Synthesis of various analog derivatives of ORG13514 as 5-HT(1A) ligands

Article abstract of DOI:10.1016/S0014-827X(99)00106-8

In connection with the development of new potential 5-HT(1A) ligands, multistep synthesis of N-substituted-3-aminomethyl-2,3-dihydro-1,4- dioxinol[2,3-b]pyridine derivatives as ORG13514 analogs are described. Their biological activity as 5-HT(1A) type lig

Full text of DOI:10.1016/S0014-827X(99)00106-8

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 791–799
Synthesis of various analog derivatives of ORG13514 as 5-HT1A
ligands
Corinne Comoy a, Abdelhakim Benarab a, Michel Leinot b, Andre´ Monteil b,
Ge´rald Guillaumet a,*
a Institut de Chimie Organique et Analytique, associe´ CNRS, Uni6ersite´ d’Orle´ans, BP 6759, 45067 Orleans Cedex 2, France
b RL-CERM, Z.I. de la Varenne, Rue H. Goudier, 63203 Riom Cedex, France
Received 19 January 1999; accepted 6 August 1999
Abstract
In connection with the development of new potential 5-HT1A ligands, multistep synthesis of N-substituted-3-aminomethyl-2,3-
dihydro-1,4-dioxinol[2,3-b]pyridine derivatives as ORG13514 analogs are described. Their biological activity as 5-HT1A type
ligands is reported and compared with ORG13514 affinity and selectivity for 5-HT1A receptors. © 1999 Elsevier Science S.A. All
rights reserved.
Keywords: 2,3-Dihydro-1,4-dioxino[2,3-b]pyridine; 5-HT1A receptor binding; Anti-depressant drug
1. Introduction
we performed synthetic and pharmacological activity
studies of ORG13514 [22] and ORG13653 [23], pyridine
isosters of MDL72832 and MDL73005, respectively
(Fig. 1).
We describe in the present paper the synthesis of
3-aminomethyl-2,3-dihydro-1,4-dioxino[2,3-b]pyridines
(1), as ORG13514 analogs, with a n-propyl- or
n-butylchain and amide or imide moiety (Fig. 2).
Serotonin (5-HT, 5-hydroxytryptamine) was discov-
ered as a central neurotransmitter about 40 years ago
and disorders of serotoninergic transmission were
known to implicate modifications in physiological, and
pathophysiological processes [1–5]. Serotonin receptors
were classified in seven types (5-HT1–7) and several
classes have been further subdivided into different sub-
types [6].
2. Chemistry
The 5-HT1A receptor subtype is the best studied and
it was shown to be involved in psychiatric disorders
such as depression [7–9] and anxiety [10,11]. Long
chain arylpiperazines with an amide or imide moiety
represent one of the most important classes of 5-HT1A
receptor ligands, for instance buspirone, the first agent
to be approved for clinical use [12–14], and gepirone.
The 2,3-dihydro-1,4-benzodioxine family, substituted
with an alkylimide group like MDL72832 and
MDL73005, was also reported to exhibit high affinity
for 5-HT1A receptors (Fig. 1) [15,16].
The general procedure for the preparation of the
various 3-aminomethyl-2,3-dihydro-1,4-dioxino[2,3-b]-
pyridines (1a–f) is reported in Scheme 1. The 3-(2,3-di-
hydro-1,4-dioxino[2,3-b]pyridine)yl methanamine (2)
was conveniently obtained in four steps. First, the
reaction of 2-chloro-3-pyridinol and epichlorhydrin in
the presence of sodium hydride in N,N-dimethylfor-
mamide afforded 2-chloro-3-(oxiranylmethoxy)pyridine
as an intermediate. Then, ring opening of this epoxide
using sodium azide followed by an intramolecular cycli-
sation and a reduction of the azide gave amine 2 [23].
The expected compounds 1a–f were obtained from 2 by
a N-alkylation using the appropriate bromoderivatives,
triethylamine and a catalytic amount of potassium io-
dide in N,N-dimethylformamide. Bromobutylimide
derivatives were commercially available or obtained by
In connection with our work concerning the prepara-
tion of products liable to affect the central nervous
system [17–21] and particularly the 5-HT1A receptor,
* Corresponding author.
E-mail address: c.comoy@meseb.u-nancy.fr (C. Comoy)
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00106-8

792
C. Comoy et al. / Il Farmaco 54 (1999) 791–799
Fig. 2.
the expected derivatives 1g and 1h in 74 and 68% yield,
respectively.
The third studied series deals with the N-methyl
substituted class (Scheme 3). The ring opening of epoxide
3 with benzylmethylamine in tetrahydrofuran followed
by an intramolecular cyclization of the obtained 1-(2-
chloro-3-pyridinyl)alcohol in the presence of sodium
hydride, in ethylene glycol dimethyl ether, gave the
expected methylamine 7 in good yield. Debenzylation of
7 by the catalytic hydrogenolysis with palladium on
carbon in methanol, in the presence of hydrochloric acid,
led to the derivative 8 in 82% yield. Then, 8 was alkylated
with appropriate imides in the presence of triethylamine
and a catalytic amount of potassium iodide, in N,N-
dimethylformamide, to afford the expected compounds
1i and 1j in 89 and 88% yield, respectively.
Fig. 1.
known procedures [18]. Bromobutylamide derivatives
were prepared according to the procedure reported in
Section 5.
The second part of our study concerned the
elaboration of derivatives 1g–h. To increase the overall
yield, the procedure outlined in Scheme 2 was carried out.
