Potent, Long-Acting, Orally Active M3 Antagonist
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 26 5025
N-[1-(3-Meth ylben zyl)p ip er id in -4-yl]-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16d ). Compound 16d was
prepared from 22 and 3-methylbenzaldehyde (73%): mp 176-
178 °C (hexane-EtOAc); 1H NMR (CDCl3) δ 1.10-2.20 (14H,
m), 2.33 (3H, s), 2.65-2.81 (2H, m), 3.01 (1H, m), 3.15 (1H,
brs, OH), 3.43 (2H, s), 3.70 (1H, m), 6.32 (1H, brd, J ) 8.0 Hz,
NH), 7.00-7.40 (7H, m), 7.58 (2H, brd, J ) 8.0 Hz); MS m/z
407 (M + H)+. Anal. (C26H34N2O2) C, H, N.
N-[1-(4-Meth ylben zyl)p ip er id in -4-yl]-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16e). Compound 16e was
prepared from 22 and 4-methylbenzaldehyde (43%): mp 200-
202 °C (hexane-EtOAc); 1H NMR (CDCl3) δ 1.04-1.88 (12H,
m), 2.01-2.15 (2H, m), 2.32 (3H, s), 2.68-2.79 (2H, m), 3.01
(1H, m), 3.13 (1H, brs, OH), 3.42 (2H, s), 3.69 (1H, m), 6.28
(1H, brd, J ) 7.9 Hz, NH), 7.10 (2H, d, J ) 8.0 Hz), 7.16 (2H,
d, J ) 8.0 Hz), 7.22-7.36 (3H, m), 7.59 (2H, brd, J ) 8.1 Hz);
MS m/z 407 (M + H)+. Anal. (C26H34N2O2) C, H, N.
(CDCl3) δ 1.12-1.89 (12H, m), 1.98-2.12 (2H, m), 2.44 (3H,
s), 2.64-2.80 (2H, m), 3.02 (1H, m), 3.14 (1H, brs, OH), 3.38
(2H, s), 3.69 (1H, m), 6.29 (1H, brd, J ) 7.8 Hz, NH), 6.67
(1H, s), 6.80 (1H, s), 7.22-7.38 (3H, m), 7.55-7.62 (2H, m);
MS m/z 413 (M + H)+. Anal. (C24H32N2O2S) C, H, N, S.
N-[1-(3-F u r ylm et h yl)p ip er id in -4-yl]-2-cyclop en t yl-2-
h yd r oxy-2-p h en yla ceta m id e (16m ). Compound 16m was
prepared from 22 and 3-furaldehyde (79%): mp 157-158 °C
(hexane-EtOAc); 1H NMR (CDCl3) δ 1.13-1.90 (12H, m),
2.00-2.14 (2H, m), 2.69-2.82 (2H, m), 3.02 (1H, m), 3.11 (1H,
brs, OH), 3.33 (2H, s), 3.69 (1H, m), 6.29 (1H, brd, J ) 8.1 Hz,
NH), 6.35 (1H, d, J ) 1.0 Hz), 7.22-7.39 (5H, m), 7.56-7.62
(2H, m); MS m/z 383 (M + H)+. Anal. (C23H30N2O3) C, H, N.
N-(1-Cycloh exylm eth ylp ip er id in -4-yl)-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16o). Compound 16o was
prepared as an oil from 22 and cyclohexanecarboxaldehyde
(14%): 1H NMR (CDCl3) δ 0.73-0.92 (2H, m), 1.03-1.90 (21H,
m), 1.92-2.20 (2H, m), 2.12 (2H, d, J ) 6.9 Hz), 2.66-2.81
(2H, m), 3.01 (1H, m), 3.18 (1H, brs, OH), 3.70 (1H, m), 6.32
(1H, brd, J ) 8.1 Hz, NH), 7.21-7.40 (3H, m), 7.59 (2H, brd,
J ) 7.5 Hz); MS m/z 399 (M + H)+. 16o‚HCl: mp 215-216 °C
(i-Pr2O/i-PrOH). Anal. (C25H38N2O2‚HCl‚0.6H2O) C, H, N.
N-(1-Cycloh ep tylm eth ylp ip er id in -4-yl)-2-cyclop en tyl-
2-h yd r oxy-2-p h en yla ceta m id e (16p ). Compound 16p was
prepared as an oil from 22 and cycloheptanecarboxaldehyde
(27%): 1H NMR (CDCl3) δ 1.00-1.91 (25H, m), 1.96-2.19 (4H,
m), 2.61-2.84 (2H, m), 3.02 (1H, m), 3.20 (1H, brs, OH), 3.72
(1H, m), 6.31 (1H, brd, J ) 7.2 Hz, NH), 7.21-7.41 (3H, m),
7.56-7.68 (2H, m); MS m/z 413 (M + H)+. 16p ‚HCl: mp 211-
212 °C (i-Pr2O-i-PrOH). Anal. (C26H40N2O2‚HCl‚0.8H2O) C, H,
N.
