Effect of linking bridge modifications on the antipsychotic profile of some phthalimide and isoindolinone derivatives

Article abstract of DOI:10.1021/jm9502201

A series of phthalimide and isoindolinone derivatives bridged to 4-(1,2- benzisothiazol-3-yl)-1-piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D₂ and serotonin 5-HT(1a) and 5-HT₂ receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. The effects of bridge length and conformation on the biological activity of these potential antipsychotic agents are discussed. A four-carbon spacer provided optimal activity within the two homologous series. Conformational investigations of the lead compound, isoindolinone 2, were conducted in an attempt to account for the superior activity observed for the butyl derivatives. On the basis of NMR and molecular modeling studies, two types of folded structures were proposed and several conformationally restrained analogues were synthesized. In general, restrictions incorporated within the linking bridge were detrimental to activity.

Full text of DOI:10.1021/jm9502201

J . Med. Chem. 1996, 39, 149-157
149
Effect of Lin k in g Br id ge Mod ifica tion s on th e An tip sych otic P r ofile of Som e
P h th a lim id e a n d Isoin d olin on e Der iva tives
Mark H. Norman,*,† Douglas J . Minick,† and Greg C. Rigdon‡
Divisions of Chemistry and of Pharmacology and Molecular Therapeutics, Glaxo Wellcome Inc.,
Research Triangle Park, North Carolina 27709
Received March 27, 1995X
A series of phthalimide and isoindolinone derivatives bridged to 4-(1,2-benzisothiazol-3-yl)-1-
piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D2 and
serotonin 5-HT1a and 5-HT2 receptors and in vivo for their ability to antagonize the
apomorphine-induced climbing response in mice. The effects of bridge length and conformation
on the biological activity of these potential antipsychotic agents are discussed. A four-carbon
spacer provided optimal activity within the two homologous series. Conformational investiga-
tions of the lead compound, isoindolinone 2, were conducted in an attempt to account for the
superior activity observed for the butyl derivatives. On the basis of NMR and molecular
modeling studies, two types of folded structures were proposed and several conformationally
restrained analogues were synthesized. In general, restrictions incorporated within the linking
bridge were detrimental to activity.
In tr od u ction
that links the amide or imide moiety with the piperazine
benzisothiazole group. The synthesis and biological
evaluation of a series of isoindolinone and phthalimide
derivatives that contain modified bridging units are
described herein.
Since the introduction of chlorpromazine nearly 40
years ago, great progress has been made in the treat-
ment of schizophrenia with neuroleptic drugs. A no-
table advancement has been the development of the
dibenzodiazepine clozapine (1) as an atypical antipsy-
chotic agent.1-7 Clozapine was found to be an effective
antipsychotic agent that did not induce concomitant
extrapyramidal side effects. However, the clinical use
of clozapine has been limited owing to the frequency
with which it causes agranulocytosis, a potentially lethal
blood dyscrasia.8-10 In the search for an antipsychotic
agent that is superior to clozapine, recent efforts have
focused on the development of compounds that act at
both dopamine and serotonin receptors.11-18
Ch em istr y
The syntheses of phthalimide derivatives 3 and 15-
22 are outlined in Scheme 1. Intermediates 5-8 were
obtained from commercial suppliers, while alkylation
of potassium phthalimide (4) with an appropriate di-
halide or halo alcohol provided intermediates 9-13.
Small amounts of the products arising from bis-alkyla-
tion were observed in some cases. The chloro alcohol
required for the preparation of the cyclopropyl deriva-
tive was obtained by the reduction of trans-diethyl 1,2-
cyclopropanedicarboxylate with lithium aluminum hy-
dride followed by treatment of the resulting diol with
tosyl chloride and (dimethylamino)pyridine.20 Mesylate
14 was obtained in good yield by the reaction of
cyclopropyl alcohol 13 with mesyl chloride in anhydrous
dichloromethane. Treatment of intermediates 5-12
and 14 with 3-(1-piperazinyl)-1,2-benzisothiazole in
refluxing acetonitrile provided the target phthalimides
15, 16, 3, and 17-22, respectively.
Isoindolinone derivatives 2, 31-33, 38, 39, and 46-
49 were prepared by a variety of methods, as outlined
in Schemes 2-4. Condensation of ethanolamine or
3-amino-1-propanol with phthalide 23 provided the
corresponding alcohols 25 and 26, respectively (Scheme
2).21,22 Attempts to prepare the cyclohexyl derivative 27
by employing a similar condensation using trans-4-
aminocyclohexanol were unsuccessful. However, when
this primary amine was reacted with methyl 2-(bro-
momethyl)benzoate (24)23 and the reaction was driven
to completion by the azeotropic removal of methanol,
compound 27 was obtained. Treatment of alcohols 25-
27 with either thionyl chloride or mesyl chloride pro-
vided alkylating agents 28-30, respectively. The chlo-
rides required for the synthesis of trans- and cis-2-
butene derivatives were prepared by the monoreduction
of phthalimide 34 followed by alkylation of isoindolinone
Recently, we disclosed a series of cyclic benzamides
with mixed dopamine D2 and serotonin 5-HT2 receptor
antagonistic activity as potential atypical antipsychotic
agents.19 One of the lead compounds, 2-[4-[4-(1,2-
benzisothiazol-3-yl)-1-piperazinyl]butyl]-1-isoindolino-
ne (2), was selected for further evaluation. The corre-
sponding phthalimide analogue 3, also exhibited potent
in vivo activities. These derivatives exhibited activities
that suggested they would be useful in the treatment
of schizophrenia and would have a low propensity to
induce extrapyramidal side effects. To further study the
structure-activity relationships within these series, we
investigated the structural requirements of the bridge
† Division of Chemistry.
‡ Division of Pharmacology and Molecular Therapeutics.
X Abstract published in Advance ACS Abstracts, November 15, 1995.
0022-2623/96/1839-0149$12.00/0 © 1996 American Chemical Society

150 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Norman et al.
Sch em e 1a
a
Reagents: (a) 2-chloroethyl ether, 1,4-dichloro-2-butyne, or cis-1,4-dichloro-2-butene, 125-170 °C; (b) trans-1,4-dibromo-2-butene or
(()-trans-2-(chloromethyl)-1-cyclopropanemethanol, DMF, 125 °C-reflux; (c) Et3N, CH2Cl2, MsCl, 0 °C; (d) 3-(1-piperazinyl)-1,2-
benzisothiazole, Et3N, CH3CN, reflux.
Sch em e 2a
a
Reagents: (a) ethanolamine or 3-amino-1-propanol, 205-210 °C; (b) trans-4-aminocyclohexanol hydrochloride, K2CO3, toluene, H2O,
reflux; (c) SOCl2, toluene, 60 °C; (d) Et3N, CH2Cl2, MsCl, 0 °C; (e) 3-(1-piperazinyl)-1,2-benzisothiazole, Et3N, CH3CN, reflux.
Sch em e 3a
a
Reagents: (a) HOAc, HCl, Sn, reflux; (b) trans- or cis-1,4-dichloro-2-butene, DMF, NaH, 0 °C-room temperature; (c) 3-(1-piperazinyl)-
1,2-benzisothiazole, Et3N, CH3CN, reflux.
