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G.-H. Kuo et al. / Bioorg. Med. Chem. 8 (2000) 2263±2275
(CDCl3) d 8.60 (dd, J=7.8, 2.0 Hz, 1H), 8.32 (m, 1H), 8.23
(dd, J=4.7, 2.0 Hz, 1H), 7.46 (m, 2H), 7.29 (m, 1H), 7.17
(m, 3H), 7.02 (m, 1H), 6.90 (m, 3H), 4.01 (m, 1H), 3.86 (s,
3H), 3.75 (m, 1H), 3.49 (m, 1H), 3.06 (m, 4H), 2.87 (m,
2H), 2.56 (m, 4H); MS (ES) m/z: 463 (M+H+). Anal
6.89 (m, 5H), 4.59 (m, 1H), 4.00 (m, 1H), 3.73 (m, 1H),
3.46 (m, 1H), 3.10 (m, 4H), 2.86 (m, 2H), 2.53 (m, 4H),
1.34 (d, J=6.0 Hz, 6H); MS (ES) m/z 507 (M+H+).
Anal (C28H34N4O3S.0.2H2O) C, H, N.
.
(C26H30N4O4 1.1H2O) C, H, N.
2-[(4-Chlorophenyl)thio]-N-[3-[4-[2-(1-methylethoxy)phe-
nyl]-1-piperazinyl]-2-hydroxypropyl]-3-pyridinecarbox-
amide (13). (Method B, foam, 70%); 1H NMR (CDCl3)
d 8.37 (dd, J=4.5, 1.5 Hz, 1H), 7.81 (dd, J=7.5, 1.5 Hz,
1H), 7.45 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H),
7.08 (dd, J=7.5, 4.7 Hz, 1H), 6.89 (m, 5H), 4.59 (m, 1H),
4.00 (m, 1H), 3.76 (m, 1H), 3.42 (m, 1H), 3.10 (m, 4H),
2.86 (m, 2H), 2.57 (m, 4H), 1.34 (d, J=6.1 Hz, 6H); MS
(ES) m/z 541 (M+H+). Anal (C28H33N4O3SCl.0.5H2O)
C, H, N.
2-(4-Chlorophenoxy)-N-[2-hydroxy-3-[4-[2-(1-methyleth-
oxy)phenyl]-1-piperazinyl]propyl]-3-pyridinecarboxamide
1
(4). (Method A, foam, 72%); H NMR (CDCl3) d 8.59
(dd, J=7.7, 1.9 Hz, 1H), 8.21 (m, 2H), 7.39 (d, J=8.8
Hz, 2H), 7.16 (m, 3H), 6.87 (m, 4H), 4.58 (m, 1H), 3.99
(m, 1H), 3.77 (m, 1H), 3.47 (m, 1H), 3.07 (m, 4H), 2.79
(m, 2H), 2.51 (m, 4H), 1.33 (d, J=6.1 Hz, 6H); MS (ES)
m/z 525 (M+H+). Anal (C28H33ClN4O4) C, H, N.
General procedure for the synthesis of 1±7, 12±15
(Method B). 2-(3,4-Dichlorophenoxy)-N-[2-hydroxy-3-[4-
[2-(1-methylethoxy)phenyl]-1-piperazinyl]propyl]-3-pyri-
dinecarboxamide (5). A mixture of the amine 28c (100
mg, 0.341 mmol), 2-(3,4-dichlorophenoxy)-3-pyridinecar-
boxylic acid (97 mg, 0.341 mmol), EDCI (65 mg, 0.341
mmol), HOBT (46 mg, 0.341 mmol), DMAP (cat.) and
triethylamine (0.23 ml) in methylene chloride (3 ml) was
stirred at 20 ꢀC for 18 h under nitrogen. The mixture was
concentrated, diluted with water and extracted with
methylene chloride. The combined organic layer was
dried (Na2SO4) and concentrated. The product was pur-
i®ed by column chromatography (silica gel) to give 69 mg
N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]-2-hy-
droxypropyl]-2-(phenylamino)-3-pyridinecarboxamide (14).
(Method B, foam, 44%); H NMR (CDCl3) d 10.42 (s,
1H), 8.28 (dd, J=4.9, 1.5 Hz, 1H), 7.73 (dd, J=7.7, 1.5
Hz, 1H), 7.68 (d, J=7.6 Hz, 2H), 7.31 (t, J=8.2 Hz,
2H), 7.20±6.84 (m, 6H), 6.65 (dd, J=7.5, 4.7 Hz, 1H),
4.57 (m, 1H), 4.00 (m, 1H), 3.68 (m, 2H), 3.36 (m, 1H),
3.10 (m, 4H), 2.81 (m, 2H), 2.65±2.38 (m, 4H), 1.33 (d,
J=6.0 Hz, 6H); MS (ES) m/z 490 (M+H+); FAB-
HRMS (M+H+). Calcd 490.2818, found 490.2825.
1
N-[3-[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]-2-hy-
droxypropyl]-2-[3-(tri¯uoromethyl)phenyl]amino]-3-pyri-
dinecarboxamide (15). (Method B, foam, 53%); 1H
NMR (CDCl3) d 10.76 (s, 1H), 8.33 (dd, J=4.4, 1.2 Hz,
1H), 8.07 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.78 (dd,
J=7.6, 1.5 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.23 (d,
J=7.7 Hz, 1H), 7.04 (brs, 1H), 6.90 (m, 4H), 6.74 (dd,
J=7.5, 4.7 Hz, 1H), 4.58 (m, 1H), 4.00 (m, 1H), 3.74
(m, 1H), 3.45 (m, 2H), 3.13 (m, 4H), 2.88 (m, 2H), 2.71±
2.42 (m, 4H), 1.33 (d, J=6.1 Hz, 6H); MS (ES) m/z 558
(M+H+). Anal (C29H34N5O3F3. 0.2H2O) C, H, N.