N-[1-(3-Meth oxyben zyl)p ip er id in -4-yl]-2-cyclop en tyl-
2-h yd r oxy-2-p h en yla ceta m id e (16f). Compound 16f was
prepared from 22 and 3-methoxybenzaldehyde (49%): mp
1
164-165 °C (hexane-EtOAc); H NMR (CDCl3) δ 1.08-1.89
(12H, m), 2.02-2.15 (2H, m), 2.67-2.79 (2H, m), 3.01 (1H, m),
3.13 (1H, brs, OH), 3.45 (2H, s), 3.70 (1H, m), 3.80 (3H, s),
6.31 (1H, brd, J ) 8.2 Hz, NH), 6.79 (1H, m), 6.84-6.88 (2H,
m), 7.18-7.36 (4H, m), 7.57-7.62 (2H, m); MS m/z 423 (M +
H)+. Anal. (C26H34N2O3) C, H, N.
N-[1-(2-P yr id ylm eth yl)p ip er id in -4-yl]-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16g). Compound 16g was
prepared from 22 and 2-pyridinecarboxaldehyde (53%): mp
1
181-182 °C (hexane-EtOAc); H NMR (CDCl3) δ 1.18-1.84
(12H, m), 2.13-2.28 (2H, m), 2.68-2.81 (2H, m), 3.12 (1H, m),
3.21 (1H, brs, OH), 3.61 (2H, s), 3.73 (1H, m), 6.35 (1H, brd, J
) 8.3 Hz, NH), 7.12-7.37 (5H, m), 7.56-7.68 (3H, m), 8.53
(1H, m); MS m/z 394 (M + H)+. Anal. (C24H31N3O2) C, H, N.
N-[1-(3-P yr id ylm eth yl)p ip er id in -4-yl]-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16h ). Compound 16h was
prepared from 22 and 3-pyridinecarboxaldehyde (68%): mp
N-(1-Cyclooctylm eth ylp ip er id in -4-yl)-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16q). Compound 16q was
prepared as an oil from 22 and cyclooctanecarboxaldehyde
(65%): 1H NMR (CDCl3) δ 1.10-1.89 (27H, m), 1.95-2.11 (4H,
m), 2.62-2.77 (2H, m), 3.02 (1H, m), 3.19 (1H, brs, OH), 3.69
(1H, m), 6.26 (1H, brd, J ) 7.5 Hz, NH), 7.20-7.39 (3H, m),
7.59 (2H, brd, J ) 8.4 Hz); MS m/z 427 (M + H)+. 16q‚HCl:
mp 196-197 °C (i-Pr2O-EtOH). Anal. (C27H42N2O2‚HCl) C, H,
N.
1
171-172 °C (hexane-EtOAc); H NMR (CDCl3) δ 1.16-2.20
(14H, m), 2.63-2.80 (2H, m), 3.03 (1H, m), 3.30 (1H, brs, OH),
3.47 (2H, s), 3.72 (1H, m), 6.40 (1H, brd, J ) 7.6 Hz, NH),
7.20-7.40 (4H, m), 7.55-7.68 (3H, m), 8.46-8.55 (2H, m); MS
m/z 394 (M + H)+. Anal. (C24H31N3O2) C, H, N.
Gen er a l P r oced u r e for Meth od C. (2R)-N-(1-Cycloh ep -
tylm eth ylpiper idin -4-yl)-2-[(1R)-3,3-diflu or ocyclopen tyl]-
2-h yd r oxy-2-p h en yla ceta m id e (15p ). To a solution of cy-
cloheptanemethanol (60 mg, 0.47 mmol) in EtOAc (3 mL) were
added Et3N (0.13 mL, 0.9 mmol) and MsCl (0.06 mL, 0.7
mmol), and the mixture was stirred at 0 °C for 1 h. The
reaction was quenched by adding saturated aqueous NaHCO3.
