Synthesis and structure - Activity relationships of carboxyflavones as structurally rigid CysLT1 (LTD4) receptor antagonists

Article abstract of DOI:10.1021/jm970179x

The synthesis and CysLT₁ receptor affinities of a new series of highly rigid 3'- and 4-'(2-quinolinylmethoxy)- or 3'- an 4-'[2-(2- quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT₁ receptor aff

Full text of DOI:10.1021/jm970179x

1428
J . Med. Chem. 1998, 41, 1428-1438
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of Ca r boxyfla von es a s
Str u ctu r a lly Rigid CysLT1 (LTD4) Recep tor An ta gon ists
Marie¨l E. Zwaagstra,† Henk Timmerman,† Andrea C. van de Stolpe,† Frans J . J . de Kanter,‡ Masahiro Tamura,§
Yasushi Wada,§ and Ming-Qiang Zhang*,†
Division of Medicinal Chemistry, Leiden/ Amsterdam Center for Drug Research, and Department of Organic Chemistry, Vrije
Universiteit, De Boelelann 1083, 1081 HV Amsterdam, The Netherlands, and Pharmaceutical Division, Tokyo Research
Laboratories, Kowa Company Ltd., 2-17-43, Noguchi-Cho, Higashimurayama, Tokyo 189, J apan
Received March 17, 1997
The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3′- and
4′-(2-quinolinylmethoxy)- or 3′- and 4′-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-car-
boxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM)
were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung
membranes. Structure-affinity relationship studies showed that the relative positions of the
carboxylic acid and the quinoline moiety were critical for CysLT1 affinities. While the carboxyl
is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole
has significant activity. The quinoline moiety may be connected to the flavone skeleton by an
ethenyl or a methoxy linker, but the substitution position is important for high affinity,
especially in the 6-carboxylated flavones. 4′-Substituted 6-carboxyflavones are essentially
inactive, whereas the 3′-substituted analogues have submicromolar CysLT1 affinity. Replace-
ment of the quinoline by other heteroaromates generally leads to decreased affinities, with
the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloro-
quinoline analogue is comparable in activity to the quinoline. Flavones having CysLT1 receptor
affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-
induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100
nM. Compound 5d (8-carboxy-6-chloro-3′-(2-quinolinylmethoxy)flavone, VUF 5087) was selected
for further research because of its high potency in the functional assay. This series contains
the most rigid CysLT1 receptor antagonists known to date, and they are useful in the
development of a CysLT1 antagonist model, which is discussed in the companion paper.
In tr od u ction
agents.11,12 Recent studies on such ‘antileukotrienes’
have demonstrated clinical efficacy in human asthma,
and both classes of agents are now considered the most
promising antiasthmatic therapeutics.2,6,13-l7
Asthma, characterized by a chronic inflammation of
the airways, affects about 5% of the population of
industrialized areas. Asthmatic reactions are mediated
by a wide range of endogenous substances, among which
cysteinyl leukotrienes (CysLTs) are most prominent.
During the last 2 decades CysLTs have been identified
as important bronchoconstrictors, and their pharmaco-
logical effects mimic the pathological changes seen in
asthma both in vitro and in vivo.l-8 The biological
actions of CysLTs are mediated via activation of at least
one specific membrane receptor, the CysLT1 receptor.9
CysLT1 receptor activation leads to bronchoconstriction,
increased mucus secretion, and bronchial hyperrespon-
siveness, all characteristic of asthma.
The unravelling of the biosynthetic pathway and the
pathological roles of CysLTs in human diseases1,10 has
led to the development of leukotriene biosynthesis
inhibitors, e.g., 5-lipoxygenase (5-LO) inhibitors and
5-lipoxygenase-activating protein (FLAP) inhibitors, and
CysLT1 receptor antagonists as potential therapeutic
Originally the development of new CysLT1 antago-
nists was mainly inspired by either FPL 55712 (sodium
7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypro-
pyl]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate), the
first CysLT1 receptor antagonist,18 or LTD4 analogues
with antagonistic properties.19-24 Later new lead struc-
tures were discovered, leading to the development of a
wide range of compounds such as indoles (e.g., ICI 204,-
219/Zafirlukast25-29), benzamides (e.g., ONO-1078/
Pranlukast30,31), thiazoles (e.g., Ro 24-5913/[(E)-4-[3-[2-
(4-cyclobutyl-2-thiazolyl)ethenyl]phenyl]amino]-2,2-di-
ethyl-4-oxobutanoic acid]32,33), and quinolines (e.g., RG
12553/[5-[7-[[3-(2-quinolinylmethoxy)phenyl]methoxy]-
4-oxo-4H-1-benzopyran-2-yl]-1H-tetrazole]34 and MK-
476/Montelukast35) as highly potent antagonists at the
CysLT1 receptor (Chart 1).
Structure-activity relationship studies on the differ-
ent classes of CysLT1 antagonists have revealed several
important structural features for high potency. It is
generally agreed that essential structural requirements
for CysLT1 receptor antagonists are (1) a lipophilic
anchor, which fits into the lipophilic pocket of the
CysLT1 receptor; (2) a central flat unit mimicking the
triene system of LTD4; (3) one or two acidic groups, as
* Corresponding author, current address: Scientific Development
Group, Department of Medicinal Chemistry, Organon Laboratories
Ltd., Newhouse ML1 5SH, Scotland, U.K. Tel: + 44 1698 732611.
Fax: + 44 1698 733252. E-mail: m.zhang@organon.akzonobel.nl.
† Leiden/Amsterdam Center for Drug Research, Vrije Universiteit.
‡ Department of Organic Chemistry, Vrije Universiteit.
§ Kowa Co. Ltd.
S0022-2623(97)00179-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/03/1998

Carboxyflavones as CysLT1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1429
Ch a r t 1. CysLT1 Receptor Antagonists from the Quinoline Class
Ch a r t 2. Evolution of the Target Structures
mimics of the peptide units or the C1-carboxylic acid of
LTD4; and (4) spacers to connect and preorganize these
elements. The lack of any of these characteristic groups
may be compensated by stronger interaction in other
regions of the receptor.36 Although several modeling
studies on CysLT1 receptor antagonists have been
reported,37-40 no general model describing the 3D align-
ment and interaction sites of all classes of ligands has
been reported yet, mainly due to the flexibility of the
ligands.
In our search for antiasthmatic drugs, we became
interested in the development of CysLT1 receptor an-
tagonists.41,42 Our attempts to find new lead structures
for CysLT1 receptor antagonists started with the syn-
thesis of a series of carboxylated flavonoid analogues
which led to identification of two new lead structures
(1 and 2), having weak CysLT1 affinities (Chart 2).42
Using 1 as a lead, we have developed a novel series of
carboxylated chalcones with potent CysLT1 antagonistic
activities.43 We now report our efforts in developing
rigid CysLT antagonists by optimization of the second
lead 2.
476 (Montelukast). This class of compounds generally
consists of a quinoline moiety connected to a central
phenyl ring by a two-atom spacer. The central phenyl
is connected to an additional, mostly aromatic group
containing an acidic substituent of variable length and
nature. The substitution pattern of the central phenyl
ring is either meta or para. The conformational freedom
of these compounds mainly arises from the flexibility
of the spacer groups. Conformational restriction of such
quinoline-containing CysLT1 antagonists can be achieved
most effectively by fixation of the spacer groups (Chart
2). The high rigidity of the target flavones (Chart 2)
would offer us the possibility to develop a general
CysLT1 antagonist model, in addition to potential an-
tiasthmatic agents.
Ch em istr y
The most convenient method for the preparation of
our target flavone derivatives is by a direct conversion
of the 2′-hydroxychalcones which we have synthesized
previously.43 Methods available for this conversion
involve either dehydrohalogenation44-46 or ring closure
under the influence of oxidants such as SeO247-49 or 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).50,51
As shown in Chart 1, the chalcones of our first series
(e.g., VUF 4936) belong to the quinoline-containing
CysLT1 receptor antagonists such as RG 12525 and MK-

1430 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Sch em e 1. Synthesis of Flavones from 2′-Hydroxychalcones
Zwaagstra et al.
Sch em e 2. Synthesis of Flavones via Cyclodehydration of 1,3-Diphenyl-1,3-propanediones
Dehydrohalogenation of chalcones appeared not suit-
able as a general synthetic strategy for our flavone
derivatives, because an unwanted bromination at the
flavone 6 or 8 position occurred. Only compound 18g
was prepared via this route. Reaction of 2′-hydroxy-
chalcones with SeO2 provided a convenient alternative
for the conversion of 3- or 4-[2-ethenyl(2-quinolinyl)]-
chalcones 4 to their corresponding flavones 5 (method
A, Scheme 1) with yields ranging from 5% to 55%.
However the same reaction failed to convert 2-quino-
linylmethoxy-substituted chalcones to the corresponding
flavones due to the cleavage of the ether bond. Since
benzyl ethers were not cleaved under the influence of
SeO2, benzyloxy-substituted chalcones 6 were used as
starting materials for hydroxyflavones 9. Alkylation of
9 and the subsequent hydrolysis of the resulting esters
10 gave access to target flavones 11 (Scheme 1).
However, the low overall yield and the difficulty to
remove traces of SeO2 urged us to look for an alternative
synthetic route to hydroxyflavones, which could be
performed on a multigram scale.
Method B (Scheme 2) was therefore developed for the
synthesis of hydroxyflavone 16. This method, which
involves coupling of a hydroxybenzoic ester with a
hydroxyacetophenone and subsequent cyclodehydration,
has been applied in the synthesis of a wide range of

Carboxyflavones as CysLT1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1431
Ta ble 1. Carboxylated Flavones and Their CysLT1 Receptor Affinities
a
no.
Ar
X-Y
position
R1
R2
R3
KD (nM) (% inhib)b
IC50c (nM)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
7a
7b
7c
10a
10b
11a
11b
11c
11d
18a
18b
18c
18d
18e
18f
18g
19a
19b
20
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
phenyl
CdC
CdC
CdC
CdC
CdC
CdC
CdC
CdC
4′
3′
3′
3′
3′
3′
3′
3′
4′
3′
3′
3′
4′
4′
3′
4′
3′
4′
4′
4′
3′
3′
3′
3′
3′
3′
4′
3′
3′
4′
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CN
H
H
H
H
H
H
H
H
H
H
H
CO2H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Cl
F
Me
Cl
H
CO2H
CO2H
CN
H
H
CO2H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
Br
Cl
CN4H
Br
270 ( 60
17 ( 4
42
100
15
17 ( 4
11 ( 3
127 ( 89
13 ( 3
28
(0%)
1730 ( 850
(28%)
408 ( 50
1750 ( 880
(50%)
55000 ( 7500
(23%)
(38%)
(32%)
17 ( 3
526 ( 88
(32%)
1100 ( 320
31 ( 9
1130 ( 210
101 ( 29
79 ( 18
210 ( 52
12 ( 3
504 ( 300
11000 ( 1900
307 + 98
382 ( 49
CdC
CdC
CdC
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CdC
CO2H
CO2H
H
phenyl
phenyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-quinolinyl
2-naphthyl
2-quinazolinyl
2-quinolinyl
2-naphthyl
2-quinazolinyl
2-benzothiazolyl
2-(1-methyl)benzimidazolyl
7-chloro-2-quinolinyl
2-quinolinyl
CO2Et
CO2Et
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CN4H
H
61
2-quinolinyl
2-quinolinyl
2-quinolinyl
CdC
CH2O
CONHSO2Ph
a
The affinity data were obtained from binding assays in guinea pig lung membranes vs [3H]LTD4. The data are means ( SD of three
b
determinations. In case no KD could be determined, percent inhibition is determined as the quotient of the maximum binding minus the
counting at 10-5 M drug concentration and the maximum binding times 100. c Determined by evaluation of the inhibitory effect of the
drug on LTD4-induced contraction of guinea pig ileum.
flavones.52-56 Although in this procedure benzyl and
tert-butyldimethylsilyl (TBDMS) proved unsuitable as
protective groups for the hydroxyl, protection of the
hydroxyl as an isopropyl ether did give good results.
Thus coupling of isopropoxybenzoate 12 with acetophe-
none 13 yielded 1,3-propanedione 14 which upon cy-
clization afforded flavone 15. Subsequent deprotection
and alkylation provided target flavones 18. Reaction
of 12 with the nonbrominated analogue of 13 gave an
unidentified mixture of products, probably due to the
instability of the latter under the required reaction
conditions.
