Blockers of Voltage-Gated Na+ Channels
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5245
(m, 2H, Ar HC-2,6), 7.43-7.30 (m, 3H, Ar HC-3,4,5), 7.15 (d
overlapping apparent t at 7.14, J ) 8.1 Hz, 1H, ArO HC-3),
7.14 (apparent t overlapping d at 7.15, J ) 7.8 Hz, 1H, ArO
HC-5), 6.89 (apparent t, J ) 7.8 Hz, 1H, ArO HC-4), 6.80 (d,
J ) 8.1 Hz, 1H, ArO HC-2), 5.15 (dd, J ) 8.38, 3.50 Hz, 1H,
CH), 4.13 (dd, J ) 9.48, 3.50 Hz, 1H, CHHO); 4.03 (dd, J )
9.48, 8.38 Hz, 1H, CHHO), 2.8 (br s, 1H, exch D2O, OH), 2.17
(s, 3H, CH3); 13C NMR δ 156.4 (1C), 139.8 (1C), 130.8 (1C),
128.5 (2C), 128.1 (1C), 126.8 (1C), 126.7 (1C), 126.2 (2C), 120.9
(1C), 113.3 (1C), 73.3 (1C), 72.6 (1C), 16.2 (1C); MS (70 eV)
m/z (%) 228 (M+, 35), 108 (100).
(2C), 70.0 (1C), 55.2 (1C), 16.3 (2C); MS (70 eV) m/z (%) 371
(M+, 2), 250 (100).
(-)-(R)-2-[(2,6-Dim et h ylp h en oxy)-1-p h en ylet h yl]-1H -
isoin d ole-1,3(2H)-d ion e [(-)-(R)-15c]. 81% yield, oil; [R]20
) -43 (c 2, CHCl3).
D
(-)-(S)-2-(2-P h en oxy-1-p h en yleth yl)-1H-isoin d ole-1,3-
(2H)-d ion e [(-)-(S)-15a ]. 45% yield, oil; [R]20 ) -42 (c 2,
D
CHCl3); IR (CHCl3): 1776, 1713 (CdO) cm-1; 1H NMR δ 7.86-
7.80 [m, 2H, Ar(CO)2N HC-4,7], 7.73-7.67 [m, 2H, Ar(CO)2N
HC-5,6], 7.60-7.57 (m, 2H, Ph HC-2,6), 7.41-7.31 (m, 3H, Ph
HC-3,4,5), 7.27-7.21 (m, 2H, ArO HC-3,5), 6.96-6.88 (m, 3H,
ArO HC-2,4,6), 5.79 (dd, J ) 9.9, 5.4 Hz, 1H, CH), 5.19
(apparent t, J ) 9.0 Hz, 1H, CHH), 4.54 (dd, J ) 9.6, 5.4 Hz,
1H, CHH); 13C NMR δ 168.3 (2C), 158.2 (1C), 136.5 (1C), 134.0
(2C), 131.7 (2C), 129.4 (2C), 128.8 (2C), 128.2 (2C), 123.3 (2C),
121.2 (2C), 114.9 (2C), 66.5 (1C), 54.4 (1C); MS (70 eV) m/z
(%) 343 (M+, 3), 236 (100).
(+)-(S)-2-(2-Meth ylp h en oxy)-1-p h en yleth a n ol [(+)-(S)-
14b]. 43% yield, oil; [R]20 ) +22 (c 2, CHCl3).
D
(-)-(R)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n ol [(-)-(R)-
14d ]. 46% yield, oil; [R]20 ) -27 (c 2, CHCl3); IR (CHCl3):
D
3541 (OH), 2855, 1170 (C-O-C) cm-1; H NMR δ 7.38-7.27
1
(m, 5H, Ar), 7.22-7.11 (m, 2H, ArO HC-3,5), 6.82-6.74 (m,
2H, ArO HC-2,6), 5.21 (dd, J ) 8.1, 3.6 Hz, 1H, CH), 3.92 (dd,
J ) 12.5, 8.1 Hz, 1H, CHH), 3.81 (dd, J ) 12.5, 3.6 Hz, 1H,
CHH), 2.21 (br d, 1H, exch D2O, OH); 13C NMR δ 156.4 (1C),
137.3 (1C), 129.3 (2C), 128.9 (2C), 128.4 (1C), 126.3 (2C), 126.2
(1C), 117.3 (2C), 81.6 (1C), 67.5 (1C); MS (70 eV) m/z (%) 248
(M+, 3), 128 (100).
