S.A. Said et al. / European Journal of Medicinal Chemistry 44 (2009) 4787–4792
4791
on a water bath for 10 h. The reaction mixture was evaporated
under reduced pressure, the residue was dissolved in water, the
alkaline solution was filtered off. The clear filtrate was acidified
with acetic acid, the obtained precipitate was collected by
filtration, dried and crystallized from ethanol to give compound
8. Yield: 75%; m.p. 144–146 ꢁC; IR (KBr) nmax: 3415 and 3396 (2
NH), 3025 (aromatic CH), 2918 (aliphatic CH), 1656 (C]N), 1565
4.1.8. Synthesis of substituted quinazolines 13 and 14
Thiourea (w0.1 g, 1 mmol) was added to 9 or 10 (1 mmol) in
100 ml ethanolic potassium hydroxide (2%). The reaction mixture
was refluxed for 6 h, and then poured gradually with stirring into
cold water. The solid formed was filtered off, washed with H2O, and
crystallized from ethanol to give 13 and 14.
(C]C), 1248 (C]S) cmꢂ1
;
1H NMR (270 MHz, DMSO-d6):
d
1.72
4.1.8.1. 4,7-Dimethyl-5-phenyl-5,6-dihydro-1H-quinazoline-2-thione
(13). Yield 65%; m.p. 174–176 ꢁC. IR (KBr) nmax: 3375 (NH), 3015
(aromatic CH), 2910 (aliphatic CH), 1658 (C]N), 1555 (C]C), 1250
(s, 3H, CH3), 4.20 (d, 1H, CH-pyrimidine), 6.82–7.70 (m, 6H, Ar–
H þ CH-pyrimidine), 8.80 and 9.90 (2s, 2H, 2 NH exchangeable
with D2O); 13C NMR (67.5 MHz, DMSO-d6)
d
20.80 (CH3), 52.95,
(C]S) cmꢂ1; 1H NMR (270 MHz, DMSO-d6):
d 1.21 and 1.70 (2s, 6H,
98.15, 144.75, 153.88 (pyramid-C), 152.10 (C]S), 126.55, 126.95,
127.80, 142.10 (Ph-C); MS m/z (%): Mþ ꢂ 1, 243 (12), 215 (65), 200
(82), 148 (35), 91 (100). Analysis calculated for C12H12N4S
(244.32): C, 58.99; H, 4.95; N, 22.93; S, 13.12. Found: C, 58.95; H,
4.91; N, 22.89; S, 13.08.
