146 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Howard et al.
physical data for the compounds are listed there. The follow-
ing compounds were prepared by literature methods: 3-benz-
isothiazolylpiperazine,6 6a -c,7 7a -c,7 5d ,14 5e,14 and 5g.15
Compounds 5d -h were converted to 7d -h by the method used
for 7a -c.7
Gen er a l Meth od for th e P r ep a r a tion of 4-Su bstitu ted
(1,2-Ben zisoth ia zol-3-yl)p ip er a zin es 8. 6-(2-(4-(1,2-Ben z-
isoth ia zol-3-yl)p ip er a zin yl)eth yl)ben zoxa zolon e (8a ). To
a solution of 1.22 g (5.02 mmol) of 6-(2-bromoethyl)benzox-
azolone and 1.10 g (5.02 mmol) of 3-(1,2-benzisothiazolyl)-
piperazine in 40 mL MIBK were added 0.53 g (5.02 mmol) of
sodium carbonate and 2 mg of sodium iodide. The mixture
was refluxed for 3 days, cooled, and evaporated. The residue
was taken up in ethyl acetate and chromatographed on silica
gel using ethyl acetate as eluent. The product fractions were
concentrated and triturated with isopropyl ether to afford a
white solid, mp 183-186 °C, 962 mg (50%). Rf ) 0.2 in ethyl
acetate. 1H-NMR (δ, DMSO-d6): 2.6-2.9 (m, 8H), 3.5 (m, 4H),
7.05 (m, 2H), 7.23 (s, 1H), 7.46 (t, 1H), 7.57 (t, 1H), 8.07 (d,
2H), 11.5 (bs, 1H). IR (cm-1, KBr): 1762 (CdO). MS (m/ e,
%): 380 (parent, 1), 232 (22), 93 (21), 81 (20), 80 (26), 78 (100),
65 (39), 63 (67), 61 (47). Anal. (C20H20N4O2S‚1/2 H2O) C, H,
N.
F igu r e 2. Effect of 8e on 5-HT2 receptor-stimulated phos-
phatidylinositol turnover in rat brain cerebral cortical slices.
Each point is the mean inhibition of the 5-HT (100 mM)-
induced effect and represents the mean of 3-5 data points (
SEM derived from separate experiments each performed in
triplicate.
5-(2-(4-(1,2-Ben zisoth ia zol-3-yl)p ip er a zin yl)eth yl)-1,3-
d ih yd r o-2(1H)-in d ol-2-on e (8b): prepared in 59% yield as
the hydrochloride salt, mp 288-288.5 °C. 1H-NMR (δ, DMSO-
d6): 3.1 (m, 2H), 3.4 (m, 4H), 3.51 (s, 2H), 3.5-3.8 (m, 4H),
4.1 (m, 2H), 6.81 (d, 1H), 7.1-7.2 (m, 2H), 7.49 (t, 1H), 7.62 (t,
1H), 8.14 (t, 2H). 13C-NMR (δ, DMSO-d6): 176.3, 162.2, 152.2,
142.5, 129.6, 128.2, 127.7, 127.0, 126.3, 124.9, 124.7, 124.1,
121.3, 19.2, 56.6, 50.5, 46.6, 35.8, 29.0. IR (cm-1, KBr): 1697
(CdO). MS (m/ e, %): 378 (parent, 1), 233 (14), 232 (100), 177
(16), 91 (11), 56 (11). Anal. (C21H22N4OS‚1.25HCl) C, H, N.
6-(4-(2-(1,2-Ben zisoth ia zol-3-yl)p ip er a zin yl)eth yl)ben -
zoth ia zolon e (8c): prepared in 77% yield as the hydrochlo-
ride hydrate, mp 288-290 °C. 1H-NMR (δ, DMSO-d6): 3.1-
3.7 (m, 10H), 4.1 (m, 2H), 7.0-8.1 (m, 7H). IR (cm-1, KBr):
1680 (CdO). MS (m/ e, %): 396 (parent, 1), 233 (16), 232 (100),
177 (19), 98 (4), 97 (4), 56 (7). Anal. (C20H20N4OS2‚HCl‚H2O)
C, H, N.
Ta ble 3. Physical Properties of 3-Benzisothiazolylpiperazine
Derivatives
compd yield, %
mp, °C
formula
8a
8b
8c
8d
8e
8f
50
59
77
19
20
25
40
50
185-187
288-288.5
288-290
291-293
C20H20N4O2S‚0.5H2O
C
C
C
C
C
21H22N4OS‚1.25HCl
20H20N4OS2‚HCl‚H2O
21H21FN4OS‚HCl‚H2O
21H21CIN4OH‚HCl‚0.5H2O
23H26N4OS‚HCl‚CH2Cl2
>300
278-279
8g
8h
289-291
C23H26N4OS‚HCl‚0.5H2O
291-293 dec
C
25H28N4OS‚HCl‚0.5H2O
locomotor activity. In particular, compound 8e opti-
mizes these properties and has modest R1 receptor
affinity and a minimal tendency to block spontaneous
locomotor activity, indicating a reduced propensity to
cause hypotension and sedation in the clinic, respec-
tively. The in vitro profile of 8e is thus a combination
of D2 receptor affinity comparable to the typical anti-
psychotic agent haloperidol and a 5-HT2A/D2 ratio
comparable to the atypical agent clozapine. The ulti-
mate confirmation of the hypothesis that this in vitro
profile combined with its favorable in vivo activity will
result in an effective antipsychotic with low EPS li-
ability awaits the outcome of clinical evaluation of 8e.
