Novel Selective Hindlimb Vasodilators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14 3039
1.55-1.90 (2H, m), 1.18 (3H, t, J ) 7.2 Hz). Anal. (C26H32N3O2-
Cl‚0.25H2O) C, H, N.
m), 2.37 (3H, s), 1.65-2.00 (2H, m), 1.30-1.65 (2H, m). Anal.
(C24H29N3O2) C, H, N.
6-(4-(N-Meth yl-2-p h en yleth yl)a m in o-1-piper idin yl)ca r -
bon yl-8-p r op yl-2(1H)-qu in olin on e Hyd r och lor id e (7): mp
233-235 °C, 1H NMR (200 MHz, DMSO-d6) δ 11.20 (1H, s),
10.87-11.10 (1H, m), 7.94 (1H, d, J ) 9.6 Hz), 7.62 (1H, d, J
) 1.6 Hz), 7.39 (1H, d, J ) 1.6 Hz), 7.20-7.40 (5H, m), 6.56
(1H, d, J ) 9.6 Hz), 3.70-4.90 (2H, m), 3.50-3.70 (1H, m),
2.90-3.50 (6H, m), 2.87 (2H, t, J ) 7.2 Hz), 2.78 (3H, d, J )
4.6 Hz), 1.90-2.30 (2H, m), 1.43-1.90 (4H, m), 0.93 (3H, t, J
) 7.2 Hz). Anal. (C27H34N3O2Cl‚0.25H2O) C, H, N.
8-(4-(N-Meth yl-2-p h en yleth yl)a m in o-1-piper id in yl)ca r -
bon yl-2(1H)-qu in olin on e Hyd r och lor id e (17): 1H NMR
(200 MHz, DMSO-d6) δ 9.90-10.20 (1H, m), 9.37 (1H, s), 7.20-
7.43 (6H, m), 7.15 (1H, d, J ) 7.4 Hz), 6.99 (1H, t, J ) 7.4
Hz), 4.40-4.80 (1H, m), 3.50-3.90 (2H, m), 2.70-3.50 (13H,
m), 1.50-2.30 (4H, m). Anal. (C24H30N3O2Cl‚3H2O) C, H, N.
Gen er a l Meth od . Meth od A. 4-(N-Meth yl-2-p h en yl-
eth yl)am in o-1-(4-pr opion ylam in o) ben zoylpiper idin e Fu -
m a r a te (18). 4-Nitrobenzoyl chloride (4.9.g, 26.4 mmol) was
added to a solution of 4-(N-methyl-2-phenylethyl)aminopip-
eridine (31; 5.0 g, 22.9 mmol) and K2CO3 (4.7 g, 34.0 mmol) in
acetone (50 mL) and water (50 mL) at 0 °C. After being stirred
for 30 min, the reaction mixture was poured into water and
extracted with AcOEt. The organic layer was washed with
water and saturated aqueous NaCl and dried (Na2SO4).
Concentration in vacuo gave 4-(N-methyl-2-phenylethyl)amino-
1-(4-nitrobenzoyl)piperidine (8.8 g). A solution of the resulting
compound (8.2 g, 22.3 mmol) in EtOH (150 mL) and CH2Cl2
(100 mL) was hydrogenated over 10% Pd-C (1.0 g) under an
atmosphere of H2 (1 atm) at 25 °C for 3 h. The reaction mixture
was filtered through a Celite pad and washed with EtOH.
Concentration in vacuo provided anilinic compound (7.5 g).
Propionyl chloride (0.45 mL, 5.3 mmol) was added to a solution
of the resulting compound (1.5 g, 4.4 mmol) and K2CO3 (1.0 g,
7.2 mmol) in acetone (30 mL) and water (15 mL) at 0 °C. The
reaction mixture was stirred for 1 h and poured into water.
