Mass spectrometric studies of the metabolites of niaprazine

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.