1- and 2-substituted naphthalenes: A new class of potential hypotensive agents

Article abstract of DOI:10.1016/j.bmcl.2004.03.080

A series of 2-substituted aminomethyloxy naphthalenes 1 and 4-(1-naphthoxy-2-substituted aminomethyl)-butanoic acids 2 were synthesized by Mannich reaction of 4-(2-naphthoxy)-butanoic acid 3 and 4-(1-naphthoxy)-butanoic acid 4 with appropriate secondary amines and para-formaldehyde. The newly synthesized compounds were tested for their hypotensive activity at 5mg/kgiv dose in cats. The results indicated that the analogue 2-(N⁴-phenyl- N¹-piperazino)-methyloxy naphthalene 1d (>N=N⁴-phenyl- N¹-piperazino) was the most active analogue when its hypotensive activity was compared to the reference compound propranolol.

Full text of DOI:10.1016/j.bmcl.2004.03.080

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2797–2800
1- And 2-substituted naphthalenes:
a new class of potential hypotensive agents
Vishnu K. Tandon,* Kunwar A. Singh and Gajendra K. Goswamy
Department of Chemistry, University of Lucknow, Lucknow 226007, India
Received 20 January 2004;accepted 22 March 2004
Abstract—A series of 2-substituted aminomethyloxy naphthalenes 1 and 4-(1-naphthoxy-2-substituted aminomethyl)-butanoic acids
2 were synthesized by Mannich reaction of 4-(2-naphthoxy)-butanoic acid 3 and 4-(1-naphthoxy)-butanoic acid 4 with appropriate
secondary amines and para-formaldehyde. The newly synthesized compounds were tested for their hypotensive activity at 5 mg/kg iv
dose in cats. The results indicated that the analogue 2-(N4-phenyl-N1-piperazino)-methyloxy naphthalene 1d (>N ¼ N4-phenyl-N1-
piperazino) was the most active analogue when its hypotensive activity was compared to the reference compound propranolol.
Ó 2004 Published by Elsevier Ltd.
Hypotensive drugs play an important role in decrease of
blood pressure in hypertensive patients. The three main
classes to which hypotensive drugs belong to are: (i)
ACE inhibitors;(ii) b-adrenergic receptor antagonists;
(iii) Ca2þ and Kþ channel blockers. During recent years
a number of compounds isolated from natural sources
have exhibited promising hypotensive activity.1;2 Enal-
april the hypotensive drug belongs to ACE inhibitors
class of compounds.3 Propranolol and atenolol the
hypotensive drugs of choice act as b-adrenergic receptor
antagonists4 while amlodepine acts as Ca2þ channel
blocker.4 Bufuralol analogues have recently been found
to act as potent b-blockers.5 cis/trans-Dicyclopropyl-
methyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine
(LNP 509), an I1 imidazoline receptor selective ligand
has been found to possess marked hypotensive activity.6
OH
O
O
O
N
N
2a-f
1a-f
Figure 1.
dose of 5 mg/kg iv in anaesthetized cats. We sought to
investigate the structure–activity relationship (SAR) of
compounds 1 and 2 in comparison with propranolol
6 (Fig. 2). Table 1 describes the hypotensive activity of
1a–f and 2a–f.12
In general N-phenyl-piperazino moiety caused maxi-
mum fall of blood pressure in both compounds 1 and 2.
Piperidino chain too caused significant fall of blood
pressure though for lesser duration of time. Other sec-
ondary amino chains viz morpholino, piperazino, N-
methyl piperazino caused almost similar effect on fall of
blood pressure, which was moderate at a dose of 5 mg/
kg iv. Introduction of a carbonyl group in 2a–f resulted
in lower fall of BP when compared to propranolol with
In our efforts to discover novel molecules having
hypotensive activity, we used molecular model of one of
the b-adrenergic receptor antagonist propranolol7–11
(Fig. 2) to synthesize 4-(1-napthoxy-2-substituted ami-
nomethyl) butanoic acids 2 and corresponding analogue
using 1- and 2-naphthols as starting materials.
