γ-Amino-Substituted Analogues of Dab-Pip
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11 2913
in diethyl ether (6) or was converted to the HCl salt by
coevaporation several times with 4 N HCl in diethyl ether,
followed by precipitation in ether and lyophilization from H2O
(compounds 7.1-7.29, 8.1, 8.2, 11-18, 20, and 21).
Gen er a l P r oced u r e for th e Red u ctive Am in a tion in
P a r a llel u sin g P ASP Tech n iqu e (Com p ou n d s 7.1-7.22).
Compound 5 (1.8 equiv) was dissolved in DCM/acetic acid (90/
10) (5 mL). The required aldehyde (1 equiv; for compounds
7.21 and 7.22, 5 equiv of aldehyde was used) and the polymer-
bound cyanoborohydride (2.5 equiv) were added. After agita-
tion overnight, the polymer-bound benzaldehyde (2.5 equiv)
was added to scavenge the excess of the starting amine
compound. After agitation for 5 h, the polymer-bound reagents
were filtered off, and the solvent was evaporated. Purification
was done on preparative TLC. Finally, Boc-deprotection was
done according to the described general procedure.
N1-Benzyl-4-oxo-4-(1-piperidinyl)-1,3-(S)-butanediamine Di-
hydrochloride (7.1). 1H NMR (D2O, 400 MHz) δ 1.58-1.74 (m,
6H, CH2), 2.29-2.48 (m, 2H, â-CH2), 3.15-3.24 (m, 2H, γ-CH2),
3.48-3.60 (m, 4H, CH2), 4.36 (s, 2H, CH2), 4.65-4.74 (m, 1H,
R-CH), 7.58 (s, 5H, Harom); MS (ES+) m/z 276 (M + H)+; LC-
MS rt 9.7 min, m/z 276, 96%; HPLC (214 nm) rt 9.92 min,
95%.
N1-(2-Chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.2). 1H NMR (D2O, 400 MHz) δ
1.53-1.75 (m, 6H, CH2), 2.29-2.42 (m, 2H, â-CH2), 3.24-3.30
(m, 2H, γ-CH2), 3.49-3.63 (m,4H, CH2), 4.53 (s, 2H, CH2Ph),
4.71-4.80 (m, 1H, R-CH), 7.49-7.67 (m, 4H, Harom); MS (ES+)
m/z 310 (M + H)+; LC-MS rt 8.2 min, m/z 310, 91%; HPLC
(214 nm) rt 14.48 min, 95%.
N1-(3-Chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.3). 1H NMR (D2O, 400 MHz) δ
1.46-1.76 (m, 6H, CH2), 2.28-2.38 (m, 2H, â-CH2), 3.13-3.23
(m, 2H, γ-CH2), 3.46-3.59 (m, 4H, CH2), 4.35 (s, 2H, CH2Ph),
4.70-4.78 (m, 1H, R-CH), 7.42-7.63 (m, 4H, Harom); MS (ES+)
m/z 310 (M + H)+; LC-MS rt 8.8 min, m/z 310, 95%; HPLC
(214 nm) rt 15.64 min, 96%.
1.42-1.73 (m, 6H, CH2), 2.28-2.37 (m, 2H, â-CH2), 3.10-3.18
(m, 2H, γ-CH2), 3.45-3.58 (m, 4H, CH2), 3.97 (s, 3H, CH3),
4.36 (s, 2H, CH2Ph), 4.69 (t, 1H, R-CH), 7.12-7.22 (m, 2H,
H
arom), 7.43-7.45 (m, 1H, Harom), 7.57-7.61 (m, 1H, Harom); MS
(ES+) m/z 306 (M + H)+; LC-MS rt 8.1 min, m/z 306, 100%;
HPLC (214 nm) rt 21.75 min, 90%.
N1-(3-Methoxybenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.9). 1H NMR (D2O, 400 MHz) δ
1.40-1.73 (m, 6H, CH2), 2.28-2.36 (m, 2H, â-CH2), 3.16 (t,
2H, γ-CH2), 3.49-3.62 (m, 4H, CH2), 3.92 (s, 3H, CH3), 4.33
(s, 2H, CH2Ph), 4.70 (t, 1H, R-CH), 7.13-7.18 (m, 3H, Harom),
7.50-7.54 (m, 1H, Harom); MS (ES+) m/z 306 (M + H)+; LC-
MS rt 7.7 min, m/z 306, 97%; HPLC (214 nm) rt 22.24 min,
96%.