35 with either trans- or cis-1,4-dichloro-2-butene
(Scheme 3). Target isoindolinones 31-33, 38, and 39
were obtained by the alkylation of 3-(1-piperazinyl)-1,2-
benzisothiazole by a method analogous to that employed
for the phthalimide derivatives. The reaction with the
sterically hindered trans-mesylate 30 proceeded with
inversion of configuration to provide the cis-cyclohexyl
product 33, albeit in poor yield.
The syntheses of the remaining isoindolinones 2 and
46-49 are outlined in Scheme 4. The butyl-, pentyl-,
and hexylisoindolinone halides 41-43 were prepared by
the reduction of the corresponding phthalimides with
tin metal in concentrated hydrochloric acid.24 Interme-
diates 41-43 were isolated as mixtures of bromides and
chlorides and reacted with piperazine benzisothiazole
to give isoindolinones 2, 46, and 47. The final two
isoindolinone targets (48 and 49) were prepared by the
condensation of amines 44 and 45 (obtained from the
reaction of phthalimides 18 and 19 with hydrazine
hydrate) with methyl 2-(bromomethyl)benzoate (24). All
of the target compounds, with the exception of com-
pound 48, were treated with ethereal hydrochloric acid
and isolated as their hydrochloride salts. 1H, 13C, and
difference NOE NMR spectra of the targets were
consistent with N-alkylated products: No O-alkylated
byproducts were observed.
Resu lts a n d Discu ssion
Radioligand-binding competition experiments were
carried out to determine the affinities of phthalimides
3 and 15-22 and isoindolinones 2, 31-33, 38, 39, and
46-49 for dopamine D2, serotonin 5-HT1a, and serotonin
5-HT2 receptors. The affinities of the compounds for
dopamine D2 receptors were determined by measuring
their ability to displace [3H]raclopride from the D2
receptors isolated from the striata of male Sprague-
Dawley rats.25 Inhibition of the binding of [3H]-8-
hydroxy-2-(di-n-propylamino)tetralin to rat hippocam-
pus tissue allowed the determination of the compounds’
affinities for serotonin 5-HT1a receptors,26 while sero-
tonin 5-HT2 binding was measured by the displacement
of [3H]ketanserin from rat frontal cortex.27 As an
indication of potential antipsychotic activity, the com-
pounds were evaluated in vivo for their ability to

Effect of Linking Bridge Modifications
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 151
Sch em e 4a
a
Reagents: (a) HOAc, HCl, Sn, reflux; (b) H2NNH2‚H2O, CH3OH, reflux; (c) 3-(1-piperazinyl)-1,2-benzisothiazole, Et3N, CH3CN, reflux;
(d) 24, toluene, 100 °C-reflux.
Ta ble 1. Receptor-Binding Affinities and in Vivo Activities of
Phthalimide Derivatives 3 and 15-22
Ta ble 2. Receptor-Binding Affinities and in Vivo Activities of
Isoindolinone Derivatives 2, 31, 33, 38, 39, and 46-49
a
b
Hydrochloride salts. D2: [3H]raclopride binding. 5-HT1a
:
[3H]-8-OH-DPAT binding. 5-HT2: [3H]ketanserin binding. c For
experimental protocol, see ref 19. Binding values are from single
determinations. 95% confidence limits are shown in brackets.28b
d
Hydrochloride salts. D2: [3H]raclopride binding. 5-HT1a
:
e Insufficient number of doses tested to determine 95% confidence
limits.
a
b
[3H]-8-OH-DPAT binding. 5-HT2: [3H]ketanserin binding. c For
experimental protocol, see ref 19. Binding values are from single
determinations. 95% confidence limits are shown in brackets.28b
d
increased from ethyl to propyl to butyl (Table 1, 15, 16,
and 3; Table 2, 31, 32, and 2). In both series, dopamine
D2 and serotonin 5-HT2 receptor binding affinities were
maintained or continued to increase with the pentyl
derivatives; however, the in vivo activity of these
analogues declined (compounds 17 and 46). The ho-
mologous isoindolinone hexyl analogue 47 exhibited
both reduced solubility and in vivo activity. Introduc-
tion of an oxygen in the middle of the five-atom bridge
also resulted in reduced activity (compounds 18 and 48).
These data indicated that the butyl bridge provided
optimal activity.
antagonize the apomorphine-induced climbing response
in mice.28a The results of these in vitro and in vivo
assays for both the phthalimide and isoindolinone series
are shown in Tables 1 and 2, respectively.28b,c The
corresponding biological data for reference compounds,
haloperidol and clozapine, are also included in Table 1.
Initially, we were interested in studying the effect of
the length of the bridging unit on biological activity. As
additional methylene groups were added to extend the
length of the spacer, both the isoindolinone and phthal-
imide series exhibited similar trends. Receptor-binding
affinities (especially dopamine D2) and in vivo activities
To gain insight into possible reasons for the superior
activity of butyl analogues 3 and 2, investigations were

152 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Norman et al.
F igu r e 1. (A) ORTEP representation of the X-ray crystal structure of isoindolinone 2. (B) Extended conformation of isoindolinone
2. Significant NOE signals are indicated. (C) Proposed folded, intramolecular hydrogen-bonded conformation of isoindolinone 2.
(D) Proposed folded conformation of isoindolinone 2 with interactions between the two terminal aromatic groups.
undertaken to study some physical and spectral proper-
ties of the isoindolinone series. Conformational infor-
mation was obtained for isoindolinone 2 via an X-ray
1
crystal structure and H NMR data. Crystals suitable
for X-ray analysis were obtained by recrystallization
from ethanol, and the crystal structure was deter-
mined.29 The resultant ORTEP representation of 2 is
shown in Figure 1A. In the solid state, the compound
exists in an extended conformation with the methylene
bridging units in an antiperiplanar arrangement. NMR
data, on the other hand, suggested that the conforma-
tion in solution was quite different. 2D-NOE experi-
ments were conducted in deuterated chloroform, and the
significant NOE signals are indicated in Figure 1B. If
the compound was in its extended conformation, the
F igu r e 2. Representative low-energy conformations of isoin-
doline 2 obtained from Monte Carlo conformational compu-
interactions between Ha-Hf and Hc-He would not be
expected to exist. In a folded or “kinked” conformation,
the closer spatial arrangements of these protons could
explain the observed NOE signals. Two types of folded
conformations are proposed and illustrated in Figure
1C,D. In a folded conformation, such as shown in
Figure 1C, an intramolecular hydrogen bond between
the protonated piperazine and the amide carbonyl may
help stabilize the folded conformation, while a π-π
interaction between the two aromatic termini may help
form a conformation of the type shown in Figure 1D.
1H NMR studies in different solvents also supported the
possibility of a folded conformation. In deuterium oxide,
the signals for the two center methylene groups (g and
f) are broadened and appear as a single multiplet,
indicating that a fast equilibrium exists between open
(Figure 1B) and folded (Figure 1C,D) conformations.
However, in deuterated chloroform the corresponding
methylene signals are sharp and separated by 0.2 ppm,
suggesting that a folded conformation may predominate.
