Two-step synthesis of new 1,2,4,5-tetrahydrospiro-[3H-2-benzazepine-3,4′-piperidines] from 4-iminopiperidines

Article abstract of DOI:10.1002/jhet.5570380405

New spiro[3H-2-benzazepine-3,4′-piperidines] and their precursors, N-substituted 4-allyl-4-N-benzyl-aminopiperidines, have been prepared as potential psychotic agents from readily available 4-iminopiperidines, by a sequence of reactions that included nucl

Full text of DOI:10.1002/jhet.5570380405

Jul-Aug 2001
Two-Step Synthesis of new 1,2,4,5-Tetrahydrospiro-
[3H-2-benzazepine-3,4'-piperidines] from 4-Iminopiperidines
Alirio Palma R., Sandra Salas, Vladimir Kouznetsov*, and Elena Stashenko
837
Laboratory of Fine Organic Synthesis, School of Chemistry, Industrial University of Santander,
A.A. 678, Bucaramanga, Colombia
Gisela Montenegro N. and Angel Fontela G.
Department of Pharmacology, Santiago de Compostela University, Campus Sur,
S/N, C.P. 15706, Santiago de Compostela, Spain
Received August 28, 2000
New spiro[3H-2-benzazepine-3,4'-piperidines] and their precursors, N-substituted 4-allyl-4-N-benzyl-
aminopiperidines, have been prepared as potential psychotic agents from readily available
4-iminopiperidines, by a sequence of reactions that included nucleophilic addition of Grignard reagents and
Brönsted acid-mediated intramolecular cyclisation. Some of the compounds prepared have been tested in
1
albine mice for spontaneous motor activity. All compounds prepared were characterized by ir and H nmr
spectroscopies and cg-ms spectrometry.
J. Heterocyclic Chem., 38, 837 (2001).
Introduction.
4-Iminopiperidines have received much attention owing
to their obvious use in fine organic synthesis [1]. Specially,
they are useful in design and subsequent synthesis of sev-
eral medicinal agents, containing 4-substituted or 4,4'-di-
substituted piperidine rings [2], such as the antihistaminic
azatadine and cycloheptadine [3,4], or related fentanyl
analgesics: carfentanyl and sufentanyl [5], alfentanyl [6],
and ohmefentanyl [7-10]. The latter is an extremely potent
analgesic agent with a high selectivity for the opiod µ-
receptor. Its potency was estimated to be 20000-50000
times that of morphine [11]. Moreover, many piperidine
derivatives spiroannulated at the C-4 position were also
patented [2]. Some well-established representatives of this
class of clinically useful compounds e.g., spiperone and
fluspiperone, are used as typical neuroleptics [12-14].
As a part of our continuing interest in developing bio-
logically active compounds that may act as analgesics,
which contain the piperidine ring with amine group at C-4,
[15-17], we report herein the synthesis of new tetrahy-
drospiro[3H-2-benzazepine-3,4'-piperidines], via
intramolecular cyclisation of 4-allyl-4-N-benzylamino-
piperidines prepared by nucleophilic addition of Grignard
reagents to 4-iminopiperidines. We also describe the
preparation of the above mentioned 4-N-benzylamino-
piperidines and the results of studies on some of their psy-
choactive properties.
Initially, C-allylation of the C=N bond of ketimines 1-8
was achieved immediately after their distillation with
allylmagnesium bromide, prepared from allyl bromide and
magnesium. From this reaction 4-allyl-4-N-benzyl-
aminopiperidines 9-16 were obtained as viscous oils with
high yields (Table 1). The simplicity of the procedure and
accessibility of the starting materials allowed us to prepare
these homoallylamines in large quantities.
Structural elucidation of homoallylamines 9-16 was car-
1
ried out by ir and H nmr spectroscopies and mass spec-
trometry. The ir spectra of amines 9-16 exhibited a single
Results and Discussion.
