Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition

Article abstract of DOI:10.1021/jm050148z

A series of novel bicyclic 1-heteroaryl-4-[ω-(1H-indol-3-yl)alkyl] piperazines was synthesized and evaluated on binding to dopamine D₂ receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D₂ receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H- indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D₂ receptor pharmacophore or the serotonin transporter pharmacophore.

Full text of DOI:10.1021/jm050148z

J. Med. Chem. 2005, 48, 6855-6869
6855
Synthesis, Structure-Activity Relationships, and Biological Properties of
1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines, Novel Potential
Antipsychotics Combining Potent Dopamine D2 Receptor Antagonism with
Potent Serotonin Reuptake Inhibition
Pieter Smid,* Hein K. A. C. Coolen, Hiskias G. Keizer, Rolf van Hes, Jan-Peter de Moes, Arnold P. den Hartog,
Bob Stork, Rob H. Plekkenpol, Leonarda C. Niemann, Cees N. J. Stroomer, Martin Th. M. Tulp,
Herman H. van Stuivenberg, Andrew C. McCreary, Mayke B. Hesselink, Arnoud H. J. Herremans, and
Chris G. Kruse
Solvay Pharmaceuticals Research Laboratories, C. J. van Houtenlaan 36, 1381 CP, Weesp, The Netherlands
Received February 15, 2005
A series of novel bicyclic 1-heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines was synthesized
and evaluated on binding to dopamine D2 receptors and serotonin reuptake sites. This class of
compounds proved to be potent in vitro dopamine D2 receptor antagonists and in addition were
highly active as serotonin reuptake inhibitors. Some key representatives showed potent
pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-
induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the
preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-
2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies
revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio.
Molecular modeling studies showed that the bifunctional activity of 45c can be explained by
its ability to adopt two different conformations fitting either the dopamine D2 receptor
pharmacophore or the serotonin transporter pharmacophore.
Introduction
EPS can become a treatment-limiting side effect.7 Cur-
rent theories have implicated the serotonergic system
in the pathophysiology of anxiety, depression, and
negative symptoms in schizophrenia. Evidence has
accumulated concerning the interaction between the
dopaminergic and the serotonergic system. It has been
demonstrated that the combined use of a neuroleptic
together with a SSRI (selective serotonin reuptake
inhibitor) such as fluvoxamine,8 fluoxetine,9 or citalo-
pram10 gives an improvement in the negative symptoms
of schizophrenia as well as a decrease in depression,
without exacerbating EPS.9 Further studies have dem-
onstrated that this improvement of the negative symp-
toms is not due to a nonspecific action of the antide-
pressant but in fact to the SSRI characteristic, as
maprotiline, an antidepressant drug acting via the
noradrenergic system, did not improve negative symp-
toms.11
However, one of the main drawbacks of the admin-
istration of a combination of compounds is the potential
for drug-drug interactions.12 Hence, a single compound
combining dopamine D2 receptor antagonism with se-
rotonin reuptake (SR) inhibition could improve on the
presently used drugs for schizophrenia, since it would
have the potential of treating positive, negative, and
depressive symptoms in schizophrenia, without the
disadvantages of potential pharmacokinetic interactions
when combining two or more drugs.
Schizophrenia is a psychiatric disorder, which is
characterized by a complex symptomatology. It ex-
presses itself as a combination of positive (delusions,
hallucinations, and conceptual disorganization) and
negative (affective flattening, social withdrawal, anhe-
donia, and poverty of thought and content of speech)
symptoms and cognitive impairment.1 The co-occurrence
of depressive symptoms is common in patients with
schizophrenia, with estimates of the prevalence in
clinical populations ranging from 25 to 60%.2 Depressive
symptoms are of great prognostic significance since they
are associated with compromised quality of life and
increased risk of psychotic relapse and suicide.3 With
the discovery of the dopaminergic system and demon-
stration that all antipsychotics have an action on this
system, it has been proposed that antipsychotic drugs
elicit their main clinical efficacy by blockade of dopam-
ine D2 receptors.4 The binding affinity of the antipsy-
chotic drugs at these receptors tends to be very strongly
correlated to their clinical effect on positive symptoms.
However, the occurrence of extrapyramidal side effects
(EPS) has also been linked to the potency of antipsy-
chotic drugs on the dopamine D2 receptor.5 Besides the
EPS, a major complication with most antipsychotic
drugs is that, although they are effective at reducing
the positive effects of psychosis, the negative symptoms,
comorbid depression, and cognitive deficits are not
treated effectively.3,6 Moreover, approximately 30% of
patients do not respond to typical antipsychotics and
In a recent publication,13 we have shown that it is
possible to combine dopamine D2 receptor antagonism
with SRI (serotonin reuptake inhibitor) effects in the
same dose range in one molecule, i.e., SLV310 (1; see
Figure 1). In this paper, we wish to demonstrate that
* To whom correspondence should be addressed. Tel: +31(0)294
477209. Fax: +31(0)294 477138. E-mail: pieter.smid@solvay.com.
10.1021/jm050148z CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/30/2005

6856 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
Figure 1.
Table 1. Synthesis of Benzdioxin Piperazine Derivatives
compound 45c, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]-
piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-
one, from a different structural class than compound 1,
has a favorable profile being the first example of a
compound having a low nanomolar activity for the D2
receptor and subnanomolar affinity for the SR site.
Compound 45c was built on the idea to combine a well-
known dopamine D2 pharmacophore such as the pip-
erazine class 2 with a SRI. This paper describes the
optimization program toward 45c starting with the
combination of eltoprazine14 (4, XdZdO, YdCH2, and
RdH in 2) and indalpine (3) to give compound class 5,
which was optimized with respect to (i) the length of
the alkyl chain between the indole and the aryl pipera-
zine moieties (i.e., 5a-e), (ii) the substitution pattern
of the indole moiety (i.e., 5f-p), and (iii) the bicyclic
heteroaryl part (i.e., compounds 15, 19, 20, 25, 31, 38a-
d, 39, and 45a-f).
(5a-p)
yield based
on 4 (%)
compd
n
R
salta
route
5a
5b
5c
5d
5e
5f
1
2
3
4
5
3
3
3
3
3
3
3
3
3
3
3
H
H
H
H
H
33
99
77
25
35
30
70
56
68
83
69
62
61
73
65
78
B
B
A
B
B
B
B
B
B
B
B
B
B
B
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
0.5 fum
4-F
5g
5h
5i
5-F
6-F
7-F
5j
5k
5l
5m
5n
5o
5p
5-OMe
4-Cl
5-Cl
6-Cl
7-Cl
5-Me
7-Me
a fum ) fumarate.
routes could be followed. Route A starts with the
coupling of a (1H-indol-3-yl)alkanoic acid15 derivative
(6) with 4 in the presence of DCC, furnishing the amide
derivatives 7, which in turn were reduced with LiAlH4
to give the corresponding compounds 5. In route B,
compounds 6 were reduced first to the alcohols 8, which
in turn were converted to the corresponding mesylate
derivatives 9. Alternatively, compounds 8c,f-p (n ) 3)
could be prepared by the Fischer-Indole synthesis of
an appropriately substituted phenylhydrazine with di-
hydropyran.16 Compounds 9 were used in the alkylation
of 4 to give 5 in a yield of 30-83% under relatively mild
conditions, making route B more broadly applicable
than route A. On the basis of the biological data of
compounds 5 (vide infra), for optimization of the bicyclic
heteroaryl moiety (see Table 2), derivative 9c with the
optimal spacer length (n ) 3) and the unsubstituted
indole was used.
Chemistry
As depicted in Scheme 1, combination of indalpine (3)
and 4 into one molecule was attempted by the synthesis
of compound 5 (see Table 1). Compound 5a (n ) 1) was
obtained via the Mannich reaction of 4 with indole in
the presence of formaldehyde in a moderate yield of
33%. Compound 5b (n ) 2) was prepared via the
alkylation of 4 with commercially available 3-(2-bromo-
ethyl)indole in an excellent yield of 99%. For the
synthesis of compounds 5c-p (n ) 3-5), two synthetic
Scheme 1a
The synthesis of 3-[3-(4-chroman-5-yl-piperazin-1-yl)-
propyl]-1H-indole 15 is depicted in Scheme 2. The
starting material, 3-(4-benzyl-piperazin-1-yl)phenol (10),17
was deprotonated with NaOMe in methanol and sub-
sequently alkylated with propargyl bromide to furnish
11 in a yield of 60%. Compound 11 was heated at 220
°C in diethylaniline yielding the ring closed derivative
13 together with its region isomer 12 in a yield of 91%
(ratio 13/12 of 3:1). The one-pot reduction of the double
bond and the removal of the benzyl in 13 with H2 and
Pd/C furnished 14 in a yield of 85%. Subsequent
alkylation of 14 with 9c yielded compound 15 in a
moderate yield of 50%.
a Reagents and conditions: (i) n ) 1: CH2O, indole, ethanol,
reflux, 18 h. (ii) n ) 2: 3-(2-bromoethyl)indole, CH3CN, KI, DIPEA,
reflux, 18 h. (iii) Compound 4, dry THF, DCC, RT, 18 h. (iv) LiAlH4,
reflux, 2 h. (v) Methanesulfonyl chloride, DIPEA, EtOAc, RT. (vi)
Compound 4, CH3CN, KI, DIPEA, reflux, 18 h.
The synthesis of compounds 19, 20, and 25 is outlined
in Scheme 3. At first, compound 1614 was converted to
19 with 9c according to route B in a yield of 50%. The

1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6857
Table 2. Lead Optimization of 5c by Exploration of the
Bicyclic Heteroaryl Moiety
of 1/2 and in a yield of 67%. Reduction of the nitro
moiety in 28b (to 29) and conversion of 29 into the
piperazine derivative 30 with BCEA was accomplished
in a yield of 35% based on 28b. Finally, compound 30
was alkylated with 9c to furnish compound 31 in a yield
of 77%.
The synthetic route21 of the last series of compounds
described in this paper, compounds 38, 39, and 45, is
depicted in Schemes 5 and 6. The known starting
material 2-amino-4-chlorophenol 32 was converted to
34a-c with the chloroacetyl chloride derivatives 33a,b
and the bromoacetyl bromide derivative 33c (37-79%
yield). Subsequent nitration of 34a-c, followed by K2-
CO3-mediated ring closure, furnished compounds 35a-c
in an overall yield of 40-70% based on 34. Methylation
of the amide moiety in 35b (to 35d) was accomplished
with methyl iodide and KOH in a yield of 90%. Reduc-
tion of the nitro group and the 4-chloro function in
35a-d (to 36a-d) and subsequent reaction of the thus
obtained aniline with BCEA‚HCl yielded the bicyclic
heteroarylpiperazine derivatives 37a-d in an average
yield of 40% over two steps. Compounds 37a-d were
converted to the C3-indolyl derivatives 38a-d via route
B in a yield of 40-70%. The amide moiety in 38a could
be reduced with LiAlH4 furnishing compound 39 in a
yield of 80%.
On the basis of the biological properties of 38b, it was
decided to prepare from this compound both enanti-
omers (i.e., 45a and 45b) together with two pairs of
indole-substituted analogues (45c-f). The synthesis of
the enantiomers of 38b is outlined in Scheme 6. Com-
mercially available 2-amino-4-chloro-6-nitro-phenol 40
was converted with chirally pure lactate derivatives
41a,b (to 42a,b) under Mitsunobu conditions with
inversion of configuration accompanied by a simulta-
neous ring closure. Reduction of the 6-nitro and 4-chloro
group in 42a,b (to 43a,b) and subsequent transforma-
tion of the thus obtained aniline with BCEA‚HCl yielded
piperazine derivatives 44a,b in a yield of 25-60% over
two steps. The thus obtained piperazine derivatives
were converted with the appropriate mesylate 9 (i.e.,
9c, 9g, and 9i) to give the end products 45a-f in a yield
of 50-80%. The enantiomeric purity of compound 45c
was determined via an HPLC method using a Chiracel
OD-R column in a comparison experiment using the (S)-
enantiomer 45d. The experiments showed that the
compounds had an enantiomeric purity of >95%.
compd
X
Y
Z
R1
R2
R3
synthesis
15
O
CH2
CH2
CH2
CH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Scheme 2
Scheme 3
Scheme 3
Scheme 3
Scheme 4
Scheme 5
Scheme 5
Scheme 5
Scheme 5
Scheme 5
19
NH CH2
NMe CH2
NH CH2
20
25
CH2 Me
31
NH C(dO) CH2
NH C(dO) O
NH C(dO) O
NH C(dO) O
NMe C(dO) O
H
H
38a
38b
38c
38d
39
Me (rac)a
Me
Me H
Me (rac)
H
H
H
H
H
H
H
NH CH2
O
45a,c,e NH C(dO) O
45b,d,f NH C(dO) O
a rac ) racemic.
(R)-Me
(S)-Me
H, 5-F, 7-F Scheme 6
H, 5-F, 7-F Scheme 6
synthesis of 20 started with the acylation of 16 with 6c
in the presence of 2-chloro-1,3-dimethyl-2-imidazolinium
tetrafluoroborate (CIP) giving 17 in a yield of 67%.
Compound 17 was formylated18 with formic acid in
acetic anhydride to give 18, and subsequent reduction
of both amides in 18 with LiAlH4 gave compound 20 in
a yield of 70% based on 17.
The racemic 3-methyl derivative of compound 19 was
prepared starting from quinoline derivative 21. Reduc-
tion of 21 to 22 was accomplished with H2 and Pt/C
under a pressure of 4 atmosphere. Crude 22 was
converted to the corresponding piperazine derivative 23
with the p-tosyl-protected bis-chloroethylene amine
(BCEA) in a yield of 50% based on 21. Subsequent
deprotection of 23 under strong acidic conditions gave
24, which was converted to 25 following route B in a
yield of 79% based on 23.
The synthetic route toward compound 31 is shown in
Scheme 4. Conversion of known 26 to key intermediate
28b could be accomplished following two routes. Ac-
cording to the literature,19 a Beckman rearrangement
of 27b (obtained in two steps from 26) furnished a
mixture of 28a and 28b in an unfavorable ratio of 3:1
but in a good combined yield of 84%. Alternatively, we
found that a Schmidt rearrangement20 of compound 26
with sodium azide and sulfuric acid in benzene gave a
mixture of 28a and the desired derivative 28b in a ratio
Results and Discussion
The affinity for dopamine D2 receptors in a membrane
preparation of CHO cells transfected with the human
Scheme 2a
a Reagents and conditions: (i) NaOMe, MeOH, followed by propargyl bromide in DMF, RT. (ii) Heat at 220 °C, diethylaniline, 1 h. (iii)
H2, Pd/C, 2 mol equiv of HCl in EtOH, 2 h, RT. (iv) Compound 9c, CH3CN, KI, DIPEA, reflux, 16 h, THF, RT.

