Substituted pyrazoles as novel selective ligands for the human dopamine D4 receptor

Article abstract of DOI:10.1016/S0968-0896(98)00134-5

Two novel series of 3-(heterocyclylmethyl)pyrazoles have been synthesised and evaluated as ligands for the human dopamine D₄ receptor. Compounds in series I (exemplified by 8k) have a phenyl ring joined to the 4-position of the pyrazole while those in series II (exemplified by 15j) have a 5-phenyl ring linked by a saturated chain to the 4-position of the pyrazole. Both series supplied compounds with excellent affinity for the human D₄ and good selectivity over other dopamine receptors. Excellent selectivity over calcium, sodium, and potassium ion channels was also achieved. Copyright (C) 1997 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00134-5

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 1731±1743
Substituted Pyrazoles as Novel Selective Ligands for the
Human Dopamine D4 Receptor
Sylvie Bourrain,* Ian Collins, Joseph G. Neduvelil, Michael Rowley,
Paul D. Leeson, Smita Patel, Shil Patel, Frances Emms, Rosemarie Marwood,
Kerry L. Chapman, Alan E. Fletcher and Graham A. Showell
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow,
Essex, CM20 2QR, UK
Received 6 November 1997; accepted 1 May 1998
AbstractÐTwo novel series of 3-(heterocyclylmethyl)pyrazoles have been synthesised and evaluated as ligands for the
human dopamine D4 receptor. Compounds in series I (exempli®ed by 8k) have a phenyl ring joined to the 4-position of
the pyrazole while those in series II (exempli®ed by 15j) have a 5-phenyl ring linked by a saturated chain to the 4-
position of the pyrazole. Both series supplied compounds with excellent anity for the human D4 and good selectivity
over other dopamine receptors. Excellent selectivity over calcium, sodium, and potassium ion channels was also
achieved. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
Before the emergence of molecular cloning, only two
types of dopamine receptors acting through G-proteins
had been de®ned: the D1 receptor which mediates the
activation of adenylyl cyclase9 and the D2 receptor
which mediates its inhibition.10 Over the past 5 years,
molecular biologists have cloned a total of ®ve dopa-
mine receptors, grouped into two families: the D1 group
Dopamine has long been known to be implicated in
schizophrenia. As early as 19601 scientists discovered
that abnormally low quantities of dopamine were pre-
sent in the brains of schizophrenic patients. Consider-
able e€orts have since been made to ®nd a cure for this
debilitating illness.2
(D1 and D512) and the D2 group (D2,13 D3,14 and
11
D415). The typical and atypical antipsychotic drugs were
subsequently tested against these new human dopamine
receptors. Clozapine, amongst its other activities, has a
sevenfold higher anity for the human D4 (hD4) recep-
tor compared to the human D2 (hD2) receptor.15 In view
of this result, it has been proposed that the atypical
antipsychotic activity observed with clozapine is due to
its high anity for the hD4 receptor, rather than to its
anity for the hD2 receptor.
Current medications that have been successfully used in
the clinic are not devoid of side e€ects. The typical
antipsychotics such as haloperidol3 (1), which treat the
positive symptoms of the illness, induce extrapyramidal
side e€ects,4 tardive dyskinesia and hyperprolactin-
aemia.5 The atypical antipsychotic clozapine6 (2), which
treats both positive and negative symptoms, has been
found to induce agranulocytosis,7 a fatal blood dis-
order, in a small number of patients. Even though the
mechanism of action of these drugs is not entirely clear
they are believed to exert their antipsychotic activity via
blockade of D2-like receptors.8
In order to determine if a selective hD4 receptor ligand
would show antipsychotic activity with a reduced side
e€ect pro®le, a program was initiated to identify novel
dopamine receptor ligands, which would be selective for
the hD4 receptor. Our approach to ®nding such ligands
began with the application of a topological similarity
model (TOPOSIM)16,17 to known nonselective dopamine
Key words: Dopamine; hD4; anity; selectivity; pyrazole.
*Corresponding author.
0968-0896/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00134-5

1732
S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
antagonists. As a result of this work, the pyrazole (3)
was identi®ed within our laboratories18,19 as a highly
selective hD4 ligand. This paper describes the synthesis
and biological evaluation of an alternative series that led
to the identi®cation of 15j, a high anity hD4 receptor
ligand with excellent selectivity over the hD2 and hD3
dopamine receptors and reduced ion channel activity
compared to the lead compound (3).
piperazine, which was deprotected with tri¯uoroacetic
acid in dichloromethane to yield 4-chlorobenzyl piper-
azine (5). Coupling of 5 with 1-chloro-3-phenyl-2-pro-
panone gave the amino ketone (6), which on
deprotonation with lithium bis(trimethylsilyl)amide
and reaction with the activated ester of acetic acid yiel-
ded the b-diketone (7). Construction of the pyrazole
ring was achieved by reaction of the crude diketone with
hydrazine hydrate in methanol to give 1-(4-chloro-
benzyl)-4-(5-methyl-4-phenyl-1H-pyrazol-3-ylmethyl)-
piperazine (8k).
Tricyclic pyrazole analogues (series II) were prepared
following the procedures highlighted in Schemes 2±4.
Scheme
2
illustrates the synthesis of dihydro-
benzo[g]indazoles (15a±h). The lithium anion derived
from a-tetralone (9) was condensed with the activated
ester of BOC-sarcosine to give the b-diketone (10), from
which the pyrazole (11) was obtained by treatment with
hydrazine hydrate. The protected amine was converted
to the quaternary ammonium salt (14) and subsequent
displacement with 4-(4-methoxyphenyl)piperazine gave
the ®nal 3-[4-(4-methoxyphenyl)-piperazin-1-ylmethyl]-
4,5-dihydro-1H-benzo[g]indazole (15a).
Scheme 3 exempli®es the preparation of the 3-[4-(4-
methoxyphenyl)-piperazin-1-ylmethyl]-1,4-dihydro-ind-
eno[1,2-c]pyrazole (15i). The lithium anion produced
from 1-indanone (16) was coupled with the activated
ester of (4-(4-methoxyphenyl)-piperazin-1-yl) acetic acid
to give the b-diketone (17). Subsequent treatment with
hydrazine hydrate in the presence of triethylamine yiel-
ded the dihydroindeno[1,2-c]pyrazole (15i).
Chemistry
Scheme 1 illustrates the procedure used to synthesise a
series of 4-phenyl pyrazole analogues (series I, 8a±n).
BOC-Piperazine was coupled with 4-chlorobenzyl
chloride (4) in ethanol to give 4-chlorobenzyl BOC-
Scheme 4 illustrates the preparation of the oxygenated
analogues of dihydrobenzo[g]indazoles (15j±l). 4-Chro-
Scheme 1. Reagents: (a) BOC-Piperazine, K2CO3, EtOH, 95%; (b) TFA, CH2Cl2, 99%; (c) 1-Chloro-3-phenyl-2-propanone, Et3N,
CH2Cl2, 99%; (d) N,N0-Carbonyl diimidazole, AcOH, LiHMDS, THF, 18%; (e) Hydrazine hydrate, MeOH, 90%.

S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
1733
manone (19) was deprotonated with sodium bis(tri-
Results and Discussion
methylsilyl)amide in THF at 78 ꢀC and treated with
diethyl oxalate to give the b-diketone (20). Reaction
with hydrazine hydrate followed by reduction with
lithium aluminium hydride in THF and subsequent
treatment with oxalyl chloride/dimethylformamide gave
the chloromethyl pyrazole (22). Displacement of the
chlorine by 4-(4-methoxyphenyl)piperazine gave 3-[4-(4-
methoxyphenyl)-piperazin-1-ylmethyl]-1,4-dihydro-5-oxa-
1,2-diazacyclopenta[a]naphthalene (15j).
The novel compounds and reference drugs such as
haloperidol (1) and clozapine (2) were tested in vitro for
their abilities to displace [3H]-spiperone from dopamine
cloned human receptors (D2 being stably expressed in
CHO cells20 and D3 and D4 in HEK293 cells21). Each
inhibition constant (Ki) was an average of at least two
experiments. Binding to voltage-sensitive ion channels
was evaluated in rat for the sodium (Na+) channel,22 in
Scheme 2. Reagents: (a) Lithium diisopropylamide, THF; (b) BOC-Sarcosine, N,N0-carbonyl diimidazole, THF, 61% (from 9); (c)
Hydrazine hydrate, MeOH, 89%; (d) HCl in EtOAc, 97%; (e) Formaldehyde, sodium cyanoborohydride, acetic acid, MeOH, 96%;
(f) Methyl iodide, EtOH, 88%; (g) 4-(4-Methoxyphenyl)piperazine, butyllithium, THF, 42%; (h) 4-(4-Methoxyphenyl) piperazine,
Hunig's base, DMF, 35%.
Scheme 3. Reagents: (a) Lithium diisopropylamide, THF; (b) (4-(4-Methoxyphenyl)-piperazin-1-yl)-acetic acid, N,N0-carbonyl diimi-
dazole, THF-DMF, 23% (from 16); (c) Hydrazine hydrate, triethylamine, MeOH-DMF, 29%.

