N-(ω)-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands

J . Med. Chem. 2003, 46, 3883-3899

3883

N-(ω-(4-(2-Meth oxyp h en yl)p ip er a zin -1-yl)a lk yl)ca r boxa m id es a s Dop a m in e D₂

a n d D₃Recep tor Liga n d s

Anneke Hackling,^†Robin Ghosh,^‡Sylvie Perachon,^§Andre´ Mann,^|Hans-Dieter Ho¨ltje,^‡Camille G. Wermuth,^|

J ean-Charles Schwartz, Wolfgang Sippl,^‡Pierre Sokoloff, and Holger Stark*^,†

Institut fu¨r Pharmazeutische Chemie, J ohann Wolfgang Goethe-Universita¨t, Marie-Curie-Strasse 9,

60439 Frankfurt am Main, Germany, Institut fu¨r Pharmazeutische Chemie, Heinrich-Heine-Universita¨t Du¨sseldorf,

Universita¨tsstrasse 1, 40225 Du¨sseldorf, Germany, Laboratoire Bioprojet, 30 rue des Francs-Bourgeois, 75003 Paris, France,

Faculte´ de Pharmacie (CNRS), Universite´ Louis Pasteur, 74 route de Rhin, 67401 Illkirch, France, and Unite´ de Neurobiology

et Pharmacologie Mole´culaire, Centre Paul Broca de l’INSERM, 2ter rue d’Ale´sia, 75014 Paris, France

Received March 28, 2003

The dopamine D₃receptor is recognized as a potential therapeutic target for the treatment of

various neurological and psychiatric disorders. Targetting high affinity and D₃versus D₂

receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations

in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with

markedly improved affinity and selectivity. Molecular modeling studies supported the structural

development. Pharmacophore models for dopamine D₂and D₃receptor ligands were developed

from their potentially bioactive conformation and were compared in order to get insight into

molecular properties of importance for D₂/D₃receptor selectivity. For the 72 compounds

presented here, an extended and more linear conformation in the aliphatic or aryl spacers

turned out to be crucial for dopamine D₃receptor selectivity. Structural diversity in the aryl

moiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolar

D₃receptor affinity, which was optimized with more rigid aryl acrylamide derivatives.

Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoyl-

amide) displayed a most promising pharmacological profile (K_i(hD₃) ) 0.5 nM; K_i(hD_2L) )

76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novel

radioligand as a pharmacological tool for various D₃receptor-related in vitro and in vivo

investigation.

In tr od u ction

special limbic areas of the central nervous system, which

are thought to control emotional and cognitive but not

locomotor functions.^4,5For a long time dopamine D₂-

like receptor antagonists have been used to treat

The neurotransmitter dopamine is implicated in vari-

ous physiological and pathophysiological processes. The

dopaminergic system regulates brain functions such as

motion, emotion, and cognition. Its effects are mediated

by dopamine receptors, which belong to the family of G

protein-coupled receptors and share the characteristic

of seven transmembrane domains. Dopamine receptors

can be divided into five different receptor subtypes and

are further classified into two families, the D₁-like (D₁

and D₅) and the D₂-like (D₂, D₃, and D₄), with related

pharmacological, structural, and genetic properties,

respectively.^1,2An imbalance within the dopaminergic

system is related to several psychiatric and neurological

disorders, e.g., Parkinson’s disease, Huntington’s dis-

ease, and schizophrenia. Medical treatment of dopamine

related disorders is often limited by side effects as a

consequence of binding to various dopamine sub-

receptors or other related monoamine receptors. There-

fore, effective therapy calls for selective dopamine sub-

receptor ligands.³Dopamine D₃receptors are relatively

few in number but display a discrete localization in

schizophrenia and related psychiatric disorders.⁶

A

suitably selective dopamine D₃receptor antagonist may

provide antipsychotic properties in the relative absence

of limiting extrapyramidal side effects.⁷Recent findings

suggest that dopamine D₃receptor agonists may have

beneficial effects for Parkinson’s patients.^8,9Further-

more, dopamine D₃receptor partial agonists are sup-

posed to be beneficial in the treatment of l-DOPA-

induced dyskinesia in Parkinson’s patients. It has

been impressively demonstrated in MPTP (1-m ethyl-

4-p henyl-1,2,3,6-tetrahydrop yridine)-treated monkeys,

a primate model for longtime Parkinson’s disease treat-

ment, that D₃receptor partial agonists normalize

exacerbated D₃receptor function.^10,11Moreover, the

treatment of drug addiction has been considered a

relevant therapeutic target for dopamine D₃receptor

partial agonists.¹²These ligands are thought to modu-

late the long-term effects caused by the reuptake-

inhibitor cocaine (second-order schedule of reinforce-

ment).¹³At the receptor site partial agonists act as

agonists or antagonists, depending on dopaminergic

activation and on receptor state. Partial agonists are

supposed to regulate receptor activation within physi-

ological limits. Consequently they should not exhibit any

rewarding activity themselves. In a recent review,

* To whom the correspondence should be addressed. Phone:

+49-69-798-29302. Fax: +49-69-798-29258. E-mail: h.stark@

pharmchem.uni-frankfurt.de.

^†J ohann Wolfgang Goethe-Universita¨t.

^‡Heinrich-Heine-Universita¨t Du¨sseldorf.

^§Laboratoire Bioprojet.

^|Universite´ Louis Pasteur.

Unite´ de Neurobiology et Pharmacologie Mole´culaire.

Published on Web 07/26/2003

3884 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Hackling et al.

discussed.¹⁴For many dopamine D₃receptor ligands

with antagonist properties, a general structure pattern

can be applied, which is divided into three subunits: an

aryl moiety, which is connected to an amide (first

subunit) and further linked via an alkyl or aryl spacer

(second subunit) to a basic residue with aryl substituent

(third subunit) (Chart 1). Among the structural develop-

ment, compounds with a basic 4-phenylpiperazino resi-

due have turned out to provide prominent selectivity

for dopamine D₃receptors (Chart 1). Compounds with

4-(2,3-dichlorophenyl)piperazino residue, e.g., NGB 2904¹⁵

or FAUC 365,¹⁶mostly provided an antagonist profile,

while compounds with 4-(2-methoxyphenyl)piperazino

residue showed antagonism, e.g., GR 103 691,¹⁷or

partial agonism, e.g., BP 897.¹⁸The acknowledged

n-butyl spacer has been exchanged to a cyclohexylethyl

spacer in some compounds.^19,20In many cases the spacer

has been linked to an aryl moiety via an amide bond or

has been coupled directly,²¹but ether bridges have been

built up as well.^22,23The lipophilic residue on the

arylamide moiety allowed diverse modifications includ-

ing aryl, biphenyl, heteroaryl, or cycloalkyl substitu-

ents.^16,17,19,24Our lead structure BP 897 combined high

affinity with pronounced preference for the human

dopamine D₃receptor compared to that for the human

D₂receptor²⁵(cf. Table 2) and has shown inhibition of

cocaine-seeking behavior in animal models.¹⁸In this

study we present a pharmacophore model for dopamine

D₃receptor ligands and one for dopamine D₂receptor

Ch a r t 1

structure-activity relationships for dopamine D₃recep-

tor partial agonists and antagonists and their potential

therapeutic application have been comprehensively

Ta ble 1. Structures, Physical Data, and Pharmacological Screening Results of Compounds with Spacer Variations

a

b

Binding assays using [¹²⁵I]iodosulpiride, in CHO cells expressing hD_2Land hD₃receptors. Ratio K_i(D₂)/K_i(D₃). ^cCrystallized from

EtOH. Crystallized from 2-propanol. ^eFor structure see Scheme 2. ^fCrystallized from EtOH/Et₂O.

d

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3885

Ta ble 2. Structures, Physical Data, and Pharmacological Screening Results of Aryl, Heteroaryl, and Arylalkyl Carboxylic Acid

Derivatives

3886 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Ta ble 2. (Continued)

Hackling et al.

a

b

d

Binding assays using [¹²⁵I]iodosulpiride, in CHO cells expressing hD_2Land hD₃receptors. Ratio K_i(D₂)/K_i(D₃). ^cRef 54. Crystallized

from EtOH/Et₂O. ^eCrystallized from MeOH/EtOH. ^fCrystallized from EtOH/H₂O. Crystallized from ethyl acetate. Crystallized from

g

h

i

k

l

m

2-propanol. Crystallized from EtOH. Crystallized from EtOH/2-propanol. Crystallized from 2-propanol/Et₂O. Crystallized from

2-propanol/EtOH. Crystallized from acetone/Et₂O. ^oCrystallized from acetone.

n

ligands, as well as a dopamine D₃receptor model

pointing out crucial binding regions between ligand and

receptor. In strong correlation to the modeling studies,

we developed 72 compounds, which displayed structural

modifications in the spacer group and in the aryl moiety.

Most of the compounds share the general structure

pattern mentioned previously and the 4-(2-methoxy-

phenyl)piperazino element. To a large extent D₃receptor

affinity was influenced by structural variations in the

aryl moiety and selectivity versus the D₂receptor by

structural variations in the spacer group. The iodinated

compound 38 (ST 280) provides a promising pharma-

cological profile and may serve, after further evaluation,

as a potential novel radioligand.

cinnamoyl chloride provided compounds 1-3 and 5

(method B). For amines with trimethylene or tetra-

methylene spacers, two methods were applied. For

method C1, preparation started with the alkylation of

1-(2-methoxyphenyl)piperazine with N-(ω-bromoalkyl)-

phthalimide. As an advantage of method C1, the inter-

mediates 68 (NAN 190)²⁷and 69²⁸could be obtained for

pharmacological testing. The phthalimides were cleaved

by hydrazinolysis to afford the desired alkanamines (c,

d ).²⁹This provided a facile way for the first compounds

but was not practical for a greater number of com-

pounds. The alternative and more economic method C2

provided the butanamine derivatives through alkylation

of 1-(2-methoxyphenyl)piperazine with 4-bromobutyro-

nitrile and subsequent catalytic reduction of the cyano

functionality (e).²⁹This preparative way allowed scaling

up as well as reducing time and expenditure of work.

