Synthesis and antispasmodic activity evaluation of bis-(papaverine) analogues

Article abstract of DOI:10.1248/cpb.52.316

A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is described along with a discussion of their structure activity relationship. The general synthetic methods of bis-(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisothiocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, N,N′-bis-[2-carbamoyl-1-(3,4- dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant (IC₅₀: 0.31 μM).

Full text of DOI:10.1248/cpb.52.316

316
Chem. Pharm. Bull. 52(3) 316—321 (2004)
Vol. 52, No. 3
Synthesis and Antispasmodic Activity Evaluation of Bis-(Papaverine)
Analogues
a
b
,b
*
Jaskiran KAUR, Narendra Nath GHOSH, and Ramesh CHANDRA
a Department of Chemistry, University of Pennsylvania; Philadelphia, Pennsylvania, 19104, U.S.A.: and b Dr. B. R.
Ambedkar Centre for Biomedical Research, University of Delhi; 110007, Delhi, India.
Received October 10, 2003; accepted December 22, 2003
A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation
of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is de-
scribed along with a discussion of their structure activity relationship. The general synthetic methods of bis-
(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisoth-
iocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a
freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph.
Among the analogues synthesized in the present study, N,N؅-bis-[2-carbamoyl-1-(3,4-dimethoxybenzyl)-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant
(IC50: 0.31 mM).
Key words papaverine; tetrahydropapaverine; dimer; antispasmodic activity; piperazine; urea
logical activity.21) A typical example is tetrandrine,22) a potent
Compounds containing symmetrical dimers of a number
antispasmodic agent. Papaverine, a benzylisoquinoline alka-
loid, is a well known smooth muscle relaxant and a vasodila-
tor.23,24) Considering these factors and in continuation to our
earlier efforts25,26) of finding a potent antispasmodic agent,
we envisaged that dimers of papaverine with suitable linkers
at nitrogen can turn out to be more potent antispasmodic
agents in comparison to papaverine.
Herein, we report the synthesis and antispasmodic activity
of a series of bis-(tetrahydropapaverine) analogues with urea
and acetyl linkers.
of natural molecules are of increasing importance in bio-
chemical as well as in medicinal chemistry research.1) The
bis(naphthalimide) DMP-840 (Fig. 1) shows antineoplastic
activity against a variety of human solid tumor cell lines in
culture2,3) and as xenografts in nude mice,4,5) and is in clini-
cal trial.6,7) Other examples under study include bis-(ben-
zonapthalimides),8) bis-(imidazoacridiones),9,10) bis-(tria-
zoloacridinones),11) bis-(anthracyclines),12,13) bis-(acridine-4-
carboxamides),14) bis-(phenazine-1-carboxamides)15,16) and
bis-(indeno[1,2-b]quinoline-6-carboxamides).17) A compara-
tive study of a variety of bis analogues with their monomeric
counterparts has revealed that there are variable but signifi-
cant gains in potency for the dimeric species.18) Due to inter-
esting biological activities and unique chemical structures,
bis analogues of various naturally occurring alkaloids serve
as lead compounds for discovery of new drugs.19)
Results and Discussion
For the purpose of this study, numerous bis-(tetrahydropa-
pverine) analogues 6—13 were readily prepared by direct re-
action of tetrahydropapaverine (5) (2 molar equivalent) with
the corresponding (i) substituted bis-(isocyanates) and (ii)
substituted bis-(isothiocyanates) in acetonitrile (Chart 1). In
a typical reaction amide 3 required for the synthesis of
tetrahydropapaverine (5) was prepared by the condensation
of homoveratryl amine (1) and homoveratric acid (2) in
xylene with azeotropic removal of water. Cyclization of
amide 3 to 3,4-dihydroisoquinoline (4) was achieved in Bis-
chler–Napierlaski fashion, in refluxing toluene with phos-
phorous oxychloride. Reduction of 3,4-dihydroisoquinoline
with sodium borohydride in methanol resulted in the forma-
tion of tetrahydropapaverine 5 (Chart 1).26) Products 6—13
were obtained in 80—85% yield and were purified by col-
umn chromatography.
