Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT(1A), and adrenergic α1 receptors

Article abstract of DOI:10.1021/jm970164z

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D₂, serotonin 5- HT(1A), and α₁-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1- methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

Full text of DOI:10.1021/jm970164z

© Copyright 1998 by the American Chemical Society
Volume 41, Number 12
J une 4, 1998
Articles
Or a lly Active Ben za m id e An tip sych otic Agen ts w ith Affin ity for Dop a m in e D2,
Ser oton in 5-HT1A, a n d Ad r en er gic r1 Recep tor s
Allen B. Reitz,* Ellen W. Baxter, Ellen E. Codd, Coralie B. Davis, Alfonzo D. J ordan, Bruce E. Maryanoff,
Cynthia A. Maryanoff,§ Mark E. McDonnell, Eugene T. Powell, Michael J . Renzi, Mary R. Schott,
Malcolm K. Scott, Richard P. Shank, and J effry L. Vaught†
Drug Discovery Division, R. W. J ohnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477
Received March 12, 1997
New antipsychotic drugs are needed because current therapy is ineffective for many schizo-
phrenics and because treatment is often accompanied by extrapyramidal symptoms and
dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related
(aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These
compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and R1-adrenergic receptors.
The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine
(mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials.
The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the
aniline nitrogen of 6 is not required for activity. Other particularly active structures include
homopiperidine amide 14 and N-methylcyclohexylamide 31.
Schizophrenia is a debilitating disease which inflicts
great emotional distress and financial loss on those who
suffer from it.1,2 The first effective antipsychotic drugs
such as chlorpromazine (1) (Chart 1), introduced in the
early 1950s, also produced undesirable effects such as
extrapyramidal symptoms and dyskinesias.3 Eliminat-
ing these unwanted effects has been a continuing goal
of antipsychotic drug research. The ideal drug would
treat both positive (hallucinations, delusions) and nega-
tive (apathy, withdrawal) symptoms of the disease.1c-g
Safer and more effective medication is expected to
improve the relatively low rate of patient compliance
observed with current therapy.4
on the market or in development modulate serotonin
(5-HT) receptors.7,8 Clozapine (2) binds with greatest
affinity to D4 receptors at physiologically relevant
concentrations,5a and risperidone (3) displays high af-
finity for both D2 and 5-HT2 receptors.9 Haloperidol (4)
is a D2 blocker that also shows affinity for 5-HT2
receptors and σ binding sites.10 Newer antipsychotics
such as olanzepine, sertindole, and ziprasidone are
useful because of their atypical biological profile
We had reported an earlier series of arylpiperazines
which showed affinity for both D2 and 5-HT1A receptors,
from which compound 5 (RWJ -25730) was chosen for
further evaluation.11,12 However, administration of 5
caused deposition of red-colored bodies in the fundus
region of dog stomachs, probably due to rapid decom-
position via a reverse-Mannich reaction in the presence
of aqueous acid (t1/2 ca. 80 min at pH 2).13 Therefore,
we embarked on a program involving replacement of the
pyrrole ring in 5 with a variety of alternatives, main-
taining roughly the same overall relationship of the
Marketed antipsychotics antagonize dopamine recep-
tors in the brain, particularly those of the dopamine D2-
D4 subtypes,1,5 and there are many different chemical
series that have been investigated as putative antipsy-
chotics.6 Many compounds with antipsychotic activity
§ Chemical Development.
† Present affiliation: Cephalon, Inc.
S0022-2623(97)00164-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/01/1998

1998 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Reitz et al.
Ch a r t 1
shown in Scheme 2. Commercially available phenol 34
was alkylated with isopropyl bromide to give isopropyl
ether 35. Catalytic reduction of 35 then afforded aniline
36, which was reacted with bis(chloroethyl)amine yield-
ing piperazine 37.
Since substituted bicyclic arylpiperazines have con-
sistently exhibited potent serotonergic binding,16,19 we
prepared and evaluated several derivatives of this
structural type (viz. 39-41 and 43). The benzodioxane
eltoprazine (38) (Chart 2) has been reported to have
strong 5-HT1A affinity and is a member of a group of
compounds investigated as “serenics”,19c,d which was the
reason we prepared derivative 39. The benzofuran-
ylpiperazine used in the preparation of compound 40
was obtained by a literature procedure.19b Since N-(1-
naphthyl)piperazine has excellent 5-HT1 receptor af-
finity,19a and substituted derivatives such as compound
42 also have a dopaminergic component to their binding
profile,16g we synthesized naphthylpiperazine 43. The
N-(2-pyrimidinyl)piperazinyl moiety is associated with
5-HT1A receptor affinity mainly because of the anxiolytic
buspirone (44),20 and we prepared corresponding con-
gener 45 in our series as well.
Remoxipride (46) is an antipsychotic which has a
benzamide functionality in its structure.21 Since we also
have a benzamide in lead compound 6, we incorporated
the remoxipride pyrrolidine amide substructure in the
design and preparation of derivative 47. 4-Fluorophen-
ylamide 48 was synthesized as a representative example
of N-arylamide substitution.
Since the benzyl C-N bond was another major site
of metabolism,18 we attempted to block this metabolism
by inserting methyl substitution as shown in Scheme
3. Reductive amination of 3-acetylbenzonitrile with (2-
isopropoxyphenyl)piperazine gave 52, which was then
hydrolyzed (NaOH/EtOH) to afford acid 53. Coupling
of 53 with piperidine using dicyclohexylcarbodiimide
(DCC) produced R-methyl derivative 54.
Chain-extended analogues of 4-substituted benza-
mides were prepared in order to investigate the effects
of increasing the distance between the amide carbonyl
and the arylpiperazine upon biological activity (Scheme
4). 4-Bromophenethyl bromide was reacted with (2-
isopropoxyphenyl)piperazine to give 55. A palladium-
mediated amidation reaction22 then produced two-
carbon spacer derivative 56. Reaction of 4′-chloro-4-
bromobutyrophenone with (2-isopropoxyphenyl)piper-
azine yielded 57 which was then subjected to the
carbonylation reaction to afford 58. Reduction of 58
sequentially led to alcohol 59 and alkane 60 as shown.
amide and arylpiperazine functionalities.14 During the
course of this effort, benzamide 6 (RWJ -37796, maza-
pertine) was identified. It binds with high affinity to
D2, D3, D4, 5-HT1A, and R1-adrenergic receptors (Ki
values < 3 nM) and has potent in vivo activity in animal
tests predictive of antipsychotic efficacy in humans.15
The combination of dopaminergic and 5-HT1A affinity
is relatively unique and has been observed in certain
other chemical series as well.16 Both 5 and 6 exhibit a
low tendency to produce catalepsy in rats, a measure
of their liability for side effects in humans.17 In this
paper we describe new structure-activity studies on
compounds related to benzamide 6, systematically vary-
ing each portion of the molecule in order to gain insight
into the structural requirements for biological activity.
Syn th etic Ch em istr y
We examined the effects of amide modification by
preparing thioamide 61 (Chart 2) from 6 upon treatment
with Lawesson’s reagent and sulfonamide 62 which was
prepared by the standard route (viz. Scheme 1) using
3-(BrCH2)PhSO2Br.23
4-Arylpiperidine variants were prepared as shown in
Scheme 5. 2-Bromophenol was reacted with isopropyl
bromide to give ether 63, which was then converted to
the corresponding Grignard reagent and treated with
N-carbethoxy-4-piperidone to afford 64. The hydroxyl
group of 64 was removed by treatment with 10% Pd/C
to give piperidine 65. Removal of the carbethoxy group
under basic conditions afforded 66 which was converted
to 67 upon reaction with the appropriate benzyl chlo-
2- and 3-Substituted benzamides were prepared by
the method shown in Scheme 1 via reaction of (halo-
methyl)benzoyl halides with amines to give (halometh-
yl)benzamides, followed by reaction with the requisite
piperazines. The compounds prepared in this manner
are listed in Table 1. For the preparation of compound
7, piperazine itself (10 mol equiv) was used in the
reaction sequence. Methyl ether 10 was prepared by
reaction of alcohol 9 with methyl iodide. The prepara-
tion of 4-fluoro derivative 33 was conducted because the
4-position on the aryl ring was found to be a major site
of oxidation during metabolism.18 The necessary pip-
erazine intermediate to prepare 33 was synthesized as