The ring opening of the 2-chloro-3-(oxiranylmeth-
oxy)pyridine (3) [24] by the N-benzyl-N-[3-(benzyl-
oxy)propyl]amine [25] in tetrahydrofuran yielded the
expected amine 4 (97%). Treatment of 4 with sodium
hydride in ethylene glycol dimethyl ether led to an
intramolecular cyclization and gave the dioxinopyridine
5 in satisfactory yield (60%). The benzyl groups were
removed by catalytic hydrogenolysis using palladium on
carbon in methanol in the presence of hydrochloric acid
to afford the derivative 6 in good yield (78%). Then, a
Mitsunobu reaction [26,27] between the alcohol 6 and
tetramethylene glutarimide or phthalimide, in the pres-
ence of equimolar quantity of triphenylphosphine and
diethyl azodicarboxylate in tetrahydrofuran, afforded
We had already described the synthesis and spectral
data of imidoethyl-3-aminomethyl-2,3-dihydro-1,4-diox-
ino[2,3-b]pyridine
derivatives
ORG13653
and
ORG13380 (Fig. 3) [23].
3. Biological results and discussion
The biological activity of 1a–j, ORG13653 and
ORG13380 was studied and the results were compared
with the affinity and the selectivity of ORG13514 for the
5-HT1A receptors. The binding affinities (pKi) were
determined on several 5-HT receptor subtypes, on a1-
and a2-adrenergic, and on D2-dopaminergic receptors
using rat brain homogenates as described in Section 5
[28–33]. Also included are the pKi values of the reference
compounds ORG13514, MDL72832 and Buspirone.
Scheme 1.

C. Comoy et al. / Il Farmaco 54 (1999) 791–799
793
Scheme 2.
0.1 mg/kg sc and 1 mg/kg po for ORG13514 and of 0.8
mg/kg sc for 1a. In comparison, buspirone had ED50
values of 1 mg/kg sc and 40 mg/kg po, 8-OH-DPAT 0.1
mg/kg sc and \10 mg/kg po, and MDL72832 0.1
mg/kg sc.
In addition studies of the effects in EEG-defined rat
sleep-waking behaviour [35–38] show that amine
ORG13514 causes a selective reduction of the total
duration of REM-sleep at very low doses (ED50=0.32
mg/kg i.p.) compared to 2.2 mg/kg i.p. for buspirone.
Moreover, this compound increases the latencies peri-
ods before REM and deep-sleep, which is characteristic
of anti-depressant drugs. The duration of the effects is
dose dependant and lasting from 4 to 8 h after
administration.
The derivatives ORG13514, 1a, 1b, 1c, 1d, 1e and 1f
were reported to display a high or very high affinity for
5-HT1A sites with pKi values of 10.9, 8.9, 9.1, 9.8, 8.5,
9.1 and 8.7, respectively. The compounds 1g, 1h, 1i, 1j,
ORG13653 and ORG13380 show much reduced affinity
in so far as their pKi values are lower than 8.0. Further-
more 1a and ORG13514 exhibited a 100 or 10 000-fold
selectivity for the 5-HT1A receptors, respectively, com-
pared to the 5-HT1B, 5-HT2A, 5-HT2C, a1, a2 and D2
receptors. Moreover, ORG13514 and 1a are around
10–100-fold more selective than MDL72832 for the
5-HT1A sites (Table 1).
Preliminary behavioural observations in rats confirm
that amines ORG13514 and 1a are very potent in the
lower lip retraction LLR test [34] with ED50 values of
Scheme 3.

794
C. Comoy et al. / Il Farmaco 54 (1999) 791–799
spectra were recorded on a R-10-10-C Nermag spec-
1
trometer. H NMR spectra were recorded on Bruker
AM 300WB or Hitachi Perkin–Elmer R-24B 60WB
spectrometers. The deuterated NMR solvents contained
99.8% deuterium with 1% v/v TMS and were obtained
1
from Aldrich Chimie. The H NMR coupling constants
(J values) were listed in Hertz (Hz) and spin multiplic-
ities were reported as singulets (s), doublets (d), triplets
(t), multiplets (m) and broad signals (br s). Chemical
shifts were reported in parts per millions (l, ppm)
downfield from tetramethylsilane (TMS) which was
used as an internal standard. Analysis indicated by the
symbols of the elements were within 90.4% of the
theoretical values.
Fig. 3.
4. Conclusions
Many new dihydropyridine analogs (1a–j) of the
N-substituted-3-aminomethyl-2,3-dihydro-1,4-dioxino-
[2,3-b]pyridine ORG13514 have been prepared with
good yields. Studies of biological activity revealed that,
among these new derivatives, only one, the compounds
1a, exhibits a 100-fold selectivity for the 5-HT1A sites
compared to the 5-HT1B, 2A, 2C, a1 or 2 and D2 receptors.
This aminopyridine 1a shows around a tenfold selectiv-
ity greater than the MDL72832.