Dimeric analogues of a number of classes of chro-
mophores joined by various cyclic and acyclic linkers are
also of current interest as potential antispasmodic agents.20)
Natural bis-(isoquinoline) alkaloids have emerged as an im-
portant structural class based upon their high degree of bio-
Reaction of tetrahydropapaverine (5) with chloroacetylchlo-
ride and triethylamine in dichloromethane lead to the forma-
tion of N-(chloroacetyl)tetrahydropapaverine (14). The reac-
tion of tetrahydropapaverine (5) and N-(chloroacetyl)tetrahy-
dropapaverine (14) in acetone in the presence of potassium
carbonate and tetrabutylammonium iodide at room tempera-
ture yielded 15 (Chart 2). The direct reaction of N-
(chloroacetyl)tetrahydropapaverine (14) (2 molar equivalent)
with piperazine or cis-2,6-dimethylpiperazine or homopiper-
azine (1 molar equivalent) in acetone in the presence of
Fig. 1
To whom correspondence should be addressed. e-mail: acbrdu@hotmail.com
© 2004 Pharmaceutical Society of Japan

March 2004
317
Chart 1
phy and obtained in 79% yield. The activation of the leaving
imidazole ring was found to be necessary for the formation
of desired ureas since the carbamoyl imidazoles were unreac-
tive towards tetrahydropapaverine even under refluxing con-
ditions for prolonged periods. Addition of triethylamine (1
molar equivalent) resulted in improved yields of ureas.
The reaction of imidazolium salt 20 (2 molar equivalent)
with piperazine or cis-2,6-dimethylpiperazine or homopiper-
azine (1 molar equivalent) in dichloromethane and triethyl-
amine (Chart 5) afforded compounds 22—24 respectively.
These compounds were purified by column chromatography
and obtained in 75—80% yield.
Antispasmodic activity studies of compounds 6—13, 15—
18, and 21—24 were performed on guinea pig ileum. Acetyl-
choline (10Ϫ3 M) was used to induce sustained contraction in
guinea pig ileum. When the contraction response to acetyl-
choline reached a steady level, papaverine was added cumu-
latively. Papaverine inhibited the acetylcholine induced con-
Chart 2
potassium carbonate and tetrabutylammonium iodide yielded traction in a concentration dependent manner. Similarly,
16—18 respectively (Chart 3). Products 16—18 were puri- acetylcholine induced contraction inhibition by tetrahydropa-
fied by column chromatography eluting with ethylacetate and paverine derivatives 6—13, 15—18, and 21—24 were stud-
hexane and obtained in 73—76% yields.
ied. Dose–response curves were obtained for papaverine and
Tetrahydropapaverine efficiently displaced one of the imi- all these derivatives. The results revealed that most of the test
dazole rings of carbonyldiimidazole26) to give tetrahydropa- compounds 6—13, 15—18, and 21—24 more potently inhib-
paverine carbamoyl imidazole 19 on refluxing it with car- ited the acetylcholine induced contractions than papaverine.
bonyldiimidazole (CDI) in tetrahyrofuran (THF) for 24 h. Table 1 summarizes the concentration of papaverine and test
The reaction of methyl iodide with carbamoyl imidazole 19 compounds producing 50% relaxation (IC50) of acetylcholine
(4 molar equivalents) in acetonitrile for one day at room tem- induced contraction for compounds 6—13 and Table 2 sum-
perature produced the imidazolium salt quantitatively. This marizes the IC50 values of compounds 15—18, and 21—24.
