International
Journal
of Mass
Spectrometry
Elsevier Scientific Publishing Company,
MASS
SPECTROMETRIC V.
ng,SANJUAN, Centre
STUDIES
ROVEI,
de Recherche
J.
OF
DOW
Delalande,
93
48 (1983) 93-96 Printed in The Netherlands
and Ion Physics,
Amsterdam
-
THE
and
10 rue
METABOLITES
M. des
STROLIN
OF
NIAPRAZINE
BENEDETTI
CarriBres,
92500 Rueil-Malmaison
, France
_
ABSTRACT Niaprazine
N iaprazine necarboxamide
(Nopron@,
sedative
(ref. 1):
agent
niaprazine rat
brain
try
of
and
depletes (refs.
the
man
Isolation ne
by
after
AND of
(ref.
R lQ- 10 quadrupole were :
source
EI)
0.15
and
mA/sec)
SP2250 (carrier perature
200
torr
the is
France)
profile
of the
identification in rat
- 3-pyridi-
is a powerful
drug
has shown that
5-hydroxytryptamine
niaprazine
drug
spectrometric
turnover
by
mass
(5 mg/kg),
in
spectrome-
dog
(5 mg/kg)
described.
and
metabolites
by
100 were
heated
80% (CI) ;
50 to with
_ GC
temperature
( 10°C
with 50 to
were
isolated
out
a SIDAR 500
from
uri-
an emitter
column
the
(l°C
ion
beam
energy
source
current
by
helium
temperature
by
1983
direct
50 to
packed flow
Elsevier Scientific Publishing Company
line
chemi450 mA
with
rate
230°C
/min). 0
70 eV;
(Gfz-nds-
desorption
from
(2 m x 2 mm id)
; injector
: data conditions
2. low2 torr
/set),
were:
system
Operating
pressure
into
300%
on a RIBERMAG
data
a.m.u.
(CI) ; electron
conditions
260°C
carried
source
introduced
a glass
mesh)
from
and DA
from
(DCI-NH3) using
(loo-120
were
equipped range
(EI)
and
Samples
GC-MS
OOZO-7381/83/0000-0000/$03_00
mass
150%
ammonia
; interface
150-180°C
studies
spectrometer
in the
CIA (EI)
(CI).
with and
oral
Unchanged
DIL-EI)
Supelcoport gas)
doses
Mass
ions
impact,
ionisation
study,
single
temperature
current
present
modifies
of
mass
for
filament
biochemical
and
metabolites
-
acquired
of the
- l-methylpropyl]
Courbevoie,
4).
Mass were
Carrion,
METHODS
metabolites
TLC
study
In the
urinary
(1 mg/kg)
MATERIALS
The
catecholamines
2 & 3).
major
l-piperaeinyl]
Laboratoire
3%
20 ml /min
; oven
tem-
94 Preparation
silylated 60%.
of
with
derivatives
1 N was then
Methanolic
-
a solution
solutions
of
of ethylacetate/BSTFA,
evaporated
on the
4/l,
DC1 emitter
the
metabolites
v/v
(Fierce)
before
the
were
during
dried
and
30 min
introduction
at
into the
ion
source. Reduction
of
N-oxides
the
min in a methanolic introduction Iution
into
of Tic13
were
made
sidues
of
RESULTS Mass lZ&le
solution the
(3%)
alkaline the
ion
source.
with
Dry
SO2: of the
adjusted
organic
AND
-
N-oxide.
were
The
acetic
and
extracted
sample
acid
was
was
then
incubated
by
ethyl
mass
bubbled
evaporated
5 before
in an aqueous
(15 min at 3OoC).
with
analyzed
then
(Matheson)
were
5 with
NaOH
phase
dioxide
N-oxides
TiC13:
to pH
O.lN
sulfur
The
acetate.
The
spectrometry
so-
solutions dry
re-
.
DISCUSSION
spectral
data
of niaprazine
1.lckssspectral&ta
its urinary
and
ofniaprazine
and
its
metabolites m/z
rrHza.blites:
f%
are
given
relative
m/z
in table
,l.
intensity)
70
CH2= +3 N
niaprazine,
MW=356
compound
MW
DIL-El
(t
niaprarine
356
70(1001, 138(12),
3561351. 122(25,,
341(2&l, 106(32),
220(S), 95(251,
206(10>, 78[431,
3
262
99(100),
262(15),
220(50),
206(10),
180
56(100),
180(55),
138(98),
95(65).
5 5 BSTFA
196
56(1001, 154(100),
196(50), 268f25).