Tetrazolylflavones were prepared from their corre-
sponding nitriles by reaction with sodium azide and
ammonium chloride. Phenylsulfonylamides were syn-
thesized by reaction of the carboxylic acid and phenyl-
sulfonylamine in the presence of a carbodiimide and
4-(dimethylamino)pyridine.26
carboxylic acid and the quinoline moiety seemed critical
for the CysLT1 affinities. Comparison of 5b,j seems to
suggest that in the 3′-substituted flavones the carboxylic
acid is preferred at the 8 position. In the 8-carboxylated
flavones, the quinoline can be attached to both the 3′
and 4′ positions, regardless of the linkers being an ether
or ethenyl group. Actually there is no significant
difference in the activities of compounds different only
in the linking unit. The 4′-substituted flavones are
generally 10-20 times less potent than their 3′-
substituted analogues (e.g., 5a vs 5b).
The position of the quinoline moiety is more critical
in the 6-carboxylated flavones. The 4′-substituted fla-
vone 5i is essentially inactive, whereas the 3′-substi-
tuted 5j has submicromolar CysLT1 affinity. The ac-
tivity of 5j clearly shows that the relative arrangement
of the carboxylic group and the heterocycle is important
for CysLT1 activity rather than the specific substitution
position of the group.
Resu lts a n d Discu ssion
Replacement of the 8-carboxylic acid by a nonacidic
ethyl ester or nitrile abolished the receptor affinity (10b
vs 11b and 5g vs 5d ). Replacement of the carboxylic
acid of 18g by a sulfonylamide gives 20 which has
comparable CysLT1 affinity. Replacement of carboxylic
acid by the well-known bioisoster tetrazole gave variable
influence on the activity (Table l).
CysLT1 receptor affinities of the flavones were deter-
mined in vitro by their ability to displace [3H]LTD4 from
its binding site on guinea pig lung membranes (Table
1), and the KD values of the most potent flavones are
approaching 10 nM. Structure-affinity relationship
analysis showed that the relative positions of the

1432 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Zwaagstra et al.
Ch a r t 3. Summarized Structure-Affinity Relationships of Carboxylated Flavones
Introduction of halogens or a methyl group at the 6
position of 8-carboxylated flavones generally did not
significantly affect the CysLT1 receptor affinities. There
is no significant difference in the affinities between
6-brominated and nonbrominated flavones (11b vs 18g
and 5b vs 5c). Within the series of 5b-f, halogen or
methyl substitution appeared not to affect CysLT1
affinity significantly except for the fluorine-substituted
analogue 5e which is somehow 10-fold less potent.
Since the chlorine and bromine analogues display
similar affinities, the decreased affinity of the fluorine
analogue is unlikely to be caused by electronic effects.
Within the series of 18, in which the quinoline moiety
of 18a was replaced by other aromatic groups, it appears
that the presence of a nitrogen atom in the aromatic
group is important for CysLT1 activity with quinoline
and 7-chloroquinoline being the groups of choice. The
naphthyl and phenyl derivatives (also compare 7a ,b vs
11a ,b and 11b vs 11c) displayed only little or no affinity,
whereas quinazoline (18c) and 1-methylbenzimidazole
(18e) derivatives retained reasonable activity.
The relative positions of the quinoline and the acidic
moiety are more critical than those previously observed
for the carboxylated chalcones.43 This most likely is due
to the increased rigidity of the flavone series. The
higher flexibility of the corresponding chalcones allows
them to adopt several conformations. The structure-
activity relationships of the present flavone series
therefore provide crucial information about the bioactive
conformation of these CysLT1 receptor antagonists,
although NOE difference spectroscopy indicated no
preferred geometry for these molecules.
tween the central phenyl ring and the quinoline may
be either trans-ethene or methoxy; the preferred sub-
stitution pattern for the central phenyl ring is meta.
Para substitution generally leads to a 10-fold decreased
affinity. The position of the carboxylic acid moiety can
be either 6, 7, or 8, with the 8-carboxylated flavone
having the highest CysLT1 affinity. Introduction of
halogens or a methyl group in the flavone 6 position does
not severely affect the CysLT1 affinity.
A selection of flavone derivatives has been shown to
antagonize the LTD4-induced contraction of guinea pig
ileum in a dose-dependent manner. With the avail-
ability of highly rigid CysLT1 antagonists such as 5b,
we are able to develop a more reliable CysLT1 antago-
nist model.57
Exp er im en ta l Section
A. P h a r m a cology. Ra d ioliga n d Disp la cem en t Stu d ies
w ith [3H]LTD4. The method is very similar to that described
previously.41 Briefly, a mixture of a total volume of 0.3 mL
containing 0.2 nM [3H]LTD4, guinea pig lung membrane
fractions ((170 µg/mL), and the testing compound in a 10 mM
piperazine-N,N′-bis(2-ethanesulfonic) acid buffer (pH 7.5) was
incubated at 22 °C for 30 min. The piperazine-N,N′-bis(2-
ethanesulfonic) acid buffer contains 10 mM CaCl2, 10 mM
MgCl2, 50 mM NaCl, 2 mM cysteine, and 2 mM glycine. The
reaction was terminated by the addition of 5 mL of ice-cold
Tris-HCl/NaCl buffer (10 mM/100 mM, pH 7.5). The mixture
was immediately filtered under vacuum (Whatman GF/C
filters), and the filters were washed once with 20 mL of ice-
cold buffer. The retained radioactivity was determined by a
liquid scintillation counter. In the saturation experiment, 2
µM LTD4 was used to define the nonspecific binding. A single,
saturable binding site with Bmax ) 988 fmol/mg of protein was
found from saturation experiments. The KD of [3H]LTD4 was
established to be 2.16 × 10-10 M, and no cooperativity was
detected when the data were analyzed by Hill plots (slope )
0.99).
Flavones 5b-d ,f and 18a , having CysLT1 receptor
affinities of 10-30 nM, were selected for determination
of their inhibitory effects against the LTD4-induced
contraction of guinea pig ileum in vitro. The IC50
values, which are the drug concentrations at which one-
half of the contraction is blocked, are shown in Table 1.
The flavones with the best CysLT1 receptor affinity also
displayed good in vivo antagonistic potency.
In Vitr o In h ibition of LTD4-In d u ced Con tr a ction of
Gu in ea P ig Ileu m . The method is similar to that described
previously.41 Male guinea pigs were killed by a sharp blow to
the head, and ileum sections were removed immediately. Each
segment (2 cm) was tied to a holder and attached to a
transducer by means of a thread, leaving the lumen open. The
ilea were then transferred to 20-mL organ baths maintained
at 29 °C and continuously aerated with 95% O2 and 5% CO2
and washed with Tyrode’s solution containing atropine (10-6
M) and pyrilamine (10-6 M). The contraction of ileum was
measured isotonically (resting tension was 1.0 g). The test
compounds were dissolved in dimethyl sulfoxide, and after 30-
min preincubation of the test compounds at different concen-
trations of (10-5 M-3.0 × 10-9 M), the contraction induced by
10-8 M LTD4 was obtained. Indomethacin (10-6 M) was added
in the organ baths 10 min before the addition of LTD4. IC50
values were calculated from the percent inhibition at the
different drug concentrations.
Con clu sion
We have described the development of a series of
carboxylated flavones, which are the most rigid CysLT1
receptor antagonists known so far. CysLT1 affinities of
8-carboxylated flavones are approaching the nanomolar
range and are comparable to those of their chalcone
precursors,43 showing that no affinity was lost upon
fixation of the molecular structures. The most impor-
tant structure-affinity relationships have been sum-
marized in Chart 3. Taking 5b (VUF 5017) as the
template of this series, we conclude that quinoline is
the optimal heterocyclic moiety. The connection be-
B. Ch em istr y. 1H and 13C NMR spectra were recorded
on a Bruker AC 200 spectrometer (1H, 200.13 MHz; 13C, 50.32

Carboxyflavones as CysLT1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1433
MHz) or a Bruker 400 MSL spectrometer (1H, 400.13 MHz;
13C, 100.63 MHz). 1H NMR chemical shifts (δ) are reported
in ppm relative to CHCl3 (δ ) 7.25 ppm) or DMSO-d5 (δ ) 2.5
ppm). 13C NMR chemical shifts (δ) are reported in ppm
relative to CDCl3 (δ ) 77.0 ppm) or DMSO-d6 (δ ) 39.5 ppm).
Coupling constants are given in Hz. 2D NMR (H-H and C-H
COSY) techniques were frequently used to support interpreta-
tion of 1D spectra. NOE difference spectra were recorded on
the Bruker 400 MSL spectrometer. The multiplicity of the
carbon signals was determined by DEPT or APT spectra or
by a combination of a normal decoupled carbon spectrum in
combination with a CH correlation. The symbols used are (p)
for primary, (s) for secondary, (t) for tertiary, and (q) for
quaternary carbon signals.
used for compound 5a above, yield 56%, mp >300 °C. 1H NMR
(400 MHz, 328 K, DMSO): δ 7.31 (s, 1H, H3), 7.55-7.59 (m,
3
1H, H6-quinoline), 7.61-7.66 (m, 1H, H5′), 7.65 (d, 1H, J )
16 Hz, PhCHdCH-quinoline), 7.75-7.79 (m, 1H, H7-quino-
3
3
line), 7.85 (d, 1H, J ) 8.6 Hz, H3-quinoline), 7.88 (d, 1H, J
) 16 Hz, PhCHdCH-quinoline), 7.93-7.96 (m, 2H, H4′, H5-
quinoline), 8.01 (d, 1H, 3J ) 8.6 Hz, H8-quinoline), 8.15 (d,
1H, 3J ) 7.8 Hz, H6′), 8.31 (d, 1H, 4J ) 2.6 Hz, H5 or H7),
4
3
8.34 (d, 1H, J ) 2.6 Hz, H5 or H7), 8.37 (d, 1H, J ) 8.6 Hz,
H4-quinoline), 8.57 (m, 1H, H2′). 13C NMR (100 MHz, 328 K,
DMSO): δ 106.72 (t), 116.69 (q), 119.90 (t), 124.83 (t), 125.68
(q), 125.97 (t), 126.20 (t), 126.87 (q), 127.47 (t), 128.43 (t),
129.32 (t), 129.51 (t), 129.90 (t), 130.58 (t), 130.67 (t), 131.17
(q), 132.74 (t), 136.22 (t), 137.03 (q), 137.76 (t), 147.44 (q),
152.59 (q), 155.01 (q), 162.37 (q), 163.60 (q), 175.08 (q), 199.89
(q). Anal. (C27H17NO4‚1.3HCl) C, H, N; Br: calcd, 15.36;
found, 14.90.
FAB (HRMS) was registered on
a Finnigan MAT 90
spectrometer equipped with a WATV Cs ion gun, operated at
a beam current of approximately 2 µA at 25 kV. High-
resolution mass spectra were recorded on a Finnigan MAT-
90. Melting points were measured on a Mettler FP-5 + FP-
52 apparatus equipped with a microscope and are uncorrected.
Starting materials were commercially available; chalcones
4 and 643 and acetophenone 1342 were prepared according to
literature procedures. All end products had elemental analysis
within 0.4% of theoretical value unless indicated otherwise.
However, compounds obtained in too small quantities to
perform the elemental analysis or having an elemental analy-
sis slightly outside of this range were found to be pure by both
spectroscopic and chromatographic criteria.
8-Ca r b oxy-6-ch lor o-3′-[2-(2-q u in olin yl)e t h e n yl]fla -
von e (5d ). The title compound was prepared by the method
used for compound 5a above, yield 8%, mp >300 °C. 1H NMR
(400 MHz, 300 K, DMSO): δ 7.35 (s, 1H, H3), 7.56-7.60 (m,
3
1H, H6-quinoline), 7.63 (t, 1H, J ) 7.8 Hz, H5′), 7.67 (d, 1H,
3J ) 16.3 Hz, PhCHdCH-quinoline), 7.75-7.79 (m, 1H, H7-
quinoline), 7.87 (d, 1H, 3J ) 8.5 Hz, H3-quinoline), 7.89 (d,
1H, 3J ) 16.3 Hz, PhCHdCH-quinoline), 7.94-7.97 (m, 2H,
H5-quinoline, H4′), 8.00 (d, 1H, 3J ) 8.3 Hz, H8-quinoline),
4
3
8.13 (d, 1H, J ) 2.7 Hz, H5 or H7), 8.17 (d, 1H, J ) 7.9 Hz,
H6′), 8.20 (d, 1H, 4J ) 2.7 Hz, H5 or H7), 8.37 (d, 1H, 3J ) 8.5
Hz, H4-quinoline), 8.61 (s, 1H, H2′). 13C NMR (100 MHz, 335
K, DMSO): δ 106.56 (t, C3), 119.91 (t, C3-quinoline), 124.88
(t, C2′), 125.32 (q), 125.61 (q), 126.00 (t, C6-quinoline), 126.26
(t, C4′ or C6′), 126.90 (t, C5 or C7), 127.49 (t, C4′ or C6′), 128.44
(t, C8-quinoline), 129.04 (q), 129.35 (t, C5′), 129.54 (t, C7-
quinoline), 129.91 (t, C-olefin), 130.56 (C5-quinoline), 131.25
(q), 132.80 (t, C-olefin), 134.82 (t, C5 or C7), 136.25 (C4-
quinoline), 137.04 (q), 147.45 (q), 152.10 (q), 155.04 (q), 162.43
(q), 163.86 (q), 175.37 (q), 199.84 (q). Anal. (C27H16ClNO4‚
1.1H2O) C, H, N, Cl.