imidazolium salt required no additional purification for final IC50 values were determined graphically from dose–response
conversion to ureas. Addition of tetrahydropapaverine to a curves obtained by measuring antispasmodic activity at six
solution of imidazolium salt in dichloromethane with triethyl- concentrations (0.1, 0.5, 1.0, 5.0, 10, 20 mM) of the com-
amine at room temperature afforded tetra substituted urea de- pounds in duplicate of triplicates.
rivative 21 (Chart 4). It was purified by column chromatogra-
The structure activity relationship of these compounds has

318
Vol. 52, No. 3
Chart 3
Chart 4
Chart 5
been focused on alterations in the linker chain. Three types tuted urea spacers 6—13 exhibited antispasmodic activities
of linkers have been introduced. First category of linkers not significantly different from papaverine. Compound 6,
consists of two urea moieties linked by spacers like benzene, with a benzene ring as a spacer, introduced between the two
substituted benzene, cyclohexane and butyl chain (6—13). amide groups, gave IC50 value of 6.17 mM. Its thio analogue 9
Second category has piperazinyl, substituted piperazinyl ring exhibited a small decrease in antispasmodic activity. Substi-
placed between two acetyl groups, as linkers (15—18). Third tution of a cyclohexane ring 8 in place of benzene ring de-
category consists of piperazinyl, substituted piperazinyl ring creased the antispasmodic activity (IC50: 9.31 mM). Com-
placed between two carbamoyl groups, as linkers (21—24).
pound 10 with an aliphatic chain as the spacer between the
Among the three types of linkers, the compounds with two thiomide groups exhibited IC50 value further lower as
third category of linkers (21—24) were found to be most po- compared to compound 8. Compounds 11 and 12 having
tent. The corresponding compounds with CH2 spacers (15— methyl group substituted in benzene ring were not as good
18), exhibited a decrease in antispasmodic activity. The com- antispasmodic agents as papaverine. They exhibited IC50 val-
pounds with trisubstituted urea spacers (6—13) were found ues similar to that exhibited by compounds 8 and 10. Substi-
to be least active among the bis-(tetrahydropapaverine) deriv- tution of a chloro group in addition to a methyl group in the
atives reported.
benzene ring (13) enhanced the antispasmodic activity.
The bis-(tetrahydropapaverine) derivatives with trisubsti-
The bis-(tetrahydropapaverine) derivatives with acetyl

March 2004
319
Table 1. Concentration of Bis-(tetrahydropapaverine) Derivatives 6—13
Producing 50% Relaxation (IC50) of Acetylcholine Induced Contractions
Table 2. Concentration of Bis-(tetrahydropapaverine) Derivatives 15—18
and 21—24 Producing 50% Relaxation (IC50) of Acetylcholine Induced
Contractions
Compound
R
IC50 (mM)a)
Compound
R
IC50 (mM)a)
15
0.61
6
7
8
6.17
6.27
9.31
16
17
0.43
1.07
9
6.39
9.98
18
21
22
0.95
0.42
0.31
10
11
9.87
12
13
9.73
7.12
23
0.75
24
0.70
a) IC50 of papaverineϭ7.31 mM. IC50’s were calculated using a mean of at least 3
measurements (all duplicates) for 6 concentrations in the range 0.1—20 mM.
a) IC50 of papaverineϭ7.31 mM. IC50’s were calculated using a mean of at least 3
measurements (all duplicates) for 6 concentrations in the range 0.1—20 mM.
linkers 15—18 exhibited significantly higher antispasmodic
activities in comparison to papaverine. Compound 15 exhib-
ited an IC50 value of 0.61 mM. Introduction of a piperazine
ring 16 between the two acetyl groups increased the antispas-
modic activity (IC50: 0.43 mM). Methyl substitution (17) in
the piperazine ring at positions 2 and 6, lead to a fall in the
activity (IC50: 1.07 mM). Substitution of homopiperazine ring
(18) in place of piperazine ring slightly increased the activity
(IC50: 0.95 mM).
to be the most potent compound among the series. However,
contrary to our predictions, none of the bis analogues were
able to beat the best compound of our previously reported26)
piperazinyl based tetra substituted urea derivative of papaver-
ine.