Orally Active Benzamide Antipsychotic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 1999
Sch em e 1
Sch em e 2
congener 8. Alcohol 9 and ether 10, which have an
oxygen two atoms removed from the piperazine in a
manner similar to 6, were also inactive, clearly estab-
lishing the need for the aryl ring for activity. Unsub-
stituted phenyl derivative 11 had no observed binding
at the D2 receptor but did have 5-HT1A and R1-adren-
ergic affinity.
Among the aryl substitutions examined, 2-alkoxy-
phenyl was the most active. In a homologous series
2-methoxy (12), 2-ethoxy (13), and 2-isopropoxy (14)
substitution revealed that increasing the size of the
alkoxy group had little effect upon 5-HT1A or R1 binding
but did have a pronounced effect upon D2 binding and
catalepsy production. The series 12-14 showed a
progression of 201, 57, and 6.3 nM D2 Ki’s and 70.0%,
47.5%, and 27.8% catalepsy at 50 mg/kg ip (60-min
pretreatment time). Compounds 12-14 were very
active in the CAR test. Indeed, the oral activity of 14
is comparable to that of 6, and 14 even displays greater
activity at the longer pretreatment time (120 min). Our
SAR program focused primarily on 2-isopropoxyphenyl
substitution, although we did examine other 2-substit-
uents as well (15-19). The electron-withdrawing CF3,
F, Cl, and CN derivatives all showed pronounced
binding to the 5-HT1A receptor (<20 nM Ki), but the D2
affinity was considerably lower (>60 nM Ki) except for
15 which had a 16 nM D2 receptor Ki. The in vivo
activity in CAR for these compounds was less than that
seen for 6 or 14. The 2-propyl derivative (19) is
noteworthy because it is an analogue of ethoxy com-
pound 13 with the ethoxy oxygen being exchanged for
a methylene group. Even though 13 and 19 have
somewhat comparable affinities at the three receptors,
19 is devoid of in vivo CAR activity. 3-Substituted
arylpiperazines (20-22) had fair affinity for the 5-HT1A
receptor (<25 nM Ki) but very little activity elsewhere.
4-Chlorophenyl analogue 23 had very little activity in
any of the tests except for a 121 nM Ki at the 5-HT1A
receptor.
ride. Since haloperidol (4) has 4-aryl-4-hydroxypiperi-
dine substitution, we wanted to prepare 69 and examine
its biological activity. Intermediate 64 was deprotected
with KOH/DMSO to give benzyl alcohol 68, which was
then converted to target alcohol 69.
Str u ctu r e-Activity Rela tion sh ip s (SAR)
The test compounds were evaluated in the conditioned
avoidance response (CAR) assay in rats as the primary
in vivo screen for antipsychotic activity (Table 2).24 This
test measures the ability of a compound to lessen the
conditioned response to a disagreeable stimulus. CAR
testing results are reported as either ED50 values for a
few selected compounds or percent inhibition at a fixed
dose. The animals were either allowed free access to
food prior to the experiment or deprived of food for the
evening before. The CAR activity (ED50 values) for 6
in Table 2 is given both ip and po so that the activity of
the other target compounds can be directly compared.
The catalepsy test in rats was used as a measure of EPS
liability,17 and data for 13 of the target compounds are
given in Table 3. Binding affinity at the D2, 5-HT1A
,
and R1A-adrenergic receptors was evaluated in competi-
tion experiments against standard radioligands in syn-
aptosomal membrane preparations as described in the
Experimental Section.
The need for the aryl moiety of the arylpiperazine
found in 6 was demonstrated by the inactivity of
derivatives 7-10. The NH compound (7) had no in vivo
or receptor binding activity, and neither did N-Me
The effect of amide modifications was systematically
examined. Primary amide 24 had modest activity which
was increased upon conversion to cyclic amide struc-
tures such as 25 and 26. As the size of the ring
increased from four- to eight-membered (25, 26, 6, 14,
Ch a r t 2

2000 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Ta ble 1. 3-(Piperazinylmethyl)benzamides
Reitz et al.
%
yield
recrystn
solvent
compda
R1
R2
mp (°C)
formulab
anal.
6
7
8
IPP
H
Me
HO(CH2)2
MeO(CH2)2
Ph
MPP
EPP
IPP
2-CF3Ph
2-FPh
2-ClPh
2-CNPh
2-PrPh
3-CF3Ph
3-ClPh
3-NO2Ph
4-ClPh
IPP
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-homopiperidinyl
N-homopiperidinyl
N-piperidinyl
N-homopiperidinyl
N-homopiperidinyl
N-homopiperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
N-piperidinyl
NH2
45
68
21
37
10
19
14
30
32
48
82
46
30
59
24
55
42
66
68
18
35
30
iPrOH/Et2O
MeOH/Et2O
MeOH/EtOAc 151-152
222-227
C26H33N3O2‚1.5HCl
C,H,N,Cl
189.5-192
C17H25N3O‚1.65C2H2O4‚0.35HCl C,H,N,H2O
C
18H37N3O‚2HNO3
C,H,N
9
iPrOH/MeOH 175.5-177.5 C20H31N3O2‚1.8C4H4O4(f)‚0.3H2O C,H,N,H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
iPrOH/MeOH 184-188
MeCN
iPrOH
C21H33N3O2‚C4H4O4(f)‚0.25H2O
C,H,N,H2O
C,H,N
134-136
196-198
C
C
C
23H29N3O‚HCl
25H33N3O2‚HCl‚1.5H2O
26H35N3O2‚HCl
C,H,N,Cl,H2O
C,H,N,H2O
C,H,N,Cl
C,H,N,Cl,F
C,H,N,F,H2O
C,H,N,Cl
C,H,N
MeOH/EtOAc 188-190
iPrOH/Et2O
iPrOH/Et2O
MeOH/Et2O
iPrOH/Et2O
MeOH/Et2O
MeCN/Et2O
iPrOH/Et2O
EtOAc
iPrOH
MeOH/Et2O
CH2Cl2
iPrOH/Et2O
iPrOH/Et2O
MeOH-Et2O
212-214
210-211.5
C27H37N3O2‚HCl
C24H28F3N3O‚HCl
192.5-194.5 C23H28FN3O‚C2H4O2‚0.14H2O
170-174
182-184
C23H28ClN3O‚HCl
C24H28N4O‚0.85C4H4O4(f)
190.5-192.5 C26H35N3O‚HCl
C,H,N,Cl
C,H,N,H2O
C,H,Nc
207-209
183-184
194-197
172-175
172-175
122-124
197-199
172-174
C24H28F3N3O‚HCl‚0.3H2O
23H28ClN3O‚HCl
C
C23H28N4O3‚C4H4O4(f)
C23H28ClN3O‚HCl‚0.5H2O
C21H27N3O2
C,H,Nd
C,H,N,Cl,H2O
C,H,N
C,H,N
C,H,N,Cl
C,H,N
IPP
IPP
IPP
N-azetidinyl
N-pyrrolidinyl
N-heptamethyl-
enimine
C24H31N3O2‚C4H4O4(m)
C25H33N3O2‚1.5HCl
C26H39N3O2‚C2H2O4
28
29
30
31
32
33
39
IPP
IPP
IPP
IPP
NEt2
NBu2
NH(cC6H11
NMe(cC6H11
N-morpholinyl
N-piperidinyl
12
24
38
10
16
32
49
EtOAc
175.5-180
163-167
C25H35N3O2‚1.5HCl
C29H43N3O2‚1.4HCl
C27H37N3O2‚2HCl‚H2O
C,H,N,Cl
iPrOH/Et2O
CH2Cl2/Et2O
iPrOH/Et2O
MeOH/Et2O
iPrOH/Et2O
C,H,N,Cl
)
170-175
C,H,N,H2Oe
)
170-172.5
145-148
204-206.5
C26H39N3O2‚C4H4O4(f)‚0.5C3H8O C,H,N
IPP
C25H33N3O3‚1.85HCl‚H2O
C26H35FN3O2‚1.5HCl
C25H31N3O3‚1.4HClO4
C,H,N,Cl,H2O
4-F-2-(OiPr)Ph
3-benzodioxanyl N-piperidinyl
C,H,N,Cl,Ff
C,H,N,Clg
iPrOH/MeOH/ 150-156
Et2O
40
41
6-benzofuranyl N-piperidinyl
40
52
iPrOH/Et2O/
hexane
MeOH/EtOAc 243.5-244
155-158
C25H29N3O2‚HCl‚H2O
C,H,N,Br,H2O
C,H,N
3-(1,2-benzoiso- N-piperidinyl
thiazolyl)
C24H28N4OS‚1.1HCl
43
45
47
1-naphthyl
2-pyrimidinyl
IPP
N-piperidinyl
N-piperidinyl
63
11
10
iPrOH/Et2O
iPrOH
EtOH/Et2O
137-140
107-108
192-195
C27H31N3O‚0.8C4H4O4(m)
21H27N5O
C28H40N4O2‚2.6HBr‚1.5H2O‚
0.5EtOH
C,H,N
C,H,N
C,H,N,Br
C
48
49
IPP
IPP
NH(4-F)Ph
17
28
MeOH/iPrOH/ 149-151
pentane
MeCN/MeOH 198-199
C
27H30FN3O2‚1.5HCl
C,H,N,F,Clh
C,H,N,H2O
C29H33N3O2‚C2H2O4‚0.1H2O
50
51
IPP
IPP
30
13
EtOH
159-161
C24H31N3O3‚C2H2O4
C,H,N
C,H,N
iPrOH
131.5-133
C26H33N3O2‚C4H4O4(f)
a
Abbreviations: IPP, (2-isopropoxyphenyl)piperazine; MPP, (2-methoxyphenyl)piperazine; EPP, (2-ethoxyphenyl)piperazine. b C4H4O4(m)
represents maleic acid, C4H4O4(f) represents fumaric acid, and C2H2O4 represents oxalic acid. Where the formula is given as symbols of
elements, the analytical data for the designated elements were within (0.4% of the calculated values except where otherwise indicated.
d
g
c C: calcd, 63.59; found, 64.22. C: calcd, 61.82; found, 62.40. e C: calcd, 61.58; found, 61.07. f C: calcd, 63.18; found, 62.59. N: calcd,
h
7.47; found, 7.03. N: calcd, 8.37; found, 7.95.
Sch em e 3
and 27), there were several trends that became evident.
activity, the six-membered ring analogue (6) has the
Although all of the compounds have potent in vivo
greatest D2 receptor affinity (2.2 nM). As the ring size

