Synthesis and structure-affinity relationship investigations of 5-aminomethyl and 5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective α1 adrenoceptor antagonists

Bioorganic & Medicinal Chemistry 11 (2003) 1065–1078

Synthesis and Structure–Aﬃnity Relationship Investigations of

5-Aminomethyl and 5-Carbamoyl Analogues of the Antipsychotic

Sertindole. A NewClass of Selective ꢀ₁Adrenoceptor Antagonists

Thomas Balle,^a,bJens Perregaard,^aAnna K. Larsen,^cMartha Teresa Ramirez,^c

Karina Krøjer Søby,^cTommy Liljefors^band Kim Andersen^a,*

^aMedicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark

^bDepartment of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken,

DK- 2100 Copenhagen, Denmark

^cBiological Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark

Received 24 May 2002; accepted 19 September 2002

Abstract—A new class ofselective a₁adrenoceptor antagonists derived from the antipsychotic drug sertindole is described. The

most potent and selective compound 1-(2-{4-[5-aminomethyl-1-(4-ﬂuorophenyl)-1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imidazo-

lidinone (11) binds with 0.50 nM aﬃnity for a₁adrenergic receptors and with more than 44 times lower aﬃnity for dopamine

D₂,D₃, D₄and serotonin 5-HT_1A, 5-HT_1B, 5-HT_2Aand 5-HT_2Creceptors. The molecular features providing high aﬃnity for adrenergic

a₁receptors and high selectivity towards dopamine D₂and serotonin 5-HT_2Aand 5-HT_2Creceptors are discussed.

Introduction

The adrenergic a₁receptors belong to the superfamily of

G-protein coupled receptors. m-RNA coding for three

1

native receptor subtypes nominated a_1A, a_1Band a_1D

have been identiﬁed in the human brain, and the pre-

2

3

sence ofthe a_1Aand a_1Dadrenoceptor subtypes have

been conﬁrmed by radioligand-binding experiments.

A common feature of ‘atypical’ antipsychotics such as

clozapine, sertindole (1, Chart 1), olanzapine and sero-

quel is nanomolar aﬃnity for a₁-adrenoceptors in addi-

tion to their aﬃnities for dopamine D₂and serotonin

5-HT_2Areceptors.⁴The contribution ofthe a₁-compo-

nent to the therapeutic eﬀect ofthese antipsychotic

agents has been thoroughly investigated. Studies seem

Chart 1. Sertindole (1) and the methoxy analogue ofsertindole ( 2).

Eﬃcacy ofthe a₁antagonist prazosin in animal models

9,10

predictive ofantipsychotic activity

and electro-

to indicate a central role ofthe a₁-component for the

physiological investigations^11,12suggest that blockade

ofnoradrenergic neurotransmission alone could be

beneﬁcial in the treatment ofschizophrenia. In contrast

to these observations, prazosin has been tested in a

small, placebo controlled, clinical trial on schizophrenic

patients without promising results.¹³Furthermore, cen-

trally acting a₁adrenoceptor antagonists may have a

potential as therapeutics for the treatment of diseases

characterised by noradrenergic over-activity such as

5,6

atypical proﬁle ofclozapine

and that a combination

ofdopamine D ₂and a₁adrenoceptor blockade could be

eﬀective as antipsychotic treatment without producing

extrapyramidal side eﬀects.^7,8

*Corresponding author. Tel.: +45-3630-1311; fax: +45-3630-1385;

e-mail: kia@lundbeck.com

PII: S0968-0896(02)00459-5

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T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

mania¹⁴and posttraumatic stress disorder.¹⁵The role of

central a₁adrenergic receptors in neurological function

has recently been reviewed.¹⁶

be used as a template for the development of selective a₁

adrenoceptor antagonists.

Evaluation ofa series ofpreviously reported analogues

31

a₁Adrenoceptor antagonists belonging to a variety of

chemical classes, such as 2,4-diaminoquinazolines, aryl

piperazines, imidazolines, dihydropyridines and

phenethylamines^17ꢀ19have primarily been developed for

the treatment ofcardiovascular diseases and benign

prostatic hyperplasia.^{17,18,20ꢀ22}Examples ofselective

compounds belonging to selected structural classes are

shown in Chart 2. Whereas prazosin is subtype unselec-

tive,²⁰(ꢀ)-SNAP-5089 [(ꢀ)-4],²³(+)-cyclazosin [(+)-5]²⁴

and SNAP-8719 (6)²⁵represent compounds selective for

a_1a, a_1band a_1dreceptors, respectively.

ofsertindole revealed that small polar substituents in

place ofthe chlorine atom in sertindole resulted in

compounds with retained or improved a₁adrenoceptor

aﬃnity.³²Interestingly, the 5-methoxy derivative (2,

Chart 1)³¹ofsertindole has an aﬃnity for adrenergic a₁

32

receptors of1.3 nM, comparable to the aﬃnity ofser-

tindole (Table 2) and 6-fold decreased aﬃnity for

dopamine D₂receptors.³¹These observations indicate a

potential for discrimination between the two types of

receptors by substitution in the area corresponding to

the indole 5-position ofsertindole with polar sub-

stituents containing some additional steric bulk.

The ‘atypical’ antipsychotic Sertindole (1) has nano-

molar aﬃnity for adrenergic (a₁), dopamine (D₁, D₂,

D₃, D₄) and serotonin (5-HT_2A, 5-HT_2C) receptors.⁴In

addition, it has been reported that sertindole is a speciﬁc

inhibitor of a_1Aadrenoceptors in rat small arteries and

binds with nanomolar aﬃnity for the adrenergic a_1a-

receptor.²⁶

We here report the preparation and in vitro pharma-

cological characterisation ofa series ofsertindole ana-

logues with enhanced aﬃnity and selectivity for a₁

adrenoceptors. In addition, the selectivity with regard to

dopamine D₂and D₄as well as setotonin 5-HT₂recep-

tors are discussed in relation to previously published

receptor interaction models for antagonists at these

receptors.^33ꢀ36The present results may be interesting in

connection to the development ofnew selective CNS

active a₁adrenoceptor antagonists and the develop-

ment ofnew antipsychotic compounds possessing

The phenyl-indole skeleton ofsertindole has previously

been used as a template for the development of selective

27ꢀ29

29

ligands for serotonin 5-HT₂

and dopamine D₂

receptors.³⁰The high aﬃnity ofsertindole and ofa ser-

ies ofclose analogues ofr adrenergic a₁adrenocep-

tors^27,28indicate that the sertindole skeleton may also

balanced antagonism ofdopamine D and adrenergic

2

a₁receptors.

Chemistry

The preparation of3-(4-piperidinyl)-1-(4-ﬂuorophenyl)-

1H-indoles substituted in the 5- and 6-positions ofthe

indole nucleus has previously been described by Perre-

gaard et al.^27,31

Preparation ofthe carboxamides 7 and 8 as well as the

aminomethyl derivatives 9 and 10 are described in

Scheme 1. 1-(4-Fluorophenyl)-1H-indole-5-carboxylic

acid, 17b was obtained by alkaline hydrolysis ofthe

corresponding cyano derivative 17a prepared according

to published procedures.³¹Activation ofthe carboxylic

acid 17b with 1,1-carbonyldiimidazole³⁷or ethyl chloro-

formate³⁸and subsequent reaction with methyl amine

or dimethyl amine aﬀorded the carboxamides 18a and

18b. Reaction ofthe carboxamides 18a and 18b with

4-piperidone hydrochloride, hydrate using acidic condi-

tions gave the 5-substituted 1-(4-ﬂuorophenyl)-3-

(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indoles 19a and

19b. Subsequent catalytic hydrogenation using platinum

as catalyst gave the corresponding piperidines 20a and

20b. The ﬁnal carboxamides 7 and 8 were obtained by

alkylation with 1-(2-chloroethyl)imidazolidin-2-one.

The corresponding aminomethyl derivatives 9 and 10

were obtained from the carboxamides 7 and 20b by

reduction with lithium aluminium hydride. Reduction of

the N-methyl-carbamoyl derivative 7 with lithium alumi-

nium hydride aﬀorded the ﬁnal N-methyl-aminiomethyl

derivative 9 directly. The N,N-dimethyl-aminomethyl

Chart 2. Selected selective a₁adrenoceptor antagonists.

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

1067

Scheme 1. Reagents: (a) KOH, EtOH, reﬂux, 24 h; (b) For R²=H: (i) 1,1-carbonyldiimidazole, THF, 20 ^ꢁC, 45 min; (ii) CH₃NH₂, 0–20 ^ꢁC, 65

min; for R²=CH₃: (i) ClCOOEt, NEt₃, CH₂Cl₂, ꢀ30 to ꢀ10 ^ꢁC, 2 h; (ii) (CH₃)₂NH, ꢀ10 to 20 ^ꢁC, 2 h; (c) 4-piperidone hydrochloride hydrate,

TFA/AcOH, reﬂux, 1 h; (d) H₂, PtO₂, AcOH, 5 h; (e) 1-(2-chloroethyl)-imidazolidin-2-one, K₂CO₃, KI, 4-methyl-2-pentanone, reﬂux, 8 h; (f)

LiAlH₄, THF, reﬂux, 3 h.

derivative 10 was obtained by reduction ofthe inter-

mediate 20b with lithium aluminium hydride followed

by alkylation with 1-(2-chloroethyl)imidazolidin-2-one

as described above.

The 5-aminomethyl and 5-acetylaminomethyl deriva-

tives 11 and 12 were obtained from the nitrile 22³¹as

outlined in Scheme 2. Catalytic hydrogenation using

platinum resulted in simultaneous reduction ofthe

double bond in the tetrahydropyridine ring and the

nitrile group giving the 5-aminomethyl derivative 11

directly. Subsequent reaction ofthe 5-aminomethyl

derivative 11 with acetyl chloride gave the 5-acetyl-

aminomethyl derivative 12.

