Synthesis of biphenyltrienes as probes for β-amyloid plaques

Article abstract of DOI:10.1021/jm051020k

We report a series of p-hydroxy-, p-amino-, p-monomethylamino-, and p-monofluoroethylamino-substituted biphenyltrienes that displayed high binding affinities to β-amyloid plaques. In an in vitro binding assay using postmortem brain homogenates of Alzheime

Full text of DOI:10.1021/jm051020k

J. Med. Chem. 2006, 49, 2841-2844
2841
Synthesis of Biphenyltrienes as Probes for â-Amyloid Plaques
†
†
,†,‡
Zhi-Ping Zhuang, Mei-Ping Kung, and Hank F. Kung*
Departments of Radiology, and Pharmacology, UniVersity of PennsylVania, Room 305, 3700 Market Street, Philadelphia, PennsylVania 19104
ReceiVed October 11, 2005
We report a series of p-hydroxy-, p-amino-, p-monomethylamino-, and p-monofluoroethylamino-substituted
biphenyltrienes that displayed high binding affinities to â-amyloid plaques. In an in vitro binding assay
using postmortem brain homogenates of Alzheimer’s patients and [1 I]9, the triene compounds showed
excellent binding affinities. When labeled with suitable radionuclides, they are useful as in vivo imaging
agents for detecting Aâ plaques in the brains of Alzheimer’s patients.
25
Introduction
Alzheimer’s disease (AD) is a neurodegenerative disease
affecting millions of elderly people. Common clinical symptoms
of AD include cognitive decline, irreversible memory loss,
disorientation, language impairment, etc. Major neuropathology
observations of postmortem AD brains include the presence of
senile plaques, neurofibrillary tangles, and neurophil threads
Figure 1. Chemical structures of various probes for Aâ aggregates.
ing.12,13 Parallel to these efforts, we have similarly prepared [ C]-
11
containing â-amyloid (Aâ) aggregates and highly phosphory-
14
lated tau proteins.1 The exact mechanisms leading to the
SB-13 (7), a stilbene derivative, for plaque imaging. As
expected, 7 displayed high accumulation in the affected cortical
areas of the brain in mild to moderate AD patients but not in
development of AD are not fully understood; however, the
formation of Aâ plaques in the brain is a pivotal event in the
pathology of Alzheimer’s disease. Significant circumstantial
evidence suggests that fibrillary Aâ plaques predominately
1
5
the age-matched control subjects.
To investigate the significance of the distance between the
two phenyl groups of stilbenes, we have added additional double
bonds (trienes) instead of one vinyl bond. None of the previously
reported ligands contains a highly conjugated polyene backbone.
To our surprise, the addition of a triene bond between the
biphenyl groups produces highly selective compounds showing
excellent binding affinity for homogenates of brain tissues from
AD patients. Reported herein are the syntheses and structure-
activity relationships of a series of derivatives as selective probes
potentially useful for detecting amyloid aggregates in the brain.
consisting of the aggregates of Aâ40 and Aâ42 peptides play
a major role in AD pathogenesis.2 The formation of Aâ
aggregates in the brain is now considered a significant event
that produces various toxic effects in neuronal cells leading to
2
the formation of neuritic plaques. In view of the critical roles
Aâ plaques play in AD, Aâ-plaque-specific imaging agents may
be useful for early detection or for monitoring the progression
and effectiveness of treatment of AD.3
-5
Several research groups have reported Aâ-plaque-specific
imaging agents based on highly conjugated dyes, such as Congo
Red and Chrysamine G.6 Thioflavin T, 5 as well as Congo
Red have been used in the fluorescent staining of plaques and
Results and Discussion
,7
Chemistry. The key step for the synthesis of biphenyltrienes
is the Wittig reaction between various aldehydes, 13, and
bisdiethyl phosphonate 12, which was readily prepared from
8
tangles in postmortem AD brain sections. More abbreviated
forms of Chrysamine G, such as styrylbeneze, including 1-4
1
,4-dibromo (or chloro)-2-butene (Scheme 1). The Wittig
(
Figure 1), have been reported as fluorescent dyes for staining
9,10
reagents, 12, and various aldehydes 13 were readily reacted in
the presence of NaH and THF under a refluxing conditions.1
The hydroxyl phenyl triene 14c was obtained from hydrolysis
of the MEM protected precursor 14b. The bisamino compound
amyloid aggregates.
