Synthesis and preliminary pharmacological evaluation of thiophene analogues of viloxazine as potentialantidepressant drugs

Article abstract of DOI:10.1016/S0968-0896(99)00070-X

A series of eight thienyloxymethylmorpholines, thiophene analogues of viloxazine, have been synthesized by three different routes. The preliminary pharmacological evaluation of this series shows antidepressant properties on the mice models used with a light sedative action. The structure-activity relationship is established in a first approximation. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00070-X

Bioorganic & Medicinal Chemistry 7 (1999) 1349±1359
Synthesis and Preliminary Pharmacological Evaluation of
Thiophene Analogues of Viloxazine as Potential
Antidepressant Drugs
Carlos Corral, a Jaime Lissavetzky, a,* Ignacio Manzanares, a Victoriano Darias, b
Marõa A. Exposito-Orta, b Jose A. Martõn Conde b and C. Carmen Sanchez-Mateo b
a
Â
Â
Instituto de Quõmica Medica (CSIC), Juan de la Cierva, 3, E-28006 Madrid, Spain
bDepartamento de Farmacognosia y Farmacodinamia, Facultad de Farmacia, Universidad de La Laguna, Tenerife, Spain
Received 15 September 1998; accepted 7 December 1998
AbstractÐA series of eight thienyloxymethylmorpholines, thiophene analogues of viloxazine, have been synthesized by three di€erent
routes. The preliminary pharmacological evaluation of this series shows antidepressant properties on the mice models used with a light
sedative action. The structure±activity relationship is established in a ®rst approximation. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
The ®rst of them (Scheme 1) starts from alkyl 3-hy-
droxythiophene-2-carboxylates 2a±e,3±6 which due to
the presence of the ester group in position 2 of the
thiophene nucleus, are stable enol compounds, in con-
trast to other 3-hydroxythiophenes. Their potassium
salts were made to react with the 4-benzyl-2-toluene-p-
sulphonyloxymethylmorpholine7 and the corresponding
derivatives 3a±e were obtained in reasonable yields
except for the case of compound 3d (only 31% yield).
These compounds were transformed into compounds
4a±e by removing the ester function by alkaline hydro-
lysis and decarboxylation of the acid group formed. The
®nal step was reached in mild conditions using the
Pearlman catalyzer8 at reduced pressure, other attempts
in more classical drastic conditions like catalytic hydro-
genation at high pressure, being unsuccessful. The yields
in title compounds (1a±e) were over 80%.
Viloxazine1 is
a
known second generation anti-
depressant drug commercialized by ICI as Vivalan, the
main inconvenience of its pharmacological pro®le being
its short biological life which obligates the patients to a
minimum of three doses per day. This fact is probably
due to a fast inactivating metabolism by hydroxylation
of the benzene nucleus in position 5.2
In this paper, we report the synthesis and a preliminary
pharmacological study of a series of thiophene analogues
of viloxazine (1a±g). The presence of the thiophene ring
instead of the benzene one can make their biological life
longer, because of the diculty of formation of the
hydroxylated metabolite responsible for this undesirable
e€ect, in the thiophene derivative, besides, the 2-thieny-
loxymethylmorpholine 1h, studied and the e€ect of the
chain position on the structure±activity relationship is
compared.
This method is not adequate for the synthesis of com-
pound 1f, because the starting material 2f, can be
obtained only in a low 15% yield,9 and it cannot be
used for compounds 1g and 1h.
Chemistry Results
The other two routes start from the epoxy derivatives 5
(Schemes 2 and 3). These compounds had been prepared
by us from the corresponding methyl 3-hydroxythiophene-
2-carboxylates (5a±c9 and 5d,f10) or from the adequate
ring-brominated methylthiophenes (5g,h11). These routes
are not advisable for the synthesis of compound 1e,
because the initial epoxyde 5e can be obtained only in a
very low yield.10
We describe three di€erent methods for the synthesis of
the 2-thienyloxymethyl-morpholines 1(a±h) (Schemes 1±3
and Table 1).
Key words: Thiophene; viloxazine; antidepressant; synthesis; pharma-
cology.
* Corresponding author.
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00070-X

1350
C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
Method II (Scheme 2) is the shortest of the three and
is made in a one step reaction of epoxy derivatives 5
with 1,2,3-oxathiazolidine 2,2-dioxide based in a patent
for the synthesis of 2-aryloxymethylmorpholines.12 The
reaction conditions were modi®ed by changing the
patent solvent (MeOH) for a non-nucleophilic solvent
(DMSO) to hinder the epoxide opening observed in
the reaction conditions described, that allows the
increase of the yields in the title compounds 1a±d and
1f±h.
sodium methoxide. The oxo group of these lactams
was reduced with lithium aluminium hydride and
the 4-benzyl-2-thienyloxymethylmorpholines (4) were
debenzylated to the title compounds 1a±d and 1f±h as
described above.
Biological Results and Discussion
The antidepressant properties of this series of thiophene
analogues of viloxazine 1a±h have been investigated in
comparison with standard drugs. The results obtained
are reported in Tables 2±10.
Method III (Scheme 3) consists in the epoxide opening
with benzylamine to obtain in a regioselective way the
aminoalcohols 6 in very good yields, which were
transformed into the 4-benzyl-2-thienyloxymethyl-
morpholin-5-ones (7) in a similar way to that described
for the benzenic series13 with chloroacetyl chloride and
These compounds showed a similar acute toxicity to
imipramine and viloxazine (ld50>150 mg/kg ip) (Table
2). The tetrabenazine test showed that title compounds
Table 1. Physical constants and method of synthesis for compounds
1a±h
Compound
Compositiona
mp (ꢀC)b
170±172c
Yield (%)
Method
1a
C
15H17NO2S
43d
47e
47e
55d
43e
40e
36d
38e
46e
21d
40e
51e
45d
42e
42e
48e
53e
49e
46e
I
II
III
I
II
III
I
II
III
I
II
III
I
II
III
II
III
II
III
1b
1c
1d
C12H17NO2S
164±166c
173±174f
145±147c
C10H15NO2S
C12H12NO2S
1e
1f
C10H15NO2S2
152±154c
167±168f
Scheme 1. Route I. (a) DMF, 150ꢀC, 17 h; (b) NaOH. Á, 1 h; (c) (i)
PdCl2, C, H2O, (ii) MeOH, [H2], 1 atm.
C11H17NO3S
C10H15NO2S
C10H15NO2S
1g
1h
113±115f
118±119f
a
Satisfactory elemental analyses (‹0.4%) for C, H, N and S were
obtained for all compounds as free bases.
b
Of the oxalates.
Recrystallized from acetone.
From compounds 2.
From compounds 5.
Recrystallized from acetone±MeOH.
c
d
e
f
Scheme 2. Route II. (a) NaOH, 50ꢀC, 1 h.
Table 2. Determination of the acute toxicity
ld50 approximately
(mg/kg)
Intraperitoneal
Compound
Oral
1a
1b
1c
1d
1e
1f
1g
190.33
192.13
208.14
165.16
206.06
212.42
173.48
155.94
163.07
186.57
>500
>500
>500
500
>500
>500
>500
>500
>500
>500
1h
Imipramine
Viloxazine
Scheme 3. Route III. (a) Benzylamine, 100ꢀC, 30 min; (b) (i) Et3N,
ClCH2COCl, (ii) Na/MeOH, Á , 8 h; (c) H4LiAl, Á, 6 h.

C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
1351
Table 3. E€ect of compounds (1a±h) on tetrabenazine induced ptosis, akinesia and hypothermia
Compound
Dose
mg/kg ip
Ptosis mean
score
30 min
Locomotor activ.
(%)
30 min
Mean decrease in
rectal temperature (ꢀC)
30 min
60 min
Control
1a
1b
1c
1d
1e
1f
1g
±
3.80‹0.13
0.40‹0.24**
3.00‹0.45
0.00
80.00*
0.00
100.00*
80.00*
100.00*
80.00*
20.00
4.05‹0.29
0.86‹0.41**
3.56‹0.23
4.90‹0.35
2.06‹0.88**
4.08‹0.31
2.00‹0.14**
3.74‹0.65
1.28‹0.43**
2.14‹0.33**
1.16‹0.23**
1.76‹0.44**
0.95‹0.32**
1.04‹0.40**
10
10
10
10
10
10
10
10
10
10
0.00‹0.00**
1.20‹0.58**
0.40‹0.24**
1.00‹0.45**
1.20‹0.83**
0.00‹0.00**
0.00‹0.00**
0.00‹0.00**
1.72‹0.25**
2.20‹0.48**
1.00‹0.31**
1.80‹0.48**
1.24‹0.19**
1.14‹0.62**
1.07‹0.29**
0.46‹0.42**
1h
Imipramine
Viloxazine
60.00*
90.00*
100.00*
Control
1a
1b
1c
1d
1e
1f
1g
±
3.20‹0.20
0.00
60.00*
60.00*
20.00
60.00*
80.00*
60.00*
80.00*
60.00*
80.00*
100.00*
4.54‹0.45
5.76‹0.32
25
25
25
25
25
25
25
25
25
25
0.40‹0.40**
0.80‹0.49**
0.20‹0.20**
0.20‹0.20**
0.40‹0.24**
0.20‹0.20**
0.20‹0.25**
0.60‹0.40**
0.20‹0.25**
0.20‹0.25**
2.40‹0.46*
1.90‹0.21**
3.84‹0.56
1.98‹0.22**
2.24‹0.31**
1.12‹0.29**
2.62‹0.34**
1.92‹0.27**
1.65‹0.29**
2.05‹0.34**
1.90‹0.31**
2.12‹0.22**
3.82‹0.77*
1.50‹0.44**
2.24‹0.31**
0.90‹0.31**
2.26‹0.26**
1.06‹0.16**
1.85‹0.37**
1.27‹0.25**
1h
Imipramine
Viloxazine
*p<0.05.
