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

J . Med. Chem. 2003, 46, 265-283

265

Syn th esis a n d Str u ctu r e-Affin ity Rela tion sh ip In vestiga tion s of

5-Heter oa r yl-Su bstitu ted An a logu es of th e An tip sych otic Ser tin d ole. A New

Cla ss of High ly Selective r₁Ad r en ocep tor An ta gon ists

Thomas Balle,^†,‡J ens Perregaard,^†Martha Teresa Ramirez,^§Anna Kirstine Larsen,^§Karina Krøjer Søby,^§

Tommy Liljefors,^‡and Kim Andersen*^,†

Medicinal Chemistry Research, H. Lundbeck A/ S, 9 Ottiliavej, DK-2500 Valby, Denmark, Department of Medicinal Chemistry,

The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark, and Biological Research,

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

Received May 16, 2002

A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly

selective and potentially CNS-active R₁-adrenoceptor antagonists is described. The compounds

are derived from the antipsychotic sertindole. The structure-affinity relationships of the

5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized

with respect to affinity for R₁adrenoceptors and selectivity in respect to dopamine (D_1-4) and

serotonin (5-HT_1A-1Band 5-HT_2A,2C) receptors. The most selective compound obtained, 3-{4-

[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl}propionitrile (15c),

has affinities of 0.99, 3.2, and 9.0 nM for the R_1a, R_1b, and R_1dadrenoceptor subtypes, respectively,

and a selectivity for adrenergic R_1areceptors in respect to dopamine D₂, D₃, and D₄and serotonin

5-HT_2Aand 5-HT_2Chigher than 900, comparable to the selectivity of prazosin. In addition, the

compound is more than 150-fold selective in respect to serotonin 5-HT_1Aand 5-HT_1Breceptors.

A new basic pharmacophore for R₁-adrenoceptor antagonists based on a previously reported

pharmacophore model for dopamine D₂antagonist is suggested.

Ch a r t 1. Structure of Sertindole (1)

In tr od u ction

Interest in the development of selective R₁-adreno-

ceptor antagonists has primarily focused on therapeutics

for the treatment of cardiovascular diseases and benign

prostatic hyperplasia.^1-3However, modulation of R₁-

adrenoceptor activity in the central nervous system

(CNS) might also be of interest in regard to treatment

of CNS-related diseases.^4,5

In human brain, all three adrenoceptor subtypes R_1A

,

R

_1B, and R_1Dare present at the mRNA level.⁶At the

protein level, radioligand-binding experiments have

confirmed the existence of R_1A⁷and R_1Dadrenoceptors.⁸

The functional role, tissue distribution and density of

the different R₁adrenoceptor subtypes, are not yet

completely understood,⁹but results indicate that func-

tional roles of the different adrenergic R₁receptor

subtypes may vary between species.¹⁰

A common feature of atypical antipsychotics such as

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

seroquel is nanomolar affinity for R₁-adrenoceptors in

addition to their affinities for dopamine D₂and seroto-

nin 5-HT_2Areceptors.¹¹The proper balanced affinities

for these receptors might underlie the improved profile

of these drugs (improved ratio between doses inducing

antipsychotic activity and extrapyramidal side effects)

as compared to classical antipsychotic drugs, such as

haloperidol.¹¹

The contribution of the R₁-component to the thera-

peutic value of these antipsychotic agents has been

studied intensively. Repeated coadministration of the

R₁-adrenoceptor antagonist prazosin and the classical

antipsychotic haloperidol was found to selectively inhibit

the firing of dopaminergic neurones in the ventral

tegmental area in rats, suggesting that the combination

would be effective as antipsychotic treatment without

producing extrapyramidal side effects.¹²Coadministra-

tion of subthreshold doses of the dopamine D₂antago-

nist raclopride and the R₁-adrenoceptor antagonist

prazosin caused significantly enhanced suppression of

conditioned avoidance behavior in rats without inducing

catalepsy.¹³It was suggested that R₁adrenoceptor

blockade in the presence of a low D₂receptor occupancy

might improve antipsychotic efficacy and thereby im-

prove the therapeutic window with regard to extra-

pyramidal side effects. Drug combination studies in the

* Corresponding author: Kim Andersen, Department of Combina-

torial Chemistry, Medicinal Chemistry Research, H. Lundbeck A/S, 9

Ottiliavej, DK-2500 Valby, Denmark, e-mail address: kia@lundbeck.com,

tel: +45 36301311, fax: +45 36301385.

^†Medicinal Chemistry Research, H. Lundbeck A/S.

^‡Department of Medicinal Chemistry, The Royal Danish School of

Pharmacy.

^§Biological Research, H. Lundbeck A/S.

Published on Web 12/11/2002

266 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

Ch a r t 2. Selected Selective R₁Adrenoceptor Antagonists Belonging to Different Chemical Classes

paw test in rats indicate a central role of the R₁-

component for the atypical profile of clozapine.¹⁴

Several lines of evidence indicate that blockade of R₁-

adrenoceptor neurotransmission alone could be benefi-

cial in the treatment of schizophrenia. Metabolic and

postmortem studies indicate hyperactivity of the nor-

adrenergic system in psychotic patients.⁴The firing

pattern of midbrain dopamine neurons in rats is modu-

lated by prazosin administration¹⁵and by electrical

stimulation of noradrenergic neurons in the locus coer-

uleus.¹⁶In addition, prazosin reversed the disruption

of prepulse inhibition of acoustic startle response in rats

induced by phencyclidine (PCP),^17,18indicating that R₁

antagonists would be beneficial in the treatment of at

least subpopulations of schizophrenic patients. In con-

trast to these pharmacological observations, prazosin

has been tested in a small placebo controlled trial on

schizophrenic patients without promising results.¹⁹

Furthermore, centrally acting R₁-adrenergic antago-

nists might have a potential as therapeutics for the

treatment of CNS-related diseases characterized by

noradrenergic overactivity such as mania⁵and post-

traumatic stress disorder.²⁰

Numerous selective adrenergic R₁antagonists have

been discovered³belonging to a variety of different

chemical classes exemplified by compounds as diverse

as prazosin (2), (R)-(-)-tamsulosin (3), phentolamine (4),

SNAP-5089 (5), cyclazosin (6), and SNAP-8719 (7)

(Chart 2). Whereas prazosin (2) is subtype unselective,

(-)-SNAP-5089 ((-)-5),²¹(+)-cyclazosin ((+)-6),²²and

SNAP-8719 (7)²³represent examples of compounds

selective for the R_1a, R_1b, and R_1dreceptor subtypes,

respectively. Based on site-directed mutagenesis studies

on the adrenergic R_1areceptor, it is suggested that a

selection of chemically highly diverse antagonists have

a conserved pharmacophore that recognize a common

site on the receptor.²⁴

small arteries²⁷and binds with sub-nanomolar affinity

for the R₁adrenoceptor subtypes R_1a, R_1b, and R_1d

25,28

The phenylindole skeleton of sertindole has previously

been used as template for the development of selective

31

antagonists of serotonin 5-HT₂^29-31and dopamine D₂

receptors.

We have recently described that the phenylindole

skeleton of sertindole (1) is a promising template for the

development of centrally acting R₁antagonists. Replace-

ment of the 5-chloro atom in sertindole (1) with polar

substituents such as substituted carbamoyl and amino-

methyl groups afforded a new class of selective R₁

adrenoceptor antagonists.²⁵The investigation revealed

that 5-substituents combining hydrogen bond acceptor

properties with steric bulk in the plane of the indole

nucleus are essential to obtain high affinity for adren-

ergic R₁receptors combined with high selectivity in

respect to dopamine D₂and serotonin 5-HT_2Aand

5-HT_2Creceptors. In this paper, we describe the replace-

ment of the 5-chloro atom in sertindole (1) with hetero-

aromatic substituents such as azoles, pyridines, and

pyrimidines full-filling these requirements. Subse-

quently, optimization of the substituent on the piperidi-

nyl nitrogen atom with focus on selectivity for R₁-

adrenergic receptors is described.

Ch em istr y

The preparation of 1-(4-fluorophenyl)-3-(4-piperidi-

nyl)-1H-indoles substituted in the 5- and 6-positions of

the indole nucleus have previously been described by

Perregaard et al.^29,32

Introduction of aromatic substituents in the indole

5-position has previously been reported in the literature.

Most procedures involve palladium-catalyzed cross-

coupling of substituted 5-bromo-1H-indole with aryl

boronic acids,³³aryl stannanes,³⁴or an arylzinc halide.³⁵

For the reverse procedure where aryl halides are reacted

with indole-5-boronic acid derivatives only a few ex-

amples have been reported.^36-38

In the present investigation, sertindole (1, Chart 1)

was selected as a lead compound for development of a

new class of centrally acting R₁adrenoceptor antago-

nists. Sertindole (1) has nanomolar affinity for adren-

ergic (R₁), dopaminergic (D₁, D₂, D₃, D₄), and seroton-

ergic (5-HT_2A, 5-HT_2C) receptors¹²and moderate affinity

for serotonin 5-HT_1Aand 5-HT_1Breceptors.^25,26In ad-

dition, it has been reported that sertindole (1) is a

specific inhibitor of the R_1Aadrenoceptor subtype in rat

We reported recently an efficient one-pot Negishi

cross-coupling procedure for the preparation of 5-het-

eroaryl-substituted 1-(4-fluorophenyl)-1H-indoles from

the corresponding 5-bromo-1-(4-fluorophenyl)-1H-indole

via halogen-metal exchange, transmetalation to the

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 267

Sch em e 1^a

a

Reagents: (a) (i) HCCSi(CH₃)₃, Pd(PPh₃)₂Cl₂, CuI, N(Et)₃, CH₃CN, reflux, 8 h (ii) KOH, MeOH/H₂O, reflux, 3 h; (b) (i) (CH₃)₃SiN₃,

sealed tube, 170 °C, 24 h (ii) CH₂Cl₂, 2 N NaOH, 2 h; (c) K₂CO₃, R²I (R²) CH₃or CH₃CH₂), acetone, reflux, 18 h, column chromatography;

(d) 4-piperidone hydrochloride hydrate, TFA/AcOH, reflux, 90 min; (e) 1-(2-chloroethyl)imidazolidin-2-one, K₂CO₃, KI, 4-methyl-2-pentanone,

reflux, 8 h; (f) H₂, PtO₂, AcOH, 5 h.

corresponding zinc chloride derivative and subsequent

palladium-catalyzed cross-coupling with heteroaryl ha-

lides.³⁹

nificant NOE (2%) was observed on the proton in the

4-position of the 1,2,3-triazole moiety of 8a by irradia-

tion of the methyl group whereas no significant NOE

was observed by irradiation of the methyl group in the

2-methyl-1,2,3-triazole derivative 10a . In none of the

cases, significant NOEs on the protons in the indole

nucleus were observed. The structures of the ethyl

derivatives 9a and 11a were confirmed accordingly.

The remaining 5-heteroaryl-substituted 1-(4-fluoro-

phenyl)-1H-indoles in the present paper were prepared

as outlined in Schemes 2 and 3 using N-Boc-protected

5-bromo-piperidinyl-1H-indole 34 as key intermediate.

The key intermediate 34 was prepared in three steps

from 5-bromo-1-(4-fluorophenyl)-1H-indole (27a ) as out-

lined in Scheme 2. Reaction of 4-piperidinone hydro-

chloride hydrate with 5-bromo-1-(4-fluorophenyl)-1H-

indole (27a ) using acidic conditions followed by catalytic

hydrogenation analogously to published procedures³²

gave the unsubstituted piperidyl compound 27c. Finally,

reaction with Boc-anhydride afforded the N-Boc-pro-

tected 5-bromo-3-piperidinyl-1H-indole 34.

Replacement of the bromine atom in 34 with hetero-

aromatic substituents was either performed by reaction

with zinc cyanide and subsequent tetrazole ring syn-

thesis as depicted in Scheme 2 or by Negishi cross-

coupling reactions⁴³as depicted in Scheme 3.

The tetrazole analogues 12a ,b and 21a were prepared

by ring synthesis as shown in Scheme 2. Reaction of

the N-Boc-protected 5-bromopiperidinyl-1H-indole 34

with zinc cyanide in DMF under tetrakis(triphenyl-

phosphine)palladium(0) catalysis using the conditions

The 1,2,3-triazole analogues of sertindole (8a -11a )

were prepared as depicted in Scheme 1 using 5-bromo-

1-(4-fluorophenyl)-1H-indole (27a )³²as starting mate-

rial. Bis(triphenylphosphine)palladium(II) chloride and

cupper(I) iodide catalyzed Sonogashira coupling^40,41with

(trimethylsilyl)acetylene and hydrolysis of the carbon-

silicon bond gave the acetylene 28. Subsequent 1,3-

dipolar cycloaddition of azidotrimethylsilane to the

triple bond in 28 and hydrolysis of the nitrogen-silicon

bond afforded the 1,2,3-triazole 29. Methylation of

compound 29 gave, after chromatographic separation

of the isomers, the 1-methyl-1,2,3-triazol-4-yl derivative

30a and the 2-methyl-1,2,3-triazol-4-yl derivative 32a .

The corresponding ethyl derivatives 31a and 33a were

prepared accordingly. The 1-methyl- and 1-ethyl-

substituted 1,2,3-triazol-5-yl derivatives (not shown)

were not isolated since only traces of these isomers were

formed. Reaction of intermediates 30a -33a with 4-pi-

peridone hydrochloride hydrate using acidic conditions

gave the substituted 5-(1,2,3-triazol-4-yl)-1-(4-fluoro-

phenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles

30b-33b. Alkylation with 1-(2-chloroethyl)imidazolidin-

2-one gave the corresponding imidazolidin-2-one deriva-

tives 30c-33c, and finally catalytic hydrogenation using

platinum as catalyst gave the final piperidinyl deriva-

tives 8a -11a . The position of the alkyl group in the

1,2,3-triazole moiety in the final analogues 8a -11a

were determined by 1D-NOESY experiments.⁴²A sig-

268 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

Sch em e 2^a

a

Reagents: (a) 4-piperidone hydrochloride hydrate, TFA/AcOH, reflux, 90 min; (b) H₂, PtO₂, AcOH, 5 h; (c) (Boc)₂O, THF/water, 60 °C,

8 h; (d) Zn(CN)₂, Pd(PPh₃)₄, DMF, 80 °C, 8 h; (e) NaN₃, toluene, reflux, 8 h; (f) K₂CO₃, CH₃I, acetone, reflux, 18 h, column chromatography;

(g) (i) HCl, MeOH, rt, 4 h (ii) 1-(2-chloroethyl)-2-imidazolidinone, K₂CO₃, KI, 4-methyl-2-pentanone, reflux, 8 h; (h) HCl, MeOH, rt, 1 h,

then 1-(2-chloroethyl)-2-oxazolidinone, K₂CO₃, KI, 4-methyl-2-pentanone, reflux, 8 h.