Meth od A. Gen er a l P r oced u r e for th e P r ep a r a tion of
F la von es 5a -k a n d 6a ,b a s Exem p lified by th e P r ep a r a -
tion of F la von e 5a . A mixture of 3′-carboxy-2′-hydroxy-4-
[2-(2-quinolinyl)ethenyl]chalcone (2.1 g, 5 mmol) and selenium
dioxide (1.22 g, 11 mmol) in 50 mL of dioxane was refluxed
for 8 h. The reaction mixture was filtered while was hot. The
crude product precipitated from the mother liquor upon cooling
and was collected by filtration. Two recrystallizations from
DMF afforded 5a as a pure crystalline solid, yield 44%, mp
268.1-270.0 °C. 1H NMR (400 MHz, 348 K, DMSO): δ 7.16
3
(s, 1H, H3), 7.57 (t, 2H, J ) 7.6 Hz, H6, H6-quinoline), 7.65
8-Ca r b oxy-6-flu or o-3′-[2-(2-q u in olin yl)e t h e n yl]fla -
von e (5e). The title compound was prepared by the method
used for compound 5a above, yield 30%, mp > 300 °C. 1H
NMR (400 MHz, 335 K, DMSO): δ 7.28 (s, 1H, H3), 7.56-
7.59 (m, 1H, H6-quinoline), 7.64 (t, 1H, 3J ) 7.8 Hz, H5′), 7.66
(d, 1H, 3J ) 16.4 Hz, H-olefin), 7.75-7.79 (m, 1H, H7-
quinoline), 7.85 (d, 1H, 3J ) 8.5 Hz, H3-quinoline), 7.89 (d,
1H, 3J ) 16.4 Hz, H-olefin), 7.94-7.97 (m, 3H, H5/7, H5-
(d, 1H, 3J ) 16.4 Hz, HR), 7.76 (ddd, 1H, 3J ) 8.3 Hz, 3J ) 6.9
4
3
Hz, J ) 1.3 Hz, H7-quinoline), 7.88 (d, 1H, J ) 8.5 Hz, H3-
3
quinoline), 7.90 (d, 1H, J ) 16.4 Hz, Hâ), 7.92-7.96 (m, 3H,
H5-quinoline, H2′, H6′), 8.01 (d, 1H, 3J ) 8.3 Hz, H8-
quinoline), 8.25-8.29 (m, 4H, H3′, H5′, H5, H7), 8.36 (d, 1H,
3J ) 8.5 Hz, H4-quinoline). 13C NMR (100 MHz, 348 K,
DMSO): δ 106.24 (t), 119.78 (t), 121.56 (q), 123.89 (q), 124.42
(t), 125.97 (t), 126.64 (t), 126.79 (q), 127.36 (t), 127.38 (t),
128.32 (t), 128.70 (t), 129.46 (t), 130.35 (q), 130.63 (t), 132.52
(t), 135.63 (t), 136.18 (t), 139.45 (q), 147.29 (q), 153.44 (q),
3
quinoline, H4′), 8.02 (d, 1H, J ) 8.4 Hz, H8-quinoline), 8.09
3
4
3
(dd, 1H, J ) 8.5 Hz, J ) 3.2 Hz, H5/7), 8.16 (d, 1H, J ) 7.8
Hz, H6′), 8.37 (d, 1H, J ) 8.5 Hz, H4-quinoline), 8.57 (br s,
1H, H2′). 13C NMR (100 MHz, 335 K, DMSO): δ 106.04 (t,
154.80 (q), 161.80 (q), 164.75 (q), 176.07 (q). Anal. (C27H17
-
2
NO4‚0.9H2O) C, H, N.
C3), 113.63 (t, C5/7, J CF ) 23.4 Hz), 119.90 (t, C3-quinoline),
2
3
123.20 (t, C5/7, J CF ) 26.8 Hz), 124.25 (q, J CF ) 7.0 Hz),
8-Car boxy-3′-[2-(2-qu in olin yl)eth en yl]flavon e (5b). The
title compound was prepared by the method used for compound
5a above, yield 52%, mp >300 °C. 1H NMR (400 MHz, 368 K,
DMSO): δ 7.20 (s, 1H, H3), 7.59 (t, 1H, 3J ) 7.7 Hz, H6), 7.62-
7.66 (m, 1H, H6-quinoline), 7.67 (t, 1H, 3J ) 7.7 Hz, H5′), 7.70
(d, 1H, 3J ) 16.3 Hz, PhCHdCHquinoline), 7.81-7.86 (m, 1H,
H7-quinoline), 7.95 (d, 1H, 3J ) 7.7 Hz, H4′ or H6′), 7.97-
8.00 (m, 1H, H4′ or H6′), 7.98 (d, 1H, 3J ) 8.6 Hz, H3-
3
124.82 (t, C2′), 125.57 (q, J CF ) 7.0 Hz), 125.97 (t, C6-
quinoline), 126.18 (t, C6′), 126.88 (q), 127.47 (t, C5-quinoline),
128.40 (t, C8-quinoline), 129.31 (t, C5′), 129.52 (t, C7-quino-
line), 129.86 (t, C-olefin), 130.52 (t, C4′), 131.26 (q), 132.79 (t,
C-olefin), 136.25 (t, C4-quinoline), 137.03 (q), 147.40 (q), 150.08
1
(q), 155.00 (q), 157.64 (q, J CF ) 247.8 Hz, C6), 162.37 (q),
163.73 (q), 175.56 (q). Anal. (C27H16FNO4‚0.7HCl) C, H,
3
N, F.
quinoline), 8.00 (d, 1H, J ) 16.3 Hz, PhCHdCH-quinoline),
8.12 (d, 1H, 3J ) 8.5 Hz, H5-quinoline), 8.17-8.20 (m, 1H, H8-
quinoline), 8.29 (m, 1H, H5/7), 8.31 (m, 1H, H5/7), 8.50 (d, 1H,
3J ) 8.6 Hz, H4-quinoline), 8.57-8.58 (br s, 1H, H2,). 13C
NMR (100 MHz, 368 K, DMSO): δ 106.64 (t, C3), 119.65 (t,
C3-quinoline), 121.70 (q), 123.93 (q), 124.40 (t, C6), 124.88 (t,
C2′), 126.35 (t, C6-quinoline), 126.42 (t, C8-quinoline), 126.76
(t, C5-quinoline), 126.81 (q), 127.50 (t, C4′ or C6′), 128.01 (t,
C-olefin), 128.66 (t, C5 or C7), 129.23 (t, C5′), 130.19 (t, C7-
quinoline), 130.29 (t, C4′ or C6′), 131.47 (q), 134.60 (t, C-olefin),
135.60 (t, C5 or C7), 136.65 (q), 137.68 (t, C4-quinoline), 145.50
(q), 153.49 (q), 154.34 (q), 161.94 (q), 164.67 (q), 176.10 (q).
Anal. (C27H17NO4‚1.3HCl) C, H, N.
8-Ca r b oxy-6-m e t h yl-3′-[2-(2-q u in olin yl)e t h e n yl]fla -
von e (5f). The title compound was prepared by the method
used for compound 5a above, yield 35%, mp >300 °C. 1H NMR
(400 MHz, 335 K, DMSO): δ 2.48 (s, 3H, ArCH3), 7.21 (s, 1H,
H3), 7.55-7.59 (m, 1H, H6-quinoline), 7.63 (t, 1H, J ) 7.5 Hz,
3
H5′), 7.64 (d, 1H, J ) 15.6 Hz, H-olefin), 7.74-7.78 (m, 1H,
H7-quinoline), 7.86 (d, 1H, 3J ) 8.5 Hz, H3-quinoline), 7.89
(d, 1H, 3J ) 15.6 Hz, H-olefin), 7.92-7.96 (m, 2H, H5-
3
quinoline, H4′), 8.02 (d, 1H, J ) 8.4 Hz, H8-quinoline), 8.06
(d, 1H, 4J ) 2.2 Hz, H5/7), 8.12 (d, 1H, 4J ) 2.2 Hz, H5/7),
3
3
8.15 (d, 1H, J ) 8.2 Hz, H6′), 8.36 (d, 1H, J ) 8.5 Hz, H4-
quinoline), 8.56 (s, 1H, H2′). 13C NMR (50 MHz, DMSO): δ
20.27 (p), 106.73 (t), 120.28 (t), 121.38 (q), 124.03 (q), 124.93
(t), 126.35 (t), 126.42 (t), 127.14 (q), 127.88 (t), 128.67 (t),
8-Ca r b oxy-6-b r om o-3′-[2-(2-q u in olin yl)e t h e n yl]fla -
von e (5c). The title compound was prepared by the method

1434 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Zwaagstra et al.
128.75 (t), 129.63 (t), 129.89 (t), 129.95 (t), 130.81 (t), 131.67
(q), 133.11 (t), 134.52 (q), 136.63 (t), 137.11 (q), 137.23 (t),
147.62 (q), 152.19 (q), 155.32 (q), 162.04 (q), 165.33 (q), 176.69
(t). Anal. (C28H19NO4‚1.9HCl) C, H; N: calcd, 2.79; found,
3.33.
1H, 3J ) 8.6 Hz, H3-quinoline), 7.92 (d, 1H, 3J ) 16.4 Hz,
H-olefin), 7.94-7.96 (m, 2H, H4, H6), 8.01 (d, 1H, 3J ) 8.3
3
Hz, H5-quinoline), 8.03 (d, 1H, J ) 8.7 Hz, H8), 8.06 (d, 1H,
3J ) 7.9 Hz, H8-quinoline), 8.21 (dd, 1H, 3J ) 8.7 Hz, 4J ) 1.9
3
Hz, H7), 8.38 (d, 1H, J ) 8.6 Hz, H4-quinoline), 8.42 (d, 1H,
4J ) 1.9 Hz, H5), 8.46 (s, 1H, H2′). 13C NMR (100 MHz, 335
K, DMSO): δ 107.59, 108.23, 117.39, 119.73, 120.28, 123.54,
124.69, 126.19, 126.85, 127.49, 128.07, 129.34, 129.68, 129.99,
130.41, 131.05, 133.02, 136.41, 136.55, 137.03, 147.03, 154.89,
157.49, 162.62, 175.38. Anal. (C27H16N2O2‚0.7H2O) C, H, N.
6-Ch lor o-8-cya n o-3′-[2-(2-q u in olin yl)et h en yl]fla von e
(5g). The title compound was prepared by the method used
for compound 5a above, yield 53%, mp 281.2-281.6 °C. 1H
NMR (400 MHz, 335 K, DMSO): δ 7.37 (s, 1H, H3), 7.56-
7.60 (m, 1H, H6-quinoline), 7.69 (d, 1H, 3J ) 16.5 Hz, H-olefin),
7.70-7.74 (m, 1H, H5′), 7.75-7.79 (m, 1H, H7-quinoline), 7.85
(d, 1H, 3J ) 8.6 Hz, H3-quinoline), 7.90-8.07 (m, 5H, H-olefin,
H4′, H6′, H5-quinoline, H8-quinoline), 8.27 (d, 1H, 4J ) 1.9
Hz, H5/7), 8.38 (d, 1H, 3J ) 8.5 Hz, H4-quinoline), 8.49 (s, 1H,
3′-(Ben zyloxy)-8-ca r boxyfla von e (7a ): yield 50%, mp
244.8-246.8 °C. 1H NMR (200 MHz, DMSO): δ 5.20 (s, 2H,
PhCH2O), 7.22 (s, 1H, H3), 7.24-7.26 (m, 1H, H4′), 7.44-7.61
(m, 7H, PhCH2O, H6, H5′), 7.82 (d, 1H, 3J ) 7.8 Hz, H6′), 7.95
(s, 1H, H2′), 8.26 (dd, 1H, 3J ) 7.8 Hz, 4J ) 1.7 Hz, H5 or H7),
H2′), 8.54 (d, 1H, 4J ) 1.9 Hz, H5/7). Anal. (C27H15
ClN2O2‚0.3H2O) C, H, N, Cl.
