Solid-phase synthesis and inhibitory effects of some pyrido[1,2-c]pyrimidine derivatives on leukocyte functions and experimental inflammation

Article abstract of DOI:10.1021/jm000997g

A number of pyrido[1,2-c]pyrimidines bearing a nitrogen, oxygen, or sulfur functionality at C-1 were synthesized on solid-phase using the iminophosphorane methodology and tested for their effects on leukocyte functions in vitro and antiinflammatory activi

Full text of DOI:10.1021/jm000997g

J . Med. Chem. 2001, 44, 1011-1014
1011
Brief Articles
Solid -P h a se Syn th esis a n d In h ibitor y Effects of Som e P yr id o[1,2-c]p yr im id in e
Der iva tives on Leu k ocyte F u n ction s a n d Exp er im en ta l In fla m m a tion
Pedro Molina,*,† Enrique Aller,† AÄ ngeles Lorenzo,† Pablo Lo´pez-Cremades,† Inmaculada Rioja,‡ Amalia Ubeda,‡
Ma Carmen Terencio,‡ and Ma J ose´ Alcaraz‡
Departamento de Quı´mica Orga´nica, Universidad de Murcia, Murcia E-30071, Spain, and Departamento de Farmacolog´ıa,
Universidad de Valencia, E-46100 Valencia, Spain
Received May 30, 2000
A number of pyrido[1,2-c]pyrimidines bearing a nitrogen, oxygen, or sulfur functionality at
C-1 were synthesized on solid-phase using the iminophosphorane methodology and tested for
their effects on leukocyte functions in vitro and antiinflammatory activity. Compound 5c was
found to be a strong scavenger of superoxide anion and an inhibitor of chemiluminescence
induced by 12-O-tetradecanoylphorbol 13-acetate in human neutrophils. These pyrido[1,2-c]-
pyrimidines inhibited the generation of PGE2 by COX-2 in RAW 264.7 macrophages stimulated
with lipopolysaccharide. Compounds 7, 5f, 6, and 8 inhibited enzyme activity, whereas the
remaining compounds also acted on the induction phase. In addition, 5a -f, 6, and 7
administered p.o. at a dose of 20 mg/kg showed antiinflammatory activity in the carrageenan
mouse paw edema model, where they inhibited PGE2 levels in inflamed paws without affecting
the content of this eicosanoid in stomachs. Inhibition of PGE2 production and superoxide
scavenging may participate in the mechanism of the antiinflammatory action of these pyrido-
[1,2-c]pyrimidine derivatives.
In tr od u ction
gastrointestinal tolerability.10 We have tested a series
of newly synthesized pyrido[1,2-c]pyrimidine derivatives
for their effects in vitro on the generation of some
important inflammatory mediators and also in vivo, to
establish their antiinflammatory effects.
In the course of our studies directed toward the
synthesis of fused azaheterocycles based on hetero-
cyclization reactions of heterocumulenes, we have de-
veloped the so-called tandem aza Wittig/electrocycliza-
tion strategy for the synthesis of fused pyridines.1
Despite the renewed interest in the adaptation of
solution-phase synthesis of azaheterocycles to the solid-
phase,2,3 there are only a few reported examples of the
aza Wittig reaction applied to single or multistep
synthesis of azaheterocycles on solid support.4-7 Herein,
we report the design and solid-phase synthesis of the
functionalized rigid pyrido[1,2-c]pyrimidine ring via an
aza Wittig reaction under mild reaction conditions.
