New generation dopaminergic agents. 6. Structure-activity relationship studies of a series of 4-(aminoethoxy)indole and 4-(aminoethoxy)indolone derivatives based on the newly discovered 3-hydroxyphenoxyethylamine D2 template

Article abstract of DOI:10.1021/jm990023s

A series of 4-(aminoethoxy)indoles 7 and a related series of 4- (aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D₂(High) and D₂(Low), respectively) of the dopamine (DA) D₂ receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D₂(High) receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D₂(High) affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D₂ agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D₂ partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D₂ agonism or antagonism.

Full text of DOI:10.1021/jm990023s

J . Med. Chem. 1999, 42, 2007-2020
2007
New Gen er a tion Dop a m in er gic Agen ts. 6. Str u ctu r e-Activity Rela tion sh ip
Stu d ies of a Ser ies of 4-(Am in oeth oxy)in d ole a n d 4-(Am in oeth oxy)in d olon e
Der iva tives Ba sed on th e New ly Discover ed 3-Hyd r oxyp h en oxyeth yla m in e D2
Tem p la te
Richard E. Mewshaw,*,† Michael B. Webb,† Karen L. Marquis,§ Georgia B. McGaughey,‡ Xiaojie Shi,§
Theodore Wasik,§ Rosemary Scerni,§ J ulie A. Brennan,§ and Terrance H. Andree§
Global Chemical Sciences and CNS Disorders Departments, Wyeth-Ayerst Research Laboratories, CN 8000,
Princeton, New J ersey 08543-8000
Received J anuary 19, 1999
A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were
synthesized and evaluated for their affinity for both the high- and low-affinity agonist states
High
(D2
and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives
(i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The
High
indolones 8 were observed to have high affinity for the D2
receptor. Comparison of their
previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed
High
the chroman analogues to be more potent, whereas little loss in D2
affinity was observed
when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several
regions of the phenoxyethylamine framework were modified and recognized as potential sites
to modulate the level of intrinsic activity. A conformational analysis was performed and a
putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore
criteria based on the McDermed model. Structure-activity relationships gained from these
studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels.
These agents should be of therapeutic value in treating disorders resulting from hypo- and
hyperdopaminergic activity, without the side effects associated with complete D2 agonism or
antagonism.
Ch a r t 1
In tr od u ction
Ever since the link between psychosis and dopamine
was established over 40 years ago, researchers have
focused on various approaches toward modulating
dopaminergic activity via the dopamine (DA) D2 recep-
tors as a potential means of treating schizophrenia.1
Unfortunately, current antipsychotics which rely on
their ability to completely block the postsynaptic D2
receptors are not efficacious in treating all schizophrenic
patients and cause motor disorders such as extrapy-
ramidal side effects (EPS). Another approach, whose
therapeutic utility is currently being investigated, is
based on identifying D2 agonists which selectively
activate the inhibitory D2 autoreceptors while weakly
antagonizing the postsynaptic D2 receptors.2 In a hy-
poactive dysfunctional state the D2 receptor would be
expected to be supersensitized and therefore be acti-
vated by an agonist of lower intrinsic activity. As such
a D2 partial agonist would theoretically be clinically
effective in treating schizophrenic forms whose etiology
is based on hyperactivity (positive symptoms) or hypo-
activity (negative symptoms).
novel framework unexploited in the dopamine field.
Soon after the discovery of the phenolic prototypes 1-4,
we reported that the angular indole 5 and indol-8-one
6 were potent D2 partial agonists.7 Previously we
reported a conformational analysis which revealed that
the roles of the chroman and benzodioxan rings were
to allow the methylamino and hydrogen bond-donating
groups ready access to the D2 agonist pharmacophore.3,8
Other ring systems such as the benzofuran, benzotet-
Recently work in our laboratories led to the discovery
of several novel scaffolds which can be used to access
the D2 agonist pharmacophore.3-5 Unlike traditionally
designed D2 agonists which exploit the phenethylamine
scaffold,6 phenols 1-4 (Chart 1) embrace a completely
† Medicinal Chemistry.
‡ Structural Biology.
§ CNS Disorders.
10.1021/jm990023s CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/07/1999

2008 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Mewshaw et al.
Sch em e 1a
a
Reagents: (a) DEAD, PPh3, 4-hydroxyindole (method A); (b) NCS, THF (method B); (c) TFAA; (d) TFA; (e) H3PO4, MeOCH2CH2OH
(method C); (f) RCl, DMF (method E); (g) Pd/C, H2 (method D).
rahydrofuran, and tetralin rings were ineffective scaf-
folds for the D2 agonist pharmacophore and led to
compounds of inferior D2 affinity.3,9 Though the phenolic
derivatives 1-4, indole 5, and indolone 6 were structur-
ally similar, quite different profiles in vitro and in vivo
were observed. Comparison of the affinities for the
agonist state (high-affinity state, D2High) of the D2
receptor of 1 (Ki ) 0.2 nM) and 2 (Ki ) 0.4 nM) clearly
revealed that beneficial conformational effects were
imparted by the pyran and dioxan rings when compared
to the more conformationally promiscuous aryloxyeth-
ylamine derivative 4.4 Even so, exploiting the simpler
phenolic template 4 by preparing the indole and in-
dolone analogues (i.e., 7a and 8a , respectively) appeared
to be an appealing strategy toward the discovery of
potentially interesting dopaminergic agents. Any con-
formational restrictions imparted by the proximal pyr-
role and lactam ring systems onto the aminoethoxy side
4-Hydroxyindole was coupled to alcohols 9 and 10 using
Mitsunobu protocol10 to afford the 4-(aminoethoxy)-
indoles 11 and 12. Removal of the Boc group was
achieved with phosphoric acid to afford 7a . Chlorination
using NCS of indoles 11 and 12 led to the 3-chloroin-
doles 13 and 14, which were hydrolyzed with phosphoric
acid in 2-methoxyethanol to produce indolones 8a ,b.
Hydrogenolysis of 8a with 10% palladium on carbon
afforded 8c. Alkylation of 8b provided indolones 8d ,e.
Treatment of 11 with trifluoroacetic anhydride (TFAA)
afforded 15 which upon exposure to TFA provided 7b.
Commercially available 4-chloro-3-nitrophenol could
be converted to the chloroethoxy derivative 16 either
by coupling 2-chloroethanol using Mitsunobu condi-
tions10 or more preferably by reacting either 1,2-bro-
mochloroethane or 1,2-dichloroethane (Scheme 2). Uti-
lization of the Bartoli indole protocol11 allowed for the
conversion of 16 to the 7-chloroindole 18. Treatment of
17 and 18 with the appropriate amines afforded indoles
7c,e. Protection of 7c using TFAA afforded amide 21.
Indole 7e when reacted with an excess of trifluoroacetic
anhydride produced 19, as well as the diacylated
product 20. Chlorination of 19 and 21 led to the
3-chloroindoles (i.e., 23 and 22, respectively). Deprotec-
tion of the trifluoroacetyl group produced indoles 7b,f,j.
Acid hydrolysis of the 3-chloroindoles 7b,f gave the
corresponding indolones 8a ,f.
chain could potentially result in a beneficial effect on
High
D2
affinity. From a synthetic point of view, the
truncated analogues of indole 5 and indolone 6 should
be more readily accessible and chemically versatile. We
now report the syntheses and structure-activity rela-
tionships (SAR) of the two new classes of 4-(aminoeth-
oxy)indole and 4-(aminoethoxy)indolone analogues (7,
8) based on the phenolic template 4.
Ch em istr y
A more expedient route to the 7-chloroindoles and
7-chloroindolones is shown in Scheme 3. Key intermedi-
ate 18 was chlorinated using trichloroisocyanuric acid
Shown in Scheme 1 is the general synthetic route
used to prepare the indoles 7a ,b and indolones 8a -e.

New Generation Dopaminergic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 2009
Sch em e 2a
a
Reagents: (a) DEAD, chloroethanol, PPh3 (method A); (b) ClCH2CH2Cl/or BrCH2CH2Cl, K2CO3, butanone (method G or H); (c)
CH2dCHMgBr; (d) RNH2, DMSO (method I); (e) TFAA; (f) NCS (method B); (g) K2CO3, MeOH/H2O; (h) H3PO4, methoxyethanol (method
C).
Sch em e 3a
a
Reagents: (a) NCS or TCICA (method J or K); (b) NR1R2, DMSO (method I); (c) H3PO4, methoxyethanol (method C).
or NCS to afford 24 which was subsequently converted
to the corresponding 4-(aminoethoxy)indoles and 4-(ami-
noethoxy)indolones.
Shown in Scheme 4 is the general route used to
prepare the 7-fluoroindolones. 4-Fluorophenol was bro-
minated using 2 equiv of bromine to afford 25 in ex-
cellent yield. Attachment of the chloroethenyl side chain
afforded 26 which was subsequently mononitrated.
Exhaustive hydrogenation of 27 led to 28 which was
converted to indolone 29 using the Gassman protocol.12
Removal of the thiomethyl group of 29 using Raney
nickel afforded 30. Target indolones (8s,u -z,a a ,a b,a c)
were prepared by treatment of the appropriate amines
with either 29 or 30.

2010 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Mewshaw et al.
Sch em e 4a
a
Reagents: (a) Br2; (b) Cl(CH2)2Br, K2CO3; (c) HNO3/H2SO4; (d) H2, Pd/C; (e) (i) MeSCH2CO2Et, SO2Cl2, (ii) NEt3, (iii) AcOH; (f) R1R2NH;
(g) Ra/Ni.
P h a r m a cology
presence of high concentrations of GTP measures the
Low
ability of the ligand to bind to the D2
receptor, while
All compounds were evaluated for their affinity to rat
striatal DA D2 receptors using the agonist [3H]quin-
pirole to label the high-affinity state (D2High) and the
antagonist [3H]spiperone plus GTP to label the low-
affinity state (D2Low). Ketanserin (30 nM) was present
in all assays with [3H]spiperone to preclude binding of
spiperone to 5-HT2 receptors. Although [3H]quinpirole
possesses high affinity for D3 receptors, it appears to
be labeling predominantly the D2 high-affinity state in
striatal tissue and may be the ligand of choice for
assessing D2 agonist binding.13,14 Additionally, the
majority of quinpirole binding (>80%) appears to be very
sensitive to inhibition by guanylylimidodiphosphate
(unpublished results). Compounds were also evaluated
for their affinity for the 5-HT1A and R1 receptors using
[3H]-8-OH-DPAT and [3H]prazosin, respectively. Se-
lected compounds were further evaluated for their
binding affinity for the human D2s, D3, and D4.4 recep-
tors, each expressed in CHO cells using the antagonist
ligand [3H]spiperone. The affinities are expressed as Ki
values using the Cheng-Prussoff equation.15
displacement of an agonist, [3H]quinpirole, in the ab-
sence of GTP measures the ligand’s ability to bind to
High
the D2
receptor (KiL ) KiD2Low; KiH ) KiD2High). The
ratio (i.e., KiL/KiH) was shown to be a reliable estimate
of the ligand’s intrinsic activity as determined by other
assays. Selected compounds which displayed impressive
affinity, selectivity, and a ratio predictive of intrinsic
activity between that of talipexole18 (KiL/KiH ) 4663)
and SDZ-208-91119 (KiL/KiH ) 1.13) were subsequently
evaluated in vivo by utilizing the well-established
phenomenon of receptor-mediated feedback inhibition
of the presynaptic neuron.20 Effects in mouse explor-
atory locomotor activity (LMA) were used as a behav-
ioral index of DA autoreceptor activation/postsynaptic
DA agonism; selective activation of DA autoreceptors
results in the inhibition of LMA, while postsynaptic DA
stimulation increases LMA. The pharmacological test
models are described in detail in the Experimental
Section.
Resu lts a n d Discu ssion
The compound’s intrinsic activity was predicted upon
the preferential antagonism of agonist versus antagonist
radioligand binding, based upon a similar method
previously reported by Lahti16 and Wasik.17 The dis-
placement of the antagonist, [3H]spiperone, in the
Str u ctu r e-Activity Rela tion sh ip s. Binding affini-
ties for the D2High, D2Low, 5-HT1A, and R1 receptors for
the 4-(aminoethoxy)indoles 7a -k and 4-(aminoethoxy)-
indolones 8a -z,a a ,a b,a c are reported in Tables 1 and

