Synthesis and pharmacological evaluation of new 4-[2-(7- heterocyclemethoxynaftalen-2-ylmethoxy)ethyl]benzoic acids as LTD4- antagonists

Article abstract of DOI:10.1016/S0223-5234(00)00142-2

A group of new 4-[2-(7-heterocyclemethoxynaftalen-2- ylmethoxy)ethyl]benzoic acids have been synthesized and pharmacologically evaluated as LTD₄-antagonists. Thiazole derivatives, especially 4-[2-[7-(4- cyclobutylthiazole-2-ylmethoxyl)naphthalen-2-ylmethoxy]ethyl]benzoic acid, present considerable activity and improved pharmacokinetic profiles in comparison with our quinoline containing lead molecule confirming the interest of our compounds as potentially oral antiasthmatics and that the 4- alkylthiazole system can be considered as bioisosteric of the quinoline ring at least in our series of compounds. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Full text of DOI:10.1016/S0223-5234(00)00142-2

Eur. J. Med. Chem. 35 (2000) 439−447
© 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0223523400001422/SCO
439
Short communication
Synthesis and pharmacological evaluation of new
4-[2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethyl]benzoic acids
as LTD4-antagonists
Berta Ballarta, Josep Martía*, Dolores Velascoa, Francisco López-Calahorraa*, Jaume Pascualb,
Maria Luisa Garcíab, Francesc Cabréb, David Mauleónb
aDepartament de Química Orgànica, Universitat of Barcelona, Martí i Franquès, 1-11, E-08028 Barcelona, Spain
bLaboratorios Menarini, S. A., Alfonso XII, 587, E- 08912 Badalona, Spain
Received 18 June 1999; revised 8 November 1999; accepted 19 November 1999
Abstract – A group of new 4-[2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethyl]benzoic acids have been synthesized and pharmacologi-
cally evaluated as LTD4-antagonists. Thiazole derivatives, especially 4-[2-[7-(4-cyclobutylthiazole-2-ylmethoxyl)naphthalen-2-ylmetho-
xy]ethyl]benzoic acid, present considerable activity and improved pharmacokinetic profiles in comparison with our quinoline containing lead
molecule confirming the interest of our compounds as potentially oral antiasthmatics and that the 4-alkylthiazole system can be considered
as bioisosteric of the quinoline ring at least in our series of compounds. © 2000 Éditions scientifiques et médicales Elsevier SAS
LTD4-antagonists / oral antiasthmatics / bioisosters / 4-alkylthiazoles
1. Introduction
highly potent in vitro LTD4 antagonist and was orally
active in animal asthma models [11].
Over the last few years numerous specific LTD4
antagonists have been prepared and advanced into clini-
cal studies demonstrating beneficial roles in human bron-
chial asthma [1–4]. Some of them, such as the indole-
based antagonist ICI-204,219 [5] (Zafirlukast), the
benzamide ONO-1078 [6] (Pranlukast), and the quinoline
MK-0476 [7] (Montelukast) are currently in advanced
clinical development as therapeutic agents for the treat-
ment of asthma.
On the basis of the large body of knowledge of
structure–activity studies of LTD4 antagonists, a pharma-
cophore hypothesis has been described [8, 9] and applied
[10] by us. This pharmacophore accounts for several
compounds in advanced development level and has been
successfully applied in our laboratories to design new
lead compounds [11, 12]. From these studies, the quino-
line containing LM-1468 (1, figure 1) emerged as a
One of the striking features of the quinoline class of
compounds was the apparent necessity for the
2-substituted quinoline functionality for potent LTD4
antagonist activity [13]. However, thiazoles, benzothiaz-
oles and other nitrogen-containing heterocycles have
been reported as quinoline bioisosters in LTD4 antago-
nism research [14–17]. These replacements maintain and,
in some cases, increase the in vitro and in vivo potency.
Based on these observations we wished to search this
kind of substitution on our quinoline-containing LTD4
antagonist of LM-1468, with the aim of increasing its
activity and improving its pharmacokinetic profile. We
report here the synthesis and preliminary pharmacologi-
cal activity of compounds 2a–2d (figure 1) that represent
the replacement of the quinoline heterocycle in com-
pound LM-1468 by 6,7-dichlorothieno[3,2-b]pyridine,
4-isopropylthiazole, 4-cyclobutylthiazole and 5-fluoro-
benzothiazole, respectively.
* Correspondence and reprints:
flc@despi.qo.ub.es
colohorra@mafalda.qui.ub.es

440
Figure 1. Compounds 1 and 2a–2d.
2. Chemistry
The next step was the preparation of the key interme-
diate 8 from 7 and (4-cyanophenyl)ethanol. Such trans-
formation proved to not be trivial and we have developed
[21] a general procedure for the synthesis of this kind of
aryl phenetyl ether using the phase transfer catalysis
(PTC) method: equimolar amounts of starting reagents, a
two phase system formed by 1:1 methylene chloride and
aqueous 50% (w/v, 12.5 M) sodium hydroxide, and
tetrabutylammonium hydrogen sulphate in a 5% molar
relation.