The ensuing method B employed the alkanamines,

obtained by method C1 or C2, and diverse acid chlorides

to afford compounds 8-44, 46-67, and BP 897. Fur-

thermore, according to standard procedures the butan-

amine derivative was added to 3-phenylfuran-2,5-dione

and delivered compound 72. Scheme 2 depicts the

reaction way for bicyclo derivatives, which resulted in

the additional formation of valuable bisamination byprod-

ucts. In the first reaction step, reductive alkylation of

1-(2-methoxyphenyl)piperazine with cis-bicyclo[3.3.0]-

octane-3,7-dione was performed.^30-32The major product

Ch em istr y

All compounds described share a 4-(2-methoxy-

phenyl)piperazino group. The general preparation path-

way is outlined in Scheme 1: divergent methods led to

the primary alkanamines (e.g., b, c, d ), which were

condensed with an activated carboxylic acid to give a

carboxamide as final product. According to method A,

1-(2-methoxyphenyl)piperazine was alkylated with iso-

meric (bromomethyl)benzonitriles by means of proce-

dures known in the literature.²⁶Subsequent reduction

of the benzonitrile (e.g., a ) to a benzylamine (e.g., b) was

achieved by treatment with lithium aluminum hydride.

Acylation of the amine with 2-naphthoyl chloride or

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3887

Sch em e 1. Synthesis of Compounds 1-3, 5, 8-44, 46-69, 72, BP 897^a

a

Reagents and conditions. Method A: (i) acetone, K₂CO₃, reflux, 6 h; (ii) dry THF, LiAlH₄, reflux, 3 h. Method B: (iii) acyl chloride,

dry CH₂Cl₂, Et₃N, ambient temperature, 3-24 h. Method C1: (iv) acetonitrile or acetone, K₂CO₃, reflux, 14 h; (v) H₂N-NH₂, MeOH,

reflux, 2 h; (vi) 2 N HCl, reflux, 1 h. Method C2: (vii) acetonitrile, K₂CO₃, reflux, 6 h; (viii) Ra-Ni, 25 bar H₂, 24 h; (ix) glacial acetic acid,

3-phenylfuran-2,5-dione, reflux, 3 h.

was the desired aminoketone (f), accompanied by the

octahydropentalene product of bisamination (6). A

second reductive amination, with ammonia, delivered

the primary amine (g) and another product of bis-

amination (7). The bisamination products were favor-

ably separated as their salts by crystallization. The pri-

mary amine (g) was treated with 2-naphthoyl chloride

according to method B to give compound 4. A versatile

synthesis for imide derivatives is described in Scheme

3. The reaction of 1-(2-methoxyphenyl)piperazine with

1,4-dibromobutane led to a quaternary spiro structure

(B), which was obtained in almost quantitative yields

by performing the reaction in n-butanol.^33,34This suit-

able synthon was treated with imides to provide com-

pounds 70 and 71.^35,36

into aryliodide 9 using molecular iodine, which was

generated in situ from NaI and chloramin T in good

yield.³⁸If [¹²⁵I]NaI were used for this regioselective

electrophile ipso-substitution, this method would enable

facile radiolabeling.

Com p u ta tion a l Meth od s

Liga n d Con str u ction . Molecular structures were

generated using the SYBYL program.³⁹Assuming physi-

ological conditions, the basic aliphatic nitrogen atom of

the piperazine was taken as protonated. The geometry

was optimized using the Tripos force field applying the

conjugate gradient method until the energy differ-

ence between successive cycles was below 0.01 kcal

mol^-1. Partial atomic charges were calculated with the

Gasteiger-Hu¨ckel method, and the dielectric function

was set to a constant value of 80.⁴⁰

While establishing a method for radiolabeling, phenyl-

stannane compound 45 was obtained as a stable inter-

mediate through cleavage of distannanes by iodine-

substituted compound 9 in the presence of palladium

catalysts³⁷(not shown). Compound 45 was reconverted

P h a r m a cop h or e Gen er a tion . The steric and elec-

trostatic information coming from partially rigid, highly

potent ligands was used to generate the pharmacophore

3888 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Sch em e 2. Synthesis of Compounds 4, 6, and 7^a

Hackling et al.

a

Reagents and conditions: (i) 1,2-dichloroethane, NaBH(OCOCH₃)₃, glacial acetic acid, ambient temperature, 2 h; (ii) NH₃in MeOH,

Pd/C, H₂, 12 h. Method B: (iii) 2-naphthoyl chloride, dry CH₂Cl₂, Et₃N, ambient temperature, 10 h.

Sch em e 3. Synthesis of Compounds 70 and 71^a

manually selected portion, and to add the remaining

portions in an iterative incremental procedure. The

scoring functions used to choose appropriate conforma-

tions comprise energy-like matching terms for paired

intermolecular interactions and overlap terms using

Gaussian functions. The Gaussian functions are used

to describe different field properties. Therefore, applying

the molecular comparison procedure within FLEXS, it

is a priori not necessary to define the pharmacophoric

features for superimpositioning molecules. This has

been demonstrated by Lemmen et al.⁴¹in an extensive

evaluation of the approach based on experimental data.

a

Reagents and conditions (for B, see refs 28 and 29): (i) xylene,

To determine the D₃pharmacophore, the following

compounds were examined in detail: compound 4,

compound I⁴², and compound II⁴³(Chart 2). Critical

features for the selected compounds were high binding

affinity for the dopamine D₃receptor and rigid molecule

structure, but not necessarily D₃receptor preference

(compound I K_i(D₃) ) 28 nM, K_i(D₂) ) 6.1 nM, K_i(D₄)

) 0.39 nM; compound II K_i(D₃) ) 1 nM, K_i(D₂) ) 25

nM). Since none of the ligands examined is completely

rigid but some are partially rigid, these three molecules

were initially decomposed into fragments (Chart 2), and

the conformational space of the restricted fragments

were then examined individually. The ring con-

formations (i.e., octahydropentalene in 4 and 4-methyl-

1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-7-ol in II)

were generated applying the simulated annealing pro-

K₂CO₃, 18-crown-6, reflux, 24 h.

models. To explain the receptor selectivity of the studied

ligands, pharmacophore models were developed for

dopamine D₂and dopamine D₃receptor ligands. The

investigated potent dopamine D₃receptor ligands are

characterized by two lipophilic/aromatic moieties, a

hydrogen bond acceptor, and a basic aliphatic nitrogen

atom.

The molecular alignments were carried out using the

FLEXS program.⁴¹FLEXS approaches flexible super-

positioning on the basis of a combinatorial matching

procedure. Pairs of molecules are aligned, one of which

is treated as rigid and the other one is flexibly fitted.

The strategy is to decompose the flexible structure into

relatively rigid portions, to start the placement using a

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3889

Ch a r t 2

cedure within SYBYL. The fragments were heated fifty

times to 1000 K and were subsequently annealed to 0

K. The generated conformations were compared with

corresponding fragments from the Cambridge Struc-

tural Database.⁴⁴Similar conformations were detected

by both approaches. The comparison of the 4-(2-meth-

oxyphenyl)piperazino fragment, which is part of com-

pound 4 and all other ligands under study, and the

conformationally restricted 4-methyl-1,2,3,4,4a,5,6,10b-

octahydrobenzo[f]quinolin-7-ol fragment of compound II

determined the common structural properties in the

basic residue of the ligands. The distal aryl moiety,

which contains the naphthamidic part, was assigned to

be planar, referring to known potent imidic ligands, e.g.,

compound 68.²⁷Taking these conformational restric-

tions into account, a conformational analysis was per-

formed for the whole structure of 4. The rotatable bonds

were scanned using a 10° increment within a 0-350°

interval. Using the Tripos force field, 992 energetically

favorable conformations were calculated for compound

4 within an energy range of 15 kcal/mol. The confor-

mational space of compounds I, II, 4, and 71 was

compared in pairs using the FLEXS program. In such

a way we succeeded in identifying at least one conformer

for each active ligand, which could be superimposed onto

at least one conformer of the other ligands. The final

superimposition of the selected conformers allowed us

to extract the geometric requirements in terms of

distances between pharmacophoric points (Figure 1).

Due to their preference for the dopamine D₂receptor

subtype, compounds 1 and 5 were examined in detail

to determine the bioactive conformation of D₂receptor

ligands. The four rotatable bonds in the alkyl-aryl

spacer, which link the basic and the aryl/acryl moiety,

were scanned using a 10° increment within a 0-350°

interval. Thus, 417 energetically favorable conforma-

tions were obtained, from which the bioactive form had

to be determined. Compound 2, which also possesses

affinity for the D₂receptor, was superimposed onto each

possible conformation of 1 and 5 using program FLEXS.

The putative bioactive conformation of compound 1 was

derived from the top scored superimposition calculated

by FLEXS. All the remaining compounds were super-

imposed onto the predicted bioactive conformation of

compound 4 for the dopamine D₃receptor and onto the

predicted bioactive conformation of compound 1 for the

D₂receptor. This procedure was performed using the

flexible fitting procedure within FLEXS. In the following

step, SYBYL’s multifit routine was used for the refine-

ment of the molecular alignment. Each structure was

relaxed using the steepest descent method up to a

F igu r e 1. Pharmacophore model for dopamine D₃and D₂

receptor ligands. Superimposition of ligands 3, 68, 71, and 4

for the D₃receptor (a) and of 18, 26, 37, and 1 for the D₂

receptor (b). Pharmacophoric points (lipophilic/aromatic moi-

eties, yellow; hydrogen bond acceptor, violet; basic aliphatic

nitrogen atom, blue) and their distances within the pharma-

cophore for dopamine D₃(c) and D₂receptor ligands (d).

Compounds are colored as follows: (a) 3 blue, 4 yellow, 68

cyan, 71 red; (b) 1 grey, 18 violet, 26 orange, 37 green.

The derived molecular alignments for dopamine D₃

and the D₂receptor ligands are shown in Figure 1. The

superimposition of the potent ligands 3, 68, 71, and 4

onto the D₃pharmacophore illustrates that the crucial

structural features, e.g., positively charged nitrogen

atoms, amidic parts, and aryl moieties, occupy a similar

area in space. The same is true for the D₂receptor. The

superimposition of ligands 18, 26, 37, and 1 onto the

D₂pharmacophore shows that the crucial features are

positioned in a similar area in space. The projection of

the D₃receptor ligands onto the pharmacophore shows

clearly that they adopt an extended and more linear

conformation. Gmeiner and co-workers very recently

confirmed linearity as a crucial structural feature for

good D₃receptor binding properties.¹⁶The distances

between the chemical features are recapitulated in

Figure 1. In contrast to the bioactive conformation

calculated for the D₃receptor, ligands at the D₂receptor

adopt a more bent conformation. The corresponding

distances between the pharmacophoric features are

different compared to those measured in the D₃phar-

macophore. Comparing both pharmacophore models, it

gradient of below 0.1 kcal mol^-1

.