In addition to this spectral data, molecular modeling
studies were undertaken to further investigate the
conformational preference of isoindolinone 2. To obtain
a qualitative picture of the conformational space open
to 2, four Monte Carlo conformational searches were
conducted using MacroModel (version 4.5) with the
MM2* force field.30 Conformational preferences for both
the free base and the hydrochloride salt of 2 were
investigated using the parameters for either a water or
chloroform continuum. All flexible bonds were allowed
to rotate, the simulations were conducted for 500
tations: (A) “open” conformation of 2 free base, (B) “folded”
hydrogen-bonded conformation of 2 hydrochloride, (C) “folded”
conformation of 2 hydrochloride with a π-π interaction.
iterations, and conformations that were within 4 kJ of
the lowest energy conformation were examined. The
results of the experiments showed that three general
families of conformations were obtained (two types of
folded conformations and open conformations). The
folded conformations corresponded to the previously
proposed conformations, and representatives for each
type are illustrated in Figure 2. The greatest variety
of conformations was predicted for the free base of
isoindolinone 2 in chloroform. In this case, a mixture
of open (Figure 2A) and folded (Figure 2B,C) conforma-
tions was produced, and no clear conformational prefer-
ence was observed. In the other experiments, however,
the lowest energy conformations were generally of the
type in Figure 2B, wherein an intramolecular hydrogen-
bonding interaction between the carbonyl and the
protonated piperazine dominated, or of the type in
Figure 2C, wherein a π-π interaction was favored. In
chloroform, conformations of the type in Figure 2B
predominated for the hydrochloride salt of 2, while a
mixture of both types of folded conformations were
obtained when water was used in the calculations.
When the free base of 2 was examined in water, all of
the conformations were similar to the type in Figure
2C. In general, these modeling results suggested that,
although isoindolinone 2 is very flexible, a preference
may exist for the folded conformations.

Effect of Linking Bridge Modifications
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 153
As a second phase of these investigations, several
analogues containing conformationally constrained four-
atom bridging units were prepared in attempts to alter
the position of the terminal pharmacophores (i.e.,
compounds 19-22, 33, 38, 39, and 49). The butynyl
derivatives 19 and 49, where a folded conformation
might be inhibited, exhibited decreased activities both
in vitro and in vivo. The trans-2-butene analogues 20
and 38 were 2.5-11.5 times less active in the mouse
climbing assay than their saturated counterparts 3 and
2, respectively. Changing the configuration of the
double bond to give cis-2-butenes 21 and 39 gave mixed
results. While phthalimide 21 showed reduced in vivo
activity, isoindolinone 39 exhibited a similar pharma-
cological profile to compound 2. The phthalimide con-
taining the cyclopropyl unit was 10 times as potent at
the dopamine D2 receptor as the trans-2-butene deriva-
tive but only one-half as active in vivo (compounds 22
and 20, respectively). The cis-cyclohexyl bridge of
compound 33 creates a folded conformation that brings
the piperazine benzisothiazole and isoindolinone group
in close proximity. This restricted conformation re-
sulted in increased dopamine D2 affinity, decreased
affinities to the serotonin receptors, and slightly reduced
in vivo activity.
tal to activity; however, a few observations are notable.
The weak activity of the butynyl derivatives 19 and 49
and the relatively good activity of cyclohexylisoindoli-
none 33 supported the possibility of a folded bioactive
conformation; however, the good activities of the butenyl
derivatives 20 and 38 discount the necessity of com-
pletely folded structure. Further experiments are cur-
rently underway in attempts to gain additional insight
into the structural and conformational requirements of
this series.
Exp er im en ta l Section
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 dimethyl-
formamide (DMF), tetrahydrofuran (THF), CH2Cl2, 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 chroma-
tography were performed using EM Science silica gel 60 (230-
400-mesh ASTM). The term flush chromatography refers to
the technique of applying suction to the bottom of a chroma-
tography column to increase the flow rate of the eluant. Thin-
layer chromatography (TLC) was performed with Analtech
silica gel FG TLC plates (250 µm). 1H NMR spectra were
determined with superconducting FT-NMR spectrometers
operating at 200, 300, and 500 MHz. 13C NMR spectra were
measured at 50.29 or 75.43 MHz. Chemical shifts are ex-
pressed in ppm downfield from internal tetramethylsilane.
Although modeling and spectral data suggest that a
folded conformation may exist in solution, no clear
conclusions can be made based on the biological results
of the conformationally restricted derivatives. On one
hand, the weak in vitro and in vivo activities of the
butynyl derivatives 19 and 49 suggested that an ex-
tended conformation may not be favorable. Further-
more, the fact that the cyclohexyl derivative 33 retains
high affinity to the dopamine D2 receptor and possesses
significant biological activity in the mouse climbing
assay may point to a folded structure as a bioactive
conformation. However, if a folded conformation is
required for good activity, then the relatively potent
activities of the butenyl derivatives (especially 20 and
38) are difficult to rationalize. Perhaps there is an
optimum conformation and distance between the ter-
minal pharmacophores that can be obtained in the
flexible butyl derivative 2 but cannot be obtained by the
restrained analogues. Additional experiments will be
necessary to further elucidate the conformational pref-
erence of these potential antipsychotic agents. Toward
this end, we are currently conducting a series of infrared
spectroscopy experiments with the homologous series
of isoindolinones (31, 32, and 2) in hopes of gaining
additional insight into the nature of the intramolecular
interactions.
1
Significant H NMR data are reported in the order: multiplic-
ity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet),
number of protons, and coupling constants in hertz (Hz).
Elemental analyses were performed by either Atlantic Micro-
lab, 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. 3-(1-Piperazinyl)-1,2-benzisothiazole bromide was pre-
pared according to the method described by Yevich et al.31
Phthalimides 5-8 were obtained form commercial suppliers,
and compounds 2, 3, and 41 were prepared as described
previously.19
(()-t r a n s-2-(Ch lor om e t h yl)-1-cyclop r op a n e m e t h a -
32
n ol. (()-trans-1,2-Cyclopropanedimethanol
(4.0 g, 0.039
mol), tosyl chloride (TsCl) (8.96 g, 0.047 mol, 1.2 equiv),
(dimethylamino)pyridine (DMAP) (5.30 g), and anhydrous CH2-
Cl2 (75.0 mL) were added to an oven-dried, 500-mL, round-
bottomed flask. The reaction mixture was placed under N2
and allowed to stir at room temperature for 24 h. Additional
portions of the reagents were added, TsCl (2.24 g), DMAP (1.0
g), and CH2Cl2 (1.0 mL). The solution was allowed to stir at
room temperature for an additional 6 d. Triethylamine (5.43
mL, 3.95 g, 0.039 mol, 1.0 equiv) was added, and the solution
was allowed to stir for 24 h. The mixture was heated at reflux
for 1.5 h, and the solvent was removed with a rotary evapora-
tor, yielding a sticky tan solid. This crude material was
purified by flash chromatography with 1:1 hexanes-EtOAc
followed by 19:1 EtOAc-MeOH as eluant to give 1.85 g (39%)
of (()-trans-2-(chloromethyl)-1-cyclopropanemethanol. 1H NMR
(CDCl3): δ 0.65 (tm, 2, J ) 8.0), 1.15 (m, 2), 1.40 (br t, 1, J )
5.0), 3.42 (m, 2), 3.55 (m, 2). A portion of the starting diol
(0.87 g) was recovered.
In summary, a series of phthalimide and isoindolinone
piperazine benzisothiazoles with a variety of different
bridging units were prepared and evaluated as potential
antipsychotic agents. A four-carbon spacer provided
optimal activity within the two homologous series (i.e.,
compounds 3 and 2). Conformational studies of isoin-
dolinone 2 indicated a linear arrangement of the mol-
ecule in the solid state, but a folded structure was
suggested by 1H NMR and molecular modeling analysis.
