Dopamine D3 and D4 receptor antagonists: synthesis and structure--activity relationships of (S)-(+)-N-(1-Benzyl-3-pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl) amino]-2-methoxybenzamide (YM-43611) and related compounds.

Article abstract of DOI:10.1021/jm9601720

In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzamide derivatives, 1, 2a-d, 5a-1, and 7, and their enantiomers, (R)-1 and (R)-5c-e, and evaluated their binding affinity for cloned dopamine D2, D3, and D4 receptors and their inhibitory

Full text of DOI:10.1021/jm9601720

2764
J . Med. Chem. 1996, 39, 2764-2772
Dop a m in e D3 a n d D4 Recep tor An ta gon ists: Syn th esis a n d Str u ctu r e-Activity
Rela tion sh ip s of (S)-(+)-N-(1-Ben zyl-3-p yr r olid in yl)-5-ch lor o-4-
[(cyclop r op ylca r bon yl)a m in o]-2-m eth oxyben za m id e (YM-43611) a n d Rela ted
Com p ou n d s
J unya Ohmori,* Kyoichi Maeno, Kazuyuki Hidaka, Kazuhiro Nakato, Mitsuyuki Matsumoto, Shoko Tada,
Hanae Hattori, Shuichi Sakamoto, Shin-ichi Tsukamoto, Shinji Usuda, and Toshiyasu Mase
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company Limited, 21, Miyukigaoka,
Tsukuba, Ibaraki 305, J apan
Received March 4, 1996X
In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzamide derivatives, 1, 2a -d ,
5a -l, and 7, and their enantiomers, (R)-1 and (R)-5c-e, and evaluated their binding affinity
for cloned dopamine D2, D3, and D4 receptors and their inhibitory activity against apomorphine-
induced climbing behavior in mice. The results indicate that D2, D3, and D4 receptors have
different bulk tolerance (D4 > D3 > D2) for the substituent of the 4-amino group (R1) on the
benzamide nuclei and that cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl groups likely
possess adequate bulkiness with respect to D3 and D4 affinity and selectivity over D2 receptors
in this series. The results also suggested that the N-substituent (R2) on the pyrrolidin-3-yl
group performs an important role in expressing affinity for D2, D3, and D4 receptors and
selectivity among the respective subtypes. One of the compounds, (S)-(+)-N-(1-benzyl-3-
pyrrolidinyl)-5-chloro-4-[(cyclopropylcarbonyl)amino]-2-methoxybenzamide (5c) (YM-43611),
showed high affinity for D3 and D4 receptors (Ki values of 21 and 2.1 nM, respectively) with
110-fold D4 selectivity and 10-fold D3 preference over D2 receptors and weak or negligible affinity
for representative neurotransmitter receptors. Compound 5c displayed potent antipsychotic
activity in inhibiting apomorphine-induced climbing behavior in mice (ED50 value, 0.32 mg/kg
sc).
Schizophrenia is one of the most severe psychiatric
illnesses and is characterized by hallucinations, delu-
sions, and disorganized thought and behavior which
result in major impairment of the patient’s social and
occupational function. Current medications utilizing
typical neuroleptic antipsychotics such as haloperidol
(Figure 1) show some promised efficacy in controlling
the positive symptoms of schizophrenia. However, their
effects are only partial, and they induce a substantial
incidence of extrapyramidal symptoms (EPS) as neuro-
logical side effects.1,2
dopamine system has been suggested to be associated
with EPS.10
Clozapine (Figure 1), an atypical antipsychotic agent,
exhibits good efficacy even in some patients with
schizophrenia who fail to respond to typical antipsy-
chotics and has a low incidence of EPS.14,15 The atypical
antipsychotic profile of clozapine is thought to result
from its affinity for a multitude of receptors, including
dopamine receptor subtypes, 5-HT2 receptors, and R1
adrenoceptors.16 In particular, the favorable effects of
clozapine are suggested to be derived from its relatively
preferential blockade of D4 over D2 receptors (ap-
proximately 10-fold selectivity).7,13 On the other hand,
quinpirole, a selective D3 receptor agonist, inhibits
rather than stimulates rat locomotor activity. The
negative symptoms of schizophrenia, which are gener-
ally resistant to antipsychotic treatment, may therefore
result from overactivity in the D3 receptor system.17
Blockade of D3 receptors may thus have a beneficial
effect on these symptoms.
Traditionally, two dopamine receptor subtypes have
been classified on the basis of pharmacological evalua-
tion, namely, the D1 and D2 receptors. Existing anti-
psychotics are considered to act via the blockade of the
classical “D2 receptor”.3-5 Recently, however, molecular
biological approaches have led to the discovery of the
novel dopamine D3 and D4 receptor isoforms,6,7 which
are classified as the D2-like (D2, D3, and D4) receptor
subfamily, and the D5 receptor,8 which is classified as
the D1-like (D1 and D5) receptor subfamily. The D2-like
receptor subfamily isoforms correspond to the classical
D2 receptors. D3 and D4 receptors are particularly
concentrated in the mesolimbic and mesolimbocortical
regions of the central nervous system, respectively,9,10
areas which are thought to control emotional and
cognitive functions and to be implicated in the pathology
of schizophrenia.11-13 In contrast, few D3 and D4
receptors are found in the nigrostriatal region, which
is rich in D2 receptors and of which blockade of the
These observations indicate that selective D3 and D4
antagonism may represent a novel and potent psycho-
tropic mechanism and may have application as an
atypical antipsychotic drug which does not induce
EPS.18,19 Despite the upsurge of interest in the physiol-
ogy and pharmacology of D3 and D4 receptors,20-24 the
limited number of selective antagonists has made it
difficult to determine their functions.25,26 This situation
prompted us to search for selective D3 and D4 receptor
antagonists and investigate their pharmacology.
Metoclopramide (Figure 1) and its derivatives are
known as antagonists of the classical D2 receptor.
Among them, nemonapride, an antipsychotic of the
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
S0022-2623(96)00172-0 CCC: $12.00 © 1996 American Chemical Society

Dopamine D3 and D4 Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2765
F igu r e 1.
Sch em e 1a
benzamide class developed in our laboratory, is recog-
nized as one of the strongest and most selective antago-
nists of the classical D2 receptor (Figure 1).27 Nem-
onapride was recently shown to possess high affinity for
D2, D3, and D4 receptors with Ki values in the sub-
nanomolar range.12 To obtain selective D3 and D4
receptor antagonists, we carried out several modifica-
tions of N-(3-pyrrolidinyl)benzamide 1, a nemonapride
analogue, based on the results of screening for our in-
house chemical file. In this paper we report the
synthesis, structure-activity relationships (SAR) in
affinity for D3, D4, and D2 receptors, and behavioral test
results in mice of the novel series of (S)- and (R)-4-
[(cycloalkylcarbonyl)amino]-N-(3-pyrrolidinyl)benz-
amides 2c,d , 5c-k , (R)-5c-e, and 7 and related com-
pounds 1, (R)-1, 2a ,b, and 5a ,b,l.28 Among these
compounds, (S)-(+)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-
4-[(cyclopropylcarbonyl)amino]-2-methoxybenzamide (5c)
showed high affinity and selectivity for D3 and D4 versus
D2 and other neurotransmitter receptors, as well as
potent inhibitory activity on apomorphine-induced climb-
ing behavior.29,30
(a) (CF3CO)2O for 2a , R1Cl for 2b-d , CH2Cl2.
a
aldehyde and subsequent deprotection of their tert-
butoxycarbonyl (BOC) group by treatment with 4 N
HCl-ethyl acetate solution. The benzoic acid parts,
4-propionylamino- (4a ) and 4-(2-methylpropionyl)amino-
(4b) 5-chloro-2-methoxybenzoic acids, were directly
prepared by acylation of benzoic acid 8 with propionyl
chloride and 2-methylpropionyl chloride. Because this
method resulted in the formation of substantial amounts
of several byproducts, 4-[(cycloalkylcarbonyl)amino]-
benzoic acids 4c-e were prepared stepwise via ester
derivatives as follows: Benzoic acid 8 was converted to
the methyl ester 1231 by treatment with dimethyl
sulfate in the presence of potassium carbonate,32 treated
with the respective cycloalkylcarbonyl chloride, and
then hydrolyzed to give the corresponding 4-cyclopropyl-
(4c), 4-cyclobutyl- (4d ), and 4-cyclopentyl- (4e) car-
bonylaminobenzoic acids, respectively. The resulting
4a -e were condensed with the appropriate 3-amino-
pyrrolidine derivatives 3a -f and 9 by means of the
mixed anhydride method27 or diphenyl phosphorazidate
method33 to afford the desired benzamide derivatives
5a-k. Compound 5l was also synthesized from 5-chloro-
2-methoxy-4-(methylamino)benzoic acid (4f)27 and pyr-
rolidine 3c by the mixed anhydride method. The (R)-
enantiomers (R)-5c-e were synthesized from (R)-
pyrrolidine 10 according to the method for the respective
enantio isomers.
