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A. Martinez et al. / European Journal of Medicinal Chemistry 35 (2000) 913–922
5.2.2.6. 4-Ethyl-5-[imino-[1-(phenylmethyl)-4-
50.43 (CH2CH2N), 53.68 (2-Cpip.), 63.38 (CH2Ph),
126.84, 127.44 (Cp), 128.03, 128.19 (Co), 128.57, 129.19
(Cm), 136.55, 138.17 (Ci ), 147.30 (5-C), 154.62 (CꢀO).
Anal. (C26H34N4OS) C, H, N.
piperazinyl]ethyl]-2-methyl-1,2,4-thiadiazolidin-3-one 14
Reagents: 5-chloro-4-ethyl-2-methyl-3-oxo-1,2,4-thia-
diazolium chloride 1 (0.23 g, 1.1 mmol), 4-aminoethyl-1-
benzylpiperazine [29] (0.24 g, 1.1 mmol), triethylamine
(0.22 g, 2.2 mmol). Purification: CH2Cl2:MeOH (40:1).
5.2.2.9. 4-Benzyl-5-[imino-[1-(phenylmethyl)-4-
piperazinyl]ethyl]-2-isopropyl-1,2,4-thiadiazolidin-
3-one 17
1
Yield: 0.05 g (13%) of colourless oil; H-NMR (CDCl3)
l: 1.15 (t, 3H, CH2CH3), 2.44 (m, 4H, 2-Hpip.), 2.48
(m, 4H, 3-Hpip.), 2.59 (t, 2H, CH2CH2N), 3.04 (s, 3H,
CH3), 3.06 (t, 2H, CH2CH2N), 3.44 (s, 2H, CH2Ph),
3.68 (q, 2H, CH2CH3), 7.22 (m, 5H, H-Ph); 13C-NMR
(CDCl3) l: 12.52 (CH2CH3), 31.85 (CH3), 38.64
(CH2CH3), 50.87 (CH2CH2N), 52.87 (3-Cpip.), 53.45
(2-Cpip.), 58.60 (CH2CH2N), 62.97 (CH2Ph), 126.93
(Cp), 128.09 (Co), 129.11 (Cm), 137.94 (Ci ), 148.23
(5-C), 155.40 (CꢀO). Anal. (C18H27N5OS) C, H, N.
Reagents: 5-chloro-4-benzyl-2-isopropyl-3-oxo-1,2,4-
thiadiazolium chloride
4 (0.35 g, 1.1 mmol), 4-
aminoethyl-1-benzylpiperazine [29] (0.24 g, 1.1 mmol),
triethylamine (0.22 g, 2.2 mmol). Purification:
CH2Cl2:MeOH (40:1). Yield: 0.13 g (27%) of colourless
1
oil; H-NMR (CDCl3) l: 1.15 (d, 6H, CH(CH3)2), 2.42
(m, 4H, 2-Hpip.), 2.43 (m, 4H, 3-Hpip.), 2.59 (t, 2H,
CH2CH2N), 3.10 (t, 2H, CH2CH2N), 3.43 (s, 2H,
CH2Ph), 4.54 (m, 1H, CH(CH3)2), 4.78 (s, 2H, CH2Ph),
7.28 (m, 10H, H-Ph); 13C-NMR (CDCl3) l: 20.92
(CH(CH3)2), 46.10 (CH2Ph), 46.93 (CH(CH3)2), 50.88
(CH2CH2N), 52.88 (3-Cpip.), 53.40 (2-Cpip.), 58.60
(CH2CH2N), 62.96 (CH2Ph), 126.93, 127.43 (Cp),
128.09, 128.19 (Co), 128.49, 129.11 (Cm), 136.49, 137.95
(Ci ), 148.37 (5-C), 154.56 (CꢀO). Anal. (C25H33N5OS)
C, H, N.
