Novel antiinflammatory analgesics: 3-(2-/4-Pyridylethyl)- benzoxazolinone and oxazolo[4,5-b]pyridin-2-one derivatives

Article abstract of DOI:10.1002/(sici)1521-4184(19993)332:2<45::aid-ardp45>3.0.co;2-0

Twenty-two new 3-[2-(2- and/or 4-pyridyl)ethyl]benzoxazolinone and oxazolo[4,5-b]pyridin-2-one derivatives have been synthesized by reacting 2- and/or 4-vinylpyridine and appropriate benzoxazolinones and oxazolo[4,5- b]pyridine-2-one. Their chemical structures have been proven by IR, ¹H-NMR, ¹³C-NMR, mass spectroscopy, and elemental analysis. The analgesic activities of these compounds were investigated by a modified Koster's Test. Test results revealed that, at 100 mg/kg dose level, most of the compounds showed significant analgesic activities when compared to aspirin. Therefore the compounds were screened for their antiinflammatory activities using the carrageenan hind paw edema test. Compounds 1, 7, 10, 11, 12, 13, 15, 18, 20, 21 were found more active than indomethacine. In gastric ulceration studies gastrointestinal bleeding was not observed at 100 mg/kg dose level in compounds 1 and 2.

Full text of DOI:10.1002/(sici)1521-4184(19993)332:2<45::aid-ardp45>3.0.co;2-0

Full Papers
Novel Antiinflammatory Analgesics:
3-(2-/4-Pyridylethyl)-Benzoxazolinone and Oxazolo[4,5-b]pyridin-2-one
Derivatives
a)
a)
b)
b)
Nesrin Gökhan* , Hakk1 Erdogan , Tugba Durlu , and Rümeysa Demirdamar
a) Hacettepe University, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry 06100, Ankara, Turkey
b) Hacettepe University, Faculty of Pharmacy, Dept. of Pharmacology 06100, Ankara, Turkey
Key Words: 2-Benzoxazolinone; oxazolo[4,5-b]pyridin-2-one; acylation; pyridylethyl; analgesic-antiinflammatory activity
Summary
Twenty-two new 3-[2-(2- and/or 4-pyridyl)ethyl]benzoxazolinone
and oxazolo[4,5-b]pyridin-2-one derivatives have been synthe-
sized by reacting 2- and/or 4-vinylpyridine and appropriate benz-
oxazolinones and oxazolo[4,5-b]pyridine-2-one. Their chemical
1
structures have been proven by IR, H-NMR, 13C-NMR, mass
Scheme 1
spectroscopy, and elemental analysis. The analgesic activities of
these compounds were investigated by a modified Koster’s Test.
Test results revealed that, at 100 mg/kg dose level, most of the
compounds showed significant analgesic activities when com-
pared to aspirin. Therefore the compounds were screened for their
antiinflammatory activities using the carrageenan hind paw edema
test. Compounds 1, 7, 10, 11, 12, 13, 15, 18, 20, 21 were found
more active than indomethacine. In gastric ulceration studies gas-
trointestinal bleeding was not observed at 100 mg/kg dose level in
compounds 1 and 2.
tion of ethylpyridine unit at 3-position may afford potential
analgesics B.
Previous study on compounds carrying both 2-benzoxaz-
olinone and ethylpyridine function in the same molecule has
shown that these function possess analgesic-antiinflamma-
[10]
tory activities . In continuation of our programme directed
to the development of new analgesic-antiinflammatory com-
pounds, 20 novel compounds with similar structure were
synthesized and examined for analgesic-antiinflammatory
activities.
Replacing the carbon by a heteroatom in a drug template is
a common strategy in medicinal chemistry. Therefore we also
reported here the synthesis and activities of 4-aza analogs of
benzoxazolinone.
Introduction
To cure if possible or at least to alleviate pain and in any
case not to cause further damage is a main goal in therapeu-
tics. Nonsteroidal antiinflammatory drugs are evidently a
major category in this respect. Although many such drugs
exist in the present pharmacopoeia, the needs are so varied
that new and better agents seem highly desirable.
Results and Discussion
The two main groups of analgesics on the market are the
opioids such as morphine, codeine, dextropropoxyphen, and
the cyclooxygenase inhibitors (nonsteroidal antiinflamma-
tory agents, NSAI) including aspirin, ibuprofen, indo-
Chemistry
Twenty new 3-[2-(2- and/or 4-pyridyl)ethyl]benzoxazoli-
none and two new 3-[2-(2- and/or 4-pyridyl)ethyl]oxaz-
olo[4,5-b]pyridin-2-one derivatives were synthesized and
evaluated for their analgesic and antiinflammatory activities.