N1-(4-Methoxybenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.10). 1H NMR (D2O, 400 MHz) δ
1.44-1.76 (m, 6H, CH2), 2.23-2.38 (m, 2H, â-CH2), 3.10-3.23
(m, 2H, γ-CH2), 3.49-3.72 (m, 4H, CH2), 3.92(s, 3H, CH3), 4.30
(s, 2H, CH2Ph), 4.64-4.72 (m, 1H, R-CH), 7.13-7.16 (m, 2H,
H
arom), 7.48-7.50 (m, 2H, Harom); MS (ES+) m/z 306 (M + H)+;
LC-MS rt 0.9 min, m/z 306, 100%; HPLC (214 nm) rt 14.18
min, 95%.
N1-(2,4-Dimethoxybenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-bu-
tanediamine Dihydrochloride (7.11). 1H NMR (D2O, 400 MHz)-
δ 1.35-1.86 (m, 6H, CH2), 2.24-2.35 (m, 2H, â-CH2), 3.02-
3.62 (m, 6H, γ-CH2, CH2), 3.93 (s, 3H, CH3), 3.95 (s, 3H, CH3),
4.30 (s, 2H, CH2Ph), 4.65-4.74 (m, 1H, R-CH), 6.71-6.77 (m,
2H, Harom), 7.27-7.29 (m, 1H, Harom); MS (ES+) m/z 336 (M +
H)+; HPLC (214 nm) rt 15.04 min, 91%.
4-Oxo-4-(1-piperidinyl)-N1-(2-thienylmethyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.12). 1H NMR (D2O, 400 MHz) δ
1.52-1.76 (m, 6H, CH2), 2.23-2.37 (m, 2H, â-CH2), 3.19-3.26
(m, 2H, γ-CH2), 3.49-3.63 (m, 4H, CH2), 4.59 (s, 2H, CH2Ph),
4.71 (t, H, R-CH), 7.21-7.23 (m, 1H, Harom), 7.32-7.38 (m, 1H,
H
arom), 7.65-7.67 (m, 1H, Harom); MS (ES+) m/z 282 (M + H)+;
LC-MS rt 2.6 min, m/z 282, 91%; HPLC (214 nm) rt 14.45 min,
99%.
4-Oxo-4-(1-piperidinyl)-N1-(4-pyridinylmethyl)-1,3-(S)-bu-
tanediamine Trihydrochloride (7.13). 1H NMR (D2O, 400 MHz)
δ 1.59-1.77 (m, 6H, CH2), 2.38-2.47 (m, 2H, â-CH2), 3.37-
3.73 (m, 6H, γ-CH2, CH2), 4.72 (s, 2H, CH2Ph), 4.75-4.82 (m,
1H, R-CH), 8.25 (m, 2H, Harom), 8.85 (m, 2H, Harom); MS (ES+)
m/z 277 (M + H)+; LC-MS rt 1.0 min, m/z 277, 95%; HPLC
(214 nm) rt 8.29 min, 96%.
N1-(4-Chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.4). 1H NMR (D2O, 400 MHz) δ
1.46-1.75 (m, 6H, CH2), 2.28-2.40 (m, 2H, â-CH2), 3.12-3.38
(m, 2H, γ-CH2), 3.45-3.62 (m, 4H, CH2), 4.27 (s, 2H, CH2Ph),
4.70-4.77 (m, 1H, R-CH), 7.42-7.61 (m, 4H, Harom); 13C NMR
(D2O, 400 MHz) 23.48, 25.13, 26.04, 26.82 (3,4,5-C(pip), â-C),
41.97, 42.22, 47.11, 47.97, 50.42 (R-C, γ-C, C-Ph, 2,6-C(pip)),
128.82, 129.49, 131.65, 135.39 (Carom), 165.77 (CO); MS (ES+)
m/z 310 (M + H)+; LC-MS rt 9.0 min, m/z 310, 96%; HPLC
(214 nm) rt 14.89 min, 95%; Anal. (C16H24ClN3O‚2.0HCl‚
0.4H2O) C, H, N.
N1-(1-Naphthylmethyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-bu-
tanediamine Dihydrochloride (7.14). 1H NMR (D2O, 400 MHz)-
δ 1.26-1.74 (m, 6H, CH2), 2.27-2.37 (m, 2H, â-CH2), 3.13-
3.60 (m, 6H, γ-CH2, CH2), 4.60-4.80 (m, 1H, R-CH), 4.87 (s,
2H, CH2Ph), 7.43-7.80 (m, 4H, Harom), 8.12-8.19 (m, 3H,
N1-[2-(Benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)-1,3-(S)-bu-
arom); MS (ES+) m/z 326 (M + H)+; LC-MS rt 10.1 min, m/z
1
H
tanediamine Dihydrochloride (7.5). H NMR (D2O, 400 MHz)
326, 98%; HPLC (214 nm) rt 16.35 min, 90%.