154(95), 226(75),
138(251. 196(4Sl,
8 8 BSTFA
372 444
56(100), 73(1001,
372(10), 444(221,
357(22), 423(50),
236(8), 234(80),
222(25), 255(18),
4
354
354(201.
339(10),
220(6),
206(63,
357(100)
78(35),
56(50).
zs3(rool
197(100)
426
SS[lOO),
262(4),
26119).
220(151,
177<183,
2
278
260(T),
220(15),
177(15),
176 262
58(100), 51[50). 51~1001,
262(S),
2Cqxrar. 2 red. so2
176(5).
161(10),
6
372
56(75).
208(61,
193(55), 194(32).
122(72), 193(33).
191(15),
206(10),
106(25),
177(201,
95(18).
136(B),
373(100) 373(1001,
106(25),
SO2
106(251. 106(24),
99(12),
56(M).
372 356
Niaprazine
161151,
106(40),
99(30),
56(75)
106(1003, 161(10),
372(10), 356(10), 78(40), 51(25).
355(1001, 106(55), 106(100),
356[60), 95(25). 356(851,
The
206,
DIL-EI 138
150,
ring. m/z
The
177,
characteristic
78 (pyridine).
279(501, 279(50),
2631100). 263(100).
279125). 177(20).
263(100),
T 263(100)
-
piperazine ions
78(5S).
354(25),
206(5),
196(18),
193(B),
179L30),
177(10),
356
7 red.TiC13
220,
lOC(30).
445(65).
355(100)
SO2
7
Other
106(75),
t38(281,
278
The
150(28),
I81(100)
1 1 red.
m/z
DCI-NH3
193(40), 56(701.
177(50),
9 BSTFA
6 red.
label)
-:
56(1001, 78(70). 426(100),
263(301,
14C
= CC-MS-EI)
4
4lll25).
(*
193(55),
178(65),
177(681.
193(351,
177(101,
95(B),
and
ion
DCI-NH3
206(22), 206(301,
mass
spectrum
70
m/z
122 and ions
341(45), 341(45),
106 were
mass
(base
193
peak)
was
were m/z
showed
due
were
spectrum
molecular
attributed
to cleavageo
attributed 341
the
showed
the
ion
m/z
the
quasi
95
197(85J.
373(100),
357(38).
nitrogen
(fluorophenyl) molecular
356.
The
opening
pyridinecarboxamide
m/z
357(B),
177(1001, 357(tool.
70(25).
to
to the
to the
(M+--CH3),
lSO(20). 78(30),
373(30),
ion
ions
of
the
of niaprazine. moiety. and
m/z
(MI-I*) m/z
357.
95 Metabol
ite
parison
3 -
The
with the
group
(m/z
DIL-EI
mass
99,
zine
base
3 was
has
been
Metabolite
ions
138,
The
thetic
some
5 -
analogy
molecular matic
The
(m/z
also
migrate
Metabolite
compound. mass
The
hydroxylation
Metabolite
56).
ions
The
metabolite
After
that
obtained
showed were
and
1 & 7 -
The
m/z
372.
thermal
176 and
ions
The
4.
180.
The
ion m/z
fluorophenyl-pipera-
mass
spectra
m/z
of the
syn-
MH+ was m/z
a NIH
gave
introduction
of
BSTFA
(m/z
194).
The
the
aro-
Metabolite
fluorine
16 a.m.u.
6). (DCI-NH3
in the
parent
in the pyridine ion
structure
m/z of
444)
it
could
(ref.
ion m/z 372
(molecular
a
NMR data,
mechanism
a modification
with
19’7.
group;
the molecular
gave of
Without
shift
indicated
derivative
hydroxylation
of the hydroxy
with
56 (DIL-EI)
BSTFA
the
DCI-NH3,
m/z
BSTFA
with
The
ring.
indicated
metabolite
spectra reduces
1) and
m/z
8 was
ions
m/z
ion m/z 354
of
ions
were
(DCI-
that the methylpro191 and
136 (m/z
193
fluorophenyl-piperazine.
ion m/z 426).
Hydroxylation
fluorine. corresponding
unchanged
7 gave
a mass
pyridine 373
molecular
in the
loss
the
metabolite
* TiC13
pyridine
metabolite
106 indicated
gave
mass
TiC13,
(metabolite
The
177 and
(molecular
208)
metabolites
to a loss
after
spectrum
N-oxides
(metabolite
reduction identical
(ref. 7).
7).
of
16 with
to
DCI-NH3
Metabolites
1 and
7
ring.