3890 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Hackling et al.

F igu r e 3. Lipophilic (A) and hydrophilic (B) interactions of

compound 4 with discrete amino acids of the dopamine D₃

receptor. Calculations were performed with the GRID DRY-

probe (A) displaying interaction zones in yellow, contoured at

an energy level of -0.45 kcal mol^-1, and with the GRID OH-

probe (B) displaying interaction zones in red, contoured at an

F igu r e 2. Compound 4 positioned in the dopamine D₃

receptor. The receptor is restricted to its binding relevant

fragments. Putative transmembrane domains are numbered

1-7. Additionally, several the ligand surrounding threonine

and serine molecules are pointed out, which allow alternative

orientations for the amide oxygen. Asp 110, the counterion to

the basic part, is shown for clarity.

energy level of -4 kcal mol^-1

.

pose. The resulting complex was minimized as described

above (Figure 2). To further analyze the properties of

the binding pocket, the molecular interaction fields for

compound 4 were calculated using program GRID and

were compared with the amino acid residues of the

ligand binding site. The hydrophilic OH probe and the

lipophilic DRY probe were chosen to examine favorable

corresponding interaction regions. As depicted in Figure

3, lipophilic regions coincided with positions of lipophilic

amino acids Met 113, Trp 342, Phe 345, and Tyr 365,

whereas hydrophilic areas coincided with positions of

hydrophilic amino acids Asp 110, Thr 179, and Thr 369.

The FLEXX program,⁴⁹which was designed to place

flexible molecules into active sites of proteins consider-

ing their physicochemical properties, was used to dock

the ligands into the binding pocket. Since Asp 110 of

the dopamine D₃receptor most probably represented the

counterion to the basic part,⁴a salt-bridge was enabled

toward the protonated nitrogen of the ligands. In the

aryl moiety, large and bulky substituents, e.g., 48, 49,

70, and 71, were tolerated, irrespective of amidic or

imidic binding. This slight effect on affinity may be due

to interactions with various amino acids near the

extracellular space (Figure 2), which allow the amide

or imide oxygens to point to various directions. Since a

number of surrounding amino acids were able to form

hydrogen bonds, the carbonyl group was able to undergo

several interactions.

can be observed that bulky substitutions in the spacer

region are not tolerated with D₃selective ligands.

GRID F ield Ca lcu la tion s. After definition of the

arrangement of the pharmacophoric descriptors, the

models were validated by closer examination of molec-

ular fields that are produced by the ligands super-

imposed onto each other in their bioactive conformation.

The GRID program⁴⁵is an approach to predict non-

covalent interactions between a molecule of known

three-dimensional structure, i.e., the ligand, and a small

group as a probe, representing chemical features of

corresponding amino acid residues. On a cube enclosing

the complete ligand, a series of calculations was per-

formed, searching for potential binding sites comple-

mentary to the functional groups. The SYBYL program

subsequently showed the contour maps superimposed

on the receptor model.

Recep tor Mod elin g. The coordinates of the bovine

rhodopsin crystal structure⁴⁶and a structure-function

analysis of rhodopsin-like receptors⁴⁷delivered the basis

for building and optimizing the human dopamine D₃

receptor using the Insight II/Discover modeling pack-

age.⁴⁸The receptor was structurally minimized with the

steepest descent method until the RMS value was below

0.1 kcal mol^-1Å^-1and subsequently minimized with

the conjugate gradient method until the RMS value was

below 0.01 kcal mol^-1Å^-1. Minimizations were per-

formed with the Consistent Valence force field, imple-

mented in Insight II/Discover, and a distance depending

dielectric constant of 4. In a first approach, compound

4 was docked manually into the binding pocket located

between the transmembrane helices 3, 5, 6, and 7. The

dock procedure within SYBYL was used for this pur-

P h a r m a cologica l Resu lts a n d Discu ssion

Bin d in g Stu d ies. Chinese hamster ovary (CHO)

cells were stably transfected with cDNA of human D_2L

and D₃receptors and cloned.^50,51With the cell lines ob-

tained, binding was determined using [¹²⁵I]iodosulpiride

in order to measure radioactivity. K_ivalues were

calculated from the IC₅₀values according to the Cheng-

Prusoff equation.⁵²All novel compounds showed moder-

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3891

ate to high binding affinities for the dopamine D₂

receptor or for the dopamine D₃receptor (K_ivalues of

750-0.33 nM) (Tables 1-4). Throughout the whole

series an important impact of the chain length and

linearity of the spacer was observed. As expected from

the modeling study results, flexible spacers showed a

good concordance between a tetramethylene chain (C₄)

and high dopamine D₃receptor affinity, whereas a

trimethylene spacer (C₃) was favorable for dopamine D₂

receptor binding. Contrary to the shorter trimethylene

spacer, the tetramethylene spacer was able to span the

distance of about 6.5 Å between the pharmacophoric

features basic aliphatic nitrogen and hydrogen bond

acceptor (Figure 1). Within pairs of compounds, which

only diverged in the length of the chain, the C₄bridge

effected generally lower K_ivalues than the C₃analogue

and was simultaneously favoring the D₃receptor (9 f

10, 15 f 16, 17 f 18, 27 f 28, 68 f 69). These results

were transferred to compounds with rigid xylene (1-3,

5) or octahydropentalene (4) spacers (Table 1). D₃

receptor binding was favored by the linear molecules 3

and 4, and D₂receptor binding by the angled ones (1,

2, 5). Obviously the aliphatic structure of the chain was

not essential for dopamine D₂-like receptor affinity.

Since compounds with C₄spacer were able to adopt both

bioactive conformations that were determined for the

D₂and D₃receptor and since affinity for both receptors

was nanomolar, selectivity toward one or the other

receptor could not be determined exclusively by the

conformational requirements of these compounds. De-

tailed comparative molecular field analyses are there-

fore needed to examine the effects of different C₄

compounds, which cause a change of binding affinity

and selectivity toward one receptor. Nevertheless, the

qualitative difference in both receptor pharmacophores

stressed important points for drug optimization.

space and interaction possibilities were accepted (8-

18) and the D₃receptor affinity was maintained below

8 nM for para-substituted compounds with C₄spacer.

The p-chlorobenzoyl derivative 8⁵⁴displayed significant

higher dopamine D₃receptor affinity than that of the

lead compound BP 897 and showed considerable D₃

receptor preference. The low nanomolar affinity values

of the three iodobenzoyl structures declined in a se-

quence of m-, o,- and p-substitution, the latter (9)⁵⁴also

giving an enhanced selectivity ratio for the dopamine

D₃receptor. Introduction of voluminous phenyl (13) and

benzoyl substituents (14) was well tolerated for binding

and selectivity. Replacement of the aryl moiety into

quinoline (19), isoquinolines (20, 21), chromone (22), and

cumarine (23) moieties delivered improved binding

properties for the isoquinoline 20. Introduction of

3-chlorobenzo[b]thiophene (24), related to FAUC 365,

or the more bulky fluorenone (26) as a potential bio-

isosteric group led to low nanomolar binding values. A

comparable fluorenone moiety was already presented

in another series¹⁵and very recently an analogue, which

only diverged in the 4-phenylpiperazino group.⁵⁵Above

that, substituted furan 25 gave an improved selectivity

ratio compared to the other heteroaryl compounds 19-

24 and 26. Naphthyl acetic acid derivatives 27-30

showed no improvement in D₃receptor affinity, with the

C₃spacer compounds having certain D₂receptor prefer-

ence. Compounds selective for the D₂receptor were not

optimized in this investigation. A consequent favorable

development of binding properties and selectivity was

observed in the series of benzyl compound with steric

hindering substituent (31), rigid cyclopropane phenyl

acetic acid derivative 32, and the 3-phenylpropionic acid

derivative 33.

Following these results and the modeling study,

molecules were established bearing the amide in a

certain distance to the steric fixed aromatic structure

(Table 3). Parallel to our development of E-cinnamide

as a valuable structural basis for further compounds

(34), some potent E-cinnamoyl derivatives have been

published.⁵⁶Isomeric Z-derivatives have been reported

to possess lower affinities.⁵⁶The group of mono-, di-, and

trisubstituted cinnamoyl amides (35-61) and analogues

(62-67) consisted of compounds with moderate to

enhanced selectivity ratios and partly high affinity. The

unsubstituted molecule 34 reached an excellent binding

affinity for the dopamine D₃receptor (K_i(D₃) ) 0.33

nM), superior to that of lead BP 897, and considerable

D₃receptor preference. p-Fluoro (35) or -chloro substitu-

tion (36) did not lead to further improvement in affinity

but increased selectivity for the chloro derivative

(ratio_(D2/D3)51), equivalent to that of the p-bromo deriva-

tive 37. Best results in this series were obtained with

the p-iodo derivative 38 (ST 280). Selectivity ratio was

raised to a value of 153 combined with subnanomolar

binding affinity. Substitution with iodine in o- (55) or

m-position (51) also resulted in low nanomolar D₃

receptor binding and high selectivity ratios but did not

exceed those of 38. Halogen monosubstitution (36) was

preferable to disubstitution (57, 58) for affinity and

selectivity scores. Electron-withdrawing as well as

electron-delivering substituents (43, 56) were introduced

without great deterioration in affinity. In contrast to the

benzamides, space-demanding substituents (44-48, 53,

Among the three synthesized dimers (compounds with

two identical elements in their structure), compound 6

showed low affinity, compound 7 bound moderately, and

compound 49 showed improved affinity for both recep-

tors. As outlined in Figure 2, the ligands bound along

the helices of the receptor protein with a moiety

positioned near the extracellular site. Assuming physi-

ological conditions, the dimers appeared to be 2-fold (6,

49) or 3-fold (7) protonated. This induced a strong shift

of the physicochemical properties compared to other

monoprotonated compounds in this series. Thus, binding

properties of compound 6 and 7 may be deteriorated

because their protonated nitrogens occupy an area

which requires an aryl moiety in the pharmacophore

model. Compound 49 comprised all required pharma-

cophoric features, but the additional, protonated dimeric

residue reaches out of the pharmacophore area. This

elongated part of the molecule had no negative effect

on D₂and D₃receptor binding. According to our receptor

model, binding deterioration was reduced in correlation

to a greater distance between the second proton and the

binding pocket. For nonsymmetrical dimeric D₃receptor

ligands with 4-phenylpiperazino and alkylamine resi-

dues, a second proximal binding site has been postu-

lated.⁵³

Variations of the naphthoyl residue were performed

with benzamides and analogues (Table 2). Divergent

benzamide substituents with different requirements in

3892 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Hackling et al.

