Non-thiol farnesyltransferase inhibitors: N-(4-tolylacetylamino-3- benzoylphenyl)-3-arylfurylacrylic acid amides

Article abstract of DOI:10.1016/j.bmc.2004.07.010

We have designed arylfurylacryl-substituted benzophenones as non-thiol farnesyltransferase inhibitors utilizing a novel aryl binding site of farnesyltransferase. These compounds display activity in the low nanomolar range. We have designed arylfurylacryl-

Full text of DOI:10.1016/j.bmc.2004.07.010

Bioorganic & Medicinal Chemistry 12 (2004) 4585–4600
Non-thiol farnesyltransferase inhibitors: N-(4-tolylacetylamino-
3-benzoylphenyl)-3-arylfurylacrylic acid amides
Andreas Mitsch,b Pia Wißner,b Katrin Silber,b Peter Haebel,b Isabel Sattler,c
Gerhard Klebeb and Martin Schlitzera,
*
aDepartment fu¨r Pharmazie–Zentrum fu¨r Pharmaforschung, Ludwig-Maximilians-Universita¨t Mu¨nchen,
Butenandtstraße 5-13, D-81377 Mu¨nchen, Germany
bInstitut fu¨r Pharmazeutische Chemie, Philipps-Universita¨t Marburg, Marbacher Weg 6, D-35032 Marburg, Germany
cHans-Kno¨ll-Institut fu¨r Naturstoff-Forschung e. V., Beutenbergstraße 11, D-07745 Jena, Germany
Received 16 March 2004; accepted 1 July 2004
Abstract—We have designed arylfurylacryl-substituted benzophenones as non-thiol farnesyltransferase inhibitors utilizing a novel
aryl binding site of farnesyltransferase. These compounds display activity in the low nanomolar range.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
CAAX-peptidomimetics exhibit a free thiol group,
which is shown to coordinate the enzyme-bound zinc
ion. However, free thiols are associated with several
adverse drug effects13 and, therefore, the development
of farnesyltransferase inhibitors is clearly directed
toward the so-called non-thiol farnesyltransferase inhib-
itors. The most frequently used replacements for cys-
teine are nitrogen-containing heterocycles. The ring
nitrogen is supposed to coordinate to the enzyme-bound
zinc, similarly to the cysteine thiol group.14 However, it
has been shown that nitrogen heterocycles can be
replaced by aryl residues lacking the ability to coordi-
nate metal atoms, without loosing too much of their
farnesyltransferase inhibitory activity.15,16 Therefore,
the existence of at least one hitherto unknown aryl bind-
ing region in the farnesyltransferaseÕs active site has
been postulated.17,18
Farnesyltransferase catalyzes the post-translational
modification of several proteins by the transfer of a
farnesyl residue from farnesylpyrophosphate to the thiol
of a cysteine side chain. Common feature of such mod-
ified proteins is the C-terminal CAAX-sequence. C rep-
resents a cysteine, which side chain is farnesylated, A
amino acids, which normally, but not necessarily, carry
aliphatic side chains, and X mostly methionine or ser-
ine.1,2
In the past years farnesyltransferase has become a major
target in the development of potential anti-cancer drugs.
Farnesyltransferase inhibitors have demonstrated their
efficiency in various cancer cell culture assays and ani-
mal models. Few compounds are in advanced stages of
clinical trials.3–12
Using docking studies of model compounds of non-thiol
farnesyltransferase inhibitors as well as a GRID analysis
of farnesyltransferaseÕs active site, we have identified
two different aryl binding clefts in the farnesyltransf-
eraseÕs active site, which we suggest to be the postulated
aryl binding regions, and assigned them as near and far
aryl binding site.19
Most inhibitors described in literature are peptidomi-
metics resembling the CAAX-tetrapeptide recognition
sequence of farnesylated proteins. The majority of these
Keywords: Non-thiol farnesyltransferase inhibitors; Structure–activity
relationships.
We have designed some arylfurylacryl-substituted ben-
zophenones as non-thiol farnesyltransferase inhibitors
utilizing the far aryl binding site.19 In this study, we
*
Corresponding author. Tel.: +49-89-2180-77804; fax: +49-89-2180-
79992; e-mail: martin.schlitzer@cup.uni-muenchen.de
0968-0896/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.010

4586
A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
describe extensive variation of the terminal aryl residue
of the arylfuryl moiety to establish some structure–activ-
ity relationships.
3. Farnesyltransferase inhibition assay
The inhibitory activity of the inhibitors was determined
using the fluorescence enhancement assay as described
by Pompliano.23 The assay employs yeast farnesyltrans-
ferase (FTase) fused to Glutathione S-transferase at the
N-terminus of the b-subunit.24
2. Chemistry
The key intermediates for the synthesis of the target
compounds 7 were the 5-aryl-2-furfurals 3, which are
either commercially available or were prepared via Su-
zuki coupling (modified from20) from 5-bromofurfural
1 and the appropriate aryl boronic acids 2. Only 5-(4-
trifluoromethylsulfanylphenyl)furfural and 5-(4-meth-
oxycarbonylphenyl)furfural were prepared in a different
manner using 5-formylfurane-2-boronic acid, 4-trifluoro-
methylsulfanylbromobenzene, and 4-bromobenzoic acid
methyl ester, respectively, as coupling partners. The fur-
furals 3 were then transformed into the corresponding 3-
biarylacrylic acids 4 via Knoevenagel condensation. The
3-biarylacrylic acids 4 were activated as acid chlorides 5
and reacted with 5-amino-2-(4-tolylacetylamino)benzo-
phenone 621 as described previously19 (Scheme 1). The
amino derivative 7aa was prepared from the nitro deriv-
ative 7t by tin-II-chloride reduction. 7aa was formylated
or acetylated to the corresponding derivatives 7ac and
7ad, respectively. The aminocarbonyl group of 7ab was
obtained by H2O2/NaOH hydrolysis from the cyano
group. Because of the incompatibility of the tolyl-
acetylaminobenzophenone substructure with strong
alkaline conditions, 2-amino protected 2,5-diamino-
benzophenone 822 was acylated with 4-cyanophenyl-
furylacrylic acid chloride yielding the intermediate 9.
Cleavage of the trifluoroacetyl protective group
occurred together with the hydrolysis of the cyano
group yielding the intermediate 10, which was acylated
with tolylacetic acid chloride to get the target compound
7ab (Scheme 2). For the preparation of 7ae 3-[5-(4-ami-
nosulfonylphenyl)-2-furyl]acrylic acid was not activated
as an acid chloride, but with N0-(3-dimethylaminoprop-
yl)-N-ethylcarbodiimid*HCl as an O-acyl isourea. The
4-arylfuryl isomers 11 were prepared in the same way
as the 5-arylfuryl derivatives 7 starting from 4-bromo-
furfural.
Farnesylpyrophosphate and the dansylated pentapep-
tide Ds-GlyCysValLeuSer were used as substrates.
Upon farnesylation of the cysteine thiol the dansyl resi-
due is placed in a lipophilic environment resulting in an
enhancement of fluorescence at 505nm, which is used to
monitor the enzyme reaction.
A homology model of yeast farnesyltransferase was pre-
pared to analyze the differences between mammalian
and yeast enzymes. Sequences for alpha and beta sub-
units of rat (Q04631 and Q02293) and yeast (P29703
and P22007) farnesyltransferase were retrieved from
SWISS-Prot25 and aligned with T-COFFEE.26 Yeast
homology models were computed based on the align-
ments and the rat template structure (PDB entry:
1qbq)27 using MODELLER.28 From 53 amino acid side
chains, which constitute the active and the aryl binding
sites, 10 differ between rat and yeast (81% identity).
These amino acid substitutions are unlikely to affect
inhibitor binding, because they are located in the periph-
ery of the proposed ligand binding site (Fig. 1), too dis-
tant for direct protein–ligand contacts. Furthermore,
most exchanges do not alter the properties of the bind-
ing side.
4. Flexible docking
Flexible docking for compounds 7d and 7t was per-
formed using the program FlexX.29 Based on the coor-
dinates of the published crystal structure27 of a ternary
complex of farnesyltransferase, a farnesylpyrophosphate
analog and N-acetyl-Cys-Val-Ile-selenoMetOH (PDB-
code 1QBQ), we have calculated the solvent accessible
surface of the farnesyltransferaseÕs active site using the
program MOLCAD as implemented in the molecular
Ar
Ar
O
Br
HO
Ar
O
III
I
II
H
O
O
H
O
B
HO
O
+
OH
1
2
4
3
O
O
Ar
Ar
O
O
IV
H
N
H
N
H
NH2
N
Cl
O
+
O
O
O
5
7
6
Scheme 1. Reagents and conditions: (I) (Ph3P)4Pd, K2CO3, toluene/ethanol/water, 5h, reflux; (II) malonic acid, pyridine/piperidine, 2h, reflux; (III)
thionyl chloride, toluene, 2h, reflux; (IV) toluene/dioxane, 2h, reflux.

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4587
NH2
NO2
O
O
O
O
H
N
H
N
N
H
N
H
I
O
O
O
O
7aa
7t
H
N
R
O
O
O
H
N
H
N
II
7ac R = H
O
O
7ad R = CH3
CN
O
O
F3C
O
F3C
H
N
H
N
N
H
NH2
IV
III
O
O
O
9
8
O
O
NH2
NH2
O
O
O
H
N
H
N
H
V
H2N
O
N
O
O
O
7ab
10
Scheme 2. Reagents and conditions: (I) SnCl2 ·H2O, ethyl acetate, 2h, reflux; (II) formic acid/acetic acid anhydride, THF, 10h, ꢀ10ꢁC to reflux or
acetic acid anhydride, DMF, 10h, ꢀ15ꢁC to rt; (III) 5-(4-cyanophenyl)-2-furylacrylic acid chloride, toluene/dioxane, 2h, reflux; (IV) NaOH/H2O2,
ethanol/dioxane, 2h, 60ꢁC; (V) tolylacetic acid chloride, toluene/dioxane, 2h, reflux.
energy score. The resulting geometries were evaluated
using the knowledge-based scoring function Drug-
Score.31 The positions of the structural water molecules
for the far aryl binding site were taken from the crystal
structure. Connolly surfaces were calculated for the ob-
tained ligand conformations and water molecules occu-
pying these regions are assumed to be replaced by the
ligand.
5. Results and discussion
As stated above, arylfurylacryl-substituted benzophe-
nones 7 (Table 1) were designed to utilize one of the aryl
binding sites19 of farnesyltransferase. Inhibitor 7a with
an unsubstituted terminal phenyl residue displayed an
Figure 1. Homology model for yeast and rat farnesyltransferases with
the docked inhibitor 7d. Amino acid side chains of rat FTase are
shown as thin lines; side chains of yeast FTase as thick lines.
IC50 value of 100nM. Replacement of the phenyl residue
by the larger 1- and 2-naphthyl moieties (7b, c) resulted
modeling software package SYBYL.30 For ligand con-
struction the central phenyl residue of the benzophenone
core structure was used as base fragment and placed into
the position previously determined.21 Subsequently, the
remaining fragments of the inhibitors were placed in
the active site using the incremental construction algo-
rithm of FlexX. The docking runs provided sets of solu-
tions, which were inspected according to their calculated
in decreased activity (IC50 values: 165 and 190nM,
respectively). A 25-fold increase in activity in compari-
son with the unsubstituted phenyl derivative was ob-
served with inhibitors 7d and 7e having a methyl or a
trifluoromethyl group in the para position of the termi-
nal phenyl of the phenylfuryl moiety (IC50 values: 4nM
both). This effect proved to be sensitive toward the posi-
tion of the substituent, since the meta trifluoromethyl

