Structure-activity relationship studies of SYA 013, a homopiperazine analog of haloperidol

Article abstract of DOI:10.1016/j.bmc.2012.01.022

Structure-activity relationship studies on 4-(4-(4-chlorophenyl)-1,4- diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes. Further exploration, using bioisosteric replacement strategies has led to the identification of several new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration as new antipsychotic agents. In addition, compound 18, a D₃ selective tropanol, has been identified as having the potential for further optimization into a useful drug which may combat neuropsychiatric diseases.

Full text of DOI:10.1016/j.bmc.2012.01.022

Bioorganic & Medicinal Chemistry 20 (2012) 1671–1678
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Structure–activity relationship studies of SYA 013, a homopiperazine analog
of haloperidol
Kwakye Peprah a, Xue Y. Zhu a, Suresh V.K. Eyunni a, Jagan R. Etukala a, Vincent Setola b, Bryan L. Roth b,
Seth Y. Ablordeppey a,
⇑
a Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA
b Department of Pharmacology, Medicinal Chemistry and Psychiatry, University of North Carolina at Chapel Hill, School of Medicine, NC 27599, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure–activity relationship studies on 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)
butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of
the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes.
Further exploration, using bioisosteric replacement strategies has led to the identification of several
new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration
as new antipsychotic agents. In addition, compound 18, a D3 selective tropanol, has been identified as
having the potential for further optimization into a useful drug which may combat neuropsychiatric
diseases.
Received 25 November 2011
Revised 2 January 2012
Accepted 11 January 2012
Available online 21 January 2012
Keywords:
Antipsychotics
Haloperidol analogs
Structure–activity relationship studies
Atypical antipsychotics
Homopiperazine
Published by Elsevier Ltd.
Benzothiazole
1. Introduction
haloperidol or the weight gain associated with several atypical
antipsychotics.8–10
There is considerable interest in the development of new anti-
psychotic drugs partially because of the side effects associated
with both typical and atypical antipsychotic drugs currently on
the market.1 Atypical antipsychotics were developed to replace
typical antipsychotics partially because of the debilitating extrapy-
ramidal side effects. One of the problems in the development of
new drugs is the fact that new structural classes of drugs often lead
to new types of off-target interactions or side effects when the gen-
eral population is exposed to the drug. Thus, we hypothesized that
there may be advantages in using known drug scaffolds as leads in
drug design while attempts are made to eliminate off-target inter-
actions. In this regard, we have focused on the typical antipsy-
chotic drug, haloperidol, taking advantage of the fact that
haloperidol binds to several receptors of interest in antipsychotic
O
OH
F
C (CH2)3
N
Cl
Haloperidol (1)
O
F
C (CH2)3
N
N
Cl
SYA 013 (2)
SYA 013 or 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluo-
rophenyl)butan-1-one is a haloperidol analog with the piperidinol
moiety replaced with a homopiperazine. It binds to the DAD2
receptor (Ki = 43.3 nM), DAD3 (Ki = 158.8 nM), DAD4 (Ki = 6.6 nM),
5HT1A (Ki = 117.4 nM) and 5HT2A (Ki = 23.3 nM) receptor. On the
other hand, it has only moderate to weak binding at the 5HT2C
receptor (Ki = 1425 nM) and Histamine H1 receptor (Ki = 189 nM).
This combination of binding affinities inspired in vivo studies that
identified SYA 013 as having atypical antipsychotic properties
without the associated catalepsy even at five times the ED50 dose.7
In addition, the low binding affinity to 5HT2C and H1 receptors
compared with clozapine for example, predicts that SYA 013 may
not induce weight gain. The current study probes the SYA 013
drug
development
(D2Ki = 0.89 nM,
5HT1A = 3600 nM;
5HT2A = 120 nM; 5HT2C = 4700 nM) and thus modifications can be
made either to enhance or diminish binding at given receptors.2–
6
In pursuit of this strategy, we have identified several agents2–6
including a homopiperazine analog of haloperidol, SYA 013 (2),7
with a pharmacological profile similar to those of current atypical
antipsychotics but potentially without the EPS associated with
⇑
Corresponding author. Tel.: +1 850 599 3867; fax: +1 850 599 3934.
E-mail address: seth.ablordeppey@famu.edu (S.Y. Ablordeppey).
0968-0896/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmc.2012.01.022

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K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
scaffold using bioisosteric replacements to design, synthesize, and
conduct structure–activity relationships that may serve as a foun-
dation for new lead compounds active at CNS receptors associated
with neuropsychiatric drug development. In particular, it is desir-
able to obtain compounds that meet the following criteria7: com-
pounds should bind with moderate affinity at the D2 receptor
(30 nM < Ki < 150 nM), as avid affinity to this receptor may lead
to induction of acute EPS; and a weak or no binding affinity to
5HT2C and histamine H1 receptors, as both receptors are reported
to be associated with weight gain and subsequently type II diabe-
tes, often observed with some of the atypical antipsychotics.
O
Cl
Cl
a
F
F
20
21
Scheme 1. Reagents and conditions: (a) Zn, HgCl2, Conc HCl, toluene, reflux, 5 h.
anhydride at 105 °C for 18 h. The yield was 20–26%. Nazarov related
cyclization11 was carried out in concentrated H2SO4 at 60 °C to yield
indanone 41 in quantitative yield. Protection of the ketone with eth-
ylene glycol afforded compound 42.
2. Chemistry
1-(4-Chlorophenyl)-1, 4-diazepane 43 was synthesized7 accord-
ing to our previous published method involving the coupling of
homopiperazine with 4-iodochlorobenzene in the presence of
CuI. 3-(4-Chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol 44 was pre-
pared as previously published by us.6
Compounds2, 3, 4, 5, 6 (Chart 1), analogs of haloperidol 1, were
reported in previous papers from this lab.6,7 including the synthetic
details as well as important intermediates. Alkylating agent 1-(4-
chlorobutyl)-4-fluorobenzene 21 was prepared by reductive deox-
ygenation of 4-chloro-1-(4-fluorophenyl)butan-1-one 20 using
Clemmensen’s reaction (Scheme 1). Refluxing a mixture of 20
and amalgamated zinc in aqueous acidic toluene for 5 h, afforded
21 after distillation.
Alkylating agents 26 and 27 were prepared from 4-fluorophenol
22 and 4-fluorobenzenethiol 23 (Scheme 2). By refluxing the mix-
ture of 4-fluorophenol 22, 3-chloropropanol, K2CO3, and KI in iPrOH,
3-(4-fluorophenoxy)propan-1-ol 24, was obtained. Methanesulfo-
nation was carried out at room temperature with Et3N as a base
afforded 3-(4-fluorophenoxy)propyl methanesulfonate 26. The
same procedure was used to prepare 3-((4-fluorophenyl)thio)pro-
pyl methanesulfonate 27.
