Imidazoline Derivatives Active on Glucose Homeostasis
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 9 1595
(2H, q, J ) 6.5 Hz, H2C-O), 3.40 (1H, dd, J ) 4.3 and 5.2 Hz,
HC-N), 2.95-2.38 (8H, ma, three H2C-N and two HC(CH3)2),
1.21 (3H, t, J ) 6.5 Hz, H3C-CH2O), 1.09, 0.96, 0.95, 0.90
(12H, 4d, J ) 6.5 Hz, two (H3C)2CH).
Compounds 2b-g (free amines as oils) were prepared by
the same procedure using acetone as solvent instead of
acetonitrile, catalytic amount of KI, and the corresponding
chloro or bromo derivative.
Eth yl 1,4-d iisobu tylp ip er a zin e-2-ca r boxyla te (2b): 1H
NMR δ 4.17-4.01 (2H, m, H2C-O), 3.16 (1H, dd, J ) 3.42
and 5.72 Hz, HC-N), 3.08-3.0, 2.73-2.64, 2.43-2.22 (7H, 3m,
three H2C-N and H-CH-N1), 2.12 (1H, dd, J ) 6.42 and 12.46
Hz, H-CH-N1), 1.97 (2H, d, J ) 7.66 Hz, H2C-N4), 1.73-1.56
(2H, m, two HC(CH3)2), 1.19 (3H, t, J ) 7.12 Hz, H3C-CH2O),
0.82 and 0.80 (12H, 2d in 1:3 ratio, two (H3C)2CH).
saturated NaHCO3 solution until basic pH and extracted with
ether. The organic phase was dried over MgSO4 and the
solvent evaporated under vacuo. The crude product was
purified by column chromatography using first petroleum
ether/ether (30:70, v/v) and then ether to afford 17 g (80%) of
6a as a colorless oil: IR (film, cm-1) ν 3340 (N-H), 1740 (Cd
O); 1H NMR δ 4.15 (2H, q, J ) 7.1 Hz, H2C-O), 3.19-1.99
(7H, m, H piperazine), 1.96 (2H, d, J ) 7.68 Hz, H2C-CH),
1.73-1.56 (1H, m, HC(CH3)2), 1.5 (1H, br s, D2O exchange,
H-N), 1.23 (3H, t, J ) 7.1 Hz, H3C-CH2O), 0.82 (6H, d, J )
6.4 Hz, (H3C)2CH).
Compounds 6b-d were prepared using the same procedure.
Eth yl 1-Isobu tyl-4-m eth ylpiper azin e-2-car boxylate (7a).
A mixture of 6a (17 g, 0.08 mol), 37% formaldehyde (10 mL,
0.13 mol), and formic acid (10 mL, 0.25 mol) in MeOH (110
mL) was refluxed for 20 h. After evaporation of the solvent,
the residue was taken up in ether and washed with saturated
NaHCO3 solution until basic pH. The organic layer was
washed with water and dried over MgSO4, and the solvent was
removed in vacuo. The crude product was purified by crystal-
lization of the hydrochloride salt from ethanol-ether. Usual
treatment of this salt afforded 15.5 g (85%) of 7a as a colorless
oil: IR (film, cm-1) ν 1745 (CdO); 1H NMR δ 4.15 (2H, q, J )
7.10 Hz, H2C-O), 3.07-2.20 (7H, m, H piperazine), 2.27 (3H,
s, H3C-N), 2.02 (2H, d, J ) 7.29 Hz, H2C-CH), 1.79-1.59
(1H, m, HC(CH3)2), 1.22 (3H, t, J ) 7.10 Hz, H3C-CH2O), 0.81
(6H, d, J ) 6.33 Hz, (H3C)2CH).
E t h yl
1,4-d icyclop en t ylp ip er a zin e-2-ca r b oxyla t e
(2c): 1H NMR δ 4.19-4.05 (2H, m, H2C-O), 3.42 (1H, dd, J
) 3.56 and 5.8 Hz, HC-N), 3.18-3.01, 2.81-2.73, 2.55-2.36,
1.78-1.27 (24H, 4m, in ratio 2:1:5:16, three H2C-N and H
cyclopentyl), 1.21 (3H, t, J ) 7.1 Hz, H3C-CH2O).