-
3
4
8.30 (dd, 1H, J ) 7.3 Hz, J ) 1.7 Hz, H5 or H7). 13C NMR
(50 MHz, DMSO): δ 69.24 (s), 106.49 (t), 111.90 (t), 118.63
(t), 118.78 (t), 121.33 (q), 123.95 (q), 124.63 (t), 127.77 (t),
127.87 (t), 128.22 (t), 129.10 (t), 129.97 (t), 132.02 (q), 136.18
(t), 136.44 (q), 153.58 (q), 158.55 (q), 161.92 (q), 165.09 (q),
176.42 (q). Anal. (C27H16O5‚0.5DMF) H, N; C: calcd, 72.21;
found, 71.61.
7-Car boxy-3′-[2-(2-qu in olin yl)eth en yl]flavon e (5h ). The
title compound was prepared by the method used for compound
5a above, yield 35%, mp >300 °C. 1H NMR (200 MHz,
DMSO): δ 7.30 (s, 1H, H3), 7.55-7.61 (m, 1H, H6-quinoline),
3
3
7.65 (t, 1H, J ) 7.8 Hz, H5′), 7.76 (d, 1H, J ) 16.3 Hz, Ha),
7.75-7.82 (m, 1H, H7-quinoline), 7.92 (d, 1H, 3J ) 9.3 Hz, H3-
quinoline), 7.96-8.09 (m, 5H, H4′, H6, H5-quinoline, H8-
4′-(Ben zyloxy)-8-ca r boxyfla von e (7b): yield 80%, mp
203.2-209.1 °C. 1H NMR (200 MHz, DMSO): δ 5.22 (s, 2H,
ArCH2O), 7.06 (s, 1H, H3), 7.19 (d, 2H, 3J ) 8.9 Hz, H3′, H5′),
7.36-7.54 (m, 6H, H6, Ph), 8.17 (d, 2H, 3J ) 8.9 Hz, H2′, H6′),
8.21-8.27 (m, 2H, H5, H7), 13.50 (br s, 1H, CO2H). 13C NMR
(50 MHz, DMSO): δ 69.28 (s), 104.83 (t), 115.10 (q), 121.35
(q), 122,98 (q), 123.89 (q), 124.48 (t), 127.60 (t), 127.78 (t),
128.20 (t), 128.25 (t), 128.95 (t), 135.79 (t), 136.25 (q), 153.52
(q), 161.14 (q), 162.36 (q), 164.99 (q), 176.14 (q).
3
quinoline, Hb), 8.13-8.17 (m, 1H, H6′), 8.16 (d, 1H, J ) 8.2
3
Hz, H5), 8.42 (d, 1H, J ) 8.4 Hz, H4-quinoline), 8.43 (d, 1H,
4J ) 1.1 Hz, H8), 8.57 (br s, 1H, H2′). 13C NMR (50 MHz,
DMSO): δ 107.32 (t), 119.84 (t), 119.90 (t), 124.94 (t), 125.14
(t), 125.23 (t), 125.76 (q), 126.19 (t), 126.34 (t), 126.88 (q),
127.65 (t), 128.18 (t), 129.46 (t), 129.60 (t), 129.83 (t), 130.48
(t), 131.31 (q), 133.11 (t), 135.60 (q), 136.65 (t), 136.97 (q),
155.05 (q), 155.15 (q), 162.65 (q), 165.81 (q), 176.60 (q).
6-Ca r boxy-4′-[2-(2-qu in olin yl)eth en yl]fla von e (5i). The
title compound was prepared by the method used for compound
5a above, yield 28%, mp >300 °C. 1H NMR (400 MHz, 330 K,
DMSO): δ 7.10 (s, 1H, H3), 7.55-7.59 (m, 1H, H6-quinoline),
7.64 (d, 1H, 3J ) 16.4 Hz, PhCHdCH-quinoline), 7.74-7.78
6-Ch lor o-3′-[2-(2-q u in olin yl)et h en yl]-8-(5-t et r a zolyl)-
fla von e (19a ). A mixture of cyanoflavone 5g (0.45 g, 1 mmol),
sodium azide (0.32 g, 5 mmol), and ammonium chloride (0.27
g, 5 mmol) in 30 mL of DMF was heated at 100 °C for 3 days.
The reaction mixture was poured into water and acidified to
pH 5. The precipitate was collected by filtration, dried, and
recrystallized from ethanol/DMF, yield 9%, mp >300 °C. 1H
NMR (400 MHz, 335 K, DMSO): δ 7.37 (s, H, H3), 7.58-7.65
(m, 3H, H6-quinoline, H5′, H-olefin), 7.76-7.80 (m, 1H, H7-
3
(m, 1H, H7-quinoline), 7.86 (d, 1H, J ) 8.7 Hz, H8), 7.89 (d,
1H, 3J ) 8.5 Hz, H3-quinoline), 7.90 (d, 1H, 3J ) 16.4 Hz,
PhCHdCH-quinoline), 7.90-7.93 (m, 1H, H5-quinoline), 7.93
3
3
(d, 2H, J ) 8.6 Hz, H3′, H5′), 8.01 (d, 1H, J ) 8.5 Hz, H8-
quinoline), 8.17 (d, 2H, 3J ) 8.6 Hz, H2′, H6′), 8.32 (dd, 1H, 3J
) 8.7 Hz, 4J ) 2.1 Hz, H7), 8.36 (d, 1H, 3J ) 8.5 Hz,
3
quinoline), 7.87 (d, 1 H, J ) 8 Hz, H3-quinoline), 7.92-8.05
(m, 5H, H4′, H6′, H-olefin, H5-quinoline, H8-quinoline), 8.25
H4-quinoline), 8.60 (d, 1H, J ) 2.1 Hz, H5). 13C NMR (100
(d, 1H, J ) 2.4 Hz, H5), 8.41 (s, 1H, H2′), 8.44 (d, 1H, J )
4
4
4
3
MHz, 328 K, DMSO): δ 106.96 (t), 118.46 (q), 118.57 (t), 119.87
(t), 122.81 (q), 126.09 (t), 126.19 (t), 126.67 (t), 126.93 (q),
127.48 (t), 127.54 (t), 128.51 (t), 129.56 (t), 130.39 (q), 130.84
(t), 132.57 (t), 134.14 (t), 136.26 (t), 139.60 (q), 147.48 (q),
154.94 (q), 162.01 (q), 162.19 (q), 166.03 (q), 176.46 (q). Anal.
(C27H17NO4‚Se(OH)2) C; H: calcd, 4.23; found, 4.69. N: calcd,
3.09; found, 5.36.
2.3 Hz, H7), 8.47 (d, 1H, J ) 8.5 Hz, H4-quinoline), 9.54 (s,
1H, CN4H). 13C NMR (50 MHz, DMSO): δ 106.08 (t), 122.25
(t), 122.36 (t), 125.04 (t), 125.31 (q), 125.52 (q), 126.19 (t),
126.61 (t), 127.33 (q), 127.42 (t), 127.93 (t), 128.74 (t), 129.55
(q), 129.65 (t), 129.89 (t), 131.42 (q), 132.11 (t), 132.24 (t),
132.53 (t), 136.73 (t), 137.19 (q), 147.68 (q), 150.59 (q), 155.37
(q), 162.72 (q), 173.22 (q), 176.49 (q). MS: m/z 477 [M•-] for
35Cl, 479 [M•-] for 37Cl.
6-Ca r boxy-3′-[2-(2-qu in olin yl)eth en yl]fla von e (5j). The
title compound was prepared by the method used for compound
5a above, yield 5%, mp 275-277 °C. 1H NMR (400 MHz, 335
K, DMSO): δ 7.21 (s, 1H, H3), 7.56-7.60 (m, 1H, H6-
3′-[2-(2-Qu in olin yl)eth en yl]-6-(5-tetr azolyl)flavon e (19b).
This compound was prepared in a similar way from the
corresponding cyano precursor as described for 19a , yield 10%,
mp >300 °C. 1H NMR (400 MHz, 335 K, DMSO): δ 7.20 (s,
1H, H3), 7.66-7.71 (m, 2H, H5′, H6-quinoline), 7.80 (d, 1H,
3J ) 16.2 Hz, H-olefin), 7.86-7.90 (m, 1H, H7-quinoline), 7.96
3
quinoline), 7.64-7.68 (m, 1H, H5′), 7.67 (d, 1H, J ) 7.8 Hz,
H8), 7.70 (d, 1H, 3J ) 16.5 Hz, H-olefin), 7.75-7.79 (m, 1H,
3
H7-quinoline), 7.88 (d, 1H, J ) 8.3 Hz, H3-quinoline), 7.93-
3
3
7.98 (m, 3H, H4′, H6′, H-olefin), 8.02 (d, 1H, J ) 8.5 Hz, H5-
(d, 1H, J ) 8 Hz, H3-quinoline), 8.05-8.18 (m, 6H, H-olefin,
quinoline), 8.08 (d, 1H, 3J ) 7.7 Hz, H8-quinoline), 8.33-8.35
H4′, H6′, H8, H5-quinoline, H8-quinoline), 8.48 (s, 1H, H2),
8.48-8.51 (m, 1H, H4-quinoline), 8.60 (d, 1H, 3J ) 8.0 Hz, H7),
8.76 (s, 1H, H5). 13C NMR (50 MHz, DMSO): δ 107.24 (t),
118.87 (t), 120.21 (t), 120.84 (t), 123.54 (q), 125.05 (t), 126.39
(t), 127.17 (q), 127.91 (t), 128.72 (t), 129.76 (t), 129.99 (t),
130.11 (q), 130.16 (t), 130.46 (t), 131.67 (t), 131.90 (t), 132.01
(q), 133.16 (t), 136.70 (t), 137.29 (q), 147.69 (q), 154.97 (q),
155.46 (q), 159.73 (q), 162.20 (q), 177.44 (q). MS: m/z 443
[M•-].
3
(m, 1H, H7), 8.37 (d, 1H, J ) 8.7 Hz, H4-quinoline), 8.49 (br
s, 1H, H2′), 8.64 (br s, 1H, H5). 13C NMR (100 MHz, 335 K,
DMSO): δ 107.39 (t), 118.86 (t), 119.78 (t), 122.85 (q), 124.84
(t), 125.96 (t), 126.07 (t), 126.29 (t), 126.87 (q), 2127.46 (t),
128.23 (q), 128.43 (t), 129.36 (t), 129.51 (t), 130.05 (t), 130.21
(t), 131.39 (t), 132.73 (q), 134.06 (t), 136.22 (t), 137.11 (q),
147.46 (q), 155.08 (q), 157.77 (q), 162.43 (q), 165.94 (q), 176.47
(q). Anal. (C27H17NO4‚SeO2) H, N; C: calcd, 61.14; found,
64.77.
8-(E t h oxyca r b on yl)-3′-[(2-q u in olin yl)m e t h oxy]fla -
von e (10a ). To a solution of 3′-(benzyloxy)flavone-8-carboxylic
acid (1.86 g, 5 mmol) in 25 mL of HMPA was added 0.13 g
(5.5 mmol) of NaH. The mixture was stirred at room temper-
ature for 30 min, and ethyl iodide (1.56 g, 10 mmol) was then
added. The reaction mixture was stirred for another 2 h at
room temperature. The reaction mixture was poured into
6-Cya n o-3′-[2-(2-qu in olin yl)eth en yl]fla von e (5k ). The
title compound was prepared by the method used for compound
5a above, yield 39%, mp 271.8-272.9 °C. 1H NMR (400 MHz,
335 K, DMSO): δ 7.24 (s, 1H, H3), 7.56-7.60 (m, 1H, H6-
quinoline), 7.65 (t, 1H, 3J ) 7.8 Hz, H5′), 7.68 (d, 1H, 3J )
16.3 Hz, H-olefin), 7.75-7.79 (m, 1H, H7-quinoline), 7.87 (d,

Carboxyflavones as CysLT1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1435
water and extracted with ethyl acetate. The combined organic
layers were washed with water and brine and dried over Na2-
SO4. Removal of the solvent and subsequent recrystallization
from ethanol yielded 3′-(benzyloxy)-8-(ethoxycarbonyl)flavone
as a crystalline product, yield 47%, mp 121.0-122.1 °C. 1H
128.54 (t), 130.03 (t), 130.35 (t), 136.21 (t), 137.41 (t), 154.47
(q), 156.73 (q), 161.19 (q), 163.38 (q), 163.98 (q), 177.41 (q).