5.2.2.7. 4-Benzyl-5-[imino-[1-(phenylmethyl)-4-
piperidinyl]]-2-isopropyl-1,2,4-thiadiazolidin-3-one 15
Reagents: 5-chloro-4-benzyl-2-isopropyl-3-oxo-1,2,4-
thiadiazolium chloride 4 (0.33 g, 1 mmol), 4-amino-1-
benzylpiperidine (0.20 g, 1 mmol), triethylamine (0.20 g,
2 mmol). Purification: CH2Cl2:MeOH (50:1). Yield: 0.08
1
g (18%) of colourless oil; H-NMR (CDCl3) l: 1.09 (d,
6H, CH(CH3)2), 1.67 (m, 4H, 3-Hpip.), 2.13 (m, 2H,
2ec-Hpip.), 2.70 (m, 2H, 2ax-Hpip.), 2.69 (c, 1H, 4-
Hpip.), 3.46 (s, 2H, CH2Ph), 4.79 (s, 2H, CH2Ph), 7.30
(m, 10H, H-Ph); 13C-NMR (CDCl3) l: 20.92
(CH(CH3)2), 32.51 (3-Cpip.), 46.29 (CH2Ph), 46.89
(CH(CH3)2), 51.40 (2-Cpip.), 60.30 (4-Cpip.), 63.20
(CH2Ph), 126.94, 127.49 (Cp), 128.12 (Co), 129.07
(Cm), 136.67, 138.50 (Ci ), 146.70 (5-C), 154.58 (CꢀO).
Anal. (C24H30N4OS) C, H, N.
5.2.2.10. 4-Benzyl-5-[imino-[1-(phenylmethyl)-4-
piperidinyl]ethyl]-2-methyl-1,2,4-thiadiazolidin-3-one 18
Reagents:5-chloro-4-benzyl-2-methyl-3-oxo-1,2,4-thia-
diazolium chloride 3 (0.33 g, 1.2 mmol), 4-aminoethyl-1-
benzylpiperidine [28] (0.26 g, 1.2 mmol), triethylamine
(0.24 g, 2.4 mmol). Purification: CH2Cl2:MeOH (40:1).
1
Yield: 0.30 g (60%) of colourless oil; H-NMR (CDCl3)
l: 1.23 (m, 3H, 4-Hpip. and 3ax-Hpip.), 1.48 (q, 2H,
CH2CH2N), 1.55 (m, 2H, 3ec-Hpip.), 1.85 (t, 2H, 2ax-
Hpip.), 2.78 (d, 2H, 2ec-Hpip.), 2.92 (t, 2H, CH2CH2N),
3.05 (s, 3H, CH3), 3.44 (s, 2H, CH2Ph), 4.79 (s, 2H,
CH2Ph), 7.25 (m, 10H, H-Ph); 13C-NMR (CDCl3) l:
31.90 (3-Cpip.), 31.97 (CH3), 33.23 (4-Cpip.), 36.99
(CH2CH2N), 46.58 (CH2Ph), 50.30 (CH2CH2N), 53.59
(2-Cpip.), 63.28 (CH2Ph), 126.78, 127.47 (Cp), 127.98,
128.14 (Co), 128.56, 129.10 (Cm), 136.38, 138.13 (Ci ),
146.60 (5-C), 155.41 (CꢀO). Anal. (C24H30N4OS) C, H,
N.
5.2.2.8. 4-Benzyl-5-[imino-[1-(phenylmethyl)-4-
piperidinyl]ethyl]-2-isopropyl-1,2,4-thiadiazolidin-
3-one 16
Reagents: 5-chloro-4-benzyl-2-isopropyl-3-oxo-1,2,4-
thiadiazolium chloride
4 (0.35 g, 1.1 mmol), 4-
aminoethyl-1-benzylpiperidine [28] (0.24 g, 1.1 mmol),
triethylamine (0.22 g, 2.2 mmol). Purification:
CH2Cl2:MeOH (40:1). Yield: 0.12 g (25%) of colourless
1
oil; H-NMR (CDCl3) l: 1.18 (d, 6H, CH(CH3)2), 1.23
(m, 3H, 4-Hpip. and 3ax-Hpip.), 1.50 (q, 2H,
CH2CH2N), 1.59 (m, 2H, 3ec-Hpip.), 1.86 (t, 2H, 2ax-
Hpip.), 2.80 (d, 2H, 2ec-Hpip.), 2.97 (t, 2H, CH2CH2N),
3.44 (s, 2H, CH2Ph), 4.56 (m, 1H, CH(CH3)2), 4.80 (s,
2H, CH2Ph), 7.25 (m, 10H, H-Ph); 13C-NMR (CDCl3)
l: 20.90 (CH(CH3)2), 32.03 (3-Cpip.), 33.34 (4-Cpip.),
37.09 (CH2CH2N), 46.14 (CH2Ph), 46.94 (CH(CH3)2),
5.3. Biological methods
5.3.1. AChE inhibition
AChE inhibitory activity was evaluated spectrophoto-
metrically at 25 °C by the method of Ellman [13], using
AChE from bovine erythrocytes and acetylthiocholine