Screening of 1a–f and 2a–f (Fig. 1) for hypotensive
activity using propranolol as standard drug resulted in
the lead compound 1d. Compound 1d exhibited marked
hypotensive activity [fall of BP 60 mm/Hg (1200)] at a
O
CH3
HO
CH2NHCH
CH3
6
* Corresponding author. Fax: +91-522-2684388;e-mail: vishnutandon@
yahoo.co.in
Figure 2.
0960-894X/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2004.03.080

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V.K.Tandon et al./ Bioorg.Med.Chem.Lett.14 (2004) 2797–2800
Table 1. Summary of hypotensive activity in cats of compounds 1a–f and 2a–f
Compound
1 mg/kg iv
% of max. effect m ꢀ SE
NA
5 mg/kg iv
% of max. effect m ꢀ SE
Fall of BP mm/Hg
Fall of BP mm/Hg
1a
1b
NA
50(>35)
10(20)
41 ꢀ 4
NA
NA
7 ꢀ 1
1c
1d
18(20)
40(160)
20(20)
12(100)
18(20)
12(120)
18(20)
20(20)
30(160)
10(20)
46(400)
21 ꢀ 2
50 ꢀ 5
21 ꢀ 2
7 ꢀ 1
D
NA
60(1200)
44(170)
30(160)
16(20)
75 ꢀ 8
52 ꢀ 5
19 ꢀ 2
17 ꢀ 2
19 ꢀ 2
38 ꢀ 4
40 ꢀ 4
47 ꢀ 5
17 ꢀ 2
41 ꢀ 4
1e
1f
2a
17 ꢀ 2
7 ꢀ 1
2b
2c
25(70)
17 ꢀ 2
14 ꢀ 2
19 ꢀ 2
8 ꢀ 1
34(40)
2d
2e
50(70)
40(500)
20(300)
50(>600)
2f
Propranolol
35 ꢀ 3
NA: not active;figure in parentheses against fall of BP indicate duration of effect in min;D: death.
similar doses in anaesthetized cats (Table 1). However,
compound 2e having piperidino moiety in it caused
considerable fall of blood pressure and can be compared
with propranolol.
O
OH
a
OH
O
+
O
O
4
On comparison of SAR of 1a–f with propranolol,
shortening of propyl amine chain by two carbon atoms
did not affect the hypotensive activity to large extent.
However, a substantial enhancement of hypotensive
activity was observed in 1d when compared with pro-
pranolol or 2d. Replacing N-phenyl-piperazine with
other secondary amines resulted in decrease of hypo-
tensive activity as observed in 2a–f. Although 2e
exhibited marked hypotensive activity none of the other
analogue was as potent as the lead the compound 1d.
b
(a) -N< = morpholino
(b) -N< = piperazino
(c) -N< = N-methyl-piperazino
(d) -N< = N-phenyl-piperazino
(e) -N< = piperidino
OH
O
O
(f) -N< = pyrrolidino
N
2
Scheme 2. 4-(1-Napthoxy-2-substituted aminomethyl)-butanoic acids.
Reagents and conditions: (a) NaOEt, 150 °C, dilute HCl;(b) HN <,
(CH2O)n.
The synthesis of 1a–f and 2a–f is depicted in Schemes 1
and 2. Both 4-(2-naphthoxy)-butanoic acids 3 and 4-(1-
naphthoxy)-butanoic acids 4 were first prepared by
Cagniant and Charaux13 in moderate yields from cor-
responding naphthol in two steps. Our improved
procedure consists of one step regioselective synthesis of
4-naphthoxy-butanoic acids 3 and 4 in excellent yields.