–1
sharp peak in the region 3322-3342 cm due to N-H
The starting imines 1-8 have been prepared in good
yields by condensation of the corresponding commercially
available benzylamines and N-substituted 4-piperidones as
described in the literature [18]. These ketimines were used
in the synthesis of tetrahydro-2-benzazepines C-3 spiroan-
nulated with a piperidine moiety as shown in Scheme 1.
stretching vibrations (Table 1). The fragmentation pattern
of 4,4-disubstituted N-ethylpiperidines 9-12 in the mass
spectra is different from that of related N-ben-
zylpiperidines 13-16. However, the spectra of both series
contain a low-intensity (<1%) molecular ion peak which
agree with the expected molecular mass (Table 2).

838
A. Palma R., S. Salas, V. Kouznetsov, E. Stashenko, G. Montenegro N., and A. Fontela G.
Vol. 38
1
Table 1
The H nmr spectra of substituted piperidines
-
,
9 16
Yields and some Physical and Spectral properties of the Homoallyl-
aminopiperidines 9-16 and N-substituted Tetrahydrospiro[3H-2-ben-
zazepine-3,4’-piperidines] 17-21
showed that the piperidine protons generated two groups
of multiplet signals: at 1.40-1.90 ppm for β-H and β'-H
protons, and at 2.14-2.80 ppm for α-H and α'-H protons.
The 4-allyl fragment gave rise to very characteristic
groups of signals (Table 3).
20
-1
No
B.p., °C/mm Hg
n
Yield, (%)
IR, cm ; ν
NH
9
10
11
12
13
14
15
16
17
18
19
20
21
165-181/10
171-175/10
180-188/10
196-207/10
165-185/10
195-208/10
[a]
1.527
1.525
1.524
1.536
1.554
1.543
1.568
1.562
1.537
1.541
1.539
1.568
--
61
60
39
47
51
32
57
89
82
90
55
54
43
3322
3339
3325
3327
3342
3326
3325
3322
3306
3315
3320
3318
3446,
Subsequent intramolecular cationic allyl cyclisation of
the homoallylamines
and
was readily carried out
13
9-11
using concentrated sulfuric acid according to described
method of spirocyclisation [19-21]. This way, the N-sub-
stituted 1,2,4,5-tetrahydrospiro[3H-2-benzazepine-3,4'-
piperidines]
-
have been obtained in 54-90 % yield
17 20
[a]
[a]
[a]
[a]
[a]
[a]
(Table 1). These new spiropiperidines were isolated by
alumina column chromatography as maroon viscous oils.
Moreover, the nitration of benzazepine hydrochloride
18
was carried out with HNO and H SO at 0°. Under these
3
2
4
reaction conditions the C-8-nitroderivative was obtained
21
1521, 1344
in 43 % overall yield as the exclusive product, according to
the orientation rules in aromatic rings. In the ir spectrum of
(δ NO )
2
[a] These compounds were isolated by alumina column chromatography.
-1
this compound bands appearing in the region
1521 cm
Table 2
Elemental Analysis and Mass Spectrometric Data of Compounds 9-21
% Found / Calculated
No
Molecular
Formula
C
H
N
MS, m/z (%)
+
.
9
C
C
C
H
N
N
N
79.15
79.07
79.29
79.41
79.29
79.41
69.53
69.74
82.45
82.63
82.42
82.63
74.29
74.47
82.63
82.50
79.23
79.07
79.60
79.41
10.13
10.08
10.32
10.29
10.13
10.29
8.37
8.55
8.87
8.98
8.81
8.98
7.51
7.62
8.49
8.75
9.93
10.08
10.06
10.29
10.73
10.85
10.23
10.29
10.40
10.29
9.49
9.57
8.29
8.38
8.27
258 (M <1), 217 (27), 160 (33), 153 (14), 138 (8), 125 (12), 110 (100), 91 (70),
17 26
2
2
2
84 (32), 72 (23), 65 (13), 58 (27)
+
.
10
H
272 (M <1), 231 (32), 174 (8), 153 (13), 127 (15), 110 (100), 105 (60),
18 28
103 (9), 84 (29), 79 (15), 70 (19)
+
.
