3448 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16
Mu¨ller et al.
6-Am in o-1-m eth yl-5-[3-p h en yl-(E,2E)-2-p r op en ylid en -
am in o]-1,2,3,4-tetr ah ydr o-2,4-pyr im idin dion e (8). 1-Methyl-
5,6-diaminouracil 7b (3.9 mmol) was dissolved in 30 mL of
MeOH and 200 µL (3.5 mmol) of acetic acid. The cinnamic
aldehyde (0.48 mL, 3.8 mmol) was added, and the mixture was
stirred for 1 h. The product precipitated after the addition of
30 mL of H2O, was filtered off, and was dried over P2O5. Yield,
91%. H NMR: 3.34 (s, 3H, CH3), 6.97 (s, 2H, NH2), 6.98 (m,
1H, CdCH), 7.20-7.55 (m, 6H, ar + CdCH), 9.47 (1H, Nd
CH), 10.71 (s, 1H, NH).
3-Ben zyl-7-m eth yl-8-p h en ylxa n th in e (9). Pyrimidine de-
rivative 6b (5.26 g, 15 mmol) was suspended in a mixture of
26 mL of 2 N NaOH and 8 mL of EtOH. The suspension was
refluxed for 1 h, then cooled to 4 °C, and diluted with 34 mL
of H2O. The solution was acidified to pH 5 by the addition of
acetic acid. The precipitated product was collected by filtration
and purified by recrystallization from H2O:EtOH (50:50). Yield,
85%. 1H NMR: δ 3.97 (s, 3H, CH3), 7.20-7.40 (m, 5H, ar),
7.45-7.60 (m, 3H, ar), 7.70-7.9 (m, 2H, ar).
was stirred for 8 h at room temperature. Excess SOCl2 was
removed by vacuum distillation. To the residue, saturated
aqueous NaHCO3 solution was added. The product was col-
1
lected by filtration. Yield, 80%. H NMR: δ 3.41 (s, 3H, CH3),
7.03 (d, 1H, CdCH), (7.30-7.70 (m, 6H, ar + CdCH), 11.12
(s, 1H, NH), 13.55 (s, 1H, NH).
3,7-Dim eth yl-8-styr ylxa n th in e (11h ). Compound 6a (0.54
g, 1.8 mmol) was dissolved in a mixture of 4 mL of EtOH and
2 mL of 2 N NaOH. The solution was refluxed for 2 h. After it
was cooled to room temperature, concentrated HCl solution
was added until a pH value of 4 was achieved. The precipitate
was collected by filtration and subsequently purified by
recrystallization from H2O:EtOH (50:50). Yield, 88%. 1H
NMR: δ 3.35 (s, 3H, CH3), 3.85 (s, 3H, CH3), 6.74 (d, 1H, Cd
CH), 7.35-7.85 (m, 6H, ar + CdCH), 11.10 (s, 1H, NH).
6-Th ioxa n th in es (12a -h ). Gen er a l P r oced u r e. A mix-
ture of xanthine 10a -h (55.4 mmol) and phosphorus penta-
sulfide (20 g, 90 mmol) in 200 mL of dry pyridine was refluxed
for 8 h. After the mixture was cooled to room temperature,
400 mL of H2O was added over a period of 2 h. The solution
was reduced in vacuo to one-third of its volume. The precipitate
was collected by filtration and suspended in 100 mL of 2 N
NaOH. The solution was filtered, and the product was pre-
cipitated by adding dilute HCl solution to achieve a pH value
of 4 and collected by filtration. The product can be purified by
recrystallization from EtOH in the presence of charcoal. 1H
NMR: 12d δ 3.49 (s, 3H, CH3), 7.40-7.60 (m, 3H, ar), 8.10-
8.30 (m, 2H, ar).
