Structure-activity relationships of a series of substituted benzamides: Potent D2/5-HT2 antagonists and 5-HT1a agonists as neuroleptic agents

Article abstract of DOI:10.1021/jm950551d

A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D₂, serotonin 5-HT₂, and serotonin 5-HT_1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) demonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent.

Full text of DOI:10.1021/jm950551d

1172
J . Med. Chem. 1996, 39, 1172-1188
Str u ctu r e-Activity Rela tion sh ip s of a Ser ies of Su bstitu ted Ben za m id es: P oten t
D2/5-HT2 An ta gon ists a n d 5-HT1a Agon ists a s Neu r olep tic Agen ts
Mark H. Norman,*,† Greg C. Rigdon,‡ William R. Hall,† and Frank Navas III†
Divisions of Chemistry and of Pharmacology and Molecular Therapeutics, Glaxo Wellcome Inc.,
Research Triangle Park, North Carolina 27709
Received J uly 24, 1995X
A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives
was prepared and evaluated as potential atypical antipsychotic agents. The target compounds
were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors,
and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5-HT2, and
serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds,
we investigated their ability to inhibit the apomorphine-induced climbing response in mice.
Selected compounds were evaluated further to determine their side-effect potentials. Structure-
activity relationships of both mono- and polysubstituted benzamides are discussed herein.
While several analogues had potent in vitro and in vivo activities indicative of potential atypical
antipsychotic activity, anthranilamide 77 (1192U90) demonstrated a superior pharmacological
profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-
1-piperazinyl)butyl)benzamide hydrochloride) was selected for further evaluation and is
currently in phase I clinical trials as a potential atypical antipsychotic agent.
Ch a r t 1
In tr od u ction
Owing to its superior atypical antipsychotic profile,
clozapine has become the standard therapy to which all
new antipsychotic agents are compared. Clozapine is
an effective antipsychotic agent that is nearly devoid
of the extrapyramidal side effects (EPS) that often
accompany typical antipsychotic agents such as
haloperidol.1-4 Its therapeutic use has been restricted,
however, because a potentially fatal blood dyscrasia,
agranulocytosis, develops in some individuals who use
clozapine.5-7 Over the past 2 decades, many neuroleptic
agents have been investigated in attempts to identify a
compound that retains a clozapine-like antipsychotic
profile without this serious side effect. Of the several
theories that have been advanced to explain clozapine’s
atypical antipsychotic profile, the mixed dopamine D2/
serotonin 5-HT2 hypothesis has been the subject of most
recent investigations.8-19 For example, compounds such
as risperidone,9 ocaperidone,10 sertindole,11 and ziprasi-
done12 are mixed D2/5-HT2 antagonists at various stages
of investigation.
We recently described the potential antipsychotic
activity associated with a series of cyclic benzamides 1
possessing mixed dopamine and serotonin antagonist
activity.19 These derivatives antagonize serotonin 5-HT2
receptors more potently than dopamine D2 receptors,
indicating that they may act as atypical antipsychotic
agents. In addition, several of these derivatives were
shown to be serotonin 5-HT1a receptor agonists, an
activity that may help to reduce the occurrence of EPS
and help relieve the anxiety that can often trigger
psychotic episodes. During the development of this
series, we also evaluated a few intermediate benzamides
(2) where the amide was not restricted by a covalent
bond to the ortho position of the aromatic ring. These
noncyclic derivatives exhibited potent in vitro and in
vivo activities, which suggested they would be effective
against both the positive and negative symptoms of
schizophrenia while inducing fewer EPS than typical
antipsychotic agents. We subsequently extended our
structure-activity relationship (SAR) investigations by
examining the potential antipsychotic activity of a series
of substituted N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piper-
† Division of Chemistry.
‡ Division of Pharmacology and Molecular Therapeutics.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
0022-2623/96/1839-1172$12.00/0 © 1996 American Chemical Society

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1173
azinyl)butyl)benzamides. In this paper, we report the
synthesis and biological evaluation of substituted ben-
zamides with the general structure 2. These investiga-
tions have resulted in the identification of a clinical
candidate antipsychotic agent, 2-amino-N-(4-(4-(1,2-
benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hy-
drochloride (77, 1192U90).
marized in Scheme 1. The appropriately substituted
benzoic acid precursors required for the preparation of
a majority of the benzamide derivatives were prepared
as follows. Treatment of amino- and hydrazinobenzoic
acids 3-5 with di-tert-butyl dicarbonate in 1,4-dioxane
provided the corresponding carbonate-protected deriva-
tives 13-15. Substituted anthranilic acids 21-23 were
obtained by the catalytic hydrogenation of o-nitrobenzoic
acids 6-8, respectively. Polysubstituted benzoic acids
9-11 were prepared by literature procedures,20,21 and
2-azidobenzoic acid (12) was obtained via a Sandmeyer
reaction using anthranilic acid and sodium azide.22
Anthranilic acids 16-20 and 24 were obtained from
commercial suppliers.
The first general approach, which provided target
benzamides 47-59, involved the condensation of sub-
stituted benzoyl chlorides 25-37 with 3-(4-(4-aminobu-
tyl)-1-piperazinyl)-1,2-benzisothiazole.23 The requisite
benzoyl chlorides were either commercially available
(compounds 29-37) or prepared by treatment of their
corresponding benzoic acids with thionyl chloride in
toluene (compounds 25-28).
The next three general methods employed the ap-
propriately substituted benzoic and anthranilic acids
directly. Reaction of benzoic acids 13-16 with isobutyl
chloroformate followed by treatment of the resulting
mixed anhydrides with 3-(4-(4-aminobutyl)-1-piperazi-
Ch em istr y
Several synthetic routes were examined for assem-
bling the desired substituted benzamides from their
benzoyl chloride, benzoic acid, and isatoic anhydride
precursors. The methods used to prepare the appropri-
ate intermediates and the five general approaches
employed to obtain the target compounds are sum-
Sch em e 1a
a
Reagents: (a) O(CO2t-Bu)2, 1,4-dioxane, 5% Na2CO3, 0-25 °C; (b) H2, 5% Pd/C; (c) SOCl2, DMF, toluene, 65-85 °C; (d) ClCO2CCl3,
1,4-dioxane, reflux; (e) N3SiMe3, CHCl3; (f) 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole, Et3N, CH2Cl2 or CHCl3, 0-25 °C; (g)
ClCO2i-Bu, THF, Et3N, 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole, -35-25 °C; (h) SiCl4, pyridine, 3-(4-(4-aminobutyl)-1-
piperazinyl)-1,2-benzisothiazole, 145 °C; (i) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-
benzisothiazole, DMF, 0-25 °C; (j) 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole, EtOH or THF, 25 °C; (k) BBr3, CH2Cl2, 1 N
ethereal HCl, 25 °C; (1) MeOH, NaOMe, 25 °C; (m) F3CCO2H, anisole, CHCl3, 25 °C; (n) MeCOCl or ClCO2Et, Et3N, CH2Cl2 or CHCl3,
0-25 °C; (o) N-((9H-fluoren-9-ylmethoxy)carbonyl)-L(or D)-valyl chloride,28 CHCl3, Na2CO3, 25 °C; (p) 4-(aminomethyl)piperidine, 25 °C.

1174 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
the demethylation of dimethoxy benzamide 47 was
assigned to be the 2-hydroxy derivative 78 due to the
NOE of the adjacent aromatic proton. Analogously, the
minor product in the demethylation of the tetrasubsti-
tuted benzamide 49 was shown to be the 2-hydroxy
isomer 81 by enhancement of the methylene of the
5-ethyl group. In each case, the more sterically hin-
dered methyl group preferentially reacted with boron
tribromide. These results are consistent with those
reported by de Paulis et al. for the preparation of
6-methoxysalicylamides.21,27
Salicylamide 82 was obtained by the basic hydrolysis
of the corresponding acetate 51. Deprotection of tert-
butyl carbamates 60-62 was effected by treatment with
trifluoroacetic acid in chloroform to provide amino and
hydrazino analogues 83-85, respectively. The final
derivatives outlined in Scheme 1 (compounds 86-89)
were derived from the acylation of o-aminobenzamide
77. Reaction of 77 with either acetyl chloride or ethyl
chloroformate provided amide 86 and carbamate 87,
while L- and D-valinamides 88 and 89 were prepared
by the condensation of benzamide 77 with N-((9H-
fluoren-9-ylmethoxy)carbonyl)-L(or D)-valyl chloride fol-
lowed by the deprotection of the FMOC protecting group
with 4-(aminomethyl)piperidine.28 Mosher amides of
both 88 and 89 were prepared to assess their optical
purity. Examination of these derivatives by both HPLC
and 19F NMR techniques indicated that the valyl amides
were pure enantiomers and that no epimerization
occurred in the synthetic process.
The syntheses of the final two benzamide derivatives
(96 and 97) are outlined in Scheme 2. Alkylation of the
sodium salt of N-methylbenzamide (90) with 1-bromo-
4-chlorobutane in dimethylformamide, followed by dis-
placement of the resulting chloride 91 with 3-(1-
piperazinyl)-1,2-benzisothiazole,23 gave benzamide 96.
An alternative route was required to prepare the
analogous N-methylanthranilamide derivative 97. Treat-
ment of primary amine 92 with trifluoroacetic anhy-
dride provided amide 93 in 86% yield. Alkylation of 93
with methyl iodide followed by hydrolysis of trifluoro-
acetamide 94 gave amine 95. The anthranilamide
target, 97, was obtained by the condensation of 95 with
isatoic anhydride in ethanol.
F igu r e 1. Significant NOE signals observed upon irradiation
of the o-methoxy groups of salicylamides 78-81.
nyl)-1,2-benzisothiazole provided target benzamides
60-63. Alternatively, azidobenzamide 50 was obtained
from a dicyclohexylcarbodiimide coupling of the primary
amine with o-azidobenzoic acid (12). Anthranilic acids
17-22 were effectively condensed with the primary
amine by employing silicon tetrachloride as a coupling
reagent as described by Chan24 and Kornet25 to give
anthranilamides 64-69, respectively. To obtain opti-
mum yields in the silicon tetrachloride-mediated reac-
tions, it was necessary to employ rigorously dried
pyridine as the solvent.
The final general method outlined in Scheme 1
involved the condensation of the primary amine with
an appropriately substituted isatoic anhydride. This
procedure produced anthranilamides 70-77 and rep-
resented an alternative to the silicon tetrachloride
coupling method. The necessary isatoic anhydrides
were commercially available or synthesized by one of
two methods. Reaction of substituted anthranilic acids
23 and 24 with trichloromethyl chloroformate gave the
corresponding 4- and 6-fluorinated isatoic anhydrides
39 and 40, respectively. Alternatively, a 40:60 mixture
of the 6-fluoro- (40) and the 3-fluoro- (41) isatoic
anhydride was obtained upon the treatment of 3-fluo-
rophthalic anhydride (38) with azidotrimethylsilane in
anhydrous chloroform. This method of isatoic anhydride
synthesis has been studied by Washburne and co-
workers and involves the overall insertion of an NH
moiety between the carbonyl and the aryl group of the
anhydride.26 The target anthranilamides 70-77 were
prepared in yields ranging from 43% to 65% by the
reaction of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-ben-
zisothiazole with isatoic anhydrides 39-46. In some
cases, a small amount of the ethyl 2-aminobenzoate was
obtained in these reactions. This byproduct results from
the addition of ethanol to the isatoic anhydride and can
be avoided by the use of tetrahydrofuran rather than
ethanol as the solvent.
Resu lts a n d Discu ssion
In the first phase of this investigation, it was neces-
sary to select a set of substituents that would provide
the greatest structural diversity within a limited num-
ber of compounds. To accomplish this, we based our
initial substituent selection on a cluster analysis strat-
egy described by Hansch and co-workers.29 In this
approach, substituents are divided into subgroups (clus-
ters) based on various physicochemical parameters
using combinations of lipophilic, electronic, molar re-
fractivity, molecular weight, and Swain and Lupton-type
constants. The cluster set that incorporated the broad-
est set of parameters was employed in our investigation.
We prepared a series of monosubstituted benzamides
that included representatives from several different
clusters designed to maximize the difference in sub-
stituent properties.
With benzamides 47-77 in hand, further functional
group manipulations allowed for the preparation of
several additional analogues. For example, monode-
methylation of dimethoxy derivatives 47 and 49 with
boron tribromide provided isomeric mixtures of o-
hydroxybenzamides 78/79 and 80/81, respectively. These
isomers were separated by flash chromatography, and
the regiochemistry was determined by a series of NOE
experiments. The NOE signals observed from irradia-
tion of the o-methoxy substituents of each isomer are
illustrated in Figure 1. The major isomer resulting from
The substituted benzamides were evaluated in in vitro
receptor binding assays at dopamine D2 and serotonin
5-HT1a and 5-HT2 receptors.19,32 As a preliminary

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1175
Sch em e 2a
a
Reagents: (a) NaH, DMF, Br(CH2)4Cl, 0 °C; (b) TFAA, CH2Cl2, 0 °C; (c) NaH, DMF, MeI, 0-25 °C; (d) K2CO3, MeOH, H2O, 25 °C; (e)
3-(1-piperazinyl)-1,2-benzisothiazole,23 MeCN, Et3N, reflux; (f) isatoic anhydride, EtOH, 25 °C.
Ta ble 1. In Vitro and in Vivo Biological Activities of Reference Standards and Monosubstituted Benzamides
antagonism of
apomorphine-induced
mouse climbinge
receptor bindingc IC50 (nM)
ED50 (mg/kg)
compd no.a
R
R′
clusterb
D2
5-HT1a
5-HT2
D2/5-HT2
ip
po
d
50
52
53
55
56
57
58
59
60
61
63
76
77
82
83
84
85
86
87
88
89
96
97
2-N3
H
4-Cl
4-OMe
4-CF3
4-t-Bu
4-NdNPh
2-NO2
4-NHBoc
3-NHBoc
4-NHAc
2-NHMe
2-NH2
2-OH
4-NH2
3-NH2
2-NHNH2
2-NHAc
2-NHCO2Et
2-NH-L-valine
2-NH-D-valine
H
H
3
1
3
5
6
9
8
3
f
19
26
57
34
27
340
230
14
3.7
5.2
15
9.0
9.1
520
540
6.4
0.70
12
37
10
3.8
12
23
6.6
3.8
5.2
5.6
5.4
8.4
1.4
1.2
7000
2000
1.8
2.1
5.6
2.3
1.5
68
26
3.7
10
12
10
15
18
5
25
1.1
9.4
2.4
12.5
5.1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
21.5
>25
>25
>25
>25
9
4
>25
25
>25
>25
>25
14
0.23
1.3
61
3
0.8
0.4
10
1
0.4
25
13
16
4
f
4.4
41
4.7
32
5.8
63
66
32
31
5.4
21
4.3
17
34
4
5
5
5
5
5
5
4
7
f
51
12
3.3
3.9
150
2.6
2.4
2.0
1.4
2.7
1.6
3.9
2.3
>25
5.8
15.6
1.5g
1.0
10.1h
21.5
>25
25
10.8
4.1
1.8
2.6
40.4
22.3
32.8
17.9
8
3
4
f
1
5
>25
10.0
22.4
2-NH2
15
0.01
10
>12
haloperidol
clozapine
40
290
360
28
1.8
0.5
26.2i
22.5j
a
b
Hydrochloride salts. Cluster set 1 (group 10) as defined by Hansch et al.29 c D2, [3H]raclopride binding; 5-HT1a, [3H]-8-OH-DPAT
binding; 5-HT2, [3H]ketanserin binding. Ratio of dopamine D2 (IC50) to serotonin 5-HT2 (IC50) receptor binding. e For experimental protocol,
d
see ref 19. f This substituent was not included in the cluster analysis reported by Hansch et al.29 95% confidence limits ) 0.7-4.2 mg/
g
h
i
j
kg. 95% confidence limits ) 5.2-19.3 mg/kg. 95% confidence limits ) 9.4-73.2 mg/kg. 95% confidence limits ) 12.8-39.8 mg/kg.
antipsychotic assay, the compounds were evaluated in
vivo for their ability to antagonize the apopmorphine-
induced climbing response in mice.33 The biological
activities of the monosubstituted benzamides and two
standards, haloperidol and clozapine, are summarized
in Table 1. Also included in Table 1 are the calculated
D2/5-HT2 receptor binding ratios. Neuroleptic agents
with D2/5-HT2 ratios > 1 have been postulated to exhibit
an atypical antipsychotic profile.8
The clusters for the initial compounds studied are
indicated in Table 1. Nonsubstituted benzamide 52,
representing cluster 1, exhibited potent receptor binding
and possessed a good D2/5-HT2 ratio of 12. This deriva-
tive was also very potent in the mouse climbing assay
when administered ip. The corresponding tertiary
amide 96 showed similar potency in vitro but reduced
activity when administered ip and comparable activity
when given orally. Compounds from cluster 3 (50, 53,