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A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
Table 1. Farnesyltransferase inhibitory activity of 5-arylfuryl deriva-
tives 7a–af
Table 1 (continued)
Compd
R
IC50 (nM)
925 45
O
Br
C
7r
Ar
O
H
N
N
H
N
O
O
7s
7t
105 65
7
NO2
35
5
Compd
R
IC50 (nM)
100 32
7a
7u
7v
710 40
925 60
NO2
7b
7c
165 22
190 16
NO2
O
7w
7x
225 65
95 10
30 18
O
O
CH3
CF3
7d
7e
4
4
1
2
O O
S
7y
O O
S
7z
125
30
6
8
7f
220 10
90 27
CF3
NH2
O
7aa
7ab
7ac
7ad
7ae
7g
7h
7i
330 62
285 38
545 107
NH2
130 34
115 45
170 65
140 22
180 34
510 76
225 48
450 16
H
N
O
O
H
H
N
S
S
7j
O O
S
4 0
7
NH2
CF3
7k
7l
S
O
O
O
derivative
7f
was
considerably
less
active
(IC50 = 220nM). Alkyl residues larger than methyl in
the para position resulted in inhibitors (7g–i) roughly
equipotent to the unsubstituted phenyl derivative 7a,
but markedly less active than the methyl or trifluoro-
methyl derivatives 7d, e with IC50 values between 90
and 130nM. Replacement of the methylene group in
the ethyl residue of inhibitor 7g by a sulfur resulted in
a further decrease of activity (7j: IC50 = 170nM).
Replacement of the terminal methyl by trifluoromethyl
somewhat attenuated this effect (7k: IC50 = 140nM)
while elongation of the chain had no significant effect
(7l: IC50 = 180nM). Introduction of an oxygen into
the innermost position of the para chains yielding aryl-
alkyl ether derivatives 7m–o resulted in decreased activ-
ity in comparison to the ethyl derivative 7g as well as to
the thioethers 7j–l (IC50 values: 225–510nM). Again,
7m
7n
7o
7p
7q
CF3
F
30
5
Cl
150 28

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4589
Figure 2. Details of farnesyltransferaseÕs active site and the far aryl binding site from slightly different perspectives. Lipophilic (brown) and
hydrophilic (green to blue) properties are displayed on the Connolly surface. The structural zinc is shown as a magenta sphere. (a) Methyl substituted
inhibitor 7d deeply buries its methyl group into a lipophilic area in the far aryl binding site. (b) Nitro substituted inhibitor 7t directs its nitro group to
a more hydrophilic area toward the rim of the far aryl binding site.
replacement of the terminal methyl by trifluoromethyl
attenuated the effect of the hetero atom. In the series
of the halogen substituted inhibitors 7p–r activity was
reduced with decreasing electronegativity and increasing
size of the halogen substituents with IC50 values from 30
to 925nM. The cyano group as a pseudo-halogen sub-
stituent fits well into this series (7s: IC50 = 105nM).
Introduction of the nitro group into the para position
produced an inhibitor of considerable activity (7t:
IC50 = 35nM). Again, the para position turned out as
the optimal position since shifting the nitro group into
the meta or ortho position increasingly resulted in a
reduction of activity (7u, v, IC50 values: 710 and
925nM, respectively). Inhibitors 7w and 7x comprising
an acetyl or a methylester moiety in the para position
showed no better activity than the unsubstituted phenyl
derivative. In contrast, the methylsulfonyl derivative
7y proved as active as the nitro derivative 7t
(IC50 = 30nM). Prolongation of the chain length consid-
erably reduced activity (7z: IC50 = 125nM). An amino
group in the para position also yielded an inhibitor
(7aa: IC50 = 30nM) equipotent to the nitro or methyl-
sulfonyl derivative. Combining an amino group with a
carbonyl or sulfonyl structure as amides and sulfon-
amides (7ab–ae), respectively, did not improve activity,
but in case of the amide derivatives 7ab–ad reduced con-
siderably inhibitory potency of the compounds (IC50
values: 285–330nM).
Some of the structure–activity relationships described
above may be explained on a structural basis. Figure
2a shows a binding mode of the para methyl substituted
inhibitor 7d obtained by flexible docking. The methyl
group is deeply buried in a hydrophobic area in the
far aryl binding site. Any substituent larger than methyl
or trifluoromethyl would prevent this favorable binding
mode, explaining the low activity of any alkyl (other
than methyl or trifluoromethyl), alkylsulfanyl, or alkyl-
oxy substituted derivative. However, considerable activ-
ity has also been obtained with substituents larger than
methyl, as for instance with nitro or methylsulfonyl. For
those inhibitors docking indicates a different binding
mode with the para substituent not that deeply buried
in the aryl binding site (what is prevented by its size),
but rather directed to a more hydrophilic area at the
rim of the aryl binding site. This is exemplified for the
nitro derivative 7t in Figure 2b. As shown in Figure 3,
inhibitors in this binding mode displace two water
Figure 3. Details of the far aryl binding site with inhibitors 7d (a) and 7t (b). The Connolly surface of both inhibitors is indicated by blue and yellow
dots, respectively. Structural water molecules (as observed in the crystal structure; PDB-code 1QBQ) not replaced by the inhibitors are indicated as
red spheres. Water molecules replaced by the inhibitors are indicated as blue and yellow spheres, respectively. The methyl substituted inhibitor 7d
replaces two more water molecules than the nitro substituted inhibitor 7t.

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A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
Table 2. Farnesyltransferase inhibitory activity of 4-arylfuryl deriva-
tives 11a–e
O
O
H
N
N
H
Ar
O
O
11
Compd
R
IC50 (nM)
60 12
11a
CH3
CF3
O
11b
11c
11d
11e
180 50
285 27
5
1
Figure 4. Details of the far aryl binding site with inhibitor 7t. From
lysine residues highlighted, Lys 294and Lys 353 are potentially acting
as hydrogen bond donors for the binding of the hydrogen bond donor
atoms in different inhibitors.
O O
S
1110 270
molecules less from the binding site than the inhibitors
capable of burying a methyl group deeply into the aryl
binding site, so that the second binding mode is strongly
disfavored. However, the reduction in activity for inhib-
itors 7u and 7y is not as pronounced as one could expect
on the basis of the number of displaced water molecules.
Common feature of the nitro or sulfonyl substituents is
a hydrogen bond acceptor property. As shown in Figure
4, two lysine side chains (Lys 294b and Lys 353b) are
located at the rim of the aryl binding site, which might
act as the appropriate hydrogen bond donors. The so
formed hydrogen bonds allow for a partial compensa-
tion of the lower gain in entropy compared to those
inhibitors displacing more water. Accordingly, inhibi-
tors bearing residues too large to fit deeply into the bind-
ing site and at the same time having no compensatory
hydrogen bonding properties are penalized in terms of
affinity. The presence of two amino acid side chains act-
ing as hydrogen bond donors might also explain the rel-
atively low activity of inhibitors 7w and 7x, since in
contrast to the nitro or sulfonyl moieties their substitu-
ents are capable of forming only one but not two hydro-
gen bonds. As demonstrated by the amino substituted
derivative 7aa, hydrogen bond donor properties seem
to be favorable as well.
furyl oxygen. Obviously, the relative position of the
furyl oxygen is important. When both regioisomers are
drawn in a conformation pointing the furyl oxygens in
identical positions, the aryl residues are in completely
different orientations, accounting for different struc-
ture–activity relationships.
In summary, the 5-arylfurylacryloyl substructure de-
signed to fit into the far aryl binding site guided us to
some highly active non-thiol farnesyltransferase inhibi-
tors. Activity of the methyl and trifluoromethyl deriva-
tives can be explained by the placement of the
terminal residue deep into the aryl binding site and the
displacement of a considerable number of water mole-
cules. Substituents too large to fit so deeply into the
binding site but having hydrogen bond donor or accep-
tor properties also yield active farnesyltransferase inhib-
itors by forming hydrogen bonds with amino acid side
chains at the rim of the far aryl binding site.
6. Experimental
1H NMR spectra were recorded on a Jeol JMN-GX-400
and a Jeol JMN-LA-500 spectrometer. Mass spectra
were obtained with a Vacuum Generator VG 7070 H
using a Vector 1 data acquisition system from Teknivent
or a AutoSpec mass spectrometer from Micromass. IR
spectra were recorded on a Nicolet 510P FT-IR-spec-
trometer. Microanalyses were obtained from a CH ana-
lyzer according to Dr. Salzer from Labormatic and from
a Hewlett-Packard CHN analyzer type 185. Melting
points were obtained with a Leitz microscope and are
uncorrected. Column chromatography was carried out
using silica gel 60 (0.062–0.200mm) from Merck. The
preparation of compounds 7q, r, and t has been pub-
lished in Ref. 19; the preparation of intermediate 8 in
Ref. 22.
The regioisomeric compounds 11a–e having the aryl
moiety in para position of the central furyl ring demon-
strated completely different structure–activity relation-
ships (Table 2), with the methyl and trifluoromethyl
derivatives 11b and 11c showing decreased activity
(IC50 values: 180 and 285nM, respectively) compared
to the unsubstituted derivative 11a (IC50 = 60nM).
Notable is also the high activity of the methoxy deriva-
tive 11d (IC50 = 5nM) and the low activity of the meth-
ylsulfonyl derivative 11e (IC50 = 1900nM). As depicted
in Figure 5, both the 5- and 4-isomers can be drawn in
a conformation identical in terms of the orientation of
the aryl substituent, but different in the position of the

