Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1′-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model

Article abstract of DOI:10.1016/j.bmcl.2017.02.036

Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7–10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7–9) were synthesized f

Full text of DOI:10.1016/j.bmcl.2017.02.036

Accepted Manuscript
Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimi-
dine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a mouse pain
model
Helio G. Bonacorso, Wilian C. Rosa, Sara M. Oliveira, Indiara Brusco, Evelyne
S. Brum, Melissa B. Rodrigues, Clarissa P. Frizzo, Nilo Zanatta
PII:
S0960-894X(17)30173-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.02.036
BMCL 24708
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 December 2016
14 February 2017
16 February 2017
Please cite this article as: Bonacorso, H.G., Rosa, W.C., Oliveira, S.M., Brusco, I., Brum, E.S., Rodrigues, M.B.,
Frizzo, C.P., Zanatta, N., Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes], and evaluation of their analgesic effects in a mouse pain model, Bioorganic & Medicinal Chemistry
Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.02.036
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Synthesis of novel trifluoromethyl-
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Helio G. Bonacorso*a, Wilian C. Rosaa, Sara M. Oliveirab, Indiara Bruscob, Evelyne S. Brumb, Melissa B.
Rodriguesa, Clarissa P. Frizzoa, and Nilo Zanattaa
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900, Santa Maria, RS,
Brazil.
bLaboratório de Neurotoxicidade e Psicofarmacologia, Departamento de Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97.105-900,
Santa Maria, RS, Brazil.

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-
d]pyrimidine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a
mouse pain model
Helio G. Bonacorsoa*, Wilian C. Rosaa, Sara M. Oliveirab, Indiara Bruscob, Evelyne S. Brumb, Melissa B.
Rodriguesa, Clarissa P. Frizzoa, and Nilo Zanattaa
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900, Santa Maria, RS, Brazil.
b Laboratório de Neurotoxicidade e Psicofarmacologia, Departamento de Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97.105-900, Santa
Maria, RS, Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-
d]pyrimidines (7–10), as well as an evaluation of their analgesic effect in a mouse pain model.
The nine new chromeno[4,3-d]pyrimidines (7–9) were synthesized from the cyclocondensation
reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones
(3) containing 5-, 6- and 7-membered spiro-cycloalkanes, with some well-known amidine salts
(4–6) [NH2CR(=NH)] — in which R = Me, Ph, and NH2 — at yields of 60–95 %. Subsequently,
three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained
Available online
through
a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-
chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation
showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100 mg/kg, p.o.) and
Ketoprofen (100 mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception.
Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300 mg/kg, p.o.) had an
anti-allodynic effect comparable to Ketoprofen (100 and 300 mg/kg, p.o.) in the arthritic pain
model, without causing locomotor alterations in the mice. These results suggest that the
compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological
pain, such as in arthritis.
Keywords:
Chromeno[4,3-d]pyrimidines
Trifluoromethyl
Spiro compounds
Arthritic pain
Analgesic effects
2016 Elsevier Ltd. All rights reserved.
Benzopyrano[4,3-d]pyrimidines
are
important
were trifluoromethyl-substituted, and, furthermore, the spiro-
carbocyclic moiety was limited to a six-membered ring.5
pharmacophores that have shown anti-inflammatory, antiplatelet,
and antithrombotic activity.1 Between 2001 and 2006, Bruno et
al. developed a large number of benzopyrano[4,3-d]pyrimidines
from 3-formylchromone and amidines, via cyclocondensation
reactions endowed with interesting pharmacological properties
such as anti-inflammatory, analgesic, and, in particular, in vitro
anti-aggregating activity. Moreover, these compounds showed
gastrointestinal tolerability and did not induce gastrolesivity.2–4
Relatively few papers have reported on the formation of
benzopyrano[4,3-d]pyrimidines with
a limited number of
substituents, starting from 3-formylchromone or its equivalents,
via [3+3] cyclocondensation reaction. Thus, in 2010, Li et al.