1176 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
Ta ble 2. In Vitro and in Vivo Biological Activities of Polysubstituted Benzamides
antagonism of
apomorphine-induced
mouse climbingd
ED50 (mg/kg)
receptor bindingb IC50 (nM)
D2 5-HT1a 5-HT2
13 74 12
1.0
58
100
4.0
38
3.0
compd no.a
R1
R2
Br
Br
Cl
Cl
Me
H
H
H
H
H
R3
R4
R5
D2/5-HT2
ip
po
c
47
48
49
54
64
65
66
67
68
69
70
71
72
73
74
75
78
79
80
81
OMe
OH
OMe
H
H
H
H
Et
Cl
H
OMe
OH
OMe
H
H
Cl
H
Me
H
H
H
1
0.06
2
58
0.7
11
1
>25
H
H
H
H
H
H
H
CF3
H
F
H
H
H
H
H
H
H
H
H
120
180
49
4.0
38
3.0
16
30
1.7
6.0
28.8
26
>25
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
OH
5.8
3.4
2.3
8.9
2.3
1.4
0.59
1.6
0.50
3.8
1.6
1.6
5.4
37.6
31.8
H
>25
2.2
>25
6.9
F
H
H
OMe
H
H
290
18
35
15
15
13
13
13
7.8
0.62
30
80
11
64
12
10
4.2
4.2
1.5
20
9.4
4.1
32
8
>50
>50
27.1
25
25
0.9
26
3
2.1
2.5
H
H
F
H
F
7.8
0.9
20.8
14.3
H
H
H
H
H
OMe
OH
OH
OMe
NO2
Cl
H
H
H
19.6
<6
H
8
5
25
20.3
14.3
OMe
Br
Br
Cl
Cl
2.2
26
15
14
6.8
6.3
0.04
2
12
2
1.5
OMe
OMe
OH
33
69
23
4.7
>25
Et
Et
>25
25.5
a
b
Hydrochloride salts. D2, [3H]raclopride binding; 5-HT1a, [3H]-8-OH-DPAT binding; 5-HT2, [3H]ketanserin binding. c Ratio of dopamine
d
D2 (IC50) to serotonin 5-HT2 (IC50) receptor binding. For experimental protocol, see ref 19.
and 59) showed good receptor binding affinities, but only
the 4-chloro derivative 53 exhibited good in vivo activity
(ip). The two compounds contained in the fourth cluster
were NHAc regioisomers, benzamides 63 and 86. From
the examination of activity of these two derivatives, it
was clear that not only the type of substituent but also
the position of substitution was critical to activity. The
4-substituted derivative 63 showed both poor D2/5-HT2
selectivity and in vivo activity, while the opposite was
true of the 2-substituted isomer 86. This dependence
on the position of the substituent relative to the amide
carbonyl was also observed in cluster 5 with amino
substitutions (compounds 77, 83, and 84). As in the
case of the NHAc derivatives, the ortho isomer provided
the best results. Anthranilamide 77 displayed high
affinities for all of the targeted receptors and a D2/5-
HT2 ratio comparable to that of clozapine. This deriva-
tive potently antagonized the apomorphine-induced
climbing response in mice, both by ip and po adminis-
tration, with ED50’s of 1.5 and 10.1 mg/kg, respectively.
The o-hydrazino derivative 85 exhibited a similar recep-
tor binding profile to 77 but had reduced in vivo activity.
Replacing the amino group of 77 with a hydroxyl group
gave salicylamide 82, which possessed a less desirable
D2/5-HT2 selectivity. (Trifluoromethyl)benzamide 56 of
cluster 6 showed good affinity and selectivity in vitro
but poor oral bioavailability, while ethyl carbamate 87
of cluster 7 retained oral activity. If the alkyl groups
of the carbamate derivatives play a minor role, then a
similar positional preference for the ortho position may
also be present within this series when in vivo activity
is examined, 87 vs 60 and 61. The final two clusters
contain relatively large substituents and are repre-
sented by the tert-butyl- and (phenylazo)benzamides 57
and 58, respectively. These sterically encumbered
derivatives exhibited weaker binding affinities to all of
the targeted receptors.
Selection of the initial substituents based on the
Hansch cluster analysis strategy, although not an
exhaustive study, allowed us to examine a broad range
of derivatives. From this initial data set, it appeared
that substituents from cluster 5 provided the best
results. Perhaps a more important observation was that
the biological activities of regioisomeric analogues were
vastly different: Compounds with the substituent in the
position ortho to the amide carbonyl demonstrated
greater in vivo activity (e.g., 77). The excellent biologi-
cal profile of the o-amino derivative 77 warranted
further investigation. Methylation of the o-amino sub-
stituent resulted in a derivative with a poor D2/5-HT2
ratio (benzamide 76), while in vivo activity was dimin-
ished when the amide nitrogen of 77 was methylated
(tertiary amide 97). Valinamide analogues 88 and 89
displayed decreased in vivo activities when adminis-
tered po.
We examined polysubstituted benzamides in the
second phase of these investigations (Table 2). Two
main structural types are represented in Table 2,
anthranilamide and salicylamide derivatives. In gen-
eral, substitution of the anthranilamide ring was det-
rimental to oral activity (compounds 64-75). Substi-
tution was tolerated best at the position ortho to the
amine substituent (e.g., methyl derivatives 64 vs 67, and
methoxy derivatives 75 vs 69). While fluorine was
tolerated at all of the positions (R2-5), the most potent
derivative was again the analogue that was substituted

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1177
Ta ble 3. Secondary Pharmacological Activities of Substituted
Benzamide Derivatives and Reference Standards in Assays
Indicating EPS Liability Potential (ip Data)
ip data revealed that all of the benzamide derivatives
exhibited therapeutic ratios equal to or greater than
that of the typical antipsychotic haloperidol, while four
of these analogues, 72, 77, 78, and 88, gave ratios
superior to that observed for clozapine.
antagonism of apomorphine-induced
stereotypyc
mouse climbingb stereotypy (mouse)b
compd no.a ED50 (mg/kg, ip)
ED50 (mg/kg, ip)
climbing
To narrow the field further, these derivatives were
evaluated orally (Table 4). Anthranilamide 77 and
salicylamide 78 exhibited excellent stereotypy/climbing
ratios (2-6 times higher than those of the standards),
while 3-fluoro anthranilamide 72, N-methylanthranil-
amide 76, and valinamide 88 were less selective.
However, when the catalepsy/climbing ratios were
compared, anthranilamide 77 continued to show a
superior selectivity with a ratio of 19. When given
orally, compound 77 exhibited therapeutic ratios ca. 2.5
times higher than those of haloperidol and clozapine.
72
76
77
78
0.9
5.8
8.9
13.5
10.2e
15.4
26.9
0.4
10
2
7
10
7
0.2
5
1.5d
1.5
88
2.6
haloperidol
clozapine
1.8
26.2f
136.1g
a
b
Hydrochloride salts. For experimental protocol, see ref 19.
c Ratio of ED50 for antagonism of apomorphine-induced stereotypy
d
to ED50 for antagonism of apomorphine-induced climbing. 95%
confidence limits ) 0.7-4.2 mg/kg. e 95% confidence limits ) 4.8-
22.1 mg/kg. f 95% confidence limits ) 9.4-73.2 mg/kg. 95%
g
confidence limits ) 79.1-234.1 mg/kg.
On the basis of these initial results, anthranilamide
77 (1192U90) was chosen to be tested in a battery of
pharmacological assays. These assays included ad-
ditional neurochemical, behavioral, and electrophysi-
ological evaluations and were designed to further evalu-
ate the antipsychotic profile of 1192U90 and assess its
potential side-effect liability. The details of these stud-
ies will be reported elsewhere; however, some of the
biological highlights are summarized as follows. Neu-
rochemical experiments indicated that 1192U90 bound
potently at dopamine D2, serotonin 5-HT1a, serotonin
5-HT2, and adrenergic R1 and R2 receptors.35 In addition
to its dopamine D2 activity, 1192U90 has been shown
ortho to the amine at R2 (3-fluoroanthranilamide 72).
This derivative and the 4-fluoro analogue 70 displayed
excellent D2/5-HT2 selectivities, while substitution with
fluorine at R4 and R5 gave derivatives with low D2/5-
HT2 ratios (compounds 66 and 71, respectively).
The potent activity of salicylamide 82, coupled with
reports of other salicylamides studied by researchers at
Astra pharmaceuticals,21,27 led us to prepare derivatives
47-49 and 78-81. The substitution patterns that we
chose to examine paralleled those found in remoxipride
and eticlopride derivatives. Remoxipride and eticlopride
have been extensively studied and shown to be selective
dopamine D2 antagonists. In our series, the dimethoxy-
benzamide that contains the remoxipride substitution,
compound 47, showed poor in vivo activity. When the
methyl of the methoxy group ortho to the bromine was
removed, a significant increase in D2 affinity was
observed (salicylamides 48 and 78). This result is
consistent with that reported for the analogous remox-
ipride derivative (3-bromo-N-[(1-ethyl-2-pyrrolidinyl)-
methyl)-2-hydroxy-6-methoxybenzamide, FLA-797).27 Un-
fortunately, a corresponding increase in affinities to the
5-HT2 receptor was not obtained, and poor D2/5-HT2
ratios resulted. The second polysubstituted salicyla-
mide substitution patterns we investigated were related
to eticlopride. These derivatives also provided disap-
pointingly poor results in our series (compounds 49, 80,
and 81).
In the next phase of our investigation, several of the
most potent derivatives were selected for further ex-
amination to assess their potential side-effect liability.
Compounds that possessed ED50’s of <20 mg/kg (po) in
the mouse climbing assay were evaluated for their
ability to inhibit apomorphine-induced stereotyped be-
havior in mice (ip and po) and for their ability to induce
catalepsy in mice (po).34 Inhibition of apomorphine-
induced stereotypic behaviors indicates dopamine recep-
tor antagonism in the extrapyramidal dopamine system,
which is associated with the induction of motor side
effects as seen with typical antipsychotic agents. The
stereotypy-to-climbing and catalepsy-to-climbing ratios
were calculated as measures of the compound’s potential
side-effect liability. The results from ip and po admin-
istration of compounds 72, 76-78, and 88 are reported
in Tables 3 and 4, respectively. The appropriate data
for antagonism of apomorphine-induced mouse climbing
and data for the standards, haloperidol and clozapine,
are also included for convenience. Examination of the
to potently bind to the dopamine D4 receptor,36
a
dopamine receptor subtype recently suggested to be
important in the atypical antipsychotic profile of cloza-
pine.37 The results of 1192U90 in behavioral models
in rats38 and monkeys39 qualitatively paralleled those
results found in the mouse assays. In other words,
1192U90 antagonized behaviors elicited by dopamine
D2 receptor agonists (indicating potential antipsychotic
activity) at lower doses than those required to antago-
nize behaviors reflecting EPS potential. In acute elec-
trophysiology studies, 1192U90 was a potent dopamine
D2 receptor antagonist in the limbic and nigro-striatal
dopamine systems as well as a serotonin 5-HT1a receptor
agonist.35 In chronic electrophysiology studies, 1192U90
reduced the number of spontaneously firing neurons in
the limbic dopamine system but not in the nigro-striatal
dopamine system.35 These results indicated that
1192U90 should have a low propensity to induce EPS.
Con clu sion s
Several mono- and polysubstituted benzamides were
readily obtained from the reaction of 3-(4-(4-aminobu-
tyl)-1-piperazinyl)-1,2-benzisothiazole with an appro-
priately substituted benzoic acid, benzoyl chloride, or
isatoic anhydride precursor. Initial substituent selec-
tion was based on the method reported by Hansch and
co-workers to obtain the most diverse set of derivatives.
The compounds were evaluated in in vitro receptor
binding assays at dopamine D2 and serotonin 5-HT1a
and 5-HT2 receptors and in vivo in the apomorphine-
induced mouse climbing assay. Structure-activity
relationships within the series of monosubstituted
derivatives revealed a preference for an amino substitu-
ent ortho to the benzamide carbonyl (i.e., anthranil-

1178 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
Ta ble 4. Secondary Pharmacological Activities of Substituted Benzamide Derivatives and Reference Standards in Assays Indicating
EPS Liability Potential (po Data)
antagonism of apomorphine-induced
induction of
stereotypyc
climbing
catalepsyd
climbing
mouse climbingb
ED50 (mg/kg, po)
stereotypy (mouse)b
ED50 (mg/kg, po)
catalepsy (mouse)b
ED50 (mg/kg, po)
compd no.a
72
76
77
78
14.3
15.6
10.1
14.3
17.9
0.5
46.7
65.0
91.1e
87.5
59.9
0.7
55.5
80.6
4
4
9
9
3
1
4
3
5
19
6
3
7
192.4f
122.7
44.5
88
haloperidol
clozapine
3.3
22.5
78.8g
161.2h
7
a
b
Hydrochloride salts. For example protocol, see ref 19. c Ratio of ED50 for antagonism of apomorphine-induced stereotypy to ED50 for
d
antagonism of apomorphine-induced climbing. Ratio of ED50 for induction of catalepsy to ED50 for antagonism of apomorphine-induced
climbing. e 95% confidence limits ) 17.6-471.5 mg/kg. f 95% confidence limits ) 98.4-375.9 mg/kg. 95% confidence limits ) 56.1-
g
h
110.9 mg/kg. 95% confidence limits ) 98.7-263.2 mg/kg.
(Hz). Elemental analyses were performed by either Atlantic
Microlab, Inc., Norcross, GA, or Galbraith Laboratories, Inc.,
Knoxville, TN. Melting points were determined with a Tho-
mas Hoover capillary melting point apparatus and are uncor-
rected.
amide 77). Further substitution on the benzamide ring
was detrimental to oral activity, but the largest toler-
ance was in the position ortho to the anthranilamide
nitrogen (e.g., 3-fluoroanthranilamide 72). Compounds
containing remoxipride and eticlopride substitution
patterns showed poor D2/5-HT2 selectivities; however,
salicylamide 78 demonstrated interesting in vivo activi-
ties. The most potent derivatives were evaluated
further to assess their oral activity and side-effect
liabilities. Compound 77 (1192U90) was shown to be a
potent, orally active derivative with efficacy-to-side
effect ratios superior to those of clozapine. Like cloza-
pine, 1192U90 more potently antagonized serotonin
5-HT2 receptors than dopamine D2 receptors, but unlike
clozapine, it also exhibited serotonin 5-HT1a agonist
properties that should alleviate the anxiety that often
precipitates psychotic episodes in schizophrenic pa-
tients. Additional biological evaluations indicated that
1192U90 should relieve the positive and negative symp-
toms of schizophrenia and have a low liability to cause
EPS. Owing to its excellent pharmacological profile,
1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-
piperazinyl)butyl)benzamide hydrochloride, has been
selected for clinical development as an antipsychotic
agent.
4-((ter t-Bu t oxyca r b on yl)a m in o)b en zoic Acid (13).
4-Aminobenzoic acid (3) (10.0 g, 72.9 mmol), 5% Na2CO3 (50
mL), and 1,4-dioxane (40 mL) were added to a 500-mL round-
bottomed flask equipped with a magnetic stir bar and addition
funnel. The solution was cooled in an ice-water bath, and a
solution of di-tert-butyl dicarbonate (23.8 g, 109 mmol, 1.5
equiv) in 1,4-dioxane (40.0 mL) was added dropwise. The ice-
water bath was removed, and the reaction mixture was allowed
to warm to room temperature and stir for 24 h. The reaction
mixture was cooled with an ice-water bath, and an additional
portion of di-tert-butyl dicarbonate (1.0 equiv) in 1,4-dioxane
(20 mL) was added dropwise. The ice-water bath was
removed, and the reaction mixture was allowed to stir at room
temperature for 2 days. The solvent was removed in vacuo,
and H2O (150 mL) was added to the resulting white solid. The
pH was adjusted to ca.2 with 1 N HCl, and the aqueous layer
was extracted with EtOAc. The organic layer was dried over
MgSO4, filtered, and concentrated to give a white solid. The
solid was triturated with hexanes and dried to give 14.80 g
(86%) of benzoic acid 13 as a white solid. 1H NMR (CDCl3):
δ 1.50 (s, 9), 7.58 (d, 2, J ) 8.8), 7.86 (d, 2, J ) 8.8), 9.76 (br
s, 1), 12.67 (br s, 1).
3-((ter t-Bu toxyca r bon yl)a m in o)ben zoic Acid (14). This
compound was prepared according to the method described for
acid 13, by employing 3-aminobenzoic acid (4) (5.0 g, 36.5
mmol), 5% Na2CO3 (25 mL), and di-tert-butyl dicarbonate (19.9
g, 91.1 mmol, 2.5 equiv). After 65 h, the reaction mixture was
worked up to give 7.48 g (86%) of benzoic acid 14 as a white
solid. 1H NMR (CDCl3): δ 1.49 (s, 9), 7.37 (t, 1, J ) 7.9), 7.54
(dd, 1, J ) 1.2, 6.5), 7.63 (dd, 1, J ) 0.9, 7.9), 8.15 (s, 1), 9.56
(br s, 1), 12.92 (br s, 1).
Exp er im en ta l Section
P h a r m a cology. Both in vitro (receptor binding affinities)
and in vivo (antagonism of apomorphine-induced mouse climb-
ing) activities of test compounds were determined by the
methods previously reported.19
Ch em istr y. Gen er a l. Unless otherwise noted, all materi-
als were obtained from commercial suppliers and used without
further purification. Anhydrous solvents such as N,N-di-
methylformamide (DMF), tetrahydrofuran (THF), dichlo-
romethane, toluene, pyridine, and dimethyl sulfoxide (DMSO)
were obtained in Sure/Seal bottles from Aldrich Chemical Co.
Triethylamine was distilled from CaH2 prior to use. All
reactions involving air- or moisture-sensitive compounds were
performed under a N2 atmosphere. Flash chromatography and
flush chromatography were performed using EM Science silica
gel 60 (230-400 mesh ASTM). The term flush chromatogra-
phy refers to column chromatography when suction is applied
to the bottom of the column to increase the flow rate of the
eluent. Thin-layer chromatography (TLC) was performed with
Analtech silica gel GF TLC plates (250 µm). 1H NMR spectra
were determined with superconducting FT NMR spectrometers
operating at 200 and 300 MHz. 13C NMR spectra were
measured at 50.29 or 75.43 MHz. Chemical shifts are ex-
pressed in ppm downfield from internal tetramethylsilane.
Significant 1H NMR data are reported in the following order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet), number of protons, and coupling constants in hertz
2-(2-(ter t-Bu toxycar bon yl)h ydr azin o)ben zoic Acid (15).
2-Hydrazinobenzoic acid hydrochloride (5) (7.5 g, 40.0 mmol),
1,4-dioxane (40 mL), and 5% aqueous Na2CO3 (75 mL) were
combined in a 500-mL round-bottomed flask and cooled in an
ice-water bath. The flask was equipped with an addition
funnel, and a solution of di-tert-butyl dicarbonate (9.6 g, 44.0
mmol, 1.1 eq) in 1,4-dioxane (20 mL) was slowly added. The
ice-water bath was removed, and the reaction mixture was
allowed to stir at room temperature for 6 h. An additional
portion of di-tert-butyl dicarbonate (0.99 g, 4.54 mmol, 0.11
eq) was dissolved in 1,4-dioxane (10 mL) and slowly added to
the reaction mixture. The reaction mixture was allowed to
stir for an additional 26 h and concentrated to give a red-
orange residue. Water (200 mL) was added to the residue,
and the mixture was cooled in an ice-water bath. The pH
was adjusted (pH ) 1) by the addition of aqueous 1 N HCl,
and the solution was extracted with EtOAc. The organic layer
was separated, dried over MgSO4, filtered, and concentrated
to give a solid. The solid was triturated with hexanes and
dried in a vacuum oven to give 9.13 g (91%) of benzoic acid 15
as a tan-beige solid. 1H NMR (DMSO-d6): δ 1.43 (s, 9), 6.77

