Serotonin 5-HT2 receptor, dopamine D2 receptor, and α1 adrenoceptor antagonists. Conformationally flexible analogues of the atypical antipsychotic sertindole

Article abstract of DOI:10.1021/jm960159f

Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-4- piperidinyl]ethyl]-2-imidazolidinone) were synthesized. Replacement of the 4- piperidinyl ring in sertindole by a 2-(methy

Full text of DOI:10.1021/jm960159f

J . Med. Chem. 1996, 39, 3723-3738
3723
Ser oton in 5-HT2 Recep tor , Dop a m in e D2 Recep tor , a n d r1 Ad r en ocep tor
An ta gon ists. Con for m a tion a lly F lexible An a logu es of th e Atyp ica l
An tip sych otic Ser tin d ole
Kim Andersen,*,† Tommy Liljefors,‡ J ohn Hyttel,† and J ens Perregaard†
Research Departments, H. Lundbeck A/ S, Ottiliavej 9, DK-2500 Copenhagen, Denmark, and Department of Medicinal
Chemistry, Royal Danish School of Pharmacy Universitetsparken, DK-2100 Copenhagen Ø, Denmark
Received February 26, 1996X
Conformationally flexible analogues of the atypical antipsychotic sertindole (1-[2-[4-[5-chloro-
1-(4-fluorophenyl)-1H-indol-3-yl]-4-piperidinyl]ethyl]-2-imidazolidinone) were synthesized. Re-
placement of the 4-piperidinyl ring in sertindole by a 2-(methylamino)ethoxy group or a
2-(methylamino)ethyl group (e.g. 1-[2-[2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yloxy]ethyl-
methylamino]ethyl]-2-imidazolidinone and 1-[3-[[2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-
ethyl]methylamino]propyl]-2-imidazolidinone results in binding affinities for serotonin 5-HT2A
and dopamine D2 receptors, as well as R1 adrenoceptors, which are very similar to those of
sertindole. (Methylamino)alkyl groups of other chain lengths, 3-(methylamino)propyloxy groups,
and 2-(methylamino)ethylsulfanyl groups do not have such properties. The capability of the
2-(methylamino)ethoxy group and the 2-(methylamino)ethyl group to replace the 4-piperidinyl
ring in sertindole is reflected in molecular modeling studies using recently published receptor-
interaction models for 5-HT2 and D2 receptors. Structure-affinity investigations concerning
the substituents in the indole nucleus and the 2-imidazolidinone ring system in the 2-(meth-
ylamino)ethoxy and the 2-(methylamino)ethyl analogues of sertindole have led to high affinity
serotonin 5-HT2A receptor antagonists with selectivity versus dopamine D2 receptors and R1
adrenoceptors (e.g. 1-[2-[[2-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yloxy]ethyl]methylamino]-
ethyl]-2-imidazolidinone and 1-[3-[[2-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]ethyl]meth-
ylamino]propyl]-2-imidazolidinone). The latter derivative has also high selectivity for 5-HT2A
receptors versus serotonin 5-HT2C receptors. Replacement of the basic amino group by nitrogen-
containing six-membered rings has led to 5-chloro-1-(4-fluorophenyl)-3-[(4-methylpiperazinyl)-
ethoxy]-1H-indole, which has high affinity for dopamine D2, versus low affinity for serotonin
5-HT2A receptors and R1 adrenoceptors.
Ch a r t 1
In tr od u ction
The development of a new series of 3-substituted 1-(4-
fluorophenyl)-1H-indoles as potent, centrally acting
dopamine D2 and serotonin 5-HT2 receptor antagonists
has been reported recently.1 Sertindole (1a , Chart 1)
is a member of this class of compounds. In several
double blind clinical studies sertindole has shown an-
tipsychotic effects comparable to those of the classical
antipsychotic haloperidol without inducing extrapyra-
midal side effects, indicating that sertindole is an
atypical antipsychotic.2 The atypical profile of sertin-
dole is reflected in its pharmacological profile since it
selectively blocks dopaminergic activity in the limbic
brain areas in rats after chronic treatment.3,4 In vitro
sertindole has high affinity for serotonin 5-HT2A and
5-HT2C receptors, dopamine D2 receptors, and R1 adreno-
ceptors. In vivo the acute central antidopaminergic and
peripheral antiadrenergic effects of sertindole are very
weak compared to its very potent and long-lasting
antiserotonergic effects.5
the indole nucleus have led to indoles with high selec-
tivity for serotonin 5-HT2 receptors versus dopamine D2
receptors and R1 adrenoceptors (e.g. Lu 26-042 (1b) and
Lu 29-066 (2), Chart 1).6,7 The pharmacological effects
of these compounds have recently been described in
animal models predictive of antipsychotic effects and
extrapyramidal side effects.8
We have recently described the development of a
receptor-interaction model for serotonin 5-HT2A receptor
antagonists by conformational analysis using molecular
mechanics (MM2(91)) and superimposition studies of
serotonin 5-HT2A receptor antagonists (Figure 3).9 Com-
parison of this model with the receptor-interaction
model for dopamine D2 receptor antagonists developed
by Liljefors and Bøgesø10 suggests a common pharma-
Extensive structure-activity investigations within
the series of 1-(4-fluorophenyl)indoles concerning varia-
tions of the substituents in the indole nucleus, changes
of the N-substituent in the 4-piperidinyl group, and
interchange of the C-3 atom and the nitrogen atom in
† H. Lundbeck A/S.
‡ Royal Danish School of Pharmacy.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
S0022-2623(96)00159-8 CCC: $12.00 © 1996 American Chemical Society

3724 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Andersen et al.
Ta ble 1. Receptor Binding Affinitites for Reference
Compounds
Ch a r t 2
receptor binding:a IC50 (nM)
serotonin 5-HT2A dopamine D2 adrenergic R1
compd
[3H]ketanserin [3H]spiperone [3H]prazosin
sertindole (1a )
Lu 26-042 (1b)
ritanserin
0.39
1.5
0.40
4.1
130
12
0.48
3.4
70
47
nemonapride
49
540
a
The IC50 values are the logarithmic mean of at least two
determinations. Two full concentration curves were measured
using five concentrations of test drug in triplicate (covering three
decades). SD-ratios were obtained by calculating the variance of
repeated measures of ratios between the first and second IC50
determination for a series of 100 drugs. In cases of ratios greater
than 3 × SD (99% confidence interval) extra determinations were
performed and outliers were discarted. The following 95% confi-
dence ratios (2 × SD-ratio) were calculated: 5-HT2A 2.05; D2 2.25;
R1 2.20.
dehyde 4 was prepared by Vilsmeier formylation16-18
of the corresponding 3-unsubstituted indole.1 Alkyla-
tion of [(methylamino)methyl]indole 5b with 1-(2-chlo-
roethyl)- and 1-(4-chlorobutyl)-2-imidazolidinone af-
forded 5c and 5d , respectively.
Reaction of indoles 6 with oxalyl chloride and subse-
quent reaction of the intermediate carboxylic acid
chloride with N-benzylmethylamine afforded the corre-
sponding amides 7.19 Reduction of the amides with
lithium aluminum hydride19 followed by arylation with
4-fluoroiodobenzene under Ullmann conditions afforded
the 2-(benzylmethylamino)ethyl derivatives 9a and
10a .20 Treatment of derivatives 9a and 10a with meth-
yl chloroformate and subsequent hydrolysis of the inter-
mediate carbamates afforded the corresponding 2-(meth-
ylamino)ethyl derivatives 9c and 10c, respectively.
Reduction of the intermediate carbamates with lithium
aluminum hydride afforded dimethylamino derivatives
9b and 10b. The (monomethylamino)ethyl derivatives
9c and 10c were converted to the corresponding tertiary
amines 9d ,e and 10d ,e by alkylation with substituted
2-chloroethyl- or 3-chloropropyl-2-imidazolidinones as
described above for the syntheses of 5c,d .
The substituted 3-(1H-indol-3-yl)propylamines 14 and
4-(1H-indol-3-yl)butylamines 15 were prepared from the
corresponding carboxylic acids 12a and 12b, respec-
tively, by a straightforward procedure. Lithium alu-
minum hydride reduction of 12a and 12b afforded the
corresponding alcohols 13a and 13b, respectively, which
were subsequently converted to the corresponding me-
sylates by standard procedures. The mesylates were
reacted with appropriate secondary amines resulting in
substituted 3-(1H-indol-3-yl)propylamines 14 and the
4-(1H-indol-3-yl)butylamine 15. The secondary amines
used as reactants were commercially available or were
prepared by standard procedures as described in the
Experimental Section. Structures of the secondary
amines and the amino groups in 14 and 15 are shown
in Table 2.
The carboxylic acids 12a and 12b used as starting
material for the preparation of 14 and 15, respectively,
were prepared by copper-catalyzed Ullmann arylation20
with 4-fluoroiodobenzene of 3-(5-chloro-1H-indol-3-yl)-
propanoic acid (11a ) and 4-(5-chloro-1H-indol-3-yl)-
butanoic acid (11b), respectively, which were prepared
as follows. Ethyl 3-[5-chloro-2-(ethoxycarbonyl)-3-in-
dolyl]propanoate and ethyl 4-[5-chloro-2-(ethoxycarbo-
nyl)-3-indolyl]butanoate were prepared according to
literature procedures.21-24 The diesters were hydro-
lyzed and subsequently decarboxylated to give the
desired 3-(5-chloro-1H-indol-3-yl)propanoic acid (11a )
and 4-(5-chloro-1H-indol-3-yl)butanoic acid (11b), re-
spectively, using standard reaction conditions.25
The 5-chloro- and 6-chloro-1-(4-fluorophenyl)-1H-in-
doles (22, 23) with (2-aminoethyl)sulfanyl (24) and (3-
cophore for serotonin 5-HT2A and dopamine D2 receptor
antagonists. Antagonists with high selectivity for se-
rotonin 5-HT2A receptors versus dopamine D2 receptors
differ from unselective serotonin 5-HT2A receptor an-
tagonists by having sterical interactions with “forbid-
den” areas at the dopamine D2 receptors.9 Ismaiel et
al. have recently discussed this model for analogues of
the serotonin 5-HT2A antagonists ketanserin and MDL
11,939.11
Structural comparisons of sertindole (1a ) with tricy-
clic compounds having high affinity for serotonin 5-HT2A
and dopamine D2 receptors (e.g. octoclothepine9,12 see
Chart 2) have previously been described using the
receptor-interaction models described above.9 These
comparisons indicate that the 1-(4-fluorophenyl)-1H-
indole part and the 4-piperidinyl group of sertindole (1a )
interacts with similar regions of space as do the tricyclic
part and the piperazinyl group, respectively, in octo-
clothepine. Within the series of tricyclic compounds the
piperazinyl group has been replaced by conformationally
flexible groups, such as the 2-aminoethoxy group in
zotepine (see Chart 2).13,14 These structural character-
istics prompted us to study structure-activity relation-
ships for analogues of sertindole (1a ) in which the
4-piperidinyl ring is replaced by conformationally flex-
ible groups. In the present paper we describe synthesis
and structure-activity relationships within series of
5-chloro- and 6-chloro-substituted 1-(4-fluorophenyl)-
1H-indoles substituted in the 3-position with ami-
noalkyl, aminoalkoxy, and (aminoalkyl)sulfanyl groups
of varying chain lengths. The structure-activity rela-
tionships are discussed in relation to the recently
published receptor-interaction models for dopamine D2
and serotonin 5-HT2 receptor antagonists.
Ch em istr y
The 5-chloro- and 6-chloro-1-(4-fluorophenyl)-1H-
indoles with aminomethyl (5), 2-aminoethyl (9 and
10), 3-aminopropyl (14), and 4-aminobutyl (15) substit-
uents in the 3-position were prepared as outlined in
Scheme 1.
The [(dimethylamino)methyl]- and [(methylamino)-
methyl]indoles 5a and 5b were prepared by reductive
amination of 5-chloro-1-(4-fluorophenyl)-1H-indol-3-car-
baldehyde (4) using dimethylamine and methylamine,
respectively, in the presence of sodium cyanoborohy-
dride under standard conditions.15 The 3-indolecarbal-

