Potential hypotensive agents: Synthesis and hypotensive activity of oxime ethers derived from 1-naphthoxepines and related compounds

Article abstract of DOI:10.1016/j.bmcl.2004.04.009

The synthesis and pharmacological evaluation of substituted oximino-ethers 1 and 2 of naphth[1,2-b]- and naphth[2,1-b]-oxepin-5-ones (4 and 8) were carried out. The hypotensive activity of oximino-ethers 1 and 2 was evaluated on anaesthetized cats. The results indicated that 1c caused a fall of 80mm/Hg for >100′ at a dose of 5mg/kg iv in anaesthetized cats.

Full text of DOI:10.1016/j.bmcl.2004.04.009

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3177–3180
Potential hypotensive agents: synthesis and hypotensive activity of
oxime ethers derived from 1-naphthoxepines and related compounds
*
Vishnu K. Tandon, Manoj Kumar, Anoop K. Awasthi, Hari O. Saxena
and Gajendra K. Goswamy
Department of Chemistry, University of Lucknow, Lucknow-226007, India
Received 17 January 2004; accepted 2 April 2004
Abstract—The synthesis and pharmacological evaluation of substituted oximino-ethers 1 and 2 of naphth[1,2-b]- and naphth[2,1-b]-
oxepin-5-ones (4 and 8) were carried out. The hypotensive activity of oximino-ethers 1 and 2 was evaluated on anaesthetized cats.
0
The results indicated that 1c caused a fall of 80 mm/Hg for >100 at a dose of 5 mg/kg ivin anaesthetized cats.
Ó 2004 Elsevier Ltd. All rights reserved.
Hypertension, the most common cardiovascular disease,
is a major risk factor in cardiovascular mortality.
Enormous efforts have been made during last three
decades in the development of new antihypertensive
agents. The b-adrenergic receptor antagonists as
antihypertensive drugs led to the development of selec-
OH
OH
NHR
O
NHR
R1
R1
II
I
1;2
tive b - and b -adrenoceptor blocking agents. The
1
2
structure activity relationship of two well-identified
classes: (i) 1-phenyl-2-aminoethanols I and (ii) 1-aryl-
oxy-3-aminopropanols II as b-blocking agents have
been studied. Most of the b-blocking drugs presently
belong to type II and are in clinical use. In an effort to
CH3
N
CH3 . HCl
O
N
H
CH3
OH
III
understand the role of ArOCH in b-blockers belonging
to class II led to the emergence of oxime ethers as
3
Figure 1. (I) 1-Phenyl-2-aminoethanols; (II) 1-aryloxy-3-amino-
2-prapanolols; (III) IPS-339.
2
selective b
2
-blockers (Fig. 1). The b
2
-selective adrener-
4
gic blocking activity of III (IPS-339) has met with
7
5;6
oximes and the oxime ethers can be prepared by nucleo-
philic substitution with various nucleophiles, a number
of oxime ethers 1 and 2 of naphth[1,2-b]-oxepin-5-ones 4
extensive exploration of oxime ethers. Martani et al.
8
and Ferrarini et al. have also reported b-adrenergic
activity of some aromatic oxime ethers.
and naphth[2,1-b]-oxepin-5-ones
maintaining the oxime ether chain present in IPS-339
8
were prepared
A number of recent publications have described the
9–11
(III, Fig. 1).
discovery and characterization of the biological,
14;15
12;13
microbiological
of novel oxime ethers.
and pharmacological
properties
The hypotensive activity of oxime ethers 1 and 2 has
been compared with the hypotensive drug propranolol
IV, Fig. 2). These results are summarized in Table 1.
16
(
To potentially further increase the usefulness of oxime
ethers, the possibility of preparing oxime ethers 1 and 2
were investigated. Since ketones are easily converted to
Substitution of R with n-propyl, iso-propyl and tert-
butyl in 1a–c caused significant fall of blood pressure in
cats at dose of 5 mg/kg iv. Replacement of R by n-propyl
group (1a) caused a fall of blood pressure (BP) of 60 mm
of Hg for 11 min whereas replacement of R by iso-pro-
pyl resulted in considerable fall of BP that is 110 mm of
Hg for 35 min. Replacement of R by tert-butyl resulted
*
0
Corresponding author. Fax: +91-522-2326665; e-mail: vishnutandon@
rediffmail.com
960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.009

