Alkoxypsoralens, Nonpeptide Blockers of K+ Channels
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4547
OCH3), 2.28 (s, 3H, 4′-CH3); 13C NMR (75 MHz, CDCl3) δ
161.11 (C-2), 156.57 (C-7), 151.83 (C-8a), 151.68 (C-4), 143.25
(C-5′), 126.48 (C-4′), 115.66 (C-6), 113.94 (C-5), 113.61 (C-4a),
111.44 (C-3), 99.95 (C-8), 70.64 (4-CH2OCH3), 59.07 (4-
CH2OCH3), 7.84 (4′-CH3); MS m/z 244 (M+, 100), 229 (3), 216
(22), 201 (10), 185 (71), 173 (46), 157 (7), 145 (57), 128 (23).
Anal. (C14H12O4) C, H.
4-(Meth oxym eth yl)-7-(ph en acyloxy)cou m ar in (5a). Com-
pound 5a was synthesized from 7-hydroxy-4-(methoxymethyl)-
coumarin (1.0 g, 4.8 mmol) and ω-chloroacetophenone (0.75 g,
4.8 mmol) according to general method A (1290 mg, 83%): mp
184 °C; 1H NMR (300 MHz, CDCl3) δ 8.05-7.02 (m, 8H,
7-OCH2COC6H5 and 5-H, 8-H, and 6-H), 6.27 (s, 1H, 3-H), 4.67
(s, 2H, 4-CH2OCH3), 3.41 (s, 2H, 7-OCH2COC6H5), 3.31 (s, 3H,
4-CH2OCH3); MS m/z 324 (M+, 25), 105 (100), 91 (8), 77 (25).
Anal. (C19H16O5) C, H.
4-(Meth oxym eth yl)-4′-p h en ylp sor a len (5b). Compound
5b was prepared from 4.0 mmol of 5a according to general
method B (771 mg, 63%): mp 191 °C; 1H NMR (300 MHz,
CDCl3) δ 7.92 (s, 1H, 5-H), 7.81 (s, 1H, 5′-H), 7.63-7.41 (m,
6H, 4′-C6H5 and 8-H), 6.53 (s, 1H, 3-H), 4.69 (s, 2H, 4-CH2-
OCH3), 3.53 (s, 3H, 4-CH2OCH3); 13C NMR (75 MHz, CDCl3)
δ 130.90 (C-1′′), 129.20 (C-3′′ and C-5′′), 128.02 (C-4′′), 127.49
(C-4′′ and C-6′′), 123.91 (C-4′), 122.22 (C-6); MS m/z 306 (M+,
100), 278 (21), 247 (49), 235 (19), 214 (10), 207 (41), 189 (25),
178 (27). Anal. (C19H14O4) C, H.
5,8-Dih yd r oxyp sor a len (10c). 10b (500 mg, 2.3 mmol)
and 3 g of zinc dust were suspended in a mixture of acetone
(30 mL) and water (100 mL) at room temperature; 10 mL of
concentrated HCl was added dropwise. After 5 h the remain-
ing zinc dust was filtered off, and the filtrate was concentrated
under reduced pressure to one-half its volume and kept at 4
°C overnight. The precipitate was collected by vacuum filtra-
tion and recrystallized from water (311 mg, 62%): mp 268 °C
(lit.51 mp 270 °C).
155.73 (C-8a), 153.32 (C-4), 130.61 (C-6), 119.84 (C-5), 114.32
(C-4a), 111.75 (C-3), 98.71 (C-8), 80.59 (C-5′), 36.27 (C-4′), 20.18
(4′-CH3), 19.57 (4-CH3); MS m/z 216 (M+, 93), 201 (100), 188
(20), 173 (80), 145 (60), 117 (14), 115 (34). Anal. (C13H12O3)
C, H.
Ch lor om eth yla tion of P sor a len s. Ca u tion : Chlorodim-
ethyl ether is lachrymatory and highly carcinogenic; therefore
the following experiments must be conducted with extreme
caution. As chloromethylated compounds are highly sensitive
to hydrolysis, 15a , 16a , and 17a were only characterized by
1H NMR and MS.