By coupling the alkylating agents 21, 26, 27, 32, 33, 34, 38, 39
and 42 with 1-(4-chlorophenyl)-1,4-diazepane 43, homopiperazine
derived analogs 9–17 (Chart 2) were synthesized as shown in
Scheme 6. By coupling the alkylating agents 21, 26, 34, and 39 with
3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol 44, compounds
7, 8, 18 and 19 were obtained (Chart 3) as shown in Scheme 7.
3. Results and discussion
Based on the binding profile of SYA 013 (Table 1), it is clear that
replacement of the piperidinol in haloperidol with the homopiper-
azine moiety has a significant effect on binding to several receptors
of interest. Replacement of the seven-membered homopiperazine
ring with the six-membered piperazine ring (3) or its bridged ana-
log, (1R,5S)-3,6-diazabicyclo[3.1.1]heptane, to form compounds 3
and 4, respectively, did not result in improved binding at any of
the receptors of interest. However, binding to D2-like receptors
was maintained. Bridging the homopiperazine ring with an ethyl-
ene group to form compound 5 again failed to improve binding
when compared to lead compound 2. We have previously shown
that the tropane analog of haloperidol (6) resulted in very potent
binding at dopamine receptors.6 Indeed, compound 6 was found
to be more potent than haloperidol at the D2 receptor and dis-
played higher potency than SYA 013 at the 5HT1A (Ki = 27.7 nM)
and 5HT2A (Ki = 30.9 nM) receptors as well. Not surprisingly then,
it also produced severe catalepsy in animal models. This observa-
tion also suggested that binding to 5HT1A or 5HT2A may not
Benzothiazole alkylating agents 32, 33 and 34 were prepared
from 2-aminothiophenol with chloroacyl chlorides in toluene at
room temperature, as described in Scheme 3.
Alkylating agents 1-(benzo[d]thiazol-2-yl)-4-iodobutan-1-one
38 and 1-(benzo[d]thiazol-2-yl)-5-iodopentan-1-one 39 were syn-
thesized from benzothiazole 35, as described in Scheme 4. Depro-
tonation of benzothiazole 35 with BuLi at ꢀ78 °C followed by
treatment with lactone 36 or 37, resulted in the corresponding
alcohols. Iodides 38 and 39 were obtained by conversion of the cor-
responding alcohols into iodides with I2, imidazole, and Ph3P in
CH2Cl2.
Alkylating agent 42 (Scheme 5) was prepared from 4-chloro-1-
(4-fluorophenyl)butan-1-one 20 in
a three step conversion.
4-Chloro-1-(4-fluorophenyl)-2-methylenebutan-1-one 40 was ob-
tained by the treatment of 20 with Eschenmoser’s salt in acetic
O
O
N
N
N
N
N
Cl
F
F
2
3
Cl
O
O
N
N
N
F
F
4
Cl
5
F
Cl
N
O
Cl
6
OH
Chart 1. Structures of compounds 2–6.

K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
1673
XH
X
OH
X
OMs
a
b
F
F
F
22 X = O
23 X = S
24 X = O
25 X = S
26 X = O
27 X = S
i
Scheme 2. Reagents and conditions: (a) KI, K2CO3, PrOH, 3-chloropropanol, 80 °C,12 h; (b) MsCl, Et3N, CH2Cl2, 5 °C–rt.
group with a sulfur atom (10, D2Ki = 751.1 nM) or with an oxygen
atom (11, D2Ki = 172.0 nM) or methylene group (12,
NH2
SH
O
N
a
a
+
Cl
Cl
n
Cl
29 n = 1
n
S
D2Ki = 139.0 nM) have each resulted in lower binding at the D2
receptor. Despite the reduction in binding affinity, compounds 11
and 12 have similar binding affinity to that of clozapine
(D2Ki = 130 nM). While compound 10 binds with a lower affinity
than SYA 013 at the 5HT1A, both 11 and 12 bind with higher affinity
at the 5HT1A receptor. All three compounds have only weak to mod-
erate binding at the 5HT2A receptor. In a previous evaluation, we
discovered that the benzothiazole moiety (unpublished observa-
tion) could substitute for the 4-fluorophenyl moiety in butyrophe-
nones. Thus, we synthesized compounds 13–15 to explore the
effect of the benzothiazole ring on the homopiperazine analog
receptor binding. Compound 13 turned out to have a lower binding
affinity at all the receptors of interest. Similarly, reducing the chain
length between the benzothiazole and the homopiperazine by one,
or three methylene groups (compounds 14 and 15, respectively),
led to further reductions in binding at all the receptors evaluated.
In fact, compound 15 has no binding affinity at any of the receptors
of interest. Insertion of a carbonyl group between the benzothiazole
ring and the first methylene group in compound 13 to form 16 and
in compound 14 to form 17 also did not result in an increase in
binding at any of the receptors of interest. A cursory look at the con-
tribution of each pharmacophoric group suggested that the tropa-
nol moiety contributes significantly to binding at the dopamine
receptors. So we hypothesized that replacement of the homopiper-
azine ring in 16 with the tropanol moiety to form compound 18
should improve binding at the dopamine receptors. Evaluation re-
vealed that compound 18 binds to the D2 receptor with an affinity
of 180 nM, 16 nM at the D3 and 508 nM at the D4 receptor. Among
the compounds synthesized and evaluated, compound 18 with 180/
16 or 11.3 for D2/D3 receptor selectivity ratio and 508/16 or 31.8 for
D4/D3 receptor selectivity ratio is the only compound with selectiv-
ity towards the D3 receptor. It is important to note that there is pre-
clinical evidence that selective antagonism at DAD3 receptors
reduces the reinforcing efficacy of drugs of abuse, reverses cognitive
deficits and shows efficacy in animal models of schizophrenia and
Parkinson’s disease and thus, selective DAD3 receptor antagonists
may hold promise in the treatment of several neuropsychiatric dis-
eases.14–16 Excision of the carbonyl from compound 18 to form
compound 19 produced an increase in binding at the D2 receptor
(D2Ki = 44 nM) and no significant changes in binding at the D3 or
D4 receptors. There was also diminished binding at the serotonin
receptors of interest for both compounds 18 and 19. Thus, it would
seem that the benzothiazole-linked aryl tropanols may constitute a
new scaffold for the development of selective D3 receptor agents.