6858 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
Scheme 3a
a Reagents and conditions: (i) CIP, DIPEA, DCM, RT, 16 h. (ii) HCOOH, (Ac)2O, 55 °C, 1 h. (iii) Compound 9c, CH3CN, KI, DIPEA,
reflux, 16 h. (iv) LiAlH4, Et2O, RT, 16 h. (v) H2, Pt/C, EtOH, 6 h, 4 atm, 40 °C. (vi) (Cl-CH2CH2)2N-Tos, chlorobenzene, PTS, 140 °C, 144
h. (vii) 6 N HCl, reflux, 18 h.
Scheme 4a
a Reagents and conditions: (i) Concentrated H2SO4, NaN3, benzene, 70 °C, 10 min. (ii) NH2OH‚HCl, 4 N NaOH, MeOH, -10 °C to RT.
(iii) TosCl, 4 N NaOH, acetone, -10 °C to RT. (iv) AlCl3, DCM, -10 °C to RT. (v) Pd/C, H2, EtOH, 3 h. (vi) BCEA‚HCl, chlorobenzene,
reflux, 66 h. (vii) Compound 9c, CH3CN, KI, DIPEA, reflux, 16 h.
D2L receptor was measured by binding studies using
[3H]spiperone as the ligand.22 The affinity for SR sites
in rat frontal cortex membranes was measured using
[3H]paroxetine.23 The results on these receptors ob-
tained with the compounds described in this paper are
given in Tables 3 and 4. The affinities are expressed as
Ki (nM) and are calculated from at least three indepen-
dent experiments.
The dopaminergic antagonist and serotonin reuptake
inhibitory activity were examined in vivo after oral (po)
administration of the compounds by respectively an-
tagonizing apomorphine induced climbing behavior24 in
mice (APO) and the potentiation of 5-hydroxytryptophan
(5-HTP; the precursor of serotonin) induced serotinin
syndrome25 in mice.
affinity of 21 nM and a SR site affinity of 0.4 nM. In
addition, the APO and 5-HTP results of 5c were rather
encouraging with ED50 values of, respectively, 10 and
22 mg/kg (po). It is also clear from Table 3 that variation
in the spacer length did not lead to better results if
compared to compound 5c. Shortening the spacer length
to n ) 1 or 2 (i.e., 5a and 5b) reduced the SR site affinity
significantly and did not result in a higher D2 receptor
affinity. Enlarging the spacer length to n ) 4 (i.e., 5d)
resulted in a better affinity for the D2 receptor but also
caused a 100-fold decrease of the SR site affinity. A
spacer length of n ) 5 (5e) did not improve this, leading
to the conclusion that a preferred combination of activity
on both of the receptors was obtained with a spacer
length of n ) 3. The next round of optimization was
directed to the substitution pattern of the indole moiety
in combination with the optimal spacer length of n ) 3.
Compounds 5f-i having a fluorine atom at the indole
Table 3 shows that the combination of eltoprozine (4)
with an indole moiety at a C3 distance (i.e., compound
5c) was promising, indeed, showing a D2 receptor

1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6859
Scheme 5a
a Reagents and conditions: (i) Pyridine/DCM, RT. (ii) HNO3‚H2O, 0 °C, 1 h. (iii) K2CO3, toluene, azeotropic distribution. (iv) MeI,
KOH, DMF, 22 h, reflux. (v) H2, Pd/C, 2 h, RT. (vi) BCEA‚HCl, chlorobenzene, reflux, 72 h. (vii) Compound 9c, CH3CN, KI, DIPEA, reflux
overnight. (viii) LiAlH4, THF, reflux, 3 h.
Scheme 6a
a Reagents and conditions: (i) (Ph)3P, DIAD, dry THF, RT, 20 h. (ii) H2, Pd/C, 2 h, RT. (iii) BCEA‚HCl, chlorobenzene, reflux, 72 h. (iv)
Compounds 9c/9g/9i, CH3CN, KI, DIPEA, reflux, 16 h.

6860 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
Table 3. In Vitro and in Vivo Test Results on Dopamine D2
Receptors (Receptor Binding and APO, Respectively) and SR
Sites (Receptor Binding and 5-HTP, Respectively) for
Compounds 3-5
Unfortunately, this was accompanied with a significant
decrease on both the in vitro and the in vivo activity at
the SR site. Finally, we prepared the 5- and 7-Me
derivatives (i.e., 5o and 5p), which both did not improve
the affinity for the D2 receptor and the SR site if
compared to 5c. In conclusion, optimal results on the
D2 receptor and SR receptor affinity are obtained when
the indole moiety is positioned at a C3 distance from
the phenyl piperazine. In compound 5c also, in vivo
activity was observed in both the APO and the 5-HTP
models. The 5-F derivative of 5c (i.e., 5g) showed an
increase in 5-HTP potency without a significant loss in
APO activity, while the 7-F derivative of 5c (i.e., 5i) was
beneficial for the APO activity. In the next stage, we
turned our attention in the direction of modifying the
benzdioxan moiety of 5c with the intention to increase
the D2 receptor affinity without decreasing the affinity
for the SR site. The novel bicyclic heteroarylpiperazine
structures were at first alkylated with the unsubstituted
indole propyl derivative 9c. The chroman- and tetrahy-
droquinoline derivatives (i.e., 15 and 19, 20 and 25)
resulted in a decrease of the affinity for the SR site
without the desired increase in D2 receptor affinity (see
Table 4). The quinolinone derivative 31 showed better
results, especially in vivo, in which the APO behavior
was improved by a factor 4. Going from the quinolinone
31 to the benzo[1,4]oxazin-3-one series 38 appeared to
be the key step in the lead optimization process.
Compound 38a showed that the D2 receptor affinity
increased by almost a factor 5, and in addition, the APO
results were more than promising with 0.9 mg/kg. On
the other hand, the 5-HTP result of 38a was rather
disappointing with 30 mg/kg. This was improved sig-
nificantly by the introduction of a methyl at the 2-posi-
tion of the oxazinone moiety (i.e., compound 38b). The
receptor binding results of 38b were unchanged if
compared to 38a, but the in vivo results changed from
0.9 to 0.13 in the APO test and from 30 to 3 mg/kg in
the 5-HTP test, an increase by a factor of 7-10-fold.
Further methylation of 38b to the 2,2-dimethyl deriva-
tive 38c decreased both the APO and the 5-HTP
component, whereas the N(Me) derivative 38d resulted
in a significant decrease of the D2 component when
compared to 38b. In addition, it is clear from Table 4
that reduction of the 3-keto functionality in the ben-
zoxazinone moiety of 38a giving compound 39 leads to
a dramatic loss of in vivo activity in both the APO and
the 5-HTP tests. The two enantiomers of the preferred
compound 38b were separately prepared (i.e., 45a and
45b), and the receptor binding assays on these deriva-
tives did not reveal a clear preference for one isomer.
The same observation could be made by comparing the
R- and S-enantiomers of its 5-F and 7-F indole deriva-
tives (compounds 45c, 45d, 45e, and 45f respectively).
On the other hand, the in vivo results of these chirally
pure compounds show interesting differences in activity.
For instance, from the in vivo results, it is clear that
the R-(-)-derivatives 45a,c,e are the better compounds
by at least a factor 3 when compared to the S-(+)-
derivatives 45b,d,f. In addition, it is clear that the
introduction of the 5-F in 45a (to 45c) even slightly
improved the already very good APO activity (0.13 to
0.08 mg/kg), and on top of this, it also had a tremendous
positive effect on the 5-HTP test, which improved by a
factor 20 (3 to 0.15 mg/kg po), a similar effect as was
in vitroa
in vivo
APOc 5-HTPd
hD2
(Ki nM)
rSRI
(Ki nM)
(ED50 mg/ (ED50 mg/
compd
n
R
kg po)
kg po)
haloperidol
indalpine (3)
2.0 ( 0.1 NAb
0.1
NA
2.0 ( 0.1
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
1 H
2 H
3 H
4 H
5 H
3 4-F
3 5-F
3 6-F
3 7-F
62.0 ( 17 176.0 ( 59
45.0 ( 17 12.0 ( 3.8
21.0 ( 9.9
0.4 ( 0.1
10
22
5.1 ( 1.2 60.0 ( 12
9.1 ( 1.8 37.0 ( 3
3.8
>30
8.1 ( 3.1
19.0 ( 3
14.6 ( 3.5
10.6 ( 4
0.4 ( 0.1
0.3 ( 0.1
1.6 ( 0.2
0.6 ( 0.1
14.0 ( 4
1.4 ( 0.4
0.5 ( 0.7
2.0 ( 0.7
7.9 ( 2.8
0.4 ( 0.9
13
15
9
32
2.0
30
4.1
28.4
3 5-OMe 15.0 ( 4
3 4-Cl
3 5-Cl
3 6-Cl
3 7-Cl
24.0 ( 3
31.6 ( 16
2.1 ( 1
4.5
86
15.5 ( 5.4
3 5-Me 10.7 ( 2.8
3 7-Me 15.9 ( 4.7 12.0 ( 5
a Calculated from three independent experiments. b NA ) not
active (>1 µM). c Antagonizing apomorphine induced climbing
behavior in mice (po). d 5-HTP induced serotonin syndrome like
behavior in mice (po).
Table 4. In Vitro and in Vivo Test Results on D2 Receptors
(Receptor Binding and APO, Respectively) and SR Sites
(Receptor Binding and 5-HTP, Respectively) for Compounds
15-45f
in vitroa
in vivo
APOb
(ED50 mg/
kg po)
5-HTPc
(ED50 mg/
kg po)
hD2
(Ki nM)
rSRI
(Ki nM)
compd
5c
21.0 ( 9.9
20.3 ( 2.7
11.3 ( 2.4
90.0 ( 45
15.0 ( 6
11.4 ( 3
4.3 ( 1.2
4.5 ( 1.1
7.4 ( 0.5
35.7 ( 7.3
17.9 ( 3.8
8.7 ( 3.9
1.0 ( 0.3
6.9 ( 1.8
4.7 ( 1.4
5.3 ( 1
0.4 ( 0.1
1.1 ( 0.3
1.1 ( 0.2
7.4 ( 3.1
2.7 ( 0.6
1.5 ( 0.9
0.6 ( 0.2
0.4 ( 0.1
2.8 ( 0.6
1.4 ( 0.4
1.5 ( 0.4
0.5 ( 0.3
1.0 ( 0.3
0.2 ( 0.1
0.7 ( 0.2
2.4 ( 1.3
3.0 ( 1
10
15
6.9
22
100
15
15
19
20
25
2.6
2.6
0.9
0.13
0.53
1.2
>100
9.0
30
31
38a
38b
38c
38d
39
3.0
7.3
5.6
100
3.0
>10
0.15
0.7
30
>20
0.13
0.3
45a
45b
45c
45d
45e
45f
0.08
0.6
0.04
0.6
1.0 ( 0.3
10
a Calculated from three independent experiments. b Antagoniz-
ing apomorphine induced climbing behavior in mice (po). c 5-HTP
induced serotonin syndrome like behavior in mice (po).
ring showed a comparable in vitro activity at the SR
site as 5c, but in addition, the D2 affinity appeared to
be slightly increased by this modification. In this
respect, it is of interest to note that the in vivo activity
of these compounds, when compared to 5c, for the APO
was improved by a factor of 2.5 with the 7-F derivative
(i.e., 5i) and for the 5-HTP was improved by a factor 11
with the 5-F derivative (i.e., 5g). The 5-OMe derivative
5j did not show any improvement in activity over 5c.
The series with a chlorine substituent at the indole ring
(i.e., compounds 5k-n) showed a significant improve-
ment in D2 affinity for the 6-Cl derivative (i.e., 5m). The
D2 affinity was increased by a factor 10 (to 2 nM), and
the compound also improved in the APO by a factor 2.