5.2. 1-[4-[N-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine-
3-ylmethyl) amino]butyl]-4,4-dimethylpiperidine-2,6-
dione (1a)
To a solution of the amine 2 [23] (1.660 g, 10.0
mmol) in dry N,N-dimethylformamide (DMF) (15 ml)
However, the ligand which shows the highest affinity
and an excellent selectivity for the 5-HT1A subtypes is
the derivative ORG13514 [22].
were
added
dropwise
1-(4-bromobutyl)-4,4-di-
methylpiperidin-2,6-dione (3.310 g, 12.0 mmol) in
DMF (6 ml), triethylamine (4.2 ml, 30.0 mmol) and
potassium iodide (0.332 g, 2.0 mmol). The mixture was
heated at 60°C. After total consumption of 2, the
solution was hydrolyzed and the product was extracted
with dichloromethane (CH2Cl2). The organic layer was
washed with a saturated sodium hydrogen carbonate
solution. After evaporation of solvent, column chro-
matography (eluent: 25:5 CH2Cl2–MeOH) afforded the
expected product 1a as a white solid (1.950 g) in 54%
yield: m.p. 208–209°C. IR (KBr): w 3500–3300 (NH),
1715 and 1660 (NꢀCO), 1190 (CꢀOꢀC) cm−1. 1H NMR
(CDC13) l 1.09 (s, 6H, CH3), 1.46–1.60 (m, 4H, CH2),
1.68 (br s, 1H, NH), 2.50 (s, 4H, CH2CO), 2.60–2.76
(m, 2H, NHCH2CH2), 2.90 (dd, 1H, CHCH2NH, J=
4.6, J=11.7), 2.97 (dd, 1H, CHCH2NH, J=6.0, J=
11.7), 3.76 (t, 2H, CH2NCO, J=7.3), 4.04 (dd, 1H,
OCH2CH, J=7.8, J=11.8), 4.25 (dd, 1H, OCH2CH,
J=1.9, J=11.8), 4.40–4.49 (m, 1H, CH), 6.85 (dd,
1H, H7, J=5.0, J=7.6), 7.17 (dd, 1H, H8, J=1.3,
J=7.6), 7.80 (dd, 1H, H6, J=1.3, J=5.0). MS (CI/
NH3): m/z 362 [M+1]. Anal. (C19H27N3O4) C, H, N.
5. Experimental
5.1. Chemistry
Organic solvents were purified when necessary by the
methods described by Perrin, Armarego and Perrin [39].
All solutions were dried over anhydrous magnesium
sulfate and evaporated on a Bu¨chi rotatory evapora-
tion. Column chromatography was performed on silica
gel (Kieselgel–Merck, 70–230 mesh for gravity
columns and 230–400 mesh for flash columns). Analyt-
ical thin-layer chromatography (TLC) was carried out
on precoated plates (silica gel, Merck 60F254) and spots
were visualized with UV light. The column chromatog-
raphy solvents employed were glass distilled and eluent
mixtures are reported as volume to volume ratios.
Melting points (uncorrected) were determined on a
Ko¨fler hotstage apparatus. Infrared spectra were
recorded on a Perkin–Elmer 297 spectrometer. Mass
Table 1
Binding of derivatives ORG13514, 1a, MDL72832 and Buspirone (pKi values)
Compounds
5-HT1A
5-HT1B
5HT2A
5-HT2C
a1
a2
D2
a
ORG13514
10.9
8.9
9.1
7.6
B5.0
6.0
6.2
6.3
5.3
6.2
6.1
B5.3
B5.3
6.3
7.5
7.0
7.8
5.5
7.0
6.6
6.3
5.6
6.5
6.3
6.8
6.4
1a a
MDL72832 b
Buspirone b
5.2
5.1
a Compounds ORG13514 and 1a were tested as fumarate.
b MDL72832 and Buspirone were tested as hydrochloride.

C. Comoy et al. / Il Farmaco 54 (1999) 791–799
795
5.3. 1,3-Dihydro-2-[4-[N-(2,3-dihydro-1,4-dioxino-
[2,3-b]pyridine-3-ylmethyl)amino]butyl]-1,3-
dioxo-2H-isoindole (1b)
hydrolyzed. The product was extracted with CH2Cl2
and purified by column chromatography (eluent: Et2O).
5.5.1. 1-(4-Bromobutyl)-2-pyrrolidone
The compound 1b was prepared according to the
method used for 1a from the amine 2 (1.660 g, 10.0
mmol) and 2-(4-bromobutyl)-1,3-dioxo-2H-isoindole
(3.385 g, 12.0 mmol). After a column chromatography
(eluent: 47:47:6 Et2O–CH2Cl2–MeOH), 1b was ob-
tained as an oil (1.910 g) in 52% yield. IR (film): w
3500–3300 (NH), 1760 and 1700 (NꢀCO), 1185
(CꢀOꢀC) cm−1. 1H NMR (CDCl3) l 1.47–1.88 (m, 4H,
CH2), 1.96 (br s, 1H, NH), 2.62–2.75 (m, 2H,
NHCH2CH2), 2.91 (dd, 1H, NHCH2CH, J=4.7, J=
11.8), 2.97 (dd, 1H, NHCH2CH, J=6.0, J=11.8), 3.77
(t, 2H, CH2NCO, J=7.2), 4.03 (dd, 1H, OCH2CH,
J=7.9, J=11.8), 4.29 (dd, 1H, OCH2CH, J=1.9,
J=11.8), 4.40–4.48 (m, 1H, CH), 6.84 (dd, 1H, H7,
J=4.6, J=7.7), 7.16 (dd, 1H, H8, J=1.6, J=7.7),
7.67–7.73 (m, 2H, Harom), 7.78–7.85 (m, 3H, H6,
This compound was obtained from 2-pyrrolidone
(1.275 g) as an oil (2.145 g) in 65% yield. IR (film): w
1
1650 (NꢀCO) cm−1. H NMR (CDC13): l 1.62–1.71
(m, 2H, CH2), 1.79–1.90 (m, 2H, CH2), 1.97–2.08 (m,
2H, CH2), 2.32 (t, 2H, COCH2, J=7.80), 3.25–3.47
(m, 6H, BrCH2, CH2NCO); Anal. Calc. (C8H14BrNO)
C, H, N.
