PAP-1, A Selective Small Molecule Kv1.3 Blocker
1259
carbonate (2.0 g) were refluxed in 30 ml of 2-butanone for 16 h. The 7.4 Hz, 3Љ-H, 5Љ-H), 7.60 (d, 1H, 3J ϭ 2.4 Hz, 5Ј-H), 7.50 (t, 2H, 3J ϭ
oily residue was recrystallized from 70% methanol to obtain a white 7.7 Hz, 4Љ-H), 7.15 (s, 1H, 8-H), 6.99 (d, 1H, 3J ϭ 2.5 Hz, 4Ј-H), 6.26
solid (123 mg, 12.3%): m.p. ϭ 90.9°C; 1H NMR (500 MHz, CDCl3): ␦ (d, 1H, 3J ϭ 9.8 Hz, 4-H) 4.59 (t, 2H, 3J ϭ 6.2 Hz, 5-OCH2CH2CH-
[ppm] ϭ 8.19 (d, 1H, 3J ϭ 9.7 Hz, 3-H), 7.59 (d, 1H, 3J ϭ 2.2 Hz, 2COC6H5), 3.28 (t, 2H, 3J ϭ 6.8 Hz, 5-OCH2CH2CH2COC6H5), 2.38
5Ј-H), 7.37 (m, 5H, 5-OCH2CH2OCH 2C6H5), 7.19 (s, 1H, 8-H), 6.95 (p, 2H, 3J ϭ 6.5 Hz, 5-OCH2CH2CH2COC6H5); MS (70 eV) m/z: 348
(d, 1H, 3J ϭ 2.0 Hz, 4Ј-H), 6.25 (d, 1H, 3J ϭ 9.7 Hz, 4-H), 4.64 (s, 2H, (34%, Mϩ), 202 (5%, [C11H6O4]ϩ), 147(99%, C10H10O), 174, (5%, [202-
5-OCH2CH2OCH2C6H5), 4.58 (t, 2H, 3J ϭ 4.62 Hz, 5-OCH2CH2OC- CO]ϩ), 105 (71%, C3H6), 77 (33%, C6H5); calculated for C21H16O5
H2C6H5), 3.88 (t, 2H, 3J ϭ 4.56 Hz, 5-OCH2CH2OCH2C6H5); MS (70 (348.36): C, 72.41%; H, 4.63%; O, 22.96%. Found: C, 72.18%; H,
eV) m/z: 336 (35%, Mϩ), 105 (5%), 91 (100%, [C7H7]ϩ); calculated for 4.75%; LogP, 3.31.
C
20H16O5 (336.35): C, 71.42%; H, 4.79%; O, 23.78%. Found: C,
5-[4-(4-Methoxyphenoxy)butoxy]psoralen (AS-67). 5-HOP
70.65%; H, 4.73%; LogP, 3.34.
(300 mg, 1.5 mmol), 1-bromo-4-(4-methoxyphenoxy)butane (600 mg,
5-(5-Phenoxypentoxy)psoralen (AS-121). 1-Bromo-5-phenoxy- 2.5 mmol, obtained by general method C), and potassium carbonate
pentane was synthesized according to general method C using 1,5- (2.0 g) were refluxed in 30 ml of acetone for 24 h. The crude product
dibromopentane instead of 1,4-dibromobutane. 5-HOP (300 mg, 1.5 was recrystallized from methanol-water (80:20) as a white solid (201
mmol), 1-bromo-5-phenoxypentane (600 mg, 2.6 mmol), and potas- mg, 35.2%): m.p. ϭ 111.5°C; 1H NMR (300 MHz, DMSO-d6): ␦ [ppm]
sium carbonate (2.0 g) were then refluxed in 30 ml of acetone for 24 h.
