σ1 Receptor Ligands
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2367
(dt, 2H), 1.85-1.96 (m, 2H), 1.31-1.44 (dq, 2H). Anal.
N-(1-Ben zylp ip er id in -4-yl)-2,5-d im eth oxyp h en yla ceta -
m id e (34): yield 71%; mp 113-114 °C (free amine), 187-190
°C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.21-7.32 (m,
5H), 6.75-6.80 (m, 3H), 5.68-5.71 (d, 1H), 3.72-3.83 (m, 1H),
3.79 (s, 3H), 3.76 (s, 3H), 3.49 (s, 2H), 3.45 (s, 2H), 2.67-2.72
(d, 2H), 2.05-2.12 (dt, 2H), 1.79-1.85 (m, 2H), 1.25-1.38 (dq,
2H). Anal. (C22H28N2O3‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-3,4-d im eth oxyp h en yla ceta -
m id e (35): yield 50%; mp 190-192 °C (HCl salt); 1H NMR
(HCl salt in DMSO-d6) δ 8.26-8.29 (d, 1H, CONH), 7.59-7.62
(m, 2H), 7.44-7.46 (m, 3H), 6.83-6.86 (m, 2H), 6.72-6.78 (m,
1H), 4.21-4.23 (d, 2H), 3.73-3.80 (m, 1H), 3.72 (s, 3H), 3.71
(s, 3H), 3.36-3.46 (m, 2H), 3.30 (s, 2H), 2.92-3.03 (m, 2H),
1.74-7.92 (m, 4H). Anal. (C22H28N2O3‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-3,5-d im eth oxyp h en yla ceta -
m id e (36): yield 56%; mp 129-130 °C (free amine), 185-187
°C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.20-7.32 (m,
5H), 6.38 (m, 3H), 5.29-5.32 (d, 1H), 3.72-3.86 (m, 1H), 3.78
(s ,6H), 3.48 (s, 2H), 3.44 (s, 2H), 2.71-2.74 (d, 2H), 2.03-
2.12 (dt, 2H), 1.82-1.85 (m, 2H), 1.26-1.39 (dq, 2H). Anal.
(C22H28N2O3‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-3,4,5-tr im eth oxyp h en yla c-
eta m id e (37): yield 79%; mp 111-112 °C (free amine), 198-
200 °C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.20-7.32
(m, 5H), 6.45 (s, 2H), 5.31-5.34 (d, 1H), 3.73-3.86 (m, 1H),
3.85 (s, 9H), 3.48 (s, 2H), 3.45 (s, 2H), 2.72-2.76 (d, 2H), 2.04-
2.13 (dt, 2H), 1.74-1.84 (m, 2H), 1.29-1.42 (dq, 2H). Anal.
(C23H30N2O4‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-3,4-(m et h ylen ed ioxy)p h e-
n yla ceta m id e (38): yield 30%; mp 144-145 °C (free amine),
210-212 °C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.20-
7.32 (m, 5H), 6.76-6.79 (d, 12H), 6.71-6.72 (d, 1H), 6.65-
6.68 (dd, 1H), 5.97 (s, 2H, OCH2O), 5.22-5.25 (d, 1H), 3.73-
3.83 (m, 1H), 3.45 (s, 4H), 2.71-2.75 (d, 2H), 2.04-2.11 (dt,
2H), 1.82-1.86 (m, 2H), 1.26-1.39 (dq, 2H). Anal.
(C21H24N2O3‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-4-(m eth ylth io)p h en yla ceta -
m id e (41): yield 73%; mp 188-190 °C (HCl salt); 1H NMR
(HCl salt in DMSO-d6) δ 8.33-8.36 (d, 1H, CONH), 7.60-7.62
(m, 2H), 7.44-7.46 (m, 3H), 7.18-7.24 (m, 4H), 4.21-4.23 (d,
2H), 3.69-3.74 (m, 1H), 3.35 (s, 2H), 3.19-3.35 (m, 2H), 2.95-
2.99 (m, 2H), 2.45 (s, 3H, SCH3), 1.87-2.00 (m, 4H). Anal.
(C21H26N2OS‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-4-a m in op h en yla cet a m id e
(43). To a solution of 4-aminophenylacetic acid (4.54 g, 0.03
mol) in aqueous NaOH (0.2 N, 35 mL) was added di-tert-butyl
dicarbonate (6.55 g, 0.03 mol). The mixture was stirred at
room temperature overnight, adjusted to pH ) 2 using 1 N
HCl, extracted with ethyl acetate (3 × 30 mL), and dried over
Na2SO4. After removal of the solvent, the product was
recrystallized from ethanol/pentane to give 7.43 g (98.5%) of
4-[(tert-butoxycarbonyl)amino]phenylacetic acid: 1H NMR
(CDCl3) δ 7.30-7.33 (d, 2H), 7.18-7.21 (d, 2H), 3.59 (s, 2H),
1.51 (s, 9H).