11
H
272 (M <1), 231 (27), 174 (25), 153 (21), 138 (10), 125 (14), 110 (100),
18 28
105 (80), 84 (35), 72 (21)
+
.
12 [a]
13
C
H
ClN
292 (M <1), 251 (17), 194 (19), 153 (15), 138 (11), 125 (61), 110 (100),
17 25
2
84 (30), 72 (20)
+
.
C
H
N
N
334 (M <1), 293 (31), 172 (71), 105 (59), 91 (100), 65 (11)
23 30
2
2
+
.
14
C
H
334 (M <1), 293 (23), 172 (64), 105 (69), 91 (100), 65 (11)
23 30
8.38
7.78
7.90
8.59
+
.
15 [a]
16
C
H
ClN
354 (M <1), 313 (13), 172 (58), 125 (38), 91 (100), 65 (10)
22 27
2
+
.
C
H
N
N
N
320 (M <1), 279 (15), 172 (39), 91 (100), 65 (10)
22 28
2
2
2
8.75
+
.
17
C
C
H
10.79
10.85
10.18
10.29
258 (M , 35), 240 (28), 226 (21), 186 (23), 172 (9), 158 (14), 124 (100),
17 26
117 (30), 110 (50), 91 (25), 84 (30), 72 (36)
Data for isomer with t =26.59 min.: 272 (M , 35), 254 (48), 240 (25), 228 (9),
200 (28), 186 (10), 172 (20), 131 (36), 124 (100), 117 (21), 110 (46), 91 (28),
+
.
18
H
18 28
R
84 (51), 72 (43), 56 (40)
+
.
Data for isomer with t =27.63 min.: 272 (M , 33), 254 (48), 240 (26), 228 (10),
R
200 (32), 186 (10), 172 (18), 131 (32), 124 (100), 117 (20), 110 (45), 91 (29),
84 (55), 72 (45), 56 (40)
+
.
19
20
C
C
H
N
N
79.31
79.41
82.70
82.63
10.28
10.29
8.79
10.20
10.29
8.44
272 (M , 33), 254 (36), 240 (22), 200 (26), 186 (11), 172 (12), 131 (20),
18 28
2
124 (100), 110 (45), 91 (12), 84 (36), 72 (39)
Data for isomer with t =37.53 min.: 334 (M , 11), 316 (9), 243 (9), 226 (7),
200 (9), 186 (27), 172 (18), 146 (20), 131 (15), 117 (9), 91 (100), 65 (10)
Data for isomer with t =38.42 min.: 334 (M , 9), 316 (10), 243 (12), 226 (6),
+
.
H
23 30
2
R
8.98
8.38
+
.
R
200 (10), 186 (28), 172 (18), 146 (19), 131 (14), 117 (10), 91 (100), 65 (10)
+
.
21
C
H
N O
68.07
68.14
8.33
8.52
13.15
13.25
Data for isomer with t =37.10 min.: 317 (M , 9), 299 (15), 285 (6),
18 27
3
2
R
273 (10), 124 (100), 110 (32), 84 (25), 72 (18), 56 (23)
Data for isomer with t =38.0 min.: 317 (M , 12), 299 (15), 285 (6), 273 (11),
+
.
R
124 (100), 110 (32), 84 (32), 72 (21), 56 (23)
35
[a] Relative to Cl.