The step from 8 to 9, removal of the MOM group, was
carried out in a conventional way described in the
literature [22] with practically quantitative yield. The last
steps for the preparation of target compounds 2a–d were
the formation of the second ether linkage by reaction
between 9 and the previously prepared heterocycles
2,3-dichloro-5-chloromethyl-thieno[3,2-b]pyridine (10a)
[23], 2-chloromethyl-4-isopropylthiazole (10b) [24],
2-chloromethyl-4-cyclobutylthiazole (10c) [24] and
5-fluoro-2-bromomethylbenzothiazole (10d) [25], finish-
ing with the hydrolysis of the cyano group.
Contrary to the former ether linkage the reaction took
place by direct reaction between 9 and 10a–d in
acetonitrile/K2CO3 in the presence of potassium iodide,
yielding compounds 11a–d without special problems.
The hydrolysis of the nitrile group into the carboxylic
acid was carried out by heating 11a–c in 35% sodium
hydroxide in ethanol, obtaining 2a–c with good yields.
However, in the case of 11d the benzothiazole system
suffered opening of the heterocyclic ring as a conse-
quence of the nucleophilic attack of the hydroxyl over the
2-position. Working in less concentrated basic conditions
it is possible to avoid the opening of the heterocycle but
in this case the nitrile is only partially converted into the
acid group. For this reason, to obtain 2d it was necessary
to change the order of the reactions: firstly, the nitrile 9
The synthesis (figure 2) starts with the commercial
2,7-dihydroxynaphtalene, protected as a methoxymethyl
(MOM) derivative (3) in the usual way [18]. Compound
3 was converted into 6 by means of the three-step method
described by Kingsbury et al. [19]: formation of the
triflate (4) over the unprotected OH, carbonilation cataly-
sed by Pd(II) in methanol/DMSO as solvent, and reduc-
tion of the methyl ester (5) giving the desired hydroxy-
methyl derivative (6).
The conversion of the hydroxyl group of 6 into a good
leaving group was more difficult than expected. After
trying several alternatives the procedure finally used
consists of the formation of the chloromethyl derivative 7
via the reaction between one equivalent of tosyl chloride
and the lithium salt of 6 in tetrahydrofuran. The yield of
7 was excellent. The process appears to pass through the
tosylate and nucleophilic substitution by the chloride
being present in the medium. The conversion of allylic
alcohols to chlorides by reaction with mesyl chloride is
described [20], but in the presence of an excess of lithium
chloride. The use of tetrahydrofuran as solvent is critical,
due to the solubility of the lithium chloride (formed in
situ) in it, favouring in this way the substitution process.
When different ethers were used as solvent the yields in
7 were clearly lower. This product (7) is unstable in
neutral aqueous medium, probably because the chloride
is substituted in some extension by water forming small
amounts of hydrochloric acid that removes the protecting
group, provoking the decomposition of the product in a
few minutes. However, it has proved that 7 is stable in
aqueous basic medium at least for a reasonable period of
time and, for this reason, was used directly in the next
reaction (carried out in aqueous basic medium) without
further manipulation.

441
Figure 2. Synthesis of compounds 3–13.
was hydrolysed in basic medium as usual giving 12; after
that the reaction between 12 and 10d was carried out as
before yielding the product of double benzylic substitu-
tion 13 that was hydrolysed in diluted basic conditions
affording 2d without opening the benzothiazole ring.
3. Biological results and discussion
The affinities of the synthesized compounds for the
LTD4 receptor were determined by specific binding of
[3H]LTD4 to guinea-pig lung membrane preparations (see

442
Table I. Pharmacological effects of synthesised compounds against LTD4 actions and preliminary pharmacokinetic parameters in mice after
oral treatment.
(4)
Compound
Binding
Ki(nM)(1) 1 h
AML % inhib.(2)
8 h
BC % inhib.(3)
Preliminary oral pharmacokinetics
CMAX (µg/mL)
2.13
TMAX
1
h
AUC (µg/mL/h)
15.43
1
2.7 ± 0.4
56.6 ± 28.0
2.69 ± 1.70
4.2 ± 1.8
6.4 ± 4.9
74.1 ± 4.0
(n = 10)
23.2 ± 10.9
(n = 4)
57.2 ± 7.6
(n = 4)
78.8 ± 6.2
(n = 4)
37.3 ± 5.5
(n = 6)
30.4 ± 10.7
(n = 4)
N.T.
77.1 ± 3.9
(n = 4)
50.9 ± 7.8
(n = 6)
47.2 ± 2.6
(n = 6)
82.5 ± 6.7
(n = 6)
2a
2b
2c
2d
4.06
4.21
5.20
1.56
2
16.8
44.7 ± 5.5
(n = 4)
41.4 ± 7.0
(n = 5)
1
20.44
21.36
9.35
0.5
2
N.T.
N.T.
(1) Ki values for competition of compounds in [3H]LTD4 specific binding to guinea-pig lung membranes. Values are the mean ± SD of at least
(2)
three experiments performed on different days.
