X.Y. Zhu et al. / European Journal of Medicinal Chemistry 53 (2012) 124e132
131
2H, J ¼ 7.8 Hz), 6.69 (t, 1H, J ¼ 7.2 Hz), 4.54 (s, 2H), 3.29 (t, 4H,
J ¼ 6.6 Hz), 2.80e2.54 (m, 4H), 2.36 (t, 2H, J ¼ 7.2 Hz), 1.80e1.70 (m,
2H), 1.58e1.52 (m, 4H). Anal. Calcd for C25H28N4O2S 0.075 EtOAc: C,
65.97; H, 6.20; N, 12.31. Found: C, 65.99; H, 6.37; N, 12.03.
Program (NIMH-PDSP). Details of the methods and radioligands
used for the binding assays were previously reported [22].
Acknowledgments
5.5.7. 1-(Benzo[d]thiazol-2-yl)-5-(isoindolin-2-yl)pentan-1-one
hydrochloride (19)
We acknowledge the financial support of the National Institute
of General Medical Studies (NIGMS) MBRS Grant
#
The product was converted into the HCl salt, followed by crys-
tallization from MeOHeEt2O to give the pure compound. Yield
1SC1GM088451-01, NIMH Psychoactive Drug Screening Program,
and a Title III Grant to Florida A&M University. This work is sup-
ported in part by the Pharmaceutical Research Center NIH/NCRR
1C06-RR12512-01 Grant. These funding sources had no involve-
ment in the study design, data collection and interpretation, or
article preparation and submission of this manuscript. The authors
would like to acknowledge Mrs. Barbara Bricker for her editorial
assistance during the writing of this manuscript.
(29%), mp: 248e250 ꢁC; 1H NMR (DMSO-d6):
d 11.36 (s, 1H),
8.22e8.19 (m, 2H), 7.64e7.60 (m, 2H), 7.32e7.24 (m, 4H), 4.37 (s,
4H), 3.33 (t, 2H, J ¼ 6.6 Hz), 3.20 (brs, 2H), 1.75 (t, 4H, J ¼ 2.7 Hz).
Calculated for C20H21ClN2OS: C, 64.42; H, 5.68; N, 7.51; Found: C,
64.51; H, 5.92; N, 7.31.
5.5.8. 1-(Benzo[d]thiazol-2-yl)-5-(4-(4-chlorophenyl)piperazin-1-
yl)pentan-1-one hydrochloride (20)
The product was converted into the HCl salt, followed by crys-
tallization from MeOHeEt2O to give the pure compound. Yield
References
(58%), mp; 227e229 ꢁC; 1H NMR (CD3OD):
d 8.18e8.15 (m, 1H),
[2] (a) P. Pacher, V. Kecskemeti, Cardiovascular side effects of new antidepres-
sants and antipsychotics: new drugs, old concerns? Curr. Pharm. Des. 10
(2004) 2463e2475;
8.12e8.09 (m, 1H), 7.65e7.56 (m, 2H), 7.26 (d, 2H, J ¼ 6.6 Hz), 7.00
(d, 2H, J ¼ 6.6 Hz), 3.85 (d, 2H, J ¼ 14.1 Hz), 3.70 (d, 2H, J ¼ 12.6 Hz),
3.39 (t, 2H, J ¼ 6.9 Hz), 3.32e3.22 (m, 6H), 3.19e3.04 (m, 2H),
1.93e1.90 (m, 4H). Anal. Calcd for C22H26Cl3N3OS: C, 54.27; H, 5.38;
N 8.63. Found: C, 54.35; H, 5.12; N 8.90.
(b) C. Howell, A.D. Wilson, W.S. Waring, Cardiovascular toxicity due to ven-
lafaxine poisoning in adults: a review of 235 consecutive cases, Br. J. Clin.
Pharmacol. 64 (2007) 192e197.
