Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine σ ligands as potential antipsychotic drugs

Article abstract of DOI:10.1021/jm980212v

Receptor antagonists may be effective antipsychotic drugs that do not induce motor side effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that 1-(2-dipropylaminoethyl)-4-methoxy- 6H-dibenzo[b,d]pyran hydrochloride 2a had selective affinity for σ receptor over dopamine D₂ receptor. This compound was designed to eliminate two bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge two benzene rings with a -CH₂O- bond to maintain the planar structure. In light of the evidence, N,Y-dipropyl-2-(4-methoxy-3- benzyloxylphenyl)ethylamine hydrochloride 10b was designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran derivative 2a, it might be more released from the rigid structure of apomorphine 1 than compound 2a. The chemical modification of compound 10b led to the discovery that N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective affinity for σ receptor and had a potent activity in an animal model when the drug was given orally. We report here the design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine derivatives 3.

Full text of DOI:10.1021/jm980212v

1076
J . Med. Chem. 1999, 42, 1076-1087
Design , Syn th esis, Str u ctu r e-Activity Rela tion sh ip s, a n d Biologica l
Ch a r a cter iza tion of Novel Ar yla lk oxyp h en yla lk yla m in e σ Liga n d s a s P oten tia l
An tip sych otic Dr u gs
Atsuro Nakazato,*,† Kohmei Ohta,‡ Yoshinori Sekiguchi,† Shigeru Okuyama,† Shigeyuki Chaki,†
Yutaka Kawashima,† and Katsuo Hatayama‡
Medicinal and Pharmaceutical Research Laboratories, Taisho Pharmaceutical Company, Ltd., 1-403 Yoshino-cho, Ohmiya,
Saitama 330-8530, J apan
Received April 6, 1998
σ Receptor antagonists may be effective antipsychotic drugs that do not induce motor side
effects caused by ingestion of classical drugs such as haloperidol. We obtained evidence that
1-(2-dipropylaminoethyl)-4-methoxy-6H-dibenzo[b,d]pyran hydrochloride 2a had selective af-
finity for σ receptor over dopamine D2 receptor. This compound was designed to eliminate two
bonds of apomorphine 1 to produce structural flexibility for the nitrogen atom and to bridge
two benzene rings with a -CH2O- bond to maintain the planar structure. In light of the
evidence, N,N-dipropyl-2-(4-methoxy-3-benzyloxylphenyl)ethylamine hydrochloride 10b was
designed. Since compound 10b had eliminated a biphenyl bond of 6H-dibenzo[b,d]pyran
derivative 2a , it might be more released from the rigid structure of apomorphine 1 than
compound 2a . The chemical modification of compound 10b led to the discovery that N,N-
dipropyl-2- [4-methoxy-3-(2-phenylethoxyl)phenyl]ethylamine hydrochloride 10g (NE- 100), the
best compound among arylalkoxyphenylalkylamine derivatives 3, had a high and selective
affinity for σ receptor and had a potent activity in an animal model when the drug was given
orally. We report here the design, synthesis, structure-activity relationships, and biological
characterization of novel arylalkoxyphenylalkylamine derivatives 3.
In tr od u ction
(quipazine) in rats. XJ 448 did not cause catalepsy in
the rat, but it did antagonize the catalepsy by haloperi-
dol. These findings suggest that selective σ receptor
antagonists may be effective antipsychotic drugs, com-
pounds that do not induce the extrapyramidal symp-
toms and tardive dyskinesia caused by ingestion of
classical D2 receptor antagonists drugs such as halo-
peridol and chlorpromazine.
Interest in σ receptors,1 which were postulated by
Martin et al.2 to account for the actions of (()-N-
allylnormetazacine (SKF10,047), has continued to grow
as they bind to typical and atypical antipsychotics.3-5
The role of σ receptors can explain the antipsychotic-
like effects of cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]
carbazole dihydrochloride (rimcazole),6-13 (-)-(S)-3-
bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethyl-
benzamide (remoxipride),14-19 R-(4-fluorophenyl)-4-(5-
fluoro-2-pyrimidinyl)-1-piperazine-butanol HCl (BMY
14802),20,21 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-me-
thylflavone HCl (NPC16377),22 cinuperone,23 1-(cyclo-
propylmethyl)-4-[2′-(4′′-fluorophenyl)-2′-oxoethyl]pipe-
ridine HBr (DuP734),24 1-cyclopropylmethyl-4-[2′-(4′′-
cyanophenyl)-2′-oxoethyl]piperidine HBr (XJ 448),25,26
and cis-3-(hexahydroazepin-l-yl)-1-(3-chloro-4-cyclohexy-
lphenyl)propene-1 HCl (SR 31742A),27 which may not
act primarily at the dopamine D2 (D2) receptor but do
have a reasonable affinity for σ receptors.
In contrast, there are several reports suggesting that
σ receptor might not be involved in the etiology and/or
pathology of schizophrenia. In a limited open-label
study, BMY14802,20,21 which has affinities for both σ
and serotonin 5-HT1A receptors,51 has proven to have
no significant improvement in psychiatric symptoms, as
measured by the total brief psychiatric rating scale
(BPRS) scores, and was dropped from the study.
Rimcazole,6-13 which has a weak but selective affinity
for σ receptor, did not equal the efficacy of haloperidol
or chlorpromazine, while rimcazole partially reduced
schizophrenic symptoms in a majority of patients in
open-label trials.
σ Receptors are distributed in the cortex and the
nucleus accumbens more so than in the striatum.28
XJ 448,25,26 which binds to σ receptor with high affinity
and selectvity, modulated dopamine turn vein the rat
frontal cortex and strongly blocked behavior induced by
apomorphine in mice and by 2-(1-piperazinyl)quinoline
In addition to the relationship between σ receptor and
schizophrenia, the molecular properties and signaling
mechanisms mediated through σ receptor have not been
fully elucidated, although a recent molecular cloning
technique revealed53,54 that the σ binding protein did
not seem to be related to both cytochrome P-450 and
neuropeptide Y receptor, which has been postulated to
be the σ receptor for long time.55,56
* Address correspondence to Atsuro Nakazato, Ph.D., 1st Labora-
tory, Medicinal Research Laboratories, Taisho Pharmaceutical Co.,
Ltd., 1-403, Yoshino-cho, Ohmiya, Saitama 330-8530, J apan. Tel: 048-
663-1111. Fax: 048-652-7254. E-mail: S10968@ccm.taisho.co.jp.
† Medicinal Research Laboratories.
These ambiguities might be ascribed to the lack of
potent and selective ligands for σ receptor currently
available. To address the physiological and clinical
‡ Pharmaceutical Research Laboratories.
10.1021/jm980212v CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/26/1999

Synthesis of Arylalkoxyphenylalkylamine σ Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1077
Sch em e 1
Sch em e 2a
a
Reagents and conditions: (a) 2-I-PhCH2-CI, K2CO3, KI, DMF
rt; (b) Cu, DMF, heat; (c) NaBH4, THF-MeOH; (d) SOCl2, THF,
DMF; (e) KCN, 18-crown-6, CH3CN; (f) H2SO4, H2O, AcOH, heat;
(g) SOCl2, PhH, heat; (h) HNPr2, Et3N, PhH, 0 °C to rt; (i) LiAlH4,
THF, heat; (j) HBr, AcOH, heat; (k) K2CO3, DMF, rt.
Ch em istr y
The synthetic work is described in two parts: (1)
preparation of 6H- dibenzo[b,d]pyran derivatives 2 and
(2) preparation of arylalkoxyphenylalkylamine deriva-
tives 3.
significance of σ ligands, discovery of potent and selec-
tive σ ligands is important.
In search of discovering σ ligands with high affinity
and selectivity, miscellaneous structures26,29-39 have
been designed, synthesized, and evaluated to date. The
σ ligands have a nitrogen atom and one or two benzene
rings. The nitrogen and benzene ring(s) may be impor-
tant for interaction with σ receptor. Furthermore, it
would seem that the distance between nitrogen and
benzene ring(s) of σ ligands is close to that of dopamine
D2 ligands. Actually, 4-[4-(p-chlorophenyl)-4-hydroxypi-
peridino]-4′-fluorobutyrophenone (haloperidol) has high
affinity for both σ and dopamine D2 receptors. The
structural estimate supports that apomorphine has
affinity for dopamine D2 and σ receptors. However,
apomorphine does not have affinity for σ receptor.40 We
have been interested in the fact that apomorphine has
a more rigid structure than haloperidol and presumed
that σ affinity is influenced by the difference of struc-
tural flexibility between apomorphine and haloperidol.
In light of the presumption, apomorphine has been
modified to flexible compounds containing one nitrogen
atom and two benzene rings: the novel 6H-dibenzo[b,d]-
pyran derivatives 2. The derivatives 2 have more
interesting structures than the known compounds41
modified from apomorphine since derivatives 2 have
been designed to eliminate two bonds of apomorphine
to produce structural flexibility for the nitrogen atom
and to bridge two benzene rings with a -CH2O- bond
to maintain the planar structure (Scheme 1). Deriva-
tives 2a and 2b have been selective for σ receptor over
D2 receptor. Because of the elevated affinity of deriva-
tives 2 (vs 1) for σ receptor, our interest has focused on
arylalkoxyphenylalkylamine derivatives of general for-
mula 3, since derivatives 3 are more released from the
rigid structure of apomorphine than derivatives 2
(Scheme 1). This attempt has led to the discovery that
compound 10g (NE-100) has a high and selective affinity
for σ receptor and has a potent activity in an animal
model when the drug has been given orally.
6H-Diben zo[b,d ]p yr a n Der iva tives. The process of
preparing 6H- dibenzo[b,d]pyran derivatives 2a and 2b
is depicted in Scheme 2. Derivative 2a was derived by
reduction (LiAlH4) of the corresponding amides pre-
pared from carboxylic acid 6 via acyl chlorides. The
carboxylic acid 6 was derived from aldehyde 5 in four
generic steps, which were reduction (LiAlH4), chloro
replacement (SO2Cl2, hexamethylphosphoric triamide),43
cyano substitution (18-crown-6, KCN), followed by hy-
drolysis (H2SO4). The aldehyde 5 was derived by Ull-
mann reaction of 2-bromo-3-(2-iodobenzyloxy)-4-meth-
oxybenzaldehyde, a compound which was prepared by
treatment of 2-bromo-3-hydroxy-4-methoxybenzalde-
hyde 4 with 2-iodobenzylbromide.
Derivative 2b was prepared from 2a by cleavage of
two ether bonds followed by recyclization in the presence
of K2CO3.
Ar yla lk oxyp h en yla lk yla m in e Der iva tives. The
process of preparing phenylalkylamine derivatives 10,
16, 19, 21, 22, and 24-26 (cf. Tables 1 and 2) is depicted
in the generic Schemes 3-7. Various phenylethylamine
derivatives 10 were prepared via the corresponding
phenylacetic acids 8 (Scheme 2). 4-Benzyloxy-3-hy-
droxybenzaldehyde 7aa and 3-hydroxy-4-(2-phenylethoxy)
benzaldehyde 7a b, the required noncommercial starting
materials for this sequence, were prepared from 3,4-
dihydroxybenzaldehyde by treatment with correspond-
ing phenylalkyl bromides in the presence of K2CO3 in
N,N-dimethylformamide (DMF). On the other hand,
esters 7a ′ were provided from commercially available
benzoic acids by acidic esterification (H2SO4/MeOH).