1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6861
Figure 2. (a) Representative D2 antagonists used for the
building of the D2 pharmacophore. (b) The D2 antagonism
pharmacophore.
observed for changing 5c to 5g. In this respect, it is of
interest to note that the introduction of a 7-F substitu-
ent at the indole moiety of 45a (to 45e) improves the
APO activity even by a factor 3 when compared to 45a
but also has a dramatic negative effect on the 5-HTP
test in which the activity was diminished by a factor
10. In conclusion, several optimization steps led to 45c
as the most promising candidate for further develop-
ment.
Molecular Modeling
A pharmacophoric model for D2 antagonism was
constructed from the well-known antagonists given in
Figure 2a. It can be summarized (see Figure 2b) as a
lipophilic aromatic area (orange) located about 6 Å from
a basic nitrogen atom (blue). Further away (7.5 Å) from
this center, there is a flat aromatic region with a
lipophilic extension (green) within the vicinity of an
H-bond accepting oxygen atom (red). This model is in
line with other models described in the literature.26
We also reproduced the SRI pharmacophore reported
recently27 based on well-established SRIs (Figure 3a).
It is characterized (see Figure 3b) by a basic nitrogen
atom (blue), a lipophilic extended aromatic region
(green) at 6.1 Å, and a lipophilic part (purple-blue).
Additionally, it was found28 that the space around the
basic nitrogen atom is sterically restricted (violet). The
presence of the same features in both pharmacophores
may account for the possibility and existence of bifunc-
tional molecules, although none of the features appeared
to overlap properly in three-dimensional space. Appar-
ently, 45c can adopt different conformations to fit in
Figure 3. (a) Representative SRIs used for the building of
the SRI pharmacophore. (b) The SRI pharmacophore.
both models. The flexibility of 45c can be assigned to
the aliphatic chain and the piperazine moiety. The
conformational behavior of the latter functionality was
further examined by semiempirical calculations on the
protonated model compound A (see Figure 4). Phe-
nylpiperazines tend to a planar orientation of the phenyl
ring with respect to the piperazine ring, in which its
π-system can conjugate with the nitrogen lone pair.29
This can be influenced by steric and electronic effects
of substituents on the aromatic ring. It was found that
the protonated piperazine ring can adopt a chair or
twisted boat conformation. In the chair conformation,

6862 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
Figure 4. Low-energy conformations and their heats of formation (h.o.f.) of the chair (upper) and twisted boat conformation
(lower) of model compound A.
macophore the molecule has taken the twisted boat
conformation. Very recently, Morphy et al.31 described
their concept of “multiple” ligands that act on different
targets. They differentiate between “conjugates”, in
which two pharmacophores are connected by a (cleav-
able) linker and (partially) overlapping pharmacophores
referring to ligands of which different features in one
molecule, overlapping to a varying extent, are respon-
sible for activity on different targets. In fact, 45c can
be considered to be from another type. The molecule as
a whole meets two different pharmacophores by its
ability to adopt two different conformations.
Further in Vivo and in Vitro Profiling of 45c. The
kinetics of 45c was studied in both in vitro and in vivo
experiments. Compound 45c has a log P of 3, which is
considered to be optimal for orally dosed drugs targeting
the CNS. The aqueous solubility of 45c (at both pH 4
and pH 7.4) exceeded 100 µg/mL, which was the highest
concentration tested. Membrane passage was tested
using LLC PK1 MDR cells in a two compartment cell
Figure 5. Compound 45c fit into the D2 antagonism phar-
culture system described.32 After 3 h of incubation with
macophore (top) and into the SRI pharmacophore (bottom).
1 µg/mL of 45c, more than 28% of the compound was
transported over this cellular membrane. This brings
the alkyl substituent can have an axial or equatorial
orientation with respect to the piperazine ring. Because
of the symmetry of the twisted boat conformation, there
is matter of only one orientation of the alkyl chain. The
three concerning low-energy conformations of compound
A and their heats of formation are given in Figure 4.
45c in the category of well membrane permeable drugs.
In addition, it was determined that 45c is a poor
substrate for P-glycoprotein.32 In vivo pharmacokinetic
studies in rats show that 45c has an oral bioavailability
of about 20%. The exposure to 45c both in plasma and
in brains appears to be proportional with a dose between
The substitution around the anilinic nitrogen atom is
3 and 30 mg/kg. No drug accumulation occurs after
almost planar due to the above-mentioned conjugation
and the subsequent sp2 character of the nitrogen atom.
Nevertheless, in the chair conformations, a “pseudo”-
axial conformation of the aromatic moiety is preferred,
while in the twisted boat conformation this ring takes
the “pseudo”-equatorial orientation. As expected, the
equatorial orientation of the alkyl chain in the chair
conformation is preferred above the axial orientation.
All conformations are within an energy range so that
they are accessible at room temperature, although the
chair conformations have a lower energy than the
twisted boat conformation. In line with these findings,
two different low-energy conformations of 45c were
found to fit in the D2 and SRI pharmacophore, having
h.o.f.s of 13.7 and 17.1 kcal/mol, respectively.30 In Figure
5, these conformations are shown in their pharmacoph-
ores. In the D2 pharmacophore, 45c has adopted the
chair equatorial conformation, while for the SRI phar-
repeated dosing. From iv studies in rats, it was calcu-
lated that 45c is a high clearance drug, with a clearance
of 120 mL/min/kg body weight. Because of its high
volume of distribution of about 7 L/kg, its plasma half-
life of about 3 h after oral dosing is in the range of 1-8
h, which is usually observed for preclinical drug candi-
dates for the central nervous system. Compound 45c
easily penetrates the brain since high brain/plasma
values of 3-6 are found in pharmacokinetic studies in
rats. Because this ratio is similar in value to that of the
volume of distribution of 45c in iv studies in rats, this
indicates that the compound has free access to the brain.
These favorable in vitro and in vivo pharmacokinetic
data showed their value in in vivo profiling tests. For
example, the antipsychotic potency of 45c was demon-
strated by the fact that 45c significantly disrupted
avoidance behavior in a conditioned avoidance response

1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6863
paradigm (CAR)33 in three independent groups of trained
rats (ED50 ) 2.5 mg/kg po, based on the free base of
45c). Thus, it can be concluded that 45c is a promising
novel antipsychotic indeed, combining strong dopamine
D2 receptor antagonism34 with SRI effects in the same
dose range.
3-{2-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]ethyl}-1H-indole (5b). To a solution of compound 4 (1.1
g, 4.5 mmol) in dry acetonitrile (40 mL) was added DIPEA
(2.3 mL, 13.5 mmol), commercially available 3-(2-bromo-ethyl)-
1H-indole (1.0 g, 4.5 mmol), and potassium iodide (0.74 g, 4.5
mmol). The mixture was refluxed overnight, after which time
TLC analysis revealed complete conversion of the starting
material 4 (DMA 0.25 ) DCM/MeOH/NH4OH, 96/3.73/0.25,
v/v/v). The mixture was concentrated in vacuo, and the crude
product was purified by silica gel column chromatography
Conclusion
A series of novel bicyclic heteroaryl-4-[3-(1H-indol-3-
yl)propyl]piperazines proved to be potent in vitro dopam-
ine D2 receptor and SR site ligands. Some key represent-
atives showed potent pharmacological in vivo activities
after oral dosing in both the antagonism of apomor-
phine-induced climbing and the potentiation of 5-HTP-
induced behavior in mice. In particular, 8-{4-[3-(5-fluoro-
1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]-
oxazin-(R)-2-methyl-3-one (45c) was very potent both
in vitro and in vivo. Molecular modeling studies showed
that the bifunctional activity of 45c can be explained
by its ability to adopt two different conformations fitting
either the dopamine D2 receptor pharmacophore or the
SR pharmacophore. In vitro and in vivo studies revealed
that 45c has favorable pharmacokinetic properties. The
antipsychotic potency of 45c was demonstrated in the
CAR paradigm. Thus, it can be concluded that 45c is a
promising novel antipsychotic indeed, combining strong
dopamine D2 receptor antagonism with SRI effects in
the same dose range, and 45c was selected for clinical
development under the acronym SLV314.
1
(DMA 0.25) to give pure 5b (1.6 g, 99%) as a white solid. H
NMR (400 MHz, DMSO-d6): δ 10.7 (s, 1H, NH-indole); 7.5 (d,
1H, J ) 8 Hz, H-arom); 7.32 (d, 1H, J ) 8 Hz, H-arom); 7.12
(d, 1H, J ) 2 Hz, H2-indole); 7.05 (t, 1H, J ) 7 Hz, H-arom);
6.95 (t, 1H, J ) 7 Hz, H-arom); 6.70 (t, 1H, J ) 7 Hz, H-arom);
6.44-6.5 (dd, 2H, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.03 (bs,
4H, piperazine); 2.9 (bt, 2H, CH2); 2.65 (m, 6H, CH2 and 4H
piperazine). Anal. (C22H25N3O2) C, H, N.
General Procedure for the Synthesis of Compounds
5c-p. Route A. To a solution of compound 4 in dry THF (5
mL/mmol) was added 3-(ω-alkyl-carboxylic acid)-1H-indole 6,15
dicyclohexylcarbodiimide (DCC, 1 equiv), and the mixture was
stirred overnight under a blanket of nitrogen. The reaction
mixture was filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography to give
compound 7. Compound 7 was dissolved in dry THF (5 mL/
mmol) and cooled to 0 °C, and to this mixture a solution of
LiAlH4 (1.5 equiv) in dry THF (10 mL/mmol) was added. The
reaction mixture was refluxed for 2 h and allowed to cool to
room temperature. To the cooled mixture was added 1 N NaOH
solution (5 mL/mmol), and the mixture was stirred for 1 h.
The mixture was extracted with DCM (2×), and the combined
organic layers were washed with water and dried on MgSO4.
The crude residue was purified by silica gel column chroma-
tography to give compound 5. The compounds were converted
to the fumaric acid salts by addition of 0.5 equiv of fumaric
acid, unless stated otherwise.
Route B. To a solution of compound 4 in dry acetonitrile
(10 mL/mmol) was added methanesulfonic acid (1H-indole-3-
yl)alkanoic ester (9)16 (1 equiv), potassium iodide (1 equiv), and
DIPEA (3 equiv). The reaction mixture was refluxed for 18 h,
after which time TLC analysis revealed complete conversion
of 4. The mixture was concentrated in vacuo, and the crude
residue was purified by silica gel column chromatography to
give compound 5. The compounds were converted to the
fumaric acid salts by addition of 0.5 equiv of fumaric acid,
unless stated otherwise.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-1H-indole (5c). Compound 5c was prepared via
route B and isolated as a white solid as the free base in a yield
of 77%. TLC analysis and silica gel column chromatography:
DMA 0.25, Rf 0.4; mp 150-152 °C. 1H NMR (400 MHz, DMSO-
d6): δ 10.7 (s, 1H, NH-indole); 7.5 (d, 1H, J ) 8 Hz, H-arom);
7.32 (d, 1H, J ) 8 Hz, H-arom); 7.06 (d, 1H, J ) 2 Hz, H2-
indole); 7.04 (t, 1H, J ) 7 Hz, H-arom); 6.95 (t, 1H, J ) 7 Hz,
H-arom); 6.7 (t, 1H, J ) 8 Hz, H-arom); 6.4-6.5 (2 × dd, 2H,
J ) 2 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.0
(bs, 4H, piperazine); 2.72 (t, 2H, CH2); 2.55 (bs, 4H, piperazine);
2.4 (t, 2H, CH2); 1.85 (q, 2H, CH2). 13C NMR (DMSO-d6): 144.1,
141.9, 136.6, 136.4, 127.5, 114.8 (6 × C-quart), 122.7, 121.0,
120.5, 118.6, 118.3, 111.6, 111.3, 110.4 (8 × CH-arom), 64.1,
64.0 (2 × C-O), 50.5, 53.4 (C-piperazin), 58.0, 27.5, 22.8 (3 ×
CH2-propyl). Anal. (C23H27N3O2) C, H, N.
3-{4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]butyl}-1H-indole (5d) Fumaric Acid Salt. Compound 5d
was prepared via route B in a yield of 25%. TLC analysis and
silica gel column chromatography: eluent DMA 0.25, Rf 0.5.
1H NMR (400 MHz, DMSO-d6): δ 10.6 (s, 1H, NH-indole); 7.5
(d, 1H, J ) 8 Hz, H-arom); 7.3 (d, 1H, J ) 8 Hz, H-arom); 7.07
(d, 1H, J ) 2 Hz, H2-indole); 7.06 (t, 1H, J ) 7 Hz, H-arom);
6.95 (t, 1H, J ) 7 Hz, H-arom); 6.7 (t, 1H, J ) 7 Hz, H-arom);
6.6 (0.5 mol equiv of fumaric acid); 6.4-6.5 (2 × dd, 2H, J )
2 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.0, 2.6 (2
Experimental Section
1H and 13C NMR spectra were recorded on a Bruker Avance
DRX600 instrument (600 MHz), a Varian UN400 instrument
(400 MHz), or a Varian VXR200 instrument (200 MHz) using
DMSO-d6 or CDCl3 with (CH3)4Si as an internal standard, as
solvents. Chemical shifts are given in ppm (δ scale). Thin-layer
chromatography was performed on Merck precoated 60 F254
plates, and spots were visualized with UV light. Column
chromatography was performed using silica gel 60 (0.040-
0.063 mm, Merck). Melting points were recorded on a Bu¨chi
B-545 melting point apparatus and are uncorrected. Mass
spectra were recorded on a Micromass QTOF-2 instrument
with MassLynx application software for acquisition and re-
construction of the data. Exact mass measurement was done
of the quasimolecular ion (MH+). Optical rotations ([R]d) were
measured on an Optical Activity polarimeter. Specific rotations
are given as deg/dm, and the concentration values are reported
as g/100 mL of the specified solvent and were recorded at 23
°C. Elemental analyses were performed on a Vario EL elemen-
tal analyzer by Solvay Pharmaceuticals (Hanover, Germany).
Yields refer to isolated pure products and were not maximized.
All test compounds have a chemical purity of at least 95%
unless stated otherwise.
3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-yl-
methyl]-1H-indole (5a). A solution of compound 4 (2.2 g, 8.5
mmol),14 indole (1 g, 8.5 mmol), and formaldehyde (37%, 0.7
mL) in ethanol (30 mL) was refluxed for 18 h. The mixture
was allowed to cool to room temperature and was concentrated
in vacuo to give crude 5a as a brown oil, which was purified
by silica gel column chromatography (EtOAc/methanol, 95/5,
v/v). Compound 5a was obtained as a white solid (850 mg,
1
33%); mp 85-86 °C. H NMR (400 MHz, DMSO-d6): δ 10.8
(s, 1H, NH-indole); 7.65 (d, 1H, J ) 8 Hz, H-arom); 7.35 (d,
1H, J ) 8 Hz, H-arom); 7.18 (d, 1H, J ) 2 Hz, H2-indole);
7.07 (t, 1H, J ) 7 Hz, H-arom); 6.98 (t, 1H, J ) 7 Hz, H-arom);
6.67 (t, 1H, J ) 7 Hz, H-arom); 6.4-6.48 (2 × d, 2H, H-arom);
4.2 (bm, 4H, OCH2CH2O); 3.7 (bs, 2H, CH2); 3.0, 2.55 (2 × bs,
8H, piperazine). HRMS (C21H24N3O2) [M + H]+: found m/z,
350.1899; calcd, 350.1869. Anal. (C21H23N3O2) C, H, N.

