5138
K. Gholivand et al. / European Journal of Medicinal Chemistry 45 (2010) 5130e5139
Table 7
1219 (s, P]O), 1011 (m, PeNamine), 970 (w, NeN), 912 (s, PeNamide),
715 (CeCl).
The enzymatic data for hAChE and candidate compounds
Compound
IC50 (mM)
log P
Km (mM)
Vm (mM/min)
Inhibition
mechanism
6.12. 4-Methoxy-N-benzoyl-N0,N00-bis (4-aminomorpholine)
Enzyme
1a
3a
7a
11a
12a
e
e
0.083
e
34.48
e
e
phosphoric triamide (10a)
e
ꢀ1.12
ꢀ0.54
ꢀ0.78
1.35
1.29
e
9.55
18.62
1.95
5.49
0.047
0.049
0.045
0.051
37.04
55.55
40.01
11.11
Mixed
Mixed
Mixed
Mixed
Yield: 68%. M.p. ¼188 ꢁC. Anal. Calc. for C16H26N5O5P (399.36):
C, 48.08; H, 6.51; N, 17.53; Found: C, 48.10; H, 6.50; N, 17.60%. 31P
NMR (202.46 MHz, d6-DMSO, ppm):
d
¼ 2.88 (m). 1H NMR
2
(500.13 MHz, d6-DMSO, ppm):
d
¼ 9.02 (s, JPNH ¼ 0 Hz; 1Hamide),
7.92 (d, 3JH,H ¼ 8.8 Hz, 2H; AreH), 6.97 (d, 3JH,H ¼ 8.8 Hz, 2H; AreH),
6.9. N-Benzoyl-N0,N00-bis (4-aminomorpholine) phosphoric
triamide (7a)
2
5.94 (d, JPNH ¼ 29.6 Hz; NHamide), 3.80 (s, 3H), 3.52 (m, 8H), 2.68
(m, 8H). 13C NMR (125.77 MHz, d6-DMSO, ppm):
d
¼ 27.00, 57.81 (d,
3JP,C ¼ 4.7 Hz), 66.00, 113.5, 125.91, 129.91, 135.90, 162.31, 167.20. IR
Yield: 88%. M.p. ¼177e179 ꢁC. Anal. Calc. for C15H24N5O4P
(KBr, n
, cmꢀ1): 3420 (w, br, NeH), 3260 (m, CeHaromatic), 1647 (vs,
(396.36): C, 45.41; H, 6.05; N, 17.66; Found: C, 45.10; H, 6.10; N,
C]O), 1448 (m, C]C), 1407 (m, CeNamide) 1211 (s, P]O), 1173 (m,
CeO), 1002 (m, PeNamine), 936 (w, NeN), 910 (m, PeNamide).
17.60%. 31P NMR (202.46 MHz, d6-DMSO, ppm):
d
¼ 4.72 (m). 1H
2
NMR (500.13 MHz, d6-DMSO, ppm):
d
¼ 8.86 (d, JPNH ¼ 5.2 Hz;
1Hamide), 7.98 (d, 3JH,H ¼ 7.8 Hz,1H; AreH), 7.58 (t, 3JH,H ¼ 7.3 Hz,1H;
6.13. N-Benzoyl-N0,N00-bis (4-aminopiperidine) phosphoric triamide
(11a)
3
2
AreH), 7.29 (t, JH,H ¼ 7.5 Hz, 2H; AreH), 4.74 (d, JPNH ¼ 27.0 Hz;
NHamide), 3.67 (m, 8H), 2.81 (m, 8H). 13C NMR (125.77 MHz, d6-
3
Yield: 75%. M.p. ¼ 204 ꢁC. Anal. Calc. for C17H28N5O2P (365.36): C,
DMSO, ppm):
133.43,136.57,169.63. IR (KBr,
CeHaromatic), 1643 (vs, C]O), 1447 (m, C]C), 1421 (m, CeNamide
d
¼ 58.97 (d, JP,C ¼ 4.8 Hz), 66.43, 131.97, 132.93,
55.83; H, 7.66; N, 19.16; Found: C, 55.80; H, 7.65; N, 19.20%. 31P NMR
n
, cmꢀ1): 3400 (w, br, NeH), 3235 (m,
¼ 2.49 (m). 1H NMR (500.13 MHz,
)
(202.46 MHz, d6-DMSO, ppm):
d
2
1212 (s, P]O), 1009 (m, PeNamine), 920 (s, PeNamide), 970 (w, NeN).
