September 2002
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(3H, s), 5.65 (1H, t, Jϭ6.0 Hz), 6.28 (1H, s), 6.50 (1H, s), 6.62 (3H, m), (KBr) cmϪ1: 1679. MS (m/z): 580 (MϩH)ϩ. Anal. Calcd for C32H38N3O5Cl:
6.70 (4H, m). IR (KBr) cmϪ1: 1640. MS (m/z): 546 (MϩH)ϩ. Anal. Calcd C, 66.25; H, 6.60; N, 7.24. Found: C, 66.31; H, 6.51; N, 7.31.
for C32H39N3O5: C, 70.43; H, 7.20; N, 7.70. Found: C, 70.55; H, 7.31; N,
7.67.
1-(3,4-Dimethoxybenzyl)-2-[4-(3-fluorophenyl)piperazine-1-yl]acetyl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (20) Synthesized in
a
1-(3,4-Dimethoxybenzyl)-2-[4-(4-methylphenyl)piperazine-1-yl]car- manner similar to that described for 18. The product was obtained as gummy
bamoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (15) Synthesized material (80%). 1H-NMR (CDCl3, 300 MHz) d: 2.63 (8H, m), 2.77 (2H, m),
in a manner similar to that described for 7. The product was obtained as 3.12 (4H, m), 3.29 (2H, s), 3.70 (3H, s), 3.82 (6H, s), 3.89 (3H, s), 5.59 (1H,
1
gummy material (82%). H-NMR (CDCl3, 300 MHz) d: 2.40 (3H, s), 2.64 t, Jϭ6.0 Hz), 6.25 (1H, s), 6.51 (1H, s), 6.63 (3H, m), 6.82 (4H, m). IR
(8H, m), 2.89 (2H, m), 3.11 (4H, m), 3.84 (3H, s), 3.86 (6H, s), 3.87 (3H, s), (KBr) cmϪ1: 1644. MS (m/z): 564 (MϩH)ϩ. Anal. Calcd for C32H38N3O5F:
5.65 (1H, t, Jϭ6.0 Hz), 6.29 (1H, s), 6.46 (1H, s), 6.57 (3H, m), 6.69 (4H, C, 68.18; H, 6.79; N, 7.45. Found: C, 68.05; H, 6.61; N, 7.59.
m). IR (KBr) cmϪ1: 1640. MS (m/z): 546 (MϩH)ϩ. Anal. Calcd for
C32H39N3O5: C, 70.43; H, 7.20; N, 7.70. Found: C, 70.51; H, 7.19; N, 7.65.
1-(3,4-Dimethoxybenzyl)-2-[4-(4-fluorophenyl)piperazine-1-yl]acetyl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (21) Synthesized in
a
4-(4-Fluorophenyl)piperazine-1-carbamoylimidazole (16) To a sus- manner similar to that described for 18. The product was obtained as gummy
pension of CDI (5.18 g, 32 mmol) in THF (50 ml) was added 1-(4-
material (83%). 1H-NMR (CDCl3, 300 MHz) d: 2.67 (8H, m), 2.87 (2H, m),
florophenyl)piperazine (5 g, 27.7 mmol). The mixture was refluxed for 24 h 3.02 (4H, m), 3.25 (2H, s), 3.66 (3H, s), 3.84 (6H, s), 3.86 (3H, s), 5.69 (1H,
before cooling to room temperature. Removal of solvent under vacuum gave t, Jϭ6.0 Hz), 6.26 (1H, s), 6.43 (1H, s), 6.61 (3H, m), 6.80 (4H, m). IR
a viscous oil which was dissolved in CH2Cl2 (100 ml), and washed twice (KBr) cmϪ1: 1634. MS (m/z): 564 (MϩH)ϩ. Anal. Calcd for C32H38N3O5F:
with 100 ml portions of water. The organic layer was dried over anhydrous C, 68.18; H, 6.79; N, 7.45. Found: C, 68.25; H, 6.71; N, 7.49.
Na2SO4, filtered and concentrated in vacuum to yield a light yellow solid.
1-(3,4-Dimethoxybenzyl)-2-(4-methylpiperazine-1-yl)acetyl-6,7-
The carbamoyl imidazole 16 (6.46 g, 85%) mp 92—93 °C obtained was used dimethoxy-1,2,3,4-tetrahydroisoquinoline (22) Synthesized in a manner
in the next step without further purification. 1H-NMR (CDCl3, 300 MHz) d: similar to that described for 18. The product was obtained as gummy mater-
1
3.17 (4H, t, Jϭ6 Hz), 3.78 (4H, t, Jϭ6 Hz), 6.89 (2H, m), 6.95 (2H, m), 7.13 ial (78%). H-NMR (CDCl3, 300 MHz) d: 2.38 (3H, s), 2.65 (8H, m), 2.87
(2H, m), 7.91 (1H, s). IR (KBr) cmϪ1: 1695. MS (m/z): 274 (M)ϩ. Anal. (2H, m), 2.98 (4H, m), 3.22 (2H, s), 3.64 (3H, s), 3.79 (6H, s), 3.85 (3H, s),
Calcd for C14H15N4OF: C, 61.30; H, 5.51; N, 20.42. Found: C, 61.21; H, 5.64 (1H, t, Jϭ6.0 Hz), 6.23 (1H, s), 6.45 (1H, s), 6.61 (3H, m). IR (KBr)
5.59; N, 20.53.