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1179
(t, 1, J ) 7.5), 6.88 (d, 1, J ) 8.2), 7.45 (tm, 1, J ) 7.7), 7.83
(dd, 1, J ) 1.5, 7.9), 8.89 (s, 1), 9.07 (br s, 1), 12.98 (br s, 1).
2-Am in o-r,r,r-tr iflu or o-p-tolu ic Acid (21). A solution
of 2-nitro-R,R,R-trifluoro-p-toluic acid (6) (5.00 g, 21.3 mmol)
in absolute EtOH (100 mL) was added to a Parr hydrogenation
bottle containing absolute EtOH (50 mL) and 5% palladium
on charcoal (100 mg). The bottle was attached to a Parr
hydrogenator, and the solution was placed under a hydrogen
atmosphere at 35 psi. The reaction mixture was shaken at
room temperature until consumption of hydrogen ceased (2
h). The solution was filtered through a millipore AP filter,
and the filtrate was concentrated with a rotary evaporator.
The residue was dried under vacuum to give 4.22 g (97%) of
toluic acid 21 as a pale yellow solid. This material was used
without further purification.
4-F lu or oisa toic An h yd r id e (39). 2-Amino-4-fluorobenzoic
acid (23) (0.97 g, 6.25 mmol) (obtained by the reduction of
4-fluoro-2-nitrobenzoic acid (8) by the method described for
compound 21), anhydrous 1,4-dioxane (20 mL), and trichlo-
romethyl chloroformate (5.0 g, 25.2 mmol, 4.0 eq) were added
to a 100-mL round-bottomed flask. The reaction mixture was
heated at reflux for 11 h. The reaction mixture was allowed
to cool and stir at room temperature overnight. The solvent
was removed with a rotary evaporator to give 1.18 g (>100%
crude) of 39 as an off-white solid. 1H NMR (DMSO-d6): δ 6.90
(dd, 1, J ) 2.3, 9.6), 7.13 (dt, 1, J ) 2.3, 7.6), 8.02 (dd, 1, J )
6.0, 8.8), 11.90 (br s, 1). This material was used without
further purification.
material was purified by flash chromatography with EtOAc:
0.1% triethylamine followed by EtOAc:0.2% triethylamine to
give 1.45 g of the free base as a yellow oil. To a solution of
the free base in EtOAc was added 2.72 mL of 1 N ethereal
HCl (1.0 eq). The solvent was removed in vacuo, and the
hydrochloride salt was recrystallized from EtOH to give 0.867
g (27%) of 3-bromo-2,6-dimethoxybenzamide 47 as a white
solid. Mp: 220-221 °C dec. 1H NMR (DMSO-d6): δ 1.56 (m,
2), 1.83 (m, 2), 3.24 (m, 6), 3.54 (m, 4), 3.78 (s, 6), 4.08 (br d,
2, J ) 13.4), 6.85 (d, 1, J ) 9.0), 7.48 (t, 1, J ) 7.5), 7.59 (d, 1,
J ) 8.9), 7.60 (tm, 1, J ) 8.1), 8.13 (t, 2, J ) 8.9), 8.38 (br t, 1,
J ) 5.6), 10.92 (br s, 1). 13C NMR (DMSO-d6): δ 20.36, 36.23,
38.01, 46.29, 50.39, 55.07, 56.12, 61.72, 106.87, 109.21, 121.16,
123.97, 124.01, 124.59, 126.92, 128.09, 132.97, 152.06, 153.45,
156.20, 162.17, 163.33. Anal. (C24H29N4O3SBr‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-br om o-2,6-d ih yd r oxyben za m id e Hyd r och lor id e (48).
Thionyl chloride (1.46 mL, 2.4 g, 20 mmol, 3.8 eq), anhydrous
DMF (0.05 mL), anhydrous toluene (15 mL), and 3-bromo-2,6-
dihydroxybenzoic acid (10)20
(1.2 g, 5.15 mmol) were added to
a flame-dried 100-mL round-bottom flask. The solution was
placed under nitrogen and heated at 60-85 °C for 1 h. The
solvent was removed in vacuo, and anhydrous CH2Cl2 (15 mL)
and triethylamine (1.08 mL, 0.782 g, 7.73 mmol) were added
to the solid residue. To this suspension was added a solution
of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.5
g, 5.15 mmol) in anhydrous CH2Cl2 (15 mL), and the reaction
mixture was allowed to stir at room temperature for 18 h. The
reaction mixture was transferred to a separatory funnel, CH2-
Cl2 was added, and the solution was washed with saturated
NaHCO3. The organic phase was separated, and the aqueous
phase was extracted with CH2Cl2. The organic extracts were
combined, dried over MgSO4, filtered, and concentrated to give
2.94 g of the crude product as a tan-beige solid. The free base
was purified by flash chromatography (2×) with 93:7 CH2Cl2:
MeOH as eluant to give 0.703 g of the free base as a yellow
solid. The free base (0.703 g, 1.39 mmol) was dissolved in CH2-
Cl2 and EtOAc, and 1 N ethereal HCl (1.39 mL, 1.0 eq) was
added. The hydrochloride salt was filtered, washed with ether,
and dried in a vacuum oven to give 0.454 g (16%) of 3-bromo-
2,6-dihydroxybenzamide 48 as an off-white solid. Mp: 228-
230 °C dec. 1H NMR (DMSO-d6): δ 1.62 (m, 2), 1.77 (m, 2),
3.00-3.70 (m, 10), 4.05 (m, 2), 6.49 (d, 1, J ) 8.8), 7.48 (tm, 1,
J ) 7.2), 7.48 (d, 1, J ) 8.8), 7.60 (t, 1, J ) 7.6), 8.13 (t, 2, J
) 8.8), 9.09 (br s, 1), 10.50 (br s, 1), 11.85 (br s, 1), 14.81 (br
s, 1). 13C NMR (DMSO-d6): δ 20.71, 26.05, 38.32, 46.47, 50.58,
55.16, 99.68, 103.61, 107.57, 121.25, 124.05, 124.68, 127.00,
128.18, 135.99, 152.15, 157.05, 159.25, 162.26, 169.57. Anal.
(C22H25BrN4O3S‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-ch lor o-5-et h yl-2,6-d im et h oxyb en za m id e H yd r och lo-
r ide (49). Toluene (100 mL) and 3-chloro-5-ethyl-2,6-dimethox-
ybenzoic acid (11)21 (4.32 g, 17.6 mmol) were added to an oven-
dried 300-mL round-bottomed flask. The solution was placed
under N2, and thionyl chloride (4.13 mL, 5.67 g, 47.6 mmol,
2.7 equiv) was added. The light yellow reaction mixture was
heated to 75 °C, and anhydrous DMF (0.25 mL) was added.
The solution was heated at 65-75 °C for 1.25 h. The solvent
was removed with a rotary evaporator to give acid chloride
27 as an orange residue. This crude acid chloride was
dissolved in anhydrous CHCl3 (50 mL) and placed under N2.
A solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothi-
azole (5.63 g, 19.4 mmol, 1.1 equiv) in anhydrous CHCl3 (20
mL) was added to the acid chloride solution. Dry triethy-
lamine (2.94 mL, 2.14 g, 2.10 mmol, 1.2 equiv) was added. The
reaction mixture was allowed to stir at room temperature for
0.75 h, and the solvent was removed with a rotary evaporator.
The resulting viscous orange residue was dissolved in CH2Cl2
and washed with saturated aqueous K2CO3. The organic
phase was dried over MgSO4, filtered, and concentrated to give
10.03 g of an orange viscous oil. The crude material was
adsorbed on silica gel and purified by flash chromatography
on silica gel with EtOAc:0.1% triethylamine as eluant to give
4.78 g of a pale yellow oil. The hydrochloride salt was prepared
by adding HCl (9.24 mL of a 1 N solution in ether, 1.0 equiv)
to a solution of the free base in EtOH. The salt was recrystal-
6-F lu or oisa toic An h yd r id e (40). 2-Amino-6-fluorobenzoic
acid (24) (3.0 g, 19.3 mmol), trichloromethyl chloroformate
(15.0 g, 75.8 mmol, 3.9 eq), and anhydrous 1,4-dioxane (60 mL)
were added to a 250-mL round-bottomed flask equipped with
a magnetic stirring bar. The solution was placed under N2
and heated at reflux for 6 h. The reaction mixture was allowed
to cool to room temperature and concentrated to give 3.8 g of
the crude product as an off-white solid. This material was
used without further purification. 1H NMR (DMSO-d6): δ 6.97
(d, 1, J ) 8.2), 7.06 (dd, 1, J ) 8.4, 10.7), 7.73 (m, 1), 11.90 (br
s, 1).
6-F lu or oisa toic An h yd r id e (40) a n d 3-F lu or oisa toic
An h yd r id e (41). Anhydrous CHCl3 (50 mL), 3-fluorophthalic
anhydride (38) (10.0 g, 60.2 mmol), and azidotrimethylsilane
(8.0 mL, 60.2 mmol, 1.0 eq) were placed under N2 in a flame-
dried 250-mL round-bottomed flask. The reaction mixture was
gently heated with a heat gun until evolution of gas was noted
and then heated at reflux for 3.5 h. The solution was allowed
to cool to room temperature, and 95% EtOH (10 mL) was
added. The milky solution was cooled with an ice-water bath,
and the resulting precipitate was filtered and dried in a
vacuum oven to give 7.78 g (71%) of the title compounds as
1
an off-white solid. Integration of the H NMR indicated a 60:
40 mixture of the 3-fluoro and 6-fluoro isomers, respectively.
41: 1H NMR (DMSO-d6) δ 7.24 (dt, 1, J ) 4.7, 8.1), 7.68 (ddd,
1, J ) 1.3, 8.2, 10.7), 7.76 (dt, 1, J ) 7.9, 0.9). This mixture
was used without further purification.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-br om o-2,6-d im et h oxyb en za m id e Hyd r och lor id e (47).
3-Bromo-2,6-dimethoxybenzoic acid (9)27 (1.48 g, 5.69 mmol)
and anhydrous toluene (50 mL) were added to a flame-dried
three-necked 100-mL round-bottomed flask equipped with a
magnetic stirring bar, nitrogen inlet, addition funnel, and
thermometer. Thionyl chloride (1.12 mL, 1.83 g, 15.4 mmol,
2.7 eq) was added dropwise to the reaction mixture at room
temperature. The addition funnel was replaced with a reflux
condenser, and the reaction mixture was heated to 65 °C. DMF
(0.03 mL) was added to the reaction mixture, and the tem-
perature was maintained at 65 °C for 2 h. The solvent was
removed in vacuo, and the residue was taken up in CHCl3 (20
mL). To this solution were added 3-(4-(4-aminobutyl)-1-
piperazinyl)-1,2-benzisothiazole (1.5 g, 5.17 mmol, 0.9 eq) in
CHCl3 (12.0 mL) and triethylamine (1.08 mL, 0.785 g, 7.76
mmol, 1.4 eq). The reaction mixture was stirred at room
temperature for 0.5 h. The solvent was removed in vacuo, and
the orange oil was dissolved in EtOAc. The organic solution
was washed with saturated K2CO3, dried over MgSO4, filtered,
and concentrated to give an orange oil (3.24 g). The crude