The resulting mixture was extracted with CH2Cl2. The organic
layer was washed with saturated aqueous NaCl, dried (Mg-
SO4), and concentrated in vacuo. The residue was dissolved
in EtOH and treated with fumaric acid (0.48 g, 4.1 mmol) and
then concentrated in vacuo. Recrystallization from EtOH gave
18 as a white powder (0.95 g, 47.9%): mp 158-160 °C; 1H
NMR (200 MHz, DMSO-d6) δ 10.04 (1H, s), 7.64 (2H, d, J )
8.6 Hz), 7.32 (2H, d, J ) 8.6 Hz), 7.10-7.30 (5H, m), 6.57 (1H,
s), 3.40-4.65 (2H, m), 2.55-3.20 (7H, m), 2.33 (2H, q, J ) 7.6
Hz), 2.32 (3H, s), 1.60-1.85 (2H, m), 1.25-1.60 (2H, m), 1.08
(3H, t, J ) 7.6 Hz). Anal. (C26H33N3O4‚H2O) C, H, N.
4-(N-Met h yl-2-p h en ylet h yl)a m in o-1-(2-m et h yl-4-p r o-
p ion yla m in o)ben zoylp ip er id in e Hyd r och lor id e (19): mp
231.5-232.5 °C, 1H NMR (300 MHz, DMSO-d6) δ 10.75-11.00
(1H, m), 10.00 (1H, s), 7.40-7.55 (2H, m), 7.20-7.40 (5H, m),
7.13 (1H, brs), 4.50-4.75 (1H, m), 3.47-4.65 (1H, m), 2.65-
3.47 (7H, m), 2.75 (3H, d, J ) 3.6 Hz), 2.31 (2H, q, J ) 7.5
Hz), 1.85-2.25 (2H, m), 2.16 (3H, brs), 1.40-1.80 (2H, m), 1.06
(3H, t, J ) 7.5 Hz). Anal. (C25H34N3O2Cl‚0.25H2O) C, H, N.
4-(N-Met h yl-2-p h en ylet h yl)a m in o-1-(3-m et h yl-4-p r o-
p ion yla m in o)ben zoylp ip er id in e Hyd r och or id e (20): mp
139-141 °C, 1H NMR (250 MHz, DMSO-d6) δ 10.70-10.90
(1H, m), 9.33 (1H, s), 7.53 (1H, d, J ) 8.3 Hz), 7.15-7.40 (7H,
m), 4.20-5.00 (1H, m), 3.50-4.10 (2H, m), 2.55-3.50 (6H, m),
2.78 (3H, d, J ) 4.8 Hz), 2.34 (2H, q, J ) 7.5 Hz), 1.85-2.25
(2H, m), 2.23 (3H, s), 1.55-1.85 (2H, m), 1.10 (3H, t, J ) 7.5
Hz). Anal. (C25H34N3O2Cl‚1.5H2O) C, H, N.
8-Me t h oxy-6-(4-(N -m e t h yl-2-p h e n yle t h yl)a m in o-1-
p ip er id in yl)ca r bon yl-2(1H)-qu in olin on e Hyd r och lor id e
(8): mp 208-210 °C, 1H NMR (200 MHz, DMSO-d6) δ 11.15-
11.40 (1H, m), 11.08 (1H, s), 7.95 (1H, d, J ) 9.8 Hz), 7.20-
7.45 (6H, m), 7.19 (1H, d, J ) 1.2 Hz), 6.60 (1H, d, J ) 9.8
Hz), 3.80-4.90 (2H, m), 3.95 (3H, s), 3.55-3.78 (1H, m), 2.85-
3.55 (6H, m), 2.80 (3H, d, J ) 4.2 Hz), 1.95-2.35 (2H, m),
1.60-1.95 (2H, m). Anal. (C25H30N3O3Cl‚1.2H2O) C, H, N.
