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H. F. Vischer et al. / Bioorg. Med. Chem. 18 (2010) 675–688
6.1.21. 4-(4-Chlorophenyl)-1-(2-(2,4-dichlorobenzyl)-2,3-dihydro-
1H-inden-1-yl)-1,2,3,6-tetrahydropyridine hydrochloride (97)
Yield: 50 mg (19%) of one diastereomer of 97 as a light brown
solid. 1H NMR (MeOH-d4): d 2.61–2.92 (m, 6H), 3.15–3.39 (m,
3H), 3.51–3.81 (m, 2H), 4.61–4.69 (m, 1H), 6.01–6.07 (m, 1H),
7.31–7.54 (m, 10H), 7.67 (d, J = 7.1 Hz, 1H). 13C (MeOH-d4): d
26.22, 37.74, 38.29, 40.69, 47.72, 47.83, 75.74, 118.08, 127.30,
127.70, 128.68, 128.96, 129.74, 130.48, 132.14, 134.00, 134.59,
135.07, 135.83, 136.27, 136.78, 138.51, 146.52. Anal. RP-HPLC Ib
(total run time 20 min): tR = 13.04 min (purity 99%), IIb:
tR = 6.78 min (purity 96%). HRMS (EI) m/z calcd for C27H24Cl3N:
469.0945 (second isotope); found: 469.0931.
J = 6.1 Hz, 1H), 6.68 (s, 2H), 7.27–7.53 (m, 12H). 13C NMR (MeOH-
d4): d 32.41, 36.00, 44.64, 51.56, 65.52, 126.53, 126.60, 127.91,
128.49, 129.71, 130.01, 130.30, 130.33, 130.51, 133.42, 134.08,
135.48, 135.89, 136.00, 137.77, 144.58, 170.70. Anal. RP-HPLC Ib:
tR = 8.22 min (purity 100%), IIa: tR = 12.37 min (purity 97%). HRMS
(ESI) m/z calcd for C27H25Cl2NO4: 381.1051; found: 381.1046.
6.2. Pharmacology
Pharmacological characterization of nonpeptidergic ligands was
performed as previously described.11
Acknowledgments
6.1.22. 4-(4-Chlorophenyl)-1-(2-(2,4-dichlorobenzyl)-2,3-
dihydro-1H-inden-1-yl)piperidin-4-ol hydrochloride (93)
Yield: 61 mg (23%) of one diastereomer of 93 as a white solid 1H
NMR (MeOH-d4): d 1.81–1.92 (m, 4H), 2.50 (br s, 1H), 2.70–3.12
(m, 5H), 3.15–3.36 (4H), 4.41–4.47 (m, 1H), 7.15–7.48 (m, 10H),
8.00 (s, 1H), 12.08 (br s, 1H). 13C (MeOH-d4): d 35.03, 35.26,
37.25, 37.94, 38.73, 44.31, 45.84, 46.37, 69.58, 75.31, 125.81,
126.00, 127.64, 127.97, 128.67, 128.76, 129.60, 131.01, 132.58,
132.80, 133.54, 133.63, 134.80, 134.83, 144.42, 144.51. Anal. RP-
HPLC Ib : tR = 6.19 min (purity 100%), IIa (total run time 30 min):
tR = 13.45 min (purity 100%). HRMS (EI) m/z calcd for C27H26Cl3NO:
485.1080; found: 485.1073.
H. F. Vischer, J. W. Hulshof, and M. H. P. Verheij were supported
by the Technology Foundation STW and M. J. Smit was supported
by the Royal Netherlands Academy of Arts and Sciences.
References and notes
1. Billstrom, M. A.; Lehman, L. A.; Scott Worthen, G. Am. J. Respir. Cell Mol. Biol.
1999, 21, 163.
2. Bodaghi, B.; Jones, T. R.; Zipeto, D.; Vita, C.; Sun, L.; Laurent, L.; Arenzana-
Seisdedos, F.; Virelizier, J. L.; Michelson, S. J. Exp. Med. 1998, 188, 855.
3. Fraile-Ramos, A.; Kledal, T. N.; Pelchen-Matthews, A.; Bowers, K.; Schwartz, T.
W.; Marsh, M. Mol. Biol. Cell. 2001, 12, 1737.
4. Soderberg-Naucler, C. J. Int. Med. 2006, 259, 219.
5. Casarosa, P.; Bakker, R. A.; Verzijl, D.; Navis, M.; Timmerman, H.; Leurs, R.; Smit,
M. J. J. Biol. Chem. 2001, 276, 1133.
6. Waldhoer, M.; Kledal, T. N.; Farrell, H.; Schwartz, T. W. J. Virol. 2002, 76, 8161.
7. McLean, K. A.; Holst, P. J.; Martini, L.; Schwartz, T. W.; Rosenkilde, M. M.
Virology 2004, 325, 241.
8. Maussang, D.; Verzijl, D.; van Walsum, M.; Leurs, R.; Holl, J.; Pleskoff, O.;
Michel, D.; van Dongen, G. A.; Smit, M. J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
13068.
9. Casarosa, P.; Menge, W. M.; Minisini, R.; Otto, C.; van Heteren, J.; Jongejan, A.;
Timmerman, H.; Moepps, B.; Kirchhoff, F.; Mertens, T.; Smit, M. J.; Leurs, R. J.
Biol. Chem. 2003, 278, 5172.
