4
S. Rybka et al.
J Enzyme Inhib Med Chem, Early Online: 1–10
H, piperazine), 2.74 (dd, 1 H, imide, J ¼ 18.50 Hz, J ¼ 5.10 Hz), 4.38 (d, 2H, CH2, J ¼ 6.70 Hz), 4.82 (d, 1H, CH, J ¼ 4.87 Hz),
2.96 (dd, 1 H, imide, J ¼ 18.45 Hz, J ¼ 9.25 Hz), 3.06 (t, 4H, 6.36–6.46 (m, 2H, ArH), 6.49–6.53 (m, 1H, ArH), 7.06–7.12 (m,
piperazine, J ¼ 5.00 Hz), 3.66–3.78 (m, 1 H, piperazine), 4.38 (d, 2H, ArH), 7.12–7.19 (m, 2H, ArH),7.19–7.25 (m, 4H, ArH),
2H, CH2, J ¼ 6.67 Hz), 4.84 (d, 1 H, CH, J ¼ 4.62 Hz), 6.98–7.10 7.27–7.38 (m, 3H, ArH); ESI-MS: 470.36 (C29H31O3N3
(m, 4 H, ArH), 7.10–7.17 (m, 2 H, ArH), 7.17–7.24 (m, 3 H, [M + H]+); Anal. calcd for C29H31O3N3 (469.57): C: 74.18, H:
ArH), 7.24–7.30 (m, 2 H, ArH) 7.30–7.39 (m, 3 H, ArH); 13C 6.65, N: 8.95; Found C: 74.12, H: 6.72, N: 8.92.
NMR (75 MHz, CDCl3) ꢀ: 32.10, 44.15, 48.56, 50.11, 50.50,
59.92, 112.10, 112.16, 115.80, 118.73, 118.74, 127.00, 127.40,
128.05, 128.71, 128.83, 129.21, 129.58, 139.71, 141.38, 151.27,
176.97, 179.60; 19F NMR (282 MHz, CDCl3) ꢀ: ꢂ62.70; ESI-MS:
508.32 (C29H28O2N3F3 [M + H]+); Anal. calcd for C29H28O2N3F3
(507.55): C: 68.63, H: 5.56, N: 8.28; Found C: 68.58, H: 5.63, N:
8.33.
N-[(4-Phenylpiperazin-1-yl)-methyl]-3-isopropyl-pyrrolidine-2,5-
dione (18)
White powdery crystals. Yield: 61%; m.p. 104–106 ꢁC; TLC:
1
Rf ¼ 0.44 (S1); H NMR (300 MHz, CDCl3) ꢀ: 0.91 (d, 3H, CH3,
J ¼ 6.92 Hz), 1.01 (d, 3H, CH3, J ¼ 6.92 Hz), 2.26–2.39 (m, 1H,
CH), 2.49 (dd, 1H, imide, J ¼ 18.20 Hz, J ¼ 4.60 Hz), 2.64–2.77
(m, 5H, imide, piperazine) 2.78–2.87 (m, 1H, imide), 3.10–3.19
(m, 4H, piperazine), 4.52 (s, 2H, CH2), 6.80–6.94 (m, 3H, ArH),
7.19–7.30 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3) ꢀ: 17.55,
20.08, 28.57, 30.20, 45.86, 49.20, 50.65, 59.74, 116.18, 119.85,
129.10, 151.17, 177.83, 180.34; ESI-MS: 316.26 (C18H25N3O2
[M + H]+); Anal. calcd for C18H25N3O2 (315.19): C: 68.54, H:
7.99, N: 13.32; Found C: 68.58, H: 8.10, N: 13.35.