1734
S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
Scheme 4. Reagents: (a) Sodium bis(trimethylsilyl)amide, THF; (b) Diethyl oxalate; (c) Aqueous HCl, 97% (from 19); (d) Hydrazine
monohydrochloride, EtOH, 95%; (e) LiAlH4, THF; (f) Oxalyl chloride, CH2Cl2, DMF, 88% (from 21); (g) 1-(4-Methoxyphenyl)
piperazine, K2CO3, DMF, 53%.
rabbit for the calcium (Ca2+) channel,23 and in ferret
for the potassium (IKR) channel.24
Alternative pyrazole-4-phenyl substituents, X (Table 1).
Introduction of a para-chloro atom on the C4-phenyl
ring is detrimental in this series suggesting that the aro-
matic rings of 3 and 8e do not interact with the hD4
receptor in the same manner. Introduction of an ortho-
methyl substituent (8f) leads to comparable hD4 anity
compared to 8c with a threefold improvement in selec-
tivity over the hD2 receptor.
As previously disclosed by our co-workers,18,19 optimi-
sation of the topological similarity model led to the dis-
covery of (3), a high anity and selective hD4 ligand.
The aim of the current study was to develop a new series
of selective analogues with comparable hD4 anity to 3,
but with reduced ion channel activity. These novel series
have a cyclic amine linked to the pyrazole ring via a
methylene spacer. The compounds prepared fall into
two discrete series. Compounds in series I (exempli®ed
by 8k) have a phenyl ring joined to the 4-position of the
pyrazole, while compounds in series II (illustrated by
15a and 15j) have a 5-phenyl ring linked by a saturated
chain to the 4-position of the pyrazole. The structure±
activity relationships (SAR) of the two series is dis-
cussed separately below as it was found not to be
transferable.
In¯uence of pyrazole substitution, R1,2 (Table 1). The
pyrazole-5-methyl substituent is optimum in this series.
The hydrogen analogue (8g) has ®vefold lower anity
at the hD4 receptor than 8c and homologation to an
ethyl group (8h) is similarly detrimental for binding.
Methyl substitution on either of the nitrogen atoms of
the pyrazole (8i and 8j) results in a marked reduction of
hD4 receptor anity. This is presumably due to a steric
e€ect and not to the removal of the hydrogen bonding
capability as other heterocycles, such as isoxazole, have
been reported to have high anity to the hD4 recep-
tor.18
SAR of series I
In¯uence of the piperazine substituent, R (Table 1). Sim-
ple alkyl substitution (e.g. 8a) is not tolerated at the hD4
receptor and introduction of a phenyl ring (8b) only
marginally improves the anity. However, addition of a
methylene spacer separating the nitrogen and the aro-
matic ring substantially improves the anity and the
selectivity at the hD4 receptor. The benzyl piperazine
(8c) has now comparable hD4 receptor anity to the
reference compound 3. Extension of the alkyl chain lin-
ker, such as in 8d, is detrimental both for binding and
selectivity. These results presumably re¯ect the impor-
tance of the lipophilicity in this region of the molecule
as well as its relative position in space.
E€ect of benzylpiperazine substitution (Table 1). Addi-
tion of a para-chloro atom to the benzyl moiety main-
tains the high hD4 anity and selectivity (8k, Ki: hD4
2.6 nM; hD2 430 nM; hD3 1700 nM) seen with 8c. Other
substitution such as meta-chloro (8l) and para-methoxy
(8m) results in a fourfold to sevenfold reduction in a-
nity. The ortho-methyl analogue (8n) has comparable
anity and selectivity to 8c and 8k.
SAR of series II
In¯uence of the piperazine substituent, R (Table 2). The
benzo[g]indazole 15b has tenfold lower anity for both

S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
1735
the hD4 and hD2 receptors compared to its analogue 8c.
However, this reduction in hD4 receptor anity can be
reversed by variation of the piperazine substituent. For
example the isoquinoline (15d) has a 16-fold higher a-
nity for the hD4 receptor compared to 15b and is at least
250-fold selective over the other dopamine receptors
(15d, Ki: hD4 3.0 nM; hD2 750 nM; hD3 1500 nM).
Substituents such as para-methoxyphenyl also confer
high hD4 anity to the molecule (15a) with even lower
hD2 anity, whereas the 5-chloro-pyridyl-2-yl anologue
(15e) has similar hD4 anity but increased hD2 binding.
These results suggest that in this small group of com-
pounds of series II the distal piperazine nitrogen does not
have to be protonated to obtain high hD4 binding anity.
Table 1. Series I. 1-substituted-4-(4-aryl pyrazol-3-ylmethyl)-piperazines
Ki (nM)a
Number
R
R1
R2
X
hD2
hD3
hD4
Haloperidol 1
Clozapine 2
1.4
7.4
440
2.0
200
3600
2.3
10
2.3
3
8a
Me
Me
Me
H
H
H
H
>1650
(14%)
>1690
(26%)
>4300
(34%)
>4480
(33%)
>3100
(33%)
1200
8b
8c
Me
H
H
440
2200
5.9
8d
8e
8f
Me
Me
Me
H
H
H
H
p-Cl
o-Me
H
370
360
870
1100
650
120
20
H
830
3.5
8g
8h
8ib
8jb
H
930
2400
1400
2750
4300
27
31
Et
H
H
640
H
1-Me
2-Me
H
1140
190
83
H
H
>1900
(28%)
8k
8l
Me
Me
Me
Me
H
H
H
H
H
H
H
H
430
320
590
610
1700
2000
215
2.6
11
19
8m
8n
1300
7.4
aAnities at the cloned human dopamine receptors expressed in cell lines. Results are the mean of at least two determinations.
bRegiochemistry determined by NOE experiments.

1736
S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
Piperazine replacement (Table 2). Replacement of the
piperazine moiety with either piperidine (15f) or tetra-
hydropyridine (15g and 15h) leads to compounds with
high hD4 anity, but reduced selectivity against the hD2
receptor. The 4-phenyl piperidine analogue 15f has
5 nM anity at the hD4 receptor, but is nonselective
(Ki; hD2 5.4 nM; hD3 12 nM). The furylethyltetra-
hydropyridine (15g) has subnanomolar anity at the
hD4 receptor but is only 60-fold selective over the hD2
receptor, and the phenethyltetrahydropyridine (15h) has
slightly lower hD4 anity with no improvement in
selectivity. These results suggest that the piperazine can
be successfully replaced by cyclic monoamines without
compromising hD4 anity, although at the expense of
receptor subtype selectivity.
In¯uence of the saturated linker group, n, X (Table 2).
The 1,4-dihydroindeno[1,2-c]pyrazole (15i) analogue of
15a has a high anity for the hD4 receptor, but with a
somewhat lower selectivity over the hD2 and hD3
receptors.
The 5-oxa-1,2-diazacyclopenta[a]naphthalene analogue
(15j) (Ki: hD4 2.6 nM; hD2>980 nM; hD3>2900 nM)
Table 2. Series II: Benzo[g]indazoles, pyrano[4,3-c]pyrazoles and 1,2-diaza-cyclopenta[a]naphtalenes.
Ki (nM)a
hD3
Number
R
X
n
hD2
hD4
7.3
15a
CH2
1
>1700
(33%)
>4400
(20%)
15b
15c
CH2
CH2
1
1
1800
154
800
220
49
19
3
15d
15e
15f
15g
15h
15i
CH2
CH2
CH2
CH2
CH2
CH2
O
1
1
1
1
1
0
1
750
730
1500
3000
12
7.4
5.4
5
34
190
220
290
470
430
0.5
3.3
1.5
2.6
15j
>980
(29%)
>2900
(22%)
15k
15l
O
O
1
1
330
3300
2550
0.95
>1850
(30%)
35
aAnities at the cloned human dopamine receptors expressed in cell lines. Results are the mean of at least two determinations.