6864 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
× bs, 8H, piperazine); 2.72 (t, 2H, CH2); 2.45 (t, 2H, CH2); 1.7
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-5-methoxy-1H-indole (5j) Fumaric Acid Salt.
Compound 5j was prepared via route B in a yield of 83%. TLC
analysis and silica gel chromatography: eluent diethyl ether,
Rf 0.15. 1H NMR (400 MHz, DMSO-d6): δ 10.5 (s, 1H, NH-
indole); 7.22 (d,1H, J ) 9 Hz, H-arom); 7.04 (d, 1H, J ) 2 Hz,
H2-indole); 6.96 (d, 1H, J ) 2 Hz, H-arom); 6.7 (m, 2H,
H-arom); 6.6 (s, 2H, fumaric acid); 6.4-6.5 (2 × dd, 2H, J )
1.5 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.78 (s,
3H, OMe); 3.04, 2.63 (2 × bs, 8H, piperazine); 2.7 (t, 2H, J )
7 Hz, CH2); 2.5 (t, 2H, CH2); 1.87 (q, 2H, CH2). HRMS
(C24H30N3O3) [M + H]+: found m/z, 408.2292; calcd, 408.2292.
Anal. (C24H29N3O3) C, H, N.
(q, 2H, CH2); 1.56 (q, 2H, CH2). Anal. (C24H29N3O2) C, H, N.
3-{5-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]pentyl}-1H-indole (5e) 2.5 Fumaric Acid Salt. Com-
pound 5e was prepared via route A. Compound 4 was
converted to 7e with known15 1H-indole-3-pentanoic acid (6e)
in a yield of 80%. TLC analysis: eluent DCM/MeOH, 95/5, v/v,
Rf 0.6; mp 70-72 °C. 1H NMR (400 MHz, CDCl3): δ 8.2 (s,
1H, NH-indole); 7.6 (d, 1H, H-arom); 7.36 (d, 1H, H-arom); 7.16
(t, 1H, H-arom); 7.1 (t, 1H, H-arom); 6.96 (s, 1H, H2-indole);
6.78 (dt, 1H, H-arom); 6.62 (d, 1H, H-arom); 6.46 (d, 1H,
H-arom); 4.22-4.34 (dm, 4H, OCH2CH2O); 3.8, 3.6, 3.0 (m, 8H,
piperazine); 2.8 (t, 2H, CH2); 2.4 (t, 2H, CH2); 1.8 (m, 4H, CH2).
Compound 7e was converted to 5e in a yield of 45%. TLC
analysis and silica gel column chromatography: eluent DMA
0.5, Rf 0.5. Compound 5e gave a white solid with 3 equiv of
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-4-chloro-1H-indole (5k) 0.5 Fumaric Acid.
Compound 5k was prepared via route B as a 0.5 fumaric acid
salt in a yield of 69%. TLC analysis and silica gel column
1
fumaric acid. H NMR (400 MHz, DMSO-d6): δ 10.6 (s, 1H,
1
chromatography: eluent EtOAc, Rf 0.2. H NMR (400 MHz,
NH-indole); 7.48 (d, 1H, J ) 8 Hz, H-arom); 7.32 (d, 1H, J )
8 Hz, H-arom); 7.04 (m, 2H, H2-indole, H-arom); 6.95 (t, 1H,
J ) 7 Hz, H-arom); 6.7 (t, 1H, J ) 7 Hz, H-arom); 6.6 (3 equiv
of fumaric acid); 6.4-6.5 (2 × dd, 2H, J ) 2 Hz, J ) 8 Hz,
H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.0, 2.7 (2 × bs, 8H,
piperazine); 2.7 (t, 2H, CH2); 2.5 (m, 2H, CH2); 1.7 (m, 2H,
CH2); 1.58 (m, 2H, CH2); 1.4 (m, 2H, CH2). Anal. (C25H31N3O2)
C, H, N.
DMSO-d6): δ 11.1 (s, 1H, NH-indole); 7.29 (d, 1H, J ) 8 Hz,
H-arom); 7.14 (d,1H, J ) 2 Hz, H2-indole); 7.0 (t, 1H, J ) 7
Hz, H-arom); 6.94 (d, 1H, J ) 8 Hz, H-arom); 6.7 (t, 1H, J )
7 Hz, H-arom); 6.6 (s, 1H, 0.5 equiv of fumaric acid); 6.4-6.5
(2 × dd, 2H, J ) 1.5 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2-
CH2O); 3.0, 2.6 (2 × bs, 8H, piperazine); 2.92 (t, 2H, J ) 7 Hz,
CH2); 2.5 (t, 2H, J ) 7 Hz, CH2); 1.87 (m, 2H, CH2). Anal.
(C23H26ClN3O2) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-4-fluoro-1H-indole (5f) 0.5 Fumaric Acid. Com-
pound 5f was prepared via route B as a 0.5 fumaric acid salt
in an unoptimized yield of 30%. TLC analysis: eluent EtOAc,
Rf 0.1; mp 207-208 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.0
(s, 1H, NH-indole); 7.15 (d, 1H, J ) 8 Hz, H-arom); 7.07 (d,
1H, J ) 2 Hz, H2-indole); 7.0 (m, 1H, H-arom); 6.62-6.72 (m,
2H, H-arom); 6.6 (s, 0.5 equiv of fumaric acid); 6.4-6.5 (2 ×
dd, 2H, J ) 2 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2-
CH2O); 3.0, 2.6 (2 × bs, 8H, piperazine); 2.8 (t, 2H, J ) 7 Hz,
CH2); 2.5 (m, 2H, CH2); 1.9 (m, 2H, CH2). Anal. (C23H26FN3O2)
C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-5-fluoro-1H-indole (5g) 0.5 Fumaric Acid.
Compound 5g was prepared via route B as a 0.5 fumaric acid
salt in a yield of 70%. TLC analysis: eluent EtOAc, Rf 0.2. 1H
NMR (400 MHz, DMSO-d6): δ 10.8 (s, 1H, NH-indole); 7.3 (dd,
1H, J ) 5 Hz, J ) 8 Hz, H-arom); 7.2 (dd, 1H, J ) 2 Hz, J )
8 Hz, H-arom); 7.15 (d, 1H, J ) 2 Hz, H2-indole); 6.85 (dt, 1H,
J ) 2 Hz, J ) 8 Hz, H-arom); 6.7 (t, 1H, J ) 7 Hz, H-arom);
6.6 (s, 0.5 equiv of fumaric acid); 6.4-6.5 (2 × d, 2H, J ) 8
Hz, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.0, 2.6 (2 × d, 8H,
piperazine); 2.7 (t, 2H, J ) 7 Hz, CH2); 2.44 (t, 2H, J ) 7 Hz,
CH2); 1.84 (m, 2H, CH2). Anal. (C23H26FN3O2) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-6-fluoro-1H-indole (5h) 0.5 Fumaric Acid Salt.
Compound 5h was prepared via route B in a yield of 56%. TLC
analysis and silica gel column chromatography: eluent EtOAc,
Rf 0.3; mp 205-206 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.8
(s, 1H, NH-indole); 7.5 (dd 1H, J ) 5 Hz, J ) 8 Hz, H-arom);
7.08 (m, 2H, H2-indole, H-arom); 6.8 (m, 1H, H-arom); 6.7 (t,
1H, J ) 7 Hz, H-arom); 6.6 (s, 0.5 equiv of fumaric acid); 6.4-
6.5 (2 × dd, 2H, J ) 1.5 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H,
OCH2CH2O); 3.0, 2.6 (2 × bs, 8H, piperazine); 2.7 (t, 2H, CH2);
2.47 (t, 2H, CH2); 1.85 (m, 2H, CH2). Anal. (C23H26FN3O2) C,
H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-7-fluoro-1H-indole (5i) 0.5 Fumaric Acid Salt.
Compound 5i was prepared via route B in a yield of 68%. TLC
analysis and silica gel chromatography: eluent EtOAc, Rf 0.25.
1H NMR (400 MHz, DMSO-d6): δ 11.2 (s, 1H, NH-indole); 7.32
(d 1H, J ) 8 Hz, H-arom); 7.14 (d,1H, J ) 2 Hz, H2-indole);
6.9-6.96 (m, 1H, H-arom); 6.82 (dd, 1H, J ) 8 Hz, J ) 11 Hz,
H-arom); 6.7 (t, 1H, J ) 7 Hz, H-arom); 6.6 (s, 0.5 equiv of
fumaric acid); 6.4-6.5 (2 × dd, 2H, J ) 1.5 Hz, J ) 8 Hz,
H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.0, 2.6 (2 × bs, 8H,
piperazine); 2.73 (t, 2H, J ) 7 Hz, CH2); 2.48 (t, 2H, J ) 7 Hz,
CH2); 1.87 (m, 2H, CH2). Anal. (C23H26FN3O2) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-5-chloro-1H-indole (5l) 0.5 Fumaric Acid Salt.
Compound 5l was prepared via route B in a yield of 62%; mp
61-63 °C (free base); mp 220-222 °C (dec) of the 0.5 equiv of
fumaric acid. 1H NMR (400 MHz, DMSO-d6): δ11.0 (s, 1H,
NH-indole); 7.54 (d, 1H, J ) 2 Hz, H-arom); 7.34 (d, 1H, J )
8 Hz, H-arom); 7.14 (d, 1H, J ) 2 Hz, H2-indole); 7.03 (dd,
1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.7 (t, 1H, J ) 8 Hz, H-arom);
6.6 (s, 1H, fumaric acid); 6.4-6.5 (2 × dd, 2H, J ) 1.5 Hz, J )
8 Hz, H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.06, 2.7 (2 × m,
10H, 8H piperazine, CH2); 2.5 (m, 2H, CH2); 1.87 (m, 2H, CH2).
HRMS (C23H27ClN3O2) [M + H]+: found m/z, 412.1798; calcd,
412.1792. Anal. (C23H26ClN3O2) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-6-chloro-1H-indole (5m) 0.5 Fumaric Acid.
Compound 5m was prepared via route B as a 0.5 fumaric acid
salt in a yield of 61%. Silica gel column chromatography:
eluent EtOAc, Rf 0.25. 1H NMR (400 MHz, DMSO-d6): δ 10.8
(s, 1H, NH-indole); 7.5 (d, 1H, J ) 8 Hz, H-arom); 7.35 (d, 1H,
J ) 1.5 Hz, H-arom); 7.14 (d,1H, J ) 2 Hz, H2-indole); 6.96
(dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.7 (t, 1H, J ) 7 Hz,
H-arom); 6.6 (s, 1H, 0.5 equiv of fumaric acid); 6.4-6.5 (2 ×
dd, 2H, J ) 1.5 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2-
CH2O); 3.0, 2.6 (2 × bs, 8H, piperazine); 2.72 (t, 2H, J ) 7 Hz,
CH2); 2.46 (t, 2H, J ) 7 Hz, CH2); 1.85 (m, 2H, CH2). Anal.
(C23H26ClN3O2) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-7-chloro-1H-indole (5n) 0.5 Fumaric Acid Salt.
Compound 5n was prepared via route B in a yield of 73%.
Silica gel column chromatography: eluent diethyl ether, Rf 0.1.
1H NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H, NH-indole); 7.5
(d, 1H, J ) 8 Hz, H-arom); 7.17 (d, 1H, J ) 2 Hz, H2-indole);
7.12 (d, 1H, J ) 8 Hz, H-arom); 6.96 (t, 1H, J ) 7 Hz, H-arom);
6.7 (t, 1H, J ) 7 Hz, H-arom); 6.6 (s, 1H, 0.5 equiv of fumaric
acid); 6.4-6.5 (2 × dd, 2H, J ) 1.5 Hz, J ) 8 Hz, H-arom); 4.2
(bm, 4H, OCH2CH2O); 3.0, 2.6 (2 × bs, 8H, piperazine); 2.72
(t, 2H, J ) 7 Hz, CH2); 2.48 (t, 2H, J ) 7 Hz, CH2); 1.86 (m,
2H, CH2). Anal. (C23H26ClN3O2) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-5-methyl-1H-indole (5o) 0.5 Fumaric Acid
Salt. Compound 5o was prepared via route B in a yield of 65%;
mp free base, 65-67 °C; fumaric acid salt: mp 215-217 °C
(dec). 1H NMR (400 MHz, DMSO-d6): δ10.6 (s, 1H, NH-indole);
7.31 (bs, 1H, H-arom); 7.23 (d,1H, J ) 8 Hz, H-arom); 7.04 (d,
1H, J ) 2 Hz, H2-indole); 6.90 (dd, 1H, J ) 1.5 Hz, J ) 8 Hz,
H-arom); 6.74 (t, 1H, J ) 8 Hz, H-arom); 6.6 (s, 1H, 0.5 equiv
of fumaric acid); 6.4-6.5 (2 × dd, 2H, J ) 1.5 Hz, J ) 8 Hz,
H-arom); 4.2 (bm, 4H, OCH2CH2O); 3.06, 2.7 (2 × m, 10H, CH2,