Jul-Aug 2001
Synthesis of new 1,2,4,5-Tetrahydrospiro[3H-2-benzazepine-3,4'-piperidines]
839
Table 3
1
Chemical Shifts (δ, ppm) and Coupling Constants (J, Hz) of Protons in H nmr Spectra of Homoallylamines 9-16
1
No
Piperidine protons
Allylic protons
Arom. protons
Benzylic protons, CHR
3
α-H, α'-H
β-H, β'-H
N-R
=CH
CH=
-CH -
H
CH
2
2
3
-CH -
-CH
3
2
9
2.38-2.48
(m)
2.14-2.29
(m)
2.26-2.38
(m)
2.37-2.53
(m)
2.22-2.32
(m)
2.40-2.55
(m)
2.35-2.53
(m)
2.55-2.80
(m)
1.40-1.55
(m)
1.45-1.53
(m)
1.53-1.58
(m)
1.54-1.62
(m)
1.44-1.58
(m)
1.56-1.64
(m)
1.52-1.63
(m)
1.70-1.90
(m)
2.42
1.08
5.09
(m)
4.94
(m)
5.01
(m)
5.02
(m)
5.02
(m)
5.11
(m)
5.14
(m)
5.30
(m)
5.83
2.24
7.18-7.34
(m)
7.04-7.28
(m)
7.02 -7.15
(m)
7.14-7.22
(m)
7.15-7.37
(m)
7.11-7.34
(m)
7.26-7.36
(m)
7.35-7.65
(m)
3.60
(s)
3.83
--
(q, J = 7.3) (t, J = 7.3)
2.23 0.92
(q, J = 7.3) (t, J = 7.3)
2.32 0.99
(q, J = 7.3) (t, J = 7.3)
2.33 0.98
(q, J = 7.3) (t, J = 7.3)
(m) (d, J = 7.7)
5.65
(m)
5.76
(m)
5.73
(m)
5.75
(m)
5.86
(m)
5.87
(m)
6.05
(m)
10
2.16
(d, J = 7.7)
2.16
(d, J = 7.7)
2.15
(d, J = 7.7)
2.25
(d, J = 7.7)
2.26
(d, J = 7.7)
2.27
(d, J = 7.7)
2.24
1.19
(d, J = 6.9)
--
(q, J = 6.8)
3.50
11 [a]
12
(s)
3.58
(s)
--
13
3.43
(s)
3.52
(s)
3.55
(s)
3.71
(s)
--
3.85, 3.95
(q, J = 6.8)
3.59
1.29
(d, J = 6.8)
--
14 [a]
15
--
(s)
3.62
(s)
3.81
--
--
--
--
--
16
(d, J = 7.7)
(s)
[a] 2.23 ppm ( 3H, s, p-CH ).
3
-1
and 1344 cm are attributed to NO asymmetric and sym-
with a mixing time of 600 ms featured cross peaks at 7.36,
1.36 ppm and at 7.98, 1.50 ppm, which established the
unambiguously identity of H-6 and H-9, respectively.
Consequently, the double doublet at 8.04 ppm corresponds
to H-7. These results are in agreement with those of related
heterocycles investigated previously [19,21].
2
1
metric vibrations, respectively. The H nmr spectrum of 21
is very similar to that of 18, except for the multiplicity of
the aromatic protons, which resonated at 7.36 (J = 8.2 Hz)
and 7.98 (J = 2.4 Hz) ppm as doublets and at 8.04 (J = 2.4
and 8.2 Hz) ppm as double doublet. A NOESY experiment
Table 4
1
Chemical Shifts (δ, ppm) and Coupling Constants (J, Hz) of Protons in H nmr Spectra of Spirobenzazepines 17-21
3
No
Piperidine protons N-R
Azepine protons [a]
Arom.