The synthetic approach to 3 involved condensation of 2-
naphtol with c-butyrolactone in presence of NaOEt and
anhydrous EtOH. Compound 4 was prepared analo-
gously to 3 from 1-naphthol according to procedure of
Tandon et al.14 The substituted butanoic acids 3 on
reaction with secondary amines and p-formaldehyde in
absolute EtOH underwent Mannich reaction resulting in
the formation of 2-substituted aminomethyloxy naph-
thalenes 1a–f15 (Scheme 1, Table 2). The substituted
butanoic acids 4 on reaction with secondary amines and
para-formaldehyde under similar reaction conditions,
resulted in the formation of corresponding 4-(1-napht-
oxy-2-substituted aminomethyl)-butanoic acids 2a–f in
good yield16 (Scheme 2, Table 3).
We envisaged the formation of 4-(2-napthoxy-2-substi-
tuted aminomethyl)-butanoic acids 517 by Mannich
reaction of 4-(2-naphthoxy)-butanoic acid 3 with sec-
ondary amines and para-formaldehyde. The formation
of 2-substituted aminomethyloxy naphthalenes 1 may be
explained by conversion of acid 3 into 2-naphthol and
OH
+
O
a
O
O
OH
3
O
b
(a) -N< = morpholino
(b) -N< = piperazino
(c) -N< = N-methyl-piperazino
(d) -N< = N-phenyl-piperazino
(e) -N< = piperidino
Table 2. Synthetic data for compounds 1a–f
Compounds
–N<
Mp (°C)
% Yield
O
1a
1b
1c
1d
1e
1f
Morpholino
Piperazino
116
94
92
90
89
90
92
76
N
(f)
-N< = pyrrolidino
N-methyl-piperazino
N-phenyl-piperazino
Piperidino
141
158
149
128
1
Scheme 1. 2-Substituted aminomethyloxy naphthalenes 1. Reagents
and conditions: (a) NaOEt, 150 °C, dilute HCl;(b) HN <, (CH2O)n.
Pyrrolidino

V.K.Tandon et al./ Bioorg.Med.Chem.Lett.14 (2004) 2797–2800
2799
Table 3. Synthetic data for compounds 2a–f
7. Rastogi, S. N.;Anand, N.;Prasad, C. R. J.Med.Chem.
1972, 15, 286.
8. Rastogi, S. N.;Anand, N.;Gupta, P. P.;Sharma, J. N. J.
Med.Chem. 1973, 16, 797.
9. Gupta, R. C.;Mukerji, S.;Chatterjee, S. K.;Rasotgi, S.
N.;Anand, N.;Dube, M. P.;Sur, R. N.;Mukerji, K. C.;
Srimal, R. C. Arzneim.Forsch. 1978, 28, 241.
10. Crowther, A. F.;Smith, L. H. J.Med.Chem. 1968, 11,
1009.
Compounds
–N<
Mp (°C)
% Yield
2a
2b
2c
2d
2e
2f
Morpholino
Piperazino
178
119
188
192
171
168
85
84
90
84
82
87
N-methyl-piperazino
N-phenyl-piperazino
Piperidino
Pyrrolidino
11. Hoffman, B. B.;Lefkowitz, R. J. In The Pharmacological
Basis of Therapeutics, 9th ed.;Goodman, Gilman, Eds.;
McGraw-Hill: USA, 1996;pp 232–233.
12. The hypotensive activity was carried out in the pharma-
cology division of Central Drug Research Institute,
Lucknow, India Pharmacology: Cats (2.5–4.0 kg) were
anaesthetized with pentobarbitone sodium (35.0 mg/kg ip)
and their blood pressure (BP) was recorded from a
carotidartery. The arterial vase was cannulated with a
polyethylene catheter, filled with sodium citrate (5%) as
anticoagulant and connected to a Hg-manometer. The
trachea was intubated and respiration was recorded
through a Marey’s tambour. BP and respiration were
recorded on a kymograph. The left femoral vein was
cannulated with a polyethylene tube for injection of drugs
and test compound. Contractions of the nictitating mem-
brane due to electrical stimulation of preganglionic
sympathetic nerve (50 Hz, 1 ms, 5–10 V for 5–101 s) were
recorded through a system of pulleys and frontal wending
lever on the kymograp. Responses of intravenous adren-
aline (2–4 lg), acetylcholine (1–2 lg), histamine (1–2 lg)
and isoprenaline (0.1 lg) on the BP were recorded before
and after the administration of 1 and 5 mg/kg iv dose of
the test compound. SE was calculated on the basis of three
to four experiments carried out for each of the compounds
reported in Table 1.