Experimental
Melting points are recorded in open capillary tubes on Buchi melting
point B-540 instrument and are uncorrected. Solvent system used through-
out the experimental work for running TLC plates was ethylacetate–hexane.
Among the tetra substituted urea derivatives 21—24, the
IC50 value of 21 was found to be 0.42 mM. Addition of a
piperazine spacer between the two carbamoyl groups further
increased the antispasmodic activity (IC50: 0.31 mM). Methyl
substitution (23) on the piperazine ring at positions 2 and 6,
lead to a fall in the activity (IC50: 0.75 mM). Substitution of
homopiperazine ring (24) in place of piperazine ring slightly
increased the activity (IC50: 70 mM).
1
The H-NMR spectra were recorded in CDCl3 as solvent (using TMS as in-
ternal standard) on a Bruker Avance Spectrospin 300 instrument at
300 MHz. Mass spectra were run on a Perkin Elmer LCMS API-2000 mass
spectrometer. IR spectra were recorded using KBr discs on a Shimadzu
FTIR-8300 spectrophotometer. Elemental analysis was carried out on Her-
aeus Rapid CHN analyser.
N,N؅-[1,4-Benzene-{diyl-bis-(iminocarbonyl)}-bis-{1-(3,4-dimethoxy-
benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}] (6) A solution
of 1,4-phenylenediisocyanate (0.192 g, 1.2 mmol) in dry acetonitrile (5 ml)
was added slowly to a solution of tetrahydropapaverine 5 (0.686 g, 2 mmol)
in dry acetonitrile (5 ml). The mixture was stirred at room temperature for
2 h. After the completion (TLC) of the reaction, evaporated off the solvent,
diluted the residue with water (25 ml) and extracted with ethylacetate
Compound 10 is the least potent and compound 22 is the
most active bis-(tetrahydropapaverine) analogue of the series.
Conclusion
N-Substituted bis-(tetrahydropapaverine) derivatives (3ϫ25 ml). The collective organic portion was washed with brine and dried
(Na2SO4). It was concentrated under reduced pressure and the residue was
chromatographed on silica gel using ethylacetate–hexane as eluent. A final
showed better antispasmodic activity in comparison with pa-
paverine in guinea pigs in preliminary screenings. Com-
pounds with tetra substituted urea linkers were found to be
more active than compounds with trisubstituted urea linkers
and compounds with acetyl linkers. Compound 22 was found
recrystallization from ethylacetate–hexane (15 : 85) afforded pure 6 as a vis-
cous solid (0.685 g, 81%). 1H-NMR (CDCl3, 300 MHz) d: 2.60 (4H, m),
3.10 (4H, m), 2.97 (4H, m), 3.29 (4H, m), 3.73 (2ϫ3H, s), 3.78 (2ϫ3H, s),
3.81 (2ϫ3H, s), 3.85 (2ϫ3H, s), 5.01 (2H, m), 5.56 (2H, s), 6.41 (2H, s),

320
Vol. 52, No. 3
6.56 (2H, s), 6.79 (4H, m), 6.97 (6H, m). IR (KBr) n cmϪ1: 1639. MS (m/z):
847 (MϩH)ϩ. Anal. Calcd for C48H54N4O10: C, 68.06; H, 6.42; N, 6.61.
Found: C, 68.15; H, 6.31; N, 6.52.
2-chloroacetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (14) (0.85 g,
2 mmol) and tetrahydropapaverine (5) (0.68 g, 2 mmol) in acetone (10 ml)
was added activated K2CO3 (1 g, 7.2 mmol) and tetrabutylammonium iodide
(0.18 g, 0.5 mmol). The mixture was stirred for 12 h at room temperature.