1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6865
8H-piperazine); 2.57 (bm, 2H, CH2); 2.40 (s, 3H, Me); 1.90 (m,
2H, CH2). HRMS (C24H30N3O2) [M + H]+: found m/z, 392.2356;
calcd, 392.2338. Anal. (C24H29N3O2) C, H, N.
OCH2); 2.9, 2.6 (2 × bs, 8H, piperazine); 2.72 (t, 2H, CH2); 2.64,
2.5 (2 × t, 4H, CH2); 1.9 (m, 4H, H-2, CH2). Anal. (C24H29N3O)
C, H, N.
5-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-1,2,3,4-
tetrahydroquinoline (19) Hydrochloric Acid Salt. 5-Pip-
erazin-1-yl-1,2,3,4-tetrahydroquinoline14 (16) was converted to
19 with 9c following route B. Compound 19 was isolated as
the hydrochloric acid salt in a yield of 50%; mp 236-239 °C
(dec). 1H NMR (400 MHz, DMSO-d6): δ 10.7 (s, 1H, NH-
indole); 7.54 (bd, 1H, J ) 8 Hz, H-arom); 7.34 (bd, 1H, J ) 8
Hz, H-arom); 7.24 (bt, 1H, J ) 7 Hz, H-arom); 7.18 (d, 1H, J
) 1.5 Hz, H2-indole); 7.08 (bt, 1H, J ) 7 Hz, H-arom); 6.9-
7.0 (m, 3H, H-arom); 3.2-3.6 (m, 12H, 8 × H-piperazine, 2 ×
CH2); 2.82 (t, 2H, CH2); 2.74 (t, 2H, CH2); 2.2 (m, 2H, CH2);
1.7 (m, 2H, CH2). HRMS (C24H31N4) [M + H]+: found m/z,
375.2562; calcd, 375.2549. Anal. (C24H30N4) C, H, N.
3-{3-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)piperazin-1-
yl]propyl}-7-methyl-1H-indole (5p) 0.5 Fumaric Acid
Salt. Compound 5p was prepared via route B in a yield of 78%.
TLC analysis and silica gel column chromatography: eluent
EtOAc, Rf 0.3. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H,
NH-indole); 7.32 (d, 1H, J ) 8 Hz, H-arom); 7.06 (d,1H, J ) 2
Hz, H2-indole); 6.82-6.92 (m, 2H, H-arom); 6.7 (t, 1H, J ) 7
Hz, H-arom); 6.6 (s, 1H, 0.5 equiv of fumaric acid); 6.4-6.5 (2
× dd, 2H, J ) 1.5 Hz, J ) 8 Hz, H-arom); 4.2 (bm, 4H, OCH2-
CH2O); 3.0, 2.6 (2 × bs, 8H, piperazine); 2.72 (t, 2H, J ) 7 Hz,
CH2); 2.48 (t, 2H, J ) 7 Hz, CH2); 2.44 (s, 3H, Me); 1.86 (q,
2H, CH2). HRMS (C24H30N3O2) [M + H]+: found m/z, 392.2362;
calcd, 392.2338. Anal. (C24H29N3O2) C, H, N.
3-(1H-Indol-3-yl)-1-[4-(1,2,3,4-tetrahydroquinolin-5-yl)-
piperazin-1-yl]propan-1-one (17). To a cooled solution of
16 (3 g, 14 mmol), 6c (RdH, m)2, 2.3 g, 12 mmol), and
2-chloro-1,3-dimethyl-2-imidazolinium tetrafluoroborate (CIP,
4.2 g, 15 mmol) in DCM (60 mL) was added DIPEA (10 mL),
and the mixture was stirred at room temperature for 16 h after
which time TLC analysis (EtOAc/hexane, 2/1, v/v) showed
complete conversion of 6c. The reaction mixture was concen-
trated in vacuo, and the residue was purified by silica gel
chromatography (Rf 0.25, EtOAc/hexane, 2/1, v/v) to furnish
1-Benzyl-4-(3-prop-2-ynyloxy-phenyl)piperazine (11).
To a solution of compound 10 (27 g, 90 mmol)17 in MeOH (200
mL) was added a solution of sodium (4.15 g, 180 mmol) in
MeOH (200 mL). The mixture was stirred for 30 min at RT
and subsequently concentrated in vacuo. The residue was
dissolved in DMF (200 mL), and a solution of propargyl
bromide (11.3 g, 95 mmol) in DMF (50 mL) was added. The
mixture was stirred overnight at room temperature. The
reaction mixture was quenched with water, and the resulting
mixture was extracted with DCM (2 × 300 mL). The combined
organic layers were washed with water, dried (MgSO4), and
concentrated to give crude 11 as a black oil, which was purified
by silica gel column chromatography (DCM/MeOH, 98/2, v/v)
1
17 (3.1 g, 67%) as a colorless oil. H NMR (400 MHz, CDCl3):
δ 8.33 (s, 1H, NH-indole); 7.62 (d, 1H, J ) 8 Hz, H-arom); 7.36
(d, 1H, J ) 8 Hz, H-arom); 7.18 (t, 1H, J ) 7 Hz, H-arom); 7.1
(t, 1H, J ) 7 Hz, H-arom); 7.04 (bs, 1H, J ) 2 Hz, H2-indole);
6.92 (t, 1H, J ) 7 Hz, H-arom); 6.24 (t, 2H, J ) 7 Hz, H-arom);
3.26, 2.82 (2 × s, 8H, H-piperazine); 3.24 (t, 2H, CH2); 3.16 (t,
2H, J ) 7 Hz, CH2); 2.76 (t, 2H, J ) 7 Hz, CH2); 2.7 (t, 2H, J
) 7 Hz, CH2); 1.86 (m, 2H, CH2).
1
to give 11 (20 g, 60%) as a colorless oil. H NMR (400 MHz,
DMSO-d6): δ 7.0-7.4 (m, 6H, H-arom); 6.4-6.6 (m, 3H,
H-arom); 4.7 (d, 2H, J ) 2 Hz, O-CH2); 3.5 (s, 2H, N-CH2);
3.1, 2.5 (2 × m, 8H, piperazine); 1.98 (s, H, CH).
1-Benzyl-4-(2H-chromen-5-yl)piperazine (13). Com-
pound 11 was dissolved in diethylaniline (45 mL), and the
solution was heated at 220 °C for 1 h, after which time TLC
analysis revealed complete conversion of 11 into two products.
The reaction mixture was allowed to cool to room temperature
and concentrated in vacuo to give a brown oil, which was
purified by silica gel column chromatography to give pure 13
(10.6 g, 69%) and 12 (3.4 g, 22%) as colorless oils. Compound
5-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-1-methyl-
1,2,3,4-tetrahydroquinoline (20) Hydrochloric Acid Salt.
A mixture of acetic anhydride (0.46 mL) and formic acid (0.24
mL) was stirred at 55 °C for 1 h. The mixture was allowed to
reach room temperature, and a solution compound 17 (1 g,
2.6 mmol) in dry THF was added slowly. The reaction mixture
was stirred overnight at room temperature after which time
TLC analysis (EtOAc) showed complete conversion of 17. The
mixture was concentrated in vacuo to give crude 18 as an oil,
which was used in the next step without further purification.
To a cooled (0 °C) solution of crude 18 (0.95 g, 2.5 mmol) in
dry diethyl ether (20 mL) was added a suspension of LiAlH4
(0.27 g, 7 mmol) in diethyl ether (10 mL). The reaction mixture
was stirred overnight at room temperature, cooled again to 0
°C, and water (1 mL), 2 N NaOH (2 mL), and water (1 mL)
were added. The mixture was filtered, and the filtrate was
concentrated in vacuo. The oily residue was purified by silica
gel chromatography (eluent: DCM/MeOH, 95/5, v/v; Rf 0.3) to
give 20 (0.7 g) in a yield of 75% based on 17. Compound 20
was isolated as a white solid after treatment with a solution
1
12: H NMR (400 MHz, CDCl3): δ 7.3-7.4 (m, 5H, phenyl);
6.84 (d, 1H, J ) 8 Hz, H-arom); 6.42 (dd, 1H, J ) 2 Hz, J ) 8
Hz, H-arom); 6.32-6.38 (m, 2H, H-4, H-arom); 5.6 (m, 1H, H3);
4.76 (dd, 2H, H-2); 3.54 (s, 2H, CH2 Bn ); 3.0, 2.6 (2 × m, 8H,
piperazine). Compound 13: 1H NMR (400 MHz, CDCl3):
δ
7.24-7.4 (m, 5H, phenyl); 7.06 (t, 1H, J ) 8 Hz, H-arom); 6.7
(m, 1H, J ) 2 Hz, J ) 8 Hz, H-4); 6.55 (d, 2H, J ) 8 Hz,
H-arom); 5.7-5.8 (dt, 1H, J ) 3 Hz, J ) 8 Hz, H-3); 4.66 (dd,
2H, J ) 2 Hz, J ) 4 Hz, H-2); 3.6 (s, 2H, CH2 Bn ); 3.0, 2.6 (2
× m, 8H, piperazine).
1-Chroman-5-yl-piperazine (14). Compound 13 (2.4 g, 8
mmol) was dissolved in ethanol containing hydrochloric acid
(2 mol equiv), and the catalyst Pd on charcoal (100 mg) was
added. The mixture was shaken for 2 h under an atmosphere
of hydrogen. The mixture was filtered and concentrated in
vacuo to give crude 14 as an oil, which was purified by silica
gel column chromatography to give pure 14 (2 g, 85%) as the
1
of HCl (1 equiv) in EtOH; free base of 20: mp 78-80 °C. H
NMR (400 MHz, CDCl3): δ 8.08 (s, 1H, NH-indole); 7.6 (d, 1H,
J ) 8 Hz, H-arom); 7.34 (d, 1H, J ) 8 Hz, H-arom); 7.22 (t,
1H, J ) 7 Hz, H-arom); 7.14 (t, 1H, J ) 7 Hz, H-arom); 7.08
(t, 1H, J ) 7 Hz, H-arom); 7.02 (d, 1H, J ) 2 Hz, H2-indole);
6.4-6.5 (2 × d, 2H, J ) 8 Hz, H-arom); 3.2 (t, 2H, J ) 6 Hz,
CH2); 2.94 (m, 4H, H-piperazine); 2.9 (s, 3H, Me); 2.84 (t, 2H,
J ) 6 Hz, CH2); 2.70 (m, 6H, H-piperazin, CH2); 2.6 (m, 2H,
CH2); 2.0 (m, 2H, CH2); 1.90 (m, 2H, CH2). HRMS (C25H33N4)
[M + H]+: found m/z, 389.2726; calcd, 389.2705. Anal.
1
hydrochloric acid salt. H NMR (400 MHz, CDCl3): δ 7.2 (t,
1H, J ) 8 Hz, H-arom); 6.7-6.8 (2 × d, 2H, J ) 8 Hz, H-arom);
4.2 (t, 2H, J ) 5 Hz, H2); 3.4, 3.2 (2 × m, 8H, piperazine); 2.8
(t, 2H, H4); 2.0 (m, 2H, H3).
3-[3-(4-Chroman-5-yl-piperazine-1-yl)propyl]-1H-in-
dole (15) 0.5 Fumaric Acid Salt. Compound 14 (1.75 g, 6
mmol) was converted with 9c via route B to give compound
15 (1.4 g, 50%) as a white solid. TLC analysis and silica gel
column chromatography: eluent: DMA 0.5 Rf 0.7. 1H NMR
(400 MHz, DMSO-d6): δ 10.7 (s, 1H, NH-indole); 7.5 (d, 1H, J
) 8 Hz, H-arom); 7.32 (d, 1H, J ) 8 Hz, H-arom); 7.06 (d, 1H,
J ) 2 Hz, H2-indole); 7.04 (t, 1H, J ) 7 Hz, H-arom); 6.9-7.0
(m, 2H, H-arom); 6.6 (s, 1H, 0.5 fumaric acid); 6.5 (d, 1H, J )
8 Hz, H-arom); 6.44 (d, 1H, J ) 8 Hz, H-arom); 4.1 (t, 2H,
(C25H32N4) C, H, N.
3-Methyl-5-(tosyl-piperazin-1-yl)-1,2,3,4-tetrahydro-
quinoline (23). To a suspension of commercially available
3-methyl-5-nitroquinoline (21, 27 g, 143 mmol) in ethanol
(1000 mL) was added platinum on charcoal (5 wt. %, 12 g).
The mixture was stirred for 6 h under a hydrogen pressure of
4 atm at a temperature of 40 °C. The mixture was filtered,
and the filtrate was concentrated in vacuo to give crude 22 as
a brown oil. To a mixture of crude 22 (14 g, 86 mmol) and the
tosyl-protected methanesulfonic acid 2-(2-methanesulfonyloxy-