Phenylacetic acids 5 were derived from aldehydes 7a
(method A) or esters 7a ′ (method B) in the five generic
steps of O-phenylalkylation, reduction, chloro replace-
ment, cyano replacement,43 and hydrolysis. In case of
O-2-phenylethylation, 2-phenylethyl bromide required
4 equiv or more to complete etherification. Chloro
replacement, by treatment with thionyl chloride in the
presence of DMF, led to good results, as was the case
in the presence of hexamethylphosphoric triamide.43
Phenylethylamine derivatives 10 were derived by re-
We report here the design, synthesis, structure-
activity relationships (SARs), and biological character-
ization of novel arylalkoxyphenylalkylamine derivatives
3.

1078 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Ta ble 1. Phenylalkylamine Derivatives: Physical Data
Nakazato et al.
no.
X1
X2
-O(CH2)n-Ar
2-OCH2-Ph
3-OCH2-Ph
2-OCH2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
4-O(CH2)2-Ph
4-(O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
m
-NR1R2
N(n-Pr)2
salta methodb mp (°C)
analysisc
d
d
10a 3-MeO
10b 4-MeO
10c 5-Cl
10d 3-MeO
10e 4-MeO
H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Oxa A, C
Oxa A, C
Oxa A, E
HCl A, C
124-126n C22H31NO2‚C2H2O4
126-127n C22H31NO2‚C2H2O4
H
H
H
H
H
H
H
H
H
H
H
H
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
Pyrrg
161-163n C21H28ClNO‚C2H2O4
e
105-107o C23H33NO2‚HCl.0.33H2Oe
137-138p C23H33NO2‚C2H2O4
d
oxa
A, C
10f
5-MeO
HCl A, C
HCl A, C
Oxa A, C
Oxa A, C
Oxa A, D
HCl B, D
HCl B, D
Oxa A, E
Oxa B, D
Oxa A, C
Oxa A, C
Oxa A, D
Oxa A, D
Oxa AC
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, C
Oxa A, E
Oxa A, E
2HCl A, C
2HCl A, C
HCl A, C
Oxa A,C
92-93q
96-97q
C23H33NO2‚HCl‚0.1H2Od
10g 4-MeO
10h 2-MeO
10i
10j
10k 5-F
101 4-Cl
10m 5-Br
10n 3-Cl
10o 3-Br
10p
10q 5-Br
10r
10s
10t
C23H33NO2‚HCld
132-133q C23H33NO2‚C2H2O4
108-110p C23H33NO2‚C2H2O4
d
d
3-MeO
3-F
137-138n C22H30FNO‚C2H2O4
d
85-86r
93-94q
C22H30FNO‚HCl‚0.067C6H5CH3
d
C22H30ClNO‚HCld
160-161p C22H30BrNO‚C2H2O4
152-153n C22H29Cl2NO‚C2H2O4
e
d
5-Cl 2-O(CH2)2-Ph
5-Br 2-O(CH2)2-Ph
d
137-138p C22H29Br2NO‚C2H2O4
d
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-O(CH2)2-Ph
2-O(CH2)3-Ph
2-O(CH2)3-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
4-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
4-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph-F-4
3-O(CH2)2-Ph-Cl-3
3-O(CH2)2-Ph-OMe-4
3-O(CH2)2-Ph-(OMe)2-3,4
3-O(CH2)2-Thi-2f
2-O(CH2)3-Ph
3-O(CH2)3-Ph
3-O(CH2)2-Ph
3-O(CH2)2-Ph
3-O(CH2)2-Ph
3-O(CH2)2Ph
139-141n C22H31NO‚C2H2O4
e
138-139p C23H32BrNO‚C2H2O4
e
5-Cl
140-141p C23H32ClNO‚C2H2O4
3-MeO
4-MeO
126-128q C21H27NO2C2H2O4‚0.1H2Od
140-142p C21H27NO2‚C2H2O4‚0.1H2Od
Pyrrg
e
10u 5-Cl
Pyrrg
171-173n C20H24ClNO‚C2H2O4
10v 3-MeO
10w 4-MeO
10x 5-Cl
10y 3-MeO
10z 4-MeO
10a a 3-MeO
10a b 4-MeO
10a c 5-Cl
10a d 5-Cl
10a e 4-MeO
10a f 5-Cl
10a g 4-PhCH2O H
10a h 3-PhCH2O H
16a 3-MeO
16b 4-MeO
16c 5-Cl
16d 5-Br
16e 5-Cl
16f
16g 5-Cl
16h 5-Cl
16i
19
21a 4-HO
21b 3-HO
22a 5-Cl
22b 4-MeO
22c 4-MeO
22d 4-MeO
22e 4-MeO
Morph
163-165n C21H27NO3‚C2H2O4‚0.1H2Od
d
Morph
158-16n
C21H27NO3‚C2H2O4
d
Morph
181-183n C20H24NO2‚C2H2O4
d
d
d
d
Pipe-Phi
Pipe-Phi
Pipe-Pd-2j
Pipe-Pd-2i
Pipe-Pd-2i
Pipe-Pm-2k
Pipe-Ph-OMe-2l
Pipe-Ph-OMe-2l
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
Pipe-Phi
Pipe-Ph-OMe-2l
Pipe-Pd-2j
Pipe-Pd-2-Me-6m
Pipe-Pm-2k
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
N(n-Pr)2
2- NH2
198-200n C27H32N2O2‚C2H2O4
182-185n C27H32N2O2‚C2H2O4
171-173n C26H31N3O2‚C2H2O4
168-170n C26H31N3O2‚C2H2O4
165-167n C25H28ClN3O‚C2H2O4‚0.1H2Od
d
176-178n C24H27ClN4O‚C2H2O4
172-173s C28H34N2O2‚2HCle
136-138p C27H31ClN2O2‚2HCle
96-98q
C29H37NO2‚HCle
110-111q C29H37NO2‚HCle
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Oxa F, G, C 114-115q C24H35NO2‚C2H2O4‚0.1H2Od
HCl F, G, C 78-79o C24H35NO2‚HCle
d
Oxa F, H
Oxa F,G,D
Oxa F, H
HCl F, H
Oza F, H
Oxa F, H
Oxa F, H
100-102q C23H32ClNO‚C2H2O4
104-105q C23H32BrNO‚C2H2O4‚0.2H2Oe
e
163-165n C27H31ClN2O‚C2H2O4
e
5-Cl
141-143t C28H33ClN2O‚C2H2O4
d
150-152n C26H30ClN3O‚C2H2O4
d
160-162p C27H32ClN3O‚C2H2O4
d
5-Cl
5-Cl
151-153n C25H29ClN4O‚C2H2O4
80-82q
C27H34ClNO‚C2H2O4
d
Oxa
HCl
HCl
I
J
J
124-125q C22H31NO2‚HCle
123-124q C22H31NO2‚HCle
167-168n C22H30ClNO‚C2H2O4
e
Oxa J , K
HCl J , K
Oxa J , K
Oxa J , K
Oxa J , K
HCl J , K
Oxa J , K
Oxa J , K
114-116q C23H32FNO2HCl‚0.33AcOEte
79-80u
C23H32ClNO2‚C2H2O4
d
110-111q C24H35NO3‚C2H2O4‚0.429H2Od
132-134p C25H37NO2‚C2H2O4‚0.1H2Od
22f
4-MeO
96-98q
C21H31SNO2‚HCl‚0.33H2Od
113-114q C24H35NO2‚C2H2O4
d
22g 3-MeO
22h 4-MeO
24
25
26a 4-MeO
26b 4-MeO
26c 4-MeO
2a
82-83p
C24H35NO2‚C2H2O4
d
4-MeO
4-MeO
HCl
HCl
HCl
HCl
L
114-115p C17H21NO2‚HCle
134-1 36p C20H27NO2‚HCle
NH(n-Pr)2
N(n-Pr)(iso-Amy)
N(n-Pr)(n-Hex)
M
M
N
N
134-136p C20H37NO2‚HCl‚0.8H2Oe
oil
oil
C25H39NO2‚HCl‚0.8H2Oe
C26H39NO2‚HCl‚0.2H2Oe
3-O(CH2)2Ph
N(n-Pr)((CH2)3-OH) HCl
HCl
HCl
162-164x C22H29NO2‚HCle
2b
242-244n C21H27NO2‚HCle
a
b
Oxa ) oxalate. Methods A-N are described in the text. c Elemental analyses for all compounds are within (0.4% of the theoretical
values for the indicated formula. Analyses were performed for all elements except O. e Analyses were performed for C, H, N. f 2-Thienyl.
d
g 1-Pyrrolidinyl. 4-Morpholinyl. 1-(4-Phenylpiperazinyl). l-[4-(2-Pyridyl)piperazinyl]. 1-[4-(2-Pyrimidinyl)piperazinyl]. 1-[4-(2-Meth-
h
i
i
k
l
oxyphenyl)piperazinyl]. 1-[4-[2-(6-Methylpyridyl)]piperazinyl]. -xRecrystallization solvents are depicted: nEtOH; oAcOEt-iso-Pr2O; piso-
m
n
PrOH; qAcOEt; toluene; MeOH; AcOEt-n-hexane; uiso-Pr2O; iso-PrOH-AcOEt.
r
s
t
x
duction (method C, LiAlH4; method D, BH3-THF) of the
corresponding amides 9 via acyl chlorides. Derivatives
10 were also prepared from phenylethyl chlorides 11,
which were synthesized from acids 8 in two steps: by
treatment with amines HNR1R2 with or without bases
(K2CO3 or diisopropylethylamine) (method E).

Synthesis of Arylalkoxyphenylalkylamine σ Ligands
Ta ble 2. Phenylalkylamine Derivatives: Biological Data
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1079
no.
