3020
K. Kubota et al. / Bioorg. Med. Chem. 19 (2011) 3005–3021
132.4, 131.3, 130.6, 129.5, 128.1, 127.9, 127.2, 126.2, 123.4, 119.4,
86.8, 79.5, 69.7, 57.4, 52.1 (2C), 50.1 (2C), 32.9, 27.6, 26.9. Anal.
Calcd for C29H32N4O5ꢂ1.5H2O: C, 65.15; H, 6.15; N, 10.42. Found:
C, 65.15; H, 6.41; N, 10.48. HRMS (ESI+) calcd for C29H33N4O5
(M+H+): 517.2445, found: 517.2431.
H, 6.62; N, 10.18. HRMS (ESI+) calcd for C30H35N4O4 (M+H+):
515.2653, found: 515.2639.
3.2.56. [(5Z)-5-{3-[4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-1,4-diazepan-1-yl]propylidene}-10,11-
dihydro-5H-dibenzo[a,d][7]annulen-3-yl]acetic acid (19f)
The title compound was synthesized from (18f) according to the
procedure to prepare (18a) (35% yield).
3.2.51. (E)-2-(11-(3-(4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)piperazin-1-yl)propylidene)-6,11-di-
hydrodibenzo[b,e]oxepin-2-yl)acetic acid ((E)-19a)
1H NMR (DMSO-d6, d ppm): 11.8–12.7 (1H, br s), 7.14–7.27 (3H,
m), 7.07–7.13 (2H, m), 6.94–7.05 (2H, m), 5.80–5.84 (1H, m), 5.03
(1H, s), 3.50 (2H, s), 3.13–3.35 (9H, m), 3.50 (3H, s), 2.41–2.90 (8H,
m), 2.17–2.28 (2H, m), 1.68–1.79 (2H, m). Anal. Calcd for
1H NMR (DMSO-d6, d ppm): 11.8–12.8 (1H, br s), 7.47 (1H, dd,
J = 1.2, 7.2 Hz), 7.28–7.41 (2H, m), 7.25 (1H, dd, J = 1.2, 7.2 Hz),
7.13 (1H, d, J = 2.0 Hz), 7.00 (1H, dd, J = 2.0, 7.6 Hz), 6.64 (1H, d,
J = 8.4 Hz), 6.02 (1H, t, J = 7.6 Hz), 4.40–5.70 (3H, br s), 3.45 (2H,
s), 3.07–3.23 (12H, m), 2.20–2.68 (6H, m), 1.69–1.78 (2H, m). Anal.
Calcd for C29H32N4O5ꢂ0.5H2O: C, 66.27; H, 6.33; N, 10.66. Found: C,
66.10; H, 6.30; N, 10.65. HRMS (ESI+) calcd for C29H33N4O5 (M+H+):
517.2445, found: 517.2433.
C
31H36N4O4ꢂ0.75H2O: C, 68.68; H, 6.97; N, 10.33. Found: C, 68.77;
H, 6.95; N, 10.25. HRMS (ESI+) calcd for C31H37N4O4 (M+H+):
529.2809, found: 529.2793.
3.2.57. (5Z)-5-{3-[4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-1,4-diazepan-1-yl]propylidene}-10,11-
dihydro-5H-dibenzo[a,d][7]annulene-3-carboxylic acid (19g)
The title compound was synthesized from (18g) according to
the procedure to prepare (19a) (40% yield).
3.2.52. (Z)-2-(11-(3-(4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)-1,4-diazepan-1-yl)propylidene)-6,11-
dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (19b)
1H NMR (DMSO-d6, d ppm): 7.75 (1H, d, J = 7.6 Hz), 7.65 (1H, br
s), 7.31 (1H, d, J = 8.0 Hz), 7.02–7.29 (4H, m), 5.86 (1H, t, J = 7.2 Hz),
5.03 (1H, s), 3.12–3.30 (9H, m), 3.01 (3H, s), 2.72–2.90 (2H, m),
2.41–2.63 (6H, m), 2.10–2.30 (2H, m), 1.70–1.79 (2H, m). Anal.