1
3-Ben zyl-7-m et h ylxa n t h in e (10). 6-Amino-1-benzyl-5-
methylaminouracil 5a (1.0 g, 4 mmol) was suspended in
triethylorthoformate (20 mL) and refluxed for 12 h. After the
mixture was cooled to room temperature, the formed precipi-
tate was filtered off and purified by recrystallization from H2O:
1
EtOH (50:50). Yield, 91%. H NMR: δ 3.85 (s, 3H, CH3), 5.09
(s, 2H, CH2), 7.10-7.35 (m, 5H, ar), 7.97 (s, 1H, CH), 11.22 (s,
1H, NH).
3-Ben zylxa n th in e (11b). 1-Benzyl-5,6-diaminouracil 7a
(6.5 g, 28 mmol) was suspended in 130 mL of triethylortho-
formate and refluxed for 8 h. After the mixture was cooled to
room temperature, the precipitate was collected by filtration
and subsequently recrystallized from H2O:MeOH (50:50).
6-Meth ylsu lfa n ylxa n th in es (13a -h ). Gen er a l P r oce-
d u r e. 6-Thioxanthine 12a -h (5 mmol) was suspended in 12.5
mL of 0.5 N NaOH. EtOH (ca. 5 mL) was added until a clear
solution was obtained. At room temperature, 7.1-20 mmol
(0.44-1.25 mL) of CH3I was added slowly. After it was stirred
for 1 h, the product was collected by filtration, washed with
H2O (10 mL), and recrystallized from H2O or a mixture of H2O:
1
Yield, 90%. H NMR: δ 5.14 (s, 2H, CH2), 7.20-7.40 (m, 5H,
ar), 8.03 (s, 1H, CH), 11.21 (s, 1H, NH), 13.45 (s, 1H, NH).
7-Meth ylxa n th in e (11c). 3-Benzyl-7-methylxanthine (10,
1.54 g, 6 mmol) and dry AlCl3 (1.6 g, 12 mmol) were suspended
in 6 mL of dry toluene. The mixture was stirred for 1 h at 70
°C. After it was cooled to room temperature, 30 mL of ice-cold
H2O was added over a period of 3 h. After it was stirred for 2
h, the precipitate was collected by filtration and dried at 80
°C. Yield, 75%. 1H NMR: δ 3.83 (s, 3H, CH3), 7.90 (s, 1H, CH),
10.86 (s, 1H, NH), 11.53 (s, 1H, NH).
1
EtOH (50:50). H NMR: 13d δ 2.66 (s, 3H, CH3), 3.55 (s, 3H,
CH3), 7.50-7.60 (m, 3H, ar), 8.10-8.30(m, 2H, ar).
6-(Hyd r oxya lk yla m in o)xa n th in es (14a -o). 6-Methyl-
sulfanylxanthine 13a -h (1 mmol) and 5 mmol of the appropri-
ate amino alcohol in 1 mL of DMSO was heated for 1 h at 150
°C. The solvent and the excess amount of alcohol were removed
in vacuo. The workup was done using four different methods:
The residue was recrystallized from EtOH (method A); prior
to recrystallization, the residue was purified by dry column
flash chromatography as previously described29 (method B);
or the residue was column chromatographed with CHCl3:
methanol (gradient from 9:1 to 3:1) (method D). A fourth
method was dissolution of the residue in methanol and
acidification to a pH value of ca. 3 by adding concentrated HCl
solution. The precipitate was then collected by filtration and
3-Meth yl-8-p h en ylxa n th in e (11d ). A suspension of 6-ami-
no-1-methyl-5-nitrosouracil (4b, 8.5 g, 35.1 mmol) and benzyl-
amine hydrochloride (8 g, 55.7 mmol) in 20 mL of benzylamine
was heated at 170 °C for 3 h. After it was cooled to room
temperature, the suspension was diluted with 40 mL of EtOH.
The precipitate was filtered off, suspended in 40 mL of H2O,
and stirred for 2 h. The white precipitate was collected by
filtration and subsequently recrystallized from acetic acid. The
collected product was washed with a large amount of H2O (ca.
