Analogues of the potential antipsychotic agent 1192U90: Amide modifications

Article abstract of DOI:10.1016/S0968-0896(98)00041-8

Analogues of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)benzamide hydrochloride (1192U90) were prepared and evaluated in receptor binding assays for the dopamine D₂, serotonin 5-HT(1a), and serotonin 5-HT₂ recepto

Full text of DOI:10.1016/S0968-0896(98)00041-8

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 811±823
Analogues of the Potential Antipsychotic Agent 1192U90:
Amide Modi®cations
Frank Navas III,a Flora L. M. Tang,b,y Lee T. Schallera
and Mark H. Normana,*,{
aDivision of Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA
bDivision of Pharmacology and Molecular Therapeutics, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA
Received 28 August 1997; accepted 12 January 1998
AbstractÐAnalogues of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)benzamide hydrochloride
(1192U90) were prepared and evaluated in receptor binding assays for the dopamine D2, serotonin 5-HT1a, and sero-
tonin 5-HT2 receptors. Eight compounds have been synthesized in which the amide group of 1192U90 has been
replaced with a variety of functional groups (i.e. ester, ketone, thioamide, butyramide, butyranilide, sulfonamide,
alkoxyamide and hydrazide). These compounds exhibited moderate to potent anities (0.55±200 nM) for all three
receptors. Several analogues exhibited improved selectivity for the 5-HT2 receptor with D2/5-HT2 binding ratios
greater than 1192U90. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
Hence, research e€orts have been focused on the dis-
covery of drugs that exhibit clozapine's atypical anti-
psychotic pro®le and lack the potential for
agranulocytosis.
Schizophrenia is a mental illness which a€ects millions
of people worldwide. Since the 1950's, drugs such as
haloperidol and chlorpromazine have been used to treat
this devastating disease. While these drugs e€ectively
treat the positive symptoms of schizophrenia (i.e. delu-
sions, hallucinations) they are ine€ective against the
negative symptoms (i.e. social withdrawal, apathy).1±4
Furthermore, these drugs may produce extrapyramidal
side e€ects (EPS) such as acute dystonia, Parkinsonism,
and tardive dyskinesia. In the 1970's a major break-
through in the treatment of this disease was achieved
with the discovery of clozapine which is e€ective against
both the positive and negative symptoms of the disease.
Clozapine also lacks the extrapyramidal side-e€ects
associated with the typical antipsychotic drugs.5±7
Unfortunately, clozapine causes agranulocytosis, a poten-
tially fatal blood dyscrasia, in up to 1% of patients.8
One approach to the discovery of new atypical anti-
psychotic agents has focused on compounds which are
mixed dopamine D2 and serotonin 5-HT2 antagonists.
Meltzer has postulated that mixed D2/5-HT2 antago-
nists that potently bind to the 5-HT2 receptor and exhi-
bit moderate anity for the D2 receptor (i.e. D2/5-HT2
ratio >1) are more likely to have good antipsychotic
activity with a lower propensity to produce extra-
pyramidal side e€ects.9 New atypical antipsychotic
agents which combine dopamine D2 and serotonin 5-
HT2 antagonism include risperidone,10 sertindole,11 ilo-
peridone,12 and the clozapine derivative olanzapine.13 In
fact, risperidone is now the most widely prescribed
antipsychotic drug in the United States.14
Anity for the 5-HT1a receptor may reduce the EPS
liability of a potential antipsychotic agent and alleviate
the negative symptom of social withdrawal. The 5-HT1a
agonist buspirone has been shown to reverse the halo-
peridol-induced catalepsy in animal models15 and
reduce stress-induced psychosocial de®cits in chronic
schizophrenic patients.16 Lowe and co-workers have
Key words: 1192U90; antipsychotic; serotonin 5-HT1a; sero-
tonin 5-HT2; dopamine D2.
*Corresponding author.
yCurrent address: Sugen, Inc., 351 Galveston Drive, Redwood
City, CA 94063, USA
{Current address: Amgen, Inc., Small Molecule Drug Dis-
covery, 1840 De Havilland Drive, Thousand Oaks, CA 91320-
1789, USA
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00041-8

812
F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
described a series of potential atypical antipsychotic
agents which are mixed 5-HT1a agonists and D2/5-HT2
antagonists.17 Similarly, Hrib and co-workers prepared
a series thiazolidinones which potently bind to the 5-
HT1a receptor as well as the D2, D4, and 5-HT2 recep-
tors.18 These compounds exhibited activity in an animal
model for the negative symptom of social withdrawal
and are believed to be 5-HT1a agonists.
We have recently disclosed the discovery of a series of
substituted benzamides with dopamine D2, serotonin 5-
HT2, and serotonin 5-HT1a binding activities.19 Struc-
ture±activity relationship investigations in this series
identi®ed the 2-aminobenzamide, 1192U90 (1), as the
lead compound (Figure 1). This compound is a mixed
D2/5-HT2 antagonist and a serotonin 5-HT1a agonist
which exhibits in vivo activity in animal models pre-
dictive of antipsychotic activity.20
Scheme 1. (a) 3-(1-Piperazinyl)-1,2-benzisothiazole, Et3N,
CH3CN, re¯ux; (b) 1.0 N HCl, THF, rt; (c) anthranilic acid, 1-
hydroxybenzotriazole hydrate, 1,3-dicyclohexylcarbodiimide,
DMF, rt.
In order to better understand the structure±activity
relationship in this series of benzamides, we have pre-
pared analogues of 1192U90 in which the amide group
has been replaced with a variety of functional groups.
We herein describe the synthesis and receptor binding
activity of these compounds.
quenching with 6-chlorohexanoyl chloride. However,
attempts via this route yielded either largely unreacted
starting material or numerous unidenti®ed products.
Stille and co-workers described the synthesis of an aryl
ketone in which phenyltrimethyltin is coupled to a bromo-
alkanoyl bromide using a palladium catalyst.23 They
reported that no reaction occurred at the primary bro-
mide site. Since 9 contained an alkyl chloride, this
approach appeared to be ideally suited for the preparation
of this intermediate. Treatment of aniline with di-tert-
butyldicarbonate in THF gave the BOC-protected aniline
(7). The dilithium anion of 7 was prepared according to a
procedure described by Muchowski and Venuti using tert-
butyllithium as a base.24 Treatment of the dilithium anion
of 7 with trimethyltin chloride gave the organotin inter-
mediate (8) that was reacted with 6-chlorohexanoyl
chloride in the presence of a palladium catalyst to give the
desired intermediate chloride (9). Displacement of the
chloride with 3-(1-piperazinyl)-1,2-benzisothiazole fol-
lowed by removal of the BOC protecting group with tri-
¯uoroacetic acid gave the desired ketone analogue (10).
Chemistry
Replacement of the amide group of 1192U90 with
other functional groups (i.e. ester, ketone, thioamide,
butyramide, butyranilide, sulfonamide, N-alkoxy-
benzamide and hydrazide) required a variety of syn-
thetic approaches which are illustrated in Schemes 1±7.
Ester 5 was synthesized in three steps from 4-iodo-1-
(tert-butyldimethylsilyloxy)butane21 (2) as shown in
Scheme 1. Reaction of 2 with 3-(1-piperazinyl)-1,2-
benzisothiazole22 gave the desired tert-butyldimethylsi-
lyl ether (3). Treatment of 3 with HCl in THF a€orded
the intermediate alcohol (4) which was condensed with
anthranilic acid in the presence of HOBt and DCC to
give the desired ester (5).
The synthesis of ketone 10 is illustrated in Scheme 2.
Initially, we attempted to prepare haloketone 9 directly
from BOC-protected aniline (7) via formation of the
dilithium anion with tert-butyllithium followed by
Treatment of 1192U90 with either Lawesson's reagent
or phosphorus pentasul®de failed to give thioamide 13.
Therefore, an alternative synthetic approach was needed
for the preparation of this compound. Wagner and
Roth prepared a series of 2-aminothiobenzamides by
reacting a variety of amines with thiazine dithione 12
which was obtained by treatment of isatoic anhydride
with P4S10.25 Thus, reaction of isatoic anhydride with
phosphorus pentasul®de in re¯uxing xylenes gave inter-
mediate 12 which was reacted with 3-(4-(4-aminobutyl)-
1-piperazinyl)-1,2-benzisothiazole26 in THF to give the
desired thioamide (13) (Scheme 3).
Figure 1. 1192U90(1).

