Synthesis of new 2-(aminomethyl)-4-phenylpyrrolo[1,2-a]-quinoxalines and their preliminary in-vivo central dopamine antagonist activity evaluation in mice

Article abstract of DOI:10.1211/0022357001777522

In the search for antipsychotic agents that are not associated with extrapyramidal side effects, efforts have been focused on finding selective D₄-receptor antagonists and investigating their pharmacology. Our laboratory has developed a synthesis program for new pyrroloquinoxalines with therapeutic potential. We have described the synthesis of some new pyrroloquinoxalines with substituted arylpiperazino or aryltetrahydropyrido chain at position 3 of the quinoxaline ring (2-(4-phenylpiperazin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3a), 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxal inium oxalate (3b), 2-[4-(3-trifluoromethylphenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinox alinium oxalate (3c), 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxaliniumox alate (3d), 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3e), and 2-(4-phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxal inium oxalate (3f)). A preliminary pharmacological study of these products was conducted using climbing behaviour induced by apomorphine (2.5 mg kg^-1, s.c.) in mice. The derivatives were administered intraperitoneally 30 min before apomorphine. Haloperidol, chlorpromazine and clozapine were used as references. Among this series, 3b, 3c and 3f revealed a central dopamine antagonist activity. The most active derivative was 3b, which exhibited a profile relatively close to clozapine.

Full text of DOI:10.1211/0022357001777522

J. Pharm. Pharmacol. 2000, 52: 1369±1375
Received January 28, 2000
Accepted August 8, 2000
# 2000 J. Pharm. Pharmacol.
Synthesis of New 2-(Aminomethyl)-4-phenylpyrrolo[1,2-a]-
quinoxalines and their Preliminary In-vivo Central Dopamine
Antagonist Activity Evaluation in Mice
J. GUILLON, M. BOULOUARD{, V. LISOWSKI*, S. STIEBING, V. LELONG{, P. DALLEMAGNE*
AND S. RAULT*
Â
Syntheval, 5 Rue Vaubenard, 14032 Caen Cedex, *Centre d'Etudes et de Recherche sur le Medicament de
Normandie, Laboratoire de Pharmacochimie, UFR des Sciences Pharmaceutiques, 1 Rue Vaubenard,
Â
Â
Â
14032 Caen Cedex and {Laboratoire de Pharmacologie, UFR des Sciences Pharmacetiques, 1 Rue
Â
Vaubenard, 14032 Caen Cedex, France
Abstract
In the search for antipsychotic agents that are not associated with extrapyramidal side
effects, efforts have been focused on ®nding selective D4-receptor antagonists and
investigating their pharmacology. Our laboratory has developed a synthesis program for
new pyrroloquinoxalines with therapeutic potential. We have described the synthesis of
some new pyrroloquinoxalines with substituted arylpiperazino or aryltetrahydropyrido
chain at position 3 of the quinoxaline ring (2-(4-phenylpiperazin-1-ylmethyl)-4-phenylpyr-
rolo[1,2-a]quinoxalinium oxalate (3a), 2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-
phenylpyrrolo[1,2-a]quinoxalinium oxalate (3b), 2-[4-(3-tri¯uoromethylphenyl)piperazin-
1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3c), 2-[4-(4-chlorophenyl)piper-
azin-1-ylmethyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3d), 2-(4-pyridin-2-ylpiper-
azin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3e), and 2-(4-phenyl-
1,2,3,6-tetrahydropyridin-1-ylmethyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3f)).
A preliminary pharmacological study of these products was conducted using climb-
1
ing behaviour induced by apomorphine (2Á5 mg kg , s.c.) in mice. The derivatives were
administered intraperitoneally 30 min before apomorphine. Haloperidol, chlorpromazine
and clozapine were used as references.
Among this series, 3b, 3c and 3f revealed a central dopamine antagonist activity. The
most active derivative was 3b, which exhibited a pro®le relatively close to clozapine.
