Synthesis and evaluation of ligands for D2-like receptors: The role of common pharmacophoric groups

Article abstract of DOI:10.1016/j.bmc.2008.12.054

Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve

Full text of DOI:10.1016/j.bmc.2008.12.054

Bioorganic & Medicinal Chemistry 17 (2009) 1716–1723
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of ligands for D2-like receptors:
The role of common pharmacophoric groups
Donald M. N. Sikazwe a, , Nancy T. Nkansah a,à, Ramazan Altundas a, Xue Y. Zhu a, Bryan L. Roth b,
Vincent Setola 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 Departments of Pharmacology, Medicinal Chemistry and Psychiatry and the NIMH Psychoactive Drug Screening Program,
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:
Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, consti-
tute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports
indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at
D2-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that
is, 40-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized
agents at D2-like receptors. Preliminary observation of binding affinities indicates that there is little pre-
dictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selec-
tivity and potency at these receptors.
Received 14 September 2008
Revised 17 December 2008
Accepted 19 December 2008
Available online 31 December 2008
Keywords:
Haloperidol analog
Antipsychotics
Published by Elsevier Ltd.
Butyrophenone
Dopamine receptor ligands
D2-like receptor ligands
Diazepane
Bicyclic analogs
1. Introduction
While the D2 and D4 subtypes have become potential targets for
drug development for several therapeutic indications, the func-
It is now widely accepted based on gene cloning and recombi-
nant DNA techniques that there are at least five major dopamine
(DA) receptor subtypes classified as D1, D2, D3, D4 and D5. Origi-
nally, these receptors were classified into only two groups, D1-like
and D2-like receptors with D1 and D5 falling into the first and D2, D3
and D4 making up the later group.1 Of the two groups, the D2-like
receptors have been the subject of great therapeutic interest be-
cause of their involvement in several psychiatric disorders.2 The
D2 subtype receptor has been identified as the primary site of ac-
tion for antipsychotic agents.3 In addition, they are also implicated
in the reinforcing and dependency-producing drugs of abuse.4 The
D4 receptor subtype mediates functions that include motor activ-
ity, initiation and inhibition of behavior and working memory.5–7
More recently, the D4 receptor subtype has attracted attention be-
cause of its association with the induction of penile erection.8–10
tions of the D3 subtype have remained largely uncertain.2
Thousands of DA ligands have appeared in the literature over
the years.2 However, a cursory evaluation of the common struc-
tural features in D2 and D4 receptor subtype ligands reveals the
consistent presence of arylcycloalkylamines in the form of alkyl-
ated arylpiperidines such as haloperidol (Chart 1) and piperazines
such as clozapine. The nature of the alkylated moieties varies and
there is little evidence to suggest the role of these alkyl moieties in
the selectivity of the ligands for each receptor subtype. In an at-
tempt to understand the structural contributions of the pharmaco-
phoric elements at D2-like receptors, we have compared the
haloperidol analog, 1 with the Merck compound, L745,870 (Chart
1).11,12 In addition, several other publications have evaluated 3-
methyl-7-azaindole and 3-methylindole moieties for D4 receptor
selectivities.13
The comparison of the binding affinity data at cloned human
D2-like receptors suggests that the presence of the butyrophenone
and the 3-methyl-7-azaindole moieties significantly affects bind-
ing affinity and selectivity of these compounds at the D2-like
receptors.11 In particular, a comparison of compound 1 and
L745,870 suggests that the presence of the 3-methyl-7-azaindole
moiety on 4-chlorophenyl piperazine confers ꢀ40-fold D4 potency
* Corresponding author. Tel.: +1 850 599 3834; fax: +1 850 599 3934.
E-mail addresses: dsikazwe@archerpharma.com (D.M.N. Sikazwe), nkansahn@
pharmacy.ucsf.edu (N.T. Nkansah), seth.ablordeppey@famu.edu (S.Y. Ablordeppey).
Current address: Medicinal Chemistry Research and Development, Archer
Pharmaceuticals, Inc., 2040 Whitfield Avenue, Sarasota, FL 34243, USA.
à
Current address: University of California, San Francisco, School of Pharmacy,
C-152, Box 0622, 521 Parnassus Avenue, San Francisco, CA 94143-0622, USA.
0968-0896/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmc.2008.12.054

D. M. N. Sikazwe et al. / Bioorg. Med. Chem. 17 (2009) 1716–1723
1717
OH
O
C
OH
CH3
N
N
Cl
F
(CH2)3
N
N
Cl
Haloperidol
L741,626
D2Ki = 11.2 nM
D4Ki = 1520.7 nM
N
H
N
D2Ki = 1.1 nM
D4Ki = 12.7 nM
N
O
Cl
N
H
N
N
Cl
F
C
(CH2)3
N
Cl
1
L745,870
Clozapine
N
H
N
D2Ki = 130 nM
D4Ki = 54 nM
D2Ki = 254 nM
D4Ki = 17 nM
D2Ki = 960 nM
D4Ki = 0.43 nM
Chart 1.