X1
X2
-O(CH2)n-Ar
m
-NR1R2
salta
σ IC50 (nM)b
D2 IC50 (nM)b
10a
10b
10c
10d
10e
10f
10g
10h
10i
3-MeO
4-MeO
5-Cl
H
2-OCH2-Ph
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
N(n-Pr)2
Oxa
Oxa
Oxa
HCl
Oxa
HCl
HCl
Oxa
Oxa
Oxa
HCl
HCl
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
2HCl
2HCl
Oxa
HCl
Oxa
Oxa
HCl
Oxa
Oxa
Oxa
Oxa
HCl
HCl
Oxa
HCl
Oxa
Oxa
Oxa
HCl
Oxa
Oxa
HCl
HCl
HCl
HCl
HCl
26
28
>1000
>1000
337
>1000
>1000
791
>1000
>1000
>1000
>1000
>1000
>1000
169
>1000
>1000
436
685
876
>1000
>1000
69
H
H
H
H
H
H
H
H
H
H
H
H
5-Cl
5-Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3-OCH2-Ph
N(n-Pr)2
2-OCH2-Ph
N(n-Pr)2
118
2.7
3-MeO
4-MeO
5-MeO
4-MeO
2-MeO
3-MeO
3-F
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
4-O(CH2)2-Ph
4-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)3-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph
4-O(CH2)2-Ph
2-O(CH2)2-Ph
3-O(CH2)2-Ph-F-4
3-O(CH2)2-Ph-Cl-3
3-O(CH2)2-Ph-OMe-4
3-O(CH2)2-Ph-(OMe)2-3,4
3-O(CH2)2-Thi-2a
3-O(CH2)3-Ph
3-O(CH2)3-Ph
3-O(CH2)2-Ph
3-O(CH2)2-Ph
3-O(CH2)2-Ph
3-O(CH2)2-Ph
3-O(CH2)2-Ph
N(n-Pr)2
N(n-Pr)2
6.6
N(n-Pr)2
7.1
N(n-Pr)2
1.3
N(n-Pr)2
6.8
N(n-Pr)2
12
10j
N(n-Pr)2
22
10k
101
10m
10n
10o
10p
10q
10r
10s
10t
5-F
N(n-Pr)2
13
4-Cl
N(n-Pr)2
18
5-Br
N(n-Pr)2
11
3-Cl
N(n-Pr)2
281
774
15
3-Br
N(n-Pr)2
H
N(n-Pr)2
5-Br
N(n-Pr)2
44
5-Cl
N(n-Pr)2
56
3-MeO
4-MeO
5-Cl
Pyrra
28
Pyrra
107
36
10u
10v
10w
10x
10y
10z
10a a
10a b
10a c
10a d
10a e
10a f
16a
16b
16d
16e
16f
16g
16h
16i
Pyrra
3-MeO
4-MeO
5-Cl
3-MeO
4-MeO
3-MeO
4-MeO
5-Cl
Morpa
373
>1000
308
328
33
>1000
112
>1000
>1000
25
>1000
>1000
163
Morpa
Morpa
Pipe-Pha
Pipe-Pha
Pipe-Pd-2a
Pipe-Pd-2a
Pipe-Pd-2a
Pipe-Pm-2a
Pipe-Ph-OMe-2a
Pipe-Ph-OMe-2a
N(n-Pr)2
66
183
137
295
51
5-Cl
4-MeO
5-Cl
143
11
88
640
13
1.0
11
3-MeO
4-MeO
5-Br
>1000
N(n-Pr)2
950
N(n-Pr)2
438
5-Cl
Pipe-Ph
142
319
118
415
169
26
180
5-Cl
Pipe-Ph-OMe-2a
Pipe-Pd-2a
Pipe-Pd-2-Me-6a
Pipe-Pm-2a
N(n-Pr)2
16
93
5-Cl
5-Cl
293
115
5-Cl
19
5-Cl
>1000
>1000
>1000
112
>1000
>1000
>1000
NTc
21a
21b
22a
22b
22c
22d
22e
22f
22g
22h
24
4-HO
3-HO
5-Cl
N(n-Pr)2
3.1
N(n-Pr)2
25
N(n-Pr)2
7.2
4-MeO
4-MeO
4-MeO
4-MeO
3-MeO
3-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
N(n-Pr)2
1.0
N(n-Pr)2
1.5
N(n-Pr)2
1.0
N(n-Pr)2
67
N(n-Pr)2
9.4
>1000
>1000
>1000
>1000
>1000
680
N(n-Pr)2
1.7
N(n-Pr)2
4.7
NH2
>1000
25
N(n-Pr)
34
26a
26b
26c
2a
N(n-Pr)(iso-Amy)
N(n-Pr)(n-Hex)
N(n-Pr)((CH2)3-OH)
2.9
1.8
619
19
>1000
>1000
>1000
5.1
990
558
>1000
158
2b
apomorphine
BMY14802
>1000
a
b
See Table 1. IC50 values from duplicate determination. c Not tested.
Various phenylpropylamine derivatives 16 were de-
rived from the corresponding ethyl phenylpropionates
13 or phenylpropionic acids 14 with the procedure of
method C, D, or H (Scheme 3). The propionates 13 were
prepared by Horner-Emmons condensation,44 followed
by hydrogenation over PtO2 (method F). The phenyl-
propionic acids 14 derived from the propionate 13 with
generic hydrolysis (NaOH) (method G).
ment, hydrolysis, reduction, chloro substitution, and
treatment with amines HNR1R2 (method I) (Scheme 4),
as shown in Scheme 2.
Hydrogenation of benzyloxy compounds 20 with Pd-
(OH)2/C (method J ) resulted in phenol derivatives 21,
which were treated with arylalkyl halides to afford
derivatives 22 (method K) (Scheme 5).
Scheme 6 depicts synthesis of primary, secondary, and
tertiary amines. Primary amine 24 was provided by
reduction of nitrile 23 with NaBH4 and trifluoroacetic
Phenylbutylamine 19 was prepared from phenylpro-
pyl chloride 17a in five steps, which were cyano replace-

1080 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Nakazato et al.
Sch em e 3a
Sch em e 6a
a
Reagents and conditions: (a) H2, 5% Pd(OH)2/C, MeOH; (b)
K2CO3, Ar(CH2)n-X, DMF. (Method J : a. Method K: b.)
Sch em e 7a
a
Reagents and conditions: (a) K2CO3, Ph(CH2)n-X, DMF, 40-
50 °C, (b) NaBH4, NaOH, THF, H2O, 0 °C to rt; (c) SOCl2, THF,
DMF; (d) KCN, 18-crown-6, CH3CN; (e) KOH, H2O, EtOH, heat;
(f) LiAlH4, THF, 0 °C to rt; (g) SOCl2, PhCH3, 75 °C; (h) HNR1R2,
PhCH3, 0 °C to rt; (i) LiAlH4, THF, heat; (j) BH3-THF, THF, heat;
(k) HNR1R2. (Method A: a-e. Method B: a, f, c-e. Method C: g-i.
Method D: g, h, j. Method E: f, c, k.)
Sch em e 4a
a
Reagents and conditions: (a) NaBH4, TFA, THF, rt to heat;
(b) EtCOCl, Py, CH2Cl2, 0 °C to rt; (c) LiAlH4, THF, heat; (d) R2-
X, K2CO3, DMF. (Method L: a. Method M: b, c. Method N: d.)
piperidine (3-PPP) and at D2 receptors labeled with [3H]-
(-)sulpiride (Table 2), using the procedure described in
the literature.46
Design of σ Liga n d s fr om Ap om or p h in e via 6H-
Diben zo[b,d ]p yr a n Der iva tives 2. 6H-Dibenzo[b,d]-
pyran derivatives 2 were designed to eliminate two
bonds of apomorphine 1 to produce structural flexibility
for the nitrogen atom and to bridge two benzene rings
with a -CH2O- bond to maintain the planar structure
of the two benzene rings. Compounds 2a and 2b bound
with a weak affinity to σ receptor but did not have an
affinity for dopamine D2 receptor. Compound 10b was
designed from 6H-dibenzo[b,d]pyran derivative 2a by
elimination of its biphenyl bond to be more released
from the rigid structure of apomorphine than derivative
2a . Compound 10b had a better affinity and selectivity
for σ receptor than did 6H-dibenzo[b,d]pyran derivatives
2b (20-fold). The dramatic change of σ affinity among
apomorphine, 2b, and 10b might have been yielded by
the difference of structural flexibility. It would seem that
the free energy of the ligand is one of important factors
in forming a stable receptor-ligand complex. However,
at present, the power of computers might not be enough
to analyze the quantitative relationship between free
energy and the receptor-ligand complex. The design
based on the qualitative difference of structural freedom
among ligands may be useful as one of the drug designs.
SARs of Ar yla lk oxyp h en yla lk yla m in e Der iva -
tives: σ Recep tor Affin ity a n d Selectivity. Com-
pounds 10a and 10c, benzyloxy analogues similar to
10b, also had good σ affinity. In light of these results,
the focus of our study was set on the effect of changes
of methylene length (n) on area B and that of substi-
tuted position on area C (Figure 1) in order to search
for the best position of the benzene ring in arylalkoxy-
phenylalkylamine derivatives 3.
a
Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, K2CO3,
EtOH, H2O, 0 °C to rt; (b) H2, PtO2, AcOEt; (c) NaOH, H2O, MeOH;
(d) SOCl2, PhCH3, 75 °C; (e) HNR1R2, PhCH3, 0 °C to rt; (f) LiAlH4,
THF, heat; (g) BH3‚THF, THF, heat; (h) LiAlH4, THF, 0 °C to rt;
(i) SOCl2, THF, DMF; (j) HNR1R2, heat. (Method C: d-f. Method
D: d, e, g. Method F: a, b. Method G: c. Method H: h, i, j.)
Sch em e 5a
a
Reagents and conditions: (a) KCN, 18-crown-6, CH3CN; (b)
KOH, H2O, EtOH, heat; (c) LiAlH4, THF, 0 °C to rt; (d) SOCl2,
THF, DMF, rt, (e) HNR1R1. (Method I: a-e.)
acid45 (method L). Acylation of primary amine 24
resulted in amide, which was reduced to yield secondary
amine 25 (method M). Furthermore, secondary amine
25 generated tertiary amines 26 by treatment with alkyl
halides (method N).
Resu lts a n d Discu ssion
Methylene (n ) 1) of compound 10b was prolonged
to ethylene (n ) 2) or propylene (n ) 3). Corresponding
compounds 10g (NE-100) and 22h had a greater in-
All compounds were examined for affinity at σ sites
labeled with [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)-

Synthesis of Arylalkoxyphenylalkylamine σ Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1081
Ta ble 3. σ Selectivities of 10d , 10g, 16b, and 22a
IC50 (nM)a
no.
σ
D2
D1
PCP
R1
5HT1A
5HT2
8800
10d 2.7 >1000 >1000 >10000 11700 3580
10g 1.3 >1000 >1000 >10000 10800 6460 >10000
16b 1.0
22a 7.2
950 >1000 >10000 14100
112 >1000 >10000 90
373 >10000
289 196
a
IC50 values from duplicate determination.
Ta ble 4. In Vivo Data: Effect for Behavior Induced by
(+)-SKF10047 (in Mice)a
F igu r e 1.
crease in σ affinity (22- and 6-folds) than did benzyloxy
compound 10b. Compounds 10g and 22h also had great
selectivity for σ binding sites over D2 receptors. The
difference in methylene length (n ) 2 and 3) did not
largely influence the affinity and selectivity for σ
binding sites, but the ethylene moiety (n ) 2) was
slightly better than the propylene moiety (10d , 10g,
22a , 10m vs 22g, 22h , 10r , and 10q). The 3-position
on area C was slightly more desirable for the substituted
position of the 2-phenylethoxy group than were the 2-
and 4-positions (10g vs 10d and 10i). The 3-(2-phe-
nylethoxy) group might control the whole conformation
of the molecular-to-yield interaction with σ receptor and/
or keep the benzene ring of 2-phenylethoxy group at a
preferable position to yield a π-π interaction between
the benzene ring and σ receptor.
The effects of several substituents (X1 and X2) and
substituted positions on the central benzene ring (area
C) were investigated next, with fixing of the dipropy-
laminoethyl group in areas D and E. The nonsubstituted
derivative 7p had a low affinity and selectivity for σ
receptor (vs 10g). The introduction of the methoxy group
led to a good affinity and selectivity for σ binding sites
on any substituted position (10d -i, 22g, and 22h vs
10p ). Hydroxy compounds 21a and 21b had a lower σ
binding affinity than the corresponding methoxy com-
pounds 10g and 10i. Halogen-substituted derivatives,
especially hydrogen-disubsutituted derivatives, had a
poor σ affinity and selectivity (10j-10o, 10q, 10r , and
22a vs 10g). In light of these results, high electron
density on the central benzene ring may be important
to produce high affinity and selectivity for σ receptor.
