Synthesis and antihypertensive activity of N-(alkyl/alkenyl/aryl)-N'- heterocyclic ureas and thioureas

Article abstract of DOI:10.1021/js930295x

A variety of N-(alkyl/alkenyl/aryl-N'-heterocyclic ureas and thioureas were synthesized as potential antihypertensives. The selected heterocyclic nuclei were the 6-substituted quinoline and the pyridine. Eleven synthesized compounds and seven related comp

Full text of DOI:10.1021/js930295x

Synthesis and Antihypertensive Activity of N-(Alkyl/alkenyl/aryl)-N
′-heterocyclic
Ureas and Thioureas
O
PA
V
AJRAGUPTA*, AUNGKANA
P
ATHOMSAKUL*, CXHUTIMA
MATAYATSUK*, LEK RUANGREANGYINGYOD*,
Y
UVADEE
W
ONGKRAJANG†, AND
WILLIAM O. FOYE
Received October 18, 1993, from the *Department of Pharmaceutical Chemistry and †Department of Physiology, Faculty of Pharmacy,
x
Mahidol University, Bangkok, Thailand, and Samuel M. Best Research Laboratory, Massachusetts College of Pharmacy and Allied Health
X
Sciences, Boston, MA 02115.
Final revised manuscript received October 17, 1995.
Accepted for publication October 26, 1995 .
rapid onset, compound 17, on isolated vascular smooth muscle
and heart muscle were also studied.
Abstract
0 A variety of N-(alkyl/alkenyl/aryl-N′-heterocyclic ureas and
thioureas were synthesized as potential antihypertensives. The selected
heterocyclic nuclei were the 6-substituted quinoline and the pyridine.
Eleven synthesized compounds and seven related compounds in the
series were evaluated orally at a dose of 100 mg/kg in conscious
deoxycorticosterone acetate/saline-treated hypertensive rats by the tail-
cuff method. Seventeen out of the eighteen tested compounds possessed
Experimental Section
Ch em istr ysMelting points were determined on a Kofler thermal
microscope and are uncorrected. Infrared (IR) spectra were run as
potassium bromide disks on a Perkin Elmer 1740 FTIR. The proton
significant antihypertensive activity (p
< 0.05). 1-n-Propyl-3-[2′-(6-
1
nuclear magnetic resonance ( H NMR) spectra were obtained with a
methoxy)quinolyl]urea (9), showing 29.1% reduction in systolic blood
pressure, was the most active compound in the series. Two other
compounds producing a fall in systolic blood pressure of the same
J EOL FX 900 (90 MHz). Chemical shifts were reported in ppm
related to the internal standard, tetramethylsilane. Mass spectra
were measured on a J EOL FX 3000 double focusing spectrometer.
TLC was carried out on 2.5 mm Merck silica gel GF 254 strips, and
the purified compounds each showed a single spot. Analytical results
from an elemental analyzer (Perkin Elmer 2400) obtained for all
compounds were within (0.4% of the theoretical value. Spectral (IR,
MS, NMR) data were compatible with the assigned structures in all
cases.
magnitude were 1-allyl-3-[2′-(6-methyl)quinolyl]thiourea (4) and 1-n-propyl-
3
-[(2 -pyridyl)methyl]urea (17). Compound 17 with rapid onset caused
′
significant relaxation (p < 0.01) of isolated rabbit femoral artery and guinea
pig atrium but had no effect on heart rate. However, none of these
exhibited higher potency than prazosin (5 mg/kg). The potency, onset,
and duration of action improved when the heterocyclic nucleus was
pyridine.