After the completion (TLC) of reaction, acetone was evaporated and diluted
the reaction mixture with water (25 ml) and extracted with ethylacetate
(3ϫ25 ml). The collective organic portion was washed with brine and dried
over Na2SO4. It was concentrated under reduced pressure and the residue
was chromatographed on silica gel using ethylacetate–hexane as eluent to
obtain pure 47 as a white solid (1.08 g, 75%) mp 74—75 °C. 1H-NMR
(CDCl3, 300 MHz) d: 2.45 (4H, m), 3.04 (4H, m), 3.39 (4H, m), 3.50 (2H,
s), 3.74 (2ϫ3H, s), 3.81 (2ϫ3H, s), 3.87 (4ϫ3H, s), 5.07 (2H, m), 6.31 (2H,
s), 6.61 (2H, s), 6.80 (6H, m). IR (KBr) n cmϪ1: 1635. MS (m/z): 727
(MϩH)ϩ. Anal. Calcd for C42H50N2O9: C, 69.40; H, 6.93; N, 3.85. Found: C,
69.51; H, 6.71; N, 3.81.
N,N؅-[4,4؅-Methylene-{diyl-bis-(phenyliminocarbonyl)}-bis-{1-(3,4-
dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}]
(7)
Synthesized, from tetrahydropapaverine (5) and 4,4Ј-methylene-bis-
(phenylisocyanate), in a manner similar to that described for 6. The product
was obtained as a light yellow solid (80%) mp 122—123 °C. 1H-NMR
(CDCl3, 300 MHz) d: 2.67 (4H, m), 3.14 (4H, m), 3.43 (4H, m), 3.79
(2ϫ3H, s), 3.82 (2ϫ3H, s), 3.83 (2ϫ3H, s), 3.87 (2ϫ3H, s), 4.11 (2H, m),
5.02 (2H, s), 5.66 (2H, s), 6.48 (2H, s), 6.64 (2H, s), 6.74 (4H, m), 6.83 (4H,
m), 6.99 (6H, m). IR (KBr) n cmϪ1: 1640.5. MS (m/z): 937 (MϩH)ϩ. Anal.
Calcd for C55H60N4O10: C, 70.49; H, 6.45; N, 5.97. Found: C, 70.35; H,
6.39; N, 5.82.
N,N؅-[trans-Cyclohexane-{diyl-bis-(iminothiocarbonyl)}-bis-{1-(3,4-
N,N؅-Bis-[2-acetyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-
dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}]
(8)
tetrahydroisoquinolinyl]piperazine (16) To
a
solution of 1-(3,4-
Synthesized, from 5 and trans-1,4-cyclohexanediisothiocyanate, in a manner
similar to that described for 6. The product was obtained as a light yellow
solid (85%) mp 118—120 °C. 1H-NMR (CDCl3, 300 MHz) d: 1.47 (8H, m),
2.32 (4H, m), 2.78 (4H, m), 2.93 (4H, s), 3.23 (2H, s), 3.71 (2ϫ3H, s), 3.77
(2ϫ3H, s), 3.83 (4ϫ3H, s), 4.88 (2H, m), 6.33 (2H, m), 6.58 (6H, m), 6.74
(2H, m). IR (KBr) n cmϪ1: 1232. MS (m/z): 885 (MϩH)ϩ. Anal. Calcd for
C48H60N4O8S2: C, 65.13; H, 6.82; N, 6.32. Found: C, 65.51; H, 6.65; N,
6.41.