The tetrazolylmethyl-indole derivatives 13 and 14 were

prepared as outlined in Scheme 3. Reduction ofthe car-

boxylic acid 17b with lithium aluminium hydride and sub-

sequent reaction with methanesulfonyl chloride gave the

chloromethyl derivative 17d as expected for benzylic alco-

hols. Reaction with sodium cyanide followed by 1,3-dipo-

lar cycloaddition with sodium azide aﬀorded the

unsubstituted tetrazole 23. Methylation ofthe N-unsub-

stituted tetrazole 23 and subsequent separation ofthe

formed isomers by column chromatography gave the

N-methyl-tetrazolylmethyl derivatives 24a and 25a.

Scheme 2. Reagents: (a) H₂, PtO₂, AcOH, 5 h; (b) ClCOCH₃, NEt₃,

CH₂Cl₂, 20 ^ꢁC, 1 h.

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T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

Scheme 3. Reagents: (a) LiAlH₄, THF, reﬂux, 2 h; (b) CH₃SO₂Cl, NEt₃, CH₂Cl₂, 0–5 ^ꢁC, 2 h; (c) NaCN, DMSO, 140 C, 40 min; (d) NaN₃, NEt₃

hydrochloride, 1,2-dimethoxyethan, reﬂux, 48 h; (e) (CH₃)₃COK, CH₃I, column chromatography; (f) 4-piperidone hydrochloride hydrate, TFA/

AcOH, reﬂux, 1 h; (g) 1-(2-chloroethyl)-imidazolidin-2-one, K₂CO₃, KI, 4-methyl-2-pentanone, reﬂux, 8 h; (h) H₂, PtO₂, AcOH, 5 h.

These were converted into the ﬁnal 1-(piperidin-4yl)

ethyl-imidazolidin-2-ones 13 and 14 as described above

for the preparation of the carboxamides in Scheme 1, with

the exception, that the order ofalkylation and reduction

to the piperidines was reversed without signiﬁcant eﬀects

on the yields ofthe reactions. The position ofthe methyl

groups in the 1- and 2-methyl-tetrazole isomers were

conﬁrmed by 2D-NOESY experiments³⁹on the tetra-

hydropyridine-substituted analogues 24c and 25c as

described in the Experimental section.

The trimethylsilyl-substituted indole 15 was prepared

from the N-boc-protected 5-bromo-piperidinyl-1H-

indole 26d as described in Scheme 4. The intermediate

26d was prepared in three steps from 5-bromo-1-(4-

ﬂuorophenyl)-1H-indole (17) as described for the pre-

paration ofthe caboxamides 7 and 8 above followed by

boc protection. Halogen metal exchange ofthe bromine

in the indole 5-position in analogy to procedures repor-

ted by us recently⁴⁰and subsequent reaction with tri-

methylsilyl chloride gave the intermediate 27a. The

N-boc-group was removed by stirring ofneat 27a at

230 ^ꢁC resulting in the deprotected piperidinyl derivative

27b. Acidic conditions were unsuccessful due to partial

removal ofthe trimethylsilyl group. Trimethylsilyl groups

at electron-rich aromatic carbons are known to be labile

under acidic conditions.⁴¹The ﬁnal product 15 was

Scheme 4. Reagents: (a) 4-piperidone hydrochloride hydrate, TFA/

AcOH, reﬂux, 90 min; (b) H₂, PtO₂, AcOH, 5 h; (c) (boc)₂O, THF/water,

achieved by alkylation ofthe deprotected piperidinyl

derivative 27b with 1-(2-chloroethyl)imidazolidin-2-one

as described above.

60^ꢁC, 8 h; (d) (i) n-BuLi, reverse addition, ꢀ78^ꢁC, 3 min; (ii) (CH₃)₃SiCl,

ꢀ78 to 20 ^ꢁC, 30 min; (e) neat, 230^ꢁC, 3 h; (f) 1-(2-chloroethyl)-

imidazolidin-2-one, K₂CO₃, KI, 2-methyl-pentanone, reﬂux, 8 h.

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

1069

Table 1.^a

Receptor

Species

Membrane source

Radioligand (mM)

Ref. Compd.

K_i(nM)

a₁

a_1a

a_1b

a_1d

D₂

D₃

D₄

5-HT_1A

5-HT_1B

5-HT_2A

5-HT_2C

Rat

Bovine^b

Hamster^b

Rat^b

Whole brain

BHK cells

Rat-1 cells

[³H]prazosin (0.25)

[³H]prazosin (0.3)

[³H]prazosin (0.5)

[³H]prazosin (0.3)

[³H]spiperone (0.5)

[³H]spiperone (0.3)

[³H]YM-09151–2 (0.06)

[³H]5-CT (2.0)

Prazosin

0.29

0.93

0.46

1.4

1.9

2.7

30

2.2

4.8

(ꢂ)-Cyclazosin

SNAP-8719

Haloperidol

Clozapine

Metitepine

Serotonin

Mianserine

Mesulergine

CHO cells

Rat

Corpus striatum

CHO cells

HeLa cells

Human^b

Rat

[³H]5-CT (1.5)

Cerebral cortex

SR-3T3 cells

[³H]ketanserin (0.5)

[³H]mesulergine (0.5)

2.5

0.37

Rat^b

^aFor detailed description ofassays, see Experimental.

^bCloned receptors.

Preparation ofthe 5,6-methylenedioxy-1 H-indole deri-

vative 16 is described in Scheme 5. Base-catalysed reac-

tion of4-piperidone with 5,6-methylenedioxy-1 H-indole

(28a) followed by catalytic hydrogenation in the pre-

sence ofplatinum according to previously published

procedures²⁷gave the piperidine 28c which was subse-

quently boc-protected. 1-Arylation with 4-ﬂuoro-iodo-

benzene using Ullmann conditions^27,42resulted in the

for sertindole and compounds prepared in the present

study are reported in Table 2. In addition, receptor-

binding aﬃnities for the a₁adrenergic receptor subtypes

a_1a, a_1band a_1dand the dopamine D₁, D₃and D₄

receptors are reported in Table 3 for selected compounds

and reference compounds. Good correlation based on

receptor-binding aﬃnities between the human clones and

Table 2. Receptor-binding aﬃnities for 5-substituted 1-(4-ﬂuoro-

phenyl)-1H-indoles and 5,6-methylenedioxy derivative 16

1-(4-ﬂuorophenyl)-5,6-methylenedioxy-1H-indole

29.

Removal ofthe boc group by means ofhydrochloric

acid in methanol and alkylation according to the pro-

cedure employed in the preparation ofthe N,N-dime-

thyl-amminomethyl derivative 10 aﬀorded the ﬁnal

product 16.

Results and Discussion

The receptor-binding assays are described in Table 1

and in detail in the Experimental section. Receptor-

binding aﬃnities (adrenergic a₁, dopamine D₂and ser-

otonin 5-HT_1A, 5HT_1B, 5HT_2Aand 5-HT_2Creceptors)

K_i(nM)^a

Compd

R

a₁

D₂

5-HT_1A5-HT_1B5-HT_2A5-HT_2C

Sertindole (1)

1.4^b

0.45^b

33

91

56

85

0.20^b

0.51^b

7

8

9

2.5 170

21

450

3.9

40

100

62

40

17

68

12

0.45

6.6

570

4.1

10

11

12

0.58 16

0.50 37

58

290

62

180

640

67

15

22

11

27

64

82

0.46

0.58

0.28

3.1

13

14

2.7

1.9

22

24

NT NT

NT

130

NT

32

10

15

16

23

0.52

100

7.7

NT

7.5

Scheme 5. Reagents: (a) 4-piperidone hydrochloride hydrate, KOH,

EtOH, reﬂux, 24 h; (b) H₂, PtO₂, AcOH/EtOH, 20 h; (c) (boc)₂O,

K₂CO₃, THF/H₂O, 60 ^ꢁC, 22 h; (d) 4-ﬂuoro-iodobenzene, K₂CO₃, KI,

ZnO, NMP, 100 ^ꢁC, 48 h; (e) (i) HCl/MeOH, rt, 4 h; (ii) 1-(2-chloro-

ethyl)-imidazolidin-2-one, K₂CO₃, KI, 2-methyl-pentanone, reﬂux, 8 h.

0.65 NT

^aFor details on assays, see Table 1.

^bRef4 .

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T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

Table 3. Receptor-binding aﬃnities for selected 5-substituted 1-(4-ﬂuorophenyl)-1H-indoles and reference compounds^a

Ki (nM)^a

Compd

R^b

a₁

a_1a

0.37

0.93

5900

a_1b

a_1d

D₂

D₃

2.6^c

NT

D₄

11^c

NT

5-HT_1A

5-HT_1B

5-HT_2A

5-HT_2C

1

3

6

Sertindole

Prazosin

SNAP-8719

1.4^c

0.29

0.33

0.83

170

0.66

0.26

1.4

0.45^c

NT

33

NT

56

NT

0.20^c

NT

0.51^c

NT

840

7

2.5

3.7

4.4

14

170

2100

NT

170

560

6000

NT

280

740

91

62

85

570

180

640

21

4.1

15

22

450

12

9

0.45

0.58

0.50

0.80

0.60

0.18

0.60

0.18

1.1

0.48

0.59

0.69

6.6

10

11

16

37

58

27

290

64

^aFor details on assays, see Table 1.

^bSee Table 2.

^cRef4 .

the corresponding cloned a_1a(bovine), a_1b(hamster),

and a_1d(rat) receptors has been documented.⁴

assay ofhuman recombinant 5-HT

receptors expres-

1A

sed in HeLa-cells using [³H]5-CT as radioligand,

whereas the previously published value was obtained in

an assay ofrat or human brain membranes using the

[³H]8-OH-DPAT radioligand. Thus, We can not

exclude that species diﬀerences may aﬀect the apparent

aﬃnity for certain compounds.