6866 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
ethylamino)ethyl ester (36 g, 86 mmol) was added DIPEA (30
mL), and the mixture was heated at 140 °C for 4 h, after which
time TLC analysis (MTBE, Rf 0.5) showed complete conversion
of the starting material. The mixture was allowed to cool to
room temperature, dissolved in dichloromethane, and washed
with 2 N NaOH. The organic layer was concentrated, and the
residue was purified by silica gel column chromatography (TLC
eluent: MTBE/PA, 1/2, v/v) to give 23 as a brown solid (16.6
g, 50% yield); mp 169-170 °C. 1H NMR (400 MHz, CDCl3): δ
7.7 (d, 2H, tosyl); 7.4 (d, 2H, tosyl); 6.9 (t, 1H, H-arom); 6.3 (2
× dd, 2H, H-arom); 2.4 (s, 3H, Me-tosyl); 1.6-3.4 (13H,
H-piperazine, H-quinoline); 1.0 (d, 3H, J ) 6 Hz, CH3).
3-Methyl-5-[piperazin-1-yl]-1,2,3,4-tetrahydroquino-
line (24). Compound 23 (2.06 g, 5.35 mmol) was suspended
in concentrated HCl (40 mL). The mixture was refluxed
overnight after which time TLC analysis (EtOAc) showed
complete conversion of the starting material. The reaction
mixture was diluted with 50 mL of ice water and 50 mL of 2
N NaOH and extracted with dichloromethane (3 × 100 mL).
The combined organic layers were washed with brine (2 × 100
mL) and dried on MgSO4. Filtration, followed by concentration
in vacuo, gave crude 24 as a yellow solid, which was used in
the next step without further purification.
5-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-3-methyl-
1,2,3,4-tetrahydroquinoline (25) 0.5 Fumaric Acid Salt.
3-Methyl-5-(piperazin-1-yl)-1,2,3,4-tetrahydroquinoline (24) was
converted to 25 with mesylate 9c following route B. Compound
25 was isolated as the fumaric acid salt in a yield of 79%; mp
210-212 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.7 (s, 1H,
NH-arom); 7.5 (d, 1H, J ) 8 Hz, H-arom); 7.32 (d, 1H, J ) 8
Hz, H-arom); 7.08 (d, 1H, J ) 2 Hz, H2-indole); 7.04 (t, 1H, J
) 7 Hz, H-arom); 6.96 (t, 1H, J ) 7 Hz, H-arom); 6.78 (t, 1H,
J ) 7 Hz, H-arom); 6.6 (s, 1H, 1/2 fumerate); 6.2 (t, 2H,
H-arom); 1.7-3.4 (19H, H-piperazine, H-quinoline, 3 × CH2
propyl); 1.0 (d, 3H, J ) 6 Hz, Me). Anal. (C25H32N4) C, H, N.
5-Nitro-3,4-dihydro-1H-quinolin-2-one (28b). The start-
ing material, 4-nitro-indan-1-one (26), was prepared as de-
scribed in the literature.20 To a solution of 26 (14.7 g, 83 mmol)
in benzene (150 mL) were added H2SO4 (95-97%, 44 mL) and
sodium azide (5.4 g in portions of 540 mg) resulting in an
exothermic reaction, and the reaction mixture was allowed to
stir for 10 min at 70 °C. The reaction mixture was allowed to
reach room temperature, the benzene layer was separated, and
to the residue suspension was added water (200 mL). The
suspension was stirred for 30 min and extracted with DCM (4
× 200 mL). The combined organic layers were washed with 1
N NaHCO3 (3 × 100 mL), dried on MgSO4, and filtered to give
a crude mixture of compounds 28a and 28b. Pure compound
28b (6.8 g, 45%) was isolated from the mixture by silica gel
chromatography (eluent: EtOAc/hexane, 1/1, v/v) and sepa-
rated from the other isomer 28a (3.9 g, 22%). The 1H NMR
data of both compounds were in complete accordance with the
data reported in the literature.20
5-Amino-3,4-dihydro-1H-quinolin-2-one (29). Compound
28b (6.2 g, 32 mmol) was dissolved in EtOH (400 mL). To the
solution was added palladium on charcoal (10%, 500 mg), and
the mixture was stirred under a blanket of hydrogen for 4 h.
Filtration over Hyflo and subsequent concentration in vacuo
yielded crude 29 in a yield of 95%, which was used in the next
step without further purification.
5-Piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one (30). To
a solution of compound 29 (4.95 g, 30.5 mmol) in chlorobenzene
(125 mL) was added BCEA HCl salt (bis{chloroethylene}-
amine, 5.7 g, 32.1 mmol), and the mixture was refluxed for 66
h. The mixture was concentrated in vacuo, and the resulting
oil was purified by silica gel chromatography (DMA 0.5-1.0)
to give 30 as a white solid in a yield of 72%. HRMS (C13H17N3O)
[M + H]+: found m/z, 232.3; calcd, 232.3.
5-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-3,4-dihy-
dro-1H-quinolin-2-one (31). Compound 30 (1.1 g, 4.8 mmol)
was converted to 31 with mesylate 9c following route B.
Compound 31 was isolated as the free base in a yield of 45%;
mp 181-182 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.8 (s,
1H, NH-arom); 7.55 (d, 1H, J ) 8 Hz, H-arom); 7.38 (d, 1H, J
) 8 Hz, H-arom); 7.0-7.14 (m, 4H, H-arom, H2-indole); 6.76
(d, 1H, J ) 8 Hz, H-arom); 6.64 (d, 1H, J ) 8 Hz, H-arom);
1.9-2.9 (18H, H-piperazine, H-quinoline, 3 × CH2). Anal.
(C24H28N4O) C, H, N.
2-Chloro-N-(5-chloro-2-hydroxyphenyl)acetamide (34a).
To a cooled (0 °C) solution of 2-amino-4-chloro-phenol (32, 100
g, 700 mmol) in DCM (400 mL) and pyridine (56 mL) was
added a solution of chloroacetyl chloride in DCM (33a, 700
mmol in 75 mL). The mixture was allowed to reach room
temperature slowly and was subsequently stirred for 18 h. The
precipitation was filtered, washed with DCM, and dried
overnight at 50 °C to give crude 34a as a brown solid (57 g,
37%), which was used in the next step without further
purification.
2-Chloro-N-(5-chloro-2-hydroxyphenyl)propiona-
mide (34b). Compound 34b was prepared in a similar fashion
as 34a starting from 32 and 33b. Compound 34b was isolated
as a purple solid in a yield of 61%, which could be used in the
next step without further purification.
2-Bromo-N-(5-chloro-2-hydroxyphenyl)-2-methyl-pro-
pionamide (34c). Compound 34c was prepared in a similar
fashion as 34a starting from 32 and 33c. Compound 34c was
isolated as a beige solid in a yield of 79%, which could be used
1
in the next step without further purification; mp 172 °C. H
NMR (400 MHz, CDCl3): δ 7.45 (d, 1H, H-arom); 7.08 (dd, 1H,
H-arom); 6.9 (d, 1H, H-arom); 2.08 (s, 6H, 2 × Me).
6-Chloro-8-nitro-4H-benzo[1,4]oxazin-3-one (35a). Com-
pound 34a (57 g, 260 mmol) was suspended in water (240 mL)
at a temperature of 0 °C. To the suspension was added HNO3
(1.5 equiv, 387 mmol) over a period of 0.75 h. The resulting
red solution was allowed to reach RT after 1 h, and water was
added (250 mL) giving a dark brown solid, which was isolated
by filtration. The resulting filtrate was washed with cold water
(3 × 200 mL) and dried at 50 °C to give the nitrated derivative
of 34a as a yellow solid in a yield of 90%. Ring closure to 35a
was established by refluxing this intermediate with potassium
carbonate in toluene/water, 50/1, v/v (51 mL) for 2 h. The
reaction mixture was allowed to reach RT, which resulted in
the precipitation of a brown solid, which was purified by silica
gel chromatography (EtOAc/PA, 1/1, v/v to 1/0, v/v) to give
compound 35a as a white solid in a yield of 70%.
6-Chloro-8-nitro-4H-benzo[1,4]oxazin-2-methyl-3-one
(35b). Compound 35b was prepared in a similar fashion as
35a starting from 34b. Compound 35b was isolated as a yellow
solid in a yield of 40%.
6-Chloro-8-nitro-4H-benzo[1,4]oxazin-2,2-dimethyl-3-
one (35c). Compound 35c was prepared in a similar fashion
as 35a starting from 34c. Compound 35c was isolated as a
1
yellow solid in a yield of 62%. H NMR (400 MHz, CDCl3): δ
9.8 (bs, 1H, NH); 7.6 (d, 1H, J ) 2 Hz, H-arom); 7.1 (d, 1H, J
) 2 Hz, H-arom); 1.6 (s, 6H, 2 × Me).
6-Chloro-8-nitro-4H-benzo[1,4]oxazin-2,4-dimethyl-3-
one (35d). To a cooled (0 °C) solution of compound 35b (8.2 g,
34 mmol) in DMF (75 mL) were added powdered KOH (2 g)
and methyl iodide (2.32 mL). A yellow precipitation was
formed. After stirring for 22 h, water (10 mL) was added and
the mixture was concentrated in vacuo. The residue was
applied to silica gel chromatography (DCM/MeOH, 99/1, v/v;
Rf 0.5) resulting in the isolation of 35d as a yellow powder in
1
a yield of 90%. H NMR (400 MHz, CDCl3): δ 7.6 (d, 1H, J )
2 Hz, H-arom); 7.15 (d, 1H, J ) 2 Hz, H-arom); 4.8 (q, 1H, J
) 7 Hz, CH); 3.4 (s, 3H, NMe); 1.6 (d, 3H, J ) 7 Hz, Me).
8-Amino-4H-benzo[1,4]oxazin-3-one (36a). Compound
35a (10 g, 43.7 mmol) was dissolved in 96% EtOH (400 mL),
and Pd/C (0.5 g) was added. The mixture was hydrogenated
at a pressure of 3 bar of hydrogen for 4 h at a temperature of
50 °C. The reaction mixture was filtered over Hyflo, and the
filtrate was concentrated in vacuo to give crude 36a in a yield
of 80% as a brown solid, which was used in the next step
without further purification.
8-Amino-4H-benzo[1,4]oxazin-2-methyl-3-one (36b).
Compound 36b was prepared in a similar fashion as 36a
starting from 35b. Compound 36b was isolated as a yellow