Dopamine receptors are the primary targets in the
treatment of schizophrenia. Most antipsychotic
(neuroleptic) drugs like haloperidol block D2
receptors in direct correlation with clinical poten-
tial but also with induction of substantial incidence
of extrapyramidal symptoms such as neurological
side effects (Tarsy 1983). In recent years, the term
atypical neuroleptic has been used to describe
antipsychotic agents that are not associated with
extrapyramidal side effects. Clozapine is the prin-
cipal example available for clinical use (Pickar &
Hsiao 1995).
5-hydroxytryptamine 5-HT2 receptors and a1-
adrenoceptors (Meltzer 1992). In particular, it
is suggested that the favourable effects of
clozapine are derived from its relatively preferential
blockade of D4 over D2 receptors (Lahti et al
1993). This observation indicates that selective D4
antagonism may represent a novel and potent
psychotropic mechanism and may have application
as an atypical antipsychotic drug, which does not
induce extrapyramidal symptoms (Taubes 1994).
Efforts have been focused on the search for
selective D4 receptor antagonists and to investigate
their pharmacology. A few selective D4 receptor
antagonists have been described (Boy®eld et al
1996; Hidaka et al 1996; Bristow et al 1997;
Unangst et al 1997; Mansbach et al 1998).
Thurkauf et al (1995) described a series of
new 1-phenyl-3-(aminomethyl)pyrroles with high
The atypical antipsychotic pro®le of clozapine is
thought to result from its af®nity for a multitude of
receptors, including dopamine receptor subtypes,
Â
Â
Correspondence: J. Guillon, Syntheval, 5 Rue Vaubenard,
14032 Caen Cedex, France.

1370
J. GUILLON ET AL
af®nity for the D4 receptor, particularly derivative 1
È
tetramethylsilane, which was used as an internal
reference. The following abbreviations were used:
s ˆ singlet, d ˆ doublet, t ˆ triplet, m ˆ multiplet.
Mass spectra were recorded on a JEOL GC mate
instrument using a direct inlet system and electron
impact ionization. Elemental analyses (C, H, N)
were performed by INSA, Rouen, France, and
agreed with the proposed structures within Æ 0Á3%
of the theoretical values.
(Figure 1). Lober et al (1999) reported the synthesis
of new azaindole derivatives like compound 2
with high af®nity for the D4 receptor. Thus it
appeared possible to access new compounds with
af®nity for the D4 receptor by binding a pipera-
zino or phenylpiperazino chain on a different
heterocycle-bearing chain or a chain with a few
nitrogen atoms, for instance clozapine and deriva-
tives 1 and 2 (Figure 1).
Our laboratory has developed a synthesis pro-
gram for new pyrroloquinoxalines with therapeutic
potential (Guillon et al 1998a, b). As part of this
program, we have described the synthesis of new
pyrroloquinoxalines 3a±f with a substituted aryl-
piperazino or aryltetrahydropyrido chain at position
3 of the quinoxaline ring (Figure 1). A preliminary
pharmacological study of these products was con-
ducted using climbing behaviour induced by apo-
morphine in mice (Protais et al 1976; Costall et al
1978), a model which has been described to reveal
central dopamine antagonist properties.
General procedure for preparation of 2-(amino-
methyl)-4-phenylpyrrolo[1,2-a]quinoxalines (8a±f).
The pH of a solution of 4-phenylpyrrolo[1,2- a]qui-
noxaline-2-carboxaldehyde (7) (0Á5 g, 1Á8 mmol) and
secondary amine (2Á2 mmol) in 35 mL methanol was
adjusted to 6 by the dropwise addition of acetic acid.
Powdered sodium cyanoborohydride (0Á32 g,
5Á05 mmol) was then added and the resultant mixture
was re¯uxed for 5 h. After removal of the methanol
by rotary evaporation, the residue was triturated in
water and extracted with methylene chloride. The
organic layer was washed with water, dried over
magnesium sulphate and evaporated to dryness.