S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
1737
has a slightly higher hD4 receptor anity compared to
its benzo[g]indazole analogue (15a) with a good hD2
selectivity pro®le.
Conclusions
Two new series of 3-(heterocyclylmethyl)pyrazoles were
synthesised and evaluated for their ability to bind selec-
tively at the hD4 receptor. Both series provided com-
pounds with high hD4 receptor binding and good
selectivity over the hD2 and hD3 receptors. In series I, it
was shown that a piperazine N-benzyl substituent is
necessary for high hD4 receptor binding; whereas, in
series II, the second basic nitrogen is not essential.
Compound 15j has no measurable anity for ion chan-
nels such as Ca2+, Na+, and IKR, nor for 5HT2,
5HT1A, and Sigma receptors. The overall pro®le of 15j
makes it a suitable candidate to test the pharmacology
of the hD4 receptor.
Compound 15k, analogue of 15h, has high hD4 anity
(Ki; hD4 0.95 nM); but in contrast to the benzo[g]ind-
azole series, the selectivity over the hD2 receptor is
improved (hD2/hD4=350).
The benzyl analogue (15l) has a similar hD4 receptor
anity compared to 15b but with a slight increase in
selectivity over the hD2 receptor. These results show
that replacing the benzo[g]indazole skeleton by a 5-oxa-
1,2-diazacyclopenta[a]naphthalene group provides ana-
logues with the best selectivity pro®le.
Ion channel pro®le
Experimental
Ion channel activity especially at the Ca2+ and IKR
channel is considered to be responsible for cardiovas-
cular imbalance.25 Further evaluation of the pyrazole
lead (3) showed that it has anity at Ca2+, IKR, and
Na+ channels (Table 3). Consequently, selective high
anity hD4 ligands from series I and II were evaluated
at these three channels. Compound 8k has no anity
for the IKR channel, modest anity for the Ca2+
channel, and has an anity of 1 mM at the Na+ chan-
nel. The benzyl analogue 8c, which is also inactive at the
IKR channel, has reduced anity at the Ca2+ channel
but still has anity for the Na+ channel. The 5-oxa-1,2-
diazacyclopenta[a]naphthalene 15k has moderate a-
nity at both the Ca2+ and the Na+ channels; whereas,
the para-methoxyphenylpiperazine analogue (15j) is
devoid of anity at Na+, Ca2+, and IKR ion channels.
Anity at other G-protein receptors was also investi-
gated with 15j being inactive (Ki:>10 mM) at 5HT2,
5HT1A, and Sigma receptors.
Biochemical methods
[3H]-Spiperone binding studies.20,21 Clonal cell lines
expressing the human dopamine D2, D3, and D4 recep-
tor subtypes were harvested in PBS (phosphate bu€ered
saline) and then lysed in 10 mM Tris-HCl (pH 7.4) buf-
fer containing 5 mM MgSO4 for 20 min on ice. Mem-
branes were centrifuged at 50,000 g for 15 min at 4 ꢀC
and the resulting pellets resuspended in assay bu€er
(50 mM Tris±HCl, pH 7.4) containing 5 mM EDTA,
1.5 mM CaCl2, 5 mM MgCl2, 5 mM KCl, 120 mM
NaCl, and 0.1% ascorbic acid at 20 mg wet weight/mL
(human D4 HEK cells), 10 mg wet weight/mL (human
D2 CHO cells and human D3 HEK cells). Incubations
were carried out for 120 min at ambient temperature
(22 ꢀC) in the presence of 0.2 nM [3H]-spiperone for
displacement studies and were initiated by the addition
of 20±100 mg protein in a ®nal assay volume of 0.5 mL.
The incubation was terminated by rapid ®ltration over
GF/B ®lters presoaked in 0.3% PEI (polyethylenimine)
and washed with ice-cold 50 mM Tris±HCl, pH 7.4.
Speci®c binding was determined by 10 mM apomor-
phine and radioactivity determined by counting in a
LKB beta counter. Binding parameters were determined
by nonlinear least-squares regression analysis, from
which the inhibition constant Ki could be calculated for
each test compound.
Table 3. Ion channel activity
c
d
Number
Ca2+a
Na+b
0.56
IKR
hD4
3
8c
1.4
>1
0.4 2.3
72% at 10
46% at 1
>10
>10
5.9
2.6
1.5
8k
15j
15k
65% at 10
>10
59% at 10
>10
>10
n. d.
Ion channel activities.22±24 Binding to the voltage-sensi-
tive sodium channel was evaluated by displacement of
[3H]-batrachotoxin (30±60 Ci/mmol, NEN, USA) bind-
ing to rat cerebral cortex. Activity at the voltage sensitive
calcium channel (diltiazem allosteric site) was evaluated
by displacement of [3H] diltiazem (60±87 Ci/mmol,
NEN, USA) binding to rabbit skeletal muscle. Binding
to the voltage sensitive potassium channels (particularly
IKR channels) was estimated by measurement of the
56% at 10
0.95
aInhibition of speci®c binding of [3H] diltiazem to rabbit skele-
tal muscle (IC50, mM).
bInhibition of speci®c binding of [3H] batrachotoxin to rat
cortex (IC50, mM).
cConcentration of drug required to increase the e€ective
refractory period 25% over baseline measurements (EC25, mM).
dAnities at the cloned human dopamine receptors stably
expressed in cell lines (Ki, nM).

