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New Benzoates as Potent 5-HT4 Receptor Agonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 617
7q: mp 224 °C; Rf 0.4 (Et2O/CH2Cl2/MeOH, 7:3:0.1); 1H NMR
(CDCl3) δ 7.8 (s, 1H, ArH), 6.25 (s, 1H, ArH), 4.52 (s, 2H, NH2),
4.37 (t, J ) 6.3 Hz, 2H, OCH2), 3,8 (s, 3H, OCH3), 3.68 (m,
2H, 2,6-morpholinyl H), 2.80 (m, 2Heq, 3,5-morpholinyl H), 2.7
(t, J ) 6.3 Hz, 2H, CH2N), 1.86 (m, 2Hax, 3,5-morpholinyl H),
1.15 (d, J ) 6.4 Hz, 3H, CH3 × 2); 13C NMR (CDCl3) δ 164.38
(CdO), 160.17 (C2), 147.80 (C4), 133.18 (C6), 109.78, 109.36,
98.09 (C3), 71.54, 61.63, 59.59, 56.60, 55.94 (OCH3), 19.03 (CH3
× 2). Anal. (C16H23N2O4Cl‚HCl‚0.5H2O).
3.68 (s, 3H, OCH3), 3.5-3.1 (m, 4H), 2.9-2.7 (m, 2H), 2.0-1.6
(m, 2H), 1.5-1.1 (m, 2H), 1.1 (s, 3H, CH3), 0.90 (s, 3H, CH3).
Anal. (C17H25N2O3Cl‚HCl‚0.5H2O).
2-(4-H yd r oxylp ip er id in o)et h yl 4-Am in o-5-ch lor o-2-
m eth oxyben zoa te Hyd r och lor id e (7i). It was prepared
according to method B from compound 10 (1.54 g, 5 mmol)
and 4-hydroxypiperidine (1.26 g, 12.5 mmol) and transformed
into the hydrochloride salt which was recrystallized from the
i-PrOH/CHCl3 mixture (1.2 g, 66%): mp 130-150 °C; Rf 0.35
(CH2Cl2/MeOH/NH4OH, 9:1:0.1); 1H NMR (CD3OD) δ 7.75 (s,
1H, ArH), 6.4 (s, 1H, ArH), 4.5 (t, J ) 5 Hz, 2H, OCH2), 3.75
(s, 3H, OCH3), 3.7-3.6 (m, 1H), 3.5 (t, J ) 5 Hz, 2H, CH2N),
3.5-3.0 (m, 4H), 1.88 (m, 4H), 1.73 (m, 4H). Anal. (C15H21N2O4-
Cl‚HCl‚H2O).
7r : mp >170 °C; Rf 0.5 (Et2O/CH2Cl2/MeOH, 7:3:0.1); 1H
NMR (CDCl3) δ 7.77 (s, 1H, ArH), 6.26 (s, 1H, ArH), 4.59 (s,
2H, NH2), 4.30 (t, J ) 6.3 Hz, 2H, OCH2), 3.97 (m, 2H, 2,6-
morpholinyl H), 3.77 (s, 3H, OCH3), 2.64-2.50 (m, 4H), 2.21
(m, 2H), 1.28 (d, J ) 6.4 Hz, 6H, CH3 × 2); 13C NMR (CDCl3)
δ 164.38 (CdO), 160.15 (C2), 147.95 (C4), 133.10 (C6), 109.71-
109.36 (C1-C5), 98.10 (C3), 66.53, 61.45, 58.78, 56.83, 55.89
(OCH3), 18.01 (CH3 × 2). Anal. (C16H23N2O4Cl‚HCl‚0.5H2O).
2-(4-Meth ylp ip er id in o)eth yl 4-Am in o-5-ch lor o-2-m eth -
oxyben zoa te (7b). It was prepared according to method B
from compound 10 and 4-methylpiperidine in dry CH3CN.