1-Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22 6867
1
solid in a yield of 90%, which was used in the next step without
further purification.
of 29%; H NMR (400 MHz, CDCl3): δ 7.9 (s, 1H, NH); 7.56
(s, 1H, NH-arom); 7.62 (d, 1H, J ) 8 Hz, H-arom); 7.34 (d,
1H, J ) 8 Hz, H-arom); 7.06-7.18 (m, 2H, H-arom); 7.0 (d,
1H, J ) 2 Hz, H2-indole); 6.86 (t, 1H, J ) 8 Hz, H-arom); 6.6
(dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.38 (dd, 1H, J ) 2 Hz,
J ) 8 Hz, H-arom); 3.17, 2.66 (2 × m, 8H, piperazine); 2.82 (t,
2H, J ) 7 Hz, CH2); 2.5 (t, 2H, J ) 7 Hz, CH2); 1.96 (m, 2H,
CH2); 1.58 (s, 6H, 2 × Me). HRMS (C25H30N4O2) [M + H]+:
found m/z, 419.2467; calcd, 419.2447. Anal. (C25H30N4O2), C,
H, N.
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-4H-benzo-
[1,4]oxazin-2,4-dimethyl-3-one (38d). Compound 38d was
prepared in the same way as described for 38a starting from
37d. Compound 38d was obtained as a white foam in an yield
of 46%. 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 1H, NH-arom);
7.62 (d, 1H, J ) 8 Hz, H-arom); 7.32 (d, 1H, J ) 8 Hz, H-arom);
7.04-7.2 (m, 2H, H-arom); 6.98 (d, 1H, J ) 2 Hz, H2-indole);
6.92 (t, 1H, J ) 7 Hz, H-arom); 6.6-6.7 (2 × dd, 2H, J ) 2 Hz,
J ) 8 Hz, H-arom); 4.58 (q, 1H, J ) 7 Hz, CH); 3.34 (s, 3H,
Me); 3.0-3.2, 2.65 (2 × bm, 8H, piperazine); 2.8 (t, 2H, J ) 7
Hz, CH2); 2.5 (t, 2H, J ) 7 Hz, CH2); 2.0 (q, 2H, CH2); 1.6 (d,
3H, J ) 7 Hz, Me). Anal. (C25H30N4O2), C, H, N.
8-Amino-4H-benzo[1,4]oxazin-2,2-dimethyl-3-one (36c).
Compound 36c was prepared in a similar fashion as 36a
starting from 35c. Compound 36c was isolated as a yellow
solid in a yield of 81%. 1H NMR (400 MHz, CDCl3): δ 10.8 (s,
1H, NH); 6.8-7.1 (m, 3H, H-arom); 1.45 (s, 6H, 2 × Me).
8-Amino-4H-benzo[1,4]oxazin-2,4-dimethyl-3-one (36d).
Compound 36d was prepared in a similar fashion as 36a
starting from 35d. Compound 36d was isolated as a white solid
1
in a yield of 85%. H NMR (400 MHz, CDCl3): δ 6.85 (t, 1H,
J ) 8 Hz, H-arom); 6.4-6.55 (ddd, 2H, J ) 2 Hz, J ) 8 Hz,
H-arom); 4.7 (q, 1H, J ) 7 Hz, CH); 3.35 (s, 3H, Me); 1.6 (d,
3H, J ) 7 Hz, Me).
8-Piperazin-1-yl-4H-benzo[1,4]oxazin-3-one (37a). To a
solution of compound 36a (5.7 g, 34.8 mmol) in chlorobenzene
(125 mL) was added BCEA hydrochloric acid (6.5 g, 36 mmol),
and the mixture was refluxed for 69 h. The reaction mixture
was concentrated in vacuo, and the residue was stirred in
EtOAc for 2 h. The resulting brown solid was filtered and
purified by silica gel chromatography (DMA 0.5-1.0) to give
pure 37a (2.44 g, 30%).
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-3,4-dihy-
dro-2H-benzo[1,4]oxazine (39) Fumaric Acid Salt. To a
suspension of lithium aluminum hydride (0.97 g, 25.5 mmol)
in dry THF (25 mL) was slowly added a solution of compound
38a (0.96 g, 2.5 mmol) in dry THF (25 mL), and the mixture
was refluxed for 3 h under a nitrogen atmosphere. The reaction
was cautiously quenched with water (1 mL) and 2 N NaOH (2
mL), and the resulting mixture was filtered over Hyflo. The
filtrate was concentrated in vacuo to give 39 as a brown solid
in a yield of 99%. Crude 39 was dissolved in EtOH (50 mL),
and fumaric acid (1 mol equiv, 286 mg) was added. The
solution was concentrated in vacuo, and the residue was
dissolved in dry ether from which it crystallized. The crystals
were isolated by filtration and dried to give pure 39 as a beige
solid in an yield of 80%; mp 200-201 °C. 1H NMR (400 MHz,
DMSO): δ 10.8 (s, 1H, NH-arom); 8.2 (s, 1H, NH); 7.51 (d,
1H, J ) 8 Hz, H-arom); 7.32 (d, 1H, J ) 7 Hz, H-arom); 6.94-
7.1 (m, 3H, H-arom); 6.6 (s, 0.5 fum); 6.56 (t, 1H, J ) 7 Hz,
H-arom); 6.18-6.26 (2 × d, 2H, J ) 8 Hz, H-arom); 4.14, 3.28
(2 × m, 4H, 2 × CH2); 3.0-3.2, 2.7 (2 × bm, 8H, piperazine);
2.78 (t, 2H, CH2); 2.58 (t, 2H, CH2); 1.9 (q, 2H, CH2). HRMS
(C23H38N4O) [M + H]+: found m/z, 377. 2365; calcd, 377.2487.
8-Piperazin-1-yl-4H-benzo[1,4]oxazin-2-methyl-3-one
(37b). Compound 37b was prepared in a similar fashion as
37a starting from 36b. Compound 37b was isolated as a yellow
1
solid in a yield of 50%. H NMR (400 MHz, CDCl3): δ 7.0 (t,
1H, H-arom); 6.7 (m, 2H, H-arom); 4.6 (q, 1H, CH); 2.95-3.1
(m, 8H, piperazine); 1.6 (d, 3H, Me).
8-Piperazin-1-yl-4H-benzo[1,4]oxazin-2,2-dimethyl-3-
one (37c). Compound 37c was prepared in a similar fashion
as 37a starting from 36c. Compound 37c was isolated as a
1
beige solid in a yield of 89%. H NMR (400 MHz, DMSO-d6):
δ 10.5 (bs, 1H, NH); 6.8 (m, 1H, H-arom); 6.5 (d, 2H, J ) 8
Hz, H-arom); 3.4 (bs, 2H, NH2+); 2.8-3.0 (m, 8H, piperazine);
1.4 (s, 6H, 2 × Me).
8-Piperazin-1-yl-4H-benzo[1,4]oxazin-2,4-dimethyl-3-
one (37d). Compound 37d was prepared in a similar fashion
as 37a starting from 36d. Compound 37d was isolated as an
oil in a yield of 90%. 1H NMR (400 MHz, CDCl3): δ 7.0 (t, 1H,
J ) 7 Hz, H-arom); 6.7 (m, 2H, H-arom); 4.6 (q, 1H, J ) 7 Hz,
CH); 3.4 (s, 3H, Me); 2.95-3.1 (m, 8H, piperazine); 1.6 (d, 3H,
J ) 7 Hz, Me).
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-4H-benzo-
[1,4]oxazin-3-one (38a). To a solution of compound 37a (2.6
g, 9.6 mmol) in acetonitrile (100 mL) were added mesylate 9c
(2.5 g, 9.7 mmol), KI (1.6 g, 9.7 mmol), and DIPEA (5.1 mL,
29 mmol), and the mixture was refluxed for 18 h. The reaction
mixture was concentrated in vacuo, and the residue was
purified by silica gel chromatography (DMA 0.25-0.5) to give
pure 38a as a beige foam in a yield of 67%. 1H NMR (400 MHz,
DMSO-d6): δ 10.5 (s, 1H, NH-indole); 7.5 (d, 1H, J ) 8 Hz,
H-arom); 7.32 (d, 1H, J ) 8 Hz, H-arom); 7.07 (d, 1H, J ) 2
Hz, H-2 indole); 7.04 (t, 1H, J ) 7 Hz, H-arom); 6.96 (t, 1H, J
) 7 Hz, H-arom); 6.83 (t, 1H, J ) 8 Hz, H-arom); 6.56 (d, 2H,
J ) 8 Hz, H-arom); 4.51 (s, 2H, CH2); 3.0, 2.6 (2 × bs, 8H,
piperazine); 2.72 (bt, 2H, CH2); 2.4 (bt, 2H, CH2); 1.84 (m, 2H,
CH2). Anal. (C23H26N4O2), C, H, N.
6-Chloro-(R)-2-methyl-8-nitro-4H-benzo[1,4]oxazin-3-
one (42a). To a cooled (0 °C) solution of commercially available
40 (37.3 g, 200 mmol), methyl (S)-(-)-lactate 41a (20 mL, 200
mmol), and triphenyl phosphine (58 g, 220 mmol) in dry THF
(2 L) was slowly added a solution of diisopropyl azodicarboxy-
late (DIAD, 43 mL, 220 mmol) in dry THF (400 mL). The
mixture was stirred for 4 days at room temperature after
which time TLC analysis (MTBE, Rf 0.5) showed complete
conversion of compound 40 into 42a. The mixture was con-
centrated in vacuo to give a red oil. The oil was dissolved in
EtOH, from which compound 42a crystallized as a brown solid
1
(38 g, 79% yield). H NMR (400 MHz, CDCl3): δ 8.8 (s, 1H,
NH); 7.6 (d, 1H, J ) 2 Hz, H-arom); 7.06 (d, 1H, H-arom); 4.85
(q, 1H, J ) 7 Hz, CH); 1.7 (d, 3H, J ) 7 Hz, CH3).
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-4H-benzo-
[1,4]oxazin-2-methyl-3-one (38b). Compound 38b was pre-
pared in the same way as described for 38a starting from 37b.
Compound 38b was obtained as a white solid in a yield of 50%;
6-Chloro-(S)-2-methyl-8-nitro-4H-benzo[1,4]oxazin-3-
one (42b). Compound 42b was obtained in a similar fashion
as 42a starting from 40 and methyl (R)-(+)-lactate 41b.
Compound 42b was obtained as a brown solid in a yield of
80%. [R]d -8 (MeOH).
(R)-2-Methyl-8-amino-4H-benzo[1,4]oxazin-3-one (43a).
To a solution of compound 42a (15 g, 62 mmol) in EtOH/EtOAc,
1/1, v/v (400 mL) was added Pd/C (0.4 g), and the reaction was
stirred under a blanket of hydrogen for 24 h. The mixture was
filtered, and the filtrate was concentrated in vacuo to give
crude 43a as a beige solid in an yield of 86%, which was used
in the next step without further purification; [R]d -42 (MeOH).
1H NMR (400 MHz, CDCl3): δ 8.2 (bs, 1H, NH); 6.76 (t, 1H, J
) 7 Hz, H-arom); 6.44 (dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom);
6.24 (dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 4.68 (q, 1H, J ) 7
Hz, CH); 3.8 (bs, 2H, NH2+); 1.6 (d, 3H, J ) 7 Hz, CH3).
1
mp 196-197 °C. H NMR (400 MHz, CDCl3): δ 7.96, 7.76 (2
× s, 2H, 2 × NH); 7.63 (d,1H, J ) 8 Hz, H-arom); 7.36 (d, 1H,
J ) 8 Hz, H-arom); 7.18 (t, 1H, J ) 7 Hz, H-arom); 7.12 (t,
1H, J ) 7 Hz, H-arom); 7.0 (d, 1H, J ) 2 Hz, H-2 indole); 6.9
(t, 1H, J ) 8 Hz, H-arom); 6.64 (d, 1H, J ) 8 Hz, H-arom);
6.44 (d, 1H, J ) 8 Hz, H-arom); 4.64 (q, 1H, CH); 3.15, 2.6 (2
× m, 8H, piperazine); 2.8 (bt, 2H, J ) 7 Hz, CH2); 2.5 (bm,
2H, CH2); 1.94 (m, 2H, CH2); 1.6 (d, 3H, CH3). Anal.
(C24H28N4O2), C, H, N.
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-4H-benzo-
[1,4]oxazin-2,2-dimethyl-3-one (38c). Compound 38c was
prepared in the same way as described for 38a starting from
37c. Compound 38c was obtained as a white foam in a yield