reported on an efficient combinatorial synthesis of substituted
benzopyrano[4,3-d]pyrimidines, via a three-component one-pot
reaction employing iodochromone, alkynes, and amidines,
together with sequential Sonogashira coupling, condensation, and
cycloaddition reaction. This protocol enabled the heterocyclic
system to be constructed efficiently, with good to excellent
yields.6
In 2006, Hegab et al. synthesized some spirocyclohexane-
substituted aldazino-, pyrazolo-, thieno-, and thiooxopyrimidino-
chromenes via reaction of the corresponding
β-
chlorocarboxaldehyde with hydrazine hydrate, mercaptoacetic
acid, and thiourea, respectively. Some of these compounds
showed good anti-inflammatory, analgesic, anticonvulsant, and
antiparkinsonian activity in comparison with indomethacin,
diclofenace, carbamazepine, and benztropine. In particular, the
spiro[chromeno[4,3-d]pyrimidine-5,1'-cyclohexane]-2(1H)-
thione showed higher anti-inflammatory activity than
indomethacin and diclofenace. However none of the molecules
In the context of spiro compounds, heterocycles, in particular,
are present in a large number of natural compounds, including
plants and animals. It is also known that spiro heterocycles have
a wide variety of biological activities; for example, spiro-
oxindole derivatives have antitumor, antibiotic, and antimicrobial
(anti-HIV and antimalarial) activity.7,8 Due to being tachykinin

antagonists, aza-spiro compounds have been used to treat
depression, anxiety, pain, and migraine.6 Some spiro heterocycles
derived from benzopyrans are aldose reductase inhibitors, and
some possess antidiabetic activity.8
In order to keep exploring the synthetic potential of
polyfunctional 2,2,2-trifluoro-1-[4-methoxy-spiro(2H-chromen-
2,10-cycloalkane)-3-yl]ethanones for synthetizing scaffolds more
complex than 5,6-dihydrobenzo[h]quinazolines (Figure 1 - II),
we wish to disclose our efforts toward studying the synthesis and
antinociceptive activity, in an arthritic pain model induced by
Due to the capacity for fluorine atom changes in the physical
and chemical properties of the molecules to which these atoms
are bonded, researchers have shown great interest in
organofluorine pharmaceuticals, which have at least one fluorine
atom in their structure and account for about 20–30 % of
approved drugs and about 40% of the new compounds entering
phase III trials.9–11 Among the properties that can be changed, the
most notable are the pKa value, the electrostatic interactions
between receptor and ligand, the increase in lipophilicity, and
increases in molecular stability within the body.9 Over the last
decade, our research group has worked on the synthesis of new
CFA in mice, of
a series of novel 4-(trifluoromethyl)-
spiro[chromeno[4,3-d]pyrimidine-5,1'- cycloalkanes] (Figure 1 –
III).
General synthesis of 4-(trifluoromethyl)spiro[chromeno[4,3-
d]pyrimidine-5,1'-cycloalkanes] (7a–c, 8a–c, and 9a–c): Firstly,
the starting materials involved in this study were synthesized
according to the reaction pathways illustrated in Scheme 1. As
depicted in Scheme 1, and according to the methodology reported
by us previously,24 the a series of 2,2,2-trifluoro-1-[4-methoxy-
spiro(2H-chromen-2,1’-cycloalkan)-3-yl]ethanones 3a–c was
synthesized from the Kabbe adducts, namely, spiro[chroman-
2,1’-cycloalkan]-4-ones (2a–c). Yields of 48–61 % were obtained
when trifluoroacetylation reactions of mixtures of enolethers and
acetals derived from a series of three spiro ketones (Kabbe
adducts)26 were performed at a reaction temperature of 60 °C for
36 h, employing anhydrous chloroform as the solvent.
trifluoromethyl-substituted heterocycles
dihydrobenzo[h]quinazolines12,13 and pyrazoles14,15 and their
associated derivatives which have shown promising
—
such as 5,6-
—
pharmacological properties such as analgesic and anti-
inflammatory activity.
