2046
M. Tobe et al. / Bioorg. Med. Chem. 8 (2000) 2037±2047
J=8.6 Hz), 8.09±8.12 (2H, m), 12.25 (1H, brs); MS
+
6-Amino-3-methyl-5-[4-[(4-oxo-4H-1-benzopyran-2-phenyl-
7-yl)oxy]butanoyl-amino]-1-pꢀhenyluracil (24d). White
.
(TOF) m/z 325 (M+H) . Anal. calcd for C19H16O5
0.15H2O: C, 69.78; H, 5.02. Found: C, 69.79; H, 5.09.
1
solid (52.7%), mp 245±246 C; H NMR (DMSO-d6) d
2.01±2.12 (2H, m), 2.44±2.50 (2H, m), 3.13 (3H, s), 4.24
(2H, J=6.3 Hz), 5.95 (2H, s), 6.98 (1H, s), 7.07±7.11 (1H,
m), 7.33±7.38 (3H, m), 7.50±7.62 (6H, m), 7.92±7.97 (1H,
Compounds 19a±19c and 24a±24d were also prepared
by using the same procedure as for 1.
m), 8.09±8.12 (2H, m), 8.46 (1H, s); MS (TOF) m/z 539
+
.
(M+H) . Anal. calcd for C30H26N4O6 0.25H2O: C, 66.35;
H, 4.92; N, 10.32. Found: C, 66.35; H, 4.90; N, 10.35.
6-Amino-3-methyl-5-[2-[(2-oxo-2H-1-benzopyran-7-yl)oxy]
acetꢀylamino]-phenyluracil (19a). White solid (55.9%), mp
234 C (Dec.); 1H NMR (DMSO-d6) d 3.14 (3H, s), 4.75
(2H, s), 6.13 (2H, br s), 6.30 (1H, d, J=8.6Hz), 7.03±7.06
(2H, m), 7.32±7.35 (2H, m), 7.54±7.66 4H, m), 7.99 (1H, d,
J=8.6 Hz), 8.69 (1H, s); MS (TOF) m/z 435 (M+H)+.
Compounds 28a±28d were also prepared by using the
same procedure as for 1.
.
Anal. calcd for C22H18N4O6 0.02H2O: C, 60.78; H, 4.18;
N, 13.19. Found: C, 60.78; H, 4.18; N, 12.89.
6-Amino-5-[(RS)-6-hydroxy-2,5,7,8-tetramethylchroman-
2-carboxamido]3-methyl-1-phenyluracil (28a). White
solid (63.7%), mp 209±210 ꢀC; 1H NMR (CDCl3) d 1.60
(3H, s), 1.90±2.04 (1H, m), 2.08 (3H, s), 2.18 (3H, s),
2.29 (3H, s), 2.30±2.38 (1H, m), 2.54±2.64 (2H, m), 3.34
(3H, s), 4.32 (1H, s), 5.17 (2H, brs), 7.27±7.36 (2H, m),
7.53±7.60 (3H, m), 8.41 (1H, s); MS (TOF) m/z 465
(M+H)+. Anal. calcd for C25H28N4O5: C, 64.64; H,
6.08; N, 12.08. Found: C, 64.75; H, 6.03; N, 12.37.
6-Amino-3-methyl-5-[4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]
butanoyl-amino]-1-phenyluracil (19b).
White solid
(66.4%), mp 231 ꢀC (Dec.); 1H NMR (DMSO-d6) d 1.99±
2.04 (2H, m), 2.43 (2 H, t, J=7.4 Hz), 3.13 (3H, s), 4.15
(2H, t, J=6.3 Hz), 5.93 (2H, s), 6.29 (1H, d, J=9.7 Hz),
6.95±7.01 (2H, m), 7.32±7.35 (2H, m), 7.52±7.65 (4H, m),
8.00 (1H, d, J=9.7 Hz), 8.43 (1H, s); MS (TOF) m/z 463
+
.
(M+H) . Anal. calcd for C24H22N4O6 0.2H2O: C,
6-Amino-5-[(R)-6-hydroxy-2,5,7,8-tetramethylchroman-
2-carboxamido]3-methyl-1-phenyluracil (28b). White
61.85; H, 4.84; N, 12.02. Found: C, 61.85; H, 5.05; N,
12.11.
ꢀ
1
solid (60.2%), mp 206±207 C; H NMR (CDCl3) d 1.60
(3H, s), 1.90±1.99 (1H, m), 2.06 (3H, s), 2.17 (3H, s), 2.28
(3H, s), 2.31±2.39 (1H, m), 2.53±2.65 (2H, m), 3.34 (3H, s),
4.50 (1H, s), 5.15 (2H, s), 7.27±7.34 (2H, m), 7.52±7.58 (3H,
6-Amino-3-methyl-5-[4-(2-oxo-2H-1-benzopyran-3-yl)car-
boxamido]-1-phenyluracil (19c). Yellow solid (79.4%),
mp 289±290 ꢀC; 1H NMR (DMSO-d6) d 3.41 (3H, s), 5.19
(2H, s), 7.36±7.45 (2H, m), 7.55±7.60 (3H, m), 7.66±7.71
(4H, m), 8.87 (1H, s), 10.56 (1H, s); MS (TOF) m/z 405
(M+H)+. Anal. calcd for C21H16N4O5: C, 62.37; H, 3.99;
N, 13.86. Found: C, 62.29; H, 3.98; N, 14.21.
m), 8.39 (1H, s); ꢀ20 +53.9ꢀ (c=2.0, CHCl3); MS (TOF)
d
m/z 465 (M+H)+. Anal. calcd for C25H28N4O5: C, 64.64;
H, 6.08; N, 12.08. Found: C, 64.58; H, 6.18; N, 12.02.
