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D. Kim et al. / Bioorg. Med. Chem. 19 (2011) 2508–2516
N-(5-(7-(4-methoxyphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-
(176 mg, 0.83 mmol) according to GP2. The residue was purified
by flash column chromatography (CH2Cl2/MeOH, 50:1) to produce
the desired acetamide C2 (143 mg, 64%); 1H NMR d (300 MHz,
DMSO-d6): 2.03 (3H, s), 2.39 (3H, s), 3.17 (3H, s), 3.53 (3H, s),
7.28 (4H, m), 7.30 (2H, d, J = 8 Hz), 7.50 (2H, d, J = 8 Hz); 13C NMR
d (75 MHz, DMSO-d6): 20.75, 24.02, 27.59, 29.50, 108.58, 118.26,
122.55, 127.65, 129.52, 133.23, 138.81, 140.69, 147.95, 150.28,
153.41, 168.64; HRMS (EI+) m/z calcd for C22H22N5O3 [M+H]+:
404.1722, found: 404.1695.
tetrahydro-1H-purin-8-yl)pyridin-3-yl)-4-methylbenzenesulfona-
mide (A8). Aryl xanthine (100 mg, 0.349 mmol) was reacted with
N-(5-bromopyridin-3-yl)-4-methyl-N-tosylbenzenesulfonamide
(252 mg, 0.524 mmol) according to GP2. The residue was purified
by flash column chromatography (EtOAc/CH2Cl2, 1:20) to produce
the desired sulfonamide A8 (78 mg, 42%); 1H NMR d (300 MHz,
DMSO-d6)): 2.33 (3H, s), 3.17 (3H, s), 3.52 (3H, s), 3.81 (3H, s),
6.97 (2H, d, J = 3 Mz), 7.29 (2H, d, J = 3 Mz), 7.31 (2H, d, J = 9 Mz),
7.54 (2H, d, J = 9 Mz), 7.67 (1H, t, J = 3 Mz), 8.14 (1H, s), 8.21 (1H,
s), 10.64 (1H, s); 13C NMR d (75 MHz, CDCl3): 21.33, 28.02, 29.89,
55.85, 109.87, 114.71, 125.39, 126.90, 127.00, 128.04, 129.31,
130.22, 136.36, 142.02, 144.16, 144.61, 147.64, 148.15, 151.25,
153.89, 160.13; HRMS (EI+) m/z calcd for C26H25N6O5S [M+H]+:
533.1607, found: 533.1595.
4.1.22. 8-(4-(Dimethylamino)phenyl)-7-(3-fluoro-4-methoxy-
phenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (D1)
7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,
7H)-dione(55 mg, 0.181 mmol) was reacted with 4-bromo-N,N-
dimethylaniline(54 mg, 0.271 mmol) according to GP1. After
removal of palladium by filteration through Celite, solution was
washed and dried. The residue was purified by flash column chro-
matography (CH2Cl2/MeOH, 20:1) to produce the desired product
D1 (87 mg, 53%); 1H NMR d (300 MHz, CDCl3): 2.96 (6H, s), 3.34
(3H, s), 3.67 (3H, s), 3.93 (3H, s), 6.53 (2H, d), 7.00 (1H, t), 7.08
(2H, m), 7.31 (2H, d); 13C NMR d (75 MHz, CDCl3): 27.92, 29.84,
39.98, 56.32, 108.69, 111.38, 113.02, 115.02, 116.13, 124.01,
128.94, 130.22, 148.39, 148.88, 150.54, 151.25, 151.76, 152.49,
153.01, 154.34; HRMS (ESI+) m/z calcd for C22H23FN5O3 [M+H]+:
424.1785, found: 424.1797.
4.1.18. 7-(3,4-Dimethoxyphenyl)-8-(4-(dimethylamino)phenyl)-
1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (B1)
7-(3,4-Dimethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-
dione (100 mg, 0.316 mmol) was reacted with 4-bromo-N,N-
dimethylaniline (95 mg, 0.474 mmol) to GP2. After removal of pal-
ladium by filteration through Celite pad, solution was washed and
dried. The residue was purified by flash column chromatography
(CH2Cl2/MeOH, 30:1) to produce the desired aniline B1 (68 mg,
49%); 1H NMR d (300 MHz, CDCl3): 2.96 (6H, s), 3.35 (3H, s), 3.69
(3H, s), 3.80 (3H, s), 3.93 (3H, s), 6.53 (2H, d), 6.83 (1H, d), 6.93
(2H, d), 7.37 (2H, d); 13C NMR d (75 MHz, CDCl3): 28.04, 29.93,
40.10, 56.13, 56.26, 108.97, 111.04, 111.39, 111.44, 115.58,
120.32, 129.49, 130.24, 148.91, 149.36, 149.70, 151.27, 151.96,
152.42, 154.41; HRMS (ESI+) m/z calcd for C23H25N5O4 [M+H]+:
436.1979, found: 436.1969.