d6-DMSO, ppm):
d
¼ 9.08 (s, JPNH ¼ 0 Hz; 1Hamide), 7.88 (d,
3JH,H ¼ 7.8 Hz, 2H; AreH), 7.48e7.69 (m, 3H; AreH), 5.69 (d,
2JPNH ¼ 30.0 Hz; NHamide), 3.40 (m, 8H), 3.04 (m, 8H),1.45 (m, 4H).13
C
6.10. 2,6-Difluoro-N-benzoyl-N0,N00-bis (4-aminomorpholine)
phosphoric triamide (8a)
NMR (125.77 MHz, d6-DMSO, ppm):
d
¼ 23.4, 25.51, 58.70 (d,
3JP,C ¼ 4.4 Hz), 127.43, 128.11, 132.00,134.00 (d, 4JP,C ¼ 7.9 Hz),167.81.
IR (KBr, n
, cmꢀ1): 3455 (w, br, NeH), 3280 (m, CeHaromatic), 1648 (vs,
Yield: 83%. M.p. ¼ 212 ꢁC. Anal. Calc. for C15H22F2N5O4P
C]O), 1451 (m, C]C), 1428 (m, CeNamide) 1211 (s, P]O), 1017 (m,
PeNamine), 902 (m, PeNamide), 926 (w, NeN).
(432.36): C, 41.63; H, 5.09; N, 16.19; Found: C, 41.60; H, 6.00; N,
16.10%. 31P NMR (202.46 MHz, d6-DMSO, ppm):
d
¼ 0.25 (m). 1H
2
NMR (500.13 MHz, d6-DMSO, ppm):
d
¼ 9.62 (d, JPNH ¼ 6.6 Hz;
3
6.14. Phenyl-N-(4-aminopiperidine) phosphate (12a)
1Hamide), 7.49 (m, 2H), 7.14 (t, JH,H ¼ 5.1 Hz, 1H; AreH), 5.99 (d,
2JPNH ¼ 30.5 Hz; 2Hamide), 3.56 (t, JH,H ¼ 4.2 Hz; 8H), 2.71 (m, 8H).
3
Yield: 88%. M.p. ¼128 ꢁC. Anal. Calc. for C11H18N2O3P (257.12): C,
13C NMR (125.77 MHz, d6-DMSO, ppm):
d
¼ 57.81 (d, 3JP,C ¼ 4.5 Hz),
51.34; H, 7.00; N, 10.89; Found: C, 51.39; H, 7.10; N, 10.91%. 31P NMR
66.13, 111.9, 111.7. IR (KBr, n
, cmꢀ1): 3445 (w, br, NeH), 3260 (m,
(202.46 MHz, d6-DMSO, ppm):
d
¼ ꢀ4.49 (s). 1H NMR (500.13 MHz,
CeHaromatic), 1671 (vs, C]O), 1463 (m, C]C), 1383 (m, CeNamide
1207 (s, P]O), 1010 (m, PeNamine), 925 (w, NeN), 912 (m,
PeNamide).
)
3
d6-DMSO, ppm):
d
¼ 7.27 (t, JH,H ¼ 7.9 Hz; 2H; AreH), 7.18 (d,
3JH,H ¼ 7.8 Hz, 2H; AreH), 6.98 (t, 3JH,H ¼ 7.3 Hz, 1H; AreH), 6.11 (br,
1H; OH), 2.99 (m, 4H), 1.66 (m, 4H), 1.34 (t, 2H). 13C NMR
6.11. 4-Chloro-N-benzoyl-N0,N00-bis (4-aminomorpholine)
phosphoric triamide (9a)
(125.77 MHz, d6-DMSO, ppm):
d
¼ 19.71, 21.90, 23.41, 25.60, 57.81,
128.91, 122.31, 120.10 (d, 3JP,C ¼ 4.8 Hz; Cipso). IR (KBr,
n
, cmꢀ1): 3220
(w, br, NeH), 3150 (m, CeHaromatic), 1452 (PePh), 1356e1392 (w,
Ph), 1171 (m, P]O), 950 (w, NeN), 876 (m, PeNamine).
