1
024
Chem. Pharm. Bull.
Vol. 63, No. 12 (2015)
the highest potency against A549 among the tested series with
IC50 values of 0.03 and 0.04µM, respectively.
N-(4-Methoxyphenyl)-7,9-dimethylpyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidin-4-amine (3b)
1
Yield 65%; mp> 300°C (decomp.). H-NMR (DMSO-
Experimental
d ) δ: 9.75 (1H, s), 8.30 (1H, s), 7.38 (1H, s), 6.73 (2H, dd,
6
3
4
3
4
Chemistry The structures of all tested compounds were
J=8.00Hz, J=1Hz), 6.66 (2H, dd, J=8.00Hz, J=1Hz),
1
13
−1
confirmed by H-NMR, C-NMR and mass spectrometry 3.99 (3H, s), 2.09 (3H, s), 1.86 (3H, s). IR (KBr) cm : 3433,
+
(
electron ionization (EI)-MS). The purities of the tested com- 3033, 2952, 1662, 1571. MS m/z: 337.00 (M +1), 231.00. Anal.
pounds were determined by elemental analysis. The com- Calcd for C H N OS: C, 64.26; H, 4.79; N, 16.65. Found; C,
18
16
4
mercial chemicals and solvents were reagent grade and used 64.10; H, 4.55; N, 16.32.
1
13
without further purification. H- and C-NMR spectra were
N-(4-Chlorophenyl)pyrido[3′,2′:4,5]thieno[3,2-d]-
measured in DMSO-d on a Varian Mercury VX-300 NMR pyrimidin-4-amine (4a)
spectrometer or Jeol LA (400MHz for H-NMR, 100MHz for
C-NMR). Chemical shifts were reported in parts per million (1H, s), 8.72 (1H, d, J=4.5Hz), 8.49 (1H, d, J=8.1Hz), 7.78
ppm) using tetramethylsilane (TMS) as an internal standard. (1H, s), 7.67 (2H, d, J=9.00Hz), 7.37 (1H, t, J=8.1Hz), 7.27
Electron impact mass spectra were recorded on Shimadzu (2H, d, J=9.00Hz). C-NMR (DMSO-d ) δ: 161.62, 161.19,
GCMS-QP 5050A gas chromatograph mass spectrometer 157.28, 150.43, 133.95, 133.20, 131.00, 129.61, 127.98, 120.29,
70eV). Elemental analysis was performed at the Microana- 118.69. IR (KBr) cm : 3415, 1686, 1571. MS m/z: 312.00 (M ),
6
1
1
Yield 50%; mp 255–256°C. H-NMR (DMSO-d ) δ: 9.39
6
13
3
3
3
3
(
3
13
6
−1
+
(
lytical Center of Cairo University, Egypt. IR spectra were 203.00. Anal. Calcd for C H ClN S: C, 57.60; H, 2.90; N,
15
9
4
recorded on a Shimadzu FT-IR 8101 PC IR spectrophotometer 17.91. Found; C, 57.32; H, 2.75; N, 17.51.
−
1
(
KBr pellets). Values were represented in cm . The synthetic
N-(4-Chlorophenyl)-7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-
procedure for the compounds was illustrated in (Chart 1).
General Procedures for the Synthesis of N-(Substituted
Phenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-amines (1H, s), 8.00 (2H, s), 7.52 (2H, d, J=9.00Hz), 7.09 (2H, d,
2–5a, b) The appropriate aniline (9mmol) was dissolved in
dry tetrahydrofuran (THF) (25mL) and Et N (1.5mL) under δ: 159.98, 157.46, 152.51, 147.16, 146.57, 132.20, 124.19, 122.74,
nitrogen atmosphere. Compound (1a or b) (4.5mmol) was 121.28, 110.00, 24.03, 18.92. IR (KBr) cm : 3438, 2919, 1665,
added slowly to the stirred solution which was then heated 1465. MS m/z: 340.00 (M ). Anal. Calcd for C H ClN S: C,
d]pyrimidin-4-amine (4b)
1
Yield 59%; mp 280–281°C. H-NMR (DMSO-d ) δ: 10.89
6
3
3
13
(
J=9.00Hz), 2.10 (3H, s), 1.92 (3H, s). C-NMR (DMSO-d6)
3
−1
+
17
13
4
under reflux for 15–20h. The reaction mixture was cooled and 59.91; H, 3.84; N, 16.44. Found; C, 60.30; H, 4.10; N, 16.63.
poured onto crushed ice. The precipitated solid was filtered N-(2,4-Dichlorophenyl)pyrido[3′,2′:4,5]thieno[3,2-d]-
off, washed with water (2×10mL) and dried. The crude solid pyrimidin-4-amine (5a)
was purified by column chromatography using 1–2 EtOAc/ Yield 56%; mp> 300°C (decomp.). H-NMR (DMSO-d ) δ:
hexane v/v as the eluent to give the desired compounds (2–5a, 9.06 (1H, s), 8.38 (1H, s), 7.71 (1H, s), 7.55 (1H, dd, J=5.00Hz,
1
6
3
4
3
4
b).