Solids were recrystallized from propan-2-ol.
Materials and Methods
2-(4-Phenylpiperazin-1-ylmethyl)-4-phenylpyrrolo-
[1,2-a]quinoxaline (8a). White crystals (69%); mp
Chemical procedures
1
150ꢀC; H NMR (d6-DMSO) d: 2Á49 (4H, m, 2
Melting points were determined on a Ko¯er block
and are uncorrected. IR spectra were recorded on a
Genesis Series FTIR spectrometer. 1H,13C and 2D-
COSY NMR spectra were recorded on a JEOL
JNM-LA 400 spectrometer (400 MHz) using d6-
DMSO as the solvent. Chemical shifts refer to
CH2), 3Á04 (4H, m, 2 CH2), 3Á60 (2H, s, CH2), 6Á67
(1H, t, J ˆ 7Á65, H-400 ), 6Á81 (2H, d, J ˆ 7Á65, H-200
and00H-600 ), 6Á88 (1H, s, H-3), 7Á10 (2H, t, J ˆ 7Á65,
H-3 and H-500 ), 7Á42 (1H, t, J ˆ 7Á80, H-7), 7Á51
(4H, m, H-30, H-40, H-50 and H-8), 7Á86 (1H, d,
Figure 1. Structures of haloperidol, clozapine, 1, 2 and the general structure of 2-(aminomethyl)-4-phenylpyrrolol[1,2-
a]quinoxalinium oxalates 3a±f.

EVALUATION OF NEW 2-(AMINOMETHYL)-4-PHENYLPYRROLO[1,2-A]QUINOXALINES
1
1371
J ˆ 7Á80, H-6), 7Á91 (2H, m, H-20 and H-60), 8Á23
(1H, d, J ˆ 7Á80, H-9), 8Á43 (1H, s, H-1). Anal. calc.
for C28H26N4: C, 72Á94; H, 4Á59; N, 12Á76. Found:
C, 72Á75; H, 4Á29; N, 12Á70%.
(62%); mp 86ꢀC; H NMR (d6-DMSO) d: 2Á49
(4H, m, 2 CH2), 3Á44 (4H, m, 2 CH2), 3Á64 (2H, s,
CH2), 6Á59 (1H, m, H-500 ), 6Á74 (1H, d, J ˆ 8Á55,
H-600 ), 6Á94 (1H, s, H-3), 7Á47 (1H, t, J ˆ 7Á60, H-7),
7Á57 (5H, m, H-30, H-40, H-50, H-400 and H-8), 7Á92
(1H, d, J ˆ 7Á60, H0-0 6), 7Á98 (2H, m, H-20 and H-60),
8Á07 (1H, m, H-3 ), 8Á28 (1H, d, J ˆ 7Á60, H-9),
8Á47 (1H, s, H-1). Anal. calc. for C27H25N5: C,
72Á94; H, 4Á59; N, 12Á76. Found: C, 72Á75; H, 4Á29;
N, 12Á70%.