Ch em istr y
Synthesis of the (S)-N-(3-pyrrolidinyl)benzamides
2a -d , 5a -l, and 7 is described in Schemes 1-3. (S)-
4-Amino-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-2-meth-
oxybenzamide (1) was obtained from 4-amino-5-chloro-
2-methoxybenzoic acid (8) and commercially available
(S)-3-amino-1-benzylpyrrolidine (9) by a previously
described procedure for (()-1.27 As shown in Scheme
1, acylation of 1 with the corresponding acyl chloride
or anhydride led to the formation of trifluoroacetyl- (2a ),
acryloyl- (2b), cyclohexylcarbonyl- (2c), and benzoyl-
(2d ) aminobenzamide derivatives, respectively. The
enantiomer (R)-1 was prepared from (R)-3-amino-1-
benzylpyrrolidine (10) by the same method.
The other 4-(acylamino)benzamide derivatives 5a -l
were synthesized from suitable benzoic acids 4a -f and
aminopyrrolidines 3a -f and 9 (Scheme 2). The pyrroli-
dine parts, 1-cyclohexyl- (3a ), 1-cycloheptyl- (3b ),
1-(bicyclo[3.3.1]non-9-yl)- (3c), 1-(2-adamantyl)- (3d ),
1-cyclohexylmethyl- (3e), and 1-phenethyl- (3f) pyrroli-
dines, were obtained from commercially available (S)-
3-[(tert-butoxycarbonyl)amino]pyrrolidine (11) by reduc-
tive alkylation with the corresponding cyclohexanone,
cycloheptanone, bicyclo[3.3.1]nonan-9-one, 2-adaman-
tanone, cyclohexanecarboxaldehyde, and phenylacet-

2766 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ohmori et al.
Sch em e 2a
a
(a) R2dO, H2, Pd/C; (b) 4 N HCl-EtOAc; (c) Me2SO4, K2CO3; (d) R1Cl, base; (e) 2 N NaOH, DMSO; (f) 3a -f or (S)-3-amino-1-
benzylpyrrolidine (9), EtOCOCl or Ph2P(O)N3, Et3N, CH2Cl2 or DMF.
Sch em e 3a
a
(a) (CF3CO)2O; (b) 4 N HCl-EtOAc; (c) 4c, EtOCOCl, Et3N, CH2Cl2; (d) K2CO3.
Compound 7, the debenzyl analogue of 5c, was
prepared by the following four steps (Scheme 3), namely,
trifluoroacetylation of pyrrolidine 9, deprotection of the
BOC group by treatment with 4 N HCl-ethyl acetate
solution, condensation with benzoic acid 4c, and treat-
ment with potassium carbonate to deprotect the tri-
fluoroacetyl group to yield the desired product.
(R)-1 ) 1.2, 1.9, and 0.55 nM, respectively) similar to
or slightly less than haloperidol and nemonapride, with
little or no selectivity for D3 and D4 versus D2 receptors
(KiD2/KiD3 ) 1.7 and 0.63; KiD2/KiD4 ) 0.89 and 2.2,
respectively). Moreover, compound 1 and (R)-1 possess
only one asymmetric carbon, which is less than the
number of nemonapride. These compounds were thus
selected as lead compounds for further studies.
Resu lts a n d Discu ssion
Initially, we investigated the effects of acyl substit-
uents of the 4-amino group (R1) on (S)-N-(1-benzyl-3-
pyrrolidinyl)-5-chloro-2-methoxybenzamides. The linear-
chained 4-acylamino analogues 4-trifluoroacetyl-, 2a ,
4-acryloyl-, 2b, and 4-propionyl-, 5a , aminobenzamides
showed 12-33-fold weaker D2 affinity (Ki values of 12-
32 nM) and 8.1-10-fold weaker D3 affinity (Ki ) 4.7-
5.9 nM) than 1, in contrast to their D4 affinity (Ki )
1.3-1.9 nM). The branched acylamino derivative 5b
exhibited a slightly greater decrease in D3 affinity than
2a ,b and 5a . Substitution of the amino group of 1 with
cycloalkycarbonyl groups such as cyclopropylcarbonyl
(5c) and cyclobutylcarbonyl (5d ) resulted in equipotent
D4 (Ki ) 2.1 and 5.2 nM) and D3 (Ki ) 21 and 36 nM)
binding with those of 5b and decreased D2 binding (Ki
) 220 and 170 nM). As a result, 5c displayed about
100-fold weaker D2 affinity than nonsubstituted 1 and
110-fold D4 selectivity and 10-fold D3 preference over
D2 receptors. The KiD2/KiD4 ratio of 5c is 15 times more
than that of clozapine (KiD2/KiD4 ) 6.7). Even though
the binding potency of cyclopentylcarbonyl derivative
The structure of the benzamides and results of
radiobinding assays for dopamine rat D2L (D2), rat D3
(D3), and human D4.7 (D4, containing seven polymorphic
tandem repeats36) receptors are summarized in Table
1. The selected compounds were also assessed behav-
iorally by examining their inhibitory activity in apo-
morphine-induced climbing in mice (Table 1), a putative
predictor of antipsychotic activity.34 Binding affinity is
presented as Ki (nM) and anticlimbing activity as ED50
(mg/kg sc) values.
The results of screening of our in-house chemical file,
including nemonapride analogues, indicated that sev-
eral series of benzamide analogues have affinity for D2-
like receptors. We also found that substituents on N-(3-
pyrrolidinyl)benzamides somewhat affect their D2, D3,
and D4 selectivity. Among these compounds, (S)-4-
amino-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-2-methoxy-
benzamide (1) and its enantiomer [(R)-1] exhibited high
affinity for D2, D3, and D4 receptors (Ki values of 1 for
D2 ) 0.98 nM, D3 ) 0.58 nM, and D4 ) 1.1 nM; those of

Dopamine D3 and D4 Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2767
Ta ble 1. Biological Data of (S)- and (R)-N-(3-Pyrrolidinyl)benzamides
receptor binding, Ki (nM)a
anticlimbing, in
compd
R1
R2
D2
D3
D4
1.1 (1.0-1.2)
miced ED50 (mg/kg sc)
b
b
c
1
H
H
Bn
Bn
Bn
0.98 (0.93-1.0)e
1.2 (1.1-1.3)
0.58 (0.56-0.60)
1.9 (1.8-2.0)
5.1 (4.8-5.4)
4.7 (4.5-4.8)
5.9 (5.5-6.2)
15 (14-16)
0.071 (0.038-0.13)
(R)-1
2a
0.55 (0.54-0.57) NTf
CF3CO
12 (12-12)
1.9 (1.8-2.1)
1.3 (1.2-1.3)
1.5 (1.4-1.6)
3.0 (2.9-3.2)
2.1 (1.9-2.3)
5.6 (5.2-6.0)
5.2 (5.0-5.5)
7.0 (6.5-7.6)
20 (18-21)
18 (16-20)
110 (96-120)
87 (82-93)
2200 (2100-2400)
2.1 (1.9-2.3)
2.7 (2.3-3.3)
3.8 (3.4-4.4)
4.4 (4.2-4.6)
3.3 (3.0-3.6)
3.4 (3.0-3.9)
NT
NT
2b
CH2CHCO Bn
27 (27-28)
5a
EtCO
Bn
32 (31-33)
0.31 (0.21-0.45)
NT
5b
5c
(R)-5c
5d
(R)-5d
5e
(R)-5e
2c
i-PrCO
c-PrCO
c-PrCO
c-BuCO
c-BuCO
c-PenCO
c-PenCO
c-HexCO
PhCO
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
50 (48-52)
220 (210-230)
190 (180-200)
170 (160-180)
240 (220-250)
740 (670-820)
690 (310-1500)
1200 (1100-1300)
630 (610-640)
21 (21-22)
0.32 (0.15-0.70)
60 (57-63)
36 (34-38)
100 (100-100)
55 (43-69)
0.45 (0.34-0.59)
0.14 (0.13-0.15)
NT
0.28 (0.16-0.49)
NT
NT
NT
150 (120-200)
200 (190-210)
200 (190-210)
2d
Bn
7
5f
5g
5h
5i
5j
5k
5l
c-PrCO
c-PrCO
c-PrCO
c-PrCO
c-PrCO
c-PrCO
c-PrCO
Me
H
14 000 (14 000-15 000) 3000 (2900-3200)
>30
c-Hex
c-Hep
BCNg
2-adamantyl
c-hexylmethyl
phenethyl
BCN
84 (83-86)
20 (19-21)
4.4 (4.3-4.5)
1.5 (1.4-1.6)
2.2 (2.1-2.3)
1.7 (1.6-1.8)
3.7 (3.5-3.9)
33 (30-35)
0.24 (0.23-0.25)
0.16 (0.15-0.17)
6.4 (6.1-6.8)
230 (220-240)
1.4 (0.37-5.1)
NT
140 (140-140)
110 (110-120)
32 (30-34)
>10
>10
NT
82 (79-85)
NT
0.81 (0.78-0.83)
0.16 (0.13-0.19)
1.1 (1.0-1.2)
260 (250-260)
0.67 (0.60-0.75) NT
nemonapride
haloperidol
clozapine
0.21 (0.16-0.27)h 0.012 (0.0082-0.019)
2.1 (1.7-2.5)
39 (36-42)
0.041 (0.033-0.050)
6.8 (5.5-8.4)
a
Ki values were determined by at least two experiments. Each inhibition curve consisted of four to eight points on each experiment.