Orally Active Benzamide Antipsychotic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2001
Sch em e 4
Sch em e 5
increases, 5-HT1A affinity increases with a maximum
Ki value of 0.13 nM for eight-membered ring congener
27. There was a large degree of lethality for 26 in the
catalepsy test, which precluded its further consideration
as a drug candidate. When the ring was opened to
afford diethylamide 28 and dibutylamide 29, good
receptor affinity was retained. Surprisingly, 29 is
basically inactive in vivo whereas 28 has good activity,
but 28 also shows a large induction of catalepsy (76.9%
at 50 mg/kg ip). Cyclohexylamide 30 was less active
than 6, whereas much of the activity was restored along
with no observed catalepsy when N-methyl substitution
was added in 31. However, when administered ip in
the CAR test, 31 had little activity at 1 mg/kg, suggest-
ing that it is less active than 6 in that test. Morpholine
amide 32 had good in vivo activity at the screening dose
but lesser D2 receptor binding (95 nM Ki). As mentioned
earlier, the 4-fluoro derivative of 6 (i.e., 33) was pre-
pared in order to potentially increase biological duration
by retarding metabolism. Compound 33 was somewhat
less active in the in vivo test when compared with 6
and had ca. 8 times less D2 receptor affinity.
vivo activity. An especially intriguing compound is 39
because it displays in vivo activity (-94% at 5 mg/kg
ip) with only modest catalepsy but has no D2 receptor
affinity (>1000 nM Ki) and excellent 5-HT1A receptor
affinity (0.34 nM Ki). Benzoisothiazolyl congener 41 had
a 74.0% level of catalepsy at 50 mg/kg ip. Pyrimidinyl
derivative 45 exhibited a 12 nM Ki for the 5-HT1A
receptor but was devoid of in vivo activity.
Analogue 47 resembles the antipsychotic benzamides
such as remoxipride, but 47 had very little activity.
4-Fluorophenylamide 48 had receptor affinity Ki’s in the
range of 10-30 nM but had no in vivo activity. Indoline
49 displayed in vivo activity and <4 nM Ki’s at 5-HT1A
and R1-adrenergic receptors without observed D2 recep-
tor affinity. Imide functionality is found in buspirone
(44) and related derivatives, so we had prepared imides
50 and 51, both of which were only modestly active in
the various tests in which they were examined.
R-Methyl derivative 54 showed considerably less
activity than 6 and was not pursued further. Chain-
extended analogues 56 and 60 were both active in vivo
and in vitro, but less so than the other more active
members of the series such as 6. Thioamide 61 was
somewhat less active than amide 6. Sulfonamide 62
had no in vivo activity but had excellent receptor
affinities with Ki’s all <10 nM.
Bicycles 39, 40, 41, and 43 all have pronounced
5-HT1A activity, anticipated to some degree by the
reported activities of 38 and 42.19a-d The in vivo CAR
activity is good except for 43, which shows very little in

2002 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Reitz et al.
Ta ble 2. Conditioned Avoidance Response (CAR) Activity and Receptor Binding Affinitya
CAR activity,
ED50 or inhibition
(dose, mg/kg)
receptor affinity (Ki, nM)
route of
admin
pretreatment
time (min)
compd
fasted/fed
fed
D2
0.8
5-HT1A
3.3
R1
8.2
5
34.72 mg/kg
[31.40, 38.25]
0.31 mg/kg
[0.26, 0.39]
32.5 mg/kg
[24.8, 54.3]
9.3 mg/kg
po
po
po
po
60
60
30
30
haloperidol
clozapine
fed
0.37
82.0
>1000
1.0
1.4
fed
111
fasted
[7.4, 11.5]
risperidone
6
fed
fed
3.1
2.2
253
1.7
0.81
1.3
0.66 mg/kg
[0.55, 0.78]
14.54 mg/kg
[10.22, 20.95]
10.96 mg/kg
[8.64, 14.07]
3.35 mg/kg
[2.55, 4.76]
25.99 mg/kg
[23.18, 44.37]
-30.2% (15)
0.4% (15)
ip
30
30
po
po
po
po
fed
60
fed
60
fasted
fed
120
7
8
9
10
11
ip
ip
ip
30
30
30
fed
fed
fed
>1000
>1000
>1000
>1000
>1000
7.2
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
44
-2.1% (5)
ND
-2.2% (5)
ip
ip
ip
ip
30
30
30
30
fed
fed
fed
fed
-82.1% (15)
-94.6% (5)
1.26 mg/kg
[1.00, 1.55]
0.85 mg/kg
[0.70, 1.12]
3.32 mg/kg
[2.04, 4.89]
11.86 mg/kg
[9.74, 14.74]
15.39 mg/kg
[4.04, 31.16]
-5.5% (5)
12
13
201
57
0.46
0.71
4.7
8.2
14
15
ip
30
30
fed
6.3
0.6
2.1
po
po
po
fasted
fed
60
120
fed
ip
ip
ip
ip
ip
ip
ip
po
ip
ip
ip
ip
po
ip
ip
ip
ip
ip
po
ip
ip
ip
ip
ip
ip
po
ip
ip
ip
ip
ip
po
po
ip
ip
ip
ip
ip
30
30
30
30
30
30
30
60
30
30
30
30
60
30
30
30
30
30
60
30
30
30
30
30
30
60
30
30
240
30
30
60
240
30
30
30
30
30
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
16
0.8
3.3
-59.7% (15)
-84.3% (15)
-68.6% (15)
-67.9% (5)
-5.3% (1)
-73.9% (5)
-5.4% (20)
-0.7% (15)
-3.7% (5)
-71.6% (15)
-36.1% (5)
-27.9% (20)
-1.3% (5)
-77.7% (15)
-4.7% (15)
-3.0% (1)
16
17
263
77
16
8.2
27
16
18
63
2.5
19
19
20
38
682
9.1
2.3
16
562
21
22
347
1.2
11.4
>1000
24
>1000
23
24
>1000
121
18
486
11.4
146
-88.5% (5)
-1.1% (20)
-87.0% (15)
-44.8% (1)
-98.3% (7.5)
-79.4% (13.4)
-24.5% (1)
-90.4% (5)
-84.7% (20)
-65.1% (1)
-60.0% (2.5)
-44.4% (2.5)
-96.2% (5)
-94.5% (15)
-93.4% (20)
-44.6% (20)
-5.6% (15)
-86.2% (15)
-17.6% (5)
-9.3% (1)
25
26
13
35
3.4
1.2
1.9
3.6
0.6
2.1
27
28
5.3
1.9
4.4
14
29
30
16
47
0.8
4.1
3.3
3.4
31
5.4
1.2
1.2
-98.9% (5)

Orally Active Benzamide Antipsychotic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2003
receptor affinity (Ki, nM)
Ta ble 2. (Continued)
CAR activity,
ED50 or inhibition
(dose, mg/kg)
route of
admin
pretreatment
time (min)
compd
fasted/fed
D2
95
5-HT1A
3.2
R1
32
-94.5% (1)
-95.4% (5)
-96.2% (20)
-22.6% (1)
-82.6% (5)
-2.6% (1)
-93.8% (5)
-68.2% (20)
-82.4% (5)
-89.6% (5)
-18.8% (15)
-17.9% (5)
-6.8% (15)
-19.4% (5)
-74.9% (15)
-2.5% (15)
-1.6% (1)
-1.4% (10)
-95.8% (15)
-9.6% (1)
-94.5% (5)
-1.6% (20)
-11.2% (5)
-92.4% (15)
-7.1% (15)
-1.1% (1)
-98.2% (15)
-95.3% (15)
-71.6% (5)
-6.7% (5)
0.75 mg/kg
[0.48, 1.18]
7.69 mg/kg
[5.50, 10.30]
7.93 mg/kg
[4.30, 16.63]
0.9% (5)
ip
ip
po
ip
ip
ip
ip
po
ip
ip
ip
ip
ip
ip
ip
ip
ip
po
ip
ip
ip
po
ip
ip
ip
ip
ip
ip
ip
ip
ip
30
30
60
30
30
30
30
30
30
30
30
30
30
30
30
30
30
60
30
30
30
60
30
30
30
30
30
30
30
30
30
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
fed
29
33
39
19
4.2
6.0
>1000
0.34
21
40
41
43
45
15
41
124
0.21
2.5
1.8
13
2.7
57
12
47
>1000
121
11
486
11
48
49
30
>1000
3.4
1.7
50
51
158
39
3.3
3.9
388
6.4
54
56
122
24
>1000
2.5
87
2.1
60
61
62
67
16
20
1.1
0.9
16
284
2.3
6.7
2.2
1.1
1.1
0.9
po
po
ip
60
240
30
fed
fed
fed
69
37
>1000
110
a
Conditioned avoidance response (CAR) testing in rats was performed as described in the Experimental Section, and the 95% confidence
limits for ED50 values are listed in brackets. Data listed for 5 and the reference compounds were taken from refs 9 and 15.
Arylpiperidine 67 was essentially as active as 6 and
had slightly greater D2 and 5-HT1A receptor affinity
(0.95 nM Ki’s) with a relatively low level of catalepsy.
This finding demonstrates that the arylpiperazine
nitrogen of 6 is not needed for biological activity.
Corresponding hydroxypiperidine 69 was not active in
vivo, with only moderate D2 receptor binding and no
5-HT1A affinity. Unlike haloperidol (4), hydroxypiperi-
dine substitution had greatly reduced activity in this
series.
As a result of our ongoing evaluation of putative
antipsychotics described in this paper, compound 6 was
chosen for clinical evaluation as the succinate salt
(mazapertine succinate). In addition to the data re-
ported elsewhere for 6,15 it has a 7.6 nM Ki for the D4
receptor, with no detectable binding (>5000 nM Ki’s)
at R-adrenergic, GABAA, GABAB, norepinephrine, and
serotonin uptake sites and the NMDA ion channel.
There was 32.4% catalepsy when 6 was administered
at 50 mg/kg ip, a dose 75 times higher than that
required for activity in the CAR test in rat (0.66 mg/kg
ED50 ip). It is reasonable to propose that this separation
between efficacy and the undesired catalepsy may be
due to the 5-HT1A receptor affinity, as it has been
reported that 5-HT1A agonists reverse neuroleptic-
induced rat catalepsy production.25 Further, 5-HT1A
partial agonists are known to improve the extrapyra-
midal symptoms and tardive dyskinesias induced by
haloperidol (4) and other typical neuroleptics in hu-
mans.26 Even though 6 inhibited reciprocal forepaw
treading,15 it is possible that the compound is a 5-HT1A
partial agonist since very few structures act as antago-
nists at both pre- and postsynaptic 5-HT1A receptors.27
The R1-adrenergic binding component of the profile of
clozapine may contribute to its favorable separation of
therapeutic from extrapyramidal effects.28 In the same
manner, the R1-adrenergic affinity seen for 6 may play
a role in its favorable therapeutic index in preclinical
models.
The log P of compound 6 was experimentally deter-
mined to be 3.85 at pH 7.3 which suggests reasonable
blood-brain barrier penetration.29 The first pKa was
found to be 6.95, so that slightly less than half would
be expected to be protonated in the blood. Compound
6 was evaluated by X-ray structure analysis and found
to be in an extended, bent conformation in the solid state
(Figure 1). The piperazine ring resides in a chair
conformation, and the amide functionality is skewed
with respect to the middle aromatic ring. The 2-iso-
propoxyphenyl ring is ca. 35° out of plane with respect
to the adjacent piperazine ring.30 The monosuccinate
salt adopts the unusual crystal habit of one dianionic
succinate and one succinate in the fully protonated form
associated in a 1:1 complex with mazapertine by hy-
drogen bonding.

