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R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 2122–2127
–CH2N(CH2CH3)2), 3.30 (s, 3H, N–CH3), 3.40 (s, 3H, N–CH3), 4.10 (t,
2H, –OCH2–), 5.90 (br s, 2H, –NH2, disappeared on D2O exchange),
7.00 (m, 1H, CH, arom), 7.30 (m, 3H, CH, arom), 9.80 (s, 1H, N]CH).
3.61 (s, 3H, N–CH3), 3.89 (s, 3H, –OCH3), 4.17 (t, 2H, –OCH2–), 7.03 (s,
1H, CH, arom), 7.31 (s, 1H, CH, arom), 7.83 (s, 1H, CH, arom); Anal.
Calc. for C21H27N5O4: C, 61.00; H, 6.58; N, 16.93%. Found: C, 60.90;
H, 6.29; N, 16.57%.
5.1.2.13. 6-Amino-5-[{3-(2-piperidin-1-yl-ethoxy)-
benzylidene}amino]-1,3-dimethyluracil (11c). Yield: 56.5%; m.p.
5.1.3.4. 1,3-Dimethyl-8-[3-methoxy-4-(2-morpholin-4-ylethoxy)-
198–202 ꢁC. 1H NMR (CDCl3):
d
1.44 (m, 2H, –CH2, piperidine), 1.59
phenylxanthine (6d). Yield: 35.75%; m.p. 264–268 ꢁC. IR: 3300,
(p, 4H, 2 ꢂ CH2, piperidine), 2.50 (br s, 4H, –N(CH2)2, piperidine),
2.81 (t, 2H, –CH2No), 3.35 (s, 3H, N–CH3), 3.55 (s, 3H, N–CH3), 4.14
(t, 2H, –OCH2–), 5.98 (s, 2H, –NH2, disappeared on D2O exchange),
6.86 (dd, 1H, CH, arom, Jo ¼ 8.34, Jm ¼ 1.75 Hz), 7.23 (t, 1H, CH, arom,
Jo ¼ 8.10 Hz), 7.74 (m, 2H, CH, arom), 9.69 (s, 1H, N]CH).
2940, 1695, 1645, 1490, 1220; 1H NMR (CDCl3 þ DMSO-d6):
d 2.54
(br s, 4H, –N(CH2)2, morpholine), 2.78 (t, 2H, –CH2No), 3.31 (s, 3H,
N–CH3), 3.54 (s, 3H, N–CH3), 3.62 (t, 4H, O(CH2)2, morpholine), 3.88
(s, 3H, –OCH3), 4.18 (t, 2H, –OCH2–), 7.02 (d, 1H, CH, arom,
Jo ¼ 8.28 Hz), 7.29 (s,1H, CH, arom), 7.73 (m, 1H, CH, arom),13.50 (br
s, 1H, N–H); Anal. Calc. for C20H25N5O5: C, 57.82; H, 6.06; N, 16.85.
Found: C, 57.38; H, 5.96; N, 16.52%.
5.1.2.14. 6-Amino-5-[{3-(2-morpholin-4-yl-ethoxy)-
benzylidene}amino]-1,3-dimethyluracil (11d). Yield: 51.7%; m.p.
196–200 ꢁC. 1H NMR (CDCl3 þ DMSO-d6):
d
2.58 (t, 4H, –N(CH2)2,
5.1.3.5. 1,3-Dimethyl-8-[3-methoxy-4-(2-pyrrolidin-4-ylethoxy)-
morpholine), 2.81 (t, 2H, –CH2No), 3.37 (s, 3H, N–CH3), 3.60 (s, 3H,
N–CH3), 3.70 (t, 4H, O(CH2)2, morpholine), 4.17 (t, 2H, –OCH2–), 5.86
(s, 2H, –NH2, disappeared on D2O exchange), 6.95 (dd, 1H, CH, arom,
Jo ¼ 8.31, Jm ¼ 1.92 Hz), 7.32 (m, 1H, CH, arom), 7.72 (m, 2H, CH,
arom), 9.71 (s, 1H, N]CH).
phenyl]xanthine (6e). Yield: 22.27%; m.p. 232–234 ꢁC. IR: 3300,
2925, 1695, 1640, 1470, 1260; 1H NMR (CDCl3 þ DMSO-d6):
d 1.71
(br s, 4H, 2 ꢂ CH2, pyrrolidine), 2.57 (br s, 4H, –N(CH2)2, pyrroli-
dine), 2.85 (t, 2H, –CH2No), 3.28 (s, 3H, N–CH3), 3.52 (s, 3H, N–CH3),
3.86 (s, 3H, –OCH3), 4.12 (t, 2H, –OCH2–), 7.04 (d, 1H, CH, arom,
Jo ¼ 7.25 Hz), 7.72 (m, 2H, CH, arom); Anal. Calc. for C20H25N5O4: C,
60.13; H, 6.30; N, 17.53. Found: C, 60.08; H, 6.08; N, 17.24%.