Ki for [125I]iodosulpride binding; rat D2L and rat D3 receptors expressed in CHO cells. c Ki for [3H]nemonapride binding; human D4.7
b
receptors expressed in CHO cells. Test results for the free base. e Values in parentheses are 95% confidence intervals. f NT ) not tested.
d
g
h
BCN ) bicyclo[3.3.1]non-9-yl. Kd value.
5e for D2, D3, and D4 receptors was several to 10 times
less than those of 5c,d , its D3 and D4 selectivity was
largely retained (KiD2/KiD3 ) 13 and KiD2/KiD4 ) 37). In
the case of analogues with greater ring expansion,
cyclohexylcarbonyl- (2c) and benzoyl- (2d ) aminobenz-
amides, D3 and D4 affinity was even weaker and
selectivity was lower than those of 5e. On the other
hand, (R)-5c-e exhibited closely similar or only slightly
decreased affinity for D2, D3, and D4 receptors and
showed similar or somewhat reduced D3 and D4 selec-
tivity over D2 receptors in comparison with those of the
corresponding (S)-enantiomers 5c-e. It was therefore
deduced that D2, D3, and D4 receptors have different
bulk tolerance (D4 > D3 > D2) for the substituent of the
4-amino group (R1) on the benzamide nuclei and that
three- to five-membered cycloalkylcarbonyl groups such
as cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl
probably have suitable bulkiness for both D3 and D4
affinity and selectivity over D2 receptors.
KiD3 ) 19, KiD2/KiD4 ) 40), related to those of 5j, was
seen. Consequently, we converted the R2 group of 5f
into the further bulky and sterically constrained bicyclic
and tricyclic substituents N-bicyclo[3.3.1]non-9-yl (BCN)
and adamantyl. The compounds 5h ,i also displayed
high affinity for both D3 and D4 receptors (Ki for D3 )
1.7-2.2 nM, D4 ) 3.8-4.4 nM) and 63-65-fold greater
D3 and 25-37-fold greater D4 selectivity against D2
receptors, respectively. The KiD2/KiD3 ratio of 5h ,i is
approximately 6 times better than that of 5c. In
contrast, the more expanded monocyclic analogue 5g
displayed increased D2 affinity (Ki ) 20 nM) and
decreased KiD2/KiD4 ratio (7.4) than 5f. Moreover, N-
unsubstituted 7 showed only weak affinity for all D2-
like receptor subtypes. Similar to 1 (R1 ) H, R2
)
benzyl), compound 5l (R1 ) Me, R2 ) BCN) showed
subnanomolar order Ki values for D2, D3, and D4
receptors with a little or no D3 and D4 selectivity against
D2 receptors. These results indicated that the combina-
tion of appropriate R1 and R2 groups is important in
improving D3 and D4 selectivity against D2 receptors in
these benzamides.
We next focused on the effects of N-substituents on
the pyrrolidine ring of 5c (R2, Table 1). The lengthening
of the N-benzyl of 5c into N-phenethyl (5k ) resulted in
similar D3 and D4 affinity but severalfold stronger D2
affinity. The saturated benzyl analogue of 5c, (S)-N-
[1-(cyclohexylmethyl)-3-pyrrolidinyl]benzamide (5j), dis-
played approximately 6-fold greater D3 affinity (Ki ) 3.7
nM) with maintained KiD2/KiD3 ratio (8.6) as compared
to 5c, although it had increased D2 affinity (Ki ) 32 nM)
and reduced KiD2/KiD4 ratio (10). For compound 5f, in
which the cyclohexyl group is directly attached to the
nitrogen atom of the pyrrolidine ring, high affinity for
both D3 and D4 receptors (Ki for D3 ) 4.4 nM, D4 ) 2.1
On this basis several interpretations of the SAR
regarding the R2 group can be suggested. With regard
to the D3 affinity, N-alicyclic derivatives such as 5f-j
may be more favorable in interacting with the receptors
than N-aralkyl derivatives such as 5c,k , a characteristic
possibly mediated by the hydrophobicity and/or aroma-
ticity of their R2 groups. For D2 affinity, despite their
greater bulkiness, compounds 5g,k exhibited a greater
increase in affinity than the corresponding 5f,c; hence,
the bulkiness of the R2 group is probably not the reason
for the diminished affinity. On the other hand, less
nM) with improved selectivity over D2 receptors (KiD2
/

2768 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ohmori et al.
29
Ta ble 2.
Affinities of 5c, Clozapine, and Haloperidol for Other Neurotransmitter Receptorsa,b
binding (Ki, nM)
receptors
5c
clozapine
haloperidol
D1
D5
>10 000
>10 000
180 (170-190)c
780 (710-860)
3.6 (3.5-3.8)
49 (46-52)
260 (240-280)
9.0 (8.0-10)
R1
5300 (4900-5700)
4300 (3400-5500)
R2
230 (220-230)
9600 (8700-11 000)
â
>10 000
>10 000
>10 000
>10 000
>10 000
5-HT1A
5-HT2A
5-HT3
M1
130 (120-130)
17 (16-18)
32 (31-33)
2.1 (2.0-2.3)
46 (44-48)
5.0 (4.5-5.6)
1900 (1700-2000)
87 (81-94)
4000 (3800-4200)
>10 000
5400 (4900-6000)
7300 (6900-7700)
1800 (1700-2000)
2500 (2400-2600)
2100 (1600-2700)
M2
H1
>10 000
a
b
See Table 1. [3H]SCH23390 binding to human cloned D1 and D5 receptors; [3H]prazosin binding to rat cortical R1 receptors;
[3H]Rx821002 binding to rat cortical R2 receptors; [3H]dihydroalprenolol binding to rat cortical â receptors; [3H]-8-OH-DPAT binding to
rat hippocampal 5-HT1A receptors; [3H]ketanserin binding to 5-HT2A receptors in rat frontal cortex; [3H]GR65630 binding to N1E-115
neuroblastoma 5-HT3 receptors; [3H]pirenzepine binding to rat cortical M1 receptors; [3H]quinucridinyl benzylate binding to rat heart M2
receptors; and [3H]pyrilamine binding to rat cortical H1 receptors. c Values in parentheses are 95% confidence intervals.
flexible analogues displayed more enhanced D3 and D4
selectivity against D2 receptors than more flexible
analogues, e.g., 5c versus 5k , 5f versus 5j, and 5h ,i
versus 5f. On this basis, the negative interaction
between the R2 group and D2 receptors may be caused
by their rigidity, which is possibly caused by their
inflexibility and/or through the effect on restriction of
pyrrolidine ring conformations.37 We therefore specu-
lated that the N-substituent on the pyrrolidin-3-yl group
(R2) of the 4-[(cyclopropylcarbonyl)amino]benzamides
plays an important role in expressing their binding
affinity for each D2-like receptor subtype and that their
hydrophobicity, aromaticity, bulkiness, and rigidity are
critical for their D2, D3, and D4 affinity and selectivity.
In in vivo study, 4-[(cycloalkylcarbonyl)amino]benz-
amides (R2 ) benzyl) 5c-e and (R)-5c displayed potent
antidopaminergic activity in inhibiting apomorphine-
induced climbing behavior, with ED50 values of 0.14-
0.45 mg/kg on subcutaneous administration. These
values are less than those of the traditional D2 antago-
nists nemonapride and haloperidol but are about 20-
fold more potent than that of the preferential D4
antagonist clozapine (Table 1). Even though their D2
affinity is 170-760-fold decreased, their ED50 values are
only 2.0-6.3 times less than that of 1. Possibly, D3, D4,
or both receptors may be implicated in apomorphine-
induced climbing behavior, at least in part. Anticlimb-
ing activity of compound 5f (R2 ) cyclohexyl) is also
potent (ED50 value, 1.4 mg/kg) but at a level slightly
less than those of 5c-e and (R)-5c, despite its increased
D2 and D3 affinity. Contrary to our expectations,
compounds 5h ,i, which have high affinity and selectivity
for both D3 and D4 receptors, showed very weak or no
anticlimbing activity. We therefore speculated that the
much greater hydrophobicity of the R2 group of these
compounds compared with that of cyclohexyl may
produce a decrease in bioavailability in this behavioral
test, because 5f,h ,i which have a more hydrophobic R2
group showed weaker activity (π coefficients of benzyl,
cyclohexyl, and adamantyl groups ) 2.01, 2.51, and 3.30,
respectively),35 although unrelated to their binding
affinity. For more reliable bioavailability discussions,
the study for brain and blood level of the compounds
should be required.
possesses weak or negligible affinity for other neuro-
transmitter receptors, namely, D1, D5, R1, R2, â, 5-HT1A
,
5-HT2A, 5-HT3, H1, M1, and M2 receptors.29 This profile
is highly specific as compared to those of haloperidol
and clozapine (Table 2). Moreover, compound 5c ex-
hibited full antagonist activity for D2, D3, and D4
receptors in in vitro functional assays.29
Con clu sion
We synthesized and evaluated a series of N-(3-
pyrrolidinyl)benzamide derivatives, 1, (R)-1, 2a -d , 5a -
l, (R)-5c-e, and 7, for their binding affinity for dop-
amine D2-like receptor subtypes. The SAR studies
indicate that the 4-substituent on the benzamide nuclei
and the N-substituent on the pyrrolidine ring play a
critical role in improving D3 and D4 selectivity over D2
receptors. Some preferential D3 and D4 antagonists
among them also exhibited potent inhibitory activity
against apomorphine-induced climbing behavior in mice.
