Y. Ikuma, H. Nakahira / Tetrahedron 67 (2011) 9509e9517
9517
4H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
158.1, 155.2, 155.1,
4.2.4.15. 2-[(3R)-3-Aminopiperidin-1-yl]-3-(2-chlorobenzyl)-8-
methoxy-5-methyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one
142.0, 135.6, 135.3, 131.9, 131.9, 129.5, 128.5, 127.2, 126.6, 122.5,
119.4, 117.0, 114.7, 114.7, 79.1, 54.9, 51.6, 46.2, 45.8, 29.4, 29.0, 28.5,
28.0, 21.6; HRMS (ESI) [MþH]þ calcd for C29H35ClN5O3 536.2423,
found 536.2410; IR (ATR): 1689, 1646, 1521, 1498, 1388, 1353, 1309,
hydrochloride (14f). 1H NMR (400 MHz, DMSO-d6)
d 8.27 (br s, 3H),
7.63 (d, J¼2.9 Hz, 1H), 7.56e7.51 (m, 2H), 7.33e7.29 (m, 1H), 7.23
(dd, J¼1.1, 7.7 Hz, 1H), 7.21e7.18 (m, 1H), 6.67 (d, J¼7.2 Hz, 1H), 5.64
(s, 2H), 3.88 (s, 3H), 3.72e3.63 (m, 1H), 3.60 (s, 3H), 3.50e3.46 (m,
1H), 3.28e3.25 (m, 1H), 3.11e3.07 (m, 1H), 2.88e2.83 (m, 1H),
1.99e1.94 (m, 1H), 1.79e1.76 (m, 1H), 1.60e1.49 (m, 2H); 13C NMR
1234, 1176, 1116, 1068, 1039 cmꢂ1
.
4.2.4.11. 2-[(3R)-3-Aminopiperidin-1-yl]-3-(2-chlorobenzyl)-6-
methoxy-5-methyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one
(100 MHz, DMSO-d6)
d 156.9, 154.9, 153.7, 140.1, 135.3, 131.9, 130.3,
hydrochloride (14a). 1H NMR (400 MHz, DMSO-d6)
d
8.43 (br s, 3H),
129.5, 129.1, 127.8, 127.0, 119.1, 117.4, 117.3, 116.4, 104.1, 55.8, 52.4,
51.2, 46.4, 46.3, 29.0, 27.3, 22.1; HRMS (ESI) [MþH]þ calcd for
C24H27ClN5O2 452.1848, found 452.1834; IR (ATR): 1670, 1508, 1471,
7.85 (d, J¼7.6 Hz, 1H), 7.50 (d, J¼7.8 Hz, 1H), 7.32e7.28 (m, 2H),
7.22e7.19 (m, 2H), 6.74 (d, J¼7.5 Hz, 1H), 5.63 (d, J¼18.0 Hz, 1H),
5.58 (d, J¼18.0 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.69e3.67 (m, 1H),
3.32e3.24 (m, 2H), 3.10e3.07 (m, 1H), 2.89e2.84 (m, 1H), 1.95 (br s,
1H), 1.75 (br s, 1H), 1.62e1.49 (m, 2H); 13C NMR (100 MHz, DMSO-
1423, 1230, 1051, 1033 cmꢂ1
.
4.2.4.16. 2-[(3R)-3-Aminopiperidin-1-yl]-3-(2-chlorobenzyl)-5,8-
dimethyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one hydrochlo-
d6)
d 157.0, 155.2, 149.1, 140.4, 135.2, 131.1, 129.5, 129.1, 128.6, 127.8,
127.2, 123.7, 118.7, 118.0, 115.1, 113.0, 56.9, 52.4, 51.1, 46.5, 46.3, 34.8,
27.3, 22.1; HRMS (ESI) [MþH]þ calcd for C24H27ClN5O2 452.1848,
found 452.1835; IR (ATR): 1673, 1594, 1483, 1444, 1247, 1074, 1051,
1041, 977 cmꢂ1. Anal. Calcd for C24H26ClN5O2$2.75HCl: C, 52.20; H,
5.25; N, 12.68, found: C, 52.25; H, 5.56, N, 12.30.