Benzoxazolinone and chlorzoxazone were acylated in PPA
with appropriate carboxylic acids and then these and oxa-
zolo[4,5-b]pyridine-2-one were treated with 2-and/or 4-
vinylpyridine (Scheme 2).
In acylation, as both the 3-nitrogen and 2-oxygen atoms are
electron-donating, both the 5- and the 6-position are activated
and therefore the regioselectivity in the C-acylation of ben-
zoxazolinone cannot be easily predicted. However, it has
been reported that the substitution is directed by the nitrogen
[1]
methacin, and paracetamol . However, each class has its
drawbacks: cyclooxygenase inhibitors induce gastrointesti-
nal lesions while opiates induce tolerance, constipation, res-
piratory depression, physical dependency, and fear of
addiction. The main objective in current pain research is to
develop new, improved non-opioid analgesics which are as
[2,3]
effective as the opioids but without their side effects
.
Interesting pharmacological properties of benzoxazole de-
[4–14]
rivatives
prompted us to investigate them further. In the
literature it is shown that acylation of the benzoxazolinone
moiety might be a means of alleviating gastrointestinal le-
[15,16]
sions
. In connection with our studies on polyheterocy-
atom of the benzoxazolinone ring and only the 6-acyl deriva-
tive is formed
tion product with H-NMR parameters (chemical shifts) and
clic compounds with biological activity, we had synthesized
6-acyl-2-benzoxazolinone having the general formula A
functionalized at 6-position which are good intermediates in
[17]
. We also proved formation of the 6-acyla-
1
[18]
our research project. Indeed, these derivatives then introduc- coupling constants (J, Hz)
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/0202/0043 $17.50 +.50/0

44
Gökhan, Erdogan, Durlu, and Demirdamar
amined compounds appeared for some of these (compounds
4, 6, 16). Base peak was resulted from a loss of 3-pyridylethyl
and 6-difluorophenyl radical and gave a peak at m/z 162
(compound 1, 3, 7, 9). Secondary cleavage occurred between
C=O and 2-benzoxazolinone ring. As a result the remaining
radical gave a peak at m/z 113. In the spectra of compounds
16 and 18, the base peak was ethylpyridine while the base
peak of compound 12 was appeared from loss of benzoyl
group and methylpyridine group.
The results of microanalyses were within ±0.4 % theoretical
values.
Pharmacology
The pharmacological results clearly indicate that some of
the title compounds possess a good analgesic activity coupled
with notable antiinflammatory properties.The analgesic ac-
tivity of the compounds were screened by a “Modified Kos-
ter’s Test” using aspirin as a reference analgesic. Test results
revealed that most of the compounds at 100 mg/kg dose level
showed significant analgesic activities when compared to
aspirin. As can be seen from Table 3, the analgesic activity
of compound 1 and 7, which displayed 86.40% and 87.18 %
analgesic activity respectively, were found to be higher than
that of aspirin (81.19 %). Although it has been reported that
the introduction of a chlorine atom in 5-position of the ben-
Scheme 2
The formula, melting points, % yields, crystallization sol-
vents, and molecular formula are shown in Table 1. All
spectral data are in accordance with the assumed structures.
In the IR spectra of the compounds, no absorption bands were
detected at 3100–3400 cm , indicating the absence of an NH
group which is evidence for the addition reaction. The lactam
and ketone C=O stretching bands were seen at about 1812–
1761 and 1698–1649 cm . Other stretching seen in the
spectra confirmed the structures.
In the H-NMR spectrum, ethylenic and aromatic protons
of all compounds are seen at expected values. The neighbour-
ing protons to nitrogen atom in benzoxazolinone and oxaz-
[21]
zoxazolinone ring causes an increase in activity , no sig-
nificant difference for5-chloroderivativeswas observed. The
compounds carrying 2,3-; 3,4-; 3,5-; and 2,6-difluorobenzoyl
group at six position of 2-benzoxazolinone ring (compounds
4, 5, 10, 14, 16, 17) showed significant analgesic activity,
although they were found to be less potent than aspirin. A
significant difference in analgesic activity is observed de-
pending on pyridyl group at the third position of the benzoxa-
zolinone ring. In general the compounds bearing a 4-pyridyl
group exhibited higher activity than those with a 2-pyridyl
group. A notable decrease in activity was seen in compounds
9 and 19 which bear 2,6-difluorobenzoyl in position 6 of the
2-benzoxazolinone. No activity has been found in oxaz-
–1
–1
1
olo[4,5-b]pyridin-2-one and the other CH protons were seen
2
at 4.04–4.40 ppm and 3.00–3.49 ppm, respectively (Table 2).
