Centrally Active Tricyclic Isoxazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2069
under nitrogen atmosphere. After stirring the reaction mixture
at room temperature overnight, it was filtered off, and the
solids were washed with dichloromethane and methanol. The
filtrate was evaporated till dryness, and the residue was
purified by column chromatography (dichloromethane/ethyl
acetate 2/1 and dichloromethane/methanol 97/3), affording 45a
(0.15 g, 28%) as a white solid: mp >300 °C (dec); 1H NMR
(400 MHz, CDCl3) δ ppm 1.91 (s, 3 H) 2.49 (br s, 4 H) 2.64 (br
s, 4 H) 2.82 (dd, J ) 13.3, 5.5 Hz, 1 H) 2.88 (dd, J ) 13.3, 6.0
Hz, 1 H) 3.02 (s, 2 H) 3.45 (s, 3 H) 3.65 (td, J ) 12.4, 5.8 Hz,
1 H) 3.75 (m, 2 H) 4.08 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.11 (m,
2 H) 4.41 (m, 1 H) 4.61 (dd, J ) 10.4, 5.8 Hz, 1 H) 6.43 (s, 1 H)
6.47 (d, J ) 2.3 Hz, 1 H) 6.62 (dd, J ) 8.7, 2.3 Hz, 1 H) 7.20
(t, J ) 7.1 Hz, 1 H) 7.31 (m, 4 H) 7.68 (d, J ) 8.7 Hz, 1 H).
HRMS Calcd for C28H36N3O4 (M + 1): 478.2706. Found:
478.2725. Anal. (C28H35N3O4) C, H, N.
The following compounds were prepared analogously.
Propionic Acid 3-[4-(2-Methyl-3-phenyl-2(E)-propen-
1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-[1]benzopy-
rano[4,3-c]isoxazol-7-yl Ester (45f). Light yellow foam:
1
yield 23%; H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J ) 7.5
Hz, 3 H) 1.91 (d, J ) 1.2 Hz, 3 H) 2.49 (br s, 4 H) 2.59 (q, J )
7.5 Hz, 2 H) 2.64 (br s, 4 H) 2.83 (dd, J ) 13.3, 5.8 Hz, 1 H)
2.89 (dd, J ) 13.3, 6.2 Hz, 1 H) 3.02 (s, 2 H) 3.68 (td, J ) 12.4,
5.8 Hz, 1 H) 4.10 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.45 (m, 1 H)
4.64 (dd, J ) 10.4, 5.8 Hz, 1 H) 6.43 (s, 1 H) 6.73 (d, J ) 2.5
Hz, 1 H) 6.74 (dd, J ) 8.3, 2.5 Hz, 1 H) 7.20 (t, J ) 7.3 Hz, 1
H) 7.30 (m, 4 H) 7.78 (d, J ) 8.3 Hz, 1 H). MS m/z 476 (MH+).
Anal. (C28H33N3O4) C, H, N.