ride (14g). 1H NMR (400 MHz, DMSO-d6)
d 8.29 (br s, 3H), 7.99 (s,
1H), 7.52e7.48 (m, 2H), 7.40e7.38 (m, 1H), 7.34e7.02 (m, 2H), 6.67
(d, J¼7.6 Hz, 1H), 5.58 (s, 2H), 3.59 (s, 3H), 3.48e3.44 (m, 1H),
3.37e3.33 (m, 1H), 3.25e3.22 (m, 1H), 3.10e3.06 (m, 1H), 2.87e2.85
(m, 1H), 1.97 (m, 1H), 1.74 (m, 1H), 1.57e1.51 (m, 2H); 13C NMR
(100 MHz, DMSO-d6)
d 158.4, 155.1, 142.3, 135.6, 135.5, 131.9, 131.8,
4.2.4.12. Methyl
2-[(3R)-3-aminopiperidin-1-yl]-3-(2-chloro-
129.4, 129.3, 128.4, 127.2, 126.7, 122.5, 119.4, 117.0, 114.7, 59.1, 51.1,
47.4, 46.2, 33.3, 28.9, 23.3, 20.7; HRMS (ESI) [MþH]þ calcd for
C24H27ClN5O 436.1899, found 436.1890; IR (ATR): 1666, 1575, 1506,
benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinoline-6-
carboxylate hydrochloride (14b). 1H NMR (400 MHz, DMSO-d6)
d
8.37 (br s, 3H), 8.30 (d, J¼7.0 Hz, 1H), 7.70 (d, J¼6.7 Hz, 1H), 7.51 (d,
1471, 1444, 1052, 1033 cmꢂ1
.
J¼7.7 Hz, 1H), 7.43e7.39 (m, 1H), 7.32e7.29 (m, 1H), 7.25e7.21 (m,
1H), 6.73 (d, J¼7.7 Hz,1H), 5.63 (d, J¼17.2 Hz,1H), 5.58 (d, J¼17.2 Hz,
1H), 3.90 (s, 3H), 3.72e3.58 (m, 2H), 3.37 (s, 3H), 3.27e3.22 (m, 1H),
3.09e3.06 (m, 1H), 2.87e2.82 (m, 1H), 1.95 (br s, 1H), 1.76 (br s, 1H),
Supplementary data
Supplementary data associated with this article can be found in
clude MOL files and InChIKeys of the most important compounds
described in this article.
1.61e1.49 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d 169.0, 157.9,
155.1, 141.6, 135.8, 135.2, 131.2, 129.8, 129.5, 129.1, 127.9, 127.2, 125.1,
122.2, 122.2, 119.0, 118.2, 53.1, 52.3, 51.1, 46.4, 46.3, 34.8, 27.4, 22.1;
HRMS (ESI) [MþH]þ calcd for C25H27ClN5O3 480.1797, found
480.1783; IR (ATR): 1722, 1658, 1577, 1527, 1496, 1471, 1267 cmꢂ1
.
References and notes
4.2.4.13. 2-[(3R)-3-Aminopiperidin-1-yl]-3-(2-chlorobenzyl)-5-
methyl-7-phenyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one hy-
1. Arulmozhi, D. K.; Portha, B. Eur. J. Pharm. Sci. 2006, 28, 96; (b) Knudsen, L. B. J.
Med. Chem. 2004, 47, 4128.
2. (a) Kieffer, T. J.; Mclntosh, C. H. S.; Pederson, R. A. Endocrinology 1995, 136, 3585;
(b) Deacon, C. F.; Nauck, M. A.; Toft-Nielson, M.; Pridal, L.; Willms, B.; Holst, J. J.
Diabetes 1995, 44, 1126.
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1783; (b) Mest, H. J.; Mentlein, R. Diabetologia 2005, 48, 616; (c) Weber, A. E. J.
Med. Chem. 2004, 47, 4135; (d) Augustyns, K.; Van der Veken, P.; Senten, K.;
Haemers, A. Expert Opin. Ther. Pat. 2003, 13, 499.