Calcd for C30H34N4O4ꢂ1.0H2O: C, 67.65; H, 6.81; N, 10.52. Found:
C, 67.43; H, 6.69; N, 10.35. HRMS (ESI+) calcd for C30H35N4O4
(M+H+): 515.2653, found: 515.2640.
The title compound was synthesized from (18b) according to
the procedure to prepare (19a) (78% yield).
1H NMR (DMSO-d6, d ppm): 11.0–13.2 (1H, br s), 7.22–7.39 (4H,
m), 7.01–7.07 (2H, m), 6.74 (1H, d, J = 8.4 Hz), 5.68 (1H, t,
J = 7.2 Hz), 4.70–5.60 (3H, br s), 3.47 (2H, s), 3.09–3.25 (12H, m),
2.59–2.72 (6H, m), 1.73–1.84 (2H, m). Anal. Calcd for
C
30H34N4O5ꢂ2.4H2O: C, 62.79; H, 6.81; N, 9.76. Found: C, 62.72;
H, 6.42; N, 9.72. HRMS (ESI+) calcd for C30H35N4O5 (M+H+):
531.2602, found: 531.2586.
Acknowledgments
3.2.53. (Z)-11-(3-(4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)piperazin-1-yl)propylidene)-6,11-di-
hydrodibenzo[b,e]oxepine-2-carboxylic acid (19c)
The authors would like to thank Mr. Kido, Ms. Negishi, Dr. Goto,
Ms. Hosokawa, and Dr. Watanabe for their biological evaluation of
the synthesized compounds and helpful suggestions.
The title compound was synthesized from (18c) according to
the procedure to prepare (19a) (48% yield).
1H NMR (CDCl3, d ppm): 7.85 (1H, d, J = 2.1 Hz), 7.72 (1H, dd,
J = 2.1, 8.6 Hz), 7.28–7.36 (4H, m), 6.83 (1H, d, J = 8.6 Hz), 5.69
(1H, t, J = 7.2 Hz), 5.27 (1H, s), 4.70–5.55 (2H, br s), 3.35 (3H, s),
3.30 (3H, s), 2.92–3.04 (4H, m), 2.62–2.80 (8H, m). Anal. Calcd for
Supplementary data
Supplementary data (synthetic scheme and characterization
data of novel compounds not listed in Section 2) associated with
this article can be found, in the online version, at doi:10.1016/
C
28H30N4O5ꢂ1.5H2O: C, 63.50; H, 6.28; N, 10.58. Found: C, 63.26;
H, 5.98; N, 10.33. HRMS (ESI+) calcd for C28H31N4O5 (M+H+):
503.2289, found: 503.2277.
References and notes
3.2.54. (Z)-11-(3-(4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-yl)-1,4-diazepan-1-yl)propylidene)-
6,11-Dihydrodibenzo[b,e]oxepine-2-carboxylic acid (19d)
The title compound was synthesized from (18d) according to
the procedure to prepare (19a) (41% yield).
1. (a) Baba, K.; Nakae, K. Prog. Med. 2008, 28, 2001; (b) Nakamura, A.; Asai, T.;
Yoshida, H.; Baba, K.; Nakae, K. J. Otolaryngol. Jpn 2002, 105, 215.
2. (a) Howarth, P. H.; Wilson, S.; Lau, L.; Rajakulasingam, K. Clin. Exp. Allergy 1991,
21, 3; (b) Bradding, P.; Feather, I. H.; Wilson, S.; Bardin, P. G.; Heusser, C. H.;
Holgate, S. T.; Howarth, P. H. J. Immunol. 1993, 151, 3853; (c)
Christodoulopoulos, P.; Cameron, L.; Durham, S.; Hamid, Q. J. Allergy Clin.
Immunol. 2000, 105, 211; (d) Horak, F. Allergy 2002, 57, 25.
