S. Komoriya et al. / Bioorg. Med. Chem. 14 (2006) 1309–1330
1329
Muto, R.; Yamaguchi, M.; Nagahara, T.; Kanno, H.
Heterocycles 2004, 63, 1555–1561.
5.59. 2-[4-[(6-Chlorobenzo[b]thien-2-yl)sulfonyl]-2-[[N-(2-
fluoroethyl)carbamoyl]methyl]piperazin-1-yl]carbonyl]thi-
eno[3,2-b]pyridine N-oxide (38d)
14. For the synthesis of 5e, see; Sorkin, E.; Kra¨henbuhl, W.;
¨
Erlenmeyer, H. Helv. Chim. Acta 1948, 31, 65–75.
15. For the synthesis of 6a, see; (a) Haginoya, N.; Kobayashi,
S.; Komoriya, S.; Yoshino, T.; Nagata, T.; Hirokawa, Y.;
Nagahara, T. Bioorg. Med. Chem. 2004, 12, 5579–5586;
For the synthesis of 6d, see; (b) Klemm, L. H.; Louris, J.
N. J. Heterocycl. Chem. 1984, 21, 785–789.
Starting with 37 (289 mg, 0.43 mmol) and 2-fluoroethyl-
amine hydrochloride (71.6 mg, 0.72 mmol), and follow-
ing the procedure for the preparation of 38a gave 38d
(88.0 mg, 33%) as a pale yellow amorphous solid.
16. For the synthesis of 6e, see; Musser, J. H.; Hudec, T. T.;
Bailey, K. Synth. Commun. 1984, 14, 947–953.
17. Takahashi, T.; Yazuka, T.; Oonuma, Y. Yakugaku Zasshi
1944, 64, 235–237.
18. Kozikowski, A. P.; Tckmantel, W.; Saxena, A.; Doctor, B.
P. Helv. Chim. Acta 1994, 77, 1256–1266.
19. Altland, H. W.; Molander, G. A. J. Heterocycl. Chem.
1977, 14, 129–134.
20. Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000,
39, 2536–2540.
21. Cunico, R. F.; Kuran, C. P. J. Org. Chem. 1992, 57, 3331–
3336.
22. Afonso, A.; Baldwin, J. J.; Doll, R. J.; Li, G.; Mallams, A.
K.; Njoroge, F. G.; Rane, D. F.; Reader, J. C.; Rossman,
R. R. Int Pub No. WO 96/31478 Oct 10, 1996.
1H NMR (CDCl3): d 2.50–3.00 (4H, m), 3.40–3.70 (3H,
m), 3.70–4.00 (2H, m), 4.20–4.60 (3H, m), 4.90–5.30
(1H, m), 6.70–6.90 (1H, br), 7.25–7.35 (1H, m), 7.42
(1H, d, J = 8.1 Hz), 7.70–7.80 (2H, m), 7.80–7.90 (2H,
m), 7.93 (1H, s), 8.29 (1H, d, J = 6.1 Hz). Anal. Calcd
for C24H22ClFN4O5S3ÆH2OÆ0.05CH2Cl2: C, 46.56; H,
4.08; Cl, 6.29; F, 3.06; N, 9.03; S, 15.51. Found: C,
46.85; H, 3.73; Cl, 6.60; F, 3.06; N, 9.05; S, 15.90. MS
(FAB) m/z 597 [(M+H)+, Cl35], 599 [(M+H)+, Cl37].
HRMS (FAB) m/z 597.0513 (M+H)+ (calcd for
C24H23ClFN4O5S3: 597.0503). IR (KBr) cmꢀ1 3434,
3316, 3072, 1664, 1629, 1550, 1519, 1450, 1415, 1357,
1253, 1160, 1099, 1051, 1004, 941.
23. To disclose conformational characteristics lurking in the
2-carbamoylthiophene moiety we performed ab initio
calculations using the Gaussian 94 program for the model
compounds A and B. We examined each relative energy
(DHF) for the various conformers of A and B in which
torsion angles (v) of the S–C–C@O moiety changed from
0° to 180°. The value of each DHF of A and B was
calculated on the basis of the energy (0 kcal/mol) of
conformer A150 (v = 150°) and B0 (v = 0°).
24. (a) Maignan, S.; Guilloteau, J.; Pouzieux, S.; Choi-
Sledeski, Y. M.; Becker, M. R.; Klein, S. I.; Ewing, W.
R.; Pauls, H. W.; Spada, A. P.; Mikol, V. J. Med. Chem.
2000, 43, 3226; (b) Maignan, S.; Guilloteau, J.; Choi-
Sledeski, Y. M.; Becker, M. R.; Ewing, W. R.; Pauls, H.
W.; Spada, A. P.; Mikol, V. J. Med. Chem. 2003, 46, 685;
(c) Guertin, K. R.; Gardner, C. J.; Klein, S. I.; Zulli, A. L.;
Czekaj, Z. M.; Gong, Y.; Spada, A. P.; Cheney, D. L.;
Maignan, S.; Guilloteau, J.; Brown, K. D.; Colussi, D. J.;
Chu, V.; Heran, C. L.; Morgan, S. R.; Bentley, R. G.;
Dunwiddie, C. T.; Leadley, R. J.; Pauls, H. W. Bioorg.
Med. Chem. Lett. 2002, 12, 1671; (d) Alder, M.; Davey, D.
D.; Phillips, G. B.; Kim, S.; Jancarik, J.; Rumennik, G.;
Light, D. R.; Whitlow, M. Biochemistry 2000, 39, 12534;
(e) The other examples have been deposited with Protein
Data Bank; 1G2L, 1G2M, 1IOE, and 1IQF.
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and human liver weight is 20 g/kg of body weight.
X=100 ¼ eꢀelkꢁ30. kel (/min) = ꢀln(X/100)/30. CLint = kel/
Cm = ꢀln[(X/100)/30]/1.0 45 20.
*
*
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Osanai, K.; Yoshino, T.; Nagata, T.; Nagamochi, M.;