Building on our general interest in the synthesis of
trifluoromethyl-substituted aza-heterocycles with promising
biological applications,16 we observed a dearth of studies
involving benzopyrano[4,3-d]pyrimidines. Thus, given that these
scaffolds exhibit most of the characteristic properties previously
described, we considered them to be valuable and possible drug
candidates for the treatment of arthritic pain.
Pathological states of pain are difficult to treat, and pain is one
of the most prevalent conditions that limits productivity and
reduces the quality of a patient's life,17 which is why it is the
main motivation for patients seeking medical care.18 In arthritis,
the joint nerves become sensitized, producing acute and chronic
pain.19 The current therapies for alleviating joint pain, although
widely used, have limited effectiveness, and some drugs lead to
adverse effects, which makes their clinical use problematic and
precludes their long-term use.20,21 In this scenario, the discovery
and development of safer and more effective therapies for
treating arthritic pain is required. The Complete Freund's
Adjuvant (CFA) has been used as an experimental model to
induce chronic inflammatory pain in rodents, similar to how M.
tuberculosis (CFA’s component) produces arthritis in
humans.22,23
Prior to use for the next reaction step, compounds 3a–c were
fully characterized by the NMR and GC-MS techniques, as well
as by comparison with data from the literature.24
In
order
to
obtain
a
novel
series
of
4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidines-5,1'-
cycloalkanes] (7a–c, 8a–c, and 9a–c), we firstly tried to find the
best reaction conditions. We initially selected the reaction
involving the guanidine hydrochloride (6) and 2,2,2-trifluoro-1-
[4-methoxy-spiro(2H-chromen-2,1’-cyclohexane)-3-yl]ethanone
(3b), in order to obtain the spirotetracyclic pyrimidine 9b — see
Table 1. The reaction showed poor results when using green
solvents such as methanol and ethanol (entries 1 and 2).
Unfortunately, in water the formation of the product was not
observed (entry 3), but when acetonitrile was used as solvent, a
better result was achieved, which led to product 9b at a 48 %
yield (entry 4). It was also determined that the presence of basic
medium for neutralizing the hydrochloric acid and releasing the
guanidine is very important for this reaction, because in the
absence of a base, the formation of product 9b was not observed
(entry 5).
In our previous work, we were pleased to disclose the
excellent reactivity of 2,2,2-trifluoro-1-[4-methoxy-spiro(2H-
chromen-2,10-cycloalkane)-3-yl]ethanones — which had been
prepared from spiro[chroman-2,10-cycloalkan]-4-ones — in the
regioselective
synthesis
of
1(2)-methyl(phenyl)-3-
(trifluoromethyl)-1,4(2,4)-dihydro-spiro(chromen[4,3-c]pyrazole-
4,n’-cycloalkanes).24 Also synthesized from spiro[chroman-2,10-
cycloalkan]-4-ones were novel 7-amine-spiro[chromeno[4,3-
b]quinoline-6,1’-cycloalkanes] (see Figure 1 – I) such as new
tacrine hybrids, which were subjected to AChE and cytotoxicity
activity and molecular docking studies, and gave promising
results.25
Among the organic and inorganic bases tested, we found that
sodium hydroxide was the best alkaline medium (entries 6–9).
Likewise, variations of the molar ratio, from 1:1:1 to 1:2.5:2.5,
were tested for the ethanone 3b, guanidine hydrochloride (6), and
NaOH, respectively, and we concluded that the best molar ratio
was 1:2:2 of (entries 10–12). Thus, it was found that the best
reaction condition to obtain the desired product 9b employed
3b:6:NaOH at a molar ratio of 1:2:2, in refluxing MeCN (82 °C)
for 24 h (Table 1, entry 11, 95 % yield).
Figure 1. Tacrines, quinazolines and pyrimidines of pharmacological
interest.

f Yield of isolated product.
Table 1. Optimization of the reaction conditionsa for the
synthesis of compound 9b.