Anal. (C28H21NO5) C, H, N.
8-Car boxy-3′-[(2-qu in olin yl)m eth oxy]flavon e (11a). The
flavone ester 10a (50 mg, 0.11 mmol) was dissolved in a 250-
mL mixture (1:1:1) of methanol, THF, and 5% LiOH water
solution. The solution was stirred at room temperature for
24 h with TLC monitoring (ethyl acetate/petroleum ether, 1:5).
The reaction mixture was then acidified with 3 M HCl, and
the precipitate was collected by filtration and washed with
water and ethanol. Recrystallization from DMF yielded the
pure product, yield 40%, mp >300 °C. 1H NMR (400 MHz,
DMSO): δ 5.48 (s, 2H, quinolineCH2O), 7.23 (s, 1H, H3), 7.31
3
NMR (200 MHz, CDCl3): δ 1.40 (t, 3H, J ) 7.1 Hz, CO2CH2-
CH3), 4.43 (q, 2H, 3J ) 7.1 Hz, CO2CH2CH3), 5.12 (s, 2H,
CH2O), 6.81 (s, 1H, H3), 7.09 (dd, 1H, 3J ) 8.3 Hz, 4J ) 2.5
Hz, H4′), 7.27-7.44 (m, 7H, H5′, H6, Ph), 7.59-7.63 (m, 1H,
3
4
H6′), 7.70-7.71 (br s, 1H, H2′), 8.26 (dd, 1H, J ) 7.6 Hz, J
) 1.8 Hz, H5/7), 8.37 (dd, 1H, 3J ) 7.9 Hz, 4J ) 1.8 Hz, H5/7).
13C NMR (50 MHz, CDCl3): δ 14.32 (p), 61.68 (s), 70.10 (s),
107.17 (t), 112.88 (t), 118.54 (t), 119.17 (t), 120.87 (q), 124.42
(t), 124.73 (q), 127.51 (t), 128.11 (t), 128.61 (t), 130.14 (t),
130.42 (t), 132.66 (q), 136.51 (t), 154.59 (q), 159.18 (q), 163.37
(q), 164.02 (q), 177.70 (q), 106.99 (q).
3
4
3
(dd, 1H, J ) 8.2 Hz, J ) 2.3 Hz, H4′), 7.51 (t, 1H, J ) 8.0
Hz, H5′), 7.58 (t, 1H, 3J ) 7.7 Hz, H6), 7.61-7.65 (m, 1H, H6-
quinoline), 7.75 (d, 1H, 3J ) 8.5 Hz, H3-quinoline), 7.78-7.81
(m, 1H, H7-quinoline), 7.84-7.85 (m, 1H, H6′), 8.00-8.05 (m,
To a solution of 3′-(benzyloxy)-8-(ethoxycarbonyl)flavone (0.9
g, 2.25 mmol) in 25 mL of methanol was added 1.13 g (18
mmol) of ammonium formate and 0.01 g of palladium on
charcoal (10% w/w). The mixture was refluxed until comple-
tion as indicated by TLC (ethyl acetate/petroleum ether, 1:10)
(about 6 h). The hot reaction mixture was filtered, and the
product was allowed to precipitate from the mother liquor.
After filtration and washing with water, the crude product
8-(ethoxycarbonyl)-3′-hydroxyflavone was recrystallized from
methanol, yield 51%, mp 224.5-225.5 °C. 1H NMR (200 MHz,
DMSO): δ 1.40 (t, 3H, 3J ) 7.1 Hz, CO2CH2CH3), 4.45 (q, 2H,
3J ) 7.1 Hz, CO2CH2CH3), 7.00-7.02 (m, 1H, H4′), 7.04 (s,
1H, H3), 7.34-7.42 (m, 1H, H6), 7.55-7.62 (m, 3H, H2′, H5′,
H6′), 8.27-8.31 (m, 2H, H5, H7), 9.91 (br s, 1H, ArOH). 13C
NMR (50 MHz, DMSO): δ 13.88 (p), 61.38 (s), 106.52 (t),
113.02 (t), 117.17 (t), 118.83 (t), 120.51 (q), 123.99 (q), 124.75
(t), 129.45 (t), 129.93 (t), 131.96 (q), 136.05 (t), 153.47 (q),
157.66 (q), 162.59 (q), 163.53 (q), 176.20 (q).
3
3H, H2′, H5-quinoline, H8-quinoline), 8.27 (dd, 1H, J ) 7.9
Hz, 4J ) 1.8 Hz, H5 or H7), 8.30 (dd, 1H, 3J ) 7.6 Hz, 4J ) 1.8
Hz, H5 or H7), 8.45 (d, 1H, 3J ) 8.5 Hz, H4-quinoline). 13C
NMR (50 MHz, DMSO): δ 70.84 (s), 106.65 (t), 112.37 (t),
118.51 (t), 119.11 (t), 119.70 (t), 121.46 (q), 123.97 (q), 124.73
(t), 126.48 (t), 127.01 (q), 127.78 (t), 128.33 (t), 129.10 (t),
129.74 (t), 130.16 (t), 132.21 (q), 136.17 (t), 136.91 (t), 146.72
(q), 153.62 (q), 156.90 (q), 158.47 (q), 161.94 (q), 165.08 (q),
176.48 (q).
8-Car boxy-4′-[(2-qu in olin yl)m eth oxy]flavon e (11b). This
compound was prepared in a similar way as described for 11a ,
yield 89%, mp 223.4-225.9 °C. 1H NMR (400 MHz, DMSO,
3
350 K): δ 5.50 (s, 2H, CH2O), 6.97 (s, 1H, H3), 7.27 (d, 2H, J
) 8.7 Hz, H3′, H5′), 7.52-7.56 (m, 1H, H6), 7.60-7.64 (m, 1H,
3
H6-quinoline), 7.69 (d, 1H, J ) 8.4 Hz, H3-quinoline), 7.77-
7.81 (m, 1 H, H7-quinoline), 7.98 (d, 1H, 3J ) 7.9 Hz,
3
H5-quinoline), 8.03 (d, 1 H, J ) 8.4 Hz, H5-quinoline), 8.16
(d, 2H, 3J ) 8.7 Hz, H2′, H6′), 8.23-8.25 (m, 2H, H5, H7),
A mixture of 8-(ethoxycarbonyl)-3′-hydroxyflavone (0.31 g,
1 mmol), 2-(chloromethyl)quinoline hydrochloride (0.24 g, 1.1
mmol), and potassium carbonate (0.28 g, 2 mmol) in 25 mL of
DMF was stirred at 100 °C for 2 days (TLC monitoring: ethyl
acetate/petroleum ether, 1:5). After cooling the reaction
mixture was poured into 100 mL of water and extracted with
ethyl acetate (3 × 50 mL). The combined organic layers were
washed with water (100 mL) and brine (100 mL) and dried
over sodium sulfate. Removal of the solvent yielded the crude
product which was further purified by recrystallization from
methanol, yield 13%, mp 161.4-162.5 °C. 1H NMR (200 MHz,
3
8.41 (d, 1H, J ) 8.4 Hz, H4-quinoline). 13C NMR (100 MHz,
DMSO): δ 71.00 (s), 104.92 (t), 115.21 (t), 119.21 (t), 121.70
(q), 123.42 (q), 123.86 (q), 124.23 (t), 126.20 (t), 126.89 (q),
127.48 (t), 128.10 (t), 128.24 (t), 128.54 (t), 129.40 (t), 135.29
(t), 136.62 (t), 146.73 (q), 153.37 (q), 156.56 (q), 160.98 (q),
162.28 (q), 164.73 (q), 175.86 (q). Anal. (C26H17NO5‚0.7H2O)
C, H, N.
8-Ca r boxy-4′-[(2-n a p h th yl)m eth oxy]fla von e (11c). This
compound was prepared in a similar way as described for 11a ,
yield 43%, mp 245.1-248.7 °C. 1H NMR (200 MHz, DMSO):
δ 5.43 (s, 2H, CH2O), 7.09 (s, 1H, H3), 7.28 (d, 2H, 3J ) 8.8
Hz, H3′, H5′), 7.57-7.65 (m, 4H, H6, 3H-naphthyl), 7.97-8.04
(m, 4H, 4H-naphthyl), 8.20-8.25 (m, 4H, H5, H7, H2′, H6′),
13.59 (br s, 1H, ArCO2H). 13C NMR (50 MHz, DMSO): δ 69.45
(s), 104.89 (t), 115.25 (t), 121.48 (q), 123.09 (q), 123.92 (q),
124.56 (t), 125.53 (t), 126.04 (t), 126.19 (t), 126.30 (t), 127.42
(t), 127.60 (t), 127.96 (t), 128.28 (t), 128.96 (t), 132.38 (q),
132.53 (q), 133.92 (q), 135.82 (t), 153.54 (q), 161.20 (q), 162.40
(q), 165.05 (q), 176.19 (q). Anal. (C27H18O5‚1.3H2O) C, H.
8-Ca r boxy-4′-[(2-qu in a zolin yl)m eth oxy]fla von e (11d ).
This compound was prepared in a similar way as described
for 11a , yield 58%, mp 264.8-266.0 °C. 1H NMR (200 MHz,
DMSO): δ 5.59 (s, 2H, CH2O), 7.07 (s, 1H, H3), 7.25 (d, 2H,
3J ) 8.8 Hz, H3′, H5′), 7.56 (t, 1H, 3J ) 7.8 Hz, H6), 7.80-
7.84 (m, 1H, H6-quinazoline), 8.17-8.19 (m, 2H, H5-quinazo-
line, H7-quinazoline), 8.21-8.28 (m, 5H, H5, H7, H2′, H6′, H8-
quinazoline), 9.69 (s, 1H, H4-quinazoline), 13.51 (br s, 1H,
ArCO2H). 13C NMR (50 MHz, DMSO): δ 70.58 (s), 104.89 (t),
115.14 (t), 121.51 (q), 123.15 (q), 123.30 (q), 123.91 (q), 124.54
(t), 127.31 (t), 127.68 (t), 128.01 (t), 128.24 (t), 128.93 (t), 134.77
(t), 135.79 (t), 149.10 (q), 153.52 (q), 161.14 (q), 161.21 (q),
161.30 (t), 162.38 (q), 165.03 (q), 176.19 (q). Anal. (C25H16N2O5‚
H2O) C, H, N.
3
CDCl3): δ 1.40 (t, 3H, J ) 7.1 Hz, CO2CH2CH3), 4.42 (q, 2H,
3J ) 7.1 Hz, CO2CH2CH3), 5.43 (s, 2H, CH2O), 6.82 (s, 1H,
H3), 7.14-7.19 (m, 1H, H4′), 7.39-7.43 (m, 1H, H6), 7.54-
7.59 (m, 1 H, H6-quinoline), 7.63 (d, 1H, 3J ) 8 .5 Hz, H3-
quinoline), 7.73-7.77 (m, 1H, H7-quinoline), 7.82-7.85 (m, 1H,
H5-quinoline), 8.01-8.09 (m, 4H, H8-quinoline, H5′, H6′, H2′),
8.21 (d, 1H, 3J ) 8.5 Hz, H4-quinoline), 8.30 (m, 1H, H5/7),
8.41 (m, 1H, H5/7). 13C NMR (50 MHz, CDCl3): δ 14.23 (p),
61.59 (s), 71.38 (s), 107.22 (t), 113.42 (t), 117.84 (t), 119.00 (t),
119.34 (t), 120.80 (q), 124.30 (t), 124.65 (q), 126.52 (t), 127.46
(q), 127.57 (t), 128.86 (t), 129.76 (t), 130.16 (t), 130.31 (t),
132.75 (q), 136.40 (t), 136.98 (t), 147.43 (q), 154.44 (q), 157.09
(q), 158.82 (q), 163.12 (q), 163.59 (q), 177.52 (q). Anal. (C28H21
NO5) C, H, N.
