2062
P. Zarantonello et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2059–2063
Moreover, the geminal aryl amino substituted lactam ring, as
OMe
Cl
Cl
Cl
O
exemplified in compounds 7–10 and 11–13, constitutes a novel
scaffold with potential application in the design of biologically ac-
tive compounds.
b
a
OMe
OH
H
Acknowledgements
c
The authors would like to thank Dr. Ceri Davies for useful dis-
cussions and the GSK analytical science department for assistance.
OMe
OMe
Cl
N
Cl
O
Cl
References and notes
e
d
O
O
OH
Br
1. Köhr, G. Cell Tissue Res. 2006, 326, 439.
MeO
2. Mayer, M. L.; Westbrook, G. L.; Guthrie, P. B. Nature 1984, 309, 261.
3. (a) Li, F.; Tsien, J. Z. N. Eng. J. Med. 2009, 361, 302; (b) McKinney, A. R. J. Physiol.
2010, 588, 107.
4. Neyton, J.; Paoletti, P. J. Neurosci. 2007, 26, 1331.
5. Mayer, M. L. Nature 2006, 440, 456.
14
Scheme 4. Reagents and conditions: (a) K2CO3, MeI, DMF, rt, overnight; (b)
cyclopentanecarbonyl chloride, AlCl3, n-hexane, 40 °C, 5 h; (c) Br2, 1,4-dioxane, rt,
2 h; (d) KOH, MeOH, rt, 2 h; (e) MeNH2, MW, 165 °C, 30 min.
6. (a) Vicini, S.; Wang, J. F.; Li, J. H.; Zhu, W. J.; Wang, Y. H.; Luo, J. H.; Wolfe, B. B.;
Grayson, D. R. J. Neurophysiol. 1998, 79, 555; (b) Yuan, H.; Hansen, K. B.; Vance,
K. M.; Ogden, K. K.; Traynelis, S. F. J. Neurosci. 2009, 29, 12045.
7. Parsons, C. G.; Quack, G.; Bresink, I.; Baran, L.; Przegalinskti, E.; Kostowski, W.;
Krzascik, P.; Hartmann, S.; Danysz, W. Neuropharmacology 1995, 34, 1239.
8. (a) Large, C. H. J. Psychopharmacol. 2007, 21, 283; (b) González-Maeso, J.;
Sealfon, S. C. Trends Neurosci. 2009, 32, 225.
9. (a) Hocking, G.; Cousins, M. J. Anesth. Analg. 2003, 97, 1730; (b) Annetta, M. G.;
Iemma, D.; Garisto, C.; Tafani, C.; Proietti, R. Curr. Drug Targets 2005, 6, 789.
10. (a) Berman, R. M.; Cappiello, A.; Anand, A.; Oren, D. A.; Heninger, G. R.;
Charney, D. S.; Krystal, J. H. Biol. Psychiatry 2000, 47, 351; (b) Zarate, C. A.;
Singh, J. B.; Carlson, P. J.; Brutsche, N. E.; Ameli, R.; Luckenbaugh, D. A.;
Charney, D. S.; Manji, H. K. Arch. Gen. Psychiatry 2006, 63, 856; (c) aan het Rot,
M.; Collins, K. A.; Murrough, J. W.; Perez, A. M.; Reich, D. L.; Charney, D. S.;
Mathew, S. J. Biol. Psychiatry 2010, 67, 139.
11. Kamaya, H.; Krishna, P. R. Anesthesiology 1987, 67, 861.
12. Morgan, C. J.; Muetzelfeldt, L.; Curran, V. H. Addiction 2010, 105, 121.
13. (a) Olney, J. W.; Labruyere, J.; Price, M. T. Science 1989, 244, 1360; (b)
Hargreaves, R. J.; Hill, R. G.; Iversen, L. L. Acta Neurochir. 1994, 60, 15.
14. Seeman, P.; Guan, H. C.; Hirbec, H. Synapse 2009, 63, 698.
15. Kapur, S.; Seeman, P. Mol. Psychiatry 2002, 7, 837.
16. Hirota, K.; Okawa, H.; Appadu, B. L.; Grandy, D. K.; Devi, L. A.; Lambert, D. G.
Anesthesiology 1999, 90, 174.
17. Hustveit, O.; Maurset, A.; Oye, I. Pharmacol. Toxicol. 1995, 77, 355.
18. Chen, X.; Shu, S.; Bayliss, D. A. J. Neurosci. 2009, 29, 600.
19. Kawano, T.; Oshita, S.; Takahashi, A.; Tsutsumi, Y.; Tanaka, K.; Tomiyama, Y.;
Kitahata, H.; Nakaya, Y. Anesthesiology 2005, 102, 93.
20. Wagner, L. E.; Gingrich, K. J.; Kulli, J. C.; Yang, J. Anesthesiology 2001, 95, 1406.
21. Coates, K. M.; Flood, P. Br. J. Pharmacol. 2001, 134, 871.
22. Shahani, S. K.; Lingamaneni, R.; Hemmings, H. C., Jr. Anesth. Analg. 2002, 95,
893.
23. Galley, H. F.; Nelson, L. R.; Webster, N. R. Br. J. Anaesth. 1995, 75, 326.
24. Behrens, M. M.; Ali, S. S.; Dao, D. N.; Lucero, J.; Shekhtman, G.; Quick, K. L.;
Dugan, L. L. Science 2007, 318, 1645.
25. (a) Olney, J. W.; Labruyere, J.; Wang, G.; Wozniak, D. F.; Price, T. M.; Sesma, M.