**p<0.01.
Table 4. E€ect of compounds (1a±h) on apomorphine induced
climbing, stereotypy and hypothermia
Table 5. E€ect of compounds (1a±h) on 5-HTP induced behaviour
Compound
Dose
mg/kg ip
Number of head
twiches x‹SEM
Syndrome
score x‹SEM
Compound
Dose
mg/kg ip mean score mean score
Stereotypy
Climbing
Mean decrease
in rectal temp
30 min (ꢀ)
Control
1a
1b
±
0.00‹0.00
0.00‹0.00
0.00‹0.00
6.20‹1.16**
0.00‹0.00
5.00‹2.77*
0.00‹0.00
0.00‹0.00
0.40‹0.24
0.00‹0.00
0.00‹0.00
1.60‹0.81
0.00‹0.00
4.20‹1.83
0.20‹0.20
13.60‹3.28**
0.00‹0.00
0.00‹0.00
20 min
20 min
25
10
25
10
25
25
10
25
25
10
25
10
25
10
25
3.00‹0.63**
15.00‹1.09**
5.00‹0.00**
19.40‹2.67**
0.00‹0.00
4.00‹0.95**
10.00‹0.55**
0.00‹0.00
3.60‹1.43*
6.20‹1.50**
3.00‹1.22*
6.80‹0.80**
6.40‹1.12**
21.40‹1.17**
Control
1a
1b
1c
1d
1e
1f
1g
±
2.67‹0.14
3.00‹0.00
2.50‹0.22
2.83‹0.17
2.50‹0.22
2.50‹0.22
2.67‹0.21
2.83‹0.17
2.50‹0.22
2.50‹0.22
2.67‹0.21
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
3.62‹0.39
1.87‹0.44*
2.40‹0.55
2.20‹0.44*
2.48‹0.61
2.73‹0.63
1.33‹0.45**
1.58‹0.42**
2.31‹0.42
1.03‹0.57**
1.17‹0.35**
10
10
10
10
10
10
10
10
10
10
1c
1d
1e
1f
1g
1h
Imipramine
Viloxazine
1h
Control
1a
1b
1c
1d
1e
1f
1g
±
2.83‹0.11
3.00‹0.00
2.67‹0.19
2.75‹0.13
3.00‹0.00
2.58‹0.26
2.75‹0.13
2.67‹0.21
2.83‹0.17
3.00‹0.00
2.83‹0.11
2.00‹0.00
2.00‹0.00
1.83‹0.17
1.92‹0.08
2.00‹0.00
1.83‹0.17
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
2.00‹0.00
3.33‹0.30
0.73‹0.57**
2.38‹0.40
Fluoxetine
25
25
25
25
25
25
25
25
25
25
1.98‹0.22**
1.17‹0.38**
1.65‹0.51**
1.38‹0.30**
1.57‹0.28**
1.53‹0.63**
1.38‹0.43**
0.72‹0.20**
*p<0.05.
**p<0.01.
1h
Imipramine
Viloxazine
Likewise they antagonize in general terms the hypo-
thermia induced by apomorphine in a similar way to
viloxazine and imipramine (Table 4).
*p<0.05
**p<0.01.
The study of their performance in the serotonin system
was made by measuring the e€ects on the 5-HTP
induced behaviour. Compounds 1b and 1c were the
most similar to ¯uoxetine (Table 5), when we consider
the total syndrome induced by 5-HTP.
1a±h antagonize signi®cantly all the symptons induced
by this drug (ptosis, akinesia and hypothermia) with
similar or better values than the antidepressant drugs
used as references (Table 3).
Finally, to predict their antidepressant pro®les without
evolving pharmacological interactions, the Porsolt test

1352
C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
was utilized (Table 6). The majority of the compounds
assayed reduced in a remarkable way, at 25 mg/kg ip
dose, the duration of the immobility, with the thiophene
isoster of viloxazine (1f), being the most active. This fact
is not related with stimulant e€ects, because these com-
pounds at the same dose decrease the spontaneous
motor activity (Table 7).
This preliminary pharmacological study was completed
with several psychopharmacological tests. So, the com-
pounds cause, in general, hypothermia (Table 8) and
potentiate pentobarbital sleeping time at a dose of 40
mg/kg ip (Table 9) and at subhypnotic dose of pento-
barbital (Table 10), which rejects metabolic involve-
ments and con®rms their sedative attributes.
Table 6. E€ect of compounds (1a±h) on the behavioural despair
(forced swimming) test
Table 7. E€ect of compounds (1a±h) on spontaneous locomotor
activity (mean‹SEM)
Compound
Dose
mg/kg ip
Duration of immobility(s)
x‹SEM
Variation
(%)
Compound Dose
mg/kg
ip
Number of light
beam interruptions
Variation
(%)
Control
1a
1b
1c
1d
1e
1f
1g
±
172.37‹12.71
185.10‹14.59
170.20‹13.22
178.40‹20.44
183.50‹8.54
153.41‹9.52
149.30‹15.09
164.00‹12.73
161.10‹10.57
125.70‹29.10
126.48‹25.50
±
30 min
204.28‹25.14
60 min
30 min 60 min
10
10
10
10
10
10
10
10
10
10
7.38
1.26
3.50
6.46
11.00
13.38
4.85
6.54
27.07
26.62
Control
1a
1b
1c
±
67.33‹6.98
90.75‹13.10
47.75‹10.44
±
±
10 204.00‹26.25
10 147.75‹4.50
10
0.14 34.78
27.67 29.08
65.49 18.31
70.50‹30.45** 55.00‹21.71
1d
1e
1f
1g
10 244.00‹18.46
10 130.25‹14.87
10 122.25‹22.35
10 198.25‹24.40
10 212.00‹13.36
10 221.25‹30.09
102.50‹11.29* 19.44 52.23
37.25‹3.01*
57.00‹6.12
80.00‹11.71
88.00‹18.00
58.50‹14.54
36.24 44.67
40.15 15.34
2.95 18.82
3.78 30.70
8.31 13.11
1h
Imipramine
Viloxazine
1h
Viloxazine
Control
1a
1b
1c
1d
1e
1f
1g
±
163.00‹6.32
±
25
25
25
25
25
25
25
25
25
25
119.40‹17.55**
133.60‹12.50*
187.80‹15.39
148.60‹11.88
154.70‹12.00
93.80‹20.36**
133.30‹12.60*
125.80‹14.10**
109.10‹7.53**
113.60‹19.92**
26.75
18.03
15.21
8.83
Control
1a
± 225.75‹14.27
25 158.00‹20.48*
97.00‹8.05
±
±
42.25‹12.79* 30.01 56.44
86.00‹15.94 66.33 11.34
40.50‹19.96* 82.72 58.25
51.00‹10.42* 20.71 47.42
1b
1c
25
25
76.00‹8.75**
39.00‹8.38**
5.09
1d
1e
1f
1g
25 179.00‹30.75
25 161.00‹33.50
25 119.00‹18.20** 68.75‹14.85
25 141.25‹24.52*
25 132.00‹37.62
25 130.50‹33.97*
42.45
18.22
22.82
33.07
30.31
117.00‹39.31
28.68 20.62
47.29 29.12
37.43 47.42
1h
Imipramine
Viloxazine
51.00‹9.80*
37.25‹7.03** 41.53 61.60
82.75‹21.14 42.19 14.69
1h
Viloxazine
*p<0.05.
**p<0.01.
*p<0.05.
**p<0.01.
Table 8. E€ect of compounds 1(a±h) on body temperature (mean‹SEM)
Compound
Dose mg/kg ip
Mean decrease in rectal temperature (ꢀC)
4 h
1 h
2 h
6 h
24 h
Control
1a
1b
1c
1d
1e
1f
1g
±
0.42‹0.11
0.46‹0.50
0.82‹0.33
0.48‹0.33
0.16‹0.39
0.88‹0.35
1.12‹0.24**
0.78‹0.09
0.74‹0.17
4.36‹0.37**
0.74‹0.24
0.74‹0.19
0.46‹0.10
0.20‹0.12
0.26‹0.25
0.10‹0.33
0.02‹0.31
0.16‹0.21
0.64‹0.15
0.16‹0.09
0.06‹0.08*
6.44‹0.41**
0.22‹0.17
0.58‹0.31
0.07‹0.08
0.14‹0.13
0.36‹0.22
0.12‹0.27
0.38‹0.28
0.09‹0.27
0.00‹0.07
0.24‹0.08
0.54‹0.10**
6.42‹0.72**
0.30‹0.10*
0.32‹0.23
0.05‹0.06
0.10‹0.13
0.22‹0.18
0.42‹0.12**
0.56‹0.38*
0.32‹0.40
0.20‹0.18
0.26‹0.15*
0.48‹0.14**
2.84‹0.46**
0.60‹0.11**
0.22‹0.22
0.26‹0.14
0.42‹0.14
0.30‹0.25
0.08‹0.16
0.06‹0.29
0.06‹0.77
0.44‹0.14*
0.02‹0.16
0.02‹0.04
0.06‹0.22
0.24‹0.14
0.12‹0.73
10
10
10
10
10
10
10
10
5
1h
Clorpromazine
Imipramine
Viloxazine
10
10
Control
1a
1b
1c
1d
1e
1f
1g
±
0.55‹0.33
1.20‹0.33
1.18‹0.33
4.24‹0.48**
1.68‹0.19*
1.38‹0.24
1.26‹0.35
2.32‹0.24**
2.12‹0.29**
5.74‹0.90**
0.50‹0.27
1.54‹0.23*
0.80‹0.33
2.20‹0.41**
2.08‹0.39**
0.62‹0.13
0.64‹0.28
1.50‹0.28*
1.36‹0.29
6.84‹0.53**
1.48‹0.38
3.62‹0.37**
1.14‹0.18
2.24‹0.56
3.96‹0.64**
0.92‹0.13
0.94‹0.22
1.16‹0.19
1.72‹0.29
7.92‹0.81**
2.55‹0.50
2.68‹0.37
3.08‹0.59
4.14‹0.28*
2.04‹0.18
3.26‹0.40
3.62‹0.56
3.26‹0.37
2.92‹0.39
6.86‹1.21**
0.62‹0.23
0.10‹0.42
0.50‹0.39
1.56‹1.20
0.58‹0.63
0.08‹0.29
0.34‹0.15
0.48‹0.27
0.58‹0.34
0.28‹0.32
25
25
25
25
25
25
25
25
5
1h
Clorpromazine
*p<0.05.