HO
Ar1
N
(CH2)n X Ar2
N
(CH2)n
(CH2)n
N
Ar1
Ar1
2a; X = CO, n = 3
2b; X = CO, n = 1
N
4; n = 1
5; n = 2
X
OH
OH
H
N
H
3a; X = N, n = 1
3b; X = CH, n = 1
3c; X = CH, n = 2
N
CH2
Ar2
Ar1
Ar1 = 4-ClPhenyl
Ar2 = 4-FPhenyl
2c
OH
Chart 2.
on L745,870 while the butyrophenone confers less than a 4-fold D2
potency. In addition, the 3-methyl-7-azaindole moiety appears to
have increased D4 selectively from 15-fold to over 2200-fold. On
the other hand, the arylpiperidine and arylpiperazine groups com-
mon among CNS drugs appear to have preferences for the D2 and
D4 subtype receptors, respectively. The aim of this study was to
further explore the role of the two alkyl moieties and their impact
on D2/D4 selectivity and potency (Charts 2 and 3).
hyde under Mannich reaction conditions, to give the desired prod-
uct, 3a (Scheme 3). Compound 3b was similarly prepared using
indole instead of 7-azaindole and the synthesis of compound 3c
was accomplished by alkylating compound 18 with 3-(2-bromoeth-
yl)-1H-indole (Scheme 4). Compound 24 (Scheme 2), which was
previously reported by our laboratory,15 served as the key interme-
diate for the synthesis of compounds 4 and 5. The first step was to
convert the commercially available benzyl-protected pyrrolidinol,
20 to the carbamate-protected pyrrolidinol (21) in order to avoid
the anticipated dechlorination that often accompanied debenzyla-
tion under hydrogenolysis conditions. Oxidation of compound 21
to form ketone 22 and subsequent Grignard reaction with 4-chloro-
phenyl magnesium bromide produced the carbamate-protected
pyrrolidinol 23. Deprotection with potassium hydroxide produced
24 and subsequent alkylation with the appropriate alkylating
agents yielded the desired compounds 4 and 5 (Schemes 3 and 4).
We have previously reported the detailed synthetic procedures
for compound 6 including the synthesis of 1-(4-chlorophenyl)-1,4-
diazepane, using CuI-catalyzed coupling of 4-chlorophenyl iodide
with 1,4-diazepane.14 Mannich reaction involving 1-(4-chloro-
phenyl)-1,4-diazepane, formaldehyde and 7-azaindole produced
compound 7 in good yield (Scheme 3). The synthesis of compounds
8 and 9 required the previously synthesized 9-methyl-3,9-diazabi-
2. Chemistry
The binding affinities of compounds 1, 2a–c, 6, 8, 10, 12 and 14
were previously reported.11,14 However, the full details of the syn-
thetic procedures for several of them were not provided nor dis-
cussed. The key intermediate for the synthesis of compounds 2a–c
and 3a–c, 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol, was
obtained by treating commercially available carbamate protected
tropinone (16) with 4-chlorophenyl magnesium bromide under
Grignard reaction conditions to form a carbamate protected amino-
alcohol (17) which was decarbamylated to the aminoalcohol 18.
Compounds 2a–c were obtained by simple alkylation of compound
18 with the appropriate alkylating groups (Scheme 1). Compound
18 was also subjected to treatment with 7-azaindole and formalde-
N
R
Cl
N
Cl
N
N
R
N
R
N
8; R = A
9; R = B
10; R = A
11; R = B
Cl
6; R = A
7; R = B
HO
CH2
N
N
O
C
Cl
N
N
R
N
R
(CH2)3
F
B
N
N
12; R = A
13; R = B
H
14; R = A
15; R = B
A
Chart 3.

1718
D. M. N. Sikazwe et al. / Bioorg. Med. Chem. 17 (2009) 1716–1723
OH
O
HO
i
ii
HN
N
N
EtO
C
O
EtO
C
O
18
16
17
Cl
Cl
iii
OH
F
X
N
(CH2)n
Cl
2a; X = CO, n = 3
2b; X = CO, n = 1
2c; X = -- , n = 1
Scheme 1. Reagents and conditions: (i) 4-Cl–Ph MgBr, (ii) KOH/ethylene glycol, (iii) 40-fluoro-4-chlorobutyrophenone/DME/KI/K2CO3 (2a); 40-fluoro-2-chloroacetophenone/
DME/KI/K2CO3 (2b); 4-fluorobenzyl bromide/DME/KI/K2CO3 (2c).
OH
OH
OH
O
iii
ii
i
EtO2C
N
Cl
EtO2C
21
N
Bzl
N
EtO2C
N
23
iv
20
22
OH
H
N
Cl
24
Scheme 2. Reagents: (i) ClCOOEt, (ii) chromic acid, (iii) 4-Cl-PhMgBr, (iv) alcoholic KOH.
Cl
Cl
HN
N
18
OH
OH
X
N
H
Cl
3a X=N
3b X=CH
Cl
HN
24
OH
N
4; X=CH
13; X=N
OH
X
N
H
N
HN
N
Cl
N
N
N
16
H
7
Cl
HN
N
Cl
N
29
X
N
H
N
N
N
H
19a; X=N
19b; X=CH
9
Cl
Cl
Cl
30
N
N
HN
HN
N
N
N
H
11
N
N
31
N
N
N
N
N
N
N
15
H
Scheme 3. Reagents: (i) CH2O, AcOH (cat), N2, rt, 18 h.

D. M. N. Sikazwe et al. / Bioorg. Med. Chem. 17 (2009) 1716–1723
1719
Cl
Cl
HN
18
N
2
OH
OH
OH
N
Cl
H
Br
Cl
a
3c
N
HN
24
H
OH
N
2
N
H
5
Scheme 4. Reagents and conditions: (a) NaHCO3, CH3CN, reflux, 4 h.