A. Science 1991, 254, 1515; (b) Seaman, J. Nat. Chem. Biol. 2008, 4, 91.
26. (a) Burak, K. Il Farmaco-Ed. Sc. 1985, 40, 285; (b) Yang, D. J.; Davisson, J. N. J.
Med. Chem. 1985, 28, 1361; (c) Cone, E. J.; Mcquinn, L.; Shannon, H. E. J.
Pharmacol. Exp. Ther. 1984, 228, 147.
benzyloxycarbonyl or tert-butyloxycarbonyl amino protected ana-
logues using either acrylonitrile or allylbromide, the reaction did
not work and the targeted quaternary protected
were not obtained. The -alkylated imino ester was then depro-
a-amino esters
a
tected. The formation of the six-membered ring in compound
11 was achieved by the use of dichlorocobalt and sodium borohy-
dride.40 In order to obtain mono-methylation of the primary ami-
no group, it was first necessary to protect it using
benzyloxycarbonylchloride.
Methylation using methyl iodide and sodium hydride gave a
mixture of compounds: one compound methylated only at the
Cbz-protected N-atom, and a bis-methylated one, which were sep-
arated through HPLC purification to afford compounds 12 and 13
after removal of the protecting group.
The biological evaluation of compounds 11–13 showed that a
piperidinone in place of the cyclohexanone was not tolerated since,
in all cases, a substantial drop of functional activity at both GluN1/
N2A and GluN1/N2B targets was observed when compared to
ketamine.
Finally, while maintaining the cyclohexanone moiety of keta-
mine, the introduction of a methoxy substituent on the aromatic
ring was evaluated.
To this purpose compound 14, bearing a methoxy group at the
aromatic ring, was then prepared following the synthetic route de-
picted in Scheme 4.
Commercially available 3-chlorophenol was methylated. Then,
the formation of the ketone was achieved through a Friedel–Crafts
acylation, at 40 °C using aluminium chloride as Lewis acid.41 After
27. Condreay, P. J.; Witherspoon, S. M.; Clay, W. C.; Kost, T. A. Proc. Natl. Acad. Sci.
U.S.A. 1999, 96, 127.
bromination, the
a
-bromoketone intermediate was transformed
28. Sullivan, E.; Tucker, E. M.; Dale, I. L. Methods Mol. Biol. 1999, 114, 125.
29. The c log P values were calculated using DAYLIGHT software version 4.9 from
Daylight Chemical Information Systems, Inc. of Aliso Viejo, CA.
30. (a) Schunk, S.; Zemolka, S.; Saunders, D.; Gruss, M.; Graubaum, PCT Int. Appl.
WO08/101659, 2008.; (b) Prashad, M.; Liu, Y.; Har, D.; Repic, O.; Blabklock, T. J.
Tetrahedron Lett. 2005, 46, 5455.
into the
a
-hydroxyketone.42 Treatment of a suitable
a-hydroxyke-
tone with an amine has long been known to induce the 1,2-shift of
an alkyl or aryl substituent to form an isomeric product of the imi-
no intermediate.43
Rearrangement using methylamine led indeed to the formation
of the desired methyl amino cyclohexanone derivative 14. The
presence of the methoxy group in 14 was tolerated, showing
appreciable activity, in particular in the GluN1/N2B assay (Table
4) when compared with ketamine.
31. (a) Katritzky, A. R.; Yang, H.; Singh, S. K. J. Org. Chem. 2005, 70, 286; (b)
Katritzky, A. R.; Galuszka, B.; Rachwal, S.; Mancheno, B.; Steel, P. J. Heterocycl.
Chem. 1994, 38, 319; (c) Katrizky, A. R.; Harris, P. A. Tetrahedron 1990, 46, 987;
(d) Kalir, A.; Edery, H.; Pelah, Z.; Balderman, D.; Porath, G. J. Med. Chem. 1969,
12, 473.
32. Ivanov, A. P.; Levin, D. Z.; Mortikov, E. S.; Promonenko, V. K. Zh. Org. Khim. 1989,
25, 629.
In summary, the identification of structurally novel analogues
of ketamine and PCP with low to moderate potency at GluN2A
and GluN2B receptors was described. In particular, some examples,
such as compounds 6 and 10, showed decreased calculated lipo-
philicity, when compared to PCP, while retaining moderate activ-
ity. Selected compounds from this series deserve to be explored
for their pharmacokinetic properties and selectivity, prior to fur-
ther SAR expansion and refinement.
33. Shue, H. J.; Chen, X.; Shih, N. Y.; Blythin, D. J.; Paliwal, S.; Lin, L.; Gu, D.;
Schwerdt, J. H.; Shah, S.; Reichard, G. A.; Piwinski, J. J.; Duffy, R. A.; Lachowicz, J.
E.; Coffin, V. L.; Liu, F.; Nomeir, A. A.; Morgan, C. A.; Varty, G. B. Bioorg. Med.
Chem. Lett. 2005, 15, 3896.
34. Burgess, K.; Ho, K. K. Tetrahedron Lett. 1992, 33, 5677.
35. Culbertson, T. P.; Sanchez, J. P.; Gambino, L.; Sesnie, J. A. J. Med. Chem. 1990, 33,
2270.
36. Alvaro, G.; Amantini, D.; Bergauer, M.; Bonetti, F.; Profeta, R. PCT Int. Appl.
WO07/042240, 2007.
37. Jaroch, S.; Matsuoka, R. T.; Overman, L. E. Tetrahedron Lett. 1999, 40, 1273.