374
Vol. 55, No. 3
tion of iminoesters 5, into amidines 6, was achieved by following literature
5-(2-Amino-5-chlorophenyl)-3-(3,4-dimethoxyphenyl)-1H-1,2,4-tria-
1
procedures.17) Melting points were measured in a Reicher Kofler Thermopan zole (3h) White solid, mp 212—214 °C, from toluene. H-NMR (DMSO-
and are uncorrected. Infrared spectra were recorded in a Perkin-Elmer 1640 d6) d: 14.5 (1H, D2O exch., br s, NH), 7.94 (1H, d, Jꢀ7.9 Hz), 7.67—7.66
1
FTIR spectrophotometer. The H- and 13C-NMR spectra were recorded in a (2H, m), 7.13—7.08 (2H, m), 6.82 (1H, d, Jꢀ8.7 Hz), 6.74 (2H D2O exch.,
Bruker AMX 300 spectrometer at 300 and 74 MHz, respectively, using TMS s, NH2), 3.86 (3H, s, CH3), 3.82 (3H, s, CH3). Anal. Calcd for
as internal standard (chemical shifts in d values, J in Hz). Mass spectra were C18H15ClN4O2: C, 58.10; H, 4.57; N, 16.94. Found: C, 58.40; H, 4.35; N,
recorded on a Kratos MS-59 spectrometer. Microanalyses were performed in 17.12.
a Perkin-Elmer 240B Elemental Analyser at the Microanalyses Service of
Production of Triazoloquinazolines 4(a—h). General Procedure12)
the University of Santiago; all results shown were within ꢁ0.4% of the theo-
1.6 ml of 50% (w/w) aqueous cyanamide (1.7 mmol) was added to a slurry
retical values. All air-sensitive reactions were carried out under argon. Flash of the [1,2,4]triazole (1 mmol) in 2-propanol (5 ml), then 133 mg of 47%
chromatography was performed on silica gel (Merck 60, 230—240 mesh)
and analytical TLC on pre-coated silica gel plates (Merck 60 F254, 0.25 mm).
(w/w) aqueous sulphuric acid were added. The mixture was heated to reflux
for 6 h, cooled to room temperature, and neutralized till the pH 7 by addition
Binding competition assays at A2A and A2B receptors were performed of 10% aqueous sodium hydroxide; after leaving overnight the mixture at
in vitro at human A2A and A2B receptors transfected in HeLa and HEK-293 5 °C, the separated product was collected, washed with cold ethanol and
cells, respectively, as previously described.19)
dried.
5-Amino-9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazoline (4a)
Physical and spectroscopic data were consistent with data in the existing lit-
Production of Triazoles 3a—h. General procedure12) Sodium methox-
ide (1.1 mmol) dissolved in absolute ethanol (2.5 ml) was added to a solution
of amidine hydrochloride (1 mmol) in absolute ethanol (3 ml). The mixture erature.12,14)
was stirred for 10 min under argon, then it was filtered, and the filtrate was
5-Amino-8-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazoline (4b)
added to a solution of the hydrazide 2 (1.1 mmol) in chlorobenzene (5 ml) White solid, mp 275—277 °C, 1H-NMR (DMSO-d6) d: 8.07 (1H, d, Jꢀ
and absolute ethanol (3 ml), kept at 70 °C, in an flask fitted with a Dean-
0.7 Hz, 7-H), 8.55 (1H, d, Jꢀ8.6 Hz, 10-H), 7.54 (1H, d, Jꢀ3.5 Hz, 5-Hfuryl),
Stark trap. Bath temperature was raised to 110 °C over 1 h and thereafter to 6.98 (3H two D2O exch., br s, NH2ꢂHfuryl), 6.82—6.81 (1H, m, Hfuryl), 6.72
130 °C. Once distillation ceased, the water separator was removed, and a (1H, dd, Jꢀ8.5, 1.3 Hz, 9-H). 13C-NMR (DMSO-d6) d: 163.12, 155.92,
compensating addition funnel containing 4-A molecular sieves was inserted 149.05, 147.41, 138.38, 137.01, 129.82, 115.93, 115.25, 115.15, 113.06,
between the flask and the condenser. More chlorobenzene (2.5 ml) was 102.51. MS m/z: 263 (21), 261 (63), 204 (13), 156 (33), 154 (100), 126 (16),
added, and the mixture was heated overnight at reflux under argon. The mix- 95 (18), 84 (17), 66 (19). Anal. Calcd for C13H8ClN5O: C, 54.65; H, 2.82; N,
ture was filtered while hot, and the filtrate was cooled, left at 5 °C for 24 h, 24.51. Found: C, 54.52; H, 3.03; N, 24.33.