The novel [(cyclopropylcarbonyl)amino]benzamide 5c
possesses high affinity for D3 and D4 receptors (Ki values
of 21 and 2.1 nM, respectively) and selectivity for D4
and D3 receptors (KiD2/KiD4 ) 110, KiD2/KiD3 ) 10) with
weak or negligible affinity for other neurotransmitter
receptors. In vivo, 5c exhibited inhibitory activity
against apomorphine-induced climbing behavior with an
ED50 value of 0.32 mg/kg (sc). To our knowledge, this
biological profile is markedly different from those of
known antipsychotics.10 Thus compound 5c may pro-
duce unique pharmacological effects, including atypical
antipsychotic effects. Further, we believe that 5c would
contribute to our understanding of the physiological and
pharmacological functions of D2-like receptor isoforms.
Exp er im en ta l Section
Ch em istr y. Melting points were measured on a Yanaco
MP-3 melting point apparatus and are uncorrected. Unless
1
stated otherwise, H NMR spectra were measured in DMSO-
d6 or CDCl3 with a J EOL FX90Q, FX100, EX400, or GX500
spectrometer; chemical shifts are expressed in δ units using
tetramethylsilane as the standard (in NMR description: s )
singlet, d ) doublet, t ) triplet, q ) quartet, se ) sextet, m )
multiplet, and br ) broad peak). Mass spectra were recorded
with a Hitachi M-80 or J EOL J MS-DX300 spectrometer. [R]20
D
was measured on a Horiba high-sensitive polarimeter (SEPA-
200). The optically pure materials (S)- (9) and (R)- (10)
3-amino-1-benzylpyrrolidine and (S)-3-[(tert-butoxycarbonyl)-
amino]pyrrolidine (11) were purchased from Tokyo Kasei Co.,
Ltd. The enantiomeric purity of 5c-e, and (R)-5c-e was
checked by HPLC analysis on a Hitachi HPLC system (L-
4000H UV detector, L-6200 pump, D-2500 chromatointegrator)
Among these benzamides, further in vitro character-
ization was done on the novel 4-[(cyclopropylcarbonyl)-
amino]benzamide 5c, which showed high affinity for D3
and D4 receptors, selectivity against D2 receptors, and
potent anticlimbing activity. Results showed that 5c

Dopamine D3 and D4 Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2769
utilizing a sugar-silica gel-based chiralcel OD-H column (4.6
i.d. × 250 mm) from Dicel Chemical Ind., Ltd., with the mobile
phase consisting of 0.1% Et2NH-EtOH and a flow rate on the
column of 0.4 mL/min at room temperature. The results
indicated that the compounds possess optical purity of at least
99.8% ee. Where elemental analyses (C, H, Cl, F, N) are
indicated only by symbols of the elements, analytical results
obtained for these elements were within 0.4% of theoretical
values except where otherwise stated.
white solid: mp 135-137 °C (EtOAc); [R]20 ) +41° (c ) 1.0
D
in THF); 1H NMR (DMSO-d6) δ 9.38 (s, 1H), 8.18 (d, 1H), 7.74
(s, 1H), 7.74 (s, 1H), 7.33 (d, 4H), 7.22-7.27 (m, 1H), 4.35 (m,
1H), 3.87 (s, 3H), 3.63 (d, 1H), 3.56 (d, 1H), 2.65-2.73 (m, 2H),
2.55-2.61 (m, 1H), 2.50 (t, 1H), 2.22-2.46 (m, 2H), 2.14-2.22
(m, 1H), 1.84 (d, 2H), 1.75 (d, 2H), 1.64-1.70 (m, 2H), 1.13-
1.45 (m, 4H); MS (FAB) m/ z 470 (M + 1). Anal. (C26H32N3O3-
Cl) C, H, N, Cl.
(S)-(+)-4-(Acr yloyla m in o)-N-(1-ben zyl-3-p yr r olid in yl)-
5-ch lor o-2-m eth oxyben za m id e (2b): 35% from 1; mp 122-
(S)-(+)-4-Am in o-N-(1-ben zyl-3-p yr r olid in yl)-5-ch lor o-
2-m eth oxyben za m id e (1). Benzamide 1 was prepared by
the previously described method for (()-1.27 To an ice/salt-
cold solution of 4-amino-5-chloro-2-methoxybenzoic acid (8;
8.06 g, 40.0 mmol) and triethylamine (6.07 g, 60.0 mmol) in
CH2Cl2 (400 mL) was added dropwise ethoxycarbonyl chloride
(4.68 g, 43.2 mmol), and the mixture was stirred for 20 min.
To this solution was added dropwise a solution of (S)-3-amino-
1-benzylpyrrolidine (9; 7.61 g, 43.2 mmol) in CH2Cl2 (50 mL),
and the mixture was stirred at the same temperature for 2 h.
The mixture was then allowed to warm to room temperature,
treated with saturated aqueous NaHCO3 (400 mL), and
extracted with CH2Cl2 (3 × 400 mL). The combined organic
layers were washed with saturated aqueous NaCl, dried over
Na2SO4, and concentrated in vacuo. The residue thus obtained
was purified by chromatography on silica gel using CHCl3-
methanol as eluent and recrystallized from ethyl acetate-
ether to give 10.7 g (74%) of benzamide 1 as a white solid:
1
123 °C (EtOAc-Et2O); [R]20 ) +45° (c ) 2.0 in MeOH); H
D
NMR (DMSO-d6) δ 9.78 (s, 1H), 8.21 (d, 1H), 7.84 (s, 1H), 7.75
(s, 1H), 7.33 (d, 4H), 7.23-7.31 (m, 1H), 6.69-6.76 (m, 1H),
6.33 (dd, 1H), 5.83 (dd, 1H), 4.36 (m, 1H), 3.88 (s, 3H), 3.65
(d, 1H), 3.58 (d, 1H), 2.70 (m, 2H), 2.45 (m, 2H), 2.14-2.33
(m, 1H), 1.70 (m, 1H); MS (FAB) m/ z 414 (M + 1). Anal.
(C22H24N3O3Cl‚0.5H2O) C, H, N, Cl; Cl: calcd, 8.38; found, 9.28.
(S)-(+)-4-(Ben zoyla m in o)-N-(1-ben zyl-3-p yr r olid in yl)-
5-ch lor o-2-m eth oxyben za m id e (2d ): 85% from 1; mp 63-
1
65 °C; [R]20 ) +31° (c ) 2.0 in MeOH); H NMR (DMSO-d6)
D
δ 7.15-7.40 (m, 11H), 5.86 (s, 1H), 5.15 (qu, 1H), 3.70 (s, 2H),
3.62 (s, 3H), 3.11 (t, 1H), 2.91-2.95 (m, 1H), 2.80-2.88 (m,
2H), 2.28 (t, 2H); MS(FAB) m/ z 464 (M + 1). Anal.
(C26H26N3O3Cl‚0.25H2O) C, H, N, Cl.
(S)-3-Am in o-1-cycloh exylp yr r olid in e Dih yd r och lor id e
(3a ‚2HCl). A solution of (S)-3-[(tert-butoxycarbonyl)amino]-
pyrrolidine (11; 10.0 g, 53.7 mmol) and cyclohexanone (5.55
g, 56.5 mmol) in methanol (250 mL) was hydrogenated under
atmospheric pressure with 10% palladium on carbon (0.20 g)
for 3 h at room temperature. The catalyst was filtered off,
and the filtrate was concentrated to a solid residue and washed
with a small amount of n-hexane to give 13.5 g (94%) of (S)-
3-[(tert-butoxycarbonyl)amino]-1-cyclohexylpyrrolidine as the
N-BOC intermediate: 1H NMR (CDCl3) δ 4.85 (br, 1H), 4.14
(m, 1H), 2.84 (m, 1H), 2.65 (m, 1H), 2.61 (m, 1H), 2.35 (m,
1H), 2.20-2.26 (m, 1H), 1.95-2.00 (m, 1H), 2.90 (m, 2H), 1.73
(m, 2H), 1.52-1.61 (m, 2H), 1.44 (s, 9H), 1.13-1.30 (m, 5H);
MS (EI) m/ z 268 (M).