1738
S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
e€ective refractory period (ERP) in the ferret papillary
muscle.
temperature, a solution of 6 (1 g, 3.1 mmol) in dry THF
(25 mL) was added. The solution was cooled to 78 ꢀC
and lithium bis(trimethylsilyl)amide (6.2 mL, 1 M in
THF) was added dropwise. The resulting mixture was
stirred for 45 min at 78 ꢀC, then overnight at room
temperature, and quenched with a saturated aqueous
solution of NH4Cl. The organic layer was separated,
dried (Na2SO4), and evaporated. The residue was
puri®ed by column chromatography on silica using pet-
roleum ether (60±80)/EtOAc to a€ord 7 as an oil
Chemistry
All melting points were taken in open capillaries and are
1
uncorrected. H NMR spectra were recorded on a Bru-
ker AM 360 (360 MHz) or AC250 (250 MHz) spectro-
meter with TMS as an internal standard. Chemical
shifts were measured in ppm and coupling constants in
Hertz. Mass spectra were obtained using a VG Quattro
(55 eV) spectrometer. Microanalysis were carried out in
the Analytical Department of Butterworth Labora-
tories, Teddington, Middlesex. Reactions were mon-
itored by thin-layer chromatography (TLC) using
precoated silica gel plates from E. Merck (Kieselgel 60
1
(210 mg, 18%). H NMR (CDCl3) d 1.86 (3H, s), 2.40±
2.58 (8H, m), 2.99 (2H, s), 3.48 (2H, s), 7.12±7.40
(9H, m).
1-(4-Chlorobenzyl)-4-(5-methyl-4-phenyl-1H-pyrazol-3-yl-
methyl)-piperazine (8k). To a solution of 7 (200 mg,
0.52 mmol) in MeOH (5 mL) was added hydrazine hydrate
(0.2 mg, 6.2 mmol). The solution was stirred at room
temperature for 1 h and evaporated. CH2Cl2 and 10%
aq NaOH solution were added to the residue. The organic
layer was separated and the aqueous extracted with
CH2Cl2. The combined organic layers were dried (Na2SO4)
and evaporated to give the free base as a gum (180 mg,
90%). The bis hydrogen oxalate salt had a mp 217±219 ꢀC
F254). Column chromatography was performed on
Fluka silica gel 60 (220±440 mesh).
1-(4-Chlorobenzyl)-piperazine (5). To a solution of 4-
chlorobenzyl chloride (1.73 g, 10.7 mmol) in EtOH
(30 mL) was added tert-butyl 1-piperazinecarboxylate
(2 g, 10.7 mmol) and K2CO3 (3 g, 21.4 mmol). The mix-
ture was heated at re¯ux overnight and the solvent
removed. The residue was partitioned between water
and CH2Cl2. The organic layer was separated, dried
(Na2SO4), and evaporated to give the required carba-
mate as an oil. To a solution of the oil in CH2Cl2
(30 mL) was added TFA (7.7 mL, 97 mmol). The solu-
tion was stirred at ambient temperature overnight, eva-
porated, and the residue partitioned between EtOAc
and a 10% solution of K2CO3 in water. The organic
layer was decanted and the aqueous phase was extrac-
ted with EtOAc. The combined organic layers were
dried (Na2SO4) and evaporated to give the title product
as a solid (2 g, 91%). 1H NMR d (CDCl3) 2.46±2.62
(4H, m), 2.99±3.12 (4H, m), 3.51 (2H, s), 7.20±7.35
(9H, m).
1
(From EtOH/Et2O). H NMR (DMSO) d 2.23 (3H, s),
2.60±2.92 (8H, m), 3.74 (2H, s), 3.84 (2H, s), 7.24±7.46
(9H, m). MS, CI+ m/z=381 for (M+H)+. Found: C,
.
.
53.62; H, 5.27; N, 9.64. C22H25N4Cl 2(CO2H)2 H2O
requires C, 53.93; H, 5.40; N, 9.68%.
The following compounds were prepared in the same
manner as 8k using the appropriate piperazine.
1-Methyl-4-(5-methyl-4-phenyl-1H-pyrazol-3-ylmethyl)-
piperazine (8a). The hydrogen oxalate salt had a mp
196±197 ꢀC (From EtOH/Et2O). 1H NMR (DMSO) d
2.24 (3H, s), 2.50±2.80 (4H, m), 2.70 (3H, s), 3.0±3.20
(4H, m), 3.47 (2H, s), 7.22±7.44 (5H, m). MS, CI+ m/
z=271 for (M+H)+. Found: C, 54.59; H, 6.37; N,
.
.
1-(4-(4-Chlorobenzyl)piperazin-1-yl)-3-phenyl-propan-2-one
(6). To a solution of 1-chloro-3-phenyl-propan-2-one
(1 g, 5.9 mmol) in CH2Cl2 (30 mL) was added 5 (1.25 g,
5.9 mmol) and Et3N (0.82 mL, 5.9 mmol). The yellow
solution was stirred overnight at ambient temperature
and water was added. The organic phase was decanted,
washed with brine, dried (Na2SO4), and evaporated.
The residue was puri®ed by column chromatography on
silica using petroleum ether (60±80)/EtOAc as eluent to
a€ord 6 as a yellow oil (1.88 g, 99%). 1H NMR (CDCl3)
d 2.36±2.56 (8H, m), 3.20 (2H, s), 3.48 (2H, s), 3.72 (2H,
s), 7.15±7.37 (9H, m).
13.40. C16H22N4 1.5(CO2H)2 0.7H2O requires C, 54.53;
H, 6.56; N, 13.03%.
1-Phenyl-4-(5-methyl-4-phenyl-1H-pyrazol-3-ylmethyl)-
piperazine (8b). The hydrogen oxalate salt had mp 185±
188 ꢀC (From EtOH/Et2O). 1H NMR (DMSO) d 2.25
(3H, s), 2.76±2.90 (4H, m), 3.12±3.32 (4H, m), 3.82 (2H,
s), 6.76±7.44 (10H, m). MS, CI+ m/z=333 for
(M+H)+. Found: C, 64.02; H, 6.31; N, 12.98.
.
.
C21H24N4 (CO2H)2 0.5H2O requires C, 64.20; H, 6.10;
N, 13.16%.
1-Benzyl-4-(5-methyl-4-phenyl-1H-pyrazol-3-ylmethyl)-
piperazine (8c). The bis hydrogen oxalate salt had mp
226±230 ꢀC (From EtOH/Et2O). 1H NMR (DMSO) d
2.23 (3H, s), 2.62±2.80 (8H, m), 3.70±3.92 (4H, s), 7.26±7.47
(10H, m). MS, CI+ m/z=347 for (M+H)+. Found: C,
1-(4-(4-Chlorobenzyl)piperazin-1-yl)-3-phenyl-pentan-2,4-
dione (7). AcOH (0.36 mL, 6.2 mmol) was added to a
stirred solution of N,N0-carbonyldiimidazole (1.02 g,
6.2 mmol) in dry THF (25 mL). After 30 min at ambient