F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
813
Scheme 2. (a) di-tert-Butyl dicarbonate, THF, re¯ux; (b) tert-butyllithium, THF, 78 ꢀC to 20 ꢀC; (c) trimethyltin chloride, THF,
70 ꢀC to 78 ꢀC; (d) 6-chlorohexanoyl chloride, bis(acetonitrile)Pd II chloride, toluene, re¯ux; (e) 3-(1-piperazinyl)-1,2-benz-
isothiazole, Et3N, CH3CN, re¯ux; (f) tri¯uoroacetic acid, CH2Cl2, anisole, rt.
The butyramide and butyranilide analogues (17 and 18,
respectively) were prepared according to the routes
illustrated in Scheme 4. Alkylation of 3-(1-piperazinyl)-
1,2-benzisothiazole with ethyl-4-bromobutyrate (14)
gave ester 15, which was subsequently hydrolyzed with
aqueous NaOH to give carboxylic acid 16. Conden-
sation of 16 with 2-aminobenzylamine in the presence
of DCC and HOBt in DMF gave analogue 17. The
butyranilide (18) was prepared from the carboxylic acid
via the formation of the mixed anhydride using iso-
butylchloroformate followed by treatment with 1,2-
phenylenediamine.
Scheme 3. (a) Phosphorus pentasul®de, xylenes, re¯ux; (b) 3-
(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole, THF, rt.
Sulfonamide 21 was conveniently prepared in one step
(Scheme 5) via treatment of 2-aminobenzene sulfon-
amide (19) with NaH followed by alkylation of the
sulfonamide salt with 8-(1,2-benzisothiazol-3-yl)-8-aza-
5-azoniaspiro[4.5]decane bromide22 (20).
For alkoxyamide 26 and hydrazide 29 the methylene
group alpha to the amide nitrogen of 1192U90 was
replaced with a heteroatom. Alkoxyamide 26 was pre-
pared in four steps from endo-N-hydroxy-5-norbornene-
2,3-dicarboximide (22) as illustrated in Scheme 6. Alkyl-
ation of 22 with 1,3-dibromopropane in the presence of
Scheme 4. (a) 3-(1-Piperazinyl)-1,2-benzisothiazole, Et3N,
CH3CN, rt to re¯ux; (b) NaOH, EtOH, re¯ux, 1.5 h; (c) 2-
aminobenzylamine, 1-hydroxybenzotriazole hydrate, 1,3-dicy-
clohexylcarbodiimide, DMF, rt; (d) isobutylchloroformate,
Et3N, THF, 15 ꢀC; (e) 1,2-phenylenediamine, 15 ꢀC to rt.
Scheme 5. (a) NaH, DMF, 0 ꢀC to re¯ux.

814
F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
Scheme 6. (a) 1,3-Dibromopropane, diisopropylethylamine, CH3CN, 70 ꢀC; (b) 3-(1-piperazinyl)-1,2-benzisothiazole, diisopropyl-
ethylamine, CH3CN, re¯ux; (c) hydrazine hydrate, EtOH, re¯ux; (d) isatoic anhydride, THF, rt.
Hunig's base gave 23 which was treated with 3-(1-
piperazinyl)-1,2-benzisothiazole to give the alkoxyimide
intermediate (24). Deprotection with hydrazine hydrate
gave hydroxylamine 25 which was converted to the
desired alkoxyamide (26) upon treatment with isatoic
anhydride in THF. In an earlier attempt to prepare this
analogue, N-hydroxyphthalimide was used in lieu of 22.
However, reaction of the corresponding bromide with 3-
(1-piperazinyl)-1,2-benzisothiazole failed to yield the
desired alkoxyphthalimide intermediate. This result is in
agreement with the ®ndings of Amlaiky and co-workers
who reported that nucleophilic attack on phthalimide
ethers of this type readily occurs at the imide carbo-
nyl group.27
with 2-aminobenzhydrazide in re¯uxing ethanol gave
the desired hydrazide analogue (29).
Discussion
The structure±activity investigations reported previously
for this series of compounds have focused on substitu-
tions on the benzamide ring as well as replacement of
the benzamide ring with heterocyclic carboxamides.19,28
In those studies, modi®cation to the amide functional
group was limited to methylation of the benzamide
nitrogen. To further develop the SAR in this series of
benzamides we focused on the amide functional group
of 1192U90. In this study, we replaced the carbonyl
group with a sulfone or thiocarbonyl, substituted the
amide nitrogen with a methylene group or an oxygen,
introduced heteroatoms alpha to the amide nitrogen,
and changed the position of the carbonyl relative to the
nitrogen. These compounds were evaluated in receptor
binding assays for the dopamine D2, serotonin 5-HT2,
and serotonin 5-HT1a receptors according to methods
described previously.26 The receptor binding data as
well as the D2/5-HT2 ratios for these compounds are
shown in Table 1. The receptor binding data for
1192U90 is included for comparison.
Hydrazide 29 was prepared in two steps as illustrated in
Scheme 7. Alkylation of 3-(1-piperazinyl)-1,2-benz-
isothiazole with 1-bromo-3-chloropropane gave chlor-
ide 28 in good yield. Treatment of this intermediate
In general, the compounds described herein exhibited
moderate to potent anities at all three receptors and
maintained favorable D2/5-HT2 binding ratios (i.e. D2/
5-HT2>1).
Replacement of the amide group of 1192U90 with either
a thioamide (13) or sulfonamide (21) resulted in small
Scheme 7. (a) 3-(1-Piperazinyl)-1,2-benzisothiazole, Et3N,
CH2Cl2, rt; (b) 2-aminobenzhydrazide, EtOH, re¯ux.

F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
815
Table 1. In vitro receptor binding anities of 1192U90 analogues
Receptor bindingb,c IC50 (nM)
d
Compounda
X
D2
10
5-HT1a
5-HT2
D2/5-HT2
5
10
C(O)OCH2
C(O)CH2CH2
C(S)NHCH2
CH2NHC(O)
NHC(O)
14
4
3
3.3
4.7
2.6
0.55
1.8
1.6
9.2
3.9
1.1
4
13
21
56
1
11.7
35
17e
18
40
120
170
13
12
3.8
200
66
21.7
16.9
13.6
3.8
21
26
S(O)2NHCH2
C(O)NHO
15
15
29
1 (1192U90)
C(O)NHNH
C(O)NHCH2
32
3.3
9.7
aHydrochloride salts unless noted otherwise.
bD2 [3H]raclopride binding; 5-HT1a, [3H]-8-OH-DPAT binding; 5-HT2, [3H]ketanserin binding.
cFor experimental protocol, see ref. 26.
dRatio of dopamine D2 IC50 to serotonin 5-HT2 IC50 receptor binding.
eFumarate salt.
changes in D2 and 5-HT2 receptor binding anities as
well as the D2/5-HT2 ratios. While the D2 and 5-HT2
receptors tolerated these structural modi®cations quite
well, the 5-HT1a receptor exhibited a 40-fold decrease in
anity for the sulfonamide analogue.
In butyramide (17) and butyranilide (18) the position of
the carbonyl group has been changed relative to the
amide nitrogen. In both cases however, the four-carbon
chain between the amide nitrogen and the piperazine
benzisothiazole group has been maintained. In a pre-
vious study the four-carbon spacer was found to pro-
vide optimal receptor binding activity in an analogous
series of phthalimides and isoindolinones.29 In general,
this structural modi®cation led to a decrease in recep-
tor anity. Most notable was the 30-fold decrease in
binding anity of butyranilide (18) for the 5-HT1a
receptor. The loss of binding anity was more sig-
ni®cant for the butyranilide analogue and may be due in
part to the decreased chain length between the aromatic
ring and the piperazine benzisothiazole moiety. Butyr-
amide 17 had the greatest selectivity in this series of
compounds with a D2/5-HT2 ratio three times greater
than 1192U90.
If the amide -NH of 1192U90 participates in signi®cant
hydrogen bonding interactions at these receptors, we
would expect substitution of the amide nitrogen with a
methylene group to reduce binding anity. However,
ketone 10 potently binds to all three receptors, and in
fact, has slightly greater anities for the D2 and 5-HT2
receptors than does 1192U90. This suggests that hydro-
gen bonding interactions of the amide hydrogen do not
contribute signi®cantly to binding at these receptors.
This is consistent with earlier observations in which the
N-methyl analogue of 1192U90 maintained its potent
binding anity for all three receptors.19 Similarly, ester
5 maintains good binding anity at these receptors.
However, both the ketone and ester exhibited less
favorable D2/5-HT2 binding ratios due to an increase in
D2 binding relative to 5-HT2.
Conclusion
Replacement of the amide group of 1192U90 with
alternative functional groups was generally well toler-
ated by the dopamine D2, serotonin 5-HT1a, and sero-
tonin 5-HT2 receptors. Several of these analogues
showed selectivity for the serotonin 5-HT2 receptor as
evidenced by their favorable D2/5-HT2 binding ratios
The presence of a heteroatom alpha to the amide nitro-
gen (i.e. hydrazide 29 and alkoxyamide 26) resulted in
small changes to the receptor binding anities. The
small increase in D2 binding exhibited by hydrazide 29
resulted in a less favorable D2/5-HT2 ratio.

