GABAAR5 Inverse Agonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 14 3653
s), 5.39 (2H, s), 6.94 (1H, d, J 1.4), 7.00 (1H, d, J 1.4); m/z
(ES+) 229 (M + H+).
was heated at reflux for 16 h and then cooled to room
temperature and filtered through a pad of Celite. The solution
was evaporated in vacuo to give 6e as a brown oil and as a
mixture of geometric isomers: δH (360 MHz, DMSO-d6): 5.97
(2H, br s), 7.40 (0.55H, m), 7.50 (0.45H, m), 8.02 (0.5H, m),
8.20 (0.5H, m), 8.56 (0.55H, m), 8.70 (0.45H, m), 8.86 (0.55H,
m), 9.04 (0.45H, m), 9.77 (1H, br s).
(b ) Gen er a l p r oced u r e for t h e Syn t h esis of 7b -f:
Eth yl [3-(P yr id in -3-yl)-1,2,4-oxa d ia zol-5-yl]ca r boxyla te
(7e). A mixture of 6e (3.0 g, 22 mmol) and 4 Å molecular sieves
in THF (120 mL) was stirred vigorously at room temperature
under nitrogen. Sodium hydride (0.96 g of a 60% dispersion
in oil, 24 mmol) was added, the mixture stirred for 0.1 h, and
then ethyl oxalyl chloride (3.0 g, 22 mmol) added. The mixture
was heated at reflux for 1 h, cooled to room temperature, and
filtered through Celite. The solvent was evaporated in vacuo
and the residue dissolved in CH2Cl2, washed with water (×2),
dried (MgSO4), and evaporated in vacuo. The residue was
chromatographed on silica gel, eluting with ethyl acetate-
hexane 50:50 to give 7e (1.30 g, 28%), δH (360 MHz, CDCl3):
1.51 (3H, t, J 7.0), 4.59 (2H, q, J 7.1), 7.47 (1H, m,), 8.43 (1H,
m), 8.78 (1H, m), 9.39 (1H, m).
(c) 6-(6-Meth ylp yr id in -2-yl)m eth yloxy-3-[3-(p yr id in -3-
yl)-1,2,4-oxa dia zol-5-yl]-7,8,9,10-tetr a h ydr o-(7,10-eth a n o)-
1,2,4-tr ia zolo[3,4-a ]p h th a la zin e (26). Prepared from the
preceding ethyl ester 7e and hydrazine 4a using the general
procedure described for 14: Mp 202-204 °C; δH (250 MHz,
CDCl3): 1.42-1.58 (4H, m), 1.90-2.08 (4H, m), 2.61 (3H, s),
3.64 (1H, br s), 4.05 (1H, br s), 5.67 (2H, s), 7.16 (1H, d, J 7.5),
7.49-7.52 (2H, m), 7.65 (1H, t, J 7.6), 8.56 (1H, m), 8.80 (1H,
m), 9.51 (1H, br s); m/z (ES+) 467 (M + H+); Anal. (C25H22N8O2‚
1.2H2O‚1.5HCl): C, H, N.
6-(6-Meth ylp yr id in -2-yl)m eth yloxy-3-[3-(p yr id in -4-yl)-
1,2,4-oxa d ia zol-5-yl]-7,8,9,10-t et r a h yd r o-(7,10-et h a n o)-
1,2,4-tr ia zolo[3,4-a ]p h th a la zin e (27). Prepared from ethyl
ester 7f and 4a using the general procedure: Mp 272-274 °C;
δH (250 MHz, CDCl3): 1.42-1.58 (4H, m), 1.90-2.05 (4H, m),
2.61 (3H, s), 3.64 (1H, br s), 4.05 (1H, br s), 5.67 (2H, s), 7.16
(1H, d, J 7.8), 7.49 (1H, d, J 7.8), 7.64 (1H, d, J 7.7), 8.13-
8.16 (2H, m), 8.84-8.86 (2H, m); m/z (ES+) 467 (M + H+); Anal.
(C25H22N8O2): C, H, N.
(b) 2-(Hydroxymethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-
imidazole was reacted with the chlorophthalazine 5a using the
general procedure given for compound 14 to give 3-(3-methyl-
1,2,4-oxadiazol-5-yl)-6-[2-{1-[2-(trimethylsilyl)ethoxy]methyl}-
imidazolyl]methyloxy-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-
triazolo[3,4-a]phthalazine; (360 MHz, CDCl3): δH 0.00 (9H, s,
SiMe3), 0.91 (2H, t, J 8.1), 1.40-1.56 (4H, m), 1.89-2.02 (4H,
m), 2.62 (3H, s), 3.53-3.58 (3H, m), 4.05 (1H, br s), 5.50 (2H,
s), 5.72 (2H, s), 7.14 (1H, d, J 1.4), 7.16 (1H, d, J 1.4); m/z
(ES+) 509 (M + H+).