2 CH3), 2.49 (t, 2H, CH2), 3.30 (t, 1H, CH), 7.19–7.40 (m, 6H, Ar-
H þ CH), 8.20 (s, 1H, NH exchangeable with D2O); MS m/z (%): Mþ,
268 (12), 224 (100), 210 (24), 196 (10), 170 (22), 92 (16). Analysis
calculated for C16H16N2S (268.38): C, 71.61; H, 6.01; N, 10.44; S,
11.95. Found: C, 71.56; H, 5.94; N, 10.39; S, 11.90.
4.1.6. Synthesis of 4-methyl-2-oxo-6-phenyl-cyclohex-3-
enecarboxylic acid ethyl ester (10)
4.1.8.2. 7-Methyl-5-phenyl-2-thioxo-2,4a,5,6-tetrahydro-3H-quinazo-
lin-4-one (14). Yield 70%; mp. 202–204 ꢁC. IR (KBr) nmax: 3444
(NH), 3026 (aromatic CH), 2904 (aliphatic CH), 1706 (C]O), 1654
(C]N), 1596 (C]C), 1245 (C]S) cmꢂ1; 1H NMR (270 MHz, DMSO-
A solution of ethyl acetoacetate (10 mmol) in sodium ethoxide
solution (0.3 g sodium metal in 140 ml absolute ethanol) was stirred
at r.t. for 1 h. The chalcone 1 (12 mmol) was added to the above
solution with stirring. The reaction mixture was refluxed for 3 h,
poured onto cold hydrochloric acid. The obtained solid was filtered
off, washed with water, dried, and crystallized frommethanol togive
10, inyield 60%; mp. 95–97 ꢁC (MeOH); IR (KBr) nmax: 3026 (aromatic
CH), 2912 (aliphatic CH),1735 (C]O, ester),1709 (C]O),1580 (C]C)
d6):
1H, CH), 6.28 (s, 1H, CH), 6.98–7.40 (m, 5H, Ar-H), 8.45 (s, 1H, NH
exchangeable with D2O); 13C NMR (67.5 MHz, DMSO-d6)
22.56
d 1.72 (s, 3H, CH3), 2.42 (d, 2H, CH2), 2.75 (d, 1H, CH), 3.25 (m,
d
(CH3), 28.55, 35.05, 46.58, 105.95, 152.66, 163.60 (cyclohexene-C),
170.99 (C]O), 185.05 (C]S), 125.65, 126.65, 128.10, 147.50 (Ph-C);
MS m/z (%): Mþ 270 (28), 255 (10), 241 (12), 212 (35), 149 (100), 134
(22), 91 (45). Analysis calculated for C15H14N2OS (270.36): C, 66.64;
H, 5.22; N, 10.36; S, 11.86. Found: C, 66.60; H, 5.18; N, 10.3; S, 11.80.
cmꢂ1; 1H NMR (270 MHz, DMSO-d6):
d 1.23 and 1.85 (2s, 6H, 2 CH3),
2.41 (t, 2H, CH2), 3.30–3.43 (m, 1H, CH), 3.56 (t, 1H, CH), 4.15 (q, 2H,
CH2), 6.25 (s, 1H, CH), 7.00–7.43 (m, 5H, Ar-H); 13C NMR (67.5 MHz,
DMSO-d6)
d
14.45, 22.46 (2CH3), 59.75 (CH2), 25.35, 34.25, 62.78,
4.1.9. Synthesis of imid 15 and bis-imids 16 and 17
124.65, 156.66 (cyclohexene-C), 169.88, 196.85 (2C]O), 125.62,
126.95,128.35,145.50 (Ph-C); MS m/z (%): Mþ ꢂ 2, 256 (10), 241 (22),
218 (42),181 (36),149 (68), 90 (100). Analysiscalculated for C16H18O3
(258.32): C, 74.40; H, 7.02. Found: C, 74.35; H, 6.95.
A mixture of 4 (0.4 g, 2 mmol) and acid anhydride, namely, 1,8-
naphthalene dicarboxylic anhydride (2 mmol), 1,2,4,5-benzeneter-
tracarboxylic acid dianhydride (1 mmol) or 1,4,5,8-naphthalene
tertracarboxylic acid dianhydride (1 mmol) in 50 ml glacial acetic
acid was heated under reflux for 6 h. The reaction mixture was
concentrated under reduced pressure, the residue was solidified
with ether, filtered off and crystallized from the proper solvents to
yield 15–17, respectively.
4.1.7. Synthesis of dimethyl-diphenyl-indazole derivatives
11 and 12
A mixture of 9 or 10 (1 mmol) and phenylhydrazine (0.11 g,
1 mmol) in 20 ml ethanol was refluxed for 6 h. The reaction
mixture was evaporated under reduced pressure, the residue was
triturated with ethyl ether. The obtained solid was filtered off, dried
and crystallized from ethanol to give 11 and 12, respectively.
4.1.9.1. 2-(6-Methyl-4-phenyl-1,4-dihydro-pyrimidin-2-ylamino)-ben-
zo[de]isoquinoline-1,3-dione (15). Yield 78%; mp. 240–242 ꢁC
(dioxane); IR (KBr) nmax: 3450–3330 (2 NH), 3024 (aromatic CH),
2910 (aliphatic CH), 1722 (2 C]O), 1655 (C]N), 1560 (C]C) cmꢂ1
;
4.1.7.1. 3,6-Dimethyl-1,4-diphenyl-4,5-dihydro-1H-indazole (11). Yield
70%; m.p. 150–152 ꢁC. IR (KBr) nmax: 3033 (aromatic CH), 2913
1H NMR (270 MHz, DMSO-d6):
d 1.74 (s, 3H, CH3), 4.15 (d, 1H, CH-
pyrimidine), 6.85–7.38 (m, 6H, Ar-H þ CH-pyrimidine), 7.55–7.90
(m, 6H, naphthyl-H), 8.18 and 8.76 (2s, 2H, 2 NH exchangeable with
D2O); MS m/z (%): Mþ þ 2 384 (19), Mþ, 382 (8), 368 (14), 231 (85),
153 (80), 125 (60), 97 (100). Analysis calculated for C23H18N4O2
(382.43): C, 72.24; H, 4.74; N, 14.65. Found: C, 72.18; H, 4.70; N,
14.60.