Macrophages play an important role in immune and
inflammatory responses and produce a wide array of
mediators, such as cytokines, oxygen and nitrogen
species, and high levels of PGE2 upon induction of COX-
2.8 In addition, reactive oxygen species (ROS), like
superoxide, have been implicated in inflammatory con-
ditions.9 There are two COX enzymes, COX-1, which
produces PGs important for physiological functions and
is expressed constitutively in most tissues, and COX-2,
induced in response to inflammatory stimuli.8 Gas-
trointestinal toxicity of nonsteroidal antiinflammatory
drugs is due to inhibition of COX-1, and accordingly,
selectivity for COX-2 inhibition would improve their
Ch em istr y
Our strategy to synthesize pyrido[1,2-c] pyrimidines
5-7 is outlined in Scheme 1. Staudinger reaction
between ethyl R-azido-â-(2-pyridyl)acrylate (1), available
in 40% yield by condensation of pyridine-2-carboxalde-
hyde with ethyl azidoacetate in the presence of NaOEt,11
and triphenylphosphine polymer bound in dry dichloro-
methane at room temperature provided the polymer-
bound iminophosphorane 2. Examination of the resin 2
by FTIR indicated that the vinyl side chain was incor-
porated. Aza Wittig reaction of the polymer-bound
iminophosphorane 2 with aromatic isocyanates in dry
dichloromethane at room temperature afforded the
carbodiimides 4 through the intermediate 3. Carbodi-
imides 4 underwent electrocyclization under the reac-
tion conditions to give the corresponding pyrido[1,2-
c]pyrimidines 5, in a completely regioselective fashion.
Compounds 5 were isolated in yields ranging from 82%
to 90%, after chromatographic purification and further
recrystallization.
Preparation of compounds 6 and 7 was achieved in
83% and 93% yields, respectively, from iminophospho-
rane 2 by reaction with carbon dioxide or carbon
disulfide in a sealed glass tube at 90 °C. The closely
related compound 8, which can be represented as a
* Corresponding author. Phone: +34-968-367496. Fax: +34-968-
364149. E-mail: pmolina@um.es.
† Universidad de Murcia.
‡ Universidad de Valencia.
10.1021/jm000997g CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

1012 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Brief Articles
Sch em e 1a
was inhibited to a lesser extent by 8, 5a , and 7 (Table
1). This effect was dependent on their superoxide
scavenging properties, since these active compounds
also inhibited the chemiluminescence generated by the
enzymatic system hypoxanthine/xanthine oxidase. The
most potent compound was 5c, with IC50 values of 0.60
(0.30-0.70) and 0.35 (0.30-0.40) µM for the assays in
human neutrophils and the cell-free system, respec-
tively. Our results indicate that a 4-H3CO substituent
in C6H5 improves the effectiveness as a superoxide
scavenger. To assess if these compounds were able to
inhibit other neutrophil functions, we tested them on
human neutrophil degranulation. None of these pyrido-
[1,2-c]pyrimidines affected elastase release by these cells
(data not shown).
Lipopolysaccharide (LPS) stimulation of RAW 264.7
macrophages for 20 h induced COX-2, which generated
a high level of PGE2 (Table 1). All pyrido[1,2-c]pyrim-
idines tested inhibited the generation of this eicosanoid
when incubated with RAW 264.7 macrophages for 20 h
in the presence of LPS. This could be due to inhibition
of COX-2 induction or activity. To test this last pos-
sibility in intact cells, we first induced COX-2 by LPS
stimulation for 20 h and then cells were washed and
incubated with test compounds for 2 h. Our results show
that the selective COX-2 activity inhibitor NS398
potently inhibited PGE2 generation in both the presence
and absence of LPS. Compounds 7, 5f, 6, and 8 exerted
similar effects on both experimental systems, which
suggests that they inhibited COX-2 activity only, whereas
the remaining compounds were more active when
incubated with LPS and thus could also act on the
induction phase. In addition, we evaluated the antiin-
flammatory activity in the carrageenan mouse paw
edema, using as reference compounds the nonselective
COX inhibitor indomethacin (45% reduction of edema
at 10 mg/kg po) and the selective COX-2 inhibitor NS398
(38% inhibition at the same dose). Compounds 5a -f, 6,
and 7 significantly inhibited edema when administered
po at a dose of 20 mg/kg. Nevertheless, we observed that
compound 8 was toxic in vivo (60% of mortality at the
above dose); thus it was not evaluated. No sign of
toxicity was observed in animals treated with the rest
of the compounds. PGE2 levels were determined in
homogenates of inflamed paws and also in homogenates
of stomachs. These active pyrido[1,2-c]pyrimidines sig-
nificantly reduced the levels of this eicosanoid in the
inflamed paws (Table 1), but they did not modify these
levels in stomach homogenates (data not shown). Thus,
inhibition of PGE2 generation from COX-2 by these
compounds was confirmed in vivo.
a
Reagents and conditions: (i) CH2Cl2, rt; (ii) Ar-NCO, CH2Cl2,
rt; (iii) solid CO2 or CS2, toluene, sealed tube, 90 °C.