Sch em e 3^a

a

Reagents: method A: (i) n-BuLi (reversed addition), THF, -78 °C, 3 min (ii) ZnCl₂/THF (1 M), -78 °C, 30 min; (iii) HetAr-X, Pd(PPh₃)₄,

DMF, 80 °C, 8 h; method B: HetAr-ZnCl/THF, Pd(PPh₃)₄, DMF, 80 °C, 8 h; method C: (i) HCl/MeOH, rt, 4 h (ii) R-Y (Y ) Cl, Br),

K₂CO₃, KI, 4-methyl-2-pentanone (CH₃CN for 20e), reflux 8 h.

described by Tschaen et al.⁴⁴gave the nitrile 35 in 90%

yield. Subsequent 1,3-dipolar cycloaddition with sodium

azide gave the tetrazole 36, and alkylation of this

intermediate with methyl iodide followed by chromato-

graphic separation of the formed isomers gave the 1-

and 2-methyl-substituted tetrazoles 37 and 38. The

position of the methyl group in the two isomers was

determined by 2-D NOESY experiments.⁴²The methyl

group of the 1-methyltetrazole isomer 38 showed NOE

cross-peaks to the indole 4- and 6-protons, whereas no

NOE cross-peaks were observed between the methyl

group in the 2-methyltetrazole isomer 37 and the

protons in the indole nucleus. Deprotection of the Boc-

group and alkylation at the piperidine nitrogen atom

was performed in a one-pot procedure (method C). The

Boc-protected intermediates 37 and 38 were treated

with a saturated solution of hydrochloric acid in metha-

nol followed by evaporation of the solvent. Subsequent

treatment with the appropriate alkylating agent, potas-

sium iodide, and an excess of base gave the imidazolidin-

2-one derivatives 12a and 21a . The oxazolidin-2-one

substituted derivative 12b was prepared accordingly.

Replacement of the bromine atom in key intermediate

34 by means of Negishi cross-couplings as depicted in

Scheme 3 were performed by two complementary meth-

ods (methods A and B).

In method A, the N-Boc-protected 5-bromo-piperidi-

nyl-1H-indole 34 was treated with n-butyllithium fol-

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 269

Sch em e 4^a

Ta ble 1. Methods and Reagents Used for the Preparation of

Intermediates 8, 13-20, and 22-24

a

Reagents: (a) 1-[2-(1,5-dioxa-9-azaspiro[5,5]undecane-9-yl)-

ethyl]imidazolidin-2-one, AcOH/TFA, reflux, 50 min; (b) H₂, PtO₂,

AcOH, 14 h; (c) NaN₃, NEt₃‚HCl, DME, reflux, 16 h.

lowed by transmetalation with zinc chloride in analogy

to procedures reported by us recently.³⁹Reversed ad-

dition of the substrate 34 to an excess of n-butyllithium

and short reaction time before addition of a solution of

3 equiv of zinc chloride in THF were found to give the

best results. Addition of the appropriate heteroaryl

halide and 5 mol % tetrakis(triphenylphosphine)-

palladium(0) afforded the heteroaryl substituted inter-

mediates 8, 13-17, 22, and 23 (Table 1) in yields

varying from 28% to 67%.

The heteroaryl-substituted intermediates 18-20 and

24 (Table 1) were prepared by the reverse method

B (Scheme 3). Deprotonation of the heteroaryl deriva-

tive or halogen/metal exchange of heteroaryl halides

followed by transmetalation to the corresponding zinc

chlorides and tetrakis(triphenylphosphine)palladium-

(0) catalyzed cross-coupling with the N-Boc-protected

5-bromo-piperidinyl-1H-indole 34 gave the 5-heteroaryl-

indoles 18-20 and 24 (Table 1) in yields varying from

28-80%.

The Boc-protected derivatives obtained by methods

A and B were easily transformed into the final com-

pounds shown in the Tables 3 and 4 by method C as

described for the preparation of the tetrazole analogues

12a ,b and 21a . Preparation of 1-methyl-1,2,3-triazol-

4-yl derivative 8a by this method confirmed the struc-

ture of 8a obtained by ring closure as described above

(Scheme 1).

The N-unsubstituted tetrazole 25a and 1,2,3-triazole

26a were prepared as outlined in Scheme 4. Reaction

of the 1,2,3-triazole 29 with 1-[2-(1,5-dioxa-9-azaspiro-

[5,5]undecane-9-yl)ethyl]imidazolidin-2-one using acidic

conditions gave the tetrahydropyridine 39. Subsequent

catalytic hydrogenation gave the N-unsubstituted 1,2,3-

triazole 26a . The N-unsubstituted tetrazole 25a was

prepared from the corresponding nitrile 40³²by reaction

with sodium azide.

Parallel organic synthesis in 96-well format was

performed as depicted in Scheme 5. N-Unsubstituted

piperidine derivatives resulting from deprotection of the

intermediates 13-15, 17-20, 22-24, and 37 were

alkylated with 24 different alkyl halides in the presence

of potassium iodide and an excess of base in a Multi-

synthech Microchem multichamber block⁴⁵containing

96 reactors using a rotating oven. The unreacted piperi-

dinyl derivatives were removed by reaction with resin-

bound isocyanate.⁴⁶Filtration and cation ion exchange

chromatography afforded the final products. The purity

of all samples was analyzed by HPLC/MS with UV and

ELSD detection. Compounds were optionally purified

by preparative HPLC/MS if the purity did not exceed

70%. Of 264 possible compounds 163 were obtained in

sufficient yield and purity to allow for pharmacological

characterization were obtained. Selected representative

examples of yields and purity of the products obtained

by this method are reported in Table 6.

Resu lts a n d Discu ssion

The receptor-binding assays are described in Table 1

and in detail in the Experimental Section. Receptor-

binding affinities (adrenergic R₁, dopamine D₂, and

serotonin 5-HT_1A, 5HT_1B, 5HT_2A, and 5-HT_2Creceptors)

for sertindole and compounds prepared in the present

study are reported in the Tables 3-5. In addition,

receptor-binding affinities for the R₁-adrenergic receptor

270 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

Sch em e 5^a

a

Reagents: (a) HCl, MeOH, rt., 4 h.

Ta ble 2. Receptor-Binding Assays Used and Receptor-Binding Affinities for Reference Compounds^a

receptor

species

membrane source

radioligand (concn) (nM)

ref compd

K_i, nM

R₁

rat

whole brain

BHK cells

Rat-1cells

[³H]prazosin (0.25)

[³H]prazosin (0.3)

[³H]prazosin (0.5)

[³H]prazosin (0.3)

[³H]SCH 23390 (0.2)

[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

29

1.9

2.7

30

2.2

4.8

R_1a

bovine^b

hamster^b

rat^b

R_1b

(()-cyclazosin

SNAP-8719

haloperidol

clozapine

metitepine

serotonin

mianserine

mesulergine

R_1d

CHO cells

D₁

rat

corpus striatum

CHO cells

HeLa cells

D₂

D₃

D₄

human^b

rat

5-HT_1A

5-HT_1B

5-HT_2A

5-HT_2C

h-5-HT_{2C (VSV)}

HeLa cells

[³H]5-CT (1.5)

cerebral cortex

SR-3T3 cells

CHO cells

[³H]ketanserin (0.5)

[³H]mesulergine (0.5)

2.5

0.37

0.92

rat^b

human^b

a

b

For detailed description af assays, see Experimental Section. Cloned receptors.

subtypes R_1a, R_1b, and R_1dand dopamine D₁, D₃, and D₄

receptors are reported in Table 5 for selected compounds

and reference compounds. Good correlation between

receptor-binding affinities observed for the cloned R_1a

(bovine), R_1b(hamster), R_1d(rat) receptors and the

corresponding human clones all expressed in LTK cells

has been documented.⁴⁷

fluenced by steric factors in this area. In the correspond-

ing tetrazole series, replacement of the methyl group

of 12a with a hydrogen (25a ) leads to a 35-fold decrease

in affinity for R₁-adrenoceptors. Apparently, the acidic

nature of the N-unsubstituted tetrazole⁴⁸leads to repul-

sion between the tetrazole anion and the receptor.

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 3.²⁵

The effect of replacement of the chlorine atom in

sertindole with five-membered heterocycles on binding

affinity for serotonin 5-HT_1Aand 5-HT_1Breceptors is

variable. The most pronounced effects are observed for

the imidazole derivative 19a having affinities enhanced

by factors of 10 and 5, respectively, and for the 2-ethyl-

1,2,3-triazol-4-yl derivative 11a having affinities re-

duced by factors of 8 and 3, respectively.

The optimal compounds with respect to affinity for

R₁-adrenoceptors and selectivity in respect to dopamine

D₂and serotonin 5-HT_2Aand 5-HT_2Creceptors are the

1,2,4-triazole 15a , the pyrazole 13a , the N-unsubsti-

tuted 1,2,3-triazole 26a , and the tetrazole 12a having

selectivity in respect to these receptors higher than 30.

These compounds have unchanged affinity for serotonin

5-HT_1Areceptors compared to sertindole (1), except for

the tetrazole 12a having 4-fold reduced affinity. Com-

pounds combining high affinity for adrenergic R₁recep-

tors with low affinity for both dopamine D₂and sero-

tonin 5-HT_2Aand 5-HT_2C, and low affinity for serotonin

5-HT_1Aand 5-HT_1Breceptors were not identified in the

present series.

Replacement of the chlorine atom in sertindole (1)

with 1-methyl- or 1-ethyl-1,2,3-triazol-4-yl (8a , 9a ),

1-methylpyrazol-4-yl (14a ), and N-unsubstituted tetra-

zole 25a (Table 3) resulted in 6-45-fold reduced affinity

for R₁-adrenoceptors. The remaining heteroaryl-substi-

tuted derivatives 10a -13a , 15a -24a , and 26a (Table

3) have essentially equipotent affinity for R₁-adreno-

ceptors compared to sertindole (1). All compounds have

significantly reduced affinities for dopamine D₂recep-

tors by factors of 35-1500 and for serotonin 5-HT_2Aand

5-HT_2Creceptors by factors of 30-1100 and 72-5700,

respectively. The structure-affinity relationships for

dopamine D₂receptors and serotonin 5-HT_2Aand 5-HT_2C

receptors seem to be essentially parallel. The serotonin

5-HT_2Creceptors seem most sensitive to the replace-

ment of the chlorine atom in sertindole as apparent by

comparing the binding affinites of the 1,2,4-triazole 15a

with sertindole. The affinity for serotonin 5-HT_2Crecep-

tors is reduced by a factor of 5700, whereas the affinities

for 5-HT_2Aand dopamine D₂receptors are reduced by

factors of 700 and 1500, respectively.

The effect of replacement of the methyl group of the

2-methyl-1,2,3-triazole 10a with an ethyl group (11a )

or a hydrogen (26a ) on affinity for the receptors studied

is negligible, indicating that the receptor-binding af-

finities for the receptors studied are essentially unin-

In an attempt to further improve the selectivity for

R₁-adrenergic receptors, the substituent on the piperi-

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 271

Ta ble 3. Receptor-binding Affinities of 2-(2-Oxoimidazolidinyl)ethyl-Substituted 5-Heteroarylindole Derivatives 8a -24a and

Sertindole 1

a

b

For description of assays see Table 2. Reference 11.

dine nitrogen atom was optimized. The intermediates

13-15, 17-20, 22-24, and 37 were alkylated in a

parallel fashion using 24 different alkylating agents.

Low molecular weight alkylating agents (M_{side chain}<

210 g/mol) were chosen in order to keep the average

molecular weight of the final products below 500 g/mol.

272 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

Ta ble 4. Receptor-Binding Affinities for 5-(2-Methyltetrazol-5-yl)indole Derivatives 12b, 5-(2-Methyl-1,2,4-triazol-3-yl)indole

Derivatives 15b-e, and 5-(Pyrimid-2-yl)indole Derivatives 22b,c

a

For detailed description of assays, see Table 2.

Of 264 possible products, 163 were obtained in suffi-

cient purity (>70%) and yield to allow for determination

of affinity by single concentration-binding studies to

adrenergic R₁, dopamine D₂, and serotonin 5-HT_2A

receptors. For the most potent compounds, K_ivalues

were determined. In general, the effect of the different

piperidine N-substituents were independent of the

indole 5-substituent. Representative examples of data

obtained by this method are given in Table 6. The most

promising compounds obtained were the 1-methyl-1,2,4-

triazol-3-yl, pyrimidin-2-yl, and 2-methyltetrazol-5-yl

derivatives 15b-e, 22b,c, and 12b. These compounds

were resynthesized, and the receptor binding affinities

are presented in Table 4.

Replacement of the imidazolidinone side chain with

an oxazolidinone side chain as in compounds 15b and

22b resulted in reduced affinity for dopamine D₂and

serotonin 5-HT_1Band 5-HT_2Areceptors. The effect was

most pronounced for 5-HT_1Breceptors, where the affin-

ity was reduced 4- to 7-fold. In contrast, no improvement

in selectivity in respect to dopamine D₂and serotonin

5-HT_2Areceptors was observed with similar replacement

in the tetrazole series, as apparent by comparison of

12a and 12b.

As apparent by comparing the propionitriles 15c and

22c (Table 4) with the corresponding imidazolidinones

15a and 22a (Table 3), this replacement resulted in

significantly reduced affinities for dopamine D₂, as well

as serotonin 5-HT_1A, 5-HT_1Band 5-HT_2Areceptors.

Despite the slightly reduced affinity for R₁adrenergic

receptors, the overall selectivity of these compounds is

enhanced significantly.

The affinities of the prepared compounds for adren-

ergic R₁receptors were essentially unchanged by re-

placement of the imidazolidinone side chain with the

side chains listed in Table 4, except for the 3-ethyl-1H-

quinazoline-2,4-dione 15e and the oxazolidinone 22b

where the affinities were reduced by factors of 5 and

14, respectively.

The affinity of the most selective compounds and

selected compounds from Tables 3 and 4 are listed in

Table 5 together with additional receptor-binding af-

finities at R₁adrenergic subtypes (R_1a, R_1b, R_1d) and

dopamine D₁, D₃, and D₄receptors.