ED25
(µg/kg, po)
64 ( 4%b
>10000
79
6.5
44
235
7600
no.
X1
O-(CH2)n-Ph
m
10a
10b
10d
3-MeO
4-MeO
3-MeO
4-MeO
4-MeO
5-Cl
2-OCH2-Ph
3-OCH2-Ph
2-O(CH2)2Ph
3-O(CH2)2Ph
3-O(CH2)2Ph
2-O(CH2)2Ph
2
2
2
2
3
2
10g (NE-100)
16b
22a
BMY14802
a
b
SKF10047: 30 mg/kg ip. Percent of control, 7a : 10 mg/kg
po.
groups of compound 10g may not be localized, one
propyl group might build the fundamental conformation
to yield σ affinity, and the others elevate σ affinity.
Some derivatives, which had a halogen or methoxy
group on the terminal benzene ring (area A), indicated
the same σ affinity and selectivity as 10g (22b-22d ),
except for twice-substituted derivative 22e. Thienyl
replacement for the phenyl group decreased somewhat
the affinity for σ binding sites (22f vs 10g).
Deta iled Stu d y of σ Selectivity. Four compounds,
10d , 10g, 16b, and 22a , were further examined for
affinity at five receptors (D1: [3H]-7-chloro-8-hydroxy-
3-m et h yl-l-ph en yl-2,3,4,5-t et r a h ydr o-1H -3-ben za -
zepine (SCH-23390), PCP: [3H]-PCP, R1: [3H]-prazosin,
5-HT1A
:
[3H]-hydroxy-2-(di-n-propylamino)tetralin,
5-HT2: [3H]ketanserin) using the procedure described
in the literature46,47 to determine the exact nature of σ
binding selectivity (Table 3). Compounds 10d and 10g
had good selectivity for σ binding sites over D1, D2, PCP,
R1, 5-HTlA, and 5-HT2 receptors. Propylene analogue
16b did not have a higher selectivity for σ binding sites
over the 5HT1A receptor. Chloro compound 22a had a
much poorer σ binding selectivity. The variation of
electron density on the central benzene ring (area C)
influences affinity for R1, 5-HT1A, and 5-HT2 receptors
in addition to D2 receptor.
Prolongation of methylene length to propylene or
butylene on area D did not appreciably affect affinity
for σ binding sites and selectivity for σ sites over D2
receptors (10d , 10g, 22a , 10m vs 16a -16d and 19).
The greatest change of σ binding affinity and selectiv-
ity was recognized by variations of amino moiety on area
E. Replacement of the dipropylamino group by cyclic
amino groups decreased σ affinity (10s-10a f and 16e-
16i) and increased D2 binding affinity (10u , 10x-10a f,
and 16e-16i), a phenomenon notable in piperazine
derivatives (10y-10a f and 16f-16i). On the basis of
10g, substitution of hydrogen atoms or other alkyl
groups for propyl groups on area E was productive. One
propyl group was essential to yield σ affinity at least
(24 vs 25). Both alkyl groups were necessary to retain
the σ affinity of compound 10g (24 and 25 vs 10g), and
length was important for σ binding selectivity (26a and
26b vs 10g). Introduction of the hydrophilic function at
the terminal position of the propyl group decreased σ
affinity (26c). The results propose that two propyl
It has been presented that compound 10g (NE-100)
has potently inhibited [3H]-(+)-N-isopentenylmetazocine
(pentazocine) binding to σ1, receptor (IC50 ) 1.5 ( 0.3
nM) but weakly affected [3H]-N,N′-di-(o-tolyl)guanidine
(DTG) binding to σ2 receptor (IC50 ) 84.6 ( 32.9
nM).48,57
In Vivo Stu d y. (+)-SKF10,047-induced stereotyped
behavior in mice was evaluated for several derivatives
using the procedure described in the literature49,50 to
confirm activity in the case of oral administration (Table
4). Compound 10b did not have activity-concerning
behavior, but compound 10a slightly antagonized the

1082 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Nakazato et al.
Ta ble 5. In Vivo Data: Effect for MAP-Induced
tetramethylsilane as an internal standard. Mass spectra (MS)
were taken on a Simazu/Kratos HV-300. Elemental analyses
were performed using a Perkin-Elmer 240C (for carbon,
hydrogen, and nitrogen) or Yokokawa-Denki IC7000P (for
halogen and sulfur). Analytical thin-layer chromatography was
conducted on precoated silica gel 60 F254 plates (Merck).
Chromatography was performed on silica gel C-200, 100-200
mesh (Wako Pure Chemical), using the solvent systems
(volume ratios) indicated below.
Hyperlocomotion (in Mice)a
% of
control
no.
X1
O-(CH2)n-Ph
m
1-F or m yl-4-m eth oxy-6H-d iben zo[b,d ]p yr a n (5). A mix-
ture of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (4) (106.3
g, 0.46 mol), 2-iodobenzyl chloride (117.6 g, 0.47 mol), K2CO3
(71.0 g, 0.51 mol), and KI (7.64 g, 46 mmol) in N,N-dimeth-
ylformamide (DMF) (800 mL) was stirred at room temperature
for 22 h. After concentration in vacuo, the residue was
partitioned between CH2Cl2 and water. The separated water
layer was extracted with CH2Cl2. The combined organic layer
was dried (Na2SO4), concentrated in vacuo, and recrystallized
from MeOH to give 2-bromo-3-(2-iodobenzyloxy)-4-methoxy-
benzaldehyde (198.0 g, 96% yield).
A mixture of 2-bromo-3-(2-iodobenzyloxy)-4-methoxyben-
zaldehyde (197.6 g, 0.44 mol) and powdered copper (201.7 g,
3.17 atom) in DMF (600 mL) was stirred and heated under
reflux for 4 h. To the cooled reaction mixture were added water
and AcOEt followed by filtration through Celite. The separated
organic layer was washed with 1 N HCl, water, and saturated
brine, dried (Na2SO4), and concentrated in vacuo. The residual
semisolid was recrystallized from AcOEt to give 5 (61.0 g, 57%
yield): mp 113-114 °C; IR (KBr) 1672, 1592, 1567, 1301, 1283,
1255, 1220, 1099, 1013 cm-1; MS m/z 240 (M+); 1H NMR
(CDCl3) δ 3.99 (3 H, s, CH3O), 5.13 (2 H, s, CH2O), 6.99 (1 H,
d, J ) 8.6 Hz, ArH), 7.30-7.48 (4 H, m, ArH), 7.73 (1 H, d, J
) 8.6 Hz, ArH), 10.27 (1 H, s, CHO).
1-Hydr oxyca r bon ylm eth yl-4-m eth oxy-6H-d iben zo[b,d ]-
p yr a n (6). To a solution of 1-formyl-4-methoxy-6H-dibenzo-
[b,d]pyran (5) (41.24 g, 171.6 mmol) in a mixture of tetrahy-
drofuran (THF) (400 mL) and MeOH (130 mL) was added
NaBH4 (1.79 g, 47.3 mmol) over 10 min followed by 1.5 h of
stirring with ice-cooling. To the solution was added dropwise
1N HCl, followed by extraction with AcOEt. The extract was
washed with saturated brine, dried (MgSO4), and concentrated
in vacuo to give crude 1-hydroxymethyl-4-methoxy-6H-diben-
zo[b,d]pyran, which was carried on to the next step.
To a solution of the crude 1-hydroxymethyl-4-methoxy-6H-
dibenzo[b,d]pyran in a mixture of THF (300 mL) and hexam-
ethyl phosphoric amide (HMPA) (60 mL) was added thionyl
chloride (18.8 mL, 30.7 g, 258 mmol) at room temperature,
and the mixture was stirred for 1.5 h. The concentrated
reaction mixture was partitioned between AcOEt and water.
The separated organic layer was washed with saturated
NaHCO3 and saturated brine, dried (MgSO4), and concentrated
in vacuo to yield crude 1-chloromethyl-4-methoxy-6H-dibenzo-
[b,d]pyran, which was carried on to the next step.
To a solution of the crude 1-chloromethyl-4-methoxy-6H-
dibenzo[b,d]pyran in CH3CN (600 mL) was added 18-crown-6
(4.54 g, 17.2 mmol) and KCN (22.36 g, 343.4 mmol), and the
mixture was stirred for 1 day at room temperature. The
concentrated reaction mixture was partitioned between AcOEt
and water. The separated organic layer was washed with
saturated NaHCO3 and saturated brine, dried (MgSO4), con-
centrated in vacuo, and recrystallized from AcOEt to give
1-cyanomethyl-4-methoxy-6H-dibenzo[b,d]pyran (32.05 g, 74%
yield): mp 131-132 °C; IR (KBr) 2246, 1505, 1417, 1277, 1268,
1139, 1102, 1016 cm-1; MS m/z 251 (M+); 1H NMR (DMSO-d6)
δ 3.82 (3 H, s, CH3O), 4.32 (2 H, s, CH2CN), 4.96 (2 H, s, CH2O),
7.06 (1 H, d, J ) 8.5 Hz, ArH), 7.15 (1H, d, J ) 8.5 Hz, ArH),
7.38-7.53 (3 H, m, ArH), 7.69 (1 H, br d, J ) 7.6 Hz, ArH).
A solution of 1-cyanomethyl-4-methoxy-6H-dibenzo[b,d]py-
ran (20.00 g) in a mixture of acetic acid (400 mL), sulfuric acid
(40 mL), and water (120 mL) was heated at reflux for 20 h
followed by concentrated in vacuo. The residue was poured
onto ice. The resultant precipitate was collected by filtration
and recrystallized from AcOEt to give 6 as a colorless crystal
(18.28 g, 85% yield): mp 142-143 °C; IR (KBr) 1691, 1479,
10g (NE-100) (10 mg/kg, ip) 4-MeO 3-O(CH2)2Ph
2
2
3
119 ( 18
98 ( 10
99 ( 10
7.3 ( 3.0
10d (10 mg/kg, ip)
16b (10 mg/kg, ip)
3-MeO 2-O(CH2)2Ph
4-MeO 3-O(CH2)2Ph
haloperidol (0.5 mg/kg, ip)
a
MAP ) methamphetamine: 1 mg/kg, ip. n ) 6.
effects of (+)-SKF10,047. Compound 10g (NE-100), a
compound in which the benzyl group of compound 10b
was replaced by a phenylethyl group, antagonized the
stereotyped behavior induced by (+)-SKF10,047 (1,160-
fold, vs BMY14802). Other compounds, namely 10d ,
16b, and 22a , had some oral activity, as compared to
BMY14802. The order of potency of (+)-SKF 10,047-
induced stereotyped behavior was 10g (NE-100) > 16b
> 10d > 22a > BMY14802 > 10a > 10b. It seems that
the remarkable effect of NE-100, compared with that
of 10d , 16b, and 22a , depends on the enteral absorption
and/or metabolic stability.
Compounds 10g (NE-100), 10d , and 16a had no
effects on the hyperlocomotion induced by methamphet-
amine in mice (Table 5), in agreement with data of in
vitro evaluation.