Replacement ofthe chlorine atom in the 5-position of

the indole moiety in sertindole (1) with aminomethyl (9–

11), acetylaminomethyl (12) and tetrazolylmethyl

groups (13–14) resulted in compounds with enhanced,

subnanomolar, aﬃnity for adrenergic a₁receptors as

apparent from Table 2. Replacement with carbamoyl

groups (7–8) resulted in slightly reduced aﬃnities.

Replacement ofthe chlorine atom in sertindole with

acetylaminomethyl (12) and tetrazolylmethyl (13–14)

substituents had no eﬀect on the binding aﬃnity for

serotonin 5-HT_1Aand 5-HT_1Breceptors. In contrast,

replacement with an aminomethyl substituent (11)

resulted in 8- to 11-fold reduced aﬃnity. Apparently,

the aﬃnity for both 5-HT_1Aand 5-HT_1Breceptors

increases gradually with increasing methyl substitution

on the amine as apparent by comparing the aﬃnity of

the aminomethyl derivatives 9–11. The same trend is

indicated for the carboxamides 7 and 8 for 5-HT_1B

receptors.

Compared to sertindole, all compounds have reduced

aﬃnity for dopamine D₂receptors. The most pro-

nounced reduction is noted for the carboxamides 7 and

8, the aminomethyl derivative 11. These compounds

have 377-, 88- and 82-fold reduced aﬃnity compared to

sertindole. These compounds are also among the least

potent at serotonin 5-HT_2Aand 5-HT_2Creceptors.

The eﬀects ofthe 5-substituents studied on the receptor-

binding aﬃnities for dopamine D₂receptors and sero-

tonin 5-HT_2Aand 5-HT_2Creceptors seem to be essen-

tially parallel, and the 5-HT_2Creceptor seems to be

more sensitive to the replacements ofthe chlorine atom

in sertindole with the substituents listed in Table 2.

Exceptions are the acetylaminomethyl derivative 12 and

the 1-methyl-tetrazolylmethyl derivative 14. These com-

pounds have 50- to 55-fold and 160- to 254-fold reduced

aﬃnity for serotonin 5-HT_2Aand 5-HT_2Creceptors,

respectively, compared to sertindole, whereas the aﬃnity

for dopamine D₂receptors is in the nanomolar range.

The most selective ofthe compounds listed in Table 2 is

the aminomethyl derivative 11 having more than 40-fold

reduced aﬃnity for the receptors listed in Table 2 com-

pared to the adrenergic a₁receptors. The receptor-

binding aﬃnities for the adrenergic a_1a, a_1b, a_1dand

dopamine D₃and D₄receptor subtypes for this com-

pound and for reference compounds are listed in Table

3. In addition, the receptor-binding aﬃnities for the

carboxamide 7 and the N,N-dimethyl-aminomethyl

derivative 10, showing a₁/D₂selectivities higher than 25,

are reported.

Sertindole has moderate aﬃnity for serotonin 5-HT_1A

(K_i=33 nM) and 5-HT_1B(K_i=56 nM) receptors as

apparent from Table 2. These data are in contrast with

the previously published receptor-binding aﬃnity for

The aﬃnities ofthe compounds 7, 10 and 11 for dopa-

mine D₃and D₄receptors are reduced with a factor of

85–1050 and 16–350 compared to sertindole, respec-

tively. Thus, aﬃnity for these receptors does not pose

problems with regard to selectivity.

6

5-HT_1Areceptors of2200 and 1050 nM.⁴³However,

the data presented in this paper is obtained from an

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

1071

In our hands, sertindole (1) binds with sub-nanomolar

aﬃnity for the three a₁adrenoceptor adrenergic sub-

types (a_1a, a_1b, a_1d) as shown in Table 3. These data are

in contrast with previously published values by Ipsen et

al. who found that sertindole was selective for the a_1a

adrenoceptor compared to a_1band a_1d.²⁶However, the

use ofdiﬀerent radioligands and/or diﬀerent assay con-

ditions may account for this discrepancy.

acetylaminomethyl-substituted derivative 12 (0.36 kcal/

mol above minimum energy conformation) (Fig. 2)

shows that these substituents may adopt conformations

where the steric bulk ofthe substituents is situated out

oﬀ the plane ofthe indole.

According to these molecular modelling results, the

dopamine D₂receptor apparently accommodates large

substituents out ofthe plane ofthe indole. In contrast,

large substituents in the plane seem to be disfavoured

for both dopamine D₂and D₄receptors. Low aﬃnity

for serotonin 5-HT_2Aand 5-HT_2Creceptors is observed

both with ‘in plane’ and ‘out ofplane’ substituents.

The aminomethyl derivative 11 binds with an aﬃnity of

0.18 nM for the a_1areceptor and have 6 and 4 times

lower aﬃnity for a_1band a_1dreceptors. In contrast, the

N,N-dimethyl-aminomethyl derivative 10 has higher

aﬃnity for the a_1breceptors compared to a_1aand a_1das

apparent from Table 3. The carboxamide 7 has similar

aﬃnities for a_1aand a_1breceptors and three times lower

aﬃnity for a_1dreceptors. Thus, none ofthe compounds

show any signiﬁcant diﬀerence in aﬃnity for the adre-

nergic a₁receptor subtypes.

27

A number ofpreviously reported data

indicate that

substituents inducing steric bulk in the area corre-

sponding to the indole 6-position in phenylindoles result

in decreased aﬃnity for a₁adrenoceptors for sub-

stituents larger than ﬂuorine. Interestingly, the aﬃnity

for adrenergic a₁receptors ofthe 5,6-methylenedioxy

derivative 16 is enhanced compared to sertindole. Electro-

static interactions compensating for the substitution in

the sterically unfavourable area of the indole 6-position

may account for the high aﬃnity of this compound. This

is evident by comparing the aﬃnity ofthe methylene-

dioxy derivative 16 with the aﬃnity ofthe correspond-

ing 5,6-propano derivative⁴⁴(not shown), where the

oxygen atoms in the 5,6-methylenedioxy moiety are

replaced with methylene groups. The latter derivative

binds with 21 nM aﬃnity for adrenergic a₁receptors³²

corresponding to a 40-fold reduction in aﬃnity.

It has previously been shown that steric bulk in the area

corresponding to the indole 5-position increased aﬃnity

for dopamine D₂receptors.³⁶In contrast, bulk in the

area corresponding to the indole 6-position resulted in

decreased aﬃnity.^27,36Similar, substitution eﬀects were

found for the dopamine D₄receptor.³⁵These obser-

vations are based on a number ofsmall lipophilic sub-

stituents such as methyl and triﬂuoromethyl groups as

well as halogen atoms. To further extend these studies,

we synthesised the trimethylsilyl-substituted derivative

15. Reduced aﬃnity ofthis compound ofr a₁, D₂and

5-HT_2Areceptors compared to sertindole indicates a

limit for the size of lipophilic indole 5-substituents. The

eﬀect is most pronounced for dopamine D₂receptors

where the aﬃnity is reduced more than 200-fold.

Apparently, the set ofmolecular features describing the

aﬃnity and selectivities for a₁adrenoceptors for the

present set ofmolecules is a delicate balance between

favourable electrostatic and unfavourable steric inter-

actions. All ofthe present molecules, except the tri-

methylsilyl derivative 15, may beneﬁt from favourable

electrostatic interactions with the adrenergic a₁recep-

tor which may explain the high aﬃnity ofthese com-

pounds despite unfavourable steric interactions as

described above. The combination ofthese efatures is

diﬃcult to address by qualitative means. We are there-

fore currently investigating this topic by means of a

3-D-QSAR analysis.

As previously mentioned, the carboxamides 7 and 8

have low aﬃnity for dopamine D₂receptors, whereas

the acetylaminomethyl and tetrazolylmethyl derivatives

12–14 (Table 2) have nanomolar aﬃnity for these

receptors.

Superimposition ofthe carboxamides 7 and 8 (Fig. 1)

shows that the carbamoyl substituents superimpose in

their minimum energy conformations inducing bulk in

the plane ofthe indole. In contrast, superimposition ofthe

minimum energy conformation of the tetrazolylmethyl

derivative 13 with a low energy conformation of the

Figure 1. Superimposition ofcarboxamides 7 (grey) and 8 (green).

Indole C3 and N1 substituents are replaced with hydrogens for clarity.

Colour code: Nitrogens: Blue; Oxygen: Red.

Figure 2. Superimposition of 12 (grey) and 13 (green). Indole C3 and

N1 substituents are replaced with hydrogens for clarity. Colour code:

Nitrogens: Blue; Oxygen: Red.

1072

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

The combination ofa hydrogen bond acceptor to

maintain high aﬃnity for adrenergic a₁receptors and

some additional steric bulk in the plane ofthe indole to

reduce aﬃnity for dopamine D₂and serotonin 5-HT_2A

and 5-HT_2Creceptors may explain the high aﬃnity and

selectivity for adrenergic a₁receptors ofthe compounds

presented in the present paper. We are currently

exploring a series ofphenylindoles where the substituent

in the indole 5-position has electron-donating properties

combined with some additional steric bulk.

Gravimetric Analysis (TGA) on a TA-instruments TGA

2950 with heating rate 10 ^ꢁC per min. Results are

reported in% (w/w). The nature ofthe solvent was

1

identiﬁed by H NMR. Solvent residuals are not repor-

ted in the NMR data. LC–MS data (Liquid Chroma-

tography Mass Spectroscopy) were obtained on a PE

Sciex API150EX equipped with a Heated Nebulizer

source operating at 425 ^ꢁC. The LC–MS pumps were

Shimadzu 8A series running with a Waters C-18 4.6ꢃ50

mm, 3.5 mm column. Solvent A: 100% H₂O+0.05%

triﬂuoroacetic acid, solvent B: 95% CH₃CN, 5%

H₂O+0.035% TFA. Gradient (2 mL/min): 10% B-

100% B in 4 min, 10% B for 1 min. Total time including

equilibration 5 min. Injection volume 10 mL from a

Gilson 215 Liquid Handler. The reported purities are

based on the integration ofthe peaks in the UV and

ELSD spectrum.

