4-[2-(5-Benzimidazole)ethyl]-1-arylpiperazines
25
4-{2-[2-(1-Naphthylmethyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine
(10)
ole, N-phenylpiperazine, H-5 pyridyl), 8.0 (m, 1H, H-4 and pyridyl), 8.3
(d, 1H, J = 4 Hz , H-3 pyridyl), 8.65 (d, 1H, J = 2 Hz, H-6 pyridyl).– MS
(70 eV); m/z (%) = 175 (100), 383 [M+]; mp 116 °C; Anal.
1-Naphthylacetic acid and diamine 4a were used.– IR (KBr): ν 3436, 2814,
1600, 1451, 1238, 803 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
4.70 (s, 2H, CH2-naphthyl), 6.80–8.10 (m, 15H, phenyl, H-4, H-6 and H-7
benzimidazole, naphthyl).– MS (70 eV); m/z (%) = 175 (100), 446 [M+]; mp
.
.
(C24H25N5 3C2H2O4 2H2O) C, H, N.
4-{2-[2-(3-Pyridyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine (17)
Synthesized using nicotinic acid and diamine 4a.– IR (KBr): ν 3423, 1626,
1600, 1232 cm–1.– 1H NMR: δ 3.00–3.60 (m, 12H, N-phenylpiperazine and
CH2CH2N), 6.80–7.30 (m, 6H, N-phenylpiperazine and H-6 benzimidazole),
7.50–7.70 (m, 3H, H-4 and H-7 benzimidazole, H-4 pyridyl), 8.24 (s, 1H and
H-2 pyridyl), 8.49 (m, 1H, H-5 pyridyl), 8.68 (d, 1H, J = 2 Hz, H-6 pyridyl),
9.35 (s, broad, 1H, NH, benzimidazole).– MS (70 eV); m/z (%) = 175 (100),
.
.
189 °C; Anal. (C30H30N4 2C2H2O4 2H2O) C, H, N.
4-{2-[2-(2-Naphthylmethyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine
(11)
383 [M+]; mp 125 °C; Anal. (C24H25N5 3C2H2O4 2H2O) C, H, N.
2-Naphthylacetic acid and diamine 4a were used.– IR (KBr): ν 3441, 1599,
1452, 1236, 758 cm–1.– 1H NMR (CDCl3): δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N ), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
4.30 (s, 2H, CH2-naphthyl), 6.80–7.80 (m, 15H, phenyl, H-4, H-6 and H-7
benzimidazole, naphthyl).– MS (70 eV); m/z (%) = 175 (100), 446 [M+]; mp
.
.
4-{2-[2-(Phenylethyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine (18)
2-Phenylpropionic acid and diamine 4a were used.– IR (KBr): ν 2947,
2819, 1602, 1495, 1244, 697 cm–1.– 1H NMR: δ 2.50–2.70 (m, 6H,
piperazine, CH2CH2N), 2.80 (m, 2H, CH2CH2N), 3.10–3.20 (m, 8H,
piperazine, CH2CH2-phenyl), 6.70–7.00 (m, 3H, N-phenylpiperazine), 7.10–
7.40 (m, 10H, benzyl, H-4, H-6 and H-7 benzimidazole, N-phenyl-
piperazine), 12.10 (s, broad, 1H, NH, benzimidazole).– MS (70 eV); m/z (%)
= 175 (100), 410 [M+]; mp 162 °C ; Anal. (C27H30N4), C, H, N.
.
.
216 °C; Anal. (C26H27ClN4 2C2H2O4 2H2O) C, H, N.
4-{2-[2-(4-Biphenylmethyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine
(12)
4-Biphenylacetic acid and diamine 4a were used.– IR (KBr): ν 2946, 2819,
1602, 1488, 1242 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
4.18 (s, 2H, CH2-biphenyl), 6.70–7.00 (m, 3H, N-phenylpiperazine), 7.10–
7.20 (m, 2H, N-phenylpiperazine), 7.20–7.70 (m, 12H, H-4, H-6 and H-7
benzimidazole, biphenyl), 12.20 (s, broad, 1H, NH benzimidazole).– MS
(70 eV); m/z (%) = 175 (100), 472 [M+]; mp 215 °C; Anal. (C32H32N4) C,
H, N.
4-{2-[2-(Phenylmethyl)-5-benzimidazolyl]ethyl}-4-(2-methoxyphenyl)-
piperazine (19)
Synthesized using phenylacetic acid and diamine 4b.– IR (KBr): ν 2937,
1500, 1454, 1241 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
3.80 (s, 3H, methoxy), 4.20 (s, 2H, CH2 , benzyl), 6.80–7.00 (m, 4H,
2-methoxyphenyl), 7.10–7.50 (m, 8H, benzyl, H-4, H-6 and H-7 benzimid-
azole), 12.2 (s, broad, 1H, NH, benzimidazole).– MS (70 eV); m/z (%) = 205
4-{2-[2-(2-Pyridylmethyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine (13)
(100), 426 [M+]; mp 197 °C; Anal. (C27H30ON4 2C2H2O4 2H2O) C, H, N.
2-Pyridylacetic acid and diamine 4a were used.– IR (KBr): ν 3402, 1657,
1495, 1051, 1027, 1006 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
4.30 (s, 2H, CH2-pyridyl), 6.70–7.00 (m, 3H, N-phenylpiperazine), 7.05 (d,
1H, J = 6Hz, H-6 benzimidazole), 7.20 (m, 3H, N-phenylpiperazine, H-5
pyridyl), 7.30–7.50 (m, 2H, H-4 and H-7 benzimidazole), 7.72 (d, 1H, J = 4
Hz, H-4 pyridyl), 8.30 (s, 1H, H-3 pyridyl), 8.49 (d, 1H, J = 2 Hz, H-6
pyridyl).– MS (70 eV); m/z (%) = 175 (100), 397 [M+]; mp 128 °C; Anal.