Subsequently, in an attempt to include alkyl, aryl, amino,
thiomethyl, etc. at the 2-position of the pyrimidine ring; and five-
, six-, and seven-membered spirocarbocyclic moieties at the 5-
position, we tried to expand the reaction scope, by applying the
optimal reaction condition determined for the synthesis of 9b to
the reaction involving ethanones 3a–c and some other
nitrogenated 1,3-dinucleophiles.
Thus,
the
novel
series
of
4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes] (7a–c, 8a–c, and 9a–c) was successfully
synthesized from the [3+3] cyclocondensation reactions of 2,2,2-
trifluoro-1-[4-methoxy-spiro(2H-chromen-2,1’-cycloalkan)-3-
yl]ethanones 3a–c with three substituted amidine chlorides —
acetamidine (4), benzamidine (5), and guanidine (6) — as shown
in Scheme 2. When the reactions were performed in refluxing
acetonitrile at 82 °C for 24 h — in accordance with the optimal
reaction condition developed for 9b and with the assistance of
TLC monitoring — yields in the range of 60–95 % were
obtained. The best results were also obtained when the solutions
of 3a–c diluted in acetonitrile were added dropwise to the
mixtures of amidines 4–6 and sodium hydroxide (powder) — the
latter was dissolved beforehand in acetonitrile at room
temperature.
Curiously, when similar reaction conditions were applied to
other
amidines,
such
as
formamidine,
2-methyl-2-
thiopseudourea, aminoguanidine, nitroguanidine, urea, and
thiourea, no reactions took place. The negative results for the
reactions using urea and thiourea were expected because these
dinucleophiles are highly electronically deactivated. However, up
until now we have not been able to explain the unsuccessful
results for the reactions
formamidine with
involving
view to
aminoguanidine and
a
isolating
the
4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes].
The
structures
of
the
novel
4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidine-5,1'-
1
cycloalkanes] (7a–c, 8a–c, and 9a–c) were deduced from: H-
and 13C-NMR experiments (solvent CDCl3), by comparison with
the NMR data of other previously synthesized chromeno[4,3-
d]pyrimidines,1–6 and from the mass spectrometry analysis (GC-
MS and HRMS). Their purity was confirmed by CHN elemental
Solvent
(15 mL)
MeOH
EtOH
Temp
(°C)
64
78
100
82
82
82
82
82
Yield (%)
(9b)f
28
analysis.
Complementarily,
2-amino-4-(trifluoromethyl)-
Entry
Base
spiro[chromeno[4,3-d]pyrimidine-5,1'-cycloheptane] (9c) had its
structure confirmed by single crystal X-ray diffraction, as shown
in Figure 2. The ORTEP clearly shows a tetracyclic structure
1
2
3
4
5
6
7
8
KOH
KOH
KOH
KOH
-
NaOH
Na2CO3
K2CO3
Et3N
34
e
with the presence of an amino group,
a trifluoromethyl
H2O
-
substituent, and a spirocycloheptane moiety at the 2-, 4- and 5-
position, respectively.
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
48
e
-
56
General
synthesis
of
2-(1H-pyrrol-1-yl)-4-
e
-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes] (10a–c): Five-membered heterocycles, such as
pyrroles, are part of the structural unit of many natural
compounds,28 essential drugs,29 and pharmacologically valuable
synthetic substances with antibacterial,30 antifungal,31
antioxidant,32 antitumor, and anti-HIV activity,33 and they are
widely used in the pharmaceutical industry34 and in functional
materials.35
e
-
e
9
82
82
82
82
-
10b
11c
NaOH
NaOH
NaOH
70
95
93
12d
a
Standard reaction condition: 3b (1.0 mmol), 6 (1.0 mmol), base (1 mmol),
for 24 h.
b
Reaction condition: 3b (1.0 mmol), amidine 6 (1.5 mmol), NaOH (1.5
mmol).
c Reaction condition: 3b (1.0 mmol), amidine 6 (2 mmol), NaOH (2 mmol).
d
Reaction condition: 3b (1.0 mmol), amidine 6 (2.5 mmol), NaOH (2.5
mmol).
e Recovery of starting materials.