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3725
Sch em e 1a
a
Reaction conditions: (a) DMF, POCl3; (b) H2NR1R2Cl, NaCNBH3, 5 Å molecular sieves; (c) (i) (COCl)2; (ii) HNCH3Bzl; (d) LiAlH4; (e)
4-F-PhI, CuI, K2CO3; (f) (i) MsCl; (ii) HNR1R2, N(CH2CH3)3; (g) ClR2, K2CO3, KI; (h) (i) ClCO2CH3; (ii) HBr, H2O; (i) (i) ClCO2CH3; (ii)
LiAlH4.
aminopropyl)oxy (25) substituents in the 3-position were
prepared as outlined in Scheme 2.
introduce the 4-fluorophenyl group in 2-(5-chloro-1H-
indol-3-ylsulfanyl)acetic acid, as described above for the
synthesis of 12a and 12b. Since the starting material
used for this procedure (e.g. 5-chloroindole) is very
expensive, we decided to develop a more convenient
synthesis for compound 18. As recently described by
Perregaard et al. reaction of 1-methylpiperazine with
3-indolinones, generated in situ, affords the correspond-
ing 3-(4-methylpiperazinyl)indoles.1 The reaction mech-
anism for this reaction is probably the formation of an
intermediate hemiaminal, which is converted to the
resulting product by elimination of water. In analogy,
it would be expected that the reaction of 3-indolinones
with alcohols and thiols results in formation of hemi-
acetals and hemimercaptals, respectively, which simi-
larly eliminate water in the formation of 3-alkoxy- and
3-alkylsulfanyl indoles. Reaction of 5-chloro-2,3-dihy-
dro-1-(4-fluorophenyl)-1H-indol-3-one (27) with 2-mer-
captoacetic acid afforded 2-[5-chloro-1-(4-fluorophenyl)-
1H-indol-3-ylsulfanyl]acetic acid (18). The reaction was
performed by heating the reactants at reflux in toluene
using a Dean-Stark apparatus with p-toluenesulfonic
acid as a catalyst, which are standard conditions for the
formation of acetals.31 This convenient procedure for
the conversion of 3-indolinones to the corresponding
3-(alkylsulfanyl)indoles and to 3-alkoxyindoles, as de-
scribed below, has to our knowledge not been described
previously. The 5-chloro-2,3-dihydro-1-(4-fluorophenyl)-
1H-indol-3-one (27) used as starting material for these
procedures was prepared by deprotection of 3-acetoxy-
5-chloro-1-(4-fluorophenyl)indole (26) by heating in an
The 1-(4-fluorophenyl)-1H-indoles substituted in the
3-position with 2-aminoethoxy and (2-aminoethyl)sul-
fanyl groups 22, 23, and 24 were prepared from the
corresponding carboxylic acids 17a , 17b, and 18, re-
spectively, by a procedure similar to that described
above for the preparation of 14 and 15. Structures of
the amino groups in 22, 23, and 24 are shown in Table
3. The preparation of carboxylic acids 17a , 17b, and
18 are described in the following.
5-Chloro- and 6-chloro-substituted 2-[1-(4-fluorophen-
yl)-1H-indol-3-yloxy]acetic acids (17) were prepared in
a two-step procedure from corresponding methyl 1-(4-
flu or oph en yl)-3-h ydr oxy-1H -in dole-2-ca r boxyla t es
(16), which were prepared as described in the litera-
ture.26,27 Alkylation of substituted methyl 1-(4-fluo-
rophenyl)-3-hydroxy-1H-indole-2-carboxylates (16) with
methyl bromoacetate gave the corresponding meth-
yl
2-[1-(4-fluorophenyl)-2-(methoxycarbonyl)-1H-in-
dol-3-yloxy]acetates.26 These diesters were hydrolyzed
and subsequently decarboxylated to give the corre-
sponding 2-[1-(4-fluorophenyl)-1H-indol-3-yloxy]acetic
acids (17).
The preparation of 2-(1H-indol-3-ylsulfanyl)acetic
acids and acetonitriles from 1H-indol-3-thiol is described
in the literature28,29 and 1-unsubstituted 1H-indol-3-
thiols are easily prepared from corresponding indoles
according to literature.30 Consequently, a possible
procedure for the preparation of 2-[5-chloro-1-(4-fluo-
rophenyl)-1H-indol-3-ylsulfanyl]acetic acid (18) is to

3726 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Andersen et al.
Ta ble 2. Substituents and Receptor Binding Affinitites for 1-(4-Fluorophenyl)indoles 5, 9, 10, 14, and 15
a
b
See footnote a in Table 1. Refer to substituents in structures in Scheme 1.
aqueous solution of sodium sulfite, according to the
procedure described by Nenizescu et al.32 By this
procedure the product was precipitated directly from the
reaction mixture, which is important to avoid oxidative
dimerization of the product to indigo type compounds.33
3-Acetoxy-5-chloro-1-(4-fluorophenyl)indole (26) was pre-
pared as previously described.1
The N,N-dimethyl-3-aminopropyloxy-substituted com-
pound (25) was prepared from the corresponding alcohol
21 by conversion to the corresponding mesylate and
subsequent reaction with dimethylamine. The alcohol
21 was prepared by reaction of the 3-indolone 27 with
1,3-propanediol in the presence of p-toluenesulfonic acid
as a catalyst.
fanyl groups (compounds 5a , 9b, 14a , 22a , and 24a ,
respectively, Figure 1). The dimethylamino-substituted
compounds were selected as representatives for the
corresponding compounds containing amino groups
NR1R2 according to Tables 2 and 3.
The structures of the compounds selected are shown
in Figure 1 and the flexible bonds of relevance for the
present study are described by indication of the corre-
sponding dihedral angles A (a-b-c-d), B (b-c-d-e),
C (c-d-e-f), D (d-e-f-g), and H (h-i-j-k). Since
the 3-substituent in the compounds included in the
present study is highly flexible, a full conformational
analysis by independent driving of all flexible bonds is
extremely time consuming. Consequently, the confor-
mational analyses were performed on the basis of the
following assumptions.
Molecu la r Mod elin g Stu d ies
To rationalize the binding affinities obtained for the
compounds prepared, molecular modeling studies of
selected compounds were performed. The studies were
performed on 5-chloro-1-(4-fluorophenyl)-1H-indoles sub-
stituted in the 3-position with (dimethylamino)methyl,
2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 2-(di-
methylamino)ethoxy, and 2-(dimethylamino)ethylsul-
The internal rotations about the bond connecting the
4-fluorophenyl group to the indole nucleus and about
the bonds in the 3-substituent are treated indepen-
dently. It seems appropriate to assume that the two
groups do not interact during the internal rotations
because of the large interatomic distance between the
two groups. Rotation about the bond connecting the

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3727
Sch em e 2a
a
Reaction conditions: (a) (i) BrCH2CO2CH3, K2CO3; (ii) KOH, H2O; (iii) Cu, NMP; (b) LiAlH4; (c) (i) MsCl; (ii) HNR1R2, N(CH2CH3)3;
(d) Na2SO3, CH3CH2OH, H2O; (e) HSCH2CO2H, p-TSA; (f) HOCH2CH2CH2OH, p-TSA.
4-fluorophenyl group to the indole nucleus results in two
minimum energy conformations, as recently reported for
corresponding 3-piperidinyl indoles (e.g. 1a ) correspond-
ing to values of angle H of (22°.9
corresponding to one of the two symmetrical global
minimum energy conformations of the 4-fluorophenyl
group relative to the indole nucleus described above.
Since some of the input structures are mirror images,
the resulting 135 input structures could be reduced to
68. The structures were minimized with full energy
minimization except for the dihedral angles A, B, C, and
D. The partially minimized structures were subse-
quently minimized with full energy minimization with-
out any conformational restrictions. Geometries of
global minimum energy conformations thus obtained
are described in Table 5. Compounds 14a and 24a have
global minimum energy conformations with the 3-sub-
stituent in coiled conformations. In these conformations
the dimethylamino group has strong attractive van der
Waals interactions with the indole ring system. For
these compounds the uncoiled conformer with lowest
conformational energy is included in the table.
For minimum energy conformations of the compounds
included in the present study it seems appropriate that
the 3-substituent has a conformation close to a stag-
gered conformation. Eclipsed conformations have cal-
culated conformational energies of 2.7-10.0 kcal/mol.
In order to study the conformational flexibility of the
bond b-c (Figure 1) in the selected compounds sepa-
rately, conformational analyses were performed on
3-ethyl-, 3-methoxy-, and 3-(methylsulfanyl)-5-chloro-
1-(4-fluorophenyl)-1H-indoles 28a , 28b, and 28c, re-
spectively. The structures of these compounds, defini-
tions of dihedral angles for flexible bonds, and confor-
mational energy curves for the internal rotations about
the bond b-c are shown in Figure 2. The calculations
show that bond b-c is highly flexible for the compounds
28a and 28c, which have conformational energies lower
than 2 kcal/mol for values of angle A (a-b-c-d) in the
interval from 45° to 180°. In contrast, the conforma-
tional energy curve for 28b is very steep near the global
minimum energy conformation. The global minimum
energy conformation for 28b was found for a value of
angle A at 180°.
The conformational analyses of compounds included
in the present study were performed by generating
input structures with values of dihedral angles A, B,
C, and D in all combinations of the following values. In
order to search for minimum energy conformations in
the interval from 45° to 315° the following input values
for angle A were used: (60°, (120°, and 180°. The
interval from 45° to 315° includes all low energy regions
in Figure 2. In order to generate all possible staggered
conformations of the 3-substituent the following values
for angles B, C, and D were used: (60° and 180°. For
all input structures the value of angle H was 22°
On the basis of conformational analyses and struc-
tural comparisons of sertindole (1a ) and related indole
derivatives an active conformation for sertindole (1a )
has been suggested.9 In this study the 2-(2-oxoimida-
zolidin-1-yl)ethyl group was replaced by a methyl group
for simplicity.9 In Figure 3 the suggested active con-
formation at the dopamine D2 and serotonin 5-HT2A
receptors for the N-methyl analogue (1a ′) of sertindole
(1a ) is superimposed on three points A, B, and C,
representing the recently reported receptor-interaction
model for serotonin 5-HT2A receptor antagonists.9 The
three fitting points are the centers of the benzene part
of the indole nucleus (A) and the 4-fluorophenyl group
(B) and a point 2.8 Å from the basic nitrogen atom in
the direction of the lone pair (C). The point C is
assumed to simulate a receptor site hydrogen bonding
with the nitrogen atom. The distances between the
three fitting points in the suggested active conformation
for 1a ′ are calculated to be 5.3, 7.7, and 8.0 Å for
distances AB, AC, and BC, respectively. To rationalize

3728 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Andersen et al.
Ta ble 3. Substituents and Receptor Binding Affinitites for 1-(4-Fluorophenyl)indoles 22-25
a
b
See footnote a in Table 1. Refer to substituents in structures in Scheme 2.
F igu r e 1. Structures of compounds included in the molecular modeling studies. Flexible bonds are described by indication of
corresponding dihedral angles A (a-b-c-d), B (b-c-d-e), C (c-d-e-f), D (d-e-f-g), and H (h-i-j-k).
the receptor binding affinities for dopamine D2 and
serotonin 5-HT2A receptors obtained for the compounds
prepared in the present study, these distances are
determined for low energy conformers of these com-
pounds.
Since the conformation of the 4-fluorophenyl group
relative to the indole nucleus is unaffected by the
replacement of the 4-piperidinyl ring with the ring-
opened side chains, the distance AB in the low energy
conformers of the compounds included in the present
study are similar to that of sertindole (1a ). To study
the variation of the distances AC and BC among the
low energy conformers obtained in the conformational
search procedure described above, these distances were
determined for conformers with conformational energies
lower than 2.0 kcal/mol. Conformers having distances
AC and BC in the intervals 6.7-8.7 and 7.0-9.0 Å,
respectively, were superimposed on the suggested re-
ceptor active conformation of sertindole (1a ′). In Fig-
ures 4-7 are shown selected least-squares superimpo-