5.5.2. 1-(4-Bromobutyl)-2-piperidone
This compound was obtained from 2-piperidone
(1.485 g) as an oil (2.245 g) in 64% yield. IR (film): w
1
1645 (NꢀCO) cm−1. H NMR (CDCl3): l 1.60–1.88
(m, 8H, CH2), 2.32 (t, 2H, COCH2, J=6.1), 3.24 (t,
2H, CH2NCO, J=5.5), 3.33–3.34 (m, 4H, BrCH2,
CH2NCO); Anal. Calc. (C9H16BrNO) C, H, N.
Harom). MS (CI/NH3): m/z 368 [M+1]. Anal. Calc.
5.5.3. 1-(4-Bromobutyl)-2-azepinone
(C20H21N3O4) C, H, N.
This compound was obtained from 2-azepinone
(1.695 g) as an oil (2.155 g) in 58% yield. IR (film): w
1
1645 (NꢀCO) cm−1. H NMR (CDCl3): l 1.60–1.94
5.4. 2-[4-[N-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine-
3-ylmethyl) amino]butyl]-1,1-dioxo-1,2-benzisothiazol-
3(2H)-one (1c)
(m, 10H, CH2), 2.50–2.54 (m, 2H, COCH2), 3.31–3.47
(m, 6H, BrCH2, CH2NCO); Anal. Calc. (C10H18BrNO)
C, H, N.
This compound, prepared according to the method
used for 1a from 2 (1.660 g, 10.0 mmol) and 2-(4-bro-
mobutyl) - 1,2 - benzisothiasol - 3(2H) - one - 1,1 - dioxide
(3.815 g, 12.0 mmol), was obtained after column chro-
matography (eluent: 47:47:6 Et2O–CH2Cl2–MeOH), as
an oil (2.225 g) in 56% yield. IR (film) w 3500–3300
5.6. 1-[4-[N-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine-3-
ylmethyl) amino]butyl]pyrrolidin-2-one (1d)
This product was prepared according to the method
used for 1a from 2 (1.660 g, 10.0 mmol) and 1-(4-bro-
mobutyl)-2-pyrrolidone (2.640 g, 12.0 mmol). Purifica-
tion by a column chromatography (eluent: 47:47:6
Et2O–CH2Cl2–MeOH) gave 1d as an oil (1.950 g) in
64% yield. IR (film): w 3500–3200 (NH), 1610 (NꢀCO),
(NH), 1715 (NꢀCO), 1160 (CꢀOꢀC), 1180 (SO2) cm−1
.
1H NMR (CDCl3): l 1.55–2.00 (m, 5H, CH2, NH),
2.68–2.81 (m, 2H, NHCH2), 2.91 (dd, 1H, CHCH2NH,
J=5.0, J=12.4), 2.98 (dd, 1H, CHCH2NH, J=5.9,
J=12.4), 3.80 (t, 2H, CH2NCO, J=7.4), 4.04 (dd, 1H,
OCH2CH, J=7.9, J=11.8), 4.29 (dd, 1H, OCH2CH,
J=2.0, J=11.8), 4.40–4.49 (m, 1H, CH), 6.84 (dd,
1H, H7, J=4.7, J=7.9), 7.17 (dd, 1H, H8, J=0.8,
J=7.9), 7.78–7.94 (m, 4H, Harom), 8.05 (dd, 1H, H6,
J=0.8, J=4.7). MS (CI/NH3): m/z 404 [M+1]. Anal.
Calc. (C19H21N3O5S) C, H, N.
1
1185 (CꢀOꢀC) cm−1. H NMR (CDCl3): l 1.44–1.64
(m, 4H, CH2), 1.68 (br s, 1H, NH), 2.01 (q, 2H,
CH2CH2CO, J=7.5), 2.37 (t, 2H, CH2CO, J=7.5),
2.61–2.75 (m, 2H, NHCH2CH2), 2.91 (dd, 1H,
CHCH2NH, J=5.0, J=12.6), 2.97 (dd, 1H,
CHCH2NH, J=6.0, J=12.6), 3.28 (t, 2H, CH2NCO,
J=7.5), 3.37 (t, 2H, CH2NCO, J=7.5), 4.03 (dd, 1H,
OCH2CH, J=7.7, J=11.6), 4.28 (dd, 1H, OCH2CH,
J=2.5, J=11.6), 4.41–4.50 (m, 1H, CH), 6.85 (dd,
1H, H7, J=4.6, J=8.2), 7.18 (dd, 1H, H8, J=1.0,
J=8.2), 7.80 (dd, 1H, H6, J=1.0, J=4.6). MS (CI/
NH3): m/z 306 [M+1]; Anal. Calc. (C16H23N3O3) C, H,
N.
5.5. Procedure used to prepare bromobutylamide
deri6ati6es
The amide (15.0 mmol) dissolved in dry DMF (20
ml) was added dropwise to a suspension of sodium
hydride (16.5 mmol, 60% dispersion in mineral oil).
