Towards a new generation of potential antipsychotic agents combining D 2 and 5-HT1A receptor activities

Article abstract of DOI:10.1021/jm061180b

We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent dopamine D₂ receptor antagonist and serotonin 5-HT_1A receptor agonist properties in the same molecule. We describe the structure-a

Full text of DOI:10.1021/jm061180b

J. Med. Chem. 2007, 50, 865-876
865
Towards a New Generation of Potential Antipsychotic Agents Combining D2 and 5-HT1A
Receptor Activities
Stephane Cuisiat,† Nathalie Bourdiol,† Vincent Lacharme,† Adrian Newman-Tancredi,‡ Francis Colpaert,§ and Bernard Vacher*,†
Pierre Fabre Research Center, 17 aVenue Jean Moulin, 81106 Castres Cedex, France
ReceiVed October 11, 2006
We report the discovery and the synthesis of novel, potential antipsychotic compounds combining potent
dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist properties in the same molecule.
We describe the structure-activity relationship that lead us to the promising derivative: N-[(2,2-dimethyl-
2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine 16. The latter has high affinity for
D2 and 5-HT1A receptors, whereas it possesses only a weak affinity for 5-HT2A sites. In cellular models of
signal transduction, 16 behaves as a silent antagonist at rD2 receptors while activating h5-HT1A receptors
with an efficacy at least equivalent to that of the prototypical 5-HT1A agonist (()-8-OH-DPAT. These dual
actions confer a unique pharmacological profile to the product. In a behavioral model predictive of positive
symptoms, 16 has an activity comparable to that of the typical antipsychotic haloperidol, while it is devoid
of cataleptogenic effects. Although it produces behaviors characteristic of 5-HT1A receptor activation in
rats, these occur at doses 100 times higher than those with (()-8-OH-DPAT. We believe that the relative
balance of D2 and 5-HT1A actions in 16 is appropriate, possibly optimal, to ensure superior efficacy and
tolerability over existing antipychotic drugs.
Introduction
still be associated with adverse effects originating from D2
blockade.9 The search for more effective and less toxic therapies
for schizophrenia, therefore, continues. Another pharmacological
approach, which has been gaining ground steadily, involves
combining D2 antagonism and 5-HT1A agonism in the same
molecule.10 Indeed, numerous mechanistic considerations11 and
preclinical evidence12 support the potential of such a combina-
tion. At present, however, compounds having varying ratios of
D2 and 5-HT1A activities for an adequate pharmacological and
clinical evaluation are lacking.
Schizophrenia is a lifelong, complex psychotic disorder. The
characteristic symptoms of the disease have been classified into
positive, negative, and cognitive. Depression is also a common
feature of the condition.1 In many patients the illness involves
repeated relapses of acute psychotic episodes interspersed with
stable phases of complete or partial remission. The introduction
of antipsychotics in the late 1950s was a major advance in the
management of schizophrenia and all effective antipsychotic
drugs identified to date block D2 receptors.2 However, although
blockade of D2 receptors improves the positive symptoms, it
also accounts for side effects that undermine compliance, in
particular extrapyramidal effects3 (EPS) and hyperprolactine-
mia.4 It took nearly three decades to obtain drugs that cause
no or minimal EPS at therapeutically relevant doses. These
second-generation derivatives, categorized as atypical in contrast
to conventional D2 blockers, combined D2 and 5-HT2 antago-
nism (e.g., clozapine, risperidone, olanzapine, and ziprazidone).5
They are claimed to be active against both positive and negative
symptoms, even though their superiority on negative symptoms
compared with that of typical antipsychotics is by no means
firmly established.6 Except for clozapine in treatment-resistant
schizophrenia, comparative studies have not shown efficacy
advantage for any one of these agents, and treatment discon-
tinuation rates are very high.7 Newer atypical agents (i.e.,
aripiprazole, bifeprunox, SSR-181507) differ in that they act
as partial agonists at D2 receptors, although they also interact
with an array of other CNS targets. Such therapeutic strategy
features the stabilization of dopamine function, instead of the
inhibition of D2 transmission caused by previous antipsychotic
drugs.8 Consequently, the capacity of drugs such as aripiprazole
to reduce positive symptoms has been questioned, and they may
The work described herein falls within this framework. Thus,
we examined the relationship between D2 and 5-HT1A activities
in novel hybrid D2 antagonists and 5-HT1A agonists, and then
we evaluated the impact of some of these derivatives in
behavioral models.
The optimal D2 and 5-HT1A pattern cannot be predicted today;
therefore, our research effort was guided by two basic consid-
erations: (1) A first-line antipsychotic treatment should control
the positive symptoms. From a mechanistic point of view, this
translates into compounds endowed with potent antagonist
properties at D2 receptors. (2) The extent of 5-HT1A stimulation
to be introduced into a dual D2/5-HT1A agent must be sufficient
to prevent catalepsy in rodents, even at high doses; taking into
account that the blockade (or perhaps the negative activation)
of D2 receptors evokes catalepsy in rodents and EPS in human.13
Previous studies from this laboratory14a have already estab-
lished that the catalepsy produced by a fixed dose of haloperidol14b
could be reversed, in a dose-related manner, by the co-
administration of 5-HT1A agonists; however, effective reversal
required an intrinsic activity at least equivalent to that of (()-
8-OH-DPAT.14c Though the context is slightly different
here, because we deal with a single agent acting at both D2
and 5-HT1A receptors, this precedent has the merit to define
a rational threshold for 5-HT1A activation. The profile we
aimed at is as follows: (1) potent D2 antagonist properties and
(2) a 5-HT1A efficacy at least equivalent to that of (()-8-OH-
DPAT.15
* To whom correspondence should be addressed. Tel.: (+33) 56371
4222. Fax: (+33) 56371 4299. E-mail: bernard.vacher@pierre-fabre.com.
† Medicinal Chemistry 1 Division.
‡ Neurobiology 2 Division.
§ Toulouse ISTMT 2.
10.1021/jm061180b CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/20/2007

866 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Cuisiat et al.
B. A Stille coupling reaction24 between 3-iodoethylbenzoate and
tributylvinyltin led to the corresponding styrene, which was then
converted to the cyclopropane IVi by a Simmons-Smith
reaction.25 The oxidation level of the intermediates IVe-i was
subsequently adjusted by reduction to the primary alcohols
(LiAlH4) then reoxidation with MnO2. Overall, this two-step
sequence delivered compounds VI with good efficiency.
The aromatic substituents of interest (i.e., R1 ) Ph, thienyl,
or furyl) were incorporated by a palladium-catalyzed reaction
(Method C). For this purpose, 3-bromobenzaldehyde was
subjected to a Suzuki cross-coupling26 reaction with the ap-
propriate boronic acids to yield the known aldehydes VIa-d
in a single step.17,27-30
Figure 1. Structure of SLV313.
Figure 2. Structure of sarizotan (left); structure of bifeprunox (right).
Finally, the pyridine analogue of VIg (i.e., VIj) was prepared
as outlined in Scheme 4.31 Addition of the Grignard reagent
derived from 1,4-dibromobutane32 on 3-bromo-5-ethylnicotinate
followed by dehydration of the resulting tertiary alcohol gave
the derivative V. The aldehyde function was then installed via
bromine-lithium exchange and trapping of the aryllithium with
N-formylmorpholine. This procedure supplied the derivative VIj
in modest yield.33
Scheme 1. General Method for the Synthesis of Compounds
4-21
Scheme 2. Preparation of Amines III
Results and Discussion
The biarylmethylamino motif, such as that found in 1, is
shared by the antidyskinetic agent 2 (sarizotan),34 the antipsy-
chotic 3 (bifeprunox),35 and a few other ligands36 interacting
with different members of the D2 receptors family; highlighting
the versatility of this chain (Figure 2).
Our efforts to find a group different from the biarylmethyl-
amino fragment in 1 that mimicked its action was totally
unrewarding as long as chemical modulations were exercised
on an arylpiperazine template. Because replacement of either
of the aromatic rings of the biaryl subunit was incompatible
with maintaining a useful level of interactions at 5-HT1A and/
or D2 receptors,37 we abandoned this strategy. The presence of
a chroman in 2 suggested another possibility. Disconnection
between C2-C3 in the dihydro-pyran part of 2 reveals an ortho-
substituted aryloxyethylamino moiety. It turned out that such a
change in connectivity produced more flexible ligands that then
withstood broad variations in the nature of R1 (see Table 1).38a
From our previous experience38b and literature precedent,38c we
selected a 2-isopropyloxyethylamino as a platform for launching
a SAR at the biaryl moiety.
First, simplifying the 4-fluorophenyl-pyridinyl to a naked
biphenyl, such as that carried by 3, led to 4. As shown in Table
1, the affinity balance in 4 was shifted in favor of the D2
component at the expense of 5-HT1A (4 vs 1). This reversal in
the order of affinities (pKi[D2] > pKi[5-HT1A]), as compared
to 1, fitted our plans (vide supra). Moreover, 3 is developed as
an antipsychotic (D2 > 5-HT1A), whereas 2 (5-HT1A > D2) was
in clinical trials for reducing levodopa-induced dyskinesia in
patients suffering from Parkinson’s disease. Compound 4
maintained a substantial affinity for 5-HT1A receptors while that
for 5-HT2A receptors was weak. In the recombinant system used,
4 appeared to be a less potent agonist at h5-HT1A receptors than
1, although the amplitude of the maximal response it attained
was encouragingly high.
Reagents and conditions: (i) 1-bromo-2-chloroethane, K2CO3, ethylm-
ethylketone, 80 °C; (ii) potassium phtalimide, DMF, 150 °C; (iii) ethano-
lamine, 25 °C.
Among the known and putative antipsychotics, the profile
of 1 (SLV313) comes closest to that which we were interested
in (Figure 1).16 This prompted us to modify the structure of 1
to obtain novel derivatives that met our pharmacological
requirements. At first we explored alternatives to the biaryl
subunit in 1, then we optimized the component that conveys
the 5-HT1A activity. In the last part of this work, we report and
discuss in vivo results on the most promising derivatives in
comparison with reference compounds.
Chemistry
The general synthetic route used for the preparation of
compounds 4-21 is described in Scheme 1. Thus, a reductive
amination between amines III and aldehydes VI provided a
convergent strategy to access the target compounds 4-21.
The amines III were either known17,18 or prepared in a
straightforward fashion (Scheme 2). Thus, a Williamson reaction
with 1,2-bromochloroethane added the two-carbon chain on
either a preformed or commercially available substituted phenol
or benzofuranol ring.19 From intermediate II, a classic, two-
step Gabriel synthesis20 served to introduce the primary amine
function present in compounds III.
The preparation of the aldehydes VI is depicted in Schemes
3 and 4. In any case, the synthesis started from a disubstituted
phenyl (or pyridyl) ring containing an ester or an aldehyde
function and a halogen atom in the meta-position.
From the commercially available 3-haloethylbenzoate (Scheme
3), a Heck coupling reaction21 with the cycloalkene of appropri-
ate ring-size delivered the unconjugated aryl-cycloalkene (Method
A). The double bond of the latter was then either isomerized
into the thermodynamic, conjugated position using rhodium-
(III) chloride22 to provide IVe-g or hydrogenated to give IVh.
The known aldehyde VIi23 was obtained according to Method
Introduction of 5-membered ring phenyl bioisosteres at the
terminal position has little influence on D2 and 5-HT1A affinities
(5, 6, and 7 vs 4). The results from GTPγS signaling, on the
other hand, revealed clear differences between these products.