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4591
O
O
O
H
N
H
N
N
H
N
H
O
O
O
O
O
I
III
O
O
O
H
N
H
N
N
H
N
H
O
O
O
O
O
IV
II
Figure 5. Conformations of the 4- and 5-arylfuryl derivatives obtained through rotation of acryloyl–furyl bond. Conformations of different
regioisomers can have identical aryl orientations but different furyl oxygen positions (I and III; II and IV), or identical furyl oxygen positions but
different aryl orientations (I and IV, II and III), accounting for different structure–activity relationships.
6.1. General procedure 1: Formation of 4- and 5-
arylfurfurals via biaryl coupling
NMR (CDCl3): 6.89 (m, 1H), 7.30 (m, 1H), 7.45 (m,
2H), 7.75–7.86 (m, 4H), 8.29 (m, 1H), 9.61 (s, 1H).
(a) Bromofurfural and 1.2equiv of the appropriate benz-
eneboronic acid derivative were dissolved or suspended
in a mixture of 30mL toluene, 15mL ethanol, and
30mL of an aqueous solution of potassium carbonate
(1M) under an argon atmosphere. After addition of
50mg tetrakis(triphenylphosphine)palladium(0) and
6.1.3. 5-(1-Naphthyl)furan-2-carbaldehyde. From 1-
naphthylboronic acid (516mg, 3mmol) according to
general procedure 1a. Purification: column chromato-
graphy (dichloromethane). Yield 554mg (82%). 1H
NMR (CDCl3): d 6.85 (m, 1H), 7.34(m, 1H), 7.47 (m,
3H), 7.78 (m, 1H), 7.84(m, 2H), 8.31 (m, 1H), 9.66 (s,
1H).
25mg
[1,10-bis(diphenylphosphine)ferrocene]palladi-
um(II) chloride per mmol bromofurfural the mixture
was heated under reflux for 5h. After cooling the mix-
ture was extracted with dichloromethane for three times.
The organic layers were combined, dried over anhy-
drous magnesium sulfate, and the solvent was evapo-
rated in vacuo.
6.1.4. 5-(4-Methylphenyl)furan-2-carbaldehyde. From 4-
methylbenzeneboronic acid (490mg, 3.6mmol) accord-
ing to general procedure 1a. Purification: column chro-
matography (dichloromethane). Yield 407mg (73%).
1H NMR (CDCl3): d 2.32 (s, 3H), 6.72 (m, 1H), 7.18
(m, 2H), 7.24(m, 1H), 7.65 (m, 2H), 9.55 (s, 1H).
(b) The appropriate bromobenzene derivative and
1.2equiv of 5-formyl-2-furan-boronic acid were dis-
solved in a mixture of 30mL dimethoxyethane and
30mL of an aqueous solution of sodium carbonate
(2M) under an argon atmosphere. After addition of
50mg tetrakis(triphenylphosphine)palladium(0) and
6.1.5. 5-(4-Trifluoromethylphenyl)furan-2-carbaldehyde.
From 4-trifluoromethylbenzeneboronic acid (684mg,
3.6mmol) according to general procedure 1a. Purifica-
tion: column chromatography (dichloromethane). Yield
526mg (73%). H NMR (CDCl3): d 6.88 (m, 1H), 7.28
(m, 1H), 7.65 (m, 2H), 7.86 (m, 2H), 9.61 (s, 1H).
1
25mg
[1,10-bis(diphenylphosphine)ferrocene]palladi-
um(II) chloride per mmol bromobenzene the mixture
was heated under reflux for 5h. After cooling the mix-
ture was extracted with dichloromethane for three times.
The organic layers were combined, dried over anhy-
drous magnesium sulfate, and the solvent was evapo-
rated in vacuo.
6.1.6. 5-(4-Ethylphenyl)furan-2-carbaldehyde. From 4-
ethylbenzeneboronic acid (450mg, 3mmol) according
to general procedure 1a. Purification: column chroma-
tography (dichloromethane). Yield 248mg (41%). 1H
NMR (CDCl3): d 1.19 (t, J = 7Hz, 3H), 2.61 (q,
J = 7Hz, 2H), 6.72 (m, 1H), 7.20 (m, 2H), 7.24(m,
1H), 7.67 (m, 2H), 9.55 (s, 1H).
6.1.1. 5-Phenylfuran-2-carbaldehyde. From benzenebo-
ronic acid (438mg, 3.6mmol) according to general pro-
cedure 1a. Purification: column chromatography
(dichloromethane). Yield 327mg (63%). 1H NMR
(CDCl3): d 6.78 (m, 1H), 7.26 (m, 1H), 7.37 (m, 3H),
7.76 (m, 2H), 9.58 (s, 1H).
6.1.7. 5-(4-Vinylphenyl)furan-2-carbaldehyde. From 4-
vinylbenzeneboronic acid (447mg, 3mmol) according
to general procedure 1a. Purification: column chromato-
graphy (dichloromethane). Yield 552mg (88%). 1H
NMR (CDCl3): d 5.28 (d, J = 11Hz, 1H), 5.78 (d,
J = 18Hz, 1H), 6.65 (dd, J = 18/11Hz, 1H), 6.77 (m,
1H), 7.22 (m, 1H), 7.40 (m, 2H), 7.71 (m, 2H), 9.57 (s,
1H).
6.1.2. 5-(2-Naphthyl)furan-2-carbaldehyde. From 2-
naphthylboronic acid (516mg, 3mmol) according to
general procedure 1a. Purification: column chromato-
graphy (dichloromethane). Yield 573mg (86%). 1H

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A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
6.1.8. 5-(4-tert-Butylphenyl)furan-2-carbaldehyde. From
4-tert-butylbenzeneboronic acid (535mg, 3mmol)
according to general procedure 1a. Purification: column
chromatography (dichloromethane). Yield 650mg
(88%). 1H NMR (CDCl3): d 1.33 (s, 9H), 6.79 (m,
1H), 7.31 (m, 1H), 7.45 (m, 2H), 7.75 (m, 2H), 9.63 (s,
1H).
to general procedure 1a. Purification: column chroma-
tography (EtOAc/hexane 3:2) and recrystallization from
toluene. Yield 358mg (46%). H NMR (DMSO-d6): d
6.98 (m, 1H), 7.35 (m, 1H), 7.73 (m, 2H), 7.91 (m,
2H), 9.71 (s, 1H).
1
6.1.17. 5-(4-Acetylphenyl)furan-2-carbaldehyde. From 4-
acetylbenzeneboronic acid (588mg, 4mmol) according
to general procedure 1a. Purification: column chroma-
tography (dichloromethane). Yield 431mg (67%). 1H
NMR (CDCl3): d 2.58 (s, 3H), 6.90 (m, 1H), 7.27 (m,
1H), 7.84(m, 2H), 7.95 (m, 2H), 9.62 (s, 1H).
6.1.9. 5-(4-Methylsulfanylphenyl)furan-2-carbaldehyde.
From 4-methylsulfanylbenzeneboronic acid (505mg,
3mmol) according to general procedure 1a. Purification:
column chromatography (dichloromethane). Yield
1
576mg (88%). H NMR (CDCl3): d 2.45 (s, 3H), 6.72
(m, 1H), 7.21 (m, 3H), 7.65 (m, 2H), 9.55 (s, 1H).
6.1.18. 4-(5-Formyl-2-furyl)benzoic acid methylester.
From 4-bromobenzoic acid methylester (860mg,
4mmol) according to general procedure 1b. Purification:
column chromatography (dichloromethane). Yield
658mg (71%). 1H NMR (DMSO-d6): d 3.89 (s, 3H),
7.45 (m, 1H), 7.68 (m, 1H), 8.01 (m, 2H), 8.07 (m,
2H), 9.67 (s, 1H).
6.1.10. 5-(4-Trifluoromethylsulfanylphenyl)furan-2-carb-
aldehyde. From 4-(trifluoromethylsulfanyl)bromobenz-
ene (475lL, 3mmol) according to general procedure
1b. Purification: column chromatography (dichloro-
methane). Yield 532mg (65%). 1H NMR (CDCl3): d
6.93 (m, 1H), 7.33 (m, 1H), 7.72 (m, 2H), 7.86 (m,
2H), 9.68 (s, 1H).
6.1.19. 5-(4-Ethylsulfonylphenyl)furan-2-carbaldehyde.
From 4-ethylsulfonylbenzeneboronic acid (642mg,
3mmol) according to general procedure 1a. Purification:
column chromatography (dichloromethane). Yield
624mg (79%). 1H NMR (CDCl3): d 1.28 (t, J = 7Hz,
3H), 3.13 (q, J = 7Hz, 2H), 7.00 (m, 1H), 7.34(m,
1H), 7.98 (m, 4H), 9.70 (s, 1H).
6.1.11. 5-(4-Ethylsulfanylphenyl)furan-2-carbaldehyde.
From 4-ethylsulfanylbenzeneboronic acid (728mg,
4mmol) according to general procedure 1a. Purification:
column chromatography (dichloromethane). Yield
1
706mg (76%). H NMR (CDCl3): d 1.34(t, J = 7Hz,
3H), 2.99 (q, J = 7Hz, 2H), 6.78 (m, 1H), 7.31 (m,
3H), 7.71 (m, 2H), 9.61 (s, 1H).
6.1.20. 4-Phenylfuran-2-carbaldehyde. From benzenebo-
ronic acid (218mg, 1.8mmol) according to general pro-
cedure 1a. Purification: column chromatography
(dichloromethane). Yield 209mg (81%). 1H NMR
(CDCl3): d 7.34(m, 1H), 7.45 (m, 2H), 7.71 (m, 2H),
8.01 (m, 1H), 8.61 (m, 1H), 9.67 (s, 1H).
6.1.12. 5-(4-Methoxyphenyl)furan-2-carbaldehyde. From
4-methoxybenzeneboronic acid (547mg, 3.6mmol)
according to general procedure 1a. Purification: column
chromatography (dichloromethane). Yield 553mg
(91%). 1H NMR (CDCl3): d 3.78 (s, 3H), 6.64(m,
1H), 6.89 (m, 2H), 7.23 (m, 1H), 7.69 (m, 2H), 9.52 (s,
1H).
6.1.21. 4-(4-Methylphenyl)furan-2-carbaldehyde. From
4-methylbenzeneboronic acid (245mg, 1.8mmol)
according to general procedure 1a. Purification: column
chromatography (dichloromethane). Yield 248mg (%).
1H NMR (CDCl3): d 2.38 (s, 3H), 7.22 (m, 2H), 7.39
(m, 2H), 7.49 (m, 1H), 7.91 (m, 1H), 9.68 (s, 1H).
6.1.13.
5-(4-Trifluoromethoxyphenyl)furan-2-carbalde-
hyde. From 4-trifluoromethoxybenzeneboronic acid
(617mg, 3mmol) according to general procedure 1a.
Purification: column chromatography (dichlorometh-
ane). Yield 702mg (91%). 1H NMR (CDCl3): d 6.78
(m, 1H), 7.23–7.26 (m, 3H), 7.77 (m, 2H), 9.57 (s, 1H).
6.1.22. 4-(4-Trifluoromethylphenyl)furan-2-carbaldehyde.
From 4-trifluoromethylbenzeneboronic acid (455mg,
2.4mmol) according to general procedure 1a. Purifica-
tion: column chromatography (dichloromethane). Yield
6.1.14. 5-(4-Ethoxyphenyl)furan-2-carbaldehyde. From
4-ethoxybenzeneboronic acid (600mg, 3mmol) accord-
ing to general procedure 1a. Purification: column chro-
matography (dichloromethane). Yield 591mg (76%).
1H NMR (CDCl3): d 1.43 (t, J = 7Hz, 3H), 4.06 (q,
J = 7Hz, 2H), 6.69 (m, 1H), 6.93 (m, 2H), 7.27 (m,
1H), 7.73 (m, 2H), 9.58 (s, 1H).
1
312mg (65%). H NMR (CDCl3): d 7.81 (m, 2H), 7.95
(m, 2H), 8.11 (m, 1H), 8.76 (m, 1H), 9.69 (s, 1H).
6.1.23. 4-(4-Methoxyphenyl)furan-2-carbaldehyde. From
4-methoxybenzeneboronic acid (365mg, 2.4mmol)
according to general procedure 1a. Purification: column
chromatography (dichloromethane). Yield 329mg
(81%). 1H NMR (CDCl3): d 3.78 (s, 3H), 6.99 (m,
2H), 7.63 (m, 2H), 7.93 (m, 1H), 8.49 (m, 1H), 9.64 (s,
1H).
6.1.15. 5-(4-Fluorophenyl)furan-2-carbaldehyde. From 4-
fluorobenzeneboronic acid (420mg, 3mmol) according
to general procedure 1a. Purification: column chroma-
tography (dichloromethane). Yield 539mg (94%). 1H
NMR (CDCl3): d 6.71 (m, 1H), 7.08 (m, 2H), 7.25 (m,
1H), 7.75 (m, 2H), 9.57 (s, 1H).
6.1.24. 4-(4-Methylsulfonylphenyl)furan-2-carbaldehyde.
From 4-methylsulfonylbenzeneboronic acid (480mg,
2.4mmol) according to general procedure 1a. Purifica-
tion: column chromatography (dichloromethane). Yield
274mg (55%). 1H NMR (CDCl3): d 3.08 (s, 3H), 7.55
6.1.16. 5-(4-Cyanophenyl)furan-2-carbaldehyde. From 4-
cyanobenzeneboronic acid (588mg, 4mmol) according