The separated organic layer was washed with H2O and brine,
dried (MgSO4), and evaporated to give the crude mesylate. To
a suspension of 18 (90 mg, 0.28 mmol), K2CO3 (100 mg, 0.73
mmol), and potassium iodide (5 mg, 0.03 mmol) in CH3CN (3
mL) was added the crude mesylate, and the mixture was
heated at 70 °C for 17 h. After being cooled to room temper-
ature, the reaction mixture was poured into H2O and extracted
with CHCl3. The organic layer was dried (MgSO4), evaporated,
and purified by silica gel column chromatography (CHCl3-
MeOH, 100:1 elution) to yield 15p (106 mg, 89%) as a white
N-[1-(4-P yr id ylm eth yl)p ip er id in -4-yl]-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16i). Compound 16i was pre-
pared from 22 and 4-pyridinecarboxaldehyde (60%): mp 154-
155 °C (hexane-EtOAc); 1H NMR (CDCl3) δ 1.14-1.98 (12H,
m), 2.08-2.18 (2H, m), 2.64-2.75 (2H, m), 3.04 (1H, m), 3.23
(1H, brs, OH), 3.46 (2H, s), 3.70 (1H, m), 6.41 (1H, brd, J )
7.8 Hz, NH), 7.20-7.38 (5H, m), 7.58-7.64 (2H, m), 8.50 (2H,
brd, J ) 9.0 Hz); MS m/z 394 (M + H)+. Anal. (C24H31N3O2) C,
H, N.
N-[1-(6-Meth ylp yr id in -2-ylm eth yl)p ip er id in -4-yl]-2-cy-
clop en tyl-2-h yd r oxy-2-p h en yla ceta m id e (16j). Compound
16j was prepared from 22 and 6-methyl-2-pyridinecarboxal-
dehyde (87%): mp 178-179 °C (hexane-EtOAc); 1H NMR
(CDCl3) δ 1.20 (1H, m), 1.36-1.90 (11H, m), 2.11-2.28 (2H,
m), 2.53 (3H, m), 2.68-2.81 (2H, m), 3.11 (1H, m), 3.15 (1H,
brs, OH), 3.59 (2H, s), 3.72 (1H, m), 6.31 (1H, brd, J ) 8.1 Hz,
NH), 7.00 (1H, d, J ) 7.6 Hz), 7.18 (1H, d, J ) 7.6 Hz), 7.22-
7.39 (3H, m), 7.52 (1H, dd, J ) 7.6, 7.6 Hz), 7.59 (2H, brd, J
) 7.1 Hz); MS m/z 408 (M + H)+. Anal. (C25H33N3O2) C, H, N.
N-[1-(3-Th ieylm eth yl)p ip er id in -4-yl]-2-cyclop en tyl-2-
h yd r oxy-2-p h en yla ceta m id e (16k ). Compound 16k was
prepared from 22 and 3-thiophenecarboxaldehyde (52%): mp
1
solid: mp 190-191 °C (hexane-CHCl3); H NMR (CDCl3) δ
1.00-1.15 (2H, m), 1.28-2.28 (23H, m), 2.05 (2H, d, J ) 7.2
Hz), 2.60-2.73 (2H, m), 3.29 (1H, m), 3.49 (1H, brs, OH), 3.68
(1H, m), 6.23 (1H, brd, J ) 8.1 Hz, NH), 7.23-7.40 (3H, m),
7.50-7.58 (2H, m); MS m/z 449 (M + H)+; [R]D -16.8 (c 1.0,
20
CHCl3). Anal. (C26H38N2O2F2) C, H, N.
1
The following compounds (16n and 19-21) were prepared
from the amines (18 and 22) and appropriate alcohols or
bromide by a method similar to that described for 15p (method
C).
163-164 °C (hexane-EtOAc); H NMR (CDCl3) δ 1.13-1.90
(12H, m), 2.03-2.18 (2H, m), 2.68-2.82 (2H, m), 3.02 (1H, m),
3.11 (1H, brs, OH), 3.50 (2H, s), 3.70 (1H, m), 6.31 (1H, brd, J
) 7.8 Hz, NH), 7.02 (1H, dd, J ) 4.9, 1.2 Hz), 7.09 (1H, m),
7.22-7.38 (4H, m), 7.56-7.64 (2H, m); MS m/z 399 (M + H)+.
Anal. (C23H30N2O2S) C, H, N, S.
N-(1-Cyclop en tylm eth ylp ip er id in -4-yl)-2-cyclop en tyl-
2-h yd r oxy-2-p h en yla ceta m id e (16n ). Compound 16n was
prepared from 22 and cyclopentanemethanol (71%): mp
169.5-171 °C (hexane-EtOAc); 1H NMR (CDCl3) δ 1.04-2.23
(23H, m), 2.25 (2H, d, J ) 7.2 Hz), 2.68-2.90 (2H, m), 3.01
(1H, m), 3.29 (1H, brs, OH), 3.69 (1H, m), 6.36 (1H, brd, J )
N-[1-(5-Met h ylt h ien -3-ylm et h yl)p ip er id in -4-yl]-2-cy-
clop en tyl-2-h yd r oxy-2-p h en yla ceta m id e (16l). Compound
16l was prepared from 22 and 5-methyl-3-thiophenecarbox-
1
aldehyde (89%): mp 187-189 °C (hexane-EtOAc); H NMR