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3729
F igu r e 2. Definition of dihedral angle A (a-b-c-d) in 3-ethyl-, 3-methoxy-, and 3-(methylsulfanyl)-5-chloro-3-(4-fluorophenyl)-
1H-indoles 28a -c and calculated conformational energy curves for internal rotation about bond b-c.
The substituted 3-(1H-indol-3-yl)propylamine 14b
(Table 2, Scheme 1) is structurally identical to sertindole
(1a ) except that the 4-piperidinyl ring is replaced by a
3-(methylamino)propyl group. This replacement results
in reduced receptor binding affinities for both dopamine
D2 receptors, serotonin 5-HT2A receptors, and R1 adreno-
ceptors by factors of 10 to 50. Replacement of the
methylene group adjacent to the indole nucleus in 14b
by a sulfur or an oxygen atom has pronounced effects
on the receptor binding affinities. The former re-
placement (24b) results in reduced affinities for the
three receptors by a factor of about 200, compared to
sertindole (1a ), whereas the latter replacement (22b)
results in receptor binding affinities, which are not
significantly different from those of sertindole (1a )
(Table 3, Scheme 2).
These results are consistent with the molecular
modeling studies performed for the N,N-dimethyl ana-
F igu r e 3. Superimposition of the suggested active confor-
logues 14a , 22a , and 24a of 14b, 22b, and 24b,
mation of the N-methyl analogue 1a ′ of sertindole (1a ) on
respectively. Low RMS-values are obtained by super-
three points (A, B, and C) representing the recently pub-
imposition of selected low energy conformers of the three
lished receptor-interaction model for 5-HT2 receptor antago-
nists.9
compounds on the suggested active conformation of the
N-methyl analogue 1a ′ of sertindole (1a ), indicating that
the spatial relationships of the primary pharmacophore
elements for these conformers are highly similar to that
of 1a ′. In the superimposition of 22a on the N-methyl
analogue 1a ′ of sertindole (1a ) in Figure 5, the 2-(di-
methylamino)ethoxy side chain occupies the same re-
gion of space as the right part of the 4-piperidinyl ring
in 1a ′ suggesting this conformation as the receptor
active conformation for 22a at the dopamine D2 and
serotonin 5-HT2 receptors. In superimpositions of low
energy conformers of 14a and 24a the 3-(dimethylami-
no)propyl and 2-(dimethylamino)ethylsulfanyl side chains
occupy regions of space, which are not occupied by the
4-piperidinyl ring in 1a ′ (Figures 4 and 6). This extra
volume may lead to steric repulsive interactions with
the receptors, and the lower receptor binding affinities
obtained for these compounds may be due to such
repulsive interactions. Conformers of 14a and 22a , in
which the 3-substituent has a conformation similar to
that of the suggested active conformation of 24a , have
conformational energies higher than 3.0 kcal/mol. This
indicates that it is unlikely that these conformers are
receptor active conformations of these compounds.
sitions of the molecules included in the study. Low
RMS-values indicate that the relative spatial relation-
ship of the benzene part of the indole nucleus, the
4-fluorophenyl group and the point, which is assumed
to simulate a receptor site hydrogen bonding with the
nitrogen atom for these conformers, are highly similar
to that of the suggested active conformation for 1a ′.
Resu lts a n d Discu ssion
The pharmacological test models have been described
previously and are described in the Experimental Sec-
tion referring to relevant references. Receptor binding
affinities (serotonin 5-HT2A, dopamine D2, and adren-
ergic R1) for reference compounds and compounds
prepared in the present study are reported in Tables
1-3. In Table 1 reference compounds are included for
comparison. The atypical antipsychotic sertindole (1a ,
Chart 1) and the 5-HT2 antagonist Lu 26-042 (1b, Chart
1) are members of the previously described series of 1-(4-
fluorophenyl)-3-(4-piperidinyl)indoles.1,6 Ritanserin was
the first centrally acting 5-HT2 antagonist identified
with considerable selectivity compared to non-5-HT
receptors,34 and nemonapride is a centrally acting,
selective dopamine D2 antagonist in respect to non-
dopamine receptors.35,36
Since the 2-(methylamino)ethoxy group seems to be
an excellent replacement group for the 4-piperidinyl ring
in 1a , further structure-affinity investigations were

3730 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Andersen et al.
F igu r e 4. Least-squares superimpositions on the N-methyl analog of sertindole 1a ′ (blue) of all conformations of 14a having
RMS values lower than 0.4 Å and conformational energy lower than 2 kcal/mol. Characteristics of the three conformers used are
as follows (angle A, angle B, angle C, angle D, conformational energy, RMS value): red (-71°, -61°, 177°, 178°, 1.8 kcal/mol, 0.1
Å), yellow (175°, -179°, -172°, 58°, 1.2 kcal/mol, 0.3 Å), and green (112°, -179°, -170°, 59°, 1.2 kcal/mol, 0.2 Å). Hydrogen atoms
are omitted for clarity.
F igu r e 5. Least-squares superimposition of the suggested active conformation of 22a on the N-methyl analog of sertindole 1a ′
(blue). The conformer of 22a used has conformational energy of 0.6 kcal/mol and the values angles A, B, C, and D are -166°,
180°, -85°, and -59°, respectively. The RMS-value obtained is 0.3 Å. Hydrogen atoms are omitted for clarity.
F igu r e 6. Least-squares superimpositions on the N-methyl analog of sertindole 1a ′ (blue) of all conformations of 24a having
RMS values lower than 0.4 Å and conformational energy lower than 2 kcal/mol. Characteristics of the two conformers of 24a used
are as follows (angle A, angle B, angle C, angle D, conformational energy, RMS value): yellow (176°, -179°, -172°, 58°, 1.5
kcal/mol, 0.3 Å) and red (117°, -178°, -173°, 57°, 1.6 kcal/mol, 0.3 Å). Hydrogen atoms are omitted for clarity.
performed on indoles substituted by this group. Re-
placement of the N-methyl group in 22b by other small
alkyl groups, such as ethyl and propargyl (22c and 22d ),
results in reduced affinity for the three receptors
studied. The N,N-dimethyl analogue (22a ) of 22b has
slightly increased affinity for dopamine D2 receptors
whereas the affinities for serotonin 5-HT2A receptors
and R1 adrenoceptors are slightly reduced. It has
previously been shown that corresponding replacement
of the 2-(2-oxoimidazolidin-1-yl)ethyl substituent by a
methyl group in analogues of sertindole (1a ) only
slightly influences the affinity for 5-HT2 and D2 recep-
tors, whereas the in vivo activity is highly influenced.1
For compounds 22e-g the N,N-dimethylamino group
in 22a is replaced by nitrogen containing six-membered
rings such as 1-piperidinyl (22e), 4-morpholinyl (22f),
and 4-methyl-1-piperazinyl (22g) rings, respectively
(Table 3). In 22e the receptor binding affinities are not
significantly different from those of the N,N-dimethyl-
amino compound 22a , suggesting that lipophilic groups
in the areas defined by the piperidinyl ring are well
accommodated by the receptors studied. The 4-mor-
pholinyl compound 22f has reduced affinity for serotonin
5-HT2A and dopamine D2 receptors and R1 adrenoceptors
by factors of 6-10, compared to compound 22a . Within
series of dopamine D2 receptor agonists it has been
shown that â-oxygen atoms reduce the base strength of
amino groups by about 1.5 pKA units and that the effect
is additive.37 It seems that the basic amino group
interacts with a carboxylic acid group at the receptors
and that this interaction is essential in order to obtain
receptor binding. A sufficiently high base strength of

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3731
F igu r e 7. Least-squares superimpositions of the suggested active conformation of 9b on the N-methyl analog of sertindole 1a ′
(blue). The conformer of 9b in red has conformational energy of 0.4 kcal/mol and the values of angles A, B, and C are 95°, 170°,
and -57°, respectively. The RMS-values obtained for the superimpositions is 0.2 Å. Hydrogen atoms are omitted for clarity.
the amino group is probably necessary for obtaining this
interaction. Possibly the reduced receptor binding
affinities obtained for 22f can be explained by reduced
base strength of the amino group as a consequence of
the two â-oxygen atoms present in this compound.
For the 2-(4-methyl-1-piperazinyl)ethoxy-substituted
derivative 22g the affinity for D2 receptors is un-
changed, whereas the affinities for serotonin 5-HT2A
receptors and R1 adrenoceptors are reduced by factors
of 17 and 5, respectively, compared to the corresponding
1-piperidinyl derivative 22e. These major changes in
receptor binding affinity are the result of the introduc-
F igu r e 8. Superimposition of the suggested active conforma-
tion of 5a on fitting points as for the other superimpositions
on the N-methyl analogue of sertindole (1a ′) (blue) except that
point C is replaced by the carboxylate oxygen atom in the
tion of a further amino group into the molecule. The
compound obtained by these rather small structural
changes is structurally different from other high affinity
dopamine D2 receptor antagonists with high selectivity
group (red) that is assumed to simulate an aspartate residue
versus serotonin 5-HT2A receptors and R1 adrenoceptors,
e.g. the benzamides. The affinity and selectivity for
dopamine D2 receptors are comparable to those of
nemonapride (Table 1).
at the receptor. In the superimposition of 5a angle C-C-C-O
in the aspartate residue-simulating group has a value of
-150°. An optimal interaction between the basic nitrogen atom
in 1a ′ and the aspartate group is obtained for a value of 120°.
The conformer of 5a has conformational energy of 0.6 kcal/
mol, and the values of angles A and B are 135° and 51°,
respectively. Hydrogen atoms are omitted for clarity.
To further explore structure-affinity relationships for
analogues of sertindole, in which the piperidinyl group
is ring-opened, the chain length of the (dimethylamino)-
alkyl substituent in the 3-position was varied from one
to four carbon atoms. Apparently the receptor binding
affinities for 5-HT2A, D2, and R1 receptors are indepen-
dent of the chain length from one to three carbon atoms
(5a , 9b, and 14a ). A chain length of four carbon atoms
(15) results in significantly reduced receptor binding
affinities. Accordingly, the receptor binding affinity is
significantly reduced for the 3-(dimethylamino)propoxy
derivative 25 having a chain length of four atoms
compared to that of the corresponding 2-(dimethylami-
no)ethoxy derivative 22a .
Replacement of one of the methyl groups in the
2-(dimethylamino)ethyl derivative 9b with (2-oxoimi-
dazolidin-1-yl)alkyl groups enhances the receptor bind-
ing affinities for the three receptors (9d and 9e), most
significantly for compound 9e with pronounced increase
in 5-HT2A receptor affinity. In the methylene (5c and
5d ) and propylene series (14b) similar replacements
result in unimproved binding affinities.
The capability of the 2-(dimethylamino)ethyl group
to replace the piperidinyl group in sertindole is reflected
in the molecular modeling studies. In Figure 7 is shown
superimposition of the suggested active conformation
of the 2-(dimethylamino)ethyl derivative 9b on the
suggested active conformation of the N-methyl analogue
of sertindole (1a ′). In the superimposition the 3-sub-
stituent interacts with similar regions of space as does
the piperidinyl group in sertindole.
Although the (dimethylamino)methyl derivative 5a
has affinity for the 5-HT2A and D2 receptors, none of its
low energy conformers can be fitted into the receptor-
interaction model. For this compound the distances
between the centers of either of the two benzene rings
(A and B) and the point C, which is assumed to simulate
a receptor site hydrogen bonding with the basic nitrogen
atom, are shorter than in the receptor-interaction model.
Similar problems have been discussed in relation to
other molecules with high affinity for 5-HT2A and D2
receptors such as ORG 522238 and dexclamol.10 To
further develop the model to accommodate molecules
with these geometrical features a carboxylate group is
included in the model (indicated in red in Figure 8).38
The carboxylate group is assumed to simulate the
aspartate residue at the receptor, which is believed to
interact with the basic amino groups in ligands binding
to the receptor.39,40 Recently a similar approach has
been descibed by ter Laak et al. for the development of
a receptor-interaction model for histamine H1 receptor
antagonists.41 In Figure 8 superimposition of the sug-
gested active conformation of the (dimethylamino)-
methyl derivative 5a using this extended receptor-
interaction model is shown. The fitting points used are
as above except that the point C is replaced by the
carboxylate oxygen atom. In the superimposition of 5a
angle C-C-C-O in the aspartate residue-simulating
group has a value of -150° compared to 120° for an