1
The H-NMR spectra of benzoxazolinone derivatives
olo[4,5-b]pyridin-2-one derivatives. According to ED val-
50
showed a singlet at 6.81–6.93 ppm, a multiplet at 7.40–
7.70 ppm attributable to H-4 proton and H-5/H-7 protons of
benzoxazolinone ring. H-5, H-6, and H-7 protons of oxaz-
olo[4,5-b]pyridin-2-one were also seen at 8.05–8.10, 7.02–
7.18, and 7.33–7.41 ppm, respectively. In addition H-3 proton
and H-3/H-5 protons of the pyridine at 8.46–8.66 and 8.40–
8.58 ppm as a doublet of doublets due to ortho and meta
coupling (J: 8 Hz, J: 2 Hz).
ues while compounds 5, 10, and 16 are found to be equally
potent, compound 1 which bears 2,5-difluorobenzoyl in po-
sition 6 and 4-pyridyl in position 3 of the 2-benzoxazolinone
ring is determined to be the most potent analgesic agent in
this series.
These findings led us to screen the compounds for their
inhibition of carrageenan induced edema. Most of the struc-
ture-activity relationship seen for the analgesic activity were
confirmed for the antiinflammatory activity. Compound 18
was the most potent derivative in this series. Except for
compound 2, 3, 5, 6, 8, 9, 16, all compounds have been found
active when compared with indomethacin (Table 3). Com-
pounds 1, 7, 10, 11, 12, 13, 15, 18, 20, 22 seem to be more
active than indomethacin.
13
Additional evidence was provided by C-NMR spectra of
13
compounds. In the C-NMR spectra of compound 6, ketone
and lactam C=O gave two peaks at 192.35 and 154.22 ppm,
respectively. The peaks at 35.98 and 42.32 ppm can be
assigned to the CH - groups between 2-benzoxazolinone and
2
13
2-/4-pyridyl group. Data in earlier reports on C-studies of
some benzoxazolinone rings supported our C assign-
13
Naturally these results are not sufficient forclear correlation
between activity and structure. Therefore more detailed stud-
ies have been planned for the future. At present it is difficult
to deduce a general relationship between chemical structure
[19,20]
ments
.
The mass spectroscopic fragmentation of 3-(2-/4-
pyridylethyl)-(5-chloro)-6-difluorobenzoyl-2-benzoxazolin-
one ring was studied under electron ionization. Molecular ion
+•
(M ) peaks which confirmed the molecular weights of ex- and antiinflammatory activity.
Arch. Pharm. Pharm. Med. Chem. 332, 45–49 (1999)

Novel Antiinflammatory Analgesics
45
Table 1. Some characteristics of the compounds 1–22.
—————————————————————————————————————————————————————————————
R1 R2 / R3
Comp.
Ar
Yield (%) Mp. °C
Formula (MW)
—————————————————————————————————————————————————————————————
1
–H
–H
–H
–H
–H
–H
–H
–H
–H
–H
–Cl
–Cl
–Cl
–Cl
–Cl
–Cl
–Cl
–Cl
–Cl
–Cl
2,5-Difluoro
2,5-Difluoro
2,3-Difluoro
2,3-Difluoro
3,4-Difluoro
3,4-Difluoro
3,5-Difluoro
3,5-Difluoro
2,6-Difluoro
2,6-Difluoro
2,5-Difluoro
2,5-Difluoro
2,3-Difluoro
2,3-Difluoro
3,4-Difluoro
3,4-Difluoro
3,5-Difluoro
3,5-Difluoro
2,6-Difluoro
2,6-Difluoro
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
64.00
72.73
73.68
64.73
64.00
65.26
72.63
80.00
81.57
81.57
63.70
79.15
39
154–155a
116–117a
C21H14N2O3F2 (380.35)
C21H14N2O3F2 (380.35)
2
3
139–140b C21H14N2O3F2 (380.35)
107–108b C21H14N2O3F2 (380.35)
4
5
154–155a
134–135a
170–172a
117–118a
130–132c
166–168c
132–134a
121–122a
104d
C21H14N2O3F2 (380.35)
C21H14N2O3F2 (380.35)
C21H14N2O3F2 (380.35)
C21H14N2O3F2 (380.35)
C21H14N2O3F2 (380.35)
C21H14N2O3F2 (380.35)
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
73.35
46.33
52.12
57.23
53.08
42.95
62.25
113–114d C21H13N2O3F2Cl (414.80)
138–140a
113–114a
135a
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
C21H13N2O3F2Cl (414.80)
138a
153–154a
98–99a
—————————————————————————————————————————————————————————————
—————————————————————————————————————————————————————————————
R1
Comp.