1180 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
lized from EtOH/ether and dried in a vacuum oven to give 2.96
g (30%) of 3-chloro-5-ethyl-2,6-dimethoxybenzamide 49 as light
tan powder. Mp: 198.5-200 °C. 1H NMR (DMSO-d6): δ 1.16
(t, 3, J ) 7.5), 1.60 (m, 2), 1.83 (br s, 2), 2.58 (q, 2, J ) 7.5),
3.20-3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (br d, 2, J )
12.1), 7.38 (s, 1), 7.49 (t, 1, J ) 7.5), 7.62 (t, 1, J ) 7.5), 8.14
(t, 2, J ) 7.0), 8.50 (t, 1, J ) 5.3), 10.66 (s, 1). 13C NMR
(DMSO-d6): δ 14.76, 20.73, 21.80, 26.46, 46.57, 50.67, 55.39,
61.89, 62.27, 121.49, 121.76, 124.30, 124.95, 127.28, 128.45,
129.16, 130.17, 134.64, 150.88, 152.48, 153.96, 162.56, 164.26.
Anal. (C26H33N4O3SCl‚HCl) C, H, N.
allowed to stir for 0.5 h and transferred to a separatory funnel
with the aid of EtOAc. The organic solution was washed with
saturated potassium carbonate, dried over MgSO4, filtered, and
concentrated to give a pale yellow solid (1.4 g). The crude
reaction mixture was purified by flash chromatography with
EtOAc:0.1% triethylamine as eluant to give 0.99 g of the free
base as a white solid. The free base was dissolved in EtOAc
and CH2Cl2, and 2.31 mL of 1 N ethereal HCl (1.0 equiv) was
added. The solvent was removed in vacuo, and the hydro-
chloride salt was recrystallized from EtOH/H2O to give 0.915
g (56%) of 4-chlorobenzamide 53 as a white solid. Mp: 209-
210 °C dec. 1H NMR (DMSO-d6): δ 1.60 (m, 2), 1.79 (m, 2),
3.15-3.37 (m, 5), 3.45 (br t, 3, J ) 12.7), 3.59 (br d, 2, J )
12.0), 4.08 (br d, 2, J ) 12.9), 7.48 (ddd, 1, J ) 1.0, 7.1, 8.1),
7.55 (dm, 2, J ) 8.6), 7.60 (ddd, 1, J ) 1.2, 7.0, 8.2), 7.90 (dm,
2, J ) 8.7), 8.13 (t, 2, J ) 8.2), 8.68 (br t, 1, J ) 5.5), 10.59 (br
s, 1). 13C NMR (DMSO-d6): δ 20.58, 26.17, 38.44, 46.32, 50.41,
55.08, 121.13, 123.95, 124.56, 126.91, 128.07, 128.25, 129.10,
133.18, 135.84, 152.05, 162.16, 165.09. Anal. (C22H25N4OSCl‚
HCl‚0.5H2O) C, H, N, H2O.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3,4-d ich lor oben za m id e Hyd r och lor id e (54). This com-
pound was prepared according to the method described for
benzamide 53, by employing 3-(4-(4-aminobutyl)-1-piperazi-
nyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol), triethylamine
(0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq), and 3,4-dichlorobenzoyl
chloride (32) (0.723 g, 3.45 mmol, 1.0 eq). The crude reaction
mixture was purified by flash chromatography with EtOAc:
0.1% triethylamine as eluant to give the free base (1.52 g) as
a white solid. The hydrochloride salt was prepared, recrystal-
lized from EtOH/H2O, and dried in a vacuum oven to given
0.88 g (51%) of 3,4-dichlorobenzamide 54 as a pale beige solid.
Mp: 208-210 °C dec. 1H NMR (DMSO-d6): δ 1.61 (m, 2), 1.82
(m, 2), 3.27 (m, 6), 3.52 (m, 4), 4.07 (br d, 2, J ) 13.4), 7.47 (t,
1, J ) 7.6), 7.60 (t, 1, J ) 7.5), 7.76 (d, 1, J ) 8.5), 7.88 (dd, 1,
J ) 2.0, 8.4), 8.12 (t, 2, J ) 8.2), 8.14 (d, 1, J ) 2.0), 8.86 (t, 1,
J ) 5.5), 11.10 (br s, 1). 13C NMR (DMSO-d6): δ 20.58, 26.07,
38.62, 46.33, 50.44, 55.08, 121.14, 123.95, 124.57, 126.91,
127.52, 128.07, 129.13, 130.59, 131.16, 133.85, 134.75, 152.07,
162.17, 163.88. Anal. (C22H24N4OSCl2‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-m eth oxyben za m id e Hyd r och lor id e (55). This compound
was prepared according to the method described for benzamide
53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-ben-
zisothiazole (1.0 g, 3.45 mmol), triethylamine (0.721 mL, 0.524
g, 5.18 mmol, 1.5 equiv), and p-anisolyl chloride (33) (0.589 g,
3.45 mmol, 1.0 equiv). The crude reaction mixture was
purified by flash chromatography with 93:7 CH2Cl2:MeOH as
eluant to give the free base as a pale beige solid (0.73 g). The
hydrochloride salt was prepared, recrystallized from EtOH,
and dried in a vacuum oven to give 0.287 g (18%) of 4-meth-
oxybenzamide 55 as a tan solid. Mp: 171-173 °C dec. 1H
NMR (DMSO-d6): δ 1.59 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.49
(br d, 2, J ) 12.1), 3.58 (br d, 2, J ) 13.8), 3.81 (s, 3), 4.07 (br
d, 2, J ) 13.4), 7.00 (dm, 2, J ) 8.9), 7.48 (ddd, 1, J ) 1.2, 7.0,
8.1), 7.60 (ddd, 1, J ) 1.0, 7.0, 8.1), 7.86 (dm, 2, J ) 8.9), 8.13
(t, 2, J ) 8.3), 8.45 (t, 1, J ) 5.6), 10.81 (br s, 1). 13C NMR
(DMSO-d6): δ 20.63, 26.35, 38.29, 46.35, 50.43, 55.13, 55.27,
113.35, 121.15, 123.96, 124.58, 126.69, 126.92, 128.08, 128.94,
152.07, 161.39, 162.17, 165.64. Anal. (C23H28N4O2S‚HCl) C,
H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-(tr iflu or om eth yl)ben za m id e Hyd r och lor id e (56). This
compound was prepared according to the method described for
benzamide 53, by employing 3-(4-(4-aminobutyl)-1-piperazi-
nyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol), triethylamine
(0.721 mL, 0.524 g, 5.18 mmol, 1.5 equiv), and 4-(trifluorom-
ethyl)benzoyl chloride (34) (0.513 mL, 0.720 g, 3.45 mmol, 1.0
equiv). After the 4-(trifluoromethyl)benzoyl chloride was
added, the ice-water bath was removed and the reaction
mixture was stirred for 1.5 h. The crude reaction mixture was
purified by flash chromatography with 1:1 EtOAc:hexanes with
0.1% triethylamine as eluant followed by EtOAc:0.1% triethy-
lamine to give 0.57 g of the free base as a solid. The
hydrochloride salt was prepared and recrystallized from EtOH
to give 0.26 g (15%) of 4-(trifluoromethyl)benzamide 56 as a
2-Azid o-N-(4-(4-(1,2-b en zisot h ia zol-3-yl)-1-p ip er a zin -
yl)bu tyl)ben za m id e Hyd r och lor id e (50). 2-Azidobenzoic
acid (12)22 (0.8 g, 5.15 mmol), 3-(4-(4-aminobutyl)-1-piperaz-
inyl)-1,2-benzisothiazole (1.5 g, 5.16 mmol, 1.0 eq), 1-hydroxy-
benzotriazole hydrate (0.768 g, 5.68 mmol, 1.1 equiv), and
anhydrous DMF (25 mL) were added to a 250-mL round-
bottomed flask equipped with a magnetic stirring bar, addition
funnel, and nitrogen inlet. The reaction mixture was cooled
in an ice-water bath, and a solution of 1,3-dicyclohexylcar-
bodiimide (1.17 g, 5.67 mmol, 1.1 equiv) in DMF (30 mL) was
added dropwise. The ice-water bath was removed, and the
reaction mixture was allowed to stir at room temperature
overnight. The reaction mixture was filtered, and the filtrate
was concentrated. The crude product was partitioned between
CH2Cl2 and saturated NaHCO3. The layers were separated,
and the aqueous layer was extracted with CH2Cl2. The organic
layers were combined, dried over MgSO4, filtered, and con-
centrated. The crude product was purified by flash chroma-
tography with CH2Cl2:MeOH (100-93%:0-7%) as eluant to
give 1.74 g of the free base as an orange oil. The free base
(1.52 g, 3.49 mmol) was dissolved in CH2Cl2, and 1 N ethereal
HCl (1.0 equiv) was added. The solvent was removed in vacuo
to give an amorphous solid. The solid was dissolved in MeOH,
and the solution was filtered. The filtrate was slowly added
to EtOAc. The precipitated solid was filtered, rinsed with
diethyl ether, and dried in a vacuum oven to give 1.24 g (51%)
of 2-azidobenzamide 50 as a pale beige solid. Mp: 163.5-164
°C. 1H NMR (DMSO-d6): δ 1.56 (quin, J ) 7.0), 1.81 (m, 2),
3.24 (m, 6), 3.46 (br d, 2, J ) 12.3), 3.56 (br d, 2, J ) 11.8),
4.05 (br d, 2, J ) 13.4), 7.22 (tm, 1, J ) 7.5), 7.33 (dd, 1, J )
1.2, 8.5), 7.48 (m, 3), 7.58 (ddd, 1, J ) 1.1, 6.9, 8.0), 8.10 (t, 2,
J ) 8.1), 8.37 (br t, 1, J ) 5.6), 10.97 (br s, 1). 13C NMR
(DMSO-d6): δ 20.85, 26.55, 38.70, 46.68, 50.74, 55.44, 119.90,
121.53, 124.34, 124.95, 125.20, 127.31, 128.45, 129.09, 129.89,
131.54, 136.79, 152.45, 162.58, 165.91. IR (KBr): 2126 cm-1
.
Anal. (C22H25N7OS‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
ben za m id e Hyd r och lor id e (52). The free base of this
compound was prepared according to the method described for
compound 82. Acylation of 3-(4-(4-aminobutyl)-1-piperazinyl)-
1,2-benzisothiazole (1.5 g, 5.17 mmol, 1.0 equiv) with benzoyl
chloride (30) (0.6 mL, 0.727 g, 5.17 mmol) over a 1-h period
gave 1.49 g of the free base, which was purified by flash
chromatography with EtOAc:0.1% triethylamine. To a solu-
tion of the free base in EtOAc was added HCl (3.8 mL of a 1
N solution in ether, 1.0 equiv). The hydrochloride salt was
recrystallized from EtOH to give 1.04 g (47%) of benzamide
52 as a pale beige solid. Mp: 200-201.5 °C. 1H NMR (DMSO-
d6): δ 1.61 (m, 2), 1.80 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J )
12.6), 3.59 (br d, 2, J ) 11.7), 4.08 (br d, 2, J ) 13.4), 7.50 (m,
4), 7.60 (t, 1, J ) 7.6), 7.87 (m, 2), 8.13 (t, 2, J ) 8.4), 8.58 (br
t, 1, J ) 5.5), 10.72 (br s, 1). 13C NMR (DMSO-d6): δ 20.59,
26.25, 38.36, 46.32, 50.41, 55.09, 121.14, 123.95, 124.56,
126.90, 127.12, 128.07, 128.16, 131.01, 134.47, 152.05, 162.16,
166.15. Anal. (C22H26N4OS‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-ch lor oben za m id e Hyd r och lor id e Hyd r a te (53). 3-(4-(4-
Aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.0 g, 3.45
mmol), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5
equiv), and CH2Cl2 (10.0 mL) were added to a flame-dried 100-
mL round-bottomed flask equipped with a magnetic stirring
bar, nitrogen inlet, and addition funnel. The reaction mixture
was cooled in an ice-water bath, and a solution of 4-chlo-
robenzoyl chloride (31) (0.61 g, 3.45 mmol, 1.0 equiv) in CH2-
Cl2 (10.0 mL) was added dropwise. The reaction mixture was

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1181
tan solid. Mp: 205-207 °C dec. 1H NMR (DMSO-d6): δ 1.62
(m, 2), 1.83 (m, 2), 3.15-3.40 (m, 6), 3.50 (br t, 2, J ) 13.0),
3.59 (br d, 2, J ) 11.6), 4.08 (br d, 2, J ) 13.3), 7.48 (ddd, 1,
J ) 1.0, 7.1, 8.1), 7.60 (ddd, 1, J ) 1.0, 6.9, 8.1), 8.08 (d, 2, J
) 8.8), 8.11 (m, 4), 8.87 (br t, 1, J ) 5.5), 10.95 (br s, 1). 13C
NMR (DMSO-d6): δ 20.63, 26.15, 38.50, 46.37, 50.47, 55.12,
121.18, 122.13, 123.99, 124.61, 125.23, 126.95, 128.11, 130.79,
138.25, 152.10, 162.20, 165.04. Anal. (C23H25N4OSF3‚HCl) C,
H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-ter t-bu tylben za m id e Hyd r och lor id e (57). This com-
pound was prepared according to the method described for
benzamide 53, by employing 3-(4-(4-aminobutyl)-1-piperazi-
nyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol), triethylamine
(0.721 mL, 0.524 g, 5.18 mmol, 1.0 equiv), and 4-tert-butyl-
benzoyl chloride (35) (0.674 mL, 0.679 g, 3.45 mmol, 1.0 equiv).
The hydrochloride salt was prepared from the free base (0.560
g) and recrystallized from EtOH to give 0.251 g (15%) of 4-tert-
butylbenzamide 57 as a tan solid. Mp: 220.5-222 °C dec. 1H
NMR (DMSO-d6): δ 1.31 (s, 9), 1.60 (m, 2), 1.82 (m, 2), 3.25
(m, 6), 3.55 (m, 4), 4.08 (br d, 2, J ) 13.3), 7.49 (m, 3), 7.62 (t,
1, J ) 7.4), 7.83 (d, 2, J ) 8.4), 8.14 (m, 2), 8.55 (t, 1, J ) 5.7),
11.06 (br s, 1). 13C NMR (DMSO-d6): δ 20.82, 26.55, 31.15,
34.77, 38.53, 46.63, 50.71, 55.39, 121.51, 124.32, 124.93,
125.28, 127.28, 127.35, 128.45, 132.11, 152.45, 154.15, 162.57,
166.47. Anal. (C26H34N4OS‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-(p h en yla zo)ben za m id e Hyd r och lor id e (58). This com-
pound was prepared according to the method described for
benzamide 53, by employing 3-(4-(4-aminobutyl)-1-piperazi-
nyl)-1,2-benzisothiazole (1.24 g, 4.27 mmol), triethylamine
(0.893 mL, 0.648 g, 6.41 mmol, 1.5 equiv), and p-(phenylazo)-
benzoyl chloride (36) (1.05 g, 4.27 mmol, 1.0 equiv). The
reaction mixture was allowed to stir for 1 h following the
addition of p-(phenylazo)benzoyl chloride. The free base was
purified by flash chromatography with 3:1 EtOAc:hexanes with
0.1% triethylamine followed by EtOAc:0.1% triethylamine and,
finally, EtOAc:0.2% triethylamine as eluant to give 1.42 g of
the compound as an orange solid. The free base was recrystal-
lized from EtOAc to give 0.781 g of the pure compound as an
orange solid. The hydrochloride salt was prepared and
recrystallized from EtOH/H2O to give 0.589 g (26%) of 4-(phe-
nylazo)benzamide 58 as an orange solid. Mp: 225-227 °C.
1H NMR (DMSO-d6): δ 1.67 (m, 2), 1.82 (m, 2), 3.36 (m, 8),
3.63 (br d, 2, J ) 10.4), 4.11 (br d, 2, J ) 11.9), 7.49 (tm, 1, J
) 7.6), 7.64 (m, 4), 7.98 (m, 4), 8.14 (m, 4), 8.82 (br t, 1, J )
5.6), 10.50 (br s, 1). 13C NMR (DMSO-d6): δ 20.65, 26.22,
38.56, 46.36, 50.45, 55.12, 119.43, 119.91, 121.16, 122.30,
122.68, 123.97, 124.58, 126.91, 127.45, 127.95, 128.09, 128.50,
128.84, 129.52, 131.98, 132.61, 136.64, 151.82, 152.07, 153.15,
153.46, 155.71, 162.17, 165.18, 165.39. Anal. (C28H30N6OS‚-
HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)-bu tyl)-
2-n itr oben za m id e Hyd r och lor id e (59). This compound
was prepared according to the method for compound 53, by
employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothia-
zole (0.99 g, 3.4 mmol), triethylamine (0.72 mL, 0.52 g, 5.1
mmol, 1.5 equiv), and 2-nitrobenzoyl chloride (37) (0.70 g, 3.4
mmol, 1.0 equiv). The crude reaction mixture was purified
by flash chromatography with EtOAc:0.1% triethylamine as
eluant to give 0.94 g of the free base as a yellow solid. the
hydrochloride salt was prepared, recrystallized from EtOH/
ether, and dried in a vacuum oven to give 0.66 g (41%) of
2-nitrobenzamide 59 as an off-white powder. Mp: 214-215
°C. 1H NMR (DMSO-d6): δ 1.61 (m, 2), 1.85 (m, 2), 3.28 (m,
6), 3.56 (m, 4), 4.09 (br d, 2, J ) 13.5), 7.48 (dd, 1, J ) 7.2,
7.8), 7.72 (m, 4), 8.06 (d, 1, J ) 8.0), 8.15 (t, 2, J ) 7.0), 8.83
(br t, J ) 5.5), 11.29 (br s, 1). 13C NMR (DMSO-d6): δ 21.44,
26.95, 39.32, 47.30, 51.39, 56.06, 122.18, 124.86, 124.99,
125.59, 127.94, 129.09, 130.07, 131.63, 133.57, 134.55, 148.01,
153.09, 163.20, 166.42. Anal. (C22H25N5O3S‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
4-((ter t-bu toxyca r bon yl)a m in o)ben za m id e Hyd r och lo-
r id e (60). This compound was prepared according to the
method described for benzamide 63, by employing 4-((tert-
butoxycarbonyl)amino)benzoic acid (13) (2.05 g, 8.65 mmol),
triethylamine (1.45 mL, 1.05 g, 10.4 mmol, 1.2 equiv), isobutyl
chloroformate (1.12 mL, 1.18 g, 8.65 mmol, 1.0 equiv), and 3-(4-
(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (2.51 g, 8.65
mmol, 1.0 equiv). The crude reaction mixture was purified
by flash chromatography with EtOAc:0.1% triethylamine as
eluant to give 0.78 g of the free base as a white solid. Impure
fractions were combined and purified by flash chromatography
with 9:1 CH2Cl2:MeOH as eluant to give 0.40 g of the free base
as a white solid. The free base obtained from each column
was combined and dissolved in EtOH and CHCl3. To a solution
of the free base was added 1 N ethereal HCl (2.41 mL, 1.0
equiv). The solvent was removed, and the hydrochloride salt
was recrystallized from EtOH to give 0.644 g (14%) of 4-((tert-
butoxycarbonyl)amino)benzamide 60 as a beige solid. Mp:
205-208 °C effervesces. 1H NMR (DMSO-d6): δ 1.49 (s, 9),
1.60 (m, 2), 1.80 (m, 2), 3.10-3.54 (m, 8), 3.59 (m, 2), 4.08 (br
d, 2, J ) 12.5), 7.55 (m, 4), 7.80 (d, 2, J ) 8.8), 8.14 (m, 2),
8.45 (br t, 1, J ) 5.4), 9.64 (s, 1), 10.80 (br s, 1). 13C NMR
(DMSO-d6): δ 20.64, 26.34, 28.01, 38.28, 46.36, 50.33, 55.12,
79.39, 117.00, 121.15, 123.96, 124.58, 126.92, 127.79, 127.96,
128.08, 142.11, 152.06, 152.54, 162.17, 165.70. Anal.
(C27H35N5O3S‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-((ter t-b u t oxyca r b on yl)a m in o)b en za m id e H yd r och lo-
r id e Hyd r a te (61). This compound was prepared according
to the method described for benzamide 63, by employing
3-((tert-butoxycarbonyl)amino)benzoic acid (14) (2.45 g, 10.3
mmol), triethylamine (1.72 mL, 1.25 g, 12.4 mmol, 1.2 equiv),
isobutyl chloroformate (1.34 mL, 1.41 g, 10.3 mmol, 1.0 equiv),
and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (3.0
g, 10.3 mmol, 1.0 equiv). After 20 h, the reaction mixture was
transferred to a separatory funnel with the aid of CH2Cl2. The
solution was washed with saturated K2CO3, dried over MgSO4,
filtered, and concentrated to give the crude free base. The
crude product was purified by flash chromatography with 95:5
CH2Cl2:MeOH as eluant to give 2.82 g of the free base as a
white solid. To a solution of the free base (1.0 g, 1.96 mmol)
in CHCl3 was added 1.96 mL of 1 N ethereal HCl (1.0 equiv).
The hydrochloride salt was recrystallized from EtOH/ether to
give 0.46 g (23%) of 3-((tert-butoxycarbonyl)amino)benzamide
61 as a white solid. Mp: 139-144 °C effervesces. 1H NMR
(DMSO-d6): δ 1.48 (s, 9), 1.59 (m, 2), 1.80 (m, 2), 3.16-3.54
(m, 8), 3.59 (br d, 2, J ) 11.8), 4.08 (br d, 2, J ) 13.1), 7.32 (t,
1, J ) 7.9), 7.48 (m, 3), 7.60 (ddd, 1, J ) 1.1, 6.9, 8.1), 8.00 (s,
1), 8.13 (t, 2, J ) 8.1), 8.50 (br t, 1, J ) 5.6), 9.49 (s, 1), 10.72
(br s, 1). 13C NMR (DMSO-d6): δ 20.84, 26.48, 29.29, 38.66,
46.62, 50.71, 55.41, 79.43, 117.68, 120.82, 121.04, 121.50,
124.31, 124.93, 127.27, 128.44, 128.72, 135.72, 139.92, 152.45,
153.12, 162.56, 166.82. Anal. (C27H35N5O3S‚HCl‚0.75H2O) C,
H, N, H2O.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
2-(2-(ter t-bu toxycar bon yl)h ydr azin o)ben zam ide (62). 2-(2-
(tert-Butoxycarbonyl)hydrazino)benzoic acid (15) (2.57 g, 10.2
mmol), anhydrous THF (30 mL), and anhydrous triethylamine
(1.70 mL, 1.23 g, 12.2 mmol, 1.2 equiv) were combined in a
flame-dried 100-mL round-bottom flask. The orange solution
was stirred under a nitrogen atmosphere and cooled between
-20 and -35 °C with a dry ice/2-propanol bath. Isobutyl
chloroformate (1.32 mL, 1.39 g, 1.0 equiv) was added, and the
mixture was allowed to stir for 5 min. A cold (-20 to -35 °C)
solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothia-
zole (2.97 g, 10.2 mmol, 1.0 equiv) in anhydrous THF (30 mL)
was slowly added. The reaction mixture was allowed to stir
between -15 and -30 °C for 0.75 h. The cold bath was
removed, and the reaction mixture was allowed to stir at room
temperature for 1.5 h. The reaction mixture was transferred
to a separatory funnel, CH2Cl2 was added, and the solution
was washed with saturated NaHCO3. The layers were sepa-
rated, and the aqueous phase was extracted with CH2Cl2. The
organic layers were combined, dried over MgSO4, filtered, and
concentrated to give 5.89 g of an orange oil. The crude product
was purified by column chromatography with 19:1 CH2Cl2:
MeOH as eluant to give 3.01 g (56%) of (2-(tert-butoxycarbo-
nyl)hydrazino)benzamide 62 as a pale beige glass. 1H NMR
(CDCl3): δ 1.45 (s, 9), 1.68 (br t, 4, J ) 3.0), 2.49 (br t, 2, J )
6.8), 2.67 (br t, 4, J ) 4.8), 3.45 (br q, 2, J ) 6.0), 3.55 (br t, 4,