Finally, all compounds were evaluated at the histamine H-1
receptors in order to explore their potential to induce weight
gain.10 Apart from compounds 13, 16 and 19, (Table 1) all com-
pounds bind with lower affinity than SYA 013 and hence can
be considered less likely to induce treatment-emergent weight
gain.
28
35
32 n = 1
30
33
n = 3
n = 3
31 n = 4
34 n = 4
Scheme 3. Reagents and conditions: toluene, rt, 16 h.
O
O
N
S
N
S
a, b
I
+
O
n
n
36
37
n = 1
38 n = 1
n = 2
n = 2
39
Scheme 4. Reagents and conditions: (a) BuLi, ꢀ78 °C, THF; (b) I2, imidazole, Ph3P,
CH2Cl2, 0 °C–rt.
O
O
Cl
Cl
a
Cl
Cl
F
F
F
20
40
b
O
O
O
c
F
42
41
Scheme 5. Reagents and conditions: (a) hexamethylenetetramine, Ac2O, 105 °C,
18 h; (b) H2SO4, 60 °C; (c) ethylene glycol, TsOH, toluene, reflux.
necessarily prevent catalepsy in animal models. Based on this pro-
file, we opined that moderating the D2 binding affinity of 6 might
lead to reduction of the catalepsy. Thus, compounds 7 and 8 were
synthesized to explore the hypothesis that D2 binding can be mod-
erated using butyrophenone bioisosteres identified in our labora-
tory.12 Both compounds indeed have diminished D2 binding
(Ki = 22.0 and 33 nM, respectively), similar to that of SYA 013 as de-
sired. However, the binding affinity at the 5HT1A and 5HT2A recep-
tors significantly reduced as well.
Based on the above observations, it was of interest to explore the
butyrophenone moiety in SYA 013 for enhancement in binding
affinity at the desired receptors. A published report has suggested
that a restricted butyrophenone moiety such as in the indenone
analog 9 might increase potency at the 5HT2A receptor.13 Synthesis
of compound 9 and its evaluation showed a moderate decrease in
5HT1A binding but over 20-fold decrease in 5HT2A receptor binding
(Ki = 477.5 nM) compared to SYA 013 suggesting that the aryl cyclo-
alkylamine moiety also plays a significant role in binding to the 5HT
receptors. In addition, there were similar decreases in binding at the
D2-like receptors. Replacement of the butyrophenone carbonyl
In conclusion, the SAR studies identified four of the homopiper-
azine and tropanol analogs, compounds 7, 8, 11 and 12, satisfy our
stated initial criteria for binding to D2 and 5HT1A receptors and
compare favorably with clozapine binding at these receptors. In
addition, the four compounds have very low binding affinity at

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K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
O
O
N
N
N
N
N
N
S
N
Cl
Cl
Cl
Cl
9
10
F
F
N
12
11
F
F
N
S
N
N
N
N
N
N
S
Cl
Cl
13
14
N
O
N
N
S
N
N
S
Cl
O
Cl
16
15
N
S
N
N
17
Cl
Chart 2. Structures of homopiperazine analogs, 9–17.
A, B, or C
21, 26, 27, 32, 33,
34, 38, 39, 42
HN
Ar N
+
N
N
Cl
Cl
43
9 - 17
Scheme 6. Reagents and conditions: Method A: (1) KI, K2CO3, DME, reflux, 16 h; (2) TsOH, MeOH, rt. Method B: KI, K2CO3, DME, reflux, 16 h. Method C: K2CO3, DME, reflux,
16 h.
F
O
N
S
N
O
N
N
Cl
Cl
Cl
OH
OH
OH
7
8
18
19
F
N
S
N
Cl
OH
Chart 3. Structures of tropanol analogs 7, 8, 18 and 19.
H
N
R
N
B or C
Cl
21, 26, 39, 34
+
Cl
OH
7, 8, 18, 19 (R is defined in chart 3)
Scheme 7. Reagents and conditions: Method B: KI, K2CO3, DME, reflux, 16 h. Method C: K2CO3, DME, reflux, 16 h.
OH
44
5HT2C and histamine H-1 receptors indicating a low propensity for
inducing weight gain. Compounds 18 and 19 show selectivity for
the D3 receptor and thus may constitute a new scaffold for
further exploration.

K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
1675
Table 1
Binding affinity constants of compounds at selected DA, 5-HT and H-1 receptors
Compd #
Binding data; Ki SEM (nM)
5-HT1A
5-HT2A
5-HT2C
D2
D3
D4
H1
Cloza
Hala
2a
140
3600
117.4 32.6
90.9 21.0
ND
2332 470
27.7 8.0
123.0 12.9
102.0 11.8
415.0 48.1
168 19
73.0 14.7
91.0 10.5
263.0 36.5
216.0 30.0
MP
8.9
120
23.6 2.7
109.6 16.0
ND
194.8 53.0
30.9 6.0
236.0 21.6
317.0 29.2
411.5 52.5
163.0 20.0
566.6 91.9
510.3 76.9
159.0 11.0
696.0 51.3
MP
17.0
4700
130
0.89
43.3 13.3
253.5 38.9
170
178.4 29.2
1.6 0.1
22.0 3.1
33.0 4.6
1021 142
751.1 92.3
172.0 28.1
139.0 25.3
258.7 48.4
MP
240
2.5
158.8 35.1
ND
220
548.1 246.0
5.1 3.0
4.1 0.6
9.7 1.1
590.0 54.3
1,020 25
208.8 43.4
3043 176
152.0 21.0
863.0 132.9
MP
1051 174
777.0 125.7
16.0 2.6
13.0 1.8
54
3.3
6.6 0.6
17.5 2.0
520
41.8 9.0
5.3 1.0
49.0 9.1
9.4 1.5
37.0 4.3
32.1 2.5
110.0 12.6
123.0 19.9
28.6 3.4
431.0 40.7
MP
1.8
440
1425 207
3552 943
ND
3513 912
872.1 178.0
MP
2434 583
3775 704
2529 223
>10,000
4097 754
1420 295
ND
188.6 16.0
157.6 36.0
ND
1014 206
8780 1625
4,149 924
1719 368
ND
800.2 69.9
509.0 71.1
1247 204
61.0 8.5
665.0 47.0
MP
3a
4a
5a
6a
7
8
9
10
11
12
13
14
15
16
17
18
19
MP
5920 769
MP
MP
1983 163
MP
180.0 29.5
44.0 3.1
495.0 91.0
MP
MP
1003 96
1215 67
126.0 20.4
508.0 1.2
432.0 91.1
129.0 12.0
ND
ND
1038b
MP
>10,000
MP
274.0 52.7
4623b
187.0 34.5
Abbreviations: MP, Missed primary assay threshold of 50% inhibition; ND, Not determined; Cloz, Clozapine; Hal, Haloperidol.
a
Results were previously reported in Ref. 7.