It has been presented that compound 10g (NE-100)
has been orally active in inhibiting the (+)-SKF10,047-
or PCP-induced head-weaving behavior in rats,51,57 PCP-
induced ataxia or decreased attention in rhesus mon-
keys,52,57 and PCP-induced ataxia or head-weaving
behavior in dogs.54,57 In light of this evidence, compound
10g (NE-100) may have antipsychotic activity and may
not have induced the extrapyramidal symptoms and
tardive dyskineasia caused by ingestion of typical an-
tipsychotics.
Con clu sion s
Arylalkoxyphenylalkylamine derivatives 3 have been
designed from 6H-dibenzo[b,d]pyran derivatives 2, based
on the relationship of σ affinity and structural flexibility
between apomorphine 1 and 6H-dibenzo[b,d]pyran de-
rivatives 2. It is proposed that the design based on the
qualitative difference of structural freedom among
ligands may be useful as one of drug designs.
N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxyl)phenyl]-
ethylamine hydrochloride 10g (NE-100), the best com-
pound among arylalkoxyphenylalkylamine derivatives
3, is a potent and selective ligand of the central σ1
binding sites. Compound 10g might be useful to address
the physiological and clinical significance of σ ligands.
Phase II clinical studies with compound 10g are in
progress.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Yanaco
MP-500D melting point apparatus and are uncorrected. In-
frared (IR) spectra were obtained on a Perkin-Elmer 1760
spectrometer. Proton nuclear magnetic resonance (NMR)
spectra were obtained using a Varian VXR-200 spectrometer.
Chemical shifts are reported in parts per million relative to

Synthesis of Arylalkoxyphenylalkylamine σ Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1083
1418, 1270, 1223, 1139, 1106, 1022 cm-1; MS m/z 270 (M+);
1H NMR (CDCl3) δ 3.91 (3 H, s, CH3O), 4.00 (2 H, s, CH2CN),
5.01 (2 H, s, CH2O), 6.89 (1 H, d, J ) 8.5 Hz, ArH), 7.02 (1 H,
d, J ) 8.5 Hz, ArH), 7.26-7.41 (3 H,m, ArH), 7.36 (1 H, m,
ArH).
7.04 (1 H, d, J ) 8.3 Hz, ArH), 7.38-7.47 (7 H, m, ArH), 9.34
(1 H, s, CHO).
3-Hyd r oxy-4-(2-p h en yleth oxy)ben za ld eh yd e (7a b). A
mixture of 3,4-dihydroxybenzaldehyde (11.65 g, 84.3 mmol),
2-phenylethyl bromide (46.83 g, 253 mmol), and K2CO3 (34.97
g 253 mmol) in DMF (55 mL) was stirred at room temperature
for 48 h. After the inorganic powder was filtered off through
Celite, the filtrate was concentrated in vacuo. To the residue
was added water and concentrated HCl to acidify the mixture,
followed by extraction with AcOEt (100 mL × 2). The combined
organic layers were dried (MgSO4), filtered, and concentrated
in vacuo. Chromatography of the residue (hexanes/AcOEt 3:1)
gave 7a b as a pale yellow oil (6.49 g, 32% yield): IR (neat)
1-(2-Dip r op yla m in oeth yl)-4-m eth oxy-6H-d iben zo[b,d ]-
p yr a n Hyd r och lor id e (2a ). A suspension of 1-hydroxycar-
bonylmethyl-4-methoxy-6H-dibenzo[b,d]pyran (6) (780 mg,
2.87 mmol) and thionyl chloride (0.42 mL, 685 mg, 5.76 mmol)
in benzene was heated at reflux for 30 min followed by
concentrated in vacuo.
A solution of the above residue in benzene (10 mL) was
added dropwise to a solution of Et3N (321 mg, 3.17 mmol) and
dipropylamine (321 mg, 3.17 mmol) while being stirred and
cooled in an ice bath. After being stirred for 1.5 h at room
temperature, the reaction mixture was washed with 1 N HCl,
saturated NaHCO3, and saturated brine, dried (MgSO4), and
concentrated in vacuo to give crude amide.
1
3398 (br), 1682, 1616, 1586, 1510 cm-1; MS m/z 242 (M+); H
NMR (CDCl3) δ 3.17 (2 H, t, J ) 6.8 Hz, CH2Ph), 4.36 (2 H, t,
J ) 6.8 Hz, CH2O), 5.62 (1 H, br s, exchangeable with D2O,
HO), 6.96 (1 H, d, J ) 8.1 Hz, ArH), 7.23-7.42 (7 H, m, ArH),
9.83 (1 H, s, CHO).
Meth od A: 4-Meth oxy-3-(2-p h en yleth oxy)p h en yla cetic
Acid (8a ). A mixture of isovanillin (152.1 g, 1.00 mol),
2-phenylethyl bromide (615.0 mL, 836.3 g, 4.52 mol), and K2-
CO3 (656.5 g, 4.75 mol) in DMF (760 mL) was stirred and
warmed at 40-50 °C for 5 h. The solvent was removed in
vacuo, and then to the residue were added water (2.0 L) and
hexanes (750 mL). After the resulting mixture (three phases)
was vigorously stirred and cooled in an ice bath for 1.5 h, the
precipitated crystal was collected by filtration, washed with
several portions of water and cold hexanes, and then air-dried
at room temperature to yield 4-methoxy-3-(2- phenylethoxy)-
benzaldehyde as a colorless crystal (247.9 g, 97% yield): mp
46-47 °C; IR (KBr) 1688, 1587, 1511 cm-1; MS m/z 256 (M+);
1H NMR (CDCl3) δ 3.19 (2 H, t, J ) 7.5 Hz, CH2Ph), 3.96 (3
H, s, CH3), 4.28 (2 H, t, J ) 7.5 Hz, CH2O), 6.98 (1 H, d, J )
8.2 Hz, ArH), 7.24-7.37 (5 H, m, ArH), 7.40 (1 H, d, J ) 1.8
Hz, ArH), 7.46 (1 H, dd, J ) 1.8, 8.2 Hz, ArH), 9.83 (1 H, s,
CHO).
To the solution of the above aldehyde (247.8 g, 0.97 mol) in
THF (760 mL) was added dropwise a solution of NaBH4 (14.2
g, 0.38 mol) in 0.5 N NaOH solution (71 mL) in portions at a
rate so as to maintain the temperature at 4-10 °C, while being
stirred and cooled in an ice bath. After the mixture was stirred
in the ice bath for 1 h and then at room temperature for 2.5 h,
0.5 N NaOH solution (71 mL) was added to the reaction
mixture. The separated organic layer was washed with satu-
rated brine (200 mL × 3), dried (MgSO4), and filtered to afford
a solution of 4-methoxy-3-(2-phenylethoxy)benzyl alcohol in
THF. To the solution was added DMF (200 mL), and then
thionyl chloride (95.0 mL, 155.0 g, 1.30 mol) was added
dropwise at a rate to keep the temperature below 60 °C while
being stirred. The mixture was stirred at ambient temperature
for 1 h before being concentrated in vacuo. The oily residue
was poured onto ice (500 g) and extracted with AcOEt (750
mL). The extract was washed with saturated brine, dried
(MgSO4), filtered, and concentrated in vacuo to yield 4-meth-
oxy-3-(2-phenylethoxy)benzyl chloride as a dark yellow oil
(259.2 g), which was carried on to the next step.
A mixture of the amide and LiAlH4 (153 mg, 4.03 mmol) in
THF (20 mL) was heated at reflux for 1 h. After the mixture
was cooled in an ice bath, saturated Na2SO4 solution was
added dropwise to the mixture, and the mixture was filtered
through Celite, and concentrated in vacuo. The residue was
chromatographed (CHCl3/MeOH 50:1), treated with 4 N HCl
in AcOEt, and recrystallized from 2-propanol/AcOEt to give
2a as a colorless crystal (557 mg, 51% yield): mp 162-164
°C; IR (KBr) 3436, 2966, 2594, 2423, 1472, 1280, 1144, 1022
1
cm-1; MS m/z 340 (M+); H NMR (DMSO-d6) δ 0.89 (6 H, t, J
) 7.4 Hz, CH3C), 1.53-1.80 (4 H, m, CCH2C), 2.93-3.13 (4 H,
m, NCH2), 3.16-3.34 (2 H, m, CH2), 3.36-3.51 (2 H, m, CH2),
3.79 (3 H, s, CH3O), 4.92 (2 H, s, CH2O), 6.99 (1 H, d, J ) 8.3
Hz, ArH), 7.04 (1 H, d, J ) 8.3 Hz, ArH), 7.33-7.53 (3 H, m,
ArH), 7.79 (1 H, br d, J ) 7.1 Hz, ArH), 10.65 (1 H, br s,
exchangeable with D2O, HCl). Anal. (C22H29NO2‚HCl) C, H,
N.
1-(2-Dip r op yla m in oeth yl)-4-h yd r oxy-6H-d iben zo[b,d ]-
p yr a n Hyd r och lor id e (2b). A solution of 1-(2-dipropylami-
noethyl)-4-methoxy-6H-dibenzo[b,d]pyran hydrochloride (2a )
(1.00g, 2.66 mmol) in 37% HBr in acetic acid (15 mL) was
heated at reflux for 8 h and concentrated in vacuo. A suspen-
sion of the above residue and K2CO3 (1.00g, 7.24 mmol) in DMF
(10 mL) was stirred at room temperature for 1 day and filtered.
The filtrate was concentrated in vacuo, chromatographed
(CHCl3/MeOH 50:1), treated with 4 N HCl in AcOEt, and
recrystallized from EtOH to give 2b as colorless crystals (g,
52% yield): mp 242-244 °C; IR (KBr) 3220, 3150, 2968, 2943,
2666, 1474, 1285, 1096, 1026 cm-1; MS m/z 340 (M+); 1H NMR
(CDMSO-d6) δ 0.89 (6 H, t, J ) 7.0 Hz, CH3C), 1.53-1.78 (4
H, m, CCH2C), 2.93-3.13 (4 H, m, NCH2), 3.13-3.50 (4 H, m,
CH2), 4.90 (2 H, s, CH2O), 6.81 (1 H, d, J ) 8.7 Hz, ArH), 6.92
(1 H, d, J ) 8.7 Hz, ArH), 7.30-7.51 (3 H, m, ArH), 7.78 (1 H,
br d, J ) 8.4 Hz, ArH), 9.18 (1 H, br s, exchangeable with
D2O, HO), 10.59 (1 H, br s, exchangeable with D2O, HCl). Anal.
(C21H27NO2‚HCl) C, H, N.