S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
1739
.
58.80; H, 5.45; N, 10.33. C22H26N4 2.1(CO2H)2 requires
C, 58.76; H, 5.68; N, 10.46%.
3.54±3.80 (2H, m), 3.79 (2H, s), 7.08±7.44 (9H, m). MS,
CI+ m/z=361 for (M+H)+. Found: C, 58.85; H, 6.00;
.
.
N, 10.17. C23H28N4 2(CO2H)2 0.5H2O requires C,
59.01; H, 6.05; N, 10.19%.
1-(2-Phenylethyl)-4-(5-methyl-4-phenyl-1H-pyrazol-3-yl-
methyl)-piperazine (8d). The hydrogen oxalate salt had
mp 190±194 ꢀC (From EtOH/Et2O). H NMR (DMSO)
The following compounds were prepared in the same
way as 8k using benzyl piperazine and either formic or
propionic acid to form the pentan-2,4-dione.
1
d 2.21 (3H, s), 2.55±2.65 (4H, m), 2.8±2.94 (8H, m), 3.59
(2H, s), 7.2±7.4 (10H, m). MS, CI+ m/z=361 for
(M+H)+. Found: C, 63.78; H, 6.43; N, 11.55.
.
C23H28N4 1.4(CO2H)2 requires C, 63.69; H, 6.38; N,
11.52%.
1-Benzyl-4-(4-phenyl-1H-pyrazol-3-ylmethyl)-piperazine
(8g). The bis hydrogen oxalate salt had a mp 226±
228 ꢀC (From EtOH/Et2O). H NMR (DMSO) d 2.66±
1
1-(3-Chlorobenzyl)-4-(5-methyl-4-phenyl-1H-pyrazol-3-yl-
methyl)-piperazine (8l). The hydrogen oxalate salt had
3.05 (8H, m), 3.80 (2H, s), 4.02 (2H, s), 7.22±7.62
(10H, m), 7.94 (1H, s). MS, CI+ m/z=333 for
(M+H)+. Found: C, 57.34; H, 5.92; N, 10.29.
mp 233±235 ꢀC (From EtOH/Et2O). H NMR (DMSO)
1
.
.
d 2.24 (3H, s), 2.60±3.00 (8H, m), 3.71 (2H, s), 3.89
(2H, s), 7.26±7.48 (9H, m). MS, CI+ m/z=381 for
(M+H)+. Found: C, 54.45; H, 4.87; N, 9.52.
C21H24N4 2(CO2H)2 H2O requires C, 57.50; H, 5.45; N,
10.41%.
.
.
C22H25N4Cl 2(CO2H)2 0.5H2O requires C, 54.79; H,
5.30; N, 9.83%.
1-Benzyl-4-(5-ethyl-4-phenyl-1H-pyrazol-3-ylmethyl)-
piperazine (8h). The bis hydrogen oxalate salt had a mp
224±227 ꢀC (From EtOH/Et2O). 1H NMR (DMSO) d
1.12 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.5 Hz), 2.70±
2.96 (8H, m), 3.76 (2H, s), 3.87 (2H, s), 7.26±7.48 (10H,
m). MS, CI+ m/z=360 for (M+H)+. Found: C, 58.80;
1-(4-Methoxyphenyl)-4-(5-methyl-4-phenyl-1H-pyrazol-3-
ylmethyl)-piperazine (8m). The hydrogen oxalate salt
had mp 222±224 ꢀC (From EtOH/Et2O). 1H NMR
(DMSO) d 2.23 (3H, s), 2.60±3.04 (8H, m), 3.64 (2H, s),
3.75 (3H, s), 3.97 (2H, s), 6.95±7.47 (9H, m). MS, CI+
m/z=377 for (M+H)+. Found: C, 56.53; H, 5.82; N,
.
.
H, 5.80; N, 9.93. C23H28N4 2(CO2H)2 0.5H2O requires
C, 59.01; H, 6.05; N, 10.19%.
.
.
9.86. C23H28N4O 2(CO2H)2 H2O requires C, 56.44; H,
5.86; N, 9.75%.
The following compounds were prepared in the same
manner as 8k using benzyl piperazine, formic acid and
methyl hydrazine in the last step.
1-(2-Methylbenzyl)-4-(5-methyl-4-phenyl-1H-pyrazol-3-yl-
methyl)-piperazine (8n). The hydrogen oxalate salt had
mp 225±228 C (From EtOH/Et2O). H NMR (DMSO)
d 2.23 (3H, s), 2.31 (3H, s), 2.66±3.00 (8H, m), 3.69 (2H,
s), 3.89 (2H, s), 7.13±7.47 (9H, m). MS, CI+ m/z=361
for (M+H)+. Found: C, 59.79; H, 6.02; N, 10.32.
1-Benzyl-4-(1-methyl-4-phenyl-1H-pyrazol-3-ylmethyl)-
piperazine (8i). The bis hydrogen oxalate had a mp
222±225 ꢀC (From EtOH/Et2O). 1H NMR (DMSO) d
2.66±3.02 (8H, m), 3.74 (2H, s), 3.85 (3H, s), 3.97 (2H,
s), 7.22±7.57 (10H, m), 7.98 (1H, s). Selective irradiation
of the ethyl group (3.74 ppm) led to enhancement of the
phenyl ortho proton and the pyrazole methyl (3.85 ppm)
signals. MS, CI+ m/z=347 for (M+H)+. Found: C,
ꢀ
1
.
C23H28N4 2(CO2H)2 requires C, 59.99; H, 5.96; N,
10.36%.
.
.
The following compounds were prepared in the same
way as 8k using benzyl piperazine and the appropriate
1-chloro-3-aryl-propanone.26
56.35; H, 5.75; N, 9.71. C22H26N4 2(CO2H)2 1.5H2O
requires C, 56.41; H, 6.01; N, 10.12%.
1-Benzyl-4-(2-methyl-4-phenyl-2H-pyrazol-3-ylmethyl)-
piperazine (8j). The bis hydrogen oxalate had a mp
214±217 ꢀC (From EtOH/Et2O). 1H NMR (DMSO) d
2.50±3.10 (8H, m), 3.69 (2H, s), 3.88 (3H, s), 4.07 (2H,
s), 7.23±7.48 (10H, m), 7.58 (1H, s). Selective irradiation
of the hydrogen (7.58 ppm) led to enhancement of the
phenyl ortho proton and the pyrazole methyl (3.88 ppm)
signals. MS, CI+ m/z=347 for (M+H)+. Found: C,
1-Benzyl-4-[4-(4-chlorophenyl)-5-methyl-1H-pyrazol-3-yl-
methyl]-piperazine (8e). The bis hydrogen oxalate had a
mp 232±233 ꢀC (From EtOH/Et2O). H NMR (DMSO)
1
d 2.33 (3H, s), 2.65±2.95 (8H, m), 3.68 (2H, s), 3.90
(2H, s), 7.35±7.50 (9H, m). MS, CI+ m/z=381 for
(M+H)+. Found: C, 54.97; H, 5.10; N, 9.74.
.
.
C22H25N4Cl 2(CO2H)2 0.4H2O requires C, 54.96; H,
5.29; N, 9.56%.
.
.
55.42; H, 5.51; N, 9.24. C22H26N4 2.25(CO2H)2 1.5H2O
requires C, 55.26; H, 5.86; N, 9.73%.
1-Benzyl-4-[5-methyl-4-(2-methylphenyl)-1H-pyrazol-3-yl-
methyl]-piperazine (8f). The bis hydrogen oxalate salt
had a mp 220±221 ꢀC (From EtOH/Et2O). 1H NMR
(DMSO) d 2.00 (3H, s), 2.04 (3H, s), 2.60±2.9 (8H, m),
2-(1-Hydroxy-2-(N-tert-butyloxycarbonyl-N-methyl)amino-
ethylidene)-3,4-dihydronapthalen-1-one (10). A solution
of LDA was prepared by the addition of n-BuLi (43 mL,