**p<0.01.

C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
Table 9. E€ect of compounds 1(a±h) on hypnotic dose of pentobarbital (40 mg/kg ip)
1353
Compound
Dose mg/kg ip
t1 (min)c
x‹SEM
t2 (min)d
x‹SEM
Variation (%)
(t1)
(t2)
Control
1a
1b
1c
1d
1e
1f
1g
±
5.58‹0.97
5.68‹0.65
5.02‹0.23
5.82‹0.49
7.39‹1.35
4.46‹0.30
5.62‹0.94
4.77‹0.33
6.43‹1.82
2.93‹0.16*a
67.26‹4.06
118.38‹8.79**b
62.13‹10.31
72.34‹3.81
98.03‹8.47**b
91.45‹6.14**b
77.34‹10.50
80.89‹5.18
±
1.79
10.03
4.30
32.44
20.07
0.72
14.52
15.23
47.49
±
10
10
10
10
10
10
10
10
2.5
76.00
7.63
7.55
45.75
35.96
14.98
20.26
9.17
1h
Diazepam
73.43‹4.22
121.69‹12.85**b
80.92
Control
1a
1b
1c
1d
1e
1f
1g
±
5.45‹0.58
5.51‹0.45
4.27‹0.53
5.85‹1.00
5.38‹0.82
4.57‹0.30
5.48‹0.95
5.40‹1.07
6.14‹0.95
3.04‹0.16*a
56.31‹3.12
115.51‹6.37**b
69.45‹7.19
±
±
25
25
25
25
25
25
25
25
2.5
1.10
21.65
7.34
1.28
16.14
0.55
0.92
12.66
44.22
105.13
23.33
62.22
128.15
49.12
42.57
76.57
32.46
85.63
91.35‹7.63**b
128.47‹5.24**b
83.97‹8.80*a
80.28‹9.16*a
99.43‹8.39**b
74.59‹7.52*a
104.53‹6.73**b
1h
Diazepam
a
*p<0.05.
**p<0.01.
t1=sleep induction time (min).
t2=sleeping time (min).
b
c
d
Table 10. E€ect of compounds 1(a±h) on subhypnotic dose of pen-
tobarbital (20 mg/kg ip)
The initial structure±activity relationship show that the
position of the morpholinomethoxy chain on the thio-
phene ring has no importance for the activity because
compounds 1g and 1h have similar pharmacological
results. Neither does the position of the substituents in
relation to the chain seem to have a remarkable e€ect.
This is illustrated by the fact that, in most of the phar-
macological tests, compounds 1c, 1g and 1h, in which
the methyl group is adjacent to the side chain show
similar behaviour.14
Dose mg/kg ip t1 (min)a
Ns=Ntb
t2 (min)a
x‹SEM
x‹SEM
Control
1a
1b
1c
1d
1e
1f
1g
±
0/6
3/6
2/6
2/6
6/6
2/6
1/6
3/6
1/6
6/6
±
±
10
10
10
10
10
10
10
10
2.5
24.00‹0.86 21.00‹1.00
6.84‹0.37 26.19‹0.12
9.39‹0.60 21.15‹1.73
14.82‹2.58 28.67‹2.34
10.85‹2.87 26.92‹7.42
5.08‹0.00 32.62‹0.00
11.20‹0.34 21.83‹0.34
10.70‹0.00 25.83‹0.00
5.97‹0.91 40.88‹0.95
1h
Diazepam
Experimental
Chemistry
Control
1a
1b
1c
1d
1e
1f
1g
±
0/6
6/6
3/6
6/6
4/6
2/6
2/6
5/6
3/6
6/6
±
±
25
25
25
25
25
25
25
25
2.5
16.22‹0.84 24.82‹2.42
14.25‹1.98 22.23‹6.03
14.10‹1.02 21.34‹0.99
15.91‹1.60 21.58‹3.97
18.04‹1.31 11.35‹7.45
13.47‹0.66 11.00‹0.35
15.97‹2.62 14.36‹2.37
Melting points were measured on a Buchi 510 apparatus
and are uncorrected. 1H NMR and 13C NMR were
recorded on a Bruker AM (200 MHz) spectrometer and
were all consistent with molecular structures (ref. 15 and
Fig. 2). Microanalyses were done on a Perkin±Elmer
240 analyzer. All the reagents used were of commercial
grade and used as received.
1h
Diazepam
21.02‹3.87 7.81‹1.23
7.13‹0.79 48.29‹4.07
a
t1=sleep induction time (min); t2=sleeping time (min).
Ns=number of sleeping mice; Nt=total number of mice.
b
The following compounds were prepared according to
the literature: 2a,3 2b,4 2c,5 2d,6 2e,3 2f,10 5a±c,9 5d,f,10
5g,h,11 and 4-benzyl-2-p-toluenesulphonyloxymethyl-
morpholine.7 Satisfactory elemental analyses (‹0.4%)
for C, H, N, and S were obtained for all the new
described compounds.
Conclusions
In conclusion, the title compounds are generally active
ip in a series of mice models predictive of antidepressant
properties, with the viloxazine thiophene isoster (1f)
being the most active in the Porsolt test. Besides, they
show a light sedative action in the same pro®le as other
antidepressant drugs.
Route 1
General procedure for the synthesis of alkyl 3 - [2 - (4 -
benzyl - morpholinyl)methoxy]thiophene - 2 - carboxylate
(3a±e). A stirred solution of 4-benzyl-2-toluene-p-sul-

1354
C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
J2,3b=12.1, J3a,3b=1.2 Hz, 1H, H-3b), 2.17 (td,
J5,6=11.1, J5a±5b=4.3 Hz, 2H, H-5), 2.01 (s, 3H, CH3).
Anal. (C19H23NO4S), C, H, N, S.
Methyl 4- allyl -3- [(4- benzyl -2- morpholinyl)methoxy] -
thiophene-2-carboxylate (3d). Yield 31%. 1H NMR
(CDCl3) d 7.23 (m, 5H, phenyl), 7.04 (s, 1H, H-12), 5.87
(ddt, J15±14=5.3, J15±16=10.4, J2±3b=14.1 Hz, 1H, H-15),
5.08 (d, J=14.1 Hz, 2H, H-16), 3.92 (m, 1H, H-2), 3.86±
3.53 (m, 4H, H-6, H-7), 3.82 (s, 3H, OCH3), 3.53 (s, 2H,
CH2N), 3.25 (d, J14±15=5.5 Hz, 2H, H-14), 2.95 (dd,
J2,3a=12.1, J3a±3b=1.43 Hz, 1H, H-3a), 2.66 (dd,
J2,3b=12.4, J3a±3b=1.2 Hz, 1H, H-3b), 2.12 (td, 2H,
J5,6=10.3, J5a±5b=4.4 Hz, 2H, H-5). Anal.
(C21H25NO4S), C, H, N, S.
Figure 1.
Methyl 4-methylthio-3-[(4-benzyl-2-morpholinyl)meth-
1
oxy]thiophene-2-carboxylate (3e). Yield 78%. H NMR
(CDCl3) d 7.29 (m, 5H, phenyl), 6.98 (s, 1H, H-12), 3.91
(m, 1H, H-2), 3.90±3.75 (m, 4H, H-6, H-7), 3.82 (s, 3H,
OCH3), 3.55 (s, 2H, CH2N), 2.83 (dd, J2,3a=12.2, J3a±
3b=1.2 Hz, 1H, H-3a), 2.57 (dd, J2,3b=12.2, J3a±3b=1.2
Hz, 1H, H-3b), 2.38 (s, 3H, SCH3), 2.20 (td, J5,6=10.5,
J5a±5b=4.5 Hz, 2H, H-5). Anal. (C19H23NO4S2), C, H,
N, S.
Figure 2.