13. Cagniant, P.;Charaux, C. Bull.Soc.Chim. 1966, 10, 3249.
14. (a) Tandon, V. K.;Chandra, A.;Khanna, J. M.;Anand,
N. Tetrahedron 1990, 46, 2871;(b) Tandon, V. K.;Chhor,
R. B.;Goswamy, G. K. Ind.J.Chem. 1998, 37B, 1027.
15. General procedure for the preparation of 2-substituted
aminomethyloxy naphthalenes 1: A mixture of 4-(2-
naphthoxy) butanoic acid 3 (2.30 g, 10 mmol), 2°-amine
(10 mmol) and para-formaldehyde (0.45 g, 15 mmol) in
anhydrous ethanol (20 mL) containing two to three drops
of concentrated HCl was refluxed for 3 h. The mixture was
cooled and additional quantities of 2°-amine (10 mmol)
and para-formaldehyde (0.45 g, 15 mmol) were added and
the mixture refluxed further for 2 h. Solvent ethanol was
distilled off in vacuo and the residue was dissolved in water
(20 mL) and extracted with diethylether (3 ꢁ 30 mL).
NaOH (20 mL) and the product thus separated was
extracted with diethylether (3 ꢁ 30 mL). The ether portion
washed with brine, dried over MgSO4, filtered and the
filtrate concentrated to distill off solvent ether. Com-
pounds 1(a–f) were obtained as solids and were crystal-
lized with ethanol, for example, 2-(N4-phenyl-N1
piperazino)-methyloxy naphthalene (1d) yield 90%;mp
158 °C;IR 2835, 1605 and 1575 cm ꢂ1; 1H NMR: d 2.24 (m,
4H, –N(CH2)2), 3.09 (m, 4H, Ph–N(CH2)2), 4.07 (s, 2H,
OCH2), 6.75–7.80 (m, 12H, phenyl and naphth-H); 13C
NMR: d 51.7, 57.9, 85.1, 105.8, 113.1, 118.0, 118.8, 123.7,
126.4, 126.8, 127.7, 129.4, 129.5, 134.6, 144.5, 157.7;MS:
m=z 318 [Mþ]. Anal. Calcd for C21H22N2O (318): C 79.24,
H 6.91, N 8.80. Found C 79.20, H 7.0, N 8.84.
O
OH
a, b
N
1
(a) -N< = morpholino
(b) -N< = piperazino
(d) -N< = N-phenyl-piperazino
(e) -N< = piperidino
(c) -N< = N-methyl-piperazino (f) -N< = pyrrolidino
Scheme 3. 2-Substituted aminomethyloxy naphthalenes 1. Reagents
and conditions: (a) NaOEt, 150 °C, dilute HCl;(b) HN <, (CH2O)n.
further reaction of 2-naphthol with para-formaldehyde
and secondary amines.
2-Substituted aminomethyloxy naphthalenes 1 have
alternatively been synthesized by reaction of 2-naphthol
with p-formaldehyde and secondary amines in support
of mechanism of formation of these compounds from 3
by Mannich reaction18 (Scheme 3).
In conclusion we have synthesized 2-substituted naph-
thalenes as hypotensive agents. Compound 1d having
better hypotensive profile than propranolol is being
further investigated for drug development.
Acknowledgements
The authors are thankful to the regional sophisticated
instrumentation centre, CDRI, Lucknow for elemental
analysis, spectral data and pharmacological activity.
This work was supported by a research grant from
University Grants Commission of India.