New Generation Dopaminergic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 2011
Ta ble 1. 4-(Aminoethoxy)indole Derivatives 7
Ki (nM)a,b
High
Low
High
compd
X
Y
R1
R2
D2
D2
5-HT1A
R1
675
60
11.5
8.5
138.5
66
/
ratio (D2Low/D2
)
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
H
H
H
Bzl
Bzl
H
H
H
H
H
H
9.7 ( 1.7
3.0 ( 0.2
5.3 ( 1.3
4.8 ( 1.1
7.4 ( 1.6
7.0 ( 0.2
/
77.1 ( 5.8
50.0 ( 2.4
30.3 ( 2.9
12.3 ( 1.0
/
39.3 ( 0.0
16.6 ( 5.9
14.4 ( 0.0
15.7 ( 0.6
14.4 ( 4.4
19.9 ( 0.0
/
29.8 ( 12.1
59.5 ( 3.3
32.9 ( 2.1
38.4 ( 6.7
/
18
30
0.4
0.5
193
4
6
3
3
2
3
COCF3
H
(CH2)4Ph
(CH2)4Ph
Bzl
Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Bzl
Bzl
4-Cl-Bzl
4-F-Bzl
Bzl
219
/
Me
H
H
H
H
H
H
H
H
/
458
229
97.5
/
0.4
1
1
685
51
7j
7k
7l
COCF3
Cl
2-thiophenemethyl
3-thiophenemethyl
n-Bu
4-MeBzl
4-Ph-Bzl
Ph(CH2)2-
PhCH2-
0% (0.1)
3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
/
/
7m
7n
7o
7p
7q
7r
1c
/
/
/
/
/
/
/
/
/
/
/
/
-CH2-
-CH2-
H
/
/
/
/
/
/
/
/
2-naphthylmethyl
/
/
/
/
0.2 ( 0.02
0.4 ( 0.2
6.7 ( 0.6
3.6 ( 0.1
1.9 ( 0.8
0.14 ( 0.01
3.3 ( 0.8
5.7 ( 3.7
130 ( 0.0
115 ( 14
35.9 ( 4.7
5.9 ( 0.3
22.5
212
254
/
16
14
19
32
18
42
2c
156
3d
4e
/
1782
5291
5f
0.4
8.5 ( 4
24
165 ( 21
6f
a
Ki values are the means of at least two experiments ( SEM (performed in triplicate, determined from nine concentrations). Values
without SEM are for a single determination only. Percentages represent inhibition of binding at the micromolar concentration shown in
parentheses. b The radioligands used were [3H]quinpirole (D2High),[3H]spiperone + GTP (D2Low), [3H]-8-OH-DPAT (5-HT1A), and [3H]prazosin
d
(R1). c Reference 3. Reference 5. e Reference 4. f Reference 7. / Not determined.
2, respectively. A direct comparison of the chroman 1
(Ki ) 0.2 nM) and the corresponding phenoxyethylamine
derivative 4 (Ki ) 3.6 nM) revealed an 18-fold difference
in affinity attributed to the conformational role of the
chroman ring (Table 1). However, when the same
comparison is made between chroman 5 (Ki ) 1.9 nM)
and 7a (Ki ) 9.7 nM), only a 5-fold difference in affinity
was observed, suggesting that the pyrrole moiety may
be having a beneficial conformational effect. Attachment
the 7-OH-(aminomethyl)chroman 1 and its indolone
analogue 6 can mimic each other in terms of hydrogen-
High
bonding capabilities with respect to the D2
receptor,
a conformational effect appears to be the obvious
explanation for the unexpected 17-fold increase in
affinity when comparing the 3-(aminoethoxy)phenol 4
with its indolone counterpart (i.e., 8a ). Apparently the
N-benzylaminoethoxy side chains of 7a and 8a become
progressively more optimized conformationally toward
accessing the D2 agonist pharmacophore when replacing
the phenol with the indole and indolone moieties. A
more detailed analysis of the cause of this effect is
of a chlorine atom at the 7 position of 7a (i.e., 7e) had
High
little effect on D2
affinity; however, an 11-fold loss
in 5-HT1A affinity and a 4-fold increase in R1 receptor
affinity were observed. The benzyl group, identified in
our earlier work3 to be the side chain of choice to induce
D2High selectivity, was again verified to impart selectivity
when comparing 7a to 7c. Incorporation of substituents
discussed below in the molecular modeling studies.
High
A 3-4-fold loss in D2
affinity was observed when
a halogen was placed in the 7-position of 8a (i.e., 8h ,s);
however, selectivity over 5-HT1A receptors improved.
at the 3-position of the indole moiety had only a slight
Attaching substituents to the benzyl group of 8a had
High
High
effect on D2
affinity (7a vs 7b, 7c vs 7d ). In general,
deleterious effects on D2
8u ,v). A loss in D2
affinity (8h vs 8j-m , 8s vs
affinity was observed when
High
no improvement of the profile of 7a was observed from
modifications of its core structure. Upon this observa-
tion, our investigation focused on establishing SAR on
the corresponding 4-(aminoethoxy)indolones 8.
comparing the secondary amines to their corresponding
tertiary amines (8a vs 8d , 8h vs 8i), a trend previously
observed in the chroman series. However, excellent
High
Surprisingly, indolone 8a revealed an even more
striking similarity to its chroman analogue 6 than the
D2
affinity could be achieved by a tertiary amine
when the benzyl group was embedded within a ring
High
above-mentioned indoles (i.e., 7a vs 5) in terms of D2
affinity. As shown in Table 2, virtually identical D2
system (8i vs 8n ,o). Replacement of the benzyl group
High
High
with other various side chains had little effect on D2
affinities were observed between indolone 6 (Ki ) 0.14
nM) and 8a (Ki ) 0.2 nM), suggesting no advantage in
utilizing the chroman ring to constrain the pharma-
cophoric elements (i.e., basic amine and NH of indolone
moiety). Since we had shown in our previous report that
affinity (8h vs 8p -r , 8s vs 8w -a c).
In tr in sic Activity a n d in Vivo Stu d ies. An assess-
ment of intrinsic activity was initially estimated based
on the ability of the compounds of this study to bind to
High
Low
the D2
and D2
affinity states of the D2 receptor.

2012 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Ta ble 2. 4-(Aminoethoxy)indolone Derivatives 8
Mewshaw et al.
Ki (nM)a,b
ratio
High
Low
High
compd
R1
R2
X
D2
D2
5-HT1A
R1
(D2Low/ D2
)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
Bzl
Me
H
H
H
H
Me
Me
H
H
H
Me
H
H
H
H
H
H
H
H
0.21 ( 0.01
2.0 ( 0.2
11.4 ( 1.2
147 ( 75
306 ( 2
276
664
6262
253
1.9
0% (0.1)
2657 ( 52
8% (1)
6564
1448 ( 150
1057
11081
4829
9.5
13.0
11% (0.1)
350
41% (1)
431
134
334
268
54
74
39
65
8
9
17
7
9
11
3
9
3
8
6
2
7
14
8
76
6
6.93 ( 0.02
0.76 ( 0.01
3.1 ( 0.03
0.23 ( 0.04
0.84 ( 0.1
0.41 ( 0.04
2.6 ( 0.7
268 ( 0.0
49.6 ( 0.9
24.1 ( 3.0
2.06 ( 0.11
14.6 ( 3.3
2.8 ( 0.04
23.4 ( 5.3
13.8 ( 1.5
4.1 ( 1.2
Bzl
(CH2)3CO-F-Ph
(CH2)4Ph
n-Bu
Bzl
Bzl
4-F-Bzl
4-Cl-Bzl
4-Me-Bzl
4-Ph-Bzl
(CH2)2Ph
CH2Ph
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-F
F
7-F
7-F
7-F
7-F
7-F
7-F
7-F
7-F
7-F
1.3 ( 0.7
1.4 ( 0.3
1895
1169
H
H
0.64 ( 0.09
17.4 ( 3.9
0.55 ( 0.11
0.44 ( 0.17
6.34 ( 2.6
0.60 ( 0.05
0.24 ( 0.12
0.63 ( 0.17
12.1 ( 1.5
4.8 ( 0.7
5.5 ( 1.0
46.7 ( 4.5
4.27 ( 2.1
2.85 ( 4.83
15.3 ( 0.1
3.94 ( 1.32
3.32 ( 1.23
5.30 ( 1.63
916 ( 46
38% (1)
17% (1)
41% (1)
41% (1)
59% (0.1)
83% (0.1)
535
25% (1)
340
625
(CH2)2
CH2
H
H
H
H
H
H
H
H
H
H
H
CH2
CH2
H
143
85
292
2-naphthyl
2-thiophenemethyl
3-thiophenemethyl
Bzl
5% (0.1)
14% (0.1)
52% (1)
21% (1)
220
2899
154
32% (1)
39% (1)
380
8s
8t
H
8u
8v
8w
8x
8y
8z
8a a
8a b
8a c
4-Ph-Bzl
3-Ph-Bzl
27.4 ( 3.72
3.92 ( 0.26
9.0 ( 0.3
21.8 ( 9.4
17.8 ( 7.6
5.60 ( 2.2
5.02 ( 0.87
16.0 ( 4.2
3.03 ( 0.36
0.93 ( 0.35
0.63 ( 0.10
0.66 ( 0.02
0.84 ( 0.43
0.65 ( 0.15
0.86 ( 0.06
2.08 ( 0.52
0.15 ( 0.07
4
2-naphthyl
2-thiophenemethyl
3-thiophenemethyl
CH2(C6H11
(CH2)2Ph
CH2Ph
121
14
33
21
9
6
7
39% (1)
24% (1)
17% (0.1)
25% (1)
13% (1)
12
)
128
268
26
(CH2)3-3-indolyl
20
a,b
See footnotes of Table 1.
A comparison of the results obtained with the six
standards using the current methodology agrees well
with that reported by Lahti et al.16 According to this
method, a reliable prediction of intrinsic activity be-
tween the range of 100% and 10% can be made based
High
on a compound’s affinity ratio (i.e., KiD2Low/KiD2
)
KiL/KiH).
As shown in Table 1 the 4-(aminoethoxy)indole de-
rivatives 7a -k were all predicted to have low intrinsic
activity (KiL/KiH e 6). Indoles 7h ,i, having halogenated
side chains, were predicted to have the lowest intrinsic
activities (KiL/KiH e 1). Comparing the predicted intrin-
sic activity ratio of 7a (KiL/KiH) ) 4] to its chroman
analogue 5 (KiL/KiH ) 18) suggests the chroman ring
may be playing a role toward increasing both affinity
and intrinsic activity.
F igu r e 1. Dose-response curves for inhibition of spontaneous
locomotor activity for 8a ,d ,h ,j,k ,l,r ,s,a a .
In contrast to the previous comparison between 5 and
7a , removal of the pyran ring of chroman 6 (i.e., 8a )
resulted in a higher predicted intrinsic activity ratio.
Halogenation of the 7-position of 8a (i.e., 8h ,s) again
led to lower intrinsic activity ratios, a trend observed
with the 4-(aminoethoxy)indoles as well as noted in our
previously reported 7-OH-(aminomethyl)chroman SAR
study.3 The introduction of large lipophilic side chains
in place of the simple benzyl side chain also resulted in
lowering the predicted intrinsic activity ratios (i.e., 8a
vs 8e,f). In general, the predicted intrinsic activity ratios
of the 4-(aminoethoxy)indolones 8a -z,a a ,a b ,a c were
observed to be much higher than their corresponding
4-(aminoethoxy)indole congeners 7a -k . Further in vivo
behavioral evaluations were performed on a selected
group of 4-(aminoethoxy)indolones (i.e., 8a ,d ,h ,j-l,r ,
s,a a ).
In vivo behavioral studies in mice revealed that all
compounds reduced spontaneous locomotor activity
(Figure 1). Our previous reports indicated a relationship
between the estimated intrinsic activity and the shape
of the locomotor activity dose-effect curve.3 Compounds
with high intrinsic activity estimates produce dose-
effects curves with an initial phase of reduced activity

