9-Substituted-8-Hydroxyadenine DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 6 2093
2-Butylamino-8-hydroxy-9-(4-methylbenzyl)adenine (9f). Yield
98%; recrystallized from MeOH, mp 282-283 °C; 1H NMR
(DMSO-d6) δ 9.63 (1H, s), 7.18 (2H, d, J ) 8.0 Hz), 7.10 (2H, d,
J ) 8.0 Hz), 6.18 (1H, t, J ) 5.6 Hz), 5.99 (2H, s), 4.74 (2H, s),
3.15 (2H, q, J ) 7.2 Hz), 2.25 (3H, s), 1.44 (2H, m), 1.28 (2H, m),
0.87 (3H, t, J ) 7.6 Hz). Anal. (C17H22N6O‚0.2H2O) C, H, N.
2-Butylamino-9-(4-fluorobenzyl)-8-hydroxyadenine (9g). Yield
77%; recrystallized from MeOH, mp 266-267 °C; 1H NMR
(DMSO-d6) δ 9.67 (1H, s), 7.33 (2H, dd, J ) 8.4, 5.6 Hz), 7.14
(2H, d, J ) 8.4, 5.6 Hz), 6.21 (1H, t, J ) 5.6 Hz), 6.01 (2H, s),
4.78 (2H, s), 3.16 (2H, q, J ) 6.0 Hz), 1.44 (2H, m), 1.29 (2H, m),
0.86 (3H, t, J ) 7.7 Hz). Anal. (C16H19FN6O‚0.1H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(4-trifluoromethylbenzyl)ade-
nine (9h). Yield 85%; recrystallized from MeOH, mp 264-266
°C; 1H NMR (DMSO-d6) δ 9.73 (1H, s), 7.69 (2H, d, J ) 8.0 Hz),
7.46 (2H, d, J ) 8.0 Hz), 6.21 (1H, t, J ) 5.6 Hz), 6.04 (2H, s),
4.89 (2H, s), 3.14 (2H, q, J ) 6.8 Hz), 1.41 (2H, m), 1.26 (2H, m),
0.83 (3H, t, J ) 7.6 Hz). Anal. (C17H19F3N6O‚0.2H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(4-nitrobenzyl)adenine (9i). Yield
45%; recrystallized from MeOH, mp 216-218 °C; 1H NMR
(DMSO-d6) δ 9.73 (1H, s), 8.19 (2H, d, J ) 8.8 Hz), 7.50 (2H, d,
J ) 8.8 Hz), 6.23 (1H, t, J ) 5.6 Hz), 6.05 (2H, s), 4.94 (2H, s),
3.12 (2H, q, J ) 6.8 Hz), 1.40 (2H, m), 1.24 (2H, m), 0.83 (3H, t,
J ) 7.4 Hz). Anal. (C16H19N7O3‚1.75H2O) C, H, N.
2-Butylamino-9-(4-butylbenzyl)-8-hydroxyadenine (9l). Yield
91%; mp 248-249 °C; 1H NMR (DMSO-d6) δ 9.61 (1H, s), 7.19
(2H, d, J ) 8.2 Hz), 7.11 (2H, d, J ) 8.2 Hz), 6.20 (1H, t, J ) 5.6
Hz), 5.99 (2H, s), 4.76 (2H, s), 3.14 (2H, m), 2.51 (2H, m), 1.49
(4H, m), 1.28 (4H, m), 0.87 (6H, m). Anal. (C20H28N6O‚0.12H2O)
C, H, N.
2-Butylamino-9-(4-tert-butylbenzyl)-8-hydroxyadenine (9m).
Yield 96%; mp 256-257 °C; 1H NMR (DMSO-d6) δ 9.66 (1H, s),
7.32 (2H, d, J ) 8.4 Hz), 7.22 (2H, d, J ) 8.4 Hz), 6.23 (1H, t, J
) 5.6 Hz), 6.06 (2H, s), 3.17 (2H, m), 1.45 (2H, m), 1.28 (2H, m),
1.24 (9H, s), 0.87 (3H, t, J ) 7.2 Hz). Anal. (C20H28N6O) C, H, N.
