GABAA Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 435
129.3, 129.2, 128.8, 128.0, 127.1, 125.1, 120.1, 103.0, 73.2, 52.7,
43.7, 34.6, 29.4, 27.0, 22.1.
4.20 (2H, m), 3.83 (2H, s), 3.67 (3H, s), 2.75-2.94 (3H, m),
1.69-1.78 (4H, m). 13C NMR (CDCl3) δ: 171.6, 170.8, 156.0,
154.3, 136.2, 129.3, 128.7(2C), 128.5, 128.1, 127.7, 126.7, 123.7,
120.6, 120.5, 102.8, 71.7, 53.1, 44.1, 34.9, 29.7, 20.4.
4-[(7-Bromo-2-naphthyl)methyl]-5-(4-piperidyl)-3-isox-
azolol Hydrobromide (6c). Compound 6c was prepared as
described for 6b using 14c (100 mg, 0.2 mmol) in a solution of
HBr in water (48%, 2 mL). Recrystalllization (MeOH/Et2O)
gave 6c (70 mg, 73%) as pale brown crystals: mp > 210 °C.
1H NMR (CD3OD) δ: 8.00 (1H, s), 7.81 (1H, d, J ) 8.4 Hz),
7.74 (1H, J ) 8.8 Hz), 7.64 (1H, s), 7.52 (1H, d, J ) 8.8 Hz),
7.44 (1H, d, J ) 8.4 Hz), 3.89 (2H, s), 3.38-3.42 (2H, m), 3.17-
3.27 (1H, m), 3.01-3.10 (2H, m), 1.91-2.07 (4H, m). 13C NMR
(CD3OD) δ: 171.1, 170.8, 139.7, 136.0, 131.9, 130.5, 130.4,
129.7, 129.2, 128.4, 126.2, 120.9, 105.3, 44.6, 33.0, 27.5. Anal.
(C19H19BrN2O2‚HBr) C,H,N.
4-[(1-Fluoro-2-naphthyl)methyl]-5-(4-piperidyl)-3-isox-
azolol Hydrobromide (6e). Compound 6e was prepared as
described for 6a using 14e (80 mg, 0.17 mmol) in a solution of
HBr in AcOH (33%, 6 mL). Recrystalllization (MeOH/Et2O)
1
gave 6e (30 mg, 44%) as colorless crystals: mp > 210 °C. H
NMR (300 MHz, CDCl3) δ: 8.03 (1H, d, J ) 8.5 Hz), 7.83-
7.86 (1H, m), 7.61 (1H, d, J ) 8.5), 7.46-7.56 (2H, m), 7.31-
7.36 (1H, m), 3.88 (2H, s), 3.36-3.43 (1H, m), 3.06-3.21 (2H,
m), 2.97-3,07(2H, m), 1.88-2.00 (4H, m). Anal. (C19H19FN2O2‚
HBr) C,H,N.
4-[(5-Bromo-2-naphthyl)hydroxymethyl]-3-isopropoxy-
5-(1-methoxycarbonyl-4-piperidyl)isoxazol (13d). From
the same procedure as described for 13b, the title compound
was prepared using 1212 (2.5 g, 6.34 mmol) in THF (9 mL),
EtMgBr (0.94 M in THF, 6.75 mL, 6.43 mmol), and 17d (1.49
g, 6.34 mmol) in THF (6.8 mL). FC (toluene/EtOAc (1:1)) gave
13d (0.95 g, 30%) as viscous oil. 1H NMR (CDCl3) δ: 8.21 (1H,
d, J ) 8.8 Hz), 7.85 (1H, s), 7.93 (2H, d, J ) 7.8 Hz), 7.55 (1H,
dd, J ) 8.8 and 1.6 Hz), 7.34 (1H, dd, J ) 7.8 and 7.8 Hz),
5.90 (1H, s), 4.86-4.98 (1H, m), 4.09 (2H, br s), 3.66 (3H, s),
2.56-2.79 (4H, m), 1.50-1.83 (4H, m), 1.36 (3H, d, J ) 6.2
Hz), 1.31 (3H, d, J ) 6.2 Hz). 13C NMR (CDCl3) δ: 171.7, 168.9,
155.7, 140.5, 134.3, 131.4, 130.1, 127.9, 127.5, 126.8, 125.7,
124.7, 122.7, 107.0, 74.0, 66.2, 52.8, 43.8, 43.7, 34.8, 29.8, 29.2,
22.2, 22.1.