(aliphatic CH), 1660 (C]N), 1602 (C]C) cmꢂ1 1H NMR (270 MHz,
;
DMSO-d6): d 1.65 and 2.20 (2s, 6H, 2 CH3), 2.38 (d, 2H, CH2), 3.46 (t,
1H, CH), 6.28 (s, 1H, CH), 6.95–7.65 (m, 10H, Ar-H); MS m/z (%):
M
þ ꢂ 1, 299 (3), 283 (21), 212 (30), 149 (100), 134 (18), 91 (45).
Analysis calculated for C21H20N2 (300.41): C, 83.96; H, 6.71; N, 9.33.
Found: C, 83.90; H, 6.66; N, 9.28.
4.1.9.2. 2,7-Bis-(6-methyl-4-phenyl-1,4-dihydro-pyrimidin-2-ylamino)-
benzo[lmn][3,8]phena-nthroline-1,3,6,8-tetraone (16). Yield 60%; m.p.
>250 ꢁC (AcOH/H2O). IR (KBr) nmax: 3520–3380 (4 NH), 3035 (aromatic
CH), 2918 (aliphatic CH), 1722, 1724 (4 C]O), 1665 (C]N), 1570 (C]C)
4.1.7.2. 6-Methyl-1,4-diphenyl-1,2,4,5-tetrahydro-indazol-3-one
(12). Yield 70%; mp. 132–134 ꢁC. IR (KBr) nmax: 3380 (NH), 3032
(aromatic CH), 2916 (aliphatic CH), 1665 (C]O), 1654 (C]N), 1560
(C]C) cmꢂ1; 1H NMR (270 MHz, DMSO-d6):
d
1.66 (s, 3H, CH3), 2.40
cmꢂ1; 1H NMR (270 MHz, DMSO-d6):
d 1.72 (s, 6H, 2 CH3), 4.18 (d, 2H, 2
(d, 2H, CH2), 3.48 (t, 1H, CH), 6.24 (s, 1H, CH), 6.98–7.45 (m, 10H, Ar-
CH-pyrimidine), 6.90–7.42 (m,12H,10 Ar-H þ 2CH-pyrimidine), 7.88(s,
2H, Ar-H), 8.22 and 8.82 (2s, 4H, 4 NH exchangeable with D2O); MS m/z
(%): Mþ, 586 (4), 552 (8), 384 (25), 355 (10), 231 (100),153 (55), 97 (64).
Analysis calculated for C32H26N8O4 (586.62): C, 65.52; H, 4.47; N, 19.10.
Found: C, 65.48; H, 4.42; N, 19.02.
H), 8.42 (s, 1H, NH exchangeable with D2O); 13C NMR (67.5 MHz,
DMSO-d6) d 22.85 (CH3), 25.48, 42.25, 106.55, 115.65, 144.95, 149.50
(cyclohexene-C), 156.88 (C]O), 112.20, 118.85, 125.90, 127.15,
128.15, 128.45, 135.60, 142.50 (2Ph-C); MS m/z (%): Mþ þ 2, 304 (4),
284 (15), 256 (12), 213 (5), 185 (8), 149 (18), 97 (25), 82 (100).
Analysis calculated for C20H18N2O (302.38): C, 79.44; H, 6.00; N,
9.26. Found: C, 79.40; H, 5.95; N, 9.2.
4.1.9.3. 2,6-Bis-(6-methyl-4-phenyl-1,4-dihydro-pyrimidin-2-ylami-
no)pyrrolo[3,4-f]isoindole-1,3,5,7-tetraone (17). Yield 65%; m.p.