Ar
Yield(%)
Mp °C
Formula (MW)
—————————————————————————————————————————————————————————————
21
22
–H
–H
4-Pyridyl
2-Pyridyl
30.72
33.28
112–114e
98–100e
C13H11N3O2 (241.25)
C13H11N3O2 (241.25)
—————————————————————————————————————————————————————————————
Recrystallization solvents = a: Ethanol/water (3:1); b: ethyl acetate/n-hexane (2:1)
c: Acetone/water (3:1) d: Dioxane/water(1:1). ** Analytical results for C, H, N were within ± 0.4 % of the calculated values.
Arch. Pharm. Pharm. Med. Chem. 332, 45–49 (1999)

46
Gökhan, Erdogan, Durlu, and Demirdamar
Table 2. 1H-NMR spectroscopic data and MS data of the compounds 1–22.
—————————————————————————————————————————————————————
Comp. No 1H-NMR (CDCl3): δ (ppm ) (J in Hz)
MS (70 eV): m/z (%)
—————————————————————————————————————————————————————
1
2
3
4
3.13–3.09 (t, 2H, CH2-Ar), 4.14–4.11 (t, 2H, N-CH2), 6.83–6.81
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.26–7.13 (m, 5H,
benzene H-3, H-4, H-6, pyridine H-2, H-6), 7.69–7.63 (m, 2H,
2-benzoxazolinone H-5, H-7), 8.52–8.50 ppm de (d, J: 8 Hz, 2H,
pyridine H-3, H-5)
275 (61) [M+•– C7H7N], 162 (100)
+•
[M
C
H10NF2],141[C7H3OF2+• ],
13
134 [M+•.– C14H10NO2F2], 113
[C6H3F2+•], 106 [C7H8N+•
]
3.16–3.13 (t, 2H, CH2-Ar), 4.18–4.14 (t, 2H, N-CH2), 6.85–6.83
(d, J: 7.32 Hz, 1H, 2-benzoxazolinone H-4), 7.30–7.14 (m, 5H,
benzene H-3, H-4, H-6, pyridine H-4, H-6), 7.66–7.55 (m, 3H,
2-benzoxazolinone H-5, H-7, pyridine H-5), 8.54–8.52 ppm de
(d, J: 8 Hz, 1H, pyridine H-3)
–
3.24–3.28 (t, 2H, CH2-Ar), 4.33–4.30 (t, 2H, N-CH2), 6.88–6.86
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.32–7.08 (m, 5H, benzene
H-4, H-5, H-6, pyridine H-2, H-6), 7.65–7.57 (m, 2H, 2-benzoxazolinone
H-5, H-7), 8.55–8.53 ppm de (d, J: 8 Hz, 2H, pyridine H-3, H-5)
275 (58) [M+•–C7H7N], 162 (100)
+•
[M
C
H10NF2],141[C7H3OF2+• ],
13
134 [M+•–C14H10NO2F2],
113 [C6H3F2+• ], 106 [C7H8N+•
]
3.28–3.24 (t, 2H, CH2-Ar), 4.33–4.30 (t, 2H, N-CH2), 6.89–6.87 (d,
J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.39–7.08 (m, 5H, benzene
H-4, H-5, H-6, pyridine H-4, H-6), 7.66–7.53 (m, 3H, 2-benzoxazolinone
H-5, H-7, pyridine H-5), 8.54–8.52 ppm de (d, J: 8 Hz, 1H, pyridine H-3)
380 (24) [M+•], 141[C7H3OF2+•],
134 [M+•–C14H10NO2F2],
113 [C6H3F2+• ], 106 (100) [C7H8N+• ],
93 (51) [C6H7N+•
]
5
6
7
8
3.13–3.09 (t, 2H, CH2-Ar), 4.15–4.11 (t, 2H, N-CH2), 6.83–6.81
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.26–7.13 (m, 5H,
benzene H-2, H-5, H-6, pyridine H-2, H-6), 7.70–7.63 (m, 2H,
2-benzoxazolinone H-5, H-7), 8.52–8.50 ppm de (d, J: 8 Hz, 2H,
pyridine H-3, H-5)
–
3.29–3.25 (t, 2H, CH2-Ar), 4.34–4.31 (t, 2H, N-CH2), 6.93–6.91
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.30–7.10 (m, 5H,
benzene H-2, H-5, H-6, pyridine H-4, H-6), 7.61–7.52 (m, 3H,
