286 N. Ullah
J Enzyme Inhib Med Chem, 2014; 29(2): 281–291
1.95–2.05 (m, 6H, CH, CH2), 2.66 (m, 2H, CH2), 2.85 (m, 2H,
5-(4-((5-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin-1-yl)-1H-
CH2), 3.50 (s, 2H, NCH2), 6.41 (s, 1H, CH), 6.76–6.80 (m, 3H, benzo[d]imidazol-2(3H)-one (6d): Following the same procedure
3Ar-H), 7.73 (s, 1H, H-40), 8.34 (s, 1H, H-20), 8.54 (s, 1H, H-60), adopted for the synthesis of 5a, the title compound 6d was obtained
10.43 (br s, 1H, NH), 10.47 (br s, 1H, NH). 13C NMR from the reductive amination of compound 6 and aldehyde (d).
(125.7 MHz, DMSO-d6) d 22.77 (CH2), 32.48 (CH2), 33.08 Yield: 42%, off-white solid, m.p. 246 ꢀC–247 ꢀC. IR (KBr, cmꢁ1
)
(CH2), 33.55 (CH2), 40.40 (CH2), 41.77 (CH), 53.65 (CH2), 3413, 3190 (CONH), 3048 (Ar-H), 2946 (Alph-H), 1686 (CO),
59.51 (NCH2), 106.90 (Ar-C), 108.38 (Ar-C), 118.98 (Ar-C), 1629, 1506, 1433 (C¼C), 1176 (C-N), 1113 (C-O); 1H NMR
127.96 (Ar-C), 128.39 (Ar-C), 129.82 (Ar-C), 131.30 (Ar-C), (500 MHz, DMSO d6) d 2.52 (br s, 4H, 2CH2), 2.99 (br s, 4H,
133.11 (Ar-C), 133.51 (Ar-C), 138.86 (Ar-C), 139.14 (Ar-C), 2CH2), 3.61 (s, 2H, NCH2), 6.50 (m, 2H, 2Ar-H), 6.73 (d,
145.46 (Ar-C), 148.52 (Ar-C), 155.58 (C¼O). Anal. Calcd for J ¼ 3.2 Hz, 1H, Ar-H), 7.31 (m, 2H, 2Ar-H), 7.76 (m, 2H, 2Ar-H),
C23H26N4O (%): C, 73.77; H, 7.00; N, 14.96. Found (%): C, 7.96 (s, 1H, H-40), 8.50 (s, 1H, H-20), 8.76 (s, 1H, H-60), 10.26 (br s,
73.69; H, 7.06; N, 14.88.
1H, NH), 10.38 (br s, 1H, NH). 13C NMR (125.7 MHz, DMSO d6) d
5-(4-(biphenyl-4-ylmethyl)piperazin-1-yl)-1H-benzo[d]imidazol- 50.08 (CH2), 52.64 (CH2), 58.98 (NCH2), 97.90 (Ar-C), 108.58
2(3H)-one (6a): Following the same procedure adopted for the (Ar-C), 109.44 (Ar-C), 115.91 (Ar-C), 116.07 (Ar-C), 123.65
synthesis of 5a, the title compound 6a was obtained from the (Ar-C), 129.01 (Ar-C), 129.08 (Ar-C), 130.21 (Ar-C), 133.38 (Ar-
reductive amination of compound 6 and aldehyde (a). Yield: 46%, C), 134.31 (Ar-C), 134.89 (Ar-C), 146.35 (Ar-C), 149.04 (Ar-C),
off-white solid, m.p. 4 260 ꢀC. IR (KBr, cmꢁ1) 3430 (CONH), 155.42 (C¼O), 161.15 (Ar-C). Anal. Calcd for C23H22FN5O
3060 (Ar-H), 2966 (Alph-H), 1705 (CO), 1622, 1511, 1438 (C¼C), (%): C, 68.47; H, 5.50; N, 17.36. Found (%): C, 68.46; H, 5.54;
1
1223 (C-N), 1169 (C-O); H NMR (500 MHz, DMSO d6) d 2.51 N, 17.28.
