R. A. F. de Ligt et al. / Bioorg. Med. Chem. 12 (2004) 139–149
147
stirred for 16 h at room temperature. The reaction mix-
ture was then concentrated in vacuo and the product
was crystallised from water. Yield 423 mg (99%). Mp
(CH , propyl), 20.56 (CH CH N, propyl), 23.72 (2C,
3 2 2
CH CH CH , cyclopentyl), 29.66 (CH , N-9), 33.45
2
2
2
3
(2C, CHCH CH , cyclopentyl), 38.85 (CH , methyla-
2
2
3
ꢀ
1
1
31–135 C C. H NMR (CDCl ) d 1.57–2.14 (m, 8H,
mine), 52.32 (CH, cyclopentyl), 55.53 (CH N, propyl),
2
3
8
4
CH ), 4.39 (q, 1H, N H), 4.62 (m, 1H, CH), 5.79 (d, 1H,
ꢃꢃCCH ), 3.17 (d, 3H, N -CH ), 3.53 (s, 3H, N-9-
116.94 (C-8), 150.99 (C-2), 150.18, 152.17, 155.72 (C-6,
+
C-5, C-4). HRMS (ESI-MS) for C H N [M+H] :
2
3
8
3
15 25
6
6
13
N H), 8.25 (s, 1H, H-2). C NMR (CDCl ): d 23.69
found, 289.2156; calcd, 289.2141.
3
(
3
2C, CH CH CH , cyclopentyl), 29.63 (CH , N-9),
3.37 (2C, CHCH CH , cyclopentyl), 41.52 (CH ,
2 2 2 3
6
4.4.13. N -Cyclopentyl-8-(N-butyl-N-methylamino)-9-
methyladenine (27). This was prepared as 24, starting
2
2
3
methylamine), 52.32 (CH, cyclopentyl), 116.91 (C-8),
51.02 (C-2), 150.36, 152.24, 155.94 (C-6, C-5, C-4).
+
6
1
HRMS (ESI-MS) for C H N [M+H] : found,
with N -cyclopentyl-8-(N-methylamino)-9-methylade-
nine (23, 39 mg, 0.16 mmol) in DMF/NaH and butyl
iodide (49 mg, 0.29 mmol). Yield 12 mg (26%, oil). H
NMR (CDCl ) d 0.93 (t, 3H, CH CH CH CH ), 1.19–
1
2
19
6
1
2
47.1572; calcd, 247.1671.
3
2
2
2
3
6
4
.4.10. N -Cyclopentyl-8-(N,N-dimethylamino)-9-methyl-
6
2.20 (m, 12H, CH CH CH CH , butyl, 4ꢃCH ), 2.94
2
2
2
3
2
8
8
3 2
adenine (24). N -Cyclopentyl-8-(N-methylamino)-9-
methyladenine (23, 76 mg, 0.31 mmol) was dissolved in
1
0
was added (53 mg, 0.34 mmol) an the reaction mixture
was stirred for 16 h at room temperature. Afterwards,
(s, 3H, N -CH ), 3.21 (m, 2H, N -CH ), 3.61 (s, 3H, N-
9-CH ), 4.59 (m, 1H, CH), 5.44 (d, 1H, N H), 8.29 (s,
6
3
1
3
.5 mL DMF and NaH (60% in mineral oil, 13.5 mg,
.31 mmol), and stirred for 15 min. Then methyl iodide
1H, H-2). C NMR (CDCl ): d 13.82 (CH , butyl),
3
3
20.19 (CH CH CH N, butyl), 23.70 (2C, CH CH CH ,
cyclopentyl), 29.38 (CH CH N, butyl), 29.68 (CH , N-
2 2 3
9), 33.43 (2C, CHCH CH , cyclopentyl), 38.85 (CH ,
2
2
2
2
2
2
2
2
3
1
organic product was extracted with CH Cl (two times,
0 mL of water was added to the mixture and the
methylamine), 50.67 (CH N, butyl), 52.31 (CH, cyclo-
2
pentyl), 116.97 (C-8), 151.02 (C-2), 149.99, 152.25,
154.67 (C-6, C-5, C-4). HRMS (ESI-MS) for C H N
6
2
2
4
matography(MeOH/CH Cl ) and the product was col-
mL). Purification was performed with column chro-
1
6
27
+
[M+H] : found, 303.2245; calcd, 303.2297.
2
2
1
lected as oil. Yield 34 mg (43%). H NMR (CDCl ) d
3
8
1
(
.50–2.17 (m, 8H, 4ꢃCH ), 2.93 (s, 3H, N -CH ), 3.60
2
3
4
.5. General procedure for the synthesis of 8-aminosub-
6
6
s, 3H, N-9-CH ), 4.64 (m, 1H, CH), 5.49 (d, 1H, N H),
3
stituted N -cyclopentyl-9-methyl adenines (28–33, 35–
7): method C
1
3
8.26 (s, 1H, H-2). C NMR (CDCl ): d 23.69 (2C,
CH CH CH , cyclopentyl), 29.66 (CH , N-9), 33.39
3
3
2
2
2
3
(
2C, CHCH CH , cyclopentyl), 41.52 (2C, CH , dime-
2
The appropriate amine was added in excess to a solu-
6
2
3
thylamine), 52.29 (CH, cyclopentyl), 116.79 (C-8),
51.09 (C-2), 150.24, 152.24, 155.88 (C-6, C-5, C-4).