Standard Errors are within 20% of the mean.
b
4.2.2. 3-(4-Fluorophenylthio)propan-1-ol (25)
4. Experimental
4.1. General
Yield 72%. 1H NMR (CDCl3): d 7.35 (2H, dd, J = 5.4, 8.4 Hz), 6.99
(2H, t, J = 8.4 Hz), 3.76 (2H, t, J = 6.0 Hz), 2.98 (2H, t, J = 7.2 Hz), 1.85
(2H, m).
Melting points were determined on a Gallenkamp (UK) appara-
tus and are uncorrected. NMR spectra were obtained on a Varian
300 MHz Mercury Spectrometer. Elemental analyses were carried
out by Atlantic Microlab, Inc., Norcross, GA, and are within 0.4%
of theory unless otherwise noted. Flash chromatography was per-
formed with Davisil grade 634 silica gel. N,N-dimethylformamide
was distilled from CaSO4 and stored over 4 Å molecular sieves. 4-
Chloro-40-fluorobutyrophenone was obtained from Sigma–Aldrich,
but was purified by distillation under reduced pressure to a color-
less liquid prior to use. Other starting materials were used without
further purification.
4.2.3. 3-((4-Fluorophenyl)thio)propyl methanesulfonate (27)
Yield 94%. 1H NMR (CDCl3): d 7.37 (2H, dd, J = 9.0, 4.8 Hz), 7.00
(2H, t, J = 9.0 Hz), 4.30 (2H, t, J = 8.0 Hz), 3.00 (3H, s), 2.78 (2H, t,
J = 7.2 Hz), 2.02 (2H, m).
4.3. General procedure for the synthesis of 32, 33 and 34
4.3.1. 2-(4-Chlorobutyl)benzo[d]thiazole (34)
A solution of 2-aminothiophenol 28 (5 g, 39.93 mmol) in tolu-
ene (50 ml) and 5-chloropentanoyl chloride (18) (6.81 g, 44 mmol)
was added dropwise with cotinuous stirring over a 15 min period
resulting in the formation of an off-white precipitate. The mixture
was allowed to continue stirring at rt overnight and then parti-
tioned between H2O (100 mL) and EtOAc (200 mL) and the organic
layer separated. The organic layer was washed with a saturated
solution of NaCl (100 mL), H2O (100 mL) dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (Combiflash) using EtOAc/Hexanes (1:9) to pro-
duce 2-(4-chlorobutyl)benzo[d]thiazole 34 as an oily liquid (5 g,
55.5%). 1H NMR (CDCl3): d 7.95 (1H, d, J = 6.2 Hz), 7.8 (1H, d,
J = 8.7 Hz), 7.46–7.40 (1H, m), 7.35–7.30 (1H, m), 3.52 (2H, t,
J = 6.6 Hz), 3.10 (2H, t, J = 7.8 Hz), 1.95–1.77 (2H, m), 1.62–1.54
(2H, m).
4.2. Synthesis
4.2.1. Synthesis of methanesulfonates 26 and 27
A mixture of 4-fluorophenol (1.12 g, 10 mmol), 3-chloropropa-
i
nol (1.4 g, 15 mmol), KI (50 mg), K2CO3 (2.76 g, 20 mmol) in PrOH
was refluxed under N2 for 12 h. The resulting mixture was diluted
with EtOAc (200 mL), and washed with water (50 mL) then brine
(50 mL). The organic layer was dried with Na2SO4, filtered and the
filtrate was concentrated in vacuo to give 3-(4-fluorophenoxy)pro-
pan-1-ol 24 as the product. The product was used for the next step
without further purification. 1H NMR (CDCl3): d 6.96 (2H, t,
J = 8.4 Hz), 6.84 (2H, dd, J = 4.5, 9.0 Hz), 4.09 (2H, t, J = 6.0 Hz),
3.85 (2H, m), 2.03 (2H, m).
To a solution of 3-(4-fluorophenoxy)propan-1-ol 24 (1.3 g,
7.6 mmol) and Et3N (3 mL) in CH2Cl2 (10 mL) was added at
room temperature MsCl (0.8 mL, 10.3 mmol). The mixture was
stirred at room temperature for 12 h followed by direct purifica-
tion through column chromatography on silica gel to provide 3-
(4-fluorophenoxy)propyl methanesulfonate 26, with a yield of
95%. 1H NMR (CDCl3): d 6.97 (2H, t, J = 8.1 Hz), 6.83 (2H, dd,
J = 4.5, 9.0 Hz), 4.44 (2H, t, J = 6.0 Hz), 4.05 (2H, t, J = 6.0 Hz),
2.21 (2H, m).
4.3.2. 2-(3-Chloropropyl)benzo[d]thiazole, 33
Using 4-chlorobutanoyl chloride, compound 33 was obtained in
72% yield. 1H NMR (CD3OD): d 8.14 (1H, d, J = 4.1 Hz), 8.02 (1H, d,
J = 4.1 Hz), 7.72–7.59 (2H, m), 3.64–3.57 (2H, m), 3.38–3.28 (2H,
m), 1.95–1.86 (2H, m).
4.3.3. 2-(Chloromethyl)benzo[d]thiazole (32)
Using 2-chloroacetyl chloride, compound 32 was obtained in
76% yield. 1H NMR (CCCl3): d 7.96 (1H, d, J = 7.5 Hz), 7.70 (1H, dd,

1676
K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
J = 7.8, 09 Hz), 7.48–7.43 (1H, m), 7.39–7.33 (1H, m), 3.32 (2H, t,
J = 6.0 Hz).
d 7.82 (2H, dd, J = 5.7, 9.0 Hz), 7.13 (2H, t, J = 9.0 Hz), 5.99 (1H, s),
5.73 (1H, s), 3.72 (2H, t, J = 6.6 Hz), 2.94 (2H, t, J = 6.0 Hz).
Compound 40 (1.2 g, 5.64 mmol) was dissolved in concentrated
H2SO4 (4 mL) and heated at 60 °C for 1 h. After cooling to room
temperature, the mixture was diluted with EtOAc (200 mL) and
washed with saturated NaHCO3 (2 ꢁ 200 mL). The organic layer
was dried over Na2SO4, and filtered. The filtrate was concentrated
in vacuo followed by column chromatography on silica gel afford-
ing 2-(2-chloroethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one 41. 1H
NMR (CDCl3): d 7.76 (1H, dd, J = 5.4, 8.4 Hz), 7.08 (2H, m), 3.83 (1H,
m), 3.76 (1H, m), 3.42 (1H, dd, J = 7.8, 17.1 Hz), 2.93 (1H, m), 2.83
(1H, dd, J = 4.2, 17.1 Hz), 2.44 (1H, m), 1.91 (1H, m).