2004 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Ta ble 3. Catalepsy Dataa
Reitz et al.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H NMR spectra were recorded on
either a Varian 390 (90 MHz), Bruker AC-300 (300 MHz), or
Bruker AM-400 (400 MHz) spectrometer. For the NMR work,
DMSO-d6 was used as solvent unless otherwise noted, and
tetramethylsilane (TMS) was used as an internal standard.
Elemental analyses were obtained primarily by Galbraith
Laboratories (Knoxville, TN) and Robertson Microlit, Madison,
NJ . Melting points were determined in open capillary tubes
with a Thomas-Hoover apparatus and are corrected. Chemical
ionization mass spectra (CI-MS) were recorded on a Finnigan
3300-6100 system with methane as the reagent gas unless
otherwise noted. Fast-atom-bombardment mass spectra (FAB)
were obtained on a VG 7070E spectrometer. An Ion Tech
saddlefield gun, which generated a primary beam of argon
atoms at 8 keV and 2 nA, was used for the FAB analysis.
Where elemental analyses are reported by symbols of elements
in the Experimental Section, the results are within 0.4% of
the calculated values. The X-ray crystal structure analysis
was obtained by the Crystalytics Co. of Lincoln, Nb. Most
reagents and solvents were purchased and used without
further purification.
dose
(mg/kg)
route of
admin
pretreatment
time (min)
catalepsy
(%)
compd
6
50
50
50
50
50
50
100
250
250
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
ip
ip
ip
ip
ip
ip
ip
po
po
ip
ip
ip
ip
ip
ip
ip
ip
ip
ip
ip
ip
ip
ip
ip
60
240
60
60
60
240
240
60
240
60
240
60
240
60
240
60
240
60
240
60
240
60
32.4
47.9
70.0
47.5
27.8
24.1
0 (3.5L)
32.5
15.5
21.8
33.9
0 (3/5L)
0 (4/5L)
34.4
17.6
76.9
36.8
0.0
12
13
14
21
26
27
28
31
33
58.1
45.2
50.0
29.0
74.0
26.3 (1/5L)
1-[3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]m et h yl]-
ben zoyl]p ip er id in e 1.5Hyd r och lor id e (6). A solution of
3-(chloromethyl)benzoyl chloride (6 mL, 42.3 mmol) in 70 mL
of THF was treated with diisopropylethylamine (33.1 mL, 0.19
mol). This solution was cooled to -78 °C and treated with
piperidine (4.18 mL, 42.3 mmol) over a period of 2 min. After
5 min, the ice bath was removed, and the solution was allowed
to warm to ambient temperature. After a total of 1 h,
(2-isopropoxyphenyl)piperazine fumarate (14.45 g, 43 mmol)
was added. The solution was stirred at ambient temperature
overnight and then at reflux for 7 h and cooled to ambient
temperature, followed by the addition of water and methylene
chloride. The organic layer was withdrawn, dried (MgSO4),
and filtered. The product was purified on silica gel (EtOAc/
39
41
67
60
60
a
Catalepsy was evaluated in rats as described in the Experi-
mental Section. Lethality, where observed, is indicated in the
catalepsy (%) column. For example, (3/5L) means that three out
of five rats died during the course of the experiment.
i
hexane, 6:4), dissolved in PrOH, treated with concentrated
HCl (ca. 2.5 mL), and then triturated with ethyl ether. The
i
resultant solid was recrystallized from PrOH/ethyl ether to
give 9.1 g (45%) of 6 as a white powder: mp 222-227 °C; FAB-
MS (thioglycerol) m/e 422 (MH+); 1H NMR (400 MHz, CDCl3)
δ 1.41 (d, 6H), 1.58 (br s, 2H), 1.70 (br s, 4H), 3.32 (br s, 2H),
3.4-3.6 (m, 5H), 3.7 (br s, 3H), 4.2 (br s, 4H), 4.68 (m, 1H),
6.92 (m, 2H), 7.18 (m, 1H), 7.48 (m, 3H), 7.60 (s, 1H), 7.96 (d,
1H). Anal. (C26H35N3O2‚1.5HCl) C, H, N, Cl.
F igu r e 1. X-ray crystal structure of mazapertine (6) succinate
(salt not shown).
Other compounds listed in Table 1 were prepared in a like
manner from the appropriate amine component and the
piperazine or piperidine counterpart. The requisite pipera-
zines were either commercially available or prepared as
described in the literature. In addition to the sesquihydro-
chloride salt of 6, a variety of other salt forms of this compound
have been prepared. The X-ray crystal structure determina-
tion was conducted on 6 as the succinate salt (Figure 1).
4-F lu or o-2-isop r op oxy-1-n it r ob en zen e (35). A sus-
pended orange mixture of 5-fluoro-2-nitrophenol (34; 10.0 g,
63.6 mmol), potassium carbonate (8.84 g, 64.0 mmol), and
2-bromopropane (6.00 mL, 63.6 mmol) in dimethylformamide
(63.0 mL) was stirred at 22 °C under argon. After 1 day, an
additional 2.0 mL of 2-bromopropane was added and the
resultant mixture was heated at 60 °C for 1 day. The reaction
mixture was then partitioned between methylene chloride and
3 N NaOH. The organic layer was separated, and the basic
aqueous layer was extracted with additional methylene chlo-
ride. The combined organic solution was washed with water
(5 × 200 mL), dried (MgSO4), filtered, and concentrated to
provide 12.02 g (95%) of an orange oil, 95% pure by GC, which
was carried on without further purification: FAB-MS m/e 200
Su m m a r y
The compounds described here provide the basis for
direct comparison of a large number of related deriva-
tives directed toward the discovery of new and safer
antipsychotic drugs for clinical use. Certain compounds
in the series show notable selectivity for the 5-HT1A
receptor such as the benzodioxanyl derivative 39.
2-Alkoxyphenyl substitution on the arylpiperazine was
preferred, such as in compounds 12-14. There is a
large tolerance for amide substitution, with homopip-
eridine 14 showing a high level of in vivo (ip and po)
activity. The N-methylcyclohexylamide 31 was also
very active. Larger amide derivatives, such as in 27,
resulted in a higher 5-HT1A affinity. The significant
lack of catalepsy for 6 could be due to its unusual
receptor binding profile which includes large 5-HT1A and
R1A binding components. Since modulation of the se-
rotonergic system (e.g., 5-HT1A) has been shown to
ameliorate the motor discoordination associated with
current neuroleptics in rats and humans, it is reason-
able to imagine that having both D2-4 and 5-HT1A
affinities in a compound such as mazapertine would be
beneficial.
1
(MH+); H NMR (90 MHz, CDCl3) δ 1.30 (d, J ) 6.0 Hz, 6H),
4.60 (septet, J ) 6.0 Hz, 1H), 6.50-6.90 (m, 2H), 7.70-8.00
(m, 1H).
4-F lu or o-2-isop r op oxya n ilin e (36). A solution of 35 (9.50
g, 45.3 mmol) and 10% palladium on carbon (0.50 g) in absolute
ethanol (100 mL) was shaken on a Parr apparatus under 53
psig of hydrogen at 22 °C for 2 h. The reaction was then