Methoxyacetic Acid 3-[4-(2-Methyl-3-phenyl-2(E)-pro-
pen-1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-[1]ben-
zopyrano[4,3-c]isoxazol-7-yl Ester (45g). White solid from
diisopropyl ether: yield 41%; mp 140.5 °C; 1H NMR (400 MHz,
CDCl3) δ ppm 1.90 (d, J ) 1.2 Hz, 3 H) 2.47 (br s, 4 H) 2.61
(br s, 4 H) 2.82 (dd, J ) 13.3, 5.6 Hz, 1 H) 2.89 (dd, J ) 13.3,
6.0 Hz, 1 H) 3.01 (s, 2 H) 3.54 (s, 3 H) 3.69 (td, J ) 12.4, 5.8
Hz, 1 H) 4.11 (dd, J ) 12.4, 10.5 Hz, 1 H) 4.28 (s, 2 H) 4.45
(m, 1 H) 4.65 (dd, J ) 10.4, 5.8 Hz, 1 H) 6.42 (s, 1 H) 6.77 (d,
J ) 2.3 Hz, 1 H) 6.78 (dd, J ) 7.3, 2.3 Hz, 2 H) 7.20 (t, J ) 7.3
Hz, 1 H) 7.31 (m, 4 H) 7.80 (d, J ) 7.3 Hz, 1 H). MS m/z
492 (MH+). Anal. (C28H33N3O5) H, N; C: calcd, 68.41; found,
67.98
The following compounds were prepared analogously
7-[2-(2-Ethoxyethoxy)ethoxy]-3-[4-(2-methyl-3-phenyl-
2(E)-propen-1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-
[1]benzopyrano[4,3-c]isoxazole (45b). White foam: yield
32%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J ) 7.1
Hz, 3 H) 2.06 (s, 3 H) 3.43 (q, J ) 7.1 Hz, 2 H) 3.53 (m, 14 H)
3.73 (m, 2 H) 3.86 (td, J ) 12.4, 5.8 Hz, 1 H) 3.92 (s, 2 H) 4.12
(m, 2 H) 4.16 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.77 (m, 2 H) 6.59
(d, J ) 2.5 Hz, 1 H) 6.67 (dd, J ) 8.7, 2.5 Hz, 1 H) 6.82 (s, 1
H) 7.31 (t, J ) 7.1 Hz, 1 H) 7.39 (m, 4 H) 7.57 (d, J ) 8.7 Hz,
1 H). Anal. (C31H41N3O5) C, H, N.
7-Cyclopentyloxy-3-[4-(2-methyl-3-phenyl-2(E)-propen-
1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-[1]benzopy-
rano[4,3-c]isoxazole (45c). White foam: yield 19%; 1H NMR
(400 MHz, CDCl3) δ ppm 1.62 (m, 2 H) 1.79 (m, 2 H) 1.86 (m,
2 H) 1.90 (d, J ) 1.2 Hz, 2 H) 1.91 (m, 2 H) 2.47 (br s, 4 H)
2.63 (br s, 4 H) 2.81 (dd, J ) 13.3, 5.4 Hz, 1 H) 2.88 (dd, J )
13.3, 6.2 Hz, 1 H) 3.01 (s, 2 H) 3.64 (td, J ) 12.4, 5.8 Hz, 1 H)
4.08 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.40 (m, 1 H) 4.60 (dd, J )
10.2, 5.8 Hz, 1 H) 4.74 (m, 1 H) 6.41 (d, J ) 2.5 Hz, 1 H) 6.42
(s, 1 H) 6.54 (dd, J ) 8.7, 2.5 Hz, 1 H) 7.20 (t, J ) 7.2 Hz, 1 H)
7.27 (m, 2 H) 7.33 (m, 2 H) 7.66 (d, J ) 8.7 Hz, 1 H). MS m/z
488 (MH+). Anal. (C30H37N3O5) C, H, N.
7-(2-Dimethylaminoethoxy)-3-[4-(2-methyl-3-phenyl-
2(E)-propen-1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-
[1]benzopyrano[4,3-c]isoxazole (45d). Light yellow solid
from diisopropyl ether: yield 24%; mp 174.9 °C; 1H NMR (400
MHz, CDCl3) δ ppm 1.91 (s, 3 H) 2.35 (s, 6 H) 2.48 (br s, 4 H)
2.63 (br s, 4 H) 2.75 (t, J ) 5.6 Hz, 2 H) 2.82 (dd, J ) 13.2, 5.5
Hz, 1 H) 2.88 (dd, J ) 13.2, 6.0 Hz, 1 H) 3.01 (s, 2 H) 3.65 (td,
J ) 12.4, 5.9 Hz, 1 H) 4.07 (m, 3 H) 4.40 (m, 1 H) 4.61 (dd, J
) 10.3, 5.9 Hz, 1 H) 6.42 (s, 1 H) 6.46 (d, J ) 2.5 Hz, 1 H) 6.60
(dd, J ) 8.7, 2.5 Hz, 1 H) 7.20 (t, J ) 7.2 Hz, 1 H) 7.31 (m, 4
H) 7.68 (d, J ) 8.7 Hz, 1 H). HRMS Calcd for C29H39N4O3:
491.3022. Found: 491.3003. Anal. (C29H38N4O3) C, H, N.
Cyclopropanecarboxylic Acid 3-[4-(2-Methyl-3-phenyl-
2(E)-propen-1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-
[1]benzopyrano[4,3-c]isoxazol-7-yl Ester (45h). White
1
foam: yield 46%; H NMR (400 MHz, CDCl3) δ ppm 1.04 (m,
2 H) 1.16 (m, 2 H) 1.83 (m, 1 H) 1.90 (s, 3 H) 2.48 (br s, 4 H)
2.62 (br s, 4 H) 2.82 (dd, J ) 13.3, 5.6 Hz, 1 H) 2.89 (dd, J )
13.3, 6.0 Hz, 1 H) 3.01 (s, 2 H) 3.67 (td, J ) 12.4, 5.9 Hz, 1 H)
4.09 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.44 (m, 1 H) 4.63 (dd, J )
10.4, 5.9 Hz, 1 H) 6.42 (s, 1 H) 6.73 (d, J ) 2.1 Hz, 1 H) 6.75
(dd, J ) 8.5, 2.1 Hz, 1 H) 7.20 (t, J ) 7.1 Hz, 1 H) 7.30 (m, 4
H) 7.77 (d, J ) 8.5 Hz, 1 H). MS m/z 488 (MH+). Anal.
(C29H33N3O4) H, N; C: calcd, 71.44; found, 71.02.
Acrylic Acid 3-[4-(2-Methyl-3-phenyl-2(E)-propen-1-yl)-
piperazin-1-ylmethyl]-3a,4-dihydro-3H-[1]benzopyrano-
[4,3-c]isoxazol-7-yl Ester (45i). Light brown foam: yield
30%; 1H NMR (400 MHz, CDCl3) δ ppm 1.90 (d, J ) 1.2 Hz, 3
H) 2.48 (br s, 4 H) 2.62 (br s, 4 H) 2.82 (dd, J ) 13.3, 5.7 Hz,
1 H) 2.90 (dd, J ) 13.3, 6.0 Hz, 1 H) 3.01 (s, 2 H) 3.69 (td, J
) 12.4, 5.8 Hz, 1 H) 4.11 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.46 (m,
1 H) 4.65 (dd, J ) 10.4, 5.8 Hz, 1 H) 6.04 (dd, J ) 10.4, 1.1
Hz, 1 H) 6.31 (dd, J ) 17.3, 10.4 Hz, 1 H) 6.42 (s, 1 H) 6.62
(dd, J ) 17.3, 1.1 Hz, 1 H) 6.78 (s, 1 H) 6.80 (dd, J ) 7.9, 2.3
Hz, 1 H) 7.20 (t, J ) 7.2 Hz, 1 H) 7.31 (m, 4 H) 7.80 (dd, J )
7.9, 0.8 Hz, 1 H). MS m/z 474 (MH+). Anal. (C28H31N3O4) C,
H, N.
2,2-Dimethyl-propionic Acid 3-[4-(2-Methyl-3-phenyl-
2(E)-propen-1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-
[1]benzopyrano[4,3-c]isoxazol-7-yl Ester (45j). White
foam: yield 67%; 1H NMR (400 MHz, CDCl3) δ ppm 1.35 (s, 9
H) 1.90 (d, J ) 1.0 Hz, 3 H) 2.48 (br s, 4 H) 2.62 (br s, 4 H)
2.82 (dd, J ) 13.3, 5.6 Hz, 1 H) 2.89 (dd, J ) 13.3, 6.0 Hz, 1
H) 3.01 (s, 2 H) 3.68 (td, J ) 12.4, 5.9 Hz, 1 H) 4.10 (dd, J )
12.4, 10.4 Hz, 1 H) 4.45 (m, 1 H) 4.64 (dd, J ) 10.4, 5.8 Hz, 1
H) 6.42 (s, 1 H) 6.69 (d, J ) 2.3 Hz, 1 H) 6.71 (dd, J ) 8.5, 2.3
Hz, 1 H) 7.20 (t, J ) 7.2 Hz, 1 H) 7.31 (m, 4 H) 7.78 (d, J ) 8.5
Hz, 1 H). MS m/z 504 (MH+). Anal. (C30H37N3O4) C, H, N.