1740
S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
2.5 M in hexane) to diisopropylamine (14.9 mL,
106 mmol) in THF (300 mL) at 0 ꢀC under argon. The
yellow solution was cooled to 78 ꢀC and 9 (14.1 mL,
106 mmol) in THF (20 mL) was added dropwise, then
stirred for 30 min. N,N0-Carbonyldiimidazole (8.6 g,
53 mmol) was added to a solution of N-BOC-sarcosine
(10 g, 53 mmol) in THF (100 mL) at 0 ꢀC under argon.
After stirring for 15 min, the resulting solution was
cannulated into the enolate solution. The mixture was
stirred at 78 ꢀC for 30 min, then warmed to room
temperature. After a further 30 min, the thick brown gel
was poured into saturated aq NH4Cl. The two phases
were separated and the aqueous layer was further
extracted with EtOAc. The combined organic extracts
were dried (MgSO4), ®ltered, and concentrated. Dry
¯ash column chromatography on silica gel, eluting with
petroleum ether (60±80)/EtOAc, gave 10 as a claret-
NaCNBH3 (1.1 g, 17.5 mmol), and AcOH (2 mL) in
MeOH (50 mL) was cooled to 0 ꢀC and formaldehyde
solution (2 mL, 38% formaldehyde in MeOH) was
added. The mixture was stirred at 0 ꢀC for 90 min, with
mild e€ervescence observed. The mixture was basi®ed
with 1 M aqueous NaOH, diluted with water, and satu-
rated with NaCl before extracting twice with EtOAc.
The organic phases were dried (MgSO4), ®ltered, and
concentrated to give 13 as an orange foam (3.17 g,
96%). 1H NMR (CDCl3) 2.35 (6H, s), 2.73 (2H, t,
J=7.7 Hz), 2.95 (2H, t, J=7.7 Hz), 3.59 (2H, s), 7.17±
7.26 (3H, m) and 7.77 (1H, d, J=7 Hz). MS, CI+ m/
z=228 for (M+H)+.
(4,5-Dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethyl-
ammonium iodide (14).
A solution of 13 (3.17 g,
13.9 mmol) and iodomethane (1.5 mL, 24.1 mmol) in 3:1
Et2O/EtOH (40 mL) was stirred at room temperature
under argon for 24 h. The solvent was evaporated to
give a yellow residue, which was washed with Et2O to
give 14 as a cream-coloured solid (4.49 g, 88%). 1H
NMR (DMSO) d 2.77 (2H, t, J=7.8 Hz), 2.94 (2H, t,
J=7.8 Hz), 3.08 (9H, s), 4.53 (2H, s), 7.23±7.35 (3H, m),
7.66 (1H, d, J=7 Hz) and 13.8 (1H, br s). MS, CI+ m/
z=228 for (M+H)+.
1
coloured oil (10.3 g, 61%). H NMR (DMSO, d) Mix-
ture of carbamate rotamers and two enol forms of
diketone observed: 1.38 and 1.43 (9H, br s), 2.56±2.62
(2H, m), 2.80±2.92 (5H, m), 4.30±4.40 (2H, m), 7.26±
7.40 (2H, m), 7.47 and 7.61 (1H, t, J=6 Hz), 7.78±7.90
(1H, m), 15.50 and 15.70 (1H, br s). MS, CI m/z=317
for (M+H)+.
(4,5-Dihydro-1H-benzo[g]indazol-3-ylmethyl)-(N-tert-butyl-
oxycarbonyl)-methylamine (11). A solution of 10 (6 g,
19 mmol) and hydrazine hydrate (5 mL, 161 mmol) in
MeOH (50 mL) was stirred at room temperature under
argon for 15 min. MeOH was removed by evaporation
and the orange residual oil was partitioned between
water and 10% MeOH±CH2Cl2. The organic extracts
were dried (MgSO4), ®ltered, and concentrated to give
3-(4-(4-Methoxyphenyl)-piperazin-1-ylmethyl)-4,5-dihydro-
1H-benzo[g]indazole (15a). n-BuLi (2.5 mL, 2.5 M in
hexane) was added cautiously at 0 ꢀC under argon to a
stirred suspension of 1-(4-methoxyphenyl)-piperazine
dihydrochloride (530 mg, 2 mmol) in THF (10 mL), giv-
ing vigorous e€ervescence and forming a yellow solu-
tion. The solution was added at room temperature to a
stirred suspension of 14 (500 mg, 2.2 mmol) in THF
(15 mL). The mixture was heated at re¯ux under argon
for 30 min, then cooled, poured into water, and extrac-
ted with EtOAc. The organic phase was dried (MgSO4),
®ltered, and concentrated to give an orange solid which
was recrystallised from EtOH to give 15a (210 mg, 42%)
1
11 as an orange foam (5.25 g, 89%). H NMR (DMSO,
d) a 1:1 mixture of two pyrazole tautomers was
observed: 1.42 (9H, s), 2.58±2.68 (2H, m), 2.74 (3H, br
s), 2.86±2.96 (2H, m), 4.38 (2H, br s), 7.16±7.28 (3H, m),
7.56±7.70 (1H, m), 12.58 and 13.04 (1H, br s). MS, CI+
m/z=314 for (M+H)+.
as white granules, mp 207±208 ꢀC. H NMR (DMSO) d
1
(4,5-Dihydro-1H-benzo[g]indazol-3-yl[g]methyl)-methyl-
amine (12). A saturated solution of HCl in EtOAc
(100 mL) was added at room temperature to a solution
of 11 (5.1 g, 16 mmol) in EtOAc (50 mL). The mixture
was chilled for 90 min, then ®ltered to collect the salt.
The salt was partitioned between 2 M aqueous Na2CO3
and EtOAc. The combined organic extracts were dried
(MgSO4), ®ltered, and concentrated to give 12 as a yel-
low crystalline solid (3.36 g, 97%). 1H NMR (DMSO) d
2.27 (3H, s), 2.66 (2H, t, J=7.7 Hz,), 2.85 (2H, t,
J=7.7 Hz), 3.33 (1H, br s), 3.63 (2H, s), 7.14±7.26 (3H,
m), 7.63 (1H, d, J=7.0 Hz) and 12.42 (1H, br s). MS,
CI+ m/z=214 (M+H)+.
2.53 (4H, br s), 2.69 (2H, t, J=7 Hz), 2.87 (2H, t,
J=7 Hz), 3.00 (4H, br s), 3.56 (2H, br s), 3.67 (3H, s),
6.78±6.87 (4H, m), 7.15±7.25 (3H, m), 7.60±7.70 (1H,
m), 12.57 and 12.96 (1H, 2Âbr s). MS CI+ m/z=375 for
(M+H)+. Found: C, 73.5; H, 6.9; N, 14.7. C23H26N4O
requires C, 73.8; H, 7.0; N, 15.0%.
3-(4-Benzylpiperazin-1-ylmethyl)-4,5-dihydro-1H-benzo[g]-
indazole (15b). (General method for the preparation of
compounds 15c±h.) A solution of 14 (500 mg, 2.2 mmol),
1-benzylpiperazine (0.20 mL, 1.1 mmol) and diisopropyl-
ethylamine (0.40 mL, 2.3 mmol) in DMF (10 mL) was
heated under argon at 80 ꢀC for 18 h. The mixture was
cooled, poured into water, and extracted with 10%
EtOAc/Et2O. The extracts were dried (MgSO4), ®ltered,
and concentrated. Flash column chromatography on
(4,5-Dihydro-1H-benzo[g]indazol-3-ylmethyl)-dimethyl-
amine (13).
A solution of 12 (3.1 g, 14.5 mmol),