Recrystallization from AcOEt/hexane afforded 7b (1.2 g,
73%): mp 123 °C; Rf 0.49 (CH2Cl2/MeOH/NH3 (aq), 9:1:0.1);
1H NMR (CDCl3) δ 7.73 (s, 1H, ArH), 6.20 (s, 1H, ArH), 4.47
(s, 2H, NH2), 4.30 (t, J ) 6.2 Hz, 2H, OCH2), 3.75 (s, 3H,
OCH3), 2.85 (m, 2H), 2.65 (t, J ) 6.2 Hz, 2H, CH2N), 2.01 (m,
2H), 1.52 (m, 2H), 1.2-1.1 (m, 3H), 0.85 (d, J ) 6 Hz, 3H,
CH3). Anal. (C16H23N2O3Cl).
2-(3-H yd r oxylp ip er id in o)et h yl 4-Am in o-5-ch lor o-2-
m eth oxyben zoa te Hyd r och lor id e (7j). It was prepared
according to method B from compound 10 (1.54 g, 5 mmol)
and 3-hydroxypiperidine as a colorless foam, which was then
converted into the HCl salt by a 4 N HCl ether solution and
recrystallized from a EtOH/CHCl3 mixture to give 1.0 g (55%)
of 7j: mp 130-150 °C; Rf 0.31 (CH2Cl2/MeOH/NH4OH, 9:1:
1
0.1); H NMR (DMSO) δ 7.62 (s, 1H, ArH), 6.48 (s, 1H, ArH),
6.19 (s, 2H, NH2), 4.61 (d, 1H, OH), 4.23 (m, 2H, OCH2), 3.77
(s, 3H, OCH3), 3.58-3.31 (m, 1H, CH), 2.92 (m, 1H), 2.75 (m,
1H), 2.63 (m, 2H, NCH2), 2.10-1.72 (m, 3H), 1.72-1.56 (m,
3H), 1.56-1.25 (m, 1H), 1.25-0.93 (m, 1H). Anal. (C15H21N2O4-
Cl‚HCl‚H2O).
2-(3-Meth ylp ip er id in o)eth yl 4-Am in o-5-ch lor o-2-m eth -
oxyben zoa te Hyd r och lor id e (7c). It was prepared accord-
ing to method B from compound 10 (0.92 g, 3 mmol) and
3-methylpiperidine (0.74 g, 7.5 mmol) to give crude compound
7c as a colorless foam, which was converted into the HCl salt
by a 4 N HCl ether solution. Recrystallization from i-PrOH/
i-Pr2O gave 7c (0.7 g, 64%): mp 205 °C; Rf 0.5 (CH2Cl2/MeOH/
2-(3-(S)-Hyd r oxylp ip er id in o)et h yl 4-Am in o-5-ch lor o-
2-m eth oxyben zoa te Hyd r och lor id e (7k ). It was prepared
according to method B from compound 10 (1.6 g, 5.3 mmol)
and 3-(S)-hydroxypiperidine (1.3g, 12.9 mmol) and then puri-
fied by chromatography on silica gel (CH2Cl2/MeOH, 9:1). The
residue was further purified through the formation of the
hydrochloride salt. It was treated with base to give 7k (0.54
1
NH3(aq), 9:1:0.1); H NMR (CDCl3) δ 7.68 (s, 1H, ArH), 6.15
1
g, 30%): mp 95-98 °C; [R]20 ) +3° (c ) 1, MeOH); H NMR
(s, 1H, ArH), 4.4 (s, 2H, NH2), 4.35 (t, J ) 6 Hz, 2H, OCH2),
3.72 (s, 3H, OCH3), 2.85 (m, 2H), 2.68 (t, J ) 6 Hz, 2H, CH2N),
1.8 (m, 1H), 1.7-1.5 (m, 5H), 0.65-0.9 (m, 4H); 13C NMR
(CDCl3) δ 164.36 (CdO), 160.12 (C2), 148.14 (C4), 133.08 (C6),
109.67, 108.84, 97.96 (C3), 61.74, 61.23, 56.86, 55.85 (OCH3),
53.91, 32.31, 30.57, 24.92, 19.94 (CH3). Anal. (C16H23N2O3-
Cl‚HCl).