Results of these investigations led us to prepare several
derivatives in which the linking bridge contained con-
formational restraints that restricted the orientations
of the two terminal pharmacophores. In general, the
restrictions imposed in the linking unit were detrimen-
N-[2-(2-Ch lor oet h oxy)et h yl]p h t h a lim id e (9). Potas-
sium phthalimide (15.0 g, 0.081 mol) as a fluffy powder and
2-chloroethyl ether (28.5 mL, 34.74 g, 0.243 mol, 3.0 equiv) as
a colorless oil were added to a 250-mL, round-bottomed flask.
The reaction mixture was heated under N2 with an oil bath
at 170 °C for 19 h. As the mixture was heated, the solution
became more liquid in consistency and brown in color. The
mixture was removed from the oil bath, and distilled H2O was
added. The solution was allowed to cool to room temperature
and extracted with CH2Cl2. The organic extracts were washed
with H2O, dried over MgSO4, filtered, and concentrated to give

154 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Norman et al.
36.1 g of a dark-orange-brown oil. This crude material was
purified by flush chromatography with 3:1 hexanes-EtOAc
as eluant to give 13.53 g (67%) of a light-orange oil, which
quickly solidified upon standing. An analytically pure white
powder was obtained by recrystallization from EtOAc. Mp:
67-70 °C. 1H NMR (CDCl3): δ 3.54 (dt, 2, J ) 6.2, 0.8), 3.72
(dt, 2, J ) 5.9, 0.6), 3.75 (dt, 2, J ) 5.8, 0.9), 3.89 (dt, 2, J )
5.4, 1.2), 7.71 (m, 2), 7.83 (m, 2). 13C NMR (CDCl3): δ 37.14,
42.70, 67.92, 70.61, 123.27, 132.06, 133.97, 168.27. Anal.
(C12H12NO3Cl) C, H, N.
N-(4-Ch lor o-2-bu tyn yl)p h th a lim id e (10), (E)-N-(4-Br o-
m o-2-bu ten yl)p h th a lim id e (11), a n d (Z)-N-(4-Ch lor o-2-
bu ten yl)p h th a lim id e (12). These compounds were prepared
according to the method described for compound 9. 1H NMR,
13C NMR, and combustion analyses were consistent with the
title compounds. See supporting information for additional
information.
(()-tr a n s-N-[[2-(Hyd r oxym eth yl)cyclop r op yl]m eth yl]-
p h th a lim id e (13). Potassium phthalimide (1.44 g, 7.62
mmol), (()-trans-2-(chloromethyl)-1-cyclopropanemethanol (1.59
g, 13.20 mmol, 1.7 equiv), and anhydrous DMF (50.0 mL) were
placed in a 100-mL, round-bottomed flask. The resulting
cloudy suspension was heated at reflux for 20 h. The reaction
mixture was allowed to cool to room temperature, and most
of the DMF was removed in vacuo with a rotary evaporator.
The residue was taken up in CH2Cl2 and washed with two
portions of H2O. The organic layers were dried over MgSO4,
filtered, and concentrated to give 3.55 g of a dark-orange oil.
This crude material was purified by flash chromatography with
5:1 hexanes-EtOAc as eluant to give 1.12 g (64%) of (()-trans-
N-[[2-(hydroxymethyl)cyclopropyl]methyl]phthalimide (13) as
a white powder. Mp: 117-118 °C. 1H NMR (CDCl3): δ 0.48
(ddd, 1, J ) 13.6, 10.3, 5.2), 0.65 (ddd, 1, J ) 13.6, 10.3, 5.0),
1.17 (m, 2), 1.52 (br s, 1), 3.45 (m, 2), 3.59 (dd, 2, J ) 7.0, 2.2),
7.70 (m, 2), 7.84 (m, 2). 13C NMR (CDCl3): δ 8.99, 16.17, 20.68,
free base as a light-yellow solid. The hydrochloride salt was
prepared by the addition of 1 N HCl in Et2O (6.5 mL, 1.0 equiv)
to a solution of the free base in EtOAc-CH2Cl2. The salt was
recrystallized from EtOH. The solids were filtered, washed
with cold EtOH, and dried in a vacuum oven to give 2.07 g
(48%) of 2-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-
phthalimide hydrochloride (15) as off-white flakes. Mp: 248-
250 °C dec. 1H NMR (DMSO-d6): δ 3.32 (m, 7), 3.52 (m, 1),
3.75 (m, 1), 4.01 (m, 1), 4.09 (m, 1), 7.46 (t, 1, J ) 7.6), 7.59 (t,
1, J ) 7.6), 7.87 (m, 4), 8.09 (d, 1, J ) 8.1), 8.14 (d, 1, J ) 8.1).
13C NMR (DMSO-d6): δ 33.04, 47.16, 51.55, 54.11, 122.12,
124.11, 125.02, 125.59, 127.89, 129.09, 132.91, 135.36, 153.06,
163.05, 168.90. Anal. (C21H20N4O2S‚HCl) C, H, N.
N-[3-[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl]p r op yl]-
p h th a lim id e Hyd r och lor id e (16), N-[5-[4-(1,2-Ben zisoth i-
a zol-3-yl)-1-p ip er a zin yl]p en tyl]p h th a lim id e Hyd r och lo-
r id e (17), N-[2-[2-[4-(1,2-Ben zisot h ia zol-3-yl)-1-p ip er a -
zin yl]eth oxy]eth yl]ph th alim ide Hydr och lor ide (18), N-[4-
[4-(1,2-Ben zisot h ia zol-3-yl)-1-p ip er a zin yl]-2-b u t yn yl]-
p h th a lim id e Hyd r och lor id e (19), (E)-N-[4-[4-(1,2-Ben -
zisot h ia zol-3-yl)-1-p ip er a zin yl]-2-b u t en yl]p h t h a lim id e
Hyd r och lor id e (20), a n d (Z)-N-[4-[4-(1,2-Ben zisoth ia zol-
3-yl)-1-p ip er a zin yl]-2-bu ten yl]p h th a lim id e Hyd r och lo-
r id e Hyd r a te (21). These compounds were prepared by the
procedure analogous to that used for compound 15. 1H NMR,
13C NMR, and combustion analyses were consistent with the
title compounds. See supporting information for additional
information.
(()-tr a n s-N-[[2-[[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zi-
n yl]m eth yl]cyclop r op yl]m eth yl]p h th a lim id e Hyd r och lo-
r id e H yd r a t e (22). (()-trans-[2-(Phthalimidomethyl)-1-
cyclopropyl]methyl methanesulfonate (14) (1.17 g, 3.78 mmol),
3-(1-piperazinyl)-1,2-benzisothiazole (0.912 g, 4.16 mmol, 1.1
equiv), triethylamine (0.633 mL, 0.459 g, 4.54 mmol, 1.2 equiv),
and CH3CN (10.0 mL) were added to a 100-mL, round-
bottomed flask. The cloudy solution was placed under N2 and
heated at reflux for 3.5 h. An additional portion of the
piperazine benzisothiazole (0.083 g, 0.10 equiv) was added, and
heating was continued for a total of 20 h. The solution was
allowed to cool to room temperature, and CH2Cl2 was added.