The 3-ethyl-1-methylpyrrolidin-2-one derivative 15d

(racemate) showed a receptor-binding profile similar to

the corresponding imidazolidinone 15a , indicating that

the N-H in the imidazolidinone 3-position has no

specific interaction contributing to the receptor-binding

affinity.

All compounds have low affinity for the dopamine D₁,

D₃, and D₄receptors. The receptor-binding affinity of

the 1,2,4-triazole (15a ) was reduced by a factor of 340,

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 273

Ta ble 5. Receptor-Binding Profiles for the Most Selective 5-Heteroarylindole Derivatives and for Reference Compounds

a

b

d

For description of assays, see Table 2. h-5-HT_2C.

^cReference 11. IC₅₀value.^{55 e}Reference 55.

1100 and 272, respectively, for these receptors compared

to sertindole (1).

highest affinity for the R_1areceptor subtype, except the

quinazoline-2,4-dione 15e which has higher affinity for

the R_1breceptor.

The imidazolidinone derivatives 12a , 13a , and 15a

all showed some degree of subtype selectivity. The

affinities for the adrenergic R_1band R_1dreceptor sub-

types were lower by a factor of 5-10 compared to the

R_1areceptor subtype. The same trend was observed with

the oxazolidinones 12b and 15b, with the propionitrile

Sertindole (1) binds with sub-nanomolar affinity for

the three R₁-adrenergic subtypes (R_1a, R_1b, R_1d) as shown

in Table 5.²⁵The affinity of the compounds of the

present investigation listed in Table 5 for the recombi-

nant R_1areceptor subtype was generally higher with a

factor of 3-25 compared to the data obtained in the R₁

assay (rat brain homogenate). All compounds have the

274 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

Ta ble 6. Examples of Yields, Purity, and Pharmacological Data Obtained from Parallel Synthesis Library

a

For detailed description of assays, see Table 2.

Ch a r t 3. Structure (1R,3S)-Tefludazine (41) and

(S)-Octeclothepin (42)

including sertindole (1). The basic features of this model,

consisting of two aromatic rings and one basic nitrogen

atom, were later used to develop receptor interaction

53,54

models for antagonists of serotonin 5-HT₂

and

55

dopamine D₄receptors. Both (1R,3S)-tefludazine and

(S)-octoclothepin, used as basis for the model, are potent

adrenergic R₁antagonists,⁵⁶suggesting that the model

can be used to rationalize the binding of adrenergic R₁

antagonists. This is further supported by a study of the

enantiomers of octoclothepin.⁵⁶The (S)-enantiomer

displays 2.5 times higher affinity for the dopamine D₂

receptor compared to the (R)-enantiomer. It was shown

that conformations exist where the two enantiomers

adopt very similar 3-D shapes and are well accom-

modated into the model. The conformational energies

for the compounds in these conformations agreed well

with the displayed eudismic ratio.⁵⁶The eudismic ratio

of the two octoclothepin enantiomers with respect to R₁

adrenoceptor affinity is comparable to the eudismic ratio

reported for dopamine D₂receptor affinity.⁵⁶As appar-

ent from the results in Table 5, (R)- and (S)-octo-

clothepin showed a similar subtype profile with decreas-

ing affinity from R_1aover R_1bto R_1dand eudismic ratios

in the range of 2.5-4.3, the S-enantiomer being consis-

tently more potent compared to the R-enantiomer.

These results indicate that the D₂pharmacophore also

can be extended to a pharmacophore for the adrenergic

R₁subtypes, R_1aR_1b, and R_1d. Accordingly it can be

assumed that the phenylindoles of the present investi-

gation bind to the R₁receptors in a conformation similar

to that reported for phenylindoles on the D₂, D₄, and

5-HT₂receptors.^53-55The selectivities obtained may be

explained by interactions between the substituents in

the 5-position in the indole nucleus and the receptors

studied as discussed in the following.

15c and with the 3-ethyl-1-methylpyrrolidin-2-one 15d .

In contrast, the oxazolidinone-substituted pyrimidine

derivative 22b bound with 100 times lower affinity for

the R_1dreceptor subtypes compared to R_1aThis indicates

that further exploration of the area around the indole

5-position may hold a potential for development of

subtype-selective ligands.

The 3-ethyl-1H-quinazoline-2,4-dione 15e displayed

subnanomolar affinity for the adrenergic R_1breceptor

(0.39 nM). Compared to the imidazolidinone 15a , the

affinity for this receptor subtype was enhanced 17 times

without significantly affecting the affinity for the R_1a

and R_1dreceptor subtypes. This could indicate an

additional binding site for aromatic substituents in the

R_1breceptor.

Sertindole (1) has been shown to antagonize the

response to the R₁-agonist phenylephrine in rat small

arteries²⁷and to inhibit the pressor response of phenyl-

ephrine after iv dosing in pithed rats (ED₅₀) 0.65 µmol/

kg).⁴⁹Similarly, compound 12a inhibits the pressor

response of phenylephrine after iv dosing in pithed rats

(ED₅₀) 1.5 µmol/kg),⁵⁰suggesting that this compound

is an R₁-adrenoceptor antagonist like sertindole. This

is further supported by the inhibition of isoniazide-

induced convulsions in mice⁵¹by the compounds 8a

(ED₅₀) 3.6 µmol/kg) and 12a (ED₅₀) 1.1 µmol/kg),⁵⁰

indicating that these compounds are centrally acting R₁-

adrenoceptor antagonists.

We recently hypothesised that steric bulk of large

substituents in the plane of the indole nucleus in the

area corresponding to the indole 5-position reduced the

affinity for dopamine D₂and serotonin 5-HT_2Aand

5-HT_2Creceptors and that compensatory electrostatic

interactions explained the high affinity for adrenergic

R₁receptors despite the repulsive steric interactions.²⁵

The present results seem to support this hypothesis.

The derivatives having “ortho” methyl-substituted 5-het-

eroaryl groups (16a -21a ) may adopt conformations

where the 5-heteroaryl group and the indole moiety are

not coplanar due to repulsion between the methyl group

and the protons in the indole 4- and 6-position. In

The Liljefors-Bøgesø pharmacophore model for dopa-

mine D₂receptor antagonists⁵²is based on superim-

position of the two potent dopamine D₂anatagonists (S)-

octoclothepin (42, Chart 3) and (1R,3S)-tefludazine (41,

Chart 3) and was validated by studies on phenylindoles

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 275

230-400 mesh ASTM or Biotage Flash40 (50 or 100 g columns)

were used. ¹H NMR spectra were recorded of all novel

compounds at 250 MHz on a Bruker AC 250 or at 500 MHz

on a Bruker Avance DRX500 instrument. Deuterated chloro-

form (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 abbrevia-

tions are used for multiplicity of NMR signals: s ) singlet, d

) doublet, t ) triplet, q ) quartet, dd ) double doublet, dt )

double triplet, tt ) triplet of triplets, m ) multiplet. NMR

signals corresponding to acidic protons are generally omitted.

Melting points are reported uncorrected. Solvent residuals in

elemental analysis samples were measured by Karl Fisher

titration (H₂O) or by Thermo Gravimetric Analysis (TGA) on

a TA-instruments TGA 2950 with heating rate 10 °C per min.

The identity of the solvent was determined by ¹H NMR.

Solvent residuals are not reported in the NMR data. LC-MS

data (Liquid Chromatography Mass Spectroscopy) were ob-

tained 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 4.6 × 50 mm,

3.5 µm column. Solvent A: 100% H₂O + 0.05% trifluoroacetic

acid, solvent B: 95% CH₃CN, 5% H₂O + 0.035% trifluoroacetic

acid. 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 µL from a Gilson 215 Liquid Handler. Preparative

HPLC-MS was run with 190 µL injections on a YMC RP18

(50 × 20 mm) column with a gradient of A/B 80/20 f 0/100

during 7 min, then isocratic 80/20 during one minute. The flow

was 22.7 mL/min throughout and detection was performed

using the MS (TIC) signal in a split system. The reported

purities are based on integration of the peaks in the UV and

ELSD spectrum.

contrast, the derivatives unsubstituted in the “ortho”

position of the 5-heteroaryl group (8a -15a ) may adopt

conformations where the two ring systems are coplanar.

The most selective compounds in the present study are

identified within the group of compounds unsubstituted

in the “ortho” position (e.g. 8a and 15a ) where coplanar

conformations are expected to be of low conformational

energy. Accordingly, this group of compounds 8a -15a

(Table 3) tends to have lower affinity for dopamine D₂

and serotonin 5-HT_2Aand 5-HT_2Creceptors compared

to the “ortho” substituted compounds 16a -21a .

The importance of favorable electrostatic interaction

between the receptor and the 5-heteroaryl moieties in

the present compounds for the affinity for adrenergic

R₁receptors is difficult to address by qualitative means.

However, comparison of the least potent of the com-

pounds listed in Table 3, the 1-methylpyrazol-4-yl

derivative 14a , with any of the compounds in Table 3

indicates the importance of a hydrogen-bond acceptor

in the position “ortho” to the point of attachment to the

indole nucleus.

We are currently investigating the structure-affinity

relationships of the present 5-heteroaryl-substituted

phenylindoles together with previously reported 5- and

6-substituted phenylindoles by a 3D-QSAR approach in

order to address the importance of the proper balance

between unfavorable steric interactions and favorable

electrostatic interactions for the affinity for adrenergic

R₁receptors of phenylindoles.

In the present study, several highly selective R₁-

adrenoceptor antagonists were obtained. The optimal

compounds with respect to overall selectivity are the

tetrazoles 12a and 12b. The selectivity of these com-

Rea gen ts. The following reagents were prepared according

to published procedures: 1-(2-chloroethyl)imidazolidin-2-

one,^32,573-(2-chloroethyl)oxazolidin-2-one,⁵⁸3-(2-chloroethyl)-

1-methyl-2-pyrrolidin-2-one,⁵⁹1-methyl-1,2,3-triazole,⁶⁰4-bromo-

1-methyl-1,2,3-triazole,⁶¹2-bromo-1-methyl-1,3,4-triazole,⁶²

5-bromo-1-methyl-1,2,4-triazole,⁶²3-bromo-1-methyl-1,2,4-tria-

zole,⁶²3-iodo-1-methylpyrazole.³⁹The reference compound,

pounds is limited by affinity for serotonin 5-HT_1A

,

5-HT_1B, 5-HT_2Aand dopamine D₂receptors. Considering

selectivity for R_1areceptors in respect to dopamine D₂,

D₃, and D₄and serotonin 5-HT_2Aand 5-HT_2C, the

optimal compound is the 1-methyl-1,2,4-triazol-3-yl-

substituted propionitrile 15c. This compound has af-

finities of 0.99, 3.2, and 9.0 nM for the R_1a, R_1b, and R_1d

adrenoceptor subtypes, respectively, and a selectivity

for adrenergic R_1areceptors in respect to dopamine D₂,

D₃, and D₄and serotonin 5-HT_2Aand 5-HT_2Chigher

than 900, comparable to the selectivity of prazosin. In

addition, the compound is more than 150-fold selective

in respect to serotonin 5-HT_1Aand 5-HT_1Breceptors.

The 5-heteroaryl-substituted 1-(4-flurophenyl)indoles

presented in this paper represent a novel class of

selective adrenergic R₁receptor ligands. The potential

of the most selective compounds for the treatment of

CNS-related diseases is currently under investigation.

Furthermore, the compounds may have a potential as

PET ligands for imaging of central adrenergic R₁recep-

tors.

SNAP 8719 (7), was prepared as described in

a patent

application.⁶³

5-Br om o-1-(4-flu or op h en yl)-1H-in d ole (27a ). 5-Bromo-

1H-indole (250 g, 1.28 mol), 1-fluoro-4-iodobenzene (510 g, 2.30

mol), K₂CO₃(530 g, 3.84 mol), CuI (90 g, 0.47 mol), and ZnO

(30 g, 0.37 mol) were heated at 100 °C in NMP (3 L) with

mechanical stirring for 24 h. Additional K₂CO₃(53 g, 0.39 mol),

CuI (9 g, 0.05 mol), and ZnO (3 g, 0.04 mol) were added, and

the mixture was stirred for further 24 h. After filtration, H₂O

(2 L) and aqueous NH₄OH (25%, 100 mL) were added, and

the aqueous phase was extracted with EtOAc (3 × 2 L). The

combined organic phases were washed with brine (500 mL)

and dried over MgSO₄. After evaporation of the solvent in

vacuo, the crude product (473 g) was purified by flash chro-

matography (EtOAc/heptane 5/95). Recrystallization from

EtOAc/heptane 5/95 gave 229 g (55%) of 27: Mp 104-105 °C

(EtOAc/heptane 5/95) (lit.³²101 °C (cyclohexane)); ¹H NMR

(CDCl₃) δ: 6.70 (d, 1H), 7.30 (d, 1H), 7.40-7.45 (m, 3H), 7.60-

7.65 (m, 2H). 7.70 (d, 1H), 7.80 (d, 1H).

5-Eth yn yl-1-(4-flu or op h en yl)-1H-in d ole (28). A mixture

of 27a (40.0 g, 0.14 mol), (trimethylsilyl)acetylene (21.4 g, 0.22

mol), Pd(PPh₃)₂Cl₂(2.9 g, 3 mol %), CuI (1.3 g, 5 mol %), NEt₃

(40 mL), and CH₃CN (150 mL) was boiled under reflux for 8

h. After the mixture was cooled to room temperature, H₂O (100

mL) was added and the resulting mixture was extracted with

EtOAc (4 × 300 mL). The combined organic phases were

washed with brine (2 × 800 mL) and dried (Na₂SO₄), and the

solvents were evaporated in vacuo. A solution of the remaining

oil and KOH (12.1 g, 0.22 mol) in a mixture of MeOH (500

mL) and H₂O (200 mL) was boiled under reflux for 3 h. The

volatile solvents were evaporated in vacuo, and a mixture of

H₂O (200 mL) and EtOAc (1000 mL) was added. The phases

were separated, and the aqueous phase was extracted with

EtOAc (250 mL). The combined organic phases were dried

Exp er im en ta l Section

Gen er a l. All reactions were carried out under a positive

pressure of nitrogen or argon. Glassware for water-sensitive

reactions was dried in an oven at 150 °C overnight. THF was

freshly distilled from sodium/benzophenone. DMF was sequen-

tially dried and stored over 3 Å molecular sieves. ZnCl₂was

flame-dried in vacuo and dissolved to 1.0 M in dry THF after

cooling to room temperature. Acetone and CH₃CN for alkyla-

tion reactions were HPLC grade. Saturated HCl/MeOH solu-

tions were prepared by saturation of MeOH with HCl gas. For

flash chromatography either silica gel of type Kiesel gel 60,

276 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

(Na₂SO₄) and the volatile solvents evaporated in vacuo.

