4788 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Brief Articles
1
generated a white solid: mp 134 °C, dec; H NMR (400 MHz,
DMSO-d6) δ 2.93-3.16 (m, 2H), 3.18-3.53 (m, 5H), 3.78-3.99
(m, 1H), 4.24-4.55 (m, 2H), 6.84-7.01 (m, 1H), 7.09-7.26 (m,
2H), 7.30-7.49 (m, 4H), 7.82 (s, 1H), 9.18 (s, 1H), 11.08 (s, 1H);
MS (ES) m/z 370.2 ([M - H]-). Anal. (C20H19F2N3O2‚1HCl‚
0.25H2O) C, H, N.
General Procedure C (Introduction of Cyclobutyl on Basic
Nitrogen): 3-{Cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]-
amino}-8-fluorochromane-5-carboxamide (26). To 19 (0.14 g,
0.35 mmol) in anhydrous MeOH (6 mL) under nitrogen at room
temperature were added cyclobutanone (0.070 mL, 0.876 mmol),
acetic acid (0.050 mL, 0.84 mmol), and sodium cyanoborohydride
(0.044 g, 0.70 mmol). The mixture was stirred at room temperature
overnight. More cyclobutanone (0.026 mL), acetic acid (0.21 mL),
and sodium cyanoborohydride (0.22 g) were added after 24 and
48 h, at which time the reaction went to completion. The workup
was the same as for Procedure B. Chromatography (5:4:1 EtOAc/
hexane/MeOH (1% NH4OH)) afforded 0.12 g (78%) of 26 as a
sticky gum. Conversion to the mono-HCl salt generated an off-
Figure 2. Acute in vivo microdialysis study of 26a. Oral treatment
with 30 mg/kg significantly (p < 0.05) increased 5-HT levels compared
to the lower dose (3 mg/kg) or vehicle-treated rats, suggesting that
this compound crosses the blood-brain barrier to activate the 5-HT1A
receptor and 5-HT transporter. These results are consistent with
published literature showing that combining SSRI treatment with a
5-HT1A antagonist increases 5-HT levels in this brain region.8
1
white solid: mp 109 °C, dec; H NMR (500 MHz, DMSO-d6) δ
1.51-1.75 (m, 2H), 1.85-2.57 (m, 7H), 2.59-2.76 (m, 2H), 3.06-
3.48 (m, 3H), 3.88-4.14 (m, 2H), 4.31-4.43 (m, 1H), 4.45-4.59
(m, 1H), 6.84-6.95 (m, 1H), 7.10-7.25 (m, 3H), 7.26-7.35 (m,
2H), 7.38-7.49 (m, 1H), 7.72-7.89 (m, 1H), 10.11-10.42 (m, 1H),
10.93 (s, 1H); MS (ES) m/z 438.2 ([M - H]-). Anal. (C25H27F2N3O2‚
1.10HCl‚0.50H2O) C, H, N. The enantiomers of 26 were separated
by chiral HPLC using a Chiralcel AD column (2 cm × 25 cm) and
16% IPA in hexane/DEA as the mobile phase. They were isolated
and characterized as mono-HCl salts. 26a (white solid): mp 129
°C, dec; [R]25D -26.76° (c 1%, DMSO); 99.5% ee by chiral HPLC;
MS (ES) m/z 440.1 ([M + H]+). Anal. (C25H27F2N3O2‚1HCl‚
500 MHz spectrometer. Chemical shifts δ are reported in ppm
relative to DMSO-d6 at 2.49 ppm or CHCl3-d at 7.27 ppm as an
internal standard. Mass spectra were recorded on a Micromass LCT
spectrometer. CHN combustion analyses were determined on a
Perkin-Elmer 2400 analyzer or were performed by Robertson
Microlit (Madison, NJ). All analyzed compounds are within (0.4%
of the theoretical value unless otherwise indicated. Optical rotations
were measured using a Jasco P-1020 polarimeter. Solvents and
reagents were used as purchased. All final targets were converted
to the HCl salt by dissolution in ethyl acetate and addition of 1 M
HCl/Et2O, followed by filtration unless otherwise indicated.
General Procedure A (Alkylation Reaction): 8-Fluoro-3-
{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}chromane-5-carbox-
amide (19). A solution of 8 (0.81 g, 3.8 mmol), 11 (n ) 1) (0.55
g, 2.1 mmol), and triethylamine (0.60 mL, 4.2 mmol) in anhydrous
DMSO (20 mL) was stirred at 90 °C for 9.5 h. The mixture was
cooled to room temperature, diluted with EtOAc, and extracted with
H2O (2×). The organic layer was treated with brine, dried over
anhydrous MgSO4, filtered, and concentrated. Chromatography (5:
4:1 EtOAc/hexane/MeOH (1% NH4OH)) afforded 0.48 g (60%)
of 19 as a peach solid. Conversion to the mono-HCl salt generated
an off-white solid: mp 122 °C, dec; 1H NMR (500 MHz, DMSO-
d6) δ 1.90-2.08 (m, 2H), 2.68-2.82 (m, 2H), 2.98-3.25 (m, 3H),
3.27-3.45 (m, 2H), 3.71-3.88 (m, 1H), 4.27-4.46 (m, 2H), 6.82-
6.98 (m, 1H), 7.08-7.21 (m, 2H), 7.22-7.27 (m, 1H), 7.27-7.37
(m, 2H), 7.43 (s, 1H), 7.81 (s, 1H), 9.00 (s, 1H), 10.95 (s, 1H);
>99.9% ee by chiral HPLC; MS (ESI) m/z 384([M - H]-). Anal.