816
F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
(i.e. D2/5-HT2 >1) and therefore may exhibit an atypi-
cal antipsychotic pro®le.
acetonitrile (50 mL). The ¯ask was equipped with a
magnetic stirring bar, re¯ux condenser and nitrogen
inlet. The stirred yellow suspension was heated at re¯ux
under nitrogen. The reaction mixture became a gold-
yellow solution upon heating. After 3 h, the oil bath was
removed and the reaction mixture was allowed to stand
at room temperature. The reaction mixture was con-
centrated in vacuo and the residue was partitioned
between EtOAc and saturated NaHCO3. The layers
were separated and the aqueous layer was extracted
with EtOAc. The organic layers were combined, dried
over MgSO4, ®ltered, and concentrated to give the crude
product as a thin-orange oil. The crude material was
puri®ed by ¯ush chromatography with EtOAc:Hex (1:1)
to give 2.87 g (61%) of the title compound as a pale-
yellow oil. A portion of this material was dried in an
abderholden apparatus under high vacuum. 1H NMR
(DMSO-d6; 300 MHz) d 0.02 (s, 6), 0.85 (s, 9), 1.48 (m,
4), 2.34 (m, 2), 2.55 (m, 4), 3.42 (m, 4), 3.59 (m, 2), 7.41
(t, 1, J=7.6), 7.53 (t, 1, J=7.6), 8.02 (d, 1, J=8.4), 8.03
(d, 1, J=7.9); 13C NMR (DMSO-d6; 75.43 MHz) d
4.91, 18.30, 22.94, 26.19, 30.57, 50.04, 52.85, 57.95,
62.74, 121.38, 124.47, 124.70, 127.68, 128.16, 152.29,
163.86. Anal. calcd for C21H35N3OSiS: C, 62.18; H,
8.70; N, 10.36. Found: C, 62.14; H, 8.75; N, 10.31.
Experimental
Pharmacology
In vitro binding anity to the dopamine D2 receptor
was determined by displacement of [3H]raclopride from
the D2 receptor.26 Binding to the serotonin 5-HT1a and
5-HT2 receptors was determined by the ability of the
compounds to displace [3H]-8-hydroxy-2-(di-n-propyl-
amino)-tetralin and [3H]ketanserin, respectively.26
Chemistry
General. Unless otherwise noted, all materials were
obtained from commercial suppliers and used without
further puri®cation. 3-(4-(4-Aminobutyl)-1-piperazinyl)-
1,2-benzisothiazole was prepared as previously reported.26
Anhydrous solvents such as dimethylformamide
(DMF), tetrahydrofuran (THF), dichloromethane, and
toluene were obtained from Aldrich Chemical Co. in
Sure/Seal bottles. All reactions involving air- or moist-
ure-sensitive compounds were performed under a N2
atmosphere. Flash chromatography and ¯ush chroma-
tography were performed using EM Science silica gel 60
(230±400-mesh ASTM). The term ¯ush chromatography
refers to column chromatography when suction is
applied to the bottom of the column to increase the ¯ow
rate of the eluant. Preparative radial chromatography
was performed using a Harrison Research Chromato-
tron. Thin-layer chromatography (TLC) was performed
with Analtech silica gel GF TLC plates (250 mm). 1H
NMR spectra were determined with superconducting
FT NMR spectrometers operating at 200, 300, and
500 MHz. 13C NMR were measured at 50.29, 75.43, or
125.706 MHz. Chemical shifts are expressed in ppm
down®eld from internal tetramethylsilane. Signi®cant
1H NMR data are reported in the following order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
quin, quintet; m, multiplet), number of protons, and
coupling constants in Hz. Elemental analyses were
performed by either Atlantic Microlab, Inc., Norcross,
GA, or Galbraith Laboratories, Inc., Knoxville, TN.
3-(4-(4-Hydroxybutyl)-1-piperazinyl)-1,2-benzisothiazole
(4). To a 250 mL round-bottomed ¯ask were added 3-(4-
(4-((tert-butyldimethylsilyl)oxy)butyl)-1-piperazinyl)-1,2-
benzisothiazole (3) (2.37 g, 5.84 mmol), 1.0 N aqueous
HCl (30 mL) and THF (30 mL). The ¯ask was equipped
with a magnetic stirring bar and the pale yellow solution
was stirred at room temperature. After 42 h, the pH of
the reaction mixture was adjusted to between 7±8 via the
addition of saturated NaHCO3. Ethyl acetate was added
and the heterogeneous mixture was transferred to a
separatory funnel. The layers were separated and the
aqueous layer was extracted with EtOAc. The organic
layers were combined, dried over MgSO4, ®ltered, and
concentrated to give 2.39 g of a yellow oil. The crude
product was used without further puri®cation. 1H NMR
(DMSO-d6; 300 MHz) d 1.47 (m, 4), 2.33 (t, 2, J=6.7),
2.55 (t, 4, J=4.6), 3.41 (m, 6), 4.50 (br s, 1), 7.41 (ddd,
1, J=1.1, 7.0, 8.1), 7.53 (ddd, 1, J=1.2, 7.0, 8.1), 8.02
(d, 1, J=8.1), 8.03 (d, 1, J=8.1); 13C NMR (DMSO-
d6; 75.43 MHz) d 23.32, 30.91, 50.03, 52.87, 58.17,
61.03, 121.37, 124.45, 124.69, 127.68, 128.14, 152.30,
163.87.
Melting points were determined with
a Thomas
Hoover capillary melting point apparatus and are
uncorrected.
4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl-2-amino-
benzoate hydrochloride (5). To a 500 mL round-bot-
tomed ¯ask were added 3-(4-(4-hydroxybutyl)-1-piper-
azinyl)-1,2-benzisothiazole (4) (1.82 g, 6.25 mmol),
anthranilic acid (1.27 g, 9.26 mmol, 1.48 equiv.), 1-
hydroxybenzotriazole hydrate (1.27 g, 9.40 mmol,
1.50 equiv.) and anhydrous DMF (30 mL). The ¯ask was
3-(4-(4-((tert-Butyldimethylsilyl)oxy)butyl)-1-piperazinyl)-
1,2-benzisothiazole (3). To a 250 mL round-bottomed
¯ask were added 4-iodo-1-(tert-butyldimethylsilyloxy)
butane21 (2) (3.65 g, 11.61 mmol), 3-(1-piperazinyl)-1,2-
benzisothiazole (2.57 g, 11.72 mmol, 1.01equiv), triethyl-
amine (2.0 mL, 1.45 g, 14.35 mmol, 1.24 equiv.) and