present research, the intraplantar administering of capsaicin led to
paw licking, which was characterized as spontaneous
nociception.
The
treatment
with
the
new
4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes] (8a–c, 9a–c, and 10a–c; 100 mg/kg, p.o.) or
Ketoprofen (100 mg/kg, p.o.) was able to prevent capsaicin-
induced nociception at 1 h after their administering, when
compared to animals treated with the vehicle (Figure 3). The
Ketoprofen had a maximum antinociceptive effect of 80 3%;
while compound 10b, which had a maximum inhibition of
83 5%, was more effective in preventing spontaneous
nociception than the other compounds; therefore, it was chosen
for the execution of subsequent tests. These results support the
peripheral antinociceptive action of the compounds tested.
Unfortunately, due to the low solubility in the vehicle used,
compounds 7a–c could not be tested.
Figure 2. ORTEP of the crystal structure of 2-amino-4-(trifluoromethyl)-
spiro[chromeno[4,3-d]pyrimidine-5,1'-cycloheptane]
(9c)
(CCDC
1420775).27 Displacement ellipsoids are drawn at the 50 % probability level.
Thus, we sought to promote further functionalization of the 2-
amino-4-(trifluoromethyl)-spiro[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes] 9a–c by a Clauson-Kaas reaction with 2,5-
dimethoxytetrahydrofuran in an acid medium.36 Notwithstanding
the achievement of the desired 2-(1H-pyrrol-1-yl)-4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidine-5,1'-
cycloalkanes] (10a–c), we were pleased to observe that the one-
pot procedure provided a better yield than the two-step protocol
for compounds 10b and 10c, in addition to not requiring a
purification step (Scheme 3).
Figure 3. Antinociceptive effect of pyrimidine compounds or Ketoprofen on
the spontaneous nociception induced by intraplantar capsaicin administering
(1 nmol/paw, i.pl.). The antinociceptive effect was evaluated at 1 h after
treatment with: the vehicle (10 mL/kg, p.o.), pyrimidine compounds (100
mg/kg, p.o.), or Ketoprofen (100 mg/kg, p.o.). **P<0.01; ***P<0.001 when
compared to the vehicle group; one-way ANOVA followed by the Bonferroni
post hoc test. Data are expressed as the mean + SEM (n = 5–8 per group).
Effects of treatments on an arthritic pain model:
Sensory alterations are the most debilitating effects in
inflammatory processes; for example, pain during movement or
stimulation, which has been one of the main motivations in
patients seeking medical care.18 In order to investigate the
antinociceptive effect of compound 10b and Ketoprofen in a
clinically relevant pain model, the animals were subjected to
intraplantar CFA injections, in an arthritic pain model with some
similarities to forms of arthritis in humans.38 Since the TRPV1
receptor is involved in arthritic pain and the compound 10b was
effective in reducing nociception capsaicin-induced, a TRPV1
agonist, we tested its effect on a CFA-induced arthritic pain
model.42 The animals that received intraplantar CFA injections
showed a decrease in paw withdrawal threshold at 48 h after the
administering (baseline 2; Time 0) in comparison with the
baseline values (baseline 1, B — before CFA injection; Figure
Effect of treatments on capsaicin-induced
nociception:
The capsaicin is a lipophillic vanilloid compound that renders
“hot” chili peppers pungent. It binds to specific vanilloid
receptors on the peripheral terminals of nociceptive neurons,
causing pain.41 The capsaicin test represents an appropriate and
simple nociception model, because the application of capsaicin in
humans and in experimental animals evokes intense pain.37 In the

4A), which were considered to be mechanical allodynia. The
treatment of animals with compound 10b (100 mg/kg, p.o.) and
Ketoprofen (100 mg/kg, p.o.) led to reductions in the CFA-
induced mechanical allodynia of up to 68 5% and 65 5%,
respectively, at 2 h after administering, when compared to
animals treated with the vehicle. Ketoprofen reduced the
In conclusion, we successfully developed an attractive
strategy for the direct assembly of the new 4-
(trifluoromethyl)spiro[chromeno[4,3-d]pyrimidines-5,1'-
cycloalkane] derivatives 7a–c, 8a–c, and 9a–c, via [3+3]
cyclocondensation reactions between 2,2,2-trifluoro-1-(4-
methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3a–c)
and different amidine chlorides (4–6), which furnished yields of
60–95 %. Furthermore, we demonstrated the use of the 2-amino-
mechanical allodynia between 0.5 and
4 h after being
administered, while compound 10b reduced the mechanical
allodynia between 0.5 and 6 h after being administered (Figure
4A).