Eth yl 1,4-d i(2′-p r op en -1′-yl)p ip er a zin e-2-ca r boxyla te
1
(2d ): H NMR δ 5.90-5.55 (2H, m, two HCd), 5.3-5.0 (4H,
m, H2Cd), 4.17 (2H, q, J ) 7.2 Hz, H2C-O), 3.62-2.0 (11H,
m, H piperazine and two H2C-CHd), 1.23 (3H, t, J ) 7.2 Hz,
H3C-CH2O).
Eth yl 1,4-d i(2′-m eth yl-2′-p r op en -1′-yl)p ip er a zin e-2-ca r -
boxyla te (2e): 1H NMR δ 4.85-4.46 (4H, m, two H2Cd), 4.15-
4.02 (2H, m, H2C-O), 3.22-2.22 (11H, m, H piperazine and
two H2C-CdC), 1.66 and 1.63 (6H, 2s, two H3C-C)), 1.20
(3H, t, J ) 7.1 Hz, H3C-CH2O).
Eth yl 1,4-d i(2′-m eth ylbu tyl)p ip er a zin e-2-ca r boxyla te
(2f): 1H NMR δ 4.15-4.02 (2H, m, H2C-O), 3.18-1.91 (9H,
m, H piperazine and two HC-N), 1.48-1.29 (4H, m, H2C-
CH3), 1.20 (3H, t, J ) 7.15 Hz, H3C-CH2O), 0.80 (6H, t, J )
6.87 Hz, two H3C-CH2), 0.81 and 0.79 (6H, 2d, J ) 6.87 Hz,
two H3C-CH).
Compounds 7b-d were prepared using the same procedure.
E t h yl 1-(2′,4′-d ich lor ob en zyl)-4-m et h ylp ip er a zin e-2-
ca r boxyla te (7b): 1H NMR δ 7.38-7.11 (3H, m, Ar-H), 4.06
(2H, q, J ) 7.09 Hz, H2C-O), 3.75 and 3.44 (2H, AB spectrum,
J ) 14.76 Hz, H2C-Ar), 3.6-2.24 (7H, m, H piperazine), 2.19
(3H, s, H3C-N), 1.16 (3H, t, J ) 7.09 Hz, H3C-CH2O).
E t h yl 1-(2′-ch lor ob en zyl)-4-m et h ylp ip er a zin e-2-ca r -
boxyla te (7c) a n d eth yl 1-(2′-m eth oxyben zyl)-4-m eth -
ylp ip er a zin e-2-ca r boxyla te (7d ): 1H NMR spectra were the
same as for 7b; particular signal for 7d δ 6.69 (3H, s, H3C-
O).
E t h yl 1,4-d in eop en t ylp ip er a zin e-2-ca r b oxyla t e (2g):
1H NMR δ 4.15-4.05 (2H, m, H2C-O), 3.22-2.5 (7H, m, H
piperazine), 1.9 (4H, s, two H2C-C(CH3)3), 1.2 (3H, t, J ) 7.17
Hz, H3C-CH2O), 0.75 (18H, s, (H3C)3-C).
E t h yl 1-Isob u t yl-4-(2′-p r op en -1′-yl)p ip er a zin e-2-ca r -
boxyla te (8a ). This compound was prepared following the
procedure described for 5a , starting from 4a (19.8 g, 0.1 mol)
and isobutyl bromide (16.4 g, 0.12 mol). After treatment the
crude product was purified by column chromatography using
petroleum ether/ether (first 70:30 then 50:50, v/v) as eluent
to afford 18 g (71%) of 8a as a colorless oil: IR (film, cm-1) ν
Eth yl 4-(2′-P r op en -1′-yl)p ip er a zin e-2-ca r boxyla te (4a ).
A suspension of 1 (23.1 g, 0.1 mol), dry K2CO3 (40 g), and KI
(4 g) in DMF (200 mL) was stirred vigorously and heated at
40 °C. After the mixture cooled, 1-bromo-2-propene (12.1 g,
0.1 mol) in DMF (80 mL) was added dropwise and the mixture
stirred at room temperature for 24 h. The solid material was
filtered and the filtrate diluted with ether and water. The
aqueous layer was extracted with ether. The organic layer was
dried over MgSO4 and concentrated. The crude product was
purified by column chromatography using petroleum ether/
ether (first 60:40 then 50:50, v/v) as eluent to give 6.1 g (31%)
of 4a as a yellow oil: IR (film, cm-1) ν 3320 (N-H), 1740 (Cd
O); 1H NMR δ 5.85-5.68 (1H, m, HCd), 5.18-5.09 (2H, m,
H2Cd), 4.13 (2H, q, J ) 7.1 Hz, H2C-O), 3.66-2.10 (9H, m,
H piperazine and H2C-Cd), 1.97 (1H, s, D2O exchange, H-N),
1.20 (3H, t, J ) 7.1 Hz, H3C-CH2O).