A solution of compound 41 (5 g, 23.5 mmol), ethylene glycol
(5 mL), and TsOH (100 mg) in toluene (50 mL) was refluxed under
N2 for 48 h. Water was removed by azeotropic distillation and the
reaction was monitored by 1H NMR. The reaction was quenched
by addition of Et3N (1 mL), diluted with EtOAc (250 mL), washed
with saturated NaHCO3 (25 mL) followed by water (25 mL). The
organic layer was dried over Na2SO4, and filtered. The filtrate was
concentrated in vacuo to obtain a mixture of 2-(2-chloro-ethyl)-5-
fluoro-inden-1-one 41 and its ethylene acetal 42 in a ratio of 1:4.
2-(2-chloroethyl)-5-fluoro-indan-1-one 41 was removed by reduc-
ing it to its 2-(2-chloroethyl)-5-fluoro-indan-1-ol with NaBH4 in
MeOH followed by column chromatography on silica gel affording
2-(2-chloro-ethyl)-5-fluoro-indan-1-one ethylene acetal 42 (4.5 g,
75% yield). 1H NMR (CDCl3): d 7.26 (1H, m), 6.92 (2H, m), 4.26
(1H, m), 4.12 (3H, m), 3.71 (1H, m), 3.60 (1H, m), 3.07 (1H, m),
2.72 (1H, m), 2.64 (1H, m), 2.16 (1H, m), 1.94 (1H, m), 1.94 (1H, m).
4.4. General procedure for the synthesis of 38 and 39
4.4.1. 1-(Benzo[d]thiazol-2-yl)-5-iodopentan-1-one, 39
To a stirred solution of benzothiazole 35 (10 g, 74.0 mmol) in dry
THF (37 mL) was added drop wise n-BuLi (37 mL 1 M solution in
THF) at ꢀ78 °C under N2. A clear orange solution was obtained. To
this resulting solution was added a solution of lactone 37 (8.14 g,
94.7 mmol) in dry THF (37 mL) at ꢀ78 °C and the mixture continu-
ously stirred at ꢀ78 °C for 1 h. After removal of the cold bath, the
reaction mixture was continuously stirred for 30 min and then
quenched with large excess of (0.1 M) HCl (300 mL). The aqueous
mixture was extracted with ethyl acetate (3 ꢁ 150 mL). The com-
bined organic extract was washed with H2O (2 ꢁ 100 mL), satu-
rated NaCl, and dried over Na2SO4. The solution was concentrated
in vacuo and the crude product was dissolved in EtOAc (50 mL),
and hexane (200 mL) was added. An orange precipitate resulted,
was collected, washed with 10% EtOAc in Hexane (200 mL), and
dried in vacuo to give the pure product 1-(benzo[d]thiazol-2-yl)-
5-hydroxypentan-1-one (6.5 g). The product was used directly
without further purification in subsequent reactions. 1H NMR
(CDCl3): d 8.20–8.16 (1H, dd, J = 1.8, 6.9 Hz), 7.99–7.96 (1H, dd,
J = 1.5, 7.2 Hz), 7.62–7.52 (2H, m), 3.74–3.72 (2H, t, J = 6.3 Hz),
3.51–3.30 (2H, t, J = 7.2 Hz), 2.00–1.88 (2H, m), 1.76–1.67 (2H, m).
To a solution of triphenylphosphine (TPP) (3.12 g, 11.9 mmol)
and imidazole (810 mg) in dichloromethane (30 mL) was added
iodine (3.02 g, 11.9 mmol) at 0–5 °C. The reaction mixture was stir-
red at 0–5 °C for 30 min. A solution of 1-(benzo[d]thiazol-2-yl)-5-
hydroxypentan-1-one (2.0 g, 8.5 mmol) in dichloromethane
(15 mL) was added drop wise in 5 min. The reaction mixture was
stirred at 0–5 °C for another 30 min, and then the ice bath was re-
moved and continuously stirred at room temperature for 12 h.
When TLC showed that the reaction was completed, the reaction
mixture was treated with water (100 mL). The two layers were
separated, and the aqueous layer was extracted with dichloro-
methane (2 ꢁ 50 mL). The combined organic extracts were washed
with water (2 ꢁ 100 mL), 10% sodium thiosulfate (50 mL), water
(100 mL) and saturated NaCl aqueous solution (75 mL), then dried
over Na2SO4 and concentrated in vacuo. The crude product was
further purified by flash chromatography (Combiflash) using
EtOAc/Hexane (1:9) to obtain the pure product 1-(benzo[d]thia-
zol-2-yl)-5-iodopentan-1-one (39) 1.8 g, in a yield of 61%. 1H
NMR (CDCl3): d 8.20–8.17 (1H, m), 8.00–7.97 (1H, m), 7.61–7.51
(2H, m), 3.34–3.29 (2H, t, J = 6.6 Hz), 3.27–3.23 (2H, t, J = 6.9 Hz),
1.98–1.92 (4H, m).
4.5. Synthesis of compound 9
4.5.1. Method A: 2-(2-(4-(4-chlorophenyl)-1,4-diazepan-1-
yl)ethyl)-5-fluoro-2,3-dihydro-1H-inden-1-one, 9
A mixture of 42 (1.2 g, 4.67 mmol), 43 (1.3 g, 5.6 mmol), KI
(100 mg, 0.5 mmol), and K2CO3 (1.2 g, 8.75 mmol) in DME
(10 mL) was heated to reflux under N2 for 16 h. The mixture was
directly purified through column chromatography on silica gel
affording 2-{2-[4-(4-chlorophenyl)-[1,4]diazepan-1-yl]-ethyl}-5-
fluoro-indan-1-one ethylene acetal. This product was dissolved in
wet MeOH, and TsOH added with stirring at rt. After stirring at rt
for 12 h, the solution was diluted with EtOAc (450 mL), followed
by washing with saturated NaHCO3 (40 mL). The organic layer
was dried over Na2SO4, and filtered. The filtrate was concentrated
in vacuo to dry and followed by column chromatography on silica
gel affording 2-(2-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)ethyl)-5-
fluoro-2,3-dihydro-1H-inden-1-one. The product was converted to
its hydrochloride salt, and recrystallized from MeOH–Et2O afford-
ing the HCl salt of 9, in a yield of 25%, mp 176–177 °C. 1H NMR
(DMSO-d6): d 11.16 (1H, br s), 7.71 (1H, dd, J = 5.4, 8.7 Hz), 7.43
(1H, d, J = 8.7 Hz), 7.27 (1H, t, J = 8.7 Hz), 7.19 (2H, d, J = 8.7 Hz),
6.75 (2H, d, J = 8.7 Hz), 3.77 (2H, m), 3.47 (2H, m), 3.34 (3H, m),
3.12 (4H, m), 2.83 (2H, m), 2.37 (1H, m), 2.23 (1H, m), 2.11 (1H,
m), 1.86 (1H, m). Calcd for C22H26Cl3FN2O:C 57.47, H 5.70 N 6.09;
Found: C 57.94, H 6.04, N 6.02.