5.1.2.15. 6-Amino-5-[{3-(2-pyrrolidin-1-ylethoxy)-
benzylidene}amino]-1,3-dimethyluracil (11e). Yield: 29.7%; m.p.
192–196 ꢁC. 1H NMR (CDCl3):
d
1.86 (br s, 4H, 2 ꢂ CH2, pyrrolidine),
5.1.3.6. 8-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-1,3-dime-
3.08 (m, 6H, –N(CH2)2, pyrrolidine and –CH2No), 3.36 (s, 3H, N–
CH3), 3.61 (s, 3H, N–CH3), 4.26 (t, 2H, –OCH2–), 6.09 (s, 2H, –NH2,
disappeared on D2O exchange), 6.92 (dd, 1H, CH, arom, Jo ¼ 8.05,
Jm ¼ 1.98 Hz), 7.32 (m, 2H, CH, arom), 7.72 (m, 1H, CH, arom), 9.68 (s,
1H, N]CH).
thylxanthine (9a). Yield: 49.29%; m.p. 230–232 ꢁC. IR: 3220, 1680,
1640, 1470, 1270; 1H NMR (CDCl3 þ DMSO-d6):
d 2.34 (s, 6H,
–N(CH3)2), 2.77 (t, 2H, –CH2No), 3.36 (s, 3H, N–CH3), 3.61 (s, 3H, N–
CH3), 3.90 (s, 3H, –OCH3), 4.13 (t, 2H, –OCH2-), 6.87 (m, 1H, CH,
arom), 7.69 (m, 2H, CH, arom); Anal. Calc. for C18H23N5O4: C, 57.89;
H, 6.20; N, 18.75. Found: C, 57.71; H, 6.25; N, 18.59%.
5.1.3. General procedure for the synthesis of various 8-(substituted-
phenyl)xanthine derivatives 6a–e, 9a–e and 12a–e
5.1.3.7. 8-[3-(2-Diethylaminoethoxy)-4-methoxyphenyl]-1,3-dime-
Benzylidene derivatives 5a–e, 8a–e and 11a–e (1.0 g, 2.5 mmol)
thus obtained were refluxed separately in thionyl chloride (20 mL)
for 30–40 min to affect cyclization. The excess thionyl chloride was
removed under reduced pressure to obtain a solid product. Ice cold
water was added to it and resultant suspension was neutralized
with ammonium hydroxide solution. The precipitate obtained was
collected by filtration, dried and recrystallized from a mixture of
DMF and methanol to afford the desired products 6a–e, 9a–e and
12a–e, respectively.
thylxanthine (9b). Yield: 36.21%; m.p. 168–170 ꢁC. IR: 3350, 1690,
1650, 1490, 1210; 1H NMR (CDCl3 þ DMSO-d6):
d 1.09 (t, 6H,
–N(CH2CH3)2), 2.65 (m, 4H, –N(CH2CH3)2), 2.95 (t, 2H, –CH2No),
3.44 (s, 3H, N–CH3), 3.67 (s, 3H, N–CH3), 3.91 (s, 3H, –OCH3), 4.19 (t,
2H, –OCH2–), 6.90 (s, 1H, CH, arom), 7.30 (s, 1H, CH, arom), 7.80 (s,
1H, CH, arom); Anal. Calc. for C20H27N5O4: C, 59.83; H, 6.78; N,
17.40. Found: C, 59.44; H, 6.51; N, 17.33%.
5.1.3.8. 1,3-Dimethyl-8-[4-methoxy-3-(2-piperidin-1-ylethoxy)-
phenyl]xanthine (9c). Yield: 60.36%; m.p. 230–232 ꢁC. IR: 3380,
5.1.3.1. 8-[4-(2-Dimethylaminoethoxy)-3-methoxyphenyl]-1,3-dime-
thylxanthine (6a). Yield: 48.28%; m.p. 246–250 ꢁC. IR: 3290, 1690,
1680, 1640, 1480, 1210; 1H NMR (CDCl3 þ DMSO-d6):
d 1.45 (m, 2H,
CH2, piperidine), 1.57 (m, 4H, 2 ꢂ CH2, piperidine), 2.51 (br s, 4H,
–N(CH2)2, piperidine), 2.78 (t, 2H, –CH2No), 3.36 (s, 3H, N–CH3),
3.61 (s, 3H, N–CH3), 3.89 (s, 3H, –OCH3), 4.16 (t, 2H, –OCH2–), 6.93
(d,1H, CH, arom, Jm ¼ 2.21 Hz), 7.35 (s,1H, CH, arom), 7.83 (s,1H, CH,
arom); Anal. Calc. for C21H27N5O4: C, 61.00; H, 6.58; N, 16.93%.