Conclusion

The present study has shown that selective a₁adreno-

ceptor antagonists can be developed by the replacement

ofthe chlorine atom in sertindole with polar sub-

stituents. Replacement ofchlorine with an aminomethyl

substituent resulted in a selective a₁adrenoceptor

antagonist, 1-(2-{4-[5-aminomethyl-1-(4-ﬂuorophenyl)-

1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imidazolidinone

(11) with subnanomolar aﬃnity for a₁adrenoceptors

and more than 44-fold lower aﬃnity for dopamine D₂,

D₃, D₄and serotonin 5-HT_1A, 5-HT_1B, 5-HT_2Aand

5-HT_2Creceptors. Electrostatic interactions with the

receptor seem to be responsible for the high aﬃnity for

adrenergic a₁receptors. In addition, new information

has been added to previously developed serotonin

5-HT_2Aand dopamine D₂and D₄receptor interaction

models. There seems to be limits to the size ofsub-

stituents allowed in the plane ofthe aromatic pharma-

cophore corresponding to the indole 5-position. In

contrast, large substituents out ofplane result in com-

pounds with high aﬃnity for both dopamine D₂and

adrenergic a₁receptors. This information may be

1-(4-Fluorophenyl)-1H-indole-5-carboxylic acid (17b).

5-Cyano-1-(4-ﬂuorophenyl)-1H-indole³¹(17a) (60.0 g,

0.25 mol) and KOH (60.0 g, 1.1 mol) was boiled under

reﬂux for 24 h in 90% EtOH (500 mL). H₂O (1.5 L) was

added and the aqueous phase extracted with diisopropyl

ether (2ꢃ500 mL). After acidifying with HCl (4 M), 60.0

g ofthe title compound 17b_ꢁ(0.24 mol, 96%) was ﬁltered

1

oﬀ and dried: mp 224–227 C; H NMR (DMSO-d₆) d:

6.90 (d, 1H), 7.45 (t, 2H), 7.55 (d, 1H), 7.60–7.72 (m,

3H), 7.85 (d, 1H), 8.40 (s, 1H), 12.70 (s, broad, 1H).

5-Cyanomethyl-1-(4-ﬂuorophenyl)-1H-indole (17e).

A

solution of1-(4-ﬂuorophenyl)-1 H-indole-5-carboxylic

acid (17b) (33.5 g, 0.13 mol) in THF (700 mL) was

added cautiously to a mixture ofLiAlH (9.8 g, 0.26

4

mol) in THF (400 mL) at 0 ^ꢁC. The resulting mixture

was boiled under reﬂux for 2 h. After cooling to 0 ^ꢁC,

H₂O (10 mL) and 14% aqueous NaOH (10 mL) was

carefully added. Filtration using Celite and evaporation

ofthe solvents aﬀorded 27 g (87%) ofcrude 1-(4-ﬂuoro-

phenyl)-5-hydoxymethyl-1H-indole (17c): mp 69–70 ^ꢁC;

¹H NMR (CDCl₃) d: 1.85–1.95 (broad s, 1H), 4.75 (s,

2H), 6.65 (d, 1H), 7.15–7.25 (m, 3H), 7.25 (d, 1H), 7.35–

7.45 (m, 3H), 7.65 (broad s, 1H). To a solution ofcrude

17c (21.5 g, 89 mmol) and NEt₃(21.5 mL) in CH₂Cl₂

(400 mL), a solution ofmethanesulof nyl chloride (15.3

g, 0.13 mol) in CH₂Cl₂(200 mL) was added at 0–5 ^ꢁC.

exploited in the development ofnew selective

a₁

antagonists.

Experimental

General

All reactions were carried out under a positive pressure

ofnitrogen or argon. Glassware ofr water-sensitive

reactions was dried in an oven at 150 ^ꢁC overnight. For

ﬂash chromatography, either silica gel oftype Kiesel gel

60, 230–400 mesh ASTM or Biotage Flash40 (50 or 100

After stirring at 0–5 ^ꢁC f or 2 h, HO (600 mL) was

2

added, the phases were separated, and the aqueous

phase was extracted with CH₂Cl₂(500 mL). The com-

bined organic phases were dried (MgSO₄), and the sol-

vents evaporated in vacuo aﬀording 27.0 g crude

5-chloromethyl-1-(4-ﬂuorophenyl)-1H-indole (17d) as

1

g columns) were used. H NMR spectra were recorded

ofall novel compounds at 250 MHz on a Bruker AC

250 or at 500 MHz on a Bruker Avance DRX500

instrument. Deuterated chloroform (99.8%D) or

DMSO-d₆(99.9%D) were used as solvents. TMS was

used as internal reference standard. Chemical shift

values are expressed in ppm values. The following

abbreviations are used for multiplicity of NMR signals:

1

an oil: H NMR (CDCl₃) d: 4.65 (s, 2H), 6.60 (d, 1H),

7.00–7.20 (m, 4H), 7.25–7.40 (m, 2H), 7.45 (d, 1H), 7.65

(s, 1H). A solution ofthe crude 17d (27.0 g) in DMSO

(300 mL) was added to a solution ofNaCN (10.5 g, 0.21

mol) in DMSO (600 mL) at 80 ^ꢁC. After heating of

the reaction mixture at 80 ^ꢁC for further 40 min, the

reaction mixture was cooled to room temperature and

H₂O (900 mL) was added. The resulting mixture was

extracted with Et₂O (2ꢃ1.5 L), and the combined organic

phases were washed with brine (2ꢃ1.5 L). Drying of

the combined organic phases (Na₂SO₄), evaporation

ofthe solvents in vacuo and puriﬁcation by column

s=singlet,

d=doublet,

t=triplet,

q=quartet,

qd=quartet ofdoublets, dd=double doublet, dt=dou-

ble triplet, tt=triplet oftriplets, m=multiplet. NMR

signals corresponding to acidic protons are generally

omitted. Melting points are reported uncorrected. Sol-

vent residuals in elemental analysis samples were mea-

sured by Karl Fisher titration (H₂O) or by Thermo

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

1073

chromatography on silica gel (EtOAc/heptane 1:3)

aﬀorded 8.2 g of5-cyanomethyl-1-(4-ﬂuorophenyl)-1 H-

indole (17e) as an oil (37% from 17b): ¹H NMR

(CDCl₃) d: 3.80 (s, 2H), 6.60 (d, 1H), 7.05–7.25 (m, 3H),

7.25 (d, 1H), 7.35–7.45 (m, 3H), 7.60 (broad s, 1H).

7.65 (dd, 2H), 7.70–7.80 (m, 2H), 8.40 (s, 1H), 8.45 (q,

broad, 1H).

Compound 19b was obtained accordingly from 18b.

N,N-Dimethyl-1-(4-ﬂuorophenyl)-3-(1,2,3,6-tetrahydro-

4-pyridyl)-1H-indole-5-carboxamide (19b). Yield 14.0 g

(92%); oil: H NMR (CDCl₃) d: 2.65 (m, 2H), 3.05 (s,

6H), 3.25 (t, 2H), 3.70 (d. 2H), 5.00 (s, broad, 1H), 6.30

(s, broad, 1H), 7.10–7.40 (m, 4H), 7.40–7.50 (m, 3H),

8.02 (s, 1H).

1-(4-Fluorophenyl)-N-methyl-1H-indole-5-carboxamide

(18a). 1-(4-Fluorophenyl)-1H-indole-5-carboxylic acid

(17b) (16.0 g, 63 mmol) was dissolved in THF (120 mL).

1,1-Carbonyldiimidazole (15.0 g, 93 mmol) was added,

and the solution was stirred at room temperature for 50

min. After cooling to 0 ^ꢁC, CH₃NH₂(125 mL, 2 M in

THF, 0.25 mol) was added keeping the solution below

10 ^ꢁC. After the addition, the solution was stirred for 20

min at 0 ^ꢁC and 45 min at room temperature. After

removal ofthe solvent in vacuo, the mixture was dis-

solved in EtOAc (250 mL), washed with H₂O (100 mL),

1

1-(4-Fluorophenyl)-N-methyl-3-(piperidin-4-yl)-1H-indole-

5-carboxamide (20a). 1-(4-Fluorophenyl)-N-methyl-3-

(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole-5-carboxamide

(19a) (6.8 g, 19.5 mmol) was dissolved in a mixture of

AcOH (150 mL) and TFA (25 mL). After the addition

a saturated aqueous solution ofNaHCO (50 mL) and

3

ofPtO (300 mg), the mixture was reacted with H₂in a

2

dried over MgSO₄. The product was recrystallised from

EtOAc/heptane 1:3 to yield 12.3 g (73%) ofthe title

compound 18a: mp 126–128 ^ꢁC (EtOAc/heptane); ¹H

NMR (DMSO-d₆) d: 2.80 (d, 3H), 6.80 (d, 1H), 7.45 (t,

2H), 7.50 (d, 1H), 7.65 (m, 2H), 7.70 (m, 2H), 8.20 (s,

1H), 8.40 (d, broad, 1H). Anal. (C₁₆H₁₃FN₂O): C, H,

N.

Parr apparatus at 3 ato for 5 h at room temperature.

Solids were ﬁltered oﬀ, and the solvent removed in

vacuo. H₂O (100 mL) was added, pH adjusted to 10 by

addition of28% aqueous NaOH, and the aqueous

phase was extracted with EtOAc (3ꢃ150 mL). After

removal ofthe solvent in vacou, the product was ﬁltered

through silica gel (EtOAc/EtOH/NEt₃50/50/5). Eva-

poration ofthe solvents in vacuo aﬀorded 4.0 g (58%)

ofthe title compound 20a as a foam: ¹H NMR (DMSO-

d₆) d: 1.65 (qd, 2H), 1.95 (d, 2H), 2.70 (t, 2H), 2.80 (d,

3H), 2.95 (t, 1H), 3.10 (d, 2H), 7.40 (t, 2H), 7.45–7,52

(m, 2H), 7.65 (m, 2H), 7.75 (d, 1H), 8.25 (s, 1H), 8.45 (q,

1H).