DIL-EI
metabolites
the
a modification
(m/z
Their
the
206,
showed
was unchanged.
ring
with
degradation
161 for
by
spectrum
by
niaprazine
2 & 6 -
Both
ring
suggested
(DIL-EI).
of
peak
suggested
spectrum
mass
Both
reduction
N-oxides
pipera-
fluorophenyl-piperazine.
silylation
aromatic
for
which
occurred
silylated
MH+ m/z 279
Metabolites
ion
was
17 a.m.u.
so2.
metabolite
shown
moiety
138 for niaprazine)
and
by the
base
122 suggested
DIL-EI
and
Metabolites
of
analysis.
The
in the
196 and
222 and
pyl-pyridinecarboxamide
occurred
N-dearylation
of the
m/z 263.
4-fluorophenyl-piperazine.
the position
pyridine
MHi
molecular
the
methylpropyl-
showed
gave
characteristic
Thecom-
fluorophenyl
in the
ref _ 5).
to the
m/z
the
niaprazine.
262.
of the
azaperone,
corresponds
MH+ was m/z 355).
NH3,
As
mass
after
NMR
9 -
of
of the
DIL-EL which
of
by
the
the loss
DCI-NH3
As confirmed
m/z
spectrum
to determine
spectrum
confirmed
ion
derivative
The
181.
4 was
if hydroxylation 8 -
were
ion m/z
was observed 106).
of
spectrum
268 (+ 72 a.m.u.>
MH+ was m/z 373) The
mass
indicated
177 and (e.g.
peak)
P.!lE+ m/z
226 and
possible
220,
N-dearylation
56 (base
the
the molecular
no change
previously
molecular
with
5 was a hydroxy was not
by
metabolite
ion m/z
ring
(m/z
showed
compound,
Metabolite
moiety
GC-MS-E1
95 and
DCI-NH3
zine.
whereas
formed
gave
of niaprazine
peak),
described
4 -
m/z
spectrum
spectrum
pyridinecarboxamide Metabolite
mass
mass gave
products 2 by
spectrum
ions (ions
GC-MS-EI)
of
metabolite
corresponding m/z
196,
179 and
characteristic
6 gave
to a loss
of
the
molecular
16 and
161 for
metabolite
of
N-oxides
the
18 a-m-u. 6;
m/z
(Cope
96 rearrangement,
Fig.
1 and
ref.
8). 0
0 NH&N-N-R Y 0
N Figure I The
_ Cope
rearrangement
DCI-NH3
MH+ or” the te 6) and gave
pectively
mass
177
of metabolites
spectra
thermal
m/z
mass
metabolite metabolite
lmetabolite
spectra
identical
MH+
m/z
products
to those
279
were
Metabolites
2).
and
373 for
2 and for
6,
in Fig.
pathways
metabolites
at
after
m/z
niaprazine
197,
2 and
177
3 and
niaprazine
7)
6;
(metaboli-
with
(ref.
of
R=@F
reduction
metnbolite
aliphatie
metabolic
R=H
6.
observed
obtained
.
The shown
showed
degradation
2 and
2: 6:
S02, res-
These
in rat,
dog
and
man
are
2.
met-8 (R .MI
met- 3 (R ,D,MJ
met2
0 Figure 2.
Eletabolism
of niaprazine
in rat
(RI,
dog
(0) and man
(M)
0
(MI.
ACKNOWLEDGEMENTS The
authors
cussion
of
and
Farny
M.
the
wish N-oxide for
the
to
thank
J.F - Anther
reduction,
C.
preparation
of
Grenot the
for for
NMR her
spectra, skilful
T.
Imbert
technical
for
dis-
assistance
manuscript.
REFERENCES 1 2 3 4 5 6 7 8
P _ DuchWe-Marullaz, G . Rispat, J .P. Perriere, J. Hache and C . Labrid, 26 (1971) 1203-1209. Therapie, P.E. Keane and M. Stroiin Eenedetti, Neuropharmacology, 18 (1979) 595-600. k’l. Strolin Berledetti and J. Dow, Neuropharmacology, 21 (1982) P.E. Keane, 163- 169. V. Rovei, M, Sanjuan, J. Dow, F. Chanoine and M. Strolin Benedetti, in psepar. and P ..A. Janssen, Arzneim. -Forsch., 7 (1971) 982-984. J. Heykants, L. Pardoel a. Daly, in : Handbook of Experimental Pharmacology, voI. XXVII 1. part 2, Bertin (1971). pp. 294- 311. Gillette, eds.) Springer Verlag, (B-3. Brodie L J.R. 5.13. Phillipson and S.S. Handa, Phytochemistry. 14 ( 1975) 2683-2690. A.C. Cope and N.A. LeBel, J, Am. Chem. Sot., 82 (1960) 4656-4662.