4282 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Garino et al.
1
(0.8 g, 97%) as a yellow oil. Rf 0.09 (EtOAc:cHex,2:1). H NMR
5.3 Hz, NCH2CH2OH), 7.28-7.41 (m, 2H, ArH), 7.43-7.48 (m,
2H, ArH), 7.52-7.60 (m, 3H, ArH), 7.69-7.72 (brd, 2H, ArH),
7.77 (dd, 1H, J ) 1.3 and 7.0 Hz, ArH), 7.91-7.95 (m, 2H, ArH),
7.99-8.02 (brd, 1H, ArH), 8.50-8.54 (m, 1H, ArH), 9.02 (brs,
1H, ArH), 9.16 (brs, 1H, NHC(O)). ESI-MS m/z [M + H]+ ) 452.
Anal. (C29H29N3O2) C, H, N.
(CDCl3) δH 3.08 (brs, 4H, NCH2CH2NH), 3.19 (brs, 4H, NCH2-
CH2NH), 7.19 (d, 1H, J ) 8.4 Hz, ArH), 7.40 (dd, 1H, J ) 2.3
and 8.4 Hz, ArH), 7.58-7.64 (m, 3H, ArH), 7.77-7.80 (m, 1H,
ArH), 8.02-8.05 (m, 1H, ArH), 8.09 (d, 1H, J ) 8.2 Hz, ArH),
8.22-8.26 (m, 1H, ArH), 8.43 (d, 1H, J ) 2.3 Hz, ArH), 8.77
(brs, 2H, NH), 9.78 (brs, 1H, NHC(O)). ESI-MS m/z [M + H]+
)
1-{4-(Phenyl)-2-[(naphthalene-1-carbonyl)-amino]-phenyl}-
4-(ethyl-aceto)-piperazine (5b). Compound 5b was prepared by
a method similar to that described for 3e using ethyl bromo-
410. Anal. (C21H20BrN3O) C, H, N.
1-{4-Bromo-2-[(naphthalene-1-carbonyl)-amino]-phenyl}-4-
(2-hydroxyethyl)-piperazine (3e). 2-Bromoethanol (5.0 µL, 0.070
mmol) was added to a vigorous stirred mixture of 3d (34 mg, 0.065)
and anhydrous K2CO3 (18 mg, 0.13 mmol) in dry acetonitrile (5
mL). The suspension was refluxed for 10 h under nitrogen. The
solvent was then removed under reduced pressure. The crude
product was dissolved in CH2Cl2 (5 mL) and extracted with water
(2 × 5 mL), and the organic layer was dried over MgSO4 and then
purified by chromatography on silica gel, using methylene chloride-
methanol (9:1) as eluent, to yield the compound 3e (27 mg, 92%)
as a white powder. M.p. 88°. Rf 0.55 (CH2Cl2:MeOH, 5:1). 1H NMR
(CDCl3) δH 2.53 (brs, 6H, NCH2CH2OH and NCH2CH2NCH2-
CH2OH), 2.91 (brs, 4H, NCH2CH2NCH2CH2OH), 3.62 (t, 2H, J
) 4.3 Hz, NCH2CH2OH), 7.08 (d, 1H, J ) 8.4 Hz, ArH), 7.25
(dd, 1H, J ) 2.2 and 8.4 Hz, ArH), 7.51-7.60 (m, 3H, ArH), 7.71
(d, 1H, J ) 7.0 Hz, ArH), 7.91-7.95 (m, 1H, ArH), 8.00 (d, 1H,
J ) 8.3 Hz, ArH), 8.45-8.48 (m, 1H, ArH), 8.92 (d, 1H, J ) 2.2
Hz, ArH), 9.10 (brs, 1H, NHC(O)). ESI-MS m/z [M + H]+ ) 454.
Anal. (C23H24BrN3O2) C, H, N.
1
acetate. Yield 47%, Rf 0.42 (EtOAc:cHex,1:1). H NMR (CDCl3)
δH 1.25 (t, 3H, NCH2CO2CH2CH3), 2.65 (brs, 4H, NCH2CH2NCH2-
CO2Et), 3.03 (t, 4H, J ) 4.7 Hz, NCH2CH2NCH2CO2Et), 3.20 (s,
2H, NCH2CO2Et), 4.17 (q, 2H, NCH2CO2CH2CH3), 7.29-7.40 (m,
2H, ArH), 7.42-7.48 (m, 2H, ArH), 7.53-7.60 (m, 3H, ArH),
7.68-7.72 (brd, 2H, ArH), 7.77 (dd, 1H, J ) 1.3 and 7.0 Hz, ArH),
7.91-7.95 (m, 2H, ArH), 7.99-8.02 (brd, 1H, ArH), 8.51-8.55
(m, 1H, ArH), 9.01 (brs, 1H, ArH), 9.20 (brs, 1H, NHC(O)). ESI-
MS m/z [M + H]+ ) 494. Anal. (C31H31N3O3) C, H, N.