The general procedures for the synthesis of N-(alkyl/alkenyl/aryl)-
N′-heterocyclic ureas and thioureas involved the reaction of the amino
compound with the isocyanate or isothiocyanate carrying the selected
side chains. When the amino compounds were commercially unavail-
able, such as 6-methyl-2-aminoquinoline, 6-methoxy-2-aminoquino-
line, and 6-methoxy-4-aminoquinoline, they were prepared by the
reported methods.10
Hypertension is a frequently occurring disease and is the
major risk factor in coronary heart diseases and cardiovas-
cular accident. The main thrust of antihypertensive therapy
consists of chronic treatment with drugs. Recently, a signifi-
cant number of compounds with the combined structural
moieties of heterocyclic rings and urea or thiourea groups were
synthesized and evaluated for biological activities. Among
compounds of this type, substantial antihypertensive activity
was found in 3-substituted-1-[4-(2-indol-3-ylethyl)piperazinyl]-
The reaction conditions varied according to the starting materials.
The reaction of allyl isocyanate with 2-amino-6-methyl- or 2-amino-
6-methoxyquinoline was employed at 80 °C to give urea compounds
and 8 while allyl isocyanate reacted with 2-(aminomethyl)pyridine
at room temperature to give compound 16. For thiourea compounds
and 11, the allyl isothiocyanate and 2-amino-6-substituted-quino-
lines were mixed together at 150 °C. For amino compounds reacting
with propyl isocyanate, the aminoquinolines were refluxed in chlo-
roform whereas 2-(aminomethyl)pyridine was mixed at 80 °C. The
1
4
1
2
ureas, pyridinylidinearylureas, (2-aminoethyl)thiourea de-
rivatives,3 2,4-diamino-6,7-dimethoxyquinoline derivatives,
and 4-(substituted-carbonylamino)-2H-1-benzopyrans.
,4
5
(
4-methoxyphenyl)ureas of quinolines and pyridine (compounds 3, 10,
6
and 18) were synthesized by mixing the reagents neat or in chloroform
at room temperature. The reaction time ranged from 0.5 to 4 h. The
physical properties of the compounds synthesized are listed in Table
Representive methods used to prepare the target ureas and
thioureas are described in the following examples.
-Allyl-3-[2′-(6-m eth yl)qu in olyl]u r ea (1)sA mixture of 2-amino-
A new series of ureas and thioureas incorporating hetero-
cyclic rings was therefore synthesized (Table 1) and tested
for antihypertensive action. Structural modification was
made by varying the chemical features on both sides of the
urea or thiourea function. The selected heterocyclic systems
on one nitrogen of urea or thiourea was either a 6-substituted
quinoline or 2-pyridylmethyl. These functions are related to
the heterocycles of the active compounds, 2,4-diamino-6,7-
dimethoxyquinoline,5 centhaquin,7 aprikalim,8 and guanyl-
hydrazones of 2-pyridine.9 The function on the other nitrogen
was varied from aliphatic groups such as propyl, heptyl, and
octyl to alkene (allyl) or aromatic (4-methoxyphenyl) in order
to provide a wide range of lipophilicity.
1
.
1
6
7
-methylquinoline (0.55 g, 3.5 mmol) and allyl isocyanate (620 µL,
.0 mmol) was heated at 80 °C for 2 h. The resulting solid was
collected and recrystallized with ethanol to give 1-allyl-3-[2′-(6-
methyl)quinolyl]urea as white needles (0.67 g, 79.76% yield) mp 176-
-1
178 °C. IR (KBr) (cm ): 3212 (N-H), 3016-3078 (aromatic CsH,
olefinic CsH), 2920-2986 (aliphatic CsH), 1688 (CdO), 1467-1616
(
aromatic CdC, cyclic CdN, olefinic CdC, NsH), 1313 (aromatic
CsN), 1131-1165 (aliphatic C-N), 822 (parasubstituted aromatic
CsH). H NMR (CDCl3): δ 2.48 (s, 3H, CH3-quinoline), 4.12 (t, J )
1
5
5
.1 Hz, 2H, NHCH2CHd), 5.21 (dd, J ) 1.6 and 10.1 Hz, allyl-Ha),
.37 (dd, J ) 1.4 and 19.5 Hz, allyl-Hb), 6.08 (m, 1H, -CH2CHdCH2),
7.00 (d, J ) 8.9 Hz, H3), 7.32 (d, J ) 9.2 Hz, H4), 9.57 (bs, 1H,
exchangeable with D2O, quinoline-NH), 10.33 (bs, 1H, exchangeable
with D2O, CONHCH2). Anal.sCalcd for C14H15N30: C, 69.69; H, 6.26;
N, 17.42. Found: C, 69.98; H, 6.24; N, 17.44.