Oral effect of compounds on airway microvascular leakage (AML) into trachea, induced
by LTD4 in guinea-pigs. Effect is expressed as % inhibition (mean ± SEM) in n treated animals with respect to control group treated with
vehicle. Compounds were administered orally at 1 µmol/kg dose, 1 and 8 h before LTD4 challenge.
(3)
Oral effect of compounds on
LTD4-induced bronchoconstriction in anaesthetized guinea-pigs (BC), expressed as percent inhibition (mean ± SEM of n animals) with respect
to the bonchospastic effect achieved in absence of treatment. Compounds were oral dosed at 6 µmol/kg 1 h before second LTD4 challenge.
(4) Preliminary plasma pharmacokinetic parameters in mice of tested compounds. Compounds were orally given at 15 mg/kg. Plasma samples
were analysed 0.5, 1, 2, 4, 6, 8 and 16 h after administration. Three animals per time were bled. Parameters were estimated from the curve
plasma levels vs. time, where each point represented the mean of three bled animals.
Pharmacology section). The in vivo oral efficacy was
assessed in LTD4-induced broncoconstriction (BC) in
anaesthetized guinea-pigs and in LTD4-induced airway
microvascular leakage (AML) into guinea-pig trachea. In
addition, a preliminary pharmacokinetic profile of these
compounds has been carried out in the mouse after single
oral administration (OP) (table I).
The in vitro tests show that the substitution of the
quinoline ring for the thiazole one (2b and 2c) maintains
the activity of our lead compound (1), contrary to that
observed in the other two cases (2a and 2d). Particularly
important is that the receptor affinity decreases when the
quinoline is substituted by the thieno[3,2-b]pyridine sys-
tem (2a) in contradiction with the observed behaviour in
previously described systems [22].
compound 1, showing a slightly longer duration of action
in the in vivo trachea permeability assay (41% inhibition
at 8 h for 2c vs. 30% inhibition for 1). The pharmacoki-
netic assay carried out in the mouse has allowed us to
observe that compounds 2b and 2c show an improved
pharmacokinetic profile in comparison to the lead com-
pound 1. Obviously, a correlation between the observed
pharmacokinetic data and the in vivo activity is not
possible to perform due to the species in these two assays
being different. According to the decreased binding
affinity, compounds 2a and 2d also display a low oral
activity in the in vivo assay.
4. Conclusions
The binding assay shows that the substitution of the
quinoline ring for the thiazole one (2b and 2c) or for the
benzothiazole system (2d) maintains the receptor affinity
of our lead compound (1). On the contrary, when the
quinoline ring is replaced by a 5,7-dichlorothieno[2,3]-
pyridine system, the binding affinity dramatically de-
creases, showing a behaviour contrary to that described
for other series of LTD4 antagonists [22].
The alkylthiazole compounds 2b and 2c have been
developed from quinoline compound LM-1468 as new
and orally active LTD4 antagonists. These compounds,
specially 2c, display remarkable in vitro and in vivo
activities as LTD4 antagonists, comparable to the lead
compound 1, with a slightly improved pharmacokinetic
profile. In this kind of compound, the alkylthiazole
system can be considered as a bioisoster of the quinoline
ring present in the structure of LM-1468. The cyclobu-
tylthiazole 2c has been selected for further development.
The compounds with a 4-alkylthiazole moiety (2b and
2c) also display the best oral in vivo activity, especially
2c that has an activity profile analogous to the lead

443
5. Experimental protocols
5.1.3. LTD4-induced airway microvascular leakage
into guinea-pig trachea
Guinea-pigs were anaesthetized with urethane and
treated with indomethacin (i.v.) and propanolol. Animals
were artificially ventilated with a constant volume by a
tracheal cannula attached to a constant volume respirator.
A catheter was inserted into the jugular vein for the
administration of LTD4 and Evans Blue. One minute after
the administration of Evans blue (30 mg/kg), the animal
was challenged with LTD4 (2 µg/kg i.v.) and 5 min later
the chest cavity was opened, and Evans blue dye was
washed out by perfusion via thoracic aorta with saline.
The trachea was then removed and Evans blue extracted.
Microvascular leakage was evaluated from the amount of
Evans blue determined spectrophotometrically and ex-
pressed as ng/mg tissue. The baseline was determined by
the administration of saline containing Evans blue. Com-
pounds were given orally 1, 3 and 8 h before LTD4
challenge. Effect of tested compounds was expressed as
percent inhibition of increase of airway microvascular
leakage with respect to vehicle treated animals.
5.1. Pharmacology
5.1.1. Radioligand binding assay of [3H]LTD4 in
guinea-pig lung membranes
Membrane fractions containing Cys-LT receptors were
prepared according to the method described by Mong et
al. [26] and protein concentration was determined using
the method of Bradford [27]. Drug competition assays
were conducted as previously described [28], briefly:
binding mixtures containing [3H]LTD4 (0.5 nM), mem-
brane preparations (150 µg protein/mL) and different
concentrations of competing agents, were incubated at
25 °C for 30 min. Binding reactions were stopped by
filtration and the radioactivity retained on rinsed filters
was determined by a liquid scintillation counter. The
specific binding was defined as the difference between the
amount of radioligand bound in the absence and presence
of LTD4 (1 µM). Data from drug competition experiments
were analysed by a non-linear least-square regression
analysis using programs of Equilibrium Binding Data
Analysis (EBDA by McPherson, Elservier-BIOSOFT)
and Ki calculated by the Cheng-Prusoff equation.
