2232
J. Obniska et al. / European Journal of Medicinal Chemistry 44 (2009) 2224e2233
7.40 (t, 1H, ArH, J ¼ 7.94 Hz), 13.16 (brs 1H, HCl). Anal. Calcd
for C25H29O2N3F3Cl (453.95), C: 66.14, H: 6.44, N: 9.26; Found
C: 66.40, H: 6.62, N: 9.13.
for C23H24O2N3F3Cl2 (502.38), C: 55.03, H: 4.82, N: 8.37;
Found C: 55.33, H: 4.65, N: 8.52.
6.1.3.13. Monohydrochloride N-[2-{4-(3-trifluoromethyl-
phenyl)-piperazin-1-yl}-ethyl]-3-(2-trifluoromethylphenyl)-pyr-
rolidine-2,5-dione (11e). White powdery crystals. Yield: 55%,
6.1.3.9. Monohydrochloride N-[2-(4-phenylpiperazin-1-yl)-
ethyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione (11a).
White powdery crystals. Yield: 68%; mp 247e249 ꢀC; TLC:
Rf ¼ 0.81 (S2); H NMR (CDCl3) d: 2.89 (dd, 1H, Hb imide,
1
mp 238e240 ꢀC; TLC: Rf ¼ 0.93 (S2). H NMR (CDCl3) d:
2.90 (dd, 1H, Hb imide, J ¼ 6.04 Hz, J ¼ 17.88 Hz), 3.06
(brs 2H, CH2eCH2), 3.40 (brs, 2H, CH2eCH2) 3.53 (dd,
1H, Ha imide, J ¼ 9.49 Hz, J ¼ 17.60 Hz), 3.65e3.86 (m, 4H
piperazine), 4.04 (brs, 4H piperazine), 4.86 (q, 1H, Hc imide,
J ¼ 6.05 Hz), 7.13e7.23 (m, 3H, ArH), 7.42 (t, 2H, ArH,
J ¼ 7.42 Hz), 7.56e7.60 (m, 2H, ArH), 7.69 (d, 1H, ArH,
J ¼ 7.98 Hz), 13.17 (brs, 1H, HCl). Anal. Calcd for
C24H24O2N3 F6Cl (500.47), C: 57.65, H: 4.84, N: 8.40; Found
C: 57.82, H: 4.76, N: 8.59.
1
J ¼ 5.90 Hz, J ¼ 18.20 Hz), 2.98 (brs 2H, CH2eCH2), 3.37
(brs, 2H, CH2eCH2), 3.50 (dd, 1H, Ha imide, J ¼ 9.36 Hz,
J ¼ 17.95 Hz), 3.60e3.71 (m, 4H, piperazine), 3.92e4.02
(m, 4H, piperazine), 4.83 (q, 1H, Hc imide, J ¼ 5.80 Hz),
6.91e7.00 (m, 2H, ArH), 7.26e7.39 (m, 3H, ArH), 7.41e
7.43 (m, 1H, ArH), 7.53e7.57 (m, 2H, ArH), 7.68 (d, 1H,
ArH, J ¼ 7.69 Hz), 12.92 (brs, 1H, HCl). Anal. Calcd for
C23H25O2N3F3Cl (467.92), C: 59.03, H: 5.38, N: 8.98; Found
C: 59.19, H: 5.23, N: 9.15.
6.1.3.14. Monohydrochloride N-[3-(4-phenylpiperazin-1-yl)-
propyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-dione (11f).
White powdery crystals. Yield: 65%; mp 203e205 ꢀC; TLC:
Rf ¼ 0.88 (S2); 1H NMR (CDCl3) d: 2.30e2.40 (m, 2H,
CH2eCH2eCH2), 2.71 (dd, 1H, Hb imide, J ¼ 5.40 Hz,
J ¼ 18.47 Hz), 2.99 (brs, 2H, piperazine), 3.12 (t, 2H, CH2e
CH2eCH2, J ¼ 4.69 Hz), 3.32 (dd, 1H, Ha imide,
J ¼ 9.66 Hz, J ¼ 18.47 Hz), 3.60e3.70 (m, 6H, piperazine),
3.77 (t, 2H, CH2eCH2eCH2, J ¼ 6.40 Hz), 4.52 (q, 1H, Hc im-
ide, J ¼ 5.54 Hz), 6.90e6.99 (m, 3H, ArH), 7.27e7.32 (m, 3H,
ArH), 7.43 (t, 1H, ArH, J ¼ 7.67 Hz), 7.62 (t, 1H, ArH,
J ¼ 7.39 Hz), 7.70 (d, 1H, ArH, J ¼ 7.95 Hz), 13.05 (brs, 1H,
HCl). Anal. Calcd for C24H27O2N3F3Cl (481.95), C: 59.81,
H: 5.65, N: 8.72; Found C: 59.68, H: 5.43, N: 8.58.
6.1.3.10. Monohydrochloride N-[2-{4-(2-fluorophenyl)-pipera-
zin-1-yl}-ethyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-di-
one (11b). White powdery crystals. Yield: 60%; mp 228e230 ꢀC;
TLC: Rf ¼ 0.84 (S2); 1H NMR (CDCl3) d: 2.89 (dd, 1H, Hb imide,
J ¼ 5.90 Hz, J ¼ 18.20 Hz), 3.25 (brs 2H, CH2eCH2), 3.41e3.57
(m, 5H, 4H piperazine, 1H, Ha imide), 3.82e4.05 (m, 6H, 4H pi-
perazine, 2H, CH2eCH2), 4.84 (q, 1H, Hc imide, J ¼ 5.90 Hz),
7.04e7.24 (m, 4H, ArH), 7.38e7.44 (m, 1H, ArH), 7.55e7.57
(m, 2H, ArH), 7.68 (d, 1H, ArH, J ¼ 7.69 Hz), 13.02 (brs, 1H,
HCl). Anal. Calcd for C23H24O2N3F4Cl (485.91), C: 56.84, H:
4.98, N: 8.65; Found C: 56.68, H: 5.09, N: 8.45.