The 4-[(tert-butoxycarbonyl)amino]phenylacetic acid was
condensed with 1-benzyl-4-aminopiperidine according to method
A to give N-(1-benzylpiperidin-4-yl)-4-[(tert-butoxycarbonyl)-
amino]phenylacetamide: 1H NMR (CDCl3) δ 7.33-7.36 (d, 2H),
7.21-7.29 (m, 5H), 7.13-7.16 (d, 2H), 6.53 (s, 1H, CONH-
phenyl), 5.19-5.22 (d, 1H), 3.76-3.82 (m, 1H), 3.45 (s, 2H),
3.49 (s, 2H), 2.69-2.73 (d, 2H), 2.04-2.11 (dt, 2H), 1.80-1.83
(m, 2H), 1.53 (s, 9H), 1.28-1.42 (dq, 2H).
(C20H22N2OF2) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-3,5-d iflu or op h en yla cet a -
m id e (18): yield 32%; mp 117-118 °C (free amine), 180-182
°C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.22-7.36 (m,
5H), 6.70-6.83 (m, 3H), 5.26-5.29 (d, 1H), 3.73-3.86 (m, 1H),
3.49 (s, 2H), 3.47 (s, 2H), 2.74-2.78 (d, 2H), 2.05-2.14 (dt,
2H),1.86-1.90 (m, 2H), 1.32-1.45 (dq, 2H). Anal. (C20H22N2-
OF2) C, H, N.
N-(1-Ben zylp ip er id in -4-yl-2-(t r iflu or om et h yl)p h en -
yla ceta m id e (19): yield 64%; mp 128-129 °C (free amine),
239-241 °C (HCl salt). 1H NMR (free amine in CDCl3) δ 7.66-
7.69 (m, 1H), 7.52-7.57 (m, 1H),7.37-7.47 (m, 2H), 7.21-7.32
(m, 5H), 5.13-5.16 (d, 1H), 3.73-3.84 (m, 1H), 3.73 (s, 2H),
3.46 (s, 2H), 2.71-2.75 (d, 2H), 2.04-2.12 (dt, 2H), 1.83-1.87
(m, 2H), 1.27-1.40 (dq, 2H). Anal. (C21H23N2OF3‚HCl) C, H,
N.
N-(1-Ben zylp ip er id in -4-yl)-3-(t r iflu or om et h yl)p h en -
yla ceta m id e (20): yield 48%; mp 110-111 °C (free amine),
184-186 °C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.43-
7.61 (m, 4H), 7.22-7.33 (m, 5H), 5.22-5.24 (d, 1H), 3.74-3.87
(m, 1H), 3.58 (s, 2H), 3.46 (s, 2H), 2.72-2.76 (d, 2H), 2.05-
2.14 (dt, 2H), 1.84-1.88 (m, 2H), 1.31-1.44 (dq, 2H). Anal.
(C21H23N2OF3‚HCl) C, H, N.
N-(1-Ben zylp ip er id in -4-yl)-4-(t r iflu or om et h yl)p h en -
yla ceta m id e (21): yield 28%; mp 124-125 °C (free amine),
209-211 °C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.58-
7.61 (d, 2H), 7.36-7.39 (d, 2H), 7.21-7.32 (m, 5H), 5.20-5.22
(d, 1H), 3.73-3.86 (m, 1H), 3.58 (s, 2H), 3.46 (s, 2H), 2.72-
2.76 (d, 2H), 2.04-2.13 (dt, 2H), 1.84-1.87 (m, 2H), 1.30-1.42
(dq, 2H). Anal. (C21H23N2OF3‚HCl) C, H, N.
N-(1-Ben zylpiper idin -4-yl)-2-n itr oph en ylacetam ide (22):
yield 59%; mp 124-125 °C (free amine), 209-211 °C (HCl salt);
1H NMR (free amine in CDCl3) δ 8.01-8.04 (m, 1H), 7.57-
7.62 (m, 1H), 7.42-7.49 (m, 2H), 7.24-7.31 (m, 5H), 5.66-
5.68 (d, 1H), 3.73-3.84 (m, 1H), 3.80 (s, 2H), 3.47 (s, 2H), 2.74-
2.78 (d, 2H), 2.06-2.14 (dt, 2H), 1.85-1.91 (m, 2H), 1.38-1.50
(dq, 2H). Anal. (C20H23N3O3‚HCl) C, H, N.
