Nicotinic Acetylcholine Receptor Binding
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4729
line29 (2.0 g, 15 mmol) and 3-aminomethypyridine (3.0 g, 28
mmol) was heated at 80 °C for 8 h. The residue was purified
on a silica gel column by elution initially with CHCl3/MeOH
(9:1) and then with CHCl3/MeOH/NH4OH 28% (7:3:0.1) to
afford 0.32 g (11%) of a solid material; mp 133-134 °C. 1H
NMR [CDCl3]: δ 3.10 (s, 3H, CH3), 3.60 (m, 4H, NCH2CH2N),
4.72 (d, 2H, CH2Ar), 7.13-9.08 (m, 4H, ArH), 9.58 (t, 1H, NH).
Anal. (C10H14N4‚2.5H2O) C, H, N.
(Z)-3-[3-(1-Meth yl-4,5-d ih yd r o-1H-im id a zol-2-yl)-2-oxi-
r a n yl]p yr id in e Tr ioxa la te (17Z). A mixture of (Z)-3-(3-
pyridyl)-2,3-epoxypropionitrile11 (0.755 g, 5.16 mmol), sodium
methoxide (0.0024 g, 0.45 mmol), and MeOH (4 mL) was
allowed to stir for 4 h. After it was cooled to 0-10 °C, a solution
of N-methylethylenediamine (0.43 g, 5.80 mmol) in MeOH (1.7
mL) was added in a dropwise manner under vigorous stirring.
After a few minutes of stirring, a solution of HCl and MeOH
(0.7 mL of a solution 7.86 N, 5.50 mmol) was added and the
mixture was allowed to stir at room temperature for 48 h. The
solvent was removed under reduced pressure to give a residue
that was purified by column chromatography, eluting with
CHCl3/MeOH/NH4OH 28% (9:1:0.1); the product was converted
into its oxalate salt (yield, 19%; mp 121-122 °C). 1H NMR
[DMSO-d6]: δ 3.05 (s, 3H, N-CH3), 3.45-3.85 (m, 4H, NCH2-
CH2N), 4.69 (d, 1H, J ) 4.46 Hz, CH-CdN), 4.81 (d, 1H, J )
4.40 Hz, ArCH), 7.40-8.70 (m, 4H, ArH). Anal. (C11H13N3O‚
3C2H2O4) C, H, N.
N-Eth yl-N-m eth yl-2-(3-p yr id yl)a ceta m id in e Dih yd r o-
ch lor id e (27d ). Compound 27d was prepared in 7% yield from
pyridine-3-acetonitrile and N-ethyl-N-methylamine‚HCl in a
manner similar to that of 27a . The free base was converted to
a hydrochloride salt and recrystallized from absolute EtOH/
anhydrous Et2O; mp 224-226 °C. 1H NMR [DMSO-d6]:
δ
0.98-1.13 (m, 3H, CH3); 3.06-3.11 (m, 3H, N-CH3); 3.49-
3.50 (m, 2H, CH2); 7.90-7.95 (m, 1H, ArH); 8.36-8.38 (d, 1H,
Ar); 8.82 (s, 1H, Ar); 9.08 (s, 1H, NH, D2O exchangeable); 9.72
(s, 1H, NH, D2O exchangeable). Anal. (C8H11N3‚2HCl) C, H,
N.