ϭ 8.18 (d, 1H, 3J ϭ 9.8 Hz, 4-H), 8.03 (d, 1H, 3J ϭ 2.3 Hz, 5Ј-H), 7.32
The crude product was recrystallized from methanol/water (80:20) as to 7.34 (m, 2H, 8-H and 4Ј-H), 6.81 to 6.87 (m, 4H, 5-OCH2(CH2)2C-
a white solid (232 mg, 42.4%): m.p. ϭ 91°C; 1H NMR (300 MHz, H2OC6H4OCH3), 6.81 to 6.87 (m, 4H, 5-OCH2(CH2)2CH2OC6H4OC-
DMSO-d6): ␦ [ppm] ϭ 8.19 (d, 1H, 3J ϭ 9.7 Hz, 4-H), 8.02 (s, 1H, H3), 6.30 (d, 1H, 3J ϭ 9.8 Hz, 3-H), 4.57 (t, 2H, 3J ϭ 5.7 Hz, 5-OC-
5Ј-H), 7.25 to 7.33 (m, 4H, 8-H, 4Ј-H and 5-OCH2CH2CH2CH2CH2
-
H2(CH2)2CH2OC6H4OCH3), 4.00 (t, 2H, 3J ϭ 5.8 Hz, 5-OCH2(CH2)2
-
OC6H5), 6.90 to 6.93 (m, 3H, 5-OCH2CH2CH2CH2CH2OC6H5), 6.30 CH2OC6H4OCH3), 3.69 (s, 3H, -OCH3), 1.91 to 1.99 (m, 4H, 5-OCH-
(d, 1H, 3J ϭ 9.7 Hz, 3-H), 4.52 (t, 2H, 3J ϭ 6.0 Hz, 5-OCH2CH2CH- 2(CH2)2CH2OC6H4OCH3); MS (70 eV) m/z: 380 (14%, Mϩ), 257 (8%),
2CH2CH2OC6H5), 4.00 (t, 2H, 3J ϭ 6.2 Hz, 5-OCH2CH2CH2CH2CH- 215 (7%), 202 (5%, [C11H6O4]ϩ), 179 (69%, [C11H15O2]ϩ), 145 (6%),
2OC6H5), 1.77 to 1.93 (m, 4H, 5-OCH2CH2CH2CH2CH2OC6H5), 1.63 137 (100%, [CH3OC6H4OCH2]ϩ), 109 (29%), 107 (18%, [C6H5OCH-
to 1.71 (m, 2H, 5-OCH2CH2CH2CH2CH2OC6H5); MS (70 eV) m/z: 364 2]ϩ), 77 (23%, [C6H5]ϩ), 55 (61%, [C4H7]ϩ), 41 (15%, [C3H5]ϩ); calc-
Mϩ (9%, Mϩ), 202 (22%, [C11H6O4]ϩ), 163 (44%, [C11H15O]ϩ), 107 ulated for C22H20O6 (380.4): C, 69.46%; H, 5.30%; O, 25.24%. Found:
(40%, [C6H5O-CH2]ϩ), 69 (100%, [C5H9]ϩ), 41 (52%, [C3H5]ϩ); calcu- C, 69.52%; H, 5.39%; LogP, 3.89.
lated for C22H20O5 (364.40): C, 72.51%; H, 5.53%; O, 21.96%. Found:
C, 72.74%; H, 5.68%; LogP, 4.40.
5-[4-(3-Methoxyphenoxy)butoxy]psoralen (AS-68). 5-HOP
(300 mg, 1.5 mmol), 1-bromo-4-(3-methoxyphenoxy)butane (600 mg,
5-(4-Benzyloxybutoxy)psoralen (PAP-6). 5-HOP (700 mg, 3.5 2.5 mmol, obtained by general method C), and potassium carbonate
mmol), benzyl-4-bromobutyl ether (850 mg, 3.5 mmol), and potas- (2.0 g) were refluxed in 30 ml of acetone for 24 h. The crude product
sium carbonate (2.0 g) were refluxed in 30 ml of 2-butanone for 24 h.