substituted
4-(trifluoromethyl)spiro[chromeno[4,3-
d]pyrimidines-5,1'-cycloalkanes] (9) in N-derivatization reactions
for the synthesis of the 2-pyrrolyl derivatives (10), by employing
2,5-dimethoxytetrahydrofuran in acetic acid medium (Clauson-
Kaas reaction) and two different methods — the first method
involved two steps and furnished overall yields of 38–49 %,
while the second one-pot method had a yield of 40–65 % and was
the most advantageous considering the experimental features.
Given that the best nociception inhibition was observed at 2 h,
this time was chosen for the analysis of the dose-response curve
(30–300 mg/kg, p.o.) in the CFA-induced arthritic pain model.
The anti-allodynic effect of post-treatment with compound 10b
and Ketoprofen occurred at doses of 100 and 300 mg/kg,
respectively. The calculated inhibitory dose (ID50) value for
compound 10b was 422.3 (113–1577) mg/kg, with maximum
inhibition of 66 8% (300 mg/kg); while for the Ketoprofen it
was 169.2 (95–301) mg/kg, with maximum inhibition of 75 11%
(300 mg/kg), at 2 h after the treatments (Fig. 4B and 4C).
Previous studies have shown that in rats and mice, non-steroidal
anti-inflammatory drugs (NSAID), such as Ketoprofen, reduce
the development of allodynia induced by the injection of
CFA.39,40 In the present study, compound 10b seemed to be as
effective as the Ketoprofen against CFA-induced arthritic pain in
mice.
We also showed that most of the tested compounds (8a–c, 9a–
c, and 10a–c, but not 7a–c) and Ketoprofen had an
antinociceptive effect in the capsaicin test, most notably
compound 10b. Moreover, compound 10b has an anti-allodynic
effect similar to Ketoprofen in an arthritic pain model, and it does
not cause any changes in the locomotor activity (data not shown).
Although the efficacy of compound 10b is not greater than the
efficacy of Ketoprofen, it could be used for the treatment of
pathological pain such as is arthritis.
Acknowledgments
The authors thank: the Coordination for Improvement of
Higher Education Personnel (CAPES) for the fellowships, and
the National Council for Scientific and Technological
Development (CNPq) for the financial support (Process numbers
306.883/2015-5 and 471.269/2013-1-CNPq/Universal).
Supplementary Material
Supplementary material for the review process was prepared
and provided as a separate electronic file.
References and notes
1. Bruno, O.; Brullo, C.; Schenone, S.; Ranise, A.;
Bondavalli, F.; Barocelli, E.; Tognolini, M.; Magnanini,
F.; Ballabeni, V. Il Farmaco 2002, 57, 753.
2. Bruno, O.; Brullo, C.; Schenone, S.; Bondavalli, F.;
Raise, A.; Tognolini, M.; Ballabeni, V.; Barocelli, E.
Bioorg. Med. Chem. 2004, 12, 553.
3. Bruno, O.; Schenone, S.; Ranise, A.; Bondavalli, F.;
Barocelli,
E.;
Ballabeni,
V.;
Chiavarini,
Figure 4. A) Time-response curve for the antinociceptive effect of the vehicle
(10 mL/kg, p.o.), compound 10b (100 mg/kg, p.o.), and Ketoprofen (100
mg/kg, p.o.) on CFA-induced mechanical allodynia, in mice evaluated
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