3732 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Ta ble 4. In Vivo Pharmacological Activity of Selected Compounds
Andersen et al.
inhibition of quipazine-induced head twitches:a ED50 (µmol/kg)
inhibition of pergolide-induced rotations:a
compd
10e
22b
22g
2 h (sc)
24 h (sc)
24 h (po)
ED50 (µmol/kg) 2 h (sc)
4.7 (1.2-18)
0.32 (0.12-0.86)
NT
0.63 (0.27-1.4)
0.035 (0.022-0.056)
0.11 (0.064-0.18)
0.10 (0.056-0.18)
NT
8.5 (1.4-53)
NTb
NT
NT
NT
>9.1
3.6 (2.1-6.1)
0.048 (0.019-0.12)
NT
NT
23b
NT
0.25 (0.071-088)
0.039 (0.020-0.078)
0.055(0.026-0.12)
NT
sertindole
Lu 26-042
ritanserin
nemonapride
0.030 (0.014-0.066)
0.052 (0.017-0.16)
0.98 (0.35-2.7)
NT
3.7 (1.5-8.9)
>17
>21
NT
0.0057 (0.0027-0.012)
a
b
95% Confidence limits are stated in brackets. NT: not tested.
optimal fit with the suggested active conformation of
the N-methyl analogue of sertindole (1a ′). Further
molecular investigations of other 5-HT2A and D2 receptor
antagonists are in progress to study the use of a
carboxylate group in the development of 3-D pharma-
cophores for serotonin 5-HT2A and dopamine D2 antago-
nists.
compared to its high affinity for 5-HT2A receptors, an
IC50 value of 150 nM in the 5-HT2C receptor binding
assay was obtained.
In Table 4 some important in vivo pharmacological
effects for selected compounds are reported. To deter-
mine the serotonin 5-HT2A antagonistic effects of the
compounds their ability to inhibit the quipazine-induced
(5-HT2 agonist) head twitch syndrome in rats was
determined.43 The antidopaminergic effects were re-
flected in their ability to inhibit pergolide-induced (D2
agonist) contralateral circling in rats with unilateral
6-OHDA lesions.44
For sertindole very potent and very long lasting
antiserotonergic effects in vivo have been reported. For
2-(dimethylamino)ethoxy derivative 22b, having a re-
ceptor-binding profile similar to that of sertindole (1a ),
the antiserotonergic effects are about ten times weaker
than for sertindole (1a ) and of a shorter duration
compared to sertindole. The antidopaminergic effects
in vivo are of similar potency as for sertindole. For the
selective 5-HT2A receptor antagonists 10e and 23b, long
lasting antiserotonergic effects are obtained in vivo. The
effects are about 10-100 times weaker than the effects
obtained for the previously reported selective serotonin
5-HT2 receptor antagonist Lu 26-042. The selective
dopamine D2 receptor antagonist 22g has potent anti-
dopaminergic effects in vivo.
The structure-affinity investigations described above
concerning variations of the 3-substituent in sertindole
(1a ) have led to the 2-aminoethyl derivative 9e and the
2-(dimethylamino)ethoxy derivative 22b having receptor
binding affinities for serotonin 5-HT2A and dopamine
D2 receptors, and for R1 adrenoceptors similar to those
of sertindole (1a ). For these two key derivatives the
structure-affinity relationships concerning changes of
the substituents in the indole nucleus and substituents
in the 2-imidazolidinone ring system were studied.
It has recently been shown that replacement of the
5-chloro substituent in sertindole (1a ) with a 6-chloro
substituent results in reduced affinity for dopamine D2
receptors, while the affinity for 5-HT2A receptors is
retained.6 Similar replacement in the 5-chloro-substi-
tuted 2-aminoethyl derivative 9e and the 2-(dimethyl-
amino)ethoxy derivative 22b result in reduced affinity
for dopamine D2 receptors by factors of 20 and 35,
respectively, whereas the affinity for serotonin 5-HT2
receptors is unaffected (10e and 23b). In addition, we
recently described that introduction of a 3-(2-propyl)
substituent in the imidazolidinone ring system reduces
the affinity for R1 adrenoceptors by a factor of 3-8,
whereas the affinities for dopamine D2 and serotonin
5-HT2A receptors are not influenced by this replace-
ment.6 Accordingly, introduction of a 3-(2-propyl) sub-
stituent in the imidazolidinone ring system in 10d and
23b reduces the affinity for R1 adrenoceptors by factors
of 29 and 15, respectively, resulting in derivatives 10f
and 23c, respectively. The derivatives 10e, 10f, 23b,
and 23c obtained by these structural changes have high
affinity for 5-HT2A receptors with a good selectivity
versus dopamine D2 receptors and R1 adrenoceptors.
Recently the atypical antipsychotic sertindole (1a ) and
the structurally related 5-HT2 antagonists Lu 26-042
(1b) and Lu 29-066 (2) have been reported to have equal
affinity for 5-HT2A and 5-HT2C receptors.8 In contrast,
the ring-opened analogues discussed in the present
paper have considerably lower affinity for 5-HT2C than
for 5-HT2A receptors (personal communication, Kristen
Frederiksen, H. Lundbeck A/S).42 For the 2-aminoethyl
derivative 9e and the 2-(dimethylamino)ethoxy deriva-
tive 22b, IC50 values of 31 nM and 14 nM, respectively,
were obtained for displacement of [3H]mesulergine from
rat 5-HT2C receptors. For the 2-aminoethyl derivative
10e, which has low affinity for D2 and R1 receptors
Con clu sion
Replacement of the 4-piperidinyl ring in sertindole
(1a ) by a 2-(methylamino)ethoxy group (22b) or a
2-(methylamino)ethyl group (9d and 9e) results in
binding affinities for serotonin 5-HT2A and dopamine
D2 receptors, as well as R1 adrenoceptors, which are very
similar to those of 1a , indicating that these groups are
excellent replacements for the 4-piperidinyl ring in
sertindole (1a ). (Methylamino)alkyl groups of other
chain lengths, 3-(methylamino)propyloxy groups, and
2-(methylamino)ethylsulfanyl groups do not have such
properties.
The capability of the 2-(methylamino)ethoxy group
(22b) and the 2-(methylamino)ethyl group (9d and 9e)
to replace the 4-piperidinyl ring in sertindole (1a ) is
reflected in molecular modeling studies using the re-
cently published receptor-interaction models for 5-HT2
and D2 receptors. Low energy conformers of 2-(methyl-
amino)ethoxy and 2-(methylamino)ethyl derivatives are
well accommodated into the model, and the 2-(methyl-
amino)ethoxy and 2-(methylamino)ethyl groups occupy
similar regions of space as do the piperidinyl group in
the suggested active conformation of sertindole (1a ).
Structure-affinity investigations concerning the sub-
stituents in the indole nucleus and the 2-imidazolidi-

