1644
I. Giorgi et al. / European Journal of Medicinal Chemistry 43 (2008) 1639e1647
A2A receptors, while others possess noncompetitive enhancer
properties, that could be accounted for by a mechanism of al-
losteric modulation. In particular, the hypothesis of such a pos-
sible pharmacodynamic property seems to be well supported
by the evidence deriving from the functional tests, which
showed that the A2A-mediated pharmacological effects of
CGS21680 were significantly improved by compound 14.
the precipitate was filtered off and crystallized from methanol
to give 13 as a white solid, 43 mg, 66% yield; m.p. >300 ꢁC.
1
Anal. C30H24N8O (C, H, N); H NMR: 10.88 (s, 1H, Exch),
8.70 (m, 2H, Exch), 8.44 (m, 2H, Arom), 7.90 (m, 2H,
Arom) 7.55e7.24 (m, 14H, Arom), 7.00 (t, J ¼ 7.4 Hz, 1H,
Arom) 5.89 (s, 2H, CH2) d, ppm. IR (cmꢂ1): 3390 (NH),
3375 (NH), 3322 (NH), 1678 (C]O). MS: m/z 512 [Mþ].
TLC: Rf ¼ 0.32 (CHCl3/CH3COOEt 8:2).
7. Experimental
7.1.4. 1-[4-(3-Benzyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ylamino)-phenyl]-3-(4-fluorophenyl)-urea (14)
Compound 14 was prepared by reaction of 12 (50 mg,
0.127 mmol) and 4-fluorophenyl isocyanate (87 mg,
0.635 mmol), following the procedure described for 13. By
crystallization from ethyl acetate the title compound was ob-
tained as a white solid, 21 mg, 32% yield; m.p. >300 ꢁC.
Anal. C30H23FN8O (C, H, N); 1H NMR: 10.88 (s, 1H,
Exch), 8.73 (s, 1H, Exch), 8.70 (s, 1H, Exch), 8.42 (m, 2H,
Arom), 7.92 (m, 2H, Arom), 7.54e7.08 (m, 14H, Arom),
5.89 (s, 2H, CH2) d, ppm. IR (cmꢂ1): 3391 (NH), 3379
(NH), 3315 (NH), 1671 (C]O). MS: m/z 530 [Mþ]. TLC:
Rf ¼ 0.32 (CHCl3/CH3COOEt 8:2).
7.1. Chemistry
Melting points were determined on a Kofler hot-stage appa-
ratus and are uncorrected. IR spectra in Nujol mulls were re-
1
corded on a Mattson Genesis series FTIR spectrometer. H
NMR spectra were recorded on a Bruker AC 200 spectrometer
in d units from TMS as an internal standard; the compounds
were dissolved in DMSO-d6. Mass spectra data were obtained
with a HewlettePackard GC/MS system 5988. TLC was per-
formed on precoated silica gel F254 plates (Merck). Microanal-
yses (C H N) were carried out on a Carlo Erba elemental
analyser (Model 1106) and were within ꢀ0.4% of the theoret-
ical values.
7.1.5. 1-[4-(3-Benzyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ylamino)-phenyl]-3-(4-trifluoromethylphenyl)-
urea (15)
7.1.1. (3-Benzyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-yl)-(4-nitrophenyl)-amine (11)
A solution of 6-chloro-9-benzyl-2-phenyl-8-azapurine 4
[11] (2.0 g, 6.2 mmol) and p-nitroaniline (2.6 g, 18.6 mmol)
in absolute ethanol (30 ml) was heated in a well stopped flask
at 85 ꢁC for 48 h. After cooling, the precipitate was filtered off
and crystallized from ethanol to give 11 as a yellow solid,
1.52 g, 58% yield; m.p. 263e264 ꢁC. Anal. C23H17N7O2 (C,
Compound 15 was prepared by reaction of 12 (50 mg,
isocyanate
0.127 mmol)
and
4-trifluoromethylphenyl
(118 mg, 0.635 mmol), following the procedure described
for 13. By crystallization from ethyl acetate the title com-
pound was obtained as a white solid, 35 mg, 48% yield;
m.p. >300 ꢁC. Anal. C31H23F3N8O (C, H, N); 1H NMR:
10.90 (s, 1H, Exch), 9.16 (s, 1H, Exch), 8.87 (s, 1H, Exch),
8.43 (m, 2H, Arom), 7.95e7.31 (m, 16H, Arom), 5.89 (s,
2H, CH2) d, ppm. IR (cmꢂ1): 3395 (NH), 3311 (NH), 1676
(C]O). MS: m/z 580 [Mþ]. TLC: Rf ¼ 0.32 (CHCl3/
CH3COOEt 8:2).