δ 1.38-1.73 (m, 6H, CH2), 2.15-2.29 (m, 2H, â-CH2), 3.05-
3.17 (m, 2H, γ-CH2), 3.28-3.58 (m, 4H, CH2), 4.28 (s, 2H, CH2-
Ph), 4.54-4.63 (m, 1H, R-CH), 5.32 (s, 2H, OCH2Ph), 7.14-
7.17 (m, 1H, Harom), 7.27-7.29 (m, 1H, Harom), 7.46-7.59 (m,
7H, Harom); MS (ES+) m/z 382 (M + H)+; LC-MS rt 11.7 min,
m/z 382, 100%; HPLC (214 nm) rt 17.56 min, 97%.
N1-(2-Naphthylmethyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-bu-
tanediamine Dihydrochloride (7.15). 1H NMR (D2O, 400 MHz)-
δ 1.11-1.60 (m, 6H, CH2), 2.22-2.37 (m, 2H, â-CH2), 3.07-
3.19 (m, 2H, γ-CH2) 3.30-3.61 (m, 4H, CH2), 4.54 (s, 2H,
CH2Ph), 4.61-4.69 (m, 1H, R-CH), 7.57-7.75 (m, 3H, Harom),
8.00-8.14 (m, 4H, Harom); MS (ES+) m/z 326 (M + H)+; LC-
MS rt 10.3 min, m/z 326, 100%; HPLC (214 nm) rt 16.83 min,
91%.
N1-[4-(Benzyloxy)benzyl]-4-oxo-4-(1-piperidinyl)-1,3-(S)-bu-
1
tanediamine Dihydrochloride (7.6). H NMR (D2O, 400 MHz)
δ 1.38-1.75 (m, 6H, CH2), 2.21-2.35 (m, 2H, â-CH2), 3.11 (t,
2H, γ-CH2), 3.44-3.63 (m, 4H, CH2), 4.30 (s, 2H, CH2Ph),
4.54-4.63 (m, 1H, R-CH), 5.27 (s, 2H, OCH2Ph), 7.19-7.21 (m,
2H, Harom), 7.47-7.57 (m, 7H, Harom); MS (ES+) m/z 382 (M +
H)+; LC-MS rt 11.2 min, m/z 382, 95%; HPLC (214 nm) rt 18.50
min, 90%.
4-Oxo-N1-(2-phenylethyl)-4-(1-piperidinyl)-1,3-(S)-butanedi-
amine Dihydrochloride (7.16). 1H NMR (D2O, 400 MHz) δ
1.66-1.78 (m, 6H, CH2), 2.06-2.34 (m, 3H, CH2), 3.02-3.31
(m, 2H, CH2), 3.42-3.66 (m, 7H, CH2), 4.61-4.69 (m, 1H,
R-CH), 7.30-7.55 (m, 5H, Harom); LC-MS rt 12.3 min, m/z 290,
96%; HPLC (214 nm) rt 20.75 min, 95%.
4-Oxo-N1-(3-phenylpropyl)-4-(1-piperidinyl)-1,3-(S)-butane-
diamine dihydrochloride (7.17). 1H NMR (D2O, 400 MHz) δ
1.64-1.73 (m, 6H, CH2), 2.00-2.14 (m, 2H, CH2), 2.25-2.38
(m, 2H, â-CH2), 2.74-2.85 (m, 2H, CH2), 3.08-3.28 (m, 4H,
γ-CH2, CH2), 3.47-3.61 (m, 4H, CH2), 4.71 (t, 1H, R-CH), 7.31-
7.51 (m, 5H, Harom); MS (ES+) m/z 304 (M + H)+; LC-MS rt
8.6 min, m/z 304, 98%; HPLC (214 nm) rt 26.30 min, 98%.
N1-(Cyclohexylmethyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-bu-
tanediamine Dihydrochloride (7.18). 1H NMR (D2O, 400 MHz)-
3-({[3-(S)-amino-4-oxo-4-(1-piperidinyl)butyl]amino}methyl)-
1
benzonitrile Dihydrochloride (7.7). H NMR (D2O, 400 MHz)
δ 1.50-1.76 (m, 6H, CH2), 2.32-2.37 (m, 2H, â-CH2), 3.20-
3.27 (m, 2H, γ-CH2), 3.48-3.61 (m, 4H, CH2), 4.41 (s, 2H, CH2-
Ph), 4.72 (t, 1H, R-CH), 7.70-7.74 (m, 1H, Harom), 7.85-7.87
(m, 1H, Harom), 7.94-7.95 (m, 2H, Harom); MS (ES+) m/z 301
(M + H)+; LC-MS rt 3.6 min, m/z 301, 96%; HPLC (214 nm) rt
13.31 min, 97%.
N1-(2-Methoxybenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-
diamine Dihydrochloride (7.8). 1H NMR (D2O, 400 MHz) δ