(c) A stirred solution of the preceding product (355 mg, 0.698
mmol) in 5 N HCl (14 mL) was heated at 40 °C for 2.3 h.
Ethanol was added and the mixture evaporated in vacuo. The
residue was azeotroped with ethanol (×2), partitioned between
dichloromethane and water, and basified with saturated
potassium carbonate solution. The organic layer was separated
and the aqueous phase re-extracted with dichloromethane
(×1). The combined organic extracts were washed with water
(×1), dried (MgSO4), and evaporated in vacuo, and the residue
was recrystallized from ethyl acetate-hexane to give 17 (0.19
g, 72%); Mp 187 °C; δH (360 MHz, CDCl3): 1.36-1.50 (4H, m),
1.88-2.00 (4H, m), 2.66 (3H, s), 3.56 (1H, br s), 4.01 (1H, br
s), 5.58 (2H, br s), 7.10 (2H, s); m/z (ES+) 379 (M + H+); Anal.
(C18H18N8O2‚ 0.05H2O): C, H, N.
3-(3-Meth yl-1,2,4-oxa d ia zol-5-yl)-6-(2-p yr id yl-N-oxid e)-
m eth yloxy-7,8,9,10-tetr ah ydr o-(7,10-eth an o)-1,2,4-tr iazolo-
[3,4-a ]p h th a la zin e (19). m-Chloroperbenzoic acid (62 mg of
a 55% purity sample, 0.20 mmol) was added to a stirred
solution of 15 (43 mg, 0.11 mmol) in dichloromethane (3 mL)
at room temperature. After stirring for 17 h, the mixture was
diluted with dichloromethane, washed with saturated potas-
sium carbonate solution (×2) and water (×1), dried (MgSO4),
and evaporated in vacuo. The residue was chromatographed
on silica gel, eluting with 95:15 CH2Cl2-methanol, and then
recrystallized from ethyl acetate/hexane to give 19 (21 mg,
47%); Mp 225-227 °C; δH (360 MHz, CDCl3): 1.42-1.54 (4H,
m), 1.92-2.02 (4H, m), 2.60 (3H, s), 3.62 (1H, br s), 4.03 (1H,
br s), 5.85 (2H, s), 7.31-7.33 (2H, m), 7.86 (1H, m), 8.33 (1H,
m); m/z (ES+) 406 (M + H+); Anal. (C20H19N7O3‚H2O): C, H,
N.
Compounds 23-25 were prepared from hydrazine 4a and
the appropriate 1,2,4-oxadiazole carboxylic ethyl ester 7b-d
using the general procedures given for the preparation of 14:
3-(3-E t h yl-1,2,4-oxa d ia zol-5-yl)-6-(6-m et h ylp yr id in -2-
yl)m eth yloxy-7,8,9,10-tetr a h yd r o-(7,10-eth a n o)-1,2,4-tr ia -
zolo[3,4-a ]p h th a la zin e (23). Mp 169-171 °C; δH (360 MHz,
CDCl3): 1.40-1.54 (7H, m), 1.90-2.00 (4H, m,), 2.60 (3H, s),
2.97 (2H, q, J 7.6), 3.61 (1H, br s), 4.01 (1H, br s), 5.62 (2H, s),
7.14 (1H, d, J 7.9), 7.49 (1H, d, J 7.6), 7.64 (1H,t, J 7.6); m/z
(ES+) 418 (M + H+); Anal.(C22H23N7O2): C, H, N.
3-(3-Isopr opyl-1,2,4-oxa d ia zol-5-yl)-6-(6-m eth ylpyr id in -
2-yl)m et h yloxy-7,8,9,10-t et r a h yd r o-(7,10-et h a n o)-1,2,4-
tr ia zolo[3,4-a ]p h th a la zin e (24). Mp 185-187 °C; δH (360
MHz, CDCl3): 1.40-1.52 (10H, m), 1.88-2.00 (4H, m), 2.60
(3H, s), 3.30 (1H, septet, J 6.8), 3.61 (1H, br s), 4.01 (1H, br
s), 5.62 (2H, s), 7.14 (1H, d, J 7.6), 7.50 (1H, d, J 7.6), 7.63
(1H, t, J 7.8); m/z (ES+) 432 (M + H+); Anal. (C23H25N7O2): C,
H, N.