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4593
(m, 1H), 7.70 (m, 2H), 7.79 (m, 2H), 8.06 (m, 1H), 9.74
(s, 1H).
4.06 (q, J = 7Hz, 2H), 6.34(d, J = 16Hz, 1H), 6.60
(m, 1H), 6.71 (m, 1H), 6.91 (m, 2H), 7.49 (d,
J = 16Hz, 1H), 7.64(m, 2H).
6.2. General procedure 2: Formation of biarylylacrylic
acids via Knoevenagel condensation
6.2.8. 3-[5-(4-Fluorophenyl)-2-furyl]acrylic acid. From
5-(4-fluorophenyl)furan-2-carbaldehyde (530mg, 2.8
mmol) according to general procedure 2. Yield 602mg
(93%). 1H NMR (DMSO-d6): d 6.31 (d, J = 16Hz,
1H), 7.00 (m, 1H), 7.08 (m, 1H), 7.26 (m, 2H), 7.38 (d,
J = 16Hz, 1H), 7.86 (m, 2H).
The aromatic aldehyde was dissolved in a mixture of
5mL pyridine and 0.2mL piperidine. After addition of
125mg malonic acid per mmol aldehyde the mixture
was heated under reflux for 2h. After cooling this mix-
ture was poured into a mixture of 60mL water, 60mL
ice, and 60mL concentrated hydrochloric acid to yield
a solid. This solid was isolated and recrystallized from
ethanol.
6.2.9. 3-[5-(4-Cyanophenyl)-2-furyl]acrylic acid. From
5-(4-cyanophenyl)furan-2-carbaldehyde (345mg, 1.75
mmol) according to general procedure 2. Yield
269mg (64%). 1H NMR (DMSO-d6): d 6.43 (d,
J = 16Hz, 1H), 7.09 (m, 1H), 7.36 (m, 1H), 7.43 (d,
J = 16Hz, 1H), 7.90 (m, 2H), 8.01 (m, 2H), 12.40 (s,
1H).
6.2.1. 3-[5-(4-tert-Butylphenyl)-2-furyl]acrylic acid. From
5-(4-tert-butylphenyl)furan-2-carbaldehyde
(640mg,
2.8mmol) according to general procedure 2. Yield
673mg (89%). 1H NMR (DMSO-d6): d 1.29 (s, 9H),
6.27 (d, J = 16Hz, 1H), 7.01 (m, 2H), 7.38 (d,
J = 16Hz, 1H), 7.45 (m, 2H), 7.71 (m, 2H).
6.2.10. 3-[5-(4-Acetylphenyl)-2-furyl]acrylic acid. From
5-(4-acetylphenyl)furan-2-carbaldehyde (424mg,
mmol) according to general procedure 2. Yield 450mg
2
1
6.2.2. 3-[5-(4-Methylsulfanylphenyl)-2-furyl]acrylic acid.
From 5-(4-methylsulfanylphenyl)furan-2-carbaldehyde
(568mg, 2.6mmol) according to general procedure 2.
(88%). H NMR (DMSO-d6): d 2.57 (s, 3H), 6.38 (d,
J = 16Hz, 1H), 7.05 (m, 1H), 7.30 (m, 1H), 7.41 (d,
J = 16Hz, 1H), 7.93 (m, 2H), 8.00 (m, 2H).
1
Yield 607mg (90%). H NMR (DMSO-d6): d 2.49 (s,
3H), 6.28 (d, J = 16Hz, 1H), 6.99 (m, 1H), 7.05 (m,
1H), 7.30 (m, 2H), 7.37 (d, J = 16Hz, 1H), 7.73 (m, 2H).
6.2.11. 3-[5-(4-Methoxycarbonylphenyl)-2-furyl]acrylic
acid. From 5-(4-methoxycarbonylphenyl)furan-2-carb-
aldehyde (650mg, 2.8mmol) according to general proce-
1
6.2.3. 3-[5-(4-Trifluoromethylsulfanylphenyl)-2-furyl]-
acrylic acid. From 5-(4-trifluoromethylsulfanylphen-
dure 2. Yield 431mg (57%). H NMR (DMSO-d6): d
3.88 (s, 3H), 6.40 (d, J = 16Hz, 1H), 7.07 (m, 1H),
7.31 (m, 1H), 7.44 (d, J = 16Hz, 1H), 7.96 (m, 2H),
8.02 (m, 2H).
yl)furan-2-carbaldehyde (490mg, 1.8mmol) according
to general procedure 2. Yield 499mg (88%). H NMR
1
(DMSO-d6): d 6.39 (d, J = 16Hz, 1H), 7.07 (m, 1H),
7.29 (m, 1H), 7.43 (d, J = 16Hz, 1H), 7.78 (m, 2H),
7.97 (m, 2H), 12.39 (s, 1H).
6.2.12. 3-[5-(4-Methylsulfonylphenyl)-2-furyl]acrylic acid.
3-[5-(4-Methylsulfanylphenyl)-2-furyl]acrylic acid (260
mg, 1mmol) and 1.5g oxone (potassium peroxomono
sulfate triple salt) were suspended in a mixture of
15mL THF, 15mL ethanol, and 10mL water. After stir-
ring at room temperature for 12h the mixture was fil-
trated. Ethanol and THF were removed in vacuo and
the resulting aqueous layer was extracted with EtOAc
for three times. The combined organic layers were dried
over anhydrous magnesium sulfate, solvent was evapo-
rated in vacuo, and the crude product was recrystallized
6.2.4. 3-[5-(4-Ethylsulfanylphenyl)-2-furyl]acrylic acid.
From 5-(4-ethylsulfanylphenyl)furan-2-carbaldehyde
(697mg, 3mmol) according to general procedure 2.
1
Yield 683mg (65%). H NMR (DMSO-d6): d 1.26 (t,
J = 7Hz, 3H), 3.02 (q, J = 7Hz, 2H), 6.31 (d,
J = 16Hz, 1H), 7.02 (m, 1H), 7.08 (m, 1H), 7.36 (m,
2H), 7.40 (d, J = 16Hz, 1H), 7.75 (m, 2H), 12.29 (s, 1H).
6.2.5. 3-[5-(4-Methoxyphenyl)-2-furyl]acrylic acid. From
5-(4-methoxyphenyl)furan-2-carbaldehyde (540mg, 2.7
mmol) according to general procedure 2. Yield 446mg
(68%). 1H NMR (CDCl3): d 3.77 (s, 3H), 6.29 (d,
J = 16Hz, 1H), 6.55 (m, 1H), 6.66 (m, 1H), 6.88 (m,
2H), 7.45 (d, J = 16Hz, 1H), 7.60 (m, 2H).
1
from ethanol. Yield 235mg (80%). H NMR (DMSO-
d6): d 3.23 (s, 3H), 6.40 (d, J = 16Hz, 1H), 7.07 (m,
1H), 7.35 (m, 1H), 7.42 (m, 1H), 7.97 (m, 2H), 8.05
(m, 2H), 12.41 (s, 1H).
6.2.13. 3-[5-(4-Ethylsulfonylphenyl)-2-furyl]acrylic acid.
From 5-(4-ethylsulfonylphenyl)furan-2-carbaldehyde
(595mg, 2.25mmol) according to general procedure 2.
6.2.6. 3-[5-(4-Trifluoromethoxyphenyl)-2-furyl]acrylic
acid. From 5-(4-trifluoromethoxyphenyl)furan-2-carbal-
dehyde (640mg, 2.5mmol) according to general proce-
dure 2. Yield 645mg (87%). H NMR (CDCl3): d 6.41
(d, J = 16Hz, 1H), 6.76 (m, 2H), 7.26 (m, 2H), 7.53
(m, 1H), 7.75 (m, 2H).
1
Yield 544mg (79%). H NMR (DMSO-d6): d 1.12 (t,
1
J = 7Hz, 3H), 3.31 (q, J = 7Hz, 2H), 6.42 (d,
J = 16Hz, 1H), 7.09 (m, 1H), 7.36 (m, 1H), 7.43 (d,
J = 16Hz, 1H), 7.93 (m, 2H), 8.08 (m, 2H).
6.2.7. 3-[5-(4-Ethoxyphenyl)-2-furyl]acrylic acid. From
5-(4-ethoxyphenyl)furan-2-carbaldehyde (582mg, 2.7
mmol) according to general procedure 2. Yield 620mg
(89%). 1H NMR (CDCl3): d 1.42 (t, J = 7Hz, 3H),
6.2.14. 3-[5-(4-Aminosulfonylphenyl)-2-furyl]acrylic acid.
From 5-(4-aminosulfonylphenyl)furan-2-carbaldehyde
(250mg, 1mmol) according to general procedure 2.
1
Yield 217mg (74%). H NMR (DMSO-d6): d 6.41 (d,