4-[(5-Bromo-2-naphthyl)methyl]-3-isopropoxy-5-(1-
methoxycarbonyl-4-piperidyl)isoxazol (14d). Compound
14d was prepared as described for 14b using 13d (0.88 g, 1.75
mmol) in in dry CH2Cl2 (7 mL), triethylsilane (450 µL, 2.8
mmol), and TFA (3.65 mL). Dry CC (toluene/EtOAc (4:1)) gave
the product as a viscous oil (0.81 g, 95%). 1H NMR (CDCl3) δ:
8.15 (1H, d, J ) 8.7 Hz), 7.69-7.74 (2H, m), 7.54 (1H, s), 7.41
(1H, dd, J ) 8.7 and 1.8 Hz), 7.30 (1H, dd, J ) 7.8 and 7.8
Hz), 4.92 (1H, hep, J ) 6.2 Hz), 4.14 (2H, br s), 3.80 (2H, s),
3.68 (3H, s), 2.73-2.83 (3H, m), 1.67-1.87 (4H, m), 1.34 (6H,
d, J ) 6.2 Hz). 13C NMR (CDCl3) δ: 170.9, 170.1, 155.8, 137.8,
134.7, 130.8, 129.6, 128.2, 127.5, 126.6, 126.5, 122.7, 103.1,
73.4, 52.8, 43.8, 34.8, 29.5, 26.8, 22.2.
4-[(1-Chloro-2-naphthyl)hydroxymethyl]-3-isopropoxy-
5-(1-methoxycarbonyl-4-piperidyl)isoxazol (13f). Com-
pound 13f was prepared as described for 13a using 1212 (0.27
g, 0.69 mmol), in dry THF (5 mL), iPrMgCl (2.0 M in hexane,
0.37 mL, 0.74 mmol), and 17f (0.14 g, 0.74 mmol) in dry THF
(2 mL). Dry CC (toluene/EtOAc (3:1)) of the crude product gave
13f as a colorless oil (0.17 g, 54%). 1H NMR (300 MHz, CDCl3)
δ: 8.26 (1H, d, J ) 9.2 Hz), 7.79-7.87 (2H, m), 7.49-7.62 (2H,
m), 7.11-7.17 (1H, m), 6.28 (1H, d, J ) 1.3 Hz), 4.89 (1H, hep,
J ) 6.1 Hz), 4.01-4.17 (2H, m), 3.65 (3H, s), 2.31-2.62 (3H,
m), 1.51-1.80 (4H, s), 1.37 (3H, d, J ) 6.1 Hz), 1.31 (3H, d, J
) 6.1 Hz). 13C NMR (CDCl3) δ: 171.8, 169.2, 156.0, 134.2,
131.0, 129.3, 128.5, 128.4, 127.8, 127.2, 127.1, 124.8, 124.7,
106.1, 74.3, 64.7, 53.1, 44.2, 44.0, 35.1, 29.9, 29.8, 22.5.
4-[(1-Chloro-2-naphthyl)methyl]-3-isopropoxy-5-(1-
methoxycarbonyl-4-piperidyl)isoxazol (14f). Compound
14f was prepared as described for 14a using 13f (0.16 g, 0.35
mmol), triethylsilane (0.09 mL, 0.56 mmol) in dry CH2Cl2 (5
mL), and TFA (1.22 mL). Dry CC (toluene/EtOAc (4:1)) of the
crude product gave 14f as a yellow oil (0.13 g, 87%). 1H NMR
(300 MHz, CDCl3) δ: 8.28 (1H, d, J ) 8.5 Hz), 7.79 (1H, d, J
) 8.0 Hz), 7.66 (1H, d, J ) 8.5 Hz), 7.45-7.60 (2H, m), 7.28
(1H, d, J ) 8.5 Hz), 4.29 (1H, hep, J ) 6.1), 4.03-4.17 (2H,
m), 3.94 (2H, s), 3.66 (3H, s), 2.66-2.85 (3H, m), 1.56-1.82
(4H, m), 1.34 (6H, d, J ) 6.1 Hz). 13C NMR (CDCl3) δ: 171.4,
170.3, 156.0, 134.4, 133.6, 131.3, 130.5, 128.3, 127.6, 127.1,
126.6, 124.7, 102.7, 73.6, 53.1, 44.1, 35.0, 29.7, 25.7, 22.5.
4-[(1-Chloro-2-naphthyl)methyl]-5-(4-piperidyl)-3-isox-
azolol Hydrobromide (6f) Compound 14f (0.12 g, 0.26 mmol)
was dissolved in a solution of HBr in water (48%, 4 mL), and
the mixture was refluxed for 1 h. The mixture was cooled and
evaporated, and the residue was evaporated twice from toluene
(5 mL) and recrystallized (MeOH/Et2O) to give 6f (72 mg, 66%)
as colorless crystals: mp > 210 °C. 1H NMR (300 MHz, CDCl3)
δ: 8.26 (1H, d, J ) 8.3 Hz), 7.84 (1H, d, J ) 8.0 Hz), 7.77 (1H,
d, J ) 8.5 Hz), 7.49-7.59 (2H, m), 7.38 (1H, d, J ) 8.5 Hz),
4.03 (2H, s), 3.33-3.39 (2H, m), 3.08-3.17 (1H, m), 2.94 (2H,
dt, J ) 12.4 and 3.6 Hz), 1.84-2.03 (4H, m). Anal. (C19H19-
ClN2O2‚HBr) C,H,N.