(brs, 4H, 2CH2), 2.99 (br s, 4H, 2CH2), 3.53 (s, 2H, NCH2), 6.49
5-(4-(3-cyclopentenylbenzyl)piperazin-1-yl)-1H-benzo[d]imid-
(m, 2H, 2Ar-H), 6.74 (m, 1H, Ar-H), 7.37–7.44 (m, 5H, 5Ar-H), azol-2(3H)-one (6e): Following the same procedure adopted for
7.57–7.63 (m, 4H, 4Ar-H), 10.26 (br s, 1H, NH), 10.38 (br s, 1H, the synthesis of 5a, the title compound 6e was obtained from the
NH). 13C NMR (125.7MHz, DMSO d6) d 50.13 (CH2), 52.80 reductive amination of compound 6 and aldehyde (e). Yield: 62%,
(CH2), 61.68 (NCH2), 97.83 (Ar-C), 108.56 (Ar-C), 109.39 (Ar-C), off-white solid, m.p. 244 ꢀC–245 ꢀC. IR (KBr, cmꢁ1) 3410, 3183
123.93 (Ar-C), 124.49 (Ar-C), 127.28 (Ar-C), 128.90 (Ar-C), (CONH), 3050 (Ar-H), 2948 (Alph-H), 1689 (CO), 1625, 1516,
129.49 (Ar-C), 130.38 (Ar-C), 136.72 (Ar-C), 137.86 (Ar-C), 1430 (C¼C), 1178 (C-N), 1115 (C-O); 1H NMR (500 MHz,
139.94 (Ar-C), 146.42 (Ar-C), 155.56 (C¼O). Anal. Calcd for DMSO d6) d 1.93 (m, 2H, CH2), 2.49 (br s, 2H, CH2), 2.63 (br s,
C24H24N4O (%): C, 74.97; H, 6.29; N, 14.57. Found (%): C, 74.90; 2H, CH2), 2.98 (br s, 4H, 2CH2), 3.49 (s, 2H, NCH2), 6.24 (br. s,
H, 6.35; N, 14.48.
1H, CH), 6.49 (m, 2H, 2CH), 6.74 (d, J ¼ 3.1 Hz, 1H, Ar-H), 7.18
5-(4-((40-fluorobiphenyl-4-yl)methyl)piperazin-1-yl)-1H-ben-
(m, 1H, Ar-H), 7.28 (m, 1H, Ar-H), 7.32 (m, 1H, Ar-H), 7.38 (m,
zo[d]imidazol-2(3H)-one (6b): Following the same procedure 1H, Ar-H), 10.27 (br s, 1H, NH), 10.39 (br s, 1H, NH). 13C NMR
adopted for the synthesis of 5a, the title compound 6b was (125.7 MHz, DMSO d6) d 22.86 (CH2), 32.78 (CH2), 32.94 (CH2),
obtained from the reductive amination of compound 6 and 50.11 (CH2), 52.77 (CH2), 62.08 (NCH2), 97.95 (Ar-C), 108.70
aldehyde (b). Yield: 55%, off-white solid, m.p. 4 260 ꢀC. IR (Ar-C), 109.49 (Ar-C), 124.28 (Ar-C), 126.08 (Ar-C), 127.75 (Ar-
(KBr, cmꢁ1) 3439 (CONH), 3065 (Ar-H), 2936 (Alph-H), 1707 C), 128.29 (Ar-C), 130.44 (Ar-C), 136.07 (Ar-C), 141.94 (Ar-C),
(CO), 1632, 1501, 1448 (C¼C), 1226 (C-N), 1179 (C-O); 1H 146.42 (Ar-C), 155.66 (C¼O). Anal. Calcd for C23H26N4O (%):
NMR (500 MHz, DMSO d6) d 2.52 (br s, 4H, 2CH2), 2.99 (br s, C, 73.77; H, 7.00; N, 14.96. Found (%): C, 73.68; H, 7.05;
4H, 2CH2), 3.53 (s, 2H, NCH2), 6.49 (m, 2H, 2Ar-H), 6.74 N, 14.86.
(d, J ¼ 3.2 Hz, 1H, Ar-H), 7.26 (m, 2H, 2Ar-H), 7.39 (m, 2H, 2Ar-
5-(4-((5-cyclopentenylpyridin-3-yl)methyl)piperazin-1-yl)-1H-
H), 7.58 (m, 2H, 2Ar-H), 7.67 (m, 2H, 2Ar-H), 10.26 (br s, 1H, benzo[d]imidazol-2(3H)-one (6f): Following the same procedure
NH), 10.37 (br s, 1H, NH). 13C NMR (125.7 MHz, DMSO d6) d adopted for the synthesis of 5a, the title compound 6f was
50.13 (CH2), 52.79 (CH2), 61.65 (NCH2), 97.86 (Ar-C), 108.60 obtained from the reductive amination of compound 6 and
(Ar-C), 109.41 (Ar-C), 115.59 (Ar-C), 123.25 (Ar-C), 126.39 aldehyde (f). Yield: 39%, off-white solid, m.p. 255 ꢀC–256 ꢀC.