4594
A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
J = 16Hz, 1H), 7.07 (m, 1H), 7.29 (m, 1H), 7.39 (m, 2H),
7.45 (d, J = 16Hz, 1H), 7.88 (m, 2H), 8.01 (m, 2H).
ture was heated under reflux for 2h and the volatiles
were evaporated in vacuo. The resulting acyl chlorides
were dissolved in toluene or dioxane (approx. 10mL)
and added to a solution of 1equiv of N-(4-amino-2-ben-
zoylphenyl)-4-tolylacetic acid amide 6 in hot toluene
(approx. 50mL). The mixtures were heated under reflux
for 2h. Then, the solvent was removed in vacuo to give
the crude products.
6.2.15. 3-[4-Phenyl-2-furyl]acrylic acid. From 4-phenyl-
furan-2-carbaldehyde (204mg, 1.2mmol) according to
general procedure 2. Yield 211mg (82%). 1H NMR
(DMSO-d6): d 6.23 (d, J = 16Hz, 1H), 7.30 (m, 2H),
7.41 (m, 3H), 7.62 (m, 2H), 8.34 (m, 1H).
6.2.16. 3-[4-(4-Methylphenyl)-2-furyl]acrylic acid. From
4-(4-methylphenyl)furan-2-carbaldehyde (223mg, 1.2
mmol) according to general procedure 2. Yield 240mg
(88%). H NMR (DMSO-d6): d 2.32 (s, 3H), 6.22 (d,
J = 16Hz, 1H), 7.22 (m, 2H), 7.36 (m, 1H), 7.39 (d,
J = 16Hz, 1H), 7.52 (m, 2H), 8.28 (m, 1H).
6.3.1. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-(5-
phenyl-2-furyl)acrylic acid amide (7a). From 3-(5-phen-
yl-2-furyl)acrylic acid (107mg, 0.5mmol) according to
general procedure 3. Purification: recrystallization from
ethanol. Yield 175mg (64%); mp 175ꢁC. IR (KBr):
m = 3435, 3323, 3057, 2925, 1662, 1637, 1554,
1
1505cmꢀ1 1H NMR (CDCl3): 2.25 (s, 3H), 3.62 (s,
.
6.2.17. 3-[4-(4-Trifluoromethylphenyl)-2-furyl]acrylic
acid. From 4-(4-trifluoromethylphenyl)furan-2-carbal-
dehyde (288mg, 1.2mmol) according to general proce-
dure 2. Yield 291mg (86%). H NMR (DMSO-d6): d
6.26 (d, J = 16Hz, 1H), 7.42 (d, J = 16Hz, 1H), 7.48
(m, 1H), 7.77 (m, 2H), 7.85 (m, 2H), 8.50 (m, 1H).
2H), 6.39 (d, J = 16Hz, 1H), 6.53 (m, 1H), 6.62 (m,
1H), 7.08 (m, 2H), 7.16–7.22 (m, 3H), 7.28 (m, 2H),
7.34–7.39 (m, 3H), 7.48 (m, 2H), 7.58 (m, 2H), 7.61
(m, 2H), 7.70 (m, 1H), 7.95 (s, 1H), 8.42 (m, 1H),
10.46 (s, 1H). MS (EI): m/z 197 (100), 344 (22), 540
(41) M+. Anal. Calcd for C35H28N2O4: C, 77.76; H,
5.22; N, 5.18. Found: C, 77.37; H, 5.22; N, 5.15.
1
6.2.18. 3-[5-(3-Trifluoromethylphenyl)-2-furyl]acrylic
acid. From 5-(3-trifluoromethylphenyl)furan-2-carbal-
dehyde (960mg, 4mmol) according to general procedure
2. Yield 806mg (89%). H NMR (DMSO-d6): d 6.38 (d,
J = 16Hz, 1H), 7.02 (m, 1H), 7.31–7.40 (m, 1H and d,
J = 16Hz, 1H), 7.63 (m, 2H), 8.08 (m, 2H).
6.3.2. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(2-naphthyl)-2-furyl]acrylic acid amide (7b). From 3-[5-
(2-naphthyl)-2-furyl]acrylic acid (264mg, 1mmol)
according to general procedure 3. Purification: recrystal-
lization from toluene/ethanol. Yield 354mg (60%); mp
210ꢁC. IR (KBr): m = 3328, 3057, 1679, 1663, 1628,
1
1
6.2.19. 3-[4-(4-Methoxyphenyl)-2-furyl]acrylic acid.
From 4-(4-methoxyphenyl)furan-2-carbaldehyde (303
mg, 1.5mmol) according to general procedure 2. Yield
307mg (84%). 1H NMR (DMSO-d6): d 3.79 (s, 3H),
6.22 (d, J = 16Hz, 1H), 6.98 (m, 2H), 7.34(m, 1H),
7.40 (d, J = 16Hz, 1H), 7.55 (m, 2H), 8.23 (m, 1H).
1549, 1506cmꢀ1. H NMR (DMSO-d6): d 2.21 (s, 3H),
3.33 (s, 2H), 6.74(d, J = 16Hz, 1H), 6.96 (m, 2H),
6.98 (m, 1H), 7.02 (m, 2H), 7.23 (m, 1H), 7.39 (d,
J = 16Hz, 1H), 7.46–7.56 (m, 4H), 7.59–7.65 (m, 2H),
7.67 (m, 2H), 7.77 (m, 1H), 7.88–7.93 (m, 4H), 7.98
(m, 1H), 8.27 (m, 1H), 10.08 (s, 1H), 10.39 (s, 1H).
MS (EI): m/z 105 (32), 212 (84), 248 (50), 344 (100),
590 (31) M+. Anal. Calcd for C39H30N2O4: C, 79.30;
H, 5.12; N, 4.74. Found: C, 79.04; H, 5.15; N, 4.92.
6.2.20. 3-[5-(2-Nitrophenyl)-2-furyl]acrylic acid. From 5-
(2-nitrophenyl)furan-2-carbaldehyde (869mg, 4mmol)
according to general procedure 2. Yield 936mg (91%).
1H NMR (DMSO-d6): d 6.07 (d, J = 16Hz, 1H), 7.01–
7.09 (m, 2H), 7.32 (d, J = 16Hz, 1H), 7.55 (m, 1H),
7.68 (m, 1H), 7.85–7.92 (m, 2H).
6.3.3. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(1-naphthyl)-2-furyl]acrylic acid amide (7c). From 3-[5-
(1-naphthyl)-2-furyl]acrylic acid (264mg, 1mmol)
according to general procedure 3. Purification: recrystal-
lization from toluene. Yield 298mg (50%); mp 110ꢁC.
IR (KBr): m = 3252, 3052, 1668, 1622, 1594, 1545,
6.2.21. 3-[5-(3-Nitrophenyl)-2-furyl]acrylic acid. From 5-
(3-nitrophenyl)furan-2-carbaldehyde (869mg, 4mmol)
according to general procedure 2. Yield 904mg (88%).
1H NMR (DMSO-d6): d 6.42 (d, J = 16Hz, 1H), 7.08
(m, 1H), 7.41 (m, 1H and d, J = 16Hz, 1H), 7.70–7.76
(m, 1H), 8.16 (m, 1H), 8.26 (m, 1H), 8.56 (m, 1H).
1
1508cmꢀ1. H NMR (CDCl3): d 2.24(s, 3H), 3.58 (s,
2H), 6.39 (d, J = 16Hz, 1H), 6.64–6.70 (m, 2H), 7.06
(m, 2H), 7.13 (m, 2H), 7.35–7.48 (m, 8H), 7.59–7.67
(m, 4H), 7.75–7.80 (2H), 7.94 (s, 1H), 8.28 (m, 1H),
8.39 (m, 1H), 10.43 (s, 1H). MS (EI): m/z 44 (100), 60
(26), 247 (92), 590 (20) M+. Anal. Calcd for
C39H30N2O4: C, 79.30; H, 5.12; N, 4.74. Found: C,
79.19; H, 5.09; N, 4.82.
6.2.22. 3-[4-(4-Methylsulfonylphenyl)-2-furyl]acrylic acid.
From 4-(4-methylsulfonylphenyl)furan-2-carbaldehyde
(250mg, 1mmol) according to general procedure 2.
1
Yield 239mg (82%). H NMR (DMSO-d6): d 3.23 (s,
3H), 6.28 (d, J = 16Hz, 1H), 7.41 (d, J = 16Hz, 1H),
7.51 (m, 1H), 7.92 (m, 4H), 8.54 (m, 1H).
6.3.4. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-methylphenyl)-2-furyl]acrylic acid amide (7d). From
3-[5-(4-methylphenyl)-2-furyl]acrylic
acid
(229mg,
6.3. General procedure 3: Activation of various acids as
acid chlorides and reaction with aromatic amines
1mmol) according to general procedure 3. Purification:
recrystallization from toluene. Yield 459mg (82%); mp
193ꢁC. IR (KBr): m = 3305, 3026, 2921, 1662, 1627,
The various carboxylic acids were dissolved in toluene
and 0.1mL SOCl2 per mmol acid was added. The mix-
1553, 1506cmꢀ1 1H NMR (CDCl3): d 2.30 (s, 3H),
.
2.34(s, 3H), 3.68 (s, 2H), 6.42 (d, J = 16Hz, 1H), 6.61

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4595
(m, 2H), 7.15 (m, 4H), 7.23 (m, 3H), 7.45 (m, 2H), 7.53–
7.62 (s, 5H), 7.69 (m, 2H), 8.00 (s, 1H), 8.50 (m, 1H),
10.52 (s, 1H). MS (EI): m/z 211 (100), 344(9), 554(31)
M+. Anal. Calcd for C36H30N2O4: C, 77.96; H, 5.45;
N, 5.05. Found: C, 77.64; H, 5.42; N, 5.83.
(s, 3H), 3.34(s, 2H), 5.30 (d, J = 11Hz, 1H), 5.89 (d,
J = 18Hz, 1H), 6.68 (d, J = 16Hz, 1H), 6.75 (dd,
J = 18/11Hz, 1H), 6.94–6.98 (m, 3H), 7.03 (m, 2H),
7.11 (m, 1H), 7.36 (d, J = 16Hz, 1H), 7.49 (m, 2H),
7.55 (m, 3H), 7.62 (m, 1H), 7.67 (m, 2H), 7.75 (m,
3H), 7.87 (m, 1H), 10.84(s, 1H), 10.36 (s, 1H). MS
(EI): m/z 105 (33), 211 (29), 344 (100), 476 (54), 566
(12) M+ Anal. Calcd for C37H30N2O4: C, 78.43; H,
5.34; N, 4.91. Found: C, 78.28; H, 5.27; N, 4.99.
6.3.5. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-trifluoromethylphenyl)-2-furyl]acrylic acid amide (7e).
From 3-[5-(4-trifluoromethylphenyl)-2-furyl]acrylic acid
(282mg, 1mmol) according to general procedure 3.
Purification: recrystallization from toluene. Yield
434mg (71%); mp 222ꢁC. IR (KBr): m = 3321, 1660,
6.3.9. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-tert-butylphenyl)-2-furyl]acrylic acid amide (7i). From
3-[5-(4-tert-butylphenyl)-2-furyl]acrylic acid (270mg,
1mmol) according to general procedure 3. Purification:
recrystallization from ethanol. Yield 316mg (53%); mp
244ꢁC. IR (KBr): m = 3423, 2962, 1666, 1626, 1551,
1
1618, 1555, 1507, 1326cmꢀ1. H NMR (DMSO-d6): d
2.25 (s, 3H), 3.37 (s, 2H), 6.74(d, J = 16Hz, 1H),
6.99–7.05 (m, 5H), 7.29 (m, 1H), 7.40 (d, J = 16Hz,
1H), 7.50 (m, 2H), 7.61–7.70 (m, 4H), 7.80 (m, 3H),
7.89 (m, 1H), 7.96 (m, 2H), 10.04(s, 1H), 10.36 (s,
1H). MS (EI): m/z 37 (57), 212 (33), 265 (100), 344
(40), 608 (50) M+. Anal. Calcd for C36H27F3N2O4: C,
71.05; H, 4.47; N, 4.60. Found: C, 71.03; H, 4.65; N,
4.78.
1
1506cmꢀ1. H NMR (DMSO-d6): d 1.29 (s, 9H), 2.23
(s, 3H), 3.34(s, 2H), 6.65 (d, J = 16Hz, 1H), 6.92 (m,
1H), 6.98 (m, 2H), 7.03 (m, 3H), 7.35 (d, J = 16Hz,
1H), 7.48 (m, 4H), 7.54 (m, 1H), 7.60–7.69 (m, 5H),
7.77 (m, 1H), 7.87 (m, 1H), 10.09 (s, 1H), 10.37 (s,
1H). MS (EI): m/z 253 (100), 326 (22), 344 (11), 596
(25) M+. Anal. Calcd for C39H36N2O4: C, 78.50; H,
6.08; N, 4.69. Found: C, 78.37; H, 6.00; N, 4.89.
6.3.6. N-[3-Benzoyl-4-(4-methylphenylacetylamino)phen-
yl]-3-[5-(3-trifluoromethylphenyl)-2-furyl]acrylic
acid
amide (7f). From 3-[5-(3-trifluoromethylphenyl)-2-fu-
ryl]acrylic acid (226mg, 1mmol) according to general
procedure 3. Purification: column chromatography with
ethylacetate/n-hexane (1:1) afterwards recrystallization
from n-hexane/acetone. Yield 256mg (42%); mp
140ꢁC. IR (KBr): m = 3263, 3086, 1669, 1642, 1624,
6.3.10. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-methylsulfanylphenyl)-2-furyl]acrylic acid amide (7j).
From 3-[5-(4-methylsulfanylphenyl)-2-furyl]acrylic acid
(260mg, 1mmol) according to general procedure 3.
Purification: recrystallization from toluene. Yield
300mg (51%); mp 219ꢁC. IR (KBr): m = 3454, 3322,
1549, 1502cmꢀ1 1H NMR (CDCl3): d 2.33 (s, 3H),
.
1
3.69 (s, 2H), 6.51 (d, J = 16Hz, 1H), 6.64(d, J = 4Hz,
1 H), 6.77 (d, J = 4Hz, 1H), 7.15 (m, 2H), 7.24 (m,
2H), 7.44–7.49 (m, 4H), 7.52–7.58 (m, 2H), 7.63 (m,
1H), 7.68 (m, 3H), 7.79 (m, 1H), 7.90 (s, 1H), 7.98 (s,
1H), 8.53 (m, 1H), 10.54(s, 1H). MS (EI): m/z 265
(100) 266 (16), 344 (25), 609 (15), 608 (39) M+. Anal.
Calcd for C36H27F3N2O4: C, 71.03; H, 4.47; N, 4.60.
Found: C, 70.91; H, 4.58; N, 4.67.
2961, 1663, 1552, 1507, 1400cmꢀ1. H NMR (DMSO-
d6): d 2.25 (s, 3H), 2.52 (s, 3H), 3.35 (s, 2H), 6.66 (d,
J = 16Hz, 1H), 6.94(m, 1H), 6.98 (m, 2H), 7.04(m,
1H), 7.06 (m, 2H), 7.33–7.38 (m, 3H), 7.49 (m, 2H),
7.55 (m, 1H), 7.64(m, 1H), 7.68 (m, H4 ), 7.77 (m,
1H), 7.88 (m, 1H), 10.09 (s, 1H), 10.36 (s, 1H). MS
(EI): m/z 243 (100), 344 (12), 586 (41) M+. Anal. Calcd
for C36H30N2O4S: C, 73.70; H, 5.15; N, 4.77. Found:
C, 73.52; H, 5.13; N, 4.55.
6.3.7. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-ethylphenyl)-2-furyl]acrylic acid amide (7g). From 3-
[5-(4-ethylphenyl)-2-furyl]acrylic acid (242mg, 1mmol)
according to general procedure 3. Purification: recrystal-
lization from toluene. Yield 379mg (67%); mp 200ꢁC.
IR (KBr): m = 3319, 2966, 2924, 1662, 1629, 1551,
6.3.11. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-trifluoromethylsulfanylphenyl)-2-furyl]acrylic
acid
amide (7k). From 3-[5-(4-trifluoromethylsulfanylphen-
yl)-2-furyl]acrylic acid (236mg, 0.75mmol) according
to general procedure 3. Purification: recrystallization
from toluene/ethanol. Yield 245mg (57%); mp 219ꢁC.
IR (KBr): m = 3386, 1654, 1540, 1507, 1408, 1166,
1
1506cmꢀ1. H NMR (DMSO-d6): d 1.19 (t, J = 7Hz,
3H), 2.24(s, 3H), 2.63 (q, J = 7Hz, 2H), 3.35 (s, 2H),
6.66 (d, J = 16Hz, 1H), 6.93 (m, 1H), 6.98 (m, 2H),
7.04(m, 3H), 7.30 (m, 2H), 7.35 (d, J = 16Hz, 1H),
7.49 (m, 2H), 7.55 (m, 1H), 7.61–7.70 (m, 5H), 7.77
(m, 1H), 7.88 (m, 1H), 10.09 (s, 1H), 10.35 (s, 1H).
MS (EI): m/z 225 (100), 344 (11), 568 (38) M+. Anal.
Calcd for C37H32N2O4: C, 78.15; H, 5.67; N, 4.93.
Found: C, 77.88; H, 5.63; N, 4.99.
1
1116cmꢀ1. H NMR (DMSO-d6): d 2.26 (s, 3H), 3.36
(s, 2H), 6.73 (d, J = 16Hz, 1H), 7.00 (m, 3H), 7.05 (m,
2H), 7.29 (m, 1H), 7.40 (d, J = 16Hz, 1H), 7.50 (m,
2H), 7.59 (m, 2H), 7.64(m, 2H), 7.69 (m, 3H), 7.90
(m, 3H), 10.08 (s, 1H), 10.40 (s, 1H). MS (EI): m/z 297
(199), 344 (22), 640 (59) M+. Anal. Calcd for
C36H27F3N2O4S: C, 67.49; H, 4.25; N, 4.37. Found: C,
67.24; H, 4.41; N, 4.48.
6.3.8. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-vinylphenyl)-2-furyl]acrylic acid amide (7h). From 3-
[5-(4-vinylphenyl)-2-furyl]acrylic acid (240mg, 1mmol)
according to general procedure 3. Purification: recrystal-
lization from toluene/ethanol. Yield 201mg (35%); mp
206ꢁC. IR (KBr): m = 3320, 3057, 2920, 1661, 1653,
6.3.12. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-ethylsulfanylphenyl)-2-furyl]acrylic acid amide (7l).
From 3-[5-(4-ethylsulfanylphenyl)-2-furyl]acrylic acid
(137mg, 0.5mmol) according to general procedure 3.
Purification: recrystallization from ethanol. Yield
162mg (54%); mp 212ꢁC. IR (KBr): m = 3326, 2921,
1625, 1553, 1507cmꢀ1 1H NMR (DMSO-d6): d 2.23
.