6.1.3.11. Monohydrochloride N-[2-{4-(2-methoxyphenyl)-pi-
perazin-1-yl}-ethyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-
2,5-dione (11c). White powdery crystals. Yield: 57%; mp
200e202 ꢀC; TLC: Rf ¼ 0.69 (S2); 1H NMR (CDCl3) d:
2.90 (dd, 1H, Hb imide, J ¼ 5.76 Hz, J ¼ 18.20 Hz), 3.07
(brs. 2H, CH2eCH2), 3.37 (brs, 2H, CH2eCH2), 3.48e
3.57 (m, 5H, 4H piperazine, 1H, Ha imide), 3.86 (s, 3H,
OCH3), 3.90e4.05 (m, 4H piperazine), 4.83 (q, 1H, Hc im-
ide, J ¼ 5.90 Hz), 6.87e6.96 (m, 3H, ArH), 7.07 (t, 1H,
ArH, J ¼ 7.43 Hz), 7.38e7.53 (m, 1H, ArH), 7.56e7.59
(m, 2H, ArH), 7.68 (d, 1H, ArH, J ¼ 7.95 Hz), 12.78
(brs, 1H, HCl). Anal. Calcd for C24H27O3N3F3Cl
(497.95), C: 57.89, H: 5.46, N: 8.44; Found C: 57.62, H:
5.40, N: 8.55.
6.1.3.15. Monohydrochloride N-[3-{4-(2-methoxyphenyl)-pi-
perazin-1-yl}-propyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-
2,5-dione (11g). White powdery crystals. Yield 51%; mp
1
161e163 ꢀC; TLC: Rf ¼ 0.76 (S2); H NMR (CDCl3) d: 2.36
(brs, 2H, CH2eCH2eCH2), 2.72 (dd, 1H, Hb imide,
J ¼ 5.50 Hz, J ¼ 18.70 Hz), 3.12 (brs, 4H, piperazine), 3.32
(dd, 1H, Ha imide, J ¼ 9.63 Hz, J ¼ 18.43 Hz), 3.49e3.62
(m, 6H, 2H, CH2eCH2eCH2, 4H, piperazine), 3.71e3.79
(m, 2H, CH2eCH2eCH2), 3.89 (s, 3H, OCH3), 4.52 (q, 1H,
Hc imide, J ¼ 5.64 Hz), 6.88e7.12 (m, 4H, ArH), 7.31 (d,
1H, ArH, J ¼ 7.70 Hz), 7.44 (t, 1H, ArH, J ¼ 7.70 Hz), 7.63
(t, 1H, ArH, J ¼ 7.43 Hz), 7.70 (d, 1H, ArH, J ¼ 7.98 Hz),
12.94 (brs, 1H, HCl). Anal. Calcd for C25H29O3N3F3Cl
(511.98), C: 58.65, H: 5.71, N: 8.21; Found C: 58.38, H:
5.53, N: 8.38.
6.1.3.12. Monohydrochloride N-[2-{4-(3-chlorophenyl)-piper-
azin-1-yl}-ethyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-
dione (11d). White powdery crystals. Yield: 77%, mp
233e235 ꢀC; TLC: Rf ¼ 0.89 (S2); 1H NMR (CDCl3) d:
2.91 (dd, 1H, Hb imide, J ¼ 5.64 Hz, J ¼ 17.69 Hz), 3.10
(brs 2H, CH2eCH2), 3.42 (dd, 1H, Ha imide, J ¼ 9.10 Hz,
J ¼ 17.95 Hz), 3.60e3.76 (m, 6H, 4H piperazine, 2H,
CH2eCH2), 3.97e4.05 (m, 4H piperazine), 4.84 (q, 1H, Hc
imide, J ¼ 5.76 Hz), 6.78e6.94 (m, 3H, ArH), 7.18e7.23
(t, 1H, ArH, J ¼ 8.20 Hz), 7.41e7.60 (m, 3H, ArH), 7.69
(d, 1H, ArH, J ¼ 7.95 Hz), 13.15 (brs, 1H, HCl). Anal. Calcd
6.1.3.16. Monohydrochloride N-[3-{4-(3-chlorophenyl)-piper-
azin-1-yl}-propyl]-3-(2-trifluoromethylphenyl)-pyrrolidine-2,5-
dione (11h). White powdery crystals. Yield: 53%; mp
1
224e227 ꢀC; TLC: Rf ¼ 0.92 (S2); H NMR (CDCl3) d: 2.06
(t, 2H, CH2eCH2eCH2, J ¼ 8.11 Hz), 2.72 (dd, 1H, Hb imide,
J ¼ 5.50 Hz, J ¼ 18.70 Hz), 2.93e3.09 (m, 4 H, 2H pipera-
zine, 2H CH2eCH2eCH2), 3.31 (dd, 1H, Ha imide,
J ¼ 9.63 Hz), 3.58e3.77 (m, 8H, 6H piperazine, 2H CH2e
CH2eCH2), 4.50 (q, 1H, Hc imide, J ¼ 5.50 Hz), 6.76e6.97