N-(1-Ben zylpiper idin -4-yl)-3-n itr oph en ylacetam ide (23):
1
yield 58%; mp 170-173 °C (HCl salt); H NMR (HCl salt in
DMSO-d6) δ 8.47-8.50 (m, 1H, CONH), 8.09-8.18 (m, 2H),
7.69-7.76 (m, 1H), 7.57-7.62 (m, 3H), 7.28-7.46 (m, 3H),
4.22-4.24 (d, 2H), 3.71-3.76 (m, 1H), 3.59 (s, 2H), 3.21-3.35
(m, 2H), 2.96-3.03 (m, 2H), 1.76-2.01 (m, 4H). Anal.
(C20H23N3O3‚HCl) C, H, N.
N-(1-Ben zylpiper idin -4-yl)-4-n itr oph en ylacetam ide (24):
yield 43%; mp 162-164 °C (free amine), 213-215 °C (HCl salt);
1H NMR(free amine in CDCl3) δ 8.18-8.26 (d, 2H), 7.43-7.46
(d, 2H), 7.22-7.33 (m, 5H), 5.30-5.33 (d, 1H), 3.73-3.86 (m,
1H), 3.61 (s, 2H), 3.47 (s, 2H), 2.75-2.79 (d, 2H), 2.05-2.14
(dt, 2H), 1.86-1.90 (m, 2H), 1.33-1.46 (dq, 2H). Anal.
(C20H23N3O3) C, H, N.
N -(1-Be n zylp ip e r id in -4-yl)-2-m e t h oxyp h e n yla ce t a -
m id e (31): yield 48%; mp 211-213 °C (HCl salt); 1H NMR
(HCl salt in DMSO-d6) δ 8.13-8.16 (d, 1H, CONH), 7.58-7.61
(m, 2H), 7.44-7.47 (m, 3H), 7.11-7.23 (m, 2H), 6.83-6.96 (m,
2H), 4.22-4.24 (d, 2H), 3.73-3.80 (m, 1H), 3.73 (s, 3H), 3.20-
3.36 (m, 2H), 2.97-3.01 (m, 2H), 1.73-1.99 (m, 4H). Anal.
(C21H26N2O2‚HCl) C, H, N.
N -(1-Be n zylp ip e r id in -4-yl)-3-m e t h oxyp h e n yla ce t a -
m id e (32): yield 60%; mp 117-118 °C (free amine), 165-167
°C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.21-7.32 (m,
6H), 6.77-6.85 (m, 3H), 5.22-5.24 (d, 1H), 3.73-3.84 (m, 1H),
3.81 (s, 3H), 3.52 (s, 2H), 3.44 (s, 2H), 2.69-2.74 (d, 2H), 2.03-
2.11 (dt, 2H), 1.81-1.91 (m, 2H), 1.23-1.37 (dq, 2H). Anal.
(C21H26N2O2‚HCl) C, H, N.
N -(1-Be n zylp ip e r id in -4-yl)-4-m e t h oxyp h e n yla ce t a -
m id e (33): yield 87%; mp 151-152 °C (free amine), 177-180
°C (HCl salt); 1H NMR (free amine in CDCl3) δ 7.21-7.32 (m,
5H), 7.12-7.16 (d, 2H), 6.85-6.90 (d, 2H), 5.17-5.20 (d, 1H),
3.73-3.85 (m, 1H), 3.81 (s, 3H), 3.48 (s, 2H), 3.36 (s, 2H), 2.68-
2.73 (d, 2H), 2.03-2.11 (dt, 2H), 1.81-1.84 (m, 2H), 1.23-1.36
(dq, 2H). Anal. (C21H26N2O2) C, H, N.
N-(1-Benzylpiperidin-4-yl)-4-[(tert-butoxycarbonyl)amino]-
phenylacetamide (1.0 g) was treated with trifluoroacetic acid
to give N-(1-benzylpiperidin-4-yl)-4-aminophenylacetamide (0.74
g, 97%): mp 171-172 °C (free amine), 230-232 °C (HCl salt);
1H NMR (free amine in CDCl3) δ 7.21-7.32 (m, 5H), 6.98-
7.01 (d, 2H), 6.64-6.67 (d, 2H)), 5.21-5.24 (d, 1H), 3.72-3.82
(m, 1H), 3.68 (s, 2H, NH2), 3.44 (s, 2H), 3.43 (s, 2H), 2.68-
2.73 (d, 2H), 2.03-2.11 (dt, 2H), 1.80-1.83 (m, 2H), 1.23-1.36
(dq, 2H). Anal. (C20H25N3O‚2HCl) C, H, N.
Gen er a l Meth od B. P r ep a r a tion of N-(1-Ben zylp ip -
er id in -4-yl)-2,4-d in itr op h en yla ceta m id e (25). To a solu-