Substituents
Protons
α-H, α'-H
2.15-2.60
(m)
β-H, β'-H
1.56-1.82
(m)
-CH -
2.45
(q)
J = 7.2
2.41
(q)
J = 7.2
2.44
(q)
J = 7.2
2.43
(q)
J = 7.1
3.46
(s)
-CH
1.10
(t)
J = 7.2
1.07
(t)
J = 7.2
1.11
(t)
J = 7.2
1.17 (t)
J = 7.1
1-H
3.67 (d, H ),
4-H
5-H
3.26
(m)
6H-9H/others
7.10-7.33
(m)
1-CH
--
5-CH
1.36
(d)
2
3
ax
ax
3
3
17
1.27(dd)
J = 10.9,
12.8
1.22 (dd)
J = 10.9,
13.6
1.50 (dd)
J = 10.2,
14.0
1.25 (dd)
J = 10.6,
14.1
1.26 (dd)
J = 10.9,
13.6
1.52 (dd)
J = 10.8,
14.0
1.22 (dd)
J = 10.9,
13.6
1.49 (dd)
J = 10.7,
13.9
A
4.09 (d, H )
B
J = 15.5
4.21
(q)
J = 6.8
4.35
(q)
J = 7.2
1.50
(d)
J = 6.8
1.48
(d)
18a
18b
19
2.20-2.56
(m)
1.53-1.74
(m)
3.33
(m)
7.11-7.26
(m)
1.36
(d)
J = 7.2
1.35
(d)
J = 7.2
1.30
(d)
J = 7.0
1.34
(d)
J = 7.1
1.32
(d)
J = 7.1
1.36
(d)
J = 6.8
1.35
(d)
2.20-2.56
(m)
1.53-1.74
(m)
3.50
(m)
7.11-7.26
(m)
J = 6.8
J = 6.8
--
2.40-2.63
(m)
1.54-1.79
(m)
3.59 (d, H ),
3.22
(m)
6.90-7.20
(m)
A
3.62 (d, H )
B
J = 15.3
4.20 (q)
J = 6.8
20a
20b
21a
21b
2.30-2.60
(m)
1.55-1.74
(m)
--
--
3.31
(m)
7.07-7.35
(m)
1.49
(d)
J = 6.9
1.46
(d)
J = 6.9
1.50
(d)
J = 6.8
1.48
(d)
2.30-2.60
(m)
1.55-1.74
(m)
3.51
(s)
4.34
(q)
J = 6.8
4.21
(q)
J = 6.8
4.35
3.42
(m)
7.07-7.35
(m)
2.33-2.66
(m)
1.51-1.62
(m)
2.41
(q)
J = 7.2
2.44
(q)
J = 7.2
1.07
(t)
J = 7.2
1.11
(t)
3.33
(m)
7.36 (d, H-6)
7.98 (d, H-9)
8.04 (dd,H-7)
7.36 (d, H-6)
7.98 (d, H-9)
8.04 (dd,H-7)
2.33-2.66
(m)
1.51-1.62
(m)
3.50
(m)
(q)
J = 6.8
J = 7.2
J = 6.8
J = 6.8
[a] Signal of the 4-H proton overlapped with signals of piperidine β,β' protons.
eq

840
A. Palma R., S. Salas, V. Kouznetsov, E. Stashenko, G. Montenegro N., and A. Fontela G.
Vol. 38
The structural assignments proposed for the spiro[3H-2-
benzazepine-3,4'-piperidines] 17-21 were also consistent
with their H and C nmr spectra (Tables 4 and 5) and
were supported by mass spectrometric data.
nitrogen and C-H bond in 18b,20b have a cis configura-
tion relative to one another. The chemical shifts of the
benzylic 1-H protons appeared in the range of 4.20-4.35
ppm as two different quartets for the spirobenzazepines 18
and 20. The second quartet observed at lower fields also
demonstrates the pseudoequatorial orientation of 1-H in
these molecules. From these results it was inferred that the
products obtained existed as diastereoisomers mixture,
which were represented in figure 1 as the cis-e,e and trans-
a,e forms. We have previously made this observation for
related compounds [18].
1
13
In contrast with mass spectra of compounds 9-16, inten-
+.
sities of molecular ion peaks (M ) in the mass spectra of
spirotetrahydro-2-benzazepines 17-20 varied between 7
and 42%. The mass spectra of benzazepines spirocon-
densed with the N-ethylpiperidine moiety 17-19 and ben-
zazepine spiroannulated with the N-benzyl-piperidine
moiety 20 show base peaks at m/z 124 and m/z 91, respec-
tively. The chemical shifts of the methyl (doublet at 1.30-
1.36 ppm) and methyne (multiplet at 3.22-3.50 ppm) pro-
1
The H nmr spectrum of compound 21, which was
obtained from the diastereomeric mixture of spirane 18, is
very similar to that of the above described compounds.
