A.M. Al-Obaid et al. / European Journal of Medicinal Chemistry 44 (2009) 2379–2391
2389
7.89–7.92 (m, 3H, ArH), 8.22 (d, 1H, J ¼ 8 Hz, ArH), 10.51 (s 1H, NH),
8.28 (d, 1H, J ¼ 8.5 Hz, quinazoline-H), 8.31 (d, 1H, J ¼ 2H, ArH), 10.7
(s, 1H, NH). Anal. for (C18H12IN3OS) C, H, N. 27: 6.78 (d, 2H,
11.83 (s, 1H, NH). Anal. for (C20H17IN2O3S) C, H, N.
d
J ¼ 9 Hz, ArH), 7.17–7.19 (m, 1H, J ¼ 4.1 Hz, thiophene-H), 7.23 (d,
2H, J ¼ 9 Hz, ArH), 7.55 (d, 1H, J ¼ 9 Hz, thiophene-H), 7.83–7.84 (dd,
1H, J ¼ 3.5, 1.5 Hz, thiophene-H), 8.14–8.17 (dd, 1H, J ¼ 6.5, 2 Hz,
quinazoline-H), 8.24–8.25 (dd, 1H, J ¼ 2.5, 1.5 Hz, quinazoline-H),
8.35 (d, 1H, J ¼ 2 Hz, quinazoline-H), 9.6 (s, 1H, NH). Anal. for
4.1.6. 2-(Thieno)-6-iodo-3-[4-(substituted sulphonamido)phenyl]-
3H-quinazolin-4-one 19–22
A mixture of compound (9, 3.55 g, 0.01 mol) and appropriate
sulfa drug (0.01 mol) was fused at 210ꢀ in oil bath for 1 h, cooled
and triturated with methanol and filtered. The resulting solid was
washed several times with water, dried and recrystallized from
suitable solvent to obtain compounds 19–22 (Table 1). 1H NMR
(C18H11ClIN3OS) C, H, N. 28:
d
7.27 (t, 1H, J ¼ 4 Hz, thiophene-H),
7.34–8.34 (m, 8H, ArH), 9.5 (s, 1H, NH). Anal. for (C18H10IN5O5S) C,
H, N. 29:
d
7.24 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.41–8.35 (m, 10 H,
(DMSO-d6), 19:
d 7.24–7.28 (m, 2H, ArH), 7.74–7.77 (m, 2H, ArH),
ArH), 12.31 (br s, 1H, NHC]O, D2O exchanged). Anal. for
7.90–7.97 (m, 3H, ArH), 8.28–8.29 (m, 2H, ArH), 8.37 (d, 1H,
J ¼ 9.0 Hz, ArH),12.05 (br s, 2H, NH2). Anal. for (C18H12IN3O3S2) C, H,
(C19H12IN3O2S) C, H, N.
4.1.10. 2-(2-Thieno)-6-iodo-3,4-dihydro-quinazolin-4-one 30
A mixture of 2-(thieno)-6-iodo-4H-3,1-benzoxazin-4-one (9,
3.55 g, 0.01 mol) and formamide (30 ml) was heated under reflux
for 3 h. On cooling, the separated solid was filtered, washed with
water and crystallized from acetic acid to yield 30 (Table 1). 1H NMR
N. 20:
d
6.81 (d, 1H, J ¼ 4.5 Hz, thiazole-H), 7.25 (d, 1H, J ¼ 4.5 Hz,
thiazole-H), 7.69–7.95 (m, 10H, ArH), 10.27 (br s, 1H, NH). Anal. for
(C21H13IN4O3S3) C, H, N. 21:
d
6.57 (d, 2H, J ¼ 8.5 Hz, ArH), 7.01 (t,
1H, J ¼ 5.0 Hz, ArH), 7.29 (t, 1H, J ¼ 5.0 Hz, ArH), 7.41 (d, 1H,
J ¼ 5.0 Hz, ArH), 7.62 (d, 2H, J ¼ 8.5 Hz, ArH), 7.86–7.88 (dd, 1H,
J ¼ 1.5, 8.5 Hz, ArH), 8.18–8.20 (m, 2H, ArH), 8.29 (d, 1H, J ¼ 8.5 Hz,
ArH), 8.35 (d, 1H, J ¼ 3.0 Hz, ArH), 8.48 (d, 1H, J ¼ 9.0 Hz, ArH), 11.38
(DMSO-d6):
d
7.25 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.70 (d, 1H,
J ¼ 0.5 Hz, thiophene-H), 7.86–7.88 (dd, 1H, J ¼ 8.5, 1.5 Hz, quina-
zoline-H), 7.91 (d, 1H, J ¼ 4.0 Hz, thiophene-H), 8.15 (d, 1H,
J ¼ 1.5 Hz, quinazoline-H), 8.34 (d, 1H, J ¼ 8.5 Hz, quinazoline-H),
12.7 (br s, 1H, NH). Anal. for (C12H7IN2OS) C, H, N.