1-(3,4-Dimethoxybenzyl)-2-[4-(4-fluorophenyl)piperazine-1-yl]car- H, 7.71; N, 8.68. Found: C, 67.23; H, 7.63; N, 8.56.
cmϪ1: 1637. MS (m/z): 484 (MϩH)ϩ. Anal. Calcd for C27H37N3O5: C, 67.05;
bamoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (10) Using 16 To
1-(3,4-Dimethoxybenzyl)-2-(morpholin-1-yl)acetyl-6,7-dimethoxy-
a solution of 16 (1.86 g, 6.8 mmol) in dichloromethane (15 ml) was added 1,2,3,4-tetrahydroisoquinoline (23) Synthesized in a manner similar to
methyl iodide (1.57 ml, 25.2 mmol). The mixture was stirred at room tem- that described for 18. The product was obtained as gummy material (79%).
perature for 12 h. Solvent was removed in vacuum to yield its cationic car-
1H-NMR (CDCl3, 300 MHz) d: 2.26 (8H, m), 2.59 (2H, m), 2.90 (4H, m),
bamoyl imidazolium salt, which was dissolved without purification in 3.66 (2H, s), 3.71 (3H, s), 3.83 (6H, s), 3.88 (3H, s), 5.67 (1H, t, Jϭ6.0 Hz),
CH2Cl2 (20 ml). To this solution added 1-(4-fluorophenyl)piperazine (1.22 g, 6.26 (1H, s), 6.51 (1H, s), 6.60 (3H, m). IR (KBr) cmϪ1: 1633. MS (m/z):
6.8 mmol) and triethylamine (0.95 ml, 6.8 mmol). The mixture was stirred at 471(MϩH)ϩ. Anal. Calcd for C26H34N2O6: C, 66.36; H, 7.28; N, 5.95.
room temperature for 24 h, then washed with 1.0 M HCl, the organic layer Found: C, 66.45; H, 7.13; N, 5.83.
dried over anhydrous Na2SO4, filtered and concentrated under vacuum to
1-(3,4-Dimethoxybenzyl)-2-[4-(pyrimidin-1-yl)piperazine-1-yl]acetyl-
yield the required tetrasubstituted urea as an oil which was column chro- 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (24) Synthesized in
a
matographed (ethylacetate–hexane) to obtain pure 10 (3.05 g, 82%).
1-(3,4-Dimethoxybenzyl)-2-chloroacetyl-6,7-dimethoxy-1,2,3,4-
manner similar to that described for 18. The product was obtained as gummy
material (81%). 1H-NMR (CDCl3, 300 MHz) d: 2.49 (8H, m), 2.85 (2H, m),
tetrahydroisoquinoline (17) To a solution of tetrahydropapaverine 5 3.10 (4H, m), 3.24 (2H, s), 3.64 (3H, s), 3.82 (6H, s), 3.85 (3H, s), 5.67 (1H,
(18.86 g, 55 mmol) and triethylamine (11.5 ml, 82 mmol) in dry dichloro- t, Jϭ6.0 Hz), 6.24 (1H, s), 6.43 (1H, s), 6.46 (1H, t, Jϭ6.0 Hz), 6.61 (3H,
methane (50 ml), chloroacetylchloride (7.24 g, 64 mmol)) was added slowly. m), 8.29 (2H, d, Jϭ6.0 Hz). IR (KBr) cmϪ1: 1632. MS (m/z): 548 (MϩH)ϩ.
During addition the reaction mixture was kept in ice. On addition the mix- Anal. Calcd for C30H37N5O5: C, 65.79; H, 6.80; N, 12.78. Found: C, 65.55;
ture was stirred at room temperature for 4 h. After the completion (TLC) of H, 6.96; N, 12.83.
the reaction, evaporated off the solvent, diluted the residue with water
1-(3,4-Dimethoxybenzyl)-2-[4-(3-methylphenyl)piperazine-1-yl]acetyl-
(150 ml) and extracted with ethylacetate (3ϫ50 ml). The collective organic 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (25) Synthesized in
a
portion was washed with brine and dried over Na2SO4. It was finally concen- manner similar to that described for 18. The product was obtained as light
1
trated and chromatographed on silica gel using ethylacetate–hexane as elu- yellow solid (81%) mp 104—105 °C. H-NMR (CDCl3, 300 MHz) d: 2.31
ent. A final recrystallization from ethylacetate–hexane (20 : 70) afforded the (3H, s), 2.55 (8H, m), 2.89 (2H, m), 3.07 (4H, m), 3.25 (2H, s), 3.80 (3H, s),
1
product as a white solid (18.74 g, 81%) mp 98—100 °C. H-NMR (CDCl3,
3.84 (6H, s), 3.86 (3H, s), 5.69 (1H, t, Jϭ6.0 Hz), 6.25 (1H, s), 6.41 (1H, s),
300 MHz) d: 2.76 (2H, m), 3.19 (4H, m), 3.55 (2H, s), 3.68 (3H, s), 3.87 6.60 (3H, m), 6.69 (4H, m). IR (KBr) cmϪ1: 1640. MS (m/z): 560 (MϩH)ϩ.