5-(2-(4-(1,2-Ben zisot h ia zol-3-yl)p ip er a zin yl)et h yl)-6-
flu or o-1,3-d ih yd r o-2(1H)-in d ol-2-on e (8d ): prepared in
19% yield as the hydrochloride hydrate, mp 291-293 °C. 1H-
NMR (δ, CD3
OD): 3.15 (m, 2H), 3.4-3.6 (m, 8H), 3.80 (m, 2H),
4.20 (d, 2H), 6.7 (d, 1H), 7.22 (d, 1H), 7.47 (t, 1H), 7.57 (t, 1H),
7.95 (d, 1H), 8.05 (d, 1H). MS (m/ e, %): 396 (M+, 1), 232 (100),
177 (53), 91. Anal. (C21H21FN4OS‚HCl‚H2O) C, H, N.
5-(2-(4-(1,2-Ben zisot h ia zol-3-yl)p ip er a zin yl)et h yl)-6-
ch lor o-1,3-d ih yd r o-2(1H)-in d ol-2-on e (8e): prepared in 20%
yield using isoamyl alcohol instead of MIBK as the hydrochlo-
ride hemihydrate, mp >300 °C. 1H-NMR (δ, DMSO-d6): 3.15-
3.60 (m, 10H), 3.72 (d, 2H), 4.10 (d, 2H), 6.88 (s, 1H), 7.28 (s,
1H), 7.48 (t, 1H), 7.60 (t, 1H), 8.14 (dd, 2H), 10.6 (s, 1H), 11.4
(bs, 1H). MS (m/ e, %): 412 (M+, 0.4), 233 (18), 232 (100), 177
(19). IR (KBr, cm-1) 1708, 1628, 1489. Anal. (C21H21ClN4-
OS‚HCl‚1/2H2O) C, H, N.
Exp er im en ta l Section
Melting points were obtained on a Hoover melting point
apparatus and are uncorrected. NMR spectra were obtained
on a Varian XL-300 or Bruker AM-300 spectrometer, with
tetramethylsilane as internal standard. IR spectra were
obtained on Perkin-Elmer 283B and 1420 spectrometers.
Mass spectra were obtained on a Finnegan 4510 mass spec-
trometer, and high-resolution mass spectra were obtained on
an AE-9 instrument. TLC analysis was carried out on EM
Kieselgel 60 F254 5 × 20 cm plates. Elemental analyses were
carried out by the Analytical Laboratory of Pfizer Central
Research and are within (0.4% of theory unless otherwise
noted. Radioisotopic ligands were purchased from New Eng-
land Nuclear, Boston, MA, or Amersham, Arlington Heights,
IL. Apomorphine hydrochloride and d-amphetamine were
purchased from Research Biochemicals Inc. (Natick, MA).
Risperidone was a gift of J anssen, Inc., tiospirone was a gift
of Bristol-Myers Squibb, Inc., and clozapine was a gift of
Sandoz, Inc. Other reagents were obtained from Sigma
Chemical Co. (St. Louis, MO).
5-(2-(4-(1,2-Ben zisot h ia zol-3-yl)p ip er a zin yl)et h yl)-1-
eth yl-1,3-d ih yd r o-2(1H)-in d ol-2-on e (8f): prepared in 25%
yield as the hydrochloride salt, mp 278-279 °C. 1H-NMR (δ,
CD3OD): 1.25 (t, 3H), 3.18 (m, 2H), 3.50 (m, 8H), 3.75 (m, 4H),
4.20 (d, 2H), 5.24 (s, 2H, CH2Cl2 - one mole), 7.0 (d, 1H), 7.30
(s+d, 2H), 7.48 (t, 1H), 7.55 (t, 1H), 7.98 (d, 1H), 8.08 (d, 1H).
MS (m/ e, %): 406 (M+, 1), 232 (100), 177, 163. Anal.
(C23H26N4OS‚HCl‚CH2Cl2) C, H, N.
5-(2-(4-(1,2-Ben zisoth ia zol-3-yl)p ip er a zin yl)eth yl)-3,3-
d im eth yl-1,3-d ih yd r o-2(1H)-in d ol-2-on e (8g): prepared in
40% yield as the hydrochloride hemihydrate, mp 289-291 °C.
1H-NMR (δ, CD3OD): 1.35 (s, 6H), 3.10 (m, 2H), 3.4-3.6 (m,
10H), 6.92 (d, 1H), 7.15 (d, 1H), 7.22 (s, 1H), 7.45 (t, 1H), 7.55
(t, 1H), 7.95 (d, 1H), 8.05 (d, 1H). MS (m/ e, %): 406 (M+, 1),
324, 232 (100), 177, 146. Anal. (C23H26N4OS‚HCl‚1/2H2O) C,
H, N.
5′-(2-(4-(1,2-Ben zoisot h ia zol-3-yl)p ip er a zin yl)et h yl)-
3,3-sp ir ocyclop e n t a n e -1,3-d ih yd r o-2(1H )-in d ol-2-on e
(8h ): prepared in 50% yield as the hydrochloride hemihydrate,
mp 291-293 °C. 1H-NMR (δ, CDCl3): 1.6-2.1 (m, 8H), 3.0-
Syn th eses. The examples presented below illustrate the
method for preparation of the compounds listed in Table 3;