F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
817
equipped with a magnetic stirring bar, addition funnel
and nitrogen inlet. The pale-yellow solution was cooled
in an ice-water bath and a solution of 1,3-dicyclohexyl-
carbodiimide (2.06 g, 9.98 mmol, 1.60 equiv) in anhy-
drous DMF (20 mL) was added dropwise. The ice-water
bath was removed and the reaction mixture was stirred
at room temperature. After 20 h, the reaction mixture
was concentrated in vacuo. Ethyl acetate was added to
the residue and the suspension was ®ltered. The ®ltrate
was washed with saturated NaHCO3, the layers were
separated, and the aqueous layer was extracted with
EtOAc. The organic layers were combined, dried over
MgSO4, ®ltered, and concentrated to give the crude
product as a mixture of ®ne solids and an orange oil.
Ethyl acetate was added to the free base and the sus-
pension was ®ltered. The ®ltrate was concentrated to
give an orange oil. The crude product was puri®ed by
¯ash chromatography with CH2Cl2 followed by
CH2Cl2:MeOH (95:5) to give 2.31 g of the free base as a
yellow±beige solid. The free base was dissolved in
CH2Cl2 and 1 N ethereal HCl (5.62 mL, 1.0 equiv) was
added. The resulting hydrochloride salt was recrys-
tallized from EtOH and H2O to give 0.985 g (35%) of
the title compound as a beige solid. Melting point 201±
6.93 (t, 1, J=7.4), 7.22 (t, 2, J=8.0), 7.43 (d, 2, J=8.0)
9.28 (s, 1); 13C NMR (DMSO-d6; 125 MHz) d 28.06,
78.84, 118.05, 121.88, 128.47, 139.46, 152.70. Anal.
calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found:
C, 68.40; H, 7.77; N, 7.28.
(2-Trimethylstannyl-phenyl)-carbamic acid tert-butyl
ester (8). To a 2 L, three-necked, round-bottomed ¯ask
was added phenyl-carbamic acid tert-butyl ester (7)
(15.0 g, 77.6 mmol) and anhydrous THF (300 mL). The
¯ask was equipped with a magnetic stirring bar, ther-
mometer, addition funnel and nitrogen inlet. The clear
colorless solution was cooled to 78 ꢀC with a dry ice/
acetone bath. The addition funnel was charged with a
solution of tert-butyllithium (1.7 M in pentane)
(110.0 mL, 187 mmol, 2.41 equiv.) and the base was
added dropwise to the stirred cold carbamate solution
while maintaining the temperature between 70 and
78 ꢀC. The cloudy yellow solution was stirred at
78 ꢀC for 30 min and between 20 and 30 ꢀC for 2 h.
The addition funnel was charged with a solution of tri-
methyltin chloride (1 M in THF) (98.0 mL, 98.0 mmol,
1.26 equiv.) and the gold-yellow reaction mixture was
cooled to 78 ꢀC with a dry ice/acetone bath. The tri-
methyltin chloride solution was added dropwise to the
cold reaction mixture. The temperature was maintained
between 70 and 78 ꢀC during the addition of the tri-
methyltin chloride. To the yellow solution was slowly
added 276 g of a 15% aqueous NH4Cl solution. The dry
ice/acetone bath was removed shortly after the addition
of NH4Cl had begun. Diethyl ether was added to the
quenched reaction and the two-phase mixture was
allowed to stir for 15 min. The mixture was transferred
to a separatory funnel and the layers were separated.
The organic layer was dried over MgSO4, ®ltered, and
concentrated to give the crude product as a yellow
liquid. The unreacted BOC-protected aniline pre-
cipitated from the yellow liquid upon standing. Hexanes
was added to the suspension and the mixture was ®l-
tered. The ®ltrate was concentrated to give the crude
product as a yellow liquid which was partially puri®ed
by ¯ash chromatography with Hex:EtOAc (93:7) as
eluant to give 6.65 g (24%) of the desired product as a
clear colorless oil. This material was used in the Stille
coupling reaction without further puri®cation. A small
portion (0.14 g) of this material was puri®ed further by
¯ash chromatography with Hex:EtOAc (98:2) as eluant
to give 0.07 g of the analytically pure product as a white
solid. Melting point 61±63.5 ꢀC. 1H NMR (DMSO-d6;
500 MHz) d 0.24 (t, 9, J=28.0 (Sn±H coupling)), 1.44 (s,
9), 7.04 (d, 1, J=8.0), 7.11 (t, 1, J=7.0), 7.24 (dt, 1,
J=1.5, 7.6), 7.38 (dd, 1, J=1.4, 7.2), 8.89 (br s, 1); 13C
NMR (DMSO-d6; 125 MHz) d 7.09, 28.71, 79.21,
125.26, 125.48, 129.14, 136.83, 144.35, 155.19. Anal.
calcd for C14H23NO2Sn: C, 47.23; H, 6.51; N, 3.93.
Found: C, 47.44; H, 6.44; N, 3.99.
203 ꢀC. H NMR (DMSO-d6; 300 MHz) d 1.75 (m, 2),
1
1.90 (m, 2), 3.24 (m, 4), 3.53 (m, 4), 4.04 (d, 2, J=13.7),
4.23 (t, 2, J=6.2), 6.51 (ddd, 1, J=1.2, 7.0, 8.1), 6.65 (br
s, 2), 6.76 (dd, 1, J=1.3, 8.4), 7.23 (ddd, 1, J=1.7, 7.0,
8.5), 7.45 (ddd, 1, J=1.2, 7.0, 8.1), 7.57 (ddd, 1, J=1.1,
7.0, 8.1), 7.73 (dd, 1, J=1.6, 8.1), 8.10 (tm, 2, J=8.8),
11.23 (br s, 1); 13C NMR (DMSO-d6; 75.43 MHz) d
20.42, 25.94, 46.72, 50.83, 55.48, 63.46, 109.06, 115.07,
116.86, 121.54, 124.35, 124.96, 127.31, 128.46, 131.00,
134.38, 151.76, 152.45, 162.56, 167.69. Anal. calcd for
.
C22H26N4O2S HCl: C, 59.11; H, 6.09; N, 12.53. Found:
C, 59.17; H, 6.11; N, 12.47.
Phenyl-carbamic acid tert-butyl ester (7). To a 250 mL,
round-bottomed ¯ask were added aniline (1.43 g,
15.35 mmol), di-tert-butyl dicarbonate (3.68 g, 16.86 mmol,
1.1 equiv.) and THF (30 mL). The ¯ask was equipped
with a magnetic stirring bar, re¯ux condenser, and
nitrogen inlet and the solution was heated at re¯ux.
After 4 h, the oil bath was removed and the reaction
mixture was allowed to cool to room temperature. The
solvent was removed in vacuo to give the crude product
as an orange liquid, which crystallized to a beige solid.
The solid was partitioned between 1.0 N aqueous HCl
and EtOAc. The layers were separated and the organic
phase was washed with 1.0 N aqueous HCl followed by
saturated aqueous NaHCO3. The organic layer was
dried over MgSO4, ®ltered and concentrated to give a
beige solid. The carbamate was recrystallized from hex-
anes and ethyl acetate to give 1.72 g (58%) of the title
compound as ®ne white needles. Melting point 134±
137 ꢀC. 1H NMR (DMSO-d6; 500 MHz) d 1.47 (s, 9),