1
H, N); H NMR: 11.61 (s, 1H, Exch), 8.46e8.34 (m, 6H,
Arom), 7.59e7.35 (m, 8H, Arom), 5.93 (s, 2H, CH2) d,
ppm. IR (cmꢂ1): 3337 (NH). MS: m/z 423 [Mþ]. TLC:
Rf ¼ 0.13 (CHCl3).
7.1.2. N-(3-Benzyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7yl-)-(4-aminophenyl)-amine (12)
7.1.6. 1-[4-(3-Benzyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ylamino)-phenyl]-3-(4-methoxyphenyl)-
urea (16)
A solution of compound 11 (150 mg, 0.33 mmol) in abso-
lute ethanol (125 ml) was stirred under hydrogen atmosphere
in the presence of 5% Pd/C (150 mg) for 12 h at room temper-
ature and pressure. The catalyst was removed by filtration, and
the filtrate evaporated under reduced pressure to give 12,
124 mg, 95% yield; m.p. 257e259 ꢁC. Anal. C23H19N7 (C,
Compound 16 was prepared by reaction of 12 (50 mg,
0.127 mmol) and 4-methoxyphenyl isocyanate (95 mg,
0.635 mmol), following the procedure described for 13. By
crystallization from ethyl acetate the title compound was ob-
tained as a white solid, 25 mg, 37% yield; m.p. 270 ꢁC.
1
H, N); H NMR: 10.59 (s, 1H, Exch), 8.39 (m, 2H, Arom),
1
7.59e7.30 (m, 10H, Arom), 6.64 (d, J ¼ 8.4 Hz, 2H, Arom),
5.86 (s, 2H, CH2), 5.09 (br s, 2H, Exch) d, ppm. IR (cmꢂ1):
3404 (NH), 3325 (NH), 3183 (NH). MS: m/z 393 [Mþ].
TLC: Rf ¼ 0.30 (CHCl3/CH3OH 9.8:0.2).
Anal. C31H26N8O2 (C, H, N); H NMR: 10.87 (s, 1H, Exch),
8.70 (s, 1H, Exch), 8.58 (s, 1H, Exch), 8.43 (m, 2H, Arom),
7.87 (m, 4H, Arom), 7.54e7.30 (m, 8H, Arom), 6.88 (m,
4H, Arom), 5.89 (s, 2H, CH2), 3.71 (s, 3H, CH3) d, ppm. IR
(cmꢂ1): 3390 (NH), 3319 (NH), 3273 (NH), 1645 (C]O).
MS: m/z 542 [Mþ]. TLC: Rf ¼ 0.39 (CHCl3/CH3COOEt 8:2).
7.1.3. {1-[4-(3-Benzyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]-
pyrimidin-7-ylamino)-phenyl]-3-phenyl}-urea (13)
To a solution of 12 (50 mg, 0.127 mmol) and 0.1 ml of N,N-
diethylaniline in anhydrous acetonitrile (15 ml), phenyl isocy-
anate (75 mg, 0.635 mmol) was added and the solution stirred
at reflux for 12 h under nitrogen atmosphere. After cooling,
7.1.7. N6-[(4-Nitro)-phenyl]-9-benzyl-2-phenyladenine (17)
A solution of 9-benzyl-6-chloro-2-phenylpurine 10 [12]
(2.0 g, 6.2 mmol) and p-nitroaniline (2.6 g, 18.6 mmol) in ab-
solute ethanol (30 ml) was heated in a well stopped flask at