A. J. Bojarski et al. / Bioorg. Med. Chem. 14 (2006) 1391–1402
1399
J = 7.3, 1.0 Hz, 1H, phenyl H-4), 4.00–3.86 (m, 1H,
cyclohexane axial H-1), 3.33 (t, J = 7.0 Hz, 2H, pyrroli-
din-2-one H-3 and H-30), 3.26–3.14 (m, 4H, piperazine
2CH2), 2.80–2.68 (m, 4H, piperazine 2CH2), 2.43–2.27
(m, 3H, cyclohexane axial H-4 and pyrrolidin-2-one
H-5 and H-50), 2.08–1.88 (m, 4H, cyclohexane equatori-
al Hꢀs and pyrrolidin-2-one H-4 and H-40), 1.88–1.71 (m,
2H, cyclohexane equatorial Hꢀs), 1.57–1.37 (m, 4H,
cyclohexane axial Hꢀs). 20Æ0.75C4H4O4: colorless crys-
tals, mp 217–219 ꢁC. Anal. (C20H29N3OÆ0.75C4H4O4)
C, H, N.
1.38 (m, 4H, cyclohexane axial Hꢀs). 24ÆC4H4O4: color-
less crystals, mp 215–217 ꢁC. Anal. (C21H28N3OF3Æ-
C4H4O4) C, H, N.
5.1.20. General procedure for the preparation of com-
pounds 17, 18, and 25–30. A solution of the appropriate
4-aryl-1-[4-(2-phthalimido)butyl]piperazine11 or 4-aryl-
1-[4-(2-phthalimido)cyclohexyl]piperazine2 (1 mmol) in
glacial acetic acid (2.26 g) was heated to 60 ꢁC and zinc
dust (5.5 mmol) was added all at once with stirring. The
reaction mixture was refluxed with stirring for 1 h, then
filtered hot and washed with glacial acetic acid. Next the
mixture was concentrated under reduced pressure, alkal-
ized by saturated NaHCO3 solution, and extracted with
CHCl3 (3 · 30 ml). The combined extracts were washed
with saturated NaHCO3 solution then with water and
dried (MgSO4). After evaporation of the solvent, the
residue was purified by column chromatography. For
pharmacological assays free bases were converted into
the hydrochloride salts in acetone solution by the treat-
ment with excess Et2O saturated with gaseous HCl.
5.1.16. 1-{4-[4-(3-Chlorophenyl)piperazin-1-yl]butyl}pyrr-
olidin-2-one (21). Compound 21 was prepared by the
general procedure in 74% yield as colorless crystals,
mp 80–82 ꢁC, Rf = 0.18 (SiO2, CHCl3/CH3OH = 19/1);
1H NMR (60 MHz) d 7.1 (t, J = 8 Hz, 1H, Ar-H.),
6.9–6.5 (m, 3H, Ar-H.), 3.7–2.8 (cluster, 8H), 2.8–1.8
(cluster, 10H), 1.7–1.1 (m, 4H, –CH2–(CH2)2–CH2–).
21ÆC4H4O4: colorless crystals, mp 126–128 ꢁC. Anal.
(C18H26N3OClÆC4H4O4) C, H, N.
5.1.17. trans-1-{4-[4-(3-Chlorophenyl)piperazin-1-yl]cy-
clohexyl}pyrrolidin-2-one (22). Compound 22 was pre-
pared by the general procedure in 50% yield as
colorless crystals, mp 170–172 ꢁC, Rf = 0.19 (SiO2,
5.1.21. 2-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-
2,3-dihydro-1H-isoindol-1-one (17). Compound 17 was
prepared by the general procedure in 38% yield as a yel-
low oil, Rf = 0.37 (Al2O3, ethyl acetate); 1H NMR
(60 MHz) d 7.9–7.6 (m, 1H, Ar-H), 7.5–7.1 (m. 3H,
Ar-H), 6.8 (s, 4H, Ar-H), 4.3 (s, 2H, dihydroisoindol-
1-one CH2), 3.7 (s, 3H, OCH3), 3.6 (t, J = 6 Hz, 2H, –
CH2–dihydroisoindol-1-one), 3.2–2.7 (m, 4H, piperazine
2CH2), 2.7–2.1 (m, 6H, piperazine 2CH2 and –CH2–pi-
perazine), 1.8–1.3 (m, 4H, –CH2–(CH2)2–CH2–).
17Æ2HClÆ0.25H2O: colorless crystals, mp 227–229 ꢁC.
Anal. (C23H29N3O2Æ2HClÆ0.25H2O) C, H, N.
1
CHCl3/CH3OH = 19/1); H NMR (300 MHz) d 7.15 (t,
J = 8.1 Hz, 1H, phenyl H-5), 6.86 (t, J = 2.2 Hz, 1H,
phenyl H-2), 6.82–6-74 (m, 2H, phenyl H-4 and H-6),
4.00–3.88 (m, 1H, cyclohexane axial H-1), 3.33 (t,
J = 6.9 Hz, 2H, pyrrolidin-2-one H-3 and H-30), 3.28–
3.14 (m, 4H, piperazine 2CH2), 2.82–2.64 (m, 4H, piper-
azine 2CH2), 2.43–2.28 (m, 3H, cyclohexane axial H-4
and pyrrolidin-2-one H-5 and H-50), 2.07–1.91 (m, 4H,
cyclohexane equatorial Hꢀs and pyrrolidin-2-one H-4
and H-40), 1.87–1.72 (m, 2H, cyclohexane equatorial
Hꢀs), 1.57–1.37 (m, 4H, cyclohexane axial Hꢀs).