Although these molecules displayed
6,17
desirable properties, such as highly conjugated, high binding
affinity and moderate lipophilicity, their partial charge prevents
them from getting across the intact blood-brain barrier (BBB).
A recent report has suggested that it may be possible to prepare
1
4e and bismonomethylamino compound 14f were synthesized
from the correspondent nitro compound 14d through reduction
and monomethylation. The bis-p-(N,N-dimethylamino) deriva-
tive 14g was prepared directly through the Wittig reaction
between the p-(N,N-dimethylamino)benzaldehyde (13e) and the
bisdiethyl phosphonate 12. One unsymmetrically substituted
derivative, N-monofluoroethyl compound 14h, was prepared by
reacting the di-amino derivative 14e with 1-bromo-2-fluoroet-
hane in the presence of potassium carbonate in DMF.
near-infrared fluorescent imaging agents for imaging the plaques
inside the brain.11
To overcome the observed brain penetration deficit associated
with the styrylbenzene series (1-4), we focused on benzothia-
zole and other backbone structures. Recently, successful uses
11
of a C-11-labeled benzothiazole derivative, [ C]PIB (8) and a
18
highly lipophilic F-18-labeled probe, [ F]FDDNP (10) for
plaque and tangle visualization in living AD patients have
demonstrated the potential usefulness of in vivo plaque imag-
In Vitro Binding of Aâ plaques in AD Brain Tissue
Homogenates. Using the in vitro binding of preformed Aâ
125
peptide aggregates and two different ligands, [ I](E,E)-1-iodo-
*
Corresponding author. Tel: (215) 662-3096. Fax: (215) 349-5035.
125
2
,5-bis-(3-hydroxycarbonyl-4-methoxy)styrylbenzene ([ I]4),
E-mail:kunghf@sunmac.spect.upenn.edu.
125
125
†
‡
and [ I] 2-[4′-dimethyl-aminophenyl]-6-iodobenzothiazole ([ I]-
6), the presence of at least two mutually exclusive binding sites
Department of Radiology.
Department of Pharmacology.
1
0.1021/jm051020k CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006

2
842 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Brief Articles
Scheme 1a
in binding affinities is observed between -NHMe and 14f, and
125
-
NMe2 and 14g (7.5 vs 837 nM using [ I]9 and 122 vs >7000
125
nM using [ I]4). This is a striking difference in binding affinity
between two seemingly related compounds; 14f has a mono-
N-methylamino, and 14g has a N,N-dimethylamino substitution
at the p position of the phenyl rings. In the same assay system,
as expected, nonradioactive 9 showed a high binding affinity
1
25
toward [ I]9 binding (Ki ) 5.0 nM), whereas it displayed a
a
i. P(OEt)3; ii. MEMCl/DIEA, CH2Cl2; iii. NaH, THF, reflux; iv. HCl,
125
very low binding affinity to the [ I]4 sites suggesting that there
THF/MeOH(2:1); v. SnCl2/EtOH; vi. NaOMe/(CH2O)n; NaBH4/MeOH; vii.
BrCH2CH2F, K2CO3/DMF; Except for 14h, all are symmetrical.
are two distinct biding sites. Both 9 and 7 showed strong
1
25
competitive binding to [ I]9 binding sites (Ki ) 5.0 and 1.2
a
Table 1. Inhibition Constants (Ki, nM) of Compounds on Ligand
Binding to Homogenates of Brain Tissue
nM, respectively). The results are consistent with previously
18
reported values. Recently, 8 has been tested in AD patients
compd
vs[125I]4
vs[125I]9
as a Aâ-plaque-specific imaging agent. It has been reported
13
3
previously that [ H]8 binds to the homogenates of postmortem
1
1
1
1
1
1
1
4
9
7
8
1
4a -OMe
>8000
150 ( 30
>4000
375 ( 150
122 ( 40
>7000
217 ( 20
5.1 ( 1.2
>5000
>3000
>10000
>8000
>4000
AD brain tissue with a high binding affinity (Kd ) 1.4 nM).3
In our laboratory, the competition of the binding sites of 8 to
4c -OH
9.0 ( 2.1
500 ( 30
9.0 ( 3.2
7.5 ( 2.5
837 ( 80
12 ( 3
4d -NO2
4e -NH2
4f -NHMe
4g -NMe2
4h-NH(CH2CH2F)2
1
25
[
I]9 showed a measured Ki value of 2.8 nM, which is
comparable to that reported previously. It was also observed
that in our study another PET imaging agent 10 that binds to
plaques as well as tangles showed a moderate binding affinity
>1000
5.0 ( 0.4
1.2 ( 0.2
2.8 ( 0.5
152 ( 20
125
18,19
toward the [ I]9 binding site (Ki ) 152 nM)
indicating
1
25
1
0 might not compete with [ I]9 for identical binding pockets
0
on amyloid plaques. There may be a third binding site not related
to 4 or 9. This observation has not been reported previously.
