Novel phthalimide derivatives, designed as leukotriene D4 receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(02)00203-2

A series of phthalimide acid derivatives was synthesized and evaluated as leukotriene D₄ receptor antagonists. The tetrazolephthalimide LASSBio 552 (7) was shown to be able to inhibit the contractile activity induced by 100 nM of LTD₄ in guinea-pig tracheal strips with an IC₅₀=31.2 μM. In addition, LASSBio 552 (7) has been showed to present a better efficacy than zafirlukast (1) used as standard.

Full text of DOI:10.1016/S0960-894X(02)00203-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1533–1535
Novel Phthalimide Derivatives, Designed as Leukotriene
D4 Receptor Antagonists
Lıdia M. Lima,a,b Fernanda C. F. de Brito,a Simone D. de Souza,a Ana L. P. Miranda,a
Carlos R. Rodrigues,a Carlos A. M. Fragaa,b and Eliezer J. Barreiroa,b,
*
a
´
LASSBio, Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, PO Box 68006, Rio de Janeiro, 21944-970, RJ, Brazil
b
´
Instituto de Quımica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21949-900, RJ, Brazil
Received 29 October 2001; accepted 12 February 2002
Abstract—A series of phthalimide acid derivatives was synthesized and evaluated as leukotriene D4 receptor antagonists. The tetra-
zolephthalimide LASSBio 552 (7) was shown to be able to inhibit the contractile activity induced by 100 nM of LTD4 in guinea-pig
tracheal strips with an IC50=31.2 mM. In addition, LASSBio 552 (7) has been showed to present a better efficacy than zafirlukast
(1) used as standard. # 2002 Elsevier Science Ltd. All rights reserved.
Asthma is the most rapidly growing therapeutic market
in the world, reflecting the world-wide increase in pre-
valence of this pathology and the increasing recogni-
tion that chronic treatment is needed for many
patients.1,2 Cysteinyl-leukotrienes C4, D4, and E4 are
products of the 5-lipoxygenase pathway of arachidonic
acid metabolism, which were characterized as the major
constituents of the slow-reacting substance of anaphyl-
axis.3,4 These substances are believed to be involved in
the development of immediate airways hyperrespon-
siveness, bronchoconstriction, and inflammatory response
associated with asthma.5À8 Recent development of
antiasthmatic drugs representing an important thera-
peutic innovation, the most important in the last 20
years, are cysteinyl leukotriene receptor antagonists.
Zafirlukast (1), is an example, of selective and compe-
titive leukotriene D4 (LTD4) receptor antagonist that
has been recently developed.9À11
In the course of a research program aiming at design,
synthesis, and pharmacological evaluation of new lead
candidates useful for asthma treatment,12 we describe in
this paper the design, synthesis and inhibitory con-
tractile effect, in guinea-pig tracheal strips induced by
LTD4, of novel phthalimide derivatives, structurally
planned as LTD4 receptor antagonists (2–8). These new
derivatives were planned by applying molecular simpli-
fication approach in the prototypes (9–10),13À16 search-
ing for a new possible bioisosteric relationship between
the quinoline and phthalimide rings (Chart 1). In addi-
tion, the highly rigid LTD4 receptor antagonist
VUF5017 (9) was used as template to obtain the
interatomic distances between nitrogen atom of the
quinoline moiety and carboxylate group that are pre-
viously designated as pharmacophoric moieties.16,17
The measured interatomic distances between oxygen
atom of the phthalimide group and ionizable nitrogen
atom of tetrazole moiety of compound 7 (LASSBio 552)
are in the same range of those showed by VUF5017 (9)
(Fig. 1), as well to all new derivatives (4–8), except for
compounds 2 and 3.
These novel phthalimide derivatives 2–8 were synthe-
sized by the route illustrated in Scheme 1,18 based on
condensation of phthalic anhydride with tyramine
[4-(2-aminoethyl)phenol] in the presence of acetic acid
at reflux, furnishing the key intermediate (12) in 80% yield.
Subsequent treatment of phenolic derivative (12) with
appropriated alkyl bromides in different O-alkylation
*Corresponding author. E-mail: eliezer@ufrj.br
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00203-2

1534
L. M. Lima et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1533–1535
Chart 1.
Scheme 1. Reagents and conditions: (a) [4-(2-aminoethyl)phenol], AcOH, 140 ꢀC, 30 min, 80%; (b) Alkyl-bromides, DMF, K2CO3, rt, 2–24 h,
63–92%; (c) HCl:AcOH (1:1), rt, 4–8 h, 72–84%; (d) HCl:AcOH (1:1), 60 ꢀC, 30 min, 72%; (e) NaN3, NH4Cl, DMF, 120 ꢀC, 72 h, 80%.
conditions, as previously described,19 allowed to obtain
esters (13–16) and nitrile (17) in good yields. Following
our synthetic route, these derivatives were submitted to
acidic hydrolysis with a mixture of hydrochloric acid
and acetic acid at room temperature or at reflux,20 to
obtain the desired phthalimide-acid derivatives (2–5 and
8) in adequate yields. Finally, we prepared the tetrazole
derivative (7) in 80% yield, by the reaction of nitrile
intermediate (17) with sodium azide and ammonium
chloride in dimethylformamide at reflux.21
assay,22,23 and zafirlukast (1) as standard (Table 1). The
analysis of these screening data showed a significant
inhibitory activity for compounds 4 (LASSBio 553) and
6 (LASSBio 483), and a highlighting activity observed
for compound 7 (LASSBio 552) (Table 1). Encouraged
by these results, LASSBio 552 (7) was selected to study
the concentration–response relationship to inhibit the
contractile activity induced by 100 nM of LTD4, pre-
senting an IC50=31.2 mM (10 nM–400 mM). Although,
LASSBio 552 has been showed to be less potent than
zafirlukast (IC50=1.03 nM [0.1 nM–100 mM]), it was
able to evoke a maximum inhibitory response, con-
trasting with zafirlukast that presented a maximum
response of effect in the range of 58% (Table 2).24 These
results suggest that LASSBio 552 presented a better
efficacy profile than the standard zafirlukast.
The pharmacological results obtained for the novel
phthalimide derivatives (2–8) are compiled in Table 1.
All compounds were evaluated in vitro using the LTD4
induced contraction of guinea-pig trachea strips bio-