4.1.23. N-(4-(7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-2,6-
dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acetamide (D2)
7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,
7H)-dione (200 mg, 0.675 mmol) was reacted with N-(4-bromo-
phenyl)acetamide (0.211 mg, 0.986 mmol) according to GP1. After
removal of palladium by filteration through Celite, solution was
washed and dried. The residue was purified by flash column chro-
matography (CH2Cl2/MeOH, 15:1) to produce the desired acetam-
ide D2 (168 mg, 57%); 1H NMR d (300 MHz,, CDCl3): 2.14 (3H, s),
3.34 (3H, s), 3.68 (3H, s), 3.91 (3H, s), 7.00 (1H, t), 7.05 (2H, m),
7.33 (1H, s), 7.42 (2H, d), 7.46 (2H, d); 13C NMR d (75 MHz,, CDCl3):
24.25, 27.56, 29.43, 55.83, 108.74, 122.56, 115.47, 118.65, 123.12,
127.60, 129.54, 139.22, 148.14, 150.01, 150.46, 151.17, 152.50,
4.1.19. N-(4-(7-(3,4-Dimethoxyphenyl)-1,3-dimethyl-2,6-dioxo-
2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acetamide (B2)
7-(3,4-Dimethoxyphenyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-
dione (100 mg, 0.316 mmol) was reacted with N-(4-bromophe-
nyl)acetamide (203 mg, 0.948 mmol) to GP2. After removal of palla-
dium by filteration through Celite pad, solution was washed and
dried. The residue was subjected to HPLC separation to produce
the desired acetamide B2 (62 mg, 44%); 1H NMR d (300 MHz, CDCl3):
2.11 (3H, s), 3.35 (3H, s), 3.67 (3H, s), 3.76 (3H, s), 3.89 (3H, s), 6.79
(1H, s), 6.87 (2H, s), 7.43 (4H, m), 7.80 (1H, s); 13C NMR d (75 MHz,
CDCl3): 24.50, 27.99, 29.82, 55.95, 56.09, 109.29, 110.88, 111.00,
119.04, 119.99, 123.74, 128.52, 129.80, 139.70, 148.49, 149.25,
149.77, 150.83, 151.67, 154.33, 168.56; HRMS (ESI+) m/z calcd for
153.97, 167.88; HRMS (ESI+) m/z calcd for
C22H20FN5NaO4
[M+Na]+: 460.1367, found: 460.1428.
4.1.24. 1-(4-(7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-2,6-
dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)-3-methylurea
(D3)
C
23H25N5O4 [M+H]+: 436.1979, found: 436.1969.
7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6-
(3H,7H)-dione(180 mg, 0.592 mmol) was reacted with 1-(4-
bromophenyl)-3-methylurea(203 mg, 0.887 mmol) according to
GP1. After removal of palladium by filteration through Celite, solu-
tion was washed and dried. The residue was purified by flash col-
umn chromatography (CH2Cl2/MeOH, 20:1) to produce the desired
urea D3 (166 mg, 62%); 1H NMR d (300 MHz, DMSO-d6): 2.60 (2H,
d), 3.16 (2H, s), 3.52 (2H, s), 3.89 (3H, s), 6.10 (1H, d), 7.14 (1H, dd),
7.21 (1H, t), 7.27 (2H, m), 7.34 (2H, m), 7.44 (1H, dd), 8.74 (1H, s);
13C NMR d (75 MHz, DMSO-d6): 26.18, 27.59, 29.50, 56.18, 108.58,
113.36, 116.17, 116.88, 120.22, 124.63, 128.18, 129.58, 142.38,
143.38, 147.72, 149.33, 150.87, 151.78, 153.42, 155.42; HRMS
4.1.20. N-(4-(1,3-Dimethyl-2,6-dioxo-7-phenyl-2,3,6,7-tetrahydro-
1H-purin-8-yl)phenyl)acetamide (C1)
1,3-Dimethyl-7-phenyl-1H-purine-2,6(3H,7H)-dione (100 mg,
0.390 mmol) was reacted with N-(4-bromophenyl)acetamide
(250 mg, 1.171 mmol) to GP2. After removal of palladium by filtera-
tion through Celite pad, solution was washed and dried. The residue
was purified by flash column chromatography (CH2Cl2/MeOH, 20:1)
to produce the desired acetamide C1 (98 mg, 65%); 1H NMR d
(300 MHz, CD2Cl2): 2.11 (3H, s), 3.35 (3H, s), 3.67 (3H, s), 3.76 (3H,
s), 3.89 (3H, s), 6.79 (1H, s), 6.87 (2H, s), 7.43 (4H, m), 7.80 (1H, s);
13C NMR d (75 MHz, CD2Cl2): 24.50, 27.99, 29.82, 55.95, 56.09,
109.29, 110.88, 111.00, 119.04, 119.99, 123.74, 128.52, 129.80,
139.70, 148.49, 149.25, 149.77, 150.83, 151.67, 154.33, 168.56;HRMS
(ESI+) m/z calcd for C23H25N5O4 [M+H]+: 436.1979, found: 436.1969.
(ESI+) m/z calcd for
C
22H22FN6O4 [M+H]+: 453.1681, found:
453.1718.
4.1.25. N-(4-(7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-2,6-
dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-methoxyphenyl)
acetamide (D4)
7-(3-Fluoro-4-methoxyphenyl)-1,3-dimethyl-1H-purine-2,6-
(3H,7H)-dione (100 mg, 0.329 mmol) was reacted with N-(4-bro-
mo-2-methoxyphenyl)acetamide (121 mg, 0.493 according to
4.1.21. N-(4-(1,3-Dimethyl-2,6-dioxo-7-p-tolyl-2,3,6,7-tetrahydro-
1H-purin-8-yl)phenyl)acetamide (C2)
1,3-Dimethyl-7-p-tolyl-1H-purine-2,6(3H,7H)-dione (150 mg,
0.55 mmol) was reacted with N-(4-bromophenyl)acetamide