H3C
EtO2C
EtO2C
EtO2C
N
N
N
N
i
iv
iii
NH
N
BOC
N
Cl
ii
N H
26
28
25
27
v
H
N
N
vi
N
N
N
Cl
N
Cl
H
9
29
Scheme 5. Reagents: (i) t-BuOH, BOC; (ii) ClCO2Et, Toluene; (iii) TFA (iv) 4-Chlorophenylboronic Acid, Cu(OAc)2, TEA, CH2Cl2, Molecular sieves, rt, 24 – 48 hr; (v) KOH,
Ethylene glycol; (vi) 7-azaindole, CH2O, AcOH (cat), BuOH, N2, rt, 18h.
cyclo[4.2.1]nonane (25) as a key intermediate.14 To obtain com-
pound 8, intermediate 25 was BOC protected and carbamylated
using ethyl chloroformate (26). N-Arylation of 27 with 4-chloro-
phenylboronic acid produced compound 28 which underwent
deprotection to now produce the secondary amine of the other
nitrogen (29) (Scheme 5). Alkylation of compound 29 with 4-
chloro-40-fluorobutyrophenone delivered the target compound 8
as desired. Compound 9 was obtained by reacting 9-(4-chloro-
phenyl)-3,9-diazabicyclo[4.2.1]nonane (29) with 7-azaindole un-
der Mannich reaction condition (Method A) (Scheme 3). The
synthesis of compound 10 was previously reported14 while
compound 11 was synthesized using the commercially available
5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane (30) as the
starting material. Compound 30 was treated with 7-azaindole
and formaldehyde under Mannich reaction condition as before to
form compound 11 (Scheme 3). The synthesis of compounds 12
and 14 were also previously reported14 and compounds 13 and
15 were synthesized using the same procedure for the synthesis
of compound 11 (Scheme 3). 3-(4-Chlorophenyl)-3-hydroxypyrrol-
idine 24, previously reported,15 (Scheme 2) and the commercially
available 1-(2-pyrimidyl)piperazine 31 served as starting materials
for the Mannich reaction mediated conversion to target com-
pounds 13 and 15, respectively (Scheme 3).
tency or D4 selectivity.11 To further explore other physicochemi-
cal aspects of the azaindole ring, we synthesized compounds
3a–c and evaluated their binding affinities for the D2-like recep-
tors. Compounds 3a [Ki (nM), D2 = 588; D4 = 7873] and 3b [Ki
(nM), D2 = 160; D4 = 3007] are analogs of L745,870 and
L741,626 with the piperazine and piperidinol moieties replaced
with the tropanol moiety respectively. Surprisingly, both com-
pounds had significantly reduced affinity for the D2 receptor. In
addition, one would have expected 3b to at least retain its binding
affinity at the D2 receptor (Ki of L741,626 at D2 = 11.2 nM) since
replacement of the piperidine ring with tropane (2a) in haloperi-
dol enhanced potency at the D2 subtype. Addition of a methylene
group to extend the chain of 3b to 3c [Ki (nM) at D2 = 53.0;
D4 = 277.5] improved affinity somewhat at all DA subtypes. In
particular, affinity was significantly improved at the D3 subtype
with moderate selectivity when compared to the D2 and D4. Com-
parison of compounds 3a and 3b also suggests that the presence
of the pyridine nitrogen in the azaindole analog detracts some-
what from binding affinity to the D2-like receptors. Further at-
tempts to improve binding affinity by synthesizing pyrrolidinol
analogs of 3b and 3c (compounds 4 and 5, respectively) were
also unsuccessful. These surprising observations led us to synthe-
size and evaluate the 3-methyl-7-azaindole and 40-fluorobutyr-
ophenone moieties on several aryl cycloalkylamine structures
shown in Chart 3.
3. Results and discussion
We recently reported that compound 6, a diazepane analog of
a
favorable atypical antipsychotic profile.14
We have previously shown that replacing the piperidine ring
in haloperidol with a tropane moiety enhanced binding affinity
to dopamine D2 receptors.15,16 Later, we compared the effect of a
40-fluorobutyrophenone and 3-methyl-7-azaindole moieties on
4-(4-chlorophenyl)piperazine and observed that the 3-methyl-
7-azaindole moiety conferred both potency and D4 selectivity.11
At the time, we were drawn to the possibility that the distance
between the aromatic ring and the N atom in the piperazine ring
might be important. That hypothesis was tested using the potent
tropane analog of haloperidol (2a) and the shorter arylalkyl
groups (2b and 2c) but we failed to achieve either increased po-
haloperidol, has
Replacement of the butyrophenone moiety with the 3-methyl-7-
azaindole moiety led to the formation of compound 7. Evaluation
of the binding affinities of the two compounds shows 7 has a 7-
and 3-fold lower affinity for the D2 and D4 receptors, respectively,
when determined using the same assay procedure in the same lab-
oratory (Table 2). The Ki values in parenthesis for compound 6 are
obtained in a different laboratory. This observation demonstrates
that the 3-methyl-7-azaindole moiety does not necessarily confer
D4 receptor potency on its own but is dependent on the amine to
which it is attached. A similar observation was made when the

1720
D. M. N. Sikazwe et al. / Bioorg. Med. Chem. 17 (2009) 1716–1723
bridged analog of compounds 6 and 7, that is, 8 [Ki (nM);
D2 = 178.4; D4 = 41.8) and 9 [Ki (nM); D2 > 10,000; D4 = 583.7] were
evaluated. Compound 8 did meet our initial criterion for further
evaluation. At 5-HT receptors, 8 has weak binding affinity for 5-
HT1A and 5-HT2C receptors but a moderate affinity for 5-HT2A recep-
tors [Ki (nM); 5-HT1A = 2332; 5-HT2A = 194.8; 5-HT2C = 3513)].