Thus, 5 and 7 lacked 5-HT1A agonist activity, whereas 6 behaved
as a partial agonist of moderate potency, reaching nearly half
of the response to 5-HT, suggesting a possible, positive
contribution of the S-3 atom in the thiophene. Such isosteric

Agents Combining D2 and 5-HT1A Receptor ActiVities
Scheme 3. Preparation of Aldehydes VIa-i
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4 867
Reagents and conditions: Method A, (i) Pd(OAc)2, PAr3, K2CO3, cycloalkene, DMF; (ii) RhCl3, EtOH, ∆; (iii) H2, Pd/C, EtOH; Method B, (iv) Pd(PPh3)4,
CuI, tributylvinyltin, 1,4-dioxane; (v) CH2ClI, Et2Zn; Method C, (vi) Pd(PPh3)4, Na2CO3, boronic acid, DME; (vii) LiAlH4, THF; (viii) MnO2, CHCl3.
Scheme 4. Preparation of Aldehyde VIj
achieved (16-19) with the exception of compound 18. The
comparison between 18 and 16 indicated that binding at D2
receptors was sensitive to steric hindrance in the region of R2
and R3 on the dihydrobenzofuran ring (DHF).
So, clearly, the substituent(s) positioned on the DHF influ-
enced affinity data. A gem-dimethyl group in position 2 on the
DHF improved both D2 and 5-HT1A affinities (14 vs 15),
although the D2 binding site does not tolerate larger groups than
a methyl at this position (vide supra). A gem-dimethyl group
in position 3 on the DHF markedly decreased the affinity for
5-HT1A subtype (19 vs 16), whereas that for D2 was preserved.39
Reagents and conditions: (i) Br(CH2)4Br, Mg, THF; (ii) HCl, PhCH3,
∆; (iii) n-BuLi, N-formylmorpholine, Et2O.
replacement, when attempted at the internal phenyl, ended up
in a dramatic loss of affinity at D2 and 5-HT1A sites (data not
shown).
Derivatives 15-17 were, at least, as potent as 8-OH-DPAT
at activating the h5-HT1A receptors (cf. Table 2). Not unexpect-
edly from the structure of 1, the pyridin-3-yl analogues 20 and
21 of 16 and 17 exhibited higher D2 and 5-HT1A affinities and
were also more potent in the GTPγS assay. Most of the
compounds 13-21 behaved as antagonists at D2 receptors.40,41
Overall, compounds 16 and 20 fulfilled the pharmacological
requirements defined at the outset: they bind with high affinities
to and are antagonists at D2 receptors while they act as potent
5-HT1A agonists. Consequently, both were investigated in vivo.
Given that, in this study, the value of the intrinsic activity of
(()-8-OH-DPAT set the target to eliminate catalepsy, it is
included as a reference in Table 2.
The finding that partial (8-10) or complete reduction (11
and 12) of the terminal aromatic nucleus gave derivatives that
still interacted with D2 and 5-HT1A receptors represented a major
step forward in the project. Within the cycloalkene subset (i.e.,
8-10), binding affinity at D2 receptors was inversely related
to the ring size of the substituent R1. No such trend was observed
at 5-HT1A receptors, and the affinities for compounds 8-10
remained of similar magnitude. All these ligands (8-11) exerted
partial agonist effects in HeLa cells. However, the gap separating
affinity (measured through [3H]8-OH-DPAT displacement) from
potency (measured through G-protein activation) was signifi-
cantly smaller with 10 than with the other derivatives. Assuming
that this difference (pKi - pEC50) somehow reflects a higher
degree of sensitivity of the functional assay toward ligands
containing a phenyl-3-cyclopenten-1-yl fragment (e.g., 10), we
settled on such a motif to optimize the remainder of the
molecule. In addition, the benzylamino-cyclopentenyl was a
novel chemo-type and, therefore, well-suited for chemical
modifications.
As a logical extension, we next refined the aryloxyethylamino
component, using 10 as a model. Again, the modulations we
incorporated were inspired by the structure of 1. Thus, the
isopropylether and the 1,4-dioxan functions in 10 and 1,
respectively, were amalgamated to give rise to the novel series
reported in Table 2. Accordingly, formation of a six-membered
di-oxygenated ring (e.g., 13) did not affect the binding at D2
sites (13 vs 10) but markedly enhanced affinity and functional
activity at 5-HT1A receptors. In contrast, reducing the size of
the fused ring (14 vs 13) turned out to be detrimental on both
D2 and 5-HT1A parameters. This trend could be reversed by
raising the lipophilicity of the molecule through removal of the
O-3 atom in the methylenedioxy (e.g., 16) and introduction of
a gem-dimethyl group next to the oxygen (e.g., 15). Thanks to
these modifications, high affinity at D2 receptors could be
The indirect dopamine receptor agonist methylphenidate
reliably produces stereotypy and hyperlocomotion in rats. The
reversal of the signs (i.e., gnawing, sniffing, rearing, and
locomotion) mediated by a high dose of methylphenidate (40
mg/kg, i.p.) was, therefore, taken as a measure of antidopam-
inergic effects in vivo. Further, because methylphenidate induces
psychotic-like symptoms in humans (e.g., delirium and hal-
lucinations), it was assumed that normalization (i.e., inhibition
of all the signs) of such a high dose of methylphenidate-induced
responses in rats is predictive of an “incisive” activity against
positive symptoms in schizophrenics.42 Consistent with this, the
D2 antagonist and typical antipsychotic haloperidol completely
counteracts all the behaviors of methylphenidate-treated rats with
an ED50 value of 0.31 mg/kg (cf. Table 3). Similarly, normaliza-
tion occurred with 16 and 20, and both compounds were more
effective than 1. Hence, these results confirmed the ability of
16 and 20 to inhibit dopamine hyperactivity in vivo. In addition,
the activity of 16 and 20 in the methylphenidate test demon-
strated that their 5-HT1A agonist properties do not mask their
D2 antagonist action. Extrapolating from this animal data, we

868 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Table 1. In Vitro Activities of Compounds 1-12
Cuisiat et al.
affinity, pKia
5-HT1A efficacy
b
c
cmpd
R1
D2
5-HT2A
5-HT1A
pEC50
Emax
1
2
3
4
5
6
7
8
9
10
11
12
8.40 ( 0.05
7.72 ( 0.05
8.81 ( 0.04
9.71 ( 0.12
9.25 ( 0.16
9.56 ( 0.07
9.47 ( 0.15
8.51 ( 0.11
8.81 ( 0.10
9.30 ( 0.06
9.25 ( 0.07
9.22 ( 0.07
8.36 ( 0.05
6.14 ( 0.02
5.67 ( 0.07
5.48 ( 0.06
6.14 ( 0.02
6.25 ( 0.02
6.46 ( 0.05
6.43 ( 0.08
5.98 ( 0.11
6.72 ( 0.10
6.19 ( 0.09
6.52 ( 0.03
6.96 ( 0.02
7.08 ( 0.03
8.64 ( 0.01
8.65 ( 0.02
7.19 ( 0.14
7.58 ( 0.06
7.33 ( 0.03
7.46 ( 0.06
7.17 ( 0.07
7.64 ( 0.30
7.91 ( 0.10
7.53 ( 0.10
7.78 ( 0.09
7.21 ( 0.03
5.77 ( 0.04
8.23 ( 0.06
7.11 ( 0.05
6.49 ( 0.20
5.85 ( 0.15
<5
45.3 ( 3.5
66.5 ( 1.9
60.8 ( 1.8
73.9 ( 2.5
phenyl
thien-2-yl
thien-3-yl
fur-2-yl
cyclohepten-1-yl
cyclohexen-1-yl
cyclopenten-1-yl
cyclopentanyl
cyclopropyl
7.17 ( 0.01
<5
47.7 ( 8.5
5.81 ( 0.07
7.33 ( 0.05
7.16 ( 0.07
6.71 ( 0.23
<5
86.5 ( 2.5
69.8 ( 3.7
54.0 ( 5.8
71.2 ( 3.5
Haloperidol
a Binding affinity values are expressed as means ( SEM of separate experiments, each performed in triplicate. b Concentration of agonist for a 50% of
[35S]GTPγS binding in HeLa cells expressing human 5-HT1A receptors, -Log EC50 (pEC50) values were estimated using the mean values of three separate
c
experiments. Emax refers to maximal agonist effect, results expressed as % relative to serotonin (100%).
Table 2. In Vitro Activities of Compounds 13-21
affinity, pKia
5-HT1A efficacy
b
c
cmpd
A
R2
R3
Y
D2
5-HT1A
pEC50
Emax
13
14
15
16
OCH2
O
O
C
C
C
C(CH3)2
C
C
H
H
H
H
CH
CH
CH
CH
CH
CH
CH
N
9.11 ( 0.08
8.59 ( 0.04
8.91 ( 0.06
9.38 ( 0.05
8.95 ( 0.24
7.94 ( 0.17
9.09 ( 0.07
9.56 ( 0.07
9.35 ( 0.10
6.26 ( 0.03
8.77 ( 0.01
7.68 ( 0.07
8.02 ( 0.03
8.24 ( 0.07
8.21 ( 0.14
8.26 ( 0.01
7.37 ( 0.14
9.02 ( 0.10
8.44 ( 0.12
8.85 ( 0.07
8.19 ( 7.30
6.87 ( 0.02
7.61 ( 0.04
8.00 ( 0.04
7.47 ( 0.11
7.49 ( 0.09
6.95 ( 0.09
8.54 ( 0.04
8.58 ( 0.01
7.55 ( 0.11
68.9 ( 4.7
70.7 ( 1.3
90.6 ( 12.2
85.6 ( 4.4
93.8 ( 5.5
77.7 ( 1.7
72.4 ( 5.5
72.4 ( 1.5
78.5 ( 1.0
82.0 ( 4.0
CH3
CH3
CH2
CH3
H
CH3
CH3
CH2
CH2CH3
H
17
18d
19
20
21
CH3
CH2
CH3
CH2
N
8-OH-DPAT
a Binding affinity values are expressed as means ( SEM of separate experiments, each performed in triplicate. b Concentration of agonist for a 50% of
[35S]GTPγS binding in HeLa cells expressing human 5-HT1A receptors, -Log EC50 (pEC50) values were estimated using the mean values of three separate
c
experiments. Emax refers to maximal agonist effect, results expressed as % relative to serotonin (100%). d Racemate.
Table 3. Activities of Compounds 16 and 20 and References in Rats
LLRa
ED50
FBPc
ED50
normalizationd
ED50
CLPf
ED50
b
cmpd
LLR/Ne
0.2
CLP/Ne
1
0.32 (0.07-1.4)
1.70 (0.63-4.5)
1.4 (0.63-3.10)
0.31 (0.17-0.57)
>10
1.10 (0.70-1.80)
0.29 (0.13-0.64)
>40
0.30 (0.16-0.55)
>10
>28
1
Haloperidol
8-OH-DPAT
16
20
0.09 (0.05-0.17)
8.3 (2.6-26)
1.8 (0.69-4.8)
0.28 (0.17-0.47)
32 (10-102)
4.7 (0.88-25)
7.5
6.2
>40
>40
>36
>137
a LLR induction scored at 15 min after treatment i.p. b ED50 effective dose values are mg/kg (95% confidence limit). c FBP at 15 min after treatment i.p.;
compounds 16 and 20 did not produced any FPT at 40 mg/kg i.p. d Potency of the compound at normalizing methylphenidate-induced behaviors (gnawing,
sniffing, rearing, and locomotion), scored 30 min after the injection i.p. e N stands for normalization. f Potency of the compound at inducing catalepsy in rats
measured by the crossed-leg position test, scored at 60 min after injection.
anticipated that 16 and 20 would relieve the psychotic symptoms
in humans in a range of doses comparable as that of haloperidol.
