M. Frezza et al. / Bioorg. Med. Chem. 16 (2008) 3550–3556
3555
hydrobromide (200 mg, 1.1 mmol) in dioxane (1 mL),
were added triethylamine (160 lL, 1.1 mmol) and then
a solution of 5 (1 mmol) in dioxane (1 mL). The reaction
mixture was refluxed for 3 h and then cooled to rt and
filtered. The solvent was evaporated in vacuo and the
residue was hydrolysed (water, 20 mL) The aqueous
solution was extracted (CHCl3, 30 mL) and the organic
layer was dried, filtered and concentrated in vacuo. The
residue thus obtained was purified by column chroma-
tography to give the compounds 3a–i as white solids.
The biological tests were made on recrystallised samples.
NMR (CDCl3, 300 MHz): d 5.47 (br s, 1H), 5.00 (t,
J = 5.7 Hz, 1H), 4.39 (t, J = 8.7 Hz, 1H), 4.27–4.19 (m,
2H), 3.03 (m, 2H), 2.74–2.65 (m, 1H), 2.33–2.19 (m,
1H), 1.52–1.48 (m, 2H), 1.22 (m, 14H), 0.84 (t, 3H,
J = 6.8 Hz). 13C NMR (CDCl3, 75 MHz): d 175.5, 66.1,
52.2, 43.4, 31.9, 30.2, 29.7, 29.6, 29.5, 29.3, 29.2, 26.7,
22.6, 14.1. Anal. Calcd for C14H28N2O4S: C, 52.47; H,
8.81; N, 8.74. Found: C, 52.43; H, 8.85; N, 8.61.
4.1.2.6. 1-Benzyl-3-(2-oxo-tetrahydro-furan-3-yl)-sul-
fonylurea (3f). Chromatography: P/EtOAc (50:50).Yield:
1
74%. Recrystallisation: P/CHCl3. Mp: 101–102 ꢁC. H
4.1.2.1. 1-Butyl-3-(2-oxo-tetrahydro-furan-3-yl)-sulfo-
nylurea (3a). Chromatography: CHCl3/MeOH (95:5).
Yield: 35%. Recrystallisation: P/toluene. Mp: 75–
NMR (aceton-d6, 300 MHz): d 7.43–7.26 (m, 5H), 6.55
(br s, 1H), 6.35 (br s, 1H), 4.43–4.21 (m, 5H), 2.77–2.66
(m, 1H), 2.37–2.22 (m, 1H). 13C NMR (aceton-d6,
75 MHz): d 175.7, 138.7, 129.1, 128.9, 128.1, 66.2, 52.7,
47.6, 30.6. Anal. Calcd for C11H14N2O4S: C, 48.88; H,
5.22; N, 10.36. Found: C, 48.78; H, 5.13; N, 10.42.
1
76 ꢁC. H NMR (CDCl3, 300 MHz): d 5.39 (br s, 1H),
4.92 (t, J = 5.4 Hz, 1H), 4.43 (t, J = 8.7 Hz, 1H), 4.30–
4.20 (m, 2H), 3.06 (m, 2H), 2.76–2.68 (m, 1H), 2.35–
2.21 (m, 1H), 1.57–1.48 (m, 2H), 1.41–1.29 (m, 2H),
0.90 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz):
d 175.4, 66.2, 52.2, 43.2, 31.5, 30.4, 19.9, 13.7. Anal.
Calcd for C8H16N2O4S: C, 40.66; H, 6.83; N, 11.86.
Found: C, 40.78; H, 6.92; N, 11.76.
4.1.2.7. 1-Phenethyl-3-(2-oxo-tetrahydro-furan-3-yl)-
sulfonylurea (3g). Chromatography: P/EtOAc (50:50).
Yield: 74%. Recrystallisation: P/EtOAc. Mp: 118–
1
119 ꢁC. H NMR (CDCl3, 300 MHz): d 7.34–7.21 (m,
5H), 5.08 (d, J = 5.1 Hz, 1H), 4.61 (t, J = 6.4 Hz, 1H),
4.39 (t, J = 8.7 Hz, 1H), 4.20–4.08 (m, 1H), 3.99–3.91
(m, 1H), 3.38 (q, J = 6.8 Hz, 2H), 2.88 (t, J = 6.9 Hz,
2H), 2.64–2.55 (m, 1H), 2.20–2.11 (m, 1H). 13C NMR
(CDCl3, 75 MHz): d 174.9, 138.1, 129.1, 128.9, 127.6,
66.1, 52.1, 44.5, 35.7, 30.6. Anal. Calcd for
C12H16N2O4S: C, 50.69; H, 5.67; N, 9.85. Found: C,
50.81; H, 5.65; N, 9.78.
4.1.2.2. 1-Pentyl-3-(2-oxo-tetrahydro-furan-3-yl)-sul-
fonylurea (3b). Chromatography: P/EtOAc (60:40).
Yield: 12%. Recrystallisation: P/toluene. Mp: 65–
66 ꢁC. H NMR (CDCl3, 300 MHz): d 5.25 (br s, 1H),
4.76 (br s, 1H), 4.45 (t, J = 9.0 Hz, 1H), 4.30–4.22 (m,
2H), 3.08 (m, 2H), 2.79–2.70 (m, 1H), 2.36–2.21 (m,
1H), 1.60–1.51 (m, 2H), 1.33–1.28 (m, 4H), 0.88 (t,
3H, J = 6.8 Hz). 13C NMR (CDCl3, 75 MHz): d 175.0,
66.0, 52.2, 43.4, 30.5, 29.1, 28.7, 22.2, 13.9. Anal. Calcd
for C9H18N2O4S: C, 43.18; H, 7.25; N, 11.19. Found: C,
43.34; H, 7.28; N, 10.76.