N,N-Dimethyl-1-(4-ﬂuorophenyl)-1H-indole-5-carboxamide

(18b). 1-(4-Fluorophenyl)-1H-indole-5-carboxylic acid

(17b) (20.0 g, 81 mmol) and NEt₃(8.0 g, 81 mmol) in

CH₂Cl₂(325 mL) was cooled to ꢀ30 ^ꢁC. Ethyl chloro-

formate (8.7 g, 81 mmol) was added, and the tempera-

ture kept below ꢀ10 ^ꢁC for 2 h. A 33% solution of

(CH₃)₂NH in ethanol (16.0 g, 117 mmol) was added at

ꢀ10 ^ꢁC. After the addition, the cooling bath was

removed, and the solution was stirred at room tem-

perature for 45 min. A solution of 0.5 M NaOH (125

mL) was added, and the mixture was extracted with

CH₂Cl₂(2ꢃ150 mL). After evaporation of the solvent,

the crude product was ﬁltered through silica gel

(EtOAc/heptane/NEt₃20/80/1), and the solvent

removed in vacuo to yield 12.0 g (52%) ofthe title

Compound 20b was obtained accordingly from 19b.

N,N-Dimethyl-1-(4-ﬂuorophenyl)-3-(piperidin-4-yl)-1H-

indole-5-carboxamide (20b). Yield 6.0 g (86%); Foam:

¹H NMR: (CDCl₃) d: 1.75 (qd, 2H), 2.1 (d, 2H), 2.85

(dt, 2H), 3.00 (tt, 1H), 3.15 (s, 6H), 3.25 (t, 2H), 7.10 (s,

1H), 7.15–7.35 (m, 3H), 7.35–7.50 (m, 3H), 7.80 (s, 1H).

5-Dimethylaminomethyl-1-(4-ﬂuorophenyl)-3-(piperidin-

4-yl)-1H-indole (21). N,N-Dimethyl-1-(4-ﬂuorophenyl)-

3-(piperidin-4-yl)-1H-indole-5-carboxamide (20b) (4.3 g,

12 mmol) in dry THF (25 mL) was added slowly to a

1

compound 18b as an oil: H NMR (CDCl₃) d: 3.10 (s,

6H), 6.70 (s, 1H), 7.20 (t, 2H), 7.20–7.35 (m, 2H), 7.35–

7.50 (m, 3H), 7.80 (s, 1H).

solution ofLiAlH (1.5 g, 40 mmol) in THF (50 mL)

4

1-(4-Fluorophenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyr-

idyl)-1H-indole-5-carboxamide (19a). A solution of1-(4-

ﬂuorophenyl)-N-methyl-1H-indole-5-carboxamide (18a)

(12.3 g, 45.8 mmol) in a mixture ofAcOH (60 mL) and

TFA (15 mL) was added during 0.5 h to a reﬂuxing

solution of4-piperidone, HCl, H ₂O (34.6 g, 0.23 mol) in

a mixture ofAcOH (50 mL) and TFA (100 mL). The

reaction mixture was boiled under reﬂux for 1 h, cooled

to room temperature, and the solvents were removed in

vacuo. H₂O (200 mL) was added and pH was adjusted

to 10 by the addition of14% aqueous NaOH. The

aqueous phase was extracted with EtOAc (3ꢃ150 mL).

The combined organic phases were washed with H₂O

(100 mL) and brine (50 mL) and dried over MgSO₄.

Evaporation ofthe solvents in vacuo aﬀorded 16.0 g

keeping the temperature below 40 ^ꢁC. The solution was

stirred for 2 h at 40 ^ꢁC. After cooling to room tempera-

ture the excess ofLiAlH was destroyed by cautious

4

drop-wise addition ofwater. Subsequently, water (100

mL) and 1 M aqueous NaOH (5 mL) were added and

the aqueous phase extracted with Et₂O (2ꢃ200 mL) to

yield 3.5 g (86%) ofcrude 21 as an oil: ¹H NMR

(CDCl₃) d: 1.70 (2H), 2.05 (d, 2H), 2.25 (s, 6H), 2.85 (td,

2H), 3.00 (tt, 1H), 3.20 (d, 2H), 3.50 (s, 2H), 7.00 (s,

1H), 7.10–7.30 (m, 3H), 7.30–7.50 (m, 3H), 7.60 (s, 1H).

1-(4-Fluorophenyl)-5-[(tetrazol-5-yl)methyl]-1H-indole

(23). A solution of5-cyanomethyl-1-(4-ﬂuorophenyl)-

1H-indole (17e) (8.2 g, 32.8 mmol), NaN₃(7.7 g, 0.29

mol), NEt₃,HCl (13.5 g, 98 mmol) in 1,2-dimethoxy-

ethane (100 mL) was boiled under reﬂux for 2 days.

After cooling to room temperature, solids were ﬁltered

oﬀ and the volatile solvents were evaporated in vacuo.

1

(100%) ofthe title compound 19a as a foam: H NMR

(DMSO-d₆) d: 2.48 (s, broad, 2H), 2.80 (d. 3H), 2.98 (t,

2H), 3.50 (d, 2H), 6.40(s, 1H), 7.45 (t, 2H), 7.50 (d, 1H),

1074

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

H₂O (100 mL) and glacial AcOH (15 mL) were added,

and the resulting mixture was extracted with EtOAc

(2ꢃ150 mL). The combined organic phases were washed

with H₂O (200 mL) and brine (200 mL) and subse-

quently dried (Na₂SO₄). Evaporation ofthe solvents in

vacuo gave 14.0 g ofcrude 1-(4-ﬂuorophenyl)-5-(tetra-

zol-5-ylmethyl)-1H-indole 23 as an oil containing some

the crude product was puriﬁed by column chroma-

tography (EtOAc/EtOH/NEt₃80/20/4) to yield 3.5 g

(57%) ofthe title compound 24c: mp 129–131 ^ꢁC

1

(EtOH); H NMR (CDCl₃) d: 2.55–2.75 (m, 4H), 2.80

(t, 2H), 3.25–3.35 (m, 2H), 3.35–3.50 (m, 4H), 3.50–3.65

(m, 2H), 4.30 (s, 3H), 4.35 (s, 2H), 4.50 (broad s, 1H),

6.20–6.25 (m, 1H), 7.10–7.25 (m, 4H), 7.30–7.45 (m,

3H), 7.90 (broad s, 1H); 2D-NOE cross peak between

d=4.30 (tetrazole N-CH₃) and d=4.35 (CH₂) absent;

MS m/z: 501 (MH⁺, 22), 142 (100), 113 (91). Anal.

1

residual acetic acid. H NMR (CDCl₃) d: 2.10 (s, 4H,

acetic acid) 4.25 (s, 2H), 6.49 (s, 1H), 7.00 (d, 1H), 7.03–

7–40 (m, 6H), 7.45 (s, 1H). The crude product was used

directly in the next step without further puriﬁcation.

.

(C₂₈H₃₁FN₈O 0.40% H₂O): C, H; N calcd 22.30, found

21.63.

1-(4-Fluorophenyl)-5-[(2-methyltetrazol-5-yl)methyl]-1H-

indole (24a) and 1-(4-ﬂuorophenyl)-5-[(1-methyltetrazol-

5-yl)methyl]-1H-indole (25a). A solution ofcrude 1-(4-

ﬂuorophenyl)-5-[(tetrazol-5-yl)methyl]-1H-indole (23)

(14.0 g) in NMP (200 mL) was cooled on an ice bath

and potassium tert-butoxide (6.4 g, 57 mmol) was added

cautiously over 20 min keeping the temperature below

20 ^ꢁC. When the addition was complete, the reaction

mixture was cooled to 0 ^ꢁC, and CH₃I (15.6 g, 0.11 mol)

was added. After stirring at room temperature for 2 h,

H₂O (200 mL) was added and the resulting mixture was

extracted with EtOAc (2ꢃ200 mL). The combined

organic phases were washed with H₂O (2ꢃ200 mL) and

brine (2ꢃ250 mL), dried (Na₂SO₄), and the volatile sol-

vents evaporated in vacuo. The resulting mixture of1-

and 2-methyl-substituted tetrazoles was separated by

column chromatography on silica gel (EtOAc/heptane

1:2). Evaporation of the fastest eluting fractions in

vacuo aﬀorded 3.7 g (37% from 17e) of1-(4-ﬂuoro-

phenyl)-5-(2-methyltetrazol-5-ylmethyl)-1H-indole (24a)

as an oil: ¹H NMR (CDCl₃) d: 4.25 (s, 3H), 4.30 (s, 2H),

6.60 (d, 1H), 7.10–7.20 (m, 3H), 7.20 (d, 1H), 7.30–7.45

(m, 3H), 7.60 (broad s, 1H).

Compound 25c was obtained accordingly from 25a.

1-(2-{4-[1-(4-Fluorophenyl)-5-[(1-methyltetrazol-5-yl)

methyl]-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl}

ethyl)-2-imidazolidinone (25c). Yield 1.6 g (66% from

25a): mp 174–176 ^ꢁC (EtOH). ¹H NMR (CDCl₃) d:

2.55–2.65 (m, 4H), 2.80 (t, 2H), 3.20–3.35 (m, 2H), 3.35–

3.50 (m, 4H), 3.50–3.65 (m, 2H), 3.80 (s, 3H), 4.35

(broad s, 1H), 4.40 (s, 2H), 6.10–6.20 (m, 1H), 7.05

(broad d, 1H), 7.15–7.30 (m, 3H), 7.30–7.45 (m, 3H),

7.75 (broad s, 1H); 2D-NOE cross peak between

d=3.80 (tetrazole N-CH₃) and d=4.40 (CH₂) present;

MS m/z: 501 (MH⁺, 6), 142 (100), 113 (97). Anal.

.

(C₂₈H₃₁FN₈O 0.53% H₂O): C, H, N.