N-[{4-(2-methylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-
pyrrolidine-2,5-dione (14)
White powdery crystals. Yield: 80%; m.p. 131–133 ꢁC; TLC:
Rf ¼ 0.50 (S1);1H NMR (300 MHz, CDCl3) ꢀ: 2.29 (s, 3H, CH3),
2.51–2.68 (m,
4 H, piperazine), 2.74 (dd, 1 H, imide,
J ¼ 18.35 Hz, J ¼ 5.25 Hz), 2.84 (t, 4H, piperazine, J ¼ 4.74 Hz),
2.99 (dd, 1 H, imide, J ¼ 18.45 Hz, J ¼ 9.25 Hz), 3.65–3.79 (m, 1
H, piperazine), 4.41 (d, 2H, CH2, J ¼ 4.36 Hz,), 4.90 (d, 1 H, CH,
J ¼ 4.36 Hz), 6.99 (d, 2H, ArH, J ¼ 7.18 Hz), 7.08–7.15 (m, 2 H,
ArH), 7.15–7.20 (m, 3 H, ArH), 7.21–7.25 (m, 3 H, ArH) 7.27–
7.39 (m, 4 H, ArH); ESI-MS: 454.40 (C29H31O2N3 [M + H]+);
Anal. calcd for C29H31O2N3 (453.58): C: 76.79, H: 6.89, N: 9.26;
Found C: 76.84, H: 6.82, N: 9.30.
N-[{4-(2-Fluorophenyl)-piperazin-1-yl}-methyl]-3-isopropyl-pyr-
rolidine-2,5-dione (19)
White powdery crystals. Yield: 82%; m.p. 88–90 ꢁC; TLC:
Rf ¼ 0.49 (S1); 1H NMR (300 MHz, CDCl3) ꢀ: 0.91 (d, 3H,
CH3, J ¼ 6.92 Hz), 1.02 (d, 3H, CH3, J ¼ 6.92 Hz), 2.26–2.39 (m,
1H, CH), 2.44 (dd, 1H, imide, J ¼ 18.20 Hz, J ¼ 4.60 Hz), 2.65–
2.79 (m, 5H, imide, piperazine) 2.80–2.87 (m, 1H, imide), 3.01–
3.10 (m, 4H, piperazine), 4.51 (s, 2H, CH2), 6.87–6.97 (m, 2H,
ArH), 6.98–7.08 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3) ꢀ:
17.57, 20.09, 28.58, 30.24, 45.85, 50.51, 59.76, 115.94, 118.97,
122.59, 124.44 140.05, 154.02, 157.27, 177.82, 180.34; 19F NMR
(282 MHz, CDCl3) ꢀ: ꢂ122.85; ESI-MS: 334.28 (C18H24N3O2F
[M + H]+); Anal. calcd for C18H24N3O2F (333.40): C: 64.84, H:
7.26, N: 12.60; Found C: 64.80, H: 7.30, N: 12.68.
N-[{4-(3-methylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-
pyrrolidine-2,5-dione (15)
White powdery crystals. Yield: 83%; m.p. 137–139 ꢁC; TLC:
1
Rf ¼ 0.46 (S1); H NMR (300 MHz, CDCl3) ꢀ: 2.32 (s, 3H, CH3),
2.49–2.64 (m,
4 H, piperazine), 2.74 (dd, 1 H, imide,
J ¼ 18.30 Hz, J ¼ 5.10 Hz), 2.96 (dd, 1 H, imide, J ¼ 18.50 Hz,
J ¼ 9.25 Hz), 3.09 (t, 4H, piperazine, J ¼ 5.13 Hz), 3.65–3.78 (m,
3 H, piperazine), 4.38 (d, 2H, CH2, J ¼ 6.41 Hz), 4.82 (d, 1 H, CH,
J ¼ 4.87 Hz), 6.66–6.73 (m, 3 H, ArH), 7.07–7.13 (m, 2 H, ArH),
7.13–7.19 (m, 2 H, ArH), 7.19–7.25 (m, 4 H, ArH), 7.27–7.38 (m,
3 H, ArH); 13C NMR (75 MHz, CDCl3) ꢀ: 21.79, 32.17, 44.11,
49.18, 50.39, 50.57, 59.99, 113.37, 116.96, 120.64, 126.99,
127.43, 128.06, 128.70, 128.85, 128.95, 129.11, 138.81, 139.75,
141.45, 151.34, 176.99, 179.63; ESI-MS: 454.40 (C29H31O2N3
[M + H]+); Anal. calcd for C29H31O2N3 (453.58): C: 76.79, H:
6.89, N: 9.26; Found C: 76.84, H: 6.92, N: 9.24.