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3733
5-Ch lor o-1-(4-flu or op h en yl)in d ole-3-ca r ba ld eh yd e (4).
Phosphorus oxychloride (12.5 g, 0.081 mol) was added to N,N-
dimethylformamide (29.5 g, 0.19 mol) at 0-5 °C. After stirring
for 10 min a solution of 5-chloro-1-(4-fluorophenyl)indole (3)
(20 g, 0.081 mol) in N,N-dimethylformamide (50 mL) was
added at 0-5 °C. The reaction mixture was stirred for 0.5 h
and subsequently poured into ice. The resulting mixture was
made alkaline with concentrated NaOH and after stirring for
1 h at room temperature the mixture was extracted with
diethyl ether (2 × 250 mL). The combined organic phases were
dried (Na2SO4), the solvents were evaporated, and the remain-
ing oil was purified by column chromatography on silica gel
(eluted with ethyl acetate/heptane 1:1) affording pure title
compound 20.1 g (90%), which crystallized from heptane: mp
152-154 °C; 1H NMR (CDCl3) δ 7.20-7.35 (m, 4 H), 7.50 (dd,
2 H), 7.85 (s, 1 H), 8. 35 (s, 1 H), 10.05 (s, 1 H). Anal. (C15H9-
ClFNO) C, H, N.
N,N-Dim eth yl-5-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-
ylm eth yla m in e Ma lea te (5a ). A mixture of 5-chloro-1-(4-
fluorophenyl)indole-3-carbaldehyde (4) (2.5 g, 0.0091 mol),
dimethylamine hydrochloride (1.5 g, 0.018 mol), 3 Å molecular
sieves (5 g), and methanol (50 mL) was stirred at room
temperature for 1 h. Sodium cyanoborohydride (0.6 g, 0.095
mol) was added, and the mixture was stirred for 24 h at room
temperature. Further 3 Å molecular sieves (5 g) and sodium
cyanoborohydride (0.6 g, 0.095 mol) were added, and the
mixture was stirred for further 24 h at room temperature. The
precipitate was filtered off, and the solvents were evaporated.
The remaining oil was purified by column chromatography on
silica gel (eluted with ethyl acetate/heptane 1:1 containing 4%
triethylamine) affording pure title compound as an oil (2.1 g,
76%). The maleate of 5a was crystallized from ethanol: mp
174-177 °C; 1H NMR (DMSO-d6) δ 2.80 (s, 6 H), 4.50 (s, 2 H),
6.05 (s, 2 H), 7.30 (broad d, 1 H), 7.40-7.55 (m, 3 H), 7.70 (dd,
2 H), 7.95 (s, 1 H), 8.10 (broad s, 1 H); MS (m/z) 303 (MH+),
none ring system in the 2-(methylamino)ethoxy deriva-
tive 22b and the 2-(methylamino)ethyl derivatives 9d
and 9e have led to high affinity serotonin 5-HT2A
receptor antagonists with selectivity versus dopamine
D2 receptors and R1 adrenoceptors (e.g. 10e, 10f, 23b,
and 23c). In addition the 2-(methylamino)ethyl deriva-
tive 10e has high selectivity for 5-HT2A receptors
compared to serotonin 5-HT2C receptors.
The antiserotonergic effects obtained in vivo for the
2-(methylamino)ethyl and 2-(methylamino)ethoxy de-
rivatives prepared in the present study are generally
weaker than the effects obtained for corresponding
piperidinyl derivatives such as sertindole (1a ) and Lu
26-042 (1b).
Replacement of the amino group in 22b by nitrogen-
containing six-membered rings has led to the structur-
ally new selective dopamine D2 receptor antagonist 22g.
This derivative has potent antidopaminergic effects in
vivo.
Exp er im en ta l Section
All reactions were carried out under a positive pressure of
nitrogen. Melting points were determined on a Bu¨chi SMP-
20 apparatus and are uncorrected. 1H NMR spectra were
recorded at 250 MHz on a Bruker AC 250 spectrometer.
Deuterated chloroform (99.8% D) or deuterated dimethyl
sulfoxide (99.9% D) were used as solvents. TMS was used as
internal reference standard. Chemical shift values are ex-
pressed in ppm-values. Mass spectra were obtained on a
Quattro MS-MS system from VG Biotech, Fisons Instruments,
Manchester, GB. The MS-MS system was connected to a HP
1050 modular HPLC system. A volume of 20-50 µL of the
sample (0.1-0.05 mg/mL) dissolved in a mixture of acetonitrile:
water:acetic acid ) 250:250:1 (v/v/v) was introduced via the
autosampler at a flow of 30 µL/min into the electrospray
source. Spectra were obtained at two sets of standard operat-
ing conditions: one to obtain molecular weight information
(MH+) and another to obtain fragmentation in the source (high
cone voltage). The background was subtracted. The relative
intensities of the molecular ions obtained in the fragmentation
spectrum are given. If the relative intensity of the MH+ ion
not is given this ion was only obtained in the molecular weight
spectra. Content of water in crystalline compounds was
determined by Karl Fischer titration. Microanalyses were
performed by Lundbeck Analytical Department and results
obtained were within 0.4% of the theoretical values for all
crystalline products.
Syn th eses of Su bstitu ted of 1-(Ch lor oa lk yl)-2-im id a -
zolid in on es a n d 1-[2-(Alk yla m in o)eth yl]-2-im id a zolid i-
n on es. 1-(2-Chloroethyl)-2-imidazolidinone, 1-(3-chloropropyl)-
2-imidazolidinone, 1-(2-chloroethyl)3-(2-propyl)-2-imidazolidi-
none, and 1-(3-chloropropyl)-3-(2-propyl)-2-imidazolidinone
were prepared according to the literature.6,45,46 1-[2-(Meth -
yla m in o)eth yl]-2-im id a zolidin on e Hyd r och lor id e. A mix-
ture of 1-(2-chloroethyl)imidazolidinone (5.0 g) and a 33%
solution of methylamine in ethanol was heated in a sealed tube
at 80 °C for 18 h. After cooling to room temperature the
volatile products were evaporated, affording 5.0 g (81%) of an
oil which was used for the preparation of 14, 22, 23, and 24
without further purification: 1H NMR (DMSO-d6) δ 2.55 (s, 3
H), 3.00 (t, 2 H), 3.20-3.45 (m, 6 H), 6.5 (broad s, 1 H).
The following compounds were prepared accordingly. 1-[2-
(Eth yla m in o)eth yl]-2-im id a zolid in on e h yd r och lor id e: 1H
NMR (DMSO-d6) δ 1.15 (t, 3 H), 2.65-3.05 (m, 4 H), 3.15-
3.45 (m, 6 H), 6.50 (broad s, 1 H).
258 (20), 223 (61), 222 (100), 162 (70), 127 (61). Anal. (C17H16
-
ClFN2‚C4H4O4) C, H, N.
The following compound was prepared accordingly. N-Meth -
y l-5-c h lo r o -1-(4-flu o r o p h e n y l)-1H -in d o l-3-y lm e t h y l-
a m in e h yd r och lor id e (5b): mp 236-238 °C (acetone); 1H
NMR (DMSO-d6) δ 2.55 (s, 3 H), 4.35 (s, 2H), 7.25 (broad d, 1
H), 7.40-7.55 (m, 3 H), 7.65 (dd, 2 H), 7.95 (s, 1 H), 8.05 (broad
s, 1 H); MS (m/z) 289 (MH+, 1), 258 (14), 223 (45) 222 (100),
162 (62) 127 (28). Anal. (C16H14ClFN2‚HCl) C, H, N.
N-Ben zyl-N-m eth yl-2-[5-ch lor o-1-(4-flu or op h en yl)-1H-
in d ol-3-yl]eth yla m in e (9a ). To a solution of 5-chloroindole
(6a ) (20 g, 0.13 mol) in dry diethyl ether (200 mL) was added
a solution of oxalyl chloride (20 g, 0.16 mol) in dry diethyl ether
(200 mL) at 0-5 °C. After stirring for 0.5 h at 0-5 °C was
added a solution of benzylmethylamine (24 g, 0.20 mol) in dry
diethyl ether at 0-5 °C, and triethylamine was slowly added
to pH at 8-9. Water and ethyl acetate (500 mL) was added,
and the organic phase was washed with brine and dried
(Na2SO4). Evaporation of the solvents afforded the crude
N-benzyl-N-methyl-2-(5-chloro-1H-indol-3-yl)-2-oxoaceta-
mide (7a ) (19.1 g) as an oil. A solution of the crude 7a (20.1
g, 0.058 mol) in dry tetrahydrofuran (200 mL) was added to a
suspension of lithium aluminum hydride (5.4 g, 0.14 mol) in
tetrahydrofuran (100 mL). After heating at reflux for 2.5 h
the reaction mixture was cooled to 0 °C and treated with water
(6 mL) and 4 N aqueous NaOH (6 mL). The precipitate was
filtered off and extracted with dichloromethane (3 × 200 mL).
The combined organic phases were dried (Na2SO4), and the
solvents were evaporated. The remaining oil was purified by
column chromatography on silica gel (eluted with ethyl
acetate) affording N-benzyl-N-methyl-2-(5-chloro-1H-indol-3-
yl)ethylamine (8a ) (16 g) as an oil: 1H NMR (CDCl3) δ 2.30
(s, 3 H), 2.65-2.80 (m, 2 H), 2.85-3.00 (m, 2 H), 3.60 (s, 2 H),
6.95 (broad s, 1 H), 7.05-7.20 (m, 2 H), 7.15-7.35 (m, 5), 7.45
(broad s, 1 H), 8.35 (broad s, 1 H). A mixture of N-benzyl-N-
methyl-2-(5-chloro-1H-indol-3-yl)ethylamine (8a ) (16 g, 0.054
mol), 4-fluoroiodobenzene (14.3 g, 0.064 mol), K2CO3 (11.1 g,
0.080 mol) and 1-methyl-2-pyrrolidinone (200 mL) was heated
at 165 °C for 8 h. After cooling to room temperature, water
(250 mL) was added and the thus formed mixture was
extracted with diethyl ether (2 × 300 mL). The combined
1-[2-(3-P r op yn yla m in o)et h yl]-2-im id a zolid in on e h y-
1
d r och lor id e: H NMR (DMSO-d6) δ 3.10-3.4 (m, 9), 3.70 (t,
2 H), 6.5 (broad s, 1 H).
1-[2-(Met h yla m in o)et h yl]-3-(2-p r op yl)-2-im id a zolid i-
1
n on e h yd r och lor id e: H NMR (CDCl3) δ 1.1 (d, 6 H), 2.65
(s, 3 H), 3.05 (t, 2 H), 3.30-3.55 (m, 6 H), 4.05 (h, 1 H), 6.90
(broad s, 2 H).