2-[4-(2-Methoxyphenyl)piperazin-1-ylmethyl]-4-
phenylpyrrolo[1,2-a]quinoxaline (8b). White crys-
tals (62%); mp 84ꢀC; 1H NMR (d6-DMSO) d: 2Á58
(4H, m, 2 CH2), 2Á97 (4H, m, 2 CH2), 3Á68 (2H, s,
CH2), 3Á76 (3H, s, CH3O), 6Á86 (2H, m, H-300 and
H-400 ), 6Á92 (2H, m, H-200 and H-500 ), 6Á98 (1H, s, H-
3), 7Á51 (1H, t, J ˆ 7Á95, H-7), 7Á61 (4H, m, H-30, H-
40, H-50 and H-8), 7Á95 (1H, d, J ˆ 7Á95, H-6), 8Á02
(2H, m, H-20 and H-60), 8Á32 (1H, d, J ˆ 7Á95, H-9),
8Á51 (1H, s, H-1); 13C NMR (CDCl3) d: 50Á0 (CH2),
52Á7 (CH3), 54Á6 (CH2), 55Á2 (CH2), 109Á0 (C-600 ),
111Á8 (C-3), 114Á6 (C-300 ), 115Á9 (C-400 ), 117Á8
(C-1), 120Á7 (C-3a), 122Á3 (C-2), 124Á0 (C-500 ),
125Á3 (C-9), 126Á1 (C-6), 126Á5 (C-7), 127Á8
(C-8), 128Á4 (C-30 and C-500)0 , 128Á5 (C-20 and C-
60), 129Á5 (C-40), 129Á9 (C-1 ), 010 35Á4 (C-9a), 137Á8
(C-10), 141Á2 (C-5a), 151Á9 (C-2 ), 152Á7 (C-4); m=z
2-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl)-
4-phenylpyrrolo[1,2-a]quinoxaline (8f ). Pale yel-
low crystals (61%); mp 153ꢀC; 1H NMR (d6-
DMSO) d: 2Á75 (2H, m, 2 CH2), 3Á04 (2H, m, 2
CH2), 3Á18 (2H, s, CH2), 3Á78 (2H, s, CH2), 6Á11
(1H, m, ˆCH), 6Á96 (1H, s, H-3), 7Á21 (1H, t,
J ˆ 7Á30, H-400 ), 7Á30 (2H, t, J ˆ 7Á30, H-300 and
H-500 ), 7Á39 (2H, d, J ˆ 7Á30, H-200 and H-600 ), 7Á48
(1H, t, J ˆ 7Á70, H-7), 7Á57 (4H, m, H-30, H-40, H-50
and H-8), 7Á93 (1H, d, J ˆ 7Á70, H-6), 8Á00 (2H, m,
H-20 and H-60), 8Á24 (1H, d, J ˆ 7Á70, H-9), 8Á41 (1H,
s, H-1). Anal. calc. for C29H25N3: C, 72Á94; H, 4Á59;
N, 12Á76. Found: C, 72Á75; H, 4Á29; N, 12Á70%.
‡
‡
(EI) 449 (M ‡ 1), 448 (M ) other major frag-
ments; 312, 285, 258, 218, 203, 191, 136. Anal.
calc. for C29H28N4O: C, 77Á65; H, 6Á29; N, 12Á49.
Found: C, 77Á53; H, 6Á43; N, 12Á60%.
General procedure for preparation of 2-(amino-
methyl)-4-phenylpyrrolo[1,2-a]quinoxalinium oxa-
lates (3a±f). To a solution of 2-(aminomethyl)-
4-phenylpyrrolo[1,2-a]quinoxalines (8a±f ) (1Á2
mmol) in propan-2-ol (30 mL) was added oxalic
acid (2Á4 mmol). The reaction mixture was heated
under re¯ux for 30 min. The precipitate was
®ltered, washed with diethyl ether and recrystal-
lized from a mixture of propan-2-ol=water (60 : 40).
2-[4-(3-Tri¯uoromethylphenyl)piperazin-1-ylmethyl]-
4-phenylpyrrolo[1,2-a]quinoxaline (8c). White
1
crystals (49%); mp < 50ꢀC; H NMR (d6-DMSO)
d: 2Á49 (4H, m, 2 CH2), 3Á13 (4H, m, 2 CH2), 3Á60
(2H, s, CH2), 6Á88 (1H, s, H-3), 6Á97 (1H, d,
J ˆ 7Á80, H-400 ), 67Á05 (1H, s, H-200 ), 7Á10 0(0 1H, d,
J ˆ 7Á80, H-600 ), 7Á31 (1H, t, J ˆ 7Á80, H-5 ), 7Á41
(1H, t, J ˆ 7Á55, H-7), 7Á51 (4H, m, H-30, H-40, H-50
and H-8), 7Á86 (1H, d, J ˆ 7Á55, H-6), 7Á92 (2H, m,
H-20 and H-60), 8Á22 (1H, d, J ˆ 7Á55, H-9), 8Á42
(1H, s, H-1). Anal. calc. for C29H25F3N4: C, 72Á94;
H, 4Á59; N, 12Á76. Found: C, 72Á75; H, 4Á29; N,
12Á70%.