New Generation Dopaminergic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 2013
((36), 151 ((66), and 153 ((63) at doses of 0.03, 0.3,
and 3 mg/kg sc, respectively, compared to 1.3 ((1.3)
contralateral rotations following vehicle treatment. In
addition, 8a ,h were tested against apomorphine (1 mg/
kg sc)-induced stereotypic sniffing and climbing behav-
iors in mice. 8h blocked apomorphine-induced climbing
and stereotypy with ED50 values of 0.24 and 0.3 mg/kg
sc, respectively, whereas 8a blocked apomorphine-
induced climbing only with an ED50 of 0.13 mg/kg sc.
Stereotypy was not significantly affected at doses of 8a
up to 3 mg/kg sc. However, 8a (0.03-1 mg/kg sc) failed
to induce apomorphine-like behaviors in mice pretreated
with reserpine (5 mg/kg sc, 20 h) and only weakly
induced stereotypy, but not climbing, in mice treated
with the D1 agonist SKF-38393 (10 mg/kg ip). These
data are in contrast to the effects of the D2 agonist
quinpirole in these assays.22 Together, these data sug-
gest that both 8a ,h are partial agonists, capable of
stimulating postsynaptic dopamine receptors under cer-
tain conditions, with 8h having lower efficacy than 8a .
High
F igu r e 2. Correlation between D2
affinity and in vivo
potency for compounds 8a ,d ,h ,j,k ,l,r ,s,a a .
followed by a second phase where motor activity is less
reduced and returns toward baseline. The initial low-
dose phase presumably is generated by stimulation of
presynaptic dopamine autoreceptors regulating firing
rates and neurotransmitter release from dopaminergic
neurons. The second high-dose phase presumably re-
sults from stimulation of postsynaptic dopamine recep-
tors. The difference in sensitivity to dopamine agonist
effects has been proposed to be related to the high
receptor reserve at presynaptic dopamine receptors with
low receptor occupancy being required to produce maxi-
mal presynaptic responses to high intrinsic activity
agonists.21 Thus, low doses of an agonist preferentially
stimulate presynaptic receptors. This type of dose-effect
curve was observed when 8a ,d were tested, consistent
with the high intrinsic activity ratios shown in Table
2. Several other analogues of 8a , specifically 8h -
l,r ,s,a a , all produced only a single-phase dose-effect
curve (Figure 1). This result is consistent with the low
intrinsic activity ratios observed for all of these ana-
logues (Table 2). Although it cannot be concluded that
these latter compounds fail to stimulate presynaptic
receptors, on the basis of these results, they appear to
have insufficient intrinsic activity to stimulate normo-
sensitive postsynaptic receptors and, therefore, show a
primarily antagonist-like profile. When the ED50 for
hypolocomotor effects of each compound was compared
with the Ki for the D2High, a statistically significant
correlation between receptor affinity and in vivo potency
was observed (Figure 2). The initial phase of hypoloco-
motion was used in the case of 8a ,d for the estimation
of this ED50. Although locomotor activity was reduced
at even higher doses of 8a ,d , as was observed in the
testing of previous compounds with high intrinsic activ-
ity,3 the mechanism for this high dose effect would not
correlate well with in vitro affinity for the D2 receptor.
Compounds 8a ,h were taken into additional assays
to address their in vivo agonist efficacy. In rats with
unilateral lesions of the nigrostriatal dopamine path-
way, direct dopamine agonists stimulate supersensitive
postsynaptic striatal receptors to induce contralateral
rotations. At doses of 0.03 and 0.3 mg/kg sc 8a produced
a mean ((SEM) of 502 ((136) and 363 ((82) contralat-
eral rotations in 60 min compared to a mean of 4 ((4)
contralateral rotations during a predrug control period
of equal length. In contrast, 8h was less effective
producing mean ((SEM) contralateral rotations of 59
Molecu la r Mod elin g Stu d ies. The majority of tra-
ditional D2 agonists have been based on the 3-OH-
phenethylamine moiety whose pharmacophoric require-
ments are represented by the McDermed DA D2 model.23
Recently, our laboratories have discovered several en-
tirely novel frameworks which can be used as scaffolds
to access the D2 agonist pharmacophore. The 7-OH-2-
(aminomethyl)chroman (1) and 7-OH-2-(aminomethyl)-
benzodioxan (2) were observed to have low-energy
conformations which adhered to most of the criteria
outlined by the McDermed D2 model. A comparison of
High
the D2
affinities of the aryloxyethylamine (4) versus
its chroman (1) and benzodioxan (2) analogues clearly
reveal that the pyran and dioxan rings are constraining
the N-benzyl-2-aminomethyl group so that the D2 ago-
nist pharmacophore can be easily accessed from analo-
gous low-energy state conformations.
A Monte Carlo conformational search was performed
on 4 and 8a using the MM3 force field as implemented
in Macromodel 6.0 where all rotatable bonds, angles and
torsions were allowed to move. Ring conformations were
allowed to be flexible. Since the McDermed model
outlines conformations which specifically examine the
basic nitrogen and aryl centroid geometry, the benzyl
substituents were not initially considered in these
calculations. The basic nitrogen was protonated in all
calculations, and a formal charge of 1 was used to ade-
quately reflect the protonation state. An initial Monte
Carlo calculation used 10 000 steps to generate confor-
mations which were not necessarily fully minimized. A
subsequent calculation to determine the local conforma-
tion for each originally generated structure ensured that
all final conformations were fully minimized.
Though the global energy conformation for the des-
benzyl analogue of 8a (i.e., 8c) did not meet the D2
agonist pharmacophore criteria as described by the
McDermed model, a conformation only 0.014 kcal/mol
higher in energy closely abided the requirements of the
D2 agonist pharmacophore (Figure 3). In analogy to
compound 8c, the D2 agonist conformation for the
desbenzyl analogue of 4 (i.e., 4′) was found to be 0.17
kcal/mol higher in energy that its global minimum. The
energy difference of 4′ and 8c between their respective
global minimum conformations suggests that the in-

2014 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Mewshaw et al.
4. Intrinsic activity could be modulated by attachment
of a halogen at the 7-position of both the indoles 7 and
the indolones 8 or by increasing lipophilicity to the side
chain appendage. In vivo studies were observed to
corroborate the predictive activity ratios of several
members of the indolone derivatives. Molecular model-
ing reveals that the indolone ring of 8 was having a
rigidifying effect which allowed easy access to the D2
agonist pharmacophore conformation. Studies in our
laboratories have been focused on expanding our knowl-
edge of the D2 agonist pharmacophore by the identifica-
tion of novel ligands belonging to a new generation of
dopaminergic agents.
F igu r e 3. Putative D2 agonist pharmacophoric conformation
of 8c.
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Thomas-
Hoover melting point apparatus and are uncorrected. 1H NMR
spectra were recorded on a Varian Unity Plus 400, Varian
VXR-300, or Varian XL-200 instrument. Chemical shifts are
reported in δ values (parts per million, ppm) relative to an
internal standard of tetramethylsilane in CDCl3 or DMSO-
d6. Infrared (IR) spectra were recorded on a Mattson Galaxy
Series FT-IR 3000 spectrophotometer and are reported in
reciprocal centimeters (cm-1). Microanalyses were obtained on
a Perkin-Elmer 2400 elemental analyzer. The mass spectra
were determined on a LKB-9000S, Kratos MS 50, or Finnigan
8230 mass spectrometer. Analytical thin-layer chromatography
(TLC) was carried out on precoated plates (silica gel, 60 F-254),
and spots were visualized with UV light and stained either
with an alcohol solution of phosphomolybdic acid or in an
iodine chamber. Where analyses in the tables are indicated
by symbols of the elements, analytical results obtained for
those elements were (0.4% of the theoretical values. Solvents
and reagents were used as purchased.
F igu r e 4. Superposition of 8a and 1 in their putative D2
agonist pharmacophoric conformations.
Ben zyl(2-h yd r oxyeth yl)ca r ba m ic Acid ter t-Bu tyl Es-
ter (9). A solution of N-benzylaminoethanol (4.8 g, 31.9 mmol)
and di-tert-butyl dicarbonate (7.5 g, 34.4 mmol) in anhydrous
THF (30 mL) was stirred at ambient temperature for 18 h.
The solvent was removed and the product purified by flash
chromatography (EtOAc-hexane, 1:1) to afford 8.0 g (99%) of
a thick oil: MS EI m/e 251 (M+); IR (film) 1675, 1690 cm-1
;
1H NMR (CDCl3) δ 1.47 (9H, s), 2.44 (bs, 1H, OH), 3.39 (2H,
bs), 3.70 (2H, bs), 4.48 (2H, bs), 7.22-7.35 (5H, m). Anal.
(C14H21NO3) C, H, N.
Meth yl(2-h yd r oxyeth yl)ca r ba m ic Acid ter t-Bu tyl Es-
ter (10). Using the same general procedure as described above
for 9 utilizing N-methylaminoethanol afforded 10 in 84% yield
as a clear oil: MS m/e 175 (M+); 1H NMR (CDCl3) δ 1.37 (9H,
s), 2.49 (3H, bs), 3.18 (2H, appt, J ) 6.04 Hz), 3.44 (2H, appq,
J ) 11.6, 5.7 Hz), 4.64 (1H, bs, OH). Anal. (C8H17NO3) C, H,
N.
F igu r e 5. Superposition of 8a and 6 in their putative D2
agonist pharmacophoric conformations.
Meth od A. Ben zyl[2-(1H-in d ol-4-yloxy)eth yl]ca r ba m ic
Acid ter t-Bu tyl Ester (11). To a solution of 9 (12.68 g, 50.5
mmol), 4-hydroxyindole (4.48 g, 33.6 mmol), and triphenylphos-
phine (14.1 g, 53.8 mmol) in anhydrous THF (130 mL) was
slowly added a solution of diethyl azidocarboxylate (9.38 g, 53.8
mmol) in THF (15 mL) at room temperature. The reaction was
allowed to stir for 16 h, then the solvent removed, and the
crude product dissolved in ether and diluted with hexanes.
After standing for 30 min, the solid was filtered and the filtrate
concentrated. The product was purified by flash chromatog-
raphy to afford 8.6 g (70%) of a yellow oil: 1H NMR (CDCl3) δ
1.44 and 1.50 (2H, s, rotamers), 3.60 and 3.71 (2H, m,
rotamers), 4.21 and 4.29 (2H, m, rotamers), 4.67 (2H, s), 6.47
(1H, appt, J ) 8.3 Hz), 6.63 (1H, appt, J ) 2.5 Hz), 7.00-7.11
dolone ring of 8c may be imparting a rigidifying effect
allowing 8c easier access than 4′ to the D2 agonist
pharmacophore (compare Ki values for 4 vs 8a : 4, Ki )
3.6 nM vs 8a , Ki ) 0.2 nM). Using the above-mentioned
putative bioactive conformation of 8c as a starting point,
the benzyl side chain was attached (i.e., 8a ) and
minimized to an analogous conformation previously
identified for chroman 1 (Figure 4). Shown in Figure 5
is the superposition of 8a and 6 in their putative D2
agonist pharmacophoric conformations.
(3H, m), 7.23-7.34 (5H, m), 8.27 (1H, bs); IR (film) 1680 cm-1
MS EI m/e 366 (M+). Anal. (C22H26N2O3) C, H, N.
;
Con clu sion s
We have identified two novel classes of D2 partial
agonists (i.e., 7 and 8) which are based on the 3-OH-
phenoxyethylamine template 4. The indolones 8 were
observed to be more potent than their phenolic prototype
Meth yl[2-(1H-in d ol-4-yloxy)eth yl]ca r ba m ic Acid ter t-
Bu tyl Ester (12). Treatment of 10 according to method A
above afforded 12 in 77% yield as a yellow oil: MS EI m/e 290
(M+); HRMS calcd for C16H22N2O3 290.1630, observed 290.1593.