1
(36%) of compound 5 as a foam; H NMR (CDCl3) d
8.60 (dd, J=7.8, 1.9 Hz, 1H), 8.22 (m, 1H), 8.11 (m, 1H),
7.49 (d, J=8.7 Hz, 1H), 7.36 (d, J=2.6 Hz, 1H), 7.19 (m,
1H), 7.08 (dd, J=8.8, 2.8 Hz, 1H), 6.89 (m, 4H), 4.58 (m,
1H), 3.98 (m, 1H), 3.79 (m, 1H), 3.43 (m, 1H), 3.08 (m,
4H), 2.82 (m, 2H), 2.50 (m, 4H), 1.33 (d, J=6.0 Hz, 6H);
MS (ES) m/z 559 (M+H+). Anal (C28H32Cl2N4O4) C,
H, N.
2-(4-Methylphenoxy)-N-[2-hydroxy-3-[4-[2-(1-methyl-
ethoxy)phenyl]-1-piperazinyl]propyl]-3-pyridinecarbox-
amide (6). (Method A, foam, 83%); 1H NMR (CDCl3) d
8.59 (dd, J=7.8, 2.0 Hz, 1H), 8.33 (m, 1H), 8.22 (m, 1H),
7.25 (m, 2H), 7.1 (m, 3H), 6.87 (m, 4H), 4.58 (m, 1H), 4.0
(m, 1H), 3.73 (m, 1H), 3.50 (m, 1H), 3.06 (m, 4H), 2.79 (m,
2H), 2.49 (m, 4H), 2.38 (m, 3H), 1.33 (d, J=6.3 Hz, 6H);
2-Chloro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-
1-piperazinyl]propyl]-3-pyridinecarboxamide (29).
A
mixture of 28c (900 mg, 3.07 mmol), 2-chloronicotinic
acid (485 mg, 3.07 mmol), EDCI (589 mg, 3.07 mmol),
HOBT (414 mg, 3.07 mmol), DMAP (cat.) and N,N-
diisopropylethylamine (2 ml) in methylene chloride (20
ml) was stirred at 20 ꢀC for 20 h. The mixture was con-
centrated, diluted with water and extracted with ether.
The organic layer was dried (Na2SO4) and concentrated.
The product was puri®ed by column chromatography
(silica gel) to give 580 mg (44%) of compound 29 as a
white foam; 1H NMR (CDCl3) d 8.47 (dd, J=4.9, 2.0 Hz,
1H), 8.09 (dd, J=7.6, 2.0 Hz, 1H), 7.35 (dd, J=7.7, 2.8
Hz, 1H), 7.01 (m, 5H), 4.59 (m, 1H), 4.00 (m, 1H), 3.75
(m, 1H), 3.51 (m, 1H), 3.12 (m, 4H), 2.89 (m, 2H), 2.61 (m,
2H), 2.52 (d, J=7.0 Hz, 2H), 1.33 (d, J=6.0 Hz, 6H); MS
(ES) m/z: 433 (M+H+). Anal (C22H29N4O3Cl.0.3H2O)
C, H, N.
MS (ES) m/z: 505 (M+H+) Anal (C29H36N4O4 0.2
.
H2O) C, H, N.
2-(4-tert-Butylphenoxy)-N-[2-hydroxy-3-[4-[2-(1-methyl-
ethoxy)phenyl]-1-piperazinyl]propyl]-3-pyridinecarbox-
amide (7). (Method B, foam, 26%); 1H NMR (CDCl3) d
8.60 (dd, J=7.8, 2.0 Hz, 1H), 8.3 (m, 1H), 8.23 (dd,
J=4.8, 1.9 Hz, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.14 (m, 3H),
6.92 (m, 4H), 4.58 (m, 1H), 3.97 (m, 1H), 3.79 (m, 1H),
3.48 (m, 1H), 3.06 (m, 4H), 2.79 (m, 2H), 2.48 (m, 4H),
1.34 (s, 9H), 1.33 (d, J=6.0 Hz, 6H); MS (ES) m/z 547
(M+H+). Anal (C32H42N4O4) C, H, N.
2-(Phenylthio)-N-[3-[4-[2-(1-methylethoxy)phenyl]-1-pi-
perazinyl]-2-hydroxypropyl]-3-pyridinecarboxamide (12).
(Method B, foam, 71%); H NMR (CDCl3) d 8.39 (dd,
J=4.9, 1.9 Hz, 1H), 7.83 (dd, J=7.8, 1.9 Hz, 1H), 7.53
(m, 2H), 7.39 (m, 3H), 7.08 (dd, J=7.8, 4.9 Hz, 1H),
General procedure for the synthesis of 8--11. 2-(3-Dimethyl-
aminophenoxy)-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-
phenyl]-1-piperazinyl]propyl]-3-pyridinecarboxamide (8).
A mixture of compound 29 (95 mg, 0.22 mmol), 3-
(dimethylamino)phenol (152 mg, 1.1 mmol) and cesium
1