3734 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Andersen et al.
organic phases were washed with brine (3 × 500 mL) and dried
(Na2SO4). Evaporation of the solvent afforded an oil that was
purified by column chromatography on silica gel (eluted with
ethyl acetate/heptane 1:3) affording pure title compound 9a
as an oil: 13.7 g (26%) 1H NMR (CDCl3) δ 2.35 (s, 3 H), 2.70-
2.80 (m, 2 H), 2.90-3.00 (m, 2 H), 3.60 (s, 2 H), 7.05-7.40 (m,
12 H), 7.55 (broad s, 1 H).
The following compound was prepared in a similar way.
N-Ben zyl-N-m eth yl-2-[6-ch lor o-1-(4-flu or op h en yl)-1H-in -
d ol-3-yl]eth yla m in e (10a ): 10a was isolated as an oil. 1H
NMR (CDCl3) δ 2.35 (s, 3H), 2.75 (m, 2 H), 3.00 (m, 2 H), 3.60
(s, 2 H), 7.05-7.40 (m, 12 H), 7.45 (d, 1 H).
Secon d a r y Am in es 5b, 9c, a n d 10c, Resp ectively. 1-[2-
[[2-[6-Ch lor o-1-(4-flu or op h e n yl)-1H -in d ol-3-yl]e t h yl]-
m eth yla m in o]eth yl]-3-(2-p r op yl)-2-im id a zolid in on e Ox-
a la te (10f). A mixture of N-methyl-2-[6-chloro-1-(4-fluorophe-
nyl)-1H-indol-3-yl]ethylamine (2.0 g, 0.0066 mol), 1-(2-chloro-
ethyl)-3-(2-propyl)imidazolidin-2-one (1.4 g, 0.0073 mol), K2CO3
(1.4, 0.0099 mol), KI (0.3 g), and methyl isobutyl ketone (100
mL) was refluxed for 18 h. The reaction mixture was cooled
and poured into water and extracted with ethyl acetate. The
combined organic phases were dried (Na2SO4), and the solvents
were evaporated in vacuo. The remaining oil was purified by
column chromatography on silica gel (eluted with ethyl acetate/
ethanol 3:1 containing 4% triethylamine) affording pure title
compound (10f) (1.5 g, 50%) as an oil. The title compound was
crystallized as its oxalate salt from acetone: 172-173 °C
(acetone); 1H NMR (DMSO-d6) δ 1.0 (d, 6 H), 2.80 (s, 3 H),
3.05-3.50 (m, 12 H), 3.90 (qui, 1 H), 7.20 (broad d, 1 H), 7.45
(t, 2 H), 7.50 (s, 1 H), 7.55 (s, 1 H), 7.60 (dd, 2 H), 7.75 (d, 1
H); MS (m/z) 457 (MH+, 23), 272 (48), 198 (71), 155 (100). Anal.
(C25H30ClFN4O‚C2H2O4) C, H, N.
N,N-Dim eth yl-2-[6-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-
3-yl]eth yla m in e Oxa la te (10b). A mixture of N-benzyl-N-
m et h yl-2-[6-ch lor o-1-(4-flu or oph en yl)-1H -in dol-3-yl]et h -
ylamine (10a ) (5.7 g, 0.014 mol), methyl chloroformate (1.6 g,
0.017 mol), K2CO3 (2.4 g, 0.017 mol), and 1,1,1-trichloroethane
(70 mL) was heated at reflux for 1.5 h, and the precipitate
was filtered off. Evaporation of the solvents afforded crude
N-methyl-N-(methoxycarbonyl)-2-[6-chloro-1-(4-fluorophenyl)-
1H-indol-3-yl]ethylamine (3.2 g) as an oil. A solution of the
crude N-(methoxycarbonyl)-2-[6-chloro-1-(4-fluorophenyl)-1H-
indol-3-yl]ethylamine (3.2 g, 0.0089 mol) in tetrahydrofuran
(50 mL) was added to a suspension of lithium aluminum
hydride (0.5 g, 0.014 mol) in tetrahydrofuran (50 mL). After
reflux for 2 h the reaction mixture was cooled to 0 °C and
carefully treated with water (0.5 mL), 4 N aqueous NaOH (0.5
mL), and then water (0.5 mL). The resulting mixture was
filtered and dried (Na2SO4). Evaporation of the solvents
afforded the title compound as an oil (2.6 g, 59%), which was
crystallized as its oxalate from acetone: mp 155-156 °C
1-[2-[[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-ylm eth -
yl]m eth yla m in o]eth yl]-2-im id a zolid in on e (5c): mp 141-
1
143 °C (ethyl acetate); H NMR (CDCl3) δ 2.30 (s, 3 H), 2.60
(t, 2 H), 3.25-3.50 (m, 6 H), 3.70 (s, 2 H), 4.50 (broad s, 2 H),
7.10-7.25 (m, 4 H), 7.35 (d, 1 H), 7.40 (dd, 2 H), 2.80 (broad
s, 1 H); MS (m/z) 401 (MH+, 3), 258 (64), 223 (100), 222 (80),
162 (60). Anal. (C21H22ClFN4O) C, H, N.
1-[4-[[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-ylm eth -
yl]m eth yla m in o]bu tyl]-2-im id a zolid in on e oxa la te (5d ):
mp 155-157 °C (acetone); 1H NMR (DMSO-d6) δ 1.80-1.95
(m, 4 H), 2.80 (s, 3 H), 3.10-3.35 (m, 6 H), 3.35-3.50 (m, 2H),
4.60 (s, 2 H), 6.65-6.75 (m, 1 H), 7.20 (broad d, 1 H), 7.35-
7.50 (m, 3 H), 7.60 (dd, 2 H), 7.70 (dd, 1 H), 7.80 (broad s, 1
H); MS (m/z) 429 (MH+), 258 (100), 223 (27), 141 (91). Anal.
(C23H26ClFN4O‚C2H2O4) C, H, N.
1
(acetone); H NMR (DMSO-d6) δ 2.85 (s, 6 H), 3.10-3.25 (m,
2 H), 3.30-3.40 (m, 2 H), 7.20 (broad d, 1 H), 7.40 (t, 2 H),
7.45 (s, 1 H), 7.55-7.65 (m, 3 H), 7.75 (d, 1 H); MS (m/z) 317
(MH+, 5), 272 (36), 237 (70) 236 (52). Anal. (C18H18
-
ClFN2‚C2H2O4) C, H, N.
1-[2-[[2-[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yl]eth -
yl]m eth yla m in o]eth yl]-2-im id a zolid in on e m a lea te (9d ):
The following compound was prepared in a similar way.
N,N-Dim eth yl-2-[5-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-
yl]eth yla m in e m a lea te (9b): mp 170-172 °C (ethyl acetate);
1H NMR (CDCl3) δ 2.90 (s, 6 H), 3.20-3.30 (m, 2 H), 3.30-
3.45 (m, 2 H), 6.30 (s, 2 H), 7.15-7.30 (m, 4 H), 7.35 (d, 1 H),
7.40 (dd, 2 H), 7.60 (broad s, 1 H); MS (m/z) 317 (MH+, 11),
272 (72), 237 (46), 236 (27). Anal. (C18H18ClFN2‚C4H4O4) C,
H, N.
1
mp 137-139 °C; H NMR (DMSO-d6) δ 2.95 (s, 3 H), 3.10-
3.55 (m, 12 H), 6.05 (s, 2 H), 6.65 (broad s, 1 H), 7.25 (broad
d, 1 H), 7.40-7.55 (m, 3 H), 7.60 (dd, 2 H), 7.65 (s, 1 H), 7.65
(broad s, 1 H); MS (m/z) 415 (MH+), 272 (33), 237 (28), 113
(100). Anal. (C22H24ClFN4O‚C4H4O4) C, H, N.
1-[3-[[2-[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yl]eth -
yl]m eth yla m in o]p r op yl]-2-im id a zolid in on e h yd r och lo-
r id e (9e): mp 171-173 °C (acetone); 1H NMR (CDCl3) δ 2.10-
2.30 (m, 2 H), 2.90 (s, 3 H), 3.05-3.60 (12 H), 4.60 (broad s, 1
H), 7.15-7.35 (m, 5 H), 7.40 (dd, 2 H), 7.60 (broad s, 1 H); MS
(m/z) 429 (MH+, 2), 272 (34), 237 (20), 127 (100), 99 (44). Anal.
(C23H26ClFN4O‚HCl) C, H, N.
1-[2-[[2-[6-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yl]eth -
yl]m eth yla m in o]eth yl]-2-im id a zolid in on e h yd r och lor id e
(10d ): mp 213-16 °C (ethanol); 1H NMR (DMSO-d6) δ
2.90 (broad s, 3 H), 3.15-3.65 (m, 12 H), 6.60 (broad s, 1 H),
7.20 (broad d, 1 H), 7.45 (t, 2 H), 7.50 (broad s, 1 H), 7.60 (s,
1 H), 7.65 (dd, 2 H), 7.85 (d, 1 H), 10.60 (broad s, 1 H); MS
(m/z) 415 (MH+, 11), 113 (100). Anal. (C22H24ClFN4O‚HCl)
C, H, N.
1-[3-[[2-[6-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yl]eth -
yl]m eth ylam in o]pr opyl]-2-im idazolidin on e oxalate (10e):
mp 112-114 °C (acetone); 1H NMR (DMSO-d6) δ 1.75-1.95
(m, 2 H), 2.80 (s, 3 H), 3.00-3.40 (m, 12 H), 6.40 (broad s, 1
H), 7.20 (broad d, 1 H), 7.40 (t, 2 H), 7.45 (s, 1 H), 7.60 (s, 1
H), 7.60 (dd, 2 H), 7.75 (d, 1 H); MS (m/z) 429 (MH+, 8), 272
(72), 237 (22) 127 (100), 99 (68). Anal. (C23H26ClFN4O‚C2H2O4)
C, H, N.
3-[5-Ch lor o-1-(4-flu or op h en yl)-1H -in d ol-3-yl]p r op a -
n ol (13a ). A mixture of 3-[5-chloro-1H-indol-3-yl]propanoic
acid23,24 (11a ) (17.5 g, 0.078 mol), 4-fluoroiodobenzene (20.8 g,
0.094 mol), CuI (2.4 g), K2CO3 (21.6 g, 0.16 mol), and N-methyl-
2-pyrrolidinone (0.20 L) was heated at 165 °C for 7 h. The
reaction mixture was cooled to room temperature, and water
(0.25 L) was added. After the mixture was acidified with
concentrated hydrochloric acid it was extracted with diethyl
ether (2 × 0.30 L). The combined organic phases were washed
with brine (3 × 0.40 L) and dried (Na2SO4). Evaporation of
the solvents afforded the crude acid 12a (26 g) as an oil. The
N-Meth yl-2-[5-ch lor o-1-(4-flu or oph en yl)-1H-in d ol-3-yl]-
eth yla m in e Ma lea te (9c). A mixture of N-benzyl-N-methyl-
2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]ethylamine (9a )
(13.7 g, 0.026 mol), methyl chloroformate (2.9 g, 0.031), K2-
CO3 (4.2 g, 0.031), and 1,1,1-trichloroethane (150 mL) was
heated at reflux for 2 h and the precipitate was filtered off.
Evaporation of the solvents afforded crude N-methyl-N-(meth-
oxycarbonyl)-2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-
ethylamine (12.2 g) as an oil. A mixture of the crude
N-(methoxycarbonyl)-2-[5-chloro-1-(4-fluorophenyl)-1H-indol-
3-yl]ethylamine (12.2 g, 0.034) and 47% hydrobromic acid (150
mL) was heated at reflux for 14 h. The reaction mixture was
poured into ice, made alkaline with concentrated NaOH and
extracted with diethyl ether (2 × 200 mL). The combined
organic phases were washed with brine and dried (Na2SO4).
Evaporation of the solvents afforded pure title compound 9c
as an oil (7.9 g, 52%), which was crystallized as its maleate
salt from ethyl acetate: mp 171-173 °C (ethyl acetate); 1H
NMR (DMSO-d6) δ 2.65 (s, 3 H), 3.05-3.20 (m, 2 H), 3.20-
3.30 (m, 2 H), 6.05 (s, 2 H), 7.20 (broad d, 1 H), 7.45 (t, 2 H),
7.50 (s, 1 H), 7.60 (dd, 2 H), 7.65 (s, 1 H), 7.80 (broad s, 1 H);
MS (m/z) 303 (MH+), 237 (82) 236 (100). Anal. (C17H16
FClN2‚C4H4O4) C, H, N.
-
The following compound was prepared in a similar way.
N-Met h yl-2-[6-ch lor o-1-(4-flu or op h en yl)-1H -in d ol-3-yl]-
eth yla m in e h em ioxa la te (10c): 1H NMR (DMSO-d6) δ 2.50
(s, 3 H), 3.05 (broad s, 4 H), 7.05 (dd, 1 H), 7.35 (t, 2 H), 7.40
(broad s, 1 H), 7.45 (s, 1 H), 7.55 (dd, 2 H), 7.65 (d, 1 H); MS
(m/z) 303 (MH+), 272 (100), 237 (33). Anal. (C17H16
FClN2‚0.5C2H2O4‚0.3H2O) C, H, N.
-
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Ter t ia r y
Am in es 5c,d , 9d ,e, a n d 10d -f fr om th e Cor r esp on d in g