2-(4-Phenylpiperazin-1-ylmethyl)-4-phenylpyrrolo-
[1,2-a]quinoxalinium oxalate (3a). White crystals
1
(58%); mp 245ꢀC; H NMR (d6-DMSO) d: 3Á09
(4H, m, 2 CH2), 3Á31 (4H, m, 2 CH2), 4Á24 (2H, s,
‡
CH2), 4Á66 (H, bs, OH and NH ), 6Á80 (1H, t,
J ˆ 7Á05, H-400 ), 6Á93 (2H, d, J ˆ 7Á05, H-200 and
H-600 ), 7Á13 (1H, s, H-3), 7Á21 (2H, t, J ˆ 7Á05, H-300
and H-500 ), 7Á53 (1H, t, J ˆ 7Á60, H-7), 7Á61 (4H, m,
H-30, H-40, H-50 and H-8), 7Á95 (1H, d, J ˆ 7Á60,
H-6), 7Á97 (2H, m, H-20 and H-60), 8Á26 (1H, d,
J ˆ 7Á60, H-9), 8Á61 (1H, s, H-1). Anal. calc. for
C30H28N4O4: C, 70Á85; H, 5Á55; N, 11Á02. Found:
C, 70Á90; H, 5Á62; N, 11Á03%.
2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]-4-phe-
nylpyrrolo[1,2-a]quinoxaline (8d). Pale yellow crys-
tals (74%); mp 81ꢀC; 1H NMR (d6-DMSO) d: 2Á67
(4H, m, 2 CH2), 3Á20 (4H, m, 2 CH2), 3Á42 (2H, s,
CH2), 6Á97 (2H, d, J ˆ 8Á05, H-300 and H-500 ), 7Á04
(1H, s, H-3), 7Á26 (2H, d, J ˆ 8Á05, H-200 and H-600 ),
7Á56 (1H, t, J ˆ 7Á75, H-7), 7Á64 (4H, m, H-30, H-40,
H-50 and H-8), 8Á00 (1H, d, J ˆ 7Á75, H-6), 8Á05
(2H, m, H-20 and H-60), 8Á37 (1H, d, J ˆ 7Á75, H-9),
8Á58 (1H, s, H-1). Anal. calc. for C28H25ClN4: C,
72Á94; H, 4Á59; N, 12Á76. Found: C, 72Á75; H, 4Á29;
N, 12Á70%.
2-[4-(2-Methoxyphenyl)piperazin-1-ylmethyl]-4-
phenylpyrrolo[1,2-a]quinoxalinium oxalate (3b).
1
White crystals (57%); mp 249ꢀC; H NMR (d6-
DMSO) d: 3Á04 (4H, m, 2 CH2), 3Á15 (4H, m, 2
CH2), 3Á77 (3H, s, CH3O), 4Á16 (2H, s, CH2), 6Á88
(2H, m, H-300 and H-400 ), 6Á94 (2H, m, H-200 and
H-500 ), 7Á10 (1H, s, H-3), 7Á20 (H, bs, OH and
2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-4-phenyl-
pyrrolo[1,2-a]quinoxaline (8e). White crystals

1372
J. GUILLON ET AL
J ˆ 6Á70, H-200 and H-600 ), 7Á53 (1H, t, J ˆ 7Á60,
H-7), 7Á59 (4H, m, H-30, H-40, H-50 and H-8),
7Á96 (1H, d, J ˆ 7Á60, H-6), 7Á99 (2H, m, H-20 and
H-60), 8Á28 (1H, d, J ˆ 7Á60, H-9), 8Á67 (1H, s, H-1).