General procedure for the synthesis of 4 - benzyl - 2 -
thienyloxymethyl morpholines (4a±e). A suspension of
the respective compound 3a±e (0.05 mol) in a 50%
ethanolic 2 N NaOH solution (100 mL) was heated at
re¯ux for 1 h. The resultant mixture was cooled to room
temperature and acidi®ed with 1 N HCl solution to pH
4. The solvent was removed in vacuo and the residue
was treated with absolute EtOH (100 mL). The inor-
ganic salts were ®ltered o€ and washed with absolute
EtOH (2Â25 mL). The combined ®ltrates were evapo-
rated and the residue was heated at reduced pressure
(0.1 mm Hg) at 200ꢀC for 30 min. The oil obtained,
once cooled, was stirred for 30 min with a 2 N NaOH
solution in EtOAc (100 mL). The organic phase was
separated, dried over anhydrous Na2SO4, and the sol-
vent was removed. The residue was chromatographed
on a silica gel column (60 g silica gel) using as eluent a
mixture of n-hexane:EtOAc (5:2) to yield as pure oils
the following compounds.
phonyloxymethylmorpholine (6.83 g, 0.02 mol) and the
corresponding potassium salt of the alkyl 3-hydroxy-
thiophene-2-carboxylates (2a±e) (0.02 mol) in DMF
(70 mL) was heated at 120±150ꢀC for 17 h. The reaction
mixture was cooled, the solvent was removed in vacuo
and the residue was extracted with EtOAc and washed
with water. The organic extracts were dried over anhy-
drous Na2SO4, the solvent was removed and the residue
was puri®ed by a ¯ash chromatography column (100 g
silica gel) using a mixture of n-hexane:EtOAc (1:1) as
eluent, to yield the following oils.
Methyl 4-phenyl-3-[(4-benzyl-2-morpholinyl)methoxy]-
thiophene-2-carboxylate (3a). Yield 70%. 1H NMR
(CDCl3) d 7.68±7.15 (m, 11H, H-12, phenyl), 3.93 (m, 1H,
H-2), 3.82 (s, 3H, OMe), 3.80±3.71 (m, 4H, H-6, H-7),
3.52 (s, 2H, CH2N), 2.87 (dd, J2,3a=12.1, J3a±3b =1.2 Hz,
1H, H-3a), 2.68 (dd, J2,3b=12.1, J3a,3b=1.2 Hz, 1H, H-
3b), 2.17 (td, J5,6=11.1, J5a±5b =4.3 Hz, 2H, H-5). Anal.
(C24H25NO4S), C, H, N, S.
4 - Benzyl - 2 - [3 - (4 - phenylthienyloxymethyl)]morpholine
(4a). Yield 67%. 1H NMR (CDCl3) d 7.67±7.12 (m,
11H, 10 phenyl, H-12), 6.31 (d, J10±12=3.4 Hz, 1H,H-
10), 3.92 (q, J=5.65 Hz, 1H, H-2), 3.90±3.71 (m, 4H H-
6, H-9), 3.49 (s, 2H, CH2N), 2.89 (dd, J2,3a=12.1, J3a±
3b=1.3 Hz, 1H, H-3a), 2.70 (dd, J2,3b=12.1, J3a±
3b=1.31 Hz, 1H, H-3b), 2.18 (td, J5,6=10.5, J5a±5b=4.5
Hz, 2H, H-5). Anal. (C22H23NO2S), C, H, N, S.
Ethyl 3-[(4-benzyl-2-morpholinyl)methoxy]-5,6-dihydro-
4H-cyclopenta[b]thiophene-2-carboxylate (3b). Yield
76%. 1H NMR (CDCl3) d 7.29 (m, 5H, phenyl), 4.05 (q,
J=5.9 Hz, 2H, OCH2), 3.92 (m, 1H, H-2), 3.90±3.67 (m,
4H, H-6, H-7), 3.50 (s, 2H, CH2N), 2.87 (dd, J2,3a=12.0,
J3a±3b=1.4 Hz, 1H, H-3a), 2.84±2.61 (m, 7H, 2CH2 cycle,
H-5, H-3b), 2.48 (quint, J=8.2 Hz, 2H, CH2 cycle), 1.37
(t, J=5.9, 3H, CH3). Anal. (C22H27NO4S), C, H, N, S.
4-Benzyl-2-[3-(5,6-dihydro-4H-cyclopenta[b]thienyloxy-
Yield 88%. 1H NMR
methyl)] morpholine (4b).
Methyl 4-methyl-3-[(4-benzyl-2-morpholinyl)methoxy]-
thiophene-2-carboxylate (3c). Yield 60%. 1H NMR
(CDCl3) d 7.27 (m, 5H, phenyl), 6.81 (q, J=1.0 Hz, 1H,
H-12), 3.92 (m, 1H, H-2), 3.90±3.73 (m, 4H, H-6, H-7),
3.83 (s, 3H, OCH3), 3.46 (s, 2H, CH2N), 2.82 (dd,
J2,3a=12.1, J3a±3b=1.2 Hz, 1H, H-3a), 2.68 (dd,
(CDCl3) d 7.29 (m, 5H, phenyl), 6.01 (s, 1H, H-10), 3.91
(m, 1H, H-2), 3.85±3.69 (m, 4H, H-6, H-7), 3.51 (s, 2H,
CH2N), 2.91 (dd, J2,3a=12.0, J3a±3b=1.3 Hz, 1H, H-
3a), 2.86±2.60 (m, 7H, 2CH2 cycle, H-5, H-3b), 2.44
(quint, J =8.3 Hz, 2H cycle). Anal. (C19H23NO2S), C,
H, N, S.

C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
1355
4 - Benzyl - 2 - [3 - (4 - methylthienyloxymethyl)]morpholine
(4c). Yield 68%. 1H NMR (CDCl3) d 7.26 (m, 5H, phen-
yl), 6.81 (dq, J12±10=3.2, J12±14=1.0 Hz, H-12), 6.12 (d,
J=3.2 Hz, 1H, H-10), 3.93 (m, 1H, H-2), 3.91±3.76 (m,
4H, H-6, H-7), 3.48 (s, 2H, CH2N), 2.89 (dd, J2±3a=12.0,
J3a±3b=1.2 Hz, 1H, H-3a), 2.63 (dd, J2±3b=12.0, J3a±
3b=1.2 Hz, 1H, H-3b), 2.18 (td, J5±6=10.5, J5a±5b =4.5
Hz, 2H, H-5), 2.01 (s, 3H, CH3). Anal. (C17H21NO2S), C,
H, N, S.
J3a±3b=1.8 Hz, 1H, H-3b), 2.71 (m, 2H, H-5), 1.83 (s, 1H,
NH); 13C NMR (free amine) (CDCl3) d 152.23 (C-9),
138.24 (C-13), 132.21 (d, J=147.0 Hz, phenyl), 130.20 (d,
J=146.3, phenyl), 127.71 (phenyl), 127.46 (phenyl),
127.27 (d, J=146.2, phenyl), 118.93 (dd, J=182.9, J10±
12=3.9 Hz, C-12), 98.34 (dd, J=183.4, J10±12=4.21 Hz,
C-10), 74.62 (d, J=143.1, C-2), 71.72 (t, J=146.7, C-7),
67.92 (t, J=143.2, C-6), 48.54 (t, J=138.0, C-3), 45.92 (t,
J=141.3, C-5). Anal. (C15H17NO2S), C, H, N, S.
4-Benzyl-2-[3-(4-allylthienyloxymethyl)]morpholine (4d).
1
2-[3-(5,6-Dihydro-4H-cyclopenta[b]thienyloxymethyl)]-
morpholine (1b). Yield 83%. Mp 164±166ꢀC (acetone)
(oxalic salt). 1H NMR (free amine) (CDCl3) d 6.04 (s, 1H,
H-10), 3.92 (m, 1H, H-2), 3.94±3.78 (m, 2H, H-7), 3.70 (td,
J5±6=10.5, J6a±6b=3.6 Hz, 2H, H-6), 3.05 (dd, J2±
3a=11.0, J3a±3b=2.1 Hz, 1H, H-3a), 2.88±2.62 (m, 7H, H-
5, H-3b, CH2 cycle), 2.44 (quint, J=5.3 Hz, 2H, CH2
cycle), 1.89 (s, 1H, NH); 13C NMR (free amine) (CDCl3) d
152.12 (C-9), 141.42 (C-16), 137.44 (C-12), 99.23 (d,
J=182.0 Hz, C-10), 74.80 (d, J=142.5 Hz, C-2), 71.01 (t,
J=147.7 Hz, C-7), 67.90 (t, J=143.1 Hz, C-6), 48.41 (t,
J=145.4 Hz, C-3), 45.79 (t, J=134.8 Hz, C-5), 29.52 (t,
J=132.3 Hz, C-15), 29.15 (t, J=136.4 Hz, C-13), 27.01 (t,
J=133.0 Hz, C-14). Anal. (C12H17NO2S), C, H, N, S.
Yield 71%. H NMR (CDCl3) d 7.11 (m, 5H, phenyl),
6.93 (dt, J12±10=3.10, J12±14=1.0 Hz, 1H, H-12), 6.26 (d,
J=3.1 Hz, 1H, H-10), 5.86 (ddt, J15±14=5.4, J15±
16b=10.2, J15±16t=14.3 Hz, 1H, H-15), 5.10 (d, J16t±
15=13.9 Hz, 2H, H-16), 3.90 (m, 1H, H-2), 3.86±3.62 (m,
4H, H-6, H-7), 3.52 (s, 2H, CH2N), 3.23 (d, J14±15=5.4
Hz, 2H, H-14), 2.93 (dd, J2±3a=12.0, J3a±3b=1.3 Hz, 1H,
H-3a), 2.68 (dd, J2,3b=12.0, J3a±3b=1.3 Hz, 1H, H-3b),
2.17 (td, J5±6=10.5, J5a±5b=4.5 Hz, 2H, H-5). Anal.