5.1.4. Oral absorption evaluation
Compounds were orally administered to male Swiss
mice at a selected dose of 15 mg/kg as suspensions in
DMSO:Tween 20:H20 (8:3:89) or intravenously as solu-
tions in Tween 20:PBS (2:98). The measurement times
were set as follows: 0.5, 1, 2, 4, 6, 8 and 16 h. After each
time the corresponding animals were humanely killed,
blood samples gathered by cardiac puncture and plasma
were obtained by centrifugation (1 500 g, 10 min).
Samples were then extracted using ethyl acetate, dried by
nitrogen stream and stored at –25 ± 5 °C until reverse
phase HPLC analysis. The area under the concentration-
–time curve (AUC) was determined by the trapezoidal
rule from the start to the 6 or 16 h period, whereas the
tmax corresponds to the time to reach the maximum
concentration (Cmax).
5.1.2. Measurement of bronchoconstriction
in anesthetized guinea-pigs
Male Dunkin Hartley guinea-pigs were anaesthetized
with urethane and treated with d-tubocurarine to prevent
spontaneous respiratory movements. Body temperature
was controlled electronically (Crison 639 K) and main-
tained at 34.5 °C. The animals were ventilated mechani-
cally through a tracheal cannula. Changes in insufflation
pressure were monitored on a Letica 2006 polygraph. The
basal value of insufflation pressure remained stable for at
least 2 h and no significant changes were produced by i.v.
saline administration. At the end of the stabilization
period (30 min) the guinea-pigs were challenged with i.v.
LTD4 (2 µg/kg). Preliminary experiments showed that at
least two reproducible responses to the spasmogen could
be evoked at an interval of 60 min in the same animal. To
assess the pharmacological modulation of these broncho-
spastic responses by the Cys-LT antagonists under study,
compounds were orally administered 1 h before the
second challenge with the spasmogen. Antagonistic effect
is expressed as percent inhibition of LTD4-induced bron-
chospasm compared with first LTD4 challenge before
treatment, or as the dose of antagonist required to inhibit
50% bronchoconstriction.
5.2. Chemistry
Melting points were determined in a Köfler apparatus
provided with a Reichert Thermovar microscope and are
uncorrected. TLC was carried out on SiO2 (silica Gel 60
F
254, Merck 0.063–0.200 mm) and spots were located
with UV light. Flash chromatography was carried out on
SiO2 (silica Gel 60 A CC, Merck). Organic extracts were
dried over anhydrous Na2SO4 and solutions were evapo-
rated under reduced pressure with a rotary evaporator. IR
spectra were recorded on a Nicolet 510 FT-IR spectrom-
eter. NMR spectra were measured with Varian Gemini-
200 (200 MHz) and Varian Gemini-300 (300 MHz)
spectrometers; data are given in δ referenced to TMS.

444
Mass spectra were measured in the electron impact (EI)
or chemical impact (CI, CH4) modes with a Hewlett-
Packard 5988A spectrometer. Elemental analyses were
performed on a Perkin Elmer 240 apparatus in the Centro
de Investigación y Desarrollo del Consejo Superior de
Investigaciones Científicas of Barcelona and in all cases
were within ± 0.4% of theoretical values. IR, 13C-NMR
and MS data are presented as supplementary material.
solvent was removed. The crude product was purified by
column chromatography with CH2Cl2 and 5 (3.1 g, 86%)
was isolated as a yellowish oil; δH (200 MHz, CDCl3)
8.50 (s, 1H, Ar), 7.93 (dd, J = 8.8 Hz, J = 1.8 Hz, 1H, Ar),
7.51 (m, 2H, Ar), 7.49 (d, J = 2.6 Hz, 1H, Ar), 7.31 (dd,
J = 8.8 Hz, J = 2.6 Hz, 1H, Ar), 5.29 (s, 2H, OCH2), 3.96
(s, 3H, CO2CH3), 3.52 (s, 3H, OCH3).
5.2.3. 7-Methoxymethoxy-2-
hydroxymethylnaphthalene 6
5.2.1. 7-Methoxymethoxy-2-naphthol 3
Commercial 60% suspension of sodium hydride (2.48 g,
62 mmol) in mineral oil was washed in inert atmosphere
three times with anhydrous hexane; the solvent was
removed by decantation and the solid was dried under
vacuum. DMF (25 mL) was added and over this suspen-
sion at room temperature and under nitrogen, 2,7-
dihydroxynaphthalene (10 g, 62 mmol) dissolved in DMF
(25 mL) and chloromethyl methyl ether (4.5 mL) were
added; the mixture was stirred for 30 min. The crude was
poured onto a mixture of water and ice (50 mL) and was
extracted with ethyl acetate. The organic layer was dried
and evaporated to give material which was purified by
column chromatography, eluting with hexane/ethyl ac-
etate (2:1); 3 (3.4 g, 27%) was obtained as a colourless
oil; δH (200 MHz, CDCl3) 7.69 (d, J = 8.8 Hz, 2H, Ar),
7.24 (d, J = 2.6 Hz, 1H, Ar), 7.04 (m, 3H, Ar), 5.29 (s, 2H,
OCH2), 4.95 (s, 1H, OH) and 3.52 (s, 3H, OCH3).
