Synthesis and cardiovascular evaluation of N-substituted 1- aminomethyl-2-naphthols

Article abstract of DOI:10.1016/S0223-5234(99)00204-4

A series of 1-alkylaminomethylnaphthols have been prepared. These compounds were readily prepared in good yields by addition of 2-naphthol to formalin and alkylamines. The hypotensive and bradycardiac effects of these compounds in normotensive rats as well as their in vitro inotropic and aortic contraction effects in isolated rat left atria and aorta have been evaluated. A higher depressor and bradycardiac activity was found for compounds substituted on nitrogen by naphthol with primary amines, i.e., ethylamine, propylamine, isopropylamine, or butylamine and with a cyclic secondary amine, i.e., pyrrolidinyl. These compounds produced biphasic changes in contractile force in isolated rat atria which was correlated to blood pressure and heart rate activity. 1-Isopropylaminomethyl-2-naphthol hydrochloride relaxed isolated rat aortic rings precontracted with high extracellular K⁺ (80 mM) and Ca²⁺ (1.9 mM). The suppressive effects of the compounds may involve a direct inhibition of Ca²⁺ channels. The biological activity of these compounds can be explained in terms of substitution on nitrogen.

Full text of DOI:10.1016/S0223-5234(99)00204-4

Eur. J. Med. Chem. 34 (1999) 877−882
© 1999 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
877
Short communication
Synthesis and cardiovascular evaluation
of N-substituted 1-aminomethyl-2-naphthols
A.Y. Shena*, C.T. Tsaib, C.L. Chena
aDepartment of Pharmaceutical Science, Foo Yin Institute of Technology, Ta-Liao, Kaohsiung County 831, Taiwan
bDepartment of Biology, National Changhua University of Education, Changhua, Taiwan
(Received 9 December 1998; revised 15 April 1999; accepted 6 May 1999)
Abstract – A series of 1-alkylaminomethylnaphthols have been prepared. These compounds were readily prepared in good yields by addition
of 2-naphthol to formalin and alkylamines. The hypotensive and bradycardiac effects of these compounds in normotensive rats as well as their
in vitro inotropic and aortic contraction effects in isolated rat left atria and aorta have been evaluated. A higher depressor and bradycardiac
activity was found for compounds substituted on nitrogen by naphthol with primary amines, i.e., ethylamine, propylamine, isopropylamine,
or butylamine and with a cyclic secondary amine, i.e., pyrrolidinyl. These compounds produced biphasic changes in contractile force in
isolated rat atria which was correlated to blood pressure and heart rate activity. 1-Isopropylaminomethyl-2-naphthol hydrochloride relaxed
isolated rat aortic rings precontracted with high extracellular K+ (80 mM) and Ca2+ (1.9 mM). The suppressive effects of the compounds may
involve a direct inhibition of Ca2+ channels. The biological activity of these compounds can be explained in terms of substitution on nitrogen.
© 1999 Éditions scientifiques et médicales Elsevier SAS
1-alkylaminomethyl-2-naphthol / blood pressure / heart rate / left atrial / aorta
1. Introduction
with a combination of potassium and calcium channel
antagonistic properties might consititute a novel anti-
arrhythmic agent with reduced proarrhythmic risk. Some
of the drugs used to treat ventricular arrhythmias have
been shown to also act on the transient outward current at
therapeutic concentrations [4–6]. The actions of TPY-â
on the cardiovascular system encouraged us to search for
and synthesize novel derivatives of aminomethylnaph-
thol. This brought forth the modification of the pyrrolidi-
nyl group in TPY-â with primary amines via the conden-
sation of 2-naphthol with primary amines. The method
exists for attaching carbon substituents to the 1-position
of 2-naphthol, and many 2-naphthols bearing such sub-
stituents are known in the literature [7]. A selection of
compounds possessing a variety of 1-substituents was
desired in order to broadly define the structure activity
relationship for this portion of the molecule. These
compounds, shown in table I, either were known in the
literature or were prepared according to well-established
synthetic methods [7, 8]. The purpose of the present study
was to evaluate the importance of the side substitution at
the 1-position of the aminomethylnaphthols.