New Generation Dopaminergic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 2015
Meth od B. Ben zyl[2-(3-ch lor o-1H-in d ol-4-yloxy)eth yl]-
ca r ba m ic Acid ter t-Bu tyl Ester (13). To a solution of 11
(6.3 g, 17.2 mmol) in THF (100 mL) was added NCS (2.3 g,
17.2 mmol) in two portions over 1 h. The reaction was allowed
to stir for 18 h and the solvent removed under vacuum. The
mixture was dissolved in ether, and the insoluble solids were
filtered. The solvent was again removed and the product
purified by chromatography (30% EtOAc-hexanes) to afford
5.65 g (82%) of white solid: mp 114-116 °C; 1H NMR (CDCl3)
δ 1.43 and 1.50 (2H, s, rotamers), 3.63 and 3.72 (2H, m,
rotamers), 4.19 and 4.25 (2H, m, rotamers), 4.75 (2H, bs), 6.49
(1H, d, J ) 7.5 Hz), 6.94 (1H, d, J ) 8.1 Hz), 7.04-7.11 (2H,
m), 7.23-7.34 (5H, m), 8.21 (1H, bs); IR (KBr) 1680 cm-1; MS
EI m/e 400/402 (M+). Anal. (C22H25ClN2O3) C, H, N.
N-Ben zyl-2-(1H-in d ol-4-yloxy)eth yla m in e (7a ). The title
compound was prepared from 11 in 26% yield according to
method C. The fumarate salt was prepared in 2-propanol: mp
158-165 °C; 1H NMR (400 MHz, DMSO-d6) δ 3.08 (2H, t, J )
5.6 Hz), 3.97 (2H, s), 4.21 (2H, t, J ) 5.6 Hz), 6.45-6.48 (2H,
m), 6.50 (2H, s), 6.93-7.15 (2H, m), 7.18-7.29 (1H, m), 7.25-
7.31 (1H, m), 7.32-7.38 (2H, m), 7.40-7.45 (2H, m) 11.06 (1H,
s). Anal. (C17H18N2O‚C4H4O4) C, H, N.
Meth od D. 4-Am in oeth oxy-1,3-d ih yd r oin d ol-2-on e (8c).
A mixture of 8a (1.93 g, 6.84 mmol) in absolute EtOH (50 mL)
containing 10% palladium on carbon (400 mg) was shaken in
a Parr hydrogenator for 4 days at room temperature. The cata-
lyst was filtered and washed with MeOH. The solvent was re-
moved under vacuum to afford a light tan solid (1.15 g, 88%):
mp 136-138 °C; MS EI m/e 192 (M+). Anal. (C10H12N2O2) C,
H, N.
Meth od E. 4-(2-Ben zylm eth yla m in oeth oxy)-1,3-d ih y-
d r oin d ol-2-on e (8d ). A mixture of 8b (480 mg, 2.33 mmol),
benzyl chloride (324 mg, 25.6 mmol), and K2CO3 (676 mg, 48.9
mmol) in anhydrous DMF (10 mL) was heated to 85 °C for 2
h, then poured into water (100 mL), and extracted with EtOAc
(2 × 150 mL). The organic layer was dried over anhydrous
MgSO4 and filtered and the solvent removed under vacuum.
The product was chromatographed (5% MeOH-CH2Cl2) to
afford a yellow oil (354 mg, 51%): MS EI m/e 296 (M+). The
fumarate salt was prepared in warm 2-propanol: mp 114-
116 °C. Anal. (C18H20N2O4‚0.5C4H4O4‚0.75H2O) C, H, N.
4-[2-[[4-(4-F lu or op h en yl)-4-oxob u t yl]m et h yla m in o]-
eth oxy]-1,3-d ih yd r oin d ol-2-on e (8e). A mixture of 8b (600
mg, 2.91 mmol), 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-di-
oxolane (1.16 g, 4.76 mmol), and K2CO3 (844 mg, 6.1 mmol) in
anhydrous DMF (12 mL) containing KI (80 mg) was allowed
to react according to method E. Purification by chromatogra-
phy (5% MeOH-CH2Cl2) afforded 800 mg of a red oil: MS EI
m/e 414 (M+); HRMS EI calcd for C23H27N2O4F 414.1955,
observed 414.1911. This material was dissolved in MeOH (25
mL) containing 2 mL of concentrated HCl and allowed to stir
at reflux temperature for 3 h. The reaction mixture was
allowed to cool and the solid filtered to afford a light yellow
solid which was washed with MeOH (5 mL) to afford 415 mg
(55%) of product as the HCl salt: mp 246-248 °C. Anal.
(C21H23FN2O3‚HCl‚0.5H2O) C, H, N.
1-(2-Ch lor oeth oxy)-4-ch lor o-3-n itr oben zen e (16). The
title compound was prepared by reacting 4-chloro-3-nitrophe-
nol with 2-chloroethanol according to method A to afford a
white solid in 93% yield: mp 46-48 °C; MS EI m/e 235, 237,
239 (M+); 1H NMR (400 MHz, DMSO-d6) δ 3.95 (2H, t, J ) 5.2
Hz), 4.36 (2H, t, J ) 5.2 Hz), 7.32 (1H, dd, J ) 3.2, J ) 8.9
Hz), 7.66 (1H, d, J ) 9 Hz), 7.69, (1H, d, J ) 3.2 Hz). Anal.
(C8H7Cl2NO3) C, H, N.
Meth od G. 1-(2-Ch lor oeth oxy)-4-ch lor o-3-n itr oben zen e
(16). To a 2-L three-neck round-bottom flask were added
4-chloro-3-nitrophenol (50 g, 0.29 mol), K2CO3 (100 g, 0.72 mol),
dichloroethane (315 g, 3.2 mol), KI (5 g), and 2-butanone (1
L). The mixture was mechanically stirred and heated to reflux
for 44 h and then allowed to cool to room temperature, and
the solids were filtered. The solvent was evaporated under
vacuum and the oil dissolved in diethyl ether (300 mL) and
washed with 10% sodium hydroxide. The organic layer was
dried over anhydrous MgSO4 and filtered and the solvent
removed under vacuum. The product was dissolved in 1:1 CH2-
Cl2-hexanes and filtered through silica. Upon concentration
54.5 g (78%) of product was afforded as a white solid.
Met h od H . 1-(2-Ch lor oet h oxy)-4-ch lor o-3-n it r ob en -
zen e (16). To a 500-mL three-neck round-bottom flask were
added 4-chloro-3-nitrophenol (10 g, 0.058 mol), K2CO3 (20 g,
0.14 mol), 1-bromo-2-chloroethane (34.5 g, 0.24 mol), and
2-butanone (200 mL). The mixture was mechanically stirred
and heated to reflux for 20 h under nitrogen and then allowed
to cool to room temperature, and the solids were filtered. The
solvent was evaporated under vacuum and the oil dissolved
in diethyl ether (300 mL) and washed with 10% sodium
hydroxide. The organic layer was dried over anhydrous MgSO4
and filtered and the solvent removed under vacuum. The
Met h yl[2-(3-ch lor o-1H -in d ol-4-yloxy)et h yl]ca r b a m ic
Acid ter t-Bu tyl Ester (14). The title compound was prepared
from 12 in 75% yield as a white solid according to method B:
mp 153-154 °C; MS FAB m/z 325 (M+ + H+); HRMS FAB
calcd for
C26H26N2O5 325.1370, observed 325.1375. Anal.
(C16H21ClN2O3) C, H, N.
N-Ben zyl-N-[2-(3-(2,2,2-tr iflu or oeth a n oyl)-1H-in d ol-4-
yloxy)eth yl]ca r ba m ic Acid ter t-Bu tyl Ester (15). To a
solution of 11 (1.85 g, 5.05 mmol) and triethylamine (0.8 mL,
0.6 g, 6 mmol) in anhydrous CH2Cl2 was added trifluoroacetic
acid anhydride (1.1 mL, 1.6 g, 7.8 mmol) over 5 min at room
temperature. The reaction mixture was stirred at room tem-
perature overnight. The reaction was washed twice with water
and then dried over anhydrous MgSO4. Filtration and evapo-
ration of solvent gave 3.38 g of residue. Purification by
chromatography (20% EtOAc-hexanes) gave the title com-
pound as an amorphous light yellow solid: 1.15 g (49%); MS
EI m/e 462 (M+); IR (KBr) 1719, 1744 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 1.33 and 1.38 (2s, 9H, rotamers), 3.50-3.63 (2m,
2H, rotamers), 4.15 (t, 2H, J ) 5.5 Hz), 4.54 (s, 2H), 6.77 (d,
1H, J ) 7.9 Hz), 7.15 (d, 1H, J ) 8.1 Hz), 7.20-7.27 (m, 4H),
7.29-7.35 (m, 2H), 8.32 (s, 1H), 12.58 (s, 1H).
1-[4-(2-Ben zyla m in oeth oxy)-1H-in d ol-3-yl]-2,2,2-tr iflu -
or oeth a n on e (7b). To a solution of 15 (1.1 g, 2.4 mmol) in
CH2Cl2 (60 mL) was added trifluoroacetic acid (TFA) (1.87 g,
16.3 mmol). The reaction mixture was allowed to stir overnight
and poured into an aqueous solution of saturated NaHCO3 (40
mL). The organic layer was dried over anhydrous MgSO4 and
filtered. Evaporation of the solvent followed by purification by
chromatography (CH2Cl2-CH3OH: 96/4) gave the 780 mg
(90%) product as a light tan oil.
To a warm solution of fumaric acid (0.26 g, 2.2 mmol) in
EtOH (15 mL) was added a warm solution of the above product
as a free base in EtOH (15 mL). This mixture was allowed to
stand at room temperature for 2 h and then filtered to give
0.54 g (54%) of the title compound as a white powder: mp >220
°C dec; MS EI m/e 362 (M+); IR (KBr) 1660 cm-1. Anal.
(C19H17F3N2O2‚0.5C4H4O4) C, H, N.
Meth od C. 4-(2-Ben zyla m in oeth oxy)-1,3-d ih yd r oin d ol-
2-on e (8a ). A mixture of 13 (5.4 g, 13.5 mmol) in 2-methoxy-
ethanol (25 mL) containing 85% phosphoric acid (10 mL) was
heated at 100 °C for 1 h. The reaction was allowed to cool and
then basified with 2 N sodium hydroxide and extracted with
CH2Cl2 (2 × 150 mL). The organic layer was dried over
anhydrous MgSO4, filtered, and chromatographed (5% MeOH-
CH2Cl2) to afford 3.28 g (86%) of a grayish white solid: mp
145-146 °C; IR (KBr) 1690 cm-1; 1H NMR (400 MHz, CDCl3)
δ 3.03 (2H, t, J ) 5.3 Hz), 3.44 (2H, s), 3.88 (2H, s), 4.14 (2H,
t, J ) 5.5 Hz), 6.50 (1H, d, J ) 7.7 Hz), 6.56 (1H, d, J ) 8.6
Hz), 7.15 (1H, appt, J ) 8.6 Hz), 7.26-7.35 (5H, m), 7.82 (1H,
bs); MS FAB m/z 383 (M+ + H+). The fumarate salt was
prepared in 2-propanol: mp 220-221 °C. Anal. (C17H18N2O2‚
C4H4O4) C, H, N.
4-(2-Meth yla m in oeth oxy)-1,3-d ih yd r oin d ol-2-on e (8b).
The title compound was prepared from 14 according to method
C in 66% yield as a grayish white solid: mp 153-156 °C; MS
EI m/e 206 (M+); HRMS EI calculated for C11H14N2O2 206.1055,
observed 206.1061. The fumarate salt was prepared in
2-propanol: mp 212-214 °C. Anal. (C11H14N2O2‚C4H4O4) C, H,
N.