1
4.1.2.8. 1-(3-phenyl-propyl)-3-(2-oxo-tetrahydro-fur-
an-3-yl)-sulfonylurea (3h). Chromatography: P/EtOAc
(60:40). Yield: 52%. Recrystallisation: P/CHCl3. Mp:
1
123–125 ꢁC. H NMR (CDCl3, 300 MHz): d 7.30–7.16
4.1.2.3. 1-Hexyl-3-(2-oxo-tetrahydro-furan-3-yl)-sul-
fonylurea (3c). Chromatography: CHCl3/MeOH (95:5).
Yield: 38%. Recrystallisation: P/toluene. Mp: 73–74 ꢁC.
1H NMR (CDCl3, 300 MHz): d 4.82 (br s, 1H), 4.48 (t,
J = 9.0 Hz, 1H), 4.38 (t, J = 6.8 Hz, 1H), 4.32–4.17 (m,
2H), 3.11 (q, J = 6.8 Hz, 2H), 2.83–2.74 (m, 1H), 2.37–
2.22 (m, 1H), 1.60–1.53 (m, 2H), 1.37–1.26 (m, 6H),
0.88 (t, 3H, J = 6.8 Hz). 13C NMR (CDCl3, 75 MHz): d
175.4, 66.2, 52.3, 43.5, 31.4, 30.4, 29.5, 26.4, 22.6, 14.1.
Anal. Calcd for C10H20N2O4S: C, 45.44; H, 7.63; N,
10.60. Found: C, 45.22; H, 7.57; N, 10.55.
(m, 5H), 5.31 (br s, 1H), 4.92 (t, J = 6.0 Hz, 1H), 4.39
(t, J = 8.7 Hz, 1H), 4.26–4.15 (m, 2H), 3.12 (q,
J = 6.4 Hz, 2H), 2.71–2.63 (m, 3H), 2.30–2.16 (m, 1H),
1.89 (quint., J = 7.5 Hz, 2H). 13C NMR (CDCl3,
75 MHz): d 175.3, 141.1, 128.6, 128.5, 126.2, 66.2,
52.3, 43.0, 32.9, 31.1, 30.5. Anal. Calcd for
C13H18N2O4S: C, 52.33; H, 6.08; N, 9.39. Found: C,
52.53; H, 6.10; N, 9.38.
4.1.2.9. 1-(4-phenyl-butyl)-3-(2-oxo-tetrahydro-furan-
3-yl)-sulfonylurea (3i). Chromatography: P/EtOAc
(50:50). Yield: 71%. Recrystallisation: P/EtOAc. Mp:
123–125 ꢁC. 1H NMR (aceton-d6, 300 MHz): d 7.29–
7.16 (m, 5H), 6.37 (d, J = 7.2 Hz, 1H), 5.92 (t,
J = 6.4 Hz, 1H), 4.41–4.22 (m, 3H), 3.14–3.06 (m, 2H),
2.73–2.66 (m, 1H), 2.62 (t, J = 7.5 Hz, 2H), 2.34–2.20
(m, 1H), 1.68–1.55 (m, 4H). 13C NMR (aceton-d6,
75 MHz): d 175.5, 143.0, 129.0, 128.9, 126.3, 66.1,
52.5, 43.4, 35.9, 31.0, 30.2, 29.9. Anal. Calcd for
C14H20N2O4S: C, 53.83; H, 6.45; N, 8.97. Found: C,
53.95; H, 6.43; N, 8.94.
4.1.2.4. 1-Octyl-3-(2-oxo-tetrahydro-furan-3-yl)-sulfo-
nylurea (3d). Chromatography: P/EtOAc (60:40).Yield:
39%. Recrystallisation: P/toluene. Mp: 73–74 ꢁC. 1H
NMR (CDCl3, 300 MHz): d 5.39 (br s, 1H), 4.88 (t,
J = 6.0 Hz, 1H), 4.43 (t, J = 9.0 Hz, 1H), 4.29–4.20 (m,
2H), 3.06 (q, J = 6.4 Hz, 2H), 2.76–2.68 (m, 1H), 2.35–
2.21 (m, 1H), 1.56–1.51 (m, 2H), 1.35–1.24 (m, 10H),
0.85 (t, 3H, J = 6.8 Hz). 13C NMR (CDCl3, 75 MHz): d
175.3, 66.2, 52.3, 43.5, 31.8, 30.5, 29.6, 29.3, 29.2, 26.8,
22.7, 14.1. Anal. Calcd for C12H24N2O4S: C, 49.29; H,
8.27; N, 9.58. Found: C, 48.65; H, 8.16; N, 9.31.
4.2. Biological tests
4.1.2.5. 1-Decyl-3-(2-oxo-tetrahydro-furan-3-yl)-sulfo-
nylurea (3e). Chromatography: P/EtOAc (60:40).Yield:
62%. Recrystallisation: P/toluene. Mp: 87–88 ꢁC. 1H
Measurement of inhibitory activity was performed
according to our previously reported protocol.9 Pre-
sented data are from one culture but are representative