Ta ble 3. Structures, Physical Data, and Pharmacological Screening Results of R,â-Unsaturated Carboxylic Acid Derivatives

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3893

Ta ble 3. (Continued)

p

r

^{a,b,d,g,h,i,l}See corresponding footnotes in Table 2. Free base crystallized while drying in vacuo. ^qFor structure, see Scheme 1. Crystallized

from MeOH.

61) only moderately deteriorated in binding properties.

Interesting exceptions were the benzo[1,3]dioxoles 59

and 60, which showed structural similarity to the

addictive drug MDMA (3,4-m ethylened ioxy-N-m ethyl-

a mphetamine).⁵⁷All cinnamoyl analogues with aryl

heterocycles (62-65), naphthyl (66), and conjugated

phenylalkadiene structure (67) showed high affinity

below 1.5 nM, but unfortunately no improvement in

selectivity.

With the amide BP 897 as lead on one hand and with

steric demands of the pharmacophore concerning the

binding pocket on the other hand, it seemed reasonable

to integrate an imide as structural feature (Table 4).

But change from amides to imides did not lead to

improved binding or selectivity properties. Analogous

imides 68 and 71 showed similar binding affinities

despite bearing differently bulky aromatic residues.

Only 70 revealed slight selectivity for the dopamine D₃

3894 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Hackling et al.

Ta ble 4. Structures, Physical Data, and Pharmacological Screening Results of Imide Compounds

b,c,i,m,l

s

t

u

See corresponding footnotes in Table 2. NAN 190.²⁷Ref 28. Crystallized from Et₂O.

receptor. Similar to analogue compounds with C₃spacer,

69 displayed remarkably high dopamine D₃receptor K_i

values and a dopamine D₂receptor preference. These

results indicated that the related aromatic or lipophilic

binding regions of the receptor were tolerant to volume

and that the linearity increased the affinity to both

receptor subtypes.

Compound 68²⁷and other structurally related com-

pounds⁵⁸have also been described as 5-HT_1Areceptor

and R₁receptor ligands.⁵⁴Thus, further pharmacological

investigations are required to clarify the ligands’ con-

fined cross affinity for related receptors.

F u n ction a l Recep tor Tests. Dopamine D₃receptor-

based treatment of cocaine abuse with the partial

agonist BP 897 was described for monkeys.¹⁸It cannot

be totally excluded that these effects may possibly be

related to antagonist properties of BP 897, which have

been published for different in vitro tests.⁵⁹Also for

other dopamine D₃receptor antagonists, inhibition of

cocaine-seeking behavior has been reported.⁶⁰The needed

optimal value of intrinsic activity of a partial agonist

for the treatment of human cocaine abusers is not

known. Therefore, compounds with different intrinsic

activity are required for pharmacological screening and

evaluation. A mitogenesis test was performed on NG

108-15 cells expressing the dopamine D₃receptor,

measuring [³H]thymidine incorporation.⁶¹From the

most promising compounds with an affinity below 4 nM

and a selectivity ratio exceeding 18, structural repre-

sentatives of comparable affinity and selectivity scores

were selected for the mitogenesis test. Lead compound

BP 897 displayed an intrinsic activity (R) of 0.6 for the

dopamine D₃receptor (dopamine: R ) 1.0) and an EC₅₀

value of 3 nM.¹⁸The p-iodo-substituted benzamide 9

revealed an intrinsic activity of 0.5 with EC₅₀-value of

1.2 ( 0.4 nM. The same intrinsic activity was obtained

for benzamide derivative 13, although bearing a more

bulky phenyl substituent. Due to its high lipophilicity

this molecule was supposed to pass the blood-brain

barrier rapidly. For heterocyclic compound 20, partial

D₃receptor agonism was found with diminished intrin-

sic activity of value 0.3 (EC₅₀) 2.5 ( 0.8 nM). In the

cinnamoyl group, compound 36 was tested and showed

with an intrinsic activity of 0.7 (EC₅₀) 10 ( 3.5 nM)

comparable values to BP 897.

Con clu sion s

Binding and selectivity properties of lead compound

BP 897 were improved remarkably by means of varia-

tions in distinct structural moieties of the molecule. The

development of ligands was supported by molecular

modeling methods, based on two pharmacophore mod-

els, one for dopamine D₃receptor and one for dopamine

D₂receptor ligands. The built model for the dopamine

D₃receptor depicted the putative amino acids respon-

sible for binding to the pharmacophore. The modeling

results clearly showed a perpendicular positioning of

ligands at the D₃receptor site. According to computa-

tional calculations, a stretched dopamine D₃receptor

binding pocket offered ideal binding facilities for a linear

ligand with a spacer length of approximately 6.5 Å. This

positive effect was determined for both aliphatic chains

(tetramethylene or octahydropentalene) and aromatic

linkers (p-xylene). Steric inflexibility of the aromatic

amidic residue resulted in advantageous affinity and

selectivity scores. Acryl amides met all these require-

ments and delivered a structural basis for new dopam-

ine D₃receptor partial agonists with high affinity and

selectivity. These results led to highly potent p-substi-

tuted 3-phenylacryl amides with tetramethylene spacer,

of which the iodo derivative 38 displayed an improved

dopamine D₃receptor selectivity up to a value of 153

combined with a subnanomolar binding affinity. This

compound gives perspective for a desired new radio-

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3895

sponding carboxylic acid chloride (2.1 mmol) was added and

the stirring continued for another 3-24 h. An additional

amount of carboxylic acid chloride (0.5-1 mmol) was added if

any residual amine was detected by TLC control (ninhydrin).

The solvent was removed under reduced pressure and the

mixture stirred with water. Water was decanted from semi-

solids and the procedure repeated to give solid crystals. Oily

products were extracted with CH₂Cl₂or ethyl acetate. If

necessary, the product was purified by rotatory chromatogra-

phy and crystallized as salt of oxalic acid.

N -(2-(4-(2-Me t h o x y p h e n y l)p ip e r a zin -1-y lm e t h y l)-

p h en ylm eth yl)-2-n a p h th a len eca r boxa m id e (1). Method A,

method B. Yield for last reaction step: 77%. ¹H NMR (DMSO-

d₆) δ 9.35 (m, 1H*, NH), 8.47 (s, 1H, Naph-1H), 8.00 (m, 4H,

4 Naph-H), 7.59 (m, 2H, 2 Naph-H), 7.48 (m, 1H, Xyl-H),

7.39 (m, 2H, 2 Xyl-H), 7.31 (m, 1H, Xyl-H), 6.94 (m, 2H, 2

MeOPh-H), 6.84 (m, 2H, 2 MeOPh-H), 4.70 (d, J ) 5.5 Hz,

2H, NH-CH₂), 4.05 (br m, 2H, 1-Pipera-CH₂), 3.89 (s, 3H,

OCH₃), 3.17 (br m, 4H, 4 Pipera-H), 2.92 (br m, 4H, 4 Pipera-

H). Anal. (C₃₀H₃₁N₃O₂‚C₂H₂O₄) C, H, N.

N -(4-(4-(2-Me t h o x y p h e n y l)p ip e r a zin -1-y lm e t h y l)-

p h en ylm eth yl)-2-n a p h th a len eca r boxa m id e (3). Method A,

method B. Yield for last reaction step: 20%. ¹H NMR (DMSO-

d₆) δ 9.23 (t, J ) 5.6 Hz, 1H*, NH), 8.52 (s, 1H, Naph-1H),

8.00 (m, 4H, 4 Naph-H), 7.61 (m, 2H, 2 Naph-H), 7.38 (m,

4H, 4 Xyl-H), 6.95 (m, 2H, 2 MeOPh-H), 6.86 (m, 2H, 2

MeOPh-H), 4.57 (d, J ) 5.6 Hz, 2H, NH-CH₂), 3.97 (br m,

2H, 1-Pipera-CH₂), 3.75 (s, 3H, OCH₃), 3.06 (br m, 4H, 4

Pipera-H), 2.92 (br m, 4H, 4 Pipera-H). Anal. (C₃₀H₃₁N₃O₂‚

1.25C₂H₂O₄) C, H, N.

Gen er a l P r oced u r e for P r ep a r a tion of Am in e P r ecu r -

sor s for 8-44, 46-67, a n d 72. Meth od C1. A mixture of 1-(2-

methoxyphenyl)piperazine‚HCl (A) (20 mmol, 4.57 g), N-(ω-

bromoalkyl)phthalimide (20 mmol), and K₂CO₃(80 mmol,

11.06 g) in 60 mL of acetonitrile or acetone was heated to reflux

for 6 h. After further addition of N-(ω-bromoalkyl)phthalimide

(2 mmol), the mixture was heated for another 8 h. To achieve

higher reaction temperatures, the use of dimethylformamide

was recommended for less reactive components. The hot

suspension was filtrated and the residue washed with acetone

several times. The filtrates were concentrated under reduced

pressure to give the phthalimide intermediate (68, 69).

N-(3-(4-(2-Meth oxyph en yl)piper azin -1-yl)pr opyl)ph th al-

im id e (68). Method C1. Yield: 98%. ¹H NMR (DMSO-d₆) δ

7.88 (m, 4H, 4 Phth-H), 6.97 (m, 4H, 4 MeOPh-H), 3.76 (s,

3H, OCH₃), 3.66 (t, J ) 6.0 Hz, 2H, Phth-CH₂), 3.28-2.74

(m, 10H, 8 Pipera-H, 1-Pipera-CH₂), 1.98 (m, 2H, CH₂-CH₂-

CH₂). Anal. (C₂₂H₂₅N₃O₃‚1.5C₂H₂O₄) C, H, N.

ligand, possibly enabling direct visualization of dopam-

ine D₃receptors in brain. For potential therapeutic

application, the selected compounds tested in the func-

tional mitogenesis test showed the pharmacologically

desired divergent partial agonism with intrinsic activi-

ties of 0.3 (20), 0.5 (9, 13), and 0.7 (36).