4-Ben zyloxy-3-h yr oxyben za ld eh yd e (7a a ). A mixture of
3,4-dihydroxybenzaldehyde (27.63 g, 0.22 mol), benzyl bromide
(35.93 g, 0.20 mol), and K2CO3 (30.41 g, 0.22 mol) in DMF (270
mL) was stirred at room temperature for 24 h. The concen-
trated reaction mixture in vacuo was dissolved in water,
acidified with concentrated HCl, and extracted with AcOEt
(200 mL × 2, and then 100 mL). The extract was washed with
0.5 N Na2HPO4 solution (400 mL × 3) to remove 3,4-
dihydroxybenzaldehyde, and then the mixture was extracted
with 1 N NaOH solution (400 mL × 2, and then 200 mL) to
exclude 3,4-dibezyloxybenzaldehyde. To the stirred aqueous
layer with cooling in an ice bath was added dropwise H3PO4
(49.0 g, 0.50 mol), followed by stirring with ice-cooling for 0.5
h. The resultant precipitate was collected by filtration, washed
with several portions of water, dried in vacuo, and recrystal-
lized from AcOEt to afford 7a a as a pale yellow crystal (22.36
g, 49% yield): mp 115-117 °C; IR (KBr) 3203 (br), 1673, 1606,
1578, 1514 cm-1; MS m/z 228 (M+); 1H NMR (CDCl3) δ 5.21 (2
H, s, CH2Ph), 5.80 (1 H, br s, exchangeable with D2O, HO),
A mixture of the above chloride, powdered KCN (97.7 g, 1.5
mol), and 18-crown-6 (13.22 g, 0.05 mol) in acetonitrile (750
mL) was vigorously stirred and heated under reflux for 7 h.
After concentration in vacuo, the residue was partitioned
between AcOEt (750 mL) and water (400 mL). The separated
organic layer was washed with water (100 mL), saturated
NaHCO3 solution (100 mL × 2), and saturated brine (100 mL),
dried (MgSO4), and then concentrated in vacuo to yield
4-methoxy-3-(2-phenylethoxy)phenylacetonitrile as a light brown
oil (247.3 g), which was carried on to the next step.
To the above nitrile was added a solution of KOH (224.4 g,
4.00 mol) in 90% aqueous EtOH, and the resulting solution
was stirred and heated under reflux for 4 h. The solvent was
removed in vacuo, and the residue was dissolved in water (450
mL). To the solution was added dropwise concentrated HCl
(330 mL) while being stirred and cooled in an ice bath, then
extracted with AcOEt (1.0 L). The organic layer was washed
with saturated brine, dried (MgSO4), filtered, concentrated in

1084 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Nakazato et al.
vacuo, and recrystallized from a mixture of toluene (600 mL)
and hexanes (400 mL) to yield 8a as a colorless crystal (217.6
g, 76% yield based on isovanillin): mp 88-89 °C; IR (KBr)
3000 (br), 1723, 1519 cm-1; MS m/z 286 (M+); 1H NMR (CDCl3)
δ 3.15 (2 H, t, J ) 7.6 Hz, CH2Ph), 3.54 (2 H, s, CH2CO), 3.84
(3 H, s, CH3), 4.19 (2 H, t, J ) 7.6 Hz, CH2O), 6.79-6.86 (3 H,
m, ArH), 7.22-7.35 (5 H, m, ArH).
tion of borane THF complex in THF (16 mL, 16 mmol) was
added dropwise to a solution of N,N-dipropyl-[4-chloro-2-(2-
phenylethoxy)phenyl]acetamide, which was derived from 4-chlo-
ro-2-(2-phenylethoxy)phenyl]acetic acid (8b) (1.51 g, 5.20
mmol) using the procedure described in the first and second
steps of method C, in THF (15 mL). The mixture was stirred
and heated under reflux for 2 h. MeOH was added to the
stirred and cooled reaction mixture, and the resulting solution
was concentrated in vacuo. After the residue had been heated
under reflux for 0.5 h with concentrated HCl (15 mL), the
solution was made basic with 40% NaOH solution and then
extracted with AcOEt. The organic layer was washed with
saturated brine, dried (MgSO4), filtered, chromatographed
(hexanes/AcOEt 5:1), treated with 4 N HCl in AcOEt, concen-
trated in vacuo, and then recrystallized from AcOEt to afford
10l as a colorless crystal (1.23 g, 59% yield): mp 93-94 °C;
IR (KBr) 2597, 2531, 2475, 1599, 1496 cm-1; MS m/z 361 (M+
Meth od B: 4-Ch lor o-2-(2-p h en yleth oxy)p h en yla cetic
Acid (8b). Methyl 4-chloro-2-hydroxybenzoate (10.42 g, 55.8
mmol), which was prepared from 4-chloro-2-hydroxybenzoic
acid by treatment with H2SO4 in MeOH, was reacted with
2-phenylethyl bromide (30.50 mL, 41.34 g, 223 mmol) and K2-
CO3 (30.87 g, 223 mmol) in DMF (100 mL), using the procedure
described in the first step of method A. The concentrated
reaction mixture was partitioned between AcOEt and water.
The separated organic layer was washed with water and
saturated brine, dried (MgSO4), filtered, and concentrated in
vacuo. A mixture of the above residue and LiAlH4 (2.12 g, 55.9
mmol) in THF (100 mL) was stirred and cooled in an ice bath
for 2 h. The reaction mixture was quenched with saturated
Na2SO4 solution, filtered through MgSO4 powder, concentrated
in vacuo, and then column chromatographed (hexanes/AcOEt
10:1) to give an intermediate benzyl alcohol derivative as a
colorless oil (12.70 g, 87% yield): IR (neat) 3368 (br), 1598,
1494 cm-1; MS m/z 264 (M+ + 2), 262 (M+); 1H NMR (CDC13)
δ 2.03 (1 H, t, J ) 7.0 Hz, exchangeable with D2O, HO), 3.11
(2 H, t, J ) 7.0 Hz, CH2Ph), 4.21 (2 H, t, J ) 7.0 Hz, CH2O),
4.53 (2 H, d, J ) 7.0 Hz, CH2O), 6.83 (1 H, d, J ) 1.5 Hz,
ArH), 6.89 (1 H, dd, J ) 1.5, 9.5 Hz, ArH), 7.15 (1 H, d, J )
9.5 Hz, ArH), 7.20-7.40 (5 H, m, ArH).
The benzyl alcohol derivative was chlorinated, cyanated, and
hydrolyzed, using the procedure described in the third, fourth,
and fifth steps of method A, before being recrystallized from
toluene to afford 8b as a colorless crystal (82% yield): mp
103.5-104.5 °C; IR (KBr) 2900 (br), 1714, 1703, 1599, 1495
cm-1; MS m/z 292 (M+ + 2), 290 (M+); 1H NMR (CDCl3) δ 3.06
(2 H, J ) 6.7 Hz, CH2Ph), 3.58 (2 H, s, CH2CO), 4.16 (2 H, t,
J ) 6.7 Hz, CH2O), 6.84 (1 H, d, J ) 2.0 Hz, ArH), 6.89 (1 H,
dd, J ) 2.0, 8.0 Hz, ArH), 7.09 (1 H, d, J ) 8.0 Hz, ArH), 7.17-
7.37 (5 H, m, ArH).
Met h od C: N,N-Dip r op yl-2-[4-m et h oxy-3-(2-p h en yl-
et h oxyl)p h en yl]et h yla m in e H yd r och lor id e (10g, NE -
100). A solution of 4-methoxy-3-(2-phenylethoxy)phenylacetic
acid (8a ) (84.0 g, 0.29 mol) and thionyl chloride (43.0 mL, 70.0
g, 0.59 mol) in toluene (420 mL) was stirred and heated at 80
°C for 2 h. After completely removing thionyl chloride in vacuo,
the residue was again dissolved in toluene (120 mL). The
solution was added dropwise to a solution of dipropylamine
(120 mL, 88.6 g, 0.88 mol) in toluene (320 mL) over 1 h, while
being stirred and cooled in an ice bath. After additional stirring
for 18 h at room temperature, the reaction mixture was washed
with water, (100 mL), 1 N HCl solution, saturated NaHCO3
solution, and saturated brine, dried (MgSO4), and filtered, and
the solvent was removed in vacuo to give an oily amide, which
was used for the next step.
1
+ 2), 359 (M+); H NMR (CDCl3) δ 0.95 (6 H, t, J ) 7.3 Hz,
CH3), 1.75 (4 H, m, CH2), 2.74-3.10 (8 H, m, CH2N, CH2Ar),
3.14 (2 H, t, J ) 6.6 Hz, CH2Ph), 4.28 (2 H, t, J ) 6.6 Hz,
CH2O), 6.88 (1 H, d, J ) 2.2 Hz, ArH), 6.90 (1 H, dd, J ) 2.2,
7.9 Hz, ArH), 7.18 (1 H, d, J ) 7.9 Hz, ArH), 7.22-7.38 (5 H,
m, ArH), 12.15 (1 H, br s, exchangeable with D2O, HCl). Anal.
(C22H30ClNO‚HCl) C, H, N, Cl.
Meth od E: 1-[2-[5-Ch lor o-2-(2-p h en yleth oxyl)p h en yl]-
eth yl-4-(2-p yr id yl)p ip er a zin e Oxa la te (10a c). To a solution
of 5-chloro-2-(2-phenylethoxy)phenylacetic acid (8b) (23.23 g,
79.9 mmol) in THF (120 mL) was added LiAlH4 (4.34 g, 114.4
mmol) in small amounts while being stirred and cooled in an
ice bath. After additional stirring for 2 h in an ice bath, the
reaction mixture was quenched with saturated Na2SO4 solu-
tion and then filtered through MgSO4 powder to yield the
solution of alcohol in THF. The solution was treated with
thionyl chloride and DMF in THF, using the procedure
described in the third step of method A, before being column
chromatographed (hexanes/AcOEt 5:1) to yield 2-[5-chloro-2-
(2-phenylethoxyl)phenyl]ethyl chlorides (11a ) as a colorless oil
(18.52 g, 79% yield): IR (neat) 1494 cm-1; MS m/z 298 (M+
+
1
4), 296 (M+ + 2), 294 (M+); H NMR (CDCl3) δ 2.96 (2 H, t, J
) 7.4 Hz, CH2), 3.09 (2 H, t, J ) 6.6 Hz, CH2), 3.52 (2 H, t, J
) 6.6 Hz, CH2), 4.15 (2 H, t, J ) 7.4 Hz, CH2), 6.73 (1 H, d, J
) 8.4 Hz, ArH), 7.09-7.38 (7 H, m, ArH).
A solution of 11a (1.50 g, 5.08 mmol) and 1-(2-pyridyl)-
piperazine (2.32 mL, 2.49 g, 15.3 mmol) in diisopropylethy-
lamine (10 mL) was stirred and heated under reflux for 10 h.
The reaction mixture was concentrated in vacuo, and column
chromatographed (hexanes/AcOEt 5:1) to give the desired free
amine (0.57 g). Treatment of the free amine with oxalic acid
(122 mg, 1.35 mmol) in EtOH and recrystallization from EtOH
gave 10a c as colorless crystal (0.49 g, 19% yield): mp 165-
167 °C; IR (KBr) 2585 (br), 1720, 1595, 1493 cm-1; MS m/z
1
423 (M+ + 2), 421 (M+); H NMR (DMSO-d6) δ 2.75-2.91 (4
H, m, CH2), 2.91-3.03 (4 H, m, CH2), 3.08 (2 H, t, J ) 7.0 Hz,
CH2Ph), 3.60-3.80 (4 H, m, CH2), 4.25 (2 H, t, J ) 7.0 Hz,
CH2O), 6.73 (1 H, dd, J ) 5.0, 8.0 Hz, ArH), 6.94 (1 H, d, J )
8.0 Hz, ArH), 7.04 (1 H, d, J ) 8.0 Hz, ArH), 7.13-7.40 (7 H,
m, ArH), 7.61 (1 H, m, ArH), 8.18 (1 H, dd, J ) 2.5, 5.0 Hz,
ArH). Anal. (C25H28ClN3O‚C2H2O4‚0.1H2O) C, H, N, Cl.