1-{4-(Phenyl)-2-[(naphthalene-1-carbonyl)-amino]-phenyl}-
4-[1-(5-phthalimido)-pentyl]-piperazine (5c). Compound 5c was
prepared by a method similar to that described for 3e using N-(5-
bromopentyl) phthalimide. Yield 99%, mp 72 °C. Rf 0.60 (MeOH:
1
CH2Cl2, 1:9). H NMR (CDCl3) δH 1.32-1.38 (m, 2H), 1.47-
1.58 (m, 2H), 1.64-1.75 (m, 2H), 2.28-2.34 (m, 2H), 2.49 (brs,
4H, NCH2CH2N(CH2)5-phthalimide), 2.96 (t, 4H, J ) 4.7 Hz,
NCH2CH2N(CH2)5-phthalimide), 3.68 (t, 2H, J ) 7.1 Hz), 7.27-
7.40 (m, 2H, ArH), 7.42-7.48 (m, 2H, ArH), 7.53-7.60 (m, 3H,
ArH), 7.68-7.72 (m, 4H, ArH), 7.73-7.80 (m, 1H, ArH), 7.82-
7.85 (m, 2H, ArH), 7.91-7.94 (m, 2H, ArH), 7.99-8.02 (brd, 1H,
ArH), 8.52-8.57 (m, 1H, ArH), 9.02 (brs, 1H, ArH), 9.20 (brs,
1H, NHC(O)). ESI-MS m/z [M + H]+ ) 623. Anal. (C40H38N4O3)
C, H, N.
1-{4-(Phenyl)-2-[(naphthalene-1-carbonyl)-amino]-phenyl}-
4-tert-butoxy Carbonyl Piperazine (4b). Phenyl boronic acid (132
mg, 1.1 mmol) was dissolved in anhydrous 1,3-dioxane (30 mL).
The appropriate bromo derivative 3b (500 mg, 1 mmol) was
dissolved in anhydrous dioxane (30 mL), and the two solutions
were mixed with dppf (17 mg, 0.03 mmol), dppf-PdII (25 mg, 0.03
mmol), and KOAc (300 mg, 3 mmol). The resulting suspension
was refluxed for 72 h. The dioxane was removed under reduced
pressure, and the catalysts were removed by filtration through silica
gel. The crude product was purified by flash chromatography with
cHex-EtOAc (9:1) as eluent, to yield the desired compound 4b as
4-[1-(5-Amino)-pentyl]-1-{4-(phenyl)-2-[(naphthalene-1-car-
bonyl)-amino]-phenyl}-piperazine (5d). Compound 5c (75 mg,
0.12 mmol) was dissolved in warm ethanol (5 mL), hydrazine
monohydrate (10 mg, 0.18 mmol) was added, and the solution was
refluxed for 3 h, cooled to room temperature, and filtered. The
filtrate was concentrated under reduced pressure, and the residue
was diluted with NaHCO3 and extracted with methylene chloride.
The organic layer was dried with MgSO4 and concentrated in vacuo.
The crude product was purified by flash chromatography with
methylene chloride-methanol (9/1) as eluent to give the compound
1
a white oil (180 mg, 36%). Rf 0.26 (EtOAc:cHex,1:9). H NMR
(CDCl3) δH 1.45 (s, 9H, CH3, tBu), 2.81 (t, 4H, J ) 4.7 Hz,
NCH2CH2NBoc), 3.43 (brs, 4H, NCH2CH2NBoc), 7.27-7.35 (m,
8H, ArH), 7.42 (d, 2H, J ) 8.5 Hz, ArH), 7.75-7.78 (m, 1H, ArH),
7.91-7.93 (m, 1H, ArH), 8.02 (d, 1H, J ) 8.3 Hz, ArH), 8.50-
8.54 (m, 1H, ArH), 8.98 (brs, 1H, ArH), 9.20 (brs, 1H, NHC(O))
ESI-MS m/z [M + H]+ ) 508. Anal. (C32H33N3O3) C, H, N.
4-Benzyl-1-{4-(phenyl)-2-[(naphthalene-1-carbonyl)-amino]-
phenyl}-piperazine (4c). Compound 4c was prepared by a method
similar to that described for 4b. Yield 80%, mp 156 °C. Rf 0.23
(EtOAc:cHex,1:9). 1H NMR (CDCl3) δH 2.51 (brs, 4H, NCH2CH2-
NCH2Ph), 2.96 (t, 4H, J ) 4.7 Hz, NCH2CH2NCH2Ph), 3.49 (s,
2H, NCH2Ph), 7.27-7.35 (m, 8H, ArH), 7.42 (d, 2H, J ) 8.5 Hz,
ArH), 7.53-7.63 (m, 5H, ArH), 7.75-7.78 (m, 1H, ArH), 7.91-
7.93 (m, 1H, ArH), 8.02 (d, 1H, J ) 8.3 Hz, ArH), 8.50-8.54 (m,
1H, ArH), 8.98 (brs, 1H, ArH), 9.20 (brs, 1H, NHC(O)). ESI-MS
m/z [M + H]+ ) 498. Anal. (C34H31N3O) C, H, N.