1182 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
J ) 4.8), 6.32 (br s, 1), 6.61 (m, 1), 6.78 (tm, 1, J ) 7.5), 7.01
(d, 1, J ) 8.2), 7.35 (m, 3), 7.47 (tm, 1, J ) 7.5), 7.81 (d, 1, J
) 8.0), 7.90 (d, 1, J ) 8.0), 8.76 (br s, 1).
J ) 5.3), 10.65 (br s, 1). 13C NMR (DMSO-d6, 75.43 MHz): δ
21.72, 27.17, 39.12, 47.42, 51.51, 56.21, 114.36, 114.67, 115.39,
115.46, 118.45, 118.54, 119.82, 120.12, 122.16, 124.97, 125.61,
127.92, 129.11, 147.27, 152.10, 153.07, 155.15, 163.18, 168.80,
168.84. MS (CI/CH4, 50 mA/s): M + 1, base (428). Anal.
(C22H26N5FOS‚HCl) C, H, N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-6-m eth ylben za m id e Hyd r och lor id e (67). Starting
material: 2-amino-6-methylbenzoic acid (20). Yield: 1.10 g
(21%). Mp: 194-196 °C. 1H NMR (DMSO-d6): δ 1.59 (m, 2),
1.80 (m, 2), 2.21 (s, 3), 3.32 (m, 6), 3.55 (m, 4), 4.10 (m, 2),
4.93 (br s, 1), 6.44 (d, 1, J ) 7.4), 6.55 (d, 1, J ) 8.0), 6.96 (t,
1, J ) 7.7), 7.50 (t, 1, J ) 7.5), 7.67 (t, 1, J ) 7.5), 8.15 (t, 2,
J ) 7.1), 8.30 (br t, 1, J ) 5.3), 10.80 (br s, 1). 13C NMR
(DMSO-d6): δ 20.68, 21.73, 27.27, 39.02, 47.37, 51.44, 56.17,
113.70, 118.82, 122.18, 124.18, 124.99, 125.61, 127.93, 129.11,
129.76, 135.30, 146.32, 153.08, 163.20, 169.29. MS (CI/CH4,
50 mA/s): M + 1, base (424). Anal. (C23H29N5SO‚HCl) C, H,
N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-4-(tr iflu or om eth yl)ben zam ide Hydr och lor ide (68).
Anhydrous pyridine (20 mL), 2-amino-R,R,R-trifluoro-p-toluic
acid (21) (1.33 g, 6.5 mmol), and 3-(4-(4-aminobutyl)-1-piper-
azinyl)-1,2-benzisothiazole (2.00 g, 6.5 mmol, 1.0 equiv) were
placed in a 100-mL round-bottom flask. The solution was
placed under N2, silicon tetrachloride (1.48 mL, 2.19 g, 13.0
mmol, 2 equiv) was slowly added with stirring, and the solution
was heated at 145 °C for 18 h. The reaction mixture was
allowed to cool to room temperature, poured onto crushed ice,
and concentrated in vacuo. Distilled H2O (200 mL) was added
to the residue, and the solution was concentrated to dryness.
Toluene (200 mL) was added to the resulting brown solid, and
the solvent was removed with a rotary evaporator. This
procedure was repeated with two additional portions of toluene
(200 mL). Distilled H2O (200 mL) was added to the residue,
and the solution was made basic (pH ) 11) by the addition of
1 N Na2CO3. The aqueous solution was extracted with EtOAc
(3 × 200 mL). The organic layers were combined, dried over
MgSO4, filtered, and concentrated. Toluene (200 mL) was
added to the residue, and the solvent was removed with a
rotary evaporator. This procedure was repeated with two
additional portions of toluene (200 mL). The crude material
was placed under high vacuum overnight and purified by flash
4-Aceta m id o-N-(4-(4-(1,2-ben zisoth ia zol-3-yl)-1-p ip er -
a zin yl)bu tyl)ben za m id e Hyd r och lor id e (63). 4-Acetami-
dobenzoic acid (16) (0.742 g, 414 mmol), triethylamine (0.693
mL, 0.503 g, 4.97 mmol, 1.2 equiv), and anhydrous THF (20
mL) were added to a flame-dried 100-mL three-necked round-
bottomed flask equipped with a magnetic stirring bar, nitrogen
inlet, thermometer, and rubber septum. The reaction mixture
was cooled to -15 °C with a dry ice/2-propanol bath. To the
reaction mixture was added isobutyl chloroformate (0.537 mL,
0.565 g, 4.14 mmol, 1.0 equiv). After 5 min, a solution of 3-(4-
(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.20 g, 4.14
mmol, 1.0 equiv) in anhydrous THF (10.0 mL) was added
dropwise. The reaction mixture was stirred at -15 °C for 1 h
and then allowed to warm to room temperature. After 18 h,
the reaction mixture was transferred to a separatory funnel
with the aid of CH2Cl2 and washed with saturated K2CO3. The
organic layer was filtered, dried with MgSO4, filtered, and
concentrated to give a yellow oil (1.70 g). The crude product
was purified by flash chromatography with 9:1 CH2Cl2:MeOH
to give 0.74 g of the free base as a white foam. To a solution
of the free base in EtOAc and CH2Cl2 was added 1.57 mL of 1
N ethereal HCl (1.0 equiv). The solvent was removed in vacuo,
and the salt was recrystallized from EtOH/H2O to give 0.474
g (23%) of 4-acetamidobenzamide 63 as a pale cream solid.
Mp: >250 °C. 1H NMR (DMSO-d6): δ 1.59 (m, 2), 2.07 (s, 3),
3.25 (m, 6), 3.46 (br t, 2, J ) 12.9), 3.59 (br d, 2, J ) 11.4),
4.08 (br d, 2, J ) 13.4), 7.48 (t, 1, J ) 7.5), 7.60 (t, 1, J ) 7.6),
7.66 (d, 2, J ) 8.7), 7.82 (d, 2, J ) 8.6), 8.13 (t, 2, J ) 8.3),
8.46 (br t, 1, J ) 5.2), 10.23 (s, 1), 10.68 (br s, 1). 13C NMR
(DMSO-d6): δ 20.67, 24.09, 26.37, 38.34, 46.40, 50.49, 55.18,
118.01, 121.19, 124.00, 124.61, 126.95, 127.98, 128.12, 128.75,
141.84, 152.11, 162.20, 165.73, 168.66. Anal. (C24H29N5O2S‚-
HCl) C, H, N.
An th r a n ila m id es 64-67 a n d 69. These compounds were
prepared from the corresponding substituted anthranilinic acid
precursors by the method described for compound 68. The
anthranilic acids employed were obtained from commercial
suppliers or prepared by known methods as indicated. The
analytical data for these 2-aminobenzamides are shown below.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-3-m eth ylben za m id e Hyd r och lor id e (64). Starting
material: 2-amino-3-methylbenzoic acid (17). Yield: 0.806 g
(54%). Mp: 208-210 °C. 1H NMR (DMSO-d6): δ 1.58 (m, 2),
1.78 (m, 2), 2.08 (s, 3), 3.31 (m, 8), 3.59 (m, 2), 4.08 (br d, 2, J
) 12.1), 6.21 (br s, 2), 6.48 (t, 1, J ) 7.6), 7.07 (d, 1, J ) 7.1),
7.39 (d, 1, J ) 7.8), 7.47 (t, 1, J ) 7.5), 7.60 (t, 1, J ) 7.5), 8.12
(t, 2, J ) 8.3), 8.30 (br t, 1, J ) 5.2), 10.58 (br s, 1). 13C NMR
(DMSO-d6): δ 18.57, 21.73, 27.27, 39.08, 47.44, 51.52, 56.24,
115.39, 115.75, 122.16, 123.95, 124.97, 125.61, 126.88, 127.92,
129.11, 133.36, 148.47, 153.08, 163.18, 170.34. MS (CI/CH4,
50 mA/s): M + 1, base (424). Anal. (C23H29N5OS‚HCl) C, H,
N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-6-ch lor oben za m id e Hyd r och lor id e (65). Starting
material: 2-amino-6-chlorobenzoic acid (18). Yield: 0.75 g
(24%). Mp: 211-213 °C. 1H NMR (DMSO-d6, 200 MHz): δ
1.59 (m, 2), 1.82 (m, 2), 3.15-3.61 (m, 10), 4.08 (br d, 2, J )
13.5), 5.23 (br s, 2), 6.61 (d, 1, J ) 7.8), 6.66 (d, 1, J ) 8.2),
7.05 (t, 1, J ) 8.0), 7.49 (t, 1, J ) 7.5), 7.62 (t, 1, J ) 7.5), 8.14
(t, 2, J ) 7.2), 8.47 (br t, 1, J ) 5.3), 10.70 (br s, 1). 13C NMR
(DMSO-d6): δ 21.70, 27.06, 39.18, 47.40, 51.48, 56.21, 114.59,
117.02, 122.16, 122.66, 124.98, 125.61, 127.93, 129.11, 130.98,
131.18, 148.13, 153.08, 163.18, 166.48. MS (CI/CH4, 50 mA/
s): M + 1, base (444). Anal. (C22H26N5SOCl‚HCl) C, H, N, S,
Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-5-flu or oben za m id e Hyd r och lor id e (66). Starting
material: 2-amino-5-fluorobenzoic acid (19). Yield: 0.65 g
(22%). Mp: 219-221 °C. 1H NMR (DMSO-d6): δ 1.58 (m, 2),
1.80 (m, 2), 3.29 (m, 6), 3.45 (m, 2), 3.59 (br d, 2, J ) 10.9),
4.08 (br d, 2, J ) 12.6), 6.30 (br s, 2), 6.71 (dd, 1, J ) 8.9, 5.1),
7.05 (dt, 1, J ) 2.7, 9.9), 7.37 (dd, 1, J ) 2.7, 10.3), 7.47 (t, 1,
J ) 7.5), 7.60 (t, 1, J ) 7.5), 8.12 (t, 2, J ) 8.3), 8.37 (br t, 1,
chromatography on silica gel with
a gradient eluant of
EtOAc:MeOH (100-98%:0-2%) to give 1.45 g of the free
amine. The product was dissolved in EtOH, and HCl (3.04
mL of a 1 N solution in ether, 1 equiv) was added. The
hydrochloride salt was recrystallized from EtOH/H2O to give
0.512 g (15%) of 2-amino-4-(trifluoromethyl)benzamide 68 as
white crystals. Mp: 205-207 °C. 1H NMR (DMSO-d6): δ 1.60
(m, 2), 1.80 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4.09 (d, 2, J ) 13.8),
6.74 (s, 2), 6.81 (d, 1, J ) 8.3), 7.07 (s, 1), 7.49 (t, 1, J ) 7.5),
7.62 (t, 1, J ) 7.5), 7.71 (d, 1, J ) 8.3), 8.14 (m, 2), 8.57 (br t,
1, J ) 5.4), 10.94 (br s, 1). 13C NMR (DMSO-d6): δ 20.75,
26.22, 38.21, 46.45, 50.55, 55.22, 110.09, 110.13, 110.18,
110.23, 112.29, 112.35, 112.40, 112.45, 117.88, 121.24, 122.23,
124.04, 124.66, 125.84, 127.00, 128.17, 129.34, 131.38, 131.79,
149.66, 152.16, 162.24, 167.88. MS (CI/CH4, 50 mA/s): M +
1, base (478). Anal. (C23H26N5OSF3‚HCl) C, H, N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-5-m eth oxyben za m id e Hyd r och lor id e (69). Start-
ing material: 2-amino-5-methoxybenzoic acid (22) (obtained
by the reduction of 2-nitro-5-methoxybenzoic acid (7) according
to the method described for compound 21). Yield: 0.313 g
(10%). Mp: 150 °C dec. 1H NMR (DMSO-d6): δ 1.60 (m, 2),
1.79 (m, 2), 3.37 (m, 12), 3.71 (s, 3), 3.88 (m, 2), 6.67 (d, 1, J )
8.8), 6.86 (dd, 1, J ) 2.7, 8.8), 7.10 (d, 1, J ) 2.7), 7.48 (t, 1, J
) 7.5), 7.62 (t, 1, J ) 7.5), 8.12 (d, 1, J ) 7.5), 8.15 (d, 1, J )
7.5), 8.37 (br t, 1, J ) 4.7). 13C NMR (DMSO-d6): δ 21.84,
27.33, 39.08, 47.54, 51.60, 56.29, 56.60, 113.18, 116.18, 118.66,
120.20, 122.16, 124.97, 125.59, 127.94, 129.09, 144.58, 150.34,
153.08, 163.22, 169.58. MS (CI/CH4, 50 mA/s): M + 1, base
(440). Anal. (C23H29N5O2S‚HCl) C, H, N, S, Cl.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-4-flu or oben za m id e Hyd r och lor id e (70). This com-
pound was prepared by the method described for compound