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3735
oil was dissolved in dry diethyl ether and added to a suspen-
sion of lithium aluminum hydride (15 g, 0.40 mol) in dry
diethyl ether (0.20 L) over 30 min. After reflux for further 2
h the reaction mixture was cooled to 0 °C and carefully treated
with water (15 mL), 4 N aqueous NaOH (15 mL), and then
water (75 mL). The resulting mixture was filtered and dried
(Na2SO4). Evaporation of the solvents afforded the title
compound as an oil (17.6 g, 74%). An analytical sample was
the solvents afforded the crude 2-[5-chloro-1-(4-fluorophenyl)-
1H-indol-3-ylsulfanyl]acetic acid (18), which was isolated as
an oil and used without further purification. A solution of the
crude acid in dry tetrahydrofuran (200 mL) was added to a
suspension of lithium aluminum hydride (7.5 g, 0.20 mol) in
dry tetrahydrofuran (200 mL) during 15 min. After reflux for
1 h the reaction mixture was cooled to 0 °C and carefully
treated with water (5 mL) and 28% aqueous NaOH (5 mL).
The precipitate was filtered off and extracted with dichlo-
romethane (3 × 500 mL). The combined organic phases were
dried (MgSO4), and the solvents were evaporated affording the
title compound (20) as an oil (25 g). Purification by column
chromatography on silica gel (eluted with ethyl acetate/
heptane 1:2) afforded the pure title compound (20) (12 g, 40%)
as an oil. An analytical sample was crystallized from ether/
heptane (1:2): mp 85-86 °C; 1H NMR (CDCl3) δ 2.10-2.50
(broad s, 1 H), 2.95 (t, 2 H), 3.70 (t, 2 H), 7.20 (broad d, 1 H),
7.25 (t, 2 H), 7.35 (d, 1 H), 7.40 (dd, 2 H), 7.45 (s, 1 H), 7.80
(broad s, 1 H). Anal. (C16H13ClFNOS) C, H, N.
1
crystallized from heptane: mp 67-69 °C; H NMR (CDCl3) δ
1.55 (broad s, 1 H), 2.00 (qui, 2 H), 2.90 (t, 2 H), 3.75 (t, 2 H),
7.10 (s, 1 H), 7.15 (broad d, 1 H), 7.20 (t, 2 H), 7.35 (d, 1 H),
7.40 (dd, 2 H), 7.60 (broad s, 1 H). Anal. (C17H15ClFNO) C,
H, N.
The following compound was prepared in a similar way.
4-[5-Ch lor o-1-(4-flu or op h e n yl)-1H -in d ol-3-yl]b u t a n ol
(13b): mp 80-82 °C (heptane/ethanol); 1H NMR (CDCl3) δ
1.35 (broad s, 1 H), 1.60-1.90 (m, 4 H), 2.80 (t, 2 H), 3.70 (t,
2 H), 7.10 (s, 1 H), 7.15 (broad d, 1 H), 7.20 (t, 2 H), 7.35 (d, 1
H), 7.40 (dd, 2 H), 7.60 (broad s, 1 H). Anal. (C18H17ClFNO)
C, H, N.
3-[6-Ch lor o-1-(4-flu or op h en yl)-1H -in d ol-3-yloxy]p r o-
p a n ol (21). To a refluxing solution of 1,3-propandiol (8.7 g,
0.115 mol) and p-toluenesulfonic acid (2.5 g) in toluene (150
mL) was added a solution of 5-chloro-2,3-dihydro-1-(4-fluo-
rophenyl)-1H-indol-3-one (27) (6 g, 0.023 mol) in toluene (100
mL) over 25 min. After reflux for further 10 min the solvents
were evaporated. Purification by column chromatography on
silica gel (eluted with ethyl acetate/heptane 1:1) afforded the
2-[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yloxy]eth a -
n ol (19a ). A mixture of methyl 5-chloro-1-(4-fluorophenyl)-
3-hydroxy-1H-indol-2-carboxylate1 (16a ) (200 g, 0.62 mol),
methyl 2-bromoacetate (125 g, 0.81 mol), K2CO3 (112 g, 0.81
mol), and acetone (2.0 L) was refluxed for 18 h. The mixture
was cooled to room temperature and filtered, and the solvents
were evaporated in vacuo. To the remaining oil (270 g) were
added methanol (1.5 L) and 3 N aqueous KOH (0.6 L). After
reflux for 1 h the solution was cooled to room temperature and
acidified by concentrated hydrochloric acid. The crystalline
product was filtered off and dissolved in ethyl acetate and dried
(Na2SO4). Evaporation of the solvents afforded 2-[2-carboxy-
5-chloro-1-(4-fluorophenyl)-1H-indol-3-yloxy]acetic acid (17a )
(240 g) as an oil, which was decarboxylated without further
purification. A mixture of the crude dicarboxylic acid, copper
(15 g), and N-methyl-2-pyrrolidinone was refluxed for 1.5 h.
The mixture was cooled to room temperature, and water (2.0
L) was added. The precipitated product was filtered off and
dissolved in ethyl acetate (1.5 L). The solution was washed
with brine (3 × 1 L) and dried (Na2SO4). Evaporation of the
solvents afforded the crude carboxylic acid (17a ) (223 g), which
was dissolved in dry diethyl ether (1.5 L). The solution was
added to a suspension of lithium aluminum hydride (70 g, 1.9
mol) in dry diethyl ether (1.0 L) over 45 min. After reflux for
additional 0.5 h the reaction mixture was cooled to 0 °C and
carefully treated with water (70 mL), 4 N aqueous NaOH, and
then water (300 mL). The reaction mixture was filtered and
dried (Na2SO4). Evaporation of the solvents afforded the
crystalline title compound (110 g, 55%). An analytical sample
was recrystallized from diethyl ether: mp 118-120 °C; 1H
NMR (CDCl3) δ 2.35 (broad s, 1 H),4.0 (t, 2 H), 4.15 (t, 2 H),
6.85 (s, 1 H), 7.10 (broad d, 1 H), 7.15 (t, 2 H), 7.40 (dd, 2 H),
7.65 (broad s, 1 H). Anal. (C16H13ClFNO2) C, H, N.
The following compound was prepared accordingly. 2-[6-
Ch lor o-1-(4-flu or oph en yl)-1H-in dol-3-yloxy]eth an ol (19b):
mp 97-98 °C (diethyl ether); 1H NMR (CDCl3) δ 4.00 (t, 2 H),
4.15 (t, 2 H), 6.80 (s, 1 H), 7.10 (d, 1 H), 7.20 (t, 2 H), 7.40 (s,
1 H), 7.35 (dd, 2 H), 7.60 (d, 1 H). Anal. (C16H13ClFNO2) C,
H, N.
5-Ch lor o-2,3-d ih yd r o-1-(4-flu or op h en yl)-1H -in d ol-3-
on e (27). To a mixture of Na2SO3‚7H2O (90 g, 0.36 mol) and
water (1.8 L) was added ethanol (1.5 L) and 3-acetoxy-5-chloro-
1-(4-fluorophenyl)-1H-indole (prepared according to literature
procedures1,47,48) (26) (60 g, 0.20 mol) at 60 °C. The resulting
mixture was refluxed for 1 h, and after stirring at room
temperature for further 18 h the precipitate was filtered off,
washed with water (300 mL) at 60 °C, and dried in vacuo
overnight at 60 °C affording the title compound (44.3 g, 85%):
mp 99-101 °C; 1H NMR (CDCl3) δ 4.20 (s, 2 H), 7.10 (s, 1 H),
7.10 (t, 2 H), 7.25 (dd, 2 H), 7.40 (broad d, 1H), 7.60 (broad s,
1 H). Anal. (C14H9ClFNO) C, H, N.
1
title compound (21) (2.4 g, 33%) as an oil: H NMR (DMSO-
d6) δ 1.95 (m, 2 H), 3.65 (m, 2 H), 4.15 (t, 2 H), 4.60 (t, 1 H),
7.20 (broad d, 1 H), 7.30-7.55 (m, 4 H), 7.55-7.65 (m, 3 H).
Gen er a l P r oced u r e for th e Con ver sion of Alcoh ols
13a , 13b, 19a , 19b, 20, a n d 21 to Cor r esp on d in g Am in es
14, 15, 22, 23, 24, a n d 25, Resp ectively. 1-[2-[2-[5-Ch lor o-
1-(4-flu or op h en yl)-1H-in d ol-3-yloxy]eth ylm eth yla m in o]-
eth yl]-2-im id a zolid in on e Ma lea te (22b). To a solution of
2-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yloxy]ethanol (19a )
(4.8, 0.016 mol) and triethylamine (5 mL) in dichloromethane
(50 mL) a solution of methanesulfonyl chloride (1.9 mL, 0.025
mol) in dichloromethane (16 mL) was added at 0-5 °C over
0.5 h. After stirring for 3 h at room temperature the reaction
mixture was washed with water (2 × 100 mL) and dried
(Na2SO4), and the solvents were evaporated in vacuo. Excess
of methanesulfonyl chloride was removed by concentrating the
remaining oil with toluene in vacuo several times. The crude
methansulfonate of 19a (6.0 g, 0.016 mol) was used without
further purification. A mixture of the crude methansulfonate,
2-[(methylamino)ethyl]-2-imidazolidinone (4.9 g, 0.034 mol),
K2CO3 (4.0 g, 0.029 mol), and methyl isobutyl ketone was
refluxed for 18 h. After cooling to room temperature, water
(100 mL) was added, and the resulting mixture was extracted
with ethyl acetate (2 × 100 mL). The combined organic phases
were washed with water (100 mL) and brine (100 mL) and
dried (Na2SO4). Evaporation of the solvents and purification
by column chromatography on silica gel (eluted with ethyl
acetate/ethanol 5:1 containing 4% triethylamine) afforded the
title compound (4.2 g, 61%) as an oil. The title compound
crystallized as its maleate from ethyl acetate: mp 183-185
1
°C; H NMR (DMSO-d6) δ 2.85 (s, 3 H), 3.20-3.55 (m, 8 H),
3.65 (broad s, 2 H), 4.40 (broad t, 2 H) 6.05 (s, 2 H), 6.65 (broad
s, 1 H), 7.2, (broad d, 1 H, 7.45 (t, 2 H), 7.55 (d, 1 H), 7.69
(7.55, 1 H), 7.60 (dd, 2 H), 7.70 (broad s, 1 H); MS (m/z) 431
(MH+, 2), 170 (33), 113 (100). Anal. (C22H24ClFN4O2‚C4H4O4)
C, H, N.
The following compounds were prepared accordingly. N,N-
Dim et h yl-3-[5-ch lor o-1-(4-flu or op h en yl)-1H -in d ol-3-yl]-
p r op yla m in e fu m a r a te (14a ): mp 172-173 °C (ethanol); 1H
NMR (DMSO-d6) δ 2.00 (qui, 2 H), 2.50 (s, 6 H), 2.65-2.90
(m, 4 H), 6.50 (s, 2 H), 7.20 (broad d, 1 H), 7.40 (t, 2 H), 7.45
(d, 1 H), 7.55 (s, 1 H), 7.60 (dd, 2 H), 7.70 (broad s, 1 H); MS
(m/z) 331 (MH+, 37), 286 (71), 258 (100), 251 (62). Anal.
(C19H20ClFN2‚C4H4O4) C, H, N.
2-[5-Ch lor o-1-(4-flu or op h e n yl)-1H -in d ol-3-ylsu lfa -
n yl]eth a n ol (20). A mixture of 5-chloro-2,3-dihydro-1-(4-
fluorophenyl)-1H-indol-3-one (27) (25.0 g, 0.10 mol), mercap-
toacetic acid (25 g, 0.27 mol), p-toluenesulfonic acid (5.0 g),
and toluene (500 mL) was refluxed for 18 h. Evaporation of
1-[2-[[3-[5-Ch lor o-1-(4-flu or op h en yl)-1H -in d ol-3-yl]-
p r op yl]m eth yla m in o]eth yl]-2-im id a zolid in on e fu m a r a te
(14b): mp 132-134 °C (ethanol); 1H NMR (DMSO-d6) δ 180-
2.00 (m, 2 H), 2.40 (s, 3 H), 2.55-2.80 (m, 6 H), 3.15-3.25 (m,
4 H), 3.30-3.40 (m, 2 H), 6.30 (s, 1 H), 6.60 (s, 2 H), 7.20 (broad