1-Pyrrolidinylmethyl-2-naphthol
hydrochloride
(TPY-â) has been shown to produce a reduction in blood
pressure (BP) and heart rate (HR) in anaesthetized
rats [1]. The ionic mechanism of the cardiovascular
activity of TPY-â has also been examined. The results
indicated that suppressive effects of TPY-â involve a
direct depressant action on heart cells and vascular
smooth cells [2]. The direct inhibition of voltage-
dependent L-type Ca2+ channels is involved in the TPY-â
mediated vasodilatory action. In addition, the inhibitory
effect of TPY-â on cardiac contractibility through the
blockade of L-type Ca2+ channels can be prevented by
TPY-â mediated inhibition of the transient outward po-
tassium current. Bril et al. [3] reported that a compound
*Correspondence and reprints

878
Table I. Hypotensive and bradycardic response following intravenous injection of aminomethylnaphthol derivatives (2.2 µmol/kg) in rats.
1
2–13
Compound R1
R2
X
HR (beats/min)a
maximum change % maximum
BP (mm Hg)a
maximum change
% maximum
N.S.
1
4 ± 2
-8 ± 4
1 ± 1
2 ± 1
4 ± 3
-5 ± 4
3 ± 2
6 ± 5
2
3
4
5
6
7
8
9
10
11
12
13
CH3
C2H5
n-C3H7
i-C3H7
C4H9
CH3
C2H5
C3H7
C4H9
H
H
H
H
HCl
HCl
HCl
HCl
HCl
-38 ± 15
-240 ± 15*
-276 ± 31*
-268 ± 54*
-328 ± 43*
-26 ± 3*
-15 ± 4*
-13 ± 5*
0
11 ± 5
62 ± 11*
67 ± 13*
65 ± 7*
75 ± 21*
7 ± 2*
4 ± 2
-10 ± 5
-75 ± 19*
-94 ± 21*
-82 ± 11*
-103 ± 16*
-16 ± 5*
-6 ± 4
10 ± 5
69 ± 16*
81 ± 18*
70 ± 20*
85 ± 15*
15 ± 4*
5 ± 4
H
CH3
C2H5
C3H7
C4H9
3 ± 2
0
0
0
0
0
TPY-
-(CH2)5-
-(CH2)2-O-(CH2)2-
-258 ± 33*
-137 ± 37*
-121 ± 17*
64 ± 15*
32 ± 8*
28 ± 8*
-81 ± 2*
-59 ± 13*
-38 ± 8*
77 ± 17*
53 ± 11*
23 ± 9*
aPercent decrease in blood pressure and heart rate were calculated from the decrease in blood pressure and heart rate of the treatment group
and the blood pressure (normally 105–120 mm Hg) and heart rate (normally 385–405 beats/min) of the control group; 2.2 µmol/kg usually
amounts to 0.4–0.5 mg/kg; values are expressed as the mean ± SEM. Asterisks indicate significant difference (t-test, calculated on the changes)
from the N.S. (normal saline). *P < 0.05.
2. Chemistry
a piperidinomethyl group into the 1-position of
2-naphthol and into the 2-position of 1-naphthol. This
indicates that the substituent ortho to the naphthylene
In the present work, reaction of 2-naphthol with
formaldehyde and methylamine in a molar ratio of 1:2:1,
respectively, in a methanol solution at 60 °C was found to
produce
2,3-dihydro-2-methyl-1H-naphth[1,2-e]-m-
oxazine (1). Upon treating 1 with hot aqueous hydrochlo-
ric acid, formaldehyde was liberated and the hydrochlo-
ride of 1-methylaminomethyl-2-naphthol (2) was formed
(figure 1) [7]. The condensation, run in the same manner
except with ethylamine, propylamine, isopropylamine or
butylamine, resulted in the formation of 1-alkyl-
aminomethyl-2-naphthols directly instead of naphthox-
azine products. Compounds 1, 2, 5, and 6 were previously
synthesized and reported [7]. The temperature and the
particular amine seem to be the important factors in
determining the course of the reaction of 2-naphthol with
formaldehyde and primary amine as reported by Burke et
al. [7].
The condensation of naphthols with formaldehyde and
secondary amines has been studied previously [8]. Reac-
tion of piperidine and formaldehyde with 1- and
2-naphthol has been shown to result in the introduction of
Figure 1. Synthetic routes for the 2,3-dihydro-2-methyl-1H-
naphth[1,2-e]-m-oxazine (1) and aminomethylnaphthol deriva-
tives (2–13).