(+)-(R)-2-(2-P h en oxy-1-p h en yleth yl)-1H-isoin d ole-1,3-
(2H)-d ion e [(+)-(R)-15a ]. 31% yield, oil; [R]20 ) +42 (c 2,
D
CHCl3).
(-)-(S)-2-[2-(2-Meth ylph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(-)-(S)-15b]. 75% yield, oil; [R]20D ) -44
1
(c 2, CHCl3); IR (CHCl3): 1778, 1730 (CdO) cm-1; H NMR δ
7.85-7.81 [m, 2H, Ar(CO)2N HC-4,7], 7.74-7.69 [m, 2H, Ar-
(CO)2N HC-5,6], 7.61-7.59 (m, 2H, Ph HC-2,6), 7.41-7.35 (m,
3H, Ph HC-3,4,5), 7.14 (apparent t, J ) 8.1 Hz, 1H, ArO HC-
5), 7.06 (d, J ) 6.0 Hz, 1H, ArO HC-3), 6.87 (d overlapping
apparent t at 6.85, J ) 8.1 Hz, 1H, ArO HC-6), 6.85 (apparent
t overlapping d at 6.87, J ) 7.8 Hz, 1H, ArO HC-4), 5.86 (dd,
J ) 9.0, 6.0 Hz, 1H, CH), 5.11 (t, J ) 9.4 Hz, 1H, CHH), 4.58
(dd, J ) 9.0, 6.0 Hz, 1H, CHH), 1.98 (s, 3H, CH3); 13C NMR δ
168.4 (2C), 156.3 (1C), 136.6 (1C), 134.1 (2C), 131.9 (1C), 130.7
(2C), 128.8 (2C), 128.4 (1C), 128.2 (2C), 126.8 (2C), 123.4 (2C),
120.9 (1C), 111.4 (1C), 66.4 (1C), 54.4 (1C), 15.9 (1C); MS (70
eV) m/z (%) 357 (M+, 6), 250 (100).
(+)-(S)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n ol [(+)-(S)-
14d ]. 37% yield, oil; [R]20 ) +36 (c 2, CHCl3).
D
(-)-(R)-2-(4-Ch lor o-2-m et h ylp h en oxy)-1-p h en ylet h a -
n ol [(-)-(R)-14e]. 42% yield, oil; [R]20 ) -26 (c 2, CHCl3);
D
IR (CHCl3): 3591 (OH), 2861, 1133 (C-O-C) cm-1; H NMR
1
δ 7.48-7.31 (m, 5H, Ar), 7.12 (s, 1H, ArO HC-3), 7.08 (d, J )
8.4 Hz, 1H, ArO HC-5), 6.70 (d, J ) 8.4 Hz, 1H, ArO HC-6),
5.14 (dd, J ) 9.2, 2.8 Hz, 1H, CH), 4.07 (dd, J ) 9.2, 9.1 Hz,
1H, CHH), 4.01 (dd, J ) 9.2, 2.8 Hz, 1H, CHH), 2.74 (br s,
1H, exch D2O, OH), 2.22 (s, 3H, CH3); 13C NMR δ 155.0 (1C),
139.6 (1C), 130.4 (2C), 128.4 (2C), 128.0 (1C), 126.3 (1C), 126.1
(2C), 125.6 (1C), 112.7 (1C), 73.5 (1C), 72.5 (1C), 16.0 (1C);
MS (70 eV) m/z (%) 262 (M+, 25), 142 (100).