(C19H23NO2S), C, H, N, S.
4-Benzyl-2-[3-(4-methylthiothienyloxymethyl)]morpholine
(4e). Yield 76%. 1H NMR (CDCl3) d 7.26 (m, 5H, phen-
yl), 6.82 (d, J=3.2, Hz, 1H, H-12), 6.21 (d, J=3.2 Hz, 1H,
H-10), 3.90 (m, 1H, H2), 3.87-3.73 (m, 4H, H-6, H-7), 3.52
(s, 2H, CH2N), 2.80 (dd, J2±3a=12.1, J3a±3b=1.0 Hz, 1H,
H-3a), 2.61 (dd, J2,3b=12.1, J3a±3b=1.0 Hz, 1H, H-3b),
2.34 (s, 3H, SCH3), 2.20 (td, J5±6=10.3, J5a±5b=4.2 Hz,
2H, H-5). Anal. (C17H21NO2S2), C, H, N, S.
2-[3-(4-Methylthienyloxymethyl)]morpholine (1c). Yield
87%. Mp 173±174ꢀC (acetone/MeOH) (oxalic salt). H
1
NMR (free amine) (CDCl3) d 6.81 (dq, J12±10=3.2, J12±
14=1.0 Hz, 1H, H-12), 6.17 (d, J=3.2 Hz, 1H, H-10), 3.95
(m, 1H, H-2), 3.91±3.77 (m, 2H, H-7), 3.68 (td, J5±6=10.8,
J6a±6b=3.9 Hz, 2H, H-6), 3.09 (dd, J2±3a=12.0, J3a±
3b=2.3 Hz, 1H, H-3a), 2.87 (dd, J2±3b=11.3, J3a±3b=2.4
Hz, 1H, H-3b), 2.70 (m, 2H, H-5), 2.09 (s, 1H, NH), 2.08
(s, 3H, CH3); 13C NMR (free amine) (CDCl3) d 155.47 (C-
9), 128.81 (C-13), 119.75 (dd, J=184.5, J10±12=5.8 Hz, C-
12), 96.69 (dd, J=183.1, J10±12=5.7 Hz, C-10), 74.32 (d,
J=143.4 Hz, C-2), 70.88 (t, J=144.0 Hz, C-7), 67.98 (t,
J=143.2 Hz, C-6), 47.96 (t, J=132.8 Hz, C-3), 45.34 (t,
J=131.5, C-5), 12.31 (qt, J=127.8, J=3.0 Hz, CH3).
Anal. (C10H15NO2S), C, H, N, S.
General procedure for the synthesis of 2-
thienyloxymethylmorpholines (1a±e) (Table 1). PdCl2 (5
g), C (12 g) and deionized water (100 mL) were mixed and
rapidly stirred while being heated to 80ꢀC and a solution
of lithium hydroxide (2.5 g) in water (10 mL) was added at
once and the heating was stopped. The mixture was stirred
overnight, ®ltered, washed with a 5% aqueous solution of
AcOH (100 mL) and with distilled water till the mother
liquors had a neutral pH. The solid obtained was dried in
vacuo at 60ꢀC over P2O5 for 24 h. The catalyst so obtained
(0.1 g) was added to a solution of the respective com-
pound 4a±e in anhydrous MeOH (10 mL) and the mixture
was hydrogenated at 1 atm, until the reaction ®nished
(control by TLC). The calalyst was ®ltered and washed
with anhydrous MeOH (10 mL) and the ®ltrates were
evaporated in vacuo to yield the free amine as a practically
pure oil, which was transformed into the oxalic salt, by
dissolving it in dry ether and adding dropwise, with stir-
ring, a saturated ethereal solution of oxalic acid to yield a
white solid, which was ®ltered and recrystallized from the
corresponding solvent.
2-[3-(4-Allylthienyloxymethyl)]morpholine (1d). Yield
96%. Mp 145±147ꢀC (acetone) (oxalic salt). 1H NMR (free
amine) (CDCl3) d 6.92 (dt, J12±10=3.1, J12±14=1.0 Hz, 1H,
H-12), 6.26 (d, J10±12=3.1 Hz, 1H, H-10), 5.86 (ddt, J15±
14=5.5, J15±16t=14.2 Hz, J15±16c=11.3 Hz, 1H, H-15),
5.10 (d, J16t±15=14.2 Hz, 2H, H-16), 3.95 (m, 1H, H-2),
3.91±3.79 (m, 2H, H-7), 3.70 (td, J6±5=10.5, J6a±6b=3.7
Hz, 2H, H-6), 3.23 (d, J14±15=5.5, J14±12=1.0 Hz, 2H, H-
14), 3.12 (dd, J2±3a=10.6, J3a±3b=2.8 Hz, 1H, H-3a), 2.96
(dd, J2±3b=9.8, J3a±3b=2.8 Hz, 1H, H-3b), 2.73 (m, 2H, H-
5), 1.82 (s, 1H, NH); 13C NMR (free amine) (CDCl3) d
153.28 (C-9), 128.94 (C-13), 135.28 (d, J=170.2 Hz,
CH=CH2), 119.45 (d, J=184.3 Hz, C-12), 115.38 (t,
J=169.4 Hz, CH=CH2), 97.32 (d, J=184.3 Hz, C-10),
74.99 (d, J=142.6 Hz, C-2), 71.03 (t, J=147.7 Hz, C-7),
68.02 (t, J=143.1 Hz, C-6), 48.13 (t, J=137.2 Hz, C-3),
45.89 (t, J=133.1, C-5), 38.24 (t, J=128.3, CH2). Anal.
(C12H17NO2S), C, H, N, S.
The following compounds were obtained according to
this procedure.
2-[3-(4-Phenylthienyloxymethyl)]morpholine (1a). Yield
92%. Mp 170±172ꢀC (acetone) (oxalic salt). H NMR
1
(CDCl3) d 7.52 (m, 2H phenyl), 7.35 (m, 3H, phenyl), 7.23
(d, J12±10=3.5 Hz, 1H, H-12), 6.34 (d, J10±12=3.5, 1H, H-
10), 3.98 (m, 1H, H-2), 3.91±3.75 (m, 2H, H-7), 3.68 (td,
J6±5=10.5, J6a±6b=3.7 Hz, 2H, H-6), 3.08 (dd, J2±
3a=12.6, J3a±3b=1.8 Hz, 1H, H-3a), 2.83 (dd, J2±3b=10.1,
2-[3-(4-Methylthiothienyloꢀxymethyl)]morpholine
(1e).
1
Yield 76%. Mp 152±154 C (acetone) (oxalic salt). H
NMR (free amine) (CDCl3) d 6.86 (d, J=3.3 Hz, 1H,

1356
C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
H-12), 6.28 (d, J=3.3 Hz, 1H, H-10), 3.97 (m, 1H, H-2),
3.92±3.74 (m, 2H, H-7), 3.65 (td, J6±5=10.7, J6a±6b=3.6
Hz, 2H, H-6), 3.12 (dd, J2±3a=11.0, J3a±3b=2.0 Hz, 1H,
H-3a), 2.85 (dd, J2±3b=11.2, J3a±3b=2.1 Hz, 1H, H-3b),
2.67 (m, 2H, CH2N), 2.40 (s, 3H, SCH3) 2.19 (s, 1H, NH);
13C NMR (free amine) (CDCl3) d 154.87 (C-9), 125.75 (C-
13), 119.60 (dd, J=183.2, J10±12=4.4 Hz, C-12), 98.22
(dd, J=184.5, J10±12=4.3 Hz, C-10), 74.61 (d, J=142.2
Hz, C-2), 71.65 (t, J=146.2 Hz, C-7), 67.95 (t, J=144.2
Hz, C-6), 48.65 (t, J=138.4 Hz, C-3), 45.88 (t, J=141.3
Hz, C-5), 16.35 (q, J=140.0 Hz, CH3). Anal.
(C10H15NO2S2), C, H, N, S.
2-[3-(4-Ethoxythienyloxymethyl)]morpholine (1f). Yield
42%. Mp 167±168ꢀC (acetone/MeOH) (oxalic salt). H
1
NMR (free amine) (CDCl3) d 6.19 (AB system JAB=4.0
Hz, 2H, H-12, H-10), 4.10 (q, J=7.1, 2H, OCH2-CH3),
3.98 (m, 1H, H-2), 3.88±3.71 (m, 2H, H-7), 3.63 (td, J6±
5=11.3, J6a±6b=3.5 Hz, 2H, H-6), 3.10 (dd, J2±3a=12.2,
J3a±3b=1.8, 1H, H-3a), 2.84 (dd, J2±3b=9.8, J3a±3b=1.8
Hz, 1H, H-3b), 2.70 (m, 2H, H-5), 1.83 (s, 1H, NH), 1.41
(t, J=7.0 Hz, 3H, CH3); 13C NMR (free amine) (CDCl3) d
147.97 (C-13), 147.34 (C-9), 98.18 (dd, J=182.9, J10±
12=4.6 Hz, C-12), 97.20 (dd, J=184.5, J10±12=4.3 Hz, C-
10), 74.69 (d, J=142.7 Hz, C-2), 71.69 (t, J=143.8 Hz, C-
7), 67.86 (t, J=141.1 Hz, C-6), 65.84 (tq, J=139.1, J15±
16=5.5 Hz, OCH2), 48.48 (t, J=136.4, C-3), 45.79 (t,
J=138.8, C-5), 14.58 (qt, J=126.6, J15±16=4.7, CH3).