6868 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 22
Smid et al.
(S)-2-Methyl-8-amino-4H-benzo[1,4]oxazin-3-one (43b).
Compound 43b was obtained in a similar fashion as 43a
starting from 42b. Compound 43b was obtained as a brown
solid in a yield of 50%, which was used in the next step without
further purification; [R]d +43 (MeOH).
8-Piperazin-1-yl-4H-benzo[1,4]oxazin-(R)-2-methyl-3-
one (44a). Compound 44a was prepared as described for the
synthesis of 37a. Pure compound 44a was obtained after silica
gel column chromatography (EtOAc/MeOH/NH4OH, 90/5/5,
v/v/v; Rf 0.1) in a yield of 80%; [R]d -42 (MeOH). 1H NMR (400
MHz, CDCl3): δ 9.0 (bs, 1H, NH); 6.9 (t, 1H, J ) 7 Hz,
H-arom); 6.5-6.6 (2 × d, 2H, J ) 8 Hz H-arom); 4.65 (q, 1H,
J ) 7 Hz, CH); 3.1 (m, 8H, piperazine); 1.65 (d, 3H, J ) 8 Hz,
CH3).
6.98-7.04 (m, 2H, H-arom); 6.86-6.94 (m, 2H, H-arom); 6.64
(dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.46 (dd, 1H, J ) 2 Hz,
J ) 8 Hz, H-arom); 4.64 (q, 1H, J ) 7 Hz, CH); 3.1-3.2 (m,
4H, H-piperazine); 2.80 (t, 2H, J ) 7 Hz, CH2); 2.65 (m, 4H,
H-piperazine); 2.5 (m, 2H, CH2); 1.94-2.0 (m, 2H, CH2); 1.62
(d, 3H, J ) 7 Hz, CH3). HRMS (C24H28FN4O2) [M + H]+: found
m/z, 423.2234; calcd, 423.2196. Anal. (C24H27FN4O2) C, H, N.
8-{4-[3-(7-Fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-
4H-benzo[1,4]oxazin-(S)-2-methyl-3-one (45f). Compound
45f was obtained from 44b and 9i via method B in a yield of
1
84%; [R]d +25 (MeOH). H NMR (400 MHz, CDCl3): δ 8.18,
8.02 (2 × bs, 2H, 2 × NH); 7.38 (d, 1H, J ) 8 Hz, H-arom);
6.98-7.04 (m, 2H, H-arom); 6.86-6.94 (m, 2H, H-arom); 6.64
(dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.46 (dd, 1H, J ) 2 Hz,
J ) 8 Hz, H-arom); 4.64 (q, 1H, J ) 7 Hz, CH); 3.1-3.2 (m,
4H, H-piperazine); 2.80 (t, 2H, J ) 7 Hz, CH2); 2.65 (m, 4H,
H-piperazine); 2.5 (m, 2H, CH2); 1.94-2.0 (m, 2H, CH2); 1.62
(d, 3H, J ) 7 Hz, CH3). HRMS (C24H28FN4O2) [M + H]+: found
m/z, 423.2217; calcd, 423.2196. Anal. (C24H27FN4O2) C, H, N.
In Vitro Kinetic Studies. The capability of the human
MDR1 P-glycoprotein pump to translocate compounds over a
cellular monolayer of PK1 LLC MDR cells was assessed. The
transport method essentially described in the literature32 was
used. Compounds were added at the start of the experiment
at 1 µg/mL to one side of the cellular layer. The bottom to top
transport was measured as well as the top to bottom transport.
The p-glycoprotein (Pgp) factor was expressed as the ratio of
the bottom to top transport and top to bottom transport. The
membrane passage was expressed as the mean percentage of
compound transported from bottom to top and from top to
bottom at 3 h after adding the compound. Compound detection
was performed using a LC/MS method.
The aqueous solubility of compounds was determined by
dissolving compounds in 10 mg/mL in DMSO. Hereafter, serial
dilutions were made in DMSO. Finally, a 1:100 dilution was
made in Episerf (Gibco) tissue culture medium. The first
concentration, which did not precipitate in this series, was
defined as the aqueous solubility of the compounds.
In Vivo Kinetic Studies of Compound 45c. In pharma-
cokinetic experiments, six male rats were daily dosed with
doses of 45c ranging from 3 to 30 mg/kg for 14 days for
multiple dose kinetics and once for single dose kinetics. For
single dose kinetics, the same animals were used for iv and
po dosing. Po dosing and blood sampling were done 1 week
after the iv dosing and blood sampling. From each animal, two
blood samples were taken per dosing session. This resulted in
six time points (0.5, 1, 2, 4, 8, and 24 h) with duplicate samples
per time point. Compound 45c concentrations in plasma were
determined by HPLC-MS.
The following parameters were obtained/calculated. Prepeak
concentrations below the limit of quantification were taken
as zero. If no sample analysis was available at a given time
point, that time point was omitted from the analysis. The
validated pharmacokinetic program Win Nonlin Professional,
version 2.1, was used for data evaluation.
Molecular Modeling Studies. Modeling studies were
carried out on Silicon Graphics Octane workstations running
Sybyl V6.9.235 Structures were first minimized by MM calcula-
tions using the Tripos Force Field with Gasteiger-Hu¨ckel
charges prior to MOPAC minimization using the AM1 method.
Pharmacophores were obtained by manual fitting of the
structures.
Acknowledgment. Karel Stegman, Jan Jeronimus,
and Cor de Korte are gratefully acknowledged for
supplying and interpreting the spectral data. Dr. An-
neke Mu¨hlebach is gratefully acknowledged for supply-
ing the elemental analysis data.
Supporting Information Available: Elemental analysis
data of the test compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
8-Piperazin-1-yl-4H-benzo[1,4]oxazin-(S)-2-methyl-3-
one (44b). Compound 44b was prepared as described for the
synthesis of 37a. Pure compound 44b was obtained after silica
gel column chromatography (EtOAc/MeOH/NH4OH, 90/5/5,
v/v/v; Rf 0.1) in a yield of 40%; [R]d +37 (MeOH).
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-4H-benzo-
[1,4]oxazin-(R)-2-methyl-3-one (45a). Compound 45a was
obtained from 44a and 9c via method B. Compound 45a was
obtained as a white solid in a yield of 55%; mp 178-180 °C;
[R]d -26 (MeOH). 1H NMR (400 MHz, CDCl3): δ 7.96, 7.84 (2
× bs, 2H, 2 × NH); 7.62 (d, 1H, J ) 8 Hz, H-arom); 7.36 (d,
1H, J ) 8 Hz, H-arom); 7.1-7.2 (m, 2H, H-arom); 7.0 (d, 1H,
J ) 2 Hz, H2-indole); 6.9 (t, 1H, J ) 8 Hz, H-arom); 6.64 (dd,
1H, J ) 1.5 Hz, J ) 8 Hz, H-arom); 6.44 (dd, 1H, J ) 1.5 Hz,
J ) 8 Hz, H-arom); 4.64 (q, 1H, J ) 7 Hz, CH); 3.1-3.2 (m,
4H, H-piperazine); 2.8 (t, 2H, J ) 7 Hz, CH2); 2.65 (m, 4H,
H-piperazine); 2.5 (m, 2H, CH2); 1.94-2.0 (m, 2H, CH2); 1.6
(d, 3H, J ) 7 Hz, CH3). HRMS (C24H28N4O2) [M + H]+: found
m/z, 405.2291; calcd, 405.2302. Anal. (C24H28N4O2) C, H, N.
8-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-4H-benzo-
[1,4]oxazin-(S)-2-methyl-3-one (45b). Compound 45b was
obtained from 44b and 9c via method B in a yield of 60%; [R]d
+27 (MeOH). 1H NMR (400 MHz, CDCl3): δ 7.9-8.0 (bs, 2H,
2 × NH); 7.62 (d, 1H, J ) 8 Hz, H-arom); 7.36 (d, 1H, J ) 8
Hz, H-arom); 7.1-7.2 (m, 2H, H-arom); 7.0 (d, 1H, J ) 2 Hz,
H2-indole); 6.9 (t, 1H, J ) 7 Hz, H-arom); 6.64 (dd, 1H, J ) 2
Hz, J ) 8 Hz, H-arom); 6.44 (dd, 1H, J ) 2 Hz, J ) 8 Hz,
H-arom); 4.64 (q, 1H, J ) 7 Hz, CH); 3.1-3.2 (m, 4H,
H-piperazine); 2.8 (t, 2H, J ) 7 Hz, CH2); 2.65 (m, 4H,
H-piperazine); 2.5 (m, 2H, CH2); 1.94-2.0 (m, 2H, CH2); 1.6
(d, 3H, J ) 7 Hz, CH3). HRMS (C24H29N4O2) [M + H]+: found
m/z, 405.2330; calcd, 405.2291. Anal. (C24H28N4O2) C, H, N.
8-{4-[3-(5-Fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-
4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c). Compound
45c was obtained from 44a and 9g via method B in a yield of
58%; [R]d -24 (MeOH). 1H NMR (400 MHz, CDCl3): δ 8.5, 8.0
(2 × bs, 2H, 2 × NH); 7.22-7.28 (m, 2H, H-arom); 7.04 (d,
1H, J ) 1.5 Hz, H2-indole); 6.84-6.96 (m, 2H, H-arom); 6.64
(dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.44 (dd, 1H, J ) 2 Hz,
J ) 8 Hz, H-arom); 4.64 (q, 1H, J ) 7 Hz, CH); 3.1-3.2 (m,
4H, H-piperazine); 2.8 (t, 2H, J ) 7 Hz, CH2); 2.65 (m, 4H,
H-piperazine); 2.5 (m, 2H, CH2); 1.94-2.0 (m, 2H, CH2); 1.6
(d, 3H, J ) 7 Hz, CH3). HRMS (C24H27FN4O2) [M + H]+: found
m/z, 423.2211; calcd, 423.2196. Anal. (C24H27FN4O2) C, H, N.
8-{4-[3-(5-Fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-
4H-benzo[1,4]oxazin-(S)-2-methyl-3-one (45d). Compound
45d was obtained from 44b and 9g via method B in a yield of
1
56%; [R]d +24 (MeOH). H NMR (400 MHz, CDCl3): δ 7.96,
7.9 (2 × bs, 2H, 2 × NH); 7.22-7.28 (m, 2H, H-arom); 7.04 (d,
1H, J ) 1.5 Hz, H2-indole); 6.84-6.96 (m, 2H, H-arom); 6.64
(dd, 1H, J ) 2 Hz, J ) 8 Hz, H-arom); 6.44 (dd, 1H, J ) 2 Hz,
J ) 8 Hz, H-arom); 4.64 (q, 1H, J ) 7 Hz, CH); 3.1-3.2 (m,
4H, H-piperazine); 2.76 (t, 2H, J ) 7 Hz, CH2); 2.65 (m, 4H,
H-piperazine); 2.5 (m, 2H, CH2); 1.94-2.0 (m, 2H, CH2); 1.62
(d, 3H, J ) 7 Hz, CH3). HRMS (C24H28FN4O2) [M + H]+: found
m/z, 423.2184; calcd, 423.2196. Anal. (C24H27FN4O2) C, H, N.
8-{4-[3-(7-Fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-
4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45e). Compound
45e was obtained from 44a and 9i via method B in a yield of
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78%; [R]d -25 (MeOH). H NMR (400 MHz, CDCl3): δ 8.18,
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JM050148Z