(+)-(R)-2-[2-(2-Meth ylph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(+)-(R)-15b]. 76% yield, oil; [R]20D ) +26
(c 2, CHCl3).
(+)-(S)-2-(4-Ch lor o-2-m et h ylp h en oxy)-1-p h en ylet h a -
n ol [(+)-(S)-14e]. 39% yield, oil; [R]20 ) +24 (c 1.6, CHCl3).
D
(-)-(S)-2-[2-(4-Ch lor oph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(-)-(S)-15d ]. 46% yield, oil; [R]20D ) -46
(-)-(R)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n ol [(-)-(R)-14f]. 39% yield, oil; [R]20 ) -13 (c 1.8,
1
(c 2, CHCl3); IR (CHCl3): 1775, 1724 (CdO) cm-1; H NMR δ
D
CHCl3); IR (CHCl3): 3599 (OH), 2866, 1183 (C-O-C) cm-1
;
7.87-7.81 [m, 2H, Ar(CO)2N HC-4,7], 7.74-7.68 [m, 2H,
Ar(CO)2N HC-5,6], 7.48-7.45 (m, 2H, Ph HC-2,6), 7.39-7.27
(m, 3H, Ph HC-3,4,5), 7.09-7.03 (m, 2H, ArO HC-3,5), 6.76-
6.70 (m, 2H, ArO HC-2,6), 5.51 (dd, J ) 9.1, 4.3 Hz, 1H, CH),
4.27 (dd, J ) 14.0, 9.2 Hz, 1H, CHH), 3.91 (dd, J ) 14.0, 4.3
Hz, 1H, CHH); 13C NMR δ 167.5 (2C), 155.8 (1C), 137.4 (1C),
133.6 (2C), 131.4 (1C), 128.7 (2C), 128.4 (2C), 128.1 (2C), 125.8
(2C), 125.6 (1C), 122.9 (2C), 116.8 (2C), 76.1 (1C), 43.7 (1C);
MS (70 eV) m/z (%) 250 (M+ - 127, 100).
1H NMR δ 7.45-7.28 (m, 5H, Ar), 6.98 (s, 2H, ArO), 5.12 (dd,
J ) 6.4, 5.3 Hz, 1H, CH), 3.89 (dd, J ) 9.6, 6.4 Hz, 1H, CHH),
3.81 (dd, J ) 9.6, 5.3 Hz, 1H, CHH), 2.93 (br s, 1H, exch D2O,
OH), 2.17 (s, 6H, CH3); 13C NMR δ 153.7 (1C), 140.2 (1C), 139.6
(1C), 132.4 (1C), 128.7 (1C), 128.5 (2C), 128.3 (2C), 128.1 (1C),
126.1 (2C), 76.5 (1C), 73.3 (1C), 16.2 (2C); MS (70 eV) m/z (%)
276 (M+, 1), 156 (100).
(+)-(S)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n ol [(+)-(S)-14f]. 36% yield, oil; [R]20D ) +16 (c 2, CHCl3).
(+)-(R)-2-[2-(4-Ch lor oph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(+)-(R)-15d ]. 81% yield, oil; [R]20D ) +30
(c 2, CHCl3).