drochloride (141c). 1H NMR (400 MHz, DMSO-d6)
d 8.47 (br s, 3H),
8.33e8.31 (m, 1H), 7.82 (d, J¼7.5 Hz, 2H), 7.76 (s, 1H), 7.67 (d,
J¼8.1 Hz, 1H), 7.53e7.49 (m, 3H), 7.43e7.39 (m, 1H), 7.32e7.28 (m,
1H), 7.25e7.21 (m, 1H), 6.75 (d, J¼7.5 Hz, 1H), 5.63 (d, J¼17.2 Hz,
1H), 5.58 (d, J¼17.2 Hz, 1H), 3.69e3.64 (m, 1H), 3.66 (s, 3H),
3.38e3.29 (m, 2H), 3.12e3.09 (m, 1H), 2.91e2.86 (m, 1H), 1.97 (br s,
1H), 1.76 (br s, 1H), 1.64e1.50 (m, 2H); 13C NMR (100 MHz, DMSO-
4. Drucker, D. J.; Nauck, M. A. Lancet 2006, 368, 1696.
5. Ahren, B. Expert Opin. Emerging Drugs 2008, 13, 593.
6. (a) Eckhardt, M.; Langkopf, E.; Mark, M.; Tadayyon, M.; Thomas, L.; Nar, H.;
Pfrengle, W.; Guth, B.; Lotz, R.; Sieger, P.; Fuchs, H.; Himmelsbach, F. J. Med.
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Chem. Abstr. 2004, 140, 357368.
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WO2005051949A1; Chem. Abstr. 2005, 143, 26614.
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Pharm. Bull. 1992, 40, 3245.
11. Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64, 3047.
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1990, 46, 7803; (b) Peter, J. G.; Simon, N. T.; Roger, W. Tetrahedron Lett. 1991, 32,
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13. (a) Minakawa, N.; Takeda, T.; Sasaki, T.; Matsuda, A. J. Med. Chem. 1991, 34, 778;
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d6) d 156.9, 154.2, 140.7, 140.0, 139.8, 138.0, 135.2, 131.1, 129.5, 129.2,
129.1, 128.1, 127.8, 127.4, 127.1, 123.1, 121.3, 118.7, 114.8, 113.9, 52.4,
51.1, 46.7, 46.3, 29.0, 27.3, 21.2; HRMS (ESI) [MþH]þ calcd for
C29H29ClN5O 498.2055, found 498.2040; IR (ATR): 1668,1596,1444,
1419, 1324, 1051, 1033, 1016 cmꢂ1
.
4.2.4.14. 2-[(3R)-3-Aminopiperidin-1-yl]-3-(2-chlorobenzyl)-8-
fluoro-5-methyl-3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one hy-
drochloride (14e). 1H NMR (400 MHz, DMSO-d6)
d 8.14 (br s, 3H),
7.80 (dd, J¼3.0, 8.7 Hz, 1H), 7.65 (dd, J¼4.5, 9.3 Hz, 1H), 7.52 (dd,
J¼1.1, 7.9 Hz, 1H), 7.47e7.42 (m, 1H), 7.33e7.29 (m, 1H), 7.25e7.21
(m, 1H), 6.66 (d, J¼6.4 Hz, 1H), 5.63 (s, 2H), 3.62 (s, 3H), 3.61e3.56
(m, 1H), 3.38e3.36 (m, 1H), 3.23e3.18 (m, 1H), 3.09e3.06 (m, 1H),
2.85e2.82 (m, 1H), 1.98e1.90 (m, 1H), 1.77e1.75 (m, 1H), 1.58e1.49
14. Suzuki, F.; Kuroda, T. J. Heterocycl. Chem. 1993, 30, 811.
15. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915.
(m, 2H); 13C NMR (75 MHz, DMSO-d6)
d
158.3, 157.7 (1J (C,F)¼
240 Hz), 154.0, 140.9 (4J (C,F)¼3.1 Hz), 135.4, 134.0, 131.0, 129.4,
128.9, 127.7, 126.9, 119.4, 117.8 (3J (C,F)¼8.7 Hz), 117.8 (3J (C,F)¼
8.7 Hz),115.7 (2J (C,F)¼31 Hz), 107.1 (2J (C,F)¼31 Hz), 58.6, 50.7, 47.4,
46.1, 33.2, 29.1, 23.5; HRMS (ESI) [MþH]þ calcd for C23H24ClFN5O
440.1648, found 440.1639; IR (ATR): 1672, 1604, 1525, 1463, 1313,
16. (a) Domingo, G. C.; Paula, M.; Ataualpa, A. C. B.; Feliu, M.; Antonio, M. E. J. Am.
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2001, 3, 444; (b) Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike, K.; Akamatsu,
H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis 2002, 2, 237.
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1245, 1213, 1110, 1051, 1000 cmꢂ1
.