Antihypertensive evaluation of the newly synthesized some
previously prepared10 compounds and was carried out. The
evaluation was performed by the indirect tail-cuff method in
deoxycorticosterone acetate/saline-treated hypertensive rats
(DHRs). The effects of the most promising compound with
1
-(4-Met h oxyp h en yl)-3-[2′-(6-m et h yl)q u in olyl]u r ea (3)s4-
Methoxyphenyl isocyanate (400 µL, 2.1 mmol) was added dropwise
to a stirred solution of 2-amino-6-methylquinoline (0.49 g, 2.1 mmol)
X
Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
2
58 / Journal of Pharmaceutical Sciences
0022-3549/96/3185-0258$12.00/0
© 1996, American Chemical Society and
American Pharmaceutical Association
Vol. 85, No. 3, March 1996
+
+

Table 1sN-(Alkyl/alkene/aryl)-N′-heterocyclic Ureas and Thioureas
X
C
Y
NH
NH
R
Compound No.
Y
X
R
Recrystn Solvent
EtOH
Mp (
°
C)
Yield (%)
a
1
2
3
4
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methyl-2-quinolyl
6-Methoxy-4-quinolyl
2-Pyridylmethyl
O
O
O
S
S
S
S
O
O
O
S
S
S
S
S
O
O
O
CH
2
3
3
2
3
3
3
2
3
3
2
3
3
3
3
2
3
3
d
CHCH
(CH
OPh
CHCH
2
176
197
236
181
178
100
105
145
208
218
178
−
−
−
−
−
−
−
−
−
−
−
178
198
238
183
180
102
105.5
147
210
220
181
80
72
88
56
63
71
77
88
62
55
57
71
68
53
40
58
75
57
a
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
)
2
2
EtOH−H O
a
DMF
CHCl −MeOH
3
a
d
2
5
6
7
8
9
(CH
(CH
(CH
2
2
2
)
2
)
6
)
7
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
a
d
CHCH
(CH
OPh
CHCH
2
−
H
2
2
O
O
a
2
)
2
−H
a
10
11
12
13
14
15
16
17
18
a
d
2
CHCl
3
−
MeOH
(CH
(CH
(CH
(CH
2
2
2
2
)
2
)
6
)
7
)
2
EtOH
EtOH
EtOH
167.5
144 145
138.4 140
−170
−
−
CHCl
CHCl
CHCl
CHCl
3
−C H
6
14
168
76
84
153
−
−
−
−
170
78
85
155
a
a
a
d
CHCH
(CH
OPh
2
3
3
3
2-Pyridylmethyl
2-Pyridylmethyl
2
)
2
a
Newly synthesized compounds.
in chloroform (30 mL). The reaction mixture was allowed to stir at
negative and positive control groups. The negative control group was
treated orally with 6% acacia alone, and the positive control group
received prazosin, orally, at a dose of 5 mg/kg. The SBP was
measured at 0, 0.5, 1, 2, 3, 4, 6, and 24 h after dosing. The
measurement was continued until the return of the SBP to the
predosed value ((10% of SBP at 0 hour).
The antihypertensive effects were evaluated by grading the reduc-
tion in SBP into four levels. The grading system was less than 10%
(-), 10-15% (+), 15-20% (++), and >20% (+++) reduction of SBP.
The statistical significance between the control and the treated groups
was accessed by analysis of variance and followed by a t test (Duncan
multiple range test). All differences having a p-value of less than
0.05 were considered to be statistically significant.