879
Figure 2. Effects of intravenous injection of 1-isopropylaminomethyl-2-naphthol (5) and dipropylaminomethyl-2-naphthol (9) on
blood pressure and heart rate in one anaestherized normotensive rat. Compounds were administered at the time indicated by an arrow.
hydroxyl group plays a role in determining the course of
the reaction [7, 8].
chain derivatives (1–2), which were not active even at a
higher dosage (data not shown).
The present results (table II) in vitro show that the
1-alkylaminomethyl-2-naphthols (3–6) and the secondary
amines with cyclic side chains (11–13), at 30 µM,
produced a biphasic effect on the contractile force in
isolated rat left atria, i.e., an initial decrease and a
sustained increase. A representative inotropic response of
an electrically driven left atrium to 1-isopropyl-
aminomethyl-2-naphthol hydrochloride (5) is depicted in
figure 3. However, the straight chain derivatives (7–10)
show the negative inotropic effect. The 4-Aminopyridine-
sensitive transient outward current (Ito) has been shown
to be present in rabbit, rat, cat, dog and human cardiac
myocytes, but not in guinea-pig cardiac myocytes [12–
15]. It has been suggested that the compound 11 (TPY-â)
mediated inhibition of Ito would reverse the rat myocar-
dial depressant effect caused by its initial inhibition of
L-type Ca2+ channels [3]. The similarity of the molecular
structure suggests that 1-isopropylaminomethyl-2-
naphthol hydrochloride (5) and other analogues work in
the same manner as compound 11 (TPY-â). In addition,
Ca2+ (1.9 mM) elicited a 100% contraction in rat aorta in
the presence of high K+ (80 mM), 5 was more potent in
suppressing the tone induced by high K+ and Ca2+ than 7
as shown in table III. High K+ has been shown to evoke
smooth muscle contraction by promoting Ca2+ influx
through voltage-sensitive Ca2+ channels which are
readily activated by membrane depolarization [16].
Therefore, extracellular Ca2+ entry is thought to be the
main cause of the high K+-induced contraction. The
present studies indicate that the suppressive effects of
3. Results and discussion
Aminonaphthols have been reported to exhibit anti-
hypertensive, adrenoceptor blocking, and Ca2+ channel
blocking activities [9–11]. As described in the experimen-
tal section, the hypotensive and bradycardiac activity of
the analogue series was tested in normotensive rats at a
dosage of 2.2 µmol/kg. Figure 2 shows the chart record-
ings of blood pressure (top traces) and heart rate (bottom
traces) of an anaesthetized rat. Intravenous injection of
compound 5 (2.2 µmol/kg) induced a maximum reduc-
tion of mean arterial pressure from 120 mm Hg to 25 mm
Hg within 30 s and the BP returned to the control value in
20 min. Along with the sudden decrease in BP, the heart
rate was also reduced from 400 beats min–1 to a minimum
value of 130 beats min–1, and it took 40 min for full
recovery to the control level. The acute hypotensive and
bradycardiac responses induced by 2.2 µmol/kg of these
compounds are summarized in table I. Substitution of the
amine hydrogen atom by alkyl groups of increasing chain
length altered the activity. In the dialkylaminomethyl-2-
naphthol series, the straight chain derivatives (7–10) had
less hypotensive and bradycardiac activity than the cyclic
analogues (11–13). An increase in the size of the
N-dialkyl group appeared to reduce hypotensive and
bradycardiac activity. Despite the limited series from
which to evaluate the structure-activity relationship, pri-
mary amine substitution (3–6) showed better potency
than secondary amine derivatives except methyl side

880
Table II. Characteristics of aminomethylnaphthols (30 µM) on the
contractile force in rat left atria stimulated at 1.0 Hz.