2016 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Mewshaw et al.
1
product was dissolved in 1:1 CH2Cl2-hexanes and filtered
through a short pad silica. Upon concentration and stand-
ing 12.9 g (95%) of light yellow crystalline solid was af-
forded.
2-(1H-In d ol-4-yloxy)ch lor oeth a n e (17). The title com-
pound was prepared from 4-hydroxyindole and 2-chloroethanol
in 57% yield according to method A to afford a white solid:
mp 62-63 °C; 1H NMR (CDCl3) δ 3.88 (2H, t, J ) 6.2 Hz),
4.38 (2H, t, J ) 6.2 Hz), 6.52 (1H, d, J ) 7.3 Hz), 6.68 (1H,
app. t, J ) 2.2 Hz), 7.02-7.12 (3H, m), 8.14 (1H, s).
7-Ch lor o-4-(2-ch lor oeth oxy)-1H-in d ole (18). To a solu-
tion of 16 (10.0 g, 42.4 mol) in THF (230 mL) stirred in a cold
bath at -50 to -40 °C was added a solution of vinylmagnesium
bromide (132 mL, 1.0 M, 0.132 mol) in THF over 2 min. After
stirring in the cold bath for 2.5 h, saturated aqueous NH4Cl
(150 mL) was added to the cold solution, and it was removed
from the cold bath. A 1 M HCl solution was added to dissolve
the precipitated solids, and the mixture was stirred for 0.5 h.
The layers were separated, and the aqueous phase was
extracted once with diethyl ether (80 mL). The organic layer
was combined, dried over anhydrous MgSO4, and filtered and
the solvent evaporated to give 15.4 g of a dark oil. Purification
by chromatography (hexanes- CH2Cl2, 2:1) afforded a solid
which was triturated with hexane and filtered to afford 3.51
g (36%) of the product as a yellowish white solid: mp 73-75
°C; MS EI m/e 229/231/233 (M+); 1H NMR (400 MHz, DMSO-
d6) δ 3.99 (t, 2H;, J ) 5.1 Hz), 4.34 (t, 2H, J ) 5.0 Hz), 6.51 (t,
1H, J ) 2.7 Hz), 6.53 (d, 1H, J ) 7.8 Hz), 7.04 (d, 1H, J ) 8.0
Hz), 7.29 (t, 1H, J ) 2.7 Hz), 11.43 (s, 1H). Anal. (C10H9Cl2-
NO) C, H, N.
IR (KBr) 1685, 1699 cm-1; H NMR (400 MHz, CDCl3) δ 3.84
and 4.01 (2t, 2H, J ) 5.0 Hz, J ) 5.3 Hz, rotamers), 4.26 and
4.31 (2t, 2H, J ) 5.5 Hz, J ) 5.0 Hz, rotamers), 4.92 and 5.00
(2s, 2H, rotamers), 6.63 and 6.66 (2d, 1H, J ) 8.8 Hz, J ) 8.8
Hz, rotamers), 7.27-7.42 (m, 6H), 8.04-8.08 (m, 1H), 9.13 (s,
1H). Anal. (C21H15ClF6N2O3) C, H, N.
[2-(1H -In d ol-4-yloxy)et h yl](4-p h en ylb u t yl)t r iflu or o-
a cetyla m id e (21). To a solution of 7c (2.38 g, 7.72 mmol) and
triethylamine (1.56 g, 15.4 mmol) in anhydrous CH2Cl2 (30
mL) at room temperature was slowly added trifluoroacetic
anhydride (2.42 g, 11.6 mmol) over 10 min. The reaction was
stirred for 1 h, then poured into a 1:1 solution of saturated
Na2CO3-water (50 mL), and extracted with CH2Cl2 (2 × 100
mL). The organic layer dried over anhydrous MgSO4 and
filtered and the solvent evaporated. Purification by flash
chromatography (20% EtOAc-hexanes) afforded 1.61 g (52%)
of an off-white solid: mp 70-72 °C; MS m/e 404 (M+); IR (KBr)
3360, 2950, 1725 cm-1
.
[2-(3-Ch lor o-1H-in d ol-4-yloxy)eth yl]-(4-p h en ylbu tyl)-
tr iflu or oa cetyla m id e (22). To a solution of 21 (1.55 g, 3.83
mmol) in anhydrous THF (20 mL) at 5 °C was added NCS (512
mg, 3.83 mmol) in two portions over 30 min. After stirring for
another 45 min the reaction was allowed to warm to room
temperature and stirred for another 3 h. The reaction mixture
was poured into EtOAc (150 mL) and washed with water (60
mL). The organic layer dried over anhydrous MgSO4 and
filtered and the solvent evaporated. Purification using flash
chromatography (20% EtOAc-hexanes) afforded 1.2 g (71%)
of a grayish white solid: mp 113-114 °C; MS m/e 438 (M+).
Anal. (C22H22ClF3N2O2) C, H, N.
Meth od I. [2-(1H-In d ol-4-yloxy)eth yl](4-p h en ylbu tyl)-
a m in e (7c). A solution of the 17 (1.80 g, 9.20 mmol) and
4-phenyl-1-aminobutane (4.12 g, 27.6 mmol) in anhydrous
DMSO (25 mL) was heated to 80 °C for 6 h. The reaction
mixture was poured into water (150 mL) and extracted with
CH2Cl2 (3 × 100 mL). The organic layers were combined, dried
over anhydrous MgSO4, and filtered and the solvent concen-
trated. Purification by flash chromatography (5-10% MeOH-
CH2Cl2) afforded 1.89 g (66%) of a tan oil: MS m/e 308 (M+).
The oxalate salt was prepared in THF: mp 202-204 °C. Anal.
(C20H24N2O‚C2H2O4‚0.5H2O) C, H, N.
N-Ben zyl-N-[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h yl]-
2,2,2-tr iflu or oa ceta m id e (23). The title compound was
prepared from 19 in 82% yield according to method B to afford
a white solid: mp 156-158 °C; MS EI m/e 430/432/434 (M+);
1
IR (KBr) 1680 cm-1; H NMR (400 MHz, CDCl3) δ 3.76 and
3.81 (2t, 2H, J ) 1.3 Hz, J ) 1.4 Hz, rotamers), 4.14 and 4.15
(2t, 2H, J ) 1.5 Hz, J ) 1.6 Hz, rotamers), 4.95 and 4.96 (2s,
2H, rotamers), 6.41 and 6.43 (2d, 1H, J ) 8.4 Hz, J ) 8.7 Hz,
rotamers), 7.095 and 7.097 (2d, 1H, J ) 8.2 Hz, J ) 8.2 Hz,
rotamers), 7.16 (d, 1H, J ) 2.5 Hz), 7.22-7.41 (m, 5H), 8.27-
8.35 (m, 1H). Anal. (C19H15Cl2F3N2O2) C, H, N.
Ben zyl[2-(7-ch lor o-1H-in d ol-4-yloxy)eth yl]a m in e (7e).
The title compound was prepared by reacting 17 with benzyl-
amine according to method I in 86% yield. The fumarate salt
was prepared in 2-propanol as colorless crystals: mp 167-
Meth od J . 3,7-Dich lor o-4-(2-ch lor oeth oxy)-1H-in d ole
(24). To a solution of 18 (4.61 g, 20.0 mmol) in acetonitrile
(100 mL) was added NCS (2.94 g, 2.20 mmol) at room
temperature. The reaction was allowed to stir for 1.5 h, then
poured into water (100 mL), and extracted with CH2Cl2 (200
mL). The organic layer was dried over anhydrous MgSO4 and
filtered, and the solvent was removed under vacuum to afford
a dark solid. Purification by chromatography (CH2Cl2-hex-
anes: 1:2) afforded 4.15 g (78%) as a white solid: mp 106-
107.5 °C; IR (KBr) 3400 cm-1; MS EI m/e 263/265/267/269 (M+);
1H NMR (CDCl3) δ 3.91 (2H, t, J ) 6.2 Hz), 4.33 (2H, t, J )
6.2 Hz), 6.47 (1H, d, J ) 8.4 Hz), 7.08-7.13 (2H, m), 8.26 (1H,
bs, NH). Anal. (C10H8Cl3NO) C, H, N.
Meth od K. 3,7-Dich lor o-4-(2-ch lor oeth oxy)-1H-in d ole
(24). To a solution of 17 (10.0 g, 37.8 mmol) in MeOH (200
mL) under nitrogen containing sodium acetate (6.0 g) and
AcOH (1 mL) was added portionwise trichloroisocyanic acid
(4.0 g, 17.2 mmol) at 2 °C. The reaction temperature was
maintained below 8 °C and the mixture was allowed to stir
for 4 h then diluted with ether (200 mL), and washed with
10% NaOH. The organic layer dried over anhydrous MgSO4
and filtered, and the solvent removed under vacuum to afford
an oil. This material was dissolved in CH2Cl2, filtered over a
short pad of silica and concentrated to afford 10.0 g (87%) a
yellowish white solid.
1
168 °C; H NMR (DMSO-d6) δ 3.01 (2H, t, J ) 5.6 Hz), 3.90
(2H, s), 4.18 (2H, t, J ) 5.6 Hz), 6.49 (1H, d, J ) 8.3 Hz), 6.53
(1H, s), 6.54-6.57 (1H, m), 7.03 (1H, d, J ) 8.3 Hz), 7.22-
7.29 (2H, m), 7.30-7.36 (2H, m), 7.37-7.39 (2H, m), 11.41 (1H,
s); MS EI m/e 300, 302 (M+). Anal. (C17H17ClN2O‚0.5C4H4O4‚
0.25C3H8O) C, H, N.
N-Ben zyl-N-[2-(7-ch lor o-1H-in d ol-4-yloxy)eth yl]-2,2,2-
tr iflu or oa ceta m id e (19) a n d N-Ben zyl-N-[2-(7-ch lor o-3-
t r iflu or oa cet yl-1H -in d ol-4-yloxy)et h yl]-2,2,2-t r iflu or o-
a ceta m id e (20). To a solution of 7e (4.55 g, 15.1 mmol) in
CH2Cl2 (200 mL) at room temperature was added triethyl-
amine (2.15 mL, 1.56 g, 15.4 mmol), followed by the addition
of trifluoroacetic acid anhydride (4.5 mL, 6.7 g, 32 mmol) over
20 min. The solution was stirred at room temperature over-
night and then washed twice with water and dried over
anhydrous MgSO4. Evaporation of the solvent gave 7.33 g of
residue which consisted primarily of the two products. Puri-
fication by chromatography on silica gel with a gradient of
CH2Cl2/hexane/EtOAc (10/80/10, 4/82/14, 0/86/14, 0/80/20) first
afforded 19 as light yellow crystals: 2.79 g (47%); mp 114-
116 °C; MS EI m/e 396 (M+); IR (KBr) 1682 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 3.79 and 3.86 (2t, 2H, J ) 5.6 Hz, J ) 5.0
Hz, rotamers), 4.28 and 4.31 (2t, 2H, J ) 5.6 Hz, J ) 5.0 Hz,
rotamers), 4.89 and 4.93 (2s, 2H, rotamers), 6.38 and 6.40 (2d,
1H, J ) 8.3 Hz, J ) 8.5 Hz, rotamers), 6.64-6.68 (m, 1H),
7.05 and 7.08 (2d, 1H, J ) 8.1 Hz, J ) 8.3 Hz, rotamers); 7.19-
7.44 (m, 6H), 8,42 (s, 1H). Anal. (C19H16ClF3N2O2) C, H, N.
Ben zyl[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h yl]a m in e
(7f). The title compound was prepared in 46% yield by reacting
24 with benzylamine according to the method I: mp 129-130
1
°C; H NMR (DMSO-d6) δ 2.98 (2H, t, J ) 5.5 Hz), 3.85 (2H,
s), 4.14 (2H, t, J ) 5.5 Hz), 6.55 (1H, d, J ) 8.3 Hz), 6.53 (1H,
s), 6.57 (1H, s), 7.11 (1H, d, J ) 8.3 Hz), 7.21-7.26 (1H, m),
7.28-7.37 (1H, m), 7.37-7.39 (2H, m), 7.40 (1H, m), 11.68 (1H,
s); MS m/e 334/336/338 (M+).
20 was then eluted off the column to afford 3.18 g (43%) of
crystalline solid: mp 152-154 °C; MS FAB m/e 493 (MH+);