E ffect s on Isola t ed Va scu la r Sm oot h Mu scle a n d Hea r t
Mu sclesRelaxation of Vascular Smooth MusclesRabbits (New Zealand
white, 1.5-2.0 kg body weight) were sacrificed and the femoral
arteries were removed, cleaned, and cut into segments (1 cm in
length). The arteries were placed in 25 mL water-jacketed organ
baths containing Krebs-Henseleit solution maintained at 37 °C and
aerated with a 95% oxygen and 5% carbon dioxide gas mixture.
Arteries were attached to a force-displacement transducer and
recorder under a resting tension of 0.5 g. After 45 min of equilibration
time, the arteries were induced to contract by a submaximal dose of
phenylephrine. After a sustained contraction was reached, compound
room temperature for 1.5 h. The resulting solid precipitated, and the
reaction mixture was filtered and recrystallized with dimethylfor-
mamide to give 1-(4-methoxyphenyl)-3-[2′-(6-methyl)quinolyl] urea
as white crystals (0.57 g, 88.32% yield) mp 236-238 °C. IR (KBr)
-1
(
cm ): 3200 (N-H), 3050-3150 (aromatic CsH), 2920-2980 (aliphatic
CsH), 1960 (CdO), 1460-1610 (aromatic CsC, cyclic CdN, NsH),
360 (C-O), 1310 (aromatic CsN), 1110-1130 (aliphatic CsN), 822
1
1
(parasubstituted aromatic CsH). H NMR (DMSO-d6): δ 2.50 (s, 3H,
CH3-quinoline), 3.75 (s, 3H, PhOCH3), 6.70-8.20 (m, 9H, 5H-
quinoline, 4H-Ph), 9.80 (bs, 1H, exchangeable with D2O, quinoline-
NH), 11.70 (bs, 1H, exchangeable with D2O, CONHPh). Anal.sCalcd
for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67 Found: C, 70.32; H,
5
.57: N, 13.75.
-Allyl-3-[(2-p yr id yl)m et h yl]u r ea (16)sA mixture of 2-(ami-
nomethyl)pyridine (580 µL, 5.6 mmol) and allyl isocyanate (500 µL,
.6 mmol) was kept at room temperature for 0.5 h. The resulting
1
5
solid was washed with diethyl ether and recrystallized with chloro-
form to give 1-allyl-3-(2′-methylpyridyl)urea as white crystals (0.62
-1
g, 57.89% yield) mp 76-78 °C. IR (KBr) (cm ): 3328 (NsH), 3014-
149 (aromatic CsH, olefinic CsH), 2903-2980 (aliphatic CsH), 1626
CdO), 1438-1595 (aromatic CdC, cyclic CdN, olefinic CdC, NsH),
290 (aromatic CsN), 1150-1248 (aromatic CsN), 754 (monosub-
3
(
1
1
stituted aromatic CsH). H NMR (CDCl3): δ 2.77 (t, J ) 5.5 Hz,
H, NHCH 2CHd), 4.42 (d, J ) 5.5 Hz, 2 H, pyridine-CH2), 5.01 (dd,
J ) 1.7 and 9.9 Hz, allyl-Ha), 5.21 (dd, J ) 1.7 and 13.1 Hz, allyl-Hb),
.77 (m, 1H CH 2CHdCH2), 6.42 (bs, 2H, exchangeable with D2O
NHCONH), 7.09 (d, J ) 7.5 Hz, H5), 7.23 (d, J ) 7.8 Hz, H3), 7.59
2
1
7 was added. The ability of test compound to relax the tissue was
examined by recording the amplitudes of contractions in gram tension.
Relaxation of vascular smooth muscle was expressed as the percent-
age reduction of the vasomotor tension from the control.
