O-[2-Hydroxy-3-(dialkylamino)propyl]ethers of (+)-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one oxime (camphor oxime) with analgesic and antiarrhythmic activities

Article abstract of DOI:10.1016/S0014-827X(00)00065-3

A novel series of O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-camphor oxime was prepared and tested for its cardiovascular, analgesic and anti-inflammatory properties. No significant anti-inflammatory and hypotensive activities were displayed by any of the compounds, whereas several of them are reasonably active as antiarrhythmic and analgesic agents. (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(00)00065-3

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 495–498
Short Communication
O-[2-Hydroxy-3-(dialkylamino)propyl]ethers of (+)-1,7,7-trimethyl
bicyclo[2.2.1]heptan-2-one oxime (camphor oxime) with analgesic
and antiarrhythmic activities
a,
a
a
a
Silvia Schenone *, Olga Bruno , Angelo Ranise , Francesco Bondavalli ,
b
b
b
Walter Filippelli , Giuseppe Falcone , Barbara Rinaldi
a
Dipartimento di Scienze Farmaceutiche dell’Uni6ersit a` , Viale Benedetto XV 3, I-16132 Genoa, Italy
b
Istituto di Farmacologia e Tossicologia, Facolt a` di Medicina e Chirurgia, II Uni6ersit a` degli Studi, Via S. Andrea delle Dame 8,
I-80138 Naples, Italy
Received 28 March 2000; accepted 12 June 2000
Abstract
A novel series of O-[2-hydroxy-3-(dialkylamino)propyl]ethers of (+)-camphor oxime was prepared and tested for its
cardiovascular, analgesic and anti-inflammatory properties. No significant anti-inflammatory and hypotensive activities were
displayed by any of the compounds, whereas several of them are reasonably active as antiarrhythmic and analgesic agents. © 2000
Elsevier Science S.A. All rights reserved.
Keywords: v-Dialkylaminohydroxy ethers of (+)-camphor oxime; Analgesic agents; Antiarrhythmic agents
1
. Introduction
istic b-blocking chain on the oxime function in order to
evaluate their potential as cardiovascular agents.
Accordingly we planned the synthesis of compounds
In earlier communications a variety of aminoethers of
2
to be tested in a preliminary screening.
cyclanone-oximes have been reported to possess interest-
ing pharmacological properties [1–3]. Even recently a
number of tricyclic ketoxime esters and ethers have been
described as showing local anaesthetic and analgesic
activities [4]. Among them in particular a series of
v-dialkylamino alkylethers of (+)-camphor oxime 1 was
recognized to be endowed, inter alia, with hypotensive,
antiarrhythmic and analgesic properties.
2
. Chemistry
The synthetic procedure is outlined in Scheme 1.
Camphor oxime [4] sodium salt was treated with
epichlorohydrin and the resulting epoxy-ether 3 was
reacted with the proper alkyl/dialkylamine to give the
target compounds 2a–2h in good yields.
It seems worthwhile to us to further investigate deriva-
tives in the bornane series by introducing the character-
3
. Pharmacology
Compounds 2a–2h were submitted to a preliminary
*
Corresponding author. Tel.: +39-010-353 8866; fax: +39-010-
3
0
53 8358.
screening for anti-inflammatory, analgesic, antiarrhyth-
mic and hypotensive activities.
E-mail address: schensil@unige.it (S. Schenone).
014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00065-3