The solution was washed with saturated K2CO3, and the
organic layers were dried over MgSO4, filtered, and concen-
trated to give 1.92 g of a viscous orange oil. This crude
material was purified by flash chromatography with 2:1
hexanes-EtOAc as eluant to give 1.30 g of the free base. The
hydrochloride salt was prepared, recrystallized from EtOH-
H2O, and dried in a vacuum oven to give 1.11 g (61%) of (()-
trans-N-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]methyl]-
cyclopropyl]methyl]phthalimide hydrochloride hydrate (22) as
an off-white powder. Mp: 246-248 °C. 1H NMR (DMSO-d6):
δ 0.74 (m, 2), 1.29 (m, 2), 3.12 (br s, 2), 3.20-3.67 (m, 8), 4.05
(m, 2), 7.45 (t, 1, J ) 7.5), 7.58 (t, 1, J ) 7.5), 7.18 (m, 4), 8.09
(d, 2, J ) 8.2), 11.12 (br s, 1). 13C NMR (DMSO-d6): δ 9.64,
12.01, 17.07, 46.24, 49.87, 50.22, 58.47, 121.16, 123.02, 124.01,
124.61, 126.93, 128.11, 131.67, 134.37, 152.08, 162.16, 168.02.
Anal. (C24H24N4O2S‚HCl‚0.5H2O) C, H, N, H2O.
Meth yl 2-(Br om om eth yl)ben zoa te (24). 2-(Bromometh-
yl)benzoyl bromide was obtained by bromination of o-toluoyl
chloride using the method of Davies and Perkin.23 The crude
2-(bromomethyl)benzoyl bromide (0.184 mol) was taken up in
CH2Cl2 (40 mL), and the solution was cooled in an ice-water
bath. Absolute MeOH (15 mL) was added, and the reaction
mixture was allowed to warm to room temperature and stir
for 0.5 h. The solution was washed with saturated K2CO3 and
extracted with EtOAc. The organic layers were dried over
MgSO4, filtered, and concentrated with a rotary evaporator
to give 42.08 g of a pale-yellow oil. This material was used
without further purification. 1H NMR (CDCl3): δ 3.94 (s, 3),
4.96 (s, 2), 7.40 (m, 3), 7.97 (m, 1).
41.57, 66.09, 123.43, 132.12, 133.95, 168.48. Anal. (C13H13
NO3) C, H, N.
-
(()-t r a n s-[2-(P h t h a lim id o m e t h y l)-1-c y c lo p r o p y l]-
m eth yl Meth a n esu lfon a te (14). (()-trans-N-[[2-(Hydroxy-
methyl)cyclopropyl]methyl]phthalimide (1.04 g, 4.50 mmol),
triethylamine (0.94 mL, 0.68 g, 6.75 mmol, 1.5 equiv), and
anhydrous CH2Cl2 (14.0 mL) were added to a 50-mL, round-
bottomed flask. The solution was placed under a N2 atmo-
sphere and cooled with an ice-water bath. To this cooled
mixture was added a solution of mesyl chloride (0.52 mL, 0.77
g, 6.75 mmol, 1.5 equiv) in CH2Cl2 (2.0 mL). Upon this
addition, the white alcohol suspension became a clear, light-
orange solution, which was allowed to stir at 0 °C for 1 h. The
reaction mixture was allowed to warm to room temperature
and washed with saturated K2CO3. The organic layers were
dried over MgSO4, filtered, and concentrated to give 1.40 g of
an off-white solid. This material was purified by flash chro-
matography on silica gel with 1:1 hexanes-EtOAc as eluant
to give 1.29 g (93%) of (()-trans-[2-(phthalimidomethyl)-1-
cyclopropyl]methyl methanesulfonate (14) as a white powder.
Mp: 118-121 °C. 1H NMR (CDCl3): δ 0.65 (dt, 1, J ) 8.6,
5.4), 0.83 (dt, 1, J ) 8.4, 5.4), 1.33 (m, 2), 2.94 (s, 3), 3.58 (dd,
1, J ) 14.2, 7.2), 3.65 (dd, 1, J ) 14.2, 6.9), 3.99 (dd, 1, J )
10.8, 7.5), 4.09 (dd, 1, J ) 10.8, 7.0), 7.74 (m, 2), 7.86 (m, 2).
13C NMR (CDCl3): δ 9.97, 16.90, 17.26, 37.79, 40.86, 73.22,
123.29, 132.09, 134.02, 168.29.
N-[2-[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl]eth yl]-
p h th a lim id e Hyd r och lor id e (15). N-(2-Bromoethyl)phthal-
imide (5) (3.48 g, 13.7 mmol), 3-(1-piperazinyl)-1,2-benzisothi-
azole (3.00 g, 13.7 mmol, 1.0 equiv), triethylamine (2.29 mL,
16.0 mmol, 1.2 equiv), and acetonitrile (30 mL) were added to
a 100-mL, round-bottomed flask. The cloudy orange solution
was heated at reflux under N2 for 3.5 h. The mixture was
allowed to cool to room temperature and diluted with CH2Cl2.
The organic solution was washed with saturated K2CO3, dried
over MgSO4, filtered, and concentrated to give 5.78 g of a
viscous orange oil. This crude material was recrystallized from
acetonitrile and dried in a vacuum oven to give 1.86 g of a tan
powder. The filtrate was concentrated, and the resulting
residue was purified by flash chromatography on silica gel with
hexanes-EtOAc as eluant to give an additional 0.71 g of the
2-(2-H yd r oxyet h yl)-1-isoin d olin on e (25). This com-
pound was prepared according to a modified procedure of
Murata.21 Ethanolamine (50.1 g, 0.82 mL) was added to a 300-
mL, round-bottomed flask equipped with a Dean-Stark trap,
a reflux condenser, a magnetic stirring bar, and a nitrogen
inlet. Phthalide (110.0 g, 0.82 mol, 1.0 equiv) was then added
as a light-tan powder with stirring. The resulting slurry was

Effect of Linking Bridge Modifications
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 155
placed under N2 and heated in an oil bath at 150 °C for 4 h.
The oil bath temperature was increased to 205-210 °C, and
the melt was heated for an additional 17 h. Water (12 mL)
was collected in the Dean-Stark trap. The product solidified
upon cooling to give a light-brown solid. The crude material
was taken up in hot toluene, and the solution was filtered hot.
The solids that formed upon cooling were filtered, washed with
cold toluene, and dried in a vacuum oven to give 129.75 g (88%)
of 2-(2-hydroxyethyl)-1-isoindolinone (25) as a light-tan pow-
der. Mp: 117-119 °C (lit.21 mp 119-120 °C). 1H NMR
(CDCl3): δ 3.28 (br s, 1), 3.69 (m, 2), 3.85 (m, 2), 4.46 (s, 2),
7.40 (m, 3), 7.73 (m, 1). 13C NMR (CDCl3): δ 45.84, 51.63,
61.30, 122.60, 123.44, 127.91, 131.34, 132.44, 141.53, 169.55.
Anal. (C10H11NO2) C, H, N.
2-(3-Hyd r oxyp r op yl)-1-isoin d olin on e (26). This com-
pound was prepared according to the method described for
compound 25. By employing 3-amino-1-propanol as the amino
alcohol, 2-(3-hydroxypropyl)-1-isoindolinone (156.83 g, 86%)
was obtained. 1H NMR (CDCl3): δ 1.91 (quintet, 2, J ) 6.2),
3.55 (br s, 2), 3.74 (t, 2, J ) 6.2), 3.82 (br s, 1), 4.38 (s, 2), 7.47
(m, 3), 7.80 (m, 1). 13C NMR (CDCl3): δ 30.85, 38.81, 50.39,
58.37, 122.73, 123.64, 128.12, 131.45, 132.30, 141.18, 169.67.