22Æ1.1C4H4O4: colorless crystals, mp 206–208 ꢁC. Anal.
(C20H28N3OClÆ1.1C4H4O4) C, H, N.
5.1.22. trans-2-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]cy-
clohexyl}-2,3-dihydro-1H-isoindol-1-one (18). Com-
pound 18 was prepared by the general procedure in
87% yield as colorless crystals, mp 162–164 ꢁC,
Rf = 0.31 (SiO2, CHCl3/CH3OH = 19/1); 1H NMR
(300 MHz) d 7.85 (d, J = 6.9 Hz, 1H, dihydroisoindol-
1-one H-7), 7.57–7.41 (m, 3H, dihydroisoindol-1-one
H-4, H-5 and H-6), 7.05–6.89 (m, 3H, phenyl H-3, H-4
and H-5), 6.87 (d, J = 7.9 Hz, 1H, phenyl H-6), 4.35
(s, 2H, dihydroisoindol-1-one CH2), 4.33–4.18 (m, 1H,
cyclohexane axial H-1), 3.87 (s, 3H, OCH3), 3.30–3.05
(m, 4H, piperazine 2CH2), 2.98–2.80 (m, 4H, piperazine
2CH2), 2.60–2.44 (m, 1H, cyclohexane axial H-4), 2.22–
2.07 (m, 2H, cyclohexane equatorial Hꢀs), 2.07–1.92 (m,
2H, cyclohexane equatorial Hꢀs), 1.71–1.50 (m, 4H,
cyclohexane axial Hꢀs). 18Æ2HClÆH2O: colorless crystals,
mp 258–260 ꢁC. Anal. (C25H31N3OÆ2HClÆH2O) C, H, N.
5.1.18. 1-{4-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]bu-
tyl}pyrrolidin-2-one (23). Compound 23 was prepared by
the general procedure in 33% yield as a yellow oil,
Rf = 0.16 (SiO2, CHCl3/CH3OH = 19/1); 1H NMR
(60 MHz) d 7.55–6.8 (m, 4H, Ar-H.), 3.5–3.0 (m, 8H),
2.7–1.7 (cluster, 10H), 1.7–1.1 (m, 4H, –CH2–(CH2)2–
CH2–). 23Æ1.6C4H4O4:colorless crystals, mp 165–167 ꢁC.
Anal. (C19H26N3OF3Æ1.6C4H4O4) C, H, N.
5.1.19. trans-1-{4-[4-(3-Trifluoromethylphenyl)piperazin-
1-yl]cyclohexyl}pyrrolidin-2-one (24). Compound 24 was
prepared by the general procedure in 53% yield as color-
less crystals, mp 162–164 ꢁC, Rf = 0.27 (SiO2, CHCl3/
CH3OH = 19/1); 1H NMR (300 MHz)
d
7.33 (t,
5.1.23. 2-[4-(4-Phenylpiperazin-1-yl)butyl]-2,3-dihydro-
1H-isoindol-1-one (25). Compound 25 was prepared
by the general procedure in 44% yield as a yellow oil,
Rf = 0.34 (SiO2, CHCl3/CH3OH = 19/1); 1H NMR
(60 MHz) d 7.9–7.6 (m, 1H, Ar-H), 7.6–7.0 (m. 5H,
Ar-H), 7.0–6.6 (m, 3H, Ar-H), 4.3 (s, 2H, dihydroisoin-
dol-1-one CH2), 3.6 (t, J = 6 Hz, 2H, –CH2– dihydrois-
oindol-1-one), 3.3–2.9 (m, 4H, piperazine 2CH2), 2.8–
2.0 (m, 6H, piperazine 2CH2 and –CH2–piperazine),
2.0–1.3 (m, 4H, –CH2–(CH2)2–CH2–). 25Æ2HCl: color-
J = 7.9 Hz, 1H, phenyl H-5), 7.10 (s, 1H, phenyl H-2),
7.12–7.01 (m, 2H, phenyl H-4 and H-6), 4.02–3.87 (m,
1H, cyclohexane axial H-1), 3.33 (t, J = 7.0 Hz, 2H,
pyrrolidin-2-one H-3 and H-30), 3.30–3.18 (m, 4H,
piperazine 2CH2), 2.82–2.66 (m, 4H, piperazine 2CH2),
2.44–2.28 (m, 3H, cyclohexane axial H-4 and pyrroli-
din-2-one H-5 and H-50), 2.08–1.92 (m, 4H, cyclohexane
equatorial Hꢀs and pyrrolidin-2-one H-4 and H-40),
1.88–1.73 (m, 2H, cyclohexane equatorial Hꢀs), 1.58–