4-[5-Bromo-1-(4-ﬂuorophenyl)-1H-indol-3-yl]-piperidine-

1-carboxylic acid tert-butyl ester (26d). Reaction of

5-bromo-1-(4-ﬂuorophenyl)-1H-indole³¹(26a) (172 g,

0.59 mol) with 4-piperidone, HCl, H₂O (550 g, 3.6 mol)

in analogy to the procedure described in the preparation

ofcompound 19a gave 220 g (100%) ofcrude 5-bromo-

1-(4-ﬂuorophenyl)-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-

indole (26b) as a white solid: ¹H NMR (CDCl₃) d: 2.40–

2.55 (m, 2H), 3.15 (t, 2H), 3.55–3.65 (m, 2H), 6.25 (s,

broad, 1H), 7.12–7.30 (m, 5H), 7.35–7.45 (m, 2H), 8.03

(s, 1H). Crude 26b (220 g) and PtO₂(5.0 g) in glacial

acetic acid (1.5 L) was treated with H₂in a Parr appa-

ratus at 2–3 ato for 24 h. Additional PtO₂(4.0 g) was

added, and reaction was continued for 24 h. Solids were

ﬁltered oﬀ and the solvent was removed in vacuo. 10%

aqueous NH₄OH (1 L) was added and the aqueous

phase was extracted with EtOAc (3ꢃ1 L). The com-

bined organic phases were dried over MgSO₄and the

solvent removed in vacuo to yield 125 g (57%) ofcrude

5-bromo-1-(4-ﬂuorophenyl)-3-(4-piperidinyl)-1H-indole

Evaporation in vacuo ofthe slowest eluting rfactions

aﬀorded 1.5 g (15% from 17e) 1-(4-ﬂuorophenyl)-5-[(1-

methyltetrazol-5-yl)methyl]-1H-indole (25a) as an oil:

¹H NMR (CDCl₃) d: 3.80 (s, 3H), 4.35 (s, 2H), 6.50 (d,

1H), 7.00 (broad d, 1H), 7.15 (t, 2H), 7.25 (d, 1H), 7.30–

7.40 (m, 3H), 7.45 (broad s, 1H).

1-(2-{4-[1-(4-Fluorophenyl)-5-[(2-methyltetrazol-5-yl)

methyl]-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl}

ethyl)-2-imidazolidinone (24c). Reaction of1-(4-Fluoro-

phenyl)-5-[(2-methyltetrazol-5-yl)methyl]-1H-indole (24a)

(3.7 g, 12 mmol) with 4-piperidone, HCl, H₂O (11.1 g,

72 mmol) in analogy to the procedure described in the

preparation of 19a gave 4.7 g (100%) ofcrude 1-(4-

ﬂuorophenyl)-5-[(2-methyltetrazol-5-yl)methyl]-3-(1,2,3,6-

tetrahydropyridin-4-yl)-1H-indole (24b) as an oil: ¹H

NMR (CDCl₃) d: 2.05–2.20 (broad s, 1H), 2.45–2.55 (m,

2H), 3.15 (t, 2H), 3.55–3.65 (m, 2H), 4.25 (s, 3H), 4.35

(s, 2H), 6.25–6.30 (m, 1H), 7.10–7.25 (m, 4H), 7.30–7.45

(m, 3H), 7.90 (broad s, 1H). Crude 24b (4.7 g, 12 mmol),

1-(2-chloroethyl)imidazolidin-2-one^31,45(2.0 g, 13

mmol), K₂CO₃(2.5 g, 18 mmol) and KI (0.60 g, 3.6

mmol) were boiled under reﬂux for 8 h in 4-methyl-2-

pentanone (150 mL). After cooling to room temperature

H₂O (100 mL) was added and the phases were sepa-

rated. The aqueous phase was extracted with CH₂Cl₂

(2ꢃ200 mL). After evaporation of the solvents in vacuo

1

(26c) as an oil: H NMR (DMSO-d₆) d: 1.78 (qd, 2H),

2.05 (d, 2H), 2.90 (td, 2H), 3.05 (m, 1H), 3.25 (d, 2H),

7.30 (d, 1H), 7.35–7.45 (m, 3H), 7.49 (s, 1H), 7.56–7.63

(m, 2H), 7.93 (d, 1H). A solution ofcrude 26c (125 g,

0.33 mol) and di-tert-butyl dicarbonate (260 g, 1.2 mol)

in 1:1 THF/H₂O mixture (1 L) was stirred overnight

with K₂CO₃(300 g, 2.2 mol) at 60 ^ꢁC. EtOAc (1 L) was

added. After separation of the two phases, the aqueous

phase was extracted with EtOAc (3ꢃ500 mL). The

combined organic phases were washed with brine (200

mL) and dried over MgSO₄. The crude product (115 g)

was washed with cold MeOH (2 L) to yield 97.0 g ofthe

title com_ꢁpound 26d (35% from 26a) as a white solid: mp

160–162 C (heptane); ¹H NMR (CDCl₃) d: 1.49 (s, 9H),

1.65 (q, 2H), 2.04 (d, 2H), 2.85–3.00 (m, 3H), 4.25 (d,

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

1075

2H), 7.03 (s, 1H), 7.15–7.35 (m, 4H), 7.39–7.43 (m, 2H),

7.78 (s, 1H); MS m/z (relative intensity): 473+475

(MH⁺, 1%), 417+419 (40%), 373+375 (100%). Anal.

(C₂₄H₂₆BrFN₂O₂): C, H, N.

4-[1-(4-Fluorophenyl)-5,6-methylenedioxy-1H-indol-3-yl]-

piperidine-1-carboxylic acid tert-butyl ester (29). A sus-

pension of4-[(5,6-methylenedioxy)-1 H-indol-3-yl]-

piperidine-1-carboxylic acid tert-butyl ester (28d) (5.0 g,

14.5 mmol), 4-ﬂuoro-iodobenzene (5.8 g, 26.1 mmol),

K₂CO₃(6.0 g, 44 mmol), CuI (1.0 g, 5.4 mmol), and

ZnO (0.34 g, 4.2 mmol) in NMP (60 mL) was stirred at

100 ^ꢁC for 48 h. After cooling to room temperature

solids were ﬁltered oﬀ, and the solid washed with

EtOAc (200 mL). The organic phase was washed with

H₂O (100 mL) and brine (3ꢃ100 mL), and the solvents

were removed in vacuo. Puriﬁcation by ﬂash chromato-

graphy (EtOAc/heptane 0/100!20/80) aﬀorded 5.0 g

4-[1-(4-Fluorophenyl)-5-(trimethylsilyl)-1H-indol-3-yl]-pi-

peridine-1-carboxylic acid tert-butyl ester (27a). 4-[5-

Bromo-1-(4-ﬂuorophenyl)-1H-indol-3-yl]-piperidine-1-

carboxylic acid tert-butyl ester (26d) (3.0 g, 6.3 mmol) in

THF (20 mL) was added during 2 min to a solution of

n-butyllithium (7.9 mL, 12.7 mmol) in THF (50 mL) at

ꢀ78 ^ꢁC. After stirring for 3 min, (CH₃)₃SiCl (2.8 g, 25

mmol) was added. The solution was heated to room

temperature during 30 min, and H₂O (50 mL) was

added. After extraction of the aqueous phase with

EtOAc (3ꢃ30 mL) and evaporation ofthe solvent in

vacuo, the crude product was puriﬁed by ﬂash chroma-

tography (EtOAc/heptane 10/90!30/70) to give 2.8 g of

the title compound. Recrystallisation (EtOAc/heptane

1/4) gave 2.6 g (88%) ofthe title compound 27a: mp 81–

(79%) ofthe title compound

29: mp 108–110 ^ꢁC

(EtOAc/heptane); ¹H NMR (CDCl₃) d: 1.49 (s, 9H),

1,66 (qd, 2H), 2.03 (d, 2H), 2.80–2.95 (m, 4H), 4.25 (s,

broad, 2H), 5.94 (s, 2H), 6.89 (s, 1H), 6.90 (s, 1H), 7.02

(s, 1H), 7.15–7.20 (m, 2H), 7.35–7.41 (m, 2H). Anal.

(C₂₅H₂₇FN₂O₄): C, H, N.

82 ^ꢁC (EtOAc/heptane); H NMR (CDCl₃) d: 0.33 (s,

1-(4-Fluorophenyl)-3-{1-[2-(2-imidazolidinon-1-yl)ethyl]-

4-piperidinyl]-N-methyl-1H-indole-5-carboxamide (7). 1-

(4-Fluorophenyl)-N-methyl-3-(piperidin-4-yl)-1H-indole-

5-carboxamide (20a) (4.4 g, 12.5 mmol), K₂CO₃(5.2 g,

38 mmol), KI (1.0 g, 6 mmol) and 1-(2-chloro-

ethyl)imidazolidin-2-one (2.2 g, 13.6 mmol) were boiled

under reﬂux for 8 h in 4-methyl-2-pentanone (250 mL).

After cooling to room temperature, solids were ﬁltered

oﬀ and the residue washed with 4-methyl-2-pentanone

(50 mL). After evaporation of the solvent, the remaining

compound was dissolved in CH₂Cl₂and washed twice

with H₂O. The crude product was puriﬁed by ﬂash

chromatography (EtOAc/MeOH/NEt₃80/15/5) to yield

3.5 g (59%) ofthe title compound 7: mp 150–155 ^ꢁC

(EtOH/Et₂O 1/1); ¹H NMR (DMSO-d₆) d: 1.75 (qd,

2H), 2.0 (d, 2H), 2.15 (t, 2H), 2.45 (t, 2H), 2.82 (d, 3H),

2.85 (t, 1H), 3.02 (d, 2H), 3.2 (q, 4H), 3.4 (q, 2H), 6.25

(s, 1H), 7.40 (t, 2H), 7.49 (m, 2H), 7.60 (m, 2H), 7.70 (d,

1H), 8.20 (s, 1H), 8.4 (q, 1H). Anal. (C₂₇H₃₂

1

9H), 1.49 (s, 9H), 1.70 (q, 2H), 2.09 (d, 2H), 2.96 (t, 2H),

3.06 (tt, 1H), 4.27 (s, broad, 2H), 7.02 (s, 1H), 7.1–7.22

(m, 2H), 7.37 (d, 1H), 7.46 (d, 1H), 7.4–7.44 (m, 2H),

7.81 (s, 1H). Anal. (C₂₇H₃₅FN₂O₂Si): C, H, N.