3-[(E)-2-(1-Meth yl-4,5-d ih yd r o-1H-2-im id a zolyl)-1-eth e-
n yl]an ilin e Dioxalate (28c). The precursor compound, 1-meth-
yl-2-[(E)-2-(3-nitrophenyl)-1-ethenyl]-4.5-dihydro-1H-imida-
zole oxalate, was prepared via a standard method from methyl
3-nitrocinnamate30 and purified on a silica gel column by
elution with EtOAc/EtOH/NH4OH 28% (8:2:0.1). This product,
obtained in 10% yield, was characterized as its oxalate salt
after recrystallization from MeOH/H2O; mp 192-195 °C. 1H
NMR [CDCl3]: δ 2.85 (s, 3H, N-CH3), 3.30 (t, 2H, CH2N), 3.70
(t, 2H, CH2N), 6.65 (d, 1H, J ) 16.0 Hz, CH-CdN), 7.52 (d,
1H, J ) 16.2 Hz, ArCH), 7.40-8.25 (m, 4H, ArH). A solution
of 1-methyl-2-[(E)-2-(3-nitrophenyl)-1-ethenyl]-4,5-dihydro-1H-
imidazole oxalate (0.75 g, 3.24 mmol) in MeOH (15 mL) and
an excess of oxalic acid (0.36 g, 4 mmol) was hydrogenated for
8 h at room temperature under pressure (20 psi) using a
catalytic amount of Raney Ni. Following removal of the
catalyst, evaporation of the solvent gave a mixture that was
purified by recrystallization from 95% EtOH/MeOH to give a
15% yield of 28c; mp 168-170 °C. 1H NMR [DMSO-d6]: δ 3.22
(s, 3H, N-CH3), 3.80-4.00 (m, 4H, NCH2CH2N), 6.65-7.20
(m, 4H, ArH), 6.92 (d, 1H, J ) 16 Hz, CH-CdN), 7.71 (d, 1H,
J ) 16 Hz, ArCH), 8.50 (broad s, 2H, NH2, D2O exchangeable).
Anal. (C12H15N3‚2C2H2O4) C, H, N.
(E)-3-[3-(1-Meth yl-4,5-d ih yd r o-1H-2-im id a zolyl)-2-oxi-
r a n yl]p yr id in e Dioxa la te (17E). Prepared in 15% yield in
a manner similar to that of 17Z from the appropriate nitrile,11
the product was characterized as an oxalate salt; mp 126-
127 °C. 1H NMR [DMSO-d6]: δ 3.10 (s, 3H, N-CH3), 3.75-
4.05 (m, 4H, NCH2CH2N), 4.36 (d, 1H, J ) 1.62 Hz, CH-Cd
N), 4.59 (d, 1H, J ) 1.74 Hz, ArCH), 7.95-8.90 (m, 4H, ArH).
Anal. (C11H13N3O‚2C2H2O4) C, H, N.
4-(N,N-Dim eth yla m in om eth yl)p yr id in e Dioxa la te (29).
A mixture of pyridine-4-carboxaldehyde (1.18 g, 11 mmol),
N,N-dimethylamine (0.5 g of gas in 10 mL of MeOH), and a
catalytic amount of 10% Pd/C was hydrogenated at 50 psi for
1 h. The catalyst was removed by filtration, and the filtrate
was evaporated to a viscous oil. A mixture of the oil and H2O
(20 mL) was extracted with Et2O (3 × 25 mL); the combined
ethereal extract was dried (K2CO3), and the solvent was
removed in vacuo to afford 0.38 g (28%) of 29 as its free base
after short-path distillation (bp 52-53 °C). The oxalate salt
was obtained as fine white needles, mp 149-150 °C after
recrystallization from absolute EtOH. The product was used
without further characterization. Anal. (C8H12N2‚2C2H2O4) C,
H, N.
4-(N,N-Dim eth yla m in oeth yl)p yr id in e Dioxa la te (30).
A solution of 4-vinylpyridine (2.1 g, 20 mmol) and dimethyl-
amine hydrochloride (3.26 g, 40 mmol) in MeOH (20 mL) was
heated at reflux for 8 h. Solvent was removed under reduced
pressure, and the residue was poured onto crushed ice (100
g). The mixture was made basic (pH 11) with 10% NaOH
solution and extracted with Et2O (4 × 50 mL); the combined
extracts were dried (Na2SO4) and filtered, and the solvent was
removed under reduced pressure. The crude product was
purified by column chromatography (silica gel) with CCl3/
MeOH (9:1) as eluent to give 2.65 g (75%) of the product. The
oil was converted to an oxalate salt and recrystallized from
95% EtOH; mp 159 °C. 1H NMR [free base, CDCl3]: δ 2.25 (s,
6H, NMe2), 2.60 (t, 2H, -CH2-), 2.75 (t, 2H, -CH2N), 7.15 (d,
2H, ArH), 8.45 (d, 2H, ArH). Anal. (C9H14N2‚2C2H2O4‚0.75
H2O) C, H, N.