The N-BOC intermediate, cyclohexylpyrrolidine (13.0 g, 48.4
mmol), was stirred with 4 N HCl-ethyl acetate solution until
evolution of gas ceased at room temperature. The resulting
precipitate was collected, washed with n-hexane, and dried
under vacuum overnight to give 11.01 g (94%) of the title
compound as a hygroscopic white solid. The product was used
without further purification in the next step: MS (EI) m/ z
168 (M).
The following examples (3b-f) were prepared by the method
described above using the appropriate aldehydes or ketones.
(S)-3-Am in o-1-cycloh ep t ylp yr r olid in e Dih yd r och lo-
r id e (3b‚2HCl). N-BOC intermediate: 96% from 11; 1H NMR
(DMSO-d6) δ 6.87 (d, 1H), 3.83 (br, 1H), 3.31 (s, 1H), 2.75 (t,
1H), 2.22-2.29 (m, 2H), 1.91-1.99 (m, 1H), 1.54-1.71 (m, 6H),
1.44-1.52 (m, 8H), 1.21 (s, 9H); MS (FAB) m/ z 283 (M + 1).
The title compound 3b, was obtained in 86% yield from the
intermediate.
mp 139-140 °C (EtOAc-Et2O); [R]20 ) +28° (c ) 2.0 in
D
MeOH); 1H NMR (CDCl3) δ 8.06 (s, 1H), 7.94 (brd, 1H), 7.29-
7.48 (m, 4H), 7.23-7.26 (m, 1H), 6.25 (s, 1H), 4.56-4.62 (m,
1H), 4.45 (brs, 1H), 3.84 (s, 3H), 3.65 (d, 1H), 3.59 (d, 1H),
2.87-2.90 (m, 1H), 2.62-2.69 (m, 2H), 2.30-2.40 (m, 2H),
1.68-1.75 (m, 1H); MS (FAB) m/ z 360 (M + 1). Anal.
(C19H22N3O3Cl) C, H, N, Cl.
(R)-(-)-4-Am in o-N-(1-ben zyl-3-p yr r olid in yl)-5-ch lor o-
2-m eth oxyben za m id e [(R)-1]. The title compound was
prepared by the method described above using (R)-3-amino-
1-benzylpyrrolidine (10). The compound exhibited the same
NMR and mass spectrum as its enantiomer 1: 80% from 8;
mp 136-138 °C (EtOAc-Et2O); [R]20 ) -28° (c ) 2.0 in
D
MeOH). Anal. (C19H22N3O3Cl) C, H, N, Cl.
Gen er a l Meth od for P r ep a r a tion of Ben za m id es 2a -
d . The compounds were prepared by acylation of 1 with acid
anhydride (for 2a ) and acid chloride (for 2b-d ).
(S)-N-(1-Ben zyl-3-p yr r olid in yl)-5-ch lor o-2-m eth oxy-4-
[(tr iflu or oa cetyl)a m in o]ben za m id e Hyd r och lor id e (2a ‚
HCl). To an ice-cold solution of compound 1 (0.50 g, 1.4 mmol)
in CH2Cl2 (50 mL) was added slowly a solution of trifluoro-
acetic anhydride (0.35 g, 1.7 mmol). After stirring for 1 h, the
reaction mixture was treated with saturated aqueous NaHCO3
(50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were washed with saturated aqueous NaCl,
dried over Na2SO4, and concentrated in vacuo to yield an oily
residue which was chromatographed on silica gel using
CHCl3-methanol as the eluent. The clear colorless syrup thus
obtained was converted into the HCl salt by treatment with 1
equiv of 4 N HCl-ethyl acetate solution in ether to provide
the title compound as a hygroscopic white solid (0.41 g, 60%):
mp 119-124 °C (Et2O); 1H NMR (CDCl3) δ 13.17 (br, 1H), 8.58
(s, 1H), 8.15 (d, 2H), 7.61 (dd, 2H), 7.44 (t, 3H), 5.13 (br, 1H),
4.25 (dd, 2H), 4.11 (s, 3H), 3.72 (br, 1H), 3.54 (m, 1H), 3.30
(br, 1H), 2.93 (br, 1H), 2.58-2.63 (m, 1H), 2.37-2.47 (m, 1H);
peaks caused by a small amount of ether observed at 3.38 (q)
and 1.09 (t); MS (FAB) m/ z 456 (M + 1). Anal. (C21H21N3O3F3-
Cl‚HCl‚0.5H2O‚0.1Et2O) C, H, N, Cl, F.
(S )-(+)-N -(1 -B e n z y l -3 -p y r r o l i d i n y l )-5 -c h l o r o -4 -
[(cycloh exylca r bon yl)a m in o]-2-m eth oxyben za m id e (2c).
To an ice-cold solution of compound 1 (0.30 g, 0.83 mmol) in
CH2Cl2 (15 mL), was added slowly a solution of cyclohexyl-
carbonyl chloride (0.15 g, 1.0 mmol). After stirring for 1 h,
the reaction mixture was treated with saturated aqueous
NaHCO3 (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were washed with saturated aqueous
NaCl, dried over Na2SO4, and concentrated in vacuo. The
residue thus obtained was purified by chromatography on
silica gel eluting with CHCl3-methanol and recrystallized
from ethyl acetate to give 0.22 g (56%) of benzamide 2d as a
(S)-3-Am in o-1-(bicyclo[3.3.1]n on -9-yl)p yr r olid in e d i-
h yd r och lor id e (3c‚2HCl): 88% from 11 (two steps); 1H NMR
(DMSO-d6) δ 10.73 (brs, 1H), 10.28 (brs, 1H), 8.80 (brs, 2H),
4.02-4.10 (m, 1H), 3.74-3.87 (m, 1H), 3.51-3.64 (m, 2H), 3.31
(m, 1H), 3.17-3.22 (m, 1H), 2.55 (m, 1H), 2.07-2.26 (m, 5H),
1.72-1.84 (m, 6H), 1.49-1.58 (m, 4H); MS (FAB) m/ z 209 (M
+ 1).
(S)-3-Am in o-1-(2-a d a m a n tyl)p yr r olid in e d ih yd r och lo-
1
r id e (3d ‚2HCl): 82% from 11 (two steps); H NMR (DMSO-
d6) δ 10.0-10.90 (m, 2H), 9.02 (s, 2H), 4.12-4.20 (m, 1H),
3.89-4.11 (m, 1H), 3.47-3.89 (m, 2H), 3.22-3.45 (m, 1H),
2.70-3.00 (m, 1H), 2.30-2.58 (m, 4H), 2.12-2.30 (m, 2H),
1.80-2.00 (m, 4H), 1.75-1.87 (m, 4H), 1.60-1.75 (m, 2H); MS
(EI) m/ z 220 (M).
(S)-3-Am in o-1-(cycloh exylm eth yl)p yr r olid in e d ih yd r o-
ch lor id e (3e‚2HCl): 77% from 11 (two steps); 1H NMR
(DMSO-d6) δ 11.07 (brs, 1H), 10.58 (brs, 1H), 8.78 (brd, 2H),
3.45-4.05 (m, 5H), 3.02-3.20 (m, 1H), 2.10-2.35 (m, 1H), 1.86
(m, 2H), 1.60-1.69 (m, 4H), 1.11-1.27 (m, 3H), 0.89-0.98 (q,
2H); MS (EI) m/ z 182 (M).
(S)-3-Am in o-1-p h en eth ylp yr r olid in e Dih yd r och lor id e
(3f‚2HCl). N-BOC intermediate: 71% from 11; 1H NMR

2770 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ohmori et al.
(CDCl3) δ 7.19-7.30 (m, 5H), 5.00 (m, 1H), 4.20 (m, 1H), 2.58-
3.10 (m, 7H), 2.20-2.40 (m, 2H), 1.56-1.71 (m, 1H), 1.49 (s,
9H); MS (FAB) m/ z 291 (M + 1). The title compound 3f was
obtained in 60% yield from the intermediate: MS (EI) m/ z
190 (M + 1).
(DMSO-d6) δ 9.45 (s, 1H), 8.18 (d, 1H), 7.79 (s, 1H), 7.73 (s,
1H), 7.33 (d, 4H), 7.25 (m, 1H), 4.35 (m, 1H), 3.87 (s, 3H), 3.63
(d, 1H), 3.56 (d, 1H), 2.65-2.73 (m, 2H), 2.37-2.50 (m, 4H),
2.13-2.22 (m, 1H), 1.64-1.72 (m, 1H), 1.09 (t, 3H); MS (FAB)
m/ z 416 (M + 1). Anal. (C22H26N3O3Cl‚0.25H2O) C, H, N, Cl.