To 1 M LiAlH4 solution in THF (0.64 mL) at 0 °C, 5
(80 mg, 0.32 mmol) in THF (15 mL) was added. The
mixture was maintained at the same temperature for 1 h,
then water (1 mL), 3.5 M NaOH (1 mL), water (1.5 mL)
and ethyl ether (10 mL) were successively added. After
stirring for 15 min the mixture was filtered through celite.
The solvent was dried and removed, the residue was
purified by column chromatography, eluting with hexane:
EtOAc (4:1) yielding 6 (46 mg, 71%) as a white solid;
m.p. 40–41 °C; δH (200 MHz, CDCl3) 7.72 (m, 3H, Ar),
7.34 (m, 2H, Ar), 7.19 (dd, J = 8.8 Hz, J = 2.6 Hz, 1H,
Ar), 5.27 (s, 2H, OCH2O), 4.78 (s, 2H, CH2O), 3.51 (s,
3H, OCH3).
5.2.4. 4-[2-(7-Methoxymethoxynaphthalen-2-
ylmethoxy)ethyl]benzonitrile 8
Thirteen molar secBuLi in cyclohexane (3.5 mL) was
added slowly to a solution of 6 (0.9 g, 4.13 mmol) in
anhydrous THF (20 mL) under nitrogen at 0 °C. The
mixture was stirred for 10 min, tosyl chloride (0.78 g,
4.13 mmol) in anhydrous THF (7 mL) was added and the
agitation was maintained for 4 h. The reaction mixture
was then poured onto a cool solution of 2% NaHCO3
(25 mL) and extracted with ethyl ether, the organic layer
was dried and the solvent was evaporated to give a white,
unstable solid. This solid was immediately dissolved in
50% NaOH (10 mL) and a solution of Bu4NHSO4
5.2.2. Methyl 7-methoxymethoxy-2-
naphthalencarboxylate 5
Anhydrous pyridine (2.4 mL) and trifluoromethane-
sulfonic anhydride (6.1 g, 21.6 mmol) were added under
nitrogen atmosphere to a solution of 3 (3.4 g, 16.6 mmol)
in anhydrous CH2Cl2 (100 mL) at 0 °C maintaining this
temperature for 1 h, after that the mixture was diluted
with ethyl ether (100 mL), washed with saturated NaHCO3
solution, water, and saturated NaCl solution. The organic
layer
was
dried
and
evaporated
to
give
7-methoxymethoxy-2-trifluomethylsulfonyloxynaphtha-
lene 4 (4.9 g, 89%) as a colourless oil, which was used
without further purification; δH (200 MHz, CDCl3) 7.78
(m, 3H, Ar), 7.32 (m, 3H, Ar), 5.30 (s, 2H, OCH2) and
3.53 (s, 3H, OCH3). To a solution of 4 (4.9 g, 14.6 mmol)
in anhydrous methanol (80 mL), Et3N (7.9 mL), DMSO
(100 mL), Pd(OAc)2 (98 mg) and 1,3-bis(diphenyl-
phosphino)propane (169 mg) were added. A flow of CO
was passed for 10 min and the reaction mixture was
heated at 75 °C for 3 h under CO atmosphere. After this
time, the reaction mixture was cooled and filtered through
celite and the solvent was removed. The residue was
dissolved in ethyl ether, successively washed with water,
5% HCl, and a saturated solution of NaCl, dried and the
(120 mg)
and
2-(4-cianophenyl)ethanol
(0.73 g,
4.95 mmol) in CH2Cl2 (10 mL) was then added; the
mixture was stirred for 3 days. CH2Cl2 (25 mL) was then
added, the organic phase was separated, the aqueous
solution was extracted twice with CH2Cl2; the resulting
organic extract was washed with saturated NaCl solution,
dried and the solvent removed. The crude product was
purified by column chromatography over silica gel con-
taining 2.5% of Et3N with hexane: CH2Cl2 6:1 as eluent,
yielding 8 (0.61 g, 43%) as a white solid; m.p. 75–75.5 °C;
δH (300 MHz, CDCl3) 7.75 (d, J = 8.7 Hz, 1H, Ar), 7.73
(d, J = 8.4 Hz, 1H, Ar) 7.59 (s, 1H, Ar), 7.57 (d, J =
8.4 Hz, 2H, Ph), 7.35 (s, 1H, Ar), 7.33 (d, J = 8.4 Hz, 2H,
Ph), 7.22 (m, 2H, Ar), 5.30 (s, 2H, OCH2O), 3.73 (t, J =