-
8-(E t h oxyca r b on yl)-4′-[(2-q u in olin yl)m e t h oxy]fla -
von e (10b). This compound was prepared in a similar way
as described for 10a , yield 64%, mp 165.1-166.3 °C. 1H NMR
3
(200 MHz, CDCl3): δ 1.44 (t, 3H, J ) 7.1 Hz, CO2CH2CH3),
4.47 (q, 2H, 3J ) 7.1 Hz, CO2CH2CH3), 5.46 (s, 2H, quino-
lineCH2O), 6.77 (s, 1H, H3), 7.15 (d, 2H, 3J ) 9.0 Hz, H3′, H5′),
7.43 (t, 1H, 3J ) 7.7 Hz, H6), 7.51-7.59 (m, 1H, H6-quinoline),
7.64 (d, 1H, 3J ) 8.5 Hz, H3-quinoline), 7.71-7.77 (m, 1H, H7-
quinoline), 7.78-7.84 (m, 1H, H5-quinoline), 8.02 (d, 2H, 3J
) 9.0 Hz, H2′, H6′), 8.07-8.11 (m, 1H, H8-quinoline), 8.20 (d,
Met h od B. E t h yl 3-Acet yl-5-b r om o-2-h yd r oxyb en -
zoa te (13). A solution of 5.18 g (20 mmol) of 3-acetyl-5-bromo-
2-hydroxybenzoic acid in 100 mL of ethanol containing 5%
sulfuric acid was refluxed for 5 h. The solvent was removed
in vacuo. The crude product was dissolved in ethyl acetate,
and the organic layer was washed with water, 10% NaHCO3,
3
3
4
1H, J ) 8.5 Hz, H4-quinoline), 8.27 (dd, 1H, J ) 7.6 Hz, J
3
4
) 1.8 Hz, H5 or H7), 8.40 (dd, 1H, J ) 7.8 Hz, J ) 1.8 Hz,
H5 or H7). 13C NMR (50 MHz, CDCl3): δ 14.21 (p), 61.51 (s),
71.07 (s), 105.64 (t), 115.34 (t), 118.88 (t), 120.54 (q), 124.14
(t), 124.62 (q), 126.73 (t), 127.50 (q), 127.61 (t), 128.41 (t),

1436 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Zwaagstra et al.
and brine. The organic layer was dried over sodium sulfate,
and the solvent was removed. The benzoate 13 was obtained
as a brown solid, yield 75%, mp 64.0-65.2 °C. 1H NMR (200
MHz, DMSO): δ 5.47 (s, 2H, CH2O), 7.27 (s, 1H, H3), 7.30-
7.32 (m, 1H, H4′), 7.50 (t, 1H, 3J ) 8.0 Hz, H5′), 7.61-7.65
(m, 1H, H6-quinoline), 7.75 (d, 1H, 3J ) 8.5 Hz, H3-quinoline),
7.78-7.83 (m, 2H, H6′, H7-quinoline), 7.99-8.05 (m, 3H, H2′,
H5-quinoline, H8-quinoline), 8.29 (br s, 1H, H5/7), 8.34 (br s,
3
MHz, CDCl3): δ 1.39 (t, 3H, J ) 7.2 Hz, CO2CH2CH3), 2.63
3
(s, 3H, COCH3), 4.38 (q, 2H, J ) 7.2 Hz, CO2CH2CH3), 8.00
(d, 1H, 4J ) 2.7 Hz, H4/6), 8.06 (d, 1H, 4J ) 2.7 Hz, H4/6),
12.07 (s, 1H, ArOH). 13C NMR (50 MHz, CDCl3): δ 13.96 (p),
30.67 (p), 62.14 (s), 110.56 (q), 116.59 (q), 127.18 (q), 137.38
(t), 138.57 (t), 160.42 (q), 167.66 (q), 198.09 (q).
1H, H5/7), 8.45 (d, 1H, J ) 8.3 Hz, H4-quinoline). 13C NMR
3
(50 MHz, DMSO): δ 70.81 (s), 106.69 (t), 112.37 (t), 116.81
(q), 118.69 (t), 119.18 (t), 119.67 (t), 123.82 (q), 125.65 (q),
126.49 (t), 127.02 (q), 127.79 (t), 128.31 (t), 129.76 (t), 130.17
(t), 130.93 (t), 131.91 (q), 136.94 (t), 138.05 (t), 146.70 (q),
152.61 (q), 156.87 (q), 158.45 (q), 162.19 (q), 163.77 (q), 175.26
(q). Anal. (C26H16BrN2O5‚1.3H2O) C, H, N.
6-Br om o-8-ca r b oxy-3′-[(2-n a p h t h yl)m et h oxy]fla von e
(18b): yield 70%, mp 211.4-212.8 °C. 1H NMR (200 MHz,
DMSO): δ 5.34 (s, 2H, CH2O), 7.23 (s, 1H, H3), 7.24-7.28 (m,
1H, H4′), 7.45-7.70 (m, 4H, H-aromatic), 7.80-8.05 (m, 6H,
H-aromatic), 8.29 (d, 1H, 4J ) 1.8 Hz, H5/7), 8.32 (d, 1H, 4J )
1.8 Hz, H5/7).
P r ep a r a tion of Meth yl 3-Isop r op oxyben zoa te (12). A
mixture of ethyl 3-hydroxybenzoate (6.64 g, 40 mmol), 2-bro-
mopropane (9.84 g, 80 mmol), and potassium carbonate (11.04
g, 80 mmol) in 100 mL of DMF was stirred at 100 °C for 24 h.
The reaction mixture was poured into water, and the product
was extracted with ethyl acetate. The combined organic layers
were washed with 1 N NaOH, water, and brine and dried over
sodium sulfate. Removal of the solvent yielded 12 as a
colorless oil, yield 49%. 1H NMR (200 MHz, CDCl3): δ 1.32
3
(d, 6H, J ) 6.0 Hz, CH(CH3)2), 3.88 (s, 3H, CO2CH3), 4.59 (h,
6-Br om o-8-ca r b oxy-3′-[(2-q u in a zolin yl)m et h oxy]fla -
von e (18c): yield 41%, mp 245.7-245.9 °C. 1H NMR (400
MHz, DMSO): δ 5.54 (s, 2H, CH2O), 7.16 (s, 1H, H3), 7.28
3
3
4
1H, J ) 6.0 Hz, CH(CH3)2), 7.05 (dd, 1H, J ) 8.2 Hz, J )
3
2.6 Hz, H4), 7.30 (t, 1H, J ) 7.9 Hz, H5), 7.52 (m, 1H, H2),
7.57 (dd, 1H, J ) 7.6 Hz, J ) 1.6 Hz, H6).
3
4
3
4
3
(dd, 1H, J ) 8.0 Hz, J ) 1.7 Hz, H4′), 7.48 (t, 1H, J ) 8.0
Hz, H5′), 7.76-7.79 (m, 2H, H6-quinazoline, H6′), 7.93 (s, 1H,
H2′), 8.02-8.04 (m, 2H, H5-quinazoline, H7-quinazoline), 8.17
(d, 1H, 3J ) 8.0 Hz, H8-quinazoline), 8.29 (d, 1H, 4J ) 2.4 Hz,
H5/7), 8.31 (d, 1H, 4J ) 2.4 Hz, H5/7), 9.65 (s, 1H, H4-
quinazoline). Anal. (C25H15BrN2O5‚1.2H2O) C, H, N, Br.
6-Br om o-8-(eth oxycar bon yl)-3′-isopr opoxyflavon e (15).
A solution of ethyl benzoate 12 (6.24 g, 30 mmol) and the
acetophenone 13 (2.87 g, 10 mmol) in 50 mL of dioxane was
slowly added to a suspension of 1.45 g (60 mmol) of NaH in
100 mL of dioxane. The reaction mixture was refluxed for 7
h. After cooling to room temperature the bulk of dioxane was
removed in vacuo, and petroleum ether was added. The
precipitate was collected by filtration and dissolved in water
(200 mL). Acidification of the water solution afforded a brown
precipitate (crude 14) which was collected by filtration, dried
in vacuo, and used in the next reaction without further
purification.
The crude 1,3-propanedione 14 (4.0 g, 9 mmol) was dissolved
in 50 mL of 99% formic acid and refluxed for 2 h. After cooling,
the reaction mixture was diluted with ice water (100 mL). The
precipitate was collected by filtration and dried in vacuo. The
crude product was further purified by recrystallization from
ethanol, yield 80%. 1H NMR (200 MHz, CDCl3): δ 1.40 (d,
6-Br om o-8-ca r boxy-3′-[(2-ben zoth ia zolyl)m eth oxy]fla -
von e (18d ): yield 52%, mp 250.7-251.4 °C. 1H NMR (400
MHz, DMSO): δ 5.70 (s, 2H, CH2O), 7.22 (s, 1H, H3), 7.34-
7.36 (m, 1H, H4′), 7.44-7.48 (m, 1H, H5), 7.52-7.56 (m, 2H,
H5-benzothiazole, H6-benzothiazole), 7.84 (d, 1H, 3J ) 7.9 Hz,
H6′), 7.98 (s, 1H, H2′), 8.00-8.04 (m, 1H, H4-benzothiazole),
8.10-8.12 (m, 1H, H7-benzothiazole), 8.31 (d, 1H, 4J ) 2.5 Hz,
4
H5/7), 8.33 (d, 1H, J ) 2.5 Hz, H5/7).
6-Br om o-8-ca r b oxy-3′-[(2-(1-m et h ylb en zim id a zolyl))-
m eth oxy]fla von e (18e): yield 82%, mp 287.4-288.5 °C. 1H
NMR (400 MHz, DMSO): δ 4.01 (s, 3H, NCH3), 5.71 (s, 2H,
CH2O), 7.23 (s, 1H, H3), 7.41-7.50 (m, 3H, H4′, H5-benzimi-
dazole, H6-benzimidazole), 7.56 (t, 1H, 3J ) 8.0 Hz, H5′), 7.77-
7.81 (m, 2H, H4-benzimidazole, H7-benzimidazole), 7.87 (d,
3
3
6H, J ) 6.0 Hz, OCH(CH3)2), 1.49 (t, 3H, J ) 7.1 Hz, CO2-
CH2CH3), 4.51 (q, 2H, 3J ) 7.1 Hz, CO2CH2CH3), 4.68 (heptet,
3
4
1H, J ) 7.7 Hz, H6′), 8.00 (s, 1H, H2′), 8.31 (d, 1H, J ) 2.1
3
Hz, H5/7), 8.33 (d, 1H, 4J ) 2.1 Hz, H5/7). Anal. (C25H17
BrN2O5‚HCl‚H2O) C, H, N.
-
1H, J ) 6.0 Hz, OCH(CH3)2), 6.88 (s, 1H, H3), 7.06-7.10 (m,
1H, H4′), 7.43 (t, 1H, 3J ) 8.0 Hz, H5′), 7.58-7.65 (m, 2H,
H2′, H6′), 8.39 (d, 1H, 4J ) 2.6 Hz, H5/7), 8.54 (d, 1H, 4J ) 2.6
Hz, H5/7). 13C NMR (50 MHz, CDCl3, DEPT): δ 14.15 (p),
21.84 (p), 61.97 (s), 70.10 (t), 106.96 (t), 113.63 (t), 118.54 (t),
119.54 (t), 130.06 (t), 132.71 (t), 138.88 (t).
6-Br om o-8-car boxy-3′-[(2-(7-ch lor oqu in olin yl))m eth oxy]-
fla von e (18f): yield 68%, mp 269.0-269.1 °C. 1H NMR (400
MHz, DMSO): δ 5.47 (s, 2H, CH2O), 7.27 (s, 1H, H3), 7.30
3
4
3
(dd, 1H, J ) 8.4 Hz, J ) 2.0 Hz, H4′), 7.51 (t, 1H, J ) 8.0
Hz, H5′), 7.55 (dd, 1H, 3J ) 8.7 Hz, 4J ) 1.7 Hz, H6-quinoline),
6-Br om o-8-(eth oxyca r bon yl)-3′-h yd r oxyfla von e (16). A
solution of 3′-isopropoxyflavone 15 (2.16 g, 5 mmol) in 25 mL
of acetic acid containing 3% concentrated sulfuric acid was
refluxed for 0.5 h. The reaction mixture was then poured into
ice and extracted with ethyl acetate. The combined organic
layers were washed with water and dilute NaHCO3 and dried
over Na2SO4. Evaporation of the solvent yielded the crude
hydroxyflavone 16 as a brownish solid, which was further
purified by recrystallization from ethanol, yield 80%, mp
242.3-243.6 °C. 1H NMR (200 MHz, CDCl3): δ 1.47 (t, 3H,
3
3
7.76 (d, 1H, J ) 8.5 Hz, H3-quinoline), 7.83 (d, 1H, J ) 7.7
Hz, H6′), 7.99 (s, 1H, H2′), 8.05-8.07 (m, 2H, H5-quinoline,
4
4
H8-quinoline), 8.28 (d, 1H, J ) 2.4 Hz, H5/7), 8.33 (d, 1H, J
) 2.4 Hz, H5/7), 8.48 (d, 1H, J ) 8.5 Hz, H4-quinoline). 13C
3
NMR (50 MHz, DMSO): δ 70.62 (s), 106.64 (t), 112.34 (t),
116.78 (q), 118.68 (t), 119.23 (t), 120.02 (t), 125.60 (q), 125.63
(q), 126.98 (t), 127.10 (t), 129.77 (t), 130.16 (t), 130.68 (t),
131.94 (q), 134.24 (q), 136.98 (t), 137.97 (t), 147.03 (q), 152.53
(q), 158.28 (q), 158.36 (q), 162.14 (q), 163.82 (q), 17.27 (q).