was recrystallized from methanol-water (80:20) as a white solid (178
The oily residue was recrystallized from 80% methanol (171 mg, mg, 31.2%): m.p. ϭ 102.5°C; 1H NMR (300 MHz, DMSO-d6): ␦ [ppm]
13.4%): m.p. ϭ 78.4°C; 1H NMR (500 MHz, CDCl3): ␦ [ppm] ϭ 8.14 (d, ϭ 8.18 (d, 1H, 3J ϭ 9.8 Hz, 4-H), 8.02 (d, 1H, 3J ϭ 1.9 Hz, 5Љ-H), 7.33
1H, 3J ϭ 9.8 Hz, 3-H), 7.55 (d, 1H, 3J ϭ 2.5 Hz, 5Ј-H), 7.34 (m, 5H, (s, 2H, 8-H and 4Ј-H), 7.15 (t, 1H, 3J ϭ 8.14 Hz, 8-H), 6.45 to 6.51 (m,
5-OCH2CH2CH2CH2OCH2C6H5), 7.13 (s, 1H, 8-H), 6.91 (d, 1H, 3J ϭ 3H, 2Љ-H, 4Љ-H and 6Љ-H), 6.29 (d, 1H, 3J ϭ 9.8 Hz, 3-H), 4.58 (t, 2H,
2.4 Hz, 4Ј-H), 6.25 (d, 1H, 3J ϭ 9.8 Hz, 4-H), 4.54 (s, 2H, 5-OCH2C- 3J ϭ 5.4 Hz, 5-OCH2(CH2)2CH2OC6H4OCH3), 4.05 (t, 2H, 3J ϭ 5.4
H2CH2CH2OCH2C6H5), 4.49 (t, 2H, 3J ϭ 6.5 Hz, 5-OCH2CH2CH2C- Hz, 5-O-CH2(CH2)2CH2OC6H4OCH3), 3.71 (s, 3H, -OCH3), 1.91 to
H2OCH2C6H5), 3.59 (t, 2H, 3J ϭ 6.1 Hz, 5-OCH2CH2CH2CH2OCH- 1.99 (m, 4H, 5-OCH2(CH2)2CH2OC6H4OCH3); MS (70 eV) m/z: 380
2C6H5), 2.00 (p, 2H, 3J ϭ 6.9 Hz, 5-OCH2CH2CH2CH2OCH2C6H5), (14%, Mϩ), 257 (8%), 202 (5%, [C11H6O4]ϩ), 179 (84%, [C11H15O2]ϩ),
1.87 (p, 2H, 3J ϭ 6.8 Hz, 5-OCH2CH2CH2CH2OCH2C6H5); MS (70 145 (6%), 137 (100%, [CH3OC6H4OCH2]ϩ), 109 (14%), 107 (32%,
eV) m/z: 364 (37%, Mϩ), 292 (10%), 202 (7%, [C11H6O4]ϩ), 174 (6%, [C6H5OCH2]ϩ), 77 (27%, [C6H5]ϩ), 55 (63%, [C4H7]ϩ), 41 (12%,
[202-CO]ϩ), 163 (12%), 91 (100%, C7H7), 71 (8%); calculated for C22
H20O5 (364.40): C, 72.51%; H, 5.53%; O, 21.95%. Found: C, 72.36%;
H, 5.46%; LogP, 4.02.
-
[C3H5]ϩ); calculated for C22H20O6 (380.4): C, 69.46%; H, 5.30; O,
25.24%. Found: C, 69.89%; H, 5.38%; LogP, 3.99.
5-[4-(3,5-Dimethoxyphenoxy)butoxy]psoralen (AS-69).
5-(3-Benzyloxypropoxy)psoralen (PAP-7). 5-HOP (1.0 g, 4.9 5-HOP (300 mg, 1.5 mmol), 1-bromo-4-(3,5-dimethoxyphenoxy)bu-
mmol), benzyl-3-bromopropyl ether (1.36 g, 5.9 mmol), and potas- tane (700 mg, 2.6 mmol, obtained by general method C) and potas-
sium carbonate (3.4 g) were refluxed in 30 ml of 2-butanone for 24 h.