4.4.2. 1-(Benzo[d]thiazol-2-yl)-4-iodobutan-1-one, 38
Using benzothiazole 35 and lactone 36, compound 38 was ob-
tained (as described for compound 39 above) in 37% yield. 1H
NMR (CDCl3): d 8.21–8.18 (1H, m), 8.00–7.97 (1H, m), 7.62–7.52
(2H, m), 3.47–3.42 (2H, t, J = 6.9 Hz), 3.37–3.32 (2H, t, J = 6.6 Hz),
2.39–2.30 (2H, q, J = 6.9 Hz).
4.4.3. Synthesis of 20-(2-chloroethyl)-50-fluoro-20,30-dihydrospi-
ro[[1,3]dioxolane-2,10-indene], 42
4.6. Synthesis of compounds 7, 8, 10–15, 19: General procedure:
Method B
A mixture of 20 (10 g, 50 mmol), hexamethylenetetraamine
(10.5 g, 75 mmol) in Ac2O (25 mL) was refluxed under N2 for 16 h
and allowed to cool to room temperature. The mixture was then
diluted with CHCl3 (500 mL), washed with 10% HCl solution (2 ꢁ
300 mL), H2O (300 mL) and saturated NaHCO3 (300 mL). The or-
ganic layer was dried over Na2SO4, and filtered. The filtrate was
concentrated in vacuo followed by column chromatography on sil-
ica gel affording the pure product as 4-chloro-1-(4-fluorophenyl)-
2-methylenebutan-1-one 40, (2.8 g, 26.4% yield). 1H NMR (CDCl3):
4.6.1. 3-(4-Chlorophenyl)-8-(3-(4-fluorophenoxy)propyl)-8-
azabicyclo[3.2.1]octan-3-ol (7)
A mixture of 3-(4-fluorophenoxy)propylmethanesulfonate 26
(0.73 g, 3.1 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-
3-ol 44 (1.0 g, 2.56 mmol), KI (0.2 g), and K2CO3 (1.10 g, 7.69 mmol)
in DME (25 ml) was heated to reflux under N2 for 16 h. The mixture
was diluted with EtOAc (450 mL), followed by washing with satu-
rated NaHCO3 (100 mL). The organic layer was dried over Na2SO4

K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
1677
and filtered. The filtrate was concentrated in vacuo to dry followed
by column chromatography on silica gel affording 3-(4-chloro-
phenyl)-8-(3-(4-fluorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-
3-ol 7 in an off white semi-solid form. The product was converted to
the HCl salt, followed by recrystallization in EtOAc–Et2O to give its
HCl salt (722 mg), in a yield of 72.3%, mp 218.4–219.2 °C. 1H NMR
(CD3OD): d 7.40 (2H, m), 7.15 (2H, m), 7.88 (2H, m), 6.77 (2H, m),
3.89 (2H, t, J = 6.3 Hz), 3.21 (3H, m), 2.53 (2H, m), 2.20 (4H, m),
1.88 (4H, m), 1.69 (2H, m). Calcd for C22H26Cl2FNO2:C 61.98, H
6.15, N 3.26; Found: C 61.48, H 6.13, N 3.23.
2.15 (2H, m), 2.07 (2H, m). Calcd for C29H34ClN3O3S2:C 60.87, H
5.99, N 7.34; Found: C 60.82, H 5.78, N 7.35.
4.6.7. 2-(3-(4-(4-Chlorophenyl)-1,4-diazepan-1-yl)propyl)benzo
[d]thiazole, 14
The product of benzothiazole 33 and amine 43 was converted to
the hydrochloride salt after crystallization from MeOH–Et2O. Yield
48%, mp 97–100 °C. 1H NMR (CD3OD): d 8.16 (1H, d, J = 4.1 Hz), 8.02
(1H, d, J = 4.1 Hz), 7.72–7.59 (2H, m), 7.21 (2H, d, J = 9.0 Hz), 6.98
(2H, d, J = 4.5 Hz), 3.92 (3H, m), 3.60 (3H, d, J = 5.7 Hz), 2.51–3.41
(7H, m), 2.52–2.34 (5H, m), 1.28–1.25 (1H, m). Calcd for
C
21H27Cl4N3Sꢂ1.5H2O:C 48.29, H 5.21, N 8.04; Found: C 48.26, H
4.6.2. 3-(4-Chlorophenyl)-8-(4-(4-fluorophenyl)butyl)-8-
azabicyclo[3.2.1]octan-3-ol HCl, 8
5.64, N 8.09.
The product of alkyl chloride 21 and amine 44 was converted
into its HCl salt and recrystallized from EtOAc to give the HCl salt
of 8 in a yield of 79.5%, mp 223.2–224.9 °C. 1H NMR (CDCl3): d 7.56
(2H, m), 7.35 (2H, m), 7.23 (2H, m), 7.00 (2H, m), 4.11 (2H, m), 3.32
(2H, m), 3.07 (2H, t, J = 16.5 Hz), 2.67 (4H, m), 2.54 (2H, m), 2.20
(4H, m), 1.79 (4H, m). Calcd for C23H28Cl2FNO:C 65.09, H 6.65, N
3.30; Found: C 64.95, H 6.66, N 3.31.
4.6.8. 2-((4-(4-Chlorophenyl)-1,4-diazepan-1-yl)methyl)benzo
[d]thiazole, 15
The product of the benzothiazole 32 and amine 43 was con-
verted to the HCl salt after recrystallization from MeOH–Et2O in
a yield of 53%, 197–199 °C. 1H NMR (CDCl3): d 8.08 (2H, t,
J = 7.8 Hz), 7.62–7.49 (2H, m), 7.29 (2H, d, J = 4.5 Hz), 7.05 (2H, d,
J = 5.1 Hz), 5.02 (2H, s), 4.99 (4H, s), 3.98–3.63 (7H, m). Calcd for
C19H21Cl2N3S:C 57.87, H 5.37, N 10.66; Found: C 57.69, H 5.26, N
10.99.