New Generation Dopaminergic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 2017
N-Meth yl-N-ben zyl[2-(3,7-d ich lor o-1H-in d ol-4-yloxy)-
eth yl]a m in e (7g). The title compound was prepared in 73%
yield by reacting 24 with 4-methylbenzylamine according to
method I: MS EI m/e 348/350/352 (M+). Anal. (C18H18Cl2N2O)
C, H, N.
4-Ch lor ob en zyl[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h -
yl]a m in e (7h ). The title compound was prepared by reacting
24 with 4-chlorobenzylamine in 60% yield according method
I: mp 115-116 °C; MS EI m/e 368/370/372/374 (M+); HRMS
calcd for C17H15N2OCl3 368.024997, observed 368.0215531.
Anal. (C17H15Cl3N2O‚0.25H2O) C, H, N.
4-F lu or ob en zyl[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h -
yl]a m in e (7i). The title compound was prepared by reacting
24 with 4-fluorobenzylamine in 64% yield according to method
I: mp 102.5-103.5 °C; MS EI m/e 352 (M+). Anal. (C17H15Cl2-
FN2O) C, H, N.
[2-(3,7-Dich lor o-1H -in d ol-4-yloxy)et h yl]t h iop h en e-2-
ylm eth yla m in e (7k ). The title compound was prepared in
76% yield by reacting 24 with 2-thiophenemethylamine ac-
cording to method I to afford an orange solid: mp 99-101 °C;
MS EI m/e 340/342/344 (M+). Anal. (C15H14Cl2N2OS) C, H, N.
[2-(3,7-Dich lor o-1H -in d ol-4-yloxy)et h yl]t h iop h en e-3-
ylm eth yla m in e (7l). The title compound was prepared in 70%
yield by reacting 24 with 3-thiophenemethylamine according
to method I to afford a yellow solid: mp 123-125 °C. Anal.
(C15H14Cl2N2OS) C, H, N.
1-Bu t yl[2-(3,7-d ich lor o-1H-in d ol-4-yloxy)et h yl]a m in e
(7m ). The title compound was prepared in 69% yield by
reacting 24 with n-butylamine according to method I to afford
a tan solid: mp 109-111.5 °C. Anal. (C14H18Cl2N2O) C, H, N.
215 °C dec; MS FAB m/e 397 (MH+). Anal. (C19H16ClF3N2O2‚
0.5C4H4O4) C, H, N.
4-[2-(4-P h en ylbu tyla m in o)eth oxy]-1,3-d ih yd r oin d ol-2-
on e (8f). The title compound was prepared from 7d in 91%
yield according method C as a grayish solid: mp 81-83 °C.
The fumarate salt was prepared from 2-propanol: mp 191-
193 °C; MS m/e 324 (M+). Anal. (C20H24N2O2‚C4H4O4‚0.1H2O)
C, H, N.
4-(2-Bu t yla m in oet h oxy)-7-ch lor o-1,3-d ih yd r oin d ol-2-
on e (8g). The title compound was prepared from 7m in 35%
yield according to method C. The fumarate salt was prepared
in EtOH: mp 218-219 °C. Anal. (C14H19ClN2O2‚0.5C4H4O4)
C, H, N.
4-(2-Ben zyla m in oeth oxy)-7-ch lor o-1,3-d ih yd r oin d ol-2-
on e (8h ). The title compound was prepared from 7f in 71%
yield according to method C as a grayish white solid: mp 161-
163 °C. The hemifumarate salt was prepared in EtOH: mp
199-200 °C; MS EI m/e 316/318 (M+). Anal. (C17H17ClN2O2‚
0.5C4H4O4) C, H, N.
4-[2-(N-Ben zyl-N-m et h yla m in o)et h oxy]-7-ch lor o-1,3-
d ih yd r oin d ol-2-on e (8i). The title compound was prepared
from 7g in 82% yield according to method C. The fumarate
salt was prepared in EtOH: mp 153-173 °C. Anal. (C18H19
ClN2O2‚0.5C4H4O4‚0.5H2O) C, H, N.
-
7-Ch lor o-4-[2-(4-flu or oben zyla m in o)]eth oxy]-1,3-d ih y-
d r oin d ol-2-on e (8j). The title compound was prepared from
7i in 82% yield according to method C: mp 148-149.5 °C; MS
EI m/e 334/336. The fumarate salt was prepared in 2-pro-
panol: mp 225-226 °C; MS EI m/e 334 (M+). Anal. (C17H16
ClFN2O6‚0.5H2O‚0.25C3H8O) C, H, N.
-
7-Ch lor o-4-[2-(4-ch lor oben zyla m in o)eth oxy]-1,3-d ih y-
d r oin d ol-2-on e (8k ). The title compound was prepared from
7h in 84% yield according to method C: mp 158-159.5 °C.
The fumarate salt was prepared in EtOH: mp 217-218 °C;
MS EI m/e 350 (M+). Anal. (C17H16Cl2N2O2‚C4H4O4) C, H, N.
7-Ch lor o-4-[2-(4-m et h ylb en zyla m in o)]et h oxy]-1,3-d i-
h yd r oin d ol-2-on e (8l). The title compound was prepared
from 7n in 76% yield according to method C. The fumarate
salt was prepared in EtOH: mp 205-206 °C; MS EI m/e 330
(M+). Anal. (C18H19ClN2O2‚C4H4O4) C, H, N.
4-{2-[(Bip h en yl-4-ylm et h yl)a m in o]et h oxy}-7-ch lor o-
1,3-d ih yd r oin d ol-2-on e (8m ). The title compound was pre-
pared from 7o in 52% yield according to method C. The
fumarate salt was prepared in EtOH: mp 221-222 °C. Anal.
(C23H21ClN2O2‚0.5 C4H4O4) C, H, N.
7-Ch lor o-4-[2-(3,4-dih ydr o-1H-isoqu in olin -2-yl)eth oxy]-
1,3-d ih yd r oin d ol-2-on e (8n ). The title compound was pre-
pared from 7p in 38% yield according to method C. The
fumarate salt was prepared in EtOH: mp 214-216.5 °C. Anal.
(C19H19ClN2O2‚0.5C4H4O4) C, H, N.
7-Ch lor o-4-[2-(1,3-d ih yd r oisoin d ol-2-yl)eth oxy]-1,3-d i-
h yd r oin d ol-2-on e (8o). The title compound was prepared
from 7q in 84% yield according to method C. The fumarate
4-Met h ylben zyl[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h -
yl]a m in e (7n ). The title compound was prepared by reacting
24 with 4-methylbenzylamine in 88% yield according to
method I to afford a reddish brown solid: mp 116-118 °C;
MS EI m/e (M+).
4-P h en ylben zyl[2-(3,7-d ich lor o-1H-in d ol-4-yloxy)et h -
yl]a m in e (7o). The title compound was prepared by reacting
24 with 4-phenylbenzylamine in 36% yield according to method
I to afford a tan oil: MS EI m/e 411/413/415 (M+).
2-[2-(3,7-Dich lor o-1H-in d ol-4-yloxy)eth yl]-1,2,3,4,4a ,8a -
h exa h yd r oisoqu in olin e (7p ). The title compound was pre-
pared 59% yield by reacting 24 with dihydroisoquinoline to
afford a brown solid: mp 179-180 °C; MS EI m/e 359/361/
363 (M+). Anal. (C19H18Cl2N2O) C, H, N.
3,7-Dich lor o-4-[2-(1,3-d ih yd r oisoin d ol-2-yl)eth oxy]-1H-
in d ole (7q). The title compound was prepared by reacting 24
with isoindoline in 59% yield: MS EI m/e 345/347/349 (M+).
2-Na p h t h yl[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h yl]-
a m in e (7r ). The title compound was prepared by reacting 24
with 2-naphthylmethylamine in 49% yield: MS EI m/e 384/
386/388 (M+).
Met h od L. [2-(3-Ch lor o-1H -in d ol-4-yloxy)et h yl]-(4-
p h en ylbu tyl)a m in e (7d ). A mixture of 22 (1.15 g, 2.62 mmol)
and K2CO3 (2.53 g, mmol) in a solution of MeOH-water (50
mL:3 mL) was heated to reflux for 3 h. The solvent was
removed under vacuum, and the crude product was dissolved
in CH2Cl2 (150 mL) and washed with water (100 mL). The
aqueous layer was extracted again with CH2Cl2 (100 mL), the
combined organic layers were dried over anhydrous MgSO4
and filtered, and the solvent was evaporated. The product was
purified by flash chromatography (5% MeOH-CH2Cl2) to
afford 847 mg (94%) of a tan oil: MS m/e 342/344 (M+). The
fumarate salt was prepared in 2-propanol: mp 195-196 °C.
Anal. (C20H23ClN2O‚0.5C4H4O4) C, H, N.
Ben zyl[2-(3,7-d ich lor o-1H -in d ol-4-yloxy)et h yl]a m in e
(7f). The title compound could also be prepared from 23 in
92% yield according to method L. The fumarate salt was
prepared as a white powder: mp 201-202 °C; MS EI m/e 334/
336/338 (M+). Anal. (C17H16Cl2N2O‚0.5C4H4O4) C, H, N.
1-[4-(2-Ben zyla m in oet h oxy)-7-ch lor o-1H -in d ol-3-yl]-
2,2,2-tr iflu or oeth a n on e (7j). The title compound was pre-
pared from 20 in 78% yield according to method L. The
fumarate salt was prepared in EtOH as a white powder: mp
salt was prepared in EtOH: mp 220-224 °C. Anal. (C18H17
ClN2O2‚C4H4O4) C, H, N.
-
7-Ch lor o-4-{2-[(n a ph th a len -2-ylm eth yl)a m in o]eth oxy}-
1,3-d ih yd r oin d ol-2-on e (8p ). The title compound was pre-
pared from 7r in 22% yield according to method C. The
fumarate salt was prepared in EtOH: mp 165-176 °C. Anal.
(C21H19ClN2O2‚0.7C4H4O4) C, H, N.
7-Ch lor o-4-{2-[(th iop h en e-2-ylm eth yl)a m in o]eth oxy}-
1,3-d ih yd r oin d ol-2-on e (8q). Treatment of 7k according to
method C afforded 1.15 g (86%) of the title compound: mp
154-155 °C. The fumarate salt was prepared in EtOH to give
a slightly yellow white powder: mp 203-204 °C; MS EI m/e
323/324 (M+). Anal. (C15H15ClN2O2S‚0.5C4H4O4) C, H, N.
7-Ch lor o-4-{2-[(th iop h en e-3-ylm eth yl)a m in o]eth oxy}-
1,3-d ih yd r oin d ol-2-on e (8r ). Treatment of 7l according to
method C afforded the title compound in 40% yield. The
fumarate salt was prepared in EtOH as a light brown solid:
mp 191.5-193 °C; MS EI m/e 323/324 (M+). Anal. (C15H15
ClN2O2S‚0.5C4H4O4) C, H, N.
-
2,6-Dibr om o-4-flu or op h en ol (25). To a solution of 4-fluo-
rophenol (25 g, 0.22 mol) in AcOH (200 mL) at room temper-