Anal. calc. for C31H27N3O4: C, 73Á65; H, 5Á38; N,
8Á31. Found: C, 73Á76; H, 5Á38; N, 8Á41%.
‡
NH ), 7Á51 (1H, t, J ˆ 7Á55, H-7), 7Á60 (4H, m, H-
30, H-40, H-50 and H-8), 7Á94 (1H, d, J ˆ 7Á55, H-6),
8Á02 (2H, m, H-20 and H-60), 8Á22 (1H, d, J ˆ 7Á55,
H-9), 8Á52 (1H, s, H-1). Anal. calc. for
C31H30N4O5: C, 69Á14; H, 5Á57; N, 10Á41. Found:
C, 68Á99; H, 5Á84; N, 10Á35%.
2-[4-(3-Tri¯uoromethylphenyl)piperazin-1-yl-
methyl]-4-phenylpyrrolo[1,2-a]quinoxalinium oxa-
Pharmacological procedures
1
late (3c). White crystals (61%); mp 185ꢀC; H
Animals. Male OF1 mice (20±25 g; Iffa Credo) were
kept in conventional plastic cages in groups of 10 and
had free access to food and water. They were housed
in a well-ventilated room at an ambient temperature
of 22ꢀC on a 12-h light±dark cycle.
NMR (d6-DMSO) d: 3Á06 (4H, m, 2 CH2), 3Á42
(4H, m, 2 CH2), 4Á21 (2H, s, CH2), 4Á56 (H, bs, OH
00
‡
and00NH ), 7Á09 (1H, d, J ˆ 7Á65, H-4 ), 7Á12 (1H, s,
H-2 ), 7Á19 (1H, s, H-3), 7Á21 (1H, d, J ˆ 7Á65, H-
600 ), 7Á42 (1H, t, J ˆ 7Á65, H-500 ), 7Á52 (1H, t,
J ˆ 7Á70, H-7), 7Á59 (4H, m, H-30, H-40, H-50 and
H-8), 7Á95 (1H, d, J ˆ 7Á70, H-6), 8Á00 (2H, m, H-20
and H-60), 8Á26 (1H, d, J ˆ 7Á70, H-9), 8Á60 (1H, s,
H-1). Anal. calc. for C31H27F3N4O4: C, 64Á58; H,
4Á72; N, 9Á72. Found: C, 64Á43; H, 4Á66; N, 10Á01%.
Apomorphine-induced climbing behaviour. Groups
of eight mice were dosed with test compounds by
the intraperitoneal route and placed individually
into cylindrical wire mesh (height 15 cm, diameter
12 cm, mesh size 1 cm) 30 min before apomorphine
administration. Climbing behaviour was assessed at
5-min intervals for 20 min, starting 10 min after the
2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]-4-phe-
nylpyrrolo[1,2-a]quinoxalinium oxalate (3d). White
crystals (82%); mp 203ꢀC; 1H NMR (d6-DMSO) d:
3Á13 (4H, m, 2 CH2), 3Á32 (4H, m, 2 CH2), 4Á29
1
apomorphine (2Á5 mg kg , s.c.) administration.
The following scoring system was used: 0, no
paw on the cage; 1, one paw on the cage; 2, two
paws on the cage; 3, three paws on the cage; and 4,
four paws on the cage. An observer unaware of the
speci®c drug treatments made all the observations.
Climbing scores at each time interval were then
summed and expressed as a climbing index; the
maximum possible index was therefore 20.
‡
(2H, s, CH2), 4Á71 (H, bs, OH and NH ), 6Á95 (2H,
d, J ˆ 7Á15, H-300 and H-500 ), 7Á14 (1H, s, H-3), 7Á24
(2H, d, J ˆ 7Á15, H-200 and H-600 ), 7Á54 (1H, t,
J ˆ 7Á75, H-7), 7Á61 (4H, m, H-30, H-40, H-50 and
H-8), 7Á96 (1H, d, J ˆ 7Á75, H-6), 7Á99 (2H, m, H-20
and H-60), 8Á27 (1H, d, J ˆ 7Á75, H-9), 8Á62 (1H, s,
H-1). Anal. calc. For C30H27ClN4O4: C, 66Á36; H,
5Á01; N, 10Á32. Found: C, 66Á49; H, 4Á81; N,
10Á09%.