The cg-ms analysis of nitrobenzazepine 21 showed that
two diastereoisomers (21a and 21b) eluted from the col-
umn at 37.14 and 38.01 minutes under the same chromato-
graphic conditions and both exhibit molecular ion peaks of
low intensity (9 and 11%) which agree with the expected
molecular mass. Unfortunately, all attempts to separate
these diastereoisomers by conventional column chro-
matography were unsuccessful.
1
tons at the C-5 position in the H nmr provide the best evi-
dence that the cyclisation of 9-11, and 13 take place. We
assume, that these tetrahydro-2-benzazepine derivatives,
as well as in the parent tetrahydrospiro[3H-2-ben-
zazepine-3,1'-cycloalkanes] adopts the semi-chair confor-
mation [19,21]. Moreover, the equatorial orientation of the
5-CH group for all spiranes 17-20 was established based
3
3
on the value of trans J
coupling constant (Table 4).
4H,5H
1
By H nmr and cg-ms data it was determined that spiro-
compounds 17 and 19 are present as a unique conformer.
The chemical shifts of the benzylic 1-H protons in the
above mentioned compounds appeared in the range of
3.59-4.09 ppm as double doublets with geminal coupling
constants of J = 15.3-15.5 Hz, indicating that these pro-
AB
tons are nonequivalent. According to chromatographic
and mass-spectral data, the spiro-tetrahydro-2-ben-
zazepines 18 and 20 obtained by our route from racemic
α-phenyl-ethylamine and 4-piperidones are formed as a
1:1 mixture of geometric isomers. The benzazepine 18
isomers eluted from an HP-5 [5%-phenyl-poly(dimethyl-
siloxane)] capillary column at 26.59 and 27.63 minutes,
using an oven temperature programmed from 120 to 280°,
at 5°/minute, while the benzazepine 20 isomers emerged
from the column at 37.53 and 38.42 minutes under the
same chromatographic conditions. For these compounds
with two methyl groups at the 1-C and 5-C positions, the
The spontaneous motor activity assay showed significant
differences (p<0.001) between the vehicle effect (distilled
water, 1 ml/100 g, IP) and that of 4-allyl-4-N-benzyl-
16
aminopiperidines 9,11,12 and
at a dose of 10 mg/kg.
None of these compounds was active at lower doses. In the
subsequent assay of the amphetamine-induced hyperactivity
9
antagonism the molecule with representative structure of
the compounds tested did not show any activity at a dose of
10 mg/kg (Figure 2). No deaths were produced by any of
these compounds, at any doses tested (10, 5 and 2 mg/kg).
1
H nmr spectra showed the presence of two pairs of dou-
blets at 1.48/1.50 and 1.35/1.36 ppm (2-benzazepine 18),
as well as at 1.46/1.49 and 1.32/1.33 ppm (2-benzazepine
20). Decoupling experiments gave additional support for
Amphetamine (5mg/Kg)
H O (1mL / 100g)
2
the structural assignment of both 1-CH (1'-CH ) and 5-
3
3
CH (5'-CH ) protons in the spectra of 18 and 20. Thus, it
Amphet.5+ 9 (10mg/Kg)
9 (5mg/Kg)
9 (10mg/Kg)
3
3
was established that the protons of the 1-CH (1'-CH )
3
3
group resonate at lower fields than the 5-CH (5'-CH )
3
3
1
protons. The dependence of the J
coupling constant on
C,H
the orientation of the free electronic pair on the nitrogen
atom was used to established the spatial orientation of the
1-CH group. Thus, the larger coupling constant observed
3
p<0.05
p<0.01
p<0.001
for the isomers 18b,20b (J
= 134 Hz) in comparison
C,H
with the coupling constant for the isomers 18a,20a (J
=
C,H
130 Hz) indicates that the free electron pair on the
Figure 2. Study of spontaneous motor activity of compound 9.