8-(Ch lor om eth yl)-5-m eth oxyp sor a len (15a ). Compound
15a was prepared from 5-MOP (0.50 g, 2.3 mmol) according
to the method of Isaacs56 given for the chloromethylation of
trioxsalen (407 mg, 67%): mp 200 °C; 1H NMR (300 MHz,
3
3
CDCl3) δ 8.16 (d, 1H, J ) 9.8 Hz, 4-H), 7.64 (d, 1H, J ) 2.2
Hz, 5′-H), 7.04 (d, 1H, 3J ) 2.2 Hz, 4′-H), 6.30 (d, 1H, 3J ) 9.8
Hz, 3-H), 5.07 (s, 2H, 8-CH2Cl), 4.29 (s, 3H, 5-OCH3); MS m/z
264 (M+, 26), 229 (100), 201 (19), 186 (24).
5-Meth oxy-8-(m eth oxym eth yl)p sor a len (15b). 15a (400
mg, 1.5 mmol) was heated under reflux in 100 mL of methanol
for 6 h. The solvent was evaporated and the crude product
recrystallized from methanol to give 15b (246 mg, 63%): mp
176 °C; 1H NMR (300 MHz, CDCl3) δ 4.91 (s, 2H, 8-CH2OCH3),
4.26 (s, 3H, 5-OCH3), 3.38 (s, 3H, 8-CH2OCH3); 13C NMR (75
MHz, CDCl3) δ 160.80 (C-2), 157.74 (C-7), 150.80 (C-8a), 149.49
(C-5), 144.90 (C-5′), 139.33 (C-4), 112.27 (C-3), 106.18 (C-6),
105.51 (C-5), 105.15 (C-4′), 103.47 (C-8), 62.18 (8-CH2OCH3),
60.03 (5-OCH3), 58.44 (8-CH2OCH3); MS m/z 260 (M+, 39), 229
(100), 201 (23), 186 (24), 173 (6), 158 (5). Anal. (C14H12O5) C,
H.
4′-(Eth oxym eth yl)-4,5′,8-tr im eth ylp sor a len (17c). 17a
(200 mg, 0.72 mmol) was heated under reflux in 50 mL of
ethanol for 6 h. The solvent was evaporated and the crude
product recrystallized from ethanol to give 17c (160 mg,
1
5,8-Dieth oxyp sor a len (10d ). To a solution of 200 mg (0.9
mmol) of 10c in anhydrous acetone (100 mL) were added
potassium carbonate (5 g) and diethyl sulfate (1.0 mL, 3.6
mmol). The mixture was heated to reflux under nitrogen; after
3 h it was poured into cold water (200 mL) and acidified with
HCl. After 24 h the product was extracted with ethyl acetate
(3 × 100 mL), the organic layers were combined, and the
solvent was removed under reduced pressure to afford a
residue, which was purified by column chromatography using
3:1 ethyl acetate/cyclohexane as eluent. The desired fractions
were concentrated and dried to give 10d as a yellowish powder
82%): mp 124 °C; H NMR (300 MHz, CDCl3) δ 7.61 (s, 1H,
5-H), 6.24 (s, 1H, 3-H), 4.62 (s, 2H, 4′-CH2OCH2CH3), 3.55 (q,
2H, 4′-CH2OCH2CH3), 2.57-2.49 (3 × s, 9H, 4-CH3, 5′-CH3 and
8-CH3), 1.25 (t, 3H, 4′-CH2OCH2CH3); 13C NMR (75 MHz,
CDCl3) δ 161.54 (C-2), 155.05 (C-5′), 154.71 (C-7), 153.36 (C-
6), 149.21 (C-8a), 125.10 (C-4′), 116.14 (C-4), 112.74 (C-3),
112.16 (C-4a), 111.61 (C-5), 109.01 (C-8), 65.47 (4′-CH2OCH2-
CH3), 62.79 (4′-CH2OCH2CH3), 19.35 (5′-CH3), 15.24 (4′-CH2-
OCH2CH3), 12.33 (4-CH3), 8.47 (8-CH3); MS m/z 286 (M+, 35),
257 (5), 241 (62), 227 (17), 213 (16), 212 (284), 199 (20), 185
(8), 141 (16), 128 (27), 115 (28), 106 (17). Anal. (C17H18O4) C,
H.