2-benzoxazolinone H-5, H-7, pyridine H-5), 8.55–8.53 ppm de
(d, J: 8 Hz, 1H, pyridine H-3)
380 (34) [M+•], 141[C7H3OF2+•],
134 [M+•–C14H10NO2F2],
113 [C6H3F2+• ], 106 (100) [C7H8N+• ],
93 (59) [C6H7N+•
]
3.29–3.26 (t, 2H, CH2-Ar), 4.35–4.31 (t, 2H, N-CH2), 6.93–6.91
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4),7.30–7.10 (m, 5H,
benzene H-2, H-4, H-6, pyridine H-2, H-6), 7.61–7.55 (m, 2H,
2-benzoxazolinone H-5, H-7), 8.56–8.54 ppm de (d, J: 8 Hz, 2H,
pyridine H-3, H-5)
275 (82) [M+•–C7H7N], 162 (100)
+•
[M
C
H10NF2],141[C7H3OF2+• ],
13
134 [M+•–C14H10NO2F2],
113 [C6H3F2+• ], 106 [C7H8N+•
]
3.29–3.25 (t, 2H, CH2-Ar), 4.35–4.31 (t, 2H, N-CH2), 6.93–6.91
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.26–7.01 (m, 5H,
benzene H-2, H-4, H-6, pyridine H-4, H-6), 7.64–7.52 (m, 3H,
2-benzoxazolinone H-5, H-7, pyridine H-5), 8.53–8.51 ppm de
(d, J: 8 Hz, 1H, pyridine H-3)
–
9
3.24–3.20 (t, 2H, CH2-Ar), 4.29–4.26 (t, 2H, N-CH2), 6.86–6.84
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.11–6.95 (m, 4H, benzene
H-3, H-5 pyridine H-2, H-6), 7.64–7.40 (m, 3H, 2-benzoxazolinone H-5,
H-7,benzene H-4), 8.51–8.49 ppm de (d, J: 8 Hz, 2H, pyridine H-3, H-5)
275 (70) [M+•–C7H7N], 162 (100)
[M+• C13H10NF2],141[C7H3OF2+• ],
134 [M+•–C14H10NO2F2],
113 [C6H3F2+• ], 106 [C7H8N+•
]
10
3.27–3.24 (t, 2H, CH2-Ar), 4.32–4.29 (t, 2H, N-CH2), 6.89–6.87
(d, J: 8.24 Hz, 1H, 2-benzoxazolinone H-4), 7.10–6.98 (m, 5H,
benzene H-3, H-4, H-5, pyridine H-4, H-6), 7.66–7.45 (m, 3H,
2-benzoxazolinone H-5, H-7, pyridine H-5), 8.53–8.51 ppm de
(d, J: 8 Hz, 1H, pyridine H-3)
–
11
3.20–3.00 (t, 2H, CH2-Ar), 4.20–3.90 (t, 2H, N-CH2), 7.50–6.90
(m, 7H, benzene H-3, H-4, H-6, 2-benzoxazolinone H-4, H-6,
pyridine H-2, H-6), 8.60–8.40 ppm de (d, J: 8 Hz, 2H, pyridine
H-3, H-5).
–
—————————————————————————————————————————————————————
Arch. Pharm. Pharm. Med. Chem. 332, 45–49 (1999)

Novel Antiinflammatory Analgesics
47
Table 2. Continued
——————————————————————————————————————————————————————
Comp. No 1H-NMR (CDCl3): δ (ppm) (J in Hz)
——————————————————————————————————————————————————————
MS (70 eV): m/z (%)
12
13
3.20–3.00 (t, 2H, CH2-Ar), 4.20–4.00 (t, 2H, N-CH2), 8.10–6.90
(m, 8H, benzene H-3, H-4, H-6, 2-benzoxazolinone H-4, H-6,
pyridine H-2, H-5, H-6), 8.60–8.50 ppm de (d,J: 8 Hz, 1H, pyridine H-3)
274 (79) [M+• –C7H8N], 182 (100)
[M+•–C13H10NOF2],113 [C6H3F2+•],
106 (85) [C7H8N+•
]
3.13–3.09 (t, 2H, CH2-Ar), 4.12–4.09 (t, 2H, N-CH2), 6.84 (s, 1H,
2-benzoxazolinone H-4), 7.44–7.05 (m, 6H, 2-benzoxazolinone H-7,
benzene H-4, H-5, H-6, pyridine H-2, H-6), 8.56–8.55 ppm de
(d,J: 8 Hz, 2H, pyridine H-3, H-5)
–
14
15
3.10–3.06 (t, 2H, CH2-Ar), 4.08-4.04 (t, 2H, N-CH2), 6.84 (s, 1H,
2-benzoxazolinone H-4), 7.40–7.08 (m, 7H, 2-benzoxazolinone H-7,