.
.
4-{2-[2-(Phenylmethyl)-5-benzimidazolyl]ethyl}-4-(3-trifluoromethyl-
phenyl)-piperazine (20)
Phenylacetic acid and diamine 4c were employed.– IR (KBr): ν 3420,
3225, 1588, 1413, 1168 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
4.10 (s, 2H, CH2 benzyl), 7.00–7.50 (m, 12H, 3-trifluoromethylphenyl,
benzyl, H-4, H-6 and H-7 benzimidazole), 12.3 (s, broad, 1H, NH, benzimid-
azole).– MS (70 eV); m/z (%) = 243 (100), 464 [M+]; mp 127 °C; Anal.
.
.
(C25H27N4 3C2H2O4 3/2H2O) C, H, N.
4-{2-[2-(3-Pyridylmethyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine (14)
.
.
(C27H27N4F3 3C2H2O4 2H2O), C, H, N.
3-Pyridylacetic acid and diamine 4a were used.– IR (KBr): ν 3436, 1656,
1050, 1026, 1006 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine,
CH2CH2N), 2.70–2.90 (m, 2H, CH2CH2N), 3.10–3.20 (m, 4H, piperazine),
4.20 (s, 2H, CH2-pyridyl), 6.70–7.00 (m, 3H, N-phenylpiperazine), 7.00 (d,
1H, J = 6Hz, H-6 benzimidazole), 7.20 (m, 3H, N-phenylpiperazine, H-5
pyridyl), 7.30–7.50 (m, 2H, H-4 and H-7 benzimidazole), 7.66 (d, 1H, J = 4
Hz, H-4 pyridyl), 8.40 (d, 1H, J = 2 Hz, H-6 pyridyl), 8.60 (s, 1H, H-2
pyridyl).– MS (70 eV); m/z (%) = 175 (100), 397 [M+]; mp 129 °C; Anal.
Radioligand binding studies
Synaptosomal membranes prepared from bovine caudate nuclei were used
in [3H]spiperone and [3H]SCH 23390 binding assays and for [3H]-8-OH-
DPAT assay synaptosomal membranes of the bovine hippocampi were
employed[8]
.
[3H]Spiperone (spec. act. 70 Ci mM–1, Amersham Buchler GmbH,
Braunschweig, Germany) binding was assayed at membrane protein concen-
tration of 0.7 mg ml–1 in a solution containing (in mM): EDTA 1, MgCl2 4,
CaCl2 1.5, KCl 5, NaCl 120, Tris-HCl 25, pH 7.4, at 37 °C for 20 min in a
total volume of 1.0 ml. Binding of the radioligand to 5-HT2 receptors was
prevented by 50 nM ketanserin. Ki values were determined by competition
binding at 0.2 nM of the radioligand and eight to ten concentrations of each
novel compound (0.1nM–0.1mM). Nonspecific binding was measured in the
presence of 1.0 mM (+)-butaclamol. The reaction was terminated by rapid
filtration through Whatman GF/C filters, further washed three times with 5.0
ml of ice-cold incubation buffer. Each point was determined in triplicate.
Retained radioactivity was measured by introducing dry filters into 10 ml of
toluene-based scintillation liquid and counting in a 1219 Rackbeta Wallac
scintillation counter at an efficiency of 51–55% for tritium. Binding of
[3H]SCH 23390 (spec. act. 80 Ci mM–1, Amersham Buchler GmbH,
Braunschweig, Germany) was examined by the same rapid filtration assay
discussed for [3H]spiperone in the absence of ketanserin. [3H]-8-OH-DPAT
(spec.act. 223 Ci mM–1, Amersham Buchler GmbH, Braunschweig, Ger-
many) binding was assayed in a solution containing (in mM): EDTA 1,
.
.
(C25H27N5 3C2H2O4 3H2O) C, H, N.
4-[2-(2-Phenyl-5-benzimidazolyl)ethyl]-1-phenylpiperazine (15)
Synthesized using benzoic acid and diamine 4a.– IR (KBr): ν 3418, 1720,
1635, 1600, 1402, 1231 cm–1.– 1H NMR (oxalic acid salt): δ 3.00–3.60 (m,
12H, piperazine, CH2CH2N), 6.70–7.00 (m, 3H, N-phenylpiperazine), 7.16
(d, 1H, J = 6 Hz, H-6 benzimidazole), 7.20 (m, 2H, N-phenylpiperazine),
7.40–7.60 (m, 5H, phenyl), 8.18 (d, 2H, J = 6 Hz, H-4 and H-7 benzimidaz-
ole).– MS (70 eV); m/z (%) = 175 (100), 382 [M+]; mp 132 °C; Anal.
.
.
(C25H26N4 2C2H2O4 1/2H2O) C, H, N.
4-{2-[2-(2-Pyridyl)-5-benzimidazolyl]ethyl}-1-phenylpiperazine (16)
2-Picolinic acid and diamine 4a were used.– IR (KBr): ν 3436, 1658, 1052,
1027, 1007 cm–1.– 1H NMR: δ 2.50–2.65 (m, 6H, piperazine, CH2CH2N),
2.70–2.90 (m, 2H, CH2CH2N), 3.20–3.40 (m, 4H, piperazine), 6.70–7.00 (m,
3H, N-phenylpiperazine), 7.00–7.60 (m, 6H, H-4, H-6 and H-7 benzimidaz-
Arch. Pharm. Pharm. Med. Chem. 331, 22–26 (1998)