(br s, 1H, NH). Anal. for (C22H14IN5O3S2) C, H, N. 22: d 3.57 (br s, 1H,
NH), 7.28 (t, 1H, J ¼ 5.0 Hz, ArH), 7.39 (d, 4H, J ¼ 9.0 Hz, ArH),
7.91–7.92 (m, 2H, ArH), 8.00–8.02 (m, 2H, ArH), 8.15–8.18 (m, 2H,
ArH), 8.32–8.34 (m, 2H, ArH). Anal. for (C19H14IN5O3S2) C, H, N.
4.1.11. 2-(2-Thieno)-6-iodo-3,4-dihydro-quinazolin-4-thione 31
Phosphorous pentasulfide (2.31 g, 0.011 mol) was added to
a solution of 2-(2-thieno)-6-iodo-3,4-dihydro-quinazolin-4-one
(30, 3.54 g, 0.01 mol) in xylene (30 ml), and the mixture was heated
under reflux for 3 h, then filtered while hot. On cooling, the
obtained solid was filtered, and washed with water, dried and
crystallized from acetic acid to give 31 (Table 1). 1H NMR (DMSO-
4.1.7. 2-(2-Thieno)-6-iodo-3-(4-sulphonamido-benzyl)-3H-
quinazolin-4-one 23
Equimolar amounts of compound (9, 3.55, 0.01 mol) and
homosulfanilamide (1.86 g, 0.01 mol) were fused together at 200ꢀ
in an oil bath for 1 h. On cooling, the solid mass dissolved in hot
glacial acetic acid (50 ml), and filtered. The filtrate was concen-
trated in vacuo and the resulting solid was filtered, washed with
water and recrystallized to afford 23 (Table 1). 1H NMR (DMSO-d6):
d6):
d
7.24 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.70 (d, 1H, J ¼ 0.5 Hz,
thiophene-H), 7.86–7.88 (dd, 1H, J ¼ 8.5, 1.5 Hz, quinazoline-H), 7.91
(d, 1H, J ¼ 4.0 Hz, thiophene-H), 8.15 (d, 1H, J ¼ 1.5 Hz, quinazoline-
H), 8.34 (d, 1H, J ¼ 8.5 Hz, quinazoline-H), 12.5 (br s, NH,
exchanged). Anal. for (C12H7IN2S2) C, H, N.
d
4.50 (s, 2H, CH2Ph), 7.25–7.27 (m, 1H, ArH), 7.34 (br s, 2H, NH2),
7.54–7.82 (dd, 4H, J ¼ 8.5 Hz, ArH), 7.68 (d, 1H, J ¼ 5.0 Hz, ArH),
7.90–7.92 (m, 2H, ArH), 8.26 (d, 1H, J ¼ 3.0 Hz, ArH), 8.34 (d, 1H,
J ¼ 9.0 Hz, ArH). Anal. for (C19H14IN3O3S2) C, H, N.
4.1.12. 2-(2-Thieno)-4-alkylthio-6-iodo-quinazolines 32, 33
A mixture of 2-(2-thieno)-6-iodo-3,4-dihydro-quinazoline-4-
thione (31, 3.7 g, 0.01 mol), the appropriate alkyl halide (0.015 mol)
and anhydrous potassium carbonate (2 g) in dry acetone (50 ml)
was heated under reflux for 3 h and the reaction mixture was
filtered while hot. The filtrate was evaporated under vacuum and
the separated solid was washed with water and crystallized from
4.1.8. 2-(2-Thieno)-6-iodo-3-hydroxy-3,4-dihydro-quinazolin-4-
one 24
A mixture of 2-(2-thieno)-6-iodo-4H-3,1-benzoxazin-4-one (9,
3.55, 0.01 mol) and hydroxylamine hydrochloride (0.7 g, 0.01 mol)
in dry pyridine (35 ml) was heated under reflux for 8 h and the
reaction mixture was then concentrated to half its volume. The
separated solid was filtered, washed with water and crystallized to
ethanol to give 32, 33 (Table 1). 1H NMR (DMSO-d6), 32:
d 2.64 (s,
afford 24 (Table 1). 1H NMR (DMSO-d6):
d 5.3 (s, 1H, OH, D2O
3H, SCH3), 7.27 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.70 (d, 1H, J ¼ 0.5 Hz,
thiophene-H), 7.86–7.88 (dd, 1H, J ¼ 8.5, 1.5 Hz, quinazoline-H), 7.91
(d, 1H, J ¼ 4.0 Hz, thiophene-H), 8.15 (d, 1H, J ¼ 1.5 Hz, quinazoline-
H), 8.34 (d, 1H, J ¼ 8.5 Hz, quinazoline-H). Anal. for (C13H9IN2S2) C,
exchanged), 7.25 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.70 (d, 1H,
J ¼ 0.5 Hz, thiophene-H), 7.86–7.88 (dd,1H, J ¼ 8.5,1.5 Hz, ArH), 7.91
(d, 1H, J ¼ 4.0 Hz, thiophene-H), 8.15 (d, 1H, J ¼ 1.5 Hz ArH), 8.34 (d,
1H, J ¼ 8.5 Hz, ArH). Anal. for (C12H7IN2O2S) C, H, N.