Compared to its un-bridged counterpart, compound 6, 8 has an 8-
fold lower affinity for the 5-HT2A receptor. These differences can
be exploited to investigate the correlation of D2/D4 affinity ligands
without substantial 5-HT binding affinity and the absence of extra-
pyramidal activity associated with typical antipsychotic agents.
Compound 10 is the boat-constrained analog of 1 and 11 is an ana-
log of 10 with the butyrophenone replaced with the 3-methyl-7-
azaindole moiety. Compound 10 has moderate affinity for the D2
and D3 receptors and a weak affinity for the D4 receptor. However,
unlike the previous two pairs of compounds, 11 has a significantly
higher affinity for all the D2-like receptors. Indeed, compound 11
has the highest D3 receptor affinity of all the compounds tested
[Ki (nM); D2 = 62.0; D3 = 11.0; D4 = 69.0] in this paper.
We have also previously shown that replacement of the piperi-
dine in haloperidol with the pyrrolidine ring (12) results in an ana-
log with reduced binding affinity at the D2 subtype.15 Separation
and evaluation of the enantiomers indicated that the (+)-enantio-
mer is the eutomer and its behavioral profile was desirable.17 Thus,
we opined that replacement of the 40-fluorobutyrophenone moiety
in 12 with the 3-methyl-7-azaindole moiety might be useful. The
results indicate that there was little or no affinity for both D2
and D3 receptor subtypes and over 100-fold lower affinity for the
D4 receptor subtype. Synthesis and evaluation of compound 15
[Ki (nM); D2 = 1170; D3 = 1500; D4 = 56.0), a 7-azaindole counter-
part of the previously reported compound 14, also resulted in
diminished binding affinity for the D2-like receptors. It is impor-
tant to note however that the binding affinities were determined
in different laboratories and hence inter-laboratory differences
(see the results for the determination of haloperidol, compound
2a and 6) may play a role as well.
(5.82 g, 30.40 mmol), Mg (0.8 g, 32.90 mmol) and I2 (ca. 1 mg)
in anhydrous Et2O (20 mL), and refluxing the mixture for 4 h.
A solution of N-carbethoxy tropinone (16) (2 g or 10.1 mmol)
in anhydrous THF (10 mL) was slowly added to the reaction mix-
ture and further refluxing continued for 18 h. The resulting mix-
ture was allowed to cool to room temperature, saturated NH4Cl
solution (50 mL) was added, and the mixture was extracted with
EtOAc (3 ꢁ 50 mL). The combined organic phase was washed
with H2O (50 mL) followed by brine (50 mL), dried over Na2SO4,
filtered, and the filtrate was concentrated in vacuo. Column
chromatography (gradient solvent of 8:2 to 7:3 hexane/EtAOc)
on silica gel afforded ethyl-3-(4-chlorophenyl)-3-hydroxy-8-aza-
bicyclo[3.2.1]octane-8-carboxylate (17) as a yellowish oil which
solidified on standing at room temperature for one day, 1.3 g,
41.5%. 1H NMR (300 MHz, CDCl3): d 1.26 (3H, t, J = 7.1 Hz), 1.55
(2H, d, J = 9.2 Hz), 1.81 (2H, d, J = 14.5 Hz), 1.96 (2H, m), 2.27
(4H, d, J = 6.8 Hz), 4.15 (2H, q, J = 7.1, J = 7.3 Hz), 7.28 (4H, d,
J = 4.0 Hz). A mixture of KOH (3.2 g, 56.5 mmol) in ethylene gly-
col (20 mL) was added to a solution of 17 (2.5 g or 8.1 mmol) in
MeOH (10 mL) and the resulting mixture was heated at 150 °C,
with constant stirring, for 4 h and then allowed to cool to room
temperature. Water (200 mL) was added, and the mixture was
extracted with EtOAc (2 ꢁ 100 mL) followed by CH2Cl2
(3 ꢁ 100 mL). The organic phases were combined, washed with
H2O (400 mL), brine (100 mL) and dried (Na2SO4). The organic
phase was filtered, and the filtrate was concentrated in vacuo
and the residue was column chromatographed on silica gel
(4:2 CH2Cl2/MeOH) to give white yellowish crystals of 3-(4-chlo-
rophenyl)-8-azabicyclo[3.2.1]octan-3-ol (18) (1.40 g, 73%). 1H
NMR (300 MHz, CDCl3): d 1.82 (4H, m), 2.17 (2H, dd, J = 3.7,
J = 3.7 Hz), 2.34 (2H d, J = 7.5 Hz), 3.56 (2H, br s), 7.27 (2H, d,
J = 8.7 Hz), 7.48 (2H, d, J = 8.7 Hz).
4.2. 4-[3-(4-Chlorophenyl)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-
yl]-1-(4-fluorophenyl)butan-1-one (2a)
Overall, these results suggest that the N-arylalkyl substituents
on aryl cycloalkylamines can modify significantly the binding
affinities of the resulting compounds at the dopamine receptor
subtypes. There does not appear to be a specific and predictable ef-
fect of the nature of the arylalkyl moiety and the binding affinity
appears to be due to a combination of effects involving the two
component parts. These observations are consistent with the fact
that the pharmacophoric elements of both typical and atypical
antipsychotic drugs are found in both the cycloalkylamine and
the arylalkyl moieties of these compounds.