4
96
S. Schenone et al. / Il Farmaco 55 (2000) 495–498
4. Experimental
a solution of the appropriate primary or secondary
amine (11 mmol) in the same solvent (10 ml). The
resulting solution was heated at reflux for 12 h and
evaporated under reduced pressure.
4.1. Chemistry
Melting points were determined with a Buchi 530
The residue was treated with 1 M HCl (20 ml) and
the solution was extracted twice with diethyl ether. The
acid solution was basified with 4 M NaOH and ex-
tracted with diethyl ether. The organic extracts were
apparatus. IR spectra were measured in KBr with a
1
Perkin–Elmer 398 spectrophotometer. H NMR spec-
tra were recorded in CDCl3 solution on a Hitachi
Perkin–Elmer R-600 (60 MHz) and on a Varian Gem-
ini 200 instrument; chemical shifts were reported as l
ppm) relative to TMS as internal standard; J is re-
ported in Hz. Analyses for C, H, N were within 90.3%
dried (an. MgSO ) and evaporated under reduced pres-
4
sure to give viscous oils which were distilled in vacuo
(only the solid compound 2h was crystallized from
absolute ethanol) (Table 1). To obtain correct values of
elemental analysis, the free bases were transformed into
the corresponding hydrochlorides with a saturated hy-
drogen chloride ether solution and purified by crystal-
lization from absolute ethanol:an. diethyl ether (1:1).
(
of the theoretical values.
4
3
.1.1. General procedure for O-glycidyl camphor oxime
A 60% sodium hydride dispersion in mineral oil (0.44
g, 11 mmol) was added to a solution of (+)-camphor
oxime (1.38 g, 10 mmol) in anhydrous DMF (10 ml).
The resulting mixture was heated with stirring at 60°C
for 1 h and cooled. A solution of epichlorohydrin (1.02
g, 11 mmol) in anhydrous DMF (10 ml) was added, the
mixture was stirred for 1 h at room temperature, and
poured into water (100 ml). The solution was extracted
thoroughly with chloroform, the extracts were washed
4
.2. Pharmacology
Anti-inflammatory activity was evaluated by car-
rageenan-induced paw edema in rats [5]; analgesic ac-
tivity was evaluated by the acetic acid writhing test in
mice [6]; antiarrhythmic activity was evaluated as pro-
tection index against ecgraphic effects from aconitine in
rats [7] and hypotensive activity, evaluated by oral
administration in conscious rats [8].
twice with water, dried (an. MgSO ) and evaporated
4
under reduced pressure to afford a liquid which was
distilled in vacuo.
3
: Yield 72%; viscous colourless liquid, bp 110–
−
1 1
1
15°C (0.2 mmHg). IR (CHCl ): 1660 (CꢀN) cm . H
5. Results and discussion
3
NMR (200 MHz): l 0.75, 0.89 and 0.96 (3s, 9H, 3CH3),
.10–2.10 (multiplets, 6H, 3CH ), 2.40–2.55 (2m, 1H,
1
The tested compounds 2a–2h showed no significant
anti-inflammatory activity and a very weak hypotensive
activity (data not reported). This last result is in con-
trast with earlier findings for congeners 1 and with the
structural features of b-blocking agents.
2
CH), 2.55–2.62 (2d, 1H of CH O epox) and 2.75–2.80
2
(
near t, 1H of CH O epox), 3.15–3.25 (m, 1H, CHO),
2
3
.87–4.00 (2dd, 1H of CH ON) and 4.13–4.25 (2d, 1H
2
of CH ON). Anal. C H NO (C, H, N).
2
13 21
2
However, a certain degree of cardiovascular action is
retained because a good level of antiarrhythmic activity
is present in several derivatives and in particular in 2h
having an ED50 of 44.31 (6.61–296.98) mg/kg i.v.
(Table 2).
4
.1.2. General procedure for O-[2-hydroxy-3-
(
dialkylamino)propyl]ethers of camphor oxime 2a–2h
A solution of the camphor oxime glycidyl ether 3
2.23 g, 10 mmol) in 95% ethanol (10 ml) was added to
(
Scheme 1.

