JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
257
(
1
8
t, 1H, ar, J ¼ 7.3 Hz), 7.23 (t, 2H, ar, J ¼ 7.6 Hz), 7.41–7.45 (m, 3H, 7-Amino-5-[2–(4-methoxyphenyl)ethyl]amino-2-phenyl-2H-pyra-
ar þ NH ), 7.58 (t, 2H, ar, J ¼ 7.6 Hz), 7.90 (d, 2H, ar, J ¼ 8.5 Hz), zolo[4,3-d]pyrimidine 11 Purified by column chromatography
2
ꢀ
.03 (d, 2H, ar, J ¼ 8.5 Hz), 8.74 (s, 1H, H-3), 8.76 (br s, 1H, NH). (cyclohexane/EtOAc/MeOH 6:4:1), Yield 58%; m.p. 142–145 C
1
Anal. Calc. for C H N .
(cyclohexane/EtOAc).
H NMR (DMSO-d6) 2.73 (t, 2H, CH2,
1
7 14 6
J ¼ 7.3 Hz), 3.38–3.41 (m, 2H, CH ), 3.73 (s, 3H, OCH ), 6.03 (br s,
2
3
7
-Amino-5-(4-methoxyphenyl)amino-2-phenyl-2H-pyrazolo[4,3-
1H, NH), 6.69 (d, 2H, ar, J ¼ 8.9 Hz), 7.04 (d, 2H, ar, J ¼ 8.9 Hz), 7.22
ꢀ
d]pyrimidine 2 Yield 62%; m.p. 253–255 C (cyclohexane/EtOAc); (br s, 2H, NH ), 7.41 (t, 1H, ar, J ¼ 7.3 Hz), 7.57 (t, 2H, ar, J ¼ 7.6 Hz),
2
1
H NMR (DMSO-d
6
) 3.82 (s, 3H, OCH
3
), 6.84 (d¸ 2H, ar, J ¼ 8.9 Hz), 7.98 (d, 2H, ar, J ¼ 7.9 Hz), 8.51 (s, 1H, H-3). Anal. Calc. for
7
.45–7.40 (m, 3H, 1 ar þ NH ), 7.58 (t, 2H, ar, J ¼ 7.7 Hz), 7.75 (d, 2H, C H N O.
2
20 20 6
J ¼ 8.9 Hz), 8.02 (d, 2H, ar, J ¼ 8.2 Hz), 8.57 (s, 1H, NH), 8.68 (s, 1H,
H-3). Anal. Calc. for C18 O.
16 6
H N
7-Amino-5-[2-(3,4-dimethoxyphenyl)ethyl]amino-2-phenyl-2H-pyra-
zolo[4,3-d]pyrimidine 12 Purified by preparative TLC (cyclohexane/
7
-Amino-5–(2,4-dichlorophenyl)amino-2-phenyl-2H-pyrazolo[4,3-
ꢀ
1
EtOAc/MeOH 6:4:1). Yield 45%; m.p. 100–102 C (H
NMR (DMSO-d ) 2.79 (t, 2H, CH
, J ¼ 7.2 Hz), 3.43–3.48 (m, 2H,
CH ), 3.72 (s, 3H, OCH ), 3.74 (s, 3H, OCH ), 6.10 (br s, 1H, NH),
2
O/MeOH). H
ꢀ
d]pyrimidine 3 Yield 58%; m.p. 251–252 C (cyclohexane/EtOAc);
6
2
1
H NMR (DMSO-d ) 7.40–7.48 (m, 3H, 2 ar þ NH), 7.54 (s, 1H, ar),
6
2
3
3
7
.53–7.61 (m, 2H, ar), 7.61–7.79 (br s, 2H, NH ), 8.02 (d, 2H,
2
6
.75 (d, 1H, ar, J ¼ 6.5 Hz), 6.84–6.87 (m, 2H, ar), 7.27 (br s, 2H,
NH
), 7.39 (t, 1H, ar, J ¼ 7.2 Hz), 7.56 (t, 2H, ar, J ¼ 7.7 Hz), 7.97 (d,
H, ar, J ¼ 7.8 Hz), 8.51 (s, 1H, H-3). Anal. Calc. for C H N O
J ¼ 7.9 Hz), 8.67 (d, 1H, J ¼ 8.9 Hz), 8.82 (s, 1H, H-3). Anal. Calc. for
2
17 2 6
C H12Cl N .
2
2
1 22 6 2.