A mixture of 18 (0.46 g, 1.94 mmol), 4-chloro-40-fluorobutyr-
ophenone (0.60 g, 3 mmol), KI (0.5 g, 3 mmol), K2CO3 (0.70 g,
5.1 mmol) in DME (10 mL) was refluxed under N2 for 18 h. The
reaction mixture was allowed to cool to room temperature, H2O
(20 mL) was added, and the mixture was extracted with EtOAc
(4 ꢁ 50 mL). The combined organic phase was washed with brine,
dried over Na2SO4 and concentrated in vacuo. Column chromatog-
raphy was carried out using CH2Cl2 followed by 2:3 EtOAc/MeOH
to afford a yellowish oil of 2a (0.18 g, 23%) which was then con-
verted to its HCl salt, mp 237.2–238.3 °C. 1H NMR (300 MHz,
CD3OD): d 2.24 (m, 6H), 2.57 (m, 2H,) 2.72 (d, J = 9.0 Hz, 2H),
3.17 (m, 2H), 3.27 (t, J = 6.6 Hz, 2H), 4.19 (br s, 2H), 7.26
(dd, JH–F = 8.7 Hz, JH–H = 8.8 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.56
(d, J = 8.7, 2H), 8.11 (dd, JH–F = 5.4 Hz, JH–H = 8.8 Hz, 2H). Anal. Calcd
for C23H26Cl2FN2Oꢂ0.5H2O: C, 61.75; H, 6.08; N, 3.13. Found: C,
61.93; H, 6.03; N, 3.20.
4. Experimental
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-
4.3. 2-[3-(4-Chlorophenyl)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-
yl]-1-(4-fluorophenyl)ethanone (2b)
formed with Davisil grade 634 silica gel. N,N-Dimethylformamide
0
was distilled from CaSO4 and stored over 4 ÅA 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.
A mixture of 18 (0.700 g, 2.94 mmol), 2-chloro-40-fluoroaceto-
phenone (0.83 g, 3.83 mmol), KI (0.800 g, 2.94 mmol), and K2CO3
(2.44 g, 17.6 mmol) in DME (10 mL) was refluxed for 18 h. The
reaction was cooled to rt, H2O (20 mL) was added, and the mixture
was extracted with EtAOc (3 ꢁ 50 mL). The combined organic
phase was washed with brine (50 mL), dried over Na2SO4, filtered,
and the filtrate was concentrated in vacuo. Column chromatogra-
phy (7:3 hexane/EtAOc) resulted in a yellowish oil of 2b (0.480 g,
44%) which was converted into an HCl salt; mp 256.8–257.5 °C.
1H NMR (300 MHz, CD3OD): d 2.28 (7H, m), 2.71 (4H, m), 4.19
4.1. Preparation of 3-(4-chlorophenyl)-8-azabicyclo
[3.2.1]octan-3-ol (18)
A Grignard reagent, p-chlorophenyl magnesium bromide,18
was generated in situ by reacting 4-bromochlorobenzene

D. M. N. Sikazwe et al. / Bioorg. Med. Chem. 17 (2009) 1716–1723
1721
(2H, br s), 7.34 (2H, t, JH–F = 8.8, JH–H = 8.8 Hz), 7.38 (2H, d, J = 8.8,
JH–H = 8.8 Hz) 7.59 (2H, d, J = 8.8), 8.18 (2H, dd, JH–F = 5.5,
JH–H = 8.8 Hz). Anal. Calcd for C21H22Cl2FNO2ꢂ0.2H2O: C, 60.94; H,
5.45; N, 3.38. Found: C, 60.96; H, 5.34; N, 3.40.
anhydrous CH3CN (5 mL) was refluxed for 4 h under N2. The reac-
tion mixture was allowed to cool to rt and H2O (15 mL) was added.
The mixture was extracted with CH2Cl2 (4 ꢁ 25 mL) and the com-
bined organic layers was washed with brine (20 mL), dried over
Na2SO4 and the filtrate was concentrated in vacuo. White crystals
of 3c (0.18 g, quantitative) were obtained after preparatory TLC
purification (4:1 CH2Cl2/MeOH), mp 186.5–187.1 °C. 1H NMR
(300 MHz, CD3OD): d 1.83 (2H, d, J = 14 Hz), 2.00 (2H, m), 2.32
(5H, m), 2.82 (2H, m), 3.03 (2H, m), 3.50 (2H, br s), 7.08 (1H, s),
7.10 (1H, dt, J = 1.2, J = 8.0 Hz), 7.28 (2H, d, J = 8.7 Hz), 7.32 (2H,
m), 7.54 (2H, d, J = 8.7Hz), 7.56 (2H, m). Anal. Calcd for
C23H25ClN2Oꢂ0.75H2O: C, 70.04; H, 6.77; N, 7.10. Found: C, 69.86;
H, 6.56; N, 7.00.
4.4. 3-(4-Chlorophenyl)-8-(4-fluorobenzyl)-8-azabicyclo
[3.2.1]octan-3-ol (2c)
A mixture of 18 (0.50 g, 2.10 mmol), 4-fluorobenzyl bromide
(0.517 g, 2.70 mmol), KI (0.350 g, 2.10 mmol), and K2CO3 (1.74 g,
12.6 mmol) was refluxed in DME (6 mL) for 18 h. After cooling to
room temperature, H2O (20 mL) was added and the mixture was ex-
tracted with EtAOc (4 ꢁ 50 mL). Organic phases were combined,
washed with brine (30 mL), dried over Na2SO4, filtered, and the fil-
trate was concentrated in vacuo. Column chromatography on silica
gel (starting with 100% hexane and then 7:3 hexane/EtAOc) yielded
a yellowish oil of 2c (0.425 g, 59%), which was then converted into an
HClsalt, mp110.4–111.1 °C. 1HNMR(300 MHz, CDCl3):d 2.09(2H, d,
J = 14 Hz), 2.18 (2H, m), 2.80 (2H, m), 3.10 (2H, d, J = 14 Hz), 3.70 (2H,
br s), 4.07 (2H, d, J = 6.0 Hz), 7.12 (2H, t, JH–F = 8.5, JH–H = 8.5 Hz), 7.26
(2H, d, J = 8.5), 7.78 (2H, d, J = 8.6 Hz), 7.87 (2H, dd, JH–F = 5.3,
JH–H = 8.5 Hz). Anal. Calcd for C20H22Cl2FNOꢂ0.25H2O: C, 62.10; H,
5.86; N, 3.62. Found: C, 62.05; H, 6.01; N, 3.60.