S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
1741
silica gel, eluting with CH2Cl2/MeOH/NH4OH (95:5:1)
gave a white solid. This was recrystallised from hexane/
EtOAc to yield 15b (127 mg, 33%) as white granules, mp
4-phenylpiperidine (150 mg, 0.9 mmol) as previously
described for the preparation of 15b, gave 15f, as a
brown oil. This was crystallised as the half-oxalate salt
from DMF/EtOH/EtOAc (45 mg, 12%), mp 228±
158±160 ꢀC. H NMR d (DMSO) 2.38 (8H, br s), 2.65
1
230 ꢀC. H NMR (DMSO; 353 K) d 1.70±1.92 (4H, m),
1
(2H, t, J=7.6 Hz), 2.84 (2H, t, J=7.6 Hz), 3.43 (2H, s),
3.49 (2H, br s), 7.14±7.32 (8H, m), 7.65 (1H, br s), 12.51
and 12.96 (1H, 2Âbr s). MS, CI+ m/z=359 for
(M+H)+. Found: C, 76.7; H, 7.2; N, 15.6. C23H26
2.40±2.56 (2H, m), 2.58±2.64 (1H, m), 2.78 (2H, t,
J=7.5 Hz), 2.90 (2H, t, J=7.5 Hz), 3.16 (2H, br d,
J=11 Hz), 3.82 (2H, s), 7.15±7.30 (8H, m) and 7.66 (1H,
d, J=7.7 Hz). MS, CI+ m/z=344 for (M+H)+. Found:
.
N4 0.1(H2O) requires C, 76.7; H, 7.3; N, 15.6%.
.
C, 73.85; H, 6.8; N, 10.8. C23H25N3 0.55(CO2H)2
requires C, 73.7; H, 6.7; N, 10.7%.
3-(4-Quinolin-2-yl-piperazin-1-ylmethyl)-4,5-dihydro-1H-
benzo[g]indazole (15c). Coupling of 14 (400 mg,
1.8 mmol) with 1-(quinolin-2-yl)piperazine (230 mg,
1.1 mmol), as previously described for the preparation
of 15b, gave 15c, crystallised as the oxalate salt from
EtOH to give brown granules (26 mg, 5%), mp 154±
155 ꢀC. 1H NMR d (DMSO) 2.73 (2H, t, J=7.7 Hz),
2.84 (4H, br s), 2.90 (2H, t, J=7.7 Hz), 3.79 (4H, br s)
7.18±7.30 (5H, m), 7.51±7.59 (2H, m), 7.65 (1H, d,
J=7.6 Hz), 7.71 (1H, d, J=7.9 Hz) and 8.06 (1H, d,
J=9.2 Hz). MS, CI+ m/z=396 for (M+H)+. Found:
3-(4-(2-Furan-2-ylethyl)-1,2,5,6-tetrahydropyridin-1-yl-
methyl)-4,5-dihydro-1H-benzo[g]indazole (15g). Coupling
of 14 (420 mg, 1.8 mmol) with 4-(2-furan-2-ylethyl)-
1,2,3,6-tetrahydropyridine29 (200 mg, 1.1 mmol), as pre-
viously described for the preparation of 15b, gave 15g as
a brown oil which was recrystallised as its half-oxalate
salt from EtOH/hexane (83 mg, 18%), mp 205±208 ꢀC.
1H NMR (DMSO) d 2.16 (2H, br s), 2.27 (2H, t,
J=7.7 Hz), 2.67±2.73 (4H, m), 2.86±2.90 (4H, m), 3.22
(2H, br s), 3.88 (2H, br s), 5.42 (1H, br s), 6.1 (1H, d,
J=3 Hz), 6.33 (1H, dd, J=3 and 2 Hz), 7.18±7.29 (3H,
m), 7.48 (1H, d, J=2 Hz) and 7.64 (1H, d, J=6.6 Hz).
MS, CI+ m/z=360 for (M+H)+. Found: C, 70.85; H,
.
C, 64.6; H, 5.5; N, 13.7. C25H25N5 1.3(CO2H)2 requires
C, 64.7; H, 5.4; N, 13.7%.
3-(4-Isoquinolin-3-yl-piperazin-1-ylmethyl)-4,5-dihydro-1H-
benzo[g]indazole (15d). Coupling of 14 (400 mg,
1.8 mmol) with 4-isoquinolin-3-yl-piperazine dihydro-
chloride27 (310 mg, 1.1 mmol), as previously described
for the preparation of 15b, gave 15d, which was recrys-
tallised twice from EtOAc/hexane, to give grey granules
(38 mg, 9%)with a mp 228±230 ꢀC. 1H NMR (DMSO) d
2.54±2.57 (4H, m), 2.71 (2H, t, J=7 Hz), 2.88 (2H, t,
J=7 Hz), 3.50±3.57 (4H, m), 3.59 (2H, br s), 6.94 (1H,
s), 7.15±7.28 (4H, m), 7.53 (1H, t, J=7.8 Hz), 7.65 (2H,
d, J=8.2 Hz), 7.85 (1H, d, J=8.1 Hz), 8.96 (1H, s),
12.56 and 12.96 (1H, 2Âbr s). MS, CI+ m/z=396 for
(M+H)+. Found: C, 75.0; H, 6.3; N, 17.3. C25H25
.
6.5; N, 10.05. C23H25N3O 0.55(CO2H)2 requires C,
70.78; H, 6.4; N, 10.27%.
3-(4-Phenethyl-1,2,5,6-tetrahydropyridin-1-ylmethyl)-4,5-
dihydro-1H-benzo[g]indazole (15h). Coupling of 14
(400 mg, 1.8 mmol) with 4-phenethyl-1,2,5,6-tetrahydro-
pyridine30 (200 mg, 1.1 mmol) as previously described
for the preparation of 15b, gave a red solid which was
recrystallised from EtOAc to give 15h (100 mg, 25%),
mp 173±174 ꢀC. 1H NMR (CDCl3) d 2.19 (2H, br s),
2.30 (2H, t, J=8.3 Hz), 2.68±2.76 (6H, m), 2.95 (2H, t,
J=6.9 Hz), 3.09 (2H, br s), 3.71 (2H, br s), 5.38±5.42
(1H, m), 7.16±7.30 (8H, m) and 7.80 (1H, d, J=7.4 Hz).
MS, CI+ m/z=370 for (M+H)+. Found: C, 80.8; H,
.
N5 0.25(H2O) requires C, 75.0; H, 6.4; N, 17.5%.
.
7.3; N, 11.3. C25H27N3 0.2(H2O) requires C, 80.5; H,
7.4; N, 11.3%.
3-(4-(5-Chloropyridin-2-yl)-piperazin-1-ylmethyl)-4,5-di-
hydro-1H-benzo[g]indazole (15e). Coupling of 14
(400 mg, 1.8 mmol) with 1-(5-chloropyridin-2-yl)-piper-
azine28 (320 mg, 1.6 mmol), as previously described for
the preparation of 15b, gave a white solid which was
recrystallised from CH2Cl2 to give 15e (87 mg, 21%),
mp 207±208 ꢀC. 1H NMR (DMSO) d 2.45±2.50 (4H, m),
2.68 (2H, t, J=7.4 Hz), 2.84 (2H, t, J=7.4 Hz), 3.40±
3.48 (4H, m), 3.56 (2H, br s), 6.84 (1H, d, J=9.1 Hz),
7.15±7.24 (3H, m), 7.56 (1H, dd, J=9.1 and 2.6 Hz),
7.60±7.70 (1H, m), 8.08 (1H, d, J=2.6 Hz), 12.56 and
12.98 (1H, 2Âbr s). MS, CI+ m/z=380 for (M+H)+.
Found: C, 66.3; H, 5.8; N, 18.1. C21H22N5Cl requires C,
66.4; H, 5.8; N, 18.4%.
Hydroxy-(4-oxo-chroman-3-ylidene)-acetic acid ethyl
ester (20).
A solution of sodium 1,1,1,3,3,3-hexa-
methyldisilylazide (35 mL, 1 M in THF) was added at
78 ꢀC under nitrogen to a stirred solution of 4-chro-
manone (19) (5 g, 34 mmol) in dry THF (100 mL). The
bright orange solution was stirred at 78 ꢀC for 20 min,
followed by addition of diethyl oxalate (4.75 mL,
35 mmol). The mixture was warmed to room tempera-
ture, becoming a thick red gel. The gel was diluted with
1 M HCl and extracted with EtOAc. The extract was
dried (MgSO4), ®ltered, and concentrated to give 20
(8.3 g, 97%) as a bright-yellow waxy solid; 1H NMR
(DMSO) d 1.30 (3H, t, J=7.5 Hz), 4.30 (2H, q,
J=7.5 Hz), 5.18 (2H, s), 7.04 (1H, d, J=8.5 Hz), 7.12
3-(4-Phenylpiperidin-1-ylmethyl)-4,5-dihydro-1H-benzo[g]-
indazole (15f). Coupling of 14 (300 mg, 1.3 mmol) with