Purification of the remaining oil by column chromatography

on silica gel (CH₂Cl₂/heptane 1:6) afforded 11.4 g (35%) of the

crystalline pure title compound (28): Mp 99-100 °C; ¹H NMR

(CDCl₃) δ: 3.00 (s, 1H), 6.55 (d, 1H), 7.20 (t, 2H), 7.25 (d, 1H),

7.35 (m, 2H), 7.40 (dd, 2H), 7.85 (broad s, 1H).

1-(4-F lu or op h en yl)-5-(1,2,3-tr ia zol-4-yl)-1H-in d ole (29).

A mixture of 28 (9.6 g, 41 mmol) and neat azidotrimethylsilane

(21.7 g, 0.19 mol) was heated in a sealed tube at 170 °C for 24

h. The reaction mixture was cooled to 0 °C, and CH₂Cl₂(150

mL) and 2 N aqueous NaOH (20 mL) were added. After the

mixture was stirred at room temperature for 2 h, H₂O (200

mL) was added and the solution acidified by addition of

concentrated aqueous HCl. The phases were separated, and

the aqueous phase was extracted with CH₂Cl₂(2 × 200 mL).

The combined organic phases were washed with brine (200

mL), dried (MgSO₄) and the volatile solvents evaporated in

vacuo affording 11.8 g (100%) of 29 as an oil: ¹H NMR (CDCl₃)

δ: 6.80 (d, 1H), 7.25 (t, 2H), 7.40 (d, 1H), 7.55 (dd, 2H), 7.60

(d, 1H), 7.75 (broad d, 1H), 8.05 (s, 1H), 8.20 (broad s, 1H).

1-(4-F lu or op h en yl)-5-(1-m et h yl-1,2,3-t r ia zol-4-yl)-1H -

in d ole (30a ) a n d 1-(4-flu or op h en yl)-5-(2-m eth yl-1,2,3-

tr ia zol-4-yl)-1H-in d ole (32a ). A mixture of 29 (6.0 g, 21.6

mmol), CH₃I (6.7 mL, 0.11 mol), K₂CO₃(6.0 g, 43.2 mmol), and

acetone (100 mL) was boiled under weak reflux for 18 h. The

solids were filtered off, and the solvent was evaporated in

vacuo. The mixture of 30a and 32a was separated by flash

chromatography (EtOAc/heptane 1:1). Evaporation of the

solvent from the fractions containing the fastest eluting

compound afforded 2.1 g (33%) pure 32a as an oil: ¹H NMR

(CDCl₃) δ: 4.25 (s, 3H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H),

7.40-7.55 (m, 3H), 7.65 (broad d, 1H), 7.85 (s, 1H), 8.10 (broad

s, 1H). Evaporation of the solvent from the fractions containing

the slowest eluting compound afforded 0.80 g (13%) pure 30a

as an oil: ¹H NMR (CDCl₃) δ: 4.15 (s, 3H), 6.70 (d, 1H), 7.20

(t, 2H), 7.30 (d, 1H), 7.50 (dd, 2H), 7.55 (d, 1H), 7.70 (broad d,

1H), 7.75 (s, 1H), 8.10 (broad s, 1H).

[1-(4-fluorophenyl)-5-(1-methyl-1,2,3-triazol-4-yl)-1H-indol-3-

yl]-1,2,3,6-tetrahydropyridin-1-yl}ethyl)imidazolidin-2-one (30c)

as an oil: ¹H NMR (CDCl₃) δ: 2.60-2.75 (m, 4H), 2.80 (t, 2H),

3.25-3.35 (m, 2H), 3.35-3.50 (m, 4H), 3.50-3.60 (m, 2H), 4.15

(s, 3H), 4.70 (broad s, 1H), 6.25-6.35 (broad s, 1H), 7.20 (t,

2H), 7.25 (s, 1H), 7.40-7.50 (m, 3H), 7.70 (broad d, 1H), 7.80

(s, 1H), 8.40 (broad s, 1H). A solution of 30c (0.70 g, 1.4 mmol)

in glacial acetic acid (100 mL) and PtO₂(70 mg) was reacted

in a Parr apparatus with H₂at 2-3 ato for 24 h. After filtration

and evaporation of the solvent, ice (50 mL) and 10% aqueous

NH₄OH were added to pH 10, and extraction with EtOAc (3

× 50 mL) was performed. The solution was dried over MgSO₄,

and the solvent was removed in vacuo to yield 0.50 g of crude

product that was purified by flash chromatography (EtOAc/

EtOH/NEt₃50/50/2) to yield a foam (0.30 g). Addition of Et₂O

and filtration afforded 0.24 g (34%) of the title compound 8a :

Mp 116-118 °C (Et₂O); ¹H NMR (CDCl₃) δ: 1.70-1.90 (m, 2H),

2.05-2.30 (m, 4H), 2.60 (t, 2H), 2.95 (tt, 1H), 3.00-3.15 (m,

2H), 3.30-3.45 (m, 4H), 3.50-3.60 (m, 2H), 4.15 (s, 3H), 4.40

(broad s, 1H), 7.05 (s, 1H), 7.20 (t, 2H), 7.45 (dd, 2H), 7.50 (d,

1H), 7.60 (broad d, 1H), 7.75 (s, 1H), 8.20 (broad s, 1H); 1D-

NOE: 2% on δ ) 8.20 (1,2,3-triazole H4) by irradiation of δ )

4.15 (N-CH₃); MS m/z: 488 (MH⁺, 29%), 194 (28%), 168 (23%),

113 (100%); Anal. (C₂₇H₃₀FN₇O‚1.80% H₂O): C, H, N.

The following derivatives were prepared accordingly:

1-(2-{4-[5-(1-Eth yl-1,2,3-tr ia zol-4-yl)-1-(4-flu or op h en yl)-

1H-in dol-3-yl]-1-piper idin yl}eth yl)im idazolidin -2-on e (9a).

The material obtained after chromatography was stirred with

EtOH. Filtration afforded 0.20 g (12%) of 9a . Mp 132-134 °C

1

(EtOH); H NMR (CDCl₃) δ: 1.60 (t, 3H), 1.70-1.95 (m, 2H),

2.05-2.30 (m, 4H), 2.55 (t, 2H), 2.90 (tt, 1H), 3.00-3.15 (m,

2H), 3.30-3.45 (m, 4H), 3.45-3.60 (m, 2H), 4.30 (broad s, 1H),

4.45 (q, 2H), 7.05 (s, 1H), 7.10 (t, 2H), 7.35-7.50 (m, 3H), 7.60

(broad d, 1H), 7.75 (s, 1H), 8.15 (broad s, 1H); 1D-NOE: 2%

on δ ) 8.15 (1,2,3-triazole H4) by irradiation of δ ) 4.45 (N-

CH₂); MS m/z: 502 (MH⁺, 100%), 113 (86%); Anal. (C₂₈H₃₂

FN₇O‚2.67% H₂O): C, H; N: calcd 19.02, found: 18.22.

-

The following derivatives were prepared accordingly using

ethyl iodide:

5-(1-Eth yl-1,2,3-tr ia zol-4-yl)-1-(4-flu or op h en yl)-1H-in -

d ole (31a ): Oil (1.5 g, 20%): ¹H NMR (CDCl₃) δ: 1.60 (t, 3H),

4.45 (q, 2H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.40-7.55

(m, 3H), 7.70 (broad d, 1H), 7.75 (s, 1H), 8.15 (broad s, 1H).

5-(2-Eth yl-1,2,3-tr ia zol-4-yl)-1-(4-flu or op h en yl)-1H-in -

d ole (33a ): Oil (2.6 g, 43%): ¹H NMR (CDCl₃) δ: 1.60 (t, 3H),

4.50 (q, 2H), 6.70 (d, 1H), 7.20 (t, 2H), 7.30 (d, 1H), 7.45 (dd,

2H), 7.45 (d, 1H), 7.65 (broad d, 1H), 7.80 (s, 1H), 8.10 (broad

s, 1H).

1-(2-{4-[1-(4-F lu or op h en yl)-5-(2-m eth yl-1,2,3-tr ia zol-4-

yl)-1H -in d ol-3-yl]-1-p ip e r id in yl}e t h yl)im id a zolid in -2-

on e (10a ). The material obtained after chromatography was

recrystallized from EtOH to give 0.60 g (50%) of 10a . Mp 203-

204 °C (EtOH); ¹H NMR (CDCl₃) δ: 1.70-1.90 (m, 2H), 2.05-

2.15 (m, 2H), 2.20-2.30 (m, 2H), 2.60 (t, 2H), 2.90 (tt, 1H),

3.05-3.15 (m, 2H), 3.35-3.50 (m, 4H), 3.50-3.60 (m, 2H), 4.25

(s, 3H), 4.40 (broad s, 1H), 7.05 (s, 1H), 7.20 (t, 2H), 7.45 (dd,

2H), 7.50 (d, 1H), 7.60 (broad d, 1H), 7.85 (s, 1H), 8.05 (broad

s, 1H); 1D-NOE: No significant NOEs observed by irradiation

of δ ) 4.25 (N-CH₃); MS m/z: 488 (MH⁺, 49%), 196 (35%), 113

(100%); Anal. (C₂₇H₃₀FN₇O): C, H, N.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yltr ia zol-4-yl)-1H-

in d ol-3-yl]-1-p ip er id in yl}eth yl)im id a zolid in -2-on e (8a ). A

mixture of 4-piperidone hydrochloride hydrate (2.5 g, 16.4

mmol), glacial acetic acid (20 mL), and trifluoroacetic acid (20

mL) was boiled under reflux. During 20 min, 30a (0.80 g, 2.7

mmol) in glacial acetic acid (10 mL) was added in small

portions. The mixture was boiled under reflux for another 1.5

h. After the mixture was cooled, the solvents were evaporated

in vacuo and H₂O (100 mL) was added. The aqueous phase

was made alkaline by the addition of concentrated aqueous

NaOH and subsequently extracted with EtOAc (3 × 100 mL).

The combined organic phases were dried (Na₂SO₄), and the

solvents evaporated in vacuo to give 0.90 g (91%) of 1-(4-

fluorophenyl)-5-(1-methyl-1,2,3-triazol-4-yl)-3-(1,2,3,6-tetrahy-

dropyridin-4-yl)-1H-indole (30b) as an oil: ¹H NMR (CDCl₃)

δ: 2.50-2.60 (m, 2H), 2.60-2.70 (broad s, 1H), 3.15 (t, 2H),

3.60-3.70 (m, 2H), 4.15 (s, 3H), 6.30-6.40 (m, 1H), 7.15-7.25

(m, 3H), 7.35-7.50 (m, 3H), 7.65 (broad d, 1H), 7.75 (s, 1H),

8.40 (broad s, 1H). A solution of 30b (0.90 g, 2.0 mmol) and

1-(2-chloroethyl)imidazolidin-2-one (0.30 g, 2.2 mmol) in 4-meth-

yl-2-pentanone (50 mL) was boiled under reflux with K₂CO₃

(0.40 g, 3.0 mmol) and KI (0.10 g, 0.6 mmol) for 8 h. After the

mixture was cooled to room temperature, water (25 mL) was

added and the aqueous phase extracted with EtOAc (3 × 50

mL). Evaporation of the solvents and flash chromatography

(EtOAc/EtOH/NEt₃50/50/2) afforded 0.70 g (64%) of 1-(2-{4-

1-(2-{4-[5-(2-Eth yl-1,2,3-tr ia zol-4-yl)-1-(4-flu or op h en yl)-

1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e

(11a ). The material obtained after chromatography was

recrystallized from EtOAc to give 1.1 g (69%) of 11a . Mp 173-

1

175 °C (EtOAc); H NMR (CDCl₃) δ: 1.60 (t, 3H), 1.75-1.95

(m, 2H), 2.05-2.15 (m, 2H), 2.20-2.35 (m, 2H), 2.60 (t, 2H),

2.95 (tt, 1H), 3.05-3.15 (m, 2H), 3.35-3.50 (m, 4H), 3.50-

3.60 (m, 2H), 4.30 (broad s, 1H), 4.55 (q, 2H), 7.10 (s, 1H), 7.20

(t, 2H), 7.35-7.50 (m, 3H), 7.60 (broad d, 1H), 7.85 (s, 1H),

8.05 (broad s, 1H); 1D-NOE: No significant NOEs observed

by irradiation of δ ) 4.55 (N-CH₂); MS m/z: 502 (MH⁺, 47%),

196 (28%), 113 (100%); Anal. (C₂₈H₃₂FN₇O): C, H; N: calcd

19.55, found: 18.69.

4-[5-Br om o-1-(4-flu or oph en yl)-1H-in dol-3-yl]piper idin e-

1-ca r boxylic Acid ter t-Bu tyl Ester (34). A solution of 27a

(172 g, 0.59 mol) and 4-piperidone hydrochloride hydrate (550

g, 3.6 mol) in glacial acetic acid (0.63 L) and trifluoro acetic

acid (1.2 L) was reacted in analogy to the method described

in the reference³²to yield 220 g (100%) of crude 5-bromo-1-

(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (27b)

(free base) as white solid: ¹H NMR (CDCl₃) δ: 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). A solution of

crude 27b (220 g, 0.59 mol) in glacial acetic acid (1.5 L) and

PtO₂(5 g) was treated with H₂in a Parr apparatus at 2-3 ato

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 277

for 24 h. Additional PtO₂(4 g) was added, and the reaction

was continued for 24 h. Solids were filtered off, and the

solvents were evaporated in vacuo. evaporation of the solvent,

10% aqueous NH₄OH (600 mL) was added and the resulting

slurry was extracted with EtOAc (3 × 400 mL). The combined

organic phases were dried (MgSO₄) and the solvent removed

in vacuo to yield 125 g (57%) of crude 5-bromo-1-(4-fluoro-

phenyl)-3-(4-piperidinyl)-1H-indole (27c) as an oil: ¹H NMR

(DMSO-d₆) δ: 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 of crude 27c

(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 K₂-

CO₃(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 (3 × 0.5 L). The combined organic phases were

washed with brine (300 mL) and dried (MgSO₄), and the

solvent was removed in vacuo. The crude product (115 g) was

washed with cold MeOH to yield 97 g of the title compound

34 (35% from 27a ) as a white solid: Mp 160-162 °C (heptane);

¹H NMR (CDCl₃) δ: 1.49 (s, 9H), 1.65 (q, 2H), 2.04 (d, 2H),

2.85-3.00 (m, 3H), 4.25 (d, 2H), 7.03 (s, 1H), 7.15-7.35 (m,

4H), 7.39-7.43 (m, 2H), 7.78 (s, 1H); MS m/z: 473 + 475

2D-NOE cross-peak between δ ) 4.22 (tetrazole N-CH₃) and

δ ) 8.13 (indole H4) and δ ) 7.59 (indole H6) present; Anal.

