil was obtained: yield
61%; 1H NMR (CDCl3)
d
7.50 (dd, J ¼ 1.4; 8.1 Hz, 1H), 7.45 (d,
J ¼ 8.1 Hz, 1H), 7.30 (s, 1H), 3.95 (t, J ¼ 7.6 Hz, 2H), 2.05 (m, 9H), 1.75
4.35. 6-(1-Adamantanecarbonyl)-3-isopropylbenzo[d]thiazol-
2(3H)-one (10)
(m, 8H), 1.35 (m, 4H), 0.90 (t, J ¼ 7.3 Hz, 3H); 13C NMR (CDCl3)
d
208.1 (IVC), 183.2 (IVC), 169.5 (IVC), 137.1 (IVC), 125.8 (IVC), 122.1
(CH), 121.8 (CH), 110.0 (CH), 47.1 (IVC), 43.1 (CH2), 39.3 (3CH2), 38.9
(CH2), 36.5 (3CH2), 28.9 (CH2), 28.0 (3CH), 22.6 (CH2), 14.0 (CH3);
LC-MS (APCIþ) m/z 406.2 (M þ Na), tr 5.54 min, lmax 240 nm, purity
98.2%.
The product was purified by silica gel column chromatography
(petroleum ether/EtOAc 98:2, v/v). A white powder was obtained:
yield 27%; mp 121 1 ꢀC; 1H NMR (CDCl3)
d
7.77 (d, J ¼ 1.7 Hz, 1H),
Please cite this article as: N. Leleu-Chavain et al., Benzo[d]thiazol-2(3H)-ones as new potent selective CB2 agonists with anti-inflammatory