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1183
71. From 4-fluoroisatoic anhydride (39) (1.18 g, 6.51 mmol)
and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (2.0
g, 6.51 mmol, 1.0 equiv) was obtained 1.31 g (43%) of 70 as a
pale yellow solid. Mp: 234-236 °C. 1H NMR (DMSO-d6): δ
1.53 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.53 (m, 4), 4.07 (d, 2, J )
13.4), 6.31 (dt, 1, J ) 2.5, 8.5), 6.45 (dd, 1, J ) 2.5, 7.2), 6.75
(br s, 2), 7.47 (t, 1, J ) 7.5), 7.60 (m, 2), 8.12 (t, 2, J ) 8.3),
8.32 (br t, 1, J ) 5.3), 10.90 (br s, 1). 13C NMR (DMSO-d6): δ
21.66, 27.25, 39.02, 47.37, 51.47, 56.17, 102.14, 102.33, 102.45,
102.63, 112.35, 112.37, 122.18, 124.97, 125.59, 127.93, 129.11,
131.51, 131.66, 152.97, 153.09, 153.13, 163.17, 163.66, 166.92,
169.10. MS (CI/CH4, 50 mA/s): M + 1, base (428). Anal.
(C22H26N5OFS‚HCl) C, H, N, S, Cl.
7.60 (t, 1, J ) 7.2), 7.80 (br s, 2), 8.03 (dd, 1, J ) 2.5, 9.1), 8.13
(t, 2, J ) 8.3), 8.52 (d, 1, J ) 2.5), 8.80 (t, 1, J ) 5.3), 10.72 (br
s, 1). 13C NMR (DMSO-d6): δ 20.72, 26.17, 38.34, 46.38, 50.48,
55.20, 112.87, 115.85, 121.18, 123.99, 124.61, 125.71, 126.95,
127.35, 128.11, 134.86, 152.11, 155.31, 162.21, 167.21. Anal.
(C22H26N6O3S‚HCl) C, H, N.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-5-ch lor oben za m id e Hyd r och lor id e (74). This com-
pound was prepared according to the method described for
compound 77, by employing 5-chloroisatoic anhydride (43)
(1.02 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-
benzisothiazole (1.5 g, 5.17 mmol, 1.0 equiv). The free base
was purified by flash chromatography with 1:1 EtOAc:hexanes
as eluant. The hydrochloride salt was prepared and recrystal-
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-6-flu or oben za m id e Hyd r och lor id e (71). 6-Fluor-
oisatoic anhydride (40) (1.5 g, 8.28 mmol) and anhydrous THF
(40 mL) were added to a flame-dried 300-mL round-bottom
flask. The reaction mixture was placed under N2, and a
solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothia-
zole (2.4 g, 8.28 mmol, 1.0 equiv) in anhydrous THF (25 mL)
was added. The reaction mixture was allowed to stir overnight
at room temperature. The reaction mixture was concentrated,
and the crude free base was purified by column chromatog-
raphy with 19:1 CH2Cl2:MeOH as eluant to give 2.79 g of the
free base as a yellow oil. The free base was dissolved in EtOAc,
and 1 N ethereal HCl (6.53 mL, 1.0 equiv) was added. The
hydrochloride salt was recrystallized from EtOH/H2O to give
2.0 g (52%) of 2-amino-6-fluorobenzamide 71 as a beige solid.
Mp: 218-220 °C. 1H NMR (DMSO-d6): δ 1.57 (m, 2), 1.80
(m, 2), 3.10-3.75 (m, 10), 4.10 (br d, 2, J ) 13.1), 5.89 (br s,
2), 6.34 (dd, 1, J ) 8.0, 10.5), 6.53 (d, 1, J ) 8.2), 7.09 (ddd, 1,
J ) 6.8, 8.0, 8.2), 7.49 (t, 1, J ) 7.6), 7.62 (t, 1, J ) 7.5), 8.15
(t, 2, J ) 7.2), 8.28 (m, 1), 10.55 (br s, 1). 13C NMR (DMSO-
d6): δ 20.75, 26.38, 38.39, 46.57, 50.66, 55.38, 101.81, 102.27,
107.65, 108.01, 111.63, 111.68, 121.49, 124.32, 124.93, 127.29,
128.44, 131.20, 131.42, 149.90, 150.03, 152.46, 158.21, 162.58,
163.05, 164.66. Anal. (C22H26FN5OS‚HCl) C, H, N.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-3-flu or oben za m id e Hyd r och lor id e (72). THF (50
mL), 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (2.55
g, 8.80 mmol) and a 60:40 mixture of 3-fluoro- and 6-fluoroi-
satoic anhydride (1.59 g, 8.80 mmol, 1.0 equiv) were placed in
a 100-mL round-bottomed flask. The reaction mixture was
allowed to stir at room temperature for 10 min, and the solvent
was removed with a rotary evaporator. The resulting viscous
oil was purified by flash chromatography (4×) on silica gel with
2:1 EtOAc:hexanes followed by EtOAc as eluant to give 0.88 g
of the title compound as its free base. This material was
dissolved in EtOAc, and HCl (1.89 mL of a 1 N solution in
ether, 1.0 equiv) was added. The hydrochloride salt was
recrystallized twice from EtOH to give 0.36 g (15% based on
3-fluoroisatoic anhydride (41)) of 2-amino-3-fluorobenzamide
72 as tan crystals. Mp: 175-176 °C. 1H NMR (DMSO-d6,
200 MHz): δ 1.59 (m, 2), 1.80 (m, 2), 3.18-3.66 (m, 10), 4.09
(br d, 2, J ) 13.3), 4.30 (br s, 2), 6.56 (ddd, J ) 5.1, 8.0, 8.0),
7.14 (dd, 1, J ) 1.4, 8.0), 7.20 (dd, 1, J ) 1.2, 8.0), 7.41 (d, 1,
J ) 8.0), 7.49 (tm, 1, J ) 7.7), 7.62 (tm, 1, J ) 7.4), 8.14 (t, 2,
J ) 6.9), 8.48 (br t, 1, J ) 5.6), 10.72 (br s, 1). 13C NMR
(DMSO-d6, 75.43 MHz): δ 20.68, 26.26, 38.17, 46.41, 50.49,
55.18, 113.99, 114.09, 116.63, 116.87, 117.32, 117.38, 121.24,
123.72, 123.75, 124.05, 124.67, 127.00, 128.17, 137.77, 137.95,
lized from EtOH/H2
O to give 1.61 g (65%) of 2-amino-5-
chlorobenzamide 74 as a white solid. Mp: 173-176 °C. 1H
NMR (DMSO-d6): δ 1.57 (m, 2), 1.78 (m, 2), 3.10-3.68 (m,
12), 4.08 (br d, 2, J ) 13.1), 6.74 (d, 1, J ) 8.9), 7.18 (dd, 1, J
) 2.4, 8.8), 7.48 (tm, 1, J ) 7.2), 7.57 (d, 1, J ) 2.4), 7.60 (tm,
1, J ) 7.2), 8.13 (t, 2, J ) 8.6), 8.45 (t, 1, J ) 5.3), 10.70 (br s,
1).
13C NMR (DMSO-d6): δ 20.64, 26.19, 38.20, 46.35, 50.44,
55.16, 116.75, 118.78, 119.04, 121.18,124.00, 124.61, 126.95,
127.44, 128.12, 131.37, 146.88, 152.11, 162.21, 167.41. Anal.
(C22H26N5OSCl‚HCl) C, H, N.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-3-m eth oxyben za m id e Hyd r och lor id e (75). This
compound was prepared by the method described for com-
pound 71. From 3-methoxyisatoic anhydride (44) (3.35 g, 0.017
mol) (obtained from 2-amino-3-methoxybenzoic acid by the
method described for compound 39) and 3-(4-(4-aminobutyl)-
1-piperazinyl)-1,2-benzisothiazole (5.33 g, 0.017 mol, 1.0 equiv)
was obtained 5.41 g of the product as the free base. A portion
of this material (1.94 g) was dissolved in EtOH (10 mL), and
HCl (4.4 mL of a 1 N solution in either, 1.0 equiv) was added.
The hydrochloride salt was recrystallized from EtOH/2-pro-
panol to give 1.93 g (65%) of 2-amino-3-methoxybenzamide 75
as off-white crystals. Mp: 136-138 °C. 1H NMR (DMSO-
d6): δ 1.59 (m, 2), 1.80 (m, 2), 3.12-3.60 (m, 6), 3.81 (s, 3),
4.09 (br d, 2, J ) 12.9), 6.13 (br s, 1), 6.54 (t, 1, J ) 8.0), 6.91
(d, 1, J ) 7.6), 7.20 (d, 1, J ) 7.8), 7.49 (t, 1, J ) 7.4), 7.62 (t,
1, J ) 7.5), 8.14 (t, 2, J ) 6.8), 8.33 (br t, 1, J ) 5.4), 10.89 (br
s, 1). 13C NMR (DMSO-d6): δ 21.68, 27.29, 39.04, 47.38, 51.48,
56.20, 56.54, 112.83, 114.92, 115.40, 120.73, 122.18, 124.98,
125.59, 127.93, 129.11, 140.50, 147.88, 153.09, 163.18, 169.79.
MS (CI/CH4, 50 mA/s):
(C23H29N5O2S‚HCl) C, H, N, S, Cl.
M + 1, base (440). Anal.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
2-(m eth yla m in o)ben za m id e Hyd r och lor id e (76). This
compound was prepared according to the method described for
benzamide 77, by employing N-methylisatoic anhydride (45)
(0.92 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-
benzisothiazole (1.5 g, 5.17 mmol, 1.0 equiv). The free base
was purified by flash chromatography with EtOAc as eluant.
The hydrochloric salt was prepared, recrystallized from EtOH/
ether, and dried in a vacuum oven to give 1.22 g (51%) of
2-(methylamino)benzamide 76 as a pale beige solid. Mp: 169-
173 °C.
1H NMR (DMSO-d6): δ 1.58 (m, 2), 1.81 (m, 2), 2.77
(s, 3), 3.30 (m, 4), 3.48 (br d, 3, J ) 13.8), 3.58 (br d, 3, J )
12.9), 4.07 (br d, 2, J ) 14.8), 6.56 (t, 1, J ) 7.4), 6.63 (d, 1, J
) 8.3), 7.29 (t, 1, J ) 7.7), 7.48 (t, 1, J ) 7.5), 7.57 (d, 1, J )
7.2), 7.61 (d, 1, J ) 7.4), 7.64 (br s, 1), 8.13 (t, 2, J ) 8.3), 8.41
(br t, 1, J ) 5.4), 11.00 (br s, 1).
13C NMR (DMSO-d6): δ 20.66,
149.63, 152.16, 152.78, 162.27, 168.00, 168.04. Anal. (C22H26
-
FNOS‚HCl) C, H, N.
26.28, 29.33, 38.08, 46.36, 50.44, 55.18, 110.55, 114.03, 115.24,
121.17, 123.99, 124.61, 126.96, 128.11, 128.20, 132.26, 149.91,
152.12, 162.20, 169.12. Anal. (C23H29N5OS‚HCl) C, H, N.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)ben za m id e Hyd r och lor id e (77). Isatoic anhydride
(46) (0.894 g, 5.48 mmol), EtOH (15.0 mL), and 3-(4-(4-
aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.59 g, 5.48
mmol, 1.0 equiv) were added to a round-bottomed flask
equipped with a magnetic stirring bar and nitrogen inlet. the
reaction mixture was stirred at room temperature for 22 h.
The solvent was removed in vacuo to give 2.35 g of a brown
oil. The crude material was purified by flash chromatography
with 19:1 CH2Cl2:MeOH as eluant to give 1.28 g of an orange
oil, which became a pale yellow solid upon standing. To a
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-5-n itr oben za m id e Hyd r och lor id e (73). This com-
pound was prepared according to the method described for
benzamide 77, by employing 5-nitroisatoic anhydride (42) (1.08
g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-ben-
zisothiazole (1.5 g, 5.17 mmol, 1.0 equiv). The free base was
purified by flash chromatography with EtOAc as eluant. The
hydrochloride salt was prepared, recrystallized from EtOH/
H2O, and dried in a vacuum oven to give 1.10 g (43%) of
2-amino-5-nitrobenzamide 73 as a yellow solid. Mp: 224-
230 °C dec. 1H NMR (DMSO-d6): δ 1.61 (m, 2), 1.80 (m, 2),
3.28 (m, 4), 3.46 (br t, 4, J ) 12.1), 3.59 (br d, 2, J ) 10.2),
4.08 (br d, 2, J ) 12.8), 6.82 (d, 1, J ) 9.3), 7.48 (t, 1, J ) 7.6),

1184 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
solution of the free base (0.35 g, 0.855 mmol) in EtOAc and
EtOH was added HCl (0.855 mL of a 1 N solution in ether,
1.0 equiv). The resulting hydrochloride salt was recrystallized
from 95% EtOH to give 0.230 g (60%) of 2-aminobenzamide
77 as a white solid. Mp: 227-228 °C. 1H NMR (DMSO-d6):
δ 1.58 (m, 2), 1.79 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J ) 12.8),
3.59 (br d, 2, J ) 12.4), 4.09 (br d, 2, J ) 13.2), 6.41 (br s, 2),
6.51 (ddd, J ) 1.1, 7.0, 8.1), 6.69 (dd, 1, J ) 1.1, 8.2), 7.13
(ddd, 1, J ) 1.5, 7.0, 8.4), 7.48 (m, 2), 7.60 (ddd, 1, J ) 1.1,
7.0, 8.0), 8.13 (t, 2, J ) 8.4), 8.29 (t, 1, J ) 5.5), 10.68 (br s, 1).
13C NMR (DMSO-d6): δ 20.64, 26.28, 37.98. 46.35, 50.42, 55.14,
114.49, 114.75, 116.26, 121.14, 123.95, 124.57, 126.10, 126.91,
128.01, 128.07, 131.51, 149.47, 152.06, 162.16, 168.85. Anal.
(C22H27N5OS‚HCl) C, H, N.
dimethylated according to the method described for compounds
78 and 79. The two resulting isomers were partially purified
by flash chromatography on silica gel with 2:1 EtOAc:hexanes
as eluant. Further purification on
a Harrison Research
chromatotron with 1:1 and 2:1 EtOAc:hexanes as eluant gave
a total of 1.07 g of the major isomer, N-(4-(4-(1,2-benzisothia-
zol-3-yl)-1-piperazinyl)butyl)-3-chloro-5-ethyl-6-hydroxy-2-meth-
oxybenzamide (80) (Rf ) 0.18 with 2:1 EtOAc:hexanes as
eluant), and 0.27 g of the minor isomer, N-(4-(4-(1,2-ben-
zisothiazol-3-yl)-1-piperazinyl)butyl)-3-chloro-5-ethyl-2-hydroxy-
6-methoxybenzamide (81) (Rf ) 0.11 with 2:1 EtOAc:hexanes
as eluant), as light orange oils. The hydrochloride salts of each
isomer were prepared independently by dissolving the free
amine in ether and adding HCl (1 equiv of a 1 N solution in
ether).
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-br om o-2-h ydr oxy-6-m eth oxyben zam ide Hydr oxide (78)
an d N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)bu tyl)-
3-br om o-6-h yd r oxy-2-m eth oxyben za m id e Hyd r och lor id e
(79). N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-
bromo-2,6-dimethoxybenzamide (47) (4.99 g, 9.35 mmol) and
anhydrous CH2Cl2 (75 mL) were added to a flame-dried 250-
mL round-bottomed flask equipped with a magnetic stirring
bar, nitrogen inlet, and pressure-equalizing addition funnel.
To this solution was added HCl (9.25 mL of a 1 N solution in
ether, 9.25 mmol, 0.99 equiv) followed by the dropwise addition
of boron tribromide (9.35 mL of a 1 N solution in CH2Cl2, 9.35
mmol, 1.0 equiv). The reaction mixture was allowed to stir at
room temperature for 0.5 h. The reaction mixture was cooled
with an ice-water bath, and 1 N NH4OH (50 mL) was added.
The solids were dissolved with the aid of CH2Cl2 and H2O. The
phases were separated, and the aqueous phase was extracted
with CH2Cl2. The organic layers were combined, washed with
H2O, dried over MgSO4, filtered, and concentrated to give 3.61
g of the crude product as a sticky yellow residue. The crude
free base was purified by flash chromatography with 97:3 CH2-
Cl2:MeOH as eluant to give 2.06 g (Rf ) 0.10) of N-(4-(4-(1,2-
benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-
methoxybenzamide (78) as an oil and 1.32 g of a mixture of
isomers. This mixture was purified by flash chromatography
with EtOAc as eluant to give 0.18 g (Rf ) 0.34) of the minor
isomer, N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-
3-bromo-6-hydroxy-2-methoxybenzamide (79), as a tan solid.
The hydrochloride salts of each isomer were prepared inde-
pendently by dissolving the free amine in EtOAc and treating
them with HCl (1 equiv of a 1 N solution in ether). The
hydrochloride salt of the major isomer was recrystallized from
EtOH/H2O to give 1.67 g (32%) of N-(4-(4-(1,2-benzisothiazol-
3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-methoxybenza-
mide hydrochloride (78) as a pale pink solid. Mp: 191-192.5
°C. 1H NMR (DMSO-d6): δ 1.54-1.90 (m, 4), 3.05-3.70 (m,
10), 3.94 (s, 3), 4.07 (br d, 2, J ) 12.8), 6.60 (d, 1, J ) 9.2),
7.47 (m, 1), 7.60 (m, 1), 7.66 (d, 1, J ) 9.0), 8.11 (d, 1, J ) 7.6),
8.14 (d, 1, J ) 7.9), 8.93 (t, 1, J ) 6.2), 10.75 (br s, 1), 14.87 (s,
1). 13C NMR (DMSO-d6): δ 10.62, 25.95, 38.58, 46.35, 50.44,
55.04, 56.69, 102.30, 103.14, 104.76, 121.17, 123.99, 124.60,
126.95, 128.10, 136.07, 152.10, 158.08, 159.27, 162.21, 168.79.
Anal. (C23H27N4O3SBr‚HCl) C, H, N.
The hydrochloride salt of the minor isomer was filtered and
dried under high vacuum in an abderholden apparatus to give
76 mg (2%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-
butyl)-3-bromo-6-hydroxy-2-methoxybenzamide hydrochloride
(79) as a white solid. Mp: 185-187 °C. 1H NMR (DMSO-d6):
δ 1.60 (m, 2), 1.83 (m, 2), 3.10-3.70 (m, 10), 3.79 (s, 3), 4.09
(m, 2), 6.70 (d, 1, J ) 8.8), 7.49 (m, 2), 7.62 (t, 1, J ) 7.5), 8.15
(t, 2, J ) 7.8), 8.47 (br t, 1, J ) 5.2), 10.65 (br s, 1), 10.99 (s,
1). 13C NMR (DMSO-d6): δ 20.50, 26.17, 38.14, 46.44, 50.55,
55.27, 61.66, 104.70, 114.00, 119.20, 121.19, 124.04, 124.63,
126.99, 128.13, 133.81, 152.13, 154.34, 156.85, 162.24, 165.15.
Anal. (C23H27N4O3SB‚HCl) C, H, N.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
3-ch lor o-5-eth yl-6-h yd r oxy-2-m eth oxyben za m id e Hyd r o-
ch lor id e (80) a n d N-(4-(4-(1,2-Ben zisot h ia zol-3-yl)-1-
p i p e r a z i n y l)b u t y l)-3-c h lo r o -5-e t h y l-2-h y d r o x y -6-
m eth oxyben za m id e Hyd r och lor id e Hyd r a te (81). N-(4-
(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-chloro-5-ethyl-
2,6-dimethoxybenzamide (49) (2.07 g, 4.0 mmol) was mono-
The hydrochloride salt of the major isomer was recrystal-
lized from EtOH/ether and dried in a vacuum oven to give 0.76
g (35%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-
3-chloro-5-ethyl-6-hydroxy-2-methoxybenzamide hydrochloride
(80) as an off-white powder. Mp: 179-181 °C. 1H NMR
(DMSO-d6): δ 1.12 (t, 3, J ) 7.3), 1.64 (m, 2), 1.81 (m, 2), 2.52
(m, 3), 3.20-3.60 (m, 9), 3.82 (s, 3), 4.06 (br d, 2, J ) 12.3),
7.38 (s, 1), 7.47 (m, 1), 7.60 (t, 1, J ) 7.5), 8.12 (t, 2, J ) 6.6),
8.83 (br t, 1, J ) 5.1), 11.25 (br s, 1), 13.60 (s, 1). 13C NMR
(DMSO-d6): δ 13.69, 20.65, 22.00, 26.04, 38.33, 46.39, 50.46,
55.15, 61.64, 110.73, 115.79, 121.24, 124.05, 124.66, 127.00,
128.16, 129.76, 132.33, 152.03, 152.16, 157.96, 162.27, 167.77
Anal. (C25H31N4O3SCl‚HCl) C, H, N.
The hydrochloride salt of the minor isomer was recrystal-
lized from 95% EtOH and dried in a vacuum oven to give 0.156
g (7%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-
3-chloro-5-ethyl-2-hydroxy-6-methoxybenzamide hydrochloride
hydrate (81) as fluffy, off-white crystals. Mp: 171-713 °C.
1H NMR (DMSO-d6): δ 1.15 (t, 3, J ) 7.6), 1.62 (m, 2), 1.81
(m, 2), 2.52 (q, 2, J ) 7.6), 3.20-3.62 (m, 10), 3.72 (s, 3), 4.08
(br d, 2, J ) 12.7), 7.40 (s, 1), 7.47 (t, 1, J ) 7.6), 7.60 (t, 1, J
) 7.5), 8.12 (t, 2, J ) 8.3), 8.78 (br t, 1, J ) 5.6), 10.63 (br s,
1), 12.64 (s, 1). 13C NMR (DMSO-d6): δ 15.77, 21.54, 22.13,
26.99, 39.34, 47.32, 51.40, 56.09, 63.26, 114.02, 117.53, 122.16,
124.97, 125.58, 127.93, 129.09, 129.13, 133.19, 153.08, 154.66,
155.93, 163.20, 168.18. Anal. (C25H31N4O3SCl‚1.25H2O) C, H,
N, H2O.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
2-h yd r oxyben za m id e Hyd r och lor id e (82). 3-(4-(4-Ami-
nobutyl)-1-piperazinyl)-1,2-benzisothiazole (3.0 g, 10.4 mmol),
triethylamine (1.74 mL, 1.26 g, 12.5 mmol, 1.2 equiv), and CH2-
Cl2 (50 mL) were added to a flame-dried 200-mL three-necked
round-bottomed flask equipped with a magnetic stirring bar,
addition funnel, and nitrogen inlet. The reaction mixture was
cooled in an ice-water bath, and a solution of acetylsalicyloyl
chloride (29) (2.06 g, 10.4 mmol, 1.0 equiv) in CH2Cl2 (20 mL)
was added dropwise. The reaction mixture was allowed to
warm to room temperature and stirred for 15 min. The
reaction mixture was washed with cold saturated NaHCO3.
The organic layers were dried over MgSO4, filtered, and
concentrated to give 5.8 g of the crude material as an orange
oi. The crude reaction mixture was purified by flash chroma-
tography with 95:5 CH2Cl2:MeOH as eluant. The product (2.93
g) was obtained as a mixture of ((4-(4-(1,2-benzisothiazol-3-
yl)-1-piperazinyl)butyl)carbamoyl)phenylacetate (51) and N-(4-
(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-hydroxyben-
zamide (82). This mixture and MeOH (30.0 mL) were added
to a 300-mL round-bottomed flask equipped with a magnetic
stirring bar, additional funnel, and nitrogen inlet. A solution
of sodium methoxide (38.5 mg, 7.12 mmol, 1.1 equiv) in MeOH
(60 mL) was added dropwise to the reaction mixture. The
reaction mixture was allowed to stir for 1.5 h, neutralized with
Dowex resin, filtered, and concentrated to give 2.68 g of the
free base as a viscous pale orange oil. To a solution of the
free base in EtOAc was added HCl (6.53 mL of a 1 N solution
in ether, 1.0 equiv). The resulting hydrochloride salt was
recrystallized from EtOH/H2O to give 2.32 g (50% based on
acetylsalicyloyl chloride) of 2-hydroxybenzamide 82 as an off-
white solid. Mp: 200-201 °C. 1H NMR (DMSO-d6): δ 1.63
(m, 2), 1.80 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J ) 12.7), 3.59 (br
d, 2, J ) 11.3), 4.07 (br d, 2, J ) 13.5), 6.89 (m, 2), 7.40 (ddd,