(C₂₆H₂₉FN₆O₂): C, H, N. The column was eluted further to give

1.2 g (20%, white foam) of 38: Mp 129-130 °C (EtOAc/heptane

1

1/4); H NMR (CDCl₃) δ: 1.50 (s, 9H), 1.72 (qd, 2H), 2.13 (d,

2H), 2.92 (t, 2H), 3.06-3.16 (m, 1H), 4.28 (s. broad, 2H), 4.42

(s, 3H), 7.10 (s, 1H), 7.18-7.25 (m, 2H), 7.42-7.48(m, 2H), 7.52

(d, 1H), 7.99 (d, 1H), 8.49 (s, 1H). 2D-NOE cross-peak between

δ ) 4.42 (tetrazole N-CH₃) and δ ) 8.49 (indole 4H) and δ )

7.99 (indole 6H) absent; Anal. (C₂₆H₂₉FN₆O₂): C, H, N.

Cr oss-Cou p lin g of 4-[5-Br om o-1-(4-flu or op h en yl)-1H-

in d ol-3-yl]p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester

(34) w ith Heter oa r yl Ha lid es (Meth od A). A solution of

34 (10.0 g, 21.1 mmol) in THF (20 mL) was added during 2

min to a solution of n-butyllithium (39.6 mL, 63.4 mmol) in

THF (210 mL) at -78 °C. After the mixture was stirred for 3

min, ZnCl₂in THF (105.6 mL, 105.6 mmol) was added. The

solution was stirred for further 30 min at -78 °C. The

heteroaryl halide (amount specified below) was added together

with Pd(PPh₃)₄(1.2 g, 5 mol %) and DMF (60 mL). The reaction

mixture was stirred at 80 °C for 8 h. After the mixture was

cooled to room temperature, H₂O (300 mL) and EtOAc (500

mL) were added and the phases were separated. The organic

phase was washed with H₂O (200 mL) and a saturated aqueous

CaCl₂solution (3 × 100 mL) and dried over MgSO₄, and the

solvent was removed in vacuo. The crude product was purified

by flash chromatography. The amount of reagents and solvents

were scaled according to the actual amount of 34 used.

(MH⁺, 1%), 417+419 (40%), 373+375(100%); Anal. (C₂₄H₂₆

-

BrFN₂O₂): C, H, N.

4-[5-Cyan o-1-(4-flu or oph en yl)-1H-in dol-3-yl]piper idin e-

1-ca r boxylic Acid ter t-Bu tyl Ester (35). A solution of 34

(26.2 g, 55.4 mmol) and Zn(CN)₂(6.5 g, 55.4 mmol) in DMF

(300 mL) was stirred at room temperature for 20 min under

argon. Pd(PPh₃)₄(3.0 g, 5 mol %) was added, and the solution

was stirred for 8 h at 80 °C. After the mixture was cooled to

room temperature, DMF was removed in vacuo, EtOAc (500

mL) was added, and the solution was extracted with H₂O (2

× 300 mL) and brine (300 mL). Evaporation of the solvent in

vacuo and flash chromatography (EtOAc/heptane 1/4 f 1/1)

gave 21.0 g (90%) of the title compound (35): Mp 85-87 °C

(EtOAc/heptane 1/4); ¹H NMR (CDCl₃) δ: 1.50 (s, 9H), 1.70

(qd, 2H), 2.05 (d, 2H), 2.90 (t, 2H), 2.99-3.06 (m, 1H), 4.27 (d,

broad, 2H), 7.15 (s, 1H), 7.20-7.27 (m, 2H), 7.40-7.48 (m, 4H),

8.03 (s, 1H); Anal. (C₂₅H₂₆FN₃O₂): C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1H-tetr a zol-5-yl)-1H-in d ol-3-

yl]p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (36). A

solution of 35 (10.2 g, 24.3 mmol), NaN₃(4.9 g, 75 mmol), and

NEt₃‚HCl (10.0 g, 72 mmol) in toluene (75 mL) was boiled

under reflux for 8 h. After the mixture was cooled to room

temperature, H₂O (100 mL) was added and the pH-value was

adjusted to 8-9. The phases were separated, and the aqueous

phase was extracted with EtOAc (3 × 200 mL). The combined

organic phases were washed with H₂O (3 × 100 mL) and brine

(50 mL) and dried (MgSO₄), and the solvents were removed

in vacuo. The crude product was recrystallized from acetone

to yield 8.0 g (71%) of 36: ¹H NMR (CDCl₃) δ: 1.45 (s, 9H),

1.65 (qd, 2H), 2.05 (d, 2H), 2.96 (s, broad, 2H), 3.05-3.15 (m,

1H), 4.13 (s, broad, 2H), 7.40.7.48 (m, 2H), 7.62 (s, 1H), 7.65-

7.70 (m, 3H), 7.88 (d, 1H), 8.42 (s, 1H); Anal. (C₂₅H₂₇FN₆O₂):

C, H; N: calcd 18.17 found 17.29.

4-[1-(4-F lu or op h en yl)-5-(2-m eth yl-tetr a zol-5-yl)-1H-in -

d ol-3-yl]p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester

(37) a n d 4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-tetr a zol-5-yl)-

1H -in d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl

E st er (38). A suspension of 36 (5.9 g, 12.7 mmol), K₂CO₃

(8.7 g, 63 mmol) and CH₃I (1.6 mL, 25 mmol) in acetone (200

mL) was stirred at 0 °C for 10 min. The temperature was

raised to 35 °C during 1 h, and stirring was continued at this

temperature for 30 min. The solids were filtered off, and the

solvent removed in vacuo. H₂O (200 mL) was added, and the

aqueous phase was extracted with EtOAc (3 × 150 mL). The

combined organic phases were washed with brine and evapo-

rated on kiesel gel. Flash chromatography (EtOAc/heptane 30/

70) afforded 3.9 g (57%, white solid) of 37: Mp 164-165 °C

(EtOAc/heptane 1/4); ¹H NMR (CDCl₃) δ: 1.50 (s, 9H), 1.72

(qd, 2H), 2.10 (d, 2H), 2.93 (s, broad, 2H), 3.04-3.14 (m, 1H),

4.22 (s, 3H), 4.27 (s, broad, 2H), 7.20 (s, 1H), 7.23-7.25 (m,

2H), 7.45-7.49 (m, 2H), 7.50 (d, 1H), 7.59 (d, 1H), 8.13 (s, 1H).

The following derivatives were prepared according to method

A.

4-[1-(4-F lu or op h en yl)-5-(1-m et h yl-1,2,3-t r ia zol-4-yl)-

1H -in d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl

Ester (8). A solution of 34 (4.7 g, 10 mmol) in THF was reacted

with 4-bromo-1-methyl-1,2,3-triazole (1.1 g, 6.8 mmol). The

crude product was purified by flash chromatography (EtOAc/

heptane 20/80 f 100/0) to yield 0.90 g (28%) of 8 as a white

foam: ¹H NMR (CDCl₃) δ: 1.50 (s, 9H), 1.69 (q, 2H), 2.12 (d,

2H), 2.94 (t, 2H), 3.09 (t, 1H), 4.18 (s, 3H), 4.28 (s, broad, 1H),

7.06 (s, 1H), 7.17-7.24 (m, 2H), 7.40-7.55 (m, 3H), 7.61 (d,

1H), 7.78 (s, 1H), 8.23 (s, 1H); MS m/z: 476 (MH⁺, 4%), 420

(46%), 376 (100%); Anal. (C₂₇H₃₀N₅FO₂): C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1-m eth ylp yr a zol-3-yl)-1H-in -

d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl E st er

(13). A solution of 34 (6.8 g, 14.4 mmol) in THF was reacted

with 1-methyl-3-iodopyrazole (3.0 g, 14.4 mmol). The crude

product was purified by flash chromatography (EtOAc/heptane

20/80 f 50/50) to yield 4.31 g (63%) of 13 as white crystals:

Mp 145-146 °C (EtOAc/heptane); ¹H NMR (CDCl₃) δ: 1.49

(s, 9H), 1.68 (q, 2H), 2.10 (d, 2H), 2.93 (t, 2H), 3.11 (t, 1H),

3.98 (s, 3H), 4.26 (s, broad, 2H), 6.57 (d, J ) 2.0 Hz, 1H), 7.04

(s, 1H), 7.17-7.24 (m, 2H), 7.39 (d, J ) 2.1 Hz, 1H), 7.42-

7.52 (m, 3H), 7.65 (d, J ) 8.6 Hz, 1H), 8.08 (s, 1H); MS m/z:

475 (MH⁺, 7%), 419 (100%), 375 (73%); Anal. (C₂₈H₃₁N₄FO₂):

C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1-m eth ylp yr a zol-4-yl)-1H-in -

d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl E st er

(14). A solution of 34 (10.0 g, 21.1 mmol) in THF was reacted

with 1-methyl-4-bromopyrazole (4.2 g, 31.7 mmol). The crude

product was purified by flash chromatography (EtOAc/heptane

20/80 f 30/70) to yield 2.8 g (28%) of 14 as white crystals:

Mp 133-136 °C (EtOAc/heptane); ¹H NMR (CDCl₃) δ: 1.49

(s, 9H), 1.71 (q, 2H), 2.10 (d, 2H), 2.94 (t, 2H), 3.05 (t, 1H),

3.96 (s, 3H), 4.27 (s, broad, 2H), 7.04 (s, 1H), 7.20-7.25 (m,

2H), 7.34 (d, 1H), 7.41-7.50 (m, 3H), 7.63 (s, 1H), 7.71 (s, 1H),

7.79 (s, 1H); MS m/z: 475 (MH⁺, 5%), 419 (86%), 375 (100%);

Anal. (C₂₈H₃₁N₄FO₂): C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1-m et h yl-1,2,4-t r ia zol-3-yl)-

1H -in d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl

Ester (15). A solution of 34 (20.0 g, 42 mmol) in THF was

reacted with 3-bromo-1-methyl-1,2,4-triazole (8.8 g, 55 mmol).

The crude product was purified by flash chromatography

(EtOAc/heptane/MeOH 50/50/0 f 100/0/0 f 90/0/10) and

crystallized from Et₂O to yield 8.0 g (40%) of 15 as white

crystals: Mp 189-191 °C (Et₂O); ¹H NMR (CDCl₃) δ: 1.50 (s,

278 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

9H), 1.70 (q, 2H), 2.12 (d, 2H), 2.95 (t, 2H), 3.13 (t, 1H), 4.00

(s, 3H), 4.28 (s, broad, 2H), 7.06 (s, 1H), 7.15-7.28 (m, 2H),

7.40-7.52 (m, 3H), 8.00 (d, 1H), 8.08 (s, 1H), 8.42 (s, 1H); MS

m/z: 476 (MH⁺, 72%), 420 (66%), 376 (100%); Anal. (C₂₇H₃₀N₅-

FO₂‚2.17% Et₂O): C, H, N.

raphy (EtOAc/heptane/NEt₃30/70/5 f 50/50/5) and recrystal-

lization from CH₂Cl₂afforded 11.5 g (80%) of 18: Mp 166-

168 °C (CH₂Cl₂); ¹H NMR (CDCl₃) δ: 1.49 (s, 9H), 1.72 (q, 2H),

2.07 (d, 2H), 2.93 (t, 2H), 3.05 (t, 1H), 3.90 (s, 3H), 4.26 (s,

broad, 2H), 6.32 (s, 1H), 7.10 (s, 1H), 7.20-7.30 (m, 3H), 7.40-

7.47 (m, 2H), 7.50 (d, 1H), 7.54 (s, 1H), 7.69 (s, 1H); Anal.

(C₂₈H₃₁FN₄O₂): C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1-m et h yl-1,3,4-t r ia zol-2-yl)-

1H -in d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl

Ester (16). A solution of 34 (10.0 g, 21.1 mmol) in THF was

reacted with 2-bromo-1-methyl-1,3,4-triazole (2.8 g, 17.3 mmol).

The crude product was purified by flash chromatography

(EtOAc/heptane/MeOH 30/70/0 f 100/0/0 f 90/0/10) to yield

2.5 g (31%) of 16 as white crystals: Mp 156-158 °C (toluene/

4-[1-(4-F lu or op h en yl)-5-(1-m eth ylim id a zol-2-yl)-1H-in -

d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl E st er

(19). 1-Methylimidazole (1.39 g, 16.9 mmol) in THF (195 mL)

was cooled to -78 °C. n-Butyllithium (14.7 mL, 23.5 mmol)

was added during 2 min. The solution was stirred for 5 min

at -78 °C, and ZnCl₂in THF (60 mL, 60 mmol) was added.

After the mixture was stirred at -78 °C for 1 h, reaction with

34 (8.30 g, 16.9 mmol) was performed following method B.

Flash chromatography (EtOAc/heptane/NEt₃30/70/4 f 70/30/

4) afforded 6.77 g which was recrystallized from toluene/

heptane 1:1 to give 4.73 g (59%): Mp 189-191 °C (toluene/

1

heptane 1:1); H NMR (CDCl₃) δ: 1.49 (s, 9H), 1.70 (q, 2H),

2.08 (d, 2H), 2.90 (t, 2H), 3.07 (t, 1H), 3.78 (s, 3H), 4.26 (s,

broad, 2H), 7.13 (s, 1H), 7.20-7.28 (m, 2H), 7.41-7.50 (m, 3H),

7.53 (d, 1H), 8.05 (s, 1H), 8.21 (s, 1H); MS m/z: 476 (MH⁺,

100%), 420 (51%), 376 (83%); Anal. (C₂₇H₃₀N₅FO₂): C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1-m et h yl-1,2,4-t r ia zol-5-yl)-

1H -in d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl

Ester (17). A solution of 34 (7.5 g, 15.8 mmol) in THF was

reacted with 5-bromo-1-methyl-1,2,4-triazole (2.1 g, 13 mmol).