9-(4-Biphenylmethyl)-2-butylamino-8-hydroxyadenine (9n).
Yield 98%; recrystallized from EtOH, mp 285-287 °C; 1H NMR
(DMSO-d6) δ 9.67 (1H, s), 7.62 (4H, m), 7.46 (2H, m), 7.35 (3H,
m), 6.24 (1H, t, J ) 5.6 Hz), 6.03 (2H, s), 4.85 (2H, s), 3.17 (2H,
q, J ) 6.8 Hz), 1.46 (2H, m), 1.28 (2H, m), 0.87 (3H, t, J ) 7.6
Hz). Anal. (C22H24N6O‚0.27H2O) C, H, N.
(2H, m), 1.41 (2H, m), 1.25 (2H, m), 0.83 (3H, t, J ) 7.2 Hz).
Anal. (C20H22N6O) C, H, N.
2-Butylamino-8-hydroxy-9-(2-naphthylmethyl)adenine (9t).
1
Yield 93%; mp 225-227 °C; H NMR (DMSO-d6) δ 10.08 (1H,
s), 7.88 (3H, m), 7.78 (1H, brs), 7.49 (3H, m), 6.85 (2H, s), 5.00
(2H, s), 3.21 (2H, m), 1.46 (2H, m), 1.26 (2H, m), 0.82 (3H, t, J
) 7.6 Hz). Anal. (C20H22N6O‚1.65H2O) C, H, N.
2-Butylamino-9-(5-chlorothiophene-2-ylmethyl)-8-hydroxyad-
enine (9u). Yield 61%; recrystallized from MeOH-CHCl3, mp
1
268-269 °C; H NMR (DMSO-d6) δ 9.65 (1H, s), 6.96 (2H, dd,
J ) 20.8, 3.6 Hz), 6.28 (1H, t, J ) 5.6 Hz), 6.03 (2H, s), 4.87 (2H,
s), 3.19 (2H, q, J ) 6.8 Hz), 1.48 (2H, m), 1.30 (2H, m), 0.88 (3H,
t, J ) 7.2 Hz). Anal. (C14H17ClN6OS) C, H, N.
2-Butylamino-8-hydroxy-9-(2-hydroxy-2,2-dimethylethyl)ad-
1
enine (9v). Yield 92%; mp 214-216 °C; H NMR (DMSO-d6) δ
9.65 (1H, s), 6.26 (1H, t, J ) 5.6 Hz), 6.12 (2H, s), 5.20 (1H, s),
3.63 (2H, s), 3.15 (2H, m), 1.44 (2H, m), 1.29 (2H, m), 1.09 (6H,
s), 0.87 (3H, t, J ) 7.2 Hz). Anal. (C13H22N6O2‚0.2H2O) C, H, N.
2-Butylamino-9-(2,2-dimethylethyl)-8-hydroxyadenine (9w).
Yield 62%; mp 213-215 °C; 1
H NMR (DMSO-d6) δ 9.57 (1H, s),
6.16 (1H, t, J ) 5.6 Hz), 5.95 (2H, s), 3.42 (2H, d, J ) 7.2 Hz),
3.17 (2H, q, J ) 6.8 Hz), 2.14 (1H, m), 1.46 (2H, m), 1.29 (2H,
m), 0.85 (9H, m). Anal. (C13H22N6O‚0.2H2O) C, H, N.