Significantly, the multiple binding sites on the Aâ plaques in
human AD brains may be important and should be carefully
considered in the future when developing in vivo imaging
agents.
*
Values are the mean ( SEM of three independent experiments, each
in duplicate.
1
8
on these aggregates was demonstrated. Recently our laboratory
has reported that [1 I] 2-(4′-dimethylaminophenyl)-6-iodo-
imidazo[1,2-a]pyridine ([1 I]9) binds to the same binding sites
as those for 6 in transgenic mice as well as in postmortem
homogenates of AD brain tissues, and 9 has a better in vivo
25
25
In summary, the results of the binding study suggest that this
series of novel ligands based on biphenyltrienes showed potent
binding toward Aâ plaques in human AD brain tissue homo-
genates. The competitive binding study showed excellent
binding affinities with biphenyltrienes containing -OH, -NH2,
1
8-20
biodistribution profile as an imaging agent.
Specific in vitro
1
25
binding of [ I]9 can be clearly measured in cortical gray matter
but not in the white matter of AD cases. The location and density
of the specific signal detected by [1 I]9 correlated with the
distribution of amyloid plaques in these brain specimens, as
confirmed by thioflavin-S staining.
In this study, we have extended the in vitro binding assay to
use the homogenates of AD brain tissue and the two ligands
for two different and mutually exclusive binding sites using two
different radiolabeled ligands, [ I]4 and [ I]9 (Table 1). We
demonstrated that the new biphenyltrienes showed variable
binding affinities depending on the substitution groups at the p
position of the phenyl groups. Generally, the biphenyltrienes
preferentially bind to the binding sites for 9. Specifially,
compounds 14c, 14e, 14f, and 14h containing substitution
-NHMe, and -NH(CH2CH2F) groups. When labeled with
25
suitable short-lived radionuclides, they may be useful as imaging
agents for detecting amyloid aggregates in the living human
brain.
Experimental Section
The reagents used in the synthesis were purchased from Aldrich
or Fluka and used without further purification unless otherwise
1
25
125
1
2 4
indicated. Anhydrous Na SO was used as a drying agent. H NMR
spectra were obtained on a Bruker spectrometer (Bruker AC 200).
The chemical shifts are reported as δ values with chloroform as
the internal reference unless otherwise mentioned. The coupling
constants are reported in Hz. Multiplicity is defined by s (singlet),
d (doublet), t (triplet), br (broad), and m (multiplet). PTLC:
preparative thin-layer chromatography, silica gel, GF, 2000 microns
from Analtech, Inc. Elemental Analysis was performed by Atlantic
Microlab, Inc.
groups, -OH, -NH2, -NHMe, and -NH(CH2CH2F) displayed
moderate binding affinities toward [125I]4, giving Ki values of
1
50, 375, 122, and 217 nM, respectively. However, these four
1
25
compounds exhibited highly potent binding toward [ I]9,
showing Ki values of 9.0, 9.0, 7.5, and 12 nM, respectively.
The binding data suggests that the biphenyltrienes are highly
competitive for the binding sites of 9 on the Aâ aggregates,
whereas the affinity for the binding sites for 4 is 15-50-fold
General Procedure for the Wittig Reaction. 1,6-Bis(4′-
methoxyphenyl)-hexa-1,3,5-triene (14a). To a suspension of NaH
(60 mg, 60% in mineral oil, 1.5 mmol) in THF (5 mL) was added
dropwise a solution of tetraethyl-2-butene-1,4-diphosphonate (12)
(164 mg, 0.5 mmol) in THF (5 mL) followed by a solution of
4-methoxybenzaldehyde (136 mg, 1 mmol) in THF (10 mL). The
mixture was stirred under reflux overnight. Isopropyl alcohol was
added to destroy the excess NaH after cooling. Ice water was added,
and the precipitate was collected by suction,washed with water,
18
lower. It is expected that the compound with a [ F]fluoroethyl
1
8
group on 14h can be prepared and that the labeled [ F]14h
may be useful as a PET imaging agent specifically targeting
Aâ plaques in the brain.