benzene H-4, H-5, H-6, pyridine H-4, H-5, H-6), 8.55–8.53 ppm de
(d,J: 8 Hz,1H, pyridine H-3)
275 (51) [M+• –C7H7N], 162 (100)
C
H10NF2],141[C7H3OF2+•],
13
+•
[M
134 [M+• –C14H10NO2F2],
113 [C6H3F2+•], 106 [C7H8N+•
]
3.28–3.25 (t, 2H, CH2-Ar), 4.32–4.29 (t, 2H, N-CH2), 6.92 (s, 1H,
2-benzoxazolinone H-4), 7.60–7.16 (m, 6H, 2-benzoxazolinone H-7,
benzene H-2, H-5, H-6, pyridine H-2, H-6), 8.58–8.56 ppm de
(d,J: 8 Hz, 2H, pyridine H-3, H-5)
–
16
17
18
19
20
3.28–3.25 (t, 2H, CH2-Ar), 4.32–4.29 (t, 2H, N-CH2), 6.92 (s, 1H,
2-benzoxazolinone H-4), 7.27–7.12 (m, 5H, benzene H-2, H-5, H-6,
pyridine H-4, H-6),7.63–7.49 (m, 2H, 2-benzoxazolinone H-7, pyridine
H-5), 8.58–8.57 ppm de (d, J: 8 Hz, 1H, pyridine H-3)
414 (20) [M+• ], 141[C7H3OF2+• ],
113 [C6H3F2+•], 106 [C7H8N+•],
93 (62) [C6H7N+•
]
3.10–3.07 (t, 2H, CH2-Ar), 4.08–4.04 (t, 2H, N-CH2),6.83–6.82 (s, 1H,
2-benzoxazolinone H-4), 7.28–7.05 (m, 6H, 2-benzoxazolinone H-7,
benzene H-2, H-4, H-6, pyridine H-2, H-6), 8.54–8.53 ppm de (d,J: 8 Hz,
2H, pyridine H-3, H-5)
–
3.32–3.29 (t, 2H, CH2-Ar), 4.25–4.21 (t, 2H, N-CH2), 6.90 (s, 1H,
2-benzoxazolinone H-4), 7.27–7.02 (m, 5H, benzene H-2, H-4, H-6,
pyridine H-4, H-6), 7.67–7.60 (m, 2H, 2-benzoxazolinone H-7, pyridine
H-5), 8.66–8.65 ppm de (d,J: 8 Hz,1H, pyridine H-3)
274 [M+• –C7H8N], 106 [C7H8N+•],
93 (62) [C6H7N+•
]
3.10–3.14 (t, 2H, CH2-Ar), 4.11–4.07 (t, 2H, N-CH2), 6.82 (s, 1H,
2-benzoxazolinone H-4), 7.56–7.14 (m, 6H, 2-benzoxazolinone H-7,
benzene H-3, H-4, H-5, pyridine H-2, H-6), 8.55–8.54 ppm
de (d,J: 8 Hz,2H, pyridine H-3, H-5)
–
3.26–3.23 (t, 2H, CH2-Ar), 4.29–4.26 (t, 2H, N-CH2), 6.82 (s, 1H,
2-benzoxazolinone H-4), 7.16–6.93 (m, 4H, benzene H-3, H-5,
pyridine H-4,H-6), 7.54–7.41 (m, 3H, 2-benzoxazolinone H-7,
pyridine H-5, benzene H-4), 8.56–8.54 ppm
–
–
–
de (d,J: 8 Hz,1H, pyridine H-3)
21
22
3.49–3.13 (t, 2H, CH2-Ar), 4.25–4.17 (t, 2H, N-CH2), 7.09–7.05 (m, 1H,
oxazolo[4,5-b]pyridin-2-one H-6), 7.21-7.18 (d,J: 6Hz, 2H, pyridine H-2,
H-6), 7.41–7.37 (d, J:8Hz, J:1.2 Hz,1H, oxazolo[4,5-b]pyridin-2-one H-7),
8.10-8.07 (dd,J:5.2Hz, J:1.2Hz,1H,oxazolo[4,5-b]pyridin-2-one H-5),
8.51–8.49 ppm de (d,J:4.6Hz, 2H, pyridine H-3, H-5)
3.35–3.28 (t, 2H, CH2-Ar), 4.38–4.31 (t, 2H, N-CH2), 7.18–7.02 (m, 3H,
pyridine H-4, H-6,oxazolo[4,5-b]pyridin-2-one H-6), 7.38–7.33 (dd,J:9.2,
J:1,4 Hz,1H, oxazolo[4,5-b]pyridin-2-one H-7), 7.60–7.52 (t, 1H, pyridine H-5),
8.09–8.05 (dd,J: 6.58 Hz, J:1.3 Hz,1H, oxazolo[4,5-b]pyridin-2-one H-5),
8.51–8.49 ppm de (dd,J:5.7Hz, J:1.76 Hz,1H, pyridine H-3)
——————————————————————————————————————————————————————
Arch. Pharm. Pharm. Med. Chem. 332, 45–49 (1999)

48
Gökhan, Erdogan, Durlu, and Demirdamar
Table 3: Analgesic activity, inhibition of carrageenan paw edema (CPE),
gastric ulceration studies of the compounds.