4.8. 3-(4-Chlorophenyl)-1-(1H-indol-3-ylmethyl)pyrrolidin-3-
ol (4)
A
solution of 3-(4-chlorophenyl)pyrrolidin-3-ol (0.60 g,
3.04 mmol), indole (0.46 g, 3.95 mmol), AcOH (6 drops, 17 M),
and CH2O (0.08 mL, 3.04 mmol) in CH2Cl2 (5 mL) was stirred at
room temperature for 18 h. The mixture was basified (10% NaOH
solution), extracted with CH2Cl2 (4 ꢁ 25 mL), the combined or-
ganic layers was washed with brine (20 mL), dried over Na2SO4
and the filtrate was concentrated in vacuo. Purification using
preparatory TLC (4.5:0.5: CH2Cl2/2 M NH3 in MeOH) gave yellow-
4.5. 3-(4-Chlorophenyl)-8-(1H-pyrrolo[2,3-b]pyridin-3-
ylmethyl)-8-azabicyclo[3.2.1]octan-3-ol (3a)
ish crystals of
4
(0.49 g, 49%), mp 56.9–57.2 °C, 1H NMR
(300 MHz, CD3OD): d 2.13 (1H, m), 2.25 (1H, m), 2.94 (1H, m),
2.98 (2H, m), 3.08 (1H, m), 3.96 (2H, s), 7.03 (1H, m), 7.10
(1H, m), 7.24 (1H, s), 7.28 (2 H, d, J = 8.7 Hz), 7.35 (1H, m),
7.45 (2H, d, J = 8.7 Hz), 7.66 (1H, m). Anal. Calcd for
C19H19ClN2Oꢂ0.4H2O: C, 68.32; H, 5.97; N, 8.39. Found: C,
68.40; H, 5.86; N, 8.28.
Method A: A mixture of 18 (0.60 g, 2.50 mmol), 7-azaindole
(0.400 g, 3.40 mmol), AcOH (6 drops, 17 M), and CH2O (0.203 g,
2.50 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for
18 h. The reaction mixture was basified with NaOH (10% aqueous
solution) and extracted with CH2Cl2 (4 ꢁ 25 mL). The combined or-
ganic phase was washed with brine (20 mL), dried over Na2SO4, fil-
tered, and the filtrate was concentrated in vacuo. Purification by
preparatory TLC (4:2 CH2Cl2/MeOH) yielded flaky white crystals
of 3a (0.46 g, 50%), mp 94.2–94.5 °C. 1H NMR (300 MHz, CD3OD):
d 1.84 (2H, d, J = 14 Hz), 2.30 (6H, m), 3.45 (2H, br s), 3.84 (2H, br
s), 7.14 (1H, dd, J = 5.0, J = 7.8 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.46
(1H, s) 7.50 (2H, d, J = 8.6 Hz), 8.20 (2H, m). Anal. Calcd for
C21H22ClN3Oꢂ0.75H2O: C, 66.13; H, 6.21; N, 11.02. Found: C,
66.12; H, 6.04; N, 10.87.
4.9. 3-(4-Chlorophenyl)-1-[2-(1H-indol-3-yl)ethyl]pyrrolidin-
3-ol (5)
A
mixture of 3-(4-chlorophenyl)pyrrolidin-3-ol (0.40 g,
2.02 mmol), 3-(2-bromoethyl)indole (0.23 g, 1.01 mmol), and NaH-
CO3 (0.68 g, 8.08 mmol) in anhydrous CH3CN (5 mL) was refluxed
for 4 h under N2. The reaction mixture was allowed to cool to room
temperature and H2O (15 mL) was added. The mixture was ex-
tracted with CH2Cl2 (4 ꢁ 25 mL), the pooled organic layers was
washed with brine (20 mL), dried over Na2SO4 and the filtrate
was concentrated in vacuo. Purification by column chromatogra-
phy (4:1 CH2Cl2/MeOH) afforded white crystals of 5 (0.15 g, 22%),
mp 54.1–55.7 °C. 1H NMR (300 MHz, CDCl3): d 2.15 (1H, m), 2.28
(1H, m), 2.60 (2H, m), 2.92 (4H, m), 3.06 (1H, d, J = 9.7 Hz), 3.25
(1H, m), 6.98 (1H, s), 7.09 (2H, m), 7.26 (2H, m), 7.38 (2H, d,
J = 8.6 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.93 (1H, br s). Anal. Calcd for
C20H21ClN2Oꢂ0.5MeOH: C, 68.99; H, 6.50; N, 7.85. Found: C,
68.80; H, 6.27; N, 7.49.