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A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
1
1
1660, 1550, 1505, 1400cmꢀ1. H NMR (DMSO-d6): d
1.27 (t, J = 7Hz, 3H), 2.26 (s, 3H), 3.04(q, J = 7Hz,
2H), 3.36 (s, 2H), 6.68 (d, J = 16Hz, 1H), 6.94–7.07
(m, 6H), 7.35–7.50 (m, 5H), 7.54(d, J = 16Hz, 1H),
7.59–7.70 (m, 5H), 7.72–7.90 (m, 2H), 10.08 (s, 1H),
10.35 (s, 1H). MS (EI): m/z 257 (100), 601 (40)
[M+H]+. Anal. Calcd for C37H32N2O4S: C, 73.98; H,
5.37; N, 4.66. Found: C, 73.63; H, 5.35; N, 5.02.
1507cmꢀ1. H NMR (DMSO-d6): d 2.24(s, 3H), 3.34
(s, 2H), 6.67 (d, J = 16Hz, 1H), 6.93 (m, 1H), 6.97 (m,
2H), 7.03 (m, 2H), 7.07 (s, 1H), 7.32 (m, 2H), 7.35 (d,
J = 16Hz, 1H), 7.48 (m, 2H), 7.54 (m, 1H), 7.62 (m,
1H), 7.67 (m, 2H), 7.76 (m, 1H), 7.80 (m, 2H), 7.87
(m, 1H), 10.08 (s, 1H), 10.35 (s, 1H). MS (EI): m/z 215
(100), 344 (33), 558 (1) M+, 559 (83) [M+H]+. Anal. Cal-
cd for C35H27FN2O4: C, 75.26; H, 4.87; N, 5.01. Found:
C, 75.47; H, 4.84; N, 5.32.
6.3.13. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-methoxyphenyl)-2-furyl]acrylic acid amide (7m). From
3-[5-(4-methoxyphenyl)-2-furyl]acrylic acid (245mg,
1mmol) according to general procedure 3. Purification:
recrystallization from toluene. Yield 427mg (75%); mp
200ꢁC. IR (KBr): m = 3321, 3054, 2940, 1663, 1609,
6.3.17. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-cyanophenyl)-2-furyl]acrylic acid amide (7s). From
3-[5-(4-cyanophenyl)-2-furyl]acrylic
acid
(182mg,
0.5mmol) according to general procedure 3. Purifica-
tion: recrystallization from ethanol. Yield 182mg
(64%); mp 200ꢁC. IR (KBr): m = 3361, 2226, 1631,
1
1551, 1506, 1489, 1253cmꢀ1. H NMR (DMSO-d6): d
2.20 (s, 3H), 3.32 (s, 2H), 3.76 (s, 3H), 6.59 (d,
J = 16Hz, 1H), 6.86 (m, 2H), 6.94–6.99 (m, 6H), 7.30
(m, 1H), 7.44 (m, 2H), 7.54–7.60 (m, 2H), 7.65 (m,
4H), 7.73 (m, 1H), 7.83 (m, 1H), 9.98 (s, 1H), 10.23 (s,
1H). MS (EI): m/z 212 (11), 227 (100), 344 (11), 570
(30) M+. Anal. Calcd for C36H30N2O5: C, 75.77; H,
5.30; N, 4.91. Found: C, 75.58; H, 5.36; N, 5.11.
1557, 1507, 1403cmꢀ1 1H NMR (DMSO-d6): d 2.26
.
(s, 3H), 3.36 (s, 2H), 6.76 (d, J = 16Hz, 1H), 6.98–7.04
(m, 5H), 7.36 (m, 1H), 7.40 (d, J = 16Hz, 1H), 7.50–
7.68 (m, 3H), 7.69 (m, 1H), 7.79 (m, 2H), 7.88–7.91
(m, 2H), 7.94(m, 4H), 10.08 (s,1H), 10.39 (s, 1H). MS
(EI): m/z 222 (100), 344 (54), 566 (83) [M+H]+. Anal.
Calcd for C36H27N3O4: C, 76.45; H, 4.81; N, 7.43.
Found: C, 76.34; H, 4.91; N, 7.40.
6.3.14. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-trifluoromethoxyphenyl)-2-furyl]acrylic acid amide
6.3.18. N-[3-Benzoyl-4-(4-methylphenylacetylamino)phen-
yl]-3-[5-(3-nitrophenyl)-2-furyl]acrylic acid amide (7u).
From 3-[5-(3-nitrophenyl)-2-furyl]acrylic acid (257mg,
1mmol) according to general procedure 3. Purification:
column chromatography with ethylacetate/n-hexane
(2:3). Yield 270mg (46%); mp 208ꢁC. IR (KBr):
m = 3383, 3291, 3066, 1670, 1628, 1540, 1513, 1502,
(7n).
From
3-[5-(4-trifluoromethoxyphenyl)-2-fur-
yl]acrylic acid (298mg, 1mmol) according to general
procedure 3. Purification: recrystallization from toluene.
Yield 496mg (79%); mp 204ꢁC. IR (KBr): m = 3324,
1683, 1658, 1631, 1555, 1507, 1400, 1261, 1223cmꢀ1
.
1H NMR (CDCl3): d 2.31 (s, 3H), 3.68 (s, 2H), 6.45
(d, J = 16Hz, 1H), 6.62 (m, 1H), 6.68 (m, 1H), 7.13–
7.24 (m, 6H), 7.41–7.47 (m, 3H), 7.56 (m, 2H), 7.62
(m, 1H), 7.64–7.70 (m, 4H), 7.99 (s, 1H), 8.50 (m, 1H),
1
1403, 1348, 1245, 1198cmꢀ1. H NMR (DMSO-d6): d
2.26 (s, 3H), 3.38 (s, 2H), 6.75 (d, J = 16Hz, 1H), 7.00
(m, 3H), 7.04(m, 2H), 7.36 (d, J = 4Hz, 1H), 7.42 (d,
J = 16Hz, 1H), 7.50 (t, J = 8Hz, 2H), 7.62 (m, 2H),
7.69 (m, 2H), 7.76 (t, J = 8Hz, 1H), 7.79 (m, 1H), 7.88
(m, 1H), 8.16–8.21 (m, 2H), 8.51 (m, 1H), 10.03 (s,
1H), 10.37 (s, 1H). MS (EI): m/z 105 (28), 212 (55),
242 (100), 344 (55), 585 (65) M+. Anal. Calcd for
C35H27N3O6: C, 71.77; H, 4.65; N, 7.18. Found: C,
71.73; H, 4.76; N, 6.99.
10.51 (s, 1H). MS (EI): m/z 44 (35), 105 (21), 281
(100), 344(23), 624(30)
+
M
. Anal. Calcd for
C36H27F3N2O5: C, 69.23; H, 4.36; N, 4.48. Found: C,
69.41; H, 4.61; N, 4.58.
6.3.15. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-ethoxyphenyl)-2-furyl]acrylic acid amide (7o). From
3-[5-(4-ethoxyphenyl)-2-furyl]acrylic
acid
(258mg,
1mmol) according to general procedure 3. Purification:
recrystallization from toluene/ethanol. Yield 404mg
(69%); mp 183ꢁC. IR (KBr): m = 3447, 2982, 1653,
6.3.19. N-[3-Benzoyl-4-(4-methylphenylacetylamino)phen-
yl]-3-[5-(2-nitrophenyl)-2-furyl]acrylic acid amide (7v).
From 3-[5-(2-nitrophenyl)-2-furyl]acrylic acid (257mg,
1mmol) according to general procedure 3. Purification:
column chromatography with ethylacetate/n-hexane
(1:1) afterwards recrystallization from n-hexane/acetone.
Yield 363mg (62%); mp 150ꢁC. IR (KBr): m = 3300,
3110, 1717, 1663, 1634, 1573, 1512, 1334, 1233,
1609, 1559, 1508cmꢀ1 1H NMR (DMSO-d6): d 1.33
.
(t, J = 7Hz, 3H), 2.24(s, 3H), 3.35 (s, 2H), 4.07 (q,
J = 7Hz, 2H), 6.64(d, J = 16Hz, 1H), 6.90 (m, 2H),
6.93 (m, 2H), 6.97–7.05 (m, 4H), 7.34 (d, J = 16Hz,
1H), 7.49 (m, 2H), 7.56 (m, 1H), 7.63 (m, 1H), 7.69
(m, 4H), 7.77 (m, 1H), 7.87 (m, 1H), 10.09 (s, 1H),
10.34(s, 1H). MS (EI): m/z 105 (15), 157 (12), 241
(100), 584(24) M +. Anal. Calcd for C37H32N2O5: C,
76.01; H, 5.52; N, 4.79. Found: C, 75.79; H, 5.46; N,
4.80.
1
1198cm ꢀ1. H NMR (DMSO-d6): d 2.26 (s, 3H), 3.37
(s, 2H), 6.54(d, J = 16Hz, 1H), 6.98 (d, J = 4Hz, 1H),
6.99 (m, 2H), 7.02 (d, J = 4Hz, 1H), 7.04 (m, 2H), 7.37
(d, J = 16Hz, 1H), 7.48 (m, 2H), 7.61 (m, 3H), 7.67
(m, 2H), 7.73–7.79 (m, 2H), 7.88–7.93 (m, 3H), 10.02
(s, 1H), 10.36 (s, 1H). MS (EI): m/z 105 (66), 212
(100), 242 (64), 344 (60), 585 (61) M+. Anal. Calcd for
C35H27N3O6: C, 71.77; H, 4.65; N, 7.18. Found: C,
71.66; H, 4.75; N, 7.15.
6.3.16. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-fluorophenyl)-2-furyl]acrylic acid amide (7p). From 3-
[5-(4-fluorophenyl)-2-furyl]acrylic acid (232mg, 1mmol)
according to general procedure 3. Purification: recrystal-
lization from toluene. Yield 447mg (80%); mp 200ꢁC.
IR (KBr): m = 3422, 3324, 1684, 1661, 1637, 1555,
6.3.20. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-acetylphenyl)-2-furyl]acid amide (7w). From 3-[5-(4-