3
3J ) 7.1 Hz, CO2CH2CH3), 4.48 (q, 2H, J ) 7.1 Hz, CO2CH2-
6-B r om o-8-c a r b o xy -4′-[(2-q u in o lin y l)m e t h o x y ]fla -
von e (18g). To a solution of the 5′-bromo-3′-carboxy-2′-
hydroxy-4-[(2-quinolinyl)methoxy]chalcone (0.52 g, 1 mmol) in
10 mL of glacial acetic acid was added dropwise 0.06 mL (1.1
mmol) of bromine. The reaction mixture was stirred at room
temperature for 3 h. The yellow precipitate was filtered and
washed with water. The dibromochalcone was dissolved in 8
mL of ethanol and 15 mL of 6% KOH solution; the reaction
mixture was stirred for 4 more h. After acidification the
precipitate was filtered and recrystallized from DMF, yield
38%, mp 261.2-263.9 °C. 1H NMR (200 MHz, DMSO): δ 5.43
CH3), 6.07 (br s, 1H, ArOH), 7.01 (s, 1H, H3), 7.04-7.06 (m,
1H, H4′), 7.39 (t, 1H, J ) 8.0 Hz, H5′), 7.57-7.60 (m, 2H, H2′,
H6′), 8.38 (d, 1H, J ) 2.6 Hz, H5/7), 8.52 (d, 1H, J ) 2.6 Hz,
H5/7). 13C NMR (50 MHz, DMSO): δ 13.81 (p), 61.83 (s),
106.57 (t), 113.08 (t), 116.78 (q), 117.25 (t), 119.04 (t), 122.82
(q), 125.68 (q), 129.97 (t), 131.29 (t), 131.69 (q), 137.89 (t),
151.90 (q), 157.68 (q), 162.12 (q), 162.86 (q), 175.02 (q).
F la von e-8-ca r boxylic Ester s 17 a n d Acid s 18. All esters
17 were prepared by alkylation of 3′-hydroxyflavone 16 with
an appropriate arylmethyl chloride as described under 10a ,
and the acids 18 were obtained by hydrolysis of the corre-
sponding esters 17 as described under 11a . Physicochemical
data of individual compounds are listed below.
3
(s, 2H, quinolineCH2O), 7.10 (s, 1H, H3), 7.26 (d, 2H, J ) 8.9
Hz, H3′, H5′), 7.60-7.66 (m, 1H, H6-quinoline), 7.69 (d, 1 H,
3J ) 8.5 Hz, H3-quinoline), 7.75-7.79 (m, 1H, H7-quinoline),
7.98-8.05 (m, 2H, H5-quinoline, H8-quinoline), 8.17 (d, 2H,
3J ) 8.9 Hz, H2′, H6′), 8.26 (d, 1H, 4J ) 1.8 Hz, H5 or H7),
6-B r om o-8-c a r b o xy -3′-[(2-q u in o lin yl)m e t h o xy ]fla -
von e (18a ): yield 75%, mp 241.6-242.0 °C. 1H NMR (400

Carboxyflavones as CysLT1 Receptor Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9 1437
4
3
(13) Harris, R. R.; Carter, G. W.; Bell, R. L.; Moore, J . L.; Brooks, D.
W. Clinical activity of leukotriene inhibitors. Int. J . Immunop-
harmacol. 1995, 17, 147-156.
(14) Drazen, J . M.; Israel, E. Treatment of chronic stable asthma with
drugs active on the 5-lipoxygenase pathway. Int. Arch. Allergy
Immunol. 1995, 107, 319-320.
8.28 (d, 1H, J ) 1.8 Hz, H5 or H7), 8.43 (d, 1H, J ) 8.5 Hz,
H4-quinoline). 13C NMR (50 MHz, DMSO): δ 70.83 (s), 104.94
(t), 115.24 (t), 116.60 (q), 116.63 (q), 119.43 (t), 123.03 (q),
125.58 (q), 126.49 (t), 126.99 (q), 127.76 (t), 128.33 (t), 128.39
(t), 129.74 (t), 130.58 (t), 136.94 (t), 137.59 (t), 146.72 (q),
152.23 (q), 156.70 (q), 161.12 (q), 162.59 (q), 163.75 (q), 174.97
(q). Anal. (C26H16BrN2O5‚0.5H2O) C, H, N, Br.
(15) Drazen, J . Clinical studies with agents active on the 5-lipoxy-
genase pathway. Allergy 1995, 50, 22-26.
6-Br om o-8-(b en zen esu lfon a m id o)-4′-[(2-q u in olin yl)-
m eth oxy]fla von e (20). The flavone-8-carboxylic acid 18g
(0.50 g, 1.0 mmol) was dissolved in 10 mL of dry DMF together
with 0.19 g (1.2 mmol) of benzenesulfonamide, 0.23 g (1.2
mmol) of EDCI, and 0.15 g (1.2 mmol) of DMAP. The reaction
mixture was stirred under ultrasound conditions overnight and
poured into water. The product was extracted with ethyl
acetate; the combined organic layers were washed with 1 M
HCl and brine and dried over sodium sulfate. Removal of the
solvent and recrystallization from DMF/ethanol yielded the
pure compound as a yellow solid, yield 16%, mp 255.6-256.5
°C. 1H NMR (400 MHz, DMSO): δ 5.56 (s, 2H, CH2O), 7.06
(16) Gillard, J . W.; Guindon, Y. The leukotrienes: Prospects for
therapy against a unique family of pathophysiological mediators.
Drugs Future 1987, 12, 453-474.
(17) Taylor, I. K. Cysteinyl leukotrienes in asthma: Current state
of therapeutic evaluation. Thorax 1995, 50, 1005-1010.
(18) Marshall, W. S.; Goodson, T.; Cullinan, G. J .; Swanson-Bean,
D.; Haisch, K. D.; Rinkema, L. E.; Fleisch, J . H. Leukotriene
receptor antagonists 1. Synthesis and structure-activity relation-
ships of alkoxyacetophenone derivatives. J . Med. Chem. 1987,
30, 682-689.
(19) Hay, D. W. P. SK&F 104353 2(S)-Hydroxy-3(R)-(2-carboxyeth-
ylthio)-3-[2-(8-phenyloctyl)phenyl]propanoic acid. Drugs Future
1990, 15, 240-244.
(20) Gleason, J . G.; Hall, R. F.; Perchonock, C. D.; Erhard, K. F.;
Frazee, J . S.; Ku, T. W.; Kondrad, K.; McCarthy, M. E.; Mong,
S.; Crooke, S. T.; Chi-Rosso, G.; Wasserman, M. A.; Torphy, T.
J .; Muccitelli, R. M.; Hay, D. W.; Tucker, S. S.; Vickery-Clark,
L. High-affinity leukotriene receptor antagonists. Synthesis and
pharmacological characterization of 2-hydroxy-3-[(2-carboxyeth-
yl)thio]-3-[2-(8-phenyloctyl)phenyl]propanoic acid. J . Med. Chem.
1987, 30, 959-961.
(21) Perchonock, C. D.; Uzinskas, I.; McCarthy, M. E.; Erhard, K.
F.; Gleason, J . G.; Wasserman, M. A.; Muccitelli, R. M.; DeVan,
J . F.; Tucker, S. S.; Vickery, L. M.; Kirchner, T.; Weichman, B.
M.; Mong, S.; Scott, M. O.; Chi-Rosso, G.; Wu, H. J .; Crooke, S.
T.; Newton, J . F. Synthesis and structure-activity relationship
studies of a series of 5-aryl-4,6-dithianonanedioic acids and
related compounds: A novel class of leukotriene antagonists. J .
Med. Chem. 1986, 29, 1442-1452.
(22) Harper, R. W.; Herron, D. K.; Bollinger, N. G.; Sawyer, J . S.;
Baldwin, R. F.; Roman, C. R.; Rinkema, L. E.; Fleisch, J . H.
Development of a series of phenyltetrazole leukotriene D4 (LTD4)
receptor antagonists. J . Med. Chem. 1992, 35, 1191-1200.
(23) Baker, S. R.; Boot, J . R.; Wishart, G. Sulukast (LY-170680):
Leukotriene D4/E4 antagonist. Drugs Future 1991, 16, 432-
436.
3
(s, 1H, H3), 7.18 (d, 2H, J ) 8.9 Hz, H3′, H5′), 7.62-7.69 (m,
4H, H3-phenyl, H4-phenyl, H5-phenyl, H6-quinoline), 7.72 (d,
1H, 3J ) 8.6 Hz, H3-quinoline), 7.79-7.83 (m, 1H, H7-
3
3
quinoline), 7.87 (d, 2H, J ) 8.9 Hz, H2′, H6′), 8.02 (d, 1H, J
) 8.1 Hz, H5-quinoline), 8.05-8.07 (m, 3H, H8-quinoline, H2-
4
phenyl, H6-phenyl), 8.13 (d, J ) 2.4 Hz, H5/7), 8.21 (d, 1H,
4J ) 2.4 Hz, H5/7), 8.46 (d, 1H, 3J ) 8.6 Hz, H4-quinoline).
13C NMR (50 MHz, DMSO): δ 71.07 (s), 105.46 (t), 115.48 (t),
117.08 (q), 119.67 (t), 122.99 (q), 125.20 (q), 126.79 (t), 127.27
(q), 127.65 (t), 127.79 (t), 128.06 (t), 128.43 (t), 128.56 (t),
129.19 (t), 130.07 (t), 133.84 (t), 136.16 (t), 137.28 (t), 139.28
(q), 142.85 (q), 146.98 (q), 151.45 (q), 157.05 (q), 161.31 (q),
162.24 (q), 162.57 (q), 175.00 (q). HRMS: m/e [M+] calcd,
640.0304; found, 640.0317 ( 0.0003. Anal. (C32H21BrN2O6S‚
1.0H2O) C, H, N, S; Br: calcd, 12.12; found, 12.70.
Ack n ow led gm en t. The authors are grateful to Dr.
Ben van Baar for providing the mass spectra and Arjan
Aalbers for assistance in flavone synthesis.
Su p p or tin g In for m a tion Ava ila ble: Table of NOE dif-
ference spectroscopy for 5b,c and 11a (1 page). Ordering
information is given on any current masthead page.
(24) Abram, T. S.; Boshagen, H.; Futler, J . E.; Cuthbert, N. J .;
Francis, H. P.; Gardiner, P. F.; Hartwig, W.; Kluender, H. C.;
Norman, P.; Meier, H.; Rosentreter, U.; Schlemmer, K. H.;
Tudhope, S. R.; Taylor, W. A. A new structural analogue
antagonist of peptide leukotrienes. The discovery of BAY x7195.
Bioorg. Med. Chem. Lett. 1993, 3, 1517-1522.
Refer en ces
(1) Mayatepek, E.; Hoffmann, G. F. Leukotrienes: Biosynthesis,
metabolism, and pathophysiologic significance. Pediatric Res.
1995, 37, 1-9.
(25) Matassa, V. G.; Brown, F. J .; Bernstein, P. R.; Shapiro, H. S.;
Maduskuie, J . T. P.; Cronk, L. A.; Vacek, E. P.; Yee, Y. K.;
Snyder, D. W.; Krell, R. D.; Lerman, C. L.; Maloney, J . J .
Synthesis and in vitro LTD4 antagonist activity of bicyclic and
monocyclic cyclopentylurethane and cyclopentylacetamide N-
arylsulfonyl amides. J . Med. Chem. 1990, 33, 2621-2629.