Jul-Aug 2001
Synthesis of new 1,2,4,5-Tetrahydrospiro[3H-2-benzazepine-3,4'-piperidines]
841
Table 5
13
C NMR Data for Isomers 18a, 18b, 20a and 20b
13
No
C NMR Resonances
18a
18b
20a
20b
δ 145.60 (9a-C), 145.15 (5a-C), 122.46-126.02 (6-C-9-C), 53.24 (3-C), 52.53 (N-1'-C), 49.14 (2'/6'-C), 48.26 (4-C), 45.00 (1-C), 35.20
(3'/5'-C), 29.27 (5-C), 21.39 (1-CH ), 21.09 (5-CH ), 12.20 (N-2'-C).
3
3
δ 143.64 (5a-C), 143.56 (9a-C), 122.46-126.02 (6-C-9-C), 52.85 (3-C), 52.51 (N-1'-C), 51.08 (1-C), 49.45 (2'/6'-C), 47.66 (4-C), 38.92
(3'/5'-C), 32.07 (5-C), 24.34 (1-CH ), 21.09 (5-CH ), 12.20 (N-2'-C).
3
3
δ 145.63 (9a-C), 145.18 (5a-C), 138.07 (quaternary), 126.86-129.43 (o,m,p-C .), 122.46-126.10 (6-C-9-C), 63.24 (N-1'-C), 53.26 (3-C),
Ar
49.34 (2'/6'-C), 48.22 (4-C), 45.03 (1-C), 35.19 (3'/5'-C), 29.26 (5-C), 21.40 (1-CH ), 21.12 (5-CH ).
3
3
δ 143.65 (5a-C), 143.54 (9a-C), 138.05 (quaternary), 126.86-129.43 (o,m,p-C .), 122.46-126.02 (6-C-9-C), 63.20 (N-1'-C), 52.85 (3-C),
Ar
51.03 (1-C), 49.45 (2'/6'-C), 47.61 (4-C), 38.88 (3'/5'-C), 32.04 (5-C), 24.32 (1-CH ), 21.06 (5-CH ).
3
3
hydroxide (pH≈ 9-10) in the cold, extraction with ether (2x50
ml), and purification by column chromatography of the dried
extracts gave the corresponding spirobenzazepines 17-20 as
brown viscous oils. Yields and some physical and spectral prop-
erties of these compounds are given in Tables 1, 2, 4 and 5.
EXPERIMENTAL
1. Chemistry.
The purity of the obtained substances and the composition of
the reaction mixtures were monitored by tlc over Alufol 60 and
Silufol UV plates. The final spiranes were isolated by column
chromatography over aluminium oxide (Brockmann activity 2)
eluting with heptane. The ir spectra were obtained from potassium
bromide pellets on a Perkin Elmer 599B-FTIR spectrophotometer.
The H and C nmr spectra were recorded on Bruker AC-200 and
AC-300 spectrometers, and are reported in ppm on the δ scale in
CDCl solvent with TMS as internal standard. Data are reported
as follows: chemical shift (integral intensity, multiplicity, cou-
pling constants in Hz and group). A Hewlett-Packard (HP) 5890A
Series II Gas Chromatograph interfaced to an HP 5972 Mass
Selective Detector (MSD) with an HP MS ChemStation Data sys-
tem was used for MS identification. The electron beam energy
was 70 eV. Mass spectra and reconstructed chromatograms were
obtained by automatic scanning in the mass range m/z 50-400
a.m.u.'s at 2.2 scan/s. Elemental analyses were performed on a
Perkin Elmer 2400 Series II analyzer. Refractive indices were
measured with a Schmidt Haesch 17452 refractometer.
Nitration of 1,2,4,5-Tetrahydrospiro[3H-2-benzazepine-3,4'-
piperidine] Hydrochloride 18.