References and notes
1. Botta, B.;Caringnani, M.;Volpe, A. R.;Botta, M.;
Corelli, F.;Delle Monache, G. Curr.Med.Chem. 2003, 10,
1845.
2. Walker, A. F.;Marakis, G.;Morris, A. P.;Robinson, P.
A. Phytother.Res. 2002, 16, 48.
3. Gryglas, P. Pol.Arch.Med.Wewn. 2001, 105, 109.
4. Mettimano, M.;Pichetti, F.;Fazzari, L.;Migneco, A.;
Specchia, L.;Spica, V. R.;Savi, L. Int.J.Clin.Pract. 2000,
54, 424.
5. Hwang, S. K.;Juhasz, A.;Yoon, S. H.;Bodor, N. J.Med.
Chem. 2000, 43, 1525.
6. Schann, S.;Bruban, V.;Pompermayer, K.;Feldman, J.;
Pfeiffer, B.;Renard, P.;Scalbert, E.;Bousquet, P.;
Ehrhardt, J. D. J.Med.Chem. 2001, 44, 1588.
16. General procedure for the preparation of 4-(1-naphthoxy-
2 substituted aminomethyl)-butanoic acids 2: A mixture of
4-(1-napthoxy)-butanoic acid 4 (2.30 g, 10 mmol), 2°-
amine and para-formaldehyde (0.45 g, 15 mmol) in anhy-
drous EtOH (20 mL) containing two to three drops of

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V.K.Tandon et al./ Bioorg.Med.Chem.Lett.14 (2004) 2797–2800
concentrated HCl was refluxed for 3 h. The general
18. An alternative procedure for the preparation of 2-substi-
tuted aminomethyloxy naphthalenes 1: 2-Naphthol
(1.44 g, 10 mmol) was added to NaOEt (prepared from
0.25 g Na and 5 mL anhydrous EtOH). After the
temperature of the solution dropped to 25 °C (room
temperature);a mixture of 2 °-amine (10 mmol) and para-
formaldehyde (0.45 g, 15 mmol) in anhydrous ethanol
(20 mL) containing two to three drops of concentrated
HCl was refluxed for 3 h. The mixture was cooled and
additional quantities of 2°-amine (10 mmol) and para-
formaldehyde (0.45 g, 15 mmol) were added and the
mixture refluxed further for 2 h. Solvent ethanol was
distilled off in vacuo and the residue was dissolved in water
(20 mL) and extracted with diethylether (3 ꢁ 30 mL).
NaOH (20 mL) and the product thus separated was
extracted with diethylether (3 ꢁ 30 mL). The ether portion
washed with brine, dried over MgSO4, filtered and the
filtrate concentrated to distill off solvent ether. Compound
1a–f were obtained as solids in 75–90% yields. The
analytical data of 1a–f were identical to those obtained
by general procedure reported for synthesis of 1 in Ref. 15.
procedure adopted for compounds 1 was followed for
synthesis of 2(a–f). The products 2(a–f) were crystallized
from EtOH, for example, 4-(1-naphthoxy)-2-[methyl-(N4-
phenyl-N1-piperazino)]-butanoic acid (2d) yield 84%;mp
192 °C;IR 3400 (OH) and 1712 (C @O) cmꢂ1; 1H NMR: d
1.86–2.38 (m, 4H, 2 ꢁ CH2), 2.66 (m, 1H, CH), 4.02 (t, 2H,
J ¼ 7:05 Hz, –OCH2), 6.74–8.48 (m, 13H, Ar–H and
COOH); 13C NMR: d 27.8, 40.7, 53.1, 55.4, 57.9, 69.6,
103.6, 113.0, 118.0, 120.1, 121.9, 125.0, 125.5, 125.7, 126.2,
127.3, 129.4, 134.0, 144.5, 155.3, 179.5;MS: m=z 404 [Mþ].
Anal. Calcd for C25H28N2O3 (404): C 74.25, H 6.93, N
6.93. Found C 74.02, H 6.86, N 7.01.
17. Proposed structure of 5.
O
OH
N
O
5