Experimental Part
——————————————————————————————
Chemistry
Cmpda
%Anal- ED50
gesicb
CPEc
Gastric ulceration
Ulcer
incidence
Lesion
length
All chemicals were obtained from Aldrich Chemical Co. (Steinheim,
Germany). Melting points were determined with a Thomas-Hoover capillary
melting point apparatus and are uncorrected. IR spectra (KBr) were recorded
on a Perkin-Elmer 1720X FT Infrared Spectrophotometer. 1H-NMR spectra
were recorded using a Bruker AC 80, 200 or 400 MHz FT NMR spectrometer
using CDCl3 and tetramethylsilane as internal standard. 13C-NMR spectra
were recorded on a Bruker AC 100 MHz spectrometer. All chemical shifts
were reported as δ (ppm values. Mass spectra were taken on a VG Analytical
70-250S or HP II Plus 5890 mass spectrometer with electron ionization (EI.
Microanalyses were performed by Institut für Pharmazeutische Chemie der
Philipps Universität Marburg (Germany) or by Scientific and Technical
Research Council of Turkey Instrumental Analysis Laboratory. The purity
of the compounds was assessed by TLC on silica gel HF254+366 (Merck).
activity
(no./gp.(±SE)) (mm/mice)
——————————————————————————————
1
86.40
12.09
*
10.37
84.62
–
79.61
77.23
31.07
59.58
40.99
38.61
69.72
34.28
33.27
60.16
64.16
64.35
67.34
52.11
79.61
25.73
43.77
80.01
45.94
69.29
43.19
65.53
–
1/8
1/8
–
0.20±0.20
2
0.40±0.23
3
–
4
69.23
71.67
*
48.90
38.52
–
–
–
5
–
–
6
–
–
7
87.18
52.58
20.23
72.44
12.56
*
59.52
46.37
80.42
34.72
88.34
–
6/8
–
0.50±0.19
6-Acyl-2-benzoxazolinone
8
–
9
–
–
These were prepared by treating 2-benzoxazolinone (or chlorzoxazone)
and carboxylic acid in polyphosphoric acid to the method reported ear-
10
11
12
13
14
15
16
17
18
19
20
21
22
–
–
lier[15,16]
.
–
–
–
–
Oxazolo[4,5-b]pyridin-2-one
29.39
64.75
37.16
73.54
64.34
45.54
16.52
*
74.42
48.74
75.63
35.53
52.24
68.46
81.13
–
6/8
–
0.60±0.27
2-Amino-3-hydroxypyridine (5.5 g, 50 mmol) was dissolved in THF
(10 ml), 1,1′-carbonyldiimidazole (12.15 g, 75 mmol) was added and the
solution was warmed under reflux with stirring for 6 h. The reaction mixture
was cooled (20 °C) and the THF removed by rotary evaporation, leaving a
residue which was dissolved in CH2Cl2. The organic layer was washed with
1.5 N NaOH (5 × 100 ml). The combined aqueous layers were cooled with
an ice bath and acidified to pH 5–6 with 2N HCl. The resulting precipitate
was collected by filtration, washed with water, and dried over P2O5 under
–
7/8
–
0.60±0.23
–
–
–
5/8
–
0.50±0.26
vacuum to yield product as a white crystalline product. Mp: 212–214 °C[3]
.
–
–
–
3-[2-(2-/4-Pyridyl)]ethyl-6-acyl-2-benzoxazolinone and
3-[2-(2-/4-Pyridyl]ethyloxazolo[4,5-b]-pyridin-2-one
*
–
–
–
*
–
–
–
To 2.5 mmol 6-Acyl-2-benzoxazolinone and oxazolo[4,5-b]pyridin-2-one
derivatives were added 7.5 mmol 2- and/4-vinylpyridine and the reaction
mixture heated under reflux in an oil bath until molten and then for 2
additional hours at 80 °C. On adding cold alcohol-water mixture, the product
separated, the resulting precipitate was collected by filtration. The crude
Aspirin 81.19
16.42
–
–
–
Indo-
methacin
–
60.00
8/8
0.60±0.17
——————————————————————————————
100mg/kg, p.o. b Results are expressed as their mean values c 2 % car-
product was recrystallized from different solvents [22]
.
a
rageenan 0.01 ml.