445
6.3 Hz, PhCH2CH2O), 3.53 (s, 3H, OCH3), 2.98 (t, J =
6.3 Hz, PhCH2CH2O).
1H, Ar), 7.56 (d, J = 8.1 Hz, 2H, Ph),7.33 (d, J = 8.1 Hz,
2H, Ph), 7.23 (m, 3H, Ar), 6.90 (d, J = 0.6 Hz, 1H,
HetCH), 5.45 (s, 2H, ArOCH2), 4.63 (s, 2H, ArCH2O)
3.73 (t, J = 6.6 Hz, 2H, PhCH2CH2O), 3.13 (sept, J = 6.9
Hz, 1H, CH(CH3)2), 2.98 (t, J = 6.6 Hz, 2H,
PhCH2CH2O), 1.34 (d, J = 6.9 Hz, 6H, CH(CH3)2).
5.2.5. 4-[2-(7-Hydroxynaphthalen-2-ylmethoxy)-
ethyl]benzonitrile 9
HCl 2 N (30 mL) was added to a solution of 8 (0.6 g,
1.73 mmol) in THF (30 mL) and isopropanol (0.5 mL)
under nitrogen; the mixture was stirred for 28 h at 30 °C.
The organic solvents were then removed, the aqueous
layer was extracted with EtOAc, the organic layer washed
with a saturated solution of NaCl, dried and evaporated,
yielding 9 (0.50 g, 97%) as a yellowish solid; m.p.
132–134 °C; δH (300 MHz, CDCl3) 7.69 (d, J = 8.7 Hz,
2H, Ar), 7.56 (d, J = 8.4 Hz, 2H, Ph), 7.46 (s, 1H, Ar),
7.32 (d, J = 8.4 Hz, 2H, Ph), 3.72 (t, J = 6.6 Hz, 2H,
PhCH2CH2O), 2.97 (t, J = 6.6 Hz, 2H, PhCH2CH2O).
5.2.8. 4-[2-[7-(4-Cyclobutylthiazole-2-ylmethoxyl)-
naphthalen-2-ylmethoxy] ethyl]benzonitrile 11c
Anhydrous K2CO3 (110 mg, 0.79 mmol), 2-chloro-
methyl-4-cyclobutylhiazole (74 mg, 0.40 mmol) solved
in anhydrous acetonitrile (2 mL), KI (15 mg) were added
to a solution of 9 (100 mg, 0.33 mmol) in anhydrous
acetonitrile (3 mL), under nitrogen and then refluxed for
3 h. After this time, the reaction mixture was cooled at
room temperature and ethyl ether (5 mL) and water
(5 mL) were added. The organic layer was separated, and
dried, the solvent was removed and the crude product was
purified by column chromatography with hexane: EtOAc
2:1 as eluent, obtaining 11c (113 mg, 62%) as a brown
oil; δH (300 MHz, CDCl3) 7.75 (d, J = 8.7 Hz, 1H, Ar),
7.73 (d, J = 8.1 Hz, 1H, Ar), 7.59 (b s, 1H, Ar), 7.56 (d,
J = 8.4 Hz, 2H, Ph), 7.33 (d, J = 8.4 Hz, 2H, Ph), 7.23 (m,
3H, Ar), 6.93 (d, J = 0.6 Hz, 1H, HetCH), 5.46 (s, 2H,
ArOCH2), 4.66 (s, 2H, ArCH2O), 3.73 (m, 3H), 3.13
(sept, J = 6.9 Hz, 1H, CH(CH3)2), 2.98 (t, J = 6.9 Hz, 2H,
PhCH2CH2O), 2.40–1.80 (m, 6H, cbutyl).
5.2.6. 4-[2-[7-(2,3-Dichlorothieno[3,2-b]pyridyl-5-
methoxy)naphthalen-2-ylmethoxy]ethyl]benzonitrile 11a
Anhydrous K2CO3 (66 mg, 0.48 mmol), 5-chloro-
methyl-2,3-dichlorothieno[3,2-b]pyridine
(60 mg,
0.24 mmol) dissolved in anhydrous acetonitrile (1 mL),
KI (15 mg) were added to a solution of 9 (60 mg,
0.24 mmol) in anhydous acetonitrile (2 mL) under nitro-
gen and the mixture was then refluxed for 3 h. The
reaction mixture was then cooled to room temperature
and ethyl ether (5 mL) and water (5 mL) were added. The
organic layer was separated and dried, the solvent was
removed and the crude product was purified by column
chromatography with hexane: EtOAc 2:1 as eluent,
obtaining 11a (60 mg, 58%) as a brown oil; δH (300
MHz, CDCl3) 8.01 (d, J = 8.4 Hz, 1H, Het), 7.73 (dd,
J = 8.7 Hz, 2H, Ar), 7.64 (d, J = 8.4 Hz, 1H, Het), 7.55 (d,
J = 8.4 Hz, 2H, Ph), 7.54 (s, 1H, Ar), 7.32 (d, J = 8.4 Hz,
2H, Ph), 7.12 (m, 3H, Ar), 5.48 (s, 2H, ArOCH2), 4.61 (s,
2H, ArCH2O), 3.72 (t, J = 6.6 Hz, 2H, PhCH2CH2O),
2.97 (t, J 6.6, 2H, PhCH2CH2O).