+
tion of 8-bromo-N -cyclopentyl-9-methyladenine (6) in
dioxane. The reaction mixture was stirred in a pressure
1
HRMS (ESI-MS) for C H N [M+H] : found,
ꢀ
ducts were purified with column chromatography.
tube at 80–120 C for 16–120 h, and the resulting pro-
1
3
21
6
2
61.1856; calcd, 261.1828.
6
6
4
methyladenine (25, LUF 5668). This was prepared as
.4.11.
N -Cyclopentyl-8-(N-methyl-N-ethylamino)-9-
4.5.1. N -Cyclopentyl-8-(N-ethylamino)-9-methyladenine
(28). This was prepared according to method C, start-
6
24, starting with N -cyclopentyl-8-(N-methylamino)-9-
methyladenine (23, 61 mg, 0.25 mmol) in DMF/NaH
ing from a 70% w/v ethylamine solution and stirred at
80 C for 48 h. Purification was performed with column
ꢀ
chromatography(MeOH/eth ly acetate). Yield 0.29 g
and ethyl iodide (10.3 mg, 0.25 mmol). Yield 24 mg
1
ꢀ
1
(
36%, oil). H NMR (CDCl ) d 1.11–1.48 (t, 3H,
(99%). Mp 77–81 C. H NMR (CDCl ) d 1.34 (t, 3H,
3
3
8
CH CH ), 1.52–2.16 (m, 8H, 4ꢃCH ), 2.92 (s, 3H, N -
CH CH ), 1.50–2.17 (m, 8H, 4ꢃCH ), 3.50 (s, 3H, CH ),
2
3
2
2
3
2
3
8
CH ), 3.41–3.22 (q, 2H, CH CH ), 3.59 (s, 3H, N-9-
3
3.56 (m, 2H, CH CH ), 4.05 (bs, 1H, N H), 4.59 (m, 1H,
2 3
2
3
6
6
CH ), 4.65 (m, 1H, CH), 5.50 (d, 1H, N H), 8.27 (s, 1H,
3
H-2). C NMR (CDCl ): d 12.50 (CH , ethyl), 23.69
2C, CH CH CH , cyclopentyl), 29.57 (CH , N-9),
CH), 5.37 (d, 1H, N H), 8.23 (s, 1H, H-2). HRMS (ESI-
+
1
3
MS) for C H N [M+H] : found, 261.1906; calcd,
3
3
13 21
6
.
261.1828. Anal. (C H N 0.4SiO ) C, H, N.
13 20 6 2
(
2
2
2
3
3
methylamine), 48.34 (CH N, ethyl), 52.38 (CH, cyclo-
3.42 (2C, CHCH CH , cyclopentyl), 38.15 (CH ,
2 2 3
6
4.5.2. N -Cyclopentyl-8-(N-cyclopentylamino)-9-methy-
ladenine (29). This was prepared according to method
C, starting from cyclopentylamine solution and stirred
2
pentyl), 116.91 (C-8), 151.06 (C-2), 150.18, 152.27,
1
55.51 (C-6, C-5, C-4). HRMS (ESI-MS) for C H N
14 23 6
+
ꢀ
[
M+H] : found, 275.1961; calcd, 275.1984.
at 120 C for 120 h. Purification was performed with
column chromatography(MeOH/ethly acetate). Yield
0.17 g (53%). Mp 62–65 C. H NMR (CDCl ) d 1.46–2.19
6
ꢀ
1
4.4.12. N -Cyclopentyl-8-(N-methyl-N-propylamino)-9-
methyladenine (26, LUF 5669). This was prepared as
3
(m, 16H, 8ꢃCH ), 3.48 (s, 3H, N-9-CH ), 4.18–4.32 (m,
2
3
6
8
8
2
methyladenine (23, 62 mg, 0.25 mmol) in DMF/NaH
4, starting with N -cyclopentyl-8-(N-methylamino)-9-
1H, N CH), 4.52 (d, 1H, N H), 4.46–4.64 (m, 1H, CH),
5.78 (d, 1H, N H), 8.21 (s, 1H, H-2). HRMS (ESI-MS) for
6
+
and ethyl iodide (49.3 mg, 0.29 mmol). Yield 26 mg
1
C H N [M+H] : found, 301.2152; calcd, 301.2141.
25
16
6
(
CH CH CH ), 1.40–2.19 (m, 10H, CH CH CH , 8H,
36%, oil).
H NMR (CDCl3) d 0.93 (t, 3H,
6
4.5.3. N -cyclopentyl-8-(N-phenylamino)-9-methylade-
nine (30). This was prepared according to method C,
2
2
3
2
2
3
8
8
4
3
ꢃCH ), 2.93 (s, 3H, N -CH ), 3.17 (t, 2H, N -CH ),
2
3
2
.60 (s, 3H, N-9-CH ), 4.57 (m, 1H, CH), 5.43 (d, 1H,
3
starting from a 70% w/v aniline solution and stirred at
ꢀ
6
13
N H), 8.27 (s, 1H, H-2). C NMR (CDCl ): d 11.25
100 C for 32 h. Purification was performed with col-
3