To a suspension of LiAH4 (21.9 g, 0.58 mol) in THF (300
mL) was added dropwise over 0.5 h a solution of the above
amide in THF (120 mL) while being stirred and cooled in an
ice bath. After stirring at room temperature for 0.5 h, the
reaction mixture was stirred and heated under reflux for 3 h.
To the cooled and stirred reaction mixture was cautiously
added saturated Na2SO4 solution to quench. Filtration through
MgSO4 powder, treatment with 4 N HCl in AcOEt (88 mL),
concentration in vacuo, and recrystallization from AcOEt gave
10g (NE-100) as a colorless crystal (89.5 g, 78% yield): mp
99-100 °C; IR (KBr) 2641, 2596, 2538, 1519 cm-1; MS m/z
Meth od F : Eth yl 3-[5-ch lor o-2-(2-p h en yl)eth oxyp h e-
n yl]pr opion ate (13a). A mixture of 5-chloro-2-(2-phenylethoxy)
benzaldehyde (32.0 g, 0.12 mol), triethyl phosphonoacetate
(55.0 g, 0.24 mol) and 6 M K2CO3 solution (40 mL, 0.24 mol)
in EtOH (100 mL) was stirred in an ice bath for 2 h. The
mixture was stirred at room temperature for 15 h followed by
filtration. The obtained light yellow solid was washed with
water and cold diisopropyl ether and carried on to the next
step without further purification.
1
355 (M+) ; H NMR (CDCl3) δ 1.00 (6 H, t, J ) 7.3 Hz, CH3),
1.70-2.02 (4 H, m, CH2), 2.89-3.07 (4 H, m, CH2N), 3.08-
3.24 (6 H, m, CH2Ph, CH2CH2Ar), 3.84 (3 H, s, CH3O), 4.20 (2
H, t, J ) 7.4 Hz, CH2O), 6.72-6.84 (3 H, m, ArH), 7.22-7.37
(5 H, m, ArH), 12.38 (1 H, br s, exchangeable with D2O, HCl).
Anal. (C23H33NO2‚HCl) C, H, N, Cl.
A suspended solution of the above solid and PtO2 (2.45 g)
in AcOEt (200 mL) was stirred under a hydrogen atmosphere
with a reaction check on TLC (hexanes/AcOEt 19:1) to avoid
a yield of ethyl 3-[5-chloro-2-(2-cyclohexyl)ethoxyphenyl]pro-
pionate as a byproduct. Filtration through Celite, concentra-
tion in vacuo, and then column chromatography (hexanes/
AcOEt 30:1) yielded 13a as a colorless oil (30.49 g, 75%
Meth od D: N,N-Dipr opyl-2-[4-ch lor o-2-(2-ph en yleth ox-
yl)p h en yl]eth yla m in e Hyd r och lor id e (10l). A 1.0 M solu-

Synthesis of Arylalkoxyphenylalkylamine σ Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1085
yield): IR (neat) 1734, 1494 cm-1; MS m/ z 334 (M+ + 2), 332
2.5, 8.6 Hz, ArH), 7.23-7.36 (5 H, m, ArH), 11.82 (1 H, br s,
exchangeable with D2O, CO2H). Anal. (C24H34ClNO C2H2O4)
C, H, N, Cl.
1
(M+); H NMR (CDCl3) δ 1.26 (3 H, t, J ) 7.1 Hz, CH3), 2.47
(2 H, t, J ) 7.7 Hz, CH2), 2.85 (2 H, t, J ) 7.7 Hz, CH2), 3.10
(2 H, t, J ) 6.7 Hz, CH2Ph), 4.13 (2 H, q, J ) 7.1 Hz, CH2O),
4.15 (2 H, t, J ) 6.7 Hz, CH2CO2), 6.72 (1 H, d, J ) 9.4 Hz,
ArH), 7.09 (1 H, d, J ) 2.6 Hz, ArH), 7.10 (1 H, dd, J ) 2.6,
9.4 Hz, ArH), 7.19-7.36 (5 H, m, ArH).
Met h od J : N,N-Dip r op yl-2-[4-h yd r oxy-3-(2-p h en yl-
eth oxy)p h en yl]eth yla m in e Hyd r och lor id e (21a ). A sus-
pended solution of free amine, obtained by treatment of 10a g
(6.5 g, 13.9 mmol) with 1 N NaOH solution, and 5% Pd(OH)2/C
(0.65 g) in MeOH (60 mL) was stirred under an atmosphere
of hydrogen. After the theoretical amount of hydrogen had
been taken up, the suspension was filtered through Celite. To
the filtrate was added dropwise 4 N HCl in AcOEt (5.2 mL,
20.8 mmol) while being stirred and cooling in ice bath.
Concentration in vacuo and recrystallization from AcOEt
yielded 21a as a colorless crystal (4.77 g, 91% yield): mp 124-
125 °C; IR (KBr) 3401, 2728, 2655, 2536, 2481, 1599, 1520
cm-1; MS m/z 342 (M+ + 1); 1H NMR (CDCl3) δ 1.00 (6 H, t, J
) 7.4 Hz, CH3), 1.77-1.96 (4 H, m, CH2), 2.90-3.07 (4 H, m,
CH2), 3.08-3.20 (6H, m, CH2), 4.26 (2 H, t, J ) 6.7 Hz, CH2O),
5.50 (1 H, br s, exchangeable with D2O, HO), 6.66 (1 H, dd, J
) 2.0, 8.1 Hz, ArH), 6.79 (1 H, d, J ) 2.0 Hz, ArH), 6.83 (1 H,
d, J ) 8.1 Hz, ArH), 7.21-7.40 (5 H, m, ArH), 12.31 (1H, br s,
exchangeable with D2O, HCl). Anal. (C22H31NO2‚HCl) C, H,
N.
Meth od G: 3-[5-Ch lor o-2-(2-p h en yl)eth oxyp h en yl]p r o-
p ion ic Acid (14a ). A mixture of 13a (16.64 g, 50.0 mmol) and
5 N NaOH solution (20 mL, 100 mmol) in EtOH (100 mL) was
stirred at room temperature for 24 h. After concentration, the
residue was dissolved in H2O and washed with Et2O. To the
water layer was added concentrated HCl for acidification, and
then the mixture was extracted with CH2Cl2. The extract was
washed with saturated brine, dried (MgSO4), filtered and
concentrated in vacuo to give 14a as a colorless oil (14.93 g,
98% yield), which was carried on to the next step: IR (neat)
3300 (br), 1708, 1494 cm-1; MS m/z 306 (M+ + 2), 304 (M+);
1H NMR (CDCl3) δ 2.52 (2 H, t, J ) 7.6 Hz, CH2), 2.85 (2 H,
t, J ) 7.6 Hz, CH2), 3.10 (2 H, t, J ) 6.7 Hz, CH2Ph), 4.16 (2
H, q, J ) 6.7 Hz, CH2O), 6.73 (1 H, d, J ) 9.5 Hz, ArH), 7.11
(1 H, d, J ) 2.5 Hz, ArH), 7.12 (1 H, dd, J ) 2.5, 9.5 Hz, ArH),
7.22-7.35 (5 H, m, ArH).
Meth od H: N,N-Dipr opyl-3-[5-ch lor o-2-(2-ph en yleth ox-
y)p h en yl]p r op yla m in e oxa la t e (16c). Treatment of 13a
(10.76 g, 32.3 mmol) with LiAlH4 (1.84 g, 48.5 mmol) in THF
(100 mL), using the procedure described for the second step
of method B, yielded alcohol as a colorless oil (8.55 g, 91%
yield): IR (neat) 3369 (br), 1596, 1493 cm-1; MS m/z 292 (M+
Meth od K: N,N-Dip r op yl-2-[3-[2-(4-flu or op h en yl)-
et h oxy]-4-m et h oxyp h en yl]et h yla m in e H yd r och lor id e
(22b). N,N-Dipropyl-2-[3-hydroxy-4-methoxyphenyl]ethylamine
hydrochloride (527 mg, 1.83 mmol), which was derived 10b
by hydrogenation using the procedure described in Method J ,
was reacted with 2-(4-fluorophenyl)ethyl chloride (3.49 g, 22.0
mmol), K2CO3 (3.77 g, 27.3 mmol), and KI (28 mg, 0.17 mmol)
in DMF (10 mL) at 60 °C for 54 h. The concentrated reaction
mixture was partitioned between AcOEt and water. The
separated organic layer was washed with 0.5 N NaOH solution
and saturated brine, dried (MgSO4), filtered, chromatographed
(CHCl3/EtOH 20:1), treated with 4 N HCl in AcOEt, and
recrystallized from AcOEt to yield 22b as a colorless crystal
(205 mg, 27% yield): mp 114-116 °C; IR (KBr) 2606, 2530,
2475, 1515 cm-1; MS m/z 374 (M+ + 1); 1H NMR (CDCl3) δ
1.00 (6 H, t, J ) 7.3 Hz, CH3), 1.77-1.98 (4 H, m, CH2), 2.93-
3.04 (4 H, m, CH2), 3.08-3.15 (6 H, m, CH2), 3.83 (3 H, s,
CH3O), 4.18 (2 H, t, J ) 7.1 Hz, CH2O), 6.73-6.84 (3H, m,
ArH), 6.94-7.06 (2 H, m, ArH), 7.22-7.32 (2 H, m, ArH), 12.34
(1 H, br s, exchangeable with D2O, HCl). Anal. (C23H32ClFNO2‚
HCl‚ 0.33AcOEt) C, H, N, Cl, F.
Meth od L: 2-[4-Meth oxy-3-(2-p h en yleth oxy)p h en yl]-
eth yla m in e Hyd r och lor id e (24). TFA (204.0 mL, 301.9 g,
2.65 mol) was added dropwise at such a rate so as to maintain
the gentle reflux to a mixture of NaBH4 (100.0 g, 2.64 mol)
and 4-methoxy-3-(2-phenylethoxy)phenylacetonitrile, which
was derived from isovanillin (201.1 g, 1.32 mol) in four steps
using the procedure described in Method A, in THF (1.0 L)
while being stirred. After the addition was complete, the
reaction mixture was allowed to heat under reflux for 2 h
before cooling in an ice bath. To the cooled mixture was added
dropwise water (100 mL) and concentrated HCl (400 mL), over
1 h, and then warmed at 50 °C for 0.5 h until evolution of
hydrogen was complete. After treatment with 10 N NaOH
solution to basify, the organic layer was separated, washed
with 1 N NaOH solution (100 mL × 2) and saturated brine
(100 mL), dried (Na2SO4), and filtered. To the filtrate was
added concentrated HCl (165 mL) and then concentrated. The
residual solid was recrystallized from 2-propanol (IPA) to give
24 as a colorless crystal (261.5g, 64% yield based on isovan-
1
+ 2), 290 (M+); H NMR (CDCl3) δ 1.59-1.82 (2 H, m, CH2),
1.67 (1H, br s, exchangeable with D2O, HO), 2.60 (2 H, t, J )
7.5 Hz, CH2), 3.09 (2 H,t, J ) 6.5 Hz, CH2Ph), 3.55 (2 H, t, J
) 6.0 Hz, CH2), 4.17 (2 H, t, J ) 6.5 Hz, CH2Ar), 6.74 (1 H, d,
J ) 10.0 Hz, ArH), 7.02-7.15 (2 H, m, ArH), 7.20-7.40 (5 H,
m, ArH).