5
(
dt, J ) 1.7 and 7.5 Hz, H4), 8.40 (d, J ) 4.1 Hz, H6). Anal.sCalcd
Effects on Cardiac MusclesGuinea pigs (300-400 g) were sacrificed
and the hearts were removed. The atrias were separated and placed
in 25 mL water-jacketed organ baths containing Krebs-Henseleit
solution maintained at 37 °C aerated with a mixture of 95% oxygen
and 5% carbon dioxide. The atrial tissue was mounted with one end
attached to a force-displacement transducer and recorder under a
resting tension of 0.5 g. After 60 min of equilibration time, a
spontaneous atrial rate and the amplitude of contraction in gram
tension were recorded. Compound 17 was added to the bath and the
changes on the rate and amplitude were observed.
for C10H13N3O: C, 62.81; H, 6.85; N, 21.97 Found: C, 62.67; H 6.73;
N, 21.60.
An tih yp er ten sive Testin gsCompounds were screened for anti-
hypertensive activity in the DHRs by the indirect tail cuff method.
The male Wistar rats, 180-200 g at starting, were placed in individual
cages after the implantation of deoxycorticosterone acetate and were
provided with a 1% sodium chloride solution for drinking water
throughout the experimental period to induce hypertension. The
systolic blood pressure (SBP) was measured indirectly from the tail
of unanesthetized rats to monitor the hypertension using an electronic
blood pressure recorder with a piezoelectric transducer (Ugo Basile,
Model 8006). Two to four weeks were allowed for the development
of hypertension. The animals with SBP exceeding 180 mmHg were
considered to be hypertensive. Before being employed in the anti-
hypertensive evaluation, the DHRs were trained to get used to the
tail-cuff.
Results and Discussion
A series of heterocyclic ureas and thioureas were prepared
for antihypertensive evaluation. Eleven new compounds were
synthesized and seven previously reported related compounds
in the same series were also prepared for the antihypertensive
evaluation. The antihypertensive effects were determined
The DHRs were distributed into 20 groups of five DHRs, eighteen
of which were drug treated, each group receiving a suspension of test
substance orally at dose of 100 mg/kg. The other two groups were
Journal of Pharmaceutical Sciences / 259
Vol. 85, No. 3, March 1996
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Table 2
s
Antihypertensive Effect of Test Compounds
The results of antihypertensive activity are summarized in
Table 2. All compounds except compound 18 were found to
possess significant oral antihypertensive action ranging from
10.0% to 29.1% reduction in SBP. The urea 9 was the most
active while urea 18 was the only inactive compound at the
tested dose. Several members of the series were found to be
marginally and moderately active; a decrease in SBP between
Reduction in SBPa
Compound
0.5 h
1 h
2 h
3 h
4 h
6 h
24 h
Control
−
+
−
−
+
−
−
+
−
−
−
+
−
−
−
++
+
+
−
−
−
−
−
+
−
−
−
+
+++
−
−
−
−
+
−
−
+
1
2
3
4
5
6
7
8
9
(NS)
(NS)
+
+++
+
+++
−
++
++
+
+++
+
−
−
−
++
+
(NS)
(NS)
1
1
0 and 15% was observed in seven compounds. Although the
0-15% reduction was weak or marginal, the decrease was
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
+
−
+
+
−
−
−
−
−
−
−
−
++
+
+
++
−
++
significant. Six compounds reducing SBP between 15 and
+
−
−
+
−
−
+
−
+
(NS)
2
0% were considered moderate in activity. However, four
compounds (2, 4, 9, and 17) displayed potent action by
lowering SBP more than 20%, as shown in Figure 1.
(NS)
The onset of antihypertensive action following the oral
administration ranged from 0.5 h to 6 h, and the duration of
action ranged from 1 h to 24 h. Compounds 2, 3, 6, and 12
were found to have a slow onset, exhibiting action at 6 h.
Compounds 1, 14, and 17 were considered to be fast acting
since these compounds showed significant antihypertensive
action within 1 h after dosing.