2-(3-P yr id yl)a ceta m id in e Dioxa la te (27a ). A solution of
pyridine-3-acetonitrile (1.00 g, 8.50 mmol), Na (0.02 g, 0.86
mmol), and dry MeOH (8 mL) was allowed to stir at room
temperature for 14 h. After the reaction mixture was cooled
to 0-10 °C, NH4Cl (0.53 g, 10.00 mmol) was added with
stirring, and the reaction mixture was allowed to stir at room
temperature for 12 h. The suspension was filtered; the filtrate
was evaporated under reduced pressure, and the residue was
washed several times with dry Et2O to remove the unreacted
nitrile. The remaining solid was dissolved in absolute EtOH;
the solution was filtered, and the filtrate was evaporated in
vacuo to afford 0.50 g (44%) of 27a as its free base. The free
base was converted to an oxalate salt; mp 190-193 °C after
recrystallization from absolute EtOH. 1H NMR [DMSO-d6]: δ
3.73 (s, 2H, CH2); 7.40-8.62 (m, 4H, ArH); 9.15 (s, 2H, NH2,
D2O exchangeable); 9.43 (s, 1H, NH, D2O exchangeable). 13C
NMR [DMSO-d6]: 35.60, 124.21, 130.45, 136.70, 149.19,
150.24, 163.40. Anal. (C7H9N3‚2C2H2O4) C, H, N.
N-Met h yl-2-(3-p yr id yl)a cet a m id in e Dih yd r och lor id e
(27b). Compound 27b was prepared in 55% yield from pyri-
dine-3-acetonitrile and CH3NH2‚HCl in a manner similar to
that of 27a . The free base was converted to a hydrochloride
salt and recrystallized from i-PrOH/MeOH; mp 214-216 °C.
1H NMR [DMSO-d6]: δ 2.81-2.82 (d, 3H, J ) 4.89 Hz,
N-CH3); 4.09 (s, 2H, CH2); 7.97-8.91 (m, 4H, ArH); 9.09
(broad s, 1H, NH, D2O exchangeable); 9.81 (broad s, 1H, NH,
D2O exchangeable); 10.44 (broad s, 1H, NH, D2O exchange-
able). 13C NMR [DMSO-d6]: 29.18, 35.33, 124.18, 130.73,
137.00, 148.99, 150.18, 161.81. Anal. (C8H11N3‚2HCl) C, H, N.
N,N-Dim eth yl-2-(3-p yr id yl)a ceta m id in e Dih yd r och lo-
r id e (27c). Compound 27c was prepared in 38% yield from
pyridine-3-acetonitrile and (CH3)2NH2‚HCl in a manner simi-
lar to that of 27a . The free base was converted to an ivory-
colored hydrochloride salt; mp 215-218 °C after recrystalli-
zation from absolute EtOH/Et2O. 1H NMR [DMSO-d6]: δ 3.10
(s, 3H, N-CH3); 3.14 (s, 3H, N-CH3); 4.34 (s, 2H, CH2); 8.00-
8.96 (m, 4H, ArH); 9.02 (broad s, 1H, NH, D2O exchangeable);
9.81 (broad s, 1H, NH, D2O exchangeable). 13C NMR [DMSO-
d6]: 33.48, 40.59, 127.14, 132.59, 142.48, 143.44, 144.84,
163.94. Anal. (C9H13N3‚2HCl‚0.25H2O) C, H, N.
3-[(1-Meth yl-1H-im id a zol-2-yl)m eth yl]p yr id in e Dioxa -
la te (32a ). Sodium hydride (60% suspension in mineral oil,
40 mg, 1.66 mmol) was added to a stirred, cold (ice bath)
solution of 3-(1H-imidazol-2-ylmethyl)pyridine (154 mg, 0.97
mmol) in anhydrous THF (10 mL). After 5 min, iodomethane
(0.066 mL, 1.06 mmol) was added, and the mixture was
allowed to stir at room temperature for 30 min. The solvent
was removed under reduced pressure, the residue was taken
up in NaOH 2 N (3 mL), and the solution was extracted with
EtOAc (2 × 25 mL). The combined extracts were dried (Na2-