Anal. (C11H13NO2) C, H, N.
tr a n s-2-(4-Hyd r oxy-1-cycloh exyl)-1-isoin d olin on e (27).
Methyl 2-(bromomethyl)benzoate (24) (30.00 g, 0.131 mol),
trans-4-aminocyclohexanol hydrochloride (20.85 g, 0.137 mol,
1.05 equiv), K2CO3 (27.15 g, 0.196 mol, 1.5 equiv), toluene (110
mL), and H2O (20 mL) were added to a 500-mL, round-
bottomed flask equipped with a magnetic stirring bar and a
Dean-Stark trap. The two-phase mixture was heated at
reflux for 19 h. The toluene-water azeotrope was collected,
and the H2O was not allowed to re-enter the reaction pot. Fresh
toluene (300 mL) was added, and the toluene-MeOH azeo-
trope was removed through the Dean-Stark trap. After an
additional 24 h of heating, the solution was decanted from the
salts into a clean, round-bottomed flask. The solvent was
removed with a rotary evaporator to give 25.16 g of a viscous
orange oil. This crude material was purified by flash chro-
matography with EtOAc-0.1% triethylamine as eluant to give
11.88 g (39%) of trans-2-(4-hydroxy-1-cyclohexyl)-1-isoindoli-
none (27) as an off-white solid. Mp: 133-134 °C. 1H NMR
(CDCl3): δ 156 (m, 4), 1.41 (m, 3), 2.11 (m, 2), 3.66 (m, 1),
4.26 (tt, 1, J ) 11.5, 3.9), 4.32 (s, 2), 7.47 (m, 3), 7.84 (dd, 1, J
) 7.7, 1.6). 13C NMR (CDCl3): δ 29.02, 34.46, 46.04, 49.67,
69.90, 122.68, 123.60, 128.01, 131.12, 133.12, 141.12, 165.11.
Anal. (C14H17NO2) C, H, N.
(CDCl3): δ 2.15 (quintet, 2, J ) 6.7), 3.58 (t, 2, J ) 6.5), 3.74
(t, 2, J ) 6.9), 4.41 (s, 2), 7.46 (m, 3), 7.81 (m, 1). 13C NMR
(CDCl3): δ 31.29, 40.17, 42.22, 50.57, 122.71, 123.63, 128.68,
131.36, 132.68, 141.11, 168.75. Anal. (C11H12NOCl) C, H, N.
2-[2-[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl]eth yl]-1-
isoin d olin on e Hyd r och lor id e (31). 2-(2-Chloroethyl)-1-
isoindolinone (28) (6.03 g, 30.82 mmol), 3-(1-piperazinyl)-1,2-
benzisothiazole (6.76 g, 30.82 mmol, 1.0 equiv), triethylamine
(5.15 mL, 3.74 g, 36.99 mmol, 1.2 equiv), and CH3CN (30.0
mL) were added to a 100-mL, round-bottomed flask. The
resulting orange mixture was placed under N2 and heated at
reflux for 24 h. The solution was allowed to cool to room
temperature and transferred to a separatory funnel with the
aid of EtOAc. The dark-orange solution was washed with
saturated K2CO3, and the organic layers were dried over
MgSO4, filtered, and concentrated to give 13.44 g of an orange
oil. This crude material was purified by flash chromatography
with 5:1 EtOAc-hexanes as eluant to give 7.15 g of 2-[2-[4-
(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-2,3-dihydro-1H-
isoindol-1-one (31).
The free amine was taken up in acetone, and HCl (24.5 mL
of a 1 N solution in ether, 1.0 equiv) was added. The salt was
recrystallized twice from 95% EtOH to give 3.05 g (24%) of
the hydrochloride salt as an off-white powder. Spectral and
analytical data indicated 1 equiv of HCl and 0.5 equiv of EtOH.
Mp: 264-267 °C dec. 1H NMR (DMSO-d6): δ 1.03 (t, 3, J )
6.9), 3.48 (m, 7), 3.70 (br d, 2, J ) 11.0), 4.02 (m, 4), 4.60 (s,
2), 7.55 (m, 6), 8.10 (t, 2, J ) 9.2), 11.28 (br s, 1). 13C NMR
(DMSO-d6): δ 8.50, 36.51, 46.17, 49.66, 50.49, 52.88, 55.94,
121.10, 122.84, 123.34, 124.01, 124.55, 126.81, 127.71, 128.05,
131.48, 131.86, 142.24, 152.06, 162.09, 168.00. Anal. (C21H22N4-
OS‚HCl‚0.5C2H6O) C, H, N.
2-[3-[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl]p r op yl]-
1-isoin d olin on e Hyd r och lor id e (32), (E)-2-[4-[4-(1,2-Ben -
zisoth ia zol-3-yl)-1-p ip er a zin yl]-2-bu ten yl]-1-isoin d olin o-
n e Hyd r och lor id e (38), (Z)-2-[4-[4-(1,2-Ben zisoth ia zol-3-
yl)-1-p ip er a zin yl]-2-bu ten yl]-1-isoin d olin on e Hyd r och lo-
r id e Hyd r a te (39), 2-[5-[4-(1,2-ben zisoth ia zol-3-yl)-1-p ip -
er azin yl]pen tyl]-1-isoin dolin on e Hydr och lor ide (46), an d
2-[6-[4-(1,2-Ben zisot h ia zol-3-yl)-1-p ip er a zin yl]h exyl]-1-
isoin d olin on e Hyd r och lor id e (47). These compounds were
prepared following the procedure described for compound 31.
1H NMR, 13C NMR, and combustion analyses were consistent
with the title compounds. See supporting information for
additional information.
(()-cis-2-[4-[4-(1,2-Ben zisoth ia zol-3-yl)-1-p ip er a zin yl]-
1-cycloh exyl]-1-isoin d olin on e Hyd r och lor id e Mon oh y-
d r a te (33). trans-2-(4-Hydroxy-1-cyclohexyl)-1-isoindolinone
(27) (3.94 g, 0.017 mol) was taken up in anhydrous CH2Cl2
(150 mL), and triethylamine (13.56 mL, 2.59 g, 0.025 mol, 1.5
equiv) was added. The orange solution was placed under N2
and cooled in an ice-water bath. To this stirred solution was
slowly added a mixture of mesyl chloride (1.98 mL, 2.93 g,
0.025 mol, 1.5 equiv) in anhydrous CH2Cl2 (3.0 mL). The
reaction mixture was allowed to stir at 0-5 °C for 1.25 h. An
additional portion of CH2Cl2 was added, and the solution was
washed with saturated K2CO3. The layers were separated, and
the aqueous phase was extracted with CH2Cl2. The organic
layers were combined, dried over MgSO4, filtered, and con-
centrated with a rotary evaporator to give 5.40 g (96%) of
trans-4-(1-oxo-2-isoindolinyl)-1-cyclohexyl methanesulfonate
(30) as an orange solid.
2-(2-Ch lor oeth yl)-1-isoin d olin on e (28). 2-(2-Hydroxy-
ethyl)-1-isoindolinone (25) (117.95 g, 0.666 mol) and toluene
(400 mL) were added to a 1-L, round-bottomed flask. The
solution was cooled with an ice-water bath, and thionyl
chloride (55.0 mL, 89.7 g, 0.754 mol, 1.13 equiv) was added
dropwise over a 0.5-h period. The slurry was allowed to stand
at room temperature for 4 h with periodic swirling.