The crude product was purified by flash chromatography

(EtOAc/heptane/MeOH 30/70/0 f 100/0/0 f 90/0/10) to yield

2.8 g (45%) of 17 as a pale yellow foam: ¹H NMR (CDCl₃) δ:

1.49 (s, 9H), 1.70 (q, 2H), 2.09 (d, 2H), 2.91 (t, 2H), 3.07 (t,

1H), 4.03 (s, 3H), 4.28 (s, broad, 2H), 7.13 (s, 1H), 7.20-7.30

(m, 2H), 7.42-7.50 (m, 3H), 7.52 (d, 1H), 7.96 (s, 1H), 8.02 (s,

1H); MS m/z: 476 (MH⁺, 100%), 420 (33%), 376 (41%); Anal.

(C₂₇H₃₀N₅FO₂): C, H, N.

1

heptane 1:1); H NMR (CDCl₃) δ: 1.49 (s, 9H), 7.69 (q, 2H),

2.10 (d, 2H), 2.89 (t, 2H), 3.05 (t, 1H), 3.77 (s, 3H), 4.25 (s,

broad, 2H), 6.99 (s, 1H), 7.09 (s, 1H), 7.15 (s, 1H), 7.15-7.25

(m, 2H), 7.4-7.55 (m, 4H), 7.97 (s, 1H); Anal. (C₂₈H₃₁FN₄O₂):

C, H, N.

4-[1-(4-F lu or op h en yl)-5-(1-m et h yl-1,2,3-t r ia zol-5-yl)-

1H -in d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl

Ester (20). 1-Methyl-1,2,3-triazole (1.71 g, 20.6 mmol) was

dissolved in THF (200 mL) and cooled to -78 °C. n-Butyl-

lithium (15.4 mL, 24.7 mmol) was added during 2 min, and

the solution was stirred for further 5 min before ZnCl₂in THF

(61.8 mL, 61.8 mmol) was added. After 30 min at -78 °C

reaction with 34 (9.75 g, 20.6 mmol) was performed following

method B. Purification by flash chromatography (EtOAc/

heptane/EtOH 30/70/2) gave 6.8 g which was recrystallized

from toluene/heptane 1:2 to yield 4.3 g (44%) of 20: Mp 137-

141 °C (toluene/heptane 1:2); ¹H NMR (CDCl₃) δ: 1.49 (s, 9H),

1.70 (q, 2H), 22.08 (d, 2H), 2.93 (t, 2H), 3.05 (t, 1H), 4.09 (s,

3H), 4.30 (s, broad, 2H), 7.15 (s, 1H), 7.20-7.30 (m, 3H), 7.40-

7.50 (m, 2H), 7.45 (d, 1H), 7.69 (s, 1H), 7.74 (s, 1H); Anal.

(C₂₇H₃₀FN₅O₂): C, H, N.

4-[1-(4-Flu or op h en yl)-5-(p yr im id in -2-yl)-1H-in d ol-3-yl]-

p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (22). A

solution of 34 (18.0 g, 38 mmol) in THF was reacted with

2-bromopyrimidine (10.0 g, 75 mmol). The crude product was

purified by flash chromatography (EtOAc/heptane 10/90 f

EtOAc/MeOH 90/10) and crystallized from Et₂O to yield 12.0

1

g (67%) of 22 as white crystals: Mp 164-166 °C (Et₂O); H

NMR (CDCl₃) δ: 1.50 (s, 9H), 1.71 (q, 2H), 2.14 (d, 2H), 2.96

(t, 2H), 3.16 (t, 1H), 4.27 (s, broad, 2H), 7.08 (s, 1H), 7.13 (t,

1H), 7.20-7.25 (m, 2H), 7.43-7.49 (m, 2H), 7.51 (d, 1H), 8.36

(d, 1H), 8.77-8.81 (m, 3H); MS m/z: 473 (MH⁺, 11%), 417

(100%), 373 (84%); Anal. (C₂₈H₂₉N₄FO₂): C, H, N.

4-[1-(4-F lu or op h en yl)-5-(p yr id in -3-yl)-1H-in d ol-3-yl]p i-

p er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (24). 3-Bromo-

pyridine was lithiated as described by Furneaux et al.⁶¹THF

(200 mL) was cooled to -100 °C (Et₂O/liquid N₂), and n-

butyllithium (19 mL, 30.4 mmol) was added. 3-Bromopyridine

(4.0 g, 25.3 mmol) was added during 2 min. After 20 min at

-100 °C, ZnCl₂in THF (60 mL, 60 mmol) was added. Hereby,

a white precipitate was formed. The temperature was shortly

raised to -30 °C to dissolve the precipitate. The solution was

thereafter stirred at -78 °C for 30 min. Reaction with 34 (10.0

g, 21.1 mmol) was performed following method B. Flash

chromatography (EtOAc/heptane/NEt₃30/70/5) afforded 8.3 g

which was recrystallized from EtOAc/heptane 1:1 to yield 6.0

g (60%) of 24: Mp 160-162 °C (EtOAc/heptane 1:1); MS m/z:

472 (MH⁺, 3%), 416 (100%), 372 (37%); ¹H NMR (CDCl₃) δ:

1.49 (s, 9H), 1.74 (q, 2H), 2.14 (d, 2H), 2.93 (t, 2H), 3.10 (t,

1H), 4.29 (s, broad, 2H), 7.11 (s, 1H), 7.20-7.30 (m, 2H), 7.36

(dd, 1H), 7.40-7.50 (m, 3H), 7.55 (d, 1H), 7.85 (d, 1H), 7.95

(dt, 1H), 8.57 (dd, 1H), 8.91 (d, 1H); Anal. (C₂₉H₃₀FN₃O₂): C,

H, N.

4-[1-(4-Flu or op h en yl)-5-(p yr im id in -5-yl)-1H-in d ol-3-yl]-

p ip er id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (23). A

solution of 34 (10.0 g, 21.1 mmol) in THF was reacted with

5-bromopyrimidine (5.0 g, 31.6 mmol). Flash chromatography

(EtOAc/heptane/NEt₃30/70/4 f 70/30/4) gave 8.2 g which was

recrystallized from toluene/heptane 1:1 to yield 5.0 g (50%) of

23: Mp 144-146 °C (toluene/heptane 1:1); MS m/z: 473 (MH⁺,

3%), 417 (100%), 373 (33%); ¹H NMR (CDCl₃) δ: 1.49 (s, 9H),

1.75 (q, 2H), 2.13 (d, 2H), 2.95 (t, 2H), 3.08 (t, 1H), 4.28 (s,

broad, 2H), 7.13 (s, 1H), 7.20-7.30 (m, 2H), 7.42 (dd, 1H),

7.43-7.50 (m, 2H) 7.57 (d, 1H), 7.85 (d, 1H), 9.02 (s, 2H), 9.19

(s, 1H); Anal. (C₂₈H₂₉FN₄O₂): C, H, N.

Cr oss-Cou p lin g of a Heter oa r ylzin c Ch lor id e w ith

4-[5-Br om o-1-(4-flu or op h en yl)-1H-in d ol-3-yl]p ip er id in e-

1-ca r boxylic Acid ter t-Bu tyl Ester (34) (Meth od B). A

solution of 34 (8.3 g, 16.9 mmol) in DMF (20 mL) was added

to a solution of heteroarylzinc chloride in THF (amount and

preparation specified below) with Pd(PPh₃)₄(5 mol %) and

DMF (30% of the total amount of THF). The solution was

stirred at 80 °C for 8 h. Workup was performed as described

in method A. The amounts of reagents and solvents were

scaled according to the actual amount of 34 used.

Dep r otection a n d Alk yla tion of 5-Heter oa r yl-Su bsti-

tu ted 4-[1-(4-F lu or op h en yl)-1H-in d ol-3-yl]p ip er id in e-1-

ca r boxylic Acid ter t-Bu tyl Ester s (8, 13-20, 22-24, a n d

37-38) (Meth od C). The 5-heteroaryl-substituted 4-[1-(4-

fluorophenyl)-1H-indol-3-yl]piperidine-1-carboxylic acid tert-

butyl ester (6.3 mmol) was dissolved in THF (20 mL), and HCl/

MeOH (30 mL) was added. The solution was stirred for 4 h,

and the solvents were removed in vacuo. 4-Methyl-2-pentanone

(30 mL) was added, and the solvent was again removed in

vacuo. K₂CO₃(5 g, 36 mmol), KI (0.5 g, 3 mmol), 4-methyl-2-

pentanone (100 mL), and an alkyl halide (R-Y) (9.5 mmol if

nothing else stated) were added, and the solution was stirred

under reflux for 8 h. The amounts of reagents and solvents

were scaled according to the actual amount of 5-heteroaryl-

The following derivatives were prepared according to method

B:

4-[1-(4-F lu or op h en yl)-5-(1-m eth ylp yr a zol-5-yl)-1H-in -

d ol-3-yl]p ip er id in e-1-ca r b oxylic Acid ter t-Bu t yl E st er

(18). 1-Methylpyrazole (3.2 g, 39 mmol) in THF (200 mL) was

cooled to -78 °C. n-Butyllithium (43 mL, 26.9 mmol) was

added during 5 min. The solution was heated slowly to room

temperature during 15 min and cooled again to -78 °C. ZnCl₂

in THF (120 mL, 120 mmol) was added, and the solution was

stirred at -78 °C for 30 min. Reaction with 34 (14.2 g, 30

mmol) was performed following method B. Flash chromatog-

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 279

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

carboxylic acid tert-butyl ester used.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,4-tr ia zol-5-

yl)-1H -in d ol-3-yl]-1-p ip e r id in yl}e t h yl)im id a zolid in -2-

on e (17a ). The crude product was purified by flash chroma-

tography (EtOAc/MeOH/NEt₃95/5/4 f 90/10/4) to yield 1.2 g

as white foam. The compound crystallized from EtOAc to give

0.90 g (49%) of the title compound (17a ): Mp 209-211 °C

Workup: H₂O (50 mL) was added to the warm mixture, and

the phases were separated. The aqueous phase was extracted

with CH₂Cl₂(100 mL). Kiesel gel was added to the combined

organic phases, and the solvents were removed in vacuo. The

resulting compound adsorbed to kiesel gel was purified using

Biotage flash 40 equipped with an FZIM-0035 solid injection

module.

The following derivatives 8a and 12a -24a were prepared

by method C using 8 and 12-24 as starting material and 1-(2-

chloroethyl)imidazolidin-2-one as alkylating agent:

1

(EtOAc). H NMR (CDCl₃) δ: 1.84 (q, 2H), 2.09 (d, 2H), 2.12

(t, 2H), 2.58 (t, 2H), 2.92 (t, 1H), 3.08 (d, 2H), 3.35-3.50 (m,

4H), 3.54 (t, 2H), 4.03 (s, 3H), 4.33 (s, broad, 1H), 7.14 (s, 1H),

2.20-2.25 (m, 2H), 7.42-7.48 (m, 3H), 7.53 (d, 1H), 7.95 (s,

1H), 8.02 (s, 1H); MS m/z: 488 (MH⁺, 100%) 370 (7%), 314

(3%); Anal. (C₂₇H₃₀N₇FO): C, H, N.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m et h ylp yr a zol-5-yl)-

1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e

(18a ). The crude product was purified by flash chromatogra-

phy (EtOAc/MeOH/NEt₃80/20/5). The resulting compound was

recrystallized from CH₂Cl₂to yield 0.80 g (26%) of 18a : Mp

248-251 °C (CH₂Cl₂); ¹H NMR (DMSO-d₆) δ: 1.75 (q, 2H), 2.03

(d, 2H), 2.18 (t, 2H), 2.45 (t, 2H), 2.90 (t, 1H), 3.03 (d, 2H),

3.15-3.30 (m, 4H), 3.42 (t, 2H), 3.90 (s, 3H), 6.25 (s, 1H), 6.40

(s, 1H), 7.31 (d, 1H), 7.43 (t, 2H), 7.48 (d, 1H), 7.50 (s, 1H),

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,3-tr ia zol-4-

yl)-1H -in d ol-3-yl]-1p ip e r id in yl}e t h yl)im id a zolid in -2-

on e (8a ). The crude product was purified by flash chroma-

tography (EtOAc/MeOH/NEt₃90/10/4 f 80/20/4) to yield 0.30

g (33%) of 8a , identical to the material described above.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(2-m et h ylt et r a zol-5-yl)-

1H-in dol-3-yl]-1piper idin yl}eth yl)im idazolidin -2-on e (12a).

The crude product was purified by flash chromatography

(EtOAc/heptane 50/50 f EtOAc/MeOH/NEt₃90/10/2) to yield

1.0 g (75%) of 12a : Mp 182-184 °C (CH₃CN); ¹H NMR

(DMSO-d₆) δ: 1.78 (qd, 2H), 2.05 (d, 2H), 2.16 (t, 2H), 2.46 (t,

2H), 2.85-2.95 (m, 1H), 3.02 (d, 2H), 3.15-3.28 (m, 4H), 3.41

(t, 2H), 4.43 (s, 3H), 6.24 (s, broad, 1H), 7.38-7.48 (m, 2H),

7.54 (s, 1H), 7.62 (d, 1H), 7.64-7.68 (m, 2H), 7.91 (d, 1H), 8.36

(s, 1H); Anal. (C₂₆H₂₉FN₈O): C, H, N.

7.58 (d, 1H), 7.60-7.70 (m, 2H), 7.80 (s, 1H); Anal. (C₂₈H₃₁

FN₆O‚1.70% CH₂Cl₂): C, H, N.

-

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth ylim id a zol-2-yl)-

1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e

(19a ). The crude product was purified by flash chromatogra-

phy (EtOAc/MeOH/NEt₃90/10/5 f 85/15/5). The resulting

compound (1.6 g) was recrystallized from 2-propanol to yield

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m et h ylp yr a zol-3-yl)-

1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e

(13a ). The crude product was purified by flash chromatogra-

phy (EtOAc/MeOH/NEt₃90/10/4 f 80/20/4) to yield 0.67 g of

pure material as well as 0.90 g containing impurities. The pure

material was washed on a filter with EtOAc to give 0.25 g

1

0.33 g (16%) of 19a : Mp 215-217 °C (2-propanol); H NMR

(DMSO-d₆) δ: 1.82 (q, 2H), 2.10 (d, 2H), 2.18 (t, 2H), 2.56 (t,

2H), 2.90 (t, 1H), 3.08 (d, 2H), 3.30-3.45 (m, 4H), 3.55 (t, 2H),

3.77 (s, 3H), 4.30 (s, 1H), 7.00 (s, 1H), 7.10 (s, 1H), 7.17 (s,

1H), 7.20 (t, 2H), 7.40-7.55 (m, 4H), 7.96 (s, 1H); Anal. (C₂₈H₃₁

FN₆O): C, H, N.