3178
V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3177–3180
CH3
CH3
The substitution of R with n-propyl, iso-propyl and tert-
O
N
H
butyl in oxime ether 2 resulted in substantial fall of BP
as reported in Table 1. It is interesting to note that
maximum effect of fall of BP and its duration was
observed in tert-butyl analogue.
OH
IV
OH
RHN
O
The comparison of oxime ethers 1 and 2 for their
hypotensive activity leads to conclusion that oxime
ethers 1 were more active hypotensive compounds.
Although 1c, the lead compound has shown the profile
of a potent hypotensive agent, 1b has also comparable
hypotensive activity. In parallel experiment propranolol
exhibited 50 mm of Hg fall for >60 min at an intrave-
nous dose of 5 mg/kg in anaesthetized cats.
N
O
OH
O
O
NHR
N
1
2
Figure 2. (IV) Propranolol; (1) 1a–c; (2) 2a–c.
in 80 mm of Hg fall of BP for >100 min at a dose of
mg/kg iv. This compound 1c also caused 60 mm of Hg
fall of BP for 75 min at a dose of 1 mg/kg iv. Based on
the hypotensive activity observed for series of oxime
ethers 1a–c, the lead compound 1c was found to be more
potent than propranolol (IV, Fig. 2).
The syntheses of oxime ethers 1a–c and 2a–c are shown
in Schemes 1 and 2, respectively. In Schemes 1 and 2, a
two-step regioselective synthesis of naphth[1,2-b]-oxe-
pin-5-one 4 and naphth[2,1-b]-oxepin-5-one 8 is de-
picted. The synthesis of 4 and 8 was achieved from
1- and 2-naphthols, respectively, by first conversion of
5
Table 1. Summary of hypotensive activity of compounds 1 and 2
Compound
Cat
1
mg/kg iv5 mg/kg iv
Fall of BP mmHg
% of maximum effect m ± SE
Fall of BP mmHg
% of maximum effect m ± SE
0
0
0
0
0
1
1
1
2
2
2
a
b
c
a
b
c
20 (2 )
20 (2 )
21 ± 2
14 ± 2
40 ± 4
17 ± 2
7 ± 1
60 (11 )
110 (35 )
80 (>100 )
50 ± 5
88 ± 8
55 ± 5
17 ± 2
70 ± 7
41 ± 4
41 ± 4
0
0
60 (75 )
18 (2 )
0
16 (2 )
80 (16 )
50 (>35 )
0
0
10 (2 )
18 (2 )
0
0
0
0
21 ± 2
35 ± 3
Propranolol
46 (40 )
50 (>60 )
OH
O
O
(
a)
O
OH
(b)
O
+
O
O
4
3
(
c)
O
O
O
O
(d)
NOH
N
6
5
(
e)
O
OH
a. n-propyl
b. iso-propyl
c. t-butyl
O
NHR
N
R =
1
Scheme 1. Synthesis of 1a–c. Reagents and conditions: (a) NaOEt, 150 °C, dil HCl; (b) PPA, 100 °C; (c) NH
2
OHÆHCl; (d) epichlorohydrin, DMF;
(e) RNH , benzene.
2