4.6.3. 1-(4-Chlorophenyl)-4-(3-((4-fluorophenyl)thio)propyl)-
1,4-diazepane, 10
The product of the reaction of methanesulfonate 27 and amine
43 was converted to the HCl salt and recrystallized from MeOH–
Et2O. Yield 69%, mp 172–173 °C. 1H NMR (DMSO-d6): d 11.2 (1H,
s), 7.63 (1H, s), 7.42 (2H, dd, J = 5.4, 9.0 Hz), 7.17 (4H, m), 6.75
(2H, d, J = 9.0 Hz), 3.75 (2H, m), 3.41 (4H, m), 3.16 (2H, m), 3.08
(2H, m), 2.99 (2H, t, J = 7.2 Hz), 2.38 (2H, m), 2.10 (2H, m), 1.98
(2H, m). Calcd for C20H26Cl3FN2S:C53.16, H 5.80, N 6.20; Found: C
53.39, H 5.98, N 6.22.
4.6.9. 8-(4-(Benzo[d]thiazol-2-yl)butyl)-3-(4-chlorophenyl)-8-
azabicyclo[3.2.1]octan-3-ol, 19
The product of the benzothiazole 34 and amine 44 was con-
verted to the HCl salt after recrystallization from MeOH–Et2O in
a yield of 37%, mp 198–200 °C. 1H NMR (DMSO-d6): d 10.92 (1H,
br s), 8.04 (1H, d, J = 8.1 Hz), 7.92 (1H, d, J = 8.1 Hz), 7.77 (2H, d,
J = 8.4 Hz), 7.47 (1H, m), 7.40 (1H, m), 7.34 (2H, d, J = 8.4 Hz),
3.98 (2H, m), 3.15 (2H, m), 3.00 (2H, m), 2.63 (2H, m), 2.46 (4H,
m), 2.08 (2H, m), 1.93 (6H, m). Calcd for C24H28Cl2N2OSꢂ0.4H2O:C
61.24, H 6.00, N 5.95; Found: C 61.29, H 6.05, N 5.85.
4.6.4. 1-(4-Chlorophenyl)-4-(3-(4-fluorophenoxy)propyl)-1,4-di
azepane, 11
4.7. Synthesis of compounds 16–18: Method C General
procedure:
The product of the methanesulfonate 26 and amine 43 was con-
verted to the HCl salt after crystallization from MeOH–Et2O, in a
yield of 53.9%, mp 207–208 °C. 1H NMR (CDCl3): d 7.23 (4H, m),
6.98 (4H, m), 4.89 (2H, s), 4.432 (2H, s), 3.66 (2H, m), 3.30 (3H,
m), 3.19 (2H, t, J = 6.6 Hz), 2.710(2H, t, J = 7.8 Hz), 1.79 (4H, m).
Calcd for C20H26Cl3FN2Oꢂ0.25H2O:C 54.56, H 6.07, N 6.36; Found:
C 54.58, H 5.902, N 6.00.
4.7.1. 1-(Benzo[d]thiazol-2-yl)-5-(3-(4-chlorophenyl)-3-hydroxy
-8-azabicyclo[3.2.1]octan-8-yl)pentan-1-one, 18
A mixture of 1-(benzo[d]thiazol-2-yl)-5-iodopentan-1-one 39
(0.635 g, 2.5 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-
3-ol 44 (680 mg, 2.85 mmol), K2CO3 (700 mg, 5.07 mmol) in DME
(10 mL) was heated to reflux under N2 for 16 h. The mixture was
diluted with EtOAc (400 mL) and washed with brine (50 mL). The
organic layer was dried over Na2SO4 and filtered. The filtrate was
concentrated in vacuo to dry followed by column chromatography
on silica gel affording 1-benzothiazol-2-yl-5-(4-phenyl-piperidin-
1-yl)-pentan-1-one. The product was converted into the HCl salt
followed by crystallization from MeOH–Et2O (520 mg) in a yield
of 43%, mp 202–204 °C. 1H NMR (DMSO-d6): d 10.46 (1H, br s),
8.24 (2H, m), 7.73 (2H, d, J = 8.7 Hz), 7.64 (2H, m), 7.36 (2H, d,
J = 9.0 Hz), 5.47 (1H, s), 4.30 (2H, m), 3.35 (4H, m), 3.14 (2H, m),
3.00 (2H, m), 2.57 (2H, m), 2.09 (2H, m), 1.88 (4H, m), 1.75 (2H,
m). Calcd for C25H28Cl2N2O2Sꢂ0.8H2O: C 59.36, H 5.58, N 5.54;
Found: C 59.46, H 5.82, N 5.57.
4.6.5. 1-(4-Chlorophenyl)-4-(4-(4-fluorophenyl)butyl)-1,4-diaze
pane, 12
The product of alkyl chloride 21 and amine 43 was converted to
the HCl salt after crystallization from MeOH–Et2O, in a yield of
83.2%, mp 206–207 °C. 1H NMR (CDCl3): d 7.21 (4H, m), 7.07 (2H,
m), 6.75 (2H, m), 4.23 (1H, m), 3.60 (6H, m), 3.00 (6H, m), 2.60
(2H, m), 2.31 (1H, m), 1.95 (2H, m), 1.65 (2H, m). Calcd for
C
21H27Cl2FN2ꢂ0.75H2O: C 61.39, H 6.99, N 6.82; Found: C 61.22, H
6.89, N 6.80.
4.6.6. 2-(4-(4-(4-Chlorophenyl)-1,4-diazepan-1-yl)butyl) benzo
[d]thiazole, 13
4.7.2. 1-(Benzo[d]thiazol-2-yl)-5-(4-(4-chlorophenyl)-1,4-diaze-
pan-1-yl)pentan-1-one, 16
The product of benzothiazole 34 and amine 43 was converted
into the tosylate salt, and re-crystallized from MeOH–Et2O, in a
yield of 15%, mp 146–147 °C. 1H NMR (DMSO-d6): d 9.29 (1H, br
s), 8.24 (2H, m), 7.64 (2H, m), 7.45 (2H, d, J = 8.1 Hz), 7.21 (2H, d,
J = 9.0 Hz), 7.08 (2H, d, J = 8.1 Hz), 6.76 (2H, d, J = 9.0 Hz), 3.77
(1H, m), 3.61 (2H, m), 3.40 (8H, m), 3.23 (3H, m), 2.26 (3H, s),
Using 1-(benzo[d]thiazol-2-yl)-5-iodopentan-1-one 39 and
amine 43, the free base of compound 16 was obtained and con-
verted to HCl salt followed by crystallization from MeOH–Et2O in
a yield of 32%. 1H NMR (CDCl3) d 8.18–8.15 (2H, d, J = 8.7 Hz),
7.97–7.94 (2H, d, J = 8.7 Hz), 7.59–7.50 (2H, m), 7.13–7.09 (2H, d,

1678
K. Peprah et al. / Bioorg. Med. Chem. 20 (2012) 1671–1678
J = 9.3 Hz), 6.57–6.54 (2H, d, J = 9 Hz), 3.49–3.39 (4H, m), 3.28 (2H,
t, J = 7.2 Hz), 2.74–2.71 (2H, m), 2.59–2.5 (4H, m), 1.96–1.8 (4H, m),
1.64–1.56 (2H, m).