There are several unexpected findings for this series of
compounds. There is a dramatic difference in binding affinities
between -OMe and 14a, and -OH and 14c (>4000 vs 9.0
nM using [1 I]9 and >8000 vs 150 nM using [125I]4). The
addition of the methyl group significantly reduces the binding
affinities to both binding sites. The same dramatic difference
and dried. The crude product was recrystallized in benzene to afford
1
3
4 mg of product (mp 244-245 °C, 23%). HNMR (200 MHz,
CDCl
.74 (m, 2H), 6.85 (d, J ) 8.5 Hz, 4H), 7.34 (d, J ) 8.7 Hz, 4H).
Anal(C20 ) H, C: calcd, 82.16; found, 81.24.
3
): δ 3.81 (s, 6H), 6.46 (s, 2H), 6.52 (d, J ) 15.6 Hz, 2H),
6
25
20 2
H O
1,6-Bis[4′-(2′′-methox-ethoxy)-methoxyphenyl]-hexa-1,3,5-
triene (14b). Prepared as described above from 4-(2′-methoxy-

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9 2843
ethoxy-)methoxy-benzaldehyde (13c, 2.1 g, 10 mmol) and 12 (1.64
g, 5 mmol) to afford 1.18 g of product (29%). HNMR (200 MHz,
stirred overnight at 90 °C. Water was added, and the mixture was
1
extracted with CH
2 2
Cl . The solvent was removed, and the residue
CDCl
6
(
(
3
): δ 3.37 (s, 6H), 3.33 (m, 4H), 3.81 (m, 4H), 5.28 (s, 4H),
.45 (d,d, J ) 6.9, 2.8 Hz, 2H), 6.51 (d, J ) 15.5 Hz, 2H), 6.76
d,d,d, J ) 15.5, 7.0, 3.2 Hz, 2H), 7.00 (d, J ) 8.7 Hz, 4H), 7.33
d, J ) 8.7 Hz, 4H). Anal(C26 ) C, H.
,6-Bis(4′-nitrophenyl)-hexa-1,3,5-triene (14d). Prepared as
described above from 4-nitro-benzaldehyde (302 mg, 2 mmol) and
was purified by PTLC (Hexane/Ethyl acetate ) 2:1) to give 7 mg
1
of product (20%). HNMR (200 MHz, CDCl
4.5 Hz 2H), 4.62 (t,d, J ) 47.3, 4.5 Hz, 2H), 6.27-6.67 (m, 10
H), 7.20-7.34 (m, 4H). Anal(C20 ) H. C: calcd, 77.89; found,
74.04. N: calcd, 9.08; found, 8.41.
3
): d 3.45 (t,d, J)26.6,
H
32
O
6
H21FN
2
1
Preparation of the Radioiodinated Ligands. The desired 125I-
labeled ligands 9 and 4 were prepared using iododestannylation
reactions. Hydrogen peroxide (50 µL, 3% w/v) was added to a
mixture of 50 µL of the correspondent tributyltin precursor (1 µg/
µL of EtOH), 50 µL of 1 N HCl, and [1 I]NaI (1-5 mCi) in a
closed vial. The reaction was allowed to proceed for 10 min at
room temperature and then terminated by the addition of 100 µL
1
12 (328 mg, 1 mmol) to afford 200 mg of product (62%). HNMR
(
200 MHz, CDCl ): δ 6.64 (d,d, J ) 7.0, 3.0 Hz, 2H), 6.70 (d, J
3
)
15.6 Hz, 2H), 7.04 (d,d,d, J ) 15.4, 7.0, 2.9 Hz, 2H), 7.54 (d,
25
J ) 8.8 Hz, 4H), 8.19 (d, J ) 8.8 Hz, 4H). Anal(C18
14 2 4
H N O ) C,
H, N.