H, N. 33:
d
1.2–1.3 (t, 3H, J ¼ 10 Hz, CH3–CH2–) 3.01–3.02 (q, 2H,
J ¼ 10 Hz, CH3–CH–), 7.27 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.70 (d, 1H,
J ¼ 0.5 Hz, thiophene-H), 7.86–7.88 (dd, 1H, J ¼ 1.5 Hz, quinazoline-
H), 7.91 (d, 1H, J ¼ 4.0 Hz, thiophene-H), 8.15 (d, 1H, J ¼ 1.5 Hz,
quinazoline-H), 8.34 (d, 1H, J ¼ 8.5 Hz, quinazoline-H). Anal. for
(C14H11IN2S2) C, H, N.
4.1.9. 2-(2-Thieno)-6-iodo-3-substitututed amino-3,4-dihydro-
quinazolin-4-one 25–29
A mixture of 2-(2-thieno)-6-iodo-4H-3,1-benzoxazin-4-one (9,
3.55 g, 0.01 mol) and the required hydrazine derivative or benzoic
acid hydrazide (0.012 mol) in n-butanol (20 ml) was heated under
reflux for 6 h. The reaction mixture was concentrated, cooled and
the separated solid was crystallized out from the proper solvent to
4.1.13. N-(Phenyl)-N0-[2-(2-thieno)-4-oxo-6-iodo-3H-quinazolin-
3-yl]-urea (34) and thiourea 35
A mixture of 2-(2-thieno)-6-iodo-3-amino-quinazolin-4-one
(25, 3.69 g, 0.01 mol), phenylisocyanate or phenylisothiocyanate
(0.015 mol) in dry dioxane (30 ml) was refluxed for 8 h. The excess
solvent was removed and the solid was crystallized from the proper
solvent to give compounds 34, 35, respectively (Table 1). 1H NMR
afford compounds 25–29 (Table 1). 1H NMR (DMSO-d6), 25:
d
5.7–
5.8 (br s, 2H, NH2, D2O exchanged), 7.27 (t, 1H, J ¼ 4 Hz, thiophene-
H), 7.73 (d, 1H, J ¼ 0.5 Hz, thiophene-H), 7.85–7.87 (dd, 1H, J ¼ 8.5,
1.5 Hz, ArH), 7.92 (d, 1H, J ¼ 4.0 Hz, thiophene-H), 8.1 (d, 1H,
J ¼ 1.5 Hz, ArH), 8.33 (d, 1H, J ¼ 8.5 Hz, ArH). Anal. for (C12H8IN3OS)
C, H, N. 26: 6.75 (t, 1H, J ¼ 7.5 Hz, ArH), 6.84 (d, 2H, J ¼ 8 Hz, ArH),
7.17 (t, 1H, J ¼ 8 Hz, ArH), 7.22 (t, 1H, J ¼ 4 Hz, thiophene-H), 7.66 (d,
1H, J ¼ 3 Hz, thiophene-H), 7.91 (d,1H, J ¼ 5 Hz, thiophene-H), 7.94–
7.96 (dd, 1H, J ¼ 8.5, 1.5 Hz, quinazoline-H), 8.02 (s, 1H, quinazoline-H),
(DMSO-d6), 34:
d
6.75 (t, 1H, J ¼ 7.5 Hz ArH), 6.84 (d, 2H, J ¼ Hz,
ArH), 7.17 (t, 2H, J ¼ 7.5 Hz, ArH), 7.22 (t, 1H, J ¼ 4 Hz, thiophene-H),
7.7 (d, 1H, J ¼ 2 Hz, thiophene-H), 7.85 (d, 1H, J ¼ 5 Hz, thiophene-
H), 7.94–7.96 (dd, 1H, J ¼ 7, 2 Hz, quinazoline-H), 8.15 (d, 1H, 1.5 Hz,