Anal. (C11H17NO3S), C, H, N, S.
Route II
3-[3-(4-Allylthienyloxy)-1,2-epoxypropane (5d). This
compound was synthesized in a similar way to that
described for compounds 5a±c9 to give an oil in a 58%
yield, which was puri®ed on a silica gel column chroma-
tography using as eluent a mixture of n-hexane:EtOAc
2-[3-(2-Methylthienyloxymethyl)]morpholine (1g). Yield
ꢀ
1
48%. Mp 113±115 C (acetone/MeOH) (oxalic salt). H
NMR (free amine) (CDCl3) d 6.57 (AB system JAB=3.7
Hz, 2H, H±12, H-13), 3.99 (m, 1H, H-2), 3.92±3.74 (m,
2H, H-7), 3.63 (td, J6±5=10.0, J6a±6b=3.5 Hz, 2H, H-6),
2.99 (dd, J2±3a=12.0, J3a±3b=2.3 Hz, 1H, H-3a), 2.82
(dd, J2±3b=10.8, J3a±3b=2.4 Hz, 1H, H-3b), 2.70 (m,
2H, H-5), 2.15 (s, 3H, CH3), 1.81 (s, 1H, NH); 13C
NMR (free amine) (CDCl3) d 157.04 (C-9), 123.80 (dd,
J=186.4, J12±13=4.2 Hz, C-13), 121.45 (dd, J=182.6,
J12±13=3.8 Hz, C-12), 101.41 (C-10), 74.08 (d, J=142.5
Hz, C-2), 71.23 (t, J=145.8 Hz, C-7), 66.94 (t, J=142.2
Hz, C-6), 47.24 (t, J=133.4, C-3), 45.10 (t, J=132.6, C-
5), 13.24 (qt, J=127.3, J=2.8, CH3). Anal. (C10H15
NO2S), C, H, N, S.
1
(10:1). H NMR (CDCl3) d 6.92 (d, J=3.0 Hz, 1H, H-5
thiophene), 6.21 (d, J=3.0 Hz, 1H, H-2 thiophene), 5.87
(m, 1H, CH), 5.13 (d, J=14.5 Hz, 2H, ˆCH2), 4.35 (dd,
J1a±1b=11.9, J1a±2=2.9 Hz, 1H, OCH2), 3.97 (dd, J1a±
1b=11.9, J1b±2=5.9 Hz, 1H, OCH2), 3.31 (m, 1H, CH),
3.18 (d, J=6.6 Hz, 2H, CH2), 2.96±2.72 (m, 2H, CH-CH2-
O). Anal. (C10H12O2S), C, H, S.
3-[3-(4-Ethoxythienyloxy)]-1,2-epoxypropane (5f). This
1
compound was synthesized as above.7 Yield 65%. H
NMR (CDCl3) d 6.30 (d, J=4.0 Hz, 1H, H-5 thio-
phene), 6.15 (d, J=4.0 Hz, 1H, H-2 thiophene), 4.25
(dd, J1a±1b=11.7, J1a±2=2.8 Hz, 1H, OCH2), 4.05 (q,
J=7.1 Hz, 2H, OCH2-CH3), 3.95 (dd, J1a±1b=11.7, J1b±
2=5.8 Hz, 1H, OCH2), 3.40 (m, 1H, CH), 2.85 (m, 2H,
CH-CH2-O), 1.41 (t, J=7.1 Hz, 3H, CH3). Anal.
(C9H12O3S), C, H, S.
2-[2-(3-Methylthienyloxymethyl)]morpholine (1h). Yield
49%. Mp 118±119ꢀC (acetone/MeOH) (oxalic salt). H
1
NMR (free amine) (CDCl3) d 6.93 (d, J=5.5 Hz, 1H, H-
12), 6.77 (d, J=5.5 Hz, 1H, H-13), 3.98 (m, 1H, H-2),
3.97±3.62 (m, 2H, H-7), 3.62 (td, J6±5=10.3, J6a±6b=3.5
Hz, 2H, H-6), 2.93 (dd, J2±3a=12.4, J3a±3b=2.3 Hz, 1H,
H-3a), 2.84 (dd, J2±3b=11.8, J3a±3b=2.3 Hz, 1H, H-3b),
General procedure for the synthesis of 2-thienyl-
oxymethylmorpholines (1a±d and 1f±h) (Table 1). A
solution of the corresponding compound 5a±d and 5f±h
(0.05 mol) in DMSO (25 mL) was added slowly to a stirred
mixture of 1,2,3-oxathiazolidine 2,2-dioxide (17 g, 0.125
mol) in a 70% solution of NaOH (15 mL) at 50±55ꢀC,
keeping this temperature during the addition. The reaction
mixture was stirred for 1 h and after a new amount of a
70% solution of NaOH (15 mL) was added and the resul-
tant mixture was stirred for 16 h at the same temperature
(50±55ꢀC). After cooling to room temperature it was dilu-
ted with water and extracted with EtOAc (2Â50 mL). The
organic extracts were washed with water, dried over
anhydrous Na2SO4 and the solvent was removed in vacuo.
The residue was puri®ed by a ¯ash silica gel (60 g) column
chromatography using MeOH as eluent to yield the free
amine as a practically pure oil, which was transformed into
its oxalic salt as described in the route I.
2.69 (m, 2H, H-5), 2.28 (s, 3H, CH3), 1.79 (s, 1H, NH); 13
C
NMR (free amine) (CDCl3) d 158.47 (C-9), 122.35 (dd,
J=188.5, J12±13=4.2 Hz, C-13), 118.94 (dd, J=189.4, J12±
13=4.2 Hz, C-12), 103.56 (C-10), 73.71 (d, J=142.5 Hz,
C-2), 70.14 (t, J=140.0 Hz, C-7), 66.31 (t, J=146.3 Hz, C-
6), 47.04 (t, J=133.8, C-3), 43.31 (t, J=135.4 Hz, C-5),
12.53 (qt, J=128.4, J15±16=3.4, CH3). Anal.
(C10H15NO2S), C, H, N, S.
Route III
General procedure for the synthesis of 1-benzylamino-3-
thienyloxy-2-propanols (6a±d and 6f±h). The corres-
ponding compound (5a±d and 5f±h) (0.017 mol) was
dissolved in benzylamine (5.45 g, 0.051 mol) and the
reaction mixture was heated at 100ꢀC for 30 min. Once
cooled, the benzylamine was distilled at reduced pres-
sure (0.1 mm Hg) and the resultant residue was washed
with n-hexane and recrystallized from a mixture of n-
hexane:EtOAc (1:1).
The following compounds were obtained according to
this procedure:
Compounds 1a (47% yield), 1b (43% yield), 1c (38%
yield), 1d (40%), which showed the same analytical
spectroscopic data, than that referred in the route I.
The following compounds were obtained according to
this procedure.

C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
1357
1-Benzylamine-3-[3-(4-phenylthienyloxy)]-2-propanol
(6a). Yield 82%. Mp 76±78ꢀC. 1H NMR (CDCl3) d 7.41
(m, 10H phenyl), 7.19 (d, J=3.0 Hz, 1H, H-5 thiophene),
6.32 (d, J=3.0 Hz, 1H, H-2 thiophene), 3.96 (m, 3H,
OCH2-CH), 3.73 (s, 2H, CH2N), 3.00 (s, 1H, NH), 2.77 (d,
J=8.0 Hz, 2H, CH2N), 2.62 (s, 1H, OH). Anal. (C20H21
NO2S), C, H, N, S.
was added dropwise with stirring and the mixture was
stirred for 18 h at room temperature, was washed with a 2
N HCl solution and after with water. The organic layer
was separated and dried over anhydrous Na2SO4. The
solvent was removed in vacuo yielding the corresponding
N-benzylchloroacetamide as an oil.
A solution of this oil in anhydrous MeOH (5 mL) was
added to a solution of sodium (0.7 g, 0.03 mol) in
anhydrous MeOH (50 mL) and the mixture was heated
at re¯ux for 8 h. The solvent was removed and the resi-
due was treated with water and EtOAc. The aqueous
layer was separated and extracted twice with EtOAc.
The combined organic extracts were washed with water,
dried over anhydrous Na2SO4 and evaporated to dry-
ness to yield an oil, which was puri®ed on a silica gel
(150 g silica gel) column chromatography using as elu-
ent a mixture of n-hexane:EtOAc (1:1). The following
compounds were obtained according to this procedure:
1-Benzylamine-3-[3-(5,6-dihydro-4H-cyclopenta[b]-thienyl-
ꢀ
1
oxy)]- 2-propanol (6b). Yield 72%. Mp 98±100 C. H
NMR (CDCl3) d 7.28(s, 5H phenyl), 6.01 (s, 1H, H-10),
3.98 (m, 3H, OCH2-CH), 3.82 (s, 2H, CH2N), 2.98 (s, 1H,
NH), 2.81 (t, J=5.90 Hz, 2H, CH2 cycle), 2.75±2.31 (m,
7H, 2CH2 cycle, CH2N and OH). Anal. (C17H21NO2S), C,
H, N, S.