3,4-Dih yd r o-6-(4-(N -m e t h yl-2-p h e n yle t h yl)a m in o-1-
p ip er id in yl)ca r bon yl-8-n itr o-2(1H)-qu in olin on e (9): mp
1
108-110 °C, H NMR (200 MHz, CDCl3) δ 10.11 (1H, s), 8.16
(1H, s), 7.59 (1H, s), 7.10-7.50 (5H, m), 4.40-4.95 (1H, m),
3.60-4.20 (1H, m), 2.60-3.30 (11H, m), 2.39 (3H, s), 1.72-
2.20 (2H, m), 1.40-1.72 (2H, m). Anal. (C24H28N4O4) C, H, N.
6-(4-(N-Meth yl-2-p h en yleth yl)a m in o-1-piper idin yl)ca r -
bon yl-8-n itr o-2(1H)-qu in olin on e Hyd r och lor id e (10): mp
150-151 °C, 1H NMR (250 MHz, DMSO-d6) δ 11.13 (1H, s),
10.38-11.00 (1H, m), 8.43 (1H, s), 8.26 (1H, s), 8.15 (1H, d, J
) 9.8 Hz), 7.22-7.42 (5H, m), 6.79 (1H, d, J ) 9.8 Hz), 4.40-
4.85 (1H, m), 3.55-4.05 (2H, m), 2.90-3.50 (6H, m), 2.78 (3H,
d, J ) 4.6 Hz), 1.92-2.30 (2H, m), 1.65-1.92 (2H, m). Anal.
(C24H27N4O4Cl‚1.5H2O) C, H, N.
3,4-Dih yd r o-7-m et h yl-6-(4-(N-m et h yl-2-p h en ylet h yl)-
a m in o-1-p ip er id in yl)ca r b on yl-2(1H )-q u in olin on e Ox-
a la te (11): mp 109-119 °C, 1H NMR (200 MHz, DMSO-d6) δ
10.15 (1H, s), 7.18-7.40 (5H, m), 7.02 (1H, brs), 6.70 (1H, s),
5.70 (2H, brs), 4.55-4.75 (1H, m), 3.25-3.57 (2H, m), 2.73-
3.25 (8H, m), 2.68 (3H, s), 2.38-2.50 (2H, m), 2.11 (3H, s),
1.74-2.25 (2H, m), 1.25-1.74 (2H, m). Anal. (C27H33N3O6‚
1.2H2O) C, H, N.
3,4-Dih yd r o-7-m eth oxy-6-(4-(N-m eth yl-2-p h en yleth yl)-
a m in o-1-p ip er id in yl)ca r bon yl-2(1H)-qu in olin on e Hyd r o-
ch lor id e (12): 1H NMR (200 MHz, DMSO-d6) δ 11.80-11.25
(1H, m), 10.14 (1H, s), 7.18-7.40 (5H, m), 6.90-7.13 (1H, m),
6.57 (1H, s), 4.50-4.80 (1H, m), 3.72 (3H, brs), 2.88-3.70 (7H,
m), 2.57-3.88 (6H, m), 2.33-2.45 (2H, m), 1.85-2.33 (2H, m),
1.35-1.85 (2H, m). Anal. (C25H32N3O3Cl‚2H2O) C, H, N.
7-Meth oxy-6-(4-(N-m eth yl-2-p h en yleth yl)a m in o-1-p ip -
er id in yl)ca r bon yl-2(1H)-qu in olin on e (13): mp 147-149
°C, 1H NMR (200 MHz, CDCl3) δ 12.61 (1H, s), 7.73, 7.75 (total
1H, d, J ) 9.6 Hz), 7.48, 7.43 (total 1H, s), 7.15-7.40 (5H, m),
6.86 (1H, s), 6.59 (1H, d, J ) 9.6 Hz), 4.74-4.92 (1H, m), 3.94
(3H, s), 3.43-3.61 (1H, m), 2.55-3.15 (7H, m), 2.36, 2.38 (total
3H, s), 1.20-2.10 (4H, m). Anal. (C25H29N3O3‚0.5H2O) C, H,
N.