Gen er a l P r oced u r e for th e Syn th esis of 2-(2-Ar yloxy-
1-p h en yleth yl)-1H-isoin d ole-1,3(2H)-d ion es (15a -f).18 The
preparation of (+)-(S)-2-[2-(2,6-dimethylphenoxy)-1-phenyl-
ethyl]-1H-isoindole-1,3(2H)-dione [(+)-(S)-15c] will be de-
scribed. To a mixture of (-)-(R)-14c (0.87 g, 3.6 mmol),
phthalimide (0.79 g, 5.4 mmol) and triphenylphosphine (1.41
g, 5.4 mmol) in 50 mL of anhydrous THF was added dropwise
1.08 g (5.37 mmol) of diisopropylazodicarboxylate (DIAD) in
50 mL of anhydrous THF. The reaction mixture was stirred
at room temperature for 24 h. The solvent was evaporated,
and the crystals of the side products were precipitated by
addition of Et2O. After their removal by filtration, column
chromatography (petroleum ether/ethyl acetate 9:1) of the
(-)-(S)-2-[2-(4-Ch lor o-2-m eth ylph en oxy)-1-ph en yleth yl]-
1H-isoin d ole-1,3(2H)-d ion e [(-)-(S)-15e]. 79% yield, oil;
[R]20D ) -59 (c 2, CHCl3); IR (CHCl3): 1776, 1714 (CdO) cm-1
;
1H NMR δ 7.85-7.81 [m, 2H, Ar(CO)2N HC-4,7], 7.74-7.70
[m, 2H, Ar(CO)2N HC-5,6], 7.59-7.55 (m, 2H, Ph HC-2,6),
7.40-7.30 (m, 3H, Ph HC-3,4,5), 7.08 (dd, J ) 8.5, 2.2 Hz, 1H,
ArO HC-5), 7.02 (d, J ) 1.9 Hz, 1H, ArO HC-3), 6.78 (d, J )
8.6 Hz, 1H, ArO HC-6), 5.81 (dd, J ) 9.9, 5.6 Hz, 1H, CH),
5.07 (apparent t, J ) 9.7 Hz, 1H, CHH), 4.53 (dd, J ) 9.5, 5.6
Hz, 1H, CHH), 1.94 (s, 3H, CH3); 13C NMR δ 168.3 (2C), 155.0
(1C), 136.4 (1C), 134.1 (2C), 131.8 (1C), 130.5 (2C), 128.8 (2C),
128.5 (2C), 128.2 (2C), 126.4 (2C), 123.4 (2C), 112.6 (1C), 66.8
(1C), 54.4 (1C), 15.8 (1C); MS (70 eV) m/z (%) 391 (M+, 4), 250
(100).
crude oil afforded 15c (1.07 g, 80%) as a yellowish oil; [R]20
)
D
1
+35 (c 2.2, CHCl3); IR (CHCl3): 1776, 1721 (CdO) cm-1; H
NMR δ 7.87-7.82 [m, 2H, Ar(CO)2N HC-4,7], 7.73-7.69 [m,
2H, Ar(CO)2N HC-5,6], 7.58-7.55 (m, 2H, Ph HC-2,6), 7.38-
7.30 (m, 3H, Ph HC-3,4,5), 6.98-6.94 (m, 2H, ArO HC-3,5),
6.91-6.86 (m, 1H, ArO HC-4), 5.85 (dd, J ) 10.0, 5.7 Hz, 1H,
CH), 5.06 (apparent t, J ) 9.8 Hz, 1H, CHH), 4.28 (dd, J )
9.5, 5.6 Hz, 1H, CHH), 2.21 (s, 6H, CH3); 13C NMR δ 168.4
(2C), 155.3 (1C), 136.8 (1C), 134.0 (2C), 132.0 (1C), 130.8 (1C),
128.9 (2C), 128.8 (2C), 128.3 (2C), 128.2 (2C), 124.0 (2C), 123.3
(+)-(R)-2-[2-(4-Ch lor o-2-m eth ylph en oxy)-1-ph en yleth yl]-
1H-isoin d ole-1,3(2H)-d ion e [(+)-(R)-15e]. 75% yield, oil;
[R]20 ) +40 (c 2, CHCl3).
D
(+)-(S)-2-[2-(4-Ch lor o-2,6-d im eth ylp h en oxy)-1-p h en yl-
eth yl]-1H-isoin d ole-1,3(2H)-d ion e [(+)-(S)-15f]. 39% yield,
oil; [R]20 ) +12 (c 2, CHCl3); IR (CHCl3): 1775, 1711 (CdO)
D
cm-1; 1H NMR δ 7.88-7.82 [m, 2H, Ar(CO)2N HC-4,7], 7.74-