(DMSO) δ 7.60 (s, 1H, ArH), 6.47 (s, 1H, ArH), 6.20 (s, 2H,
NH2), 4.66 (d, 1H, OH), 4.25 (m, 2H, OCH2), 3.78 (s, 3H, OCH3),
3.63-3.28 (m, 1H, CH), 2.94 (m, 1H), 2.77 (m, 1H), 2.66 (m,
2H, NCH2), 2.09-1.72 (m, 3H), 1.72-1.53 (m, 3H), 1.53-125
(m, 1H), 1.25-0.91 (m, 1H). Anal. (C15H21N2O4Cl‚HCl‚H2O).
2-(3-(R)-Hyd r oxylp ip er id in o)eth yl 4-Am in o-5-ch lor o-
2-m eth oxyben zoa te Hyd r och lor id e (7l). It was prepared
according to method B from compound 10 (1.6 g, 5.2 mmol)
and 3-(R)-hydroxypiperidine (1.3 g, 12.9 mmol) and then
purified by chromatography on silica gel (CH2Cl2/MeOH, 9:1).
The residue was further purified through the formation of the
hydrochloride salt. It was treated with base to give 7l (0.54
g, 30%): mp 95-98 °C; [R]20 ) -3.5° (c ) 1, MeOH); 1H NMR
(DMSO) δ 7.60 (s, 1H, ArH), 6.47 (s, 1H, ArH), 6.21 (s, 2H,
NH2), 4.66 (d, 1H, OH), 4.25 (m, 2H, OCH2), 3.78 (s, 3H, OCH3),
3.60-3.34 (m, 1H, CH), 2.94 (m, 1H), 2.78 (m, 1H), 2.66 (m,
2H, NCH2), 2.09-1.72 (m, 3H), 1.72-1.55 (m, 3H), 1.55-1.31
(m, 1H), 1.25-0.97 (m, 1H). Anal. (C15H21N2O4Cl‚HCl‚0.5H2O).
2-(4-Ca r boxa m id op ip er id in o)eth yl 4-Am in o-5-ch lor o-
2-m eth oxyben zoa te (7n ). It was prepared according to
method B from compound 10 (1.0 g, 3.2 mmol) and 4-piperidi-
necarboxamide (0.82 g, 6.4 mmol) in dry DMF at 50 °C for 5
h. Purification by flash chromatography (CH2Cl2/MeOH, 9:1)
and recrystallization from CHCl3/hexane yielded 7n (0.8 g,
71%): mp 137 °C; Rf 0.4 (CH2Cl2/MeOH, 8:2); 1H NMR (CDCl3)
δ 7.79 (s, 1H, ArH), 6.27 (s, 1H, ArH), 5.61 (s, 2H, CONH2),
4.51 (s, 2H, NH2), 4.34 (t, J ) 6.0 Hz, OCH2), 3.82 (s, 3H,
OCH3), 3.01 (m, 2H), 2.72 (t, J ) 6.0 Hz, 2H, CH2N), 2.18-
2.06 (m, 3H), 1.9-1.6 (m, 4H); 13C NMR (CD3OD) δ 175.7
(CONH), 169.0 (CO2), 164.5 (C2), 154.0 (C4), 136.7 (C6), 112.9-
111 (C1-C5), 101.3 (C3), 65.2, 60.5-58.9, 57.0, 45.8, 32.1. Anal.
(C16H22N3O4Cl).