Orally Active Benzamide Antipsychotic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2005
filtered over Celite, diluted with chloroform, dried (MgSO4),
filtered, and concentrated to afford 8.37 g of 36 as a purple
oil, 97% pure by GC, which was carried on without further
purification: EI-MS m/e 169 (M+); 1H NMR (90 MHz, CDCl3)
δ 1.30 (d, J ) 6.0 Hz, 6H), 3.50-3.70 (br s, 2H), 4.50 (septet,
J ) 6.0 Hz, 1H), 6.30-6.70 (m, 3H).
stirred overnight at room temperature. The reaction was
concentrated by evaporation, and the residue was dissolved
in water (50 mL). Addition of acetic acid (5 mL) caused a white
precipitate to form which was filtered to give 53 as a white
solid (1.26 g, 77%): CI-MS m/e 369 (M
+).
1-[3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]-1-eth yl]-
ben zoyl]p ip er id in e Oxa la te Hyd r a te (54). Compound 53
was dissolved in DMF (11 mL) and treated portionwise at room
temperature with 1,1′-carbonyldiimidazole (0.32 g, 2.0 mol).
The reaction was stirred at room temperature for 1.5 h and
then treated with piperidine (0.314 g, 3.7 mmol). After stirring
for an additional 2 h, water (105 mL) was added and the
mixture was extracted with ether. The ether layer was washed
with saturated NaCl solution, separated, dried (K2CO3),
filtered, and evaporated to give 54 (free base) as a yellow oil
(0.60 g). This material was dissolved in EtOH and treated
with oxalic acid (0.17 g, 1.9 mmol). Addition of ether caused
a solid to precipitate which was collected by filtration, affording
54 (oxalate salt) as a white solid (0.123 g, 14%): mp 124-130
°C; 1H NMR (300 MHz, DMSO-d6) δ 1.22 (d, 6H), 1.55 (d, 3H),
1.35-1.70 (m, 6H), 2.75-3.65 (m, 12H), 4.08-4.20 (m, 1H),
4.50-4.60 (m, 1H), 6.80-6.85 (m, 4H), 7.30-7.60 (s, 4H).
Anal. C, H, N.
1-(4-F lu or o-2-isop r op oxyp h en yl)p ip er a zin e (37).
A
crude solution of 36 (8.35 g, 47.9 mmol) prepared as described
above, bis(2-choroethyl)amine hydrochloride (12.83 g, 71.9
mmol), and triethylamine (10.00 mL, 71.7 mmol) in chloroben-
zene (70 mL) was heated at reflux for 25 h. The dark-brown
reaction mixture was then partitioned between 3 N NaOH and
methylene chloride. The organic layer was separated, dried
(MgSO4), filtered, and concentrated to yield 15.9 g of 37 as a
brown oil. This crude free base was dissolved in MeOH,
treated with fumaric acid (5.25 g), and diluted with ether. The
monofumarate salt precipitated, was collected by filtration, and
was dried in a vacuum oven at 60 °C to furnish 11.38 g of a
brown solid of 37, which was used without further purifica-
tion: CI-MS m/e 239 (MH+); 1H NMR (90 MHz, CD3OD) δ 1.30
(d, J ) 6.0 Hz, 6H), 3.00-3.40 (m, 8H), 4.60 (septet, J ) 6.0
Hz, 1H), 6.50-7.00 (m, 5H).
1-[3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]m et h yl]-
ben zoyl]-2-p ip er id on e F u m a r a te (51). A solution of 2-pip-
eridinone (10.0 g, 0.101 mol) and pyridine (16.35 g, 0.207 mol)
in benzene (300 mL) was cooled in an ice bath and treated
dropwise over 5 min with 3-(chloromethyl)benzoyl chloride
(19.2 g, 0.102 mol). The resulting mixture was stirred
overnight at ambient temperature. Water (300 mL) was then
added, and the organic layer was separated, washed with 1 N
HCl (200 mL) and three 200-mL portions of water, dried
(NaSO4), filtered, and concentrated to give 16.5 g of a yellow
oil. Addition of ether with cooling afforded 7.25 g of a cream-
colored crystalline solid. The 1H NMR was consistent with
the structure being N-[3-(chloromethyl)benzoyl]-2-piperidone.
A mixture of the intermediate prepared above (6.25 g, 0.025
mol), (2-isopropoxyphenyl)piperazine fumarate (8.40 g, 0.025
mol), potassium iodide (4.50 g, 0.027 mol), triethylamine (9.57
g, 0.095 mol), and N-methyl-2-pyrrolidinone (50 mL) was
stirred for 5.5 h at ambient temperature, treated with water
(250 mL), and extracted into ethyl ether (100 mL). The organic
layer was separated, dried (Na2SO4), filtered, and concentrated
to give 6.3 g of an orange oil. This material was purified on
200 g of flash silica gel (1:1 EtOAc/methylene chloride) to give
3.40 g of 51 (free base) as a clear oil. Treatment of the oil
1-[4-[2-[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]et h yl]-
ben zoyl]p ip er id in e Oxa la te (56). N-(2-Isopropoxyphenyl)-
piperazine (30.6 g, 139 mmol), 4-bromophenethyl bromide (44.0
g, 167 mmol), sodium iodide (4.85 g, 37.5 mmol), and N,N-
diisopropylethylamine (73.6 g, 570 mmol) were dissolved in
200 mL of anhydrous DMSO, and the solution was stirred
under argon for 3 days. The reaction mixture was then poured
into saturated aqueous sodium bicarbonate and extracted
several times with ether. The ether extracts were combined,
washed successively with aqueous sodium bicarbonate solution
and brine, dried (MgSO4), and concentrated to provide a sticky
brown solid. This material was purified on a Waters Delta
Prep 3000 LC apparatus (35:65-0:100 hexanes/dichloro-
methane) to afford 34.9 g (62%) of aralkylpiperazine 55 as a
light-brown solid. A mixture of this material (5.0 g, 12.4
mmol), piperidine (3.17 g, 37.2 mmol), and Cl2Pd(PPh3)2 (0.39
g, 0.558 mmol) under 1 atm of carbon monoxide was heated
at 100 °C for 3 days. An additional 0.39 g of palladium catalyst
was added to the reaction mixture which was heated for an
additional 4 days. The reaction mixture was cooled, and
chloroform and water were added to the resultant black solid.
The layers were separated, and the aqueous layer was
extracted with chloroform several times. The chloroform
extracts were combined, dried (Na2SO4), and concentrated to
provide a dark-brown oil which was purified on flash silica
gel (10:90-0:100 hexanes/chloroform) to provide 1.13 g of pure
56 (free base) as a green solid. This material was dissolved
in acetone, and oxalic acid (0.33 g) was added; upon treatment
with diethyl ether and hexanes, a cream-colored solid precipi-
tated, which was recrystallized from methanol/ether to provide
0.69 g (13%) of compound 56: mp 202-205.5 °C; 1H NMR (300
MHz, DMSO-d6) δ 1.27 (d, J ) 6.0 Hz, 6H), 1.33-1.68 (m, 6H),
2.85-3.05 (m, 2H), 3.05-3.33 (m, 10H), 3.40-3.70 (br s, 2H),
4.62 (pentet, J ) 6.0 Hz, 1H), 6.85-7.00 (m, 4H), 7.30 (s, 4H).
Anal. (C27H37N3O2‚C2H2O4) C, H, N.
1-[4-[4-[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]-4-oxo-
bu tyl]ben zoyl]p ip er id in e F u m a r a te (58). (2-Isopropoxy-
phenyl)piperazine (41.0 g, 186 mmol), 4′-bromo-4-chlorobu-
tyrophenone (58.4 g, 223 mmol), sodium iodide (6.49 g, 50.2
mmol), and N,N-diisopropylethylamine (98.6 g, 763 mmol)
were dissolved in 435 mL of anhydrous DMSO. After 7 days
the reaction mixture was poured into saturated aqueous
bicarbonate solution and then extracted into ether. The ether
extracts were combined, washed successively with aqueous
sodium bicarbonate and brine, dried (MgSO4), and concen-
trated to provide a sticky brown solid. This material was
purified on a Waters Delta Prep 3000 LC apparatus (45:55-
0:100 hexanes/dichloromethane) to afford 19.0 g (23%) of the
desired halobutyrophenone piperazine 57 as a light-brown
solid. A mixture of this material (5.0 g, 11.2 mmol), piperidine
(2.87 g, 33.7 mmol), and Cl2Pd(PPh3)2 (0.35 g, 0.505 mmol) was
i
with fumaric acid (0.90 g) in PrOH (20 mL) produced a white
solid which was recrystallized from iPrOH affording 1.80 g
1
(13%) of 51 as a white powder: mp 131.5-133 °C; H NMR
(400 MHz, DMSO-d6) δ 1.25 (d, 6H), 1.89 (m, 4H), 2.50 (m,
2H), 2.60 (s, 4H), 3.00 (s, 4H), 3.66 (s, 2H), 3.71 (m, 2H), 4.58
(q, 1H), 6.90 (d, 4H), 7.40 (m, 1H), 7.46 (m, 2H), 7.52 (s, 1H).
Anal. (C26H33N3O3‚C4H4O4) C, H, N.
3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]-1-eth yl]ben -
zon itr ile (52). A mixture of (2-isopropoxyphenyl)piperazine
(7.28 g, 33 mmol), 3-acetylbenzonitrile (4.80 g, 33 mmol), and
titanium isopropoxide (11.74 g, 41 mmol) was stirred at room
temperature for 2 h, heated to 80 °C for several minutes, and
then cooled to room temperature. Methanol (150 mL) was
added, and the mixture was heated to dissolve most of the
solids. After cooling to room temperature, sodium borohydride
(2.27 g, 60 mmol) was added in portions and the mixture was
stirred overnight at room temperature. The reaction mixture
was concentrated on a rotary evaporator, and the residue was
partitioned between 3 N NaOH and CH2Cl2. The organic layer
was separated, dried (K2CO3), filtered, and evaporated to an
oily residue which was passed through flash grade silica gel
using 4:1 hexane/EtOAc as eluant to give 52 as an oil (1.55 g,
13.5%): 1H NMR (300 MHz, CDCl3) δ 1.30-1.36 (d, 6H), 1.36-
1.42 (d, 3H), 2.47-2.58 (m, 2H), 2.60-2.75 (m, 2H), 3.00-3.20
(br s, 4H), 3.40-3.50 (q, 1H), 4.51-4.68 (p, 1H), 6.80-7.00 (m,
4H), 7.40-7.70 (m, 4H).
3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]-1-eth yl]ben -
zoic Acid (53). A solution of 52 (1.55 g, 4.4 mmol), 10 N
NaOH (10 mL), and EtOH (10 mL) was refluxed for 8 h and