Sch em e 2
zwitterionic species, was prepared by aza Wittig reac-
tion of the iminophosphorane derived from triphenyl-
phosphine and 2-(2-azidophenyl)pyridine with carbon
disulfide in toluene in a sealed glass tube at 90 °C
(Scheme 2). All compounds prepared in this work gave
satisfactory elemental analyses and spectral data (IR,
1H NMR, 13C NMR, and MS) that are consistent with
the structures proposed.
The acute inflammatory response to carrageenan has
been related to COX-2 activity12 and the generation of
reactive species.13 We have shown that inhibition of
PGE2 production may participate in the mechanism of
the antiinflammatory action of our compounds. On the
other hand, superoxide scavengers may protect against
the toxicity of ROS; also they may prevent the biological
effects of peroxynitrite. Interestingly, these pyrido[1,2-
c]pyrimidines, in contrast to indomethacin, did not
modify the levels of PGE2 in stomachs indicating that
they do not inhibit constitutive COX-1 activity in vivo,
and thus they present a profile of better gastric toler-
ability.
Biologica l Resu lts a n d Discu ssion
These pyrido[1,2-c]pyrimidines were not cytotoxic for
either human neutrophils or RAW 264.7 macrophages,
as estimated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay (data no
shown). In human neutrophils, compound 5c was found
to be a strong inhibitor of chemiluminescence induced
by 12-O-tetradecanoylphorbol 13-acetate (TPA), which

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 1013
Ta ble 1. Biological Effects of Compoundsa
carrageenan edema
chemiluminescence
% inhib neutrophils % inhib H/XO ng PGE2/mLb
RAW 264.7 macrophages stimulated with LPS
ng PGE2/mL
(inflamed paw)
b
compd
IC50
ng PGE2/mLc
edema (µL)
control
5a
5b
5c
5d
5e
5f
6
25.1 ( 1.9
16.2 ( 1.9
157.1 ( 7.0
82.2 ( 9.5**
92.4 ( 8.2**
91.6 ( 7.3**
103.9 ( 7.9**
101.9 ( 8.7**
80.8 ( 6.3**
121.9 ( 4.5*
105.2 ( 12.6**
ND
128.2 ( 9.6
70.6 ( 8.8**
71.0 ( 5.2**
78.7 ( 6.9**
82.5 ( 5.8**
83.3 ( 4.3**
76.9 ( 6.2**
85.4 ( 2.1*
89.7 ( 5.3*
ND
52.3 ( 2.0**
31.1 ( 2.3**
75.9 ( 1.8**
44.4 ( 3.1**
38.8 ( 2.7**
24.8 ( 2.8**
29.9 ( 2.6**
51.8 ( 3.5**
53.7 ( 2.0**
ND
57.1 ( 2.7**
49.1 ( 1.6**
93.3 ( 0.9**
49.6 ( 1.7**
31.3 ( 1.8**
32.2 ( 3.5**
26.6 ( 1.9**
43.3 ( 3.6**
51.6 ( 1.5**
ND
10.9 ( 0.9**
13.3 ( 0.7**
12.0 ( 1.1**
11.8 ( 0.8**
8.2 ( 0.5**
14.8 ( 1.0**
16.9 ( 0.8**
12.8 ( 0.6**
16.9 ( 0.9**
3.7 ( 0.0**
1.6 µM (0.1-8.4)
1.7 µM (0.3-7.7)
3.5 µM (2.8-5.1)
1.5 µM (0.4-2.5)
0.4 µM (0.1-1.0)
ND
11.0 ( 0.5**
13.5 ( 0.6
9.6 ( 0.6**
8.9 ( 0.4**
10.6 ( 0.5**
9.5 ( 0.6**
10.6 ( 0.8**
8.2 ( 0.5**
10.3 ( 0.2**
2.1 ( 0.5**
ND
7
8
1.7 µM (1.0-2.2)
ND
2.1 nM (1.0-3.5)
NS398
97.2 ( 4.1**
53.0 ( 6.8**
a
Data show mean ( SEM (n ) 6-12). In vitro experiments: results obtained at 10 µM or IC50 with 95% CL. Carrageenan edema:
NS398 was administered at 10 mg/kg po and compounds 5a -7 at 20 mg/kg po. Paw edema values at 3 h after carrageenan: *p < 0.05;
b
**p < 0.01. ND: not determined. H/XO: hypoxanthine/xanthine oxidase. Cells were stimulated with LPS for 20 h in either the presence
or absence (control) of test compounds. c After a 20-h stimulation with LPS, cells were washed and incubated for 2 h with test compounds
and arachidonic acid.