3-(3-P h en yl-1,2,4-oxa d ia zol-5-yl)-6-(6-m eth ylp yr id in -2-
yl)m eth yloxy-7,8,9,10-tetr a h yd r o-(7,10-eth a n o)-1,2,4-tr ia -
zolo[3,4-a ]p h th a la zin e (25). δH (360 MHz, CDCl3): 1.36-
1.62 (4H, m), 1.87-2.08 (4H, m), 2.60 (3H, s), 3.61 (1H, br s),
4.04 (1H, br s), 5.64 (2H, s), 7.14 (1H, d, J 7.6), 7.48-7.66 (5H,
m), 8.24-8.32 (2H, m); m/z (ES+) 466 (M + H+).
6-(6-Meth ylp yr id in -2-yl)m eth yloxy-3-[3-(p yr id in -3-yl)-
1,2,4-oxa d ia zol-5-yl]-7,8,9,10-t et r a h yd r o-(7,10-et h a n o)-
1,2,4-tr ia zolo[3,4-a ]p h th a la zin e (26). (a ) Gen er a l P r oce-
d u r e for th e Syn th esis of 6b-f: 3-P yr id ylca r boxa m id e
Oxim e (6e). A solution of 3-cyanopyridine (10.0 g, 96 mmol)
in ethanol (100 mL) was added to a stirred slurry of hydroxy-
lamine hydrochloride (13.3 g, 192 mmol) and potassium
carbonate (15.9 g, 120 mmol) in ethanol (150 mL). The mixture
Gen er al P r ocedu r e for th e P r epar ation of 8a-c. 6-Ch lo-
r o-3-(3-fu r yl)-7,8,9,10-tetr a h yd r o-(7,10-eth a n o)-1,2,4-tr ia -
zolo[3,4-a ]p h th a la zin e (8a ). To a solution of 4a (1.0 g, 4.45
mmol), in xylene (20 mL), were added triethylamine (0.67 g,
6.7 mmol) and 3-furoyl chloride (0.58 g, 4.4 mmol). The mixture
was stirred at room temperature for 1 h and then heated at
reflux for 16h. The solution was cooled to room temperature,
the solvent evaporated under reduced pressure, and the
residue partitioned between CH2Cl2 (150 mL) and water (30
mL). The aqueous phase was separated and extracted further
with CH2Cl2 (×2). The combined extracts were dried (Na2SO4)
and evaporated, and the residue was chromatographed on
silica gel eluting with ethyl acetate to afford 8a (0.75 g, 56%);
δH (250 MHz, CDCl3): 1.41-1.55 (4H, m, 2), 1.90-2.05 (4H,
m, 2), 3.57 (1H, s), 4.04 (1H, s), 7.30-7.31 (1H, m), 7.59-7.60
(1H, m), 8.61 (1H, s); m/z (ES+) 301 (M + H+).
Compounds 28-30 were prepared from 8a -c, respectively,
and 6-methyl-2-pyridylcarbinol as described for 14:
3-(3-F u r yl)-6-(6-m eth ylp yr id in -2-yl)m eth yloxy-7,8,9,10-
t et r a h yd r o-(7,10-et h a n o)-1,2,4-t r ia zolo[3,4-a ]p h t h a la -
zin e (28). Mp 205-206 °C; δH (250 MHz, CDCl3): 1.38-1.56
(4H, m), 1.84-2.02 (4H, m), 2.63 (3H, s), 3.58 (1H, s), 3.96 (1H,
s), 5.58 (2H, s), 7.14 (1H, d, J 7.6), 7.26 (1H, s), 7.31 (1H, d, J
7.7), 7.55-7.56 (1H, m), 7.64 (1H, dd, J 7.7 and 7.6), 8.50 (1H,
s); m/z (ES+) 388 (M + H+); Anal. (C22H21N5O2‚0.25 H2O): C,
H, N.
3-(2-F u r yl)-6-(6-m eth ylp yr id in -2-yl)m eth yloxy-7,8,9,10-
t et r a h yd r o-(7,10-et h a n o)-1,2,4-t r ia zolo[3,4-a ]p h t h a la -
zin e (29). δH (360 MHz, CDCl3): 1.40-1.56 (4H, m), 1.86-
2.00 (4H, m), 2.62 (3H, s), 3.56 (1H, br s), 3.96 (1H, br s), 5.58
(2H, s), 6.58-6.62 (1H, m) 7.12 (1H, d, J 7.6), 7.32 (1H, d, J
7.6), 7.43 (1H, d, J 1.8), 7.60-7.68 (2H, m); m/z (ES+) 388 (M
+ H+); Anal. (C22H21N5O2): C, H, N.