2-Butylamino-9-cyclohexylmethyl-8-hydroxyadenine (9x). Yield
70%; mp 230-231 °C; 1H NMR (DMSO-d6) δ 9.56 (1H, s), 6.17
(1H, t, J ) 5.6 Hz), 5.95 (2H, s), 3.45 (2H, d, J ) 7.2 Hz), 3.17
(2H, q, J ) 6.8 Hz), 1.82 (1H, m), 1.66 (2H, m), 1.55 (2H, m),
1.46 (2H, m), 1.29 (2H, m), 1.13 (3H, m), 0.95 (3H, m), 0.87 (3H,
t, J ) 7.2 Hz). Anal. (C16H26N6O‚0.1H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(2-pyridylmethyl)adenine (9y). Yield
67%; recrystallized from MeOH, mp 172-174 °C; 1H NMR
(DMSO-d6) δ 9.67 (1H, s), 8.46 (1H, m), 7.73 (1H, dt, J ) 7.6,
1.8 Hz), 7.25 (1H, 7.12 (1H, d, J ) 8.0 Hz), 6.18 (1H, t, J ) 5.6
Hz), 5.98 (2H, s), 4.91 (2H, s), 3.09 (2H, q, J ) 6.8 Hz), 1.38 (2H,
m), 1.20 (2H, m), 0.82 (3H, t, J ) 7.2 Hz). Anal. (C15H19N7O‚
H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(3-pyridylmethyl)adenine (9z). Yield
60%; recrystallized from MeOH-H2O, mp 216-218 °C; 1H NMR
(DMSO-d6) δ 9.57 (1H, s), 8.55 (1H, d, J ) 1.6 Hz), 8.47 (1H, dd,
J ) 4.8, 1.6 Hz), 7.68 (1H, d, J ) 7.6 Hz), 7.34 (1H, m), 6.23
(1H, t, J ) 5.6 Hz), 6.02 (2H, s), 4.83 (2H, s), 3.15 (2H, q, J ) 7.0
Hz), 1.44 (2H, m), 1.28 (2H, m), 0.85 (3H, t, J ) 7.6 Hz). Anal.
(C15H19N7O) C, H, N.
2-Butylamino-8-hydroxy-9-(4-pyridylmethyl)adenine (9aa).
Yield 75%; recrystallized from MeOH-H2O, mp 205-207 °C; 1H
NMR (DMSO-d6) δ 9.72 (1H, s), 8.49 (1H, dd, J ) 4.4, 2.0 Hz),
7.20 (2H, d, J ) 7.0 Hz), 6.22 (1H, t, J ) 5.6 Hz), 6.05 (2H, s),
4.83 (2H, s), 3.12 (2H, q, J ) 7.0 Hz), 1.39 (2H, m), 1.25 (2H, m),
0.83 (3H, t, J ) 7.6 Hz). Anal. (C15H19N7O‚0.5H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(2-pyrazylmethyl)adenine (9ab).
Yield 44%; recrystallized from MeOH-H2O, mp 188-190 °C; 1H
NMR (DMSO-d6) δ 9.67 (1H, s), 8.61 (31H, s), 8.54 (2H, dd, J )
8.8, 2.4 Hz), 6.17 (1H, t, J ) 5.6 Hz), 6.02 (2H, s), 4.98 (2H, s),
3.08 (2H, q, J ) 6.8 Hz), 1.35 (2H, m), 1.22 (2H, m), 0.81 (3H, t,
J ) 7.2 Hz). Anal. (C14H18N8O‚0.65H2O) C, H, N.
2-Butylamino-9-(3,4-dichlorobenzyl)-8-hydroxyadenine (9o).
Yield 96%; mp 269-270 °C; 1H NMR (DMSO-d6) δ 9.73 (1H, s),
7.57 (2H, m), 7.24 (2H, dd, J ) 8.8, 1.8 Hz), 6.22 (1H, t, J ) 5.6
Hz), 6.05 (2H, s), 4.80 (2H, s), 3.14 (2H, q, J ) 6.8 Hz), 1.43 (2H,
m), 1.26 (2H, m), 0.85 (3H, t, J ) 7.6 Hz). Anal. (C16H18Cl2N6O‚
0.15H2O) C, H, N.
2-Butylamino-9-(3,4-difluorobenzyl)-8-hydroxyadenine (9p).