After stirring 15 min, 1,4-dibromobutane (30.0 mmol)
in dry DMF (5 ml) was added. The mixture was heated
at 80°C for 24 h then cooled to room temperature and
5.7. 1-[4-[N-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine-
3-ylmethyl) amino]butyl]piperidin-2-one (1e)
This compound was prepared according to the
method used for derivative 1a from 2 (1.660 g, 10.0

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C. Comoy et al. / Il Farmaco 54 (1999) 791–799
mmol) and 1-(4-bromobutyl)piperidin-2-one (2.810 g,
12.0 mmol). Column chromatography (eluent: 47:47:6,
Et2O–CH2C12–MeOH) gave the desired product 1e as
an oil (1.595 g) in 50% yield. IR (film): w 3500–3200
D2O): l 1.80–1.91 (m, 2H, CH2), 2.58–2.82 (m, 4H,
CH2N), 3.52 (t, 2H, CH2O, J=6.0), 3.56 (d, 1H,
NCH2Ph, J=13.3), 3.79 (d, 1H, NCH2Ph, J=13.3),
3.98 (d, 2H, OCH2CH, J=4.7), 4.00–4.10 (m, 1H,
CH), 4.45 (s, 2H, OCH2Ph), 7.15–7.38 (m, 12H, H7,
H8, Harom), 7.98 (dd, 1H, H6, J=1.9, J=3.8); Anal.
Calc. (C25H29N2O3C1) C, H, N.
1
(NH), 1610 (NꢀCO), 1190 (CꢀOꢀC) cm−1. H NMR
(CDC13): l 1.42–1.85 (m, 9H, CH2, NH), 2.36 (t, 2H,
CH2CO, J=6.5), 2.62–2.76 (m, 2H, NHCH2CH2), 2.92
(dd, 1H, CHCH2NH, J=4.7, J=13.0), 2.97 (dd, 1H,
CHCH2NH, J=5.9, J=13.0), 3.26 (t, 2H, CH2NCO,
J=7.1), 3.36 (t, 2H, CH2NCO, J=7.1), 4.04 (dd, 1H,
OCH2, CH, J=7.9, J=11.8), 4.28 (dd, 1H, OCH2CH,
J=2.4 J=11.8), 4.43–4.51 (m, 1H, CH), 6.84 (dd, 1H,
H7, J=4.7, J=7.9), 7.18 (dd, 1H, H8, J=1.2, J=7.9),
7.80 (dd, 1H, H6, J=1.2, J=4.7). MS (CI/NH3): m/z
320 [M+1]; Anal. Calc. (C17 H25N3O3) C, H, N.
5.10. 3-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine)yl-N-
benzyl-N-[3-(benzyloxy)propyl]methanamine (5)
To a suspension of sodium hydride (0.048 g, 60%
dispersion in mineral oil, 1.2 mmol) in ethylene glycol
dimethyl ether (DME) (5 ml) was added dropwise the
alcohol 4 (0.440 g, 1.0 mmol) in DME (7 ml). The
mixture was heated to 80°C for 20 h. After hydrolysis,
the product was extracted with CH2C12 and the organic
layer was washed with saturated sodium hydrogen car-
bonate solution, dried over magnesium sulfate and
5.8. 1-[4-[N-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine-
3-ylmethyl) amino]butyl]hexahydro-2H-azepine-2-one
(1f)
evaporated.
A flash chromatography (eluent: 1:1,
This compound, prepared according to the method
used for 1a from 2 (1.660 g, 10.0 mmol) and 1-(4-bro-
mobutyl)-2-azepinone (2.980 g, 12.0 mmol), was ob-
tained after column chromatography (eluent: 47:47:6,
Et2O–CH2C12–MeOH) as an oil (1.565 g) in 47%
yield. IR (film): w 3600–3200 (NH), 1630 (NꢀCO), 1160
Et2O–CH2C12) gave the expected compound 5 as an oil
(0.240 g) in 60% yield. IR (film): w 1280 and 1220
(CꢀOꢀC) cm−1. H NMR (CDC13): l 1.73–1.89 (m,
1
2H, CH2), 2.62–2.75 (m, 2H, CH2CH2N), 2.71 (dd, 1H,
CHCH2N, J=5.9, J=13.6), 2.85 (dd, 1H, CHCH2N,
J=4.7, J=13.6), 3.53 (t, 2H, OCH2CH2, J=6.9), 3.55
(d, 1H, NCH2Ph, J=13.5), 3.75 (d, 1H, NCH2Ph,
J=13.5), 3.81 (dd, 1H, OCH2CH, J=6.9, J=10.4),
4.25 (dd, 1H, OCH2CH, J=1.4, J=10.4), 4.27–4.45
(m, 1H, CH), 4.46 (s, 2H, OCH2Ph), 6.81 (dd, 1H, H7,
J=4.7, J=8.3), 7.12 (d, 1H, H8, J=8.3), 7.14–7.37
(m, 10H, Harom), 7.79 (d, 1H, H6, J=4.7); Anal. Calc.
(C25H28N2O3) C, H, N.
1
(CꢀOꢀC) cm−1. H NMR (CDC13): l 1.45–1.79 (m,
10H, CH2), 2.41 (br s, 1H, NH), 2.46–2.53 (m, 2H,
CH2CO), 2.71–2.80 (m, 2H, NHCH2CH2), 2.92 (dd,
1H, CHCH2NH, J=5.0, J=13.1), 2.97 (dd, 1H,
CHCH2NH, J=6.2, J=13.1), 3.28–3.41 (m, 4H,
CH2NCO), 4.04 (dd, 1H, OCH2CH, J=7.1, J=11.4),
4.27 (dd, 1H, OCH2CH, J=1.4, J=11.4), 4.51–4.61
(m, 1H, CH), 6.85 (dd, 1H, H7, J=4.7, J=7.6), 7.18
(dd, 1H, H8, J=0.9, J=7.6), 7.80 (dd, 1H, H6, J=0.9,
J=4.7). MS (CI/NH3): m/z 334 [M+1]; Anal. Calc.