4-[(5-Bromo-2-naphthyl)methyl]-5-(4-piperidyl)-3-isox-
azolol Hydrobromide (6d). Compound 6d was prepared as
described for 6b using 13d (140 mg, 0.29 mmol) in a solution
of HBr in water (48%, 3 mL). Recrystalllization (MeOH/Et2O)
gave 6d (100 mg, 74%) as colorless crystals: mp > 210 °C. 1H
NMR (CD3OD) δ: 8.14 (1H, d, J ) 8.7 Hz), 7.82 (1H, d, J )
7.9 Hz), 7.75 (1H, d, J ) 7.9 Hz), 7.72 (1H, s), 7.53 (1H, d, J
) 8.7 Hz), 7.35 (1H, dd, 7.9 and 7.9 Hz), 3.92 (2H, s), 3.18-
3.43 (3H, m), 3.01-3.10 (2H, m), 1.95-2.07 (4H, m), Anal.
(C19H19BrN2O2‚HBr‚0.5 H2O) C,H,N.
3-Benzyloxy-4-[(1-fluoro-2-naphthyl)hydroxymethyl]-
5-(1-methoxycarbonyl-4-piperidyl)isoxazol (13e). Com-
pound 13e was prepared as described for 13a using 11 (0.40
1-Bromo-7-bromomethylnaphthalene (16b).17 A solution
of 15b17 (0.2 g, 0.9 mmol) in CCl4 (5 mL) was treated under
reflux with N-bromosuccinimide (NBS) (a total of 170 mg, 0.95
mmol) and benzoyl peroxide (a total of 3 mg, 0.012 mmol) over
a period of 3 h. Each of the reagents was added in three equal
portions every 1 h. After being stirred for 40 h at 75 °C, the
reaction mixture was filtered while warm and concentrated
to give the crude product. FC (petroleum ether (80-100 °C))
and recrystalllization (petroleum ether (40-65 °C)) gave the
product as colorless crystals (170 mg; 62%): mp 112-116 °C.
1H NMR (CDCl3) δ: 8.22 (1H, s), 7.78-7.84 (3H, m), 7.56 (1H,
dd, J ) 8.5 and 1.8 Hz), 7.33 (1H, dd, J ) 8.5 and 7.4 Hz),
4.70 (2H, s). 13C NMR (CDCl3) δ: 136.8, 134.3, 131.8, 130.6,
129.4, 127.8, 127.1, 127.0, 122.9, 33.6. Anal. (C11H8Br2) C,H,N.
8-Bromonaphthalene-2-carbaldehyde (17b). 2-Nitro-
propane (350 µL, 3.9 mmol) was added to a solution of NaOEt
(3.8 mmol) in EtOH (8 mL). A colorless precipitate was formed
immediately. Compound 16b (1.13 g, 3.8 mmol) was added to
the mixture, and stirring was continued for 65 h at room
temperature. The reaction mixture was filtered and concen-
trated, and to the residue were added Et2O (100 mL) and water
i
g, 0.9 mmol) in dry THF (3 mL), PrMgCl (1.9 M in hexane,
0.47 mL, 0.9 mmol), and 17e (0.17 g, 1.0 mmol) in dry THF (2
mL). Dry CC (toluene/EtOAc (3:1)) of the crude product gave
the product as a colorless oil (0.15 g, 35%). 1H NMR (300 MHz,
CDCl3) δ: 8.03-8.07 (1H, m), 7.84-7.87 (1H, m), 7.60-7.70
(2H, m), 7.52-7.56 (2H, m), 7.23-7.32 (4H, m), 7.18 (1H, d, J
) 8.5 Hz), 6.28 (1H, s), 5.23 (2H, s), 4.12-4.21 (2H, m), 3.69
(3H, s), 2.60-2.97 (3H, m), 1.58-1.83 (4H, s). 13C NMR (CDCl3)
δ: 172.1, 169.5, 156.0, 135.8, 134.5, 129.3, 128.6, 128.5, 128.1,
127.7, 127.2, 126.8, 125.5, 124.3, 123.7, 120.8, 120.7, 106.4,
71.9, 61.1, 53.0, 44.1, 44.0, 35.0, 29.8.
3-Benzyloxy-4-[(1-fluoro-2-naphthyl)methyl]-5-(1-meth-
oxycarbonyl-4-piperidyl)isoxazol (14e). Compound 14e
was prepared as described for 14a using 13e (0.13 g, 0.3 mmol),
triethylsilane (0.07 mL, 0.43 mmol) in dry CH2Cl2 (2 mL), and
TFA (0.65 mL, 8.4 mmol). Dry CC (toluene/EtOAc (4:1)) of the
crude product gave 14e as a colorless oil (80 mg, 58%). 1H NMR
(300 MHz, CDCl3) δ: 8.04 (1H, d, J ) 8.7 Hz), 7.79-7.83 (1H,
m), 7.46-7.56 (3H, m), 7.19-7.31 (6H, m), 5.25 (2H, s), 4.14-