dimethoxybenzyl)-2-chloroacetyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (14) (0.85 g, 2 mmol) and piperazine (0.086 g, 1 mmol) in acetone
(10 ml) was added activated K2CO3 (1 g, 7.2 mmol) and tetrabutylammo-
nium iodide (0.18 g, 0.5 mmol). The mixture was stirred for 12 h at room
temperature. After the completion (tlc) of reaction, acetone was evaporated
and diluted the reaction mixture with water (25 ml) and extracted with ethyl-
acetate (3ϫ25 ml). The collective organic portion was washed with brine
and dried over Na2SO4. It was concentrated under reduced pressure and the
residue was chromatographed on silica gel using ethylacetate–hexane as elu-
ent to obtain pure 16 as a pale yellow solid (0.64 g, 76%) mp 80—82 °C. 1H-
NMR (CDCl3, 300 MHz) d: 2.84 (8H, m), 2.90 (4H, m), 2.93 (4H, m), 3.09
(4H, m), 3.62 (4H, s), 3.69 (2ϫ3H, s), 3.73 (2ϫ3H, s), 3.79 (4ϫ3H, s),
5.07 (2H, m), 6.25 (1H, s), 6.27 (1H, s), 6.60 (2H, m), 6.75 (6H,
m). IR (KBr) n cmϪ1: 1638. MS (m/z): 853 (MϩH)ϩ. Anal. Calcd for
C48H60N4O10: C, 67.58; H, 7.08; N, 6.79. Found: C, 67.69; H, 7.17; N, 6.84.
N,N؅-Bis-[2-acetyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolinyl]-2,6-dimethylpiperazine (17) Synthesized, from
a solution of 14 and 2,6-dimethylpiperazine, in a manner similar to that de-
scribed for 16. The product was obtained as a pale yellow solid (73%) mp
63—64 °C. 1H-NMR (CDCl3, 300 MHz) d: 1.85 (6H, s), 2.76 (8H, m), 2.87
(4H, m), 2.92 (4H, m), 3.11 (4H, m), 3.55 (2H, s), 3.61 (2H, s), 3.71 (2ϫ3H,
s), 3.78 (2ϫ3H, s), 3.89 (4ϫ3H, s), 5.13 (2H, m), 6.24 (1H, s), 6.35 (1H, s),
6.65 (2H, m), 6.79 (6H, m). IR n (KBr) cmϪ1: 1639. MS (m/z): 882
(MϩH)ϩ. Anal. Calcd for C50H64N4O10: C, 68.16; H, 7.32; N, 6.35. Found:
C, 68.21; H, 7.21; N, 6.41.
N,N؅-Bis-[2-acetyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolinyl]homopiperazine (18) Synthesized, from a solu-
tion of 14 and homopiperazine, in a manner similar to that described for 16.
The product was obtained as a light yellow solid (75%) mp 100—102 °C.
1H-NMR (CDCl3, 300 MHz) d: 2.53 (10H, m), 2.81 (8H, m), 2.97 (4H, m),
3.31 (4H, m), 3.72 (2ϫ3H, s), 3.77 (2ϫ3H, s), 3.83 (4ϫ3H, s), 5.57 (2H,
m), 6.15 (1H, s), 6.18 (1H, s), 6.69 (8H, m). IR (KBr) n cmϪ1: 1635. MS
(m/z): 867 (MϩH)ϩ. Anal. Calcd for C49H62N4O10: C, 67.87; H, 6.04; N,
7.20. Found: C, 67.81; H, 6.11; N, 7.31.
N,N؅-Bis-[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline]urea (21) To a solution of cationic carbamoyl imida-
zolium salt of 19 (0.88 g, 2 mmol) and tetrahydropapaverine (0.68 g,
2 mmol) in anhydrous dichloromethane was added triethylamine (0.27 ml,
2.0 mmol). The mixture was stirred at room temperature for 12 h, then
washed with 1.0 M HCl (10 ml), the organic layer dried over anhydrous
Na2SO4, filtered and concentrated under vacuum to yield the required tetra
substituted urea as an oil which was column chromatographed (ethylac-
etate–hexane) to obtain pure 21 as a white solid (1.12 g, 79%) mp 68—
69 °C. 1H-NMR (CDCl3, 300 MHz) d: 2.43 (4H, m), 2.92 (4H, m), 3.35 (4H,
m), 3.72 (2ϫ3H, s), 3.79 (2ϫ3H, s), 3.88 (4ϫ3H, s), 5.05 (2H, m), 6.30
(2H, s), 6.55 (2H, s), 6.67 (6H, m). IR (KBr) n cmϪ1: 1633.5. MS (m/z): 713
(MϩH)ϩ. Anal. Calcd for C41H48N2O9: C, 69.08; H, 6.78; N, 3.92. Found: C,
69.18; H, 6.71; N, 3.81.