(C18H27N3O3) C, H, N.
5.11. 3-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine)yl-N-
(3-hydroxy propyl)methanamine (6)
5.9. 1-(2-Chloro-3-pyridinyloxy)-3-[N-benzyl-N-[3-
(benzyloxy) propyl]amino]propan-2-ol (4)
To a solution of 5 (0.405 g, 1.0 mmol) in MeOH (10
ml) were added a few concentrated hydrochloride acid
drops and palladium on 10% carbon (0.040 g). The
mixture was stirred at room temperature in a Parr
apparatus under hydrogen pressure (45 psi). After 24 h,
the palladium catalyst was filtered and washed with
MeOH. The solution was neutralized with K2CO3 and 6
was obtained, after column chromatography (eluent:
9:1, CH2C12–MeOH), as an oil (0.175 g) in 78% yield.
To
a solution of 2-chloro-3-(oxiranylmethoxy)-
pyridine 3 [24] (0.925 g, 5.0 mmol) in dry tetrahydro-
furan (THF) (30 ml) was added dropwise N-benzyl-N-
[3-(benzyloxy)propyl]amine [25] (3.810 g, 14.9 mmol).
The mixture was then heated to 60°C for 24 h. After
total consumption of 3, the solution was allowed to
cool to room temperature and hydrolyzed with water
(50 ml). The product was extracted with CH2Cl2. The
organic layer was washed with a saturated sodium
hydrogen carbonate solution. The solvents were re-
moved under reduced pressure and the crude product
was purified by column chromatography (eluent: 1:1,
Et2O–CH2C12) to give the expected alcohol as an oil
(2.135 g) in 97% yield. IR (film): w 3600–3200 (OH),
IR (film): w 3500–3100 (NH, OH) cm−1 1H NMR
.
(CDC13, D2O): l 1.71–1.83 (m, 2H, CH2), 2.88–3.08
(m, 4H, CH2N), 3.82 (t, 2H, CH2OH, J=5.1), 4.03 (dd,
1H, OCH2CH, J=7.9, J=11.4), 4.29 (dd, 1H,
OCH2CH, J=2.0, J=11.4), 4.47–4.55 (m, 1H, CH),
6.88 (dd, 1H, H7, J=4.6, J=8.2), 7.20 (dd,1H, H8,
J=1.0, J=8.2), 7.83 (dd,1H, H6, J=1.0, J=4.6);
Anal. Calc. (C11H16N2O3) C, H, N.
1290 and 1210 (CꢀOꢀC) cm−1 1H NMR (CDC13,
.

C. Comoy et al. / Il Farmaco 54 (1999) 791–799
797
5.12. 8-[3-[N-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine-3-
ylmethyl) amino]propyl]-8-azaspiro[4.5]decane-7,9-dione
(1g)
and was obtained as an oil (1.860 g) in 90% yield. IR
(film): w 3500–3200 (OH), 1285 and 1205 (CꢀOꢀC) cm−1
.
1H NMR (CDC13): l 2.30 (s, 3H, CH3), 2.60 (dd, 1H,
CH2N, J=4.7, J=12.4), 2.72 (dd, 1H, CH2N, J=8.9,
J=12.4), 3.50 (d, 1H, CH2Ph, J=13.1), 3.72 (d, 1H,
CH2Ph, J=13.1), 4.00–4.06 (m, 3H, OCH2, OH), 4.08–
4.17 (m, 1H, CH), 7.11–7.35 (m, 7H, H8, H7, Harom), 7.97
(dd, 1H, H6, J=1.4, J=4.7).
To a solution of alcohol 6 (0.460 g, 2.1 mmol) in dry
THF (8 ml) were added triphenylphosphine (0.700 g, 2.7
mmol) and tetramethylene glutarimide (0.516 g, 3.1
mmol). The mixture was stirred for 15 min and cooled
to 0°C. Diethyl azodicarboxylate (0.42 ml, 2.68 mmol)
was added dropwise. After stirring for 2 h at room
temperature, the solution was hydrolyzed and the
product was extracted with CH2C12. Column chro-
matography (eluent: 95:5, Et2O–MeOH) gave the ex-
pected derivative 1g as an oil (0.570g) in 74% yield. IR
(film): w 3600–3300 (NH), 1710 and 1650 (NꢀCO), 1185
(CꢀOꢀC) cm−1. 1H NMR (CDC13): l 1.48–1.58 (m, 2H,
CH2), 1.66–1.84 (m, 9H, CH2, NH), 2.62 (s, 4H,
CH2CO), 2.63–2.75 (m, 2H, NHCH2CH2), 2.94 (dd, 1H,
CHCH2NH, J=4.7, J=12.6), 3.00 (dd, 1H,
CHCH2NH, J=5.5, J=12.6), 3.87 (t, 2H, CH2NCO,
J=7.1), 4.08 (dd, 1H, OCH2CH, J=7.9, J=11.3), 4.34
(dd, 1H, OCH2CH, J=2.4, J=11.3), 4.42–4.52 (m, 1H,
CH), 6.88 (dd, 1H, H7, J=4.7, J=7.9), 7.21 (dd, 1H,
H8, J=1.2, J=7.9), 7.83 (dd, 1H, H6, J=1.2, J=4.7).