2006 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Reitz et al.
heated at 100 °C for 20 h under 1 atm of carbon monoxide. An
additional 0.35 g of palladium catalyst was added to the
reaction mixture which was then heated for an additional 20
h, cooled, and treated with chloroform and water. The layers
were separated, and the aqueous layer was extracted with
chloroform several times. The chloroform extracts were
combined, dried (Na2SO4), and concentrated to provide a dark-
brown oil which was purified on flash silica gel (0:100-1:99
methanol/chloroform) to give 1.25 g of pure 58 (free base) as a
golden-brown oil. This material was dissolved in acetone, and
fumaric acid (0.30 g) was added. Upon addition of diethyl
ether and hexanes a fluffy white solid precipitated, which was
recrystallized from acetone/ether to provide 0.74 g (11%) of
washed with saturated aqueous NaCl, dried (MgSO4), and
concentrated to an oily residue. Chromatography of this
material on flash silica (1.1:98.5-2.5:97.5 methanol/methylene
chloride) afforded 61 which was converted to its hydrochloride
salt in ethereal HCl (3.61 g, 77%): mp 221-224 °C dec
(uncorrected); FAB-MS m/e 438 (MH+); 1H NMR (400 MHz,
DMSO-d6) δ 1.28 (d, 6H), 1.52 (m, 2H), 1.68 (m, 4H), 3.00-
3.20 (m, 4H), 3.38 (m, 2H), 3.50 (q, 4H), 4.20-4.40 (m, 2H),
4.42 (s, 2H), 4.60 (m, 1H), 6.80-7.00 (m, 4H), 7.32 (m, 1H),
7.40-7.55 (m, 2H), 7.67 (m, 1H). Anal. (C26H35N3O2‚HCl) C,
H, N.
1-[3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]m et h yl]-
p h en ylsu lfon yl]p ip er id in e Hyd r a te (62). N-Bromosuccin-
imide (6.27 g, 35 mmol), m-toluenesulfonyl chloride (6.72 g,
35 mmol), and benzoyl peroxide (0.67 g, 1.9 mmol) were
combined in CCl4 (40 mL) and heated at reflux for 2 h. The
reaction mixture was filtered and washed with CCl4. The
filtrate was concentrated to give 3-(bromomethyl)benzene-
sulfonyl chloride (9.74 g) as a viscous yellow oil. A mixture of
this material (4.68 g, 17.4 mmol) in THF (100 mL) was cooled
to 0-5 °C in an ice-water bath and treated with a solution of
piperidine (1.72 g, 20.2 mmol), triethylamine (3.08 g, 30.5
mmol), and THF (40 mL) over 20 min. The resulting mixture
was warmed to ambient temperature and filtered, and the
solution was concentrated. A solution of the resulting oil (3.12
g, 9.81 mmol), (2-isopropoxyphenyl)piperazine (3.30 g, 9.81
mmol), and triethylamine (1.27 g, 12.5 mL, 10 mmol) in THF
(50 mL) was heated to reflux for 4.5 h and then stirred at
ambient temperature overnight. The reaction mixture was
filtered and concentrated to a residue which was partitioned
between methylene chloride and 3 N NaOH. The organic layer
was separated, dried (MgSO4), filtered, and evaporated to yield
an oil which was purified by chromatography on flash silica
gel (9:1 hexane/ethyl acetate) to give 62 (free base). This
material was triturated with Et2O/HCl, affording 62 as a tan,
crystalline solid (0.65 g, 12%): mp 189-191 °C; FAB-MS m/e
458 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 1.27 (d, 6H), 1.37
(m, 2H), 1.57 (m 4H), 2.95 (m, 4H), 3.05 (m, 2H), 3.20 (q, 2H),
3.32 (m, 2H), 3.55 (m, 2H), 4.52 (m, 2H), 4.65 (m, 1H), 6.80-
7.00 (m, 4H), 7.72 (m, 1H), 7.82 (m, 1H), 8.05 (m, 2H). Anal.
(C25H35N3O4S‚0.75C4H8O‚H2O) C, H, N, H2O.
1
58: mp 154-155.5 °C; H NMR (300 MHz, DMSO-d6) δ 1.23
(d, J ) 6.0 Hz, 6H), 1.40 (br s, 2H), 1.48-1.68 (br s, 4H), 1.87
(pentet, J ) 6.8 Hz, 2H), 2.45 (t, J ) 6.9 Hz, 2H), 2.55 (br s,
4H), 2.88 (br s, 4H), 3.05 (t, J ) 6.8 Hz, 2H), 3.20 (br s, 2H),
3.58 (br s, 2H), 4.57 (pentet, J ) 6.0 Hz, 1H), 6.61 (s, 2H),
6.77-6.95 (m, 4H), 7.49 (d, J ) 8.1 Hz, 2H), 8.02 (d, J ) 8.1
Hz, 2H). Anal. (C29H39N3O3‚1.1C2H2O4) C, H, N.
1-[4-[4-[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]-4-h y-
d r oxybu tyl]ben zoyl]p ip er id in e Bisoxa la te (59). To a
solution of compound 58 (4.98 g, 10.4 mmol) described above
in 200 mL of EtOH was added NaBH4 (0.47 g, 12.5 mmol).
The reaction mixture was stirred for 20 h under argon and
then was cooled in ice. Cold 1 N HCl (20 mL) was added
dropwise, and the reaction mixture was stirred for 1 min and
then basified with solid potassium carbonate. The resulting
mixture was extracted with chloroform; the organic extracts
were combined, dried (Na2SO4), and concentrated to provide
a green foam which was purified on flash silica gel (1:99-5:
95 methanol/chloroform) to give 1.25 g of 59 (free base) as a
yellow foam. This compound was dissolved in hot methanol,
and oxalic acid (0.33 g) was added. When ether and hexanes
were added, a white precipitate formed. This solid was
recrystallized from methanol/ether to afford 0.44 g (9%) of 59:
mp 141-144.5 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.27 (d, J
) 6.0 Hz, 7H), 1.40-1.82 (br m, 11H), 2.85-3.75 (br m, 13H),
4.55-4.70 (m, 2H), 6.83-7.02 (m, 4H), 7.34 (d, J ) 8.0 Hz,
2H), 7.41 (d, J ) 8.0 Hz, 2H). Anal. (C29H41N3O3‚2C2H2O4)
C, H, N.
1-[4-[4-[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]b u t yl]-
ben zoyl]p ip er id in e Dih yd r obr om id e (60). A solution of
59 (3.20 g, 6.67 mmol), 20% palladium hydroxide on charcoal
(1.00 g), and concentrated HCl (1.7 mL, 20.0 mmol) in 100 mL
of 95% ethanol was shaken under 60 psig of hydrogen at 50
°C for 8 days. The reaction mixture was cooled, filtered
through Dicalite, and concentrated to provide an olive-green
foam. To this material was added saturated aqueous sodium
bicarbonate and chloroform. The resulting mixture was passed
through Dicalite, and the layers were separated. The aqueous
layer was extracted with chloroform; the organic extracts were
combined, dried (Na2SO4), and concentrated to provide a light-
brown oil which was purified on flash silica gel (1:99 methanol/
chloroform) to give 2.46 g of 60 (free base) as a golden-brown
oil. This compound was dissolved in hot methanol, and
concentrated HBr (1.1 mL) was added. A tan precipitate
formed when ether and hexanes were added. This solid was
recrystallized from methanol/ether to afford 1.36 g (32%) of
60: mp 197.5-198.5 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.28
(d, J ) 6.1 Hz, 6H), 1.35-1.78 (m, 10H), 2.67 (br t, 2H), 2.90
(br t, J ) 11.7 Hz, 2H), 3.06-3.40 (m, 6H), 3.56 (br d, J )
10.8 Hz, 6H), 4.62 (pentet, J ) 6.0 Hz, 1H), 6.00-6.70 (br s,
1H), 6.82-7.05 (m, 4H), 7.29 (s, 4H), 9.25-9.45 (br s, 1H).
Anal. (C29H41N3O2‚2HBr) C, H, N; Br: calcd, 25.55; found,
24.68.
1-Br om o-2-isop r op oxyben zen e (63). A mixture of 2-bro-
mophenol (23.2 mL, 0.20 mol), potassium carbonate (33.2 g,
0.24 mol), and 2-bromopropane (28.0 mL, 0.30 mol) in DMF
(200 mL) was stirred in a preheated oil bath (60 °C) for 5 h.
The cooled reaction mixture was then partitioned between
ether and water. The layers were separated, and the aqueous
phase was extracted with ether. The combined organic solu-
tion was washed with copious amounts of water and 3 N
NaOH, dried (MgSO4), filtered, and concentrated in vacuo to
furnish 39.3 g (91%) of 63 as a pale-yellow oil which was
carried on without further purification. The structure was
1
supported by GC/MS and 90-MHz H NMR.
1-Car beth oxy-4-(2-isopr opoxyph en yl)-4-piper idin ol (64).
To a suspended solution of Mg chips (10.07 g, 0.414 mol) in
anhydrous ether (150 mL) at 22 °C under argon was added
1,2-dibromoethane (ca. 0.15 mL), and 63 (43.7 g, 0.20 mol) in
200 mL of ether was added dropwise. After 50% of the aryl
halide was added, the reaction began to reflux vigorously, and
the flask was cooled in an ice bath. After the refluxing had
subsided somewhat, the ice bath was removed and the
remaining aryl halide was added over a 1.5-h period. The
resultant Grignard reagent was cooled in a dry ice/ether bath
for 2 h and then treated with 34.0 mL (0.221 mol) of
1-carbethoxy-4-piperidone. Upon complete addition of ketone,
the reaction mixture was allowed to warm to 22 °C and stirred
for 2 h. The reaction was then quenched with cold aqueous
ammonium chloride resulting in an emulsion which was
separated by addition of 1 M HCl. The aqueous phase was
extracted with additional ether, and the combined organic
solution was washed with 10% aqueous sodium bisulfite, 1 M
HCl, and saturated aqueous NaHCO3 and dried (K2CO3).
Filtration and concentration yielded 56.36 g of 64 as a yellow
viscous oil which was carried on without further purification:
1-[3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er a zin yl]m et h yl]-
th ioben zoyl]p ip er id in e Hyd r och lor id e (61). A solution of
6 (3.86 g, 9.2 mmol) and toluene (50 mL) was treated with
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-di-
sulfide (2.22 g, 5.5 mmol), and the resulting mixture was
heated at 90 °C for 1 h. The reaction was cooled followed by
the addition of toluene (50 mL) and then thoroughly mixed
with excess 3 N NaOH. The organic layer was separated,