3. (a) Holgate, S. T.; Canonica, G. W.; Simons, F. E. R.; Taglialatela, M.; Tharp, M.;
Timmerman, H.; Yanai, K. Clin. Exp. Allergy 2003, 33, 1305; (b) Morphy, R.;
Rankovic, Z. J. Med. Chem. 2005, 48, 6523.
4. (a) Gyoten, M.; Nagaya, H.; Fukuda, S.; Ashida, Y.; Kawano, Y. Chem. Pharm. Bull.
2003, 51, 122; (b) Fukuda, S.; Midoro, K.; Kamei, T.; Gyoten, M.; Kawano, Y.;
Ashida, Y.; Nagaya, H. J. Pharmacol. Exp. Ther. 2002, 303, 1283; (c) Fukuda, S.;
Midoro, K.; Gyoten, M.; Kawano, Y.; Ashida, Y.; Nabe, T.; Kohno, S.; Nagaya, H.
Eur. J. Pharmacol. 2003, 476, 239.
1H NMR (CDCl3, d ppm): 7.73–7.86 (2H, m), 7.25–7.36 (4H, m),
6.84 (1H, d, J = 8.6 Hz), 5.67 (1H, t, J = 7.3 Hz), 5.27 (1H, s), 4.70–
5.79 (2H, br s), 3.40 (3H, s), 3.30 (3H, s), 3.24–3.35 (4H, m), 2.69–
2.92 (8H, m), 1.97–2.04 (2H, m). Anal. Calcd for
C29H32N4O5ꢂ1.5H2O: C, 64.07; H, 6.49; N, 10.31. Found: C, 63.77;
H, 6.20; N, 10.14. HRMS (ESI+) calcd for C29H33N4O5 (M+H+):
517.2445, found: 517.2432.
5. Kubota, K.; Kurebayashi, H.; Miyachi, H.; Tobe, M.; Onishi, M.; Isobe, Y. Bioorg.
Med. Chem. Lett. 2009, 19, 2766.
3.2.55. [(5Z)-5-{3-[4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl)piperazin-1-yl]propylidene}-10,11-di-
hydro-5H-dibenzo[a,d][7]annulen-3-yl]acetic acid (19e)
The title compound was synthesized from (18e) according to
the procedure to prepare (19a) (35% yield).
6. Ohmori, K.; Hasegawa, K.; Tamura, T.; Miyake, K.; Matsubara, M.; Masaki, S.;
Karasawa, A.; Urayama, N.; Horikoshi, K.; Kajita, J.; Hasegawa, M.; Taniguchi,
K.; Komada, T.; Kawamoto, Y. Arzneimittelforschung 2004, 54, 809.
7. (a) Markham, A.; Wagstaff, A. Drugs 1998, 55, 269; (b) Graul, A. Drugs Future
1996, 21, 1017; (c) Simpson, K.; Jarvis, B. Drugs 2000, 59, 301.
8. Harry, L. Y.; Francis, S. J. Med. Chem. 1964, 609.
9. Gyermek, L. Int. Rev. Neurobiol. 1966, 9, 95.
10. Oshima, E.; Otaki, S.; Sato, H.; Kumazawa, T.; Obase, H.; Ishii, A.; Ishii, H.;
Ohmori, K.; Hirayama, N. J. Med. Chem. 1992, 35, 2074.
11. Yale, H. L.; Beer, B.; Plusces, J.; Spitzmiller, E. R. J. Med. Chem. 1970, 13, 713.
1H NMR (DMSO-d6, d ppm): 11.4–13.0 (1H, br s), 6.97–7.26 (7H,
m), 5.81 (1H, t, J = 7.2 Hz), 5.12 (1H, s), 3.52 (2H, s), 3.18–3.43 (5H,
m), 3.10 (3H, s), 2.67–2.95 (6H, m), 2.18–2.47 (8H, m). Anal. Calcd
for C30H34N4O4ꢂ1.5H2O: C, 66.52; H, 6.89; N, 10.34. Found: C, 66.26;