4-[(5,6-Methylenedioxy)-1H-indol-3-yl]-piperidine-1-carb-

oxylic acid tert-butyl ester (28d). 5,6-Methylenedioxy-

1H-indole (28a) (6.5 g, 40 mmol) and 4-piperidone,

HCl, H₂O (17.9 g, 0.12 mol) were added to a solution of

KOH (10.1 g, 0.18 mol) in EtOH (200 mL) at 5 ^ꢁC. The

solution was boiled under reﬂux for 14 h. After cooling

to room temperature, solids were ﬁltered oﬀ, and the

solvents removed in vacuo. The remaining material was

puriﬁed by column chromatography (EtOAc/EtOH/

TEA 70/30/5) to yield 7.5 g ofcrude 5,6-methylene-

dioxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (28b)

as a yellow solid. ¹H NMR (DMSO-d₆) d: 2.36 (s,

broad, 2H), 2.95 (t, 2H), 3.44 (s, broad, 2H), 5.94 (s,

2H), 6.03 (s, 1H), 6.89 (s, 1H), 7.19 (s, 1H),7.23 (s, 1H).

Reaction ofcrude 28b (7.5 g) with H₂in analogy to the

procedure described in the preparation of 20a gave 5.7 g

ofcrude 5,6-methylenedioxy-3-(piperidin-4-yl)-1 H-

indole (28c) as an oil: ¹H NMR (DMSO-d₆) d: 1.50 (qd,

2H), 1.82 (d, 2H), 2.61 (t, 2H), 2.72 (tt, 1H), 2.98 (d,

2H), 5.89 (s, 2H), 6.81 (s, 1H), 6.87 (s, 1H), 6.99 (s, 1H).

A solution ofcrude 28c (5.7 g), (Boc)₂O (6.4 g, 29

mmol) and K₂CO₃(10.0 g, 73 mmol) in THF (400 mL)

and H₂O (200 mL) was stirred for 14 h at 60 ^ꢁC. Addi-

tional (Boc)₂O (5.0 g, 23 mmol) and K₂CO₃(3.3 g, 24

mmol) were added, and the solution was stirred for

further 5 h. After cooling to room temperature, the

phases were separated, and the aqueous phase extracted

with EtOAc (3ꢃ250 mL). The combined organic phases

were washed with brine (100 mL), dried (MgSO₄), and

the solvents evaporated in vacuo. The resulting 6.9 g

was puriﬁed by ﬂash chromatography (EtOAc/heptane

40/60) to give 6.8 g (49% from 28a) ofthe title com-

pound 28d as pink crystals: mp 191–192 ^ꢁC (EtOAc/

.

FN₅O₂2.71% EtOH):N, H; C calcd 66.96, found 65.69.

Compound 8 was prepared accordingly from 20b.

N,N-Dimethyl-1-(4-ﬂuorophenyl)-3-{1-[2-(2-imidazolidinon-

1-yl)ethyl]-4-piperidinyl}-1H-indole-5-carboxamide (8).

1

Yield 0.60 g (29%): mp 172–176 (acetone); H NMR

(CDCl₃) d: 1.80 (dq, 2H), 2.05 (d, 2H), 2.15 (t, 2H), 2.55

(t, 2H), 2.90 (tt, 1H), 3.10 (m, 8H), 3.40 (m, 4H), 3.50

(m, 2H), 4.80 (s, broad, 1H), 7.10 (s, 1H), 7.15–7.40 (m,

3H), 7.35–7.50 (m, 3H), 7.80 (s, 1H). Anal.

.

(C₂₈H₃₄FN₅O₂1/3 mol acetone): C, H, N.

1-{4-[1-(4-Fluorophenyl)-5-methylaminomethyl-1H-indol-

3-yl]-1-piperidinyl}ethyl-2-imidazolidinone (9). Compound

7 (2.0 g, 4.2 mmol) and LiAlH₄(0.33 g, 9 mmol) were

boiled under reﬂux in dry THF (150 mL) for 3 h. After

cooling to room temperature the excess ofLiAlH was

4

destroyed by cautious drop-wise addition ofwater.

Subsequently water (100 mL) and 1 M aqueous NaOH

(5 mL) were added and the aqueous phase extracted

with EtOAc (3ꢃ100 mL). After removal of the solvent

in vacuo, the crude product was puriﬁed by ﬂash

chromatography (EtOAc/MeOH/NEt₃80/15/5) to yield

1

heptane); H NMR (CDCl₃) d: 1.48 (s, 9H), 1.98 (q,

2H), 2.00 (d, 2H), 2.8–2.95 (m, 3H), 4.20 (s, broad, 2H),

5.92 (s, 2H), 6.81 (s, 1H), 6.82 (s, 1H), 6.98 (s, 1H).

Anal. (C₁₉H₂₄N₂O₄): C, H, N.

1076

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

0.30 g ofthe title compound 9 as an oil, ¹H NMR

(DMSO-d₆) d: 1.72 (q, 2H), 1.97 (d, 2H), 2.12 (t, 2H),

2.28 (s, 3H), 2.45 (t, 2H), 2.77 (tt, 1H), 3.00 (d. 2H),

3.10–3.60 (m, 6H),3.72 (s, 2H), 6.25 (s, 2H), 7.14 (d.

1H), 7.35–7.45 (m, 4H), 7.55–7.65 (m, 3H). LC–MS m/

z: 438 (MH⁺, 100%). Purity UV: >98%; purity ELSD

>99%.

compound 13 after precipitatation with fumaric acid

from MeOH: Yield: 0.25 g (22%); mp 171–173 ^ꢁC

(MeOH). H NMR (DMSO-d₆) d: 1.75–1.95 (m, 2H),

1

1.95–2.15 (m, 2H), 2.45–2.60 (m, 2H), 2.70–2.85 (m,

2H), 2.95 (tt, 1H), 3.15–3.35 (m, 6H), 3.35–3.50 (m, 2H),

4.30 (broad s, 5H), 6.35 (broad s, 1H), 6.60 (s, 4.5H),

7.10 (broad d, 1H), 7.35–7.45 (m, 4H), 7.60 (dd, 2H),

7.70 (broad s, 1H); MS m/z: 503 (MH⁺, 11), 419 (10),

.

1-(2-{4-[5-Dimethylaminomethyl-1-(4-ﬂuorophenyl)-1H-

indol-3-yl]-1-piperidinyl}ethyl)-2-imidazolidinone (10). 5-

Dimethylaminomethyl-1-(4-ﬂuorophenyl)-3-(piperidin-4-

yl)-1H-indole (21) (3.5 g, 10 mmol) was reacted with 1-

(2-chloroethyl)imidazolidin-2-one^31,45in analogy to the

procedure described in the preparation of 7: Yield 1.0 g

194 (82), 168 (69), 113 (100). Anal. (C₂₈H₃₃FN₈O 2.25

C₄H₄O₄): C, H, N.

Compound 14 was obtained accordingly from 25c.

1-(2-{4-[1-(4-Fluorophenyl)-5-[(1-methyltetrazol-5-yl)

methyl]-1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imidazolidi-

none, 2.5 fumarate (14). The title compound 14 was

obtained after precipitation with fumaric acid from

(21%): mp 155–165 ^ꢁC (acetone); H NMR (CDCl₃) d:

1

1.80 (q, 2H), 2.05 (d, 2H), 2.18 (t, 2H), 2.25 (s, 6H), 2.57

(t, 2H), 2.85 (tt, 1H), 3.08 (d, 2H), 3.40 (q, 4H), 3.45–

3.55 (m, 4H), 4.40 (s, 1H), 7.00 (s, 1H), 7.15 (m, 3H),

7.30–7.50 (m, 3H), 7.60 (s, 1H). Anal. (C₂₇H₃₄FN₅O):

C, H, N.

EtOH: Yield: 0.25 g (17%); mp 169–171 ^ꢁC (EtOH). H

1

NMR (DMSO-d₆) d: 1.75–2.00 (m, 2H), 2.00–2.15 (m,

2H), 2.55–2.75 (m, 2H), 2.85 (t, 2H), 2.95 (tt, 1H), 3.20–

3.50 (m, 8H), 4.00 (s, 3H), 4.40 (s, 2H), 6.40 (broad s,

1H), 6.60 (s, 5H), 7.05 (broad d, 1H), 7.30–7.50 (m, 4H),

7.50 (dd, 2H), 7.65 (broad s, 1H); MS m/z: 503 (MH⁺,

100), 446 (7), 419 (10), 194 (36), 168 (32), 113 (65). Anal.

1-(2- {4-[5-Aminomethyl-1-(4-ﬂuorophenyl)- 1H-indol-3-

yl]-1-piperidinyl}ethyl)-2-imidazolidinone (11). 1-(2-{4-

[5-Cyano-1-(4-ﬂuorophenyl)- 1H-indol-3-yl]-1,2,3,6-tetra-

hydropyridin-1-yl}ethyl)-2-imidazolidinone³¹(22) (4.6

g, 11 mmol) was reacted with H₂as described in the

preparation of 20a, except, no TFA was used. The crude

product was puriﬁed by preparative HPLC (Merck

Hibar 250–25, LiChrosorb RP-8, 7 mM) (EtOH/25%

aqueous NH₃solution 100/4). Yield 0.92 g (20%); mp

.

(C₂₈H₃₃FN₈O 2.50 C₄H₄O₄): C, H, N.