Exp er im en ta l Section

Ch em istr y. Gen er a l P r oced u r es. Melting points were

determined on an Electrothermal IA 9000 digital or a Bu¨chi

512 melting point apparatus and are uncorrected. ¹H NMR

spectra were recorded on a Bruker DPX 400 Avance (400 MHz)

spectrometer. Chemical shifts are expressed in ppm downfield

1

from internal Me₄Si as reference. H NMR data are reported

in the following order: multiplicity (br, broad; s, singlet; d,

doublet; t, triplet; m, multiplet); approximate coupling con-

stants in Hertz (Hz); number of protons; *, exchangeable by

D₂O; Naph, naphthyl; Xyl, xylenyl; MeOPh, 2-methoxyphenyl;

Pipera, piperazinyl; Ph, phenyl; Isoq, isoquinolinyl; Phth,

phthalimidyl; Mal, maleic acid. Elemental analyses (C, H, N)

were measured on Perkin-Elmer 240 B or Perkin-Elmer 240

C instruments and were within (0.4% of theoretical values

for all compounds. Preparative, centrifugally accelerated,

rotatory chromatography was performed using a Chromatotron

7924T (Harrison Research) and glass rotors with 4 mm layers

of silica gel 60 PF₂₅₄containing gypsum (Merck). Thin-layer

chromatography (TLC) was performed on silica gel PF₂₅₄plates

(Merck). The spots were visualized with fast blue salt B,

ninhydrin or by UV absorption at 254 nm. Spectral data and

elemental analyses are shown for intermediates (a -g, 68, 69,

B) and parent compounds, which were obtained by different

reactions or methods, and additionally the most potent com-

pounds (1, 3, 4, 8, 9, 11, 13, 14, 20, 22, 25, 34, 37, 38, 40, 51,

55, 57, 58, 60, 66, 70).

Gen er al P r ocedu r e for P r epar ation of ((Am in om eth yl)-

p h en yl)m et h yl Der iva t ives 1-3, 5. Met h od A. 1-(2-

Methoxyphenyl)piperazine‚HCl (A) (5.5 mmol, 1.26 g) and

K₂CO₃(11 mmol, 1.52 g) were added under ice-cooling to a

solution of bromomethyl-benzonitrile (5 mmol, 1 g) in 30 mL

of acetone and then heated to reflux for 6 h. After cooling to

ambient temperature, the solid was removed by filtration, the

residue washed with acetone, and the filtrate was concentrated

in vacuo. The residue (4-(4-(2-methoxyphenyl)piperazin-1-

ylmethyl)benzonitrile, e.g., (a) was dissolved in 15 mL of

freshly distilled THF and slowly added under ice-cooling to a

suspension of LiAlH₄(95%) (10 mmol, 0.38 g) in 15 mL of

freshly distilled THF. After stirring at room temperature for

30 min, the mixture was heated to reflux for 3 h. After cooling

again to ambient temperature, saturated NH₄Cl solution was

added to the mixture to perform hydrolization. The organic

layer was separated and the aqueous phase extracted with

ethyl acetate twice. The combined organic phases were evapo-

rated to dryness. The product obtained 4-(4-(2-methoxyphenyl)-

piperazin-1-ylmethyl)benzylamine, e.g., (b) was pure enough

to be used in the following reaction step (method B) without

further purification.

N-(4-(4-(2-Meth oxyph en yl)piper a zin -1-yl)bu tyl)p h th a l-

im id e (69). Method C1. Yield: 75%. ¹H NMR (DMSO-d₆) δ

7.88 (m, 4H, 4 Phth-H), 7.00 (m, 4H, 4 MeOPh-H), 3.79 (s,

3H, OCH₃), 3.63 (t, J ) 6.3 Hz, 2H, Phth-CH₂), 3.28-2.74

(m, 10H, 8 Pipera-H, 1-Pipera-CH₂), 1.65 (m, 4H, CH₂-CH₂-

CH₂-CH₂). Anal. (C₂₃H₂₇N₃O₃‚C₂H₂O₄) C, H, N.

The N-(ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)phthal-

imide (18 mmol) and hydrazine hydrate (22 mmol, 1.07 g) in

30 mL of methanol were heated to reflux for 2 h. To the hot

solution was added 20 mL of 2N HCl, and reflux was continued

for one more hour. After cooling to ambient temperature, the

mixture was filtrated, the residue washed with methanol, and

the filtrate evaporated to dryness. This residue was suspended

in water and alkalized with 2N NaOH. Extraction with ethyl

acetate (or CH₂Cl₂) delivered an oily product (c, d ), which was

pure enough for the following reaction step (method B).

3-(4-(2-Meth oxyph en yl)piper azin -1-yl)pr opylam in e (c).²⁹

4-(4-(2-Met h oxyp h en yl)p ip er a zin -1-ylm et h yl)b en zo-

n itr ile (a ). Method A. Yield: 87%. ¹H NMR (DMSO-d₆) δ 7.88

(d, J ) 8.0 Hz, 2H, NC-Ph-3H, NC-Ph-5H), 7.63 (d, J )

8.0 Hz, 2H, NC-Ph-2H, NC-Ph-6H), 7.00 (m, 2H, 2 MeOPh-

H), 6.89 (m, 2H, 2 MeOPh-H), 3.92 (s, 2H, 1-Pipera-CH₂),

3.77 (s, 3H, OCH₃), 3.05 (br m, 4H, 4 Pipera-H), 2.80 (br m,

4H, 4 Pipera-H). Anal. (C₁₉H₂₁N₃O‚C₂H₂O₄) C, H, N.

4-(4-(2-Met h oxyp h en yl)p ip er a zin -1-ylm et h yl)b en zyl-

a m in e (b). Method A. Yield: 83%. ¹H NMR (DMSO-d₆) δ 7.36

(m, 4H, 4 Xyl-H), 6.96 (m, 2H, 2 MeOPh-H), 6.87 (m, 2H, 2

MeOPh-H), 3.87 (s, 2H, 1-Pipera-CH₂), 3.81 (s, 3H, OCH₃),

3.51 (s, 2H, NH₂-CH₂), 2.95 (br m, 4H, 4 Pipera-H), 2.63 (br

m, 4H, 4 Pipera-H). C₁₉H₂₅N₃O.

1

Method C1. Yield: 91%. H NMR (DMSO-d₆) δ 11.25 (s, 1H*,

Pipera⁺-H), 8.18 (s, 1H*, H₃N⁺), 7.03 (m, 4H, 4 MeOPh-H),

3.78 (s, 3H, OCH₃), 3.51 (m, 4H, 4 Pipera-H), 3.22 (m, 2H,

1-Pipera-CH₂), 3.14 (m, 4H, 4 Pipera-H), 2.94 (m, 2H,

H₃N⁺CH₂), 2.12 (m, 2H, CH₂-CH₂-CH₂). C₁₄H₂₃N₃O‚2HCl.

4-(4-(2-Meth oxyph en yl)piper azin -1-yl)bu tylam in e (d).²⁹

Method C1. Yield: 93%. ¹H NMR (DMSO-d₆) δ 6.98 (m, 4H, 4

MeOPh-H), 6.05 (s, 4H, 4 Mal), 3.79 (s, 3H, OCH₃), 3.35 (m,

8H, 8 Pipera-H), 2.92 (t, J ) 7.0 Hz, 2H, 1-Pipera-CH₂), 2.84

Gen er a l P r oced u r e for P r ep a r a tion of Am id es 1-3, 5,

8-44, a n d 46-67. Meth od B. A mixture of the amine (2

mmol), triethylamine (6 mmol, 0.84 mL), and 10 mL of dry

CH₂Cl₂was stirred under argon for 10 min. Then the corre-

3896 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

Hackling et al.

(t, J ) 7.1 Hz, 2H, H₃N⁺CH₂), 1.70 (m, 2H, CH₂), 1.58 (m, 2H,

CH₂). Anal. (C₁₅H₂₅N₃O‚2C₂H₄O₄) C, H, N.

1-Pipera-CH₂), 1.70 (m, 2H, CONH-CH₂-CH₂), 1.58 (m, 2H,

1-Pipera-CH₂-CH₂). Anal. (C₂₉H₃₃N₃O₃‚C₂H₂O₄‚H₂O) C, H, N.

N-(4-(4-(2-Meth oxyph en yl)piper azin -1-yl)bu tyl)isoqu in -

olin e-3-ca r boxa m id e (20). Method C, method B. Yield for

last reaction step: 25%. ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H,

Isoq-4H), 9.01 (t, J ) 6.0 Hz, 1H*, NH), 8.50 (s, 1H, Isoq-

1H), 8.24 (d, J ) 8.1 Hz, 1H, Isoq-H), 8.18 (d, J ) 8.1 Hz, 1H,

Isoq-H), 7.87 (m, 1H, Isoq-H), 7.80 (m, 1H, Isoq-H), 6.96

(m, 4H, 4 MeOPh-H), 3.77 (s, 3H, OCH₃), 3.40 (m, 2H,

CONH-CH₂), 3.38-3.02 (m, 10H, 8 Pipera-H, 1-Pipera-

CH₂), 1.65 (m, 4H, Pipera-CH₂-CH₂-CH₂). Anal. (C₂₅H₃₀N₄O₂‚

C₂H₂O₄‚0.3H₂O) C, H, N.

Meth od C2. A mixture of 1-(2-methoxyphenyl)piperazine‚

HCl (A) (20 mmol, 4.57 g), 4-bromobutyronitrile (25 mmol, 2.5

mL), and K₂CO₃(44 mmol, 6.14 g) in 50 mL of acetonitrile

was heated to reflux for 6 h. After further addition of 10 mmol

(1 mL) of 4-bromobutyronitrile, the mixture was heated for

another 6 h. The cooled mixture was filtrated, the residue

washed with acetone, and the combined filtrates evaporated

to dryness to afford a yellow oil, which was pure enough for

the following reaction step. The 4-(4-(2-methoxyphenyl)piper-

azin-1-yl)butyronitrile (e)²⁹obtained (17.4 mmol, 4.5 g) was

subjected to catalytic hydrogenation using freshly prepared

Raney nickel (from 5 g of aluminum-nickel alloy, according

to standard procedures) in 150 mL of aqueous solution of

ammonia and 20 bar hydrogen for at least 24 h. Cautious

filtration and concentration under reduced pressure delivered

an oily product (d ), which crystallized after some time.