Compound
Maximal force of contraction (%)
phase 1
phase 2
1
2
3
4
5
6
7
8
100 ± 18 (3)
100 ± 20 (3)
90 ± 16* (5)
85 ± 17* (5)
82 ± 13* (6)
83 ± 17* (5)
78 ± 19* (4)
80 ± 21* (4)
88 ± 15* (4)
97 ± 19* (4)
77 ± 12* (5)
90 ± 21* (5)
89 ± 16* (6)
100 ± 16 (3)
100 ± 19 (3)
220 ± 36* (4)
235 ± 42* (5)
238 ± 29* (5)
219 ± 23* (5)
78 ± 19* (4)
80 ± 21* (4)
88 ± 15* (4)
97 ± 19* (4)
225 ± 49* (4)
160 ± 23* (4)
120 ± 25* (5)
9
10
11
12
13
Figure 3. Effect of 1-isopropylaminomethyl-2-naphthol (5)
and dimethylaminomethyl-2-naphthol (7) on the contractile
force of isolated rat left atria. Stimuli were driven at 1 Hz with
2 times the threshold. The presence of compound 5 (30 µM)
produced a biphasic response, while compound 7 (30 µM)
produced only a negative intropic effect.
Values are means ± SEM. Number of preparations (n) is given in
parentheses.*P < 0.05 compared with the respective control by
student t test.
these compounds could interfere with Ca2+ influx through
the depolarized cell membrane to induce relaxation of rat
aorta. The results observed are consistent with previous
findings that 11 (TPY-â) or aminonaphthols effectively
suppressed the voltage-gated Ca2+ current [2, 17, 18].
In conclusion, the biological activity of these com-
pounds can be explained in terms of substitution on
nitrogen. The development of N-substituted 1 amino-
methyl-2-naphthols with dual effects would be of poten-
tial therapeutic advantage.
Analyses indicated by the symbols of the elements were
within ± 0.4% of the theoretical values. Infrared spectra
were obtained on a Shimadzu IR-408 spectrophotometer.
Nuclear magnetic resonance spectra were recorded on a
Varian Gemini T-300 spectrometer at the National Sun
Yat-Sen University, Kaohsiung, and are expressed in
parts per million (δ) with tetramethylsilane used as an
internal standard. Mass spectra recorded for the purposes
of structure confirmation were obtained on a Jeol
JMS-HX 110 mass spectrometer at the National Sun
Yat-Sen University, Kaohsiung. Elemental analysis was
performed on a CHN-O-Rapid Heraeus Elemental Ana-
lyzer at the National Cheng-Kung University, Tainan.
Thin layer chromatography was carried out on precoated
silica gel F254 chromatographic plates (20 × 20 cm;
0.2 mm). Methylamine, ethylamine, propylamine, isopro-
pylamine and butylamine were all obtained from the
Tokyo Chemical Industry Co. (TCI). 2-Naphthol was the
product of the Sigma Co. All other reagents used in this
study were EP grade products of E Merck.
4. Experimental protocols
4.1. Chemistry
Melting points were determined on a Yanagimoto
MP-3 micromelting apparatus and are uncorrected.
Table III. Effects of dimethylaminomethyl-2-naphthol (7) and
1-isopropylaminomethyl-2-naphthol hydrochloride (5) on the rat
aortic contraction induced by KCl and Ca.
Compound
Contraction (% of Control)
Dialkylaminomethyl-2-naphthol derivatives were syn-
thesized previously [8]. The synthesis and characteriza-
tion of 1-alkylaminomethyl-2-naphthol will be reported
here.
KCl (80 mM) + Ca (1.9 mM)
Control
100 ± 3.9
79 ± 4.8
50.4 ± 6.4
15.3 ± 1.0
7 (45 µM)
5 (45 µM)
5 (150 µM)
4.1.1. 2,3-Dihydro-2-methyl-1H-naphth[1,2-e]-m-oxa-
zine (1)
Following the procedure of Burke et al. [7], to a cooled
solution of 12.4 g of 25% aqueous methylamine (0.1 mol)
Percentages of the control contraction were calculated and presen-
ted as mean ± SEM (n = 4). *P < 0.05 as compared with the
respective control.

881
in 60 mL of methanol was added 18.5 mL of 37%
(0.2 mol) aqueous formaldehyde in 40 mL of methanol
and 14.4 g of 2-naphthol (0.1 mol) in 50 mL of methanol.
After 1.5 h of gentle refluxing at 60 °C, the reaction
mixture was poured into 400 mL of cold water. The
product (95% yield) was collected and recrystallized
from methanol. M.p. 68–70 °C, IR (nuzol) cm–1: 2 994
(aromatic C–H), 2 909 (CH3), 1 427 (C–O), 1 214 (C–N).