3736 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Andersen et al.
Ta ble 5. Global Minimum Energy Conformations for Compounds Included in the Molecular Modeling Study. For Compounds
Having Global Minimum Energy Conformations with the 3-Substituent in a Coiled Conformation, the Conformation and
Conformational Energy of the Uncoiled Conformation with Lowest Energy Is Indicated
dihedral angles
conformational energy,
compd
A
B
C
D
kcal/mol
conformer
5a
9b
14a
60°
-54°
52°
-72°
178°
-179°
-84°
-63°
-
-
0.0
0.0
0.0
0.8
0.0
0.0
1.0
global minimum (uncoiled)
global minimum (uncoiled)
global minimum (coiled)
local minimum (uncoiled)
global minimum (uncoiled)
global minimum (coiled)
local minimum (uncoiled)
69°
100°
76°
-172°
105°
120°
55°
63°
-
-53°
-56°
58°
55°
22a
24a
-170°
66°
-52°
57°
-172°
Ta ble 6. Forcefield Parameters Added to the MM2(91)
5-Ch lor o-1-(4-flu or oph en yl)-3-(2-(1-piper idin yl)eth oxy)-
1H-in d ole (22e): mp 82-84 °C (n-heptane); 1H NMR (CDCl3)
δ 1.40-1.55 (m, 2 H), 1.55-1.70 (m, 4 H), 2.50 (t, 4H), 2.85 (t,
2 H), 4.15 (t, 2 H), 6.85 (s, 1 H), 7.15 (broad d, 1 H), 7.20 (t, 2
H), 7.30 (d, 1 H), 7.40 (dd, 2 H), 7.65 (broad s, 1 H); MS (m/z)
373 (MH+, 1), 260 (2), 112 (100). Anal. (C21H22ClFN2O) C,
H, N.
5-C h lo r o -1-(4-flu o r o p h e n y l)-3-(2-(4-m o r p h o lin y l)-
eth oxy)-1H-in d ole m a lea te (22f): mp 185-187 °C (ethyl
acetate); 1H NMR (DMSO-d6) δ 3.15-3.40 (m, 4 H), 3.40-3.60
(m, 2 H), 3.75-3.95 (m, 4 H), 4.40 (t, 2 H), 6.10 (s, 2 H), 6.25
(broad d, 1 H), 7.40 (t, 2 H), 7.50 (d, 1 H), 7.55 (s, 1 H), 7.60
(dd, 2 H), 7.70 (broad s, 1 H); MS (m/z) 375 (MH+, 2), 114 (100).
Anal. (C20H20ClFN2O2‚C4H4O4) C, H, N.
5-Ch lor o-1-(4-flu or op h en yl)-3-[(4-m eth ylp ip er a zin yl)-
eth oxy]-1H-in d ole d im a lea te (22g): mp 196-198 °C (ethyl
acetate); 1H NMR (DMSO-d6) δ 2.70-3.40 (m, 8 H), 2.80 (s, 3
H), 2.95 (t, 2 H), 4.20 (t, 2 H), 6.15 (s, 4 H), 7.20 (broad d, 1
H), 7.40 (t, 2 H), 7.45 (s, 1 H), 7.50 (d, 1 H), 7.55 (broad s, 1
H), 7.60 (dd, 2 H); MS (m/z) 388 (MH+, 4), 127 (100). Anal.
(C21H23ClFN3O‚2(C4H4O4)) C, H, N.
N,N-Dim eth yl-2-[6-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-
3-yloxy]eth yla m in e (23a ): mp 66-68 °C (n-heptane); 1H
NMR (CDCl3) δ 2.40 (s, 6 H), 2.80 (t, 2 H), 4.10 (t, 2 H), 6.80
(s, 1 H), 7.10 (d, 1 H), 7.20 (t, 2 H), 7.35 (broad s, 1 H), 7.40
(dd, 2 H), 7.60 (d, 1 H); MS (m/z) 333 (MH+), 72 (100). Anal.
(C18H18ClFN2O) C, H, N.
Force-Fielda
atom types
V1
V2
V3
Torsional Parameters (kcal/mol)
C(sp3)-C(sp2)-C(sp2)-N(sp2) (1-2-2-40)
O(sp3)-C(sp2)-C(sp2)-N(sp2) (6-2-2-40)
N(sp3)-C(sp3)-C(sp3)-S (sp3) (8-1-1-15)
C(sp2)-C(sp2)-C(sp2)-S(sp3) (2-2-2-15)
0. 15.
0. 15.
0. 0.
0.
0.
0.35
0. 16.25 0.
S(sp3)-C(sp2)-C(sp2)-N(sp2) (15-2-2-40) 0. 16.25 0.
H-C(sp2)-C(sp2)-S(sp3)
C(sp2)-C(sp2)-S(sp3)-C(sp3) (2-2-15-1) -1.8 1.
H-C(sp3)-S(sp3)-C(sp2)
(5-1-15-2) 0. 0.
C(sp3)-C(sp3)-S(sp3)-C(sp2) (1-1-15-2)
0.0 0.0
(5-2-2-15)
0. 16.25 0.
-0.7
0.5
0.5
atom types I0 (Å)
Bond Length and Stretching Constant
C(sp2)-S(sp3)
(2-15) 1.765
k (mdyn Å-1
)
4.0
kθ (mdyn Å
atom types θ0 (deg)
Bond Angles and Bending Constants
rad-2
)
S(sp3)-C(sp2)-C(sp2)
C(sp3)-S(sp3)-C(sp2)
C(sp2)-S(sp3) out-of-plane
(2-2-15)
(1-15-2)
(2-15)
120.0
94.0
0.5
0.6
0.05
a
The constants were chosen in analogy with parameters for
similar combinations of atoms in the standard forcefield parameter
list or in analogy with parameters for similar combinations of
atoms published by Kao et al.52
1-[2-[[2-[6-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yloxy]-
et h yl]m et h yla m in o]et h yl]-2-im id a zolid in on e (23b ): mp
1
100-102 °C (diethyl ether); H NMR (CDCl3) δ 2.40 (s, 3 H),
s, 1 H), 7.40 (t, 2 H), 7.45 (d, 1 H), 7.55 (s, 1 H), 7.60 (dd, 2 H),
7.70 (broad s, 1 H); MS (m/z) 429 (MH+, 20), 286 (4), 113 (100).
Anal. (C23H26ClFN4O‚C4H4O4) C, H, N.
2.65 (t, 2 H), 2.90 (t, 2 H), 3.30-3.40 (m, 4 H), 3.45-3.60 (m,
2 H), 4.10 (t, 2 H), 4.50 (broad s, 1 H), 6.80 (s, 1 H), 7.10 (broad
d, 1 H), 7.20 (t, 2 H), 7.35 (broad s, 1 H), 7.40 (dd, 2 H), 7.60
(d, 1 H); MS (m/z) 431 (MH+, 3), 170 (65), 113 (100). Anal.
(C22H24ClFN4O2) C, H, N.
N,N-Dim eth yl-4-[5-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-
3-yl]bu t yla m in e m a lea t e (15): mp 131-133 °C (ethyl
acetate); 1H NMR (DMSO-d6) δ 1.70-2.95 (m, 4 H), 2.80 (s, 6
H), 2.75-2.85 (m, 2 H), 3.00-3.15 (m, 2 H), 6.25 (s, 2 H), 7.10-
7.25 (m, 4 H) 7.35 (d, 1 H), 7.40 (dd, 2 H), 7.55 (broad s, 1 H);
1-[2-[[2-[6-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yloxy]-
eth yl]m eth yla m in o]eth yl]-3-(2-p r op yl)-2-im id a zolid in o-
n e oxa la te (23c): mp 165-167 °C (acetone); 1H NMR (DMSO-
d6) δ 1.00 (d, 6 H), 2.80 (s, 3 H), 3.10-3.55 (m, 10 H), 3.90 (h,
1 H), 4.40 (m, 2 H), 7.15 (broad d, 1 H), 7.40 (t, 2 H), 7.45 (s,
1 H), 7.50 (broad s, 1 H), 7.60 (dd, 2 H), 7.65 (d, 1 H); MS
MS (m/z) 345 (MH+, 15), 300 (85), 265 (100). Anal. (C20H22
ClFN2‚C4H4O4) C, H, N.
-
N,N-Dim eth yl-2-[5-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-
3-yloxy]eth yla m in e sesqu ifu m a r a te (22a ): mp 165-167
°C (ethanol); 1H NMR (DMSO-d6) δ 2.60 (s, 6 Η), 3.15 (t, 2 H),
4.30 (t, 2 H), 6.60 (s, 3 H), 7.20 (broad d, 1 H), 7.40 (t, 2 H),
7.45 (s, 1 H), 7.50 (d, 1 H), 7.60 (dd, 2 H), 7.65 (broad s, 1 H);
MS (m/z) 333 (MH+), 72 (100). Anal. (C18H18ClFN2O‚1.5-
(C4H4O4)) C, H, N.
(m/z) 473 (MH+, 10), 212 (62), 155 (100). Anal. (C25H30
ClFN4O2‚C2H2O4) C, H, N.
-
N,N-Dim eth yl-2-[5-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-
3-ylsu lfa n yl]et h yla m in e h yd r och lor id e (24a ): mp 200-
1
202 °C (acetone); H NMR (DMSO-d6) δ 2.70 (s, 6 H), 3.05-
3.30 (m, 4 H), 7.30 (dd, 1 H), 7.45 (t, 2 H), 7.55 (d, 1 H), 7.75
(broad s, 1 H), 7.70 (dd, 2 H), 8.10 (s, 1 H); MS (m/z) 349 (MH+,
1), 276 (100), 104 (34), 58 (64). Anal. (C18H18ClFN2S‚HCl) C,
H, N.
1-[2-[[2-[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-ylsu l-
fa n yl]eth ylm eth yl]a m in o]eth yl]-2-im ida zolidin on e (24b):
mp 65-67 °C (acetone); 1H NMR (CDCl3) δ 2.95 (s, 3 H), 3.35-
3.75 (m, 15 H), 4.90 (s, 1 H), 7.35 (t, 2 H), 7.40 (bd, 1 H), 7.50
(d, 1 H), 7.65 (d, 1 H), 7.75 (s, 1 H), 7.85 (broad s, 1 H); MS
(m/z) 447 (MH+, 4), 276 (100), 202 (13), 113 (51). Anal.
(C22H24ClFN4OS‚HCl‚0.85H2O) C, H, N.
N,N-Dim eth yl-2-[5-ch lor o-1-(4-flu or op h en yl)-1H-in d ol-
3-yloxy]p r op yla m in e m a lea te (25): mp 122-124 °C (ethyl
acetate/diethyl ether); 1H NMR (DMSO-d6) δ 2.20-2.40 (m, 2
H), 2.90 (s, 6 H), 3.30-3.40 (m, 2 H), 4.10 (t, 2 H), 6.20 (s, 2
H), 6.85 (s, 1 H), 7.10-7.25 (m, 3 H), 7.30 (d, 1 H), 7.40 (dd, 2
1-[2-[[2-[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yloxy]-
eth yl]eth ylam in o]eth yl]-2-im idazolidin on e m aleate (22c):
mp 155-157 °C (ethyl acetate); 1H NMR (DMSO-d6) δ 1.30 (t,
3 H), 3.20-3.55 (m, 10 H), 3.55-3.80 (m, 2 H), 4.35-4.50 (m,
2 H), 6.05 (s, 2 H), 6.65 (s, 1 H), 7.25 (broad d, 1 H), 7.40 (t, 2
H), 7.50 (d, 1 H), 7.55 (s, 1 H), 7.60 (dd, 2 H), 7.70 (broad s, 1
H); MS (m/z) 445 (MH+, 3), 184 (41), 113 (100). Anal. (C23H26
ClFN4O2‚C4H4O4) C, H, N.
-
1-[2-[[2-[5-Ch lor o-1-(4-flu or op h en yl)-1H-in d ol-3-yloxy]-
et h yl]-3-p r op yn yla m in o]et h yl]-2-im id a zolid in on e ox-
a la te (22d ): mp 139-141 °C (acetone); 1H NMR (DMSO-d6) δ
2.75 (t, 2 H), 3.00 (t, 2 H), 3.10-3.30 (m, 5 H), 3.40 (t, 2 H),
3.65 (broad s, 2 H), 4.15 (t, 2 H), 6.25 (broad s, 1 H),7.20 (broad
d, 1 H), 7.40 (t, 2 H), 7.45 (s, 1 H), 7.50 (d, 1 H), 7.55 (broad s,
1 H), 7.60 (dd, 2 H); MS (m/z) 455 (MH+, 3), 194 (41), 113 (100).
Anal. (C24H24ClFN4O2‚C2H2O4) C, H, N.

Flexible Analogues of Antipsychotic Sertindole
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3737
H), 7.60 (broad s, 1 H); MS (m/z) 347 (MH+), 86 (52), 58 (100).
Anal. (C19H20ClFN2O‚C4H4O4) C, H, N.
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r1 Ad r en ocep tor s. Affinity of test compounds to R1
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An ta gon ism of Qu ip a zin e-In d u ced Hea d Tw itch es.
The experimental details are given by Arnt et al.43 Test
compounds were injected sc or po to rats 2 or 24 h before
quipazine (15 µmol/kg, sc). Head twitches were counted 30-
40 min after the quipazine treatment. The number of head
twitches in the drug treated group (at least four animals per
dose) was expressed in percent of the number of head twitches
in a quipazine-treated control group.
An ta gon ism of P er golid e-In d u ced Cir clin g Beh a vior
in Ra ts w ith Un ila ter a l 6-OHDA Lesion s. This test
method is described in detail by Arnt and Hyttel.44 Contralat-
eral circling is induced in 6-OHDA lesioned rats in response
to administration of pergolide (0.050 µmol/kg, sc). Test
compounds were injected sc 2 h before pergolide. The effect
of individual doses of test drugs is calculated as percent of the
mean effect of control sessions one week before and one week
after the test session for each rat (at least four rats per dose).
Com p u ta tion a l Meth od s. Conformational energies and
energy-minimized geometries were calculated using the mo-
lecular mechanics program MM2(91) developed by Allinger
and co-workers.51,53 In addition to standard force field param-
eters, constants listed in Table 6 were chosen in analogy with
parameters for similar combinations of atoms in the MM2-
(91) force field parameter list or in analogy with parameters
reported by Kao et al.52 As in previous work, all calculations
were done on the unprotonated amines with unshared electron
pairs represented by a pseudoatom.10 Conformational energy
curves were calculated by using the driver option implemented
in MM2(91) with an angle increment of 10° and with full
energy minimization except the dihedral angle(s) used as
driving angle(s). The construction of input structures for
MM2(91) and the studies on molecular superimposition were
done by means of the molecular modeling program Mac-
Mimic.53 Fitting points used in the superimpositions were the
centers of the two benzene rings (e.g. the benzene part of the
indole nucleus (A) and the 4-fluorophenyl group (B)) and a
point 2.8 Å from the basic nitrogen atom in the direction of
the lone pair (C). The point C is assumed to simulate a
receptor site hydrogen bonding with the nitrogen atom.
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K. T.; McDonald, I. A. 3-(2-Carboxyindol-3-yl)propionic Acid De-
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Ack n ow led gm en t. We acknowledge the very skill-
ful technical assistance of Ms. Tine Rasmussen and Ms.
Anette Sørensen, Ms. Birgitte Kratgaard for the prepa-
ration of the manuscript, and Mr. Lars Læssøe-Larsen
for programming helpful tools for the molecular model-
ing studies. Finally, we thank all from the staff of the
Lundbeck Research Departments, who have contributed
to the fulfillment of the present study. This work was
supported by grants (to Tommy Liljefors) from the
Danish Medical Research Council and the Lundbeck
Foundation.
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Indole-2(and 3)-Carboxylic Acids. Can. J . Chem. 1962, 40, 559-
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ration of 3-Hydroxy, 3-Alkoxy and 3-Alkyl Derivatives. J .
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