Drugs and drug solutions of the new compounds
to be tested and reference drugs (with the exception
of haloperidol) were dissolved immediately before
use in 0Á9% saline. R( )Apomorphine (HCl) and
chlorpromazine (HCl) were purchased from RBI.
Clozapine (HCl) was synthesized by Syntheval SA.
Solutions of haloperidol were prepared by appro-
priate dilutions in 0Á9% saline of a commercially
2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-4-phenyl-
pyrrolo[1,2-a]quinoxalinium oxalate (3e). White
1
crystals (59%); mp 241ꢀC; H NMR (d6-DMSO)
d: 2Á90 (4H, m, 2 CH2), 3Á63 (4H, m, 2 CH2), 4Á07
‡
(2H, s, CH2), 5Á00 (H, bs, OH and NH ), 6Á64 (1H,
m, H-500 ), 6Á79 (1H, d, J ˆ 8Á30, H-600 ), 7Á06 (1H, s,
H-3), 7Á51 (1H, m, H-7), 7Á57 (5H, m, H-30, H-40,
H-50, H-400 and H-8), 7Á94 (1H, d, J ˆ 7Á85, H-6),
8Á00 (2H, m, H-20 and H-60), 8Á10 (1H, m, H-300 ),
8Á22 (1H, d, J ˆ 7Á85, H-9), 8Á49 (1H, s, H-1). Anal.
calc. for C29H27N5O4: C, 68Á36; H, 5Á34; N, 13Á74.
Found: C, 68Á36; H, 5Á29; N, 13Á69%.
1
available solution (Haldol, 2 mg mL , Janssen-
Cilag S.A.). Intraperitoneal or subcutaneous injec-
tions of drugs were given at a volume of
0Á4 mL=20 g.
Results and Discussion
2-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-ylmethyl)-
4-phenylpyrrolo[1,2-a]quinoxalinium oxalate (3f).
Chemistry
1
White crystals (45%); mp 248ꢀC; H NMR (d6-
The 2-(aminomethyl)-4-phenylpyrrolo[1,2-a]quin-
oxaline oxalates 3a±f were prepared according to
the sequence as shown in Figure 2. Reaction of
commercially available phenylenediamine with 1-
phenylpropan-1,2-dione in acetic acid gave the
methylphenylquinoxaline 4. Treatment of ethyl
DMSO) d: 2Á72 (2H, m, 2 CH2), 3Á30 (2H, m, 2
CH2), 3Á71 (2H, s, CH2), 4Á18 (H, bs, OH and
‡
NH ), 4Á37 (2H, s, CH2), 6Á15 (1H, m, ˆCH),
7Á19 (1H, s, H-3), 7Á28 00 (1H, t, J ˆ 6Á70, H-400 ),
7Á35 (2H, t, J ˆ 6Á70, H-3 and H-500 ), 7Á44 (2H, d,

EVALUATION OF NEW 2-(AMINOMETHYL)-4-PHENYLPYRROLO[1,2-A]QUINOXALINES
1373
bromopyruvate in re¯uxing ethanol led to ethyl 4-
phenylpyrrolo[1,2-a]quinoxaline-2-carboxylate (5).
Reduction of the ester group of 5 with LiAlH4 in
anhydrous tetrahydrofuran gave the alcohol 6,
subsequently oxidized into the attempted aldehyde
7 using MnO2 in re¯uxing chloroform (Guillon et
al 1998a, b). The aldehyde 7 was then engaged in a
reductive amination with NaBH3CN and secondary
amines to give the quinoxalines 8a±f (Borch et al
1971; Lane 1975; Thurkauf et al 1995). Treatment
of 8a±f with oxalic acid in re¯uxing propan-2-ol
converted the compounds into their oxalate 3a±f,
respectively.
