Notes
4-(Meth oxym eth oxy)-1-p en tyn ylben zen e (9c): prepared
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4175
3-H, Ph-5-H), 6.07 (s, 2H, Mal), 4.06 (m, 3H, O-CH2, CH), 2.82
(t, J ) 7.4 Hz, 2H, Im-CH2), 2.09 (m, 2H, Im-CH2-CH2); MS
m/z 226 (M•+, 12), 209 (1), 153 (1), 109 (100), 82 (36). Anal.
(C14H14N2O‚C4H4O4‚0.25H2O) C, H, N.
according to 8c (yield, 98%); oil; 1H NMR (CDCl3) δ 7.32 (d, J
) 8.7 Hz, 2H, Ph-2-H, Ph-6-H), 6.94 (d, J ) 8.7 Hz, 2H, Ph-
3-H, Ph-5-H), 5.16 (s, 2H, O-CH2), 3.47 (s, 3H, O-Me), 2.36 (t,
J ) 7.0 Hz, 2H, CtC-CH2), 1.61 (m, 2H, CH2-Me), 1.04 (t, J
) 7.4 Hz, 3H, CH2-Me); MS m/z 204 (M•+, 43), 145 (11), 45
(100). Anal. (C13H16O2) C, H, N.
3-(1H -Im id a zol-4-yl)p r op yl 4-P r op yn ylp h en yl E t h er
(14b). Triphenylphosphine (6 mmol, 1.57 g) was dissolved in
20 mL of THF under N2 atmosphere together with 12 (5 mmol,
1.13 g) and 10c (5 mmol, 0.80 g) and cooled in an ice bath.
Then diethyl azodicarboxylate (6 mmol, 0.95 mL) was added
dropwise followed by additional stirring for 72 h at ambient
temperature. Evaporation under reduced pressure and puri-
fication by column chromatography (eluent: EtOAc) afforded
the Boc-protected product 13b which was deprotected by
stirring in 25 mL of methanolic NH3 (10%) at ambient
temperature for 6 h. The residue was concentrated under
reduced pressure and subjected to column chromatography
[eluent: CH2Cl2 (90%), MeOH (10%)] to give the title com-
pound as an oil, which was crystallized as hydrogen maleate
from EtOH/Et2O: 1H NMR (Me2SO-d6) δ 8.88 (s, 1H, Im-2-
H), 7.42 (s, 1H, Im-5-H), 7.30 (d, J ) 8.6 Hz, 2H, Ph-2-H, Ph-
6-H), 6.87 (d, J ) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.04 (s, 2H,
Mal), 4.01 (t, J ) 6.1 Hz, 2H, O-CH2), 2.78 (t, J ) 7.5 Hz, 2H,
Im-CH2), 2.06 (m, 2H, Im-CH2-CH2), 2.00 (s, 3H, Me); MS m/z
240 (M•+, 16), 158 (100), 109 (100), 82 (23). Anal. (C15H16N2O‚
C4H4O4‚0.5H2O) C, H, N.
1-(3,3 -Dim e t h ylb u t yn yl)-4 -(m e t h oxym e t h oxy)b e n -
zen e (9d ): prepared according to 8c (yield, 98%); oil; 1H NMR
(CDCl3) δ 7.31 (d, J ) 8.8 Hz, 2H, Ph-2-H, Ph-6-H), 6.93 (d, J
) 8.8 Hz, 2H, Ph-3-H, Ph-5-H), 5.16 (s, 2H, CH2), 3.46 (s, 3H,
O-Me), 1.30 (s, 9H, t-Bu); MS m/z 218 (M•+, 49), 203 (10), 173
(27), 45 (100). Anal. (C14H18O2‚0.2H2O) C, H, N.
4-(Met h oxym et h oxy)-1-[(t r im et h ylsilyl)et h yn yl]b en -
zen e (9e): prepared according to 8c (yield, 79%); oil; 1H NMR
(CDCl3) δ 7.39 (d, J ) 8.6 Hz, 2H, Ph-2-H, Ph-6-H), 6.95 (d, J
) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 5.17 (s, 2H, CH2), 3.47 (s, 3H,
O-Me), 0.24 (s, 9H, Si-Me3); MS m/z 234 (M•+, 41), 219 (15),
189 (17), 130 (25), 45 (100). Anal. (C13H18O2Si) C, H, N.