(S)-(+)-N-(1-Ben zyl-3-p yr r olid in yl)-5-ch lor o-4-[(cyclo-
p r op ylca r bon yl)a m in o]-2-m eth oxyben za m id e (5c): 86%
5-Ch lor o-2-m eth oxy-4-(p r op ion yla m in o)ben zoic Acid
(4a ). To an ice-cold solution of 8 (0.76 g, 3.7 mmol) and
pyridine (0.63 g, 7.9 mmol) in CH2Cl2 (20 mL) was added
propionyl chloride (0.36 g, 3.9 mmol) dropwise. The mixture
was stirred overnight at room temperature, poured onto
aqueous 1 N HCl (20 mL), and extracted with CH2Cl2 (3 × 15
mL). The combined organic extracts were dried over Na2SO4
and concentrated in vacuo. The residue thus obtained was
purified by chromatography on silica gel eluting with CHCl3-
methanol to give 0.60 g (62%) of (propionylamino)benzoic acid
4a as a white solid: 62%; 1H NMR (DMSO-d6) δ 12.70 (br,
1H), 9.41 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 3.79 (s, 3H), 2.49
(q, 2H), 1.10 (t, 3H); MS (FAB) m/ z 258 (M + 1).
from 4c; mp 102-104 °C (Et2O); [R]20 ) +41° (c ) 2.0 in
D
1
MeOH); H NMR (CDCl3) δ 9.77 (s, 1H), 8.17 (d, 1H), 7.78 (s,
1H), 7.73 (s, 1H), 7.31-7.33 (m, 4H), 7.25 (m, 1H), 4.34 (m,
1H), 3.85 (s, 3H), 3.63 (d, 1H), 3.56 (d, 1H), 2.65-2.72 (m, 2H),
2.38-2.46 (m, 2H), 2.10-2.22 (m, 2H), 1.67 (m, 1H), 0.81-
0.85 (m, 4H); MS (FAB) m/ z 428 (M + 1). Anal. (C23H26N3O3-
Cl) C, H, N, Cl.
(R)-(-)-N-(1-Ben zyl-3-p yr r olid in yl)-5-ch lor o-4-[(cyclo-
p r op ylca r bon yl)a m in o]-2-m et h oxyben za m id e [(R)-5c]:
76% from 4c; exhibited same NMR and mass spectrum as its
enantiomer 5c; mp 102-103 °C (Et2O); [R]20 ) -41° (c ) 2.0
D
5-Ch lor o-2-m eth oxy-4-[(2-m eth ylpr opion yl)am in o]ben -
zoic Acid (4b). The title compound was prepared by the
method described for 4a using 2-methylpropionyl chloride:
35% yield; mp 133-134 °C (EtOAc); 1H NMR (DMSO-d6) δ 9.41
(br, 1H), 7.72 (s, 2H), 3.79 (s, 3H), 2.89 (q, 1H), 1.13 (d, 6H);
MS (FAB) m/ z 272 (M + 1).
in MeOH). Anal. (C23H26N3O3Cl) C, H, N, Cl.
(S )-(+)-N -(1 -B e n z y l -3 -p y r r o l i d i n y l )-5 -c h l o r o -4 -
[(cyclobu tylca r bon yl)a m in o]-2-m eth oxyben za m id e (5d ):
79% from 4d ; mp 109-110 °C (EtOAc-Et2O); [R]20D ) +36° (c
) 2.0 in MeOH); 1H NMR (CDCl3) δ 9.31 (s, 1H), 8.19 (d, 1H),
7.76 (s, 1H), 7.72 (s, 1H), 7.33 (d, 4H), 7.25 (m, 1H), 4.35 (m,
1H), 3.88 (s, 3H), 3.63 (d, 1H), 3.56 (d, 1H), 3.44 (t, 1H), 2.68
(m, 2H), 2.38-2.46 (m, 2H), 2.12-2.29 (m, 5H), 1.94 (m, 1H),
1.83 (m, 1H), 1.69 (m, 1H); MS (FAB) m/ z 442 (M + 1). Anal.
(C24H28N3O3Cl) C, H, N, Cl.
Meth yl 4-Am in o-5-ch lor o-2-m eth oxyben zoa te (12).31
A
solution of benzoic acid 8 (20.0 g, 99.2 mmol), potassium
carbonate (16.5 g, 119 mmol), and dimethyl sulfate (13.6 g,
109 mmol) in dimethyl sulfoxide (400 mL) was heated to reflux
for 4 h.32 After cooling to room temperature, the reaction
mixture was poured onto ice-water (500 g), and the resulting
precipitate was filtered, washed with H2O, and recrystallized
from methanol to give 16.0 g (75%) of methyl ester as a white
solid: 1H NMR (CDCl3) δ 7.83 (s, 1H), 6.29 (s, 1H), 4.46 (brs,
2H), 3.84 (s, 3H), 3.83 (s, 3H); MS (EI) m/ z 215 (M).
(R )-(-)-N -(1 -B e n z y l -3 -p y r r o l i d i n y l )-5 -c h l o r o -4 -
[(cyclobu tylca r bon yl)a m in o]-2-m eth oxyben za m id e [(R)-
5d ]: 97% from 4d ; exhibited the same NMR and mass
spectrum as its enantiomer 5d ; mp 110-112 °C (Et2O); [R]20
D
) -37° (c ) 2.0 in MeOH). Anal. (C24H28N3O3Cl) C, H, N,
Cl.
5-Ch lor o-4-[(cyclop r op ylca r bon yl)a m in o]-2-m eth oxy-
ben zoic Acid (4c). To an ice-cold solution of 12 (37.8 g, 175
mmol) and pyridine (30.5 g, 386 mmol) in CH2Cl2 (700 mL)
was added dropwise cyclopropylcarbonyl chloride (20.2 g, 193
mmol) in CH2Cl2 (100 mL). The solution was allowed to warm
to room temperature, stirred for 4 h, and then poured into H2O
(1 L). The organic layer was washed with saturated aqueous
NaCl (200 mL) and then H2O (200 mL), dried over Na2SO4,
and evaporated in vacuo. The solid residue was washed with
ether and dried under vacuum to give 43.1 g (87%) of acylated
intermediate. The product (41.8 g) was dissolved in DMSO
(120 mL) at 60 °C. The solution was cooled in a water bath
and added dropwise to aqueous 2 N NaOH (200 mL), and the
mixture was stirred for 30 min and then acidified with aqueous
6 N HCl to pH 1. The resulting precipitate was collected,
washed with H2O, and dried in vacuo to give 36.7 g (94%) of
(S)-(+)-N-(1-Ben zyl-3-p yr r olid in yl)-5-ch lor o-4-[(cyclo-
p en tylca r bon yl)a m in o]-2-m eth oxyben za m id e (5e): 78%
from 4e; mp 120-121 °C (EtOAc-Et2O); [R]20 ) +35° (c )
D
1
2.0 in MeOH); H NMR (CDCl3) δ 8.36 (s, 1H), 8.19 (d, 1H),
8.09 (d, 1H), 7.86 (s, 1H), 7.30-7.35 (m, 4H), 7.23-7.27 (m,
1H), 4.60 (m, 1H), 3.97 (s, 3H), 3.69 (d, 1H), 3.60 (d, 1H), 2.87-
2.92 (m, 1H), 2.77-2.84 (m, 1H), 2.64-2.70 (m, 2H), 2.31-
2.40 (m, 2H), 1.98-2.03 (m, 2H), 1.88-1.94 (m, 2H), 1.77-
1.84 (m, 2H), 1.66-1.74 (m, 3H); MS (FAB) m/ z 456 (M + 1).
Anal. (C25H30N3O3Cl‚0.25H2O) C, H, N, Cl.
(R)-(-)-N-(1-Ben zyl-3-p yr r olid in yl)-5-ch lor o-4-[(cyclo-
pen tylcar bon yl)am in o]-2-m eth oxyben zam ide [(R)-5e]: 68%
from 4e; exhibited the same NMR and mass spectrum as its
enantiomer 5e; mp 122-123 °C (EtOAc-Et2O); [R]20 ) -36°
D
(c ) 2.0 in MeOH). Anal. (C25H30N3O3Cl) C, H, N, Cl.
(S )-(+)-5-Ch lor o-N -(1-cycloh e xyl-3-p yr r olid in yl)-4-
[(cyclopr op ylca r bon yl)a m in o]-2-m eth oxyben za m id e (5f):
1
4c as a white solid: mp 167-169 °C; H NMR (DMSO-d6) δ
12.71 (br, 1H), 9.78 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 3.77 (s,
3H), 2.15 (m, 1H), 0.82-0.86 (m, 4H); MS (FAB) m/ z 270 (M
+ 1).
74% from 4c; mp 137-139 °C (n-hexane-EtOAc-Et2O); [R]20
D
1
) +35° (c ) 2.0 in MeOH); H NMR (CDCl3) δ 8.33 (s, 1H),
8.20 (s, 1H), 8.03 (br, 2H), 4.58 (m, 1H), 3.95 (s, 3H), 2.94 (m,
1H), 2.79 (m, 1H), 2.73 (m, 1H), 2.43 (dd, 1H), 2.31 (m, 2H),
2.07 (m, 1H), 1.90 (m, 2H), 1.75 (m, 3H), 1.59-1.65 (m, 2H),
1.25 (m, 5H), 1.12-1.14 (m, 2H), 0.93-0.97 (m, 2H); MS (FAB)
m/ z 420 (M + 1). Anal. (C22H30N3O3Cl) C, H, N, Cl.