-

1

(9.8%) of 13a : Mp 203-204 °C; H NMR (CDCl₃) δ: 1.82 (q,

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,3-tr ia zol-5-

yl)-1H -in d ol-3-yl]-1-p ip e r id in yl}e t h yl)im id a zolid in -2-

on e (20a ). The crude product was purified by flash chroma-

tography (EtOAc/MeOH/NEt₃80/20/4) resulting in 2.0 g which

was recrystallized twice from EtOAc/heptane 1:4 to yield 0.70

g (22%) of 20a : Mp 236-238 °C; ¹H NMR (CDCl₃) δ: 1.85 (qd,

2H), 2.10 (d, 2H), 2.25 (t, 2H), 2.58 (t, 2H), 2.85-2.95 (m, 1H),

3.10 (d, 2H), 3.36-3.47 (m, 4H), 3.54 (t, 2H), 4.09 (s, 3H), 4.30

(s, broad, 1H) 7.15 (s, 1H), 7.19-7.30 (m, 3H), 7.40-7.49 (m,

2H), 2.10 (d, 2H), 2.24 (t, 2H), 2.59 (t, 2H), 2.95 (t, 1H), 3.08

(d, 2H), 3.36-3.50 (m, 4H), 3.56 (t, 2H), 3.98 (s, 3H), 4.23 (s,

1H), 6.56 (d, J ) 2 Hz, 1H), 7.05 (s, 1H), 7.15-7.24 (m, 2H),

7.39 (d, J ) 2.2 Hz, 1H), 7.42-7.48 (m, 3H), 7.65 (dd, ¹J ) 8,6

3

Hz, J ) 1.7 Hz, 1H) 8.08 (d, J ) 1.4 Hz, 1H); MS m/z: 487

(MH⁺, 100%), 369 (17%), 292 (3%); Anal. (C₂₈H₃₁N₆FO): C, H,

N.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m et h ylp yr a zol-4-yl)-

1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e

(14a ). The crude product was purified by flash chromatogra-

phy (EtOAc/MeOH/NEt₃95/5/4 f 90/10/4) to yield 1.0 g as

white foam. The compound crystallized upon addition of EtOAc

to give 0.36 g (29%) of 14a : Mp 221-223 °C; ¹H NMR (DMSO-

d₆) δ: 1.73 (q, 2H), 2.03 (d, 2H), 2,16 (t, 2H), 2.48 (t, 2H), 2.85

(t, 1H), 3.04 (d, 2H), 3.23 (q, 4H), 3.40 (t, 2H), 3.84 (s, 3H),

6.20 (s, broad, 1H), 7.35-7.42 (m, 4H), 7.46 (d, 1H), 7.59-

7.67 (m, 2H), 7.81 (s, 1H), 7.87 (s, 1H), 8.13 (s, 1H); MS m/z:

487 (MH⁺, 100%), 369 (3%); Anal. (C₂₈H₃₁N₆FO): C, H, N.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,4-tr ia zol-3-

yl)-1H -in d ol-3-yl]-1-p ip e r id in yl}e t h yl)im id a zolid in -2-

on e (15a ). The crude product was purified by flash chroma-

tography (EtOAc/MeOH/NEt₃95/5/4 f 90/10/4) and crystallized

from EtOAc to yield 1.2 g (65%) of 15a : Mp 204-206 °C

2H), 7.53 (d, 1H), 7.70 (d, 1H), 7.73 (s, 1H); Anal. (C₂₇H₃₀

FN₇O): C, H, N.

-

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m et h ylt et r a zol-5-yl)-

1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e

(21a ). The crude product was purified by flash chromatogra-

phy (EtOAc/MeOH/NEt₃80/20/4) to give 0.60 g which was

recrystallized from toluene to give 0.30 g (41%) of 21a : Mp

1

203-205 °C (toluene); H NMR (DMSO-d₆) δ: 1.75 (qd, 2H),

2.01 (d, 2H), 2.14 (t, 2H), 2.84-2.94 (m,1H), 3.02 (d, 2H), 3.10-

3.25 (m, 4H), 3.35-3.45 (t, 2H), 4.20 (s, 3H), 6.23 (s, broad,

1H), 7.40-7.49 (m, 2H), 7.59 (s, 1H), 7.61 (d, 1H), 7.62-7.72

(m, 4H), 8.18 (s, 1H); Anal. (C₂₆H₂₉FN₈O‚2.21% toluene): C,

H, N.

1-(2-{4-[1-(4-Flu or oph en yl)-5-(pyr im idin -2-yl)-1H-in dol-

3-yl]-1-p ip er id in yl}eth yl)im id a zolid in -2-on e (22a ). The

crude product was purified by flash chromatography (EtOAc/

MeOH/NEt₃90/10/4 f 80/20/4). The resulting material was

washed on a filter with EtOAc to yield 1.8 g (62%) of 22a : Mp

1

(EtOAc); H NMR (CDCl₃) δ: 1.83 (q, 2H), 2.21 (d, 2H), 2.25

(t, 2H), 2.58 (t, 2H), 2.97 (t, 1H), 3.08 (d, 2H), 3.35-3.45 (m,

4H), 3.54 (t, 2H), 3.98 (s, 3H), 4.58 (s, broad, 1H), 7.07 (s, 1H),

7.15-7.25 (m, 2H), 7.42-7.50 (m, 3H), 7.97 (d, 1H), 8.06 (s,

1H), 8.42 (S, 1H); MS m/z: 488 (MH⁺, 100%) 370 (19%), 293

(3%); Anal. (C₂₇H₃₀N₇FO‚1.25% EtOAc): C, H, N.

1

217-219 °C; H NMR (CDCl₃) δ: 1.85 (q, 2H), 2.15 (d, 2H),

2.26 (t, 2H), 2.59 (t, 2H), 2.02 (t, 1H), 3.09 (d, 2H), 3.30-3.50

(m, 4H), 3.55 (t, 2H), 4.59 (s, 1H), 7.09 (s, 1H), 7.13 (t, 1H),

7.15-7.24 (m, 2H),7.44-7.48 (m, 2H), 7.50 (d, 1H), 8.35 (d,

1H), 8.78-8.82 (m, 3H); MS m/z: 485 (MH⁺, 100%), 367 (10%),

290 (7%); Anal. (C₂₈H₂₉N₆FO): C, H, N.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,3,4-tr ia zol-2-

yl)-1H -in d ol-3-yl]-1-p ip e r id in yl}e t h yl)im id a zolid in -2-

on e (16a ). The crude product was purified by flash chroma-

tography (EtOAc/MeOH/NEt₃95/5/4 f 90/10/4) to yield 60 mg

(5%) of 16a as a white solid: Mp 122-126 °C; ¹H NMR (CDCl₃)

δ: 1.85 (q, 2H), 2.09 (d, 2H), 2.12 (t, 2H), 2.58 (t, 2H), 2.90 (t,

1H), 3.08 (d, 2H), 3.34-3.42 (m, 4H), 3.55 (t, 2H), 3.78 (s, 3H),

4,18 (s, broad, 1H), 7.14 (s, 1H), 7.20-7.25 (m, 2H), 7.41-7-

49 (m, 3H), 7.53 (d, 1H), 8.05 (s, 1H), 8.21 (s, 1H); MS m/z:

488 (MH⁺, 100%) 314 (24%), 241 (10%); Anal. (C₂₇H₃₀N₇FO‚

4.32% EtOAc and 1.64% H₂O): C, H, N.

1-(2-{4-[1-(4-Flu or oph en yl)-5-(pyr im idin -5-yl)-1H-in dol-

3-yl]-1-p ip er id in yl}eth yl)im id a zolid in -2-on e (23a ). The

crude product was purified by flash chromatography (EtOAc/

MeOH/NEt₃90/10/5 f 50/50/5) and washed on a filter with

EtOAc to yield 1.2 g (59%). Mp 228-230 °C; ¹H NMR (DMSO-

d₆) δ: 1.75 (q, 2H), 2.07 (d, 2H), 2.18 (t, 2H), 2.44 (t, 2H), 2.95

(t, 1H), 3.05 (d, 2H), 3.22 (q, 4H), 3.41 (t, 2H), 6.19 (s, broad,

280 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2

Balle et al.

1H), 7.37-7.47 (m, 2H), 7.50 (s, 1H), 7.60-7.62 (m, 2H), 7.64-

7.69 (m, 2H), 8.16 (s, 1H), 9.15 (s, 1H), 9.19 (s, 2H); MS m/z:

485 (MH⁺, 100%), 367 (17%), 290 (3%); Anal. (C₂₈H₂₉N₆FO):

C, H, N.

(s, 3H), 7.38 (t, 1H), 7.41-7.48 (m, 2H), 7.52 (s, 1H), 7.58 (d,

1H), 7.62-7.70 (m, 2H) 8.31 (d, 1H), 8.77 (s, 1H), 8.89 (d, 2H);

MS m/z: 426 (MH⁺, 100%), 384 (95%), 373 (95%); Anal. (C₂₆H₂₄

-

FN₅): C, H, N.

1-(2-{4-[1-(4-F lu or op h en yl)-5-(p yr id in -3-yl)-1H-in d ol-3-

yl]-1-p ip er id in yl}et h yl)im id a zolid in -2-on e (24a ). The

crude product was purified by flash chromatography (EtOAc/

MeOH/NEt₃75/25/5). The remaining compound (2.0 g) was

recrystallized from 2-propanol to yield 0.30 g (7%) of 24a : Mp

200-203 °C (2-propanol); ¹H NMR (DMSO-d₆) δ: 1.75 (q, 2H),

2.04 (d, 2H), 2.16 (t, 2H), 2.45 (t, 2H), 2.94 (t, 1H), 3.03 (d,

2H), 3.15-3.25 (m, 4H), 3.42 (t, 2H), 6.25 (s, 1H), 7.42 (t, 2H),

7.40-7.45 (m, 2H), 7.46-7.50 (m, 2H), 7.54 (d, 1H), 7.58 (d,

1H), 7.62-7.68 (m, 2H), 8.02 (s, 1H), 8,13 (d, 1H), 8.54 (d, 1H),

8.95 (s, 1H); Anal. (C₂₉H₃₀FN₅O) H, N; C: calcd, 72.03, found

71.46.

The following derivatives 12b, 15b, and 22b were prepared

by method C using 37, 15 and 22 as starting material and

3-(2-chloroethyl)oxazolidin-2-one as alkylating agent:

3-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m et h ylt et r a zol-5-yl)-

1H-in d ol-3-yl]-1-p ip er id in yl}eth yl)oxa zolid in -2-on e Ox-

a la te (12b). The crude product was purified by flash chroma-

tography (EtOAc/heptane/NEt₃80/20/4 f 75/25/4) to give 0.70

g that was precipitated with oxalic acid from EtOH to give

0.50 g (54%) of the oxalate of 12b: Mp 212-215 °C (EtOH);

¹H NMR (DMSO-d₆) δ: 1.99 (q, 2H), 2.19 (d, 2H), 3.00 (m, 2H),

3.17 (m, 3H), 3.54 (m, 4H), 3.62 (t, 2H), 4.30 (t, 2H), 4.43 (s,

3H), 7.41-7.45 (m, 2H), 7.60-7.68 (m, 4H), 7.92 (d, 1H), 8.43

(s, 1H); MS m/z: 490 (MH⁺, 100%); Anal. (C₂₆H₂₈FN₇O₂‚

C₂H₂O₄): C, H, N.

The following derivative 15d was prepared by method C

using 15 as starting material and 3-(2-chloroethyl)-1-methyl-

pyrrolidin-2-on as alkylating agent:

3-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,4-tr ia zol-3-

yl)-1H-in d ol-3-yl]-1-p ip er id in yl}eth yl)-1-m eth ylp yr r oli-

d in -2-on e Oxa la te (15d ). The crude product was purified by

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

90/10) and precipitated with oxalic acid from EtOH to give 0.40

g (26%) of the oxalate of 15d : Mp 174-177 °C (EtOH, dec);

¹H NMR (DMSO-d₆) δ: 1.65 (q, 1H), 1.70-1.78 (m, 1H), 1.95-

2.12 (m, 3H), 2.12-2.27 (m, 3H), 2.38-2.49 (m, 1H), 2.76 (s,

3H), 3.02-3.19 (m, 3H), 3.19-3.30 (m, 2H), 3.30-3.35 (t, 2H),

3.45-3.65 (m, 2H, 3.95 (s, 3H), 7.40-7.46 (m, 2H), 7.53 (s, 1H),

7.55 (d, 1H), 7.60-7.70 (m, 2H), 7.89 (d, 1H), 8.35 (s, 1H), 8.50

(s, 1H); MS m/z: 501 (MH⁺, 100%), 370 (50%), 293 (5%); Anal.

(C₂₉H₃₃FN₆O‚1.1C₂H₂O₄): C, H, N.

The following derivative 15e was prepared by method C

(except CH₃CN was used as solvent) using 15 as starting

material and 3-(2-chloroethyl)-1H-quinazoline-2,4-dione as

alkylating agent:

3-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,4-tr ia zol-3-

yl)-1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)-1H -q u in a zolin e-

2,4-d ion e (15e). The crude product was purified by flash

chromatography (EtOAc/heptane 30/70 f EtOAc/MeOH/NEt₃

90/10/2) followed by recrystallization from EtOAc to yield 0.16

1

g (14%) of 15e: Mp 241-244 °C (EtOAc); H NMR (DMSO-

3-(2-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,4-tr ia zol-3-

yl)-1H -in d ol-3-yl]-1-p ip er id in yl}et h yl)oxa zolid in -2-on e

1.1Oxa la te (15b). The crude product was purified by flash

chromatography (EtOAc/MeOH/NEt₃80/20/4 f 75/25/4) giving

1.0 g containing impurities. Precipitation with oxalic acid from

EtOAc/heptane/EtOH 20/30/50 gave 0.5 g (38%) of the oxalate

15b: Mp 225-226 °C; ¹H NMR (DMSO-d₆) δ: 2.04 (q, 2H),

2.21 (d, 2H), 3.03 (t, 2H), 3.12-3.22 (m, 3H), 3.50-3.60 (m,

4H), 3.60-3.68 (t, 2H), 3.92 (s, 3H), 4.30 (t, 2H), 7.38-7.48

(m, 2H), 7.52 (s, 1H), 7.54 (d, 1H), 7.60-7.68 (m, 2H), 7.88 (d,

1H), 8.35 (s, 1H), 8.49 (s, 1H); MS m/z: 489 (MH⁺, 100%), 448

(6%), 370 (4%); Anal. (C₂₇H₂₉FN₆O₂‚1.1C₂H₂O₄): C, H, N.