1
(158 mg, 64%): mp 119 °C (lit.52 mp 105 °C); H NMR (300
3
3
MHz, CDCl3) δ 8.13 (d, 1H, J ) 9.8 Hz, 4-H), 7.61 (d, 1H, J
) 2.2 Hz, 5′-H), 6.92 (d, 1H, 3J ) 2.2 Hz, 4′-H), 6.28 (d, 1H, 3J
) 9.8 Hz, 3-H), 4.40 (two q, 4H, 5- and 8-OCH2CH3), 1.47 (two
t, 6H, 5- and 8-OCH2CH3); 13C NMR (75 MHz, CDCl3) δ 160.65
(C-2), 150.41 (C-7), 145.11 (C-5′), 144.08 (C-8a), 143.51 (C-5),
139.65 (C-4), 127 (C-8), 115.55 (C-6), 112.78 (C-3), 108.27 (C-
4a), 105.16 (C-4′), 69.95 and 69.43 (5- and 8-OCH2CH3), 15.62
(5- and 8-OCH2CH3); MS m/z 274 (M+, 55), 246 (24), 217 (100),
189 (17), 161 (13), 133 (6), 105 (8), 77 (10). Anal. (C15H14O5)
C, H.
4 ′-(T r i e t h y l a m m o n i o m e t h y l )-4 ,5 ′,8 -t r i m e t h y l -
p sor a len Ch lor id e (17d ). Compound 17d was prepared from
17a (200 mg, 0.72 mmol) according to the method of Hansen58
1
given for 16f (247 mg, 91%): mp 214 °C; H NMR (300 MHz,
DMSO) δ 7.02 (s, 1H, 5-H), 6.40 (s, 1H, 3-H), 4.80 (s, 2H, 4′-
CH2N+(CH2CH3)3), 3.33 (m, 6H, 4′-CH2N+(CH2CH3)3), 2.75-
2.50 (3 × s, 9H, 4-CH3, 5′-CH3, 8-CH3), 1.34 (t, 9H, 4′-
CH2N+(CH2CH3)3); 13C NMR (75 MHz, DMSO) δ 159.83 (C-
5′), 124.89 (C-4′), 104.57 (4′-CH2N+(CH2CH3)3), 52.83 (4′-
CH2N+(CH2CH3)3), 18.81 (5′-CH3), 13.28 (4-CH3), 8.10 (4′-
CH2N+(CH2CH3)3), 7.91 (8-CH3); MS (thermospray, LC/MS)
m/z 378 (MH+, 21), 342 (29), 201 (15), 277 (40), 258 (39), 241
(86), 102 (100). Anal. (C21H28O3NCl) C: calcd, 66.74; found,
66.31. H: calcd, 7.46; found, 7.50. N: calcd, 3.71; found, 3.71.
UV-A Ir r a d ia tion . Irradiations were performed by means
of a 150-W Heraeus Fluotest mercury-vapor lamp; irradiation
intensities, determined with a Holtkamp UV-A meter 360,
were 4.5 and 1.3 mW/cm2 at a distance of 20 and 45 cm,
respectively.
Th er m a l Tr a n sition Stu d ies. Melting studies were per-
formed in 2-mL quartz cuvettes using a HP 8845A diode-array
spectrophotometer fitted with a J ulabo F20-C heating control-
ler. The temperature was directly measured in the cuvettes
with a digital thermometer. Heating was applied at a rate of
1 °C min-1, with absorbance (260 nm) and temperature data
sampling at 1-min intervals. DNA helix f coil transition
temperatures (Tm) were determined at the midpoint of the
Gen er a l Meth od C: Tr a n sfer Hyd r ogen a tion of P so-
r a len s. To a solution of the required psoralen (1 g) in ethanol
(200 mL) were added cyclohexene (5 mL) and a suspension of
10% palladium on carbon (1 g) in ethanol (20 mL). After the
mixture was stirred and heated to reflux for 36 h, the catalyst
was filtered off and the solvent was removed under reduced
pressure to afford a residue, which was recrystallized from
methanol (modified after Heindel30).
Compounds 1130,51 (from 8-MOP) and 1253 (from 6b) were
prepared according to general method C.
4′,5′-Dih yd r o-4,4′-d im eth ylp sor a len (13). Compound 13
was prepared from 7b (1.0 g, 4.7 mmol) according to general
method C (727 mg, 72%): mp 146 °C; 1H NMR (300 MHz,
CDCl3) δ 7.47 (s, 1H, 5-H), 7.01 (s, 1H, 8-H), 6.11 (s, 1H, 3-H),
3
4.80 (t, 1H, 5′-H) and 4.20 (q, 1H, 5′-H), 3.59 (m, 1H, J ) 6.8
Hz, 4′-H), 2.40 (s, 3H, 4-CH3), 1.37 (d, 3H, 3J ) 6.8 Hz, 4′-
CH3); 13C NMR (75 MHz, CDCl3) δ 163.80 (C-7), 162.04 (C-2),