4-P r op yn ylp h en ol (10b). A solution of 8b (20 mmol, 3.0
g) in 100 mL of DMF was heated together with EtSNa (50
mmol, 4.21 g) under reflux for 1 h. The resulting suspension
was then concentrated under reduced pressure, extracted with
CH2Cl2, filtered, and evaporated again. Column chromatog-
raphy (eluent: CH2Cl2) afforded the title compound as a light-
yellow oil (yield, 2.67 g, 98%): 1H NMR (CDCl3) δ 7.27 (d, J )
8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.81 (d, J ) 8.6 Hz, 2H, Ph-2-H,
3-(1H -Im id a zol-4-yl)p r op yl 4-p en t yn ylp h en yl et h er
(14c): prepared according to 14b; crystallized as hydrogen
1
Ph-6-H), 5.22 (br*, 1H, OH), 2.02 (s, 3H, Me); MS m/z 132 (M•+
100), 103 (18). Anal. (C9H8O‚0.8H2O) C, H, N.
,
maleate from EtOH/Et2O; H NMR (Me2SO-d6) δ 8.89 (s, 1H,
Im-2-H), 7.43 (s, 1H, Im-5-H), 7.30 (d, J ) 8.6 Hz, 2H, Ph-2-
H, Ph-6-H), 6.87 (d, J ) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.05 (s,
2H, Mal), 4.01 (t, J ) 6.1 Hz, 2H, O-CH2), 2.79 (t, J ) 7.4 Hz,
2H, Im-CH2), 2.36 (t, J ) 7.0 Hz, 2H, CtC-CH2), 2.06 (m,
2H, Im-CH2-CH2), 1.53 (m, 2H, CH2-Me), 0.98 (t, J ) 7.3 Hz,
3H, Me); MS m/z 268 (M•+, 13), 131 (6), 109 (100), 82 (14). Anal.
(C17H20N2O‚C4H4O4‚0.25H2O) C, H, N.
4-P en tyn ylp h en ol (10c). Meth od A: Prepared according
to 10b (yield, 98%). Meth od B: To a solution of 9c (10 mmol,
2.04 g) in 20 mL of THF was added 5 mL of 10% methanolic
HCl followed by stirring at ambient temperature for 24 h.
Removal of the solvent under reduced pressure and purifica-
tion by column chromatography (eluent: CH2Cl2) afforded the
product as a light-yellow oil (yield, 1.52 g, 95%): 1H NMR
(CDCl3) δ 7.27 (d, J ) 8.7 Hz, 2H, Ph-3-H, Ph-5-H), 6.74 (d, J
) 8.7 Hz, 2H, Ph-2-H, Ph-6-H), 4.99 (s*, 1H, OH), 2.36 (t, J )
7.0 Hz, 2H, CtC-CH2), 1.61 (m, 2H, CH2-Me), 1.04 (t, J )
7.3 Hz, 3H, CH2-Me); MS m/z 160 (M•+, 79), 131 (100). Anal.
(C11H12O‚0.25H2O) C, H, N.
4-(3,3-Dim eth ylbu tyn yl)p h en ol (10d ). Meth od A: Pre-
pared according to 10b (yield, 95%). Meth od B: Prepared
according to 10c (yield, 90%); crystallized from light petroleum;
mp 90 °C; 1H NMR (CDCl3) δ 7.26 (d, J ) 8.6 Hz, 2H, Ph-3-H,
Ph-5-H), 6.73 (d, J ) 8.6 Hz, 2H, Ph-2-H, Ph-6-H), 4.86 (br*,
1H, OH), 1.30 (s, 9H, t-Bu); MS m/z 174 (M•+, 57), 159 (100),
144 (13). Anal. (C12H14O) C, H, N.
4-(3,3-Dim et h ylbu t yn yl)p h en yl 3-(1H -im id a zol-4-yl)-
p r op yl eth er (14d ): prepared according to 14b; crystallized
as hydrogen maleate from EtOH/Et2O; 1H NMR (Me2SO-d6) δ
8.90 (s, 1H, Im-2-H), 7.43 (s, 1H, Im-5-H), 7.27 (d, J ) 8.7 Hz,
2H, Ph-2-H, Ph-6-H), 6.87 (d, J ) 8.7 Hz, 2H, Ph-3-H, Ph-5-
H), 6.06 (s, 2H, Mal), 4.01 (t, J ) 6.1 Hz, 2H, O-CH2), 2.80 (t,
J ) 7.5 Hz, 2H, Im-CH2), 2.07 (m, 2H, Im-CH2-CH2), 1.27 (s,
9H, t-Bu); MS m/z 282 (M•+, 14), 267 (4), 159 (7), 109 (100), 82
(11). Anal. (C18H22N2O‚C4H4O4‚0.5H2O) C, H, N.
3-(1H-Im id a zol-4-yl)p r op yl 4-[(Tr im eth ylsilyl)eth yn yl]-
p h en yl Eth er (14e). This was prepared according to 14b.