818
F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
tert-Butyl-N-(2-(6-chlorovaleryl)phenyl)carbamate (9).
To a 300 mL, round-bottomed ¯ask were added 6-
chlorohexanoyl chloride (3.6 g, 18.7 mmol), bis(aceto-
nitrile)Pd II chloride (54 mg) and toluene (25 mL). A
solution of (2-trimethylstannyl-phenyl)-carbamic acid
tert-butyl ester (8) (6.53 g, 18.3 mmol) in toluene (50 mL)
was added to the acid chloride solution. The ¯ask was
equipped with a re¯ux condenser and a nitrogen inlet
and the pale-yellow solution was heated at re¯ux. After
1 h, the oil bath was removed and the reaction mixture
was allowed to cool to room temperature. The reaction
mixture was ®ltered and the ®ltrate was concentrated to
give the crude product as a gold±yellow liquid. The
crude product was partitioned beween Et2O and H2O.
The layers were separated and the organic layer was
washed with H2O. The organic layer was dried over
MgSO4, ®ltered, and concentrated to give the crude
product as an orange liquid. The crude product was
partially puri®ed by ¯ash chromatography with Hex:-
EtOAc (16:1) as eluant to give 4.39 g of the title com-
pound as a pale-yellow liquid. A solid precipitated from
the yellow liquid upon standing. Hexanes was added
and the suspension was ®ltered to give analytically pure
product (0.538 g) as clear colorless plates. The ®ltrate
was concentrated to give 3.82 g of slightly impure pro-
duct as a pale-yellow liquid which was used without
further puri®cation. Melting point 53.5±55 ꢀC. 1H NMR
(DMSO-d6; 300 MHz) d 1.42 (m, 2), 1.46 (s, 9), 1.61
(quin, 2, J=7.4), 1.74 (quin, 2, J=7.1), 3.06 (t, 2,
J=7.2), 3.63 (t, 2, J=6.7), 7.11 (ddd, 1, J=1.2, 7.2, 8.3),
7.56 (ddd, 1, J=1.6, 7.4, 8.7), 8.02 (dd, 1, J=1.6, 8.1),
8.19 (dd, 1, J=1.2, 8.5), 10.78 (s, 1); 13C NMR (DMSO-
d6; 75.43 MHz) d 23.48, 26.20, 28.25, 32.26, 39.46, 45.64,
80.44, 119.04, 122.01, 122.55, 131.62, 134.63, 140.56,
152.58, 204.95. MS (CI/CH4, 50 mA/s): M+Na+ (348),
base (216). Anal. calcd for C17H24ClNO3: C, 62.67; H,
7.42; N, 4.30. Found: C, 62.75; H, 7.43; N, 4.30.
layers were combined and extracted with EtOAc. The
organic layers were combined, dried over MgSO4, ®l-
tered, and concentrated to give the crude product as an
orange liquid, which contained white solids. The crude
amine was puri®ed by ¯ash chromatography with
CH2Cl2:MeOH (98:2) followed by CH2Cl2:MeOH
(96:4) as eluant to give 1.07 g of the free base. The free
base (1.07 g) was dissolved in CH2Cl2 and 1.0 N ethereal
HCl (2.6 mL, 1.0 equiv) was added. The hydrochloride
salt was recrystallized from EtOH and H2O to give
0.758 g (19%) of the title compound as a beige solid.
Melting point 237±239 ꢀC. 1H NMR (DMSO-d6;
300 MHz) d 1.36 (m, 2), 1.64 (quin, 2, J=7.4), 1.74 (m,
2), 2.95 (t, 2, J=7.1), 3.17 (m, 2), 3.34 (m, 4), 3.59 (d, 2,
J=11.3), 4.07 (d, 2, J=12.9), 6.53 (ddd, 1, J=1.2, 7.0,
8.1), 6.74 (dd, 1, J=1.3, 8.4), 7.20 (s, 2), 7.22 (ddd, 1,
J=1.6, 6.8, 8.4), 7.46 (ddd, 1, J=1.2, 7.0, 8.4), 7.58
(ddd, 1, J=1.2, 7.0, 8.1), 7.76 (dd, 1, J=8.1, 1.6), 8.11
(t, 2, J=8.4), 10.24 (br s, 1); 13C NMR (DMSO-d6;
75.43 MHz) d 23.25, 24.19, 26.12, 38.39, 46.74, 50.78,
55.68, 114.68, 116.83, 117.30, 121.55, 124.35, 124.97,
127.31, 128.47, 131.61, 134.32, 151.40, 152.45, 162.57,
202.21. MS (CI/CH4, 50 mA/s): M+1, base (409). Anal.
.
calcd for C23H28N4OS HCl: C, 62.08; H, 6.57; N, 12.59.
Found: C, 62.16; H, 6.59; N, 12.57.
1H-Benzo[d][1,3]thiazine-2,4-dithione (12). To a 100 mL
round-bottomed ¯ask were added isatoic anhydride
(0.56 g, 3.43 mmol), phosphorus pentasul®de (2.98 g,
6.70 mmol, 1.95 equiv.) and xylenes (25 mL). The ¯ask
was equipped with a magnetic stirring bar, re¯ux con-
denser and nitrogen inlet and the suspension was heated
at re¯ux under nitrogen. After 16 h, the oil bath was
removed and the reaction mixture was allowed to cool
to room temperature. The reaction mixture was ®ltered
and the ®ltrate was concentrated in vacuo. The ®ltered
maroon solids were washed with THF and the ®ltrate
was combined with the crude product. The THF was
removed in vacuo to give the crude product as a maroon
solid. The crude product was puri®ed by ¯ash chroma-
tography with Hex:EtOAc (3:1) as eluant to give 0.27 g
(37%) of the title compound as a dark maroon solid.
Melting point 232.5±235.5 ꢀC. 1H NMR (DMSO-d6;
500 MHz) d 7.34 (tm, 1, J=7.7), 7.48 (d, 1, J=8.2), 7.81
(tm, 1, J=7.7), 8.23 (dd, 1, J=1.4, 8.4), 13.89 (br s, 1);
13C NMR (DMSO-d6; 125 MHz) d 120.15, 126.23,
126.70, 127.32, 137.75, 137.89, 187.20, 214.05. Anal.
calcd for C8H5NS3: C, 45.47; H, 2.38; N, 6.63. Found:
C, 45.60; H, 2.42; N, 6.53.
1-(2-Aminophenyl)-6-(4-(1,2-benzisothiazol-3-yl)-1-piper-
azinyl)-1-hexanone hydrochloride (10). To a 250 mL,
round-bottomed ¯ask were added tert-butyl-N-(2-(6-
chlorovaleryl)phenyl)carbamate (9) (2.92 g, 8.96 mmol),
3-(1-piperazinyl)-1,2-benzisothiazole (1.94 g, 8.85 mmol,
1.0 equiv.), triethylamine (2.0 mL, 1.45 g, 14.35 mmol,
1.6 equiv.), and CH3CN (50 mL). The ¯ask was equip-
ped with a magnetic stirring bar, re¯ux condenser and
nitrogen inlet and the reaction mixture was heated at
re¯ux. After 42 h the reaction mixture was concentrated
to give a beige solid. Dichloromethane (30 mL), anisole
(7.0 mL), and tri¯uoroacetic acid (30 mL) were added to
the solid and the orange solution was stirred under a
nitrogen atmosphere at room temperature for 1 h. The
reaction mixture was concentrated and the resulting
orange liquid was partitioned between saturated K2CO3
and EtOAc. The layers were separated and the organic
layer was washed with saturated K2CO3. The aqueous
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-
butyl)thiobenzamide hydrochloride (13). 1H-Benzo[d]
[1,3]thiazine-2,4-dithione (12) (2.9 g, 13.7 mmol) was
dissolved in anhydrous THF (40 mL) in a 1 L round-
bottomed ¯ask. The ¯ask was equipped with a magnetic
stirring bar, rubber septum, and nitrogen inlet. To the

F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
819
red±orange solution was slowly added a solution of 3-(4-
(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (4.2 g,
14.4 mmol, 1.05 equiv) in anhydrous THF (35 mL) via
syringe. The reaction mixture was stirred under nitrogen
at room temperature for 15 min. Thin-layer chromato-
graphy (CH2Cl2:MeOH, 95:5) indicated that the reac-
tion was incomplete. Another 0.25 equiv. of 3-(4-(4-
cool to room temperature. Ethyl acetate was added to
the reaction mixture and the solution was washed with
saturated aqueous K2CO3. The organic layer was dried
over MgSO4, ®ltered, and concentrated to give the crude
product as an orange liquid. The crude product was
puri®ed by ¯ash chromatography with Hex:EtOAc (1:1)
as eluant to give 1.65 g (70%) of the title compound as a
yellow oil. 1H NMR (CDCl3; 500 MHz) d 1.27 (t, 3,
J=7.2), 1.88 (quin, 2, J=7.3), 2.38 (t, 2, J=7.3), 2.47 (t,
2, J=7.1), 2.68 (m, 4), 3.56 (m, 4), 4.15 (q, 2, J=7.2),
7.35 (t, 1, J=7.5), 7.46 (t, 1, J=7.5), 7.81 (d, 1, J=8.1),
7.91 (d, 1, J=8.2); 13C NMR (CDCl3; 125 MHz) d
14.21, 22.09, 32.21, 50.04, 52.91, 57.68, 60.22, 120.48,
123.77, 123.86, 127.42, 128.01, 152.71, 163.88, 173.48.
Anal. calcd for C17H23N3O2S: C, 61.23; H, 6.95; N,
12.60. Found: C, 61.25; H, 6.97; N, 12.60.
aminobutyl)-1-piperazinyl)-1,2-benzisothiazole
(1.0 g,
3.45 mmol) in anhydrous THF (10 mL) was slowly
added to the orange suspension via syringe. After stir-
ring at room temperature for 15 min, the reaction mix-
ture was ®ltered and the ®ltrate was concentrated to give
7.6 g of the crude product as a viscous red±orange resi-
due. The crude product was combined with 0.62 g of
crude product obtained in an earlier reaction and the
combined material was partially puri®ed by ¯ash chro-
matography with CH2Cl2:MeOH (97:3) as eluant to give
1
1.0 g of an orange oil. H NMR and thin-layer chroma-
4-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyric acid
(16). To a 300 mL, round-bottomed ¯ask was added 4-
tography (CH2Cl2:MeOH, 95:5) indicated that impu-
rities remained in the product. A second attempt to
purify the free base by ¯ash chromatography with
CH2Cl2:MeOH (97:3) as eluant failed to remove the
impurities as indicated by 1H NMR. The desired free
base was ®nally puri®ed by radial chromatography
using CH2Cl2 followed by CH2Cl2:MeOH (99:1) and
®nally CH2Cl2:MeOH (97:3) as eluant to give 0.718 g of
the desired material as a yellow oil. The amine was dis-
solved in EtOAc and 1.69 mL of 1.0 N ethereal HCl
(1.0 equiv.) was added. The hydrochloride salt was ®l-
tered, washed with EtOAc and Et2O, and recrystallized
from EtOH to give 0.23 g of the title compound as a
yellow solid. Melting point 198±201 ꢀC. 1H NMR
(DMSO-d6; 200 MHz) d 1.78 (m, 4), 3.05±3.80 (m, 10),
4.10 (br d, 2, J=12.7), 5.74 (br s, 2), 6.59 (t, 1, J=7.5),
6.74 (d, 1, J=8.0), 7.08 (m, 2), 7.50 (t, 1, J=7.7), 7.63 (t,
1, J=7.6), 8.15 (t, 2, J=7.2), 10.30 (m, 1), 10.83 (m, 1);
13C NMR (DMSO-d6; 75.43 MHz) d 21.74, 25.35, 45.37,
47.32, 51.43, 56.10, 118.56, 118.78, 122.18, 124.98,
125.59, 127.93, 128.49, 129.11, 129.37, 130.98, 143.37,
153.08, 163.20, 197.17. MS (CI/CH4, 50 mA/s) M+1,
(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyric
acid
ethyl ester (15) (3.34 g, 10.0 mmol), 0.1 N aqueous
NaOH (40 mL) and EtOH (1.5 mL). The ¯ask was
equipped with a magnetic stir bar and re¯ux condenser
and the reaction mixture was heated at re¯ux for 1.5 h.
The reaction mixture was cooled in an ice-water bath
and the pH was adjusted to ꢁ6±7 via the addition of
1.0 N aqueous HCl. The reaction mixture was extracted
with CH2Cl2. The organic layer was dried over MgSO4,
®ltered and the ®ltrate was concentrated to give 0.88 g of
the product as an oil which solidi®ed to a white solid
(1H NMR data shown below). White solids were ®ltered
from the aqueous phase and dried to give 1.82 g of a
second crop of the carboxylic acid. The aqueous ®ltrate
was partially concentrated in vacuo and the white solids
were ®ltered, washed with water, and dried to give a
third crop of the desired material (0.40 g) for a total
yield of 3.1 g (100%). This material was used without
1
further puri®cation. H NMR (DMSO-d6; 200 MHz) d
1.72 (m, 2), 2.29 (t, 2, J=7.2), 2.40 (t, 2, J=7.0), 2.61
(br t, 4, J=4.6), 3.45 (br t, 4, J=4.5), 7.45 (tm, 1,
J=7.4), 7.54 (tm, 1, J=8.01), 8.07 (d, 2, J=8.2).
.
base (426). Anal. calcd for C22H27N5S2 HCl: C, 57.19;
H, 6.11; N, 15.16. Found: C, 56.95; H, 6.17; N, 14.98.
N-(2-Aminobenzyl)-4-(4-(1,2-benzothiazol-3-yl)-1-piper-
azinyl) butyramide fumarate (17). To a 1-L, round-bot-
tomed ¯ask were added 4-(4-benzo[d]isothiazol-3-yl-
piperazin-1-yl)-butyric acid (16) (1.38 g, 4.52 mmol), 2-
aminobenzylamine (0.65 g, 5.32 mmol, 1.18 equiv.), 1-
hydroxybenzotriazole hydrate (0.61 g, 4.51 mmol,
1.0 equiv), and DMF (25 mL). The ¯ask was equipped
with a magnetic stirring bar and an addition funnel.
4-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyric acid
ethyl ester (15). To a 250 mL, round-bottomed ¯ask
were added 3-(1-piperazinyl)-1,2-benzisothiazole (1.54 g,
7.02 mmol), triethylamine (1.50 mL, 1.09 g, 10.8 mmol,
1.53 equiv) and CH3CN (30 mL). The ¯ask was equip-
ped with a magnetic stirring bar, addition funnel and
nitrogen inlet and a solution of ethyl-4-bromobutyrate
(1.44 g, 7.4 mmol, 1.05 equiv) in CH3CN (10 mL) was
slowly added dropwise to the stirred reaction mixture at
room temperature. The addition funnel was replaced
with a re¯ux condenser and the reaction mixture was
heated at re¯ux under N2. After 6 h, the oil bath was
removed and the gold±yellow solution was allowed to
A
solution of 1,3-dicyclohexylcarbodiimide (1.2 g,
5.82 mmol, 1.29 equiv.) in DMF (15 mL) was added
dropwise to the stirred reaction mixture. Additional
portions of 1-hydroxybenzotriazole hydrate (0.12 g,
0.89 mmol, 0.2 equiv.) and DMF (10 mL) were added to
the reaction mixture which was allowed to stir at room