6-Amino-5-[(S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-
carboxamido]3-methylꢀ-1-phenyluracil (28c). White solid
(64.8%), mp 206±207 C; 1H NMR (CDCl3) d 1.60 (3H,
s), 1.93±1.99 (1H, m), 2.07 (3H, s), 2.17 (3H, s), 2.28
(3H, s), 2.31±2.39 (1H, m), 2.57±2.65 (2H, m), 3.34 (3H,
6-Amino-3-methyl-5-[2-[(4-oxo-4H-1-benzopyran-2-phenyl-
6-yl)oxy]acetylamino]-1-phenyluracil (24a). White solid
(58.6%), mp 288 ꢀC (Dec.); 1H NMR (DMSO-d6) d 3.15
(3H, s), 4.76 (2H, s), 6.10 (2H, s), 7.04 (1H, s), 7.34±7.45
(2H, m), 7.53±7.62 (8H, m), 7.80±7.83 (1H, m), 8.10±8.13
(2H, m), 8.74 (1H, s); MS (TOF) m/z 511 (M+H)+.
s), 4.94 (1H, s), 5.15 (2H, s), 7.27±7.34 (2H, m), 7.52±
20
d
7.55 (3H, m), 8.39 (1H, s); ꢀ
53.9ꢀ (c=2.0, CHCl3);
MS (TOF) m/z 465 (M+H)+. Anal. calcd for
C25H28N4O5: C, 64.64; H, 6.08; N, 12.08. Found: C,
64.75; H, 6.03; N, 12.37.
.
Anal. calcd for C28H22N4O6 1.2H2O: C, 63.20; H, 4.62;
N, 10.53. Found: C, 63.03; H, 4.42; N, 10.36.
6-Amino-3-methyl-5-[4-[(4-oxo-4H-1-benzopyran-2-phenyl-
6-yl)oxy]butanoyl-amino]-1-phenyluracil (24b). White solid
6-Amino-5-[(RS)-6-methoxy-2,5,7,8-tetramethylchroman-2
-carboxamido]3-methyl-1-phenyluracil (28d). White crys-
(64.6%), mp 224±225 ꢀC; H NMR (DMSO-d6) d 2.02±
tals (57.9%), mp 210±211 ꢀC; H NMR (CDCl3) d 1.61
1
1
2.07 (2H, m), 2.44±2.50 (2H, m), 3.13 (3H, s), 4.16 (2H,
J=6.5Hz), 5.93 (2H, s), 7.03±7.04 (1H, m), 7.32±7.61
(10H, m), 7.74±7.79 (1H, m), 8.10±8.13 (2H, m), 8.44 (1H,
s); MS (TOF) m/z 539 (M+H)+. Anal. calcd for
C30H26N4O6 2H2O: C, 62.71; H, 5.26; N, 9.75. Found: C,
62.58; H, 5.25; N, 9.59.
(3H, s), 1.98±2.00 (1H, m), 2.12 (3H, s), 2.21 (3H, s),
2.28 (3H, s), 2.31±2.36 (1H, m), 2.59±2.62 (2H, m), 3.35
(3H, s), 3.62 (3H, s), 5.18 (2H, s), 7.28±7.36 (2H, m),
7.52±7.58 (3H, m), 8.42 (1H, s); MS (TOF) m/z 479
(M+H)+. Anal. calcd for C26H30N4O5: C, 65.26; H,
6.32; N, 11.71. Found: C, 65.17; H, 6.13; N, 11.72.
.
6-Amino-3-methyl-5-[2-[(4-oxo-4H-1-benzopyran-2-phenyl-
7-yl)oxy]acetylamino]-1-phenyluracil (24c). White solid
(61.0%), mp 214 ꢀC (Dec.); 1H NMR (DMSO-d6) d 3.18
(3H, s), 4.83 (2H, s), 6.17 (2H, s), 7.00 (1H, s), 7.08±7.21
(1H, m), 7.34±7.37 (2H, m), 7.46±7.61 (7H, m), 7.96±7.99
Biology
Picryl chloride (PC)-induced contact hypersensitivity re-
action (CHR). PC-induced CHR was assessed by the
method of Asherson and Ptak.13 Male ICR mice were
sensitized by applying 100 mL of 7% (w/v) PC solution
in acetone to the shaved abdomen. Seven days later, the
mice were challenged by applying 20 mL of 1% (w/v) PC
solution, either in olive oil for po or in acetone for
(1H, m), 8.16±8.29 (2H, m), 8.85 (1H, s); MS (TOF) m/z
+
.
511 (M+H) . Anal. calcd for C28H22N4O6 0.6H2O: C,
64.51; H, 4.49; N, 10.75. Found: C, 64.31; H, 4.60; N,
10.66.