The Boc-protected product 13e was deprotected by stirring in
25 mL of methanolic hydrazine solution (10%) at ambient
temperature for 30 min. The residue was concentrated under
reduced pressure and subjected to column chromatography
[eluent: CH2Cl2 (90%), MeOH (10%)] to separate the title
compound from 14a giving it as an oil which was crystallized
as hydrogen maleate from EtOH/Et2O: 1H NMR (Me2SO-d6)
δ 8.86 (s, 1H, Im-2-H), 7.42 (m, 3H, Im-5-H, Ph-2-H, Ph-6-H),
6.93 (d, J ) 8.5 Hz, Ph-3-H, Ph-5-H), 6.06 (s, 2H, Mal), 4.06
(t, 2H, O-CH2), 2.81 (t, J ) 7.3 Hz, 2H, Im-CH2), 2.09 (m, 2H,
Im-CH2-CH2), 0.23 (s, 9H, Si-Me3); MS m/z 298 (M•+, 6), 283
(3), 175 (5), 147 (4), 109 (100), 82 (23); IR (KBr) ν˜ 3432 (br),
3141 (m), 2957 (m, C-H), 2877 (m, C-H), 2155 (w, CtC), 1574
(vs, CdC), 1510 (vs, CdC). Anal. (C17H22N2OSi‚C4H4O4‚
0.75H2O) C, N; H: calcd, 6.48; found, 6.04.
4-[(Tr im eth ylsilyl)eth yn yl]p h en ol (10e): prepared from
(4-iodophenoxy)trimethylsilane (7) according to 8c; crystallized
from light petroleum (yield, 85%); mp 68 °C; 1H NMR (CDCl3)
δ 7.33 (d, J ) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.72 (d, J ) 8.6
Hz, 2H, Ph-2-H, Ph-6-H), 5.43 (br*, 1H, OH), 0.23 (s, 9H, Si-
Me3); MS m/z 190 (M•+, 31), 175 (100), 116 (13). Anal. (C11H14
-
OSi) C, H, N.
4-(3-Hyd r oxyp r op yl)-1H-im id a zole-1-ca r boxylic Acid
1,1-Dim eth yleth yl Ester (12).27 3-(1H-Imidazol-4-yl)pro-
panol (11; 10 mmol, 3.7 g)11 was dissolved in 20 mL of MeCN
and 5 mL of dioxane/H2O (1:1). After addition of 5 mL of Et3N,
DMAP (1 mmol, 0.12 g), and Boc2O (12 mmol, 2.62 g), the
solution was stirred at ambient temperature for 2 h followed
by evaporation to dryness. The residue was subjected to
column chromatography [eluent: CH2Cl2 (90%), MeOH (10%)]
to give the title compound as an oil which crystallized at 4 °C
(yield, 2.21 g, 97%): mp 76-78 °C; 1H NMR (Me2SO-d6) δ 8.08
(s, 1H, Im-2-H), 7.21 (s, 1H, Im-5-H), 4.47 (t, J ) 5.1 Hz, 1H,
OH), 3.43 (m, 2H, O-CH2), 2.50 (t, J ) 7.7 Hz, 2H, Im-CH2),
1.71 (m, 2H, Im-CH2-CH2), 1.56 (s, 9H, t-Bu); MS m/z (FAB+)
227 (M + H•+, 17), 171 (81), 127 (40), 109 (15), 81 (11). Anal.
(C11H18N2O3‚0.5H2O) C, H, N.
P h a r m a cology. Gen er a l Meth od s: Hista m in e H3-Re-
cep tor Assa y on Syn a p tosom es fr om Ra t Cer ebr a l Cor -
tex. The new compounds were tested for their H3-receptor
antagonist activity at least in triplicate in an assay with K+-
evoked depolarization-induced release of [3H]histamine from
synaptosomes according to Garbarg et al.23
Hista m in e H3-Recep tor An ta gon ist Activity in Vivo in
Mou se. In vivo testing of all compounds was performed at
least in triplicate after oral administration to Swiss mice as
described by Garbarg et al.23
4-Eth yn ylph en yl 3-(1H-im idazol-4-yl)pr opyl eth er (14a):
for preparation see 14e; crystallized as hydrogen maleate from
In Vitr o Scr een in g a t Oth er Hista m in e Recep tor s. All
compounds were screened in duplicate for histamine H2-recep-
tor activity at isolated spontaneously beating guinea pig right
1
EtOH/Et2O; H NMR (Me2SO-d6) δ 8.89 (s, 1H, Im-2-H), 7.42
(m, 3H, Im-5-H, Ph-2-H, Ph-6-H), 6.94 (d, J ) 8.4 Hz, 2H, Ph-