L. M. Lima et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1533–1535
1535
(BR.) for financial support. We are very grateful for
Analytical Center of NPPN (UFRJ-BR.) and Instituto
de Quımica (UFRJ-BR.).
References and Notes
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Figure 1. Interatomic distances between the main pharmacophore
groups of the VUF5017 and LASSBio 552 (7) (showing the super-
imposition of the most stable conformations). Hydrogen atoms are
not shown for clarity.
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Table 1. Inhibitory contractile effect of phthalimide derivatives (2–8)
in guinea-pig tracheal strips induced by LTD4 (100 nM)
Compd
(100 mM)
na
% Contractionb
% Inhibitionc
Control
26
04
03
03
05
03
05
06
05
100.0Æ0.0
41.3Æ7.2
101.5Æ0.8
91.4Æ3.7
80.3Æ7.6
97.6Æ11.9
73.9Æ7.9
52.4Æ6.4
93.7Æ5.2
0.0 n.s.d
58.7*
Zafirlukast (1)
LASSBio 482 (2)
LASSBio 485 (3)
LASSBio 553 (4)
LASSBio 484 (5)
LASSBio 483 (6)
LASSBio 552 (7)
LASSBio 551 (8)
À1.5 n.s.d
8.6*
19.7*
2.4 n.s.d
26.1*
47.6*
6.3 n.s.d
an=number of independent experiments.
b% of contraction, considering contraction obtained in the vehicle
presence 100.0%.
c% of inhibition obtained by comparison with control group.
dn.s., not significant.
*P<0.05 (Student’s t-test). Results are expressed as meanÆSEM.
Table 2. Comparison of the pharmacological effects of zafirlukast (1)
and LASSBio 552 (7), using the LTD4 (100 nM) induced contraction
of guinea-pig tracheal strips bioassay
15. Youssefyeh, R. D.; Magnien, E.; Lee, T. D. Y.; Chan, W.-
K.; Lin, C. J.; Galemmo, R. A.; Johnson, W. H.; Tan, J.;
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koom, P. H. J.; Gelens, E.; Timmerman, H.; Zhang, M.-Q.
J. Med. Chem. 1998, 41, 1439.
a
b
Compd
Emax
IC50
Zafirlukast (1)
LASSBio 552 (7)
58.7%
100.0%
1.03Â10À9 M
31.2Â10À6 M
aEmax, maximum effect.
bIC50, concentration to produce 50% of effect.
17. Palomer, A.; Pascual, J.; Cabre, F.; Garcia, L.; Mauleon,
D. J. Med. Chem. 2000, 43, 392.
18. Lima, L. M. PhD. Thesis, Universidade Federal do Rio de
Janeiro, March 2001.
19. Lima, L. M.; Barreiro, E. J.; Fraga, C. A. M. Synth.
Commun. 2000, 30, 3291.
20. Shah, J. H.; Swartz, G. M.; Papathanassiu, A. E.; Treston,
A. M.; Fogler, W. E.; Madsen, J. W.; Green, S. J. J. Med.
Chem. 1999, 42, 3014.
21. Zwaagstra, M. E.; Timmerman, H.; Tamura, M.; Tohma,
T.; Wada, Y.; Onogi, K.; Zhang, M.-Q. J. Med. Chem. 1997,
40, 1075.
In summary, we were able to design a new phthalimide
derivative possessing adequate structural requirements
to antagonize the contractile effect of LTD4 in guinea-
pig tracheal strips, in a dose dependent manner, estab-
lishing a new bioisosteric relationship between phthali-
mide ring, present in LASSBio 552 (7) and quinoline
ring present in prototypes (9–10).
22. Arakida, Y.; Suwa, K.; Ohga, K.; Yokota, M.; Miyata,
K.; Yamada, T.; Honda, K. J. Pharmacol. Exp. Ther. 1998,
287, 633.
Acknowledgements
23. Bernstein, P. R. Am. J. Respir. Crit. Care Med. 1998, 157,
S220.
24. Brito, F. C. F. M.Sc. Thesis, Universidade Federal do Rio
de Janeiro, July 2001.
Thanks are due to FAPERJ (BR.), CNPq (BR., grants
No. 50.0033/96–5, No. 460200/003 and fellowships to
LML, FCFB, ALPM, CRR, CAMF, EJB) and FUJB