Pharmacology
Table 1 shows the dose-dependency of the climb-
ing behaviour induced by apomorphine after intra-
Figure 2. Preparation of the 2-(aminomethyl)-4-phenylpyrrolo[1,2-a]quinoxaline oxalates 3a±f. Reagents: i. C6H5-CO-CO-CH3,
CH3COOH; ii. Br-CH2CO-COOC2H5, C2H5OH; iii. AlLiH4, tetrahydrofuran; iv. MnO2, CHCl3; v. HNR1R2, NaBH3CN, CH3OH;
vi. (COOH)2, (CH3)2CHOH.

1374
J. GUILLON ET AL
peritoneal administration of haloperidol, chlorpro-
mazine, clozapine and quinoxalines 3a±f.
The replacement of the piperazine ring (com-
pound 3a) by a 3,4-dehydropiperidine ring in
compound 3f led to an increase of activity, prob-
ably due to the absence of a basic amine. Sub-
stitution of the phenylpiperazine with a parachloro
(compound 3d) had no effect on activity.
Further biological characterization in-vitro (in
particular selectivity towards dopamine receptor
subtype studies) and in-vivo will be necessary to
determine the real therapeutic potential of these
new compounds as neuroleptics, and perhaps to
aim structural arrangement in this chemical series
from the leading compound 3b.
Among the pharmacological references used, the
two typical neuroleptics were the most effective,
particularly haloperidol (1 mg kg ) which com-
1
pletely antagonized the apomorphine-induced
climbing behaviour. Clozapine was also active in
this model, but this effect was quantitatively less
important. The present data corroborate the work of
Protais et al (1976) and Costall et al (1978).
Among the new pyrroloquinoxalines, three
compounds (3b, 3c and 3f) demonstrated activity in
this test but at larger doses than the reference drugs.
The most active derivative was 3b, which exhibited
a pro®le relatively close to clozapine. It seems
dif®cult to deduce the structure±activity relatioship
from these preliminary results. In terms of sub-
stitution on the phenyl group, the best results were
obtained with the orthomethoxy substitutent (3b)
and the metatri¯uoromethyl substitutent (3c),
which have almost different electronical behaviour.
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Haloperidol
0
0Á1
0Á3
1
0
1
2
4
0
5
10
20
0
100
0
10
33
100
0
100
150
225
0
100
0
100
0
100
150
225
14Á12Æ 2Á05
3Á50Æ 0Á53*
0Á25Æ 0Á02***
0Á00
Chlorpromazine
Clozapine
13Á21Æ 1Á35
6Á87Æ 1Á25*
4Á25Æ 0Á22**
0Á00
15Á20Æ 1Á65
12Á50Æ 1Á25
4Á50Æ 0Á46*
1Á50Æ 0Á07***
15Á71Æ 1Á06
16Á50Æ 1Á55
14Á12Æ 1Á56
14Á00Æ 1Á65***
2Á75Æ 0Á80***
0Á00
3a
3b
3c
15Á11Æ 1Á56
9Á87Æ 0Á78*
5Á25Æ 0Á45**
0Á00
È
È
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3d
3e
3f
15Á71Æ 1Á06
17Á12Æ 1Á01
14Á12Æ 1Á55
13Á62Æ 1Á70
14Á00Æ 1Á51
11Á50Æ 1Á44
8Á25Æ 0Á74*
3Á25Æ 0Á55**
Mansbach, R. S., Brooks, E. W., Sanner, M. A., Zorn S. H.
(1998) Selective dopamine D4 receptor antagonists reverse
apomorphine-induced blockage of prepulse inhibition.
Psychopharmacology 135: 194±200
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*P < 0Á05, **P < 0Á01, ***P < 0Á001 vs vehicle-treated
groups (Student's t-test).

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