To complement the profile associated with the blockade of
D2 receptors, the cataleptogenic potential of compounds 16 and
20 (along with that of references) was evaluated in rats.43 As
discussed in the introduction, the absence of cataleptogenic
effects is considered as an absolute requirement for any new
antipsychotic. As shown in Table 3, haloperidol evoked cata-
lepsy at the same doses as those that normalized methylpheni-
date-induced behaviors (i.e., from 0.30 mg/kg onward); this
result fully agrees with the high capacity of this drug to block
D2 subtypes in striatal structures.44 In contrast, no cataleptogenic
activity was observed with compounds 16 and 20 at doses up
to 40 mg/kg, despite their definite D2 antagonist properties in
vivo (vide supra). Additional studies showed that catalepsy was
restored when 16-treated animals were pretreated with the
selective 5-HT1A antagonist WAY-100635 (1 mg/kg, i.p.); this
is direct evidence that the anticataleptogenic properties of 16

Agents Combining D2 and 5-HT1A Receptor ActiVities
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4 869
Table 4. Experimental Details for Each of the Binding Assaysa
incubation
binding
site
[3H]ligand
(nM)
Kd
(nM)
tissue
(mg/mL)
time
(min)
nonspecific
binding (µM)
buffer
5-HT1A
5-HT2A
D2
8-OH-DPAT (0.2)
ketanserin (0.2)
YM-09151-2 (0.05)
3.1
3.1
0.036
rat cortex (10)
rat cortex (10)
rat striatum (1)
30
30
60
B
B
A
5-HT (10)
methysergide (10)
(+)-butaclamol (1)
a Incubation temperature 23 °C. Buffer A: Tris-HCl 50 mM, pH 7.4; NaCl 120 mM; KCl 5 mM. Buffer B: Tris-HCl 50 mM, pH 7.4; pargyline 10 µM;
CaCl2 4 mM; ascorbic acid 0.1%.
are mediated by its 5-HT1A agonist action.45 Importantly,
catalepsy did not appear upon repeated administration of 16,
indicating that no tachyphilaxis to the 5-HT1A anticataleptogenic
effects developed over (sub)chronic treatment (data not shown).
If the ratio CLP/normalization gave an indication about the
therapeutic margin for antipsychotic-like versus EPS-like effects,
then a favorable index was achieved with compounds 16 and
20 (Table 3). In essence, compounds 16 and 20 may be as
effective as the typical antipsychotics on the positive symptoms
while resembling the atypical ones with respect to EPS.46
In the present study, we used lower lip retraction (LLR) as a
sensitive marker of central 5-HT1A activation.47 Flat body
posture48 (FBP) was also recorded as it represents one compo-
nent of the “5-HT syndrome” in rats.49 After i.p. administration,
all the compounds, except haloperidol, produced dose-related
LLR and FBP (Table 3). In the case of 16, LLR was not
observed up to 8.3 mg/kg; a dose that is 25 and 100-fold higher
than that of 1 and 8-OH-DPAT, respectively. Regarding FBP,
the rank-order of the compounds in Table 3 was the same as
for LLR, but the dose-response curves were shifted rightwards.
The mechanism accounting for the low incidence of LLR (and
FBP) observed with 16 is likely related to the dual activity at
both D2 and 5-HT1A receptors. In any case, D2 blockade seems
to reduce the behavioral signs attributable to 5-HT1A activation.
Practically, there is a range of doses (i.e., 1.1 to 8.3 mg/kg) in
which one can benefit from 5-HT1A stimulation yet being free
from any 5-HT behavioral manifestation. The span of doses
separating the antipsychotic-like effects from the only element
of the “5-HT syndrome” present (i.e., FBP) is even more
impressive (i.e., 1.1 vs 32 mg/kg). However, the overlap between
LLR in rat and any mild clinical symptoms in human, as well
as the link between FBP and serotoninergic side effects, is a
matter of great uncertainty.
devoid of cataleptogenic effects. This absence of catalepsy
resulted from 5-HT1A receptors stimulation. In addition, the
doses of 16 and 20 that produced 5-HT1A signs in rats far exceed
those of the prototypical agonist (()-8-OH-DPAT and are not
commensurate with their high efficacy in vitro.50
Several lines of evidence indicate that compounds 16 and
close relatives may combine the advantages of typical and
atypical antipsychotics. Further pharmacological characterization
of 16, and a few other members of the series, focusing on aspects
that limit the therapeutic utility of available drugs (i.e., negative
symptoms and cognitive deficits), are being published.51 The
data collected on these various aspects support the view that
16 may represent the prototype of a novel class of more
“complete” antipsychotic agents.
Experimental Section
Chemistry. Melting points were determined on a Bu¨chi 530
1
melting point apparatus and were not corrected. H NMR spectra
were recorded on a Bruker Avance 400 spectrometer operating at
400 MHz for 1H and 100 MHz for 13C. Chemical shifts are reported
in δ value (ppm) relative to an internal standard of tetramethylsilane.
Infrared (IR) spectra were obtained on a Nicolet FT 510 P spectra
photometer. Microanalyses were obtained on a Fison EA 1108/
CHN analyzer. Mass spectra (TSQ 7000 Finnigan, Thermoelectron
Corporation) were determined by electron spay ionization (ESI) or
atmospheric pressure chemical ionization (APCI) techniques.
Analytical thin-layer chromatography were carried out on precoated
plates (silicagel, 60 F 254 Merck).
General Procedure for the Preparation of III. The following
three-step preparation was used to synthesize all the amines III
described in this paper.
2-Chloroethoxyaryl Ether (II). Potassium carbonate (1.6 equiv)
and 1-bromo-2-chloroethane (3.5-4 equiv) were added to a solution
of the corresponding phenol or benzofuranol derivative I (1 equiv)
in ethylmethylketone (0.2-0.5 M). The reaction mixture was heated
with stirring at 80 °C for 22 h then cooled to room temperature
and concentrated in vacuo. Water was added and the product was
extracted with methylene chloride. The combined organic layer was
washed with sodium hydroxide (1 M), then with water and brine,
dried over magnesium sulfate, and concentrated in vacuo. The ether
II was not purified unless otherwise noted.
Finally, if the ratio LLR/normalization gave an estimate of
the (optimal) balance between D2 and 5-HT1A properties, then
on this index, also, compound 16 stood out. In contrast, 20 may
display too much 5-HT1A activity relative to D2.
Conclusions
2-Aminoethoxyaryl Ether (III). Potassium phtalimide (1.05
equiv) was added by portion to a solution of II (1 equiv) in DMF
(0.6 M), and the reaction mixture was plunged in a preheated oil
bath at 150 °C. The mixture was stirred for 2 h then cooled to
room temperature, poured into water, and extracted with methylene
chloride. The combined organic layer was washed with brine, dried
over magnesium sulfate, and concentrated in vacuo. The solid
obtained was recrystallized before cleavage of the phtalimido group.
The phtalimido derivative (1 equiv) was dissolved in ethanolamine
(0.3 M), and the solution was stirred at room temperature for 18 h.
The reaction mixture was poured into cold water, and the product
was extracted with methylene chloride. The combined organic layer
was washed with brine, dried over sodium sulfate, and concentrated
in vacuo. The amine III was used without purification, unless
otherwise noted.
In this paper, we report the process through which we
discovered a series of structurally novel, potential antipsychotic
agents. Among the compounds prepared, 16 and 20 exhibited
high binding affinity for D2 and 5-HT1A receptors and only a
weak affinity for 5-HT2A receptors. They acted as antagonists
at D2 and as potent agonists at 5-HT1A sites. Compounds 16
and 20 differ from 1 by their binding profiles (D2 > 5-HT1A
)
and higher functional activity at h5-HT1A receptors. Conceptu-
ally, the compounds described in this work differ from the
second-generation antipsychotics, regardless of whether those
possess a 5-HT1A component (e.g., aripiprazole, ziprazidone,
and clozapine) or not (e.g., risperidone, olanzapine, and sertin-
dole) by their lack of interaction at 5-HT2A receptors.
In preclinical models, compounds 16 and 20 proved as
effective as the typical antipsychotic haloperidol and were
2-(Benzo[1,3]dioxol-4-yloxy)-ethylamine (IIIc). Synthesized
according to the general procedure above from 2-[2-benzo[1,3]-

870 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Cuisiat et al.
dioxol-4-yloxy)-ethyl]-isoindole-1,3-dione (6.50 g, 21 mmol) and
ethanolamine (42 mL), compound IIIc was obtained as a yellow
oil (3.30 g, 87%): 1H NMR (CDCl3) δ 3.1 (t, J ) 5.2 Hz, 2H),
4.11 (t, J ) 5.2 Hz, 2H), 5.95 (s, 2H), 6.52 (d, J ) 8.1 Hz, 1H),
6.55 (d, J ) 8.1 Hz, 1H), 6.76 (dd, J ) 8.2, 8.1 Hz, 1H).
2-(2,2-Dimethyl-benzo[1,3]dioxol-4-yloxy)-ethylamine (IIId).
From 2-[2-(2,2-dimethyl-benzo[1,3]dioxol-4-yloxy)-ethyl]-isoin-
dole-1,3-dione (1.30 g, 3.83 mmol) and ethanolamine (8 mL), the
product was purified by flash column chromatography (silica gel,
methylene chloride/methanol/ammonia, 95:4.5:0.5) to give IIId as
pale yellow oil (0.65 g, 80%): 1H NMR (CDCl3) δ 1.69 (s, 3H),
1.70 (s, 3H), 3.08 (t, J ) 5.2 Hz, 2H), 4.10 (t, J ) 5.2 Hz, 2H),
6.42 (d, J ) 8.1 Hz, 1H), 6.54 (d, J ) 8.5 Hz, 1H), 6.69 (dd, J )
8.3, 8.1 Hz, 1H).
mL per g of LiAlH4) was added dropwise. After 10 min at 0 °C
and 30 min at room temperature, the solid that formed was filtered
off and washed with diethyl ether. The filtrate was concentrated in
vacuo, and the residue obtained was used as such in the next step.
Step viii. The alcohol from step vii was dissolved in chloroform
(20 mL/g) and manganese(IV) oxide was added in one portion (5
g per g of alcohol). The suspension was vigorously stirred for 16
h then filtered on a pad of silica, eluting with chloroform. The
filtrate was concentrated in vacuo to give the aldehydes VIe-i,
which were used as such in the next step or purified by flash column
chromatography.
3-Cyclohepten-1-yl-benzaldehyde (VIe). From IVe, the alde-
hyde VIe was prepared in 88% yield (over 2 steps). It was purified
by flash column chromatography (silica gel, cyclohexane/ethyl
acetate, 90:10); yellow oil: 1H NMR (CDCl3) δ 1.54-1.60 (m,
2H), 1.66-1.69 (m, 2H), 1.83-1.87 (m, 2H), 2.29-2.34 (m, 2H),
2.77-2.83 (m, 2H), 6.17 (t, J ) 6.7 Hz, 1H), 7.45 (dd, J ) 7.7,
7.6 Hz, 1H), 7.57 (dd, J ) 6.5, 1.6 Hz, 1H), 7.59 (d, J ) 9.2, 1
Hz, 1H), 7.82 (s, 1H), 10.01 (s, 1H).
3-Cyclohexen-1-yl-benzaldehyde (VIf). From IVf, the aldehyde
VIf was prepared in 83% yield (over 2 steps). It was purified by
flash column chromatography (silica gel, cyclohexane/ethyl acetate,
90:10); yellow oil: 1H NMR (CDCl3) δ 1.59-1.71 (m, 2H), 1.78-
1.82 (m, 2H), 2.22-2.25 (m, 2H), 2.41-2.44 (m, 2H), 6.21-6.23
(m, 1H), 7.46 (dd, J ) 7.7, 7.6 Hz, 1H), 7.63 (dd, J ) 7.7, 1 Hz,
1H), 7.73 (dd, J ) 8.2, 1 Hz, 1H), 7.88 (d, J ) 1 Hz, 1H), 10.02
(s, 1H).