N-[{4-(4-Fluorophenyl)-piperazin-1-yl}-methyl]-3-isopropyl-pyr-
rolidine-2,5-dione (20)
White powdery crystals. Yield: 80%; m.p. 121–123 ꢁC; TLC:
1
Rf ¼ 0.37 (S1); H NMR (300 MHz, CDCl3) ꢀ: 0.91 (d, 3H, CH3,
J ¼ 6.67 Hz), 1.01 (d, 3H, CH3, J ¼ 6.92 Hz), 2.27–2.38 (m, 1H,
CH), 2.49 (dd, 1H, imide, J ¼ 18.25 Hz, J ¼ 4.65 Hz), 2.64–2.77
(m, 5H, imide, piperazine) 2.78–2.87 (m, 1H, imide), 3.00–3.12
(m, 4H, piperazine), 4.51 (s, 2H, CH2), 6.76–6.88 (m, 2H, ArH),
6.89–6.99 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3) ꢀ: 17.55,
20.07, 28.57, 30.21, 45.86, 50.21, 50.65, 59.69, 115.35, 115.64,
117.90, 118.00, 147.81 158.79, 177.82, 180.32; 19F NMR
(282 MHz, CDCl3) ꢀ: ꢂ124.41; ESI-MS: 334.28 (C18H24N3O2F
[M + H]+); Anal. calcd for C18H24N3O2F (333.40): C: 64.84, H:
7.26, N: 12.60; Found C: 64.83, H: 7.24, N: 12.64.
N-[{4-(2-methoxyphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-
pyrrolidine-2,5-dione (16)
White powdery crystals. Yield: 45%; m.p. 90–92 ꢁC; TLC:
Rf ¼ 0.38 (S1); 1H NMR (300 MHz, CDCl3) ꢀ: 2.59–2.79 (m,
5H, imide, piperazine), 2.85–3.09 (m, 5H, imide, piperazine),
3.66–3.77 (m, 1H, imide), 3.86 (s, 3H, CH3) 4.39 (d, 2H, CH2,
J ¼ 6.50 Hz), 4.79 (d, 1H, CH, J ¼ 5.13 Hz), 6.82–6.93 (m, 3H,
ArH), 6.93–7.04 (m, 1H, ArH), 7.06–7.13 (m, 2H, ArH), 7.15– N-[{4-(2-Chlorophenyl)-piperazin-1-yl}-methyl]-3-isopropyl-pyr-
7.25 (m, 4H, ArH), 7.27–7.38 (m, 4H, ArH); ESI-MS: 470.36 rolidine-2,5-dione (21)
(C29H31O3N3 [M + H]+); Anal. calcd for C29H31O3N3 (469.57):
C: 74.18, H: 6.65, N: 8.95; Found C: 74.25, H: 6.70, N: 8.89.
White powdery crystals. Yield: 82%; m.p. 111–113 ꢁC; TLC:
1
Rf ¼ 0.46 (S1); H NMR (300 MHz, CDCl3) ꢀ: 0.93 (d, 3H, CH3,
J ¼ 6.92 Hz), 1.03 (d, 3H, CH3, J ¼ 6.92 Hz), 2.29–2.39 (m, 1 H,
N-[{4-(3-methoxyphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-
CH), 2.51 (dd, 1 H, imide, J ¼ 18.20 Hz, J ¼ 4.60 Hz), 2.67–2.80
pyrrolidine-2,5-dione (17)
(m, 5H, imide, piperazine), 2.81–2.90 (m, 1H, imide), 2.99–3.07
White powdery crystals. Yield: 75%; m.p. 107–109 ꢁC; TLC: (m, 4H, piperazine), 4.52 (s, 2H, CH2), 6.91–7.04 (m, 2 H, ArH),
1
Rf ¼ 0.40 (S1); H NMR (300 MHz, CDCl3) ꢀ: 2.46–2.63 (m, 4H, 7.16–7.23 (m, 1 H, ArH), 7.33 (dd, 1 H, ArH, J ¼ 7.95 Hz,
piperazine), 2.72 (dd, 1H, imide, J ¼ 18.50 Hz, J ¼ 5.10 Hz), 2.95 J ¼ 1.54 Hz); ESI-MS: 350.30 (C18H24O2N3Cl [M + H]+); Anal.
(dd, 1H, imide, J ¼ 18.35 Hz, J ¼ 9.35 Hz), 3.09 (t, 4H, pipera- calcd for C18H24O2N3Cl (349.86): C: 61.79, H: 6.91, N: 12.01;
zine, J ¼ 5.13 Hz), 3.66–3.76 (m, 1H, imide), 3.79 (s, 3H, CH3) Found C: 61.76, H: 7.02, N: 12.06.