[3] (a) K.R. Starr, G.W. Price, J.M. Watson, P.J. Atkinson, R. Arban, S. Melotto,
L.A. Dawson, J.J. Hagan, N. Upton, M.S. Duxon, A novel 5-HT1A/B autoreceptor
antagonist and serotonin reuptake inhibitor, is anxiolytic and displays fast
onset activity in the rat high light social interaction test, Neuro-
psychopharmacology 32 (2007) 2163e2172;
5.5.9. 1-(Benzo[d]thiazol-2-yl)-5-(4-pyrimidin-2-yl-piperazin-1-
yl)-pentan-1-one hydrochloride (21)
The product was converted into the HCl salt, followed by crys-
tallization from MeOHeEt2O to give the pure compound. Yield
(b) P. Blier, C. De Montigny, Current advances and trends in the treatment of
depression, Trends Pharmacol. Sci. 15 (1994) 220e226.
(35%), mp: 202e203 ꢁC; 1H NMR (DMSO-d6):
d 11.06 (brs, 1H), 8.41
[4] J.P. Guilloux, D.J. David, B.P. Guiard, F. Chenu, C. Repérant, M. Toth, M. Bourin,
A.M. Gardier, Blockade of 5HT1A receptors by (þ/ꢀ)-pindolol potentiates
cortical 5HT outflow, but not antidepressant-like activity of paroxetine:
microdialysis and behavioral approaches in 5HT1A receptor knockout mice,
Neuropsychopharmacology 31 (2006) 2162e2172.
[5] A. Khan, Vilazodone: a novel dual-acting serotonergic antidepressant for
managing major depression, Expert Opin. Investig. Drugs 18 (2009)
1753e1764.
(d, 2H, J ¼ 4.8 Hz), 8.25e8.21 (m, 2H), 7.68e7.61 (m, 2H), 6.74 (t, 1H,
J ¼ 4.8 Hz), 4.65 (d, 2H, J ¼ 7.8 Hz), 3.54e3.50 (m, 2H), 3.47e3.38 (m,
2H), 3.34e3.30 (m, 2H), 3.17e3.11 (m, 2H), 3.05e2.94 (m, 2H),
1.87e1.82 (m, 2H), 1.79e1.71 (m, 2H). Anal. C20H25Cl2N5OS: C,
52.86; H, 5.55; N, 15.41. Found: C, 52.66; H, 5.66; N, 15.36.
[6] A.M. Birch, P.A. Bradley, J.C. Gill, F. Kerrigan, P.L. Needham, N-Substituted (2,3-
dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D(2) antagonists/
5HT(1A) partial agonists with potential as atypical antipsychotic agents,
J. Med. Chem. 42 (1999) 3342e3355.
[7] M. Tatsumi, K. Groshan, R.D. Blakely, E. Richelson, Pharmacological profile of
antidepressants and related compounds at human monoamine transporters,
Eur. J. Pharmacol. 340 (1997) 249e258.
5.5.10. 1-(Benzo[d]thiazol-2-yl)-5-(4-phenyl-piperazin-1-yl)-
pentan-1-one hydrochloride (22)
The product was converted into the HCl salt, followed by crys-
tallization from MeOHeEt2O to give the pure compound. Yield
(37%). mp: 216e217 ꢁC; 1H NMR (DMSO-d6):
d 10.85 (brs, 1H),
[8] R.H. Howland, Vilazodone: another novel atypical antidepressant drug,
J. Psychosoc. Nurs. Ment. Health Serv. 49 (2011) 19e22.
[9] J.E. Frampton, Vilazodone (Viibryd): a new antidepressant, Med. Lett. Drugs
Ther. 53 (2011) 53e54.