1
1745 (CdO); H NMR δ 5.79-5.75 (1H, m, HCd), 5.24-5.14
(2H, m, H2Cd), 4.12 (2H, q, J ) 7.2 Hz, H2C-O), 3.10-2.24
(11H, m, H piperazine, H2C-Cd and H2C-CH(CH3)2), 1.72-
1.62 (1H, m, H-C(CH3)2, 1.19 (3H, t, J ) 7.2 Hz, H3C-CH2O),
0.82 and 0.79 (6H, 2d, J ) 6.2 Hz, (H3C)2CH).
Eth yl 1-isobu tyl-4-(2′-m eth yl-2′-pr open -1′-yl)piper azin e-
2-ca r boxyla te (8b): prepared like compound 8a starting from
4b; 1H NMR δ 4.77 (2H, br s, H2Cd), 4.45-4.15 (2H, m, H2C-
O), 3.20-2.08 (11H, H piperazine, H2C-N1 and H2C-N4), 1.63
(3H, s, H3C-Cd), 1.20 (3H, t, J ) 7.13 Hz, H3C-CH2O), 0.82
and 0.79 (6H, 2d, J ) 6.35 Hz, (H3C)2CH).
Compounds 4b and 4c were prepared by the same procedure
using the corresponding bromo derivative.
Eth yl 1-m eth yl-4-isobu tylpiper azin e-2-car boxylate (8c):
obtained as described for 7a starting from 4c; 1H NMR δ 4.14
(2H, q, J ) 7.1 Hz, H2C-O), 3.71-2.12 (7H, m, H piperazine),
2.27 (3H, s, H3C-N), 2.02 (2H, d, J ) 7.37 Hz, H2C-N), 1.79-
1.59 (1H, m, HC(CH3)2), 1.22 (3H, t, J ) 7.10 Hz, H3C-CH2O),
0.81 (6H, d, J ) 7.37 Hz, (H3C)2CH).
P r ep a r a tion of Dicyclop r op ylm eth yl Ester In ter m ed i-
a tes 18 a n d 19 (Sch em e 2). N-Ben zyl-N-m eth yleth a n ol-
a m in e (9). This compound was prepared following the same
procedure as for 7a . The crude product was purified by
distillation (E15 ) 140-142 °C); 151 g (1 mol) of N-benzyl-
ethanolamine afforded 138 g (84%) of 9: IR (film, cm-1) ν 3500
(OH), 1590 (CdC); 1H NMR δ 7.20 (5H, s, Ar-H), 3.80 (1H, br
s, D2O exchange, H-O), 3.54 (2H, t, J ) 5.6 Hz, H2C-O), 3.49
(2H, s, H2C-Ar), 2.47 (2H, t, J ) 5.6 Hz, H2C-N), 2.13 (3H,
s, J ) 7.2 Hz, H3C-N).
Eth yl 1-Isobu tyl-4-(tr ip h en ylm eth yl)p ip er a zin e-2-ca r -
boxyla te (5a ). A mixture of 316 (40 g, 0.1 mol), dry K2CO3 (40
g), KI (4 g), and isobutyl bromide (16.4 g, 0.12 mol) in
acetonitrile (400 mL) was heated at 80 °C with stirring for 15
h. After filtration of solid material, the filtrate was diluted
with ether and washed with water. The aqueous layer was
extracted with ether, and the combined organic layers were
dried over MgSO4. Solvents were removed in vacuo, and this
crude 5a was used in the next step without purification.
Compounds 5b-d were prepared using the corresponding
chloro derivatives.
Eth yl 1-Isobu tylp ip er a zin e-2-ca r boxyla te (6a ). Crude
5a was dissolved in acetone (600 mL) containing 12 M HCl
(25 mL). After 3 h stirring at room temperature, the solvent
was removed in vacuo and the residue was partitioned between
ether and water. The aqueous layer was treated with a