and the separated solid was collected by filtration.
5-Amino-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazoline (4c) White solid,
5-(2-Amino-5-chlorophenyl)-3-(2-furyl)-1H-1,2,4-triazole (3a) Physi- mp 280—283 °C, from EtOH (lit. 282—285 °C).12,14) 1H-NMR (DMSO-d6)
cal and spectroscopic data were consistent with data in the existing litera- d: 8.22 (1H, dd, Jꢀ7.9, 1.0 Hz, 7-H), 7.91 (1H, d, Jꢀ1.1 Hz, 5-Hfuryl), 7.86
ture.12)
(2H, br s, D2O exch., NH2), 7.72—7.67 (1H, m, 10-H), 7.56 (1H, d, Jꢀ
8.2 Hz, 8-H), 7.42—7.36 (1H, m, 9-H), 7.27 (1H, d, Jꢀ3.0 Hz, Hfuryl), 6.73
5-(2-Amino-4-chlorophenyl)-3-(2-furyl)-1H-1,2,4-triazole (3b) White
1
solid, mp 249—251 °C, from toluene. H-NMR (DMSO-d6) d: 8.07 (1H, s, (1H, dd, Jꢀ3.3, 1.8 Hz, Hfuryl). 13C-NMR (DMSO-d6) d: 155.86, 152.09,
5-Hfuryl), 7.74 (1H, d, Jꢀ8.5 Hz, Hphenyl), 7.45 (1H, d, Jꢀ3.3 Hz, Hfuryl), 6.98 145.80, 145.52, 145.45, 145.02, 132.61, 125.26, 123.74, 123.49, 113.47,
(3H, br s, two D2O exch., NH2ꢂ3Hphenyl), 6.81 (1H, dd, Jꢀ3.5, 1.7 Hz, 112.54. MS m/z: 253 (17), 252 (67), 251 (100), 145 (10), 108 (11), 84 (11),
Hfuryl), 6.71 (1H, dd, Jꢀ8.5, 2.0 Hz, 6Hphenyl). Anal. Calcd for C12H8ClN4O: 66 (11).
C, 55.29; H, 3.48; N, 21.49. Found: C, 55.52; H, 3.33; N, 21.33.
5-Amino-2-(2-furyl)benzo[g][1,2,4]triazolo[1,5-c]quinazoline (4d)
5-(2-Aminophenyl)-3-(2-furyl)-1H-1,2,4-triazole (3c) White solid, mp White solid, mp 309—311 °C, from AcOEt/MeOH. IR (KBr) cmꢃ1: 3364,
234—236 °C, from toluene, (lit. 210—212 °C, from ethanol).14) 1H-NMR 1694, 1582, 1583, 1109, 759. 1H-NMR (DMSO-d6) d: 8.91 (1H, s, 7-H),
(DMSO-d6) d: 9.43 (1H, br s, D2O exch., NH), 7.82 (1H, d, Jꢀ8.20 Hz, 8.15 (1H, d, Jꢀ8.3 Hz, Harom), 8.05 (1H, s, 12-H), 8.00 (1H, d, Jꢀ8.4 Hz,
Hphenyl), 7.72 (1H, s, 5-Hfuryl), 7.19 (1H, d, Jꢀ8.1 Hz, Hphenyl), 7.10 (1H, d, Harom), 7.94 (1H, d, Jꢀ0.7 Hz, 5-Hfuryl), 7.60—7.55 (1H, m, Harom), 7.50 (1H,
Jꢀ3.3 Hz, Hfuryl), 6.88 (1H, d, Jꢀ8.1 Hz, Hphenyl), 6.75 (1H, dd, Jꢀ8.0, 7.2
Hz, Hphenyl), 6.65 (1H, dd, Jꢀ3.3, 1.8 Hz, Hfuryl).