3-Cyclopenten-1-yl-benzaldehyde (VIg). From IVg, the alde-
hyde VIg was prepared in 96% yield (over 2 steps). It was not
purified at this stage; colorless oil: 1H NMR (CDCl3) δ 2.01-
2.07 (m, 2H), 2.53-2.58 (m, 2H), 2,68-2.74 (m, 2H), 6.30 (br s,
1H), 7.49 (dd, J ) 7.6, 7.5 Hz, 1H), 7.70-7.73 (m, 2H), 7.91 (s,
1H), 10.02 (s, 1H).
3-Cyclopentanyl-benzaldehyde (VIh). A solution of (3-ethyl-
benzoate)cyclopentene (0.80 g, 4.64 mmol) in ethyl acetate (24 mL)
containing diisopropylethyl amine (3.20 mL, 18.6 mmol) and a
catalytic amount of Pd(0) (5% on C) was stirred under hydrogen
(balloon) for 4 h at room temperature. The suspension was filtered
on Celite, and the filtrate was washed with HCl (1 N), water, and
brine, dried over sodium sulfate, and filtered, and the solvent was
evaporated in vacuo. The reduction-oxidation was followed as
above, and the compound was isolated by flash column chroma-
tography (silica gel, cyclohexane/ethyl acetate, 88:12) to give VIh
(0.59 g, 70% over 2 steps) as a colorless oil: 1H NMR (DMSO-
d6) δ 1.39-1.57 (m, 2H), 1.64-1.68 (m, 2H), 1.75-1.81 (m, 2H),
2.04-2.20 (m, 2H), 2.98-3.21 (m, 1H), 7.51 (dd, J ) 7.67, 7.5
Hz, 1H), 7.60 (d, J ) 7.6 Hz, 1H), 7.71 (d, J ) 7.5 Hz, 1H), 7.79
(s, 1H), 10.03 (s, 1H).
5-Cyclopenten-1-yl-pyridine-3-carboxaldehyde (VIj). A solu-
tion of 3-bromo-5-cyclopenten-1-yl-pyridine (1 g, 4.46 mmol) in
25 mL of diethyl ether was added to a solution of n-butyl lithium
(1.6 M in hexane, 4.20 mL, 6.68 mmol) in 25 mL of diethyl ether
at -60 °C. The reaction mixture was stirred for 2 h at -60 °C,
and then 4-morpholinecarboxaldehyde (1.40 mL, 13.38 mmol) was
added. The reaction mixture was stirred for 1 h at -60 °C and
then quenched with water, washed with brine, dried over magnesium
sulfate, filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, cyclohexane/ethyl
acetate, 80:20) to afford VIj (0.38 g, 49%) as an off-white solid,
mp ) 50 °C: 1H NMR (CDCl3) δ 2.09-2.11 (m, 2H), 2.60-2.62
(m, 2H), 2.70-2.73 (m, 2H), 6.49 (s, 1H), 8.32 (s, 1H), 8.89 (s,
1H), 8.93 (s, 1H), 10.10 (s, 1H).
2-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl-
amine (IIIe). From 2-[2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-
yloxy)-ethyl]-isoindole-1,3-dione (18 g, 0.056 mol) and ethanola-
mine (180 mL), compound IIIe was obtained as a pale yellow solid
1
(10.20 g, 88%): mp ) 56 °C; H NMR (CDCl3) δ 1.50 (s, 6H),
3.02 (s, 2H), 3.06 (t, J ) 5.6 Hz, 2H), 4.07 (t, J ) 5.6 Hz, 2H),
6.75 (m, 3H).
2-(2-Spirocyclopropane -2,3-dihydro-benzofuran-7-yloxy)-
ethylamine (IIIf). From 2-[2-spirocyclopropane-2,3-dihydro-ben-
zofuran-7-yloxy)-ethyl]-isoindole-1,3-dione (3 g, 8.94 mmol) and
ethanolamine (15 mL), the product was purified by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
98:1.5:0.5) to give IIIf as a yellow oil (0.55 g, 30%): 1H NMR
(CDCl3) δ 0.69 (t, J ) 6.4 Hz, 2H), 1.28 (t, J ) 6.4 Hz, 2H), 1.49
(s, 2H), 3.06 (t, J ) 5.6 Hz, 2H), 3.32 (s, 2H), 4.07 (t, J ) 5.6 Hz,
2H), 6.80-6.84 (m, 3H).
2-(2-Ethyl-2-methyl-2,3-dihydro-benzofuran-7-yloxy)-ethy-
lamine (IIIg). From 2-[2-(2-ethyl-2-methyl-2,3-dihydro-benzofuran-
7-yloxy)-ethyl]-isoindole-1,3-dione (0.72 g, 2.05 mmol) and eth-
anolamine (4 mL), compound IIIg was obtained as a yellow oil
(0.32 g, 70%), which was used as such in the next step: 1H NMR
(CDCl3) δ 0.95 (t, J ) 7.6 Hz, 3H), 1.44 (s, 3H), 1.61 (br s, 2H),
1.78 (q, J ) 7.6 Hz, 2H), 2.85 (t, J ) 5.6 Hz, 2H), 3.58 (t, J ) 5.6
Hz, 2H), 6.73-6.80 (m, 3H).
2-(3,3-Dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethy-
lamine (IIIh). From 2-[2-(3,3-dimethyl-2,3-dihydro-benzofuran-
7-yloxy)-ethyl]-isoindole-1,3-dione (2 g, 5.93 mmol) and ethano-
lamine (10 mL), the product was purified by flash column
chromatography (silica gel, methylene chloride/ethanol/ammonia,
95:4.5:0.5) to afford IIIh as a yellow oil (1.05 g, 85%): 1H NMR
(CDCl3) δ 1.34 (s, 6H), 1.66 (br s, 2H), 3.09 (t, J ) 5.2 Hz, 2H),
4.07 (t, J ) 5.2 Hz, 2H), 4.29 (s, 2H), 6.75-6.81 (m, 2H), 6.82-
6.86 (m, 1H).
General Procedure for the Preparation of Aldehydes (VIe-
i), Method A. Step i. To a solution of ethyl 3-iodobenzoate (1
equiv) in DMF (5 mL/g) was successively added the corresponding
cycloalkene (5 equiv), tetrabutylammonium bromide (1 equiv),
potassium carbonate (2.5 equiv), tris-(o-tolyl) phosphine (0.05
equiv), and palladium acetate (0.025 equiv). The reaction mixture
was heated at 110 °C for 16 h then cooled to room temperature,
poured into water, and extracted with ethyl acetate. The combined
organic layer was washed with brine and dried over magnesium
sulfate, and the solvent was removed in vacuo. Purification of the
residue was effected either by distillation or flash column chro-
matography.
Step ii. The product from step i was dissolved in ethanol (3 mL/
mmol) and rhodium(III) chloride was added (0.1 equiv). The
reaction mixture was heated at 80 °C for 16 h then cooled to room
temperature. The catalyst was filtered off (Celite), and the solvent
was removed in vacuo. Purification of the product IV was effected
either by distillation or flash column chromatography.
Step vii. The ester IV was dissolved in diethyl ether, and this
solution was added dropwise to a suspension of LiAlH4 (1.1 equiv)
in diethyl ether maintained at 0 °C. The reaction mixture was slowly
warmed to room temperature and stirred until all the starting
material was consumed (TLC). The reaction mixture was then
cooled to 0 °C, and a 10% aqueous sodium hydroxide solution (5
General Procedure for the Formation of Products 4-21 from
III and VI. A methanol solution (0.3 M) of the amine III (1 equiv)
and aldehyde VI (1 equiv) was stirred at room temperature for 15
h. The reaction mixture was cooled to 0 °C, and potassium
borohydride (2 equiv) was added by portions. The reaction was
then allowed to warm to room temperature and stirred for 4 h. The
mixture was concentrated to one-third of its volume, poured into
water, and extracted with ethyl acetate, the combined organic layer
was washed with brine, dried over sodium sulfate, and filtered, and

Agents Combining D2 and 5-HT1A Receptor ActiVities
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4 871
the solvent removed in vacuo. The residue was purified by flash
column chromatography. The purified product (1 equiv) was then
dissolved in ethanol and to this solution was added an ethanol
solution of the appropriate acid (1 equiv). The mixture was
concentrated to one-third its volume, and the salt that crystal-
lized out was filtered, washed with ether, and dried. The purity
of the salified material was systematically controlled by HPLC
before pharmacological tests (HPLC: chrom type, fixed WL
chromatogram, 220 nm; column type, symmetry C8 5µ 250 × 4.6
mm WAT; temperature, 25 °C; flow, 1 mL/min; peak quantification,
area).
(3-Fur-2-yl-benzyl)-[2-(2-isopropoxy-phenoxy)-ethyl]-amine
(7). Reductive amination between IIIa (0.32 g, 1.64 mmol) and
VId (0.28 g, 1.64 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
95:4.5:0.5) gave 0.32 g (56%) of 7 as a yellow oil: 1H NMR
(DMSO-d6) δ 1.17 (d, J ) 6 Hz, 6H), 2.86 (t, J ) 5.6 Hz, 2H),
3.82 (s, 2H), 4.04 (t, J ) 5.6 Hz, 2H), 4.45 (hept, J ) 6 Hz, 1H),
6.58-6.60 (m, 1H), 6.85-6.89 (m, 2H), 6.91-6.95 (m, 2H), 6.97-
6.99 (m, 1H), 7.26 (d, J ) 7.6 Hz, 1H), 7.36 (dd, J ) 7.7, 7.6 Hz,
1H), 7.57 (d, J ) 7.7 Hz, 1H), 7.89 (s, 1H), 7.99 (s, 1H). As the
oxalate salt: white powder, mp ) 193 °C; HPLC purity 95.5%
(eluent, acetonitrile/water/KH2PO4, 400:600:6.8 g, pH 4); IR (KBr)
ν 3542, 3432, 2838, 1702, 1500 cm-1; 1H NMR (DMSO-d6) δ 1.22
(d, J ) 6 Hz, 6H), 3.30 (t, J ) 4.5 Hz, 2H), 4.24 (t, J ) 4.5 Hz,
2H), 4.35 (s, 2H), 4.56 (hept, J ) 6 Hz, 1H), 6.62-6.64 (m, 1H),
6.73-6.90 (m, 1H), 6.93-7.05 (m, 4H), 7.43-7.53 (m, 2H), 7.74
(d, J ) 7.5 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H); 13C NMR (DMSO-
d6) δ 21.8 (2C), 45.2, 50.4, 65.5, 70.2, 106.3, 112.1, 115.4, 115.8,
120.9, 122.1, 123.6, 124.8, 128.8, 129.2, 130.6, 133.5, 143.1, 147.4,
148.3, 152.5, 164.5 (2C). Anal. (C22H25NO3‚C2H2O4) C, H, N.