S. Schenone et al. / Il Farmaco 55 (2000) 495–498
497
Table 1
Yields, physical and spectroscopic data of compounds 2a–2h
a
Comp. B.p. (°C
mmHg))
Yield (%)
1H NMR l (ppm)
Formula
(C, H, N)
(
2
2
2
2
2
2
2
2
a
b
c
d
e
f
155–160 (0.2)
160–165 (0.2)
145–150 (0.2)
170–175 (0.3)
160–165 (0.3)
155–160 (0.3)
m.p. 97–98
87
75
75
76
80
68
45
65
0.81, 0.92 and 1.02 (3s, 9H, 3CH ), 1.03 (t, J=6.6, 6H, 2CH Et), 1.35–2.02
C17H32N O2
3
3
2
(
(
m, 6H, 3CH ), 2.14 (near s, 1H, CH), 2.30–2.85 (m, 6H, 3CH N), 3.45–3.70
2
2
m, 1H, OH, disappears with D O), 3.90–4.21 (m, 3H, CHO+CH O)
2
2
0.79, 0.92 and 1.00 (3s, 9H, 3CH ), 1.06 (d, J=7.2, 6H, 2CH isopr.)
C16H30N O2
3
3
2
1
.35–2.01 (m, 6H, 3CH ), 2.11 (near s, 1H, CH), 2.28–3.11 (m, 3H,
2
CHN+CH N), 3.80–4.20 (m, 3H, CHO+CH O), NH and OH not detectable
2
2
0.80, 0.91 and 1.00 (3s, 9H, 3CH ), 1.15–2.02 (m, 10H, 5CH ), 2.15 (near s,
C17H30N O2
3
2
2
1
H, CH), 2.25–2.80 (m, 6H, 3CH N), 3.40–3.60 (m, 1H, OH, disappears with
2
D O), 3.90–4.20 (m, 3H, CHO+CH O)
2
2
0.80, 0.92 and 1.00 (3s, 9H, 3CH ), 1.15–2.05 (m, 12H, 6CH ), 2.15 (near s,
C18H32N O2
3
2
2
1
H, CH), 2.25–2.80 (m, 6H, 3CH N), 3.90–4.20 (m, 3H, CHO+CH O), 4.68
2
2
(
near s, 1H, OH, disappears with D O)
2
0.80, 0.92 and 1.00 (3s, 9H, 3CH ), 1.10–2.00 (m, 6H, 3CH ), 2.11 (near s,
C17H30N O3
3
2
2
1
H, CH), 2.20–2.80 (m, 6H, 3CH N), 3.20–3.50 (m, 1H, OH, disappears with
2
D O), 3.60–3.80 (m, 4H, 2CH O morph.), 3.90–4.20 (m, 3H, CHO+CH O)
2
2
2
0.80, 0.92 and 1.00 (3s, 9H, 3CH ), 1.12–2.00 (m, 14H, 7CH ), 2.12 (near s,
C19H34N O2
3
2
2
1
H, CH), 2.30–2.90 (m, 6H, 3CH N), 3.65–3.85 (m, 1H, OH, disappears with
2
D O), 3.95–4.20 (m, 3H, CHO+CH O)
2
2
g
h
0.80, 0.91 and 1.00 (3s, 9H, 3CH ), 1.08 (d, J=6, 6H, 2CH pip), 1.29–2.00
C20H36N O2
3
3
2
(
m, 10H, 4CH +2CH pip), 2.01 (near s, 1H, CH), 2.27–3.03 (m, 6H,
2
3
CH N), 3.70–4.14 (m, 4H, CHO+CH O+OH, 1H disappears with D O)
2 2 2
175–180 (0.3)
0.80, 0.92 and 1.01 (3s, 9H, 3CH ), 1.15 (d, J=6.6, 6H, 2CH morph),
C19H34N O3
3
3
2
1
.40–2.02 (m, 6H, 3CH ), 2.13 (near s, 1H, CH), 2.20–3.00 (m, 6H, 3CH N),
2
2
3
.40–4.30 (m, 6H, 3CHO+CH O+OH, 1H disappears with D O)
2
2
a
−1
All of 2a–2h have an O–H absorption at 3420 and a CꢀN absorption at 1660 cm
in the IR spectra.
Table 2
a
Activity against ventricular fibrillation caused by aconitine in albino rats
Comp.
Dose (mg/kg p.o.)
Appearance time (s9SE) of extrasystoles
178918.2
Death time (s9SE)
669920.6
b
Control (aconitine HCl)
Quinidine
d
d
25
50
50
50
50
50
50
50
12.5
421921.5
294926.2
981923.5
789921.3
731928.7
814922.5
d
d
2
2
2
2
2
2
2
2
a
b
c
d
e
f
c
212927.4
316923.2
233928.1
d
d
c
d
811927.1
194929.6
208923.5
239922.6
701924.2
707926.9
802925.3
c
c
g
h
189918.7
206919.3
287927.1
715922.7
806920.8
902929.1
2
5
5
0
d
d
a
b
c
Ten animals (200–250 g) per group.
5 mg/kg i.v. until death.
Statistically significant value calculated in comparison with the test performed with aconitine only (PB0.05).
Statistically significant value calculated in comparison with the test performed with aconitine only (PB0.01).
1
d
Once again the antinociceptive activity is present in
almost all compounds 2a–2h, likewise their analogues
; a maximum of activity is elicited by the piperidine
harrhytmic and analgesic features of the earlier
analogues 1 without substantial strengthening of
potency.
1
derivative 2d with an ED50 of 57.12 (38.18–85.46)
mg/kg o.s. in the acetic acid writhing test (Table 3).
In conclusion this series of terpenoid hydrox-
yaminoethers 2a–2h seems to maintain only the anti-
In any case the antinociceptive action of these cam-
phor oxime derivatives is superior to that shown by the
other carbocyclic oxime derivatives recently reported
[4].

4
98
S. Schenone et al. / Il Farmaco 55 (2000) 495–498
Table 3
Analgesic activity by acetic acid writhing test a
b
Comp.
Dose
mg/kg p.o.)
Mean number of writhes in 25 min period after treatment 9SE
46.195.7
Decrease relative to control (%)
(
Control (acetic
acid)
0.5%
Indomethacin
5
50
50
50
23.693.9
34.593.7
27.292.9
25.192.4
33.494.2
28.995.1
24.793.3
26.594.2
28.393.6
25.992.8
26.895.2
−53
−26
−41
−45
−28
−37
−48
−42
−38
−44
−42
2
2
2
2
a
b
c
d
12.5
2
5
0
5
2
2
2
2
e
f
g
h
50
50
50
50
a
Each compound was tested on a group of ten mice (20–25 g).
Mean value of five determinations.
b
droxypropyl)oximes of 1,3,3-trimethyl-5-endo-(1-piperidinyl or 4-
morpholinyl)-2-oxabicyclo[2.2.2]octan-6-ones with platelet
antiaggregating and local anaesthetic activities, Farmaco 47
1992) 1249–1262.
Acknowledgements
We thank MURST (Cofinanziamento Nazionale)
and CNR for financial grant and A. Panaro, C. Rossi
and F. Tuberoni for analytical support.
(
[
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9
-exo-(dialkylaminomethyl)-,
and
9-endo-(aralkyl)-tricy-
clo[5.2.1.02,6]decane-8-ketoxime esters and ethers with local
anaesthetic and analgesic activities, Farmaco 53 (1998) 197–208.
5] C.A. Winter, E.A. Risley, G.W. Nuss, Carrageenin-induced
edema in hind paw of the rat as an assay for anti-inflammatory
drugs, Proc. Soc. Exp. Biol. Med. 111 (1962) 544–547.
6] J.E. Davies, D.N. Kellet, J.C. Pennington, The anti-inflammatory
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