Orally Active Benzamide Antipsychotic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2007
i
CI-MS (CH4) m/e 308 (MH+), 290 (M - 18), 248 (M - PrO);
1H NMR (90 MHz, CDCl3) δ 1.1-1.5 (m, 9H), 1.8-2.2 (m, 4H),
3.1-3.5 (m, 2H), 3.9-4.3 (m, 4H), 4.35 (s, 1H, exchangeable),
4.45-4.85 (septet, 1H), 6.8-7.0 (m, 2H), 7.1-7.4 (m, 2H).
DMSO-d6) δ 1.1-1.5 (m, 8H), 2.3-3.2 (m, 7H), 4.3-4.7 (septet,
1H), 6.6-7.2 (m, 3H), 7.3-7.5 (m, 1H), 8.7-9.0 (m, 1H), 9.1-
9.5 (m, 1H).
1-[3-[[4-[2-(1-Meth yleth oxy)p h en yl]-4-h yd r oxy-1-p ip er -
idin yl]m eth yl]ben zoyl]piper idin e Hydr och lor ide 0.25Hy-
d r a te (69). A suspended solution of 68 (2.61 g, 9.6 mmol),
N-[3-(chloromethyl)benzoyl]piperidine (2.43 g, 10.2 mmol), and
triethylamine (3.0 mL, 21.5 mmol) in N-methylpyrrolidinone
(9 mL) was stirred in a preheated oil bath (80 °C) for 20 h.
Upon cooling to room temperature, the reaction mixture was
diluted with ether (200 mL) and washed once with water. The
aqueous phase was extracted with additional ether (2 × 100
mL). The combined ethereal solution was washed with water
(3 × 150 mL), dried over MgSO4, filtered, and concentrated to
provide an oil which was purified by flash chromatography
on silica gel (3:97 methanol/chloroform) to give 69 as a light-
yellow oil. This oil was dissolved in 2-propanol and acidified
to pH 3 with concentrated HCl. The acidified solution was
treated with hexane and ether resulting in precipitation of the
hydrochloride salt which was collected by filtration and dried
under high vacuum to provide 69 hydrochloride (1.95 g, 43%)
as a white powder (mp 148-154 °C): IR (KBr) cm-1 3387 (OH
stretch), 1618 (CO stretch); CI-MS (CH4) m/e 437 (MH+), 418
1-Ca r beth oxy-4-(2-isop r op oxyp h en yl)p ip er id in e (65).
A solution of 64 (36 g), 10% palladium on carbon (1.80 g), 5
mL of concentrated HCl, and 125 mL of MeOH was shaken
on a Parr apparatus under 55.5 psig of hydrogen at 22 °C for
3 days. The reaction was filtered through Celite and concen-
trated to a residue. This material was partitioned between
ether and water. The organic solution was dried (MgSO4),
filtered, and concentrated to yield 29.34 g of 65 as a light-
yellow oil which was carried forward without further purifica-
tion: CI-MS (CH4) m/e 292 (MH+); 1H NMR (90 MHz, CDCl3)
δ 1.1-1.4 (m, 9H), 1.5-1.9 (m, 3H), 2.6-3.1 (m, 3H), 3.9-4.6
(septet, 6H), 6.7-6.9 (m, 2H), 7.0-7.2 (m, 2H).
4-(2-Isop r op oxyp h en yl)p ip er id in e Hyd r och lor id e (66).
A mixture of crude 65 (29.3 g) and sodium hydroxide pellets
(6.12 g, 0.106 mol) in DMSO (100 mL) was stirred in a
preheated oil bath at 100 °C for 4 days. The reaction mixture
was then poured into water (200 mL), and the crude product
was extracted into methylene chloride. The methylene chlo-
ride extracts were dried over MgSO4, filtered, and concentrated
to afford 21.34 g of a crude dark-brown oil. This oil was
dissolved in 1 N HCl and washed with ether. The acidic
aqueous solution was basified with 3 N NaOH, and the product
was extracted into methylene chloride. The combined meth-
ylene chloride extracts were dried (MgSO4), filtered, and
concentrated to yield 13.34 g of a semisolid which was
1
(M - 18); H NMR (CDCl3, 400 MHz) δ 1.4 (d, 6H), 1.6-1.8
(m, 4H), 2.2 (d, 2H), 3.25-3.45 (m, 6H), 3.2-3.3 (m, 2H), 4.15-
4.20 (m, 2H), 4.20-4.30 (m, 2H), 4.65-4.75 (m, 1H), 4.85 (s,
1H), 6.9-7.0 (m, 2H), 7.2-7.3 (m, 2H), 7.4-7.6 (m, 3H), 8.0
(s, 1H), 12.5 (br s, 1H). Anal. (C27H36N2O3‚HCl‚0.25H2O) C,
H, N, Cl, H2O.
P h a r m a cologica l Met h od s. P r ep a r a t ion of Mem -
br a n es fr om Ra t Br a in Cor tex a n d Str ia tu m . Rats
(Charles River, male, Wistar) were received at 5-6 weeks of
age (110-140 g of body weight) in filtered crates from
Kingston, NY. The rats were group-housed for 1-4 weeks in
a temperature- and humidity-controlled room and given food
(Wayne Lab Blox) ad libitum. Water was given ad libitum
through an automatic water system. Animals had equal hours
(12-12) of dark and light. Each rat (150-200 g of body weight,
7-12 weeks of age) was killed by cervical dislocation, and the
brain was immediately excised. The cerebral cortex and
corpus striatum were dissected out, weighed, and homogenized
separately in 20 or 40 vol of 5 mM Na-HEPES-buffered sucrose
(0.3 M) solution (pH ) 7.5 at 23 °C), using a motor-driven
Teflon pestle fit to a glass tube with a tolerance of 0.25 mm.
The homogenate was centrifuged (4-8 °C) at 1000g for 10 min,
and the resulting supernatant was centrifuged at 48000g for
10 min. The pellet that formed (P2 fraction) was resuspended
in 20 vol of 3 mM K2PO4-KH2PO4 solution (pH ) 7.5 at 23
°C, used in all assays) with an Ultra-turrax (J anke & Kunkel)
homogenizer and then incubated for 30 min at 25 °C. Each
suspension was centrifuged at 42000g for 10 min, and the
resulting sediment was resuspended in either 30 vol (cerebral
cortex) or 50 vol (corpus striatum) of the 3 mM phosphate-
buffered solution. All radioligands were purchased from New
England Nuclear.
i
dissolved in PrOH and acidified to pH 3 with concentrated
HCl. The acidified solution was treated with ether resulting
in precipitation of the hydrochloride salt of 66 which was
collected by filtration and dried under vacuum to provide 11.21
1
g of a beige powder: CI-MS (CH4) m/e 220 (MH+); H NMR
(90 MHz, CDCl3) δ 1.1-1.4 (d, 6H), 1.6-2.2 (m, 3H), 2.8-3.6
(m, 6H), 4.4-4.8 (septet, 1H), 6.7-7.2 (m, 4H), 9.0-9.5 (m,
2H).
1-[3-[[4-(2-Isop r op oxyp h en yl)-1-p ip er id in yl]m et h yl]-
ben zoyl]p ip er id in e Hyd r och lor id e (67). A suspended
mixture of 66 (3.75 g, 14.6 mmol), N-[3-(chloromethyl)benzoyl]-
piperidine (3.45 g, 14.5 mmol), and triethylamine (4.50 mL,
32.2 mmol) in N-methylpyrrolidinone (15 mL) was stirred in
a preheated oil bath (80 °C) for 18 h. The reaction mixture
was partitioned between methylene chloride and water. The
organic layer was separated, washed with water, dried (Mg-
SO4), filtered, and concentrated to afford 5.90 g of a brown
oil. Flash chromatography of this material over silica gel (4:
96 MeOH/chloroform) and conversion to the corresponding HCl
salt provided 67 (2.66 g, 47%) as off-white needles: FAB-MS
1
m/e 421 (MH+); H NMR (400 MHz, DMSO-d6) δ 1.30 (d, J )
6.0 Hz, 6H), 1.40-1.70 (m, 6H), 1.9-2.1 (m, 4H), 3.10-3.20
(m, 3H), 3.35-3.45 (m, 2H), 3.55-3.65 (m, 2H), 3.85-3.95 (m,
2H), 4.35-4.40 (m, 2H), 4.60 (septet, J ) 6.0 Hz, 1H), 6.90 (t,
J ) 8.0 Hz, 1H), 7.00 (d, J ) 8.0 Hz, 1H), 7.10 (d, J ) 8.0 Hz,
1H), 7.20 (t, J ) 8.0 Hz, 1H), 7.45 (d, J ) 8.0 Hz, 1H), 7.55 (t,
J ) 8.0 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J ) 8.0 Hz, 1H). Anal.
(C27H36N2O2‚HCl) C, H, Cl; N: calcd, 6.13; found, 5.71.
D2 Affin it y. Binding was determined using membranes
prepared from rat striatum. The receptor was labeled with
0.05 nM [3H]spiperone by incubation at 37 °C for 45 min.
Nonspecific binding was determined using 1 µM haloperidol.
Under these conditions, specific binding constituted 75% of
total binding, and the Ki values for some known drugs were
0.37 nM for haloperidol and 82 nM for clozapine. The data
from this assay were analyzed by calculating the percent
inhibition of the tritiated ligands by given concentrations of
the test compound. Ki values were obtained from the logit
analysis of concentration-inhibition curves. The results of the
logit analysis (ED50) were converted to Ki values using the
Cheng-Prusoff equation.31
4-(2-Isopr opoxyph en yl)-4-piper idin ol (68). A suspended
solution of 64 (18.52 g, 60.3 mmol) and sodium hydroxide
pellets (4.82 g, 120.5 mmol) in DMSO (100 mL) was stirred in
a preheated oil bath (105 °C) for 1 day. The cooled reaction
mixture was poured into a beaker containing 200 mL of
aqueous NaCl and extracted with CH2Cl2 (3 × 200 mL). The
combined CH2Cl2 solution was then washed with H2O (3 ×
200 mL), dried over Na2SO4, filtered, and concentrated to yield
10.50 g of a brown viscous oil. This crude free base was
i
dissolved in PrOH (100 mL), and the solution was filtered and
acidified with concentrated HCl to a pH of 3. The acidified
solution was diluted with Et2O and a brown crystalline solid
precipitated. The HCl salt was collected by filtration and dried
in a vacuum oven at 50 °C for 20 h to give 68 (8.60 g, 61%):
CI-MS (CH4) m/e 235 (MH+), 218 (M - 18); 1H NMR (90 MHz,
D4 Affin ity. Binding was determined by Cerep (France)
using membranes from a human recombinant D4.4 receptor.
The receptor was labeled with 0.5 nM [3H]spiperone, and 10
mM (+)-butaclamol was used for determination of nonspecific
binding.