2-(2-Meth ylp ip er id in o)eth yl 4-Am in o-5-ch lor o-2-m eth -
oxyben zoa te Hyd r och lor id e (7d ). It was prepared accord-
ing to method B from compound 10 (0.92 g, 3 mmol) and
2-methylpiperidine (0.74 g, 7.5 mmol) as a colorless foam,
which was converted into the HCl salt by a 4 N HCl ether
solution. Recrystallization from i-PrOH/i-Pr2O gave 7d (0.9
g, 80%): mp 185 °C; Rf 0.47 (CH2Cl2/MeOH/NH4OH, 9:1:0.1);
1H NMR (CDCl3) δ 7.8 (s, 1H, ArH), 6.25 (s, 1H, ArH), 4.47 (s,
2H, NH2), 4.35 (t, J ) 6.2 Hz, 2H, OCH2), 3.82 (s, 3H, OCH3),
3.0-2.7 (m, 3H), 2.35 (m, 2H), 1.6 (m, 4H), 1.25 (m, 2H), 1.1
(d, J ) 6 Hz, 3H, CH3); 13C NMR (CDCl3) δ 164.48 (CdO),
160.25 (C2), 147.71 (C4), 133.31 (C6), 109.87, 109.46, 98.18 (C3),
61.77, 56.02-55.96, 53.29, 52.06, 34.64, 26.12, 24.03, 19.56
(CH3). Anal. (C16H23N2O3Cl‚HCl).
2-(cis-2,6-Dim eth ylp ip er id in o)eth yl 4-Am in o-5-ch lor o-
2-m eth oxyben zoa te (7e). It was prepared from compound
10 (0.92 g, 3 mmol) and 2,6-dimethylpiperidine (1.0 g, 9 mmol)
as a colorless foam. It was triturated with Et2O and recrystal-
lized from AcOEt/Hexane to give 7e (0.4 g, 39%): mp 109-
111 °C; Rf 0.3 (CH2Cl2/MeOH/NH4OH, 9:1:0.1); 1H NMR
(CDCl3) δ 7.8 (s, 1H, ArH), 6.25 (s, 1H, ArH), 4.47 (s, 2H, NH2),
4.25 (t, J ) 6 Hz, 2H, OCH2), 3.8 (s, 3H, OCH3), 3.0 (t, J ) 6
Hz, 2H, CH2N), 2.5 (m, 2H, 2,6-piperidinyl H), 1.5-1.7 (m, 3H),
1.4-1.2 (m, 3H), 1.15 (d, J ) 6 Hz, 6H, CH3 × 2); 13C NMR
(CDCl3) δ 164.42 (CdO), 160.31 (C2), 147.75 (C4), 133.26 (C6),
109.81, 109.4, 98.13 (C3), 61.8, 56.72, 56.01 (OCH3), 46.33,
34.44, 24.59, 21.55 (CH3). Anal. (C17H25N2O3Cl).
[2-[(4-Am in o-5-ch lor o-2-m eth oxyben zoyl)oxy]eth yl]p y-
r id in iu m Br om id e (8d ). A solution of compound 10 (0.62 g,
2.0 mmol) in pyridine (20 mL) was refluxed for 5 h; 20 mL of
ether was added to the cooled reaction mixture, and the crude
compound 8d was collected by filtration. Recrystallization
from EtOH/i-Pr2O gave 8d (0.6 g, 78%) as a white solid: mp
2-(3,3-Dim eth ylp ip er id in o)eth yl 4-Am in o-5-ch lor o-2-
m eth oxyben zoa te Hyd r och lor id e (7f). It was prepared
according to method B from compound 10 and 3,3-dimethylpi-
peridine in toluene and transformed into the hydrochloride salt
(1.5 g, 80%): mp 260 °C dec; Rf 0.5 (CH2Cl2/MeOH/NH4OH,
9:1:0.1); 1H NMR (DMSO) δ 10.3 (s, 1H, HCl), 7.65 (s, 1H,
ArH), 6.48 (s, 1H, ArH), 6.26 (s, 2H, NH2), 4.55 (m, 2H, OCH2),
1
223 °C; H NMR (D2O) δ 8.75 (m, 2H, pyridinyl H), 8.35 (m,
1H, pyridinyl H), 7.83 (m, 2H, pyridinyl H), 7.01 (s, 1H, ArH),