1-Benzylamine-3-[3-(4-methylthienyloxy)]-2-propanol
(6c). Yield 87%. Mp 83±85ꢀC. 1H NMR (CDCl3) d 7.33
(s, 5H, phenyl), 6.87 (d, J=3.0 Hz, 1H, H-5 thiophene),
6.21 (d, J=3.0 Hz, 1H, H-2 thiophene), 4.03 (m, 3H,
OCH2-CH), 3.47 (s, 2H, CH2N), 3.08 (s, 1H, NH), 2.89 (d,
J=7.5 Hz, 2H, CH2N), 2.63 (s, 1H, OH), 2.13 (s, 3H,
CH3). Anal. (C15H19NO2S), C, H, N, S.
4-Benzyl-2-[3-(4-phenylthienyloxymethyl)]morpholin-5-
one (7a). Yield 84%. Mp 118±120ꢀC (PriOH). H NMR
1
(CDCl3) d 7.54±7.13 (m, 11H, phenyl and H-5 thiophene),
6.30 (d, J=3.5 Hz, 1H, H-2 thiophene), 4.58 (d, J=9.8
Hz, 2H, OCH2CO), 4.28 (d, J=3.5 Hz, 2H, OCH2), 4.25±
3.81 (m, 1H, CH), 3.93 (s, 2H, CH2N), 3.29 (m, 2H,
CH2N). Anal. (C22H21NO3S), C, H, N, S.
1-Benzylamine-3-[3-(4-allylthienyloxy)]-2-propanol (6d).
ꢀ
1
Yield 88%. Mp 62±64 C. H NMR (CDCl3) d 7.31 (s,
5H, phenyl), 6.90 (d, J=3.0 Hz, 1H, H-5 thiophene), 6.19
(d, J=3.0 Hz, 1H, H-2 thiophene), 5.88 (m, 1H, CH), 5.13
(d, J=14.5 Hz, 2H, ˆCH2), 3.92 (s, 3H, OCH2-CH), 3.71
(s, 2H, CH2N), 3.21 (d, J=6.6 Hz, 2H, CH2), 3.00 (s, 1H,
NH), 2.77 (d, J=8.0 Hz, 2H, CH2N), 2.63 (s, 1H, OH).
Anal. (C17H21NO2S), C, H, N, S.
4-Benzyl-2-[3-(5,6-dihydro-4H-cyclopenta[b]thienyloxy-
methyl)]morpholin-5-one (7b). Yield 81%. Mp 93±95ꢀC
(PriOH). 1H NMR (CDCl3) d 7.28 (s, 5H, phenyl), 6.02 (s,
1H, H-2 thiophene), 4.63 (d, J=4.2 Hz, 2H, OCH2CO),
4.27 (d, J=3.5 Hz, 2H, OCH2), 4.24±3.80 (m, 1H, CH),
3.94 (s, 2H, CH2N), 3.27 (m, 2H, CH2N), 2.81 (m, 2H,
CH2 cycle), 2.73-2.32 (m, 4H, 2 CH2 cycle). Anal.
(C19H21NO3S), C, H, N, S.
1-Benzylamine-3-[3-(4-ethoxythienyloxy)]-2-propanol
(6f). Yield 82%. Mp 76±78ꢀC. 1H NMR (CDCl3) d 7.27
(m, 5H, phenyl), 6.19 (AB system, JAB=3.9 Hz, 2H, H-2
and H-5 thiophene), 4.00 (m, 3H, OCH2-CH), 3.89 (q,
J=7.5 Hz, 2H, OCH2-CH3), 3.85 (s, 2H, CH2N), 2.83 (s,
2H, NH and OH), 2.80 (d, J=6.5 Hz, 2H, CH2N), 1.37 (t,
J=7.5 Hz, 3H, CH3). Anal. (C16H21NO3S), C, H, N, S.
4-Benzyl-2-[3-(4-methylthienyloxymethyl)]morpholin-5-
one (7c). Yield 85%. Mp 71±73ꢀC (n-hexane:EtOAc). 1H
NMR (CDCl3) d 7.33 (s, 5H, phenyl), 6.87 (d, J=3.0 Hz,
1H, H-5 thiophene), 6.21 (d, J=3.0 Hz, 1H, H-2 thio-
phene), 4.55 (d, J=4.3 Hz, 2H, OCH2CO), 4.28 (d, J=3.5
Hz, 2H, OCH2), 4.25±3.81 (m, 1H, CH), 3.95 (s, 2H,
CH2N), 3.27 (m, 2H, CH2N), 2.13 (s, 3H, CH3). Anal.
(C17H19NO3S), C, H, N, S.
1-Benzylamine-3-[3-(2-methylthienyloxy)]-2-propanol
(6g). Yield 92%. Mp 78±80ꢀC. 1H NMR (CDCl3) d 7.31
(s, 5H, phenyl), 7.00 (d, J=4.5 Hz, 1H, H-5 thiophene),
6.85 (d, J=4.5 Hz, H-4 thiophene), 4.05 (s, 3H, OCH2-
CH), 3.82 (s, 2H, CH2N), 2.91 (s, 2H, OH and NH), 2.67
(d, J=7.0 Hz, 2H, CH2N), 2.13 (s, 3H, CH3). Anal.
(C15H19NO2S), C, H, N, S.
4-Benzyl-2-[3-(4-allylthienyloxymethyl)]morpholin-5-one
1
(7d). Yield 80%. Oil. H NMR (CDCl3) d 7.31 (s, 5H,
phenyl), 6.92 (d, J=3.05 Hz, 1H, H-5 thiophene), 6.28 (d,
J=3.0 Hz, 1H, H-2 thiophene), 5.88 (m, 1H, CH), 5.13 (d,
J=14,5 Hz, 2H, ˆCH2), 4.65 (d, J=4.3 Hz, 2H,
OCH2CO), 4.38 (d, J=3.2 Hz, 2H, OCH2), 4.21±3.83 (m,
1H, OCH), 3.94 (s, 2H, CH2N), 3.25 (m, 2H, CH2N), 3.12
(d, J=6.6 Hz, 2H, CH2). Anal. (C19H21NO3S), C, H, N, S.
1-Benzylamine-3-[2-(3-methylthienyloxy)]-2-propanol
(6h). Yield 80%. Mp 73±75ꢀC. 1H NMR (CDCl3) d 7.29
(s, 5H, phenyl), 6.56 (s, 2H, H-4 and H-5 thiophene), 3.99
(s, 3H, OCH2-CH), 3.81 (s, 2H, CH2N), 2.77 (d, J=7.2
Hz, 2H, CH2N), 2.53 (s, 2H, OH and NH), 2.06 (s, 3H,
CH3). Anal. (C15H19NO2S), C, H, N, S.
4-Benzyl-2-[3-(4-ethoxythienyloxymethyl)]morpholin-5-
one (7f). Yield 83%. Mp 76±78ꢀC (PriOH). H NMR
1
General procedure for the synthesis of 4-benzyl-2-
thienyloxy-methylmorpholin-5-ones (7a-d and 7f-h). A
mixture of the corresponding compound 6a±d and 6f±h
(0.03 mol) and triethylamine (4.2 mL, 0.03 mol) was
dissolved in anhydrous CH2Cl2 (15 mL). The reaction
mixture was cooled at 0ꢀC and a solution of chloro-
acetyl chloride (2.28 mL, 0.03 mol) in CH2Cl2 (5 mL)
(CDCl3) d 7.28 (m, 5H, phenyl), 6.17 (AB system,
JAB=3.5 Hz, 2H, H-5 and H-2 thiophene), 4.63 (d, J=3.3
Hz, 2H, OCH2CO), 4.32 (d, J=4.0 Hz, 2H, OCH2), 4.24±
3.32 (m, 3H, CH and OCH2-CH3), 3.94 (s, 2H, CH2N),
3.29 (m, 2H, CH2N), 1.37 (t, J=7.5 Hz, 3H, CH3). Anal.
(C18H21NO4S), C, H, N, S.

1358
C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
4-Benzyl-2-[3-(2-methylthienyloxymethyl)]morpholin-5-
1
General procedure for the synthesis of 2-thienyloxy-
methylmorpholines (1a±d and 1f±h) (Table 2). These
compounds were synthesized as described in route I.
The yields for compounds 1f±h, from compounds 4f±h
are 1f (83%), 1g (91%) and 1h (93%). Their analytical
and spectroscopic data identical to those described in
route II.
one (7g). Yield 79%. Oil. H NMR (CDCl3) d 7.31 (s,
5H, phenyl), 7.02 (d, J=4.5 Hz, 1H, H-5 thiophene),
6.85 (d, J=4.5 Hz, 1H, H-4 thiophene), 4.59 (d, J=9.6
Hz, 2H, OCH2CO), 4.25 (d, J=3.5 Hz, 2H, OCH2),
4.24±3.80 (m, 1H, CH), 3.92 (s, 2H, CH2N), 3.26 (m,
2H, CH2N), 2.12 (s, 3H, CH3). Anal. (C17H19NO3S), C,
H, N, S.
Pharmacological assays
4-Benzyl-2-[2-(3-methylthienyloxymethyl)]morpholin-5-
1
one (7h). Yield 83%. Oil. H NMR (CDCl3) d 7.29 (s,
Male and female albino Swiss mice (22±28 g) were pur-
chased from Interfauna (Barcelona, Spain) and were
housed in groups of 10/cage for a minimum of three
days prior to behavioural studies with free access to
standard laboratory food and tap water and maintained
on a 12/12 h light±dark cycle (light from 8.00 a.m. to
8.00 p.m.). All compounds under study were dissolved
in 0.9% saline and administered ip. Control animals
received, under the same conditions, 0.9% saline solu-
tion. Each experimental dose group consisted of 5 ani-
mals unless otherwise stated and the ambient
temperature was 22‹1ꢀC, except for the potentiation of
barbiturate sleeping time which were carried out in a
room maintained at 30‹1ꢀC.