4.6. 3-(4-Chlorophenyl)-8-(1H-indol-3-ylmethyl)-8-azabicyclo
[3.2.1]octan-3-ol (3b)
A
mixture of 18 (0.50 g, 2.10 mmol), indole (0.250 g,
2.1 mmol), AcOH (6 drops, 17 M), and CH2O (0.065 g, 2.10 mmol)
in CH2Cl2 (5 mL) was stirred at room temperature for 18 h. The
reaction mixture was basified (10% aq NaOH solution), extracted
with CH2Cl2 (4 ꢁ 25 mL), the pooled organic layers were com-
bined, washed with brine (20 mL), dried over Na2SO4 and the fil-
trate was concentrated in vacuo. Purification by preparatory TLC
(4.5:0.5 CH2Cl2/2 M NH3 in MeOH) yielded yellowish crystals of
3b (0.39 g, 51%). Mp 72.4–73.1 °C, 1H NMR (300 MHz, CD3OD):
d 1.83 (2H, d, J = 14 Hz), 2.26 (5H, m), 2.37 (2H, d, J = 6.1 Hz),
2.40 (1H, d, J = 7.2 Hz), 3.35 (1H, s), 3.84 (2H d, J = 11.0 Hz),
7.04 (1H, m), 7.11 (1H, m), 7.26 (2H, d, J = 8.6 Hz), 7.36 (1H,
m), 7.52 (2H, d, J = 8.6 Hz), 7.70 (1H, m). Anal. Calcd for
C22H23ClN2Oꢂ1.0H2O: C, 68.65; H, 6.55; N, 7.28. Found: C,
68.43; H, 6.29; N, 7.04.
4.10. 3-{[4-(4-Chlorophenyl)-1,4-diazepan-1-yl]methyl}-1H-
pyrrolo[2,3-b]pyridine, HCl (7)
Using Method A and 1-(4-chlorophenyl)-1,4-diazepane and 7-
azaindole as starting materials, compound 7 was obtained as the
HCl salt, mp 158.0–159.0 °C. 1H NMR (300 MHz, CDCl3): d 9.30
(1H, br s), 8.28 (1H, d, J = 4.5 Hz), 7.96 (1H, dd, J = 1.5, 7.5 Hz),
7.19 (1H, s), 7.12 (2H, d, J = 9.0 Hz), 7.03 (1H, dd, J = 4.8,
8.1 Hz), 6.58 (2H, d, J = 9.0 Hz), 3.79 (2H, s), 3.51 (2H, t,
J = 4.8 Hz), 3.47 (2H, t, J = 6.3 Hz), 2.78 (2H, t, J = 4.8 Hz), 2.65
(2H, t, J = 4.8 Hz), 1.90 (2H, m). Anal. Calcd for
C19H21ClN4ꢂHClꢂ0.35H2O: C, 59.49; H, 5.78; N, 14.60. Found: C,
59.40; H, 5.54; N, 14.59.
4.7. 3-(4-Chlorophenyl)-8-(1H-pyrrolo[2,3-b]pyridin-3-ylethyl)-
8-azabicyclo[3.2.1]octan-3-ol (3c)
A mixture of 18 (0.200 g, 0.84 mmol), 3-(2-bromoethyl)-1H-in-
dole (0.094 g, 0.42 mmol), and NaHCO3 (0.14 g, 1.68 mmol) in

1722
D. M. N. Sikazwe et al. / Bioorg. Med. Chem. 17 (2009) 1716–1723
Table 1
4.11. 9-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-3-(4-
Binding affinity constants of synthetic compounds to D2-like receptors
chlorophenyl)-3,9-diazabicyclo[4.2.1]nonane (9)
Compound
Binding data of compounds,a Ki SEM (nM)
The method of Michaels and Zaugg was followed.19 to deliver
intermediate 29 as previously reported in Ref. 14. A mixture of
3-(4-chlorophenyl)-3,9-diazabicyclo[4.2.1]nonane, 29 (0.130 g,
0.55 mmol), 7-azaindole (0.130 g, 1.1 mmol), AcOH (6 drops,
17 M) CH2O (0.016 g, 0.53 mmol) in butanol (8 mL) was refluxed
overnight under N2. The excess butanol was removed in vacuo
and residue was extracted with methylene chloride (3 ꢁ 60 mL).
The organic phase was dried (Na2SO4) and removed. The crude
product was purified on silica gel column with 1:1 CH2Cl2 and
EtOAc to yield compound 9 (80 mg, 62.2%) as a white hygroscopic
crystalline solid. Mp 194–196 °C. 1H NMR (300 MHz, CDCl3): d 8.30
(m, 1H), 8.05 (m, 1H), 7.04 (m, 4H), 6.56 (d, J = 6.5 Hz, 2H), 3.58 (d,
J = 6.5 Hz, 2H), 3.50 (m, 6H), 3.12 (m, 1H), 2.20–1.10 (m, 6H). Anal.
Calcd. for C21H23N4Clꢂ0.125H2O: C, 68.33; H, 6.35; N, 15.18. Found:
C, 68.17; H, 6.30, N, 14.92.
D2
D3
D4
D2/D4
Haloperidol
1.1 0.07 [0.89]
1.6 0.14 [0.31]
1231 145
1050 209
588 57.6
160.3 11.8
53.0 6.4
5.5 3.0 [4.6]
5.1 3.0 [0.71]
>10,000
172 33
128 13
25.0 1.7
18.0 1.6
2874 584
3074 553
12.7 7.2 [10.0]
5.3 0.99 [12.1]
789 363
1015 179
7873 1437
3007 561
277.5 26.5
816.5 194.4
MPA
0.10 [0.09]
0.30 [0.03]
1.60
1.03
0.07
0.05
0.19
—
—
2a
2b
2c
3a
3b
3c
4
MPA
MPA
5
a
Data obtained from the NIMH-PDSP and those in square brackets are from Ref. 15.
Ki is the mean value obtained on triplicate or quadruplicate determinations unless
otherwise indicated. MPA = Missed primary assay threshold of 50% inhibition.