d, Jꢀ7.6 Hz, Harom), 7.29 (1H, d, Jꢀ3.4 Hz, Hfuryl), 6.75 (1H, dd, Jꢀ3.3,
1.7 Hz, Hfuryl). 13C-NMR (DMSO-d6) d: 163.42, 155.77, 149.45, 147.66,
5-(3-Amino-2-naphtyl)-3-(2-furyl)-1H-1,2,4-triazole (3d) White solid, 139.18, 137.76, 130.07, 116.17, 115.50, 115.40, 113.30, 103.39. MS m/z:
mp 232—234 °C. IR (KBr) cmꢃ1: 3468, 3372, 3040, 1630, 1607, 1223,
301 (100), 272 (5), 194 (20), 167 (6), 140 (12), 108 (8), 63 (3). Anal. Calcd
1051, 743. 1H-NMR (DMSO-d6) d: 14.3 (1H, br s, D2O exch., NH), 8.05 for C17H11N5O: C, 67.77; H, 3.68; N, 23.24. Found: C, 67.92; H, 3.86; N,
(1H, s, 5-Hfuryl), 7.90 (1H, s), 7.73 (1H, d, Jꢀ8.1 Hz), 7.54 (1H, d, Jꢀ 23.54.
8.3 Hz), 7.33 (1H, t, Jꢀ7.5 Hz,), 7.23—7.11 (3H, m), 6.70 (3H two D2O
5-Amino-9-chloro-2-(2-pyridyl)[1,2,4]triazolo[1,5-c]quinazoline (4e)
exch., m, NH2). MS m/z: 277 (20), 276 (100), 219 (7), 168 (14), 154 (8), 140 White solid, mp 207—209 °C, from AcOEt. IR (KBr) cmꢃ1: 3362, 1654,
(8), 128 (6), 127 (6), 66 (6). Anal. Calcd for C18H12N4O: C, 69.55, H, 4.36; 1616, 1558, 1508, 1108, 61. 1H-NMR (DMSO-d6) d: 8.69 (1H, d, Jꢀ4.2 Hz,
N, 20.26. Found: C, 69.52; H, 4.66; N, 20.33.
5-(2-Amino-5-chlorophenyl)-3-(2-pyridyl)-1H-1,2,4-triazole (3e) White
6-Hpyr), 8.15 (1H, d, Jꢀ2.4 Hz), 8.02 (1H, dd, Jꢀ7.7, 1.7 Hz), 7.99—7.85
(m, 2H), 7.77 (1H, d, Jꢀ8.7 Hz), 7.59—7.55 (m, 1H), 6.12 (2H D2O exch.,
s, NH2). 13C-NMR (DMSO-d6) d: 162.73, 159.52, 153.34, 153.02, 148.91,
solid, mp 233—235 °C, from toluene (lit. 207—209 °C).15) IR (KBr) cmꢃ1
:
3265, 1684, 1651, 1604, 1481, 808. 1H-NMR (DMSO-d6) d: 10.34 (1H, D2O 145.50, 137.58, 135.03, 132.08, 130.45, 125.50, 125.38, 124.98, 122.02.
exch., s, NH), 8.95 (1H, D2O exch., s, NH), 8.65 (1H, d, Jꢀ5.0 Hz, 6-Hpyr), Anal. Calcd for C14H9ClN6O: C, 56.67; H, 3.06; N, 28.32. Found: C, 56.60;
8.00 (1H, d, Jꢀ7.9 Hz, Hpyr), 7.95—7.93 (1H, m), 7.65 (d, 1H, Jꢀ2.5 Hz),
7.56—7.52 (1H, m), 7.44 (1H, dd, Jꢀ8.7, 2.6 Hz, 4-Hphenyl), 7.17 (1H, d, Jꢀ
H, 3.12; N, 28.11.