1-{4-(Phenyl)-2-[(naphthalene-1-carbonyl)-amino]-phenyl}-
piperazine (4d). Compound 4d was prepared by a method similar
to that described for 3d. Yield 88%, mp 118°C. Rf 0.45 (MeOH:
CH2Cl2, 1:9). 1H NMR (CDCl3) δH 3.03 (brs, 8H, NCH2CH2NH),
4.32 (brs, 1H, NCH2CH2NH), 7.31-7.41 (m, 2H, ArH), 7.43-
7.49 (m, 2H, ArH), 7.55-7.59 (m, 3H, ArH), 7.67-7.71 (brd, 2H,
ArH), 7.75 (dd, 1H, J ) 1.3 and 7.0 Hz, ArH), 7.91-7.95 (m, 2H,
ArH), 8.00 (brd, 1H, ArH), 8.46-8.50 (m, 1H, ArH), 9.00 (brs,
1H, ArH), 9.06 (brs, 1H, NHC(O)). ESI-MS m/z [M + H]+ ) 408.
Anal. (C27H25N3O) C, H, N.
1
5d (50 mg, 84%) as brown oil. Rf 0.09 (MeOH:CH2Cl2, 1:9). H
NMR (CDCl3) δH 1.26-1.36 (m, 2H), 1.42-1.53 (m, 4H), 2.30
(m, 2H), 2.49 (brs, 4H, NCH2CH2N(CH2)5NH2), 2.71 (t, 2H, J )
6.9 Hz), 2.98 (t, 4H, J ) 4.7 Hz, NCH2CH2N(CH2)5NH2), 3.49
(brs, 2H, NCH2CH2N(CH2)5NH2), 7.29 (d, 1H, J ) 8.3 Hz, ArH),
7.36-7.40 (m, 1H, ArH), 7.46 (t, 2H, J ) 7.3 Hz, ArH), 7.53-
7.61 (m, 3H, ArH), 7.69-7.72 (m, 2H, ArH), 7.77-7.79 (m, 1H,
ArH), 7.92-7.95 (m, 2H, ArH), 8.01 (d, 1H, J ) 8.2 Hz, ArH),
8.52-8.56 (m, 1H, ArH), 9.02 (brs, 1H, ArH), 9.22 (brs, 1H,
NHC(O)). ESI-MS m/z [M + H]+ ) 493. Anal. (C32H36N4O) C,
H, N.
(S)-(-)-1-{4-(Phenyl)-2-[(naphthalene-1-carbonyl)-amino]-
phenyl}-4-[1-(3-phenyl)-propan-3-ol]-piperazine (5e). (S)-(-)-
3-Chloro-1-phenyl-1-propanol (17 mg, 0.09 mmol) was added to a
vigorous stirred mixture of 4d (40 mg, 0.09 mmol) and anhydrous
potassium carbonate (31 mg, 0.22 mmol) in dry acetonitrile (5 mL),
and then the suspension was stirred at room temperature for 10 h
under nitrogen. After that time, the suspension was concentrated.
The crude product was chromatographied with methylene chloride-
methanol (9/1) as eluent to give 5e (42 mg, 86%) as a yellow oil.
Rf 0.64 (MeOH:CH2Cl2, 1:9). 1H NMR (CDCl3) δH 1.86-1.90 (m,
2H), 2.51-2.74 (m, 5H), 3.03 (t, 4H, J ) 4.7 Hz, NCH2CH2NCH2-
CH2CH(Ph)OH), 3.36-3.49 (m, 1H), 4.92-4.95 (m, 1H), 7.27-
7.39 (m, 8H, ArH), 7.43-7.49 (m, 2H, ArH), 7.52-7.62 (m, 3H,
ArH), 7.70 (brd, 2H, ArH), 7.77 (dd, 1H, J ) 1.3 and 7.0 Hz, ArH),
7.91-7.95 (m, 2H, ArH), 7.99 (brd, 1H, ArH), 8.50-8.54 (m, 1H,
ArH), 9.02 (brs, 1H, ArH), 9.14 (brs, 1H, NHC(O)). ESI-MS m/z
1-{4-(Phenyl)-2-[(naphthalene-1-carbonyl)-amino]-phenyl}-
4-(2-hydroxyethyl)-piperazine (5a). Compound 5a was prepared
by a method similar to that described for 3e. Yield 77%, mp 183
°C. Rf 0.65 (MeOH:CH2Cl2, 1:9). 1H NMR (CDCl3) δH 2.51-2.57
(m, 6H, NCH2CH2NCH2CH2OH), 2.74 (brs, 1H, NCH2CH2OH),
2.98 (t, 4H, J ) 4.7 Hz, NCH2CH2NCH2CH2OH), 3.62 (t, 2H, J )
[M + H]+ ) 542. [R]20 ) -24° (c ) 1.10, CHCl3). Anal.
D
(C36H35N3O2) C, H, N.