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4597
acetylphenyl)-2-furyl]acrylic acid (128mg, 0.5mmol)
according to general procedure 3. Purification: column
chromatography (EtOAc/n-hexane 3:2). Yield 93mg
(32%); mp 208ꢁC. IR (KBr): m = 3328, 1684, 1659,
6.3.24. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-aminophenyl)-2-furyl]acrylic acid amide (7aa). N-[3-
Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-(4-nitrophe-
nyl)-2-furyl]acrylic acid amide 7t (5.01g, 8.6mmol) and
tin(II) chloride dihydrate (8.38g, 37mmol) were dis-
solved in 100mL EtOAc. The mixture was heated under
reflux for 2h. Then, a saturated sodium bicarbonate
solution was added to reach a pH of 8. After extraction
with EtOAc for three times the organic layers were com-
bined and dried with anhydrous magnesium sulfate.
Solvent was evaporated in vacuo. Purification: recrystal-
lization from tetrahydrofuran/n-hexane. Yield 2.48g
(89%); mp 182ꢁC. IR (KBr): m = 1653, 1611, 1547,
1552, 1506, 1400cmꢀ1 1H NMR (DMSO-d6): d 2.24
.
(s, 3H), 2.49 (s, 3H), 3.34 (s, 2H), 6.73 (d, J = 16Hz,
1H), 6.97–7.05 (m, 5H), 7.31 (m, 1H), 7.39 (d,
J = 16Hz, 1H), 7.49 (m, 2H), 7.55 (m, 1H), 7.62 (m,
1H), 7.68 (m, 2H), 7.77 (m, 1H), 7.88 (m, 3H), 8.03
(m, 2H), 10.09 (s, 1H), 10.41 (s, 1H). MS (EI): m/z 44
(100), 75 (76), 91 (94), 239 (60), 582 (14) M+. Anal. Cal-
cd for C37H30N2O5: C, 76.27; H, 5.19; N, 4.81. Found:
C, 76.18; H, 5.12; N, 4.97.
1
1488cmꢀ1. H NMR (DMSO-d6): d 2.26 (s, 3H), 3.37
6.3.21. 4-(5-{2-[3-Benzoyl-4-(4-tolylacetylamino)]phenyl-
aminocarbonyl}vinyl-2-furyl)benzoic acid methylester
(s, 2H), 6.57 (d, J = 16Hz, 1H), 6.65 (m, 2H), 6.73 (m,
1H), 6.86 (m, 1H), 6.99 (m, 2H), 7.06 (m, 2H), 7.31 (d,
J = 16Hz, 1H), 7.46–7.53 (m, 4H), 7.57 (m, 1H), 7.64
(m, 1H), 7.69 (m, 2H), 7.77 (m, 1H), 7.87–7.91 (m,
1H), 10.08 (s, 1H), 10.27 (s, 1H). MS (EI): m/z 212
(100), 239 (19), 344 (94). 555 (50) M+. Anal. Calcd for
C35H29N3O4: C, 75.66; H, 5.26; N, 7.56. Found: C,
75.34; H, 5.28; N, 7.44.
(7x).
From
3-[5-(4-methoxycarbonylphenyl)-2-fur-
yl]acrylic acid (136mg, 0.5mmol) according to general
procedure 3. Purification: column chromatography (Et-
OAc/n-hexane 3:2). Yield 154mg (51%); mp 235 ꢁC. IR
1
(KBr): m = 3341, 1720, 1661, 1553, 1508, 1276cmꢀ1. H
NMR (DMSO-d6): d 2.26 (s, 3H), 3.37 (s, 2H), 3.88 (s,
3H), 6.75 (d, J = 16Hz, 1H), 7.00 (m, 3H), 7.06 (m,
2H), 7.30 (m, 1H), 7.40 (d, J = 16Hz, 1H), 7.51 (m,
2H), 7.58 (m, 2H), 7.62–7.71 (m, 2H), 7.78 (m, 1H),
7.90 (m, 3H), 8.04(m, 2H), 10.09 (s, 1H), 10.14 (s,
1H). MS (EI): m/z 255 (100), 344 (35), 598 (46) M+.
Anal. Calcd for C37H30N2O6: C, 74.23; H, 5.05; N,
4.68. Found: C, 74.06; H, 5.16; N, 4.80.
6.3.25. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-formylaminophenyl)-2-furyl]acrylic acid amide (7ac).
Formic acid (0.5mL) and 0.2mL acetanhydride were
dissolved in 30mL THF. The solution was cooled to
ꢀ10ꢁC. Then, a solution of N-[3-benzoyl-4-(4-tolylace-
tylamino)phenyl]-3-[5-(4-aminophenyl)-2-furyl]acrylic
acid amide 7aa (278mg, 0.5mmol) in 20mL THF was
added and the mixture was stirred for 12h. Because
the reaction has not run completely, additional 2mL
formic acid were added and the mixture was heated un-
der reflux until no educt was left (monitored by TLC).
After cooling, the mixture was poured into a saturated
sodium chloride solution. The resulting mixture was ex-
tracted with EtOAc for three times and the combined
organic layers were washed with sodium bicarbonate
solution, citric acid solution, and brine. After drying
with anhydrous magnesium sulfate the solvent was
evaporated in vacuo. Purification: recrystallization from
toluene/ethanol. Yield 180mg (58%); mp 235ꢁC. IR
6.3.22. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-methylsulfonylphenyl)-2-furyl]acrylic acid amide (7y).
From 3-[5-(4-methylsulfonylphenyl)-2-furyl]acrylic acid
(221mg, 0.75mmol) according to general procedure 3.
Purification: recrystallization from toluene/ethanol.
Yield 356mg (77%); mp 217ꢁC. IR (KBr): m = 3268,
1689, 1659, 1632, 1594, 1579, 1540, 1410, 1298cmꢀ1
.
1H NMR (DMSO-d6): d 2.25 (s, 3H), 3.25 (s, 3H),
3.35 (s, 2H), 6.75 (d, J = 16Hz, 1H), 6.98 (m, 2H),
7.03 (m, 3H), 7.36 (m, 1H), 7.41 (d, J = 16Hz, 1H),
7.50 (m, 2H), 7.56 (m, 1H), 7.63 (m, 1H), 7.68 (m,
2H), 7.77 (m, 1H), 7.89 (m, 1H), 7.99 (m, 4H), 10.10
(s, 1H), 10.43 (s, 1H). MS (ESI): m/z 519 (30), 619
(100) [M+H]+, 641 (77) [M+Na]+, 657 (40) [M+K]+.
Anal. Calcd for C36H30N2O6S: C, 69.89; H, 4.89; N,
4.53. Found: C, 69.52; H, 4.75; N, 4.50.
1
(KBr): m = 3433, 2922, 1675, 1607, 1560, 1510cmꢀ1. H
NMR (DMSO-d6): d 2.24(s, 3H), 3.35 (s, 2H), 6.64
(d, J = 16Hz, 1H), 6.92 (m, 1H), 6.98 (m, 3H), 7.04
(m, 2H), 7.35 (d, J = 16Hz, 1H), 7.49 (m, 2H), 7.56
(m, 1H), 7.61–7.76 (m, 9H), 7.88 (m, 1H), 10.05 (s,
1H), 10.06 (s, 1H), 10.33 (s, 1H). MS (EI): m/z 44
(100), 240 (36), 583 (4) M+. Anal. Calcd for
C36H29N3O5: C, 74.09; H, 5.01; N, 7.29. Found: C,
73.79; H, 4.97; N, 7.19.
6.3.23. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-ethylsulfonylphenyl)-2-furyl]acrylic acid amide (7z).
From 3-[5-(4-ethylsulfonylphenyl)-2-furyl]acrylic acid
(306mg, 1mmol) according to general procedure 3.
Purification: recrystallization from toluene/ethanol.
Yield 185mg (29%); mp 230ꢁC. IR (KBr): m = 3443,
6.3.26. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-acetylaminophenyl)-2-furyl]acrylic acid amide (7ad).
N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-(4-am-
inophenyl)-2-furyl]acrylic acid amide 7aa (555mg,
1mmol) was dissolved in dry DMF under an argon
atmosphere. The mixture was cooled to ꢀ5ꢁC and
2mL acetanhydride were added. After stirring for 12h
the mixture was poured into a saturated solution of so-
dium chloride to yield a solid. Purification: recrystalliza-
tion from toluene/ethanol. Yield 335mg (56%); mp
1
1700, 1653, 1508, 1145cmꢀ1. H NMR (DMSO-d6): d
1.13 (t, J = 7Hz, 3H), 2.26 (s, 3H), 3.32 (q, J = 7Hz,
2H), 3.36 (s, 2H), 6.76 (d, J = 16Hz, 1H), 6.99–7.07
(m, 5H), 7.36–7.40 (m, 1H), 7.43–7.49 (m, 1H), 7.51
(m, 2H), 7.58 (m, 2H), 7.63–7.70 (m, 2H), 7.79 (m,
1H), 7.91 (m, 1H), 7.96 (m, 2H), 8.02 (m, 2H), 10.09
(s, 1H), 10.43 (s, 1H). MS (ESI): m/z 43 (60), 57 (46),
105 (56), 212 (43), 289 (100), 632 (12) M+. Anal. Calcd
for C37H32N2O6S: C, 70.24; H, 5.10; N, 4.43. Found:
C, 69.91; H, 5.12; N, 4.48.
1
232ꢁC. IR (KBr): m = 3308, 1653, 1603, 1505cmꢀ1. H