N,N؅-[1,4-Benzene-{diyl-bis-(iminothiocarbonyl)}-bis-{1-(3,4-
dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}]
(9)
Synthesized, from 5 and 1,4-phenylenediisothiocyanate, in a manner similar
to that described for 6. The product was obtained as a white solid (85%) mp
1
126—128 °C. H-NMR (CDCl3, 300 MHz) d: 2.80 (4H, m), 3.24 (8H, m),
3.75 (2ϫ3H, s), 3.83 (2ϫ3H, s), 3.87 (4ϫ3H, s), 5.29 (2H, m), 6.48 (2H,
m), 6.60 (6H, m), 6.73 (10H, m). IR (KBr) n cmϪ1: 1260. MS (m/z): 879
(MϩH)ϩ. Anal. Calcd for C48H54N4O8S2: C, 65.58; H, 6.19; N, 6.37. Found:
C, 65.51; H, 6.15; N, 6.42.
N,N؅-[1,4-Butane-{diyl-bis-(iminothiocarbonyl)}-bis-{1-(3,4-
dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}] (10)
Synthesized, from 5 and 1,4-butanediisothiocyanate, in a manner similar to
that described for 6. The product was obtained as a white solid (83%) mp
56—58 °C. 1H-NMR (CDCl3, 300 MHz) d: 1.64 (4H, m), 2.90 (4H, m), 2.98
(4H, m), 3.27 (4H, m), 3.58 (4H, m), 3.72 (2ϫ3H, s), 3.84 (2ϫ3H, s), 3.86
(4ϫ3H, s), 5.12 (2H, m), 5.61 (2H, m), 6.30 (2H, s), 6.67 (2H, m), 6.79 (6H,
m). IR (KBr) n cmϪ1: 1254. MS (m/z): 859 (MϩH)ϩ. Anal. Calcd for
C46H58N4O8S2: C, 64.31; H, 6.80; N, 6.52. Found: C, 64.49; H, 6.75; N,
6.42.
N,N؅-[1,3-Benzene-{diyl-bis-(iminocarbonyl)-2-methyl}-bis-{1-(3,4-
dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}] (11)
Synthesized, from 5 and 2-methyl-m-phenylenediisocyanate, in a manner
similar to that described for 6. The product was obtained as a white solid
1
(81%) mp 171—172 °C. H-NMR (CDCl3, 300 MHz) d: 2.70 (4H, m), 2.97
(4H, m), 3.14 (4H, m), 3.44 (3H, s), 3.76 (2ϫ3H, s), 3.79 (2ϫ3H, s), 3.88
(4ϫ3H, s), 5.12 (2H, m), 5.70(2H, m), 6.30 (2H, m), 6.67 (6H, m), 6.79
(3H, m), 6.91 (2H, m). IR (KBr) n cmϪ1: 1618. MS (m/z): 861 (MϩH)ϩ.
Anal. Calcd for C49H56N4O10: C, 68.35; H, 6.55; N, 6.50. Found: C, 68.27;
H, 6.65; N, 6.41.