2018 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Mewshaw et al.
ature was slowly added dropwise bromine (78 g, 0.49 mol)
while being mechanically stirred. After 1 h the reaction
mixture was poured into ice water (1.5 L) followed by 100 mL
of saturated aqueous sodium bisulfite. The solid precipitate
was filtered and dried to afford 51.8 g (86%) of a white solid:
filtered and air-dried to afford 1.3 g of product. The ether layer
dried over anhydrous MgSO4 and filtered, and the solvent
removed under vacuum to afford another 1.5 g of product: total
yield 2.8 g (67%); mp 192-193 °C; MS EI m/e 229/231 (M+);
1H NMR (CDCl3) δ 3.53 (2H, s), 3.80 (2H, t, J ) 5.7 Hz), 4.25
(2H, J ) 5.7 Hz), 6.46 (1H, dd, J ) 3.3, 9.2 Hz), 6.93(1H, app
t, J ) 9.2 Hz), 7.70 (1H, bs).
1
mp 54-55 °C; H NMR (CDCl3) δ 5.69 (1H, s, OH), 7.25 (2H,
d, J ) 7.5 Hz); MS EI m/e 268/270/272 (M+). Anal. (C6H3Br2-
FO) C, H, N.
4-(2-Ben zyla m in oeth oxy)-7-flu or o-3-th iom eth yl-1,3-d i-
h yd r oin d ol-2-on e (31). The title compound was prepared
from 29 (1.5 g, 5.44 mmol) and benzylamine (2.33 g, 21.8 mmol)
in DMSO (8 mL) according to method I to afford 1.14 g (61%)
1-(2-Ch lor oeth oxy)-2,6-d ibr om o-4-flu or oben zen e (26).
A mixture of 25 (55 g, 0.20 mol), K2CO3 (60 g, 0.43 mol),
1-bromo-2-chloroethane (32.5 g, 0.23 mol), and 2-butanone (500
mL) was heated to reflux for 2 h and allowed to cool to ambient
temperature. The solids were filtered, and the solvent was
removed under vacuum to afford an oil. The oil was dissolved
in ether (300 mL), washed with water, dried over anhydrous
MgSO4, treated with decolorizing carbon, and filtered through
Solka floc to afford 65.9 g (97%) of an oil: MS EI m/e 330/332/
334/336 (M+); 1H NMR (CDCl3) δ 3.89 (2H, t, J ) 6.1 Hz), 4.23
(2H, t, J ) 6.1 Hz), 7.28 (2H, d, J ) 7.5 Hz).
1
of a yellow oil: MS EI m/e 346 (M+); H NMR (CDCl3) δ 1.96
(3H, s), 2.96-3.13 (2H, m), 3.89 (2H, AB, J ) 13 Hz), 4.10-
4.21 (2H, m), 4.28 (1H, s), 6.46 (1H, dd, J ) 9, 3 Hz), 6.95 (1H,
app t, J ) 9 Hz), 7.21-7.40 (5H, m).
4-(2-Cycloh exylm et h yla m in oet h oxy)-7-flu or o-3-t h io-
m eth yl-1,3-d ih yd r oin d ol-2-on e (32). The title compound
was prepared from 29 in 48% yield according to method I: MS
EI m/e 352 (M+).
4-[2-(Bip h en yl-3-ylm et h yla m in o)et h oxy]-7-flu or o-3-
th iom eth yl-1,3-d ih yd r oin d ol-2-on e (33). The title com-
pound was prepared from 29 in 61% yield according to method
I: MS EI m/e 422 (M+).
4-{2-[3-(1H -In d olyl)p r op yla m in o]et h oxy}-7-flu or o-3-
th iom eth yl-1,3-d ih yd r oin d ol-2-on e (34). The title com-
pound was prepared from 29 in 64% yield according to method
I.
4-[2-(2-Th ien yl)a m in oet h oxy]-7-flu or o-3-t h iom et h yl-
1,3-d ih yd r oin d ol-2-on e (35). The title compound was pre-
pared from 29 in 77% yield according method I: MS EI m/e
352 (M+).
4-[2-(3-Th ien yl)a m in oet h oxy]-7-flu or o-3-t h iom et h yl-
1,3-d ih yd r oin d ol-2-on e (36). The title compound was pre-
pared from 29 according to method I and converted to its
fumarate salt in EtOH to afford a white solid: mp 152.5-155
°C; MS EI m/e 352 (M+). Anal. (C16H17FN2O2S2‚C4H4O4) C, H,
N.
1-(2-Ch lor oet h oxy)-2,6-d ib r om o-4-flu or o-3-n it r ob en -
zen e (27). To a solution of 26 (65.8 g, 0.20 mol) in concentrated
sulfuric acid (165 mL) maintained at room temperature using
a water bath was slowly added a solution of HNO3 in H2SO4
(10 mL of HNO3 in 165 mL of H2SO4). The reaction was
allowed to stir at room temperature for 1 h, then poured into
ice (1.5 L), and extracted with CH2Cl2 (2 × 300 mL). The
combined organic layers were washed with aqueous Na2CO3
(150 mL), dried over anhydrous MgSO4, and filtered, and the
solvent was removed under vacuum to afford 73.3 g (97%) of
a white crystalline solid: mp 56-57 °C; MS EI m/e 375/377/
379/381; 1H NMR (CDCl3) δ 3.91 (2H, t, J ) 5.9 Hz), 4.29 (2H,
d, J ) 5.9 Hz), 7.54 (8.1 Hz). Anal. (C8H5Br2ClFNO3) C, H, N.
1-(2-Ch lor oeth oxy)-4-flu or o-3-a m in oben zen e (28). A
solution of 27 (73.2 g, 0.19 mol) in ethanol (1.1 L) containing
7.3 g of 10% palladium on carbon was hydrogenated at 40 psi
for 2 days. The catalyst was filtered, and the solvent was
removed. The residue was dissolved in ether (300 mL) and
washed with saturated aqueous Na2CO3 (200 mL). The organic
layer separated, washed with water, dried over anhydrous
MgSO4, and filtered, and the solvent removed to afford an oil
which solidified to afford 32.5 g (90%) of a dark solid: mp 42-
43 °C; MS EI m/e 189/191 (M+); 1H NMR (CDCl3) δ 3.40-3.60
(2H, bs, NH2), 3.77 (2H, d, J ) 6 Hz), 4.14 (2H, d, J ) 6 Hz),
6.19-6.23 (1 H, m), 6.36 (1H, dd, J ) 7, 3 Hz), 6.88 (1H, dd,
J ) 11, 9 Hz). Anal. (C8H9ClFNO) C, H, N.
Meth od M. 4-(2-Ben zyla m in oeth oxy)-7-flu or o-1,3-d i-
h yd r oin d ol-2-on e (8s). To a solution of 31 (1.05 g, 3.04 mmol)
in EtOH (50 mL) was added 2 teaspoons of Raney nickel at
room temperature. After 2 h the catalyst was filtered, the
solvent removed, and the solid dissolved in a minimum amount
of a solution of MeOH in CH2Cl2 and passed through a silica
gel column (5% MeOH in CH2Cl2) to afford 590 mg (65%) of a
1
pale yellow solid: mp 162-163 °C; MS EI m/e 300 (M+); H
NMR (DMSO-d6) δ 2.80 (2H, t, J ) 6 Hz), 3.42 (2H, s), 3.74
(2H, s), 4.03 (2H, t, J ) 6 Hz), 6.54 (1H, d, J ) 9, 3 Hz), 7.01
(1H, app t, J ) 9 Hz), 7.18-7.34 (5H, m), 10.81 (1H, d, J ) 10
Hz). The fumarate salt was prepared in EtOH to afford a
yellow solid: mp 202-203 °C. Anal. (C17H17FN2O2‚0.5C4H4O4)
C, H, N.
4-(2-Ben zyla m in oeth oxy)-7-flu or o-1,3-d ih yd r oin d ol-2-
on e (8s). The title compound could also be prepared by
treatment of 30 with benzylamine according to method I in
82% yield.
4-(2-Am in oeth oxy)-7-flu or o-1,3-dih ydr oin dol-2-on e (8t).
A mixture of 8s (1.8 g, 6.0 mmol) and 10% palladium on carbon
in EtOH (250 mL) at room temperature was hydrogenated at
54 psi for 11 h. The catalyst was filtered through Celite and
the solvent evaporated to afford 1.21 g (96%) of a tan solid:
mp 138-141 °C; MS m/e 210 (M+). The fumarate salt was
prepared in EtOH: mp 218-221 °C. Anal. (C10H11FN2O2‚
0.5C4H4O4‚0.25H2O) C, H, N.
4-(2-Ch lor oeth oxy)-7-flu or o-3-th iom eth yl-1,3-dih ydr oin -
d ol-2-on e (29). To a solution of ethyl(methylthio)acetate (7.2
g, 53.4 mmol) in anhydrous CH2Cl2 (200 mL) at -78 °C was
added sulfuryl chloride (8.1 g, 59.7 mmol), and the mixture
was stirred for 20 min. A solution of 29 (10.0 g, 52.8 mmol)
and Proton Sponge (13.9 g) in CH2Cl2 (100 mL) was added
dropwise and stirred for 2 h, followed by the addition of
triethylamine (6.5 g, 64.5 mmol). The temperature was main-
tained at -78 °C, and the reaction mixture was allowed to
stir for 1 h. After warming to room temperature, the mixture
was poured into brine (200 mL), dried over anhydrous MgSO4,
and filtered, and the solvent was removed to afford an oil.
AcOH (75 mL) was added to the oil and the mixture allowed
to stand for 18 h; then the solvent was removed under vacuum.
The residue was partitioned between ether (400 mL) and 2.5
N aqueous HCl (150 mL). The organic layer was separated,
and dried over anhydrous MgSO4, and filtered, and the solvent
was removed to afford a solid. Trituration of the solid with a
small amount of ether (30 mL) afforded 8.8 g (60%) of a yellow
solid: mp 140-141 °C; MS EI m/e 275/277 (M+); 1NMR (CDCl3)
δ 2.14 (3H, s), 3.79-3.87 (2H, m), 4.25-4.33 (2H, m), 4.35 (1H,
s), 6.51 (1H, dd, J ) 9.1, 3.3 Hz), 6.99 (1H, app. t, J ) 9.1 Hz),
8.09 (1H, s). Anal. (C11H11ClFNO2S) C, H, N.
4-{2-[(Bip h en yl-4-ylm et h yl)a m in o]et h oxy}-7-flu or o-
1,3-d ih yd r oin d ol-2-on e (8u ). Treatment of 30 with biphenyl-
2-ylmethylamine according to method I afforded the title
compound in 42% yield. The fumarate salt was prepared in
EtOH: mp 193-198 °C; MS EI m/e 376 (M+). Anal. (C23H21
FN2O2‚C4H4O4) C, H, N.
-
4-(2-Ch lor oeth oxy)-7-flu or o-1,3-dih ydr oin dol-2-on e (30).
To a solution of 29 (5.0 g, 18.1 mmol) in formic acid (75 mL)
was added Raney nickel (10 g), and the mixture was stirred
at room temperature for 6 h. The reaction mixture was diluted
with ether (150 mL) and the catalyst filtered through Celite;
and upon addition of water a precipitate formed. The solid was
4-{2-[(Bip h en yl-3-ylm et h yl)a m in o]et h oxy}-7-flu or o-
1,3-d ih yd r oin d ol-2-on e (8v). The title compound was pre-
pared from 33 in 29% yield according to method M; MS EI
m/e 376 (M+). The fumarate salt was prepared in EtOH: mp
200-201 °C. Anal. (C23H21FN2O2‚C4H4O4) C, H, N.