4598
A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
NMR (DMSO-d6): 2.07 (s, 3H), 2.26 (s, 3H), 3.36 (s,
2H), 6.66 (d, J = 16Hz, 1H), 6.93 (m, 1H), 6.99 (m,
3H), 7.06 (m, 2H), 7.36 (d, J = 16Hz, 1H), 7.50 (m,
2H), 7.58 (m, 1H), 7.62–7.72 (m, 7H), 7.78 (m, 1H),
mixture was stirred at room temperature for 5h. Purifi-
cation: column chromatography (EtOAc). Yield 172mg
(73%); mp 255ꢁC. IR (KBr): m = 3336, 1664, 1618, 1548,
1
1508, 1154cmꢀ1. H NMR (DMSO-d6): d 2.26 (s, 3H),
7.90 (m, 1H), 10.08 (s, 2H), 10.35 (s, 1H). MS (EI): m/
z 212 (100), 254(95), 326 (60), 344(90), 597 (11) M
Anal. Calcd for C37H31N3O5: C, 74.36; H, 5.23; N,
7.03. Found: C, 74.54; H, 5.29; N, 7.38.
3.35 (s, 2H), 6.74(d, J = 16Hz, 1H), 6.99 (m, 2H),
7.01–7.06 (m, 3H), 7.30 (m, 1H), 7.40 (m, 3H), 7.49–
7.57 (m, 3H), 7.63–7.70 (m, 3H), 7.78 (m, 1H), 7.89–
7.97 (m, 3H), 10.12 (s, 1H), 10.44 (s, 1H). MS (EI): m/
z 212 (84), 326 (90), 344 (100), 619 (11) M+. Anal. Calcd
for C35H29N3O6S: C, 67.84; H, 4.72; N, 6.78. Found: C,
67.57; H, 4.67; N, 6.57.
+
.
6.3.27. N-(3-Benzoyl-4-trifluoroacetylaminophenyl)-3-[5-
(4-cyanophenyl)-2-furyl]acrylic acid amide (9). From 3-
[5-(4-cyanophenyl)-2-furyl]acrylic acid (239mg, 1mmol)
and N-(4-amino-2-benzoylphenyl)-trifluoroacetic acid
amide (308mg, 1mmol) according to general procedure
3. Purification: recrystallization from ethanol. Yield
338mg (72%). 1H NMR (DMSO-d6): d 6.78 (d,
J = 16Hz, 1H), 7.04(m, 1H), 7.37 (m, 1H), 7.34 (d,
J = 16Hz, 1H), 7.54(m, 3H), 7.66–7.73 (m, 3H), 7.89
(m, 1H), 7.95 (m, 4H), 8.00 (m, 1H), 10.54 (s, 1H),
11.31 (s, 1H).
6.3.31. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-(4-
phenyl-2-furyl)acrylic acid amide (11a). From 3-(4-phen-
yl-2-furyl)acrylic acid (191mg, 0.9mmol) according to
general procedure 3. Purification: recrystallization from
toluene. Yield 379mg (70%); mp 228ꢁC. IR (KBr):
m = 3299, 1655, 1629, 1560, 1509cmꢀ1
.
1H NMR
(DMSO-d6): d 2.24(s, 3H), 3.34(s, 2H), 6.61 (d,
J = 16Hz, 1H), 6.97 (m, 2H), 7.03 (m, 2H), 7.27 (m,
2H), 7.35–7.41 (m, 3H), 7.45–7.50 (m, 2H), 7.56 (m,
1H), 7.60–7.64(m, 3H), 7.67 (m, 2H), 7.76 (m, 1H),
7.87 (m, 1H), 8.30 (m, 1H), 10.07 (s, 1H), 10.35 (s,
1H). MS (ESI-HR): Calcd for C35H27N2O4: 539.1971.
Found: 539.2003 [M+H]+. Anal. Calcd for
C35H27N2O4: C, 77.76; H, 5.22; N, 5.18. Found: C,
77.52; H, 5.20; N, 5.37.
6.3.28. N-[3-Benzoyl-4-aminophenyl]-3-[5-(4-carbamoyl-
phenyl)-2-furyl]acrylic acid amide (10). N-(3-Benzoyl-4-
trifluoroacetylaminophenyl)-3-[5-(4-cyanophenyl)-2-fu-
ryl]acrylic acid amide (9) (423mg, 0.8mmol) was sus-
pended in a mixture of 15mL ethanol and 15mL
dioxane. Five milliliters of an aqueous solution of so-
dium hydroxide (20 %) and 4mL of an aqueous solution
of H2O2 (30%) were added and the mixture was heated
to 60ꢁC for 2h. After cooling the mixture was extracted
with EtOAc for three times. The combined organic lay-
ers were dried over anhydrous magnesium sulfate and
solvent was evaporated in vacuo. Purification: recrystal-
lization from ethanol. Yield 287mg (79%). IR (KBr):
6.3.32. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[4-
(4-methylphenyl)-2-furyl]acrylic acid amide (11b). From
3-[4-(4-methylphenyl)-2-furyl]acrylic
acid
(230mg,
1mmol) according to general procedure 3. Purification:
recrystallization from toluene/ethanol. Yield 422mg
(85%); mp 256ꢁC. IR (KBr): m = 3425, 1671, 1623,
1
1
m = 3466, 3348, 2922, 1634, 1567, 1416, 1249cmꢀ1. H
1560, 1515cmꢀ1. H NMR (DMSO-d6): 2.24(s, 3H),
NMR (DMSO-d6): d 6.70 (d, J = 16Hz, 1H), 6.86 (m,
1H), 6.96 (m, 3H), 7.32 (d, J = 16Hz, 1H), 7.35 (m,
1H), 7.54(m, 1H), 7.61 (m, 2H), 7.68 (m, 1H), 7.74
(m, 1H), 7.93 (m, 4H), 9.99 (s, 1H).
2.29 (s, 3H), 3.34(s, 2H), 6.60 (d, J = 16Hz, 1H), 6.97
(m, 2H), 7.03 (m, 2H), 7.19 (m, 2H), 7.23 (m, 1H),
7.35 (m, 1H), 7.46–7.50 (m, 4H), 7.55 (m, 1H), 7.62
(m, 1H), 7.67 (m, 2H), 7.75 (m, 1H), 7.86 (m, 1H),
8.24(m, 1H), 10.06 (s, 1H), 10.33 (s, 1H). MS (EI): m/
z 211 (60), 34(31), 554(100) M
C36H30N2O4: C, 77.96; H, 5.45; N, 5.05. Found: C,
77.77; H, 5.47; N, 5.03.
6.3.29. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-aminocarbonylphenyl)-2-furyl]acrylic
+. Anal. Calcd for
acid
amide
(7ab). From N-[3-benzoyl-4-aminophenyl]-3-[5-(4-car-
bamoylphenyl)-2-furyl]acrylic acid amide 10 (165mg,
0.3mmol) and 4-tolylacetic acid (45mg, 0.3mmol)
according to general procedure 3. Purification: recrystal-
lization from ethanol. Yield 54mg (23%); mp 198 ꢁC. IR
6.3.33. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[4-
amide
(4-trifluoromethylphenyl)-2-furyl]acrylic
acid
(11c). From 3-[4-(4-trifluoromethylphenyl)-2-furyl]-
acrylic acid (282mg, 1mmol) according to general pro-
cedure 3. Purification: recrystallization from toluene.
Yield 381mg (71%); mp 248ꢁC. IR (KBr): m = 3422,
1
(KBr): m = 3431, 1654, 1616, 1558, 1508, 1401cmꢀ1. H
NMR (DMSO-d6): d 2.24(s, 3H), 3.34(s, 2H), 6.74
(d, J = 16Hz, 1H), 6.98 (m, 3H), 7.03 (m, 2H), 7.22
(m, 1H), 7.34(m, 1H), 7.94 (m, 2H), 7.56 (m, 1H),
7.62 (m, 1H), 7.66 (m, 2H), 7.77 (m, 1H), 7.83–7.89
(m, 3H), 7.94–8.00 (m, 2H), 10.09 (s, 1H), 10.42 (s,
1H). MS (EI-HR): Calcd for C36H29N3O5: 583.2107.
Found: 583.2132 M+.
3125, 1669, 1620, 1559, 1508, 1326cmꢀ1 1H NMR
.
(DMSO-d6): d 2.24(s, 3H), 3.34(s, 2H), 6.64(d,
J = 16Hz, 1H), 6.93–9.98 (m, 2H), 7.02 (m, 2H), 7.38
(m, 2H), 7.45–7.50 (m, 2H), 7.56 (m, 1H), 7.60–7.68
(m, 3H), 7.76 (m, 3H), 7.85 (m, 3H), 8.46 (m, 1H),
10.07 (s, 1H), 10.37 (s, 1H). MS (EI): m/z 212 (24),
265 (41), 344 (30), 476 (28), 608 (100) M+. Anal. Calcd
for C36H27F3N2O4: C, 71.05; H, 4.47; N, 4.80. Found:
C, 70.82; H, 4.62; N, 4.78.
6.3.30. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[5-
(4-aminosulfonylphenyl)-2-furyl]acrylic acid amide (7ae).
3-[5-(4-Aminosulfonylphenyl)-2-furyl]acrylic acid (125
mg, 0.42mmol) and N0-(3-dimethylaminopropyl)-N-eth-
ylcarbodiimid*HCl (84mg, 0.44mmol) were suspended
in 5mL THF. N-(4-Amino-2-benzoylphenyl)-4-tolylace-
tic acid amide (131mg, 0.38mmol) was added and the
6.3.34. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[4-
(4-methoxyphenyl)-2-furyl]acrylic acid amide (11d).
From
3-[4-(4-methoxyphenyl)-2-furyl]acrylic
acid

A. Mitsch et al. / Bioorg. Med. Chem. 12 (2004) 4585–4600
4599
(244mg, 1mmol) according to general procedure 3.
Purification: column chromatography (EtOAc/n-hexane
3:2). Yield 106mg (21%); mp 241ꢁC. IR (KBr):
50% inhibition) were calculated from initial velocity of
three independent measurements of four to five different
concentrations of the respective inhibitor.
m = 3317, 1671, 1662, 1512, 1251cmꢀ1
.
1H NMR
(DMSO-d6): d 2.26 (s, 3H), 3.36 (s, 2H), 3.78 (s, 3H),
6.60 (d, J = 16Hz, 1H), 6.98 (m, 4H), 7.05 (m, 2H),
7.25 (m, 1H), 7.36 (d, J = 16Hz, 1H), 7.48–7.59 (m,
5H), 7.62–7.70 (m, 3H), 7.70 (m, 1H), 7.88 (m, 1H),
8.20 (m, 1H), 10.08 (s, 1H), 10.34(s, 1H). MS (EI):
m/z 227 (80), 344 (39), 570 (100) M+. Anal. Calcd for
C36H30N2O5: C, 75.77; H, 5.30; N, 4.91. Found: C,
75.51; H, 5.32; N, 5.18.
9. Molecular modeling
30
All molecular modeling was carried out using SYBYL
version 6.8/6.9 running on a Silicon Graphics O2
(R10000). Flexible docking was performed using
FlexX29 version 1.11. During ligand construction, the
FlexX command MAPREF and the perturbate algo-
rithm was used for the placement of the base fragment.
Default parameters were employed except the MAX_
6.3.35. N-[3-Benzoyl-4-(4-tolylacetylamino)phenyl]-3-[4-
(4-methylsulfonylphenyl)-2-furyl]acrylic
ENERGY value, which was set to 10kJmolꢀ1
.
acid
amide
(11e). From 3-[4-(4-methylsulfonylphenyl)-2-furyl]-
acrylic acid (228mg, 0.8mmol) according to general pro-
cedure 3. Purification: recrystallization from toluene/
ethanol. Yield 244mg (56%); mp 248ꢁC. IR (KBr):
Acknowledgements
The pGEX-DPR1 and pBC-RAM2 plasmids were
kindly provided by Prof. F. Tamanoi (UCLA). Finan-
cial support by the Deutsche Pharmazeutische Gesellsc-
haft is gratefully acknowledged. I.S. wishes to thank
Prof. Dr. S. Grabley for generous support and Ms. S.
Egner for technical assistance. We are grateful to Dr.
M. Bo¨hm for helpful discussions.
m = 3307, 1671, 1623, 1508, 1308cmꢀ1
.
1H NMR
(DMSO-d6): d 2.26 (s, 3H), 3.29 (s, 3H), 3.37 (s, 2H),
6.66 (d, J = 16Hz, 1H), 6.99 (m 2H), 7.05 (m, 2H),
7.40 (m, 2H), 7.50 (m, 2H), 7.58–7.70 (m, 4H), 7.78
(m, 1H), 7.87–7.97 (m, 5H), 8.52 (m, 1H), 10.09 (s,
1H), 10.38 (s, 1H). MS (EI): m/z 212 (45), 275 (58),
326 (100), 344 (60), 618 (10) M+. Anal. Calcd for
C36H30N2O6S: C, 69.89; H, 4.89; N, 4.53 found: C,
69.64; H, 4.55; N, 4.44.
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