Treatment of the above alcohol (3.24 g, 11.1 mmol) with
thionyl chloride (1.22 mL, 1.99 g, 16.7 mmol) in a mixture of
THF (25 mL) and DMF (5 mL) using the procedure described
in the third step of method A yielded crude 17a (3.21 g) as a
colorless oil. The crude product was carried on to the next step.
The crude 17a (604 mg) was heated at 80 °C in dipropylamine
(5 mL) for 39 h, and then concentrated in vacuo. Column
chromatography (hexanes/AcOEt 5:1), treatment with oxalic
acid, and then recrystallization from AcOEt gave 16c as a
colorless crystal (380 mg, 52% yield based on the alcohol): mp
100-102 °C; IR (KBr) 2585 (br), 1719, 1632, 1493 cm-1; MS
m/z 375 (M+ + 2), 373 (M+); 1H NMR (CDCl3) δ 0.93 (6 H, t, J
) 7.4 Hz; CH3), 1.50-1.69 (4 H, m, CH2), 1.78-1.93 (2 H, m,
CH2), 2.57 (2 H, t, J ) 7.2 Hz, CH2Ar), 2.78-2.96 (6 H, m,
CH2N), 3.09 (2 H, t, J ) 6.6 Hz, CH2Ph), 4.18 (2 H, t, J ) 6.6
Hz, CH2O), 6.76 (1 H, d, J ) 8.7 Hz, ArH), 7.04 (1 H, d, J )
2.5 Hz, ArH), 7.14 (1 H, dd, J ) 2.5, 8.7 Hz, ArH), 7.21-7.37
(5 H, m, ArH), 11.84 (1 H, br s, exchangeable with D2O, CO2H).
Anal. (C23H32ClNO‚C2H2O4) C, H, N, Cl.
Meth od I: N,N-Dip r op yl-4-[5-ch lor o-2-(2-p h en yleth ox-
y)p h en yl]b u t yla m in e Oxa la t e (19). Oily 4-[5-chloro-2-(2-
phenylethoxy)phenyl]butanol (18) was derived from the crude
17a by cyano replacement, hydrolysis, and reduction described
in method A (4th and 5th steps) and method E (first step) in
66% yield: IR (neat) 3350 (br), 1596, 1494 cm-1; MS m/z 306
(M+ + 2), 304 (M+); 1H NMR (CDCl3) δ 1.40 (1 H, s,
exchangeable with D2O, HO), 1.47-1.68 (4 H, m, CH2), 2.54
(2 H, m, CH2), 3.10 (2 H, t, J ) 6.5 Hz, CH2Ph), 3.59 (2 H, m,
CH2), 4.15 (2 H, t, J ) 6.5 Hz, CH2O), 6.71 (1 H, dd, J ) 4.0,
6.5 Hz, ArH), 7.01-7.40 (7 H, m, ArH).
illin): mp 114-115 °C; IR (KBr) 2958 (br), 1604, 1520 cm-1
;
1
MS m/z 272 (M+ + 1); H NMR (CDCl3) δ 2.92-3.03 (2 H, m,
CH2), 3.03-3.25 (4 H, m, CH2), 3.79 (3 H, s, CH3O), 4.19 (2 H,
t, J ) 7.4 Hz, CH2O), 6.73-6.82 (3H, m, ArH), 7.15-7.34 (5
H, m, ArH), 8.31 (3 H, br s, exchangeable with D2O, NH2, HCl).
Anal. (C17H21NO2‚HCl) C, H, N.
Compound 19 was generated from 18 using the procedure
described in the second and third steps of method H in a 31%
yield as a colorless crystal: mp 80-82 °C (recrystallized from
AcOEt); IR (KBr) 2602 (br), 1720, 1703, 1626, 1490 cm-1; MS
m/z 398 (M+ + 2), 387 (M+); 1H NMR (CDCl3) δ 0.97 (6 H, t, J
) 7.3 Hz, CH3), 1.47-1.74 (8 H, m, CH2), 2.54 (2 H, t, J ) 7.1
Hz, CH2), 2.91-2.95 (6 H, m, CH2N), 3.10 (2 H, t, J ) 6.7 Hz,
CH2Ph), 4.18 (2 H, t, J ) 6.7 Hz, CH2O), 6.75 (1 H, d, J )8.6
Hz, ArH), 7.03 (1 H, d, J ) 2.5 Hz, ArH), 7.11 (1 H, dd, J )
Met h od
M:
N-P r op yl-2-[4-m et h oxy-3-(2-p h en yl-
eth oxy)p h en yl]eth yla m in e Hyd r och lor id e (25). Propionyl
chloride (17.67 g, 135.8 mmol) was added dropwise over 20
min to a solution of 24 (38.00 g, 123.4 mmol) and triethylamine
(27.48 g, 271.6 mmol) in CH2Cl2 (190 mL) while being stirred

1086 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Nakazato et al.
and cooled in an ice bath. After stirring for 12 h at room
temperature, the reaction mixture was concentrated in vacuo
and then partitioned between AcOEt and water. The separated
organic layer was washed with 1 N HCl solution, saturated
NaHCO3 solution, and saturated brine, dried (Na2SO4), fil-
tered, and then concentrated in vacuo to give amide, which
was used for the next step.
Reduction of the above amide with LiAlH4 (10.54 g, 277.7
mmol) in THF (380 mL), treatment with 4 N HCl in AcOEt
(46 mL, 184 mmol), and recrystallization from IPA using the
procedure described in the third step of method C, yielded 25
as a colorless crystal (34.97 g, 81% yield): mp 134-136 °C;
IR (KBr) 2769 (br), 1519 cm-1; MS m/z 314 (M+ + 1); 1H NMR
(CDCl3) δ 0.99 (3 H, t, J ) 7.4 Hz, CH3), 1.87-1.99 (2 H, m,
CH2), 2.80-3.02 (2 H, m, CH2), 3.02-3.28 (6 H, m, CH2), 3.82
(3 H, s, CH3O), 4.17 (2 H, t, J ) 7.4 Hz, CH2O), 6.73-6.81 (3
H, m, ArH), 7.18-7.36 (5 H, m, ArH), 9.73 (2 H, br s,
exchangeable with D2O, NH, HCl). Anal. (C20H27NO2‚HCl) C,
H, N.
Meth od N: N-Hexyl-N-p r op yl-2-[4-m eth oxy-3-(2-p h e-
n yleth oxy)p h en yl]eth yla m in e Hyd r och lor id e (26b). A
mixture of 25 (432 mg, 1.23 mmol), 1-iodohexane (0.92 mL,
1.32 g, 6.23 mmol), and K2CO3 (379 mg, 2.74 mmol) in DMF
(4.5 mL) was stirred at room temperature for 24 h. The
reaction mixture was poured into water, extracted with AcOEt,
washed with 1 N NaOH solution and saturated brine, dried
(MgSO4), filtered, concentrated, column chromatographed
(hexanes/AcOEt 1:1), and then treated with 4 N HCl in AcOEt
to yield 26b as a colorless oil (354 mg, 66% yield): IR (neat)
2439 (br), 1516 cm-1; MS m/e 398 (M+ + 1); 1H NMR (CDCl3)
δ 0.89 (3 H, t, J ) 6.5 Hz, CH3), 1.00 (3 H, t, J ) 7.4 Hz, CH),
1.24-1.37 (6 H, m, CH2), 1.68-1.93 (4 H, m, CH2), 2.92-3.08
(4 H, m, CH2), 3.09-3.20 (6 H, m, CH2), 3.84 (3 H, s, CH3O),
4.20 (2 H, t, J ) 7.5 Hz, CH2O), 6.72-6.84 (3 H, m, ArH), 7.21-
7.38 (5 H, m, ArH), 12.34 (1 H, br s, exchangeable with D2O,
HCl). Anal. (C26H39NO2‚HCl‚0.2H2O) C, H, N.
Ra d ioliga n d Bin d in g Stu d y. Male Wistar rats (200-250
g, J apan SLC, J apan) were decapitated, and the brains were
rapidly removed. The entire brain or striatum (D2 receptor
binding) was homogenized in 20 volumes of 50 mM Tris/HCl
(pH 7.7) buffer (Tris buffer), using a Physcotoron homogenizer.
The homogenate was centrifuged at 50000g for 10 min, and
the pellet was rehomogenized with Tris buffer and recentri-
fuged; this procedure was repeated twice. The final pellet was
resuspended with Tris buffer and was used for radioligand
binding assay.
σ (2 nM [3H]-(+)-3-PPP), D1 (1 nM [3H]-SCH23390), D2 (15
nM [3H]-sulpiride), PCP (5 nM [3H]-PCP), R1 (0.2 nM [3H]-
prazosin), 5-HT1A (0.2 nM [3H]-8-OH-DPAT), and 5-HT2 (5 nM
[3H]-ketanserin) receptor sites were determined according to
the methods of Tanaka et al.46 and Billard et al.47 Briefly, 1
mL of membrane suspension and radiolabeled ligand was
incubated with various concentrations (at least five) of unla-
beled drugs. Incubations were terminated by rapid filtration
through a Whatman GF/B glass fiber filter that had been
soaked for at least 4 h in a solution of 0.5% polyethylenimine
and then washed with Tris buffer. The filter-bound radioactiv-
ity was measured using a liquid scintillation spectrometer. IC50
values from competitive inhibition experiments were deter-
mined using the Marquardt-Levenberg nonlinear curve fitting
procedure of the RS/1 program (BBN Research System)
running on a VAX/VMS system.
Effects on (+) SKF 10,047-In d u ced Ster eotyp ed Beh a v-
ior in Mice.49,50 Male ICR mice (J apan SLC, J apan), 25-30
g, were placed individually into clear acrylic cages (24 m ×
17.5 m × 12 cm) and allowed a minimum of 1 h to acclimatize
to the new environment (10 mice in each group). Then, 30 min
after administration of the vehicle, (+) BMY14802 (po),
phenylalkylamine derivatives (po), and (+) SKF10,047 (30 mg/
kg, ip) were administered. Behavioral rating was begun at 10
min after (+) SKF10,047 injection and studied 5 min thereafter
for 40 min. The rating scale for stereotyped behavior is (0)
control behavior, (1) sniffing, grooming, and rearing, (2)
nondirectional movements, reciprocal forepaw treading, and
sniffing greater than that in rating 1, (3) turning, circling, or
backpedaling behavior, (4) continuous circling, weaving, or
backpedaling behavior, (5) dyskinetic extension and flexion of
limbs, head, and neck. Ten mice for vehicle and each of three
different doses of drugs were used to observe dose-response
reactions. The total score of the control groups was defined as
100%, and the percent of control of each treatment group was
calculated and ED25 values determined.
Effects on Meth a m p h eta m in e (MAP )-In d u ced Hyp er -
locom otion in Mice. Male ICR mice (20-30 g, Charles River,
J apan) were used. We have described the handling procedures
in detail.51
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