and a Title III Grant to Florida A&M University. This work was sup-
ported in part by the Pharmaceutical Research Center NIH/NCRR 1
C06-RR12512-01 grant. The authors acknowledge Mrs. Barbara
Bricker for editorial assistance.
The free base was converted to the HCl salt, mp 242 °C. 1H NMR
(CD3OD): d 8.14–8.05 (2H, m), 7.61–7.51 (2H, m), 7.16 (2H, br s),
6.79 (2H, br s), 3.85–3.45 (13H, m), 2.30 (2H, m), 1.90 (3H, m).
Calcd for C23H28Cl3N3OS .3H2O:C 49.78, H 5.09, N 7.57; Found:C
49.68, H 5.28, N 7.43.
References and notes
1. Baldessarini, R. J.; Tarazi, F. I. In Goodman
s The Pharmacological Basis of
Therapeutics; Brunton, L., Lazo, J., Parker, K., Eds., 11th ed.; McGraw-Hill: New
York, 2006; pp 461–500.
4.7.3. 1-(Benzo[d]thiazol-2-yl)-4-(4-(4-chlorophenyl)-1,4-diaze-
pan-1-yl)butan-1-one, 17
2. Sikazwe, D. M. N.; Nkansah, N. T.; Altundas, R.; Zhu, X. Y.; Roth, B. L.;
Ablordeppey, S. Y. Bioorg. Med. Chem. 2009, 17, 1716.
3. Ablordeppey, S. Y.; Lyles-Eggleston, M.; Bricker, B.; Zhang, W.; Zhu, X. Y.;
Goodman, C.; Roth, B. L. Bioorg. Med. Chem. Lett. 2006, 16, 3219.
4. Sikazwe, D. M. N.; Li, S.; Mardenborough, L.; Cody, V.; Roth, B. L.; Ablordeppey,
S. Y. Bioorg. Med. Chem. Lett. 2004, 14, 5739.
The product of 1-(benzo[d]thiazol-2-yl)-4-iodobutan-1-one 38
and amine 43 was converted to the hydrochloride salt followed
by crystallization from MeOH–Et2O. Yield 22%, mp 194–195 °C.
1H NMR (DMSO-d6): d 10.83 (1H, br s), 8.23 (2H, m), 7.64 (2H,
m), 7.19 (2H, d, J = 9.0 Hz), 6.76 (2H, d, J = 9.0 Hz), 3.78 (2H, m),
3.50 (2H, m), 3.40 (4H, m), 3.16 (4H, m), 2.35(1H, m), 2.11 (3H,
m). Calcd for C22H26Cl3N3OS: C 54.27, H 5.38, N 8.63; Found:C
54.71, H 5.33, N 8.64.
5. Lyles-Eggleston, M.; Altundas, R.; Xia, J.; Sikazwe, D. M. N.; Fan, P.; Yang, Q.; Li,
S.; Zhang, W.; Zhu, X.; Schmidt, A. W.; Vanase-Frawley, M.; Shrihkande, M.;
Villalobos, A.; Borne, R. F.; Ablordeppey, S. Y. J. Med. Chem. 2004, 47, 497.
6. Sikazwe, D. M. N.; Lyles-Eggleston, M. D.; Li, S.; Ablordeppey, S. Y. Bioorg. Med.
Chem. Lett. 2003, 13, 3779.
7. Ablordeppey, S. Y.; Altundas, R.; Bricker, B.; Zhu, X. Y.; Suresh Kumar, E. V.;
Jackson, T.; Khan, A.; Roth, B. L. Bioorg. Med. Chem. 2008, 16, 7291.
8. Reynolds, G. P.; Hill, M. J.; Kirk, S. L. J. Psychopharmacol. 2006, 20, 15.
9. Reynolds, G. P.; Zhang, Z. J.; Zhang, X. B. Lancet 2002, 359, 2086.
10. (a) Kim, S. F.; Huang, A. S.; Snowman, A. M.; Teuscher, C.; Snyder, S. H. PNAS
2007, 104, 3456; (b) Kroeze, W. K.; Hufeisen, S. J.; Popadak, B. A.; Renock, S. M.;
Steinberg, S.; Ernsberger, P., et al Neuropsychopharmacology 2003, 28, 519.
11. Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3, 1531.
12. Peprah, K.; Zhu, X. Y.; Eyunni, S. V. K.; Setola, V.; Roth, B. L.; Ablordeppey, S. Y.
Bioorg. Med. Chem. 2012, 20, 1291.
4.8. Receptor binding studies
Binding affinities reported in Table 1 were conducted by the Na-
tional Institute of Mental Health Psychoactive Drug Screening Pro-
gram (NIMH-PDSP). Details of the methods and radioligands used
for the binding assays were previously reported.17
13. Raviña, E.; Casariego, I.; Masaguer, C. F.; Fontenla, J. A.; Montenegro, G. Y.;
Rivas, M. E.; Loza, M. I.; Enguix, M. J.; Villazon, M.; Cadavid, M. I.; Demontis, G.
C. J. Med. Chem. 2000, 43, 4678.
14. Micheli, F.; Heidbreder, C. Recent Pat CNS Drug Discov. 2006, 1, 271.
15. Heidbreder, C. A.; Newman, A. H. Ann. N Y Acad. Sci. 2010, 1187, 4.
16. Micheli, F. ChemMedChem 2011, 6, 1152.
Acknowledgments
We gratefully acknowledge the financial support of the National
Institute of General Medical Studies (NIGMS) for MBRS Grant No.
1SC1GM088451-01, NIMH Psychoactive Drug Screening Program,
17. Shapiro, D. A.; Renock, S.; Arrington, E.; Chiodo, L. A.; Liu, L. X.; Sibley, D. R.;
Roth, B. L.; Mailman, R. Neuropsychopharmacology 2003, 28, 1400.