(C21H21F2N3O2‚1.20HCl) C, H, N. Chiral separation of 19 was
carried out by SFC on a Chiralcel AS column (2 cm × 25 cm)
using 40% MeOH in CO2 (100 bar). The enantiomers were isolated
and characterized as mono-HCl salts. 19a (white solid): mp 89
°C, dec; [R]25D +19.8° (c 1%, DMSO); MS (ES) m/z 384.2 ([M -
H]-). Anal. (C21H21F2N3O2‚1HCl‚1.20H2O) C, H. N: calcd 9.47,
0.40H2O) C, H, N. 26b (white solid): mp 129 °C, dec; [R]25
D
+27.56° (c 1%, DMSO); 95% ee by chiral HPLC; MS (ES) m/z
438.2([M - H]-). Anal. (C25H27F2N3O2‚1HCl‚0.50H2O) C, H, N.
Acknowledgment. The authors thank Discovery Analytical
Chemistry for HPLC and NMR studies, and Dr. Douglas M.
Ho for X-ray studies. We thank Dr. Minsheng Zhang and Mr.
Andrew Steiner for the synthesis of some intermediates and final
compounds.
Supporting Information Available: Details of synthesis and
analytical data for all final targets, biological assays, and in vivo
microdialysis. This material is available free of charge via the
References
(1) Blackwell, B. Adverse effects of antidepressant drugs. Part 1:
Monoamine oxidase inhibitors and tricyclics. Drugs 1981, 21, 201-
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(2) Evrard, D. A.; Harrison, B. L. Recent approaches to novel antidepres-
sant therapy. Annu. Rep. Med. Chem. 1999, 34, 1-9.
(3) Katz, M. M.; Tekell, J. L.; Bowden, C. L.; Brannan, S.; Houston, J.
P.; Berman, N.; Frazer, A. Onset and early behavioral effects of
pharmacologically different antidepressants and placebo in depression.
Neuropsychopharmacology 2004, 29, 566-579 and references
therein.
(4) Kreiss, D. S.; Lucki, I. Effects of acute and repeated administration
of antidepressant drugs on extracellular levels of 5-hydroxytryptamine
measured in vivo. J. Pharmacol. Exp. Ther. 1995, 274, 866-876.
(5) (a) Briner, K.; Dodel, R. C. New approaches to rapid onset
antidepressants. Curr. Pharm. Des. 1998, 4, 291-302. (b) Schechter,
L. E.; Kelly, M. G. An overview of 5-HT1A receptor antagonists:
historical perspective and therapeutic targets. Serotonin 1997, 2, 299-
309.
(6) Ballesteros, J.; Callado, L. F. Effectiveness of pindolol plus serotonin
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found 10.06. 19b (white solid): mp 87°C, dec; [R]25 -16.0° (c
D
1%, DMSO); >99.9% ee by chiral HPLC; MS (ES) m/z 386.1 ([M
+ H]+).
General Procedure B (Reductive Amination): 8-Fluoro-3-
{[2-(5-fluoro-1H-indol-3-yl)ethyl]amino}chromane-5-carbox-
amide (20). To 8 (0.38 g, 1.8 mmol) in anhydrous MeOH (29 mL)
under nitrogen at room temperature were added 12 (n ) 0) (0.33
g, 1.89 mmol), acetic acid (0.23 mL, 4.32 mmol), and sodium
cyanoborohydride (0.23 g, 3.6 mmol). The mixture was stirred at
room temperature overnight, quenched with 1 N NaOH/H2O, and
concentrated. The residue was taken up in CH2Cl2/H2O and
extracted with CH2Cl2 (3×). The organic layer was treated with
brine, dried over anhydrous MgSO4, filtered, and concentrated.
Chromatography (5:4:1 EtOAc/hexane/MeOH (1% NH4OH)) af-
forded 0.53 g (79%) of 20. Conversion to the mono-HCl salt
(7) Romero, L.; Artigas, F. Preferential potentiation of the effects of
serotonin uptake inhibitors by 5-HT1A receptor antagonists in the
dorsal Raphe pathway: role of somatodendritic autoreceptors. J.
Neurochem. 1997, 68, 2593-2603.