significance was determined by analysis of variance (ANOVA)
followed by Dunnett’s t-test for multiple comparisons.
We have shown that pyrido[1,2-c]pyrimidine deriva-
tives may potentially provide new superoxide scaven-
gers and antiinflammatory agents.
Resin -Bou n d Im in op h osp h or a n e 2. A suspension of
resin-bound triphenylphosphine (200 mg, loading 3 mmol/g)
in dry CH2Cl2 (2 mL) placed within a polypropylene tube was
evaluated and then sealed under N2. A solution of the vinyl
azide 1 (262 mg, 1.2 mmol) in dry CH2Cl2 (7 mL) was injected
into the suspension. The reaction mixture was shaken gently
for 2 h. The supernatant was removed, the resin was washed
with dry CH2Cl2 (4 × 3 mL) and dried under vacuum.
Exp er im en ta l Section
P h a r m a cology. [5,6,8,11,12,14,15(n)-3H]PGE2 was from
Amersham Iberica (Madrid, Spain) and [9,10-3H]oleic acid from
DuPont (Itisa, Madrid, Spain). NS398 was purchased from
Cayman Chemicals (SPI-Bio, Massy, France). The rest of the
reagents were from Sigma Chemical Co. (St. Louis, MO).
Ch em ilu m in escen ce a n d Ela sta se Relea se. Human
neutrophils (2.5 × 106 cells/mL) were purified as previously
described14 and incubated with luminol (40 µM) and TPA (1
µM). Chemiluminescence was recorded with a Microbeta trilux
counter (Wallac, Turku, Finland). Superoxide anions were also
generated by the hypoxanthine/xanthine oxidase system.15 In
another set of experiments, elastase release after stimulation
with cytochalasin B (10 µM) and N-formyl-L-methionyl-L-
leucyl-L-phenylalanine (10 nM) was measured.16
Cell Cu ltu r e. The mouse macrophage cell line RAW 264.7
was cultured in DMEM medium containing 2 mM L-glutamine,
100 U/mL penicillin, 100 µg/mL streptomycin and 10% fetal
bovine serum. Cells were resuspended at a concentration of 2
× 106/mL and co-incubated with Escherichia coli LPS (1 µg/
mL) at 37 °C for 20 h in the presence of test compounds or
vehicle. PGE2 levels were assayed in culture supernatants by
radioimmunoassay.17 The mitochondrial-dependent reduction
of MTT to formazan18 was used to assess the possible cytotoxic
effects of compounds.
Syn th esis of 1-Ar ylim in o-1H-p yr id o[1,2-c]p yr im id in es
5. Gen er a l P r oced u r e. A mixture of resin-bound iminophos-
phorane 2 (390 mg) and dry CH2Cl2 (2 mL) was placed in a
polypropylene tube and deoxygenated by purging with N2. A
solution of the appropriate isocyanate (1.2 mmol) in dry CH2-
Cl2 (2 mL) was injected into the suspension. After shaking at
room temperature for 2 h the supernatant was removed, and
the resin was washed with dry CH2Cl2 (4 × 4 mL). The
combined supernatants were concentrated to dryness. The
resulting crude product was purified by flash chromatography
on silica gel using AcOEt/hexane (3:2) to give 5.