5H, phenyl), 6.52 (s, 2H, H-4 and H-5 thiophene), 4.56 (d,
J=10.3 Hz, 2H, OCH2CO), 4.32 (d, J=3.0 Hz, 2H,
OCH2), 4.98±3.87 (m, 1H, CH), 3.94 (s, 2H, CH2N), 3.25
(m, 2H, CH2N), 1.99 (s, 3H, CH3). Anal. (C17H19NO3S),
C, H, N, S.
General procedure for the synthesis of 4-benzyl-2-
thienyl-oxymethylmorpholines (4a±d and 4f±h). A mix-
ture of the respective compound 7a±d, 7f±h (0.02 mol)
and 15 g of LiAlH4 in 200 mL of Et2O was heated under
re¯ux for 6 h and then cooled. EtOAc (100 mL) was
added and the mixture was heated under re¯ux for 10
min to decompose LiAlH4. The organic phase was
washed with water (two 100 mL portions) dried and
evaporated to give an oil as residue, which was chro-
matographed in a silica gel column as described in
route I.
LD50 in mice
The ld50 was calcultated from the lethality within 3
days after po and ip administration of the drugs.16.
The following compounds were obtained according to
this procedure.
E€ect on tetrabenazine-induced ptosis, hypothermia and
suppression of locomotor activity
Compounds 4a (79% yield), 4b (82% yield), 4c (72%
yield), 4d (76% yield), which showed the same analytical
and spectroscopic data, as those referred in route I.
Mice with a rectal temperature between 36 and 38ꢀC
prior to the experiment were used. Mice received ip each
test drug 30 min before the administration of tetra-
benazine (32 mg/kg ip), which was dissolved in 0.1 M
tartaric acid followed by adjustment to pH 6 with
NaOH 10%. 30 min after the intraperitoneally injection
of tetrabenazine the animals were placed at the center of
a disk (20 cm in diameter) and the akinesia and the
degree of ptosis exhibited by each mouse was estimated
within 10 s. Mice were judged not to be akinetic if it eli-
cited one or more of the following responses: (1) walk to
the edge of the disk and look over the side, (2) mice move
180ꢀ in place, (3) mice display head movement of 90ꢀ in
one direction inmediately followed by a 45ꢀ movement in
the opposite direction. The degree of ptosis was rated
according to the following rating scale: 0, eyes open; 1,
one-quarter closed; 2, half closed, 3, three-quarters
closed; and 4, completely closed.
4 - Benzyl - 2 - [3 - (4 - ethoxythienyloxymethyl)]morpholine
(4f). Yield 74%. 1H NMR (CDCl3) d 7.28 (m, 5H, phen-
yl), 6.12 (AB system JAB=3.25 Hz, 2H, H-10, H-12), 4.02
(q, J=6.8, 2H, OCH2-CH3), 3.96 (m, 1H, H-2), 3.92±3.69
(m, 4H, H-6, H-7), 3.50 (s, 2H, CH2N), 2.93 (dd, J2±
3a=12.0, J3a=3b=1.3 Hz, 1H, H-3a), 2.65 (dd, J2±3=12.0,
J3a±3b=1.3 Hz, 1H, H-3b), 2.21 (td, J5±6=10.4, J5a±
5b=4.5 Hz, 2H, H-5), 1.38 (t, J=7.0 Hz, 3H, CH3). Anal.
(C18H23NO3S), C, H, N, S.
4 - Benzyl - 2 - [3 - (2 - methylthienyloxymethyl)]morpholine
(4g). Yield 80%. 1H NMR (CDCl3) d 7.31 (m, 5H,
phenyl), 6.57 (AB system JAB=3.8 Hz, 2H, H-10, H-
12), 3.94±3.62 (m, 5H, H-2, H-6, H-7), 3.51 (s, 2H,
CH2N), 2.86 (dd, J2±3a=12.0, J3a=3b=1.2 Hz, 1H, H-
3a), 2.71 (dd, J2±3b=12.1, J3a±3b=1.2 Hz, 1H, H-3b),
2.16 (td, J5±6=10.5, J5a±5b=4.6 Hz, 2H, H-5), 2.09 (s,
3H, CH3). Anal. (C17H21NO2S), C, H, N, S.
The rectal temperature of each group was measured
with a thermistor thermometer (Panlab 0331) 30 and 60
min after ip administration of tetrabenazine.
4 - Benzyl - 2 - [2 - (3 - methylthienyloxymethyl)]morpholine
(4h). Yield 74%. 1H NMR (CDCl3) d 7.36 (m, 5H, phen-
yl), 6.93 (d, J=5.5 Hz, 1H, H-12) 6.77 (d, J=5.5 Hz, 1H,
H-13), 3.97±3.61 (m, 5H, H-2, H-6, H-7), 3.50 (s, 2H,
CH2N), 2.85 (dd, J2±3a=12.0, J3a=3b=1.3 Hz, 1H, H-3a),
2.70 (dd, J2±3b=12.0, J3a±3b=1.3 Hz, 1H, H-3b), 2.19 (td,
J5±6=10.5, J5a±5b=4.5 Hz, 2H, H-5), 2.03 (s, 3H, CH3).
Anal. (C17H21NO2S), C, H, N, S.
E€ect on apomorphine-induced climbing, hypothermia
and stereotyped behaviour in mice
According to the protocol proposed by Puech et al.17
apomorphine (16 mg/kg) was injected subcutaneously to
groups of 6 mice 30 min after ip administration of the
drug. Mice were immediately placed in individual wire

C. Corral et al. / Bioorg. Med. Chem. 7 (1999) 1349±1359
1359
mesh cages (10Â10Â20 cm high) and 20 min later were
Interaction with barbiturate-induced sleep in mice
rated for climbing and stereotyped behaviour. Stereo-
typy was scored (0±3) according to their intensity.
Climbing behaviour was rated according to the follow-
ing scale: four paws on the bottom of the cage (no
climbing)=0; two paws on the wall=1; four paws on
the wall=2.
Sodium pentobarbital at a subhypnotic dose of 20 mg/kg
or at a hypnotic dose of 40 mg/kg was injected ip to groups
of 6 mice 30 min after ip administration of the drug. The
number of mice which lose righting re¯ex at subhypnotic
dose, the latency and the duration of the sleep (loss and
recovery of the righting re¯ex) were recorded.
Temperature was measured before and 30 min after
apomorphine administration. Mice with a rectal tem-
perature between 36 and 38ꢀC prior to experiment were
used.
Statistical analysis
Data were analysed by one-way analysis of variance
(ANOVA) followed by Student's unpaired t-test.20
A
probability level of 0.05 or less was accepted as signi®cant.
The chi-square test was used for the percentage of loco-
motor activity in tetrabenazine test. Ptosis induced by
tetrabenazine, stereotypy and climbing behaviour induced
by apomorphine, and number of head twitches and syn-
drome induced by 5-HTP were analyzed using the Mann±
Whitney test for non-parametric data.
E€ect on 5-hydroxytryptophan (5-HTP) syndrome in
mice
Test drugs were administered ip 30 min before 50 mg/kg
L-5-HTP. The mice were then placed into glass bell jars
and 14 min later the number of head twitches was
counted in ®ve 2-min intervals (between 14 and 16, 24
and 26, 34 and 36, 44 and 46 and 54 and 56 min).
Mice were also observed at these intervals for the pre-
sence or absence of whole body tremor, forepaw tread-
ing, hind-lamb abduction and outstretched posture with
the abdomen resting on the cage ¯oor. The total score
for each mouse was calculated (maximum possible
score=25, including into the syndrome the presence or
absence of head-twitches).
References
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E€ect on the forced swimming test in mice (Porsolt
test)18,19
This test was performed according to the method
described by Porsolt et al. One hour after ip adminis-
tration of the test drugs, mice were individually forced
to swim in a transparent glass vessel (25 cm high, 10 cm
in diameter) ®lled with 6 cm of water at 21±24ꢀC. The
total duration of immobility (s) was measured during
the last 4 min of a single 6 min test session. Mice were
considered immobile when they made no further
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keep their heads above the water. Each experimental
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7. McLoughlin, B. J. Morpholine Derivatives: UK Patent
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14. Compound 1c in some tests at higher doses (Tables 5 and
8) di€ers somewhat from 1g and 1h.
E€ect on spontaneous motor activity in mice
Locomotor activity was recorded with a photocell
activity meter for 15 min beginning 30 and 60 min after
ip administration of each test drug.
15. The numbering used for the assignment of the NMR data
is exempli®ed for compound 1d (Fig. 2).
16. Turner, R. In Screening Methods in Pharmacology; Aca-
demic Press: New York, 1965; pp. 60±68.
17. Puech, A.; Chermat, R.; Poncelet, M.; Doare, L.; Simon,
P. Psychopharmacology 1981, 75, 84.
E€ect on normal body temperature
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1977, 229, 327.
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20. Tallarida, R. J.; Murray, R. B. In Manual of Pharmacolo-
gic Calculations with Computer Programs. 2nd ed.; Springer
Verlag: New York, 1986, pp 131±134.
The rectal temperature of the mice was measured with a
thermistor thermometer (Panlab 0331) prior to the
experiment and 1, 2, 4, 6 and 24 h after ip administra-
tion of each test drug. Mice with a rectal temperature
between 36 and 38ꢀC prior to experiment were used.