820
F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
temperature for 3 days. Ethyl acetate was added to the
reaction mixture and the organics were washed with
saturated aqueous K2CO3. The layers were separated
and the aqueous phase was extracted with EtOAc. The
organic layers were combined, dried over MgSO4, ®l-
tered, and concentrated to give the crude product as a
pale orange oil. The crude material was puri®ed by ¯ash
chromatography with CH2Cl2:MeOH (95:5) as eluant to
give 1.56 g of the free base as an orange oil. The free
base (0.48 g, 1.2 mmol) was dissolved in EtOH and
CH2Cl2 and fumaric acid (0.14 g, 1.2 mmol, 1.0 equiv.)
was added. The solution was ®ltered and the ®ltrate was
concentrated to give a pale-yellow oil. Ethyl acetate was
added to the oil and crystallization was initiated via
scraping the wall of the ¯ask with a spatula. The sus-
pension was heated and the product was ®ltered as an
o€-white solid. The solid was dried to give 0.349 g
(63%) of the desired product. Melting point 135±136 ꢀC.
1H NMR (DMSO-d6; 300 MHz) d 1.73 (quin, 2, J=7.0),
2.19 (t, 2, J=7.3), 2.36 (t, 2, J=7.1), 2.58 (m, 4), 3.44
(m, 4), 4.12 (br d, 2, J=6.1), 6.49 (dt, 1, J=1.0, 7.3),
6.61 (m, 2), 6.96 (m, 2), 7.44 (ddd, 1, J=1.1, 7.0, 8.1),
7.56 (ddd, 1, J=1.2, 7.0, 8.1), 8.05 (d, 1, J=8.2), 8.06
(d, 1, J=8.2), 8.23 (br t, 1, J=6.0); 13C NMR (DMSO-
d6; 75.43 MHz) d 23.23, 34.04, 40.13, 50.43, 53.27, 58.03,
115.45, 116.58, 122.02, 123.14, 125.09, 125.34, 128.28,
128.80, 130.13, 135.29, 147.20, 152.93, 164.43, 167.48,
EtOAc (2:1):0.1% Et3N, Hex:EtOAc (1:1):0.1% Et3N,
EtOAc:0.1% Et3N and EtOAc:0.2% Et3N as eluant)
obtained in an earlier reaction to give a total of 0.9 g
of impure amine. Approximately 0.4 g of this material
was applied to
a chromatotron and eluted with
CH2Cl2:MeOH (97:3) to give 0.14 g of the desired
compound. The pure free base was dissolved in
EtOAc and 0.35 mL of 1 N ethereal HCl (1.0 equiv.)
was added. The resulting white solid was ®ltered and
dried in a vacuum oven to give 0.116 g of the desired
hydrochloride salt. The impure fractions from the
chromatotron run were combined with the remaining
partially puri®ed amine and the material was puri®ed
by ¯ash chromatography with CHCl3:MeOH (9:1) as
eluant. The free base (0.21 g) was dissolved in EtOAc
and CH2Cl2 and 0.53 mL of 1 N ethereal HCl
(1.0 equiv.) was added. The second crop of the desired
hydrochloride salt was ®ltered as a white solid and
dried in a vacuum oven to give another 0.19 g. The
two crops of the hydrochloride salt were combined
and dried further in a vacuum oven to give a ®nal yield
of 0.24 g (5.4%). Melting point 177±181 ꢀC. 1H NMR
(DMSO-d6; 300 MHz) d 2.10 (m, 2), 3.25 (m, 2), 3.25±
3.90 (m, 8), 4.05 (m, 2), 4.70±5.90 (br s, 2), 6.54 (t, 1,
J=7.1), 6.73 (d, 1, J=8.0), 6.90 (t, 1, J=7.0), 7.21 (d, 1,
J=7.9), 7.47 (t, 1, J=7.5), 7.60 (t, 1, J=7.5), 8.12 (t, 2,
J=9.0), 9.38 (s, 1); 13C NMR (DMSO-d6; 75.43 MHz) d
19.47, 32.54, 46.55, 50.65, 55.28, 115.87, 116.14, 121.24,
123.33, 124.05, 124.67, 125.43, 125.82, 127.01, 128.17,
141.80, 152.15, 162.28, 169.99. Anal. calcd for
.
173.24. Anal. calcd for C22H27N5OS 0.5 C4H4O4: C,
61.65; H, 6.25; N, 14.98. Found: C, 61.58; H, 6.30; N,
14.89.
.
C21H25N5OS HCl: C, 58.39; H, 6.07; N, 16.21. Found:
C, 58.12; H, 6.04; N, 16.12.
20-Amino-4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyr-
anilide hydrochloride (18). To a ¯ame-dried 100 mL,
three-necked round-bottomed ¯ask equipped with a
magnetic stirring bar, rubber septum, thermometer, and
nitrogen inlet was added 4-(4-benzo[d]isothiazol-3-yl-
piperazin-1-yl)-butyric acid (16) (2.70 g, 8.84 mmol),
Et3N (2.59 mL, 1.88 g, 18.6 mmol, 2.1 equiv.) and THF
(35 mL). The suspension was cooled to 15 ꢀC with an
isopropyl alcohol/CO2 bath and isobutylchloroformate
(1.15 mL, 1.21 g, 8.84 mmol, 1.0 equiv.) was added while
maintaining the temperature at 15 ꢀC. After 10 min, a
solution of o-phenylenediamine (1.05 g, 9.72 mmol,
1.1 equiv.) in THF (20 mL) was added to the cold reac-
tion mixture. The isopropyl alcohol/CO2 bath was
removed and the reaction mixture was allowed to stir at
room temperature for 1 h. The solvent was removed in
vacuo and the crude product was partitioned between
EtOAc and saturated aqueous K2CO3. The organic
phase was dried over MgSO4, ®ltered, and the ®ltrate
was concentrated to give an oil. The free base was
partially puri®ed by ¯ash chromatography with
EtOAc:0.1% Et3N, EtOAc:0.2% Et3N, EtOAc:0.4%
Et3N and ®nally MeOH as eluant. The impure material
obtained from this column was combined with 0.1 g of
partially puri®ed free base (¯ash chromatography Hex:-
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)
butyl)benzenesulfonamide hydrochloride (21). To
a
100 mL, ¯ame-dried, three-necked, round-bottomed
¯ask equipped with a magnetic stirring bar, rubber sep-
tum, glass stopper and nitrogen inlet was added sodium
hydride (80% dispersion in oil) (0.139 g, 4.62 mmol).
The sodium hydride was washed three times with hex-
anes. The waste hexanes were removed with the aid of a
2 mL pasteur pipet. Anhydrous DMF (10 mL) was
added to the sodium hydride and the grey suspension
was cooled under nitrogen in an ice-water bath. A solu-
tion of 2-aminobenzene sulfonamide (19) (0.73 g,
4.20 mmol) in anhydrous DMF (5.0 mL) was slowly
added to the cold NaH suspension via syringe. After
several minutes, a solution of 8-(1,2-benzisothiazol-3-
yl)-8-aza-5-azoniaspiro[4.5]decane bromide22 (20) (1.5 g,
4.2 mmol) in anhydrous DMF (12 mL) was added to the
sulfonamide salt and the reaction mixture was allowed
to stir at 0 ꢀC under N2. After 0.5 h, the ice-water bath
was replaced with an oil bath and the reaction mixture
was heated at re¯ux under N2. After 18 h, the oil bath
was removed and the reaction mixture was allowed to
cool to room temperature. The reaction mixture was