(Ar-C), 128.49 (Ar-C), 129.53 (Ar-C), 130.40 (Ar-C), 136.46 (Ar- IR (KBr, cmꢁ1) 3332 (CONH), 3030 (Ar-H), 2951 (Alph-H),
C), 137.38 (Ar-C), 137.83 (Ar-C), 146.41 (Ar-C), 155.59 (C¼O), 1689 (CO), 1644, 1506, 1450 (C¼C), 1222 (C-N), 1176 (C-O);
160.90 (Ar-C), 162.17 (Ar-C). Anal. Calcd for C24H23FN4O 1H NMR (500 MHz, DMSO d6) d 1.95 (m, 2H, CH2), 2.51 (br s,
(%): C, 71.62; H, 5.76; N, 13.92. Found (%): C, 71.55; H, 5.83; 2H, CH2), 2.66 (m, 2H, CH2), 2.98 (br s, 4H, 2CH2), 3.54 (m, 2H,
N, 13.86.
NCH2), 6.42 (br s, 1H, CH), 6.50 (m, 2H, 2Ar-H), 6.74 (m, 1H,
5-(4-((5-phenylpyridin-3-yl)methyl)piperazin-1-yl)-1H-benzo[d] Ar-H), 7.74 (s, 1H, H-40), 8.36 (s, 1H, H-20), 8.57 (s, 1H, H-60),
imidazol-2(3H)-one (6c): Following the same procedure adopted 10.26 (br s, 1H, NH), 10.40 (br s, 1H, NH). 13C NMR
for the synthesis of 5a, the title compound 6c was obtained from (125.7 MHz, DMSO d6) d 22.69 (CH2), 32.40 (CH2), 33.01
the reductive amination of compound 6 and aldehyde (c). Yield: (CH2), 50.06 (CH2), 52.66 (CH2), 59.06 (NCH2), 97.92 (Ar-C),
44%, off-white solid, m.p. 241ꢀC–242 ꢀC. IR (KBr, cmꢁ1) 3433, 108.61 (Ar-C), 109.46 (Ar-C), 123.31 (Ar-C), 128.31 (Ar-C),
3195 (CONH), 3038 (Ar-H), 2936 (Alph-H), 1683 (CO), 1639, 130.40 (Ar-C), 131.21 (Ar-C), 133.04 (Ar-C), 139.03 (Ar-C),
1506, 1443 (C¼C), 1177 (C-N), 1119 (C-O); 1H NMR (500MHz, 145.56 (Ar-C), 146.37 (Ar-C), 148.52 (Ar-C), 155.61 (C¼O).
DMSO d6) d 2.51 (br s, 4H, 2CH2), 2.99 (br s, 4H, 2CH2), 3.62 (s, Anal. Calcd for C22H25N5O (%): C, 70.38; H, 6.71; N, 18.65.
2H, NCH2), 6.50 (m, 2H, 2Ar-H), 6.73 (d, J ¼ 3.2 Hz, 1H, Ar-H), Found (%): C, 70.30; H, 6.75; N, 18.55.
7.41 (m, 1H, Ar-H), 7.47 (m, 2H, 2Ar-H), 7.70 (m, 1H, Ar-H), 7.96
(s, 1H, H-40), 8.51 (s, 1H, H-20), 8.77 (s, 1H, H-60), 10.26 (br. s, 1H, Pharmacology
NH), 10.38 (br. s, 1H, NH). 13C NMR (125.7MHz, DMSO-d6) d
50.11 (CH2), 52.67 (CH2), 59.01 (NCH2), 97.88 (Ar-C), 108.58
Rat-cloned D2L dopaminergic receptors
(Ar-C), 109.44 (Ar-C), 123.29 (Ar-C), 126.93 (Ar-C), 127.09 Human-cloned dopamine D2L receptors stably expressed in C6
(Ar-C), 128.16 (Ar-C), 129.15 (Ar-C), 130.40 (Ar-C), 133.57 (Ar- rat glioma cells (kindly donated by Professor Roberto Maggio,
`
C), 134.56 (Ar-C), 135.19 (Ar-C), 136.99 (Ar-C), 146.37 (Ar-C), Universita di L’Aquila, Italy) were radiolabeled with
149.04 (Ar-C), 155.58 (C¼O). Anal. Calcd for C23H23N5O (%): C, [3H]spiroperidol according to Scarselli et al. with minor modi-
71.67; H, 6.01; N, 18.17. Found (%): C, 71.60; H, 6.06; N, 18.08. fications23. The incubation buffer (120 mM NaCl, 5.0 mM KCl,