Since the result was not significant compared to control (p<0.01), analgesic
activity value was not found.
Pharmacology
Female albino mice, weighing 22±2 g, were used (local breed). The
animals were housed in groups of six, with food and water ad libitum, and
were allowed to get accustomed to their environment for at least two days
before the experiments.
It is well known that antiinflammatory compounds can
exhibit ulcerogenic properties. Therefore, the ulcerogenic
activities of the six compounds were screened. In gastric
ulceration studies gastrointestinal bleeding was not observed
at 100 mg/kg dose level in compounds 1 and 2. We choose 1
and 2 as lead compounds and further experiments are now
starting.
Analgesic Activity[23]
A modified Koster test was used. Compounds were given orally to mice
in groups of 6 at a dose level of 100 mg/kg. 1 h later stretching was induced
by i.p. injection of 3% solution of acetic acid at 300 mg/kg. Two control
groups (n = 6 received gum arabic syrup 1 h prior to injection of acetic acid.
Animals were placed in glass cages 5 min after acetic acid injection, and the
number of stretches per animal was recorded during a 10-min period;
analgesic activity was calculated by using the formula.
Acknowledgements
%analgesic activity= (n – n′)/n × 100
n and n′ indicate average number of stretches of control and test group,
respectively. Acetylsalicylic acid (ASA) was used as a reference analgesic
and administered according to the test protocol. The experiment was repeated
in two different dose levels (25 and 50 mg/kg) for the compounds which have
significant statistical differences between the treatments and the control
group.
We are very grateful Prof. Dr. W. Hanefeld (Philipps-Universität Marburg,
Marburg-Germany) for helping in 1H-/13C-NMR and elemental analysis.
This study was supported by the Hacettepe University Research Fund (pro-
ject no.: 97.T01.102.011) and the Scientific and Technical Research Council
of Turkey.
Arch. Pharm. Pharm. Med. Chem. 332, 45–49 (1999)

Novel Antiinflammatory Analgesics
49
Anti-Inflammatory Activity[24,25]
[9] Y. Katsura, S. Nishino, H. Takasugi, Chem. Pharm. Bull. 1991, 39,
2937.
Carrageenan induced mouse paw edema (CPE was measured using a
Peacock Dial Thickness Gauge. Six mice per group were used. After oral
administration of the compounds (100 mg/kg), 0.01 ml 2% carrageenan was
injected subcutaneously into the plantar surface of the right hind paw and 2 h
later the volume of the edema was measured by a dial thickness gauge. The
antiedematous effects of drugs were estimated in terms of percent inhibition.
[10] C. Safak, H. Erdogan, E. Palaska, R. Sunal, S. Duru, J. Med. Chem.
1992, 35, 1296.
[11] G. Pilli, H. Erdogan, R. Sunal, Arzneim.-Forsch./Drug Res 1993, 43,
1351.
[12] E. Palaska, S. Ünlü, H. Erdogan, C. Safak, B. Gümüsel, R. Demirdamar,
Gastrointestinal Ulceration Studies[26]
Eur. J. Med. Chem. 1993, 28, 963.
[13] E. Palaska, S. Ünlü, F. Özkanli, G. Pilli, H. Erdogan, C. Safak, R.
Gastric ulceration: Mice were fasted for 24 h (with water ad libitum.
Compounds were suspended in a methylcellulose vehicle and administered
orally by gavage in a volume of 0.5 ml/100 g of body weight. The animals
were sacrificed after 4 h, and the stomachs were examined for lesions under
a dissecting microscope. The compounds were administered in a single dose
at 100 mg/kg and for 5 days.
Demirdamar, B. Gümüsel, Arzneim.-Forsch./Drug Res. 1995, 45, 693.
[14] N. Gökhan, H. Erdogan, B.C. Tel, R. Demirdamar, Eur. J. Med. Chem.
1996, 31, 625.
[15] J.P. Bonte, D. Lesieur, C. Lespagnol, J.C. Cazin, Eur. J. Med. Chem.-
Chim. Ther. 1974, 9, 491.
Statistical Analysis
[16] P. Renard, D. Lesieur, C. Lespagnol, M. Cazin, C. Brunet, J.C. Cazin,
Eur. J. Med. Chem.-Chim. Ther. 1980, 15, 543.
Student t-test analysis of variance: ANOVA, two-factors (Pharmacologic
Calculation System-Version 4-1) was employed.
[17] H. Aichaoui, J.H. Poupaert, D. Lesieur, J.P. Hénichart, Tetrahedron
1991, 47, 6649.
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Received: August 6, 1998 [FP326]
Arch. Pharm. Pharm. Med. Chem. 332, 45–49 (1999)