1
recrystallized from EtOH (method C). H NMR: R-14i δ 0.95
1
200 mL) and dried at 110 °C. Yield, 46%. H NMR: δ 3.48 (s,
(t, 3H, CH3), 1.52.1,71 (m, 2H, CH2), 3.35-3.65 (m, 3H, CH2-
CH), 3.52 (s, 3H, CH3), 4.2 (vbr, 1H, OH), 7.50-7.70 (m, 3H,
ar) 8.05-8.25 (m, 2H, ar), 10.08 (d, 1H, NH).
3H, CH3), 7.40-8.20 (m, 5H, ar).
7-Meth yl-8-p h en ylxa n th in e (11e). 3-Benzyl-7-methyl-8-
phenylxanthine (9, 3.32 g, 10 mmol) was dissolved in 100 mL
of dry toluene, BBr3 (10 g, 40 mmol) was added, and the
mixture was stirred at 80 °C for 2 h. After the mixture was
cooled to room temperature, 30 mL of ice-cold H2O was added
over a period of 1 h. The mixture was stirred for 2 h. The
product was collected by filtration and purified by recrystal-
Tr icyclic P u r in on e Der iva t ives (15-30). 1-Methyl-
4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-9-ium-5-one chloride
(15), 4-benzyl-1-methyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]-
purin-9-ium-5-one chloride (16), 1,4-dimethyl-4,5,7,8-tetrahy-
dro-1H-imidazo[2,1-i]purin-9-ium-5-on chloride (17), 1,4,8-
trimethyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-9-
ium-5-one chloride (R-18), 1,4,8-trimethyl-(8S)-4,5,7,8-tetra-
hydro-1H-imidazo[2,1-i]purin-9-ium-5-one chloride (S-18), 8-eth-
yl-1,4-dimethyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-9-
ium-5-one chloride (RS-19), 8-ethyl-1,4-dimethyl-(8-R)-4,5,7,8-
tetrahydro-1H-imidazo[2,1-i]purin-9-ium-5-one chloride (R-19),
8-ethyl-1,4-dimethyl-(8-S)-4,5,7,8-tetrahydro-1H-imidazo[2,1-
i]purin-9-ium-5-one chloride (S-19), 1,4,7-trimethyl-4,5,7,8-
tetrahydro-1H-imidazo[2,1-i]purin-9-ium-5-one chloride (RS-
20), 1,4,7-trimethyl-(7R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-
i]purin-9-ium-5-one chloride (R-20), 1,4,7-trimethyl-(7S)-4,5,7,8-
tetrahydro-1H-imidazo[2,1-i]purin-9-ium-5-one chloride (S-20),
1-methyl-2-phenyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-
9-ium-5-one chloride (21), 1,4-dimethyl-2-phenyl-4,5,7,8-tet-
rahydro-1H-imidazo[2,1-i]purin-9-ium-5-one chloride (22), 8-eth-
1
lization from H2O. Yield, 80%. H NMR: δ 3.94 (s, 3H, CH3),
7.40-7.60 (m, 3H, ar), 7.70-7.90 (m, 2H, ar), 10.90 (s, 1H,
NH), 11.60 (s, 1H, NH).
3,7-Dim eth yl-8-ph en ylxan th in e (11f). Compound 6c (1.65
g, 6 mmol) was suspended in 13 mL of 2 N NaOH and 4 mL
of EtOH and refluxed for 1 h. The mixture was cooled to 4 °C
and diluted with 17 mL of H2O. Acetic acid was added until
the product precipitated. The solid was collected by filtration
and washed with 20 mL of H2O. The product could be
recrystallized from acetic acid. Yield, 85%. 1H NMR: δ 3.39
(s, 3H, CH3), 3.97 (s, 3H, CH3), 7.44-7.83 (m, 5H, ar), 11.16
(s, 1H, NH).
3-Meth yl-8-styr ylxa n th in e (11g). Compound 8 (9.46 g, 35
mmol) was dissolved in 50 mL of thionyl chloride. The solution