1,6-Bis(4′-dimethylaminophenyl)-hexa-1,3,5-triene (14g). Pre-
pared as described above from 4-dimethyaminobenzaldehyde (149
3
of sat. NaHSO . The reaction mixture was either directly extracted
mg, 1 mmol) and 12 (164 mg, 0.5 mmol) to afford 60 mg of product
(styrylbenzenes) with ethyl acetate (3 × 1 mL) or extracted after
neutralization with a saturated sodium bicarbonate solution (thiofla-
vins). The combined extracts were evaporated to dryness. For
styrylbenzenes, the residues were dissolved in 100 µL of EtOH
and purified by HPLC using a reversed phase column (Waters
µbondpad, 3.9 × 300 mm) with an isocratic solvent of 65%
acetonitrile-35% trifluoroacetic acid (0.1%) in a flow rate of 0.8
mL/min. [1 I]9 was purified on a PRP-1 column (Hamilton, 4.1 ×
250 mm) eluted with an isocratic solvent of 90% acetonitrile-
10% 3,3-dimethyl-glutaric acid (5 mM, pH 7.0) and a flow rate of
1.0 mL/min. The desired fractions containing the product were
collected, condensed, and re-extracted with ethyl acetate. The no-
carrier-added products were evaporated to dryness and redissolved
in 100% EtOH (1 µCi/µL). The final 1 I probes, with a specific
activity of 2200 Ci/mmol and a greater than 95% radiochemical
purity, were stored at -20 °C up to six weeks for in vitro binding
studies.
Binding Assays Using Homogenates of AD Brain Tissue.
Postmortem brain tissues were obtained from AD patients during
autopsies, and the neuropathological diagnosis was confirmed by
current criteria (NIA-Reagan Institute Consensus Group, 1997). The
homogenates were then prepared from dissected gray matters in
phosphate buffered saline (PBS at pH 7.4) at a concentration of
approximately 100 mg wet tissue/mL (motor-driven glass homog-
enizer with a setting of 6 for 30 s). The homogenates were aliquoted
into 1 mL-portions and stored at -70 °C for three to six months
without the loss of the binding signal.
1
(
)
38%). HNMR (200 MHz, CDCl
6.9, 2.9 Hz, 2H), 6.47 (d, J ) 13.8 Hz, 2H), 6.68 (d, J ) 8.8
3
): δ 2.97 (s, 12 H), 6.42 (d,d, J
Hz, 4H), 6.70 (m, 2H), 7.30 (d, J ) 8.9 Hz, 4H). Anal(C22
26 2
H N )
C: calcd, 82.97; found, 76.55. H: calcd, 8.23; found, 8.65. N:
calcd, 8.8; found, 7.89.
4
-(2′-Methoxyethoxy-)methoxybenzaldehyde (13c). To a solu-
tion of 4-hydroxybenzaldehyde (3.7 g, 30 mmol) and diisopropyl-
ethylamine (7.6 mL) in CH Cl (60 mL) was added dropwise
MEMCl (5.0 mL) in CH Cl (17 mL) at 0 °C. The mixture was
stirred at RT for 3 h and quenched with HCl (60 mL, 0.5 N). The
mixture was extracted with CH Cl . The organic phase was washed
with NaOH solution (1 N) and water. The separated organic phase
was dried under Na SO , filtered, and concentrated to give 6.2 g
of product (97%), which was pure enough to be used in the next
25
2
2
2
2
2
2
25
2
4
1
reaction. HNMR (200 MHz, CDCl
H), 3.83 (m, 2H), 5.41 (s, 2H), 7.16 (d, J ) 8.7 Hz, 2H), 7.83 (d,
J ) 8.7 Hz, 2H), 9.90 (s, 1H).
,6-Bis(4′-hydroxyphenyl)-hexa-1,3,5-triene (14c). To a solu-
3
): δ 3.36 (s, 3H), 3.54 (m,
2
1
tion of 14b (237 mg, 0.54 mmol) in a mixed solvent (15 mL, THF/
MeOH ) 2:1) was added HCl (2 mL, concentrated). The mixture
was stirred overnight at RT. Water was added, and the mixture
was extracted with ethyl acetate. In general, the work up gave the
crude product, which was purified by PTLC (Hex/EA ) 2:1 as the
1
developing solvent) to give 44 mg of product (31%). HNMR (200
MHz, CDCl
3
): δ 6.44 (d,d, J ) 6.7, 2.7 Hz, 2H), 6.49 (d, J )
1
)
4.5 Hz, 2H), 6.70 (m, 2H), 6.75 (d, J ) 8.6 Hz, 4H), 7.27 (d, J
8.6 Hz, 4H), 7.55 (s, 2H). Anal(C18
,6-Bis(4′-aminophenyl)-hexa-1,3,5-triene (14e). A mixture of
4d (180 mg, 0.56 mmol) and SnCl (1.05 g) in EtOH (20 mL)
H
16
2 2
O ‚1/2 H O) C, H.
