R. Nirogi et al. / European Journal of Medicinal Chemistry 103 (2015) 289e301
295
Table 4
Structure and in vitro potencies of bicyclic aminopiperidine series compounds.
a
Compound
Cy
R
1
4
5HT R EC50 (nM) /Emax (%)
PRX-03140/VRX-3011
N.A.
N.A.
58/48
Lit. 17e52/30-61% [22]
4a
88/89
4b
39/87
4
4
4
c
>10,000
>10,000
1061/19
d
e
N.A. Not applicable.
a
In vitro assay. Values are the geometric mean of three to six determinations. CHO stable cell line expressing human 5-HT4eR and reporter gene was used.
7
.1 Hz, 1H), 4.71 (s, 1H), 4.19 (q, J ¼ 7.1 Hz, 2H), 2.14 (bs, 2H), 1.21 (t,
2 4
layer was dried over anhydrous Na SO and the solvent was
removed under reduced pressure to obtain a crude solid which was
þ
J ¼ 7.1 Hz, 3H). Mass (m/z): 181.4 (M þ H) . Anal. (C
9
H
12
N
2
O
2
) C, H,
N.
triturated with hexanes to obtain compound 11 (21.0 g) as off-white
ꢁ
1
solid in 95% yield. m.p. 134e137 C. H NMR (CDCl
3
): d 8.41 (d,
4
.2.3. Ethyl 3-isopropylimidazo[1,5-a]pyridine-1-carboxylate (10)
J ¼ 7.0 Hz, 1H), 8.0 (d, J ¼ 9.1 Hz, 1H), 7.17 (t, J ¼ 6.5 Hz, 1H), 6.88 (t,
13
To a stirred solution of compound 8 (48.4 g, 268.6 mmol s) in
J ¼ 6.6 Hz, 1H), 3.58e3.44 (m, 1H), 1.32 (d, J ¼ 6.8 Hz, 6H). C NMR
ꢁ
toluene (500 mL) cooled at 0 C isobutyryl chloride (30.0 mL,
68.6 mmol s) was added over a period of 15 min. After stirring the
(DMSO-d
6
):
d
164.5, 144.6, 134.3, 124.3, 123.4, 119.6, 119.1, 113.7,
þ
2
25.3, 20.6. Mass (m/z): 205.1 (M þ H) . Anal. (C11
12 2 2
H N O ) C, H, N.
reaction mass for additional 15 min, the volatiles were removed
under reduced pressure and the intermediate 9, thus obtained was
4.3. Synthesis of tert-butyl 6-aminomethyl-3-azabicyclo[3.1.0]
diluted with dichloroethane (500 mL). After cooling the reaction
hexane-3-carboxylate (22h)
ꢁ
mass to 0 C, POCl
of 15 min. The reaction mixture was then gradually heated to 90 C
3
(60.0 mL, 618.0 mmol) was added over a period
ꢁ
4.3.1. tert-Butyl 6-hydroxymethyl-3-azabicyclo[3.1.0]hexane-3-
carboxylate (14)
ꢁ
and was stirred for 24 h. The reaction mass was cooled to 0 C and
then quenched by adding saturated aqueous NaHCO
reaction mass then extracted with ethylacetate (2 ꢂ 300 mL). The
organic layer was dried over anhydrous Na SO and the volatiles
3
solution. The
Di-tert-butyl dicarbonate (16.96 g, 77.0 mmol s) was added to a
solution of 6-hydroxymethyl-3-azabicyclo[3.1.0]hexane 13 (8.0 g,
70.0 mmol s) and triethylamine (15.7 mL, 112.0 mmol s) in DCM
(150 mL) at 10 C. The reaction mass was stirred for 2 h at 10 C,
while monitoring the progress of the reaction by TLC. The reaction
mass was washed with chilled water (50 mL), brine solution
2
4
ꢁ
ꢁ
were removed under reduced pressure. The crude mass was puri-
fied by silica gel column chromatography to obtain compound 10
1
(
40.0 g) as light yellow gummy liquid in 65% yield. H NMR (CDCl
3
):
d
1
1
8.17 (d, J ¼ 9.3 Hz, 1H), 7.92 (d, J ¼ 6.9 Hz, 1H), 7.06 (t, J ¼ 6.8 Hz,
2 4
(50 mL) and dried over Na SO . The organic phase was concen-
trated under vacuum to obtain a crude residue, which was further
purified by flash chromatography using EtOAc: n-hexane (50:50) to
H), 6.77 (t, J ¼ 6.8 Hz, 1H), 4.47 (q, J ¼ 7.2 Hz, 2H), 3.43e3.30 (m,
13
H), 1.49 (d, J ¼ 6.9 Hz, 6H), 1.44 (t, J ¼ 7.2 Hz, 3H). C NMR
OD): 163.7, 163.4, 145.4, 134.4, 124.3, 122.4, 118.8, 113.8, 59.8,
(
CD
3
d
afford the title compound 14 as light brown gummy liquid (7.84 g)
ꢀ
1
1
2
5.5, 19.2, 13.5. IR (cm ): 2963, 2871, 1693, 1634, 1538, 1408, 1324,
in 52% yield. H NMR (CDCl
3
):
d
3.68e3.42 (m, 4H), 3.40e3.30 (m,
þ
1
210, 1058, 928, 784, 753, 698. Mass (m/z): 233.2 (M þ H) . Anal.
2H), 1.69 (s, 1H), 1.43 (s, 11H), 0.98e0.92 (m, 1H). Mass (m/z): 214.3
þ
(
C
13
16
H N
2
O
2
) C, H, N.
(M þ H) . Anal. (C11
3
H19NO ) C, H, N.
4
.2.4. 3-Isopropylimidazo[1,5-a]pyridine-1-carboxylic acid (11)
To a stirred solution of compound 10 (25.0 g, 107.6 mmol s) in a
4.3.2. tert-Butyl 6-methanesulfonyloxymethyl-3-azabicyclo[3.1.0]
hexane-3-carboxylate (15)
mixture of ethanol (400 mL) and water (150 mL) at r.t, sodium-
hydroxide (5.28 g,129.2 mmol s) was added over a period of 15 min.
The reaction mass was gradually heated to reflux and stirred at this
temperature for 6 h. The reaction mixture was concentrated to its
one third volume under reduced pressure and the residue was
acidified with acetic acid (8.1 mL, 135.6 mmol s) and extracted with
A solution of methanesulfonylchloride (4.42 g, 38.0 mmol s) in
DCM (25.0 mL) was added to a solution of compound 14 (7.8 g,
36.0 mmol s) and triethylamine (7.70 mL, 55.0 mmol s) in DCM
(100.0 mL) at 0 C. The reaction mass was stirred over night at r.t,
while monitoring the progress of the reaction by TLC. The reaction
mass was washed with chilled water (50 mL), brine solution
ꢁ
5
% methanol in dichloromethane solution. The combined organic
2 4
(50 mL) and dried over Na SO . The organic phase was