3-Cyclohept-1-enyl-benzyl)-[2-(2-isopropoxy-phenoxy)-ethyl]-
amine (8). Reductive amination between IIIa (0.44 g, 2.23 mmol)
and VIe (0.50 g, 2.23 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
98:1.5:0.5) afforded 0.55 g (65%) of 8 as a yellow oil: 1H NMR
(CDCl3) δ 1.29 (d, J ) 6.4 Hz, 6H), 1.52-1.56 (m, 2H), 1.62-
1.65 (m, 2H), 1.78 (s, 1H), 1.80-1.85 (m, 2H), 2.25-2.30 (m,
2H), 2.58-2.62 (m, 2H), 3.03 (t, J ) 5.2 Hz, 2H), 3.86 (s, 2H),
4.13 (t, J ) 5.2 Hz, 2H), 4.41 (hept, J ) 6.4 Hz, 1H), 6.09 (t, J )
6.8 Hz, 1H), 6.88-6.93 (m, 4H), 7.20-7.25 (m, 3H), 7.29 (s, 1H).
As an oxalate salt: white powder, mp ) 179 °C; HPLC purity
95.6% (eluent, acetonitrile/water/KH2PO4, 400:600:6.8 g, pH 4);
IR (KBr) ν 3579, 3424, 2917, 1609, 1503 cm-1; 1H NMR (DMSO-
d6) δ 1.27 (d, J ) 6 Hz, 6H), 1.54-1.57 (m, 2H), 1.59-1.63 (m,
2H), 1.81-1.89 (m, 2H), 2.22-2.29 (m, 2H), 2.55-2.62 (m, 2H),
3.30 (t, J ) 5.2 Hz, 2H), 4.26 (t, J ) 5.2 Hz, 2H), 4.27 (s, 2H),
4.51 (hept, J ) 6 Hz, 1H), 6.08 (t, J ) 6.5 Hz, 1H), 6.88-6.95
(m, 3H), 6.99-7.64 (m, 1H), 7.27-7.34 (m, 3H), 7.36 (s, 1H);
13C NMR (DMSO-d6) δ 21.8(2C), 26.2, 26.3, 28.1, 31.8, 31.9, 45.1,
50.6, 65.5, 70.2, 115.4, 115.8, 120.9, 122.1, 125.6, 127, 127.9,
128.4, 130.4, 132.5, 143.8, 144.3, 147.4, 148.2, 164.3 (2C). Anal.
(C25H33NO2‚C2H2O4) C, H, N.
3-Cyclohex-1-enyl-benzyl)-[2-(2-isopropoxy-phenoxy)-ethyl]-
amine (9). Reductive amination between IIIa (0.47 g, 2.56 mmol)
and VIf (0.47 g, 2.56 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
99:0.5:0.5) afforded 0.43 g (46%) of 9 as a pale yellow oil: 1H
NMR (CDCl3) δ 1.29 (d, J ) 6 Hz, 6H), 1.63-1.68 (m, 2H), 1.74-
1.80 (m, 2H), 2.17-2.21 (m, 2H), 2.38-2.42 (m, 2H), 3.03 (t, J )
5.2 Hz, 2H), 3.86 (s, 2H), 4.13 (t, J ) 5.2 Hz, 2H), 4.42 (hept, J
) 6.4 Hz, 1H), 6.10-6.12 (m, 1H), 6.91-6.93 (m, 4H), 7.18-
7.21 (m, 1H), 7.25-7.27 (m, 3H), 7.38 (s, 1H). As an oxalate salt:
white powder, mp ) 165 °C; HPLC purity 97% (eluent, acetonitrile/
water/KH2PO4, 400:600:6.8 g, pH 4); IR (KBr) ν 3435, 2926, 1702,
1495 cm-1; 1H NMR (DMSO-d6) δ 1.22 (d, J ) 6 Hz, 6H), 1.59-
1.62 (m, 2H), 1.69-1.74 (m, 2H), 2.18-2.20 (m, 2H), 2.33-2.37
(m, 2H), 3.28 (t, J ) 5.1 Hz, 2H), 4.25 (t, J ) 5.1 Hz, 2H), 4.30
(s, 2H), 4.56 (hept, J ) 6 Hz, 1H), 6.17-6.20 (m, 1H), 6.87-6.97
(m, 2H), 7.01-7.03 (m, 2H), 7.39-7.38 (m, 2H), 7.42-7.44 (m,
1H), 7.10 (s, 1H); 13C NMR (DMSO-d6) δ 21.8, 21.7(2C), 22.4,
25.2, 26.6, 33.8, 45, 50.5, 65.4, 70.2, 115.4, 115.8, 120.9, 122.1,
124.9, 125, 126.3, 128.1, 128.5, 132.5, 135.4, 142.1, 147.4, 148.3,
164.5 (2C). Anal. (C24H31NO2‚C2H2O4) C, H, N.
[2-(2-Isopropoxy-phenoxy)-ethyl]-(3-phenyl-benzyl)-amine (4).
Reductive amination between IIIa (0.30 g, 1.53 mmol) and VIa
(0.28 g, 1.53 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
95:4.5:0.5) afforded 0.39 g (70%) of 4 as a pale yellow oil: 1H
NMR (CDCl3) δ 1.37 (d, J ) 6 Hz, 6H), 3.18 (t, J ) 5.1 Hz, 2H),
4.07 (s, 2H), 4.27 (t, J ) 5.1 Hz, 2H), 4.55 (hept, J ) 6 Hz, 1H),
6.98-7.06 (m, 5H), 7.32-7.44 (m, 6H), 7.66-7.77 (m, 3H). As
the oxalate salt: white powder, mp ) 182 °C; HPLC purity 99.7%
(eluent, acetonitrile/water/KH2PO4, 450:550:6.8 g, pH 4); IR (KBr)
1
ν 3432, 2973, 1752, 1500 cm-1; H NMR (DMSO-d6) δ 1.22 (d,
J ) 6 Hz, 6H), 3.32 (t, J ) 5.2 Hz, 2H), 4.27 (t, J ) 5.2 Hz, 2H),
4.38 (s, 2H), 4.57 (hept, J ) 6 Hz, 1H), 6.91 (dd, J ) 7.5, 1 Hz,
1H), 6.95 (dd, J ) 7.6, 1 Hz, 1H), 7.03 (dd, J ) 7.9, 1.4 Hz, 2H),
7.4 (t, J ) 7.3 Hz, 1H), 7.5 (t, J ) 7.8 Hz, 2H), 7.51-7.66 (m,
2H), 7.68-7.72 (m, 3H), 7.87 (s, 1H); 13C NMR (DMSO-d6) δ
21.8(2C), 45.2, 50.3, 65.6, 70.2, 115.5, 115.8, 121, 122.1, 126.6-
(2C), 126.9, 127.6, 128.3, 128.9(2C), 129.1, 133.5, 139.5, 140.4,
147.4, 148.3, 164.5(2C). Anal. (C24H27NO2‚C2H2O4) C, H, N.
2-(2-Isopropoxy-phenoxy)-ethyl]-(3-thien-2-yl-benzyl)-
amine (5). Reductive amination between IIIa (0.38 g, 1.95 mmol)
and VIb (0.36 g, 1.95 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
95:4.5:0.5) gave 0.44 g (67%) of 5 as a yellow oil: 1H NMR
(CDCl3) δ 1.30 (d, J ) 6 Hz, 6H), 3.05 (t, J ) 5.2 Hz, 2H), 3.91
(s, 2H), 4.15 (t, J ) 5.2 Hz, 2H), 4.45 (hept, J ) 6 Hz, 1H), 6.89-
6.93 (m, 4H), 7.07 (dd, J ) 5.1, 3.7 Hz, 1H), 7.25-7.34 (m, 4H),
7.49 (d, J ) 7.6 Hz, 1H), 7.60 (s, 1H). As the oxalate salt: white
powder, mp ) 195 °C; HPLC purity 99% (eluent, acetonitrile/water/
KH2PO4, 400:600:6.8 g, pH 4); IR (KBr) ν 3410, 3038, 2852, 1701
cm-1; 1H NMR (DMSO-d6) δ 1.22 (d, J ) 6 Hz, 6H), 3.30 (t, J )
5.2 Hz, 2H), 4.24 (t, J ) 5.2 Hz, 2H), 4.35 (s, 2H), 4.54 (hept, J
) 6 Hz, 1H), 6.89 (dt, J ) 7.5, 1.5 Hz, 1H), 6.94 (dt, J ) 7.6, 1.5
Hz, 1H), 7.03 (dt, J ) 6.5, 1.4 Hz, 2H), 7.16 (dd, J ) 5, 3.7 Hz,
1H), 7.46-7.52 (m, 2H), 7.53 (dd, J ) 3.5, 1 Hz, 1H), 7.58 (dd,
J ) 5, 1 Hz, 1H), 7.70 (d, J ) 5 Hz, 1H), 7.83 (s, 1H); 13C NMR
(DMSO-d6) δ 21.8 (2C), 45.2, 50.3, 65.5, 70.2, 115.5, 115.8, 120.9,
122.1, 123.9, 125.6, 126, 126.9, 128.4, 128.9, 129.3, 133.7, 134,
142.7, 147.4, 148.3, 164.5 (2C). Anal. (C22H25NO2S‚C2H2O4) C,
H, N.
2-(2-Isopropoxy-phenoxy)-ethyl]-(3-thien-3-yl-benzyl)-
amine (6). Reductive amination between IIIa (0.35 g, 1.79 mmol)
and VIc (0.34 g, 1.79 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
95:4.5:0.5) afforded 0.47 g (71%) of 6 as a yellow oil: 1H NMR
(CDCl3) δ 1.19 (d, J ) 6 Hz, 6H), 2.92 (t, J ) 5.2 Hz, 2H), 3.80
(s, 2H), 4.05 (t, J ) 5.2 Hz, 2H), 4.34 (hept, J ) 6 Hz, 1H), 6.92-
6.94 (m, 4H), 7.28-7.32 (m, 1H), 7.36-7.43 (m, 3H), 7.47-7.52
(m, 3H), 7.61 (s, 1H). As the oxalate salt: white powder, mp )
190 °C; HPLC purity 90% (eluent, acetonitrile/water/KH2PO4, 400:
1
600:6.8 g, pH 4); IR (KBr) ν 2973, 1752, 1617, 1503 cm-1; H
NMR (DMSO-d6) δ 1.22 (d, J ) 6 Hz, 6H), 3.29 (t, J ) 5.1 Hz,
2H), 4.24 (t, J ) 5.1 Hz, 2H), 4.34 (s, 2H), 4.56 (hept, J ) 6 Hz,
1H), 6.89 (dt, J ) 7.5, 1.4 Hz, 1H), 6.95 (dt, J ) 7.6, 1.4 Hz, 1H),
7.03 (dt, J ) 7, 1.4 Hz, 1H), 7.44-7.48 (m, 2H), 7.55 (dd, J ) 5,
0.8 Hz, 1H), 7.67 (dd, J ) 5, 3 Hz, 1H), 7.75 (d, J ) 5 Hz, 1H),
7.86 (d, J ) 3 Hz, 1H), 7.89 (s, 1H); 13C NMR (DMSO-d6) δ 21.8
(2C), 45.1, 50.4, 65.5, 70.2, 115.5, 115.8, 120.9, 121.3, 122.1, 125.9,
126.3, 127.2, 127.6, 128.5, 129.1, 133.3, 135.4, 140.9, 147.4, 148.3,
164.6 (2C). Anal. (C22H25NO2S‚C2H2O4) C, H, N.
3-Cyclopent-1-enyl-benzyl)-[2-(2-isopropoxy-phenoxy)-ethyl]-
amine (10). Reductive amination between IIIa (0.29 g, 1.49 mmol)
and VIg (0.26 g, 1.49 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
95:4.5:0.5) afforded 0.29 g (56%) of 10 as a colorless oil: 1H NMR
(DMSO-d6) δ 1.20 (d, J ) 6 Hz, 6H), 1.91-1.98 (m, 2H), 2.45-
2.51 (m, 2H), 2.62-2.67 (m, 2H), 2.87 (t, J ) 5.6 Hz, 2H), 3.77
(s, 2H), 4.03 (t, J ) 5.6 Hz, 2H), 4.48 (hept, J ) 6.4 Hz, 1H),

872 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Cuisiat et al.