V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3177–3180
3179
O
O
HON
OH
+
OH
(
a)
O
(b)
O
(c)
O
O
O
8
9
7
(
d)
O
OH
O
N
RHN
O
N
(
e)
O
a. n-propyl
b. iso-propyl
c. t-butyl
O
R =
10
2
Scheme 2. Synthesis of 2a–c. Reagents and conditions: (a) NaOEt, 150 °C, dil HCl; (b) PCl
DMF; (e) RNH , benzene.
5
3 2
, AlCl , benzene; (c) NH OHÆHCl; (d) epichlorohydrin,
2
Table 2. Substituted 5-[(3-alkyl amino-2-hydroxypropyl)oximino]-2,3,4,5-tetrahydronaphth[1,2-b]-oxepines 1 and 5-[(3-alkyl amino-2-hydroxyprop-
yl)oximino]-2,3,4,5-tetrahydronaphth[2,1-b]-oxepines 2
Compound
R
Free base/hydrochloride
Yield (%)
Mp (°C)
a
1a
1b
1c
2a
2b
2c
n-Propyl
iso-Propyl
tert-Butyl
n-Propyl
iso-Propyl
tert-Butyl
Hydrochloride
b
82
84
90
82
78
88
188
68
Free base
Hydrochloride
a
175
163
174
183
a
Hydrochloride
Hydrochloride
a
a
Hydrochloride
a
Recrystallized from anhydrous ethanol–ether.
Hydrochloride could not be isolated due to hygroscopic nature.
b
naphthols into naphthoxy butyrates and subsequent
hydrolysis to the corresponding acids 3 and 7, respec-
tively. The compound 3 on cyclization with PPA gave
ketone 4 whereas regioselective cyclization of 7 was
analytical and pharmacological data. One of the authors
G.K.G. is grateful to University Grants Commission for
award of fellowship.
17
accomplished with PCl
of ketone 8 analogous to the procedure reported by
Tandon and co-workers.
5 3
and AlCl leading to formation
17;18
References and notes
1
. Bisi, A.; Rampa, A.; Budreisi, R.; Gobbi, S.; Belluti, F.;
Loan, P.; Valoti, E.; Chiarini, A.; Valenti, P. Bioorg. Med.
Chem. 2003, 11, 1353.
Oxime ethers 1 and 2 were prepared from 5-oximino-
naphth[1,2-b]-oxepine 5 and 5-oximino-naphth[2,1-b]-
oxepine 9, respectively. Oximes 5 and 9 were prepared
from ketones 4 and 8, respectively, by reaction with
19
2
3
. McGavin, J. K.; Keating, G. M. Drugs 2002, 62, 2677.
. Leclerc, G.; Mann, A.; Wermuth, C. G.; Bieth, N.;
Schwartz, J. J. Med. Chem. 1977, 20, 1657.
. Imbs, J. L.; Miesch, F.; Schwartz, J.; Velly, J.; Leclerc, G.;
Mann, A.; Wermuth, C. G. Brit. J. Pharmacol. 1977, 60,
357.
1
2
equivof NH OHÆHCl in ethanolic NaOH. The sodium
salts of oximes 5 and 9 were reacted with epichlorohydrin
in anhydrous DMF to form epoxides 6 and 10, respec-
tively. The epoxides 6 and 10 on heating with aliphatic
primary amines in benzene afforded oxime ethers 1 and 2,
respectively (Table 2). The hydrochloride salts of 1 and 2
were prepared for pharmacological evaluation.
4
5. Leclerc, G.; Amlaiky, N.; Rouot, B. Eur. J. Med. Chem.
982, 17, 69.
1
6
7
8
. Rakhit, S.; Bouzoubaa, M.; Leclerc, G.; Leger, J. M.;
Carpy, A. Eur. J. Med. Chem. 1986, 21, 411.
. Martani, A.; Magli, M.; Orzalesi, G.; Selleri, R. Farmaco
Ed. Sci. 1975, 30, 370.
. Ferrarini, P. L.; Mori, C.; Primofiore, G.; Da Settimo, A.;
Breschi, M. C.; Martinotti, E.; Nieri, P.; Ciucci, M. A.
Eur. J. Med. Chem. 1990, 25, 489.
In conclusion we have described the synthesis and
hypotensive activity of new series of oxime ether 1 and 2.
Compounds 1b and 1c have shown promising hypo-
tensive activity. Compound 1c is being further evaluated
for future drug development.
9. Watson, K. G.; Brown, R. N.; Cameron, R.; Chalmers, O.
K.; Hamilton, S.; Jin, B.; Krippner, G. Y.; Luttick, A.;
McConnell, D. B.; Reece, P. A.; Ryan, J.; Stanislawski,
P. C.; Tucker, S. P.; Wu, W. Y.; Barnard, D. L.; Sidwell,
R. W. J. Med. Chem. 2003, 46, 3181.
Acknowledgements
We are grateful to the RSIC and Pharmacology division
of Central Drug Research Institute, Lucknow, India for
10. Metodiewa, D.; Koceva-Chyla, A.; Kochma, A.; Skoli-
mowski, J.; Jozwiak, J. Anticancer Res. 1999, 19, 1255.