A
condenser was attached, and the reaction mixture was heated
at 60 °C for 3 h. The toluene and excess thionyl chloride were
removed by distillation under aspirator pressure. The hot
residue was poured into petroleum ether (500 mL), forming a
brown solid. The crude solid was filtered and taken up in hot
toluene. The solution was filtered hot, and the hot toluene
solution was poured into petroleum ether (300 mL) with
stirring. The solid that formed was filtered, washed with
petroleum ether, and dried in a vacuum oven to give 103.08 g
of a powdery tan solid. A second crop of 15.99 g was obtained,
which gave a total of 119.07 g (91%) of 2-(2-chloroethyl)-1-
isoindolinone (28). Mp: 80-81 °C (lit.21 mp 81-82 °C). 1H
NMR (CDCl3): δ 3.80 (t, 2, J ) 5.4), 3.96 (t, 2, J ) 5.4), 4.57
(s, 2), 7.50 (m, 3), 7.86 (m, 1). 13C NMR (DMSO-d6): δ 7.50,
48.74, 54.98, 128.01, 128.60, 133.08, 136.68, 137.15, 147.11,
172.80. Anal. (C10H10NOCl) C, H, N.
2-(3-Ch lor op r op yl)-1-isoin d olin on e (29). This compound
was prepared according to the method described for compound
28. By employing 2-(3-hydroxypropyl)-1-isoindolinone (26)
(127.53 g), 130.94 g (94%) of the crude chloride was obtained.
A small sample (5 g) was purified by flash chromatography
with 4:1 hexanes-EtOAc as eluant to give 4.29 g of an
analytically pure, white solid. Mp: 56-57.5 °C. 1H NMR
This solid (5.27 g, 0.017 mL), 3-(1-piperazinyl)-1,2-ben-
zisothiazole (3.92 g, 0.079 mol, 1.05 equiv), triethylamine (2.85
mL, 2.07 g, 0.020 mol, 1.2 equiv), and CH3CN (20 mL) were
combined, placed under N2, and heated at reflux for 2.5 d. The
mixture was allowed to cool to room temperature and washed
with saturated K2CO3. The organic layers were dried over
MgSO4, filtered, and concentrated with a rotary evaporator
to give 8.29 g of a viscous orange oil. This crude material was
purified by flash chromatography with EtOAc as eluant. The
material isolated was purified further by flash chromatography
with 2:1 EtOAc-hexanes as eluant yielding 0.224 g of a sticky
orange oil. The hydrochloride salt of this free base was formed,
recrystallized from EtOH, and dried in a vacuum oven to give
0.120 g (2%, based on trans-2-(4-hydroxy-1-cyclohexyl)-1-

156 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Norman et al.
isoindolinone) of (()-cis-2-[4-[4-(1,2-benzisothiazol-3-yl)-1-pip-
erazinyl]-1-cyclohexyl]-1-isoindolinone hydrochloride monohy-
drate (33) as light-peach crystals. Mp: 231-232 °C. 1H NMR
(DMSO-d6): δ 1.72 (m, 2), 1.95 (m, 2), 2.20 (m, 2), 2.35 (m, 2),
3.33 (m, 2), 3.45 (m, 1), 3.77 (br d, 2, J ) 13.4), 3.85 (br d, 2,
J ) 12.2), 4.05 (br d, 2, J ) 13.4), 4.20 (quintet, 1, J ) 3.7),
4.74 (s, 2), 7.46 (m, 2), 7.58 (m, 3), 7.67 (d, 1, J ) 7.3), 8.11
(dd, 2, J ) 8.0, 4.7), 10.80 (br s, 1). 13C NMR (DMSO-d6): δ
23.37, 25.25, 45.96, 47.95, 48.75, 62.03, 121.17, 122.51, 123.15,
123.91, 124.56, 126.93, 127.69, 128.07, 131.13, 132.37, 142.06,
152.09, 162.15, 167.08. Anal. (C25H28N4OS‚HCl‚H2O) C, H,
N, H2O.
3-yl)-1-piperazinyl]ethoxy]ethyl]phthalimide (18) (7.45 g, 0.017
mol) was placed in a 100-mL, round-bottomed flask and taken
up in MeOH (20 mL). To this stirred solution was added
dropwise hydrazine hydrate (1.49 g of an 85% solution in H2O,
0.025 mol, 1.5 equiv), and the mixture was heated at reflux
under N2 for 2 h. The reaction mixture was allowed to cool to
room temperature, and 1 N HCl (50.0 mL) was added. The
resulting precipitate was filtered and washed with distilled
H2O. The filtrate was made basic by the addition of 50%
NaOH and extracted with CH2Cl2. The organic layers were
dried over MgSO4, filtered, and concentrated with a rotary
evaporator to give 5.31 g of 3-[4-[2-(2-aminoethoxy)ethyl]-1-
piperazinyl]-1,2-benzisothiazole (44) as a viscous orange oil.
1-Isoin d olin on e (35). Phthalimide (30.0 g, 0.204 mol) was
placed in a 500-mL, round-bottomed flask with glacial acetic
acid (150.0 mL), concentrated HCl (75.0 mL), and tin metal
(58.08 g, 0.489 mL, 2.4 equiv). The creamy slurry was heated
in an oil bath at reflux. As the solution was heated, the
phthalimide dissolved, resulting in a light-yellow solution. The
reaction mixture was allowed to heat at reflux for 2 h, the
solution was filtered hot, and the tin shavings were washed
with fresh acetic acid. The majority of the acetic acid was
removed with a rotary evaporator, resulting in a light-yellow
creamy solution. This material was taken up in CH2Cl2 and
washed with distilled H2O and a saturated sodium chloride
solution. The organic layer was dried over MgSO4, filtered,
and concentrated to give 17.61 g of a light-yellow solid. This
crude material was purified by flash chromatography with
EtOAc as eluant to give 11.93 g (47%) of 1-isoindolinone (35)
as a light-yellow powder. Mp: 150-151 °C (lit.33 mp 150-
152 °C). 1H NMR (CDCl3): δ 4.48 (s, 2), 7.48 (m, 2), 7.57 (m,
1), 7.76 (br s, 1), 7.88 (m, 1). 13C NMR (CDCl3): δ 45.83,
123.16, 123.64, 127.95, 131.69, 143.72, 172.35. Anal. (C8H7-
NO) C, H, N.
A solution of toluene (100 mL) and 44 (5.31 g, 0.017 mol)
was heated in an oil bath at 100-110 °C. A solution of methyl
2-(bromomethyl)benzoate (24) (3.97 g, 0.017 mL, 1.0 equiv) and
toluene (25 mL) was added to the amine solution dropwise,
over a 15-20-min period. The reaction mixture was heated
under N2 for 0.75 h after the addition was complete. The
solution was allowed to cool to room temperature and washed
with saturated K2CO3. The organic layers were dried over
MgSO4, filtered, and concentrated to give 6.22 g of a red-orange
oil. This crude material was purified by flash chromatography
with EtOAc-0.2% triethylamine as eluant followed by recrys-
tallization from an EtOAc-EtOH solution to give 0.95 g (13%
based on 24) of 48 as a tan solid. 1H NMR indicated a small
amount of EtOAc present in the sample. Mp: 108-110 °C.