1-(2-{4-[1-(4-Fluorophenyl)-5-(trimethylsilyl)-1H-indol-3-

yl]-1-piperidinyl}ethyl)-2-imidazolidinone (15). Neat 4-[1-

(4-ﬂuorophenyl)-5-(trimethylsilyl)-1H-indol-3-yl]-piper-

idine-1-carboxylic acid tert-butyl ester (27a) (2.5 g, 5.3

mmol) was heated to 230 ^ꢁC during 3 h. After cooling to

room temperature, EtOAc (75 mL) and H₂O (50 mL)

were added, and the aqueous phase was extracted with

EtOAc (3ꢃ75 mL). The combined organic phases were

dried (MgSO₄) and the solvent evaporated in vacuo to

give 2.0 g ofcrude 1-(4-ﬂuoro-phenyl)-3-(piperidin-4-

yl)-5-trimethylsislyl-1H-indole (27b). Crude 27b (1g, 2.7

mmol) was reacted with 1-(2-chloroethyl)imidazolidin-

2-one^31,45in analogy to the procedure described in the

preparation of 24c. The crude product was puriﬁed by

ﬂash chromatography (EtOAc/heptane/MeOH 50/40/

10) and recrystallised from EtOAc/heptane to give 0.40

g (31%) ofthe title compound 15: mp 182–184 ^ꢁC

(EtOAc/heptane); ¹H NMR (DMSO-d₆) d: 0.28 (s, 9H),

1.73 (q, 2H), 1.97 (d, 2H), 2.15 (t, 2H), 2.44 (t, 2H), 2.85

(tt, 1H), 3.01 (d, 2H), 3.17–3.22 (m, 4H), 3.40 (t, 2H),

6.19 (s, broad), 7.30 (d, 1H), 7.36–7.40 (m, 3H), 7.48 (d,

1H), 7.50–7.60 (m, 2H), 7.79 (s, 1H); (C₂₇H₃₅FN₄OSi):

C, H, N.

171–175 ^ꢁC (Et₂O); H NMR (CDCl₃) d: 1.85 (d, 2H),

1

2.10 (d, 2H), 2.25 (td, 2H), 2.60 (t, 2H), 2.90 (tt, 1H),

3.10 (d, 2H), 3.4 (q, 4H), 3.6 (q, 2H), 3.95 (s, 2H), 4.70

(s, broad, 1H), 7.00 (s, 1H), 7.10–7.25 (m, 3H), 7.30–

.

7.50 (m, 3H), 7.60 (s, 1H). Anal. (C₂₆H₃₂FN₅O 1.0%

H₂O): H, N; C: calcd 68.22, found 67.51.

N-(1-(4-Fluorophenyl)-3-{1-[2-(2-imidazolidin-2-one-1-yl)-

ethyl]-piperidin-4-yl}-1H-indol-5-ylmethyl)-acetamide

(12). Acetyl chloride (0.33 g, 4.2 mmol) was added

slowly to a solution of1-(2-{4-[5-aminomethyl-1-(4-

ﬂuorophenyl)-1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imi-

dazolidinone (11) (1.7 g, 3.9 mmol) and NEt₃(1.1 mL)

in CH₂Cl₂(25 mL) at 0 ^ꢁC. The solution was stirred for

1 h at room temperature before evaporation of the sol-

vent in vacuo. The crude product was puriﬁed by col-

umn chromatography (EtOAc/EtOH/NEt₃80/20/4) to

give 0.93 g ofcrude product, which was crystallised

from EtOAc to give 0.55 g (27%) of the title compound

12: mp 167 ^ꢁC; H NMR (CDCl₃) d: 1.82 (qd, 2H), 2.03

1

(s, 3H), 2.04 (d, 2H), 2.23 (t, 2H), 2.58 (t, 2H), 2.83 (tt,

1H), 3.10 (d, 2H), 3.30–3.45 (m, 4H), 3.55 (t, 2H), 4.55

(d, 2H), 4.67 (s, broad, 1H), 5.95 (s, broad, 1H), 7.06 (s,

1H), 7.10–7.25 (m, 3H), 7.33–7.43 (m, 3H), 7.60 (s, 1H).

Anal. (C₂₇H₃₂FN₅O₂): C, H, N.

1-{4-[1-(4-Fluorophenyl)-5,6-methylenedioxy-1H-indol-3-

yl]-1-piperidinyl}ethyl-2-imidazolidinone (16). A solution

of4-[1-(4-Fluorophenyl)-5,6-methylenedioxy-1 H-indol-

3-yl]-piperidine-1-carboxylic acid tert-butyl ester (29)

(1.5 g, 3.4 mmol) in THF (30 mL) was reacted with a

saturated solution ofHCl in MeOH (20 mL) of r 4 h at

room temperature. Evaporation ofthe solvent and

reaction with 1-(2-chloroethyl)imidazolidin-2-one^31,45in

analogy to the procedure described in the preparation of

7, except an excess ofK ₂CO₃(10 equivalents) was used,

aﬀorded_ꢁ0.62 g (42%) ofthe title compound 16: mp

1-(2-{4-[1-(4-Fluorophenyl)-5-[(2-methyltetrazol-5-yl)

methyl]-1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imazolidinone,

2.25 fumarate (13). Reaction of1-(2-{4-[1-(4-ﬂuoro-

phenyl)-5-[(2-methyltetrazol-5-yl)methyl]-1H-indol-3-yl]-

1,2,3,6-tetrahydropyridin-1-yl}ethyl)-2-imidazolidinone

(24c) (1.5 g, 3.0 mmol) with H₂in analogy to the pro-

cedure described in the preparation of 20a gave the title

1

216–217 C (EtOAc/heptane); H NMR (DMSO-d₆) d:

1.64 (qd, 2H), 1.95 (d, 2H), 2.10 (t, 2H), 2.41 (t, 2H),

T. Balle et al. / Bioorg. Med. Chem. 11 (2003) 1065–1078

1077

2.70 (tt, 1H), 2.99 (d, 2H), 3.13–3.23 (m, 4H), 3.39 (t,

2H), 5.96 (s, 2H), 6.23 (s, broad, 1H), 6.98 (s, 1H), 7.13

(s, 1H), 7.21 (s, 1H), 7.32–7.40 (m, 2H), 7.53–7.59 (m,

2H). Anal. (C₂₅H₂₇FN₄O₃): C, H, N.

For details regarding the source ofthe membranes,

radioligand, and radioligand concentration, refer to

Table 1. Data shown in tables are means from a mini-

mum oftwo full concentration–response curves using 10

concentrations ofdrugs (covering 3 decades). The

results are given as K_ivalues (nM) derived from com-

puter-ﬁtted IC₅₀values converted to K_ivalues using the

Cheng–Prusoﬀ equation. Standard errors for pK_i-values

were within 0.3 for all reported compounds.

Pharmacology

Cell lines and animals. CHO cell lines expressing the rat

a_1d,human D₃, and human D₄receptors and BHK cell

lines expressing bovine a_1areceptors were generated in-

house at H. Lundbeck A/S using standard stable trans-

fection techniques. The Rat-1 cell line expressing the

hamster a_1breceptor was obtained from the University

ofUtah, Utah, USA. The HeLa cells expressing the

5-HT_1Areceptor were obtained from Dr. Hamblin

(Duke University, NC, USA) and those expressing the

5-HT_1Breceptor from Medical Center University,

Washington, USA. The SR-3T3 cells expressing the rat

5-HT_2Creceptors were purchased from the American

Type Culture Collection.

Molecular modelling

Conformational analysis was performed in Macromodel

version 7⁴⁶using the MMFFs forceﬁeld⁴⁷on the entire

molecules protonated at the piperidine nitrogens. Cal-

culations were performed using the default aqueous

solvation model implemented in Macomodel. Molecules

were built in their proposed receptor-active conforma-

tions³³with the imidazolidinone-ethyl side chains in an

extended conformation. Energy minimisations were

performed without constraints. Conformational analy-

sis ofthe substituents in the indole 5-positions were

performed by systematic drives around ﬂexible bonds.

The templates for superimpositions (7 and 13) were in

the lowest possible energy minimum with the imidazoli-

dinone-ethyl side chains in an extended conformation.

The superimposed molecules were in the lowest energy

minimum (8) or in a local minimum 0.36 kcal/mol

above the the lowest energy minimum (12), both with

the the imidazolidinone-ethyl side chain in an extended

conformation. Indole C3 and N1 substituents are

removed in Figures 1 and 2 for clarity.

Brain preparations were generated from male Sprague–

Dawley rats weighing approximately 220 g. The animals

were decapitated prior to brain extraction.

In vitro binding assays. a₁and serotonin receptors: The

tissues were homogenised in ice-cold 50 mM Tris, pH

7.7, using an Ultra-Turrax and the homogenates either

kept on ice or stored at ꢀ80 ^ꢁC until used. The assay

buﬀer subsequently used contained 50 mM Tris, pH 7.7.

Non-speciﬁc binding for the a₁assays was deﬁned as the

binding in the presence ofprazosin (1 mM) for the a₁

(rat brain) and ofWB-4101 (1 mM) for the cloned a_1a,

a_1b,and a_1dassays, respectively. For the serotonin

assays, non-speciﬁc binding was deﬁned using meter-

goline (1 mM) for the 5-HT_1Aassay, 5-HT (10 mM) for

the 5-HT_1Bassay and mianserine (1 mM) for both the

5-HT_2Aand 5-HT_2Cassays. In All the a₁assays samples

were incubated at 25 ^ꢁC for 20 min. The 5-HT_1Aand

5-HT_1Bassays were incubated for 15 min at 37 ^ꢁC

whereas the 5-HT_2Aand 5-HT_2Cassays were incubated

for 30 min at 37 ^ꢁC. In All assays bound and free

radioactivity were separated by vacuum ﬁltration on

GF/B ﬁlters and counted in a scintillation counter

(Wallac Trilux).

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Article Doi

Synthesis and structure-affinity relationship investigations of 5-aminomethyl and 5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective α1 adrenoceptor antagonists

DOI: 10.1016/S0968-0896(02)00459-5

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