3180
V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3177–3180
1
1
1. Metodiewa, D.; Koceva-Chyla, A.; Kochma, A.; Skoli-
19. General procedure for preparation of 1a–c and 2a–c.
Compound 6 or 10 (1.42 g, 5 mmol) was dissolved in
benzene (10 mL) and amine (a–c) (5 mmol) was added to
the solution. The mixture was heated for 12 h in a steel
bomb at 150 °C. The solution was cooled and the solvent
was removed in vacuo. The oil thus obtained was dissolved
in anhydrous ether and ethereal hydrochloric acid solution
added. The precipitated hydrochloride was filtered and
mowski, J.; Jozwiak, J. Anticancer Res. 1999, 19, 1249.
2. Rossello, A.; Bertini, S.; Lapucci, A.; Macchia, M.;
Martinelli, A.; Rapposelli, S.; Herreros, E.; Macchia, B.
J. Med. Chem. 2002, 45, 4903.
1
3. Papadaki-Valiraki, A.; Papakonstantinou-Garofalias, S.;
Marakos, P.; Chytyroglou-Lada, A.; Hosoya, M.;
Balzarini, J.; de Clercq, E. Farmaco 1993, 48, 1091.
4. Venhuis, B. J.; Dijkstra, D.; Wustrow, D.; Meltzer, L. T.;
Wise, L. D.; Johnson, S. J.; Wikstrom, H. V. J. Med.
Chem. 2003, 46, 4136.
1
2
crystallized from anhydrous EtOH and Et O to give 1a–c
or 2a–c. For example; 5-[(3-tert-butylamino-2-hydroxy-
propyl)oximino]-2,3,4,5-tetrahydronaphth-[1,2-b]-oxepineÆ
HCl (1c). Yield 90%; mp 175 °C; IR (KBr): m 3200–
1
1
5. El-Hadri, A.; Nicolle, E.; Leclerc, G. Pharmazie 2003, 58, 13.
6. The hypotensive activity of oxime ether 1 and 2 was carried
out in the pharmacology division of Central Drug Research
Institute, Lucknow, India. Cats (2.5–4.0 kg) were anaesthe-
tized with pentobarbitone sodium (35.0 mg/kg ip) and their
blood pressure (BP) was recorded from a carotid artery.
7. Tandon, V. K.; Chhor, R. B.; Goswamy, G. K. Ind. J.
Chem. 1998, 37B, 1027.
À1
þ
3500 cm (OH and NH); MS m=z (free base): 356 (M ).
1
H NMR (400 MHz, CCl
(m, 2H, C -H), 2.02 (bh, 2H, CHOH and NH), 2.72 (m,
3H, C -H and NCH ), 3.54–3.68 (m, 3H, OCH and
CHOH), 3.94 (t, 2H, J ¼ 7:05 Hz, C -H), 6.88–7.87 (m,
4
5H, naphth-H), 8.17 (m, 1H, naphth H). C NMR (CCl ,
4 3 3
, d): 1.42 (s, 9H, (CH ) C), 1.93
3
4
2
2
2
1
3
1
1
d): 25.92, 31.30, 37.84, 48.30, 72.70, 73.20, 76.52, 106.30,
120.20, 121.90, 125.00, 125.60, 126.22, 127.32, 136.70,
155.82, 164.60. Anal. Calcd for C21H N O (356): C,
28 2 3
70.78; H, 7.86; N, 7.86. Found: C, 70.92; H, 7.66; N, 7.92.
8. (a) Tandon, V. K.; Khanna, J. M.; Chandra, A.; Anand,
N. Tetrahedron 1990, 46, 2871; (b) Huckle, D.; Lockhart,
I. M.; Webb, N. E. J. Chem. Soc. 1971, 2252.