5.2.9. 4-[2-(7-Hydroxy-2-naphtylmethoxy)ethyl]benzoic
acid 12
Thirty-five percent aqueous NaOH (10 mL) was added
to a solution of 9 (250 mg, 0.82 mmol) in ethanol
(20 mL) The solution was refluxed for 3 h. The homoge-
neous reaction mixture was cooled to 0 °C and 3 M HCl
was added until a precipitate formed. The solvent was
removed and the residue was dissolved in ethyl ether; the
organic solution was dried and evaporated, yielding 12
(238 mg, 90%) as a slightly brown solid; m.p. 205–207 °C;
δH (300 MHz, CD3OD) 7.99 (d, J = 8.4 Hz, 2H, Ar),
7.80–7.60 (m, 4H, Ar), 4.64 (s, 2H, ArCH2O), 3.76 (t,
J = 6.6 Hz, 2H, PhCH2CH2O), 2.99 (t, J = 6.6 Hz, 2H,
PhCH2CH2O).
5.2.7. 4-[2-[7-(4-Isopropylthiazole-2-ylmethoxy)-
naphthalen-2-ylmethoxy]ethyl] benzonitrile 11b
Anhydrous K2CO3 (136 mg, 0.98 mmol), 2-chloro-
methyl-4-isopropylthiazole (88 mg, 0.50 mmol) solved in
anhydrous acetonitrile (2 mL) and KI (15 mg) were
added to a solution of 9 (125 mg, 0.41 mmol) in anhy-
drous acetonitrile (3 mL), under nitrogen and then re-
fluxed for 3 h. The reaction mixture was then cooled to
room temperature and ethyl ether (5 mL) and water
(5 mL) were added. The organic layer was separated and
dried, the solvent was removed and the crude product was
purified by column chromatography with hexane: EtOAc
2:1 as eluent, obtaining 11b (108 mg, 60%) as a yellow-
ish solid; m.p. 75–76 °C; δH (300 MHz, CDCl3) 7.74 (d,
J = 8.7 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H, Ar), 7.59 (b s,
5.2.10. 5-Fluorobenzotiazol-2-il 4-[2-[7-(5-
fluorobenzothiazole-2-ylmethoxy) naphthalen-2-
ylmethoxy]ethyl]benzoate 13
Anhydrous K2CO3 (265 mg, 1.90 mmol), 2-bromo-
methyl-5-fluorobenzothiazole (207 mg, 0.84 mmol)
solved in anhydrous acetonitrile (5 mL), KI (15 mg) were
added to a solution of 12 (130 mg, 0.42 mmol) in
anhydrous acetonitrile (10 mL), under nitrogen and then
refluxed for 3 h. The reaction mixture was cooled at room
temperature and ethyl ether (10 mL) and water (10 mL)

446
were added. The organic layer was separated and dried,
the solvent removed and the crude product was purified
by column chromatography with hexane: EtOAc 7:3 as
eluent, obtaining 13 (205 mg, 75%) as an orange solid;
m.p. 122–123 °C; δH (300 MHz, CDCl3) 8.06 (d, J = 7.8
Hz, 2H, Ph), 7.83–7.68 (m, 6H, Ar), 7.59 (bs, 1H, Ar),
7.35 (d, J = 7.8 Hz, 2H, Ph), 7.30–7.15 (m, 5H, Ar), 5.73
(s, 2H, CO2CH2Het), 5.58 (s, 2H, OCH2Het), 4.64 (s, 2H,
ArCH2O), 3.75 (t, J = 6.6 Hz, 2H, PhCH2CH2O), 3.01 (t,
J = 6.6 Hz, 2H, PhCH2CH2O).
5.2.13. 4-[2-[7-(4-Cyclobutylthiazole-2-ylmethoxyl)-
naphthalen-2-ylmethoxy]ethyl]benzoic acid 2c
Thirty-five percent aqueous NaOH (5 mL) was added
to a solution of 11c (80 mg, 0.17 mmol) in ethanol (7 mL)
The solution was refluxed for 3 h. The homogeneous
reaction mixture was cooled to 0 °C, 3 M HCl was added
until a precipitate formed. The solvent was removed and
the residue was dissolved in ethyl ether; the organic
solution was dried and evaporated, yielding 2c (67 mg,
84%) as an oil. Anal. C28H27NO4S.1/2H2O; δH (300
MHz, CDCl3) 8.60–8.20 (b s, OH), 8.05 (d, J = 8.4 Hz,
2H, Ph), 7.72 (d, J = 9.0 Hz, 1H, Ar), 7.71 (d, J = 8.4 Hz,
1H, Ar), 7.45 (s, 1H, Ar), 7.33 (d, J = 8.4 Hz, 2H, Ph),
7.22 (m, 2H, Ar), 7.10 (d, J = 2.7 Hz, 1H, Ar), 6.92 (d,
J = 0.9 Hz, 1H, Het CH), 5.46 (s, 2H, ArOCH2), 4.65 (s,
2H, ArCH2O), 3.73 (m, 3H), 3.00 (t, J = 6.6 Hz, 2H,
PhCH2CH2O), 2.20–1.85 (m, 6H, cbutyl).