3-(2-{4-[1-(4-Flu or oph en yl)-5-(pyr im idin -2-yl)-1H-in dol-

3-yl]-1-piper idin yl}eth yl)oxazolidin -2-on e (22b). The crude

product was purified by flash chromatography (EtOAc/heptane

70/30 f EtOAc/MeOH/NEt₃90/10/4) to give 1.1 g which was

recrystallized from EtOAc/CH₂Cl₂to give 0.90 g (67%) of 22b

(free base): Mp 175-176 °C (EtOAc/CH₂Cl₂); ¹H NMR (DMSO-

d₆) δ: 1.79 (qd, 2H), 2.03 (d, 2H), 2.18 (t, 2H), 2.87-2.97 (m,

1H), 3.06 (d, 2H), 3.30-3.40 (m, 4H), 3.63 (t, 2H), 4.30 (t, 2H),

7.38 (t, 1H), 7.40-7.47 (m, 2H), 7.50 (s, 1H), 7.58 (d, 1H), 7.63-

7.70 (m, 2H), 8.30 (d, 1H), 8.77 (s, 1H), 8.88 (d, 2H); MS m/z:

486 (MH⁺, 100%), 367 (6%), 271 (3%); Anal. (C₂₈H₂₈FN₅O₂):

C, H, N.

d₆) δ: 1.75 (qd, 2H), 2.00 (d, 2H), 2.18 (t, 2H), 2.60 (t, 2H),

2.80-2.90 (m, 1H), 3.10 (s, broad, 2H), 3.90 (s, 3H), 4.10 (s,

broad, 2H), 7.15-7.25 (m, 2H), 7.38-7.43 (m, 2H), 7.45 (s,

broad, 1H), 7.52 (d, 1H) 7.60-7.70 (m, 3H, 7.85 (d, 1H), 7.95

(d, 1H), 8.30 (s, 1H), 8.50 (s, 1H); MS m/z: 464 (MH⁺, 100%),

370 (30%), 293 (3%); Anal. (C₃₂H₃₀FN₇O₂): C, H; N: calcd 17.40

found 16.74.

1-(2-{4-[5-(Tet r a zol-5-yl)-1-(4-flu or op h en yl)-1H-in d ol-

3-yl]-1-p ip er id in yl}eth yl)im id a zolid in -2-on e Hyd r och lo-

r id e (25a ). A suspension of 1-(2-{4-[5-cyano-1-(4-fluorophenyl)-

1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imidazolidinone (40) (7.0

g, 16.2 mmol) (prepared according to the method described in

Perregaard et al.³²), NEt₃‚HCl (7.5 g, 55 mmol), and sodium

azide (4.2 g, 64 mmol) in DME (100 mL) was boiled under

reflux for 16 h. After the mixture was cooled to room temper-

ature, H₂O (500 mL), NEt₃(5 mL), and EtOAc (500 mL) were

added. The phases were separated and the organic solvents

evaporated in vacuo. The remaining viscous oil was stirred

with methanol (25 mL), and solids were filtered off. Methanol

was evaporated, and the remaining crystalline product was

washed successively with acetone and H₂O. The hydrochloride

of the title compound (25a ) precipitated from ethanol by adding

HCl/ether. The crystalline product was stirred with H₂O and

finally filtered off and dried to yield 1.3 g (16%): Mp 193-

197 °C; ¹H NMR (DMSO-d₆) δ: 2.20-2.40 (m, 4H), 3.20-3.80

(m, 13H), 6.60 (s, 1H), 7.40 (t, 2H), 7.60-7.70 (m, 4H), 7.95

(d, 1H), 8.75 (s, 1H); MS m/z: 475 (MH⁺, 100%), 113 (75%);

Anal. (C₂₅H₂₇FN₈O‚HCl‚1.80% H₂O): C, H, N.

1-[2-[4-[1-(4-F lu or op h en yl)-5-(1,2,3-tr ia zol-4-yl)-1H-in -

dol-3-yl]-1-piper idin yl]eth yl]im idazolidin -2-on e (26a). 1-[2-

(1,5-Dioxa-9-azaspiro[5.5]undecan-9-yl)ethyl]imidazolidin-2-

one (17.0 g, 63 mmol) (prepared by boiling 1,5-dioxa-9-

azaspiro[5.5]undecane with 1-(2-chloroethyl)imidazolidin-2-one

and K₂CO₃in 4-methyl-2-pentanone under reflux) was dis-

solved in AcOH (30 mL) and TFA (12 mL) and added during

30 min to a refluxing solution of 29 (5.8 g, 21 mmol) in AcOH

(30 mL) and TFA (12 mL). The solution was boiled under reflux

for 50 min. After the mixture was cooled to room temperature,

the solvents were removed in vacuo. H₂O (50 mL) was added

and pH adjusted to 4-5 using 2 N aqueous NaOH. The

aqueous phase was extracted with EtOAc (3 × 50 mL), washed

with brine (50 mL), and dried over MgSO₄. The product

was purified by flash chromatography (EtOAc/EtOH/NEt₃

50/60/4) to yield 2.0 g of 1-(2-{4-[1-(4-fluorophenyl)-5-(1,2,3-

The following derivatives 15c and 22c were prepared by

method C using 15 and 22 as starting material and 3-bromo-

propionitrile as alkylating agent:

3-{4-[1-(4-F lu or op h en yl)-5-(1-m eth yl-1,2,4-tr ia zol-3-yl)-

1H-in d ol-3-yl]-1-p ip er id in yl}p r op ion itr ile Oxa la te (15c).

The crude product was purified by flash chromatography

(EtOAc/heptane 50/50 f EtOAc/MeOH 90/10) and precipitated

with oxalic acid from EtOH to give 0.45 g (34%) of the oxalate

of 15c: Mp 216-217 °C (EtOH); ¹H NMR (DMSO-d₆) δ: 1.95

(qd, 2H), 2.12 (d, 2H), 2.76 (t, 2H), 2.93 (t, 2H), 3.02-3.15 (m,

3H), 3.32 (d, 2H), 3.93 (s, 3H), 7.40-7.47 (m, 2H), 7.48 (s, 1H),

7.54 (d, 1H), 7.60-7.68 (m, 2H), 7.89 (d, 1H), 8.32 (s, 1H), 8.48

(s, 1H); MS m/z: 429 (MH⁺, 100%), 388 (12%), 241 (3%); Anal.

(C₂₅H₂₅FN₆‚C₂H₂O₄‚0.55% H₂O): C, H, N.

3-{4-[1-(4-F lu or op h en yl)-5-p yr im id in -2-yl-1H-in d ol-3-

yl]-1-p ip er id in yl}p r op ion itr ile (22c). The free base was

recrystallized from EtOAc/CH₂Cl₂90/10 to give 0.96 g (63%)

of 22c: Mp 182-183 °C (EtOAc/CH₂Cl₂); ¹H NMR (DMSO-d₆)

δ: 1.81 (q, 2H), 2.03 (d, 2H), 2.25 (t, 2H), 2.60-2.70 (s, broad,

2H), 2.70-2.80 (m, 2H), 2.83-2.95 (m, 1H), 3.02 (d, 2H), 3.33

Selective R₁Adrenoceptor Antagonists

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 2 281

triazol-4-yl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl}ethyl-

9-imidazolidin-2-one (39) as an oil: ¹H NMR (DMSO-d₆) δ:

2.55-2.68 (m, 4H) 2.70-2.80 (t, 2H), 3.17-3.35 (m, 6H), 3.40-

3.60 (m, 3H), 6.25 (s, 1H), 6.35 (broad, s, 1H), 7.45 (t, 3H),

7.68 (d, 1H), 7.70 (d, 1H), 7.72 (s, 1H), 7.78 (d, 1H), 8.37 (s,

1H) 8.40 (s, 1H). A solution of crude 39 (2.0 g, 4.2 mmol) was

treated with H₂as described in the preparation of 8a . Solids

were filtered off, and the solvent was evaporated in vacuo. The

crude product was purified by preparative HPLC and freeze-

dried to give 0.30 g (20%) of the trifluoroacetate salt of the

title compound: ¹H NMR (DMSO-d₆) δ: 1.95-2.15 (m, 4H),

2.15-2.25 (m, 2H), 2.30 (d, 2H), 3.15-3.25 (m, 1H), 3.25-3.35

(m, 2H), 3.35-3.55 (m, 4H), 3.75 (d, 2H), 6.65 (s, broad, 1H),

7.40 (m, 3H), 7.55 (m, 2H), 7.65 (m, 2H), 7.70 (d, 1H), 8.25 (s,

1H), 8.32 (s, broad, 1H), 9.85 (s, broad, 1H). Liberation of the

free base by addition of aqueous NH₄OH and extraction with

EtOAc afforded the title compound 26a as a pale yellow oil:

Anal. (C₂₆H₂₈FN₇O): C, H, N.

rats weighing approximately 220 g. The animals were decapi-

tated prior to brain extraction.

In Vitr o Bin d in g Assa ys. r₁a n d Ser oton in Recep tor s.

The tissues were homogenized 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 subse-

quently used contained 50 mM Tris, pH 7.7. Nonspecific

binding for the R₁assays was defined as the binding in the

presence of prazosin (1 µM) for the R₁(rat brain) and of WB-

4101 (1 µM) for the cloned R_1a, R_1b, and R_1dassays. For the

serotonin assays, the nonspecific binding was defined using

metergoline (1 µM) for the 5-HT_1Aassay, 5-HT (10 µM) for the

5-HT_1Bassay and mianserine (1 µM) for both the 5-HT_2Aand

5-HT_2Cassays. In all the R₁assays, 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_2C

assays 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).

P a r a llel Syn th esis. Each of the intermediates 13-15, 17-

20, 22-24, and 37 (1.0 mmol) were dissolved in THF (30 mL)

and reacted overnight with a saturated solution of HCl in

MeOH (15 mL) at room temperature. The solvents were

removed in vacuo, H₂O (50 mL) was added, and pH was

adjusted to 10 by addition of 25% aqueous ammonium hydrox-

ide. The aqueous phase was extracted with CH₂Cl₂(3 × 30

mL), and the combined organic phases were dried over MgSO₄.

After evaporation of the solvent in vacuo, stock solutions of

the piperidinyl derivatives were prepared by dissolving to 0.2

M by addition of DMSO. Stock solutions of alkyl halides were

prepared by dissolving the halides in as little DMF as possible.

Solutions were subsequently diluted to 0.2 M by addition of

CH₃CN. Blocks (Multisyntech Microchem Blocks⁴⁵) containing

96 1.2 mL reactors fitted with frits were loaded with K₂CO₃

(40 mg, 0.3 mmol) and KI (10 mg, 0.06 mmol). From the stock

solutions, the piperidinyl derivatives (0.15 mL, 0.03 mmol),

the alkyl halide (0.225 mL, 0.045 mmol), and CH₃CN (0.3 mL)

were added, and the reactors were closed and rotated in an

oven at 70 °C for 14 h. After the mixture was cooled to 50 °C,

isocyanate resin (30 mg, 1 mmol/g) was added, and the reactors

were again closed and rotated at 50 °C for 2 h. After the

mixture was cooled to room temperature, solids were filtered

off and washed with CH₃CN (2 × 0.3 mL). The combined

organic phases were purified using SCX ion exchange chro-

matography as follows: Columns (Varian Bond Elut-SCX 500

mg/3 mL) were conditioned with acetic acid in methanol (10%,

3 mL). The combined organic phases from the sample was

added and washed with MeOH (3 mL) and CH₃CN (3 mL).

Finally, the sample was eluted with 4 M ammonia in MeOH

(3 mL). Between each step a slight air pressure was applied.

The solvents were evaporated in vacuo, and the solutions

diluted to 2 mM with DMSO. The identity and purity of the

compounds was determined by HPLC/MS analysis with UV

and ELSD detection. Compounds with purity of 70% or above

were submitted for biological evaluation. The remaining

compounds were purified by preparative LC/MS.⁶⁵The follow-

ing alkylating agents were used for the preparation of the

examples given in Table 6: 3-bromo-propionitrile, 3-(2-chloro-

ethyl)oxazolidin-2-one, 3-(2-chloroethyl)-1H-quinazoline-2,4-

dione, 3-(2-chloroethyl)-1-methylpyrolidin-2-one.

Dop a m in e Recep tor s. The D₁and D₂tissues were homog-

enized in ice-cold 50 mM phosphate buffer, pH 7.4, using an

Ultra-Turrax and the homogenates were kept on ice or stored

at -80 °C until used. The homogenization buffer was also used

as assay buffer. For the D₃receptor, 25 mM Tris containing

6.0 mM MgCl₂and 1.0 mM EDTA, pH 7.4, was used as

homogenization and assay buffer. The D₄receptor was ho-

mogenized and tested in 50 mM Tris containing 5 mM MgCl₂,

5 mM EDTA, 5 mM KCl, 1.5 mM CaCl₂, pH 7.4. To define

nonspecific binding, Z-glupentizol (1 µM) was used for the D₁

assay, ADTN (10 µM) for the D₂assay, haloperidol (10 µM)

for the D₃assay, and clozapine (10 µM) for the D₄assay.

Incubation times and temperatures were 60 min at 30 °C for

the D₁assay, 15 min at 37 °C for the D₂assay, and 60 min at

25 °C for both the D₃and D₄assays. All assays were

terminated by vacuum filtration on GF/B filters and counted

in a scintillation counter (Wallac Trilux).

For details regarding the membrane source, radioligand,

and radioligand concentration, refer to Table 2. Data shown

in tables are means from a minimum of two full concentra-

tion-response curves using 10 concentrations of drugs (cover-

ing 3 decades). The results are given as K_ivalues (nM) derived

from computer fitted IC₅₀values converted to K_ivalues using

the Cheng-Prusoff equation. Standard errors for pK_ivalues

were within 0.3 for all reported compounds.

Note Ad d ed a fter ASAP P ostin g. This manuscript

was posted ASAP on 12/11/2002 with an error in a

compound number in the abstract. The correct version

was posted 12/13/2002.

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J M020938Y

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

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