(S)-N-[1-(Bicyclo[3.3.1]n on -9-yl)-3-pyr r olidin yl]-5-ch lor o-
4-[(cyclop r op ylca r b on yl)a m in o]-2-m et h oxyb en za m id e
(5h ): 71% from 4c; mp 159-163 C (MeOH); 1H NMR (CDCl3)
δ 9.80 (s, 1H), 8.20-8.21 (d, 1H), 7.80-7.81 (m, 2H), 4.35-
4.45 (m, 1H), 3.84 (s, 3H), 2.76-2.81 (m, 1H), 2.50-2.56 (m,
2H), 2.25-2.31 (m, 1H), 2.12-2.17 (m, 2H), 1.92-1.96 (m, 3H),
1.75-1.85 (m, 6H), 1.64-1.67 (m, 3H), 1.44-1.52 (m, 2H),
1.35-1.38 (m, 2H), 0.84-0.85 (m, 4H); MS (FAB) m/ z 460 (M
+ 1). Anal. (C25H34N3O3Cl) C, H, N, Cl.
The following examples (for 4d ,e) were prepared by the
method described for 4c using the appropriate acyl chloride.
5-Ch lor o-4-[(cyclob u t ylca r b on yl)a m in o]-2-m et h oxy-
ben zoic a cid (4d ): 89% from 12 (two steps); mp 174-176
°C;1H NMR (DMSO-d6) δ 12.70 (br, 1H), 9.26 (br, 1H), 7.89 (s,
1H), 7.72 (s, 1H), 3.80 (s, 3H), 3.42 (m, 1H), 1.68-2.41 (m, 6H);
MS (FAB) m/ z 284 (M + 1).
5-Ch lor o-4-[(cyclop en tylca r bon yl)a m in o]-2-m eth oxy-
ben zoic a cid (4e): 77% from 12 (two steps); mp 160-162 °C;
1H NMR (DMSO-d6) δ 12.73 (brs, 1H), 9.41 (s, 1H), 7.76 (s,
1H), 7.73 (s, 1H), 3.79 (s, 3H), 3.03 (m, 1H), 1.86-1.92 (m, 2H),
1.63-1.79 (m, 4H), 1.51-1.63 (m, 2H); MS (FAB) m/ z 298 (M
+ 1).
Gen er a l Meth od for P r ep a r a tion of Ben za m id es 5a -k
a n d (R)-5c-e. The compounds 5a ,c-f,h ,i and (R)-5c-e were
prepared by the method described for the preparation of 1
utilizing the appropriate (S)- or (R)-aminopyrrolidines 3a -f,
9, and 10 and benzoic acids 4a ,c-e. The compounds 5b,g,j,k
were prepared by the diphenyl phosphorazidate method33
utilizing the aminopyrrolidines 3b,e,f and 9 and benzoic acids
4b,c.
(S)-(+)-N-[1-(2-Ad a m a n tyl)-3-p yr r olid in yl]-5-ch lor o-4-
[(cyclopr op ylca r bon yl)a m in o]-2-m eth oxyben za m id e (5i):
71% from 4c; mp 162-168 °C (EtOH); [R]20 ) +20° (c ) 1.0
D
1
in THF); H NMR (CDCl3) δ 9.81 (s, 1H), 8.21-8.23 (d, 1H),
7.80-7.81 (m, 2H), 4.35-4.45 (m, 1H), 3.84 (s, 3H), 2.80-2.85
(m, 1H), 2.56-2.61 (m, 1H), 2.47-2.51 (m, 1H), 2.22-2.26 (m,
1H), 2.02-2.19 (m, 5H), 1.85-1.95 (m, 2H), 1.79-1.81 (m, 4H),
1.65-1.69 (m, 5H), 1.41-1.44 (m, 2H), 0.84-0.85 (m, 4H); MS
(FAB) m/ z 472 (M + 1). Anal. (C26H34N3O3Cl‚0.5H2O) C, H,
N, Cl; Cl: calcd, 7.37; found, 8.30.
(S)-(+)-N-(1-Ben zyl-3-pyr r olidin yl)-5-ch lor o-2-m eth oxy-
4-(p r op ion yla m in o)ben za m id e (5a ): 72% from 4a ; mp 147-
149 °C (Et2O-EtOH); [R]20D ) +43° (c ) 1.0 in THF); 1H NMR

Dopamine D3 and D4 Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2771
(S)-(+)-N-(1-Ben zyl-3-pyr r olidin yl)-5-ch lor o-2-m eth oxy-
4-[(2-m eth ylp r op ion yl)a m in o]ben za m id e (5b). To an ice-
cold solution of benzoic acid 4b (0.30 g, 1.10 mmol), pyrrolidine
8 (0.23 g, 1.30 mmol), and triethylamine (0.17 g, 1.66 mmol)
in DMF (20 mL) was added dropwise diphenyl phosphorazidate
(0.37 g, 1.35 mmol). The reaction mixture was stirred at the
same temperature for 4 h and then allowed to warm up to
room temperature. The reaction was quenched with saturated
aqueous NaHCO3, the mixture was diluted with ethyl acetate
(30 mL), and the organic layer was washed with saturated
aqueous NaCl. The organic extract was dried over Na2SO4
and concentrated in vacuo to yielded an amorphous residue
which was chromatographed on silica gel using CHCl3-
methanol as the eluent. The white solid thus obtained was
recrystallized from ether to provide the title compound as a
The product (1.07 g, 4.38 mmol) was stirred with 4 N HCl-
ethyl acetate solution until evolution of gas ceased at room
temperature. The solution was evaporated under vacuum, and
the solid residue was washed with ether and dried in vacuo
to yield the title compound (0.75 g, 78%) as a white solid: MS
(FAB) m/ z 183 (M + 1).
(S)-(+)-5-Ch lor o-4-[(cyclop r op ylca r b on yl)a m in o]-2-
m et h oxy-N-(3-p yr r olid in yl)b en za m id e H yd r och lor id e
(7‚HCl). To an ice-cold solution of benzoic acid 4c (0.88 g,
3.25 mmol), pyrrolidine 6‚HCl (0.71 g, 3.25 mmol), and
triethylamine (0.82 g, 8.12 mmol) in DMF (50 mL) was added
dropwise diphenyl phosphorazidate (1.07 g, 3.90 mmol). The
reaction mixture was stirred at room temperature overnight
and then evaporated in vacuo. The residue was diluted with
ethyl acetate (30 mL) and washed with saturated aqueous
NaHCO3 and then saturated aqueous NaCl. The organic layer
was dried over Na2SO4 and concentrated in vacuo to yielded
an amorphous residue which was chromatographed on silica
gel using CHCl3-methanol as the eluent to provide the
N-trifluoroacetyl intermediate as a white solid (1.23 g, 87%):
1H NMR (CDCl3) δ 8.37 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.92
(dd, 1H), 4.67-4.77 (m, 1H), 3.88-4.13 (m, 1H), 3.95 (s, 3H),
3.58-3.83 (m, 3H), 2.26-2.44 (m, 1H), 2.00-2.18 (m, 1H),
1.62-1.68 (m, 1H), 1.12-1.16 (m, 2H), 0.95-0.99 (m, 2H); MS
(FAB) m/ z 434 (M + 1).
white solid (0.26 g, 55%): mp 95-97 °C (Et2O); [R]20 ) +35°
D
1
(c ) 2.0 in MeOH); H NMR (CDCl3) δ 8.37 (s, 1H), 8.19 (d,
1H), 8.09 (d, 1H), 7.88 (s, 1H), 7.28-7.35 (m, 3H), 7.23-7.26
(m, 2H), 4.59-4.64 (m, 1H), 3.98 (s, 3H), 3.69 (d, 1H), 3.61 (d,
1H), 2.87-2.92 (m, 1H), 2.59-2.70 (m, 3H), 2.32-2.41 (m, 2H),
1.70-1.75 (m, 1H), 1.31 (s, 3H), 1.30 (s, 3H); MS (FAB) m/ z
430 (M + 1). Anal. (C23H28N3O3Cl) C, H, N, Cl.
(S)-(+)-5-Ch lor o-N-(1-cycloh ep t yl-3-p yr r olid in yl)-4-
[(cyclopr opylcar bon yl)am in o]-2-m eth oxyben zam ide (5g):
52% from 4c; mp 98-100 °C (Et2O); [R]20 ) +37° (c ) 2.0 in
D
MeOH);1H NMR (CDCl3) δ 9.77 (s, 1H), 8.14 (d, 1H), 7.79 (s,
1H), 7.77 (s, 1H), 4.32 (m, 1H), 3.84 (s, 3H), 2.74 (m, 1H), 2.68
(m, 1H), 2.52 (m, 1H), 2.35-2.41 (m, 2H), 2.06-2.17 (m, 2H),
1.48-1.73 (m, 11H), 1.38-1.42 (m, 2H), 0.81-0.86 (m, 4H);
MS (FAB) m/ z 434 (M + 1). Anal. (C23H32N3O3Cl) C, H, N,
Cl.