N,N؅-[1,3-Benzene-{diyl-bis-(iminocarbonyl)-4-methyl}-bis-{1-(3,4-
dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline}] (12)
Synthesized, from 5 and 4-methyl-m-phenylenediisocyanate, in a manner
similar to that described for 6. The product was obtained as a viscous solid
1
(82%). H-NMR (CDCl3, 300 MHz) d: 2.71 (4H, m), 2.95 (4H, m), 3.11
(4H, m), 3.31 (3H, s), 3.73 (2ϫ3H, s), 3.79 (2ϫ3H, s), 3.86 (4ϫ3H, s), 5.10
(2H, m), 5.70 (2H, m), 6.30 (2H, m), 6.71 (6H, m), 6.80 (3H, m), 7.01 (2H,
m). IR (KBr) n cmϪ1: 1620. MS (m/z): 861 (MϩH)ϩ. Anal. Calcd for
C49H56N4O10: C, 68.35; H, 6.55; N, 6.50. Found: C, 68.37; H, 6.63; N, 6.42.
N,N؅-[1,3-Benzene-{diyl-bis-(iminocarbonyl)-4-chloro-6-methyl}-bis-
{1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line}] (13) Synthesized, from 5 and 4-chloro-6-methyl-m-phenylenediiso-
cyanate, in a manner similar to that described for 51. The product was ob-
N,N؅-Bis-[2-carbamoyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinyl]piperazine (22) To a solution of cationic
carbamoyl imidazolium salt of 19 (0.88 g, 2 mmol) and piperazine (0.086 g,
1 mmol) in dichloromethane was added triethylamine (0.27 ml, 2.0 mmol).
The mixture was stirred at room temperature for 12 h, then washed with
1.0 M HCl (10 ml), the organic layer dried over anhydrous Na2SO4, filtered
and concentrated under vacuum to yield the required tetra substituted urea as
an oil which was column chromatographed (ethylacetate–hexane) to obtain
pure 22 as a light yellow solid (0.61 g, 75%) mp 73—74 °C. 1H-NMR
1
tained as a viscous solid (84%). H-NMR (CDCl3, 300 MHz) d: 2.68 (4H,
m), 2.98 (4H, m), 3.24 (4H, m), 3.61 (3H, s), 3.72 (2ϫ3H, s), 3.79 (2ϫ3H,
s), 3.87 (4ϫ3H, s), 5.13 (2H, m), 5.85 (2H, m), 6.30 (2H, m), 6.67 (6H, m),
7.05 (2H, m), 7.99 (2H, s), 8.05 (1H, s). IR n (KBr) cmϪ1: 1654. MS (m/z):
895.5 (MϩH)ϩ. Anal. Calcd for C49H55N4O10Cl: C, 65.72; H, 6.19; N, 6.25.
Found: C, 65.57; H, 6.24; N, 6.41.
N,N؅-Bis-[2-acetyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline] (15) To a solution of 1-(3,4-dimethoxybenzyl)-

March 2004
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References
(CDCl3, 300 MHz) d: 2.73 (8H, m), 2.88 (4H, m), 2.92 (4H, m), 3.03 (4H,
m), 3.67 (2ϫ3H, s), 3.71 (2ϫ3H, s), 3.77 (4ϫ3H, s), 5.05 (2H, m), 6.23
(1H, s), 6.26 (1H, s), 6.58 (2H, m), 6.72 (6H, m). IR n (KBr) cmϪ1: 1637.
MS (m/z): 825 (MϩH)ϩ. Anal. Calcd for C46H56N4O10: C, 66.97; H, 6.84; N,
6.79. Found: C, 66.58; H, 6.71; N, 6.81.
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1
(76%) mp 82—83 °C. H-NMR (CDCl3, 300 MHz) d: 2.73 (10H, m), 3.07
(4H, m), 3.15 (4H, m), 3.29 (4H, m), 3.64 (2ϫ3H, s), 3.82 (2ϫ3H, s), 3.89
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Acknowledgements We are grateful to University Grant Commission
for the award of SRF to one of us (JK), New Delhi and Dr. B. R. Ambedkar
Centre for Biomedical Research for providing financial assistance and re-
search facilities for carrying out this work.