MS (CI/NH3): m/z 374 [M+1]; Anal. Calc.
(C20H27N3O4) C, H, N.
The alcohol described above (0.337 g, 1.1 mmol) was
then treated in the presence of sodium hydride to give,
after column chromatography (eluent: 1:1, petroleum
ether–AcOEt), the expected amine 7 as an oil (0.178 g)
in 60% yield. IR (film): w 1190 (CꢀOꢀC) cm−1. 1H NMR
(CDC13): l 2.35 (s, 3H, CH3), 2.72 (dd, 1H, CH2N,
J=7.1, J=13.3), 2.79 (dd, 1H, CH2N, J=5.0, J=
13.3), 3.53 (d, 1H, CH2Ph, J=12.8), 3.65 (d, 1H, CH2Ph,
J=12.8), 3.93 (dd, 1H, CH2O, J=7.6, J=11.4), 4.33
(dd, 1H, CH2O, J=2.4, J=11.4), 4.39–4.48 (m, 1H,
CH), 6.83 (dd, 1H, H7, J=4.7, J=7.7), 7.15 (dd, 1H,
H8, J=1.2, J=7.7), 7.24–7.32 (m, 5H, Harom), 7.53 (dd,
1H, H6, J=1.2, J=4.7); Anal. Calc. (C16H18N2O2) C, H,
N.
5.15. 3-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine)yl-N-
methylmethanamine (8)
The compound 8 was obtained according to the
method used for the preparation of 6 from the amine 7
(2.106 g, 7.8 mmol). After column chromatography
(eluent: CH2C12), 8 was obtained as an oil (1.380 g) in
82% yield. IR (film): w 3500–3150 (NH), 1185 (CꢀOꢀC)
cm−1. 1H NMR (CDC13, D2O): l 2.50 (s, 3H, CH3), 2.91
(dd, 1H, CH2N, J=4.7, J=12.8), 2.97 (dd, 1H, CH2N,
J=6.4, J=12.8), 4.04 (dd, 1H, OCH2, J=7.7, J=11.6),
4.29 (dd, 1H, OCH2, J=2.2, J=7.7), 4.46–4.55 (m, 1H,
CH), 6.86 (dd, 1H, H7, J=4.6, J=7.7), 7.18 (dd, 1H,
H8, J=1.0, J=7.7), 7.82 (dd, 1H, H6, J=1.0, J=4.6).
MS (CI/NH3): m/z 181 [M+1]; Anal. Calc. (C9H12N2O2)
C, H, N.
5.13. 1,3-Dihydro-2-[3-[N-(2,3-dihydro-1,4-dioxino-
[2,3-b]pyridine-3-ylmethyl)amino]propyl]-1,3-dioxino-
2H-isoindole (1h)
The amine 1h was prepared according to the method
used for 1g from 6 (0.500 g, 2.23 mmol) and phthalimide
(0.491 g, 3.34 mmol). Column chromatography (eluent:
47:47:6 Et2O–CH2Cl2–MeON) gave the expected
product 1h as a white solid (0.582 g) in 68% yield: m.p.
164–165°C. IR (KBr): w 3500–3200 (NH), 1760 and 1700
(NꢀCO), 1185 (CꢀOꢀC) cm−1. 1H NMR (CDC13): l 1.50
(br s, 1H, NH), 1.82–1.92 (m, 2H, CH2), 2.65–2.80 (m,
2H, NHCH2), 2.89–3.00 (m, 2H, CHCH2NH), 3.80 (m,
2H, CH2NCO), 4.04 (m, 1H, OCH2CH), 4.29 (m, 1H,
OCH2CH), 4.38–4.46 (m, 1H, CH), 6.85 (m, 1H, H7),
7.16 (m, 1H, H8), 7.68–7.70 (m, 2H, Harom), 7.79–7.88
(m, 3H, H6, Harom). MS (CI/NH3): m/z 354 [M+1]; Anal.
Calc. (C19H19N3O4) C, H, N.
5.16. 8-[4-[N-(2,3-Dihydro-1,4-dioxino[2.3-b]pyridine-3-
ylmethyl)-N-methylamino]butyl]-8-azaspiro[4.5]-decane-
7,9-dione (1i)
The compound 1i was prepared according to the
method used for 1a from 8 (1.800 g, 10.0 mmol) and
8 - (4 - bromobutyl) - 8 - azaspiro[4.5]decane - 7,9 - dione
(3.625 g, 12.0 mmol). Column chromatography (eluent:
Et2O) gave the expected derivative 1i (3.570 g) in 89%
yield. IR (film): w 1705 and 1650 (NꢀCO), 1175 (CꢀOꢀC)
5.14. 3-(2,3-Dihydro-1,4-dioxino[2,3-b]pyridine)yl-
N-methyl-N-benzyl-methanamine (7)
1
The compound 7 was obtained in two steps according
to the method used for 5 from the epoxide 3 (1.250 g,
6.7 mmol) and N-methyl-N-benzylamine (1.621 g, 13.4
mmol). After distillation of the N-methyl-N-benzyl-
amine in excess, the expected alcohol was purified by
chromatography (eluent: 1:1, petroleum ether–Et2O)
cm−1. H NMR (CDC13): l 1.31–1.51 (m, 8H, CH2),
1.57–1.68 (m, 4H, CH2), 2.23 (s, 4H, COCH2), 2.29–2.46
(m, 2H, NCH2CH2), 2.51 (s, 3H, NCH3), 2.58 (dd, 1H,
CHCH2N, J=7.1, J=13.8), 2.65 (dd, 1H, CHCH2N,
J=4.7, J=13.8), 3.68 (t, 2H, -mCH2NCO, J=7.1), 3.92
(dd, 1H, OCH2, J=7.1, J=11.1), 4.27 (dd, 1H, OCH2,

798
C. Comoy et al. / Il Farmaco 54 (1999) 791–799
J=2.4, J=11.1), 4.31–4.38 (m, 1H, CH), 6.76 (dd, 1H,
H7, J=4.7, J=7.9), 7.09 (dd, 1H, H8, J=2.0, J=7.9),
7.72 (dd, 1H, H6, J=2.0, J=4.7). MS (CI/NH3): m/z
402 [M+1]; Anal. Calc. (C22H31N3O4) C, H, N.