N-(4-(4-(2-Meth oxyp h en yl)p ip er a zin -1-yl)bu tyl)-4-oxo-

4H-ch r om en e-3-ca r boxa m id e (22). Method C, method B.

1

Yield for last reaction step: 29%. H NMR (DMSO-d₆) δ 9.23

(t, J ) 5.7 Hz, 1H*, NH), 8.09 (m, 1H, Chromene-H), 7.93

(m, 1H, Chromene-H), 7.77 (m, 1H, Chromene-H), 7.58 (m,

1H, Chromene-H), 6.97 (m, 4H, 4 MeOPh-H), 6.87 (s, 1H,

Chromene-2H), 3.81 (s, 3H, OCH₃), 3.44 (m, 2H, CONH-

CH₂), 3.30 (m, 10H, 8 Pipera-H, 1-Pipera-CH₂), 1.72 (m, 2H,

CONH-CH₂-CH₂), 1.64 (m, 2H, 1-Pipera-CH₂-CH₂). Anal.

(C₂₅H₂₉N₃O₄‚C₂H₂O₄‚0.5H₂O) C, H, N.

4-(4-(2-Met h oxyp h en yl)p ip er a zin -1-yl)b u t yr on it r ile

1

(e).²⁹Method C2. Yield: 93%. H NMR (DMSO-d₆) δ 6.99 (m,

4H, 4 MeOPh-H), 3.78 (s, 3H, OCH₃), 3.02 (t, J ) 4.7 Hz, 4H,

4 Pipera-H), 2.54 (t, J ) 4.6 Hz, 4H, 4 Pipera-H), 2.49 (m,

partially covered by DMSO 2H, NC-CH₂), 2.43 (t, J ) 6.9 Hz,

2H, 1-Pipera-CH₂), 1.79 (m, 2H, CH₂-CH₂-CH₂). C₁₅H₂₁N₃O.

5-(4-Ch lor oph en yl)-N-(4-(4-(2-m eth oxyph en yl)piper azin -

1-yl)bu tyl)fu r a n -2-ca r boxa m id e (25). Method C, method B.

Yield for last reaction step: 9%. ¹H NMR (DMSO-d₆) δ 8.61

(t, J ) 5.4 Hz, 1H*, NH), 7.96 (d, J ) 8.4 Hz, 2H, ClPh-2H,

ClPh-6H), 7.54 (d, J ) 8.4 Hz, 2H, ClPh-3H, ClPh-5H), 7.16

(m, 2H, 2 Furan-H), 6.97 (m, 4H, 4 MeOPh-H), 3.78 (s, 3H,

OCH₃), 3.41 (m, 12H, CONH-CH₂, 8 Pipera-H, 1-Pipera-

CH₂), 1.72 (m, 2H, CONH-CH₂-CH₂), 1.58 (m, 2H, 1-Pipera-

CH₂-CH₂). Anal. (C₂₆H₃₀ClN₃O₃‚2C₂H₂O₄) C, H, N.

(E)-N-(4-(4-(2-Met h oxyp h en yl)p ip er a zin -1-yl)b u t yl)-

cin n a m oyla m id e (34). Method C, method B. Yield for last

reaction step: 20%. ¹H NMR (DMSO-d₆) δ 8.21 (t, J ) 5.5 Hz,

1H*, NH), 7.56 (m, 2H, 2 Ph-H), 7.41 (m, 4H, 3 Ph-H, Ph-

CH), 6.96 (m, 4H, 4 MeOPh-H), 6.64 (d, J ) 15.9 Hz, 1H,

CO-CH), 3.79 (s, 3H, OCH₃), 3.40 (m, 12H, CONH-CH₂, 8

Pipera-H, 1-Pipera-CH₂), 1.68 (m, 2H, CONH-CH₂-CH₂),

1.51 (m, 2H, 1-Pipera-CH₂-CH₂). Anal. (C₂₄H₃₁N₃O₂‚C₂H₂O₄‚

0.5H₂O) C, H, N.

(E)-4-Br om o-N-(4-(4-(2-m et h oxyp h en yl)p ip er a zin -1-

yl)bu tyl)cin n a m oyla m id e (37). Method C, method B. Yield

for last reaction step: 12%. ¹H NMR (DMSO-d₆) δ 8.22 (t, J )

5.4 Hz, 1H*, NH), 7.61 (d, J ) 8.4 Hz, 2H, Ph-2H, Ph-6H),

7.52 (d, J ) 8.4 Hz, 2H, Ph-3H, Ph-5H), 7.39 (d, J ) 15.8

Hz, 1H, Ph-CH), 6.98 (m, 2H, 2 MeOPh-H), 6.89 (m, 2H, 2

MeOPh-H), 6.65 (d, J ) 15.8 Hz, 1H, CO-CH), 3.79 (s, 3H,

OCH₃), 3.22 (br m, 10H, CONH-CH₂, 8 Pipera-H), 3.01 (br

m, 2H, 1-Pipera-CH₂), 1.67 (m, 2H, CONH-CH₂-CH₂), 1.50

(m, 2H, 1-Pipera-CH₂-CH₂). Anal. (C₂₄H₃₀BrN₃O₂‚C₂H₂O₄‚

0.5H₂O) C, H, N.

(E)-4-Iod o-N-(4-(4-(2-m et h oxyp h en yl)p ip er a zin -1-yl)-

bu tyl)cin n a m oyla m id e (38). Method C, method B. Yield for

last reaction step: 56%. ¹H NMR (CDCl₃) δ 7.67 (d, J ) 7.9

Hz, 2H, I-Ph-2H, I-Ph-6H), 7.55 (d, J ) 15.6 Hz, 1H, Ph-

CH), 7.21 (d, J ) 7.9 Hz, 2H, I-Ph-3H, I-Ph-5H), 7.02 (s,

1H, NH), 6.92 (m, 4H, 4 MeOPh-H), 6.48 (d, J ) 15.6 Hz,

1H, CO-CH), 3.86 (s, 3H, OCH₃), 3.43 (s, 2H, CONH-CH₂),

3.20 (s, 4H, PhN(CH₂)₂), 2.80 (s, 4H, PhN(CH₂-CH₂)₂), 2.57

(s, 2H, 1-Pipera-CH₂), 1.69 (s, 4H, CONH-CH₂-CH₂-CH₂).

Anal. (C₂₄H₃₀IN₃O₂) C, H, N.

4-Ch lor o-N-(4-(4-(2-m et h oxyp h en yl)p ip er a zin -1-yl)-

bu tyl)ben za m id e (8). Method C, method B. Yield for last

reaction step: 39%. ¹H NMR (DMSO-d₆) δ 8.60 (m, 1H*, NH),

7.87 (d, J ) 7.9 Hz, 2H, Cl-Ph-2H, Cl-Ph-6H), 7.54 (d, 2H,

Cl-Ph-3H, Cl-Ph-5H), 6.96 (m, 4H, 4 MeOPh-H), 3.79 (s,

3H, OCH₃), 3.29 (m, 2H, CONH-CH₂), 3.19-2.90 (m, 10H, 8

Pipera-H, 1-Pipera-CH₂), 1.69 (m, 2H, CONH-CH₂-CH₂),

1.57 (m, 2H, 1-Pipera-CH₂-CH₂). Anal. (C₂₂H₂₈ClN₃O₂‚

C₂H₂O₄) C, H, N.

4-Iodo-N-(4-(4-(2-m eth oxyph en yl)piper azin -1-yl)bu tyl)-

ben za m id e (9). Method C, method B. Yield for last reaction

1

step: 39%. H NMR (DMSO-d₆) δ 8.49 (m, 1H*, NH), 7.82 (d,

J ) 7.0 Hz, 2H, I-Ph-2H, I-Ph-6H), 7.60 (d, J ) 7.0 Hz,

2H, I-Ph-3H, I-Ph-5H), 6.90 (m, 2H, 2 MeOPh-H), 6.85

(m, 2H, 2 MeOPh-H), 3.74 (s, 3H, OCH₃), 3.29 (br m, 2H,

CONH-CH₂), 2.92 (br m, 4H, PhN(CH₂)₂), 2.5 (hidden by

DMSO 4H, PhN(CH₂-CH₂)₂), 2.32 (m, 2H, 1-Pipera-CH₂),

1.50 (m, 4H, CONH-CH₂-CH₂-CH₂). Anal. (C₂₂H₂₈IN₃O₂) C,

H, N.

4-Ace t yl-N -(4-(4-(2-m e t h oxyp h e n yl)p ip e r a zin -1-yl)-

bu tyl)ben za m id e (11). Method C, method B. Yield for last

reaction step: 26%. ¹H NMR (DMSO-d₆) δ 8.49 (t, J ) 5.4 Hz,

1H*, NH), 8.03 (d, J ) 8.4 Hz, 2H, Ph-2H, Ph-6H), 7.06 (d,

J ) 8.4 Hz, 2H, Ph-3H, Ph-5H), 6.87 (m, 4H, 4 MeOPh-H),

3.77 (s, 3H, OCH₃), 3.31 (m, 2H, CONH-CH₂), 2.94 (br m, 4H,

PhN(CH₂)₂), 2.62 (s, 3H, COCH₃), 2,5 (hidden by DMSO 4H,

PhN(CH₂-CH₂)₂), 2.35 (t, J ) 7.1 Hz, 2H, 1-Pipera-CH₂), 1.57

(m, 2H, CONH-CH₂-CH₂), 1.53 (m, 2H, 1-Pipera-CH₂-CH₂).

Anal. (C₂₄H₃₁N₃O₃) C, H, N.