Table 2
Binding affinity constants of synthetic compounds to D2-like receptors
Compound
Binding data of synthetic compounds,a Ki SEM (n) in nM
4.12. 2-{(1H-Pyrrolo[2,3-b]pyridin-3-yl)methyl}-5-(4-
chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane (11)
D2
D3
D4
D2/D4
Clozapineb 130
240
54
2.4
6b
43.3 13.3 (130) 158.8 35.1 (567)
6.6 0.6 (56)
6.6 (2.3)
Using method
A
and 5-(4-chlorophenyl)-2,5-diazabicy-
7c
970 (n = 2)
178.4 29.2
>10,000
370 (219–631)
548.1 246.0
335.5 178.0
18.6 (14.5–24.0) 5.1
8b
41.8 9.0
4.3
clo[2.2.1]heptane and 7-azaindole as starting materials, compound
11 was obtained as the free base, mp 176–178 °C. 1H NMR (CDCl3):
d 10.03 (1H, br s), 8.29 (1H, d, J = 4.5 Hz), 8.01 (1H, d, J = 8.1 Hz),
7.22 (1H, s), 7.13 (2H, d, J = 9.0 Hz), 7.05 (1H, dd, J = 4.8, 7.8 Hz),
6.47 (2H, d, J = 9.0 Hz), 4.18 (1H, s), 3.85 (2H, s), 3.60 (1H, s), 3.36
(1H, d, J = 9.0 Hz), 3.29 (1H, d, J = 9.0 Hz), 2.93 (1H, d, J = 9.6 Hz),
2.73 (1H, d, J = 9.6 Hz), 2.00 (1H, d, J = 9.3 Hz), 1.86 (1H, d,
J = 9.3 Hz). Anal. Calcd for C19H19ClN4: C, 67.35; H, 5.65; N, 16.54.
Found: C, 67.10; H, 5.74; N, 16.25.
9
583.7 114.9
>17
10c
11c
12c
13
14b
15c
170.0 (123–234) 220.0 (148–339)
62.0 (38.0–100) 11.0 (7.94–15.1)
513.0 (447–589) 0.33
69.0 (56.2–85.1) 0.90
33.0 (21.9–50.1) 200.0 (144.5–275.4) 11.0 (8.9–12.3)
3.0
—
15
MPA
MPA
244.1 106.0
1500 (912–2399)
1213 260
6.5 0.8
56.0 (45.7–69.2) 21
98.0 15.3
1170 (n = 2)
a
Dataobtainedfrom theNIMH-PDSP. Data forcompounds 6(parenthesis) 7, 10, 11,
12, and 15 were provided by A. W. Schmidt, at Pfizer laboratories as described in Ref.
15. Ki is the mean value obtained on triplicate or quadruplicate determinations unless
otherwise indicated. MPA = Missed primary assay threshold of 50% inhibition.
4.13. 3-(4-Chlorophenyl)-1-(1H-pyrrolo[2,3-b]pyridin-3-
ylmethyl)pyrrolidin-3-ol (13)
b
Binding data were previously reported (Ref. 14).
The data in brackets is the range of the mean relative to the SEM.
c
Using Method A and 3-(4-chlorophenyl)pyrrolidin-3-ol, 24 and
7-azaindole as starting materials, compound 13 was obtained in
37% yield, mp 62.9–63.2 °C. 1H NMR (300 MHz, CD3OD): d 2.15
(1H, m), 2.90 (1H, m), 2.95 (2H, m), 3.05 (1H, m), 3.93 (2H, s),
7.12 (1H, dd, J = 5.0, J = 7.8 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.39 (1H,
s), 7.47 (2H, d, J = 8.6 Hz), 8.16 (2H, m). Anal. Calcd for
C18H18ClN3Oꢂ0.4H2O: C, 64.53; H, 5.66; N, 12.54. Found: C, 64.48;
H, 5.57; N, 12.39.
Acknowledgments
We gratefully acknowledge the financial support of the National
Institute of General Medical Studies (NIGMS) for MBRS Grant No.
GM 08111, NIMH Psychoactive Drug Screening Program, RCMI
Grant No. G12 RR 03020 from NCRR, and a Title III Grant to Florida
A&M University. The authors also acknowledge Dr Abdul Khan in
the synthesis of compounds 8 and 9 and Dr. A. W. Schmidt at Pfizer
Global Research for conducting the original binding studies for
several of the reported compounds. This work was supported in
part by the Pharmaceutical Research Center NIH/NCRR 1 C06-
RR12512-01 Grant.
4.14. 3-{(4-(Pyrimidin-2-yl)piperazin-1-yl)methyl}-1H-pyrrolo
[2,3-b]pyridine (15)
Using method A and 1-(2-pyrimidyl)piperazine and 7-azain-
dole, produced compound 15 as a solid, mp 185–187 °C. 1H NMR
(CDCl3): 9.00 (1H, br s), 8.31 (1H, dd, J = 1.5, 5.1 Hz), 8.28 (2H, d,
J = 4.8 Hz), 8.09 (1H, dd, J = 1.5, 7.8 Hz), 7.24 (1H, s), 7.08 (1H, dd,
J = 4.8, 8.4 Hz), 6.45 (1H, t, J = 4.8 Hz), 3.83 (4H, t, J = 5.4Hz), 3.73
(2H, s), 2.54 (4H, t, J = 5.4 Hz). Anal. Calcd for C16H18N6: C, 65.29;
H, 6.16; N, 28.55. Found: C, 65.02; H, 6.20; N, 28.26.
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