Compounds 4, 9, 14, and 17 had a long duration of
antihypertensive action of about 24 h, which would suit the
regimen of a once-daily dose. Moreover, the effect of com-
pound 9 was not only potent at 24 h but also superior to the
effect of prazosin at 24 h. The SBP of DHRs treated with
compound 9 and prazosin returned to the predosed value at
10
11
12
13
14
15
16
17
18
(NS)
++
−
++
++
−
+
++
−
−
+++
Prazosin
+++
+++
+++
+++
+++
+++
a
−
) <10%; + ) 10−15; ++ ) 15−20%; +++ ) >20% reduction in SBP
after dosing. NS indicates that the observed effect was not statistically significant
at the p < 0.05 level as compared to the control.
3
0 and 26 h, respectively.
The summarized results in Table 3 showed the propyl ureas
(2, 9, and 17) to be more potent than the propyl thioureas (5,
1
2, and 15). In addition to their potency, the propyl ureas 9
and 17 produced sustained reduction in SBP. It appeared that
urea derivatives were more effective than thioureas. The allyl
derivatives of 6-methylquinoline was exceptional since the
1
-allyl-3-[2′-(6-methyl)quinoline] (1) was less active than the
allyl thiourea (4) analogue.
An increase in the size or length of the chain resulted in a
decrease in activity. The (4-methoxyphenyl)ureas 3, 10, and
1
3 were only marginally active or inactive. Exceptionally,
when the alkyl of quinolylthiourea was lengthened from
propyl (5) to heptyl (6) or octyl (7), the antihypertensive effect
and duration increased, but the activity was still not as potent
as that of the allyl derivative (4). Thus, the short side chain
of about three carbon atoms in length in both ureas and
thioureas contributed to good activity. Between the short side
chains, allyl versus propyl, propylureas displayed better
activity than allyl ureas, but the same conclusion could not
be drawn for the thiourea derivatives. In contrast, the
antihypertensive effect and duration were decreased dramati-
cally when the allyl group in thiourea 4 was replaced by the
propyl group in thiourea 5.
Figure 1sThe time course of the antihypertensive effect of the propylureas (2,
9
, 17) and allylthiourea (4) on SBP. Each point represented the mean of five
DHRs. *p < 0.05 as compared with the control.
after a single oral administration at a dose of 100 mg/kg to
conscious DHRs using the indirect tail-cuff method.
Table 3sStructure−Activity Relationships of Test Compounds
X
C
Y
NH
NH
R
Reduction in SBPa
Y
X
R
)
CH
2
d
CHCH
2
R
)
CH (CH )
3 2 2
R
)
3
CH OPh
R
)
CH (CH )
3 2 6
R
)
3 2 7
CH (CH )
6
-Methyl-2-quinolyl
O
S
O
S
S
O
++ (1)
+++ (4)
++ (8)
+++ (2)
(5)
+++ (9)
+
NA
+
NA
NA
(3)
NA
++ (6)
NA
NA
++ (7)
NA
++ (14)
NA
NA
+
6-Methoxy-2-quinolyl
(10)
+
(11)
+
+
(12)
(15)
+
(13)
6
2
-Methoxy-4-quinolyl
-Pyridylmethyl
NA
++ (16)
NA
NA
+++ (17)
−
(18)
a
−
)
<10%; + ) 10
−
15%; ++ ) 15−20%; +++ ) >20% reduction in systolic blood pressure. The maximum effects within 6 h after dosing were significant at the
p < 0.05 level as compared to the control. The number of the compound is indicated in parentheses. NA indicates that the specified compounds were not included in
the synthesis and testing.
2
60 / Journal of Pharmaceutical Sciences
Vol. 85, No. 3, March 1996
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Concerning the substitution at the 6-position of quinoline,
equipotency was found in six pairs (1 versus 8, 2 versus 9, 3
versus 10, 5 versus 12, 6 versus 13, and 7 versus 14), whereas
the potencies of the methyl analogues were greater than those
of methoxy derivatives in one pair (4 versus 11). However,
there seemed to be no distinct relationship between the
activity and the 6-substituent in the quinoline ring. It was
not possible to reveal the structure-activity relationship
regarding the position of the substituent in the quinolyl
thioureas because only one 4-substituted derivative was
synthesized.