experimental room in their home cages. They were
weighed and the test or reference compound (buspirone,
8-OH-DPAT, MDL72832) was administered. Immedi-
ately following treatment the rats were placed individu-
ally into the observation cages and 15, 30 and 45 min later
they are scored for lower lip retraction as follows:
0=lower incisors hidden or hardly visible (not differ-
ent from untreated rats);
5.17. 1,3-Dihydro-2-[4-[N-(2,3-dihydro-1,4-dioxino-
[2,3-b]pyridine-3-ylmethyl)-N-methylamino]butyl]-
1,3-dioxo-2H-isoindole (1j)
0.5=lower incisors partly visible;
The compound 1j was prepared according the method
used for 1a from 8 (1.800 g, 10.0 mmol). Column
chromatography (eluent: Et2O) afforded the expected
product 1j as an oil (3.350 g) in 88% yield. IR (film): w
1760 and 1700 (NꢀCO), 1185 (CꢀOꢀC) cm−1. 1H NMR
(CDCI3): l 1.41–1.73 (m, 4H, CH2), 2.27 (s, 3H, NCH3),
2.36–2.52 (m, 2H, NCH2CH2), 2.63 (dd, 1H, CHCH2N,
J=4.9, J=12.0), 2.70 (dd, 1H, CHCH2N, J=6.1,
J=12.0), 3.67 (t, 2H, CH2NCO, J=7.1), 3.95 (dd, 1H,
OCH2, J=7.9, J=11.8), 4.30 (dd, 1H, OCH2, J=1.9,
J=11.8), 4.32–4.41 (m, 1H, CH), 6.79 (dd, 1H, H7,
J=7.7, J=4.6), 7.10 (dd, 1H, H8, J=7.7, J=1.6),
7.64–7.71 (m, 2H, Harom), 7.73–7.80 (m, 3H, H6, Harom).
MS (CI/NH3): m/z 382 [M+1]; Anal. Calc.
(C21N23N3O4) C, H, N.
1=lower incisors completely visible.
After the last observation the rats are replaced in their
home cages. They are used at most three times in
similar experiments with periods of rest of at least five
days between experiments. Hereafter they are sacrificed
using CO2-gas.
6.3. Method of test for modification of EEG-defined
sleep-waking beha6iour in rats [35–38]
The rats (male rats, 250–350 g at surgery, 400–650 g
during the experiment) are weighed and the test com-
pound given by ip, sc or po administration at 8.00–9.00
h or at 18.00–19.00 h (winter-time). Following adminis-
tration, each rat is immediately connected to the record-
ing cable and placed in the experimental cage after which
recording is started. The point of time of administration
and start of recording are recorded. The hypnograms for
the different rats are synchronized with respect to the
recording start time. Between the administration of the
first and the last rat a time span of 20 to 30 min elapses.
The rats are left in their cages for 8, 24 or 29 h and are
inspected for external signs of toxicity before they are
replaced in their housing cages. The recordings of EEG
and EMG from rats which show an abnormal sleep-wak-
ing behaviour, are visually inspected. A wash-out period
of at least two weeks is allowed before the rats are used
again in another experiment. The rats are used at most
for fifteen experiments after which they are sacrificed
with CO2-gas.
6. Pharmacology
6.1. Binding experiments [28–33]
Radioligand binding studies were carried out on sev-
eral different brain membrane fractions as follows: in
vitro test for inhibition of 8-OH-DPAT binding to
5-HT1A receptor in rat brain hippocampal membrane
homogenates; in vitro test for inhibition of 5-HT binding
to 5-HT1B receptor in rat brain striatal membrane
homogenates; in vitro test for inhibition of 5-HT binding
to 5-HT1D receptor in pig brain striatal membrane
homogenates; in vitro test for inhibition of ketanserin
binding to 5-HT2A receptor in rat brain frontal cortex
membrane homogenates; in vivo test for inhibition of
mesurlergine binding to 5-HT2C receptor in pig brain
choro¨ıd plexus membrane homogenates; in vitro test for
inhibition of prazosine binding to a1-adrenoreceptor in
rat brain cortex membrane homogenates; in vitro test for
inhibition of ranwolsane binding to a2-adrenergic recep-
tors in rat brain cortex membrane homogenates and the
in vitro test for the inhibition of spiperone binding to
dopaminergic D2 receptors in rat brain striatal mem-
brane homogenates.
Acknowledgements
We are grateful to Riom Laboratories-CERM and
Organon for their multiform support. The authors thank
Mrs M. Obert for typing the manuscript.
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