F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
821
concentrated and the residue was partitioned between
H2O and EtOAc. The organic layer was dried over
MgSO4, ®ltered, and concentrated to give an orange oil.
The crude free base was puri®ed by ¯ash chromato-
graphy with EtOAc:Hex (1:1): 0.1% Et3N followed by
EtOAc:Hex (2:1): 0.1% Et3N as eluant to give 0.645 g of
the free base as an oil. The free base was dissolved in
EtOAc and 1.45 mL of 1 N ethereal HCl (1.0 equiv.) was
added. The hydrochloride salt was recrystallized from
EtOH and H2O to give 0.412 g (20%) of the title com-
pound as an o€-white solid. Melting point 214±216 ꢀC.
1H NMR (DMSO-d6; 200 MHz) d 1.46 (m, 2), 1.75 (m,
2), 2.80 (m, 2), 3.00±3.65 (m, 8), 4.09 (br d, 2, J=13.1),
5.97 (br s, 2), 6.65 (ddd, 1, J=1.2, 7.1, 8.1), 6.86 (dd, 1,
J=1.2, 8.2), 7.30 (ddd, 1, J=1.6, 7.1, 8.5), 7.60 (m, 4),
1.0 equiv.), N,N-diisopropylethylamine (2.0 mL, 1.48 g,
11.5 mmol, 1.25 equiv.), and CH3CN (100 mL). The
¯ask was equipped with a magnetic stirring bar, re¯ux
condenser, and nitrogen inlet and the reaction mixture
was heated at re¯ux under a N2 atmosphere. After 4 h,
the oil bath was removed and the reaction mixture was
allowed to stand at room temperature overnight. Ethyl
acetate and saturated aqueous NaHCO3 were added to
the ¯ask and the mixture was transferred to a separa-
tory funnel. The organic layer was separated and the
aqueous layer was extracted with EtOAc. The organic
layers were combined and concentrated in vacuo to
give an orange oil. The crude product was puri®ed by
¯ash chromatography with CH2Cl2:MeOH (98:2) as
eluant to give 3.27 g of the free base. The free base was
dissolved in EtOAc and 7.43 mL of 1 N ethereal HCl
(1.0 equiv.) was added. The solvent was removed in
vacuo and the salt was recrystallized from EtOH to give
2.2 g (51%) of the title compound as a white solid.
Melting point 196±200 ꢀC. 1H NMR (DMSO-d6;
300 MHz) d 1.49 (d, 1, J=8.7), 1.57 (d, 1, J=8.7), 2.07
(m, 2), 3.29 (m, 8), 3.52 (m, 4), 4.01 (m, 4), 6.14 (s, 2),
7.46 (t, 1, J=7.5), 7.58 (t, 1, J=7.7), 8.11 (t, 2, J=8.3),
11.33 (br s, 1); 13C NMR (DMSO-d6; 75.43 MHz) d
22.64, 42.55, 44.43, 46.74, 51.00, 51.30, 53.14, 74.19,
121.55, 124.37, 124.97, 127.32, 128.47, 134.89, 152.45,
8.14 (d, 1, J=7.9), 8.17 (d, 1, J=7.4), 10.95 (br s, 1); 13
C
NMR (DMSO-d6; 50.29 MHz) d 20.46, 26.33, 41.66,
46.56, 50.63, 55.20, 115.45, 117.22, 120.19, 121.53,
124.34, 124.97, 127.31 128.47, 129.38, 133.78, 145.56,
.
152.49, 162.59. Anal. calcd for C21H27N5S2O2 HCl: C,
52.32; H, 5.85; N, 14.53. Found: C, 52.42; H, 5.87;
N, 14.51.
4-(3-Bromo-propoxy)-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-
3,5-dione (23). endo-N-Hydroxy-5-norborene-2,3-dicar-
boxamide (22) (9.8 g, 54.7 mmol) and CH3CN (200 mL)
were combined in a 1 L round-bottomed ¯ask. To the
stirred suspension was added dropwise 1,3-dibromo-
propane (17.0 mL, 167.5 mmol, 3.06 equiv.) followed by
the dropwise addition of N,N-diisopropylethylamine
(19.5 mL, 111.9 mmol, 2.04 equiv). The ¯ask was equip-
ped with a re¯ux condenser and a nitrogen inlet and the
reaction mixture was heated at 70 ꢀC under nitrogen for
5.5 h and allowed to stir at room temperature overnight.
The reaction mixture was concentrated and EtOAc was
added to the crude product. The suspension was ®ltered
and the solids were washed with EtOAc. The combined
®ltrates were concentrated to give a yellow±orange oil.
The crude bromide was puri®ed by ¯ash chromato-
graphy with Hex:EtOAc (4:1) followed by Hex:EtOAc
(3:1) as eluant to give 13.85 g (84%) of the desired pro-
duct as a white solid. Melting point 58.5±60.5 ꢀC. 1H
NMR (CDCl3; 500 MHz) d 1.50 (d, 1, J=9.1), 1.76 (dt,
1, J=9.0, 1.7), 2.16 (quin, 2, J=6.2), 3.18 (dd, 2, J=1.4,
2.8), 3.42 (s, 2), 3.58 (t, 2, J=6.4), 4.09 (t, 2, J=5.9),
6.16 (t, 2, J=1.8); 13C NMR (CDCl3; 125 MHz) d 29.16,
31.37, 42.57, 44.72, 51.37, 75.02, 134.54, 172.01. Anal.
calcd for C12H14NO3Br: C, 48.02; H, 4.70; N, 4.67.
Found: C, 48.15; H, 4.67; N, 4.69.
.
162.56, 172.62. Anal. calcd for C23H26N4O3S HCl: C,
58.16; H, 5.73; N, 11.79. Found: C, 58.19; H, 5.75; N,
11.75.
O-[3-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-propyl]-
hydroxylamine (25). To a 100 mL, round-bottomed ¯ask
were added the free base of 2-(3-(4-(1,2-benzisothiazol-
3-yl)-1-piperazinyl)propoxy-2,3,3A,4,7,7A-hexahydro-
4,7-methano-1H-isoindoline-1,3-dione (24) (2.49 g,
5.68 mmol), hydrazine hydrate (55% aq solution, 0.38 g,
6.45 mmol, 1.14 equiv.), and EtOH (95%, 10 mL). The
¯ask was equipped with a magnetic stirring bar, re¯ux
condenser and nitrogen inlet and the yellow solution
was heated at re¯ux. After 0.75 h, the oil bath was
removed and the reaction mixture was concentrated in
vacuo. The crude product was partitioned between
EtOAc and 1 N aqueous HCl. The layers were separated
and the pH of the aqueous solution was adjusted to ꢁ12
with 1 N aqueous NaOH. The basic aqueous phase was
extracted with EtOAc. The organic layer was dried over
MgSO4, ®ltered, and concentrated to give 1.28 g (77%)
of the desired product as a yellow oil. The product was
1
used without further puri®cation. H NMR (DMSO-d6;
300 MHz) d 1.68 (quin, 2, J=7.0), 2.37 (t, 2, J=7.4),
2.56 (br t, 4, J=4.7), 3.42 (br t, 4, J=4.7), 3.55 (t, 2,
J=6.5), 5.89 (s, 2), 7.41 (t, 1, J=7.6), 7.54 (t, 1, J=7.5),
8.03 (d, 1, J=7.9), 8.04 (d, 1, J=8.4); 13C NMR
(DMSO-d6; 75.43 MHz) d 25.85, 50.04, 52.91, 55.24,
73.52, 121.39, 124.47, 124.71, 127.67, 128.17, 152.29,
163.87.
2-(3-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)propoxy-
2,3,3A,4,7,7A-hexahydro-4,7-methano-1H-isoindoline-
1,3-dione hydrochloride (24). To a 500 mL, round-bot-
tomed ¯ask was added 4-(3-bromo-propoxy)-4-aza-tri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione (23) (2.77 g, 9.23 mmol),
3-(1-piperazinyl)-1,2-benzisothiazole (2.02 g, 9.21 mmol,