Table 4sEffects of Compound 17 on Vascular Smooth Muscle and
Cardiac Muscle
Gram tension (SEM)
Tissue
control
compound 17
% Reduction
a
a
artery
atrium
0.84 (0.01)
0.42 (0.02)
0.67 (0.03)
0.28 (0.02)
17.78
31.79
a
n
) 6, p < 0.01.
in order to delineate the mechanisms involved in the media-
tion of the cardiovascular actions.
To explore further the effect of a heterocyclic nucleus on
activity, the pyridylmethyl urea compounds 16-18 were
prepared. This change caused a dramatic improvement in
potency, onset, and duration of the activity, comparing the
propyl derivatives 2 and 17.
It may be concluded that in the comparison between urea
and thiourea analogues, the propylureas were found to be
more potent than the propylthioureas. Concerning the alkyl/
alkenyl/aryl groups, compounds containing propyl and allyl
groups attained good antihypertensive activity, whereas the
compounds with longer aliphatic chains or aromatic groups
showed modest effects. In regard to the heterocyclic groups,
there was no distinct differences in activity between the
In summary, 17 of 18 compounds tested in the present study
possessed significant antihypertensive action in DHRs. How-
ever, none of the test compounds had higher potency than
prazosin. Since the effect of 1, 4, 9, and 17 were both potent
and long, they were considered as promising candidates for
further pharmacological investigation.
References and Notes
1. Glamkoski, E. J .; Reitano, P. A.; Woodward, D. J . J . Pharm.
Sci. 1987, 67, 1773-1774.
2
. Ludden, C. T.; Scriabine, A.; Ulm, E. M.; Morgan, G.; Fisher,
M. H.; Ruyl, W. V. Experientia 1979, 35, 799-801.
3. Tilley, J . W.; Levitan, P.; Kierstead, R. W. J . Med. Chem. 1980,
2
3, 1387-1392.
4
5
6
. Tilley, J . W.; Ramuz, H.; Hefti, F.; Gerold, M. J . Med. Chem.
6
-methylquinoline and 6-methoxyquinoline derivatives. An
1
980, 23, 1438-1439.
improvement in both potency and onset was observed when
the quinoline nucleus was replaced by 2-pyridylmethyl.
. Campbell, S. F.; Hardstone, J . D.; Palmer, M. J . J . Med. Chem.
1988, 31, 1031-1035.
. Ashwood, V. A.; Cassidy, F.; Coldwell, M. C.; Evans, J . M.;
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Compound 17, with rapid onset, was selected for in vitro
pharmacological testing. It significantly relaxed both vascular
smooth muscle and cardiac muscle (Table 4) but had no effect
on heart rate. The maximal reductions of the femoral artery
vasoconstriction and the cardiac contraction were found to be
7. Gulati, A.; Hussain, G.; Srimal, R. C. Drug Dev. Res. 1991, 23,
307-323.
8
. Chevalier, P.; Rouillard, C.; Montay, G. J . Pharm. Sci. 1994,
8
3, 372-374.
9
. Foye, W. O.; Almasian, B.; Eisenberg, M. S.; Maher, T. J . J .
Pharm. Sci. 1990, 79, 527-530.
1
8% (0.4 mg/mL) and 32% (1.2 mg/mL), respectively. These
1
0. Vajragupta, O.; Pananookooin, S.; Tuntiwachwuttikul, T.; Foye,
effects suggest that the antihypertensive action could be
accounted for by a relaxation of vascular smooth muscle and
cardiac muscle. Pharmacological studies should be continued
W. O. J . Sci. Soc. Thailand 1988, 14, 51-59.
J S930295X
Journal of Pharmaceutical Sciences / 261
Vol. 85, No. 3, March 1996
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