The intermediate (1.01 g, 2.33 mmol) in a solution of MeOH
(50 mL) and H2O (10 mL) was treated with K2CO3 (0.64 g,
4.66 mmol) for 1 h at room temperature. The reaction mixture
was evaporated under vacuum, and the amorphous residue
was purified by chromatography on silica gel eluting with 1%
NH4OH/CHCl3-MeOH (2:1), treated with 1 equiv of 4 N HCl-
ethyl acetate solution in ethyl acetate, and dried under vacuum
to give the title compound (0.23 g, 29%) as a white solid: mp
(S)-(+)-N-[1-(Cycloh exylm eth yl)-3-p yr r olid in yl]-5-ch lo-
r o -4-[(c y c lo p r o p y lc a r b o n y l)a m in o ]-2-m e t h o x y b e n z-
a m id e (5j): 38% from 4c; mp 170-171 °C (EtOAc-Et2O);
213-214 °C (EtOAc); [R]20 ) +15° (c ) 1.0 in MeOH); 1H
D
[R]20 ) +37° (c ) 1.0 in THF); 1H NMR (DMSO-d6) δ 9.79 (s,
NMR (CDCl3 + DMSO-d6) δ 8.41 (s, 1H), 8.34 (d, 1H), 8.28 (s,
1H), 8.09 (s, 1H), 4.79-4.83 (m, 1H), 4.04 (s, 3H), 3.47-3.56
(m, 2H), 3.37-3.41 (m, 1H), 3.25-3.32 (m, 1H), 2.39 (se, 1H),
2.19 (se, 1H), 1.78-1.82 (m, 1H), 1.08-1.12 (m, 2H), 0.92-
0.97 (m, 2H); MS (FAB) m/ z 338 (M + 1). Anal. (C16H20N3O3-
Cl‚HCl‚0.5H2O) C, H, N, Cl; Cl: calcd, 18.50; found, 19.02.
D
1H), 8.15 (d, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 4.34 (m, 1H), 3.84
(s, 3H), 2.65-2.70 (m, 1H), 2.56 (dd, 1H), 2.46 (dd, 1H), 2.09-
2.34 (m, 5H), 1.77 (t, 2H), 1.64 (m, 4H), 1.42 (m, 1H), 1.12-
1.25 (m, 3H), 0.83-0.86 (m, 6H); slight CHCl3 peak observed
at 8.32 (s), which was derived from the eluent of column
chromatography; MS (FAB) m/ z 434 (M + 1). Anal.
(C23H32N3O3Cl‚0.02CHCl3) C, H, N, Cl.
Biology. Exp r ession of Recom bin a n t Recep tor s a n d
Ra d iobin d in g Assa ys. The cloning of cDNAs, transfection
into Chinese hamster ovary (CHO) cells, and membrane
preparations for rat D2L (D2), rat D3 (D3), and human D4.7 (D4,
containing seven polymorphic tandem repeats) receptors have
been described in our previous reports.29,36 Radioligand bind-
ing assays on D2 and D3 receptors were carried out in 30 mM
HEPES-NaOH, 100 mM NaCl, and 10 mM MgCl2 (pH 7.4),
including either D2 or D3 receptor-expressed CHO cell mem-
brane, 0.25 nM [125I]iodosulpride, and vehicle, competing drug,
or nonspecific ligand. In studies on D4 receptors, the reaction
buffer consisted of 50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl,
1.5 mM CaCl2, 5 mM MgCl2, and 5 mM EDTA (pH 7.4),
including D4 receptor-expressed CHO cell membrane, 0.26 nM
[3H]nemonapride, and vehicle, competing drug, or nonspecific
ligand. The nonspecific ligands were used as follows: 10 µM
sulpiride for D2 receptors, 10 µM quinpirole for D3 receptors,
and 1 mM dopamine for D4 receptors, respectively. After the
reaction mixture was incubated at 25 °C for 60 min, the assay
was terminated by a standard filtration method. The condi-
tions of radioligand receptor binding assays for D1, D5, R1, R2,
â, 5-HT1A, 5-HT2A, 5-HT3, H1, M1, and M2 receptors were
described previously.29,36 In all binding studies, the IC50 value
was calculated by logit-log analysis with linear least-squares
regression and converted to the Ki value as described previ-
(S)-(+)-5-Ch lor o-4-[(cyclop r op ylca r b on yl)a m in o]-2-
m eth oxy-N-(1-p h en eth yl-3-p yr r olid in yl)ben za m id e fu -
m a r a te (5k ‚C4H4O4): 43% from 4c; amorphous (wash with
1
EtOH); [R]20 ) +29° (c ) 2.0 in MeOH); H NMR (CDCl3) δ
D
8.31 (s, 1H), 8.28 (d, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.19-7.31
(m, 5H), 6.80 (s, 2H), 4.76 (m, 1H), 4.01 (s, 3H), 3.34 (m, 1H),
3.18 (m, 1H), 2.85-3.15 (m, 5H), 2.65 (m, 1H), 2.43 (m, 1H),
1.98 (m, 1H), 1.61 (m, 1H), 1.11-1.15 (m, 2H), 0.92-0.97 (m,
2H); MS (FAB) m/ z 442 (M + 1). Anal. (C24H28N3O3-
Cl‚C4H4O4‚1.5H2O) C, H, N, Cl.
(S)-(+)-N-[1-(Bicyclo[3.3.1]n on -9-yl)-3-p yr r olid in yl]-5-
ch lor o-2-m eth oxy-4-(m eth yla m in o)ben za m id e (5l). The
title compound was prepared from 5-chloro-2-methoxy-4-
(methylamino)benzoic acid (4f)27 and pyrrolidine 3c using the
method described for 1: 30% from benzoic acid; mp 183-184
1
°C (EtOAc); [R]20 ) +45° (c ) 1.0 in THF); H NMR (CDCl3)
D
δ 8.11 (s, 1H), 8.08 (br, 1H), 6.10 (s, 1H), 4.70 (brd, 1H), 4.63
(m, 1H), 3.94 (s, 3H), 2.95 (d, 3H), 2.74 (d, 1H), 2.45 (dd, 1H),
2.17-2.28 (m, 2H), 1.65-2.06 (m, 13H), 1.48-1.53 (m, 2H),
1.40-1.43 (m, 2H); MS (FAB) m/ z 406 (M + 1). Anal.
(C22H32N3O2Cl) C, H, N, Cl.
(S)-3-Am in o-1-(tr iflu or oa cetyl)p yr r olid in e Hyd r och lo-
r id e (6‚HCl). To a solution of 11 (1.00 g, 5.37 mmol) and
pyridine (0.51 g, 6.44 mmol) in CH2Cl2 (25 mL) was added
dropwise trifluoroacetic anhydride (1.24 g, 5.91 mmol). The
reaction mixture was stirred overnight at room temperature
and then evaporated in vacuo. The remaining oil was diluted
with ethyl acetate (50 mL), washed with H2O (50 mL) twice,
dried over Na2SO4, and then concentrated under vacuum. The
crude product was purified by chromatography on silica gel
eluting with CHCl3-MeOH to give the N-BOC intermediate
as an oil (1.18 g, 90%): 1H NMR (CDCl3) δ 4.67-4.74 (m, 1H),
4.17-4.40 (m, 1H), 3.36-3.99 (m, 4H), 1.82-2.30 (m, 1H), 1.45
(s, 9H); MS (FAB) m/ z 227 (M - H2O + 1).
ously.38
[
125I]Iodosulpride and [3H]nemonapride were pur-
chased from Amersham and DuPont-New England Nuclear,
respectively.
Beh a vior a l Test on Ap om or p h in e-In d u ced Clim b-
in g.30,34 Male ICR mice (30-40 g) (N ) 8-12) were individu-
ally habituated for 2 h in wire mesh cages. Apomorphine was
subcutaneously injected 15 min after the administration of test
compounds. Climbing behavior was scored every 1 min for
30 min beginning 10 min after treatment with apomorphine
according to the intensity scale 0 ) absent, 0.5 ) occasional,
and 1 ) continuous.

2772 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
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Ack n ow led gm en t. We thank Drs. K. Murase, T.
Yamaguchi, and K. Koshiya for their encouragement
and helpful discussion, Dr. Y. Tasaki and Ms. T.
Nomura for biochemical studies, and the staff of the
Structure Analysis Department for measurements of
NMR, mass spectra, and elemental analyses at the
Institute for Drug Discovery Research, Yamanouchi
Pharmaceutical Co., Ltd.
Su p p or tin g In for m a tion Ava ila ble: Chiral HPLC chart
for compounds 5c-e and (R)-5c-e (6 pages). Ordering
information is given on any current masthead page.
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