822
F. Navas III et al./Bioorg. Med. Chem. 6 (1998) 811±823
2-Amino-N-(3-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)
propoxy)benzamide hydrochloride (26). To a 300 mL,
round-bottomed ¯ask were added O-[3-(4-benzo[d]iso-
thiazol-3-yl-piperazin-1-yl)-propyl]-hydroxylamine (25)
(1.27 g, 4.34 mmol), isatoic anhydride (0.75 g,
4.57 mmol, 1.05 equiv) and THF (28 mL). The orange
solution was stirred at room temperature under a nitro-
gen atmosphere for 18 h. The reaction mixture was
concentrated and the crude product was puri®ed by
¯ash chromatography with EtOAc:MeOH (95:5) as
eluant to give 1.54 g of the free base as a viscous yellow
oil. The amine was dissolved in CH2Cl2 and 3.74 mL
(1.0 equiv.) of 1 N ethereal HCl was added. The solvent
was removed in vacuo and the salt was dissolved in
MeOH (ꢁ4 mL). The methanol solution was ®ltered and
the ®ltrate was slowly added to rapidly stirred EtOAc
(75 mL). The solid was ®ltered, washed with Et2O, and
dried to give 0.79 g (40%) of the title compound as an
o€-white solid. Melting point 106±112 ꢀC (softens and
2-Amino-N0-(3-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)
propyl)benzhydrazide hydrochloride hydrate (29). 2-Amino-
benzhydrazide (0.79 g, 5.23 mmol), 3-[4-(3-chloro-
propyl)-piperazin-1-yl]-benzo[d]isothiazole (28) (1.55 g,
5.24 mmol, 1.0 equiv.) and absolute EtOH (25 mL) were
combined in a 100 mL, round-bottomed ¯ask and stir-
red at re¯ux under a N2 atmosphere. After 24 h, the oil
bath was removed and the reaction mixture was allowed
to stand at room temperature for 2 days. The solvent was
removed in vacuo and the crude product was partially
puri®ed by ¯ash chromatography with CH2Cl2:MeO-
H:Et3N, 96:3:1 as eluant. A second ¯ash chromato-
graphic separation with CH2Cl2:MeOH (98:2):0.1%
Et3N followed by CH2Cl2:MeOH (97:3):0.3% Et3N as
eluant gave 1.41 g of the free base. This material was
combined with 0.51 g of the free base obtained in an
earlier reaction (puri®ed by ¯ash chromatography with
CH2Cl2:MeOH:Et3N (96:3:1) as eluant). The combined
crops of the free base were dissolved in CH2Cl2 and the
solution was washed with saturated aqueous NaHCO3.
The organic layer was separated, dried over MgSO4,
®ltered, and the ®ltrate was concentrated to give 1.67 g
(58% yield based on the two reactions) of the desired
free base as a yellow amorphous solid. The amine was
dissolved in CH2Cl2 and 4.0 mL of 1 N ethereal HCl
(1.0 equiv.) was added to the solution. The solvent was
removed in vacuo and the salt was crystallized from
MeOH:EtOAc:Et2O to give 0.944 g (29%) of the title
compound as an o€-white solid. Melting point 83±93 ꢀC
(softens and shrinks). 1H NMR (DMSO-d6; 300 MHz) d
1.93 (m, 2), 2.91 (t, 2, J=6.0), 3.31 (t, 2, J=7.2), 3.45
(br s, 4), 3.80 (br s, 4), 6.49 (ddd, 1, J=1.2, 7.1, 8.1),
6.71 (dd, 1, J=1.2, 8.3), 7.13 (ddd, 1, J=1.6, 7.0, 8.4),
7.45 (ddd, 1, J=1.1, 7.1, 8.1), 7.51 (dd, 1, J=1.6, 7.9),
7.57 (ddd, 1, J=1.1, 7.1, 8.1), 8.00 (br s, 2), 8.08 (d, 1,
J=8.1), 8.13 (d, 1, J=7.9); 13C NMR (DMSO-d6;
75.43 MHz) d 21.73, 46.86, 49.23, 51.03, 55.14, 113.16,
115.03, 116.72, 121.52, 124.36, 124.96, 127.33, 128.34,
128.46, 132.38, 149.94, 152.46, 162.58, 168.87. MS (CI/
CH4, 50 mA/s) M+1, base (411). Anal. calcd for
1
shrinks). H NMR (DMSO-d6; 300 MHz) d 2.13 (m, 2),
3.44 (m, 6), 3.66 (br d, 2, J=10.8), 3.99 (br t, 2, J=5.2),
4.09 (br d, 2, J=13.1), 6.49 (ddd, 1, J=1.4, 7.1, 8.1),
6.71 (dd, 1, J=1.2, 8.3), 7.16 (ddd, 1, J=1.4, 7.1, 8.4),
7.38 (dd, 1, J=1.6, 7.9), 7.46 (ddd, 1, J=1.1, 6.8, 8.1),
7.58 (ddd, 1, J=1.1, 6.8, 7.9), 8.09 (d, 1, J=8.1), 8.13
(d, 1, J=8.1), 10.98 (br s, 1); 13C NMR (DMSO-d6;
75.43 MHz) d 22.58, 46.86, 51.13, 54.20, 73.76, 111.79,
115.03, 116.79, 121.56, 124.35, 124.99, 127.31, 128.18,
128.49, 132.75, 149.98, 152.47, 162.54, 167.97. Anal.
.
calcd for C21H25N5O2 HCl: C, 56.30; H, 5.85; N, 15.63.
Found: C, 56.07; H, 5.90; N, 15.45.
3-[4-(3-Chloropropyl)-piperazin-1-yl]-benzo[d]isothiazole
(28). To a 250 mL, round-bottomed ¯ask were added 3-
(1-piperazinyl)-1,2-benzisothiazole (3.0 g, 13.7 mmol), 1-
bromo-3-chloropropane (4.31 g, 27.4 mmol, 2.0 equiv.),
triethylamine (2.86 mL, 2.1 g, 25.2 mmol, 1.8 equiv.) and
CH3CN (50 mL). The reaction mixture was stirred under
a N2 atmosphere at room temperature for 21 h. The
reaction mixture was partitioned between saturated aqu-
eous NaHCO3 and CH2Cl2. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2.
The organic layers were combined, dried over MgSO4,
®ltered, and the ®ltrate was concentrated to give an
orange liquid. The crude product was puri®ed by ¯ash
chromatography with CH2Cl2 followed by CH2Cl2:
MeOH (99:1) as eluant to give 3.44 g (85%) of the title
compound as a yellow oil, which solidi®ed to a pale-yel-
.
.
C21H26N6OS HCl 0.75 H2O: C, 54.77; H, 6.24; N, 18.25;
Cl, 7.70. Found: C, 54.87; H, 6.20; N, 18.05; Cl, 7.73.
Acknowledgements
The authors wish to thank Mr Richard A. Dennis and
Mr Steve Garrett for the preparation of compounds 12
and 7, respectively.
low solid. Melting point 52±53.5 ꢀC. H NMR (CDCl3;
1
500 MHz) d 2.00 (quin, 2, J=6.8), 2.58 (t, 2, J=7.1), 2.68
(t, 4, J=4.9), 3.56 (t, 4, J=4.9), 3.64 (t, 2, J=6.5), 7.35 (t,
1, J=7.6), 7.46 (t, 1, J=7.5), 7.80 (d, 1, J=8.2), 7.90 (d,
1, J=8.2); 13C NMR (CDCl3; 125 MHz) d 29.82, 43.13,
50.02, 53.02, 55.42, 120.51, 123.82, 123.84, 127.47, 127.98,
152.70, 163.85. Anal. calcd for C14H18N3SCl: C, 56.84;
H, 6.13; N, 14.20. Found: C, 56.87; H, 6.10; N, 14.16.
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