[10] K. Peprah, X.Y. Zhu, S.V.K. Eyunni, J.R. Etukala, V. Setola, B.L. Roth,
S.Y. Ablordeppey, Structureeactivity relationship studies of SYA 013,
8.26e8.22 (m, 2H), 7.68e7.59 (m, 2H), 7.24 (dd, 2H, J ¼ 7.2, 8.7 Hz),
6.97 (d, 2H, J ¼ 7.8 Hz), 6.84 (t, 1H, J ¼ 7.2 Hz), 3.80e3.77 (m, 2H),
3.55e3.52 (m, 2H), 3.35e3.31 (t, 2H, J ¼ 6.6 Hz), 3.17e3.07 (m, 6H),
1.85e1.81 (m, 2H), 1.78e1.71 (m, 2H). Anal. Calcd for
C22H26ClN3OS$0.7H2O: C, 61.65; H, 6.11; N, 9.80. Found: C, 61.82; H,
6.45; N 9.62.
a
homopiperazine analog of haloperidol, Bioorg. Med. Chem. 20 (2012)
1671e1678.
[11] (a) O. Mnie-Filali, L. Lambás-Señas, L. Zimmer, N. Haddjeri, 5-HT7 receptor
antagonists as a new class of antidepressants, Drug News Perspect. 20 (2007)
613e618;
5.5.11. 1-(Benzo[d]thiazol-2-yl)-5-(4-phenyl-piperidin-1-yl)-
pentan-1-one hydrochloride (23)
(b) S.M. Bromidge, B. Bertani, M. Borriello, S. Faedo, L.J. Gordon, E. Granci,
M. Hill, H.R. Marshall, L.P. Stasi, V. Zucchelli, G. Merlo, A. Vesentini,
J.M. Watson, L. Zonzini, 6-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-
3(4H)-ones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake
inhibitors, Bioorg. Med. Chem. Lett. 18 (2008) 5653e5656.
The product was converted into the HCl salt, followed by crys-
tallization from MeOHeEt2O to give the pure compound. Yield
(39%), mp: 204e205 ꢁC; 1H NMR (DMSO-d6):
d 10.71 (brs, 1H),
8.26e8.22 (m, 2H), 7.68e7.59 (m, 2H), 7.34e7.29 (m, 2H), 7.23e7.18
(m, 3H), 3.54e3.51 (m, 2H), 3.30e3.24 (m, 2H), 3.12e3.05 (m, 2H),
2.93e3.01 (m, 2H), 2.83e2.75 (m, 1H), 2.02e2.15 (m, 2H), 1.90e1.94
(m, 2H), 1.88e1.82 (m, 2H), 1.77e1.70 (m, 2H). Anal. Calcd for
C23H28Cl2N2OS: C, 66.57; H, 6.56; N, 6.75. Found: C, 66.37; H, 6.56;
N, 6.77.
[12] M.J. Millan, Dual- and triple-acting agents for treating core and co-morbid
symptoms of major depression: novel concepts, new drugs, Neuro-
therapeutics 6 (2009) 53e77.
[13] N.T. Hatzenbuhler, R. Baudy, D.A. Evrard, A. Failli, B.L. Harrison, S. Lenicek,
R.E. Mewshaw, A. Saab, U. Shah, J. Sze, M. Zhang, D. Zhou, M. Chlenov,
M. Kagan, J. Golembieski, G. Hornby, M. Lai, D.L. Smith, K.M. Sullivan,
L.E. Schechter, T.H. Andree, Advances toward new antidepressants with dual
serotonin transporter and 5-HT1A receptor affinity within
a class of 3-
aminochroman derivatives, J. Med. Chem. 51 (2008) 6980e7004.
[14] J.M. Watson, L.A. Dawson, Characterization of the potent 5-HT(1A/B) receptor
antagonist and serotonin reuptake inhibitor, preclinical evidence for hastened
onset of antidepressant/anxiolytic efficacy, CNS Drug Rev. 13 (2007) 206e223.
[15] T. Heinrich, H. Böttcher, R. Gericke, G.D. Bartoszyk, S. Anzali, C.A. Seyfried,
H.E. Greiner, C.V. Amsterdam, Synthesis and structureeactivity relationship in
5.6. Receptor binding studies
Binding affinities reported in Tables 1e4 were conducted by the
National Institute of Mental Health Psychoactive Drug Screening