6.23-6.25 (m, 1H), 6.85-6.88 (m, 2H), 6.92-6.98 (m, 2H), 7.20
(d, J ) 7.4 Hz, 1H), 7.26 (dd, J ) 7.6, 7.4 Hz, 1H), 7.31 (d, J )
7.6 Hz, 1H), 7.42 (s, 1H). As an oxalate salt: white powder, mp )
191 °C; HPLC purity 97% (eluent, acetonitrile/water/KH2PO4, 400:
1H NMR (DMSO-d6) δ 1.92-1.99 (m, 2H), 2.32-2.51 (m, 2H),
2.63-2.68 (m, 2H), 2.98 (t, J ) 5.6 Hz, 2H), 3.93 (s, 2H), 4.21 (t,
J ) 5.6 Hz, 2H), 4.22 (s, 4H), 6.27-6.28 (m, 1H), 6.47 (dd, J )
8.2, 1 Hz, 1H), 6.55-6.58 (m, 2H), 6.69 (dd, J ) 8.3, 8.2 Hz,
1H), 7.25-7.38 (m, 2H), 7.37 (d, J ) 7.5 Hz, 1H), 7.51 (s, 1H);
13C NMR (DMSO-d6) δ 22.7, 32.6, 32.8, 45.9, 51.3, 63.7, 63.8,
66.5, 106.2, 110.1, 119.8, 124.8, 126.2, 126.3, 127.6, 128.3, 133.6,
134.7 (2C), 136.2, 141.7, 144, 147.5, 167.3 (2C). Anal. (C22H25-
NO3‚C4H4O4) C, H, N.
1
600:6.8 g, pH 4); IR (KBr) ν 3051, 2973, 2848, 1723 cm-1; H
NMR (DMSO-d6) δ 1.22 (d, J ) 6 Hz, 6H), 1.93-2.01 (m, 2H),
2.49-2.51 (m, 2H), 2.64-2.67 (m, 2H), 3.27 (t, J ) 4.9 Hz, 2H),
4.24 (t, J ) 4.9 Hz, 2H), 4.30 (s, 2H), 4.56 (hept, J ) 6 Hz, 1H),
6.30-6.32 (m, 1H), 6.89 (dd, J ) 7.4, 7.3 Hz, 1H), 6.95 (dd, J )
7.5, 6.9 Hz, 1H), 7.01-7.04 (m, 2H), 7.37-7.42 (m, 2H), 7.48-
7.50 (m, 1H), 7.62 (s, 1H); 13C NMR (DMSO-d6) δ 21.8 (2C),
22.7, 32.6, 32.8, 45, 50.5, 65.4, 70.2, 115.4, 115.8, 120.9, 122.1,
125.7, 126.7, 127, 128.4, 128.6, 132.7, 136.4, 141.5, 147.4, 148.3,
164.5 (2C). Anal. (C23H29NO2‚C2H2O4) C, H, N.
[2-(Benzo[1,3]dioxol-4-yloxy)-ethyl]-(3-cyclopent-1-enyl-ben-
zyl)-amine (14). Reductive amination between IIIc (0.27 g, 1.34
mmol) and VIg (0.23 g, 1.34 mmol) and then purification by flash
column chromatography (silica gel, methylene chloride/methanol/
ammonia, 98:1.5:0.5) afforded 0.40 g (89%) of 14 as a yellow oil:
1H NMR (CDCl3) δ 1.97-2.05 (m, 2H), 2.17 (s, 1H), 2.50-2.55
(m, 2H), 2.69-2.73 (m, 2H), 3.02 (t, J ) 5.2 Hz, 2H), 3.86 (s,
2H), 4.21 (t, J ) 5.2 Hz, 2H), 5.91-5.96 (m, 2H), 6.15-6.20 (m,
1H), 6.52 (d, J ) 8.2 Hz, 1H), 6.75 (t, J ) 8.2 Hz, 1H), 7.19 (d,
J ) 7.4 Hz, 1H), 7.26-7.28 (m, 1H), 7.33 (d, J ) 7.6 Hz, 1H),
7.47 (s, 1H). As a fumarate salt: white powder, mp ) 133 °C;
HPLC purity 97.4% (eluent, acetonitrile/water/KH2PO4, 350:650:
3-Cyclopentanyl-benzyl)-[2-(2-isopropoxy-phenoxy)-ethyl]-
amine (11). Reductive amination between IIIa (0.37 g, 1.88 mmol)
and VIh (0.33 g, 1.88 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
95:4.5:0.5) gave 0.51 g (77%) of 11 as a yellow oil: 1H NMR
(DMSO-d6) δ 1.21 (d, J ) 6 Hz, 6H), 1.51-1.53 (m, 2H), 1.62-
1.65 (m, 2H), 1.73-1.76 (m, 2H), 1.97-2.00 (m, 2H), 2.84 (t, J )
5.7 Hz, 2H), 2.90-2.93 (m, 1H), 3.74 (s, 2H), 4.02 (t, J ) 5.7 Hz,
2H), 4.45 (hept, J ) 6.4 Hz, 1H), 6.81-6.87 (m, 2H), 6.92-6.98
(m, 2H), 7.07 (d, J ) 7.5 Hz, 1H), 7.12 (d, J ) 7.6 Hz, 1H), 7.18-
7.32 (m, 2H). As an oxalate salt: white powder, mp ) 178 °C;
HPLC purity 98.3% (eluent, acetonitrile/water/KH2PO4, 400:600:
1
6.8 g, pH 4); IR (KBr) ν 2949, 2843, 1637, 1464 cm-1; H NMR
(DMSO-d6) δ 1.94-1.99 (m, 2H), 2.33-2.51 (m, 2H), 2.64-2.67
(m, 2H), 2.96 (t, J ) 5.6 Hz, 2H), 3.89 (s, 2H), 4.19 (t, J ) 5.6
Hz, 2H), 5.96 (s, 2H), 6.27 (s, 1H), 6.57 (s, 2H), 6.60-6.64 (m,
2H), 6.78 (dd, J ) 8.1, 8.2, 1H), 7.25 (dd, J ) 9.3, 7.4 Hz, 1H),
7.30 (d, J ) 7.5 Hz, 1H), 7.37 (d, J ) 7.6 Hz, 1H), 7.49 (s, 1H);
13C NMR (DMSO-d6) δ 22.7, 32.6, 32.8, 46, 51.2, 66.7, 100.8,
102.5, 109.2, 122, 124.8, 126.2, 126.3, 127.6, 128.3, 124.6, 135
(2C), 136, 136.2, 141.7, 142.3, 148.4, 167 (2C). Anal. (C21H23-
NO3‚C4H4O4) C, H, N.
1
6.8 g, pH 4); IR (KBr) ν 3416, 3052, 2955, 1721, 1501 cm-1; H
NMR (DMSO-d6) δ 1.22 (d, J ) 6 Hz, 6H), 1.49-1.56 (m, 2H),
1.64-1.67 (m, 2H), 1.75-1.78 (m, 2H), 1.99-2.03 (m, 2H), 2.95-
3.01 (m, 1H), 3.28 (t, J ) 5.3 Hz, 2H), 4.23 (t, J ) 5.2 Hz, 2H),
4.27 (s, 2H), 4.56 (hept, J ) 6 Hz, 1H), 6.89-6.97 (m, 2H), 7.01
(d, J ) 7.8 Hz, 2H), 7.01-7.04 (m, 2H), 7.27-7.34 (m, 3H), 7.40
(s, 1H); 13C NMR (DMSO-d6) δ 21.8 (2C), 25 (2C), 34.1 (2C),
39, 45.1, 50.6, 65.4, 70.2, 115.4, 115.8, 120.9, 122.1, 127.2, 127.5,
128.4, 128.5, 132.5, 146.5, 147.4, 148.3, 164.5 (2C). Anal. (C23H31-
NO2‚C2H2O4) C, H, N.
(3-Cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-benzo[1,3]dioxol-
4-yloxy)-ethyl]-amine (15). Reductive amination between IIId
(0.64 g, 3.06 mmol) and VIg (0.53 g, 3.06 mmol) and then
purification by flash column chromatography (silica gel, methylene
chloride/methanol/ammonia, 95:4.5:0.5) afforded 0.76 g (68%) of
15 as a colorless oil: 1H NMR (CDCl3) δ 1.67 (s, 6H), 1.99-2.05
(m, 2H), 2.50-2.55 (m, 2H), 2.69-2.73 (m, 2H), 3.02 (t, J ) 5.2
Hz, 2H), 3.85 (s, 2H), 4.21 (t, J ) 5.2 Hz, 2H), 6.19-6.20 (m,
1H), 6.44 (d, J ) 7.8 Hz, 1H), 6.49 (d, J ) 8.3 Hz, 1H), 6.70 (dd,
J ) 8.2, 8.1 Hz, 1H), 7.19 (d, J ) 7.4 Hz, 1H) 7.25-7.35 (m, 2H),
7.41 (s, 1H). As a fumarate salt: white powder, mp ) 150 °C;
HPLC purity 95.3% (eluent, acetonitrile/water/KH2PO4, 350:650:
3-Cyclopropyl-benzyl)-[2-(2-isopropoxy-phenoxy)-ethyl]-
amine (12). Reductive amination between IIIa (0.16 g, 0.79 mmol)
and VIi (0.12 g, 0.79 mmol) and then purification by flash column
chromatography (silica gel, methylene chloride/methanol/ammonia,
99:0.5:0.5) afforded 0.15 g (57%) of 12 as a pale yellow oil: 1H
NMR (CDCl3) δ 0.68 (dd, J ) 10.8, 5.2 Hz, 2H), 0.92 (dd, J )
13.6, 5.6 Hz, 2H), 1.31 (d, J ) 6 Hz, 6H), 1.84-1.92 (m, 1H),
3.03 (t, J ) 5.2 Hz, 2H), 3.84 (s, 2H), 4.11 (t, J ) 5.2 Hz, 2H),
4.44 (hept, J ) 6 Hz, 1H), 6.93-6.99 (m, 5H), 7.07 (s, 1H), 7.12
(d, J ) 7.6 Hz, 1H), 7.21 (dd, J ) 7.6, 7.5 Hz, 1H). As an hemi-
fumarate salt: white powder, mp ) 99 °C; HPLC purity 97.8%
(eluent, acetonitrile/water/KH2PO4, 400:600:6.8 g, pH 4); IR (KBr)
1
6.8 g, pH 4); IR (KBr) ν 3589, 1631, 1501, 1466 cm-1; H NMR
(DMSO-d6): δ 1.61 (s, 1H), 1.77-1.99 (m, 2H), 2.48-2.51 (m,
2H), 2.63-2.67 (m, 2H), 2.92 (t, J ) 5.6 Hz, 2H), 3.84 (s, 2H),
4.12 (t, J ) 5.6 Hz, 2H), 6.26 (s, 1H), 6.48 (d, J ) 8.2 Hz, 1H),
6.6 (s, 2H), 6.61 (d, J ) 6.5 Hz, 1H), 6.71 (dd, J ) 8.21, 8, 1H),
7.23 (d, J ) 7.4 Hz, 1H), 7.29 (dd, J ) 7.5, 7.3 Hz, 1H), 7.34 (d,
J ) 7.6 Hz, 1H), 7.46 (s, 1H); 13C NMR (DMSO-d6) δ 22.7, 25.4
(2C), 32.6, 32.8, 46.2, 51.4, 66.7, 102.3, 108.5, 117.9, 121.3, 124.7,
126.1, 126.2, 127.6, 128.3, 134.6, 134.7 (2C), 136.1, 136.5, 141.7,
142.2, 147.9, 167.1 (2C). Anal. (C23H27NO3‚C4H4O4) C, H, N.