5-Amino-9-chloro-2-(2-thienyl)[1,2,4]triazolo[1,5-c]quinazoline (4f)
8.7 Hz). 13C-NMR (DMSO-d6) d: 165.85, 149.57, 149.21, 148.55, 144.56, White solid, mp 290—292 °C, from toluene. H-NMR (DMSO-d6) d: 8.16
138.11, 134.25, 131.26, 126.10, 125.86, 123.15, 121.83, 121.73. MS m/z: (1H, d, Jꢀ2.5 Hz, Harom), 7.94 (2H D2O exch., s, NH2), 7.90 (1H, d, Jꢀ
272 (100), 271 (26), 245 (30), 243 (90), 215 (13), 179 (17), 105(27), 79 3.6 Hz, 5-Hthienyl), 7.80 (1H, d, Jꢀ5.0 Hz, 3 Hthienyl), 7.68 (1H, dd, Jꢀ8.9,
1
(15), 78 (37), 75 (15).
5-(2-Amino-5-chlorophenyl)-3-(2-thienyl)-1H-1,2,4-triazole (3f) White
2.6 Hz, Harom), 7.55 (1H, d, Jꢀ8.9 Hz, Harom), 7.26 (1H, dd, Jꢀ4.8, 3.8 Hz, 4-
Hthienyl). 13C-NMR (DMSO-d6) d: 158.84, 150.96, 144.82, 143.81, 132.44,
solid, mp 252—255 °C, from cyclohexane. 1H-NMR (DMSO-d6) d: 14.2 132.25, 129.46, 128.48, 128.40, 126.98, 126.87, 122.20, 114.06. MS m/z:
(1H, D2O exch., br s, NH), 8.04 (1H, dd, Jꢀ3.6, 1.1 Hz, 5-Hthienyl), 7.96 (1H, 301 (100), 300 (85), 178 (14), 151 (8), 137 (10), 124 (41), 102 (12), 97 (12),
dd, Jꢀ4.9, 1.2 Hz, Hthienyl), 7.80 (1H, d, Jꢀ2.4 Hz, Hthienyl), 7.33—7.28 (2H, 84 (46), 78 (11), 69 (12). Anal. Calcd for C13H8ClN5S: C, 51.75; H, 2.67; N,
m,
H
phenylꢂNHH), 6.94 (1H, d, Jꢀ8.94 Hz, Hphenyl), 6.89 (2H, br s,
23.21. Found: C, 51.54; H, 2.69; N, 23.38.
H
aromꢂNHH). Anal. Calcd for C12H9ClN4O: C, 52.08; H, 3.26; N, 20.25.
5-Amino-9-chloro-2-phenyl-[1,2,4]triazolo[1,5-c]quinazoline (4g)
White solid, mp 296—298 °C, from toluene. (lit. 295—297 °C).14) 1H-NMR
(DMSO-d6) d: 8.29—8.26 (2H, m), 8.20 (1H, d, Jꢀ2.4 Hz), 8.00 (2H, D2O
Found: C, 52.52; H, 3.03; N, 20.43.
5-(2-Amino-5-chlorophenyl)-3-phenyl-1H-1,2,4-triazole (3g) White
solid, mp 254—256 °C, from toluene. (lit. 257—258 °C).15) 1H-NMR exch., s, NH2), 7.70 (1H, dd, Jꢀ8.9, 2.6 Hz), 7.59—7.56 (4H, m). 13C-NMR
(DMSO-d6) d: 14.5 (1H, br s, NH), 8.07 (2H, d, Jꢀ6.9 Hz), 7.91 (1H, s),
7.52 (3H one D2O exch., m, NHH), 7.16 (1H, d, Jꢀ7.1 Hz), 6.85 (3H one
D2O exch., m, NHH).
(DMSO-d6) d: 162.61, 151.01, 144.96, 143.72, 132.14, 130.60, 129.87,
128.99, 127.03, 126.87, 122.18, 114.33. MS m/z: 296 (80), 295 (100), 178
(8), 148 (8), 147 (10), 137 (10), 130 (13), 129 (13), 118 (17), 103 (15), 91