J=2.00Hz), 7.47 (1H, dd, J=8.00Hz, J=2.00Hz), 7.24 (1H,
13
N-(4-Tolyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine m), 6.83 (2H, m). C-NMR (DMSO-d ) δ: 161.33, 150.25,
6
(2a)
136.59, 130.92, 130.81, 130.67, 130.55, 129.11, 119.64. IR (KBr)
1
−1
+
Yield 53%; mp 276–278°C. H-NMR (DMSO-d ) δ: 11.07 cm : 1659, 1470. MS m/z: 345.00 (M ), 203.00. Anal. Calcd
6
3
4
(
1H, s), 8.71 (1H, dd, J=4.80Hz, J=2.00Hz), 7.93 (1H, d, for C H Cl N S: C, 51.89; H, 2.32; N, 16.14. Found; C, 52.01;
15 8 2 4
3
3
J=8.00Hz), 7.44 (1H, s), 7.16 (1H, t, J=8.00Hz); 6.71 (4H, H, 2.54; N, 16.42.
3
4
−1
dd, J=8.4Hz, J=1.2Hz), 2.30 (3H, s). IR (KBr) cm : 3427,
2
for C H N S: C, 65.73; H, 4.14; N, 19.16. Found; C, 66.13; H,
N-(2,4-Dichlorophenyl)-7,9-dimethylpyrido[3′,2′:4,5]-
+
988, 1621, 1561. MS m/z: 294.00 (M +2), 203.00. Anal. Calcd thieno[3,2-d]pyrimidin-4-amine (5b)
1
Yield 63%; mp> 300°C (decomp.). H-NMR (DMSO-d ) δ:
16
12
4
6
3
4.54; N, 19.56.
9.49 (1H, s), 8.40 (1H, s), 7.69 (1H, s), 7.63 (1H, d, J=9.00Hz),
N-(4-Tolyl)-7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]- 7.41 (1H, d, J=9.00Hz), 6.68 (1H, s), 2.89 (3H, s), 2.60 (3H,
s). C-NMR (DMSO-d ) δ: 161.99, 158.07, 157.28, 150.43,
Yield 58%; mp 300°C. H-NMR (DMSO-d ) δ: 10.99 (1H, 144.09, 129.61, 126.00, 122.00, 118.69, 20.26, 13.87. IR (KBr)
s), 8.38 (1H, s), 7.82 (1H, s), 7.65 (2H, d, J=9.00Hz, H-16), cm : 3301, 2905, 1692, 1574. MS m/z: 374.00 (M ), 231.00.
3
13
pyrimidin-4-amine (2b)
6
1
6
3
−1
+
3
7
.23 (2H, d, J=9.00Hz), 2.24 (6H, s), 1.98 (3H, s). IR (KBr) Anal. Calcd for C H Cl N S: C, 54.41; H, 3.22; N, 14.93.
17 12 2 4
1
−
+
cm : 3440, 3033, 2832, 1662, 1570. MS m/z: 322.00 (M +2), Found; C, 54.79; H, 3.38; N, 15.26.
231.00. Anal. Calcd for C H N S: C, 67.47; H, 5.03; N, 17.49.
General Procedures for the Synthesis of N-(Substituted
Benzyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-amines
1
8
16
4
Found; C, 67.67; H, 5.38; N, 17.60.
N-(4-Methoxyphenyl)pyrido[3′,2′:4,5]thieno[3,2-d]- (6–8a, b) The appropriate benzylamine (9mmol) was dis-
pyrimidin-4-amine (3a) solved in dry DCM (25mL) and Et N (1.5mL) under nitrogen
Yield 60%; mp> 300°C (decomp.). H-NMR (DMSO-d ) δ: atmosphere. Compound (1a or b) (4.5mmol) was added slowly
3
1
6
3
4
9
.89 (1H, s), 8.88 (1H, dd, J=5.00Hz, J=2.00Hz), 8.60 (1H, to the stirred solution which was then heated under reflux
d, J=8.00Hz), 7.99 (1H, s), 7.41 (1H, t, J=8.00Hz), 6.46 (2H, for 6–9h. The reaction mixture was cooled and poured onto
dd, J=8.00Hz, J=1Hz), 6.37 (2H, dd, J=8.00Hz, J=1Hz), crushed ice. The precipitated solid was filtered off, washed
.20 (3H, s). IR (KBr) cm : 3395, 2907, 1643, 1461. MS m/z: with water (2×10mL) and dried. The crude solid was purified
08.00 (M ), 203.00. Anal. Calcd for C H N OS: C, 62.32; H, by column chromatography over silica gel using 1–5 EtOAc/
3
3
3
4
3
4
−1
4
3
+
1
6
12
4
3.92; N, 18.17. Found; C, 61.93; H, 3.70; N, 17.98.
hexane v/v as the eluent to give the desired compounds (6–8a,
b).