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1185
1, J ) 1.7, 7.2, 8.8), 7.47 (ddd, 1, J ) 1.1, 6.9, 8.1), 7.60 (ddd,
1, J ) 1.1, 7.0, 8.1), 7.90 (dd, 1, J ) 1.4, 7.9), 8.12 (t, 2, J )
8.4), 8.98 (br t, 1, J ) 5.5), 10.80 (br s, 1), 12.68 (s, 1). 13C
NMR (DMSO-d6): δ 20.60, 25.99, 38.38, 46.35, 50.44, 55.06,
115.07, 117.31, 118.43, 121.14, 123.95, 124.57, 126.90, 127.69,
128.07, 133.59, 152.05, 160.09, 162.16, 169.03. Anal.
(C22H26N4O2S‚HCl) C, H, N.
(m, 2), 3.29 (q, 2, J ) 5.8, 6.6), 3.37 (m, 2), 3.54 (br s, 4), 4.05
(br s, 2), 6.99 (t, 1, J ) 7.5), 7.12 (d, 1, J ) 8.0), 7.46 (m, 2),
7.58 (t, 1, J ) 7.6), 7.73 (dd, 1, J ) 1.3, 7.5), 8.06 (br s, 1), 8.09
(d, 1, J ) 8.2), 8.13 (d, 1, J ) 8.2), 8.78 (t, 1, J ) 5.6), 9.18 (s,
1), 10.27 (br s, 3), 11.18 (br s, 1). 13C NMR (DMSO-d6): δ
20.62, 26.15, 38.25, 46.40, 50.51, 55.15, 114.43, 118.83, 120.41,
121.24, 124.07, 124.68, 127.01, 128.17, 128.36, 132.07, 145.66,
152.14, 162.30, 167.93. MS (CI/CH4, 50 mA/s): + 1 (425), base
(291). Anal. (C22H28N6OS‚2HCl‚0.5H2O) C, H, N, Cl, H2O.
4-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)ben za m id e Hyd r och lor id e (83). N-(4-(4-(1,2-Ben-
zisothiazol-3-yl)-1-piperazinyl)butyl)-4-((tert-butoxycarbonyl)-
amino)benzamide (60) (800 mg, 1.57 mmol), anisole (1.5 mL),
anhydrous CHCl3 (15 mL), and trifluoroacetic acid (15 mL)
were added to a 500-mL round-bottomed flask equipped with
a magnetic stirring bar and nitrogen inlet. The reaction
mixture was stirred for 0.5 h at room temperature. The
solvent was removed in vacuo to obtain an oil. The crude oil
was dissolved in EtOAc, washed with saturated K2CO3, dried
over MgSO4, filtered, and concentrated to give a yellow solid.
The crude amine was purified by flash chromatography with
EtOAc:0.2% triethylamine to give 0.37 g of the amine as an
oil. To a solution of the amine in EtOAc and CH2Cl2 was added
0.90 mL of 1 N ethereal HCl (1.0 equiv). The solvent was
removed in vacuo, and the hydrochloride salt was recrystal-
lized from EtOH/H2O to give 200 mg (29%) of 4-aminobenza-
mide 83 as a tan solid. Mp: 213.5-214.5 °C. 1H NMR
(DMSO-d6): δ 1.56 (m, 2), 1.77 (m, 2), 3.27 (m, 6), 3.45 (br t,
2, J ) 12.5), 3.59 (br d, 2, J ) 11.9), 4.08 (br d, 2, J ) 13.2),
5.61 (br s, 2), 6.54 (d, 2, J ) 8.6), 7.48 (ddd, 1, J ) 1.1, 7.1,
8.1), 7.60 (m, 3), 8.12 (m, 3), 10.65 (br s, 1). 13C NMR (DMSO-
d6): δ 20.65, 26.52, 38.11, 46.37, 50.44, 55.15, 112.43, 121.16,
123.96, 124.58, 126.91, 128.08, 128.62, 151.44, 152.06, 162.18,
166.20. Anal. (C22H27N5OS‚HCl) C, H, N.
3-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)ben za m id e Hyd r och lor id e Hyd r a te (84). This com-
pound was prepared according to the method described for
compound 83, by employing N-(4-(4-(1,2-benzisothiazol-3-yl)-
1-piperazinyl)butyl)-3-((tert-butoxycarbonyl)amino)benza-
mide (61) (1.77 g, 3.47 mmol), anisole (3.0 mL), anhydrous
CHCl3 (30 mL), and trifluoroacetic acid (30 mL). The crude
amine was purified by flash chromatography with EtOAc:0.1%
trimethylamine followed by EtOAc:0.2% triethylamine to give
1.16 of the free base as an orange oil. The hydrochloride salt
was prepared and recrystallized from EtOH/ether to give 0.31
g (20%) of 3-aminobenzamide 84 as a rust-orange solid. Mp:
122-130 °C effervesces. 1H NMR (DMSO-d6): δ 1.59 (m, 2),
1.80 (m, 2), 3.05-3.75 (m, 10), 4.08 (br d, 2, J ) 13.0), 6.10 (br
s, 2), 6.79 (d, 1, J ) 7.4), 7.13 (m, 3), 7.48 (ddd, 1, J ) 1.0, 6.9,
8.1), 7.60 (ddd, 1, J ) 1.1, 6.9, 8.1), 8.13 (t, 2, J ) 8.4), 8.38
(br t, 1, J ) 5.5), 10.77 (br s, 1). 13C NMR (DMSO-d6): δ 20.66,
26.35, 38.36, 46.40, 50.49, 55.20, 114.21, 115.93, 117.63,
121.21, 124.05, 124.64, 126.98, 128.14, 128.72, 135.61, 146.36,
152.13, 162.22, 166.77. Anal. (C22H27N5OS‚HCl‚0.5H2O) C,
H, N, H2O.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
2-h yd r a zin oben za m id e Dih yd r och lor id e Hyd r a te (85).
N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-(2-(tert-
butoxycarbonyl)hydrazino)benzamide (62) (2.85 g, 5.43 mmol),
anhydrous anisole (5 mL), and anhydrous CHCl3 (75 mL) were
combined in a 500-mL round-bottom flask. To the stirred pale
yellow solution was added trifluoroacetic acid (25 mL). The
reaction mixture was allowed to stir under a nitrogen atmo-
sphere for 10 min, and the solution was concentrated in vacuo.
The residue was transferred to a separatory funnel with the
aid of CHCl3 and washed with saturated NaHCO3. The layers
were separated, and the aqueous phase was extracted with
CHCl3. The organic layers were combined, washed with
saturated NaHCO3, dried over MgSO4, filtered, and concen-
trated to give an orange liquid. The crude product was purified
by column chromatography with a gradient eluant of 97-
95% CH2Cl2 to 3-5% MeOH to give 1.54 g of the free base as
a partially solidified yellow oil. The free base (1.41 g, 3.32
mmol) was dissolved in CH2Cl2, and 1 N ethereal HCl (6.8 mL,
2.05 equiv) was added. The resulting dihydrochloride salt was
recrystallized from EtOH/H2O/ether to give 1.1 g (40%) of
2-hydrazinobenzamide 85 as a gold yellow solid. Mp: 222-
226 °C. 1H NMR (DMSO-d6): δ 1.62 (m, 2), 1.83 (m, 2), 3.17
2-Aceta m id o-N-(4-(4-(1,2-ben zisoth ia zol-3-yl)-1-p ip er -
a zin yl)bu tyl)ben za m id e Hyd r och lor id e (86). This com-
pound was prepared according to the method described for
benzamide 53, by employing 2-amino-N-(4-(4-(1,2-benzisothia-
zol-3-yl)-1-piperazinyl)butyl)benzamide (77) (1.3 g, 3.17 mmol),
triethylamine (0.66 mL, 0.48 g, 4.78 mmol, 1.5 equiv), CH2Cl2
(25 mL), and acetyl chloride (0.226 mL, 0.25 g, 3.17 mmol, 1.0
equiv). The reaction mixture was stirred in an ice-water bath
for 1 h and allowed to warm to room temperature. The
reaction mixture was worked up after 18 h. The free base was
purified by flash chromatography with EtOAc:0.1% triethy-
lamine as eluant to give 1.09 g of the free base as an oil. To
a solution of the free base (1.04 g, 2.30 mmol) in EtOAc was
added 2.30 mL of 1 N ethereal HCl (1.0 equiv). The solvent
was removed in vacuo, and the hydrochloride salt was recrys-
tallized from EtOH to give 0.859 g (56%) of 2-acetamidoben-
zamide 86 as a beige solid. Mp: 189.5-190.5 °C. 1H NMR
(DMSO-d6): δ 1.67 (m, 2), 1.84 (m, 2), 2.10 (s, 3), 3.10-3.75
(m, 10), 4.09 (br d, 2, J ) 12.9), 7.16 (tm, 1, J ) 7.7), 7.49 (t,
2, J ) 7.8), 7.62 (t, 1, J ) 7.4), 7.78 (dm, 1, J ) 7.8), 8.13 (d,
1, J ) 7.6), 8.16 (d, 1, J ) 7.8), 8.36 (d, 1, J ) 8.2), 8.84 (br t,
1, J ) 5.2), 10.86 (br s, 1), 11.24 (br s, 1). 13C NMR (DMSO-
d6): δ 20.61, 24.78, 25.99, 38.40, 46.33, 50.41, 55.08, 120.46,
121.07, 121.16, 122.49, 123.96, 124.58, 126.92, 128.09, 131.68,
138.78, 152.06, 162.17, 168.08, 161.18. Anal. (C24H29N5O2-
S‚HCl) C, H, N.
Eth yl N-(2-(((4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zi-
n yl)b u t yl)a m in o)ca r b on yl)p h en yl)ca r b a m a t e H yd r o-
ch lor id e (87). 2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-
piperazinyl)butyl)benzamide (77) (1.5 g, 3.66 mmol),
triethylamine (0.638 mL, 0.463 g, 4.58 mmol, 1.25 equiv), and
anhydrous CHCl3 (10 mL) were added to a flame-dried 50-mL
round-bottomed flask. The reaction mixture was placed under
N2 and cooled with an ice-water bath, and a solution of ethyl
chloroformate (0.385 mL, 0.437 g, 4.03 mmol, 1.1 equiv) in
anhydrous CHCl3 (10 mL) was added dropwise. After the
addition of ethyl chloroformate was complete, the ice-water
bath was removed and the reaction mixture was allowed to
stir at room temperature for 18 h. Additional portions of
triethylamine (0.51 mL, 0.37 g, 3.66 mmol, 1.0 equiv) and ethyl
chloroformate (0.35 mL, 0.4 g, 3.66 mmol, 1.0 equiv) were
added to the reaction mixture. The solution was allowed to
stir at room temperature for 4 days. The reaction mixture was
transferred to a separatory funnel, CH2Cl2 was added, and the
solution was washed with saturated NaHCO3. The layers were
separated, and the aqueous phase was extracted with CH2-
Cl2. The organic layers were combined, dried over MgSO4,
filtered, and concentrated to give 1.74 g of the crude product
as an orange oil. The free base was purified by flash chro-
matography with EtOAc:hexanes (2:1):0.1% triethylamine
followed by EtOAc:0.1% triethylamine as eluant to give 0.49
g of the free base as an oil. HCl (0.96 mL of 1 N solution in
ether, 1.0 equiv) was added to a solution of the free base (0.46
g, 0.96 mmol) in CH2Cl2 and EtOAc. The hydrochloride salt
was filtered and dried in vacuum oven to give 0.385 g (20%)
of ethyl carbamate 87 as a white solid. Mp: 195-195.5 °C.
1H NMR (DMSO-d6): δ 1.24 (t, 3, J ) 7.2), 1.62 (m, 2), 1.83
(m, 2), 3.26 (m, 6), 3.47 (m, 2), 3.61 (m, 2), 4.07 (m, 2), 4.14 (q,
2, J ) 7.2), 7.10 (tm, 1, J ) 7.7), 7.49 (m, 2), 7.60 (ddd, 1, J )
1.1, 7.0, 8.1), 7.79 (dd, 1, J ) 1.5, 7.9), 8.12 (tm, 2, J ) 8.4),
8.20 (dd, 1, J ) 0.9, 8.3), 8.89 (br t, 1, J ) 5.5), 10.85 (br s, 1),
10.97 (s, 1). 13C NMR (DMSO-d6): δ 14.41, 20.68, 26.01, 38.47,
46.44, 50.53, 55.16, 60.61, 118.62, 119.59, 121.25, 121.70,
124.04, 124.67, 127.00, 128.18, 128.24, 132.18, 139.30, 152.16,
152.91, 162.24, 168.36. Anal. (C25H31N5O3S‚HCl) C, H, N.