7
-Amino-5-benzylamino-2-phenyl-2H-pyrazolo[4,3-d]pyrimidine
5
Purified by preparative TLC (Et O/cyclohexane/EtOAc 3:1:1). Yield General procedure for the synthesis of the pyrazolo[4,3-d]pyrimi-
2
ꢀ
1
6
4
0%; m.p. 143–145 C (cyclohexane/EtOAc). H NMR (DMSO-d
.49 (d, 2H, CH
6
)
dine-7-amine derivatives 4, 13 and 14
2
, J ¼ 6.3 Hz), 6.71 (t, 1H, NH, J ¼ 6.3 Hz), 7.18 (t, 1H, To a suspension of the methoxy-substituted pyrazolopyrimidine
ar, J ¼ 7.1 Hz), 7.26–7.34 (m, 6H, 4 ar þ NH ), 7.39 (t, 1H, ar, derivatives 2, 11 and 12 (1.02 mmol) in anhydrous CH Cl (20 mL),
2
2
2
J ¼ 7.4 Hz), 7.55 (t, 2H, ar, J ¼ 7.5 Hz), 7.95 (d, 2H, ar, J ¼ 7.6 Hz), a 1 M BBr
3
solution (2.60 mL for 2, 11 and 5.2 mL for 12) in CH
2
Cl
2
ꢀ
8
.48 (s, 1H, H-3). Anal. Calc. for C18
H N
16 6
.
was added at 0 C, under nitrogen atmosphere. The mixture was
stirred at room temperature for 20–24 h (compounds 4, 13) or
1
6 h (compound 14), then was diluted with water (10 mL) and
7
-Amino-5-(2-phenylethyl)amino-2-phenyl-2H-pyrazolo[4,3-d]pyr-
neutralized with NaHCO saturated solution. The organic solvent
was removed under reduced pressure and the obtained precipi-
tate was collected by filtration and recrystallized. The crude deriva-
tive 4 was first purified by column chromatography (eluent CHCl /
3
MeOH 9:1) and then recrystallized.
3
imidine 6 Purified by column chromatography (cyclohexane/
EtOAc/MeOH 6:4:1). Yield 65%; m.p. 168–171 C (cyclohexane/
EtOAc). H NMR (DMSO-d
ꢀ
1
6
) 2.86 (t, 2H, CH
2
, J ¼ 7.1 Hz), 3.45–3.50
(
(
m, 2H, CH ), 6.12 (br s, 1H, NH), 7.18–7.32 (m, 7H, 5 ar þ NH ), 7.39
2
2
t, 1H, ar, J ¼ 7.5 Hz), 7.56 (t, 2H, ar, J ¼ 7.5 Hz), 7.98 (d, 2H, ar,
J ¼ 7.7 Hz), 8.52 (s, 1H, H-3). Anal. Calc. for C19
18 6
H N .
7
-Amino-5-(4-hydroxyphenyl)amino-2-phenyl-2H-pyrazolo[4,3-
ꢀ
d]pyrimidine 4 Yield 67%; m.p. 223–225 C (EtOAc/cyclohexane);
1
7
-Amino-5-(3-phenylpropyl)-2-phenyl-2H-pyrazolo[4,3-d]pyrimi-
H NMR (DMSO-d ) 6.65 (d, 2H, ar, J¼ 8.8 Hz), 7.30–7.45 (m, 3H,
6
dines 7 Purified by column chromatography (eluent cyclohexane/ 2 ar þ NH ), 7.57 (t, 2H, ar, J ¼ 7.6 Hz), 7.63 (d, 2H, ar, J ¼ 8.8 Hz),
2
ꢀ
1
EtOAc/MeOH 6:4:1). Yield 58%; m.p. 159–162 C (EtOAc). H NMR 8.01 (d, 2H, ar, J¼ 8.3 Hz), 8.41 (s, 1H, NH), 8.65 (s, 1H, H-3), 8.85 (s,
(
(
(
DMSO-d ) 1.83–1.86 (m, 2H, CH ), 2.64 (t, 2H, CH , J ¼ 7.4 Hz), 3.27 1H, OH). Anal. Calc. for C17
H N O.
14 6
6
2
2
m, 2H, CH
2
), 6.20 (br s, 1H, NH), 7.19–7.30 (m, 7H, 5 ar þ NH
2
), 7.40
t, 1H, ar, J ¼ 9.0 Hz), 7.56 (t, 2H, ar, J ¼ 7.6 Hz), 7.97 (d, 2H, ar,
7
-Amino-5-(4-hydroxyphenethyl)amino-2-phenyl-2H-pyrazolo[4,3-
J ¼ 7.9 Hz), 8.50 (s, 1H, H-3). Anal. Calc. for C H N .