1H NMR (CDCl3): δ 2.69 (m, 6), 3.49 (br t, 4, J ) 5.0), 3.66 (t,
2, J ) 5.6), 3.74 (dt, 2, J ) 1.0, 5.2), 3.82 (br t, 2, J ) 4.7),
4.57 (s, 2), 7.34 (ddd, 1, J ) 8.2, 7.0, 1.1), 7.47 (m, 4), 7.82 (m,
3). 13C NMR (CDCl3): δ 42.36, 49.80, 51.55, 53.28, 57.82,
68.59, 69.77, 120.53, 122.63, 123.57, 123.85, 127.50, 127.87,
127.97, 131.23, 132.71, 141.64, 152.73, 163.74, 168.55. Anal.
(C23H26N4O2S‚0.15C4H8O2) C, H, N.
(E)-2-(4-Ch lor o-2-b u t en yl)-1-isoin d olin on e (36). So-
dium hydride (1.54 g of an 80% oil dispersion, 1.25 equiv) was
placed under N2 in an oven-dried, 500-mL, round-bottomed
flask. The sodium hydride was washed with hexanes (2×),
and the waste hexanes were removed with a pipet. Anhydrous
DMF (100 mL) was added to the washed sodium hydride. To
this gray suspension was added a solution of 1-isoindolinone
(5.47 g, 0.041 mol) in dry DMF (50.0 mL). In a separate oven-
dried, 500-mL, round-bottomed flask, trans-1,4-dichloro-2-
butene (13.51 g, 0.103 mol, 2.5 equiv) and dry DMF (100.0 mL)
were placed. This solution was cooled in an ice-water bath,
and the 1-isoindolinone solution was slowly added via a
cannula. After the addition was complete, the reaction
mixture was allowed to warm to room temperature and stir
for 0.5 h. The majority of the DMF was removed with a rotary
evaporator, and the residue was taken up in CH2Cl2 and
washed several times with H2O. The organic layers were dried
over MgSO4, filtered, and concentrated to give 20.12 g of a
dark-orange oil. This crude material was purified by flash
chromatography with 1:1 hexanes-EtOAc as eluant to give
6.48 g (71%) of (E)-2-(4-chloro-2-butenyl)-1-isoindolinone (36)
as a light-yellow oil. The 1H and 13C NMR spectra of this
material were consistent for the N-alkylated product. 13C
NMR (CDCl3): δ 43.45, 43.99, 49.61, 122.78, 123.79, 128.08,
129.26, 129.56, 131.43, 132.54, 141.16, 168.28.
(Z)-2-(4-Ch lor o-2-bu ten yl)-1-isoin d olin on e (37). This
compound was prepared according to the method described for
compound 36. Alkylation of 1-isoindolinone (35) (5.75 g, 0.043
mol) with cis-1,4-dichloro-2-butene (6.25 g, 0.047 mol, 1.1
equiv) in anhydrous DMF provided 3.43 g (36%) of (Z)-2-(4-
chloro-2-butenyl)-1-isoindolinone (37) after purification by
flash chromatography. 1H, 13C, and difference NOE NMR
spectra of the light-orange oil were consistent with the
N-alkylated product. 13C NMR (CDCl3): δ 38.42, 38.50, 49.57,
122.77, 123.75, 128.08, 129.01, 129.44, 131.43, 132.44, 141.15,
168.26.
2-[4-[4-(1,2-Ben zisot h ia zol-3-yl)-1-p ip er a zin yl]-2-b u -
tyn yl]-1-isoin d olin on e Hyd r och lor id e (49). 3-[4-(4-Amino-
2-butynyl)-1-piperazinyl]-1,2-benzisothiazole (45) was pre-
pared according to the method described above for compound
44. From N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-2-
butynyl)phthalimide (19) (12.54 g, 0.630 mol), hydrazine
hydrate (2.66 g of an 85% aqueous solution), and MeOH (30
mL), 6.23 g (72.3%) of 3-[4-(4-amino-2-butynyl)-1-piperazinyl]-
1,2-benzisothiazole was obtained as a crude orange oil.
Amine 45 (6.23 g, 0.022 mol) was taken up in toluene (50
mL). To the stirred mixture was added a solution of methyl
2-(bromomethyl)benzoate (24). The resulting orange solution
was heated at reflux under N2 for 18 h. The reaction mixture
was allowed to cool to room temperature and transferred to a
separatory funnel. The solution was washed with saturated
K2CO3, dried over MgSO4, filtered, and concentrated to give
an orange oil. This crude material was purified by flash
chromatography on flash silica gel with 3:1 EtOAc-hexanes
as eluant. The hydrochloride salt of the pure free base was
prepared by the addition of 1 N HCl. The salt was recrystal-
lized from EtOH-EtOAc and dried in a vacuum oven to give
0.24 g (3%) of 2-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-
2-butynyl]-1-isoindolinone hydrochloride (49) as an off-white
powder. Mp: 194-196 °C. 1H NMR (DMSO-d6): δ 3.40 (m,
3), 3.51 (m, 3), 4.08 (m, 2), 4.22 (br s, 2), 4.59 (s, 2), 4.61 (s, 2),
7.48 (m, 2), 7.58 (m, 1), 7.63 (m, 2), 7.71 (dt, 1, J ) 7.5, 1.0),
8.10 (dt, 1, J ) 8.2, 0.9), 8.14 (dt, 1, J ) 8.2, 0.9), 12.00 (s, 1).
13C NMR (DMSO-d6): δ 31.32, 44.53, 49.05, 49.85, 73.23, 84.95,
121.13, 122.91, 123.54, 123.98, 124.56, 126.91, 127.96, 128.07,
131.42, 131.70, 141.76, 152.03, 162.15, 166.80. Anal. (C23H22N4-
OS‚HCl) C, H, N.
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 2, 3, 15-22, 31-33, 38, 39,
and 46-49 were determined by the methods previously
reported.19
2-(5-Ch lor op en tyl)- a n d 2-(5-Br om op en tyl)-1-isoin d oli-
n on e (42) a n d 2-(6-Ch lor oh exyl)- a n d 2-(6-Br om oh exyl)-
1-isoin d olin on e (43). These compounds were prepared by
the method described for compound 35. See supporting
information for additional information.
Ack n ow led gm en t. We acknowledge the technical
assistance of F. Tang for performing the receptor-
binding assays and R. Harper for determining the data
for the apomorphine-induced mouse climbing assay. The
2-[2-[2-[4-(1,2-Ben zisoth iazol-3-yl)-1-piper azin yl]eth oxy]-
eth yl]-1-isoin d olin on e (48). N-[2-[2-[4-(1,2-Benzisothiazol-

Effect of Linking Bridge Modifications
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 157
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authors also thank G. Painter, J . Shockor, D. Heyer, J .
Bentley, and W. Andrews for their assistance and advice
regarding NMR and molecular modeling experiments.
We are grateful to J . Downey for his technical assistance
in the preparation of some key intermediates and to L.
Cotterman for proofreading this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Crystal data, posi-
tional parameters, bond lengths, and bond angles for the
single-crystal X-ray structure of 2 as well as complete experi-
mental details and spectral data for compounds 10-12, 16-
21, 32, 38, 39, 46, and 47 (21 pages). Ordering information is
given on any current masthead page.
(22) Kato, K.; Yoshida, M. Diels-Alder Reaction of N-Vinylimides.
Nipon Kagaku Zasshi, 1966, 87, 1098-1100.
(23) Davies, W.; Perkins, W. H. The Chlorination and Bromination
of the Toluic Acids and the Preparation of Phthalaldehydic Acids.
J . Chem. Soc. 1922, 121, 2202-2215.
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