(26) Yee, Y. K.; Bernstein, P. R.; Adams, E. J .; Brown, F. J .; Cronk,
L. A.; Hebbel, K. C.; Vacek, E. P.; Krell, R. D.; Snyder, D. W. A
novel series of selective leukotriene antagonists: Exploration
and optimization of the acidic region in 1,6-disubstituted indoles
and indazoles. J . Med. Chem. 1990, 33, 2437-2451.
(27) Brown, F. J .; Yee, Y. K.; Cronk, L. A.; Hebbel, K. C.; Krell, R.
D.; Snyder, D. W. Evolution of a series of peptidoleukotriene
antagonists: Synthesis and structure-activity relationships of
1,6-disubstituted indoles and indazoles. J . Med. Chem. 1990, 33,
1771-1781.
(28) J acobs, R. T.; Brown, F. J .; Cronk, L. A.; Aharony, D.; Buckner,
C. K.; Kusner, E. J .; Kirkland, K. M.; Neilson, K. L. Substituted
3-(Phenylmethyl)-1H-indole-5-carboxamides and 1-(Phenylm-
ethyl)indole-6-carboxamides as potent, selective, orally active
antagonists of the peptidoleukotrienes. J . Med. Chem. 1993, 36,
394-409.
(29) Brown, F. J . In The Search for Antiinflammatory Drugs. Case
Histories from Concept to Clinic; Merluzi, V. J ., Adams, J ., Eds.;
Birkhauser: Boston, 1995; pp 161-189.
(2) Chung, K. F. Leukotriene receptor antagonists and biosynthesis
inhibitors: Potential breakthrough in asthma therapy. Eur.
Respir. J . 1995, 8, 1203-1213.
(3) Thien, F. C. K.; Walters, E. H. Eicosanoids and asthma: an
update. Prostaglandins Leukotrienes Essent. Fatty Acids 1995,
52, 271-288.
(4) Denzlinger, C.; Haberl, C.; Wilmanns, W. Cysteinyl leukotriene
production in anaphylactic reactions. Int. Arch. Allergy Immunol.
1995, 108, 158-164.
(5) Chanarin, N.; J ohnston, S. L. Leukotrienes as a target in asthma
therapy. Drugs 1994, 47, 12-24.
(6) Pauwels, R. A.; J oos, G. F.; Kips, J . C. Leukotrienes as
therapeutic target in asthma. Allergy 1995, 30, 615-622.
(7) Hay, D. W. P.; Torphy, T. J .; Undem, B. J . Cysteinyl leukotrienes
in asthma: Old mediators up to new tricks. Trends Pharmacol.
Sci. 1995, 16, 304-309.
(8) Henderson, J . W. R. The role of leukotrienes in inflammation.
Ann. Intern. Med. 1994, 121, 684-697.
(9) Another receptor specific for LTC4 has been identified and
termed CysLT2 receptor. The biological effects of CysLT2 receptor
activation remain unclear. Currently there are no selective
antagonists reported for CysLT2 receptors. For
a review of
leukotriene receptors, see: Metters, K. M. Leukotriene receptors.
J . Lipid Mediat. Cell Signal. 1995, 12, 413-427.
(10) Samuelsson, B. Leukotrienes: Mediators of immediate hyper-
sensitivity reactions and inflammation. Science 1983, 220, 568-
575.
(11) Sprecher, V. A.; Beck, A.; Gerspacher, M.; Bray, M. A. Peptido-
leukotriene antagonists: state of the art. Chimia 1992, 46, 304-
311.
(30) Toda, M.; Nakai, H.; Kosuge, S.; Konno, M.; Arai, Y.; Miyamoto,
T.; Obata, T.; Katsube, N.; Kawasaki, A. A potent antagonist of
the slow-reacting substance of anaphylaxis. Adv. Prostaglandin
Thromboxane Leukotriene Res. 1985, 15, 307-308.
(31) Nakai, H.; Konno, M.; Kosuge, S.; Sakuyama, S.; Toda, M.; Arai,
Y.; Obata, T.; Katsube, N.; Miyamoto, T.; Okegawa, T.; Ka-
wasaki, A. New potent antagonists of leukotrienes C4 and D4.
1. Synthesis and structure-activity relationships. J . Med. Chem.
1988, 31, 84-91.
(12) Brooks, C. D. W.; Summers, J . B. Modulators of leukotriene
biosynthesis and receptor activation. J . Med. Chem. 1996, 39,
2629-2654.

1438 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 9
Zwaagstra et al.
(32) Yamada, N.; Yamada, K.; Takahashi, K.; Nakao, E.; Kadowaki,
S.; Umezu, K. Pharmacological profile of the novel, potent and
selective peptide leukotriene antagonist (E)-2,2-Diethyl-3′-[2-
[2-(4-isopropyl)thiazolyl]ethenyl]siccinanilic acid. Arzneim.-For-
sch./ Drug Res. 1994, 44, 749-753.
(33) O’Donnell, M.; Crowley, H. J .; Yaremko, B.; O’Neill, N.; Welton,
A. F. Pharmacologic actions of Ro 24-5913, a novel antagonist
of leukotriene D4. J . Pharmacol. Exp. Ther. 1991, 259, 751-
758.
(34) Huang, F. C.; Galemmo, J . R. A.; Poli, G. B.; Learn, K. S.;
Morrissette, M. M.; J ohnson, J . W. H.; Dankulich, W. P.;
Campbell, H. F.; Carnathan, G. W.; VanInwegen, R. G. Develop-
ment of a novel series of (2-quinolinylmethoxy)phenyl-containing
compounds as high-affinity leukotriene D4 Receptor antagonists.
4. Addition of chromone moiety enhances leukotriene D4 receptor
binding affinity. J . Med. Chem. 1991, 34, 1704-1707.
(35) Labelle, M.; Belley, M.; Gareau, Y.; Gauthier, J . Y.; Guay, D.;
Gordon, R.; Grossman, S. G.; J ones, T. R.; Leblanc, Y.; McAuliffe,
M.; McFarlane, C.; Masson, P.; Metters, K. M.; Oiumet, N.;
Patrick, D. H.; Piechuta, H.; Rochette, C.; Sawyer, N.; Xiang, Y.
B.; Pickett, C. B.; Ford-Hutchinson, A. W.; Zamboni, R. J .; Young,
R. N. Discovery of MK-0476, a potent and orally active leukot-
riene D4 receptor antagonist devoid of peroxisomal enzyme
induction. Bioorg. Med. Chem. Lett. 1995, 5, 283-288.
(36) Sprecher, V. A.; Beck, A.; Gerspacher, M.; Sallmann, A.;
Anderson, G. P.; Subramanian, N.; Niederhauser, U.; Bray, M.
A. Strategies in the design of peptidoleukotriene antagonists.
J . Lipid Mediators 1993, 6, 265-273.
(37) Young, R. N. The development of new anti-leukotriene drugs:
L-648,051 and L-649,923, specific leukotriene D4 antagonists.
Drugs Future 1988, 13, 745-759.
(38) Terada, H.; Goto, S.; Hori, H.; Taira, Z. In QSAR and Drug
Design - New Developments and Applications; Fujita, T., Ed.;
1995; pp 341-367.
(39) Palomer, A.; Giolitti, A.; Garcia, M. L.; Fos, E.; Cabre, F.;
Mauleon, D.; Carganico, G. In QSAR and Molecular Modelling:
Concepts, Computational Tools and Biological Applications;
Sanz, F., Giraldo, J ., Manaut, F., Eds.; Prous Science Publish-
ers: Barcelona, 1995; pp 444-450.
(40) Hermann, R. B.; Herron, D. K. OVID and SUPER: Two overlap
programs for drug design. J . Comput.-Aided. Mol. Des. 1991, 5,
511-524.
(44) Emilewicz, T.; Kostanecki, V. S. Chem. Ber. 1898, 31, 696.
(45) Pfister, J . R. Neue 1,4-Benzopyron-6-carbonsauren und Ver-
fahren zu ihrer Herstellung und Verwendung. Ger. Offen. C 07
D 311.30, Apr. 17, 1975.
(46) Matsumura, H.; Tsuchiya, T.; Takeda, T.; Imafuku, K. Synthesis
of 6- and 8-phenyl-substituted flavonoids. Bull. Chem. Soc. J pn.
1983, 56, 2037-2043.
(47) Awad, W. I.; El-Neweihy, M. F.; Selim, S. F. Studies on
3-acylcatechols. II. A new synthesis of 8-hydroxyflavone. Chem.
Ind. 1960, 25, 1333-1336.
(48) Makrandi, J . K. An efficient procedure for cyclisation of 2′-
hydroxychalcones into flavones. Chem. Ind. 1989, 607.
(49) Hsu, K. K.; Chang, S. F. Synthesis of 2-(2-quinoxalyl) chromone
derivatives. T’aiwan K’o Hsuch 1976, 30, 146-52.
(50) Shanker, C. G.; Mallaiah, B. V.; Srimannarayana, G. Dehydro-
genation of chromanones and flavanones by DDQ: A facile
method for the synthesis of chromones and flavones. Synthesis
1983, 310-311.
(51) Imafuku, K.; Honda, M.; McOmie, J . F. W. Cyclodehydrogenation
of 2′-hydroxychalcones with DDQ: A simple route for flavones
and aurones. Synthesis 1987, 199-201.
(52) Baker, W. Molecular rearrangement of some o-acyloxyacetophe-
nones and the mechanism of the production of 3-acylchromones.
J . Chem. Soc. 1933, 1381-1389.
(53) Wu, E. S. C.; Cole, T. E.; Davidson, T. A.; Dailey, M. A.; Doring,
K. G.; Fedorchuk, M.; Loch, J . T.; Thomas, T. L.; Blosser, F. C.;
Borrelli, A. R.; Kinsolving, C. R.; Parker, R. B.; Strand, J . C.;
Watkins, B. E. Flavones. 2. Synthesis and structure-activity
relationship of flavodilol and its analogues, a novel class of
antihypertensive agents with catecholamine depleting proper-
ties. J . Med. Chem. 1989, 32, 183-192.
(54) Erickson, R. H.; Natalie, K. J ., J r.; Bock, W.; Lu, Z.; Farzin, F.;
Sherill, R. G.; Meloni, D. J .; Patch, R. J .; Rzesotarski, W. J .;
Clifton, J .; Pontecorvo, M. J .; Bailey, M. A.; Naper, K.; Karbon,
W. (Aminoalkoxy)chromones. Selective s-receptor ligands. J .
Med. Chem. 1992, 35, 1526-1535.
(55) Ares, J . J .; Outt, P. E.; Kakodkar, S. V.; Buss, R. C.; Geiger, J .
C. A convenient large-scale synthesis of 5-methoxyflavone and
its application to analog preparation. J . Org. Chem. 1993, 58,
7903-7905.
(56) Doria, G.; Romeo, C.; Giraldi, P.; Lauria, F.; Sberze, P.; Tibolla,
M.; Corno, M. L.; Cadelli, G.; Montoro, C. Antiallergic agents. I.
Substituted 4-oxo-4H-1-benzopyran-6-carboxylic acids. Eur. J .
Med. Chem.-Chim. Ther. 1978, 13, 33-39.
(57) The development of a CysLT1 antagonist model using VUF 5017
and VUF 4918 as templates will be described in the companion
paper: Zwaagstra, M. E.; Schoenmakers, S. H. H. F.; Nederk-
oorn, P. H. J .; Gelens, E.; Timmerman, H.; Zhang, M.-Q.
Development of a three-dimensional CysLT1 (LTD4) antagonist
model with an incorporated amino acid residue from the recep-
tor. J . Med. Chem. 1998, 41, 1439-1445.
(41) Zhang, M. Q.; Wada, Y.; Sato, F.; Timmerman, H. (Piperi-
dinylalkoxy)chromones: Novel antihistamines with additional
antagonistic activity against leukotriene D4. J . Med. Chem. 1995,
38, 2472-2477.
(42) Zwaagstra, M. E.; Timmerman, H.; Abdoelgafoer, R. S.; Zhang,
M. Q. Synthesis of carboxylated flavonoids as potential LTD4
antagonists. Eur. J . Med. Chem. 1996, 31, 861-874.
(43) Zwaagstra, M. E.; Timmerman, H.; Tamura, M.; Tohma, T.;
Wada, Y.; Onogi, K.; Zhang, M. Q. Synthesis and structure-
activity relationships of carboxylated chalcones: A novel series
of CysLT1 (LTD4) receptor antagonists. J . Med. Chem. 1997, 40,
1075-1089.
J M970179X