Yield: 80%. M.p. ¼ 201e205 ꢁC. Anal. Calc. for C15H23ClN5O4P
(404.86): C, 44.45; H, 5.68; N, 17.29; Found: C, 44.10; H, 5.60; N,
6.15. 4,40-Bis(morpholine)diazene (1b)
17.30%. 31P NMR (202.46 MHz, d6-DMSO, ppm):
d
¼ 2.31 (m). 1H
2
NMR (500.13 MHz, d6-DMSO, ppm):
d
¼ 9.08 (s, JPNH ¼ 0.0 Hz;
Yield: 60%. M.p. ¼156 ꢁC. Anal. Calc. for C8H16N4O2 (200.12): C,
1Hamide), 7.91 (d, 3JH,H ¼ 8.5 Hz, 2H; AreH), 7.54 (d, 3JH,H ¼ 8.1 Hz, 2H;
AreH), 5.63 (d, 2JPNH ¼ 30.0 Hz; 2Hamine), 3.53 (m, 8H), 2.67 (m, 8H).
55.83; H, 7.66; N, 19.16; Found: C, 55.80; H, 7.65; N, 19.20%. 1H NMR
(500.13 MHz, d6-DMSO, ppm):
d
¼ 3.71 (m, 8H), 3.05 (m, 8H). 13C
13C NMR (125.77 MHz, d6-DMSO, ppm):
66.13 (s), 128.40, 129.81, 133.43, 132.61 (d, JP,C ¼ 8.6 Hz; Cipso),
d
¼ 57.97 (d, 3JP,C ¼ 4.6 Hz),
4
NMR (125.77 MHz, d6-DMSO, ppm):
d
¼ 49.87, 65.31. IR (KBr,
n,
cmꢀ1): 2960, 1448, 1264, 1108, 1085, 985, 857.
136.91, 167.00. IR (KBr, n
, cmꢀ1): 3331 (w, br, NeH), 3265 (m,
CeHaromatic), 1651 (vs, C]O), 1432 (m, C]C), 1396 (m, CeNamide),
6.16. Dimethyl phenyl phosphonic acid (1d)
Table 8
Yield: 68%. Anal. Calc. for C8H11O3P (186.23): C, 51.55; H, 5.91;
Found: C, 51.50; H, 5.95%. 31P NMR (202.46 MHz, d6-DMSO, ppm):
The enzymatic data for hBChE and candidate compounds.
Compound
IC50 (mM)
log P
Km (mM)
Vm (mM/min)
Inhibition
mechanism
d
¼ 22.29 (s). 1H NMR (500.13 MHz, d6-DMSO, ppm):
d
¼ 7.75 (d,
3JP,H ¼ 6.5 Hz, 2H; AreH), 7.51 (m, 1H; AreH), 7.43 (m, 2H), 3.71 (d,
3JP,H ¼ 10.85 Hz, 6H; OCH3). 13C NMR (125.77 MHz, d6-DMSO, ppm):
Enzyme
1a
3a
7a
11a
12a
e
e
0.11
40.32
71.43
66.38
23.49
55.56
27.78
e
2.45
1.62
2.14
0.43
1.58
ꢀ1.12
ꢀ0.54
ꢀ0.78
1.35
1.29
0.067
0.085
0.050
0.075
0.067
Mixed
Mixed
Mixed
Mixed
Mixed
d
¼ 52.48 (d, 2JP,C ¼ 5.0 Hz), 127.83 (d, 1JP,C ¼ 189.0 Hz; Cipso), 128.39
(d, 2JP,C ¼ 15.1 Hz), 131.70 (d, 3JP,C ¼ 8.8 Hz), 132.48. IR (KBr,
n
, cmꢀ1):
3365 (m, CeHaromatic), 1436 (m, PePh), 1178 (s, P]O), 1136 (s, CeO),
791 (s, PeO).