254
To a stirred and cooled (0°) mixture of conc. H SO and 65%
2
4
HNO (1.7 ml), 1.0 g (2.91 mmole) of benzazepine hydrochlo-
3
1
13
ride 18 was added by portions. After the addition was complete,
the dark yellow suspension was stirred at room temperature for
18 hours. The reaction mixture was then neutralized with ammo-
nium hydroxide (pH≈ 9) in the cold. The chloroform layer was
separated, dried over anhydrous sodium sulfate and the solvent
was evaporated. The residue was then purified by column chro-
matography. The mononitroderivative 21 was obtained in 43%
(0.4 g) as maroon viscous oil. Yield and spectral properties of this
compound are given in tables 1, 2, and 4.
3
2. Pharmacology.
The spontaneous motor activity assay was always carried out
at the same hour of the day in a thermostated (22 1°) chamber
with a twelve-hour (8 a.m-8 p.m.) light/darkness cycle. All
General Procedure for Reaction of Ketimines 1-8 with Allyl-
experiments used albine male mice (Charles River CD1), 27
3
magnesium Bromide.
g in weight. The animals were utilised only once in order to
avoid tolerance, sensitisation and learning alteration effects on
their response. For the adaptation of the mice to the chamber
environment, they were maintained for at least 48 hours in
groups of 20, in 52x28 cm cages, with free water and food
access. All compounds, dissolved in distilled water, were admin-
istered intraperitoneally at 0.01 ml/g. Solutions were prepared
immediately before the administration. Statistical analysis was
performed by means of the Newman-Keuls test from the
GradPhad Prism program.
A solution (0.10 mole) of the ketimines (1-8) dissolved in dry
ether (30 ml) was added dropwise to a stirred solution of allyl-
magnesium bromide, prepared from allyl bromide (0.30 mole)
and metallic magnesium (0.60 mole) in dry ether (100 ml). After
the addition was complete, the reaction mixture was heated to 35°
and vigorously stirred for four hours. Work-up of the reaction
mixture with a cold saturated solution of ammonium chloride,
extraction with ether (3x100 ml), and vacuum distillation of the
dried extracts afforded the corresponding 4-allyl-4-N-benzyl-
aminopiperidines as yellow or brown viscous oils. Yields and
some physical and spectral properties of these compounds are
given in Tables 1-3.
Modification of Spontaneous Motor Activity.
The Panlab (Ref. 0603) activity boxes were used. Each one
consists of a 34.5 cm x 34.5 cm plate, capable of electromagnetic
field generation. A 27.5 cm x 27.5 cm cage with three mice, was
placed over the plate. All the time the mice had free access to
food and water. The electromagnetic field is affected by animal
displacement, registering every movement as a step. These sig-
nals were detected by means of an automated Actisystem PanLab
(DAS 16 V.1). Three batches of three mice each were used. The
vehicle and/or new molecules 9, 11, 12 and 16 at a dose of 10
mg/kg via intraperitoneally were supplied to the animals. Those
General Procedure for Cyclisation of Homoallylamines 9-11, 13
Under Acidic Conditions.
To a stirred and cooled (0°) solution of homoallylamines 9-11
and 13 (1.0 g) and chloroform (2.0 ml) was added concentrated
sulfuric acid (2.0 ml) dropwise for five minutes. The reaction
mixture was heated at 80° and vigorously shaken for three hours,
and reaction progress was monitored by tlc. Neutralisation of the
reaction mixture with a concentrated solution of ammonium

842
A. Palma R., S. Salas, V. Kouznetsov, E. Stashenko, G. Montenegro N., and A. Fontela G.
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molecules which showed some effect (activity) over mice, were
employed in three additional batches, and depending upon results
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Hyperactivity antagonism induced by amphetamine was eval-
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neous motor activity assay. Compound 9 at concentration of 10
mg/kg was administered intraperitoneally to the animals, thirty
minutes before the administration of dextroamphetamine sulfate
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minute-intervals during the next 60 minutes after amphetamine
administration.
Acknowledgements.
The authors are thankful to COLCIENCIAS for financial sup-
port (grants No 1102-05-110-97 and 1115-05-353-96).
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