New Generation Dopaminergic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11 2019
7-Flu or o-4-{2-[(n a p h th a len -2-ylm eth yl)a m in o]eth oxy}-
1,3-d ih yd r oin d ol-2-on e (8w ). Treatment of 30 with 2-naph-
thylmethylamine according to method I afforded the title
compound in 82%yield: MS EI m/e 350 (M+). The fumarate
2. 5-HT1A a n d r1 Recep tor s. The 5-HT1A and R1 receptor
binding assays are modifications of those used by Hall et al.,24
and Morrow et al.,25 respectively. Compounds were evaluated
for their affinity at 5-HT1A receptors using rat hippocampal
homogenates labeled with [3H]-8-OH-DPAT (1.8 nM). Samples
were incubated for 10 min at 37 °C and incubations terminated
by adding cold buffer (50 mM Tris, pH 7.7). Affinity at the R1
receptors was determined using rat cortical homogenates
labeled with [3H]prazosin (0.2 nM). Samples were incubated
at 25 °C for 30 min. Incubations were then terminated by the
addition of cold buffer (50 mM Tris, pH 7.4) followed by rapid
filtration using a TomTec 96 cell harvester. Bound radioactiv-
ity was counted as above. Test compounds were run in
triplicate, using at least eight concentrations. All analyses
were done using nonlinear regression. In competition experi-
ments, apparent Ki values were calculated from IC50 values
by the method of Cheng and Prusoff.15
Mou se Hyp olocom otion .26 Spontaneous locomotor activity
effects were tested in mice (25-30 g, Charles River CF-1). Test
compounds, dissolved in 0.25% Tween 80, were administered
at several dose levels (10-12 mice/dose) immediately prior to
testing. Horizontal activity counts were collected 10-20 min
after dosing using infrared monitors (Omnitech Digiscan)
surrounding an open field (8 × 8 in.) in a darkened room. Data
were analyzed by one-way ANOVA followed by Dunnett’s
comparison to control post-hoc analyses and by nonlinear
regression analysis followed by inverse prediction to obtain
potency estimates.
In d u ction or An ta gon ism of Ster eotyp y a n d Clim b-
in g.27,28 Induction of apomorphine-like stereotypy and climbing
behaviors was tested in mice (20-30 g, Charles River CF-1)
treated with the D1 agonist SKF-38393 (10 mg/kg ip) im-
mediately prior to drug or reserpine (5 mg/kg sc) 20-24 h prior
to drug. Tests for antagonism of apomorphine-induced stereo-
typy and climbing behavior were conducted in mice treated
with apomorphine (1 mg/kg sc) 30 min after drug. Drug,
dissolved in 0.25% Tween 80, was administered subcutane-
ously at 5 dose levels (6 mice/dose) for each test. After the final
injection, mice were scored for stereotypy (2-point scale) and
climbing (3-point scale) every 5 min for a total of 30 min.
Accumulated scores were analyzed by one-way ANOVA fol-
lowed by Dunnett’s comparison to control test and by nonlinear
regression analysis followed by inverse prediction to obtain
potency estimates.
salt was prepared in EtOH: mp 189-193 °C. Anal. (C21H19
FN2O2‚0.5C4H4O4) C, H, N.
-
7-F lu or o-4-{2-[(th iop h en e-2-ylm eth yl)a m in o]eth oxy}-
1,3-d ih yd r oin d ol-2-on e (8x). Prepared from 35 according to
method M in 30% yield. The fumarate salt was prepared from
EtOH as yellow crystals: mp 184-185.5 °C; MS EI m/e 306
(M+). Anal. (C15H15FN2O2S‚0.5 C4H4O4‚0.25H2O) C, H, N.
7-F lu or o-4-{2-[(th iop h en e-3-ylm eth yl)a m in o]eth oxy}-
1,3-d ih yd r oin d ol-2-on e (8y). The title compound was pre-
pared from 36 according to method M in 21% yield to afford a
1
light yellow solid: mp 154-157 °C; MS EI m/e 306 (M+); H
NMR (DMSO-d6) δ 2.80 (2H, t, J ) 6 Hz), 3.42 (2H, s), 3.74
(2H, s), 4.03 (2H, t, J ) 6 Hz), 6.54 (1H, d, J ) 9, 3 Hz), 7.01
(1H, app t, J ) 9 Hz), 7.18-7.34 (5H, m), 10.81 (1H, d, J ) 10
Hz). The fumarate salt was prepared in EtOH to afford a
yellow solid: mp 186.5-187 °C. Anal. (C15H15FN2O2S‚0.5
C2H4O4) C, H, N.
4-[2-(Cycloh exylm eth yla m in o)eth oxy]-7-flu or o-1,3-d i-
h yd r oin d ol-2-on e (8z). The title compound was prepared
from 32 as a light brown crystal in 28% according to method
M: mp 215-216 °C; MS EI m/e 306 (M+). Anal. (C17H23FN2O2‚
C4H4O4) C, H, N.
4-[2-(3,4-Dih yd r o-1H-isoqu in olin -2-yl)eth oxy]-7-flu or o-
1,3-d ih yd r oin d ol-2-on e (8a a ). Treatment of 30 with di-
hydroisoquinoline according to method I afforded the title
compound in 45% yield. The fumarate salt was made in
EtOH: mp 230-235 °C. Anal. (C19H19FN2O2‚0.5C4H4O4‚
0.25H2O).
4-[2-(1,3-Dih yd r oisoin d ol-2-yl)eth oxy]-7-flu or o-1,3-d i-
h yd r oin d ol-2-on e (8a b). Treatment of 30 with isoindoline
according to method I afforded the title compound in 75% yield
as a thick oil: MS EI m/e 312 (M+). The fumarate salt was
prepared in EtOH: mp 210-212 °C. Anal. (C18H17FN2O2‚
0.5C4H4O4‚0.25C4H8O) C, H, N.
4-{2-[3-(1H-In d olyl)p r op yla m in o]eth oxy}-7-flu or o-1,3-
d ih yd r oin d ol-2-on e (8a c). The title compound was prepared
from 34 in 19% yield according to method M: MS EI m/e 367
(M+). The fumarate salt was prepared in EtOH: mp 189-190
°C. Anal. (C21H22FN3O2‚C4H4O4) C, H, N.
Molecu la r Mod elin g. All computations were performed
using Macromodel 6.0 (Columbia University, Department of
Chemistry, New York, NY 10027) and a Silicon Graphic
workstation. All molecular mechanics calculations utilized
MM3 as implemented in Macromodel 6.0.
Ackn owledgm en t. The authors wish to thank Bruce
Hoffman, J ames Mattes, and Dr. Mei-Yi Zhang for their
analytical assistance.
Recep tor Bin d in g Assa ys. 1. Dop a m in e D2 High - a n d
Low -Affin ity Sta tes. The affinity of dopaminergic agents for
the high- and low-affinity states of the D2 receptor was
determined using conventional in vitro receptor binding
methodology. Affinity for the high-affinity state was deter-
mined by measuring the ability of various drugs to inhibit [3H]-
quinpirole (4 nM) binding to striatal membranes (approxi-
mately 0.3 mg of protein). Incubation buffer was 50 mM Tris,
pH 7.4, containing 1 mM EDTA, 5 mM KCl, 1.5 mM CaCl2,
and 4 mM MgCl2 (NaCl was omitted to promote high-affinity
agonist binding). Incubation was at 25 °C for 1 h. Sulpiride
(10 µM) was used to define specific binding. Affinity for the
low-affinity state of the D2 receptor was determined by
measuring the ability of various drugs to inhibit [3H]spiperone
(1 nM) binding to striatal membranes (approximately 0.3 mg
of protein). Incubation buffer was 50 mM Tris, pH 7.4,
containing 125 mM NaCl, 5 mM KCl, 1 mM CaCl2, and 1 mM
MgCl2; 1 mM GppNHp was present in all tubes to shift binding
to the low-affinity state, and 30 nM ketanserin was present
in all tubes to exclude binding to 5-HT2 receptors. Incubation
was at 37 °C for 5 min. All incubations were terminated by
adding cold buffer followed by rapid filtration using a TomTec96
cell harvester. Bound radioactivity was counted using a Wallac
1205 BetaPlate Counter. Ki values were calculated from IC50
values by the method of Cheng and Prusoff,15 using nine
concentrations of the drug, in triplicate.
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