1H NMR (300 MHz, DMSO): δ 7.82 (d, J = 8.4 Hz, 1H),
7.65 (m, 2H), 7.48 (m, 1H), 7.38 (m, 1H), 7.03 (d, J = 9.0
Hz, 1H), 4.82 (s, 2H), 4.22 (s, 2H), 2.53 (s, 3H). MS m/z
(relative intensity): 128 M+ (100), 144 (72), 156 (42).
Anal. C13H13NO (C, H, N).
188–190 °C (dec). IR (nuzol) cm–1: 3 486 (NH), 3 442
(OH), 2 990 (aromatic C–H), 2 913 (CH2, CH3), 1 426
(C–O). H NMR (300 MHz, D2O): δ 7.89 (m, 3H), 7.5
(dd, J = 8.7, 7.2 Hz, 1H), 7.42 (dd, J = 7.5, 7.5 Hz, 1H),
7.20 (d, J = 9.0 Hz, 1H), 4.54 (s, 2H), 3.04 (t, J = 7.2 Hz,
2H), 1.70 (m, 2H). 0.92 (t, J = 7.5 Hz, 3H). MS m/z
(relative intensity): 128 M+ (42), 215(30). Anal.
C14H17NO HCl (C, H, N).
1
4.1.5. 1-Isopropylaminomethyl-2-naphthol hydrochloride
(5)
The product was prepared by a method similar to that
described in the procedure for compound 3. It was
recrystallized from absolute alcohol (yield 70%). M.p.
183–185 °C (dec.). IR (nuzol) cm–1: 2 990 (aromatic
C–H), 2 989 (C–C–C), 1 440 (C–O). 1H NMR (300 MHz,
DMSO): δ 8.07 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 8.7 Hz,
1H), 7.85 (d, J = 6.6 Hz, 1H), 7.55 (dd, J = 7.2, 7.5 Hz,
1H), 7.37 (m, 2H), 4.09 (bs, 2H), 3.45 (m, 1H), 1.37 (s,
3H). 1.34 (s, 3H). MS m/z (relative intensity): 128 M+
(42), 215(12). Anal. C14H17NO HCl (C, H, N, O).
4.1.2. 1-Methylaminomethyl-2-naphthol hydrochloride
(2)
Following the procedure of Burke et al. [7], a solution
of 0.013 mol of 2,3-dihydro-2-methyl-1H-naphth[1,2-e]-
m-oxazine and 1.0 mL of concentrated aqueous hydro-
chloric acid in 60 mL of 85% aqueous propanol-1 was
distilled for about 30 min. After the distillation was
interrupted, 60 mL of acetone was added to the reaction
mixture. Upon cooling and filtration the product was
obtained (91% yield). M.p. 187–189 °C (dec.). IR (nuzol)
cm–1: 2 987 (aromatic C–H), 2 904 (CH3), 1 443 (C–O).
1H NMR (300 MHz, D2O): δ 7.93 (m, 3H), 7.62 (dd, J =
8.7, 7.2 Hz, 1H), 7.45 (dd, J = 7.5 Hz, 1H), 7.24 (d, J =
9.6 Hz, 1H), 4.62 (s, 2H), 2.73 (s, 3H). MS m/z (relative
intensity): 128 M+ (100), 156 (42), 187 (26). Anal.
C12H13NO HCl (C, H, N).
4.1.6. 1-butylaminomethyl-2-naphthol hydrochloride (6)
The product was prepared by a method similar to that
described in the procedure for compound 3. It was
recrystallized from absolute alcohol. M.p. 150–153 °C
(dec.). IR (nuzol) cm–1: 3 473 (broad, OH, NH), 3 006
(aromatic C–H), 2 916 (CH3), 1 436 (C–O), 1 299 (C–N).
1H NMR (300 MHz, D2O): δ 7.86 (m, 3H), 7.59 (dd, J =
8.1, 6.9 Hz, 1H), 7.42 (dd, J = 7.5, 7.5 Hz, 1H), 7.15 (d,
J = 8.7 Hz, 1H), 4.43 (s, 2H), 3.31 (m, 1H), 1.84 (m, 1H),
1.62 (m, 1H), 1.36 (d, J = 7.2 Hz, 3H), 0.96 (t, J = 7.5 Hz,
3H). MS m/z (relative intensity): 128 M+ (100), 156 (52),
229 (17). Anal. C15H19NO HCl (C, H, N).