1-P h en ylim in o-3-eth oxyca r bon yl-1H-p yr id o[1,2-c]p y-
r im id in e (5a ): 90%, mp 99-100 °C, red prisms; IR (Nujol)
3
1711 cm-1; 1H NMR δ (CDCl3) 1.30 (t, 3H, J ) 7.1 Hz, CH3),
3
4.27 (q, 2H, J ) 7.1 Hz, CH2O), 6.74 (s, 1H, H4), 6.91 (t, 1H,
3J ) 7.1 Hz, phenyl Hp), 7.05 (t, 1H, 3J ) 6.9 Hz, H7), 7.22 (m,
3
3H), 7.50 (m, 3H), 9.44 (d, 1H, J ) 7.1 Hz, H8); 13C NMR δ
(CDCl3) 13.96 (CH3), 61.81 (CH2O), 96.52 (C-4), 118.35 (C7),
131.23 (C-8), 136.87 (C-6), 146.31 (C-1), 147.62 (phenyl Ci),
148.68 (C-4a), 151.79 (C-3), 164.64 (CdO); MS (EI) m/z 293
(M+, 41), 264 (100). Anal. (C17H15N3O2) C, H, N.
COX-2 Activity in In ta ct Cells. RAW 264.7 macrophages
stimulated for 20 h with LPS (4 × 105/well) were washed and
Hank’s buffer supplemented with arachidonic acid (10 µM) was
added for a 2-h incubation with test compounds to determine
their effects on COX-2 activity. Supernatants were collected
for the measurement of PGE2 accumulation for the last 2 h by
radioimmunoassay as above.
1-(4-Meth ylph en yl)im in o-3-eth oxycar bon yl-1H-pyr ido-
[1,2-c]p yr im id in e (5b): 87%, mp 132-133 °C, red prisms.
1-(4-Met h oxyp h en yl)im in o-3-et h oxyca r b on yl-1H -p y-
r ido[1,2-c]pyr im idin e (5c): 90%, mp 146-147 °C, red prisms.
1-(4-F lu or op h en yl)im in o-3-eth oxyca r bon yl-1H-p yr id o-
[1,2-c]p yr im id in e (5d ): 87%, mp 126-127 °C, red prisms.
Ca r r a geen a n P a w Ed em a . The antiinflammatory activity
of these compounds was assessed by the carrageenan paw
edema test in mice.19 Compounds or vehicle (Tween 80/saline:
1/99, v/v) were administered po 1 h before injection of carra-
geenan (0.05 mL; 3% w/v in saline) into the subplantar area
of the right hind paw. The volumes of injected and contralat-
eral paws were measured at 1, 3 and 5 h after induction of
edema by using a plethysmometer (Ugo Basile, Comerio, Italy).
At the end of the experiment (5 h after carrageenan), the
animals were killed by cervical dislocation and the right hind
paws and stomachs were homogenized to determine PGE2.
Sta tistica l An a lysis. The results are presented as mean
( SEM; n represents the number of experiments. Inhibitory
concentration 50% (IC50) values were calculated from at least
4 significant concentrations (n ) 6). The level of statistical
1-(4-Ch lor oph en yl)im in o-3-eth oxyca r bon yl-1H-p yr id o-
[1,2-c]p yr im id in e (5e): 70%, mp 161-162 °C, red prisms.
1-(4-Br om op h en yl)im in o-3-eth oxyca r bon yl-1H-p yr id o-
[1,2-c]p yr im id in e (5f): 79%, mp 136-137 °C, red prisms.
Syn t h esis of 1-Oxo(t h ioxo)-1H -p yr id o[1,2-c]p yr im -
id in es 6 a n d 7. Gen er a l P r oced u r e. A mixture of resin-
bound iminophosphorane 2 (390 mg) and excess solid carbon
dioxide, or carbon disulfide, in dry toluene (15 mL) was heated
in a sealed glass tube at 90 °C for 12 h. After cooling, the resin
was separated by filtration and washed with CH2Cl2 (4 × 3
mL). The combined supernatant was concentrated to dryness
to give 6 or 7 which was recrystallized from toluene.
Eth yl 1-oxo-1H-p yr id o[1,2-c]p yr im id in e-3-ca r boxyla te
(6): 85%, mp 198-200 °C, yellow prisms.

1014 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Brief Articles
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Ack n ow led gm en t. This work was supported by
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