10. Hulshof, J. W.; Casarosa, P.; Menge, W. M.; Kuusisto, L. M.; van der Goot, H.;
Smit, M. J.; de Esch, I. J.; Leurs, R. J. Med. Chem. 2005, 48, 6461.
11. Hulshof, J. W.; Vischer, H. F.; Verheij, M. H.; Fratantoni, S. A.; Smit, M. J.; de
Esch, I. J.; Leurs, R. Bioorg. Med. Chem. 2006, 14, 7213.
12. Schall, T. J.; McMaster, B. E.; Dairaghi, D. J. World (PTC) Patent WO0217969,
2002.
6.1.23. 1-(2-(2,4-Dichlorobenzyl)-2,3-dihydro-1H-inden-1-yl)-
4-phenylpiperazine dihydrochloride (96)
Yield: 48 mg (22%) of one diastereomer of 96 as a white solid.
1H NMR (MeOH-d4): d 2.72–2.97 (m, 3H), 3.05–3.55 (m, 8H),
3.69–3.88 (m 2H), 4.64–4.72 (m, 1H), 6.88–7.08 (m, 2H), 7.19–
7.54 9 m, 9H), 7.74 (d, J = 7.2 Hz, 1H). 13C (MeOH-d4): d 37.56,
38.05, 40.90, 50.58, 76.79, 118.22, 122.92, 127.46, 128.73, 128.78,
129.44, 130.41, 130.51, 132.52, 133.79, 134.00, 134.66, 136.28,
136.55, 146.84, 150.63. Anal. RP-HPLC Ib: tR = 7.07 min (purity
100%), IIa: tR = 4.13 min (purity 98%), IIb (total run time 30 min):
tR = 19.11 min (purity 98%). HRMS (EI) m/z calcd for C26H26Cl2N2:
436.1473; found: 436.1471.
13. Schall, T. J.; McMaster, B. E.; Dairaghi, D. J. World (PTC) Patent WO0217900,
2002.
14. McMaster, B. E.; Schall, T. J.; Penfold, M. E.; Wright, J. J.; Dairaghi, D. J. World
(PTC) Patent WO03018549, 2003.
6.1.24. 1-(2-(2,4-Dichlorobenzyl)-2,3-dihydro-1H-inden-1-yl)-
4-methylpiperazine dihydrochloride (95)
Yield: 105 mg (46%) of one diastereomer of 95 as a light yellow
solid. 1H NMR (MeOH-d4): d 2.61–3.03 (m, 4H), 2.93 (s, 5H), 3.12–
3.87 (m, 8H), 4.55–4.64 (m, 1H), 7.15–7.49 (m, 6H), 7.72 (d,
J = 7.1 Hz, 1H). 13C (MeOH-d4): d 37.59, 38.05, 40.99, 43.36, 47.18,
51.93, 77.02, 127.37, 128.72, 129.35, 130.46, 132.33, 133.98,
134.55, 136.27, 136.76, 146.61. Anal. RP-HPLC Ib (total run time
20 min): tR = 12.99 min (purity 95%), IId: tR = 12.70 min (purity
96%). HRMS (EI) m/z calcd for C21H24Cl2N2: 374.1317; found:
374.1311.
15. Buzas, A.; Champagnac, A.; Dehnel, A.; Lavielle, G.; Pommier, M. J. Med. Chem.
1980, 23, 149.
16. Monro, A. M.; Quinton, R. M.; Wrigley, T. I. J. Med. Chem. 1963, 6, 255.
17. Kwartler, C. E.; Lucas, P. J. Am. Chem. Soc. 1947, 69, 2582.
18. Kumagai, T.; Okubo, T.; Kataoka-Okubo, H.; Chaki, S.; Okuyama, S.; Nakazato, A.
Bioorg. Med. Chem. 2001, 9, 1349.
19. Jilek, J.; Pomykacek, J.; Dlabac, A.; Bartosova, M.; Protiva, M. Coll. Czech. Chem.
Commun. 1980, 45, 504.
20. Jilek, J. O.; Metysova, J.; Pomykacek, J.; Protiva, M. Coll. Czech. Chem. Commun.
1974, 39, 3338.
21. Bartl, V.; Jilek, J.; Metysova, J.; Valchar, M.; Dlabac, A.; Wildt, S.; Protiva, M. Coll.
Czech. Chem. Commun. 1984, 49, 1810.
22. Houlihan, W. J.; Shapiro, M. J.; Chin, J. A. J. Org. Chem. 1997, 62, 1529.
23. Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E.
J. J. Org. Chem. 1993, 58, 5886.
24. Gu, X. H.; Yu, H.; Jacobson, A. E.; Rothman, R. B.; Dersch, C. M.; George, C.;
Flippen-Anderson, J. L.; Rice, K. C. J. Med. Chem. 2000, 43, 4868.
25. Smits, R. A.; Lim, H. D.; Stegink, B.; Bakker, R. A.; de Esch, I. J.; Leurs, R. J. Med.
Chem. 2006, 49, 4512.
6.1.25. N-Benzyl-2-(2,4-dichlorobenzyl)-2,3-dihydro-1H-inden-
1-amine fumarate (98)
Yield: 20 mg (8%) of one diastereomer of 98 as a white solid. 1H
NMR (MeOH-d4): d 2.69–2.79 (m, 2H), 2.89–2.95 (m, 1H), 3.02–
3.08 (m, 1H), 3.17–3.25 (m, 1H), 4.14–4.21 (m, 2H), 4.62 (d,