N -(4-(4-(2-Me t h oxyp h e n yl)p ip e r a zin -1-yl)b u t yl)b i-

p h en yl-4-ca r boxa m id e (13). Method C, method B. Yield for

1

last reaction step: 44%. H NMR (DMSO-d₆) δ 8.57 (m, 1H*,

NH), 7.95 (d, J ) 8.2 Hz, 2H, NCOPh-2H, NCOPh-6H), 7.77

(d, J ) 8.2 Hz, 2H, NCOPh-3H, NCOPh-5H), 7.72 (m, 2H,

OCPhPh-2H, OCPhPh-6H), 7.48 (m, 2H, OCPhPh-3H,

OCPhPh-5H), 7.41 (m, 1H, OCPhPh-4H), 6.97 (m, 4H, 4

MeOPh-H), 3.79 (s, 3H, OCH₃), 3.35 (m, 12H, CONH-CH₂,

8 Pipera-H, 1-Pipera-CH₂), 1.72 (m, 2H, CONH-CH₂-CH₂),

1.60 (m, 2H, 1-Pipera-CH₂-CH₂). Anal. (C₂₈H₃₃N₃O₂‚C₂H₂O₄)

C, H, N.

(E)-4-Cya n o-N-(4-(4-(2-m eth oxyp h en yl)p ip er a zin -1-yl)-

bu tyl)cin n a m oyla m id e (40). Method C, method B. Yield for

1

last reaction step: 3%. H NMR (DMSO-d₆) δ 8.31 (t, J ) 5.4

Hz, 1H*, NH), 7.87 (d, J ) 7.8 Hz, 2H, Ph-2H, Ph-6H), 7.46

(d, J ) 7.8 Hz, 2H, Ph-3H, Ph-5H), 7.48 (d, J ) 15.8 Hz, 1H,

Ph-CH), 6.98 (m, 2H, 2 MeOPh-H), 6.89 (m, 2H, 2 MeOPh-

H), 6.77 (d, J ) 15.8 Hz, 1H, CO-CH), 3.79 (s, 3H, OCH₃),

3.24 (br m, 10H, CONH-CH₂, 8 Pipera-H), 3.08 (br m, 2H,

1-Pipera-CH₂), 1.68 (m, 2H, CONH-CH₂-CH₂), 1.52 (m, 2H,

1-Pipera-CH₂-CH₂). Anal. (C₂₅H₃₀N₄O₂‚2C₂H₂O₄) C, H, N.

(E)-3-(3-Iod op h en yl)-N-(4-(4-(2-m eth oxyp h en yl)p ip er -

a zin -1-yl)bu tyl)a cr yla m id e (51). Method C, method B. Yield

for last reaction step: 30%. ¹H NMR (CDCl₃) δ 7.85 (s, 1H,

N-(4-(4-(2-Meth oxyp h en yl)p ip er a zin -1-yl)bu tyl)ben zo-

p h en on e-4-ca r boxa m id e (14). Method C, method B. Yield

for last reaction step: 10%. ¹H NMR (DMSO-d₆) δ 8.75 (t, J )

5.3 Hz, 1H*, NH), 8.01 (d, J ) 8.2 Hz, 2H, NCOPh-2H,

NCOPh-6H), 7.81 (d, J ) 8.2 Hz, 2H, NCOPh-3H, NCOPh-

5H), 7.76 (d, J ) 7.4 Hz, 2H, PhCOPh-2H, PhCOPh-6H),

7.72 (m, 1H, PhCOPh-4H), 7.59 (m, 2H, PhCOPh-3H,

PhCOPh-5H), 6.97 (m, 4H, 4 MeOPh-H), 3.79 (s, 3H, OCH₃),

3.35 (m, 2H, CONH-CH₂), 3.25-2.82 (10H, 8 Pipera-H,

Dopamine D2 and D3 Receptor Ligands

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18 3897

I-Ph-2H), 7.66 (d, J ) 7.9 Hz, 1H, I-Ph-H), 7.53 (d, J )

15.6 Hz, 1H, Ph-CH), 7.45 (d, J ) 7.8 Hz, 1H, I-Ph-H), 7.09

(br m, 6H, I-Ph-H, NH, 4 MeOPh-H), 6.49 (d, J ) 15.6 Hz,

1H, CO-CH), 3.86 (s, 3H, OCH₃), 3.46 (m, 2H, CONH-CH₂),

3.26 (s, 4H, PhN(CH₂)₂), 2.84 (s, 4H, PhN(CH₂-CH₂)₂), 2.67

(s, 2H, 1-Pipera-CH₂), 1.81 (m, 4H, CONH-CH₂-CH₂-CH₂).

Anal. (C₂₄H₃₀IN₃O₂) C, H, N.

(E)-3-(2-Iod op h en yl)-N-(4-(4-(2-m eth oxyp h en yl)p ip er -

a zin -1-yl)bu tyl)a cr yla m id e (55). Method C, method B. Yield

for last reaction step: 39%. ¹H NMR (CDCl₃) δ 7.88 (d, J )

7.9 Hz, 1H, I-Ph-H), 7.82 (d, J ) 15.4 Hz, 1H, Ph-CH), 7.54

(d, J ) 7.8 Hz, 1H, I-Ph-H), 7.32 (m, 2H, I-Ph-H), 7.05 (m,

2H, 2 MeOPh-H), 6.93 (m, 3H, 2 MeOPh-H, NH), 6.43 (d, J

) 15.4 Hz, 1H, CO-CH), 3.86 (s, 3H, OCH₃), 3.48 (m, 2H,

CONH-CH₂), 3.28 (s, 4H, PhN(CH₂)₂), 2.97 (s, 4H, PhN(CH₂-

CH₂)₂), 2.73 (s, 2H, 1-Pipera-CH₂), 1.85 (m, 2H, CONH-CH₂-

CH₂), 1.74 (m, 2H, Pipera-CH₂-CH₂). Anal. (C₂₄H₃₀IN₃O₂) C,

H, N.

(E)-3,4-Dich lor o-N-(4-(4-(2-m eth oxyp h en yl)p ip er a zin -

1-yl)bu tyl)cin n a m oyla m id e (57). Method C, method B.

Yield for last reaction step: 5%. ¹H NMR (DMSO-d₆) δ 8.19

(m, 1H*, NH), 7.85 (s, 1H, Ph-2H), 7.67 (d, J ) 8.4 Hz, 1H,

Ph-6H), 7.57 (d, J ) 8.4 Hz, 1H, Ph-5H), 7.40 (d, J ) 15.8

Hz, 1H, Ph-CH), 6.99 (m, 2H, 2 MeOPh-H), 6.89 (m, 2H, 2

MeOPh-H), 6.70 (d, J ) 15.7 Hz, 1H, CO-CH), 3.79 (s, 3H,

OCH₃), 3.22 (m, 12H, CONH-CH₂, 8 Pipera-H, 1-Pipera-

CH₂), 1.66 (m, 2H, CONH-CH₂-CH₂), 1.54 (m, 2H, 1-Pipera-

CH₂-CH₂). Anal. (C₂₄H₂₉Cl₂N₃O₂‚C₂H₂O₄) C, H, N.

(E)-2,4-Dich lor o-N-(4-(4-(2-m eth oxyp h en yl)p ip er a zin -

1-yl)bu tyl)cin n a m oyla m id e (58). Method C, method B.

Yield for last reaction step: 3%. ¹H NMR (DMSO-d₆) δ 8.32

(m, 1H*, NH), 7.70 (m, 3H, 2 Ph-2H, Ph-CH), 7.50 (d, J )

7.9 Hz, 1H, Ph-H), 6.99 (m, 2H, 2 MeOPh-H), 6.89 (m, 2H,

2 MeOPh-H), 6.70 (d, J ) 15.7 Hz, 1H, CO-CH), 3.79 (s, 3H,

OCH₃), 3.22 (m, 12H, CONH-CH₂, 8 Pipera-H, 1-Pipera-

CH₂), 1.68 (m, 2H, CONH-CH₂-CH₂), 1.52 (m, 2H, 1-Pipera-

CH₂-CH₂). Anal. (C₂₄H₂₉Cl₂N₃O₂‚C₂H₂O₄‚1.5H₂O) C, H, N.

with 1 bar H₂for 12 h under TLC control. The catalyst was

removed by filtration and the filtrate evaporated in vacuo. The

residue was suspended in water and extracted with dichloro-

methane. Again fractionated crystallization with oxalic acid

delivered a bis-adduct (bis(7-(4-(2-methoxyphenyl)piperazin-

1-yl)bicyclo[3.3.0]oct-3-yl)amine, 7) and a distinct major prod-

uct (7-(4-(2-metoxyphenyl)piperazin-1-yl)bicyclo[3.3.0]octane-

3-amine, g). The free base (ca. 0.5 mmol, 0.15 g) of this amine

was treated according to method B with 2-naphthoyl chloride

(0.53 mmol, 0.1 g) to provide the amide 4. For compound 4,

absolute conformation has not been confirmed yet, and minor

percentage of diastereomeres cannot be excluded.

7-(4-(2-Met h oxyp h en yl)p ip er a zin -1-yl)b icyclo[3.3.0]-

octa n e-3-on e (f). Yield: 32%. ¹H NMR (DMSO-d₆) δ 6.98 (m,

2H, 2 MeOPh-H), 6.90 (m, 2H, 2 MeOPh-H), 3.79 (s, 3H,

OCH₃), 3.51 (br m, 1H, NCH), 3.21 (br m, 8H, 8 Pipera-H),

2.68 (m, 2H), 2.46 (m, partially covered by DMSO 2H), 2.39

(m, 2H), 2.13 (m, 1H), 2.08 (m, 1H), 1.63 (m, 2H). Anal.

(C₁₅H₂₆N₂O₂‚C₂H₄O₄‚H₂O) C, H, N.

7-(4-(2-Met h oxyp h en yl)p ip er a zin -1-yl)b icyclo[3.3.0]-

1

octa n e-3-a m in e (g). Yield: 49%. H NMR (DMSO-d₆) δ 6.97

(m, 2H, 2 MeOPh-H), 6.93 (m, 2H, 2 MeOPh-H), 3.79 (m,

4H, 3 OCH₃, NCH), 3.10 (m, 1H), 2.95 (m, 4H, 4 Pipera-H),

2.54 (m, partially covered by DMSO 4H, 4 Pipera-H), 2.29

(m, 2H), 2.10 (m, 2H), 2.03 (m, 2H), 1.57 (m, 1H), 1.38 (m,

1H), 1.21 (m, 2H). C₁₉H₂₉N₃O.