(6H, s), 3.91 (3H, s), 5.56 (1H, t, Jϭ6.0 Hz), 6.24 (1H, s), 6.53 (1H, s), 6.75 Anal. Calcd for C33H41N3O5: C, 70.81; H, 7.38; N, 7.50. Found: C, 70.69; H,
(3H, m). IR (KBr) cmϪ1: 1642.9. MS (m/z): 420 (MϩH)ϩ. Anal. Calcd for 7.56; N, 7.32.
C22H26NO5Cl: C, 62.92; H, 6.24; N, 3.34. Found: C, 62.91; H, 6.04; N, 3.27.
1-(3,4-Dimethoxybenzyl)-2-[4-(3-chlorophenyl)piperazine-1-yl]acetyl-
1-(3,4-Dimethoxybenzyl)-2-[4-(4-methylphenyl)piperazine-1-yl]acetyl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (26) Synthesized in
a
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (18) A solution of 1-(3- manner similar to that described for 18. The product was obtained as gummy
1
chlorophenyl)piperazine (0.97 g, 5 mmol) in DMF (10 ml) was added slowly material (82%). H-NMR (CDCl3, 300 MHz) d: 2.26 (3H, s), 2.65 (8H, m),
to a solution of 17 (2 g, 4.7 mmol) and activated K2CO3 (2 g, 14.4 mmol) in 2.85 (2H, m), 3.17 (4H, m), 3.29 (2H, s), 3.78 (3H, s), 3.81 (6H, s), 3.84
DMF (15 ml). The mixture was stirred for 3 h at 60 °C. After the completion (3H, s), 5.63 (1H, t, Jϭ6.0 Hz), 6.29 (1H, s), 6.40 (1H, s), 6.67 (3H, m),
(TLC) of reaction, diluted the reaction mixture with water (500 ml) and ex- 6.69 (4H, m). IR (KBr) cmϪ1: 1645. MS (m/z): 560 (MϩH)ϩ. Anal. Calcd
tracted with ethylacetate (3ϫ50 ml). The collective organic portion was for C33H41N3O5: C, 70.81; H, 7.38; N, 7.50. Found: C, 70.61; H, 23; N, 7.31.
washed with brine and dried over Na2SO4. It was finally concentrated and
Pharmacological Methods Antispasmodic activity: isolated guinea pig
chromatographed on silica gel using ethylacetate–hexane as eluent to obtain ileum. Guinea pigs of both sexes (300—500 g) were killed by cervical dislo-
pure 18 as a gummy material (2.26 g, 82%). 1H-NMR (CDCl3, 300 MHz) d: cation and exsanguinated. The abdomen was opened and the terminal ileum
2.60 (8H, m), 2.87 (2H, m), 3.02 (4H, m), 3.25 (2H, s), 3.65 (3H, s), 3.86 carefully dissected, repeatedly washed and the connective tissue removed.
(6H, s), 3.87 (3H, s), 5.66 (1H, t, Jϭ6.0 Hz), 6.22 (1H, s), 6.46 (1H, s), 6.61 Intestinal segments of 1.0 to 1.5 cm length were set up under 1 g resting ten-
(3H, m), 6.81 (4H, m). IR (KBr) cmϪ1: 1685. MS (m/z): 580 (MϩH)ϩ. Anal.
sion in a 10 ml organ bath with Tyrode’s solution: (mM: NaCl 137, KCl 2.7,
Calcd for C32H38N3O5Cl: C, 66.25; H, 6.60; N, 7.24. Found: C, 66.17; H, CaCl2 1.8, MgCl2 1.05, NaHCO3 11.9, NaH2PO4 0.42, glucose 5.6). The
6.54; N, 7.29.
bath temperature was maintained at 37 °C and aerated with compressed air.
Tension changes in the tissues were monitored using force displacement
transducer amplifier connected to physiograph (Polyrite, Recorders and
1-(3,4-Dimethoxybenzyl)-2-[4-(4-chlorophenyl)piperazine-1-yl]acetyl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (19) Synthesized in
a
manner similar to that described for 18. The product was obtained as gummy Medicare System).
material (83%). 1H-NMR (CDCl3, 300 MHz) d: 2.52 (8H, m), 2.82 (2H, m),
After 30 min of equilibration period, concentration–response curves to
3.13 (4H, m), 3.27 (2H, s), 3.71 (3H, s), 3.79 (6H, s), 3.85 (3H, s), 5.63 (1H, the cumulative addition of acetylcholine (ACh) (0.1 nm—0.1 mM) were con-
t, Jϭ6.0 Hz), 6.21 (1H, s), 6.56 (1H, s), 6.67 (3H, m), 6.89 (4H, m). IR
structed every 30 min. After constant responses had been obtained, concen-