Isonicotinic Acid 3-[4-(2-Methyl-3-phenyl-2(E)-propen-
1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-[1]benzopy-
rano[4,3-c]isoxazol-7-yl Ester (45k). White foam: yield
24%; 1H NMR (400 MHz, CDCl3) δ ppm 1.91 (d, J ) 1.0 Hz, 3
H) 2.48 (br s, 4 H) 2.63 (br s, 4 H) 2.84 (dd, J ) 13.3, 5.7 Hz,
1 H) 2.91 (dd, J ) 13.3, 6.2 Hz, 1 H) 3.02 (s, 2 H) 3.72 (td, J
) 12.4, 5.9 Hz, 1 H) 4.14 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.48 (m,
1 H) 4.68 (dd, J ) 10.4, 5.9 Hz, 1 H) 6.43 (s, 1 H) 6.88 (s, 1 H)
6.89 (dd, J ) 7.9, 2.3 Hz, 1 H) 7.21 (t, J ) 7.2 Hz, 1 H) 7.31
(m, 4 H) 7.86 (dd, J ) 7.9, 1.2 Hz, 1 H) 7.99 (dd, J ) 6.0, 1.7
Hz, 2 H) 8.88 (dd, J ) 6.0, 1.5 Hz, 2 H). MS m/z 525 (MH+).
Anal. (C31H32N4O4) C, H, N.
General Procedure for the Preparation of Compounds
45e-k. Acetic Acid 3-[4-(2-Methyl-3-phenyl-2(E)-propen-
1-yl)piperazin-1-ylmethyl]-3a,4-dihydro-3H-[1]benzopy-
rano[4,3-c]isoxazol-7-yl Ester (45e). To a solution of 7-hy-
droxy-3-[4-(2-methyl-3-phenyl-2(E)-propen-1-yl)piperazin-1-
ylmethyl]-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazole 44
(0.1 g, 0.24 mmol) and triethylamine (0.05 mL, 0.36 mmol) in
dichloromethane (4 mL) stirred at 0 °C, was added acetyl
chloride (0.02 mL, 0.28 mmol) dropwise. After stirring for 3 h
at room temperature, a saturated aqueous NaHCO3 solution
was added, the organic layer was separated, dried (Na2SO4),
and filtered, and the solvent was evaporated. The residue was
purified by column chromatography (dichloromethane/metha-
nol 98/2), affording 45e (0.07 g, 63%) as a yellow solid after
recrystallization from diisopropyl ether: mp 125.5 °C; 1H NMR
(400 MHz, CDCl3) δ ppm 1.90 (s, 3 H) 2.30 (s, 3 H) 2.46 (br s,
4 H) 2.62 (br s, 4 H) 2.82 (dd, J ) 13.1, 5.6 Hz, 1 H) 2.89 (dd,
J ) 13.1, 6.0 Hz, 1 H) 3.01 (s, 2 H) 3.68 (td, J ) 12.4, 5.9 Hz,
1 H) 4.10 (dd, J ) 12.4, 10.4 Hz, 1 H) 4.45 (m, 1 H) 4.64 (dd,
J ) 10.4, 5.9 Hz, 1 H) 6.42 (s, 1 H) 6.73 (d, J ) 2.3 Hz, 1 H)
6.75 (dd, J ) 8.3, 2.3 Hz, 1 H) 7.20 (t, J ) 7.2 Hz, 1 H) 7.31
(m, 4 H) 7.79 (d, J ) 8.3 Hz, 1 H). HRMS Calcd for C27H32N3O4
(M + 1): 462.2393. Found: 462.2376.