Yield 100%; recrystallized from MeOH-(CH3)2CO, mp 217-219
1
°C; H NMR (DMSO-d6) δ 10.54 (1H, s), 7.69 (2H, s), 7.40 (2H,
m), 7.16 (1H, t, J ) 4.0 Hz), 4.85 (2H, s), 3.16 (2H, m), 1.47 (2H,
m), 1.29 (2H, m), 0.84 (3H, t, J ) 7.6 Hz). Anal. (C16H18F2N6O‚
HCl‚0.3H2O) C, H, N.
2-Butylamino-9-(2-chloro-4,5-methylenedioxylbenzyl)-8-hy-
droxyadenine (9q). Yield 65%; recrystallized from EtOH, mp
2-Butylamino-8-hydroxy-9-(2-methylpyridine-3-ylmethyl)ad-
enine (9ac). Yield 66%; recrystallized from MeOH, mp 215-217
1
214-215 °C; H NMR (DMSO-d6) δ 9.70 (1H, s), 7.10 (1H, s),
1
6.59 (1H, brs), 6.24 (1H, t, J ) 5.6 Hz), 6.05 (2H, s), 6.03 (2H, s),
4.79 (2H, s), 3.13 (2H, q, J ) 7.0 Hz), 1.42 (2H, m), 1.27 (2H, m),
0.85 (3H, t, J ) 7.4 Hz). Anal. (C17H19ClN6O3) C, H, N.
2-Butylamino-8-hydroxy-9-(2-phenylethyl)adenine (9r). Yield
93%; recrystallized from MeOH-H2O, mp 204-205 °C; 1H NMR
(DMSO-d6) δ 9.52 (1H, s), 7.11-7.59 (5H, m), 6.22 (1H, t, J )
5.6 Hz), 5.98 (2H, s), 3.86 (2H, m), 3.17 (2H, m), 2.98 (2H,m),
1.47 (2H, m), 1.31 (2H, m), 0.88 (3H, t, J ) 7.6 Hz). Anal.
(C17H22N6O‚1.35H2O) C, H, N.
°C; H NMR (DMSO-d6) δ 9.70 (1H, m), 8.32 (1H, d, J ) 3.1
Hz), 7.37 (1H, d, J ) 7.7 Hz), 7.14 (1H, dd, J ) 7.7, 3.1 Hz), 6.20
(1H, t, J ) 6.4 Hz), 6.00 (2H, s), 4.82 (2H, s), 3.12 (2H, m), 2.60
(3H, s), 1.39 (2H, m), 1.25 (2H, m), 0.84 (3H, t, J ) 7.1 Hz).
Anal. (C16H21N7O‚0.25H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(5-methylpyridine-3-ylmethyl)ad-
enine (9ad). Yield 79%; recrystallized from MeOH, mp 221-222
1
°C; H NMR (DMSO-d6) δ 9.65 (1H, m), 8.35 (1H, s), 8.31 (1H,
s), 7.50 (1H, s), 6.23 (1H, m), 6.02 (2H, s), 4.80 (2H, s), 3.16 (2H,
m), 2.25 (3H, s), 1.44 (2H, m), 1.28 (2H, m), 0.86 (3H, t, J ) 7.2
Hz). Anal. (C16H21N7O‚1.2H2O) C, H, N.
2-Butylamino-8-hydroxy-9-(1-naphthylmethyl)adenine (9s).
Yield 100%; recrystallized from MeOH, mp 249-251 °C; 1H NMR
(DMSO-d6) δ 9.72 (1H, s), 8.39 (1H, d, J ) 7.8 Hz), 7.95 (1H,
m), 7.86 (1H, m), 7.56 (2H, m), 7.43 (1H, t, J ) 7.6 Hz), 7.35
(1H, s), 6.19 (1H, t, J ) 5.6 Hz), 6.03 (2H, s), 5.28 (2H, s), 3.12
2-Butylamino-8-hydroxy-9-(6-methylpyridine-3-ylmethyl)ad-
enine (9ae). Yield 98%; recrystallized from MeOH, mp 248.5-
252 °C; 1H NMR (DMSO-d6) δ 9.78 (1H, m), 8.42 (1H, d. J ) 2.2