(3-Cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-2,3-dihydro-
benzofuran-7-yloxy)-ethyl]-amine (16). Reductive amination be-
tween IIIe (4.80 g, 0.023 mol) and VIg (4 g, 0.023 mol) and then
purification by flash column chromatography (silica gel, methylene
chloride/methanol/ammonia, 95:4.5:0.5) afforded 7.35 g (88%) of
16 as a colorless oil: 1H NMR (CDCl3) δ 1.47 (s, 3H), 1.50 (s,
3H), 1.91-1.98 (m, 2H), 2.45-2.51 (m, 2H), 2.62-2.67 (m, 2H),
3.04 (t, J ) 5.6 Hz, 2H), 3.85 (s, 2H), 4.18 (t, J ) 5.6 Hz, 2H),
6.18 (s, 1H), 6.74 (m, 3H), 7.19 (d, J ) 7.4 Hz, 1H), 7.25 (t, J )
8.7 Hz, 1H), 7.32 (d, J ) 7.6 Hz, 1H), 7.41 (s, 1H). As a fumarate
salt: white powder, mp ) 139 °C; HPLC purity 99.1% (eluent,
acetonitrile/water/KH2PO4, 350:650:6.8 g, pH 4); IR (KBr) ν 3060,
2967, 1719, 1463 cm-1; 1H NMR (DMSO-d6) δ 1.39 (s, 6H), 1.94-
1.97 (m, 2H), 2.50-2.55 (m, 2H), 2.60-2.69 (m, 2H), 2.96 (t, J )
5.6 Hz, 2H), 2.99 (s, 2H), 3.91 (s, 2H), 4.11 (t, J ) 5.6 Hz, 2H),
6.27 (s, 1H), 6.56 (s, 2H), 6.70-6.74 (m, 1H), 6.77-6.80 (m, 2H),
7.28-7.33 (m, 2H), 7.37 (d, J ) 7.6 Hz, 1H), 7.50 (s, 1H); 13C
NMR (DMSO-d6) δ 22.7, 27.8 (2C), 32.6, 32.8, 42.4, 46, 51.2,
1
ν 3414, 2976, 1709, 1618, 1499 cm-1; H NMR (DMSO-d6) δ
0.60-0.67 (m, 2H), 0.91-0.96 (m, 2H), 1.22 (d, J ) 6 Hz, 6H),
1.86-1.92 (m, 1H), 2.95 (t, J ) 5.6 Hz, 2H), 3.88 (s, 2H), 4.08 (t,
J ) 5.6 Hz, 2H), 4.5 (hept, J ) 6 Hz, 1H), 6.56 (s, 2.4H), 6.87-
6.9 (m, 2H), 6.97-7.03 (m, 3H), 7.09 (s, 1H), 7.13 (d, J ) 7.4 Hz,
1H), 7.21 (dd, J ) 7.5, 7.4 Hz, 1H); 13C NMR (DMSO-d6) δ 9.3
(2C), 14.8, 21.8 (2C), 45.7, 51.1, 66.5, 70.4, 115.2, 116.3, 121.1,
121.7, 125.1, 126, 126.1, 128.2, 134.6 (2C), 135.3, 143.9, 147.3,
148.7, 167.1 (2C). Anal. (C21H27NO2‚1.2C4H4O4) C, H, N.
(3-Cyclopent-1-enyl-benzyl)-[2-(2,3-dihydro-benzo[1,4]dioxin-
5-yloxy)-ethyl]-amine (13). Reductive amination between IIIb
(0.50 g, 2.56 mmol) and VIg (0.44 g, 2.56 mmol) and then
purification by flash column chromatography (silica gel, methylene
chloride/methanol/ammonia, 95:4.5:0.5) gave 0.49 g (55%) of 13
as a yellow oil: 1H NMR (CDCl3) δ 1.85 (s, 1H), 1.85-2.05 (m,
2H), 2.50-2.55 (m, 2H), 2.68-2.73 (m, 2H), 3.05 (t, J ) 5.6 Hz,
2H), 3.87 (s, 2H), 4.14 (t, J ) 5.6 Hz, 2H), 4.23-4.27 (m, 2H),
4.28-4.32 (m, 2H), 6.18-6.20 (m, 1H), 6.54 (d, J ) 8.2 Hz, 1H),
6.55 (d, J ) 8.3 Hz, 1H), 6.74 (d, J ) 8.2, 8.3 Hz, 1H), 7.19 (d,
J ) 7.4 Hz, 1H), 7.24-7.28 (m, 1H), 7.31 (d, J ) 7.6 Hz, 1H),
7.47 (s, 1H). As a fumarate salt: white powder, mp ) 138 °C;
HPLC purity 99.4% (eluent, acetonitrile/water/KH2PO4, 350:650:
6.8 g, pH 4); IR (KBr) ν 3500, 2842, 1594, 1501, 1332, 1117 cm-1
;

Agents Combining D2 and 5-HT1A Receptor ActiVities
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4 873
66.3, 86.9, 113.6, 118, 120.2, 124.8, 126.2, 126.3, 127.7, 128.3,
128.4, 134.7 (2C), 136, 136.2, 141.7, 142.7, 147.1, 167.3 (2C). Anal.
(C24H29NO2‚C4H4O4) C, H, N.
(5-Cyclopent-1-enyl-pyridin-3-yl-methyl)-[2-(2,2-dimethyl-2,3-
dihydro-benzofuran-7-yloxy)-ethyl]-amine (20). Reductive ami-
nation between IIIe (0.77 g, 3.71 mmol) and VIj (0.64 g, 3.71
mmol) and then purification by flash column chromatography (silica
gel, methylene chloride/methanol/ammonia, 98:1.5:0.5) gave 1.17
g (87%) of 20 as a colorless oil: 1H NMR (CDCl3) δ 1.74 (s, 6H),
2.02-2.07 (m, 2H), 2.50-2.56 (m, 2H), 2.69-2.71 (m, 2H), 3.01-
3.04 (m, 4H), 3.86 (s, 2H), 4.19 (t, J ) 5.2 Hz, 2H), 6.28 (s, 1H),
6.74-6.77 (m, 3H), 7.71 (s, 1H), 8.49 (s, 1H), 8.57 (s, 1H). As a
maleate salt: white powder, mp ) 169 °C; HPLC purity 99.9%
(eluent, acetonitrile/water/KH2PO4, 350:650:6.8 g, pH 4); IR (KBr)
ν 3434, 3038, 2971, 1621, 1577, 1463 cm-1; 1H NMR (DMSO-d6)
δ 1.41 (s, 6H), 1.96-2.04 (m, 2H), 2.49-2.51 (m, 2H), 2.68-
2.71 (m, 2H), 3.01 (s, 2H), 3.34-3.57 (m, 4H), 4.25 (t, J ) 4.8
Hz, 2H), 4.30 (s, 2H), 6.02 (s, 2H), 6.42 (m, 1H), 6.77 (dd, J )
7.7, 7.6 Hz, 1H), 6.84 (dd, J ) 6.9, 1.6 Hz, 1H), 7.99 (s, 1H), 8.55
(s, 1H), 8.81 (s, 1H); 13C NMR (DMSO-d6) δ 22.6, 27.8 (2C), 32.3,
33, 42.3, 45.9, 47.9, 64.9, 87.2, 113.9, 118.6, 120.3, 127.6, 128.7,
128.9, 131.2, 134.2, 135.9 (2C), 138.6, 142.3, 147, 147.1, 149.1,
167.1 (2C). Anal. (C23H28N2O2‚C4H4O4) C, H, N.
(3-Cyclopenten-1-yl-benzyl)-[2-(2-spiro-cyclopropyl-2,3-dihy-
dro-benzofuran-7-yloxy)-ethyl]-amine (17). Reductive amination
between IIIf (0.30 g, 1.46 mmol) and VIg (0.25 g, 1.46 mmol)
and then purification by flash column chromatography (silica gel,
methylene chloride/methanol/ammonia, 95:4.5:0.5) gave 0.45 g
(86%) of 17 as a pale yellow oil: 1H NMR (CDCl3) δ 0.69 (t, J )
6.4 Hz, 2H), 1.22 (t, J ) 6.4 Hz, 2H), 1.23 (s, 1H), 2.00-2.03 (m,
2H), 2.49-2.25 (m, 2H), 2.68-2.71 (m, 2H), 3.01 (t, J ) 5.2 Hz,
2H), 3.31 (s, 2H), 3.84 (s, 2H), 4.17 (t, J ) 5.2 Hz, 2H), 6.18 (s,
1H), 6.79-6.84 (m, 3H), 7.18 (d, J ) 7.4 Hz, 1H), 7.25 (t, J ) 7.6
Hz, 1H), 7.31 (d, J ) 7.6 Hz, 1H), 7,40 (s, 1H). As a maleate salt:
white powder, mp ) 180 °C; HPLC purity 98.3% (eluent,
acetonitrile/water/KH2PO4, 400:600:6.8 g, pH 4); IR (KBr) ν 3454,
2998, 2957, 2841, 1621, 1461 cm-1; 1H NMR (DMSO-d6) δ 0.78
(t, J ) 6.4 Hz, 2H), 1.06 (t, J ) 6.4 Hz, 2H), 1.96-1.99 (m, 2H),
2.49-2.52 (m, 2H), 2.66-2.68 (m, 2H), 3.30-3.33 (m, 4H), 4.21-
4.24 (m, 4H), 6.02 (s, 2H), 6.32 (s, 1H), 6.81-6.84 (m, 3H), 7.36-
7.38 (m, 2H), 7.51 (d, J ) 7.6 Hz, 1H), 7.60 (s, 1H); 13C NMR
(DMSO-d6) δ 11.7 (2C), 22.7, 32.6, 32.9, 35.7, 45.5, 50.5, 64.8,
67.9, 113.8, 118.2, 121, 125.9, 126.8, 127.1, 128.3, 128.5, 128.7,
131.9, 135.9 (2C), 136.4, 141.4, 142.1, 147.8, 167.1 (2C). Anal.
(C24H27NO2‚C4H4O4) C, H, N.
(5-Cyclopent-1-enyl-pyridin-3-ylmethyl)-[2-(2-spiro-cyclopro-
pyl-2,3-dihydro-benzofuran-7-yloxy)]-ethylamine (21). Reductive
amination between IIIf (0.44 g, 2.17mmol) and VIj (0.38 g, 2.17
mmol) and then purification by flash column chromatography (silica
gel, methylene chloride/methanol/ammonia, 95:4.5:0.5) delivered
0.60 g (76%) of 21 as a colorless oil: 1H NMR (CDCl3) δ 0.69 (t,
J ) 6.8 Hz, 2H), 1.23 (t, J ) 6.4 Hz, 2H), 2.00-2.08 (m, 2H),
2.53-2.62 (m, 2H), 2.69-2.74 (m, 2H), 3.01 (t, J ) 5.2 Hz, 2H),
3.31 (s, 2H), 3.85 (s, 2H), 4.17 (t, J ) 5.2 Hz, 2H), 6.28 (s, 1H),
6.78-6.84 (m, 3H), 7.70 (s, 1H), 8.39 (s, 1H), 8.57 (s, 1H). As a
fumarate salt: white powder, mp ) 162 °C; HPLC purity 96.3%
(eluent, acetonitrile/water/KH2PO4, 350:650:6.8 g, pH 4); IR (KBr)
ν 3434, 2958, 285, 1729, 1642 cm-1; 1H NMR (DMSO-d6) δ 0.75
(t, J ) 6.4 Hz, 2H), 1.07 (t, J ) 6.4 Hz, 2H), 1.94-2.01 (m, 2H),
2.49-2.51 (m, 2H), 2.65-2.70 (m, 2H), 2.92 (t, J ) 5.6 Hz, 2H),
3.29 (s, 2H), 3.87 (s, 2H), 4.10 (t, J ) 5.6 Hz, 2H), 6.41 (s, 1H),
6.60 (s, 2H), 6.78-6.85 (m, 3H), 8.41 (d, J ) 1.4 Hz, 1H), 8.60
(d, J ) 1.8 Hz, 1H); 13C NMR (DMSO-d6) δ 11.8 (2C), 22.7, 32.3,
32.9, 35.8, 47, 49.6, 67.7, 67.8, 87.2, 113, 117.3, 121, 127.9, 128,
131.1, 132.3, 134.3 (2C), 134.6, 139.1, 142.9, 145.3, 147.7, 147.9,
166.4 (2C). Anal. (C24H27NO2‚C4H4O4) C, H, N.