Binding assays were carried out in 12 × 75 mm borosilicate
glass tubes. For competition studies, the reaction mixture contained
50 µL of AD brain tissue homogenates (containing 20-50 µg
1
1
2
protein), 50 µL of [1 I]9 (diluted in PBS, 0.02-0.04 nM for [ I]-
25
125
was refluxed overnight. Water was added, and the mixture was
made basic with an NaOH solution (40%). The mixture was
extracted with EA. The separated organic phase was dried under
-
7
-10
9), and 50 µL of inhibitors (10 -10 M diluted serially in PBS
containing 0.1% bovine serum albumin) in a final volume of 1 mL.
Similarly, [1 I]4 (diluted in PBS, 0.02-0.04 nM) was used for the
binding assay. Nonspecific binding was defined in the presence of
600 nM 9 or 4 in the same assay tubes. The mixture was incubated
at 37 °C for 2 h, and the bound and free radioactivities were
separated by vacuum filtration through Whatman GF/B filters using
a Brandel M-24R cell harvester followed by 2 × 3 mL washes of
PBS at room temperature. The filters containing the bound I-125
ligand were counted in a gamma counter (Packard 5000) with 70%
counting efficiency. The results of the inhibition experiments were
based on the assumption that the compounds under evaluation
competed for the same binding site with the hot ligand, and the
data was subjected to nonlinear regression analysis with the EBDA
25
2 4
Na SO , filtered, and concentrated to give the crude product, which
was purified by PTLC (Hexane/Ethyl acetate ) 1:1) to give 50
1
mg of product (34%). HNMR (200 MHz, CDCl
7.0, 3.0 Hz, 2H), 6.44 (d, J ) 15.2 Hz, 2H), 6.59 (d, J ) 8.5
Hz, 4H), 6.70 (d,d,d, J ) 15.5, 7.0, 3.0 Hz, 2H), 7.18 (d, J ) 8.5
Hz, 4H). Anal(C18 ) H, N. C: calcd, 82.41; found, 80.09.
,6-Bis(4′-methylaminophenyl)-hexa-1,3,5-triene (14f). To a
suspension of 14e (15 mg, 0.06 mmol) in MeOH (3 mL) was added
NaOMe (30 mg) in solid form followed by (CH O) (18 mg, 0.6
mmol) in solid form. The mixture was stirred under reflux for 2 h.
NaBH (44 mg, 1.2 mmol) was added in portions after the reaction
3
): δ 6.39 (d,d, J
)
18 2
H N
1
2
n
4
mixture was cooled. The resulting mixture was stirred under reflux
for 1 h. Ice water was added, and the mixture was extracted with
and Ligand programs 21 by which the K
values were calculated.
i
CH
2 2 2 4
Cl . The organic phase was dried under Na SO , filtered,
Acknowledgment. This work was supported by grants from
the National Institutes of Health (AG022559 to H.F.K and AG-
21868 to M-P. K.) and the Institute for the Study of Aging (M-
P. K.). We thank Dr. George Barrio for kindly providing cold
FDDNP for the competition study.
concentrated, and purified by PTLC (Hexane/Ethyl acetate ) 2:1)
1
to give 15 mg of product (90%). HNMR (200 MHz, CDCl
3
): δ
.85 (s, 6H), 6.40 (d,d, J ) 6.9, 2.9 Hz, 2H), 6.46 (s, J ) 15.6 Hz,
H), 6.55 (d, J ) 8.6 Hz, 4H), 6.68 (m, 2H), 7.26 (d, J ) 8.9 Hz,
H). Anal(C20 ‚H O) C, H, N.
-(4′-Aminophenyl)-6-[4′-(2′-fluoroethylamino)phenyl]-hexa-
2
2
4
H
22
N
2
2
1
1
,3,5-triene (14h). To a solution of 14e (30 mg, 0.11 mmol) and
Supporting Information Available: Elemental analysis data
for the compounds used in this study. This material is avaliable
free of charge via the Internet at http://pubs.acs.org.
1-bromo-2-fluoroethane (100 mg, 0.78 mmol) in DMF (3 mL) was
2 3
added K CO (160 mg, 5 eq) and KI (5 mg). The mixture was

2
844 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Brief Articles
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