5.2.11. 4-[2-[7-(2,3-Dichlorothieno[3,2-b]pyridyl-5-
methoxy)naphthalen-2-ylmethoxy]ethyl]benzoic acid 2a
Thirty-five percent aqueous NaOH (5 mL) was added
to a solution of 11a (55 mg, 0.11 mmol) in ethanol
(7 mL). The solution was refluxed for 3 h, the homoge-
neous reaction mixture was cooled to 0 °C, 3 M HCl was
added until a precipitate formed. The solvent was re-
moved and the residue was dissolved in ethyl ether; the
organic solution was dried and evaporated, yielding 2a
(52 mg, 88%) as a yellow solid; m.p. 141–142 °C; anal.
C28H21Cl2NO4S.1/2H2O; δH (300 MHz, CDCl3) 8.06 (d,
J = 8.1 Hz, 2H, Ph), 8.04 (d, J = 8.4 Hz, 1H, Het), 7.71
(d, J = 8.4 Hz, 1H, Het), 7.69 (d, J = 7.5 Hz, 1H, Ar),
7.68 (d, J = 8.7 Hz, 1H, Ar), 7.34 (d, J = 8.1 Hz, 2H, Ph),
7.31 (s b, 1H, Ar), 7.22 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H,
Ar), 7.18 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H, Ar), 7.01 (d,
J = 2.4 Hz, 1H, Ar), 5.45 (s, 2H, ArOCH2), 4.65 (s, 2H,
ArCH2O), 3.76 (t, J = 6.6 Hz, 2H, PhCH2CH2O), 3.00 (t,
J = 6.6 Hz, 2H, PhCH2CH2O).
5.2.14. 4-[2-[7-(5-fluorobenzothiazole-2-ylmethoxy)-
naphthalen-2-ylmethoxy]ethyl]benzoic acid 2d
Two percent aqueous NaOH (4 mL) was added to a
solution of 13 (150 mg, 0.23 mmol) in ethanol (12 mL).
The solution was refluxed for 24 h the homogeneous
reaction mixture was cooled 0 °C, 3 M HCl was added
until a precipitate formed. The solvent was removed and
the residue was purified by column chromatography with
hexane:EtOAc 3:2 as eluent, yielding 2d (79 mg, 71%) as
a yellow solid; m.p. 165–167 °C; anal. C28H22FNO4S.
1/2H2O; δH (300 MHz, CD3COCD3) 8.15 (dd, J = 8.7
Hz, J = 5.4 Hz, 1H, Ar), 8.01 (d, J = 8.4 Hz, 2H, Ph),
7.92–7.80 (m, 3H, Ar), 7.73 (s ample, 1H, Ar), 7.48 (m,
1H, Ar), 7.46 (d, J = 8.4 Hz, 2H, Ph), 7.34 (m, 3H, Ar),
5.74 (s, 2H, OCH2Het), 4.71 (s, 2H, Ar CH2O), 3.83 (t,
J = 6.3 Hz, 2H, PhCH2CH2O), 3.06 (t, J = 6.3 Hz, 2H,
PhCH2CH2O).
5.2.12. 4-[2-[7-(4-Isopropylthiazole-2-ylmethoxy)-
naphthalen-2-ylmethoxy]ethyl]benzoic acid 2b
Thirty-five percent aqueous NaOH was added to a
solution of 11b (100 mg, 0.23 mmol) in ethanol (10 mL).
The solution was refluxed for 3 h. The homogeneous
reaction mixture was then cooled to 0 °C, 3 M HCl was
added until a precipitate formed. The solvent was re-
moved and the residue was dissolved in ethyl ether; the
organic solution was dried and evaporated, yielding 2b
(72 mg, 68%) as a yellow solid; m.p. 117–118 °C; %
anal. C27H27NO4S.1/2H2O; δH (300 MHz, CDCl3) 8.06
(d, J = 8.1 Hz, 2H, Ph), 7.72 (d, J = 8.4 Hz, 1H, Ar), 7.71
(d, J = 8.4 Hz, 1H, Ar), 7.41 (s ample, 1H, Ar), 7.34 (d,
J = 8.1 Hz, 2H, Ph), 7.22 (m, 2H, Ar), 7.08 (d, J = 2.4 Hz,
Ar), 6.91 (d, J = 0.6 Hz, 1H, HetCH), 5.46 (s, 2H,
ArOCH2), 4.65 (s, 2H, ArCH2O), 3.73 (t, J = 6.6 Hz, 2H,
PhCH2CH2O), 3.13 (sept, J = 6.9 Hz, 1H, CH(CH3)2),
2.98 (t, J = 6.6 Hz, 2H, PhCH2CH2O), 1.35 (d, J = 6.9
Hz, 6H, CH(CH3)2).
Acknowledgements
This work has been supported by Laboratorios Me-
narini, S. A. (project no. 2253, Fundació Bosch i Gimpera).
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