sium carbonate (2.0 g) were refluxed in 30 ml of acetone for 24 h. The
The oily residue was recrystallized from 70% methanol (700 mg, crude product was recrystallized from methanol/acetone (80:20) as a
40.4%): m.p. ϭ 75.2°C; 1H NMR (500 MHz, CDCl3): ␦ [ppm] ϭ 8.06 (d, white solid (182 mg, 29.6%): m.p. ϭ 139°C; 1H NMR (300 MHz,
1H, 3J ϭ 9.7 Hz, 3-H), 7.57 (d, 1H, 3J ϭ 2.2 Hz, 5Ј-H), 7.29 (m, 5H, DMSO-d6): ␦ [ppm] ϭ 8.19 (d, 1H, 3J ϭ 9.8 Hz, 4-H), 8.03 (d, 1H, 3J ϭ
3J ϭ 6.3 Hz, 5-OCH2CH2CH2OCH2C6H5), 7.15 (s, 1H, 8-H), 6.98 (d, 2.1 Hz, 5Ј-H), 7.34 (s, 2H, 8-H and 4Ј-H), 6.31 (d, 1H, 3J ϭ 9.8 Hz,
1H, 3J ϭ 2.2 Hz, 4Ј-H), 6.21 (d, 1H, 3J ϭ 9.8 Hz, 4-H), 4.58 (t, 2H, 3-H), 6.07 (s, 3H, 2Љ-H, 4Љ-H and 6Љ-H), 4.58 (t, 2H, 3J ϭ 5.4 Hz,
3J ϭ 6.1 Hz, 5-OCH2CH2CH2OCH2C6H5), 4.55 (s, 2H, 5-OCH2CH2
CH2OCH2C6H5), 3.73 (t, 2H, 3J ϭ 5.7 Hz, 5-OCH2CH2CH2OCH2C6
-
5-OCH2(CH2)2CH2OC6H3(OCH3)2), 4.05 (t, 2H, 3J ϭ 5.4 Hz,
5-OCH2(CH2)2CH2OC6H3(OCH3)2), 3.69 (s, 6H, -(OCH3)2), 1.93 to
-
H5), 2.18 (p, 2H, 3J ϭ 6.1 Hz, 5-OCH2CH2CH2OCH2C6H5); MS (70 1.97 (m, 4H, 5-OCH2(CH2)2CH2OC6H3(OCH3)2); MS (70 eV) m/z: 410
eV) m/z: 350 (25%, Mϩ), 202 (9%, [C11H6O4]ϩ), 174 (5%, [202-CO]ϩ), (12%, Mϩ), 209 (100%, [C12H17O3]ϩ), 202 (5%, [C11H6O4]ϩ), 167
91 (100%, [C7H7]ϩ); calculated for C21H18O5(350.37): C, 71.99%; H, (75%, [(CH3O)2C6H3OCH2]ϩ), 137 (34%, [CH3OC6H4OCH2]ϩ), 122
5.18%; O, 22.83%. Found: C, 71.64%; H, 5.34%; LogP, 3.66.
(15%), 107 (10%, [C6H5OCH2]ϩ), 77 (11%, [C6H5]ϩ), 55 (46%,
5-(4-Phenyl-3-oxobutoxy)psoralen (KP-1). 4-Chlorobutyro- [C4H7]ϩ), 41 (6%, [C3H5]ϩ); calculated for C23H22O7 (410.43): C,
phenone (497 mg, 2.7 mmol) and sodium iodide (445 mg, 2.9 mmol) 67.31%; H, 5.40%; O, 27.29%. Found: C, 66.92%; H, 5.60%; LogP,
were refluxed in 30 ml of acetone for 1.5 h to obtain the iodo deriv- 3.94.
ative. To this slurry were added 5-HOP (500 mg, 2.5 mmol), potas-
sium carbonate (2.0 g), and the resulting mixture was then refluxed
5-[4-(4-Nitrophenoxy)butoxy]psoralen (AS-78). 5-HOP (300
mg, 1.5 mmol), 1-bromo-4-(4-nitrophenoxy)butane (700 mg, 2.7
for 140 h. The solid residue was recrystallized from a petroleum mmol, obtained by general method C), and potassium carbonate (2.0
ether/acetone (90:10) mixture (295 mg, 34.3%): m.p. ϭ 129.1°C; 1H g) were refluxed in 30 ml of acetone for 24 h. The crude product was
NMR (500 MHz, CDCl3): ␦ [ppm] ϭ 8.13 (d, 1H, 3J ϭ 9.9 Hz, 3-H), recrystallized from methanol/acetone (80:20) as a yellow solid (291
8.01 (d, 2H, 3J ϭ 7.9 Hz, 4J ϭ 0.95 Hz, 2Љ-H, 6Љ-H), 7.62 (t, 1H, 3J ϭ mg, 49.1%): m.p. ϭ 132°C; 1H NMR (300 MHz, DMSO-d6): ␦ [ppm] ϭ