1186 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Norman et al.
N-(2-(N-(4-(4-(1,2-Ben zisot h ia zol-3-yl)-1-p ip er a zin yl)-
bu tyl)ca r ba m oyl)p h en yl)-L-va lin a m id e Tr iflu or oa ceta te
Hyd r a te (88). 2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-
piperazinyl)butyl)benzamide (77) (2.39 g, 5.84 mmol), anhy-
drous CHCl3 (60 mL), and 5% aqueous Na2CO3 (60 mL) were
added to a 300-mL round-bottomed flask. To the two-phase
reaction mixture was added a solution of N-((9H-fluoren-9-
ylmethoxy)carbonyl)-L-valyl chloride28 (3.3 g, 9.22 mmol, 1.58
equiv). The two-phase reaction mixture was allowed to stir
for 10 min at room temperature and transferred to a separa-
tory funnel. CHCl3 was added, and the organic layer was
separated, dried over MgSO4, filtered, and concentrated to give
6.48 g of the crude product as a pale yellow oil. This crude
material was purified by flash chromatography with 95:5
EtOAc:MeOH as eluant to give 4.5 g (95%) of N-(4-(4-(1,2-
benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-((N-((9H-fluoren-9-
ylmethoxy)carbonyl)-L-valyl)amino)benzamide as a white glass.
1H NMR (CDCl3): δ 1.00 (d, 3, J ) 6.9), 1.07 (d, 3, J ) 6.8),
1.64 (m, 4), 2.36 (m, 3), 2.62 (m, 4), 3.38 (m, 2), 3.53 (br t, 4, J
) 4.8), 4.37 (m, 4), 5.55 (d, 1, J ) 8.6), 6.83 (br s, 1), 7.10 (t, 1,
J ) 7.6), 7.30 (m, 4), 7.48 (t, 4, J ) 7.1), 7.66 (t, 2, J ) 8.1),
7.82 (m, 4), 8.61 (d, 1, J ) 8.3), 11.59 (br s, 1).
This FMOC-protected compound (3.57 g, 4.88 mmol), CHCl3
(110 mL), and 4-(aminomethyl)piperidine (50 mL) were added
to a 500-mL round-bottomed flask. The reaction mixture was
stirred under nitrogen at room temperature for 0.5 h. The
reaction mixture was transferred to a separatory funnel, and
CHCl3 (150 mL) was added. The organic layer was washed
with H2O (3 × 250 mL), separated, dried over MgSO4, filtered,
and concentrated to give 5.67 g of the crude product as a yellow
oil. The free base was purified by column chromatography on
silica gel with 85:15 EtOAc:MeOH as eluant to give 2.13 g of
the free base as a viscous oil. A portion of the free base (1.17
g) was purified further by semipreparative HPLC (Vydac C-18
column) with 0.1% CF3CO2H/H2O:0.1% CF3CO2H/CH3CN gra-
dient 9:1-1:9. The appropriate fractions were combined,
concentrated, dissolved in H2O and MeOH, and lyophilized to
give 0.87 g (48%) of L-valinamide 88 as a white powder. 1H
NMR (DMSO-d6): δ 1.01 (t, 6, J ) 6.5), 1.60 (m, 2), 1.77 (m,
2), 2.18 (m, 1), 3.30 (m, 8), 3.61 (m, 2), 3.95 (m, 1), 4.10 (m, 2),
7.25 (t, 1, J ) 7.7), 7.48 (tm, 1, J ) 7.5), 7.58 (m, 2), 7.76 (d,
1, J ) 7.8), 8.13 (t, 2, J ) 9.0), 8.24 (d, 1, J ) 8.4), 8.40 (br s,
1), 8.89 (br t, 1, J ) 4.8), 10.33 (br s, 1), 11.48 (s, 1). 13C NMR
(DMSO-d6): δ 17.96, 18.05, 20.90, 25.92, 29.88, 46.63, 50.67,
55.31, 58.78, 121.26, 121.58, 123.01, 123.95, 124.02, 124.69,
126.97, 128.21, 128.25, 131.83, 137.09, 152.16, 157.69, 158.11,
158.54, 158.96, 162.17, 166.70, 168.00. Anal. (C27H36N6-
O2S‚2.35CF3CO2H‚0.75H2O) C, H, N, F, H2O.
N-(2-(N-(4-(4-(1,2-Ben zisot h ia zol-3-yl)-1-p ip er a zin yl)-
bu tyl)ca r ba m oyl)p h en yl)-D-va lin a m id e Tr iflu or oa ceta te
Hyd r a te (89). This compound was prepared according to the
method described for compound 88, by employing 2-amino-N-
(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide (77)
(2.33 g, 5.7 mmol), N-((9H-fluoren-9-ylmethoxy)carbonyl)-D-
valyl chloride28 (3.22 g, 9.0 mmol, 1.58 equiv), anhydrous
CHCl3 (120 mL), and 5% aqueous Na2CO3 (60 mL). The crude
intermediate was purified to give 3.42 g (82%) of N-(4-(4-(1,2-
benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-((N-((9H-fluoren-9-
ylmethoxy)carbonyl)-D-valyl)amino)benzamide as a white solid.
1H NMR (CDCl3): δ 1.01 (d, 3, J ) 6.8), 1.07 (d, 3,J ) 6.8),
1.64 (m, 4), 2.36 (m, 3), 2.62 (br t, 4, J ) 4.5), 3.42 (m, 2), 3.53
(br t, 4, J ) 4.8), 4.37 (m, 4), 5.55 (d, 1, J ) 8.6), 6.80 (br s, 1),
7.10 (t, 1, J ) 7.2), 7.36 (tm, 4, J ) 4.4), 7.48 (tm, 4, J ) 7.6),
7.67 (t, 2, J ) 8.2), 7.80 (m, 4), 8.62 (dm, 1, J ) 8.9), 11.58 (br
s, 1).
This FMOC-protected intermediate (3.47 g, 4.75 mmol),
CHCl3 (100 mL), and 4-(aminomethyl)piperidine (50 mL) were
reacted as described for compound 88. The crude material was
purified by column chromatography with 85:15 EtOAc:MeOH
to give 1.99 g of the free base as a viscous oil. A portion (0.61
g) of the free base was applied to a semipreparative column,
and 0.54 g (57%) of D-valinamide 89 was obtained as a white
powder. 1H NMR (DMSO-d6): δ 1.01 (t, 6, J ) 6.5), 1.60 (m,
2), 1.78 (m, 2), 2.18 (m, 1), 3.32 (m, 8), 3.62 (m, 2), 3.95 (m, 1),
4.10 (br d, 2, J ) 10.5), 4.56 (br s, 3), 7.24 (t, 1, J ) 7.7), 7.48
(t, 1, J ) 7.7), 7.58 (m, 2), 7.77 (d, 1, J ) 7.5), 8.13 (m, 2), 8.23
(d, 1, J ) 8.1), 8.34 (br s, 3), 8.90 (br t, 1, J ) 5.3), 10.54 (br
s, 1), 11.49 (s, 1). 13C NMR (DMSO-d6): δ 18.91, 18.97, 21.78,
26.86, 30.80, 47.52, 51.55, 56.21, 59.69, 122.18, 122.51, 123.98,
124.87, 124.95, 125.61, 127.90, 129.12, 129.20, 132.72, 138.00,
153.09, 158.68, 159.11, 159.54, 159.98, 163.12, 167.62, 168.91.
Anal. (C27H36N6O2S‚2.35CF3CO2H‚0.75H2O) C, H, N, F, H2O.
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
2,2,2-tr iflu or oa ceta m id e (93). 3-(4-(4-Aminobutyl)-1-pip-
erazinyl)-1,2-benzisothiazole (6.0 g, 20.7 mmol) and anhydrous
CH2Cl2 (50 mL) were added to a flame-dried three-necked 250-
mL round-bottomed flask equipped with a magnetic stirring
bar, thermometer, addition funnel, and nitrogen inlet. The
solution was cooled in an ice-water bath, and a solution of
trifluoroacetic anhydride (4.40 mL, 6.53 g, 31.1 mmol, 1.5
equiv) in CH2Cl2 (20 mL) was added dropwise over a 0.5-h
period. The reaction mixture was allowed to stir for 2 h.
Saturated K2CO3 (50 mL) was slowly added to the cold reaction
mixture. The reaction mixture was transferred to a separatory
funnel, and the solution was extracted with CH2Cl2. The
organic layers were dried over MgSO4, filtered, and concen-
trated to give 6.87 g (86%) of trifluoroacetamide 93 as an
orange oil. The crude material was used without further
purification. 1H NMR (CDCl3): δ 1.71 (br s, 4), 2.51 (br t, 2,
J ) 6.2), 2.71 (t, 4, J ) 4.8), 3.41 (m, 2), 3.59 (t, 4, J ) 4.9),
7.36 (t, 1, J ) 7.9), 7.49 (t, 1, J ) 7.9), 7.83 (d, 1, J ) 8.0), 7.90
(d, 1, J ) 7.9).
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl-1-p ip er a zin yl)bu tyl)-N-
m eth yl-2,2,2-tr iflu or oacetam ide (94). Sodium hydride (0.587
g, 19.6 mmol) as an 80% dispersion in oil was added to a flame-
dried three-necked 250-mL round-bottomed flask equipped
with a rubber septum, magnetic stirring bar, addition funnel,
and nitrogen inlet. The sodium hydride was washed three
times with hexanes, and anhydrous THF (30.0 mL) was added.
The suspension was cooled in an ice-water bath, and a
solution of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)bu-
tyl)-2,2,2-trifluoroacetamide (93) (6.87 g, 17.8 mmol) in anhy-
drous THF (30.0 mL) was slowly added over a 35-min period.
The ice-water bath was removed, and a solution of methyl
iodide (1.1 mL, 2.53 g, 17.8 mmol) in anhydrous THF (20 mL)
was added dropwise. The yellow-orange solution was allowed
to warm to room temperature and stir for 4 days. The excess
NaH was quenched with water (15 mL), and the THF was
removed in vacuo. The residue was partitioned between H2O
and CH2Cl2. The two phases were separated, and the aqueous
phase was extracted two additional times with CH2Cl2. The
organic layers were combined, dried over MgSO4, filtered, and
concentrated to give the crude product as an orange oil. The
crude free base was purified by flash chromatography with
EtOAc as eluant to give 4.55 g (64%) of N-methyltrifluoroac-
etamide 94 as a white solid. 1H NMR (CDCl3): δ 1.59 (m, 2),
1.71 (m, 2), 2.47 (t, 2, J ) 7.0), 2.68 (m, 4), 3.04 and 3.14 (2 s,
3, NCH3 tautomers), 3.45 (m, 2), 3.58 (m, 4), 7.36 (t, 1, J )
7.2), 7.48 (t, 1, J ) 7.5), 7.82 (d, 1, J ) 7.7), 7.91 (d, 1, J )
8.0).
N-(4-(4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl)bu tyl)-
N-m eth ylben za m id e Hyd r och lor id e (96). Sodium hydride
(1.67 g, 55.7 mmol, 2.5 equiv of an 80% oil dispersion) was
added to a flame-dried three-necked 250-mL round-bottomed
flask equipped with a magnetic stirring bar, addition funnel,
and N2 inlet. The sodium hydride was washed with hexanes
(3×), and the waste hexanes were removed each time with a
pipet. To the washed sodium hydride was added anhydrous
DMF (20.0 mL), and the resulting suspension was cooled in
an ice bath. To the cooled reaction mixture was added a
solution of N-methylbenzamide (90) (3.0 g, 22.2 mmol, 1.0
equiv) in anhydrous DMF (15.0 mL). The reaction mixture
was allowed to stir until hydrogen evolution ceased, and
1-bromo-4-chlorobutane (2.81 mL, 4.19 g, 24.4 mmol, 1.1 equiv)
was added dropwise. The ice bath was removed, and the
reaction mixture was allowed to warm to room temperature.
After stirring at room temperature for 0.5 h, the reaction
mixture was cooled in an ice bath and the excess NaH was
quenched with distilled H2O (10 mL). The solvent was
removed in vacuo, and the residue was partitioned between
saturated aqueous K2CO3 and CH2Cl2. The organic layers
were dried over MgSO4, filtered, and concentrated to give 6.17

SAR of a Series of Substituted Benzamides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1187
g of a yellow oil. The crude material was purified by flash
chromatography with 1:2 hexanes:ethyl acetate as eluant to
give 3.02 g (60%) of chloride 91 as a pale yellow oil. Chloride
91 (1.5 g, 6.65 mmol), 3-(1-piperazinyl)-1,2-benzisothiazole
(1.60 g, 7.3 mmol, 1.1 equiv), triethylamine (1.39 mL, 1.01 g,
9.98 mmol, 1.5 equiv), and acetonitrile (25.0 mL) were added
to a 100-mL round-bottomed flask equipped with a magnetic
stirring bar, condenser, and N2 inlet. The reaction mixture
was heated to reflux under nitrogen overnight. The solvent
was removed in vacuo, and the residue was partitioned
between saturated aqueous potassium carbonate and ethyl
acetate. The organic layers were dried over MgSO4, filtered,
and concentrated to give 3.64 g of an orange oil. The crude
material was purified by flash chromatography with 2:1 ethyl
acetate:hexanes:0.1% triethylamine followed by ethyl acetate:
0.1% triethylamine as eluant to give 1.40 g of a yellow oil. The
free base was taken up in ethyl acetate, and HCl (3.53 mL of
a 1 N solution in ether, 1.0 equiv) was added. The resulting
salt was recrystallized from EtOH/Et2O to give 0.76 g (26%)
of the title compound as a white solid. Mp: 151-154 °C. 1H
NMR (DMSO-d6): δ 1.57-1.83 (m, 4), 2.98 (m, 4), 3.26 (m, 4),
3.55 (m, 5), 4.07 (br d, 2, J ) 12.6), 7.44 (m, 6), 7.60 (t, 1, J )
7.3), 8.13 (t, 2, J ) 8.1), 11.07 (br s, 1). 13C NMR (DMSO-d6):
δ 20.29, 23.68, 36.91, 45.74, 46.27, 50.40, 55.22, 121.14, 123.95,
124.56, 129.15, 136.70, 152.06, 162.17, 170.15. Anal. (C23H28N4-
OS‚HCl) C, H, N.
2-Am in o-N-(4-(4-(1,2-ben zisoth iazol-3-yl)-1-piper azin yl)-
bu tyl)-N-m eth ylben za m id e Hyd r och lor id e (97). N-(4-(4-
(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-N-methyl-2,2,2-
trifluoroacetamide (94) 2.0 g, 5.0 mmol), MeOH (50 mL), and
20.0 mL of K2CO3 (7% aqueous solution) were added to a 250-
mL round-bottomed flask equipped with a magnetic stir bar.
The reaction mixture was allowed to stir at room temperature
for 6 h. The MeOH was removed in vacuo, and the solution
was extracted with CH2Cl2. The organic layers were dried over
MgSO4, filtered, and concentrated to give 1.41 g (93%) of 3-(4-
(4-(methylamino)butyl)-1-piperazinyl)-1,2-benzisothiazole (95)
as a yellow oil. 1H NMR (CDCl3): δ 1.45 (m, 1), 1.55 (m, 4),
2.45 (s, 5), 2.69 (m, 6), 3.58 (m, 4), 7.36 (tm, 1, J ) 7.7), 7.48
(tm, 1, J ) 7.4), 7.83 (d, 1, J ) 8.6), 7.93 (d, 1, J ) 8.6).
This amine (1.4 g, 4.6 mmol), isatoic anhydride (0.750 g,
4.6 mmol, 1.0 equiv), and EtOH (25.0 mL) were added to a
100-mL round-bottomed flask equipped with a magnetic stir
bar and nitrogen inlet. The reaction mixture was placed under
a N2 atmosphere and allowed to stir at room temperature for
20 h and to stand for 6 h without stirring. The reaction
mixture was concentrated in vacuo to give the crude product
as a brown-orange liquid. The free base was purified by flash
chromatography with EtOAc:0.1% triethylamine as eluant to
give 1.06 g of the free base. To a solution of the free base (1.06
g, 2.50 mmol) in EtOAc was added 2.5 mL of 1 N ethereal HCl
(1.0 equiv). The solvent was removed in vacuo, and the solid
was recrystallized from EtOH and ether to give 0.625 g (30%)
of N-methylbenzamide 97 as a tan solid. Mp: 188-189 °C.
1H NMR (DMSO-d6): δ 1.61 (br s, 4), 2.93 (s, 3), 2.95-3.72
(m, 10), 4.07 (br d, 2, J ) 12.0), 5.13 (br s, 2), 6.58 (td, 1, J )
7.4, 1.1), 6.73 (dd, 1, J ) 0.8, 8.1), 7.02 (dd, 1, J ) 1.4, 7.7),
7.09 (ddd, 1, J ) 1.7, 7.3, 8.0), 7.48 (ddd, 1, J ) 1.0, 7.1, 7.9),
7.60 (ddd, 1, J ) 1.0, 6.9, 8.0), 8.13 (t, 2, J ) 8.2), 10.85 (br s,
1). 13C NMR (DMSO-d6): δ 20.36, 24.20, 46.34, 50.40, 55.13,
115.50, 120.26, 121.16, 123.97, 124.58, 126.92, 127.36, 128.09,
129.69, 145.35, 152.06, 162.18, 169.86. Anal. (C23H29N5OS‚-
HCl) C, H, N.
McDaniel for their synthetic assistance, and Ms. L.
Cotterman for proofreading this document.
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