2008 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Reitz et al.
(4) Frances, A. J .; Weiden, P. Promoting Compliance With Outpa-
tient Drug Treatment. Hosp. Community Psychiatry 1987, 38,
1158-1160.
5-HT1A Affin ity. Binding was determined using mem-
branes prepared from rat cerebral cortex. The receptor was
labeled with 3 nM [3H]-8-OH-dipropylaminotetralin (8-OH-
DPAT) by incubation at 25 °C for 20 min. Nonspecific binding
was determined using 1 µM serotonin.
r1-Ad r en er gic Affin ity. Binding was determined using
membranes prepared from rat cerebral cortex. The receptor
was labeled with 0.06 nM [3H]prazosin by incubation at 25 °C
for 20 min. Nonspecific binding was determined using 10 µM
norepinephrine.
(5) (a) Seeman, P. Dopamine Receptor Sequences: Therapeutic
Levels of Neuroleptics Occupy D2-Receptors, Clozapine Occupies
D4. Neuropsychopharmacology 1992, 7, 261-284. (b) Sibley, D.
R.; Monsma, F. J ., J r. Molecular Biology of Dopamine Receptors.
Trends Pharmacol. Sci. 1992, 7, 61-69. (c) Seeman, P.; Guan,
H.-C.; Van Tol, H. H. M. Dopamine D4 Receptors Elevated in
Schizophrenia. Nature 1993, 365, 441-445. (d) Sokoloff, P.;
Martres, M.-P.; Giros, B.; Bouthenet, M.-L.; Schwartz, J .-C. The
Third Dopamine Receptor (D3) as a Novel Target for Antipsy-
chotics. Biochem. Pharmacol. 1992, 43, 659-666. (e) Civelli, O.;
Bunzow, J . R.; Grandy, D. K.; Zhou, Q.-Y.; Van Tol, H. H. M.
Molecular Biology of the Dopamine Receptors. Eur. J . Pharma-
col. - Mol. Pharmacol. Sect. 1991, 207, 277-286. (f) Thurkaff,
A.; Yuan, J .; Chen, X.; Wasley, J . W. F.; Paneitz, G.; Meade, R.;
Woodruff, K. H.; Huston, K.; Ross, P. C. 3-Aminomethylbiphen-
yls. A New Class of Dopamine Receptor Ligands. Med. Chem.
Res. 1996, 6, 69-80 and references therein.
(6) (a) McDonnell, M. E.; Reitz, A. B. Recent Advances in Antipsy-
chotic Research. Expert Opin. Ther. Pat. 1994, 4, 1221-1231.
(b) Howard, H. R.; Seeger, T. F. Novel Antipsychotics. In Annual
Reports in Medicinal Chemistry; Bristol, J . A., Ed.; Academic
Press: San Diego, 1993; Vol. 28, Chapter 5, pp 39-47. (c)
Cipollina, J . A. New Antipsychotic Agents: A Patent Overview
- 1991. Curr. Opin. Ther. Pat. 1992, 2, 485. (d) Horn, A. S.
Dopamine Receptors. In Comprehensive Medicinal Chemistry;
Emmett, J . C., Ed.; Pergamon Press: New York, 1990; Vol. 3, p
229. (e) Kane, J .; Honigfeld, G.; Singer, J .; Meltzer, H. Clozapine
for the Treatment-Resistant Schizophrenic. Arch. Gen. Psychia-
try 1988, 45, 789-796. (f) Honigfeld, G.; Patin, J .; Singer, J . Adv.
Ther. 1984, 1, 77-97. (g) Kaiser, C.; Setler, P. E. Antipsychotic
Agents. In Burger’s Medicinal Chemistry, Wolff, M. E., Ed.; J ohn
Wiley & Sons: New York, 1980; Part III, p 859.
Con d ition ed Avoid a n ce Resp on se. This test was modi-
fied from that described by Martin et al.11 Trained rats (N )
4) were run in a 1-h session on two consecutive days. Animals
had access to food and water up until being placed in the test
chambers for that data indicated as fed, or the animals were
not allowed access to food overnight prior to the experiment.
Test sessions consisted of 60 trials, 1/min. Only animals that
exhibited greater than 90% CAR on day 1 were given the test
compound on day 2.
Ca ta lep sy Test in th e Ra t. Male, Sprague-Dawley rats
were obtained from Charles River Laboratories (Kingston, NY)
ranging in weight between 170 and 240 g on the day of the
test. The experiment was conducted in a quiet room with the
experimenter unaware of the drug or dose level administered.
Groups of five rats were treated with drug. In each test
session, two control groups were used for the production of
catalepsy; animals treated with saline (or vehicle) served as a
negative control, and animals treated with haloperidol (2 mg/
kg) were a positive control. If 2 mg/kg haloperidol failed to
produce greater than 80% catalepsy, data from that session
were not used. To begin a test session, the rat’s forepaw was
gently placed on a black cork (3.5 cm high) and the time until
the forepaw was removed was recorded. Each rat was given
three trials with a maximum time of 60 s on the cork for each
trial. The sum of the three trials was taken as the score for
each rat. Percent catalepsy was defined as the percent of 3
min (maximum time) that a rat permitted its forepaw to rest
on the cork.
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Ack n ow led gm en t. We wish to acknowledge the
assistance of our colleagues listed as follows during the
course of this project: A. Abdel-Magid, D. J . Bennett,
P. S. Blum, R. E. Boyd, K. R. J acobs, E. Malloy, M. E.
Ortegon, C. R. Rasmussen, R. G. Sherrill, F. J . Villani,
N. Yim, W.-N. Wu, and D. Wustrow.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for mazapertine succinate (6), including unit cell
parameters, standard errors, tables of atomic coordinates,
thermal parameters, and bond lengths (32 pages); table of
structure factors (10 pages). Ordering information is given on
any current masthead page.
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