1742
S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
(1H, dd, J=8.5 and 8.5 Hz), 7.58 (1H, dd, J=8.5 and
8.5 Hz) and 7.79 (1H, d, J=8.5 Hz). MS, CI+ m/z=249
for (M+H)+.
(5H, m), 6.98 (1H, dd, J=8 and 8 Hz), 7.17 (1H, dd,
J=8 and 8 Hz), 7.52±7.62 (1H, m), 12.84 and 13.14 (1H,
2Âbr s). MS, CI+ m/z=377 for (M+H)+. Found: C,
69.9; H, 6.4; N, 14.5. C22H24N4O2 requires C, 70.2; H,
6.4; N, 14.9%.
Ethyl benzo-[b]-2H-pyrano-[4,3-c]-1H-pyrazole-3-carboxyl-
ate (21). A solution of 20 (5.27 g, 21 mmol) and hydra-
zine monohydrochloride (1.5 g, 21 mmol) in EtOH
(80 mL) was heated at re¯ux under nitrogen for 3 h. The
mixture was cooled, then poured into water, and
extracted with EtOAc. The extract was dried (MgSO4),
®ltered, and concentrated to give 21 (4.93 g, 95%) as a
3-(4-Phenethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-1,4-di-
hydro-5-oxa-1,2-diazacyclopenta[a]naphthalene
(15k).
Coupling of 22 (250 mg, 1.1 mmol) with 4-phenethyl-
1,2,5,6-tetrahydropyridine (210 mg, 1.1 mmol), as pre-
viously described for the preparation of 15j, gave an oil
which was puri®ed by preparative TLC on silica, eluting
with EtOAc/hexane (2:1). The brown solid (300 mg) was
recrystallised from EtOAc/hexane to give 15k (47 mg,
yellow solid; 1H NMR (DMSO)
d 1.32 (3H, t,
J=7.1 Hz), 4.30 (2H, q, J=7.1 Hz), 5.46 (2H, s), 6.95
(1H, d, J=8 Hz), 7.02 (1H, dd, J=8 and 8 Hz), 7.23
(1H, dd, J=8 and 8 Hz), 7.62 (1H, d, J=8 Hz) and 14.1
(1H, br s). MS, CI+ m/z=245 for (M+H)+.
11%) as pale pink granules, mp 177±179 ꢀC. H NMR
1
(CDCl3) d 2.04 (2H, br s), 2.29 (2H, t, J=8 Hz), 2.62
(2H, apparent t, J=6 Hz), 2.73 (2H, t, J=8 Hz), 3.02
(2H, br s), 3.61 (2H, s), 5.26 (2H, s), 5.39 (1H, br s),
6.94±7.02 (2H, m), 7.16±7.22 (4H, m), 7.26±7.30 (2H, m)
and 7.71 (1H, dd, J=8 and 2 Hz). MS, CI+ m/z=372
for (M+H)+. Found: C, 76.75; H, 6.67; N, 10.96.
3-Chloromethyl-benzo-[b]-2H-pyrano[4,3-c]-1H-pyrazole
(22). A solution of LiAlH4 (3 mL, 1 M in THF) was
added to a stirred solution of 21 (360 mg,1.5 mmol) in
THF (20 mL) at 0 ꢀC under nitrogen. After 3 h, the
reaction was quenched by cautious addition of water,
then extracted with EtOAc. The extracts were dried
(MgSO4), ®ltered, and concentrated to give a yellow
solid. A solution of oxalyl chloride in CH2Cl2 (0.9 mL,
2 M in CH2Cl2) was diluted with CH2Cl2 (10 mL) and
cooled to 0 ꢀC with stirring. DMF (0.14 mL, 1.8 mmol)
was added dropwise, giving vigorous e€ervescence after
a brief induction period. The mixture was stirred at 0 ꢀC
for 10 min, then warmed to room temperature, forming
a white suspension. The suspension was cooled to 0 ꢀC
and a solution of the crude yellow solid in DMF (2 mL)
was added. The yellow solution was heated at re¯ux for
2 h, then cooled and poured into brine. The mixture was
extracted with Et2O. The extracts were dried (MgSO4),
®ltered, and concentrated to give a yellow oil. The oil
was further partitioned between water and Et2O. The
ethereal solution was dried (MgSO4), ®ltered, and con-
.
C24H25N3O 0.2(H2O) requires C, 76.85; H, 6.83; N,
11.20%.
3-(4-Benzylpiperazin-1-ylmethyl)-1,4-dihydro-5-oxa-1,2-di-
azacyclopenta[a]naphthalene (15l). Coupling of 22
(250 mg, 1.1 mmol) with 1-benzylpiperazine (200 mg,
1.1 mmol) as previously described for the preparation of
15j gave a yellow oil which solidi®ed on trituration to
give 15l (360 mg, 88%), characterised as the bis hydrogen
oxalate. White granules, mp 234±236 ꢀC (From DMF).
1H NMR (DMSO) d 2.64±3.00 (8H, m), 3.78 (2H, br s),
3.97 (2H, s), 5.30 (2H, s), 6.93 (1H, d, J=8 Hz), 6.99
(1H, dd, J=8 and 8 Hz), 7.20 (1H, ddd, J=8, 8 and
2 Hz), 7.38±7.40 (5H, m) and 7.58 (1H, dd, J=8 and
2 Hz). MS, CI+ m/z=361 for (M+H)+. Found: C,
.
.
56.60; H, 5.00; N, 9.92. C22H24N4O 2(CO2H)2 0.5(H2O)
requires C, 56.83; H, 5.32; N, 10.20%.
1
centrated to give 22 (285 mg, 88%) as a yellow oil; H
NMR (DMSO) d 4.78 (2H, s), 5.30 (2H, s), 6.93±7.05
(2H, m), 7.22 (1H, ddd, J=8, 8 and 2 Hz) and 7.57 (1H,
d, J=8 Hz).
2-(1-Hydroxy-2-(4-(4-methoxyphenyl)-piperazin-1-yl)-
ethylidene)-indan-1-one dihydrochloride (17). A solution
of LDA was prepared at room temperature by the
addition of n-BuLi (6.5 mL, 2.5 M in THF) to diisopro-
pylamine (2.25 mL, 62 mmol) in dry THF (100 mL)
under argon. The yellow solution was cooled to 78 ꢀC
and a solution of 16 (2.12 g, 16 mmol) in dry THF
(10 mL) was added dropwise. The resulting yellow solu-
tion was stirred at 78 ꢀC for 40 min. N,N0-Carbonyl-
diimidazole (1.3 g, 8 mmol) was added portionwise to
a stirred solution of (4-(4-methoxyphenyl)-piperazin-1-
yl)-acetic acid (2 g, 8.4 mmol) in 3:1 THF/DMF (40 mL)
at room temperature. After 15 min, the solution was
cannulated into the previously prepared solution of 16
in LDA. The resulting grey±green slurry was stirred at
78 ꢀC for 15 min, then warmed to room temperature
and poured into dilute aq NH4Cl. The mixture was
3-(4-(4-Methoxyphenyl)-piperazin-1-ylmethyl)-1,4-dihydro-
5-oxa-1,2-diazacyclopenta[a]naphthalene (15j).
A sus-
pension of 22 (280 mg, 1.3 mmol), 1-(4-methoxy-
phenyl)piperazine (25 mg, 0.77 mmol) and K2CO3
(200 mg, 1.4 mmol) in DMF (10 mL) was stirred at room
temperature under nitrogen for 48 h. The mixture was
diluted with water and extracted with 10% EtOAc/
Et2O. The extracts were dried (MgSO4), ®ltered, and
concentrated to give a yellow solid, which was recrys-
tallised from EtOH to give 15j (241 mg, 53%) as cream-
coloured granules, mp 190±192 ꢀC (From EtOH). 1H
NMR (DMSO) d 2.51 (4H, br s), 3.01 (4H, br s), 3.58
(2H, br s), 3.67 (3H, s), 5.20±5.36 (2H, m), 6.79±6.93

S. Bourrain et al./Bioorg. Med. Chem. 6 (1998) 1731±1743
1743
extracted with EtOAc. The extract was dried (MgSO4),
9. Kebabian, J. W.; Greengard, P. Science 1971, 174, 1346.
®ltered, and concentrated to give a brown oil. The oil
was redissolved in EtOAc and a saturated solution of
HCl in EtOAc was added. After cooling at 0 ꢀC for 24 h,
the brown precipitate was collected to give 17 (820 mg,
23%). 1H NMR (CDCl3) d 3.20±3.70 (8H, m), 3.62 (2H,
s), 3.71 (3H, s), 4.70 (2H, s), 6.88 (2H, d, J=9 Hz), 7.03
(2H, d, J=9 Hz), 7.45 (1H, d, J=7 Hz), 7.62±7.59 (2H,
m) and 8.14 (1H, br d, J=7 Hz).
10. Onali, P.; Olianas, M. C.; Gessa, G. L. Mol. Pharmacol.
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3-(4-(4-Methoxyphenyl)-piperazin-1-ylmethyl)-1,4-dihydro-
A suspension of 17
1-indeno[1,2-c]pyrazole (15i).
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(300 mg, 0.82 mmol), hydrazine hydrate (1 mL,
20 mmol), and Et3N (0.3 mL, 2 mmol) in 1:1 MeOH/
DMF (10 mL) was stirred at room temperature under
argon for 24 h. The solution was poured into water and
extracted with EtOAc. The extracts were dried
(MgSO4), ®ltered, and concentrated. Flash column
chromatography on silica gel, eluting with 2% MeOH/
CH2Cl2, gave a yellow solid which was recrystallised
from EtOH/water to give 15i (70 mg, 29%) as yellow
crystals, mp 176±178 ꢀC (from EtOH/H2O); 1H NMR
(DMSO) d 2.55±2.58 (4H, m), 3.01±3.04 (4H, m), 3.27
(2H, s), 3.58 (2H, s), 3.67 (3H, s), 6.79 (2H, d,
J=9.2 Hz), 6.87 (2H, d, J=9.2 Hz), 7.24 (1H, dd, J=7.4
and 7.4 Hz), 7.32 (1H, dd, J=7.4 and 7.4 Hz), 7.51 (1H,
d, J=7.4 Hz), 7.59 (1H, br d, J=7.4 Hz) and 12.58 (1H,
br s). MS, CI+ m/z=361 for (M+H)+. Found: C, 71.0;
15. Van Tol, H. H. M.; Bunzow, J. R.; Guan, H. C.; Sunahara,
R. K.; Seeman, P.; Niznik, H. B.; Civelli, O. Nature 1991, 350, 610.
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Emms, F.; Marwood, R.; Patel, S.; Patel, S.; Ragan, C. I.;
Freedman, S. B.; Leeson P. D. J. Med. Chem. 1996, 39, 1943.
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.
H, 6.5; N, 14.9. C22H24N4O 0.6(H2O) requires C, 71.2;
H, 6.8; N, 15.1%.
21. McAllister, G.; Knowles, M. R.; Ward-Booth, S. M.; Sin-
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Acknowledgements
The authors would like to thank S. R. Thomas for
NMR and mass spectra assistance, S. Thomson and K.
L. Moss for pharmacokinetics data and D. O'Connor
and P. Hunt for helpful discussions.
22. Catterall, W. A.; Morrow, C. S.; Daly, J. W.; Brown, G. B.
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