N-(7-(4-(2-Meth oxyp h en yl)p ip er a zin -1-yl)bicyclo[3.3.0]-

octa n e-3-yl)-2-n a p h th a len eca r boxa m id e (4). Yield for last

1

reaction step: 26%. H NMR (DMSO-d₆) δ 8.52+8.43 (d, J )

7.3 Hz, 1H, NH), 7.43 (s, 1H, Naph-1H), 7.96 (m, 4H, 4 Naph-

H), 7.60 (m, 2H, 2 Naph-H), 6.93 (m, 4H, 4 MeOPh-H), 6.87

(m, 4H, 4 MeOPh-H), 4.47+4.31 (m, 1H, NH-CH) 3.77 (s,

6H, 2 OCH₃), 2.95 (br m, 4H, 4Pipera-H), 2.5 (hidden by

DMSO 4H, 4 Pipera-H), 2.39 (m, 1H, 1-Pipera-CH), 2.19 (m,

4H, 4 CHH), 1.72 (m, 2H, HC-CH), 1.45-1.00 (4H, 4 CHH).

Anal. (C₃₀H₃₅N₃O₂‚0.75H₂O) C, H, N.

Gen er a l P r oced u r e for P r ep a r a tion of N-Alk yla ted

Im id es 70, 71. A mixture of 1-(2-methoxyphenyl)piperazine‚

HCl (10 mmol, 2.29 g), K₂CO₃(20 mmol, 2.76 g), and 1,4-

dibromobutane (15 mmol, 1.79 mL) in 100 mL n-butanol was

heated to reflux for 3 h. The hot suspension was filtrated and

concentrated under reduced pressure to deliver 8-(2-methoxy-

phenyl)-8-aza-5-azoniaspiro[4,5]decane-bromide (B). This in-

termediate (4 mmol, 1.31 g), K₂CO₃(5 mmol, 0.69 g), the

dicarboximide (4 mmol), and a catalytic amount of 18-crown-6

were dissolved in 20 mL of xylene and heated to reflux under

argon for 24 h. After filtration of the hot mixture, the filtrate

was evaporated to dryness. The obtained colored oil was stirred

in diethyl ether and crystallized.

8-(2-Meth oxyp h en yl)-8-a za -5-a zon ia sp ir o[4,5]d eca n e-

br om id e (B). Yield: 70%. ¹H NMR (DMSO-d₆) δ 6.99 (m, 4H,

4 MeOPh-H), 3.81 (s, 3H, OCH₃), 3.63 (m, 4H, N⁺(CH₂)₂), 3.59

(m, 4H, N⁺(CH₂)₂), 3.30 (br m, 4H, Ph-N(CH₂)₂), 2.10 (m, 4H,

N⁺(CH₂-CH₂)₂. Anal. (C₁₅H₂₃BrN₂O‚0.75H₂O) C, H, N.

N-(4-(4-(2-Met h oxyp h en yl)p ip er a zin -1-yl)b u t yl)-2,3-

n a p h th a len ed ica r boxim id e (70). Yield for last reaction

step: 59%. ¹H NMR (DMSO-d₆) δ 8.52 (s, 2H, Naph-1H,

Naph-4H), 8.27 (m, 2H, Naph-5H, Naph-8H), 7.79 (m, 2H,

Naph-6H, Naph-7H), 6.87 (m, 4H, 4 MeOPh-H), 3.75 (s, 3H,

OCH₃), 3.69 (t, J ) 6.7 Hz, 2H, Phth-N-CH₂), 2.92 (m, 4H,

Ph-N(CH₂)₂), 2.47 (partially hidden by DMSO 4H, Ph-

N(CH₂-CH₂)₂), 2.34 (t, J ) 6.7 Hz, 2H, 1-Pipera-CH₂), 1.68

(m, 2H, Phth-N-CH₂-CH₂), 1.49 (m, 2H, 1-Pipera-CH₂-

CH₂₎. Anal. (C₂₇H₂₉N₃O₃) C, H, N.

(E)-3-(Ben zo[1,3]dioxol-4-yl-N-(4-(4-(2-m eth oxyph en yl)-

p ip er a zin -1-yl)bu tyl)a cr yla m id e (60). Method C, method

1

B. Yield for last reaction step: 37%. H NMR (CDCl₃) δ 7.55

(d, J ) 15.7 Hz, 1H, Ph-CH), 7.05 (m, 2H, (CH₂O₂)Ph-H, NH),

6.94 (m, 4H, 2 (CH₂O₂)Ph-H, 2 MeOPh-H), 6.84 (m, 2H, 2

MeOPh-H), 6.73 (d, J ) 15.8 Hz, 1H, CO-CH), 5.88 (s, 2H,

(CH₂O₂)Ph), 3.87 (s, 3H, OCH₃), 3.46 (m, 2H, CONH-CH₂),

3.27 (s, 4H, PhN(CH₂)₂), 2.93 (s, 4H, PhN(CH₂-CH₂)₂), 2.71

(s, 2H, 1-Pipera-CH₂), 1.83 (m, 2H, CONH-CH₂-CH₂), 1.72

(m, 2H, Pipera-CH₂-CH₂). Anal. (C₂₅H₃₁N₃O₄) C, H, N.

N-(4-(4-(2-Met h oxyp h en yl)p ip er a zin -1-yl)b u t yl)-3-(2-

n a p h th yl)a cr yla m id e (66). Method C, method B. Yield for

last reaction step: 10%. ¹H NMR (DMSO-d₆) δ 8.14 (t, J ) 5.4

Hz, 1H*, NH), 8.06 (s, 1H, Naph-1H), 7.93 (m, 3H, 3 Naph-

H), 7.72 (d, J ) 8.6 Hz, 1H, Naph-H), 7.56 (m, 3H, 2 Naph-

H, Naph-CH), 6.92 (m, 4H, 4 MeOPh-H), 6.76 (d, J ) 15.7

Hz, 1H, CO-CH), 3.76 (s, 3H, OCH₃), 3.23 (m, 2H, CONH-

CH₂), 2.95 (m, 4H, PhN(CH₂)₂), 2.5 (hidden by DMSO 4H,

PhN(CH₂-CH₂)₂), 2.34 (m, 2H, 1-Pipera-CH₂), 1.51 (m, 4H,

CONH-CH₂-CH₂-CH₂). Anal. (C₂₈H₃₃N₃O₂) C, H, N.

P r ep a r a tion of Bicyclo Der iva tives 4, 6, a n d 7. Reduc-

tive alkylation of 1-(2-methoxyphenyl)piperazine‚HCl (5 mmol,

0.96 g) was performed with cis-bicyclo[3.3.0]octane-3,7-dione

(5 mmol, 0.69 g), triacetoxyborohydride (5 mmol, 1.06 g), and

1 mL of glacial acetic acid in 80 mL of dichloroethane. The

mixture was stirred at ambient temperature for 2 h. Then, a

half-saturated solution of NaHCO₃was added, followed by

extraction with dichloromethane. The unified organic phases

were washed, dried, and concentrated in vacuo. The oily

product was dissolved in ethanol. Addition of oxalic acid led

to fractionated crystallization. In minor yields the dimer 3,7-

bis(4-(2-methoxyphenyl)piperazin-1-yl)bicyclo[3.3.0]octane (6)

was obtained, but the major product was 7-(4-(2-methoxy-

phenyl)piperazin-1-yl)bicyclo[3.3.0]octane-3-one (f). This ke-

tone (1.4 mmol) was dissolved in 50 mL of a methanolic

solution of NH₃with a catalytic amount of palladium on

activated charcoal (200 mg). The mixture was hydrogenated

P h a r m a cologica l Testin g. Bin d in g Stu d ies.⁶²Human

D_2Land D₃receptors were expressed in stably transfected

Chinese hamster ovary (CHO) cells.^50,51These cell lines were

cultured in Dulbecco’s Modified Eagle Medium supplemented

in 10% fetal calf serum in an atmosphere of 5% CO₂. Cells

were harvested from culture dishes in the presence of 0.2%

trypsin, centrifuged at 2000g for 5 min and homogenized in

10 mM Tris-HCl, pH 7.4, containing 5 mM MgCl₂using a

Polytron. The homogenate was centrifuged at 20 000g for 15

min at 4°C, and the pellet was resuspended by sonication in

3898 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 18

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50 mM Tris-HCl, pH 7.4, containing (in milimolar): NaCl, 120;

KCl, 5; CaCl₂, 2; and MgCl₂, 8 (incubation buffer). Membranes

were used either immediately or after storage at -70 °C. A

membrane volume of 200 µL, diluted in incubation buffer

supplemented with 0.2% bovine serum albumin, was added

to polystyrene tubes containing (in 100 µL) 0.1 nM [¹²⁵I]iodo-

sulpiride and drug diluted in 100 µL of incubation buffer.

Nonspecific binding was determined in the presence of 1 µM

enomapride. Incubations were run at 30°C for 30 min. Reac-

tions were stopped by vacuum filtration through Whatman

GF/B glass-fiber filters coated in 0.3% polyethylenimine with

automated cell harvester (Brandel-Beckman, Gaithersburg,

MD). Filters were rinsed three times with 5 mL of ice-cold

incubation buffer and counted by liquid scintillation in 5 mL

of ACS II (Amersham).

F u n ction a l Recep tor Tests.⁶²NG 108-15 cells expressing

the human D₃receptor were cultured in Dulbecco’s Modified

Eagle Medium supplemented in 10% fetal calf serum in an

atmosphere of 5% CO₂and plated in collagen-coated 96-well

plates. After a 24-hour culture, cells were washed twice with

culture medium without feral calf serum and incubated for

16 h with 1 µM forskoline and quinpirole in increasing

concentrations, in the absence or presence of compounds at

1.5, 3, 30, or 300 nM. Then, [³H]thymidine (1 µCi/well) was

added for 2 h and cells were harvested by vacuum filtration

through Whatman GF/C glass-fiber filters using an automated

cell harvester. The filters were rinsed 15 times with 200 µL of

phosphate buffered saline. Radioactivity was counted by liquid

scintigraphy in 5 mL of ACS (Amersham).

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Ack n ow led gm en t. This study was supported by

grants from the European Community (QLG4-CT-1999-

00075), and the NIDA/NIH (1RO1DA 115 34-01).

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J M030836N

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N-(ω)-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands

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