Found: C, 60.90; H, 6.31; N, 16.74%.
1650, 1495, 1215; 1H NMR (CDCl3 þ DMSO-d6):
d 2.23 (s, 6H,
–N(CH3)2), 2.65 (t, 2H, –CH2No), 3.24 (s, 3H, N–CH3), 3.48 (s, 3H, N–
CH3), 3.84 (s, 3H, –OCH3), 4.09 (t, 2H, –OCH2–), 7.07 (d, 1H, CH,
arom, Jo ¼ 8.47 Hz), 7.68 (m, 2H, CH, arom); Anal. Calc. for
C18H23N5O4: C, 57.89; H, 6.20; N, 18.75. Found: C, 57.53; H, 6.05; N,
18.67%.
5.1.3.9. 1,3-Dimethyl-8-[4-methoxy-3-(2-morpholin-4-ylethoxy)-
5.1.3.2. 8-[4-(2-Diethylaminoethoxy)-3-methoxyphenyl]-1,3-dime-
phenylxanthine (9d). Yield: 53.32%; m.p. 250–252 ꢁC. IR: 3350,
thylxanthine (6b). Yield: 19.11%; m.p. 176–180 ꢁC. IR: 3300, 1690,
1690, 1650, 1480, 1250; 1H NMR (CDCl3 þ DMSO-d6):
d 2.62 (t, 4H,
1650, 1490, 1210; 1H NMR (CDCl3 þ DMSO-d6):
d
1.08 (t, 6H,
–N(CH2)2, morpholine), 2.88 (t, 2H, –CH2No), 3.41 (s, 3H, N–CH3),
3.64 (s, 3H, N–CH3), 3.73 (t, 4H, O(CH2)2, morpholine), 3.90 (s, 3H,
–OCH3), 4.26 (t, 2H, –OCH2-), 6.96 (d, 1H, CH, arom, Jo ¼ 8.28 Hz),
7.76 (m, 2H, CH, arom) and 13.20 (br s, 1H, N–H); Anal. Calc. for
C20H25N5O5: C, 57.82; H, 6.06; N, 16.85. Found: C, 57.57; H, 6.03; N,
16.65%.
–N(CH2CH3)2), 2.65 (m, 4H, –N(CH2CH3)2), 2.94 (t, 2H, –CH2No),
3.44 (s, 3H, N–CH3), 3.67 (s, 3H, N–CH3), 3.94 (s, 3H, –OCH3), 4.12 (t,
2H, –OCH2–), 6.98 (s, 1H, CH, arom), 7.37 (s, 1H, CH, arom), 7.51 (s,
1H, CH, arom); Anal. Calc. for C20H27N5O4: C, 59.83; H, 6.78; N,
17.40. Found: C, 59.41; H, 6.29; N, 17.12%.
5.1.3.3. 1,3-Dimethyl-8-[3-methoxy-4-(2-piperidin-1-ylethoxy)-
5.1.3.10. 1,3-Dimethyl-8-[4-methoxy-3-(2-pyrrolidin-4-ylethoxy)-
phenyl]xanthine (6c). Yield: 20.12%; m.p. 204–206 ꢁC. IR: 3350,
phenyl]xanthine (9e). Yield: 80.48%; m.p. 234–236 ꢁC. IR: 3200,
2940, 1695, 1640, 1480, 1225; 1H NMR (CDCl3 þ DMSO-d6):
d
1.45
2925,1690,1670,1490,1210; 1H NMR (CDCl3 þ DMSO-d6):
d 1.67 (br
(m, 2H, CH2, piperidine), 1.57 (p, 4H, 2 ꢂ CH2, piperidine), 2.52 (br s,
4H, –N(CH2)2, piperidine), 2.80 (t, 2H, –CH2No), 3.38 (s, 3H, N–CH3),
s, 4H, 2 ꢂ CH2, pyrrolidine), 2.86 (br s, 4H, –N(CH2)2, pyrrolidine),
3.12 (t, 2H, –CH2No), 3.12 (s, 3H, N–CH3), 3.37 (s, 3H, N–CH3), 3.88