3,4-Dih yd r o-4-(4-(N -m e t h yl-2-p h e n yle t h yl)a m in o-1-
p ip er id in yl)ca r bon yl-2(1H)-qu in olin on e Hyd r och lor id e
(14): 1H NMR (200 MHz, DMSO-d6) δ 10.50-10.80 (1H, m),
10.06 (1H, s), 6.80-7.40 (9H, m), 4.20-4.70 (3H, m), 2.90-
3.70 (7H, m), 2.77 (3H, d, J ) 4.6 Hz), 2.40-2.70 (2H, m),
1.90-2.30 (2H, m), 1.40-1.90 (2H, m). Anal. (C24H30N3O2Cl‚
1.5H2O) C, H, N.
5-(4-(N-Meth yl-2-p h en yleth yl)a m in o-1-pip er idin yl)ca r -
bon yl-2(1H)-qu in olin on e Hyd r och lor id e (15): 1H NMR
(200 MHz, DMSO-d6) δ 11.95 (1H, s), 10.50-10.80 (1H, m),
7.00-7.90 (9H, m), 6.54 (1H, d, J ) 9.8 Hz), 4.65-4.85 (1H,
m), 2.60-3.90 (11H, m), 1.60-2.30 (4H, m). Anal. (C24H28N3O2-
Cl‚2.5H2O) C, H, N.
1-(2-Meth oxy-4-p r op ion yla m in o)ben zoyl-4-(N-m eth yl-
2-p h en yleth yl)a m in op ip er id in e Hyd r och lor id e (21): 1H
NMR (200 MHz, DMSO-d6) δ 10.84-11.18 (1H, m), 10.15 (1H,
s), 7.49 (1H, s), 7.01-7.44 (7H, m), 4.52-4.76 (1H, m), 3.75
(3H, brs), 2.51-3.70 (11H, m), 2.34 (2H, q, J ) 7.6 Hz), 1.81-
2.30 (2H, m), 1.40-1.81 (2H, m), 1.08 (3H, t, J ) 7.6 Hz). Anal.
(C25H34N3O3Cl) C, H, N.
1-(3-Meth oxy-4-p r op ion yla m in o)ben zoyl-4-(N-m eth yl-
2-p h en yleth yl)a m in op ip er id in e Hyd r och lor id e (22): 1H
NMR (200 MHz, DMSO-d6) δ 10.81-11.10 (1H, m), 9.18 (1H,
s), 8.06 (1H, d, J ) 8.2 Hz), 7.16-7.44 (5H, m), 7.06 (1H, d, J
) 1.6 Hz), 6.97 (1H, dd, J ) 1.6, 8.2 Hz), 3.74-4.30 (2H, m),
3.86 (3H, s), 2.70-3.74 (7H, m), 2.77 (3H, d, J ) 4.4 Hz), 2.42
(2H, q, J ) 7.4 Hz), 1.90-2.32 (2H, m), 1.55-1.90 (2H, m),
1.06 (3H, t, J ) 7.4 Hz). Anal. (C25H34N3O3Cl) C, H, N.
4-(N-Meth yl-2-ph en yleth yl)am in o-1-(3-n itr o-4-pr opion -
yla m in o)ben zoylp ip er id in e Hyd r och lor id e (24): 1H NMR
(200 MHz, DMSO-d6) δ 10.80-11.10 (1H, m), 10.51 (1H, s),
7.97 (1H, s), 7.66-7.80 (2H, m), 7.20-7.46 (5H, m), 4.25-4.75
3,4-Dih yd r o-7-(4-(N -m e t h yl-2-p h e n yle t h yl)a m in o-1-
p ip er id in yl)ca r bon yl-2(1H)-qu in olin on e (16): mp 140-
1
142 °C, H NMR (200 MHz, CDCl3) δ 8.91 (1H, s), 7.10-7.38
(6H, m), 6.97 (1H, dd, J ) 1.4, 7.6 Hz), 6.90 (1H, d, J ) 1.4
Hz), 3.65-4.00 (1H, m), 2.88-3.10 (3H, m), 2.52-2.88 (8H,