1
2
0
20
6
ꢀ
d]pyrimidine 13 Yield 89%; m.p. 241–244 C (EtOAc/EtOH). H NMR
(
(
DMSO-d
6
) 2.73 (t, 2H, CH
2
, J ¼ 7.3 Hz), 3.38–3.40 (m, 2H, CH
2
), 6.03
br s, 1H, NH), 6.68 (d, 2H, ar, J ¼ 8.3 Hz), 7.04 (d, 2H, ar, J ¼ 8.3 Hz),
7
-Amino-2-methyl-5-phenylamino-2H-pyrazolo[4,3-d]pyrimidine
8
ꢀ
1
7.22 (br s, 2H, NH ), 7.41 (t, 1H, ar, J ¼ 7.4 Hz), 7.56 (t, 2H, ar,
Yield 42%; m.p. 252–254 C (EtOH). H NMR (DMSO-d ) 4.05 (s, 3H,
2
6
J ¼ 7.7 Hz), 7.97 (d, 2H, ar, J ¼ 7.8 Hz), 8.51 (s, 1H, H-3), 9.14 (s, 1H,
Me), 6.84 (t, 1H, ar, J ¼ 7.2 Hz), 7.19–7.21 (m, 4H, 2 ar þ NH
d, 2H, ar, J ¼ 7.2 Hz), 7.87 (s, 1H, H-3), 8.62 (br s, 1H, NH). Anal.
Calc. for C H N .
2
), 7.75
18 6
OH). Anal. Calc. for C19H N O.
(
1
2 12 6
7
-Amino-5-(3,4-dihydroxyphenethyl)amino-2-phenyl-2H-pyra-
ꢀ
1
zolo[4,3-d]pyrimidine 14 Yield 50%; m.p. 242–243 C (EtOH).
NMR (DMSO-d ) 2.65 (t, 2H, CH
, J ¼ 7.1 Hz), 3.37–3.41 (m, 2H,
CH ), 6.03 (t, 1H, NH, J ¼ 5.8 Hz), 6.59–6.47 (d, 1H, ar, J ¼ 8.0 Hz),
H
7
-Amino-5-benzylamino-2-methyl-2H-pyrazolo[4,3-d]pyrimidine
9
ꢀ
1
6
2
Yield 80%; m.p. 213–214 C (EtOH); H NMR (DMSO-d ) 3.98 (s, 3H,
6
2
CH
2
1
3
), 4.45 (d, 2H, CH2, J ¼ 6.4 Hz), 6.47 (br s, 1H, NH), 7.05 (br s,
H, NH ), 7.16–7.32 (m, 5H, ar), 7.70 (s, 1H, H-3). IR: 3326, 3179,
658. Anal. Calc. For C H N .
6
.63–6.66 (m, 2H, ar), 7.23 (br s, 2H, NH
J ¼ 7.4 Hz), 7.56 (t, 2H, ar, J ¼ 7.6 Hz), 7.97 (d, 2H, ar, J ¼ 7.7 Hz),
.51 (s, 1H, H-3), 8.62 (br s, 1H, OH), 8.74 (br s, 1H, OH). Anal. Calc.
for C19
2
), 7.40 (t, 1H, ar,
2
1
3 14 6
8
18 6 2
H N O .
7
-Amino-2-benzyl-5-benzylamino-2H-pyrazolo[4,3-d]pyrimidine 10
ꢀ
1
Yield 40%; m.p. 174–175 C (cyclohexane/EtOAc). H NMR (DMSO-
) 4.45 (d, 2H, CH ), 6.58 (br s, 1H, Synthesis of 5,7-dichloro-2-phenyl-2H-pyrazolo[4,3-d]pyrimidine 55
, J ¼ 6.3 Hz), 5.45 (s, 2H, CH
NH), 7.11 (br s, 2H, NH ), 7.15–7.36 (m, 10H, ar), 7.87 (s, 1H, H-3). A suspension of the pyrazolopyrimidine-5,7-dione derivative 54
Anal. Calc. for C H N .
(2 mmol) and N,N-dimethylaniline (3.95 mmol) in phosphorus
d
6
2
2
2
0
2
1
9 18 6