(3-Cyclopent-1-enyl-benzyl)-[2-(2-ethyl-2-methyl-2,3-dihydro-
benzofuran-7-yloxy)-ethyl]-amine (18). Reductive amination be-
tween IIIg (0.68 g, 3.07 mmol) and VIg (0.53 g, 3.07 mmol) and
then purification by flash column chromatography (silica gel,
methylene chloride/methanol/ammonia, 95:4.5:0.5) afforded 0.42
g of 18 as a yellow oil (36%): 1H NMR (CDCl3) δ 0.95 (t, J )
7.6 Hz, 2H), 1.42 (s, 3H), 1.77 (q, J ) 7.6 Hz, 2H), 1.97-2.05 (m,
2H), 2.50-2.54 (m, 2H), 2.68-2.73 (m, 2H), 2.98 (ABq, ∆νAB
)
68.8 Hz, J ) 15.2 Hz, 2H), 3.02 (t, J ) 5.2 Hz, 2H), 4.16 (t, J )
5.2 Hz, 2H), 5.3 (s, 1H), 6.70-6.76 (m, 3H), 7.14 (d, J ) 7.2 Hz,
1H), 7.25 (t, J ) 7.7 Hz, 1H), 7.32 (d, J ) 7.6 Hz, 1H), 7.40 (s,
1H). As a fumarate salt: white powder, mp ) 108 °C; HPLC purity
95.1% (eluent, acetonitrile/water/KH2PO4, 350:650:6.8 g, pH 4);
1
IR (KBr) ν 3431, 2966, 1706, 1593 cm-1; H NMR (DMSO-d6)
0.88 (t, J ) 7.2 Hz, 3H), 1.33 (s, 3H), 1.65-1.72 (m, 2H), 1.94-
1.99 (m, 2H), 2.50-2.55 (m, 2H), 2.65 (q, J ) 6.8 Hz, 2H), 2.97
(ABq, ∆νAB ) 60.8 Hz, J ) 15.6 Hz, 2H), 2.93 (t, J ) 5.6 Hz,
2H), 3.88 (s, 2H), 4.10 (t, J ) 5.6 Hz, 2H), 6.26 (s, 1H), 6.57 (s,
2H), 6.70 (t, J ) 8 Hz, 1H), 6.77-6.79 (m, 2H), 7.16-7.31 (m,
2H), 7.35 (d, J ) 7.4 Hz, 1H), 7.47 (s, 1H); 13C NMR (DMSO-d6)
δ 8.2, 22.7, 25.6, 32.6, 32.8, 33.1, 39.4, 46, 51.2, 66.5, 89.4, 113.8,
118, 120.1, 124.8, 126.1, 126.2, 127.7, 128.3, 128.4, 134.6 (2C),
136.1, 136.2, 141.7, 142.5, 147.4, 167 (2C). Anal. (C25H31NO2‚
C4H4O4) C, H, N.
Radioligand Binding. The membrane preparations and binding
assays were performed as described previously: 5-HT1A, D2,52 and
53
5-HT2A
.
The binding parameters are summarized in Table 4. At
the end of the incubation period, the tube contents were filtered
under vacuum through GF/B filters with two 5 mL washes of Tris-
HCl buffer (50 mM, pH 7.4 at 25 °C). The radioactivity retained
on the filters was measured by scintillation spectroscopy in 4 mL
of scintillation fluid (emulsifier safe, Packard). The results of
displacement experiments were analyzed using the nonlinear
regression program KELL RADLIG version 6 (Biosoft, Cambridge,
U.K.),54 and pKi values are given as means ( SEM of three
experiments, each comprising 6-7 concentrations differing by one
log unit interval. The -log of Ki values (pKi) were calculated from
the Cheng-Prusoff equation Ki ) IC50/(1 + [radioligand]/Kd). The
Kd values of the different ligands are reported in Table 4. [3H]8-
OH-DPAT (TRK.850: 160-240 Ci/mmol) was purchased from
Amersham; [3H]ketanserin (NET-791: 60-90 Ci/mmol) and [3H]-
YM-09151-2 (NET-1004: 70-87 Ci/mmol) from NEN; 5-HT
from Sigma; methysergide maleate and (+)-butaclamol hydrochlo-
ride from RBI.
[35S]GTPγS Binding in HeLa Cells. The membrane prepara-
tions and binding assays were performed as described previously.55
Cells were harvested in ice-cold 20 mM Hepes buffer containing
EDTA (10 mM, pH 7.4) at rt and were homogenized and
centrifuged at 40 000 g at 4 °C for 15 min. The pellet was suspended
in ice-cold 20 mM Hepes containing EDTA (0.1 mM) and
centrifuged at 40 000 g at 4 °C for 15 min. The final pellet was
suspended in 20 mM Hepes containing MgCl2 (10 mM), pargyline
(10 µM), GDP (30 µM), and NaCl (100 mM). The membranes
(100-50 µg/tube) were incubated in the presence of the test
(3-Cyclopent-1-enyl-benzyl)-[2-(3,3-dimethyl-2,3-dihydro-
benzofuran-7-yloxy)-ethyl]-amine (19). Reductive amination be-
tween IIIh (0.60 g, 2.89 mmol) and VIg (0.50 g, 2.89 mmol) and
then purification by flash column chromatography (silica gel,
methylene chloride/methanol/ammonia, 98:1.5:0.5) afforded 0.86
g (82%) of 19 as a colorless oil: 1H NMR (CDCl3) δ 1.33 (s, 6H),
1.98-2.05 (m, 2H), 2.50-2.54 (m, 2H), 2.69-2.73 (m, 2H), 3.05
(t, J ) 5.2 Hz, 2H), 3.83 (s, 2H), 4.18 (t, J ) 5.2 Hz, 2H), 4.26 (s,
2H), 6.07-6.09 (m, 1H), 6.71-6.77 (m, 2H), 7.02 (t, J ) 7.9 Hz,
1H), 7.19 (d, J ) 7.4 Hz, 1H), 7.24 (dd, J ) 7.6, 7.4 Hz, 1H), 7.33
(d, J ) 7.6 Hz, 1H), 7.42 (s, 1H). As a fumarate salt: white powder,
mp ) 139 °C; HPLC purity 97.9% (eluent, acetonitrile/water/KH2-
PO4, 450:550:6.8 g, pH 4); IR (KBr) ν 3441, 2959, 2893, 1705,
1
1618 cm-1; H NMR (DMSO-d6) δ 1.27 (s, 6H), 1.92-1.99 (m,
2H), 2.46-2.51 (m, 2H), 2.63-2.68 (m, 2H), 2.99 (t, J ) 5.6 Hz,
2H), 3.49 (s, 2H), 4.15 (t, J ) 5.6 Hz, 2H), 4.19 (s, 2H), 6.27-
6.28 (m, 1H), 6.56 (s, 2H), 6.74-6.84 (m, 3H), 7.27 (d, J ) 7.4
Hz, 1H), 7.31 (t, J ) 7.4 Hz, 1H), 7.38 (d, J ) 7.4 Hz, 1H), 7.52
(s, 1H). 13C NMR (DMSO-d6) δ 22.7, 27 (2C), 32.6, 32.8, 41.8,
46, 51.3, 66.3, 83.8, 113.4, 115.1, 121.1, 124.8, 126.2, 126.2, 127.6,
128.3, 134.6 (2C), 136.1, 136.2, 138, 141.7, 142.7, 146.9, 167.2
(2C). Anal. (C24H29NO2‚C4H4O4) C, H, N.

874 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 4
Cuisiat et al.
compounds for 1 h at 30 °C. After 15 min at 0 °C, [35S]GTPγS
(specific activity ≈ 1100 Ci/mmol) was added to a final concentra-
tion of 0.1 nM. The membranes were then incubated for an
additional 30 min at 30 °C. The reaction was terminated by filtration
through Whatman filters using a Brandel harvester, and radioactivity
was counted by liquid scintillation spectrometry. Compounds were
tested at six concentrations from 10-10 M to 10-5 M. Concentration
effect is expressed as -log(M) of the test compound versus % of
basal [35S]GTPγS binding. Values are expressed as % of the
stimulation obtained with 5-HT (10-5 M) according to the following
formula: % stimulation ) [(Emaxcompound - 100)/(Emax5-HT -
100)100]. Each concentration-response experiment was per-
formed in triplicate and replicated three times. Each concentration-
response experiment included 5-HT (10-5 M). The pEC50 values
were estimated using the mean values of three separate experiments
by means of nonlinear regression using the program GraphPad
Prism. [35S]GTPγS (1100 Ci/mmol) was obtained from Amersham
(Les Ulis, France); 5-HT was obtained from Sigma (St Louis,
U.S.A.).
Behavioral Effects Induced by 5-HT1A Agonists. The method
used was similar to those described previously.56 Behavioral
observations were made at 15 min after the injection, each lasting
for a total of 10 min. The animals were observed individually during
the 10 min period. During each of these observation periods, the
presence (1) or absence (0) of LLR was recorded. The LLR was
considered present if the animal showed uninterrupted signs for at
least 3 s. This cycle was repeated 10 times during a 10 min period;
the incidence of a particular behavior could vary from 0 to 10 for
any observation period. An injection volume of 10 mL/kg was used
throughout, and doses refer to the weight of the free base.
Compounds were tested in five animals per dose. Dose-response
functions were determined from the percentage of rats showing LLR
scores of 1 or more. These criteria were based upon the incidence
of each particular behavior observed in saline-treated animals. ED50
values and their 95% confidence limits were calculated by Litchfield
and Wilcoxon probit analysis.57 FBP was scored present (1) if it
occurred during the entire observation period, otherwise, the score
was 0. On each day, only two animals in each group received the
same dose of the same drug.
The measures used in this study were the mean duration values
for catalepsy in the cross-legged position and the percentage
incidence of catalepsy defined as one or more observations of
catalepsy lasting 30 s in an individual animal. Dose-response
functions were determined from the percentage of rats showing a
duration of catalepsy for at least 30 s. ED50 values and their 95%
confidence limits were calculated by Litchfield and Wilcoxon probit
analysis.57
Acknowledgment. The authors wish to thank Drs. M. B.
Assie´, A. Auclair, L. Bardin, C. Cosi, R. Depoortere, and J. C.
Martel who contributed to this project. We thank Dr. J.-P. Ribet
and Mr. P. Zalavari for analytical support. Mr. L. Petitpas’
assistance for bibliographic searches is also very much appreci-
ated.
Supporting Information Available: Experimental and analyti-
cal data for intermediates: If-h, IIc-h, corresponding Gabriel’s
adducts, IVe-g, and V; pKb and Emax values for compounds 1, 16,
20, and haloperidol. This material is available free of charge via
the Internet at http://pubs.acs.org.
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