4.1.3. 1-Ethylaminomethyl-2-naphthol hydrochloride (3)
To a solution of 3.6 g of 2-naphthol (0.025 mol) and
4.7 mL of 37% aqueous formaldehyde (0.06 mol) in
30 mL of methanol 1.6 g of 70% ethylamine (0.025 mol)
in 10 mL methanol was added dropwise. After 1.5 h of
gentle refluxing at 60 °C the oily residue was dissolved in
absolute alcohol. The hydrochloride was obtained by
treating a cold alcohol solution of the product with
concentrated hydrochloric acid (yield 60%). M.p.
175–177 °C (dec.). IR (nuzol) cm–1: 3 454 (broad, NH,
OH), 3 010 (aromatic C–H), 2 909 (CH3). 1H NMR (300
MHz, D2O): δ 7.88 (m, 3H), 7.59 (dd, J = 8.7, 7.2 Hz,
1H), 7.42 (dd, J = 7.5 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H),
4.54 (s, 2H), 3.16 (q, J = 7.5 Hz, 2H). 1.29 (t, J = 7.5 Hz,
3H). MS m/z (relative intensity): 128 M+ (100), 156 (57),
201 (47). Anal. C12H13NO HCl (C, H, N).
4.2. Measurement of BP and HR by intravenous injection
The in vivo experiments have been described previ-
ously [2]. In brief, Wistar rats (250–300 g) of either sex
were used in these studies. The animals were housed in an
animal room with a light/dark cycle of 12 h/12 h and
were fed rat chow and tap water ad libitum. The animals
were anaesthetized with urethane (Aldrich, 1.0 g/kg IP,
supplemented with 300 mg/kg i.v. if necessary). The
trachea was intubated to keep the airway patent. Femoral
arterial blood pressure was measured through a PE 50
tubing filled with heparin solution (25 units/mL) (Sigma)
connected to a polygraph (Lectromed, U.K.) via a trans-
ducer (PDCR 75, Lectromed, UK). The femoral vein was
cannulated for drug administration. The HR was derived
by means of a cardiotachometer that was triggered by the
arterial pressure pulse. The BP and HR were monitored
4.1.4. 1-Propylaminomethyl-2-naphthol hydrochloride
(4)
The product was prepared by a method similar to that
described in the procedure for compound 3. It was
recrystallized from absolute alcohol (yield 65%). M.p.

882
continuously. Rectal temperature was monitored and
maintained between 37 and 38 °C.
4.5. Statistical analysis
Values are expressed as means ± standard error of the
mean (SEM). Statistical analysis was performed with a
paired t test, and a P value smaller than 0.05 was regarded
as statistically significant.
4.3. Measurement of contractile force in isolated rat left
atria
Acknowledgements
Experiments were performed following the methods
described previously [2]. In brief, the hearts were quickly
removed and rinsed in ice-cold Tyrode’s solution. Then,
left atria were dissected and mounted at 0.5 g resting
tension on stainless steel hooks in a 50 mL organ bath,
and bathed at 37 °C in physiological saline solution
containing (mM): NaCl 118, KCl 4.8, CaCl2 2.5,
MgSO4 1.2, KH2PO4 1.2, NaHCO3 24, glucose 11. The
bath was aerated with 95% O2 and 5% CO2 mixture. One
end of the preparation was fixed to the bottom of the bath
and the other end was connected by a hook to the level of
a force-displacement transducer (Ugo Basile, Comero,
Italy). Stimuli were delivered as rectangular pulses of
5 ms duration at 2 times the threshold via two platinum
electrodes placed on either side of the muscle. The tissues
were always allowed to equilibrate for 90 min before the
experiments were begun [2, 19].
This work was supported by a grant from the National
Science Council (NSC 87-2314-B-242-001). The authors
thank Drs Sheng-Nan Wu, Chih-Tsao Chiu and Che-Ming
Teng for their helpful suggestions. The technical assis-
tance of Hui-Ya Chang is also greatly appreciated.
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